Clinical significance of 5-S-cysteinyldopa monitoring in patients with malignant melanoma.

5-S-cysteinyldopa is a precursor of melanin. Its serum and urinary level can reflect melanoma progression. In this study the concentration changes of 5-S-CD in melanomas of all stages were examined, and patients were monitored during and after treatment. Serum samples were taken from 479 melanoma patients with different Stages on 1924 occasions, from June 1996 to December 2000. Levels of 5-S-CD were determined by HPLC. The mean/median value of 5-S-CD in the Stage I-II-III patients and in the control group ranged around the normal level. Significant difference was found between Stage III and Stage IV as well as between patients with no evidence of disease and patients with tumor burden. In Stage IV 69.7% sensitivity, 61.5% specificity and 79.3% positive predictive value were evaluated. The survival of patients with normal 5-S-CD level (n=235) differed significantly from cases having elevated marker concentration (n=244). One hundred eighty cases were regularly monitored on 1210 occasions. Recurrence development was noticed in 57 patients. In 24.6% of these patients suffering from any type of disease progression the increasing marker level preceded the detection of metastasis by conventional methods. Serum 5-S-CD in Stage IV is sensitive enough to detect distant metastasis, and its predictive value has a great importance. It is a reliable marker for monitoring the clinical course in malignant melanoma.

Freeze dried ondansetron: first observations with the fast dissolving oral antiemetic Zofran Zydis for the prophylaxis of the cisplatin-induced emesis in gynecological cancer patients.

Oral antiemetics are seldom taken by patients (women, children or those having tumors of the buccal area, mouth or esophagus), who find it difficult to swallow. In addition to anatomical reasons, the side effects of cytostatics require medication. Fast dissolving ondansetron is a new preparation, which instantaneously disintegrates and disperses in the saliva. The purpose of this paper was to evaluate the antiemetic effectivity of the product Zofran Zydis. Thirty six patients treated with cisplatin (50 mg/m2) in 55 chemotherapy courses were given 2x8 mg fast dissolving ondansetron in a prospective non randomised study. 75% complete response and 11% major response rates were found. Authors conclude that fast dissolving ondansetron is a new and effective preparation that enriches the panel of available supporting drugs.

The cost effectiveness of dual phase 201Tl thyroid scan in detecting thyroid cancer for evaluating thyroid nodules with equivocal fine-needle aspiration results: the preliminary Taiwanese experience.

The purposes of this study were to assess the helpfulness of dual phase 201Tl thyroid scan for differentiating malignant from benign thyroid lesions in cases of thyroid nodules with equivocal fine-needle aspiration (FNA) biopsy results. In addition, for thyroid nodules with equivocal FNA biopsy results, we try to make a decision analysis model compared the FNA biopsy alone strategy (strategy A) with decision strategy for the assistance of dual phase 201Tl thyroid scan (strategy B) before diagnostic thyroidectomy as thyroid cancer evaluation strategies for hypothetical cohorts of estimated 17,280-29,160 Taiwanese patients/per year with equivocal FNA biopsy results. Based on the findings of surgical histopathology, dual phase 201Tl thyroid scan sensitivity, specificity, and accuracy were 100%, 90%, and 96%, respectively, in cases of 27 thyroid nodules with equivocal FNA biopsy results. In cost effectiveness analysis, the strategy B showed a cost saving of 16,340,480-27,574,560 US dollars in unnecessary diagnostic thyroidectomy cost. The total cost of strategy B showed a cost saving of 13,932,232-23,520,564 US dollars than that of strategy A. The preliminary data indicate that dual phase 201Tl thyroid scan can save the cost of unnecessary diagnostic thyroidectomy in Taiwanese patients with equivocal FNA biopsy results. In addition, we may provide a noninvasive diagnostic method--dual phase 201Tl thyroid scan, as the first priority for Taiwanese patients with equivocal FNA biopsy before diagnostic thyroidectomy under the coverage of the national health insurance system in Taiwan.

Prostate cancer and the food supplement, PC-SPES. Minireview.

Cancer of the prostate has now become the most frequently diagnosed cancer in the male population in America and indeed its incidence has increased in many westernised countries. Surgery, radiotherapy and androgen ablation form the mainstay of its treatment. However, these treatment modalities are ineffective in a large percentage of patients due to grade of tumor at presentation, sensitivity to radiotherapy, hormone-insensitive profile of tumor cell population, etc. Because of the woeful ineffectiveness of these standard treatment modalities on the overall survival rate from prostate cancer in the past fifty years, a more radical approach to the treatment of this cancer is justified. To this end some of the latest innovative approaches are now being tested as tools in prostate cancer research, including those pioneered in molecular and cellular biology and immunology. There has also arisen a considerable interest in the modification of diet and the use of herbs and a great interest has been stimulated in PC-SPES, a herbal food supplement sold in the USA. This product, which is composed of eight herbs, is recommended as a food supplement for those suffering from prostate cancer and there are many anecdotal, scientific and clinical claims for its efficacy. This is a review of some of the in vivo and in vitro research carried out on this product.

