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Importance: Asymmetric oropharynx uptake on positron emission tomography (PET)/computed tomography (CT) is a common incidental finding and often prompts otolaryngology referral to rule out malignancy; however, the true risk of malignancy based on this finding is unknown., Objective: To identify the incidence of oropharynx cancer in patients with incidental asymmetric oropharynx PET uptake., Design, Setting, and Participants: In this retrospective cohort study, patients 18 years and older undergoing PET/CT scans at Mayo Clinic between January 2001 and December 2018 were included. Patients with a history or pretest suspicion of oropharynx cancer were excluded. Data were analyzed from March 2021 to December 2023., Exposure: Blinded radiologic review of imaging studies, including measurement of maximum standardized uptake values (SUVmax) of the ipsilateral side of concern and contralateral side. Retrospective medical record review for associated clinical data., Main Outcomes and Measures: The primary study outcome was the incidence of oropharynx cancer diagnosis in patients with asymmetric oropharynx PET uptake. The primary outcome was formulated before data collection., Results: Of the 1854 patients identified with asymmetric oropharynx PET uptake, 327 (17.6%) met inclusion criteria. Of these, 173 (52.9%) were male, and the median (range) age was 65.0 (24.8-90.7) years. The mean (SD) follow-up interval was 52.1 (43.4) months. A total of 18 of 327 patients (5.5%) were newly diagnosed with oropharynx cancer. The most common diagnosis was squamous cell carcinoma (n = 9), followed by lymphoma (n = 8), and sarcoma (n = 1). Patients with an incidental diagnosis of oropharynx cancer had higher mean (SD) ipsilateral SUVmax (8.7 [3.7] vs 5.3 [1.9]) and SUVmax ratio (3.0 [1.6] vs 1.6 [0.6]) compared with patients with normal examination findings. SUVmax ratio and difference were found to be good discriminators of oropharynx cancer, with areas under the receiver operating characteristic curve of 86.3% (95% CI, 76.4-94.6) and 85.8% (95% CI, 74.8-94.6), respectively. Patients with a new diagnosis of oropharynx cancer were more likely to have a corresponding CT abnormality than those with normal examination findings (6 of 18 [33%] vs 24 of 295 [8.1%]). Patients with concerning lesions on oropharynx palpation by an otolaryngology health care professional were significantly more likely to be diagnosed with oropharynx cancer compared with patients with normal examination findings (odds ratio, 28.4; 95% CI, 6.6-145.8)., Conclusions and Relevance: In this cohort study, while incidental asymmetric oropharynx PET uptake was common, a new diagnosis of oropharynx cancer was not and potentially results in a large volume of unnecessary referrals and work-up. Using SUVmax ratio, SUVmax difference, and CT correlation may increase the benefit of referral. Patients with a palpable oropharynx lesion and asymmetric oropharynx PET uptake should undergo confirmatory biopsy.

Purpose: Minibeam radiation therapy (MBRT) is characterized by the delivery of submillimeter-wide regions of high "peak" and low "valley" doses throughout a tumor. Preclinical studies have long shown the promise of this technique, and we report here the first clinical implementation of MBRT., Methods and Materials: A clinical orthovoltage unit was commissioned for MBRT patient treatments using 3-, 4-, 5-, 8-, and 10-cm diameter cones. The 180 kVp output was spatially separated into minibeams using a tungsten collimator with 0.5 mm wide slits spaced 1.1 mm on center. Percentage depth dose (PDD) measurements were obtained using film dosimetry and plastic water for both peak and valley doses. PDDs were measured on the central axis for offsets of 0, 0.5, and 1 cm. The peak-to-valley ratio was calculated at each depth for all cones and offsets. To mitigate the effects of patient motion on delivered dose, patient-specific 3-dimensional-printed collimator holders were created. These conformed to the unique anatomy of each patient and affixed the tungsten collimator directly to the body. Two patients were treated with MBRT; both received 2 fractions., Results: Peak PDDs decreased gradually with depth. Valley PDDs initially increased slightly with depth, then decreased gradually beyond 2 cm. The peak-to-valley ratios were highest at the surface for smaller cone sizes and offsets. In vivo film dosimetry confirmed a distinct delineation of peak and valley doses in both patients treated with MBRT with no dose blurring. Both patients experienced prompt improvement in symptoms and tumor response., Conclusions: We report commissioning results, treatment processes, and the first 2 patients treated with MBRT using a clinical orthovoltage unit. While demonstrating the feasibility of this approach is a crucial first step toward wider translation, clinical trials are needed to further establish safety and efficacy., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Introduction: We performed a retrospective analysis of patients with multiple myeloma (MM) receiving palliative radiotherapy (RT) and assessed factors associated with local control, with a focus on dose/fractionation and cytogenetics., Materials and Methods: We included patients who received palliative RT for MM at our institution. Cytogenetics were collected via fluorescence in situ hybridization. Follow-up imaging was used to assess local control., Results: A total of 239 patients with 362 treated lesions were included. Eighty-six (36.0%) patients had high-risk cytogenetics. Most lesions received 20 Gray (Gy) in 5 fractions (131, 36.2%), 8 Gy in 1 fraction (93, 25.7%), or 30 Gy in 10 fractions (48, 13.3%). At a median follow-up of 4.3 years, 4-year local progression was 13.4% (95% confidence interval [CI]: 10.3-17.5). No cytogenetic abnormalities were correlated with local progression, nor were double- and triple-hit status. There was a nonsignificant trend toward association between number of treated lesions and local progression (HR for >3 vs. 1: 2.43 [95% CI: 0.88-6.74], P = .059). Among patients with >3 treated lesions, equivalent dose in 2 Gy fractions ≥20 Gy reduced progression (HR: 0.05 [95% CI: 0.01-0.23], P = .0001)., Conclusion: In this large study of patients with MM, modern palliative RT achieved excellent rates of long-term local control. Although there was no dose-response observed in the overall cohort, patients with high volume symptomatic disease may benefit from EQD2 ≥20 Gy. High-risk cytogenetics did not appear to influence radioresponsiveness, and standard radiation doses appear to be effective for all MM patients regardless of cytogenetics., Competing Interests: Disclosure The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this article., (Copyright © 2024 Elsevier Inc. All rights reserved.)

