Search

BackgroundNovel second-line treatments are needed for patients with advanced urothelial cancer (UC). Interim analysis of the phase III KEYNOTE-045 study showed a superior overall survival (OS) benefit of pembrolizumab, a programmed death 1 inhibitor, versus chemotherapy in patients with advanced UC that progressed on platinum-based chemotherapy. Here we report the long-term safety and efficacy outcomes of KEYNOTE-045.Patients and methodsAdult patients with histologically/cytologically confirmed UC whose disease progressed after first-line, platinum-containing chemotherapy were enrolled. Patients were randomly assigned 1 : 1 to receive pembrolizumab [200 mg every 3 weeks (Q3W)] or investigator's choice of paclitaxel (175 mg/m2 Q3W), docetaxel (75 mg/m2 Q3W), or vinflunine (320 mg/m2 Q3W). Primary end points were OS and progression-free survival (PFS) per Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST v1.1) by blinded independent central radiology review (BICR). A key secondary end point was objective response rate per RECIST v1.1 by BICR.ResultsA total of 542 patients were enrolled (pembrolizumab, n = 270; chemotherapy, n = 272). Median follow-up as of 26 October 2017 was 27.7 months. Median 1- and 2-year OS rates were higher with pembrolizumab (44.2% and 26.9%, respectively) than chemotherapy (29.8% and 14.3%, respectively). PFS rates did not differ between treatment arms; however, 1- and 2-year PFS rates were higher with pembrolizumab. The objective response rate was also higher with pembrolizumab (21.1% versus 11.0%). Median duration of response to pembrolizumab was not reached (range 1.6+ to 30.0+ months) versus chemotherapy (4.4 months; range 1.4+ to 29.9+ months). Pembrolizumab had lower rates of any grade (62.0% versus 90.6%) and grade ≥3 (16.5% versus 50.2%) treatment-related adverse events than chemotherapy.ConclusionsLong-term results (>2 years' follow-up) were consistent with those of previously reported analyses, demonstrating continued clinical benefit of pembrolizumab over chemotherapy for efficacy and safety for treatment of locally advanced/metastatic, platinum-refractory UC.Trial registrationClinicalTrials.gov: NCT02256436.

Background: The use of pioglitazone, a thiazolidinedione (TZD), may increase the risk of bladder cancer in patients with type 2 diabetes. In this study, we assessed the risk of bladder cancer associated with the use of TZDs and between pioglitazone and rosiglitazone, an alternative TZD.Methods: We conducted a retrospective cohort study of patients with type 2 diabetes mellitus who initiated treatment with a TZD (n = 18 459 patients) or a sulfonylurea (SU) (n = 41 396 patients) between July 1, 2000, and August 31, 2010, using The Health Improvement Network database in the United Kingdom. Incident cancers were identified for 196 708 person-years of follow-up. Cox proportional hazards regression models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for risk of bladder cancer in the TZD cohort compared with the SU cohort (referent), adjusted for potential confounders. Risk associated with increasing duration of drug exposure was also examined. All statistical tests were two-sided.Results: We identified 60 incident bladder cancers in the TZD cohort and 137 cancers in the SU cohort. No difference in bladder cancer risk was found between the two cohorts (TZD vs SU, HR = 0.93, 95% CI = 0.68 to 1.29) in analyses that did not account for duration of exposure. However, the risk of bladder cancer was increased among patients with the longest duration of TZD vs SU therapy (≥ 5 years of use, HR = 3.25, 95% CI = 1.08 to 9.71) and among those with the longest time since initiation of therapy (≥ 5 years since first use, HR = 2.53, 95% CI = 1.12 to 5.77). Risk of bladder cancer also increased with increasing time since initiation of pioglitazone (P (trend) < .001) and rosiglitazone (P (trend) = .006). Comparison of pioglitazone to rosiglitazone use did not demonstrate difference in cancer risk (P = .49).Conclusion: Long-term TZD therapy (≥ 5 years) in patients with type 2 diabetes may be associated with an increased risk of bladder cancer, which may be common to all TZDs. [ABSTRACT FROM AUTHOR]

Objective: Some preclinical in vivo studies and limited human data suggest a possible increased risk of bladder cancer with pioglitazone therapy. This is an interim report of an ongoing cohort study examining the association between pioglitazone therapy and the risk of bladder cancer in patients with diabetes.Research Design and Methods: This study includes 193,099 patients in the Kaiser Permanente Northern California diabetes registry who were ≥40 years of age between 1997 and 2002. Those with prior bladder cancer were excluded. Ever use of each diabetes medication (defined as two or more prescriptions within 6 months) was treated as a time-dependent variable. Cox regression-generated hazard ratios (HRs) compared pioglitazone use with nonpioglitazone use adjusted for age, sex, race/ethnicity, diabetes medications, A1C, heart failure, household income, renal function, other bladder conditions, and smoking.Results: The group treated with pioglitazone comprised 30,173 patients. There were 90 cases of bladder cancer among pioglitazone users and 791 cases of bladder cancer among nonpioglitazone users. Overall, ever use of pioglitazone was not associated with risk of bladder cancer (HR 1.2 [95% CI 0.9-1.5]), with similar results in men and women (test for interaction P = 0.8). However, in the a priori category of >24 months of therapy, there was an increased risk (1.4 [1.03-2.0]). Ninety-five percent of cancers diagnosed among pioglitazone users were detected at early stage.Conclusions: In this cohort of patients with diabetes, short-term use of pioglitazone was not associated with an increased incidence of bladder cancer, but use for more than 2 years was weakly associated with increased risk. [ABSTRACT FROM AUTHOR]

No study has comprehensively examined associated factors (adverse health outcomes, health behaviors, and demographics) affecting cognitive function in long-term testicular cancer survivors (TC survivors). TC survivors given cisplatin-based chemotherapy completed comprehensive, validated surveys, including those that assessed cognition. Medical record abstraction provided cancer and treatment history. Multivariable logistic regression examined relationships between potential associated factors and cognitive impairment. Among 678 TC survivors (median age = 46; interquartile range [IQR] = 38-54); median time since chemotherapy = 10.9 years, IQR = 7.9-15.9), 13.7% reported cognitive dysfunction. Hearing loss (odds ratio [OR] = 2.02; P = .040), neuropathic pain (OR = 2.06; P = .028), fatigue (OR = 6.11; P < .001), and anxiety/depression (OR = 1.96; P = .029) were associated with cognitive impairment in multivariable analyses. Being on disability (OR = 9.57; P = .002) or retired (OR = 3.64; P = .029) were also associated with cognitive decline. Factors associated with impaired cognition identify TC survivors requiring closer monitoring, counseling, and focused interventions. Hearing loss, neuropathic pain, fatigue, and anxiety/depression constitute potential targets for prevention or reduction of cognitive impairment in long-term TC survivors., (© The Author(s) 2024. Published by Oxford University Press.)

Background and Objective: Until recently, the standard first-line treatment for advanced urothelial carcinoma (UC) was platinum-based combination chemotherapy followed by avelumab maintenance therapy for patients without progressive disease (PD). For patients with advanced UC who experience PD or recurrence, standard-of-care treatment is pembrolizumab monotherapy based on the phase 3 KEYNOTE-045 study. This post hoc analysis of the KEYNOTE-045 study evaluated the efficacy of pembrolizumab compared with chemotherapy by the best response to prior platinum-based chemotherapy., Methods: Patients with advanced UC that progressed or recurred after first-line platinum-based chemotherapy were randomly assigned 1:1 to receive either pembrolizumab 200 mg every 3 wk (Q3W) for ≤2 yr or investigator's choice of chemotherapy (paclitaxel [175 mg/m 2 ], docetaxel [75 mg/m 2 ], or vinflunine [320 mg/m 2 ], each Q3W). Endpoints included overall survival (OS) from the initiation of the last treatment prior to death, objective response rate (ORR), and duration of response (DOR) as per Response Evaluation Criteria in Solid Tumors version 1.1 from the date of the first response., Key Findings and Limitations: An objective response to pembrolizumab was observed in all groups in terms of a prior response to first-line platinum-based chemotherapy. Median OS, ORR, and median DOR were numerically greater with pembrolizumab than with chemotherapy across subgroups. Patients with PD as the best response to prior platinum-based chemotherapy had the poorest OS outcomes. Limitations include a lack of formal hypothesis testing., Conclusions and Clinical Implications: When compared with chemotherapy, prolonged OS and durable responses to second-line pembrolizumab were observed independently of the response to or type of prior platinum-based chemotherapy. These findings further support pembrolizumab as second-line treatment for advanced UC., (Copyright © 2024 Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA., The Author(s). Published by Elsevier B.V. All rights reserved.)

Competing Interests: Disclosure The authors report no relevant conflicts, including financial interests, activities, relationships, and affiliations. This study was supported by Grant 129784-IRG-16-188-38-IRG from the American Cancer Society (VN) and Burroughs Wellcome Fund (MG).

