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Several prospective studies report improved outcomes with pretreatment nutrition interventions prior to radiation therapy for head and neck cancer (HNC), but none have assessed similar interventions before surgery for HNC.POINT, a pilot randomized controlled trial, was conducted to evaluate a multimodal nutrition intervention. Patients undergoing primary surgery with free flap reconstruction for HNC were randomly assigned to the control arm or a preoperative multimodal nutrition intervention.POINT included 49 patients. Nutrition risk scores did not change significantly for either the intervention or control group. Control patients had a significant decrease in body weight in the preoperative period (p 0.001). Conversely, weight among intervention patients did not significantly decrease (p = 0.680). The intervention mitigated weight loss in patients with dysphagia (p = 0.001).Preoperative nutrition optimization shows potential to reduce weight loss normally experienced by patients with head and neck cancer prior to surgical extirpation, especially among those with subjective dysphagia.

Introduction: Standard of care for radiosensitization in head and neck squamous cell carcinoma (HNSCC) is concurrent chemoradiotherapy (CCRT) with high-dose cisplatin. The optimal chemoradiation regimen for patients medically unfit for cisplatin is unclear. We compared our experience with concurrent cetuximab (CTX) versus other cytotoxic non-cisplatin agents. Methods: We reviewed 53 patients between 2011 and 2017 with HNSCC treated with CCRT ineligible for cisplatin. Chemotherapy and radiotherapy treatment tolerance was evaluated in those receiving CTX versus non-CTX chemotherapy (NCC). Of the NCC regimens, the majority were carboplatin/paclitaxel and were dosed at an area under the curve (AUC) of 2 and 45–50 mg/m2, respectively. Standard radiation dosing was 70 Gray (Gy) in the definitive setting and 60–66 Gy in the postoperative setting. Patient characteristics and treatment toxicities were evaluated using categorical methods. Results: Patients were well balanced overall including differences between performance status and the comorbidity score. NCC patients experienced more radiation treatment breaks (52.4% vs. 21.9%, p = 0.022), radiation delays >1 week (33.3% vs. 3.1%, p < 0.01), and chemotherapy dose-limiting toxicity (61.9% vs. 28.1%, p = 0.015) compared to CTX patients. Nutritional dependence on a PEG tube was more likely in the NCC cohort (52.4% vs. 22.6%, p = 0.027). Conclusion: Our results suggest decreased treatment tolerance in non-cisplatin cytotoxic chemotherapy compared to cetuximab. Further prospective study is needed to clarify optimal chemotherapy in patients unable to receive cisplatin.

ImportanceTimely initiation of postoperative radiation therapy (PORT) is associated with reduced recurrence rates and improved overall survival in patients with head and neck squamous cell carcinoma (HNSCC). Measurement of the association of social-ecological variables with PORT delays is lacking.ObjectiveTo assess individual and community-level factors associated with PORT delay among patients with HNSCC.Design, Setting, and ParticipantsThis prospective cohort study carried out between September 2018 and June 2022 included adults with untreated HNSCC who were enrolled in a prospective registry at a single academic tertiary medical center. Demographic information and validated self-reported measures of health literacy were obtained at baseline visits. Clinical data were recorded, and participant addresses were used to calculate the area deprivation index (ADI), a measure of community-level social vulnerability. Participants receiving primary surgery and PORT were analyzed. Univariable and multivariable regression analysis was performed to identify risk factors for PORT delays.ExposuresSurgical treatment and PORT.Main Outcomes and MeasuresThe primary outcome was PORT initiation delay (>42 days from surgery). Risk of PORT initiation delay was evaluated using individual-level (demographic, health literacy, and clinical data) and community-level information (ADI and rural-urban continuum codes).ResultsOf 171 patients, 104 patients (60.8%) had PORT delays. Mean (SD) age of participants was 61.0 (11.2) years, 161 were White (94.2%), and 105 were men (61.4%). Insurance was employer-based or public among 65 (38.5%) and 75 (44.4%) participants, respectively. Mean (SD) ADI (national percentile) was 60.2 (24.4), and 71 (41.8%) resided in rural communities. Tumor sites were most commonly oral cavity (123 [71.9%]), with 108 (63.5%) classified as stage 4 at presentation. On multivariable analysis, a model incorporating individual-level factors with health literacy in addition to community-level factors was most predictive of PORT delay (AOC= 0.78; R2, 0.18).Conclusions and RelevanceThis cohort study provides a more comprehensive assessment of predictors of PORT delays that include health literacy and community-level measures. Predictive models that incorporate multilevel measures outperform models with individual-level factors alone and may guide precise interventions to decrease PORT delay for at-risk patients with HNSCC.

Assess outcomes of pediatric facial reconstruction with fibula free flaps.Free flap reconstruction of complex maxillofacial defects in pediatric patients is rare. Post-operative complications, donor site morbidity, impact on craniofacial growth, and oro-dental rehabilitation are unknown. Our study assesses the outcomes of pediatric maxillofacial reconstruction with composite fibula free flaps.Retrospective chart review.Multi-institutional retrospective chart review from 2000 to 2020 on pediatric patients undergoing maxillomandibular reconstruction with fibula free flaps.Eighty-seven patients underwent 89 surgeries; 5 maxillary and 84 mandibular defects. Median age: 12 years. Defects were acquired following resection of sarcoma/carcinoma 44% or benign tumors 50%. 73% of cases had immediate free flap reconstruction. Closing osteotomies were reported in 74%; 1 in 40%, 2 in 27%, and more than 2 in 6.7%. Hardware was used in 98% and removed in 25%. 9.2% demonstrated long-term hardware exposure, greater than 3 months following reconstruction. Short-term complications: wound infection 6.7%, flap salvage/failure 2.2%, fistula 1.1%, and compromised craniofacial growth: 23%. Two patients developed trismus. Long-term fibula donor site complications: hypertrophic scarring: 3.4%, dysesthesia: 1.1%, and long-term gait abnormality: 1.1%. Dental rehabilitation was performed in 33%. Post-operative speech outcomes showed 94% with fully intelligible speech.Pediatric maxillary and mandible defects repaired with fibula free flaps demonstrated complication rates comparable to the adult free flap population. Long-term follow-up did not demonstrate adverse outcomes for craniofacial growth. Hardware for flap retention was utilized and remained in place with minimal exposure. Post-operative gait abnormality is rare.3 Laryngoscope, 2022.

