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Background: Recurrent head and neck squamous cell carcinoma (rHNSCC) represents a significant global health burden with an unmet medical need. In this study we determined the safety and efficacy of RM-1929 photoimmunotherapy in patients with heavily pretreated rHNSCC., Methods: RM-1929 (anti-EGFR-IR700 dye conjugate) was infused, followed by tumor illumination. We evaluated safety, tumor response, and pharmacokinetics., Results: Nine patients were enrolled in Part 1 (dose-finding) and 30 patients in Part 2 (safety and efficacy). No dose-limiting toxicities were experienced in Part 1; 640 mg/m 2 with fixed light dose (50 J/cm 2 or 100 J/cm) was recommended for Part 2. Adverse events (AEs) in Part 2 were mostly mild to moderate but 19 (63.3%) patients had AE ≥Grade 3, including 3 (10.0%) with serious AEs leading to death (not treatment related). Efficacy in Part 2: unconfirmed objective response rate (ORR) 43.3% (95% CI 25.46%-62.57%); confirmed ORR 26.7% (95% CI 12.28%-45.89%); median overall survival 9.30 months (95% CI 5.16-16.92 months)., Conclusions: Treatment was well tolerated. Responses and survival following RM-1929 photoimmunotherapy in heavily pretreated patients with rHNSCC were clinically meaningful and warrant further investigation., Clinical Trial Information: NCT02422979., (© 2021 The Authors. Head & Neck published by Wiley Periodicals LLC.)

Objective: Review long-term clinical and quality-of-life outcomes following free flap reconstruction for osteonecrosis., Study Design: Retrospective multi-institutional review., Setting: Tertiary care centers., Methods: Patients included those undergoing free flap reconstructions for osteonecrosis of the head and neck (N = 232). Data included demographics, defect, donor site, radiation history, perioperative management, diet status, recurrence rates, and long-term quality-of-life outcomes. Quality-of-life outcomes were measured using the University of Washington Quality of Life (UW-QOL) survey., Results: Overall flap success rate was 91% (n = 212). Relative to preoperative diet, 15% reported improved diet function at 3 months following reconstruction and 26% at 5 years. Osteonecrosis recurred in 14% of patients (32/232); median time to onset was 11 months. Cancer recurrence occurred in 13% of patients (29/232); median time to onset was 34 months. Results from the UW-QOL questionnaire were as follows: no pain (45%), minor or no change in appearance (69%), return to baseline endurance level (37%), no limitations in recreation (40%), no changes in swallowing following reconstruction (28%), minor or no limitations in mastication (29%), minor or no speech difficulties (93%), no changes in shoulder function (84%), normal taste function (19%), normal saliva production (27%), generally excellent mood (44%), and no or minimal anxiety about cancer (94%)., Conclusion: The majority of patients maintained or had advancement in diet following reconstruction, with low rates of osteonecrosis or cancer recurrence and above-average scores on UW-QOL survey suggesting good return of function and quality of life.

Secondary revision of osseous flap reconstructions of the maxilla can enhance facial symmetry, but can be challenging due to the absence of normal anatomy and landmarks. We report four cases of maxillectomy reconstruction with scapula tip flap employing a novel combined approach with preoperative virtual surgical planning (VSP) and intraoperative navigation (ION) for secondary revision. VSP was employed to superimpose mirrored normal anatomy upon the reconstructed anatomy, and ION used for real-time intraoperative anatomical mapping. VSP and ION can be used to optimize maxillary bony revisions and recontouring, thereby improving anatomic symmetry and funtionality. Laryngoscope, 131:E2655-E2659, 2021., (© 2021 The American Laryngological, Rhinological and Otological Society, Inc.)

Objectives: Evaluate the rate of complications, readmissions, emergency department presentations, and surgical success rates amongst three standard surgical treatment options for obstructive sleep apnea: upper airway stimulation, transoral robotic surgery, and expansion sphincter pharyngoplasty., Study Design: Retrospective cohort., Setting: Tertiary care center., Methods: Patients were included who were aged ≥18 years old and underwent upper airway stimulation, transoral robotic surgery, or expansion sphincter pharyngoplasty between January 2011 and May 2020., Results: 345 patients were identified: 58% (n = 201) underwent upper airway stimulation, 10% (n = 35) underwent transoral robotic surgery, and 32% (n = 109) patients underwent expansion sphincter pharyngoplasty. There were 22 emergency department presentations and 19 readmissions, most of which were experienced by patients receiving transoral robotic surgery (six emergencies, seven readmissions) and expansion sphincter pharyngoplasty (12 emergencies, 11 readmissions). Patients with upper airway stimulation had four emergencies and one readmission. Only 2% of the upper airway stimulation cohort had a complication, whereas this was 20% and 12% for the transoral robotic surgery and expansion sphincter pharyngoplasty cohorts, respectively. Patients experienced the highest surgical success rate with upper airway stimulation (69%), whereas patients who received transoral robotic surgery and expansion sphincter pharyngoplasty had success rates of 50% and 51%, respectively., Conclusion: Treating obstructive sleep apnea with upper airway stimulation led to lower rates of complications, emergency department presentations, and readmissions in this series. In those for whom upper airway stimulation is appropriate, it may be more effective in successfully treating obstructive sleep apnea than transoral robotic surgery and expansion sphincter pharyngoplasty., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: The oncologic outcomes of surgery alone for patients with American Joint Committee on Cancer 7th edition (AJCC 7th) pN2a and pN2b human papillomavirus-associated oropharynx squamous cell carcinoma (HPV+OPSCC) are not clear., Methods: The authors performed a 12-institution retrospective study of 344 consecutive patients with HPV+OPSCC (AJCC 7th pT0-3 N3 M0) treated with surgery alone with 6 months or more of follow-up using univariate and multivariate analyses., Results: The 2-year outcomes for the entire cohort were 91% (182 of 200) disease-free survival (DFS), 100% (200 of 200) disease-specific survival (DSS), and 98% (200 of 204) overall survival (OS). The 18 recurrences within 2 years were 88.9% (16 of 18) local and/or regional recurrences and 11.1% (2 of 18) distant metastases. Recurrences were not significantly associated with smoking, pT stage, or pN stage. The 16 patients with locoregional recurrences within 2 years all underwent successful salvage treatments (median follow-up after salvage: 13.1 months), 43.8% (7 of 16) of whom underwent salvage surgery alone for a 2-year overall salvage radiation need of 4.5% (9 of 200). The 2-year outcomes for the 59 evaluable patients among the 109 AJCC 7th pT0-2 N2a-N2b patients with 1 to 3 pathologic lymph nodes (LNs) were as follows: local recurrence, 3.4% (2 of 59); regional recurrence, 8.4% (5 of 59); distant metastases, 0%; DFS, 88.1% (52 of 59); DSS, 100% (59 of 59); OS, 96.7% (59 of 61); and salvage radiation, 5.1% (3 of 59)., Conclusions: With careful selection, surgery alone for AJCC 7th pT0-T2N0-N2b HPV+OPSCC with zero to 3 pathologic LNs without perineural invasion, extranodal extension, or positive margins results in high DFS, DSS, OS, and salvage treatment success. Because of the short-term follow-up, these data support further investigation of treatment de-escalation in this population., (© 2021 American Cancer Society.)

Objectives/hypothesis: The literature on outcomes of end-to-side (ETS) anastomoses for microvascular reconstruction of the head and neck is limited. This series reviews ETS in free tissue transfer (FTT) across multiple institutions to better understand their usage and associated outcomes., Study Design: Retrospective review of 2482 consecutive patients across three tertiary institutions., Methods: Adult patients (> 18) who received a FTT from 2006 to 2019 were included., Results: Two hundred and twenty-one FTT were identified as requiring at least one ETS anastomosis. These ETS cases had a failure rate of 11.2% in comparison to 3.8% in a cohort of end-to-end (ETE) cases (P < .001). ETS cases were significantly more likely to have a prior neck dissection (P < .001), suggesting the ETS method was utilized in select circumstances. A second ETS anastomosis improved survival of the FTT (P = .006), as did utilization of a coupler over suture (P = .002). Failure due to venous thrombosis was significantly more common with one ETS anastomosis instead of two ETS anastomoses (P = .042)., Conclusions: ETS is effective but is often used as a secondary technique when ETE is not feasible; as such, in this series, ETS was associated with higher failure. A second anastomosis and the use of the coupler for completing the anastomoses were associated with lower rates of failure., Level of Evidence: 3 Laryngoscope, 131:1286-1290, 2021., (© 2020 The Authors. The Laryngoscope published by Wiley Periodicals LLC on behalf of American Laryngological, Rhinological and Otological Society Inc, "The Triological Society" and American Laryngological Association (ALA).)

