RARE INTRACRANIAL MULTIFOCAL NON-GERMINOMATOUS GERM CELL TUMOR IN AN 18-YEAR-OLD MALE: A CASE REPORT.

Intracranial germ cell tumors are rare brain tumors that are distinguished based on their histology and selected tumor markers. Non-germinomatous germ cell tumors are a diverse group of such tumors having the poorest prognosis. Most commonly, they are located in the suprasellar and pineal regions. Since the exact treatment protocol has not yet been established, there is currently no standardized modality of management. We present a case of intracranial multifocal non-germinomatous germ cell tumor in an 18-year-old male, along with relevant literature review. We describe initial diagnostic and treatment procedures in a young adult presented with diplopia and ataxic gait. Neuroradiological findings and elevated alpha fetoprotein and beta chain of the human chorionic gonadotropin tumor markers indicated the possible mixed germ cell tumor. Chemotherapy regimen was adjusted accordingly, biopsy was not performed. The patient's clinical condition improved significantly and his alpha fetoprotein values decreased remarkably after initiation of chemotherapy. In conclusion, initial evaluation with neuroimaging, tumor markers, and cytology from cerebrospinal fluid is important as guidance to further treatment and prognosis. In selected cases, biopsy may not be indicated to start adjuvant chemotherapy. We emphasize the importance of specific treatment modality selection based mainly on tumor markers, regardless of the precise histologic classification.

Real-world safety and efficacy of nivolumab for ≥ 2nd line treatment of metastatic renal cell carcinoma: A retrospective cohort study in Croatia, Hungary, and Malta.

The objective of our study was to assess the real-world safety and efficacy of nivolumab in the second- or later-line treatment of metastatic renal cell carcinoma (mRCC). We conducted a multicenter, retrospective, observational study of real-world data from patients who were treated with nivolumab under a patient expanded access program from 2015 to 2017 in Croatia, Hungary, and Malta. The primary safety endpoint was the discontinuation of therapy because of adverse events. The primary efficacy endpoint was overall survival (OS). We collected data from 87 patients with a median (interquartile range (IQR)) age of 63 (57-68) years, and 21% were females. The median (IQR) follow-up was 11 (5-31) months. Treatment was discontinued because of toxicity in 4 (5%) patients. Four (5%) patients experienced treatment-related adverse events of grade 3 or 4. The OS was 18.0 (95% CI: 11.0 to 28.6) months, and the PFS was 8.5 (95% CI: 4.9 to 12.1) months. Our study indicated a good safety and efficacy profile of nivolumab in the second- or later-line treatment of mRCC patients in a real-world clinical practice environment, which is comparable with the findings of the registrational trial.

Safety and efficacy of nivolumab as a second line therapy in metastatic renal cell carcinoma: a retrospective chart review.

AIM: To assess diseases outcomes and tolerability of real-life second-line nivolumab in a series of metastatic renal cell carcinoma (mRCC) patients. METHODS: This retrospective chart review involved prospectively monitored patients (named patient program) treated with second-line nivolumab for mRCC at the University Hospital Centre Zagreb from February 2016 to March 2018. RESULTS: The study enrolled 30 patients, 5 of whom (16.7%) had a complete response. The mean ± standard deviation therapeutic response time to nivolumab treatment was 14.07 ± 8.92 months, with a minimum treatment duration of 2 months and a maximum of 24 months. The median duration of therapy was 17 months (mean: 15.8 months; range: 3-24 months), and 50% (n=15/30) of patients remained alive at the end of follow up. The most common adverse events associated with nivolumab were fatigue (26.67%; n=8/30), anemia (10.0%; n=3/30), adrenal insufficiency (6.67%; n=2/30: G1=1, G2=1), grade 2 pneumonitis (6.67%; n=2/30), grade 2 neuropathy (6.67%; n=2/30), rash (6.67%; n = 2/30: G1=1, G2=1), and hepatitis (3.33%; n=1/30). CONCLUSION: The present study indicates acceptable patient responses and tolerability of nivolumab in mRCC.

Treatment of germ cell testicular cancer.

