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Purpose: Many patients with locoregionally advanced human papillomavirus-negative head and neck squamous cell carcinoma (HNSCC) relapse. ctDNA has the potential to identify minimal residual disease, but its clinical utility for virus-negative HNSCC is not well understood., Experimental Design: We retrospectively evaluated a personalized, commercial ctDNA assay (Signatera, Natera) during clinical care of patients treated for predominantly newly diagnosed human papillomavirus-negative HNSCC. Signatera utilizes 16-plex PCR from matched tumor and blood. Objectives were to understand ctDNA detectability and correlate changes posttreatment with disease outcomes., Results: Testing was successful in 100/116 (86%) patients (median age: 65 years, 68% male, 65% smokers); testing failed in 16 (14%) because of insufficient tissue. Oral cavity (55, 47%) tumors were most common; most had stage III to IV disease (82, 71%), whereas 17 (15%) had distant metastases. Pretreatment, 75/100 patients with successful testing (75%) had detectable ctDNA (range: 0.03-4049.69 mean tumor molecules/mL). No clinical features predicted ctDNA detectability or levels (multivariate analysis). At a median follow-up of 5.1 months (range: 0.2-15.1), 55 (55%) had >1 test result (range: 1-7; 194 samples). Of 55 patients, 17 (31%) remained ctDNA positive after starting treatment. Progression-free survival was significantly worse for patients who were ctDNA positive versus ctDNA negative posttreatment (HR, 7.33; 95% confidence interval, 3.12-17.2; P < 0.001); 1-year overall survival was 89.1% versus 100%, respectively (HR, 7.46; 95% confidence interval, 0.46-119.5; P = 0.155)., Conclusions: Tumor-informed ctDNA testing is feasible in nonviral HNSCC. ctDNA positivity is an indicator of disease progression and associated with inferior survival. Further research is warranted to understand whether ctDNA may be leveraged to guide therapy in HNSCC., (©2024 The Authors; Published by the American Association for Cancer Research.)

Importance: Timely diagnosis and treatment are of paramount importance for patients with head and neck cancer (HNC) because delays are associated with reduced survival rates and increased recurrence risk. Prompt referral to HNC specialists is crucial for the timeliness of care, yet the factors that affect the referral and triage pathway remain relatively unexplored. Therefore, to identify barriers and facilitators of timely care, it is important to understand the complex journey that patients undertake from the onset of HNC symptoms to referral for diagnosis and treatment., Objective: To investigate the referral and triage process for patients with HNC and identify barriers to and facilitators of care from the perspectives of patients and health care workers., Design, Participants, and Setting: This was a qualitative study using semistructured interviews of patients with HNC and health care workers who care for them. Participants were recruited from June 2022 to July 2023 from HNC clinics at 2 tertiary care academic medical centers in Boston, Massachusetts. Data were analyzed from July 2022 to December 2023., Main Outcomes and Measures: Themes identified from the perspectives of both patients and health care workers on factors that hinder or facilitate the HNC referral and triage process., Results: In total, 72 participants were interviewed including 42 patients with HNC (median [range] age, 60.5 [19.0-81.0] years; 27 [64%] females) and 30 health care workers (median [range] age, 38.5 [20.0-68.0] years; 23 [77%] females). Using thematic analysis, 4 major themes were identified: the HNC referral and triage pathway is fragmented; primary and dental care are critical for timely referrals; efficient interclinician coordination expedites care; and consistent patient-practitioner engagement alleviates patient fear., Conclusions and Relevance: These findings describe the complex HNC referral and triage pathway, emphasizing the critical role of initial symptom recognition, primary and dental care, patient information flow, and interclinician and patient-practitioner communication, all of which facilitate prompt HNC referrals.

Importance: Major head and neck surgery with microvascular free tissue transfer reconstruction is complex, with considerable risk of morbidity. Little is known about patients' experiences, including decision-making prior to, and regret following, free flap surgery., Objective: To characterize patient experiences and decision regret of patients undergoing head and neck reconstructive free flap surgery., Design, Setting, and Participants: This mixed-methods cohort study comprising semistructured interviews was conducted June to August 2021 at a single tertiary academic cancer center. Participants underwent head and neck reconstructive surgery with microvascular free tissue transfer (flap) more than 3 months before recruitment (range, 3 months to 4 years). Interview transcripts were qualitatively analyzed for themes. Participants also completed a Decision Regret Scale questionnaire., Exposure: Microvascular free flap surgery for head and neck reconstruction., Main Outcomes and Measures: Thematic analysis of interviews, decision regret score., Results: Seventeen participants were interviewed. Median (IQR) age was 61 (52-70) years. Overall, 7 participants were women (49%), and 10 of 17 were men (59%). The most common free flap was fibula (8/17, 47%). Three major themes with 9 subthemes were identified: theme 1 was the tremendous effect of preoperative counseling on surgical decision-making and satisfaction, with subthemes including (1) importance of clinical care team counseling on decision to have surgery; (2) emotional context colors preoperative understanding and retention of information; (3) expectation-setting affects satisfaction with preoperative counseling; and (4) desire for diversified delivery of preoperative information. Theme 2 was coexisting and often conflicting priorities, including (1) desire to survive above all else, and (2) desire for quality of life. Theme 3 was perception of surgery as momentous and distressing, including (1) surgery as a traumatic event; (2) centrality of mental health, emotional resolve, and gratitude to enduring surgery and recovery; and (3) sense of accomplishment in recovery. On the Decision Regret Scale, most participants had no regret (n = 8, 47%) or mild regret (n = 5, 29%); 4 had moderate-to-severe regret (24%)., Conclusions and Relevance: In this mixed-methods cohort study, patient experiences surrounding major head and neck reconstructive free flap surgery were described. Opportunities to improve support for this complex and vulnerable population, and to mitigate decision regret, were identified.

