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Background The risk of malignancy from nodules with atypia of undetermined significance cytology is estimated between 5% and 15%, though more recent studies suggest rates upwards of 48%. This study sought to characterize preoperative predictors of malignancy to aid in clinical decision-making. Methods We performed a single institution retrospective review of all adult patients with unilateral thyroid nodules demonstrating atypia of undetermined significance cytology between March 1, 2013 and June 1, 2019 who underwent surgical resection (n = 266). Univariate and multivariate logistical analysis was performed using clinical and demographic variables to identify potential preoperative characteristics associated with malignant disease. Results Malignancy was identified on final pathology in 24.7% of patients with atypia of undetermined significance cytology. Age, sex, exposure to ionizing radiation, family history of thyroid cancer, Hashimoto’s disease, Afirma suspicious results, and smoking were not associated with malignancy on both univariate and multivariate analysis. Nodule size >4 cm was independently associated with malignancy risk on both univariate (odds ratio 2.44, 1.09–5.43, P Conclusion The results of this study demonstrate that nodules with atypia of undetermined significance cytology >4 cm are strongly associated with malignancy. We recommend strong consideration of surgery for all patients with thyroid nodules >4 cm and atypia of undetermined significance cytology.

Pretransplant malignancy is associated with decreased patient and graft survival. Current US guidelines recommend a 2- to 5-year, tumor-free waiting period before transplantation. No large studies have examined the specific, modern day risk of pretransplant thyroid malignancy on patient and graft survival after renal transplant.The United Network for Organ Sharing database was queried for all adult isolated renal transplant recipients between 2003 and 2019. Patient characteristics, rates of post-transplant malignancy, and survival were compared between patients with pretransplant thyroid malignancy and without pretransplant thyroid malignancy.Eighty-six patients had pretransplant thyroid malignancy diagnosed after listing and before renal transplantation. Both overall and graft survival were similar between cohorts (P.05). There was no significant association between pretransplant thyroid malignancy and patient (hazard ratio: 0.66; P = .31) or graft (hazard ratio:0.32; P = .11) survival on multivariate analysis. Waitlist duration for pretransplant thyroid malignancy patients was significantly increased (1,444 vs 438 days; P.01), which translated to increased dialysis duration (2,234 vs 1,201 days, P.01). Pretransplant thyroid malignancy patients did not experience increased post-transplant malignancy (P = .21).Given no association with decreased patient or allograft survival, our findings suggest that pretransplant thyroid malignancy patients are unnecessarily subjected to increased wait-list duration before transplant. We recommend an individualized approach for pretransplant thyroid malignancy patients diagnosed before or after listing.

Sickle cell disease (SCD) is characterized by hemolytic anemia, which can trigger oxidative stress, inflammation, and tissue injury that contribute to disease complications. Bone marrow mesenchymal stromal cells (MSCs) tightly regulate hematopoietic stem cell (HSC) homeostasis in health and disease, but their functionality in SCD remains unclear. We identified for the first time that murine SCD MSCs have altered gene signatures, reduced stem cell properties, and increased oxidative stress, due in part to hemolysis. Murine SCD MSCs had lower HSC maintenance ability in vitro and in vivo, as manifested by increased HSC mobilization and decreased HSC engraftment after transplant. Activation of Toll-like receptor-4 through p65 in MSCs further contributed to MSC dysfunction. Transfusions led to an improved MSC and HSC oxidative state in SCD mice. Improving the regulation between MSCs and HSCs has vital implications for enhancing clinical HSC transplantation and gene therapy outcomes and for identification of new molecular targets for alleviating SCD complications.

Approximately 1.2 million people are living with HIV in the United States, with 16,000 in San Francisco. Many HIV-positive individuals have difficulty maintaining follow-up clinic visits under normal circumstances, and this is complicated by the coronavirus disease 2019 (COVID-19) pandemic as many institutions transition to a telehealth-focused model of care to maintain patient and provider safety. However, it was unknown how telehealth would impact patient attendance and perceptions about their care, particularly in populations at high risk of appointment nonattendance. To quantify the impact of telehealth on retention in care for a vulnerable HIV-infected population and to identify patient perspectives of telehealth and its effect on appointment attendance, we studied patients at the University of California, San Francisco (UCSF) 360 Wellness Center, an HIV primary care clinic in urban San Francisco, California. Anonymous surveys were conducted to assess patient perceptions of telehealth, and 21% of patients sent surveys responded. Appointment attendance rates for all visits were analyzed before and after the shelter-in-place order in San Francisco on March 16, 2020. With the transition to telehealth, the overall nonattendance rate decreased by ∼3%. Most common perceived strengths of telehealth included convenience and safety, whereas disadvantages included technical barriers and unfamiliarity. Despite barriers and disadvantages listed by patients, a majority are willing to attend telehealth visits, as 80.5% of respondents reported being equally or more likely to attend telehealth visits. This is a critical finding during the COVID-19 pandemic and beyond; we believe that telehealth can improve appointment attendance for vulnerable populations who often face barriers to receiving health care.

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.

OBJECTIVES/HYPOTHESIS Dysphagia is a treatment-related complication of head and neck cancer (HNCA). We demonstrate the predictive value of a modified head and neck swallow scale (m-HNSW) adapted from the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Head and Neck 35 (EORTC-QLQ-H&N35). STUDY DESIGN Retrospective Cohort Study. METHODS Retrospective, single-center cohort study utilizing a prospectively collected database of HNCA patients in a high-volume tertiary referral center. 736 HNCA patients more than 2 years from completion of treatment were identified. EORTC-QLQ-H&N35 data collected from at least one of three defined episodes of care were used. The m-HNSW uses three questions to form a 9-point dysphagia scale. A Cox proportional hazards model was used to determine the effect of the m-HNSW while controlling for demographics, tumor staging, site, and treatment. RESULTS Using data from 3, 6, 12 months from treatment, we analyzed a subset that included 328 patients. Three months after the completion of therapy, the m-HNSW score had a significant association with 1 (HR = 1.24, P = .0005) and 5 year survival (HR = 1.19, P = .0002) after accounting for body mass index. Six (HR = 1.14, P = .014) and 12 month (hazard ratio (HR) = 1.33, P

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.

Background and aims Patients with obesity are at high risk of suffering from arterial and venous peripheral vascular disease (PVD). Bariatric surgery is an effective strategy to achieve weight reduction for patients with obesity. The long-term impact of bariatric surgery on obesity-related morbidity is subject to increasing research interest. This study aimed to ascertain the impact of bariatric surgery on the long-term occurrence of PVD in patients with obesity. Methods The study population was extracted from the Clinical Practice Research Datalink, a nation-wide database containing primary and secondary care records of consenting patients. The intervention cohort was 2959 patients who had undergone bariatric surgery during follow-up; their controls were 2959 propensity-score-matched counterparts. The primary endpoint was development of any PVD: arterial or venous. Secondary endpoints were incident peripheral arterial disease alone, incident peripheral venous disease alone. Results Three hundred forty-six patients suffered a primary endpoint during follow-up. Bariatric surgery did not improve peripheral vascular disease rates as a whole, but it was associated with significantly lower event rates of arterial disease (HR = 0.560, 95%CI 0.327–0.959, p = 0.035) but higher event rates of venous disease (HR = 1.685, 95%CI 1.256–2.262, p < 0.001). Conclusions Bariatric surgery was associated with significantly reduced long-term occurrence of arterial disease but increased occurrence of venous disease in patients with obesity.

The vessel-depleted neck presents a unique and challenging scenario for reconstructive surgery of the head and neck. Prior surgery and radiation often result in significant scarring and damage to the neck vasculature, making identification of suitable recipient vessels for microvascular free tissue transfer exceedingly difficult. Therefore, alternative reconstructive techniques and/or vessel options must be considered to obtain a successful reconstructive outcome for a patient. In this article, we discuss our experience and approach to the management of the vessel-depleted neck, emphasizing the importance of preoperative planning and having multiple backup options prior to surgery. The various preoperative imaging modalities and available options for recipient arteries and veins are presented in detail. Additionally, we discuss modifications of select free flaps to maximize their utility in successful reconstruction. Together with thoughtful preoperative planning, these techniques can help aid the reconstructive surgeon in addressing the complex decisions associated with the vessel-depleted neck.

