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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.

Germline pathogenic and likely pathogenic (P/LP) variants in

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.

Background Prostate cancer risk stratification using single-nucleotide polymorphisms (SNPs) demonstrates considerable promise in men of European, Asian, and African genetic ancestries, but there is still need for increased accuracy. We evaluated whether including additional SNPs in a prostate cancer polygenic hazard score (PHS) would improve associations with clinically significant prostate cancer in multi-ancestry datasets. Methods In total, 299 SNPs previously associated with prostate cancer were evaluated for inclusion in a new PHS, using a LASSO-regularized Cox proportional hazards model in a training dataset of 72,181 men from the PRACTICAL Consortium. The PHS model was evaluated in four testing datasets: African ancestry, Asian ancestry, and two of European Ancestry—the Cohort of Swedish Men (COSM) and the ProtecT study. Hazard ratios (HRs) were estimated to compare men with high versus low PHS for association with clinically significant, with any, and with fatal prostate cancer. The impact of genetic risk stratification on the positive predictive value (PPV) of PSA testing for clinically significant prostate cancer was also measured. Results The final model (PHS290) had 290 SNPs with non-zero coefficients. Comparing, for example, the highest and lowest quintiles of PHS290, the hazard ratios (HRs) for clinically significant prostate cancer were 13.73 [95% CI: 12.43–15.16] in ProtecT, 7.07 [6.58–7.60] in African ancestry, 10.31 [9.58–11.11] in Asian ancestry, and 11.18 [10.34–12.09] in COSM. Similar results were seen for association with any and fatal prostate cancer. Without PHS stratification, the PPV of PSA testing for clinically significant prostate cancer in ProtecT was 0.12 (0.11–0.14). For the top 20% and top 5% of PHS290, the PPV of PSA testing was 0.19 (0.15–0.22) and 0.26 (0.19–0.33), respectively. Conclusions We demonstrate better genetic risk stratification for clinically significant prostate cancer than prior versions of PHS in multi-ancestry datasets. This is promising for implementing precision-medicine approaches to prostate cancer screening decisions in diverse populations.

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.

Simple Summary Previous studies have shown heavy intake of different alcoholic beverages affects prostate cancer (PCa) clinical outcomes differently. However, the intake patterns of specific alcoholic beverages for PCa status are understudied. The study's objective is to evaluate intake patterns of total alcohol and three types of alcoholic beverage (beer, wine, and spirits) by PCa risk and aggressiveness status. This study included 10,029 men with European ancestry (4676 non-PCa men and 5353 PCa patients). We found PCa patients had a similar total heavy alcohol intake compared with non-PCa men. However, PCa patients were likely to drink more wine and spirits than non-PCa men. Patients with aggressive PCa drank more beer but not wine and spirits. Interestingly, heavy wine intake was inversely associated with PCa aggressiveness. These findings suggest that the intake patterns of specific alcoholic beverages differ by PCa status, and this information might help develop personalized alcohol intervention for PCa patients. 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.

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.

IntroductionProstate cancer risk stratification using single-nucleotide polymorphisms (SNPs) demonstrates considerable promise in men of European, Asian, and African genetic ancestries, but there is still need for increased accuracy. We evaluated whether including additional SNPs in a prostate cancer polygenic hazard score (PHS) would improve associations with clinically significant prostate cancer in multi-ancestry datasets.MethodsIn total, 299 SNPs previously associated with prostate cancer were evaluated for inclusion in a new PHS, using a LASSO-regularized Cox proportional hazards model in a training dataset of 72,181 men from the PRACTICAL Consortium. The PHS model was evaluated in four testing datasets: African ancestry, Asian ancestry, and two of European Ancestry—the Cohort of Swedish Men (COSM) and the ProtecT study. Hazard ratios (HRs) were estimated to compare men with high versus low PHS for association with clinically significant, with any, and with fatal prostate cancer. The impact of genetic risk stratification on the positive predictive value (PPV) of PSA testing for clinically significant prostate cancer was also measured.ResultsThe final model (PHS290) had 290 SNPs with non-zero coefficients. Comparing, for example, the highest and lowest quintiles of PHS290, the hazard ratios (HRs) for clinically significant prostate cancer were 13.73 [95% CI: 12.43-15.16] in ProtecT, 7.07 [6.58-7.60] in African ancestry, 10.31 [9.58-11.11] in Asian ancestry, and 11.18 [10.34-12.09] in COSM. Similar results were seen for association with any and fatal prostate cancer. Without PHS stratification, the PPV of PSA testing for clinically significant prostate cancer in ProtecT was 0.12 (0.11-0.14). For the top 20% and top 5% of PHS290, the PPV was 0.19 (0.15-0.22) and 0.26 (0.19-0.33), respectively.ConclusionWe demonstrate better genetic risk stratification for clinically significant prostate cancer than prior versions of PHS in multi-ancestry datasets. This is promising for implementing precision-medicine approaches to prostate cancer screening decisions in diverse populations.