A case-control study of lung cancer in Polish women.

This study was undertaken to examine the influence of active and passive smoking, cancer family history, occupational exposure, usual diet and alcohol consumption on female lung cancer risk. A total of 242 women with histologically confirmed primary lung cancer and 352 healthy controls were involved in the study. All subjects were interviewed in the hospital. Data were analysed using multivariate logistic regression. Multivariate analysis has shown that smoking was the most strongly active risk factor in female lung cancer. Positive dose-response relationship was observed between lung cancer risk and number of pack-years. Passive smoking exposure during childhood significantly increased the risk (OR=2.65). There was also observed a significantly increased risk of lung cancer among women who had siblings with history of cancer (OR=3.42). Occupational exposure to coal dust, acid fumes (sulphuric and/or hydrochloric) and materials used for rubber making significantly increased the risk. Frequent intake of carrots (at least five times a week) and also daily intake of other vegetables significantly lowered the risk (OR=0.13, OR=0.24). A significant protective effect was also observed in women frequently using margarine on bread (OR=0.14). Vodka drinkers showed significantly higher risk than non-drinking women. The analysis of dose-response relationship in reference to vodka drinking also confirmed significant influence of this factor on the risk.

Nonmelanoma skin cancers and risk of subsequent malignancies: a cancer registry-based study in Bulgaria.

Analysis of new primary tumors following nonmelanoma skin cancers (NMSC) has a public health and risk assessment interest, as well as potential implications for etiologic inference. The aim of this study is to evaluate the risk of the second primary tumors occurrence after NMSC development. A cohort of 2620 cases (1335 males and 1285 females) with nonmelanoma skin cancers registered in Bulgarian National Cancer Registry in 1993 was examined. The follow-up period represented a total of 15,856 person-years at risk. Over this period 128 (83 in men, 45 in women) new secondary tumors were established. After NMSC appearance, both genders show higher risk for the second primary tumors occurrence. This risk is greater for men. For both sexes after NMSC development there is increased risk for occurrence of second primary cancers of head and neck, thyroid, lung, larynx, bladder, colon, as well as cutaneous malignant melanoma, non-Hodgkin's lymphoma and leukemias. The results of considering only basal cell carcinomas show an elevated risk in patients of both sexes for appearance of second primary tumors of head and neck, bladder, larynx, lung and colon as well as non-Hodgkin's lymphoma and cutaneous malignant melanoma. The results of considering only squamous cell carcinomas show an increased risk in persons of both sexes for development of second primary cancers of head and neck, skin, thyroid, lung, stomach, as well as leukemias, non-Hodgkin's lymphoma and cutaneous malignant melanoma. The association between NMSC and subsequent increased risk for appearance of second primary skin and visceral tumors determine the necessity of monitoring the patients with NMSC.

Molecular diversity of gammadelta T cells in peripheral blood from patients with B-cell chronic lymphocytic leukaemia.

To characterize circulating gammadelta T cell subpopulations in B chronic lymphocytic leukaemia patients (n=30), TCR Vgamma and Vdelta gene-segment use was analyzed by RT-PCR using a panel of subfamily-specific oligonucleotide primers. All results were compared with those obtained with specimens from healthy donors (n=10). The cells expressing Vdelta1+ TCR displayed the highest relative increase in B-CLL patients (particularly observed in 60% of cases), but Vdelta3+ T lymphocytes also expanded in leukaemic peripheral blood (10% of studied cases). Both mentioned gammadelta T cell subsets were significantly more frequent in the most severe stages of disease--Rai III+IV. The analysis of Vgamma region usage in TCR formation revealed that gammadelta T cells from B-CLL patients predominantly expressed a Vgamma9 segment (26 of 30 cases), usually linked to Cgamma1 region. It should be noticed that the dominant TCR genes expression in a 50% of healthy donors was Vdelta2+/Vgamma9+, however, Vgamma4 and Vgamma8 transcripts were also observed (2 and 3 of 10 cases, respectively). The above results indirectly indicate that gammadelta T lymphocyte expansion was driven by the oligo- or polyclonal proliferation and can reflect specific response against the autologous tumor cells.

Immune-mediated complications during interferon alpha therapy in chronic myelogenous leukemia.