For patients with metastatic triple-negative breast cancer (TNBC), treatment with pembrolizumab is dependent on the accurate determination of programmed death ligand 1 (PD-L1) expression using immunohistochemistry (IHC). This study evaluated the interobserver concordance in assessing PD-L1 expression on TNBC samples using the commercial 22C3 IHC assay and an in-house assay based on the E1L3N antibody. Concordance between the 22C3 and the E1L3N IHC assays was evaluated on TNBC samples read by a commercial laboratory and a Brigham and Women's Hospital breast pathologist (BWH reader). Each slide was given a PD-L1 combined positive score (CPS) and was considered PD-L1 positive or negative based on the CPS cutoff of 10. Interobserver concordance for the assays was also evaluated on a subset of samples between 2 and 3 independent readers. On 71 samples, 2 independent readers (1 BWH reader and commercial laboratory) using E1L3N and 22C3, respectively, reached agreement on PD-L1 status (positive/negative) on 64 samples (90.1%). Using 22C3, 2 independent readers reached agreement on PD-L1 status on 30 of 36 samples (83.3%), and 3 independent readers reached agreement on 16 of 27 samples (59.3%). Using E1L3N, 2 BWH readers reached agreement on PD-L1 status on 18 of 27 samples (66.7%). Three BWH readers reached an agreement on 2 of 12 of the most challenging samples (16.7%). In conclusion, concordance between E1L3N and 22C3 testing using CPS for PD-L1 in metastatic TNBC was >90%. However, certain cases were challenging to agree upon using current threshold criteria, highlighting the need for more standardized evidence-based methods to assess PD-L1 expression., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Context.—: The Nottingham Grading System (NGS) developed by Elston and Ellis is used to grade invasive breast cancer (IBC). Glandular (acinar)/tubule formation is a component of NGS., Objective.—: To investigate the ability of pathologists to identify individual structures that should be classified as glandular (acinar)/tubule formation., Design.—: A total of 58 hematoxylin-eosin photographic images of IBC with 1 structure circled were classified as tubules (41 cases) or nontubules (17 cases) by Professor Ellis. Images were sent as a PowerPoint (Microsoft) file to breast pathologists, who were provided with the World Health Organization definition of a tubule and asked to determine if a circled structure represented a tubule., Results.—: Among 35 pathologists, the κ statistic for assessing agreement in evaluating the 58 images was 0.324 (95% CI, 0.314-0.335). The median concordance rate between a participating pathologist and Professor Ellis was 94.1% for evaluating 17 nontubule cases and 53.7% for 41 tubule cases. A total of 41% of the tubule cases were classified correctly by less than 50% of pathologists. Structures classified as tubules by Professor Ellis but often not recognized as tubules by pathologists included glands with complex architecture, mucinous carcinoma, and the "inverted tubule" pattern of micropapillary carcinoma. A total of 80% of participants reported that they did not have clarity on what represented a tubule., Conclusions.—: We identified structures that should be included as tubules but that were not readily identified by pathologists. Greater concordance for identification of tubules might be obtained by providing more detailed images and descriptions of the types of structures included as tubules., Competing Interests: The authors have no relevant financial interest in the products or companies described in this article., (© 2024 College of American Pathologists.)

Abstract: Unirradiated patients with relapsed/refractory (R/R) B-cell non-Hodgkin lymphoma (NHL) who undergo anti-CD19 chimeric antigen receptor T-cell therapy (CART) have a predominant localized pattern of relapse, the significance of which is heightened in individuals with limited/localized disease before CART. This study reports on the outcomes of patients with R/R NHL and limited (<5 involved sites) disease bridged with or without radiotherapy. A multicenter retrospective review of 150 patients with R/R NHL who received CART with <5 disease sites before leukapheresis was performed. Bridging treatment, if any, was administered between leukapheresis and CART infusion. Study end points included relapse-free survival (RFS), event-free survival (EFS), and overall survival. Before CART infusion, 48 patients (32%) received bridging radiotherapy (BRT), and 102 (68%) did not. The median follow-up was 21 months. After CART infusion, BRT patients had higher objective response (92% vs 78%; P = .046) and sustained complete response rates (54% vs 33%; P = .015). Local relapse in sites present before CART was lower in the BRT group (21% vs 46%; P = .003). BRT patients had improved 2-year RFS (53% vs 44%; P = .023) and 2-year EFS (37% vs 34%; P = .039) compared with patients who did not receive BRT. The impact of BRT was most prominent in patients who had ≤2 pre-CART involved disease sites, with 2-year RFS of 62% in patients who received BRT compared with 42% in those who did not (P = .002). BRT before CART for patients with limited (<5 involved disease sites) R/R NHL improves response rate, local control, RFS, and EFS without causing significant toxicities., (© 2024 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

The majority of breast cancers have a solid tumor growth pattern and are seen on mammography as dense masses with defined borders. Cancers detected as asymmetry are rare, and little has been published about their pathologic features. These cancers do not form discrete masses, and a border is not evident. This retrospective case series was undertaken to identify malignancies presenting as asymmetry, to describe their histologic and biologic features and to correlate these features with the mammographic appearance. During the 7.5 years of the study, 18,419 coreneedle biopsies were performed and 42 cases of malignancy presenting as asymmetry were diagnosed (0.2%). The majority were invasive carcinomas (30% or 71%), followed by ductal carcinoma in situ (9% or 21%) and lymphoma (3% or 7%). The invasive carcinomas could be divided into 3 groups: very small unifocal (T1a) carcinomas, larger unifocal carcinomas, and cases with multiple foci of invasion. The latter group had a higher rate of lymph node metastases and more stage III cancers. The invasive carcinomas were predominantly of special histologic types and associated with a minimal stromal response. In contrast, the cases of ductal carcinoma in situ tended to be of higher grade and elicited periductal fibrosis, which likely contributed to the increased density seen on mammography. Although most of the invasive carcinomas were of favorable biologic type (97%) and were stage I (67%), triple-negative carcinomas and stage III carcinomas were also detected. When evaluating core needle biopsies performed for asymmetry, pathologists should be aware that these cancers can have a subtle infiltrative appearance with little or no desmoplastic response, mirroring their appearance by imaging., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: H. pylori eradication therapy (HPE) can lead to tumor regression in H. pylori -positive (HPP) gastric mucosa-associated lymphoid tissue (MALT) lymphoma. However, some patients do not have detectable H. pylori (HP) infection ( H. pylori -negative [HPN]) and the guidelines differ in their initial approach to HPN patients. The National Comprehensive Cancer Network (NCCN) recommends proceeding to radiation therapy, whereas European Society for Medical Oncology suggests HPE for every patient, even those who are HPN. To address this issue, we evaluated the effectiveness of HPE in limited-stage gastric MALT lymphoma., Materials and Methods: We retrospectively reviewed patients newly diagnosed with stage IE gastric MALT lymphoma between January 2002 and December 2022. The primary outcome was the complete remission (CR) rate defined as no macroscopic findings of lymphoma and negative gastric biopsy at the follow-up gastric endoscopy., Results: Fifty-two patients were reviewed, and HP infection was detected in 19 (36.5%) patients-14 by immunostaining, three by serology, and one each by stool antigen and urea breath test. All 19 HPP and eight of the 33 HPN patients received HPE treatment. The CR rate was 63% (12/19) in HPP patients and 13% (1/8) in HPN patients ( P = .033). After a median follow-up of 89.7 months, only two of the 12 HPP patients achieving CR have relapsed; the one HPN patient who received HPE remains in CR at 12+ months., Conclusion: For limited-stage HPP gastric MALT lymphoma, HPE is an effective and durable first-line treatment and should be used. For HPN patients, the CR rate with HPE is very low in our experience and is thus in support of the NCCN guideline.

