BACKGROUND:Melanoma brain metastases (BM) carry high morbidity and mortality despite advances in systemic therapy. Combined immune checkpoint inhibition (ICI) with ipilimumab and nivolumab (ipi/nivo) demonstrates intracranial activity, but the influence of prior systemic therapy exposure is poorly defined. This is the first real-world study evaluating outcomes of melanoma BM treated with stereotactic radiosurgery (SRS) and concurrent ipi/nivo, focusing on the impact of prior ICI or targeted therapy. PATIENTS AND METHODS:We retrospectively analyzed 68 patients with 413 melanoma BM treated with concurrent SRS and ipi/nivo from 2015 to 2025. Primary endpoints were overall survival (OS) and intracranial progression-free survival (iPFS). Secondary endpoints included local and distant control, radionecrosis, and leptomeningeal disease. Univariable and multivariable Cox models identified predictors of outcome. RESULTS:Median OS was 24.0 months (12- and 24-month OS: 64% and 50%). ICI-naive patients had longer OS (50.5 vs. 17.6 months; P = 0.007) and iPFS (15.1 vs. 5.9 months) than those with prior ICI. On multivariable analysis, prior ICI (HR 2.23, 95% confidence interval [CI] 1.13-4.41), prior BRAF/MEKi (HR 2.26, 95% CI 1.01-5.04), and ≥11 SRS-treated lesions (HR 3.22, 95% CI 1.43-7.21) predicted worse outcomes, while higher graded prognostic assessment (GPA) favored OS (HR 0.46, 95% CI 0.29-0.75). At 24 months, local progression was 11%, distant 49%, radionecrosis 7%, and leptomeningeal disease 4%. CONCLUSION:Concurrent SRS with ipi/nivo provides durable intracranial control with low toxicity. Patients with prior ICI or targeted therapy represent a high-risk subgroup with poorer outcomes, supporting exploration of intensified or novel strategies.

Background: Chronic lymphedema is a common late effect after completion of head and neck cancer (HNC) treatment, contributing to substantial symptom burden and negatively impacting quality of life. No effective approaches are available to treat this progressive condition. This study aimed to evaluate the preliminary efficacy of photobiomodulation (PBM) therapy for chronic lymphedema in HNC survivors. Methods: This was a pilot, randomized, wait-list controlled trial. Eligible HNC survivors included those with chronic lymphedema after completion of complete decongestive therapy. Participants were randomized (1:1) to 1 of 2 arms: intervention group (active) or wait-list control group (control). The active group received 12 PBM therapy sessions (twice a week for 6 weeks). The control group completed the study assessments and was then offered the same dose of PBM therapy as the active group. Lymphedema and fibrosis (LEF), symptom burden, jaw range of motion, and neck range of motion were measured at baseline, end-of-intervention, 4-week, and 8-week post-intervention. Results: Twenty five HNC survivors were randomized to the active group (n = 12) and the control group (n = 13). About 91.7% planned PBM treatment sessions were completed. No adverse events were reported. Compared to the control group, the active group demonstrated improvements at 8-week post-intervention in the severity of external LEF ( P < .001), symptom burden (eg, Soft Tissue and Neurologic Toxicity subscale, Cohen’s d = − 0.47), and neck range of motion (eg, extension, Cohen’s d = 0.65). Conclusion: PBM therapy may improve chronic lymphedema-associated outcomes. Future large randomized controlled trials are warranted to examine the efficacy of PBM therapy for HNC-related chronic lymphedema.

