Publications by authors named "David J Vaughn"

109 Publications

Identification of 22 susceptibility loci associated with testicular germ cell tumors.

Nat Commun 2021 07 23;12(1):4487. Epub 2021 Jul 23.

Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

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 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.
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http://dx.doi.org/10.1038/s41467-021-24334-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8302763PMC
July 2021

Use of Medications for Treating Anxiety or Depression among Testicular Cancer Survivors: A Multi-Institutional Study.

Cancer Epidemiol Biomarkers Prev 2021 06 13;30(6):1129-1138. Epub 2021 Apr 13.

Indiana University, Indianapolis, Indiana.

Background: This study examined sociodemographic factors, cisplatin-related adverse health outcomes (AHO), and cumulative burden of morbidity (CBM) 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 score encompassed the number and severity of cisplatin-related AHOs. Multivariable logistic regression models assessed the relationship of individual AHOs and CBM 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 scores. In the multivariable model, higher CBM scores were significantly associated with medication use for anxiety and/or depression ( < 0.0001). In addition, tinnitus ( = 0.0009), PSN ( = 0.02), and having health insurance ( = 0.05) were significantly associated with greater use of these medications, whereas being employed ( = 0.0005) and vigorous physical activity ( = 0.01) were significantly associated with diminished use.

Conclusions: TCS with higher CBM 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.
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http://dx.doi.org/10.1158/1055-9965.EPI-20-1762DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8172470PMC
June 2021

Predicting Outcomes in Men With Metastatic Nonseminomatous Germ Cell Tumors (NSGCT): Results From the IGCCCG Update Consortium.

J Clin Oncol 2021 05 6;39(14):1563-1574. Epub 2021 Apr 6.

St Bartholomew's Hospital, London, United Kingdom.

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.
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http://dx.doi.org/10.1200/JCO.20.03296DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8099402PMC
May 2021

Survival and New Prognosticators in Metastatic Seminoma: Results From the IGCCCG-Update Consortium.

J Clin Oncol 2021 05 17;39(14):1553-1562. Epub 2021 Mar 17.

Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy. Current affiliation: Vita-Salute San Raffaele University and IRCCS San Raffaele Hospital and Scientific Institute, Milan, Italy.

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.
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http://dx.doi.org/10.1200/JCO.20.03292DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8099394PMC
May 2021

Assessment and Management of Cardiovascular Risk Factors Among US Veterans With Prostate Cancer.

JAMA Netw Open 2021 02 1;4(2):e210070. Epub 2021 Feb 1.

Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia.

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.
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http://dx.doi.org/10.1001/jamanetworkopen.2021.0070DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7905496PMC
February 2021

Surveillance of postchemotherapy subcentimeter residual retroperitoneal mass in metastatic nonseminomatous germ cell tumor: Does how you measure matter?

Urol Oncol 2021 02 8;39(2):136.e11-136.e17. Epub 2020 Dec 8.

Division of Hematology/Oncology, University of Pennsylvania, Philadelphia, PA. Electronic address:

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.
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http://dx.doi.org/10.1016/j.urolonc.2020.11.026DOI Listing
February 2021

Lower abdominal and pelvic radiation and testicular germ cell tumor risk.

PLoS One 2020 11;15(11):e0239321. Epub 2020 Nov 11.

Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, United States of America.

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.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0239321PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7657535PMC
December 2020

Blood-based gene expression signature associated with metastatic castrate-resistant prostate cancer patient response to abiraterone plus prednisone or enzalutamide.

Prostate Cancer Prostatic Dis 2021 06 2;24(2):448-456. Epub 2020 Oct 2.

Division of Hematology/Oncology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.

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.
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http://dx.doi.org/10.1038/s41391-020-00295-zDOI Listing
June 2021

Clinical and Genome-Wide Analysis of Multiple Severe Cisplatin-Induced Neurotoxicities in Adult-Onset Cancer Survivors.

Clin Cancer Res 2020 12 30;26(24):6550-6558. Epub 2020 Sep 30.

Department of Medicine, University of Chicago, Chicago, Illinois.

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, = 104 and controls, = 196) was also performed.

