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PURPOSE: The purposes of this study were to: 1) estimate the prevalence and trends of American oral and maxillofacial surgery (OMS) programs in recruiting head and neck oncologic surgery (HNOS) -trained faculty, performing HNOS oncologic procedures and microvascular reconstruction, and presenting HNOS research at academic meetings; 2) estimate whether HNOS and microvascular reconstruction involvement varies among programs with or without a program director or chair trained in HNOS; 3) estimate whether HNOS involvement varies among those OMS programs that regularly attend and do not attend tumor board; 4) estimate whether HNOS involvement varies among those programs that have and have not presented HNOS research at an academic meeting; 5) estimate whether HNOS involvement varies among doctor of medicine-integrated and 4-year OMS programs. MATERIALS AND METHODS: Investigators developed and distributed a survey to all US OMS program directors and/or chair composed of questions regarding faculty prevalence and recruitment, frequency and trends in cases, and the priority of applicants for residency with regard to HNOS. There were 18 close-ended questions, and one open-ended question. Responses were recorded in categorical, Likert, ordinal, and numerical format. Bivariate associations were calculated using Fisher exact test and logistic regression. RESULTS: Sixty-three of 101 surveys were returned (62.3%). Ten program directors or chair completed a fellowship in HNOS (15.9%). Programs with an HNOS-trained program director or chair were more likely to have another HNOS-trained faculty member (P = .01), performed more malignant tumor resections (P < .001), neck dissections (P < .001), and microvascular free-flap reconstructions (P = .02) than programs without program directors or chair trained in HNOS. Programs that regularly attended tumor board performed an increasing number of malignant tumor resections (P = .008); and neck dissections (P = .003) than programs that did not regularly attend their institution's tumor board. Presentations of HNOS-related research at national meetings did not differ between doctor of medicine-integrated and 4-year OMS programs (P = .7). There was no difference in the prevalence of HNOS-trained program directors and chair between doctor of medicine-integrated and 4-year programs (P = .7). CONCLUSIONS: This study's data and comments suggest that programs involved in HNOS have a strong involvement in expanded scope OMS and related academic activities. [ABSTRACT FROM AUTHOR]

PURPOSE: To assess the reliability and effectiveness of intraoperative navigation in restoring normal orbital and globe dimensions in traumatic and postablative orbital defects. MATERIALS AND METHODS: To address the research purpose, the investigators initiated a retrospective cohort study and enrolled a sample of subjects that underwent primary or secondary reconstruction for unilateral orbital deformities secondary to traumatic injury or tumor surgery during the study enrollment period. Using computed tomographic datasets, pre- and postoperative orbital volume and globe projection were measured using Analyze software (Mayo Clinic Biomedical Imaging Resource, Rochester, MN). Intraclass correlation coefficient (ICC) was used to evaluate the reliability between preoperative unaffected orbit and the postoperative affected orbital and globe dimensions. A matched pairs t test was used to assess the difference in pre- and postoperative orbital volume and globe projection. RESULTS: The sample was composed of 23 subjects that underwent orbital reconstruction secondary to traumatic of postablative defects. There was a linear and reliable relationship between preoperative unaffected and postoperative affected orbital volumes (ICC, 0.67; 95% CI, 0.37 to 0.86), and preoperative unaffected and postoperative affected globe projections was high (ICC, 0.87; 95% CI, 0.69 to 0.94). There was a significant difference in pre- and postoperative mean orbital volume (30.6 vs 25.5 cm(3), P <= 0.001), and pre- and postoperative globe projection (51.2 vs 53.6 mm, P <= 0.001). CONCLUSIONS: The results of this study suggest that intraoperative navigation-assisted orbital reconstruction is reliable in restoring orbital volume and globe projection to pretraumatic and preablative conditions. [ABSTRACT FROM AUTHOR]

Preclinical murine data indicate that fragment crystallizable (Fc)-dependent depletion of intratumoral regulatory T cells (Treg) is a major mechanism of action of anti-CTLA-4. However, the two main antibodies administered to patients (ipilimumab and tremelimumab) do not recapitulate these effects. Here, we investigate the underlying mechanisms responsible for the limited Treg depletion observed with these therapies. Using an immunocompetent murine model humanized for CTLA-4 and Fcγ receptors (FcγR), we show that ipilimumab and tremelimumab exhibit limited Treg depletion in tumors. Immune profiling of the tumor microenvironment (TME) in both humanized mice and humans revealed high expression of the inhibitory Fc receptor, FcγRIIB, which limits antibody-dependent cellular cytotoxicity/phagocytosis. Blocking FcγRIIB in humanized mice rescued the Treg-depleting capacity and antitumor activity of ipilimumab. Furthermore, Fc engineering of antibodies targeting Treg-associated targets (CTLA-4 or CCR8) to minimize FcγRIIB binding significantly enhanced Treg depletion, resulting in increased antitumor activity across various tumor models. Our results define the inhibitory FcγRIIB as an immune checkpoint limiting antibody-mediated Treg depletion in the TME, and demonstrate Fc engineering as an effective strategy to overcome this limitation and improve the efficacy of Treg-targeting antibodies., (©2023 The Authors; Published by the American Association for Cancer Research.)

Background: Although orbital fractures are common, prediction of outcomes in orbital surgery can be quite challenging., Purpose: We aim to identify predictors of intraoperative difficulty, operating time, and postoperative examination abnormalities in subjects undergoing post-traumatic orbital reconstructions., Study Design, Setting, and Sample: This is a retrospective cohort study of all consecutive orbital operations performed at a private, Level 1 trauma center in Portland, Oregon, USA over an 82-month period. All subjects that underwent exploration of the internal orbit for traumatic indications during the study period were included in the cohort., Predictor Variables: Four plating styles, surgical approach (transorbital vs transantral), days from injury to first surgery, fracture size (approximated as a rectangle using linear measurements from computed tomography scans), anteroposterior fracture position, and medial wall involvement were examined., Outcome Variables: The primary outcome variable was intraoperative difficulty (defined as requiring revision after intraoperative imaging or return to the operating room). Secondary outcome variables included operating time and postoperative examination abnormalities., Covariates: Age and sex were included., Analyses: χ 2 and Regression analyses were performed using a significance level of P < .05., Results: One hundred and sixty four orbital operations were performed (90 isolated injuries and 74 combined orbital/midface injuries) on 155 subjects (73% male, mean age 39.8 years, standard deviation 16.7). In subjects with isolated orbital fractures, medial wall involvement was associated with intraoperative difficulty (P = .01). When using a transantral approach, intraoperative difficulty was more likely in more anterior fractures (P = .02). Plating style was associated with operating time (P = .03), with median times from 81 to 105 minutes (range 21 to 248 minutes). Postoperative examination abnormalities were more likely in the transorbital approach group (P = .01). Neither days to first surgery nor intraoperative difficulty were associated with postoperative examination abnormalities. Postoperative eyelid changes were seen in 13.6% of transorbital approaches and 0% of transantral approaches. Correction of gaze restriction and enophthalmos were more likely than correction of diplopia (P < .01)., Conclusions and Relevance: Medial wall involvement is associated with intraoperative difficulty in orbital surgery. Anteriorly positioned fractures are better treated transorbitally, while posterior fractures may be amenable to transantral repair, thus avoiding risk of lower eyelid changes., (Copyright © 2023 American Association of Oral and Maxillofacial Surgeons. Published by Elsevier Inc. All rights reserved.)

Despite pre-clinical murine data supporting T regulatory (Treg) cell depletion as a major mechanism by which anti-CTLA-4 antibodies function in vivo, the two main antibodies tested in patients (ipilimumab and tremelimumab) have failed to demonstrate similar effects. We report analogous findings in an immunocompetent murine model humanized for CTLA-4 and Fcy receptors (hCTLA-4/hFcyR mice), where both ipilimumab and tremelimumab fail to show appreciable Treg depletion. Immune profiling of the tumor microenvironment (TME) in both mice and human samples revealed upregulation of the inhibitory Fcy receptor, FcyRIIB, which limits the ability of the antibody Fc fragment of human anti-CTLA-4 antibodies to induce effective antibody dependent cellular cytotoxicty/phagocytosis (ADCC/ADCP). Blocking FcyRIIB in humanized mice rescues Treg depleting capacity and anti-tumor activity of ipilimumab. For another target, CC motif chemokine receptor 8 (CCR8), which is selectively expressed on tumor infiltrating Tregs, we show that Fc engineering to enhance binding to activating Fc receptors, while limiting binding to the inhibitory Fc receptor, leads to consistent Treg depletion and single-agent activity across multiple tumor models, including B16, MC38 and MB49. These data reveal the importance of reducing engagement to the inhibitory Fc receptor to optimize Treg depletion by TME targeting antibodies. Our results define the inhibitory FcyRIIB receptor as a novel immune checkpoint limiting antibody-mediated Treg depletion in tumors, and demonstrate Fc variant engineering as a means to overcome this limitation and augment efficacy for a repertoire of antibodies currently in use or under clinical evaluation in oncology., Competing Interests: COI: The authors declare no financial conflicts of interests relevant to this work.