Background: Head and neck surgical oncology and reconstruction are uniquely suited to address burdens of disease in underserved areas. Since these efforts are not well known in our specialty, we sought to understand global outreach throughout our society of surgeons., Methods: Survey distributed to members of the American Head and Neck Surgery involved in international humanitarian head and neck surgical outreach trips., Results: Thirty surgeons reported an average of seven trips to over 70 destinations. Identification of candidates, finances, on-site patient care, complications, long-term post-surgical care, ethics, and educational goals are reported. We report a success rate of 90% on 125 free flaps performed in these settings., Conclusions: The effort to answer the call for alleviating the global burden of surgical disease is strong within our specialty. There is a shared focus on humanitarian effort and teaching. Ethics of high resource surgeries such as free flap reconstruction remains controversial., (© 2021 The Authors. Head & Neck published by Wiley Periodicals LLC.)

Objectives: To compare time spent on day of surgery and post-surgical outcomes for sialendoscopy procedures at an ambulatory surgery center versus in a hospital operating room., Methods: Retrospective chart review for patients who underwent sialendoscopy for sialadenitis or sialolithiasis from March 2017 to May 2020 were included. Surgery location (ambulatory surgery center or hospital operating room) was compared. Primary outcomes included total time in hospital, operative time, total time in operating room. and recovery time. Secondary outcomes included rate of symptoms resolutions, requiring further medical management, and requiring further surgical intervention., Results: A total of 321 procedures were included. Sialendoscopy in an ambulatory surgery center compared to main operating room decreased median hospital time (166 min reduction, p < 0.001), operative time (18 min reduction, p < 0.001), total time in operating room (34 min reduction, p < 0.001), and recovery time (64 min reduction, p < 0.001). Sialendoscopy in an ambulatory surgery center had similar rates of post-operative resolution of symptoms and further medical or surgical intervention compared to procedures in a hospital operating room., Conclusion: Sialendoscopy can be safely performed in an ambulatory surgery center for sialadenitis or appropriate sialolithiasis cases while decreasing hospital time, operative time, total time in operating room time, and recovery time., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Objectives/hypothesis: Predictors of free tissue transfer (FTT) failure and the need for postoperative revision (POR) have been extensively studied; however, there are little data evaluating outcomes when intraoperative revision (IOR) at initial surgery is required. This study seeks to better understand the impact IOR of the pedicle has on FTT outcomes., Study Design: Retrospective review of 2482 consecutive patients across three tertiary institutions., Methods: Adult patients (>18) who received a FTT and underwent anastomotic revision from 2006 to 2019 were included. Logistic regression was performed to predict revision, and recursive partitioning was performed to classify risk of failure based on type of revision and vessels revised., Results: Failure rates for IOR (19%) and POR (27%) were higher compared to a nonrevised failure rate of 2% (P < .01 and P < .01, respectively). Intraoperative venous revision (IORv, n = 13), arterial (IORa, n = 114), and both (IORb, n = 11) were associated with failure rates of 8% (odds ratio [OR] 3.5, P = .23), 18% (OR = 9.0, P < .01), 45% (OR = 35.3, P = <.01), respectively. Arterial revision was most common among IOR (83%, P < .01). Postoperative venous revision (PORv, n = 35), arterial (PORa, n = 36), and both (PORb, n = 11) were associated with failure rates of 20% (OR = 15.7, P < .01), 27% (OR = 10.6, P < .01), and 39% (OR = 27.0, P < .01), respectively. Failure rate for flaps that had POR after IOR (PORi, n = 11) was 45% (OR = 18.2, P < .01). Diabetes predicted IOR (P = .006); tobacco use, heavy alcohol use, and prior radiation predicted POR (P = .01, P = .05, and P = .01, respectively)., Conclusion: Both IOR and POR were associated with increased failure compared to nonrevised flaps. The risk of failure increases sequentially with intraoperative or POR of the vein, artery, or both vessels. Revision of both vessels and POR after IOR are strongly predictive of failure., Level of Evidence: 3 Laryngoscope, 131:1035-1041, 2021., (© 2020 American Laryngological, Rhinological and Otological Society Inc, "The Triological Society" and American Laryngological Association (ALA).)

Background: Aggressive squamous cell carcinomas (SCCs) present frequently in the context of chronic skin injury occurring in patients with the congenital blistering disease recessive dystrophic epidermolysis bullosa. Recently, these cancers were shown to harbor mutation signatures associated with endogenous deaminases of the active polynucleotide cytosine deaminase family, collectively termed APOBEC, and clock-like COSMIC [Catalogue of Somatic Mutations in Cancer] signatures, which are associated with normal aging and might result from cumulative DNA replication errors. We present a case of a nasal septal SCC arising in the context of recurrent injury, but also modest past tobacco use. Our genetic analysis of this tumor reveals unusually high APOBEC and clock-like but low tobacco-related COSMIC signatures, suggesting that chronic injury may have played a primary role in somatic mutation. This case report demonstrates how signature-based analyses may implicate key roles for certain mutagenic forces in individual malignancies such as head-and-neck SCC, with multiple etiological origins., Case Presentation: We report the case of a 43-year-old male former smoker who presented with congestion and swelling following a traumatic nasal fracture. During surgery, the mucosa surrounding the right nasal valve appeared abnormal, and biopsies revealed invasive keratinizing SCC. Frozen section biopsies revealed multiple areas to be positive for SCC. Gene sequencing showed loss of PTEN (exons 2-8), CDKN2A/B and TP53 (exons 8-9), MYC amplification, and BLM S338*. Exome sequencing data also revealed that 36% of mutations matched an APOBEC mutational signature (COSMIC signatures 2 and 13) and 53% of mutations matched the clock-like mutation signature (COSMIC signature 5). These proportions place this tumor in the 90th percentile bearing each signature, independently, in a reference data set combining cutaneous and The Cancer Genome Atlas (TCGA) head and neck SCC data. In contrast, few mutations harbored a tobacco-related COSMIC signature 4, representing about the 10th percentile in our reference SCC data set. The patient was treated with partial rhinectomy with local flap reconstruction, bilateral neck dissection, and adjuvant radiation therapy; the patient remains disease-free to date., Conclusion: Based on comparative mutational signature analysis, we propose that the history of tobacco use and traumatic injury may have collaborated in activating APOBEC enzymes and the clock-like mutational process, ultimately leading to cancer formation. Clinical awareness of the relationship between epithelial injury and tumorigenesis should enhance earlier detection of this particularly aggressive type of cancer.

Objectives: Local reconstruction of central skull base defects may be inadequate for large defects or reoperative cases; free tissue transfer may be necessary. Inset of the flap and management of the pedicle can be challenging. We report our experience and approaches., Methods: Retrospective review identifying seven patients with central skull base defects who underwent free flap reconstruction from 2016 to 2020., Results: Four patients with recurrent nasopharyngeal carcinoma, one with recurrent craniopharyngioma, one with clival-cervical chordoma, and one with meningioma of the middle cranial fossa were analyzed. Six defects were closed with an anterolateral thigh free flap and one with a radial forearm free flap. In two patients, the flap was secured in an onlay fashion to the defect via a Caldwell-Luc transmaxillary approach. In one patient, the flap was passed transorally, and the pedicle was delivered into the neck via Penrose drain. In two patients, a parapharyngeal technique and in two others, a retropharyngeal was used for nasopharyngeal inset with endoscopic assistance. There were no flap failures, with an average follow-up time of 20.1 (range 3.2-47.1) months. One patient required flap repositioning on postoperative day three due to midline shift and intracranial contents compression. The transoral inset flap necessitated flap repositioning on postoperative day 13 to improve the nasopharyngeal airway., Conclusion: Free flap reconstruction of the central skull base is challenging, but transmaxillary, transoral, parapharyngeal, and retropharyngeal approaches can be used with endoscopic assistance to ensure secure inset flap and avoid airway obstruction., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Objectives/hypothesis: To review the management of failed free tissue transfers among four large institutions over a 13-year period to provide data and analysis for a logical, algorithmic, experience-based approach to the management of failed free flaps., Study Design: Retrospective case series., Methods: A multi-institutional retrospective chart review of free tissue transfers to the head and neck region between 2006 and 2019 was performed. Patients with a failed free flap during their hospitalization after surgery to the head and neck were identified and reviewed. Patient age, co-morbidities, risk factors, flap characteristics, tumor specifics, and length of hospital stay were reviewed, collected, and analyzed., Results: One hundred eighteen flap failures met criteria. The most common failed flap in this review was the osteocutaneous flap 52/118 (44%). The recipient site of the initial free flap (P < .001) was the only statistically significant parameter strongly correlated with management. Osteocutaneous flap failures, fasciocutaneous, bowel, and muscle-only flaps tended to be managed most commonly with a second free flap. Myocutaneous flap failures were managed equally with either a second free flap or a regional flap., Conclusions: The most important factor in management of a failed free flap is the recipient site. A second free flap is often the preferred treatment, but in the acute setting, local or regional flaps may be viable options depending on the recipient site, circumstances of flap loss, and patient- specific comorbidities. An algorithm for management of the acute flap loss is presented in this review., Level of Evidence: 4 Laryngoscope, 131:518-524, 2021., (© 2020 The American Laryngological, Rhinological and Otological Society, Inc.)

