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Purpose: Pembrolizumab improved survival in patients with recurrent or metastatic head and neck squamous-cell carcinoma (HNSCC). The aims of this study were to determine if pembrolizumab would be safe, result in pathologic tumor response (pTR), and lower the relapse rate in patients with resectable human papillomavirus (HPV)-unrelated HNSCC., Patients and Methods: Neoadjuvant pembrolizumab (200 mg) was administered and followed 2 to 3 weeks later by surgical tumor ablation. Postoperative (chemo)radiation was planned. Patients with high-risk pathology (positive margins and/or extranodal extension) received adjuvant pembrolizumab. pTR was quantified as the proportion of the resection bed with tumor necrosis, keratinous debris, and giant cells/histiocytes: pTR-0 (<10%), pTR-1 (10%-49%), and pTR-2 (≥50%). Coprimary endpoints were pTR-2 among all patients and 1-year relapse rate in patients with high-risk pathology (historical: 35%). Correlations of baseline PD-L1 and T-cell infiltration with pTR were assessed. Tumor clonal dynamics were evaluated (ClinicalTrials.gov NCT02296684)., Results: Thirty-six patients enrolled. After neoadjuvant pembrolizumab, serious (grades 3-4) adverse events and unexpected surgical delays/complications did not occur. pTR-2 occurred in eight patients (22%), and pTR-1 in eight other patients (22%). One-year relapse rate among 18 patients with high-risk pathology was 16.7% (95% confidence interval, 3.6%-41.4%). pTR ≥10% correlated with baseline tumor PD-L1, immune infiltrate, and IFNγ activity. Matched samples showed upregulation of inhibitory checkpoints in patients with pTR-0 and confirmed clonal loss in some patients., Conclusions: Among patients with locally advanced, HPV-unrelated HNSCC, pembrolizumab was safe, and any pathologic response was observed in 44% of patients with 0% pathologic complete responses. The 1-year relapse rate in patients with high-risk pathology was lower than historical., (©2020 American Association for Cancer Research.)