Results: Age at clinical examination ( = 6.4 × 10) and cumulative cisplatin dose ( = 5.4 × 10) were positively associated with multiple severe neurotoxicity risk, as were high serum platinum levels ( = 0.02), tobacco use (ever smoker, = 0.001 and current smoker, = 0.002), and hypertension ( = 0.01) after adjustment for age and cumulative cisplatin dose. Individuals with multiple severe neurotoxicities were more likely to experience dizziness/vertigo ( = 0.01), Raynaud phenomenon ( = 3.7 × 10), and symptoms consistent with peripheral motor neuropathy ( = 4.3 × 10) after age and dose adjustment. These patients also reported poorer overall health ( = 2.7 × 10) and a greater use of psychotropic medications ( = 0.06). GWAS identified no genome-wide significant SNPs. Gene-based association analysis identified ( = 3.9 × 10) and ( = 5.5 × 10) as near genome-wide significant. Decreased 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 as a potentially important risk factor.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-2682DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7744329PMC
December 2020

What radiologists should know about microRNA (miRNA) serum biomarkers for germ cell tumors.

Abdom Radiol (NY) 2021 02 17;46(2):745-748. Epub 2020 Aug 17.

Division of Hematology/Oncology, Hospital of the University of Pennsylvania, University of Pennsylvania Health System, 3400 Spruce St, Philadelphia, PA, USA.

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.
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http://dx.doi.org/10.1007/s00261-020-02703-3DOI Listing
February 2021

First-line immune checkpoint inhibitor use in cisplatin-eligible patients with advanced urothelial carcinoma: a secular trend analysis.

Future Oncol 2020 Jan 16;16(2):4341-4345. Epub 2019 Dec 16.

Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.

 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. 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. Among 1181 cisplatin-eligible patients, the quarterly proportion who received first-line ICI increased from 1 to 42% (p <0.001), while the proportion who received cisplatin-based chemotherapy decreased from 53 to 33% (p = 0.018). Patients receiving ICI were older than those receiving cisplatin (median age: 75 vs 68). Our analysis suggests rising off-label ICI use in cisplatin-eligible individuals, potentially because of ICI's favorable toxicity profile.
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http://dx.doi.org/10.2217/fon-2019-0578DOI Listing
January 2020

Pulmonary Metastasectomy for Germ Cell Tumors.

Ann Thorac Cardiovasc Surg 2019 Dec 13;25(6):289-295. Epub 2019 Nov 13.

Divison of Thoracic Surgery, Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.

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.
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http://dx.doi.org/10.5761/atcs.ra.19-00070DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6923721PMC
December 2019

Effectiveness of First-line Immune Checkpoint Blockade Versus Carboplatin-based Chemotherapy for Metastatic Urothelial Cancer.

Eur Urol 2019 10 28;76(4):524-532. Epub 2019 Jul 28.

Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA.

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.
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http://dx.doi.org/10.1016/j.eururo.2019.07.032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6822167PMC
October 2019

Clinical and Genome-Wide Analysis of Serum Platinum Levels after Cisplatin-Based Chemotherapy.

Clin Cancer Res 2019 10 11;25(19):5913-5924. Epub 2019 Jul 11.

Department of Medicine, University of Chicago, Chicago, Illinois.

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 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 = 2.13 × 10). We observed a significant, positive association between residual platinum values and luteinizing hormone (age-adjusted = 6.58 × 10). Patients with high residual platinum levels experienced greater Raynaud phenomenon than those with medium or low levels (age-adjusted OR = 1.46; = 0.04), as well as a higher likelihood of developing tinnitus (age-adjusted OR = 1.68, = 0.07). GWAS identified one single-nucleotide polymorphism (SNP) meeting genome-wide significance, rs1377817 ( = 4.6 × 10, a SNP intronic to ).

Conclusions: This study indicates that residual platinum values are correlated with several cisplatin-related toxicities. One genetic variant is associated with these levels.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-0113DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6774840PMC
October 2019

Cardiovascular toxicities of therapy for genitourinary malignancies.

Urol Oncol 2020 03 16;38(3):121-128. Epub 2019 May 16.

Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA; Division of Cardiology, Department of Medicine, University of Pennsylvania, Philadelphia, PA.

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.
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http://dx.doi.org/10.1016/j.urolonc.2019.04.029DOI Listing
March 2020

Adverse Health Outcomes in Relationship to Hypogonadism After Chemotherapy: A Multicenter Study of Testicular Cancer Survivors.

J Natl Compr Canc Netw 2019 05;17(5):459-468

Indiana University, Melvin and Bren Simon Cancer Center, Indianapolis, Indiana.

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.
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http://dx.doi.org/10.6004/jnccn.2018.7109DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6712564PMC
May 2019

Clinical and Genome-wide Analysis of Cisplatin-induced Tinnitus Implicates Novel Ototoxic Mechanisms.

Clin Cancer Res 2019 07 5;25(13):4104-4116. Epub 2019 Apr 5.

Department of Medicine, University of Chicago, Chicago, Illinois.