Objectives: The literature remains scarce in terms of comparing different anesthesia modalities in sialendoscopy. Due to the lack of a standard of care or guidelines to anesthetic care, it is generally accepted that surgeons perform these surgeries under the anesthetic modality in which they are most comfortable. In this study, we evaluate time spent on the day of surgery and post-surgical outcomes for patients receiving sialendoscopy under monitored anesthesia care versus general anesthesia., Materials and Methods: We retrospectively assessed patients who underwent sialendoscopy using a solely endoscopic approach for sialadenitis or sialolithiasis from March 2017 to December 2019. Anesthesia modality (monitored anesthesia care versus general anesthesia) was compared. Main outcomes included total time in hospital, operative time, total time in operating room, anesthesia time, and recovery time. Secondary outcomes included rate of resolution of symptoms, requiring further medical management, requiring further surgical intervention, and complications., Results: A total of 172 procedures were included. Sialendoscopy under monitored anesthesia care center compared to general anesthesia decreased median hospital time (141 min reduction), anesthesia time (46 min reduction), operative time (24 min reduction), time in operating room (43 min reduction), and recovery time (56 min reduction). Utilizing monitored anesthesia care demonstrated similar rates of post-operative resolution of symptoms, complications, and further medical or surgical intervention compared to the general anesthesia cohort., Conclusion: Sialendoscopy can be safely performed under monitored anesthesia care for appropriate sialadenitis or sialolithiasis cases while decreasing hospital time, operative time, time in operating room, anesthesia time, and recovery time while maintaining similar post-operative outcomes. Monitored anesthesia care should be considered for solely endoscopic cases as guided by surgeon and patient comfort., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Oral squamous cell carcinoma (OSCC) is the most common subsite of head and neck cancer, with a 5-year survival rate of only 50%. There is a pressing need for animal models that recapitulate the human disease to understand the factors driving OSCC carcinogenesis. Many laboratories have used the chemical carcinogen 4-nitroquinoline-1-oxide (4NQO) to investigate OSCC formation. The importance of the 4NQO mouse model is that it mimics the stepwise progression observed in OSCC patients. The 4NQO carcinogen model has the advantage that it can be used with transgenic mice with genetic modification in specific tissue types to investigate their role in driving cancer progression. Herein, we describe the basic approach for administering 4NQO to mice to induce OSCC and methods for assessing the tissue and disease progression., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Introduction: The progression and clinical course of head and neck squamous cell carcinoma (HNSCC) relies on complex interactions between cancer and stromal cells in the tumor microenvironment (TME). Among the most abundant of these stromal cells are cancer-associated fibroblasts (CAFs). While their contribution to tumor progression is widely acknowledged, and various CAF-targeted treatments are under development, the relationship between CAF density and the clinicopathologic course of HNSCC has not been clearly defined. Here we examine the published evidence investigating the relationship of cancer-associated fibroblasts to local recurrence and indicators of prognostic significance in HNSCC., Methods: We conducted a meta-analysis of existing publications that compare the relationship between CAF density, local recurrence, and clinically significant pathologic criteria of disease development (T stage, nodal positivity, clinical stage, vascular invasion, perineural invasion, Ki67 expression, and differentiation). Thirteen studies met the selection criteria, providing a total study population of 926 patients. Forest plots and risk ratios were generated to illustrate overall relationships., Results: Higher CAF density within the tumor microenvironment is associated with advanced T stage, nodal infiltration, clinical stage, vascular invasion, perineural invasion, Ki67 expression, and differentiation (p <0.05). High CAF density is also associated with increased rates of local recurrence (p <0.001)., Conclusions: Across multiple studies, increased CAF density is correlated with histopathological criteria of poor prognosis in HNSCC. These findings highlight that CAFs may play a pivotal role in HNSCC development and progression. Staining for CAFs may represent a valuable addition to current pathologic analysis and help to guide prognosis and treatment. Understanding the mechanisms by which CAFs reciprocally interact with cancer cells will be crucial for optimization of TME-focused treatment of HNSCC., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2020 Knops, South, Rodeck, Martinez-Outschoorn, Harshyne, Johnson, Luginbuhl and Curry.)

Background: Locoregional recurrence rates following parotidectomy for cancer remain as high as 20-30%. The auriculotemporal nerve (ATN) may allow parotid cancers to spread from the facial nerve (FN) toward the skull base, causing local recurrence., Methods: Retrospective review of 173 parotidectomies for malignancy. Preoperative and post-recurrence imaging were reviewed by a neuroradiologist for signs of tumor adjacent to the ATN., Results: Clinical and imaging signs of possible ATN involvement correlated with FN weakness and sacrifice. Eight patients had pathologically confirmed tumor from the ATN or V3. Forty-four percent of local recurrences had post-recurrence imaging showing tumor along the course of the ATN. Locoregional failure along the ATN was also associated with preoperative FN weakness, intraoperative FN sacrifice, and failure to complete recommended adjuvant therapy., Conclusions: Parotid cancers may invade the FN and spread to the skull base via the ATN. If not appropriately managed, this may lead to local recurrence., (© 2020 Wiley Periodicals LLC.)

Objective: To describe the natural history of bone segment union in head and neck free flap procedures and detail the association of poor segment union with postoperative complications., Study Design: Case series with chart review., Setting: Single tertiary care referral center., Subjects and Method: Patients with mandibular or maxillary defects reconstructed with osseous or osteocutaneous free flaps were analyzed (n = 104). Postoperative computed tomography or positron emission tomography/computed tomography scans were reviewed for signs of osseointegration and nonunion. Postoperative wound complications were correlated with imaging findings., Result: Thirty-seven percent of appositions had partial union on nonunion. Appositions between osteotomized free flap segments form complete unions at a higher rate than appositions with native bone (65% vs 53%, P = .0006). If an apposition shows a gap of ≥1 mm, the chances of failing to form a complete union are greatly increated (79% vs 8%, P = .0009). Radiographic nonunion was associated with an increased likelihood of postoperative wound complications (40% vs 19%, P = .025) and in most cases was present before development of complications., Conclusion: Radiographic evidence of partial union or nonunion of free flap osseous segments greatly exceeds reported rates of clinically evident nonunion. Unions likely form between free flap appositions before unions to the native bone. If initial bone segments are >1-mm apart, the chance of progression to complete union is low. Incomplete osseointegration appears to be a marker for development of wound complications.

SMARCB1 (integrase interactor 1) is a tumor suppressor gene encoded on chromosome 22q11.2 that encodes a core subunit of SWI/SNF chromatin remodeling complexes and plays a critical role in regulating gene expression and chromatin structure. We describe a case of SMARCB1 (integrase interactor 1)-deficient sinonasal carcinoma of the left maxillary sinus in a 63-year-old woman with an initial presentation of numbness of the maxillary teeth and facial swelling., (Copyright © 2020 American Association of Oral and Maxillofacial Surgeons. Published by Elsevier Inc. All rights reserved.)

Psychological stressors have been implicated in the progression of various tumor types. We investigated a role for stress in tumor immune cell chemotaxis in the B16F10 mouse model of malignant melanoma. We exposed female mice to 6-hour periods of restraint stress (RST) for 7 days, then implanted B16F10 malignant melanoma tumor cells and continued the RST paradigm for 14 additional days. We determined serum corticosterone and liver catecholamine concentrations in these mice. To evaluate the tumor microenvironment, we performed IHC and examined cytokine expression profiles using ELISA-based analysis of tumor homogenates. We found that tumors in mice subjected to RST grew significantly slower, had reduced tumor C-C motif ligand 2 (CCL2), and contained fewer F4/80-positive macrophages than tumors from unstressed mice. We observed a concomitant increase in norepinephrine among the RST mice. An in vitro assay confirmed that norepinephrine downregulates CCL2 production in both mouse and human macrophages, and that pretreatment with the pan-β-adrenergic receptor inhibitor nadolol rescues this activity. Furthermore, RST had no effect on tumor growth in transgenic CCL2-deficient mice. This study suggests that stress reduces malignant melanoma by reducing recruitment of tumor-promoting macrophages by CCL2., (©2020 American Association for Cancer Research.)

