Single-Cell Transcriptomic Analysis of Primary and Metastatic Tumor Ecosystems in Head and Neck Cancer.

The diverse malignant, stromal, and immune cells in tumors affect growth, metastasis, and response to therapy. We profiled transcriptomes of ∼6,000 single cells from 18 head and neck squamous cell carcinoma (HNSCC) patients, including five matched pairs of primary tumors and lymph node metastases. Stromal and immune cells had consistent expression programs across patients. Conversely, malignant cells varied within and between tumors in their expression of signatures related to cell cycle, stress, hypoxia, epithelial differentiation, and partial epithelial-to-mesenchymal transition (p-EMT). Cells expressing the p-EMT program spatially localized to the leading edge of primary tumors. By integrating single-cell transcriptomes with bulk expression profiles for hundreds of tumors, we refined HNSCC subtypes by their malignant and stromal composition and established p-EMT as an independent predictor of nodal metastasis, grade, and adverse pathologic features. Our results provide insight into the HNSCC ecosystem and define stromal interactions and a p-EMT program associated with metastasis.

Hallmarks of transcriptional intratumour heterogeneity across a thousand tumours.

Each tumour contains diverse cellular states that underlie intratumour heterogeneity (ITH), a central challenge of cancer therapeutics1. Dozens of recent studies have begun to describe ITH by single-cell RNA sequencing, but each study typically profiled only a small number of tumours and provided a narrow view of transcriptional ITH2. Here we curate, annotate and integrate the data from 77 different studies to reveal the patterns of transcriptional ITH across 1,163 tumour samples covering 24 tumour types. Among the malignant cells, we identify 41 consensus meta-programs, each consisting of dozens of genes that are coordinately upregulated in subpopulations of cells within many tumours. The meta-programs cover diverse cellular processes including both generic (for example, cell cycle and stress) and lineage-specific patterns that we map into 11 hallmarks of transcriptional ITH. Most meta-programs of carcinoma cells are similar to those identified in non-malignant epithelial cells, suggesting that a large fraction of malignant ITH programs are variable even before oncogenesis, reflecting the biology of their cell of origin. We further extended the meta-program analysis to six common non-malignant cell types and utilize these to map cell-cell interactions within the tumour microenvironment. In summary, we have assembled a comprehensive pan-cancer single-cell RNA-sequencing dataset, which is available through the Curated Cancer Cell Atlas website, and leveraged this dataset to carry out a systematic characterization of transcriptional ITH.

Epigenetic regulation during cancer transitions across 11 tumour types.

Chromatin accessibility is essential in regulating gene expression and cellular identity, and alterations in accessibility have been implicated in driving cancer initiation, progression and metastasis1-4. Although the genetic contributions to oncogenic transitions have been investigated, epigenetic drivers remain less understood. Here we constructed a pan-cancer epigenetic and transcriptomic atlas using single-nucleus chromatin accessibility data (using single-nucleus assay for transposase-accessible chromatin) from 225 samples and matched single-cell or single-nucleus RNA-sequencing expression data from 206 samples. With over 1 million cells from each platform analysed through the enrichment of accessible chromatin regions, transcription factor motifs and regulons, we identified epigenetic drivers associated with cancer transitions. Some epigenetic drivers appeared in multiple cancers (for example, regulatory regions of ABCC1 and VEGFA; GATA6 and FOX-family motifs), whereas others were cancer specific (for example, regulatory regions of FGF19, ASAP2 and EN1, and the PBX3 motif). Among epigenetically altered pathways, TP53, hypoxia and TNF signalling were linked to cancer initiation, whereas oestrogen response, epithelial-mesenchymal transition and apical junction were tied to metastatic transition. Furthermore, we revealed a marked correlation between enhancer accessibility and gene expression and uncovered cooperation between epigenetic and genetic drivers. This atlas provides a foundation for further investigation of epigenetic dynamics in cancer transitions.

Targeted Proteomic Quantitation of NRF2 Signaling and Predictive Biomarkers in HNSCC.