Background Polygenic hazard scores (PHS) can identify individuals with increased risk of prostate cancer. We estimated the benefit of additional SNPs on performance of a previously validated PHS (PHS46). Materials and method 180 SNPs, shown to be previously associated with prostate cancer, were used to develop a PHS model in men with European ancestry. A machine-learning approach, LASSO-regularized Cox regression, was used to select SNPs and to estimate their coefficients in the training set (75,596 men). Performance of the resulting model was evaluated in the testing/validation set (6,411 men) with two metrics: (1) hazard ratios (HRs) and (2) positive predictive value (PPV) of prostate-specific antigen (PSA) testing. HRs were estimated between individuals with PHS in the top 5% to those in the middle 40% (HR95/50), top 20% to bottom 20% (HR80/20), and bottom 20% to middle 40% (HR20/50). PPV was calculated for the top 20% (PPV80) and top 5% (PPV95) of PHS as the fraction of individuals with elevated PSA that were diagnosed with clinically significant prostate cancer on biopsy. Results 166 SNPs had non-zero coefficients in the Cox model (PHS166). All HR metrics showed significant improvements for PHS166 compared to PHS46: HR95/50 increased from 3.72 to 5.09, HR80/20 increased from 6.12 to 9.45, and HR20/50 decreased from 0.41 to 0.34. By contrast, no significant differences were observed in PPV of PSA testing for clinically significant prostate cancer. Conclusions Incorporating 120 additional SNPs (PHS166 vs PHS46) significantly improved HRs for prostate cancer, while PPV of PSA testing remained the same.

Purpose: Studies have shown the increased incidence of urinary tract cancers which are associated with a decrease in glomerular filtration rate (GFR). We hypothesized that patients with GFR < 60 ml/min/1.73 m2 have an increased risk for higher staging and histology grades of cancers and, therefore, the increased risk for cancer recurrence and cancer-related death. Methods: Retrospective clinical data and pathology reports were completed for 2116 patients. Patients were divided into two subgroups regarding GFR ; the first group with GFR < 60 ml/min/1.73 m2 and the second group with GFR > 60 ml/min/1.73 m2 and regarding cancer recurrence. Cancers were also divided by stages (1-4) according to TNM classification. Patients were followed-up during 3 years. Results: We have found significantly higher number of cancers with higher histology grades and higher staging in group of patients with GFR < 60 ml/min/1.73 m2 in all urinary tract localizations. GFR was the strongest predictor for higher cancer histology grade and only significant predictor for higher cancer staging. Patients with GFR < 60 ml/min/1.73 m2 had OR for higher histology grade, higher staging, and cancer recurrence of 10.7, 5.3, and 11.3 compared to patients with GFR > 60 ml/min. Conclusions: Higher staging and histology grades in patients with urinary tract cancers are associated with reduced GFR. Reduced GFR in these patients is a risk factor for cancer recurrence and cancer-related survival. Possible involvement of uremic toxins must be taken into account especially when cancers are predominantly located in estrogen sensitive organs. These patients should be intensively monitored and probably be more aggressively treated.