Objective: To determine which patient or surgical factors affect the likelihood of unplanned readmission (within 30 days) after total laryngectomy (TL)., Methods: Retrospective chart review of all patients who underwent TL at a single institution from April 2007 through August 2016. Primary outcome was unplanned readmission to the hospital within 30 days of discharge. Univariable and multivariable logistic regression were performed to identify risk factors for unplanned readmission., Results: Two hundred seventy-eight patients met inclusion criteria. Twenty-nine patients (10.4%) had unplanned readmissions within 30 days. The most common reasons for readmission were pharyngocutaneous fistula (n = 15), neck abscess (n = 3), and wound breakdown (n = 4). Average time to unplanned readmission was 11.2 days (range 0-27 days). Fistula (OR 30.259; 95% CI, 9.186, 118.147; P ≤ .001), postoperative pneumonia (OR 9.491; 95% CI, 1.783, 53.015; P = .008), and history of cardiac disease (OR 7.074; 95% CI, 2.324, 25.088, P = .001) were independently associated with an increased risk of 30-day unplanned readmission on multivariate analysis. However, return to OR on initial admission was associated with a lower risk of unplanned readmission (OR 0.075; 95% CI, 0.009, 0.402; P = .007). Unplanned readmission was associated with a delay in initiation of adjuvant radiation (OR 1.494; 95% CI, 1.397, 1.599; P < .001)., Conclusion: Unplanned readmission occurs in a small but significant number of TL patients. Patients who have a 30-day unplanned readmission may be at risk for a delay in initiation of adjuvant therapy., Level of Evidence: 4 Laryngoscope, 130:1725-1732, 2020., (© 2019 The American Laryngological, Rhinological and Otological Society, Inc.)

Staphylococcus aureus osteomyelitis is a debilitating infection of bone. Treatment of osteomyelitis is impaired by the propensity of invading bacteria to induce pathological bone remodeling that may limit antibiotic penetration to the infectious focus. The nonsteroidal anti-inflammatory drug diflunisal was previously identified as an osteoprotective adjunctive therapy for osteomyelitis, based on the ability of this compound to inhibit S. aureus quorum sensing and subsequent quorum-dependent toxin production. When delivered locally during experimental osteomyelitis, diflunisal significantly limits bone destruction without affecting bacterial burdens. However, because diflunisal's "quorum-quenching" activity could theoretically increase antibiotic recalcitrance, it is critically important to evaluate this adjunctive therapy in the context of standard-of-care antibiotics. The objective of this study is to evaluate the efficacy of vancomycin to treat osteomyelitis during local diflunisal treatment. We first determined that systemic vancomycin effectively reduces bacterial burdens in a murine model of osteomyelitis and identified a dosing regimen that decreases bacterial burdens without eradicating infection. Using this dosing scheme, we found that vancomycin activity is unaffected by the presence of diflunisal in vitro and in vivo Similarly, locally delivered diflunisal still potently inhibits osteoblast cytotoxicity in vitro and bone destruction in vivo in the presence of subtherapeutic vancomycin. However, we also found that the resorbable polyester urethane (PUR) foams used to deliver diflunisal serve as a nidus for infection. Taken together, these data demonstrate that diflunisal does not significantly impact standard-of-care antibiotic therapy for S. aureus osteomyelitis, but they also highlight potential pitfalls encountered with local drug delivery., (Copyright © 2020 American Society for Microbiology.)

The bacterial pathogen Staphylococcus aureus is capable of infecting a broad spectrum of host tissues, in part due to flexibility of metabolic programs. S. aureus , like all organisms, requires essential biosynthetic intermediates to synthesize macromolecules. We therefore sought to determine the metabolic pathways contributing to synthesis of essential precursors during invasive S. aureus infection. We focused specifically on staphylococcal infection of bone, one of the most common sites of invasive S. aureus infection and a unique environment characterized by dynamic substrate accessibility, infection-induced hypoxia, and a metabolic profile skewed toward aerobic glycolysis. Using a murine model of osteomyelitis, we examined survival of S. aureus mutants deficient in central metabolic pathways, including glycolysis, gluconeogenesis, the tricarboxylic acid (TCA) cycle, and amino acid synthesis/catabolism. Despite the high glycolytic demand of skeletal cells, we discovered that S. aureus requires glycolysis for survival in bone. Furthermore, the TCA cycle is dispensable for survival during osteomyelitis, and S. aureus instead has a critical need for anaplerosis. Bacterial synthesis of aspartate in particular is absolutely essential for staphylococcal survival in bone, despite the presence of an aspartate transporter, which we identified as GltT and confirmed biochemically. This dependence on endogenous aspartate synthesis derives from the presence of excess glutamate in infected tissue, which inhibits aspartate acquisition by S. aureus Together, these data elucidate the metabolic pathways required for staphylococcal infection within bone and demonstrate that the host nutrient milieu can determine essentiality of bacterial nutrient biosynthesis pathways despite the presence of dedicated transporters., Competing Interests: The authors declare no competing interest., (Copyright © 2020 the Author(s). Published by PNAS.)

Objective: To determine the frequency at which patients with osteocutaneous free flap reconstruction of the head and neck develop long-term complications and identify predisposing perioperative factors., Study Design: A prospectively maintained database of free flaps performed at a single institution over a 10-year period was queried., Setting: Single tertiary care referral center., Subjects and Methods: In total, 250 osseous or osteocutaneous free flaps (OCFFs) for mandibular or maxillary reconstruction were analyzed. Data were collected on demographics, preoperative therapy, resection location, adjuvant treatment, complications, and subsequent surgeries, and multivariate analysis was performed. Subgroup analysis based on perioperative factors was performed., Results: The median follow-up time was 23 months. In 185 patients with at least 6 months of follow-up, 17.3% had at least 1 long-term complication, most commonly wound breakdown, fistula or plate extrusion (13.5%), osteoradionecrosis or nonunion (6.5%), and infected hardware (5.9%). Prior chemoradiotherapy and cancer diagnosis predisposed patients to long-term complications. At the 5-year follow-up, 21.7% of patients had experienced a long-term complication., Conclusions: Long-term complications after OCFF occurred in 17% of patients. In this series, a preoperative history of chemoradiation and those undergoing maxillary reconstruction were at high risk for the development of long-term complications and thus warrant diligent follow-up. However, OCFFs can often enjoy long-term viability and survival, even in the case of perioperative complications and salvage surgery.

Objectives: Reconstruction of the midface has many inherent challenges, including orbital support, skull base reconstruction, optimizing midface projection, separation of the nasal cavity and dental rehabilitation. Subscapular system free flaps (SF) have sufficient bone stock to support complex reconstruction and the option of separate soft tissue components. This study analyzes the effect of virtual surgical planning (VSP) in SF for midface on subsite reconstruction, bone segment contact and anatomic position., Materials and Methods: Retrospective cohort of patients with midface defects that underwent SF reconstruction at a single tertiary care institution., Results: Nine cases with VSP were compared to fourteen cases without VSP. VSP was associated with a higher number of successfully reconstructed subunits (5.9 vs 4.2, 95% CI of mean difference 0.31-3.04, p = 0.018), a higher number of successful bony contact between segments (2.2 vs 1.4, 95% CI of mean difference 0.0-1.6, p = 0.050), and a higher percent of segments in anatomic position (100% vs 71%, 95% CI of mean difference 2-55%, p = 0.035). When postoperative bone position after VSP reconstruction was compared to preoperative scans, the difference in anteroposterior, vertical and lateral projection compared to the preoperative 'ideal' bone position was <1 cm in 82% of measurements. There were no flap losses., Conclusion: VSP may augment SF reconstruction of the midface by allowing for improved subunit reconstruction, bony segment contact and anatomically correct bone segment positioning. VSP can be a useful adjunct for complex midface reconstruction and the benefits should be weighed against cost., Competing Interests: Declaration of Competing Interest None declared for all authors, (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: When treated nonsurgically with definitive chemoradiation, smokers with human papillomavirus (HPV)-positive oropharyngeal squamous cell carcinoma (OPSCC) have a worse prognosis compared with their nonsmoking counterparts. To the authors' knowledge, the prognostic significance of smoking in surgically treated patients is unknown., Methods: The current study is a retrospective case series of patients with HPV-positive OPSCC who underwent upfront transoral robotic surgery at a single institution from 2010 through 2017. Exclusion criteria were nonoropharyngeal primary tumors, histology other than SCC, HPV-negative tumors, previous history of head and neck cancer, and/or previous head and neck radiotherapy. Recurrence-free survival (RFS), overall survival, and disease-specific survival were compared using the Kaplan-Meier method and the log-rank test. Smoking history was categorized as never smokers (<1 pack-year), current smokers (smoking at the time of the cancer diagnosis), and former smokers., Results: A total of 258 patients met the study criteria. The average age was 60 years, and approximately 87% of patients were male. A total of 148 patients (57.4%) were smokers whereas 110 (42.6%) reported never smoking. There were 44 active smokers (17.1%) and 104 former smokers (40.3%). The median follow-up was 3.23 years. There were 17 patients of disease recurrence. Smoking pack-year history was not found to be significant for RFS (hazard ratio, 1.01; 95% CI, 0.99-1.03 [P = .45]). There was no significant difference in RFS noted between never and ever smokers (92% vs 89.8%; P = .85) nor was there a difference observed between never, former, and current smokers (92% vs 91.5% vs 86.1%, respectively; P = .69)., Conclusions: A smoking history is common in patients with HPV-positive OPSCC. In the current study, HPV-positive smokers were found to have excellent survival and locoregional control, similar to their nonsmoking counterparts. The results of the current study do not support the exclusion of smokers with early-stage, HPV-positive OPSCC from transoral robotic surgery-based deintensification trials., (© 2020 American Cancer Society.)

