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  Volume 12 Issue 1
1 Methadone versus morphine as a first-line strong opioid for cancer pain: A randomized double-blind study
Snezana BOSNJAK, Snezana SUSNJAR
This was the first randomized study designed to compare the effectiveness and tolerability of methadone (7.5 mg orally every 12 hours and 5 mg every 4h as needed) and morphine (15 mg slow-release every 12 hours and 5 mg every 4 h as needed), as a first-line opioid for severe pain caused by advanced cancer.
More than 80% of cancer patients develop pain before death. Morphine is the standard first-line strong opioid according to the WHO. Methadone is an alternative second-line strong opioid. Methadone has been stated to have a number of potential advantages over morphine: improved pain control (particularly in patients with neuropathic pain), decreased toxicity (particularly constipation) and lower development of tolerance. In addition, the cost of treatment with methadone is also lower, which is important for low-income countries. So far, no studies have directly compared methadone and morphine on a double-blind basis.
A total of 103 patients, from 7 international research centers, were randomized after stratification by characteristics of the pain (neuropathic vs. non-neuropathic) to receive methadone (49 patients) or morphine (54 patients). The study duration was 4 weeks. The Institute for Oncology and Radiology of Serbia participated with 34 patients and was nominated the best research center on the basis of the quality of data. The primary objective of the study was to evaluate the difference in pain intensity and opioid-induced toxicity (sedation, nausea and vomiting, confusion and constipation), comparing the baseline score with the score at week 4 for each study arm. Methadone did not produce superior analgesic efficiency or overall tolerability at 4 weeks compared with morphine. The blind global satisfaction ratings of both drugs by patients and investigators did not show any difference between methadone and morphine. However, patients receiving methadone had more opioid toxicity-related dropouts. Methadone is a useful alternative strong opioid in developing countries because of its lower cost. Two-times daily dosing regimen of methadone used in the study proved to be effective and feasible. Close monitoring of patients in the first week after initiation of methadone treatment is mandatory.

1. Bruera E, Palmer JL, Bosnjak S, Rico MA, Moyano J, Sweeney C et al. Methadone versus morphine as a first-line strong opioid for cancer pain: A randomized double-blind study. J Clin Oncol 2004;22:185-92.
2 HPV-prophylactic vaccine: A new way of prevention against cervical carcinoma
This was the first randomized study designed to compare the effectiveness and tolerability of methadone (7.5 mg orally every 12 hours and 5 mg every 4h as needed) and morphine (15 mg slow-release every 12 hours and 5 mg every 4 h as needed), as a first-line opioid for severe pain caused by advanced cancer.
More than 80% of cancer patients develop pain before death. Morphine is the standard first-line strong opioid according to the WHO. Methadone is an alternative second-line strong opioid. Methadone has been stated to have a number of potential advantages over morphine: improved pain control (particularly in patients with neuropathic pain), decreased toxicity (particularly constipation) and lower development of tolerance. In addition, the cost of treatment with methadone is also lower, which is important for low-income countries. So far, no studies have directly compared methadone and morphine on a double-blind basis.
A total of 103 patients, from 7 international research centers, were randomized after stratification by characteristics of the pain (neuropathic vs. non-neuropathic) to receive methadone (49 patients) or morphine (54 patients). The study duration was 4 weeks. The Institute for Oncology and Radiology of Serbia participated with 34 patients and was nominated the best research center on the basis of the quality of data. The primary objective of the study was to evaluate the difference in pain intensity and opioid-induced toxicity (sedation, nausea and vomiting, confusion and constipation), comparing the baseline score with the score at week 4 for each study arm. Methadone did not produce superior analgesic efficiency or overall tolerability at 4 weeks compared with morphine. The blind global satisfaction ratings of both drugs by patients and investigators did not show any difference between methadone and morphine. However, patients receiving methadone had more opioid toxicity-related dropouts. Methadone is a useful alternative strong opioid in developing countries because of its lower cost. Two-times daily dosing regimen of methadone used in the study proved to be effective and feasible. Close monitoring of patients in the first week after initiation of methadone treatment is mandatory.

1. Greenlee RT, Hill-Harmon MB, Murray T, Thun M. Cancer statistics, 2001. CA Cancer J Clin 2001;50:7-33.
2. Bosch FX, Lorincz A, Munoz N, Meijer CJ, Shah KV. The causal relation between human papillomavirus and cervical cancer. J Clin Pathol 55, 2002;55:244-65.
3. Munoz N et al. Epidemiologic classification of human papillomavirus types associated with cervical cancer. N Engl J Med 2003;348:518-27.
4. Schlecht NF et al. Human papillomavirus infection and time to progression and regression of cervical intraepithelial neoplasia. J Natl Cancer Inst 2003;95:1336-43.
5. Goldie SJ et al. A comprehensive natural history model of HPV infection and cervical cancer to estimate the clinical impact of a prophylactic HPV-16/18 vaccine. Int J Cancer 2003;106:896-904.
6. Stanimirovic B, Kuljic-Kapulica N, Antic N, Stanimirovic V, Vasiljevic M, Popovic-Lazic J. HPV typing in cervical squamous intraepithelial lesions(SIL)- our experience after 1000 studied patiens. Archive of Oncology 1999;7(2):43-8.
7. Koutsky LA, Holmes KK, Critchlow CW et al. A cohort study of the risk of cer- vical intraepithelial neoplasia grade 2 or 3 in relation to papillomavirus infec- tion. N Engl J Med 1992;327:1272-8.
8. Mandic A, Vujkov T. Human papillomavirus vaccine as a new way of pre- venting cervical cancer: A dream or the future. Ann Oncol 2004;15:197-200.
9. Zhou J, Sun XY, Stenzel DJ, Frazer IH. Expression of vaccinia recombinant HPV 16 L1 and L2 ORF proteins in epithelial cells is sufficient for assembly of HPV virion-like particles. Virology 1991;185:251-7 .
10. Kirnbauer R, Booy F, Cheng N, Lowy DR, Schiller JT. Papillomavirus L1 major capsid protein self-assembles into virus-like particles that are highly immuno- genic. Proc Natl Acad Sci USA 1992;89:12180-4.
11. Da Silva DM, Velders MP, Nieland JD, Schiller JT, Nickoloff BJ, Kast WM. Physical interaction of human papillomavirus virus-like particles with immune cells. Int Immunol 2001;13(5):633-41.
12. Koutsky L, Ault K, Wheeler C, Brown D, Barr E, Alvarez F et al. A controlled trial of human papillomavirus type 16 vaccine. N Engl J Med 2002;347/21:1645-51.
3 Diagnostic and therapeutic management of primary cardiac lymphoma
Vladimir BALTIC
Primary cardiac lymphoma (PCL) can be defined as non-Hodgkin's lymphoma (NHL) that involves e heart and/pericardium, or as NHL with tumor mass localized in heart (1,2). Primary cardiac lymphoma accounts for 1.3% to 2% of all cardiac tumors and 0.5% of extranodal lymphomas (1). Primary and secondary lymphomas appear most frequently in case of immunocompromised HIV-infected persons (3). In HIV-infected persons the risk of development of systemic non-Hodgkin's lymphoma is 60 to 200 times that in the general population. A meta-analysis of cohort studies that included 14 936 HIV-infected persons showed that the relative risk in the era of highly active antiretroviral therapy (HAART), as compared with the pre-HAART era, was 0.58 (4). Primary cardiac lymphomas are most often localized in the right atrium and rarely in other heart cavities or in valves. As a rule neoplasia always involves pericardium also. However, secondary lymphoma always involves pericardium, epicardium or infiltrates into myocardium (3,4). Pathognomonic clinical presentation of PCL is not typical and depends on the size and localization of primary lesion. Prognostic factors are also difficult for identification. Retrospective analysis of 60 immunocompetent patients showed that the disease was presented as right heart insufficiency (20%), pericardial pain (17%), cardiac tamponade (12%), heart rhythm abnormalities, vena cava superior syndrome (8%), acute myocardial infarction, dyspnea, etc. (3). Systemic symptoms were found in 17% of patients, and elevated laboratory values for LDL and ESR were registered in case of 16% and 20% of patients, respectively. To diagnose the disease following techniques can be used: cytological analysis of pericardial exudates, echocardiography, CT, MRI, and scintigraphy with Tc99mSESTAMIB. When indicated angiography can also be used (3). Transesophageal echocardiography and MRI are the techniques of high specificity and sensitivity (Figure 1,2) (4). ECG-gated MRI provides the image of cardiac tumor mass that is isointensive with the signal of normal myocardium T1W and T2W images. The application of gadolinium contrast medium elevates the signal intensity (Figure 3) (4).
Figure 1. Echocardiogram Obtained at the Time of Diagnosis. The apical four-chamber view (Panel A) and the subcostal four-chamber view (Panel B) show that right atrial cavity is filled by mass of echoes, indicating the presence of a tumor. RA denotes right atrium, LA left atrium, RV right ventricle, and LV left ventricle

Figure 2. Cardiac MRI Studies. One frame from a cine acquisition (in which the blood appears bright), obtained in a paraseptal long-axis view to the right of the intreventricular septum (Panel A), shows a large, lobulated mass extending into the right atrial cavity from its attachment along the floor of the chamber (straight arrow). The mass protrudes partially into the tricuspid orifice, which is demarcated by the closed tricuspid-valve leaflet (curved arrow). A small pericardial effusion is also visible (arrowhead). A spin-echo image with T2 weighting (in which the blood appears black), acquired in the orientation of the four-chamber view near the inferior surface of the heart (Panel B), shows a bulky mass lesion (straight arrow) yhat occupies most of the right atrial cavity at this level. A small pericardioal effusion, probably with some deposition of fibrin along the pericardial surfaces, may be contributing to apparent thickening of the right atrial free wall (curved arrow). A short-axis spin-echo image obtained after the intravenous administration of 0.1 mmol of gadolinium per kilogram (Panel C) shows extension of the tumor underneath the basal portion of the interventricular septum (arrow). The signal intensity in the tumor is less strongly enhanced that of the normal myocardium. AO denotes ascendings aorta, SVC superior vena cava, RVO right ventricular outflow tract, RA right atrium, RV right ventricle, and LV left ventricle.
Figure 3. Endomyocardial -Biopsy Specimen. There is a diffuse infiltrateof neoplastic cells under the endocardium (Panel A, hematoxylin and eosin, x125). Examination at a higher magnification (Panel B) shows that the cells have a high nuclear-to-cytoplasmic ratio (hematoxylin and eosin, x500). In situ hybridization studies show that most of the lymphoma cells contain nuclear Epstein-Barr virus-encoded RNA (Panel C, x125).
Endomocardial biopsy was performed in 50% of patients to obtain histologically confirmed diagnosis. Centroblasts and B-cell immunoblasts (CD20+, Ki67+, CD3-, and EBV-) were predominant (4).
The shown characteristics are typical for diffuse B-cell NHL of high-grade malignancy. The prognosis of disease course in patients with PCL associated with HIV infection is poor. The results of present clinical researching show that 50% to 73% of patients affected with PCL, after the treatment with poly-chemotherapy, develop CR that persists longer than 33 months in 20% of all cases. The applied treatment regimen consists of CHOP (cyclophosphamide, hydroxydaunomicin [doxorubicin], Oncovin [vincristine], prednisone) or CHOP combined with Rituximab (CD20 monoclonal antibody) (4).

1. McAllister HA, Fengolio JJ. Tumors of the cardiovascular systems. In: Atlas of tumor pathology. 2nd Series. Fascicle 15. Washington, DC: Armed Forces Institute of Pathology; 1978. p. 99-100.
2. Caiirins P, Butany J, Fulop J, Rakowski H, Hasram S. Cardiac presentation of non-Hodgkin's lymphoma. Arch Pathol Lab Med 1978;111:80-3.
3. Ceresoli GL, Ferreri AJM, Bucc E, Ripa C, Ponzoni M, Villa E. Primary cardiac lymphoma in immunocompetent patient. Cancer 1997;80:1497-506.
4. Kaplan LD, Afridi NA, Holmvang G, Yukerberg LR. Case 31-2003: A 44-year- old man with HIV infection and right atrial mass. N Engl J Med 2003,349:14;1367-77.
4 Application of MCC-465 or doxorubicin (DXR) encapsulated in PEG immunolyposome, in patients with metastatic stomach cancer
Vladimir BALTIC
Goren et al. prepared immunoliposome for the first time in 1996 (Figure 1). This liposome was conjugated to MoAb against HER-2 positive tumors. On the basis of their and other authors' experience Matsamura et al. (2003) prepared immunoliposome-encapsulated form of DXR (Figure 1). The liposome was chemically conjugated to PEG and F(ab')2 fragments of the human monoclonal antibody GAH, which can recognize antigen molecules on plasmatic membranes of different types of tumor cells. The anti-tumor activity of MCC-465 against GAH-positive human stomach cancer B37 cells was clearly shown in pharmacokinetic studies phase I.
Figure 1. Schematic diagram of MCC-465
Taken from: Ann Oncol 2004;15(3):518.
MTD for MCC-465 is 45.5 mg/m2 using the 3-week schedule. The authors recommend MCC-465 dose of 32.5 mg/m2 for phase II study.
1. Matsumura Y, Goth M, Muro K et al. Phase I and pharmacokinetics study of MCC-465. a doxorubicin (DXR) encapsulated in PEG immunoliposome, in patients with metastatic stomach cancer. Ann Oncol 2004;15:517-25.
Books Received
Medical and Scientific Meetings
  Issue 2
1 Revised Bethesda Guidelines for hereditary nonpolyposis colorectal cancer (Lynch syndrome) and microsatellite instability
Umar A, Boland CR, Terdiman JP, Syngal S, de la Chapelle A, R.schoff J et al. J Natl Cancer Inst 2004;96:261-8.
Microsatellite instability is characterized by the size variation of specific sequence of DNA bases or nucleotides, which contains mono, di, tri, or tetra tandem repeats. About 15% of colorectal cancers are characterized by microsatellite instability. This feature arises through defective DNA mismatch repair, which is related either to a germinative mutation or a failure to express a mismatch-repair gene (1). Germ line mutation in one of several DNA mismatch genes is found in hereditary nonpolyposis colorectal cancer (HNPCC, also known as Lynch syndrome). HNPCC is the most common hereditary colon cancer syndrome, and is estimated to account for about 2-4% of all colorectal cancers. HNPCC is an autosomal dominant condition, characterized by increased lifetime risk of early onset colorectal cancer as well as excess of extracolonic cancers (2). On the other hand microsatellite instability is also present in sporadic colorectal cancers where DNA mismatch repair deficiency is the result of MLH1 mismatch repair gene inactivation due to methylation suppression of the MLH1 promoter region. Methylation of cytosine in CpG rich gene promoter region leads to loss of gene expression (3). In 1991, the International Collaborative Group on Hereditary Nonpolyposis Colorectal Cancer (ICG-HNPCC) developed the original Amsterdam Criteria, established minimal clinical diagnostic criteria to identifying kindreds that eventually led to the association of the HNPCC syndrome and for recruiting HNPCC patients for collaborative studies (4). Revised, Amsterdam criteria II took into account other types of HNPCC-associated cancers, endometrial, small bowel, and renal pelvis cancers (5). In 1996 US National Cancer Institute (NCI) hosted an International Workshop on HNPCC, which led to the development of the Bethesda guidelines. The Bethesda guidelines represent clinical and histopathologic criteria for identification of colorectal tumors that should be tested for microsatellite instability (6). To consider revision and improvement of the Bethesda guidelines, another HNPCC workshop was held by the NCI in Bethesda, MD in 2002. These Revised Bethesda Guidelines (Table 1) were published in the form of a commentary in February 2004, in the Journal of the National Cancer Institute to update the original Bethesda Guidelines on testing colorectal tumors for microsatellite instability (7). The revised criteria aim to simplify the decision process for genetic testing in high-risk individuals, and propose that tumors should be tested for microsatellite instability (and if found to be microsatellite instability positive, tested for HNPCC mutations). The authors of the commentary also make recommendations for the process of molecular evaluation patients identified as being at risk. The Workshop participants suggested that additional mononucleotide markers should be added to the panel of five (original NCI microsatellite panel included BAT25, BAT26, D2S123, D5S346, D17S250 [8]) microsatellites to improve sensitivity in the evaluation of microsatellite instability. Suggestions are also made for future research priorities for the clinical and molecular evaluation of microsatellite instability.

1. Haydon AMM, Jass JR. Emerging pathways in colorectal-cancer development. Lancet Oncol 2002;3:83-8.
2. Lynch HT, de la Chapelle A. Hereditary colorectal cancer. N Engl J Med 2003;348:919-32.
3. Narayan S, Roy D. Role of APC and DNA mismatch repair genes in the development of colorec- tal cancer. Molecular Cancer (Internet). 2003;2(1):41 Avilable from: http://www.molecular-can-
4. Vasen HF, Mecklin JP, Khan PM, Lynch HT. The International Collaborative Group on Hereditary Non-polyposis Colorectal Cancer (ICG-HNPCC). Dis Colon Rectum 1991;34:1535-49.
5. Vasen HF, Watson P, Mecklin JP, Lynch HT. New clinical criteria for hereditary nonpolyposis col- orectal cancer (HNPCC, Lynch syndrome) proposed by the International Collaborative group on HNPCC. Gastroenterology. 1999;116:1453-6.
6. Rodriguez-Bigas MA, Boland CR, Hamilton SR, Henson DE, Jass JR, Khan PM, et al. A National Cancer Institute Workshop on Hereditary Nonpolyposis Colorectal Cancer Syndrome: meeting highlights and Bethesda Guidelines. J Natl Cancer Inst 1997;89:1758-62.
7. Umar A, Boland CR, Terdiman JP, Syngal S, de la Chapelle A, R.schoff J et al. Revised Bethesda Guidelines fo Hereditary Nonpolyposis Colorectal Cancer (Lynch Syndrome) and Microsatellite Instability. J Natl Cancer Inst 2004;96:261-8.
8. Boland CR, Thibodeau SN, Hamilton SR, Sidransky D, Eshleman JR, Burt RW et al. A National Cancer Institute Workshop on Microsatellite Instability for cancer detection and familial predispo- sition: development of international criteria for the detection of microsatellite instability in col- orectal cancer. Cancer Res 1998;58:5248-57.
2 Ovarian cancer: Importance of our own immune system
Ovarian cancer is the sixth most common cancer in women worldwide and the leading cause of death from gynecological cancer (1,2). Seventy-five percent of all epithelial cancers will have spread beyond the ovaries at the time of diagnosis and more than half of patients will have remission after surgical debulking and primary chemotherapy; nevertheless, overall five-year survival remains lower than 25 % percent (3,4). Tumor stage, residual disease after surgical debulking, and the response to chemotherapy are the factors that affect the outcome of ovarian carcinoma (4,5). Do we have organism defense system against these or some other malignant cells or don't we? Is our immunity system to weak to recognize and attack such a malignant changes in these cells or we still don't know the power of our immune system? Until the end of the 19th century the possibility that a tumor could be rejected merely by the body's immune defense was just a vision, but after 100 years of preclinical and clinical research in the field the vision of cancer immunotherapy became real and has, with multiple tools, successfully entered clinical standard practice. Immune defense against pathogens and tumors is mediated through antigen-specific and nonspecific immune mechanisms. Non-specific immune responses are procured by cells of the macrophage and NK cell lineage and/or by soluble factors such as inflammatory cytokines. The functioning of the antigen-specific immune system is based on a division of labor between T cells and antibody-producing B cells (6). Ovarian carcinoma may be recognized and attacked by the immune system. The tumor may contain a lymphocytic infiltrate, and these tumor-associated lymphocytes exhibit oligoclonal expansion, recognize tumor antigens, and display tumor-specific cytolytic activity in vitro (7-11). Lin Zhang and colleagues find a very interesting relationship between tumorinfiltrating T cells and clinical outcome in advanced ovarian cancer. Their study indicates that the presence or absence of intratumoral T cells correlates with the clinical outcome of advanced ovarian carcinoma after surgical debulking and adjuvant chemotherapy (12). They performed immunohistochemical analysis of 186 frozen specimens from advancedstage ovarian carcinomas to assess the distribution of tumor-infiltrating T cells and conducted outcome analyses. Molecular analyses were performed in some tumors by real-time polymerase chain reaction. Results of this study are very interesting. CD3+ tumor-infiltrating T cells were detected within tumor-cell islets (intratumoral T cells) in 102 of the 186 tumors (54.8%); they were undetectable in 72 tumors (38.7 percent); the remaining 12 tumors (6.5 percent) could not be evaluated. There were significant differences in the distributions of progression-free survival and overall survival according to the presence or absence of intratumoral T cells (P<0.001 for both comparisons). The five-year overall survival rate was 38.0 percent among patients whose tumors contained T cells and 4.5 percent among patients whose tumors contained no T cells in islets. Significant differences in the distributions of progression- free survival and overall survival according to the presence or absence of intratumoral T cells (P<0.001 for both comparisons) were also seen among 74 patients with a complete clinical response after debulking and platinum-based chemotherapy: the five-year overall survival rate was 73.9 percent among patients whose tumors contained T cells and 11.9 percent among patients whose tumors contained no T cells in islets. The presence of intratumoral T cells independently correlated with delayed recurrence or delayed death in multivariate analysis and was associated with increased expression of interferon-g, interleukin-2, and lymphocyte-attracting chemokines within the tumor. The absence of intratumoral T cells was associated with increased levels of vascular endothelial growth factor (VEGF). This finding also points to the importance of vascular density in tumor and increase level of VEGF as another important factor which could effect on treatment and clinical outcome. They did not find the association between the presence and absence of T cells and age, histological type, or tumor grade. Univariate analysis revealed that the presence or absence of T cells (P<0.001) and the extent of residual tumor (P<0.001) correlated with overall survival but that tumor grade (P=0.06 for the comparison of grade 1 with grade 3; P=0.30 for the comparison of grade 2 with grade 3), histological type of tumor (P=0.41), inclusion or noninclusion of paclitaxel in the chemotherapeutic regimen (P=0.74), and age (<55 years vs.>55 years, P=0.25) did not. The presence or absence of intratumoral T cells and the extent of residual tumor but not age, tumor grade, or type of first-line chemotherapy were independent prognosticators of progression- free survival and overall survival in a multivariate analysis. The histological type of the tumor predicted overall survival but not progression-free survival. A very complex network of interacting cells and molecules mediates cellular immune responses against infectious pathogens and cancer. Specificity of the system is determined by the interaction of antigen binding receptors (TCR) on tumor-specific T cells. The latter are presented to the TCR as peptides assembled into the antigen-presenting groove of HLA-I or HLA-II antigens on the surface of tumor cell and/or antigen presenting dendritic cells (DC). T cells represent the only immune mechanism that can see inside a cancer cell. This is important because most cancer specific proteins, including those determining the malignant phenotype, are not expressed on the cell surface and not accessible to antibodies. Subsequent to fragmentation of tumor proteins in the proteasome the resulting peptides associate with HLA-I and 2-microglobulin in the endoplasmatic reticulum. This peptide-HLA-b2-microglobulin complex is than stable enough to integrate into the cell surface where it can be recognized by TA-specific cytotoxic T cells (CTLs) (13).
Figure 1. Patterns of T-Cell Infiltration in Ovarian Carcinoma (Zhang L, Conejo-Garcia JR, Katsaros D, Gimotty PA, Massobrio M, Regnani G et al. Intratumoral T Cells, Recurrence, and Survival in Epithelial Ovarian Cancer N Engl J Med 2003; 348:203-13)
Panel A shows double immunofluorescent detection of cytokeratin (fluorescein; green) and CD3 (Texas red; red) demonstrating the organization of cytokeratin-positive tumor cells in well-defined tumor islets and the presence of CD3+ tumor-infiltrating T lympho- cytes both within tumor islets and in peritumoral stroma. Panel B shows that T cells appear in tumor islets as well as in tumor stroma; there is an abundance of intratumoral T cells. In Panel C, no intratumoral T cells were detected: T cells are restricted exclusive- ly to the peritumoral stroma in this specimen. In Panel D, real-time quantitative poly- merase-chain-reaction analysis of the constitutive CD3e chain of the T-cell receptor in 16 tumors containing T cells and 10 tumors without T cells reveals overexpression of CD3e in the former, reflecting a greater number of T cells. The y axis represents the expression of CD3e in relation to glyceraldehyde-3-phosphate dehydrogenase messenger RNA (mRNA). Panels E and F show four-color flow-cytometric analysis of T cells derived from a fresh stage III ovarian carcinoma with use of monoclonal antibodies against CD3, CD4, and CD8. Gating was carried out on viable CD45+ leukocytes, which comprised up to 35 percent of all cells harvested after mechanical dispersion and enzymatic digestion of solid tumor nodules. T cells represent the most prevalent tumor-infiltrating immune cells. The quantification of CD3+CD4+ T cells is shown in Panel E, and the quantification of CD3+CD8+ T cells is shown in Panel F. Panels G, H, and I show an immunohistochem- ical analysis of CD4+ and CD8+ T cells in ovarian carcinoma. Panel G shows the corre- lation of the number of CD4+ T cells with that of CD8+ T cells according to the immuno- histochemical analysis of tumors containing T cells and those without T cells. Both intra- tumoral and peritumoral T cells were counted. A close correlation was noted (R2=0.66). In the specimen shown in Panel H, both intratumoral and peritumoral CD4+ T cells are present. Intratumoral and peritumoral CD8+ T cells are present in the adjacent section shown in Panel I. APC denotes allophycocyanin.
Figure 2. Survival Analyses of Patients with Ovarian Carcinoma, According to the Presence or Absence of Intratumoral T Cells (Zhang L, Conejo-Garcia JR, Katsaros D, Gimotty PA, Massobrio M, Regnani G et al. Intratumoral T Cells, Recurrence, and Survival in Epithelial Ovarian Cancer N Engl J Med 2003; 348:203-13).
Panels A and B show Kaplan-Meier curves for the duration of progression-free survival and overall survival, respectively, according to the presence or absence of intratumoral T cells in 174 patients with stage III or IV epithelial ovarian cancer and complete, partial, or no response to therapy. Panels C and D show Kaplan-Meier curves for the duration of progression-free survival and overall survival, respectively, according to the presence or absence of intratumoral T cells in 74 patients with stage III or IV epithelial ovarian cancer and a complete response to therapy. Panels E and F show survival curves stratified according to the extent of residual disease for the 74 patients with a complete response to therapy, according to the presence or absence of intratumoral T cells. Optimal debulking was defined by residual tumor of less than 1 cm, and suboptimal debulking by residual tumor of 1 cm or more. P values were derived with the use of the log-rank statistics.
1. Greenlee RT, Hill-Harmon MB, Murray T, Thun M. Cancer statistics, 2001. CA Cancer J Clin 2001;50:7-33.
2. Bosch FX, Lorincz A, Munoz N, Meijer CJ, Shah KV. The causal relation between human papillomavirus and cervical cancer. J Clin Pathol 55, 2002;55:244-65.
3. Munoz N et al. Epidemiologic classification of human papillomavirus types associated with cervical cancer. N Engl J Med 2003;348:518-27.
4. Schlecht NF et al. Human papillomavirus infection and time to progression and regression of cervical intraepithelial neoplasia. J Natl Cancer Inst 2003;95:1336-43.
5. Goldie SJ et al. A comprehensive natural history model of HPV infection and cervical cancer to estimate the clinical impact of a prophylactic HPV-16/18 vaccine. Int J Cancer 2003;106:896-904.
6. Stanimirovic B, Kuljic-Kapulica N, Antic N, Stanimirovic V, Vasiljevic M, Popovic-Lazic J. HPV typing in cervical squamous intraepithelial lesions(SIL)- our experience after 1000 studied patiens. Archive of Oncology 1999;7(2):43-8.
7. Koutsky LA, Holmes KK, Critchlow CW et al. A cohort study of the risk of cer- vical intraepithelial neoplasia grade 2 or 3 in relation to papillomavirus infec- tion. N Engl J Med 1992;327:1272-8.
8. Mandic A, Vujkov T. Human papillomavirus vaccine as a new way of pre- venting cervical cancer: A dream or the future. Ann Oncol 2004;15:197-200.
9. Zhou J, Sun XY, Stenzel DJ, Frazer IH. Expression of vaccinia recombinant HPV 16 L1 and L2 ORF proteins in epithelial cells is sufficient for assembly of HPV virion-like particles. Virology 1991;185:251-7 .
10. Kirnbauer R, Booy F, Cheng N, Lowy DR, Schiller JT. Papillomavirus L1 major capsid protein self-assembles into virus-like particles that are highly immuno- genic. Proc Natl Acad Sci USA 1992;89:12180-4.
11. Da Silva DM, Velders MP, Nieland JD, Schiller JT, Nickoloff BJ, Kast WM. Physical interaction of human papillomavirus virus-like particles with immune cells. Int Immunol 2001;13(5):633-41.
12. Koutsky L, Ault K, Wheeler C, Brown D, Barr E, Alvarez F et al. A controlled trial of human papillomavirus type 16 vaccine. N Engl J Med 2002;347/21:1645-51.
Medical and Scientific Meetings
  Issue 3
1 Response of Established Human Breast Tumors to Vaccination with Mammaglobin-A cDNA
Narayanan K, Jaramillo A, Benshoff ND, Campbell LG et al. JNCI 2004;96(18):1388-96.
A novel breast cancer-associated antigen, mammaglobin-A, is expressed in 80% of primary breast tumors. The characterization of immune responses against this highly expressed breast cancer-specific antigen would be of value in the development of new therapeutic strategies for breast cancer. The authors developed an in vivo model using human leukocyte antigen-A*0201/human CD8+ (HLA-A2+/hCD8+) double-transgenic mice to define the epitopes and to study the level of protection acquired by mammaglobin-A cDNA vaccination toward mammaglobin-A+/HLA-A2+ breast cancer cell lines. Mammaglobin-A epitopes were identified using an HLA class I peptide binding prediction computer program, and their activity was verified using gamma interferon ELISPOT and cytotoxicity assays. The HLA-A2+/hCD8+ mouse represents a valuable animal model to characterize the HLA-A*0201-restricted CD8+ CTL immune response to mammaglobin-A in vivo, and the data reported here demonstrate the immunotherapeutic potential of mammaglobin-A for the treatment and/or prevention of breast cancer.
2 Five-Year Outcomes After Prostatectomy or Radiotherapy for Prostate Cancer: The Prostate Cancer Outcomes Study
Potosky AL, Davis WW, Hoffman RM et al. JNCI 2004;96(18):1358-67.
Men treated for clinically localized prostate cancer with either radical prostatectomy or external beam radiotherapy usually survive many years with the side effects of these treatments. Authors presents treatment-pecific quality-of-life outcomes for prostate cancer patients 5 years after initial diagnosis. At 5 years after diagnosis, men treated with radical prostatectomy for localized prostate cancer continue to experience worse urinary incontinence than men treated with external beam radiotherapy. However, the two treatment groups were more similar to each other with respect to overall sexual function, mostly because of a continuing decline in erectile function among the external beam radiotherapy patients etween years 2 and 5.
3 Probabilities of Death From Breast Cancer and Other Causes Among Female Breast Cancer Patients
Schairer C, Mink PJ, Carroll L et al. JNCI 2004;96(17):1311-21.
Among cancer patients, probabilities of death from that cancer and other causes in the presence of competing risks are optimal measures of prognosis and of mortality across demographic groups. We used data on breast cancer patients from the Surveillance, Epidemiology, and End Results (SEER) Program in a competing-risk analysis. The probability of death from breast cancer versus other causes varied substantially ccording to stage, tumor size, ER status, and age at diagnosis in both white and black patients.
Medical and Scientific Meetings
Simposium Articles: Supportive Care in Canser Patients: 1st Belgrade Education Symposium, October 2, 2004, Belgrade, Serbia and Montenegro
  Issue 4
1 Progress in nanoscience, nanotechnology, and nanomedicine
In 2002 there were a few international conferences on nanoscience and nanotechnology in USA (Foresight conference), Europe and Japan (First Japan-UK Nanotechnology Summer School). Also, there were two meetings in Serbia where nanotechnology and biomedicine joint together: one international (SAUM, Belgrade) and other domestic (Academy of Studenica, Studenica).
Big progress has been done in nanotechnology in fabrication of nano-dendritic structure with branches under 3 nm (1nm =10-9m). For the first time researchers from National Institute for Materials Science (Japan), Furuya and Hasegawa produced this dendritic structure under electron beam irradiation using the vapor deposition properties of organometallic gases. Also, they fabricated nano-dendric structures on the substrate by delivering a gas containing the target element to the vicinity of the substrate with a newly developed gas delivery system while maintaining a high vacuum in the electron microscope sample chamber. The size of the structure as a whole and the location of formation can be controlled easily, and combinations of numerous types of substrates and gas sources are possible. This research result is expected to find wide application in research and development of surface-effect devices, nanosized catalyzed, biosensors, and nanobiomedical devices.
Another significant progress has been done in nanoscienece in the field nano-controllers. Two researchers Lidija Matija and Sršan Ribar found solution how to overcome problems with classical control theory in nanoscience and its application in nanotechnology. For the first time in nanoscience they proposed application of fractional calculus rather than classical one. Currently dominant approach to nanotechnology is from physics point of view. However, a chemical approach to nanotechnology is more natural to biological solutions. The first system has more solid phase state, while the second one has more liquid phase state. It is quite obvious that new nanotechnological systems will be on the border on these two phases. Fractal calculus is basic scientific approach to develop control system, which can control all three states: liquid, liquid/solid, and solid.
2 Low-grade cervical intra-epithelial neoplasia: Does the regression depend on our own gene map and human papillomavirus status?
Authors from France published in Obstetrics & Gynecology some interesting results about patients with low-grade cervical intra-epithelial neoplasia (CIN) who have a very good chance of experiencing spontaneous regression. Xavier Sastre-Garau and his colleagues (1) analyzed the probability of regression of these lesions according to the human leukocyte antigen (HLA-DR) and human papilloma virus (HPV) status. The human leukocyte antigen (HLA)-DRB1*13 allele frequency is lower in women with cervical carcinoma than in the general population, suggesting that this allele could exert a protective effect against progression of cervical intraepithelial neoplasia (CIN) associated with human papillomaviruses (HPV). The study sample was composed of 86 women with CIN1 who agreed to regular colposcopic follow-up and no immediate treatment. Biopsy specimens were taken under colposcopy for histology and for the determination of HPV and HLA status. Cases were classified into 3 groups: CIN1 regression, persistence for at least 12 months, or progression to CIN2 or CIN3.
The rate of spontaneous regression (95% confidence interval) at 24 months was 51.6% (39-61.6%) overall compared with 34.7% (13.4-50.8%) in HPV16/18 positive cases and 59.9% (43.7-71.4%) in HPV16/18-negative cases (P = .051). The rate of regression was 71.8% (40.8-86.5%) in patients with HLA-DRB1*13 and 45.9% (31.5-57.2%) in patients with other genotypes (P = .03). Regression reached 90.5% (38.9-98.5%) at 18 months in DRB1*13 patients with HPV16/18-negative-associated CIN (15.1% of the cases). In multi-variable analysis, HLA-DRB1*13 allele and HPV16/18-negative status were independently associated with an increased probability for regression (adjusted hazard ratio 2.1 [1.0-4.1] and 2.5 [1.2-5.4], respectively). They showed that subset of approximately 15% of CIN1 highly likely to show spontaneous regression can be defined using two biologic parameters that characterize the viral causative agent and the host.
1. Sastre-Garau X, Cartier I, Jourdan-Da Silva N, De Crémoux P, Lepage V, Charron D. Regression of Low-Grade Cervical Intraepithelial Neoplasia in Patients With HLA-DRB1*13. Gen Obstet Gynecol 2004;104:751-5.
3 Endometrial cancer: Advanced disease and chemotherapy
Aljosa MANDIC.
According to the Register of Cancer the standard incidence rates of endometrial cancer in central part of Serbia are 9.1 in 1996 and 12.3 in 1999 per 100 000. Endometrial cancer is still the most curable among ten most common cancers in women because PMB, as a leading clinical symptom, occurs mostly when disease is still limited to the uterine corpus (International Federation of Gynecology and Obstetrics [FIGO] stage I and II in which the probability of long-term disease-free survival is high) (1). Patients with endometrial cancer who have localized disease are usually curable by hysterectomy and bilateral salpingo-oophorectomy. Best results are obtained with either of two standard treatments: hysterectomy or hysterectomy and adjuvant radiation therapy (when deep invasion of the myometrial muscle [one half the depth] or grade 3 tumor with myometrial invasion is present). Where is the place of progestogen therapy in treatment of endometrial cancer?
Progestogen therapy was subscribed widely in the past. A meta-analysis of 6 randomized trials involving a total of 3,339 women has shown no survival benefit for adjuvant progestogen therapy in endometrial cancer (2). A subsequently published randomized trial of 1012 women also failed to demonstrate any survival benefit (3). It is shown that surgery and radiotherapy are the two most combined modalities of treatment for endometrial cancer in early stages of the disease.
Is there any place of chemotherapy in advanced endometrial cancer?
US researchers have now, for the first time, presented the final results of the pivotal trial that first demonstrated the benefits of adding cisplatin to doxorubicin in patients with endometrial carcinoma.
J. Tate Thigpen (University of Mississippi School of Medicine, Jackson, Missouri) and colleagues showed, at the initiation of the study, doxorubicin and cisplatin ranked as the most active agents in endometrial carcinoma (4). This trial of stage III, IV, or recurrent disease evaluated whether combining these agents increases response rate (RR) and prolongs progression-free survival (PFS) and overall survival (OS) over doxorubicin alone. 281 of patients were eligible for study. Regimens were doxorubicin 60 mg/m2 intravenously or doxorubicin 60 mg/m2 plus cisplatin 50 mg/m2 every 3 weeks until disease progression, unacceptable toxicity, or a total of 500 mg/m2 doxorubicin.
There were 12 (8%) complete (CR) and 26 (17%) partial responses (PR) among 150 patients receiving doxorubicin versus 25 (19%) CRs and 30 (23%) PRs among patients receiving the combination. The overall response rate was higher among patients receiving the combination (42%) compared with patients receiving doxorubicin (25%; P = .004). Median PFS was 5.7 and 3.8 months, respectively, for the combination and single agent. The PFS hazard ratio was 0.736 (95% CI, 0.577 to 0.939; P = .014). Median OS was 9.0 and 9.2 months, respectively, for the combination and single agent. Overall death rates were similar in the two groups (hazard ratio, 0.928; 95% CI, 0.727 to 1.185). Nausea, vomiting, and hematological toxicities were common. The combination produced more grade 3 to 4 leukopenia (62% vs. 40%), thrombocytopenia (14% vs. 2%), anemia (22% vs. 4%), and nausea/vomiting (13% vs. 3%).
Compared with doxorubicin alone, combination treatment was associated with a significantly improved overall response rate (42 percent vs. 25 percent) and increased progression-free survival (5.7 months vs. 3.8 months), but, at the same time, it had a negligible impact on overall survival (9.0 vs.9.2 months), and increased toxicity.

1. Mandic A, Vujkov T. Endometrial cancer: Diagnostic methods in postmenopausal vaginal bleeding. Arch Oncol 2003;11(2):97-101.
2. Martin-Hirsch PL, Lilford RJ, Jarvis GJ. Adjuvant progestagen therapy for the treatment of endometrial cancer: review and meta-analyses of published randomised controlled trials. Eur J Obstet Gynecol Reprod Biol 1996;65(2):201-7.
3. COSA-NZ-UK Endometrial Cancer Study Groups. Adjuvant medroxyprogesterone acetate in high-risk endometrial cancer. Int J Gynecol Cancer 1998;8:387-91.
4. Thigpen JT, Brady MF, Homesley HD, Malfetano J, DuBeshter B, Burger RA et al. Phase III Trial of Doxorubicin With or Without Cisplatin in Advanced Endometrial Carcinoma: A Gynecologic Oncology Group Study. J Clin Oncol 2004;22:3902-8.

Mammographic density and breast cancer after ductal carcinoma in situ
Habel LA, Dignam JJ, Land SR et al. JNCI 2004;96(19):1467-72.
Women with ductal carcinoma in situ (DCIS) are at substantially increased risk for a second breast cancer, but few strong predictors for these subsequent tumors have been identified. We used Cox regression modeling to examine the association between mammographic density at diagnosis of DCIS of 504 women from the National Surgical Adjuvant Breast and Bowel Project B-17 trial and risk of subsequent breast cancer events. In this group of patients, mostly 50 years old or older, approximately 6.6% had breasts categorized as highly dense (i.e., =75% of the breast occupied by dense tissue). After adjusting for treatment with radiotherapy, age, and body mass index, women with highly dense breasts had 2.8 (95% confidence interval [CI] = 1.3 to 6.1) times the risk of subsequent breast cancer (DCIS or invasive), 3.2 (95% CI = 1.2 to 8.5) times the risk of invasive breast cancer, and 3.0 (95% CI = 1.2 to 7.5) times the risk of any ipsilateral breast cancer, compared with women with less than 25% of the breast occupied by dense tissue. Our results provide initial evidence that the risk of second breast cancers may be increased among DCIS patients with highly dense breasts.


The ubiquitin-mediated protein degradation pathway in cancer: therapeutic implications
Burger AM, Seth AK. Eur J Cancer 2004;40(15):2217-29.
The highly conserved eukaryotic ubiquitin-proteasome system (UP-S) plays a pivotal role in protein homeostasis and is critical in regulating normal and cancer-related cellular processes. The hierarchical nature of the UP-S provides a rich source of molecular targets for specific intervention and has therefore arisen as a promising approach to innovative anticancer therapies. The first in class proteasome inhibitory agent Bortezomib (Velcade) has recently obtained regulatory approval for the treatment of multiple myeloma. Ubiquitin-mediated degradation is a complex process that is comprised of well defined steps involving ubiquitin-activating enzymes (E1s), ubiquitin-conjugating enzymes (E2s) and ubiquitin ligases (E3s). Although a single E1 activates the ubiquitin conjugation machinery, a large number of E2 conjugating enzymes and E3 ligases are now known to exist. Proteins tagged with ubiquitin are subsequently recognised by the proteasome for digestion and fragmentation. The enzymatic nature, multitude of E3s and their specific substrate recognition predestines them as therapeutic targets. This article will review known inhibitors of the proteasome and their molecular mechanisms as well as ongoing developments and promising avenues for targeting substrate-specific E3 ligases that are likely to yield a new class of therapeutics that will serve and complement the armamentarium of anticancer drugs.


The interplay between Src and integrins in normal and tumor biology
Playford MP, Schaller MD. Oncogene 2004;23(48):7928-46.
Src family nonreceptor protein tyrosine kinases transduce signals that control normal cellular processes such as cell proliferation, adhesion and motility. Normally, cellular Src is held in an inactive state, but in several cancer types, abnormal events lead to elevated kinase activity of the protein and cause pleiotropic cellular responses inducing transformation and metastasis. A prerequisite of the ability of a cancer cell to undergo metastasis into distant tissues is to penetrate surrounding extracellular matrices. These processes are facilitated by the integrin family of cell adhesion molecules. As is the case with Src, altered integrin activity or substrate affinity can contribute to the neoplastic phenotype. Therefore, understanding the interplay between Src and integrin function has been of intense interest over the past few years. This review focuses on the role of Src and integrin signaling in normal cells and how this is deregulated in human cancer. We will identify the key players in the integrin-mediated signaling pathways involved in cell motility and apoptosis, such as FAK, paxillin and p130(CAS), and discuss how Src signaling affects the formation of focal adhesions and the extracellular matrix. FAK, paxillin and p130(CAS), and discuss how Src signaling affects the formation of focal adhesions and the extracellular matrix.

7 Supportive care in cancer patients
(The first Belgrade Education Symposium under the auspices of the Multinational Association of Supportive Care in Cancer)
The international education Symposium "Supportive care in cancer patients" was organized in Belgrade (October 2nd, 2004), under the auspices of the Institute for Oncology and Radiology of Serbia and Multinational Association of Supportive Care in Cancer (MASCC). The goal of the Symposium was to promote supportive care discipline in the region of Central and Eastern Europe. The need for the course was identified through requests from oncologists and other relevant clinicians involved in the care of patients with cancer. The main learning objectives were: (1) to increase awareness and applicable knowledge of supportive care, its goals and achievements, (2) to highlight the concept of quality of life in oncology, (3) to cover evaluation and management of common physical symptoms (cancer pain, dyspnoea), complications of cancer (bone metastases, anorexia/cachexia) and of major toxicities induced by anticancer treatment (nausea and vomiting, myelosuppression, febrile neutropenia), and (4) to present philosophy and the key concepts of end of life care. The course was also intended to inspire and motivate the audience with the best international lecturers. Topics were reviewed and discussed by the many leading international experts willing to donate their time and experience to this symposium.
The Symposium had 154 participants, mainly physicians (oncologists, internal medicine specialists, general practitioners, geriatricians, young doctors in training for general oncology), but also nurses and other relevant clinicians (clinical psychologists) from Serbia and Montenegro and other European countries (Bosnia & Herzegovina, Bulgaria, Greece, France, Slovenia). A total of 68 completed evaluation forms were returned. Using the 1-5 scale, the overall rating of the Symposium topic was 4.63, of the content 4.65, while the organization and duration were rated 4.65 and 4.40, respectively (Table 1). The topic and the content of the Symposium were most frequently described as 'systematization of the existent knowledge' (20/68, 29.4%) or "stimulative for further work" (20/68, 29.4%). The most frequent responses to the question 'How would you describe methods of work applied in the Symposium?' were: "illustrative and easy to remember" (24/63, 38.1%), 'usual' (22/63, 34.9%) or "up-to-date, but without active involvement of participants" (10/63, 15.9%). The technical facilities provided were described as "satisfactory in the given conditions" (27/66, 40.9%) as well as "pleasant and inspiring" (22/66, 33.3%). Taking into consideration the content, quality of presentation as well as quality of slides / visual support the speakers were given the average rating of = 4. The overall rating of the quality of the education offered at this Symposium was 4.50 (range 1: poor; 5: excellent): more than 90% of participants graded the Symposium as very good (24/68, 35.3%) or excellent (40/68, 58.8%). Every effort was made to provide the participants with congress material of high quality. All presentations were published in the scientific journal Archive of Oncology, the only journal in our country specialized in oncology. Moreover, MASCC has strongly supported us by sending free copies of the official journal "Supportive care in cancer" and copies of recently published guidelines for the prevention and treatment of cancer-therapy induced oral and gastrointestinal mucositis.
In our opinion the education results achieved justify organization of such symposiums in the future. The broadening of the topics to include evaluation and management of other physical symptoms/complications of cancer (tumor-induced nausea and vomiting, fatigue, intestinal obstruction), other treatment toxicities (cancer-therapy induced oral mucositis), psychological symptoms of cancer (depression, delirium), as well as social and spiritual support was suggested. Moreover, longer duration of the Symposium was proposed as well as more active involvement of participants through thematic workshops. The Symposium was intended to bring together oncologists, other relevant clinicians, and representatives of the pharmaceutical industry to facilitate cooperation and communication between them. Moreover, the intention was also to increase awareness in public of supportive care as a discipline in oncology: successful press conference was organized and the Symposium received extensive media coverage on both national and local TV. The message conveyed is that supportive care is to be acknowledged as a discipline which is capable of helping the patient and the family achieve the best possible quality of life in every phase of malignant disease, and consequently an integral part of comprehensive cancer care. Oncologists, other relevant clinicians, the public in general, being banded together and gathered around this Symposium, may further negotiate with the regulatory authorities and advocate for the successful removal of barriers to effective supportive and palliative care.
The Symposium was supported by: Serbian Medical Association-Section for Oncology, Ministry of Health, Republic of Serbia, Ministry of Science and Environmental Protection, Republic of Serbia, French Ministry of Foreign Affairs, International Association for Hospice and Palliative Care (IAHPC), and European Association for Palliative Care (EAPC), Center for Palliative Care in Eastern Europe (EAPC-EAST).

