Purpose The genetic differences between Human papilloma Virus (HPV)-positive and negative head and neck squamous cell carcinomas (HNSCC) remain largely unknown. In order to identify differential biology and novel therapeutic targets for both entities we determined mutations and copy number aberrations in a large cohort of locoregionally-advanced HNSCC. Experimental Design We performed massively parallel sequencing of 617 cancer-associated genes in 120 matched tumor/normal samples (42.5% HPV-positive). Mutations and copy number aberrations were determined and results validated with a secondary method. Results The overall mutational burden in HPV-negative and HPV-positive HNSCC was similar with an average of 15.2 versus 14.4 somatic exonic mutations in the targeted cancer-associated genes. HPV-negative tumors showed a mutational spectrum concordant with published lung squamous cell carcinoma analyses with enrichment for mutations in TP53, CDKN2A, MLL2, CUL3, NSD1, PIK3CA and NOTCH genes. HPV-positive tumors showed unique mutations in DDX3X, FGFR2/3 and aberrations in PIK3CA, KRAS, MLL2/3 and NOTCH1 were enriched in HPV-positive tumors. Currently targetable genomic alterations were identified in FGFR1, DDR2, EGFR, FGFR2/3, EPHA2 and PIK3CA. EGFR, CCND1, and FGFR1 amplifications occurred in HPV-negative tumors, while 17.6% of HPV-positive tumors harbored mutations in Fibroblast Growth Factor Receptor genes (FGFR2/3) including six recurrent FGFR3 S249C mutations. HPV-positive tumors showed a 5.8% incidence of KRAS mutations, and DNA repair gene aberrations including 7.8% BRCA1/2 mutations were identified. Conclusions The mutational makeup of HPV-positive and HPV-negative HNSCC differs significantly, including targetable genes. HNSCC harbors multiple therapeutically important genetic aberrations, including frequent aberrations in the FGFR and PI3K pathway genes.

IMPORTANCE Patients with frailty have higher risk for postoperative mortality and complications; however, most research has focused on small groups of high-risk procedures. The associations among frailty, operative stress, and mortality are poorly understood.OBJECTIVE To assess the association between frailty and mortality at varying levels of operative stress as measured by the Operative Stress Score, a novel measure created for this study. DESIGN, SETTING, AND PARTICIPANTSThis retrospective cohort study included veterans in the Veterans Administration Surgical Quality Improvement Program from April 1, 2010, through March 31, 2014, who underwent a noncardiac surgical procedure at Veterans Health Administration Hospitals and had information available on vital status (whether the patient was alive or deceased) at 1 year postoperatively. A Delphi consensus method was used to stratify surgical procedures into 5 categories of physiologic stress. EXPOSURES Frailty as measured by the Risk Analysis Index and operative stress as measured by the Operative Stress Score. MAIN OUTCOMES AND MEASURES Postoperative mortality at 30, 90, and 180 days. RESULTS Of 432 828 unique patients (401 453 males [92.8%]; mean (SD) age, 61.0 [12.9] years), 36 579 (8.5%) were frail and 9113 (2.1%) were very frail. The 30-day mortality rate among patients who were frail and underwent the lowest-stress surgical procedures (eg, cystoscopy) was 1.55% (95% CI, 1.20%-1.97%) and among patients with frailty who underwent the moderate-stress surgical procedures (eg, laparoscopic cholecystectomy) was 5.13% (95% CI, 4.79%-5.48%); these rates exceeded the 1% mortality rate often used to define high-risk surgery. Among patients who were very frail, 30-day mortality rates were higher after the lowest-stress surgical procedures (10.34%; 95% CI, 7.73%-13.48%) and after the moderate-stress surgical procedures (18.74%; 95% CI, 17.72%-19.80%). For patients who were frail and very frail, mortality continued to increase at 90 and 180 days, reaching 43.00% (95% CI, 41.69%-44.32%) for very frail patients at 180 days after moderate-stress surgical procedures. CONCLUSIONS AND RELEVANCEWe developed a novel operative stress score to quantify physiologic stress for surgical procedures. Patients who were frail and very frail had high rates of postoperative mortality across all levels of the Operative Stress Score. These findings suggest that frailty screening should be applied universally because low-and moderate-stress procedures may be high risk among patients who are frail.

IMPORTANCE Surgical treatment comparisons in rare diseases are difficult secondary to the geographic distribution of patients. Fortunately, emerging technologies offer promise to reduce these barriers for research. OBJECTIVE To prospectively compare the outcomes of the 3 most common surgical approaches for idiopathic subglottic stenosis (iSGS), a rare airway disease. DESIGN, SETTING, AND PARTICIPANTS In this international, prospective, 3-year multicenter cohort study, 810 patients with untreated, newly diagnosed, or previously treated iSGS were enrolled after undergoing a surgical procedure (endoscopic dilation [ED], endoscopic resection with adjuvant medical therapy [ERMT], or cricotracheal resection [CTR]). Patients were recruited from clinician practices in the North American Airway Collaborative and an online iSGS community on Facebook. MAIN OUTCOMES AND MEASURES The primary end point was days from initial surgical procedure to recurrent surgical procedure. Secondary end points included quality of life using the Clinical COPD (chronic obstructive pulmonary disease) Questionnaire (CCQ), Voice Handicap Index-10 (VHI-10), Eating Assessment Test-10 (EAT-10), the 12-Item Short-Form Version 2 (SF-12v2), and postoperative complications. RESULTS Of 810 patients in this cohort, 798 (98.5%) were female and 787 (97.2%) were white, with a median age of 50 years (interquartile range, 43-58 years). Index surgical procedures were ED (n = 603; 74.4%), ERMT (n = 121; 14.9%), and CTR (n = 86; 10.6%). Overall, 185 patients (22.8%) had a recurrent surgical procedure during the 3-year study, but recurrence differed by modality (CTR, 1 patient [1.2%]; ERMT, 15 [12.4%]; and ED, 169 [28.0%]). Weighted, propensity score-matched, Cox proportional hazards regression models showed ED was inferior to ERMT (hazard ratio [HR], 3.16; 95% CI, 1.8-5.5). Among successfully treated patients without recurrence, those treated with CTR had the best CCQ (0.75 points) and SF-12v2 (54 points) scores and worst VHI-10 score (13 points) 360 days after enrollment as well as the greatest perioperative risk. CONCLUSIONS AND RELEVANCE In this cohort study of 810 patients with iSGS, endoscopic dilation, the most popular surgical approach for iSGS, was associated with a higher recurrence rate compared with other procedures. Cricotracheal resection offered the most durable results but showed the greatest perioperative risk and the worst long-term voice outcomes. Endoscopic resection with medical therapy was associated with better disease control compared with ED and had minimal association with vocal function. These results may be used to inform individual patient treatment decision-making.

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