PD-L1 testing guides therapeutic decision-making for head and neck squamous cell carcinoma (HNSCC). We sought to understand whether chemoradiation therapy (CRT) influences the PD-L1 combined positive score (CPS) and other biomarkers of response to immunotherapy. PD-L1 expression was assessed using immunohistochemistry, and bulk RNA sequencing was performed on 146 HNSCC patients (65 primary sites, 50 paired local recurrences, and 31 paired regional recurrences). PD-L1 was scored using the CPS of ≥1, ≥20, and ≥50. Overall, 98 %, 54 %, and 17 % of HNSCCs had a CPS ≥1, ≥20, and ≥50, respectively. When using a cut-off of ≥1, CRT did not significantly change CPS at the locoregional recurrent site. However, there were significant changes when using CPS ≥20 or ≥50. The CPS changed for 32 % of patients when using a CPS ≥20 (p < 0.001). When using a CPS ≥50, there was a 20-23 % (p = 0.0058-0.00067) discordance rate at the site of locoregional recurrence. Oral cavity cancers had a significantly higher discordant rate than other primary sites for CPS ≥50, 44 % (8/18, p = 0.0058) and 58 % (7/12, p = 0.00067) discordance at the site of local and regional recurrence, respectively. When evaluating the 18 gene IFN-ɣ signature predictive of response to anti-PD-1 blockade, there was a statistically significant increase in the IFN-ɣ signature in recurrent larynx cancer (p = 0.02). Our study demonstrates that when using a higher cut-off of CPS ≥20 and ≥50, a repeat biopsy may be warranted after CRT for local and regional recurrent HNSCCs., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: S.I.P. has received consultancy payments from Abbvie, Astrazeneca/MedImmune, Cue Biopharma, Fusion Pharmaceuticals, MSD/Merck, Newlink Genetics, Oncolys Biopharma, Replimmune, Scopus Biopharma, and Sensei Bio. S.I.P. has received grants/research support from Abbvie, Astrazeneca/MedImmune, Cue Biopharma, Merck, and Tesaro. R.B.B. has received consultancy payments from Merck, Regeneron, Macrogenics, and Bristol Myers Squibb. R.B.B. has received institutional research grants from Bristol Myers Squibb. All other authors declare no potential conflicts of interest., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Patients with HPV-unrelated head and neck squamous cell carcinoma (HPV-unrelated HNSCC) show only modest benefit from treatment with PD-1 inhibitors (PD-1i). Targeting transforming growth factor β (TGF-β) may make PD-1i more effective by inducing T cell responses. In this issue of the JCI, Redman et al. performed a clinical trial in 14 patients with HPV-unrelated HNSCC using bintrafusp alfa, a bifunctional fusion protein that blocks PD-L1 and TGF-β. Primary tumors displayed pathologic responses with 5 of 14 patients having at least a partial response. While no primary tumor or metastatic lymph node demonstrated a complete pathologic response, the findings suggest that concurrent neoadjuvant inhibition of PD-L1 and TGF-β may provide a rational strategy to improve pathologic response and clinical outcome in patients with HPV-unrelated HNSCC.

Objective: Provide a narrative review of the literature describing immunological concepts and novel approaches in the treatment of head and neck squamous cell carcinoma., Background: In 2016, two anti-PD1 antibodies, nivolumab and pembrolizumab, were shown to improve overall survival in patients with recurrent/metastatic HNSCC and were approved by the US Food and Drug Administration (FDA) for use in the second line, cisplatin-resistant setting, although the overall response rates were only about 15%. More recently, pembrolizumab was approved for use in the first-line R/M setting as monotherapy in patients with CPS >1 or in combination with chemotherapy regardless of PD-L1 expression. Interestingly, while response rates with combination therapy were increased compared to pembrolizumab alone, the duration of response was shorter than might be expected. Based on a growing amount of evidence in other types of cancer treated with various combinations of immunotherapy, similar concepts are being studied in HNSCC, both in pre-clinical models and in clinical trials., Methods: A review of the literature was conducted using the Medline-PubMed and ClinicalTrials.gov databases. Main topics were selected for review, including basic immunology background, checkpoint inhibition, neoadjuvant immunotherapy, the combination of immunotherapy with radiation therapy and chemotherapy, intratumoral immunotherapy, and future prospects., Conclusions: There is an ongoing effort, which is supported by an increasing body of evidence, to enhance response rates with combinations of immunotherapy with other immunotherapy agents, targeted small molecules, chemotherapy, radiation therapy, and surgery. The clinician and the scientist should be familiarized with basic immunologic concepts, key findings in recent clinical trials, and current indications for administering immunotherapy.

Primate hair and skin are substrates upon which social interactions occur and are host-pathogen interfaces. While human hair and skin microbiomes display body site specificity and immunological significance, little is known about the nonhuman primate (NHP) hair microbiome. Here, we collected hair samples ( n  = 158) from 8 body sites across 12 NHP species housed at three zoological institutions in the United States to examine the following: (1) the diversity and composition of the primate hair microbiome and (2) the factors predicting primate hair microbiome diversity and composition. If both environmental and evolutionary factors shape the microbiome, then we expect significant differences in microbiome diversity across host body sites, sexes, institutions, and species. We found our samples contained high abundances of gut-, respiratory-, and environment-associated microbiota. In addition, multiple factors predicted microbiome diversity and composition, although host species identity outweighed sex, body site, and institution as the strongest predictor. Our results suggest that hair microbial communities are affected by both evolutionary and environmental factors and are relatively similar across nonhuman primate body sites, which differs from the human condition. These findings have important implications for understanding the biology and conservation of wild and captive primates and the uniqueness of the human microbiome. IMPORTANCE We created the most comprehensive primate hair and skin data set to date, including data from 12 nonhuman primate species sampled from 8 body regions each. We find that the nonhuman primate hair microbiome is distinct from the human hair and skin microbiomes in that it is relatively uniform-as opposed to distinct-across body regions and is most abundant in gut-, environment-, and respiratory-associated microbiota rather than human skin-associated microbiota. Furthermore, we found that the nonhuman primate hair microbiome varies with host species identity, host sex, host environment, and host body site, with host species identity being the strongest predictor. This result demonstrates that nonhuman primate hair microbiome diversity varies with both evolutionary and environmental factors and within and across primate species. These findings have important implications for understanding the biology and conservation of wild and captive primates and the uniqueness of the human microbiome.

Melanoma is the most common cause of skin cancer-related death in the United States. Cutaneous melanoma is most prevalent in the head and neck. The long-term prognosis has been poor and chemotherapy is not curative. Complete surgical resection with locally advanced disease can be challenging and melanoma is resistant to radiation. Advances made in immunotherapy and genomically targeted therapy have transformed the treatment of metastatic melanoma; as of 2021, the 5-year survival for metastatic melanoma is greater than 50%. Ongoing clinical studies are underway to integrate these life-saving therapies into the presurgical or postsurgical settings. This article reviews that effort., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: The coronavirus disease 2019 (COVID-19) pandemic has impacted health care delivery worldwide. Cancer is a leading cause of death, and the impact of the pandemic on cancer diagnoses is an important public health concern., Methods: This cross-sectional study retrospectively analyzed the electronic medical records of 80,138 cancer patients diagnosed between January 1, 2019, and May 31, 2021. Outcome measures included weekly number of new cancer cases and trends in weekly cancer cases, before and after the pandemic; patient demographics; and positive COVID-19 test rates., Results: Beginning March 4, 2020, defined as the onset of the pandemic, weekly cancer cases declined precipitously (-110.0 cases per week [95% confidence interval, -190.2 to -29.8]) for 4 weeks, followed by a moderate recovery (+23.7 cases per week [9.1 to 38.4]) of 10 weeks duration. Thereafter, weekly cancer cases trended slowly back toward pre-COVID-19 baseline levels. Following the pandemic onset, there was a cumulative year-over-year decline in cancer cases overall of 7.3%, including a 20.2%, 14.3%, and 12.8% decline in nonmelanoma skin cancer, breast cancer, and prostate cancer, respectively. Changes in case volumes were accompanied by variations in patient characteristics, including region, age, gender, race, insurance coverage, and COVID-19 positive test rates (P < .01 for all). Among patients tested for COVID-19, 5.3% had a positive result., Conclusions: The data in this study demonstrate a substantial reduction in cancer diagnoses following the onset of COVID-19, which appear to reach expected pre-COVID norms 12 months later. The largest reduction was noted among cancers that are typically screen-detected or identified as part of a routine wellness examination., (© 2021 American Cancer Society.)

