Douglas R. Farquhar

RNA Oncoimmune Phenotyping of HPV-Positive p16-Positive Oropharyngeal Squamous Cell Carcinomas by Nodal Status

Importance Clinical trials that deintensify treatment for patients with suspected human papillomavirus (HPV)-positive oropharyngeal squamous cell carcinoma (OPSCC) use p16 expression to identify HPV-mediated tumors and guide treatment. While p16 staining has a strong correlation with good outcomes, approximately 12% of p16-positive patients have recurrent disease. Biomarkers that reveal tumor-specific characteristics, such as nodal involvement, may change therapy decisions. Objective To assess whether if a tumor-specific genetic signature exists for node-negative vs node-positive HPV 16–positive/p16-positive OPSCCs. Design, Setting, and Participants This was a retrospective cohort study with randomized case selection for p16 OPSCCs undertaken at a university-based, tertiary care cancer center. Samples were collected from patients with p16-positive OPSCC. A total of 21 HPV 16/p16–positive tumors were used in this study. Main Outcomes and Measures Gene expression profiles of node-negative vs node-positive tumor samples were evaluated using a differential expression analysis approach and the sensitivity and specificity of a molecular signature was determined. Results Among the 21 patients in the study (3 women, 18 men; mean [SD] age, 54.6 [9.6] years), 6 had node-negative disease and 15 had node-positive disease. Using differential expression analysis, we found 146 genes that were significantly different in patients with node-negative disease vs those with node-positive disease, of which 15 genes were used to create a genetic signature that could distinguish node-negative–like from node-positive–like disease. The resultant molecular signature has a sensitivity of 88.2% (95% CI, 63.6%-98.5%) and specificity of 85.7% (95% CI, 42.1%-99.6%). The positive likelihood ratio of this signature was 6.1 (95% CI, 1.0-38.2) and the negative likelihood ratio was 0.1 (95% CI, 0.04-0.5). Given this population’s prevalence of node-positive disease of 70.8%, the positive- and negative-predicative values for this gene signature were 93.7% (95% CI, 70.8%-98.9%) and 75.0% (95% CI, 44.1%-92.0%), respectively. In addition, we developed a gene signature using agnostic, machine learning software that identified a 40-gene profile that predicts node-negative disease from node-positive disease (area under the curve, 0.93; 95% CI, 0.63-1.00). Conclusions and Relevance Many HPV-16 and p16-positive tumors are treated as “lower-risk,” but they do not have similar genetic compositions at the biological level. The identification of subgroups with unique expression patterns, such as those with nodal metastases, may guide physicians toward alternative or more aggressive therapies. In our study, unguided clustering suggested that that the larger biological characteristics of a tumor could be a better prognostic biomarker.

Poor oral health affects survival in head and neck cancer

INTRODUCTIONnPoor oral health has emerged as a risk factor for squamous cell carcinoma of the head and neck (HNSCC) but its impact on survival has not been examined. We sought to estimate the impact of oral health indicators on survival in a population-based HNSCC cohort.nnnMATERIALS AND METHODSnCases (n=1381) and age-, sex- and race-matched controls (n=1396) were participants in the Carolina Head and Neck Cancer Epidemiologic Study (CHANCE). Vital status was determined via linkage with the National Death Index. Survival was considered at 5years post-diagnosis or study-enrollment for controls. Oral health was assessed using self-reported indicators including frequency of routine dental exams and tooth brushing. We used Kaplan-Meyer analyses and Cox regression to estimate adjusted hazard ratios (HR) and 95% confidence intervals (CI).nnnRESULTSnRoutine dental visits during the preceding 10years were associated with decreased mortality risk (>10 visits: HR=0.6, 95% CI=0.4-0.8) after adjusting for confounders. This effect was most pronounced for oral cavity cancer-(e.g., >10 visits: HR=0.4, 95% CI=0.2-0.9). Dental visits were also positively associated with survival among controls. No other routine health screening (e.g., eye exams) was associated with survival.nnnCONCLUSIONnWe found significant associations between markers of oral health and survival among both HNSCC cases and controls. This association was most pronounced for sites closer to the dentition. Oral health may have a direct effect on tumor biology due to the associated immune or inflammatory response. It may also represent a proxy for wellness or unmeasured social determinants of health.