The original version of this Article contained an error in the spelling of the author Manuela Gago-Dominguez, which was incorrectly given as Manuela G. Dominguez. This has now been corrected in both the PDF and HTML versions of the Article.

Genetic models for cancer have been evaluated using almost exclusively European data, which could exacerbate health disparities. A polygenic hazard score (PHS1) is associated with age at prostate cancer diagnosis and improves screening accuracy in Europeans. Here, we evaluate performance of PHS2 (PHS1, adapted for OncoArray) in a multi-ethnic dataset of 80,491 men (49,916 cases, 30,575 controls). PHS2 is associated with age at diagnosis of any and aggressive (Gleason score ≥ 7, stage T3-T4, PSA ≥ 10 ng/mL, or nodal/distant metastasis) cancer and prostate-cancer-specific death. Associations with cancer are significant within European (n = 71,856), Asian (n = 2,382), and African (n = 6,253) genetic ancestries (p, A polygenic hazard score (PHS1) improves prostate cancer screening accuracy in European patients. Here, the authors test the performance of a version compatible with OncoArray genotypes (PHS2) in a multi-ethnic dataset and find that it risk-stratifies men for any, aggressive, and fatal prostate cancer.

Disruption of element homeostasis may contribute to increased susceptibility of men to cancer development. Whether environmental low-level metal exposure could contribute to the pathogenesis of testicular cancer is unknown. Comparison of the level of 18 elements in whole blood, serum and urine and parameters of oxidative stress/antioxidant status between men with testicular germ cell tumors (TGCT) and healthy men showed significant difference between the groups in most parameters. The results of linear discriminant analysis with a discrimination rate of 96% indicated whole blood Ca, Co, Cu, Fe, K, Mg, Na and Zn, serum Ca, Cu, Na and Ni, and urine Cd, Co, Fe and Mn being the strongest predictors of illness. TGCT patients had a significant increase in serum and blood Cu and decrease in serum Fe and blood Zn with cancer progression. Significantly higher concentrations of Al, As, Pb, and Ni in whole blood/serum of men with TGCT confirm the hypothesis that low-level environmental exposure to these elements may contribute to cancer development. Relationship between elements concentrations and treatment outcomes should be carefully monitored during cancer treatment since high concentrations of commonly used platinum-based chemotherapeutics may additionally disturb the homeostasis of elements.

In the version of this article originally published, the names of the equally contributing authors and jointly supervising authors were switched. The correct affiliations are: “These authors contributed equally: David V. Conti, Burcu F. Darst. These authors jointly supervised this work: David V. Conti, Rosalind A. Eeles, Zsofia Kote-Jarai, Christopher A. Haiman.” The error has been corrected in the HTML and PDF versions of the article.

There are two major histologic types of testicular cancer: pure seminoma and nonseminomatous germ cell tumours which include embryonic carcinoma, choriocarcinoma, yolc sac tumours and teratomas. Rarely, in 2% of cases, teratomas may contain elements of somatic cancer, such as sarcoma or adenocarcinoma and it is then referred to as a ''teratoma with somatic type malignancy''. The histology of somatic malignant elements most commonly includes adenocarcinoma and various types of sarcomas; however, so far as the primitive neuroectodermal tumors (PNETs) are concerned the experience is quite limited. Here we report an unusual case of a testicular seminoma that relapsed 6 months after surgery as a teratoma with somatic neuroendocrine differentiation situated in retroperitoneal lymph nodes.

International audience; Prostate cancer is a highly heritable disease with large disparities in incidence rates across ancestry populations. We conducted a multiancestry meta-analysis of prostate cancer genome-wide association studies (107,247 cases and 127,006 controls) and identified 86 new genetic risk variants independently associated with prostate cancer risk, bringing the total to 269 known risk variants. The top genetic risk score (GRS) decile was associated with odds ratios that ranged from 5.06 (95% confidence interval (CI), 4.84-5.29) for men of European ancestry to 3.74 (95% CI, 3.36-4.17) for men of African ancestry. Men of African ancestry were estimated to have a mean GRS that was 2.18-times higher (95% CI, 2.14-2.22), and men of East Asian ancestry 0.73-times lower (95% CI, 0.71-0.76), than men of European ancestry. These findings support the role of germline variation contributing to population differences in prostate cancer risk, with the GRS offering an approach for personalized risk prediction.

