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Objective/hypothesis: Elevation of the superficial musculoaponeurotic system (SMAS) with or without fat graft interposition during superficial parotidectomy prevents a concave facial deformity and Frey's syndrome. Study Design: Retrospective, case-control study. Methods: Charts for 248 patients who underwent superficial parotidectomy were reviewed for pathologic, radiographic, clinical, and operative data. Sixteen patients who underwent SMAS elevation and 34 patients who underwent SMAS elevation with fat graft interposition were included in two study groups. Nonreconstructed controls were randomly selected from a pool of patients who had unilateral, superficial parotidectomy and were matched based on pathologic specimen volume. Patients were surveyed for their postoperative symptoms. Results: Patients undergoing SMAS elevation alone (n = 16) compared with controls (n = 19) had greater facial symmetry (12% vs. 32%, P = .147) and a lower incidence of symptomatic Frey's syndrome (6.3% vs. 18.6%, P = .382). Patients undergoing SMAS elevation and fat graft interposition (n = 34) compared with controls (n = 38) had less facial asymmetry (9% vs. 39%, P = .002) and a lower incidence of symptomatic Frey's syndrome (6% vs. 28%, P = .04). Complications among the study and control groups were comparable. Conclusions: Simultaneous reconstruction of a superficial parotidectomy defect using SMAS elevation with or without fat grafting may improve postoperative facial symmetry and decrease the incidence of symptomatic Frey's syndrome without increasing complications. [ABSTRACT FROM AUTHOR]

Objectives: Tumors involving the vagus nerve are often clinically silent. We offer a case series with different clinical presentations and distinctive post-surgical sequelae that highlight some of the challenges associated with managing cervical vagal nerve tumors., Methods: Single-institution, retrospective review of patients with tumors involving the vagus nerve. We describe clinical presentations and postoperative sequelae of five patients who underwent surgical management of vagal nerve pathology with atypical presentation or subsequent clinical course., Results: Here, we present five patients treated at our institution for vagal tumors. In four of the five patients, the presenting symptoms resolved after surgery. Two patients presented with intractable neurogenic cough, and another two presented with autonomic symptoms, one with syncope/palpitations and the other with intractable sweating. The final patient presented with a rapidly enlarging vagal paraganglioma and developed intractable cough after resection. We present two patients with novel approach to vagal paragangliomas that underwent ligation of feeding blood supply without removing the tumor, resulting in resolution of an intractable cough in one patient and resolution of severe nighttime sweating in the other., Conclusion: Management of tumors associated with the cervical vagus nerve that present with symptoms or rapid growth poses a clinical dilemma. Consideration of the tumor origin with either enucleation of schwannomas or ligation of feeding vessels may preserve function while addressing the presenting symptoms., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Free flap (FF) reconstruction of traumatic injuries to the head and neck is uncommon., Methods: Multi-institutional retrospective case series of patients undergoing FF reconstruction for a traumatic injury (n = 103)., Results: Majority were gunshot wounds (GSW; 85%, n = 88) and motor vehicle accidents (11%, n = 11). Majority underwent osseous reconstruction (82%, n = 84). FF failures (9%, n = 9/103) occurred in GSW patients (100%, n = 9/9) and when multiple subsites were injured (89%, n = 8/9). Preoperative antibiotics correlated with lower rates of a neck washouts (4% vs. 19%) (p = 0.01) and 30-day readmissions (4% vs. 17%) (p = 0.02)., Conclusions: All FF failures occurred in the setting of a GSW and the majority involved multiple subsites. Preoperative antibiotics correlated with lower rates of postoperative washout procedures and 30-day readmission., (© 2024 The Author(s). Head & Neck published by Wiley Periodicals LLC.)

Purpose: We evaluated whether IDO-inhibitor BMS986205 (IDOi) + PD-1 inhibitor nivolumab enhanced T-cell activity and augmented immune-mediated antitumor responses in untreated, resectable HNSCC. We employed response-adaptive surgical timing to identify responders to immunotherapy and enhance their response., Patients and Methods: Patients with HNSCC were 3:1 randomized to receive nivolumab with or without BMS986205 PO daily (NCT03854032). In the combination arm, BMS986205 was initiated 7 days prior to nivolumab. Patients were stratified by HPV status. Response-adaptive surgical timing involved response assessment by radiographic criteria 4 weeks after nivolumab in both arms. Non-responders underwent surgical resection, while responders received 4 more weeks of randomized therapy before surgery. Biomarker analysis utilized pathologic treatment response (pTR) and RNA sequencing., Results: Forty-two patients were enrolled, and the addition of IDOi to nivolumab did not result in greater rate of radiographic response (p=0.909). Treatment was well-tolerated with only 2 (5%) patients experiencing grade 3 immune-related adverse events. The addition of IDO-inhibitor augmented rates of pTR in patients with high baseline IDO RNA expression (p<0.05). Response-adaptive surgical timing demonstrated reliability in differentiating pathologic responders versus non-responders (p=0.009). A pretreatment NK cell signature, PD-L1 status, and IFN-g expression in the HPV- cohort correlated with response. HPV+ cohort found B-cell and CAF signatures predictive of response/non-response., Conclusions: Response-adaptive surgical timing enhanced treatment response. IDO-inhibitor BMS986205 augmented pTR in patients with high IDO1-expression in baseline samples, indicating a need for identifying and targeting resistant nodes to immunotherapy. HPV-status-dependent signatures predicting response to immunotherapy in HNSCC warrant further study.

Objective: Application of virtual reality (VR) for surgical planning may improve clinical outcomes for head and neck cancer (HNC) resection. There is a lack of randomized trials and meaningful metrics to assess such technological applications. Our objective was to evaluate the feasibility of a VR protocol for oncologic surgical planning and assess the impact on surgical outcomes., Methods: A randomized controlled trial utilizing a VR Case Enhancement Protocol (VRCEP) versus standard of care (SOC) surgical planning was conducted. The primary endpoint was feasibility, defined as >80% successful VRCEPs. Metrics included surgeon task-load burden (TLB) using the NASA Task-Load Index and "margin events," defined as "the need for defect-driven margins, positive frozen margins, and/or positive final margins." Margin events were used to calculate a margin event score (MES) per case and margin event rate (MER) per cohort., Results: Thirty-four patients were included in the final analysis (17 VRCEP, 17 SOC) with 94.4% of eligible VRCEP cases completed (17/18). Surgeon TLB was unchanged with VRCEP. Cases undergoing VRCEP were associated with a lower mean MES (0.27 vs. 0.94, p = 0.014) and MER (11.6% vs. 35.6%, p = 0.0041). VRCEP was associated with decreased defect-driven margins (10% vs. 53.3%, p = 0.032). Although not statistically significant, positive frozen and final margin rates were lower in VRCEP., Conclusion: Completion of the VRCEP was feasible with no significant increase in surgeon TLB appreciated. VRCEP yielded fewer MEs. Further investigation into the benefit of VR in HNC resection is warranted. Margin events may represent useful metrics for assessing novel surgical technologies., Level of Evidence: 2 Laryngoscope, 2024., (© 2024 The American Laryngological, Rhinological and Otological Society, Inc.)

Background: Head and neck osteoradionecrosis (ORN) of the midface requiring free flap (FF) reconstruction is uncommon. This multi-institutional study was designed to review outcomes for this rare patient population., Methods: Retrospective multi-institutional review of FF reconstruction for midface ORN (2005-2022; n = 54)., Results: The FF survival rate was 87% (n = 54). Patients were less likely to be tolerating a regular diet at 3 months postoperative if they had a preoperative history of prior head and surgery (80% vs. 95%; p = 0.02), a pathologic fracture (50% vs. 90%; p = 0.04), exposed bone intraorally (43% vs. 94%; p = 0.002), or a fistula (67% vs. 96%; p = 0.03). Mean albumin was higher in patients whose FF survived (3.6 ± 0.5 vs. 2.7 ± 1.4; p = 0.03). Patients with low prealbumin were more likely to undergo a hematoma evacuation (27% vs. 0%; p = 0.02)., Conclusion: In this series of midface ORN requiring FF reconstruction preoperative nutritional status impacted postoperative complications. Preoperative occurrence of a fistula, pathologic fracture, and intraoral bone exposure correlated with decreased tolerance of a regular diet following reconstruction., (© 2024 The Author(s). Head & Neck published by Wiley Periodicals LLC.)

