Early, precise, and safe clinical evaluation of the pharmacodynamic effects of novel agents in the intact human tumor microenvironment.

Introduction: Drug development is systemically inefficient. Research and development costs for novel therapeutics average hundreds of millions to billions of dollars, with the overall likelihood of approval estimated to be as low as 6.7% for oncology drugs. Over half of these failures are due to a lack of drug efficacy. This pervasive and repeated low rate of success exemplifies how preclinical models fail to adequately replicate the complexity and heterogeneity of human cancer. Therefore, new methods of evaluation, early in the development trajectory, are essential both to rule-in and rule-out novel agents with more rigor and speed, but also to spare clinical trial patients from the potentially toxic sequelae (high risk) of testing investigational agents that have a low likelihood of producing a response (low benefit). Methods: The clinical in vivo oncology (CIVO®) platform was designed to change this drug development paradigm. CIVO precisely delivers microdose quantities of up to 8 drugs or combinations directly into patient tumors 4-96 h prior to planned surgical resection. Resected tissue is then analyzed for responses at each site of intratumoral drug exposure. Results: To date, CIVO has been used safely in 6 clinical trials, including 68 subjects, with 5 investigational and 17 approved agents. Resected tissues were analyzed initially using immunohistochemistry and in situ hybridization assays (115 biomarkers). As technology advanced, the platform was paired with spatial biology analysis platforms, to successfully track anti-neoplastic and immune-modulating activity of the injected agents in the intact tumor microenvironment. Discussion: Herein we provide a report of the use of CIVO technology in patients, a depiction of the robust analysis methods enabled by this platform, and a description of the operational and regulatory mechanisms used to deploy this approach in synergistic partnership with pharmaceutical partners. We further detail how use of the CIVO platform is a clinically safe and scientifically precise alternative or complement to preclinical efficacy modeling, with outputs that inform, streamline, and de-risk drug development.

Gender inequities in ENT: Insights from women speakers at American Head and Neck Society meetings.

BACKGROUND: Gender inequity exists across national speakers at American Head and Neck Society (AHNS) conferences. This qualitative study explores potential causes of this disparity by surveying women invited to speak at AHNS between 2007 and 2019 and examining advice, resources, and meaningful actions from "those who made it." METHODS: An internet search for contact information for the 131 female AHNS was performed. An electronic survey was distributed via email. Deidentified qualitative responses were coded by two independent researchers into themes. Themes characterize barriers that female head and neck (HN) surgeons face and describe ways to mitigate the impact of these for the next generation. RESULTS: Contact information for 73/131 female AHNS speakers was obtained via internet search. Email responses were received from 22/73 (30%). Of those, respondents specialized in otolaryngology (n = 17), medical oncology (n = 2), palliative care (n = 1), vascular surgery (n = 1), and thoracic surgical oncology (n = 1). All speakers worked in academic settings at varying stages of their career with 81.8% (18/22) of respondents fellowship-trained (primarily HN surgery). Concerns about gender disparity in ENT were grouped into the following themes: (1) recruiting women to ENT, (2) removing barriers to career advancement, (3) diversifying ENT's national presence, and (4) improving the broader culture of HN surgery. Respondents emphasized a need for diversifying leadership, early exposure to otolaryngology in medical school, and connecting students with female role models. Outstanding research, involvement at annual meetings, and committee membership were consistently deemed important for establishing a national presence in the field. Implicit bias, "boys clubs" culture, and burdensome childcare responsibilities were described as barriers to career advancement. CONCLUSIONS: While encouraging more women to enter otolaryngology residencies, increasing the number female role models and establishing strong mentoring networks may help to mitigate challenges. Meaningful progress requires the efforts of both male and female allies within the specialty. Simple solutions, such as educating on implicit bias, removing demographics from applications, and eliminating hidden penalties for maternity leave, may help improve diversity and mitigate barriers to career progression for underrepresented groups within ENT.

Proton Treatment Suppresses Exosome Production in Head and Neck Squamous Cell Carcinoma.