Purpose: In computer surgical planned (CSP) fibular reconstructions of the mandible, custom plates facilitate accurate and efficient transfer of the digital plan intraoperatively by a way of predrilled fixation holes. Stock plates are more easily accessible and are more economical but typically preclude the utilization of these predictive holes. The purpose of this article is to describe an accurate and economical alternative to custom plates, while still having the ability to create predictive holes for plate alignment and execution of a digital surgical plan., Methods: An in vitro accuracy study was performed on a point-of-care resin-printed predictive hole guide termed "prebent plate analog" (PPA). Twenty stock 2.0 reconstruction plates prebent against a 3-dimensional printed mandibular model reconstructed with a 2-piece fibula were used to fabricate 20 PPAs. The proximal and distal 4 holes of each prebent plate and corresponding PPA were assessed using a heat map overlay, measuring difference in millimeters between matching points of the predictive hole segments. The median distance from the points of reference in the PPA versus the prebent plate was calculated for each predictive hole position in addition to the average error of the PPA to the stock plate., Results: Eighteen PPAs were used for statistical analysis; 2 were damaged in transport. The mean error between the body (-0.265) and condylar segments (-0.116 mm) and mean difference in error between the proximal predictive holes (-0.124 mm) and distal predictive holes (-0.215 mm) on the PPA were not statistically different (P = .061, P = .314 general estimating equation regression, respectively). The mean error across the PPA predictive holes and corresponding holes of the prebent plates was -0.194 mm (P < .001, general estimating equation regression)., Conclusions: The PPA is a precise and accurate analog that faithfully replicates the position of proximal and distal components of a prebent stock plate, thereby allowing for predictive hole placement in lieu of a custom plate in fibula mandibular reconstruction cases., (Copyright © 2021 American Association of Oral and Maxillofacial Surgeons. Published by Elsevier Inc. All rights reserved.)

Purpose: Definitive or postoperative chemoradiation (CRT) is curative for human papillomavirus-associated (HPV+) oropharynx cancer (OPC) but induces significant toxicity. As a deintensification strategy, we studied primary transoral surgery (TOS) and reduced postoperative radiation therapy (RT) in intermediate-risk HPV+ OPC., Methods: E3311 is a phase II randomized trial of reduced- or standard-dose postoperative RT for resected stage III-IVa (American Joint Committee on Cancer-seventh edition) HPV+ OPC, determined by pathologic parameters. Primary goals were feasibility of prospective multi-institutional study of TOS for HPV+ OPC, and oncologic efficacy (2-year progression-free survival) of TOS and adjuvant therapy in intermediate-risk patients after resection. TOS plus 50 Gy was considered promising if the lower limit of the exact 90% binomial confidence intervals exceeded 85%. Quality of life and swallowing were measured by functional assessment of cancer therapy-head and neck and MD Anderson Dysphagia Index., Results: Credentialed surgeons performed TOS for 495 patients. Eligible and treated patients were assigned as follows: arm A (low risk, n = 38) enrolled 11%, intermediate risk arms B (50 Gy, n = 100) or C (60 Gy, n = 108) randomly allocated 58%, and arm D (high risk, n = 113) enrolled 31%. With a median 35.2-month follow-up for 359 evaluable (eligible and treated) patients, 2-year progression-free survival Kaplan-Meier estimate is 96.9% (90% CI, 91.9 to 100) for arm A (observation), 94.9% (90% CI, 91.3 to 98.6]) for arm B (50 Gy), 96.0% (90% CI, 92.8 to 99.3) for arm C (60 Gy), and 90.7% (90% CI, 86.2 to 95.4) for arm D (66 Gy plus weekly cisplatin). Treatment arm distribution and oncologic outcome for ineligible or step 2 untreated patients (n = 136) mirrored the 359 evaluable patients. Exploratory comparison of functional assessment of cancer therapy-head and neck total scores between arms B and C is presented., Conclusion: Primary TOS and reduced postoperative RT result in outstanding oncologic outcome and favorable functional outcomes in intermediate-risk HPV+ OPC., Competing Interests: Robert L. FerrisThis author is a member of the Journal of Clinical Oncology Editorial Board. Journal policy recused the author from having any role in the peer review of this manuscript.Stock and Other Ownership Interests: NovasentaConsulting or Advisory Role: Merck, Pfizer, EMD Serono, Numab, Macrogenics, Aduro Biotech, Novasenta, Sanofi, Zymeworks, Bristol Myers SquibbResearch Funding: Bristol Myers Squibb, AstraZeneca/MedImmune, Merck, Tesaro, Novasenta Gregory S. WeinsteinPatents, Royalties, Other Intellectual Property: Olympus Shuli LiEmployment: TakedaStock and Other Ownership Interests: Takeda Harry QuonEmployment: Johns Hopkins HospitalLeadership: Pistevo HealthStock and Other Ownership Interests: Oncospace, Pistevo HealthHonoraria: Sanofi/RegeneronConsulting or Advisory Role: Pinnacle Biologics, Tactile MedicalResearch Funding: Toshiba, Vibrent HealthPatents, Royalties, Other Intellectual Property: Filed under Hopkins, we have several patents related to mobile informatics solutionsOther Relationship: EPIC Ranee MehraStock and Other Ownership Interests: GlaxoSmithKline (I)Consulting or Advisory Role: Bayer, Rakuten MedicalResearch Funding: AstraZeneca, Merck Christine H. ChungConsulting or Advisory Role: Bristol Myers Squibb, CUE Biopharma, Mirati Therapeutics, Sanofi/Regeneron, ExelixisResearch Funding: AstraZeneca, Bristol Myers Squibb, Lilly, Merck, Regeneron, Ignyta, Pfizer, Brooklyn ImmunoTherapeutics, Iovance BiotherapeuticsTravel, Accommodations, Expenses: AstraZeneca, Mirati Therapeutics Maura L. GillisonConsulting or Advisory Role: Bristol Myers Squibb, Merck, EMD Serono, Kura Oncology, BioNTech, Shattuck Labs, Bayer, Debiopharm Group¸ Ipsen, Gilead Sciences¸ Bicara Therapeutics, Nektar¸ Istari, LLX Solutions, OncLive, Seagen, Kura Oncology, Mirati Therapeutics, Sensei BiotherapeuticsResearch Funding: Bristol Myers Squibb, Genocea Biosciences, Cullinan Oncology, Genentech, Agenus, Kura Oncology Umamaheswar DuvvuriConsulting or Advisory Role: ACTIVARTIS BiotechResearch Funding: Kolltan Pharmaceuticals, Medrobotics Bert W. O'Malley JrPatents, Royalties, Other Intellectual Property: Receive royalties from University of Pennsylvania via a licensed technology to Olympus Inc Neil D. GrossHonoraria: Intuitive SurgicalConsulting or Advisory Role: PDS Biotechnology, Verb Surgical, Sanofi/Regeneron, Shattuck LabsResearch Funding: Regeneron, MedImmune, GenentechPatents, Royalties, Other Intellectual Property: UpToDate R. Bryan BellHonoraria: Merck, RegeneronConsulting or Advisory Role: MacrogenicsSpeakers' Bureau: Merck, RegeneronResearch Funding: Bristol Myers Squibb/Celgene Nabil F. SabaHonoraria: Merck, CUE Biopharma, BioNTech AG, GlaxoSmithKlineResearch Funding: Bristol-Myers Squibb, ExelixisTravel, Accommodations, Expenses: Merck, Pfizer, Blueprint Medicines Barbara BurtnessConsulting or Advisory Role: Merck, Debiopharm Group, CUE Biopharma, Maverick Therapeutics, Rakuten Medical, Nanobiotix, Macrogenics, ALX Oncology, IO Biotech, Ipsen, Genentech/Roche, Kura Oncology, Merck KGaA, PPD Global, ExelixisResearch Funding: Merck (Inst), Aduro Biotech (Inst), Formation Biologics (Inst), Bristol Myers (Inst), CUE Biopharma (Inst)Travel, Accommodations, Expenses: Merck, Debiopharm GroupNo other potential conflicts of interest were reported.

This article includes updates in the management of mandibular trauma and reconstruction as they relate to maxillomandibular fixation screws, custom hardware, virtual surgical planning, and protocols for use of computer-aided surgery and navigation when managing composite defects from gunshot injuries to the face., (Copyright © 2021 Elsevier Inc. All rights reserved.)