BackgroundPolygenic hazard scores (PHS) can identify individuals with increased risk of prostate cancer. We estimated the benefit of additional SNPs on performance of a previously validated PHS (PHS46).Materials and Method180 SNPs, shown to be previously associated with prostate cancer, were used to develop a PHS model in men with European ancestry. A machine-learning approach, LASSO-regularized Cox regression, was used to select SNPs and to estimate their coefficients in the training set (75,596 men). Performance of the resulting model was evaluated in the testing/validation set (6,411 men) with two metrics: (1) hazard ratios (HRs) and (2) positive predictive value (PPV) of prostate-specific antigen (PSA) testing. HRs were estimated between individuals with PHS in the top 5% to those in the middle 40% (HR95/50), top 20% to bottom 20% (HR80/20), and bottom 20% to middle 40% (HR20/50). PPV was calculated for the top 20% (PPV80) and top 5% (PPV95) of PHS as the fraction of individuals with elevated PSA that were diagnosed with clinically significant prostate cancer on biopsy.Results166 SNPs had non-zero coefficients in the Cox model (PHS166). All HR metrics showed significant improvements for PHS166 compared to PHS46: HR95/50 increased from 3.72 to 5.09, HR80/20 increased from 6.12 to 9.45, and HR20/50 decreased from 0.41 to 0.34. By contrast, no significant differences were observed in PPV of PSA testing for clinically significant prostate cancer.ConclusionIncorporating 120 additional SNPs (PHS166 vs PHS46) significantly improved HRs for prostate cancer, while PPV of PSA testing remained the same.

Testicular germ cell tumors (TGCT) are the most common tumor in young white men and have a high heritability. In this study, the international Testicular Cancer Consortium assemble 10,156 and 179,683 men with and without TGCT, respectively, for a genome-wide association study. This meta-analysis identifies 22 TGCT susceptibility loci, bringing the total to 78, which account for 44% of disease heritability. Men with a polygenic risk score (PRS) in the 95th percentile have a 6.8-fold increased risk of TGCT compared to men with median scores. Among men with independent TGCT risk factors such as cryptorchidism, the PRS may guide screening decisions with the goal of reducing treatment-related complications causing long-term morbidity in survivors. These findings emphasize the interconnected nature of two known pathways that promote TGCT susceptibility: male germ cell development within its somatic niche and regulation of chromosomal division and structure, and implicate an additional biological pathway, mRNA translation., Testicular germ cell tumors are highly heritable, and the authors present the largest genome association study, identifying 22 novel loci, which account for a third of those identified to date. Implicated pathways include male germ cell development and differentiation, and chromosomal segregation.

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.

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., Germinativni rak testisa je maligna novotvorina podrijetla primordijalne zametne stanice. Iako čini oko 1% svih malignih novotvorina muškaraca, najčešći je malignom mlađe muške populacije s najvećom incidencijom u dobi od 15 do 35 godina. Incidencija raka testisa povećala se globalno posljednjih nekoliko desetljeća, s prosječnim porastom u incidenciji od 7% godišnje u Hrvatskoj u razdoblju od 1983. do 2007. godine. S obzirom na histološku sliku, germinativni rak testisa dijeli se na seminome i neseminome koji se razlikuju u načinu liječenja i odgovoru na terapiju. Unatoč porastu u incidenciji, obećavajuća okolnost je da je rak testisa postao model izlječivog tumora. Zbog napretka u dijagnostičkim postupcima, sofisticiranih tehnika zračenja, a osobito uvođenja kemoterapijskih protokola baziranih na platini zajedno s naprednim postkemoterapijskim kirurškim tehnikama, izlječivost se očekuje u oko 95% svih dijagnosticiranih bolesnika s rakom testisa i oko 70% bolesnika s uznapredovalom bolešću. U ovom preglednom radu usredotočit ćemo se na strategije liječenja germinativnog raka testisa.