Proton therapy (PT) is emerging as an effective and less toxic alternative to conventional X-ray-based photon therapy (XRT) for patients with advanced head and neck squamous cell carcinomas (HNSCCs) owing to its clustered dose deposition dosimetric characteristics. For optimal efficacy, cancer therapies, including PT, must elicit a robust anti-tumor response by effector and cytotoxic immune cells in the tumor microenvironment (TME). While tumor-derived exosomes contribute to immune cell suppression in the TME, information on the effects of PT on exosomes and anti-tumor immune responses in HNSCC is not known. In this study, we generated primary HNSCC cells from tumors resected from HNSCC patients, irradiated them with 5 Gy PT or XRT, and isolated exosomes from cell culture supernatants. HNSCC cells exposed to PT produced 75% fewer exosomes than XRT- and non-irradiated HNSCC cells. This effect persisted in proton-irradiated cells for up to five days. Furthermore, we observed that exosomes from proton-irradiated cells were identical in morphology and immunosuppressive effects (suppression of IFN-γ release by peripheral blood mononuclear cells) to those of photon-irradiated cells. Our results suggest that PT limits the suppressive effect of exosomes on cancer immune surveillance by reducing the production of exosomes that can inhibit immune cell function.

Managing Oromandibular Hardware Failure after Free Flap Surgery.

Hardware failure after oromandibular reconstruction using free tissue transfer can delay additional therapies directed at cancer treatment and prevent patients from returning to normal oral function. Understanding and strict adherence to principles of rigid fixation is critical in preventing complications. Early surgical intervention for hardware exposure as well as utilization of locoregional flaps may prevent the need for more extensive revision surgery.

Small extravesicular microRNA in head and neck squamous cell carcinoma and its potential as a liquid biopsy for early detection.

BACKGROUND: The objective was to assess secretion of small extracellular vesicular microRNA (exo-miRNA) in head and neck squamous cell carcinoma (HNSCC) according to human papillomavirus (HPV) status, and determine the translational potential as a liquid biopsy for early detection. METHODS: This study employed a combination of cell culture and case-control study design using archival pretreatment serum. Small extracellular vesicles (sEV) were isolated from conditioned culture media and human serum samples via differential ultracentrifugation. miRNA-sequencing was performed on each sEV isolate. RESULTS: There were clear exo-miRNA profiles that distinguished HNSCC cell lines from nonpathologic oral epithelial control cells. While there was some overlap among profiles across all samples, there were apparent differences in exo-miRNA profiles according to HPV-status. Importantly, differential exo-miRNA profiles were also apparent in serum from early-stage HNSCC cases relative to cancer-free controls. CONCLUSIONS: Our findings indicate that exo-miRNA are highly dysregulated in HNSCC and support the potential of exo-miRNA as biomarkers for HNSCC.

Association of Neoadjuvant Pembrolizumab for Oral Cavity Squamous Cell Carcinoma With Adverse Events After Surgery in Treatment-Naive Patients.

Importance: Pembrolizumab, a monoclonal antibody targeting programmed cell death 1, is currently approved by the US Food and Drug Administration for recurrent or metastatic head and neck squamous cell carcinoma (HNSCC). The potential neoadjuvant role of programmed cell death 1 inhibitors in primary surgical management of HNSCC and effects on surgical outcomes are poorly understood. Objective: To evaluate the incidence of postoperative adverse events in treatment-naive patients with advanced oral cavity cancer receiving neoadjuvant pembrolizumab when compared with matched controls, as part of a window-of-opportunity multi-institutional clinical trial assessing neoadjuvant pembrolizumab for locally advanced HNSCC. Design, Setting, and Participants: This retrospective cohort study at a single tertiary academic institution included treatment-naive patients with local regionally advanced oral cavity squamous cell carcinoma (OCSCC) who were undergoing surgical resection. Exposures: Patients with local regionally advanced resectable OCSCC who received neoadjuvant pembrolizumab were retrospectively reviewed for postoperative adverse events. Controls were matched by age, race, smoking status, and overall cancer stage based on historical data at the same institution. Matched-cohort analysis was performed using a McNemar test to assess differences between the groups. Main Outcomes and Measures: Incidence of adverse events following surgical resection of advanced OCSCC within 30 days of surgery and on continued follow-up. Results: A total of 64 patients (32 as part of the prospective clinical trial and 32 as controls; mean [SD] age, 59.6 [10.3] years; 28 [44%] women) were included in the analysis. Postoperative adverse events in the 32 patients receiving pembrolizumab included lymphedema (n = 20 [63%]), trismus (n = 7 [22%]), return to operating room (n = 7 [22%]), wound infection (n = 7 [22%]), fistula (n = 6 [19%]), wound dehiscence (n = 4 [13%]), flap failure (n = 3 [9%]), and hematoma (n = 2 [6%]). The matched control group demonstrated similar complication rates without considerable differences, except for trismus (n = 16 [50%]), which was greater by a difference of 28.1% (95% CI, 5.6%-50.6%) in the control group. Conclusions and Relevance: This cohort study examined surgical complications among patients with local regionally advanced OCSCC treated with neoadjuvant pembrolizumab and found that serious adverse events were similar to those in patients who underwent standard-of-care treatment. This suggests that there is no increased perioperative morbidity in the use of preoperative treatment with immunotherapy. Further prospective studies are needed to validate these findings for oral cavity cancer and other subsites of the head and neck.

