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Introduction Head and neck reconstructive surgery using a flap is increasingly common. Best practices and outcomes for postoperative radiotherapy (poRT) with flaps have not been specified. We aimed to provide consensus recommendations to assist clinical decision-making highlighting areas of uncertainty in the presence of flaps. Material and methods Radiation, medical, and surgical oncologists were assembled from GORTEC and internationally with the Head and Neck Cancer International Group (HNCIG). The consensus-building approach covered 59 topics across four domains: (1) identification of postoperative tissue changes on imaging for flap delineation, (2) understanding of tumor relapse risks and target volume definitions, (3) functional radiation-induced deterioration, (4) feasibility of flap avoidance. Results Across the 4 domains, international consensus (median score ≥ 7/9) was achieved only for functional deterioration (73.3%); other consensus rates were 55.6% for poRT avoidance of flap structures, 41.2% for flap definition and 11.1% for tumor spread patterns. Radiation-induced flap fibrosis or atrophy and their functional impact was well recognized while flap necrosis was not, suggesting dose-volume adaptation for the former. Flap avoidance was recommended to minimize bone flap osteoradionecrosis but not soft-tissue toxicity. The need for identification (CT planning, fiducials, accurate operative report) and targeting of the junction area at risk between native tissues and flap was well recognized. Experts variably considered flaps as prone to tumor dissemination or not. Discrepancies in rating of 11 items among international reviewing participants are shown. Conclusion International GORTEC and HNCIG-endorsed recommendations were generated for the management of flaps in head and neck radiotherapy. Considerable knowledge gaps hinder further consensus, in particular with respect to tumor spread patterns.

OBJECTIVES/HYPOTHESIS Dysphagia is a treatment-related complication of head and neck cancer (HNCA). We demonstrate the predictive value of a modified head and neck swallow scale (m-HNSW) adapted from the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Head and Neck 35 (EORTC-QLQ-H&N35). STUDY DESIGN Retrospective Cohort Study. METHODS Retrospective, single-center cohort study utilizing a prospectively collected database of HNCA patients in a high-volume tertiary referral center. 736 HNCA patients more than 2 years from completion of treatment were identified. EORTC-QLQ-H&N35 data collected from at least one of three defined episodes of care were used. The m-HNSW uses three questions to form a 9-point dysphagia scale. A Cox proportional hazards model was used to determine the effect of the m-HNSW while controlling for demographics, tumor staging, site, and treatment. RESULTS Using data from 3, 6, 12 months from treatment, we analyzed a subset that included 328 patients. Three months after the completion of therapy, the m-HNSW score had a significant association with 1 (HR = 1.24, P = .0005) and 5 year survival (HR = 1.19, P = .0002) after accounting for body mass index. Six (HR = 1.14, P = .014) and 12 month (hazard ratio (HR) = 1.33, P

Osteoradionecrosis is a relatively rare but potentially morbid and costly complication of radiation therapy for head and neck cancer. Multidisciplinary diagnosis and treatment are essential. Despite evidence guiding individual aspects of care for osteoradionecrosis, there is a lack of broad consensus on the overall diagnosis and management of this condition. This study comprehensively reviews the literature, with a focus on the past 10 years, to guide evaluation and treatment.

