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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. [ABSTRACT FROM AUTHOR]

Hydroxyurea is approved for treating children and adults with sickle cell anemia (SCA). Despite its proven efficacy, concerns remain about its mutagenic and carcinogenic potential that hamper its widespread use. Cell culture‐ and animal‐based investigations indicate that hydroxyurea's genotoxic effects are due to indirect clastogenicity in select cell types when high dose and time thresholds are exceeded (reviewed by Ware & Dertinger, 2021). The current study extends these preclinical observations to pediatric patients receiving hydroxyurea for treatment of SCA. First, proof‐of‐principle experiments with testicular cancer patients exposed to a cisplatin‐based regimen validated the ability of flow cytometric blood‐based micronucleated reticulocyte (MN‐RET) and PIG‐A mutant reticulocyte (MUT RET) assays to detect clastogenicity and gene mutations, respectively. Second, these biomarkers were measured in a cross‐sectional study with 26 SCA patients receiving hydroxyurea and 13 SCA patients without exposure. Finally, a prospective study was conducted with 10 SCA patients using pretreatment blood samples and after 6 or 12 months of therapy. Cancer patients exposed to cisplatin exhibited increased MN‐RET within days of exposure, while the MUT RET endpoint required more time to reach maximal levels. In SCA patients, hydroxyurea induced MN‐RET in both the cross‐sectional and prospective studies. However, no evidence of PIG‐A gene mutation was found in hydroxyurea‐treated children, despite the fact that the two assays use the same rapidly‐dividing, highly‐exposed cell type. Collectively, these results reinforce the complementary nature of MN‐RET and MUT RET biomarkers, and indicate that hydroxyurea can be clastogenic but was not mutagenic in young patients with SCA. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Introduction: Testicular cancer survivors (TCS) have an increased risk of additional cancers, including prostate cancer. Our understanding of the natural history of prostate cancer in testicular cancer survivors is very limited due to its rare incidence. Methods: Using the Surveillance, Epidemiology, and End Results (SEER) Registry from 1978 to 2011, we identified 282 TCS with subsequent prostate cancer and examined the tumor grade and clinical outcomes in contrast to men with primary prostate cancer in the general population. Results: TCS with a subsequent prostate cancer diagnosis were more likely to be diagnosed at a younger age than men with primary prostate cancer (65.2% vs. 37.6% for age ≤65, 34.8% vs. 62.4% for age >65, p<0.001) and were more likely to have grade III/IV tumors (46.2% vs. 37.0%, p<0.002). Longer latency between testicular and prostate cancer diagnoses was associated with a higher risk of grade III/IV (p<0.001) cancer. Despite the increased risk for high-grade tumors, 10-year prostate cancer-specific survival and overall survival were not significantly different between TCS and men with primary prostate cancer. Based on the available information in SEER, we found that prior history of radiotherapy for testicular cancer had no impact on tumor grade or survival outcomes. Conclusions: Prostate cancer in TCS was more likely to be diagnosed at a younger age and with higher grades. Risks of grade III/IV disease increased with longer latency between testicular and prostate cancer diagnoses. Radiotherapy for testicular cancer did not appear to have a significant impact on the outcome of subsequent prostate cancer. [ABSTRACT FROM AUTHOR]