Competing Interests: Scott C Lester; royalties from Empyrean Medical Systems.

Proton therapy has emerged as a crucial tool in the treatment of head and neck and skull-base cancers, offering advantages over photon therapy in terms of decreasing integral dose and reducing acute and late toxicities, such as dysgeusia, feeding tube dependence, xerostomia, secondary malignancies, and neurocognitive dysfunction. Despite its benefits in dose distribution and biological effectiveness, the application of proton therapy is challenged by uncertainties in its relative biological effectiveness (RBE). Overcoming the challenges related to RBE is key to fully realizing proton therapy's potential, which extends beyond its physical dosimetric properties when compared with photon-based therapies. In this paper, we discuss the clinical significance of RBE within treatment volumes and adjacent serial organs at risk in the management of head and neck and skull-base tumors. We review proton RBE uncertainties and its modeling and explore clinical outcomes. Additionally, we highlight technological advancements and innovations in plan optimization and treatment delivery, including linear energy transfer/RBE optimizations and the development of spot-scanning proton arc therapy. These advancements show promise in harnessing the full capabilities of proton therapy from an academic standpoint, further technological innovations and clinical outcome studies, however, are needed for their integration into routine clinical practice.

Lymphocytic lobulitis (LL) is characterized by prominent lymphocytic infiltrates centered on lobules. Sclerosing lymphocytic lobulitis (SCLL) associated with diabetes mellitus (DM) or autoimmune disease (AI) was the first type to be described. Subsequently, non-sclerosing LL (NSCLL) was reported as an incidental finding in prophylactic mastectomies due to high risk germline mutations or a family history of breast cancer. The two types of LL were distinguished by stromal features and a predominant population of B-cells in the former and T-cells in the latter. In this study, 8 cases of NSCLL detected clinically or by screening were compared to 44 cases of SCLL. One case of NSCLL presented as a palpable mass, 2 as masses on screening, and 5 as MRI enhancement. In contrast, 80% of SCLL cases presented as palpable masses. Half the cases of NSCLL were associated with a BRCA1 or 2 mutation compared to 1 case of SCLL (2%). Three additional cases of NSCLL were associated with a strong family and/or personal history of breast cancer. Almost half (52%) of SCLL cases were associated with DM or AI, but only 25% of NSCLL. Immunoperoxidase studies confirmed a predominance of T-cells in NSCLL and B-cells in SCLL associated with DM or AI. It is important for pathologists to be aware of this new observation that NSCLL can be detected as a palpable mass or an imaging finding in diagnostic biopsies, as its presence can be indicative of a significant risk for breast cancer., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest. Acknowledgement Assistance with preparation of the figures was provided by Mary E. Lester (marylesterdesign.com)., (Copyright © 2024. Published by Elsevier Inc.)

Abstract: Immune checkpoint inhibitors (ICIs) have demonstrated remarkable response rates in relapsed or refractory Hodgkin lymphoma (HL). Still, most patients eventually progress. Patterns of progression after ICIs are not well described and are essential to defining the role of local therapies in combination with ICIs. We identified patients who received ICIs for HL between 2013 and 2022. Fludeoxyglucose-18 positron emission tomography (FDG-PET) before initiating ICI and at progression on/after ICI were reviewed, and areas of active HL were recorded. An exploratory analysis of treatable progression included patients with ≤5 sites of disease on pre-ICI FDG-PET and progression only at pre-ICI sites. Ninety patients were identified; 69 had complete records, and of these, 32 (52%) had relapsed at ICI initiation, 17 (25%) were refractory, and 16 (23%) received ICI as first-line therapy. Forty-five of 69 patients had ≤5 sites of disease (limited) on pre-ICI FDG-PET. Patients with >5 sites of disease had a higher risk of progression, and every site of disease >5 sites conferred an additional 1.2x higher chance of progression. At a median follow-up of 4.0 years, 41 of 69 patients had progressed on/after ICIs (cumulative incidence 66.4%), and of these, 22 of 41 patients progressed only at pre-ICI sites (cumulative incidence 39.4%). In an exploratory analysis, the cumulative incidence of a treatable progression among 45 patients with limited disease was 34%. The cumulative incidence of any progression among this cohort was 58.9%. More than one-third of patients with limited disease before ICIs experienced progression only at pre-ICI sites of disease. These patients could be candidates for radiation during or after ICIs., (© 2024 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Objectives: To investigate the relationship between nutritional supplementation and radiation dose to the pharyngeal constrictor muscles and larynx for head and neck (HN) cancer patients undergoing radiotherapy., Methods: We retrospectively analyzed radiotherapy (RT) dose for 231 HN cancer patients, focusing on the pharyngeal constrictors and larynx. We defined nutritional supplementation as feeding tube utilization or >10% weight loss from baseline within 90 days after radiotherapy completion. Using deformable image registration (DIR), we mapped each patient's anatomical structures to a reference coordinate system, and corresponding deformations were applied to dose matrices. Voxel doses were utilized as features for ridge logistic regression models, optimized through 5-fold cross-validation. Model performance was assessed with area under the curve of a receiver operating curve (AUC) and F1 score. We built and compared models using 1) pharyngeal constrictor voxels, 2) larynx voxels, 3) clinical factors and mean regional dose metrics, and 4) clinical factors and dose-volume histogram metrics. Test set AUCs were compared among the models, and feature importance was evaluated., Results: DIR of the pharyngeal constrictors and larynx yielded mean Dice coefficients of 0.80 and 0.84, respectively. Pharyngeal constrictors voxels and larynx voxel models had AUC of 0.88 and 0.82, respectively. Voxel-based dose modeling identified the superior to middle regions of the pharyngeal constrictors and the superior region of larynx as most predictive of feeding tube use/weight loss. Univariate analysis found treatment setting, treatment laterality, chemotherapy, baseline dysphagia, weight, and socioeconomic status predictive of outcome. An aggregated model using mean doses of pharyngeal constrictors and larynx subregions had an AUC of 0.87 and the model using conventional DVH metrics had an AUC of 0.85 with p-value of 0.04. Feature importance calculations from the regional dose model indicated that mean doses to the superior-middle pharyngeal constrictor muscles followed by mean dose to the superior larynx were most predictive of nutritional supplementation., Conclusions: Machine learning modeling of voxel-level doses enables identification of subregions within organs that correlate with toxicity. For HN radiotherapy, doses to the superior-middle pharyngeal constrictors are most predictive of feeding tube use/weight loss followed by the doses to superior portion of the larynx., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Madhavan, Gamez, Garces, Lester, Ma, Mundy, Neben Wittich, Qian, Routman, Foote and Shiraishi.)