Learning Objectives: Identify factors associated with skin graft take in fibula free flaps (FFF) and radial forearm free flaps (RFFF) donor sites., Study Objectives: To determine which factors are associated with decreased skin graft take at the donor site in FFF and RFFF in head and neck patients., Design: Retrospective Chart Review Case Series., Setting: Multicenter Tertiary Care., Methods: A multicenter retrospective review was performed at three institutions identifying patients who underwent free tissue transfer, specifically either FFF or RFFF, between 2007 and 2017. Patient demographics, medical history, and social history were examined including age, gender, BMI, smoking status, diabetes and preoperative anticoagulation use. Preoperative, intraoperative data, and postoperative data were also examined including tourniquet use, type of flap, area of skin graft, if the skin graft had a donor site or if it was taken from the flap, wound NPWT use, cast use, use of physical therapy, DVT prophylaxis, limb ischemia, heparin drip, and postoperative aspirin use. Statistical analysis was used to determine which factors were significantly associated with skin graft take., Results: 1415 patients underwent a forearm or fibula flap and 938 patients underwent split-thickness skin graft. Of these, 592 patients had sufficient information and were included in the final analysis. There were 371 males and 220 females. The average age was 55.7. Complete skin graft take was seen in 480 patients (81.1%). On univariate analysis, patients with diabetes (p = .003), type of flap (fibula p < .001), skin graft area (p = .006), tourniquet use (p = .003), DVT prophylaxis (p = .008) and casting (p = .003) were significantly associated with decreased skin graft take rate. In a multivariate analysis, diabetes (OR 2.17 (95%CI 1.16-3.98)), fibula flaps (OR 2.86 (95%CI 1.79-4.76)), an increase in skin graft area (OR 1.01 (95%CI 1.01-1.01)), post-operative aspirin (OR 2.63 (95%CI 1.15-5.88), and casting (OR 2.94 (95%CI 1.22-7.14)) were associated with poor rates of skin graft take., Conclusion: Several factors affect skin graft take rate and should be considered when performing a skin graft for a donor site defect., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Purpose: Our objective was to understand which variables are associated with hematoma formation at both the donor and recipient sites in head and neck free tissue transfer and if hematoma rates are affected by tourniquet use., Methods: Patients were identified who underwent free tissue transfer at three institutions, specifically either a radial forearm free flap (RFFF) or a fibula free flap (FFF), between 2007 and 2017. Variables including use of tourniquet, anticoagulation, treatment factors, demographics, and post-operative factors were examined to see if they influenced hematoma formation at either the free tissue donor or recipient site., Results: 1410 patients at three institutions were included in the analysis. There were 692 (49.1%) RFFF and 718 (50.9%) FFF. Tourniquets were used in 764 (54.1%) cases. There were 121 (8.5%) hematomas. Heparin drips (p < .001) and DVT prophylaxis (p = .03) were significantly associated with hematoma formation (OR 95% CI 12.23 (4.98-30.07), 3.46 (1.15-10.44) respectively) on multivariable analysis., Conclusions: Heparin Drips and DVT prophylaxis significantly increased hematoma rates in free flap patients while tourniquets did not affect rates of hematoma., Competing Interests: Declaration of competing interest None of the authors has a financial interest in any of the products, devices, or drugs mentioned in this manuscript., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Introduction: The strength of glottic closure with recurrent laryngeal nerve (RLN) stimulation has been indirectly measured experimentally by determining the squeezing pressure on a balloon inserted between the vocal folds, termed laryngeal adductory pressure (LAP). In this study, we sought to measure glottic closing force (GCF) directly and compare these results to LAP measures obtained with identical stimulation parameters., Methods: In canines, a method for measuring GCF was developed in which a suture was looped through a lateral thyrotomy hole, around the vocal process and back, then attached to a force gauge. The RLN was maximally stimulated and GCF recorded. The LAP was then measured as previously described, using the same stimuli. This process was repeated at 9 stimulation frequencies in 10-Hz intervals from 20 to 100 Hz. The GCF and LAP were compared using Pearson's correlation coefficient (PCC)., Results: Both sides were measured in 16 dogs, resulting in 32 data sets. The LAP measures were obtained at all frequencies, while GCF was obtained in 246 of 288 (85.4%) attempts. The maximum GCF for each dog typically occurred at 80 to 100 Hz and averaged 0.287 ± 0.106 newtons. Plotting GCF versus LAP for each hemilaryngeal preparation, the mean PCC was 0.932 ± .042 (range, 0.802-0.987). The mean PCC did not differ between control (n = 26) and postoperative (n = 6) hemilarynges., Conclusion: This method for measuring GCF appears valid. The high Pearson's correlation coefficient indicates strong covariance between GCF and LAP, demonstrating that they are both measures of the same physical property. The LAP is easier to perform and more consistently obtained.

Importance: Damage to the recurrent laryngeal nerve (RLN) is highly detrimental to voice, swallow, and cough. The optimal method for reconstitution of a nerve gap after injury is unknown., Objective: To evaluate multiple methods of RLN reconstruction., Design, Setting, and Participants: This study used an established canine model of RLN injury to examine purpose-bred, conditioned, female, 20-kg mongrel hounds at Washington University. A total of 32 dogs were examined, with 63 experiments performed., Interventions: Surgical transection or excision of the RLN with reconstruction by multiple methods., Main Outcomes and Measures: Six months after injury repair, laryngeal adductor pressures (LAPs), spontaneous and stimulable movement, and graft axon counts by histologic analysis were assessed., Results: Simple RLN transection with direct neurorrhaphy provided a mean (SD) recovery of 55.5% (12.5%) of baseline LAPs (P = .18 for comparison of LAP recovery among cases from the conventional nerve graft [39.4% (22.2%)]; P = .63 for comparison of LAP recovery among cases from the reverse autograft [60.8% (27.5%)]). Revascularized grafts provided a recovery of 54.5% (46.4%) while short and long acellular grafts provided recoveries of 60.4% (NA) and 39.5% (17.0%). Two of 11 polyglycolic acid reconstructions provided a measurable LAP with a mean (SD) recovery of 37.1% (8.9%) of baseline. Reconstruction with a neural conduit in any condition provided no measurable LAP recovery., Conclusions and Relevance: Conventional nerve grafting resulted in no significant difference in recovery of LAP function compared with simple neurorrhaphy or reverse autograft. Conventional and revascularized nerve grafts provided similar recovery. The use of bioengineered acellular nerve grafts or nerve conduits for reconstruction resulted in poor recovery of function.