Significance Cytometry technologies are able to profile immune cells at single-cell resolution. They are widely used for both clinical diagnosis and biological research. We developed a deep learning model for analyzing cytometry data. We demonstrated that the deep learning model accurately diagnoses the latent cytomegalovirus (CMV) in healthy individuals. In addition, we developed a method for interpreting the deep learning model, allowing us to identify biomarkers associated with latent CMV infection. The deep learning model is widely applicable to other cytometry data related to human diseases., Cytometry technologies are essential tools for immunology research, providing high-throughput measurements of the immune cells at the single-cell level. Existing approaches in interpreting and using cytometry measurements include manual or automated gating to identify cell subsets from the cytometry data, providing highly intuitive results but may lead to significant information loss, in that additional details in measured or correlated cell signals might be missed. In this study, we propose and test a deep convolutional neural network for analyzing cytometry data in an end-to-end fashion, allowing a direct association between raw cytometry data and the clinical outcome of interest. Using nine large cytometry by time-of-flight mass spectrometry or mass cytometry (CyTOF) studies from the open-access ImmPort database, we demonstrated that the deep convolutional neural network model can accurately diagnose the latent cytomegalovirus (CMV) in healthy individuals, even when using highly heterogeneous data from different studies. In addition, we developed a permutation-based method for interpreting the deep convolutional neural network model. We were able to identify a CD27- CD94+ CD8+ T cell population significantly associated with latent CMV infection, confirming the findings in previous studies. Finally, we provide a tutorial for creating, training, and interpreting the tailored deep learning model for cytometry data using Keras and TensorFlow (https://github.com/hzc363/DeepLearningCyTOF).

Alzheimer’s disease (AD) is a pervasive neurodegenerative disorder that disproportionately affects women. Since neural anatomy and disease pathophysiology differ by sex, investigating sex-specific mechanisms in AD pathophysiology can inform new therapeutic approaches for both sexes. Previous bulk human brain RNA sequencing studies have revealed sex differences in dysregulated molecular pathways related to energy production, neuronal function, and immune response; however, the sex differences in disease mechanisms are yet to be examined comprehensively on a single-cell level. We leveraged nearly 74,000 cells from human prefrontal and entorhinal cortex samples from the first two publicly available single-cell RNA sequencing AD datasets to perform a case versus control sex-stratified differential gene expression analysis and pathway network enrichment in a cell type-specific manner for each brain region. Our examination at the single-cell level revealed sex differences in AD prominently in glial cells of the prefrontal cortex. In the entorhinal cortex, we observed the same genes and networks to be perturbed in opposing directions between sexes in AD relative to healthy state. Our findings contribute to growing evidence of sex differences in AD-related transcriptomic changes, which can fuel the development of therapies that may prove more effective at reversing AD pathophysiology. Supplementary Information The online version contains supplementary material available at 10.1007/s12035-021-02591-8.

IntroductionSurgery is the primary treatment for resectable, non-metastatic recurrent head and neck squamous cell carcinoma (HNSCC). We explore the safety and oncologic benefit of intraoperative Cesium-131 (Cs-131) brachytherapy combined with salvage local and/or regional surgical resection.Methods and MaterialsFindings were reported from a single arm multi-institutional prospective phase 1/2 trial involving surgery plus Cs-131 (surgery + Cs-131) treatment. The results of two retrospective cohorts—surgery alone and surgery plus intensity modulated radiation therapy (surgery + ReIMRT)—were also described. Included patients had recurrent HNSCC and radiation history. Safety, tumor re-occurrence, and survival were evaluated.ResultsForty-nine patients were enrolled in the surgery + Cs-131 prospective study. Grade 1 to 3 adverse events (AEs) occurred in 18 patients (37%), and grade 4 AEs occurred in 2 patients. Postoperative percutaneous endoscopic gastrostomy (PEG) tubes were needed in 10 surgery + Cs-131 patients (20%), and wound and vascular complications were observed in 12 patients (24%). No cases of osteoradionecrosis were reported in the surgery + Cs-131 cohort. We found a 49% 2-year disease-free survival at the site of treatment with a substantial number of patients (31%) developing metastatic disease, which led to a 31% overall survival at 5 years.ConclusionsAmong patients with local/regional recurrent HNSCC status-post radiation, surgery + Cs-131 demonstrated acceptable safety with compelling oncologic outcomes, as compared to historic control cohorts.Clinical Trial RegistrationClinicalTrials.gov, identifiers NCT02794675 and NCT02467738.

Alexander disease (AxD) is a rare and fatal neurodegenerative disorder caused by mutations in the gene encoding glial fibrillary acidic protein (GFAP). In this report, a mouse model of AxD (GFAPTg;Gfap+/R236H) was analyzed that contains a heterozygous R236H point mutation in murine Gfap as well as a transgene with a GFAP promoter to overexpress human GFAP. Using label-free quantitative proteomic comparisons of brain tissue from GFAPTg;Gfap+/R236H versus wild-type mice confirmed upregulation of the glutathione metabolism pathway and indicated proteins were elevated in the peroxisome proliferator-activated receptor (PPAR) signaling pathway, which had not been reported previously in AxD. Relative protein-level differences were confirmed by a targeted proteomics assay, including proteins related to astrocytes and oligodendrocytes. Of particular interest was the decreased level of the oligodendrocyte protein, 2-hydroxyacylsphingosine 1-beta-galactosyltransferase (Ugt8), since Ugt8-deficient mice exhibit a phenotype similar to GFAPTg;Gfap+/R236H mice (e.g., tremors, ataxia, hind-limb paralysis). In addition, decreased levels of myelin-associated proteins were found in the GFAPTg;Gfap+/R236H mice, consistent with the role of Ugt8 in myelin synthesis. Fabp7 upregulation in GFAPTg;Gfap+/R236H mice was also selected for further investigation due to its uncharacterized association to AxD, critical function in astrocyte proliferation, and functional ability to inhibit the anti-inflammatory PPAR signaling pathway in models of amyotrophic lateral sclerosis (ALS). Within Gfap+ astrocytes, Fabp7 was markedly increased in the hippocampus, a brain region subjected to extensive pathology and chronic reactive gliosis in GFAPTg;Gfap+/R236H mice. Last, to determine whether the findings in GFAPTg;Gfap+/R236H mice are present in the human condition, AxD patient and control samples were analyzed by Western blot, which indicated that Type I AxD patients have a significant fourfold upregulation of FABP7. However, immunohistochemistry analysis showed that UGT8 accumulates in AxD patient subpial brain regions where abundant amounts of Rosenthal fibers are located, which was not observed in the GFAPTg;Gfap+/R236H mice., Graphical abstract, Highlights • Models of AxD provide insight into functions of astrocytes related to neuropathology. • PPAR pathway found upregulated in AxD mice may be neuroprotective. Fatty acid binding protein (Fabp7) was upregulated in AxD mice and human CNS samples. • Depleted levels in the classical constituents of myelin were observed in AxD mice. • UGT8 may be related to myelin deficits in AxD., In Brief The article contains the first whole brain proteomic survey from a mouse model of Alexander disease (AxD). Several novel findings include activation of the PPAR signaling pathway, which has been reported to be protective in models of amyotrophic lateral sclerosis (ALS). Another finding related to the gliosis phenotype in AxD mice was the upregulation of fatty acid binding protein 7 (FABP7), which induces an NF-κB inflammatory response and counteracts the anti-inflammatory effects of PPAR signaling.