Background Human papillomavirus has been implicated in the carcinogenesis of squamous cell carcinoma of the anal canal. p16 expression and the presence of human papillomavirus DNA have been used to define human papillomavirus-positive patients, but neither approach has been validated against the standard of human papillomavirus E6/7 mRNA expression at this disease site. Objective This study aimed to evaluate the acceptability of p16 immunohistochemistry as a surrogate to E6/7 mRNA expression in identifying human papillomavirus-mediated squamous cell carcinoma of the anal canal. Design This was a retrospective analysis of a previously constructed tissue microarray. Settings This study was conducted at a tertiary academic center. Patients Biopsies and resection specimens from patients diagnosed with squamous cell carcinoma of the anal canal at the study institution from 2005 to 2015 were reviewed for sample adequacy. Main outcome measures Concordance between p16 positivity by immunohistochemistry and E6/7 mRNA expression by in situ hybridization was evaluated. Sensitivity, specificity, and positive predictive value were assessed. Results Among the 25 patients evaluated, p16 and E6/7 mRNA results were concordant in 24 of 25 specimens (96%). Of the 24 concordant samples, there were 23 true positives (p16+ and E6/7+) and 1 true negative (p16- and E6/7-). One specimen was discordant (p16- and E6/7+) between p16 and E6/7 mRNA (4%). This resulted in a sensitivity of 96% and a specificity of 100%. Positive predictive value of p16 immunohistochemistry for E6/7 mRNA expression was 100%. Limitations This study was limited by its retrospective nature and small sample size. It only assessed diagnostic parameters rather than prognostic implications. Conclusions In this study, the clinically prevalent method of p16 immunohistochemistry showed excellent concordance with the standard of E6/7 mRNA expression and demonstrated its potential to serve as a surrogate for identifying human papillomavirus-induced squamous cell carcinoma of the anal canal. See Video Abstract at http://links.lww.com/DCR/B448. Evaluando la confiabilidad y el valor predictivo positivo de p, como sustituto de la expresin de arnm de e / , mediada por el virus del papiloma humano, en carcinoma de clulas escamosas del canal anal ANTECEDENTES:El virus del papiloma humano se ha relacionado en la carcinogenesis del carcinoma de celulas escamosas del canal anal. La expresion de p16 y la presencia de ADN del virus del papiloma humano, se han utilizado para definir a los pacientes positivos al virus del papiloma humano. Pero ninguno de estos enfoques, han sido validados frente al estandar de oro de la expresion del ARNm del virus del papiloma humano E6 / 7, en este sitio de la enfermedad.OBJETIVO:El estudio tuvo como objetivo, evaluar la aceptabilidad de la inmunohistoquimica del p16, como sustituto de la expresion de ARNm de E6 / 7, en la identificacion del carcinoma de celulas escamosas del canal anal, mediada por virus del papiloma humano.DISENO:Fue un analisis retrospectivo de un microarreglo de tejido previamente construido.AJUSTE:El estudio se realizo en un centro academico terciario.PACIENTES:Se revisaron biopsias y muestras de reseccion de pacientes diagnosticados con carcinoma de celulas escamosas del canal anal, en la institucion del estudio, entre 2005 y 2015 para determinar la idoneidad de la muestra.PRINCIPALES MEDIDAS DE RESULTADO:Se evaluo la concordancia entre la positividad de p16 por inmunohistoquimica y la expresion de ARNm de E6 / 7 por hibridacion in situ. Se evaluaron la sensibilidad, especificidad y valor predictivo positivo.RESULTADOS:Entre los 25 pacientes evaluados, los resultados del ARNm de p16 y E6 / 7 fueron concordantes en 24/25 muestras (96%). De las 24 muestras concordantes, hubo 23 positivos verdaderos (p16 + y E6 / 7 +) y un negativo verdadero (p16- y E6 / 7-). Una muestra fue discordante (p16- y E6 / 7 +) entre p16 y ARNm de E6 / 7 (4%). Esto resulto en una sensibilidad del 96% y una especificidad del 100%. El valor predictivo positivo de la inmunohistoquimica de p16 para la expresion de ARNm de E6 / 7 fue del 100%.LIMITACIONES:El estudio estuvo limitado por su naturaleza retrospectiva y por el tamano pequeno de la muestra. Solamente evaluo los parametros de diagnostico, en lugar de las implicaciones pronosticas.CONCLUSIONES:En este estudio, el metodo clinico prevalente de inmunohistoquimica p16, mostro una excelente concordancia con el estandar de oro de la expresion de ARNm de E6 / 7 y demostro su potencial para servir, como sustituto para identificar el carcinoma de celulas escamosas del canal anal, inducido por el virus del papiloma humano. Consulte Video Resumen en http://links.lww.com/DCR/B448.