PURPOSE:We conducted a phase 2 clinical trial reducing both dose and volume of adjuvant radiation in patients with human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma (OPSCC). We also examined whether postoperative circulating tumor DNA (ctDNA) was prognostic for outcomes. METHODS AND MATERIALS:Eligible patients had pT0 to pT3 pN0 to pN1 HPV-associated OPSCC (American Joint Committee on Cancer 8th edition) treated with primary transoral robotic surgery and neck dissection. Adjuvant radiation therapy (RT) was delivered in 25 fractions over 5 weeks. We reduced RT volumes in 2 ways: the primary oropharyngeal resection bed was omitted in select patients (pT1-T2 tumors with negative margins and no lymphovascular invasion or perineural invasion), and the contralateral neck targets were reduced to mirror the pathologically involved ipsilateral nodal levels. We also reduced RT doses: 50 Gy was given to primary resection beds requiring treatment and to ipsilateral neck levels with pathologically positive nodes; 45 Gy was delivered to other at-risk ipsilateral nodal regions and the contralateral neck. Concurrent chemotherapy was prescribed for positive margins and extranodal extension, although optionally omitted when extranodal extension was ≤1 mm. Baseline HPV ctDNA was collected after surgery and measured at 3 subsequent timepoints. RESULTS:We enrolled 150 patients between October 2018 and June 2022. One patient withdrew, leaving 149 patients treated per protocol. At a median follow-up of 48 months (IQR, 38-59 months), no patients developed local recurrence while 2 experienced regional recurrences. The estimated 5-year locoregional control (LRC) rate was 98.0% (95% CI, 95.3%-100%). Both regional recurrences were successfully salvaged. Ten patients (6.7%) developed distant metastases, and 3 (2.0%) died of disease. At 24 months post-RT, the median MD Anderson Symptom Inventory for head and neck cancer scores were dysphagia-2, xerostomia-2, and interference with work-0. For 79 patients with available blood samples, detectable postoperative HPV ctDNA was associated with subsequent metastatic disease but not LRC. CONCLUSIONS:Now with mature follow-up, our adjuvant RT strategy with reduced doses and volumes maintained high LRC with favorable toxicity in selected patients with HPV-associated OPSCC.

OBJECTIVE:Head and neck cancer (HNC) survivors treated with radiation therapy are at increased risk for both lymphedema and carotid artery atherosclerosis. The coexistence of these conditions creates complex management challenges, yet no clinical practice guidelines currently address this overlap. This report aims to develop a preliminary clinical care pathway to guide lymphedema treatment in irradiated HNC survivors at risk for carotid atherosclerosis. METHODS:A comprehensive literature search was conducted in June 2023 and updated in September 2025 using three primary MeSH components: head and neck cancer, lymphedema therapy, and atherosclerosis. Searches were performed across PubMed, Embase, and CINAHL, along with relevant professional organization resources. A multidisciplinary working group-including experts in radiation oncology, preventive cardiology, rehabilitation, and lymphedema management-reviewed the evidence and developed a proposed care pathway. RESULTS:The search identified 85 unique articles. After title and abstract screening, one article underwent full-text review; however, none directly addressed lymphedema management in irradiated HNC survivors at risk for carotid atherosclerosis. To address this gap, the working group developed a preliminary clinical care pathway based on the available evidence and expert consensus. CONCLUSION:This pathway represents an initial effort to guide the management of lymphedema in irradiated HNC survivors with coexisting cardiovascular risk. It integrates limited published evidence with multidisciplinary clinical expertise in oncology, cardiovascular risk assessment, and lymphedema care. Further validation and refinement are needed to support clinical implementation.

Photobiomodulation (PBM) has emerged as a non-invasive approach for managing oral conditions such as oral mucositis, periodontal disease, and post-surgical wound healing. Despite encouraging clinical outcomes, no consensus exists regarding optimal PBM treatment protocols, particularly with respect to laser wavelength, power, and exposure time. A key barrier is the limited understanding of how light propagates through the heterogeneous and complex structures of the oral cavity. We utilize Monte Carlo (MC) simulations to model light propagation in oral tissues to better understand PBM dose distribution for dental and oral disease applications. Monte Carlo simulations were performed using both simplified cubic geometry and a human head phantom. Our results demonstrate a significant angular dependence on 810 nm light transport. Furthermore, the limited penetration depth-restricted to only a few millimeters of cortical tissue-suggests that transdermal delivery is insufficient for targeting the intraoral cavity, necessitating an internal light source for effective treatment. The results provide mechanistic insights into how light scattering and absorption govern therapeutic dose delivery in the oral cavity. These findings will contribute to the rational design of PBM protocols for oral diseases, supporting the establishment of standardized, evidence-based treatment parameters. Ultimately, this work aims to bridge the gap between clinical practice and biophysical modeling, enabling safer and more effective PBM therapy in dentistry.

