Gemcitabine and Cisplatin Versus Methotrexate, Vinblastine, Doxorubicin, and Cisplatin in Advanced or Metastatic Bladder Cancer: Results of a Large, Randomized, Multinational, Multicenter, Phase III Study.

PURPOSE: Gemcitabine plus cisplatin (GC) and methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) were compared in patients with locally advanced or metastatic transitional-cell carcinoma (TCC) of the urothelium. PATIENTS AND METHODS: Patients with stage IV TCC and no prior systemic chemotherapy were randomized to GC (gemcitabine 1,000 mg/m2 days 1, 8, and 15; cisplatin 70 mg/m2 day 2) or standard MVAC every 28 days for a maximum of six cycles. RESULTS: Four hundred five patients were randomized (GC, n = 203; MVAC, n = 202). The groups were well-balanced with respect to prognostic factors. Overall survival was similar on both arms (hazards ratio [HR], 1.04; 95% confidence interval [CI], 0.82 to 1.32; P = .75), as were time to progressive disease (HR, 1.05; 95% CI, 0.85 to 1.30), time to treatment failure (HR, 0.89; 95% CI, 0.72 to 1.10), and response rate (GC, 49%; MVAC, 46%). More GC patients completed six cycles of therapy, with fewer dose adjustments. The toxic death rate was 1% on the GC arm and 3% on the MVAC arm. More GC than MVAC patients had grade 3/4 anemia (27% v 18%, respectively) and thrombocytopenia (57% v 21%, respectively). On both arms, the RBC transfusion rate was 13 of 100 cycles and grade 3/4 hemorrhage or hematuria was 2%; the platelet transfusion rate was four patients per 100 cycles and two patients per 100 cycles on GC and MVAC, respectively. More MVAC patients, compared with GC patients, had grade 3/4 neutropenia (82% v 71%, respectively), neutropenic fever (14% v 2%, respectively), neutropenic sepsis (12% v 1%, respectively), and grade 3/4 mucositis (22% v 1%, respectively) and alopecia (55% v 11%, respectively). Quality of life was maintained during treatment on both arms; however, more patients on GC fared better regarding weight, performance status, and fatigue. CONCLUSION: GC provides a similar survival advantage to MVAC with a better safety profile and tolerability. This better-risk benefit ratio should change the standard of care for patients with locally advanced and metastatic TCC from MVAC to GC.

A phase II multicentre study of irinotecan (CPT 11) in combination with cisplatin (CDDP) in metastatic or locally advanced penile carcinoma (EORTC PROTOCOL 30992).

BACKGROUND: The aim of this study is to determine efficacy and feasibility of the combination regimen irinotecan and cisplatin in patients with cisplatin advanced penile cancer. PATIENTS AND METHODS: Patients with T3, T4, N1, N2, N3 or M1 cisplatin advanced penile cancer were treated with a combination of irinotecan (60 mg/m(2)) on days 1, 8 and 15 and cisplatin (80 mg/m(2)) administered every 28 days. Patients were treated either in the neo-adjuvant setting for T3 or N1-N2 disease with a maximum of four cycles before surgery or up to eight cycles for T4 or N3 or M1 disease. The study was designed with the aim to exclude a response rate (complete response + partial response) <30% (alpha = 10%, power = 95%). RESULTS: Twenty-eight patients were included and evaluated for toxicity, and 26 eligible patients were evaluated for response. Toxicity was acceptable with three cases of grade 3 diarrhoea and two cases of grade 4 neutropenic fever. There were eight responses (two complete response and six partial response) (30.8%, 80% confidence interval 18.8% to 45.1%): three patients undergoing histological verification after chemotherapy had no evidence of malignancy. CONCLUSION: The study fails to demonstrate a response rate significantly >30%. The observation regarding M0 patients suggests to repeat this study in the neo-adjuvant setting.

Phase I study of TZT-1027, a novel synthetic dolastatin 10 derivative, for the treatment of patients with non-small cell lung cancer.