Our warmest thanks go to all the lecturers, participants and sponsors.
Svetislav JELIC, Chairman of the Symposium
Snezana BOSNJAK, Co-chairman

Press Release: The 2004 Nobel Prize in Physiology or Medicine
The Nobel Assembly at Karolinska Institutet has today decided to award The Nobel Prize in Physiology or Medicine for 2004 jointly to Richard Axel and Linda B. Buck for their discoveries of "odorant receptors and the organization of the olfactory system" (4 October 2004)
Summary. The sense of smell long remained the most enigmatic of our senses. The basic principles for recognizing and remembering about 10,000 different odours were not understood. This year's Nobel Laureates in Physiology or Medicine have solved this problem and in a series of pioneering studies clarified how our olfactory system works. They discovered a large gene family, comprised of some 1,000 different genes (three per cent of our genes) that give rise to an equivalent number of olfactory receptor types. These receptors are located on the olfactory receptor cells, which occupy a small area in the upper part of the nasal epithelium and detect the inhaled odorant molecules. Each olfactory receptor cell possesses only one type of odorant receptor, and each receptor can detect a limited number of odorant substances. Our olfactory receptor cells are therefore highly specialized for a few odours. The cells send thin nerve processes directly to distinct micro domains, glomeruli, in the olfactory bulb, the primary olfactory area of the brain. Receptor cells carrying the same type of receptor send their nerve processes to the same glomerulus. From these micro domains in the olfactory bulb the information is relayed further to other parts of the brain, where the information from several olfactory receptors is combined, forming a pattern. Therefore, we can consciously experience the smell of a lilac flower in the spring and recall this olfactory memory at other times.
Richard Axel, New York, USA, and Linda Buck, Seattle, USA, published the fundamental paper jointly in 1991, in which they described the very large family of about one thousand genes for odorant receptors. Axel and Buck have since worked independent of each other, and they have in several elegant, often parallel, studies clarified the olfactory system, from the molecular level to the organization of the cells.
The olfactory system is important for life quality. When something tastes really good it is primarily activation of the olfactory system which helps us detect the qualities we regard as positive. A good wine or a sunripe wild strawberry activates a whole array of odorant receptors, helping us to perceive the different odorant molecules. A unique odour can trigger distinct memories from our childhood or from emotional moments - positive or negative - later in life. A single clam that is not fresh and will cause malaise can leave a memory that stays with us for years, and prevent us from ingesting any dish, however delicious, with clams in it. To lose the sense of smell is a serious handicap - we no longer perceive the different qualities of food and we cannot detect warning signals, for example smoke from a fire. Olfaction is of central importance for most species. All living organisms can detect and identify chemical substances in their environment. It is obviously of great survival value to be able to identify suitable food and to avoid putrid or unfit foodstuff. Whereas fish has a relatively small number of odorant receptors, about one hundred, mice - the species Axel and Buck studied - have about one thousand. Humans have a somewhat smaller number than mice; some of the genes have been lost during evolution.
Smell is absolutely essential for a newborn mammalian pup to find the teats of its mother and obtain milk - without olfaction the pup does not survive unaided. Olfaction is also of paramount importance for many adult animals, since they observe and interpret their environment largely by sensing smell. For example, the area of the olfactory epithelium in dogs is some forty times larger than in humans.
A large family of odorant receptors. The olfactory system is the first of our sensory systems that has been deciphered primarily using molecular techniques. Axel and Buck showed that three per cent of our genes are used to code for the different odorant receptors on the membrane of the olfactory receptor cells. When an odorant receptor is activated by an odorous substance, an electric signal is triggered in the olfactory receptor cell and sent to the brain via nerve processes. Each odorant receptor first activates a G protein, to which it is coupled. The G protein in turn stimulates the formation of cAMP (cyclic AMP). This messenger molecule activates ion channels, which are opened and the cell is activated. Axel and Buck showed that the large family of odorant receptors belongs to the G protein-coupled receptors (GPCR).
All the odorant receptors are related proteins but differ in certain details, explaining why they are triggered by different odorous molecules. Each receptor consists of a chain of amino acids that is anchored into the cell membrane and traverses it seven times. The chain creates a binding pocket where the odorant can attach. When that happens, the shape of the receptor protein is altered, leading to G protein activation.
One type of odorant receptor in each olfactory receptor cell. Independently, Axel and Buck showed that every single olfactory receptor cell expresses one and only one of the odorant receptor genes. Thus, there are as many types of olfactory receptor cells as there are odorant receptors. It was possible to show, by registering the electrical signals coming from single olfactory receptor cells, that each cell does not react only to one odorous substance, but to several related molecules - albeit with varying intensity. Buck's research group examined the sensitivity of individual olfactory receptor cells to specific odorants. By means of a pipette, they emptied the contents of each cell and showed exactly which odorant receptor gene was expressed in that cell. In this way, they could correlate the response to a specific odorant with the particular type of receptor carried by that cell.
Most odours are composed of multiple odorant molecules, and each odorant molecule activates several odorant receptors. This leads to a combinatorial code forming an "odorant pattern" - somewhat like the colours in a patchwork quilt or in a mosaic. This is the basis for our ability to recognize and form memories of approximately 10,000 different odours. Olfactory receptor cells activate micro regions in the olfactory bulb. The finding that each olfactory receptor cell only expresses one single odorant receptor gene was highly unexpected. Axel and Buck continued by determining the organization of the first relay station in the brain. The olfactory receptor cell sends its nerve processes to the olfactory bulb, where there are some 2,000 well-defined microregions, glomeruli. There are thus about twice as many glomeruli as the types of olfactory receptor cells.
Axel and Buck independently showed that receptor cells carrying the same type of receptor converge their processes into the same glomerulus, and Axel's research group used sophisticated genetic technology to demonstrate in mice the role of the receptor in this process. The convergence of information from cells with the same receptor into the same glomerulus demonstrated that also glomeruli exhibit remarkable specificity (see figure).

In the glomeruli we find not only the nerve processes from the olfactory receptor cells but also their contacts with the next level of nerve cells, the mitral cells. Each mitral cell is activated only by one glomerulus, and the specificity in the information flow is thereby maintained. Via long nerve processes, the mitral cells send the information to several parts of the brain. Buck showed that these nerve signals in turn reach defined micro regions in the brain cortex. Here the information from several types of odorant receptors is combined into a pattern characteristic for each odour. This is interpreted and leads to the conscious experience of a recognizable odour.
Pheromones and taste. The general principles that Axel and Buck discovered for the olfactory system appears to apply also to other sensory systems. Pheromones are molecules that can influence different social behaviours, especially in animals. Axel and Buck, independent of each other, discovered that pheromones are detected by two other families of GPCR, localized to a different part of the nasal epithelium. The taste buds of the tongue have yet another family of GPCR, which is associated with the sense of taste.
REFERENCE. Buck L, Axel R. Cell 1991;65:175-87.

Book Review
Book Recieved
Meetings and Congress Reports
Medical and Scientific Meetings
  Volume 11 Issue 1
1 Telemedicine - Beyond 2000 (Conditions of Development)
Editor-in-chief, Rashid L. Bashshur, Ph.D.
Telemedicine Journal and e-Health 2001;7(4):273.

In "Telemedicine Journal and e-Health", Volume 7, Number 4, 2001, Editor-in-chief, Rashid L. Bashshur, Ph.D. has written an editorial titled "Where we are in Telemedicine/Telehealth, and where we go from here". He has presented the following excerpts taken form his introductory remarks at the opening session of an international symposium on the state-of-art in telemedicine , conducted on the campus of the University of Michigan on August 23-25, 2001:
- symposium prelude
- the promise of telemedicine
- accessibility enhancement
- cost containment
- quality improvement
- second generation of telemedicine
The paper is useful for understanding the philosophy of telemedicine and telecare and is certainly need to be read. On the author's opinion, the most significant part is one with list of exclusive conditions which must be observed to improve telemedicine (access, cost and quality). This part should convince all health professionals dealing with telemedicine that despite low level of present status of telemedicine in Serbia and a lot of skepticism among health professionals of real benefit of telemedicine in Serbia under present conditions, must deal with the problems, not to give up and wait until better times comes.
"I believe that the promises held by telemedicine and the hoped for impact on access, cost, and quality are not likely to be manifest unless certain NOT mutually exclusive conditions are observed: · * Enhanced access to healthcare via telemedicine will be achieved only with the ubiquitous distribution of telemedicine systems/networks. The infrastructure must be within the reach of rich and poor alike, consistent with the Alma Ata declaration of healthcare as a right in 1978, to which this country and other countries are signers. In fact, the need for increased access to healthcare, lower cost for healthcare, and increased quality of such care is generally inversely related to a population's or region's economic status. To achieve enhanced access, these systems must become more affordable, and both the public and private sectors must assume their respective shares in this investment.
* The key to cost containment is effective substitution of telemedicine for traditional and more costly arrangements. Normally, at least initially, technology contributes to an increase in the cost of care as it often adds to the diagnostic and treatment armamentarium. This is the case despite the fact that the increased capabilities should improve diagnostic accuracy and health outcomes. The production function for health (or the combination of all services needed to produce a unit of health-including doctor and nurse time, diagnostic tests, therapeutic regiment, and other services) must change to encompass lesser intensity of service and increased efficiency.
* About quality of care, telemedicine's potential contribution can be realized only through large-scale diffusion of and conversion to telemedicine, certainly beyond that observed to date. This requires broad provider and institutional adoption and acceptance. A more complete integration of information technology into routine clinical practice, greater use of information technology and artificial intelligence in clinical decision-making, and standardized electronic medical records are essential. This integration is necessary to create a critical mass and to derive the full benefits of integrative technology related to diagnosis and treatment, as well as the reduction of diagnostic and treatment errors (after all an error is simply quality compromised in some fashion). By whatever name, these problems can be reduced through greater reliance on accurate information about patients, automated clinical decision support, artificial intelligence and professional interaction.
* Telemedicine will not realize its full potential regionally, nationally, and certainly internationally without greater investment in information technology. The information highway has only reached some places recently while in others its development is nascent. Even in developed countries, there are significant interstices between the highway networks where the technology is not available. The current disjuncture between the enormous and everexpanding capabilities of information technology and our ability to exploit these capabilities must be bridged. Prudent investment in information technology is challenging because of its fast obsolescence, the technological imperative (if it exists we must have it) on the one hand, and our limited ability to utilize these capabilities, on the other. Indeed, there must be long-term commitment and investment by the public and private sectors. The economic "pay off," or return on investment, must be deferred.
* Provider institutions must adapt administrative policies to accommodate telemedicine and more broadly health informatics and bio-informatics. Institutional, organizational and national policies must face new assumptions and new realities derived from the development of telemedicine and health informatics. The medical establishment must rethink the manner in which it provides services. It must also address the medical needs of areas where such services are absent or in short supply.
Summing up, the second generation of telemedicine has made great strides in terms of technology, geography, and interest when compared with the first. There seems little doubt that this interest and the advancing technology have assured its future in some form or another. However, with an informed public policy and smart private action, we have the opportunity to derive more benefits, assure a more prudent investment, and improve health and well-being of people everywhere. Perhaps one of the most unique and significant attributes of telemedicine technology is its integrative capacity, in establishing networks, and in building partnerships. More benefits and more dividends can be achieved through establishing integrative telemedicine systems that incorporate all diagnostic and clinical services within healthcare institutions, for states and provinces to develop comprehensive and ubiquitous networks within their boundaries, and for the countries of the world to share healthcare resources. We must not think of telemedicine only in terms of serving remote or otherwise medically disenfranchised populations. To do so would not only relegate telemedicine to a second tier or level of medical care, but would also ignore its capabilities for greater system integration and coordination and more efficient production of health."
Prepared by Svetozar ZDRAVKOVIC
2 New Telemedicine Center Creates Virtual "Front-Door" to M.D. Anderson
Kathleen CHARTER
Texas Medical Center News 2002 Nov 15; 24(21)

Six physicians made history at The University of Texas M.D. Anderson Cancer Center Oct. 22, when they "linked up" in the first telemedicine consultation held in the cancer center's new telehealth center. Funded with a $2 million grant from the SBC Foundation, SBC Communications' philanthropic arm, the new center provides remote practitioners with a virtual "front door" to the cancer center. SBC Communications is the parent company of Southwestern Bell. Houston M.D. Anderson physicians Henry Mark Kuerer, M.D., Ph.D., a surgical oncology assistant professor; Nuhad K. Ibrahim, M.D., a breast medical oncology associate professor; and George H. Perkins, M.D., a radiation oncology assistant professor, discussed treatment options for a 43-year old Hispanic breast cancer patient with Orlando-based M.D. Anderson affiliates Nikita Shah, M.D., a medical oncologist; Daniel Bucholz, M.D., a radiation oncologist; and Michael Kahky, M.D., a surgical oncolgist. "This has been a dream for years by a number of us," said John Mendelsohn, M.D., the cancer center's president. "M.D. Anderson has a wealth of educational opportunities to share, and this new door of technology is our way to extend care to the world." Since M.D. Anderson's clinical telemedicine program's inception in 1994, nearly 1,500 activities have been conducted annually. "It is one of the largest telemedicine oncology programs in the world," said Margaret Kripke, Ph.D., M.D. Anderson executive vice president and chief academic officer. "With this new center, we will continue training even more of tomorrow's leading researchers today." The 3,000 square-foot SBC Telehealth Center, located in M.D. Anderson's Faculty Center, is comprised of a 65-seat classroom, an administrative conference room and the telemedicine room where consultations are held. Rooms feature state-of-the-art audiovisual and telecommunications equipment that allows specialists to examine electronic diagnostic images, pathology slides and other data from a patient's medical record. In addition, the classroom features a touch panel to independently control classroom functions from the podium, eye-level monitors which allow instructors to maintain eye contact at all times, a "blue screen" for special effects, television-friendly lighting, and a rear-screen projection system that will support a variety of formats, including high-definition television. Adding to this new telecommunications technology, and located across the street in M.D. Anderson's main clinical facility, is the newly updated SBC Auditorium that seats 300. "M.D. Anderson views patient care as multidisciplinary," Mendelsohn said. "This new center will host patient-care teams as they develop the best possible patient-care plans." In addition to conducting long-distance medical consultations, patient and professional educational programs, and research exchanges with affiliates in Orlando and Madrid, as well as other institutions across the nation and globe, the SBC Telehealth Center is bridging the digital divide by making live Internet broadcasts and "on demand" Internet video available to worldwide audiences. The center's distance education area will also provide interactive television facilities for teaching graduate-level courses from The University of Texas Graduate School of Biomedical Sciences. "Having the facilities on campus, in the same building as our faculty offices, will save our educators travel time and time away from patients," said Stephen Tomasovic, Ph.D., vice president for educational programs. "With this well-equipped telecommunication center in place, we are supporting M.D. Anderson's mission of 'Making Cancer History,'" Mendelsohn said.
Texas Medical Center News [Internet] Texas Medical Center;©1996-2002 [cited 2003 Mar 25]. Available from
3 Telemedicine news - 1
In an effort to take quality healthcare across India and into neighbouring nations, a Calcutta-based private group has decided to open several treatment centres equipped with telemedicine facilities connecting all the units with both Calcutta and an Ohio-based hospital in the United States. To begin with, B.M. Birla Heart Research Centre plans to open 15 treatment centres-cum-diagnostic facilities in places like Siliguri, Burdwan, Midnapore, Malda, Ranchi, Bhubaneswar, and a few towns in the Northeast. The treatment centres will have doctors and diagnostic facilities. "They will be equipped with telemedicine connections, through which experts in Calcutta can opine on a patient's condition after a look at the investigation results, including X-rays and ECGs," said M.L. Pachisia of the Heart Research Centre. If required, cases can be seen by experts at the Cleveland Clinic in Ohio.
The Telegraph - Calcutta, February 28, 2003
4 Telemedicine news - 2
Initial user feedback on a futuristic experiment in France allowing medical professionals in different locations to view three-dimensional images of patients' organs has been extremely positive. The 'Argonaute 3D' project allows a virtual representation of an organ to be produced from traditional two-dimensional scans, highlighting any tumours. Doctors and other medical staff can then simultaneously view the representation from any angle. Combined with videoconferencing at the consultation stage, the system allows all the necessary medical professionals to view and discuss the problem area before surgery takes place. The scheme is a collaboration between telecommunications company France Telecom and the Institute for Research into Cancer of the Digestive System (IRCAD) in Strasbourg.
Future Health Bulletin, February 28, 2003
5 Telemedicine technology news - 1
Titan Corp. is developing a "sensor glove" designed to record and transmit patients' vital signs almost instantly to doctors who are helping make decisions on medical treatment from half a world away. The glove, which would be worn by medics in the field, would record an injured soldier's pulse rate, body temperature, blood pressure, and blood-oxygen level. The information would be relayed to doctors using wireless technology. A short video by NBC KNSD/7 TV in San Diego is available on the Titan Web site (requires Real Player or Windows Media Player).
Augusta Chronicle, December 26, 2002
6 Telemedicine technology news - 2
Asthma sufferers could soon benefit from a system which allows their doctors to keep track of their condition via mobile phone. The system connects an electronic lung capacity measuring device, known as a peak flow meter, to a mobile phone which gathers, records, and submits accurate asthma data in real-time to doctors. This system, the brainchild of telemedicine firm e-San, will allow doctors to receive immediate alerts of patients whose conditions have deteriorated. For the duration of the trial, 100 asthma patients in the Slough area of the UK will be given a free mobile device - O2's XDA, which is a combined phone and personal digital assistant. There are around 3.5 million asthmatics in the UK, which has one of the worst records for the condition in Europe.
BBC News, March 3, 2003
7 Telemedicine technology news - 3
Wellogic and WorldCare recently announced the activation of a turnkey telemedicine system that will enable WorldCare clients to receive expert second opinion medical consultations rendered by the WorldCare Consortium: The Cleveland Clinic, Duke University Health System, Johns Hopkins Medicine, and Partners HealthCare System, which includes Massachusetts General Hospital and Brigham and Women's Hospital. Wellogic Consult will enable clinical users in referring locations to assemble a complete electronic patient record and securely transmit the record to a reviewing hospital. Advanced image compression, combined with advanced Web services technology and deep user interface design, makes Consult ideal for the transmission of all components of an electronic patient record, from text and scanned documents to DICOM images and digitized radiology films, over any connection, even dial-up.
PR Newswire, March 3, 2003
Telemedicine Today
Telemedicine Journal and e-Health
Journal of Telemedicine and Telecare
British Journal of Healthcare Computing
Telemedicine and Telehealth Networks
1 Prognostic value of magnetic resonance imaging-guided stereotactic biopsy in the evaluation of recurrent malignant astrocytoma compared with a lesion due to radiation effect
McGirt MJ, Bulsara KR, Cummings TJ, New KC, Little KM, Friedman HS et al.
J Neurosurg 2003;98(1):14-20.
This study was undertaken to determine the prognostic value of differentiating between recurrent malignant glioma and a lesion due to radiation effect by performing stereotactic biopsy has not been assessed. Between 1995 and 2001, 114 patients underwent magnetic resonance (MR) imaging-guided stereotactic biopsy to differentiate lesions caused by a recurrence of malignant astrocytoma and by radiation effect. All patients had previously undergone tumor resection (World Health Organization Grade III or IV) followed by radiotherapy. Disease diagnosis based on biopsy and patient characteristics were assessed as predictors of survival according to results of a multivariate Cox regression analysis. With the aid of stereotactic biopsy the authors demonstrated prognostic significance in differentiating recurrent malignant astrocytoma from a lesion due to radiation effect in patients presenting more than 5 months after having undergone radiotherapy. In patients who presented earlier than 5 months after radiothera- py, radiation effect on biopsy was not associated with an improved rate of survival compared with that in patients harboring recurrent malignant astrocytoma.
2 Activity and expression of human telomerase in normal and malignant cells in gastric and colon cancer patients
Nowak J, Januszkiewicz D, Lewandowski K, Nowicka-Kujawska K, Pernak M, Rembowska J et al.
Eur J Gastroenterol Hepatol 2003;15(1):75-80.

The aim of this study was to investigate the expression of three components of the telomerase complex (hTR, hTERT and TP1), along with telomerase activity in malignant and normal cells. Addition of Ifosfamide and Etoposide to Standard Chemotherapy for Ewing's Sarcoma and Primitive Neuroectodermal Tumor of Bone Expression of hTERT, hTR and TP1 has been studied by the reverse transcriptase polymerase chain reaction (PCR) technique. It can be concluded that all the cancer cells tested have higher telomerase expression and activity than normal cells. Therefore, telomerase can be a good cancer marker, provided that quantita-tive analysis is carried out.
3 Multiple Colorectal adenomas, Classic adenomatous polyposis, and germ-line mutations in MYH
Sieber MO, Lipton L, Crabtree M, Heinimann K, Fidalgo P, Phillips KSR et al.
N Engl J Med 2003;348:791-9.
Germ-line mutations in the base-excision-repair gene MYH have been associated with recessive inheritance of multiple colorectal adenomas. Tumors from affected persons displayed excess somatic transversions of a guanine-cytosine pair to a thymineadenine pair (G:C -->T:A) in the APC gene. Six patients with multiple adenomas and eight patients with polyposis had biallelic germline MYH variants. In the group with multiple adenomas, about one third of patients with more than 15 adenomas had biallelic MYH mutations. In the polyposis group, no patient with biallelic MYH mutations had severe disease (>1000 adenomas), but three had extracolonic disease. No clearly pathogenic MTH1 or 0GG1 mutations were identified. Germ-line MYH mutations predispose persons to a recessive phenotype, multiple adenomas, or polyposis coli. For patients with about 15 or more colorectal adenomas - especially if no germ-line APC mutation has been identified and the family history is compatible with recessive inheritance - genetic testing of MYH is indicated for diagnosis and calculation of the level of risk in relatives. Clinical care of patients with biallelic MYH mutations should be similar to that of patients with classic or attenuated familial adenomatous polyposis.
4 Addition of Ifosfamide and Etoposide to Standard Chemotherapy for Ewing's Sarcoma and Primitive Neuroectodermal Tumor of Bone
Grier EH, Krailo DM, Tarbell JN, Link PM, Fryer JH Ch, Pritchard Jd et al.
N Engl J Med 2003;348:694-701.
Ewing's sarcoma and primitive neuroectodermal tumor of bone are closely related, highly malignant tumors of children, adolescents, and young adults. A new drug combination, ifosfamide and etoposide, was highly effective in patients with Ewing's sarcoma or primitive neuroectodermal tumor of bone who had a relapse after standard therapy. A total of 518 patients met the eligibility requirements. Of 120 patients with metastatic disease, 62 were randomly assigned to the standard-therapy group and 58 to the experimental-therapy group. There was no significant difference in five-year event-free survival between the treatment groups (P=8.81). Among the 398 patients with nonmetastatic disease, the mean (±SE) five-year event-free survival among the 198 patients in the experimentaltherapy group was 69±3 percent, as compared with 54±4 percent among the 200 patients in the standard-therapy group (P=0.005). Overall survival was also significantly better among patients in the experimental-therapy group (72±3.4 percent vs. 61±3.6 percent in the standard-therapy group, P=0.01). The addition of ifosfamide and etoposide to a standard regimen does not affect the outcome for patients with metastatic disease, but it significantly improves the outcome for patients with nonmetastatic Ewing's sarcoma, primitive neuroectodermal tumor of bone, or primitive sarcoma of bone.
5 Clinical trials and regulations
In January's issue of European Journal of Cancer, Grossi F et al reported the geography of clinical cancer research publications from 1995 to 1999 (EJC 2003; 39: 106-111). The authors performed the Medline search to collect the data concerning reported phase I, II and III trials dealing with antineoplastic treatment and supportive therapy, as well. More than 40 countries were included in this search. The United States ranked first by both the number of papers and the mean impact factor (IF) of papers in which the trials were reported. According to this analysis Yugoslavia was among the top 25 countries by number of reported papers (15). The total IF for that period was 57, 296, and mean IF was 3,18 which placed Yugoslavia in top 10 countries after Canada, Netherlands, UK, Australia, USA, Finland, Israel, France and Austria. Although there is some experience in conducting clinical trials in Serbia, still legislative documents are lacking. Good clinical practice (GCP) is an international, ethical and scientific quality standard for designing, conducting, recording and reporting of clinical studies. The harmonization of different national GCPs (USA, Europe, Japan) was finally achieved, thus facilitating the mutual acceptance of clinical data by different regulatory authorities. These regulations, in accordance with European Union Directives concerning clinical trials, are hopefully expected to be incorporated into the Law on pharmaceutical products in Serbia very soon. However, there is substantial concern about GCP has already become an obstacle to progress for clinical trials in the treatment of breast cancer (The Statement of Barcelona, EJC 2002; 38: 2210-3). Although GCP was basically created to protect research subjects' confidentiality, ensure that ethical principles are applied and none of adverse events, especially serious side effects of new drugs, to be overlooked, the conduction of clinical trials according to GCP rules became very difficult for researchers and prohibitively expensive. Hence, the authors called for common sense to be allowed to prevail and introduced two watchwords: education (of public, ethics committees and clinical scientists) and partnership (between patients, clinical researchers and the politicians responsible for bureaucracy governing the development of new drug).
6 Morphine in cancer pain management: a practical guide
Morphine is the strong opioid of choice for the relief of chronic severe pain associated with cancer. If given according to well-established principles, morphine relieves pain in 80% of patients. A practical guide for morphine administration in cancer pain management was recently published in the Journal of Supportive Care in Cancer reviewing the clinical guidelines of the Harry R. Horvitz Center (a World Health Organization Center for palliative medicine). The pharmacokinetics of morphine is presented in details and how it is altered by age, renal and hepatic function, concomitant medications, gender and ethnic differences. The indications for morphine use in cancer pain management are clearly stated. It is pointed out that the morphine is indicated for severe cancer pain, whether somatic, visceral or neuropathic although morphine-poorly-responsive pain syndromes do exist. The practical recommendations for dose titration (initial morphine dose and rescue doses for breakthrough pain) to achieve adequate balance between analgesia and adverse effects are particularly useful. One of the advantages of morphine in comparison with other strong opioids is the possibility of drug administration by several different routes (oral, sublingual/buccal, rectal, parenteral, epidural, intrathecal, vaginal and topical). The article gives a detailed description of the routes of morphine administration (indications, advantages, disadvantages and dose conversions). The major adverse effects of morphine (gastrointestinal, neuropsychiatric, respiratory) are summarized with the aim to help clinicians to prevent and manage them effectively. Together with already existing guidelines (1, 2) a practical guide presented in this article could help clinicians to further improve the effectiveness of cancer pain management with morphine and the quality of supportive care received by cancer patients.

1. Hanks GW, de Conno F, Cherny N, et al. Morphine and alternative opioids in cancer pain: the EAPC recommendations. Br J Cancer 2001; 84:587-93.
2. Cherny N, Ripamonti C, Pereira J, et al. Strategies to manage the adverse effects of oral morphine: an evidence based report. J Clin Oncol 2001;19:2542-54. rug).
Book Review
Meetings and Congress Reports
Medical and Scientific Meetings
  Issue 2
1 A growing network of cancer-susceptibility genes
Venkitaraman RA
N Engl J Med 2003;348:1917-9.

In the search for genes that are relevant to disease, new contexts are discovered for "old" molecules. Several genes are particular- ly versatile, in that they are individually responsible for more than one disase. A study by Howlett et al. Provides an interesting example: mutation of BRCA2, a breast-cancer-susceptibility gene, may cause Fanconi's anemia. Genetic instability is charac- teristic of BRCA 2-deficient cells, which accumulate broken and deformed chromosomes as they divide. Similar abnormalities also occur in cells that lack BRCA1, another breast-cancer-sus- ceptibility gene. Genetic instability can be triggered by the failure to repair breaks in double-stranded DNA caused by ionizing radi- ation. BRCA2 and BRCA1 protein are essential for recombination but dispensable for end-joining. In dividing cells deficient in either protein, breaks in double-stranded DNA are repaired predomi- nantly through error-prone mechanisms, leading to chromosomal aberrations and an increased rate of mutation. The centrality of DNA-repair reactions - as mediated by RAD51 and BRCA2 - in preserving chromosomal structure and preventing carcinogenesis is emphasized by work exposing a connection between suscepti- bility to breast cancer and Fanconi's anemia, a rare, autosomal recessive disease that confers an increased risk of acute myeloid leukemia and squamous-cell carcinoma. At least eight subtypes of Fanconi's anemia (designated A, B, C, D1, D2, E, F and G), each with a distinct genetic cause, have been recognized. Germ-line mutations in six different genes (accounting for all subtypes except B and D1) have been identified. Two findings have cemented the connection between breast-cancer proteins and Fanconi's anemia. The first was the discovery that FANCD2, the gene mutated in patients with the subtype D2, links Fanconi's anemia proteins to BRCA1. These findings suggest that BRCA2 is the gene mutated in Fanconi's anemia D1 and, possibly B. The serine-threonine kinases ATM (which is mutant in patients with ataxia-telangiectasia) and CHEK2 are enzymatic components of the machinery by which cells sense and signal the presence of breaks in double-stranded DNA. In this case, the aberrations in DNA recombination that promote carcinogenesis by causing genetic instability may also be the Achilles? heel of the cancers that arise in this setting.
Figure 1. Cancer-Susceptibility Genes and DNA Repair. Several genes (ATM, CHEK2, BRCA1, and BRCA2) whose inactivation predisposes people to breast and other cancers participate in the error-free repair of breaks in double-stranded DNA by homologous recombination. The process starts when ATM and CHEK2 protein kinases signal the presence of double-stranded breaks by phosphorylating (red arrows) proteins such as BRCA1, inducing their migration to sites where DNA is repired. BRCA2 carries the DNA-recombination enzyme RADS1 to the same sites. It is guided there by the DNA-binding structures formed between its carboxy terminal and Dss1. The concetreted activity of these proteins culminates in error-free DNA repair by recombination. Two findings1,2 connect Fanconi's anemia proteins to this pathway. First, a complex of Fancon's anemia proteins - termed A, C, D2, E, F, and G - triggers the ubiquitination of the D2 protein alone and its colocalization with BRCA1. Second, BRCA2 is mutated in a small group of patients with Fanconi's anemia. This work emphasizes the importance of the homologous recombination pathway in the pathogenesis of disorders involving chromosomal instability. Ub denotes mono-ubiquitin.
2 A randomized trial of aspirin to prevent colorectal adenomas in patients with previous colorectal cancer
Sandler SR, Halabi S, Baron AJ, Budingers S, Paskett E, Keresztes R et al.
N Engl J Med 2003;348:883-90.

Experimental studies in animals and observational studies in humans suggest that aspirin and other nonsteroidal antiinflamatory drugs (NSAIDs) may decrease a risk of colorectal adenomas,the precursors to most colorectal neoplasia.Randomized clinical trials have demonstrated the reduction innumber and size of adenomas in patients with familial adenomatous polyposis (FAP) (Snadler RS et al.). The Colorectal Adenoma Prevention Study and Eastern Cooperative Oncology Group (ECOG) in the M.D. Anderson Cancer Center randomly assigned 635 patients with colorectal cancer to receive either aspirin 325 mg aspirin per day or placebo. One or more adenomas were found in 17% of patients in the aspirin group and 27% in patients of the placebo group. Relative risk of recurrent adenoma in the aspirin group was 0.65. The time to the detection of a first adenoma was longer in theaspirin group than in the placebo group (hazard risk ratio for thedetection of a new polyp, 0.64). Daily use of aspirin is associated with a significant reduction inthe incidence of colorectal adenomas in patients with previous colorectal cancer.
Figure 1. Kaplan-Meier Estimates of the Time to a First Adenoma
Table 2. Number of Colonoscopic Examinations after Randomization
3 Adjuvant treatment with interferon alfa did not contribute to survival or relapse-free survival in completely resected locally advanced renal cell carcinoma
Messing et al. (1) reported in April issue of Journal of Clinical Oncology the results of randomized, phase III trial of adjuvant interferon alfa compared with observation for 283 eligible patients with locally advanced (pT3-4 and/or node positive disease) renal cell carcinoma completely resected by radical nephrectomy and lymphadenectomy. In the treatment arm interferon was given daily for 5 days every 3 weeks for up to 12 cycles. At median follow-up of 10.4 years, median survival was 7.4 years in the observation arm and 5.1 years in the treatment arm. Median recurrence-free survival was 3.0 years in the observation arm and 2.2 years in the interferon arm. Although no lethal toxicities were observed, severe (grade 4) toxicities including Neutrogena, myalgia, fatigue, depression, and other neurological toxicities occurred in 11.4% of those randomly assigned to interferon treatment. The results of the study are in accordance with those from two other phase-III randomized trials (2,3) which compared interferon alfa given as adjuvant treatment with observation after complete resection: none showed a delay in time to relapse or improvement of overall survival associated with interferon alfa therapy. Data are lacking for study of interleukin-2 adjuvant therapy in a randomized trial. Thus, the standard management for localized tumors after nephrectomy remains surveillance. Success of an adjuvant treatment program depends on drugs capable of eradicating metastases. The outcome of three adjuvant trials (1-3) reflects the lack of effective systemic therapy to treat metastatic disease. Three decades of extensive clinical investiga- tions have identified only two agents that have an effect on survival for patients with metastatic disease. Treatment with high-dose bolus interleukin-2 achieved durable responses in small proportion of highly selected patients. A modest survival benefit for interferon alfa therapy in metastatic renal cell carcinoma was observed in two-phase III trials comparing interferon alfa with vinblastine or medroxyprogesterone. Given the high proportion of patients with metastases and the associated poor survival, this malignancy must be regarded as a priority for studies in tumor biology and development of novel, mechanism-driven therapy (4).
1. Messing EM, Manola J, Wilding G et al. Phase III study of interferon alfa-NL as adjuvant treatment for resectable renal cell carcinoma: An Eastern Cooperative Oncology Group/Intergroup Trial. J Clin Oncol 2003; 21:1214-22.
2. Porzsolt F. Adjuvant therapy of renal cell cancer with interferon alfa-2a. ProcAmSocClin Oncol 1992;11:202, (abstr 622).
3. Pizzocaro G, PivaL, Costa A et al. Adjuvant interferon to radical nephrectomy in Robson`s stage II and III renal cell cancer: A multicenter randomized study with some biological evaluations. Proc Am Soc Clin Oncol 1997;16:318a (abstr. 1132).
4. Motzer RJ: Renal Cell Carcinoma: A Priority Malignancy for Development and Study of Novel Therapies (editorial). J Clin Oncol 2003; 21:1193-4.
4 National Comprehensive Cancer Network-Guidelines for the management of prostate cancer
Douglas Scherr, Peter W. Swindle, Peter T. Scardino
Guidelines for the management of prostate cancer issued by the National Comprehensive Cancer Network (NCCN) assembled a Prostate Cancer Panel composed of 17 leading experts in field of prostate including urologists, radiation oncologists and medical oncologists provide a basis for rationale treatment decisions. These guidelines represent concensus recommendations and evidence based for physicians in prostate cancer treatment. The initial stratification point in the guidelines is based on the anticipated life expectancy of the individual patient (>5 or <5 years) and whether the patient is symptomatic from the prostatic cancer. If the life expectancy is > 5 years, the recommended intervention is based on clinical stage, prostate-specific antigen (PSA) level, Gleason score, and presence of symptoms. These assessments establish the patient's risk of recurrence after therapy (low, intermediate, high or very high). The guidelines also describe the appropriate use of observation ("watchful waiting") vs. active intervention in certain patients. After radical therapy, patients should be monitored with PSA determinations, digital rectal examination and bone scans. Patients who exhibit increasing PSA levels after radiotherapy are candidates for surgery as the additional option. If PSA begins to increase after prostatectomy, androgen ablation, radiotherapy or observation is treatment of choice. Systemic salvage therapy generally consists of androgen ablation; the benefit of total androgen blockade vs. monotherapy remains controversial. Relapse after initial androgen ablation is treated with an antiandrogen, if none had been administered previously. Patients refractory to further hormonal therapy are observed or receive palliative therapy, including chemotherapy. The NCCN guidelines serve to provide a framework on which physicians can base optimal treatment. Specific disease characteristics, life longevity and personal preferences of the patient are fundamental for treatment recommendation.
(Source: Urology 2003;61 (Suppl 2A), 14-24)
Meetings and Congress Reports
Medical and Scientific Meetings
  Issue 3
Medical Meeting
XXXX Annual Meeting of the Oncologists of Serbia
XVII Meeting of Oncology and Radiology of Serbia
Institute for Oncology and Radiology of Serbia
Srbian Medical Association
November 5-7, 2003 - Belgrade, Yugoslavia
XVII Meeting of Oncology Nurses and Technicians of Republic of Serbia
  Issue 4
1 Adjuvant ovarian function supression under reinvestigation
The role of adjuvant endocrine therapy is well established for the treatment of endocrine-responsive breast cancer (BC) patients. Adjuvant ovarian function suppression (OFS) was the first endocrine treatment proved to be efficacious in breast cancer. Adjuvant chemotherapy showed to be superior in younger thus premenopausal patients compared to older ones, which is explained by the fact that chemotherapy very often leads to amenorrhea in younger patients. However, it seems that the benefit from adjuvant chemotherapy is more dependent on age than on menopausal status (1). Furthermore, women aged <35 years with steroid receptor (SR) - positive disease treated with adjuvant chemotherapy alone seemed to have the worst outcome in comparison with other patients (1).
According to EBCTCG analysis published in 1998 (2), tamoxifen is as effective in premenopausal as is in postmenopausal SR - positive breast cancer patients. Due to this report, tamoxifen ± chemotherapy was accepted as one of standard adjuvant treatments in premenopausal endocrine-responsive patients. The latest report of ZEBRA (3) and ABCSG 05 trials (4), revealed that adjuvant LH-RH analogs given to these women alone or with tamoxifen might have equal effect to or might be superior to adjuvant CMF (cyclophosphamide, methotrexate, and fluorouracil) chemotherapy. Due to inconclusive data presented in current trials, these are the main open questions waiting to be resolved:
1. What is the role of ovarian suppression, e.g. does it add to the benefit of combined chemotherapy + tamoxifen?
2. Does adjuvant chemotherapy add to the efficacy of combined OFS + tamoxifen?
3. What is the best mode of OFS, e.g. is permanent OFS superior to temporary OS?
4. What is the role of aromatase inhibitors in combination with OFS in premenopausal patients? To address these questions tailored treatment investigation for premenopausal endocrine-responsive patients was designed. Three complementary studies, coordinated by International Breast Cancer Study Group (IBCSG), are being conducted (5,6): SOFT (Suppression of Ovarian Function Trial) for those women whose doctors prefer to use tamoxifen and TEXT (Tamoxifen and Exemestane Trial) and PERCHE (Premenopausal Endocrine Responsive Chemotherapy Trial) for patients who are considered for OFS from the beginning of adjuvant treatment. Eight thousand premenopausal SR-positive breast cancer patients are intended to be included in these trials.
Many oncologists and patients are concerned about the consequence of the early menopause related mainly to the osteoporosis, lipid metabolism and cardiovascular complications and sexual activity. How to get over it is another important issue need to be further investigated in order to ensure good quality of life to these women.

1. Craig Henderson: Endocrine Therapy, Chemotherapy, of Both as Adjuvant Systemic Treatment of Patients With Early Breast Cancer, in: Educational book, Annual Meeting of American Society of Clinical Oncology. J Clin Oncol 2001;Suppl: 53-60.
2. Early Breast Cancer Trialists' Collaborative Group: Polychemotherapy for early breast cancer: an overview of the randomised trials. Lancet 1998;352:930-42.
3. Jonat W, Kaufmann M, Sauerbrei W, Blamey R, Cuzick J, Namer M et al. Goserelin Versus Cyclophosphamide, Methotrexate, and Fluorouracil as Adjuvant Therapy in Premenopausal Patients With Node-Positive Breast Cancer: The Zoladex Early Breast Cancer Research Association Study. J Clin Oncol 2002;20:4628-35.
4. Jaskesz R, Hausmaninger H, Kubista E, Gnant M, Menzel C, Bauernhofer T et al. Randomized Adjuvant Trial of Tamoxifen and Goserelin Versus Cyclophosphamide, Methotrexate, and Fluorouracil: Evidence for the Superiority of Treatment with Endocrine Blockade in Premenopausal Patients With Hormone-Responsive Breast Cancer - Austrian Breast and Colorectal Cancer Study Group Trial 5. J Clin Oncol 2002;20(24):4621-7.
5. Gelber RD, Castiglione-Gertsch M, Coates AS, Goldhirsch A for the International Breast Cancer Study Group (IBCSG), Breast International Group (BIG) and North American Breast Intergroup. Tailored Treatment Investigation for Premenopausal Women with Endocrine Responsive (ER+ and/or PgR+) Breast Cancer: The Open Questions. The Breast 2003;12 Suppl 1:S43(Abstr P103).
6. Francis P, Fleming G, Nasi ML, Pagani O, Perez E, Walley B, for the International Breast Cancer Study Group (IBCSG), Breast International Group (BIG) and North American Breast Intergroup. Tailored Treatment Investigation for Premenopausal Women with Endocrine Responsive (ER+ and/or PgR+) Breast Cancer: The SOFT, TEXT and PERCHE Trials. The Breast 2003;12 Suppl 1:S44 (Abstr P104).
2 Step forward in tumor's cytogenetics: Vulvar and vaginal cancer
Vulvar and vaginal cancer are a rare gynecologic malignancy. Vulvar cancer accounts for 5% of all female genital cancers and 1% of all malignancies in women (1). The most common histology of vulvar cancer is squamous cell carcinoma accounting for about 87% of these lesions. Malignant melanoma is the second most common cancer occurring in the vulva, accounting for about 6% of lesions. Other less common histological types include Bartholin's gland adenocarcinoma, sarcoma, basal cell carcinoma, and invasive Paget's disease (2).Changes in genetic code of normal cells, which become abnormal with malignant potential and abnormalities of tumor's cells karyotypes, nowadays are still gray fields of molecular oncology. Only few cases had been analyzed by chromosome banding techniques and karyotyped, and also the number subjected to molecular cytogenetic analysis remains low. F. Micci and colleagues, Norwegian Radium Hospital, Department of Cancer Genetics, analyzed cytogenetically 51 tumors of vulva and vagina, and found karyotypic abnormalities in 37 (3). All tumors were analyzed by G-banding, sometimes supplemented by multicolor fluorescence in situ hybridization, and a subset of tumors was also analyzed by comparative genomic hybridization. The two cytogenetically abnormal cases of Paget's disease both had two clones, one with gain of chromosome 7 as the sole change, the other with loss of the X chromosome among, in one case, other aberrations. Researches also found 31 cytogenetically abnormal squamous cell carcinomas, and different clonal karyotypic abnormalities were seen. Intratumor heterogeneity with multiple clones was observed in 11 cases. The clones were cytogenetically unrelated in eight tumors but related in three, indicating that in the latter clonal evolution had taken place from a single malignantly transformed cell. The main chromosomal imbalances were gains of, or from, chromosome arms 3q, 5p, 8q, 9q, and 19q, and loss from 11q. Breakpoint clusters were seen in 11q13-23, 2q22-35, and 19q13, as well as in the centromeres and pericentromeric bands of chromosomes 3, 8, 9, 13, 14, and 22.
1. DiSaia PJ, Creasman WT. Invasive carcinoma of the vulva. In: Clinical gyne- cologic oncology. St. Louis: Mosby-Year Book; 1997. p. 202-32.
2. Giselle B. Ghurani and Manuel A. Penalver: An update on vulvar cancer. Am J Obstet Gynecol 2001;185:294-9.
3. Micci F. Cytogenetic characterization of tumors of the vulva and vagina. Genes Chromosomes Cancer 2003;38(2):137-48.
3 Is HE4 new biomarker for early detection of ovarian cancer or CA125 is still alone?
Epithelial ovarian cancer belongs to the most common and most deadly of all types of ovarian carcinomas. Ovarian cancer is the sixth most common cancer in women worldwide and the leading cause of death from gynecological cancer. The three screening techniques available at this time (pelvic examination, CA-125 level, and vaginal ultrasound) do not actually diagnose ovarian cancer but only suggest its presence. As a biomarker, CA125 is still the best available diagnostic test for epithelial ovarian cancer. Unfortunately it is not so specific and it is not very effective in identifying early stage disease. It is useful in diagnosing late stage cancers, and in detecting the recurrence of tumors after chemotherapy and radiation. Also it could give false-positive results in some cases. Recently Scientists at the Pacific Northwest Research Institute (PNRI) in Seattle, Washington, announced a new biomarker for ovarian cancer. The researchers describe a molecule, HE4, associated with ovarian cancer cells. They performed experiments to explore whether quantitation of HE4 protein levels in serum can be used as a biomarker for ovarian carcinoma. Because the molecule is secreted readily into the blood, its presence should be detectable when simple and inexpensive clinical blood tests are developed. A double determinant ("Sandwich") ELISA was constructed and shown to detect a signal at the 160-pg level. Blinded studies on sera from postmenopausal patients with ovarian carcinoma and controls indicate that the specificity and sensitivity of the HE4-based ELISA is equivalent to that of the CA125 assay. The new biomarker HE4 proved to be at least as effective as CA125. There where no false-positive results occurred, HE4's sensitivity to ovarian carcinoma was 40% higher than that of CA125. The possibility that a simple and inexpensive blood test can be developed for clinical use is already being studied in a licensing agreement with Fujirebio Diagnostics Inc., the creator of CA125 but still there are many things to be done before it really showed some benefits in early diagnosis of ovarian cancer.
1. Boyle P, Maisonneuve P, Autier P. Towards cancer control in women. J Epidemiol Biostat 1998;3:137-68.
2. Landis SH, Murray T, Bolden S, Wingo PA: Cancer statistics, 1999. CA Cancer J Clin 1999;49:8-31.
3. Hellstr.m I, Raycraft J, Hayden-Ledbetter M, Ledbetter JA, Schummer M, McIntosh M et al. The HE4 (WFDC2) Protein Is a Biomarker for Ovarian Carcinoma". Cancer Res 2003;63:3695-700.
4 Mechanism of paclitaxel resistance: Bcl-2 down-regulation?
Chemotherapy is the standard adjuvant therapy following cytoreductive surgery in treatment of the advanced ovarian carcinoma. In new therapy standards emerged after the publication of a trial by the Gynecologic Oncology Group (GOG) in 1996 and the first reports of a intergroup trial in 1998 that confirmed GOG. The results demonstrated that patients treated with cisplatin/paclitaxel regiment had significantly higher response rates, progression-free survival and overall survival compared with the previous standard treatment of cisplatin and cyclophosphamide (1,2) Consensus statements were published in 1998, recommending that optimal treatment of advanced disease following cytoreductive surgery was chemotherapy with a taxane and platinum compound (3). Paclitaxel belong to the group of taxanes. Paclitaxel is an antimicrotubule agent that promotes the assembly of microtubules from tubulin dimers and stabilises microtubules by preventing depolymerisation. This stability results in the inhibition of the normal dynamic reorganisation of the microtubule network that is essential for vital interphase and mitotic cellular functions (4). Decrease in sensitivity of the tumor cell to the chemotherapy is one of the most important problems that occur nowdays effecting results of chemotherapy. Investigate the mechanism of the resistance is also one of the goal in modern oncology. C. Ferlini and colleagues, Laboratory of Antineoplastic Pharmacology, Department of Obstetrics and Gynaecology, Universit. Cattolica Sacro Cuore, Rome, Italy reported about Bcl-2 down-regulation as a novel mechanism of paclitaxel resistance. Mitochondrial was investigated as an additional target of taxanes. Isolated mitochondria were incubated in the presence of taxanes with or without stimulation of the mitochondrial respiratory state. To evaluate the binding of [14C]paclitaxel to isolated mitochondria, mitochondrial proteins were precipitated yielding 18.6 ± 2.1 cpm/µg of protein. After stimulation of the respiratory state, binding of [14C]paclitaxel increased up to 163.2 ± 46.7 cpm/µg of protein. CPM values after Bcl-2 immunoprecipitation were 62.8-fold higher than those of the control antibody, thereby indicating the involvement of Bcl-2 in paclitaxel binding. A panel of A2780 cell lines resistant to increasing doses of paclitaxel alone or to high doses of paclitaxel/cyclosporine A (A2780 TC cells) was established. In both cases, Bcl-2 expression was consistently down-regulated, whereas levels of other members of the Bcl-2 family, such as Bax and Bcl-x, did not change in paclitaxel-resistant cell lines. When A2780TC cells were stably transfected with a Bcl-2 construct, paclitaxel sensitivity was partially restored, thereby supporting a direct role of Bcl-2 down-regulation in the maintenance of drug-resistance. Than they examined Bcl-2 by immunohistochemistry in a small subset of ovarian cancer paclitaxel-resistant patients and it was noticed that the protein is down-regulated in this clinical setting with respect to the expression levels found in drug-sensitive tumors (5). This very interesting findings point to Bcl-2 as an additional intracellular target of taxanes and that its down-regulation is involved in taxane resistance.
1. McGuire WP, Hoskins WJ, Brady MD et al. Cyclophosphamide and cisplatin compared with paclitaxel and cisplatin in patients with stage III and stage IV ovarian cancer. N Engl J Med 1996;334:1-6.
2. Eisenhauer EA, ten Bokkel Huinink WW, Swenerton KD. European, Canadian randomised trial of paclitaxel in relapsed ovarian cancer: high-dose versus low-dose and long versus short infusion. J Clin Oncol 1994;12:2654-66.
3. Berek JS, Bertelsen K, du Bois A. Advanced epithelial ovarian cancer:1998 consensus statements. Ann Oncol 10Suppl 1:1999:87-92.
4. Mandic A, Vujkov T, Malbasa Z. Paclitaxel or docetaxel combined with plat- inum in advanced ovarian cancer. J BUON 2003;8:19-22.
5. Ferlini C, Raspaglio G, Mozzetti S, Distefano M, Filippetti F, Martinelli E et al. Bcl-2 down-regulation is a novel mechanism of paclitaxel resistance. Mol Pharmacol 2003;64(1):51-8.
5 Characteristics of Hodgkin's lymphoma after infectious mononucleosis
Vladimir BALTIC
Characteristics of Hodgkin's lymphoma after infectious mononucleosis The etiology of Hodgkin's lymphoma is unknown. However, some epidemiological studies have revealed there is a several fold increase risk of Hodgkin's lymphoma shortly after EBV-induced infectious mononucleosis, the typical clinical manifestation of primary Epstein-barr virus (EBV) infection in adolescence. Hjalgrim et al. have compared the incidence of Hodgkin's lymphoma in Danish cohort of 17,045 patients with the serum-positive EBV infection and 26,614 patients lacking serological evidence of the infection, to the Swedish cohort of 21,510 patients with infectious mononucleosis. The follow-up for Hodgkin's lymphoma started on 1 April, 1968 and terminated on 31 December, 1997. During the period 46 patients with Hodgkin's lymphoma were registered in both groups, but the histological confirmation of the disease was obtained in 32 patients. In all paraffin sections, using a sensitive immunohistochemical technique, the presence of EBV latent membrane protein was demonstrated in Reed-Sternberg cells. The relative risk of EBV positive and EBV negative Hodgkin's lymphoma after infectious mononucleosis is graphically shown in Figure 1.revious colorectal cancer. As it can be seen, there is a causal relationship between the EBV-induced infectious mononucleosis and EBV-positive Hodgkin's lymphoma in young adults. Hodgkin's lymphoma has been assessed to develop in 1 of 1,000 patients affected by infectious mononucleosis.
Taken from: N Engl J Med, 2003:349;14:1330
1. Epstein-Barr virus and Kaposi's sarcoma herpesvirus/human herpesvirus 8. Vol 70. IARC monographs on the evaluation of carcinogenic risks to humans. Lyon: IARC Press; 1997.
2. Mueller NE. Epstein-Barr virus and Hodgkin's disease: an epidemiological paradox. Epstein Barr Virus Rep 1997;4:1-2.
3. Hjalgrim H, Askling J, Sorensen P et al. Risk of Hodgkin«s disease and other cancers after infectious mononucleosis. J Natl Cancer Inst 2000;92:1522-8.
4. Hjalgrim H, Rostgaard K, Askling J et al. Hematopoietic and lymphatic can- cers in relatives of patients with infectious mononucleosis. J Natl Cancer Inst 2002;94:678-81.
5. Zhou XG, Sandvey K, Li PJ et al. Epstein-Barr virus (EBV) in Chinese pediatric Hodgkin disease: Hodgkin disease in young children is a EBV-related lym- phoma. Cancer 2001;92:1621-31.
6. Hjalgrim H, Askling J, Rostgaard K et al. Characteristics of Hodgkin«s lym- phoma after infectious mononucleosis. N Engl J Med 2003;349:1324-32.
Meetings and Congress Reports
Medical and Scientific Meetings
  Volume 10 Issue 1
1 Obstacle to cancer therapy
Cancer cells are wily. Drug therapies may temporarily halt tumor growth, but all too often the agents lose their effectiveness as the cells genetic versatility allows them to become resistant. Researcher hoped that so-called antiangiogenesis therapies, which are aimed at preventing the growth of the new vessels, needed to nourish tumors rather than at the tumors themselves, might circumvent this problem. But recent work suggests that tumors may be able to get around angiogenesis inhibitors, too. The latest example comes from Joanne Yu, Robert Kerbel and their colleagues at Sunnybrook and Women's College Health Sciences Center in Toronto, Canada. They report that tumors in which the p53 tumor suppressor gene has been inactivated, which happens in 50% of human cancers are much less responsive to angiogenesis inhibitors than comparable tumors in which the gene is still functional. Researchers already knew that cancer cells could counteract the inhibitors by pouring out more of the factors that promote new blood vessel growth. But loss of the p53 gene apparently renders tumor cells better able to survive in the low-oxygen conditions present in tumors deprived of an ample blood supply. James Pluda who just left the National Cancer Institute in Frederick, MA where he oversaw antiangiogenesis trials, for MedImmune Inc. in Gaithersburg, MA describes the Kerbel team's experiments as "a very nice piece of work" one that will help researchers decipher results from clinical trials of angiogenesis inhibitors. Already some 40 agents are being used worldwide against a wide range of cancers. Neither Pluda nor others expect the new results to preclude development of the inhibitors. But, Pluda notes, the findings "give us something to look at if patients whose cancers initially respond then progress". However, Kembel's team outline additional strategies that might get around the problem of tumor resistance to antiangiogenesis therapy such as upping the dose of the inhibitors of giving them with drugs that specifically target hypoxic cancer cells. The trick to defeating cancer this work shows once again will be to outmaneuver the huge enemy.
Strategies for Cancer Gene Therapy
Many gene therapy protocols to date have concentrated upon treatments for cancer. Though many cancers have a genetic predisposition, they all involve acquired mutations, and as they progress their cells become less differentiated and more heterogeneous with respect to the mutations they carry. In general cancers have at least one mutation to a prooncogene (yielding an oncogene) and at least one to a tumor suppressor gene, allowing the cancer to proliferate. The range of different cancers encountered and the mutations they carry, have led to a variety of strategies for gene therapy namely, immunopotentiation, oncogene inactivation, tumor suppressor gene replacement, molecular chemotherapy and drug resistance genes. The aim of immunopotentiation is to enhance the response of the immune system to cancers, thereby leading to their destruction. Passive immunotherapy aims to increase the pre-existing immune response to the cancer whilst active immunotherapy initiates an immune response against an unrecognized or poorly antigenic tumor. This strategy usually involves harvesting tumor infiltrating lymphocytes and treating them to express increased cytokines e.g. IL-2 and TNF-alpha. Oncogene inactivation uses the same techniques employed for dominantly inherited monogenic diseases. The oncogene may be targeted at the level of DNA, RNA, transcription or protein product. Despite multiple genetic abnormalities, restoration of the tumor suppressor gene, such as p53, can be sufficient to cause cellular apoptosis and arrest tumor growth. Moreover, expression of p53 is synergistic with chemotherapeutic drugs such as cisplatin. And adjacent tumor cells that have not been transduced are killed in what is termed the bystander effect. The p53 gene has been identified as important in a range of cancers and though less elegant than oncogene inactivation techniques, this method has proved robust enough to be included in a number of clinical trials. Other tumor suppressor genes may also prove useful, e.g. BRCA1sv. An alternative means of killing a tumor cell is to transduce a gene coding for a toxic product, known as molecular chemotherapy. The gene of choice is usually herpes simplex virus thymidine kinase (HSV/TK) which converts the pro-drug ganciclovir into toxic metabolites. The effected cell is supported via the gap junctions of adjancet cells until the toxin burden is too great killing both the affected cell and its neighbors. An advantage to this system is that all the transduced cells will be killed, allowing allogenic tumor cells to be prepared in advance. Phases of human trials are preliminary designed to demonstrate safety and efficacy and will not provide complete cures. The patients chosen have advanced metastatic cancer and early results are comparable to single agent chemotherapy. Colleagues at M.D Anderson Cancer Center in Houston, Texas have the great success in the field of cancer gene therapy.
Proprotein convertases and the pathophysiology of human disease: prospective considerations
From the apparent variety of physiologically important substrates that may require proteolytic activation by proprotein convertases, we can presume that reduced, excessive or ectopic production of one or the other of these enzymes will cause serious pathological conditions in humans, manifesting either as generalized physiological imbalances or as localized anomalies. The clinical symptoms that such abnormal expression could induce will probably be very pleotropic due to the relatively broad distribution of many of these enzymes. For example, excessive or deficient production or activation of hormones or their receptors have been implicated in the pathogenesis of endocrinopathic disorders. Considering the really critical role of proprotein convertases in prohormone processing these enzymes must contribute to the pathophysiology of several very serious endocrine diseases such as ACTH deficiency, Cushing's disease, disorders of glucose metabolism and hyperparathyroidsm. Probably, cancer, atherosclerosis and psoriasis are three pathologies in which the contribution of growth factors appears to be crucial. Most polypeptide growth factors are fragments of larger precursor proteins and many are generated by cleavage after sequences of basic residues that could be recognized by proprotein convertases. Numerous growth-regulatory molecules play critical roles in inducing the fibroproliferative response that contributes to the formation of the advanced lesions of atherosclerosis. These molecules determine whether the potentially occlusive fibrous plaque lesions of atherosclerosis will progress, regress or remain unchanged. The group includes PDGF, EGF, FGF, colony-stimulating factors, TGF-beta and TNF. Psoriasis, number of neurological disorders, hypertension, viral (HIV infection) and bacterial infections are examples of pathologies. The multifunctional nature of furin, ubiquitously expressed proprotein convertase has been implicated in many physiological and pathological process as a cancerogenesis, tumor progression. This multifunctional nature of furin has opened a way for extensive analysis of furin as a therapeutic target. Laboratory at LSUHSC, New Orleans has developed a potentially therapeutically useful inhibitor which a represents a compound for further development. This compound exhibits therapeutically effect on tumor progression and metastasis.
Something about cancer meetings
Very soon, Oncogenetics 2002 will be held during May 2002 in Dublin, Ireland. Sessions will cover, genomic analysis, gene expression, pathways, proteomics, bioinformatics and epigenetic in cancer research. Details are available on the American Association for Cancer Research (AACR) website, Progress and New Hope in the Fight Against Cancer, a public forum highlighting the latest Discoveries is the title of meeting on 6th April 2002 in San Francisco, California. There will be possibility for meeting the world's research experts, connect with advocacy and support groups. The 93rd Annual Meeting of American Association for Cancer Research will be in held Moscone Convention Center, San Francisco, California, April 6-10, 2002. The AACR Annual Meeting provides the ideal environment for the cross-fertilization of ideas on cutting-edge basic, translational and clinical cancer research. See website of AACR mentioned above.
Newly designated National Cancer Institute of USA director roundly applauded by cancer community
The cancer community is expressing unanimous approval of President's of the USA appointment of Andrew von Eschenbach, MD as director of the National Cancer Institute (NCI). Dr. von Eschenbach was director of the Genitourinary Cancer Center and Prostate Cancer Research Program at the University of Texas M.D. Anderson Cancer Center.
Dr. Miroslav S. SARAC
Louisiana State University Health Sciences Center New Orleans
Department of Biochemistry and Molecular Biology
New Orleans, LA 70112, U.S.A
Meetings and Congress Reports
Books Received
Medical and Scientific Meetings
  Issue 2

1 Early diagnosis of recurrent breast cancer with FDG-PET in patients with progressive elevation of serum tumor markers
Suarez M, Perez-Castejon MJ, Jimenez A, Domper M, Ruiz D, Montz R, Carreras JL.
Q J Nucl Med 2002;46(2):113-21.

