Neutrophil-to-lymphocyte ratio in primary mediastinal germ cell tumors: A retrospective analysis of >20 years single institution experience.

OBJECTIVES: To obtain information on outcome stratified by histology, extent and primary treatment patients' data with primary malignant mediastinal germ cell tumors treated between 1998 and 2018 were retrospectively analyzed. METHODS: The primary treatment for localized malignant mediastinal germ cell tumors was neoadjuvant bleomycin + etoposid + cisplatin (BEP) ± surgery (n = 22); or surgery ± adjuvant BEP (n = 16). For disseminated disease (n = 21) first line BEP ± second line chemotherapy were administered. For nonseminomas (NS) the NLR at start of BEP was analyzed in relation to disease-free survival (DFS), progression-free survival (PFS), and overall survival (OS). RESULTS: After neoadjuvant treatment the 5-year DFS was 100% for seminomas (S), and 63.4% for NS. The 5-year OS was 100% for S, and 76.9% for NS. The 5-year DFS and OS after surgery ± BEP for S was 72.9% and 100%, for NS was 75% and 87.5%, respectively. The 5-year PFS and OS of metastatic patients for S was 60% and 80%, while the median PFS and OS of NS were 5.7 and 11.1 months, respectively. Objective response (P = 0.006) and low NLR (P = 0.043) were independent prognostic markers of longer OS. CONCLUSIONS: We confirmed the good outcome of BEP-treated S, while NS had poorer prognosis. Previously published prognostic models for NS were validated. Based on NLR and response a new prognostic model was developed.

Association of Genomic Domains in BRCA1 and BRCA2 with Prostate Cancer Risk and Aggressiveness.

Pathogenic sequence variants (PSV) in BRCA1 or BRCA2 (BRCA1/2) are associated with increased risk and severity of prostate cancer. We evaluated whether PSVs in BRCA1/2 were associated with risk of overall prostate cancer or high grade (Gleason 8+) prostate cancer using an international sample of 65 BRCA1 and 171 BRCA2 male PSV carriers with prostate cancer, and 3,388 BRCA1 and 2,880 BRCA2 male PSV carriers without prostate cancer. PSVs in the 3' region of BRCA2 (c.7914+) were significantly associated with elevated risk of prostate cancer compared with reference bin c.1001-c.7913 [HR = 1.78; 95% confidence interval (CI), 1.25-2.52; P = 0.001], as well as elevated risk of Gleason 8+ prostate cancer (HR = 3.11; 95% CI, 1.63-5.95; P = 0.001). c.756-c.1000 was also associated with elevated prostate cancer risk (HR = 2.83; 95% CI, 1.71-4.68; P = 0.00004) and elevated risk of Gleason 8+ prostate cancer (HR = 4.95; 95% CI, 2.12-11.54; P = 0.0002). No genotype-phenotype associations were detected for PSVs in BRCA1. These results demonstrate that specific BRCA2 PSVs may be associated with elevated risk of developing aggressive prostate cancer. SIGNIFICANCE: Aggressive prostate cancer risk in BRCA2 mutation carriers may vary according to the specific BRCA2 mutation inherited by the at-risk individual.

Outcome of Restarted Sunitinib Treatment in Patients with Metastatic Renal Cell Carcinoma: a Retrospective Trial and Combined Case Reports from Literature.

In practice it is still not clear whether a drug holiday in sunitinib (Su) treatment can be safety, without impairing the overall outcome of patients with metastatic renal cell carcinoma (mRCC). The aim was to retrospectively evaluate the outcome in patients who restarted Su after an interruption of ≥3 months and a combined analysis of case studies from literature. From 556 patients treated between January 2006 and March 2016 a group of 38 patients were selected whose treatment was interrupted for other reasons than disease progression. During interruption Su was restarted in case of RECIST-defined progression. The primary objective was the objective response (OR) and progression free survival (PFS) of baseline and restarted therapy. The secondary objective was the overall survival (OS) calculated from the start of baseline treatment. Multivariate survival analysis was also applied. The major causes of interruption were toxicity (39%) and patient' choice (24%). Median duration of interruption was 7 (range 3-41) months. The OR of baseline and restarted treatment was 63% and 39%, respectively. After a median follow-up of 76 (95% CI 65-79) months the median PFS of baseline and restarted treatment was 21 (18-27) and 14 (10-18) months, respectively. The median OS was 61 (56-80) months. In multivariate analysis the lack of OR of restated treatment was an independent predictor of shorter PFS of restarted Su. According to our findings and also on combined case studies from literature restarted Su can be effective in selected cases of patients who progressed during treatment holiday.