Evaluating the Rising Incidence of Thyroid Cancer and Thyroid Nodule Detection Modes: A Multinational, Multi-institutional Analysis.

Importance: There is epidemiologic evidence that the increasing incidence of thyroid cancer is associated with subclinical disease detection. Evidence for a true increase in thyroid cancer incidence has also been identified. However, a true increase in disease would likely be heralded by an increased incidence of thyroid-referable symptoms in patients presenting with disease. Objectives: To evaluate whether modes of detection (MODs) used to identify thyroid nodules for surgical removal have changed compared with historic data and to determine if MODs vary by geographic location. Design, Setting, and Participants: This was a retrospective analysis of pathology and medical records of 1328 patients who underwent thyroid-directed surgery in 16 centers in 4 countries: 4 centers in Canada, 1 in Denmark, 1 in South Africa, and 12 in the US. The participants were the first 100 patients (or the largest number available) at each center who had thyroid surgery in 2019. The MOD of the thyroid finding that required surgery was classified using an updated version of a previously validated tool as endocrine condition, symptomatic thyroid, surveillance, or without thyroid-referable symptoms (asymptomatic). If asymptomatic, the MOD was further classified as clinician screening examination, patient-requested screening, radiologic serendipity, or diagnostic cascade. Main Outcomes and Measures: The MOD of thyroid nodules that were surgically removed, by geographic variation; and the proportion and size of thyroid cancers discovered in patients without thyroid-referable symptoms compared with symptomatic detection. Data analyses were performed from April 2021 to February 2022. Results: Of the 1328 patients (mean [SD] age, 52 [15] years; 993 [75%] women; race/ethnicity data were not collected) who underwent thyroid surgery that met inclusion criteria, 34% (448) of the surgeries were for patients with thyroid-related symptoms, 41% (542) for thyroid findings discovered without thyroid-referable symptoms, 14% (184) for endocrine conditions, and 12% (154) for nodules with original MOD unknown (under surveillance). Cancer was detected in 613 (46%) patients; of these, 30% (183 patients) were symptomatic and 51% (310 patients) had no thyroid-referable symptoms. The mean (SD) size of the cancers identified in the symptomatic group was 3.2 (2.1) cm (median [range] cm, 2.6 [0.2-10.5]; 95% CI, 2.91-3.52) and in the asymptomatic group, 2.1 (1.4) cm (median [range] cm, 1.7 [0.05-8.8]; 95% CI, 1.92-2.23). The MOD patterns were significantly different among all participating countries. Conclusions and Relevance: This retrospective analysis found that most thyroid cancers were discovered in patients who had no thyroid-referable symptoms; on average, these cancers were smaller than symptomatic thyroid cancers. Still, some asymptomatic cancers were large, consistent with historic data. The substantial difference in MOD patterns among the 4 countries suggests extensive variations in practice.

