Browsing by Subject "Testicular cancer"
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Item A Call to Action to Review the USPSTF's Recommendation for Testicular Self-Examination(Sage, 2022) Rovito, Michael J.; Allen, Keri; Nangia, Ajay; Craycraft, Mike; Cary, Clint; Lutz, Michael; Lyon, Timothy; Fadich, Ana; Baird, Bryce; Welch, Morgan Garrett; Alcantara, Alexie; Urology, School of MedicineWe urge the United States Preventive Services Task Force (USPSTF) to call for a formal review of the evidence regarding testicular self-examination (TSE). Twelve years have since passed since the evidence was last formally analyzed where normally re-reviews occur in 5-year cycles. If they would decide to move forward with this action, we ask for the USPSTF to review their methods for establishing recommendations to optimize their rating system operationalization process. Finally, emerging evidence demonstrates a net positive effect of TSE. This stands in contrast to the assertions of TSE's supposed harm that is prevalent in the literature as well as the rationale behind the USPSTF's "D" rating of TSE.Item A Cross-Sectional Analysis of Testicular Cancer Symptom Recognition and Stage of Diagnosis(Sage, 2022) Rovito, Michael J.; Craycraft, Mike; Adams, Wesley B.; Maresca, Michael; Saab, Mohamad M.; Cary, Clint; Gooljar, Chayna; Martinez, Sydney; Zanet, Rama Abu; Urology, School of MedicineThere is a need to further explore the relationship between atypical symptom reporting and stage diagnosis to help develop a clearer defined list of possible testicular cancer (TC) symptoms that could assist physicians diagnose the disease earlier. A cross-sectional study was employed to explore possible associations between TC symptom presentation and stage of diagnosis. An original 40-item survey was distributed among 698 TC survivors to determine the potential impact of several risk factors, experiences, and behaviors upon diagnosis. This analysis aimed to explore how certain patient-driven experiences (e.g., symptoms, perceptions, and behaviors) could serve as catalysts for seeking medical care for testicular health concerns. Experiencing hot flashes or having no symptoms had a positive association with later-stage diagnosis while change in shape had a significant negative association with later-stage diagnosis. While the logistic regression model explained relatively low variance in the data (R2 = .1415), it was statistically significant (χ2p < .001). Pain (odds ratio [OR] = 1.6524, p < .05), hot flashes (OR = 5.7893, p < .01), and no symptoms experienced (OR = 12.4836, p < .01) were all significant predictors of a more advanced stage diagnosis. The concern around uncommon/atypical symptoms are that they are indistinct and do not serve as clear signs that TC is present. However, perhaps in tandem with other more overt symptoms, their discovery can serve in a more confirmatory role for a suspect case. If observed with other uncommonly reported symptoms, these uncommon symptoms could provide another pathway in the TC diagnostic process. Clinical and patient education is warranted to increase awareness of uncommon TC symptoms.Item A phase 1 study of combined guadecitabine and cisplatin in platinum refractory germ cell cancer(Wiley, 2021) Albany, Costantine; Fazal, Zeeshan; Singh, Ratnakar; Bikorimana, Emmanuel; Adra, Nabil; Hanna, Nasser H.; Einhorn, Lawrence H.; Perkins, Susan M.; Sandusky, George E.; Christensen, Brock C.; Keer, Harold; Fang, Fang; Nephew, Kenneth P.; Spinella, Michael J.; Medicine, School of MedicinePurpose: Germ cell tumors (GCTs) are cured with therapy based on cisplatin, although a clinically significant number of patients are refractory and die of progressive disease. Based on preclinical studies indicating that refractory testicular GCTs are hypersensitive to hypomethylating agents (HMAs), we conducted a phase I trial combining the next-generation HMA guadecitabine (SGI-110) with cisplatin in recurrent, cisplatin-resistant GCT patients. Methods: Patients with metastatic GCTs were treated for five consecutive days with guadecitabine followed by cisplatin on day 8, for a 28-day cycle for up to six cycles. The primary endpoint was safety and