CAFs exhibit increased LC3 puncta per cell compared to NF.

CAF secreted HGF mediates HNSCC glycolysis.

Includes legends for all supplementary figures. S1: CAFs exhibit increased LC3 puncta per cell compared to NF. S2: CAF autophagy inhibition significantly decreases HNSCC in vitro progression. S3: IL-6 and IL-8 induce fibroblast autophagy. S4: bFGF treatment increases autophagy regulated secreted factors. S5: Autophagy inhibition reduces HNSCC in combination therapy, and does not affect CAF proliferation.

Despite therapeutic advancements, there has been little change in the survival of patients with head and neck squamous cell carcinoma (HNSCC). Recent results suggest that cancer-associated fibroblasts (CAF) drive progression of this disease. Here, we report that autophagy is upregulated in HNSCC-associated CAFs, where it is responsible for key pathogenic contributions in this disease. Autophagy is fundamentally involved in cell degradation, but there is emerging evidence that suggests it is also important for cellular secretion. Thus, we hypothesized that autophagy-dependent secretion of tumor-promoting factors by HNSCC-associated CAFs may explain their role in malignant development. In support of this hypothesis, we observed a reduction in CAF-facilitated HNSCC progression after blocking CAF autophagy. Studies of cell growth media conditioned after autophagy blockade revealed levels of secreted IL6, IL8, and other cytokines were modulated by autophagy. Notably, when HNSCC cells were cocultured with normal fibroblasts, they upregulated autophagy through IL6, IL8, and basic fibroblast growth factor. In a mouse xenograft model of HNSCC, pharmacologic inhibition of Vps34, a key mediator of autophagy, enhanced the antitumor efficacy of cisplatin. Our results establish an oncogenic function for secretory autophagy in HNSCC stromal cells that promotes malignant progression. Cancer Res; 77(23); 6679–91. ©2017 AACR.

Despite aggressive therapies, head and neck squamous cell carcinoma (HNSCC) is associated with a less than 50% 5-year survival rate. Late-stage HNSCC frequently consists of up to 80% cancer-associated fibroblasts (CAF). We previously reported that CAF-secreted HGF facilitates HNSCC progression; however, very little is known about the role of CAFs in HNSCC metabolism. Here, we demonstrate that CAF-secreted HGF increases extracellular lactate levels in HNSCC via upregulation of glycolysis. CAF-secreted HGF induced basic FGF (bFGF) secretion from HNSCC. CAFs were more efficient than HNSCC in using lactate as a carbon source. HNSCC-secreted bFGF increased mitochondrial oxidative phosphorylation and HGF secretion from CAFs. Combined inhibition of c-Met and FGFR significantly inhibited CAF-induced HNSCC growth in vitro and in vivo (P < 0.001). Our cumulative findings underscore reciprocal signaling between CAF and HNSCC involving bFGF and HGF. This contributes to metabolic symbiosis and a targetable therapeutic axis involving c-Met and FGFR.Significance: HNSCC cancer cells and CAFs have a metabolic relationship where CAFs secrete HGF to induce a glycolytic switch in HNSCC cells and HNSCC cells secrete bFGF to promote lactate consumption by CAFs. Cancer Res; 78(14); 3769–82. ©2018 AACR.

Legends for all supplemental figures

To evaluate the effect of histopathologic skin invasion on 2- and 5-year disease-free survival (DFS) and overall survival (OS) in patients treated with primary surgery for locally advanced oral cavity squamous cell carcinoma (OCSCC).A retrospective case-control study was performed comparing previously untreated patients with pT4a OCSCC with and without skin invasion.Academic medical center.Propensity score-matched cohorts were derived by age, sex, surgical margins, pathologic N classification, adjuvant treatment, and primary tumor site. The Kaplan-Meier method was used to evaluate 2- and 5-year OS and DFS, which were compared between cohorts via the log rank (Mantel-Cox) test statistic.Overall 25 patients were identified to have pathologic skin invasion, and 50 were selected for the matched control group. OS was significantly lower for patients with skin invasion as compared with controls at 2 years (30.8% vs 53.3%,Histopathologic skin invasion in OCSCC is associated with dismal prognosis in patients who underwent primary surgical treatment. OS outcomes for patients with skin invasion are comparable to survival of patients with recurrent/metastatic disease and T4N2 disease.

To optimize the delivery of multimodal analgesia to patients undergoing major head and neck oncologic surgeries.Pilot study included patients enrolled to receive either scheduled acetaminophen and as-needed opioids (control group) or scheduled acetaminophen, gabapentin, ketorolac, and as-needed opioids (experimental group). RCT, a hybrid type 1 effectiveness-implementation pragmatic trial, was designed to test the effectiveness of the intervention. Arm A received scheduled acetaminophen and as-needed opioids. Arm B received scheduled gabapentin, ketorolac, a regional nerve block at the free tissue donor site, scheduled acetaminophen and as-needed opioids.Pilot: Thirty-one patients undergoing major head and neck surgery were enrolled. Mean MMEs administered in control group (n = 15) was 251.60 mg (SD = 224.57 mg); mean MMEs in Experimental group (n = 16) was 195.78 mg (SD = 131.08 mg), p = 0.401. LOS was 8.0 days in control versus 7.0 days in experimental group (p = 0.054). RCT: Interim analysis for safety and futility was planned during trial's design after 30 patients (n = 14 Arm A, and n = 16 Arm B). Mean MMEs administered were 135.1 mg in Arm A, (SD = 86.0 mg) versus mean MME of 51.3 mg in Arm B (SD = 43.3 mg, (p 0.05)). Given clear superiority results, the trial was prematurely terminated. Functional pain scores, LOS, and complications were similar between the arms (p 0.05). Variability of mean MME was compared before and after implementation of the management protocols: SD in RCT#1 was 181.46 mg versus 124.6 mg in RCT#2.Multimodal analgesia significantly reduced the need for opioids in patients undergoing major head and neck surgery.1, Randomized Clinical Trial Laryngoscope, 2022.

