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Pazopanib, a tyrosine kinase inhibitor, is one of the new registered first-line therapeutic options in the treatment of metastatic clear cell renal carcinoma. Our aim was to evaluate the efficiency and toxicity of first-line pazopanib therapy administered for patients with metastatic clear cell renal carcinoma with good- and medium prognosis according to MSKCC criteria. Between January and May, 2011, 24 patients have been treated with pazopanib in 8 oncology centers in Hungary, out of them 21 patients' data were analyzed. The mean age was 65.3 (49-81) years, 10 males and 11 females. According to MSKCC the prognosis was good and medium in 3 and 18 cases, respectively. Daily dose of pazopanib was 800 mg administered continuously in 28 day cycles. Dose reduction was performed according to the instructions of the registration study. Tumor response was evaluated according to RECIST 1.0. Currently 6 (28.6%) patients are on treatment. Dose reduction was necessary in 6 (28.6%) cases with an average duration of 14.55 (7-150) days. Mean±SE daily dose was 692.97±13.67 (400-800) mg. Median PFS was 12.41 months (95% CI 11.52-12.94 months). Complete remission (CR), as the best tumor response occurred in 2 (9.5%) cases. Partial remission (PR), stable disease (SD) and progression was observed in 6 (28.6%), 10 (47.6%) and 3 (14.3%) cases, respectively. Objective tumor response was observed in 8 pts (38%). Median survival could not be statistically analyzed yet due to the insignificant number of fatal outcomes. Median follow-up was 25.22 months (95% CI 2.47-28.1 months). As common side-effect fatigue, weakness and diarrhea occurred in 11 (52.4%), 9 (42.9%) and 8 (38%) cases, respectively. Besides these, worsening of high blood pressure and ALT/AST elevation was observed in 5 (23.8%) and 6 (28.6%) cases, respectively. Based on the initial Hungarian experiences, pazopanib is a well tolerable product and can be administered safely. According to our results its efficiency in terms of tumor response and progression-free survival is comparable to the results of the registration study.

Despite of its rich vascularization and extensive circulatory communication with neighboring organs, penile metastases are rare. Even more infrequent is a penile metastasis of rectum tumors. Since the first report of rectal carcinoma with metastasis to the penis (Ehbert 1870), approximately 50 cases have been reported, most of them from the USA, the remaining from Western Europe, the Middle East and Japan. The first Hungarian case is reported now of penile metastasis of a rectal carcinoma. The case of a 65-year-old man is presented: isolated penile metastasis discovered 4.5 years after the primary rectal cancer resection. IHC tissue diagnosis and detailed clinical investigations confirmed metastatic rectal adenocarcinoma. As our patient refused penectomy and KRAS mutation was proven, FOLFIRI chemotherapy was initiated without cetuximab. This was followed by chemoradiotherapy that resulted only in transient regression. Currently the patient receives the FOLFOX regimen. At present the patient is in good performance status,without pain. The size and the number of penile metastases have not shown significant changes. According to the literature the average survival of patients with penile metastases treated with radiochemotherapy is 8 months. New chemotherapeutic modalities may improve the survival.

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 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.

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 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.

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 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.

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 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).

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 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.

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 (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.

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 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.