Purpose: To assess any correlation between swallowing dysfunction and radiation dose to 5 subregions of the larynx., Methods and Materials: A cohort of 136 patients with head and neck cancer, treated with either photon or proton radiation therapy, was assessed using an endpoint of patient-reported swallowing scores, evaluated with the European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire-H&N35 survey, within 1 month after treatment. Five subregions of the larynx were contoured, and dosimetric metrics were extracted for each subregion as well as the total larynx. Univariate and multivariate logistic regression statistical analyses were used to determine statistical correlation with the dose metrics and clinical variables. Univariate regression models were statistically compared using a non-nested model test., Results: Under univariate analysis, unilateral versus bilateral nodal irradiation (P = .004), concurrent chemotherapy (P = .007), and surgery (P = .015) were statistically significant predictors of poor swallowing score. Unilateral versus bilateral irradiation was statistically significant under multivariate analysis (P = .039). The epiglottis was the most predictive subregion of swallowing score, with a majority (21 of 25) of dosimetric variables being identified as statistically significant. The maximum dose to the epiglottis was the most significant dosimetric variable tested for poor swallowing score in both univariate (P = .003) and multivariate (P = .051) analyses. Comparison of univariate models indicated a general preference for epiglottic variables with the mean dose to the epiglottis being preferred at a statistically significant level in many cases., Conclusions: These results show the relatively increased sensitivity of the epiglottis compared with the rest of the larynx when considering patient-reported decrements in quality-of-life swallowing score and support both the inclusion of the epiglottis in standard larynx contours and the assessment of the epiglottis dose during plan evaluation. Our data suggest that keeping the mean and max doses to the epiglottis <20 to 37 Gy and <53 to 60 Gy, respectively, will reduce swallowing difficulties., Competing Interests: Dr Foote reports royalties from Elsevier and UpToDate. No other disclosures were reported., (© 2024 The Author(s).)

Objectives: Social determinants of health (SDOH) can influence access to cancer care, clinical trials, and oncologic outcomes. We investigated the association between SDOH, distance from treatment center, and treatment type with outcomes in human papillomavirus associated oropharyngeal squamous cell carcinoma [HPV(+)OPSCC] patients treated at a tertiary care center., Study Design: Retrospective review., Methods: HPV(+)OPSCC patients treated surgically from 2006 to 2021 were selected from our departmental Oropharyngeal Cancer RedCap database. Demographic data, treatment, and oncologic outcomes were extracted. Distance was calculated in miles between the centroid of each patient zip code and our hospital zip code (zipdistance)., Results: 874 patients (89 % male; mean age: 58 years) were identified. Most patients (96 %) reported Non-Hispanic White as their primary race. 204 patients (23 %) had a high-school degree or less, 217 patients (25 %) reported some college education or a 2-year degree, 153 patients (18 %) completed a four-year college degree, and 155 patients (18 %) had post-graduate degrees. Relative to those with a high-school degree, patients with higher levels of education were more likely to live further away from our institution (p < 0.0001). Patients who received adjuvant radiation therapy elsewhere lived, on average, 104 miles further away than patients receiving radiation at our institution (Estimate 104.3, 95 % CI 14.2-194.4, p-value = 0.02). In univariable Cox PH models, oncologic outcomes did not significantly differ by zipdistance., Conclusions: Education level-and access to resources-varied proportionally to a patient's distance from our center. Patients travelling further distances for surgical management of OPSCC were more likely to pursue adjuvant radiation therapy at an outside institution. Distance traveled was not associated with oncologic outcomes. Breaking down barriers to currently excluded populations may improve access to clinical trials and improve oncologic outcomes for diverse patient populations., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

BACKGROUNDHER2-targeting therapies have great efficacy in HER2-positive breast cancer, but resistance, in part due to HER2 heterogeneity (HET), is a significant clinical challenge. We previously described that in a phase II neoadjuvant trastuzumab emtansine (T-DM1) and pertuzumab (P) clinical trial in early-stage HER2-positive breast cancer, none of the patients with HER2-HET tumors had pathologic complete response (pCR).METHODSTo investigate cellular and molecular differences among tumors according to HER2 heterogeneity and pCR, we performed RNA sequencing and ERBB2 FISH of 285 pretreatment and posttreatment tumors from 129 patients in this T-DM1+P neoadjuvant trial. A subset of cases was also subject to NanoString spatial digital profiling.RESULTSPretreatment tumors from patients with pCR had the highest level of ERBB2 mRNA and ERBB signaling. HER2 heterogeneity was associated with no pCR, basal-like features, and low ERBB2 expression yet high ERBB signaling sustained by activation of downstream pathway components. Residual tumors showed decreased HER2 protein levels and ERBB2 copy number heterogeneity and increased PI3K pathway enrichment and luminal features. HET tumors showed minimal treatment-induced transcriptomic changes compared with non-HET tumors. Immune infiltration correlated with pCR and HER2-HET status.CONCLUSIONResistance mechanisms in HET and non-HET tumors are distinct. HER2-targeting antibodies have limited efficacy in HET tumors. Our results support the stratification of patients based on HET status and the use of agents that target downstream components of the ERBB signaling pathway in patients with HET tumors.TRIAL REGISTRATIONClinicalTrials.gov NCT02326974.FUNDINGThis study was funded by Roche and the National Cancer Institute.