The reported donor site morbidity of the fibula free flap (FFF) is low; however, several uncommon complications have been reported with tibia fracture rarely being reported. We present a case of a pathological tibial fracture in the setting of chronic osteomyelitis after FFF. A 54-year-old female presented with a benign fibro-osseous lesion of the right mandible and was treated with mandibulectomy and reconstructed with a left FFF. Approximately 1 year following surgery, the patient presented to the emergency department. Imaging showed a pathological fracture of the distal third of the tibial shaft with persistent erythema and cellulitis of the lateral prior graft harvest site without signs of systemic infection. She was taken to the operating room for irrigation and debridement with culture and biopsy as well as external fixation of the tibial fracture. Intraoperative biopsy and culture demonstrated fracture site change with callus formation and negative culture. The patient was discharged on 6 weeks of IV vancomycin and ceftriaxone. In conclusion, tibial fracture following FFF is an uncommon complication, yet it can be exacerbated by chronic osteomyelitis. This report highlights the importance of close observation and comprehensive wound care of donor sites after free flap harvest for head and neck reconstruction., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Objective: The modified frailty index (mFI-5) is a National Surgical Quality Improvement Program-derived 5-factor index that has been proven to reflect frailty and predict morbidity and mortality. We hypothesize that mFI-5 is a valid predictive measure in the transoral robotic surgery (TORS) population., Methods: Retrospective study utilizing the TriNetX US-collaborative health records network querying for TORS patients. Cohorts were stratified by mFI-5 score which uses five ICD-10 codes: nonindependent functional status, hypertension, obstructive respiratory disease, heart failure, and diabetes mellitus. Cohorts were matched by age using propensity score matching. Outcome measures included survival, infection, pneumonia, tracheostomy dependence, and percutaneous endoscopic gastrostomy dependence. Reported odds ratios were normalized to mFI-5 = 0., Results: A total of 9,081 patients were included in the final analysis. Greater mFI-5 scores predicted decreased survival and increased incidence of postoperative infection and pneumonia. Odds of 5-year mortality were 1.93 (p = 0.0003) for mFI-5 = 2 and 1.90 (p = 0.0002) for mFI-5 = 3. Odds of 2-year mortality were 1.25 (p = 0.0125) for mFI-5 = 1, 1.58 (p = 0.0002) for mFI-5 = 2, and 1.87 (p = 0.003) for mFI-5 = 3. Odds of postoperative infection were 1.51 (p = 0.02) for mFI-5 = 2 and 1.78 (p = 0.05) for mFI-5 = 3. Two-year odds of developing pneumonia were 1.69 (p = 0.0001) for mFI-5 = 2 and 2.84 (p < 0.0001) for mFI-5 = 3. Two-month odds of pneumonia were 1.50 (p = 0.0259) for mFI-5 = 2 and 2.55 (p = 0.0037) for mFI-5 = 3. mFI-5 = 4 or 5 had too few patients to analyze. Using polynomial regression to model age versus incident 5-year post-TORS death (R 2  = 0.99), mFI-5 scores better predicted survival than age alone., Conclusion: This study demonstrates that mFI-5 predicts mortality, pneumonia, and postoperative infection independently of age., Level of Evidence: 4 Laryngoscope, 134:4278-4283, 2024., (© 2024 The Authors. The Laryngoscope published by Wiley Periodicals LLC on behalf of The American Laryngological, Rhinological and Otological Society, Inc.)

Immune checkpoint inhibition (ICI) has emerged as a critical treatment strategy for squamous cell carcinoma of the head and neck (HNSCC) that halts the immune escape of the tumor cells. Increasing evidence suggests that the onset, progression, and lack of/no response of HNSCC to ICI are emergent properties arising from the interactions within the tumor microenvironment (TME). Deciphering how the diversity of cellular and molecular interactions leads to distinct HNSCC TME subtypes subsequently governing the ICI response remains largely unexplored. We developed a cellular-molecular model of the HNSCC TME that incorporates multiple cell types, cellular states, and transitions, and molecularly mediated paracrine interactions. An exhaustive simulation of the HNSCC TME network shows that distinct mechanistic balances within the TME give rise to the five clinically observed TME subtypes such as immune/non-fibrotic, immune/fibrotic, fibrotic only and immune/fibrotic desert. We predict that the cancer-associated fibroblast, beyond a critical proliferation rate, drastically worsens the ICI response by hampering the accessibility of the CD8+ killer T cells to the tumor cells. Our analysis reveals that while an Interleukin-2 (IL-2) + ICI combination therapy may improve response in the immune desert scenario, Osteopontin (OPN) and Leukemia Inhibition Factor (LIF) knockout with ICI yields the best response in a fibro-dominated scenario. Further, we predict Interleukin-8 (IL-8), and lactate can serve as crucial biomarkers for ICI-resistant HNSCC phenotypes. Overall, we provide an integrated quantitative framework that explains a wide range of TME-mediated resistance mechanisms for HNSCC and predicts TME subtype-specific targets that can lead to an improved ICI outcome., Competing Interests: Conflict of Interest: The authors declare no conflict of interest exists.

Background: Vessel grafting is an important technique in head and neck free tissue transfer (FTT) reconstruction when a tension-free anastomosis is not otherwise feasible. To our knowledge, there are limited data regarding interposition artery grafts for arterial anastomoses in head and neck reconstruction. Here, we present a multi-institutional cohort of arterial interposition grafts for FTT reconstruction for head and neck defects., Methods: A retrospective review was conducted at four tertiary care institutions for patients who underwent FTT reconstruction for head and neck defects which utilized an interposition artery graft for the arterial anastomosis. Charts were reviewed for type and length of artery grafts harvested, surgical indication, indication for artery graft, types of flaps harvested, and various preoperative characteristics (including history of radiation or previous FTT reconstruction surgery). Postoperative complications within postoperative day 30 were measured and reported., Results: Nine patients met inclusion criteria. The lateral circumflex femoral artery (either transverse or descending branches) (n = 3) and facial artery (n = 3) were the most commonly harvested arteries. The scalp (n = 5) was the most common primary defect site. Seven grafts were harvested initially and in a planned fashion, while two were harvested as salvage techniques (either for flap salvage or vein graft failure). In planned grafts, arteries were the preferred interposition grafting method due to either size match preferences (n = 4) or similarities in wall thickness (n = 3) between graft and recipient artery. There were no reported cases of unplanned readmission, postoperative hematoma, fistula formation, wound infection, or donor site morbidities. Two patients required unplanned return to the operating room for flap compromise, both of which ultimately resulted in flap failure secondary to clot formation at both arterial and venous anastomoses., Conclusions: When arterial pedicle length is insufficient, interposition artery grafting is both a feasible and viable technique to achieve tension-free arterial anastomoses for select cases of highly complex head and neck free tissue reconstruction., (© 2024 Wiley Periodicals LLC.)

Staphylococcus aureus is responsible for a substantial number of invasive infections globally each year. These infections are problematic because they are frequently recalcitrant to antibiotic treatment. Antibiotic tolerance, the ability of bacteria to persist despite normally lethal doses of antibiotics, contributes to antibiotic treatment failure in S. aureus infections. To understand how antibiotic tolerance is induced, S. aureus biofilms exposed to multiple anti-staphylococcal antibiotics are examined using both quantitative proteomics and transposon sequencing. These screens indicate that arginine metabolism is involved in antibiotic tolerance within a biofilm and support the hypothesis that depletion of arginine within S. aureus communities can induce antibiotic tolerance. Consistent with this hypothesis, inactivation of argH, the final gene in the arginine synthesis pathway, induces antibiotic tolerance. Arginine restriction induces antibiotic tolerance via inhibition of protein synthesis. In murine skin and bone infection models, an argH mutant has enhanced ability to survive antibiotic treatment with vancomycin, highlighting the relationship between arginine metabolism and antibiotic tolerance during S. aureus infection. Uncovering this link between arginine metabolism and antibiotic tolerance has the potential to open new therapeutic avenues targeting previously recalcitrant S. aureus infections., (© 2024. The Author(s).)