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.

ObjectivesA polygenic hazard score (PHS1)—weighted sum of 54 single-nucleotide polymorphism genotypes—was previously associated with age at prostate cancer (PCa) diagnosis and improved PCa screening accuracy in Europeans. Performance in more diverse populations is unknown. We evaluated PHS association with PCa in multi-ethnic populations.DesignPHS1 was adapted for compatibility with genotype data from the OncoArray project (PHS2) and tested for association with age at PCa diagnosis, at aggressive PCa diagnosis, and at PCa death.SettingMultiple international institutions.ParticipantsMen with available OncoArray data from the PRACTICAL consortium who were not included in PHS1 development/validation.Main Outcomes and MeasuresPHS2 was tested via Cox proportional hazards models for age at PCa diagnosis, age at aggressive PCa diagnosis (any of: Gleason score ≥7, stage T3-T4, PSA≥10 ng/mL, nodal/distant metastasis), and age at PCa-specific death.Results80,491 men of various self-reported race/ethnicities were included (30,575 controls, 49,916 PCa cases; genetic ancestry groups: 71,856 European, 6,253 African, 2,382 Asian). Median age at last follow-up was 70 years (IQR 63-76); 3,983 PCa deaths, 5,806 other deaths, 70,702 still alive. PHS2 had 46 polymorphisms: 24 directly genotyped and 22 acceptable proxies (r2 ≥0.94). PHS2 was associated with age at PCa diagnosis in the multi-ethnic dataset (z=54, p-16) and in each genetic ancestry group: European (z=56, p-16), Asian (z=47, p-16), African (z=29, p-16). PHS2 was also associated with age at aggressive PCa diagnosis in each genetic ancestry group (p-16) and with age of PCa death in the full dataset (p-16). Comparing the 80th and 20th percentiles of genetic risk, men with high PHS had hazard ratios of 5.3 [95% CI: 5.0-5.7], 5.9 [5.5-6.3], and 5.7 [4.6-7.0] for PCa, aggressive PCa, and PCa-specific death, respectively. Within European, Asian, and African ancestries, analogous hazard ratios for PCa were 5.5 [5.2-5.9], 4.5 [3.2-6.3], and 2.5 [2.1-3.1], respectively.ConclusionsPHS2 is strongly associated with age at PCa diagnosis in a multi-ethnic dataset. PHS2 stratifies men of European, Asian, and African ancestry by genetic risk for any, aggressive, and fatal PCa.Summary boxesWhat is already known on this topicGenetic risk stratification can identify men with greater predisposition for developing prostate cancer, but these risk models may worsen health disparities, as most have only been validated for men of European ancestryA polygenic hazard score was previously associated with age at prostate cancer diagnosis and improved PCa screening accuracy in EuropeansPerformance of the polygenic hazard score in multi-ethnic populations is unknownWhat this study addsIn a dataset from 80,491 men of various self-reported race/ethnicities, the polygenic hazard score was associated with age at prostate cancer diagnosis, aggressive prostate cancer diagnosis, and prostate cancer death.PHS stratifies men of European, Asian, and African ancestry by genetic risk for any, aggressive, and fatal prostate cancer.