Background: Approximately 75% of all head and neck cancer patients are treated with radiotherapy (RT). RT to the oral cavity results in acute and late adverse events which can be severe and detrimental to a patient's quality of life and function. The purpose of this study was to explore associations between RT dose to a defined oral cavity organ-at-risk (OAR) avoidance structure, provider- and patient-reported outcomes (PROs), opioid use, and hospitalization., Methods: This was a retrospective analysis of prospectively obtained outcomes using multivariable modeling. The study included 196 patients treated with RT involving the oral cavity for a head and neck tumor. A defined oral cavity OAR avoidance structure was used in all patients for RT treatment planning. Validated PROs were collected prospectively. Opioid use and hospitalization were abstracted electronically from medical records., Results: Multivariable modeling revealed the mean dose to the oral cavity OAR was significantly associated with opioid use ( p = 0.0082) and hospitalization ( p = 0.0356) during and within 30 days of completing RT., Conclusions: The findings of this study may be valuable in RT treatment planning for patients with tumors of the head and neck region to reduce the need for opioid use and hospitalization during treatment.

Anti-CD19 chimeric antigen receptor T-cell therapy (CART) has revolutionized the outcomes of relapsed and/or refractory B-cell non-Hodgkin lymphoma. However, CART is still limited by its availability, toxicity, and response durability. Not all patients make it to the CART infusion phase due to disease progression. Among those who receive CART, a significant number of patients experience life-threatening cytokine release syndrome toxicity, and less than half maintain a durable response with the majority relapsing in pre-existing sites of disease present pre-CART. Radiation therapy stands as a promising peri-CART and salvage treatment that can improve the outcomes of these patients. Evidence suggests that bridging radiotherapy prior to CART controls the disease during the manufacturing period, augments response rates and local control, cytoreduces/debulks the disease and decreases the severity of cytokine release syndrome, and may prolong disease-free intervals and survival especially in patients with bulky disease. Consolidative radiotherapy for residual post-CART disease alters the pattern of relapse and improves local recurrence-free and progression-free survivals. Salvage radiotherapy for relapsed post-CART disease has favorable survival outcomes when delivered comprehensively for patients with limited relapsed disease and palliates symptoms for patients with diffuse relapsed disease. The biology of the disease during the peri-CART period is poorly understood, and further studies investigating the optimal timing and dosing of radiation therapy (RT) are needed. In this review, we tackle the most significant challenges of CART, review and propose how RT can help mitigate these challenges, and provide The Mayo Clinic experts' approach on incorporating RT with CART., (© 2023 Wiley Periodicals LLC.)

Most patients with solitary bone plasmacytomas (SBP) progress to multiple myeloma (MM) after definitive radiation therapy as their primary treatment. Whether the presence of high-risk (HR) cytogenetic abnormalities by fluorescence in situ hybridization (FISH) in the clonal plasma cells, obtained either directly from the diagnostic SBP tissue or the corresponding bone marrow examination at the time of diagnosis, is associated with a shorter time to progression (TTP) to MM is unknown. This study evaluated all patients diagnosed with SBP at the Mayo Clinic from January 2012 to July 2022. The presence of del(17p), t(14;16), t(4;14), or +1q (gain or amplification) by FISH in clonal plasma cells was defined as HR. A total of 114 patients were included in this cohort, and baseline FISH was available for 55 patients (48%), of which 22 were classified as HR (40%). The median TTP to MM for patients with SBP and HR FISH was 8 months (95% confidence interval [CI], 6.3-26) compared with 42 months (95% CI, 25-not reached [NR]) in patients with SBP without HR FISH (P < .001). In a multivariate analysis, only HR FISH was a significant predictor for shorter TTP to MM, independent of minimal marrow involvement and an abnormal serum free light chain ratio at diagnosis. Deletion (17p) and gain 1q abnormalities were the most common FISH abnormalities responsible for the short TTP to MM. Thus, assessing for HR FISH abnormalities in clonal plasma cells derived from either the diagnostic SBP tissue or the staging bone marrow examination of patients with newly diagnosed SBP is feasible and prognostic for a shorter TTP to MM., (© 2023 by The American Society of Hematology.)

Objectives: To investigate and describe the patterns of regional metastases and recurrences after surgical treatment of oropharyngeal squamous cell cancer (OPSCC)., Materials and Methods: Retrospective study of patients diagnosed with OPSCC from 2006 to 2021 at a tertiary referral center. Only patients treated with surgery including a neck dissection were included. Patients with unknown human papillomavirus (HPV) status, prior head and neck cancer, distant metastases, or synchronous head and neck cancer were excluded., Results: A total of 928 patients were included. 89% were males, the average age was 58.6 years (range: 25.2-87.5), 874 (94%) were HPV(+), and 513 (55.3%) had a tonsil cancer. Among cN + patients, the most commonly involved levels at presentation were level II (85.2%), level III (33.3%), and level IV (9.4%). In cN0 patients, metastases were only observed in level II (16.2%) and level III (9.2%). Nodal recurrence occurred in 48 (5.2%) patients after a median time of 1.0 years (interquartile range: 0.6-2.0). Nodal recurrence incidence was similar in HPV(+) and HPV(-) patients (5.0% vs. 7.4%, p = 0.44). The most common levels for regional recurrence were ipsilateral level II (45.8%), contralateral level II (43.8%), and ipsilateral level V (25.0%). Multivariable analysis revealed that pN was a significant predictor for regional recurrence (p = 0.02)., Conclusion: There is no difference in the distribution of regional metastases and recurrences in HPV(+) and HPV(-) OPSCC patients. Our findings align with the established understanding that regional metastases predominantly manifest in the ipsilateral level II-IV at presentation. Moreover, the data support the clinical recommendation to restrict elective neck dissection in cN0 patients to ipsilateral levels IIa and III, excluding level IIb. Regional recurrence is significantly associated with pN status., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Ltd.)