PURPOSE: The purpose of this phase I study was to evaluate the maximum-tolerated dose (MTD), dose-limiting toxicity (DLT), the recommended dose for phase II study, pharmacokinetics, and antitumor activity of TZT-1,027 (soblidotin) in patients with non-small cell lung cancer (NSCLC) when administered every 3-4 weeks. METHODS: Eligible patients had the following characteristics: stage III/b or IV NSCLC that was refractory to conventional therapy or for which no standard therapy was available; Eastern Cooperative Oncology Group (ECOG) performance status (PS) or=20 and <75 years. The patients were administered TZT-1,027 in escalating doses from 0.5 to 5.6 mg/m(2). Pharmacokinetic samples were collected during each treatment course. RESULTS: Forty-nine patients were enrolled. Three patients had DLTs, including neutropenia, neutropenia complicated by fever, myalgia, and neuropathic pain. The common toxicities included constipation, anorexia, alopecia, nausea, leukopenia, and neutropenia. One complete response and three partial responses were observed. The pharmacokinetic parameters (AUC and C (max)) of TZT-1,027 tended to increase linearly with dose. CONCLUSIONS: DLTs included neutropenia, neutropenia complicated by fever, myalgia, and neuropathic pain. The MTD was 4.8 mg/m(2). The recommended phase II study dose of TZT-1027 is 4.8 mg/m(2) administered every 3-4 weeks.

A Retrospective Analysis of the First 41 mCRPC Patients with Bone Pain Treated with Radium-223 at the National Institute of Oncology in Hungary.

Radium-223 dichloride is an alpha-emitting radiopharmaceutical which significantly prolongs overall survival in patients with castration-resistant prostate cancer (CRPC) and symptomatic bone metastases. This was a retrospective analysis of the efficacy and safety of Radium-223 in the first 41 patients treated at a single center in Hungary. Radium-223 was given at a dose of 50 kBq/kg intravenously every 4 weeks for up to 6 cycles. Between 23rd July 2014 and 23rd February 2016, 41 patients were treated. Patient demographics, laboratory values, treatment outcomes and adverse events were collected from medical records. The mean age was 72.2 years (SD: 7.1). 24 patients received Radium-223 as first-line treatment (58%), 7 patients as second (17%), 3 as third (7.3%), 6 as (14.6%), and 1 as fifth-line therapy (2.4%). The mean number of cycles administered was 5.5 (SD: 1.1). The most common side effects were anemia (32% grade 1-3), nausea (28%, grade 1), diarrhea (4%, grade 2), thrombocytopenia (4%, grade 3). The mean baseline PSA level was 307.2 ng/ml (SD: 525.7), which increased to a mean value of 728.5 ng/ml (SD: 1277) by the end of treatment. The baseline mean ALP of 521.1 U/L (SD: 728) decreased to 245.1 U/L (SD: 283.5). The majority of patients experienced a decrease (37%) or complete cessation (43%) of bone pain intensity. In our symptomatic prostate cancer patient population, Radium-223 proved to be efficient in terms of pain relief, with moderate side effects. No PSA response was detected, while alkaline phosphatase levels significantly decreased.

Intensive induction-sequential chemotherapy with BOP/VIP-B compared with treatment with BEP/EP for poor-prognosis metastatic nonseminomatous germ cell tumor: a Randomized Medical Research Council/European Organization for Research and Treatment of Cancer study.

PURPOSE: The aim of this randomized trial was to assess the potential therapeutic advantage of an intensive induction-sequential chemotherapy schedule (bleomycin, vincristine, cisplatin [BOP])/etoposide, ifosfamide, cisplatin, and bleomycin [VIP-B]), compared with a regimen based on bleomycin, etoposide, and cisplatin (BEP) (BEP/etoposide and cisplatin [EP]) for the treatment of patients with poor-prognosis metastatic nonseminomatous germ cell tumors (NSGCTs). PATIENTS AND METHODS: Patients had one or more of the following: a retroperitoneal mass > or = 10 cm in diameter; mediastinal or supraclavicular mass > or = 5 cm in diameter; at least 20 lung metastases (any size); liver, bone, or brain metastases; and serum beta human chorionic gonadotropin (betaHCG) > or = 10,000 IU/L or alfa fetoprotein (AFP) > or = 1,000 IU/L. A total of 380 patients were accrued between May 1990 and June 1994 into this joint Medical Research Council (MRC)/European Organization for Research and Treatment of Cancer (EORTC) trial; of these, nine patients were deemed ineligible. RESULTS: There was no significant difference between the two arms in the proportion of patients who achieved a complete response (CR) with chemotherapy alone, ie, 79 of 185 assessable patients (57%) with BEP/EP and 72 of 186 (54%) with BOP/VIP-B (P = 0.687). With a median follow-up of 3.1 years (maximum, 5.8), a total of 107 patients (28%) had progressive disease. There was no significant difference in time to first disease progression, or failure-free or overall survival between the two arms (P = 0.21, 0.101, and 0.190, respectively). The 1-year failure-free survival rates for BEP/EP and BOP/VIP-B were 60% (95% confidence interval [CI], 53% to 67%) and 53% (95% CI, 47% to 61%). Grade 3 or 4 myelosuppression, febrile neutropenia, and weight loss were more pronounced with BOP/VIP-B than with BEP/EP, and there were more toxic deaths with BOP/VIP-B than BEP/EP (18 [9%] v nine [5%]). CONCLUSION: The intensive BOP/VIP-B therapy was associated with more toxicity, but there was no evidence of an improvement in response rate or survival compared with treatment with BEP/EP.