Several prospective randomized studies have shown that the treatment of chronic myeloid leukemia with interferon alpha (IFNalpha) prolongs the survival by comparison with conventional chemotherapy. However, long-term treatment with Interferon alpha can produce or exacerbate immune-mediated complications (IMC). The purpose of this study was to analyze the experience with IMC in patients with chronic myelogenous leukemia (CML) undergoing IFNalpha treatment. The occurrence of IMC was evaluated in 76 patients (47 male; 29 female) with Philadelphia chromosome (Ph)-positive CML. Diagnostic criteria of IMC were performed in patients with symptoms suggestive of particular disorders. Well-documented and clinically evident complications developed in 7 patients after a median of 19 months (range 1-84) of IFNalpha treatment. These included 9.2% patients with Ph-positive CML treated with IFNalpha-containing regimens. Hypothyroidism (H) occurred in 1 patient (1.3%), immune-mediated hemolysis (HEM) in 2 patients (2.6%) and connective tissue disorders (CTD) in 4 patients (5.3%) (2 systemic lupus erythematosus--SLE, 1 Raynaud's phenomena and 1 mixed connective tissue disease--MCTD). IFNalpha was discontinued in 3 patients and the dose was reduced in 2 patients. Five of 7 patients (75%) with immune-mediated complications had some degree of cytogenetic response at the time of the event. The association with female sex was strong and significant (86% vs 33.6%, x2; 48; p = 0.02). The frequency of IMC of clinical relevance with interferon alpha therapy in CML increased (long-term therapy). The patients treated with interferon alpha should be monitored for signs and symptoms of autoimmunity.

Expression of cell-cycle related proteins in Helicobacter pylori gastritis and association with gastric carcinoma.

Helicobacter pylori (H. pylori) infection is associated with changes in epithelial turnover, through their significance of these in gastric carcinogenesis is still controversial. The purpose of this study was to determine the influence of H. pylori infection on cell proliferation and the relation with the cell-cycle regulators, and finally to provide insights into the mechanism by which H. pylori may lead to gastric carcinogenesis. We investigated Ki-67, p53, p21(Waf1/Cip1), cyclin D1 expression in 55 patients with H. pylori gastritis, and compared the results with patients those of non-H. pylori gastritis patients (n=21), gastric adenocarcinoma patients (n=8) and samples with normal gastric mucosa (n=12). Gastric biopsies were histologically evaluated for inflammatory reaction, intestinal metaplasia and atrophy according to the Sydney system. Overexpression of Ki-67, p53, p21(Waf1/Cip1) and cyclin D1 was found in H. pylori gastritis patients (32.7%, 10.9%, 20.0% and 7.3%, respectively), whereas only scattered expression in cells in the neck region of the crypts, but no overexpression was found in gastric antral epithelial cells in biopsy specimens from patients with non-H. pylori gastritis and noninflammed mucosa. A significant relationship was found between the grade of H. pylori colonization and Ki-67, p53, p21(Waf1/Cip1) and cyclin D1 expression. Expression was significantly higher in patients with intestinal metaplasia with atrophy, whereas no overexpression was found in patients without intestinal metaplasia with atrophy (p=0.05). H. pylori infection is associated with increased cell proliferation, increased epithelial DNA damage, and atrophy, which might contribute to the development of gastric cancer. Even if the exact mechanism has not been elucidated yet, our results suggest that H. pylori infection acts as a cofactor in gastric carcinogenesis.

Contemporary therapeutic options for children with high risk neuroblastoma.

Despite the use of aggressive chemotherapy, stage 4 high risk neuroblastoma still has a very poor prognosis, which is estimated at 25%. Therefore, novel treatment approaches are needed. Increasing number of reports has been concerned with the use of novel treatment modalities. Literature regarding intensive induction, local therapy, myeloablative therapy and immunotherapy and biotherapy was reviewed in order to draw conclusions and recommendations for the management of children with high risk neuroblastic tumors.

High expression of Bcl-2 protein in acute myeloid leukemia cells is associated with poor response to chemotherapy.

Flow cytometric expression of bcl-2 protein was analyzed in 67 newly diagnosed acute myeloblastic leukemia (AML) patients using an anti-bcl-2 monoclonal antibody by direct immunofluorescence technique and results were correlated with FAB subtype, CD34 expression and clinical outcome. The number of bcl-2+ cells in each sample was heterogenous (range, 19% to 96%), with a mean of 81%. The percentage of bcl-2+ cells was higher in M0 and M1 types according to French-American-British classification. The mean fluorescence index (MFI), expressed as the ratio of sample channel:control mean channel was significantly higher (p=0.01) in M0 (19.0) and M1 (17.6) than M4 (11.7) and M5 (8.9) cytotypes. In addition, bcl-2 MFI significantly correlated both with CD34 positivity and with CD34 MFI. High percentage expression of bcl-2 and MFI index of bcl-2 was associated with a low complete remission rate after intensive chemotherapy (40.4% in cases with 20% and more positive cells vs 72% in cases with less than 20% positive cells). By statistical analysis we also demonstrated that both bcl-2 high MFI (>16) and CD34 expression are independent prognostic factors for achieving CR in AML.

Cladribine decreases the level of angiogenic factors in patients with chronic lymphocytic leukemia.