toxicity including dose-limiting toxicity (DLT) and maximum tolerated dose (MTD). Results: The number of patients enrolled was 14. The majority of patients were heavily pretreated. MTD was determined to be 30 mg/m2 guadecitabine followed by 100 mg/m2 cisplatin. The major DLTs were neutropenia and thrombocytopenia. Three patients had partial responses by RECIST criteria, two of these patients, including one with primary mediastinal disease, completed the study and qualified as complete responses by serum tumor marker criteria with sustained remissions of 5 and 13 months and survival of 16 and 26 months, respectively. The overall response rate was 23%. Three patients also had stable disease indicating a clinical benefit rate of 46%. Conclusions: The combination of guadecitabine and cisplatin was tolerable and demonstrated activity in patients with platinum refractory germ cell cancer.Item A Phase II Study Assessing the Safety and Efficacy of ASP1650 in Male Patients with Relapsed Refractory Germ Cell Tumors(Springer, 2022) Adra, Nabil; Vaughn, David J.; Einhorn, Lawrence H.; Hanna, Nasser H.; Funt, Samuel A.; Rosales, Matt; Arozullah, Ahsan; Feldman, Darren R.; Medicine, School of MedicineClaudin6(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/m2 safety lead-in group, and 13 in 1500 mg/m2 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/m2 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.Item Adverse Health Outcomes in Relationship to Hypogonadism After Chemotherapy: A Multicenter Study of Testicular Cancer Survivors(National Comprehensive Cancer Network, 2019-05-01) Abu Zaid, Mohammad; Dinh, Paul C., Jr.; Monahan, Patrick O.; Fung, Chunkit; El-Charif, Omar; Feldman, Darren R.; Hamilton, Robert J.; Vaughn, David J.; Beard, Clair J.; Cook, Ryan; Althouse, Sandra; Ardeshir-Rouhani-Fard, Shirin; Sesso, Howard D.; Huddart, Robert; Mushiroda, Taisei; Kubo, Michiaki; Dolan, M. Eileen; Einhorn, Lawrence H.; Fossa, Sophie D.; Travis, Lois B.; Platinum Study Group; Medicine, School of MedicineBackground: 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.Item Cisplatin, environmental metals, and cardiovascular disease: an urgent need to understand underlying mechanisms(BMC, 2021-10-10) Clasen, Suparna C.; Dinh, Paul C., Jr.; Hou, Lifang; Fung, Chunkit; Sesso, Howard D.; Travis, Lois B.; Medicine, School of MedicineSignificantly increased risks of cardiovascular disease occur in testicular cancer survivors given cisplatin-based chemotherapy. The postulated mechanism of platinum-based chemotherapy's vascular toxicity has been thought secondary to its different early- and late- effects on vascular injury, endothelial dysfunction, and induction of a hypercoagulable state. We highlight for the first time the similarities between platinum-associated vascular adverse events and the vascular toxicity associated with other xenobiotic-metal contaminants. The vascular toxicity seen in large epidemiologic studies of testicular cancer survivors may in part be similar and mechanistically linked to the risk seen in environmental heavy metal contaminants linked to cardiovascular disease. Future research should be directed to better understand the magnitude of the adverse cardiovascular effects of platinum and to elucidate the underlying mechanisms of action.Item Epigenetic Targeting of Platinum Resistant Testicular Cancer(Bentham Science Publishers, 2016) Sonnenburg, Daniel; Spinella, Michael J.; Albany, Costantine; Department of Medicine, Indiana University School of MedicineThe involvement of epigenetic aberrations in the development and progression of tumors is now well established. However, little is known of the epigenetic alterations in testicular cancer and particularly in platinum refractory germ cell tumors. Germ cell derived testicular cancers, as compared to somatic tumors, appear to have a unique epigenetic profile that features more extensive DNA hypomethylation. Emerging data from clinical specimens suggest that epigenetic aberrations, especially DNA hypermethylation, can contribute to chemotherapy resistance and poor clinical outcomes in testicular germ cell tumors. Recent data indicate that testicular cancer cells, even those resistant