Germ-cell testicular cancer (GCTC) is a malignant neoplasm derived from the primordial germ cell. Although it accounts for approximately 1% of all malignancies in men, it is the most common cancer of younger male population, with the highest incidence between ages 15 and 35. Testicular cancer incidence rate has risen globally over the past several decades, with the average increase in the incidence of testicular cancer in Croatia of 7% per annum from the year 1983 to 2007. Two main groups are seminomas and non-seminomas, each accounting for 50% of cases, and they differ in treatment modalities and response to therapy. Despite increase in the incidence rate, a promising circumstance is that GCTC has become a model of curable cancer. Because of advances in diagnostic procedures, sophisticated radiation techniques and especially the introduction of cisplatin based chemotherapy protocols together with advanced postchemotherapy surgical techniques, curability is expected in about 95% of all patients diagnosed with testicular cancer and over 70% of patients with advanced disease. In this review, we will focus on treatment strategies of primary GCTC.

Skin autoimmunity might be associated with increased efficacy of atezolizumab in metastatic urothelial carcinoma: a case report.

Atezolizumab is a monoclonal antibody immune checkpoint inhibitor that binds to programmed death ligand 1 to selectively prevent its interaction with programmed cell death-1 (PD-1) and B7.1 (CD80) receptors. We present a case of a 61-year-old man with metastatic urothelial carcinoma of the right ureter and urinary bladder. After gemcitabine/cisplatin as the first-line chemotherapy and surgery, the patient received atezolizumab 1200 mg i.v. q3w. Following the first atezolizumab administration, he noted vitiligo periorally, on his hands, legs, and the scalp. The patient's overall survival (OS) of >26 months and continuing response to atezolizumab treatment is considerably better than median OS in the SAUL study of 8.7 months (IMvigor211-like patients' OS 10.0 months). This case indicates that increased efficacy of atezolizumab can be associated with cutaneous immune related adverse events, reflecting the known Th17 polarization of these diseases and showing that individuals with cutaneous adverse events could benefit from PD-1 checkpoint blockade in the therapy of metastatic urothelial carcinoma.

WHICH PATIENTS WILL BENEFIT MOST FROM DOCETAXEL ADDITION TO ANDROGEN DEPRIVATION THERAPY (ADT) IN METASTATIC CASTRATE-SENSITIVE PROSTATE CANCER (MCSPC)?

Docetaxel improved the outcome of patients with mCSPC and became standard of care after CHAARTED, STAMPEDE arm C and GETUG-AFU 15 clinical trials and after subsequent meta-analysis. Patients with high-volume (CHAARTED definition) and high-risk (LATITUDE definition) disease, who have good performance status and are fit for chemotherapy, seem to benefit the most from addition of docetaxel to the androgen deprivation therapy. Results from TITAN trial with apalutamide showed the activity in the same setting. However, predictive biomarkers are still lacking. We have direct evidence of overall survival benefit from abiraterone, apalutamide and enzalutamide for patients with high-volume disease who are not fit for chemotherapy, as well as for patients with low-volume disease. Clinical trials will show is there place for triple therapy in clinical practice. Before obtaining the results of new clinical trial results, physicians should base their treatment decision on risks and benefits of each current approach and consider the patient´s other health issues such as access, costs, patient and patient´s preferences.

THE PROSTATE CENTER: MULTIDISCIPLINARITY, ORGANIZATION OF DIAGNOSTIC WORK-UP AND TREATMENT OF PROSTATE CANCER.

The aim of this paper is to show the results of prostate cancer treatment in Prostate Center of Department of Urology at the University Hospital Center Zagreb. The answer to growing demands for prostate cancer treatment due to increasing incidence is the formation of specialized, multidisciplinary units/centers that deal mainly with prostate cancer. The need was recognized by European School of Oncology and European Association of Urology, who have proposed their concepts of validating such centers with the aim of promoting high-quality prostate cancer treatment. Following these trends, the Department of Urology at the University Hospital Center Zagreb has established the Prostate Center. This new unit offers specialized and individualized approach to workup, treatment and follow up for prostate cancer patients based on multidisciplinarity. The Prostate Center was also established as a platform for education and research.

Clinical utility of [68Ga]Ga-PSMA-11 PET/CT in initial staging of patients with prostate cancer and importance of intraprostatic SUVmax values.

