Personalized circulating tumor DNA for monitoring disease status in head and neck squamous cell carcinoma.

BACKGROUND: Many patients with locoregionally advanced HPV-negative head and neck squamous cell carcinoma (HNSCC) relapse. Circulating tumor (ct)DNA has the potential to identify minimal residual disease, but its clinical utility for virus-negative HNSCC is not well understood. METHODS: We retrospectively evaluated a personalized, commercial ctDNA assay (Signatera™, Natera) during clinical care of patients treated for predominantly newly diagnosed HPV-negative HNSCC. Signatera™ utilizes 16-plex PCR from matched tumor and blood. Objectives were to understand ctDNA detectability and correlate changes post-treatment with disease outcomes. RESULTS: Testing was successful in 100/116 (86%) patients (median age: 65, 68% male, 65% smokers); testing failed in 16 (14%) due to insufficient tissue. Oral cavity (55, 47%) tumors were most common; most had stage III-IV disease (82, 71%) while 17 (15%) had distant metastases. Pre-treatment, 75/100 patients with successful testing (75%) had detectable ctDNA (range: 0.03-4049.69 MTM/mL). No clinical features predicted ctDNA detectability or levels (multivariate analysis). At 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, 17 (31%) remained ctDNA positive after starting treatment. Progression-free survival was significantly worse for patients who were ctDNA positive vs. negative post-treatment (HR 7.33, 95%CI 3.12-17.2, p<0.001); 1-year overall survival was 89.1% vs. 100%, respectively (HR 7.46, 95%CI 0.46-119.5; p=0.155). CONCLUSIONS: Tumor-informed ctDNA testing is feasible in non-viral 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.

Gender Bias in Artificial Intelligence-Written Letters of Reference.

OBJECTIVE: Letters of reference (LORs) play an important role in postgraduate residency applications. Human-written LORs have been shown to carry implicit gender bias, such as using more agentic versus communal words for men, and more frequent doubt-raisers and references to appearance and personal life for women. This can result in inequitable access to residency opportunities for women. Given the known gendered language often unconsciously inserted into human-written LORs, we sought to identify whether LORs generated by artificial intelligence exhibit gender bias. STUDY DESIGN: Observational study. SETTING: Multicenter academic collaboration. METHODS: Prompts describing identical men and women applying for Otolaryngology residency positions were created and provided to ChatGPT to generate LORs. These letters were analyzed using a gender-bias calculator which assesses the proportion of male- versus female-associated words. RESULTS: Regardless of the gender, school, research, or other activities, all LORs generated by ChatGPT showed a bias toward male-associated words. There was no significant difference between the percentage of male-biased words in letters written for women versus men (39.15 vs 37.85, P = .77). There were significant differences in gender bias found by each of the other discrete variables (school, research, and other activities) chosen. CONCLUSION: While ChatGPT-generated LORs all showed a male bias in the language used, there was no gender bias difference in letters produced using traditionally masculine versus feminine names and pronouns. Other variables did induce gendered language, however. ChatGPT is a promising tool for LOR drafting, but users must be aware of potential biases introduced or propagated through these technologies.

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.

Portrait of a Surgeon: Artificial Intelligence Reflections.

Text-to-image artificial intelligence (AI) programs are popular public-facing tools that generate novel images based on user prompts. Given that they are trained from Internet data, they may reflect societal biases, as has been shown for text-to-text large language model programs. We sought to investigate whether 3 common text-to-image AI systems recapitulated stereotypes held about surgeons and other health care professionals. All platforms queried were able to reproduce common aspects of the profession including attire, equipment, and background settings, but there were differences between programs most notably regarding visible race and gender diversity. Thus, historical stereotypes of surgeons may be reinforced by the public's use of text-to-image AI systems, particularly those without procedures to regulate generated output. As AI systems become more ubiquitous, understanding the implications of their use in health care and for health care-adjacent purposes is critical to advocate for and preserve the core values and goals of our profession.

