István Bodrogi

Publications of István Bodrogi

• An international expanded-access programme of everolimus: addressing safety and efficacy in patients with metastatic renal cell carcinoma who progress after initial vascular endothelial growth factor receptor-tyrosine kinase inhibitor therapy.

  Authors: Viktor Grünwald, Pierre I Karakiewicz, Sevil E Bavbek, Kurt Miller, Jean-Pascal Machiels, Se-Hoon Lee, James Larkin, Petri Bono, Sun Young Rha, Daniel Castellano, Christian U Blank, Jennifer J Knox, Robert Hawkins, Oezlem Anak, Marianne Rosamilia, Jocelyn Booth, Nicoletta Pirotta, István Bodrogi

  European journal of cancer (Oxford, England : 1990). 07/2011; 48(3):324-32.

  The RECORD-1 trial established the clinical benefit of everolimus in patients with metastatic renal cell carcinoma (mRCC) after failure of initial vascular endothelial growth factor receptor-tyrosineThe RECORD-1 trial established the clinical benefit of everolimus in patients with metastatic renal cell carcinoma (mRCC) after failure of initial vascular endothelial growth factor receptor-tyrosine kinase inhibitor (VEGFr-TKI) therapy. The REACT (RAD001 Expanded Access Clinical Trial in RCC) study was initiated to address an unmet medical need by providing everolimus prior to commercial availability, and also to further assess the safety and efficacy of everolimus in patients with VEGFr-TKI-refractory mRCC. REACT (Clinicaltrials.gov: NCT00655252) was a global, open-label, expanded-access programme in patients with mRCC who were intolerant of, or who had progressed on or after stopping treatment with, any available VEGFr-TKI therapy. Patients received everolimus 10mg once daily, with dose and schedule modifications allowed for toxicity. Patients were closely monitored for the development of serious and grades 3/4 adverse events (AEs). Response was assessed by RECIST every 3months for the first year and every 6months thereafter. A total of 1367 patients were enroled. Safety findings and tumour responses were consistent with those observed in RECORD-1, with no new safety issues identified. The most commonly reported serious AEs were dyspnoea (5.0%), pneumonia (4.7%) and anaemia (4.1%), and the most commonly reported grades 3/4 AEs were anaemia (13.4%), fatigue (6.7%) and dyspnoea (6.5%). Best overall response was stable disease in 51.6% and partial response in 1.7% of patients. Median everolimus treatment duration was 14weeks. Everolimus is well tolerated in patients with mRCC and demonstrates a favourable risk-benefit ratio.

• A randomized, double-blind, placebo-controlled phase II study of vandetanib plus docetaxel/prednisolone in patients with hormone-refractory prostate cancer.

  Authors: József Horti, Anders Widmark, Arnulf Stenzl, Miriam H Federico, Raymond P Abratt, Nick Sanders, Gillian M Pover, István Bodrogi

  Cancer biotherapy & radiopharmaceuticals. 04/2009; 24(2):175-80.

  Vandetanib (ZACTIMA) is a once-daily oral anticancer drug that selectively inhibits vascular endothelial growth factor receptor, epidermal growth factor receptor, and rearranged during transfectionVandetanib (ZACTIMA) is a once-daily oral anticancer drug that selectively inhibits vascular endothelial growth factor receptor, epidermal growth factor receptor, and rearranged during transfection signaling. This randomized (1:1), double-blind study evaluated vandetanib (100 mg/day) or placebo in combination with docetaxel (D; 75 mg/m(2) every 3 weeks) and prednisolone (P; 2 x 5 mg/day) in 86 patients with metastatic hormone-refractory prostate cancer (mHRPC). The primary assessment was prostate-specific antigen (PSA) response (confirmed reduction of >or=50% from baseline) and a greater number of patients showed a PSA response with placebo + DP (67%) versus vandetanib + DP (40%); hazard ratio = 2.23 (one-sided 80% confidence limit = 2.90; one-sided p = 0.99). More patients experienced progression events (disease progression or death from any cause) with vandetanib + DP (65%) versus placebo + DP (60%); hazard ratio = 1.13 (one-sided 80% confidence limit = 1.44; one-sided p = 0.67). The overall incidence of adverse events was similar in both groups, although more patients experienced adverse events, leading to permanent discontinuation with vandetanib + DP (28%) versus placebo + DP (12%). However, the safety and tolerability profile for vandetanib was similar to that previously reported; adverse events that occurred more frequently in the vandetanib + DP arm were hypertension (14% vs. 2%), erythematous rash (14% vs. 2%), and exfoliative rash (12% vs. 2%). In this study of patients with mHRPC, vandetanib + DP did not demonstrate any efficacy benefit, compared with placebo + DP.

• European consensus conference on diagnosis and treatment of germ cell cancer: a report of the second meeting of the European Germ Cell Cancer Consensus Group (EGCCCG): part II.