Filgrastim during combination chemotherapy of patients with poor-prognosis metastatic germ cell malignancy. European Organization for Research and Treatment of Cancer, Genito-Urinary Group, and the Medical Research Council Testicular Cancer Working Party, Cambridge, United Kingdom.

PURPOSE: To determine the effect of r-metHu granulocyte colony-stimulating factor (G-CSF) on the proportion of patients with metastatic poor-prognosis malignant germ cell tumors who receive full dose-intensity combination chemotherapy. PATIENTS AND METHODS: In a phase III study patients received six cycles of BEP/EP (etoposide, and cisplatin, plus or minus bleomycin) or six cycles of BOP/VIP-B (bleomycin, vincristine, cisplatin/etoposide, ifosfamide, cisplatin, bleomycin). A subset were secondarily randomized to receive or not receive filgrastim. Filgrastim 5 microg/kg/day was administered subcutaneously on days 3 through 9 after each BOP and on days 6 through 19 after each VIP, BEP, or EP cycle. RESULTS: Eighty-five percent of 120 eligible patients randomized to filgrastim received at least six chemotherapy cycles compared with 70% of 130 patients randomized to not receive filgrastim (VCP = .003). Patients in the filgrastim-arm achieved significantly higher dose-intensities. Neutropenic fever occurred in 25 of 128 filgrastim-patients and in 38 of 129 non-filgrastim-patients (P = .052). Twelve and three toxic deaths occurred in the non-filgrastim- and filgrastim-arms, respectively. Nine of the 12 toxic deaths and all of the three toxic deaths were associated with febrile grade 4 neutropenia. Failure-free and overall survival were similar in both arms. CONCLUSION: During combination chemotherapy in patients with malignant germ cell tumors, the routine use of filgrastim significantly improved the delivery of the planned treatment schedule without effect on failure-free or overall survival. The use of filgrastim was associated with a clinically important reduction in the number of toxic deaths, confined to the experimental intensified-chemotherapy schedule. This study does not support the routine use of filgrastim during standard chemotherapy with BEP.

Gemcitabine and cisplatin versus methotrexate, vinblastine, doxorubicin, and cisplatin in advanced or metastatic bladder cancer: results of a large, randomized, multinational, multicenter, phase III study.