Purpose To determine the optimal dose‐volume constraint for laryngeal sparing using three commonly employed intensity modulated radiation therapy (IMRT) approaches in patients with oropharyngeal cancer treated to the bilateral neck. Materials and methods Thirty patients with stage II‐IVA oropharynx cancers received definitive radiotherapy with split‐field IMRT (SF‐IMRT) to the bilateral neck between 2008 and 2013. Each case was re‐planned using whole‐field IMRT (WF‐IMRT) and volumetric modulated arc therapy (VMAT) and plan quality metrics and dose to laryngeal structures was evaluated. Two larynx volumes were defined and compared on the current study: the Radiation Therapy Oncology Group (RTOG) larynx as defined per the RTOG 1016 protocol and the MDACC larynx defined as the components of the larynx bounded by the superior and inferior extent of the thyroid cartilage. Results Target coverage, conformity, and heterogeneity indices were similar in all techniques. The RTOG larynx mean dose was lower with WF‐IMRT than SF‐IMRT (22.1 vs 25.8 Gy; P

Background Human papillomavirus (HPV) associated head and neck squamous cell carcinoma (HNSCC) has a better prognosis than HNSCC due to other risk factors. However, there is significant heterogeneity within HPV-associated HNSCC and 25% of these patients still do poorly despite receiving aggressive therapy. We currently have no good molecular tools to differentiate and exclude this “high-risk” sub-population and focus on “low-risk” patients for clinical trials. This has been a potential barrier to identifying successful de-escalation treatment strategies in HPV-associated HNSCC. We conducted an analysis of molecular markers with a well-known role in the pathogenesis of HPV-associated HNSCC and hypothesized that these markers could help independently predict recurrence and prognosis in these patients and therefore help identify at the molecular level “low-risk” patients suitable for de-escalation trials. Methods We analyzed 24 tumor specimens of patients with p16+ HNSCC who underwent definitive resection as primary treatment. Tissue microarray (TMA) was generated from the 24 pathology blocks and immunohistochemistry (IHC) was performed using highly specific antibodies for our chosen biomarkers (PI3K-PTEN, AKT pathway, mTOR, 4EBP1, S6, and pAMPK, ERCC-1). Transcriptome data was also obtained for 7 p16+ HNSCC patients from The Cancer Genome Atlas (TCGA). Data from the TMA and TCGA were analyzed for association of relapse-free survival (RFS) and overall survival (OS) with protein and gene expression of the chosen biomarkers. Results Increased pAMPK protein activity by IHC and AMPK gene expression by TCGA gene expression data was correlated with improved RFS with a trend towards statistical significance. Conclusions This data suggests that increased pAMPK activity and expression may portend a better prognosis in HPV-associated HNSCC undergoing primary definitive resection. However, these findings require validation in larger studies.

IntroductionSurgery is the primary treatment for resectable, non-metastatic recurrent head and neck squamous cell carcinoma (HNSCC). We explore the safety and oncologic benefit of intraoperative Cesium-131 (Cs-131) brachytherapy combined with salvage local and/or regional surgical resection.Methods and MaterialsFindings were reported from a single arm multi-institutional prospective phase 1/2 trial involving surgery plus Cs-131 (surgery + Cs-131) treatment. The results of two retrospective cohorts—surgery alone and surgery plus intensity modulated radiation therapy (surgery + ReIMRT)—were also described. Included patients had recurrent HNSCC and radiation history. Safety, tumor re-occurrence, and survival were evaluated.ResultsForty-nine patients were enrolled in the surgery + Cs-131 prospective study. Grade 1 to 3 adverse events (AEs) occurred in 18 patients (37%), and grade 4 AEs occurred in 2 patients. Postoperative percutaneous endoscopic gastrostomy (PEG) tubes were needed in 10 surgery + Cs-131 patients (20%), and wound and vascular complications were observed in 12 patients (24%). No cases of osteoradionecrosis were reported in the surgery + Cs-131 cohort. We found a 49% 2-year disease-free survival at the site of treatment with a substantial number of patients (31%) developing metastatic disease, which led to a 31% overall survival at 5 years.ConclusionsAmong patients with local/regional recurrent HNSCC status-post radiation, surgery + Cs-131 demonstrated acceptable safety with compelling oncologic outcomes, as compared to historic control cohorts.Clinical Trial RegistrationClinicalTrials.gov, identifiers NCT02794675 and NCT02467738.