  Authors: Susanne Krege, Jörg Beyer, Rainer Souchon, Peter Albers, Walter Albrecht, Ferran Algaba, Michael Bamberg, István Bodrogi, Carsten Bokemeyer, Eva Cavallin-Ståhl [......] Niels E Skakkebaek, Aslam Sohaib, Sergei Tjulandin, Padraig Warde, Stefan Weinknecht, Lothar Weissbach, Christian Wittekind, Eva Winter, Lori Wood, Hans von der Maase

  European urology. 04/2008; 53(3):497-513.

  OBJECTIVES: The first consensus report that had been presented by the European Germ Cell Cancer Consensus Group (EGCCCG) in 2004 has found widespread approval by many colleagues throughout the world.OBJECTIVES: The first consensus report that had been presented by the European Germ Cell Cancer Consensus Group (EGCCCG) in 2004 has found widespread approval by many colleagues throughout the world. In November 2006, the group met a second time under the auspices of the Department of Urology of the Amsterdam Medical Center, The Netherlands. METHODS: Medical oncologists, urologic surgeons, radiation oncologists as well as pathologists from several European countries reviewed and discussed the data that had emerged since the 2002 conference and incorporated the new data into updated and revised guidelines. As for the first meeting the methodology of evidence-based medicine (EBM) was applied. The results of the discussion were compiled by the writing committee. All participants have agreed to this final update. RESULTS: The second part of the consensus paper includes the treatment of metastasised disease, residual tumour resection, salvage therapy, follow-up, and late toxicities. CONCLUSIONS: Whereas the vast majority of the recommendations made in 2004 remain valid 3 yr later, refinements in the treatment of early-stage as well as of advanced-stage testicular cancer have emerged from clinical trials. Despite technical improvements, expert clinical skills will continue to be one of the major determinants for the prognosis of patients with germ cell cancer. In addition, the particular needs of testicular cancer survivors have been acknowledged.

• European consensus conference on diagnosis and treatment of germ cell cancer: a report of the second meeting of the European Germ Cell Cancer Consensus group (EGCCCG): part I.

  Authors: Susanne Krege, Jörg Beyer, Rainer Souchon, Peter Albers, Walter Albrecht, Ferran Algaba, Michael Bamberg, István Bodrogi, Carsten Bokemeyer, Eva Cavallin-Ståhl [......] Niels E Skakkebaek, Aslam Sohaib, Sergei Tjulandin, Padraig Warde, Stefan Weinknecht, Lothar Weissbach, Christian Wittekind, Eva Winter, Lori Wood, Hans von der Maase

  European urology. 04/2008; 53(3):478-96.

  OBJECTIVES: The first consensus report presented by the European Germ Cell Cancer Consensus Group (EGCCCG) in the year 2004 has found widespread approval by many colleagues throughout the world. InOBJECTIVES: The first consensus report presented by the European Germ Cell Cancer Consensus Group (EGCCCG) in the year 2004 has found widespread approval by many colleagues throughout the world. In November 2006, the group met a second time under the auspices of the Department of Urology of the Amsterdam Medical Center, Amsterdam, The Netherlands. METHODS: Medical oncologists, urological surgeons, radiation oncologists as well as pathologists from several European countries reviewed and discussed the data that had emerged since the 2002 conference, and incorporated the new data into updated and revised guidelines. As for the first meeting, the methodology of evidence-based medicine (EBM) was applied. The results of the discussion were compiled by the writing committee. All participants have agreed to this final update. RESULTS: The first part of the consensus paper describes the clinical presentation of the primary tumor, its treatment, the importance and treatment of testicular intraepithelial neoplasia (TIN), histological classification, staging and prognostic factors, and treatment of stage I seminoma and non-seminoma. CONCLUSIONS: Whereas the vast majority of the recommendations made in 2004 remain valid 3 yr later, refinements in the treatment of early- and advanced-stage testicular cancer have emerged from clinical trials. Despite technical improvements, expert clinical skills will continue to be one of the major determinants for the prognosis of patients with germ cell cancer. In addition, the particular needs of testicular cancer survivors have been acknowledged.

• [Effect of angiogenesis inhibitors on renal cell carcinoma]

  Authors: István Bodrogi

  Magyar onkologia. 02/2007; 51(2):145-53.