Burnout has been previously assessed in head and neck microvascular reconstructive surgeons (HNMVS), but not in the context of modifiable workplace factors.Anonymous, cross-sectional survey. The Abbreviated Maslach Burnout Inventory - Human Services Survey for Medical Personnel (aMBI-HSS) was utilized to assess emotional exhaustion (EE), depersonalization (DP), and personal achievement (PA). Modifiable risk factors were also evaluated.High risk of burnout by EE, DP, and PA was demonstrated in 24%, 9%, and 27% of respondents, respectively. EE was associated with10% dedicated research time, lack of autonomy over clinic schedule, inadequate inpatient support, and lack of supportive clinical partner. DP was associated with3 operative days, difficulty balancing academic commitments, and lack of supportive clinical partner. Dedicated research time and two or fewer days of block time were protective.Burnout was associated with several modifiable workplace factors. Addressing these may prevent moderate to severe burnout in HNMVS.

The incidence of Merkel cell carcinoma (MCC) continues to increase. Understanding of MCC biology has advanced rapidly, with current staging providing valuable prognostic information. MCC treatment often is multidisciplinary. Surgery remains an important component in the staging and treatment, most commonly involving wide excision of the cancer and sentinel lymph node biopsy. Lymphadenectomy is used to treat nodal disease. Radiotherapy enhances locoregional control and possibly survival. Systemic therapies, in particular novel immunotherapies, may be promising in the treatment of advanced or recurrent and metastatic disease.

Background The coronavirus disease 2019 pandemic has led to increased telemedicine visits. This study examines current preferences and barriers for telemedicine among patients with head and neck cancer. Methods Single institution retrospective analysis of 64 patients scheduling visits with the head and neck surgical oncology clinic at a tertiary academic medical center. Data were collected detailing patient preferences and barriers regarding telemedicine appointments. Patients electing to participate in telemedicine were compared to those preferring in‐person appointments. Results Most patients (68%) were not interested in telemedicine. Preference for in‐person examination was the most common reason for rejecting telemedicine, followed by discomfort with or limited access to technology. Patients elected telemedicine visits to avoid infection and for convenience. Conclusions When given a choice, patients with head and neck cancer preferred in‐person visits over telemedicine. Although telemedicine may improve health care access, patient preferences, technology‐related barriers, and limitations regarding cancer surveillance must be addressed moving forward.

Background Immunotherapy agents are used to treat advanced head and neck lesions. We aim to elucidate relationship between immunotherapy and surgical wound complications. Methods Retrospective multi-institutional case series evaluating patients undergoing ablative and flap reconstructive surgery and immunotherapy treatment. Main outcome wound complications. Results Eight-two (62%) patients received preoperative therapy, 89 (67%) postoperative, and 33 (25%) in both settings. Forty-one (31%) patients had recipient site complications, 12 (9%) had donor site. Nineteen (14%) had major recipient site complications, 22 (17%) had minor. There was no statistically significant difference in complications based on patient or tumor-specific variables. Preoperative therapy alone demonstrated increased major complications (odds ratio [OR] 3.7, p = 0.04), and trend to more donor site complications (OR 7.4, p = 0.06), however treatment in both preoperative and postoperative therapy was not. Conclusions Preoperative immunotherapy may be associated with increased wound complications. Controlled studies are necessary to delineate this association and potential risks of therapy.

The incidence of head and neck squamous cell carcinomas (HNSCCs) is rising in developed countries. This is driven by an increase in HNSCCs caused by high-risk human papillomavirus (HPV) infections or HPV + HNSCCs. Compared to HNSCCs not caused by HPV (HPV– HNSCCs), HPV + HNSCCs are more responsive to therapy and associated with better oncologic outcomes. As a result, the HPV status of an HNSCC is an important determinant in medical management. One method to determine the HPV status of an HNSCC is increased expression of p16 caused by the HPV E7 oncogene. We identified novel expression changes in HPV + HNSCCs. A comparison of gene expression among HPV+ and HPV- HNSCCs in The Cancer Genome Atlas demonstrated increased DNA repair gene expression in HPV + HNSCCs. Further, DNA repair gene expression correlated with HNSCC survival. Immunohistochemical analysis of a novel HNSCC microarray confirmed that DNA repair protein abundance is elevated in HPV + HNSCCs.

BACKGROUND Lymph node yield (LNY) is a proposed quality indicator in neck dissection for oral cavity squamous cell carcinoma (OCSCC). METHODS Retrospective series including 190 patients with OCSCC undergoing neck dissection between 2016 and 2018. A change in pathologic grossing protocol was initiated during the study period to assess residual adipose tissue. A generalized linear model was used to assess the impact of multiple variables on LNY. RESULTS Mean LNY was 28.59 (SD = 17.65). The protocol identified a mean of 10.32 lymph nodes per case. Multivariable analysis identified associations between LNY and use of the pathology protocol (P = .02), number of dissected lymph node levels (P

This study was performed to identify treatment related toxicities in older adults undergoing concurrent chemoradiotherapy for head and neck cancer and nutritional and skeletal muscle measures that might identify frailty. Imaging analysis was done with the following skeletal muscle measurements: skeletal muscle index (SMI), skeletal muscle density (SMD), and skeletal muscle gauge (SMG). Patients were dichotomized by age into younger (

BACKGROUND While quality of life (QOL), psychosocial health, and adverse treatment outcomes have been studied in head and neck cancer (HNC) patients, decision regret is an important and understudied complication that can negatively impact future health care decision making. METHODS Data collected using a HNC patient registry with questionnaires administered at initial consultation visits plus 3 and 6 months after treatment completion was retrospectively analyzed. A visual analog anxiety scale and the University of Washington Quality of Life were given at clinic visits. Decision regret was determined using a validated scale. Demographic and clinical variables were collected retrospectively and at baseline. RESULTS Patients with higher anxiety and lower self-reported QOL had higher concurrent regret at 3-month (n = 140) and at 6-month (n = 82) post-treatment. Later disease stage at presentation, nonprimary surgical treatment, and lower health literacy were associated with greater regret. CONCLUSIONS Decision regret was highest in HNC patients with high anxiety, low QOL, and more advanced disease.

