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.

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 (AE15) mg/m 2 cisplatin underwent extensive audiometric testing, clinical examination, completed questionnaires, and had crude serum platinum levels measured. Associations between serum platinum and various risk factors and toxicities were assessed after fitting a biexponential model adjusted for follow-up time and cumulative cisplatin dose. A genome-wide association study (GWAS) was performed using the serum platinum residuals of the dose and timeadjusted model. Results: Serum platinum levels exceeded the reference range for approximately 31 years, with a strong inverse relationship with creatinine clearance at follow-up (age-adjusted P ¼ 2.13 Â 10 À3). We observed a significant, positive association between residual platinum values and luteinizing hormone (ageadjusted P ¼ 6.58 Â 10 À3). Patients with high residual platinum levels experienced greater Raynaud phenomenon than those with medium or low levels (age-adjusted OR high/low ¼ 1.46; P ¼ 0.04), as well as a higher likelihood of developing tinnitus (age-adjusted OR high/low ¼ 1.68, P ¼ 0.07). GWAS identified one single-nucleotide polymorphism (SNP) meeting genomewide significance, rs1377817 (P ¼ 4.6 Â 10 À8 , a SNP intronic to MYH14). Conclusions: This study indicates that residual platinum values are correlated with several cisplatin-related toxicities. One genetic variant is associated with these levels.

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.

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 cisplatintreated testicular cancer survivors using logistic regression. Casecontrol genome-wide association study (GWAS; cases, n ¼ 104 and controls, n ¼ 196) was also performed.Results: Age at clinical examination (P ¼ 6.4 Â 10 À16 ) and cumulative cisplatin dose (P ¼ 5.4 Â 10 À4 ) were positively associated with multiple severe neurotoxicity risk, as were high serum platinum levels (P ¼ 0.02), tobacco use (ever smoker, P ¼ 0.001 and current smoker, P ¼ 0.002), and hypertension (P ¼ 0.01) after adjustment for age and cumulative cisplatin dose. Individuals with multiple severe neurotoxicities were more likely to experience dizziness/vertigo (P ¼ 0.01), Raynaud phenomenon (P ¼ 3.7 Â 10 À9 ), and symptoms consistent with peripheral motor neuropathy (P ¼ 4.3 Â 10 À14 ) after age and dose adjustment. These patients also reported poorer overall health (P ¼ 2.7 Â 10 À5 ) and a greater use of psychotropic medications (P ¼ 0.06). GWAS identified no genomewide significant SNPs. Gene-based association analysis identified RGS17 (P ¼ 3.9 Â 10 À5 ) and FAM20C (P ¼ 5.5 Â 10 À5 ) as near genome-wide significant. Decreased FAM20C expression was associated with increased cisplatin sensitivity in tumor cell lines.Conclusions: Certain survivors are more susceptible to cisplatininduced neurotoxicity, markedly increasing likelihood of developing numerous neuro-otological symptoms that affect quality of life. Genome-wide analysis identified genetic variation in FAM20C as a potentially important risk factor.

<div>AbstractPurpose:<p>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.</p>Experimental Design:<p>Eligible TCS given 300 or 400 (±15) mg/m² 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.</p>Results:<p>Serum platinum levels exceeded the reference range for approximately 31 years, with a strong inverse relationship with creatinine clearance at follow-up (age-adjusted <i>P</i> = 2.13 × 10⁻³). We observed a significant, positive association between residual platinum values and luteinizing hormone (age-adjusted <i>P</i> = 6.58 × 10⁻³). Patients with high residual platinum levels experienced greater Raynaud phenomenon than those with medium or low levels (age-adjusted OR_high/low = 1.46; <i>P</i> = 0.04), as well as a higher likelihood of developing tinnitus (age-adjusted OR_high/low = 1.68, <i>P</i> = 0.07). GWAS identified one single-nucleotide polymorphism (SNP) meeting genome-wide significance, rs1377817 (<i>P</i> = 4.6 × 10⁻⁸, a SNP intronic to <i>MYH14</i>).</p>Conclusions:<p>This study indicates that residual platinum values are correlated with several cisplatin-related toxicities. One genetic variant is associated with these levels.</p></div>