Background: Medication related osteonecrosis of the jaw (MRONJ) requiring free flap (FF) reconstruction is uncommon with limited reported findings., Methods: Multicenter, retrospective case series of 49 consecutive adult patients presenting with advanced MRONJ requiring FF reconstruction from 2010 to 2022. Perioperative complications and outcomes were analyzed., Results: Eighty-two percent (n = 40) of cases were of the mandible and 18% (n = 9) were of the maxilla. The mean follow-up was 15 months (±19.6). The majority of FF survived (96%, n = 47). FF reconstructions of the maxilla were more likely to require postoperative debridement (56%, 95% CI [27, 81%] vs. 15%, 95% CI [7, 25%], p = 0.008) or develop intraoral bone exposure (56%, 95% CI [27, 81%] vs. 18%, 95% CI [9, 27%], p = 0.02). Most patients (71%, n = 35) received preoperative antibiotics which was associated with a higher rate of FF survival (100% vs. 86%, 95% CI [60, 96%], p = 0.02) and fewer complications., Conclusions: Patients undergoing FF reconstruction for MRONJ do well with high rates of FF success. MRONJ of the maxilla have a higher rate of some complications. Preoperative antibiotics correlated with higher FF survival and fewer postoperative complications., (© 2024 The Authors. Head & Neck published by Wiley Periodicals LLC.)

Importance: For patients treated with immune checkpoint inhibitors (ICIs), recent data suggest that obesity has a beneficial effect on survival outcomes in various cancer types. Reports on this association in head and neck cancer are limited., Objectives: To compare overall survival (OS) to 5 years and functional outcomes in patients with head and neck squamous cell carcinoma (HNSCC) treated with ICIs based on pretreatment body mass index (BMI)., Design, Setting, and Participants: This retrospective population-based cohort study used data obtained from the TriNetX Global Collaborative Network database to identify patients with HNSCC who received ICI treatment between January 1, 2012, and December 31, 2023, resulting in a total of 166 patients (83 with BMI of 20.0-24.9 [normal BMI] and 83 with BMI of ≥30.0 [obesity BMI]) after propensity score matching (PSM) for pretreatment medical comorbidities and oncologic staging., Exposure: Normal BMI vs obesity BMI., Main Outcomes and Measures: Overall survival and functional outcomes (dysphagia, tracheostomy dependence, and gastrostomy tube dependence) were measured to 5 years after ICI treatment and compared between patients with obesity BMI and normal BMI. Additional analyses compared OS and functional outcomes in the cohort with normal BMI and cohorts with overweight BMI (25.0-29.9) and underweight BMI (<20.0)., Results: Among the 166 patients included in the PSM analysis (112 men [67.1%]; mean [SD] age, 62.9 [15.4] years), obesity BMI was associated with significantly improved OS at 6 months (hazard ratio [HR], 0.54 [95% CI, 0.31-0.96]), 3 years (HR, 0.56 [95% CI, 0.38-0.83]), and 5 years (HR, 0.62 [95% CI, 0.44-0.86]) after ICI treatment, compared with patients with normal BMI. Obesity BMI was also associated with decreased risk of gastrostomy tube dependence at 6 months (odds ratio [OR], 0.41 [95% CI, 0.21-0.80]), 1 year (OR, 0.41 [95% CI, 0.21-0.78]), 3 years (OR, 0.35 [95% CI, 0.18-0.65]), and 5 years (OR, 0.34 [95% CI, 0.18-0.65]). Obesity was also associated with decreased risk for tracheostomy dependence at 1 year (OR, 0.52 [95% CI, 0.28-0.90]), 3 years (OR, 0.45 [95% CI, 0.45-0.90]), and 5 years (OR, 0.45 [95% CI, 0.45-0.90]). There were no differences in rates of dysphagia or immune-related adverse events between cohorts at any points., Conclusions and Relevance: Using population-level data for patients with HNSCC treated with ICIs, these results suggest that having obesity was associated with improved 6-month, 3-year, and 5-year OS compared with having normal BMI. Additionally, obesity was associated with decreased gastrostomy and tracheostomy tube dependence compared with normal BMI. Further investigation is required to understand the mechanism of these findings.

Introduction: Oral cavity squamous cell carcinoma (OSCC) occurs most frequently in patients >60 years old with a history of tobacco and alcohol use. Epidemiological studies describe increased incidence of OSCC in younger adults (<45 years). Despite its poor prognosis, knowledge of OSCC tumor microenvironment (TME) characteristics in younger adults is scarce and could help inform possible resistance to emerging treatment options., Methods: Patients with OSCC were evaluated using TCGA-HNSC (n=121) and a stage and subsite-matched institutional cohort (n=8) to identify differential gene expression focusing on the extracellular matrix (ECM) and epithelial-mesenchymal transition (EMT) processes in younger (≤45 years) vs. older adults (≥60 years). NanoString nCounter analysis was performed using isolated total RNA from formalin-fixed paraffin-embedded (FFPE) tumor samples. Stained tumor slides from young and old OSCC patients were evaluated for CD8 + T-cell counts using immunohistochemistry., Results: Younger OSCC patients demonstrated significantly increased expression of ECM remodeling and EMT process genes, as well as TME immunosuppression. Gene set enrichment analyses demonstrated increased ECM pathways and concurrent decreased immune pathways in young relative to old patients. Transcripts per million of genetic markers involved in ECM remodeling including LAMB3, VCAN, S100A9, COL5A1, and ITGB2 were significantly increased in tumors of younger vs. older patients (adjusted p-value < 0.10). Young patient TMEs demonstrated a 2.5-fold reduction in CD8 + T-cells as compared to older patients (p < 0.05)., Conclusion: Differential gene expression impacting ECM remodeling and TME immunosuppression may contribute to disease progression in younger adult OSCC and has implications on response to evolving treatment modalities, such as immune checkpoint inhibitor therapy., 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. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Estephan, Kumar, Stewart, Banoub, Linnenbach, Harshyne, Martinez-Outschoorn, Mahoney, Curry, Johnson, South and Luginbuhl.)

Objectives: Certain low-level immune-related adverse events (irAEs) have been associated with survival benefits in patients with various solid tumors on immune checkpoint inhibitors (ICIs). We aimed to investigate the association between irAEs and response to neoadjuvant ICIs in patients with head and neck squamous cell carcinoma (HNSCC) and to identify differences in circulating cytokine levels based on irAE status., Methods: This was a retrospective cohort study including three neoadjuvant clinical trials from July 2017 to January 2022: NCT03238365 (nivolumab ± tadalafil), NCT03854032 (nivolumab ± BMS986205), NCT03618654 (durvalumab ± metformin). The presence and type of irAEs, pathologic treatment response, and survival were compared. Canonical linear discriminant analysis (LDA) was performed to identify combinations of circulating cytokines predictive of irAEs using plasma sample multiplex assay., Results: Of 113 participants meeting inclusion criteria, 32 (28.3%) developed irAEs during treatment or follow-up. Positive p16 status was associated with irAEs (odds ratio [OR] 2.489; 95% CI 1.069-6.119; p = 0.043). irAEs were associated with pathologic treatment response (OR 3.73; 95% CI 1.34-10.35; p = 0.011) and with higher OS in the combined cohort (HR 0.319; 95% CI 0.113-0.906; p = 0.032). Patients with irAEs within the nivolumab cohort had significant elevations of select cytokines pre-treatment. Canonical LDA identified key drivers of irAEs among all trials, which were highly predictive of future irAE status., Conclusions: irAEs are associated with response to neoadjuvant ICI therapy in HNSCC and can serve as clinical indicators for improved clinical outcomes. irAEs can be predicted by concentrations of several circulating cytokines prior to treatment., (© 2024 The Author(s). Cancer Medicine published by John Wiley & Sons Ltd.)