Importance: Proliferative verrucous leukoplakia (PVL) is an aggressive oral precancerous disease characterized by a high risk of transformation to invasive oral squamous cell carcinoma (OSCC), and no therapies have been shown to affect its natural history. A recent study of the PVL immune landscape revealed a cytotoxic T-cell-rich microenvironment, providing strong rationale to investigate immune checkpoint therapy., Objective: To determine the safety and clinical activity of anti-programmed cell death 1 protein (PD-1) therapy to treat high-risk PVL., Design, Setting, and Participants: This nonrandomized, open-label, phase 2 clinical trial was conducted from January 2019 to December 2021 at a single academic medical center; median (range) follow-up was 21.1 (5.4-43.6) months. Participants were a population-based sample of patients with PVL (multifocal, contiguous, or a single lesion ≥4 cm with any degree of dysplasia)., Intervention: Patients underwent pretreatment biopsy (1-3 sites) and then received 4 doses of nivolumab (480 mg intravenously) every 28 days, followed by rebiopsy and intraoral photographs at each visit., Main Outcomes and Measures: The primary end point was the change in composite score (size and degree of dysplasia) from before to after treatment (major response [MR]: >80% decrease in score; partial response: 40%-80% decrease). Secondary analyses included immune-related adverse events, cancer-free survival (CFS), PD-1 ligand 1 (PD-L1) expression, 9p21.3 deletion, and other exploratory immunologic and genomic associations of response., Results: A total of 33 patients were enrolled (median [range] age, 63 [32-80] years; 18 [55%] were female), including 8 (24%) with previously resected early-stage OSCC. Twelve patients (36%) (95% CI, 20.4%-54.8%) had a response by composite score (3 MRs [9%]), 4 had progressive disease (>10% composite score increase, or cancer). Nine patients (27%) developed OSCC during the trial, with a 2-year CFS of 73% (95% CI, 53%-86%). Two patients (6%) discontinued because of toxic effects; 7 (21%) experienced grade 3 to 4 immune-related adverse events. PD-L1 combined positive scores were not associated with response or CFS. Of 20 whole-exome sequenced patients, all 6 patients who had progression to OSCC after nivolumab treatment exhibited 9p21.3 somatic copy-number loss on pretreatment biopsy, while only 4 of the 14 patients (29%) who did not develop OSCC had 9p21.3 loss., Conclusions and Relevance: This immune checkpoint therapy precancer nonrandomized clinical trial met its prespecified response end point, suggesting potential clinical activity for nivolumab in high-risk PVL. Findings identified immunogenomic associations to inform future trials in this precancerous disease with unmet medical need that has been difficult to study., Trial Registration: ClinicalTrials.gov Identifier: NCT03692325.

Lung cancers and mediastinal masses can invade the veins in the upper mediastinum and neck. It can be challenging to determine management options and the feasibility of resection particularly when tumors involve the major venous junctions. Furthermore, impaired flow in these veins can have devastating complications such as Paget-Schroetter syndrome, which describes a constellation of symptoms (arm swelling, cyanosis, pain) due to stenosis of the subclavian vein. This section will provide an overview of venous drainage of the brain, which can be divided into two major systems-superficial medullary venous system and deep medullary venous system. The anatomy and function of the great veins of the neck and upper mediastinum, including the internal jugular vein, subclavian vein, and brachiocephalic (i.e., innominate) vein will be described. Also discussed will be principles of ligation of the venous structures and the importance of keeping the venous junctions intact to facilitate and maximize the development of collateral flow. This section will also discuss ensuing complications when blood flow is impaired, such as development of upper extremity deep venous thrombosis and cerebral venous thrombosis (CVT). CVT can result in a stroke and is an umbrella term that refers to problems in cerebral venous outflow due to numerous etiologies., Competing Interests: Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://med.amegroups.com/article/view/10.21037/med-23-15/coif). The series “Venous Surgery of the Mediastinum” was commissioned by the editorial office without any funding or sponsorship. A.S. served as the unpaid Guest Editor of the series. The authors have no other conflicts of interest to declare., (2024 Mediastinum. All rights reserved.)