  Sporadic renal cell carcinomas are characterized by EGFR (HER-1) and EGFR-2 (HER-2) expression, however, signal transduction inhibitors of this pathway were clinically ineffective. Clear cell renalSporadic renal cell carcinomas are characterized by EGFR (HER-1) and EGFR-2 (HER-2) expression, however, signal transduction inhibitors of this pathway were clinically ineffective. Clear cell renal cell cancer is hormone-, irradiation- and chemotherapy resistant with moderate sensitivity to immunotherapy. The only clinically effective class of agents in case of this tumor type was proved to be the angiosuppressive agents. In 2005 FDA approved sorafenib for the first line treatment while in 2006 sunitinib for second line treatment in the cytokine resistant medium-risk renal cell carcinoma. This was followed by the European approval of both agents for second line treatment of renal cell cancer. Sunitinib was approved for first line treatment of renal cell cancer in Europe based on a phase III trial comparing it to interferon. Temsirolimus obtained its approval for the treatment of high risk renal cell cancer patients in 2007. Last but not least, FDA approval is on the way in case of bevacizumab as well to treat renal cell cancer. Based on the data demonstrated on the ASCO'2007, various modalities have to be developed for various stages of progression of clear cell renal cell cancer.

• [Molecular pathology and targeted therapy of clear cell renal cancer]

  Authors: József Tímár, László Kopper, István Bodrogi

  Magyar onkologia. 02/2006; 50(4):309-14.

  The golden standard of care for advanced renal cell cancer (RCC) was until now the cytokine therapy with relatively low response rates. Advances of molecular genetics in RCC revealed severalThe golden standard of care for advanced renal cell cancer (RCC) was until now the cytokine therapy with relatively low response rates. Advances of molecular genetics in RCC revealed several molecular targets such as VHL and angiogenic genotype or EGFR in the clear cell variant. Among the novel targeted agents, multiple tyrosine kinase inhibitors were proved to be clinically effective against advanced clear cell renal cancer, changing the standard of care. It is a further question how molecular diagnostics can improve these results by the detection of these targets or gene defects in individual tumors.

• [Detection of late ototoxic side effect of cisplatin by distortion otoacoustic emission (DPOAE)]

  Authors: Krisztina Biró, László Noszek, Péter Prekopp, Krisztián Nagyiványi, Lajos Géczi, István Gaudi, István Bodrogi

  Magyar onkologia. 02/2006; 50(4):329-35.

  Cisplatin-based chemotherapy results in high cure rate in testicular cancer. The issue of toxicity is of special concern in young men with a probability of cure of at least 70-80% even inCisplatin-based chemotherapy results in high cure rate in testicular cancer. The issue of toxicity is of special concern in young men with a probability of cure of at least 70-80% even in disseminated disease. As the literature shows, the ototoxic side effects of cisplatin have been studied mostly by conventional method. The authors used distortion product otoacoustic emission to detect the long-term ototoxic effect of cisplatin in 223 patients with a median follow-up time of 4.27 years (range 0.5-20 years) and a median age of 37 years (range 18-55 years). Cisplatin (20 mg/m(2) body surface) was administered for five days per cycle, in combination with other antitumor drugs. The control group consisted of 40 testicular cancer patients who did not receive chemotherapy, with a median age of 35 years (range 16-54 years). A detailed medical history based on a standardized questionnaire evaluated hearing complaints and audiological risk factors, such as head injuries, chronic otitis media, previous noise exposure and familial hearing loss. DPOAE was measured at 8 frequencies from 750 to 8000 Hz. No amplitude changes were detected in patients receiving =300 mg/m(2) cisplatin. At higher doses, contrary to the literature, not only high frequencies were affected: our method could detect significant hearing impairment at lower frequencies important for speech perception in patients receiving at least 400 mg/m(2) cisplatin. The lower frequencies where significant amplitude changes were detected were 3000 Hz at 400 mg/m(2), and 1500, 2000 and 3000 Hz at 500-600 mg/m(2). We detected the worst hearing in the case of patients who had symptomatic ototoxicity. Age and the cumulative dose of cisplatin proved statistically significant risk factors, while smoking or noise exposure did not have predictive value. As a conclusion, DPOAE is a fast, noninvasive and reliable method for the detection of late ototoxicity in testicular cancer patients. In our study hearing loss correlated with the cumulative dose of cisplatin. Hearing impairment contributes to the already compromised situation of cancer patients.

• Increased predisposition to cancer in brothers and offspring of testicular tumor patients.

  Authors: Sarolta Gundy, Mária Babosa, Márta Baki, István Bodrogi

  Pathology oncology research : POR. 02/2004; 10(4):197-203.

  Cancer susceptibility was examined in first-degree relatives of 293 testicular tumor patients (TTPs) and 586 age-matched healthy males. Significantly increased risk was found in the families of TTPsCancer susceptibility was examined in first-degree relatives of 293 testicular tumor patients (TTPs) and 586 age-matched healthy males. Significantly increased risk was found in the families of TTPs (OR: 1.4; CI: 1.08-1.79), however, except for testicular cancer of 7 brothers (OR: 11.7; CI: 1.42-256.5), and 6 various childhood tumors (bilateral Wilms' tumor, neuroblastoma, medulloblastoma, ALL, histiocytosis-X, testicular tumor) of 200 offspring (OR: 12.9; CI: 1.54-286.2), no association with other malignancies was observed. No differences were seen between the fertility of patients and controls when occupational or socio-economic status of the families was taken into account. However, the majority of the controls (85%) fathered the first child between 20-30 years of age, while only 61% of TTPs had the first child in the same age group. TTPs fathered more girls than boys (P=0.009), and the lower male - higher female ratio of index children was also identical, irrespective of the conception taking place before or after the father's treatment. Occupations did not, but smoking might have influenced cancer susceptibility of the patients. Aggregation of fraternal testicular tumors, and both dramatically increased cancer risk and altered sex ratio of the offspring indicate a remarkable role of hereditary factors in tumorigenesis and later consequences of a certain portion of testicular malignancies, which must be refined by molecular studies.