While ipilimumab/nivolumab has demonstrated promising intracranial activity among patients with melanoma brain metastases (BM), patients with prior immune checkpoint inhibition (ICI) exposure may be at higher risk of worse intracranial disease control. We evaluated outcomes of patients with melanoma BM treated with ipilimumab/nivolumab and stereotactic radiosurgery (SRS) with or without prior ICI. Overall survival (OS) and intracranial progression-free survival (iPFS) were estimated from SRS using a non-parametric method, and Cox proportional hazards models were used to test clinically relevant factors. 64 consecutive patients with 393 treated BM between 2015 and 2024 were included with median follow-up of 20.2 months from SRS. 34 (53%) patients were alive at analysis. The 2-year OS and iPFS for the entire cohort was 52.1% and 36.4%, respectively. 32 patients (50%) had prior exposure to ICI. Performance status, age, number of BM, and receipt of surgery were not significantly different among patients with or without prior ICI. Patients with prior ICI had smaller BM (largest median diameter 19 mm vs 22.5 mm, p=0.022) and were less likely to have extracranial metastases (53.1% vs 78.1%, p=0.035). Patients with prior ICI exposure trended towards worse iPFS (median iPFS 4.3 months vs 13.5 months, p = 0.29) and had worse survival after SRS (median OS 17.6 months vs 50.5 months, p = 0.017). On univariate analysis, receipt of prior ICI (HR 2.16, 95% CI 1.13 – 4.11, p = 0.019), no upfront surgery (HR 0.38, 95% CI 0.20 – 0.72, p = 0.003), and number of treated BM (HR 1.04, 95% CI 1 – 1.08, p = 0.043) were significantly associated with OS. While ipilimumab/nivolumab with SRS demonstrates encouraging intracranial control, patients with prior ICI exposure are at higher risk of poor outcomes and may benefit from additional treatment strategies.

BACKGROUND:Limited understanding of the biology predisposing certain human papillomavirus-related (HPV+) oropharyngeal squamous cell carcinomas (OPSCCs) to relapse impedes therapeutic personalization. We aimed to identify molecular traits that distinguish recurrence-prone tumors. METHODS:Fifty HPV+ OPSCCs that later recurred (cases) and 50 nonrecurrent controls matched for stage, therapy, and smoking history were RNA-sequenced. Groups were compared by gene set enrichment analysis, and select differences were validated by immunohistochemistry. Features discriminating groups were scored in each tumor using gene set variation analysis, and scores were evaluated for recurrence prediction ability. RESULTS:Cases downregulated pathways linked to antitumor immunity (FDR-adjusted P < .05) and contained fewer tumor-infiltrating lymphocytes (P < .001), including cytotoxic T-cells (P = .005). Cases also upregulated pathways related to cell division and other aspects of tumor progression. Upregulated and downregulated pathways were respectively used to define a tumor progression score (TPS) and immune suppression score (ISS) for each tumor. Correlation between TPS and ISS (r = .603, P < .001) was potentially explained by observed upregulation of DNA repair pathways in cases, which might enhance their progression directly and by limiting cytosolic DNA-induced inflammation. Accordingly, cases contained fewer double-strand breaks based on staining for phospho-RPA32 (P = .006) and γ-H2AX (P = .005) and downregulated the cytosolic DNA sensing pathway. A combined score derived from TPS and ISS optimized recurrence prediction and stratified survival in a manner generalizable to 3 external cohorts. CONCLUSIONS:We describe a potential link in HPV+ OPSCCs between reduced DNA damage and other tumor-intrinsic and immune-related contributors to recurrence risk, opening opportunities to detect and target this high-risk biology.

