Browsing by Author "Dinh, Paul C."

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    Clinical and Genome-wide Analysis of Cisplatin-induced Tinnitus Implicates Novel Ototoxic Mechanisms
    (American Association for Cancer Research, 2019-07-01) Charif, Omar El; Mapes, Brandon; Trendowski, Matthew R.; Wheeler, Heather E.; Wing, Claudia; Dinh, Paul C.; Frisina, Robert D.; Feldman, Darren R.; Hamilton, Robert J.; Vaughn, David J.; Fung, Chunkit; Kollmannsberger, Christian; Mushiroda, Taisei; Kubo, Michiaki; Gamazon, Eric R.; Cox, Nancy J.; Huddart, Robert; Ardeshir-Rouhani-Fard, Shirin; Monahan, Patrick; Fossa, Sophie D.; Einhorn, Lawrence H.; Travis, Lois B.; Dolan, M. Eileen; Medicine, School of Medicine
    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 (n= 762) were dichotomized to cases (moderate/severe tinnitus; n=154) and controls (none; n=608). Logistic regression was used to evaluate associations with comorbidities and SNP dosages in 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 (P=0.007) and cumulative cisplatin dose (P=0.007). CisIT prevalence was not significantly greater in 400 mg/m2-treated TCS compared to 300 (P=0.41), but doses >400 mg/m2 (median 580, range 402–828) increased risk by 2.61-fold (P<0.0001). CisIT cases had worse hearing at each frequency (0.25–12 kHz, P<0.0001), and reported more vertigo (OR=6.47; P<0.0001) and problems hearing in a crowd (OR=8.22; P<0.0001) than controls. Cases reported poorer health (P=0.0005) and greater psychotropic medication use (OR=2.4; P=0.003). GWAS suggested a variant near OTOS (rs7606353, P=2×10−6) and OTOS eQTLs were significantly enriched independently of that SNP (P=0.018). OTOS 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. OTOS, expressed in the cochlear lateral wall, was implicated as protective. Future studies should investigate otoprotective targets in supporting cochlear cells.
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    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 Medicine
    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.
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    Prevalence and Risk Factors for Ototoxicity After Cisplatin-based Chemotherapy
    (Springer Nature, 2023-02) Sanchez, Victoria A.; Dinh, Paul C.; Rooker, Jennessa; Monahan, Patrick O.; Althouse, Sandra K.; Fung, Chunkit; Sesso, Howard D.; Einhorn, Lawrence H.; Dolan, M. Eileen; Frisina, Robert D.; Travis, Lois B.; Biostatistics and Health Data Science, Richard M. Fairbanks School of Public Health
    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. Descriptive statistics evaluated the prevalence of ototoxicity, defined as self-reported hearing loss and/or tinnitus. We compared patients with and without tinnitus or hearing loss using Chi-square test, two-sided Fisher’s exact test, or two-sided Wilcoxon rank sum test. To evaluate ototoxicity risk factors, a backward selection logistic regression procedure was performed. Results Of 145 TC survivors, 74% reported ototoxicity: 68% tinnitus; 59% hearing loss; and 52% reported both. TC survivors with tinnitus were more likely to indicate hypercholesterolemia (P = 0.008), and difficulty hearing (P < .001). Tinnitus was also significantly related to age at survey completion (OR = 1.79; P = 0.003) and cumulative cisplatin dose (OR = 5.17; P < 0.001). TC survivors with hearing loss were more likely to report diabetes (P = 0.042), hypertension (P = 0.007), hypercholesterolemia (P < 0.001), and family history of hearing loss (P = 0.044). Risk factors for hearing loss included age at survey completion (OR = 1.57; P = 0.036), hypercholesterolemia (OR = 3.45; P = 0.007), cumulative cisplatin dose (OR = 1.94; P = 0.049), and family history of hearing loss (OR = 2.87; P = 0.071). Conclusions Ototoxicity risk factors included age, cisplatin dose, cardiovascular risk factors, and family history of hearing loss. Three of four TC survivors report some type of ototoxicity; thus, follow-up of cisplatin-treated survivors should include routine assessment for ototoxicity with provision of indicated treatments.