About 50% of patients with locally advanced head and neck squamous cell carcinoma (HNSCC) experience recurrences after definitive therapy. The presurgical administration of anti-programmed cell death protein 1 (PD-1) immunotherapy results in substantial pathologic tumor responses (pTR) within the tumor microenvironment (TME). However, the mechanisms underlying the dynamics of antitumor T cells upon neoadjuvant PD-1 blockade remain unresolved, and approaches to increase pathologic responses are lacking. In a phase 2 trial (NCT02296684), we observed that 45% of patients treated with two doses of neoadjuvant pembrolizumab experienced marked pTRs (≥50%). Single-cell analysis of 17,158 CD8 + T cells from 14 tumor biopsies, including 6 matched pre-post neoadjuvant treatment, revealed that responding tumors had clonally expanded putative tumor-specific exhausted CD8 + tumor-infiltrating lymphocytes (TILs) with a tissue-resident memory program, characterized by high cytotoxic potential (CTX + ) and ZNF683 expression, within the baseline TME. Pathologic responses after 5 weeks of PD-1 blockade were consistent with activation of preexisting CTX + ZNF683 + CD8 + TILs, paralleling loss of viable tumor and associated tumor antigens. Response was associated with high numbers of CD103 + PD-1 + CD8 + T cells infiltrating pretreatment lesions, whereas revival of nonexhausted persisting clones and clonal replacement were modest. By contrast, nonresponder baseline TME exhibited a relative absence of ZNF683 + CTX + TILs and subsequent accumulation of highly exhausted clones. In HNSCC, revival of preexisting ZNF683 + CTX + TILs is a major mechanism of response in the immediate postneoadjuvant setting.

Objectives: Virtual surgical planning, 3D-printed osteotomy guides and preoperatively-bent or custom-milled mandibular reconstruction plate (VSP/3Dprinted-guide/plate) have been shown to ease intraoperative decision making and reduce operative time. Few studies have examined outcomes of VSP/3Dprinted-guide/plate specifically for mandibular osteoradionecrosis (mORN) cases, which pose unique challenges. We aimed to examine reconstruction accuracy, functional outcomes, and postoperative complications following osseous-free-flap reconstruction with VSP/3Dprinted-guide/plate for mORN., Materials and Methods: Single academic medical center retrospective case series of ORN-related osseous-free-flap mandibular reconstructions with VSP/3Dprinted-guide/plate between January 2015 and March 2021. Most cases were performed by the same two-surgeon team. Outcomes include reconstruction accuracy (assessed by 3D-overlay computer models with cephalometric and donor-bone segment length measurements), complications and function., Results: Twenty-six cases were identified with a mean follow-up of 85 weeks. Most patients were male (69 %); mean age was 64 years. 3D-model-overlay demonstrated minimal deviation between planned and actual reconstruction among 18 evaluable cases: intercondylar distance = 1.46 mm (SD 2.4); intergonial distance = 1.82 mm (SD 2.0); anterior-posterior distance = 2.14 mm (SD 1.9); gonial angle = 3.33 degrees (SD 2.4). Mean change donor-bone segment length inferiorly 4.39 mm (SD 4.3) and superiorly 3.43 mm (SD 4.0)., Complications: returned to operating room (N = 2), minor primary/neck site infection/dehiscence (N = 11). Function improved postoperatively: 20/21 (95 %) cases with preoperative pain, resolved; 13/20 (65 %) with preoperative trismus, improved; 21/24 (87 %) with preoperative malocclusion/jaw malignment, improved., Conclusions: This is the largest series of VSP/3Dprinted-guide/plate surgery for mORN to date. Mandibular reconstruction for ORN is aided by VSP/3Dprinted-guide/plate with accurate results, acceptable complications, and improved function., 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 © 2022 Elsevier Ltd. All rights reserved.)

Importance: Circulating tumor tissue-modified viral (TTMV) human papillomavirus (HPV) DNA is a dynamic, clinically relevant biomarker for HPV-positive oropharyngeal squamous cell carcinoma. Reasons for its wide pretreatment interpatient variability are not well understood., Objective: To characterize clinicopathologic factors associated with TTMV HPV DNA., Design, Setting, and Participants: This cross-sectional study included patients evaluated for HPV-positive oropharyngeal squamous cell carcinoma at Dana-Farber Cancer Institute in Boston, Massachusetts, between December 2019 and January 2022 and who were undergoing curative-intent treatment., Exposures: Clinicopathologic characteristics including demographic variables, tumor and nodal staging, HPV genotype, and imaging findings., Main Outcomes and Measures: Pretreatment circulating TTMV HPV DNA from 5 genotypes (16, 18, 31, 33, and 35) assessed using a commercially available digital droplet polymerase chain reaction-based assay, considered as either detectable/undetectable or a continuous score (fragments/mL)., Results: Among 110 included patients, 96 were men (87%) and 104 were White (95%), with a mean (SD) age of 62.2 (9.4) years. Circulating TTMV HPV DNA was detected in 98 patients (89%), with a median (IQR) score of 315 (47-2686) fragments/mL (range, 0-60 061 fragments/mL). Most detectable TTMV HPV DNA was genotype 16 (n = 86 [88%]), while 12 patients (12%) harbored other genotypes. Circulating TTMV HPV DNA detection was most strongly associated with clinical N stage. Although few patients had clinical stage N0 disease, only 4 of these 11 patients (36%) had detectable DNA compared with 94 of 99 patients (95%) with clinical stage N1 to N3 disease (proportion difference, 59%; 95% CI, 30%-87%). Among patients with undetectable TTMV HPV DNA, more than half (7 of 12 [58%]) had clinical stage N0 disease. The TTMV HPV DNA prevalence and score increased with progressively higher clinical nodal stage, diameter of largest lymph node, and higher nodal maximum standardized uptake value on positron emission tomography/computed tomography. In multivariable analysis, clinical nodal stage and nodal maximum standardized uptake value were each strongly associated with TTMV HPV DNA score. Among 27 surgically treated patients, more patients with than without lymphovascular invasion had detectable TTMV HPV DNA (12 of 12 [100%] vs 9 of 15 [60%])., Conclusions and Relevance: In this cross-sectional study, circulating TTMV HPV DNA was statistically significantly associated with nodal disease at HPV-positive OPSCC diagnosis. The few patients with undetectable levels had predominantly clinical stage N0 disease, suggesting assay sensitivity for diagnostic purposes may be lower among patients without cervical lymphadenopathy. Mechanisms underlying this association, and the use of this biomarker for surveillance of patients with undetectable baseline values, warrant further investigation.