PURPOSE: Gemcitabine plus cisplatin (GC) and methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) were compared in patients with locally advanced or metastatic transitional-cell carcinoma (TCC) of the urothelium. PATIENTS AND METHODS: Patients with stage IV TCC and no prior systemic chemotherapy were randomized to GC (gemcitabine 1,000 mg/m2 days 1, 8 and 15; cisplatin 70 mg/m2 day 2) or standard MVAC every 28 days for a maximum of six cycles. RESULTS: Four hundred five patients were randomized (GC, n = 203; MVAC, n = 202). The groups were well-balanced with respect to prognostic factors. Overall survival was similar on both arms (hazards ratio [HR], 1.04; 95% confidence interval [CI], 0.82 to 1.32; P = .75), as were time to progressive disease (HR, 1.05; 95% CI, 0.85 to 1.30), time to treatment failure (HR, 0.89; 95% CI 0.72 to 1.10), and response rate (GC, 49%; MVAC, 46%). More GC patients completed six cycles of therapy, with fewer dose adjustments. The toxic death rate was 1% on the GC arm and 3% on the MVAC arm. More GC than MVAC patients had grade 3/4 anemia (27% v 18%, respectively), and thrombocytopenia (57% v 21%, respectively). On both arms, the RBC transfusion rate was 13 of 100 cycles and grade 3/4 hemorrhage or hematuria was 2%; the platelet transfusion rate was four patients per 100 cycles and two patients per 100 cycles on GC and MVAC, respectively. More MVAC patients, compared with GC patients, had grade 3/4 neutropenia (82% v 71%, respectively), neutropenic fever (14% v 2%, respectively), neutropenic sepsis (12% v 1%, respectively), and grade 3/4 mucositis (22% v 1%, respectively) and alopecia (55% v 11%, respectively). Quality of life was maintained during treatment on both arms; however, more patients on GC fared better regarding weight, performance status, and fatigue. CONCLUSION: GC provides a similar survival advantage to MVAC with a better safety profile and tolerability. This better-risk benefit ratio should change the standard of care for patients with locally advanced and metastatic TCC from MVAC to GC.

Prospective randomized trial of docetaxel versus doxorubicin in patients with metastatic breast cancer.

PURPOSE: This phase III study compared docetaxel and doxorubicin in patients with metastatic breast cancer who had received previous alkylating agent-containing chemotherapy. PATIENTS AND METHODS: Patients were randomized to receive an intravenous infusion of docetaxel 100 mg/m(2) or doxorubicin 75 mg/m(2) every 3 weeks for a maximum of seven treatment cycles. RESULTS: A total of 326 patients were randomized, 165 to receive doxorubicin and 161 to receive docetaxel. Overall, docetaxel produced a significantly higher rate of objective response than did doxorubicin (47.8% v 33.3%; P =.008). Docetaxel was also significantly more active than doxorubicin in patients with negative prognostic factors, such as visceral metastases (objective response, 46% v 29%) and resistance to prior chemotherapy (47% v 25%). Median time to progression was longer in the docetaxel group (26 weeks v 21 weeks; difference not significant). Median overall survival was similar in the two groups (docetaxel, 15 months; doxorubicin, 14 months). There was one death due to infection in each group, and an additional four deaths due to cardiotoxicity in the doxorubicin group. Although neutropenia was similar in both groups, febrile neutropenia and severe infection occurred more frequently in the doxorubicin group. For severe nonhematologic toxicity, the incidences of cardiac toxicity, nausea, vomiting, and stomatitis were higher among patients receiving doxorubicin, whereas diarrhea, neuropathy, fluid retention, and skin and nail changes were higher among patients receiving docetaxel. CONCLUSION: The observed differences in activity and toxicity profiles provide a basis for therapy choice and confirms the rationale for combination studies in early breast cancer.

Allele loss of tumour suppressor genes on chromosome 17 in human testicular germ cell tumours.

The molecular genetics of testicular germ cell tumours (TGCT) are still largely unknown. We investigated 20 TGCT tumours for allelic losses (LOH) of tumour supressor genes BRCA1, TP53 and of THRA1 on chromosome 17. We observed an overall loss of 50% for the whole chromosome. Detailed deletion mapping revealed no losses for the BRCA1 gene, 42% LOH for THRA1 and 11% allelic loss for the region telomeric to BRCA1. We observed 11% LOH for TP53. Our results suggest that allelic losses of BRCA1 and TP53 genes do not play a pivotal role in TGCT but that dysfunction of THRA1 or tumour suppressor gene(s) in this region may have an impact in the development of this cancer.

Do metallothioneins affect the response to treatment in testis cancers?

PURPOSE: Data on the involvement of elevated metallothionein (MT) expression in resistance to some of the commonly used anticancer treatments are scattered and conflicting. This encouraged us to examine further the contribution of metallothionein expression to the development of this resistance phenotype. PATIENTS AND METHODS: Formalin-fixed, paraffin-embedded blocks of primary untreated germ cell testicular tumor specimens, obtained from 77 patients following radical orchiectomy, were examined for their MT expression using monoclonal antibody and immunohistochemistry. Clinical staging, the chemotherapeutic schedule and evaluation of response to treatment (defining objective response) were performed according to UICC criteria. RESULTS: All tumor types, including seminomas and nonseminomas, expressed MT, regardless of their histology and clinical stage. The immunoreactivity of MT showed a significant positive correlation with the clinical sensitivity of cancer to antitumor therapy (P = 0.0001). CONCLUSION: In patients with germ cell testicular tumors, high MT expression, as detected by immunohistochemistry, predicts a better response rate to chemotherapy whereas tumors lacking or demonstrating low MT expression show a worse prognosis. These data do not support the hypothesis that MT overexpression contributes to cisplatinum resistance, at least in this tumor type.