Importance: Little is known about treatment outcomes for T4 oropharyngeal squamous cell carcinoma (OPSCC), particularly in the era of human papillomavirus (HPV)-related disease., Objective: To evaluate oncologic outcomes for T4 OPSCC treated with primary surgical and nonsurgical therapies., Design, Setting, and Participants: Retrospective cohort study of 131 patients from a single academic hospital, who were treated for T4a or T4b OPSCC (with any N stage and without distant metastatic disease at presentation) between 1998 and 2012 and had a minimum 2-year follow-up (the median follow-up time was 34.6 months). This study was conducted between January 1, 1998, and November 1, 2012., Interventions: Sixty-nine patients underwent nonsurgical therapy, 47 (68%) of whom had p16-positive tumors. Nonsurgical treatment paradigms included induction chemotherapy followed by chemoradiotherapy (n = 36 [54%]), concurrent chemoradiotherapy (n = 29 [43%]), and induction chemotherapy followed by radiation therapy alone (n = 2 [3%]). Sixty-two patients underwent surgical treatment, 50 (81%) of whom had p16-positive tumors. Fifty-seven surgical patients (92%) received adjuvant therapy., Main Outcomes and Measures: Overall survival (OS) was the primary outcome measure. Secondary outcome measures included disease-specific survival (DSS), disease-free survival (DFS), 2-year gastrostomy and tracheostomy tube rates, and major complication rates., Results: Significant baseline differences between the surgical vs nonsurgical groups included age (mean 59.8 vs 55.4 years [P = .005]), sex (male, 95% vs 84% [P = .04]), body mass index (<18.5 [calculated as weight in kilograms divided by height in meters squared], 3% vs 16% [P = .02]), and smoking history of 10 or more pack-years (48% vs 77% [P = .003]). For p16-positive patients, Kaplan-Meier estimates of OS, DSS, and DFS were significantly higher for surgically treated patients than for the nonsurgical group (χ(2)(1) = 7.335 for log-rank P = .007, χ(2)(1) = 8.607 for log-rank P = .003, and χ(2)(1) = 7.763 for log-rank P = .005, respectively). For p16-negative patients, Kaplan-Meier estimates of OS and DSS were higher for the surgical group but did not reach statistical significance (χ(2)(1) = 2.649 for log-rank P = .10 and χ(2)(1) = 2.077 for log-rank P = .15, respectively), while estimates of DFS were significantly higher for patients treated with primary surgery (χ(2)(1)= 3.869 for log-rank P = .049. In a multivariable Cox survival analysis, p16-positive immunohistochemical status had a significant positive association with OS (hazard ratio [HR], 0.55; 95% CI, 0.32-0.95 [P = .03]), DSS (HR, 0.45; 95% CI, 0.22-0.92 [P = .03]), and DFS (HR, 0.55; 95% CI, 0.32-0.95 [P = .03]), and nonsurgical treatment had a significant negative association with OS (HR, 2.79; 95% CI, 1.51-5.16 [P = .001]), DSS (HR, 3.38; 95% CI, 1.59-7.16 [P = .002]), and DFS (HR, 2.59; 95% CI, 1.51-4.45 [P = .001])., Conclusions and Relevance: Primary surgical treatment may be associated with improved outcomes in patients with T4 OPSCC. p16 Immunohistochemical status remains a strong prognostic indicator even in patients with locally advanced disease.