PURPOSE: To study the clinical characteristics of bilateral testicular tumors in the cisplatin era. PATIENTS AND METHODS: Between November 1988 and November 1998 2386 testicular cancer patients were treated in our Department and 72 bilateral germ cell testicular cancer patients were retrospectively explored (3%). The incidence, the clinical and histological characteristics and, in the case of asynchronous tumor, the interval between the two tumors were analyzed. RESULTS: During the 10 years 19 synchronous (26.4%) and 53 asynchronous bilateral germ cell testicular cancers (73.6%) were treated. The incidence of bilateral synchronous seminoma was 68.4%. Among the asynchronous tumors 9 concordant seminomas and 9 concordant nonseminomas were detected. In the first, second and third 5-year follow-up period 39.6, 30.2, and 28.2% of asynchronous tumors were diagnosed. The incidence of seminoma after the first castration in the 5, 10 and 15 years was 19, 37.5, and 60%, respectively. The overall survival rates of synchronous and asynchronous testicular cancer were 84 and 93%. In cases of asynchronous tumor the prevalence of stage I cancer was significantly greater in a regularly controlled population (p=0.014) than in the not regularly followed population, but the survival rate was good in both groups. Nonseminoma showed up earlier as first and second tumor than seminoma (p=0.05, p=0.045). The interval between the two asynchronous tumors was shorter in the case of nonseminoma than in the case of seminoma (p=0.002). CONCLUSION: The prognosis of bilateral germ cell testicular cancer is good because of the high incidence rate of seminoma and the effective treatment. With regular follow-up the early diagnosis of second testicular tumors is probable. The interval between the tumors depends on the patients' age and the histology of the second tumor, in the case of seminoma it is longer. The effect of the previous treatment on the incidence of seminoma and the interval between the two asynchronous tumors requires further investigations.

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 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.

To determine whether mdm-2 protein level is aberrant in germ cell testicular tumors (GCTT) and if so, what is the relationship between mdm-2 overexpression and other disease parameter including histologic subtypes, p53 status, metastatic potential, and clinical stage, 81 testicular germ-cell tumors were screened for their mdm-2 expression at the protein levels using immunohistochemistry (IHC) and Western blot (WB) analysis. Overall, in this study 45 (55.6%) tumors showed positive mdm-2 nuclear immunoreactivity. The incidence of mdm-2 immunostaining was significantly higher (p = 0.0007) in non-seminomas (NSGCT) than in seminomas (S). The frequency of positive tumor was higher in tumors from metastatic patients than in tumors of patients free from metastasis (p = 0.011). Mdm-2 expression was detected significantly more frequently in tumors of advanced stages, i.e. II/B, II/C, and III versus tumors of early stages (I and II/A) (p = 0.0098). A significant difference could be established between the three stages of disease and the expression of mdm-2 (chi 2 = 0.0386), namely the incidence of mdm-2 expression increased with an advanced stage. Using Western blotting 22 (68.8%) out of 32 tumors overexpressed the mdm-2 oncoprotein of 90 kd (p90). Mdm-2 expression as detected by immunostaining may provide a reliable prognostic tool to subgroup of patients with more aggressive GCTT.

Bcl-2 expression has been studied extensively in a variety of human tumors. However, there are lack of clinical data in regard to its expression in germ cell testicular tumors (GCTTs). In this study we screened bcl-2 expression in 70 patient with GCTTs using the immunohistochemistry (IHC) and streptavidin biotin alkaline phosphatase method. Furthermore, we correlated this expression with metastatic behaviour and clinical stage. Overall, 41 (58%) carcinomas stained with anti-bcl-2 (DAKO-124) monoclonal antibody, By histologic type, these lesions included 11 (42.3%) of 26 seminomas (S) and 30 (68.18%) of 44 non seminomatous germ cell testicular tumors (NSGCT). The incidence of bcl-2 immunostaining was higher (P = 0.05, two-tailed, Fisher's test) in NSGCT than in seminomas. Bcl-2 expression was higher in tumors from metastatic patients than in tumors from metastatic-free patient (p = 0). There was a significant difference between the three stages of disease as to the expression of bcl-2 (chi 2 = 0). High level of bcl-2 was clearly dominant in tumors of advanced stages. The present finding revealed that bcl-2 expression occurs in GCTTs. Further, they suggested that bcl-2 is associated with a more progressed malignant phenotype in these tumors.

Data concerning the involvement of elevated metallothionein (MT) expression in drug resistance are obviously scattered and contrasting. The presence of the MT gene product protein was screened in 51 untreated human germ cell testicular tumours, furthermore a relationship between MT expression and clinical resistance was investigated. Using monoclonal antibody and immunoenzyme staining elevated MT level could be demonstrated in nuclei and cytoplasm of both seminomas and non seminomatous germ cell testis tumours. Thirty-one tumours (61%) showed extensive, 15 (29%) focal positive staining. In contrast teratomas expressed this antigen negatively or scarcely. The highest level of MT was stated in early stages (I, IIA) compared with progressed stages (IIB, III) (p = 0.0004). Between the high level of MT and clinical resistance a converse correlation could be shown because the resistant tumours expressed no or low, while the sensitive tumours significantly high level of MT protein which can be used as an useful marker to identify patient subgroups sensitive to anticancer therapy, at least in testis tumours.