A Pilot Comparison between Caregiver’s and Patient’s Perceived Quality of Life in Chronic Rhinosinusitis

Introduction Chronic rhinosinusitis negatively impacts a patient’s quality of life, but current studies only address the patient’s perception of their disease. Caregivers living with the patient may have an alternative perception of the severity of the quality of life disturbance that patient’s experience with chronic rhinosinusitis. Methods This was a prospective cohort study that enrolled patients with a confirmed chronic rhinosinusitis diagnosis who presented to clinic with a caregiver. At the initial visit, patients completed a Rhinosinusitis Disability Index. The caregiver completed a Rhinosinusitis Disability Index based on their perception of the patient’s symptoms in addition to a Modified Caregiver Strain Index and a Short Form-36 to assess caregiving strain and overall health, respectively. Statistical analyses were performed with significance defined as Pu2009<u20090.05 a priori. Results A total of 44 total subjects (22 patient and caregiver pairs) were enrolled. Patients reported a total Rhinosinusitis Disability Index of 36.8 (confidence interval: 26.9, 46.6), and caregivers reported a total Rhinosinusitis Disability Index of 50.4 [confidence interval: 38.8, 61.9] (Pu2009=u20090.02). The principal differences between patient and caregiver scores were noted in the emotional and physical domains (Pu2009=u20090.01 and Pu2009=u20090.05, respectively). Only the functional domain was not statistically different (Pu2009=u20090.20). The patient’s total Rhinosinusitis Disability Index is positively correlated with the caregiver’s total Modified Caregiver Strain Index with a spearman coefficient of .60 (p ≤ 0.005). Conclusions Caregivers experience greater strain as the patient’s quality of life declines. Caregivers perceive patients to have worse quality of life than patients report. Based on these data, caregivers may provide additional insight to the quality of life disturbance of chronic rhinosinusitis. In addition, the societal impact of chronic rhinosinusitis may be underestimated.

HPV-Positive Oropharyngeal Squamous Cell Carcinoma among Patients Taking Adalimumab for Autoimmune Disorders:

T he incidence of human papillomavirus (HPV)–associated oropharyngeal cancer (OPSCC) is rising and now accounts for the majority of oropharyngeal carcinomas. Recent evidence has linked immune dysregulation to both the reactivation of viral infections such as HPV and the risk of viral-associated cancers. However, this association has not been investigated in oropharyngeal cancer. In addition, many patients with autoimmune disease are now treated with biopharmaceuticals (biologics), potent immunosuppressants that may compound this risk. Tumor necrosis factor a (TNFa)–blocking agents in particular have been associated with reactivation of latent viruses, including HPV. However, a link between biologics and oropharyngeal carcinoma also remains unexplored. The purpose of this study is to characterize the presentation, treatment course, and outcomes in patients with HPVpositive OPSCC on biologics treated at a single tertiary care cancer center.

Predictors of Adverse Outcomes in Free Flap Reconstruction: A Single-Institution Experience

Objective Understanding the independent predictors of poor outcomes in free flap surgery is essential for patient selection. We aim to determine the independent predictors of major complications, flap survival, and extended hospital stays. Study Design Retrospective cohort study. Setting Tertiary medical center. Subjects and Methods We reviewed medical records from all vascularized tissue transfers in the head and neck between 2007 and 2014 at our institution. We recorded demographics, medical comorbidities, disease characteristics, flap characteristics, and intraoperative events. We defined outcomes as major complications in the 30-day postoperative period, flap death or partial flap survival, and a length of stay ≥14 days. We used bivariate and multivariate methods to test for associations. Results Of 170 free flap operations, 44% had major complications; 11% fully or partially failed; and 27% required an extended hospital stay. Independent predictors of major complications were age ≥60 years (odds ratio [OR], 3.7; P = .001), revision surgery (OR, 3.5; P = .004), and a prior neck dissection (OR, 3.5; P = .004). Independent predictors of flap failure were revision surgery (OR, 4.1, P = .01) and the use of a plate (OR, 3.7; P = .03). Revision surgery was independently associated with a longer stay (OR, 3.0; P = .01), and the use of a radial forearm flap was associated with a shorter stay (OR, 0.3, P = .047). Conclusion These results underscore that caution is warranted in revision flap surgery, patients with prior neck operations, and patients aged ≥60 years.