• [Different histological findings in two specimens from pulmonary metastasectomy in the same patient]

  Authors: Ferenc Czeyda-Pommersheim, Zoltán Sulyok, Olga Esik, István Bodrogi, Ilona Péter, István Köves

  Orvosi hetilap. 02/2004; 145(3):139-45.

  INTRODUCTION: Out of the 3310 thoracic surgical procedures performed between 1980 and 2000 at the Department of Surgery of the National Institute of Oncology in Budapest, 258 were pulmonaryINTRODUCTION: Out of the 3310 thoracic surgical procedures performed between 1980 and 2000 at the Department of Surgery of the National Institute of Oncology in Budapest, 258 were pulmonary metastasectomies involving 236 patients. Primary tumors were the following in order of decreasing frequency: testicular cancer, colorectal cancer, renal cancer, soft tissue tumor, breast cancer and others. METHODS: In the present study the authors report two patients with multiple pulmonary metastases. The primary tumor was non-seminoma testicular cancer in case one and endometrial cancer in case two (previously treated for thyroid cancer). Histological examination of resected specimens revealed unsuspected focal inactive tuberculosis in the first case and medullary thyroid cancer in the second. CONCLUSIONS: In the reported two cases the following conditions of metastasectomy were given: 1. satisfactory cardiopulmonary status, 2. possibility of surgical radicality, 3. locoregional disease control, 4. prior chemotherapy in chemosensitive tumor (case one). The generally accepted condition of metastasectomy-lack of clinically manifest disease in other distant organs--was not fulfilled in case two (suspected liver metastases).

• The incidence, prognosis, clinical and histological characteristics, treatment, and outcome of patients with bilateral germ cell testicular cancer in Hungary.

  Authors: Lajos Géczi, Frederic Gomez, Mihály Bak, István Bodrogi

  Journal of cancer research and clinical oncology. 06/2003; 129(5):309-15.

  PURPOSE: To examine the incidence, prognosis, clinical and histological characteristics, treatment, and outcome of patients with bilateral testicular cancer in the referral center in Hungary, toPURPOSE: To examine the incidence, prognosis, clinical and histological characteristics, treatment, and outcome of patients with bilateral testicular cancer in the referral center in Hungary, to determine which parameters might predict a second testicular tumor. METHODS:. Clinical parameters-such as time of original surgery, histology of primary tumor, extent of the disease, serum marker concentrations, history of testicular abnormalities, treatment, response to treatment, follow-up period, data on second carcinoma-of bilateral testicular tumors among the 2,386 patients with testicular cancer treated between November 1988 and November 1998 were analyzed. RESULTS: The incidence of patients with synchronous testicular tumor was 0.8% (19 of 2,386 patients). The clinical stages were 8 I/A, 5 I/B, 1 II/A, 2 II/B, 1 III/A, and 2 III/B. Median follow-up time was 93 months and the 5-year overall survival was 84%. The incidence of patients with metachronous testicular cancer (median age 28 years and 35 years at first and second tumor diagnosis) was 2.2% (53 of 2,386 patients) and the median time to second tumor was 76 months (range 18-203 months). The clinical stages at the first and second tumor diagnosis were: 14 I/A, 21 I/B, 15 II/A, 2 II/B, and 1 III/B, and 26 I/A, 16 I/B, 3 II/A, 1 II/B, 7 III/B, respectively. The median follow-up time was 42 months and the 5-year overall survival was 93%. In thirteen patients with metachronous cancers, two family histories of testicular cancer, five cases of undescended testicles, seven cases of testicular atrophy, and one case of azoospermia were detected. There was a non-significant trend to a longer cancer interval after chemotherapy and radiotherapy and a tendency to a greater incidence of asynchronous seminoma after chemotherapy. Clinical stage I tumors were more frequent in the surveyed group than among patients not followed up according to the institutional protocol ( P = 0.01), but the survival rate was good in both groups. Seminoma as a second tumor was diagnosed in an older age group (median 38 years, range 25-49 years) than nonseminoma (median 32 years, range 21-51 years, P < 0.045).The interval till the appearance of a metachronous testicular cancer depended on tumor histology: in seminoma cases it was longer than in nonseminoma cases (median time: 121 months versus 50 months, P = 0.002). CONCLUSIONS: The overall incidence of bilateral testicular cancer in the referral center in Hungary was 3%. We could not identify clinical factors which predicted a higher risk for metachronous testicular cancer. With regular follow-up the early diagnosis of second testicular tumors is probable; therefore education, self-examination of the remaining testicle, and long-term follow-up are important in early detection.