Outcomes in Patients With Metastatic Renal Cell Carcinoma Who Develop Everolimus-Related Hyperglycemia and Hypercholesterolemia: Combined Subgroup Analyses of the RECORD-1 and REACT Trials.

BACKGROUND: Hyperglycemia and hypercholesterolemia are class effects of mammalian target of rapamycin inhibitors. The purpose of this study was to characterize safety and efficacy of patients with metastatic renal cell carcinoma (mRCC) treated with everolimus in RECORD-1 (REnal Cell cancer treatment with Oral RAD001 given Daily) and REACT (RAD001 Expanded Access Clinical Trial in RCC) who developed these events. PATIENTS AND METHODS: Adults with vascular endothelial growth factor-refractory mRCC received everolimus 10 mg/d in the randomized RECORD-1 (n = 277) and open-label REACT (n = 1367) studies. Outcomes included safety, treatment duration, overall response, and progression-free survival for patients who developed hypercholesterolemia or hyperglycemia. RESULTS: In RECORD-1, 12% (33 of 277) and 20% (55 of 277) of patients developed any grade hyperglycemia or hypercholesterolemia, respectively, with only 6% (78 of 1367) and 1% (14 of 1367) of the same events, respectively, in REACT. Median everolimus treatment duration was similar for patients with hyperglycemia or hypercholesterolemia (RECORD-1, 6.2 and 6.2 months, respectively; REACT, 4.4 and 4.5 months, respectively), but longer than the overall populations (RECORD-1, 4.6 months; REACT, 3.2 months). In RECORD-1/REACT, 82%/68% of patients with hyperglycemia and 75%/71% of patients with hypercholesterolemia achieved partial response or stable disease. The incidence of clinically notable Grade 3 or 4 adverse events, other than anemia and lymphopenia, appeared to be similar across trials and subgroups. Although there was a trend for improved progression-free survival with development of hyperglycemia or hypercholesterolemia, the association was not statistically significant. CONCLUSION: Hyperglycemia and hypercholesterolemia were observed in low numbers of patients, and although these events might be associated with improved response to everolimus, the differences were not significant. These findings should be validated with prospective biomarker studies.

[First Hungarian experience with pazopanib therapy for patients with metastatic renal cancer]. / Áttétes vesedaganatos betegek pazopanibterápiájával szerzett elsõ hazai tapasztalatok.

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.

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.

BACKGROUND AND OBJECTIVES: 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-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. PATIENTS AND METHODS: 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. RESULTS: 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. CONCLUSION: Everolimus is well tolerated in patients with mRCC and demonstrates a favourable risk-benefit ratio.

Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: a randomised open-label trial.

BACKGROUND: Cabazitaxel is a novel tubulin-binding taxane drug with antitumour activity in docetaxel-resistant cancers. We aimed to compare the efficacy and safety of cabazitaxel plus prednisone with those of mitoxantrone plus prednisone in men with metastatic castration-resistant prostate cancer with progressive disease after docetaxel-based treatment. METHODS: We undertook an open-label randomised phase 3 trial in men with metastatic castration-resistant prostate cancer who had received previous hormone therapy, but whose disease had progressed during or after treatment with a docetaxel-containing regimen. Participants were treated with 10 mg oral prednisone daily, and were randomly assigned to receive either 12 mg/m(2) mitoxantrone intravenously over 15-30 min or 25 mg/m(2) cabazitaxel intravenously over 1 h every 3 weeks. The random allocation schedule was computer-generated; patients and treating physicians were not masked to treatment allocation, but the study team was masked to the data analysis. The primary endpoint was overall survival. Secondary endpoints included progression-free survival and safety. Analysis was by intention to treat. This study is registered at ClinicalTrials.gov, NCT00417079. FINDINGS: 755 men were allocated to treatment groups (377 mitoxantrone, 378 cabazitaxel) and were included in the intention-to-treat analysis. At the cutoff for the final analysis (Sept 25, 2009), median survival was 15·1 months (95% CI 14·1-16·3) in the cabazitaxel group and 12·7 months (11·6-13·7) in the mitoxantrone group. The hazard ratio for death of men treated with cabazitaxel compared with those taking mitoxantrone was 0·70 (95% CI 0·59-0·83, p<0·0001). Median progression-free survival was 2·8 months (95% CI 2·4-3·0) in the cabazitaxel group and 1·4 months (1·4-1·7) in the mitoxantrone group (HR 0·74, 0·64-0·86, p<0·0001). The most common clinically significant grade 3 or higher adverse events were neutropenia (cabazitaxel, 303 [82%] patients vs mitoxantrone, 215 [58%]) and diarrhoea (23 [6%] vs one [<1%]). 28 (8%) patients in the cabazitaxel group and five (1%) in the mitoxantrone group had febrile neutropenia. INTERPRETATION: Treatment with cabazitaxel plus prednisone has important clinical antitumour activity, improving overall survival in patients with metastatic castration-resistant prostate cancer whose disease has progressed during or after docetaxel-based therapy. FUNDING: Sanofi-Aventis.