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    Solid and Hematologic Neoplasms After Testicular Cancer: A US Population-Based Study of 24 900 Survivors
    (Oxford University Press, 2020-03-17) Milano, Michael T.; Dinh, Paul C.; Yang, Hongmei; Zaid, Mohammad Abu; Fossa, Sophie D.; Feldman, Darren R.; Monahan, Patrick O.; Travis, Lois B.; Fung, Chunkit; Medicine, School of Medicine
    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. Results: The median age at TC diagnosis was 33 years. Initial management comprised chemotherapy (n = 6340), radiotherapy (n = 9058), or surgery alone (n = 8995). During 372 709 person-years of follow-up (mean = 15 years), 1625 TCS developed solid-SMN and 228 (107 lymphomas, 92 leukemias, 29 plasma cell dyscrasias) developed heme-SMN. Solid-SMN risk was increased 1.06-fold (95% CI = 1.01 to 1.12), with elevated risks following radiotherapy (SIR = 1.13, 95% CI = 1.06 to 1.21) and chemotherapy (SIR = 1.36, 95% CI = 1.12 to 1.41) but not surgery alone (SIR = 0.83, 95% CI = 0.75 to 0.92). Corresponding risks for seminoma were 1.13 (95% CI = 1.06 to 1.21), 1.28 (95% CI = 1.02 to 1.58), and 0.87 (95% CI = 0.74 to 1.01) and for nonseminoma were 1.05 (95% CI = 0.67 to 1.56), 1.25 (95% CI = 1.08 to 1.43), and 0.80 (95% CI = 0.70 to 0.92), respectively. Thirty-year cumulative incidences of solid-SMN after radiotherapy, chemotherapy, and surgery alone were 16.9% (95% CI = 15.7% to 18.1%), 10.1% (95% CI = 8.8% to 11.5%), and 8.8% (95% CI = 7.8% to 9.9%), respectively (P < .0001). Increased leukemia risks after chemotherapy (SIR = 2.68, 95% CI = 1.70 to 4.01) were driven by statistically significant sevenfold excesses of acute myeloid leukemia 1 to 10 years after TC diagnosis. Risks for lymphoma and plasma cell dyscrasias were not elevated. Conclusions: We report statistically significant excesses of solid-SMN affecting 1 in 6 TCS 30 years after radiotherapy, and 2.7-fold risks of leukemias after chemotherapy, mostly acute myeloid leukemia. Efforts to minimize chemotherapy and radiotherapy exposures for TC should continue. TCS should be counseled about cancer prevention and screening.
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    Use of Medications for Treating Anxiety or Depression among Testicular Cancer Survivors: A Multi-Institutional Study
    (American Association for Cancer Research, 2021-06) ArdeshirRouhaniFard, Shirin; Dinh, Paul C.; Monahan, Patrick O.; Fossa, Sophie D.; Huddart, Robert; Fung, Chunkit; Song, Yiqing; Feldman, Darren R.; Hamilton, Robert J.; Vaughn, David J.; Martin, Neil E.; Kollmannsberger, Christian; Einhorn, Lawrence; Kroenke, Kurt; Travis, Lois B.; Medicine, School of Medicine
    Background: This study examined sociodemographic factors, cisplatin-related adverse health outcomes (AHO), and cumulative burden of morbidity (CBMPt) 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 CBMPt score encompassed the number and severity of cisplatin-related AHOs. Multivariable logistic regression models assessed the relationship of individual AHOs and CBMPt 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 CBMPt scores. In the multivariable model, higher CBMPt scores were significantly associated with medication use for anxiety and/or depression (P < 0.0001). In addition, tinnitus (P = 0.0009), PSN (P = 0.02), and having health insurance (P = 0.05) were significantly associated with greater use of these medications, whereas being employed (P = 0.0005) and vigorous physical activity (P = 0.01) were significantly associated with diminished use. Conclusions: TCS with higher CBMPt 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.