Purpose: The role of elective pelvic nodal irradiation in salvage radiotherapy (sRT) remains controversial. Utilizing 18F-DCFPyL PET/CT, this study aimed to investigate differences in disease distribution after whole pelvic (WPRT) or prostate bed (PBRT) radiotherapy and to identify risk factors for pelvic lymph node (LN) relapse., Methods: This retrospective study included patients with PSA > 0.1 ng/mL post-radical prostatectomy (RP) or post-RP and sRT who underwent 18F-DCFPyL PET/CT. Disease distribution on 18 F-DCFPyL PET/CT after sRT was compared using Chi-square tests. Risk factors were tested for association with pelvic LN relapse after RP and salvage PBRT using logistic regression., Results: 979 18 F-DCFPyL PET/CTs performed at our institution between 1/1/2022 - 3/24/2023 were analyzed. There were 246 patients meeting criteria, of which 84 received salvage RT after RP (post-salvage RT group) and 162 received only RP (post-RP group). Salvage PBRT patients (n = 58) had frequent pelvic nodal (53.6%) and nodal-only (42.6%) relapse. Salvage WPRT patients (n = 26) had comparatively lower rates of pelvic nodal (16.7%, p = 0.002) and nodal-only (19.2%, p = 0.04) relapse. The proportion of distant metastases did not differ between the two groups. Multiple patient characteristics, including ISUP grade and seminal vesicle invasion, were associated with pelvic LN disease in the post-RP group., Conclusion: At PSA persistence or progression, salvage WPRT resulted in lower rates of nodal involvement than salvage PBRT, but did not reduce distant metastases. Certain risk factors increase the likelihood of pelvic LN relapse after RP and can help inform salvage RT field selection., Competing Interests: Disclosure Manuj Agarwal is the holder of a patent, US 8192381B2, a device to treat and/or prevent shoulder subluxation, and serves as the American Brachytherapy Society Education Council Chair. Yu-Ning Wong receives travel support from the Prostate Cancer Foundation. Vivek Narayan declares institutional research grants from Merck, Bristol-Myers Squibb, Regeneron, Pfizer and Janssen, receives consulting fees from Eisai, AstraZeneca, Merck, Regeneron, Janssen, Myovant Sciences, Exelixis and Amgen, receives payment or honoraria from Pfizer, and participates on the Clinical Trial Adjudication Committee at Myovant Sciences. Samuel Takvorian receives grants or contracts from the NIH/National Cancer Institute, participates in the Advisory Board at Genentech and AstraZeneca, and serves on the ASCO Clinical Practice Committee. Austin Pantel receives institutional support from Progenics, receives consulting fees from Blue Earth, Progenics, and GE, and obtains travel support from Blue Earth and GE. Naomi B. Haas receives consulting fees from Merck, Bristol-Myers Squibb, Eisai, and Exelixis, and participates in the Data Safety Monitoring Board at Johns Hopkins. All other authors report no relevant disclosures., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Cardiovascular disease (CVD) is a significant cause of morbidity and mortality in men with prostate cancer; however, data on racial disparities in CVD outcomes are limited., Objectives: We quantified the disparities in CVD according to self-identified race and the role of the structural social determinants of health in mediating disparities in prostate cancer patients., Methods: A retrospective cohort study of 3,543 prostate cancer patients treated with systemic androgen deprivation therapy (ADT) between 2008 and 2021 at a quaternary, multisite health care system was performed. The multivariable adjusted association between self-reported race (Black vs White) and incident major adverse cardiovascular events (MACE) after ADT initiation was evaluated using cause-specific proportional hazards. Mediation analysis determined the role of theme-specific and overall social vulnerability index (SVI) in explaining the racial disparities in CVD outcomes., Results: Black race was associated with an increased hazard of MACE (HR: 1.38; 95% CI: 1.16-1.65; P  < 0.001). The association with Black race was strongest for incident heart failure (HR: 1.79; 95% CI: 1.32-2.43), cerebrovascular disease (HR: 1.98; 95% CI: 1.37-2.87), and peripheral artery disease (HR: 1.76; 95% CI: 1.26-2.45) ( P < 0.001). SVI, specifically the socioeconomic status theme, mediated 98% of the disparity in MACE risk between Black and White patients., Conclusions: Black patients are significantly more likely to experience adverse CVD outcomes after systemic ADT compared with their White counterparts. These disparities are mediated by socioeconomic status and other structural determinants of health as captured by census tract SVI. Our findings motivate multilevel interventions focused on addressing socioeconomic vulnerability., Competing Interests: Supported by the American Heart Association Strategically Focused Research Network Cardio-Oncology Disparities award (Drs Demissei, Yancy, Narayan, and Ky [PI]) and the National Institutes of Health grant K24 HL167127-01A1 (Dr Ky [PI] and Ms. Smith and Ko). Dr Ky is PI of a Pfizer investigator-initiated study in cardio-oncology disparities unrelated to this work. The authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2024 Published by Elsevier on behalf of the American College of Cardiology Foundation.)

Aims: To resolve the ongoing controversy surrounding the impact of teratoma (TER) in the primary among patients with metastatic testicular non-seminomatous germ-cell tumours (NSGCT)., Patients and Methods: Using the International Germ Cell Cancer Collaborative Group (IGCCCG) Update Consortium database, we compared the survival probabilities of patients with metastatic testicular GCT with TER (TER) or without TER (NTER) in their primaries corrected for known prognostic factors. Progression-free survival (5y-PFS) and overall survival at 5 years (5y-OS) were estimated by the Kaplan-Meier method., Results: Among 6792 patients with metastatic testicular NSGCT, 3224 (47%) had TER in their primary, and 3568 (53%) did not. In the IGCCCG good prognosis group, the 5y-PFS was 87.8% in TER versus 92.0% in NTER patients (p = 0.0001), the respective 5y-OS were 94.5% versus 96.5% (p = 0.0032). The corresponding figures in the intermediate prognosis group were 5y-PFS 76.9% versus 81.6% (p = 0.0432) in TER and NTER and 5y-OS 90.4% versus 90.9% (p = 0.8514), respectively. In the poor prognosis group, there was no difference, neither in 5y-PFS [54.3% in TER patients versus 55.4% (p = 0.7472) in NTER], nor in 5y-OS [69.4% versus 67.7% (p = 0.3841)]. NSGCT patients with TER had more residual masses (65.3% versus 51.7%, p < 0.0001), and therefore received post-chemotherapy surgery more frequently than NTER patients (46.8% versus 32.0%, p < 0.0001)., Conclusion: Teratoma in the primary tumour of patients with metastatic NSGCT negatively impacts on survival in the good and intermediate, but not in the poor IGCCCG prognostic groups., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Silke Gillessen: Personal honoraria: advisory boards from Amgen, MSD; invited speaker ESMO, Swiss group for Clinical Cancer Research (SAKK), German-speaking European School of Oncology (DESO), Swiss Academy of Multidisciplinary oncology (SAMO); travel grant from AstraZeneca, Bayer. Institutional honoraria: advisory boards or in Independent Data Monitoring-/Steering Committees from AAA International, Amgen, AstraZeneca, Astellas Pharma, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, DAIICHI Sankyo, Innomedica, Ipsen, Meister-ConCept, Modra Pharmaceuticals, MSD, Myriad Genetic, Novartis, Orion, Pfizer, Roche, Telixpharma; invited speaker SAKK, ASCO GU, ESMO, PeerVoice, Silvio Grasso Consulting, WebMD-Medscape. Patent for a research method for biomarker WO2009138392. Karim Fizazi: Participation to advisory boards and talks for: Amgen, Astellas, Astrazeneca, Bayer, Clovis, Daiichi Sankyo, Janssen, MSD, Novartis/AAA, Pfizer, Sanofi. Honoraria go to Gustave Roussy, my institution. Participation to advisory boards with personal honorarium for Arvinas, CureVac, Macrogenics and Orion. Darren Feldman: Consulting: BioNTech, Telix, Renibus, Xencor. Research Funding: Telix, Exelixis, BMS, Decibel. Royalties: UpToDate. All other authors did not declare any conflicts of interest., (Crown Copyright © 2024. Published by Elsevier Ltd. All rights reserved.)

Background: Testicular germ cell tumor (TGCT) is the most common cancer among young White men. TGCT is highly heritable, although there are no known high-penetrance predisposition genes. CHEK2 is associated with moderate TGCT risk., Objective: To identify coding genomic variants associated with predisposition to TGCT., Design, Setting, and Participants: The study involved 293 men with familial or bilateral (high risk; HR)-TGCT representing 228 unique families and 3157 cancer-free controls., Outcome Measurements and Statistical Analysis: We carried out exome sequencing and gene burden analysis to identify associations with TGCT risk., Results and Limitations: Gene burden association identified several genes, including loss-of-function variants of NIN and QRSL1. We identified no statistically significant association with the sex- and germ-cell development pathways (hypergeometric overlap test: p = 0.65 for truncating variants, p = 0.47 for all variants) or evidence of associations with the regions previously identified via genome-wide association studies (GWAS). When considering all significant coding variants together with genes associated with TGCT on GWAS, there were associations with three major pathways: mitosis/cell cycle (Gene Ontology identity GO:1903047: observed/expected variant ratio [O/E] 6.17, false discovery rate [FDR] 1.53 × 10 -11 ), co-translational protein targeting (GO:0006613: O/E 18.62, FDR 1.35 × 10 -10 ), and sex differentiation (GO:0007548: O/E 5.25, FDR 1.90 × 10 -4 )., Conclusions: To the best of our knowledge, this study is the largest to date on men with HR-TGCT. As in previous studies, we identified associations with variants for several genes, suggesting multigenic heritability. We identified associations with co-translational protein targeting, and chromosomal segregation and sex determination, identified via GWAS. Our results suggest potentially druggable targets for TGCT prevention or treatment., Patient Summary: We searched for gene variations that increase the risk of testicular cancer and found numerous new specific variants that contribute to this risk. Our results support the idea that many gene variants inherited together contribute to the risk of testicular cancer., (Published by Elsevier B.V.)

Background: No study has quantified the impact of pain and other adverse health outcomes on global physical and mental health in long-term US testicular cancer survivors or evaluated patient-reported functional impairment due to pain., Methods: Testicular cancer survivors given cisplatin-based chemotherapy completed validated surveys, including Patient-Reported Outcomes Measurement Information System v1.2 global physical and mental health, Patient-Reported Outcomes Measurement Information System pain questionnaires, and others. Multivariable linear regression examined relationships between 25 adverse health outcomes with global physical and mental health and pain-interference scores. Adverse health outcomes with a β^  of more than 2 are clinically important and reported below., Results: Among 358 testicular cancer survivors (median age = 46 years, interquartile range [IQR] = 38-53 years; median time since chemotherapy = 10.7 years, IQR = 7.2-16.0 years), median adverse health outcomes number was 5 (IQR = 3-7). A total of 12% testicular cancer survivors had 10 or more adverse health outcomes, and 19% reported chemotherapy-induced neuropathic pain. Increasing adverse health outcome numbers were associated with decreases in physical and mental health (P < .0001 each). In multivariable analyses, chemotherapy-induced neuropathic pain (β^ = -3.72; P = .001), diabetes (β^ = -4.41; P = .037), obesity (β^ = -2.01; P = .036), and fatigue (β^ = -8.58; P < .0001) were associated with worse global mental health, while being married or living as married benefited global mental health (β^ = 3.63; P = .0006). Risk factors for pain-related functional impairment included lower extremity location (β^ = 2.15; P = .04) and concomitant peripheral artery disease (β^ = 4.68; P < .001). Global physical health score reductions were associated with diabetes (β^ = -3.81; P = .012), balance or equilibrium problems (β^ = -3.82; P = .003), cognitive dysfunction (β^ = -4.43; P < .0001), obesity (β^ = -3.09; P < .0001), peripheral neuropathy score (β^ = -2.12; P < .0001), and depression (β^ = -3.17; P < .0001)., Conclusions: Testicular cancer survivors suffer adverse health outcomes that negatively impact long-term global mental health, global physical health, and pain-related functional status. Clinically important factors associated with worse physical and mental health identify testicular cancer survivors requiring closer monitoring, counseling, and interventions. Chemotherapy-induced neuropathic pain must be addressed, given its detrimental impact on patient-reported functional status and mental health 10 or more years after treatment., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Purpose: This study's objective was to report cancer control and toxicity outcomes after proton radiation therapy (RT) in testicular seminoma and to compare secondary malignancy (SMN) risks with photon-based treatment alternatives., Methods and Materials: Consecutive patients with stage I-IIB testicular seminoma treated with proton RT at a single institution were retrospectively analyzed. Kaplan-Meier estimates for disease-free and overall survival were computed. Toxicities were scored using Common Terminology Criteria for Adverse Events version 5.0. Photon comparison plans, including 3-dimensional conformal RT (3D-CRT) and intensity modulated RT (IMRT)/volumetric arc therapy (VMAT), were created for each patient. Dosimetric parameters and SMN risk predictions for different in-field organs-at-risk were compared between the techniques. Excess absolute SMN risks were estimated with organ equivalent dose modeling., Results: Twenty-four patients were included (median age, 38.5 years). The majority of patients had stage II disease (IIA, 12 [50.0%]; IIB, 11 [45.8%]; IA, 1 [4.2%]). Seven (29.2%) and 17 (70.8%) patients had de novo and recurrent disease, respectively (de novo/recurrent: IA, 1/0; IIA, 4/8; IIB, 2/9). Most acute toxicities were mild (grade 1 [G1], 79.2%; G2, 12.5%) with G1 nausea being most common (70.8%). No serious events (G3-5) occurred. With a median follow-up time of 3 years (interquartile range, 2.1-3.6 years), 3-year disease-free and overall survival rates were 90.9% (95% confidence interval, 68.1%-97.6%) and 100% (95% confidence interval, 100%-100%), respectively. There were no documented late toxicities in the follow-up period, including worsening serial creatinine levels suggestive of early nephrotoxicity. Proton RT had significant reductions in mean organ-at-risk doses to the kidneys, stomach, colon, liver, bladder, and body compared with both 3D-CRT and IMRT/VMAT. Proton RT had significantly lower SMN risk predictions compared with 3D-CRT and IMRT/VMAT., Conclusions: Cancer control and toxicity outcomes using proton RT in stage I-IIB testicular seminoma are consistent with existing photon-based RT literature. However, proton RT may be associated with significantly lower SMN risks., Competing Interests: John P. Christodouleas reports employee status at Elekta Inc., grant funding from Merck & Co. Inc. unrelated to this work, and royalties from Wolters Kluwer unrelated to this work. No other disclosures were reported., (© 2023 The Authors.)