The NFE2L2 (NRF2) oncogene and transcription factor drives a gene expression program that promotes cancer progression, metabolic reprogramming, immune evasion, and chemoradiation resistance. Patient stratification by NRF2 activity may guide treatment decisions to improve outcome. Here, we developed a mass spectrometry-based targeted proteomics assay based on internal standard-triggered parallel reaction monitoring to quantify 69 NRF2 pathway components and targets, as well as 21 proteins of broad clinical significance in head and neck squamous cell carcinoma (HNSCC). We improved an existing internal standard-triggered parallel reaction monitoring acquisition algorithm, called SureQuant, to increase throughput, sensitivity, and precision. Testing the optimized platform on 27 lung and upper aerodigestive cancer cell models revealed 35 NRF2 responsive proteins. In formalin-fixed paraffin-embedded HNSCCs, NRF2 signaling intensity positively correlated with NRF2-activating mutations and with SOX2 protein expression. Protein markers of T-cell infiltration correlated positively with one another and with human papilloma virus infection status. CDKN2A (p16) protein expression positively correlated with the human papilloma virus oncogenic E7 protein and confirmed the presence of translationally active virus. This work establishes a clinically actionable HNSCC protein biomarker assay capable of quantifying over 600 peptides from frozen or formalin-fixed paraffin-embedded archived tissues in under 90 min.

A centrosomal Cdc20-APC pathway controls dendrite morphogenesis in postmitotic neurons.

The ubiquitin ligase anaphase-promoting complex (APC) recruits the coactivator Cdc20 to drive mitosis in cycling cells. However, the nonmitotic functions of Cdc20-APC have remained unexplored. We report that Cdc20-APC plays an essential role in dendrite morphogenesis in postmitotic neurons. Knockdown of Cdc20 in cerebellar slices and in postnatal rats in vivo profoundly impairs the formation of granule neuron dendrite arbors in the cerebellar cortex. Remarkably, Cdc20 is enriched at the centrosome in neurons, and the centrosomal localization is critical for Cdc20-dependent dendrite development. We also find that the centrosome-associated protein histone deacetylase 6 (HDAC6) promotes the polyubiquitination of Cdc20, stimulates the activity of centrosomal Cdc20-APC, and drives the differentiation of dendrites. These findings define a postmitotic function for Cdc20-APC in the morphogenesis of dendrites in the mammalian brain. The identification of a centrosomal Cdc20-APC ubiquitin signaling pathway holds important implications for diverse biological processes, including neuronal connectivity and plasticity.

Patient Navigation for Timely, Guideline-Adherent Adjuvant Therapy for Head and Neck Cancer: A National Landscape Analysis.

BACKGROUND: Aligned with the NCCN Clinical Practice Guidelines in Oncology for Head and Neck Cancers, in November 2021 the Commission on Cancer approved initiation of postoperative radiation therapy (PORT) within 6 weeks of surgery for head and neck cancer (HNC) as its first and only HNC quality metric. Unfortunately, >50% of patients do not commence PORT within 6 weeks, and delays disproportionately burden racial and ethnic minority groups. Although patient navigation (PN) is a potential strategy to improve the delivery of timely, equitable, guideline-adherent PORT, the national landscape of PN for this aspect of care is unknown. MATERIALS AND METHODS: From September through November 2022, we conducted a survey of health care organizations that participate in the American Cancer Society National Navigation Roundtable to understand the scope of PN for delivering timely, guideline-adherent PORT for patients with HNC. RESULTS: Of the 94 institutions that completed the survey, 89.4% (n=84) reported that at least part of their practice was dedicated to navigating patients with HNC. Sixty-eight percent of the institutions who reported navigating patients with HNC along the continuum (56/83) reported helping them begin PORT. One-third of HNC navigators (32.5%; 27/83) reported tracking the metric for time-to-PORT at their facility. When estimating the timeframe in which the NCCN and Commission on Cancer guidelines recommend commencing PORT, 44.0% (37/84) of HNC navigators correctly stated ≤6 weeks; 71.4% (60/84) reported that they did not know the frequency of delays starting PORT among patients with HNC nationally, and 63.1% (53/84) did not know the frequency of delays at their institution. CONCLUSIONS: In this national landscape survey, we identified that PN is already widely used in clinical practice to help patients with HNC start timely, guideline-adherent PORT. To enhance and scale PN within this area and improve the quality and equity of HNC care delivery, organizations could focus on providing better education and support for their navigators as well as specialization in HNC.