Simple Summary Human papillomavirus (HPV) has been associated with multiple cancers in the anogenital and upper aerodigestive tracts. In the head and neck region, HPV-positive cancers are common in oropharynx, with rising incidence and a well-established association with more favorable patient outcomes. However, the relationship with prognosis of sinonasal squamous cell carcinoma (SNSCC) has been much less often studied and is presently unclear. To better elucidate this relationship, we performed a systematic review and meta-analysis of the biomedical literature to determine the aggregate effect across studies. In doing so, we observed significantly better overall survival associated with HPV-positive SNSCC. Therefore, we conclude that HPV testing may be useful for determining patient prognosis and potentially guiding treatment decisions. Abstract Human papillomavirus (HPV) is detectable in a subset of sinonasal squamous cell carcinoma (SNSCC), but the impact on patient outcomes is presently unclear due to a modest number of studies with limited statistical power. Therefore, we conducted a systematic review and meta-analysis to better clarify this relationship. A PubMed search was conducted to identify all studies reporting on overall (OS) or disease-free survival (DFS) for SNSCC by HPV status. Hazard ratios (HR) and corresponding 95% confidence intervals (CI) were extracted or, when not provided, indirectly estimated from each manuscript. Summary survival curves for 5-year OS and estimating survival probability by HPV status at pre-specified time intervals from study-specific Kaplan-Meier curves generated 2-year DFS. Log HRs and log CIs were combined across studies to generate summary estimates and a corresponding 95% CIs for OS and DFS. We identified ten unique studies reporting on OS and four for DFS. We observed a significant association between HPV and OS (summary HR = 0.51, 95% CI: 0.38–0.70) with relatively low heterogeneity between studies. These results indicate that HPV is a significant predictor of more favorable survival for SNSCC, and thus may be a useful biomarker for prognostication and, potentially, treatment modulation.

Background The 5-year overall survival (OS) rate remains at 50% for patients with locally advanced head and neck squamous cell carcinoma (LAHNSCC), thereby underscoring the need for improved treatments. An antidiabetic agent, metformin, was found in retrospective studies to improve survival in patients with HNSCC. Therefore, the authors conducted a phase 1 dose escalation study combining metformin with chemoradiotherapy in patients with LAHNSCC. Methods Nondiabetic patients with LAHNSCC were enrolled in the current study to receive escalating doses of metformin and CRT based on the modified toxicity probability interval design. Metformin cohort doses included 2000 mg, 2550 mg, and 3000 mg daily in divided doses in addition to cisplatin (at a dose of 100 mg/m2 on days 1, 22, and 43) and standard radiotherapy (70 grays). Adverse events were categorized as per the National Cancer Institute Common Terminology Criteria for Adverse Events (version 4.03). Results Twenty patients were enrolled, 2 of whom withdrew consent. The median age of the patients was 56 years and the majority were male (83%), were white (88%), had p16-positive disease (72%), and were tobacco users (61%). The median length of metformin exposure was 28.5 days. The most common grade ≥3 toxicities were nausea (11%), vomiting (11%), mucositis (6%), acute kidney injury (17%), anemia (6%), and leukopenia (11%). Dose-limiting toxicities included diarrhea and acute kidney injury. After a median follow-up of 19 months, the 2-year overall survival and progression-free survival rates were 90% and 84%, respectively. No hypoglycemia events or lactic acidosis were observed. Cisplatin administration did not appear to affect metformin pharmacokinetics. The maximum tolerated dose for metformin could not be determined given the limited number of patients who tolerated metformin during chemoradiotherapy. Conclusions To the authors' knowledge, the current study is the first phase 1 trial combining metformin with chemoradiotherapy. Rates of overall survival and progression-free survival were encouraging in this limited patient population, and warrant further investigation in a phase 2 trial.