The Italian Network for Tumor Biotherapy (Network Italiano per la Bioterapia dei Tumori [NIBIT]) Foundation hosted its annual 2020 Think Tank meeting virtually, at which representatives from academic, clinical, industry, philanthropic, and regulatory organisations discussed the role of neoadjuvant immunotherapy for the treatment of cancer. Although the number of neoadjuvant immunotherapeutic trials is increasing across all malignancies, the Think Tank focused its discussion on the status of neoadjuvant trials in cutaneous melanoma (CM), muscle-invasive urothelial bladder cancer (MIBC), head and neck squamous cell carcinoma (HNSCC), and pancreatic adenocarcinoma (PDAC). Neoadjuvant developments in CM are nothing short of trailblazing. Pathologic Complete Response (pCR), pathologic near Complete Response, and partial Pathologic Responses reduce 90-100% of recurrences. This is in sharp contrast to targeted therapies in neoadjuvant CM trials, where only a pCR seems to reduce recurrence. The pCR rate after neoadjuvant immunotherapy varies among the different malignancies of CM, MIBC, HNSCC, and PDAC and may be associated with different reductions of recurrence rates. In CM, emerging evidence suggests that neoadjuvant immunotherapy with anti-CTLA-4 plus anti-PD1 is a game changer in patients with palpable nodal Stage III or resectable Stage IV disease by curing more patients, reducing recurrences and the need for surgical interventions, such as lymph node dissections and metastasectomies. The Think Tank panel discussed future approaches on how to optimise results across different tumour types. Future approaches should include reducing monocyte-mediated (tumour-associated macrophages) and fibroblast-mediated (cancer-associated fibroblasts) barriers in the tumour microenvironment to facilitate the recruitment of immune cells to the tumour site, to reduce immune-suppressive mediators, and to increase antigen presentation at the site of the tumour., Competing Interests: Conflicts of interest statement M.M. was a consultant/advisory board member for Bristol Myers Squibb, Roche, Astra Zeneca, Merck Sharp Dohme, Philogen, Merck Serono, Glaxo Smith Kline, Sanofi, Pierre Fabre, Eli-Lilly, Amgen, Cosmos, Alfasigma, and owns shares of Epigen Therapeutics. C.B. received commercial research grants from Novartis, Bristol-Myers Squibb, and NanoString; is a paid advisory board member for Bristol-Myers Squibb, MSD, Roche, Novartis, GlaxoSmithKline, AstraZeneca, Pfizer, Lilly, GenMab, and Pierre Fabre; and holds ownership interest in Uniti Cars, Neon Therapeutics, and Forty Seven. A.N. received honoraria Roche, Merck, AstraZeneca, and Janssen Pharmaceuticals. A.M.D.G. was a consultant and/or advisor to Incyte, Pierre Fabre, Bristol Myers Squibb, Merck Sharp Dohme, and Sanofi and has received compensated educational activities from Bristol Myers Squibb, Merck Sharp Dohme, Pierre Fabre, and Sanofi. R.I. was a CMO at bitbio, BoD of bluebird and Surface oncology, and SAB member of Harpoon. M.L. was employed by iOnctura SA as Chief Medical Officer. B.F. received consulting fees from Turnstone Bio, PrimeVax, UltiVue, AstraZeneca, and Boehringer Ingelheim; conducted contracted research at Macrogenics, OncoSec, BMS, Akoya, NanoString, Incyte, Shimadzu, and Viralytics/Merck; was cofounder of and holds ownership interest in UbiVac. R.B.B. has received research funds from Bristol-Myers Squibb and is on the speakers bureau for Merck and Regeneron. He is an advisory board member for Macrogenics. G.T. was a consultant/advisory board member for Bristol Myers Squibb, Astra Zeneca, Merck Sharp Dohme, and Merck Serono. A.M.M.E. is/has been consultant/advisory board member for Biocad, BioInvent, BioNTech, BMS, CatalYm, Ellipses, GSK, ISA pharmaceuticals, Ellipses, GSK, IO Biotech, ISA pharmaceuticals, Merck&Co/MSD, Nektar, Novartis, Pfizer, Roche, Sellas, SkylineDx, RiverD, TigaTx, and TTxDiscovery., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Surgical resection of head and neck squamous-cell carcinoma (HNSCC) is associated with high rates of local and distant recurrence, partially mitigated by adjuvant therapy. A pre-existing immune response in the patient's tumor is associated with better outcomes following treatment with conventional therapies, but improved options are needed for patients with poor anti-tumor immunity. We hypothesized that local delivery of tumor antigen-specific T-cells into the resection cavity following surgery would direct T-cells to residual antigens in the margins and draining lymphatics and present a platform for T-cell-targeted immunotherapy. We loaded T-cells into a biomaterial that conformed to the resection cavity and demonstrated that it could release T-cells that retained their functional activity in-vitro , and in a HNSCC model in-vivo . Locally delivered T-cells loaded in a biomaterial were equivalent in control of established tumors to intravenous adoptive T-cell transfer, and resulted in the systemic circulation of tumor antigen-specific T-cells as well as local accumulation in the tumor. We demonstrate that adjuvant therapy with anti-PD1 following surgical resection was ineffective unless combined with local delivery of T-cells. These data demonstrate that local delivery of tumor-specific T-cells is an efficient option to convert tumors that are unresponsive to checkpoint inhibitors to permit tumor cures., Competing Interests: CONFLICTS OF INTEREST MJG and MRC receive research funding from Bristol Myers-Squibb, Jounce, and Mavupharma that is unrelated to the content of this manuscript. The remaining authors declare no competing interests. Funders had no input in the content of the manuscript., (Copyright: © 2021 Sharon et al.)

Background: Checkpoint inhibitors targeting programmed death receptor-1 (PD-1) have been tested in the neoadjuvant setting for the treatment of locoregionally advanced head and neck squamous cell carcinoma (HNSCC); however, response rates are modest. We hypothesized that adding stereotactic body radiation therapy (SBRT) to anti-PD-1 would be safe prior to definitive surgical resection and would enhance pathological response compared with historical cohorts of patients with locoregionally advanced HNSCC treated with checkpoint inhibitor alone., Methods: The Neoadjuvant Immuno-Radiotherapy Trial was an investigator-initiated single institution phase Ib clinical trial that enrolled patients with previously untreated locally advanced HPV-positive and HPV-negative HNSCC between 2018 and 2019. Eligible patients were treated with neoadjuvant SBRT at a total dose of either 40 Gy in 5 fractions or 24 Gy in 3 fractions, delivered in a 1-week timespan, with or without nivolumab, prior to definitive surgical resection. Patients were then planned for treatment with adjuvant nivolumab for 3 months. The primary safety endpoint was unplanned delay in surgery considered to be at least possibly related to neoadjuvant treatment. The primary efficacy endpoints included pathological complete response (pCR), major pathological response (mPR), and the rate of clinical to pathological downstaging after neoadjuvant treatment., Results: Twenty-one patients underwent neoadjuvant treatment, which was well tolerated and did not delay surgery, thus meeting the primary endpoint. Tissue responses were characterized by robust inflammatory infiltrates in the regression bed, plasma cells and cholesterol clefts. Among the entire study group, the mPR and pCR rate was 86% and 67%, respectively. Clinical to pathological downstaging occurred in 90% of the patients treated., Conclusion: These data demonstrate that radiation delivered only to the gross tumor volume combined with immunotherapy was safe, resulted in a high rate of mPR and should be further evaluated as a locally focused neoadjuvant therapy for patients with head and neck cancer., Trial Registration Number: This study is registered with clinicaltrials.gov (NCT03247712) and is active, but closed to patient accrual., Competing Interests: Competing interests: The Earle A. Chiles Research Institute receives research funding from Bristol-Myers Squibb, none of which was used in the conduct of this trial; and AstraZeneca. RSL reports grants from Bristol Myers Squibb, personal fees from Merck, personal fees from Sanofi, personal fees from Regeneron, personal fees from Oncolys, outside the submitted work; MRC reports research grants from Jounce Therapeutics, grants from Nanobiotix, outside the submitted work. KHY reports non-financial support and material support for clinical trial from Eli Lilly; sponsored project agreement and institutional grant support from Bristol-Myers Squibb; and other support from AstraZeneca, outside the submitted work; CBB reports a consultant/advisory relationship with PrimeVax and Bristol-Myers Squibb; stock ownership and scientific board membership in PrimeVax and BioAI; and holds a patent on image processing systems and methods for displaying multiple images of a biological specimen that was outside the submitted work; WJU reports grants from Bristol-Myers Squibb, grants and other institutional support from Galectin Therapeutics, grants and other institutional support from Astra Zeneca, grants and other institutional support from Prometheus, grants and other institutional support from Merck, outside the submitted work; MJG reports grants from Bristol Myers Squibb, grants from Mavupharma, outside the submitted work; RBB reports grants and personal fees from Bristol Myers Squibb, grants and personal fees from Merck, personal fees from Regeneron, outside the submitted work. All other authors declare no competing interests., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Competing Interests: Disclosure The authors have nothing to disclose.