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 ( = 762) were dichotomized to cases (moderate/severe tinnitus; = 154) and controls (none; = 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 ( = 0.007) and cumulative cisplatin dose ( = 0.007). CisIT prevalence was not significantly greater in 400 mg/m-treated TCS compared with 300 ( = 0.41), but doses >400 mg/m (median 580, range 402-828) increased risk by 2.61-fold ( < 0.0001). CisIT cases had worse hearing at each frequency (0.25-12 kHz, < 0.0001), and reported more vertigo (OR = 6.47; < 0.0001) and problems hearing in a crowd (OR = 8.22; < 0.0001) than controls. Cases reported poorer health ( < 0.0001) and greater psychotropic medication use (OR = 2.4; = 0.003). GWAS suggested a variant near (rs7606353, = 2 × 10) and eQTLs were significantly enriched independently of that SNP ( = 0.018). 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. , expressed in the cochlear lateral wall, was implicated as protective. Future studies should investigate otoprotective targets in supporting cochlear cells.
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http://dx.doi.org/10.1158/1078-0432.CCR-18-3179DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6903403PMC
July 2019

Efficacy of Split Schedule Versus Conventional Schedule Neoadjuvant Cisplatin-Based Chemotherapy for Muscle-Invasive Bladder Cancer.

Oncologist 2019 05 6;24(5):688-690. Epub 2019 Feb 6.

Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania, USA

Neoadjuvant cisplatin-based chemotherapy (NAC; 70 mg/m) 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 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 (
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http://dx.doi.org/10.1634/theoncologist.2018-0561DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6516116PMC
May 2019

Association of Inherited Pathogenic Variants in Checkpoint Kinase 2 (CHEK2) With Susceptibility to Testicular Germ Cell Tumors.

JAMA Oncol 2019 Apr;5(4):514-522

Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

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.
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http://dx.doi.org/10.1001/jamaoncol.2018.6477DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6459214PMC
April 2019

Efficacy of BGJ398, a Fibroblast Growth Factor Receptor 1-3 Inhibitor, in Patients with Previously Treated Advanced Urothelial Carcinoma with Alterations.

Cancer Discov 2018 07 30;8(7):812-821. Epub 2018 May 30.

Novartis Pharmaceuticals Corporation, East Hanover, New Jersey.

BGJ398, a potent and selective pan-FGFR antagonist, was prospectively evaluated in patients with metastatic urothelial carcinoma bearing a diverse array of alterations. Patients ( = 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. BJG398 is active in patients with alterations in , 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. .
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http://dx.doi.org/10.1158/2159-8290.CD-18-0229DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6716598PMC
July 2018

Cumulative Burden of Morbidity Among Testicular Cancer Survivors After Standard Cisplatin-Based Chemotherapy: A Multi-Institutional Study.

J Clin Oncol 2018 05 4;36(15):1505-1512. Epub 2018 Apr 4.

Sarah L. Kerns, Chunkit Fung, AnnaLynn M. Williams, and Deepak M. Sahasrabudhe, University of Rochester Medical Center, Rochester; Darren R. Feldman, Memorial Sloan Kettering Cancer Center, New York, NY; Patrick O. Monahan, Shirin Ardeshir-Rouhani-Fard, Mohammad I. Abu Zaid, Timothy E. Stump, Ryan Cook, Lawrence H. Einhorn, and Lois B. Travis, Indiana University, Indianapolis, IN; Howard D. Sesso, Brigham and Women's Hospital; Clair Beard, Dana-Farber Cancer Institute, Boston, MA; Robert J. Hamilton, Princess Margaret Cancer Centre, Toronto, Ontario; Christian Kollmannsberger, University of British Columbia, Vancouver, British Columbia, Canada; David J. Vaughn, University of Pennsylvania, Philadelphia, PA; Robert A. Huddart, The Royal Marsden Hospital, London, United Kingdom; Jeri Kim, MD Anderson Cancer Center, Houston, TX; and Sophie D. Fossa, Oslo University Hospital, Oslo, Norway.