OBJECTIVES:Survivors of head and neck cancer (HNC) are at high risk for developing lymphedema and fibrosis (LEF). Once diagnosed with LEF, survivors must engage in a lifelong program of self-care to minimize long-term adverse effects. However, evidence-based LEF self-management (SM) programs are lacking. To fill this void, we developed and pilot-tested a LEF-SM program for HNC survivors. MATERIALS AND METHODS:The LEF-SM Program was developed using the Information-Motivation-Behavioral Skills model of health behavior change as a framework. The program was pilot tested in a three-group randomized controlled trial evaluating feasibility and preliminary efficacy. Fifty-nine participants were randomized to: Usual care (n = 20), usual care plus LEF-SM Program (n = 20), and usual care plus LEF-SM Program plus lymphedema therapist follow-up (n = 19). Assessments were conducted at baseline, 3-, 6-, 9-, and 12-month. Outcomes included feasibility and preliminary efficacy (LEF progression, symptom burden, and jaw range of motion). Multivariate covariance pattern model analysis was used to test differences between groups. RESULTS:1) Feasibility: 97.4% of the participants completed three of three planned LEF self-management skill training sessions, 92.1% completed at least two of three planned motivational interviewing sessions, and 82.3% completed at least two of three planned lymphedema therapist follow-up sessions. Participant satisfaction with the LEF-SM Program was high. No adverse events were reported. 2) Preliminary Efficacy: Compared to usual care, LEF-SM Program (± follow-up) showed a decrease in LEF severity and symptom burden (p < 0.05). CONCLUSION:The LEF-SM Program is feasible and potentially efficacious. Further testing is warranted for this novel program addressing an unmet need for HNC survivors. TRIAL REGISTRATION:This study was registered on January 22, 2017, at ClinicalTrials.gov, a service of the US National Institute of Health (NCT03030859). The URL of the trial registry record:https://www. CLINICALTRIALS:gov/study/NCT03030859.

Dermatofibrosarcoma protuberans (DFSP) is a rare cutaneous soft tissue sarcoma and affects an estimated 1,500 people annually in the United States. DFSP frequently exhibits extensive local infiltration. Initial treatment is through surgical excision, and care should be taken to ensure that negative margins are achieved to minimize recurrence. Although DFSP has a reported high rate of recurrence, metastasis is more uncommon. Fibrosarcomatous DFSP is an aggressive variant with an increased risk for local recurrence and metastasis. If achieving negative margins or resection is not feasible, radiation therapy or systemic treatment are options that may be considered by a multidisciplinary team. The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) outline recommended treatment options available for DFSP.

