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Am J Otolaryngol ; 42(3): 102915, 2021 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-33482566


OBJECTIVES: While smoking is associated with worse outcomes in HPV-positive oropharyngeal squamous cell carcinoma (OPSCC), the magnitude of this association is unclear given the heterogenous smoking definitions and outcomes. Our objective was to investigate the association between smoking, survival, and recurrence in HPV-related OPSCC using multiple smoking metrics reported in the literature. MATERIALS AND METHODS: This was a retrospective cohort study of 375 adults with p16+ OPSCC undergoing surgical resection (n = 272) or definitive chemoradiation (n = 103) at a tertiary academic institution from 2006 to 2017. The primary outcome was overall survival (OS). Secondary outcomes included disease-free survival (DFS), disease-specific survival (DSS), and recurrence. We used multiple smoking metrics commonly cited in previous studies, including ever versus never smokers, current versus former/never smokers, ≤10 versus >10 pack-year, ≤20 versus >20 pack-year, and continuous pack-year. RESULTS: There were 375 patients, median age 58 years, with 326 (87%) males, and median follow-up of 52 months. Of all smoking metrics, >20 pack-year history was the strongest predictor of both OS (HR 2.24, 95% CI: 1.19-4.20) and DFS (HR 1.67, 95% CI: 1.04-2.66) on univariable and multivariable analysis after adjusting for age, overall stage, and comorbidities. Patients with >20 pack-year smoking history were also more likely to have recurrence (HR 1.59, 95% CI: 0.95-2.67) after adjusting for overall stage. CONCLUSION: Heavier smoking >20 pack-years was the strongest smoking metric associated with 2-times worse survival and recurrence. Our findings suggest that >20 pack-year smoking history may be a more useful cutoff for risk stratification models but requires further validation.

Head Neck ; 43(1): 108-115, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32918302


BACKGROUND: Oropharyngeal squamous cell carcinoma (OPSCC) epidemiology has not been examined previously in the nationwide Veterans Affairs (VA) population. METHODS: Joinpoint regression analysis was applied to OPSCC cases identified from VA administrative data from 2000 to 2012. RESULTS: We identified 12 125 OPSCC cases (incidence: 12.2 of 100 000 persons). OPSCC incidence declined between 2000 and 2006 (annual percent change [APC] = -4.27, P < .05), then increased between 2006 and 2012 (APC = 7.02, P < .05). Significant incidence increases occurred among white (APC = 7.19, P < .05) and African American (APC = 4.87, P < .05) Veterans and across all age cohorts. The percentage of never-smokers increased from 8% in 2000 to 15.7% in 2012 (P < .001), and 2-year overall survival improved from 31.2% (95% confidence interval (CI) [30-33.4]) to 55.7% (95% CI [54.4-57.1]). CONCLUSIONS: OPSCC incidence is increasing across all racial and age cohorts in the VA population. Smoking rates remain high among Veterans with OPSCC and gains in survival lag those reported in the general population.

Otolaryngol Clin North Am ; 53(6): 981-994, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32917423


This article outlines the ways that transoral robotic surgery and transoral laser microsurgery relate to treatment de-escalation in the treatment of head and neck cancer. Treatment de-escalation has particular importance in context of human papillomavirus-related oropharynx squamous cell carcinoma, which responds well to therapy but leaves many survivors with decades of treatment-related sequelae. We compare these less invasive transoral approaches with previously used open approaches to the oropharynx. We discuss the topic of treatment de-escalation in human papillomavirus-related disease and outline completed and ongoing clinical trials investigating the choice of primary treatment modality and de-escalation of adjuvant therapy.

Hum Mol Genet ; 28(4): 572-583, 2019 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-30335132