Purpose In this multicenter study, we evaluated the cumulative burden of morbidity (CBM) among > 1,200 testicular cancer survivors and applied factor analysis to determine the co-occurrence of adverse health outcomes (AHOs). Patients and Methods Participants were ≤ 55 years of age at diagnosis, finished first-line chemotherapy ≥ 1 year previously, completed a comprehensive questionnaire, and underwent physical examination. Treatment data were abstracted from medical records. A CBM score encompassed the number and severity of AHOs, with ordinal logistic regression used to assess associations with exposures. Nonlinear factor analysis and the nonparametric dimensionality evaluation to enumerate contributing traits procedure determined which AHOs co-occurred. Results Among 1,214 participants, approximately 20% had a high (15%) or very high/severe (4.1%) CBM score, whereas approximately 80% scored medium (30%) or low/very low (47%). Increased risks of higher scores were associated with four cycles of either ifosfamide, etoposide, and cisplatin (odds ratio [OR], 1.96; 95% CI, 1.04 to 3.71) or bleomycin, etoposide, and cisplatin (OR, 1.44; 95% CI, 1.04 to 1.98), older attained age (OR, 1.18; 95% CI, 1.10 to 1.26), current disability leave (OR, 3.53; 95% CI, 1.57 to 7.95), less than a college education (OR, 1.44; 95% CI, 1.11 to 1.87), and current or former smoking (OR, 1.28; 95% CI, 1.02 to 1.63). CBM score did not differ after either chemotherapy regimen ( P = .36). Asian race (OR, 0.41; 95% CI, 0.23 to 0.72) and vigorous exercise (OR, 0.68; 95% CI, 0.52 to 0.89) were protective. Variable clustering analyses identified six significant AHO clusters (χ P < .001): hearing loss/damage, tinnitus (OR, 16.3); hyperlipidemia, hypertension, diabetes (OR, 9.8); neuropathy, pain, Raynaud phenomenon (OR, 5.5); cardiovascular and related conditions (OR, 5.0); thyroid disease, erectile dysfunction (OR, 4.2); and depression/anxiety, hypogonadism (OR, 2.8). Conclusion Factors associated with higher CBM may identify testicular cancer survivors in need of closer monitoring. If confirmed, identified AHO clusters could guide the development of survivorship care strategies.
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http://dx.doi.org/10.1200/JCO.2017.77.0735DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5959198PMC
May 2018

Health-Related Quality-of-Life Analysis From KEYNOTE-045: A Phase III Study of Pembrolizumab Versus Chemotherapy for Previously Treated Advanced Urothelial Cancer.

J Clin Oncol 2018 06 28;36(16):1579-1587. Epub 2018 Mar 28.

David J. Vaughn, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA; Joaquim Bellmunt and Toni K. Choueiri, Dana-Farber Cancer Institute, Boston, MA; Yves Fradet, CHU de Québec-Université Laval, Quebec City, Quebec, Canada; Jae Lyun Lee, Asan Medical Center and University of Ulsan College of Medicine, Seoul, Republic of Korea; Lawrence Fong, University of California, San Francisco, San Francisco; David I. Quinn, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA; Nicholas J. Vogelzang, Comprehensive Cancer Centers of Nevada, Las Vegas, NV; Miguel A. Climent, Fundación Instituto Valenciano de Oncología, Valencia, Spain; Daniel P. Petrylak, Smilow Cancer Hospital, Yale University, New Haven, CT; Andrea Necchi, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico Istituto Nazionale dei Tumori, Milan; Cora N. Sternberg, San Camillo and Forlanini Hospitals, Rome, Italy; Winald Gerritsen, Radboud University Medical Center, Nijmegen; Ronald de Wit, Erasmus University Medical Center Cancer Institute, Rotterdam, the Netherlands; Howard Gurney, Westmead Hospital and Macquarie University, Sydney, New South Wales, Australia; Stephane Culine, Hôpital Saint-Louis, Paris, France; Yabing Mai, Haojie Li, and Rodolfo F. Perini, Merk & Co., Inc., Kenilworth, NJ; and Dean F. Bajorin, Memorial Sloan Kettering Cancer Center, New York, NY.

Purpose In the phase III KEYNOTE-045 study ( ClinicalTrials.gov identifier: NCT02256436), pembrolizumab significantly prolonged overall survival compared with investigator's choice of chemotherapy in patients with previously treated advanced urothelial cancer. Here, we report the results of health-related quality-of-life (HRQoL) analyses from the KEYNOTE-045 trial. Patients and Methods Patients were randomly assigned 1:1 to pembrolizumab 200 mg or investigator's choice of docetaxel 75 mg/m, paclitaxel 175 mg/m, or vinflunine 320 mg/m administered intravenously every 3 weeks. Key prespecified HRQoL analyses were time to deterioration (TTD) and mean change from baseline to week 15 in European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30 global health status/quality-of-life score. Results Of 542 patients who were randomly assigned, 519 were included in HRQoL analyses (pembrolizumab, n = 266; chemotherapy, n = 253). HRQoL compliance was > 95% at baseline and approximately 88% at week 15 for both groups. Pembrolizumab prolonged TTD in global health status/quality-of-life score compared with chemotherapy (median, 3.5 months v 2.3 months; hazard ratio, 0.72; nominal one-sided P = .004). Mean (95% CI) change from baseline to week 15 in global health status/quality-of-life score was 0.69 (-2.40 to 3.77) with pembrolizumab and -8.36 (-11.84 to -4.89) with chemotherapy (mean difference, 9.05 points; 95% CI, 4.61 to 13.50; nominal two-sided P < .001). Conclusion Pembrolizumab prolonged TTD in HRQoL compared with chemotherapy. Patients who were treated with pembrolizumab had stable or improved global health status/quality of life, whereas those who were treated with investigator's choice of chemotherapy experienced declines in global health status/quality of life. Combined with efficacy and safety outcomes, these data support pembrolizumab as standard of care for patients with platinum-refractory advanced urothelial cancer.
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http://dx.doi.org/10.1200/JCO.2017.76.9562DOI Listing
June 2018