e18068 Background: Chronic lymphedema is a common late effect after completion of head and neck cancer (HNC) treatment, contributing to substantial symptom burden and negatively impacting quality of life. To date, no evidence-based effective approaches are available to treat this progressive condition. Findings from a single-group, pre-post design study showed the feasibility, acceptability, and potential efficacy of photobiomodulation (PBM) for treatment of HNC-related chronic lymphedema. This study aimed to further evaluate preliminary efficacy of PBM therapy for chronic lymphedema in HNC survivors. Methods: This was a pilot, randomized, wait-list controlled trial conducted during the COVID pandemic. Eligible HNC survivors included those with chronic lymphedema after completion of initial lymphedema therapy. Participants were randomized to one of two arms: intervention arm or wait-list control arm. Study assessments were conducted at baseline (pre-intervention), end-of-intervention, 4-week, and 8-week post-intervention. Participants in the intervention arm received a total of 12 PBM therapy sessions (twice a week for 6 weeks). Participants in the wait-list control arm underwent the same study assessments and were then offered the same frequency and dose of PBM therapy as the intervention arm, after completion of the initial 8-week post-intervention assessment. Outcome measures included severity of external lymphedema and fibrosis (LEF), symptom burden, jaw range of motion, and neck range of motion. Of note, assessment of internal lymphedema was not feasible due to exam limitations associated with COVID. Linear mixed-effects models were used as statistical analysis methods. Results: Of the 25 eligible patients enrolled in the study, 12 patients were randomized to the intervention arm and 13 patients to the wait-list control arm. In the intervention arm, two patients withdrew from the study before attending the PBM therapy sessions due to disease progression and family obligation. Regarding the intervention completion, 110 of 120 (91.7%) planned treatments sessions (12 sessions per patient x 10 patients = 120 sessions) were completed. Reasons for missing the PBM therapy sessions included job conflict, family obligations, and COVID infection. No adverse events were reported. Compared to the wait-list control arm, the intervention arm demonstrated improvements at 8-week post-intervention in the severity of external LEF (p < 0.05), symptom burden (e.g., Soft Tissues and Neurologic Toxicity subscale, Cohen’s d = - 0.47), and neck range of motion (e.g., extension, Cohen’s d = 0.65). Conclusions: Our findings indicate that PBM therapy may improve chronic lymphedema associated outcomes. Future large RCTs are warranted to examine the efficacy of PBM therapy for HNC-related chronic lymphedema. Clinical trial information: NCT04482855 .

To the Editor: Previous studies have shown that male sex is a significant predictor of poor outcomes in patients with squamous cell carcinoma. 1 O'Connor D.M. Murad F. Danesh M.J. et al. Immune status does not independently influence cutaneous squamous cell carcinoma metastasis and death when stratified by tumor stage: a dual-center retrospective cohort analysis of primary N0 disease. J Am Acad Dermatol. 2022; 87: 1295-1302https://doi.org/10.1016/j.jaad.2022.08.050 Abstract Full Text Full Text PDF PubMed Scopus (4) Google Scholar ,2 Duran J. Morgan F.C. Karia P.S. Schmults C.D. An evaluation of high-stage cutaneous squamous cell carcinoma outcomes by sex. Br J Dermatol. 2017; 177: 1131-1133https://doi.org/10.1111/bjd.15208 Crossref Scopus (9) Google Scholar Basal cell carcinoma (BCC) has a higher incidence in men, but the prognostic role of sex in BCC outcomes is poorly defined. 3 Asgari M.M. Moffet H.H. Ray G.T. Quesenberry C.P. Trends in basal cell carcinoma incidence and identification of high-risk subgroups, 1998-2012. JAMA Dermatol. 2015; 151: 976-981https://doi.org/10.1001/jamadermatol.2015.1188 Crossref PubMed Scopus (111) Google Scholar Our objective was to examine the impact of biological sex on outcomes in advanced BCC.

The NCCN Guidelines for Merkel Cell Carcinoma (MCC) provide recommendations for diagnostic workup, clinical stage, and treatment options for patients. The panel meets annually to discuss updates to the guidelines based on comments from expert review from panel members, institutional review, as well as submissions from within NCCN and external organizations. These NCCN Guidelines Insights focus on the introduction of a new page for locally advanced disease in the setting of clinical node negative status, entitled "Clinical N0 Disease, Locally Advanced MCC." This new algorithm page addresses locally advanced disease, and the panel clarifies the meaning behind the term "nonsurgical" by further defining locally advanced disease. In addition, the guideline includes the management of in-transit disease and updates to the systemic therapy options.