Schwannomas are common, highly morbid and medically untreatable tumors that can arise in patients with germ line as well as somatic mutations in neurofibromatosis type 2 (NF2). These mutations most commonly result in the loss of function of the NF2-encoded protein, Merlin. Little is known about how Merlin functions endogenously as a tumor suppressor and how its loss leads to oncogenic transformation in Schwann cells (SCs). Here, we identify nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB)-inducing kinase (NIK) as a potential drug target driving NF-κB signaling and Merlin-deficient schwannoma genesis. Using a genomic approach to profile aberrant tumor signaling pathways, we describe multiple upregulated NF-κB signaling elements in human and murine schwannomas, leading us to identify a caspase-cleaved, proteasome-resistant NIK kinase domain fragment that amplifies pathogenic NF-κB signaling. Lentiviral-mediated transduction of this NIK fragment into normal SCs promotes proliferation, survival, and adhesion while inducing schwannoma formation in a novel in vivo orthotopic transplant model. Furthermore, we describe an NF-κB-potentiated hepatocyte growth factor (HGF) to MET proto-oncogene receptor tyrosine kinase (c-Met) autocrine feed-forward loop promoting SC proliferation. These innovative studies identify a novel signaling axis underlying schwannoma formation, revealing new and potentially druggable schwannoma vulnerabilities with future therapeutic potential.

Neurilemoma/genética , Neurofibromatose 2/genética , Neurofibromina 2/genética , Proteínas Serina-Treonina Quinases/genética , Animais , Comunicação Autócrina/genética , Carcinogênese/genética , Caspase 1/genética , Proliferação de Células/genética , Modelos Animais de Doenças , Regulação Neoplásica da Expressão Gênica , Fator de Crescimento de Hepatócito/genética , Humanos , Camundongos , Terapia de Alvo Molecular , NF-kappa B/genética , Neurilemoma/complicações , Neurilemoma/tratamento farmacológico , Neurilemoma/patologia , Neurofibromatose 2/complicações , Neurofibromatose 2/tratamento farmacológico , Neurofibromatose 2/patologia , Complexo de Endopeptidases do Proteassoma/genética , Proteínas Proto-Oncogênicas c-met/genética , Células de Schwann , Transdução de Sinais/genética
Oncotarget ; 9(1): 718-725, 2018 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-29416648


Mutations in the tumor suppressor gene NF2 lead to Neurofibromatosis type 2 (NF2), a tumor predisposition syndrome characterized by the development of schwannomas, including bilateral vestibular schwannomas with complete penetrance. Recent work has implicated the importance of COX-2 in schwannoma growth. Using a genetically engineered murine model of NF2, we demonstrate that selective inhibition of COX-2 with celecoxib fails to prevent the spontaneous development of schwannomas or sensorineural hearing loss in vivo, despite elevated expression levels of COX-2 in Nf2-deficient tumor tissue. These results suggest that COX-2 is nonessential to schwannomagenesis and that the proposed tumor suppressive effects of NSAIDs on schwannomas may occur through COX-2 independent mechanisms.

J Health Care Poor Underserved ; 28(2): 694-706, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28529218


PURPOSE: To characterize the quality of health care at student-run free clinics (SRFCs) by analyzing hypertension management and outcomes at the Indiana University Student Outreach Clinic (IUSOC). METHODS: A retrospective review of medical records was conducted for hypertensive patients managed at IUSOC over 15 months (N = 64). Indiana University Student Outreach Clinic's hypertension control rate was compared with National Health and Nutrition Examination Survey (NHANES) data. RESULTS: Blood pressure control rates increased significantly over the study period. Indiana University Student Outreach Clinic's control rate did not differ significantly with the NHANES national average, but was significantly greater than the NHANES group with no usual source of care. Similarly, IUSOC patients without insurance or with unknown insurance status had greater control rates than an uninsured NHANES group, but did not differ significantly from an insured NHANES group. CONCLUSIONS: Despite unfavorable demographic characteristics, records for patients with hypertension who used IUSOC as a regular provider of primary care compared favorably with national data.

Anti-Hipertensivos/uso terapêutico , Hipertensão/tratamento farmacológico , Atenção Primária à Saúde/organização & administração , Qualidade da Assistência à Saúde , Clínica Dirigida por Estudantes/organização & administração , Adulto , Idoso , Anti-Hipertensivos/administração & dosagem , Pressão Sanguínea , Índice de Massa Corporal , Diabetes Mellitus/epidemiologia , Feminino , Comportamentos de Risco à Saúde , Humanos , Hipertensão/epidemiologia , Hipertensão/terapia , Indiana , Cobertura do Seguro/estatística & dados numéricos , Seguro Saúde/estatística & dados numéricos , Masculino , Pessoa de Meia-Idade , Inquéritos Nutricionais , Atenção Primária à Saúde/normas , Estudos Retrospectivos , Fatores Sexuais , Fatores Socioeconômicos , Clínica Dirigida por Estudantes/normas , Estudantes de Medicina