BACKGROUND: As in disease recurrence, providing clinicians with the exact extent of the disease at the time of initial diagnosis is key in the management and individual treatment of prostate cancer (PC) patients. Intending to examine the usefulness of gallium- 68 PSMA-11 positron emission tomography/computed tomography ([68Ga]Ga-PSMA-11 PET/CT) and to determine if there is a correlation between prostate-specific antigen (PSA) serum values, WHO/ISUP (World Health Organization/International Society of Urological Pathology's) grade group of the tumor and SUVmax (maximized standardized uptake value) values we retrospectively analyzed PET/CT studies performed for initial staging of the disease. PATIENTS AND METHODS: We retrospectively evaluated 34 studies of patients who underwent [68Ga]Ga-PSMA-11 PET/CT as part of the initial staging of prostate cancer. All patients had prostate cancer confirmed by histological assessment after biopsy and had Gleason score and PSA serum values obtained. The mean PSA value was 33.8 ± 40.9 nmol/L (range 2.2-232). RESULTS: Nineteen patients had extended disease (55.9%). The mean SUVmax in prostate lesions was 19.5 ± 12.6. The mean value of SUVmax of PET studies in the high-risk group was significantly higher than those of low risk (23.5 ± 13.2 and 10.6 ± 5.4, p < 0.05). A positive correlation was observed between the ISUP group and SUVmax value of prostate lesions (Pearson's r = 0.557, p < 0.01). A positive correlation was also found in the comparison between PSA values and SUVmax (Pearson's r = 0.34, p < 0.05). CONCLUSIONS: In our study, [68Ga]Ga-PSMA-11 PET/CT scans detected the extended disease in more than half of the patients. Locating disease beyond the prostate gland allowed better informed clinical decisions and modified treatment. A positive correlation was found between intraprostatic SUVmax values and the ISUP group of prostate cancer. High-risk patients had SUVmax values that were significantly higher than those of low-risk patients. The correlation between the Gleason score and SUVmax value can be explained by the increased intensity of PSMA expression as the tumor grade increases.

Final Results from SAUL, a Single-arm International Study of Atezolizumab in Unselected Patients with Pretreated Locally Advanced/Metastatic Urinary Tract Carcinoma.

BACKGROUND AND OBJECTIVE: We assessed the safety of atezolizumab in unselected patients (including understudied populations typically excluded from clinical trials) with pretreated urinary tract carcinoma (UTC). The prespecified final analysis updates previously reported safety and efficacy data. METHODS: The single-arm prospective SAUL study (NCT02928406) enrolled 1004 patients with locally advanced/metastatic urothelial/non-urothelial UTC that had progressed during/after one to three prior treatment lines for advanced UTC (or <12 mo after [neo]adjuvant therapy). Broad eligibility criteria allowed enrollment of patients with complex comorbidities approximating the real-world setting. Patients received atezolizumab 1200 mg every 3 wk until disease progression or unacceptable toxicity. The primary endpoint was safety. Secondary endpoints included duration of response and overall survival (OS). KEY FINDINGS AND LIMITATIONS: The treated cohort included 10% of patients with poor performance status, 5% with creatinine clearance <30 ml/min, and 4% with autoimmune disease. At median follow-up of 55 mo, median atezolizumab duration was 2.8 mo (range 0-62); 68 patients (7%) continued atezolizumab for >4 yr. Treatment-related grade ≥3 adverse events occurred in 16% of patients (death in 1%); 8% discontinued atezolizumab for adverse events. Median OS was 8.6 mo (95% confidence interval 7.8-9.7) and 136 patients (14%) had OS longer than 4 yr. Limitations include the small sample size for some subgroups of special interest. CONCLUSIONS AND CLINICAL IMPLICATIONS: Long-term safety and efficacy data continue to show a benefit of atezolizumab in unselected patients with UTC. Remarkably, 14% of patients lived for >4 yr after starting atezolizumab. These results can inform multidisciplinary team discussions and treatment decision-making for patients with UTC with complex comorbidities. PATIENT SUMMARY: The SAUL study looked at how well tolerated a drug called atezolizumab was in patients with urinary tract cancer who had already received up to three previous treatments for their cancer, including people who are usually not included in clinical trials because of other medical conditions. The length of survival after starting treatment was also assessed. Overall, the results show that atezolizumab was well tolerated. People for whom other therapies had failed lived for about 8.6 months on average after starting treatment, and 14% of the patients were still alive after 4 years.

[Clinical guidelines for diagnosing, treatment and monitoring patients with testicular cancer--Croatian Oncology Society and Croatian Urology Society, Croatian Medical Association]. / Klinicke upute za dijagnostiku, lijecenje i pracenje bolesnika oboljelih od raka testisa Hrvatskoga Onkoloskog Drustva i Hrvatskoga Uroloskog Drustva Hrvatskoga Lijecnickog Zbora.