BACKGROUND Triweekly high-dose cisplatin (100 mg/m2 ) with concurrent radiation therapy is the current standard of care in the definitive or appropriate postoperative setting in head and neck squamous cell carcinoma (HNSCC). We compared triweekly 100 mg/m2 with alternative weekly 40 mg/m2 and weekly

Head and neck cancer patients require close clinical follow up to monitor and address sequelae of treatment and for adequate cancer surveillance. The goal of this study is to determine barriers and risk factors for head and neck cancer patients who are lost-to-follow-up.A chart review of the Head and Neck Cancer Registry was performed to identify patients who were lost-to-follow-up (LTF). LTF was defined as missing two consecutive appointments as recommended by their oncologic surgeon. Those identified as LTF were contacted via email and phone to complete a 16-question survey addressing possible barriers to follow up.Of the 353 patients reviewed, 53 met the criteria for LTF (15%). Forty-eight participants were contacted, and 23 surveys were completed (48%). Of the 23 patients that responded, 22% reported difficulty scheduling an appointment, 30% had transportation barriers, 22% had personal or work obligations that prevented follow up, 17% did not follow up because they "felt better," and 39% were following up with an otolaryngologist or oncologist closer to home. Only three participants (13%) were aware of the recommended 5-year surveillance period.Head and neck cancer patients have a variety of reasons they are lost to follow-up. Understanding these barriers is critical to creating a patient-centered model that balances both clinical surveillance needs and reasonable expectations for patients. Improvements can be made to educate patients on the recommended length of follow-up and its importance.

This article provides best practice guidelines regarding nasopharyngolaryngoscopy and OHNS clinic reopening during the COVID‐19 pandemic. The aim is to provide evidence‐based recommendations defining the risks of COVID‐19 in clinic, the importance of pre‐visit screening in addition to testing, along with ways to adhere to CDC guidelines for environmental, source, and engineering controls.

Objectives/hypothesis New advances in osseous microvascular mandibular rigid fixation are being employed at many institutions. These include standardized prebent/preformed reconstruction plates as well as computer-aided design/computer-aided manufacturing (CAD/CAM) custom plates that are patient specific. Our goal was to assess and compare the outcomes of both of these new technologies when utilized for mandibular microvascular reconstruction. Study design Retrospective chart review. Methods Subjects were categorized into two groups according to their mandibular rigid fixation technique: group 1 = prebent/preformed plates and group 2 = CAD/CAM custom plates. Primary outcome measures were 1) perioperative complications (defined as deep tissue infection, wound dehiscence resulting in bone exposure, and/or plate exposure) and 2) reoperation rates for mandibular hardware failure/explantation. Statistical analysis consisted of χ2 , Fisher exact test, and multivariable regression models. Results A total of 142 subjects underwent microvascular mandibular reconstruction in a 6-year period. Eighty-nine subjects utilized prebent/preformed plates, and 53 employed CAD/CAM custom plates. Perioperative complications occurred in 32 of 89 (35.9%) subjects with prebent/preformed plates and 11 of 53 (20.7%) subjects using CAD/CAM custom plates. Reoperation requiring hardware explantation occurred in 18 of 89 (20.2%) subjects and three of 53 (5.6%) using CAD/CAM custom plates. Statistical comparison of perioperative complications between the two groups approached significance (P = .0556), and the rate of reoperation was significant favoring CAD/CAM implants (P = .0180). Conclusions In our experience, CAD/CAM custom plates utilized for rigid fixation during microvascular mandibular reconstruction demonstrated fewer complications and statistically lower reoperation rates when compared with prebent/preformed plates. Level of evidence 2c Laryngoscope, 129:1081-1086, 2019.

Head and neck squamous cell carcinoma (HNSCC) is associated with low survival, and the current aggressive therapies result in high morbidity. Nutraceuticals are dietary compounds with few side effects. However, limited antitumor efficacy has restricted their application for cancer therapy. Here, we examine combining nutraceuticals, establishing a combination therapy that is more potent than any singular component, and delineate the mechanism of action. Three formulations were tested: GZ17-S (combined plant extracts from Arum palaestinum, Peganum harmala and Curcuma longa); GZ17-05.00 (16 synthetic components of GZ17-S); and GZ17-6.02 (3 synthetic components of GZ17S; curcumin, harmine and isovanillin). We tested the formulations on HNSCC proliferation, migration, invasion, angiogenesis, macrophage viability and infiltration into the tumor and tumor apoptosis. GZ17-6.02, the most effective formulation, significantly reduced in vitro assessments of HNSCC progression. When combined with cisplatin, GZ17-6.02 enhanced anti-proliferative effects. Molecular signaling cascades inhibited by GZ17-6.02 include EGFR, ERK1/2, and AKT, and molecular docking analyses demonstrate GZ17-6.02 components bind at distinct binding sites. GZ17-6.02 significantly inhibited growth of HNSCC cell line, patient-derived xenografts, and murine syngeneic tumors in vivo (P

