Smoking, Drinking, and Dietary Risk Factors for Head and Neck Cancer in Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial Participants.

Importance: There is a paucity of large-scale prospective studies evaluating the risk of developing head and neck cancer (HNC) associated with smoking, drinking, and dietary habits. Objective: To determine the association of smoking, drinking, and dietary habits with the risk of developing HNC. Design, Setting, and Participants: A nested cohort survival analysis of Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial participants was performed. Participants were between 55 and 74 years of age and recruited at 10 centers across the US from November 1993 to July 2001. Participants who developed HNC were matched with controls based on demographics and family history of HNC for analysis of smoking habits; for the analysis of drinking and dietary habits, matching was performed on smoking status and duration in addition to demographics and family history of HNC. Data analysis was performed from January to November 2023. Exposures: Smoking, drinking, and dietary habits. Main Outcome and Measure: Diagnosis of HNC. Results: In total, 139 926 participants (51% female; mean [SD] age, 62.6 [5.4] years) were included in the analysis of smoking habits with a median (IQR) follow-up time of 12.1 (10.3-13.6) years, 571 of whom developed HNC. HNC risk associated with smoking increased the closer the proximity of the head and neck subsite to the lungs, with the greatest risk associated with smoking observed in laryngeal cancer (current smoker hazard ratio [HR], 9.36; 95% CI, 5.78-15.15 compared to a nonsmoker). For analysis of drinking and dietary habits, 94 466 participants were included in the analysis of smoking habits with a median (IQR) follow-up time of 12.2 (10.5-13.6) years, 264 of whom developed HNC. HNC risk increased with heavy drinking (HR, 1.85; 95% CI, 1.44-2.38) and decreased with consumption of whole grains (HR, 0.78; 95% CI, 0.64-0.94/oz per day), whole fruits (HR, 0.90; 95% CI, 0.82-0.98/cup per day), and overall healthy eating, as scored by Healthy Eating Index 2015 (HR, 0.87; 95% CI, 0.78-0.98/10 points). Conclusions and Relevance: In this nested cohort study, the risk of HNC associated with smoking was higher for subsites that were closer to the lungs; heavy drinking was associated with greater HNC risk, while healthy eating was associated with a modest reduction in HNC risk.

Poor Dental Health as a Risk Factor for Alveolar Ridge Malignancies.

OBJECTIVE: To determine the association between poor dental health and risk of oral cavity squamous cell cancer (OCSCC) at individual tumor subsites. STUDY DESIGN: Case-control and cross-sectional METHODS: A case-control study was performed using a population-based cohort in North Carolina (Carolina Head and Neck Cancer Epidemiology Study [CHANCE]). A secondary cross-sectional analysis was performed with an institutional cohort (WashU/Siteman). Cases were adults with primary OCSCC and an identifiable tumor subsite. In the CHANCE cohort, controls were adults without head and neck cancer. In the Washington University/Siteman cohort, patients with tongue cancer served as the comparator group. We used number of missing teeth (categorized 0-6, 7-24, 25-28) as a surrogate for poor dental health, which was self-reported in CHANCE and measured on a pretreatment computed tomography scan in the WashU/Siteman study. Adjusted odds ratios (aORs) for missing teeth were estimated for each tumor subsite using binomial logistic regression models. RESULTS: Near complete tooth loss (25-28 teeth) was associated with a 3.5-fold increased risk of alveolar ridge malignancy (aOR: 3.51; 95% confidence interval [CI]: 1.14-11.01, P = .03) in the CHANCE study. This association was confirmed in our cross-sectional analysis (WashU/Siteman study) where missing 25-28 teeth was associated with an increased risk of alveolar ridge compared to tongue cancer (aOR: 4.60; 95% CI: 1.97-11.10, P = .001). CONCLUSIONS: This study suggests an association between poor dental health and risk of alveolar ridge cancer independent of smoking, alcohol use, age, race, and sex. Future prospective and translational studies are needed to confirm this association and elucidate the mechanism of dental disease in alveolar ridge malignancies.

Stromal Reprogramming by FAK Inhibition Overcomes Radiation Resistance to Allow for Immune Priming and Response to Checkpoint Blockade.