Squamous cell carcinomas of the head and neck (HNSCC) arise from mucosal keratinocytes of the upper aero-digestive tract. Despite a common cell of origin and similar driver-gene mutations which divert cell fate from differentiation to proliferation, HNSCC are considered a heterogeneous group of tumors categorized by site of origin within the aero-digestive mucosa, and the presence or absence of HPV infection. Tobacco use is a major driver of carcinogenesis in HNSCC and is a poor prognosticator that has previously been associated with poor immune cell infiltration and higher mutation numbers. Here, we study patterns of mutations in HNSCC that are derived from the specific nucleotide changes and their surrounding nucleotide context (also known as mutation signatures). We identify that mutations linked to DNA adducts associated with tobacco smoke exposure are predominantly found in the larynx. Presence of this class of mutation, termed COSMIC signature 4, is responsible for the increased burden of mutation in this anatomical sub-site. In addition, we show that another mutation pattern, COSMIC signature 5, is positively associated with age in HNSCC from non-smokers and that larynx SCC from non-smokers have a greater number of signature 5 mutations compared with other HNSCC sub-sites. Immunohistochemistry demonstrates a significantly lower Ki-67 proliferation index in size matched larynx SCC compared with oral cavity SCC and oropharynx SCC. Collectively, these observations support a model where larynx SCC are characterized by slower growth and increased susceptibility to mutations from tobacco carcinogen DNA adducts.

Background: Parotidectomy is a common treatment option for parotid neoplasms and the complications associated with this procedure can cause significant morbidity. Reconstruction following parotidectomy is utilized to address contour deformity and facial nerve paralysis. This study aims to demonstrate national trends in parotidectomy patients and identify factors associated with adverse postoperative outcomes. This study includes the largest patient database to date in determining epidemiologic trends, reconstructive trends, and prevalence of adverse events following parotidectomy., Methods: A retrospective review was performed for parotidectomies included in the ACS-NSQIP database between January 2012 and December 2017. CPT codes were used to identify the primary and secondary procedures performed. Univariate and multivariate analysis was utilized to determine associations between pre- and perioperative variables with patient outcomes. Preoperative demographics, surgical indications, and common medical comorbidities were collected. CPT codes were used to identify patients who underwent parotidectomy with or without reconstruction. These pre- and perioperative characteristics were compared with 30-day surgical complications, medical complications, reoperation, and readmission using uni- and multivariate analyses to determine predictors of adverse events., Results: There were 11,057 patients who underwent parotidectomy. Postoperative complications within 30 days were uncommon (1.7% medical, 3.8% surgical), with the majority of these being surgical site infection (2.7%). Free flap reconstruction, COPD, bleeding disorders, smoking, and presence of malignant tumor were the strongest independent predictors of surgical site infection. Readmission and reoperation were uncommon at an incidence of 2.1% each. The strongest factors predictive of readmission were malignant tumor and corticosteroid usage. The strongest factors predictive of reoperation were free flap reconstruction, malignant tumor, bleeding disorder, and disseminated cancer. Surgical volume/contour reconstruction was relatively uncommon (18%). Facial nerve sacrifice was uncommon (3.7%) and, of these cases, only 25.5% underwent facial nerve reinnervation and 24.0% underwent facial reanimation., Conclusions: There are overall low rates of complications, readmissions, and reoperations following parotidectomy. However, certain factors are predictive of adverse postoperative events and this data may serve to guide management and counseling of patients undergoing parotidectomy. Concurrent reconstructive procedures are not commonly reported which may be due to underutilization or underreporting.

In recent years, vaccines against tumor antigens have shown potential for combating invasive cancers, including primary tumors and metastatic lesions. This is particularly pertinent for breast cancer, which is the second-leading cause of cancer-related death in women. MUC1 is a glycoprotein that is normally expressed on glandular epithelium, but is overexpressed and under-glycosylated in most human cancers, including the majority of breast cancers. This under-glycosylation exposes the MUC1 protein core on the tumor-associated form of the protein. We have previously shown that a vaccine consisting of MUC1 core peptides stimulates a tumor-specific immune response. However, this immune response is dampened by the immunosuppressive microenvironment within breast tumors. Thus, in the present study, we investigated the effectiveness of MUC1 vaccination in combination with four different drugs that inhibit different components of the COX pathway: indomethacin (COX-1 and COX-2 inhibitor), celecoxib (COX-2 inhibitor), 1-methyl tryptophan (indoleamine 2,3 dioxygenase inhibitor), and AH6809 (prostaglandin E2 receptor antagonist). These treatment regimens were explored for the treatment of orthotopic MUC1-expressing breast tumors in mice transgenic for human MUC1. We found that the combination of vaccine and indomethacin resulted in a significant reduction in tumor burden. Indomethacin did not increase tumor-specific immune responses over vaccine alone, but rather appeared to reduce the proliferation and increase apoptosis of tumor cells, thus rendering them susceptible to immune cell killing., Competing Interests: Pinku Mukherjee is the founder and Chief Scientific Officer (CSO) of OncoTAb, Inc., a startup company that owns patents and rights to the TAB004 antibody and markets the TAB004-based ELISA as a Laboratory Developed Test under the commercial name AgkuraTM Personal Score. OncoTAb, Inc. provided support in the form of salary for Pinku Mukherjee, but did not have any role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. This commercial affiliation does not alter our adherence to PLOS One policies on sharing data and materials. Other authors declare no financial interests.

Background: Marijuana has numerous roles as an agonist in the endocannabinoid signaling system (ESS). This study evaluated monoclonal antibodies across experimental techniques to establish a framework for studying ESS receptors, CB1 and CB2., Methods: Tissue from five patients with head and neck cancer were used to generate cell lines and formalin-fixed paraffin-embedded (FFPE) sections, which were analyzed by western blot (WB), immunohistochemistry (IHC), and immunofluorescence (IF). Subgroup analysis was performed on FFPE sections from 8 marijuana users and 10 controls by IHC. Results were compared across methods for consistency., Results: In all patients, WB and IF were CB1 positive, whereas IHC was negative. Select samples were CB2 positive by WB, but failed IF and IHC applications. In subgroup analysis, 1 of 8 users and 3 of 10 nonusers were CB1 positive., Conclusions: Interpretation of CB1/CB2 antibody data should be performed cautiously and confirmation of findings across multiple experimental methods is recommended., (© 2019 Wiley Periodicals, Inc.)

Objective: To determine the diagnostic accuracy of fine-needle aspiration (FNA) and imaging modalities for low-grade mucoepidermoid carcinoma (MEC) of the parotid gland., Methods: Retrospective chart review of patients diagnosed with low-grade MEC of the parotid gland following surgical excision between January 2010 and June 2018. Imaging from patients with MEC were randomly mixed with imaging from patients with benign pathology and reviewed in a blinded fashion. Main outcome measure was sensitivity., Results: A total of 24 patients were confirmed to have had low-grade MEC on final pathology, with a total of 31 FNAs performed between them. Twelve of 31 FNAs were positive for low-grade MEC, with a sensitivity of 39%. A total of 27 imaging studies were reviewed, which included 16 patients with low-grade MEC and 11 patients with benign pathology. Of these 27 imaging studies, 10 were declared indeterminate. Of the remaining 17 imaging studies, 13 were reviewed as malignant (11 true positive and 2 false positive) and 4 as benign (4 true negative). Overall magnetic resonance imaging (MRI) sensitivity for low-grade MEC was 100% (9/9) with 95% CI (0.66-1.0) when considering indeterminate results as positive for malignancy., Conclusion: This study reaffirms that for low-grade MEC, sensitivity of FNA is poor. MRI provides an important diagnostic tool in the evaluation of salivary gland neoplasms, due to its increased sensitivity for low-grade MEC when considering indeterminate results as positive. This provides confidence in the diagnosis of benign tumors and allows appropriate counseling of all options to the patient, including observation. Imaging and low threshold of excision should be considered despite an inflammatory or benign FNA.