Background Atezolizumab, a humanised monoclonal antibody targeting PD-L1, is approved for locally advanced/metastatic urothelial carcinoma. SAUL evaluated atezolizumab in a broader, pretreated population, including patients ineligible for the pivotal IMvigor211 phase 3 trial of atezolizumab. Objective To determine the safety and efficacy of atezolizumab in an international real-world setting. Design, setting, and participants Between November 2016 and March 2018 (median follow-up 12.7mo), 1004 patients with locally advanced or metastatic urothelial or nonurothelial urinary tract carcinoma who experienced progression during or after one to three prior therapies for inoperable, locally advanced, or metastatic disease were enrolled. Patients with renal impairment, treated central nervous system metastases, or stable controlled autoimmune disease were eligible; 10% had Eastern Cooperative Oncology Group performance status (ECOG PS) 2 and 98% were platinum pretreated (Clinicaltrials.gov: NCT02928406). Intervention Atezolizumab 1200mg every 3wk until progression or unacceptable toxicity. Outcome measurements and statistical analysis The primary endpoint was safety. Secondary efficacy endpoints included overall survival (OS), progression-free survival (PFS), and overall response rate (ORR). Results and limitations The median treatment duration was 2.8mo (range 0–19); 22% remained on treatment and 8% discontinued because of toxicity. Grade ≥3 adverse events occurred in 45% of patients. The most common grade ≥3 treatment-related adverse events were fatigue, asthenia, colitis, and hypertension (each in 1%). Median OS was 8.7mo (95% confidence interval [CI] 7.8–9.9). The 6-mo OS rate was 60% (95% CI 57–63%), median PFS was 2.2mo (95% CI 2.1–2.4), and the ORR was 13% (95% CI 11–16%; 3% complete responses). Among IMvigor211-like patients (excluding ECOG PS 2 and other IMvigor211 exclusion criteria), median OS was 10.0mo (95% CI 8.8–11.9) and 6-mo OS was 65% (95% CI 61–69%). Conclusions SAUL confirms the tolerability of atezolizumab in a real-world pretreated population with urinary tract carcinoma. Efficacy overall and in the IMvigor211-like subgroup is consistent with previous pivotal anti-PD-L1/PD-1 urothelial carcinoma trials. These results support the use of atezolizumab in urinary tract carcinoma, including patients with limited treatment options. Patient summary In this international study we investigated the efficacy and safety of atezolizumab treatment for advanced urinary tract cancer in a large population of pretreated patients, including those who would not normally be candidates for clinical trials. Patients tolerated the treatment well, even if they had autoimmune disease, were being treated with corticosteroids, or had disease that had spread to their brain. Life expectancy in this study for patients typical of everyday clinical practice was similar to that seen in trials that enrolled only selected fitter patients.

Genome-wide association studies (GWAS) and fine-mapping efforts to date have identified more than 100 prostate cancer (PrCa)-susceptibility loci. We meta-analyzed genotype data from a custom high-density array of 46,939 PrCa cases and 27,910 controls of European ancestry with previously genotyped data of 32,255 PrCa cases and 33,202 controls of European ancestry. Our analysis identified 62 novel loci associated (PC, p.Pro1054Arg) in ATM and rs2066827 (OR = 1.06; P = 2.3 × 10(−9); T>G, p.Val109Gly) in CDKN1B. The combination of all loci captured 28.4% of the PrCa familial relative risk, and a polygenic risk score conferred an elevated PrCa risk for men in the ninetieth to ninety-ninth percentiles (relative risk = 2.69; 95% confidence interval (CI): 2.55–2.82) and first percentile (relative risk = 5.71; 95% CI: 5.04–6.48) risk stratum compared with the population average. These findings improve risk prediction, enhance fine-mapping, and provide insight into the underlying biology of PrCa(1).

Field of metastatic renal cell cancer (mRCC) treatments is now evolving at a rapid and unprecedented pace. Nivolumab prolongs survival in patients with metastatic kidney cancer with a favorable safety profile as demonstrated in the Check-Mate 025 clinical trial. Nivolumab compared to everolimus prolonged survival in patients with mRCC while exibiting favorbale safety profile. In this study we present the results of nivolumab treatment in patients with mRCC within named patient program (NPP) at UHC Zagreb. In 30% of included patients survival was longer than 30 months and 16.6% patients had a complete response., Područje liječenja metastatskog raka bubrega (mRCC) je područje ubrzanog razvoja terapijskih mogućnosti. Nivolumab produljuje preživljenje bolesnika s metastatskim rakom bubrega uz dobar sigurnosni profil što je pokazano u kliničkoj studiji CheckMate025. Nivolumab u usporedbi s everolimusom produljuje preživljenje kod bolesnika sa mRCC uz povoljni sigurnosni profil lijeka. U ovoj analizi smo prikazali rezultate liječenja bolesnika nivolumabom u NPP u Kliničkom bolničkom centru Zagreb tijekom 2016. do 2018. 30% bolesnika ima preživljenje dulje od 30 mjeseci, a 16.6% je imalo kompletni odgovor na terapiju.