The effects of radiotherapy (RT) on tumor immunity in pancreatic ductal adenocarcinoma (PDAC) are not well understood. To better understand if RT can prime antigen-specific T-cell responses, we analyzed human PDAC tissues and mouse models. In both settings, there was little evidence of RT-induced T-cell priming. Using in vitro systems, we found that tumor-stromal components, including fibroblasts and collagen, cooperate to blunt RT efficacy and impair RT-induced interferon signaling. Focal adhesion kinase (FAK) inhibition rescued RT efficacy in vitro and in vivo, leading to tumor regression, T-cell priming, and enhanced long-term survival in PDAC mouse models. Based on these data, we initiated a clinical trial of defactinib in combination with stereotactic body RT in patients with PDAC (NCT04331041). Analysis of PDAC tissues from these patients showed stromal reprogramming mirroring our findings in genetically engineered mouse models. Finally, the addition of checkpoint immunotherapy to RT and FAK inhibition in animal models led to complete tumor regression and long-term survival. SIGNIFICANCE: Checkpoint immunotherapeutics have not been effective in PDAC, even when combined with RT. One possible explanation is that RT fails to prime T-cell responses in PDAC. Here, we show that FAK inhibition allows RT to prime tumor immunity and unlock responsiveness to checkpoint immunotherapy. This article is highlighted in the In This Issue feature, p. 2711.

The Impact of Treatment Delay on Malunion and Nonunion After Open Reduction of Mandible Fractures.

Importance: Time to surgical intervention is an oft-investigated potentially modifiable risk factor for complications after mandible fracture. Objective: To identify novel risk factors for malunion/nonunion after mandible fracture and determine the impact of treatment delay on malunion and nonunion after open reduction of mandible fractures. Design: Retrospective cohort. Setting and Participants: Encounter billing records from the New York State Inpatient Databases, State Emergency Department Databases, and State Ambulatory Surgery Databases. Patients aged 18 years and older with isolated mandible fracture in the emergency department or inpatient setting from January 1, 2006 to September 30, 2015. Main Outcomes and Measures: Mandibular Malunion/Nonunion. Results: A total of 19,152 adults were diagnosed with isolated mandible fracture. After fracture, 247 patients (1.3%) developed mandibular malunion or nonunion. In multivariable analysis, patients with open fractures (odds ratio [OR] 1.93, confidence interval [95% CI] 1.40-2.65), body fractures (OR 2.00, 1.50-2.65), alcohol abuse (OR 1.61, 1.22-2.11), diabetes mellitus (OR 1.57, 1.02-2.42), and Medicaid insurance (OR 1.46, 1.03-2.07) had increased risk, whereas patients with subcondylar fractures had reduced risk (OR 0.45, 0.28-0.72) of mandibular malunion/nonunion. The risk of mandibular malunion/nonunion after open reduction increased with treatment delay until 6-7 days after presentation (OR 1.84, 1.11-3.06). Conclusion and Relevance: Although treatment delay is often unavoidable, these findings suggest that physicians should consider early intervention in patients requiring open reduction of mandible fractures when able.

Prolonged time to extubation after general anaesthesia is associated with early escalation of care: A retrospective observational study.

BACKGROUND: Prolonged time to extubation after general anaesthesia has been defined as a time from the end of surgery to airway extubation of at least 15 min. This occurrence can result in ineffective utilisation of operating rooms and delays in patient care. It is unknown if unanticipated delayed extubation is associated with escalation of care. OBJECTIVES: To assess the frequency of 'prolonged extubation' after general anaesthesia and its association with 'escalation of care before discharge from the postanaesthesia care unit', defined as administration of reversal agents for opioids and benzodiazepines, airway re-intubation and need for ventilatory support. In addition, we tried to identify independent factors associated with 'prolonged extubation'. DESIGN: Single-centre retrospective study of cases performed from 1 January 2010 to 31 December 2014. SETTING: A large US tertiary academic medical centre. PATIENTS: Adult general anaesthesia cases excluding cardiothoracic, otolaryngology and neurosurgery procedures, classified as: Group 1 - regular extubation (≤15 min); Group 2 - prolonged extubation (≥16 and ≤60 min); Group 3 - very prolonged extubation (≥61 min). MAIN OUTCOME MEASURES: First, cases with prolonged time to extubation; second, instances of escalation of care per extubation group; third, independent factors associated with prolonged time to extubation. RESULTS: A total of 86 123 cases were analysed. Prolonged extubation occurred in 8138 cases (9.5%) and very prolonged extubation in 357 cases (0.4%). In Groups 1, 2 and 3 respectively, naloxone was used in 0.4, 4.1 and 3.9% of cases, flumazenil in 0.03, 0.6 and 2% and respiratory support in 0.2, 0.7 and 2%, and immediate re-intubation occurred in 0.1, 0.3 and 2.8% of cases. Several patient-related, anaesthesia-related and procedure-related factors were independently associated with prolonged time to extubation. CONCLUSION: Prolonged time to extubation occurred in nearly 10% of cases and was associated with an increased incidence of escalation of care. Many independent factors associated with 'prolonged extubation' were nonmodifiable by anaesthetic management.

Occlusion and Functional Outcomes after Complete Temporomandibular Joint Resection with Soft Tissue Reconstruction.