Objectives/hypothesis: Chronic frontal sinus infection is managed with a combination of medical and surgical interventions. Frontal bone osteomyelitis due to recurrent infection following trauma or prior open surgery may require more significant debridement. Free tissue transfer may allow for extensive debridement with replacement of tissue, and definitive eradication of osteomyelitis., Study Design: Retrospective chart review., Methods: Patients undergoing free flap obliteration of the frontal sinus for frontal bone osteomyelitis at a single institution were included in the study. Clinical, radiologic, and surgical data were collected. Surgeries before and after free flap obliteration were compared by Wilcoxon signed rank test., Results: Fifteen patients were identified; however, one patient had less than 6 months of follow-up and was excluded from analysis. Of the remaining 14 patients, mean follow-up duration was 26 months (range, 6-120 months). Mean number of surgeries prior to free flap was 3.7 (range, 1-8 surgeries). Free flap obliteration resolved chronic frontal sinusitis in all patients. Two patients experienced postoperative infection, and the overall complication rate was 29%. Eight patients underwent cranioplasty (six immediate, two delayed) without complication. All patients received planned courses of postoperative antibiotics. A statistically significant decrease in the number of surgeries after free flap obliteration was observed P ≤ .01)., Conclusions: Extensive debridement followed by free tissue transfer and antibiotics offers a definitive treatment for complicated, recurrent frontal osteomyelitis. Simultaneous cranioplasty provides immediate protective and aesthetic benefit without complication. Consideration should be given for free tissue transfer and cranioplasty earlier in the algorithm for treatment of refractory frontal sinus osteomyelitis., Level of Evidence: 4 Laryngoscope, 129:1497-1504, 2019., (© 2018 The American Laryngological, Rhinological and Otological Society, Inc.)

Objective: The purpose of this study is to assess CD169 expression in metastatic and nearby tumor-free lymph nodes of patients with head and neck squamous cell carcinoma (SCC)., Study Design: Retrospective analysis based on immunohistochemistry., Setting: Tertiary care center., Subjects and Methods: The abundance of CD169 + cells in the subcapsular sinuses (SCSs) of lymph nodes was assessed immunohistochemically in paraffin-embedded tissue samples derived from 22 patients with oral cavity and oropharyngeal SCC., Results: SCSs of lymph nodes harboring metastatic SCC contained significantly fewer CD169 + macrophages (106.5 ± 113.6 cells/mm 2 ) compared to nearby tumor-free lymph nodes (321.3 ± 173.4 cells/mm 2 , P < .001). This observation extended to 21 of the 22 cases investigated. In addition, 6 patients who later developed recurrent disease contained lower numbers of CD169 + cells (268.6 ± 169.5 cells/mm 2 ) in nearby tumor-free lymph nodes compared to 341.0 ± 176.1 cells/mm 2 in those who remained disease free ( P = .399). Human papillomavirus (HPV)-positive patients (n = 4) had a 6-fold lower number of CD169 + cells in metastatic nodes (61.2 ± 85.5 cells/mm 2 ) compared to nearby tumor-free lymph nodes (369.5 ± 175.5 cells/mm 2 , P = .028). In comparison, HPV-negative patients had only a 3-fold reduction (116.6 ± 118.5 cells/mm 2 vs 310.6 ± 176.2 cells/mm 2 , P < .001)., Conclusion: Metastatic spread of SCC to regional lymph nodes is associated with lower abundance of CD169 + macrophages in the SCSs of draining lymph nodes. These results set the stage for an in-depth investigation into the mechanism(s) by which metastatic SCC controls CD169 + macrophage abundance and its significance as it relates to prognosis and treatment response.

Staphylococcus aureus is able to infect virtually all organ systems and is a frequently isolated etiologic agent of osteomyelitis, a common and debilitating invasive infection of bone. Treatment of osteomyelitis requires invasive surgical procedures and prolonged antibiotic therapy, yet is frequently unsuccessful due to extensive pathogen-induced bone damage that can limit antibiotic penetration and immune cell influx to the infectious focus. We previously established that S. aureus triggers profound alterations in bone remodeling in a murine model of osteomyelitis, in part through the production of osteolytic toxins. However, staphylococcal strains lacking osteolytic toxins still incite significant bone destruction, suggesting that host immune responses are also major drivers of pathologic bone remodeling during osteomyelitis. The objective of this study was to identify host immune pathways that contribute to antibacterial immunity during S. aureus osteomyelitis, and to define how these immune responses alter bone homeostasis and contribute to bone destruction. We specifically focused on the interleukin-1 receptor (IL-1R) and downstream adapter protein MyD88 given the prominent role of this signaling pathway in both antibacterial immunity and osteo-immunologic crosstalk. We discovered that while IL-1R signaling is necessary for local control of bacterial replication during osteomyelitis, it also contributes to bone loss during infection. Mechanistically, we demonstrate that S. aureus enhances osteoclastogenesis of myeloid precursors in vitro, and increases the abundance of osteoclasts residing on bone surfaces in vivo. This enhanced osteoclast abundance translates to trabecular bone loss, and is dependent on intact IL-1R signaling. Collectively, these data define IL-1R signaling as a critical component of the host response to S. aureus osteomyelitis, but also demonstrate that IL-1R-dependent immune responses trigger collateral bone damage through activation of osteoclast-mediated bone resorption., Competing Interests: The authors have declared that no competing interests exist.

Integrase interactor 1 (INI1) is a tumor suppressor gene that is ubiquitously expressed in all nucleated cells. The loss of INI1 protein activity was first demonstrated in aggressive pediatric tumors, including atypical teratoid/rhabdoid (AT/RT) tumor of the central nervous system and malignant rhabdoid tumor of the kidney. Subsequently, INI1 deficiency was discovered in other pediatric and some adult neoplasms. The spectrum of INI1-negative tumors includes a wide variety of neoplasms that occur over a wide age range, are variably aggressive, and have a variable rhabdoid component on histopathologic evaluation. In this report, the authors describe a 27-year-old gravid woman with INI1-deficient carcinoma of the lacrimal gland, previously not described in this location.

Objectives: (1) To define patient demographics and common symptoms in patients who undergo styloidectomy for stylohyoid pain syndrome (Eagle's syndrome). (2) To evaluate the effectiveness of styloidectomy in reducing symptoms of Eagle's syndrome., Methods: Retrospective chart review and prospective case series. We retrospectively gathered demographic data on all patients at a single institution who underwent styloidectomy during a 5-year period. Using a patient symptom survey, we also gathered prospective data on a cohort of these patients presenting during the second half of the timeframe., Results: Thirty-two patients underwent styloidectomy for Eagle's syndrome between November 2010 and June 2015. Of these patients, 22 (68.8%) were female, 29 (90.6%) were Caucasian, and 10 (31.3%) reported history of tonsillectomy. Mean age was 46.0 years, and mean BMI was 26.1 kg/m 2 . Nineteen patients completed the prospective survey. Average styloid length was 45.3 mm. Most severe preoperative symptoms were neck pain, otalgia, globus, facial pain, headache, and discomfort with neck turning. Thirteen of 17 individual symptoms demonstrated significant decrease in symptom scores after styloidectomy. Aggregate symptom scores also showed significant decrease postsurgically. Longer styloid length correlated with increased scores for dysphagia and odynophagia but not with conglomerate symptom scores., Conclusions: Patients with Eagle's syndrome were mostly female, Caucasian, and had near-normal BMI. There is wide variability in presenting symptoms of Eagle's syndrome, but nearly all demonstrate improvement after styloidectomy. Thus, in appropriately selected patients, styloidectomy can effectively and reliably produce improvement in patient symptoms.

Background: Metformin, an oral anti-hyperglycemic drug which inhibits mitochondrial complex I and oxidative phosphorylation has been reported to correlate with improved outcomes in head and neck squamous cell carcinoma (HNSCC) and other cancers. This effect is postulated to occur through disruption of tumor-driven metabolic and immune dysregulation in the tumor microenvironment (TME). We report new findings on the impact of metformin on the tumor and immune elements of the TME from a clinical trial of metformin in HNSCC. Methods: Human papilloma virus-(HPV-) tobacco+ mucosal HNSCC samples ( n = 12) were compared to HPV+ oropharyngeal squamous cell carcinoma (OPSCC) samples ( n = 17) from patients enrolled in a clinical trial. Apoptosis in tumor samples pre- and post-treatment with metformin was compared by deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay. Metastatic lymph nodes with extra-capsular extension (ECE) in metformin-treated patients ( n = 7) were compared to archival lymph node samples with ECE ( n = 11) for differences in immune markers quantified by digital image analysis using co-localization and nuclear algorithms (PD-L1, FoxP3, CD163, CD8). Results: HPV-, tobacco + HNSCC (mean Δ 13.7/high power field) specimens had a significantly higher increase in apoptosis compared to HPV+ OPSCC specimens (mean Δ 5.7/high power field) ( p < 0.001). Analysis of the stroma at the invasive front in ECE nodal specimens from both HPV-HNSCC and HPV+ OPSCC metformin treated specimens showed increased CD8+ effector T cell infiltrate (mean 22.8%) compared to archival specimens (mean 10.7%) ( p = 0.006). Similarly, metformin treated specimens showed an increased FoxP3+ regulatory T cell infiltrate (mean 9%) compared to non-treated archival specimens (mean 5%) ( p = 0.019). Conclusions: This study presents novel data demonstrating that metformin differentially impacts HNSCC subtypes with greater apoptosis in HPV-HNSCC compared to HPV+ OPSCC. Moreover, we present the first in vivo human evidence that metformin may also trigger increased CD8+ Teff and FoxP3+ Tregs in the TME, suggesting an immunomodulatory effect in HNSCC. Further research is necessary to assess the effect of metformin on the TME of HNSCC.