Objectives: Examine accuracy and factors impacting accuracy for mandibular reconstruction with virtual surgical planning, 3D printed osteotomy guides and preoperatively bent mandibular reconstruction plate (VSP/3Dprinted-guide/plate)., Method: Retrospective review of osseous-free-flap mandibular reconstructions with VSP/3Dprinted-guide/plate between January 2015 and July 2020 at a single academic medical center.Patient demographics, disease, and treatment variables were extracted. Accuracy was assessed by 3D-model-overlay with cephalometric and donor-bone segment length measurements. Multivariate analyses were performed to determine factors impacting cephalometric accuracy., Results: 60 cases met criteria: 41 (68%) cancer, 14 (23%) osteoradionecrosis (ORN), 5 (8%) secondary mandibular reconstruction. Thirteen cases (22%) were Brown class III or IV. Thirty-nine cases (65%) had ≥2 flap bone segments. Average donor-bone length was 82 mm (SD: 28). 3D-model-overlay accuracy demonstrated minimal deviation between planned and actual reconstruction: intercondylar distance = 2.10 mm (SD: 2.2); intergonial distance = 2.23 mm (SD: 1.9); anterior-posterior distance (APD) = 1.76 mm (SD: 1.5); gonial angle (GA) = 3.11 degrees (SD: 2.4). Mean change in donor-bone segment length inferiorly was 2.67 mm (SD: 2.6) and superiorly 3.27 mm (SD: 3.2). Higher number of donor-bone segments was associated with decreased accuracy in GA ( p  = .023) and longer donor-bone length was associated with decreased accuracy in APD ( p  = .031)., Conclusion: To our knowledge this is the largest series assessing surgical accuracy of VSP/3Dprinted-guide/plate for osseous-free-flap mandibular reconstruction. We demonstrate highly accurate results, with increased number of donor-bone segments and donor-bone length associated with decreased accuracy. Our findings further support VSP/3Dprinted-guide/plate as a reliable and accurate tool for mandibular reconstruction., Level of Evidence: Level 4., Competing Interests: The authors and institution have no other funding support and no conflict of interests to declare., (© 2022 The Authors. Laryngoscope Investigative Otolaryngology published by Wiley Periodicals LLC on behalf of The Triological Society.)

Objective: To demonstrate feasibility of a recently developed preoperative assessment tool, the Vulnerable Elders Surgical Pathways and Outcomes Analysis (VESPA), to characterize the baseline functional status of patients undergoing major head and neck surgery and to examine the relationship between preoperative functional status and postoperative outcomes., Study Design: Case series with planned data collection., Setting: Two tertiary care academic hospitals., Methods: The VESPA was administered prospectively in the preoperative setting. Data on patient demographics, ablative and reconstructive procedures, and outcomes including total length of stay, discharge disposition, delay in discharge, or complex discharge planning (delay or change in disposition) were collected via retrospective chart review. VESPA scores were calculated and risk categories were used to estimate risk of adverse postoperative outcomes using multivariate logistic regression for categorical outcomes and linear regression for continuous variables., Results: Fifty-eight patients met study inclusion criteria. The mean (SD) age was 66.4 (11.9) years, and 58.4% of patients were male. Nearly one-fourth described preoperative difficulty in either a basic or instrumental activity of daily living, and 17% were classified as low functional status (ie, high risk) according to the VESPA. Low functional status did not independently predict length of stay but was associated with delayed discharge (odds ratio [OR], 5.0; 95% CI, 1.2-21.3; P = .030) and complex discharge planning (OR, 5.7; 95% CI, 1.34-24.2; P = .018)., Conclusion: The VESPA can identify major head and neck surgical patients with low preoperative functional status who may be at risk for delayed or complex discharge planning. These patients may benefit from enhanced preoperative counseling and more comprehensive discharge preparation.