Free tissue reconstruction in the "vessel-depleted" neck: A multi-institutional cohort study.

OBJECTIVES: Much of the literature on free tissue reconstruction in the "vessel-depleted" neck is focused on identification of vessels outside the pretreated field and data on free flap outcomes when infield microvascular anastomosis is performed remain scarce. We aim to report on free flap outcomes and recipient vessel choice in a large cohort of patients with prior radiation and neck dissection (RTND) to the ipsilateral side of vessel anastomosis. METHODS: A retrospective review was performed including patients who received head and neck free tissue transfer following prior RTND to the ipsilateral side of vessel anastomosis. Pretreatment data, free flap type, defect site, and recipient vessel choice were reported. Recipient vessel choice was stratified according to neck dissection level and prior free flap. Primary outcome was free flap survival (total failure, partial failure, success) within 30 days after surgery. RESULTS: This study included 72 free flap cases in 68 patients. Free flap success was 94.4%; one case (1.4%) resulted in total flap loss and three cases (4%) had partial flap loss. The facial (35%), external carotid (ECA) (25%), and superior thyroid arteries (16%) were the most common recipient arteries. The external jugular (EJV) (38%), facial (30%), and internal jugular veins (IJV) (15%) were the most common recipient veins. The superior thyroid artery was used less frequently with a prior level 2-3/4 neck dissection compared to a prior level 1-3/4 neck dissection (6% vs. 17%, p = 0.83). The facial artery (7% vs. 67%, p < 0.01) and vein (13% vs. 46%, p = 0.04) were used less frequently when a prior free flap with ipsilateral anastomosis was performed. The superior thyroid, ECA, IJV, and EJV were more commonly used in this subgroup. CONCLUSION: Free tissue transfer with infield microvascular anastomosis in a neck with prior RTND can be safely done with comparable outcomes to surgically naïve, non-irradiated necks.

National analysis of positive surgical margins in oropharyngeal salivary gland malignancies.

OBJECTIVE: Positive surgical margins (PSM) are associated with worse survival in oropharyngeal salivary gland malignancies (OPSGM), but existing literature is limited to small series. Our objective was to identify risk factors for PSM using the national cancer database (NCDB), including a transoral robotic surgical (TORS) approach. METHODS: NCDB was queried for patients with T1-T4a OPSGM undergoing resection between 2010 and 2017. Risk factors for PSM were determined using logistic regression. Overall survival (OS) was analyzed using Kaplan-Meier and Cox proportional hazards models. RESULTS: Of 785 patients, 165 (21.0 %) had PSM. Age, stage T4a tumors (OR 2.00, 95 % Confidence Interval [CI]: 1.03-3.88), adenoid cystic carcinoma (OR 2.02, 95 % CI: 1.29-3.18), and treatment at lower volume institutions (OR 1.68, 95 % CI: 1.09-2.59) were all independently associated with PSM. TORS versus a non-robotic approach was not associated with PSM (23.9 % vs 20.4 %, p 0.358), respectively. Positive margins were independently associated with a worse OS than negative margins (HR 1.63, 95 % CI: 1.03-2.59). Adjuvant radiation therapy was associated with improved survival in high grade tumors with positive margins. CONCLUSION: This study represents the largest review assessing risk factors for positive margins in OPSGM. Histologic type (adenoid cystic carcinoma), age, T4a tumor stage and treatment at a lower volume institution were all predictive of positive margins. With increasing use of TORS over the last decade, there does not appear to be a greater risk of positive margins using this modality in select patients. LEVEL OF EVIDENCE: N/A.

Stage Migration and Survival Trends in Laryngeal Cancer.