to platinum, are highly sensitive to low doses of demethylating agents. Based on these promising preclinical studies, we suggest that DNA methylation inhibitors in combination with chemotherapeutic agents may offer a path to overcome acquired drug resistance in testicular cancer, laying the foundation and rationale for testing this class of epigenetic drugs in the clinical setting. In this mini-review we provide a brief overview of the promise of DNA methylation therapy to treat patients with refractory cancer of the testes.Item Hearing Loss and Use of Medications for Anxiety and/or Depression in Testicular Cancer Survivors Treated with Cisplatin-Based Chemotherapy(2020-05) Ardeshirrouhanifard, Shirin; Song, Yiqing; Travis, Lois; Monahan, Patrick; Wessel, JenniferTesticular cancer is the most common solid tumor among young men. Although testicular cancer survivors (TCS) are expected to live for over 40 years after cancer diagnosis, they are at risk for chemotherapy adverse effects such as hearing loss (HL), tinnitus, and psychosocial effects. The aim of this study was to investigate factors associated with discrepancies between subjective and objective HL, factors associated with HL, and factors associated with the use of medications for anxiety/depression. TCS were enrolled in the Platinum Study. Sociodemographic characteristics, health behaviors, morbidities, and prescription medications were assessed though self-reporting using validated questionnaires. Bilateral pure-tone air conduction thresholds were collected at frequencies 0.25-12 kHz. To assess HL severity, hearing thresholds were classified according to American Speech-Language-Hearing Association criteria. Multivariable multinomial, ordinal, and binomial logistic regressions were used to test factors for association with discrepancy between subjective and objective HL, cisplatin-induced HL, and use of medications for anxiety/depression, respectively. Patients with HL at only extended high frequencies (10-12 kHz) could perceive hearing deficits; thus, it would be preferable for these frequencies to be included in audiometric assessments of cisplatin-treated adult-onset cancer survivors. Age, no noise exposure, and mixed/conductive HL were significantly associated with more underestimation of HL severity. Hearing aid use and education were significantly associated with less underestimation of HL severity. Having tinnitus was associated with more overestimation of HL severity. Age, cumulative cisplatin dose, and hypertension showed significant association with greater HL severity, whereas post-graduate education was associated with less HL severity. Factors associated with more use of medications for anxiety/depression were tinnitus, and peripheral sensory neuropathy, while being employed and engaging in physical activity were significantly associated with less use of anxiety/depression medications. The sole use of patient-reported measures of HL might not be well-suited to evaluate HL in cancer survivors; thus, the use of audiometry may complement patient-reported HL. In terms of modifiable risk factors of cisplatin-induced HL, healthcare providers should monitor patients’ blood pressure and manage hypertension appropriately. In addition, healthcare providers need to effectively manage tinnitus and peripheral neuropathy to improve treatment outcomes of anxiety and depression.Item How to Manage Cisplatin-Based Chemotherapy-Related Cardiovascular Disease in Patients With Testicular Cancer(Elsevier, 2022-09-20) Kadambi, Sindhuja; Clasen, Suparna C.; Fung, Chunkit; Medicine, School of MedicineItem Pharmacogenomics of cisplatin‐induced neurotoxicities: Hearing loss, tinnitus, and peripheral sensory neuropathy(Wiley, 2022) Zhang, Xindi; Trendowski, Matthew R.; Wilkinson, Emma; Shahbazi, Mohammad; Dinh, Paul C.; Shuey, Megan M.; Regeneron Genetics Center; Feldman, Darren R.; Hamilton, Robert J.; Vaughn, David J.; Fung, Chunkit; Kollmannsberger, Christian; Huddart, Robert; Martin, Neil E.; Sanchez, Victoria A.; Frisina, Robert D.; Einhorn, Lawrence H.; Cox, Nancy J.; Travis, Lois B.; Dolan, M. Eileen; Medicine, School of MedicinePurpose: 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.