Testicular tumors are the most common solid tumors in men between 15 and 34 years of age. The worldwide incidence of these tumors has doubled in the past 40 years. Germ cell tumors comprise 95% of malignant tumors arising in the testes and they are classified either as seminoma or nonseminoma. Testicular cancers have a high cure rates even in disseminated stage of the disease. The chemotherapy mostly contributed to these results but surgery is an inevitable part of successful treatment. In a significant number of these patients treatment algorithms with minimum side effects are designed with the intention to maintain same cure rates as previously used, more aggressive therapy. The following text presents the clinical guidelines in order to standardize the procedures and criteria for diagnosis, management, treatment and follow-up of patients with testicular cancer in Republic of Croatia.

[Clinical guidelines for diagnosing, treatment and monitoring patients with bladder cancer--Croatian Oncology Society and Croatian Urology Society, Croatian Medical Association]. / Klinicke upute za dijagnostiku, lijecenje i pracenje bolesnika oboljelih od raka mokracnog mjehura Hrvatskoga Onkolokog Drustva i Hrvatskoga Uroloskog Drustva Hrvatskoga Lijecnickog Zbora.

Urothelial cancer is the most common bladder cancer. Hematuria is the most common presenting symptom in patients with bladder cancer. The most common diagnostics of bladder cancer is performed by transurethral resection of bladder after which pathohistological diagnosis is set. It is necessary to determine whether the cancer penetrated in muscle layer (muscle-invasive cancer) or not (muscle-noninvasive cancer). Decision on therapeutic modality depends on the clinical stage of disease and on prognostic and risk factors. For muscle non-invasive bladder cancer transurethral resection is preferred with or without intravesical instillation of Bacillus Calmette-Guérin (BCG). For invasive cancer the method of choice is radical cystectomy. Radiotherapy is used in radical and palliative purposes. Metastatic disease is most frequently treated by chemotherapy metotrexate/vinblastine/doxorubicine/cisplatin (MVAC) or gemcitabine/cisplatin (GC). The purpose of this article is to present clinical recommendations to set standards of procedures and criteria in diagnostics, treatment and follow up of patients with bladder cancer in the Republic of Croatia.

Biochemical activity induced by a germline variation in KLK3 (PSA) associates with cellular function and clinical outcome in prostate cancer.

Genetic variation at the 19q13.3 KLK locus is linked with prostate cancer susceptibility. The non-synonymous KLK3 SNP, rs17632542 (c.536T>C; Ile163Thr-substitution in PSA) is associated with reduced prostate cancer risk, however, the functional relevance is unknown. Here, we identify that the SNP variant-induced change in PSA biochemical activity as a previously undescribed function mediating prostate cancer pathogenesis. The 'Thr' PSA variant led to small subcutaneous tumours, supporting reduced prostate cancer risk. However, 'Thr' PSA also displayed higher metastatic potential with pronounced osteolytic activity in an experimental metastasis in-vivo model. Biochemical characterization of this PSA variant demonstrated markedly reduced proteolytic activity that correlated with differences in in-vivo tumour burden. The SNP is associated with increased risk for aggressive disease and prostate cancer-specific mortality in three independent cohorts, highlighting its critical function in mediating metastasis. Carriers of this SNP allele had reduced serum total PSA and a higher free/total PSA ratio that could contribute to late biopsy decisions and delay in diagnosis. Our results provide a molecular explanation for the prominent 19q13.3 KLK locus, rs17632542 SNP, association with a spectrum of prostate cancer clinical outcomes.

Replication of genetic susceptibility loci for testicular germ cell cancer in the Croatian population.