The lack of comprehensive diagnostics and consensus analytical models for evaluating the status of a patient's immune system has hindered a wider adoption of immunoprofiling for treatment monitoring and response prediction in cancer patients. To address this unmet need, we developed an immunoprofiling platform that uses multiparameter flow cytometry to characterize immune cell heterogeneity in the peripheral blood of healthy donors and patients with advanced cancers. Using unsupervised clustering, we identified five immunotypes with unique distributions of different cell types and gene expression profiles. An independent analysis of 17,800 open-source transcriptomes with the same approach corroborated these findings. Continuous immunotype-based signature scores were developed to correlate systemic immunity with patient responses to different cancer treatments, including immunotherapy, prognostically and predictively. Our approach and findings illustrate the potential utility of a simple blood test as a flexible tool for stratifying cancer patients into therapy response groups based on systemic immunoprofiling., Competing Interests: Declaration of interests This research was funded by BostonGene, Corp. N.F. is the Chief Medical Officer of BostonGene, Corp., and all authors affiliated with BostonGene, Corp. were employees thereof at the time the study was performed. M.F.G., A.Bagaev, D.D., A.Z., B.S., E.T., P.T., and A.A.S. are inventors on patents related to this work., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: There is sparse literature on the effect of preoperative immunotherapy on complications after surgery for primary head and neck squamous cell carcinoma (HNSCC). The objectives are to compare complication rates in patients receiving surgery with and without neoadjuvant immune checkpoint inhibitors (nICI) for primary HNSCC and to evaluate factors associated with increased odds of surgical complications., Methods: A retrospective review of patients who underwent ablation and free flap reconstruction or transoral robotic surgery (TORS) for primary HNSCC between 2017-2021 was conducted. Complications were compared between patients who underwent surgery with or without nICI before and after propensity score matching. Regression analysis to estimate odds ratios was performed., Results: A total of 463 patients met inclusion criteria. Free flap reconstruction constituted 28.9% of patients and TORS constituted 71.1% of patients. nICI was administered in 83 of 463 (17.9%) patients. There was no statistically significant difference in surgical, medical, or overall complications between patients receiving surgery with or without nICI. In the unmatched cohort, multivariable model identified non-White race, former/current smoking history, free flap surgery, and perineural invasion as factors significantly associated with increased complications. In the matched cohort, multivariable model identified advanced age and free flap surgery as factors significantly associated with increased complications., Plain Language Summary: It is safe to give immunotherapy before major surgery in patients who have head and neck cancer. Advanced age, non-White race, current/former smoking, free flap surgery, and perineural invasion may be associated with increased the odds of surgical complications., (© 2023 The Authors. Cancer published by Wiley Periodicals LLC on behalf of American Cancer Society.)

Mesenchymal-epithelial plasticity driving cancer progression in cancer-associated fibroblasts (CAFs) is undetermined. This work identifies a subgroup of CAFs in human breast cancer exhibiting mesenchymal-to-epithelial transition (MET) or epithelial-like profile with high miR-200c expression. MiR-200c overexpression in fibroblasts is sufficient to drive breast cancer aggressiveness. Oxidative stress in the tumor microenvironment induces miR-200c by DNA demethylation. Proteomics, RNA-seq and functional analyses reveal that miR-200c is a novel positive regulator of NFκB-HIF signaling via COMMD1 downregulation and stimulates pro-tumorigenic inflammation and glycolysis. Reprogramming fibroblasts toward MET via miR-200c reduces stemness and induces a senescent phenotype. This pro-tumorigenic profile in CAFs fosters carcinoma cell resistance to apoptosis, proliferation and immunosuppression, leading to primary tumor growth, metastases, and resistance to immuno-chemotherapy. Conversely, miR-200c inhibition in fibroblasts restrains tumor growth with abated oxidative stress and an anti-tumorigenic immune environment. This work determines the mechanisms by which MET in CAFs via miR-200c transcriptional enrichment with DNA demethylation triggered by oxidative stress promotes cancer progression. CAFs undergoing MET trans-differentiation and senescence coordinate heterotypic signaling that may be targeted as an anti-cancer strategy., Competing Interests: Conflict of Interest: The authors declare no competing interests., (Copyright: © 2024 Lin et al.)

Objective: To assess if there is increased risk of free flap failure in renal failure patients undergoing head and neck reconstruction. We seek to primarily assess free flap outcomes based on stages of chronic kidney disease (CKD) and secondarily determine increased risk for postoperative complications., Methods: Retrospective chart review was performed at five tertiary care centers. Patients were identified that had undergone microvascular free flap reconstruction of the head and neck with diagnosis of renal failure, classified as Stage 3 CKD or higher. Demographic data was collected. Outcomes in the postoperative period were examined., Results: Seventy-three patients met inclusion criteria. The average patient age was 69 years with a male predominance (n = 48). The majority of patients had CKD Stage 3 (n = 52). Overall flap failure rate was 12.33% (n = 9, CKD stage 3 = 7.69%, CKD stage 4 = 30%, CKD stage 5 = 18%). There was an increased risk of flap failure on multivariate analysis for CKD stage 4/5 patients when compared to CKD 3 patients (p = 0.0095). When compared to matched controls, there was an increased risk of flap failure in CKD patients (p = 0.01) as well as an increased risk of overall complications (p < 0.0001)., Conclusions: Patients with CKD undergoing head and neck reconstruction are at a higher risk of flap failure and overall complications. When comparing CKD stages there may be increased risk of flap failure in later stages of CKD compared to CKD 3. Appropriate patient counseling is recommended pre-operatively in this patient population with consideration for regional flaps in the appropriate patient., Level of Evidence: 3 Laryngoscope, 134:688-694, 2024., (© 2023 The American Laryngological, Rhinological and Otological Society, Inc.)

Introduction: Mandibular resection and reconstruction are common but complex procedures in head and neck surgery. Resection with adequate margins is critical to the success of the procedure but technical training is restricted to real case experience. Here we describe our experience in the development and evaluation of a mandibular resection and reconstruction simulation module., Methods: 3D printed (3DP) models of a mandible with a pathologic lesion were developed from imaging data from a patient with an ameloblastoma. During an educational conference, otolaryngology trainees participated in a simulation in which they reviewed a CT scan of the pathologic mandible and then planned their osteotomies before and after handling a 3DP model demonstrating the lesion. The adequacy of the osteotomy margins was assessed and components of the simulation were rated by participants with pre- and post-training surveys., Results: 52 participants met criteria. After reviewing the CT scan, 34 participants (65.3 %) proposed osteotomies clear of the lesion. This proportion improved to 48 (92.3 %, p = 0.001) after handling the 3D model. Among those with initially adequate margins (n = 33), 45.5 % decreased their margins closer to the ideal, 27.2 % made no revision, 21.2 % widened their margins. 92 % of participants found the simulation beneficial for surgical planning and technical training. After the exercise, the majority of participants had increased confidence in conceptualizing the boundaries of the lesion (69.2 %) and their abilities to ablate (76.5 %)., Conclusions: The structured mandibulectomy simulation using 3DP models was useful in the development of trainee experience in segmental mandible resection., Lay Summary: This study presents the first mandibulectomy simulation module for trainees with the use of 3DP models. The use of a 3DP model was also shown to improve the quality of surgical training., Competing Interests: Declaration of competing interest No funding or conflicts of interest., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Importance: Due to lack of data from high-powered randomized clinical trials, the differences in functional and survival outcomes for patients with oropharyngeal squamous cell carcinoma (OPSCC) undergoing primary transoral robotic surgery (TORS) vs primary radiation therapy and/or chemoradiation therapy (RT/CRT) are unclear., Objectives: To compare 5-year functional (dysphagia, tracheostomy dependence, and gastrostomy tube dependence) and survivorship outcomes in patients with T1-T2 OPSCC receiving primary TORS vs RT/CRT., Design, Setting, and Population: This national multicenter cohort study used data from a global health network (TriNetX) to identify differences in functional and survival outcomes among patients with OPSCC who underwent primary TORS or RT/CRT in 2002 to 2022. After propensity matching, 726 patients with OPSCC met inclusion criteria. In the TORS group, 363 (50%) patients had undergone primary surgery, and in the RT/CRT group, 363 (50%) patients had received primary RT/CRT. Data analyses were performed from December 2022 to January 2023 using the TriNetX platform., Exposure: Primary surgery with TORS or primary treatment with radiation therapy and/or chemoradiation therapy., Main Outcomes and Measures: Propensity score matching was used to balance the 2 groups. Functional outcomes were measured at 6 months, 1 year, 3 years, 5 years, and more than 5 years posttreatment and included dysphagia, gastrostomy tube dependence, and tracheostomy dependence according to standard medical codes. Five-year overall survivorship was compared between patients undergoing primary TORS vs RT/CRT., Results: Propensity score matching allowed a study sample with 2 cohorts comprising statistically similar parameters with 363 (50%) patients in each. Patients in the TORS cohort had a mean (SD) age of 68.5 (9.9) vs 68.8 (9.7) years in RT/CRT cohort; 86% and 88% were White individuals, respectively; 79% of patients were men in both cohorts. Primary TORS was associated with clinically meaningful increased risk of dysphagia at 6 months (OR, 1.37; 95% CI, 1.01-1.84) and 1 year posttreatment (OR, 1.71; 95% CI, 1.22-2.39) compared with primary RT/CRT. Patients receiving surgery were less likely to be gastrostomy tube dependent at 6 months (OR, 0.46; 95% CI, 0.21-1.00) and 5 years posttreatment (risk difference, -0.05; 95% CI, -0.07 to -0.02). Differences in overall rates of tracheostomy dependence (OR, 0.97; 95% CI, 0.51-1.82) between groups were not clinically meaningful. Patients with OPSCC, unmatched for cancer stage or human papillomavirus status, who received RT/CRT had worse 5-year overall survival than those who underwent primary surgery (70.2% vs 58.4%; hazard ratio, 0.56; 95% CI, 0.40-0.79)., Conclusions and Relevance: This national multicenter cohort study of patients undergoing primary TORS vs primary RT/CRT for T1-T2 OPSCC found that primary TORS was associated with a clinically meaningful increased risk of short-term dysphagia. Patients treated with primary RT/CRT had an increased risk of short- and long-term gastrostomy tube dependence and worse 5-year overall survival than those who underwent surgery.