We investigated the serum concentration of basic fibroblast growth factor (bFGF) and transforming growth factor beta1 (TGFbeta1), using an enzyme linked immunosorbent assay (ELISA) in a group of 18 chronic lymphocytic leukemia (CLL) patients, before and after a successful treatment with cladribine (2-chlorodeoxyadenosine, 2-CdA) and 16 healthy volunteers. The serum level of bFGF was found to be significantly lower in the control group (median 0.15 pg/ml, range 0.0-15.7 pg/ml), when compared to the untreated CLL patients (median 41.4 pg/ml, range 2.1-292.6 pg/ml) (p=0.0002). After a successful 2-CdA treatment we observed a significantly lower level of this cytokine (median 10.55 pg/ml, range 0.4-140.4 pg/ml) (p=0.0019) in the same patients. However, the level of bFGF in this group was still higher than in the control group (p=0.003). The levels of TGFbeta1 were higher in the group of untreated CLL patients (median 31.36 ng/ml, range 14.36-75.71 ng/ml) than in the control group (median 28.35 ng/ml, range 10.85-70.10 ng/ml) (p=0.029). After the 2-CdA treatment serum concentration of this cytokine decreased significantly (median 20.34 ng/ml, range 3.02-43.85 ng/ml) (p=0.031) with similar levels present to that of the healthy control group (p=0.3). In conclusion, we have shown that the serum concentration of bFGF and TGFbeta1 in CLL patients were significantly reduced after 2-CdA chemotherapy that resulted in remission. The level of these factors might correlate with the activity of the disease.

Angiogenesis and Bcl-2 protein expression in patients with endometrial carcinoma.

Considering the particular importance of angiogenesis and tumor suppressor genes expression in solid tumors, angiogenesis and Bcl-2 protein expression were evaluated in order to specify their role in the biology of endometrial carcinoma. Clinical material comprised 66 patients (postmenopausal, aged 52 to 76 years) with endometrial adenocarcinoma. For evaluation of angiogenesis immunohistochemical method was applied using DAKO EPOS Anti-Human Von Willebrand Factor/HRP antibodies. Morphometric method was applied to count angiogenic points (microvessels + single endothelial cells), using a light microscope with morphometric appliance. Angiogenic points density (APD) was defined as the density of AP per square mm. Immunohistochemical staining for Bcl-2 cytosomic protein expression was performed using MoAb124 (dilution 1:80, Dako A/S, Denmark) monoclonal antibodies. The percentage of 10% positive cells was considered as Bcl-2 positive tissue expression. Positive cytoplasmic reaction of Bcl-2 in 51.3% of patients with Stage I endometrial cancer, and in 23.8% and 0% of patients with II and III FIGO stage, respectively, was observed. No relationship between Bcl-2 tissue cytoplasmatic expression and tumor grade was found. However, an inverse correlation between cytoplasmatic expression of Bcl-2 and FIGO stage was observed. The APD (angiogenic points density) was increasing with the clinical (FIGO) stage of endometrial cancer, but it was not observed in the case of tumor histologic grade. Bcl-2 expression and angiogenesis may be a useful parameter in evaluation of the biology of endometrial adenocarcinoma as the study conducted showed the influence of Bcl-2 protein expression upon angiogenesis.

Assessment of coagulation disorders and cancer procoagulant activity in patients with myelodysplastic syndromes.

Hemostatic disorders mainly due to thrombocytopenia represent an important clinical problem in patients with myelodysplastic syndromes (MDS). Much less is known about the possible coagulation abnormalities. Thirty patients with MDS were studied. Activity of cancer procoagulant (CP), concentrations of activation markers of coagulation and fibrinolysis such as thrombin-antithrombin complexes (TAT), prothrombin fragment 1+2 (F1+2) and D-dimers (DD) as well as standard coagulation tests were determined. Coagulation abnormalities concerned mainly patients with RAEB and RAEB-t. In this group the mean values of TATand F1+2 concentrations were significantly higher than in control indicating chronic coagulation activation similar to that observed in acute leukemias. CP activity in MDS patients did not differ from the control group.

Malignant melanoma associates with Th1/Th2 imbalance that coincides with disease progression and immunotherapy response.

The immunological dysfunction associated with human cancer is well known phenomenon. It comprises number of pathological changes within immune network including imbalance in cytokines of Th1/Th2 origin. The objectives of our study were (i) to evaluate the abnormalities in serum levels of selected cytokines in malignant melanoma patients with regional lymph node metastases as compared to normal values, (ii) to examine the relationship between postoperative cytokine levels and disease progression and (iii) to correlate cytokine profile changes during IFN-alpha therapy with the disease progression and potential therapeutical response. Nine Th1/Th2 related cytokines and sIL-2R were determined in 26 malignant melanoma patients at clinical stage III prior and during adjuvant immunotherapy. Control group consisted of 26 healthy persons. Patients were treated with rIFN-alpha according to EORTC Melanoma group protocol 18952. Cytokines were quantified in patients sera using commercial ELISA kits. Majority of melanoma patients showed significantly lower values of IL-2 and IFN-gamma and pathologically elevated levels of IL-4, IL-6, IL-10 as compared to healthy subjects what indicates disease associated Th1/Th2 imbalance. In addition increased IL-12 and IL-15 values were noted in some patients (54% and 27%, respectively). All patients who manifested early relapse during immunotherapy had significantly lower pretreatment levels of IL-2 and IL-12 than those remaining without progression and probably benefiting from the treatment. Cytokine changes during immunotherapy disclosed that decreases in IL-2 and IL-12 and raises in IL-6 and IL-10 values occurred at least one month prior to relapse. Moreover, the continuous elevation of TNF-alpha and sIL-2R could be observed in patients who remained without progression during 10 months lasting immunotherapy. Our data illustrate that malignant melanoma associates with Th1/Th2 perturbances which are directed towards extended Th2 responses and that measurement of selected cytokines of Th1/Th2 category may be used as an early signal of disease deterioration and for evaluation of immunotherapy response.