Purpose: Surgery often represents the best chance for disease control in locoregionally recurrent squamous cell carcinoma of the head and neck (SCCHN). We investigated dual immune-checkpoint inhibition [anti-PD-1, nivolumab (N), and anti-KIR, lirilumab (L)] before and after salvage surgery to improve disease-free survival (DFS)., Patients and Methods: In this phase II study, patients received N (240 mg) + L (240 mg) 7 to 21 days before surgery, followed by six cycles of adjuvant N + L. Primary endpoint was 1-year DFS; secondary endpoints were safety, pre-op radiologic response, and overall survival (OS). Correlatives included tumor sequencing, PD-L1 scoring, and immunoprofiling., Results: Among 28 patients, the median age was 66, 86% were smokers; primary site: 9 oral cavity, 9 oropharynx, and 10 larynx/hypopharynx; 96% had prior radiation. There were no delays to surgery. Grade 3+ adverse events: 11%. At the time of surgery, 96% had stable disease radiologically, one had progression. Pathologic response to N + L was observed in 43% (12/28): 4/28 (14%) major (tumor viability, TV ≤ 10%) and 8/28 (29%) partial (TV ≤ 50%). PD-L1 combined positive score (CPS) at surgery was similar regardless of pathologic response ( P = 0.71). Thirteen (46%) recurred (loco-regional = 10, distant = 3). Five of 28 (18%) had positive margins, 4 later recurred. At median follow-up of 22.8 months, 1-year DFS was 55.2% (95% CI, 34.8-71.7) and 1-year OS was 85.7% (95% CI, 66.3-94.4). Two-year DFS and OS were 64% and 80% among pathologic responders., Conclusions: (Neo)adjuvant N + L was well tolerated, with a 43% pathologic response rate. We observed favorable DFS and excellent 2-year OS among high-risk, previously treated patients exhibiting a pathologic response. Further evaluation of this strategy is warranted. See related commentary by Sacco and Cohen, p. 435 ., (©2021 The Authors; Published by the American Association for Cancer Research.)

Background: Cutaneous changes of facial vascularized composite allotransplants (fVCAs) are extensively described in the literature. Parts of the nose, nasal, and oral cavities are included in most fVCAs. Distinctively, the nose and mouth are lined by mucosa. Little is known about the histopathology and complications of the mucosa involved in fVCA patients., Methods: The study constitutes a retrospective cohort study of nine fVCA patients. Medical records were reviewed for information about changes of oral and nasal mucous membranes. Types of mucosal lesions were recorded and analyzed. Uni- and multivariate generalized estimating equation (GEE) models were used to assess the odds of developing mucosal inflammation in the presence of clinico-pathologic variables., Results: A total of 186 clinical encounters with examination of oral and nasal mucous membranes were included. Membranes were devoid of clinical pathology in 101 instances (53% of all clinical assessments). Ulcerations/erosions (27%), edema (18%), and erythema (14%) were the most common lesions. Oral lesions affected the lips (58%), buccal mucosa (38%), and palate (5%). Sinonasal processes predominantly affected nasal vestibules and septae. In univariate analysis, sirolimus, skin rejection, and skin Banff grade were associated with the presence of an acute inflammatory mucosal lesion (p<0.05). In multivariate analysis, skin Banff grade and sirolimus were independent predictors of mucosal inflammation., Conclusion: Pathologies of fVCA mucous membranes are more common than previously reported. Mucosal assessment plays an important role in the pleomorphic allograft rejection process evaluation rather than diagnosis and treatment based on cutaneous pathology.  A closer look at the pathophysiology of fVCA mucosal rejection and inflammation is warranted., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: The impact of COVID-19 on patients with cancer is emerging, but data are urgently needed for head and neck cancer (HNC) patients or survivors who are inherently high-risk for severe illness and mortality with SARS-CoV-2 infection., Methods: This multi-institution, academic cohort study collected comprehensive data on clinical risk factors, COVID-19 symptoms and viral testing patterns, information about hospitalization rates, and predictors of survival among HNC patients with active disease or in remission. The primary endpoint was 30-day all-cause mortality from the date of confirmed COVID-19. We performed multivariate analysis to understand the prognostic value of clinical and laboratory parameters on outcomes., Results: Thirty-two patients with COVID-19 and HNC were included. Median age was 70 (range: 38-91) with 38% aged 75+, and 34% resided in long-term care facilities (LTCF). Thirteen (41%) had active cancer, with 6 (19%) on cancer therapy within 4 weeks of COVID-19 diagnosis. New or worsening cough and fatigue were the most commonly reported presenting symptoms. More than 30% required >1 SARS-CoV-2 test before confirming a positive result. Twenty (63%) required hospitalization. At data cutoff, 7 (22%) had died (1 on active cancer treatment), with a 30-day all-cause mortality of 18.9% (95%CI: 11.4-33.6) among all patients, and 71.5% (95%CI: 38.2-92.3) among those requiring intensive care unit (ICU) admission. ICU admission and residing in a LTCF predicted worse outcomes (p < 0.01), while age, gender, and recent treatment did not., Conclusions: We observed high 30-day all-cause mortality among HNC patients with COVID-19, but most were not on active cancer therapy., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Objectives  To describe the technical aspects and early clinical outcomes of patients undergoing percutaneous magnetic resonance imaging (MRI)-guided tumor cryoablation along the intracranial trigeminal nerve. Design  This study is a retrospective case review. Setting  Large academic tertiary care hospital. Participants  Patients who underwent MRI-guided cryoablation of perineural tumor along the intracranial trigeminal nerve. Main Outcome Measures  Technical success, pain relief, local control. Results  Percutaneous MRI-guided cryoablation of tumor spread along the intracranial portion of the trigeminal nerve was performed in two patients without complication, with subsequent pain relief, and with local control in the patient with follow-up imaging. Conclusions  Percutaneous MRI-guided cryoablation is a feasible treatment option for malignancies tracking intracranially along the trigeminal nerve., Competing Interests: Conflict of Interest T.C.L. reports grants from National Institutes of Health, during the conduct of the study. J.P.G reports no personal disclosures. The advanced multimodality image guided operating suite was supported in part by the national institutes of health (grant P41 EB 015898). J.W.L reports other from SleepMed/DigiTrace, other from Advance Medical, other from United Sleep Diagnostics, grants from NIH, outside the submitted work. Other authors have reported no conflict of interest., (© Thieme Medical Publishers.)