Objectives/hypothesis: We present our experience with telemedicine visits in an otolaryngology outpatient setting within our institution's Center for Head and Neck Surgery., Study Design: Retrospective chart review., Methods: A review of telemedicine outpatient encounters examining patient demographics, visit type, and wait times was conducted. Internet-based navigation applications were used to calculate travel distance and estimate commute time to our clinic. Patient survey responses were reviewed., Results: Two hundred fifty telemedicine encounters were reviewed between December 2015 and June 2017. The average age of patients was 50 years (range, 4-87 years). Patients waited an average of 10 minutes for their telemedicine appointments and avoided an average estimated commute time of 78 minutes (64 miles). The majority of visits were postoperative encounters (70%). Clinical follow-up of recent results or nonpostoperative complaints accounted for the remaining 30% of visits. All patients were offered a post-telemedicine survey, and 78 (31%) completed the survey. Of the respondents, 95% of patients reported that they were satisfied with their visit. Among patients who were dissatisfied, wait time and technical issues were cited as reasons., Conclusions: With appropriate patient selection, telemedicine is an effective way to safely conduct outpatient clinic visits while maintaining high patient satisfaction. It can be particularly useful for institutions with large catchment areas to minimize travel times and increase ease of communication., Level of Evidence: 4. Laryngoscope, 128:2072-2075, 2018., (© 2018 The American Laryngological, Rhinological and Otological Society, Inc.)

Objective: To assess the pathological outcomes of surgically-managed human papillomavirus (HPV) positive oropharyngeal squamous cell carcinoma (OPSCC) using the 8th Edition of the American Joint Committee on Cancer Staging Manual (AJCC-8ed)., Materials and Methods: A retrospective review was conducted of 156 patients with previously untreated OPSCC who underwent primary TORS between March 2010 and February 2015 to evaluate the impact of the new AJCC-8ed pathologic staging system. Only patients who had complete pathologic staging with neck dissection and at least 2 years of follow-up records or disease recurrence within 2 years were included for analysis., Results and Conclusions: Of the 156 patients, 116 patients had neck dissections and adequate follow-up data. There were 10 total recurrences, including 2 regional recurrences and 1 local recurrence. Lymph node size, number of positive lymph nodes, and presence of any positive nodes were not associated with recurrence for HPV-positive patients. The presence of extranodal extension approached significance. Pathologic N-stage was not predictive of recurrence under the AJCC-7ed or the AJCC-8ed systems. Cancer staging under the AJCC-8ed, but not the AJCC-7ed system was significantly associated with recurrence. In conclusion, pathologic node status as defined in the AJCC-8ed pathologic staging system does not appear to drive prognosis for surgically managed patients. While the new AJCC-8ed staging is an improvement in prognostication, the use of T-stage alone is still a better predictor of recurrence. TORS with adjuvant therapy determined by pathologic findings provides excellent locoregional control for HPV-positive OPSCC., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Objective: To assess the incidence of first bite syndrome (FBS) in transoral robotic surgical (TORS) patients undergoing transcervical arterial ligation., Methods: Retrospective case series of all patients diagnosed with FBS following prophylactic transcervical arterial ligation of branches of the external carotid system between March 2010 and December 2016 at a single academic center., Results: Six patients with FBS after TORS with transcervical arterial ligation were evaluated, representing 7% of all patients who underwent neck dissection with concomitant transcervical arterial ligation (6 of 83). Median presentation of FBS was 63 days, with an average duration of 66 days. Treatment ranged from observation to botulinum toxin injection., Conclusion: Patients who undergo transcervical arterial ligation to minimize bleeding complications following TORS are at risk of developing first bite syndrome., Level of Evidence: 4. Laryngoscope, 128:1589-1593, 2018., (© 2017 The American Laryngological, Rhinological and Otological Society, Inc.)

Objectives: 1) review benefits and risks of cannabis use, with emphasis on otolaryngic disease processes; 2) define and review the endocannabinoid signaling system (ESS); and 3) review state and federal regulations for the use and research of cannabis and ESS modulators., Methods: This manuscript is a review of the current literature relevant to the stated objectives., Results: Cannabis (marijuana) use is increasing. It is the most widely used illicit substance in the world. There is increasing interest in its therapeutic potential due to changing perceptions, new research, and legislation changes controlling its use. The legal classification of cannabis is complicated due to varied and conflicting state and federal laws. There are currently two synthetic cannabinoid drugs that are FDA approved. Current indications for use include chemotherapy-related nausea and vomiting, cachexia, and appetite loss. Research has demonstrated potential benefit for use in many other pathologies including pain, inflammatory states, and malignancy. Data exists demonstrating potential antineoplastic benefit in oral, thyroid, and skin cancers., Conclusions: ESS modulators may play both a causal and therapeutic role in several disorders seen in otolaryngology patients. The use of cannabis and cannabinoids is not without risk. There is a need for further research to better understand both the adverse and therapeutic effects of cannabis use. With increasing rates of consumption, elevated public awareness, and rapidly changing legislation, it is helpful for the otolaryngologist to be aware of both the adverse manifestations of use and the potential therapeutic benefits when talking with patients.

Objectives/hypothesis: To evaluate functional outcomes and complication rate after total laryngectomy (TL) for dysfunctional larynx with end-stage dysphagia., Study Design: Retrospective chart review., Methods: Chart review was performed on all patients who underwent TL from January 2008 to July 2016 at a single tertiary academic medical center. Patients who underwent TL for dysfunctional larynx without preoperative evidence of malignancy were included. Main outcome measures were post-TL functional swallowing and speech outcomes, and complication rate., Results: The study included 19 patients from a cohort of 278 consecutive patients. All patients were previously treated with radiotherapy (RT), whereas 13/19 (68%) previously received chemoradiotherapy. The median time from RT to TL was 10.98 years (range, 0.67-23.94 years). Aspiration was evident preoperatively in 17/19 (89%) patients, with 11 experiencing recurrent aspiration pneumonia. Seventeen of 19 (89%) patients were nil per os (NPO) requiring enteral nutrition. Six of 19 (32%) patients had surgical complications, including three (16%) pharyngocutaneous fistulas. At 3-month and 1-year postoperative follow-up, there was significant improvement in mean Functional Oral Intake Scale (FOIS) score and aspiration, recurrent pneumonia, enteral nutrition, and NPO status rates (P < .05). At 1-year follow-up, no patients were NPO, and only one patient required gastrostomy tube supplementation. Mean FOIS score increased from 1.3 to 6.1 (P = .001). Eight of 13 patients (62%) were actively using a tracheoesophageal prosthesis at 1-year follow-up., Conclusions: Laryngectomy for dysfunctional larynx eliminates the morbidity of aspiration while improving diet and reducing gastrostomy tube dependence with an acceptable complication rate., Level of Evidence: 4. Laryngoscope, 128:597-602, 2018., (© 2017 The American Laryngological, Rhinological and Otological Society, Inc.)

Objectives: To determine the rate of unplanned readmission after transoral robotic surgery (TORS), and to determine which patient or surgical factors increase the likelihood of readmission., Materials and Methods: Retrospective chart review of all patients who underwent TORS for squamous cell carcinoma at our institution from March 2010 through July 2016. Primary outcome was unplanned readmission to the hospital within 30 days of discharge. Univariable and multivariable logistic regression were performed to identify risk factors for unplanned readmission., Results: 297 patients met eligibility criteria. 23 patients (7.7%) had unplanned readmissions within 30 days. Most common reasons for readmission were oropharyngeal bleed (n = 13) and pain/dehydration (n = 10). Average time to unplanned readmission was 6.52 days (range 0-25 days). Discharge on clopidogrel was the only variable independently associated with an increased risk of 30-day unplanned readmission on multivariable analysis with an OR = 6.85 (95% CI 1.59-26.36). Unplanned return to the operating room during initial hospitalization (OR = 7.55, 95% CI 1.26-38.50) and discharge on clopidogrel (OR = 10.45, 95% CI 1.06-82.69) were associated with increased risk of postoperative bleeding. Bilateral neck dissection (OR = 5.17, 95% CI 1.15-23.08) was associated with significantly increased odds of unplanned readmission secondary to pain and dehydration., Conclusion: Unplanned readmission following TORS occurs in a small but significant number of patients. Oropharyngeal bleeding and dehydration were the most common reasons for unplanned readmission following TORS., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Objective  Naso- or orbitocutaneous fistula (NOF) is a challenging complication of orbital exenteration, and it often requires surgical repair. We sought to identify the incidence and risk factors for NOF after orbital exenteration. Study Design  Retrospective chart review, systematic review, meta-analysis. Setting  Tertiary care center. Participants  Patients undergoing free flap reconstruction following orbital exenteration. Records were reviewed for clinicopathologic data, operative details, and outcomes. Main Outcome Measures  Univariate analysis was used to assess risk factors for incidence of postoperative NOF. PubMed and Cochrane databases were searched for published reports on NOF after orbital exenteration. Rates of fistula and odds ratios for predictive factors were compared in a meta-analysis. Results  Total 7 of 77 patients (9.1%) developed NOF; fistula formation was associated with ethmoid sinus involvement ( p  < 0.05) and minor wound break down ( p  < 0.05). On meta-analysis, pooled rates of fistula formation were 5.8% for free flap patients and 12.5% for patients receiving no reconstruction. Conclusion  Immediate postoperative wound complications and medial orbital wall resection increased the risk for NOF. On review and meta-analysis, reconstruction of orbital exenteration defects decreased the risk for fistula formation, but published series did not demonstrate a significant decrease in risk with free flaps compared with other methods of reconstruction.