Objective To characterize and identify risk factors for 30-day surgical site infections (SSIs) in patients with head and neck cancer who underwent microvascular reconstruction. Study Design Cross-sectional study with nested case-control design. Setting Nine American tertiary care centers. Subjects and Methods Hospitalized patients were included if they underwent head and neck cancer microvascular reconstruction from January 2003 to March 2016. Cases were defined as patients who developed 30-day SSI; controls were patients without SSI at 30 days. Postoperative antibiotic prophylaxis (POABP) regimens were categorized by Gram-negative (GN) spectrum: no GN coverage, enteric GN coverage, and enteric with antipseudomonal GN coverage. All POABP regimens retained activity against anaerobes and Gram-positive bacteria. Thirty-day prevalence of and risk factors for SSI were evaluated. Results A total of 1307 patients were included. Thirty-day SSI occurred in 189 (15%) patients; median time to SSI was 11.5 days (interquartile range, 7-17). Organisms were isolated in 59% of SSI; methicillin-resistant Staphylococcus aureus (6%) and Pseudomonas aeruginosa (9%) were uncommon. A total of 1003 (77%) patients had POABP data: no GN (17%), enteric GN (52%), and antipseudomonal GN (31%). Variables independently associated with 30-day SSI were as follows: female sex (adjusted odds ratio [aOR], 1.6; 95% CI, 1.1-2.2), no GN POABP (aOR, 2.2; 95% CI, 1.5-3.3), and surgical duration ≥11.8 hours (aOR, 1.9; 95% CI, 1.3-2.7). Longer POABP durations (≥6 days) or antipseudomonal POABP had no association with SSI. Conclusions POABP without GN coverage was significantly associated with SSI and should be avoided. Antipseudomonal POABP or longer prophylaxis durations (≥6 days) were not protective against SSI. Antimicrobial stewardship interventions should be made to limit unnecessary antibiotic exposures, prevent the emergence of resistant organisms, and improve patient outcomes.

Objectives To develop and validate an algorithm to predict occult nodal metastasis in clinically node negative oral cavity squamous cell carcinoma (OCSCC) using machine learning. To compare algorithm performance to a model based on tumor depth of invasion (DOI). Materials and methods Patients who underwent primary tumor extirpation and elective neck dissection from 2007 to 2013 for clinical T1-2N0 OCSCC were identified from the National Cancer Database (NCDB). Multiple machine learning algorithms were developed to predict pathologic nodal metastasis using clinicopathologic data from 782 patients. The algorithm was internally validated using test data from 654 patients in NCDB and was then externally validated using data from 71 patients treated at a single academic institution. Performance was measured using area under the receiver operating characteristic (ROC) curve (AUC). Machine learning and DOI model performance were compared using Delong’s test for two correlated ROC curves. Results The best classification performance was achieved with a decision forest algorithm (AUC = 0.840). When applied to the single-institution data, the predictive performance of machine learning exceeded that of the DOI model (AUC = 0.657, p = 0.007). Compared to the DOI model, machine learning reduced the number of neck dissections recommended while simultaneously improving sensitivity and specificity. Conclusion Machine learning improves prediction of pathologic nodal metastasis in patients with clinical T1-2N0 OCSCC compared to methods based on DOI. Improved predictive algorithms are needed to ensure that patients with occult nodal disease are adequately treated while avoiding the cost and morbidity of neck dissection in patients without pathologic nodal disease.

Background The osteocutaneous radial forearm free flap (OCRFFF) for mandibular reconstruction has been well described. Despite this flap's utility in the repair of such defects, the indications for the OCRFFF have continued to expand in recent years. The advantages of the OCRFFF allow for a high degree of versatility in the reconstruction of the various anatomical and aesthetic units of the head and neck. In this review, the authors aim to explore the successful utilization of the OCRFFF beyond the reconstruction of composite mandibular defects. Methods A retrospective chart review was performed. All subjects who underwent OCRFFF reconstruction at a tertiary academic center between January 2004 and December 2014 were identified. A total of six patients undergoing this procedure for indications other than composite mandibular defects of the head and neck were included. Results A total of six patients underwent OCRFFF reconstruction for correction of nonmandibular defects. Flap success was experienced in six of six cases (100%). Indications included midface maxillary reconstruction (N = 2), orbit reconstruction (N = 1), frontal sinus and forehead reconstruction (N = 2), and subglottic stenosis reconstruction (N = 1). There were no immediate perioperative complications. On long-term follow-up, one subject developed a nasocutaneous fistula following radiation and eventually required maxillary hardware removal. Conclusion As a result of its growing role and versatility, the OCRFFF should be incorporated as a multipurpose tool in the armamentarium of reconstructive microvascular surgeons in the repair of composite head and neck defects beyond the mandible.

Parathyroid glands undergo a variable descent during embryologic development and can be found anywhere in the neck from the level of the mandible to the mediastinum. To the best of our knowledge, we present the first report of a patient who was found to have bilateral parathyroid adenomas in her pyriform sinuses. A middle-aged woman with renal failure and secondary hyperparathyroidism presented with dysphagia and was found to have bilateral pyriform sinus masses on endoscopy. We performed direct laryngoscopy and surgical excision of these masses, and they were found to be parathyroid adenomas. Her dysphagia improved postoperatively, and she continues to be followed by her endocrinologist, who manages her secondary hyperparathyroidism medically. The differential diagnosis for hypopharyngeal masses is wide and should include parathyroid adenomas, even in patients with bilateral masses.