Background: The aim of this work is to assess the diagnostic value of positron emission tomography (PET) with 18F-fluorodeoxyglucose (FDG), in the early detection of tumour recurrence in already treated breast cancer patients in apparent complete remission and with a progressive elevation of tumour markers CEA and/or CA 15.3 without any other clinical or instrumental signs of relapses. Methods: The author studied 45 women (mean age 58+/-12, range 35-80 years) with histological diagnosis of breast cancer who underwent a tumour marker-guided whole body FDG-PET. All patients were in remission, without any other clinical or instrumental signs of relapses, except for the progressive elevation of CA 15.3 and/or CEA, tested during the follow-up. FDG-PET results were controlled by pathology when histological sampling was possible, by other conventional imaging modalities (US, X-rays, CT, MRI) and/or by clinical follow-up up to 12 months at least. Results: FDG-PET findings were evaluated in 38 patients: 27 resulted positive. Among these 27 PET positive patients 24 were true positive and 3 false positive. Tumour marker guided FDG-PET was also able to discover 3 unknown neoplasms not visualized by other modalities. PET revealed 54 sites of intense focal FDG uptake. The anatomical distribution of these sites was 19 skeleton, 18 lymph node basins, 5 liver, 5 pelvic region, 1 lung, 1 pericardium, 1 pleura, 1 contralateral breast, 2 peritoneum and 1 thyroid bed. Forty-eight of these 54 sites of FDG accumulation were confirmed to be metastases. FDG-PET resulted negative in 11 patients and only in 2 of them the other diagnostic modalities were able to discover metastatic lesions; we had 9 true negative and 2 false positive results. On the basis of our investigation the performances of tumour marker guided FDG- PET per patient are as follows: sensitivity 92% (24/26), specificity 75% (9/12), positive predictive value 89% (24/27), negative predictive value 82% (9/11), accuracy 87% (33/38). Conclusions: This study demonstrated the clinical utility of tumour marker-guided PET in the follow-up of breast cancer patients. This diagnostic approach allowed to modify the clinical management in those patients in whom a tumor relapse or unexpected primary neoplasm was discovered.
2 Image fusion between 18FDG-PET and MRI/CT for radiotherapy planning of oropharyngeal and nasopharyngeal carcinomas
Nishioka T, Shiga T, Shirato H, Tsukamoto E, Tsuchiya MDK, Kato T et al.
Int J Radiat Oncol Biol Phys 2002;53(4):1051-7.

Purpose: Accurate diagnosis of tumor extent is important in three-dimensional conformal radiotherapy. This study reports the use of image fusion between (18)F-fluoro-2-deoxy-D-glucose positron emission tomography (18FDG-PET) and magnetic resonance imaging/computed tomography (MRI/CT) for better targets delineation in radiotherapy planning of head-and-neck cancers. Methods and materials: The subjects consisted of 12 patients with oropharyngeal carcinoma and 9 patients with nasopharyngeal carcinoma (NPC) who were treated with radical radiotherapy between July 1999 and February 2001. Image fusion between 18FDG-PET and MRI/CT was performed using an automatic multimodality image registration algorithm, which used the brain as an internal reference for registration. Gross tumor volume (GTV) was determined based on clinical examination and 18FDG uptake on the fusion images. Clinical target volume (CTV) was determined following the usual pattern of lymph node spread for each disease entity along with the clinical presentation od each patient. Results: Except for 3 cases with superficial tumors, all the other primary tumors were detected by 18FDG-PET. The GTV volumes for primary tumors were not changed by image fusion in 19 cases (89%), increased by 49% in one NPC, and decreased by 45% in another NPC. Normal tissue sparing was more easily performed based on clearer GTV and CTV determination on the fusion images. In particular, parotid sparing became possible in 15 patients (71%) whose upper neck areas near the parotid glands were tumor-free by 18FDG-PET. Within a mean follow-up period of 18 months, no recurrence occurred in the areas defined as CTV, which was treated prophylactically, except for 1 patient who experienced nodal recurrence in the CTV and simultaneous primary site recurrence. Conclusion: This preliminary study showed that image fusion between 18FDG-PET and MRI/CT was useful in GTV and CTV determination in conformal RT, thus sparing normal tissues.
3 Virtual endoscopy: current perspectives
Kuwayama H, Limuro M, Kitazumi Y, Luk G.
J Gastroenterol 2002;37 Suppl 13:100-5.

Virtual endoscopy is a new method for evaluating the gastrointestinal tract using either thin-section computed tomography (CT) or magnetic resonance imaging (MRI). The acquired data are then subjected to computer manipulation to render images simulating the conventional endoscopic view. CT and MR imaging data can provide information that is not accessible endoscopically. These important features include information on tissue extending through and beyond organ walls and the anatomic context of the entire gastrointestinal tract, which permits correct anatomic localization of the lesion. Many clinical studies have shown that it is a safe, noninvasive, well-tolerated alternative to conventional endoscopy. Virtual endoscopy may have potential as a method of screening for colorectal cancer. This review describes the technique, reviews reported results, and discusses the present and future applications of this technique, focusing on CT colography (CTC).
1 What's New in the World of Telemedicine - 1
Medem, Inc. has launched a service that allows doctors to per form online consultations with their patients through a Medem- operated secure electronic mail network. The service would allow doctors to set their own fees (if any), which would have to be paid out of the patient's pocket. Results of a Medem survey indicated that most physicians planning to offer the online service expect to use the level of their patients' co-payments as a baseline for setting online consultation fees, or approximately $20-30. Research shows that primary care physicians expect to perform five to ten online consultations per week. Since doctors are already doing much of this work via telephone without reimbursement, it is likely that many will opt into this service, which at the above rates could provide roughly $5,000 to $15,000 of extra income per year. Medem would receive $2.50 per consultation for which a patient is billed.
(Source:, July 8/15, 2002)
2 What's New in the World of Telemedicine - 2
In the region of Extremadura, Spain, a Grand Opening Celebration was held to recognize the success of a (still ongoing) telemedicine pilot project between the Health Center of Olivenza and the Provincial Hospital San Sebastian. Teleconsultations in dermatology, cardiology, radiology, and vascular surgery are being conducted. In February and March of 2002, 187 teleconsults were conducted. The average waiting time for a patient to be seen by a specialist dropped from a range of 8-26 weeks down to a maximum of one week during the pilot. In addition the number of transfers was significantly reduced. The Extremadura Minister announced plans to expand the current telemedicine pilot to include additional specialty services, and the objective for 2003 is to establish telemedicine capability in all regions.
(Source: Business Wire, May 30, 2002)
3 What's New in the World of Telemedicine - 3
Amal Cancer Centre in Amman, Jordan recently opened a telepathology section. The new section will help in the diagnosis of cancer and other diseases through direct contact and consultation with specialists at telepathology centers at Rotterdam and Leiden Universities in the Netherlands. Physicians in Jordan and Holland will conduct diagnostic, support, or educational services in anatomic or clinical pathology by viewing gross or microscopic images.
(Source: The Jordan Times, June 23, 2002)
Telemedicine Today
Telemedicine Journal and e-Health
Journal of Telemedicine and Telecare
British Journal of Healthcare Computing
Telemedicine and Telehealth Networks
Book Review
Meetings and Congress Reports
Medical and Scientific Meetings
Extended Abstracts: Symposium on Manuscript Peer Reviewing in Biomedical Journals
  Issue 3
Medical Meeting
XXXIX Annual Meeting of the Oncologists of Serbia
XVI Meeting of Oncology and Radiology of Serbia
Institute for Oncology and Radiology of Serbia
Srbian Medical Association
November 14-15, 2002 - Belgrade, Yugoslavia
XV Meeting of Oncology Nurses and Technicians of Republic of Serbia
  Issue 4
1 Nobel prize for "Physiology or Medicine" 2002: when a worm brings you under the spotlights
Nobel prize for physiology or medicine was awarded to: Sydney Brenner, University of California, Berkeley, John Sulston, Cambridge, and Robert Horvitz, Cambridge, Massachusetts.
The Laureates have identified key genes regulating organ devel- opment and programmed cell death and have shown that corresponding genes exist in higher species, including man. Sydney Brenner (Berkeley, CA) established C. elegans as a novel experimental model organism. This provided a unique opportunity to link genetic analysis to cell division, differentiation and organ development, and to follow these processes under the microscope. Brenner`s discoveries carried out in Cambridge, UK laid the foundation for this year's prize. John Sulston (Cambridge, UK) mapped a cell lineage where every cell division and differentiation could be followed in the development of a tissue in C. elegans. He showed that specific cells undergo programmed cell death as an integral part of the normal differentiation process, and he identified the first mutation of a gene participating in the cell death process. Robert Horvitz (Cambridge, MA) has discovered and characterized key genes controlling cell death in C. elegans. He has shown how these genes interact with each other in the cell death process and that corresponding genes exist in humans. For more information on this and other Nobel prizes see
2 New concepts in combination oncological therapeutics
Will a single agent, chosen on the basis of molecular profiling, be sufficient to remove the selective advantage enjoyed by cancer cells? Not according to current thinking. Combined oncological therapeutics will be defined using many interventions. Potentially, combination non-specific cytotoxic agents might initially cytoreduce large bulk tumor masses. Clinical and preclinical synergy of classical DNA-directed non specific cytotoxic agents with targeted therapies (12,13) suggests that classical cytotoxic agents modulate important cellular signaling pathways so, when com- bined with targeted agents, they will lead to enhanced clinical efficacy. Concepts of dose-response should be considered and exploited to reduce exposure to toxic agents. Careful phase I biomarker-targeted trials could confirm unique mechanisms of classical cytotoxic agent action discovered in vitro that may lead to innovative and unexpected combination therapies. Combination cancer therapeutics might require identification of mutated upstream signal transduction genes using high throughput genomic profiles, and identification of downstream signals with high throughput proteomic profiles with therapeutic targets individually selected. New epidermal growth factor receptor tyrosine kinase inhibitors (e.g. ZD1839/Iressa, cetuximab) will expand the repertoire of signal transduction targets. Many angiogenesis inhibitors that variously target vascular endothelial growth factor receptor tyrosine kinase, fibroblast growth factor receptor tyrosine kinase and the a v b 3 integrin may be useful antineoplastic agents. The challenge of understanding or predicting efficacy with these agents will be to reproducibly quantify whether drug-induced phosphorylation of other downstream signal transduction intermediates is translated into the clinical setting. Moreover, we are now challenged with redefining the concept of clinical efficacy-is lack of tumor proliferation and metastatic spread without ablation sufficient to define efficacy? Will all of this come to pass? Only innovative well-designed translational investigations will reveal the answer. But the future today is far brighter than it was 10 years ago. And "combination chemotherapy" will take on a totally different nuance and mean- ing than it has today.
3 Virtual colonoscopy
Schairer C, Mink PJ, Carroll L et al. JNCI 2004;96(17):1311-21.
Studies in populations at varied risk show reproducible sensitivity of 90% for polyps 10 mm or greater with 93% specificity and per-patient sensitivity of greater with 93% specificity and per-patient sensitivity of 96-100%. Sensitivity for polyps 6-9 mm is about 80%, with detection of smaller polyps being poor. These results nearly equal the rates for colonoscopy. The addition of computer-aided detection, now in early trials, should improve accuracy. Accepted indications, based on published data, include: follow-up after incomplete colonoscopy, obstructing neoplasm in the distal colon, and contraindications to colonoscopy. Individuals carry a lifetime risk of colorectal cancer of 6% with an increased incidence after age 50. Colorectal cancer is the second most common cause of cancer death in the USA. Slow progression in the adenoma-to-carcinoma sequence suggests that dis- ease is largely preventable by regular screening. Less than a third of eligible patients undergo screening. Screening strategies for colon cancer include: fecal occult blood-testing, which fails to detect 95% of polyps (colonoscopy, which can miss 6% of adenomas of 10 mm or larger( and double-contrast barium enema, which can miss up to 20% of polyps over 10 mm. Only an estimated 6% of patients in a screening population will be found to harbour an adenoma of 10 mm or greater. Furthermore only about 3% of all adenomas progress to cancer. Screening with colonoscopy, as some advocate, would not seem prudent given the low but definite risk of perforation and associated risks of sedation and bleeding. Advantages of screening with CTC include avoidance of an invasive procedure and sedation. CTC also more accurately localises masses and detect clinically significant extracolonic abnormalities. The major disadvantage is the inability to biopsy polyps. False-positive results can cause unnecessary follow-up colonoscopy. Flat adenomas, which may account for 8-33% of adenomas and more frequently harbour high-grade dysplasia, are harder to detect.

European bodies reach an uneasy truce on embryonic stem-cell research
Schairer C, Mink PJ, Carroll L et al. JNCI 2004;96(17):1311-21.
On September 30 in Brussels, after a bitter dispute with the European Parliament over research involving the use of human embryonic stem cells, the European Union (EU) Council of Science Ministers eventually approved the Sixth Framework Research Programme. But the approval, which will allow the 5-year, 17.5 billion Euro programme to launch officially in early November, unexpectedly included a 1-year moratorium on stem- cell research funding. The Council - the central decision-making body of the EU - and the Parliament had reached an unwritten agreement in June over the approval of the Framework Programme, which allowed EU funding of stem-cell research in countries where it was not prohibited (Lancet 2001; 358: 1972). However, the Council adopted a unilateral decision in late July - under the Danish presidency of the EU - to embargo such financing until the end of 2003. The Parliament protested the Council's decision on grounds that it was not a consensus agreement and the moratorium did not have par- liamentary approval. Several members of the Parliament's Committee on Industry, External Trade, Research and Energy, headed by socialist Carlos Westendorp, threatened that, if the moratorium went forward without consultation, Parliament could block the programme's entire budget - or even sue the Council via the EU Court of Justice. The Committee went as far as querying the constitutional legality of the Council decision. The threat prompted representatives from the two parts to negotiate again and to reach an agreement. This stipulates that "further provisions on the funding of research activities involving the use of human embryos and human embryonic stem cells will be established before the end of 2003, on the basis of a new proposal (based on an in-depth ethical, technical, and political study) from the European Commission and in consultation with the European Parliament". Until then, says the statement Commission "will not propose to finance such research projects, unless they involve (already established) banked or isolated human embryonic stem cells in culture". The new commitment also stipulates that "proposals for [funding] research projects involving (human embryonic stem cells) will be submitted to a regulatory committee (where al EU countries will be represented)". Commenting on this latest compromise, which Italy was the only country to oppose, Westendorp noted: "What we`ve learned from all this is that any future agreement with the Council must be confirmed in writing."

. News. Ann Oncol 2002; 13:1694.
2. Brenner DE. New concepts in combination oncological thera- peutics. Ann Oncol 2002:13:1698.
3. Gollub MJ. Virtual colonoscopy. Lancet 2002;360:964.
4. Bosch H. European bodies reach an uneasy truce. Lancet 2002; 360:1080.

Books Review
Books Received
Meetings and Congress Reports
Medical and Scientific Meetings
  Volume 9 Issue 1
1 American Telemedicine Association's advisories for consumers who choose to use the internet to obtain information about healthcare or seek medical treatment
The American Telemedicine Association (ATA) is a non-profit association established in 1993 and headquartered in Washington, DC. ATA promotes the deployment of telemedicine to improve the delivery of health care for all individuals. Its members include physicians, allied health professionals, technologists and healthcare administrators. A Board of Directors, elected by the membership, governs the Association. ATA maintains a Web site at ATA provides these advisories for consumers who choose to use the Internet to obtain information about healthcare or seek medical treatment:
1. Consumers should make sure that Web sites used to obtain information about health and medicine are provided by a reliable and credible source such as recognized and credentialed health care providers, and use sources that are based on qualified authorities. The source of the information should be clearly labeled and annotated. The ATA endorses the concept of professional societies accrediting Web sites that provide consumers health and medical information.
2. In some cases commercial interests such as a drug manufacturer may sponsor or contribute information to a Web site. Consumers should look for assurances that the information provided in these cases is objective and does not favor the sponsor's products.
3. At this time consumers should exercise caution in using Web sites that offer online diagnosis of an individual's medical condition and prescribed treatment and medication for the diagnosed condition. There are currently no recognized accreditation or regulatory authorities overseeing the operation of these sites.
4. It is a widely recognized conflict of interest for health professionals that prescribe medicines to have any direct financial relationship with an entity that sells those medications. Therefore, consumers are cautioned against obtaining prescribed medicines from Web sites that offer both diagnosis of condition and direct sales of the prescribed medicine.
5. Medical professionals in almost all developed nations are required to obtain credentials from a recognized authority in order to practice medicine. For example, health professionals in the United States are issued a license to practice medicine by individual state authorities. Consumers seeking medical treatment from health professionals over the Internet should receive clear assurances that they will be interacting with a qualified professional holding the appropriate credentials and that the professional is able to legally practice medicine in the consumer's location.
6. Clinical consultation over the Web by credentialed providers should include procedures that protect the patient including:
- Informed consent;
- Information security and privacy protection measures; and
- Documentation of the clinical encounter.
Specialty medical societies are encouraged to develop guidelines to ensure that clinical consultations provided over the Internet are consistent with accepted medical practices.
2 A brief view on current status of telemedicine in Serbia
Svetozar Zdravkovic
Serbia belongs to the group of middle developed countries. This fact determines the level of development of telecommunication infrastructure, which can hardly be regarded as a satisfactory one: small number of base ISDN connectors, insufficient number of qualitative leased lines, telephone switchboard systems and units are on average much longer in operation than in other countries of the region, mobile telephone operators use network with GSM protocol which offers transfer rate of 9800 b/sec for data exchange which is insufficient for computer communications (except for e-mail), 2 MB connectors are more dream than reality. Although the statement of Serbian Prime Mminister of providing significant investments in the development telecommunication infrastructure is very encouraging, the change of current status will need at least several years. According to all mentioned facts, the one of the possible solutions can be the selection of Academic Computer Network as a telecommunication backbone for the purpose of telemedicine. There are several reasons for this suggestion:
- Academic Computer Network exists, functions and connects all university centers in Serbia (in Belgrade, Novi Sad, Nis, Kragujevac, Subotica, Zrenjanin), where all main clinical centers, institutes and other specialized health institutions are concentrated;
- investment in further development is with the highest cost-benefit rate
- possibility for connection with health institutions abroad, because Academic Computer Network has recently become a part of European Academic Computer Network.
Managers of the Academic Computer Network are willing to help, so physicians and all professionals in health service who are involved in telemedicine should work together and make possible faster development of telemedicine services.
Our experience in the use of telemedicine modest. There are a few health institutions with such experience: Military Medical Academy in Belgrade, Institute of Oncology Sremska Kamenica, Military Hospital in Nis and Clinical Medical Center in Belgrade. Mostly used telemedicine services are telepathology and teleconferencing for the purpose of medical education and consultations (teleeducation and teleconsultation). Live video broadcasting of medical procedures (such as laparoscopic surgery done by the Institute of Oncology in Sremska Kamenica) for the purpose of teleconsulatations does not meet the regulated conditions, such as minimum transfer rate of 384 Kb/sec. This leads to the possibility of establishing video computer conferencing center which should serve only for medical needs and which would be accessed by Academic Computer Network (provided Quality of Service - it could ensure transfer rate of minimum 384 Kb/sec. between any two peers of connection). The development of telemedicine services has the priority in the high developed countries (USA, Canada, countries of European Community, Japan), because telemedicine reduces the expenses of medical care, improves prevention and protection with better, faster and more direct health education. As the country with developed health culture, we should follow this trend and join more activities in developing telemedicine in our country.
3 American Telemedicine Aassociation's special interest group for telepathology - Clinical guidelines for telepathology
Special Interest Group for Telepathology:
Yukako Yagi - Chair Mark Newberger
Ronald Weinstein, MD - Co Chair Ikuo Tofukuji
John Gilbertson, MD Jason Kaar, JD
Bulert Celasun, MD
Bruce Williams DVM
Mike J Becich, MD, PhD George Naxera
Robert Dawson, MD Paul Fontelo, MD
James McGee, MD, PhD Katsushige Yamashiro, MD
Bruce Dunn, MD Francisco G. La Rosa, MD

General Information:
Our Mission

1 Introduction
2 Scope
3 The Practice of Telepathology: Responsibilities of the Pathologist
3.1 Primary Diagnosis Telepathology
3.1.1. Technicians, Technologists and Pathologist's Assistants in Primary Diagnosis Telepathology
3.2. Second Opinion Telepathology
3.2.1. Responsibilities of the Referring Pathologist
3.2.2. Responsibilities of the Consulting Pathologist
4 Training and Quality Control
4.1 Training of Pathologists
4.2 Training of Technicians, Technologists and Pathologist's Assistants
4.3 Quality Control
5 Documentation and Archiving
6 Data Integrity and Security
A Draft Version 2.4; May 20, 1999; The American Telemedicine Association
1 Introduction
This is a working draft of clinical guidelines for telepathology written with the expectation that others will rewrite it and add to it. To keep this document generally applicable it steers clear of technical specifications or implementation issues and concentrates on the responsibilities of the pathologist in telepathology.

2 Scope
For the purpose of this document, Telepathology will be defined as electronic, multimedia communication between pathologists for the purpose of primary diagnoses and diagnostic consultation second opinion. It may also be extended to include similar diagnostic communication between other physicians (non-pathologists) and a laboratory staff by qualified laboratory personnel - trained technicians, technologists, or a pathologist's assistants - and a remote pathologist and when the laboratory personnel is under the supervision of a pathologist.
The concepts discussed in this document should be generally applicable to all three types of telepathology; static (store and forward), dynamic (synchronous), and hybrid (static-dynamic) implementations.
3 The Practice of Telepathology: Responsibilities of the Pathologist
Pathologists have been sending each other cases for diagnostic second opinion for many years. This collaboration has traditionally involved the sending of stained slides, unstained slides, tissue blocks, wet tissue, pathology reports and cover letters via courier or through conventional mail. The system has worked well, and is the "gold standard" by which diagnoses are compared between institutions. In defining guidelines for second opinion telepathology, pathologists should borrow, whenever possible, from the workflows and responsibilities set up in the courier based system.
Guidelines for primary opinion telepathology should be driven from best practices in conventional laboratory procedures. It is understood that pathologists often work in central offices geographically separated from both the clinics (where cytology and surgical samples are obtained) and the histology laboratories (where cytology preparations and tissue are processed and slides are made).
Sections 3.1 and 3.2 detail proposed responsibilities of pathologists and laboratory personnel in both primary diagnosis telepathology (section 3.1) and second opinion telepathology (section 3.2). Though the discussion is framed in a telepathology environment involving multiple institutions, the responsibilities are similar if telepathology occurs within a single institution.
3.1 Primary Diagnosis Telepathology
In telepathology, specimens at a referring site are diagnosed by pathologists at a remote site. In primary diagnosis telepathology, the diagnostic effort and responsibility resides entirely with the pathologist at the remote site. The medical responsibilities for a site initiating a telepathology session for primary diagnosis, are similar to those of a laboratory sending glass slides by courier or conventional mail to another pathologist for primary diagnosis in a traditional environment. These include:
1. The laboratory must identify the case appropriately. Traditionally this has meant, at a minimum, local accession number and the patient's name as well as some indication of what material has been sent (the number or slides, blocks, reports, etc.) In the telepathology environment this must be extended to the appropriate documentation of images and information sent.
2. The laboratory must insure that all appropriate clinical information is conveyed to the remote pathologist. Traditionally this has usually meant an appropriately filled out requisition and/or the surgeon's operative report, however it can include additional information (for example, X-rays in bone pathology cases) or direct access to the clinicians involved depending on the situation and pathologists medical judgement. If, in the judgement of the pathologists involved, the system cannot provide adequate clinical information to the remote pathologist, telepathology should not be used to render a diagnosis or telepathology should be supplemented by other mechanisms.
3. The laboratory must insure that the remote pathologist has adequate access to appropriate diagnostic material. In a practice setting in which primary telepathology diagnoses are rendered, and a pathologist is not present at a referring site, a methodology must be employed which insure that video sampling of gross tissues and glass slides is inclusive.
4. In addition to the medical responsibilities discussed above, the laboratory has responsibilities for data handling, archiving and security as discussed below.
3.1.1. Technicians, Technologists and Pathologist's Assistants in Primary Diagnosis Telepathology

Pathologist's Assistants, technologists and technicians have traditionally worked under the supervision of Pathologists in anatomic pathology laboratories. Appropriately trained personnel (pathologist's assistants, technologists and technicians) should be able to present cases and relevant materials, via telepathology, to other pathologists at remote sites.
1. Presenting Personnel should be adequately trained in the use of telepathology equipment and the limitations of telepathology
2. A pathologist should supervise the support personnel, and support personnel should have access to other pathologists throughout the telepathology session.
3.1.2. Responsibilities of the Pathologist in Primary Diagnosis Telepathology
In primary diagnosis telepathology, diagnostic effort and responsibility resides entirely with the pathologist at the remote site. If the remote pathologist supervises referring site, the pathologist takes on the roles and responsibilities of both referring and consulting pathologist in Section
3.2. Second Opinion Telepathology
In second opinion telepathology, diagnostic effort and responsibility resides with both the pathologists at the local site (referring pathologist) and the pathologist at the remote site (consulting pathologist).
3.2.1. Responsibilities of the Referring Pathologist
The medical responsibilities for a pathologist initiating a second opinion telepathology session are similar to those of a pathologist sending glass slides by courier to a consulting pathologist in a traditional environment. These include:
1. The referring pathologist must identify the case appropriately. Traditionally this has meant, at a minimum, local accession number and the patient's name as well as some indication of what material has been sent (the number or slides, blocks, reports, etc.) In the telepathology environment this must be extended to the appropriate labeling of images and documentation of the number of images sent.
2. The referring pathologist must insure that all appropriate clinical information is conveyed to the consulting pathologist. Traditionally for second opinion this has usually meant a cover letter and a copy of the referring pathologist's report, however it can include additional information (for example, X-rays in bone pathology cases) depending on the situation and the referring pathologist's medical judgement. If in the judgement of the referring pathologist, the telepathology system proposed for the consultation can not, adequately provide all of the appropriate clinical information to the consulting pathologist, telepathology should not be used for the consultation or telepathology should be supplemented by other mechanisms.
3. The referring pathologist must insure that the consulting pathologist has adequate access to appropriate diagnostic material. One of a pathologist's cardinal responsibilities is to appropriately sample specimens so as to arrive at the accurate diagnosis. The pathologists traditionally sub-sample gross specimens into blocks, and those blocks are then sub-sampled in the creation of slides. In traditional courier based consultations, it is not uncommon to have, on the judgement of the referring pathologist, only a subset of slides sent to the consulting pathologist. In some implementations of telepathology, a further level of sub sampling in which images representing selected fields from a slide are sent to the consulting pathologist. In these implementations, it is the responsibly of the referring pathologist to select these fields appropriately.
4. The referring pathologist must render a final report on a case. As in traditional pathology consultations, it is the responsibility of the referring pathologist, when receiving an opinion from a consulting pathologist, to reconcile his or her understanding of the case - and any clinical or pathological information not available to the consulting pathologist - with the opinion of the consulting pathologist and then reach an appropriate diagnosis. This responsibility should also exist in consultations based on telepathology. The use of telepathology should not relieve the referring pathologist of the responsibly to render to a final report on a case.
5. In addition to the medical responsibilities discussed above, the referring pathologist has responsibilities for data handling, archiving and security as discussed below.
3.2.2. Responsibilities of the Consulting Pathologist
A pathologist receiving a case via telepathology has a number of medical responsibilities similar to those of a pathologist receiving a case via courier:
1. The consulting pathologist should insure that he/she has received all materials sent by the referring pathologist. This has traditionally been done, in the courier-based model, by comparing the material listed in the cover letter (or other documentation) to the material received.
2. The pathologist must insure that appropriate standard operating procedures are in place at the referring site to insure that all the clinical information or pathologic material (tissue, blocks, etc.) necessary to adequately examine a case is available. If in the judgement of the consulting pathologist, the telepathology system proposed can not provide the necessary information to the consulting pathologist, telepathology should not be used for the consultation or telepathology should be supplemented by other mechanisms. If clinical information deemed necessary by the consulting pathologist is not available by any mechanism, an unqualified opinion should not be rendered.
3. In the traditional courier-based consultation, it is the responsibility of the consulting pathologist to determine if the material sent by the referring pathologist is of adequate quality to render a diagnosis. For example, it has been up to the consulting pathologist to determine if the slides proffered were adequately cut and/or stained. The quality needed for a diagnosis depends directly on the skill of the consulting pathologist and the diagnostic question involved. Consistent with the traditional, courier-based practice, it is the responsibility of the consulting pathologist to determine if the image quality is adequate for diagnosis. If the consulting pathologist feels that image quality and/or video image sampling are not adequate, he/she should request that the glass slides and or blocks be sent for analysis. This is consistent with traditional, courier-based practice.
4. The consulting pathologist should transmit his/her opinion/diagnosis to the referring pathologist in a mutually agreed upon manner. Observations that could effect patient care in a time sensitive manner should be transmitted directly to the referring pathologist.
5. In addition to the medical responsibilities discussed above, the consulting pathologist has responsibilities for data handling, archiving and security as discussed below.
4 Training and Quality Control
4.1 Training of Pathologists
Because the effectiveness and accuracy of telepathology depends critically on the skill and judgement of the pathologist, both referring and consulting pathologists practicing telepathology should be trained in telepathology.
1. Training should occur on the individual systems that the pathologist uses.
2. Training should occur also in general telepathology/imaging principles and limitations. The implementation of this training is an issue that requires discussion and consensus. Possibilities could include general web-based seminars and tests supported by the ATA, CAP, USCAP, etc. followed by practical examinations provided be the same organizations. (The CAP has similar programs ongoing for standard glass slide pathology.)
4.2 Training of Technicians, Technologists and Pathologist's Assistants
In an environment in which a technologist, a technician, or a pathologist's assistant is supervised by a local or a remote pathologist, he/she should be trained specifically in telepathology techniques.
4.3 Quality Control
Pathologists providing consultation by telepathology should be required to have at least 10% of their cases re-examined by another pathologist, comparing the transmitted images to the microscopic slide and any discrepancies should be noted.
5 Documentation and Archiving
The telepathology interaction is a vital part of a patient's care and as such must be documented in the medical record. To this end:
1. A diagnostic consultation by telepathology shall generate a formal report by the consulting pathologist. This report shall become a permanent part of the patient medical record. It is recommended that all reports, letters, clinical information and possibly static (still) images transmitted from the referring site to the pathologist as part of the telepathology encounter should be archived at the consultant's institution. This practice is consistent with that applied to courier based consultations.
2. All reports, letters, clinical information and static (still) images involved in a diagnostic consultation by telepathology, as well as the consultant's report, shall be archived as part of the medical record at the referring institution. This practice is consistent with those applied to courier based consultations. (Because image archiving requires special equipment not available at all institutions, the referring institution may allow the consulting institution or a third party to archive telepathology information, as long as the archiving is done under the rules or the referring institution.)
3. The telepathology encounter, and the general opinion of the consulting pathologist, shall be documented in the final report of the referring pathologist. This practice is consistent with those applied to courier based consultations.
4. Dynamic, real time images generated during a telepathology session need not be archived. Static (still) images shall be archived at that same image quality, file size and format that was used in the telepathology encounter. Static (still) images should be archived for at least as long as the glass slides involved in the case.
For cases in which diagnoses are based exclusively by static images, the entire image file should be archived.
6 Data Integrity and Security
By its nature, the telepathology encounter involves transmission and storage of confidential patient information. Though it is understood that no security system is foolproof and that the specific security mechanisms needed will depend on the specific telepathology implementation, parties engaging in telepathology shall insure that the telepathology system provides reasonable privacy and confidentiality by security measures including:
1. Message Security: A telepathology shall occur over secure networks, or shall be adequately encrypted. It is the responsibility of the consulting laboratory to provide a secure station for receiving diagnostic reports. Verifiable digital signatures may be allowed.
2. System Authentication: When appropriate, the system should authenticate itself unambiguously to all users, for example, using a third party certificate and private key.
3. User Authentication: The referring pathologist, consulting pathologist and all other persons using the system (administrators, assistants, etc.) shall be adequately authenticated to each other and to the system. This authentication should involve, at a minimum, a user name and password.
4. Activity Logs: All accesses to the system shall be logged by user and by case. The logs shall be reviewed on a regular basis and the review documented.
5. Access Restriction: Within the security policy of the individual institution, the system should limit access to legitimate users.
6. Archiving: The system shall have adequate back up and archive mechanisms in place.

4 What is Telemedicine?
The basic question today, when high technology has involved in medicine very deep, is: What is telemedicine and what kind of services we call telemedicine services? One answer on that question is made by Jonathan D. Linkous in his article published on official web site of American Telemedicine Association (ATA) with title: Toward a rapidly evolving definition of telemedicine.
Toward a rapidly evolving definition of telemedicine
Jonathan D. LINKOUS
Last Spring an article was published in the ATA News Digest regarding the market size for telemedicine. The article described several market research reports that are available that depict the size of the market for telemedicine and make projections for the market in the future. Since that time, a number of comments were provided to ATA regarding the market reports including criticisms of what the reports included, or did not include when determining market size. This gives rise to a perennial point of discussion regarding the definition of telemedicine.
Most of the market reports use a "traditional" definition of telemedicine that is largely based on hub and spoke systems, interactive video or sophisticated store-forward technology, and the provision of data sent telephonically to a specialist for interpretation. Several surveys have even ignored teleradiology and concentrated solely on face-to-face video consults. This most certainly captured the definition of telemedicine as perceived 12 to 24 months ago. However, recent technology innovations and soon-to-be-deployed new approaches call for broadening the traditional thinking about what should be included as part of telemedicine.
This should not be a surprising development as telemedicine has been in a constant state of change over the past five years. Recent innovations in the use of computer-driven diagnostic systems, micro-sensors, and interactive medical technology will probably push the definition even further.
So why even bother being concerned about the definition? This is an important issue for several reasons: defining allowable services to be reimbursed under Medicare and other forms of insurance; defining eligible services to be included within existing grant and loan programs; and defining the services affected by state medical licensure laws. For vendors of services and products it is important to identify the current and future market. For medical centers it is important in determining which department (information services vs. medicine) has control over.
ATA has used the following broad definition of telemedicine: "Telemedicine is the use of medical information exchanged from one site to another via electronic communications for the health and education of the patient or healthcare provider and for the purpose of improving patient care." Note that this is not restrictive as to what information is transmitted, how it is transmitted, or how the information is used once received.
Thus, what is and is not telemedicine? For example, while comprehensive home care monitoring services with a multi-mode device is considered telemedicine, is a wireless heart monitor or a portable emergency notification system? Is it telemedicine if the patient data is generated but instead of transmitting the raw data to a physician, it is read and analyzed by a computer? Are miniaturized biosensors that take vital signs or test for the presence of various conditions and transmit the data considered telemedical peripheral devices? Clearly, the types of products and services considered part of telemedicine is evolving. The telemedicine of today is relatively simple. The telemedicine of tomorrow gets more complex as the possibilities expand.
5 Protecting the privacy of patients' health information summary of the final regulation
Overview: Each time a patient sees a doctor, is admitted to a hospital, goes to a pharmacist or sends a claim to a health plan, a record is made of their confidential health information. For many years, the confidentiality of those records was maintained by our family doctors, who kept our records sealed away in file cabinets and refused to reveal them to anyone else. Today, the use and disclosure of this information is protected by a patchwork of state laws, leaving large gaps in the protection of patients' privacy and confidentiality. There is a pressing need for national standards to control the flow of sensitive patient information and to establish real penalties for the misuse or disclosure of this information. President Clinton and Congress recognized the need for national patient record privacy standards in 1996 when they enacted the Health Insurance Portability and Accountability Act of 1996 (HIPAA). That law gave Congress until August 21, 1999, to pass comprehensive health privacy legislation. After three years of discussion in Congress without passage of such a law, HIPAA provided HHS with the authority to craft such privacy protections by regulation. Following the principles and policies laid out in the recommendations for national health information privacy legislation the Administration submitted to Congress in 1997, the Administration drafted regulations to guarantee patients new rights and protections against the misuse or disclosure of their health records and the President and Secretary Donna E. Shalala released them in October of last year. During an extended comment period, HHS received, electronically or on paper, more than 52,000 communications from the public. This final rule provides the first comprehensive federal protection for the privacy of health information. However, because of the limitations of the HIPAA statute, these protections do not fully achieve the Administration's goal of a seamless system of privacy protection for all health information. Members of both parties in Congress will need to pass meaningful, comprehensive privacy protection for American patients that would extend the reach of the standards being finalized today to all entities that hold personal health information. For other HHS Press Releases and Fact Sheets pertaining to the subject of this announcement, please click here for our Press Release and Fact Sheet search engine at:
Note by editors: More details about this matter will be found in next issues of Archive of Oncology
6 Telepsychiatry
Current Telepsychiatry Activity in the U.S., Australia, Canada, and Norway

Telemedicine Today's last full survey of telepsychiatry was in the summer of 1994 (Vol. 2, no. 2). At the time, we identified 9 programs in the U.S. that were actively seeing patients, as well as one in Canada and one in Norway. The five most active programs were Norfolk (NE) Regional Medical Center (about 420 consultations/year); U. of SC (about 288/year); E. Montana (about 116/year); E. OREGON (about 48/year); and U. of KS (40/year). Total consultations in 1994 among the 9 U.S. programs: about 948. A lot has happened in the ensuing years. Last year's Telemedicine Today survey of active telemedicine programs, done cooperatively with the Association of Telemedicine Service Providers, documented 25 programs in the U.S. doing 3,460 telemental health consultations in 1996 (Vol. 5, no. 4). Among the 19 programs in the U.S. we were able to interview for this current survey, we found that an aggregate total of about 720 consultations/month are being done - or about 8,640/year. This is nearly a 10-fold increase since 1994.
7 Telecardiology
Telecardiology has been here for a long time. Telephones, and modifications of telephones, have been conceived of and used for auscultating heart and breath sounds for over 70 years. More sophisticated techniques for transmitting heart sounds more accurately have been used since the 1960's FAXes are used for transmitting EKGs, ad EKG tracings (rhythm strips and 12-lead) can be transmitted easily over phone lines. However, not until the past 10 years has the technology been available for doing echocardiograms -- often the gold standard test for diagnosis -- over a distance. meanwhile, for most telemedicine systems, cardiology is one of the most requested applications. It is an area of medical care that is particularly anxiety-inducing for many rural practitioners, who greatly appreciate expert backup for those newborns with oddball murmers, and those late-night E.R. visits. This issue takes a close look at five programs around North America doing tele-echocardiography. One program is doing this along with a full interactive history and physical, including tele-stethoscopy. We've chosen these programs because they represent different strategies for delivering cardiac care (see Table). Two are store-and-forward systems, three are real time. One is broadband, one ISDN, one fractional T1, two use standard phone lines. Each one of these programs has taken a critical look at the important issue of efficacy -- of whether in fact the telecardiology technology can reliably transmit the information needed to make good clinical decisions. A few of the programs have also looked (more or less formally) at costs and benefits. The strong consensus is that tele-echocardiography, both real time and tore-and-forward, and telestethoscopy are effective ways of transmitting diagnostic-quality information. There is an emerging body of data that suggests they are quite cost-effective, as well. Currently only real-time tele-echocardiography is reliably reimbursed; this may change as efficacy studies of the store-and-forward options accumulate.
8 Teledermatology
Kuopio, Finland. Real Time and Store-and-Forward Teledermatology
Since late 1994, teledermatology has been deployed between Mäntyharju Municipal Health Center, Mikkeli Central Hospital, and Kuopio University Hospital. Supported in part by contributions from the Etelä-Savo Hospital District and the Finnet telephone companies, it is an ISDN-mediated system running at 128 to 384 Kbps, using PictureTel 2000 equipment with far-end camera control and autofocus. A second camera is used for still-image captures at approximately 2x the resolution (704 x 576 lines) of the video image. Initial trials found that the higher bandwidth was necessary for most consultations. While most cases (now totaling nearly 100) have been done interactively and with the still-image capture system, some cases have been handled in pure store-and-forward mode by taking photos of lesions, developing and scanning them, then sending them as compressed GIF or JPEG files over the Internet as email attachments. This process will be greatly foreshortened in the future by using digital cameras (see Store and Forward Teledermatology at OHSU, last issue - Ed.). The technology as currently constituted appears most suitable for eczemas, most ulcers, and nodular or bullous diseases, where the information obtained is frequently diagnostic. For skin tumors, the technology may be most useful for advising the general practitioner how to proceed with a biopsy, or when to triage to a specialist. To date, patients have not been billed, and consultations are on demand, rather than regularly scheduled. Contact: Dr. Raimo Suhonen, Chief, Dep't of Dermatology, Mikkeli Central Hospital, 50100 Mikkeli, Finland;;
9 Current status of telesurgery
Telesurgery is the provision of surgical care over a distance, with direct, real-time visualization of the operative field. It may be categorized as follows:
1) Telepresence surgery. Uses a computerized interface to transmit the surgeons actions at a surgical workstation to the operative site at the remote surgical unit, with haptic (force feedback) input to transmit to the surgeon the tactile environment of the operative field
2) Telerobotics. Remote control with a robotic arm, usually in conjunction with a laparoscope, without haptic feedback
3) Telementoring. An experienced surgeon acts as a preceptor for a remote inexperienced surgeon by observing the surgeon via interactive video. Teleproctoring is an extension of telementoring, referring to documentation of performance for privileging purposes. Related fields: virtual reality and computer generated educational and training scenarios.
Telemedicine Today
Telemedicine Journal and e-Health
Journal of Telemedicine and Telecare
British Journal of Healthcare Computing
Telemedicine and Telehealth Networks
1 A revolution in cancer biology
Bogomir DIMITRIJEVIC, Institute for Nuclear Sciences "Vinca", Laboratory for Radiobiology and Molecular Genetics, Belgrade, Yugoslavia
Traditionally, tumors have been categorized on the basis of histology. Achievements of this analytical approach limit our ability to adequately classify and diagnose malignant diseases. DNA microarrays offer analysis of thousands of genes at once and provide molecular profile of an individual patient's tumor. When such profiles are analyzed with pattern recognition software designed for cluster analysis, new classes of cancer emerge that transcend distinctions based on histological appearance alone. The ultimate goal is to move beyond correlation and classification and to reach new insights into molecular pathology and to set the stage for more rational therapeutic approaches and drug design.
The preliminary version of the human genome sequence is already available and is being continually refined. This foundation should engage the next (and greatest) challenge of biology and medicine - the comprehensive understanding of the structure and function of the cell and the organism thus addressing questions of life, death and disease. Living systems are much too complex to be studied on one gene or one protein at a time. For this reason biomedical science deals with this complexity by studying the activity of many genes or proteins in parallel, the approach known as molecular profiling.
The current focus of molecular profiling is the large-scale analysis of gene expression using new DNA array technology. The goals in the practice of oncology range from insights into pathogenesis, cancer diagnosis and prediction of clinical outcome to identification of therapeutic targets. There have been several reports recently published that show how DNA arrays can be applied to the analysis and classification of cancer. It is very realistic that this trend will follow an exponential growth. Published results are not only breathtaking demonstration of great potentials of the new technology; at least one of them has explicit clinical value. Namely, gene expression profiling of diffuse large B-cell lymphoma (DLBCL) provided means to distinguish patients with distinct disease outcome. Conventional methods for classification of cancer were unable to distinguish between any DLBCL subtypes. This has been accomplished with specialized microarrays (lymphochips) for the study of non-Hodgkin's lymphoma. Therefore, gene expression profiling was able to subdivide a single diagnostic category of lymphoma into two apparently distinct diseases. This appears to be the first step in the approach that will generate information needed to tailor treatment to the individual patient. A realistic possibility for personalized therapy deserves pompous designation - a revolution in cancer biology.
2 Are you ready for the revolution or when did you ask last time the World Wide Web about the Human Genome Project?
Dimitar JAKIMOV, Dragana CETOJEVIC-SIMIN, Institute of Oncology Sremska Kamenica, Yugoslavia
The beginning of new millennium is an interesting phenomenon, especially when you have some big, important and revolutionary staff to think and talk about. This phenomenon seams like some kind of acceleration of the historical happenings, up to the levels of unpleasantness, particularly when it happens in a domain such as fundamental science is. Genome sequencing projects carried out by groups around the World represent one of the biggest scientific challenges that has ever been undertaken.
To mark the publication of the initial sequencing and analysis of the human genome, the journal Nature set up special section on the human genome - the Genome Gateway - a web site that provides a comprehensive overview of current knowledge, upholding the principle at the heart of the Human Genome Project: free and unrestricted access to all genome related material through these web pages. The section comprises a huge set of papers that, for the most part, report the findings of the international consortia of scientists that make up the Human Genome Project. More than 2,500 authors from 20 laboratories contributed to these papers. It also delves into the opportunities offered to biologists by the genome and explores the approaches and tools needed to exploit these opportunities. The News and Views articles provide the context, communicate the excitement, and present a critical evaluation of the papers.
This is a short overview of the content you can find on the specified internet addresses.