Testicular tumors are the most common solid tumors in men between age 15- 34 years. 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 as seminoma and nonseminoma. Testicular cancer has high cure rates even in disseminated stage of disease. The chemotherapy mostly contributed to these results, but surgery is an unavoidable part of this success. In significant number of these patients treatment algorithms today have intention to offer the same cure rates with minimally aggressive therapy. The following text presents the clinical guidelines in order to standardize procedures and criteria for diagnosis, treatment, and follow-up of patients with testicular cancer in the Republic of Croatia.

Bladder cancer is the second most common malignancy of urinary system according to data from the Croatian National Cancer Registry for 2015. In 90% of cases the underlying histology is urothelial carcinoma. Difference in survival in patients with muscle-invasive disease (MIBC) compared to the survival of patients with non-muscle invasive disease (NMIBC) is enormous. Management of NMIBC, traditionally, has been focused on the reduction of subsequent bladder recurrence and prevention of disease progression and is primarily based on transurethral resection (TUR) of the tumor, followed by intravesical therapy based on estimated individual risk of recurrence. Conversely, in patients with MIBC radical cystectomy remains the corne stone of the treatment, optimally in conjunction with neoadjuvant platinum-based chemotherapy in cisplatin-eligible patients. At the moment of diagnosis, 4–6% of patients already have distant metastases, and post cystectomy recurrence could be expected in 50% of patients. Treatment options in metastatic disease range from cisplatin-based chemotherapy, immunotherapy, palliative radiotherapy and finally supportive care. Landmark feature of bladder cancer is the high prevalence of somatic mutations which enabled profound change for decades held treatment paradigm for advanced bladder cancer leading to regulatory approval of whole array of novel immunotherapy agents. These emerging therapeutics (programmed death ligand-1 (PD-L1) and programmed cell death protein-1 (PD-1)) belong to the class of inhibitors of checkpoint proteins, which are key targets that regulate T-cell mediated immune response.

Rak testisa najčešći je solidni tumor u muškaraca u dobi od 15. do 34. godine. Incidencija raka testisa u svijetu udvostručena je u posljednjih 40 godina. Tumori zametnih stanica čine 95% svih tumora testisa, a podijeljeni su u dva osnovna histološka tipa: seminomi i neseminomi. Osobito značenje daje im velik postotak izlječivosti i u diseminiranoj fazi bolesti. Tom je uspjehu najviše pridonijela kemoterapija, ali kirurgija je i dalje neizostavan dio uspješnog liječenja. U znatnog dijela bolesnika danas se nastoji odrediti terapijski minimum kojim se izbjegava niz nuspojava, a dovodi do jednakog uspjeha kao i donedavno agresivniji terapijski pristup. U tekstu koji slijedi iznesene su kliničke upute radi standardizacije dijagnostike, liječenja i praćenja bolesnika s tumorima zametnih stanica testisa u Republici Hrvatskoj., Testicular tumors are the most common solid tumors in men between age 15- 34 years. 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 as seminoma and nonseminoma. Testicular cancer has high cure rates even in disseminated stage of disease. The chemotherapy mostly contributed to these results, but surgery is an unavoidable part of this success. In significant number of these patients treatment algorithms today have intention to offer the same cure rates with minimally aggressive therapy. The following text presents the clinical guidelines in order to standardize procedures and criteria for diagnosis, treatment, and follow-up of patients with testicular cancer in the Republic of Croatia.