Despite the success of checkpoint blockade in some cancer patients, there is an unmet need to improve outcomes. Targeting alternative pathways, such as costimulatory molecules (e.g. OX40, GITR, and 4-1BB), can enhance T cell immunity in tumor-bearing hosts. Here we describe the results from a phase Ib clinical trial (NCT02274155) in which 17 patients with locally advanced head and neck squamous cell carcinoma (HNSCC) received a murine anti-human OX40 agonist antibody (MEDI6469) prior to definitive surgical resection. The primary endpoint was to determine safety and feasibility of the anti-OX40 neoadjuvant treatment. The secondary objective was to assess the effect of anti-OX40 on lymphocyte subsets in the tumor and blood. Neoadjuvant anti-OX40 was well tolerated and did not delay surgery, thus meeting the primary endpoint. Peripheral blood phenotyping data show increases in CD4+ and CD8+ T cell proliferation two weeks after anti-OX40 administration. Comparison of tumor biopsies before and after treatment reveals an increase of activated, conventional CD4+ tumor-infiltrating lymphocytes (TIL) in most patients and higher clonality by TCRβ sequencing. Analyses of CD8+ TIL show increases in tumor-antigen reactive, proliferating CD103+ CD39+ cells in 25% of patients with evaluable tumor tissue (N = 4/16), all of whom remain disease-free. These data provide evidence that anti-OX40 prior to surgery is safe and can increase activation and proliferation of CD4+ and CD8+ T cells in blood and tumor. Our work suggests that increases in the tumor-reactive CD103+ CD39+ CD8+ TIL could serve as a potential biomarker of anti-OX40 clinical activity.

Purpose: Utilization of technology to aid in the assessment, planning, and management of complex craniomaxillofacial injuries is increasingly common. Limited data exist regarding the implication of intraoperative CT/3-Dimensional imaging on decision making in the management of zygomaticomaxillary complex (ZMC) fractures. This study characterizes the utilization of the intraoperative CT scanner for ZMC fracture surgery and analyzes the impact of the intraoperative CT scanner on fracture management. Using these findings, we sought to propose an algorithm to guide the appropriate utilization of intraoperative 3-Dimensional imaging in ZMC fracture surgery., Methods: This retrospective case series evaluates the use of the intraoperative CT scanner for orbitozygomatic trauma surgery at a level 1 trauma center from February 2011 to September 2016. We evaluated the preoperative CT images assessing for the number of displaced sutures, the presence of adjacent fractures requiring fixation, the presence of comminution of the zygomaticomaxillary buttress or body of the zygoma, as well as the number of axes displaced ≥ 5 mm. This information was evaluated to provide guidance on the appropriate utilization of the intraoperative scanner in ZMC fracture management., Results: A total of 71 patients were identified to have intraoperative facial CT scans and surgery for ZMC fractures over the study time period. There was a 23.9% (17/71) CT directed revision rate. There was a significantly increased likelihood of CT directed revision for fractures with adjacent fractures requiring fixation, and those with ≥ 2 axes displaced ≥ 5 mm. Using these findings, we proposed the ZYGOMAS algorithm outlining the indications for use of intraoperative CT in management of ZMC fractures., Conclusions: If available, intraoperative CT/3-Dimensional imaging should be utilized in the management of ZMC fractures with the requirement for orbital floor reconstruction, where adjacent fractures require fixation and/or when ≥ 2 axes are displaced ≥ 5 mm., (Copyright © 2020 American Association of Oral and Maxillofacial Surgeons. Published by Elsevier Inc. All rights reserved.)

Purpose: Understanding the role of transoral surgery in oropharyngeal cancer (OPC) requires prospective, randomized multi-institutional data. Meticulous evaluation of surgeon expertise and surgical quality assurance (QA) will be critical to the validity of such trials. We describe a novel surgeon credentialing and QA process developed to support the ECOG-ACRIN Cancer Research Group E3311 (E3311) and report outcomes related to QA., Patients and Methods: E3311 was a phase II randomized clinical trial of transoral surgery followed by low- or standard-dose, risk-adjusted post-operative therapy with stage III-IVa (AJCC 7th edition) HPV-associated OPC. In order to be credentialed to accrue to this trial, surgeons were required to demonstrate active hospital credentials and technique-specific surgical expertise with ≥20 cases of transoral resection for OPC. In addition, 10 paired operative and surgical pathology reports from the preceding 24 months were reviewed by an expert panel. Ongoing QA required <10% rate of positive margins, low oropharyngeal bleeding rates, and accrual of at least one patient per 12 months. Otherwise surgeons were placed on hold and not permitted to accrue until re-credentialed using a new series of transoral resections., Results: 120 surgeons trained in transoral minimally invasive surgery applied for credentialing for E3311 and after peer-review, 87 (73%) were approved from 59 centers. During QA on E3311, positive final pathologic margins were reported in 19 (3.8%) patients. Grade III/IV and grade V oropharyngeal bleeding was reported in 29 (5.9%) and 1 (0.2%) of patients., Conclusions: We provide proof of concept that a comprehensive credentialing process can support multicenter transoral head and neck surgical oncology trials, with low incidence of positive margins and *grade III/V oropharyngeal bleeding., 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 © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Competing Interests: Disclosure The authors have nothing to disclose.

Background: In this study we determine the survival in patients with HPV-positive oropharyngeal carcinoma treated with transoral robotic surgery (TORS), neck dissection and risk-adapted adjuvant therapy., Methods: We retrospectively identified 122 patients with HPV-positive oropharyngeal carcinoma treated with TORS and neck dissection between 2011 and 2018. Survival probability was calculated. We determined the effect of the type of neck dissection performed (modified radical neck dissection-MRND vs. selective neck dissection - SND), extranodal extension (ENE), margin status, and presence of ≥ 5 metastatic nodes on survival., Results: Our patient population had a five-year overall survival of 91.0% (95% C.I. 85-97%). The five-year probability of recurrence or cancer-associated death was 0.0977 (95% C.I. 0.0927-0.1027). The five-year probability of cancer-associated death was 0.0528 (95% C.I. 0.048-0.0570). All patients who died of their disease had distant metastasis. Our PEG dependence rate was 0%. Patients with ENE and positive margins who underwent adjuvant chemoradiation did not have worse survival. Presence of ≥ 5 metastatic nodes portended worse survival after controlling for age, positive ENE and margins. Low yield (<18 nodes) on neck dissection worsened DFS on multivariable analysis. Furthermore, patients who underwent SND did not have worse OS than those who underwent MRND., Conclusion: Our study demonstrates that surgery could be simplified by performing TORS with SND rather than MRND. The one true poor prognostic factor in HPV-positive oropharyngeal carcinoma patients who undergo surgery is high nodal burden. Patients with high nodal burden are much more likely to die from their disease., 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 © 2020 Elsevier Ltd. All rights reserved.)

Background: Obesity is a known factor for the development of abnormal respiratory physiology. However, several studies have found that obesity does not hinder functional recovery in patients hospitalized for postacute care following a stroke or cardiovascular event. This study was designed to determine the effect of overweight and obesity on patients with acute pulmonary disease, hospitalized in an inpatient rehabilitation facility (IRF)., Objective: To investigate the impact of body mass index (BMI) on indices of function, specifically, the functional independence measure (FIM) among patients with pulmonary related debility admitted to a rehabilitation hospital., Design: Retrospective cohort study., Setting: Pulmonary unit in an acute freestanding rehabilitation hospital., Patients: All patients admitted to an IRF with a diagnosis of pulmonary related debility over a 6-year period., Methods: The data used in the study included the patient height and weight (measured on admission) and FIM (scored on admission and discharge)., Main Outcome Measures: The primary study outcome measure was the change in FIM per day by the patients' BMI category., Results: For the 381 patients admitted during the observation period, BMI was compared with FIM score changes per day (FIM efficiency). After adjusting for age and sex, the FIM efficiency only slightly differed by BMI, failing to reach statistical significance. However, age did significantly influence the outcome (P = .05)., Conclusion: This study demonstrates that among a large group of patients with a pulmonary related debility, there was no statistically significant correlation between BMI and FIM efficiency. The overweight patients were similar in progression to those who were underweight, normal weight, and obese. However, this study found that increased age adversely affected the outcome of rehabilitation., Level of Evidence: III., (© 2019 American Academy of Physical Medicine and Rehabilitation.)