Background: Although high-grade salivary gland cancers (SGCs) often express androgen receptor (AR) and/or HER-2/neu, therapeutically targeting these receptors in SGC remains investigational. We investigated the prevalence of receptor expression and the benefit of adjuvant HER-2 directed therapy in the high-risk postoperative setting and explored the clinical utility of sequentially targeting these receptors in the setting of advanced disease., Materials and Methods: We clinically annotated 95 patients with SGC (excluding adenoid cystic carcinoma) treated at our institution from 2002 to 2019 and recorded AR, HER-2/neu status, and tumor genomic profiling results when available. Clinicopathologic information was then integrated with outcomes., Results: Of 95 patients, most had high-risk histologies, with salivary duct carcinoma (SDC) as the most frequent diagnosis (43, 45%). Thirty-five (37%) experienced recurrence (51% SDC). HER-2/neu was positive (1-3+) by immunostaining in 34 of 52 (65%) evaluable cases. There was no difference in survival based on HER-2/neu or AR expression. Nine of 17 (53%) patients with HER-2+ SDC received adjuvant chemoradiation with trastuzumab. Median disease-free survival (DFS) and overall survival (OS) were longer among patients with HER-2/neu 3+ staining tumors who received adjuvant trastuzumab versus those who did not (DFS, 117 vs. 9 months; p = .02; OS, 74 vs. 43 months; p = .02), with no difference among other HER-2/neu subgroups (0-2+). Two of nine (22%) patients treated with adjuvant trastuzumab demonstrated recurrence, both with low HER-2/neu staining intensity (1+). Longer time to recurrence (hazard ratio, 0.94; p = .01) predicted improved outcomes. Both androgen deprivation and HER-2-directed therapies had clinical benefit beyond the first-line metastatic setting, with partial response observed beyond second-line use., Conclusion: Although prospective data are lacking, the use of adjuvant trastuzumab in high-risk patients with SGC appears beneficial, particularly among patients with tumors exhibiting HER-2/neu 3+ immunostaining., Implications for Practice: Results of this study showed an improved disease-free and overall survival in patients treated with adjuvant trastuzumab for high-risk salivary gland cancers with strong HER-2/neu staining intensity. Following recurrence or metastatic spread, sequential HER-2, and androgen-directed therapies may benefit certain patients with salivary gland cancer., (© AlphaMed Press 2020.)

Background: Radiation therapy for squamous cell cancer of the head and neck with unknown primary (head and neck CUP) has been associated with significant levels of swallowing toxicity. We examined the effect of changes in mucosal dose on development of laryngeal strictures and percutaneous endoscopic gastrostomy (PEG) dependence., Methods: Retrospective analysis of 58 patients with head and neck CUP treated with intensity-modulated radiation therapy (IMRT) at the Dana Farber Cancer Institute from August 2004 through July 2013., Results: There were no significant differences between any recurrences for groups treated to 56 versus ≥60 Gy to the mucosal surfaces. However, mucosal dose and chemotherapy type were associated with stricture on multivariable analysis; median PEG dependence was decreased for patients treated to 56 Gy. A larynx-sparing approach was associated with improved outcomes for strictures and PEG use., Conclusion: In this single institution study, a 56 Gy IMRT-based mucosal dose demonstrated significant improvements in swallowing toxicity. Additional benefit was seen with larynx-sparing IMRT., (© 2019 Wiley Periodicals, Inc.)