BACKGROUND: During the last two decades, significant advancements in the treatment of laryngeal cancer have occurred. Although survival of head and neck cancer patients has improved over time, the temporal trend of laryngeal cancer survival is an area of controversy. METHODS: From 2004 to 2016, 77,527 patients who had laryngeal cancer treated with curative intent in the United States were identified in the National Cancer Database. Relative and observed survival rates were assessed for temporal trends. Multinomial logistic regression investigated the relationship between American Joint Committee on Cancer (AJCC) stage and increasing calendar year. RESULTS: No significant improvement in 2- or 5-year observed survival (OS) or relative survival (RS) was observed. The 5-year RS ranged from 61.72 to 63.97%, and the 5-year OS ranged from 54.26 to 56.52%. With each increasing year, the proportion of stage 4 disease increased, with risk for stage 4 disease at the time of diagnosis increasing 2.2% annually (adjusted odds ratio [aOR], 1.022; 95% confidence interval [CI], 1.017-1.028; p < 0.001). This increase was driven by a 4.7% yearly increase in N2 disease (aOR, 1.047; 95% CI, 1.041-1.053; p < 0.001), with an annual 1.2% increase in T3 disease (aOR, 1.012; 95% CI, 1.007-1.018; p < 0.001) and a 1.2% increase in T4 disease (aOR, 1.012; 95% CI, 1.005-1.018; p < 0.001). CONCLUSION: Despite advances in the field, laryngeal cancer survival in the United States is not improving over time. This may be due to an increase in the proportion of stage 4 disease, driven primarily by increasing nodal disease. To achieve survival improvement commensurate with scientific and technologic advances, efforts should be made to diagnose and treat laryngeal cancer at earlier stages to prevent further stage migration.

Time to Surgery and Survival in Head and Neck Cancer.

BACKGROUND: The COVID-19 pandemic has required triage and delays in surgical care throughout the world. The impact of these surgical delays on survival for patients with head and neck squamous cell carcinoma (HNSCC) remains unknown. METHODS: A retrospective cohort study of 37 730 patients in the National Cancer Database with HNSCC who underwent primary surgical management from 2004 to 2016 was performed. Uni- and multivariate analyses were used to identify predictors of overall survival. Bootstrapping methods were used to identify optimal time-to-surgery (TTS) thresholds at which overall survival differences were greatest. Cox proportional hazard models with or without restricted cubic splines were used to determine the association between TTS and survival. RESULTS: The study identified TTS as an independent predictor of overall survival (OS). Bootstrapping the data to dichotomize the cohort identified the largest rise in hazard ratio (HR) at day 67, which was used as the optimal TTS cut-point in survival analysis. The patients who underwent surgical treatment longer than 67 days after diagnosis had a significantly increased risk of death (HR, 1.189; 95% confidence interval [CI], 1.122-1.261; P < 0.0001). For every 30-day delay in TTS, the hazard of death increased by 4.6%. Subsite analysis showed that the oropharynx subsite was most affected by surgical delays, followed by the oral cavity. CONCLUSIONS: Increasing TTS is an independent predictor of survival for patients with HNSCC and should be performed within 67 days after diagnosis to achieve optimal survival outcomes.

Free vascularized parascapular fat flap for parotidectomy reconstruction.

OBJECTIVE: The contour defect resulting after parotidectomy can be cosmetically unappealing. Multiple reconstructive efforts have been reported to mitigate this problem. We describe a novel technique of vascularized parascapular fat reconstruction based on the circumflex scapular vessels and evaluate its outcomes. METHODS: Consecutive patients who underwent parotidectomy with or without additional resections and vascularized parascapular fat flap reconstruction in 2020 were included. Demographic, morphologic, intraoperative, and postoperative data were assessed. RESULTS: Eight patients (3 female) were included. Median cut-to-close time was 247 (range 209-298) minutes, including tumor ablation. None of the patients had any wound complications, and all except one was discharged on postoperative day 1. Flap monitoring was not performed. None reported any significant donor site morbidity except scar formation. At last follow up, all patients reported satisfactory facial contour. CONCLUSION: Vascularized parascapular fat flap reconstruction of parotidectomy contour defects has satisfactory cosmetic outcomes with minimal morbidity and short hospitalization courses.

Nasal and paranasal sinus mucosal melanoma: Long-term survival outcomes and prognostic factors.