Purpose: Complex orbital fractures can be surgically challenging because the orbital cavity contains several vital anatomic structures and visibility is limited. We present a case in which computer-aided surgical simulation (CASS), surgical navigation (SN), and a patient-specific implant (PSI) were used. Furthermore, the reported data regarding this topic were systematically searched and investigated., Patients and Methods: A patient with a complex, failed orbital reconstruction was referred to our department. Despite the use of advanced tools, including a preformed PSI using a 1:1 mirrored, individual 3-dimensional model, several challenges remained. A systematic search of the relevant databases, scientific journals, and bibliographies of the included reports was conducted. Clinical studies involving CASS and SN in the treatment of at least 5 patients reported between 2016 and 2018 were included., Results: The final reconstruction was planned virtually, and a milled PSI was produced and implanted under guidance of SN. The clinical outcome was acceptable to the patient. The literature search showed that superior results can be obtained when CASS and SN are involved in the treatment regimen. The average technical accuracy for SN has been reported to be less than 1 mm, and volume restoration has been reported to be significantly superior to that achieved with traditional methods., Conclusions: New technological advancements such as CASS involving SN seem to improve the outcomes of orbital reconstruction, especially in complex cases. Furthermore, planning, execution, and evaluation will be facilitated. Real-time guidance can also be used as a training tool for novice surgeons; however, factors such as financial investments, challenges in implementation, and a steep learning curve must be considered., (Copyright © 2019. Published by Elsevier Inc.)

Surgery remains a primary modality of treatment for the majority of solid tumor malignancies. While advancements in surgical technique and instrumentation have improved the quality of life for cancer patients, local tumor recurrence and metastasis after surgery remain challenging and result in a high rate of mortality and decrease quality of life. It is therefore urgent to explore effective methods to eliminate residual microscopic disease in the surgical site and/or circulating tumor cells (CTCs) to inhibit tumor recurrence and minimize the risk of distant metastasis. Recently, advances in bioengineering technology have facilitated the development of drug delivery systems (DDSs) for the release of chemotherapy and immunotherapy agents, which could be used to enhance the effectiveness of surgical resection. In this review, we survey the rapidly evolving fields of local and systemic controlled DDSs, utilizing a variety of formulations and devices, such as implantable wafers, injectable/sprayable hydrogels, micro/nanoparticles, and cellular particles. Opportunities and challenges for the clinical translations of these delivery systems are also discussed., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Fractures of the orbital floor have traditionally been treated through transorbital approaches. Transconjunctival approaches risk entropion, whereas transcutaneous approaches risk ectropion or hypertrophic scarring. The intraoral transantral approach to the orbital floor has the advantage of minimizing the risk of any eyelid changes while providing appropriate access to reduce the herniated orbital contents and restore orbital volume. This article describes 4 plating methods for reconstructing a fractured orbital floor using a transantral approach. Many prior descriptions of transantral treatment of the orbital floor have relied heavily on the use of an endoscope. This article describes an osteotomy technique that does not require an endoscope but requires only a high-quality headlight for visualization., (Copyright © 2019 American Association of Oral and Maxillofacial Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: Although many studies have demonstrated that obesity is correlated with an increased risk of chronic disease, some have reported a paradox by which those in the higher weight categories actually recover better during hospitalization. This study was designed to determine whether this obesity paradox is also reflected in the recovery of patients with traumatic brain injury (TBI) undergoing care in a rehabilitation hospital., Objective: To investigate the association between body mass index (BMI) and the functional progress of patients with TBI, admitted to a rehabilitation hospital., Design: Retrospective cohort study., Methods: The study included all patients admitted to the brain injury unit of a rehabilitation hospital over a 6-year period. The data used for this study included patient height and weight (measured on admission) and functional independence measurements (scored on admission and discharge)., Main Outcome Measures: Functional independence measure (FIM) change per day, BMI category., Results: For the 444 patients admitted, the overall FIM efficiency did not differ significantly by BMI (P = .93). After adjusting for age and gender, overweight and obese patients had the lowest FIM efficiency (1.04 for both groups), followed by the underweight and normal weight groups (1.11 and 1.26, respectively)., Conclusion: This study demonstrated that higher BMI was not significantly correlated with the rate of functional recovery among patients admitted to a rehabilitation hospital for TBI., Level of Evidence: III., (© 2019 American Academy of Physical Medicine and Rehabilitation.)

Purpose: In bimaxillary procedures, it is important to know how the chosen sequence affects the surgical outcome. The purpose of this study was to explore whether the theoretical advantages of using the mandible-first procedure were supported by clinical data., Materials and Methods: The authors performed a retrospective investigation on a cohort compiled from 3 published retrospective studies. The sample was composed of patients treated at the Radboud University Nijmegen Medical Centre (Nijmegen, the Netherlands) from 2010 to 2014 and the Odense University Hospital (Odense, Denmark) from 2011 to 2015. The inclusion criterion was bimaxillary surgery without maxillary segmentation. The exclusion criterion was lack of a virtual surgical plan. The primary outcome variable was surgical accuracy, defined as the mean difference between the obtained outcome and the virtual surgical plan. The primary predictor variable was the comparison between mandible-first and maxilla-first sequencing. Secondary predictors were inferior maxillary repositioning and counterclockwise (CCW) rotation. The confounding variable was the virtually planned reposition. Results were analyzed by mixed-model regression encompassing all variables, followed by a detailed analysis of positive results using 2-sample t tests., Results: Overall, 145 patients were included for analysis (98 women; mean age, 28 years). Operating on the mandible first notably influenced maxillary positioning and placed the maxilla 1.5 mm posterior and with 1.4° of CCW rotation compared with virtual surgical planning. The interaction of surgical sequence with maxillary rotation showed similar surgical accuracy between maxilla-first surgery with clockwise rotation and mandible-first surgery with CCW rotation. Inferior maxillary repositioning resulted in the maxilla being placed 1.7 mm (maxilla-first sequence) and 2.0 mm (mandible-first sequence) posterior to the planned position., Conclusion: Surgical accuracy was considerably influenced by sequencing in bimaxillary procedures. It remains important to know how the chosen sequence affects the surgical outcome so that the virtual surgical plan can be adjusted accordingly., (Copyright © 2019 American Association of Oral and Maxillofacial Surgeons. All rights reserved.)

Objective: To investigate the effects of body mass index (BMI) on the rehabilitation process in patients with a recent knee replacement., Design: This retrospective cohort study included all patients admitted to a rehabilitation hospital, with a recent diagnosis of knee replacement and available hospital admission data including height and weight, between 2014 and 2017., Setting: Rehabilitation hospital., Participants: Study participants included patients who had undergone knee replacement surgery (N=742), with available BMI data., Interventions: None., Main Outcome Measures: FIM scores, including FIM change per day (FIM efficiency) by BMI category., Results: The chart review identified 742 patients who had undergone knee replacement surgery, with available BMI data. The identified patients ranged in age from 58 to 85 years, with a mean age of 70 years. Of the patients included in the study, 24 were male, 49 were female, 73 were within the normal weight class, 180 in the overweight class, 189 in the obese class I, 143 in the obese class II, and 157 patients were classified as obese class III. The mean FIM efficiency was highest in the obese class II category (3.96). In a multivariate analysis after controlling for age, obese classes II and III had significantly better FIM efficiency., Conclusion: This study did not demonstrate that obesity adversely affects the rate of recovery during hospitalization after knee replacement surgery., (© 2019 The Authors.)

The fibula free flap is a workhorse flap used to reconstruct ablative, osseous defects in the upper and lower jaws. Traditionally, the fibula free flap is inset into the defect freehand; dental implants are placed secondarily; and final prosthetic rehabilitation often occurs more than 1 year after ablative surgery. Virtual surgical planning and rapid prototyping of cutting guides and guide stents for head and neck reconstruction have facilitated improved accuracy in fibular transfer. This article describes the Jaw in a Day technique, allowing maxillary or mandibular resection, fibular free flap reconstruction, immediate implant placement, and prosthetic rehabilitation in a single operation., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Head and neck cancers, including those of the lip and oral cavity, nasal cavity, paranasal sinuses, oropharynx, larynx and nasopharynx represent nearly 700,000 new cases and 380,000 deaths worldwide per annum, and account for over 10,000 annual deaths in the United States alone. Improvement in outcomes are needed for patients with recurrent and or metastatic squamous cell carcinoma of the head and neck (HNSCC). In 2016, the US Food and Drug Administration (FDA) granted the first immunotherapeutic approvals - the anti-PD-1 immune checkpoint inhibitors nivolumab and pembrolizumab - for the treatment of patients with recurrent squamous cell carcinoma of the head and neck (HNSCC) that is refractory to platinum-based regimens. The European Commission followed in 2017 with approval of nivolumab for treatment of the same patient population, and shortly thereafter with approval of pembrolizumab monotherapy for the treatment of recurrent or metastatic HNSCC in adults whose tumors express PD-L1 with a ≥ 50% tumor proportion score and have progressed on or after platinum-containing chemotherapy. Then in 2019, the FDA granted approval for PD-1 inhibition as first-line treatment for patients with metastatic or unresectable, recurrent HNSCC, approving pembrolizumab in combination with platinum and fluorouracil for all patients with HNSCC and pembrolizumab as a single agent for patients with HNSCC whose tumors express a PD-L1 combined positive score ≥ 1. These approvals marked the first new therapies for these patients since 2006, as well as the first immunotherapeutic approvals in this disease. In light of the introduction of these novel therapies for the treatment of patients with head and neck cancer, The Society for Immunotherapy of Cancer (SITC) formed an expert committee tasked with generating consensus recommendations for emerging immunotherapies, including appropriate patient selection, therapy sequence, response monitoring, adverse event management, and biomarker testing. These consensus guidelines serve as a foundation to assist clinicians' understanding of the role of immunotherapies in this disease setting, and to standardize utilization across the field for patient benefit. Due to country-specific variances in approvals, availability and regulations regarding the discussed agents, this panel focused solely on FDA-approved drugs for the treatment of patients in the U.S.