Purpose: Cisplatin is widely used and highly ototoxic, but patient-reported functional impairment because of cisplatin-related hearing loss (HL) and tinnitus has not been comprehensively evaluated., Patients and Methods: Testicular cancer survivors (TCS) given first-line cisplatin-based chemotherapy completed validated questionnaires, including the Hearing Handicap Inventory for Adults (HHIA) and Tinnitus Primary Function Questionnaire (TPFQ), each of which quantifies toxicity-specific functional impairment. Spearman correlations evaluated associations between HL and tinnitus severity and level of functional handicap quantified with the HHIA and TPFQ, respectively. Associations between HL or tinnitus and five prespecified adverse health outcomes (cognitive dysfunction, fatigue, depression, anxiety, and overall health) were evaluated., Results: HL and tinnitus affected 137 (56.4%) and 147 (60.5%) of 243 TCS, respectively. Hearing aids were used by 10% TCS (14/137). Of TCS with HL, 35.8% reported clinically significant functional impairment. Severe HHIA-assessed functional impairment was associated with cognitive dysfunction (odds ratio [OR], 10.62; P < .001), fatigue (OR, 5.48; P = .003), and worse overall health (OR, 0.19; P = .012). Significant relationships existed between HL severity and HHIA score, and tinnitus severity and TPFQ score ( P < .0001 each). TCS with either greater hearing difficulty or more severe tinnitus were more likely to report cognitive dysfunction (OR, 5.52; P = .002; and OR, 2.56; P = .05), fatigue (OR, 6.18; P < .001; and OR, 4.04; P < .001), depression (OR, 3.93; P < .01; and OR, 3.83; P < .01), and lower overall health (OR, 0.39; P = .03; and OR, 0.46; P = .02, respectively)., Conclusion: One in three TCS with HL report clinically significant functional impairment. Follow-up of cisplatin-treated survivors should include routine assessment for HL and tinnitus. Use of the HHIA and TPFQ permit risk stratification and referral to audiologists as needed, since HL adversely affects functional status and is the single largest modifiable risk factor for cognitive decline and dementia in the general population.

Purpose: Deficits in speech understanding constitute one of the most severe consequences of hearing loss. Here we investigate the clinical and genetic risk factors for symmetric deterioration of speech recognition thresholds (SRT) among cancer survivors treated with cisplatin., Methods: SRT was measured using spondaic words and calculating the mean of measurements for both ears with symmetric SRT values. For clinical associations, SRT-based hearing disability (SHD) was defined as SRT≥15 dB hearing loss and clinical variables were derived from the study dataset. Genotyped blood samples were used for GWAS with rank-based inverse normal transformed SRT values as the response variable. Age was used as a covariate in association analyses., Results: SHD was inversely associated with self-reported health (p = 0.004). Current smoking (p = 0.002), years of smoking (p = 0.02), BMI (p < 0.001), and peripheral motor neuropathy (p = 0.003) were positively associated with SHD, while physical activity was inversely associated with SHD (p = 0.005). In contrast, cumulative cisplatin dose, peripheral sensory neuropathy, hypertension, and hypercholesterolemia were not associated with SHD. Although no genetic variants had an association p value < 5 × 10 -8 , 22 genetic variants were suggestively associated (p < 10 -5 ) with SRT deterioration. Three of the top variants in 10 respective linkage disequilibrium regions were either positioned within the coding sequence or were eQTLs for genes involved in neuronal development (ATE1, ENAH, and ZFHX3)., Conclusion: Current results improve our understanding of risk factors for SRT deterioration in cancer survivors. Higher BMI, lower physical activity, and smoking are associated with SHD. Larger samples would allow for expansion of the current findings on the genetic architecture of SRT., (© 2022 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Background: Immune checkpoint inhibitors are a standard therapy in metastatic urothelial carcinoma (UC). Long-term follow-up is necessary to confirm durability of response and identify further safety concerns., Patients and Methods: In KEYNOTE-045, patients with metastatic UC that progressed on platinum-containing chemotherapy were randomly assigned 1:1 to receive pembrolizumab or investigator's choice of paclitaxel, docetaxel, or vinflunine. Primary end points were progression-free survival (PFS) per RECIST v1.1 by blinded independent central review (BICR) and overall survival (OS). In KEYNOTE-052, cisplatin-ineligible patients with metastatic UC received first-line pembrolizumab. The primary end point was objective response rate (ORR) per RECIST v1.1 by BICR., Results: A total of 542 patients (pembrolizumab, n = 270; chemotherapy, n = 272) were randomly assigned in KEYNOTE-045. Median follow-up was 62.9 months (range, 58.6-70.9; data cutoff October 1, 2020). At 48 months, OS rates were 16.7% for pembrolizumab and 10.1% for chemotherapy; PFS rates were 9.5% and 2.7%, respectively. Median duration of response (DOR) was 29.7 months (range, 1.6+ to 60.5+) for pembrolizumab and 4.4 months (range, 1.4+ to 63.1+) for chemotherapy; 36-month DOR rates were 44.4% and 28.3%, respectively. A total of 370 patients were enrolled in KEYNOTE-052. Median follow-up was 56.3 months (range, 51.2-65.3; data cutoff September 26, 2020). Confirmed ORR was 28.9% (95% CI, 24.3-33.8), and median DOR was 33.4 months (range, 1.4+ to 60.7+); 36-month DOR rate was 44.8%. Most treatment-related adverse events for pembrolizumab in either study were grade 1 or 2 and manageable, which is consistent with prior reports., Conclusion: With approximately 5 years of follow-up, pembrolizumab monotherapy continued to demonstrate durable efficacy with no new safety signals in patients with platinum-resistant metastatic UC and as first-line therapy in cisplatin-ineligible patients. Clinical trial registry and ID: ClinicalTrials.gov, NCT02256436 (KEYNOTE-045) and NCT02335424 (KEYNOTE-052)., (Copyright © 2022. Published by Elsevier Ltd.)

Claudin6(CLDN6) is a tight junction protein of claudin-tetraspanin family and is of the earliest molecules expressed in embryonic epithelium. CLDN6 is frequently aberrantly expressed in testicular germ-cell tumors(GCT). ASP1650 is a chimeric-mouse/human-IgG1 antibody directed against CLDN6. Two-part, open-label, phase-II trial investigating ASP1650 in patients with relapsed/refractory GCT and no curable options. Part1 was a safety lead-in to establish the recommended-phase-II-dose(RP2D). Part2 was a phase-II study designed to evaluate the antitumor effects of ASP1650. CLDN6 expression was centrally assessed on archival tumor tissue using immunohistochemistry. The primary objectives were to establish the RP2D(safety lead-in) and the antitumor activity(phase-II) of ASP1650. Nineteen male patients were enrolled: 6 patients in 1000 mg/m 2 safety lead-in group, and 13 in 1500 mg/m 2 group. Median age 37.2 years(range,20-58). Histology was non-seminoma in 17/19 patients. Median number of previous chemotherapy regimens was 3. Thirteen patients had prior high-dose chemotherapy. No dose-limiting toxicity events were reported at any study drug dose. A RP2D of 1500 mg/m 2 every 2 weeks was established. No partial or complete responses were observed. The study was stopped at the end of Simon Stage-I due to lack of efficacy. 15/16 subjects with available tissue had CLDN6 positive staining. The mean percent membrane staining was 71.6% and the mean membrane H score was 152.6(SD 76). ASP1650 did not appear to have clinically meaningful single-agent activity in relapsed/refractory GCT. CLDN6 expression seems ubiquitous in all elements of GCT and is worthy of investigation as a diagnostic biomarker and therapeutic target. (Clinical trial information: NCT03760081)., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

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., (©2022 American Association for Cancer Research.)

Introduction: Despite high curability, patients with metastatic germ cell tumors (GCT) in the United States general population persistently face inferior outcomes compared with those treated in specialty referral centers. We characterized guideline discordant management in patients with metastatic GCT who experienced relapse after first-line chemotherapy and compared those who were initially treated in community practices vs. academic referral centers., Patients/methods: Retrospective analysis of 53 patients with relapsed GCT between 2005 and 2018. First-line GCT management was assessed against the National Comprehensive Cancer Network guidelines. Guideline discordant management, predictors of discordance, and associations with outcomes were assessed., Results: Of 53 patients with relapsed GCT, 34% received guideline discordant care in the first-line setting. Guideline discordant care was more prevalent in patients initially treated in community practices (12/30, 40%) vs. those initially treated in academic centers (3/22, 14%), though in multivariate logistic regression, this difference was not statistically significant (odds ratio: 4.07, P = 0.08). Most patients in community settings who received guideline discordant care were undertreated (10/12, 83%). There were 3 major reasons for guideline discordant care: (1) failure to resect residual masses after chemotherapy (27%, 4/15), (2) mismanagement of chemotherapy-related adverse events (27%, 4/15), and (3) under staging at diagnosis, resulting either insufficient chemotherapy regimen intensity (13%, 2/15) and/or inappropriately receiving primary surgical resection for metastatic disease (20%, 3/15)., Conclusion: Under treatment was identified in nearly half of patients initially treated in a community setting who later developed relapsed GCT. Referral to specialized centers for a second opinion should be considered for all metastatic GCT patients in the first-line setting and all patients with post-chemotherapy residual disease. More effective methods should be developed to facilitate second opinions from expert centers in the United States., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Purpose: Cisplatin is a critical component of first-line chemotherapy for several cancers, but causes peripheral sensory neuropathy, hearing loss, and tinnitus. We aimed to identify comorbidities for cisplatin-induced neurotoxicities among large numbers of similarly treated patients without the confounding effect of cranial radiotherapy., Methods: Utilizing linear and logistic regression analyses on 1680 well-characterized cisplatin-treated testicular cancer survivors, we analyzed associations of hearing loss, tinnitus, and peripheral neuropathy with nongenetic comorbidities. Genome-wide association studies and gene-based analyses were performed on each phenotype., Results: Hearing loss, tinnitus, and peripheral neuropathy, accounting for age and cisplatin dose, were interdependent. Survivors with these neurotoxicities experienced more hypertension and poorer self-reported health. In addition, hearing loss was positively associated with BMIs at clinical evaluation and nonwork-related noise exposure (>5 h/week). Tinnitus was positively associated with tobacco use, hypercholesterolemia, and noise exposure. We observed positive associations between peripheral neuropathy and persistent vertigo, tobacco use, and excess alcohol consumption. Hearing loss and TXNRD1, which plays a key role in redox regulation, showed borderline significance (p = 4.2 × 10 -6 ) in gene-based analysis. rs62283056 in WFS1 previously found to be significantly associated with hearing loss (n = 511), was marginally significant in an independent replication cohort (p = 0.06; n = 606). Gene-based analyses identified significant associations between tinnitus and WNT8A (p = 2.5 × 10 -6 ), encoding a signaling protein important in germ cell tumors., Conclusions: Genetics variants in TXNRD1 and WNT8A are notable risk factors for hearing loss and tinnitus, respectively. Future studies should investigate these genes and if replicated, identify their potential impact on preventive strategies., (© 2022 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