Predicting Cardiovascular Disease Among Testicular Cancer Survivors After Modern Cisplatin-based Chemotherapy: Application of the Framingham Risk Score.

Clin Genitourin Cancer 2018 08 5;16(4):e761-e769. Epub 2018 Feb 5.

Department of Oncology, Oslo University Hospital Radium Hospital, and Oslo University, Faculty of Medicine Oslo, Norway.

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.
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http://dx.doi.org/10.1016/j.clgc.2018.01.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6063791PMC
August 2018

Clinical and Genetic Risk Factors for Adverse Metabolic Outcomes in North American Testicular Cancer Survivors.

J Natl Compr Canc Netw 2018 03;16(3):257-265

Testicular cancer survivors (TCS) are at significantly increased risk for cardiovascular disease (CVD), with metabolic syndrome (MetS) an established risk factor. No study has addressed clinical and genetic MetS risk factors in North American TCS. TCS were aged <55 years at diagnosis and received first-line chemotherapy. Patients underwent physical examination, and had lipid panels, testosterone, and soluble cell adhesion molecule-1 (sICAM-1) evaluated. A single nucleotide polymorphism in rs523349 (5-α-reductase gene, ), recently implicated in MetS risk, was genotyped. Using standard criteria, MetS was defined as ≥3 of the following: hypertension, abdominal obesity, hypertriglyceridemia, decreased high-density lipoprotein (HDL) cholesterol level, and diabetes. Matched controls were derived from the National Health and Nutrition Examination Survey. We evaluated 486 TCS (median age, 38.1 years). TCS had a higher prevalence of hypertension versus controls (43.2% vs 30.7%; <.001) but were less likely to have decreased HDL levels (23.7% vs 34.8%; <.001) or abdominal obesity (28.2% vs 40.1%; <.001). Overall MetS frequency was similar in TCS and controls (21.0% vs 22.4%; =.59), did not differ by treatment (=.20), and was not related to rs523349 (=.61). For other CVD risk factors, TCS were significantly more likely to have elevated low-density lipoprotein (LDL) cholesterol levels (17.7% vs 9.3%; <.001), total cholesterol levels (26.3% vs 11.1%; <.001), and body mass index ≥25 kg/m (75.1% vs 69.1%; =.04). On multivariate analysis, age at evaluation (<.001), testosterone level ≤3.0 ng/mL (odds ratio [OR], 2.06; =.005), and elevated sICAM-1 level (OR, 3.58; =.001) were significantly associated with MetS. Metabolic abnormalities in TCS are characterized by hypertension and increased LDL and total cholesterol levels but lower rates of decreased HDL levels and abdominal obesity, signifying possible shifts in fat distribution and fat metabolism. These changes are accompanied by hypogonadism and inflammation. TCS have a high prevalence of CVD risk factors that may not be entirely captured by standard MetS criteria. Cancer treatment-associated MetS requires further characterization.
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http://dx.doi.org/10.6004/jnccn.2017.7046DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6345519PMC
March 2018

Phase 2 Study of Weekly Paclitaxel Plus Estramustine in Metastatic Hormone-Refractory Prostate Carcinoma: ECOG-ACRIN Cancer Research Group (E1898) Trial.

Clin Genitourin Cancer 2018 04 16;16(2):e315-e322. Epub 2017 Oct 16.

University of Wisconsin Carbone Cancer Center, Madison, WI.

Introduction: This multicenter phase 2 study assessed the combination of estramustine and weekly paclitaxel with metastatic castration-resistant prostate cancer (CRPC).

Patients And Methods: We enrolled 77 patients who had received no prior chemotherapy for CRPC between 1998 and 2000; a total of 74 subjects were eligible for the study. Each 8-week cycle included paclitaxel 90 mg/m provided intravenously weekly for 6 weeks, followed by 2 weeks off therapy and oral estramustine 280 mg twice daily for 3 days beginning 24 hours before the first dose of paclitaxel. The primary end point was rate of objective or prostate-specific antigen (PSA) response at 16 weeks. A 50% response rate was considered of further interest.