Purpose: Optimal integration of local therapy and systemic immune therapy for patients with mucosal melanoma (MM) is uncertain. We evaluated treatment patterns and outcomes following radiation therapy (RT) in combination with immune checkpoint inhibition (ICI) in MM. Methods and Materials: Thirty-seven patients with localized (n = 32, 87%) or node -positive (n = 5, 14%) MM were treated across institutions with RT to the primary tumor with or without oncologic resection (n = 28, 76%) and ICI from 2012 to 2020. Recurrence rates were estimated using cumulative incidence in the presence of the competing risk of death. Results: Mucosal sites were head/neck (n = 29, 78%), vaginal (n = 7, 19%), and anorectal (n = 1, 3%). Patients received ICI prior to concurrent with RT (n = 14, 38%), following RT (n = 5, 14%), or at recurrence (n = 18, 49%). The objective response rate for evaluable patients was 31% for ICI as initial treatment (95% CI, 11%-59%) and 19% for ICI at recurrence (95% CI, 4%-46%). Median follow-up was 26 months for living patients; median overall survival (OS) was 54 months (95% CI, 31 months -not reached). Two-year OS was 85%; distant metastasis -free survival 44%. The 2 -year cumulative incidence of local recurrence (LR) was 26% (95% CI, 13%-41%). For 9 patients with unresectable disease, 2 -year OS was 88% (95% CI, 35%-98%); LR was 25% (95% CI, 3%-58%). For 5 patients with positive nodes at diagnosis, 2 -year OS was 100%; LR was 0%. Conclusions: High rates of local control were achieved with RT with or without oncologic resection and ICI for localized and locally advanced MM. In particular, favorable local control was possible even for patients with unresectable or node -positive disease. Although risk of distant failure remains high, patients with MM may benefit from aggressive local therapy including RT in the setting immunotherapy treatment. (c) 2023 The Author(s). Published by Elsevier Inc. on behalf of American Society for Radiation Oncology. This is an open access article under the CC BY -NC -ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Purpose: To identify the characteristics, indications, and toxicities among patients receiving proton beam therapy (PBT) in the final year of life at an academic medical center. Materials and Methods: A retrospective review of patients who received PBT within the final 12 months of life was performed. Electronic medical records were reviewed for patient and treatment details from 2010 to 2019. Patients were followed from the start of PBT until death or last follow-up. Acute (3 months) toxicities were graded using the Common Terminology Criteria for Adverse Events v5.0. Imaging response was assessed using the Response Evaluation Criteria in Solid Tumors v1.1. The chi 2 test was used to evaluate factors associated with palliative treatment. Simple logistic regression was used to evaluate factors associated with toxicity. Results: Bet299 patients were treated at the end of life (EOL) out of 5802 total patients treated with PBT (5.2%). Median age was 68 years (19-94 years), 58% male. The most common cancer was nonsmall cell lung cancer (27%). Patients were treated for symptom palliation alone (11%), durable control (57%), curative intent (16%), local recurrence (14%), or oligometastatic disease (2%). Forty-five percent received reirradiation. Median treatment time was 32 days (1-189 days). Acute toxicity was noted in 85% of the patients (31% G1, 53% G2, 15% G3). Thirteen patients (4%) experienced chronic toxicity. Breast and hematologic malignancy were associated with palliative intent chi 2 (1, N = 14) = 17, P = .013; (chi 2 (1, N = 14) = 18, P = .009). Conclusion: The number of patients treated with PBT at the EOL was low compared to all comers. Many of these patients received treatment with definitive doses and concurrent systemic therapy. Some patients spent a large portion of their remaining days on treatment. A prognostic indicator may better optimize patient selection for PBT at the EOL.