Purpose: Programmed death-1 (PD-1) inhibitors are approved for the treatment of patients with recurrent and metastatic squamous cell carcinoma of the head and neck (SCCHN). Ongoing and planned randomized phase 3 trials are testing the benefit of combining PD-1/programmed death-ligand 1 (PD-L1) inhibitors with chemoradiation for patients with locoregionally confined SCCHN. Few studies have investigated relationships among potential predictive pathologic biomarkers such as PD-L1, PD-L2, and PD-1 in this population and associations between these markers and clinical characteristics., Methods and Materials: We retrospectively reviewed records and pathology from 81 patients with locoregional oropharynx SCCHN treated with curative intent. Samples were analyzed for PD-L1, PD-L2, PD-1, CD8, and CD56 expression using immunohistochemistry. Human papilloma virus (HPV) status was determined by p16-immunohistochemistry and confirmed by in situ hybridization or polymerase chain reaction-based HPV typing. Correlations between HPV status, clinical features, and recurrence status with immune markers in both tumor and tumor-associated stroma were determined. Hazard ratios were estimated via Cox proportional hazards model., Results: Tumor PD-L1 expression was inversely associated with age (P = .01) and the highest levels of expression (>30% of tumor cells) were observed in HPV-associated tumors. There was a correlation between tumor and stromal PD-L1 expression (P = < .0001). PD-1 and CD8 expression within tumor deposits was associated with HPV status (P = 0.003 and P = .008, respectively) and decreased local recurrence (P = .001 and P < .001, respectively). In addition to the association between tumor and stromal PD-1 (P < .0001), PD-1 was also correlated with tumor PD-L1 expression (P < .001). CD56+ natural killer cell infiltrates correlated with PD-L1 expression., Conclusions: In patients with untreated oropharyngeal SCCHN, HPV-associated tumors displayed the highest levels of PD-L1 expression and PD-1+ and CD8+ immune cells. Locally recurrent tumors had lower levels of PD-L1, PD-1, and CD-8 positivity. Whereas almost all SCCHN tumors had CD56+ infiltrating natural killer cells, most tumors didn't have PD-L2 expression. These associations may help predict which patients may benefit most from immunotherapeutic approaches., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Objectives: To characterize specific serious toxicities of reRT with intensity modulated radiation therapy (IMRT) for squamous cell carcinoma of the head and neck (SCCHN) and identify treatment-related predictors of toxicity for patient counseling and decision-making., Materials/methods: 75 consecutive patients with recurrent or 2nd primary SCCHN received reRT from 8/2004-02/2013. All patients had prior definitive or postoperative RT. Objective endpoints of "serious toxicity" were defined as: hospitalization during reRT, tracheotomy after reRT, hemorrhage, soft tissue complication requiring operative intervention, or other CTCAE grade ≥4 toxicity., Results: Patients received definitive (n=41,55%) or postoperative (n=34,45%) reRT (median dose 60Gy, range 59.4-70Gy). Most patients (88%) had concurrent chemotherapy. With a median follow-up of 1.4years, 39 (52%) patients had at least one serious toxicity: hospitalization during reRT (24%), surgically-managed soft tissue complication (19%), and/or urgent tracheotomy (18%). There were no grade 5 acute toxicities but there were 4 fatal hemorrhages (median 8.3months) including 2 attributed to local-regional recurrence (LRR). Most patients (69%) had a percutaneous endoscopic gastrostomy (PEG) tube at last follow-up; those with a LRR had higher PEG tube-dependence rates (86% vs. 53%, p=0.001). LRR, site of reRT, and laryngeal RT dose, were marginally associated with toxicity-risk., Conclusions: Patients considering reRT should be counseled on the high rate of PEG tube-dependence, and events of urgent tracheotomy, hospitalization, hemorrhage, and operative intervention, which typically occur months after reRT completion. Further study of baseline patient function and cumulative radiation dose to the larynx and other organs-at-risk may improve estimates of serious toxicity-risk after reRT., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Purpose: To describe patterns of failure (POF) after reirradiation (reRT) with intensity modulated radiation therapy (IMRT) for recurrent/second primary squamous cell carcinoma of the head and neck., Methods: From 08/2004-02/2013, 75 consecutive patients received reRT with IMRT. Gross tumor was generally treated with a 5mm planning target volume (PTV) margin. For postoperative cases, a 5mm PTV was added to the clinical target volume which included the postoperative bed. Elective neck coverage was not standard. POF were characterized by correlating the recurrent tumor location on CT-imaging with the reRT IMRT plan., Results: Patients received definitive reRT (55%) or postoperative reRT (45%) to a median 60Gy (range, 59.4-70Gy). Most patients (88%) received concurrent chemotherapy including induction (16%). The median overall survival was 1.8years. Isolated local-regional recurrence (LRR) was the most common failure-type (2-year cumulative incidence [CI] 22.5% [95% C.I. 13.6-32.7%]), but concurrent LRR and distant-failure occurred frequently (2-year CI LRR+distant-failure 19.6% [95% C.I. 11.3-29.5%]); isolated distant-failure was rare (2-year CI 5.7% [95% C.I. 1.8-12.8%]). The 2-year in-field control was 65% (95% C.I. 52-81%) reflecting encouraging control within the irradiated target. Patients with gross disease were more likely to recur in-field (p=0.02), whereas postoperative patients were more likely to recur out-of-field/marginally than in-field (p=0.02)., Conclusions: POF after reRT differ when treating gross disease or postoperatively and should be considered when delineating reRT targets. Aggressive local therapy resulted in favorable in-field control, yet there remains a high competing risk of regional and distant micrometastatic disease. Better systemic agents are needed to control clinically occult local-regional and distant disease., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Purpose: The clinical impact of next-generation sequencing (NGS) in patients with head and neck squamous cell carcinoma (HNSCC) has not been described. We aimed to evaluate the clinical impact of NGS in the routine care of patients with HNSCC and to correlate genomic alterations with clinical outcomes., Experimental Design: Single-center study examining targeted NGS platform used to sequence tumor DNA obtained from 213 HNSCC patients evaluated in outpatient head and neck oncology clinic between August 2011 and December 2014. We correlated tumor genomic profiling results with clinical outcomes., Results: PI3K/RTK pathway activation occurred frequently [activating PIK3CA mutation or amplification (13%), PTEN inactivation (3%), RAS activation (6%), EGFR or ERBB2 activation (9%)]. Alterations in pathways affecting cell-cycle regulation [CCND1 amplification (9%), CDKN2A inactivation (17%), BRCA2 inactivation (2%)] and squamous differentiation [NOTCH1 inactivation (8%) andEP300 inactivation (6%)] were identified. PIK3CA amplification (n = 43), not PIK3CA mutation, was associated with significantly poorer progression-free survival (P = 0.0006). Oncogenic RAS mutations (n = 13) were associated with significantly poorer progression-free survival (P = 0.0001) and lower overall survival (P = 0.003). Eight patients with advanced, treatment-refractory HNSCC enrolled on clinical trials matched to tumor profiling results, and 50% achieved a partial response., Conclusions: Incorporation of NGS clinical assays into the routine care of patients with HNSCC is feasible and may readily facilitate enrollment into clinical trials of targeted therapy with a higher likelihood of success. Data can be utilized for discovery of genomic biomarkers of outcome. PIK3CA amplification and RAS mutations were frequently identified and associated with poorer prognosis in this cohort. Clin Cancer Res; 22(12); 2939-49. ©2016 AACR., (©2016 American Association for Cancer Research.)