Background: Hyperbaric oxygen (HBO) therapy is sometimes used to assist in wound healing after major head and neck cancer surgery. However, there is concern that HBO treatments might enhance the growth of any residual microscopic disease. This was studied in a mouse model of squamous cell carcinoma (SCC)., Methods: SCC-VII/SF tumor cells were cultured, and then injected (3 × 10(3) cells) into C3H/HeJ mice in 5 groups: subcutaneous (SQ) control (n = 13), SQ-immediate (n = 12), SQ-delayed (n = 13), tail vein control (n = 8), and tail vein immediate (n = 9). The 3 experimental groups were subjected to HBO therapy, 2.4 atm for 90 minutes, 5 days per week for 4 weeks, starting on postinjection day 3 ("immediate") or 10 ("delayed"). Tumors in the SQ mice were measured 3 times per week. Lung metastases in the tail vein mice were counted at necropsy., Results: At postimplantation day 28, when the immediate group completed its HBO therapy, the tumor volume in the SQ-immediate group was 49.1% higher than the control group, and the SQ-delayed group was 105.1% higher than controls (p < .05). Two weeks later, the SQ-immediate group and SQ-delayed group tumor volumes were still significantly higher than controls, but the difference was smaller (18.4% and 43.8%, respectively; p < .05 only for the delayed group). The tail vein groups had similar numbers of lung metastases, with a mean of 8.7 metastases in the control group and 9.0 metastases in the HBO group (not significant [NS])., Conclusion: This study suggests that HBO therapy does accelerate the growth of microscopic foci of SCCs. This finding differs from some earlier studies and warrants further study., (© 2014 Wiley Periodicals, Inc.)

Conjunctive consolidation, one method of multivariable analysis by arranging data into clusters, is intuitive and transparent. An unexpected consequence in writing this article was the discovery of just how useful it is in critically analyzing articles and in designing new projects. It has stimulated a fresh understanding as to the value of multivariable thinking in all clinical research. This article is organized into the sequential steps for performing conjunctive consolidation for critically analyzing an article of interest and for completing the process, pending all required data are available. Investigators, particularly those who perform clinical research, should consider conjunctive consolidation as a valuable method of multivariable analysis with which to report data.

Multivariable analyses are complex statistical methods to evaluate the impact of multiple variables on outcomes of interest. Books have been written on each of these methods detailing the mathematical and statistical objectives and processes. However, we have found very little in the way of brief reports that help the nonstatistically trained physician obtain a basic understanding of multivariable analyses in order to have some understanding of the increasing literature using these methods. This work is organized in 2 parts. This article, Part A, addresses the "big 4" algebraic methods of multivariable analysis. The primary focus of Part A is to present a brief "primer" to help the reader understand the methods and uses; it expressly avoids the many details of statistical assumptions, calculations, and myriad branching alternatives. Part B will concentrate on conjunctive consolidation and will focus on enough information to allow the interested reader to actually perform the analysis. For the statistical scholar, we have included references to several voluminous serious works.

Volatile elements have a fundamental role in the evolution of planets. But how budgets of volatiles were set in planets, and the nature and extent of volatile-depletion of planetary bodies during the earliest stages of Solar System formation remain poorly understood. The Moon is considered to be volatile-depleted and so it has been predicted that volatile loss should have fractionated stable isotopes of moderately volatile elements. One such element, zinc, exhibits strong isotopic fractionation during volatilization in planetary rocks, but is hardly fractionated during terrestrial igneous processes, making it a powerful tracer of the volatile histories of planets. Here we present high-precision zinc isotopic and abundance data which show that lunar magmatic rocks are enriched in the heavy isotopes of zinc and have lower zinc concentrations than terrestrial or Martian igneous rocks. Conversely, Earth and Mars have broadly chondritic zinc isotopic compositions. We show that these variations represent large-scale evaporation of zinc, most probably in the aftermath of the Moon-forming event, rather than small-scale evaporation processes during volcanism. Our results therefore represent evidence for volatile depletion of the Moon through evaporation, and are consistent with a giant impact origin for the Earth and Moon.