Influence of luteinizing hormone-releasing hormone agonists on human mammary carcinoma cell lines and their xenografts.

The specific binding of luteinizing hormone-releasing hormone (LH-RH) agonist in estradiol-dependent MCF-7 and estradiol-independent MDA-MB-231 human breast cancer cells has been studied using [3H]Ovurelin [(D-3H-Phe6),des-Gly10-LH-RH- ethylamide]. The results of Scatchard analyses suggest the presence of a single class of receptor sites, both in cell suspensions and membrane fractions. Evaluation of these peptide receptors appears to reflect additional characteristics of biological behaviour of these human breast cancer cells. The synthetic LH-RH agonist Ovurelin [(D-Phe6),des-Gly10-LH-RH-ethylamide] can directly interfere (25-30%) with the proliferation of MDA-MB-231 human breast cancer cells in culture. The inhibitory effect of Ovurelin in vitro was negligible in the MCF-7 cell line. In the in vivo experiments the treated immunosuppressed mice bearing either MCF-7 or MDA-MB-231 xenografts responded to the high-dose LH-RH analogue Zoladex depot and Decapeptyl depot therapy. Since the MDA-MB-231 tumour was found to be ER-negative it seems possible that the regression of this xenograft results from the direct antitumor action of the LH-RH agonist.

Thoracic surgery of testicular cancer patients.

Between 1 January 1980 and 31 December 1991 the authors treated 1450 patients with malignant testicular tumours. Out of them, in 42 patients aged 18-43 years with stage III non-seminoma germ cell testicular cancer, thoracic surgical interventions took place on 44 occasions since the combined cytostatic treatment did not result in a sufficient regression, or disease progression occurred. In one case the lesion was inoperable. In 43 cases successful resection was performed. In 27 cases unilateral, in two cases bilateral thoracotomy and in 15 cases median sternotomy took place. Solitary lesions were found in 26 and multiple ones in 18 cases, respectively. Two patients died in the direct postoperative phase. Forty patients were followed up for 4 to 130 months. Due to disease progression four and seven patients were lost within 12 and 12-24 months, respectively. Currently, 31 patients are alive 4 to 130 months following surgery (29 of them tumour-free, two with tumour). Based on adequate indications the thoracic surgery is justified both from diagnostic and therapeutic points of view. The metastasectomy might offer an advance in the management of these patients.

Glutathione related enzymes in human testicular germ cell tumors and normal testes.

In this study, the activity of the glutathione related enzymes, namely glutathione S-transferase (GST), glutathione reductase (GSSG-R), Selenium-dependent and -independent glutathione peroxidase (GPX) of various TGC tumors (n = 18) obtained from untreated patients, was compared to that of the corresponding enzymes of normal testicular tissues (n = 5). The enzymes of all tumorous tissues except teratomas were significantly less active, than the corresponding enzymes of nontumorous tissues. The GST was in seminomas 4.3-20-, in embryonal carcinomas 47-, and in mixed tumors 13-47-fold less active than in the normal testes. The GST activity of teratomas was about half of that of the normal tissues. The Se-independent GPX, component of GST alfa class, comprised about 90 percent of the total GPX activity in normal testis; however it was absent or barely detectable in all TGC tumors except teratomas. The latter had about the same GPX activity as the tumor-free testicular tissues. Apart from the teratoma, the GSSG-R activity of all TGC tumors was also suppressed to about one third of that of the normal testis. The insufficient function of glutathione related enzymes of TGC tumors may contribute to their sensitivity against treatment. The poorer prognosis of teratomas, however, may be explained by the relatively higher activity of their detoxifying enzymes.

Differential expression of glutathione S-transferases in germ cell tumors of human testes.