Neoadjuvant-Intent Immunotherapy in Advanced, Resectable Cutaneous Squamous Cell Carcinoma.

Importance: In clinical trials, preoperative immune checkpoint inhibitors (ICIs) have shown clinical activity in advanced cutaneous squamous cell carcinoma (cSCC). However, these studies excluded patients with relevant comorbidities. Objective: To evaluate radiologic and pathologic response rates to neoadjuvant-intent programed cell death protein 1 (PD-1) ICIs in a clinical population. Design, Setting, and Participants: This cohort study of patients who were treated with neoadjuvant cemiplimab or pembrolizumab for advanced cSCC from January 2018 to January 2023 was conducted at 2 academic institutions in Boston, Massachusetts. Median follow-up was 9.5 months (range, 1.2-40.5). Exposures: Cemiplimab or pembrolizumab. Main Outcomes and Measures: Primary outcomes were radiologic and pathologic response rates. Secondary outcomes were 1-year recurrence-free survival, progression-free survival, disease-specific survival, and overall survival. Results: This cohort study included 27 patients (including 9 patients [33.3%] with a history of lymphoma). Most patients were male (18 of 27 [66.7%]), with a median age of 72 years (range, 53-87 years). Most primary tumors were located on the head/neck (21 of 27 [77.8%]). There were no unexpected delays in surgery. The median number of doses before surgery was 3.5 (range, 1.0-10.0). Five patients (18.5%) ultimately declined to undergo planned surgery due to clinical responses or stability, and 1 (3.7%) did not undergo surgery due to progressive disease. The overall pathologic response rate (pathological complete response [pCR] or major pathological response) was 47.4% (9 of 19), and the overall radiologic response rate (radiologic complete response or partial response) was 50.0% (8 of 16). The pCR rate (7 of 19 [36.8%]) was higher than the radiologic complete response rate (2 of 16 [12.5%]). The pCR rate among patients with cSCC and concomitant lymphoma was 25.0%. The 1-year recurrence-free survival rate was 90.9% (95% CI, 50.8%-98.7%), progression-free survival was 83.3% (95% CI, 27.3%-97.5%), disease-specific survival was 91.7% (95% CI, 53.9%-98.8%), and overall survival was 84.6% (95% CI, 51.2%-95.9%). Conclusions and Relevance: The results of this cohort study support the reproducibility of neoadjuvant-intent immunotherapy for cSCC in the clinical setting, including for patients with a history of lymphoma. Outside of clinical trials, it is not infrequent for patients to opt out of surgery for regressing tumors. The inclusion of higher-risk patients and preference for nonsurgical treatment are 2 factors that might explain the numerically lower pathologic response rate in this institutional experience.

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.

Current and Emerging Diagnostic, Prognostic, and Predictive Biomarkers in Head and Neck Cancer.

Head and neck cancers (HNC) are a biologically diverse set of cancers that are responsible for over 660,000 new diagnoses each year. Current therapies for HNC require a comprehensive, multimodal approach encompassing resection, radiation therapy, and systemic therapy. With an increased understanding of the mechanisms behind HNC, there has been growing interest in more accurate prognostic indicators of disease, effective post-treatment surveillance, and individualized treatments. This chapter will highlight the commonly used and studied biomarkers in head and neck squamous cell carcinoma.

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.

Circulating Tumor HPV DNA for Surveillance of HPV-Positive Oropharyngeal Squamous Cell Carcinoma: A Narrative Review.