Everyone's genome!
"The human genome underlies the fundamental unity of all members of the human family, as well as the recognition of their inherent dignity and diversity. In a symbolic sense, it is the heritage of humanity". Universal Declaration on the Human Genome and Human Rights (
Biology as a data-rich subject is a relatively new phenomenon. The genomic data has the potential to be (indeed, is already) a powerful integrative force across the spectrum of biological sciences. These information needs to be navigable by the whole research community in order to be maximally effective and it also needs to be accessible and comprehensive. The Nature's Genome Gateway is contribution to this process.
Humans are much more than simply the product of a genome, but in a sense we are, both collectively and individually, defined within the genome. The mapping, sequencing and analysis of the human genome are therefore a fundamental advance in self-knowledge; it will strike a personal chord with many people. And application of this knowledge will, in time, materially benefit almost everyone in the world.
Sequencing and cell cycling
Every organism must have cells that can replicate indefinitely. Can the draft human genome sequence tell us how the cell cycle works and how it evolved?
Genome sequencing has revealed surprisingly little about the cell cycle. The two main conclusions of comparative analysis were drawn well before the first eukaryotic genome was sequenced: the machinery that regulates the cell cycle has been highly conserved in eukaryotic evolution, and the size of protein families such as the Cdks and cyclins has expanded as organisms have become bigger and acquired more cell types. Comparing sequenced genomes has strengthened but not altered these conclusions. Disappointingly, comparing fully sequenced genomes does not explain how differences have evolved between the cell cycles of different organisms. For example, a conserved pathway (the mitotic exit network) is required for cytokinesis in budding and fission yeast, but is required to complete mitosis in budding but not in fission yeast. Men live, and must avoid cancer, for thirty times as long as mice, and it is much easier to induce mouse cells to proliferate indefinitely in vitro. Can comparing the sequence and expression of two genomes reveal the source of these differences? Getting a positive answer to such questions will require a marked improvement in our ability to turn raw sequence data into biological knowledge.
Genomics and cancer
Identification of the genes that cause oncogenesis is a central aim of cancer research. All cancers are caused by abnormalities in DNA sequence. Throughout life, the DNA in human cells is exposed to mutagens and suffers mistakes in replication, resulting in progressive, subtle changes in the DNA sequence in each cell. Occasionally, one of these somatic mutations alters the function of a critical gene, providing a growth advantage to the cell in which it has occurred and resulting in the emergence of an expanded clone derived from this cell. Additional mutations in the relevant target genes, and consequent waves of clonal expansion, produce cells that invade surrounding tissues and metastasize. Cancer is the most common genetic disease: one in three people in the western world develop cancer, and one in five die from it. Around 30 recessive oncogenes (tumour suppressor genes) and more than 100 dominant oncogenes have been identified. In the past, the most successful way to identify such genes was to narrow their location to a small part of the genome using mapping strategies, and then to screen candidate genes in the region for mutations in cancer cases. However, this strategy has its limitations. Mapping information can be confusing or misleading. Moreover, some cancer genes leave no obvious 'identifiers' in the genome and therefore cannot be readily positioned using such maps (for example, dominant oncogenes that are activated by single nucleotide substitutions leading to a single amino-acid change). These mutated genes are essentially invisible to conventional detection and their identification has usually depended upon selection of likely candidates on the basis of the biological features associated with cancer.
How will the genome sequence help us to identify the remaining cancer genes? One possibility is to generate a longer list of plausible candidates by searching for paralogues of known cancer genes.
Was this really a useful way of generating likely candidate cancer genes? Mutated cancer genes do recur in certain gene families (for example, signaling kinases and GDP binding proteins), but these families are often large and, in most cases, only a minority of members are implicated in cancer. In fact, the diversity of structure and function of cancer genes is striking. For example, hardly any of the known recessive oncogenes have strong homology to any other, and their proteins are associated with diverse biological and biochemical functions. Moreover, many close relatives of important cancer-related genes (for example, the genes for p73 and p63, which show sequence similarity to TP53 are not known to be mutated in cancer (although it is possible that they are significantly altered by changes in expression). So we may learn more about the mutations driving cancer if we are not too heavily influenced by past experience. Instead, we should persevere in exploring every gene or protein, whatever its structure or putative function, as a possible candidate.
By simply mining the genome sequence for similarity to known cancer genes, we may miss an opportunity. In addition to many more gene sequences, the working draft contains information concerning the organization of genes, their structures and ordering along the chromosomes. Cancers are characterized by disruption and disorganization of genomes. Perhaps we could use the genome sequence as a template against which we can detect structural alterations of the genome in cancer cells.
To do this we need to compare the working draft (and ultimately the finished sequence) with corresponding sequences from cancer cell genomes. However, there is very little cancer genome sequence available, and what is available is patchy. The largest body of sequence from cancer genomes originates from programs that sample clones in complementary DNA libraries constructed from neoplastic tissues (for example, the Cancer Genome Anatomy Project (CGAP, In principle, we could try and compare these with the working draft for the somatic base substitutions and small insertions and deletions that often result in inactivation of tumour suppressor genes or activation of dominantly acting oncogenes. In practice, however, these databases contain relatively little sequence and do not sample most transcripts in any single tumour. Moreover, the available sequence is mostly from untranslated regions of genes (whereas the cancer-causing mutations cluster in the coding regions). Even if the rare, meaningful somatic mutations could be detected, they would be buried in the debris of sequence errors (both in the cDNA libraries and in the genomic sequence) or camouflaged in a forest of innocuous polymorphisms.
Elucidating the complexity of cancer at the genomic level will require much more sequence data from cancer genomes, which will need to be configured appropriately for the task at hand. So, the working draft will not immediately reveal the natures of the abnormalities in cancer cell genomes. To facilitate these analyses we will need the finished sequence, which will form a structural framework for a new generation of massive-scale comparisons of cancer cell and normal genomes. Ultimately, it may also prompt a shift away from strategies that depend upon primary genomic localization and allow systematic genome-wide searches for mutations. New technology will be required; there is no single technology at present that will detect all the types of abnormality (large deletions, rearrangements, base substitutions, small insertions and deletions, amplifications, and epigenetic changes such as methylation) that are present in cancer cells. Sequencing of genomic libraries constructed from cancer genomes would come closest to this goal, but given the diversity of cancers and the effort and cost required to obtain reasonable coverage of a human genome this is a daunting challenge.
Immunology in the genomic view
The outstanding problems facing immunology are whole system issues: curing allergic and autoimmune disease and developing vaccines to stimulate stronger immune responses against pathogenic organisms and cancer.
The human genome sequence contains a list of all the parts controlling beneficial and harmful immune responses. To identify these parts, the immediate hurdles of gene identification and genome assembly will need to be overcome. The ultimate challenge will be to bridge the gulf between a list of sequences and whole organism biology.
In contrast to the 'reverse genetics' strategies, which create mutants in predicted immunological genes using a bottom-up strategy, perhaps the greatest contribution made to immunology by the genome sequence lies in facilitating 'forward genetics' approaches. These start with an altered immunological trait and proceed from the top down to identify the causative gene. The trait may be a difference between strains of mice or a difference in human families. Research efforts can be focused on genes with key roles in immunological processes, regardless of sequence or expression pattern.
The complete list of parts provided by the human genome sequence will, on its own, not solve the major questions facing immunologists. Rather, it will form the basis of experiments designed to understand how the parts fit together to control immune responses.
Available resources
There are a number of resources currently available for perusing the human genome. 'Human Genome Central' attempts to gather together the most useful web sites. See:
The best starting point for the uninitiated will be a site such as those of NCBI, Ensembl or the University of Santa Cruz (UCSC). These sites offer a mixture of genomic viewers and web-searchable datasets, and allow analysis of the human genome sequence without the need to run complex software locally.
For more involved analysis, it might be necessary to download some of the data locally. Useful downloadable sequence-oriented datasets include protein datasets (available from Ensembl and NCBI) and the assembled DNA sequence for regions of the genome, available at UCSC. Other genomic datasets are also available, such as the global physical map from The Genome Sequencing Center in St Louis and the single nucleotide polymorphism (SNP) database from NCBI. Raw sequence data is available from the International Nucleotide Database (GenBank/EMBL/DDBJ), but this data is generally more difficult to handle because it is very fragmentary, can contain contaminating nonhuman DNA and may include misleading information such as incorrect map assignment.
This loose network of sites will probably coalesce into a more coordinated network of sites offering informative web pages and resources. NCBI, Ensembl and UCSC are developing new, more accessible resources that will become available within the next year.
Conclusion: Add to favorites!
On this web site, accompanying the description of the sequence, there are a lot of data-mining papers that interrogate the genome from distinct biological perspectives. These range from broad topicsócancer, addiction, gene expression, immunology and evolutionary genomics to the more focused: membrane trafficking, cytoskeleton, cell cycle and circadian clock. The findings reported by these authors are likely to be indicative of many people's experiences with the draft human genome: frustrating and rewarding in equal measures.
A suite of interwoven maps is one of the features available on line. The key map for the entire project is the whole-genome clone-based physical map constructed by the International Human Genome Mapping Consortium. It provided the scaffold upon which the sequence was assembled. The cytogenetic map plots landmarks across the genome and anchors the physical map to the underlying chromosomal positions. A comparison of the genetic and physical maps charts the rate of recombination or exchange between each pair of our 46 chromosomes ó that occurs as the genome is passed on through generations. Finally, the International SNP asingle nucleotide polymorphismo Map Working Group documents 1.42 million polymorphic sites in the genome, providing for the first time a variant in virtually every gene and in each genomic region. This map of human variation will facilitate efforts to reconstruct our evolutionary history and dissect the genetic basis of human traits and disease. Analysis of the draft genome sequence itself provides the first panoramic view of the landscape of our genome.
One principle at the heart of the Human Genome Project, reflected in the Universal Declaration on the Human Genome and Human Rights, is free and unlimited access to the sequence. In keeping with this principle, the entire content of this section, plus additional features and commentary, is available without restriction.

References 1. Available from:
3 Nuclear Myosin
Rajko IGIC, Department of Anesthesiology and Pain Management, Cook County Hospital, Chicago, IL, USA
Motility of the cells or intracellular particles is very important phenomenon in biology. It represents one of the crowning achievements of evolution (Lodish et al, 1995).
Some cells move and reach locations more favorable for growth, such as migrations of embryonic cells that form the organs of multicellular organisms, while most of the cells in the body do not migrate. Nevertheless, they exhibit changes in their morphology. For example, the contraction of muscle cells, movements of microvilli and filopodia, the separation of chromosomes, and the transport of membrane vesicles. These functions are mediated within cells by molecules called "motor proteins," including the muscle protein myosin.
It has been suspected for long that cellular nucleus must also have a motor protein responsible for movements of various nuclear particles. The researchers have found that nuclear processes, such as transcription, involve large molecular complexes and require energy (Alberts, 1998), and that the abundance of actin in the nucleus (Rando et al., 2000) suggests a role for myosin in the nucleus. However, exact nature of this motor protein was not known.
A few months ago, a nuclear motor protein was identified by the researchers at the University of Illinois at Chicago led by Professor Primal de Lanerolle (Dragovic-Pestic et al, 2000). They showed the presence of a protein called myosin I in the nucleus. Nuclear myosin I is similar to muscle myosin, but it contains a unique 16-amino acid aminoterminal extension. The authors showed that this extension is essential for targeting myosin I to the nucleus. They have also shown that this myosin is in a complex with RNA polymerase II. Other experiments showed that nuclear myosin I plays an active role in RNA synthesis.
These results are very exciting because they provide an important insight into the molecular mechanisms required to express genes. They also suggest similarities between muscle contraction and transcription. A great deal is known about the role of myosin in muscle contraction and it may be possible to apply this knowledge to better understanding the regulation of gene expression. Because transcription is essential for cell growth and division, improved understanding of transcription at the molecular level may provide new ways to treat cancers and other proliferative diseases.

1. Alberts B. The cell as a collection of protein machines: preparing the next generation of molecular biologists. Cell 1998;92:291-4.
2. Dragovic-Pestic L, Stojiljkovic Lj, Philimonenko AA, Nowak G, Ke Y, Settlage RE et al. A Myosin I isoform in the Nucleus. Science 2000;290:337-41.
3. Lodish H, Baltimore D, Berk A, Zipursky SL, Matsudaira P, Darnell J. Molecular Cell Biology, 3 ed. New York: Scientific American Books; 1995. p. 991.
4. Rando OJ, Zhao K, Grabtree GR. Searching for a function for nuclear actin. Trends Cell Biol 2000;10;92-7. (Illustrated by H. Fazlic).
4 Fundamental Research in Serbia - YES or NO
Pavle Milenkovic and Nevenka Stojanovic, Institute for Medical Research, Belgrade, Yugoslavia
Most of the governments in the world believe that only applied research programs will lead to the progress. It is not recognized that already existing fundamental research is always the basis for successful applied research. The so-called strategic research programs are sometimes in fact misleading and do not distinguish basic-fundamental research from the basic strategic research. Fundamental research is concerned with foundation of new knowledge. The basic-fundamental strategic research is oriented to the formation of new frontiers leading to applicable product. This does not mean that fundamental research is not potentially applicable but the period of recognition is too long and is often not foreseen by the government and mostly by the scientists as well. The examples are numerous. The structure of DNA became, after 40 years, the basis for genetic engineering and forensic medicine. The magnetic resonance imaging is now widely used but the scientific basis was founded in the fifties. More than seventy percent of clinical tools used in cardiology are based on fundamental research not initially aimed to be utilized in cardiology. Several pharmaceutical companies realized that basic research might be the basis for new ideas and therefore new drugs. The examples also involve the development of hemopoietic growth factors as useful drugs during the period of about 20 years period, starting from initial description, research on function, isolation, and large-scale production by recombinant technology.
In Serbia, research is continuously supported through the projects founded by Ministry of Science and Technology. The limited economic resources are faced with around 15,000 researchers located at universities and institutes. It is obvious that financial support of the researches has been aimed to prevent the leaking of the scientific basis to better positions in more developed countries. But in the economic reality the appropriate support of research projects failed, inevitably causing the overall results. Therefore, new changes in our society and expected economic renewal in future need a new strategy in the foundation and funding of scientific research. However, the long-term strategic plan for development of Serbia does not exist. Last year, the National Advisory Board for science and technology promoted a document on strategy of scientific and technologic development. It emphasized that strategic applied research had a priority in the future. Although this seems reasonable for the country of this size and economy, as the long-term national interest it might be dangerous. The experience of more developed countries demonstrate that fundamental research has good impact on productivity, that new technology depends mainly on the advances in fundamental research and that there is an interdependence between national strength in industry and strengths in fundamental research. In global world economy there is an obvious question: Does the engagement of a small country in basic research seem to be the waste of financial resources? Financial support of fundamental research might be expensive and of high risk in cost/benefit relation. However, the benefits are obvious and in fact strategic.
By minimizing fundamental research we shall be faced, in near future, with the technologies developed in more advanced countries, which we might not even understand. Continuous education of high quality young scientists is essential if we want survival of science in Serbia. Fundamental research is a critical part of research education and the basis for new knowledge.

1. dos Remedios C. The value of fundamental research. A discussion paper prepared for the IUPAB council. available from: URL: http:// www:
2. Koenig R. Help needed to rebuild science in Yugoslavia. Science 2000;290:690-93.
5 Eminent scientist of the year award
Dubravka STRIBER DEVAJA, Svetozar ZDRAVKOVIC, Institute of Oncology Sremska Kamenica, Yugoslavia
The International Research Promotion Council (IRPC) is an international organization committed to promote academic and research achievements of scientists and
researchers in different branches of science. Along with other awards the IRPC - Asia Pacific Chapter has decided to further its aims by selecting and conferring "Eminent Scientist of the Year" award and "Outstanding Research Team" award in the field of science and medicine. This is done by the Award Selection Committee of IRPC comprised of eminent scientists and after careful assessment of the achievements of the research team. By decision of IRPC the Institute of Oncology Sremska Kamenica was awarded international reward for 2000 in the field of medicine for the article "Hospital Cancer Data Registry". The award consists of the gold medal for the main author and medal showing the emblem of IRPC to the research team, Certificate of Excellence award winner. The authors of the article: Dubravka Striber Devaja, B.S.E.E, Svetozar Zdravkovic, B.S.E.E. and Prof. Vladimir Vit. Baltic, M.D. Ph.D. were selected for the title: Eminent Scientist of the Year 2000 & Millennium Golden International Award Winner. "Recent Advances & Research Updates" is published exclusively for IRPC as the special issue of the journal. The authors of the article from the Institute of Oncology Sremska Kamenica are the first from similar medical institutions in Yugoslavia who won this award.
6 Diskobolos 2001
Dubravka STRIBER DEVAJA, Svetozar ZDRAVKOVIC, Institute of Oncology Sremska Kamenica, Yugoslavia
Every year JISA (Yugoslav Association of Information Technology) assigns the Diskobolos reward for the best solutions in the field of Information Technology (IT). At the end of the year the JISA pronounce the best achievement of the year. Diskobolos picture reminds us of the new optical storage era we use in IT field. The Judges for the Diskobolos prize are twelve most eminent IT experts and members of JISA. On December 21, 2000 the Institute of Oncology Sremska Kamenica was awarded the year's main informatics reward in the field of national health DISKOBOLOS 2000 for the article: "Telemedicine and multimedial interactive communication in the Internet environment". The authors of this article are: Dubravka Striber Devaja, Svetozar Zdravkovic, Vladimir Vit. Baltic, Vladimir Ivanovic. The Institute of Oncology is the first medical institution which won the award twice, in 1999 and 2000. Last year the Institute of Oncology Sremska Kamenica was awarded DISKOBOLOS 1999 for the realization of the project: Registries of malignant tumours".
7 Report on the quality control system audit at the Institute of Oncology Sremska Kamenica
Branislava Jovanovic, Sava Marjanov, Institute of Oncology Sremska Kamenica, Yugoslavia
Mrs. Pamela Bankes, a quality controller from British Standard Institution (BSI) visited the Institute of Oncology Sremska Kamenica on February 22-23, 2001 and carried out the audit of the established quality control system - BS EN ISO:1994.
The quality control system at the Institute of Oncology Sremska Kamenica was initiated in 1996 and its successful implementation was confirmed with the award of BSI Certificate on April 22, 1998.
In 1999, the Institute of Oncology entered a Yugoslav contest for quality system award - the statute of Oscar for Quality - and won the fourth place and Medal for Quality.
Mrs. Pamela Bankes carried out the audit of quality control system in all organizational units at the Institute and did not find any nonconformity with the established system. Her general assessment was that the Institute succeeded to maintain the effective quality system during the past period. She also gave recommendations for the improvement of the system.
The implemented improvements of the quality control system at the Institute were demonstrated in: the objectives of the quality system, as defined in the Policy of Quality and their implementation, the re-evaluation by the management, as a process of re-checking of all data obtained from the quality system and identification of all possibilities for continuos improvement, the internal audit of quality system, performed twice a year, the analysis of the complaints expressed by customers-patients, to recognize the most troublesome processes and give recommendations for their improvements the analysis of nonconformity trend, identification of basic causes and implementation of recommended activities their for correction and prevention.
At the end of her visit, Mrs. Pamela Bankes expressed her great pleasure that the Institute of Oncology is among the institutions certified by BSI for Qualify Control System. The next audit to be performed by BSI is foreseen for August, 2001. By that time, the Institute of Oncology should conform its certified quality system with the new version of quality standards ISO 9000:2000.
Book Review
Book Received
Meetings and Congress Reports
Medical and Scientific Meetings
  Issue 2
Closing Statement

7th International Inter University Conference on Telemedicine took place in Monastery Studenica between May 23rd and 26th of 2001. About 80 international participants presented over 30 orig- inal papers and 3 invited lectures. The Conference Proceedings is published as the 4th - "Annals of the Academy of Studenica" in the form of CD-ROM.
The participants thank to the Institute of Oncology for organizational effort and relaxing atmosphere that set the stage for successful and dynamic exchange of research results and experiences from various fields of Telemedicine.
The Academy announces the best paper award to Mark L. Manwaring for the original contribution related to the Remote monitoring of intracranial pressure. The best national paper award goes to the paper "Telemedicine and Multimedia interactive communication in internet environment" authored by Dubravka Striber Devaja, Svetozar Zdravkovię and Vladimir Vit. Baltię for the contribution to the national telemedicine practice.
High interest for the Conference shows that we are catching up with contemporary telemedicine developments and confirms the need for introducing the telemedicine to the national health care system. Future developments require both considerable investment to the communication and medical infrastructure and multidisciplinary research projects.
The Conference participants support foundation of YUTEM-the Yugoslav Telemedicine Association that should bring all interested parties together in an effort to develop modern national Telemedical infrastructure to the benefit of patients. We are looking forward to meeting again and presenting the initial results of the pilot projects of YUSTEM-Yugoslav Telemedical System.
For the Programme Committee
Full Prof. Dr. Zoran Jovanovic
Full Prof. Dr. Veljko Malbasa
Ass. Prof. Dr. Miroslav Despotovic
2 Openinig Address
Dear Conference President V.V. Baltic and and Co-President Professor P Spasic,
The Officers, Board of Directors, and Members of the American Telemedicine Association send our very best wishes for a successful Telemedicicine Conference in Studenica. The program for your conference promises to be very interesting and exciting. The topics which you plan to discuss are at the forefront of the field of telemedicine. We are confident that the presentations at the Conference will lead to significant advancements in the field of telemedicine and will also help move forward the agenda for glob- al telemedicine. This will be of benefit to people throughout the world.
Congratulations on organizing this splendid conference. Very best wishes for every possible success at what will certainly be an unforgettable international conference.
Most sincerely yours,
Ronald S. Weinstein, M.D.
Secretary, American Telemedicine Association Washington, D.C., USA
On the occasion of the return to Serbian informatics environment Microsoft and its partners from Serbia organized a conference named Synergy in the Sava Center on June 7, 2001. It was attended by several thousands of participants interested to hear lectures, and get information about recent achievements and the newest products from the field of informatics technology presented by Microsoft. The guests and participants were welcomed and addressed by Mr. Zoran Djindjic, Serbian Prime Minister, Mr. Michael Lacombe, vice president of Microsoft, Mr. Ian Wise from Compaq Computer and Microsoft representatives Mr. Goran Radman and Mr. Dejan Cvetkovic. The lectures were organized in four sections covering productivity, infrastructure, management and development - or to use the words of the organizer - technologies of today in service for future. A very interesting lecture on new technology for development of Internet web applications based on "web services" and named Microsoft.NET (Microsoft dot net) was presented by Rafael Lukawiecki, Project Botticelli. Microsoft is planning to open its offices in Yugoslavia as soon as possible and to secure its copyright and intellectual ownership on its products as a primary task. It is, among other things, precon- ditioned by the average income of our citizens which, according to Microsoft representatives for this region, must be higher if the company wants to make profit. On the other hand, Mr. Radman said that daily rate of any Microsoft software package, when paid on installments, is not higher than a price for a cup of coffee. Microsoft will help the development of information systems in government institutions by the unification of software solutions. The company plans to open its agency offices and all those who have Microsoft registered software programs shall have all privileges of legal users as everywhere. These plans leave open enough space for a sound competition. The development of Internet and existing telecommunication system in Serbia were also discussed. The government of Serbia is the one to make the next move. The appearance of Microsoft on our market is certainly positive and encouraging and we hope that the state of Serbia will not be too idle to use all benefits from this cooperation because the information systems and Internet present the future of any country, including Serbia.
4 3D Monitor about to appear or
News of Journal "Mikro", June 4, 2001;3(106)
Recently founded company Actuality Systems, Riding, Massachusetts is going to present its new 20 inches, spherical monitor at the Society Information Display conference to be held in San Hose. The monitor, temporarily named Helios, is designed for tridimensional display of a picture showing much more details than a traditional flat monitors. The users will be able to circle around the screen and watch the picture from any angle within the range of 360 degrees. The company says that 3D monitor will find its use in molecular and medical structures visualization, mechanical modeling, aeronautical and astronomical shots for flight control purposes and satellite positioning, and of course - for fun! Actuality Systems company was founded in 1997 as a progeny of the Massachusetts Technology Institute.
Telemedicine Today
Telemedicine Journal and e-Health
Journal of Telemedicine and Telecare
British Journal of Healthcare Computing
Telemedicine and Telehealth Networks
1 Intracellular signaling pathways: main object of molecular oncology
Alexander G. TATOSYAN, Cancer Research Center Moscow, Russia
The harmonic functioning of a multicellular organism is determined by the ability of its cells to interact as well as their adequate response to environmental changes. Surface receptors are those "sense organs" which react to extracellular factors and inform the cell as appropriate. Specific interaction between the external signals, called "impulse", generated on the cellular membrane is amplified and transmitted inside the cell through certain signal chains. Some of the signals are sent to the nucleus, where they initiate the expression of particular genes. The cells' response to the signal stimulus may be different such as cell division (or, on the contrary, repression of this process), differentiation, proliferation, apoptosis, hormone secretion and others. The maintenance of a normal cellular phenotype results from an equilibrium between these processes. When this equilibrium is disrupted, the cell is at risk of entering a state of malignant transformation. There is a great diversity in the intracellular signaling pathways in cells. Because of their extraordinary complexity, our knowledge of these pathways is very fragmentary and decoding them is still at an early stage. We know that signaling pathways probably function in networks in which there are interconnections, and points of convergence and divergence. To understand the structure and the regulation of these networks is one of the major goals of modern biology: intracellular signaling is a topic that concerns nearly all of the research undertaken in functional molecular biology. It is studied particularly during oncogenesis and in several diseases apart from cancer. In its simplified form the signal transduction mechanism in the cell is a direct interaction between specific proteins in strictly determined order. A number of key proteins may be used in several signal transduction pathways. Different types of kinases and mines the intracellular signal trunsduction. During any malignant transformation, the reverse picture is observed - the signal system undergoes specific changes to make the transformed cell independent of environmental conditions and surrounding tissues. This is evident when one examines genes that are altered in cancers; many alterations are found in proteins that transmit signals, such as transcription factors, receptors, intracellular effectors, etc. Cancer, as many other diseases, is a disease of cellular signaling. Understanding how "intracellular signaling" functions requires even a partial knowledge acquired about this very complex network to be constantly integrated at the more complex level of the whole cell. Therefore, it is important to make continuously the links between signaling and intracellular transport, signaling and cellular differentiation, and signaling and morphogenesis, signaling and cell cycle. Protooncogenes and suppressor genes play an essential role in the transmission of signals that control these processes. Understanding their precise role in normal cells is an important step in the understanding of cellular dysfunction in the regulation of the proliferation and differentiation during oncogenesis. On other hand the development of methods to analyze structural and functional anomalies of carcinogenic molecular factors represents an ultimate goal of the basic researches undertaken in order to progress in the diagnosis and the treatment of cancer. The introduction of innovative treatments resulting from research into the clinics for the benefit of the patients constitutes an essen- tial mission of molecular oncology at present period.
2 Ask nature- cyanobacteria in cancer drug research
Dragana CETOJEVIC-SIMIN, Institute of Oncology Sremska Kamenica, Yugoslavia
Despite the fact that natural products are the most successful source of drug leads, their use in drug discovery has fallen out of favour. Of the new drugs approved between 1983 and 1994 up to 80% of antibacterials and anticancer drugs were derived from natural products (including taxol, docetaxel and camptothecin). Thay are likely to continue to be sources of new commercially viable drug leads. The chemical novelty associated with natural products is higher than that of any other source: 40% of the chemical scaffolds in a published data- base of natural products are absent from syntetic chemistry. Biologically active natural products are generally small molecules with drug-like properties and are capable of being absorbed and metabolized by the body, what additionally lowers the develop- ment costs. Microalgae are widespread group of photosynthetic organisms. Cyanobacteria, procariotic microalgae, produce a wide array of low molecular weight secondary metabolites with biological activity. Experimental studies in animal models have demonstrated an inhibitory effect of Spirulina fusiformis on oral carcinogenesis. Cryptophycin 1 is a remarkably potent antiprolif- erative compound that shows excellent antitumor activity against mammary, colon and pancreatic adenocarcinomas in mouse xenographs. At picomolar concentrations it blocks cells in the G2/M phase of the cell cycle by apparent action on microtubules resulting in powerfull antitumor activity, many-fold greater than paclitaxel or the vinca alkaloids. Tubercidin stabilizes micro- tubules against vinblastine- induced depolimerization, a taxol- like effect. Curacin A is a potent antimitotic agent, inhibitor of micro- tubule assembly. Tolyporphin, Welwitinindolinone and Welwistatin bind to P-glicoprotein, circumventing multiple drug resistance and may be useful in the treatment of drug-resistant tumors. With the ability to manipulate the yealds and the diversi- ty of metabolites through changes in culture conditions, microal- gae should be examined more closely for their ability to provide novel chemical diversity for drug discovery.
1. Harvey A. Strategies for discovering drygs from previously unexplored natural products. Drug Discovery Today 2000;7:294- 300.
2. Adams GD. Heterocyst formation in cyanobacteria. Curr Opin Microbiol 2000;3:618-24.
3. Kondo T, Ishiura M.The circadian clocks of plants and cyanobacteria. Trends Plant Sci 1999;5:171-6.
3 DA-125 a novel anthracycline derivative showing high-affinity DNA binding and topoisomerase II inhibitory activities, exerts cytotoxicity via c-Jun N-terminal kinase pathway
Sang GK, Mina S, Keon WK et al. Cancer Chemother Pharmacol 200l;47:511-8.
DA-12 (8S,10S)-8-(3-Aminopropanoyloxyacetyl)-10- [(2,6- dideoxy-2-fluoro- -L-talopryranosyl)oxy]- 7,8,9,10 - tetrahydro-6,8,11-trihydroxy-1-methoxy-5,12-nephthacene-doe hydrocloride is a novel anthracycline derivative with anticancer activity.
4 The potential clinical value of GML and the p53 gene as a pre- dictor of chemosensitivity for colorectal cancer
Hashimoto Y, Ueda K, Minami K, et al. Int J Clin Oncol 200l;6:90-6.
GML expressio and p53 mutation in colorectal cancer may be useful predictive genetis markers for sensitivity to MMC an 5-FU, respectively.
Book Review
Book Received
Meetings and Congress Reports
Medical and Scientific Meetings
  Issue 3
1 The 13th symposium of cardiologists of Yugoslavia
The 13th Symposium of cardiologists of Yugoslavia was held in Novi Sad October 17-20, 2001. Among the sessions about cardiology and cardiosurgery, one interesting session about telemedicine was held on October 19, 2001 with the title "Telemedicine in cardiology - after birth ...". There were four lec- tures in the field of cardiology mostly describing transfer of EKG signals over mobile telephony system, aspects of DICOM standards in EKG devices and teleconsultations between Clinic of car- diology and outpatient departments. The special lecture was done by Institute of oncology Sremska Kamenica, Dubravka Striber Devaja and Svetozar Zdravkovic with the title: "Telemedicine on the Institute of oncology Sremska Kamenica - our experiences". As the institution with some results in using telemedicine, the organizer of the Symposium has called the Institute to present its experiences, although the session has concern only cardiological aspects of telemedicine. The lecture was well accepted from audience both from physicians and engineers. In the discusion after lecrurers, the conclusion was made to improve cooperation among medical institutions themselves on one side, and medical institutions and proffesional companies dealed with technology used in telemedicne on other side. The use of telemedicine in Yugoslavia is still from case to case, so a real effort had to be done from everybody included in telemedicine to reach the objective - telemedicine in everyday practice.
2 Telemedicine guidelines and technical standards affecting telemedical transmissions
As telemedicine matures, various policies are being adopted that affect the equipment and services used in telemedicine. The following information provides links to various clinical guidelines and technical standards that are used in telemedicine applications.
Clinical Guidelines:
- Telehomecare Clinical Guidelines (
- Clinical Guidelines for Telepathology (
- ACR Teleradiology Guidelines ( pdf_standards/diag/telerad.pdf)
Technical Standards
- DICOM (Digital Imaging and Communications in Medicine) is the industry standard for transferral of radiologic images and other medical information between computers. (
- HL7 is a standard for the electronic interchange of clinical, financial and administrative information among independent health care oriented computer systems; e.g., hospital information systems, clinical laboratory systems, enterprise systems and pharmacy systems. (
- H.320 encompasses a set of standards for narrow band visual telephone systems and terminal equipment, commonly used in interactive live video applications for telemedicine. Developed by the International Telecommunications Union (ITU) H.320 specifies technical requirements for narrow band visual telephone systems and terminal equipment, typically for videoconferencing and videophone services. It describes a generic system configuration consisting of a number of elements, definition of communication modes and terminal types, call control arrangements, terminal aspects and interworking requirements. The full standards are available for purchase from ITU at
- The Association for the Advancement of Medical Instrumentation has a standards program consists of over 100 technical committees and working groups that produce Standards, Recommended Practices and Technical Information Reports for many medical devices. Information about the program and standards that have been created are available at
3 DICOM: The value and importance of an imaging standard
DICOM (Digital Imaging and Communications in Medicine) is the industry standard for transferral of radiologic images and other medical information between computers. Patterned after the Open System Interconnection of the International Standards Organization, DICOM enables digital communication between diagnostic and therapeutic equipment and systems from various manufacturers.
Such connectivity is important to cost-effectiveness in health care. DICOM users can provide radiology services within facilities and across geographic regions, gain maximum benefit from existing resources, and keep costs down through compatibility of new equipment and systems. For example, workstations, CT scanners, MR imagers, film digitizers, shared archives, laser printers, and host computers and mainframes made by multiple vendors and located at one site or many sites can "talk to one another" by means of DICOM across an "open-system" network. As a result, medical images can be captured and communicated more quickly, physicians can make diagnoses sooner, and treatment deci- sions can be made sooner.
The DICOM 3.0 standard evolved from versions 1.0 (1985) and 2.0 (1988) of a standard developed by the American College of Radiology (ACR) and National Electrical Manufacturers Association (NEMA). To support the implementation and demonstration of DICOM 3.0, the RSNA Electronic Communications Committee began to work with the ACR-NEMA MedPacs ad hoc section in 1992. This committee, chaired by Robert Hindel, PhD, established the concept of the central test node (CTN), a central exchange point that obviated the need for vendors to make pre- arrangements in order to exchange images directly with one another. At the RSNA annual meeting and scientific assembly, held at McCormick Place in Chicago, images compliant with DICOM 3.0 reside on the CTN and remain available to all partici- pants on the network, including those on the technical exhibit floors.
With funds from RSNA, the Electronic Radiology Laboratory (ERL) at the Mallinckrodt Institute of Radiology developed software that was the first of its kind to implement the written technical specification of the DICOM standard. The software was installed on the CTN for demonstrating the standard over a local area network in the infoRAD section of RSNA '92. Mallinckrodt produced more sophisticated software, which was demonstrated across a wide area network at RSNA '93. In January 1994, an access to the source code and documentation would provide users and developers a model for understanding the standard and for design considerations and a set of utilities that would be useful for initial testing in developers' laboratories.
The following organizations have been involved in support of the DICOM effort:
American College of Radiology
Mallinckrodt Institute of Radiology
National Electrical Manufacturers Association
Radiological Society of North America.
4 Telemedicine and E-Health
E-health is a very broad term that encompasses many different activities related to the use of the Internet for healthcare. Many of these activities have focused on administrative functions such as claims processing or records storage. However, there is an increasing use of e-health related to patient and clinical care. With this development, the world of e-health and telemedicine began to merge and ATA started to address clinical and patient care issues related to e-health. Information provided here focuses on clinical care and patient education aspects of e-health and is targeted to the health provider.
A Guide to E-Health for the Healthcare Professional
An Introduction (
What Your Patients Should Know (
Telemedicine and Telehealth: Principles, Policies, Performance and Pitfalls
Adam William Drakins and Margaret Ann Cary