Glutathione S-transferase (GST) isoenzymes alfa, mu and pi were assessed by Western blotting in normal testes, seminomas and non-seminomatous germ cell tumors (NSGCTs). GST alfa and mu were strongly expressed in all normal specimens (n = 6), the pi isoform, however, could not or barely be detected. Ten (92%) of 11 seminomas had GST pi and only 2 (16%) showed alfa expression. In contrast, twelve (80%) of 15 NSGCTs showed a significant level of GST alfa and only 2 (13%) had GST pi expression. The absence or paucity of mu isoform was characteristic for all neoplastic testicular tissues. A statistically significant relationship (P = 0.021) could be established between GST alfa and stages of disease, i.e., alfa isoform was prevalent in the later stage (IIB, III) NSGCT tumors. These results suggest that the poor prognosis of the later stage NSGCTs may be due to their high GST alfa content, while the GST pi does not seem to have role in this relation.

MRP expression of testicular cancers and its clinical relevance.

BACKGROUND: The expression of a multidrug resistance associated protein (MRP) has been investigated in a variety of human tumors. However, there is a lack of data regarding its expression in germ cell testicular tumors (GCTTs). PATIENTS AND METHODS: MRP expression was examined by immunohistochemistry (IHC) using mouse monoclonal antibody (MRPm6) against human MRP in 56 testis cancer specimens. This antigen was also correlated with the histology, metastatic behavior, clinical stage and tumor suppressor protein p53 immunostaining of GCTTs. RESULTS: All testis tumors, regardless of their histology, metastatic status and clinical stage gave positive signals. MRP was positive not only in the cytoplasm but, very interestingly, in the nuclei. CONCLUSION: Our results suggested that ala GCTTs express high levels of MRP protein with no relation to any of clinicopathological variables investigated here. Since germ cell tumors are very sensitive to chemotherapy, the role of MRP as mediator of drug resistance seems unconvincing in this malignancy. MRP is located in the cytoplasm and the nuclei of tumor cells and may be involved in transportation and/or redistribution certain substrates from the nucleus to the cytoplasm.

mdm-2 expression in human testicular germ-cell tumors and its clinical value.

BACKGROUND: In germ cell testicular tumors (GCTT) mdm-2 gene was analyzed for amplification and transcripts but not for protein. The purpose of this study is to determine whether mdm-2 protein level is aberrant in GCTT and if so, what is the relationship between mdm-2 overexpression and other disease parameters including histologic subtypes, p53 status, metastatic potential and clinical stage. METHODS: 81 testicular germ-cell tumors were screened for their mdm-2 expression at the protein levels using immunohistochemistry (IHC) and Western blot (WB) analysis. RESULTS: Of 81 GCTTs 45 (55.55%) showed mdm-2 nuclear immunoreactivity, 34 (41.97%) of which were strongly positive. The incidence of mdm-2 immunostaining was significantly higher (P = 0.0007) in non-seminomas (NSGCT) than in seminomas (SGCT). The frequency of positive tumor was higher in tumors from metastatic patients than in tumors from metastatic-free patients (P = 0.011). mdm-2 expression was detected significantly more frequently in tumors of advanced stages, i.e. IIB, IIC and III versus tumors of early stages (I and II/A) (P = 0.0098). A significant difference between the three stages of disease as to the expression of mdm-2 (chi 2 = 0.0386) could be established, namely the incidence of mdm-2 expression increased with an increase in stage. Using Westem blotting 22 (68.75%) out of 32 tumors overexpressed the mdm-2 oncoprotein of 90 kd (p90). CONCLUSIONS: mdm-2 expression as detected by immunohistochemistry may provide a reliable prognostic tool to isolate subgroups of patients with more aggressive GCTT.

Multidrug resistance of testis cancers: the study of clinical relevance of P-glycoprotein expression.