Genome-wide association studies in patients with testicular germ-cell tumors (TGCT) from Great Britain and the United States have identified six susceptibility loci in or near biologically plausible candidate genes. However, these loci have not been replicated in an independent European sample. We performed a genetic replication study of previously identified TGCT susceptibility loci in a Croatian case-control sample and performed additional analyses as concerning histological subtypes or tumor staging. We analyzed six single-nucleotide polymorphisms [rs2900333 (ATF7IP), rs210138 (BAK1), rs755383 (DMRT1), rs995030 (KITLG), rs4624820 (SPRY4), and rs4635969 (TERT/CLPTM1L)], each representing one of the published susceptibility loci/genes. Five susceptibility loci were found to be also associated in the Croatian population with P-values between 2.1e-10 (rs995030; odds ratio [OR] 3.08) and 0.01739 (rs4635969; OR 1.37), which remained statistically significant after correction for multiple testing. Although rs2900333 near ATF7IP just showed borderline association with all-TGCT (OR 1.24, P = 0.062), it showed significant association with the more aggressive forms of the tumor (OR 1.51, P = 0.0067)-a clinically interesting finding, which however has to be replicated in an independent sample. Assessment of cumulative risks revealed that men with at least seven risk alleles have a more than 2.5-fold increased disease risk (OR = 2.73, 95% confidence interval = 1.98-3.79). In summary, we independently replicated the majority of TGCT susceptibility loci identified previously in a Croatian sample and suggested a possible role of genetic variation near ATF7IP in regulating disease progression.

Environmental exposure to xenoestrogens and oestrogen related cancers: reproductive system, breast, lung, kidney, pancreas, and brain.

The role of steroids in carcinogenesis has become a major concern in environmental protection, biomonitoring, and clinical research. Although historically oestrogen has been related to development of reproductive system, research over the last decade has confirmed its crucial role in the development and homeostasis of other organ systems. As a number of anthropogenic agents are xenoestrogens, environmental health research has focused on oestrogen receptor level disturbances and of aromatase polymorphisms. Oestrogen and xenoestrogens mediate critical points in carcinogenesis by binding to oestrogen receptors, whose distribution is age-, gender-, and tissue-specific. This review brings data about cancer types whose eatiology may be found in environmental exposure to xenoestrogens. Cancer types that have been well documented in literature to be related with environmental exposure include the reproductive system, breast, lung, kidney, pancreas, and brain. The results of our data mining show (a) a significant correlation between exposure to xenoestrogens and increased, gender-related, cancer risk and (b) a need to re-evaluate agents so far defined as endocrine disruptors, as they are also key molecules in carcinogenesis. This revision may be used to further research of cancer aetiology and to improvement of related legislation. Investigation of cancers caused by xenoestrogens may elucidate yet unknown mechanisms also valuable for oncology and the development of new therapies.

Cancer risk and the complexity of the interactions between environmental and host factors: HENVINET interactive diagrams as simple tools for exploring and understanding the scientific evidence.

BACKGROUND: Development of graphical/visual presentations of cancer etiology caused by environmental stressors is a process that requires combining the complex biological interactions between xenobiotics in living and occupational environment with genes (gene-environment interaction) and genomic and non-genomic based disease specific mechanisms in living organisms. Traditionally, presentation of causal relationships includes the statistical association between exposure to one xenobiotic and the disease corrected for the effect of potential confounders. METHODS: Within the FP6 project HENVINET, we aimed at considering together all known agents and mechanisms involved in development of selected cancer types. Selection of cancer types for causal diagrams was based on the corpus of available data and reported relative risk (RR). In constructing causal diagrams the complexity of the interactions between xenobiotics was considered a priority in the interpretation of cancer risk. Additionally, gene-environment interactions were incorporated such as polymorphisms in genes for repair and for phase I and II enzymes involved in metabolism of xenobiotics and their elimination. Information on possible age or gender susceptibility is also included. Diagrams are user friendly thanks to multistep access to information packages and the possibility of referring to related literature and a glossary of terms. Diagrams cover both chemical and physical agents (ionizing and non-ionizing radiation) and provide basic information on the strength of the association between type of exposure and cancer risk reported by human studies and supported by mechanistic studies. Causal diagrams developed within HENVINET project represent a valuable source of information for professionals working in the field of environmental health and epidemiology, and as educational material for students. INTRODUCTION: Cancer risk results from a complex interaction of environmental exposures with inherited gene polymorphisms, genetic burden collected during development and non genomic capacity of response to environmental insults. In order to adopt effective preventive measures and the associated regulatory actions, a comprehensive investigation of cancer etiology is crucial. Variations and fluctuations of cancer incidence in human populations do not necessarily reflect environmental pollution policies or population distribution of polymorphisms of genes known to be associated with increased cancer risk. Tools which may be used in such a comprehensive research, including molecular biology applied to field studies, require a methodological shift from the reductionism that has been used until recently as a basic axiom in interpretation of data. The complexity of the interactions between cells, genes and the environment, i.e. the resonance of the living matter with the environment, can be synthesized by systems biology. Within the HENVINET project such philosophy was followed in order to develop interactive causal diagrams for the investigation of cancers with possible etiology in environmental exposure. RESULTS: Causal diagrams represent integrated knowledge and seed tool for their future development and development of similar diagrams for other environmentally related diseases such as asthma or sterility. In this paper development and application of causal diagrams for cancer are presented and discussed.