Majority of non-Hodgkin lymphoma (NHL) patients who achieve partial response (PR) or stable disease (SD) to CAR T-cell therapy (CAR T) on day +30 progress and only 30% achieve spontaneous complete response (CR). This study is the first to evaluate the role of consolidative radiotherapy (cRT) for residual fluorodeoxyglucose (FDG) activity on day +30 post- CAR T in NHL. We retrospectively reviewed 61 patients with NHL who received CAR T and achieved PR or SD on day +30. Progression-free survival (PFS), overall survival (OS), and local relapse-free survival (LRFS) were assessed from CAR T infusion. cRT was defined as comprehensive - treated all FDG-avid sites - or focal. Following day +30 positron emission tomography scan, 45 patients were observed and 16 received cRT. Fifteen (33%) observed patients achieved spontaneous CR, and 27 (60%) progressed with all relapses involving initial sites of residual FDG activity. Ten (63%) cRT patients achieved CR, and four (25%) progressed with no relapses in the irradiated sites. The 2-year LRFS was 100% in the cRT sites and 31% in the observed sites (P<0.001). The 2-year PFS was 73% and 37% (P=0.025) and the 2-year OS was 78% and 43% (P=0.12) in the cRT and observation groups, respectively. Patients receiving comprehensive cRT (n=13) had superior 2- year PFS (83% vs. 37%; P=0.008) and 2-year OS (86% vs. 43%; P=0.047) compared to observed or focal cRT patients (n=48). NHL patients with residual FDG activity following CAR T are at high risk of local progression. cRT for residual FDG activity on day +30 post-CAR T appears to alter the pattern of relapse and improve LRFS and PFS.

PET/CT is used to evaluate relapsed/refractory non-Hodgkin lymphoma (NHL) prior to chimeric antigen receptor T-cell (CAR-T) infusion at two time points: pre-leukapheresis (pre-leuk) and pre-lymphodepletion chemotherapy (pre-LD). We hypothesized that changes in PET/CT between these time points predict outcomes after CAR-T. Metabolic tumor volume (MTV), total lesion glycolysis (TLG), and other metrics were calculated from pre-leuk and pre-LD PET/CT scans in patients with NHL who received axicabtagene ciloleucel, and assessed for association with outcomes. Sixty-nine patients were analyzed. While single time point PET/CT characteristics were not associated with risk of PD or death, increases from pre-leuk to pre-LD in parenchymal MTV, nodal MTV, TLG of the largest lesion, and total number of lesions were associated with increased risk of death (p < 0.05 for all). LASSO analysis identified increasing extranodal MTV and increasing TLG of the largest lesion as strong predictors of death (AUC 0.74). Greater pre-LD total MTV was associated with higher risk of grade 3+ immune effector cell-associated neurotoxicity syndrome (ICANS) (p = 0.042). Increasing metabolic disease burden during CAR-T manufacturing is associated with increased risk of progression and death. A two variable risk score stratifies prognosis prior to CAR-T infusion and may inform risk-adapted strategies., (© 2023. Springer Nature Limited.)

Purpose: The optimal approach to incorporate radiation therapy (RT) in conjunction with chimeric antigen receptor (CAR) T-cell therapy (CART) for relapsed/refractory (r/r) B-cell non-Hodgkin lymphoma (bNHL) remains unclear. This study documented the RT local control rate among patients who received bridging radiation therapy (BRT) before CART and compares it with those who received salvage radiation therapy (SRT) after CART. This article further reports on a promising way to use SRT for post-CART disease and identifies predictors for RT in-field recurrence., Methods and Materials: We retrospectively reviewed 83 patients with r/r bNHL who received CART and RT, either as BRT pre-CART infusion (n = 35) or as SRT post-CART infusion (n = 48), between 2018 and 2021. RT was defined as comprehensive (compRT; ie, treated all sites of active disease) or focal (focRT). Limited disease was defined as disease amenable to compRT, involving <5 active disease sites., Results: At time of RT, patients who received BRT before CART had bulkier disease sites (median diameter, 8.7 vs 5.5 cm; P = .01) and were treated to significantly lower doses (median equivalent 2-Gy dose, 23.3 vs 34.5 Gy; P = .002), compared with SRT post-CART. Among 124 total irradiated sites identified, 8 of 59 (13%) bridged sites and 21 of 65 (32%) salvaged sites experienced in-field recurrence, translating to 1-year local control rates (LC) of 84% and 62%, respectively (P = .009). Patients with limited post-CART disease (n = 37) who received compSRT (n = 26) had better overall survival (51% vs 12%; P = .028), freedom from subsequent progression (31% vs 0%; P < .001), and freedom from subsequent event (19% vs 0%; P = .011) compared with patients with limited disease who received focSRT (n = 11)., Conclusions: BRT followed by CART appears to be associated with improved LC compared with SRT in r/r bNHL. Nonetheless, SRT offers a promising salvage intervention for limited (<5 sites) relapsed post-CART disease if given comprehensively., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Purpose: To evaluate the clinical patterns of utilization of OncotypeDX Recurrence Score (RS) in early-stage, hormone receptor-positive, human epidermal growth factor receptor 2-negative breast cancer (BC) at an academic center with previously established internal reflex testing guidelines., Methods: RS testing in accordance with preexisting reflex criteria and predictors of utilization outside of reflex criteria were retrospectively analyzed for the years 2019-2021 in a quality improvement evaluation. Patients were grouped according to OncotypeDX testing within (cohort A) or outside (cohort B) of predefined criteria which included a cap at age older than 65 years., Results: Of 1,687 patients whose tumors had RS testing, 1,087 were in cohort A and 600 in cohort B. In cohort B, nearly half of patients were older than 65 years (n = 279; IQR, 67-72 years). For patients older than 65 years, those with RS testing were younger (median age: 69 v 73 years), with higher grade cancers (G2-3: 84.9% v 54.7%) and were more likely to be treated with chemotherapy (15.4% v 4.1%). Issues for implementation of RS testing in older patients were identified, including potential structural barriers related to the current policy on the reimbursements of genomic tests., Conclusion: Internal guidelines may facilitate standardized utilization of the RS in early-BC. Our data suggest that clinicians preferred broader utilization of RS across the age spectrum, with therapeutically important consequences. Modifying the current policy for reimbursement of RS testing and in internal reflexive testing criteria for those older than 65 years is warranted.