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 95 th 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., (© 2021. The Author(s).)

Background: This study examined sociodemographic factors, cisplatin-related adverse health outcomes (AHO), and cumulative burden of morbidity (CBM Pt ) scores associated with medication use for anxiety and/or depression in testicular cancer survivors (TCS)., Methods: A total of 1,802 TCS who completed cisplatin-based chemotherapy ≥12 months previously completed questionnaires regarding sociodemographic features and cisplatin-related AHOs [hearing impairment, tinnitus, peripheral sensory neuropathy (PSN), and kidney disease]. A CBM Pt score encompassed the number and severity of cisplatin-related AHOs. Multivariable logistic regression models assessed the relationship of individual AHOs and CBM Pt with medication use for anxiety and/or depression., Results: A total of 151 TCS (8.4%) used medications for anxiety and/or depression. No cisplatin-related AHOs were reported by 511 (28.4%) participants, whereas 622 (34.5%), 334 (18.5%), 287 (15.9%), and 48 (2.7%), respectively, had very low, low, medium, and high CBM Pt scores. In the multivariable model, higher CBM Pt scores were significantly associated with medication use for anxiety and/or depression ( P < 0.0001). In addition, tinnitus ( P = 0.0009), PSN ( P = 0.02), and having health insurance ( P = 0.05) were significantly associated with greater use of these medications, whereas being employed ( P = 0.0005) and vigorous physical activity ( P = 0.01) were significantly associated with diminished use., Conclusions: TCS with higher CBM Pt scores had a higher probability of using medications for anxiety and/or depression, and conversely, those who were employed and physically active tended to have reduced use of these medications., Impact: Healthcare providers should encourage TCS to increase physical activity to improve both physical and mental health. Rehabilitation programs should assess work-related skills and provide career development counseling/training., (©2021 American Association for Cancer Research.)

Background: Precision medicine approaches for managing patients with metastatic castrate-resistant prostate cancer (mCRPC) are lacking. Non-invasive approaches for molecular monitoring of disease are urgently needed, especially for patients suffering from bone metastases for whom tissue biopsy is challenging. Here we utilized baseline blood samples to identify mCRPC patients most likely to benefit from abiraterone plus prednisone (AAP) or enzalutamide., Methods: Baseline blood samples were collected for circulating tumor cell (CTC) enumeration and qPCR-based gene expression analysis from 51 men with mCRPC beginning treatment with abiraterone or enzalutamide., Results: Of 51 patients (median age 68 years [51-82]), 22 received AAP (abiraterone 1000 mg/day plus prednisone 10 mg/day) and 29 received enzalutamide (160 mg/day). The cohort was randomly divided into training (n = 37) and test (n = 14) sets. Baseline clinical variables (Gleason score, PSA, testosterone, and hemoglobin), CTC count, and qPCR-based gene expression data for 141 genes/isoforms in CTC-enriched blood were analyzed with respect to overall survival (OS). Genes with expression most associated with OS included MSLN, ARG2, FGF8, KLK3, ESRP2, NPR3, CCND1, and WNT5A. Using a Cox-elastic net model for our test set, the 8-gene expression signature had a c-index of 0.87 (95% CI [0.80, 0.94]) and was more strongly associated with OS than clinical variables or CTC count alone, or a combination of the three variables. For patients with a low-risk vs. high-risk gene expression signature, median OS was not reached vs. 18 months, respectively (HR 5.32 [1.91-14.80], p = 0.001). For the subset of 41 patients for whom progression-free survival (PFS) data was available, the median PFS for patients with a low-risk vs high-risk gene expression signature was 20 vs. 5 months, respectively (HR 2.95 [1.46-5.98], p = 0.003)., Conclusions: If validated in a larger prospective study, this test may predict patients most likely to benefit from second-generation antiandrogen therapy.