Importance: Human papillomavirus (HPV)-positive oropharyngeal squamous cell carcinoma has an overall favorable prognosis, yet a subset of patients will experience devastating disease recurrence. Current surveillance standards for detection of recurrent disease are imperfect. There is growing interest in improving detection of recurrent disease through the use of plasma-based assays able to detect circulating tumor HPV DNA. Observations: Although most circulating tumor HPV DNA assays remain in the research domain, the circulating tumor tissue-modified viral HPV DNA assay became commercially available in the United States in early 2020 and has been increasingly used in the clinical setting. With the rapidly increasing incidence of HPV-positive oropharyngeal squamous cell carcinoma and concomitant expansion of biomarker capabilities for this disease, it is critical to reexamine current posttreatment surveillance practices and to determine whether emerging technologies may be used to improve outcomes for a growing survivor population. However, caution is advised; it is not yet known whether biomarker-based surveillance is truly beneficial, and as is true with any intervention, it has the capacity to cause harm. Conclusions and Relevance: Using Margaret Pepe's classic 5 phases of biomarker development for early detection of cancer as a framework, this article reviews the current state of knowledge, highlights existing knowledge gaps, and suggests research that should be prioritized to understand the association between biomarker-based surveillance and patient outcomes. Specific attention is paid to the commercially available tumor tissue-modified viral HPV DNA assay, given its increasing clinical use. This review may serve as a road map for future research and a guide for clinicians considering its adoption in practice. Enrollment of patients into clinical trials incorporating biomarker-based surveillance should be prioritized.

Circulating tumor-tissue modified HPV DNA testing in the clinical evaluation of patients at risk for HPV-positive oropharynx cancer: The IDEA-HPV study.

OBJECTIVES: While survival outcomes are favorable for Human Papillomavirus (HPV)-positive oropharyngeal squamous cell carcinomas (OPSCCs), early diagnosis may minimize treatment-related morbidity and mortality. This study evaluated circulating tumor tissue-modified viral (TTMV)-HPV DNA plasma testing to facilitate early diagnosis of HPV-positive OPSCCs. METHODS: In this prospective exploratory cohort study, patients presenting to an Otolaryngology-Head and Neck Surgery clinic with unexplained signs or symptoms considered high-risk for HPV-positive OPSCC were recruited between March 2021-October 2022. Circulating TTMV-HPV DNA testing was performed, and results were shared with subjects and treating clinicians. Clinicians were surveyed regarding the perceived clinical utility of the test. RESULTS: Thirty-nine subjects were included. Most subjects were women (N = 23, 59 %), white (N = 32, 82 %) and never-smokers (N = 20, 51 %) with median age 60 years. Circulating TTMV-HPV DNA was detected in 2/39 subjects, both subsequently diagnosed with HPV-positive OPSCC. Both were white men aged 70-80 years with a neck mass. One subject with undetectable TTMV-HPV DNA was also diagnosed with HPV-positive OPSCC through excisional neck mass biopsy. Other eventual diagnoses included 3 HPV-negative head and neck squamous cell carcinomas and 4 other malignancies. Testing was perceived as helpful in clinical decision-making for 26/38 (68 %) subjects, and useful for similar future patients for 32/37 (86 %) subjects. CONCLUSION: Circulating TTMV-HPV DNA testing is feasible and holds potential as a diagnostic aid for HPV-positive OPSCC alongside standard clinical workup. Clinicians should be cognizant of its limitations, as a negative test does not necessarily indicate the absence of disease. Further studies to evaluate its utility are warranted.

Negative Predictive Value of Circulating Tumor Tissue Modified Viral (TTMV)-HPV DNA for HPV-driven Oropharyngeal Cancer Surveillance.

PURPOSE: Human papillomavirus (HPV) is causally linked to oropharyngeal squamous cell carcinoma (OPSCC). Consensus guidelines recommend clinical exams and imaging in decreasing frequency as part of posttreatment surveillance for recurrence. Plasma tumor tissue modified viral (TTMV)-HPV DNA testing has emerged as a biomarker which can inform disease status during surveillance. EXPERIMENTAL DESIGN: This retrospective observational cohort study involved 543 patients who completed curative-intent therapy for HPV-associated OPSCC between February 2020 and January 2022 at eight U.S. cancer care institutions. We determined the negative predictive value (NPV) of TTMV-HPV DNA for recurrence when matched to physician-reported clinical outcome data (median follow-up time: 27.9 months; range: 4.5-154). RESULTS: The cohort included mostly men with a median age of 61 who had locoregionally advanced disease. HPV status was determined by p16 positivity in 87% of patients, with a positive HPV PCR/ISH among 55%; while pretreatment TTMV-HPV DNA status was unknown for most (79%) patients. Patients had a mean of 2.6 tests and almost half had three or more TTMV-HPV DNA results during surveillance. The per-test and per-patient sensitivity of the assay was 92.5% [95% confidence interval (CI): 87.5-97.5] and 87.3% (95% CI: 79.1-95.5), respectively. The NPV for the assay was 99.4% (95% CI: 98.9-99.8) and 98.4% (95% CI: 97.3-99.5), respectively. CONCLUSIONS: TTMV-HPV DNA surveillance testing yields few false negative results and few missed recurrences. These data could inform decisions on when to pursue reimaging following first disease restaging and could inform future surveillance practice. Additional study of how pretreatment TTMV-HPV DNA status impacts sensitivity for recurrence is needed.

