Personalized ctDNA for Monitoring Disease Status in Head and Neck Squamous Cell Carcinoma.

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.

Perspectives on Referral Pathways for Timely Head and Neck Cancer Care.

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.

Patient Experience of Head and Neck Surgery With Free Flap Reconstruction.

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.

The jugular-subclavian junction and venous drainage of the brain.

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.

Personal Social Networks and Care-Seeking for Head and Neck Cancer: A Qualitative Study.

OBJECTIVES: To investigate the role of patients' personal social networks (SNs) in accessing head and neck cancer (HNC) care through patients' and health care workers' (HCWs) perspectives. STUDY DESIGN: Qualitative study. SETTING: Tertiary HNC centers at 2 academic medical centers, including 1 safety net hospital. METHODS: Patients with newly diagnosed HNC, and HCWs caring for HNC patients, aged ≥18 years were recruited between June 2022 and July 2023. Semistructured interviews were conducted with both patients and HCWs. Inductive and deductive thematic analysis was performed with 2 coders (κ = 0.82) to analyze the data. RESULTS: The study included 72 participants: 42 patients (mean age 57 years, 64% female, 81% white), and 30 HCWs (mean age 42 years, 77% female, 83% white). Four themes emerged: (1) Patients' SNs facilitate care through various forms of support, (2) patients may hesitate to seek help from their networks, (3) obligations toward SNs may act as barriers to seeking care, and (4) the SN composition and dedication influence care-seeking. CONCLUSION: Personal SNs play a vital role in prompting early care-seeking among HNC patients. SN-based interventions could enhance care and improve outcomes for HNC patients.

Nivolumab for Patients With High-Risk Oral Leukoplakia: A Nonrandomized Controlled Trial.

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.

Preexisting tumor-resident T cells with cytotoxic potential associate with response to neoadjuvant anti-PD-1 in head and neck cancer.

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.

Virtual planning and 3D-printed guides for mandibular reconstruction: Factors impacting accuracy.

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.

Accuracy and outcomes of virtual surgical planning and 3D-printed guides for osseous free flap reconstruction of mandibular osteoradionecrosis.

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.

Association of Pretreatment Circulating Tumor Tissue-Modified Viral HPV DNA With Clinicopathologic Factors in HPV-Positive Oropharyngeal Cancer.

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.

Dramatic response to targeted therapy in an aggressive olfactory neuroblastoma: illustrative case.

BACKGROUND: Olfactory neuroblastomas are rare sinonasal tumors that arise from the olfactory epithelium. The authors presented a case of an olfactory neuroblastoma with extensive cranial invasion that demonstrated dramatic response to sorafenib, a tyrosine kinase inhibitor. OBSERVATIONS: A 54-year-old man with history of prostate cancer and melanoma presented with left-sided proptosis and was found to have a 6.5-cm Kadish stage D olfactory neuroblastoma with cranial invasion that was refractory to chemotherapy and everolimus. However, it demonstrated dramatic response to sorafenib, causing extensive skull base defects that prompted operative repair. Genomic analysis of the tumor revealed mutations in TSC1 and SUFU. The patient developed disease progression with liver metastases 35 months after starting sorafenib, prompting a change to lenvatinib. He experienced progression of his olfactory neuroblastoma 10 months following this change and died in hospice 1 month later. LESSONS: The authors reviewed the clinical presentation and management of a large olfactory neuroblastoma with dramatic response to sorafenib. They highlighted prior uses of targeted therapy in the management of refractory olfactory neuroblastoma within the context of current standard treatment regimens. Targeted therapies may play a vital role in the management of refractory olfactory neuroblastoma.

Association between radiation dose to organs at risk and acute patient reported outcome during radiation treatment for head and neck cancers.

BACKGROUND: Associations between patient-reported outcomes and dose to organs at risk (OARs) may promote management and guide future investigations. METHODS: We retrospectively evaluated PROs and OAR dose in head and neck (H&N) cancer. RESULTS: In 169 patients, we identified weak associations between: "Difficulty swallowing/chewing" and increased mean RT dose to the oral cavity, larynx, pharyngeal constrictor muscles (PCM) and contralateral parotid; "choking/coughing" and larynx mean dose; "problems with mucus in mouth and throat" and oral cavity, contralateral parotid mean dose and parotid V30, contralateral submandibular gland and PCM mean dose; "difficulty with voice/speech" and oral cavity, contralateral parotid, contralateral submandibular gland and larynx mean dose; and "dry mouth" and ipsilateral submandibular gland, oral cavity and PCM mean dose. CONCLUSION: We identified weak associations between PRO and dose to OARs-these data can guide on treatment management, patient counseling, and serve as a baseline for future investigations.