The primary objective of graphing research data is to communicate key information visually in a rapid, accurate, and concise way. Graphs might be considered visual take-home lessons of the major point(s) of the manuscript. In choosing a graph, it is tempting to concentrate only on ways of illustrating summary statements characterizing the group(s). However, individual patients are unique, and their characteristics or outcomes may not be predicted by a group summary. Consequently, if possible, graphs should demonstrate individual responses as well as group summaries. "Graphical literacy," "graphical excellence," and "graphical acumen" are achievable with work and collaboration. To produce a well-designed graph, a combination of by-subject detail and overall results should be the goal within the same illustration. The practice gap addressed in this article is that little attention from authors, reviewers, editors, and publishers seems to be paid to graphical literacy. The purpose of this article is to present some practical guidelines for choosing or evaluating more appropriate data displays.

Surveys with questionnaires play a vital role in decision and policy making in society. Within medicine, including otolaryngology, surveys with questionnaires may be the only method for gathering data on rare or unusual events. In addition, questionnaires can be developed and validated to be used as outcome measures in clinical trials and other clinical research architecture. Consequently, it is fundamentally important that such tools be properly developed and validated. Just asking questions that have not gone through rigorous design and development may be misleading and unfair at best; at worst, they can result in under- or overtreatment and unnecessary expense. Furthermore, it is important that consumers of the data produced by these instruments understand the principles of questionnaire design to interpret results in an optimal and meaningful way. This article presents a practical guide for understanding the methodologies of survey and questionnaire design, including the concepts of validity and reliability, how surveys are administered and implemented, and, finally, biases and pitfalls of surveys.

In 1958, Edward L. Kaplan and Paul Meier collaborated to publish a seminal paper on how to deal with incomplete observations. Subsequently, the Kaplan-Meier curves and estimates of survival data have become a familiar way of dealing with differing survival times (times-to-event), especially when not all the subjects continue in the study. "Survival" times need not relate to actual survival with death being the event; the "event" may be any event of interest. Kaplan-Meier analyses are also used in nonmedical disciplines. The purpose of this article is to explain how Kaplan-Meier curves are generated and analyzed. Throughout this article, we will discuss Kaplan-Meier estimates in the context of "survival" before the event of interest. Two small groups of hypothetical data are used as examples in order for the reader to clearly see how the process works. These examples also illustrate the crucially important point that comparative analysis depends upon the whole curve and not upon isolated points., (Copyright 2010 American Academy of Otolaryngology-Head and Neck Surgery Foundation. Published by Mosby, Inc. All rights reserved.)

A systematic review is a transparent and unbiased review of available information. The published systematic review must report the details of the conduct of the review as one might report the details of a primary research project. A meta-analysis is a powerful and rigorous statistical approach to synthesize data from multiple studies, preferably obtained from a systematic review, in order to enlarge the sample size from smaller studies to test the original hypothesis and/or to generate new ones. The objective of this article is to serve as an easy to read practical guide to understand systematic reviews and meta-analyses for those reading them and for those who might plan to prepare them.

The 95 percent confidence interval about the mean demarcates the range of values in which the mean would fall if many samples from the universal parent population were taken. In other words, if the same observation, experiment, or trial were done over and over with a different sample of subjects, but with the same characteristics as the original sample, 95 percent of the means from those repeated measures would fall within this range. This gives a measure of how confident we are in the original mean. It tells us not only whether the results are statistically significant because the CI falls totally on one side or the other of the no difference marker (0 if continuous variables; 1 if proportions), but also the actual values so that we might determine if the data seem clinically important. In contrast, the P value tells us only whether the results are statistically significant, without translating that information into values relative to the variable that was measured. Consequently, the CI is a better choice to describe the results of observations, experiments, or trials.