OBJECTIVE: To determine prognostic factors and survival patterns for different treatment modalities for nasal cavity (NC) and paranasal sinus (PS) mucosal melanoma (MM). METHODS: Patients from 1973 to 2013 were analyzed using the Surveillance, Epidemiology, and End Results (SEER) database. Kaplan-Meier method and multivariable cox proportional hazard modeling were used for survival analyses. RESULTS: Of 928 cases of mucosal melanoma (NC = 632, PS = 302), increasing age (Hazard Ratio [HR]:1.05/year, p < 0.001), T4 tumors (HR: 1.81, p = 0.02), N1 status (HR: 6.61, p < 0.001), and PS disease (HR: 1.50, p < 0.001) were associated with worse survival. Median survival length was lower for PS versus NC (16 versus 26 months, p < 0.001). Surgery and surgery + radiation therapy (RT) improved survival over non-treatment or RT alone (p < 0.001). Adding RT to surgery did not yield a survival difference compared with surgery alone (p = 0.43). Five-year survival rates for surgery and surgery + RT were similar, at 27.7% and 25.1% (p = 0.43). CONCLUSION: Surgery increased survival significantly over RT alone. RT following surgical resection did not improve survival.

National treatment trends in human papillomavirus-positive oropharyngeal squamous cell carcinoma.

BACKGROUND: Human papillomavirus (HPV)-mediated oropharyngeal cancer (OPC) is associated with dramatically improved survival in comparison with HPV-negative OPC and can be successfully treated with surgical and nonsurgical approaches. National treatment trends for OPC were investigated with the National Cancer Data Base (NCDB). METHODS: The NCDB was reviewed for primary HPV-mediated OPC in 2010-2014. Multivariable regression was used to identify predictors of both nonsurgical therapy and receipt of adjuvant chemoradiation (CRT). RESULTS: There were 13,363 patients identified with a median age at diagnosis of 58 years. The incidence of triple-modality treatment (surgery with adjuvant chemotherapy) decreased from 23.7% in 2010 to 16.9% in 2014 (R2  = 0.96), whereas the incidence of nonsurgical treatment increased from 63.9% to 68.7% (R2  = 0.89). Hospitals in the top treatment volume quartile (quartile 1 [Q1]; n = 29) had a lower rate of positive margins (16.3%) than bottom-quartile centers (n = 741; rate of positive margins, 36.4%; P < .001); Q1 hospitals used surgical therapy significantly more. Independent predictors of nonsurgical therapy included older age, advanced disease, lower hospital volume, and living closer to the hospital or outside the Pacific United States. In surgically treated patients, younger age, lower hospital volume, nodal disease, positive surgical margins, and extranodal extension (ENE) also predicted more adjuvant CRT use. CONCLUSIONS: The use of upfront surgical treatment decreased from 2010 to 2014. Hospital volume shows a strong, inverse correlation with the rate of positive surgical margins. The upfront treatment strategy is predicted not only by staging but also by patient-, geographic-, and hospital-specific factors. Lower hospital volume remains independently associated with increased triple-modality therapy after adjustments for positive margins, ENE, and pathologic staging.

Predictive factors for prolonged operative time in head and neck patients undergoing free flap reconstruction.

PURPOSE: Defining the predictive factors associated with prolonged operative time may reduce post-operative complications, improve patient outcomes, and decrease cost of care. The aims of this study are to 1) analyze risk factors associated with prolonged operative time in head and neck free flap patients and 2) determine the impact of lengthier operative time on surgical outcomes. METHODS: This retrospective cohort study evaluated 282 head and neck free flap reconstruction patients between 2011 and 2013 at a tertiary care center. Perioperative factors investigated by multivariate analyses included gender, age, American Society of Anesthesiologists class, tumor subsite, stage, flap type, preoperative comorbidities, and perioperative hematocrit nadir. Association was explored between operative times and complications including flap take back, flap survival, transfusion requirement, flap site hematoma, and surgical site infection. RESULTS: Mean operative time was 418.2 ± 88.4 (185-670) minutes. Multivariate analyses identified that ASA class III (beta coefficient + 24.5, p = .043), stage IV tumors (+34.8, p = .013), fibular free flaps (-44.8, p = .033 for RFFF vs. FFF and - 67.7, p = .023 for ALT vs FFF) and COPD (+36.0, p = .041) were associated with prolonged operative time. History of CAD (-43.5, p = .010) was associated with shorter operative time. There was no statistically significant association between longer operative time and adverse flap outcomes or complications. CONCLUSION: As expected, patients who were medically complex, had advanced cancer, or underwent complex flap reconstruction had longer operative times. Surgical planning should pay special attention to certain co-morbidities such as COPD, and explore innovative ways to minimize operative time. Future research is needed to evaluate how these factors can help guide planning algorithms for head and neck patients.

