Impact of Population Pharmacogenomics on Cisplatin-Induced Neurotoxicities in Testicular Cancer Survivors.

Background: Cisplatin is a commonly used chemotherapeutic across numerous cancer types that can cause neurotoxicities in patients, including peripheral sensory neuropathy, tinnitus, hearing loss, and vertigo.

Objective: We aimed to evaluate, for the first time, how genetic ancestry impacts cisplatin-induced neurotoxicities and if disparities are related to population differences in allele frequency.

Methods: In a cohort of cisplatin-treated testicular cancer survivors, relationships between genetic ancestry and neurotoxicities, medications, and lifestyle factors were assessed using logistic regression and Kruskal-Wallis tests and multiple pairwise comparisons using the Wilcoxon rank-sum test (Benjamini-Hochberg adjustment).

Factors associated with longitudinal progression of the cumulative burden of morbidity and overall mortality after cisplatin-based chemotherapy for testicular cancer.

Background: To comprehensively evaluate the longitudinal progression of cumulative burden of morbidity (CBM) in testicular cancer survivors (TCS) following standard-dose cisplatin-chemotherapy and the impact of modifiable risk factors on morbidity and early-mortality.

Methods: Participants completed first-line chemotherapy ≥6 months before baseline assessments with comprehensive questionnaires and physical-examinations. Based on follow-up assessments (median: 7 years later), longitudinal progression of adverse health outcomes (AHOs) and CBM score (encompassing AHO number and severity) was examined.

Cognitive function in long-term testicular cancer survivors: impact of modifiable factors.

No study has comprehensively examined associated factors (adverse health outcomes, health behaviors, and demographics) affecting cognitive function in long-term testicular cancer survivors (TC survivors). TC survivors given cisplatin-based chemotherapy completed comprehensive, validated surveys, including those that assessed cognition. Medical record abstraction provided cancer and treatment history.

Comprehensive Audiologic Analyses After Cisplatin-Based Chemotherapy.

Importance: Cisplatin is highly ototoxic but widely used. Evidence is lacking regarding cisplatin-related hearing loss (CRHL) in adult-onset cancer survivors with comprehensive audiologic assessments (eg, Words-in-Noise [WIN] tests, full-spectrum audiometry, and additional otologic measures), as well as the progression of CRHL considering comorbidities, modifiable factors associated with risk, and cumulative cisplatin dose.

Objective: To assess CRHL with comprehensive audiologic assessments, including the WIN, evaluate the longitudinal progression of CRHL, and identify factors associated with risk.

Prevalence and risk factors for ototoxicity after cisplatin-based chemotherapy.

Purpose: Ototoxicity is a prominent side effect of cisplatin-based chemotherapy. There are few reports, however, estimating its prevalence in well-defined cohorts and associated risk factors.

Methods: Testicular cancer (TC) survivors given first-line cisplatin-based chemotherapy completed validated questionnaires.

Comprehensive association analysis of speech recognition thresholds after cisplatin-based chemotherapy in survivors of adult-onset cancer.

Purpose: Deficits in speech understanding constitute one of the most severe consequences of hearing loss. Here we investigate the clinical and genetic risk factors for symmetric deterioration of speech recognition thresholds (SRT) among cancer survivors treated with cisplatin.

Methods: SRT was measured using spondaic words and calculating the mean of measurements for both ears with symmetric SRT values.

Associations of Body Fat Distribution and Cardiometabolic Risk of Testicular Cancer Survivors After Cisplatin-Based Chemotherapy.

Background: It is unknown how body fat distribution modulates the cardiometabolic risk of testicular cancer survivors after cisplatin-based chemotherapy.

Methods: For 455 patients enrolled in the Platinum Study at Memorial Sloan Kettering Cancer Center, visceral (VAT) and subcutaneous (SAT) adipose tissue was quantified on prechemotherapy computed tomography. The VAT-to-SAT ratio was calculated as a quantitative measure of central adiposity.

Pharmacogenomics of cisplatin-induced neurotoxicities: Hearing loss, tinnitus, and peripheral sensory neuropathy.

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.

Cisplatin, environmental metals, and cardiovascular disease: an urgent need to understand underlying mechanisms.

Significantly 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.

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

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.

Associations of adiponectin and leptin with brain natriuretic peptide in African Americans: the Jackson Heart Study.

Unlabelled: Brain natriuretic peptide (BNP) is elevated in decompensated systolic and diastolic heart failure. The plasma levels of adipokines, such as adiponectin and leptin, may provide evidence for mechanistic differences in BNP concentrations. African-American-specific associations are limited in the literature.

Solid and Hematologic Neoplasms After Testicular Cancer: A US Population-Based Study of 24 900 Survivors.

Background: No large US population-based study focusing on recent decades, to our knowledge, has comprehensively examined risks of second malignant solid and hematological neoplasms (solid-SMN and heme-SMN) after testicular cancer (TC), taking into account initial therapy and histological type.

Methods: Standardized incidence ratios (SIR) vs the general population and 95% confidence intervals (CI) for solid-SMN and heme-SMN were calculated for 24 900 TC survivors (TCS) reported to the National Cancer Institute's Surveillance, Epidemiology, and End Results registries (1973-2014). All statistical tests were two-sided.

Adverse Health Outcomes Among US Testicular Cancer Survivors After Cisplatin-Based Chemotherapy vs Surgical Management.

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.

Associations of leptin and adiponectin with incident type 2 diabetes and interactions among African Americans: the Jackson heart study.

Background: Growing evidence suggests that leptin is critical for glycemic control. Impaired leptin signaling may also contribute to low adiponectin expression in obese individuals. We assessed the association of leptin and adiponectin with incident type 2 diabetes (T2D), their interactions with sex and obesity status, and mediation by insulin resistance.

Testicular Cancer Survivorship.

Testicular cancer (TC) is the most common cancer among men aged 18 to 39 years. It is highly curable, with a 10-year relative survival approaching 95% due to effective cisplatin-based chemotherapy. Given the increasing incidence of TC and improved survival, TC survivors (TCS) now account for approximately 4% of all US male cancer survivors.

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

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.

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

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.

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

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).

Smoking cessation, weight gain, and risk of stroke among postmenopausal women.

The relationship between smoking cessation, concurrent weight gain, and stroke events is not yet understood. Thus, we examined the association between smoking cessation and subsequent stroke risk and whether the association was modified by concurrent weight gain. In 2017, we analyzed data from 109,498 postmenopausal US women enrolled in the Women's Health Initiative from 1993 to 1998.

Genetic and Modifiable Risk Factors Contributing to Cisplatin-induced Toxicities.

Effective administration of traditional cytotoxic chemotherapy is often limited by off-target toxicities. This clinical dilemma is epitomized by cisplatin, a platinating agent, which has potent antineoplastic activity due to its affinity for DNA and other intracellular nucleophiles. Despite its efficacy against many adult-onset and pediatric malignancies, cisplatin elicits multiple off-target toxicities that can not only severely impact a patient's quality of life but also lead to dose reductions or the selection of alternative therapies that can ultimately affect outcomes.