Oral tongue carcinoma among young patients: An analysis of risk factors and survival

INTRODUCTIONnThe incidence of oral tongue squamous cell carcinoma (OTSCC) in younger adults has rapidly increased over the past two decades. While tobacco and alcohol use may be less likely to cause these tumors, it remains controversial whether differences also exist in their prognosis. Our aim is to examine the risk factors for cancer among young (<45u202fyears old) OTSCC patients at our institution, and to compare their recurrence and survival with older patients in a matched cohort.nnnMATERIALS AND METHODSnAll OTSCC patients seen at our institution between 2000 and 2015 were reviewed. Patients under 45 who with sufficient treatment information were matched 1:1 on race, T-stage, and N-stage with patients 45 and older. Three-year recurrence and survival were determined in stratified and adjusted Cox regression models.nnnRESULTSnOf 397 OTSCC patients were seen at our institution, 117 (29%) were less than 45u202fyears old. Younger patients were significantly more likely to be female, (50% vs. 39%; pu202f=u202f0.04) and to abstain from tobacco (51% vs. 39%; pu202f<u202f0.01). Young patients in the matched cohort were significantly more likely to have a recurrence (HR 3.9 95% CI 1.4-10.5). There was no difference in overall survival.nnnCONCLUSIONnYounger OTSCC patients in a matched cohort were more likely to recur within 3u202fyears, although there was no difference in overall mortality. Differences in risk factors and recurrence between older and younger patients suggest that some cancer among younger patients may be distinct from traditional OTSCC.

Depth of invasion on pathological outcomes in clinical low-stage oral tongue cancer patients

OBJECTIVESnDepth of invasion was added to the eighth edition American Joint Committee on Cancer guidelines for T staging of HPV-negative oral cavity squamous cell carcinoma. Our aim was to determine the impact of depth of invasion on pathological variables and outcomes in low-stage tongue cancer patients. We also examine the impact of tumor thickness and tumor clinical staging for comparison.nnnSUBJECTS AND METHODSnAll clinical T1/T2 N0 HPV-negative tongue squamous cell carcinoma patients who received elective neck dissections at our institution between 2000 and 2015 were included. Logistic regression models and Cox proportional hazard models were used to examine pathological variables, recurrence, and 3-year disease-free survival.nnnRESULTSnSixty-seven patients met criteria; the mean age was 52.0 (SD: 17.7). Depth of invasion was a significant predictor of occult metastasis (OR: 2.0, pxa0=xa00.05) and lymphovascular invasion (OR: 4.1, pxa0=xa00.02), and tumor thickness was a significant predictor of lymphovascular invasion (OR: 3.3, pxa0=xa00.04). None of the variables were predictive of recurrence or disease-free survival.nnnCONCLUSIONnDepth of invasion at biopsy may be a potential useful metric to inform on regional management selection in this radiographic node-negative population.

Office-based laryngology: Technical and visual optimization by patient-positioning maneuvers: Head Turn Maneuvers to Visualize the Laryngopharynx

To qualitatively and quantitatively assess the effect of discrete head postures/maneuvers during flexible laryngoscopy on visualization of specific anatomical structures within the laryngopharynx.