Diagnostic performance of computed tomography features in detecting oropharyngeal squamous cell carcinoma extranodal extension.

OBJECTIVES: Accurate pre-treatment imaging determination of extranodal extension (ENE) could facilitate the selection of appropriate initial therapy for HPV-positive oropharyngeal squamous cell carcinoma (HPV + OPSCC). Small studies have associated 7 CT features with ENE with varied results and agreement. This article seeks to determine the replicable diagnostic performance of these CT features for ENE. METHODS: Five expert academic head/neck neuroradiologists from 5 institutions evaluate a single academic cancer center cohort of 75 consecutive HPV + OPSCC patients. In a web-based virtual laboratory for imaging research and education, the experts performed training on 7 published CT features associated with ENE and then independently identified the "single most (if any) suspicious" lymph node and presence/absence of each of the features. Inter-rater agreement was assessed using percentage agreement, Gwet's AC1, and Fleiss' kappa. Sensitivity, specificity, and positive and negative predictive values were calculated for each CT feature based on histologic ENE. RESULTS: All 5 raters identified the same node in 52 cases (69%). In 15 cases (20%), at least one rater selected a node and at least one rater did not. In 8 cases (11%), all raters selected a node, but at least one rater selected a different node. Percentage agreement and Gwet's AC1 coefficients were > 0.80 for lesion identification, matted/conglomerated nodes, and central necrosis. Fleiss' kappa was always < 0.6. CT sensitivity for histologically confirmed ENE ranged 0.18-0.94, specificity 0.41-0.88, PPV 0.26-0.36, and NPV 0.78-0.96. CONCLUSIONS: Previously described CT features appear to have poor reproducibility among expert head/neck neuroradiologists and poor predictive value for histologic ENE. KEY POINTS: • Previously described CT imaging features appear to have poor reproducibility among expert head and neck subspecialized neuroradiologists as well as poor predictive value for histologic ENE. • Although it may still be appropriate to comment on the presence or absence of these CT features in imaging reports, the evidence indicates that caution is warranted when incorporating these features into clinical decision-making regarding the likelihood of ENE.

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.

Unusual presentation of HPV-positive squamous cell carcinoma of the nasolacrimal duct as carcinoma of unknown primary.

Most human papillomavirus (HPV)-positive carcinomas of unknown primary (CUP) in the cervical lymph nodes are ultimately found to arise from the oropharynx, which has by far the highest prevalence of HPV-positivity among head and neck tumors. However, HPV is also detected in a subset of tumors from other sites. In this case report, we describe the first reported instance of a lacrimal sac carcinoma presenting as an HPV-positive CUP. A 64-year-old male presented with isolated right-sided neck swelling, found on core biopsy to be HPV-positive squamous cell carcinoma (SCC). Initial diagnostic workup did not reveal a primary site, and he was treated for T0N1M0 oropharyngeal SCC with chemoradiation. Shortly afterwards he developed epiphora and was found to have an FDG-avid lesion along his inferior right orbit. Biopsy revealed HPV-positive SCC, presumed to be the true primary site of his previously diagnosed CUP. He was treated with surgical resection, proton-beam radiation, and carboplatin-paclitaxel. He had an excellent outcome with no evidence of disease 18 months following treatment completion. This case underscores the importance of continued vigilance and thorough investigation for a primary tumor site even when cervical nodal metastases are HPV-positive. While the vast majority of HPV-positive head and neck tumors arise in the oropharynx, other anatomical sites may also harbor HPV-positive malignancies.