One of the most common cellular gene which negatively regulates the cell cycle, thus functioning as tumour suppressor gene, is the p-53 gene. The presence of this mutated gene has been correlated with, the aggressiveness of several malignant neoplasmas. Expression of the p-53 gene product protein was screened in 55 untreated human germ cell testicular tumours, furthermore a relationship between p-53 expression and clinical resistance was investigated. Using monoclonal antibody and immunoenzyme staining elevated p-53 level could be demonstrated in nuclei of embryonal carcinoma (84%) and seminoma components (56%). Most of the choriocarcinoma cases showed positive staining. Teratomas expressed this antigen negatively or scarcely. In seminomas the highest level of p-53 was stated in stage I. In contrast the opposite tendency could be demonstrated in embryonal carcinomas where p-53 was ++ positive in stage III. Between the high level of p-53 and clinical resistance a converse correlation could be stated because the resistant tumours expressed no or low, the sensitive tumours high level of p-53 protein (P 0.01). These results suggest that elevated p-53 expression could be a prognostic marker of sensitivity in testis cancer.

The authors investigated the PSA concentration and the preoperative prostate volume of 113 histologically proved BPH and 31 prostate cancer patients. There was no correlation between the age of the patients and the volume of the prostate. Whereas, correlation was proved between the marker concentration and the prostate volume (p < 0.0001). The prostate volume and the PSA concentration ratio correlated between the BPH and tumorous patients (PSA density). The difference was highly significant (p < 0.001). The use of PSAD improves further the diagnostical value of PSA.

The most frequently reported alteration of multidrug-resistant cells is overexpression of a 170 kD glycoprotein (P-glycoprotein or P-170) encoding by the MDR1 gene family. Expression of the multidrug-resistance gene product P-glycoprotein was screened in 55 untreated human germ cell testicular tumors using monoclonal antibody (C219) and immunoenzyme staining. In samples out of 17 seminomatous germ cell testicular tumors (SGCT) 2 seminomas, and out of 38 non-seminomatous tumors (NSGCT) 20 carcinomas (15 teratomas, 4 embryonal carcinomas, 1 with Yolk sac differentiation and 1 embryonal rhabdomyosarcoma) showed high expression of P-glycoprotein. NSGCT-s, which are more refractory than seminomas to anticancer chemotherapy, frequently expressed P-glycoprotein. These immunohistochemically detected elevated P-170 expressions were correlated by the overexpression of MDR1 mRNA gene sequences. A relationship between clinical resistance and P-glycoprotein expression seems thus to exist in 4 teratomas 3 embryonal carcinomas, and 1 seminomas. A significant correlation (p < 0.02) between P-170 expression and clinical drug resistance in stage II-III germ cell testicular tumors could be demonstrated. The results suggest that a multidrug resistant phenotype may also occur and P-glycoprotein might contribute to drug resistance in testicular tumors.

The authors compared the effectivity of doxycyclin or ofloxacin after combined chemotherapy of testicular cancer patients during the leukopenic periods. Between 1988 and 1991 200 patients were randomized and 194 were evaluated. One hundred and fifty two patients had been treated by cytostatic treatment earlier 2.5 or 2.9 times and 17 by irradiation. The average age was 30.1 in the doxycyclin group and 31.5 years in ofloxacin group. The patients characteristics in average age and previous treatments were not significant in the two groups. Doxycyclin was applied at the first day 200 mg and the following days 100 mg for 6.8 days and ofloxacin was given 2 times 100 mg day for 8.0 days. The preventive antibiotic treatment was insufficient in 16 or 6 cases requiring the the new antibiotic therapy. The development of the new infectional lesions was significantly higher in doxycyclin group and it needed the other antibiotic therapy. The condition of the patients did not require systemic antimycotic or antiviral therapy. The toxicity was lower in oflaxacin group. Tarivid is suitable for preventing the infection in neutropenic periods after the cytostatic therapy. The number of infections are decreased the completion with some penicillins. Regarding to previous cytostatic drugs the cephalosporins are suggested for prevention during the neutropenic periods.