Purpose: To provide clinical guidance for centers wishing to implement photon spatially fractionated radiation therapy (SFRT) treatments using either a brass grid or volumetric modulated arc therapy (VMAT) lattice approach., Methods: We describe in detail processes which have been developed over the course of a 3-year period during which our institution treated over 240 SFRT cases. The importance of patient selection, along with aspects of simulation, treatment planning, quality assurance, and treatment delivery are discussed. Illustrative examples involving clinical cases are shown, and we discuss safety implications relevant to the heterogeneous dose distributions., Results: SFRT can be an effective modality for tumors which are otherwise challenging to manage with conventional radiation therapy techniques or for patients who have limited treatment options. However, SFRT has several aspects which differ drastically from conventional radiation therapy treatments. Therefore, the successful implementation of an SFRT treatment program requires the multidisciplinary expertise and collaboration of physicians, physicists, dosimetrists, and radiation therapists., Conclusions: We have described methods for patient selection, simulation, treatment planning, quality assurance and delivery of clinical SFRT treatments which were built upon our experience treating a large patient population with both a brass grid and VMAT lattice approach. Preclinical research and patient trials aimed at understanding the mechanism of action are needed to elucidate which patients may benefit most from SFRT, and ultimately expand its use., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Associazione Italiana di Fisica Medica e Sanitaria. Published by Elsevier Ltd. All rights reserved.)

Purpose: Purpose: Subtotal skin electron beam therapy may be an option for patients with cutaneous lymphoma receiving radiation therapy to treat large areas of their skin but may benefit from sparing specific areas that may have had previous radiation therapy, are of specific cosmetic concern, and/or show no evidence of disease. We report here on the design, implementation, and dosimetric characteristics of a reusable and transparent customizable shield for use with the large fields used to deliver total skin electron beam therapy at extended distance with a conventional linear accelerator., Methods and Materials: A shield was designed and manufactured consisting of acrylic blocks that can be mounted on a steel frame to allow patient-specific shielding. The dosimetry of the device was measured using radiochromic film., Results: The shield is easy to use and well-tolerated for patient treatment, providing minimal electron transmission through the shield with a sharp penumbra at the field edge, with no increase in x-ray dose. We report on the dosimetry of a commercial device that has been used to treat more than 30 patients to date., Conclusions: The customizable shield is well suited to providing patient-specific shielding for subtotal skin electron beam therapy., Competing Interests: William Breen reports being on the scientific advisory board for GE Healthcare, with all payments made to his institution. John Lucido reports receiving an honorarium paid to his institution for work as grant referee for Global Bridges Oncology and consulting fees paid to his institution by Varian Medical Systems. Aaron Mangold reports currently receiving research grants paid to his institution by Regeneron, Corbus, Incyte, Pfizer, Eli Lilly, Argenyx, Palvella, Abbview, Priovant, and Merck and previous research grants in the past 36 months for Kyowa Kirin, Miragen, Sun Pharma, Elorac, Janssen, and Novartis. He also is currently receiving consulting fees paid to him from Janssen and Boehringer Ingelheim and paid to his institution from Argenyx, Incyte, Regeneron, Clarivate, and Pfizer, previously received consulting fees paid to him from Kyowa Kirin, Clarivate, Soligenix, Phlecs, Incyte, Eli Lilly, Momenta, UCB, and Bristol Myers Squibb, and is currently receiving payment for manuscript writing (for a separate manuscript) from Janssen. He holds a patent for “Topical Ruxolitinib for Treating Lichen Planus” (PCT/US2021/053149; 63/086,898) and has filed for a patent for “Methods and Materials for Assessing and Treating Cutaneous Squamous Cell Carcinoma” (63/423,254). Aaron Mangold is also currently on the Advisory Board for Bristol Myers Squibb currently the President of Pacific Dermatology Society, the Chair of the Community Outreach Committee for the American Academy of Dermatology, on the Board of Directors for the US Cutaneous Lymphoma Consortium, was previously the President of the Arizona Dermatology and Dermatological Society and a Board Member for the Arizona Medical Association (all unpaid), has personal stock ownership of Intellia Therapeutics and Editas, and is receiving medical writing support from Pfizer and Janssen. Chris Deufel reports being a board member of the American Brachytherapy Society., (© 2023 The Author(s).)

Objective: Failure to recognize symptoms of non-human papillomavirus-associated oropharyngeal squamous cell carcinoma (HPV(-)OPSCC) at presentation can delay diagnosis and treatment. We aim to identify patient factors and provider practice patterns that delay presentation and care in HPV(-)OPSCC., Methods: Retrospective review at a tertiary care center. Patients with HPV(-)OPSCC receiving treatment from 2006 to 2016. Patients were excluded if their date of symptom onset or diagnosis was unknown after thorough review of the electronic medical record or their tissue was not tested for HPV or p16. Clinical data, workup, and care timelines were abstracted. Univariate and multivariable linear regressions were performed to determine associations between patient and provider factors and delays in care., Results: Of 70 included patients, 52 (74%) were male and mean age was 60.5 (SD = 9.0). Median time to diagnosis was 69 days (IQR = 32-127 days), with a median latency of 30 days (IQR = 12-61 days) from symptom onset to first presentation and 19.5 days (IQR = 4-46 days) from the first presentation to diagnosis. Most patients visited at least 2 providers (n = 52, 74%) before diagnosis. Evaluation by 3 or more providers prior to diagnosis was associated with significant delays in diagnosis of nearly a year (357.7 days, p < 0.001) and being treated or prescribed analgesia prior to diagnosis was significantly associated with delays in diagnosis (p = 0.004) on univariate regression analysis., Conclusions: Delays in care related to evaluations by multiple providers and misdiagnosis prolonged time to diagnosis in HPV(-)OPSCC. Improved patient and provider education is necessary to expedite the diagnosis of HPV(-)OPSCC., Level of Evidence: 4 Laryngoscope, 133:1394-1401, 2023., (© 2022 The American Laryngological, Rhinological and Otological Society, Inc.)