A multi-institutional study evaluating and describing atypical parathyroid tumors discovered after parathyroidectomy.

Objective: To describe common intraoperative and pathologic findings of atypical parathyroid tumors (APTs) and evaluate clinical outcomes in patients undergoing parathyroidectomy. Methods: In this multi-institutional retrospective case series, data were collected from patients who underwent parathyroidectomy from 2000 to 2018 from three tertiary care institutions. APTs were defined according to the AJCC eighth edition guidelines and retrospective chart review was performed to evaluate the incidence of recurrent laryngeal nerve injury, recurrence of disease, and disease-specific mortality. Results: Twenty-eight patients were identified with a histopathologic diagnosis of atypical tumor. Mean age was 56 years (range, 23-83) and 68% (19/28) were female. All patients had an initial diagnosis of primary hyperparathyroidism with 21% (6/28) exhibiting clinical loss of bone density and 32% (9/28) presenting with nephrolithiasis or renal dysfunction. Intraoperatively, 29% (8/28) required thyroid lobectomy, 29% (8/28) had gross adherence to adjacent structures and 46% (13/28) had RLN adherence. The most common pathologic finding was fibrosis 46% (13/28). Postoperative complications include RLN paresis/paralysis in 14% (4/28) and hungry bone syndrome in 7% (2/28). No patients with a diagnosis of atypical tumor developed recurrent disease, however there was one patient that had persistent disease and hypercalcemia that is being observed. There were 96% (27/28) patients alive at last follow-up, with one death unrelated to disease. Conclusion: Despite the new AJCC categorization of atypical tumors staged as Tis, we observed no recurrence of disease after resection and no disease-specific mortality. However, patients with atypical tumors may be at increased risk for recurrent laryngeal nerve injury and incomplete resection.

Descriptors in Letters of Recommendation for Otolaryngology Residency Across Gender, Race, and Time.

OBJECTIVE: To determine whether differences exist in the descriptors used in letters of recommendations for Otolaryngology - Head and Neck Surgery (OHNS) residency candidates, comparing race and gender as depicted in visual letters of recommendation (VLORs) from the 2014 and 2019 application cycles. DESIGN: Four hundred thirty-three LORS (284 narrative LORs and 149 standardized LORs) and 63 medical student performance evaluations for 104 candidates who interviewed at the University of Cincinnati OHNS residency program in 2014 and 2019 were analyzed. Descriptors from LORs and medical student performance evaluations were collected by two reviewers and QSR NVivo 12 was used to generate a word cloud that grouped words by synonym and weighted them by frequency. Reviewers coded these synonyms into one of eight descriptor categories. Race and gender were self-reported from residency applications. The average of each category frequency for each race and gender were compared using student t-tests. SETTING: University of Cincinnati OHNS Residency Program. PARTICIPANTS: 104 OHNS applicants that interviewed at the University of Cincinnati in 2014 and 2019. RESULTS: Of the 104 candidates reviewed, 39 were female (37.5%). 66/104 (63%) of applicants identified as white, 31/104 (30%) as non-white, and 7/104 (7%) preferred not to say. No significant differences were found between male vs female descriptors. However, white applicants had more "leadership" descriptors (1.3% vs 0.5%, p = 0.01) and fewer "intelligence" words (6.6% vs 4.8%, p = 0.02) than non-white applicants. Applicants in 2019 were described with more team player (14.2% vs 9.6%, p < 0.0001), leadership (1.6% vs 0.7%, p = 0.047), and reserved (1.7% vs 0.7%, p = 0.02) words, but fewer grindstone (25.2% vs 32.1%, p < 0.0001) and ability/agentic (27.9% vs 32.6%, p < 0.0001) words than applicants in 2014. CONCLUSIONS: In VLORs for OHNS residency, male and female applicants are described similarly, but white applicants are described as leaders more frequently and as intelligent less frequently than non-white counterparts. Regardless, it is encouraging to see applicants described with a more humanistic vocabulary in 2019.

Montgomery's Aperture: An External Anatomic Landmark for Surgical Identification of the Anterior Commissure.