Detection of circulating tumor human papillomavirus DNA before diagnosis of HPV-positive head and neck cancer.

Human papillomavirus (HPV), most commonly HPV16, causes a growing subset of head and neck squamous cell carcinomas (HNSCCs), including the overwhelming majority of oropharynx squamous cell carcinomas in many developed countries. Circulating biomarkers for HPV-positive HNSCC may allow for earlier diagnosis, with potential to decrease morbidity and mortality. This case-control study evaluated whether circulating tumor HPV DNA (ctHPVDNA) is detectable in prediagnostic plasma from individuals later diagnosed with HPV-positive HNSCC. Cases were participants in a hospital-based research biobank with archived plasma collected ≥6 months before HNSCC diagnosis, and available archival tumor tissue for HPV testing. Controls were biobank participants without cancer or HPV-related diagnoses, matched 10:1 to cases by sex, race, age and year of plasma collection. HPV DNA was detected in plasma and tumor tissue using a previously validated digital droplet PCR-based assay that quantifies tumor-tissue-modified viral (TTMV) HPV DNA. Twelve HNSCC patients with median age of 68.5 years (range, 51-87 years) were included. Ten (83.3%) had HPV16 DNA-positive tumors. ctHPV16DNA was detected in prediagnostic plasma from 3 of 10 (30%) patients with HPV16-positive tumors, including 3 of 7 (43%) patients with HPV16-positive oropharynx tumors. The timing of the plasma collection was 19, 34 and 43 months before cancer diagnosis. None of the 100 matched controls had detectable ctHPV16DNA. This is the first report that ctHPV16 DNA is detectable at least several years before diagnosis of HPV16-positive HNSCC for a subset of patients. Further investigation of ctHPV16DNA as a biomarker for early diagnosis of HPV16-positive HNSCC is warranted.

Cancer-Related Activity Limitations Among Head and Neck Cancer Survivors.

OBJECTIVES/HYPOTHESIS: To characterize self-reported cancer-related activity limitations among a broad population of head and neck (HNC) survivors and identify sociodemographic factors associated with these limitations. STUDY DESIGN: Cross-sectional analysis of data from the National Health Interview Survey. METHODS: The study population included individuals who completed the National Health Interview Survey (NHIS) from 1997 to 2018 and self-reported a cancer diagnosis. Data regarding activity limitations, cancer history, mental health, and demographics were extracted from the NHIS. Poisson regression was used to evaluate associations between demographics and cancer-related limitations, and a descriptive analysis was performed to identify the most common types of cancer-related limitations experienced by HNC survivors. RESULTS: Individuals with HNC were more than twice as likely to report having a disability caused by cancer when compared to individuals with other cancers (24% vs. 11%, P < .001). Cancer-related disability was highest among HNC survivors who were Black (adjusted prevalence ratio (aPR) = 1.57, 95% CI = 1.13-2.18), were aged 50 to 64 (aPR = 1.74, 95% CI = 1.1-2.74), had high school or lower education (aPR = 2.40, 95% CI = 1.07-5.37), and had Medicaid insurance (aPR = 2.58, 95% CI = 1.62-4.10). Among HNC patients who reported a cancer-related limitation, the most common limitations included difficulty working (78%), going out (51%), and socializing (42%). CONCLUSIONS: Cancer-related activity limitations are more common among HNC survivors compared to survivors of other cancers, and disproportionately affect socioeconomically disadvantaged HNC survivors. Clinicians should be aware of the limitations experienced by HNC survivors to provide counseling and resources to help patients cope with these limitations. LEVEL OF EVIDENCE: 3 Laryngoscope, 132:593-599, 2022.