Germ cell testicular tumors (GCTTs) are very sensitive to anticancer treatment. However some patients ultimately die of their disease due to tumor resistance. Multidrug resistance is mediated by the mdr1 gene product P-glycoprotein (P-gp) which is one important mechanism of drug resistance. This study attempted to examine the correlation between P-gp and tumor progression and to evaluate the clinical relevance of P-gp immunoreactivity in patients with GCTT. Expression of the P-glycoprotein was screened in 48 primary human GCTTs, that have not been treated with chemotherapy, using monoclonal antibody (C219) and immunoenzyme staining. Of the samples from 14 seminomatous germ cell testicular tumors (SGCT, 2 seminomas (14%), and of 34 non-seminomatous tumors (NSGCT) 18 (53%) showed high expression of P-glycoprotein. This difference proved to be significant (P = 0.006). The expression of P-gp showed a statistically significant positive correlation with cancers of advanced stages (P = 0.003) and cancers that showed resistance to chemotherapy (P = 0.0052). Detection of P-gp expression in patients with GCTTs before the application of anti-cancer treatment can be used as a useful prognostic marker to isolate patient subgroups with worse prognosis and less susceptibility to chemotherapy.

Is p53 expression, detected by immunohistochemistry, an important parameter of response to treatment in testis cancer?

BACKGROUND: Several prior studies revealed positive p53 expression via immunohistochemistry (IHC) in a large percentage of germ cell testicular cancers (GCTTs). However, the predicting and prognostic value of this protein remains to be defined. Therefore, the aim of our study was to further clarify the role of p53 protein in GCTTs and to look for correlations between its gene expression and other disease parameters, including histological subtype, stage and clinical resistance sensitivity. Furthermore, we correlated p53 protein expression with that of MDRI gene product protein (Pgp) in order to examine the interrelationship between these two markers. PATIENTS AND METHODS: 77 untreated patients with GCTTs were investigated for their p53 expression using monoclonal antibody and immunohistochemistry in paraffin-embedded specimens. There were 34 patients with stage I, 16 with stage II, 27 with stage III disease. RESULTS: All tumor types, except differentiated teratomas, were immunoreactive for p53 to a various extent ranging from scarcely positive to homogeneously stained tumor cells. Seminomas (S) and embryonal carcinoma (EC) components showed the most positive nuclear staining. p53 expression showed a significant inverse correlation with the stage of disease (P < 0.0003). There was a significant positive relationship between p53 immunoreactivity and response to treatment (P = 0.0012), i.e. high levels of p53 expression correlated with clinical sensitivity of the tumors to chemotherapy. We could demonstrate a statistically significant opposite relationship between p53 and Pgp immunoreactivity (P < 0.0005). CONCLUSION: Our results show that p53 status in tumor cells may be a strong determinate of susceptibility to chemotherapy and that p53 overexpression has a favorable prognosis in terms of response to treatment in GCTTs. Moreover, the findings provide clinical evidence for the presense of significant relationship between p53 and MDR1/Pgp immunoreactivity. They also suggest that patients resistant to chemotherapy and lacking p53 expression might benefit from an alternative appropriately designed chemotherapeutic regimen to achieve further successful treatment in GCTTs.

Drug resistance and sensitivity of germ cell testicular tumors: evaluation of clinical relevance of MDR1/Pgp, p53, and metallothionein (MT) proteins.

BACKGROUND: Although in vitro and clinical studies indicate that overexpression of P-glycoprotein (Pgp), p53, or metallothionein (MT) is involved in modulating drug resistance/sensitivity of cancer cells, the clinical relevance of the overexpression remains to be elucidated. MATERIALS AND METHODS: In this paper the expression and clinical value of Pgp, p53, and MT were evaluated immunohistochemically in 77 specimens of germ cell testicular tumors (GCT). We also studied the interrelationship(s) between the investigated markers. RESULTS: Pgp positivity correlated with cancers of advanced stages (P = 0.000). p53 and MT immunostaining does not predict a poor response to chemotherapy, but rather is correlated to a favorable clinical outcome (P = 0.001, P = 0.00006 respectively). We obtained an inverse association between Pgp and p53 (P = 0.0005), and positive strong association between p53 and MT immunoreactivity (P = 0.0002). CONCLUSIONS: Based on our results in patients with germ cell testicular tumors we assume that the poor clinical outcome seen in certain Pgp positive tumors is the consequence of Pgp association with a more progressive malignant phenotype, rather than its role in multidrug resistance (MDR). p53 and MT immunoreactivity predicts a better response rate to chemotherapy, wheres tumors lacking or demonstrating low MT and or p53 expression show a worse prognosis.

Vitiligo and malignant melanoma.

Six patients with vitiligo and malignant melanoma are reported. The relationship between vitiligo and melanoma seems to be a firm one. This process is supposed to represent an expression of induced autoimmunity.