OBJECTIVES: This study evaluates the consistency of palpable identification of an external landmark for the anterior commissure (AC), termed Montgomery's aperture (MA), in cadaveric and surgical settings. METHODS: Part 1: In human cadaveric larynges, palpation of the external laryngeal framework was used to identify MA by three blinded otolaryngologists. The vertical height (VH) of the thyroid cartilage and distance from MA to the inferior border of the thyroid cartilage were measured, larynges were bisected, and the AC was identified and measured. Surface anatomy was demonstrated visually using 3D imaging. Part 2: Retrospectively collected case series used palpation of MA in thyroplasty type 1 (TT1) and compared the result to ½ VH. RESULTS: Part 1: MA was identified in seven cadavers by three surgeons. In four of seven MA was palpated at the location of AC. The average difference between the AC and MA was -0.95 ± 0.96 mm. The average difference between AC and ½VH was 0.08 ± 0.72 mm. Part 2: In 49 patients (57% females) who underwent TT1, MA correlated within ½VH in 67% of cases. MA was inferior to ½VH in 27% of cases, on average 1.08 mm ± 0.51 mm below ½VH. MA was not palpable in 6% (3 of 49) of patients. CONCLUSION: We define the MA as the external indentation or flattening of the thyroid cartilage located within 1 millimeter inferior or at ½ VH of the thyroid cartilage. MA is a reliable, reproducible, palpable landmark for the anterior commissure. It serves as an important landmark that can be used in laryngoplastic surgery in which accurate prediction of the glottis is important.

Trends in Diagnosis of Noninvasive Follicular Thyroid Neoplasm With Papillarylike Nuclear Features and Total Thyroidectomies for Patients With Papillary Thyroid Neoplasms.

Importance: Increasing detection of early-stage papillary thyroid neoplasms without improvements in mortality has prompted development of strategies to prevent or mitigate overtreatment. Objective: To determine adoption rates of 2 recent strategies developed to limit overtreatment of low-risk thyroid cancers: (1) a new classification, noninvasive follicular thyroid neoplasm with papillarylike nuclear features (NIFTP), and (2) hemithyroidectomy for selected papillary thyroid carcinomas (PTCs) up to 4 cm in size. Design, Setting, and Participants: This is a cross-sectional analysis of 3368 pathology records of 2 cohorts of patients from 18 hospitals in 6 countries during 2 time periods (2015 and 2019). Participating hospitals were included from the US (n = 12), Canada (n = 2), Denmark (n = 1), South Korea (n = 1), South Africa (n = 1), and India (n = 1). The records of the first 100 patients per institution for each year who underwent thyroid-directed surgery (hemithyroidectomy, total thyroidectomy, or completion thyroidectomy) were reviewed. Main Outcomes and Measures: Frequency of diagnosis of NIFTP, PTCs, and thyroidectomies during the study period. Results: Of the 790 papillary thyroid neoplasms captured in the 2019 cohort, 38 (4.8%) were diagnosed as NIFTP. Diagnosis of NIFTP was observed in the US, South Africa, and India. There was minimal difference in the total proportion of PTCs in the 2015 cohort compared with the 2019 cohort (778 [47.1%] vs 752 [44.5%]; difference, 2.6% [95% CI, -16.9% to 22.1%]). The proportion of PTCs eligible for hemithyroidectomy but treated with total thyroidectomy in the 2 cohorts demonstrated a decreasing trend from 2015 to 2019 (341 of 453 [75.3%] vs 253 of 434 [58.3%]; difference, 17.0% [95% CI, -1.2% to 35.2%]). Conclusions and Relevance: Results of this cohort study showed that the 2 mitigation strategies for preventing overtreatment of early-stage thyroid cancer have had mixed success. The diagnosis of NIFTP has only been applied to a small proportion of thyroid neoplasms compared with expected rates. However, more patients eligible for hemithyroidectomy received it in 2019 compared with 2015, showing some success with this deescalation strategy.

Human Papillomavirus and Survival of Sinonasal Squamous Cell Carcinoma Patients: A Systematic Review and Meta-Analysis.