Objective To review a single institution's outcomes of free flap reconstruction of the head and neck in patients aged ≥80 years as compared with those <80 years. Study Design Retrospective cohort study. Setting Tertiary academic hospital. Subjects and Methods Patients aged ≥ 80 years who underwent free flap reconstruction of the head and neck between 2007 and 2013 were identified and matched by type of reconstruction with a cohort of younger patients. Outcome measures included flap success, length of stay, discharge disposition, complications, and 2-year mortality. Associations between complications and comorbidities were also evaluated. Results Sixty-six patients aged ≥80 years were identified, and a paired sample <80 years old was selected. There were 3 flap failures per group and 1 perioperative mortality in the elderly group. There was no significant difference in length of stay or major complications between groups. Significantly more elderly patients were discharged to a nursing facility. There was no significant difference in mortality rates at 2 years postoperatively. No associations were seen between level of comorbidity and complications among the elderly group. Conclusion Free flap reconstruction of the head and neck remains a viable option in patients of advanced age. Similar outcomes in terms of flap success, complications, and length of hospitalization can be achieved as compared with younger patients undergoing similar reconstructions. The role of comorbid disease as a predictor of complications remains unclear. There is no significant difference in 2-year mortality for elderly free flap patients versus younger controls.

Objectives: To assess risk factors for cerebrospinal fluid (CSF) leak and complications after microvascular reconstruction of cranio-orbitofacial resection with orbital exenteration (CFOE)., Study Design: Retrospective case series., Methods: Seventy consecutive patients at a tertiary hospital underwent 76 procedures with microvascular reconstruction of CFOE defects. Patients were stratified by extent of skull base exposure and presence or absence of dural resection. Patients with exposure of the orbital apex and roof alone were classified as minimal skull base exposure (MS) (n = 32). Those with skull base exposure beyond the orbital apex and roof were classified as significant skull base exposure (SS) (n = 38) and were subdivided into those with dural exposure (SSe) (n = 15) and those with dural resection (SSr) (n = 23). The main outcome measure was incidence of postoperative CSF leak according to univariate and multivariate analysis of risk factors, including previous radiation, surgery, and location of defect., Results: Intraoperative leaks occurred in five and four patients in the MS and SSe groups, respectively, with no postoperative leaks. In the SSr group, five patients developed a postoperative CSF leak and three required operative management. Multivariate analysis revealed middle fossa exposure to be the only significant predictor of CSF leak (P = 0.03). The overall complication rate was 31.6%. Major complications were greater in the SS group compared to the MS group (P = 0.05)., Conclusion: In this series, middle fossa resection increased the risk of postoperative CSF leak after microvascular reconstruction of CFOE defects, and complication rates were greater with more complex defects., Level of Evidence: 4. Laryngoscope, 127:835-841, 2017., (© 2016 The American Laryngological, Rhinological and Otological Society, Inc.)

PurposeTo describe prognostic factors and survival outcomes in patients who underwent orbital exenteration for periocular non-melanoma cutaneous malignancies.MethodsThe authors performed an institutional review board-approved retrospective review of all patients who underwent orbital exenteration for non-melanoma periocular cutaneous malignancies at a tertiary care hospital system over a 10-year period. Patient demographics, tumor, and treatment data were recorded. Survival outcomes included disease-free survival (DFS) and overall survival (OS). Log-rank tests were used to test for difference in survival curves among various potential prognostic indicators, and multivariate analysis was performed using Cox's proportional hazards model.ResultsForty-nine patients with an average age of 70.3 years were followed with a median follow-up of 17.5 months. At 2 years the OS was 78% while the DFS was 61%. The mean DFS for basal cell carcinoma (BCC), squamous cell carcinoma (SCC), and sebaceous gland carcinoma (SGC) were 52.6, 39.2 and 28.1 months, respectively. Multivariate analysis demonstrated that only positive final surgical margin was predictive of worse outcome (P=0.002). Recurrences were most frequent in the first 2 years.ConclusionsDespite the relatively more aggressive nature of periocular malignancies that have invaded the orbit, orbital exenteration offers an overall 2-year DFS of ~60%. BCC had the greatest mean survival time, however this was not statistically significant. We found worse prognosis with positive final surgical margins and recommend a multidisciplinary surgical approach to achieve complete resection when indicated.

A subgroup of breast cancers has several metabolic compartments. The mechanisms by which metabolic compartmentalization develop in tumors are poorly characterized. TP53 inducible glycolysis and apoptosis regulator (TIGAR) is a bisphosphatase that reduces glycolysis and is highly expressed in carcinoma cells in the majority of human breast cancers. Hence we set out to determine the effects of TIGAR expression on breast carcinoma and fibroblast glycolytic phenotype and tumor growth. The overexpression of this bisphosphatase in carcinoma cells induces expression of enzymes and transporters involved in the catabolism of lactate and glutamine. Carcinoma cells overexpressing TIGAR have higher oxygen consumption rates and ATP levels when exposed to glutamine, lactate, or the combination of glutamine and lactate. Coculture of TIGAR overexpressing carcinoma cells and fibroblasts compared with control cocultures induce more pronounced glycolytic differences between carcinoma and fibroblast cells. Carcinoma cells overexpressing TIGAR have reduced glucose uptake and lactate production. Conversely, fibroblasts in coculture with TIGAR overexpressing carcinoma cells induce HIF (hypoxia-inducible factor) activation with increased glucose uptake, increased 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase-3 (PFKFB3), and lactate dehydrogenase-A expression. We also studied the effect of this enzyme on tumor growth. TIGAR overexpression in carcinoma cells increases tumor growth in vivo with increased proliferation rates. However, a catalytically inactive variant of TIGAR did not induce tumor growth. Therefore, TIGAR expression in breast carcinoma cells promotes metabolic compartmentalization and tumor growth with a mitochondrial metabolic phenotype with lactate and glutamine catabolism. Targeting TIGAR warrants consideration as a potential therapy for breast cancer., (© 2016 by The American Society for Biochemistry and Molecular Biology, Inc.)

We report that Mucin1 (MUC1), a transmembrane glycoprotein that is overexpressed in >80% of pancreatic ductal adenocarcinoma (PDA), induced a pro-angiogenic tumor microenvironment by increasing the levels of neuropilin-1 (NRP1, a co-receptor of vascular endothelial growth factor (VEGF)) and its ligand VEGF. Expression of tumor-associated MUC1 (tMUC1) positively correlated with NRP1 levels in human and mouse PDA. Further, tMUC1 hi PDA cells secreted high levels of VEGF and expressed high levels of VEGF receptor 2 (VEGFR2) and its phosphorylated forms as compared with tMUC1 low/null PDA. This enabled the tMUC1 hi /NRP1 hi PDA cells to (a) induce endothelial cell tube formation, (b) generate long ectopic blood vessels and (c) enhance distant metastasis in a zebrafish xenograft model. Concurrently, the proteins associated with epithelial-to-mesenchymal transition, N-cadherin and Vimentin, were highly induced in these tMUC1/NRP1 hi PDA cells. Hence, blocking signaling via the NRP1-VEGF axis significantly reduced tube formation, new vessel generation and metastasis induced by tMUC1 hi PDA cells. Finally, we show that blocking the interaction between VEGF 165 and NRP1 with a NRP1 antagonist significantly reduced VEGFR signaling and PDA tumor growth in vivo. Taken together, our data suggest a novel molecular mechanism by which tMUC1 may modulate NRP1-dependent VEGFR signaling in PDA cells., Competing Interests: Dr. Pinku Mukherjee is a board member in OncoTab. Dr. Lopamudra Das Roy is an employee of OncoTab. The other authors declare no conflict of interest.