Excerpt from book review from TELEMEDICINE JOURNAL ANSD e-HEALTH, Volume 7 Number 2, 2001 by Norman E. Alessi, M.D. as reviewer
"...This book is well written and should be read by administrators, physicians, allied health professionals, and policy makers involved with the delivery of healthcare... ".
Telemedicine Today
Telemedicine Journal and e-Health
Journal of Telemedicine and Telecare
British Journal of Healthcare Computing
Telemedicine and Telehealth Networks
1 Perhaps not everyone knows that...
Ann Oncol 2001;12:1337.
The CD155 gene, which encodes a transmembrane protein facil- itating poliovirus entry to the cell, is overexpressed in colorectal carcinoma. Moreover, overexpression begins at an early stage in tumorigenesis and continues to late stages. Previous studies in rat have shown that the Tage4 gene (tumor associated glycoprotein E4), which exhibits 40% identity with human CD155, is overexpressed in colon tumour cells. Consequently, researchers at Nantes University Hospital have now used reverse transcription-polymerasr chain reaction and immunohistochemical analyses to examine CD155 expression in human colorectal carcinoma. CD155 mRNA levels were increased in six of six colorectal cancer tissues compared with the tumour free colon mucosa, while immunohistochemical analysis revealed an increased level of CD155 protein in 12 of 12 samples. The relative expression of different CD155 variant transcripts was similar in the various normal and cancer samples tested, indicating that this overexpression is not associated with a particular mRNA variant.
2 Changed trends of cancer mortality in the elderly
Levi F, Lucchini F, Negri, Boyle P, La Vecchia C.
Ann Oncol 2001;12:1467-177.
Between the late 1980s and the late 1990s total cancer mortality at age 65 to 84 has been declining in the European Union (UE) (-5.5% in males, -4.5% in females), in United States (US) males (-2.3%), but not females (+4.4%), and in Japanese females (-5.6%), but not males (+6.3%). Cancer mortality in the elderly rose for both sexes in eastern Europe. Gastric cancer mortality declined in all the areas. Lung cancer rates declined over the last decade by 8.5% in males in the EU, and by 0.9% in the US. Rates were still increasing in eastern Europe, in Japanese males and females in all areas. Pancreatic mortality rates were increasing in both sexes in the EU and Japan up to the late 1980s, and in eastern Europe up to the 1990s, whereas rates for US males have been declining certification may have played a role in these trends. Mortality from leukemia in the elderly increased in eastern Europe and Japan, but was stable in the US and the EU.
3 Radon: A likely carcinogen at all exposures
Darby S, Hill D, Doll R.
Ann Oncol 2001;12:1341-51.
Estimates are uncertain, but residential radon is probably responsible for about 2000 lung cancer deaths per year in the United Kingdom, or around 6% of the total, making it the second biggest cause after smoking. Over 80% of the deaths are estimated to occur at ages less than 75 and over 80% in smokers or ex-smokers. Around 90% of radon-induced deaths in the United Kingdom probably occur as a result of exposures to radon concentrations below the currently recommended action level of 200 Bq mexp-3 . Further work is needed to obtain more reliable estimates of the risk of lung cancer associated with residential radon and on the cost-effectiveness of various intervention strategies before the most appropriate policies can be developed for managing exposure to this natural carcinogen.
Book Review
Book Received
Meetings and Congress Reports
Medical and Scientific Meetings
  Issue 4
Medical and Scientific Meetings
  Volume 8 Issue 1
1 Hydroxyurea is an usually well-tolerated antitumor agent, but its side effects include cutaneous lesions that appear mainly during long-term continuous therapy. The reported rate of such adverse reactions varies from 2 to 35%. A patient is described with chronic myeloproliferative disease in a form of myelofibrosis who developed lichenoid skin changes after several years of treatment with hydroxyurea. The changes consisted of: xerosis, scalling, hyperpigmentation, atrophy, erythema of the face and hands and ungual atrophy. The histological changes were similar to those seen in lichen planus.
2 The goals of health policy in Serbia until the year 2010 The general goals of health policy Contemporary concept of health protection starts from the commonly accepted value that the most important goal of the development of a society is the improvement of quality of life of people, and that health is the basic component of quality of life. Therefore, the protection and the improvement of health get the central position in all developing strategies. On the other hand, the fact that the capability for the development of a society depends on health of the population is accepted. Therefore, health and healthy environment become the integral part of the total developing policy of a society.
In accordance with these principles, and according to the performed analyses and studies, the following General goals of health policy in Serbia until the year 2010 were stated:
1. Preservation and improvement of the biological integrity of the nation;
2. Prolongation of a life-time of population;
3. Improvement of quality of life of people;
4. Improvement of health condition of population;
5. Provision of equality in achieving health protection;
6. Raising of quality and efficiency of health protection;
7. Improvement of material position of health facilities and health workers;
8. Greater influence of users of health protection in making and realizing decisions considering health protection.
3 In the November 15 issue of the journal Blood, a team of scientists from the National Cancer Institute reports that four out of four patients with hairy cell leukemia, an uncommon cancer of immune B cells, had "major responses" to a recombinant immunotoxin called LMB-2. All of the patients previously had not responded to standard treatments for the cancer, including chemotherapy and removal of the spleen. Robert Kreitman, M.D., lead author on the study, said one patient in this early stage clinical trial had a complete remission after treatment with the immunotoxin and has not relapsed 16 months later. For the three other patients, Kreitman and colleagues observed partial responses, detecting a 98% to 99.8% reduction in malignant circulating cells. All of the side effects were reversible and usually lasted less than a week. These included fever, nausea, vomiting, and rush.
4 Matched urine and serum DNA samples were obtained before surgery from 30 patients with clinically organ-confined solid renal masses (25 with malignant tumors and five with tumors of low malignant potential) and were subjected to microsatellite analysis. Nineteen (76%) of the 25 patients with malignant tumors were found to have one or more microsatellite DNA alterations in their urine specimen, and 15 were found to have alterations in their serum DNA by microsatellite analysis. In every case, the microsatellite changes in urine or serum were identical to those found in the primary tumor. Three of five patients with tumors of low malignant potential were found to have DNA alterations in their urine, but none displayed alterations in their serum. Microsatellite alterations were not identified in either the urine or the serum samples from normal control subjects. These data suggest that microsatellite DNA analysis of urine specimens provides a potentially valuable tool for the early detection of resectable kidney cancer. Furthermore, microsatellite analysis of serum samples reveals evidence of circulating tumor-specific DNA in approximately half of these patients and may reflect the propensity of these tumors to spread to distant sites at an early stage.
5 17-allylamino,17-demethoxygeldanamycin (17AAG) is the first inhibitor of heat shock protein 90 (Hsp90) to enter a phase I clinical trial in cancer. Inhibition of Hsp90, leads to depletion of important oncogenic proteins, including Raf-1 and mutant p53. In two independent in vitro human tumor cell panels, authors observed a positive relationship between DT-diaphorase expression level and growth inhibition by 17AAG. Stable, high-level expression of the active NQO1 gene transfected into the DT-diaphorase-deficient (by NQO1 mutation) BE human colon carcinoma cell line resulted in a 32-fold increase in 17AAG growth-inhibition activity. Increased sensitivity to 17AAG in the transfected cell line was also confirmed in xenografts. The extent of depletion of Raf-1 and mutant p53 protein confirmed that the Hsp90 inhibition mechanism was maintained in cells with high and low levels of DT-diaphorase. 17AAG was shown to be a substrate for purified human DT-diaphorase.
6 The study confirms that excessive body weight increases breast cancer risk in postmenopausal women. On the contrary, in premenopausal women, excessive body weight may be protective among women who have a lower-body type of fat accumulation (low WHR). An upper-body fat accumulation (high WHR) is a predictor of breast cancer risk in premenopausal women, and this effect is especially pronounced among subjects who are overweight.
7 Prostate cancer is the most commonly diagnosed malignancy and the second leading cause of cancer-related deaths in the Western male population. Despite the tremendous efforts that have been made to improve the early detection of this disease and to design new treatment modalities, there is still an urgent need for new markers and therapeutic targets for the management of prostate cancer patients. Using differential display analysis to compare the mRNA expression patterns of normal versus tumor tissue of the human prostate, we identified a cDNA, DD3, which is highly overexpressed in 53 of 56 prostatic tumors in comparison to nonneoplastic prostatic tissue of the same patients. Reverse transcription-PCR analysis using DD3-specific primers indicated that the expression of DD3 is very prostate specific because no product could be amplified in 18 different normal human tissues studied. Also, in a sampling of other tumor types and a large number of cell lines, no expression of DD3 could be detected. Molecular characterization of the DD3 transcription unit revealed that alternative splicing and alternative polyadenylation occur. The fact that no extensive open reading frame could be found suggests that DD3 may function as a noncoding RNA. The DD3 gene was mapped to chromosome 9q21-22, and no homology of DD3 to any gene present in the computer databases was found. This data indicate that DD3 is one of the most prostate cancer-specific genes yet described, and this makes DD3 a promising marker for the early diagnosis of prostate cancer and provides a powerful tool for the development of new treatment strategies for prostate cancer patients.
8 Parathyroid hormone-related protein (PHTrP) is produced by prostate carcinoma cells and tumors, but little is known of its role in prostate carcinogenesis. The goal of this study was to evaluate PTHrP expression in the regulation of prostate carcinoma growth using human and animal models. PTHrP expression was assessed in prostate cancer cell lines in vitro. Seven of nine cell lines produced PTHrP, and increased expression was seen during cell proliferation. The MatLyLu rat prostate carcinoma model was used to determine the effects of PTHrP overexpression on prostate tumor growth. PTHrP overexpression did not alter proliferation of the cells in vitro. However, when PTHrP overexpression cells were injected into rat hind limbs, primary tumor growth and tumor size were significantly enhanced as compared with control cells. To evaluate PTHrP in human prostate carcinoma patients, immunohistochemistry was performed on metastatic bone lesions. Immunolocalization of PTHrP protein was found in the cytoplasm and nucleus of cancer cells in the bone microenvironment. Because nuclear localization of PTHrP has been associated with an inhibition of apoptosis, the ability of full-length PTHrP to protect prostate cancer cells from apoptotic stimuli was examined. Cells transfected with full-length PTHrP showed significantly increased cell survival after exposure to apoptotic agents as compared with cells producing no PTHrP (plasmid control) or cells transfected with PTHrP lacking its nuclear localization signal. To determine the mechanism of action of PTHrP in prostate cancer cells, the parathyroid hormone PTHrP receptor status of the cells was determined. These cell lines did not demonstrate parathyroid hormone PTHrP receptor-mediated binding of iodinated PTHrP or steady-state receptor message by Northern blot analysis, but they did have a detectable receptor message by reverse transcription-PCR analysis. In summary, PTHrP is expressed in many prostate cancer cell lines in vitro and in metastatic bone lesions in vivo. PTHrP expression positively influences primary tumor size in vivo and protects cells from apoptotic stimuli. These data suggest that PTHrP plays an important role in the promotion of prostate tumor establishment and/or progression.
9 Patients at advanced stage of colorectal cancer with liver metastases have been treated with deep hyperthermia alone or in combination with chemotherapy (5-FU+FA+MMC). Hyperthermia was achieved by arrangements of capacitive electrodes with a radiofrequency field of 13.56 MHz (RF-DHT). This prospective open single-arm clinical study with 80 patients suffering from liver metastases from colorectal cancer gives some first hints, that deep RF-hyperthermia alone may have a substantial beneficial effect on overall survival time of patients with liver metastases from colorectal cancer. Long lasting no-change, partial and even some complete remissions could be observed. The overall median survival time from progression of metastases or relapse was 24.5 months and survival rates at 1,2 or 3 years from first diagnosis of metastases or progression were twice as high as expected from patients treated with chemotherapy.
10 The association between drug-resistance and three markers for invasive capacity: cathepsin D (Cath D), urokinase type plasminogen activator (uPA) and inhibitor of plasminogen activator type 1 (PAI-1) was examined in nine cervical and laryngeal carcinoma cell lines resistant to different cytostatics. All drug resistant cell lines had increased concentration of cathepsin D. uPA levels were similar in parental and drug resistant cervical carcinoma cells, but significantly higher in all examined drug resistant laryngeal carcinoma cells. In cervical carcinoma cells, PAI-1 concentrations were similar in parental and cisplatin resistant, but significantly higher in doxorubicin resistant cells. In laryngeal carcinoma cells, no increase in concentrations of PAI-1 was determined in the three from five resistant cell lines. There was no uPA in conditioned medium of parental or drug resistant cells. PAI-1 was detected in conditioned medium. Its levels were significantly increased in the medium of two cervical and three laryngeal drug resistant carcinoma cells.
11 Myo-Inositol is one of a relatively few compounds that has an inhibitory effect on carcinogenesis of the lung in experimental animals when administered during the post-initiation period. It prevents pulmonary adenoma formation in A/J mice when fed in the diet subsequent to administrations of benzo(a)pyrene or the tobacco specific carcinogen 4 (methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) to the mice. A second compound, dexamethasone, also prevents pulmonary neoplasia under the same conditions. Experiments in which both myo-inositol and dexamethasone were administered together in the diet showed an additive inhibitory effect.
12 Extracts from European mistletoe (Viscum album L., VAL) are used for complementary cancer treatment. Viscotoxins (VT) and whole plant extracts with high amounts of the VT have been shown to stimulate functional activity of granulocytes. Authors stimulated neutrophils from healthy donors in vitro with aqueous VT-free VAL extracts and mistletoe lectins (ML) in the presence of E.coli and studied phagocytosis and respiratory burst by flow cytometry. The VT-free VAL extract significantly stimulated granulocyte activity, and this effect correlated with the content of the ML, although the ML exerted no influence at relevant concentrations. Co-incubation of the cells with VAL in the presence of VT further increased granulocyte response. From these data it is suggested that (1) a non-VT non-ML component of the VAL extracts activated granulocytes and (2) different activation pathways may be involved in the stimulation by the whole plant extract and the VT.
13 This report demonstrates the potential efficacy of allogeneic hematopoietic transplantation for mantle-cell lymphoma (MCL) and provides the first evidence suggestive of graft-versus-malignancy in MCL. Data supportive of this concept include 1) achievement of remission concomitant with GVHD, 2) the conversion from a positive PCR status early after transplant to negative PCR status over time and 3) that the only relapse was in a patient who failed to engraft.
14 Testing stool for occult blood at the time of digital rectal examination (DRE) does not increase the number of false-positive test results or the cost per cancer detected in asymptomatic patients at average risk for colorectal cancer. These are the conclusions of a study of medical records of consecutive asymptomatic patients at average risk for colorectal cancer who were referred for colonscopy to evaluate a positive faecal occult blood test result obtained by DRE or spontaneously passed stool samples.
15 The new strategies are dependent on the techniques of molecular biology, which are able both to identify potential target tumor antigens at the gene level, and to help to unravel the complexities of immune mechanisms required. Vaccine delivery systems can also be genetic, with DNA vaccines able to act as viral mimics and enter several antigen processing pathways. One difficulty faced by tumor antigens is that they may be weak, and therefore fail to engage the immune system. Attaching genes encoding alert signals appears to solve this problem. Author have focused initially on idiotypic determinants of B-cell tumors, where the encoding variable region genes can induce protective anti-idiotypic immunity if delivered as a fusion protein with a fragment of Tetanus toxin. This model may have relevance for alternative tumor antigens.
16 In low-risk patients with cancer who have fever and granulocytopenia, oral therapy with ciprofloxacin plus amoxicillin-clavulanate is as effective as intravenous therapy. These are the conclusion of a prospective multicenter trial, in which 353 febrile patients with cancer who had granulocytopenia. Treatment was successful in 86% of the patients in the oral-therapy group and 84% of those in the intravenous-therapy group.
17 Authors investigated the occurrence of malignant tumors affecting bone tissue in a population of mummeries and skeletons, which had been excavated from the large necropolis of Thebes-West, Upper Egypt. This study material comprised a series of at least 415 individuals dating from approx. 1500-500 B.C. They identified at least 4 cases showing malignant tumors affecting the skeleton. In two cases, multiple mixed osteolytic-osteoblastic lesions suggested multiple metastases from carcinomas. Two further individuals presented with multiple osteolyses most suggestive of multiple myeloma.
18 Inositol hexaphosphate (IP6) is abundant in cereals and legumes, particularly in the bran part of mature seeds. Experimental studies using 7,12-dimethylbenz(alpha)anthracene (DMBA) and N-methylnitrosourea (NMU) in rats and mice in vivo, as well as human cell lines in vitro demonstrate a reproducible and striking anti-cancer action of IP6. This data shows that pure IP6 is definitively more effective than a high fiber diet in preventing experimental mammary tumors. Thus, for cancer prevention, prophylactic intake of IP6 may be not only more effective, but also more practcial than gorging on large quantities of fiber.
19 The combination of lumpectomy, radiation therapy, and tamoxifen was effective in the prevention of invasive cancer for patients with ductal carcinoma in situ (DCIS). These are the results of a randomized trial on 1804 women with the disease who were assigned lumpectomy, radiation therapy (50 Gy), and placebo or lumpectomy, radiation therapy, and tamoxifen. Women in the tamoxifen group had fewer breast cancer events at five years than did those on placebo.
20 Lymphoproliferative diseases that occur in immunocompromised patients are frequently associated with herpesviruses. These patients often fare poorly after treatment with conventional chemotherapy. Authors reported previously that patients with AIDS-related Burkitt's lymphoma (BL) responded to parenteral azidothymidine (AZT) and IFN-sigma. They found that EBV-positive lymphoma cells derived from these patients cultured with AZT express CD95 and undergo apoptosis. AZT-mediated apoptosis was caspase dependent and occurred despite Fas receptor blockade. In contrast, EBV-negative lymphomas were resistant to AZT-induced apoptosis, as were EBV-positive lymphomas that expressed high levels of bcl-2. Primary effusion lymphoma (PEL) cell lines infected with human heperpesvirus type 8 required IFN-alpha to potentiate AZT-induced apoptosis. INF-alpha did not up-regulate CD95 in BL or PEL but did induce expression of the death receptor ligand, CD95 ligand. AZT-sensitive lymphomas also accumulated significantly higher intracellular AZT monophospate than did resistant lymphomas. This data demonstrated distinct apoptotic responses to AZT and IFN-alpha in herpesvirus-associated lymphomas. EBV-positive BL cells that expressed low BCL-2 levels were sensitive to AZT alone; PEL cells required the addition of IFN-alpha to enhance apoptosis, and EBV-negative lymphomas were insensitive to both agents. AZT-sensitive BL cells transfected with BCL-2 became resistant. Susceptibility to antivirus-mediated apoptosis may be exploited to improve the therapy of certain herpesvirus-associated lymphomas.
21 The use of three courses of neoadjuvant chemotherapy with cisplatin, methotrexate, and vinblastine before cystectomy or radiotherapy does not yield the 10% improvement in three-year survival that was judged to be necessary for its introduction into routine use. These are the conclusions of a large trial with 976 patients with T2, G3, T3, T4a, No-Nx, or M0 transitional-cell carcinoma of the bladder undergoing curative cystectomy or radiotherapy. Median survival in the chemotherapy group was 44 months compared with 37.5 months for the no-chemotherapy group.
22 To assess the levels of prostaglandin (PG)E2 in plasma and unstimulated saliva of patients with advanced soft tissue sarcoma receiving high-dose epirubicin. PGE2 levels were determined in plasma and unstimulated salive of 10 healthy controls, and of 10 patients with advanced soft tissue sarcoma treated with high-dose epirubicin (180 mg/m2). Plasma from patients free of epirubicin-related stomatitis was taken prior to treatment and on day 7 of the chemotherapy cycle. Unstimulated saliva was used for PGE2 determination to avoid parotid gland contribution to the whole salivary volume, and patients without evidence of stomatitis were selected to avoid false salivary levels of PGE2 which could be caused by plasma leakage into the oral cavity. The determination of PGE2 was performed with the ELISA technique. Controls had a median PGE2 plasma level of 151 pg/ml (range 47-227.5) and salivary level of 111 pg/ml (range 59.5-245.5). Patients with soft tissue sarcoma presented levels which were not statistically different: median plasma level 125 pg/ml (range 47-220) , median salivary level 134 pg/ml (range 63-196). On day 7, the plasma levels were significantly higher (median 218 pg/ml, range 103-950, p=0.031) and the salivary levels were significantly lower (median 49 pg/ml, range 13-245, p=0.021). The results of study are in accordance with the relevant literature data in rats. Increase of PGE2 plasma levels and decrease of its salivary levels is possibly related to two independent mechanisms of action of anthracyclines. Decrease of salivary PGE2 levels following epirubicin can only speculatively be related to the development of stomatitis, as none of the patients with low salivary PGE2 following epirubicin administration developed any signs of stomatitis during the observation period.
23 Cytologic examination of fluid accumulated in a serous cavity is of paramount importance, because the presence of cancer cells in such a specimen denotes that the patient has cancer that is not only advanced, but also almost always inoperable and thus incurable. The purpose of study by Yerci et al. was to define the role of diagnosing malignancy in effusions of serous cavities, and to report the current number and positivity rates of pleural, pericardial and peritoneal effusions submitted to their pathology department. This retrospective study included 2058 fluid specimens (1094 pleural, 908 peritoneal, and 56 pericardial) belonging to 1000 male and 1058 female patients, and which were evaluated in the pathology department during the period between January 1994 and March 1998. Specimens were reviewed, calssified, and evaluated statistically. 1645 cases were diagnosed as benign, 188 cases as malignant, 12 cases as suspicious, and 213 as unsatisfactory material. The malignant cases represented 9% of all cases, and most of them were diagnosed as adenocarcinoma. Adenocarcinomas are most common tumors found in a serous cavity effusion. In most cases of a malignant effusion, a previously documented tumor exists. Nonmalignant effusions exceed malignant ones, and they are usually lymphocytic.
24 The cleaved confirmation of antithrombin has potent antiangiogenic and antitumor activity in mouse models. Antithrombin, a member of the serpin family, functions as an inhibitor of thrombin and other enyzmes. Cleavage of the carboxyl-terminal loop of antithrombin induaes a conformational change in the molecule. The latent form of intact antithrombin, which is similar in confirmation to the cleaved molecule, also inhibited angiogenesis and tumor growth. These data provide further evidence that the clotting and fibrinolytic pathways are directly involved in the regulation of angiogenesis and it might be speculated that interventions on these pathways might interfere with tumor progression.
25 Most of the human immunodeficiency virus 1 (HIV-1) protease inhibitors antiretrovirals are also potent inhibitors (and occasionally inducers) of hepatic and intestinal cytochrome P450 systems and, therefore, have the potential to alter the elimination of any substance that utilises these metabolic pathways. The authors describe a patient infected with HIV-1 who was treated with ritonavir and saquinavir and then experienced a prolonged effect from a small dose of methylenedioxymetanphetamine (MDMA or ecstasy) and a nearly fatal reaction from a small dose of gamma-hydroxybutyrate (GHB). The metabolism of benzodiazepines and opiates typically involves P450.
26 Cervical cancer emerges from cervical intraepitheial neoplasia (CIN) induced by high-risk HPV (HR-HPV) infections. Howerever, the vast majority of CIN lesions regresses spontaneously, and only a few lewsions persist or progress to invasive carcinoma. On the basis of morphological criteria, it is not possible to differentiate high-grade lesioins that will progress to invsive cancers. In most cervical carcinomas, human papilomavirus (HPV) genomes are integrated into host cell chromosomes and transcrobed into mRNAs encompassing viral and cellular sequences. In contrast, in early preneoplastic lesions, HPV genomes persist as episomes, and derived transcripts contain excusively viral sequendec. Thus, detection of HPV transcripts derived from integrated HPV genomes may specifically indicate both CIN lesions at high risk for progression as well as invasive cervical cancers. Here, authores established a protocol for the amplificaton of papillomavirus oncogene transcripts (APOT) from cervical specimens taht allowsus to distinguish episome-from integrate-derived HPV mRNAs. Cervical swab and biopsy samples from 549 patients attending outpatient clinics for cervical dysplasia were screened for the presence of HPV DNA, and 155 samples taht were positive for either HPVtype 16 (n=143) or 18(n=12) were subjected to the APOT assay. In samples derived from normal cervical epithelia (n=19) or low-grade cervical lesions (CIN I, n=10), no integrate-derived HPV transcripts were found. In contrast, in 1 (5%) of 22 samples derived from CIN II lesions, and 10 (16%) of 64 samples from patients with cervical cancer, integrate-derived HPV transcripts were detected. Thus, detection of integrate-derived HPV transcripts in cervical swabs or biopsy specimens by the APOT assay points to advanced dysplasia or invasive cervical cancer.
27 SEREX (serological analysis of recombinant tumor cDNA expression libraries) has been applied to several different tumor types and has led to the identification of a wide range of tumor antigens. In this study, a breast cancer library and a normal testicular library were analyzed using autologusand allogeneic breast cancer sera. Thirty genes were isolated, including 27 known genes and 3 previously unknow genes. Among the known genes, two cancer-tstis (CT) antigens, NY-ESO-1 and SSX2, previously defined by SEREX analysis, were found. In addition, ING1, a cadidate breast cancer suppressor gene, was isolated. This ING1 gene product was also recognized by 2 or 14 allogeneic sera from breast cancer patients but not 12 normal adult sera. Comparison of ING1 cDNA from normal and tumor tissues showed no mutation in the index breast cancer case and revealed the presence of at last three different mRNA trascriptors with variable transcription initiation sites and exon usage. Tissue-specific expression of these transcriptors was found in normal tissues and tumor cell line mRNAs. Furthermore, a novel gene, designated as ING2, sharing 76% nucleotide homology with ING1 was identified in the breast cancer cDNA library. The basis of the immunogenicity of ING1 and the biological role of ING1 and ING2 need further exploration.
28 It is generally considered that MHC class I restriced antigens are recognized by CD8+ T cells, whereas MHC class II-restricted antigens are recognized by CD4+T cells. In the present study, authors report an MHC class I-restricted CD4+T cell isolated from the tumor infiltrating lymphocytes (TILs) of a patient with metastatic melanoma. TIL 1383 I recognized by TIL 1383 I was tyrosinase, and the epitope was the 398-376 peptide. Antibody blocking assays confirmed that TIL 1383 I was HC class I restridted, and the CD4 and CD8 coreceptors did not contribute significantly to antigen recognition. TIL 1383 I was weakly cytolytic and secreted cytokines in a pattern consistent with it being a Th1 cell. The avidity of TIL 1383 I for peptide pulsed targets is 10-100-fold lower than most melanoma-reactive CD8+T cell clones. These CD4+T cells may represent a relatively rare population of T cells that express a T-cell receptor capable of cross-reating with an MHC class I/peptide complex with sufficient affinity to allow triggering in the absence of the CD4 corecptor.
29 The signaling pathways critical for cell survival are mediated in part by the composition and integrity of the extracellular matrix and the action of its component on specific cell adhesion receptors. With-drawal of anchorage-dependent epithelial cells from their association with ECM result in apoptotic cell death. Consistently, the matrix metalloproteinases (MMPs) or their inhibitors (TIMPs) have been suggested to regulate apoptosis. In this report, authors investigated whether bcl-2 inhibiton of apoptosis involves regulation of TIMP expression. Authors have found that bcl.-2 overexpression induces TIMP-1 expression in breast epithelial cell lines (MCF10A, MCF10AneoT.TG3B, and MCF-7), whereas it has no effect on TIMP-2 expression. They demonstrated that TIMP-1 inhibits cell death induced by hydrogen peroxide, Adriamycin, or X-ray irradiation. In addition, TIMP-1 overexpression inhibits apoptosis after the loss of cell adhesion (anoikis) in MCF10A cells, sugesting that the antiapoptotic activity of TIMP-1 does not depend on its ablity to stabilize cell-matrix intgeractions. Authors also showed that TIMP-1 overexpression is associated with constitutive activation of focal adhesion kinase, a signaling molecule known to be critical for the cell survival pathway.
30 The one-hybrid system with an inverted CCAAT box as the DNA target sequence was used to identify proteins acting on key DNA sequences of the promoter of the topoisomerase IIa gene. Screening of cDNA libraries from the leukemia Jurket cell line and from the adult human thymus relulted in the isolation of a novel protein of 793 amino acids (89, 758 Da). This protein has in vitro CCAAT binding properties and has been called ICBBP90. Adult thzmus, fetal thymus, fetal liver, and bone marrow, known as active tissues in terms of cell proliferation, are the tisuses richest in ICBP90 mRNA. In contrast, highly diferentiated tissues and cells such as the central nervous system and peripheral leukocytes are freee of ICBP90 mRNA. Western blotting experiment s showed a simultaneous epxression of topoisomerase IIa and ICB90 in proliferating human lung fibroblats. Simultaneous epxression of both proteins has also been observed inHeLa cells, but in both proliferating and confluent cells. Overexpression of ICBP90 in COS-1-transfected cells induced an enhanced expression of endogenous topoisomerase IIa. Immunohistochemistry experiments showed that topoisomerase IIa and ICBP90 were coexpressed in proliferating areas of paraffin-embedded human appendix tissues and high-grade breast carcinoma tissues. Authors have identified ICBP90, which is a novel CCAAT binding protein, and their results suggest that it may be involved in topoisomerase IIa expression. ICBP90 may also be useful as a new proliferation marker for cancer tissues.
1 Lukatela and Turvey (September 1998) have nicely studied the reading process using written Serbo-Croatian language in its Cyrillic and Roman forms. I would like to suggest that the authors include a third alphabet in their investigations. In 1985, I devised a combined alphabet, Slavica, to be used instead of the two existing alphabets. My intention was to bring about a closer association among the four nationalities in the Yugoslav area, "who speak practically one language, but write in two different alphabets" (Igic, 1987). The basis for the Slavica alphabet is the Roman alphabet, which provides 17 of 30 letters or 30 phonemes. Eight Cyrillic letters are used in those cases where the Roman alphabet uses diacritic signs and combined letters: . These letters are rendered by their Cyrillic equivalents. Five common letters - a, e, o, j, k - are also included in the new alphabet. Thus, the Slavica alphabet follows the principle of one grapheme for one sound, a principle also carried out in the Cyrillic alphabet. In 1988 and 1989, the new alphabet was tested by students of the primary school in Buje, Republic of Croatia (see Figure), and it was especially attractive to the people of Bosnia, Vojvodina, and Istria (Igic, 1997b). Despite the positive response of Yugoslav and other reviewers of the Slavica alphabet (Milivojevic, 1991), with strong opposition only in the Croatian media, its wider acceptance was prevented by the civil war in Yugoslavia. Serbs, Croats, Montenegrins, and Bosnian Muslims are one ethnos, and they speak the same language, Serbo-Croatian. Whereas Croats now use only the Roman alphabet, Serbs and Montenegrins mainly use the Cyrillic alphabet. The language itself is being progressively modified to make it reflect three separate traditions by the introduction of new words and the legal suppression of others (Lewison & Igic, 1999). Bosnian Muslims speak Serbo-Croatian but are adding new words and calling it Bosniak. Before the civil war they were using both the Roman and Cyrillic alphabets; now they are using the Roman alphabet only. However, the latest experiences of the Bosnian Muslims, Serbs, and Croats, especially in Bosnia and Herzegovina (Igic, 1997a), might soon bring them to be in favor of needed alphabetical reform. Practically all readers of Serbo-Croatian who know both Cyrillic and Roman alphabets can easily read the Slavica alphabet. Therefore, it would also be interesting to test the decoding process for the three alphabets of the same language.

Figure. Poster against tobacco smoking prepared by Ivana Batop, a sixth grade student at the primary school in Buje, Istria, Republic of Croatia. Text of the poster , which means "smoking is dangerous to your health", is written in the Slavica alphabet. Medical students printed and distributed 40.000 copies of this poster and three similar posters throughout Yugoslavia from 1989 to 1992, always several weeks before January 31, which is known as "A Day Without a Cigarette".
2 Prim. Dr. Vladimir Ljikar, the chief of Sector for hygiene and protection of the environment at the Institute for health protection in Novi Sad, beside many other recognitions for his professional and scientific activities, was awarded the Medal for his merits in the field of defence and the first level security. During the NATO bombing, Dr. Ljikar successfully organized the work on the examination of the formed contamination in the air, drinkable water, food, above-ground waters, and after the bombing he and his associates participated in the work of the UN Commission considering the examination of the previous contaminations.
3 Formal reception on the occasion on awarding the annual rewards of Serbian Medical Society- Society of Doctors of Vojvodina: After considering the suggestions of Branches and Specialized Assemblies of the Socitey, the jury chosen for awarding the annual rewards of SMS-SDU decided to give the following rewards:
1. For life-work achievement - Prof.dr Boris Nedvide, Novi Sad
2. For scientific research work - Prof. dr Stevan Popovic, Novi Sad
3. For protection of health of the population - Prim. dr Zorica Bopkov-Jagodic, Zrenjanin
4. For many years of successful work in the primary health protection - (was not awarded)
5. For the best grades during the Meical studies - dr Jovan Obradovic
6. For the best grades during the Medical studies - dr Branislav Markov
7. For the best student work - Natasa Prvulovic
8. The members of the families of the deceased were given the memorials:
- Prof.dr Miladin Mirilov (1931-1998)
- Dr Dragic Isakov (1952-1998)
4 On the occasion of the Day of the Institute, the following rewards were awarded:
a) For scientific - research work
1. Dr sci med Jasna Mihailovic - for doctoral dissertation and entire scientific - research activity
2. Prof.dr Marica Miladinov-Mikov - for her geat contribution in scientific - medical journalism and the highest competence index at the Institute.
3. Ass.dr Dusko Kozic - for hist important presented and published scientific - research work and high competence index.
4. Dubravka Devaja, BSEE and Svetozar Zdravkovic, BSEE - for creating a programme Registries of malignant neoplasms.
b) For supreme results in diagnostisc and tretmant
1. Ass.dr Andrija Golubovic - for introduction of localization of sentinel lymphoid nods methodology as an important improvement in efficient breast cancer therapy.
2. Dr ing. Zlatko Selir - for an important improovement of protection during the application of high therapeutic dosec of radioactive isotopes
3. Ass.dr Roberst Semnic - for supreme diagnostic competence verified by taking the first place at the competition at the European Congress of Radiologists
c) For the most humane deed
1. The surgical team led by doc.dr Milan Breberina - for the operation performed during the bombing near by the Institute.
2. Djordje Elez - for extreme involvement in maintaining the appliances of the Imaging Diagnostics Centre, so that they managed to function successfully during the whole time of the NATO aggression on our contry.
Books Review
Meetings and Congress Reports
Medical and Scientific Meetings
  Issue 2
1 In vivo masurement of myocardial oxidative metabolism and blood flow does not show changes in cancer patients undergoing doxorubicin therapy
Nony P, Guastalla JP, Rebattu P, Landais P, Lievre M, Bontemps L, et al. Cancer Chemother Pharmacol 2000;45:375-80.
The aim was to investigate in patients receiving doxorubicin whether any alteration in myocardial oxidative metabolism or blood flow as assessed by positron emission tomography (PET) could be observed either after the first dose of the drug, or during its chronic administration. Using PET for both acute and chronic toxicity evaluations, no significant effect of doxorubicin was observed either one the flux through the tricarboxylic acid (TCA) cycle or on myocardial blood flow. However, systolic left ventricular function showed a small but significant impairment after the administration of 300 mg/m2 of doxorubicin..
2 The role of p53 in gemcitabine-mediated cytotoxicity and radiosensitization
Chen M, Hough AM, Lawrence TS. Cancer Chemother Pharmacol 2000;45:369-74.
The results suggest that p53 status may influence dFdCyd-mediated apoptosis, cytotoxicity, and cell cycle progression but do not support an importante role for p53 in radiosensitization.
3 Increase in tumor GADD153 mRNA level following treatment correlates with response to paclitaxel
De las Alas MM, Christen RD, Gately DP, Weiner DE, Khalid B, Kirmani S, et al. Cancer Chemother Pharmacol 2000;45:381-8.
An increase in GADD153 mRNA level reflects chemotherapy-induced damage sufficient to be manifest as a clinically detectable reduction in tumor volume. Measurement of the change in GADD153 mRNA level successfully indentified patients destined to respond as early as 24 h posttreatment.
4 Modulation of plasma uridine concentration by 5-(phenylselenenyl) acyclouridine, an inhibitor of uridine phosphorylase: relevance to chemotherapy
Ashour OM, Al Safarjalani ON, Naguib FNM, Goudgaon NM, Schinazi RF, Kouni MH, et al. Cancer Chemother Pharmacol 2000;45:351-61.
PSAU (5-(phenylselenenyl)-acyclouridine) is a new potent adn specific inhibitor of uridine phosphorylase (UrdPase, EC 2. 4. 2. 3), the enzyme responsible for uridine catabolism. The effectivens of the PSAU plus uridine combination in elevating and sustaining high plasma uridine concentration may be useful to rescue or portect from host toxicity of various chemotherapeutic pyrimidline analogs as well as in the management of medical disorders that are remedied by administration of uridine.
5 Magnetic resonance imaging of prostatic cancer: Does detection vary between high and low Gleason score tumors?
Ikonen S, Karkkainen P, Kivisaari L, Salo JO, Taari K, Vehmas T, et al. Prostate 2000;43:43-8.
Endorectal MRI detects poorly differentiated prostate cancer lesions more accurately than clinically insignificant tumors.
6 Role of virtual computed tomographic colonography in patients with colorectal cancer and obstructing colorectal lesions
Morrin MM, Farrell RJ, Raptopoulos V, McGee JB, Bleday R, Kruskal JB. Dis Colon Rectum 2000;43:303-11.
Computed tomographic colongraphy has an overall staging accuracy of 81 percent for colorectal cancer and is superior to barium enema in visualizing colonic segments proximal to obstructing colorectal lesions.
7 Expression of tumor suppressor gene p16INK4 products in primary gastric cancer
Tsujie M. Yamamoto H, Tomita N, Sugita Y, Ohne M. Sakita I, et al. Oncology 2000;58:126-36.
Recent studies have shown that the cyclin-dependent kinase (CDK) inhibitor p27Kip1 represents an indicator for patients' outcome in several human malignancies including gastric cancer. However, the clinicopathologic value of another class of CDK inhibitor, p16INK4, has not been determined. In a retrospective study, authors examined the expression of p16INK4 by immunohistochemical assay of 80 samples of primary gastric cancers and their adjacent nonneoplastic mucosas. Less than 10% of non-tumor gastric mucosal cells were p16INK4 positive, whereas the expression of p16INK4 in gastric cancer cells varied widely from 0 to 100% (mean, 24.5%). The expression of p16INK4 was not seen in 11.3% (9/80) of the cancer cases, but in 65% (52/80) this protein was even overexpressed when compared with the nonneoplastic mucosa. A clinocopathologic survey indicated that a low or no expression of p16INK4 was associated with poorly differentiated carcinoma (p=0.0133), but the level of expression did not correlate with other parameters including patients' prognosis or with the expression of the pRb protein. In an effort to explore the underlying mechanism for the p16INK4-negative cases, a prospective study was also performed on 20 cases of gastric cancer to compare the level of the p16INK4 protein with the methylation status of the p16INK4 promoter. Gastric cancer tissues with methylation expressed significantly lower levels of the p16INK4 protein (p=0.0013) and two of them lacked p16INK4 expression altogether, whereas all the cancer tissues without methylation expressed it. These findings suggest that the p16INK4 protein may be associated with differentiation of gastric cancer tissues and that methylation of the p16INK4 promoter may, in part account for the loss of p16INK4 expressions.
8 DNA repair protein Ku80 suppresses chromosomal aberrations and malignant transformation
Difilippantonio MJ, Zhu J, Chen HT, Meffre E, Nussenzweig MC, Max EE, et al. Nature 2000;404:510-4.
Cancer susceptibility genes have been classified into two groups: gatekeepers and caretakers. Gatekeepers are genes that control cell proliferation and death, whereas caretakers are DNA repair genes whose inactivation leads to genetic instability. Tumors results from a specific set of chromosomal translocations and gene amplifications involving Igh and c-Myc, reminiscent of Burkitt“s lymphoma. Authors conclude that Ku80 is a caretaker gene that maintains the integrity of the genome by a mechanism involving the suppression chromosomal rearrangemets.
9 BRCA1 and BRCA2 have a limited role in familial prostate cancer
Sinclair CS, Berry R, Schaid D, Thibodeau SN, Couch FJ. Cancer Res 2000;60:1371-5.
Thus, BRCA1 and BRCA2 appear to have a limited role in familial prostate cancer, and families with both prostate and breast cancer may result from mutations in other predisposition genes.
10 Quality of life in survivors of colorectal carcinoma
Ramsey SD, Andersen MR, Etzioni R, Moinpour C, Peacock S, Potosky A, et al. Cancer 2000;88:1294-303.
Colon carcinoma is a common malignancy that accounts for a substantial share of all cancer-related morbidity and mortality. However, little is known with regard to general and disease specific quality of life in survivors of colorectal carcinoma, particularly from community-based samples of cases across stage and survival times from diagnosis. Subjects with colorectal carcinoma were recruited from the National Cancer Institute's Ssurveillance, Epidemiology, and End Results cancer registry. Subjects completed two self-administered surveys: the Functional Assessment of Cancer Therapy Scales for Colorectal Cancer (FACT-C) and the Health Utilities Index (HUI) Mark III. One hundred seventy-three respondents (average age: 70.4 years, 71.4% female) completed the survey. In the first 3 years after diagnosis, quality of life was lower and varied substantially among respondents. After 3 years, respondents in all TNM stages of disease except Stage IV reported a relatively uniform and high quality of life. Pain, functional well-being, and social well-being were affected most substantially across all stages and times from diagnosis. Low income status was associated with worse outcomes for pain, ambulation, and social and emotional well-being. Only emotional well-being scores improved significantly over time in both surveys. Those individuals who achieve a long term remission from colorectal carcinoma may experience a relatively high quality of life, although deficits remain for several areas, particularly in those of low socioeconomic status. Sampling design may have excluded the most severely ill patients.
11 Selective augmentations of intratumoral 5-fluorouracil concentration by local immunotherapy with OK-432 and fibrinogen
Amano M, Sekimoto M, Monden T, Tomita N. Ohue M, Haba A, et al. Dis Colon Rectum 2000;43:402-7.
In patients with colorectal cancer, selective high 5-fluorouracil concentration in the cancer tissue could be achieved by a combination of 5'-deoxy-5-fluorouridine and local immunotherapy with a mixture of OK-432 and fibrinogen.
12 Antiangiogenic and antitumor activities of cyclooxygenase-2 inhibitors
Masferred JL, Leahy KM, Koki AT, Zweifel BS, Settle SL, Woerner BM, et al. Cancer Res 2000;60:1306-11.
Authors provide evidence that cyclooxygenase (COX)-2-derived prostaglandins contribute to tumor growth by inducing newly formed blood vessels (neoangiogenesis) that sustain tumor cell viability and growth. COX-2 is expressed within human tumor neovasculature as well as in neoplastic cells present in human colon, breast, prostate, and lung cancer biopsy tissue. COX-1 is broadly distributed in normal, as well as in neoplastic, tissues. The contribution of COX-2 to human tumor growth was indicated by the ability of celecoxib, an agent that inhibits the COX-2 enzyme, to suppress growth of lung and colon tumors implanted into recipient mice. Mechanistically, celecoxib demonstrated a potent antiangiogenic activity. In a rat model of angiogenesis, authors observe that corneal blood vessel formation is suppressed by celecoxib, but not by a COX-1 inhibitor. These and other data indicate that COX-2 and COX-2 derived prostaglandins may play a major role in development of cancer through numerous biochemical mechanisms, including stimulation of tumor cell growth and neovascularization. The ability of celecoxib to block angiogenesis and suppress tumor growth suggests a novel application of this anti-inflammatory drug in the treatment of human cancer.
13 Tumor necrosis factor-alpha and fas activate complementary fas-associated death domain-dependent pathways that enhance apoptosis induced by gamma-irradiation
Kimura K, Gelmann EP. Biol Chem 2000;275:8610-7.
Activation of either tumor necrosis factor receptor 1 or Fas induces a low level of programmed cell death in LNCaP human prostate cancer cells. Authors have shown that LNCap cells are entirely resistant to gama-radiation-induced apoptosis, but can be sensitized to irradiation by TNF-alpha. Fas activation also sensitized LNCap cells to irradiation, causing nearly 40% cell death 72 h after irradiation. Caspase-8 was cleaved and activated after exposure to tumor necrosis factor (TNF)-alpha. However, after exposure to anti-Fas antibody caspase-8 cleavage occurred only between the 26-kDa N-terminal prodomain and the 28-kDa C-terminal region that contains the protease components. Although anti-Fas antibody plus irradiation induced apoptosis that could be blocked by the pancaspase inhibitor zVAD, there was no meassurable caspase-8 activity after exposure to anti-Fas antibody. The effector caspases-6 and -7, and to a lesser extent caspase-3, were activated by TNF-alpha, but not by anti-Fas antibody. Anti-Fas antibody, like TNF-alpha also activated serine proteases that contributed to cell death. Exposure of LNCaP cells simultaneously to TNF-alpha and anti-Fas antibody CH-11 resulted in marked enhancement of apoptosis that occurred very rapidly and was still furher augmented by irradiation. Rapid apoptosis that ensued from combined treatment with TNF-alpha, anti-Fas antibody, and irradiation was completely blocked either by zVAD or expression of dominant negative Fas-associated death domain. Their data shows that there are qualitative differences in caspase activation resulting from either TNF receptor 1 or Fas. Simultaneous activation of these receptors was synergistic and caused rapid epithelial cell apoptosis mediated by the caspase cascade.
14 Human papillomavirus vaccines
Breitburd F, Coursaget P. Sem Cancer Biol 1999;9:431-4.
Genital human papillomavirus (HPV) infections are the viral sexually transmitted diseases most frequently diagnosed that include anogenital condylomas and squamous intra-epithelial lesions, among which the precursors of invasive carcinomas of the uterine cervix. In animal PV models, vaccination against L1 and/or L2 viral capsid proteins provides an efficient protection against infection, involving virus type-specific neutralizing antibodies. Vaccination against non-structural E1, E2, E6 of E7 viral proteins does not prevent infection, unless administered altogether, but tends to stimulate regression, warranting the design of therapeutic vaccines. Prophylactic vaccines based on the use of virus-like particles (VLPs) obtained by auto-assembly of L1 or L1 and L2 proteins produced by recombinant DNA technology are under phase I/II clinical trials for HPV 6/11 associated with condylomas and for HPV16, the most frequent oncogenic genotype. Second generation vaccines are chimeric proteins or VLPs incorporating one of the structural proteins (L1 or L2) fused to a non-structural protein (E6, E7 or E2), which should induce both humoral and cellular immunity. Vaccine valency (number of genotypes), route of administration (humoral versus local immunity), vaccines (children, young adults, gender) and forms of vaccines (recombinant $Lsalmonella typhimurium*I$L, edible plants expressing L1 and L2 proteins, DNA vaccines, synthetic antigenic peptides) are under study. End points to evaluate vaccine efficacy in phase III trials should include viral DNA detection and typing, and screening for low or high grade intraepithelial lesions. Therapeutic vaccines based on recombinant HPV E6 and/or E7 vaccinia virus, L2-E7 fusion proteins or E7 peptides corresponding to cytotoxic T cell epitopes are currently tested (phase I/II trials) in patients with cervical carcinomas of advanced clinical stages or high grade intraepithelial lesions. Animal studies, phase I/II clinical trials and implementation of the community support that HPV vaccines will constitute an efficient means to prevent carcinoma of the uterine cervix.
15 Overexpression of the heat shock protein HSP70 family and p53 protein and prognosis for patients with gastric cancer
Maehara Y, Oki E, Abi T, Tokunaga E, Shibahara K, Kakeji Y, et al. Oncology 2000;58:144-51.
Authors findings show that the expresion of HSP70 is not associated with tumor advance-related characteristics or with the prognosis of gastric cancer. Measurements of HSP70 expression do not appear to be a useful prognostic marker.
16 Phase I trial of interleukin-2 and high-dose arginine butyrate in metastatic colorectal cancer
Douillard JY, Bennouna J, Vavasseur F, Deporte-Fety R, Thomare P, Giacalone F, et al. Cancer Immunol Immunother 2000;49:56-61.
Interleukin-2 (IL-2) and sodium butyrate allow rats to be cured of peritoneal carcinomatosis from colon cancer. Authors performed a phase I trial of IL-2 and high-dose arginine butyrate (ArgB) in patients with advanced metastatic colorectal cancer. From April to July 1997, six patients were included in the trail; they had a median age of 52 years, four had a performance status of 0, two had a performance status of 1 with normal biological functions. All patients had received at least two prior lines of chemotherapy. A fixed dose of 18 MIU/m2 IL-2, was administered by subcutaneous injection and ArgB was delivered via continuos intravenous infusion on days 1-6 with escalating doses starting at 2 g kg-1 day-1. The planned dose escalation was not possible because of toxicities. A daily ArgB dose of 2 g/kg was delivered for nine cycles. Level 2 (4 g/kg) could not be delivered in three of the six patients because of liver toxicity. The dose-limiting toxicities were fatigue and liver function disturbances. The maximum tolerated dose for ArgB was 3 g kg-1 day-1, in combination with IL-2 at 12 MIU m2 day-1. No clinical response was seen. Pharmacokinetic analysis showed large intra- and interindiviual variations. This schedule with a high dose of ArgB proved to be highly toxic with liver insufficiency. Authors will be running another trial with lower doses of ArgB calculated from the schedule used in the experimental model, starting at a dose of 20 mg kg-1 day-1 for ArgB and 200 000 UI kg-1 day-1 IL-2, every 8 h.
17 Differential modulation of chemosensitivity to alkylating agents and platinum compounds by DNA repair modulators in human lung cancer cell lines
Heim MM, Eberharot W, Seeber S, Mēller MR J Cancer Res Clin Oncol 2000;126:198-204.
Modulation of DNA repair represents one strategy to overcome cellular drug resistance to alkylating agents and platinum compounds. The effects of different known DNA repair modulators such as O6-benzylguanine (6 mg/ml), fludarabine (25 ng/ml), aphidicolin (8.5 ng/ml), pentoxifylline (1.4 mg/ml) and methoxamine (12.4 mg/ml) on the cytotoxicity of mafosfamide, chlorambucil, 1,3-bis-(2-chloroethyl)-1-nitrosourea (BCNU), cisplatin and carboplatin were tested in human lung cancer cell lines. Chemosensitivity of the human adenocarcinoma cell line MOR/P and the cisplatin-resistant subline MOR/CPR as well as the large-cell lung cancer cell line L23/P and its cisplatin-resistant counterpart L23/CRP were evaluated by the MTT colorimetric assay. O6-benzylguanine, an inhibitor of O6-alkylguanine-DNA alkyltransferase, significantly sensitised MOR/P and MOR/CPR cells to the cytotoxic effect of BCNU. Fludarabine, methoxamine and aphidicolin did not change the chemosensitivity of the parental and cisplatin-resistant cell lines to any cytotoxic drug tested. Interestingly, O6-benzylguanine enhanced the chemoresistance of parental and cisplatin-resistant cell lines to platinum compounds. Also, pentoxifylline increased resistance of the MOR cell lines to mafosfamide. Modulation of DNA repair elicits not only chemosensitisation but may also enhance cellular resistance to DNA-affine drugs.
18 An unaffected individual from a breast/ovarian cancer family with germline mutations in both BRCA1 and BRCA2
Moslehi R, Russo D, Phelan C, Jack E, Antman K, Narod S. Clin Genet 2000;57:70-3.
Currently many centers offer testing for three specific mutations, 185delAG, 5382 insC, and 617delT, in the BRCA1 and BRCA2 genes to Ashkenazi Jewish individuals at high risk for breast and ovarian cancer. Authors recently tested members of a family with multiple cases of breast and ovarian cancer (Family R014). The proband in this family tested positive for the 185delAG mutation. The unaffected sister of the proband tested positive for both the 185delAG and the 6174delT mutations. Further testing and review of the family history suggest that both mutations may have come from a maternal grandfather and passed down for two generations. Counseling of the unaffected double heterozygote individual in this family is complicated by lack of information on the risk of breast, ovarian, and other cancers in such individuals. A better understanding of these risk will depende on the indentification and study of more individuals carrying mutations in both the BRCA1 and BRCA2 genes. Their study empahasizes the importance of testing Ashkenazi Jewish individuals from high-risk breast and ovarian cancer families for all three common BRCA1 and BRCA2 mutations indentified in this ethnic group.
19 p53 status in breast carcinomas revealed by FASAY correlates well with p53 protein accumulation determined by immunohistochemistry
Smardova J, Vagunda V, Jandakova E, Vagundova M, Koukalova H, Kovarik J et al. Neoplasmat 1999;46:384-9.
The prognostic and predictive value of p53 mutation in breast cancer is still conflicting. The choice of the p53 status detection method may account for some discrepancies. In this pilot study authors compared two differently-based methods for detection of p53 alteration in 32 breast carcinoma samples: the immunohistochemical method using Bp53,DO1 and DO11 monclonal antibodies for analysis of the p53 protein accumulation in cell nuclei and the functional mthod FASAY. FASAY - functional analysis of the separated alleles in yeast - tests the capability of the human p53 to transactivate a reporter with a p53 binding site RGC driving the ADE2 gene in yeast. In their group the percentage of breast cancers with accumulated p53 protein was 50%, as well as percentage of mutant p53 scored by FASAY was 50%. Although the agreement of both methods, when comparing the results of individual patients was high (94%), their results show that immunohistochemistry does not reflect the p53 status quite exactly.
20 Targeting therapy using a monoclonal antibhody against tumor vascular endothelium
Tsunoda S, Tsutsumi Y, Nakagawa S, Mayumi T Yakugaku Zasshi 2000;120:256-64.
Recent studies have revealed that the targeting therapy using monoclonal antibody against tumor associated antigens did not have a clinically satisfactory effect due to various physiological characters of tumor. Authors propose a novel approach targeting tumor vascular endothelium to solve the inefficiency of common tumor missile therapy. In this study, the tissue distribution of anti-tumor vascular endothelium monoclonal antibody (TES-23) produced by immunizing with plasma membrane vesicles obtained from isolated rat tumor-derived endothelial cells (TECs) was assessed in various tumor-bearing animals. Radiolabeled TES-23 dramatically accumulated in KMT-17 fibrosarcoma, a source of isolated TECs after intravenous injection. In Meth-A fibrosarcoma, Colon-26 adenocarcinoma in BALB/c mice and HT - 1080 human tumor tissue in nude mice, radioactivites of 1251-TES-23 were also up to fifty times higher than those of control antibody with little distribution to normal tissues. Furthermore, immunostaining of human tissue sections showed specific binding of TES-23 on endothelium in esophagus and colon cancers. These results indicate that tumor vascular endothelial cells express a common antigen in different tumor types of various animal species. In order to clarify the eficacy of TES-23 as a drug carrier, and immunoconjugate, composed of TES-23 and neocarzinostatin, was tested for its antitumor effect in vivo. The immunoconjugate (TES-23-NCS) caused a marked regression of the tumor, KMT-17 in rats and Meth-A in mice. Thaus, from a clinical view, TES-23 would be a novel drug carrier because of its high specificity to tumor vascular endothelium and its application to many types of cancer.
21 Mismatch repair proteins and microsatellites hit clinical practice
Adv Anat Pathol 2000;7:85-93. Stahl J. Adv Anat Pathol 2000;7:85-93.
Hereditary nonpolyposis colon cancer (HNPCC) is one of the most common familial cancers with characteristic molecular changes that are different from those found in familial adenomatous polyposis (FAP) coli. Genetic mutations in the germline and somatic cells lead to loss of expression of one of the two most commonly involved mismatch repair genes, hMSH2 or hMLH1, and consequently, to expansion of certain repetitive DNA sequences (microsatellite instability (MSI)). The paper describes a distinct subtype of "HNPCC-like" sporadic colonis carcinoma that can easily be identified by immunohistochemistry. Recognition of this subtype of colonic cancer is important because it occurs in the younger age group and is associated with better survival, but also a five-fold chance of developing a second colorectal carcinoma compared to "conventional" colorectal carcinomas.
22 The duration of antigen receptor signalling determines CD4+ versus CD8+T-cell lineage fate
Yasutomo K, Doyle C, Miele L, Germain RN. Nature 2000;404:506-10.
Signals elicited by binding of the T-cell antigen receptor and the CD4/C8 co-receptor to major histocompatibility complex (MHC) molecules control the generation of CD4+ (helper) or CD8+ (cytotoxic) T cells from thymic precursors that initially express both co-receptor proteins. These precursors have unique, clonally distributed T-cell receptors with unpreddictable specificity for the self-MHC molecules involved in this differentiation process. However, the mature T cells that emerge express only the CD4 (MHC class II-binding) or CD8 (MHC class I-binding) co-receptor that complements the MHC class-specificity of the T-cell receptor. How this matching of co-receptor-defined lineage and T-cell-receptor specificity is achieved remains unknown, as does whether signalling by the T-cell receptors, co-receptors and/or general cell-fate regulators such as Notch-1 contributes to initial lineage choice, to subsequent differentiation processes or to both. Here authors show that the CD4 versus CD8 lineage fate of immature thymocytes is controlled by the co-receptor-influenced duration of initial T-cell receptor-dependent signalling. Nothc-1 does not appear to be essential for this fate determination, but it is selectively required for CD8+ T-cell maturation after commitment directed by T-cell receptors. This indicates that the signals constraining CD4 versus CD8 lineage decisions are distinct from those that support subsequent differentiation events such as silencing of co-receptor loci.
23 Erythropoietin in radiation oncology - a review
Henke M, Guttenberger R. Oncology 2000;58:175-82.
The therapeutic potential of erythropoietin gains increasing attention among radiation oncologists because the prognosis is better for patients with high blood hemoglobin levels following radiotherapy. Further, the means to manipulate the hemoglobin level, their indication and administration need to be clarified. Available experimental and clinical data on hypoxia, anemia and on their treatment with erythropoietin have been extensively disscussed at an international conference in Freiburg, Germany, in June 1999.
24 Janssen-Cilag receives expanded approval for the marketing EPREX®/ERYPO®
Janssen-Cilag Press Release
Beerse, Belgium, March 31, 2000 - Janssen-Cilag announced today that it has received an expanded indication in Europe via the manual recognition procedure to market EPREX®/ERYPO® (epoetin alfa) for the "tretment of anemia and reduction of transfusion requirements in adult patients receiving chemotherapy for solid tumors, malignant lymphoma or multiple myeloma at risk of transfusion as assessed by the patient's general status (eg cardiovascular status, pre-existing anemia at the start of chemotherapy)".
Previously, the use of EPREX/ERYPO in Europe was restricted to cancer patients receiving platinum-containing chemotherapy. The European Member States reached the decision to aprove the extended indication on February 10, 2000. Janssen-Cilag is now awaiting implementation of the approval at the national level by the competent authorities.
Approval for the expanded indication was based on two large multi-center, placebo-controlled trials of 520 cancer chemotherapy patients in Europe. Published results from one of the trials determined that "epoetin alfa is highly effective in increasing hemoglobin, reducing transfusion requirements, reducing fatigue and increasing energy, acitivity levels and overall quality of life in cancer patients receiving non-platinum chemotherapy1".
EPREX/ERYPO is a genetically engineered version of erythropoietin, a naturally occurring hormone produced by the kidney that stimulates bone marrow to produce red blood cells. The main function of red blood cells is to carry oxygen needed for energy throughout the body. Anemia is an abnormally low level of red blood cells, and is assessed primarily through measurements of hemoglobin and hematocrit values.
In addition to cancer chemotherapy, EPREX/ERYPO is approved in Europe for the treatment of anemias associated with adjunctive therapy in autologous blood pre-deposit programs and reduction of allogeneic blood exposure in orthopedic surgery. EPREX/ERYPO is widely used for patients with chronic renal failure.
Epoetin alfa has been used to treat more than three million patients worldwide. It has proven to be effectie with a good safety profile when administered according to the prescrubing information. Janssen-Cilag is a member of the Jonhson & Jonhson family of companies.