Key Points Question Are selective serotonin reuptake inhibitors (SSRIs), specifically fluoxetine hydrochloride, associated with a lower mortality risk among patients with COVID-19? Findings In this multicenter cohort study analyzing electronic health records of 83 584 patients diagnosed with COVID-19, including 3401 patients who were prescribed SSRIs, a reduced relative risk of mortality was found to be associated with the use of SSRIs—specifically fluoxetine—compared with patients who were not prescribed SSRIs. Meaning These findings suggest that SSRI use may reduce mortality among patients with COVID-19, although they may be subject to unaccounted confounding variables; further investigation via large, randomized clinical trials is needed., This cohort study investigates whether use of selective serotonin reuptake inhibitors is associated with a reduction in the relative risk of mortality for patients with COVID-19., Importance Antidepressant use may be associated with reduced levels of several proinflammatory cytokines suggested to be involved with the development of severe COVID-19. An association between the use of selective serotonin reuptake inhibitors (SSRIs)—specifically fluoxetine hydrochloride and fluvoxamine maleate—with decreased mortality among patients with COVID-19 has been reported in recent studies; however, these studies had limited power due to their small size. Objective To investigate the association of SSRIs with outcomes in patients with COVID-19 by analyzing electronic health records (EHRs). Design, Setting, and Participants This retrospective cohort study used propensity score matching by demographic characteristics, comorbidities, and medication indication to compare SSRI-treated patients with matched control patients not treated with SSRIs within a large EHR database representing a diverse population of 83 584 patients diagnosed with COVID-19 from January to September 2020 and with a duration of follow-up of as long as 8 months in 87 health care centers across the US. Exposures Selective serotonin reuptake inhibitors and specifically (1) fluoxetine, (2) fluoxetine or fluvoxamine, and (3) other SSRIs (ie, not fluoxetine or fluvoxamine). Main Outcomes and Measures Death. Results A total of 3401 adult patients with COVID-19 prescribed SSRIs (2033 women [59.8%]; mean [SD] age, 63.8 [18.1] years) were identified, with 470 receiving fluoxetine only (280 women [59.6%]; mean [SD] age, 58.5 [18.1] years), 481 receiving fluoxetine or fluvoxamine (285 women [59.3%]; mean [SD] age, 58.7 [18.0] years), and 2898 receiving other SSRIs (1733 women [59.8%]; mean [SD] age, 64.7 [18.0] years) within a defined time frame. When compared with matched untreated control patients, relative risk (RR) of mortality was reduced among patients prescribed any SSRI (497 of 3401 [14.6%] vs 1130 of 6802 [16.6%]; RR, 0.92 [95% CI, 0.85-0.99]; adjusted P = .03); fluoxetine (46 of 470 [9.8%] vs 937 of 7050 [13.3%]; RR, 0.72 [95% CI, 0.54-0.97]; adjusted P = .03); and fluoxetine or fluvoxamine (48 of 481 [10.0%] vs 956 of 7215 [13.3%]; RR, 0.74 [95% CI, 0.55-0.99]; adjusted P = .04). The association between receiving any SSRI that is not fluoxetine or fluvoxamine and risk of death was not statistically significant (447 of 2898 [15.4%] vs 1474 of 8694 [17.0%]; RR, 0.92 [95% CI, 0.84-1.00]; adjusted P = .06). Conclusions and Relevance These results support evidence that SSRIs may be associated with reduced severity of COVID-19 reflected in the reduced RR of mortality. Further research and randomized clinical trials are needed to elucidate the effect of SSRIs generally, or more specifically of fluoxetine and fluvoxamine, on the severity of COVID-19 outcomes.

Purpose of review Platelet transfusion can be life-saving but carries a risk of infection or alloimmunization and is limited by insufficient donor sources and restricted unit shelf life. Generating sufficient platelets in vitro to replace a unit of collected blood remains a challenge. Here, we examine the latest advances in the regulation of megakaryocyte maturation and expansion along with platelet formation and survival. We also discuss alternative therapies investigated to induce platelet production. Recent findings Recent studies examined candidate niche cells in the bone marrow microenvironment for promoting platelet formation and developed an explant-based bioreactor to enhance platelet production ex vivo. Chemical inhibitors were examined for their ability to promote megakaryocyte maturation and expansion. Microparticles from megakaryocytes or platelets were found to improve megakaryocyte maturation and platelet formation. Membrane budding was identified as a novel mode of platelet formation. Lastly, a chemical inhibitor to improve cold-stored platelets was identified. Summary Recent advances in the regulation of megakaryocyte expansion and platelet production provide exciting promise for the development of improved approaches to generate platelets in vitro. These findings bring the field one step closer to achieving the ultimate goal of creating a unit of platelets without the need for donation.

Objective The aim of this study is to evaluate the effect of bariatric surgery on long-term risk of VTEs in a large cohort of patients with obesity. Background Obesity is a well-established risk factor for VTEs, such as pulmonary embolism and deep vein thrombosis. The rising prevalence of obesity and its associated co-morbidities, including VTE, represent a growing public health issue. Methods A nested, retrospective matched cohort study was designed and conducted on prospectively collected national electronic healthcare records data from the Clinical Practice Research Datalink. Eight thousand, one hundred twelve patients were included in the study: the 4056 patients on the database who had undergone bariatric surgery, and equal numbers of age, sex, and body mass index matched controls. The primary endpoint was the occurrence of VTEs; secondary endpoints were the occurrence of deep vein thrombosis alone, pulmonary embolism alone. Results Patients were followed up for a median of 10.7 years. The bariatric surgery cohort had a significantly lower occurrence of the primary outcome [hazard ratio (HR) 0.601; 95% confidence interval (CI) 0.430-0.841, P = 0.003]; mainly driven by a reduction in deep vein thrombosis (HR 0.523; 95% CI 0.349-0.783, P = 0·002) and not in pulmonary embolism (HR 0.882; 95% CI 0.511-1.521, P = 0.651). Conclusions The results of this nation-wide study set out to characterize the impact of bariatric surgery on long-term risk of thromboembolic events outline a significant reduction in thromboembolic events, driven by a reduction in deep vein thrombosis.

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

Simple Summary Human papillomavirus (HPV) has been associated with multiple cancers in the anogenital and upper aerodigestive tracts. In the head and neck region, HPV-positive cancers are common in oropharynx, with rising incidence and a well-established association with more favorable patient outcomes. However, the relationship with prognosis of sinonasal squamous cell carcinoma (SNSCC) has been much less often studied and is presently unclear. To better elucidate this relationship, we performed a systematic review and meta-analysis of the biomedical literature to determine the aggregate effect across studies. In doing so, we observed significantly better overall survival associated with HPV-positive SNSCC. Therefore, we conclude that HPV testing may be useful for determining patient prognosis and potentially guiding treatment decisions. Abstract 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.

Machine learning applied to electronic medical records can be used to create personalized lab-test reference ranges and to quantify disease risk, which will pave the way for precision medicine in clinical care.

Central lymph node metastasis is very common in differentiated thyroid cancers, especially in papillary thyroid carcinomas (PTCs). Although therapeutic central neck dissection for clinically apparent disease (cN1a) is widely accepted, there continues to be ongoing debate regarding the role of elective/prophylactic central compartment dissection for clinically node-negative (cN0) necks. This chapter outlines the pertinent surgical anatomy of the central compartment, the indications and ongoing debate for central neck dissection in differentiated thyroid cancer, and detailed surgical technique in performing a safe central neck dissection.