OBJECTIVES/HYPOTHESIS Characterization of leadership within otolaryngology is key to evaluating trends and promoting program advancement. This study evaluates representation of women in otolaryngology holding residency and fellowship directorships, or chair positions, comparing sex differences in academic rank, years in practice, and scholarly activity. STUDY DESIGN Cross sectional analysis. METHODS A comprehensive list of otolaryngology residency and fellowship directors from Accreditation Council for Graduate Medical Education-accredited programs in 2017 to 2018 was compiled. Academic rank and years in practice were determined from departmental websites, with online search tools used as secondary resources. The h-index was utilized as a measure of research productivity. Regression analysis was performed to analyze these variables. RESULTS Among the 306 directorships, women held 57 (18.6%) of these positions, 27 (26.5%) residency and 30 (14.7%) fellowship directorships. Of the 99 chair positions, five (5.1%) were held by women. The majority (53.6%) of male directors were full professors, whereas only 26.3% of females were full professors (P = .04). Mean years in practice for female directors (13.9 ± 6.8) was less than that of male directors (20.3 ± 9.4, P

As care delivery becomes ever more complex, and physicians and health care systems face increasing demands, improved efficiency within radiation oncology departments is essential. The workflow required for quality radiation treatment delivery necessitates detailed communication between multiple specialized team members and emerging technologies, sometimes at different locations. In this study, we compare the time required for completion of several components of this process, before and after whiteboard implementation, hypothesizing that whiteboard usage would decrease the time required to complete the designated task, thereby improving workflow. We retrospectively reviewed dosimetric workflow data from 578 patients treated between January 2015 and January 2017 (320 pre- and 258 post-whiteboard). The whiteboard system cataloged various patient clinical factors as well as workflow metrics. Departmental workflow was then examined and time from simulation date to contour approval, plan approval, and start date of the prescribed therapy were compared. Statistical analyses were performed using Mann-Whitney tests or paired t tests. There was a 17% reduction in the time from simulation to contour approval, 3.0 to 2.5 days, respectively (p = 0.007). There was also a 24% reduction in the time from simulation to plan approval, 6.3 to 4.8 days (p

Highlights • Early stage tonsillar cancers may be treated with unilateral neck radiotherapy (RT). • We performed a dosimetric study comparing three common radiotherapy modalities. • No significant differences in target coverage existed between all plans. • Laryngeal doses were reduced using whole-field intensity modulated RT and VMAT. • Shorter treatment times and required monitor units were also associated with VMAT., Background and purpose Minimizing radiation dose exposure to nearby organs is key to limiting clinical toxicities associated with radiotherapy. Several treatment modalities such as split- or whole-field intensity-modulated radiotherapy (SF-IMRT, WF-IMRT) and volumetric modulated arc therapy (VMAT) are being used to treat tonsillar cancer patients with unilateral neck radiotherapy. Herein, we provide a modern dosimetric comparison of all three techniques. Materials and methods Forty patients with tonsillar cancer treated with definitive, ipsilateral neck SF-IMRT were evaluated. Each patient was re-planned with WF-IMRT and VMAT techniques, and doses to selected organs-at-risk (OARs) including the larynx, esophagus, and brainstem were compared. Results No significant differences in target coverage existed between plans; however, the heterogeneity index improved using WF-IMRT and VMAT relative to SF-IMRT. Compared to SF-IMRT, WF-IMRT and VMAT plans had significantly lower mean doses to the supraglottic larynx (31 Gy, 18.5 Gy, 17 Gy; p

OBJECTIVES: Salvage surgical resection is the preferred treatment for head and neck squamous cell carcinoma (HNSCC) patients who develop locally recurrent disease after failing primary therapy. However, salvage surgical resection is not always feasible, and survival outcomes for those that do undergo salvage remain poor. It is well known that patients with adverse pathological features (extracapsular extension (ECE) of lymph nodes (LN), positive margins, peri-neural spread (PNI), lymphovascular invasion (LVI), and multiple LN metastases) at the time of primary surgical resection are likely to have relatively poor outcomes. However, the impact of adverse pathological features on outcomes in the salvage setting remains controversial. MATERIALS AND METHODS: We retrospectively analyzed 73 patients at a single institution from 2008–2017 who developed recurrence and subsequently underwent salvage surgery (SS) after definitive curative-intent therapy including radiation. Demographic and disease control outcomes were reviewed. Kaplan-Meier curves were used to estimate relapse free survival (RFS) and overall survival (OS). RESULTS: Median age at diagnosis was 61 years (range 40–86), 49/73 (67%) were male, and 55/73 (75%) had smoked. Patients with any adverse pathological features at SS had worse RFS (HR 3.15 p=0.0008) and worse OS (3.97 p=0.0008). Patients who relapsed