The International Testicular Cancer Linkage Consortium: a clinicopathologic descriptive analysis of 461 familial malignant testicular germ cell tumor kindred.

OBJECTIVES: Familial aggregation of testicular germ cell tumor (TGCT) has been reported, but it is unclear if familial TGCT represents a unique entity with distinct clinicopathologic characteristics. Here we describe a collection of familial TGCT cases from an international consortium, in an effort to elucidate any clinical characteristics that are specific to this population. MATERIALS AND METHODS: Families with >or=2 cases of TGCT enrolled at 18 of the sites participating in the International Testicular Cancer Linkage Consortium were included. We analyzed clinicopathologic characteristics of 985 cases from 461 families. RESULTS: A majority (88.5%) of families had only 2 cases of TGCT. Men with seminoma (50% of cases) had an older mean age at diagnosis than nonseminoma cases (P = 0.001). Among individuals with a history of cryptorchidism, TGCT was more likely to occur in the ipsilateral testis (kappa = 0.65). Cousin pairs appeared to represent a unique group, with younger age at diagnosis and a higher prevalence of cryptorchidism than other families. CONCLUSIONS: Clinicopathologic characteristics in these familial TGCT cases were similar to those generally described for nonfamilial cases. However, we observed a unique presentation of familial TGCT among cousin pairs. Additional studies are needed to further explore this observation.

[Metachronous metastasis from rectal adenocarcinoma to the penis--case report]. / Metakrón penismetastasis rectum-adenocarcinomából.

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.

Multinational, double-blind, phase III study of prednisone and either satraplatin or placebo in patients with castrate-refractory prostate cancer progressing after prior chemotherapy: the SPARC trial.

PURPOSE: This multinational, double-blind, randomized, placebo-controlled, phase III trial assessed the efficacy and tolerability of the oral platinum analog satraplatin in patients with metastatic castrate-refractory prostate cancer (CRPC) experiencing progression after one prior chemotherapy regimen. PATIENTS AND METHODS: Nine hundred fifty patients were randomly assigned (2:1) to receive oral satraplatin (n = 635) 80 mg/m(2) on days 1 to 5 of a 35-day cycle and prednisone 5 mg twice daily or placebo (n = 315) and prednisone 5 mg twice daily. Primary end points were progression-free survival and overall survival (OS). The secondary end point was time to pain progression (TPP). RESULTS: A 33% reduction (hazard ratio [HR] = 0.67; 95% CI, 0.57 to 0.77; P < .001) was observed in the risk of progression or death with satraplatin versus placebo. This effect was maintained irrespective of prior docetaxel treatment. No difference in OS was seen between the satraplatin and placebo arms (HR = 0.98; 95% CI, 0.84 to 1.15; P = .80). Compared with placebo, satraplatin significantly reduced TPP (HR = 0.64; 95% CI, 0.51 to 0.79; P < .001). Satraplatin was generally well tolerated, although myelosuppression and GI disorders occurred more frequently with satraplatin. CONCLUSION: Oral satraplatin delayed progression of disease and pain in patients with metastatic CRPC experiencing progression after initial chemotherapy but did not provide a significant OS benefit. Satraplatin was generally well tolerated. These results suggest activity for satraplatin in patients with CRPC who experience progression after initial chemotherapy.

Younger age-at-diagnosis for familial malignant testicular germ cell tumor.