Background Free tissue transfer is a mainstay in reconstruction of complex head and neck defects. The purpose of this study was to determine if perioperative complications were more common in patients with body mass index (BMI) >30 kg/m2 undergoing free flap reconstruction. Methods A multi-institutional retrospective cohort was created. Medical complications, surgical complications, and procedural variables were recorded. Logistic regression was used to investigate univariate and multivariate associations between outcomes and predictors. Results Of 582 cases, 128 patients (22%) had BMI >30. Surgical complications occurred in 153 cases (26.3%), with an adjusted odds ratio (OR) for association of surgical complications with BMI >30 of 0.92 (p = .71). Medical complications occurred in 178 cases (30.6%), with an adjusted OR of 0.78 (p = .26). Age and advanced comorbidity status (Adult Comorbidity Evaluation-27 [ACE-27] 2 or 3) were associated with medical complications (p 30 does not predict medical or surgical complications in patients undergoing head and neck free flap surgery. © 2015 Wiley Periodicals, Inc. Head Neck, 2015

Background The purpose of this study was to determine the benefit of 1-vein versus 2-vein outflow in microvascular free tissue transfers. Methods A retrospective review reflects the experience of 6 surgeons. Analysis included all patients who underwent reconstruction at a single institution between January 2004 and December 2012. Results Three hundred nine patients underwent a total of 317 microvascular free flap reconstructions for head and neck defects. Two hundred thirteen of 317 flaps (67.2%) used 1 venous anastomosis and 104 (32.8%) used 2 venous anastomoses. Venous congestion necessitated urgent take back in 37 of 57 patients (64.9%) requiring exploration for perioperative complications. Thirty of 37 flaps (81.1%) with venous congestion had 1 vein anastomosis, whereas 7 (18.9%) had dual vein outflow (p = .03). Overall flap success was 303 of 317 (95.6%), despite an 18.0% (57 of 317) perioperative take back rate. Conclusion Coapting 2 veins was shown to minimize venous congestion. © 2015 Wiley Periodicals, Inc. Head Neck, 2015

Background The purpose of this study was to assess the impact of bone harvest length and multiple osteotomies on osteocutaneous radial forearm free flap (RFFF) complication rates. Methods A retrospective chart review was conducted for patients undergoing osteocutaneous RFFF reconstruction during an 8-year period. Results One hundred fifty-five osteocutaneous RFFF procedures were performed. Recipient-site flap complications were 18 of 55 (32.7%) when bone harvest length was less than 7 cm and 40 of 100 (40.0%) when it was ≥7 cm. No osteotomies were performed in 69 of 155 cases with a corresponding complication rate of 30.4% (21 of 69). One osteotomy was utilized in 69 of 155 flaps, whereas 17 of 155 required more than 1 osteotomy; complications were experienced in 42% (29 of 69) and 47% (8 of 17) of these cases, respectively. Conclusion Osteocutaneous RFFF complication rates were only slightly higher when the bone length was ≥7 cm or when multiple osteotomies were required. © 2015 Wiley Periodicals, Inc. Head Neck, 2015

Mandibular reconstruction presents unique functional and aesthetic challenges to the reconstructive surgeon. This review will cover current techniques for mandibular reconstruction, including the various plating strategies for rigid fixation, the choice of osseous donor site, and the concurrent reconstruction of associated soft tissue defects. Recent developments and future horizons in mandibular reconstruction including the use of virtual surgical planning and tissue engineering will also be addressed.

Carcinoma showing thymus-like differentiation is a rare tumor of the thyroid gland, which is structurally similar to thymic tissue. Overall, it has a favorable prognosis. Radiotherapy has been shown to be an effective local treatment, but there have been reports of distant recurrence. It has been suggested that adding chemotherapy may decrease the risk of recurrence. Here, we present a case report of a patient with a large tumor and extrathyroidal extension. The patient was treated with surgery, radiotherapy, and cisplatin with acceptable toxicity. The patient is free of locally recurrent or distant disease at 3 years.

Importance Free flap reconstruction of the head and neck is routinely performed with success rates around 94% to 99% at most institutions. Despite experience and meticulous technique, there is a small but recognized risk of partial or total flap loss in the postoperative setting. Historically, most microvascular surgeons involve resident house staff in flap monitoring protocols, and programs relied heavily on in-house resident physicians to assure timely intervention for compromised flaps. In 2003, the Accreditation Council for Graduate Medical Education mandated the reduction in the hours a resident could work within a given week. At many institutions this new era of restricted resident duty hours reshaped the protocols used for flap monitoring to adapt to a system with reduced resident labor. Objectives To characterize various techniques and frequencies of free flap monitoring by nurses and resident physicians; and to determine if adapted resident monitoring frequency is associated with flap compromise and outcome. Design, Setting, and Participants This multi-institutional retrospective review included patients undergoing free flap reconstruction to the head and/or neck between January 2005 and January 2015. Consecutive patients were included from different academic institutions or tertiary referral centers to reflect evolving practices. Main Outcomes and Measures Technique, frequency, and personnel for flap monitoring; flap complications; and flap success. Results Overall, 1085 patients (343 women [32%] and 742 men [78%]) from 9 institutions were included. Most patients were placed in the intensive care unit postoperatively (n = 790 [73%]), while the remaining were placed in intermediate care (n = 201 [19%]) or in the surgical ward (n = 94 [7%]). Nurses monitored flaps every hour (q1h) for all patients. Frequency of resident monitoring varied, with 635 patients monitored every 4 hours (q4h), 146 monitored every 8 hours (q8h), and 304 monitored every 12 hours (q12h). Monitoring techniques included physical examination (n = 949 [87%]), handheld external Doppler sonography (n = 739 [68%]), implanted Doppler sonography (n = 333 [31%]), and needle stick (n = 349 [32%]); 105 patients (10%) demonstrated flap compromise, prompting return to the operating room in 96 patients. Of these 96 patients, 46 had complete flap salvage, 22 had partial loss, and 37 had complete loss. The frequency of resident flap checks did not affect the total flap loss rate (q4h, 25 patients [4%]; q8h, 8 patients [6%]; and q12h, 8 patients [3%]). Flap salvage rates for compromised flaps were not statistically different. Conclusions and Relevance Academic centers rely primarily on q1h flap checks by intensive care unit nurses using physical examination and Doppler sonography. Reduced resident monitoring frequency did not alter flap salvage nor flap outcome. These findings suggest that institutions may successfully monitor free flaps with decreased resident burden.