Human papillomavirus (HPV) is detectable in a subset of sinonasal squamous cell carcinoma (SNSCC), but the impact on patient outcomes is presently unclear due to a modest number of studies with limited statistical power. Therefore, we conducted a systematic review and meta-analysis to better clarify this relationship. A PubMed search was conducted to identify all studies reporting on overall (OS) or disease-free survival (DFS) for SNSCC by HPV status. Hazard ratios (HR) and corresponding 95% confidence intervals (CI) were extracted or, when not provided, indirectly estimated from each manuscript. Summary survival curves for 5-year OS and estimating survival probability by HPV status at pre-specified time intervals from study-specific Kaplan-Meier curves generated 2-year DFS. Log HRs and log CIs were combined across studies to generate summary estimates and a corresponding 95% CIs for OS and DFS. We identified ten unique studies reporting on OS and four for DFS. We observed a significant association between HPV and OS (summary HR = 0.51, 95% CI: 0.38-0.70) with relatively low heterogeneity between studies. These results indicate that HPV is a significant predictor of more favorable survival for SNSCC, and thus may be a useful biomarker for prognostication and, potentially, treatment modulation.

Trends in Number of Women Speakers at the American Head and Neck Society Meetings, 2007-2019.

Importance: The number of female speakers at American Head and Neck Society (AHNS) conferences should ideally be consistent with the number of women entering head and neck surgery fellowships to ensure gender equity in the field. Yet the presence of women speakers at the annual AHNS meetings, which is specific to the field of head and neck cancer, endocrine and microvascular reconstructive surgery, has yet to be studied. Objective: To determine whether the proportion of female speakers at the AHNS has increased in a manner consistent with the numbers of women entering fellowships since 2007. Design, Setting, and Participants: This qualitative study assessed 13 final meeting programs from AHNS national/international conferences from 2007 to 2019. The number of male and female participants in different roles throughout the meeting were retrospectively tracked. Participants were male and female speakers at AHNS national/international conferences who took part in the roles of scientific session presenter, scientific session moderator, expert panelist, miscellaneous moderator, and named lecturers/keynote speaker. Gender of the speaker was determined by searching names on the internet and using available published pronouns. Main Outcomes and Measures: Number of speaking opportunities for men and women in different roles from 2007 to 2019 as well as number of men and women entering AHNS fellowships since 2007 and new active AHNS members since 2012. Results: In this qualitative study, from 2007 to 2019, 4059 speakers were identified. Of these speakers, 902 (22%) were women and 3157 (78%) were men. Overall, there was a strong correlation between increasing years and number of women speakers from 2007 to 2019 (ρ = 0.75; 95% CI, 0.72-0.78). There were 2096 invited speaking roles that excluded research presentations, of which 400 were offered to female participants (19.1%) across the study period. There were 131 different women that made up all 400 of the opportunities that were offered to women in the years surveyed. There was a strong correlation in the proportion of women as presenters for oral abstracts, expert panelists, and miscellaneous moderators between the years but no correlation in scientific session moderators and named lecturers/keynote speakers. Of the 45 named lecturers/keynote speakers in the programs tracked, only 2 were women. Conclusions and Relevance: In this study, from 2007 to 2019, the presence of women at ANHS has increased overall, reflecting the changing demographic characteristics of those entering in head and neck oncology and microvascular surgery fellowships. However, a strong disparity continues to exist for preeminent speaking opportunities.

Management of dermatofibrosarcoma protuberans.

PURPOSE OF REVIEW: Provide an up to date review of the diagnosis, workup and treatment of dermatofibrosarcoma protuberans (DFSP). DFSP can be a challenging disease to manage and adequate understanding of the most up to date literature can help provide comprehensive treatment strategies. RECENT FINDINGS: DFSP is an infiltrative cutaneous sarcoma. It tends to have deep local invasion with a high risk of local recurrence, but a low risk of distant metastasis. It presents typically as a slow growing, asymptomatic skin lesion. It presents rarely in the head and neck, only 15% of the time. Recent data has discussed the role of wide local excision (WLE) vs. Mohs surgery. In addition, for unresectable disease the role of systemic therapy and immunomodulatory agents such as Imatinib has shown success. SUMMARY: Typically, surgical management is the first line for DFSP, however the risk for local recurrence still remains high with negative margins. Due to this risk, lifelong surveillance is required after initial diagnosis and management. Similar to other head and neck tumors, most recurrences happen within the first 3 years after treatment. DFSP can be treated with WLE or Mohs. For aggressive disease that is considered unresectable systemic therapy does exist, including molecular targeted therapies.