• [Role of gemcitabine/cisplatin in the treatment of advanced and metastatic bladder cancer]

  Authors: István Bodrogi

  Magyar onkologia. 02/2003; 47(2):198-203.

  M-VAC combination chemotherapy was considered as the "gold standard" of the treatment of advanced and metastatic bladder cancers. Arrival of gemcitabine or taxanes in the 90s attracted attentionM-VAC combination chemotherapy was considered as the "gold standard" of the treatment of advanced and metastatic bladder cancers. Arrival of gemcitabine or taxanes in the 90s attracted attention since their efficacy was combined with low toxicity profiles. Gemcitabine/cisplatin combination became the most frequently studied treatment modality in the past 3 years. Multicentric, multinational randomized phase-III study indicated that in bladder cancer the gemcitabine/cisplatin combination is equal to M-VAC while in the case of the former the risk to benefit ratio is lower. Accordingly, gemcitabine/cisplatin combination is a safer treatment option in advanced and metastatic bladder cancer and is a real alternative to M-VAC. In the case of patients where cisplatin cannot be administered due to poor renal function, the new drugs with better toxicity profiles provide further treatment options.

• [Positron emission tomography in the investigation of malignant testicular tumors]

  Authors: Beáta Kálvin, Teréz Márián, László Galuska, Szabolcs Szakáll, Lajos Géczi, Olga Esik, Lajos Trón, István Bodrogi

  Orvosi hetilap. 06/2002; 143(21 Suppl 3):1286-9.

  Thirty-three [18F]-FDG and ten [11C]-methionine (altogether 43) PET studies were performed in 37 (24 non-seminoma and 13 seminoma) patients. All results were assessed on the basis of histology (orThirty-three [18F]-FDG and ten [11C]-methionine (altogether 43) PET studies were performed in 37 (24 non-seminoma and 13 seminoma) patients. All results were assessed on the basis of histology (or cytology) or clinical follow-up. PET scan identified metastatic disease in 13 cases while 30 investigations resulted in a negative medical report. There were 3 false-positive cases and no false-negative results were obtained. The false-positive results were likely to occur due to FDG accumulation in benign lesions. There were no false-positive findings with the use of [11C]-methionine. Sensitivity, specificity and accuracy were 100%, 91% and 93%, respectively, using both tracers.

• [Lung resistance protein analysis in testicular cancer]

  Authors: László Mándoky, Lajos Géczi, Zoltán Doleschall, Orsolya Csuka, István Bodrogi, Mihály Bak

  Magyar onkologia. 02/2002; 46(4):339-45.

  Germ cell testicular cancers are well-curable neoplasms, because total remission can be achieved in about 80% of the cases. However, 15-20% of the patients die due to drug resistance (DR). A numberGerm cell testicular cancers are well-curable neoplasms, because total remission can be achieved in about 80% of the cases. However, 15-20% of the patients die due to drug resistance (DR). A number of mechanisms of the multidrug resistance phenotype are known, including MDR/P-glycoprotein (P-gp) and the so-called multidrug resistance associated protein (MRP). Lung Resistance Protein (LRP) is an ATP dependent membrane transporter protein associated with MDR. In our present work we studied the expression of LRP in testicular cancers. LRP expression was determined by immunohistochemistry (IH), Western blot (WB) and RT-PCR techniques. Clinical resistance was defined in accordance with the clinical oncologic rules. In 29 (41%) of 70 primary testicular tumours and in 22 (63%) of 35 cases, elevated LRP levels were established by IH and WB, respectively. In the latter 63%, the LRP mRNA levels were elevated as well. Six cases of the 15 seminomas and 23 cases of the nonseminomatous germ cell tumours (NSGCT) proved to be positive. No relationship was demonstrated between LRP expression and the stage of the disease. Despite the LRP positivity of 6 tumour samples, all of the seminomas proved sensitive. Of the 39 sensitive NSGCT, 27 cases were LRP-negative, whereas 11 tumour samples of 16 patients belonging to the resistant group proved LRP-positive (p=0.04). The authors concluded that the expression of LRP is responsible for clinical drug resistance in non-seminomatous testicular cancer patients.

• [Early diagnosis of testicular cancer]

  Authors: Lajos Géczi, Zsolt Horváth, Enikô Beczássy, László Kisbenedek, Mihály Bak, István Bodrogi

  Magyar onkologia. 01/2001; 44(4):275-283.