Objective: In a busy practice, time is a commodity in rare supply, and keeping abreast of the relevant medical literature is a daunting task. Even after reading an article carefully, important information may be lost because of undue attention to the methodological minutia., Method: Fundamental to reducing a complex article into a well-organized and consistent format is the technique of quantitatively diagramming the principal components in the design and findings of the study. This approach allows a coherent brief summary statement of the article, and a platform for a focused scientific discussion and analysis of the clinical applicability of the findings., Conclusions: The technique of diagramming an article is a tool that the senior author has used for years and has found it valuable in capturing the scientific fundamentals of a manuscript. Once prepared, the diagram has proven to be useful in clarifying presentations during journal club, preparing the background and significance sections of grant applications, reviewing articles as a journal editor and as a journal reviewer, and easily retrieving documents to support evidence-based practice efforts.

Case reports have been vital to the advancement of medicine, providing a mechanism for scholarly education and for sharing new discovery and rare observations. However, journals are increasingly reluctant to publish this type of manuscript. Additionally, case reports and limited case series are infrequently cited, potentially interfering with the impact factor of a journal. The increasing emphasis on evidence-based medicine may have artificially decreased the value of case reports. This article describes the value of case reports to medicine, citing 3 examples that have significantly improved the practice of medicine. We also provide criteria for effective reporting, which include the elements of both surprise and closure. In summary, we offer support for the contention that case reports are fundamental to the scholarly practice of medicine and enhance the intent of a quality medical journal.

Background: Analysis of geographical variation in utilization of medical resources is often used to identify regions of overutilization or underutilization., Methods: We surveyed the membership of the American Head and Neck Society regarding their recommended frequency of office visits and 13 imaging studies and blood tests for their patients after potentially curative therapy for upper aerodigestive tract cancers., Results: Of the 1322 members surveyed, 610 (46%) responded: 420 responses (32%) were assessable. Responses were compared by US Census Region, Metropolitan Statistical Area, and managed care organization penetration rate. Overseas members (16% of assessable responses) comprised a separate category for the regional analysis. There were statistically significant variations in practice patterns among Census Regions for office visits, complete blood count, computed tomography of the head, sonography, and esophagoscopy. Non-US members recommended significantly more blood tests, imaging studies, and endoscopy than US members for routine cancer surveillance. Only the frequency of office visits differed significantly among Metropolitan Statistical Areas. Surprisingly, the penetration rate of managed care organizations had no significant effect on posttreatment surveillance intensity., Conclusions: This analysis indicates that only a small portion of the wide variation in observed follow-up practice patterns can be explained by geographical determinants.

The objective was to analyze the impact of clinical beliefs on surgical decision making in the posttreatment follow-up of patients with upper aerodigestive tract cancer. Clinical beliefs, defined as perceived benefits and risks of surveillance, were examined. All 824 members of the Society of Head and Neck Surgeons (SHNS) and 522 members of the American Society for Head and Neck Surgery, who were not SHNS members, were surveyed using TNM stage-specific clinical vignettes to measure surgical decision making in the posttreatment follow-up of patients with upper aerodigestive tract cancer. Controlling for physician demographic and practice characteristics, the relationship between clinical beliefs and diagnostic test ordering practices of surgeons was examined using Poisson and negative binomial regression analysis. Age 50 and over and South Central U.S. practice location were significant predictors of the frequency of surveillance testing in at least three TNM stage I models as was the clinical belief that no survival benefit results from the follow-up of patients with TNM stage I cancers. Less than 15% of the variability in follow-up intensity was explained by the TNM stage I models. Predictive ability was substantially improved for the TNM stage II-IV models by including lower TNM stage practice patterns as an independent variable. Most models predicted at least 50% of the variation in follow-up testing. The two clinical beliefs with the greatest impact on surgical decision making in the posttreatment follow-up of patients with upper aerodigestive tract cancer are that surveillance: i) permits palliative treatment and improves quality of life and ii) provides no survival benefit for patients with TNM stage I cancers. Knowledge of lower TNM stage practice patterns can be used to further improve predictive ability for higher stage models.