Forty two to 57% of patients with metastatic renal cell carcinoma (mRCC) receive the second-line therapy according to available data. In our analysis we wanted to determine the percentage of patients within intermediate/poor prognostic group mRCC who continued the treatment with the second line following progression on the first line and the percentage of patients who were not able to receive the second line treatment. Patients received sunitinib (first started on 12 August 2018) or pazopanib (first started on May 2014) at University Hospital Center Zagreb. The latest treatment started in December 2018. Our results show that 39.4% of patients who received sunitinib and 37.9% of patients who received pazopanib, did not receive the second line treatment, which is consistent with available data. The question arises whether we could have helped those patients if we had access to newer therapeutic options., Prema literaturnim podacima oko 42% do 57% bolesnika smetastatskim karcinomom bubrega primi drugu liniju liječenja. Retrospektivnom analizom naših podataka htjeli smo prikazati postotak bolesnika s metastatskim karcinomom bubrega koji pripadaju srednjoj/lošoj prognostičkoj skupini a koji su nastavili liječenje drugom linijom nakon progresije na prvolinijsko liječenje. Također smo htjeli prikazati postotak bolesnika koji nisu bili u mogućnosti nastaviti drugolinijsko liječenje. Bolesnici su primali sunitinib (prvi bolesnik je započeo liječenje u svibnju 2014.) i pazopanib (prvi bolesnik je započeo liječenje 12. kolovoza 2018) u Kliničkom bolničkom centru Zagreb. Uključeni su bili bolesnici koji su liječenje započeli do kraja prosinca 2018. godine. 39.4% bolesnika koji su primali sunitinib i 37.9% bolesnika koji su primali pazopanib, nije primilo drugu liniju liječenja, što se podudara s literaturnim podacima. Nameće se pitanje, jesmo li navedenim bolesnicima mogli pomoći da smo imali dostupne novije terapijske opcije.

Increased levels of metallothionein (MT) have recently been found in the blood serum of men with newly diagnosed testicular germ cell tumors (TGCT). In light of previously published results, the aim of this study was to investigate the difference in serum MT levels among patients with different stages of TGCT and compare MT with commonly used markers (α- fetoprotein, β-human chorionic gonadotropin and lactate dehydrogenase). The concentration of total MT was determined in the serum of 25 men with TGCT (seminoma or non-seminoma) by differential pulse voltammetry. Serum samples were obtained prior to chemotherapy, after two cycles of chemotherapy and 1 year after chemotherapy. A statistically significant difference in MT levels in patients with different stages of TGCT was observed in the serum of patients with non-seminoma obtained before chemotherapy. Although not significant, an increase in serum MT levels commensurate with the disease stage increase was also observed in patients with seminomatous TGCT. The results indicate that, in combination with the existing markers, MT could be useful for the identification of the histological type of tumor and stage of the disease before biopsy diagnosis.

Genome-wide association studies (GWAS) and fine-mapping efforts to date have identified more than 100 prostate cancer (PrCa)-susceptibility loci. We meta-analyzed genotype data from a custom high-density array of 46,939 PrCa cases and 27,910 controls of European ancestry with previously genotyped data of 32,255 PrCa cases and 33,202 controls of European ancestry. Our analysis identified 62 novel loci associated (P < 5.0 × 10-8) with PrCa and one locus significantly associated with early-onset PrCa (≤55 years). Our findings include missense variants rs1800057 (odds ratio (OR) = 1.16; P = 8.2 × 10-9; G>C, p.Pro1054Arg) in ATM and rs2066827 (OR = 1.06; P = 2.3 × 10-9; T>G, p.Val109Gly) in CDKN1B. The combination of all loci captured 28.4% of the PrCa familial relative risk, and a polygenic risk score conferred an elevated PrCa risk for men in the ninetieth to ninety-ninth percentiles (relative risk = 2.69; 95% confidence interval (CI): 2.55-2.82) and first percentile (relative risk = 5.71; 95% CI: 5.04-6.48) risk stratum compared with the population average. These findings improve risk prediction, enhance fine-mapping, and provide insight into the underlying biology of PrCa 1 .