Pathologic Features Associated With Molecular Subtypes of Well-Differentiated Thyroid Cancer.

OBJECTIVE: To determine the association between pathologic features and molecular classes (BRAF-like, RAS-like, and non-BRAF-like non-RAS-like [NBNR]). METHODS: Retrospective review of a merged database containing 676 patients, 84% (571/676) were assigned to a molecular class from publicly accessible sequenced data of thyroid neoplasms. RESULTS: The merged cohort included 571 neoplasms: 353 (62%) BRAF-like, 172 (30%) RAS-like, and 46 (8.1%) NBNR. Lymph node metastasis (any N1 disease) was present in 166/337 (49%) of BRAF-like, 23/164 (14%) of RAS-like, and 0/46 (0%) of NBNR and are significantly different (P < .001). Gross extra-thyroidal extension was observed in 27 patients, including 24/331 (7%) of BRAF-like, 2/160 (1%) of RAS-like, and 1/46 (2%) of NBNR (P = .01). N1B lymph node metastases or T4 disease was present in 74/333 (22%) of BRAF-like, 10/160 (6%) of RAS-like, and 1/46 (2%) of NBNR (P < .0001). Distant metastasis was present in 4/151 (2.6%) of BRAF-like, 2/50 (4%) of RAS-like and 0/46 for NBNR (P = .627). Angioinvasion was present in 0/81 (0%) of BRAF-like, 3/53 (6%) of RAS-like, and 3/46 (7%) of NBNR (P = .08); and multifocality was present in 27/81 (33%) of BRAF-like, 9/53 (17%) of RAS-like, and 1/46 (2%) for NBNR (P = .0001). CONCLUSION: Pathological features of metastasis, gross extra-thyroidal extension, and multifocality were more prevalent in BRAF-like samples compared to RAS-like and NBNR. A trend towards increased frequency of angioinvasion in RAS-like and NBNR cancers compared to BRAF-like samples was observed. Further studies are needed to evaluate if preoperative knowledge of molecular mutations in thyroid tumors aids in decision-making regarding extent of surgery.

Osteoradionecrosis: Exposing the Evidence Not the Bone.

Osteoradionecrosis is a relatively rare but potentially morbid and costly complication of radiation therapy for head and neck cancer. Multidisciplinary diagnosis and treatment are essential. Despite evidence guiding individual aspects of care for osteoradionecrosis, there is a lack of broad consensus on the overall diagnosis and management of this condition. This study comprehensively reviews the literature, with a focus on the past 10 years, to guide evaluation and treatment.

Absent Posterior Belly of Digastric Muscle.

OBJECTIVE: Report a unique case of absent posterior belly of digastric muscle, with a literature review and discussion of its clinical importance. METHODS: Present a case report and review the current literature including PUBMED search terms; "absent posterior digastric", "digastric muscle", "posterior belly". RESULTS: While there were multiple reports of accessory anterior and posterior bellies and absence of anterior belly, there is a paucity of literature on absence of posterior belly of digastric muscle. CONCLUSION: To our knowledge, this is the first report of an absent posterior belly of the digastric muscle. The posterior belly of the digastric muscle is an important landmark in neck dissection, and its absence makes knowledge of other anatomic landmarks critically important. Laryngoscope, 131:1501-1502, 2021.

Successful use of a therapeutic trial of graduated volume and dose escalation for postoperative head and neck radiotherapy in a Fanconi anemia patient.