Despite aggressive therapies, head and neck squamous cell carcinoma (HNSCC) is associated with a less than 50% 5-year survival rate. Late-stage HNSCC frequently consists of up to 80% cancer-associated fibroblasts (CAF). We previously reported that CAF-secreted HGF facilitates HNSCC progression; however, very little is known about the role of CAFs in HNSCC metabolism. Here, we demonstrate that CAF-secreted HGF increases extracellular lactate levels in HNSCC via upregulation of glycolysis. CAF-secreted HGF induced basic FGF (bFGF) secretion from HNSCC. CAFs were more efficient than HNSCC in using lactate as a carbon source. HNSCC-secreted bFGF increased mitochondrial oxidative phosphorylation and HGF secretion from CAFs. Combined inhibition of c-Met and FGFR significantly inhibited CAF-induced HNSCC growth in vitro and in vivo (P < 0.001). Our cumulative findings underscore reciprocal signaling between CAF and HNSCC involving bFGF and HGF. This contributes to metabolic symbiosis and a targetable therapeutic axis involving c-Met and FGFR. Significance: HNSCC cancer cells and CAFs have a metabolic relationship where CAFs secrete HGF to induce a glycolytic switch in HNSCC cells and HNSCC cells secrete bFGF to promote lactate consumption by CAFs. Cancer Res; 78(14); 3769–82. ©2018 AACR.

Despite therapeutic advancements, there has been little change in the survival of patients with head and neck squamous cell carcinoma (HNSCC). Recent results suggest that cancer-associated fibroblasts (CAF) drive progression of this disease. Here, we report that autophagy is upregulated in HNSCC-associated CAFs, where it is responsible for key pathogenic contributions in this disease. Autophagy is fundamentally involved in cell degradation, but there is emerging evidence that suggests it is also important for cellular secretion. Thus, we hypothesized that autophagy-dependent secretion of tumor-promoting factors by HNSCC-associated CAFs may explain their role in malignant development. In support of this hypothesis, we observed a reduction in CAF-facilitated HNSCC progression after blocking CAF autophagy. Studies of cell growth media conditioned after autophagy blockade revealed levels of secreted IL6, IL8, and other cytokines were modulated by autophagy. Notably, when HNSCC cells were cocultured with normal fibroblasts, they upregulated autophagy through IL6, IL8, and basic fibroblast growth factor. In a mouse xenograft model of HNSCC, pharmacologic inhibition of Vps34, a key mediator of autophagy, enhanced the antitumor efficacy of cisplatin. Our results establish an oncogenic function for secretory autophagy in HNSCC stromal cells that promotes malignant progression. Cancer Res; 77(23); 6679–91. ©2017 AACR.

Background Resections involving oral cavity mucosa, bone, and skin present a unique challenge. Optimizing outcomes often requires technically demanding reconstruction. The purpose of this study is to evaluate outcomes of several reconstructive approaches for patients with composite through-and-through defects, with a focus on the osteocutaneous radial forearm free flap (RFFF). Methods We conducted a retrospective evaluation of the cohort of patients treated for composite through-and-through defects with cutaneous involvement who underwent free flap reconstruction from August 2012 through October 2015. Results Seventeen patients received a single flap (12 cases of osteocutaneous RFFF), whereas 10 patients underwent a combination of flaps. Complication rates and functional outcomes were favorable in patients who underwent osteocutaneous RFFFs. The supraclavicular artery island flap (SCAIF) was used as a second flap in 3 cases. Conclusion The osteocutaneous RFFF provides a valuable reconstructive option for complex composite resection defects involving skin. When 2 flaps are required, the SCAIF is a viable alternative to a second free flap or pectoralis flap.

Hyaluronan (HA) is a ligand for the CD44 receptor which is crucial to cancer cell proliferation and metastasis. High levels of CD44 expression in many cancers have encouraged the development of HA-based carriers for anti-cancer therapeutics.The objective of this study was to determine whether HA conjugation of anticancer drugs impacts CD44-specific HA-drug uptake and disposition by human head and neck cancer cells.The internalization and cellular disposition of hyaluronan-doxorubicin (HA-DOX), hyaluronan-cisplatin (HA-Pt), and hyaluronan-cyanine7 (HA-Cy7) conjugates were investigated by inhibiting endocytosis pathways, and by inhibiting the CD44-mediated internalization pathways that are known to mediate hyaluronan uptake in vitro.Cellular internalization of HA was regulated by CD44 receptors. In mouse xenografts, HA conjugation significantly enhanced tumor cell uptake compared to unconjugated drugs.The results suggested that the main mechanism of HA-based conjugate uptake may be active transport via CD44 in conjunction with a clathrin-dependent endocytic pathway. Other HA receptors, hyaluronan-mediated motility receptor (RHAMM) and lymphatic vessel endothelial hyaluronan receptor (LYVE-1), did not play a significant role in conjugate uptake.HA conjugation significantly increased CD44-mediated drug uptake and extended the residence time of drugs in tumor cells.

Objectives: We performed a retrospective study of cases from 2005 to 2010 at an academic tertiary care center to analyze the factors that influence morbidity in surgical management of thyroid malignancy. Methods: The rates of recurrent laryngeal nerve (RLN) injury and hypoparathyroidism (HPT) were analyzed in the entire cohort. The comparison groups were 1) primary surgery versus revision; 2) total thyroidectomy versus total thyroidectomy combined with neck node dissection; and 3) two groups defined by surgical technique according to the RLN approach: Group 1, in which the RLN was identified inferiorly in the tracheoesophageal groove, and group 2, in which the RLN was identified near the cricothyroid joint point of entry. Results: We reviewed 308 patients who underwent surgery for thyroid cancer. Thirty-six (11.7%) had temporary HPT, and 8 (2.6%) had permanent HPT. Of a total of 586 RLNs at risk, 16 (2.7%) had temporary damage and 2 (0.3%) had permanent damage. The incidences of temporary RLN injury significantly differed between the primary-surgery and revision-surgery groups (2.5% versus 15.6%; p = 0.001), and also between the groups with total thyroidectomy and thyroidectomy with neck dissection (1.2% versus 7.8%; p = 0.027). The incidences of temporary HPT were significantly different between the groups with primary surgery and revision surgery (6.6% versus 31.3%; p = 0.001), between the groups with total thyroidectomy and total thyroidectomy with neck dissection (4.7% versus 15.6%; p = 0.009), and between group 1 and group 2 (surgical technique in terms of RLN approach; 8.2% versus 17.9%; p = 0.011). Permanent HPT and permanent RLN injury both occurred rarely in this cohort, with no significant differences among comparison groups. Conclusions: Our study shows a higher incidence of temporary RLN injury and temporary HPT in revision surgery cases and in total thyroidectomy with neck dissection. Temporary HPT was significantly more common when the RLN was identified near the cricothyroid joint.