Purpose: The classification of the International Germ Cell Cancer Collaborative Group (IGCCCG) plays a pivotal role in the management of metastatic germ cell tumors but relies on data of patients treated between 1975 and 1990., Materials and Methods: Data on 9,728 men with metastatic nonseminomatous germ cell tumors treated with cisplatin- and etoposide-based first-line chemotherapy between 1990 and 2013 were collected from 30 institutions or collaborative groups in Europe, North America, and Australia. Clinical trial and registry data were included. Primary end points were progression-free survival (PFS) and overall survival (OS). The survival estimates were updated for the current era. Additionally, a novel prognostic model for PFS was developed in 3,543 patients with complete information on potentially relevant variables. The results were validated in an independent data set., Results: Compared with the original IGCCCG publication, 5-year PFS remained similar in patients with good prognosis with 89% (87%-91%) versus 90% (95% CI, 89 to 91), but the 5-year OS increased from 92% (90%-94%) to 96% (95%-96%). In patients with intermediate prognosis, PFS remained similar with 75% (71%-79%) versus 78% (76%-80%) and the OS increased from 80% (76%-84%) to 89% (88%-91%). In patients with poor prognosis, the PFS increased from 41% (95% CI, 35 to 47) to 54% (95% CI, 52 to 56) and the OS from 48% (95% CI, 42 to 54) to 67% (95% CI, 65 to 69). A more granular prognostic model was developed and independently validated. This model identified a new cutoff of lactate dehydrogenase at a 2.5 upper limit of normal and increasing age and presence of lung metastases as additional adverse prognostic factors. An online calculator is provided (https://www.eortc.org/IGCCCG-Update)., Conclusion: The IGCCCG Update model improves individual prognostication in metastatic nonseminomatous germ cell tumors. Increasing age and lung metastases add granularity to the original IGCCCG classification as adverse prognostic factors., Competing Interests: Silke GillessenConsulting or Advisory Role: Astellas Pharma, Janssen, Bayer, Orion Pharma GmbH, Tolero Pharmaceuticals, MSD Oncology, Roche, Amgen, PfizerSpeakers' Bureau: Janssen-CilagPatents, Royalties, Other Intellectual Property: Method for biomarker (WO 3752009138392 A1)Travel, Accommodations, Expenses: ProteoMedixOther Relationship: ProteoMediX, Aranda Pharma Gedske DaugaardConsulting or Advisory Role: Sanofi/Aventis, Astellas Pharma, Bayer, MSD Oncology, Bristol-Myers Squibb/PfizerTravel, Accommodations, Expenses: Astellas Pharma Ronald De WitHonoraria: Sanofi, Merck Sharp and DohmeConsulting or Advisory Role: Sanofi, Merck Sharp and Dohme, Janssen, Bayer, Astellas PharmaResearch Funding: Sanofi, BayerTravel, Accommodations, Expenses: Bayer Costantine AlbanyStock and Other Ownership Interests: AdvaxisHonoraria: Sanofi, AstraZeneca, Seattle GeneticsConsulting or Advisory Role: Seattle Genetics, AstraZeneca/MedImmuneSpeakers' Bureau: SanofiResearch Funding: Astex Pharmaceuticals, Merck, Bristol-Myers Squibb, Lilly, BayerTravel, Accommodations, Expenses: Sanofi Alexey TryakinConsulting or Advisory Role: BioCad, Roche/Genentech, Bristol-Myers Squibb, Eisai, Merck Sharp and DohmeSpeakers' Bureau: Bayer Health, BioCad, Lilly, Merck Serono, Sanofi, Amgen, Bristol-Myers Squibb, Eisai, Merck Sharp and DohmeTravel, Accommodations, Expenses: Novartis, BioCad, Bayer, Veropharm, Sanofi Karim FizaziHonoraria: Janssen, Sanofi, Astellas Pharma, BayerConsulting or Advisory Role: Janssen Oncology, Bayer, Astellas Pharma, Sanofi, Orion Pharma GmbH, Curevac, AstraZeneca, ESSA, Amgen, Bristol-Myers Squibb, Clovis OncologyTravel, Accommodations, Expenses: Janssen, MSD Olof StahlHonoraria: Bayer Ugo De GiorgiConsulting or Advisory Role: Pfizer, Janssen, Astellas Pharma, Sanofi, Bristol-Myers Squibb, Bayer, Ipsen, Merck, MSD, PharmaMar, NovartisResearch Funding: Sanofi, AstraZeneca, RocheTravel, Accommodations, Expenses: Bristol-Myers Squibb, Ipsen, Janssen, Pfizer, Roche Aaron HansenConsulting or Advisory Role: Merck, GlaxoSmithKline, Bristol-Myers Squibb, EisaiResearch Funding: Karyopharm Therapeutics, Merck, Bristol-Myers Squibb, Boehringer Ingelheim, GlaxoSmithKline, Roche/Genentech, Janssen, AstraZeneca/MedImmune, Astellas Pharma, Macrogenics Robert HuddartEmployment: Aspen Parkside HopsitalLeadership: Cancer Clinic London Limited liability partnershipHonoraria: Janssen OncologyConsulting or Advisory Role: Bristol-Myers Squibb, Roche, Merck Sharp and Dohme, Janssen Oncology, Nektar, BayerSpeakers' Bureau: Roche, MSD, RocheResearch Funding: Merck Sharp and Dohme, Roche, Bristol-Myers Squibb, JanssenPatents, Royalties, Other Intellectual Property: Royalties for drug discovery from JanssenTravel, Accommodations, Expenses: Janssen Oncology, Roche/Genentech, MSD Oncology, Nektar Andrea NecchiEmployment: BayerStock and Other Ownership Interests: BayerHonoraria: Roche, Merck, AstraZeneca, Janssen, Foundation Medicine, Bristol-Myers SquibbConsulting or Advisory Role: Merck Sharp and Dohme, Roche, Bayer, AstraZeneca, Clovis Oncology, Janssen, Incyte, Seattle Genetics/Astellas, Bristol-Myers Squibb, Rainier Therapeutics, GlaxoSmithKline, FerringResearch Funding: Merck Sharp and Dohme, AstraZeneca, IpsenTravel, Accommodations, Expenses: Roche, Merck Sharp and Dohme, AstraZeneca, Janssen, Rainier TherapeuticsOther Relationship: Bayer Christopher SweeneyStock and Other Ownership Interests: LeuchemixConsulting or Advisory Role: Sanofi, Janssen Biotech, Astellas Pharma, Bayer, Genentech/Roche, AstraZeneca, Pfizer, Amgen, Celgene, LillyResearch Funding: Janssen Biotech, Astellas Pharma, Sanofi, Bayer, Dendreon, PfizerPatents, Royalties, Other Intellectual Property: Leuchemix, Parthenolide, Dimethylaminoparthenolide. Exelixis: Abiraterone plus cabozantinib combination Xavier Garcia Del MuroConsulting or Advisory Role: Pfizer, Bristol-Myers Squibb, Ipsen, Roche, Lilly, PharmaMar, EUSA Pharma, GlaxoSmithKlineSpeakers' Bureau: Pfizer, Bristol-Myers Squibb, Astellas Pharma, EisaiResearch Funding: AstraZenecaTravel, Accommodations, Expenses: Pfizer, Roche Daniel HengConsulting or Advisory Role: Pfizer, Novartis, Bristol-Myers Squibb, Janssen, Astellas Pharma, Ipsen, Eisai, MerckResearch Funding: Pfizer, Novartis, Exelixis, Bristol-Myers Squibb, Ipsen Anja LorchHonoraria: MSD Oncology, Merck, MSDConsulting or Advisory Role: Bristol-Myers Squibb, Novartis, AstraZeneca, Roche, MSD Oncology, Janssen Oncology, Ipsen, Merck, PfizerTravel, Accommodations, Expenses: Ipsen, AstraZeneca Eric WinquistHonoraria: Merck, Bayer, Eisai, Amgen, RocheResearch Funding: Roche/Genentech, Merck, Pfizer, Eisai, Ayala Pharmaceuticals Peter GrimisonResearch Funding: Tilray, Pfizer, MSD, Gilead Sciences, Boston Biomedical, Tigermed, Halozyme, Specialised Therapeutics, Medimmune, Pfizer, ASLAN Pharmaceuticals, Genentech, Eisai, Five Prime Therapeutics, QED Therapeutics, Janssen-Cilag Darren FeldmanResearch Funding: Novartis, Seattle Genetics, Decibel Therapeutics, Astellas PharmaOther Relationship: UpToDate Angelika TerbuchResearch Funding: Roche, AstraZeneca, MSD, Bristol-Myers Squibb Marcus HentrichConsulting or Advisory Role: Amgen, Janssen-Cilag, Sanofi, Hexal, Jazz Pharmaceuticals, TakedaSpeakers' Bureau: Amgen, Janssen-Cilag, Sanofi, Takeda, Bristol-Myers Squibb, Gilead SciencesTravel, Accommodations, Expenses: Celgene, Janssen-Cilag, Takeda Carsten BokemeyerHonoraria: Merck KGaA, Sanofi, Roche, Bayer, Bristol-Myers Squibb, AstraZeneca, Merck Sharp and DohmeConsulting or Advisory Role: Lilly/ImClone, Merck Serono, Sanofi, Bayer Schering Pharma, Merck Sharp and Dohme, GSO, AOK Health InsuranceResearch Funding: Abbvie, ADC Therapeutics, Agile Therapeutics, Alexion Pharmaceuticals, Amgen, Apellis Pharmaceuticals, Astellas Pharma, AstraZeneca, Bayer, BerGenBio, Blueprint Medicines, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Daiichi Sankyo, Eisai, Gilead Sciences, Glycotope GmbH, GlaxoSmithKline, Incyte, iOMEDICO, Isofol Medical, Janssen-Cilag, Karyopharm Therapeutics, Lilly, Millennium, MSD, Nektar, Novartis, Rafael Pharmaceuticals, Roche, Springworks Therapeutics, Taiho PharmaceuticalTravel, Accommodations, Expenses: Merck Serono, Sanofi, Pfizer, Bristol-Myers Squibb Jonathan ShamashSpeakers' Bureau: Pfizer/EMD Serono David VaughnResearch Funding: Merck Sharp and Dohme, Roche/Genentech, Astellas Pharma Cora SternbergConsulting or Advisory Role: Bayer, MSD, Pfizer, Roche, Incyte, AstraZeneca, Merck, Medscape, UroToday, Astellas Pharma, Genzyme, Immunomedics, Foundation Medicine Axel HeidenreichHonoraria: Amgen, Astellas Pharma, Bayer, Ferring, Ipsen, Janssen-Cilag, Sanofi, TakedaConsulting or Advisory Role: Astellas Pharma, Bayer, Janssen-Cilag, Clovis Oncology, BMS Global, AstraZeneca, MSD OncologySpeakers' Bureau: Amgen, Astellas Pharma, Bayer, Ipsen, Johnson and Johnson, Sanofi, Takeda, PfizerResearch Funding: Astellas Pharma, Bayer, Sanofi, Bristol-Myers Squibb Joerg BeyerHonoraria: Roche, Janssen Oncology, AstraZeneca, Astellas Pharma, Bayer, IpsenNo other potential conflicts of interest were reported.