Results: Eligible patients received a median of 3 cycles (range, 1-10 cycles). The response rate among patients with measurable disease was 34% (95% confidence interval [CI], 19-52). The PSA response rate was 58% (95% CI, 47-70). Clinical benefit rate was 45% (95% CI, 33-57). The median progression-free survival was 5.9 months (95% CI, 4.4-6.7). The median overall survival was 17.6 months (95% CI, 14.6-20.8). The most common clinical grade 3/4 toxicities were fatigue (14%) and sensory neuropathy (7%). Grade 3/4 hematologic toxicities included lymphopenia (21%) and anemia (9%). There was one toxicity-related death. Quality-of-life scores improved by week 8, but the change was not statistically significant.

Conclusion: The combination has activity defined by PSA declines in CRPC but did not meet the protocol-specified end point for efficacy as defined by objective response rate. Since this study was conducted, more effective, better-tolerated regimens have been developed.
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http://dx.doi.org/10.1016/j.clgc.2017.10.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5975965PMC
April 2018

Clinical and Genome-Wide Analysis of Cisplatin-Induced Peripheral Neuropathy in Survivors of Adult-Onset Cancer.

Clin Cancer Res 2017 Oct 13;23(19):5757-5768. Epub 2017 Jun 13.

Department of Medical Oncology, Indiana University, Indianapolis, Indiana.

Our purpose was to characterize the clinical influences, genetic risk factors, and gene mechanisms contributing to persistent cisplatin-induced peripheral neuropathy (CisIPN) in testicular cancer survivors (TCSs). TCS given cisplatin-based therapy completed the validated EORTC QLQ-CIPN20 questionnaire. An ordinal CisIPN phenotype was derived, and associations with age, smoking, excess drinking, hypertension, body mass index, diabetes, hypercholesterolemia, cumulative cisplatin dose, and self-reported health were examined for 680 TCS. Genotyping was performed on the Illumina HumanOmniExpressExome chip. Following quality control and imputation, 5.1 million SNPs in 680 genetically European TCS formed the input set. GWAS and PrediXcan were used to identify genetic variation and genetically determined gene expression traits, respectively, contributing to CisIPN. We evaluated two independent datasets for replication: Vanderbilt's electronic health database (BioVU) and the CALGB 90401 trial. Eight sensory items formed a subscale with good internal consistency (Cronbach α = 0.88). Variables significantly associated with CisIPN included age at diagnosis (OR per year, 1.06; = 2 × 10), smoking (OR, 1.54; = 0.004), excess drinking (OR, 1.83; = 0.007), and hypertension (OR, 1.61; = 0.03). CisIPN was correlated with lower self-reported health (OR, 0.56; = 2.6 × 10) and weight gain adjusted for years since treatment (OR per Δkg/m, 1.05; = 0.004). PrediXcan identified lower expressions of and and higher expression as associated with CisIPN ( value for each < 5 × 10) with replication of meeting significance criteria (Fisher combined = 0.0089). CisIPN is associated with age, modifiable risk factors, and genetically determined expression level of Further study of implicated genes could elucidate the pathophysiologic underpinnings of CisIPN. .
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http://dx.doi.org/10.1158/1078-0432.CCR-16-3224DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5626588PMC
October 2017

Bilateral Lung Transplantation for Bleomycin-Associated Lung Injury.

Oncologist 2017 05 30;22(5):620-622. Epub 2017 Mar 30.

Division of Hematology/Oncology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA

This report details the successful use of bilateral lung transplantation for the management of severe postoperative bleomycin-associated lung injury. This case highlights that the extremely favorable prognosis of advanced testicular germ cell tumors after systemic chemotherapy (>90% cure rate) should not preclude lung transplant consideration in all cases, despite current guidance that considers an advanced malignancy to be a contraindication for lung transplant listing. 2017;22:620-622.
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http://dx.doi.org/10.1634/theoncologist.2016-0437DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5423508PMC
May 2017

Multi-Institutional Assessment of Adverse Health Outcomes Among North American Testicular Cancer Survivors After Modern Cisplatin-Based Chemotherapy.

J Clin Oncol 2017 Apr 27;35(11):1211-1222. Epub 2017 Feb 27.