1 Littlewood TJ, et al. Proc ASCO 1999; 18:574a.
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Medical and Scientific Meetings
  Issue 3
1 Syk gene may be a tumor suppressor in breast cancers
Reuters Medical News
WESTPORT, Aug 17 (Reuters Health)

The Syk tyrosine kinase is lost in aggressive breast cancers and is a potential tumor suppressor, researchers report in the August 17th issue of Nature. Dr. Susette C.Mueller, of Georgetown University Medical School, in Washington, DC, and colleagues examined Syk expression in cultured human breast cells and tissues ranging from normal to progressively more invasive cancers. They found that Syk was found in normal breast in the cells lining the ducts, benign breast lesions, and less aggressive cancers, while invasive breast cancers lacked the protein. "That started ringing a lot of bells", Dr Mueller told Reuters Health. Next, they introduced the Syk gene into Syk-negative breast cancer cells and found that this significantly inhibited tumor growth and metastasis in immunodeficient mice. Conversely, introducing a form of the Syk gene that inhibits the function of the normal gene into a Syk-positive breast cancer increased its ability to form tumors. Dr. Mueller noted that most tyrosine kinases are thought to promote cancer, not suppress it. "Lots of tyrosine kinases, when they are not regulated correctly, actually cause cancer", she said. "This is kind of unusual. It seems to block excessive growth and excessive invasion". In examining tumors with a normal Syk gene that were growth-inhibited, they found that the tumors had trouble with cell division. "It looked like they were trying to divide. They had multiple nuclei that were stuck together, but something was abnormal about it", she said. "The chromosomes were not separating properly, they kept being stuck together". She noted that one of the proteins Syk is known to modify is tubulin, which makes up the mitotic spindle. Why the Syk gene is not expressed in invasive breast cancers is not clear, according to Dr. Mueller. The gene appears to be present, but could be mutated. In the future, she suggested that this work could potentially be useful in treating breast cancers through the introduction of the Syk gene.
2 Telomere shortening in gastric carcinoma with aging despite telomerase activation
Furugori E, Hirayama R, Nakamura KI, Kammori M, Esaki Y, Takubo K. J Cancer Res Clin Oncol 2000;126:481-5.
In this study, authors analyzed both telomere length and telomerase activity in surgical and autopsy samples of non-neoplastic mucosa and carcinomas of the stomach. Telomere length, determined by Southern blot analysis, demonstrated progressive shortening with age in non-neoplastic gastric mucosal specimens from 38 human subjects aged between 0 and 99 years, with an average annual loss rate of 46 base pairs (bp). The mean (±SD) telomere length in 21 gastric carcinomas was 7.0±1.6 x 10 base pairs (1.6 kbp). In 20 (95%) of the 21 subjects, the values were smaller than those in the non-neoplastic gastric mucosa (mean shortehning 1.8kbp), although a strong correlation was observed for the paired data (r=0.69, P=0.0004). Similarly, telomere lengths in carcinomas were shorter than those for intestinal metaplasia (a mean difference of 1.1 kbp). Telomerase activity, estimated using the telomeric repeat amplification protocol assay, was positive in 18 (86%) of the 21 gastric carcinomas, without significant differences among the three histological types (well, moderately, and poorly differentiated adenocarcinomas) or with sex or age. The resul suggest that telomere length and possibly shortening rates vary with the individual, and that examination of both non-beoplastic mucosa and tumoris is necessary to improve our understanding of the significance of telomerase in neoplasia.
3 Apoptotic cell death: its implications for imaging in the next millennium
Blankenberg FG, Tait JF, Strauss HW. Eur J Nucl Med 2000;27:359-67.
Apoptosis, also known as programmed cell death, is an indispensable component of normal human growth and development, immunoregulation and homeostasis. Apoptosis is nature's primary opponent of cell proliferation and growth. Strict coordination of these two phenomena is essential not only in normal physiology and regulation but in the prevention of disease. Programmed cell death causes susceptible cells to undergo a series of stereotypical enzymatic and morphologic changes governed by ubiquitous endogenous biologic machinery encoded by the human genome. Many of these changes can be readily exploited to create macroscopic images using existing technologies such as lipid proton magnetic resonance (MR) spectroscopy, diffusion-weighted MR imaging and radionuclide receptor imaging with radiolabeled annexin V. In this review the cellular phenomenon of apoptotic cell death and the imaging methods which can detect the process in vitro and in vivo are first discussed. Thereafter an outline is provided of the role of apoptosis in the pathophysiology of clinical disorders including stroke, neurodegenerative diseases, pulmonary inflammatory diseases, myocardial ischemia and inflammation, myelodysplastic disorders, organ transplantation, and oncology, in which imaging may play a critical role in diagnosis and patient management. Objective imaging markers of apoptosis may soon become measures of therapeutic success or failure in both current and future treatment paradigms. Since apoptosis is a major factor in many diseases, quantification and monitoring the process could become important in clinical decision making.
4 Development of a new vaccine formulation that enhances the immunogenicity of tumor-associated antigen CaMBr
Perico ME, Mezzanzanica D, Luison E, Alberti P, Panza L, Russo G, Canevari S. Cancer Immunol Immunother 2000;49:296-304.
Aberrant glycosylation is one of the most constant traits of malignant cells. The CaMBr1 hexasaccharide antigen, originally defined on the human breast carcinoma cell line MCF7, is expressed on some normal tissues but overexpressed in a high percentage of human breast ovary, prostate and lung carcinomas. CaMBr1 overexpression is associated with poor prognosis. The epitope consists of the tetrasaccharide Fuc(alpha~1-2)Gal(`beta~1-3)GalNAc(`beta~1-3(Gal`alpha~-0-spacer, which has recently become available as a synthetic oligosaccharide. Here authors report the CaMBr1 tetrasaccharide conjugation to two different carrier proteins (CRM197 and KLH) and the evaluation of conjugate immunogenicity in mice following their administration in various vaccine formulations with two adjuvants (MPL-SE and Detox-PC). Radioimmunoassay to determine the level and isotype of anti-tetrasaccharide antibodies in mouse sera, and cytofluorimetric analysis and 51Cr-release assay on human tumor cells, to evaluate specificity of binding and complement-dependent lysis respectively, indentified CaMBr1-CRM197, in association with the MPL-SE adjuvant, as the best vaccine formulation. This combination induced (1) production of tetrasaccharide-specific antibodies, with negligible side-effects; (2) antibodies with complement-mediated cytotoxic activity on human CaMBr1-positive cells and (3) a high titer of IgG1 detected in sera obtained 3 months after the first injection, indicating that the anti-tetrasaccharide antibody response was mediated by T cell activation. The availability of CaMBr1-glycoconjugate in the minimal and functional antigenic structure and the identification of an efficacious vaccine formulation opens the way to exploring the activity of this glycoconjugate in a clinical setting.
5 Sequential administration of interferon`gamma~and interleukin-2 in metastatic renal cell carcinoma: results of a phase II trial
Schmidinger M, Steger GG, Wenzel C, Locker GJ, Brodowicz T, Budinsky AC et al. Cancer Immunol Immunother 2000;49:395-400.
Because of the known efficacy of several cytokines in the treatment of advanced renal cell cancer (RCC), authors have conducted a phase II trial of the efficacy and toxicity of subcutaneous interferon <Gamma>(IFN<Gamma>) and interleukin-2 (IL-2). 63 patients with progressive metastatic RCC were treated with 100 mg recombinant IFN<Gamma>1b administered three times weekly during weeks 1 and with 4.5 MU recombinant IL-2 administered on 4 consecutive days during weeks 3 and 4, every 6 weeks. 11% of patients had on objective response (CR: 3%, PR 8%), 33% had SD. Toxicity was generally mild. The median duration of remissions (CR+PR) was 9.6 months; the median duration of SD 8 months. A significant survival benefit was evident at a median observation time of 51 months for patients (44%) responding to therapy (P<0.0001). Authors conclude that sequential treatment with IFN<Gamma>and IL-2 may prolong survival in patients with metastatic RCC responding to therapy.
6 The impact of FDG positron emission tomography imaging on the management of lymphomas
Shah N, Hoskin P, McMillan A, Gibson P, Lowe J, Wong WL. Br J Radiol 2000;73:482-7.
The role of 2-(F-18)-fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) imaging in the management of patients with lymphoma has been evaluated. 29 patients (12 Hodgkin's disease, 17 non Hodgkin's lymphoma (NHL)) who underwent FDG-PET imaging during their lymphoma treatment programme were reviewed retrospectively. Correlation between FDG-PET and CT was evaluated, together with the impact upon clinical management of the findings on FDG-PET imaging. FDG-PET added extra information to the findings on clinical examination and CT in 12 patients (41%). This was seen both in patients with negative and positive CT scan. Two false positive FDG-PET scans were seen, reflecting FDG uptake in extranodal sites. Information from FDG-PET imaging resulted in a change in clinical management in 10 patients (34%); in two, initial management was altered, and in eight consolidation therapy after completion of initial chemotherapy was influenced. These changes in clinical management occurred in six patients with high grade NHL, two with low grade NHL and two with Hodgkin's disease. No specific subgroup was identified in whom FDG-PET was particularly discriminant.
7 Transperineal magnetic resonance image guided prostate biopsy
D'Amico AV, Tempany CM, Cormack R, Hata N, Jinzaki M, Tuncali K, Weinstein M, Richie JP. J Urol 2000;164:385-7.
Authors report the findings of a transperineal magnetic resonance image (MRI) guided biopsy of the prostate in a man with increasing prostate specific antigen who was not a candidate for a transrectal ultrasound guided biopsy. Using an open configuration 0.5 Tesla MRI scanner and pelvic coil, a random sextant sample was obtained under real time MRI guidancefrom the peripheral zone of the prostate gland as well as a single core from each MRI defined lesion. The patient had previously undergone proctocolectomy for ulcerative colitis and, therefore, was not a candidate for transrectal ultrasound guided biopsy. Prior attempts to make the diagnosis of prostate cancer using a transurethral approach were unsuccessful. The random sextant samples contained benign prostatic hyperplasia, whereas Gleason grade 3 + 3 = 6 adenocarcinoma was confirmed in 15% and 25% of the 2 cores obtained from the MRI targeted specimens of 2 defined lesions. The procedure was well tolerated by the patient. Transperineal MRI guided biopsy is a new technique that may be useful in detecting prostate cancer in men with increasing prostate specific antigen who are not candidates for transrectal ultrasound guided biopsy.
8 Sentinel node analysis increases detection of GI cancer micrometastasis
Reuters Medical News
WESTPORT, Aug 15 (Reuters Health)

In patients with gastrointestinal neoplasms, lymphatic mapping and sentinel lymphadenectomy are feasible, accurately predict the tumor status of regional lymph nodes, and identify abnormal lymphatic drainage, researchers report in the August issue of the Archives of Surgery. Noting that intraoperative lymphatic mapping and sentinel lymphadenoctomy have already been shown to be useful for melanoma, Dr. Anton J. Bilchik and colleagues from the John's Health Center, in Santa Monica, California, prospectively tested these techniques in 65 patients with gastrointestinal cancers.
Using isosulfan blue dye, the researchers found at least one sentinel lymph node in 95% of patients. The mapping only added about 10 minutes to the surgery, they noted.
Using hematoxylin-eosin staining, multiple sectioning and cytokeratin immunohistochemistry, they identified 36 cases of nodal metastases, of which 89% had at least one posivite sentinel node. Fifteen of these cases (42%) had metastases only to the sentinel node. "Based on the sentinel node focused analysis, 23% of the neoplasms were upstaged," they write. The report also noted that in 8% of cases, "lymphatic mapping identified aberrant lymphatic drainage that altered the extent of the lymphadenectomy".
In addition, the sentinel node was the only positive node in all T1 stage cancers and 70% of T2 stage cancers, implying that "sentinel node analysis may be particularly relevant in identifying micrometastatic spread from T1-T2 neoplasms".
"The preliminary findings of this feasibility study suggest that lymphatic mapping with focused examination of the sentinel nodes improves the staging of gastrointestinal neoplasms and may affect the selection of patients for adjuvant therapy", Dr. Bilchik and colleagues write. A prospective phase II trial is now ongoing to investigate these possibilities, they note.
9 D3 lymph node dissection in gastric cancer: evaluation of postoperative mortality and complications
Gunther K, Horbach T, Merkel S, Meyer M, Schnell U, Klein P, Hohenberger W. Surgery Today 2000;30:700-5.
Since November 1995 authors have been performing a D3 lymph node dissection in patients undergoing an operation for gastric cancer with a curative intent. The aim of the their study was to evaluate whether this procedure results in an increased postoperative mortality of complication rate in a Western population. Between November 1995 and August 1997 the postoperative courses of 76 patients were retrospecively assessed (45.3 lymph nodes per patient, lymph node ratio: 0.16). The patient outcome was compared with data from a historic control group of patients (n=383) in whom the newly established D2 dissection was studied in our department. Regarding the demographic, clinical, and tumor-pathologic data, and the choice of resection and reconstructive procedures, the two groups differed only slightly. The postoperative mortality of 1% was lower (vs 6.8%) while the overall complication rate of 34% (vs 32.1%) was identical. in particular, no anastomotic leakage (vs 9.4%) and fewer nonsurgical complications (17.1% vs 27.9%) occurred. The reoperation rate was 1% vs 9.7%. However, in 6% of the patients drainage tubes had to be inserted under computed tomographic guidance. The average hospital stay remained unchanged (21.9 vs 20.7 days). A D3 dissection was shown to be feasible while demonstrating no disadvantages in the patients when compared with the D2 procedure.
10 Brachytherapy yields excellent long-term results in prostate carcinoma
Reuters Medical News
WESTPORT, Jun 30 (Reuters Health)

Prostate brachyterapy, the implantation of small, radioactive metal seeds within the prostate gland, provides excelent long-term, disease-free survival, according to a report in the July 1st issue of Cancer. Dr. Haakon Ragde of the Northwest Prostate Institute, in Seattle, Washington, and colleagues studied the effects of brachytherapy in 229 prostate cancer patients, 147 of whom were low-risk for extracapsular spread and 82 of whom faced a higher risk. The overall median follow-up was 93 months, and half the surviving patients were followed for at least 122 months, the authors report. Only four patients died from prostate cancer, yielding a disease-specific 10-year survival rate of 98%. By the 10-year evaluation point, 70% of the patients had shown no evidence of prostate cancer by clinical examination or by measurement of prostate-specific antigen (PSA) levels, the report indicates. In fact, the mean PSA level of this group was only 0.16 ng/mL. Results differed somewhat in the two risk groups, the investigators observe. The low-risk group. which received only brachytherapy, had a 66% control rate at 10 years. The high-risk group, which received brachyterapy plus external beam radiation therapy, showed a 79% control rate. Most disease recurrences occurred within the first 5 years of treatment, the researchers note. After 5 years, the failure rate averaged only 1.5% per year, and there were no treatment failures after 115 months (in 109 men). "The addition of 77 more patients to our ongoing analysis of prostate brachytherapy with up to 12 years of follow-up confirms the previously documented excellent results for men with localized prostate carcinoma", the authors conclude. "The apparent benefit of adding external beam radiation to brachytherapy in selected high-risk patients is demonstrated by the excellent results achieved in this group", the researchers write. "However", they add, "we do not yet feel that the data support the addition of external beam radiation to every brachytherapy patient".
11 Accelerated hyperfractionated radiotherapy in supratentorial malignant astrocytomas
Genc M, Zorlu AF, Atahan IL. Radiother Oncol 2000;56:233-8.
To determine the safety and effectiveness of accelerated hyperfractionated radiotherapy in the treatment of supratentorial malignant astrocytomas. Between June 1995-July 1997, 75 patients were enrolled to a prospective phase II study. A total dose of 60 Gy was delivered in 2 Gy b.i.d. fractions with an interval of 6-8 h, 5 days per week, in an overall time of 3 weeks. The treatment protocol was planned to give 40 Gy to a treatment volume covering the contrast-enhancing lesion and oedema (+ 3-cm margin) and additional 20 Gy to the volume encompassing the contrast-enhancing lesion alone with a 1-cm margin based on preoperative magnetic resonance imaging and/or CT findings. The patients had a median age of 46 years and a median Karnofsky performance status score of 80. Histology consisted of anaplastic astrocytoma (AA) in 16 (21%) and glioblastoma multiforme (GBM) in 59 (79%) patients. Median survival was 11 months for all patients; 10 months for GBM patients and 40 months for AA patients. Survival rates at 1 and 3 years were 41%, 11% for all patients; 62, 37% for AA patients and 35, 6% for GBM patients, respectively. Multivariate analysis revealed significant impact of age, histology and neurological functional class on survival. The incidence of grade 3 or worse late neurological toxicity was 5.3%. Although accelerated hyperfractionated radiotherapy showed no significant advantage on survival, it shortened the treatment period from 6 to 3 weeks. Radiotherapy was well tolerated and the incidence of late toxicity is acceptable.
12 An integrated service digital network (ISDN)-based international telecommunication between Samsung Medical Center and Hokkaido University using telecommunication helped radiotherapy planning and information system (THERAPIS)
Huh SJ, Shirato H, Hashimoto S, Shimizu S, Kim DY, Ahn YC et al. Radiother Oncol 2000;56:121-3.
This study introduces the integrated service digital network (ISDN)-based international teleradiotherapy system (THERAPIS) in radiation oncology between hospitals in Seoul, South Korea and in Sapporo, Japan. THERAPIS has the following functions: (1) exchange of patient's image data, (2) real-time teleconference, and (3) communication of the treatment planning, dose calculation and distribution, and of portal verification images between the remote hospitals. Authors preliminary results of applications on eight patients demonstrated that the international telecommunication using THERAPIS was clinically useful and satisfactory with sufficient bandwidth for the transfer of patient data for clinical use in radiation oncology.
13 15-LOX-1: a novel molecular target of nonsteroidal anti-inflammatory drug-induced apoptosis in colorectal cancer cells
Shureigi I, Dongning C, Lee JJ, Peiying Y, Newman RA, Brenner DE et al. J Natl Cancer Inst 1999;92:1136-42.
Nonsteroidal anti-inflammatory drugs (NSAIDs) appear to act via induction of apoptosis-programmed cell death- as potential colorectal cancer chemopreventive agents. NSAIDs can alter the production of different metabolites of polyunsaturated fatty acids (linoleic and arachidonic acids) through effects on lipoxygenases (LOXs) and cyclooxygeneses. 15-LOX-1 is the main enzyme for metabolizing colonic linoleic acid to 13-S- hydroxyoctadecadienoic acid (13-S-HODE), which induces apoptosis. In human colorectal cancers, the expression of this enzyme is reduced. NSAIDs can increase 15-LOX enzymatic activity in normal leukocytes, but their effects on 15- LOX in neoplastic cells have been unknown. Authors tested the hypothesis that NSAIDs induce apoptosis in colorectal cancer cells by increasing the protein sxpression and enzymatic activity of 15-LOX-1. Authors assessed 15-LOX-1 protein expression and enzymatic activity, 13-S-HODE levels, and 15-LOX-1 inhibition in association with cellular growth inhibition and apoptosis induced by NSAIDs (primarily sulindac and NS-398) in two colorectal cancer cell lines (RKO and HT-29). All values are two-sided. Sulindac and NS-398 progressively increased 15-LOX-1 protein expression in RKO cells (at 24, 48, and 72 hours) in association with subseguent growth inhibition and apoptosis. Increased 13-S-HODE levels and the formation of 15-hydroxyeicosatetraenoic acid on incubation of the cells with the substrate arachidonic acid confirmed the enzymatic activity of 15-LOX-1. Inhibition of 15-LOX-1 in RKO cells by treatment with caffeic acid blocked NS-398-induced 13-S-HODE production, cellular growth inhibition, and apoptosis (P=.007, P<.001, and P<.0001, respectively); growth inhibition and apoptosis were restored by adding exogenous 13-S-HODE (P<.0001 for each) but not its parent compound, linoleic acid (P=1.0 for each). Similar results occurred with other NSAIDs and in HT-29 cells. These data identify 15-LOX-1 as a novel molecular target of NSAIDs for inducing apoptosis in colorectal carcinogenesis.
14 "Gene shaving" as a method for identifying distinct sets of genes with similar expression patterns
Hastie T, Tibshirani R, Eisen MB, Alizadeh A, Levy R, Staudt L et al. Genome Biology 2000;1(2).
Large gene expression studies, such as those conducted using DNA arrays, often provide millions of different pieces of data. To address the problem of analyzing such data, authors describe a statistical method, which they have called "gene shaving". The method identifies subsets of genes with coherent expression patterns and large variation across conditions. Gene shaving differs from hierarchical clustering and other widely used methods for analyzing gene expression studies in that genes may belong to more than one cluster, and the clustering may be supervised by an autocome measure. The technique can be "unsupervised", that is, the genes and samples are treated as unlabeled, or partially or fully supervised by using known properties of the genes or samples to assist in finding meaningful groupings. Authors illustrate the use of the gene shaving method to analyze gene expression measurements made on samples from patients with diffuse large B-cell lymphoma. The method identifies a small cluster of genes whose expression is highly predictive of survival. The gene shaving method is a potentially useful tool for exploration of gene expression data and identification of interesting clusters of genes worth further investigation.
15 ...but data release remains an open question
Nature 2000;406

On of the question marks hanging over cooperation in structural genomics is how and when the structures of proteins and other macromolecules should be made public. At a meeting in Cambridge in April, organized by the Wellcome Trust, scientists from public agencies in nine countries agreed that there should be timely release of all data. But a loophole remains in that, for the next couple of years, the decision of when a structure is complete and ready for a database is left to researchers themselves. This is because there is no agreement or way of defining when a protein structure is accurate and complete - is largely a matter of personal judgement. Arriving at an automatic cutoff point based on "numerical criteria" of quality is "now key goal", says John Norvell, head of the US Protein Structure Initiative based at the National Institute of General Medical Sciences. This would allow for clear rules on the timing of data release. An early agreement between researchers on data access is also critical to facilitating collaboration with industry. As several delegates at a meeting organized by the Organisation for Economic Cooperation and Development in Florence in June pointed out, researchers may be reluctant to put valuable structural data into the public domian. The Cambridge meeting agreed that data released should be accompanied by a short research paper, published simultaneously on the Internet.
16 Genome website set up to help with sequence analysis
Nature 2000;406.

London. After PubMed Central and Biomed Central comes 'Human Genome Central' - a 'master website' being set up by the International Human Genome Seguencing Consortium to provide access to tools for analysing the sequence data being produced by its members. The consortium says that although the raw sequence data are already available in three public databases - Genbank, the European Molecular Biology Laboratory Database and the DNA Database of Japan - analysing this data is a daunting and time-consuming task. The new website has therefore been designed to give users "comprehensive and comprehensible" ancillary information and tools. These should provide visitors to the site with a picture of the genome that is continually updated. The information available will include the overlaps between clones, the location of each clone, an integrated sequence that merges the individual clones, and annotation of gene content.
17 Improving therapy of colorectal cancer with new agents - Next steps in colorectal cancer
Cassidy J.

The data presented at the meeting and reviewed in this activity indicate that we may be entering a new era in the therapy colorectal cancer. 5-FU has been mainstay of therapy of this disease for over 40 years. It seems likely that fluoropyrimidines will still be an integral part of therapy - but 5-FU will be replaced by more convenient, less toxic, and possibly more active oral fluoropyrimidines. Capecitabine has the added advantage over UFT that it produces tumor-specific activation of 5-FU in the cancer site. It is for these reasons that, on current evidence, I would favor this agent as the optimal way of giving fluoropyrimidine in the future. The next major steps forward in this disease are, however, likely to be achieved by novel combinations of the active drugs that have been reviewed so far. Phase III trials of irinotecan in combination with 5-FU demonstrated that efficacy, including survival, can be enhanced by combining irinotecan with fluoropyrimidines. Similarly, the combination of oxaliplatin with 5-FU/LV has also been shown to produce dramatic improvements in response rate. A logical step in our attempts to further improve efficacy is to use highly active fluoropyrimidine agents such as capecitabine, which achieves superior response rates compared with a standard bolus 5-FU/LV schedule (Mayo Clinic regimen). A number of phase I trials exploring oral fluoropyrimidines in combination with irinotecan or oxaliplatin have been conducted and recommended doses for more extensive clinical development have been established. The next few years should see these combinations enter large-scale comparative studies. In addition, as radiotherapy has been shown to upregulate TP activity, the combination of capecitabine with radiotherapy is being explored and the updated results presented by Dr. Tanner are encouraging. The results of phase II trials for all of these combination regimens are eagerly awaited. It is also worth noting that these new agents are not necessarily restricted to colorectal cancer. The promising efficacy and safety shown by capecitabine has also been demonstrated in small scale pilot trials that have been performed in pancreatic, hepatocellular, gall bladder cancer patients, and a host of other solid tumor types. Recently presented phase II results of capecitabine monotherapy and phase I results of capecitabine/gemcitabine combination therapy in metastatic pancreatic cancer are encouraging, and phase II and III trials of capecitabine/gemcitabine combination therapy are planned following demonstration of a favorable safety profile and high antitumor activity. In conclusion, the future of therapy in colorectal cancer is likely to involve the use of combinations and/or sequences of all of the new agents discussed above. The adjuvant use of such active combinations is being actively pursued and it seems likely that we will be able to cure a higher proportion of our patients in the near future by the judicious application of these new therapies.
18 Improved efficiency of gene transfer to the transplanted lung by retrograde vascular gene delivery
Jeppsson A, Pellegrini C, Lee R, O'Brien T, Miller VM, Tazelaar HD et al. Transplant International 2000;13:241-6.
Experiments were designed to evaluate the efficiency of antegrade compared to retrograde vascular gene transfection of donor lungs used for transplantation. Rat donor lungs (n=5/group) were transduced with an adenoviral vector encoding for - galactosidase (AdGal), either antegrade in the pulmonary artery (Group A, 3x108 pfu, Group B, 3x109 pfu) or retrograde into the pulmonary vein (Group C, 3x108 pfu), immediately after pneumoplegia. After storage a 4!C for 1 h, the transduced lungs were transplanted orthotopically in syngeneic animals. The lungs ere assessed for transgene expression by ELISA and X-Gal-staining at day 7 after operation. Inflammation was graded based on the extent of inflammatory cell infiltration. Transgene expression was similar between Groups A (1.7±0.7 ng/mg protein) and B (2.1±1.0 ng/mg protein). With retrograde delivery, there was a four-fold (8.3±2.6 ng/mg protein) increase (P`0.05) in transgene expression compared to either group A or B. In all groups, pneumocytes were transduced most frequently. The degree of inflammation correlated positively with the extent of transgene expression (r=0.75, P<0.01). The efficiency of vascular gene delivery to transplanted lungs can be improved by retrograde delivery of the vector via the pulmonary vein. Transgene expression predominates in pneumocytes following both antegrade and retrograde delivery The severity of inflammation in the transplanted lung appears to correlate with the extent of transgene expression.
19 Medicine can prevent war
Igic R. Pak Armed Forces Med J 1999;49:80.
Like a cancer, war destroys the normal functions of society, spreads rapidly leaving destruction in its wake, and is the most serious threat to millions of lives. because war is medical problem, medical doctors have a special opportunity and obligation to fight for peace. In September 1998 author suggested to the British Medical Journal, several International Medical Journals and the World Association of Medical Editors (WAME) that an international meeting be organized on medicine's role in thepromotion of peace and prevention of war. That is a good first step. However, his idea is to gather medical professionals from varioud countries to give their opinion on this important topic - the prevention of war and other war-related major threats to the health of global society. This could be the basis for the permanent preventive activities of our profession. The begining of a new millenium is a perfect time for a big convocation of the healthcare force to present the medical, social and political solutions that may influence public opinion in all countries and save countless lives from the most serious disease that destroys humanity.
Books Received
Meetings and Congress Reports
Medical and Scientific Meetings
  Issue 4
1 AT - cell-selective interleukin 2 mutein exhibits potent antitumor activity and is well tolerated in vivo
Shanafelt AB, Lin Y, Shanafelt M-C, Forte CP, Dubois-Stringfellow N, Carter C et al.
Nature Biotechnology 2000;18:1197-202.

Human interleukin 2 (IL-2; Proleukin) is an approved therapeutic for advanced-stage metastatic cancer; however, its use is restricted because of severe systemic toxicity. Its function as a central mediator of T-cell activation may contribute to its efficacy for cancer therapy. However, activation of natural killer (NK) cells by therapeutically administered IL-2 may mediate toxicity. Here we have used targeted mutagenesis of human IL-2 to generate a mutein with 3,000-fold in vitro selectivity for T cells over NK cells relative to wild-type IL-2. We compared the variant, termed BAY 50-4798, with human IL-2 (Proleukin) in a therapeutic dosing regimen in chimpanzees and found that although the T-cell mobilization and activation properties of BAY 50-4798 were comparable to human IL-2, BAY 50-4798 was better tolerated in the chimpanzee. BAY 50-4798 was also shown to inhibit metastasis in a mouse tumor model. These results indicate that BAY 50-4798 may exhibit a greater therapeutic index than IL-2 in humans in the treatment of cancer and AIDS.
2 Declaration of Helsinki revised, holds researchers responsible after trials
Reuters Medical News (November 17)
LONDON (Reuters Health) Oct 10 - Revisions to the Declaration of Helsinki newly adopted by World Medical Association (WMA) hold researchers to the standard of "the best current prophylactic, diagnostic, and therapeutic methods" for research and follow-up treatment. On Saturday, the 52nd General Assembly of the WMA, held in Edinburgh, Scotland, unanimously voted to strengthen protections for individual research subjects and for the populations of host countries. "No population in any country should be used as a guinea pig without benefiting from the results of the research", Dr. Anders Milton of Sweden, chairman of the World Medical Association, told Reuters Health. As an example, he said "When human research is carried out in a country, there should be a reasonable chance of the drug being used there". Dr. Milton added, "We also say that for individuals participating in a study, either the control group or the test group, that at the conclusion of the study should have access to the best proven treatment for the disease state in question". Long considered the "cornerstone of research ethics", the Declaration of Helsinki calls for "absolute transparency regarding economic incentives involved in research", said Dr. Delon Human, Secretary General of the WMA. Not only must subjects be adequately informed regarding risks and benefits in language they can understand, but institutional affiliations and possible conflicts of interest must be clarified to subjects, ethical review committees and publishers. The WMA is an independent confederation of professional national associations from approximately 70 countries and represents 8 million doctors. This is the fifth time that the Helsinki document has been revised since its adoption in 1964. The full text of the revised declaration is available on the WMA Web site at
3 Early oophorectomy protects against breast cancer in BRCA1/2 mutation carriers
Reuters Medical News (November 17)
PHILADELPHIA (Reuters Health) Oct 10- Findings presented at the annual meeting of the American Society of Human Genetics further substantiate the benefit of bilateral prophylactic oophorectomy in significantly reducing the risk of breast cancer in women who carry mutations of the BRCA1 or BRCA2 genes. In a multicenter case-control study Dr. Andrea Eisen of the University of Pennsylvania School of Medicine and colleagues compared data on 415 matched pairs of mutation carriers to estimate the magnitude of the risk reduction conferred by oophorectomy. All the cases had breast cancer, while the controls were apparently free of breast cancer. The researchers found the overall odds ratio for breast cancer with bilateral oophorectomy to be 0.42. The greatest reductions in breast cancer risk was attained when oophorectomy was performed before age 40 (odds ratio 0.24). "The effect is lost if (the surgery) is at age 50 or later", Dr. Eisen said. "Although these data support the case for prophylactic oophorectomy, there are adverse events to consider", Dr. Eisen noted. These include quailty of life effects owing to premature menopause and an increased risk of osteoporosis and coronary heart disease. Commentators agreed that early prophylactic surgery provides optimal protection. "We consider 35 possibly to be the optimum age of surgery for breast cancer prevention, "Dr. Steven A. Narod, a co-moderator of the session, said. "It's better to have prophylactic oophorectomy with hormone replacement therapy than no prophylactic oophorectomy at all, " added Dr. Narod, who is at the Center for Research in Women's Health in Toronto, Canada. "We try to titrate the estrogen to treat the acute symptoms, and then wean them off of it after a few years".
4 Ultrasonography effectively measures tamoxifen's effect on endometrium
Reuters Medical News (November 17)
WESTPORT, CT (Reuters Health) Oct 12-Researchers in Israel, who followed 58 postmenopausal women after termination of tamoxifen treatment for breast cancer, found that transvaginal ultrasonography is a valuable tool in assessing tamoxifen's effects on the endometrium. Dr. Ilan Cohen, of Sapir Medical Centre, in Kfar-Saba, and associates in this prospective study, observed a significant decrease in median thickness of the endometrium, from 7.75 mm just before tamoxifen discontinuation, to 5.2 mm 6 months later. When performed about every 6-months over the next 30 months, ultrasonography showed that the endometrial thickness remained "constantly low". The investigators note in the September issue of the British Journal of Obstetrics and Gynaecology that previous studies found transvaginal ultrasonography to be of limited value in evaluating women taking tamoxifen. In these studies, ultrasonography yielded many false-positives and disparities with sonographic and histologic results. The authors believe their "findings are extremely important when using ultrasonography to assess the endometrium in postmenopausal breast cancer patients following discontinuation of tamoxifen treatment".
Dr. Cohen's group concludes that tamoxifen causes thickening of the endometrium of the subendometrial tissue or both. An endometrial thickness greater than that observed before stopping tamoxifen therapy or an increase in thickness "should alert the clinician to the possible existence of endometrial pathology".
5 High-dose chemo plus stem cell support promising for primary refractory NHL
Reuters Medical News (November 17)
WESTPORT, CT (Reuters Health) Oct 10- High-dose chemoradiotherapy (HDT) followed by autologous stem cell transplantation (ASCT) should be used for certain patients with primary refractory aggressive non-Hodgkin's lymphoma (NHL), according to a report in the October 1st issue of Blood. While HDT/ASCT is the treatment of choice for patients with relapsed NHL, its role in primary refractory aggressive NHL has not been demonstrated, the authors explain. Tarun Kewalramani and colleagues from Memorial Sloan-Kettering Cancer Center in New York reviewed the outcomes of 90 consecutive patients with primary refractory aggressive NHL who were eligible for HDT/ASCT based on disease sensitivity to chemotherapy. Half the patients had partial remissions with induction chemotherapy, and half failed induction therapy. Forty-three patients (50.6%) experienced complete or partial remissions with second-line chemotherapy (ICE-ifosfamide, carboplatin, and etoposide), the authors report, and 42 patients (38 ICE-sensitive and 4 in whom ICE failed) underwent HDT/ASCT. There were no transplant-related deaths, the investigators observe, although 4 patients died within 100 days after stem-cell reinfusion, all from lymphoma or its complications. Overall 3-year survival for the entire group was 25%, the report indicates, whereas survival in the HDT/ASCT subgroup was 52.5%. Event-free survival rates were 22% and 44.2%, respectively. "Our data strongly suggest that patients with primary refractory aggressive NHL should be treated with second-line chemotherapy with the intent of performing HDT/ASCT for those patients with chemosensitive disease", the authors conclude.
6 Hereditary nonpolyposis colorectal cancer: screening can impact cancer mortality
Isselbacher JK. (November 17)

Hereditary nonpolyposis colorectal cancer (HNPCC) is a disease characterized by the early onset of colorectal cancer (CRC) and by other non-GI malignancies such as endometrial and renal cell carcinomas. HNPCC is a disease due to a germline mutation in one of the five DNA mismatch repair genes and is inherited as an autosomal dominant trait. Individuals who inherit HNPCC have an 80 percent lifetime risk of developing CRC. Therefore, efforts are aimed at identifying individuals at risk by genetic testing and early endoscopic screening. Järvinen and colleagues (2000) report the results of a 15-year endoscopic screening for CRC in HNPCC. They followed up 252 asymptomatic individuals from 22 families with HNPCC, all at 50 percent risk of being a carrier of one of the five possible mismatch repair gene mutations. Of this total number, 133 individuals chose to undergo colonoscopic screening at 3-year intervals while 119 chose to avoid screening despite prior counseling. When genetic testing became available in 1996, it was offered to 205 individuals; 193 accepted-namely, 116 in the study group and 77 in the control group. Mutations in a mismatch repair gene were found in 44 and 46 individuals in the study and control groups, respectively. CRC developed in 6 percent of the screened group and 16 percent of the control group with screening thereby reducing the rate of CRC by 62 percent in the screened group. In those who tested positive for a mutation, CRC rates were 18 percent in the screened group vs. 41 percent in the control group. Most importantly, CRC detected in the screened group consisted of local disease not associated with death. The authors conclude that colonoscopic screening for individuals at risk for HNPCC can reduce their risk of CRC by 50 percent, prevent death associated with CRC, and decrease mortality by up to 65 percent. It remains to be determined if colonoscopic surveillance programs every 3 years will be the optimal frequency or if shorter intervals will further improve both morbidity and mortality.
7 Genome expression reveals origin of Reed-Sternberg cell (November 17)
Using advanced genomic techniques, researchers from Georgetown University, Human Genome Sciences Inc, and the National Cancer Institute have demonstrated that the Reed-Sternberg (R-S) cell the pathognomonic feature of Hodgkin's disease, has a B-cell origin. The article is published in the July 15 issue of Blood. Evidence collected over the past several years has suggested a B-cell origin for the Reed-Sternberg cell, primarily the finding of rearranged immunoglobulin genes among R-S cells. However, the R-S cell is very scarce in Hodgkin's tumors, hindering attempts to characterize R-S cell function and to define its origins. In the Blood study, researches prepared distinct cDNA expression libraries from Hodgkin's derived cell lines, germinal center B-cells, dendritic cells, and R-S cells. For the R-S cells, cDNA was prepared from single viable cells, isolated by using advanced optical and isolation devices. The cDNA libraries were sequenced using automated seguencing techniques. The first result was the identification of more than 27,000 ESTs (expressed sequence tags, or single gene identifier sequences) from Hodgkin's disease sources. Of these ESTs, 2666 represented genes already present in genome databases. Previously, only 100 named genes had been identified as expressed in Hodgkin's disease. In general, the researchers found that preparations from single R-S cells had gene expression panels very similar to those identified through pooled Hodgkin's disease lines and sources, suggesting that their microdissection method gave valid representations of expressed genes in Hodgkin's disease. By comparing the expression of panels of known genes from a variety of different sources, the researchers could infer the cell origin of the R-S cells. As expected for cells derived of B-cell origin, R-S cells express the immunoglobulin genes as well as other B-cell lineage-specific surface proteins, including BL34, B7, CD20, CD80 and NF-B. By way of comparison, there was minimal overlap with genes normally expressed by dendritic cells, including Mac1, CD68, and a variety of chemoattractants such as MCP-4. The technological power of such genomic screens could, in principal, be applied to any malignant cell population or other cell source. As clinicians and pathologists attempt to come to terms with dozens of different surface antigens, and possibly scores of known oncogenes, the prospect of understanding disease using thousands of different genes is at once tantalizing and daunting.
8 Computed tomography/magnetic resonance based volume changes of the primary tumour in patients with prostate cancer with or without androgen deprivation
Lilleby W, Fosa SD, Knutsen BH, Abildgaard A, Skovlund E, Lien H.
Radiother Oncol 2000;57:195-200.

To evaluate changes of the volume of the cancerous prostatic gland during androgen deprivation (AD) started immediately after diagnosis (IAD). Hypothetically, these data would assist the radiotherapist to determine the appropriate duration of pre-radiotherapy downsizing neoadjuvant luteinizing hormone releasing hormone (LHRH) treatment. A second aim was to assess any increase of the prostatic volume during the 1st year of diagnosis in patients who were allocated to a deferred treatment policy (DAD) group, all with T1-3pN1-2M0 prostate cancer, had regular computed tomography/magnetic resonance (CT/MR) examinations during the 1st year after randomization within the EORTC-GU trial 30846. Pre-treatment prostate specific antigen (PSA) values were available in only 12 patients. In the IAD group the prostate gland decreased with significant difference as compared with the DAD patients (P=0.033). As compared with the pre-treatment situation the prostate gland in the IAD group was reduced in size by 18, 35, and 46% at 1,6, and 12 months, respectively. In four of six evaluable IAD patients the prostatic volume continued to shrink after achievement of the nadir PSA level (at 3 months). In three of the 13 DAD patients the prostate volume increased by ~25% during the 1st 3 months after randomization. If neoadjuvant androgen deprivation is applied before local treatment to downsize the volume of the cancerous prostate gland, our limited data suggest that such treatment should last at least 6 months in order to achieve a maximal effect in the majority of patients. In about 1/4 of untreated patients an increase in the prostate volume by~25% may occur within 3 months of diagnosis. If no AD is given, radiotherapy should start within this period.
9 An IL6 promoter polymorphism is associated with a lifetime risk of development of kaposi sarcoma in men infected with human immunodeficiency virus
Foster CB, Lehrnbecher T, Samuels S, Stein S, Mol F, Metcalf JA et al.
Blood 2000;96:2562-7.

Kaposi sarcoma (KS) is an angioproliferative inflammatory condition that occurs commonly in patients infected with human immunodeficiency virus (HIV). Inflammatory cytokines and growth factors promote the development of KS. Because physiologically important cytokine polymorphisms modulate host inflammatory responses, we investigated the association between KS and common regulatory polymorphisms in 5 proinflammatory cytokine genes encoding interleukin (IL) IL-1alpha, IL-1beta, tumor necrosis factor (TNF) alpha, TNF-beta, and IL-6 and in the IL-1 receptor antagonist (IL1RN). Authors also examined the contribution of stromal-derived factor 1 and chemokine receptor 5 (Delta32) polymorphisms to KS development. The population consisted of 115 HIV-infected men with KS and 126 deceased HIV-infected men without KS. The only strong association was observed between an IL6 promoter polymorphism (G-174C) and susceptibility to KS in HIV-infected men (P=.0035). Homozygotes for IL6 allele G, associated with increased IL6 production, were overrepresented among patients with KS (P=.0046), whereas allele C homozygotes were underrepresented (P=.0062). Substantial in vitro evidence indicates that IL-6 contributes to the pathogenesis of KS. Our results show that IL6 promoter genotypes associated with altered gene expression are risk factors for development of KS. Identification of a genetic risk factor for development of KS has important clinical implications for prevention and therapy.
10 Measurement of breast skin viscoelasticity and a pilot study on the potential radioprotective effect of a zinc-based cream
Gorodetsky R, Andriessen A, Polyansky I, Vexler A.
J Wound Care 1999;8:514-8.

Radiation-induced late skin effects were studied in patients with breast cancer in relation to different protocols of fractionated radiotherapy in three different medical centres, in Israel, the UK and the USA. The mechanical properties of skin were evaluated in breasts of healthy volunteers, and non-irradiated and irradiated breasts of patients, using a newly developed viscoelasticity skin analyser (VESA). The increase of the dose of radiation per fraction was found to have more impact on the development of radiation-induced late skin effects than the elevation of the total dose given. In addition, a pilot sutdy on the possible radioprotective effect of external application of a cream containing zinc oxide on radiation-induced early skin changes in patients with breast cancer was initiated. Non-invasive measurement of trace elements and zinc pharmacokinetics in the skin of healthy controls following the application of the zinc oxide cream were performed by unique diagnostic X-ray spectrometry (DXS). Application of the cream, followed by thorough skin cleansing, significantly increased the amount of residual zinc in the skin, but continuous daily treatment did not cause further build-up of the dermal zinc level. The radioprotective effect of the zinc oxide cream on the skin is now being studied.
11 CT-targeted irradiation of the breast and internal mammary lymph nodes using a 5-field technique
Scrimger RA, Connors SG, Halls SB, Starreveld AA.
Int J Radiat Oncol Biol Phys 2000;48:983-9.

The purpose was to develop an effective and resource-efficient radiotherapy technique to treat the breast and regional nodes, including the ipsilateral internal mammary nodes. Eighty female patients who underwent MRI scans for a variety of indications had coronal, T1-weighted images of the chest performed to determine the position of the internal mammary chain (IMC). Based on these results, a 5-field treatment technique was developed that would include the breast, supraclavicular fossa, and ipsilateral IMC, while maintaining a low dose to the heart, lungs, and contralateral breast. This technique was implemented in a cohort of 13 patients. The lateral position of the right and left IMC were measured in three cephalo-caudad positions: at the clavicular heads, upper manubrium, and midsternum (at the 2nd/3rd rib interspace). The mean lateral separation between the right and left IMC chains at each level (and 95% confidence interval) at each level were 5.8 cm (4.67-7.00), 5.6 cm (4.49-6.73), and 5.9 cm (4.66-7.19), respectively. Treatment was delivered to 13 patients using a 5-field technique, with tangential photon fields for the breast, anterior and posterior supraclavicular/axillary field, and a matching anterior electron field. Three-dimensional treatment planning of a representative case confirmed adequate coverage of the planning target volume (PTV). The median dose to the whole heart was 10 Gy, and 20% of the ipsilateral lung received more than 20Gy. Seven of the 13 patients treated experienced moist desquamation at the junction of the electron field and breast tangents, and 1 patient had persistent ulceration at 3 months“ follow-up. The 5-field technique described in this paper provides good coverage to the breast and regional nodes with acceptable toxicy, and without requiring three-dimensional treatment planning or intensity-modulated radiotherapy techniques.
12 Preliminary analysis of a randomized clinical trial of adjuvant postoperative RT vs. postoperative RT plus 5-FU and levamisole in patients with TNM stage II-III resectable rectal cancer
Cafiero F, Gipponi M, Peressini A, Bertoglio S, Lionetto R.
J Surg Oncol 2000;75:80-8.

Two-hundred eighteen patients with TNM stage II-III resectable rectal cancer, enrolled into a randomized clinical trial, were assessed for efficacy and toxicity of adjuvant postoperative radiation therapy (RT) vs. those of combined RT and chemotherapy (CT), with 5-fluorouracil (5-FU) plus levamisole. End points were overall survival, disease-free survival, the rate of loco-regional recurrence, and treatment-related toxicity. Patients in arm I underwent RT (50Gy) in daily fractions of 2 Gy, 5 days/week for 5 weeks. Patients in arm II began with 5-FU (450 mg/m(2)/day intravenous bolus, days 1-5) plus levamisole (150 mg/day orally, days 1-3); postoperative RT was delivered during week 2 at the same dosage and schedule as in arm I. The other five cycles of CT (5-FU every 28 days and levamisole every 15 days for the length of 5-FU administration) continued after the end of RT if clinical and hemato-biochemical parameters were normal. RT was completed or modified in 170 (90%) of 189 evaluable patients undergoing RT (both treatment groups). Only 44 (59%) of 75 evaluable patients of arm II completed or had an adjustment of the CT schedule; the remaining 31 patients (41%) had to stop or never started the CT regimen. Patients undergoing combined RT and CT had more severe toxicity (enteritis, P=0.03). There was one CT-related death (gastrointestinal bleeding) in this subset. No significant difference was observed in outcome of patients in the two study groups, nor for pattern of recurrence (heterogeneity chi (2)=4.82; d.f.=2; P=0.08). These preliminary findings suggest a similar efficacy, coupled with less morbidity, of postoperative RT alone compared with a combined regimen of postoperative RT and CT in patients undergoing radical surgery for stage II-III rectal cancer.
13 A common variant in BRCA2 is associated with both breast cancer risk and prenatal viability
Healey SC, Dunning AM, Teare MD, Chase D, Parker L, Burn J et al.
Nature Genetics 2000;26:362-4.

Inherited mutations in the gene BRCA2 predispose carriers to early onset breast cancer, but such mutations account for fewer than 2% of all cases in East Anglia. It is likely that low penetrance alleles explain the greater part of inherited susceptibility to breast cancer; polymorphic variants in strongly predisposing genes, such as BRCA2, are candidates for this role. BRCA2 is thought to be involved in DNA double strand break-repair 1,2. Few mice in which Brca2 is truncated survive to birth; of those that do, most are male, smaller than their normal littermates and have high cancer incidence 3,4. Here we show that a common human polymorphism (N372H) in exon 10 of BRCA2 confers an increased risk of breast cancer: the HH homozygotes have a 1.31-fold (95% Cl, 1.07-1.61) greater risk than the NN group. Moreover, in normal female controls of all ages there is a significant deficiency of homozygotes compared with that expected from Hardy-Weinberg equlibrium, whereas in males there is an excess of homozygotes: the HH group has an estimated fitness of 0.82 in females and 1.38 in males. Therefore, this variant of BRCA2 appears also to affect fetal survival in a sex-dependent manner.
14 Obesity and hypertension independently linked to risk of kidney cancer in men
Reuters Medical News (November 17)
WESTPORT, CT (Reuters Health) Nov 2 - A new prospective study confirms that high body-mass index and elevated blood pressure independently increase the long-term risk of renal-cell cancer in men, according to a report in the November 2nd issue of the New England Journal of Medicine. "Previous studies have shown that obesity and hypertension may increase the risk of renal-cell cancer", Dr. Wong-Ho Chow from the National Cancer Institute, Bethesda, Maryland, told Reuters Health. The advantage of this study, she said, is that they had actual measurements of hypertension and higher body weight, so they could look at the dose-response relationship in a more precise manner. Dr. Chow noted the prospective design of their study, which included baseline measurements of body-weight and blood pressure. They also followed the subjects for cancer incidence, not cancer mortality, for an average of 16 years. "As opposed to other studies, in this study, subject self-reporting does not bias the information", she added. Dr. Chow and an international team collected data on 363,992 Swedish men who underwent physical examination from 1971 to 1992. These subjects were followed until the end of 1995 or death. Using the Swedish Cancer Registry, the researcher identified 759 cases of renal-cell cancer and 136 cases of renal-pelvis cancer in this cohort. After adjusting the data for other risk factors, the investigators found that "compared with men in the lowest three eighths of the cohort for body-mass index, men in the middle three eighths had a 30% to 60% greater risk of renal-cell cancer, and men in the highest two eighths had nearly double the risk". In addition, they found "a direct association between higher blood pressures and a higher risk of renal-cell cancer". However, thy did not observe any association between blood pressure or obesity and renal-pelvis cancer. Dr Chow told Reuters Health that it seems that regardless of the level of blood pressure or body-weight at baseline, if blood pressure goes up, the risk of renal-cell cancer goes up, or if weight increases, the risk increases. "We also have a suggestion that if a patient's blood pressure is reduced, it may reduce the risk of renal-cell cancer". Dr. Chow noted that no one really knows exactly what the mechanism for this association is, "but hypertension is so insidious it can cause all kinds of damage to the kidney and it could make the kidney more susceptible to other carcinogens", she explained. In terms of obesity, Dr. Chow said, obese patients have higher levels of growth factors, which may be related to an increased risk of cancer. "We have pretty much confirmed the relationship between obesity and hypertension and the risk of renal-cell cancer, which were not widely known before", Dr Chow concluded. "I think physicians should advise their patients that reducing the risk of renal-cell cancer is one more benefit of controlling weight and blood pressure", she added.
15 The farnesyl protein transferase inhibitor SCH66336 synergizes with taxanes in vitro and enhances their antitumor activity in vivo
Shi B, Yaremko B, Hjian G, Terracina G, Bishop WR, Liu M et al.
Cancer Chemother Pharmacol 2000;46:387-93.

SCH66336 is an orally active, farnesyl protein transferase inhibitor. SCH66336 inhibits ras farnesylation in tumor cells and suppresses tumor growth in human xenograft and transgenic mouse cancer models in vivo. The taxanes, paclitaxel (Taxol) and docetaxel (Taxotere) block cell mitosis by enhancing polymerization of tubulin monomers into stabilized microtubule bundles, resulting in apoptosis. We hypothesized that anticancer combination therapy with SCH66336 and taxanes would be more efficacious than single drug therapy. We tested the efficacy of SCH66336 and taxanes when used in combination against tumor cell proliferation in vitro, against NCI-H460 human lung tumor xenografts in nude mice, and against mammary tumors in wap-ras transgenic mice. SCH66336 synergized with paclitaxel in 10 out of 11 tumor cells lines originating from breast, colon, lung, ovary, prostate, and pancreas. SCH66336 also synergized with docetaxel in four out of five cell lines tested. In the NCI-H460 lung cancer xenograft model, oral SCH66336 (20 mg/kg twice daily for 14 days) and intraperitoneal paclitaxel (5 mg/kg once daily for 4 days) caused a tumor growth inhibition of 56% by day 7 and 65% by day 14 compared to paclitaxel alone. Male transgenic mice of the wap-ras/F substrain»FVB/N-TgN(WapHRAS)69LlnYSJL1 spontaneously develop mammary tumors at 6-9 weeks of age which have been previously shown to be resistant to paclitaxel. Paclitaxel resistance was confirmed in the present study, while SCH66336 inhibited growth of these tumors. Most importantly, SCH66336 was able to sensitize wap-ras/F mammary tumors to paclitaxel chemotherapy. Clinical investigation of combination therapy using SCH66336 and taxanes in cancer patients is warranted. Further, SCH66336 may be useful for sensitizing paclitaxel-resistant tumors to taxane treatment.
16 Placebo-controlled trials needed for interferon alpha treatment of cutaneous melanoma
Reuters Medical News (November 17)
WESTPORT, CT (Reuters Health) Oct 26 - Because of significant toxicities and financial costs of interferon therapy, New York-based researchers do not endorse interferon alpha as the standard of care for melanomas, at least "until the results of randomized, placebo-controlled trials evaluating the survival advantages of interferon alpha for melanoma become available". In a report in the October issue of the Journal of the American Academy of Dermatology, Drs. Arash Kimyai-Asadi and Adil Usman of The New York University School of Medicine, summarized the findings of randomized trials of interferons for melanoma. None of the trials reviewed included a placebo group, the investigators report. Four of the studies failed to show any statistically significant overall survival benefit in patients receiving interferon compared with those receiving only observation. One study, the researchers note, found no survival benefit of interferon alpha. There was, however, a statistically increased disease-free survival in patients with melanoma thicker than 1.5 mm who were randomized to interferon alpha or to observation alone. Another study comparing patients who received interferon alpha with those who were only observed showed a decreased rate of metastases in patients who received interferon alpha, they add. A study published in 1996 was the first and only trial to show a statistically significant survival benefit in subjects receiving interferon alpha. Among patients with "melanomas either deeper than 4 mm or with clinically or histologically evident lymph node metastases", statistically significant 0.7-year and 1-year increases in disease-free survival and overall survival, respectively, were observed. "In summary, the randomized trials of interferons for melanoma fail to show an overall survival benefit", they conclude. "Any prolongation in disease-free survival can be explained by the placebo effect, and any such prolongation without a concomitant prolongation in life expectancy is of questionable value in light of the significant toxicities of interferon therapy".
17 Phase I clinical trial of a recombinant canarypoxvirus (ALVAC) vaccine expressing human carcinoembryonic antigen and the B7.1 co-stimulatory molecule
Cassidy J.