Background: The risk of delayed autoimmunity occurring months or years after discontinuation of immunotherapy is frequently asserted in the literature. However, specific cases were rarely described until 2018, when a wave of reports surfaced. With expanding I-O indications in the adjuvant/neoadjuvant curative setting, growing numbers of patients will receive limited courses of immunotherapy before entering routine surveillance. In this context, under-recognition of DIRE could pose a growing clinical hazard., Methods: The aim of this study was to characterize DIRE through identification of existing reports of delayed post-treatment irAE in cancer patients treated with immunotherapy. We performed a PubMed literature review from 2008 through 2018 to determine the median data safety reporting window from existing I-O clinical trials, which we then applied to define the DIRE cutoff, and collated all qualifying reports over the same time span. DIRE was defined as new immune-related adverse events (irAE) manifesting ≥90 days after discontinuation of immunotherapy., Results: Median duration of I-O clinical trials data safety reporting was 90 days (82% ≤ 90 days). DIRE cutoff was thus set as ≥90 days post-immunotherapy. We identified 23 qualifying cases; 21 by literature review and 2 from our institution. Median off-treatment interval to DIRE was 6 months (range: 3 to 28). Median cumulative immunotherapy exposure was 4 doses (range: 3 to 42). Involvement included endocrine, neurologic, GI, pulmonary, cardiac, rheumatologic and dermatologic irAE., Conclusions: As immunotherapy indications expand into the curative setting, often with brief exposure and potentially sequenced with multimodality treatments, it will be necessary to recognize an emerging diagnostic complex, which we have termed delayed immune-related events (DIRE). Clinical vigilance has the potential to reduce morbidity from diagnostic delay, as irAE are generally manageable with prompt initiation of treatment - or from misdiagnosis - as misattribution can lead to unnecessary or harmful interventions as we describe. DIRE should therefore figure prominently in the differential diagnosis of patients presenting with illnesses of unclear etiology, irrespective of intervening treatments or interval post-immunotherapy, both of which can confound diagnosis. Increased recognition will rest on delineation of DIRE as a clinical diagnostic entity.

Objective: Self-inflicted gunshot wounds (SIGSWs) to the craniomaxillofacial region are uncommon injuries but are associated with a high mortality rate. Therefore, treating these patients is a rare occurrence even in the largest trauma centers. As with many rare conditions, data specifically addressing this injury pattern are scarce. Because of the proximity of the blast, even low-velocity injuries can be associated with significant avulsion of tissue, comminution of structures, and tissue die back. Previous case reports have recommended the use of prophylactic antibiotics, but no study has specifically investigated the postinjury infection rate or microbial patterns in this patient population. The purpose of this study was to answer the following clinical question: "Among patients with SIGW to the maxillofacial region, what is the prevalence of postinjury infection, and are there any microbial patterns that can guide empiric antibiotic selection?", Study Design: We designed retrospective cohort study at a level I trauma center in Portland, Oregon. Data on 17 patients who had sustained a SIGSW involving the maxilla or the mandible and survived their initial injury were collected from 2010 to 2017., Results: Patients who had a culture-positive infection within 30 days of their injury were defined to have a postinjury infection. Six of the 17 patients (35%) developed a postinjury infection, with an average time to infection of 11 days from initial injury (range 3-19 days). Of the 17 subjects, 15 (88%) received a course of prophylactic antibiotics, on average, for 14 days (range 3-24 days). Of the 6 cases of postinjury infection, culture grew gram-negative bacteria in 4 cases-anaerobic bacteria in 2 and polymicrobial organisms in 2. There was no clear pattern or prevalence of any specific bacterium, but cultures notably included Staphylococcus aureus, Enterobacter species, Bacteroides species, and Escherichia coli., Conclusions: SIGSWs are associated with a high rate of postinjury infection (35%) despite prophylactic antibiotic usage in 88% of these cases. Given the antimicrobial patterns observed in this study, prophylactic antibiotics in this patient population should include empiric coverage for gram-negative and anaerobic bacteria., (Copyright © 2019 Elsevier Inc. All rights reserved.)

The immune system has a vital role in the development, establishment, and progression of head and neck squamous cell carcinoma (HNSCC). Immune evasion of cancer cells leads to progression of HNSCC. An understanding of this mechanism provides the basis for improved therapies and outcomes for patients. Through the tumor's influence on the microenvironment, the immune system can be exploited to promote metastasis, angiogenesis, and growth. This article provides an overview of the interaction between immune infiltrating cells in the tumor microenvironment, and the immunologic principles related to HNSCC. Current immunotherapeutic strategies and emerging results from ongoing clinical trials are presented., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Purpose: Previously described techniques for microvascular fibula reconstruction of Brown Class II to IV maxillectomy defects are complex, require multiple osteotomies, result in a short pedicle, and inadequately reconstruct the dental alveolus in preparation for endosseous implants. This report describes a simplified technique for Brown Class II to IV defects that re-creates facial support, allows for dental reconstruction with appropriately positioned implants, and maintains adequate pedicle length., Materials and Methods: A retrospective chart review was performed of all patients with Brown Class II to IV maxillectomy defects immediately reconstructed with a biaxial double-barrel fibula flap technique. The reconstructive surgeon evaluated each patient at least 1 month after reconstruction for enophthalmos, facial symmetry, nasal patency, satisfactory jaw position, deglutition, intelligible speech, and intraoperative need for vein grafting., Results: The sample was composed of 6 patients (mean age, 54 yr; range, 33 to 78 yr; 67% women) who underwent reconstruction with the biaxial double-barrel fibula flap technique for Brown Class II to IV defects. None of these patients required vein grafting. None of these patients had flap failure. Diagnoses for these patients were a hybrid odontogenic tumor (n = 1), squamous cell carcinoma (n = 3), adenoid cystic carcinoma (n = 1), and sinonasal melanoma (n = 1). All 6 patients had excellent facial contour and malar projection, regular oral intake, 100% intelligible speech, and a new maxillary skeletal Class I relation without need for intraoperative vein grafting. One patient developed enophthalmos related to inferior rectus sacrifice and removal of orbital fat. Complications included development of nasal synechia and occlusion of the maxillary sinus ostium (n = 1)., Conclusions: The biaxial double-barrel fibula flap technique achieves the goals of providing adequate facial support and an alveolar segment amenable to implant dentistry. It allows for intelligible speech, deglutition, orbital support, and separation of the oronasal, orbital, and sinus cavities. In addition, it minimizes the need for vein grafting., (Copyright © 2018 American Association of Oral and Maxillofacial Surgeons. Published by Elsevier Inc. All rights reserved.)

Purpose: It remains unclear to what extent patient-specific printed plates can improve surgical outcomes in orthognathic procedures. This study aimed to quantify the surgical accuracy of patient-specific printed plates in vitro and to compare the results with patients' actual surgical outcomes., Patients and Methods: This in vitro study enrolled 20 postoperative orthognathic surgical patients, all treated with inferior maxillary repositioning. The preoperative midfaces were re-created in a 3-dimensionally printed model. The osteotomy and screw holes were placed at prespecified positions using a 3-dimensional guide. The dental segment was repositioned by means of the patient-specific plates. The primary outcome was the mean reposition at 3 dental reference points. The primary predictor variable was the obtained surgical reposition in vitro compared with the virtual surgical plan. Confounding variables were gender, age, occlusion, and bimaxillary surgery. The secondary outcome was surgical accuracy, and the secondary predictor was the in vitro outcomes versus the patients' surgical outcomes. Surgical accuracy was defined as the difference between the obtained reposition and the virtual surgical plan on a continuous scale. The differences were recorded in 3 dimensions according to the positive value of the 3 axes: right, anterior, and posterior. The results were analyzed using mixed-model regression and 1-sample t tests., Results: In the 20 patients (age, 18 to 64 years; 40% of patients were women), the mean planned reposition was 2.9 mm anterior and 1.8 mm inferior. In all models, the osteotomy edge was rounded off to position the plate in the predetermined position. Overall, the maxilla was positioned 0.5 mm anterior and 0.3 mm inferior to the planned position using patient-specific plates., Conclusions: The patient-specific plates positioned the maxilla in close approximation to the planned position without surgically relevant differences. The osteotomy edge must be carefully inspected for interference with the patient-specific plates to avoid displacement of the planned maxillary repositioning., (Copyright © 2018 American Association of Oral and Maxillofacial Surgeons. Published by Elsevier Inc. All rights reserved.)