Chunkit Fung, Annalynn M. Williams, and Sarah L. Kerns, University of Rochester Medical Center, James P. Wilmot Cancer Institute, Rochester; Darren R. Feldman, Memorial Sloan Kettering Cancer Center, New York, NY; Howard D. Sesso, Brigham and Women's Hospital; Clair J. Beard, Dana-Farber Cancer Institute, Boston, MA; Patrick Monahan, Mohammad Abu Zaid, Ryan Cook, Sandra Althouse, Shirin Ardeshir-Rouhani-Fard, Lawrence H. Einhorn, and Lois B. Travis, Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, IN; Robert J. Hamilton, Princess Margaret Cancer Center, Toronto, Ontario; Christian K. Kollmannsberger, University of British Columbia, Vancouver, British Columbia, Canada; David J. Vaughn, University of Pennsylvania, Philadelphia, PA; Steve E. Lipshultz, Wayne State University School of Medicine; Steve E. Lipshultz, Children's Hospital of Michigan; Steve E. Lipshultz, Karmanos Cancer Institute, Detroit, MI; and Sophie D. Fossa, Oslo University Hospital, Radium Hospital, Oslo, Norway.

Purpose To provide new information on adverse health outcomes (AHOs) in testicular cancer survivors (TCSs) after four cycles of etoposide and cisplatin (EPX4) or three or four cycles of bleomycin, etoposide, cisplatin (BEPX3/BEPX4). Methods Nine hundred fifty-two TCSs > 1 year postchemotherapy underwent physical examination and completed a questionnaire. Multinomial logistic regression estimated AHOs odds ratios (ORs) in relation to age, cumulative cisplatin and/or bleomycin dose, time since chemotherapy, sociodemographic factors, and health behaviors. Results Median age at evaluation was 37 years; median time since chemotherapy was 4.3 years. Chemotherapy consisted largely of BEPX3 (38.2%), EPX4 (30.9%), and BEPX4 (17.9%). None, one to two, three to four, or five or more AHOs were reported by 20.4%, 42.0%, 25.1%, and 12.5% of TCSs, respectively. Median number after EPX4 or BEPX3 was two (range, zero to nine and zero to 11, respectively; P > .05) and two (range, zero to 10) after BEPX4. When comparing individual AHOs for EPX4 versus BEPX3, Raynaud phenomenon (11.6% v 21.4%; P < .01), peripheral neuropathy (29.2% v 21.4%; P = .02), and obesity (25.5% v 33.0%; P = .04) differed. Larger cumulative bleomycin doses (OR, 1.44 per 90,000 IU) were significantly associated with five or more AHOs. Increasing age was a significant risk factor for one to two, three to four, or five or more AHOs versus zero AHOs (OR, 1.22, 1.50, and 1.87 per 5 years, respectively; P < .01); vigorous physical activity was protective (OR, 0.62, 0.51, and 0.41, respectively; P < .05). Significant risk factors for three to four and five or more AHOs included current (OR, 3.05 and 3.73) or former (OR, 1.61 and 1.76) smoking ( P < .05). Self-reported health was excellent/very good in 59.9% of TCSs but decreased as AHOs increased ( P < .001). Conclusion Numbers of AHOs after EPX4 or BEPX3 appear similar, with median follow-up of 4.3 years. A healthy lifestyle was associated with reduced number of AHOs.
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http://dx.doi.org/10.1200/JCO.2016.70.3108DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5455601PMC
April 2017

Pembrolizumab as Second-Line Therapy for Advanced Urothelial Carcinoma.

N Engl J Med 2017 03 17;376(11):1015-1026. Epub 2017 Feb 17.

From Dana-Farber Cancer Institute, Boston (J.B., T.K.C.); Parc de Salut Mar, Hospital del Mar Medical Research Institute, Barcelona (J.B.), and Fundación Instituto Valenciano de Oncología, Valencia (M.A.C.) - both in Spain; Erasmus MC Cancer Institute, Rotterdam (R.W.), and Radboud University Medical Center, Nijmegen (W.G.) - both in the Netherlands; Abramson Cancer Center, University of Pennsylvania, Philadelphia (D.J.V.); Centre Hospitalier Universitaire de Québec-Université Laval, Quebec, QC, Canada (Y.F.); Asan Medical Center and University of Ulsan College of Medicine, Seoul, South Korea (J.-L.L.); the University of California, San Francisco, San Francisco (L.F.); Comprehensive Cancer Centers of Nevada, Las Vegas (N.J.V.); Smilow Cancer Hospital, Yale University, New Haven, CT (D.P.P.); Fondazione IRCCS Istituto Nazionale dei Tumori, Milan (A.N.); Westmead Hospital and Macquarie University, Sydney (H.G.); the University of Southern California Norris Comprehensive Cancer Center and Hospital, Los Angeles (D.I.Q.); Hôpital Saint-Louis, Paris (S.C.); San Camillo and Forlanini Hospitals, Rome (C.N.S.); Merck, Kenilworth, NJ (Y.M., C.H.P., R.F.P.); and Memorial Sloan Kettering Cancer Center, New York (D.F.B.).