Therapy using anti-PD-1 immune checkpoint inhibitors (ICI) has revolutionized the treatment of many cancers including head and neck squamous cell carcinomas (HNSCC), but only a fraction of patients respond. To better understand the molecular mechanisms driving resistance, we performed extensive analysis of plasma and tumor tissues before and after a 4-week neoadjuvant trial in which HNSCC patients were treated with the anti-PD-1 inhibitor, nivolumab. Luminex cytokine analysis of patient plasma demonstrated that HPV pos nonresponders displayed high levels of the proinflammatory chemokine, interleukin-8 (IL-8), which decreased after ICI treatment, but remained higher than responders. miRNAseq analysis of tetraspanin-enriched small extracellular vesicles (sEV) purified from plasma of HPV pos nonresponders demonstrated significantly lower levels of seven miRNAs that target IL-8 including miR-146a. Levels of the pro-survival oncoprotein Dsg2, which has been to down-regulate miR-146a, are elevated with HPV pos tumors displaying higher levels than HPV neg tumors. Dsg2 levels decrease significantly following ICI in responders but not in nonresponders. In cultured HPV pos cells, restoration of miR-146a by forced expression or treatment with miR-146a-loaded sEV, reduced IL-8 level, blocked cell cycle progression, and promoted cell death. These findings identify Dsg2, miR-146a, and IL-8 as potential biomarkers for ICI response and suggest that the Dsg2/miR-146a/IL-8 signaling axis negatively impacts ICI treatment outcomes and could be targeted to improve ICI responsiveness in HPV pos HNSCC patients., (© 2023 The Authors. Molecular Carcinogenesis published by Wiley Periodicals LLC.)

Objectives: This study sought to analyze the effects of perioperative blood transfusions and vasopressors on 30-day surgical complications and 1-year mortality after reconstructive surgery in head and neck free tissue transfer (FTT) and to identify predictors of administration of perioperative blood transfusions or vasopressors., Materials and Methods: TriNetX (TriNetX LLC, Cambridge, USA), an international population-level electronic health record database, was queried to identify subjects that underwent FTT requiring perioperative (intraoperative to postoperative day 7) vasopressors or blood transfusions. Primary dependent variables were 30-day surgical complications and 1-year mortality. Propensity score matching was used to control for population differences, and covariate analysis was used to identify preoperative comorbidities associated with perioperative vasopressor or transfusion requirements., Results: 7,631 patients met inclusion criteria. Preoperative malnutrition was associated with increased odds of perioperative transfusion (p = 0.002) and vasopressor requirement (p < 0.001). Perioperative blood transfusion (n = 941) was associated with increased odds of any surgical complication (p = 0.041) within 30 days postoperatively and specifically increased odds of wound dehiscence (p = 0.008) and FTT failure (p = 0.002), respectively. Perioperative vasopressor was (n = 197) was not associated with 30-day surgical complications. Vasopressor requirement was associated with increased hazards-ratio of mortality at 1-year (p = 0.0031)., Conclusion: Perioperative blood transfusion in FTT is associated with increased odds for surgical complications. Judicious use as a hemodynamic support measure should be considered. Perioperative vasopressor use was associated with an increased risk of one-year mortality. Malnutrition is a modifiable risk factor for perioperative transfusion and vasopressor requirement. These data warrant further investigation to assess causation and potential opportunity for practice improvement., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: [Zachary D. Urdang MD PhD has received honoraria from TriNetX-LLC to attend their annual member summit]., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Tumor hypoxia (oxygen deficiency) is a major contributor to radiotherapy resistance. Ultrasound-sensitive microbubbles containing oxygen have been explored as a mechanism for overcoming tumor hypoxia locally prior to radiotherapy. Previously, our group demonstrated the ability to encapsulate and deliver a pharmacological inhibitor of tumor mitochondrial respiration (lonidamine (LND)), which resulted in ultrasound-sensitive microbubbles loaded with O 2 and LND providing prolonged oxygenation relative to oxygenated microbubbles alone. This follow-up study aimed to evaluate the therapeutic response to radiation following the administration of oxygen microbubbles combined with tumor mitochondrial respiration inhibitors in a head and neck squamous cell carcinoma (HNSCC) tumor model. The influences of different radiation dose rates and treatment combinations were also explored. The results demonstrated that the co-delivery of O 2 and LND successfully sensitized HNSCC tumors to radiation, and this was also enhanced with oral metformin, significantly slowing tumor growth relative to unsensitized controls ( p < 0.01). Microbubble sensitization was also shown to improve overall animal survival. Importantly, effects were found to be radiation dose-rate-dependent, reflecting the transient nature of tumor oxygenation.

Objective: In head and neck cancer (HNC), positive margins are strongly predictive of treatment failure. We sought to measure the accuracy of localization of margin sampling sites based on conventional anatomic labels using a digital 3D-model., Methods: Preoperative CT scans for 9 patients with HNC treated operatively at our institution were imported into a multiplanar radiology software, which was used to render a digital 3D model of each tumor intended to represent the resection specimen. Surgical margin labels recorded during the operative case were collected from pathology records. Margin labels (N = 64) were presented to participating physicians.Participants were asked to mark the anatomic location of each surgical margin using the 3D-model and corresponding radiographic planes for reference.For each individual margin, the 3D coordinates of each participant's marker were used to calculate a mean localization point called the geometric centroid. Mean distance from individual markers to the centroid was compared between participantsand margin types., Results: Amongst 7 surgeons, markers were placed a mean distance of 12.6 mm ([SD] = 7.5) from the centroid.Deep margins were marked with a greater mean distance than mucosal/skin margins (19.6 [24.8] mm vs. 15.3 [14.9] mm, p = 0.034). When asked to relocate a margin following re-resection, surgeons marked a point an average of 20.6 [12.4] mm from their first marker with a range of 3.9- 45.1 mm., Conclusions: Retrospective localization of conventionally labeled margins is an imprecise process with variability across the care team. Future interventions targeting margin documentation and communication may improve sampling precision., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Ltd.)

Objective: To assess whether preoperative tracheostomy (PreOT) increases risk of complications after total laryngectomy (TL) and to determine if timing of tracheostomy creation is associated with an increased risk., Study Design: Retrospective cohort study., Setting: Tertiary care hospital between 2007 and 2020., Methods: Inclusion criteria were patients who underwent primary or salvage TL for oncologic treatment. Dependent variables of interest included surgical complications, such as wound dehiscence, infection, hematoma, complete flap failure, fistula formation, and stoma stenosis, as well as medical complications. Categorical variables were compared with chi-square test or Fisher exact test, and continuous variables were compared with an independent t test. Multivariable regression was conducted to assess predictors of complications after laryngectomy., Results: A total of 306 patients were included. Primary TL was performed in 161 (53%) patients and salvage in 145 (47%) patients. Of the patients undergoing primary laryngectomy, 105 (65%) received a PreOT. Of the patients undergoing salvage laryngectomy, 86 (59%) received a PreOT. In both primary and salvage cases, there was no association between PreOT and surgical or medical complications. Additionally, there was no significant association between timing of tracheostomy and surgical complications. On multivariable analysis, the presence of a PreOT was not associated with surgical complications. In salvage cases, those with a PreOT had a significantly longer average length of stay than those without a PreOT (12 vs 9 days, P = .008)., Conclusion: PreOT in patients undergoing primary and salvage laryngectomies was not associated with surgical or medical complications postlaryngectomy. Timing of tracheostomy in relation to laryngectomy was not found to adversely affect clinical outcomes., (© 2022 American Academy of Otolaryngology-Head and Neck Surgery Foundation.)

Nasopharyngeal tumors in the proximity of the internal carotid artery are often difficult to dissect. Here, we describe a combined transcervical and endoscopic endonasal approach that provides improved internal carotid artery protection and confident tumor resection. Laryngoscope, 133:105-108, 2023., (© 2022 The American Laryngological, Rhinological and Otological Society, Inc.)