PURPOSE/OBJECTIVE(S) Given the historical toxicity of radiotherapy for head & neck cancer, there has been an emphasis on de-escalation for patients with favorable disease features. The use of unilateral radiation to cervical nodes is a prominent de-escalation strategy in well-lateralized tonsil cancers. However, the safety of this approach for patients with AJCC-7 N2b disease was less well-established in the landmark studies guiding its use. The study hypothesis was that unilateral radiation for AJCC-7 T1-2N2b tonsillar cancer results in a low rate of contralateral nodal failure. MATERIALS/METHODS This study was a retrospective chart review of 66 patients treated from 2005 to 2016 at two academic institutions. Eligible patients had AJCC-7 T1-2N2b squamous cell carcinoma of the tonsil and were treated with unilateral radiation therapy. The primary endpoint was the rate of contralateral nodal failure at the time of last follow-up. Ipsilateral recurrence rates and overall survival were additional endpoints of interest. When available, data were collected regarding the presence of clinical extracapsular extension (ECE). Human papillomavirus/p16 status was also assessed. RESULTS The median age at diagnosis was 55.5 years and 53 patients (80.3%) were male. 38 patients (57.6%) had T1 disease and 28 patients (42.4%) had T2 disease based upon AJCC-7 staging. Of the 52 patients who had information on tumor HPV status, all were positive. In regards to systemic therapy, 18 patients (27.3%) had induction therapy, 26 (39.4%) had concurrent therapy, and 4 (6.1%) had both. The median time to last post-radiation follow-up was 80.9 months; 87.9% of patients remained alive at last follow-up and median OS was not reached. Contralateral nodal failure occurred in 2/66 (3.0%) patients at 3.6 and 20.9 months, respectively. Both patients underwent salvage treatment. The first survived an additional 65 months and the second remains alive at last follow-up 37 months after recurrence. Sixteen patients (24.2%) were felt to have extracapsular extension by clinical exam, radiology, or pathology; one of the two contralateral recurrences occurred in this group. Two patients (3%) experienced recurrence at the treated primary site and/or neck. Overall locoregional control at both 2 and 5 years was 93.9% and the median duration of control was not reached. CONCLUSION The use of unilateral radiation for AJCC-7 T1-2N2b tonsillar cancer resulted in low rates of contralateral nodal failure. This outcome demonstrates the safety of considering unilateral treatment in patients with a high ipsilateral nodal burden. Further assessments are needed to determine the impact of radiation volume reduction on patient quality of life.