Cytotoxicity and mode of action of the potential cytostatic drug oracin.

Primary screening in vitro and study on the mode of action of oracin in Ehrlich ascites carcinoma cells have been performed. The measure of the cytotoxic effect was the degree of inhibition of 14C-adenine and 14C-valine incorporation into TCA insoluble fraction of Ehrlich ascites carcinoma (EAC) cells. The inhibitory effect was characterized by IC50 values. The biosynthesis of nucleic acides indicated by the incorporation of 14C-adenine was more sensitive (IC50 = 66 micromol/ l) than the biosynthesis of proteins indicated by the incorporation of 14C-valine (IC50 = 196 micromol/l). To elucidate the biochemical mode of action, the effect of oracin on dynamics of biosynthesis of macromolecules indicated by the incorporation rate of [14C] labeled precursors (adenine, thymidine, uridine, valine) into appropriate macromolecules of EAC cells was studied. Oracin inhibited incorporation of all four precursors into the trichloracetic acid - insoluble fraction of Ehrlich ascites cells. The extent of inhibition was dependent on both time and drug concentration. We found that oracin inhibited activity of topoisomerase II by 100% at concentration 5 to 15 micromol/l.

Nuclear receptors in early hormone refractory prostate cancer and their relationship to apoptosis-related proteins.

The expression of several genes involved in apoptosis and cell cycle control can be regulated by steroid hormones and related agents via their nuclear receptors. Members of the bcl-2 gene family participate in the regulation of apoptosis in a diverse range of cell types and are implicated in the development of hormone refractory prostate cancer and resistance to anti-cancer therapy. The aim of this study, therefore, was to examine the expression of several nuclear receptors in relation to the expression of apoptosis and cell cycle related proteins in a series of patients with early hormone refractory prostate cancer. Analysis of protein expression revealed only a weak association between Bcl-2 and AR. Bax positivity and p27Kip1 expression were significantly more frequent in the AR-positive tumors, whereas RXRbeta expression was more frequently observed in the AR-negative group. The expression of AR, Bax and p27Kip1 was inversely related, and the expression of RXRbeta directly related, to Gleason pattern status. These results suggest that the immunophenotype of early hormone refractory prostate cancer may be different to that seen in more advanced stage disease. Androgen withdrawal therapy employing anti-androgens may elicit different signalling pathways that may be dependent on ARstatus and ARsensitivity.

In vitro comparative antileukemic activity of various glucocorticoids in childhood acute leukemia.

Resistance to glucocorticoids is nowadays one of the strongest adverse risk factors in the treatment of childhood acute lymphoblastic leukemia (ALL). Differential in vitro antileukemic activity of various glucocorticoids and their cross-resistance pattern in childhood acute lymphoblastic and myeloblastic leukemia was determined by means of the MTT assay in 49 successfully tested samples of childhood acute leukemia. The equivalent antileukemic concentrations of respective drugs against lymphoblasts in de novo ALL samples were: 35 microM of hydrocortisone; 8 microM of prednisolone; 1.6 microM of methylprednisolone; 0.47 microM of dexamethasone and 0.23 microM of betamethasone. In comparison to initial ALL samples, the group of relapsed ALL was more resistant to: prednisolone (38-fold, p=0.004), dexamethasone (>32-fold, p=0.004), methylprednisolone (37-fold, p=0.039), betamethasone (38-fold, p=0.018) and hydrocortisone (33-fold, p=0.030). The group of acute myeloid leukemia (AML) samples were resistant to: prednisolone (>83-fold, p<0.001), dexamethasone (>32-fold, p<0.004), methylprednisolone (>65-fold, p=0.003), betamethasone (>66-fold, p=0.004) and hydrocortisone (61-fold, p=0.007), when compared to ALL at presentation. A significant cross-resistance between all used glucocorticoids as well as between glucocorticoids and other tested anti-leukemic drugs was found. In some individual cases in vitro glucocorticoid cross-resistance was less pronounced and relatively good antileukemic activity of betamethasone was observed.