Objective: Determine which variables impact postoperative discharge destination following head and neck microvascular free flap reconstruction., Study Design: Retrospective review of prospectively collected databases., Methods: Consecutive patients undergoing head and neck microvascular free flap reconstruction between January 2010 and December 2019 (n = 1972) were included. Preoperative, operative and postoperative variables were correlated with discharge destination (home, skilled nursing facility [SNF], rehabilitation facility, death)., Results: The mean age of patients discharged home was lower (60 SD ± 13, n = 1450) compared to those discharged to an SNF (68 SD ± 14, n = 168) or a rehabilitation facility (71 SD ± 14, n = 200; p < 0.0001). Operative duration greater than 10 h correlated with a higher percentage of patients being discharged to a rehabilitation or SNF (25% vs. 15%; p < 0.001). Patients were less likely to be discharged home if they had a known history of cardiac disease (71% vs. 82%; p < 0.0001). Patients were less likely to be discharged home if they experienced alcohol withdrawal (67% vs. 80%; p = 0.006), thromboembolism (59% vs. 80%; p = 0.001), a pulmonary complication (46% vs. 81%; p < 0.0001), a cardiac complication (46% vs. 80%; p < 0.0001), or a cerebral vascular event (25% vs. 80%; p < 0.0001). There was no correlation between discharge destination and occurrence of postoperative wound infection, salivary fistula, partial tissue necrosis or free flap failure. Thirty-day readmission rates were similar when stratified by discharge destination., Conclusion: There was no correlation with the anatomic site, free flap donor selection, or free flap survival and discharge destination. Patient age, operative duration and occurrence of a medical complication postoperatively did correlate with discharge destination., Level of Evidence: 4 Laryngoscope, 133:95-104, 2023., (© 2022 The American Laryngological, Rhinological and Otological Society, Inc.)

Background: Few standardized methods exist for evaluating the postoperative outcomes of osteocutaneous free flaps. We propose an anatomic-based scoring system for midface free flap reconstruction., Methods: One hundred and twelve patients across four institutions underwent osteocutaneous reconstruction of the midface. Postoperative scans were scored based on the number of independent osseous subunits reconstructed (Subunit Score), the number of different bony appositions with bony contact (Contact Score), and the number of osseous segments in anatomic position (Position Score). These were added together to create a Total Score., Results: Osteocutaneous radial forearm flaps had the lowest Subunit Score (p = 0.001). Fibula flaps had the highest Contact Score (p = 0.0008) and Position Score (p = 0.001). Virtual surgical planning was associated with an increased Subunit Score (p = 0.02) and Total Score (p = 0.04)., Conclusions: We propose a novel scoring system for osseous midface reconstruction based on postoperative imaging scans. This can help guide management decisions and create a common language to compare outcomes., (© 2022 The Authors. Head & Neck published by Wiley Periodicals LLC.)

Staphylococcus aureus is the major causative agent of bacterial osteomyelitis, an invasive infection of bone. Inflammation generated by the immune response to S. aureus contributes to bone damage by altering bone homeostasis. Increases in the differentiation of monocyte lineage cells into bone-resorbing osteoclasts (osteoclastogenesis) promote bone loss in the setting of osteomyelitis. In this study, we sought to define the role of Toll-like receptor (TLR) signaling in the pathogenesis of S. aureus osteomyelitis. We hypothesized that S. aureus-sensing TLRs 2 and 9, both of which are known to alter osteoclastogenesis in vitro , promote pathological changes to bone, including increased osteoclast abundance, bone loss, and altered callus formation during osteomyelitis. Stimulation of osteoclast precursors with S. aureus supernatant increased osteoclastogenesis in a TLR2-dependent, but not a TLR9-dependent, manner. However, in vivo studies using a posttraumatic murine model of osteomyelitis revealed that TLR2-null mice experienced similar bone damage and increased osteoclastogenesis compared to wild type (WT) mice. Therefore, we tested the hypothesis that compensation between TLR2 and TLR9 contributes to osteomyelitis pathogenesis. We found that mice deficient in both TLR2 and TLR9 ( Tlr2/9 -/- ) have decreased trabecular bone loss in response to infection compared to WT mice. However, osteoclastogenesis is comparable between WT and Tlr2/9 -/- mice, suggesting that alternative mechanisms enhance osteoclastogenesis in vivo during osteomyelitis. Indeed, we discovered that osteoclast precursors intracellularly infected with S. aureus undergo significantly increased osteoclast formation, even in the absence of TLR2 and TLR9. These results suggest that TLR2 and TLR9 have context-dependent roles in the alteration of bone homeostasis during osteomyelitis.

Objectives: To define rates of occult metastases in salvage oral cavity and oropharyngeal cancer resection requiring free flap, to examine the location of occult metastases, and to determine associations between occult metastasis and survival., Study Design: Retrospective cohort study., Setting: Two tertiary care referral centers., Methods: We identified previous cases of irradiation with recurrent or second primary oral cavity or oropharyngeal squamous cell carcinoma that had no evidence of regional metastasis and required free tissue transfer reconstruction of the primary site. Patients who underwent elective neck dissection or exploration were reviewed. The main outcome measures were the presence and location of occult nodal metastasis. Disease-free survival and overall survival were measured. Odds ratios and hazard ratios were used for analysis., Results: A total of 83 patients were included: 52 with oral cavity primary tumors and 31 with oropharynx. An overall 78 (94%) underwent elective salvage neck dissection. Occult metastases were found in 9 (11.5%) patients. The most common nodal station for occult metastasis was level 2. Neither elective neck dissection nor the presence of occult metastasis was significantly associated with regional disease-free or overall survival. Oropharyngeal primary tumors were associated with higher risk of occult metastasis (odds ratio, 1.38; P < .01) and worse overall survival (hazard ratio, 2.09; P = .01)., Conclusion: There is a low incidence of occult metastasis in postradiated recurrent or second primary oral cavity and oropharyngeal tumors. Elective neck dissection and occult nodal metastases were not associated with regional or overall survival. This series may help surgeons make decisions regarding the extent of neck surgery after prior radiation, especially when free flap reconstruction is required.

Osteomyelitis, or bone infection, is a major complication of accidental trauma or surgical procedures involving the musculoskeletal system. Staphylococcus aureus is the most frequently isolated pathogen in osteomyelitis and triggers significant bone loss. Hypoxia-inducible factor (HIF) signaling has been implicated in antibacterial immune responses as well as bone development and repair. In this study, the impact of bone cell HIF signaling on antibacterial responses and pathologic changes in bone architecture was explored using genetic models with knockout of either Hif1a or a negative regulator of HIF-1α, Vhl . Deletion of Hif1a in osteoblast-lineage cells via Osx-Cre ( Hif1a ΔOB ) had no impact on bacterial clearance or pathologic changes in bone architecture in a model of post-traumatic osteomyelitis. Knockout of Vhl in osteoblast-lineage cells via Osx-Cre ( Vhl ΔOB ) caused expected increases in trabecular bone volume per total volume (BV/TV) at baseline and, intriguingly, did not exhibit an infection-mediated decline in trabecular BV/TV, unlike control mice. Despite this phenotype, bacterial burdens were not affected by loss of Vhl . In vitro studies demonstrated that transcriptional regulation of the osteoclastogenic cytokine receptor activator of NF-κB ligand (RANKL) and its inhibitor osteoprotegerin (OPG) is altered in osteoblast-lineage cells with knockout of Vhl . After observing no impact on bacterial clearance with osteoblast-lineage conditional knockouts, a LysM-Cre model was used to generate Hif1a ΔMyeloid and Vhl ΔMyeloid mouse models to explore the impact of myeloid cell HIF signaling. In both Hif1a ΔMyeloid and Vhl ΔMyeloid models, bacterial clearance was not impacted. Moreover, minimal impacts on bone architecture were observed. Thus, skeletal HIF signaling was not found to impact bacterial clearance in our mouse model of post-traumatic osteomyelitis, but Vhl deletion in the osteoblast lineage was found to limit infection-mediated trabecular bone loss, possibly via altered regulation of RANKL-OPG gene transcription., 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 © 2022 Ford, Hurford, Fulbright, Curry, Peek, Spoonmore, Cruz Victorio, Johnson, Peck and Cassat.)