Background: Patients with advanced urothelial carcinoma that progresses after platinum-based chemotherapy have a poor prognosis and limited treatment options.

Methods: In this open-label, international, phase 3 trial, we randomly assigned 542 patients with advanced urothelial cancer that recurred or progressed after platinum-based chemotherapy to receive pembrolizumab (a highly selective, humanized monoclonal IgG4κ isotype antibody against programmed death 1 [PD-1]) at a dose of 200 mg every 3 weeks or the investigator's choice of chemotherapy with paclitaxel, docetaxel, or vinflunine. The coprimary end points were overall survival and progression-free survival, which were assessed among all patients and among patients who had a tumor PD-1 ligand (PD-L1) combined positive score (the percentage of PD-L1-expressing tumor and infiltrating immune cells relative to the total number of tumor cells) of 10% or more.

Results: The median overall survival in the total population was 10.3 months (95% confidence interval [CI], 8.0 to 11.8) in the pembrolizumab group, as compared with 7.4 months (95% CI, 6.1 to 8.3) in the chemotherapy group (hazard ratio for death, 0.73; 95% CI, 0.59 to 0.91; P=0.002). The median overall survival among patients who had a tumor PD-L1 combined positive score of 10% or more was 8.0 months (95% CI, 5.0 to 12.3) in the pembrolizumab group, as compared with 5.2 months (95% CI, 4.0 to 7.4) in the chemotherapy group (hazard ratio, 0.57; 95% CI, 0.37 to 0.88; P=0.005). There was no significant between-group difference in the duration of progression-free survival in the total population (hazard ratio for death or disease progression, 0.98; 95% CI, 0.81 to 1.19; P=0.42) or among patients who had a tumor PD-L1 combined positive score of 10% or more (hazard ratio, 0.89; 95% CI, 0.61 to 1.28; P=0.24). Fewer treatment-related adverse events of any grade were reported in the pembrolizumab group than in the chemotherapy group (60.9% vs. 90.2%); there were also fewer events of grade 3, 4, or 5 severity reported in the pembrolizumab group than in the chemotherapy group (15.0% vs. 49.4%).

Conclusions: Pembrolizumab was associated with significantly longer overall survival (by approximately 3 months) and with a lower rate of treatment-related adverse events than chemotherapy as second-line therapy for platinum-refractory advanced urothelial carcinoma. (Funded by Merck; KEYNOTE-045 ClinicalTrials.gov number, NCT02256436 .).
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http://dx.doi.org/10.1056/NEJMoa1613683DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5635424PMC
March 2017

Variants in and Other Mendelian Deafness Genes Are Associated with Cisplatin-Associated Ototoxicity.

Clin Cancer Res 2017 07 30;23(13):3325-3333. Epub 2016 Dec 30.

Department of Medical Oncology, Indiana University, Indianapolis, Indiana.

Cisplatin is one of the most commonly used chemotherapy drugs worldwide and one of the most ototoxic. We sought to identify genetic variants that modulate cisplatin-associated ototoxicity (CAO). We performed a genome-wide association study (GWAS) of CAO using quantitative audiometry (4-12 kHz) in 511 testicular cancer survivors of European genetic ancestry. We performed polygenic modeling and functional analyses using a variety of publicly available databases. We used an electronic health record cohort to replicate our top mechanistic finding. One SNP, rs62283056, in the first intron of Mendelian deafness gene (wolframin ER transmembrane glycoprotein) and an expression quantitative trait locus (eQTL) for met genome-wide significance for association with CAO ( = 1.4 × 10). A significant interaction between cumulative cisplatin dose and rs62283056 genotype was evident, indicating that higher cisplatin doses exacerbate hearing loss in patients with the minor allele ( = 0.035). The association between decreased expression and hearing loss was replicated in an independent BioVU cohort ( = 18,620 patients, Bonferroni adjusted < 0.05). Beyond this top signal, we show CAO is a polygenic trait and that SNPs in and near 84 known Mendelian deafness genes are significantly enriched for low values in the GWAS ( = 0.048). We show for the first time the role of in CAO and document a statistically significant interaction between increasing cumulative cisplatin dose and rs62283056 genotype. Our clinical translational results demonstrate that pretherapy patient genotyping to minimize ototoxicity could be useful when deciding between cisplatin-based chemotherapy regimens of comparable efficacy with different cumulative doses. .
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http://dx.doi.org/10.1158/1078-0432.CCR-16-2809DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5493516PMC
July 2017
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