Outcomes of Open vs Endoscopic Skull Base Surgery in Patients 70 Years or Older

Importance The use of skull base surgery in patients 70 years or older is increasing, but its safety in this age group has not been evaluated to date. Objectives To describe outcomes in a cohort of patients 70 years or older undergoing skull base surgery and to evaluate whether age, type of disease process, and approach (endoscopic vs traditional open surgery) are associated with increased intraoperative and postoperative complications in this population. Design, Setting, and Participants This retrospective cohort study analyzed a population-based sample of 219 patients 70 years or older from a database of 1720 patients who underwent skull base surgery at University of North Carolina Hospitals, Chapel Hill, a tertiary referral center, between October 2007 and June 2017. Data were collected from June 2016 to July 2017 and analyzed in July 2017 and August 2017. Exposure Skull base surgery. Main Outcomes and Measures Data collected included demographic characteristics, surgical approach, and disease process. Intraoperative findings and postoperative complications were analyzed by age, surgical approach, and malignancy status. Results Of the 219 patients, 166 were aged 70.0 to 79.9 years and 53 patients were older than 80 years (mean [SD] age, 76.4 [4.7] years); 120 (54.8%) were men and 160 (73.7%) were white. There were 161 (73.5%) endoscopic and 58 (26.5%) open operations. The most common pathologic processes among the 219 patients were nonsellar malignant (81 [37.0%]), nonsellar benign (53 [24.2%]), and pituitary (49 [22.4%]) tumors. The most common intraoperative and postoperative complications were intraoperative major bleeding (5 of 219 patients [2.3%]) and postoperative bleeding (9 [4.1%]). Thirty-day mortality was zero. There was no clinically meaningful difference in complications between patients aged 70.0 to 79.9 years vs those older than 80 years, endoscopic vs open surgery, or benign vs malignant neoplasms. Specifically, between the endoscopic and open surgery groups, there was no difference in intraoperative major bleeding (3.9%; 95% CI, −0.7% to 12.9%), postoperative cerebrospinal fluid leak (−0.6%; 95% CI, −3.4% to 5.6%), or postoperative bleeding (1.5%; 95% CI, −3.9% to 10.6%). Conclusions and Relevance Skull base surgery is a safe option in persons 70 years or older, with similar outcomes across age ranges, surgical approaches, and disease processes.

Association of Standardized Tracheostomy Care Protocol Implementation and Reinforcement With the Prevention of Life-Threatening Respiratory Events

Importance Mucus plugging after tracheostomy is a preventable cause of respiratory distress. Implementation of standardized tracheostomy care guidelines may reduce the occurrence of fatal respiratory compromise. Objective To determine the effect of implementing and reinforcing a standardized tracheostomy care protocol on the occurrence of acute life-threatening respiratory events. Design, Setting, and Participants Retrospective cohort study of adult patients who received a tracheostomy between May 2014 and August 2016 at a tertiary care center. Main Outcomes and Measures Patient demographics, tracheostomy indication, rapid response for mucus plugging and other acute events, duration of hospital stay, and levels of care that the patients received were recorded through examination of clinical logs. Statistical analysis was conducted between patients before protocol implementation and patients after protocol implementation in terms of rapid-response use, and intragroup comparison of the mean length of stay in various hospital units was also analyzed. Results A total of 247 patients (89 women [36%]; mean [SD] age, 58.5 [12.3] years), 117 preprotocol and 130 postprotocol, met inclusion criteria. Of the 130 patients in the postprotocol cohort, 123 (93%) were on the new tracheostomy care protocol. Preprotocol rapid-response rate was 21 of 117 patients (17.9%) and postprotocol response rate was 12 of 130 patients (9.2%) for a difference of 8.7% (95% CI, 0.2%-18.0%). In terms of mucus plugging, preprotocol rate was 8 of 117 patients (6.8%) and the postprotocol rate was 1 of 130 patients (0.8%) for a difference of 6.0% (95% CI, 1.3%-12.2%). Intragroup difference of the mean time spent (days) in various care units between patients in the no rapid-response group vs rapid-response group demonstrated clinically meaningful longer stay for rapid responses in both preprotocol and postprotocol groups for the intensive care unit (preprotocol, 2.03; 95% CI, 1.03-3.03 vs postprotocol, 3.02; 95% CI, 1.49-4.45) and step down units (preprotocol, 1.40; 95% CI, 0.77-2.02 vs postprotocol, 2.11; 95% CI, 0.78 to 3.44). Conclusions and Relevance Implementation and reinforcement of a standardized tracheostomy care protocol was associated with a reduction in the occurrences of rapid-response calls for life-threatening mucus plugging and is recommended for clinical practice. In addition, length of stay in the intensive care unit and intermediate surgical care unit was increased in a clinically meaningful way for patients who experienced a rapid-response event.