Archive of Oncology 1999;7(3):130-6.
 
NEWS
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: ielsg@ticino.com
  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.
  16. MELANOMA CENTER OPENED AT THE MEDICAL CENTRE OF BEZANIJSKA KOSA
- 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.
© Institute of Oncology Sremska Kamenica, Novi Sad, Last updated March 8, 2000