PURPOSE:Standard treatment for basal cell carcinoma (BCC) is surgical resection. However, a subset of locally advanced BCCs may be unresectable, or surgery would result in unacceptable functional or cosmetic defects. Outcomes after definitive radiation therapy for locally advanced BCC in the contemporary era are not well established. We sought to determine locoregional control and disease-specific survival after definitive radiation therapy for locally advanced BCC. METHODS AND MATERIALS:Patients with locally advanced BCC treated with definitive radiation therapy between 2005 and 2020 from 4 academic tertiary care institutions were included. Locally advanced BCCs were defined as patients with unresectable disease, or locations where margin negative resection would lead to unacceptable cosmetic or functional deficit. Additionally, a set of 5 risk factors (size ≥4 cm, the presence of bone invasion, PNI, immunocompromised patient, and recurrent disease) was separately defined and outcomes were investigated. RESULTS:Six hundred eight locally advanced BCC cases were identified, of which 140 were treated with definitive radiation therapy. Median follow-up was 22.9 months (1.5-207.2 months). One hundred one (72.1%) tumors were treated with upfront definitive radiation therapy, whereas 39 (27.9%) were treated for a recurrence. Five-year Kaplan-Meier estimated locoregional control was 78%. The majority of locoregional failures were local recurrences (95.5%). Larger tumor diameter was a risk factor for locoregional failure (P = .045), whereas recurrent disease was not (P = .29). Cumulative incidence of BCC-related mortality at 5 years was 9.5%. Patients with 0 risk factors had a 5-year FF-LRF of 92.4%, whereas those with 1+ risk factors had a 5-year freedom from locoregional failure of 68.5% (P = .004). CONCLUSIONS:Definitive radiation therapy for locally advanced BCC has excellent locoregional control, with tumor size representing the only risk factor for recurrence in this study.

Background:Limited understanding of the biology predisposing certain human papillomavirus-related (HPV+) oropharyngeal squamous cell carcinomas (OPSCCs) to relapse impedes therapeutic personalization. We aimed to identify molecular traits that distinguish recurrence-prone tumors. Methods:50 HPV+ OPSCCs that later recurred (cases) and 50 non-recurrent controls matched for stage, therapy, and smoking history were RNA-sequenced. Groups were compared by gene set enrichment analysis, and select differences were validated by immunohistochemistry. Features discriminating groups were scored in each tumor using gene set variation analysis, and scores were evaluated for recurrence prediction ability. Results:Cases downregulated pathways linked to anti-tumor immunity (FDR-adjusted p<.05) and contained fewer tumor-infiltrating lymphocytes (p<.001), including cytotoxic T-cells (p=.005). Cases also upregulated pathways related to cell division and other aspects of tumor progression. Upregulated and downregulated pathways were respectively used to define a tumor progression score (TPS) and immune suppression score (ISS) for each tumor. Correlation between TPS and ISS (r=.603, p<.001) was potentially explained by observed upregulation of DNA repair pathways in cases, which might enhance their progression directly and by limiting cytosolic DNA-induced inflammation. Accordingly, cases contained fewer double-strand breaks based on staining for phospho-RPA32 (p=.006) and γ-H2AX (p=.005) and downregulated pro-inflammatory components of the cytoplasmic DNA sensing pathway. A combined score derived from TPS and ISS optimized recurrence prediction and stratified survival in a manner generalizable to three external cohorts. Conclusions:We provide novel evidence that limiting genomic instability makes tumor-intrinsic and immune-mediated contributions to HPV+ OPSCC recurrence risk, opening opportunities to detect and target this treatment-resistant biology.