Purpose: The classification of the International Germ-Cell Cancer Collaborative Group (IGCCCG) has been a major advance in the management of germ-cell tumors, but relies on data of only 660 patients with seminoma treated between 1975 and 1990. We re-evaluated this classification in a database from a large international consortium., Materials and Methods: Data on 2,451 men with metastatic seminoma treated with cisplatin- and etoposide-based first-line chemotherapy between 1990 and 2013 were collected from 30 institutions or collaborative groups in Australia, Europe, and North America. Clinical trial and registry data were included. Primary end points were progression-free survival (PFS) and overall survival (OS) calculated from day 1 of treatment. Variables at initial presentation were evaluated for their prognostic impact. Results were validated in an independent validation set of 764 additional patients., Results: Compared with the initial IGCCCG classification, in our modern series, 5-year PFS improved from 82% to 89% (95% CI, 87 to 90) and 5-year OS from 86% to 95% (95% CI, 94 to 96) in good prognosis, and from 67% to 79% (95% CI, 70 to 85) and 72% to 88% (95% CI, 80 to 93) in intermediate prognosis patients. Lactate dehydrogenase (LDH) proved to be an additional adverse prognostic factor. Good prognosis patients with LDH above 2.5× upper limit of normal had a 3-year PFS of 80% (95% CI, 75 to 84) and a 3-year OS of 92% (95% CI, 88 to 95) versus 92% (95% CI, 90 to 94) and 97% (95% CI, 96 to 98) in the group with lower LDH., Conclusion: PFS and OS in metastatic seminoma significantly improved in our modern series compared with the original data. The original IGCCCG classification retains its relevance, but can be further refined by adding LDH at a cutoff of 2.5× upper limit of normal as an additional adverse prognostic factor., Competing Interests: Jörg BeyerHonoraria: Roche, Janssen Oncology, AstraZeneca, Astellas Pharma, Bayer, Ipsen Gedske DaugaardConsulting or Advisory Role: Sanofi/Aventis, Astellas Pharma, Bayer, MSD Oncology, Bristol-Myers Squibb/PfizerTravel, Accommodations, Expenses: Astellas Pharma Darren R. FeldmanResearch Funding: Novartis, Seattle Genetics, Decibel Therapeutics, Astellas PharmaOther Relationship: UpToDate Alexey TryakinConsulting or Advisory Role: BioCad, Roche/Genentech, Bristol-Myers Squibb, Eisai, Merck Sharp & DohmeSpeakers' Bureau: Bayer Health, BioCad, Lilly, Merck Serono, Sanofi, Amgen, Bristol-Myers Squibb, Eisai, Merck Sharp & DohmeTravel, Accommodations, Expenses: Novartis, BioCad, Bayer, Veropharm, Sanofi Olof StahlHonoraria: Bayer Enrique Gonzalez-BillalabeitiaTravel, Accommodations, Expenses: Bristol-Myers Squibb, Pfizer, Janssen-Cilag, Astellas Pharma, Sanofi, Roche Ugo De GiorgiConsulting or Advisory Role: Pfizer, Janssen, Astellas Pharma, Sanofi, Bristol-Myers Squibb, Bayer, Ipsen, Merck, MSD, PharmaMar, NovartisResearch Funding: Sanofi, AstraZeneca, RocheTravel, Accommodations, Expenses: Bristol-Myers Squibb, Ipsen, Janssen, Pfizer, Roche Stephane CulineConsulting or Advisory Role: Bayer, Janssen, Astellas PharmaSpeakers' Bureau: Takeda, JanssenResearch Funding: Astellas PharmaTravel, Accommodations, Expenses: Ipsen, Janssen Ronald De WitHonoraria: Sanofi, Merck Sharp & DohmeConsulting or Advisory Role: Sanofi, Merck Sharp & Dohme, Janssen, Bayer, Astellas PharmaResearch Funding: Sanofi, BayerTravel, Accommodations, Expenses: Bayer Aaron HansenConsulting or Advisory Role: Merck, GlaxoSmithKline, Bristol-Myers Squibb, EisaiResearch Funding: Karyopharm Therapeutics, Merck, Bristol-Myers Squibb, Boehringer Ingelheim, GlaxoSmithKline, Roche/Genentech, Janssen, AstraZeneca/MedImmune, Astellas Pharma, Macrogenics Marko BebekHonoraria: Roche, Novartis, Janssen Oncology, Sanofi, Sandoz, Astellas PharmaResearch Funding: Roche, Astellas PharmaTravel, Accommodations, Expenses: Roche, Astellas Pharma, Sanofi, Janssen, Novartis Angelika TerbuchResearch Funding: Roche, AstraZeneca, MSD, Bristol-Myers Squibb Costantine AlbanyStock and Other Ownership Interests: AdvaxisHonoraria: Sanofi, AstraZeneca, Seattle GeneticsConsulting or Advisory Role: Seattle Genetics, AstraZeneca/MedImmuneSpeakers' Bureau: SanofiResearch Funding: Astex Pharmaceuticals, Merck, Bristol-Myers Squibb, Lilly, BayerTravel, Accommodations, Expenses: Sanofi Marcus HentrichConsulting or Advisory Role: Amgen, Janssen-Cilag, Sanofi, Hexal, Jazz Pharmaceuticals, TakedaSpeakers' Bureau: Amgen, Janssen-Cilag, Sanofi, Takeda, Bristol-Myers Squibb, Gilead SciencesTravel, Accommodations, Expenses: Celgene, Janssen-Cilag, Takeda Jourik A. GietemaResearch Funding: Roche/Genentech, Abbvie, Siemens Robert A. HuddartEmployment: Aspen Parkside HospitalLeadership: Cancer Clinic London limited liability partnershipHonoraria: Janssen OncologyConsulting or Advisory Role: Bristol-Myers Squibb, Roche, Merck Sharp & Dohme, Janssen Oncology, Nektar, BayerSpeakers' Bureau: Roche, MSDResearch Funding: Merck Sharp & Dohme, Roche, Bristol-Myers Squibb, JanssenPatents, Royalties, Other Intellectual Property: Royalties for drug discovery from JanssenTravel, Accommodations, Expenses: Janssen Oncology, Roche/Genentech, MSD Oncology, Nektar Anja LorchHonoraria: MSD Oncology, Merck, MSDConsulting or Advisory Role: Bristol-Myers Squibb, Novartis, AstraZeneca, Roche, MSD Oncology, Janssen Oncology, Ipsen, Merck, PfizerTravel, Accommodations, Expenses: Ipsen, AstraZeneca Daniel Y. C. HengConsulting or Advisory Role: Pfizer, Novartis, Bristol-Myers Squibb, Janssen, Astellas Pharma, Ipsen, Eisai, MerckResearch Funding: Pfizer, Novartis, Exelixis, Bristol-Myers Squibb, Ipsen Christopher J. SweeneyStock and Other Ownership Interests: LeuchemixConsulting or Advisory Role: Sanofi, Janssen Biotech, Astellas Pharma, Bayer, Genentech/Roche, AstraZeneca, Pfizer, Amgen, Celgene, LillyResearch Funding: Janssen Biotech, Astellas Pharma, Sanofi, Bayer, Dendreon, PfizerPatents, Royalties, Other Intellectual Property: Leuchemix, Parthenolide, Dimethylaminoparthenolide. Exelixis: Abiraterone plus cabozantinib combination Eric WinquistHonoraria: Merck, Bayer, Eisai, Amgen, RocheResearch Funding: Roche/Genentech, Merck, Pfizer, Eisai, Ayala Pharmaceuticals Peter GrimisonResearch Funding: Tilray, Pfizer, MSD, Gilead Sciences, Boston Biomedical, Tigermed, Halozyme, Specialised Therapeutics, Medimmune, Pfizer, ASLAN Pharmaceuticals, Genentech, Eisai, Five Prime Therapeutics, QED Therapeutics, Janssen-Cilag Andrea NecchiEmployment: BayerStock and Other Ownership Interests: BayerHonoraria: Roche, Merck, AstraZeneca, Janssen, Foundation Medicine, Bristol-Myers SquibbConsulting or Advisory Role: Merck Sharp & Dohme, Roche, Bayer, AstraZeneca, Clovis Oncology, Janssen, Incyte, Seattle Genetics/Astellas, Bristol-Myers Squibb, Rainier Therapeutics, GlaxoSmithKline, FerringResearch Funding: Merck Sharp & Dohme, AstraZeneca, IpsenTravel, Accommodations, Expenses: Roche, Merck Sharp & Dohme, AstraZeneca, Janssen, Rainier TherapeuticsOther Relationship: Bayer Ben TranHonoraria: Astellas Pharma, Janssen-Cilag, Sanofi, Tolmar, Amgen, Bristol-Myers SquibbConsulting or Advisory Role: Amgen, Astellas Pharma, Bayer, Sanofi, Tolmar, Janssen-Cilag, Bristol-Myers Squibb, Ipsen, MSD Oncology, IQvia, Novartis, Pfizer/EMD Serono, AstraZeneca, Roche Molecular DiagnosticsResearch Funding: Astellas Pharma, Janssen-Cilag, Amgen, Pfizer, Genentech, AstraZeneca, Bayer, Bristol-Myers Squibb, Merck Sharp & Dohme, IpsenTravel, Accommodations, Expenses: Amgen, Astellas Pharma Axel HeidenreichHonoraria: Amgen, Astellas Pharma, Bayer, Ferring, Ipsen, Janssen-Cilag, Sanofi, TakedaConsulting or Advisory Role: Astellas Pharma, Bayer, Janssen-Cilag, Clovis Oncology, BMS Global, AstraZeneca, MSD OncologySpeakers' Bureau: Amgen, Astellas Pharma, Bayer, Ipsen, Johnson & Johnson, Sanofi, Takeda, PfizerResearch Funding: Astellas Pharma, Bayer, Sanofi, Bristol-Myers Squibb Jonathan ShamashSpeakers' Bureau: Pfizer/EMD Serono Cora N. SternbergConsulting or Advisory Role: Bayer, MSD, Pfizer, Roche, Incyte, AstraZeneca, Merck, Medscape, UroToday, Astellas Pharma, Genzyme, Immunomedics, Foundation Medicine David J. VaughnResearch Funding: Merck Sharp & Dohme, Roche/Genentech, Astellas Pharma Ignacio DuranHonoraria: Bristol-Myers Squibb, Ipsen, Roche/Genentech, Janssen Oncology, MSD Oncology, Astellas Pharma, EUSA PharmaConsulting or Advisory Role: Roche/Genentech, MSD Oncology, Bayer, Bristol-Myers Squibb, Seattle Genetics, Pharmacyclics, Janssen Oncology, Novartis, ImmunomedicsResearch Funding: Roche/Genentech, AstraZeneca Spain, Janssen Oncology, Astellas PharmaTravel, Accommodations, Expenses: Roche/Genentech, AstraZeneca Spain, Ipsen Carsten BokemeyerHonoraria: Merck KGaA, Sanofi, Roche, Bayer, Bristol-Myers Squibb, AstraZeneca, Merck Sharp & DohmeConsulting or Advisory Role: Lilly/ImClone, Merck Serono, Sanofi, Bayer Schering Pharma, Merck Sharp & Dohme, GSO, AOK Health InsuranceResearch Funding: Abbvie, ADC Therapeutics, Agile Therapeutics, Alexion Pharmaceuticals, Amgen, Apellis Pharmaceuticals, Astellas Pharma, AstraZeneca, Bayer, BerGenBio, Blueprint Medicines, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Daiichi Sankyo, Eisai, Gilead Sciences, Glycotope GmbH, GlaxoSmithKline, Incyte, iOMEDICO, Isofol Medical, Janssen-Cilag, Karyopharm Therapeutics, Lilly, Millennium, MSD, Nektar, Novartis, Rafael Pharmaceuticals, Roche, Springworks Therapeutics, Taiho PharmaceuticalTravel, Accommodations, Expenses: Merck Serono, Sanofi, Pfizer, Bristol-Myers Squibb Anna PatrikidouConsulting or Advisory Role: Basilea Richard CathomasHonoraria: Janssen-Cilag, Astellas Pharma, Bristol-Myers Squibb, Debiopharm GroupConsulting or Advisory Role: Astellas Pharma, Bristol-Myers Squibb, Pfizer, Roche, MSD Oncology, Janssen-Cilag, Bayer, Sanofi, IpsenTravel, Accommodations, Expenses: AstraZeneca Silke GillessenConsulting or Advisory Role: Astellas Pharma, Janssen, Bayer, Orion Pharma GmbH, Tolero Pharmaceuticals, MSD Oncology, Roche, Amgen, PfizerSpeakers' Bureau: Janssen-CilagPatents, Royalties, Other Intellectual Property: Method for biomarker (WO 3752009138392 A1)Travel, Accommodations, Expenses: ProteoMedixOther Relationship: ProteoMediX, Aranda PharmaNo other potential conflicts of interest were reported.

Importance: Cardiovascular disease is a leading cause of mortality in patients with prostate cancer, and androgen deprivation therapy (ADT) may worsen cardiovascular risk. Adherence to guideline-recommended assessment and management of cardiovascular risk factors (CVRFs) in patients initiating ADT is unknown., Objective: To describe CVRF assessment and management in men with prostate cancer initiating ADT and overall., Design, Setting, and Participants: A cross-sectional analysis of 90 494 men treated within the US Veterans Health Administration diagnosed with prostate cancer between January 1, 2010, and December 31, 2017, was conducted. Participants included men with a history of atherosclerotic cardiovascular disease (ASCVD), and treatment with ADT within 1 year of diagnosis. Data analysis was conducted from September 10, 2019, to July 1, 2020., Main Outcomes and Measures: Rates of comprehensive CVRF assessment, uncontrolled CVRFs, and untreated CVRFs. Comprehensive CVRF assessment was defined as recorded measures for blood pressure, cholesterol, and glucose levels; CVRF control as blood pressure lower than 140/90 mm Hg, low-density lipoprotein cholesterol 130 mg/dL, and hemoglobin A1c less than 7%; and CVRF treatment as receipt of cardiac risk-reducing medications. Multivariable risk difference regression assessed the association between ASCVD and initiation of ADT and these outcomes., Results: Of 90 494 veterans, median age was 66 years (interquartile range, 62-70 years); and 22 700 men (25.1%) received ADT. Overall, 68.1% (95% CI, 67.8%-68.3%) of the men received comprehensive CVRF assessment; 54.1% (95% CI. 53.7%-54.4%) of those assessed had uncontrolled CVRFs, and 29.6% (95% CI, 29.2%-30.0%) of those with uncontrolled CVRFs were not receiving corresponding cardiac risk-reducing medication. Compared with the reference group of patients without ASCVD not receiving ADT, patients with ASCVD not receiving ADT had a 10.4% (95% CI, 9.5%-11.3%) higher probability of comprehensive CVRF assessment, 4.0% (95% CI, 2.9%-5.1%) lower risk of uncontrolled CVRFs, and 22.2% (95% CI, 21.1%-23.3%) lower risk of untreated CVRFs. Similar differences were observed in patients with ASCVD receiving ADT. In contrast, patients without ASCVD receiving ADT had only a 3.0% (95% CI, 2.1%-3.9%) higher probability of comprehensive CVRF assessment, 2.6% (95% CI, 1.6%-3.5%) higher risk of uncontrolled CVRFs, and 5.4% (95% CI, 4.2%-6.6%) lower risk of untreated CVRFs., Conclusions and Relevance: These findings suggest that veterans with prostate cancer had a high rate of underassessed and undertreated CVRFs, and ADT initiation was not associated with substantial improvements in CVRF assessment or management. These findings highlight gaps in care and the need for interventions to improve CVRF mitigation in this population.