Margin Analysis in Head and Neck Cancer: State of the Art and Future Directions.

BACKGROUND: The status of surgical margins is the most important prognosticator for patients undergoing surgical resection of head and neck squamous cell carcinoma (HNSCC). Despite this, analysis of surgical margins is fraught with inconsistencies, including the ways in which margins are sampled and interpreted. Fundamentally, even the definition what constitutes a "clear" (or negative) margin may vary between institutions, surgeons, and pathologists. METHODS: The PubMed database was queried for articles relevant to the topic, and experts in the field were consulted regarding key articles for inclusion. Abstracts were reviewed and the full text was accessed for articles of particular interest. RESULTS: Data regarding various approaches to traditional margin analysis have been published without consensus. Several next-generation technologies have emerged in recent years that hold promise. CONCLUSION: An overview and appraisal of traditional margin analysis techniques are provided. Additionally, we explore novel technologies that may assist in more accurate margin assessment, guide the extent of surgical resections intraoperatively, and inform decisions regarding adjuvant treatment postoperatively.

A TRPC5-regulated calcium signaling pathway controls dendrite patterning in the mammalian brain.

Transient receptor potential (TRP) channels have been implicated as sensors of diverse stimuli in mature neurons. However, developmental roles for TRP channels in the establishment of neuronal connectivity remain largely unexplored. Here, we identify an essential function for TRPC5, a member of the canonical TRP subfamily, in the regulation of dendrite patterning in the mammalian brain. Strikingly, TRPC5 knockout mice harbor long, highly branched granule neuron dendrites with impaired dendritic claw differentiation in the cerebellar cortex. In vivo RNAi analyses suggest that TRPC5 regulates dendrite morphogenesis in the cerebellar cortex in a cell-autonomous manner. Correlating with impaired dendrite patterning in the cerebellar cortex, behavioral analyses reveal that TRPC5 knockout mice have deficits in gait and motor coordination. Finally, we uncover the molecular basis of TRPC5's function in dendrite patterning. We identify the major protein kinase calcium/calmodulin-dependent kinase II ß (CaMKIIß) as a critical effector of TRPC5 function in neurons. Remarkably, TRPC5 forms a complex specifically with CaMKIIß, but not the closely related kinase CaMKIIα, and thereby induces the CaMKIIß-dependent phosphorylation of the ubiquitin ligase Cdc20-APC at the centrosome. Accordingly, centrosomal CaMKIIß signaling mediates the ability of TRPC5 to regulate dendrite morphogenesis in neurons. Our findings define a novel function for TRPC5 that couples calcium signaling to a ubiquitin ligase pathway at the centrosome and thereby orchestrates dendrite patterning and connectivity in the brain.

Preoperative laboratory data are associated with complications and surgical site infection in composite head and neck surgical resections.

OBJECTIVES: 1) Describe normal/abnormal preoperative laboratory testing incidence in head and neck (H&N) composite resections and 2) determine complication, surgical site infection (SSI), and transfusion predictors by laboratory test. METHODS: The 2006 to 2013 NSQIP databases were queried for H&N composite resections. Laboratory data was categorized within, under, or above the normal reference range according to NSQIP definitions. Overall complications and SSI were analyzed with multivariable logistic regression analysis. RESULTS: From 2006 to 2013, there were 1193H&N composite resections, of which 1135 (95.1%) underwent ≥1 preoperative laboratory test. Complete blood counts were obtained in 92.3%, basic metabolic panels in 90.7%, coagulation studies in 56.2%, and liver function tests (LFTs) in 52.6%. Low sodium was found in 11.5%, increasing complication odds by 2.30 (p = 0.005). High AST comprised 10.0% and increased complication odds (OR = 2.93, p = 0.012). Additionally, 9.2% had a high white blood cell (WBC) count and 3.5% had high platelets, increasing complications by 1.92 (p = 0.030) and 3.13 (p = 0.015), respectively. BUN, creatinine, total bilirubin, albumin, alkaline phosphatase, INR, PT, and aPTT abnormal values did not affect postoperative complications. Increased SSI odds were appreciated with low sodium (OR: 2.83, p = 0.002), high AST (OR: 6.85, p < 0.001), and high alkaline phosphatase (OR: 5.46, p = 0.007). Importantly, INR had no effect on transfusion rates. High PT, aPTT, or low platelets did not change transfusion odds. CONCLUSION: Inflammatory markers are associated with complications but not SSI. High LFTs and low sodium are associated with complications and SSI. Coagulopathies did not increase transfusion rates. These findings identify laboratory studies to focus on during H&N resection preoperative assessments.