Background Patients with newly diagnosed, resected, head and neck squamous cell carcinoma (HNSCC) with high-risk (positive margins, extracapsular spread [ECE]) or intermediate-risk pathological features have an estimated 1-year disease free survival (DFS) of 65% and 69%, respectively.1 PD-1/PD-L1 immune checkpoint blockade has improved survival of patients with recurrent/metastatic HNSCC, and preclinical models indicate radiation upregulates PD-L1.2 Therefore, we hypothesized that pre and post-operative administration of the PD-1 inhibitor pembrolizumab would improve 1-year DFS for patients with resectable, loco-regionally advanced (clinical T3/4 and/or ≥2 nodal metastases) HNSCC (NCT02641093). Methods Eligible patients received pembrolizumab (200 mg I.V. x 1) 1-3 weeks before resection. Adjuvant pembrolizumab (q3 wks x 6 doses) was administered with weekly cisplatin (40mg/m2 X 6) and radiation (60-66Gy) for those with high-risk features and radiation alone for patients with intermediate-risk features. The primary endpoint was DFS, which was compared by log-rank test to historical controls (RTOG 9501). Evidence of pathological response to neoadjuvant pembrolizumab was evaluated by comparing pre- and post-surgical tumor specimens for treatment effect (TE) defined as tumor necrosis and/or histiocytic inflammation and giant cell reaction to keratinaceous debris. Response was classified as none (NPR, Results Sixty-six of 84 enrolled patients had received adjuvant pembrolizumab and therefore were evaluable for DFS at the time of interim analysis. Patient characteristics included: median age 59 (range of 27 – 76) years; 30% female; 85% oral cavity, 11% larynx, and 2% human papillomavirus negative oropharynx; 85% clinical T3/4 and 68% ≥2N; 41(51%) high-risk (positive margins, 49%; ECE, 80%). At a median follow-up of 16 months, 1-year DFS was 66% (95%CI 0.48-0.84) in the high-risk group (p=1) and 91% (95%CI 0.79-1) in the intermediate-risk group (versus 69% in RTOG 9501, p=0.05) (figure 1). Among 70 patients evaluable for pathological response, TE was scored as NPR in 40, PPR in 27, and MPR in 3 patients. Patients with pathological response that were also evaluable for DFS (PPR + MPR) had significantly improved 1-year DFS when compared with those with NPR (100% versus 57%, p=0.0033; HR = 0.18 [95%CI 0.05-0.64]) (figure 2). PPR/MPR was associated with robust macrophage infiltration via Nanostring. Conclusions Neoadjuvant and adjuvant pembrolizumab led to high DFS in intermediate-risk, but not high-risk, resected HNSCC patients. Pathological response to neoadjuvant pembrolizumab was associated with high 1-year DFS. Acknowledgements We’d like to acknowledge the UCCC clinical trials office for their hard work on this study as well as our patients. We’d also like to acknowledge Merck & Co, Inc as they partially funded the clinical trial. Trial Registration NCT02641093 Ethics Approval This study was approved by the University of Cincinnati IRB with approval number 2015-6798 References Cooper JS, Pajak TF, Forastiere AA, et al. Postoperative concurrent radiotherapy and chemotherapy for high-risk squamous-cell carcinoma of the head and neck. N Engl J Med 2004;350(19):1937-1944. doi:10.1056/NEJMoa032646 Oweida A, Lennon S, Calame D, et al. Ionizing radiation sensitizes tumors to PD-L1 immune checkpoint blockade in orthotopic murine head and neck squamous cell carcinoma. Oncoimmunology2017;6(10):e1356153. Published 2017 Aug 3. doi:10.1080/2162402X.2017.1356153

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.

To determine the association between pathologic features and molecular classes (BRAF-like, RAS-like, and non-BRAF-like non-RAS-like [NBNR]).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.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).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.

OBJECTIVES: Salvage surgical resection is the preferred treatment for head and neck squamous cell carcinoma (HNSCC) patients who develop locally recurrent disease after failing primary therapy. However, salvage surgical resection is not always feasible, and survival outcomes for those that do undergo salvage remain poor. It is well known that patients with adverse pathological features (extracapsular extension (ECE) of lymph nodes (LN), positive margins, peri-neural spread (PNI), lymphovascular invasion (LVI), and multiple LN metastases) at the time of primary surgical resection are likely to have relatively poor outcomes. However, the impact of adverse pathological features on outcomes in the salvage setting remains controversial. MATERIALS AND METHODS: We retrospectively analyzed 73 patients at a single institution from 2008–2017 who developed recurrence and subsequently underwent salvage surgery (SS) after definitive curative-intent therapy including radiation. Demographic and disease control outcomes were reviewed. Kaplan-Meier curves were used to estimate relapse free survival (RFS) and overall survival (OS). RESULTS: Median age at diagnosis was 61 years (range 40–86), 49/73 (67%) were male, and 55/73 (75%) had smoked. Patients with any adverse pathological features at SS had worse RFS (HR 3.15 p=0.0008) and worse OS (3.97 p=0.0008). Patients who relapsed

Summary 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.

Aims This study aims to evaluate the long-term effect of bariatric surgery on cardiovascular outcomes of patients with obesity. Methods and results A nested cohort study was carried out within the Clinical Practice Research Datalink. The study cohort included the 3701 patients on the database who had undergone bariatric surgery and 3701 age, gender, and body mass index-matched controls. The primary endpoint was the composite of fatal or non-fatal myocardial infarction and fatal or non-fatal ischaemic stroke. Secondary endpoints included fatal or non-fatal myocardial infarction alone, fatal or non-fatal ischaemic stroke alone, incident heart failure, and mortality. The median follow-up achieved was 11.2 years. Patients who had undergone bariatric surgery had a significantly lower occurrence of major adverse cardiovascular events [hazard ratio (HR) 0.410, 95% confidence interval (CI) 0.274–0.615; P Conclusion The results of this large, nationwide cohort study support the association of bariatric surgery with lower long-term risk of major cardiovascular events and incident heart failure in patients with obesity.

Purpose Idiopathic intracranial hypertension (IIH) is a syndrome that is characterized by persistently high intracranial pressure and associated with high rates of morbidity and visual loss. Its exact etiology and clinical picture is poorly understood, but it is known to be associated with obesity. The aim of this study was to investigate the prevalence and clinical manifestations of IIH using a large nationwide database of British subjects. Materials and methods The anonymized healthcare records of patients with a BMI of ≥ 30 kg/m2 were extracted from the Clinical Practice Research Datalink (CPRD), and analyzed. Results The patients with IIH were older and more likely to have peripheral vascular disease, ischemic heart disease, and anemia; to have had a previous myocardial infarction; and have used non-steroidal anti-inflammatory drugs (NSAIDs) and steroids. Multivariate analysis with adjustment for confounders showed that anemia (p = 0.033) and the use of NSAIDs (p = 0.011) were the only factors independently associated with IIH. Increases in BMI beyond the threshold of obesity did not independently increase risk of IIH. Conclusions IIH is a multifactorial disease; the risk of which is increased in patients with a background of anemia, and those who use NSAIDs. Across BMI categories beyond the threshold for obesity (BMI ≥ 30 kg/m2), there is no continuation of the previously described “dose-response” relationship between BMI and IIH. Ethical approval Scientific approval for the study was granted from the Regulatory Agency’s Independent Scientific Advisory Committee and ethical approval by the Health Research Authority IRAS Project ID: 203143. ISAC approval registration number 16_140R2.

OBJECTIVES/HYPOTHESIS This study evaluates the existence and nature of maternity and paternity leave policies for residents during otolaryngology training. The study sought to survey program directors (PDs) on the impact of parental leave. STUDY DESIGN Cross-sectional survey. METHODS An electronic survey was sent to 103 otolaryngology residency PDs. A link to a 10-page, 30-question survey was provided. Descriptive statistics and comments were collected. RESULTS Forty-one respondents (39.8%) completed the survey, all of whom were from university-based programs. Programs from the Midwest (n = 11, 26.8%), Northeast (n = 12, 29.3%), South (n = 12, 29.3%) and West (n = 6, 14.6%) were represented. Sixteen (42%) programs reported having a written formal maternity leave policy for trainees, and 13 (32%) programs had a paternity-specific policy. Four programs reported using short-term disability, whereas 11 programs reported using the Family Medical Leave Act to accommodate parental leave. Policies primarily followed the Accreditation Council for Graduate Medical Education and American Board of Otolaryngology guidelines, with factors such as clinical duties and call schedules left to the programs' discretion. Although the majority of PDs (56%) reported support of residents who planned to become pregnant during training, many expressed concerns regarding the burden on co-residents and the difficulty of fulfilling training obligations for the resident taking leave. CONCLUSIONS Many institutions do not have parental leave policies and logistics regarding leave are left to the discretion of individual programs. Surveyed PDs addressed the challenges of becoming a parent during training and the potential burden placed on the program when trainees take leave. LEVEL OF EVIDENCE 4 Laryngoscope, 129:1093-1099, 2019.

Introduction Paediatric traumatic brain injury (pTBI) is one of the most frequent neurological presentations encountered in emergency departments worldwide. Every year, more than 200,000 American children suffer pTBIs, many of which lead to long-term damage. Objectives We aim to review the existing evidence on the efficacy of the decompressive craniectomy (DC) in controlling intracranial pressure (ICP) and improving long-term outcomes in children with pTBI. Methods A comprehensive search of the MEDLINE and EMBASE databases led to the screening of 212 studies, 12 of which satisfied inclusion criteria. Data extracted included the number and ages of patients, Glasgow Coma Scale scores at presentation, treatment protocols and short- and long-term outcomes. Results Each of the nine studies including ICP as an outcome reported that it was successfully controlled by DC. The 6–12 month outcome scores of patients undergoing DC were positive, or superior to those of medically treated groups in nine of 11 studies. Mortality was compared in only two studies, and was lower in the DC group in both.Very few studies are currently available investigating short- and long-term outcomes in children with TBI undergoing DC. Conclusion The currently available evidence may support a beneficial role of DC in controlling ICP and improving long-term outcomes.