One of the clinical hallmarks of hereditary cancer susceptibility disorders is a younger-than-usual age at diagnosis. Familial aggregation of testicular germ cell tumor (TGCT) has been reported, but data on whether familial TGCT cases are diagnosed at an earlier age are inconclusive. Here we compared the age at diagnosis of familial TGCT cases with that of population cases in several countries. Familial TGCT is defined as affected individuals from families with >or=2 cases of TGCT. Age at diagnosis of familial cases from the United States, Canada, United Kingdom, Australia and New Zealand, Norway, and Hungary was compared to cases identified in population-based cancer registries from the respective country, using the generalized estimation equation method. Age at diagnosis was statistically significantly younger for familial TGCT cases from North America (P = 0.024), the United Kingdom (P < 0.0001), and Australia and New Zealand (P = 0.0033) compared with population cases. When stratified by histology, the difference in age at diagnosis distribution between familial and population cases was observed for seminoma cases from North America (P = 0.002) and the United Kingdom (P < 0.0001) and non-seminoma cases from the United Kingdom (P = 0.029) and Australia and New Zealand (P = 0.0023). In summary, we found that the age at diagnosis for familial TGCT cases is, on the average, 2-3 years younger than that for the population cases in North America, United Kingdom, and Australia and New Zealand. The younger age at diagnosis might be suggestive of a genetic basis for familial TGCT.

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

Vandetanib (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.

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

BACKGROUND: 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 are curable because of an intact and effective apoptotic pathway. PATIENTS AND METHODS: 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. RESULTS: 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. CONCLUSION: 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.

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.

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.

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. 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.

Analysis of the DND1 gene in men with sporadic and familial testicular germ cell tumors.

A base substitution in the mouse Dnd1 gene resulting in a truncated Dnd protein has been shown to be responsible for germ cell loss and the development of testicular germ cell tumors (TGCT) in the 129 strain of mice. We investigated the human orthologue of this gene in 263 patients (165 with a family history of TGCT and 98 without) and found a rare heterozygous variant, p. Glu86Ala, in a single case. This variant was not present in control chromosomes (0/4,132). Analysis of the variant in an additional 842 index TGCT cases (269 with a family history of TGCT and 573 without) did not reveal any additional instances. The variant, p. Glu86Ala, is within a known functional domain of DND1 and is highly conserved through evolution. Although the variant may be a rare polymorphism, a change at such a highly conserved residue is characteristic of a disease-causing variant. Whether it is disease-causing or not, mutations in DND1 make, at most, a very small contribution to TGCT susceptibility in adults and adolescents.

Bevacizumab plus interferon alfa-2a for treatment of metastatic renal cell carcinoma: a randomised, double-blind phase III trial.

BACKGROUND: Vascular endothelial growth factor (VEGF) inhibition is a valid therapeutic approach in renal cell carcinoma. Therefore, an investigation of the combination treatment of the humanised anti-VEGF monoclonal antibody bevacizumab with interferon alfa was warranted. METHODS: In a multicentre, randomised, double-blind, phase III trial, 649 patients with previously untreated metastatic renal cell carcinoma were randomised to receive interferon alfa-2a (9 MIU subcutaneously three times weekly) and bevacizumab (10 mg/kg every 2 weeks; n=327) or placebo and interferon alfa-2a (n=322). The primary endpoint was overall survival. Secondary endpoints included progression-free survival and safety. An interim analysis of overall survival was prespecified after 250 deaths. On the basis of new second-line therapies that became available while the trial was in progress, which could have confounded analyses of overall survival data, we agreed with regulatory agencies that the pre-planned final analysis of progression-free survival would be acceptable for regulatory submission. The protocol was amended to allow the study to be unblinded at this point. The final analysis of progression-free survival is reported here. Efficacy analyses were done by intention to treat. This trial is registered with centerwatch.com, number BO17705E. FINDINGS: 325 patients in the bevacizumab plus interferon alfa group and 316 in the placebo plus interferon alfa group received at least one dose of study treatment. At the time of unblinding, 230 progression events had occurred in the bevacizumab plus interferon alfa group and 275 in the control group; there were 114 deaths in the bevacizumab plus interferon alfa group and 137 in the control group. Median duration of progression-free survival was significantly longer in the bevacizumab plus interferon alfa group than it was in the control group (10.2 months vs 5.4 months; HR 0.63, 95% CI 0.52-0.75; p=0.0001). Increases in progression-free survival were seen with bevacizumab plus interferon alfa irrespective of risk group or whether reduced-dose interferon alfa was received. Deaths due to adverse events were reported in eight (2%) patients who received one or more doses of bevacizumab and seven (2%) of those who did not receive the drug. Only three deaths in the bevacizumab arm were considered by investigators to be possibly related to bevacizumab. The most commonly reported grade 3 or worse adverse events were fatigue (40 [12%] patients in the bevacizumab group vs 25 [8%] in the control group) and asthenia (34 [10%] vs 20 [7%]). INTERPRETATION: The combination of bevacizumab with interferon alfa as first-line treatment in patients with metastatic renal cell carcinoma results in a significant improvement in progression-free survival, compared with interferon alfa alone.