Face transplantation is being performed with increasing frequency. Facial edema, fluid collections, and lymphadenopathy are common postoperative findings and may be due to various etiologies, some of which are particular to face transplantation. The purpose of this study was to demonstrate how postoperative imaging and image-guided minimally invasive procedures can assist in diagnosing and treating complications arising from face transplantation. Retrospective evaluation of 6 consecutive cases of face transplantation performed at Brigham and Women's Hospital between April 2009 and March 2014 was performed with assessment of postoperative imaging and image-guided procedures, including aspiration of postoperative fluid collection, lymph node biopsy, and treatment of salivary gland leak. Through these cases, we demonstrate that early postoperative imaging and image-guided procedures are key components for the management of complications following face transplantation., (© 2015 by American Journal of Neuroradiology.)

Among the major complications of transsphenoidal surgery, less attention has been given to severe postoperative epistaxis, which can lead to devastating consequences. In this study, we reviewed 551 consecutive patients treated over a 4 year period by the senior author to evaluate the incidence, risk factors, etiology and management of immediate and delayed post-transsphenoidal epistaxis. Eighteen patients (3.3%) developed significant postoperative epistaxis - six immediately and 12 delayed (mean postoperative day 10.8). Fourteen patients harbored macroadenomas (78%) and 11 of 18 (61.1%) had complex nasal/sphenoid anatomy. In the immediate epistaxis group, 33% had acute postoperative hypertension. In the delayed group, one had an anterior ethmoidal pseudoaneurysm, and one had restarted anticoagulation on postoperative day 3. We treated the immediate epistaxis group with bedside nasal packing followed by operative re-exploration if conservative measures were unsuccessful. The delayed group underwent bedside nasal hemostasis; if unsuccessful, angiographic embolization was performed. After definitive treatment, no patients had recurrent epistaxis., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Background: Severe facial injuries can compromise the upper airway by reducing airway volume, obstructing or obliterating the nasal passage, and interfering with oral airflow. Besides the significant impact on quality of life, upper airway impairments can have life-threatening or life-altering consequences. The authors evaluated improvements in functional airway after face transplantation., Methods: Between 2009 and 2011, four patients underwent face transplantation at the authors' institution, the Brigham and Women's Hospital. Patients were examined preoperatively and postoperatively and their records reviewed for upper airway infections and sleeping disorders. The nasal mucosa was biopsied after face transplantation and analyzed using scanning electron microscopy. Volumetric imaging software was used to evaluate computed tomographic scans of the upper airway and assess airway volume changes before and after transplantation., Results: Before transplantation, two patients presented an exposed naked nasal cavity and two suffered from occlusion of the nasal passage. Two patients required tracheostomy tubes and one had a prosthetic nose. Sleeping disorders were seen in three patients, and chronic cough was diagnosed in one. After transplantation, there was no significant improvement in sleeping disorders. The incidence of sinusitis increased because of mechanical interference of the donor septum and disappeared after surgical correction. All patients were decannulated after transplantation and were capable of nose breathing. Scanning electron micrographs of the respiratory mucosa revealed viable tissue capable of mucin production. Airway volume significantly increased in all patients., Conclusions: Face transplantation successfully restored the upper airway in four patients. Unhindered nasal breathing, viable respiratory mucosa, and a significant increase in airway volume contributed to tracheostomy decannulation.