Reconstructive outcomes after complete temporomandibular joint (TMJ) resection, including the condyle and glenoid fossa bone, are poorly defined in the literature. We described our technique and reviewed occlusion and functional outcomes of 6 consecutive patients undergoing complete TMJ resection and reconstruction with anterolateral thigh free tissue transfer and intermaxillary fixation with elastic bands for 6 to 8 weeks. At median follow-up of 14 months, median Mandibular Function Impairment Questionnaire score was 32 (range, 4-38), indicating mild to moderate impairment. Subjective occlusion was normal in 4 of 6 patients. Premature occlusal contact was seen in 2 of 6 patients. Maximal interincisor distance and horizontal mandibular shift with jaw abduction ranged from 29 to 40 mm and 5 to 8 mm, respectively. Four of 6 tolerated regular diets while 2 adhered to mechanical soft diets; no patients were feeding tube dependent. Soft tissue-only reconstruction after complete TMJ resection resulted in good subjective and objective occlusion in 4 of 6 patients and no cases of severe functional impairment.

Trend of surgery for orbital cellulitis: An analysis of state inpatient databases.

OBJECTIVES/HYPOTHESIS: To evaluate the trend and factors associated with surgical management of orbital cellulitis. STUDY DESIGN: Retrospective database study. METHODS: Study using the State Inpatient Databases (SIDs) from 2008 to 2015. Patients with an International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) diagnosis code for orbital cellulitis were identified in the SIDs for the following states: Arkansas, Florida, Iowa, Maryland, Nebraska, New York, and Wisconsin. Surgery was defined as an ICD-9-CM procedure code for orbitotomy and/or functional endoscopic sinus surgery. The trend of surgery over time was evaluated using the Cochran-Armitage test. Multivariable logistic regression models were used to identify patient- and hospital-level factors associated with surgery. RESULTS: From 2008 to 2013, the number of hospitalizations for orbital cellulitis ranged from 1,349 to 1,574, but declined to 865 in 2014. From 2008 to 2015, the number of surgeries ranged from 103 to 154. For children (n = 3,041), age, ophthalmologic comorbidity, and conjunctival edema were significantly associated with surgery, whereas for adults (n = 7,961), male gender, private insurance, optic neuritis, and cranial nerves III/VI/VI palsy were associated with surgery. CONCLUSIONS: Although the number of inpatient hospitalizations for orbital cellulitis has markedly declined, the number of surgeries for orbital cellulitis has remained fairly stable, leading to an observed higher proportion of hospitalized patients undergoing surgery. Future directions include extending the time frame to the present day to assess current rates of hospitalization and surgery. Knowledge of surgical trends and patient- and hospital-level characteristics associated with surgery may help improve management guidelines for and understanding of this vision-threatening disease. LEVEL OF EVIDENCE: NA Laryngoscope, 130:567-574, 2020.

Predicting Hearing Loss After Radiotherapy and Cisplatin Chemotherapy in Patients With Head and Neck Cancer.

Importance: Accurate, accessible predictions of posttreatment hearing loss for patients with head and neck cancer prior to the initiation of treatment are a necessary part of informed patient decision-making. Objective: To develop a prediction model for postradiotherapy and/or post-cisplatin chemotherapy hearing loss for patients with head and neck cancer. Design, Setting, and Participants: A retrospective cohort study was conducted at a tertiary academic medical center among 242 patients (482 ears) with head and neck cancer who were treated with radiotherapy and/or cisplatin from October 1, 2014, to July 31, 2018, and had follow-up audiometric data available. Exposures: Radiotherapy and cisplatin chemotherapy. Main Outcomes and Measures: Patient hearing level, as measured by the mean of pure tone audiometry at 1, 2, and 4 kHz on completion of treatment. A multivariable mixed model for predicting the posttreatment pure tone average was developed using only information available to clinicians at the beginning of treatment. Results: A total of 242 patients (482 ears; 56 women and 186 men; mean [SD] age, 60 [10] years) were included in the analysis. All patients in the study received radiotherapy, and 105 (43.4%) received cisplatin chemotherapy. The mean (SD) total cumulative cisplatin dose was 298 (109) mg/m2. Patients' ears received a mean (SD) cochlear radiotherapy dose of 15 (13) Gy. The fixed-effects predictions from the predictive model agreed with 77% (95% CI, 73%-81%) of the variability in the posttreatment pure tone average. This predictive model also had a sensitivity of 80% and a specificity of 75% for predicting an observed posttreatment pure tone average greater than 35 dB (area under the receiver operating characteristic curve, 0.85). Conclusions and Relevance: To our knowledge, this study develops the first accurate prediction model of posttreatment hearing in patients with head and neck cancer that is feasible for use in the clinical setting before the initiation of treatment. This research confirms that exposure of the cochlea to cisplatin chemotherapy and radiotherapy is associated with hearing loss in patients with head and neck cancer. Finally, this research motivates future studies of ototoxic effects to better understand the adverse effects of head and neck cancer treatment.