Randomized, placebo-controlled phase II study of vandetanib plus docetaxel in previously treated non small-cell lung cancer.

PURPOSE: Vandetanib is a once-daily oral inhibitor of vascular endothelial growth factor receptor-2 and epidermal growth factor receptor kinase activity. The activity of vandetanib plus docetaxel was assessed in patients with previously treated non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: This two-part study comprised an open-label run-in phase and a double-blind randomized phase. Eligible patients had locally advanced or metastatic (stage IIIB/IV) NSCLC after failure of first-line platinum-based chemotherapy. The primary objective of the randomized phase was to prolong progression-free survival (PFS) in patients receiving vandetanib (100 or 300 mg/d) plus docetaxel (75 mg/m2 intravenous infusion every 21 days) versus placebo plus docetaxel. The study was designed to have more than 75% power to detect 50% prolongation at a one-sided significance level of P < .20. Secondary objectives included objective response rate, overall survival, safety and tolerability. RESULTS: In the randomized phase (n = 127), median PFS was 18.7 weeks for vandetanib 100 mg plus docetaxel (n = 42; hazard ratio v docetaxel = 0.64; one-sided P = .037); 17.0 weeks for vandetanib 300 mg plus docetaxel (n = 44; hazard ratio v docetaxel = 0.83; one-sided P = .231); and 12 weeks for docetaxel (n = 41). There was no statistically significant difference in overall survival among the three treatment arms. Common adverse events included diarrhea, rash, and asymptomatic prolongation of corrected QT (QTC) interval. CONCLUSION: The primary objective was achieved, with vandetanib 100 mg plus docetaxel demonstrating a significant prolongation of PFS compared with docetaxel in relation to the prespecified significance level. On the basis of these encouraging data, phase III evaluation of vandetanib 100 mg plus docetaxel in second-line NSCLC has been initiated.

[Effect of angiogenesis inhibitors on renal cell carcinoma]. / Angiogenezisgátlók hatása metasztatikus vesesejtes rákban.

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.

Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma.

BACKGROUND: Interferon alfa is widely used for metastatic renal-cell carcinoma but has limited efficacy and tolerability. Temsirolimus, a specific inhibitor of the mammalian target of rapamycin kinase, may benefit patients with this disease. METHODS: In this multicenter, phase 3 trial, we randomly assigned 626 patients with previously untreated, poor-prognosis metastatic renal-cell carcinoma to receive 25 mg of intravenous temsirolimus weekly, 3 million U of interferon alfa (with an increase to 18 million U) subcutaneously three times weekly, or combination therapy with 15 mg of temsirolimus weekly plus 6 million U of interferon alfa three times weekly. The primary end point was overall survival in comparisons of the temsirolimus group and the combination-therapy group with the interferon group. RESULTS: Patients who received temsirolimus alone had longer overall survival (hazard ratio for death, 0.73; 95% confidence interval [CI], 0.58 to 0.92; P=0.008) and progression-free survival (P<0.001) than did patients who received interferon alone. Overall survival in the combination-therapy group did not differ significantly from that in the interferon group (hazard ratio, 0.96; 95% CI, 0.76 to 1.20; P=0.70). Median overall survival times in the interferon group, the temsirolimus group, and the combination-therapy group were 7.3, 10.9, and 8.4 months, respectively. Rash, peripheral edema, hyperglycemia, and hyperlipidemia were more common in the temsirolimus group, whereas asthenia was more common in the interferon group. There were fewer patients with serious adverse events in the temsirolimus group than in the interferon group (P=0.02). CONCLUSIONS: As compared with interferon alfa, temsirolimus improved overall survival among patients with metastatic renal-cell carcinoma and a poor prognosis. The addition of temsirolimus to interferon did not improve survival. (ClinicalTrials.gov number, NCT00065468 [ClinicalTrials.gov].).