Background Few data exist on the relationship of cisplatin-related adverse health outcomes (AHOs) with disability, unemployment, and self-reported health (SRH) among testicular cancer survivors (TCS). Methods A total of 1815 TCS at least 1 year postchemotherapy underwent clinical examination and completed questionnaires. Treatment data were abstracted from medical records. A cumulative burden of morbidity score (CBMPt) encompassed the number and severity of platinum-related AHOs (peripheral sensory neuropathy [PSN], hearing loss, tinnitus, renal disease). Multivariable regression assessed the association of AHOs and CBMPt with employment status and SRH, adjusting for sociodemographic and clinical characteristics. Unemployment was compared with a male normative population of similar age, race, and ethnicity. Results Almost 1 in 10 TCS was out of work (2.4%, disability leave; 6.8%, unemployed) at a median age of 37 years (median follow-up = 4 years). PSN (odds ratio [OR] = 2.89, 95% confidence interval [CI] = 1.01 to 8.26, grade 3 vs 0, P  = .048), renal dysfunction defined by estimated glomerular filtration rate (OR = 12.1, 95% CI = 2.06 to 70.8, grade 2 vs 0, P  = .01), pain (OR = 10.6, 95% CI = 4.40 to 25.40, grade 2 or 3 vs 0, P  < .001), and CBMPt (OR = 1.46, 95% CI = 1.03 to 2.08, P  = .03) were associated with disability leave; pain strongly correlated with PSN (r 2 = 0.40, P  < .001). Statistically significantly higher percentages of TCS were unemployed vs population norms (age-adjusted OR = 2.67, 95% CI = 2.49 to 3.02, P  < .001). PSN (OR = 2.44, 95% CI = 1.28 to 4.62, grade 3 vs 0, P  = .006), patient-reported hearing loss (OR = 1.82, 95% CI = 1.04 to 3.17, grade 2 or 3 vs 0, P  = .04), and pain (OR = 3.75, 95% CI = 2.06 to 6.81, grade 2 or 3 vs 0, P  < .001) were associated with unemployment. Increasing severity of most cisplatin-related AHOs and pain were associated with statistically significantly worse SRH. Conclusions Our findings have important implications regarding treatment-associated productivity losses and socioeconomic costs in this young population. Survivorship care strategies should include inquiries about disability and unemployment status, with efforts made to assist affected TCS in returning to the workforce. [ABSTRACT FROM AUTHOR]

We evaluated for the first time, to our knowledge, adverse health outcomes (AHOs) among US testicular cancer survivors (TCS) given chemotherapy (n = 381) vs surgery-only patients (n = 98) managed at a single institution, accounting for non-treatment-related risk factors to delineate chemotherapy's impact. Chemotherapy consisted largely of bleomycin-etoposide-cisplatin (BEP) administered in three or four cycles (BEPx3, n = 235; BEPx4, n = 82). Incidence of at least 3 AHOs was lowest in surgery-only TCS and increased with BEPx3, BEPx4, and other cisplatin-based regimens (12.2%, 40.8%, 52.5%, 54.8%; P  <  .0001). Multivariable modeling assessed associations of risk factors and treatment with hearing impairment, tinnitus, peripheral neuropathy, and Raynaud phenomenon. Risk for each AHO statistically increased with both increasing chemotherapy burden (P  < .0001) and selected modifiable risk factors (P  < .05): hypertension (odds ratio [OR] = 2.40) and noise exposure (OR ≥ 2.3) for hearing impairment; noise exposure for tinnitus (OR ≥ 1.69); peripheral vascular disease for neuropathy (OR = 8.72); and current smoking for Raynaud phenomenon (OR = 2.41). Clinicians should manage modifiable risk factors for AHOs among TCS. [ABSTRACT FROM AUTHOR]

Background Testicular cancer is the most common cancer among men aged 15 to 40 years, and the incidence of testicular cancer is steadily increasing. Despite successful treatment outcomes and the rate of survival at 5 to 10 years being 95%, survivors can experience late effects of both their cancer and the treatment they received, including secondary malignant neoplasms (SMNs). We discuss the development of non–germ cell SMNs that develop after diagnosis and treatment of testicular cancer and their effect on mortality. Results Patients diagnosed with testicular cancer frequently choose postoperative surveillance if they are diagnosed with clinical stage I disease. These patients may experience an increased risk for developing SMNs following radiation exposure from diagnostic imaging. Similarly, radiotherapy for testicular cancer is associated with increased risks of developing both solid tumors and leukemia. Studies have reported that patients exposed to higher doses of radiation have an increased risk of developing SMNs when compared with patients who received lower doses of radiation. Patients treated with chemotherapy also experience an increased risk of developing SMNs following testicular cancer, though the risk following chemotherapy and radiation therapy combined is not well described. A large population-based study concluded that the rate ratios for both cancer-specific and all-cause mortality for SMNs among testicular cancer survivors were not significantly different from those of matched first cancers. Conclusions Although it is known that patients who receive adjuvant chemotherapy or radiotherapy or who undergo routine diagnostic or follow-up imaging for a primary testicular cancer are at an increased risk for developing SMNs, the extent of this risk is largely unknown. It is critically important that research be conducted to determine this risk and its contributing factors as accurately as possible. [ABSTRACT FROM AUTHOR]