This review highlights the contributions of American oral and maxillofacial surgeons to the field of orthognathic surgery. The present state of the art and science of orthognathic surgery is the harvest of yesterday's innovation and research. An improved understanding of the biological and surgical principles and the routine involvement of orthodontics have fueled widespread adoption of a coordinated approach to the treatment of dentofacial problems. Technologic advances in rigid internal fixation, virtual surgical planning with computer-aided manufacturing of occlusal splints and cutting guides, custom implants, and worldwide interest in the correction of dentofacial and craniofacial deformities have resulted in highly predictable, efficient, and safe treatment, which scarcely resembles the situation 70 years ago., (Copyright © 2018 American Association of Oral and Maxillofacial Surgeons. Published by Elsevier Inc. All rights reserved.)

Surgeons have unique in situ access to tumors enabling them to apply immunotherapies to resection margins as a means to prevent local recurrence. Here, we developed a surgical approach to deliver stimulator of interferon genes (STING) ligands to the site of a purposeful partial tumor resection using a gel-based biomaterial. In a range of head and neck squamous cell carcinoma (HNSCC) murine tumor models, we demonstrate that although control-treated tumors recur locally, tumors treated with STING-loaded biomaterials are cured. The mechanism of tumor control required activation of STING and induction of type I IFN in host cells, not cancer cells, and resulted in CD8 T-cell-mediated cure of residual cancer cells. In addition, we used a novel tumor explant assay to screen individual murine and human HNSCC tumor responses to therapies ex vivo We then utilized this information to personalize the biomaterial and immunotherapy applied to previously unresponsive tumors in mice. These data demonstrate that explant assays identify the diversity of tumor-specific responses to STING ligands and establish the utility of the explant assay to personalize immunotherapies according to the local response. Significance: Delivery of immunotherapy directly to resection sites via a gel-based biomaterial prevents locoregional recurrence of head and neck squamous cell carcinoma. Cancer Res; 78(21); 6308-19. ©2018 AACR ., (©2018 American Association for Cancer Research.)

Identifying tumor antigen-specific T cells from cancer patients has important implications for immunotherapy diagnostics and therapeutics. Here, we show that CD103 + CD39 + tumor-infiltrating CD8 T cells (CD8 TIL) are enriched for tumor-reactive cells both in primary and metastatic tumors. This CD8 TIL subset is found across six different malignancies and displays an exhausted tissue-resident memory phenotype. CD103 + CD39 + CD8 TILs have a distinct T-cell receptor (TCR) repertoire, with T-cell clones expanded in the tumor but present at low frequencies in the periphery. CD103 + CD39 + CD8 TILs also efficiently kill autologous tumor cells in a MHC-class I-dependent manner. Finally, higher frequencies of CD103 + CD39 + CD8 TILs in patients with head and neck cancer are associated with better overall survival. Our data thus describe an approach for detecting tumor-reactive CD8 TILs that will help define mechanisms of existing immunotherapy treatments, and may lead to future adoptive T-cell cancer therapies.

Amyloids are fibrous protein assemblies that are often described as irreversible and intrinsically pathogenic. However, yeast cells employ amyloid-like assemblies of the RNA-binding protein Rim4 to control translation during meiosis. Here, we show that multi-site phosphorylation of Rim4 is critical for its regulated disassembly and degradation and that failure to clear Rim4 assemblies interferes with meiotic progression. Furthermore, we identify the protein kinase Ime2 to bring about Rim4 clearance via phosphorylation of Rim4's intrinsically disordered region. Rim4 phosphorylation leads to reversal of its amyloid-like properties and degradation by the proteasome. Our data support a model in which a threshold amount of phosphorylation, rather than modification of critical residues, is required for Rim4 clearance. Our results further demonstrate that at least some amyloid-like assemblies are not as irreversible as previously thought. We propose that the natural pathways by which cells process these structures could be deployed to act on disease-related amyloids., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Purpose: The use of technology to aid in assessment, planning, and management of complex craniomaxillofacial injuries is increasingly common. Preoperative computed tomography (CT) evaluation is considered the standard of care, and intraoperative imaging is becoming increasingly accessible. Limited data exist regarding the implication of intraoperative CT on decision making in the management of all sites of facial fractures. The purposes of this study were to characterize the use of an intraoperative CT scanner for craniomaxillofacial surgery within our institution, to quantify the effect of intraoperative CT on surgical decision making, and to attempt to provide guidance on when to use this technology., Patients and Methods: This retrospective case series characterizes the use of an intraoperative CT scanner for craniomaxillofacial trauma surgery at a level 1 trauma center in Portland, Oregon, from February 2011 to September 2016. We evaluated the following variables: the number of intraoperative CT scans performed for craniomaxillofacial surgery including the number of scans for each patient, the number of scans for each operative visit, the CT-directed revision rate (overall and for specific preoperative diagnoses), and the indication for imaging. This information was evaluated to provide guidance on appropriate use of an intraoperative scanner., Results: A total of 161 patients were identified to have intraoperative facial CT scans from February 2011 to September 20, 2016, at Legacy Emanuel Medical Center. A total of 212 intraoperative facial CT scans were performed across 168 separate operations. The overall CT-directed revision rate was 28%. CT-directed revision rates for fracture subsites are as follows: orbital, 31%; zygomaticomaxillary complex, 24%; Le Fort I, 8%; Le Fort II and III, 23%; naso-orbital-ethmoidal, 23%; mandible, 13%; and frontal sinus, 0%. No CT-directed revisions were performed during removal of hardware, during placement of craniofacial implants, or in temporomandibular joint replacement surgery., Conclusions: If available, intraoperative CT should be routinely considered in the operative management of orbital fractures and pan-facial fractures, as well as complex zygomaticomaxillary complex, Le Fort II and III, and naso-orbital-ethmoidal fractures. Consideration also should be given to the use of intraoperative CT in cases of complex mandible fractures involving severe comminution or the condylar region. Intraoperative CT should not be routinely used for the management of Le Fort I fractures or frontal sinus fractures., (Copyright © 2017 American Association of Oral and Maxillofacial Surgeons. Published by Elsevier Inc. All rights reserved.)

Purpose: Virtual surgical planning (VSP) is an indispensable aid in craniomaxillofacial reconstruction, yet no protocol is established in facial gunshot wounds. We review our experience with computer-aided reconstruction of self-inflicted facial gunshot wounds (SIGSW'S) and propose a protocol for the staged repair., Methods: A retrospective case series enrolling patients with SIGSW's managed with the Functional Anatomic Computer Engineered Surgical protocol (FACES) was implemented. Subjects were evaluated at least one month postoperatively. Outcome variables were jaw position, facial projection, oro-nasal communication, lip competence, feeding tube and tracheostomy dependence, descriptive statistics were computed. The FACES protocol implemented during the initial hospitalization is as follows 1) damage control; 2) selective debridement; 3) VSP reconstruction back converted into navigation software 4) navigation assisted midfacial skeletal reconstruction; 5) computer aided oro-mandibular reconstruction with or without microvascular free flaps using custom cutting guides/hardware; 6) navigation assisted, computer aided palatomaxillary reconstruction with or without microvascular free flaps using cutting guides/hardware; 7) navigation assisted reconstruction of the internal orbit; 8) and confirmation of accurate reconstruction using intraoperative CT., Results: The sample was composed of 10 patients, mean age of 43 years (range, 28 - 62 years, 70% M), 100% with SIGSW's to the submental/submandibular region. All had satisfactory facial projection (n=10), nine had satisfactory jaw position, were decannulated by one month's follow up and were feeding tube independent (90%). All traumatic oro-antral communications were closed (n=8, 7 surgical, 1 obturator), seven had adequate lip competence (70%). Complications included fibula malunion (n=1), plate exposure (n=2) infection (n=2), intracranial abscess (n=1) and microstomia (n=2)., Conclusion: Computer-aided surgery is an indispensable tool in the reconstruction of SIGSW's. Successfully implemented, it proved to be a useful adjunct for: the restoration of orbital volume, facial projection and symmetry; the inset of composite tissue, and the facilitation of dental implant supported prosthetic rehabilitation., (Copyright © 2017 American Association of Oral and Maxillofacial Surgeons. Published by Elsevier Inc. All rights reserved.)