Auditory Brainstem Implant Array Position Varies Widely Among Adult and Pediatric Patients and Is Associated With Perception.

OBJECTIVES: The auditory brainstem implant (ABI) provides sound awareness to patients who are ineligible for cochlear implantation. Auditory performance varies widely among similar ABI cohorts. We hypothesize that differences in electrode array position contribute to this variance. Herein, we classify ABI array position based on postoperative imaging and investigate the relationship between position and perception. DESIGN: Retrospective review of pediatric and adult ABI users with postoperative computed tomography. To standardize views across subjects, true axial reformatted series of scans were created using the McRae line. Using multiplanar reconstructions, basion and electrode array tip coordinates and array angles from vertical were measured. From a lateral view, array angles (V) were classified into types I to IV, and from posterior view, array angles (T) were classified into types A to D. Array position was further categorized by measuring distance vertical from basion (D1) and lateral from midline (D2). Differences between array classifications were compared with audiometric thresholds, number of active electrodes, and pitch ranking. RESULTS: Pediatric (n = 4, 2 with revisions) and adult (n = 7) ABI subjects were included in this study. Subjects had a wide variety of ABI array angles, but most were aimed superiorly and posteriorly (type II, n = 7) from lateral view and upright or medially tilted from posterior view (type A, n = 6). Mean pediatric distances were 8 to 42% smaller than adults for D1 and D2. In subjects with perceptual data, electrical thresholds and the number of active electrodes differed among classification types. CONCLUSIONS: In this first study to classify ABI electrode array orientation, array position varied widely. This variability may explain differences in auditory performance.

Repair of complex pharyngocutaneous fistula using a staged temporoparietal fascial flap.

INTRODUCTION: PCF is the most common major complication after salvage total laryngectomy (TL), especially for previously irradiated patients with laryngeal or hypopharyngeal cancer. METHODS/RESULTS: A 65-year-old woman presented with recurrent bilateral supraglottic SCC requiring salvage TL 5.5years after initial T1N0M0 epiglottic SCC resection. Her post-operative course was complicated by PCF development one month post-operatively and surgical fistula closure was delayed for adjuvant chemoradiotherapy. The fistula persisted despite local wound therapy, several primary closures, pectoralis flap reconstruction with multiple revisions, and extensive hyperbaric oxygen treatments. Given her prior history, she underwent a staged right temporoparietal fascial flap reconstruction for persistent complex fistula, with second-stage flap takedown and complete inset of the TPFF skin island into the PCF. CONCLUSION: This case demonstrates the utility of staged TPFF in complex PCF repair, with minimal morbidity, especially in a patient with prior irradiation and flap use that complicates tissue availability.

Cell-intrinsic drivers of dendrite morphogenesis.

The proper formation and morphogenesis of dendrites is fundamental to the establishment of neural circuits in the brain. Following cell cycle exit and migration, neurons undergo organized stages of dendrite morphogenesis, which include dendritic arbor growth and elaboration followed by retraction and pruning. Although these developmental stages were characterized over a century ago, molecular regulators of dendrite morphogenesis have only recently been defined. In particular, studies in Drosophila and mammalian neurons have identified numerous cell-intrinsic drivers of dendrite morphogenesis that include transcriptional regulators, cytoskeletal and motor proteins, secretory and endocytic pathways, cell cycle-regulated ubiquitin ligases, and components of other signaling cascades. Here, we review cell-intrinsic drivers of dendrite patterning and discuss how the characterization of such crucial regulators advances our understanding of normal brain development and pathogenesis of diverse cognitive disorders.