Superficial angiomyxoma is an uncommon benign mesenchymal neoplasm that usually arises in dermis/subcutis of the extremities or trunk. Some tumors are associated with Carney complex. When arising in breast, these tumors are not well-recognized, mainly due to a lack of uniform nomenclature in the literature. This study therefore aims to improve recognition of angiomyxomas of the breast region. Forty cases were identified: demographics, presence of Carney complex, imaging and histologic features, PRKAR1A expression, and outcomes were evaluated. There were 22 female and 18 male patients (median age 40 years, range: 14 to 72). Most tumors presented as slowly-growing masses (77%). All but one were solitary, and median size was 1.5 cm. Tumors were superficial (dermal/subcutaneous) in 52.5% and deep/parenchymal in 47.5%. Nine involved the nipple-areola complex. All showed characteristic features of superficial angiomyxoma: poorly circumscribed, hypocellular, myxoid neoplasms with lobulated (55%) or infiltrative (45%) architecture, bland spindled fibroblasts, prominent thin-walled vessels, and admixed neutrophils. Tumors involving the nipple-areola complex infiltrated through areolar smooth muscle, and deep/parenchymal tumors showed entrapment of lobules mimicking myxoid fibroadenoma. Mitoses were typically absent, as was significant atypia. Cystic change was common. Two-thirds showed loss of PRKAR1A expression by immunohistochemistry. Two patients had Carney complex (7%). Recurrence after incomplete excision occurred in 1 patient. Angiomyxoma of breast may arise at superficial, nipple-areola or deep/parenchymal locations, where it can be difficult to recognize classic histologic features. Loss of expression of PRKAR1A is not invariable, but may be a helpful diagnostic clue. Recognizing angiomyxoma is important for 2 reasons: first, the recurrence rate is low and therefore wide excision is not essential, and second, it may allow detection of Carney complex in some patients., Competing Interests: Conflicts of Interest and Source of Funding: The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: Dose de-escalation of adjuvant therapy (DART) in patients with HPV(+)OPSCC was investigated in two prospective Phase II and III clinical trials (MC1273 and MC1675). We report the 30-day morbidity and mortality associated with primary TORS resection in patients enrolled in these trials., Materials and Methods: Patients with HPV(+)OPSCC, who underwent TORS resection between 2013 and 2020 were considered in this analysis. The severity of postoperative transoral bleeding was graded using both the Hinni Grade (HG) transoral surgery bleeding scale and the Common Terminology for Adverse Events (CTCAE) v5.0. Post-surgical complications within 30 days of surgery, as well as rates of tracheostomy, PEG and nasogastric tube placement., Results: 219 patients were included. A total of 7 (3.2 %) patients had a tracheostomy placed at the time of surgery, and all were decannulated within 26 days (median: 5, range: 2-26). There were 33 (15.1 %) returns to the emergency department (ED) with 10 (4.6 %) patients requiring readmission. Using the HG scale, 10 (4.6 %) patients experienced ≥ Grade 3 bleeding with no Grade 5 or 6 bleeds. In contrast, using the CTCAE scale, 15 patients (6.8 %) experienced ≥ Grade 3 bleeding with no Grade 5 bleeds. There was one post-operative death in a patient withdrawn from the trial, and no deaths related to hemorrhage., Conclusion and Relevance: TORS for HPV(+)OPSCC in carefully selected patients at a high volume center was associated with low morbidity and mortality., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: We seek to inform radiotherapy (RT) delivery for adenoid cystic carcinoma of the head and neck (ACC) by evaluating RT techniques and recurrence patterns., Methods: We identified patients with ACC treated with curative-intent RT from 2005 to 2021. Imaging was reviewed to determine local recurrence (LR)., Results: Ninety-one patients were included. The 5-year LR risk was 12.2% (6.6-22.7). One patient each experienced a marginal and out-of-field recurrence. Patients receiving >60 Gy postoperatively had a 5-year LR risk of 0% compared to 10.7% (4.2-27.2) with ≤60 Gy. Those receiving 70 and <70 Gy definitively had a 5-year LR risk of 15.2% (2.5-91.6) and 33.3% (6.7-100.0), respectively. No patients had regional nodal failure., Conclusions: Modern, conformal RT for ACC results in low rates of LR. Doses >60 and 70 Gy may improve control in the postoperative and definitive settings, respectively. Elective nodal treatment can be omitted in well-selected patients., (© 2022 Wiley Periodicals LLC.)

Purpose: Our objective was to report the prospective results of mucosal sparing radiation therapy in human papillomavirus-related oropharyngeal squamous cell carcinoma., Methods and Materials: From March 2016 through May 2019, patients were enrolled in this institutional review board-approved prospective cohort study at a multisite institution. Inclusion criteria included p16+ American Joint Committee on Cancer seventh edition pathologic T1 or T2, N1 to N3, and M0 oropharyngeal cancers. Proton therapy (PT) was delivered to at-risk nodal regions, excluding the primary mucosal site. Secondary to insurance denial for PT, intensity modulated radiation therapy (IMRT) was allowed. European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Head and Neck Module and Patient-Reported Outcomes Measurement Information System surveys (quality of life [QOL]) and modified barium swallowing impairment profiles (MBSImP) were obtained at baseline before radiation therapy, then 3 and 12 months after radiation therapy. Kaplan-Meier estimates were calculated for time-to-event clinical outcomes, and repeated measures mixed models were used to explore changes in QOL over time. A comparison of QOL and swallowing outcomes with standard-of-care treatment was analyzed., Results: There were 61 evaluable patients with a median follow-up of 38 months (range, 10-64); 44 (72%) were treated with PT and 17 (28%) were treated with IMRT. The 2-year local control, locoregional control, distant metastasis-free survival, and overall survival were 98%, 97%, 98%, and 100%, respectively. There were 6 grade ≥3 events related to treatment. Two IMRT patients required percutaneous endoscopic gastrostomy tube placement during treatment secondary to significant nausea due to dysgeusia. Patients noted significant QOL improvement over time in the pain, swallowing, speech, social eating, social contact, mouth opening, and use of pain medication domains (all P < .02). The MBSImP overall severity score as well as oral and pharyngeal impairment scores showed stability with no significant change over time. For the 44 patients treated with PT, the mean D95 to the primary target was 10.7 Gy (standard deviation = 12.5 Gy)., Conclusions: Mucosal sparing radiation is well tolerated in select resected human papillomavirus-related oropharyngeal squamous cell carcinoma with a low risk of recurrence at the mucosal primary site, a low rate of percutaneous endoscopic gastrostomy tube placement, and few radiation-related grade ≥3 adverse events., (Copyright © 2022 Elsevier Inc. All rights reserved.)