Variability of chromosomes in the VUP permanent cell line derived from uveal malignant melanoma.

A permanent cell line [VUP] derived 31 years ago from human malignant melanoma of the choroid has been characterized by genetically firmly anchored heteronuclearity. The most significant chromosomal changes of this cell line are: high instability of the chromosome No. 13 with the rise of new chromosomes formed by translocations, homologous stability of chromosomes 6, 15, and X. Structural changes were not revealed in chromosomes 15 and 22. The variability of chromosomes was studied both by classical conventional methods as well as with GTG banding and DNA hybridization in situ (FISH). Structural diversity was demonstrated in a number of morphologically congruent chromosomes. For example, X chromosome classified morphologically as chromosome No. 10 was determined by means of FISH technique, as a centric fragment Xq with translocated acentric fragment of other chromosomes. Furthermore, mar-t, previously considered to be q arm of chromosome No. 4, is formed by a centric fragment of chromosome No. 13 and an acentric fragment of chromosome No. 1.

The role of neoadjuvant chemotherapy in marginally resectable or unresectable stage III non-small cell lung cancer.

The study was undertaken to test whether marginally resectable or unresectable stage IIIa-IIIb non-small cell lung cancer (NSCLC) patients could reach complete resectability after induction chemotherapy. Fifty six patients were included into the study and treated either by vinorelbine 35 mg/m2 day 1 and cisplatin 75 mg/m2 day 1 (n=28) or by vinorelbine 30 mg/m2 day 1 and 8 and cisplatin 80 mg/m2 day 1 (n=28). Cycles were repeated every 21 days. At the completion of induction therapy patients assessed to be resectable underwent thoracotomy. Radiation therapy was applicated in nonresected cases. The minimal follow up was 24 months. 32% of patients with marginally resectable or unresectable stage IIIa-IIIb NSCLC could reach a complete resectability after induction chemotherapy. Survival of patients stage IIIa was comparable to stage IIIb. Responders and resected patients survived significantly longer comparing to the patients with stable disease and progression, respectively to the incompletely resected plus nonresected patients. Perioperative complications were rare and there were no treatment-related deaths in our study. The main surgery-related complication was late bronchopleural fistula.

Efficacy and toxicity of MDR versus HDR brachytherapy for primary vaginal cancer.

The retrospective analysis includes a group of 50 patients with primary, invasive vaginal cancer treated with brachytherapy in the period of 1982-1993. Over 80% cases were squamous cell carcinoma. There were 14 patients in stage I according to FIGO classification and 20%, 36%, and 16% of patients in stage II, III and IV, respectively. Twenty one patients (42%) received MDR brachytherapy using Cs137 source, the remaining 29 (58%) were treated with HDR using Co60 or Ir192 sources. Among 50 patients 31 (62%) received also external beam irradiation. An overall 5-year actuarial disease-free survival was 40%, and it was 78.6% (11/14), 40% (4/10), 27.8% (5/18), 0% (0/8) for stage I, II, III and IV, respectively. For MDR or HDR5-year disease-free survival was 38% and 41%, respectively. No influence of dose rate on survival has been found (p=0.7). Local failure occurred in 20 patients (40%). Recurrences appeared in 10 patients (20%). Late complications rate was 0% and 17% for MDR and HDR, respectively. Effectiveness of brachytherapy MDR and HDR was similar, whereas serious late complications developed more often after HDR brachytherapy.

Aerosol orgotein (Ontosein) for the prevention of radiotherapy-induced adverse effects in head and neck cancer patients: a feasibility study.

Orgotein is an anti-inflammatory superoxide dismutase agent successfully used in treating several inflammatory diseases. It is also used in treating radiation-induced adverse effects in difference malignancies, notably breast, lung, bladder, prostate, cervix, and head and neck cancers. It is administered either topically or parenterally. To our knowledge, it has never been used before for prophylaxis of radiation-induced adverse effects or in aerosol form. Here we report on the results from a feasibility study on aerosol orgotein (Ontosein) for prevention of acute and deferred radiation-induced adverse effects in patients treated for head and neck malignancies. Our results show that aerosol orgotein administered before each radiation therapy session may impart some benefits in both incidence and severity of acute and deferred radiation-induced adverse effects in head and neck cancer patients, when compared with historical controls. In addition, aerosol orgotein administration is easy and convenient for both the patient and the radiotherapist.

Genetic polymorphism of N-acetyltransferase and glutathione S-transferase related to neoplasm of genitourinary system. Minireview.