Comprehensive Clinical and Genetic Analysis of CHEK2 in Croatian Men with Prostate Cancer.

Germline pathogenic and likely pathogenic (P/LP) variants in CHEK2 have been associated with increased prostate cancer (PrCa) risk. Our objective was to analyze their occurrence in Croatian PrCa men and to evaluate the clinical characteristics of P/LP variant carriers. Therefore, we analyzed CHEK2 in 150 PrCa patients unselected for age of onset, family history of PrCa or clinical outcome, and the frequency of identified variants was compared to findings in 442 cancer-free men, of Croatian ancestry. We identified four PrCa cases harboring a P/LP variant in CHEK2 (4/150, 2.67%), which reached a statistical significance (p = 0.004) as compared to the control group. Patients with P/LP variants in CHEK2 developed PrCa almost 9 years earlier than individuals with CHEK2 wild-type alleles (8.9 years; p = 0.0198) and had an increased risk for lymph node involvement (p = 0.0047). No association was found between CHEK2 status and further clinical characteristics, including the Gleason score, occurrence of aggressive PrCa, the tumor or metastasis stage. However, carriers of the most common P/LP CHEK2 variant, the c.1100delC, p.Thr367Metfs15*, had a significantly higher Gleason score (p = 0.034), risk for lymph node involvement (p = 0.0001), and risk for developing aggressive PrCa (p = 0.027). Thus, in a Croatian population, CHEK2 P/LP variant carriers were associated with increased risk for early onset prostate cancer, and carriers of the c.1100delC, p.Thr367Metfs15* had increased risk for aggressive PrCa.

Environmental Exposure to Metals, Parameters of Oxidative Stress in Blood and Prostate Cancer: Results from Two Cohorts.

We studied the potential role of exposure to various metal(oid)s (As, Cd, Cr, Hg, Ni, and Pb) in prostate cancer. Two cohorts were established: the Croatian cohort, consisting of 62 cases and 30 controls, and the Serbian cohort, consisting of 41 cases and 61 controls. Blood/serum samples were collected. Levels of investigated metal(oid)s, various parameters of oxidative stress, and prostate-specific antigen (PSA) were determined in collected samples. A comparison of the measured parameters between 103 prostate cancer patients and 91 control men from both Croatian and Serbian cohorts showed significantly higher blood Hg, SOD, and GPx levels and significantly lower serum SH levels in prostate cancer patients than in controls. Correlation analyses revealed the significant relationship between certain parameters of oxidative stress and the concentrations of the measured metal(loid)s, pointing to the possible role of metal(oid)-induced oxidative stress imbalance. Furthermore, a significant inverse relationship was found between the blood Pb and the serum PSA in prostate cancer patients, but when the model was adjusted for the impacts of remaining parameters, no significant association between the serum PSA and the measured parameters was found. The results of the overall study indicate a substantial contribution of the measured metal(loid)s to the imbalance of the oxidant/antioxidant system. Although somewhat conflicting, the results of the present study point to the possible role of investigated metal(oid)s in prostate cancer, especially for Hg, since the obtained relationship was observed for both cohorts, followed by the disturbances in oxidative stress status, which were found to be correlated with Hg levels. Nevertheless, further studies in larger cohorts are warranted to explain and confirm the obtained results.

Patterns of Disease Progression and Outcome of Patients With Testicular Seminoma Who Relapse After Adjuvant or Curative Radiation Therapy.