Background: Approximately 70% to 80% of patients with metastatic nonseminomatous germ cell tumor (NSGCT) treated with cisplatin-based chemotherapy achieve a complete response, defined as normalization of serum tumor markers and either no residual retroperitoneal mass (RRM) or an RRM <1.0 cm. While there is universal agreement that patients with an RRM ≥1.0 cm should undergo retroperitoneal lymph node dissection (RPLND), many institutions including ours recommend surveillance for patients who achieve a complete response. However, studies have not defined which axis of the RRM should be considered when deciding between surveillance and RPLND., Patients and Methods: Good-risk metastatic NSGCT patients treated with cisplatin-based chemotherapy who achieved a complete response and underwent surveillance were identified using our institution's electronic medical records. A post-hoc review was performed by a blinded radiologist. The RRM dimensions in the transaxial short axis (TSA), transaxial long axis (TLA), and craniocaudal axis (CCA) were recorded. Differences in the frequency of recurrence between groups with an RRM <1.0 cm and ≥1.0 cm in the TLA and CCA were assessed using the Fisher exact test., Results: Thirty-nine patients who met study criteria were included. At a median follow-up of 63.8 months, 2 patients (5.1%) recurred. Both were successfully treated with salvage chemotherapy and RPLND. Thirteen (33%) and 27 (69%) patients had an RRM ≥1.0 cm in the TLA and CCA, respectively. There were no statistically significant differences in the risk of recurrence between patients with an RRM <1.0 cm and ≥1.0 cm in the TLA (P = 0.54) or CCA (P = 0.53)., Conclusions: Surveillance is an effective strategy in good-risk NSGCT patients with a postchemotherapy RRM <1.0 cm in the TSA. Our study suggests referencing the TSA and not the TLA or CCA may avoid unnecessary postchemotherapy RPLNDs., (Copyright © 2020 Elsevier Inc. All rights reserved.)

MicroRNAs expressed by germ cell tumors represent a novel approach to detection of metastatic disease during staging, surveillance, and recurrence post-therapy. It has particular promise in settings of equivocal imaging, such as clinical stage I GCT, tumor marker negative stage IIA, or after chemotherapy. These miRNAs have the potential to change typical serum marker evaluation and imaging surveillance schedules.

Purpose: Cisplatin is a first-line chemotherapeutic for many cancers, but causes neurotoxicity including hearing loss, tinnitus, and peripheral sensory neuropathy. However, no study has comprehensively characterized risk factors for developing multiple (>1) severe neurotoxicities., Experimental Design: The relationship between multiple severe neurotoxicities and age, cumulative cisplatin dose, medical history, and lifestyle/behavioral factors was evaluated in 300 cisplatin-treated testicular cancer survivors using logistic regression. Case-control genome-wide association study (GWAS; cases, n = 104 and controls, n = 196) was also performed., Results: Age at clinical examination ( P = 6.4 × 10 -16 ) and cumulative cisplatin dose ( P = 5.4 × 10 -4 ) were positively associated with multiple severe neurotoxicity risk, as were high serum platinum levels ( P = 0.02), tobacco use (ever smoker, P = 0.001 and current smoker, P = 0.002), and hypertension ( P = 0.01) after adjustment for age and cumulative cisplatin dose. Individuals with multiple severe neurotoxicities were more likely to experience dizziness/vertigo ( P = 0.01), Raynaud phenomenon ( P = 3.7 × 10 -9 ), and symptoms consistent with peripheral motor neuropathy ( P = 4.3 × 10 -14 ) after age and dose adjustment. These patients also reported poorer overall health ( P = 2.7 × 10 -5 ) and a greater use of psychotropic medications ( P = 0.06). GWAS identified no genome-wide significant SNPs. Gene-based association analysis identified RGS17 ( P = 3.9 × 10 -5 ) and FAM20C ( P = 5.5 × 10 -5 ) as near genome-wide significant. Decreased FAM20C expression was associated with increased cisplatin sensitivity in tumor cell lines., Conclusions: Certain survivors are more susceptible to cisplatin-induced neurotoxicity, markedly increasing likelihood of developing numerous neuro-otological symptoms that affect quality of life. Genome-wide analysis identified genetic variation in FAM20C as a potentially important risk factor., (©2020 American Association for Cancer Research.)

Background: Testicular germ cell tumor (TGCT) incidence has increased in recent decades along with the use and dose of diagnostic radiation. Here we examine the association between reported exposure to diagnostic radiation and TGCT risk., Methods: We conducted a case-control study of men with and without TGCT recruited from hospital- and population-based settings. Participants reported on exposures to 1) x-ray or CT below the waist and 2) lower GI series or barium enema, which consists of a series of x-rays of the colon. We also derived a combined measure of exposure. We used logistic regression to determine the risk of developing TGCT according to categories of exposures (0, 1-2, or ≥3 exposures) and age at first exposure, adjusting for age, year of birth, race, county, body mass index at diagnosis, family history of TGCT, and personal history of cryptorchidism., Results: There were 315 men with TGCT and 931 men without TGCT in our study. Compared to no exposures, risk of TGCT was significantly elevated among those reporting at least three exposures to x-ray or CT (OR≥3 exposures, 1.78; 95% CI, 1.15-2.76; p = 0.010), lower GI series or barium enema (OR≥3 exposures, 4.58; 95% CI, 2.39-8.76; p<0.001), and the combined exposure variable (OR≥3 exposures, 1.59; 95% CI, 1.05-2.42; p = 0.029). The risk of TGCT was elevated for those exposed to diagnostic radiation at age 0-10 years, compared to those first exposed at age 18 years or later, although this association did not reach statistical significance (OR, 2.00; 95% CI, 0.91-4.42; p = 0.086)., Conclusions: Exposure to diagnostic radiation below the waist may increase TGCT risk. If these results are validated, efforts to reduce diagnostic radiation doses to the testes should be prioritized., Competing Interests: The authors have declared that no competing interests exist.

The cardiovascular consequences of systemic cancer therapies are becoming increasingly important for the growing population of patients living with cancer. In particular, patients with genitourinary malignancies are at significant risk for cardiovascular toxicities, due to both prevalent underlying risk factors and the known adverse effects of commonly used therapies. Moreover, improving survival outcomes and novel combination treatment approaches for genitourinary malignancies may predispose to a growing risk for cardiovascular morbidity. As such, knowledge of these potential cardiovascular risks is essential for the optimal care of these patients. This review highlights the cardiovascular toxicities associated with common therapeutic agents for genitourinary malignancies., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Aim:  Standard first-line treatment of advanced urothelial cell carcinoma involves cisplatin-based chemotherapy, with carboplatin or immune checkpoint inhibitor therapy (ICI) reserved for cisplatin-ineligible individuals. Methods: Using a large de-identified electronic health record-derived database of patients with advanced urothelial cell carcinoma in the USA, we examined trends in utilization of first-line systemic therapies in cisplatin-eligible patients from 1 January 2015 to 31 March 2018. Results: Among 1181 cisplatin-eligible patients, the quarterly proportion who received first-line ICI increased from 1 to 42% (p trend  <0.001), while the proportion who received cisplatin-based chemotherapy decreased from 53 to 33% (p trend  = 0.018). Patients receiving ICI were older than those receiving cisplatin (median age: 75 vs 68). Conclusion: Our analysis suggests rising off-label ICI use in cisplatin-eligible individuals, potentially because of ICI's favorable toxicity profile.

Germ cell tumors (GCTs) are the most common malignancy among young men in the United States. Although prognosis is favorable and response to cisplatin-based chemotherapy regimens is good, 10%-20% of patients with thoracic metastases require surgical management following completion of chemotherapy. Pulmonary metastasectomy (PM) has been employed for GCT patients with lung metastases for several decades. Outcomes have been excellent thus far. However, there have been no randomized controlled trials of PM in GCT and, as new surgical techniques are developed, there is variability in management. This article reviews the existing data on current management of pulmonary metastases in GCT, with attention paid to timing of surgery, surgical approaches, and complications.

Background: Limited data compare first-line carboplatin-based chemotherapy and immune checkpoint blockade in cisplatin-ineligible metastatic urothelial carcinoma (mUC) patients. The primary evidence guiding treatment decisions was a recent Food and Drug Administration/European Medicines Agency safety alert based on emerging data from two ongoing phase III trials, reporting shorter survival in programmed death-ligand 1 (PD-L1)-negative patients receiving immunotherapy. Final results from these trials are unknown., Objective: To compare survival in cisplatin-ineligible mUC patients receiving first-line immunotherapy versus those receiving carboplatin-based chemotherapy., Design, Setting, and Participants: We conducted a retrospective cohort study of 2017 mUC patients receiving first-line carboplatin-based chemotherapy (n = 1530) or immunotherapy (n = 487) from January 1, 2011 to May 18, 2018 using the Flatiron Health electronic health record-derived database., Outcome Measurements and Statistical Analysis: The primary outcomes were overall survival (OS), comparing 12- and 36-mo OS, and hazard ratios before and after 12 mo. Propensity score-based inverse probability of treatment weighting (IPTW) was used to address confounding in Kaplan-Meier and Cox regression model estimates of comparative effectiveness., Results and Limitations: IPTW-adjusted OS rates in the immunotherapy group were lower at 12 mo (39.6% [95% confidence interval {CI} 34.0-45.3%] vs 46.1% [95% CI 43.4-48.8%]) but higher at 36 mo (28.3% [95% CI 21.8-34.7%] vs 13.3% [95% CI 11.1-15.5%]) relative to the chemotherapy group. Immunotherapy treatment demonstrated inferior OS during the first 12 mo relative to carboplatin-based chemotherapy (IPTW-adjusted hazard ratio [HR] 1.37, 95% CI 1.15-1.62), but superior OS beyond 12 mo (IPTW-adjusted HR 0.50, 95% CI 0.30-0.85). Limitations include retrospective design and potential unmeasured confounding., Conclusions: In the setting of mUC, clinicians and patients should carefully consider how to balance the short-term benefit of chemotherapy against the long-term benefit of immunotherapy., Patient Summary: To determine the optimal first-line therapy for metastatic bladder cancer patients who are unfit for cisplatin, we compared carboplatin-based chemotherapy versus immunotherapy using real-world data. Survival in the 1st year of treatment was lower with immunotherapy relative to chemotherapy, but for patients surviving beyond the 1st year, immunotherapy was superior., (Copyright © 2019 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Purpose: Serum platinum is measurable for years after completion of cisplatin-based chemotherapy (CBC). We report the largest investigation of serum platinum levels to date of 1,010 testicular cancer survivors (TCS) assessed 1-35 years after CBC and evaluate genetic contributions to these levels., Experimental Design: Eligible TCS given 300 or 400 (±15) mg/m 2 cisplatin underwent extensive audiometric testing, clinical examination, completed questionnaires, and had crude serum platinum levels measured. Associations between serum platinum and various risk factors and toxicities were assessed after fitting a biexponential model adjusted for follow-up time and cumulative cisplatin dose. A genome-wide association study (GWAS) was performed using the serum platinum residuals of the dose and time-adjusted model., Results: Serum platinum levels exceeded the reference range for approximately 31 years, with a strong inverse relationship with creatinine clearance at follow-up (age-adjusted P = 2.13 × 10 -3 ). We observed a significant, positive association between residual platinum values and luteinizing hormone (age-adjusted P = 6.58 × 10 -3 ). Patients with high residual platinum levels experienced greater Raynaud phenomenon than those with medium or low levels (age-adjusted OR high/low = 1.46; P = 0.04), as well as a higher likelihood of developing tinnitus (age-adjusted OR high/low = 1.68, P = 0.07). GWAS identified one single-nucleotide polymorphism (SNP) meeting genome-wide significance, rs1377817 ( P = 4.6 × 10 -8 , a SNP intronic to MYH14 )., Conclusions: This study indicates that residual platinum values are correlated with several cisplatin-related toxicities. One genetic variant is associated with these levels., (©2019 American Association for Cancer Research.)