Purpose: Leukoplakia is common with a 1 % incidence in the population and may harbor preneoplastic changes. Diode lasers provide both precision and coagulation for excision of superficial lesions in clinical and operative settings with little damage to deeper tissue. We aim to determine the rate of oral and oropharyngeal hyperkeratosis and dysplasia recurrence after treatment with diode laser., Materials and Methods: Patients with oral or oropharyngeal hyperkeratotic or mild dysplastic lesions treated with pulsed diode laser between 2013 and 2020 at a tertiary academic institution were analyzed. The main outcome measure was recurrence of hyperkeratosis and dysplasia after treatment., Results: Fourteen patients received diode laser treatment for hyperkeratotic or mild dysplastic lesions of the oral cavity or oropharynx. Demographic features included 9 (64.3 %) females and mean age of 66.6 years. In these 14 patients, 18 distinct lesions were identified. Eleven (61.1 %) lesions were located on the oral tongue, 4 (22.2 %) on the buccal mucosa, 2 (11.1 %) on the hard palate, and 1 (5.6 %) on the soft palate. Average time from lesion clinical diagnosis to the first diode laser treatment was 8.3 months with an average number of 1.4 treatments per lesion. Three (16.7 %) lesions experienced recurrence after the most recent treatment. None of the lesions underwent malignant transformation. None of the patients experienced bleeding, tethering, or dysarthria after treatment. One patient developed pyogenic granuloma and reported chronic tongue pain., Conclusions: Pulsed diode laser treatment of leukoplakia was well tolerated with low complication rates and reasonable control of precancerous lesions., Competing Interests: Declaration of competing interest None., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Progress in the management of rare diseases, including rare cancers, is dependent upon clinical trials; however, as many as 32% of rare-disease trials go uncompleted or unpublished due to insufficient accrual. Monitoring practices may differ between institutions. We sought to survey the regulatory standards for various trial types among major U.S. cancer centers. A 10-question survey was designed using Qualtrics assessment software. The survey was sent via email to an internal server of member institutions of the Association of American Cancer Institutes (AACI). Of 103 AACI centers, 31% completed the survey ( n = 32). Respondents differed in their definitions of a rare disease, minimum expectations for rare tumor studies, and frequency of accrual monitoring by their institutional Protocol Review and Monitoring Committee. Seventy-three percent of respondents did not close trials based on low accrual. Strategies to optimize accrual included investigator incentives for high accrual and penalties for low accrual in 37% and 13% of respondents, respectively.

Background: Outcomes and cost of soft tissue versus bony midface free flap reconstruction (MR) with and without virtual surgical planning (VSP) were evaluated., Methods: Retrospective review of MR including ischemic time (IT), operative duration (OD), length of stay (LOS), and total cost (TC). Eighty-one soft tissue and 76 bony MR (VSP = 23) were reviewed., Results: Bony MR was used for higher complexity defects (p = 0.003) and was associated with higher IT (p < 0.001), OD (p < 0.001), LOS (p = 0.032), and TC (p < 0.001). VSP was associated with a mean 111.2 ± 37.9 minute reduction in OD (p = 0.004) compared to non-VSP bony flaps. VSP was associated with higher itemized cost, but no increase in TC (p = 0.327)., Conclusions: Bony MR was used for higher complexity MR and was associated with increased TC, LOS, OD, and IT. VSP shortened OD with no significant increase in TC., (© 2022 Wiley Periodicals LLC.)

Objective: To compare the experiences of patients who received sialendoscopy under general anesthesia (GA) with those who received monitored anesthesia care (MAC)., Methods: Patients who underwent sialendoscopy for sialadenitis or sialolithiasis from July 1, 2020, to July 31, 2021, were offered inclusion to this prospective observational study. A survey was sent to consenting patients on post-operative day 1 to record aspects of their pre-, intra-, and post-operative experience. The primary outcome was overall satisfaction. Secondary outcomes included pain tolerability and preference for similar anesthetic modality in the future., Results: Seventy-five patients completed the post-operative survey (86% response rate), of which 39 patients received GA and 36 received MAC. Patient overall satisfaction was similar between groups (GA: "Poor/Average/Good" = 23%, "Excellent" = 77%; MAC: "Poor/Average/Good" = 25%, "Excellent" = 75%, p = 1.00). Tolerability of immediate post-operative pain was likewise similar between the GA (82%) and MAC (97%) groups (p = 0.058). Patients who received MAC reported intra-operative pain as "none/tolerable" 72% of the time and "uncomfortable" 28% of the time. Patients who received GA would prefer the same anesthetic in the future more often than in the MAC group (85% versus 61%, respectively, OR 3.50, 95% CI 1.17-10.50, p = 0.035)., Conclusion: In regard to patient satisfaction, both MAC and GA are acceptable anesthetic choices in sialendoscopy for appropriate cases. Patients report similar overall satisfaction and post-operative pain tolerance under either anesthetic modality. Patients who undergo GA report higher rates of preference for similar anesthetic modality in the future. Further study is needed to determine the most appropriate criteria for anesthesia modality selection., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Importance: Incidence of perioperative free flap compromise is low, with successful salvage in up to 70%. When the flap is compromised a second time, the value of intervening is unknown., Objective: To assess the outcomes of a second revascularization attempt for compromised free flaps., Design, Setting, and Participants: This multicenter retrospective medical record review included patients undergoing head and neck reconstruction with free flaps at 6 US medical centers from January 1, 2000, through December 30, 2020. Patients were 18 years or older with a history of head and neck defects from cancer, osteoradionecrosis, or other wounds. Of 3510 flaps identified, 79 were successfully salvaged once, became compromised a second time, and underwent attempted salvage., Main Outcome and Measure: Flaps with a history of initial compromise and successful revascularization demonstrating second episodes of compromise followed by second salvage attempts., Results: A total of 79 patients (mean age, 64 years; 61 [77%] men) were included in the analysis. Of the 79 flaps undergoing second salvage attempts, 24 (30%) survived while 55 (70%) demonstrated necrosis. Arterial or venous thrombectomy was performed in 17 of the 24 (71%) flaps that survived and 23 of the 55 (42%) flaps demonstrating necrosis (odds ratio, 3.38; 95% CI, 1.21-9.47). When venous compromise was encountered, changing the anastomotic vein was associated with decreased survival compared with not changing the vein (29 of 55 [53%] flaps vs 10 of 24 [42%] flaps); vein revision to an alternative branch was completed in 1 of the 24 (4%) flaps that survived and 19 of the 55 (35%) flaps with necrosis (odds ratio, 0.08; 95% CI, 0.00-0.60). Factors that were not associated with flap survival following second salvage attempts included flap type, cause of flap failure, postoperative complications, patient comorbidities, and heparin administration after second salvage., Conclusions and Relevance: In this cohort study, second salvage was successful in 30% of free flaps. Flaps that underwent arterial or venous thrombectomy demonstrated better survival, while vein revision to neighboring branch veins was associated with worse flap outcomes.

Objective: Determine if age correlated with surgical or medical complications following head and neck free flap reconstruction., Study Design: Retrospective review of prospectively collected databases., Methods: Patients undergoing head and neck free flap reconstruction at three tertiary care institutions were included (n = 1972). Cohorts were based on age (<65, 65-75, 75-85, and >85). Outcomes reviewed operative duration, length of stay, surgical complications (free flap failure, fistula, hematoma, dehiscence, and infection), and medical complications (thromboembolism, stroke, cardiac, and pulmonary)., Results: Anatomic site (P < .0001) and donor site varied by age (P < .0001). There was no difference in operative duration (P = .3) or length of hospitalization (P = .8) by age. The incidence of medical complications increased with increasing age. Pulmonary complication rates: <65 (3.9%), 65 to 75 (4.8%), 75 to 85 (7.1%), and >85 (11%) (P = .02). Cardiac complication rates: <65 (2.0%), 65 to 75 (7.3%), 75 to 85 (6.1%), and >85 (16.4%) (P < .0001). Mortality increased with age: <65 (0.4%), 65 to 75 (0.8%), 75 to 85 (1.1%), and >85 (4.1%) (P < .003). Medical complications correlated with mortality rates: pulmonary (3.5% vs. 0.6%; OR: 5.5; 95% CI: 1.5-20.0; P = .004); cardiac (3.3% vs. 0.6%; OR: 6.0; 95% CI: 1.6-21.8; P = .002); thromboembolism (4.6% vs. 0.7%; OR: 7.3; 95% CI: 1.6-33.6; P = .003); stroke (42% vs. 0.5%; OR: 149; 95% CI: 40-558; P < .0001); and sepsis (5% vs. 0.7%; OR 7.5; 95% CI: 1.0-60.5; P = .03). Age did not correlate with free flap success (P = .5), surgical complications (hematoma, P = .33; fistula, P = .23; infection, P = .07; and dehiscence, P = .37), or thirty-day readmission (P = .3)., Conclusion: Following free flap reconstruction, patient age did not correlate with development of a surgical complication. Patient age did correlate with development of a medical complication. Postoperative medical complications were found to correlate with perioperative mortality., Level of Evidence: 4 Laryngoscope, 132:772-780, 2022., (© 2021 The American Laryngological, Rhinological and Otological Society, Inc.)