PURPOSE: Radiation therapy is a possible treatment strategy for patients with testicular seminoma after orchiectomy in clinical stage I or II disease. Little is known about the outcome of patients who experience a relapse after radiation therapy. METHODS AND MATERIALS: Data from 61 patients who relapsed after adjuvant or curative radiation therapy from 17 centers in 11 countries were collected and retrospectively analyzed. Primary outcomes were disease-free and overall survival. Secondary outcomes were time to relapse, stage at relapse, treatment for relapse, and rate of febrile neutropenia during chemotherapy for relapse. RESULTS: With a median follow-up of 9.9 years (95% confidence interval [CI], 7.5-10.9), we found a 5-year disease-free survival of 90% (95% CI, 79-95) and a 5-year overall survival of 98% (95% CI, 89-100). Sixty-six percent of patients had stage III disease at time of relapse and 93% of patients fell into the good prognosis group per the International Germ Cell Cancer Collaborative Group classification. The median time to relapse after radiation therapy was 15.6 months (95% CI, 12-23). Twenty-two (36%) patients relapsed more than 2 years after radiation therapy and 7 (11.5%) patients relapsed more than 5 years after radiation therapy. One-third of relapses was detected owing to patients' symptoms, whereas two-thirds of relapses were detected during routine follow-up. The majority (93%) of cases were treated with cisplatin-based chemotherapy. The rate of febrile neutropenia during chemotherapy was 35%. Five patients experienced a second relapse. At last follow-up, 55 patients (90%) were alive without disease. Only 1 patient died owing to disease progression. CONCLUSIONS: Cisplatin-based chemotherapy for patients with seminoma who have relapsed after treatment with radiation therapy alone leads to excellent outcomes. Patients and physicians should be aware of possible late relapses after radiation therapy.

Intake Patterns of Specific Alcoholic Beverages by Prostate Cancer Status.

BACKGROUND: Previous studies have shown that different alcoholic beverage types impact prostate cancer (PCa) clinical outcomes differently. However, intake patterns of specific alcoholic beverages for PCa status are understudied. The study's objective is to evaluate intake patterns of total alcohol and the three types of beverage (beer, wine, and spirits) by the PCa risk and aggressiveness status. METHOD: This is a cross-sectional study using 10,029 men (4676 non-PCa men and 5353 PCa patients) with European ancestry from the PCa consortium. Associations between PCa status and alcohol intake patterns (infrequent, light/moderate, and heavy) were tested using multinomial logistic regressions. RESULTS: Intake frequency patterns of total alcohol were similar for non-PCa men and PCa patients after adjusting for demographic and other factors. However, PCa patients were more likely to drink wine (light/moderate, OR = 1.11, p = 0.018) and spirits (light/moderate, OR = 1.14, p = 0.003; and heavy, OR = 1.34, p = 0.04) than non-PCa men. Patients with aggressive PCa drank more beer than patients with non-aggressive PCa (heavy, OR = 1.48, p = 0.013). Interestingly, heavy wine intake was inversely associated with PCa aggressiveness (OR = 0.56, p = 0.009). CONCLUSIONS: The intake patterns of some alcoholic beverage types differed by PCa status. Our findings can provide valuable information for developing custom alcohol interventions for PCa patients.

Association Study between Polymorphisms in DNA Methylation-Related Genes and Testicular Germ Cell Tumor Risk.

BACKGROUND: Testicular germ cell tumors (TGCT), histologically classified as seminomas and nonseminomas, are believed to arise from primordial gonocytes, with the maturation process blocked when they are subjected to DNA methylation reprogramming. SNPs in DNA methylation machinery and folate-dependent one-carbon metabolism genes have been postulated to influence the proper establishment of DNA methylation. METHODS: In this pathway-focused investigation, we evaluated the association between 273 selected tag SNPs from 28 DNA methylation-related genes and TGCT risk. We carried out association analysis at individual SNP and gene-based level using summary statistics from the Genome Wide Association Study meta-analysis recently conducted by the international Testicular Cancer Consortium on 10,156 TGCT cases and 179,683 controls. RESULTS: In individual SNP analyses, seven SNPs, four mapping within MTHFR, were associated with TGCT risk after correction for multiple testing (q ≤ 0.05). Queries of public databases showed that three of these SNPs were associated with MTHFR changes in enzymatic activity (rs1801133) or expression level in testis tissue (rs12121543, rs1476413). Gene-based analyses revealed MTHFR (q = 8.4 × 10-4), methyl-CpG-binding protein 2 (MECP2; q = 2 × 10-3), and ZBTB4 (q = 0.03) as the top TGCT-associated genes. Stratifying by tumor histology, four MTHFR SNPs were associated with seminoma. In gene-based analysis MTHFR was associated with risk of seminoma (q = 2.8 × 10-4), but not with nonseminomatous tumors (q = 0.22). CONCLUSIONS: Genetic variants within MTHFR, potentially having an impact on the DNA methylation pattern, are associated with TGCT risk. IMPACT: This finding suggests that TGCT pathogenesis could be associated with the folate cycle status, and this relation could be partly due to hereditary factors.