BACKGROUND: Patients with the heritable disease, Fanconi anemia (FA), have a 500-fold risk of developing head and neck squamous cell carcinomas (HNSCC). However, the use of conventional cytotoxic agents including radiation therapy and cisplatin-based chemotherapy is contraindicated in patients with FA due to underlying DNA repair defects. METHODS/RESULTS: We present a young FA patient with recurrent HNSCC and high-risk pathologic features treated with a therapeutic trial of chemoradiation. This novel strategy employs a gentle radiation dose and volume escalation with concurrent pembrolizumab. The patient completed the entire course of therapy with no treatment delays or interruptions. CONCLUSIONS: The FA patient population has a clear need for adjuvant treatment regimens given their predilection for HNSCC. A therapeutic trial may allow FA and other radiosensitive patients to trial radiation with the option to terminate treatment before any severe side effects occur and for some to complete a full course of treatment.

Female Representation in Otolaryngology Leadership Roles.

OBJECTIVES/HYPOTHESIS: Characterization of leadership within otolaryngology is key to evaluating trends and promoting program advancement. This study evaluates representation of women in otolaryngology holding residency and fellowship directorships, or chair positions, comparing sex differences in academic rank, years in practice, and scholarly activity. STUDY DESIGN: Cross sectional analysis. METHODS: A comprehensive list of otolaryngology residency and fellowship directors from Accreditation Council for Graduate Medical Education-accredited programs in 2017 to 2018 was compiled. Academic rank and years in practice were determined from departmental websites, with online search tools used as secondary resources. The h-index was utilized as a measure of research productivity. Regression analysis was performed to analyze these variables. RESULTS: Among the 306 directorships, women held 57 (18.6%) of these positions, 27 (26.5%) residency and 30 (14.7%) fellowship directorships. Of the 99 chair positions, five (5.1%) were held by women. The majority (53.6%) of male directors were full professors, whereas only 26.3% of females were full professors (P = .04). Mean years in practice for female directors (13.9 ± 6.8) was less than that of male directors (20.3 ± 9.4, P < .0001). Similarly, mean h-index for female directors (11 ± 7.2) was lower than for males (17.5 ± 12.5, P = .0001). After controlling for academic rank and years of practice in a multivariable regression, the h-index remained lower for women than for men (P = .03). CONCLUSIONS: Women are disproportionately underrepresented in positions of residency and fellowship directorships, and chair positions, consistent with other specialties. Women in leadership had lower academic ranks, fewer years of practice, and lower h-indices than their male counterparts. This may represent a shift in academic otolaryngology as female otolaryngologists seek early involvement in leadership. LEVEL OF EVIDENCE: 4 Laryngoscope, 130:1664-1669, 2020.

Are Standardized Letters of Recommendation in Residency Applications Correlated With Objective Data?

OBJECTIVE: To evaluate whether the standardized letter of recommendation (SLOR), commonly used for medical students applying to otolaryngology residency, correlates with objective data in the application. BACKGROUND: Standardized letters of recommendation using Likert-type scales for different attributes are commonly used by evaluators because of their high interrater reliability and efficiency in preparation and interpretation. Given that these are subjectively scored, it is unknown how well these correlate with objective data. METHODS: Applications to the University of Cincinnati otolaryngology residency were evaluated in the academic cycle of 2017-2018. Standardized letters of recommendation were scored to determine whether certain attributes were correlated with objective data (United States Medical Licensing Examination [USMLE] scores and number of presentations/publications) provided in their application. Spearman correlations were used to evaluate the strength of the relationship between the subjective score in certain attributes with objective data. RESULTS: There were 217 applications to the University of Cincinnati that contained SLORs. Of these applications, 474 standardized letters were scored in categories of medical knowledge, research, and commitment to academic medicine. Total publications and presentations were weakly correlated with commitment to academic medicine (0.35, P < .0001, n = 369) and with research (0.44, P < .0001, n = 355). Medical knowledge was weakly correlated with Step 1 scores (0.20, P < .0001) and Step 2 scores (0.18, P = .0002). CONCLUSIONS: Subjective research and commitment to academic medicine rating scores were weakly correlated with greater academic productivity. Similarly, medical knowledge scores were weakly correlated with Step 1/2 scores. Further research may be needed to assess how to interpret SLOR scores in addition to the information available in an otolaryngology application. LEVEL OF EVIDENCE: 4.