Purpose of review The review evaluates the expanding role of scapular free flaps and its application in various complex head and neck defects. Recent findings The recent literature published focuses on the use of three-dimensional modeling for maxillectomy defects, expanded uses in both the megaflap, the various application of the scapular tip flap, and the feasibility of osseointegrated implants. Summary The subscapular system of flaps remains a versatile option in head and neck reconstruction. It continues to be one of the best options for large defects requiring generous soft tissue, muscle, and bone. Three-dimensional modeling is currently being applied to complex maxillary defects resulting in increased accuracy and efficiency of reconstruction. Expanded uses have also adopted the latissimus dorsi muscle in conjunction with the scapular bony flap to be used in large defects with resulting decreased fistula rates. Finally, there is sufficient evidence that supports the use of dental implantation into the scapula bone with successful retention rates.

The aim of this study was to validate the American Thyroid Association (ATA) sonographic risk assessment of thyroid nodules.The ATA sonographic risk assessment was prospectively applied to 206 thyroid nodules selected for ultrasound-guided fine-needle aspiration (US-FNA), and analyzed with The Bethesda System for Reporting Thyroid Cytopathology (TBSRTC), as well as surgical pathology for the subset undergoing surgical excision.The analysis included 206 thyroid nodules averaging 2.4 cm (range 1-7 cm; standard error of the mean 0.07). Using the ATA US pattern risk assessment, nodules were classified as high (4%), intermediate (31%), low (38%), and very low (26%) risk of malignancy. Nodule size was inversely correlated with sonographic risk assessment, as lower risk nodules were larger on average (p 0.0001). Malignancy rates determined by cytology/surgical pathology were high 100%, intermediate 11%, low 8%, and very low 2%, which were closely aligned with ATA malignancy risk estimates (high 70-90%, intermediate 10-20%, low 5-10%, and very low 3%). ATA US pattern risk assessment also appropriately predicted the proportion of nodules classified as malignant or suspicious for malignancy through TBSRTC classification-high (77%), intermediate (6%), low (1%), and very low 0%-as well as benign TBSRTC classification-high (0%), intermediate (47%), low (61%), and very low (70%) (p 0.0001). Malignancy rates of surgically excised, cytologically indeterminate nodules followed ATA sonographic risk stratification (high 100%, intermediate 21%, low 17%, and very low 12%; p = 0.003).This prospective study supports the new ATA sonographic pattern risk assessment for selection of thyroid nodules for US-FNA based upon TBSRTC and surgical pathology results. In the setting of indeterminate cytopathology, nodules categorized as atypia of undetermined significance/follicular lesion of undetermined significance with ATA high-risk sonographic patterns have a high likelihood of being malignant.

Background Human papillomavirus (HPV)-positive oropharyngeal cancer is generally associated with excellent response to therapy, but some HPV-positive tumors progress despite aggressive therapy. The purpose of this study was to evaluate viral oncogene expression and viral integration sites in HPV16- and HPV18-positive squamous cell carcinoma lines. Methods E6/E7 alternate transcripts were assessed by reverse transcriptase-polymerase chain reaction (RT-PCR). Detection of integrated papillomavirus sequences (DIPS-PCR) and sequencing identified viral insertion sites and affected host genes. Cellular gene expression was assessed across viral integration sites. Results All HPV-positive cell lines expressed alternate HPVE6/E7 splicing indicative of active viral oncogenesis. HPV integration occurred within cancer-related genes TP63, DCC, JAK1, TERT, ATR, ETV6, PGR, PTPRN2, and TMEM237 in 8 head and neck squamous cell carcinoma (HNSCC) lines but UM-SCC-105 and UM-GCC-1 had only intergenic integration. Conclusion HPV integration into cancer-related genes occurred in 7 of 9 HPV-positive cell lines and of these 6 were from tumors that progressed. HPV integration into cancer-related genes may be a secondary carcinogenic driver in HPV-driven tumors. © 2017 Wiley Periodicals, Inc. Head Neck 39: 840-852, 2017.

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.

Background: Although most thyroid nodules with indeterminate cytology are benign, in most of the world, surgery remains as the most frequent diagnostic approach. We have previously reported a 10-gene thyroid genetic classifier, which accurately predicts benign thyroid nodules. The assay is a prototype diagnostic kit suitable for reference laboratory testing and could potentially avoid unnecessary diagnostic surgery in patients with indeterminate thyroid cytology. Methods: Classifier performance was tested in two independent, ethnically diverse, prospective multicenter trials (TGCT-1/Chile and TGCT-2/USA). A total of 4061 fine-needle aspirations were collected from 15 institutions, of which 897 (22%) were called indeterminate. The clinical site was blind to the classifier score and the clinical laboratory blind to the pathology report. A matched surgical pathology and valid classifier score was available for 270 samples. Results: Cohorts showed significant differences, including (i) clinical site patient source (academic, 43% and 97% for TGCT-1 and -2, respectively); (ii) ethnic diversity, with a greater proportion of the Hispanic population (40% vs. 3%) for TGCT-1 and a greater proportion of African American (11% vs. 0%) and Asian (10% vs. 1%) populations for TGCT-2; and (iii) tumor size (mean of 1.7 and 2.5 cm for TGCT-1 and -2, respectively). Overall, there were no differences in the histopathological profile between cohorts. Forty-one of 155 and 45 of 115 nodules were malignant (cancer prevalence of 26% and 39% for TGCT-1 and -2, respectively). The classifier predicted 37 of 41 and 41 of 45 malignant nodules, yielding a sensitivity of 90% [95% confidence interval; CI 77–97] and 91% [95% CI 79–98] for TGCT-1 and -2, respectively. One hundred one of 114 and 61 of 70 nodules were correctly predicted as benign, yielding a specificity of 89% [95% CI 82–94] and 87% [95% CI 77–94], respectively. The negative predictive values for TGCT-1 and TGCT-2 were 96% and 94%, respectively, whereas the positive predictive values were 74% and 82%, respectively. The overall accuracy for both cohorts was 89%. Conclusions: Clinical validation of the classifier demonstrates equivalent performance in two independent and ethnically diverse cohorts, accurately predicting benign thyroid nodules that can undergo surveillance as an alternative to diagnostic surgery.

(1) To evaluate whether admission volume and case complexity are associated with mortality rates and (2) evaluate whether admission volume and case complexity are associated with cost per admission.Retrospective case series.Tertiary academic hospital.The Vizient database was queried for inpatient admissions between July 2015 and March 2017 to an otolaryngology-head and neck surgery service. Data collected included admission volume, length of stay, intensive care unit (ICU) status, complication rates, case mix index (CMI), and cost data. Regression analysis was performed to evaluate the relationship between cost, CMI, admission volume, and mortality rate.In total, 338 hospitals provided data for analysis. Mean hospital admission volume was 182 (range, 1-1284), and mean CMI was 1.69 (range, 0.66-6.0). A 1-point increase in hospital average CMI was associated with a 40% increase in odds for high mortality. Admission volume was associated with lower mortality, with 1% lower odds for each additional case. A 1-point increase in CMI produces a $4624 higher total cost per case (95% confidence interval, $4550-$4700), and for each additional case, total cost per case increased by $6.For otolaryngology inpatient services at US academic medical centers, increasing admission volume is associated with decreased mortality rates, even after controlling for CMI and complication rates. Increasing CMI levels have an anticipated correlation with higher total costs per case, but admission volume is unexpectedly associated with a significant increase in average cost per case.