Background: Perioperative management of advanced osteoradionecrosis of the head and neck requiring free flap (FF) reconstruction varies. Our objectives included assessment of practice patterns and outcomes., Methods: Multi-institutional, retrospective review of FF reconstruction for head and neck osteoradionecrosis (n = 260)., Results: Administration of preoperative antibiotics did not correlate with reduction in postoperative complications. Preoperative alcohol use correlated with higher rates of hardware exposure (p = 0.03) and 30-day readmission (p = 0.04). Patients with FF compromise had higher TSH (p = 0.04) and lower albumin levels (p = 0.005). Prealbumin levels were lower in patients who required neck washouts (p = 0.02) or a second FF (p = 0.03). TSH levels were higher in patients undergoing postoperative debridement (p = 0.03) or local flap procedures (p = 0.04)., Conclusion: Malnutrition, hypothyroidism, and substance abuse correlated with a higher incidence of postoperative wound complications in patients undergoing FF reconstruction for advanced osteoradionecrosis. Preoperative antibiotics use did not correlate with a reduction in postoperative wound complications., (© 2021 Wiley Periodicals LLC.)

Purpose: We hypothesize that the addition of the phosphodiesterase-5 inhibitor tadalafil to the PD-1 inhibitor nivolumab, is safe and will augment immune-mediated antitumor responses in previously untreated squamous cell carcinoma of the head and neck (HNSCC)., Patients and Methods: We conducted a two-arm multi-institutional neoadjuvant randomized trial in any-stage resectable HNSCC (NCT03238365). Patients were stratified at randomization by human papillomavirus (HPV) status. Patients in both arms received nivolumab 240 mg intravenously on days 1 and 15 followed by surgery on day 28. Those in the combination therapy arm also received tadalafil 10 mg orally once daily for 4 weeks. Imaging, blood, and tumor were obtained pretreatment and posttreatment for correlative analysis., Results: Neoadjuvant therapy was well-tolerated with no grade 3 to 5 adverse events and no surgical delays. Twenty-five of 46 (54%) evaluable patients had a pathologic treatment response of ≥20%, including three (7%) patients with a complete pathologic response. Regardless of HPV status, tumor proliferation rate was a negative predictor of response. A strong pretreatment T-cell signature in the HPV-negative cohort was a predictor of response. Tadalafil altered the immune microenvironment, as evidenced by transcriptome data identifying enriched B- and natural killer cell gene sets in the tumor and augmented effector T cells in the periphery., Conclusions: Preoperative nivolumab ± tadalafil is safe in HNSCC and results in more than 50% of the patients having a pathologic treatment response of at least 20% after 4 weeks of treatment. Pretreatment specimens identified HPV status-dependent signatures that predicted response to immunotherapy while posttreatment specimens showed augmentation of the immune microenvironment with the addition of tadalafil., (©2021 The Authors; Published by the American Association for Cancer Research.)

This report describes the first use of a novel workflow for in-house computer-aided design (CAD) for application in a resource-limited surgical outreach setting. Preoperative computed tomography imaging obtained locally in Haiti was used to produce rapid-prototyped 3-dimensional (3D) mandibular models for 2 patients with large ameloblastomas. Models were used for patient consent, surgical education, and surgical planning. Computer-aided design and 3D models have the potential to significantly aid the process of complex surgery in the outreach setting by aiding in surgical consent and education, in addition to expected surgical applications of improved anatomic reconstruction.

In an era where the incidence of oropharyngeal cancer is growing steadily, there have been few studies exploring functional outcomes for individuals whose definitive cancer management approach includes transoral robotic surgical (TORS) resection. This study was designed to examine swallow-related outcomes in individuals newly diagnosed with base of tongue cancer whose treatment plan included surgical resection via TORS. The aims of this study were to determine whether TORS resection for early stage BOT SCCA affected: (a) lingual strength, (b) swallow safety and efficiency, (c) oral intake, and (d) swallowing-related quality of life. Nine individuals meeting the inclusion criteria were recruited to participate from March 2017 to April 2018. Each participant was evaluated at four distinct time points: (a) preoperatively, (b) 1 week postoperatively, (c) 1 month postoperatively, and (d) 3 months postoperatively. The following data were collected at each time point: (a) maximum isometric lingual pressure, (b) Penetration-Aspiration Scale score, (c) Yale Pharyngeal Residue Severity Rating Scale scores, (d) Functional Oral Intake Scale score, and (e) EAT-10 score. Data analysis revealed that a significant decline in maximum isometric lingual pressure, EAT-10 scores, and Functional Oral Intake Scale scores occurred between preoperative baseline measurements and 1 week post surgery. All participants in the study demonstrated a return to levels at or near their baseline level of function for maximum isometric lingual pressure, EAT-10 score, and Functional Oral Intake Scale score by 1 or 3 months post surgery. There were no significant changes in swallow safety or efficiency observed at any time point during the study., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC part of Springer Nature.)

Objective: The mainstay of treatment in sinonasal malignancy (SNM) is surgery, and when combined with chemoradiation therapy, often leads to the best overall prognosis. Nasal endoscopy is essential for post-treatment surveillance along with physical exam and radiologic evaluation. The ability to directly visualize the sinus cavities after surgery may also improve early detection of tumor recurrence and is another reason to potentially advocate for surgery in these patients., Methods: A retrospective chart review of medical records of patients with pathologically proven SNM was conducted from 2005 to 2019., Results: The nasal cavity and maxillary sinus were the most common primary tumor sub-sites. The most common pathology was squamous cell carcinoma (42%). The median time to recurrence was 9.8 months. Recurrence was initially detected endoscopically in 34.3% patients, by imaging in 62.7% patients, and by physical exam in 3.0% patients. 67 (29%) total recurrences were detected on follow-up, of which 46 (68.7%) were local. Twenty-three of the local recurrences were identified via nasal endoscopy. Thirteen recurrences were identified via endoscopic surveillance within the surgically patent paranasal sinuses while 13 were identified within the nasal cavity; 5 patients had multiple sites of recurrence., Conclusion: Local recurrence of SNM is the most common site for recurrent disease and nasal endoscopy identified half of these cases. 50% of these recurrences were within the paranasal sinuses and would not have been easily identified if the sinuses were not open for inspection. Thus, open sinus cavities aid in the detection of tumor recurrence and is another advantage of surgery in the management of SNM., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Objectives: To determine the rate of gastrostomy tube dependence after transoral robotic surgery (TORS), and to determine which patient or surgical factors increase the likelihood of gastrostomy tube dependence., Methods: Retrospective chart review of all patients who underwent TORS for oropharyngeal squamous cell carcinoma (OPSCC) at a single institution from January 2011 through July 2016. Patients who underwent TORS for recurrent OPSCC were excluded. Primary outcome was gastrostomy tube (g-tube) dependence. Univariable and multivariable logistic regression were performed to identify risk factors for g-tube dependence at 3-months and 1-year., Results: A total of 231 patients underwent TORS during the study period. At 3-month follow-up, 58/226 patients (25.7%) required g-tube. At 1-year and 2-year follow-up, 8/203 (3.9%) and 5/176 (2.8%), remained dependent on g-tube, respectively. Advanced T stage (T3) (OR = 6.07; 95% CI, 1.28-28.9) and discharge from the hospital with enteral access (OR = 7.50; 95% CI, 1.37-41.1) were independently associated with increased risk of postoperative gastrostomy tube dependence at 1 year on multivariable analysis., Conclusions: Long-term gastrostomy tube dependence following TORS is rare, particularly in patients that receive surgery alone. Patients with advanced T stage tumors have poorer functional outcomes. Early functional outcomes, as early as discharge from the hospital, are a strong predictor for long-term functional outcomes., (Copyright © 2021 Elsevier Inc. All rights reserved.)

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.