  PURPOSE: The authors analyze their 3-year results of the "educational and early detection program for testicular cancer". The goals of the program are to reduce the duration of symptoms and toPURPOSE: The authors analyze their 3-year results of the "educational and early detection program for testicular cancer". The goals of the program are to reduce the duration of symptoms and to improve early detection. METHODS: Advertisements were placed in the media describing the early signs of testicular cancer, the risks factors, the correct method of self-investigation and the importance of early detection. Between 1 April, 1995 and 1 April, 1998 5056 volunteers were examined. They underwent physical and ultrasound examination of the testicles, and in case of suspicious findings, tumor markers (alpha-fetoprotein, human choriogonadotropin) were checked. RESULTS: Testicular tumors were found in 1.28% of patients with symptoms (testicular enlargement or nodules). No tumor was found in the population that was symptom-free, or in patients with pain, sensitivity to palpation, or unrelated complaints. Of the patients with a palpable lump and swollen testicles, 4.5 and 3.9% were found to have tumors respectively. In total 32 testicular tumors were detected in 30 patients: 15 (2 bilateral) seminomas, 13 non-seminomas and 4 benign tumors. The occurrence of malignant testicular tumors was most frequent, 1.6% in the age group between 15 and 40 years. The stages were as follows: 9 I/A, 9 I/B, 1 I/S, 3 II/A, 1 II/B and 2 III/B. One patient was lost to follow-up after castration. All the other patients achieved complete remission. CONCLUSION: Despite the increasing incidence of testicular cancer screening of asymptomatic men does not lead to detection of tumors. The awareness of the early signs associated with cancer, self-examination, ultrasound examination of the testicle help in establishing an early diagnosis, nevertheless a widescale program for the early detection of testicular cancer is not justifiable. Effective early detection should be based on an educational program for the population at risk, the appropriate training of doctors and staff engaged in the health care of the young, and the initiation and facilitation of early ultrasound examination at the first symptoms. Serum markers play a limited role in early diagnosis.

• DNA Ploidy Pattern in Pure Seminomas.

  Authors: Zoltán Sápi, Jorgosz Szapanidisz, Bernadette Tóth, István Bodrogi

  Pathology oncology research : POR. 01/1995; 1(1):71-74.

  Nuclear extract and image cytometry was used to determine the DNA ploidy pattern of 31 pure seminomas. At least 5-year but usually 10-year follow-up was available to compare the clinical outcome toNuclear extract and image cytometry was used to determine the DNA ploidy pattern of 31 pure seminomas. At least 5-year but usually 10-year follow-up was available to compare the clinical outcome to the DNA ploidy pattern. In 24 cases (77.4%) the DNA indexes (DI) showed tetraploid (1,8 < DI < 2,2) pattern confirming the recent cytogenetic and flow cytometric DNA studies of others. However, in 7 cases (22,6%) the tumors were aneuploid. Out of these aneuploid cases 2 had two subpopulations and 2 had less than 1,8 DI. These latter cases (providing the loss of chromosomal DNA) had elevated AFP levels in serum that raises the question of nonseminomatous transformation without any morphological evidence. Usually, the aneuploid cases had worse prognoses but there was no significant difference. Because of the small number of aneuploid cases wider clinicopathologic studies are required to confirm our results.

• Expression and prognostic value of the lung resistance-related protein (LRP) in germ cell testicular tumors.

  Authors: László Mándoky, Lajos Géczi, Zoltán Doleschall, István Bodrogi, Orsolya Csuka, Miklós Kásler, Mihály Bak

  Anticancer research. 24(2C):1097-104.

  BACKGROUND: Lung resistance-related protein (LRP) was first detected in a non-P-glycoprotein-mediated multidrug-resistant lung cancer cell line and has been shown to be the major human vault protein.BACKGROUND: Lung resistance-related protein (LRP) was first detected in a non-P-glycoprotein-mediated multidrug-resistant lung cancer cell line and has been shown to be the major human vault protein. The aim of this study was to evaluate the expression of LRP in germ cell testicular tumors (GCT) and to determine the correlation between LRP expression and the clinical outcome of these tumors. PATIENTS AND METHODS: Seventy cases of primary testicular tumors were investigated. LRP protein was detected by immunohistochemistry and Western blotting methods. LRP mRNA was determined with RT-PCR. Patients' clinical parameters and tumor response to treatment were recorded. RESULTS: With immunohistochemistry, LRP was detected in 29 (41%) out of 70 primary testicular tumors. Twenty-two (63%) out of 35 tumors expressed LRP mRNA and LRP protein on examination by RT-PCR and Western blotting, respectively. Pure teratomas showed significantly higher LRP expression compared to other types of GCTs (p=0.0418). No relationship was demonstrated between the LRP immunostaining and stage of disease (p=0.2263). A significantly higher proportion of patients with LRP-negative tumors achieved complete response than those with LRP-positive tumors (p=0.0155). Patients whose tumors showed expression of LRP had significantly shorter overall survival (p=0.0428) than LRP-negative patients. CONCLUSION: Immunohistochemistry is a reliable method to evaluate LRP expression in testicular germ cell tumors. A positive correlation was found between LRP immunostaining and pure teratomas. LRP expression was associated with an adverse clinical outcome and shorter overall survival. Our findings suggest that LRP has prognostic value in testicular germ cell tumors and can predict clinical outcome.