The generation of cytotoxic effector T cells requires delivery of two signals, one derived from a specific antigenic epitope and one from a costimulatory molecule. A phase I clinical trial was conducted with a non-replicating canarypoxvirus (ALVAC) constructed to express both human carcinoembryonic antigen (CEA) and the B7.1 costimulatory molecule. This was the first study in cancer patients to determine if the delivery of costimulation with a tumor vaccine was feasible and improved immune responses. Three cohorts of six patients, each with advanced CEA-expressing adenocarcinomas, were treated with increasing doses of an ALVAC-CEA-B7.1 vaccine (4.5x106, 4.5x107, and 4.5x108 plaque-forming units, PFU). Patients were vaccinated by intramuscular injection every 4 weeks for 3 months and monitored for side-effects, tumor growth and anti-CEA immune responses. ALVAC-CEA-B7.1 at doses up to 4.5x108 PFU was given without evidence of significant toxicity or autoimmune reactions. Three patients experienced clinically stable disease that correlated with increasing CEA-specific precursor T cells, as shown by in vitro interferon-<Gamma>enzyme-linked immunoassay spot tests (ELISPOT). These three patients underwent repeated vaccination resulting in augmented CEA-specific T cell responses. This study represents the first use of costimulation to enhance antitumor vaccines in cancer patients. This approach resulted in CEA-specific immunity associated with stable diseases in three patients. This study also demonstrated that CEA-specific T cell responses could be sustained by repeated vaccinations. Although the number of patients was small, the addition of B7.1 to virus-based vaccines may improve immunological and stable diseases to vaccination against tumor-associated antigens with tolerable toxicity.

... (from Yugoslavia)
Glas osiguranika 2000;(21):1-2.
The newly elected Serbian Minister of Health, Dr Nada Kostic, has been working at the Clinical Hospital Center "Dr Dragisa Misovic" since 1984. She specialized in endocrinology. She says that she sees her life, first of all filled with her work with patients but also with giving lectures to students of the Faculty of Medicine. She is supposed to change her title of a docent into the title of a professor, soon, according to the regulations of law.