Genetically determined risk factors may considerably contribute to the development of neoplastic diseases, including neoplasm of urinary organs, e.g. bladder and prostate cancers. It is believed that they may result, among others, from the differences in the metabolism of environmental carcinogens and mechanisms of DNA repair. There is a clear evidence that the kind and rate of metabolism is genetically determined by polymorphic enzyme coding genes participating in the process of xenobiotic transformation. Genetic polymorphism has been confirmed for a number of enzymes involved in the reaction of oxidation or conjugation of exo- and endogenous xenobioties. Gene variability may alter the expression or enzymatic activity of coded enzymes. Therefore, the cancer risk assessment should also be based on individual differences in the ability to activate (phase I) or to detoxify (phase II) possible carcinogens. In the present study, the information on the significance of glutathione 5-transferase (GST) and N-acetyltransferase (NAT) gene families in protection of human health and incidence of various diseases is summarized. The role of hereditary polymorphisms of GST and NAT genes involved in the etiology of neoplasm of urinary organs is controversial. That is why, special attention has to be focused on the recent information on a possible role of GST and NAT polymorphisms in the predisposition to urinary bladder, prostate and urothelial transitional cell carcinoma.

New approach to human high-risk papillomavirus (HR-HPV) genotyping.

Human high-risk papillomaviruses (HR-HPVs) are involved in the induction of invasive cervical cancer. The aim of this study was to introduce a simple, semi-automated and reproducible approach suitable for HR-HPV detection in clinical practice. The procedure is based on DNA isolation, nested polymerase chain reaction, single strand conformational polymorphism and evaluation of HR-HPV genotypes with Gel-Pro software. The clinical performance of the new approach was assessed in two different patient materials: 1) cervical smears with cytological classification Pap2-3 or Pap3 lacking nuclear atypia (anisonucleosis and polychromasia) or koilocytotic atypia and without any previous therapy 2) formalin-fixed, paraffin-embedded cervical carcinoma and lymph node sections. Using the new approach we detected HR-HPV DNA in 64% patient samples cytologically classified as Pap2-3 or Pap3 respectively and in 80% formalin-fixed, paraffin-embedded lymph node sections histologically classified as lymph nodes without carcinoma cell infiltration. The combination of methods described in this study results in increased sensitivity of HR-HPV identification allowing detection of HPV DNA in a very small amount of target DNA so that it can be widely used in distinguishing the pre- malignant lesions and in determination of invading carcinoma cells to lymph nodes in patients with advanced cervical cancer. The new approach is useful in unambiguous HR-HPV genotyping even in double-HPV infection.

Nm23H1 and p53 proteins are differentially correlated to metastasis in breast carcinoma.

The prognostic significance of nm23H1 and p53 proteins as predictors of nodal involvement and distant recurrence was evaluated in 63 cancer and 47 benign lesions of the breast. Assessment was carried out by immunohistochemical staining using nm23H1 and p53 antibodies. Results show no relation of nm23H1 either to the malignant nature when compared to benign lesions or to the nodal status. P53 protein, on the other hand, showed significantly increased expression in malignant lesions (p=0.001) and correlated well with nodal positivity (p=0.03). A follow-up study of 5 years showed that among the cases showing recurrence, those with positive mn23H1 showed a shorter distant recurrence free survival (DRFS, p=0.01), while p53 expression had no effect. This result did not agree with the previous reports showing nm23H1 as an antimetastatic gene. This is the first report of positive correlation between nm231-11 and distant recurrence in breast cancers, though such a correlation was reported earlier in certain other cancers. Since nm23H1 is an NDP kinase, having more involvement in signal transduction of cell proliferation, it is not difficult to comprehend such a role for nm23H1 during recurrence. Combining the expression of both proteins, lesions positive for both p53 and nm23H1 had significantly reduced distant recurrence free survival (DRFS), when compared to those negative for both proteins (p=0.0006). It can be concluded that nni23H1 alteration has a potential in predicting DRFS, while p53 alteration has the potential to predict lymph node involvement.

PK11195, an isoquinoline carboxamide ligand of the mitochondrial benzodiazepine receptor, increased drug uptake and facilitated drug-induced apoptosis in human multidrug-resistant leukemia cells in vitro.

The isoquinoline peripheral benzodiazepine receptor ligand PK11195 increased drug (daunomycin)- and fluorochrome (calcein-AM) uptake and induced apoptosis detected by flow cytometry (FCM) technique, DNA electrophoretic analysis and poly(ADP-ribose) polymerase (PARP) cleavage in human multidrug-resistant myeloid leukemia (BL-60/VCR) and ovarian carcinoma (A2780/ADR) cells in vitro. The position of PK11195 with respect to drug-resistance modulator (DRM) efficiency, compared to the reference DRMs with the aid of FCM technique, was as follows: PSC833 > verapamil > PK11195 > vincristine. Our data show up to now not indicated observation that PK11195 possesses multidrug resistance modulating activity.

CT densitometry of the brain: a novel method for early detection and assessment of irradiation induced brain edema.