Human papillomavirus (HPV) was recently identified as a risk factor for oropharyngeal squamous cell carcinoma (SCC) independent of tobacco and alcohol use. The prognosis of patients with HPV-related oropharyngeal carcinomas is better than that for patients with non-HPV-related cancers. Researchers and clinicians can test for HPV infection in cancer by (1) testing directly for HPV DNA and (2) testing for overexpression of the downstream p16 protein; there is currently no consensus regarding which is the better test. The chances of developing a reliable oropharyngeal HPV screening test for high-risk populations are promising. Such a test would allow for secondary prevention by identifying individuals with precursor or early-stage cancerous lesions that are more amenable to treatment. HPV testing has particular significance in SCC of an unknown primary site in head and neck cancer. Successful HPV testing of nodal metastasis can localize cancer specifically to the oropharynx. The optimal evaluation for SCC of an unknown primary in the head and neck has yet to be determined. Some studies have shown that the tonsillar fossa is the most probable primary site, followed closely by the base of the tongue. Biopsies often miss tonsillar carcinoma in the deep crypts of the lymph tissue, as well as in those rare cases in which the primary tumor is located contralateral to the metastatic lymph node. Recently, there has been an increase in the number of reports of diagnosed synchronous bilateral HPV-related tonsillar carcinomas. This increase has profound implications for the surgical approach of SCC of an unknown primary site in the head and neck and in tonsillar carcinoma, and it supports the need for bilateral tonsillectomy. We present 2 cases of incidentally discovered synchronous bilateral tonsillar carcinoma, and we review the literature.

Radiation-induced fibrosis (RIF) is a major side effect of radiotherapy in cancer patients with no effective therapeutic options. RIF involves excess deposition and aberrant remodeling of the extracellular matrix (ECM) leading to stiffness in tissues and organ failure. Development of preclinical models of RIF is crucial to elucidate the molecular mechanisms regulating fibrosis and to develop therapeutic approaches. In addition to radiation, the main molecular perpetrators of fibrotic reactions are cytokines, including transforming growth factor-β (TGF-β). We hypothesized that human oral fibroblasts would develop an in vitro fibrotic reaction in response to radiation and TGF-β. We demonstrate here that fibroblasts exposed to radiation followed by TGF-β exhibit a fibrotic phenotype with increased collagen deposition, cell proliferation, migration and invasion. In this in vitro model of RIF (RIFiv), the early biological processes involved in fibrosis are demonstrated, along with increased levels of several molecules including collagen 1α1, collagen XIα1, integrin-α2 and cyclin D1 mRNA in irradiated cells. A clinically relevant antifibrotic agent, pentoxifylline, and a curcumin analogue both mitigated collagen deposition in irradiated fibroblast cultures. In summary, we have established an in vitro model for RIF that facilitates the elucidation of molecular mechanisms in radiation-induced fibrosis and the development of effective therapeutic approaches.

Importance Ficlatuzumab can be used to treat head and neck squamous cell carcinoma (HNSCC) by inhibiting c-Met receptor-mediated cell proliferation, migration, and invasion. Objective To understand the effect of ficlatuzumab on HNSCC proliferation, migration, and invasion. Design, Setting, and Participants The effects of ficlatuzumab on HNSCC proliferation, invasion, and migration were tested. Mitigation of c-Met and downstream signaling was assessed by immunoblotting. The tumor microenvironment has emerged as an important factor in HNSCC tumor progression. The most abundant stromal cells in HNSCC tumor microenvironment are tumor-associated fibroblasts (TAFs). We previously reported that TAFs facilitate HNSCC growth and metastasis. Furthermore, activation of the c-Met tyrosine kinase receptor by TAF-secreted hepatocyte growth factor (HGF) facilitates tumor invasion. Ficlatuzumab is a humanized monoclonal antibody that sequesters HGF, preventing it from binding to and activating c-Met. We hypothesized that targeting the c-Met pathway with ficlatuzumab will mitigate TAF-mediated HNSCC proliferation, migration, and invasion. Representative HNSCC cell lines HN5, UM-SCC-1, and OSC-19 were used in these studies. Exposures for Observational Studies The HNSCC cell lines were treated with ficlatuzumab, 0 to 100 µg/mL, for 24 to 72 hours. Main Outcomes and Measures Ficlatuzumab inhibited HNSCC progression through c-Met and mitogen-activated protein kinase (MAPK) signaling pathway. Results Ficlatuzumab significantly reduced TAF-facilitated HNSCC cell proliferation (HN5, P P P = .002; UM-SCC-1, P = .01; and OSC-19, P = .04), and invasion (HN5, P = .047; UM-SCC-1, P = .03; and OSC-19, P = .04) through a 3-dimensional peptide-based hydrogel (PGmatrix). In addition, ficlatuzumab also inhibited the phosphorylation of c-Met at Tyr1234/1235 and p44/42 MAPK in HNSCC cells exposed to recombinant HGF. Conclusions and Relevance We demonstrate that neutralizing TAF-derived HGF with ficlatuzumab effectively mitigates c-Met signaling and decreases HNSCC proliferation, migration, and invasion. Thus, ficlatuzumab effectively mitigates stromal influences on HNSCC progression.