Purpose: Cisplatin, a commonly used chemotherapeutic, results in tinnitus, the phantom perception of sound. Our purpose was to identify the clinical and genetic determinants of tinnitus among testicular cancer survivors (TCS) following cisplatin-based chemotherapy., Experimental Design: TCS ( n = 762) were dichotomized to cases (moderate/severe tinnitus; n = 154) and controls (none; n = 608). Logistic regression was used to evaluate associations with comorbidities and SNP dosages in genome-wide association study (GWAS) following quality control and imputation (covariates: age, noise exposure, cisplatin dose, genetic principal components). Pathway over-representation tests and functional studies in mouse auditory cells were performed., Results: Cisplatin-induced tinnitus (CisIT) significantly associated with age at diagnosis ( P = 0.007) and cumulative cisplatin dose ( P = 0.007). CisIT prevalence was not significantly greater in 400 mg/m 2 -treated TCS compared with 300 ( P = 0.41), but doses >400 mg/m 2 (median 580, range 402-828) increased risk by 2.61-fold ( P < 0.0001). CisIT cases had worse hearing at each frequency (0.25-12 kHz, P < 0.0001), and reported more vertigo (OR = 6.47; P < 0.0001) and problems hearing in a crowd (OR = 8.22; P < 0.0001) than controls. Cases reported poorer health ( P < 0.0001) and greater psychotropic medication use (OR = 2.4; P = 0.003). GWAS suggested a variant near OTOS (rs7606353, P = 2 × 10 -6 ) and OTOS eQTLs were significantly enriched independently of that SNP ( P = 0.018). OTOS overexpression in HEI-OC1, a mouse auditory cell line, resulted in resistance to cisplatin-induced cytotoxicity. Pathway analysis implicated potassium ion transport (q = 0.007)., Conclusions: CisIT associated with several neuro-otological symptoms, increased use of psychotropic medication, and poorer health. OTOS , expressed in the cochlear lateral wall, was implicated as protective. Future studies should investigate otoprotective targets in supporting cochlear cells., (©2019 American Association for Cancer Research.)

Background: This study examined the prevalence of hypogonadism, its clinical and genetic risk factors, and its relationship to adverse health outcomes (AHOs) in North American testicular cancer survivors (TCS) after modern platinum-based chemotherapy., Patients and Methods: Eligible TCS were <55 years of age at diagnosis and treated with first-line platinum-based chemotherapy. Participants underwent physical examinations and completed questionnaires regarding 15 AHOs and health behaviors. Hypogonadism was defined as serum testosterone levels ≤3.0 ng/mL or use of testosterone replacement therapy. We investigated the role of 2 single nucleotide polymorphisms (rs6258 and rs12150660) in the sex hormone-binding globulin (SHBG) locus implicated in increased hypogonadism risk in the general population., Results: Of 491 TCS (median age at assessment, 38.2 years; range, 18.7-68.4 years), 38.5% had hypogonadism. Multivariable binary logistic regression analysis identified hypogonadism risk factors, including age at clinical evaluation (odds ratio [OR], 1.42 per 10-year increase; P= .006) and body mass index of 25 to <30 kg/m2 (OR, 2.08; P= .011) or ≥30 kg/m2 (OR, 2.36; P= .005) compared with <25 kg/m2. TCS with ≥2 risk alleles for the SHBG SNPs had a marginally significant increased hypogonadism risk (OR, 1.45; P= .09). Vigorous-intensity physical activity appeared protective (OR, 0.66; P= .07). Type of cisplatin-based chemotherapy regimen and socioeconomic factors did not correlate with hypogonadism. Compared with TCS without hypogonadism, those with hypogonadism were more likely to report ≥2 AHOs (65% vs 51%; P= .003), to take medications for hypercholesterolemia (20.1% vs 6.0%; P<.001) or hypertension (18.5% vs 10.6%; P= .013), and to report erectile dysfunction (19.6% vs 11.9%; P= .018) or peripheral neuropathy (30.7% vs 22.5%; P= .041). A marginally significant trend for increased use of prescription medications for either diabetes (5.8% vs 2.6%; P= .07) or anxiety/depression (14.8% vs 9.3%; P= .06) was observed., Conclusions: At a relatively young median age, more than one-third of TCS have hypogonadism, which is significantly associated with increased cardiovascular disease risk factors, and erectile dysfunction. Providers should screen TCS for hypogonadism and treat symptomatic patients.

Neoadjuvant cisplatin-based chemotherapy (NAC; 70 mg/m 2 ) is standard of care for muscle-invasive bladder carcinoma (MIBC). Many patients (pts) cannot receive cisplatin because of renal impairment, and administration of cisplatin 35 mg/m 2 on day 1 + 8 or 1 + 2 (i.e., split schedule) is a commonly used alternative. In this retrospective analysis, we compared complete (pT0) and partial (

Importance: Approximately 50% of the risk for the development of testicular germ cell tumors (TGCTs) is estimated to be heritable, but no mendelian TGCT predisposition genes have yet been identified. It is hypothesized that inherited pathogenic DNA repair gene (DRG) alterations may drive susceptibility to TGCTs., Objective: To systematically evaluate the enrichment of germline pathogenic variants in the mendelian cancer predisposition DRGs in patients with TGCTs vs healthy controls., Design, Setting, and Participants: A case-control enrichment analysis was performed from January 2016 to May 2018 to screen for 48 DRGs in 205 unselected men with TGCT and 27 173 ancestry-matched cancer-free individuals from the Exome Aggregation Consortium cohort in the discovery stage. Significant findings were selectively replicated in independent cohorts of 448 unselected men with TGCTs and 442 population-matched controls, as well as 231 high-risk men with TGCTs and 3090 ancestry-matched controls. Statistical analysis took place from January to May 2018., Main Outcomes and Measures: Gene-level enrichment analysis of germline pathogenic variants in individuals with TGCTs relative to cancer-free controls., Results: Among 205 unselected men with TGCTs (mean [SD] age, 33.04 [9.67] years), 22 pathogenic germline DRG variants, one-third of which were in CHEK2 (OMIM 604373), were identified in 20 men (9.8%; 95% CI, 6.1%-14.7%). Unselected men with TGCTs were approximately 4 times more likely to carry germline loss-of-function CHEK2 variants compared with cancer-free individuals from the Exome Aggregation Consortium cohort (odds ratio [OR], 3.87; 95% CI, 1.65-8.86; nominal P = .006; q = 0.018). Similar enrichment was also seen in an independent cohort of 448 unselected Croatian men with TGCTs (mean [SD] age, 31.98 [8.11] years) vs 442 unselected Croatian men without TGCTs (at least 50 years of age at time of sample collection) (OR, >1.4; P = .03) and 231 high-risk men with TGCTs (mean [SD] age, 31.54 [9.24] years) vs 3090 men (all older than 50 years) from the Penn Medicine Biobank (OR, 6.30; 95% CI, 2.34-17.31; P = .001). The low-penetrance CHEK2 variant (p.Ile157Thr) was found to be a Croatian founder TGCT risk variant (OR, 3.93; 95% CI, 1.53-9.95; P = .002). Individuals with the pathogenic CHEK2 loss-of-function variants developed TGCTs 6 years earlier than individuals with CHEK2 wild-type alleles (5.95 years; 95% CI, 1.48-10.42; P = .009)., Conclusions and Relevance: This multicenter case-control analysis of men with or without TGCTs provides evidence for CHEK2 as a novel moderate-penetrance TGCT susceptibility gene, with potential clinical utility. In addition to highlighting DNA-repair deficiency as a potential mechanism driving TGCT susceptibility, this analysis also provides new avenues to explore management strategies and biological investigations for high-risk individuals.

Background: Testicular cancer survivors (TCSs) are at increased risk of cardiovascular disease (CVD) after cisplatin-based chemotherapy (CBCT). Identifying at-risk survivors would allow early intervention, but risk prediction tools such as the Framingham Risk Score (FRS) have not been applied to TCSs given modern chemotherapy., Methods: TCSs > 1 year post-CBCT were evaluated. Associations between FRS and clinical, socioeconomic, and lifestyle measures and treatment regimen (4 cycles, etoposide and cisplatin [EP × 4]); 3 or 4 cycles, bleomycin plus EP (BEP × 3, BEP × 4) were analyzed with general linear multivariable models. Controls from the National Health and Nutrition Examination Survey were matched 1:1 to TCSs by age, race, and education with differences in mean FRS evaluated with 2-sided t tests., Results: Of 787 TCSs (median age, 37.3 years; median follow-up, 4.2 years), 284, 342, and 161 received EP × 4, BEP × 3, or BEP × 4, respectively. TCSs had higher median systolic blood pressure (126 vs. 119 mm Hg; P < .001), but fewer were smokers (8.4% vs. 28.2%; P < .001) than controls. In multivariable analysis, no significant differences in FRS between EP × 4, BEP × 3, and BEP × 4 were observed, but less than college education (P < .001) and lack of vigorous exercise (P = .006) were associated with higher FRS. Mean FRS did not differ between TCSs and controls (6.8% vs. 7.3%; P = .67)., Conclusion: This is the first study to apply the office-based FRS to TCSs. Chemotherapy regimen (BEP × 3 vs. EP × 4) was not associated with FRS, but less educated and less vigorously active patients had higher FRS, and present a high-risk subgroup for intense follow-up and counseling., (Copyright © 2018 Elsevier Inc. All rights reserved.)

BGJ398, a potent and selective pan-FGFR antagonist, was prospectively evaluated in patients with metastatic urothelial carcinoma bearing a diverse array of FGFR3 alterations. Patients ( N = 67) who were unable to receive platinum chemotherapy were enrolled. The majority (70.1%) had received two or more prior antineoplastic therapies. BGJ398 was administered orally at 125 mg/day on a 3 weeks on, 1 week off schedule until unacceptable toxicity or progression. The primary endpoint was the response rate. Among 67 patients treated, an overall response rate of 25.4% was observed and an additional 38.8% of patients had disease stabilization, translating to a disease control rate of 64.2%. The most common treatment-emergent toxicities were hyperphosphatemia, elevated creatinine, fatigue, constipation, and decreased appetite. Further examination of BGJ398 in this disease setting is warranted. Significance: BJG398 is active in patients with alterations in FGFR3 , resulting in both reductions in tumor volume and stabilization of disease. Our data highlight putative mechanisms of resistance to the agent, which may be useful in following disease status. Cancer Discov; 8(7); 812-21. ©2018 AACR. This article is highlighted in the In This Issue feature, p. 781 ., (©2018 American Association for Cancer Research.)