The purpose of the study was to examine if the CT densitometric analysis during radiotherapy (RT) of brain tumors is suitable for the early detection of RT induced brain edema (BE), predicting related neurological progress, and assessing the effects of different edema therapies. Planimetric CT-densitograms were constructed by modifying the "High-Lighting" method. Three theoretical density regions were defined and color-coded on the images of the brain. These were defined as edema (10-20 HU), mild edema, and normal brain (29-38 HU). Corresponding axial CT slices were created at the mid-level of the lesion and that of the periventricular white matter to verify the changes in perifocal and diffuse BE. The monitoring was performed on 50 solitary brain tumor patients treated with RT. During RT courses weekly CT-densitometric examinations were carried out. We experienced that changes in densitograms coincided with clinical symptoms, furthermore, preceded the latter. With the use of preventive edema medication based on diuretics and along with adjunctive edema medication adopted to densitograms, the 5-7 week irradiation was completed without ultimate worsening in performance state in 49 of 50 cases and besides we succeeded in avoiding the routine usage of steroids. Based on our findings the CT-densitometry is suitable for early detection and continuous assessment of BE and preventing patient distress during RT. This simple, reproducible and non-invasive procedure could provide an additional clinical tool for new treatment strategies.

Does renal carcinoma affect the expression of P-selectin on platelets?

We studied changes in the expression of P-selectin on the blood platelet plasma membrane. The aim of the study was to determine the influence of renal carcinoma on P-selectin expression associated with changes in platelet morphology. Venous blood was collected from 30 patients with renal carcinoma and from 24 control subjects for cytometric analysis and to evaluate platelet morphology. P-selectin being the CD62P receptor on blood platelets was marked by anti-CD61/62P MoAb, and the results were presented as the percentage of CD62P-positive cells. Changes in the expression of the CD62P on the platelet plasma membrane during activation were investigated by flow cytometry in a comparative study of in vivo activation and in vitro platelet reactivity. Platelet activation reflected by P-selectin expression was higher in the group of patients (4.45 +/-1.96), compared to control (2.48 +/-1.66) (p < 0.05). However, adenosine diphosphate [ADP] -stimulated platelet reactivity in renal cancer patients increased only by 0.24% (p > 0.05), while following activation by thrombin by 0.54% (p < 0.05). Moreover, a higher (4.72 +/-2.02), statistically significant percentage of platelets with P-selectin expression was found in patients with disseminated neoplastic changes in renal parenchyma, compared to patients with a single localized neoplastic lesion (4.17 +/-1.89) (p < 0.05). A statistically significant difference was noted in the platelet count and anisocytosis in renal cancer patients. Renal cancer enhances P-selectin expression. It is due to the presence of intensified thrombinogenesis and other platelet agonists in the blood.

Carcinogenic effect of combined administration of 2,4-diaminoanisole sulfate, 4,4'-thiodianiline and N,N'-diethylthiourea in male Wistar rats.

Male Wistar rats were divided into two groups. Rats of group 1 were fed basal powdered diet containing 610 ppm 2,4- diaminoanisole sulfate (DAAS), 46 ppm 4,4'-thiodianiline (TDA) and 200 ppm N,N'-diethylthiourea (DETU) for 52 weeks (DTD treatment). Rats of group 2 were maintained on basal diet throughout the experiment as controls. At 52 weeks all surviving rats were sacrificed and subjected to an autopsy. Thyroid, lungs, stomach, liver, spleen, kidneys, testes and all gross lesions suspected of being a tumor were removed. After DTD treatment, the incidence of thyroid hyperplasia and papillary thyroid carcinoma was 59% (10/17) and 65% (11/17), respectively. Hepatocellular adenoma was induced in 2 of 17 rats (12%). Papillary thyroid carcinoma metastasis was found in the lung of 1 rat. No neoplastic tumors were found in kidney, spleen, stomach and testis tissue.

Detection of cervical lymph node metastases in nasopharyngeal carcinomas: comparison between technetium-99m methoxyisobutylisonitrile single photon emission computed tomography and magnetic resonance imaging.

We compared the effectiveness technetium-99m methoxyisobutylisonitrile (Tc-99m MIBI) single photon emission computed tomography (SPECT) and magnetic resonance imaging (MRI) of head and neck in evaluating cervical lymph node (LN) metastasis in nasopharyngeal carcinomas (NPC). Forty NPC patients with cervical LN metastases confirmed histopathologically underwent Te-99m MIBI SPECT and MRI of the head and neck to evaluate cervical LN metastases. For 16 LN lesions with discordant results between Tc-99m MIBI SPECT and MRI, Tc-99m MIBI SPECT could correctly detect 1 metastatic and 10 benign LN lesions as well as MRI could correctly detect 3 metastatic and 2 benign LN lesions. Agreement positive results of Tc-99m MIBI SPECT and MRI could correctly detect all of the remaining 24 metastatic LN lesions. Tc-99m MIBI SPECT has a better specificity but a lower sensitivity for detecting cervical LN metastases in NPC when compared with MRI. The combined use of Tc-99m MIBI SPECT and MRI could increase the accuracy compared with the single use of either Te-99m MIBI SPECT or MRI to detect cervical LN metastases in NPC.