OBJECTIVE:Undergoing surgery and adjuvant radiotherapy (aRT) at the same facility has been associated with higher overall survival (OS) in head and neck squamous cell carcinoma. Our study investigates whether undergoing surgery and aRT at the same academic facility is associated with higher OS in major salivary gland cancer (MSGC). METHODS:The 2006-2018 National Cancer Database was queried for patients with MSGC undergoing surgery at an academic facility and then aRT. Multivariable binary logistic and Cox proportional hazards regression models were implemented. RESULTS:Of 2801 patients satisfying inclusion criteria, 2130 (76.0%) underwent surgery and aRT at the same academic facility. Residence in a less populated area (adjusted odds ratio [aOR] 1.69, 95% confidence interval [CI] 1.16-2.45), treatment without adjuvant chemotherapy (aOR 1.97, 95% CI 1.41-2.76), and aRT duration (aOR 1.02, 95% CI 1.01-1.04) were associated with undergoing surgery and aRT at different facilities on multivariable logistic regression adjusting for patient demographics, clinicopathologic features, and adjuvant therapy (p < 0.01). Five-year OS was higher in patients undergoing surgery and aRT at the same academic facility (68.8% vs. 61.9%, p < 0.001). Undergoing surgery and aRT at different facilities remained associated with worse OS on multivariable Cox regression (aHR 1.41, 95% CI 1.10-1.81, p = 0.007). CONCLUSION:Undergoing surgery and aRT at the same academic facility is associated with higher OS in MSGC. Although undergoing surgery and aRT at the same academic facility is impractical for all patients, academic physicians should consider same-facility treatment for complex patients who would most benefit from clear multidisciplinary communication. LEVEL OF EVIDENCE:4 Laryngoscope, 134:3620-3632, 2024.

Purpose/Objective(s) This prospective “Radvax” trial combined HFRT to one metastatic lesion with pembrolizumab (pembro) in melanoma patients progressing through anti-PD1 therapy. Immune profiling was undertaken to characterize dynamic immune features occurring before and after RT, and correlate these changes to clinical response. Materials/Methods In this prospective trial, melanoma patients were required to have disease progression (by RECIST v1.1) after ≥ 2 doses of anti-PD1, an index lesion ≥1 cm amenable to HFRT, and ≥1 other lesion that was not radiated to follow for “abscopal” response. Pembro was given 1 week prior to RT, and then continued after RT. The HFRT dose was 8 Gy x 3 fractions or 17 Gy x 1 fraction. Response of unirradiated metastatic lesions (abscopal response) was measured by RECIST. High dimensional flow cytometry and single-cell RNA/TCR-sequencing were performed on peripheral CD8 T cells from Radvax patients and from a pembro-only control cohort. Results In metastatic melanoma patients progressing through anti-PD1, 7 of 16 had an objective response to HFRT + pembro (abscopal response), including 4 complete and 3 partial responses. Responses are durable, with 3/4 complete responders alive with no evidence of progression >5 years after HFRT, and 1/3 partial responders alive, now with slow progression >6 years after HFRT. Of the 5 patients who received HFRT to a nodal metastasis, 4 had CR/PR. In contrast to a cohort of pembro-only patients who exhibited a robust increase in proliferating PD1+ CD8 T cells that peaked one week after the first cycle of pembro, RadVax patients had a marginal increase in proliferating PD1+ CD8 T cells at this timepoint, consistent with relative refractoriness to PD1 blockade. However, an increase in proliferating CD8 T cells was observed in RadVax patients two weeks after HFRT. In clinical responders, the composition of proliferating CD8 T cells after HFRT was characterized by an increase in early effector-memory (EMearly) and central memory (CM) CD8 T cells. Moreover, a post-HFRT increase in developmental relatedness between EMearly/CM T cells with recently activated CD8 T cells was observed, suggesting the EMearly/CM population may have been newly primed after HFRT. In non-responders, the post-HFRT composition of proliferating CD8 T cells did not increase in either recently activated or EMearly/CM CD8 T cells. Conclusion This analysis provides insights into how addition of HFRT can elicit durable clinical response to anti-PD-1 in a subset of melanoma patients who fail to respond to anti-PD1 alone. After addition of HFRT to pembro, patients who subsequently respond show an increase in treatment-responsive effector and memory CD8 T cells that may result from new T cell priming. The expansion of these non-exhausted effector and memory CD8 T cells after HFRT may explain the durability of observed responses. In patients who received HFRT to lymph node metastases, response rates were particularly high, suggesting the site of irradiation may influence efficacy.