Between the period of 1981 and 1991 at the National Institute of Oncology 1300 patients suffering from non-seminoma testicular cancer were treated by chemotherapy. Among them 19 cases of femoral head necrosis, one side or bilateral, were observed. Authors collected and compared the data of 16 patients of osteonecrosis and 28 without it. The aim of the study was the determination of the causes of osteonecrosis and searching for possible relation between antineoplastic therapy and osteoporosis. High alcohol consumption was found in 15 cases in the osteonecrotic group, versus one among the others. Bone mineral content measurement was performed by quantitative computed tomography. Average ages at the time of densitometry: osteonecrotic group 39.17, patients without osteonecrosis 33.91. The relative bone mineral content was found 65.94% in the osteonecrosis (A) group and 77.92% in the group without osteonecrosis. A significant difference was found in the level of serum calcium and the steroid dose applied during chemotherapy.

Chromosomal aberrations were studied in peripheral blood lymphocytes from only surgery treated testicular cancer patients and treated with chemo- and/or radiotherapy. A distinct increase in spontaneous aberration frequency over the level of 27 healthy controls in 27 patients treated with surgery alone was found. Our data suggest the existence of a certain degree of chromosome instability, which may be a factor to the development of testicular tumour. The frequency of aberrant cells was much higher in 102 treated patients than in the controls. The decrease in aberrant cells was only time-dependently gradual in VPB and X-ray treated patients, while the second line combined treatment modalities caused the highest frequency of aberrant cells in the first two years after the end of courses. The possible relationship between the persistence of chromosomal aberrations and the development of malignancies are discussed in this paper.

The antibody-dependent cell mediated cytotoxicity of peripheral blood mononuclear cells from 92 patients with germinal cell tumours and 60 healthy male controls was measured against 0, Rh(D) positive human red blood cells sensitized with anti-D antibody. To determine the maximal K-cell activity the enzym-like kinetic model of citotoxicity was employed in which maximal activity was measured in presence of target-cell excess. To avoid variation due to the individual sensitivity of target erythrocytes red blood cells were obtained from a single donor. It was demonstrated that compared to the control group the K-cell activity of patients with germinal cell tumours was significantly enhanced. Cytotoxic activity of patients with clinically detectable tumours was significantly higher than that of patients with no detectable tumour. The K-cell activity of patients with detectable tumours was significantly increased after chemotherapy.

The data of 1286 testis cancer persons were analyzed by the authors, which were identified in Hungary between 1981 and 1986. The comparison was carried out with international findings in this field. The incidence rate of testis tumor in Hungary reaches a value of 4.16/100,000 men/year, which seems to be quite near to the frequency of cases occurred in Northern-Europe. The patient's age was 32.9 year in the mean at the time of the diagnosis, and the age-specific incidence rate was the highest (11.2) between 25-34 years, according to international experiences. A significant difference was found in the frequency of testis cancer among 19 counties of Hungary. The extremely high testis cancer incidence in the county Vas (West-Hungary) requires further explanations. A seasonal pattern according to the patients birth months was shown, which did not correlate with data of other Hungarian authors concerning seasonal pattern of the undescendent testis.

The 5-year survival of patients with malignant testicular tumors rose during the past 25 years from 10-25% depending on stage to 55-100% after radical castration performed from high inguinal opening, retroperitoneal lymphadenectomy, ultra-tension irradiation and adjuvant chemotherapy. It is stressed that patients diagnosed at stage T1-2, N0-2, M0 may even recover perfectly upon complex therapy. Three to five-year long or even longer survival may be reached with 50% of the patients at the stage T1-3, N1-3, M1. Patients at stage T4, N3-4, M1 die because of the recurrence of the tumor and/or the complication of the adjuvant treatment within 1-3 years and even the interdisciplinary work which is very effective in other stages fails to change this at the present time.