Assessment of Preoperative Functional Status Prior to Major Head and Neck Surgery: A Pilot Study.

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.

Neoadjuvant and Adjuvant Nivolumab and Lirilumab in Patients with Recurrent, Resectable Squamous Cell Carcinoma of the Head and Neck.

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.

Full facial retransplantation in a female patient-Technical, immunologic, and clinical considerations.

There is limited experience with facial retransplantation (fRT). We report on the management of facial retransplantation in a facial vascularized composite allotransplant recipient following irreversible allograft loss 88 months after the first transplant. Chronic antibody-mediated rejection and recurrent cellular rejection resulted in a deteriorated first allograft and the patient underwent retransplantation. We summarize the events between the two transplantations, focusing on the final rejection episode. We describe the surgical technique of facial retransplantation, the immunological and psychosocial management, and the 6-month postoperative outcomes. Removal of the old allograft and inset of the new transplant were done in one operation. The donor and recipient were a good immunological match. The procedure was technically complex, requiring more proximal arterial anastomoses and an interposition vein graft. During the first and second transplantation, the facial nerve was coapted at the level of the branches. There was no hyperacute rejection in the immediate postoperative phase. Outcomes 6 months postoperatively are promising. We provide proof-of-concept that facial retransplantation is a viable option for patients who suffer irreversible facial vascularized composite allograft loss.

Hospitalization rates and 30-day all-cause mortality among head and neck cancer patients and survivors with COVID-19.

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.

Pathologies of oral and sinonasal mucosa following facial vascularized composite allotransplantation.

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.

MRI and CT Guided Cryoablation for Intracranial Extension of Malignancies along the Trigeminal Nerve.

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.

Neoadjuvant Nivolumab or Nivolumab Plus Ipilimumab in Untreated Oral Cavity Squamous Cell Carcinoma: A Phase 2 Open-Label Randomized Clinical Trial.

Importance: Novel approaches are needed to improve outcomes in patients with squamous cell carcinoma of the oral cavity. Neoadjuvant immunotherapy given prior to surgery and combining programmed cell death protein 1 (PD-1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) immune checkpoint inhibitors are 2 strategies to enhance antitumor immune responses that could be of benefit. Design, Setting, and Participants: In this randomized phase 2 clinical trial conducted at 1 academic center, 29 patients with untreated squamous cell carcinoma of the oral cavity (≥T2, or clinically node positive) were enrolled between 2016 to 2019. Interventions: Treatment was administered with nivolumab, 3 mg/kg, weeks 1 and 3, or nivolumab and ipilimumab (ipilimumab, 1 mg/kg, given week 1 only). Patients had surgery 3 to 7 days following cycle 2. Main Outcomes and Measures: Safety and volumetric response determined using bidirectional measurements. Secondary end points included pathologic and objective response, progression-free survival (PFS), and overall survival. Multiplex immunofluorescence was used to evaluate primary tumor immune markers. Results: Fourteen patients were randomized to nivolumab (N) and 15 patients to nivolumab/ipilimumab (N+I) (mean [SD] age, 62 [12] years; 18 men [62%] and 11 women [38%]). The most common subsite was oral tongue (n = 16). Baseline clinical staging included patients with T2 (n = 20) or greater (n = 9) T stage and 17 patients (59%) with node-positive disease. Median time from cycle 1 to surgery was 19 days (range, 7-21 days); there were no surgical delays. There were toxic effects at least possibly related to study treatment in 21 patients, including grade 3 to 4 events in 2 (N), and 5 (N+I) patients. One patient died of conditions thought unrelated to study treatment (postoperative flap failure, stroke). There was evidence of response in both the N and N+I arms (volumetric response 50%, 53%; pathologic downstaging 53%, 69%; RECIST response 13%, 38%; and pathologic response 54%, 73%, respectively). Four patients had major/complete pathologic response greater than 90% (N, n = 1; N+I, n = 3). With 14.2 months median follow-up, 1-year progression-free survival was 85% and overall survival was 89%. Conclusions and Relevance: Treatment with N and N+I was feasible prior to surgical resection. We observed promising rates of response in both arms, supporting further neoadjuvant studies with these agents. Trial Registration: ClinicalTrials.gov Identifier: NCT02919683.