Background: Large cohort longitudinal studies have almost unanimously concluded that metabolic health in obesity is a transient phenomenon, diminishing in older age. We aimed to assess the fate of insulin sensitivity per se over time in overweight and obese individuals. Methods: Individuals studied using the hyperinsulinaemic-euglycaemic clamp at the Garvan Institute of Medical Research from 2008 to 2010 (n = 99) were retrospectively grouped into Lean (body mass index (BMI) &lt, 25 kg/m2) or overweight/obese (BMI &ge, 25 kg/m2), with the latter further divided into insulin-sensitive (ObSen) or insulin-resistant (ObRes), based on median clamp M-value (M/I, separate cut-offs for men and women). Fifty-seven individuals participated in a follow-up study after 5.4 &plusmn, 0.1 years. Hyperinsulinaemic-euglycaemic clamp, dual-energy X-ray absorptiometry and circulating cardiovascular markers were measured again at follow-up, using the same protocols used at baseline. Liver fat was measured using computed tomography at baseline and proton magnetic resonance spectroscopy at follow-up with established cut-offs applied for defining fatty liver. Results: In the whole cohort, M/I did not change over time (p = 0.40), it remained significantly higher at follow-up in ObSen compared with ObRes (p = 0.02), and was not different between ObSen and Lean (p = 0.41). While BMI did not change over time (p = 0.24), android and visceral fat increased significantly in this cohort (ptime &le, 0.0013), driven by ObRes (p = 0.0087 and p = 0.0001, respectively). Similarly, systolic blood pressure increased significantly over time (ptime = 0.0003) driven by ObRes (p = 0.0039). The best correlate of follow-up M/I was baseline M/I (Spearman&rsquo, s r = 0.76, p = 1.1 &times, 10&minus, 7). Conclusions: The similarity in insulin sensitivity between the ObSen and the Lean groups at baseline persisted over time. Insulin resistance in overweight and obese individuals predisposed to further metabolic deterioration over time.

e18050 Background: Adenoid cystic carcinoma (ACC) is a rare malignancy of glandular tissue with a high rate of local recurrence and metastatic disease for which clinical behavior varies widely. Currently, no standard therapy exists, and available therapies have low response rates. Therefore, prognostic biomarkers to determine optimal treatment strategies are urgently needed. Here we investigate the molecular landscape and therapeutic targets of ACC. Methods: ACC samples were analyzed using next generation sequencing (NGS) (NextSeq, 592 gene panel) or whole exome sequencing (NovaSeq) (Caris Life Sciences, Phoenix, AZ). Pathogenic fusion events were detected using whole transcriptome sequencing (NovaSeq). Statistical significance was determined using the Chi-square test and adjusted for multiple comparisons. Tumor infiltrating Immune cell fractions were determined using the QuanTIseq deconvolution algorithm and WTS data. Results: 327 ACC patients were identified, median age of 58 years, 62% female and 62% metastatic disease. The most frequent mutations (excluding indeterminate results) involved genes in the NOTCH pathway ( NOTCH1 16% [41 of 298 cases]), chromatin remodeling ( ARID1A 24.3% [27 of 138 cases], KDM6A 12.5% [28 of 224 cases], KMT2C 10.7% [21 of 197 cases]) and TP53 10.2% (25 of 246 cases). Chromatin remodeling genes were co-mutated with NOTCH1. NOTCH1 mutations were found in 41 cases, 18 primary and 23 metastatic were associated with reduced median overall survival (mOS 1.8 years vs 3.8 years, p = 0.01). Mutations were most frequent in the PEST (n = 35), NRR (n = 18), PEST+NRR (n = 16) and EGF-like domains (n = 11). PEST domain mutations were found exclusively in ACC originating from the head and neck (H&N). GSEA showed that MYC, E2F and G2M target pathways were enriched in NOTCH1 mutated ACC regardless of the presence of MYB fusions. All three pathways were enriched in PEST domain mutations whereas only MYC targets were enriched in NRR and NRR+PEST domain mutations indicating that PEST domain mutations drive transcriptomic changes in NOTCH1 mutated ACC. MYC gene expression was significantly upregulated in NOTCH1 mutated ACC. Fusion events were detected in 45% (104/231). MYB:NFIB was the most common fusion (40%) and was more frequent in H&N origin than other sites. There was no difference in the mOS between MYB fusion positive and negative ACC (4.4 years vs 5.5 years, p = 0.14). M2-polarized macrophages, myeloid dendritic cells and neutrophils were significantly higher in metastatic compared to primary ACC while NK cells were more abundant in primary tumor. Conclusions: ACC is a genetically heterogenous disease with an immune-excluded microenvironment. NOTCH1 mutations were associated with worse, while MYB:NFIB fusion was not associated with prognosis. Our study shows that M2 macrophages and MYC are potential novel therapeutic targets in ACC.

6031 Background: Salvage surgery for locally recurrent head and neck squamous cell carcinoma (rHNSCC) results in local control rates of 33-50% but only 20-40% of patients achieve long-term survival necessitating additional therapy (Haque et al., Oral Oncol. 2019). Many patients are ineligible for re-irradiation and chemotherapy alone after salvage surgeryhas shown no survival benefit. The clinical activity and tolerability of immune checkpoint inhibitors has been demonstrated in metastatic HNSCC, but the benefit after salvage surgery (SS) has not been studied. Here we report the results of a multi-center phase II investigation of nivolumab, a PD-1 inhibitor, after SS in recurrent HNSCC (NCT03355560). Methods: HNSCC patients undergoing curative-intent SS were enrolled to receive 6 months of nivolumab beginning 4-11 weeks after surgery. All received radiation with or without chemotherapy as prior definitive therapy and had no other curative treatment options at the time of surgery. Key exclusion criteria included: distant metastatic disease, gross residual disease, or a history of immunodeficiency, autoimmunity, or pneumonitis. The primary endpoint was 2-year disease-free survival (DFS) measured by Kaplan Meier curves. Safety was evaluated by CTCAE v5.0. Results: 39 patients were enrolled. Median age was 68 years (range, 49-85). 12/39 (31%) were female. 34/39 (87%) were white. Disease sites included oropharynx 9/39 (23%), oral cavity 14/39 (36%), and larynx 16/39 (41%). P16 status was 26% (+), 48% (-), and 26% (unknown). 17/39 (44%) had high risk pathologic features (positive margins or extranodal spread) at time of SS. 28/39 (72%) patients experienced treatment-related adverse events (TRAE), the most common of which were fatigue (26%), hypothyroidism (10%) and acneiform rash (13%). Grade 3-4 TRAEs were rare, occurring in 3/39 (8%) patients and included diarrhea, oral pain, neck pain, productive cough, stridor, and COPD exacerbation. 3/39 (8%) required treatment discontinuation and there were no grade 5 events. The 2-year DFS was 60% (95%CI 0.39-0.91). 2-year overall survival was 74% (95% CI 0.54-1). In single-cell multiplex cytokine analysis, patients who relapsed following adjuvant nivolumab had a significantly higher proportion of peripheral blood CD8 T cells which displayed a polyfunctional cytokine profile. IFN-γ and Granzyme were the dominant CD8 cytokines in both responders and non-responders, however CD8 expression of MIP1a and TNF-α were significantly higher in patients who ultimately relapsed. Conclusions: Nivolumab after salvage surgery in rHNSCC is well tolerated and shows promising antitumor activity in this high-risk patient population with unmet need. Immunotherapy after salvage surgery should be studied in randomized clinical trials. Clinical trial information: NCT03355560.