• Apoptosis regulation and spontaneous apoptosis index of testicular germ cell tumors are associated with differentiation and resistance to systemic treatment.

  Authors: László Mandoky, Béla Szende, Lajos Géczi, István Bodrogi, Miklós Kásler, Mihály Bak

  Anticancer research. 28(3A):1641-9.

  Cisplatin-based chemotherapy can cure more than 80% of metastatic germ cell testicular tumors (GCT). Germ cells are particularly susceptible to apoptosis and it is reasonable to presume that GCTs areCisplatin-based chemotherapy can cure more than 80% of metastatic germ cell testicular tumors (GCT). Germ cells are particularly susceptible to apoptosis and it is reasonable to presume that GCTs are curable because of an intact and effective apoptotic pathway. The expression of p53 and p21 was investigated in conjunction with the spontaneous apoptotic index in 20 refractory and 50 chemosensitive GCTs, with a complete follow-up. To detect a differentiation-dependent alteration in the apoptotic pathway, all of the histological tumor types were examined separately. Embryonal carcinoma components showed significantly higher p53 expression compared to other histological subtypes of GCTs. p21 was barely detectable in the majority of tumors. Seminomatous components showed no p21 expression. Mature teratomas and syncytiotrophoblasts showed significantly higher p21 expression than other tumor subtypes. Embryonal carcinomas showed significantly higher apoptotic indices than other non-seminomatous components. On the other hand, choriocarcinomas and mature teratomas showed the lowest spontaneous apoptotic potential. The apoptotic index correlated with the fraction of p53-positive cells, but not with the p21 expression rate. The refractory group showed significantly lower p53 expression, higher p21 expression and a higher apoptosis index than the sensitive group. Our results suggest that the p53 and p21 expression levels and the apoptosis index seem to be important factors in the issue of the chemosensitivity of GCTs. The protein expression pattern reflects a differentiation-dependent preference for G1/S-phase arrest in terminally differentiated syncytiotrophoblasts and mature teratoma cells, while p53 mediated apoptosis induction is meaning to less differentiated tumor types.

• A molekuláris onkogenezis mechanizmusai gyakori daganatokban = Mechanisms of molecular oncogenesis in common malignancies

  Authors: Edit Oláh, István Bodrogi, Lajos Géczi, József Horti, Szabolcs Kökény, Tamás Orbán, János Papp, Tamás Pulay, Nóra Klára Udvarhelyi

  Munkacsoportunk két évtizede megkezdett kutatási programját folytatta, amelynek fő célkitűzése új molekuláris rákgenetikai ismeretek szerzése a rák iránti fokozott genetikai fogékonyság molekulárisMunkacsoportunk két évtizede megkezdett kutatási programját folytatta, amelynek fő célkitűzése új molekuláris rákgenetikai ismeretek szerzése a rák iránti fokozott genetikai fogékonyság molekuláris tényezőinek megismerésére. Vizsgálataink a Magyarországon gyakori daganatos megbetegedésekre (emlőrák, vastagbélrák, ivarszervi daganatok), elsősorban ezek familiáris formáira irányultak. Folytattuk, illetve megkezdtük a daganatszindrómák hajlamosító génjeinek elemzését örökletes emlő- és petefészekrákokban (BRCA1/2, CHEK2), familiáris adenomatozus polyposisban (APC), és herediter, nem a polyposis talaján kialakuló vastagbélrák szindróma (HNPCC) "mutátor gén"-jeiben (MSH2, MLH1). Az emlőrákos családokon, valamint kohorszokon nyert kutatási eredmények adatainak nemzetközi szintű összesítése, molekuláris epidemiológiai kiértékelése révén az örökletes daganatok kialakulására hajlamosító mutációt hordozók rákkockázatáról, a prevenciós tényezőkről és a betegség genetika-klinikai-pathológiai összefüggéseiről szereztünk további új ismereteket. Nemzetközi együttműködésben hozzájárultunk a csírasejtes hererákra hajlamosító első genetikai variánsok azonosításához. Daganatos megbetegedésre hajlamosító gének (BRCA1, STK11) esetében elemeztük az alternatív splicing szerepét a betegség kialakulásában. Újabban megkezdett génexpressziós profilvizsgálatok révén bepillantást nyertünk a molekuláris genetikai útvonalak és a metabolikus útvonalak kölcsönhatásába. | We have extended our molecular cancer genetic studies that were initiated in Hungary two decades ago and were aimed at providing new knowledge on molecular cancer genetics, with a focus on genetic susceptibility to cancer. The studies were conducted on common malignancies in Hungary (breast, colorectal and genitourinary cancers). Extended analysis of the predisposing genes of cancer syndromes was initiated or continued for hereditary breast- and/or ovarian cancer (BRCA1, BRCA2, CHEK2), for familial adenomatous polyposis (APC), for Peutz-Jeghers syndrome (STK11), and for hereditary non-polyposis colorectal carcinoma, HNPCC ("mutator genes" such as MSH2, MLH1). Forwarding the result and data of our molecular genetic analysis on breast cancer families and cancer cohorts for international data integration and molecular epidemiological analysis resulted in generation of new knowledge on cancer risk for the carriers of deleterious germ-line mutations, and on genetic-clinical and pathological correlations in development of breast cancer. Participating in international studies we have contributed to identification of new genetic variants predisposing to germ cell testicular cancer. The role of alternative splicing in development of cancer was investigated in cancer susceptibility genes BRCA1 and STK11. By recent introduction of gene-expression profiling we have gained preliminary insight into the interaction of metabolic and molecular pathways.