19 ... (from Yugoslavia)
Glas osiguranika 2000;(21):1-2.
According to the words of Nebojsa Janovski, who is the coordinator for health within the G17 Plus, which is the non-governmental expert organization, whose members are chosen according to the criteria of expertise and ethical behaviour, this organization and the Independent syndicate of doctors and pharmacists of Serbia have joined their mutual efforts for doing the some job. During the first phase, the situation in the health system was analyzed, the second phase implies a search for the urgent solutions, which would lead to the improvement of the current situation in the health system, while the third phase is characterized by the long-term projects. Among others, the urgent solutions consider the acceptance of the humanitarian aid. The problem are also the medications, which, as was emphasized by Janovski, come at the end of the medical procedure, as well as the importance of the diagnostic processes. The diagnosing is a specific problem - many health facilities are short on the equipment: the chemicals or the key apparatuses, which causes the enormous crowds in the health care centers, insisting in the hospitalized treatment, which is, again, very expensive, etc.
G17 Plus, tries to point out the basic problems, and as we are facing the limited material possibilities, the need for saving and economical use of goods was emphasized.
The qualitative health protection can be expected only after the process of "healing" of the health system itself.
Books Received
Meetings and Congress Reports
Medical and Scientific Meetings
  Volume 7 Issue 1
1 Hepatocellular carcinoma (HCC) is a common tumor world-wide with extremely poor prognosis. Recent studies have shown that inositol hexaphosphate (IP6), a naturally occurring carbohydrate, has novel anti-cancer function in various in vitro and in vivo models. The aim of this study was to assess whether IP6 could inhibit the growth of human hepatocellular carcinoma. We treated HepG2, a human liver cancer cell line in vitro with IP6 and evaluated its effect on growth and differentiation. IP6 treatment of HepG2 cells caused a dosedependent growth inhibition. Compared to other cancer cell lines, HepG2 cells were quite sensitive to IP6 IC50 (50% inhibition of cell growth) of IP6 being <1.0 mM (0.338 mM). Treatment with IP6 decreased the ability of HepG2 cells to form colonies, as assessed in the plating efficiency assay. Morhpological changes induced by IP6 drastically decreased the rate of production of a-fetoprotein (AFP), a tumor marker of HCC, indicating also that IP6 treatment leads to differentiation of malignant liver cells. Further, IP6 treatment caused a decreased expression of mutant p53 protein in HepG2 cells, with no significant change in the expression of wild-type p53. The expression of p21 WAF1 protein was increased by 1.5 fold, as determined by immunocytochemical staining and ELISA assay. These data demonstrate that IP6 inhibits the growth, and induces differentiation, and a less agressive phenotype of HepG2 cells, suggesting a role of IP6 in the treatment of HCC.
2 99mTc-MIBI retention index quantified from its early and delayed sintigraphy is a good indicator to predict the chemosensitivity of anthracyclines in unterated breast cancer.
3 Metallothionein (MT), acting as an antioxidant and zinc binding protein, may play an important role in regulation of apoptosis. Its differential expression has been documented in various human tumours.The incidence of APC in HCC was markedly higher than that in control liver of adjancent cirrhotic liver. The negative correlation of numbers of APC with MT expression was statistically significant.This investigation is important in understanding the mechanisms of the drug resistance of tumour cells, and may help to design better treatment strategies.
4 Results of the experiments indicate that oltipraz has a dose-dependent inhibitory effect on HBV replication and specifically blocks HBV transcription in 2.2.15 cells. In addition, oltipraz induces endogenous wild-type p53 protein in a dose- and time-course-dependent manner. Taken together, we speculate that the effects of olitpraz against replication of HBV and specific blocking of HBV transcription may be through the induction of p53-mediated pathway in 2.2.15 cells. In addition to its known chemopreventive action on aflatoxin B1 hepatocarcinogenesis, oltipraz was shown here to inhibit HBV replication. These dual effects put oltipraz as the excellent candidate for the chemopreventive agent of human hepatocellular carcinoma.
5 Cyclooxygenease-2 has been reported to play an important role in colorectal carcinogenesis. The effects of meloxicam (a COX-2 inhibitor) on the growth of two colon cancer cell lines that express COX-2 (HCA-7 and Moser-S) and a COX-2 negative cell line (HCT-116) were evaluated. The growth rate of these cells eas measured folowing treatment with meloxicam. HCA-7 and Moser-S colony size were siginificantly reduced following treatment with meloxicam; however, there was no significant change in CHT-116 colony size with treatment. In vivo studies were performed to evaluate the effect of meloxicam on the growth of HCA-7 cells when xenografted into nude mice. We observed a 51% reduction in tumor size after 4 weeks of treatment. Analzsis of COX-1 and COX-2 protein levels in HCA-7 tumor lysates revealed a slight decrease in COX-2 expression levels in tumors taken from mice treated with meloxicam and no detectable COX-1 expression. Here we report that meloxicam significantly inhibited HCA-7 colony and tumor growth but had no effect on the growth of the COX-2 negative HCT-116 cells.
6 The p16 protein is an inhibitor of cyclin-dependent kinase 4 (Cdk4) and is encoded by the multiple tumor-supressor 1 gene, called also MTS1, CDKN2, or p16INK4agene . The tissues were microdetected to enrich tumor cell content of the samples and the isolated genomic DNAs were amplified for CDKN2 gene, exon 1 and 2, resulting into analyzable products of 156 bp, 245 bp and 190 bp. The exon 2 amplification products of 245 bp were screened for point mutations using PCR-SSCP. All samples harvested the studied regions of exon 1 and 2 of the gene and hence no deletions were detected. No mutations in the analyzed 210 bp gene region were observed in the particular patient specimens. These results suggest that mechanisms other than genetic alterations (by transcriptional or post-transcriptional mechanisms)might be important for inactivation of the p16 gene product in late stage metastatic melanoma.
7 The characterization of the genes encoding melanoma-associatioed antigens MART-1 or gp 100, recognized by T cells, has opened new possibilities for the development of immunization strategies for patients with metastatic melanoma. With the use of recombinant adenoviruses expressing either MART-1 or gp100 to immunize patients with metastatic melanoma, we evaluated the safety, immunologic, and potential therapeutic aspects of these immunizations. Recombinant adenoviruses expressing MART-1 or gp100 were safely administred. One of 16 patients with metastatic melanoma receiving the recombinant adenovirus MART-1 alone experienced a complete response. Other patients achieved objective responses, but they had received IL-2 along with an adenovirus, and their responses could be attributed to the cytokine. Immunologic assays showed no consistent immuniyation to the MART-1 or gp100 transgenes expressed by the recombinant adenoviruses. High levels of neturalizing antibody were found in the pretreatment sera of the patients. High doses of recombinant adenoviruses could be safely administered to cancer patients. High levels of neutralizing antibody present in patients“ sera prior to treatment may have impaired the ability of these viruses to immunize patients against melanoma antigens.
8 The relationship between cutaneous malignant melanoma and sunlamp use was examined in a Caucasian population in Connecticut.Study subjects consisted of 624 newly diagnosed cases of first primary invasive cutaneous malignant melanoma and 512 controls.141 (23%) cases and 95 (19%) controls reported ever having used sunlamps. Those who used more than one type of sunlamp had a threefold higher risk for melanoma compared to never users. Subgroup analyses showed that sunlamp use was associated with a greater increase in risk for melanoma among those who used sunlamps at home and those who were first exposed to sunlamps prior to 1971. The first use of sunlamps before the age of 25 showed somewhat higher risk for melanoma compared to first use later in life.
9 A case-control study was performed with 129 cases of colorectal carcinoma in situ and 258 matched controls, in Tokyo from January 1991 to March 1993.
There was a significant, positive association between serum total cholesterol levels and the risk of colorectal carcinoma in situ after adjustment for age, sex, body mass index, smoking status and alcohol consumption.
A modest increase of colorectal carcinoma in situ risk was observed in the highest category (>=116 mg/dl) of fasting plasma glucose levels.
The strong association with serum triglyceride levels and the weak association with fasting plasma glucose levels support the hypothesis that hyperinsulinaemia may play an important role in colorectal carcinogenesis.
10 This study explored the ecologic relationship between pancreatic cancer incidence and measures of cigarette smoking, income, and solid waste collection for Florida‘s 67 counties.
County-specific incidence rates for pancreatic cancer ranged from 0 to 9.1 per 100 000 per year and were significantly correlated with income (r = 0.35), cigarette smoking (r = 0.47). The correlation between pancreatic cancer and solid waste was largely attributable to one sub-component of solid waste, yard trash (grass clippings, and tree and shrub trimming) (r = 0.42).
These data suggest that some factor associated with grass and tree trimmings, e.g. insecticides and herbicides, may increase the risk for pancreatic cancer.
11 The case group comprised 105 patients with newly diagnosed papillary thyroid carcinoma. Of the 2 control groups the first one was recruited among patients with injuries, and the other was composed of patients with polznodose nontoxic goiter. When cases were compared with the first control group, the following factors were significatly related to papillary thyroid cancer: residence at an endemic goiter area, goiter, diagnostic X-rays, other malignant tumors in personal history and malignant tumors in first and second degree relatives. When cases were compared with the second control group, papillary thyroid cancer was related with other primary tumors in personal history and malignant tumors in family members.
12 The discordance rate between clinical and autopsy doagnoses of malignant neoplasms is large. This conclusion is based upon a study of a review of 1105 cases (654 male and 451 female) with a mean age of about 48 years. Four hundred thirty-three neoplasms were detected, 250 of which were malignant. One hundred eleven malignant neoplasms in 100 patients had been either undiagnosed or misdiagnosed. In 57 patients the malignant neoplasm was defined as the direct cause of death. The discordance between clinical and autopsy diagnoses of malignant neoplasms in the study was of 44%. Respiratory and gastrointestinal tract were the most frequently missed or misdiagnosed.
13 These are the results of a large randomized, confirmatory trial which included 1387 patients with metastatic prostate cancer. All had bilateral orchidectomy, 700 were randomly assigned to receive flutamide and 687 received placebo. The use of flutamide did not significantly improve prognosis overall or in a subgroup of patients with minimal disease.
14 In retrospective, non-radnomized study were analyzed 45 patients with local recurrences of rectal carcinoma treated by combined external beam radiotherapy (EBRT) and "High dose rate (HDR) remote afterloading" brachytherapy in the period from January 1st, 1988 to May 1st, 1988. Depending on the localization of the local recurrent disease, 20 patients were with vaginal relapase, 13 with vaginal and presacral, 9 with perineal and 3 with presacral and rectal. Combined radiotherapy was applied as follows: 33 patients (73.3%) had EBRT with endovaginal brachytherapy, 3(6.7%) EBRT plus intraluminal brachytherapy and 9 (20%) patients EBRT plus interstitial brachytherapy. Techniques with 3 and 4 field for EBRT were used and doses ranged 45-65 Gy with conveniet fractionation were applied, combined with the doses ranged 15-35 Gy for brachytherapy. Radiotherapy was planned according to the computer tomography cross image on simulator with computer planning. Complete regression of the tumor was observed in 19 patients (42.2%), and partial in 23 patients (51.1%). Median followup period was 34 months (8-72). Acute radiation adverse effects were registered in 32 patients, and late sequels in 6 (13.3%). Overall 3-year survival rate was 54% and desease-free survival rate was 34% in the same period.
15 Currently there are at leas 22 countries world-wide where national, regional or pilot population-based breast cancer screening programes have been established. The 1990 survey was sent to ten contries in the IBSN-international breast cancer screening Net-Word and was completed by nine countries. The 1995 survey was sent to and completed by the 13 countries in the organization at that time and ad additional nine countries in the European Network. The programmes vary in how they have been organized and have changed from 1990 to 1995.
The most notable change is the increase in the number of countries that have implemented or plan to implement an organized breast cancer screening programme. a second major change is in guidelines with age 50 being the lower age limit recommended for initiation of mammography screening in about two-thirds of countries. The screening interval for women over 50 years of age is 2 years in most contries.
There is much greater variation among countries in the upper age limit for screening, with age 69 set by about half the contries.
Mammography is the dominant detection method; clinical examination of the breast is performed in addition to mammograpy on only eight countries and breast self-examination is added as a third method in four countries.
1 The Society of Physicians of Vojvodina has made a decision to start an informative journal "VOX MEDICORUM". Being a physician, you can fully perceive health problems and problems of our profession, so you are kindly asked to write your opinions, attitudes and viewpoints in regard to them in our informative journal. In this way you have an opportunity to turn to the auditorium of 5000 physicians in Vojvodina who will most certainly welcome your ideas, wellintentioned suggestions and useful advice. Please be so kind to write your suggestions considering the profile of our journal as well as possibility of your financial support. Expecting your letters, thank you in advance.
Vox Medicorum 1999;1:3.
2 Platform of the Assembly of the Medical Society of Serbia E Society of Physicians of Vojvodina
The Assembly of the MSS-SPV. The Platform consists of items as follows:
1. It is necessary to solve the material status of the health care system as well as the position of health workers.
2. The Medical Society of Serbia has to be an influential and relevant partner to Ministry of Health in creating strategy and realization of vital measures in providing health care for all.
3. It is necessary to derogate the present bylaw and other acts which regulate activities of the Medical Association of Serbia and pass the law on Medical Association according to suggestions of MSS, whereas till the beginning of work of Medical Association or in case it stops working, MSS is obliged to take its activities in accordance with the law.
4. Respect only professional and scientific competence when selecting persons for managerial positions in health institutions.
5. Obtain full publicity of activities, principles and ways of acquiring health insurance money and of financial distribution.
6. Absolute respect of ethical and moral principles in medicine and condemnation of all who have violated them recently.
7. Respect for the autonomy of the University and request for full democratization of the society.
8. MSS-SPV has not been fully informed by MSS and it has not respected requests of MSS-SPV, so in the future we expect members of MSS-SPV to be regularly, timely and adequately informed on activities and events in MSS and gain timely responses on their requests.
Vox Medicorum 1999;1:5.
3 Vice-president of the Executive Council of Vojvodina, Prof. Dr. Pavle Budakov and Provincial Secretary of Health, Prof. Dr. Dragoljub Zoricic made an official visit to the Institute of Oncology, that is Center of Diagnostic Imaging, on January 21, 1999. On this occasion they were introduced with the new diagnostic equipment: Computerized Tomograph (CT) and a new ultrasonography apparatus and had a conversation with the director of the Institute and manager of the Center of Diagnostic Imaging. The guests were informed about the 4-year achievements of the magnetic resonance imaging, as well as with the first results achieved after purchasing a new scanner. It has been stated that our patients are mostly from Vojvodina, especially from Novi Sad where these highly specialized institutions are localized, and that problems the Center of Diagnostic Imaging faces are mostly financial due to irregular payments of their services. The esteemed guests were pleased that such an outstanding diagnostic center was founded in Vojvodina and on this occasion promised support in further development of th is Center, as well as improvement of entire health care system in Vojvodina.
Mladen Prvulovic
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  Issue 2
1 The study group comprised 170 patients with colorectal carcinoma who had been opereted in Bydgoszcz (Poland) between 1994 and 1997. Prior to surgical intervention, all patients submitted a through history concerning familial colorectal cancer or other neoplasms. Group I - families with HNPCC features (heredetary non-polyposis colorectal cancer; group II - HNPCC suspicion in the family; group III - sporadic colorectal cancer cases - singular colorectal cancer cases in the family. Authors noted 4 families complying with ICG-HNPCC criteria (2.4%) and 21 families with suspicion of HNPCC (12.3%). The remaining 145 patients (85.3%) presented with sporadic colorectal cancer cases. The results demonstrate, that nearly 15% of colorectal cancer patients operated upon in our clinic are of familial origin. The percentage of families with HNPCC amounts 2.4%.
2 Agw-adjusted liver cancer mortality rates have been increasing for both men and women in Japan since 1970: however, increases in mortality rates in men are much greater than those in women. Alcohol consumption is more important than hepatitis C virus infections as a major cause of liver cancer deaths in Japanese men.
3 In surveys done by International Psycho-Oncology Society a decade apart in 1986 and 1996, the frequency of revealing the diagnosis of cancer to the patients varies from less than 25% in several countries, and up to 90% in countries such as the US. However, orrespective of cultural factors, oncologists must often give bad news and do it in the most kind and sensitive way. It is more important how bad news is given than the words that are actually used.
4 Authors examined the influence of tumor stage on the circulating levels of Vascular Endothelial Growth Factor (VEGF) in sera from breast cancer patients. Thirty women with breast cancer who were studied did not receive any prior therapy. In patients with stage IV breast cancer there was a significant increase in VEGF levels compared to stage II disease. The study suggests that large tumor burden was associated with significantly increased serum levels of VEGF.
5 Changes over time of mortality rates from cutaneous malignant melanoma (CMM) in Belgium were analysed, based on people (n=3695) aged 25-84 years, who died of CMM from 1954 to 1992. The age-adjusted mortality rates (per 10 5 ) for the age sroup 25-84 years old increased from 0.5 in 1954 to 3.0 in 1992 in men, and from 0.8 in 1954 to 2.2 in 1992 in women. The average annual percentage change in men (-0.003%) was stable over the period 1973-1982, and increased to 4.4% over the period 1983-1992. In women, the average annual increase was 4.6% over the period 1973-1982, and continued to increase to 6.8% over the period 1983-1992.
6 Three cases of women with chronic liver inflammation caused by hepatitis B (two) and C (one) viral infections, were followed up to twelve years after diagnosis. As conventional therapy was ineffective and the patients progressed into decompensated liver disease, they superinfected with massive doses of an attenuated variant (MTH-68/B) of the apathogenic avian Bursal Disease virus. Clinical symptoms and biochemical abnormalities were resolved in two patients. Cirrhosis was stabilized and significant clinical improvement was achieved in the third patient - who before the virus therapy was moribund.
7 The angiogenic factors Platelet Derived Endothelial Cell Growth Factor (PD-ECGF), basic Fibroblast Growth Factor (bFGF) and Vascular Endothelial Growth Factor (VEGF) were determined immunohistochemically in 168 non-small cell lung carcinomas to investigate whether the expression of these parameters is correlated with lymph node metastasis of patients. Only 43% of the patients had lymph node involvement when all factors were negative whereas 77% showed metastasis when all factors were positive (one factor positive: 53%, two factors positive: 68).
8 Growth factor-stimulated phospholipase D (PLD) catalyzes the hydrolysis of phosphatidycholine generating phosphaditic acid which may act as a second messenger during cell proliferation. Authors measured PLD activity in human gastric carcinoma to evaluate its role in gastric carcinogenesis. The mean ratio of PLD activity in gastric carcinoma and adjacent noncancerous mucosa was 1.63. This ratio was significantly higher in patients with larger tumors (>=5cm).
9 Sixty nine patients with urogenital cancers (renal, bladder and prostate cancer) were studied to determine whether the serum concentrations of Vascular Endothelial Growth Factor (VEGF) and basic Fibroblast Growth Factor (b-FGF) reflected the status of the patients and/or the prognosis of the disease. Renal cell carcinoma patients expressed the highest levels of VEGF indicating that these tumors are more VEGF dependent. The values of b-FGF could be considered normal in all three malignancies. No correlation was observed between the expression of VEGF and b-FGF, nor between VEGF and b-FGF and patients survival.
10 New drugs registrations adopted up to June 30, 1998. List of drugs with the permition for usage of the Federal Ministry for Work, health and Social Welfare up to June 30, 1998:
- cytostatic antibiotics: Daunorubicin-Hlorid and Darubicin;
- other drugs for neoplasm therapy: Irinotekan.
11 Besides anatomically-based radiodiagnostics, functional imaging may be used for characterizing soft tissue sarcomas (STS). This study evaluates positron emission tomography (PET) with three different radiotracers (fluorine-18 deoxyglucose (FDG), carbon-11 aminoisobutyric acid <sup>a</sup>AIB<sup>o</sup> and oxygen-15-labeled water <sup>a</sup>015-water<sup>o</sup>) for imaging STS and the detection of local recurrence.....Besides FDG, AIB and 015-water were shown to accumulate in primary and recurrent STS of different histologic type. A precise differentiation from normal muscle was found for all tracers. FDG and AIB differentiated biable tumor from blood vessels. PET using FDG, AiB and 015-water is suitable for functional imaging of STS and the detection of sarcoma recurrence.
12 This study evaluates the tolerance and efficacy of Intraperitoneal Chemohyperthermia (IPCH) with Mitomycin C (MMC) associated with surgery, in peritoneal carcinomatosis of gastric origin....IPCH appears as a safe new therapeutic approach in gastric cancers with peritoneal carcinomatosis with small malignant granulations (stage 1 and 2) and randomized trials are now needed to clearly evaluate its efficacy.
13 Several studies have evidenced that IGF-I may play a role in the growth regulation of many cancer cell lines, and recently GH and IGF-1 have been recognized as stimulators of lymphopoiesis and immune function. We investigated whether there are differences among health-old people and old people suffering from lung cancer at different stages of disease in the 24-hour secretory profiles of GH und iGF-1....Lung cancer is associated with an altered regulation of GH-IGF-1 system, that might play a role in the clinical course of neoplastic disease.
14 Serum concentrations of tumor necrosis factor-a (TNF-a), interleukin (IL)-1b, IL-2 and IL-6 were determined by enzyme-linked immunosorbent assay or chemiluminescent enzyme immunoassay in 46 Japanese patients with metastatic breast cancer....These results suggest that IL-6 levels are elevated and may be an aggressive parameter in patients with metastatic breast cancer. Higher IL-6 serum levels are found to predict a poorer response to chemo-endocrine therapy, and to represent a poorer prognostic predictor in metastatic breast cancer.
15 Advanced ovarian carcinoma is a chemosensitive tumor, but its prognosis is poor with 20 to 30% 5-year survival using conventional therapy. increasing doses of chemotherapy might improve the prognosis because of the doseeffect....Toxicity of HDC with HSCS is acceptable for poor-prognosis patients. In the long term, this therapy is not beneficial for chemotherapy refractory patients, despite objective response rates better than the conventional treatment, confirming the dose effect for alkylating agents in ovarian cancer. On the other hand, the results seem better than classical therapy in case of chemosensitive disease and should be confirmed prospectively in a larger cohort of patients.
16 In patients with H. pylori infection and noulcer, of functional, dyspepsia, treatment with omeprazole and antibiotics to eradicate the infection is more likely to resolve symptoms than treatment with omeprazole alone. These are the results of a randomized, placebocontrolled trial comparing the efficacy of treatment for two weeks with 20 mg of omeprazole orally twice daily, 500 mg of amoxicillin three times daily (with 500 mg of tetracycline three times daily substituted for amoxicillin in patients allergic to penicillin), and 400 mg of metronidazole three times daily (160 patients) with that of omeprazole alone (158 patients) for resolving symptoms of dyspepsia in patients with H. pylori infection but no evidence of ulcer disease on upper gastrointestinal endoscopy. One month after the completion of treatment, 132 of 150 patients (88%) in the group assigned to receive omeprazole and antibiotics tested negative for H. pylori as compared with 7 of 152 (5%) in the omeprazole-alone group. One year later, dyspepsia had resolved in 33 of 154 patients (21%) in the omeprazole and antibiotics group, as compared with 11 of 154 (7%) in the omeprazole-alone group (95% Cl: 7%-22%; p<0.001).
....preoperative chemotherapy with a combination of cisplatin and fluorouracil does not improve overall survival among patients with epidermoid cancer or adenocarcinoma of the esophagus.
17 The loss of DNA mismatch repair system was reported in hereditary non-poliposis colon cancer and in other tumours. The aim of this study was to detect the protein expression pattern of hMSH2 and hMLH1 in oral squamous cell carcinoma (SCC) by immunohistochemistry in paraffin-embedded tissues.....These data suggest that examination of hMSH2 and hMLH1 protein expression by immunohistochemistry is important in oral SCC. The analysis of mismatches expression in these cases of oral SCC might suggest that an absent nuclear staining for both hMSH2 and hML1 could constitute a hallmark of potential phenotype mutator for this type of neoplasia.
18 Recent evidence supports the involvement of integrins in angiogenesis: blockade of avb5 integrins disrupts angiogenesis leading to decreased blood vessel formation and hence decreased tumor growth. We hypothesized that av antagonistis could inhibit tumor growth in tumor cells devoid of avb3 integrins. We evaluated SM256 and SD983, novel small molecules that are specific av antagonistis in mouse models of angiogenesis and tumorigenesis, and compared them with standards....In the mouse xenograft model, usng human colon carcinoma RKO cells that do not express avb3 but express avb5, tumor growth was inhibited by SG 545 (10 mg/kg/day) and flavopiridol (5 mg/kg/every other day) 40% and 70%, respectively (p`0.05). Although the proliferative index (measured by BrdU incorporation) was not significantly changed with SM 256, SG545 or flavopiridol (29-32%), the apoptotic index increased significantly (p<0.05) in the SM 256 and SG545-treated groups (2.3-2.7%) compared with controls (1,1%), suggesting increased cell death contributed to decreased tumor volumes. Neovascularization decreased with SM 256 and SG 545 treatment. The data demonstrate that potent selective av antagonists can target endothelial cells, tumor cells, inhibit angiogenesis and inhibit tumor growth.
19 Topoisomerase I (topo I) inhibitors are promising anticancer agents with demonstrated activity against a wide range of solid tumors. Quantitative information on topol mRNA levels in tumor bi9psies may predict response to topo I inhibitors....We conclude that topol PATTY is a new assay tat quantitates topol mRNA levels in cell lines and small tumor samples.
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  Issue 3
1 Twenty four patients with 38 skin lesions were treated. The patients were divided in 3 groups: 16 patients with T1N0M0 basal cell carcinoma (group A); 4 patients with T1N0M0 spin-squamous cell carcinoma (group B); and 4 patients with disseminated malignant melanoma (group C). Local injection of lidocaine and 0.5 to 1.5 U bleomycin into the tumor was followed by application of 3 types of electrical stimuli. All patients of group A and group B responded positively to the treatment. Three group C patients had a positive response with a virtual disappearance of the metastatic nodules, while in the 4th patient persistent tumor was histologically confirmed.
2 Among 417 patients with DTC treated between 1980-1997, 31 cases (7.5%) have died from cancer, living 1-10 years (mean 3,3 ±1.8). We compared the main prognostic factors related to the tumor, host, and treatment modalities in the lethal group (LG) and the surviving group (AG) of patients. Age and sex appear to be significant prognostic factors (p=0.00001). Locally advanced (68%) and metastatic cases (26%) predominated in the LG (p=0.007 and p=0.03 respectively). Thyroidectomy was the surgical treatment of choice, but in 2/3 of the LG tumor was macroscopically left behind (p=0.00001). Therefore, more patients from the LG required aggressive primary radiation therapy (RT) i.e. external beam (EBRT) and prolonged 131I RT (RIOT) (p=0.007 and p=0.024 respectively). These patients had mainly G1-G3 papillary tumors. The vast majority of the LG cases (24/31) showed perisistent disease. Finally 29 of 31 patients in the LG developed distant metastases. Although the difference was not significant, cancer specific mortality (CSM) was 4% (14 patients) for papillary cancer, 14% for 12 follicular cancer and 16% for 5 low differentiated cases. Our study revealed that persistent disease was the main reason for death from DTC (78%, p=0.006). We believe that aggressive primary treatment plays a central role for the final disease outcome. The percentage of 7,5% CSM in DTC aligns our results with those of other investigators. Although the current, treatment for DTC is efficient, still the "magic bullet", 131I, misses its target in some patients. Future research in tumour molecular biology and patients“ genetics are required to demarcate those cases bearing lethal potential.
3 Ongoing protocols
1. IELSG 1: Retrospective evaluation of low-grade MALT lymphoma primarily arising at non-gastric sites. Registered patients: 267. The accrual should be completed later 31 May 1999. Chairmen. Enrico Roggero and Emanuele Zucca.
2. IELSG 3: Randomized trial of observation vs. chlorambucil after anti-Helicobacter pylori therapy in low-grade gastric lymphoma. This UKLG, IELSG and GELA trial is the first randomized study to assess treatment in this disease. The recruitment is excellent (180 cases december 1998) and the accrual continues.
3. IELSG 4: Prospective randomized trial of chemotherapy vs. chemotherapy plus irradiation in diffuse large-cell gastric lymphoma. Chairmen: Giovanni Martinelli and Carlo Tondini.
New protocols
1. IELSG 5: Retrospective evaluation of primary testicular lymphomas. Chairmen: Mary Gospodarowicz, Tariq Mughal and Umberto Vitolo.
2. IELSG 6: A randomized trial to determine the effect of consolidation with Rituximab (IDEX C2B8-Mabthera/Rituxan) in patients with CD 20 + marginal zone lymphomas who have received induction therapy. Chairmen: Catherine Thieblemon, Enrico Roggero.
3. IELSG 7: Retrspective evaluation of Central Nervous System lymphomas. Chairmen: J. Y. Blay and Andre“s Ferreri.
4. IELSG 8: retrospective evaluation of intestinal lymphomas. Chairmen: Sergio Cortelazzo and Carlo Tondini.
5. IELSG 9: Retrospective evaluation of primary mediastinal large B-cell lymphomas. Chairmen: Pier Luigi Zinzani, Maurizio Martelli and Marilena Bertini.
During the next IELSG meeting that will take place in Lugano in June 1999 before the Lymphoma Conference, these protocols will be presented and discussed. Oncology centers intersted in these trials can contact the IELSG.
International Extranodal Lymphoma Study group Trials centre coordination: Oncology Institute of Southern Switzerland Ospedale San Giovanni CH-6500 Bellinzona - Switzerland Tel.: +41 91 820 91 11, Fax: +41 91 820 91 82, E-mail:
4 Differential polymerase chain reaction (DPCR) is a sensitive technique for detecting c-erb-B2 amplification in Mullerian-derived tumours. Of 25 Mullerian-derived tumours, 17 demonstrated amplified c-erb-B2 by DPCR. The reexamination of 25 samples by dot blot and immunohistochemical technique revealed c-erb-B2 amplification and expression of 52.0 and 40.0%, respectively. The relationship between the amplification of c-erb-B2 and common prognostic factors such as grading, stage and survival showed that moderately and poorly-differentiated tumours of grades 2 and 3, respectively, had a much higher percentage (68%) of amplified c-erb-B2 gene than well-differentiated tumours (40%).
5 Preoperative chemotherapy with a combination of cisplatin and fluorouracil does not improve overall survival among patients with epidermoid cancer of adenocarcinoma of the esophagus.
6 Platinum-based treatment of ovarian cancer increases the risk of secondary leukemia. This is the conclusion of a case-control study of secondary leukemia in a population-based cohort of 28,971 women in North America and Europe who had been diagnosed with invasive ovarian cancer between 1980 and 1993. The relative risk of leukemia was 4.0 (95% confidence interval (95%Cl):1.4-11.4). The relative risks for treatment with carboplatin and for treatment with cisplatin were 6.5(95%Cl.1.2-36.6) and 3.3 (95%Cl:1.1-9.4), respectively. The authors found evidence of a dose-response relation, with relative risks reaching 7.6 at doses of 1000 mg or more of platinum (p for trend 0.001). Radiotherapy without chemotherapy (median dose 18.4 Gy) did not increase the risk of leukemia. The substantial benefit that platinum-based treatament offers patients with advanced disease outweighs the relatively small excess risk of leukemia, the authors say.
7 The authors conclude that the familial occurrence in about 6% of cases of papillary thyroid microcarcinoma is associated with an unfavourable prognosis, and suggest a more radical treatment (and careful follow-up) than for those with no positive family history.
8 Mycoplasma contamination of cell cultures is a frequently observed problem. Authors addressed the question of whether mycoplasma contamination affects the most frequently used cytotoxicity assay, the tetrazolium based MTT assay.They contaminated C6 glioma cells with mycoplasma and performed MTT assays with doxorubicin, vincristine, etoposide and cisplatinum under various conditions. Due to an additional reduction of tetrazolium by mycoplasmas, contaminated cells appeared up to 15 fold resistant to doxorubicin, vincristine and etoposide, but not to cisplatinum. Differences decreased with decreasing drug doses and decreasing plated cell count.
9 Data were analysed from a large case-control study (583 cases, 608 controls) of malignant melanoma, carried out in southern Ontario, Canada. Significant risk increases were identified with several measures of intermittent exposure, including beach vacations in adolescence and in the past 5 years, previous sunburn, and use of sunbeds and sunlamps. Chronic exposure, indicated by days of outdoor activity during adolescence and by occupation in recent adult life, was associated with significantly reduced risk. Subgroup analyses showed: no major risk differences by body site of melanoma; stronger association of lentigo maligna melanoma with intermittent exposure, more pronounced effects of beach vacations and sunburn in younger subjects, and consistently higher risks for intermittent exposures among subjects with skin more susceptible to burning.
10 Blood cells of cancer patients contain greatly elevated amounts of vascular endothelial growth factor (VEGF), and this reservoir may have a role in tumor angiogenesis and metastasis formation. These are the results of an analysis of VEGF concentrations in serum, plasma, whole blook, and peripheral blook mononuclear cells (PBMNCs) and platelets in 56 cancer patients and 52 healthy controls. The VEGF concentrations in the lysed whole blook samples were higher in cancer patients than in healthy controls (median, 464 vs. 298 pg/ml;P 0.0001). The highest Blook-VEGF values were found in disseminated cancer. The cancer patients regularly had higher Blood -VEGF concentrations than heallty individuals with comparable leukocyte or platelet counts. VEGF content of isolated pBMNCs and platelets was several times higher in cancer patients than in healthy controls. Very little or no VEGF was found in the plasma. The authors conclude that VEGF in the bloodstream is transported by blook cells, including leukocytes and platelets.
11 There is no convincing evidence that eradication of H. pylori relieves the symptoms of functional dyspepsia. This is the conclusion of a multicentre randomised duoble blind placebo controlled trial in Australia.278 patients infected with H. pylori who had functional dyspepsia were randomised to receive omeprazole 20 mg twice daily, amoxicillin 1000 mg twice daily, and clarithromycin 500 mg twice daily or placebo for seven days. H. pylori was eradicated in 113 patients (85%) in the treatment group and 6 patients (4%) in the placebo group. At the 12 months follow-up there was no significant difference betwen patients trated successfully (by intent to treat) in the eradication arm (24%, 94% Cl: 17%-32%) and patients treated successfully in the placebo group (22%, 15%-30%). Changes in symptom scores and quality of life did not significantly differ betwen the treatment and placebo groups.
12 Rituximab is a chimeric monoclonal antibody directed against the B-cell CD20 antigen wich has been utilized for therapy of B-cell non Hodgkin“s lymphoma (NHL). A previous clinical trial demonstrated that treatment with four weekly doses of 375 mg/m2 of Rituximab in patients with relapsed or refractory low-grade or follicular B-cell non-Hodgkin“s lymphoma was well tolerated and had significant clinical activity. The safety profile and efficacy achieved in this pilot study of extended treatment with Rituximab compares favorably with those seen with four weekly doses. Further studies are warranted to investigate whether this of other extended Rituximab schedules will result in increased efficacy in all or in certain subgroups of patients with low-grade or follicular NHL.
13 Treatment of neuroblastoma has remained a major challenge in pediatric oncology because the assessment of the individual prognosis, particularly in disseminated disease is still obscure. Previous studies have correlated clinical outcome with activity levels of telomerase, a cellular reverse transcriptase which has been detected in the majority of human malignant tumors. TA was present in 14 of 69 (20%) samples, including 3 of 22 stage IVS, 8 of 14 stage IV, 1 of 10 stage III, 1 of 7 stage II and 1 of 14 stage I neuroblastomas and 0 of 2 ganglioneuromas. We found a strong statistical correlation between the presence of TA and poor clinical prognosis with regard to all tumor stages. Multivariate analysis revealed TA as an independent prognostic marker.In particular, the analysis of TA in IVS neuroblastomas distinguished two different prognostic groups. Our data suggest that TA is an independent prognostic marker in neuroblastoma which, in combination with other markers such as MYCN, may prove useful in assessing the individual patients“s prognosis.
14 The aim of study was evaluation of the independence occurence of CA 15-3 and MCA in serum of women with breast cancer. Relationship between the concentration of these antigens and patient age, stage of the clinical progression, histopathological grade, presence of metastases to the axillary lymph nodes and histological type of neoplasm was evaluated. The studies were carried out on the serum of 131 women aged 25-81 years (age average 53 years), treated in the Surgial Department in the Chair of Oncology at Karol Marcinkowski Medical University. The MCA concentration was determined by means of the immunoenzymatic assay by Roche (Austria) and the contents of CA 15-3 was obtained due to the Abbott immunofluorescent method (U.S.A) The study showed that CA 15-3 and MCA serum concentrations in healthy women remained within acceptable values. A slight percentage of the increased antigen concentrations was revealed in the serum of women with a benign breast neoplasm. However, in women with breast cancer there was the most significant level of CA 15-3 (40%) and of MCA (31.4%). The higher clinical stage the higher median of CA 15-3 concentration was noted. There is no such a correlation as far as MCA is concerned. The higher the histological grade the lower the value of CA 15-3. The data analyses indicated that the biggest percentage of elevated results was MCA and CA 15-3 in the serum of women with lobular cancer. The study suggests some valuable hints how to determine antigens in the serum. Especially CA 15-3 can put forward information helpful to establish a diagnosis. It may also be needed as far as the assessment of the clinical stage of the disease is concerned. It also has prognostic value.
15 The epidemiology and molecular biology of colorectal cancer are reviewed with a view to understanding their interrelationship. Risk factors for colorectal neoplasia include a positive family history, meat consumption, smoking, and alcohol consumption. Important inverse associations exist with vegetables, nonsteroidal anti-inflammatory drugs (NSAIDs), hormone replacement therapy, and physical activity. There are several molecular pathways to colorectal cancer, especially the APC (adenomatous polyposis coli)-b-catenin-Tcf (T-cell factor; a transcriptional activator) pathway and the pathway involving abnormalities of DNA mismatch repair. These are important, both in inherited syndromes (familial adenomatous polyposis aFAPo and hereditary nonpolyposis colorectal cancer aHNPCCo, respectively) and in sporadic cancers. Other less well defined pathways exist. Expression of key genes in any of these pathways may be lost by inherited or acquired mutation or by hypermethylation. The roles of several of the environmental exposures in the molecular pathways either are established (e.g., inhibition of cyclooxygenase-2 by NSAIDs) or are suggested (e.g., meat and tobacco smoke as a source of specific blood-borne carcinogens; vegetables as a source of folate, antioxidants, and inducers of detoxifying enzymes). The roles of other factors (e.g., physical activity) remain obscure even when the epidemiology is quite consistent. There is also evidence that some metabolic pathways, e.g., those involving folate and heterocyclic amines, may be modified by polymorphisms in relevant genes, e.g., MTHFR (methylenetetrahydrofolate reductase) and NAT1 (N-acetyltransferase 1) and NAT2. There is at least some evidence that the general host metabolic state can provide a milieu that enhances or reduces the likelihood of cancer progression. Understanding the roles of environmental exposures and host susceptibilities in molecular pathways has implications for screening, treatment, surveillance, and prevention.
- The instrument "mole max 2" can register all pigmentary akin lesions
- The price of the examination is 100 YU dinars
The Medical Centre of Bezanijska Kosa has got a new centre for the early discovery of skin cancers - "Melanoma Centre", which is a single and unique one in the Balkans. Any pigmentary skin lesion can be examined there by the instrument "mole max 2" and highly skilled medical professionals.
17 A gene known as the fragile histidine triad (FHIT) gene has been identified as a tumor suppressor gene and shown to be altered in numerous types of cancer. Eighty percent of women with breast cancer who have a defect in the BRCA2 gene also have loss of heterozygosity in the FHIT gene, compared with 40% of women whose breast cancer is not associated with an inherited genetic defect (known as sporadic breast cancer). Based on data presented by Carlo Croce's group, this suppressor gene seems to be more ubiquitous. In his award lecture Dr Croce emphasized that this new suppressor gene could be a very common finding in many tumors, probably more so than a mutated p53.
18 Liver involvement is an important problem in colorectal cancer, which is present in 40%-70% of patients with metastatic disease. However, the liver is the sole site of metastases in only about half of the cases . Stangl et al. determined the natural history of colorectal liver metastases in a recent prospective series on 1099 patients. Thirty-one percent of the patients underwent liver resection and complete tumor clearance was achieved in 78% of those cases. The five-year survival was 32% after hepatic resection. In contrast, if surgery was not possible the median survival of patients receiving chemotherapy or no treatment was 12 and 7.5 months, respectively. It can be concluded from this and other large series, that unresectable liver metastases from colorectal cancer are nearly always fatal within five years. After liver resection, about 40% of the recurrences seem again confined to the liver and a three-year survival of 33% has been reported in this situation. However, more often relapses occur outside the liver. This underlines the need for better diagnostic tools to screen patients for extrahepatic disease before surgery. Promising options are whole-body positron emission tomography with (fluorine-18)-2-fluoro-2-deoxy-D-glucose or the detection of genetic material of micrometastases by molecular amplification methods. Despite the fact, that adjuvant chemotherapy has been proven very successful in primary colorectal cancer, there is only recent evidence of a benefit after liver surgery.
19 Angiogenesis, the process whereby endothelial cells divide and migrate to form new blood capillaries, has been assessed in tumours by measuring microvessel density. High microvessel density is a significant adverse prognostic factor in breast cancer. The angiogenic factor, basic fibroblast growth factor (bFGF), has been associated with tumorigenesis and metastasis in several human cancers. There are few quantitative studies of bFGF expression in normal tissues compared to cancer. Levels of bFGF were more than 10-fold higher in tumour cytosols compared to reduction mammoplasty tissue and 3-fold compared to non neoplastic cytosols from the same breast as the tumour (P`0.0001). Immunohistochemistry showed bFGF protein was localised exclusively in the stroma whereas no bFGF staining was observed in the epithelial cells. High bFGF levels were significantly related to high ER (P=0.01). Similarly, high bFGF levels were significantly related to low grade (P=0.046), and to small tumour size (P=0.04). No significant relationship was obeserved between bFGF and microvessel count, EGFR or age. In univariate analysis and in a Cox proportional hazard model bFGF did not reach significance for overall or relapse free survival. Their results show that although bFGF is elevated in breast carcinomas compared to normal breast tissue it is not related to microvessel density and it is not an independent predictor of survival in breast cancer patients. Basic FGF may be one of multiple factors that synergise with other growthfactors such as VEGF to enhance angiogenesis.
20 The principal agent in the etiology of cervical cancer, i.e., human papillomavirus (HPV) type 16, encodes three oncoproteins, E5, E6, and E7. Structural and mutational studies have identified two potential zinc-finger domains as critical for E6 protein function. We investigated several assays to identify and characterze compounds that interfere with the binding of zinc to E6. Methods: Thirty-six compounds vere selected on the basis of their structure, which would facilitate their participation in sulfhydryl residue--specific redox reactions, and were tested for their ability to release zinc from E6 protein. The zinc-ejecting compounds were then tested for their ability to inhibit E6 binding to E6-associated protein (E6AP) and E6-binding protein (E6BP),two coactivators of E6-mediated cellular transformation. The binding of E6 to E6BP and E6AP was measured by use of surface interactions by measuring changes in refractive index) and by use of in vitro translation assays. The compounds were also tested for their effects on the viability of HPV-containing cell lines. Nine of the 36 tested compounds ejected zinc from E6. Two of the nine compounds inhibited the interaction of E6 with E6AP and E6BP, and one of these two, 4,4“ - dithiodimorpholine, selectively inhibited cell viability and induced higher levels of p53 protein (associated with the induction of apoptosis (programmed cell death) in tumorigenic HPV-containing cells. We have described assay systems to identify compounds, such as 4,4“- dithiodimorpholine, that can potentially interfere with the biology and pathology of HPV. These assay systems may be useful in the development of drugs against cervical cancer, genital warts, and asymptomatic infections by genital HPVs.
21 The incidence of colorectal cancer in persons under 46 years of age is substantially higher in Hong Kong than in Scotland and many other countries. Consequently, we examined whether there is a hereditary predisposition for colorectal cancer in this Southern Chinese population. Authors investigated the incidence of microsatellite instability (MSI) at 10 DNA sites in 117 colorectal cancer specimens from Chinese patients of various ages. Those tumors with new alleles at 405 or more of the sites investigated were identified as highly unstable MSI (MSI-H). In young patients, we also searched for germline mutations in three mismatch repair genes (hMSH2, h MLH1, and hMSH6). The incidence of MSI- H varied statistically significantly vith age, being observed in more than 60% of those younger than age 31 years at diagnosis and in fewer than 15% of those age 46 years or older. In 15 patients (`46 years old) whose colorectal cancers showed MSI-H, eight possessed germline mutations in either hMSH2 or hMLH1. When mutations in hMSH6 were included, more than 80% of Chinese colorectal cancer patients younger than 31 years had germline mutations in mismatch repair genes. We found a novel germline missense mutation in hMSH6 in a 29-year-old man whose tumor showed no MSI. Two patients had a 4-base-pair insertion in exon 10 causing a truncated protein; this insertion is a common polymorphism with a population allele frequency in Chinese of 5.6%. Their results indicate that germline mutations in mismatch repair genes contribute substantially to the pathogenesis and high incidence of colorectal cancer in young Hong Kong Chinese. However, because young Chinese and Causasians show similar proportions of colorectal cancers with MSI-H, despite the higher incidence in the former, additional factors may underlie the high susceptibility of young Chinese to colorectal cancer.
22 Although antifolates are popular agents for use in chemotherapy, they display minimal toxicity against slow-growing tumors and are toxic to actively replicating cells in nomal tissues. These drugs are converted intracellularly into polyglutamate derivatives by the enzyme folylpolygutamyl synthetase (FPGS). Because tumoris with high expression of FPGS often respond to nontoxic antifolate doses, we investigated whether augmenting tumoral FPGS activity by genedelivery would enhance tumoral antifolate sensitivity. 9L rat gliosarcoma cells were stably transfected with a human FPGS complementary DNA (cDNA), producing 9L/FPGS cells. The sensitivity of these cells to the antifolates methotrexate and edatrexate was measured in culture and in subcutaneous tumors, as was their ability to increase the chemosensitivity of nearby nontransfected cells, i.e., a bystander effect. The antifolate sensitivity of nonselected cells transduced with a hybrid amplicion vector that expressed FPGS was also ascertained. Results: In comparision with 9L cells, 9L/FPGS cells displayed enhanced sensitivity to 4-hour pulses of antifolate. Subcutaneous 9L/FPGS tumors responded as well to methotrexate given every third day as 9L tumors did to daily treatment. A modest bystander efect was observed with edatrexate treatment in culture and in vivo. The observed bystander effect appeared to result from the release of antifolates by transfected cells after the removal of extracellular drug. In culture, enhanced antifolate sensitivity was also seen in other stably transfected rodent and human glioma cell lines, including one with high preexisting FPGS activity, and in canine and human glioblastoma cell lines transduced with a vector bearing FPGS cDNA. FPGS gene delivery enhances the antifolate sensitivity of several glioma cell lines and merits.
23 The purpose of this retrospective study was assessment of correlation between Tc-99 m sesta MIBI uptake and some prognostic factors of breast cancer. The following prognostic factors have been included in this study: size of the tumour, age of the patients, axilla node invovlvement, oestrogen and progesterone receptor (ER, PR) status, grading system of Bloom-Richardson and Ki-67 antigen expresion. 79 patients were enrolled in this study, with 85 lesions confirmed as primary breast cancers. Mean age of patients was 53 years. Scintimammography (SMM) was performed after intravenous injection of 740MBq. At 5-10 min after injection standard planar images were obtained in prone latral and anterior supine views. Assessment fo correlation between known prognostic factors of breast cancer and uptake of MIBI (evaluated as a tumour to background ratio-TBR) was performed used non-parametric (Kendall-tau correlation) statistical analysis. There were 85 breast cancers (73 invasive ductal carcinomas, 11 DCIS (ductal carcinoma in situ) and 1 lobular carcinoma. There was positive correlation between TBR Tc-99m MIBI uptake and size of the tumour (t=0.19, p=0.01), presence of axilla node invovlvement (t00,2, p=0.006) and also grade of the IDC tumours evaluated using Bloom-Richardson“s ctiteria (t=0.18, 0.03). There were negative correlation between TBR and presence of PR (t=0.16, p=0.02) and bordeline negative correlation between TBR and age of patients (t=0.135, p=0.065). Patients who are younger and/or have PR or ER negative cancers have higher Tc-99m MIBI uptake. Patients who presented with high grade of malignancy (B-R) also have higher uptake of radiotracer. Also those with higher uptake of radiotracer often had axillary node involvement. This would suggest that more aggressive.
24 Since 1997 they have prospectively tried to assess/confirm the diagnostic value of MR-Cholangiopancreaticography (MRCP) and MR-Angiography in patients suffering from pancreatic carcinoma. Till today we have studied 116 adult patients with two 1,5 Tesla MRT scanners using a body phased-array coil. 27 patients with benign diseases of the pancreas, 58 with carcinoma of the pancreas, 15 with no disorder of the pancreatobiliary system, 14 with hepatic abnormalities and 2 with other tumors. MR examinations included routinely T1-weighted (TSE, SE), T1- weighted fat-suppressed (TSE, SE), T2 weighted fast turbo spin-echo (UTS, Haste), T2- weighted fat-suppressed fast turbo spin-echo (SPIR), 2D- cholangiopancreaticography (images were obtained with breath- held) or 3D- cholangiopancreaticography (images were obtained in coronal and axial plane with respiratory triggering). In cases with pancreatic cancer we added MR-angiography. MR images were retrospectively compared with CT, ERCP amd sonography data. Summarizing the results confirm that MRCP is a safe and non-invasive technique for studying pancreatic and biliary diseases which yields information in many cases complemontory to ERCP and PTC. MRCP images can also be used as a guide for subsequent interventional procedures. MRCP will, therefore, allow the restriction of ERCP and PTC to more therapeutical indications and cases offering special problems. Considering staging and follow-up of pancreatic cancer, MRCP crosssectional images and MR-angiography should be performed, allowing the visualization of the extraductal anatomy/pathology. These techniques may provide the clinicians with complementary information compared to other conventional imaging methods like US and CT. Clinicians engaged in pancreatic oncology, therefore, should have MRCP, MR-angiography and MR imaging available in addition to the conventional diagnostic tools.
25 The differential diagnostic utility of AFP, CEA, CA19.9 and TPA was evaluated in liver tumors. They were determined in the sera of 61 patients with primary hepatocellular carcinoma (HCC), 18 with secondary liver metastasis, 61 of benign liver cirrhosis in comparison to 20 normal healthy control subjects. The association of either HBV or HCV infection and HCC was also studied through the assay of HbSAg, HbSAb, and HCV-Ab. The optimal cut-off values were determined using the diagnostic accuracy measurements and the receiver operating characteristic 8ROC) curves. AFP at on optimal cut_off value of 100 ng/ml and TPA at 160 U/L showed the highest sensitivity and specificity in detecting liver meta`stasis (100% and 87% for AFP; 100% and 54% for TPA respectively). The obtained data indicated that the combined assay of AFP and TPA resulted in a better discrimination of HCC among patients with hepatic focal lesions. HCV-Ab was detected in a higher ratio of HCC patients (83.6%) compared to HbsAg (68.9%), and both vere detected in (34%) of HCC patiens. This high incidence of HCV-Ab may suggest the implication of HCV in the molecular events leading to hepatic carcinogenesis.
26 In gynecological carcinomas p53 overexpression has been associated with an aggressive tumor type and shorter overall survival. They compared p53 values analysed by a new quantitative luminometric immunoassay (LIA) applicable on tumor cytosol immunohistochemistry (IH). In 83 breast and 43 ovarian cancers p53 was analysed by LIA and IH (Byk- Sangtec, FRG) and by IH using monoclonal antibodies (MOAB/BP53- Bio Genex, FRG). In breast cancer 32 cases (39%) were immunhistochemically (IH) positive. LIA values renged from 0.01 to 101ng/mg protein (p), median (IH negative cases) =0.208 and median (IH positives)=0.857 ng/mg p. Using a cut off <0.2 ng/mg p for a very low expression only 11% (3/27) were IH positive and ~0.8 for very high expresion only 16% (3/20) were IH negative. In ovarian cancer values ranged from from 0.01 to 66.1 mg/mg p. 48.8% (21/43) were IH positive, median (IH negatives) = 0.234 and median (IH positives)=1.43ng/mg p. At a cut off `0,2 ng/mg p 25% (3/12) were IH positive and at a cut off <0.8 ng/mg p only 14% (2/14) were IH negative. The quantitative LIA determination of p53 in cytosols of gynecological carcinomas shows a good correlation to immunohistochemistry in cases of very high and very low expression.
27 Soluble interleukin-2 receptors (sIL-2R) are measurable in the sera of patients with ovarian cancer and several other benign and malignant diseases. however, the function of these sIL-2R is still unclear. Since high levels of sIL-2R are thought to be an indicator of an activated immune system we investigated the correlation of sIL-2R concentration and prognosis of ovarian cancer patients. sIL-2R measurement was performed on the preoperative sera of 130 patients with benign, and 119 patients with malignant ovarian tumors. The IMMULITE® sIL-2R assay by DPC Biermann, Bad Nauheim, Germany was used. in ovarian cancer patients sIL-2R concentrations were significantly higher than in those with bening tumors. By defining the 95th percentile of the sIL-2R concentration distribution in patients with benign diseases as the cut-off (1200 U/ml) 35% of the ovarian cancer patients had elevated concentrations. Concentrations. Concentrations of sIL-2R increased with FIGO stage. FIGO-III patients with highly elevated sIL-2R concentrations tended to have better prognosis than those with sIL-2R levels within normal range in contrast to FIGO IV patients. Since sIL-2R concentrations indicate on immunological activation in ovarian cancer patients our data give hints of the possible role of sIL-2R in the assessment of the risk of recurrence in ovarian cancer patients.
28 Angiogenesis is necessary for growth and invasiveness of malignant tumors. Vascular endothelial growth factor (VEGF) is considered to play a key role in tumor angiogenesis. Few data are available with regard to serum levels of VEGF in patients with ovarian tumors. Authors investigated the diagnostic value of serum VEGF in patients with ovarian neoplasms 841 ovarian carcinomas, 20 cystadenomas) and 20 healthy women were included into the study. VEGF serum concentrations were determined by a commercially available ELISA. Statistical analysis revealed significant differences in VEGF serum values of ovarian cancer patients vs. healthy controls or patients with cystadnomas. No difference could be seen between serum levels of healthy controls or patients with cystadenomas. No difference could be seen between serum levels of healthy controls and women with benign ovarian tumors. For ovarian cancer patients vs. normal controls a sensitivity of 71% and a specificity of 65% resulted. The sensitivity of 71% and a specificity of 65% resulted. The sensitivity and specificity of cancer patients vs. patients with benign neoplasms were 71% and 65%, respectively. Their results suggest that VEGF has potential as a serum marker with diagnostic relevance in ovarian neoplasms.
29 In order to explore whether apoptosis is associated with angiogenesis in lung cancer, immunohistochemisty was employed to determine the pro-apoptotic factors Fas ligand (Fas) and caspase-3 (Cas-3) in 70 squamous cell lung carcinomas. Furhermore, the vascular endothelia growth factor (VEGF) and the microvessel density (MVD) were analyzed. The comparison between MVD and the pro-apoptotic factors demonstrated that the apoptotic factors are inversely related to MVD (Cas-3: p=0.011, FasL. not significant). In order to confirm this result, FasL and Cas-3 were also compared with the expression of VEGF. Again, an inverse correlation between VEGF and the pro-apoptotic factors was found (Cas-3: p=0.019, FasL: p=0.008). The inverse correlation between angiogenesis and apoptosis may be explained by the activation of pro- apoptotic and anti-angiogenic factors caused by hypoxia.
30 Histopathological and genetis studies support the hypothesis that aberrant crypt foci (ACF) represent on of the earliest that aberrant crypt foci (ACF) represent on of the earliest events in colon carcinogenesis. The purpose of this study is to make use of 1H MRS in conjuncion with multivariate methods of analysis to ascertain the validity of the above mentioned hypothesis. ACF, colonic mucosa and tumor samples taken from thirty- two carcinogen (azoxymethane)- treated Sprague Dawley rats, and of colon mucosa taken from ten healthy animals, were investigated ex vivo by 1H MRS and analyzed using multivariate methods of analysis. The H magnetic resonance peak intensities and areas of ACF lie between those from normal and carcinogen-treated mucosa samples and tumors. Multivariate analysis classification of the spectra suggests that the ACF exibit biochemical characteristic intermediate between the control and AOM-mucosa samples and the tumor groups. The use of sophisticated methods of data classification has enabled us to support the hypothesis that ACF represent preneoplastic lesions of the colon.
31 The influence of doxorubicin and N-acetyl cysteine (NAC) on caffeine metabolism was examined on an animal model (BALB/c) mice). The animals were divided into four equal groups of 10 each. The first group received doxorubicin only, in a single dose of 15 mg/kg intraperitoneally. The second group received NAC only, in a single dose of 400 mg/kg intraperitoneally. The third group received, doxorubicin and NAC simultaneously at previously mentioned doses. The fourth group was the control one and it received 0,9% sodium chloride solution intraperitoneally (10 ml/kg). Animals of all groups were kept under the controlled conditions for 24 hours after the drug administration and thereafter were given caffeine intraperitoneally in a dose of 20 mg/kg. Eight-hour urine samples were collected for measuring the quantities of caffeine metabolites in urine by the method of high performance liquid chromatography (HPLC). After collecting urine samples, all animals were sacrificed and liver and heart from each animal were prepared for measuring glutathione content. To confirm and point out the influence that doxorubicin and N-acetyl cysteine have on microsomal caffeine metabolism, aside from measuring the quantities of caffeine and some of its metabolites excreted in urine, we also followed two urinary caffeine matabolites ratios as well. We calculated the ratio between 3,7-dimethylxanthine and 3,7-dimethyl uric acid (3,7X/3,7U) and the ratio between 3,7-dimethyl uric acid and 1 methylxanthine plus 1,3 dimethyl uric acid (3,7U/1X+1,3U). The quantities of caffeine metabolites excreted in urine were lower in the group treated with doxorubicin and in the group treated with NAC than in the control group, but the difference was insignificant. The quantities of caffeine matabolites excreted in the group treated with doxorubicin and NAC simultaneously were significantly lower than in the control group. Generally speaking, the quantities of caffeine metabolites excreted in urine were lower in this group when compared to groups treated with doxorubicin and NAC only. The ratio between 3,7X/3,7U was significantly lower in the group treated with NAC and doxorubicin simultaneously and in the group treated with NAC only, than in the control group and in the group treated with doxorubicin only, while the ratio between 3,7U/1X+1,3U was significantly higher in the group treated with doxorubicin and NAC simultaneously than in the other groups. Glutathione levels in liver and heart showed no difference among the groups. These differences seem to suggest that microsomal oxidative metabolism of caffeine was inhibited, probably by the inhibition of cytochrome P-450 1A2. NAC did not show any protective effect when administrated with doxorubicin. On the contrary, it seemed that it had increased toxicity of doxorubicin, since all animals in the group treated simultaneously with doxorubicin and N-acetyl cysteine had died within 48-72 hours after the drug administration, while that was not the case in the other groups.
32 High-dose chemotherapy with autologous stem-cell transplantation is used increasingly in the treatment of poor-prognosis primary breast cancer. Because these patients may be cured with standart multimodality therapy, it is important to address both the efficacy of transplantation, and its effect on the delivery of standard treatments including local radiaton therapy. Patients with high risk primary breast cancer were treated with high-dose cyclophosopamide and thiotepa and stem-cell transplant following surgery and conventional-dose adjuvant chemotherapy. Outcome, including sites of failure and delivery of local radiation therapy, was assessed for 103 patients. Overall and disease-free survival rates at 18 months were 83% (±4%) and 77% (±4%) respectively. Twenty patients (19,4%) received radiation therapy prior to transplant. of the remaining 83,77 received radiation therapy after transplant. Overall, 5 (19,2%) of 26 first sites of recurrence were local alone. For patients receiving radiation prior to transplant, 3 of 7 (43%, 95% Cl: 6%-80%) sites of first recurrence were local, while 2 of 19 (10.5%, 95% Cl: 0%-24,5%) sites of first recurrence were local alone in patients receiving post-transplant radiation or no radiation. Transplantation does not appear to significantly compromise the delivery or outcome of local radiation therapy for primary breast cancer.
33 The analysis of ultrasonographic pictures of malignant ovarian tumours and the comparison of ultrasonography with post-operative evaluation. 163 women with the diagnosis of ovarian tumour were subjected to ultrasonographic examination. In 38 patients, post-operative histopathological investigation revealed the presence of a malignant neoplastic process. They compared ultrasonographic pictures of the outline and thickness of the capsule, internal structure (cystoid, solid, partly cystoid partly solid), the presence of endo- and exophytic excrescences, the presence of ascites and enlarged periaortal lymph nodes or metastases to liver parenchyma with the status observed during operation. 1. Ultrasonography is an important investigation in the early diagnostics of ovarian pathologies. 2. Ultrasonographic picture of ovarian tumour may indicate the presence of malignant process. 3. Malignant tumours coexist significantly more often with the following ultrasonographic features: thick capsule of varying thickness and blurred outline, partly cystoid partly solid structure of the tumour, non homogenous internal echogenicity, multilocular lesion.
34 Infliximab (a chimeric monoclonal antibody to tumor necrosis factor-a) is an efficacious treatment for fistulas in patients with Crohn“s disease. This is the result of a randomized, multicenter, double-blind, placebocontrolled trial in 94 adult patients who had draining abdominal or perianal fistulas of at least three months“ duration as a complication of the disease. The antibody was administered in two different doses. Fifty-five percent of the patients assigned to receive 5 mg of infliximab per kilogram, and 38% of those assigned to 10 mg per kilogram had closure of all fistulas, as compared with 13% of the patients assigned to placebo (p=0.001 and p=0.04, respectively).
35 Postoperative radiation therapy did not lower the recurrence rate among patients with ductal carcinomas in situ (DCIS) that had been excised with margins of 10 mm or more. This is the result of a retrospective analysis of data on margin widths (direct measurement or ocular micrometry), and standardized evaluation of the tumor for nuclear grade, comedonecrosis, and size of 469 specimens of DCIS from patients who had been treated with breast-conserving surgery with or without postoperative radiation therapy, according to the choice of the patient or her physician. The authors come to the conclusion that patients in whom the margin width between the tumor and resection is less than 1 mm can benefit from postoperative radiation therapy.
36 The incidence of Kaposi“s sarcoma (KS) is increased severalfold in individuals infected with human immunodeficiency virus-1 (HIV). Human herpesvirus 8 (HHV8) has also been implicated in KS. They investigated several factors that may determine the onset of KS, particularly HHV8 infection in individuals after becoming seropositive for HIV. They studied 366 individuals belonging to different HIV-exposure categories (i.e., homosexual activity, intravenous drug use, and heterosexual contact) for whom a negative HIV serologictest and then a positive HIV serologic test were available within a 2-year period. HHV8 antibody testing was performed by use of an immunofluorescence assay on the first serum sample available after the first positive HIV test. Actuarial rates of progression of KS and of other acquired immunodeficiency syndrome (AIDS)-defining diseases were estimated by use of time-to-event statistical methods. All statistical tests were two-sided. Twenty-one of the 366 study participants developed AIDS-related KS, and 83 developed AIDS without KS. One hundred forty (38,3%) participants had detectable anti-HHV8 antibodies. The actuarial progression rate to KS among persons co-infected with HIV/HHV8 was nearly 30% by 10 years after HIV seroconve sion. Increasing HHV8 antibody titers increased the risk of developing KS (for seronegative versus highest titer a1:125 serum dilutiono adjusted relative hazard aRHo=51.82; 95% confidence interval aCIo = 6.08-441.33) but not of other AIDS-defining diseases (adjusted RH=1.14; 95% CI=0.72-1.80). HHV8-seropositive homosexual men compared with HHV8-seropositive participants from other HIV-exposure categories showed an increased risk of KS that approached statistical significance (adjusted RH=6.93; 95% CI=0.88-54.84). Approximately one third of individuals co-infected with HIV/HHV8 developed KS within 10 years after HIV seroconversion. Progression to KS increased with time after HIV seroconversion. Higher antibody titers to HHV8 appear to be related to faster progression to KS but not to other AIDS-defining diseases.
37 The efficiency of Chlorambucil in the induction of apoptosis was investigated in the study, and measurable apoptosis parameters were compared to the other prognostic factors with the aim of possible prediction of clinical response to the therapy in the patients with CD5 + B-cell chronic lymphocytic leukemia (B-CLL). Seven newly diagnosed patients, initially treated with daily high-doses of Chlorambucil (HD-CLB) were analyzed. Quantitative analysis of apoptosis parameters on semi-fine sections obtained from peripheral blood was performed prior and during the first five days of therapy. The level of spontaneous apoptosis (SA) was determined, as well as the maximal response by apoptosis (MAR), and the time needed to establish maximal response by apoptosis (TMAR), respectively. The results revealed that the level of SA in the studied group of patients was 11.39%-20.50%. In three patients with achieved criteria for complete remission (CR) was observed high level of SA, TMAR 2-4 days and MAR 23.42-26.36%, respectively. All patients with CR were with negative LDT, non-diffuse involvement of bone marrow and clinical stage B. Criteria for partial remission (PR) were achieved in 4 patients. Within this group, all three measurable parameters of apoptosis could have been determined in only one patient, while in the rest was noticed the increased percentage of apoptotic cells on the last day of follow-up. In all patients was observed negative LDT, diffuse bone marrow involvement, and 2 out of 4 patients had CLPL of cytomorphological type and clinical stage B. By comparing the obtained values of measurable apoptotic parameters with the clinical response to the applied therapy with HD-CLB, it is possible to divide our patients into two groups: patients who have achieved CR have the highest percentage of cells dying due to the therapy-induced apoptosis, as well as the higher values of measurable parameters compared to the certain parameters of the patients with the criteria for PR. Our preliminary results of therapeutic response to the apoptosis might be useful for the timely decision upon the duration of therapy and change of modality of treatment for every patient during the follow-up period.
38 Hospital cancer date registry is a computerized data base for the collection, management and analysis of data on cancer patients. Data is stored on-line using HR software which is developed in the Institute of oncology Sremska Kamenica, Novi Sad. It can be the part of the population registry which is also developed by the Institute itself. The HR software collect a minimum database on every patient primarily treated by this hospital. The minimum data set includes details of staging, initial treatment and follow-up. Data searches can be performed on any data item collected. HR software is prepared to work on the PC computers and for the network environment. We finished the testing period of the program and now we are educating the staff for coding and for input the data to the software. The date started of the registry can be the 1 January, 2000.
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  Issue 4
1 Positron emission tomography (PET) with fluorodeoxyglucose (FDG) allows the visualization of metabolic tissue activity. Use of FDG in in-vivo cancer imaging is based on enhanced glycolysis in tumor cells. In vivo exprements have demonstrated the potential use of FDG PET in squamouscell head and neck tumors and the detection of tumor involvement in lymph nodes... The FDG concentration is a representative of the glycolytic activity of exogenous glucose. It has to be realized that uptake of FDG in malignant tumors is not only dependent of an increased expression of GLUT, but also depends on physiologic factors, such as tissue oxygenation, blood flow and peritomoral reactions. Consequently, FDG PET therefore may be considered as a highly sensitive techniwue, but with a relative low specificity. Therefore, a careful selection of patient groups must be performed to overcome this problem. In vivo experiments have demonstrated the potential use of FDG PET in squamous cell head and neck tumos and the detection of tumor involvement in lymph nodes. In these studies, a clear correlation was found between the proportions of the cells in the S+G2/M phases and the FDG uptake. The results suggested that enhanced glucose metabolism is associated with the proliferative activity of the head and neck tumors and justified further studies.
2 Thirty-nine oral squamous cell carcinomas were assessed for bcl-2 protein expression by immunostaining of tumour sections. Twenty-three per cent of these tumours showed strong nuclear staining for bcl-2 protein. Tumours of the sheek and tongue together accounted for 77% of overexpression of this protein. When bcl-2 expression was compared with p53 expression, they were found to be non-overlapping. These results suggest that overexpression of either of these genes may substitute each other in the development of oral carcinomas of Indians.
3 The presence of high risk human papilloma virus (HPV) 16 and 18 was examined in 100 oral cancer patients of Indian descent, 80 patients with potentially malignant oral lesions and corresponding clinically mucosa from 48 of these patients. Additionally, presence of HPV-33, -6 and -11 was also studied in 86 oral cancers, 50 potentially malignant oral lesions and 30 corresponding normal oral mucosa. All the patients with oral cancer and oral lesions, were long term tobacco-chewers, and a majority of the patients were in Advanced Stages III and IV. The DNA samples were amplified by polymerase chain reaction (PCR) using HPV L1 consensus primers. Typing of HPV was performed by Southern hybridization analysis of the PCR products using HPV-16, -18; -33, potentially malignant lesions and 15 out of 48 (31%) of the corresponding normal mucosa in the patients with oral lesions. HPV-18 was not detected in any of the oral cancers, oral lesions and normal mucosa. HPV-33 and the low-resk HPV-6 and -11 were also not detected in the oral cancers, oral lesions and corresponding normal mucosa. A significantly higher prevalence of HPV-16 was observed in oral lesions (27 out of 80,34%) as compared to oral cancers (15 out of 100,15%). The observed difference of 19% (95% confidence interval aCIo: 6%, 331%), between these two proportions was statistically significant at the 5% level of significance. Our data indicates that HPV-16 may play a direct role in a certain proportion of oral cancers; whereas in a subpopulation of oral cancers HPV-16 infection may be vital in the early events associated with development of potentially malignant oral lesions, and the presence of the virus not essential in the progression of the oral lesion to frank malignancy.
4 The gene for Cyclin D1 (CCND1) lies within chromosomal region 11q13 and codes for a cell cycle regulator essential for G1 phase progresion. This G1-cyclin is a putative protooncogene whose clonal rearrangement and/or amplification and mRNA overexpression occurs in several types of human neoplasias, including head and neck squamous cell carcinomas. Data from the literature suggest that amplification and overexpression of the CCND1 gene could lead to destabilisation of cell cycle control mechanisms and uncontrolled cell prolifereation. We developed a differential PCR system for the determination of CCND1 gene amplification in head and neck squamous cell carcinomas. A 115 bp CCND1 fragment and a 150 bp g-interferon fragment are amplified simultaneously in the same reaction tube under optimized conditions. Statistical analysis of amplification data obtained by differential PCR revealed excellent correlation with amplification data obtained by conventional Southern hybridization.
5 Authors reported a case of primary CD 30-positive anaplastic large cell lymphoma of the lip. While extranodal involvement is not uncommon in Ki-1 (CD30) anaplastic large cell lymphoma, this is first reported case of primary lip involvement. The clinical features and clinical outcome in Ki-1 anaplastic large cell lymphoma are discussed.
6 On the basis of promising data on the use of fluorine-18-2-fluoro-2-deoxy-D-glucose (F18-FDG) whole body positron emission tomography (WB-FDG-PET) in the staging of patients with lymphoma, we initiated a pilot series to evaluate the role of WB-FDG-PET in the staging of extranodal B-cell lymphoma of the mucosa-associated lymphoid tissue (MALT) type. WB-FDG-PET documented no lymphoma in any of the 10 patients studied, as no focal tracer uptake was demonstrated in either gastric or extragastric lesions or in involved lymph nodes, irrespective of histologic grading. In three patients the scan showed a false negative result with respect to the MALT lesions but showed focal tracer uptake indicating tumor spread, which, however, was ruled out by further follow-up and biopsy, respectively, and was thus rated false positive. Due to these results, the study was discontinued prematurely after the first ten patients.
7 Vaccination with irradiated granulocyte-macrophage colonuy-stimulating factor (GM-CSF)-secreting gene-transduced cancer induces tumoricidal immune responses. In a Phase I human gene therapy trial, eight immunocompetent prostate cancer (PCA) patients were treated with autologous, GM-CSF-secreting, irradiated tumor vaccines prepared from ex vivo retroviral transduction of surgically harvested cells. Expansion of primary cultures of autologous vaccine cells was successful to meet trial specifications in 8 of 11 cases (73%); the yields of the primary culture cell limited the number of courses of vaccination. Side effects were pruritis, erythema, and swelling at vaccination sites. Vaccine site biopsies manifested infiltrates of dendritic cells and macrophages among prostate tumor vaccine cells. Vaccination activated new T-cell and B-cell immune responses against PCA antigens. T-cell responses, evaluated by assessing delayed-type hypersensitivity (DTH) reactions against untransduced autologous tumor cells, were evident in two of eight patients before vaccination and in seven of eight patients after treatment. Reactive DTH site biopsies manifested infiltrates of effector cells consisting of CD45RO+-T-cells and degranulating eosinophils consistent with activation of both Th1 and Th2 T-cell responses. A distinctive eosinophilic vasculitis was evident near autologous tumor cells at vaccine sites, and at DTH sites. B-cell responses were also induced. Sera from three of eight vaccinated men contained new antibodies recognizing polypeptides of 26, 31, and 150 KDa in protein extracts from prostate cells. The 150-kDa polypeptide was expressed by LNCaP and PC-3 PCA cells, as well as by normal prostate epithelial cells, but not by prostate stromal cells. No antibodies against prostate-specific antigen were detected. These data suggest that both T-cell and B-cell immune responses to human PCAQ can be generated by treatment with irradiated, GM-CSF gene-transduced PCA vaccines.
8 Over the last decade, scientists have produced many recombinant immunotoxins-small, bioengineered antibodies linked to a toxin-as part of an experimental strategy to directly target and deliver deadly poisons to tumor cells. However, despite the great promise of this approach, therehave been no published reports of cancer patients responding to a recombinant immunotoxin. That is, until now. In the November 15 issue of the juornal Blood, a team of scientists from the National Cancer Institute reports that four of four patients with hairy cell leukemia, an uncommon cancer of imune B cells, had "major responses" to a recombinant immunotoxin called LMB-2. All of the patients previously had not responded to standard treatments for the cancer, including chemotherapy and removal of the spleen. Robert Kreitman, M.D., lead author on the study, said one patient in this early stage clinical trial had acomplete remission after treatment with the immunotoxin and has not relapsed 16 months later. For the three other patients, Kreitman and colleagues observed partial responses, detecting a 98% to 99.8% reduction in malignant circulating cells. All of the side effects were reverible and usu eally lasted less than a week. These included fever, nausea, vomiting, and rash."This offers a proof of principl that recombinant immunotoxins will one day have an important role in treating cancer", said Ira Pastan, M.D., senior author on the paper. "But there is still much work to be done to maximize their potential for cancer patients".
9 Organ-confined renal malignancies can be cured in the majority of patients, whereas more extensive lesions have a poor prognosis. We sought to develop a noninvasive test for renal cancer detection based on a novel molecular approach. Matched urine and serum DNA samples were obtained before surgery from 30 patients with clinically organ-confined solid renal masses (25 with malignant tumors and five with tumors of low malignant potential) and were subjected to microsatellite analysis. Serum samples and urine samples obtained from 16 indivuduals without clinical evidence of genitourinary malignancy served as controls. Nineteen (76%) of the 25 patients with malignant tumors were found to have one or more microsatellite DNA alterations in their urine specimen, and 15 (60) were found to have alterations in their serum DNA by microsatellite analysis. In every case, the microsatellite changes in urine or serum were identical to those found in the primary tumor. Three of five patients with tumors of low malignant potential were found to have DNA alterations in their urine, but none displaved alterations in their serum. Moreover, microsatellite alterations were not identified in either the urine or the serum samples from normal control subjects and patients with hematuria due to nephrolithiasis (renal stones). These data suggest that microsatellite DNA analysis of urine specimens provides a potentially valuable tool for the early detection of resectable kidney cancer. Furthermore, microsatellite analysis of serum samples reveals evidence of circulating tumor-specific DNA in approximately half of these patients and may reflect the propensity of these tumors to spread to distand sites at an early stage.
10 To our knowledge, 17-allylamino, 17-demethoxygeldanamycin (17AAG) is the first inhibitor of heat shock protein 90 (Hsp9=) to enter a phase I clinical trial in cancer. Inhibition of Hsp90, a chaperone protein (a protein that helps other proteins avoid misfolding pathways that produce inactive or aggregated states), Ieads to depletion of important oncogenic proteins, including Raf-1 and mutant p53 (also known as TP 53). Given its ansamycin benzoquinone sructure, we quinone-metabolizing enzyme DT-diaphorase. The antitumor activity of 17AAG and tther Hsp90 inhibitors was determined by use of a spectrophotometric assay, and protein expression was determined by means of wesern immunoblotting. In two independent in vitro human tumor cell panels, we observed a positive realtionship between DT-diaphorase expression level and growth inhibition by 17AAG. Stable, high-level expression of the active NQO1 gene transfected into the DT-diaphorasedeficient (by NQO1 mutation) BE human colon carcinoma cell line resulted in a 32-fold increase in 17AAG growthinhibition activity. Increased sensitivity to 17AAG in the transfected cell line was also confirmed in xenografts. The extent of depletion of Raf-1 and mutant p53 protein confirmed that the Hsp90 inhibition mechanism was maintained in cells with high and low levels of DT-diaphorase. 17AAG was shown to be a substrate for purified human DT-diaphorase. These results suggest that the antitumor activity and possibly the toxicologic properties of 17AAG in humans may be influenced by the expression of DT-diaphorase. Careful monitorng for NQO1 polymorphism and the level of tumor DT-diaphorase activity is thereforerecommended in clinical trials with 17AAG.
11 Our results support a favourable prognostic significance of cathepsin-D expression in advanced ovarian cancer, but underscore the importance of considering both epithelial and stromal cell expression. We could not confirm the prognostic significance of nm23 expression in the present cohort of advanced ovarian cancer patients.
12 Metyl-b-cyclodextrin (MEBCD) was investigated for its effect on the antitumoral activity of various antineoplastic agents (doxorubicin(DOX), docetaxel (DXL), 5-fluorouracil (5-FU) and cisplatin (CDDP)) in three different human parental sensitive cancer cell lines (K562 S, MCF7 S and A2780 S) and their multidrug resistant variant sublines (K562 R, MCF7 R and A2780 R). At non-cytotoxic concentrations, MEBCD was able to increase significantly DOX and DXL cytotoxic activity in all the cell lines tested. The sensitisation ratios ranged from 3.1 to 14.3. Moreover, intracellular DOX accumilation, was also increased when cells were treated with MEBCD combined with DOX. The effects of MEBCD in resistant sublines were greater than in their parental sensitive cell lines.
13 From 65 studies identified, ther seems to be no standard therapy for advanced biliary cancer. Despite anecdotal reports of symptomatic palliation and survival advantages, most studies involved only a small number of patients and were performed in a phase II approach. In addition, the benefit of adjuvant treatment remains largely unproven. No clear trend in favour of radiation therapy could be seen when the studies included a control group. The only randomised chemotherapeutic series seemed to suggest a benefit of treatment in advanced disease, but due to the small number of patients included, definitive evidence from large, randomised series concerning the benefit of non-surgical oncological intervention as compared with supportive care is still lacking.
14 The expression of alternatively spliced CD44 adhesion molecules has been implicated in the pathogenesis and metastasis of colorectal cancer. Using RT-PCR authors delineated the exon composition of CD44mRNAs in normal colorectal mucosa, including isolated colonic crypts, in colorectal carcinomas and their hepatic metastases. They identified by RT-PCR eight variant transcripts expressed in colorectal carcinomas and their metastases, but also constitutvely in normal colorectal epithelia. Despite expression of these transcripts in colorectal cancers and their metastases, monoclonal antibodies specific for standard or variant epitopes encoded by exons v5 and v6 stained only a few neoplastic lesions. These data point to a differentiation-specific CD44 expression and splicing pattern in proliferating colorectal epithelia.
15 Local reccurrence of high-grade non-Hodgkin's lymphoma (NHL) is usually treated with intensive chemotherapy and/or radiotherapy. When these modalities are inadequate or no longer possible, selective arterial embolisation can be an alternative treatment to radiotherapy and chemotherapy.Authors think that embolisation may have played a part in achieving and maintaining complete response of the lymphoma. after radiation therapy, chemotherapy was inadequate and embolisation was the only local treatment which could be applied for this patient. Authors suggest that in such cases, it could be an alternative for adjuvant therapy of hypervascularised tumours, especially if radiotherapy is no longer possible.
16 The study, prompted by a number of articles presaging the imminent of biomedical journals due to the rise of their electronic spread, analysed 54 Web sites of the journals included in the Oncology section of the Science Citation Index, Journal Citation Reports (1994) and the sites of 10 other leading digitised biomedical journals. The aim was to determine quantitive and qualitative differences in terms of information content existing between the two media. The analysis confirmed theat there are limits to the information contained in the scientific journals currently on the Internet and upholds the authors' conclusion that, in the oncology field, the printed journal will continue to have and important role for a most individual users for some time.
17 The attention of pathologists is now turned towards the standardisation of protocols, statistical guidelines and large conclusive studies in quantitive pathology, aimed at providing the necessary objectivity in diagnostic work. Moreover, image analysis systems have to be frequently upgraded to extend the spectrum of potential applications. The benefits of quantitative methods are particulary tangible in areas where conventional diagnosis may be difficult.
18 The acid labile derivative of Daunomycin cis-aconityl Daunomycin (cAD), was coupled to an amphoteric polypeptide, (EAK), which was selected for conjugation on the basis of its pharmacological and immunological properties.
19 Authors report the case of an infiltrating lobular breast tumour in a female HIV-seropositive patient (heterosexual transmission). In this case, the relapse observed after the first diagnosis occured despite good clinical and bilogical prognostic factors, and when the patient's CD4 count was more than 500/mm3. Neither biological characterisation nor the CD4 count predicted the progression of the disease. Their results may also support the hypothesis that HIV infection may have a permissive effect on breast cancer development regardless of tumour biology and CD4 lymphocyte count.
20 Cell kinetic data may be important indicators of clinical behaviour in many types of cancer. Recently, several antibodies to cell-cycle associated antigens have been characterised. This overview summarises the advantages and disadvantages of different methods for the assessment of cell proliferation. Moreover, the prognostic value of proliferative activity in gastric cancer is discussed and suggestions for future research are given.
21 The aim of the study was to analyse retrospectively the clinical features and effect of treatment in 94 MCL patients diagnosed and treated in one centre between 1980 and 19996, and to find out different factors influencing the treatment results and prognosis. The median age of patients was 66 years, and 77% were over 60 years old. Of the patients, 76% had advanced disease, the performance status (PS) was WHO 0-1 in 86%, and B symptoms were present in 35% of the cases. Bone marrow infiltration was found in 61% and overt leukaemia in 12% of the patients. Of the patients, 47% achieved complete remission with first-or secind-line therapy. The median duration of remission, time to treatment failure (TTF), and survival were 28, 18, and 41 months, respectively. In multivariate analyses, age, stage and leukaemic disease were significantly associated with TTF, and age, stage, leukaemic disease and lactate dehydrogenase (LDH) with survival. Long-term prognosis is poor in MCL. None of the conventional chemotherapies seems curative. A prospective randomised trial should be made to evaluate the benefit of anthracycline-containing regimens in MCL.
22 Authors reviewed the relationships between ERBB2 amplification and/or overexpession in human breast cancer and the clinicopathological patrameters described in the literature (97 studies involving 22 616 patients) in order to draw conclusions regarding its clinical interest.
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Medical and Scientific Meetings
  Volume 6 Issue 1
1 The classification of receptors involved in the emetic reflex has completely changed during the past 10 years. Today investigational agents acting as combined 5HT3 antagonists/5-HT4 agonists, dopamine D2/D3 antagonists and the neurokinin1 antagonists are in focus. Positron emission tomography (PET) is rapidly advancing as an investigational tool in the detection and staging of cancer and in the evaluation of response to treatment. It is emphasized that PET could also be useful in further investigations of the pathophysiology of emesis. Though antiemetic treatment has been optimized, delayed emesis, emesis during multiple cycles and, especially, refractory emesis after chemotherapy continue to present significant challenges requiring further clinical investigations, as does the syndrome of chronic nausea and vomiting in patients with advanced cancer.
2 The emergence of herpesvirus resistance to antiviral drugs is a matter of concern, and its clinical importance among patients with malignancy needs to be elucidated. Future investigations may furthermore help to clarify the role of novel antiviral agents, such as cidofovir, lobucavir, and compound 1263W94, and of the adoptive immunotherapy with virus-specific CTL clones in severely immunodeficient cancer patients.
3 Heparan sulfate proteoglycans are one of the major components of extracellular matrix and are secreted at different levels by several normal and tumoral cells. Perlecan, the basement membrane proteoglycan, has structural domains involved in cell/matrix interactions and growth factor storage. Metastatic melanoma cells show an increase in perlecan expression as compared to low metastatic ones. We examined whether reduction of perlecan expression could down-modulate the malignant phenotype in melanoma clones.
These results further indicate the importance of perlecan as a regulator of growth factor activity affecting the biological properties of metastatic cells, and suggest the potential use of antisense perlecan DNA in anti-melanoma gene therapy approaches.
4 Liver diseases associated with chronic hepatitis B virus (HBV) infection, including hepatocellular carcinoma, account for more than 1 million deaths annually worldwide. The recently developed individual biochemical and molecular markers of aflatoxin exposure, i.e., aflatoxin-albumin adducts in blood and a specific GC to TA transversion mutation in codon 249 of the p53 gene (249ser p53 mutation) in hepatocellular carcinomas, permit a better quantitative estimation of aflatoxin exposure in different populations of the world.
Experimental and epidemiologic studies demonstrate an interaction between HBV infection and aflatoxins in hepatocarcinogenesis.
5 Fig. 2. Structures of Nicotine, N' nitrosonor-nicotine (NNN), and 4-(methyl-nitrosami-ino)-1-(3-pyridyl)-1-butanone (NNK)
6 Fig. 1. Scheme linking nicotine addiction to lung cancer through the major pulmonary carcinogens of tabacco smoke - polynuclear aromatic hydrocarbons (PAH) and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK).
7 A ribonucleoprotein enzyme, telomerase, is a key component in maintaining telomere length. Because the majority of cancers express telomerase but most normal somatic tissues do not, we measured the level of telomerase expression in primary breast cancer specimens for correlation with traditional prognostic indicators and disease outcome. Telomerase activity was measured in frozen human breast cancer specimens by use of the Telomeric Repeat Amplification Protocol (TRAP) assay.
Telomerase activity in human breast cancers is associated with a more aggressive tumor phenotype in patients.
8 Pregnancy associated breast cancer (PABC) includes cancers concurrent with pregnancy, diagnosed up to 1 year following delivery, or at anytime while the patient is lactating. However, assuming a long latency period, breast cancer diagnosed even up to 5 years following a delivery may have concurrently existed with pregnancy and therefore been subjected to the hormonal milieu of pregnancy.
Pregnancy is not a cause of breast cancer. Breast cancer occurs coincidentally with pregnancy and lactation. PABC has been associated with a poor prognosis that may be related to an incompletely understood hormonal influence and an often reported diagnostic delay.
Options in the treatment of breast carcinoma during pregnancy are limited by potential fetal injury secondary to both radiation and chemotherapy.
Surgery is a treatment of choice when breast cancer occurs early in the first and second trimesters. In general, surgical breast procedures may be undertaken in pregnant women with essentially no risk to the fetus or the continuation of pregnancy.
If a diagnosis of breast cancer is made during the third trimester of pregnancy definitive surgical management can be immediately instituted followed by little to no radiation treatment delay after delivery.
M.D. Anderson Cancer Center in conjunction with The Baylor College of Medicine recently presented data on a 5-fluorouracil, doxorubicin, and cyclophosphamide treatment protocol given to second and third trimester pregnant patients following MRM. Early results from their study demonstrated no severe neonatal abnormalities and generally good maternal outcome. However, in utero exposure to these chemotherapeutic agents may cause difficulty later in life.
Tumors from patients with PABC are more commonly estrogen negative although high false negative rates may occur with standard assay techniques. The treatment of breast cancer during pregnancy is complicated by potential fetal injury secondary to both radiation and chemotherapy. Currently, MRM remains the treatment of choice when this disease occurs during the first trimester and early during the second trimester. Although there is little data on breast conservation therapy in these women, this type of treatment may be considered later during pregnancy with avoidance of the radiotherapy until after delivery.
9 Free and N1-acetylated polyamine levels were higher in the neoplastic tissue than surrounding mucosa of the same patient. On the contrary, PAO activity was significantly lower in the neoplastic tissue than surrounding mucosa. It seems that PAO activity dose not play an important role in the increased free polyamine levels in human colorectal carcinoma. Instead, the low PAO activity observed in our study let us to hypothesize that polyamine analogues can have an antitumoral effect on colorectal carcinoma.
Table 1. Polyamine levels and PAO activity in neoplastic and normal colorectal tissue (Number of cases = 30).
10 Diastolic left ventricular parameters and R-R intervals significantly differed before and after completed chemotherapy in our patients: peak filling rate (PFR: 1.8±0.6 vs. 2.2±0.7 EDV/sec) and time to filling rate (TPFR: 182±48 vs. 2.25±50 msec), R-R: 723±51 vs. 620±45 msec, p<0.01. Ejection fraction, as a systolic parameter /did not significantly differ before and after completed chemotherapy (EF: 59±7 vs. 58±6%), p<0.05.
Table 2. Left ventricular systolic and diastolic parameters in 32 female patients with breast cancer before and after the end of chemotherapy.
11 In the intact stomach, Helicobacter pylori associated gastritis is considered to be a risk factor for cancer. After partial gastrectomy increased mucosal cell proliferation associated with chronic bile reflux has been claimed to increase the risk for cancer in the gastric stump, whereas the influence of H. pylori infection is not so clear.
The mean labelling index (LI) was 30.8%. There was no clear association between H. pylori infection and proliferation rate. A significant difference in proliferation rate was seen between patients with a reconstruction type known to be associated with bile reflux and those with a reconstruction without bile reflux. The difference was small in H. pylori negative patients but strong in those with bile reflux and H. pylori infection. The LI increased with age. Smoking had no significant effect on proliferation whereas use of NSAIDs seemed to inhibit proliferation. Ki-67 is a convenient method for assessing the proliferation rate of the gastric epithelium. Bile reflux and H. pylori infection seem to have a synergistic effect on cell proliferation in the gastric remnant and may explain the increased risk of cancer after partial gastrectomy.
Table 2. Ki-67 labeling index (LI) and Helicobacter pylori status according to reconstruction type
12 Several dimethylsilane tetramines [homologs of spermine with an Si(CH3)2 group in the central carbon chain], a carbon analog of the dimethylsilane tetramines [containing C(CH3)2 instead of Si(CH3)2] and a dimethylsilane hexamine were studied with regard to their cytotoxic activity and their ability to interact with double-stranded DNA. All polyamine analogs exerted cytostatic effects to several cell lines at micromolar concentrations. Their ability to condense DNA was comparable to and their ability to displace ethidium bromide from binding to DNA was superior to that of spermine. Their cytostatic effect was not correlated with the depletion of cellular spermidine concentrations. It is suggested that the new polyamine analogs act mainly by displacing spermidine from binding sites which are essential for the promotion of cell growth.
13 Vascularization is an important step in tumor growth and metastasis. Tumor neovascularization can be considered, therefore, as a good target for antineoplastic therapy. In order to target saporin, a powerful plant toxin, in proximity of the tumor we fused the saporin coding sequence to that for placental growth factor-2 (P1GF-2). P1GF is an angiogenic factor involved in tumor neovascularization. The fusion protein P1Gt transfection of mammalian cells and released in the culture medium as a 57.5 kDa polypeptide. Selectivity and cytotoxic activity are reported as a preliminary step towards the evaluation of its in vivo antitumor activity.
14 In this article authors evaluated the role of gallium-67 scintigraphy in the staling of low-grade non-Hodgkin's lymphomas (LGNHL), the relationship between the expression of CD71 on the surface of the neoplastic cells and the 67Ga uptake by the tumour, and the contribution of 67Ga scan in defining the prognosis of LGNHL. They concluded that because of the low sensitivity in tumour detection and, in general, the low interest in evaluating the extension of disease at diagnosis in LGNHL patients, 67Ga scan should not be used for staging, but should be considered an adjunctive tool in defining the prognosis and the therapeutic strategy in patients with follicular lymphomas.
15 Single-photon emission tomography (SPET) with technetium-99m sestamibi (MIBI) was used in the assessment of 30 patients with previously resected malignant melanoma when the clinical examination raised the suspicion of lymph node metastasis. Using MIBI, 16 out of 17 lymph node metastases were detected and confirmed by histology. No false-positive results were obtained during this prospective study. It is concluded that MIBI scintigraphy may be useful in the early detection of lymph node metastases of malignant melanomas.
16 In this article, the classification of cervical lymph nodes, the status of current imaging studies for the detection of nodal metastases, the classification of variable neck dissection, and the potential effect of imaging studies on the management of head and neck cancer patients are reviewed. A single nodal metastasis reduces the patients' prognosis by approximately one - half, regardless of location or size of the primary tumor in the head and neck. Sensitivity and specificity of the physical examination for the diagnosis of nodal metastasis is unsatisfactory, resulting in both false negatives and false positives of 25 to 40%. CT and MRI have improved the accuracy of nodal staging over physical examination. Clinically occult normal-sized nodes with central necrosis or with extracapsular spread can be identified as metastases by CT or MR. Many borderline-sized nodes without necrosis or extracapsular spread remain indeterminate, however, by current #state of the art# CT or MR. Size has been a widely used criterion to determine the presence of nodal metastases. Because size data are a continuum, the relative sensitivity and specificity of any size criteria can be adjusted by changes in the threshold, depending on clinical setting. Small metastatic nodes can still be missed, and conversely, large reactive nodes cannot be differentiated consistently from metastatic nodes. Many authors consider contrast-enhanced CT a standard method for assessment of extracapsular spread. Although the incidence of extracapsular spread increases as lymph node size, it has been reported that 23% of nodes less than 1 cm in diameter revealed extracapsular spread on pathologic analysis. Accurate preoperative diagnosis of extracapsular spread in normal-size nodes is an extremely important factor that affects surgical management of the N0 neck. Despite the superior contrast resolution of MR over CT, MR has added little to the ability to differentiate benign from malignant adenopathy. Signal intensity of metastatic nodes does not differ consistently from that of normal nodes on T1w and T2w images. Central necrosis is considered to be a characteristic finding for metastatic lymph nodes, which appears high in signal intensity on T2w images and low in signal intensity on T1w images. US has been used extensively for evaluation of cervical nodal metastasis. US criteria for metastasis include size, grouping of nodes, and shape of nodes. Reactive benign nodes as well as small metastatic nodes appear as homogeneous hypoechoic tissue. None of the US-specific criteria have been found to accurately predict presence of metastases. With development of more tissue-specific imaging techniques, patients can be better characterized according to the status of nodal disease.
17 The Third International Congress on Peer Review in Biomedical Publication was held in Prague (Czech Republic) from September 18-20, 1997. The Conference on peer review and global communication, with special reference to the importance of using electronics in editing, reviewing and publishing of scientific reports, was held the day after the Congress. All participants have generally agreed that the peer review system, in spite of its numerous deficiencies, is still the best way for the evaluation of the manuscripts. British researches have found out that the best reviews are those written by the referees who are familiar with statistics. They have also noticed that the reviews of manuscripts, when the authors and the institutions they come from are not known to the referee, do not lag in quality from those when the authors are known. The majority of the editors are of the opinion that reviews should not be done in a single blind, not even in double blind manner. Some of them believe that referees should sign their reviews. It would make them more responsible and would prevent data stealing from competitive researches which happens in completely closed system. The participants of the Congress expressed their discontent with the evaluation of journals, particularly clinical ones, by means of JIF (Journal impact factor). JIF presents a ratio between the number of citations and the number of published articles. Therefore, BMJ (British Medical Journal) has recently constituted a working group with an assignment to establish more unabridged criteria for the evaluation of the journals. Because of the increase of the average number of authors signing one paper, Rannie et al (JAMA 278:585,1997) suggest to replace the word author with the word contributor.
During the Conference on peer reviews and global communication an interesting debate was raised on the subject of prospective disappearing of paper issues of biomedical journals up to 2020. It seems that the arguments of the skeptics are much stronger, at least for the moment being, and I believe that printing of many biomedical journals will continue in the next century.
My report titled Civil War and Scientific Activity in Former Yugoslav Republics has excited inters of many participants and a number of reporters. The international co-authorship has been expressed by an undimensioned "Salton's Index" - SI - which has been defined as a number of co-authorial articles between two countries divided by a square root of the number of papers in the given period - SI=NAB/sq.root(NA X NB). The existing data clearly show an increase of the co-authorship between Serbia and Croatia till 1990, when it suddenly drops (almost to 50%), and slowly begins to increase again since last year.. The co-authorship between Serbia and Slovenia has been always very low, at this moment it is only half of the range it had in 1991. Co-authorship between Slovenia and Croatia had a trend of increase till 1992 when it gradually begins to decline. The scientists from Croatia and Slovenia have been mostly cooperated with the scientists from Germany and Italy. Scientists from Serbia cooperated most frequently with the colleagues from France in previous times but now prevails the co-authorship with the scientists from Great Britain and USA. The use of typical Serbian and Croatian names did not show any "ethnical cleansing" among Croatian and Serbian scientists in Belgrade and Zagreb. However, the changes have happened outside the capitals of these former republics. It would be very useful if appropriate ministries in Serbia and Croatia prepare a detail report on the migration of scientists during the war and after war period.
A new non-invasive test kit instantly identifies osteoporosis of those who are in danger from developing the crippling disease. The kit which has been developed by the United Kingdom company Cortecs Diagnostics is now being used by general practitioners. Cortecs is also working with pharmacists throughout Britain to make the test available in shops.
Called Osteosal, the kit enables the doctor or pharmacist to sample the patient“s urine in a hand-held optical diagnostic tool called InstaQuant. It measures the resorption of bone markers in urine which, if found in high quantities, indicate osteoporosis, its potential development and an increased risk of fracture.
To quantify this accurately the rapid test is placed in the hand-held InstaQuant optical reader to provide a quantitative definition.

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  Issue 2
1 The health care policy is closely determined and defined in the form of thirty -two aims presented in the document titled "The aims and measures of the health care policy in Serbia up to 2010". They clearly show that health care policy has been formulated as an organized and comprehensive social activity, as twenty out of thirty-two aims require for their fulfillment the predominant role and contribution of other nonhealth-care social structures. First of all, it refers to aim 1 (health and quality of life), aim 2 (better living conditions for handicapped persons), aim 4 (health for old people), aim 11 (injuries and poisoning), aim 12 (mental disorders and suicides), aim 13 (smoking, the abuse of alcohol and psychoactive substances), aim 14 (quality of waters), aims 15 an 16 (disposition of liquid and solid waste materials), aim 17 (quality of air), aim 18 (quality and sanitary conditions in food preparation) and aim 19 (occupational health protection ).
Till the year 2000 all health care priorities will be defined within a unique health care system and insurance, to ensure the most favorable