e18056 Background: Adenoid cystic carcinoma (ACC) is a rare malignancy of glandular tissue with a high rate of local recurrence and metastatic disease. Despite being regarded as an indolent disease, the clinical course of recurrent and metastatic ACC (R/M ACC) is highly variable. Responses to chemotherapy (chemo) are uniformly poor. Several multi-targeted tyrosine-kinase inhibitors (mTKIs), EGFR inhibitors (EGFRi) and other targeted agents have been studied in single-arm early phase trials with response rates ranging from 0-16% and progression free survival ranging from 2.5-17 months. However, there have been no comparative clinical trials and it is not known if one treatment strategy is superior. We undertook this retrospective study to assess the real-world clinical outcomes in patients with adenoid cystic carcinoma using the Caris Life Sciences database. Methods: Real world overall survival (rwOS) for cases of ACC was obtained from insurance claims data and Kaplan-Meier estimates were calculated from the date of collection to the date of last contact. Cases were divided into subgroups based on treatment received – chemo (including platinum agents, taxanes, 5FU, topoisomerase inhibitors, anthracyclines), EGFRi (cetuximab, erlotinib, lapatinib), mTKIs (pazopanib, axitinib, sunitinib, cabozantinib, lenvatinib, sorafenib) and immune checkpoint inhibitors (ICIs) (atezolizumab, ipilimumab, pembrolizumab, nivolumab). Results: 368 patients (pts) were identified with ACC, 16 were locally recurrent and 216 tumors were taken from metastatic sites. 50 pts received chemo, 6 were treated with EGFRi and 15 with mTKIs. Pts who received combination EGFRi and chemo or mTKI and chemo were excluded. The median overall survival (mOS) all patients with metastatic ACC was 2.8 years (yrs). The mOS of pts with R/M ACC was 3 yrs for chemo, 2.9 yrs for EGFRi and 1.5 yrs for mTKIs. There was no significance in mOS between chemo vs mTKIs (HR 0.85, 95% CI 0.3 - 2, p = 0.72) and chemo vs EGFRi (HR = 0.88, 95% CI 0.3 - 2.5, p = 0.78). We further compared the outcomes of those treated with EGFRi (n = 8) with mTKIs (n = 19) in the entire cohort. For most pts, these agents were given as front line therapy. 25% (2/8) of patients had received treatment prior to EGFRi and 20% (4/9) prior to mTKIs (p = 1). There was no significant difference in mOS with HR 0.6 (95% CI 0.16 - 2.6), p = 0.6. We also compared the mOS of patients who received ICIs (n = 22) with those who did not (n = 346) but there was no significant difference (mOS 3.19 vs 3.17 yrs respectively, HR 0.87, 95% CI 0.47- 1.61, p = 0.65). Conclusions: There was no significant difference in the mOS between pts with R/M ACC who were treated with chemo, EGFRi or TKIs and in those who received ICIs compared to those who did not in our limited patient population. This highlights the need for predictive biomarkers for better patient selection with the goal of personalizing treatment strategies for this disease.

Background The prognostic value of pretreatment complete blood count (CBC) data, including absolute lymphocyte count (ALC) and the neutrophil-to-lymphocyte ratio (NLR), has been reported for many diseases with decreased ALC and increased absolute neutrophil count (ANC) and NLR values correlating with worse outcomes. There is minimal data relating these hematologic parameters to oropharyngeal squamous cell carcinoma (OPSCC) prognosis. This study evaluates the prognostic value of pretreatment CBC data in OPSCC on overall survival (OS) and progression-free survival (PFS) in relation to HPV status. Methods A single-institutional retrospective review of patients with pretreatment hematologic data who received radiation for OPSCC was performed. Univariate and multivariate (UVA/MVA) Cox proportional hazard regression analyses were performed to identify prognostic variables. Translational studies related outcomes to the degree of tumor-infiltrating lymphocytes (TILs) in histologic specimens. Results From 2007 to 2018, 201 patients were treated for OPSCC. Median follow-up was 40 months. 3-year OS was 86.2% in the HPV-positive cohort, 46.3% for HPV-negative. Median NLR was 3.04. NLR ≥ 3 was associated with worse PFS (HR 1.67, p = 0.044. In the subset of 158 HPV + patients, MVA revealed increasing ALC to be associated with improved OS (HR 0.53; p = 0.040) and PFS (HR = 0.48; p = 0.0075). On UVA, high-TIL infiltration at diagnosis was associated with improved OS. Conclusion In a cohort of HPV + OPSCC patients, increasing ALC is associated with improved OS and PFS. Our study is the first to identify pre-treatment ALC as an independent prognostic factor in HPV-associated OPSCC.

Background The proinflammatory state and metabolic changes associated with obesity contribute to cerebrovascular disease. Bariatric surgery can achieve a reliable reduction in body weight and improved metabolic profile in obese patients. However, its impact on cerebrovascular morbidity remains unexplored. This study investigates the effect of bariatric surgery on long-term risk of major cerebrovascular events. Methods A retrospective cohort study was designed. Data was extracted from the Clinical Practice Research Datalink. 4212 bariatric surgery patients were compared to 4212 age, sex, and BMI-matched controls. The primary composite endpoint was occurrence of any major adverse cerebrovascular event. Secondary endpoints included composite endpoints of ischaemic events, haemorrhagic events, individual components of the primary endpoint alone and all-cause mortality. An adjusted Cox proportional hazards model was implemented to analyse time to event data. Results Mean follow-up length was 11.4 years. The primary endpoint occurred in 73 patients. The bariatric surgery group had significantly lower adjusted major cerebrovascular event rates (HR 0.352, 95 %CI 0.195−0.637). Bariatric surgery was associated with lower rates of ischaemic events (HR 0.315, 95 %CI 0.156−0.635), particularly from transient ischaemic attacks (HR 0.364, 95 %CI 0.171−0.775). There was no difference in the rate of haemorrhagic events (HR 0.442, 95 %CI 0.147−1.330) or acute ischaemic stroke (HR 0.221, 95 %CI 0.046−1.054). In total 229 patients died during follow-up. Overall, all-cause mortality was significantly lower in the bariatric surgery group (HR 0.352, 95 %CI 0.195−0.637). Conclusions This study identifies an association between bariatric surgery and lower long-term risk of major adverse cerebrovascular events in patients with obesity.

Summary Background To provide junior doctors with tools to improve patient care in their workplace, a partnership was developed between the Clinical Excellence Commission (CEC) and the Royal Australasian College of Physicians (RACP) to help trainee consultants carry out clinical practice improvement (CPI) projects during clinical work. Methods Based on a patient-care problem they wished to resolve, trainee consultants attended a 2–day face-to-face workshop to learn quality-improvement methods, describe their proposals and refine them using CPI methodology. They were provided with continuing supervision, participated in a mid-point review and were responsible for driving their projects. Trainee consultants attended a 2–day face-to-face workshop to learn quality-improvement methods Results Examples of five projects are: reducing mislabelled specimens leaving an emergency department, from 82 in the baseline period to 18 following the intervention; creating a multidisciplinary team to reduce hypoglycaemic episodes on a diabetic ward, from 23 episodes at baseline to three episodes over the same time period after the intervention; establishing an acute paediatric review clinic that reduced avoidable admissions of pneumonia by 74 per cent; providing 100 per cent of patients in a palliative care unit with an effective pain-management plan; developing an education package to increase staff confidence in recognising and responding to anaphylaxis in children, producing an increase in confidence from 51 per cent at baseline to 100 per cent after the intervention. Discussion Involving a learned college such as the RACP in patient-care improvement, with educational input from a partner organisation, shows how junior staff can become effective leaders in improving patient care.

Objective Outflow venous stenting as an adjunct to catheter-directed thrombolysis (CDT) is performed to prevent recurrent thrombosis and to reduce the risk of post-thrombotic syndrome. Historical data show that stenting improves outcomes of surgical thrombectomy in patients with iliofemoral deep venous thrombosis (DVT), and recent observational data suggest that stenting improves long-term outcomes of CDT. However, the impact of stenting during CDT on acute safety outcomes is unknown. We sought to investigate the contemporary trends, safety outcomes, and resource utilization of adjunctive stent placement in patients undergoing CDT. Methods Patients with proximal lower extremity and caval DVT were identified within the National Inpatient Sample from January 2005 to December 2013. From this data set, we stratified our patients into three groups: patients who received CDT alone, patients who received CDT plus angioplasty, and patients who received CDT plus angioplasty with stenting. We used an inverse probability treatment weighting algorithm to create three weighted cohorts. Cochran-Armitage test was used to evaluate the trends of stent placement among patients treated with CDT. The primary outcome was a composite end point of all-cause mortality, gastrointestinal bleed, or intracranial hemorrhage. Results A total of 138,049 patients were discharged with a principal diagnosis of proximal and caval DVT; 7097 of these patients received CDT (5.1%). From this group, 2854 (40.2%) were treated with CDT alone, 2311 (32.6%) received adjunctive angioplasty alone, and 1932 (27.2%) received adjunctive angioplasty and stent. Adjunctive stenting had a significantly lower rate of primary composite outcome compared with CDT alone (2.7% vs 3.8%; P = .04). Stent placement was associated with a similar length of stay compared with angioplasty and CDT alone groups (6.8 vs 6.9 vs 7.1 days, respectively; P = .94) and higher in-hospital charges ($115,164.01 ± $76,985.31 vs $98,089.82 ± $72,921.94 vs $80,441.63 ± $74,024.98; P Conclusions This nationwide study suggests that one in four patients undergoing CDT is treated with adjunctive stent placement in the United States. This observational study showed that adjunctive stenting does not adversely affect the acute safety outcomes of CDT; however, it was associated with increased hospital charges.