• Influence of hMLH1 methylation, mismatch repair deficiency and microsatellite instability on chemoresistance of testicular germ-cell tumors.

  Authors: Judit Olasz, László Mándoky, Lajos Géczi, István Bodrogi, Orsolya Csuka, Mihály Bak

  Anticancer research. 25(6B):4319-24.

  BACKGROUND: Cisplatin-based chemotherapy can cure more than 80% of metastatic germ-cell testicular tumors (GCTs). The response to cisplatin-based chemotherapy has been related to MicrosatelliteBACKGROUND: Cisplatin-based chemotherapy can cure more than 80% of metastatic germ-cell testicular tumors (GCTs). The response to cisplatin-based chemotherapy has been related to Microsatellite Instability (MSI), which is caused by genetic or epigenetic changes in genes of the DNA Mismatch Repair (MMR) pathway. PATIENTS AND METHODS: We investigated 15 refractory and 36 chemosensitive GCTs for immunohistochemical loss of hMLH1, hMSH2 and hMSH6 protein expressions, in conjunction with hMLH1 gene methylation and MSI of GCTs, with a complete follow-up. RESULTS: A loss of either of the MMR protein expressions was detected in 14 cases (27.5%). Pathological hMLH1 protein expression was seen in 10 cases (19.6%). hMLH1 methylation was found in 11 cases (21.60%) and was highly correlated with loss of hMLH1 expression (p < 0.0001) and with immunohistochemically-detected MMR deficiency (p = 0.0005). MSI was found in 16 cases (31.4%). There was no correlation between hMLH1 methylation and MSI. Neither hMLH1 methylation status, nor MSI correlated with any of the clinicopathological parameters investigated (tumor stage, histology, resistance to systemic treatment). CONCLUSION: hMLH1 gene methylation was detected as a common alteration in GCTs, and correlated with the loss of hMLH1 protein expression (p < 0.0001). Neither hMLH1 gene methylation, MMR deficiency, nor MSI showed a relationship with the relevant clinicopathological parameters.

• Clinical relevance of HER-2/neu expression in germ-cell testicular tumors.

  Authors: László Mándoky, Lajos Géczi, István Bodrogi, József Tóth, Orsolya Csuka, Miklós Kásler, Mihály Bak

  Anticancer research. 24(4):2219-24.

  BACKGROUND: Amplification and/or overexpression of HER-2/neu are associated with poor clinical outcome in several epithelial tumors. However, the exact prognostic role of HER-2/neu expression inBACKGROUND: Amplification and/or overexpression of HER-2/neu are associated with poor clinical outcome in several epithelial tumors. However, the exact prognostic role of HER-2/neu expression in testicular germ-cell tumors is equivocal. PATIENTS AND METHODS: Since teratomas are relatively chemoresistant tumors, we evaluated the HER-2/neu alterations of 59 primary testicular teratomas and mixed germ-cell tumors containing teratomatous components using the standardized immunohistochemical method (IHC) (HercepTest) and Fluorescence in Situ Hybridization (FISH). RESULTS: HER-2/neu overexpression was detected in 14 (24%) out of 59 specimens. With IHC, teratomatous and choriocarcinoma components showed significantly higher HER-2/neu expression compared to other histological subtypes of GCTs (p=0.0095). A statistically significant correlation (p=0.0004) can be established between HER-2/neu status and clinical stage of the disease. Similarly, a significant correlation was observed between HER-2/neu overexpression and clinical outcome (p=0.0077). None of the specimens had definite HER-2/neu gene amplification. CONCLUSION: Our results suggest that HER-2/neu overexpression is associated with an adverse clinical outcome and has a prognostic role in testicular germ-cell tumors. Further studies are needed to evaluate the exact background of HER-2/neu overexpression in germ-cell tumors and the role of anti-HER-2/neu antibodies in the treatment regimens for this malignancy.