6576 Background: Immune checkpoint inhibitors (ICIs) are FDA approved for use in head and neck squamous cell cancer (HNSCC), however, only ~20% patients achieve a response. Identification of biomarkers of response or toxicity remains a challenge. Polyfunctional T-cells, or T-cells producing multiple cytokines, have been recognized as contributors to durable immunity against various cancers. However, their role has not been studied prospectively in HNSCC patients receiving ICIs. To look for an early predictor of response, we used single-cell functional proteomic profiling (IsoPlexis) on blood samples pre- and post- first dose of nivolumab (nivo) in patients on our phase-II study of locally recurrent HNSCC (NCT03355560). Methods: HNSCC patients who failed definitive radiation +/-chemotherapy and were subsequently treated with curative intent salvage resection were enrolled to receive 6 months of nivo beginning 4 to 11 weeks after surgery. Blood samples were collected before and after the first dose of nivo. Peripheral blood mononuclear cells were isolated, enriched for CD8+ T cells and using the 32-plex IsoCode technology, single-cell cytokine signals were captured and polyfunctional strength of CD8+ T cells was evaluated across four groups (effector, stimulatory, regulatory, inflammatory). A comparison analysis was performed between pre- and post- nivo treatment and between patients who relapsed (non-responders) vs those who did not (responders). Results: Thirty-three of 39 planned patients have been enrolled, of which 28 are evaluable and 5/28 (18%) developed recurrence. Median age is 68 years (range 51-85), 9/28 (32%) patients are female, 26/28 (93%) are white, disease sites include oropharyngeal 6/28 (21%), oral cavity 11/28 (39%) and larynx 11/28 (39%). Samples were evaluated at a median follow up of 5.9 months from enrollment. Single-cell analysis demonstrated a strong upregulation of polyfunctional human CD8+ T cell subsets in responders. Polyfunctional Strength Index (PSI) was enhanced in CD8+ T cells across the responders’ samples, composed largely of effector cytokines (granzyme-β, IFN-γ, MIP-1α, perforin, TNF-α). Conclusions: Single-cell functional proteomic analysis revealed significantly upregulated polyfunctional profiles and an increase in effector cytokines in patients who responded to nivo. This data provides important insights into PD-1 inhibitor triggered T-cell activity and may be used to predict response to ICIs in HNSCC patients using a blood test. Clinical trial information: NCT03355560 .

Although early complications of microvascular free flaps and regional pedicled flaps of the head and neck are well described in the literature, there is relatively limited knowledge regarding their long-term complications. We describe the case of a 62-year-old gentleman who underwent primary resection and adjuvant radiation therapy for supraglottic squamous cell carcinoma who subsequently underwent salvage total laryngectomy with pectoralis major muscle flap reconstruction. During a later esophageal dilation for complaints of dysphagia, a new exophytic lesion of the hypopharynx was biopsied on endoscopy. The lesion was excised via transoral robotic surgery with final pathology revealing squamous cell carcinoma completely confined to the skin paddle of the pectoralis flap and arising from the epidermis of the skin flap. No further therapy was undertaken and there has been no evidence of recurrence 2 years after resection. Synchronous cutaneous malignancy is a rare complication of free and pedicled flap reconstruction, however its diagnosis is increasing. Given the concern for recurrent mucosal tumors arising in the upper aerodigestive tract which may require extensive resection with or without adjuvant therapy, it is important to determine the etiology of the underlying malignancy to guide appropriate treatment.

The sinoatrial node (SAN) is the primary pacemaker of the heart. The human SAN is poorly understood due to limited primary tissue access and lack of robust in vitro derivation methods. We developed an efficient strategy, using a dual SHOX2:GFP; MYH6:mCherry knock-in reporter line, to generate and

Food insecurity among U.S. older adults has more than doubled since 2001 and is higher in those who are frail. Given the growing aging population and the importance of physical functioning and adequate food intake, the increase in food insecurity is a public health concern. This study examined the association between domains of physical limitations and food security in U.S. older adults. Data were from the National Health and Nutrition Examination Survey (2007–2012) participants 60 years of age and older (n = 5969). Physical limitations were defined as some or much difficulty on 19 activities, categorized into 5 domains and an index score. Food security status was categorized as full, marginal, low, or very low, and also dichotomized into food secure and food insecure (marginal, low, or very low food security). Multinomial and logistic regression models were used to estimate odds ratios (OR) and adjusted ORs (aOR) with food security as the dependent variable and physical limitations as independent variables. Older adults with 4 or more physical limitations were more likely to report very low food security than older adults without limitations (aOR:2.62, 95% CI:1.43, 4.81). The strongest correlates of food insecurity were Instrumental Activities of Daily Living (aOR:1.49; 95% CI:1.10, 2.01), Leisure and Social Activities (aOR:1.56; 95% CI:1.37, 2.14), and General Physical Activities (aOR:1.50; 95% CI:1.08, 2.07). Physical functioning is important for food security among older adults. Interventions should incorporate assessment of physical functioning, and provide resources for food acquisition, preparation, and intake for older adults with physical limitations., Highlights • Food insecurity was higher among older adults with physical functioning limitations compared to those without limitations. • All five domains of physical functioning were significantly associated with food insecurity (P

Evidence-based medicine is the gold standard practice model for patient management. Our aim was to determine whether decisions made by pediatric subspecialists regarding management of obstructive sleep apnea in children without tonsillar hypertrophy adhered to this model or were based on clinical experiences.Single-institution prospective study.Multidisciplinary upper airway center in an academic pediatric hospital.Twelve pediatric subspecialists representing 8 specialties participating in upper airway clinics and management conferences. Real-time decisions made in treatment conferences and upper airway clinics were collected. Physicians were queried regarding the basis of their decisions, and these decisions were then classified into 10 categories.Over 13 days (10 case conferences, 3 half-day clinics), 324 decisions were made for 58 patients (mean age = 8.9 ± 7.4 years, mean body mass index percentile = 75 ± 29); 34% (n = 108) of decisions were evidence based; 59% (n = 193) were nonevidence based; and 7% (n = 23) were based on parental preference. Providers were able to cite specific studies for20% of these decisions. There was no significant increase in the proportion of evidence-based decisions made over time.We deemed 34% of decisions regarding the management of obstructive sleep apnea in children without tonsillar hypertrophy to be evidence based and found that sharing the basis for decisions did not improve the percentage of evidence-based decisions over time. These findings reflect significant evidence gaps and highlight the need for a systematic literature evaluation to identify best practice in managing this population. We recommend that these evidence gaps be further characterized and incorporated into an agenda for future research.

Objectives/Hypothesis Persistent obstructive sleep apnea (OSA) is demonstrated in 40% of children after adenotonsillectomy. We previously evaluated the basis of management decisions in children with OSA without tonsillar hypertrophy and found that 61% of decisions were non–evidence based. The aim of this study was to identify gaps in evidence for the management of children with OSA without tonsillar hypertrophy. Study Design Case series. Methods We recorded all real-time decisions made by pediatric subspecialists from eight disciplines that participated in an upper airway clinic and management conferences. Practitioners were immediately queried regarding the basis of their decisions, and non–evidence-based decisions were categorized. Results During 10 case conferences and five clinics, 507 decisions were made for 63 children (43% with Down syndrome, 20% with Pierre Robin sequence). The 309 non–evidence-based decisions most commonly pertained to follow-up timing and appropriate subspecialty clinic location (116/309, 38%) as well as timing for repeat polysomnography (35/309, 11%), especially in children at high risk for persistent OSA after treatment. Additional gaps identified included the likelihood of OSA improvement from weight loss, and effectiveness of sleep surgical procedures (i.e., lingual tonsillectomy, posterior midline glossectomy, and craniofacial surgery) alone or in combination. Conclusions Identified gaps in evidence included timing and location of follow-up, appropriate use of polysomnography for surveillance, effectiveness of specific surgical procedures performed alone and in combination, and the use of oral appliances and continuous positive airway pressure therapy in children with Down syndrome. We also found a need for studies to compare the effectiveness of these treatment options in diverse patient populations. Level of Evidence 4 Laryngoscope, 126:758–762, 2016