Purpose/Objective(s) Cisplatin-based chemoradiation is an established organ-preserving strategy for locally advanced laryngeal squamous cell carcinoma, but long-term survival remains suboptimal, warranting an improved approach. Immunotherapy has been studied in the metastatic and unresectable recurrent setting, but additional data are needed to assess its role in definitive therapy. The study hypothesis was that the use of immunotherapy in conjunction with chemoradiation would be safe and result in improved laryngectomy-free survival (LFS) compared to standard of care chemoradiation. Materials/Methods This trial was an open-label, single-arm, prospective, multi-institutional study. The study included a Phase I run-in portion to assess safety in the first 6 enrolled patients and a planned subsequent Phase II component. Due to slow accrual, the study was closed after enrollment of 9 patients and the data were allowed to mature. The primary endpoint of the Phase II portion was LFS at 18 months. Study patients had Stage III or IV (T1-3; N0-3; M0) laryngeal squamous cell carcinoma and were candidates for larynx preservation. Pembrolizumab was given as a 200 mg flat dose 3 weeks prior to the start of chemoradiation and was then given q21 days until the completion of chemoradiation. Cisplatin was given at a dose of 100 mg/m2 q21 days during radiation with allowed dose modifications for toxicities. Radiation was prescribed to a total dose of 70 Gy in 35 daily fractions using IMRT with an elective nodal dose of 56-63 Gy. Results A total of 9 patients with a median age of 54 were enrolled from 2017 to 2019. The median follow-up time was 30.1 months. None of the enrolled patients required laryngectomy, resulting in 100% LFS at 18 months for evaluable patients. The 18-month overall survival (OS) rate was 66.7%; of the 3 patient deaths, 2 were due to co-morbid conditions (diabetes, peripheral arterial disease) rather than malignancy. The remaining 6 patients were alive at the time of last follow-up and the median duration of OS was not reached. There were 27 Grade 3 toxicities, with 2 attributable to pembrolizumab. Nearly all Grade 4 (n = 4) and Grade 5 (n = 1) toxicities occurred in a single patient with poorly-controlled diabetes; the Grade 5 toxicity was due to diabetic ketoacidosis. One patient had late Grade 4 laryngeal edema requiring tracheostomy 8 months after chemoradiation; the edema has since resolved and the tracheostomy was reversed. Conclusion The use of concurrent pembrolizumab with chemoradiation for locally advanced larynx cancer resulted in high LFS. Most toxicities were attributable to chemoradiation and the majority of Grade 4 and 5 toxicities occurred in a patient with poorly-controlled diabetes. A case of late Grade 4 laryngeal edema could have been related to immunotherapy. Future studies with concurrent immunotherapy with chemoradiation should account for this possibility.

OBJECTIVES/HYPOTHESIS Hypothyroidism is a relatively common complication of head and neck squamous cell carcinoma (HNSCC) treatment. The objective of this study was to determine whether the addition of programmed death ligand-1 (PD-1) or programmed death ligand-1 (PD-L1) inhibition (anti-PD-1/PD-L1 therapy) to standard treatment increases the risk of hypothyroidism in HNSCC. STUDY DESIGN Retrospective Cohort. METHODS This is a retrospective, single institutional cohort study. Patients who received radiotherapy (RT) for HNSCC were identified in the electronic medical record. Patient factors collected include age, sex, body mass index (BMI), smoking status, alcohol use, Charlson comorbidity index, and HNSCC treatment records. The rate of hypothyroidism for patients with HNSCC receiving RT (+/- chemotherapy and surgery) (RT group, n = 101) was compared to that of HNSCC patients receiving RT (+/- chemotherapy and surgery) + anti-PD-1/PD-L1 therapy, either concurrently or after RT (RT + anti-PD-1/PD-L1 group, n = 38). RESULTS There was no significant difference in the rate of clinical or subclinical hypothyroidism between the two groups. Multinomial logistic regression found no significant difference in hypothyroidism based on age, sex, or BMI. CONCLUSIONS The addition of anti-PD-1/PD-L1 therapy to standard HNSCC treatment does not significantly increase the risk of developing hypothyroidism. LEVEL OF EVIDENCE 3 Laryngoscope, 131:E2413-E2419, 2021.

Background Patients with newly diagnosed, resected, head and neck squamous cell carcinoma (HNSCC) with high-risk (positive margins, extracapsular spread [ECE]) or intermediate-risk pathological features have an estimated 1-year disease free survival (DFS) of 65% and 69%, respectively.1 PD-1/PD-L1 immune checkpoint blockade has improved survival of patients with recurrent/metastatic HNSCC, and preclinical models indicate radiation upregulates PD-L1.2 Therefore, we hypothesized that pre and post-operative administration of the PD-1 inhibitor pembrolizumab would improve 1-year DFS for patients with resectable, loco-regionally advanced (clinical T3/4 and/or ≥2 nodal metastases) HNSCC (NCT02641093). Methods Eligible patients received pembrolizumab (200 mg I.V. x 1) 1-3 weeks before resection. Adjuvant pembrolizumab (q3 wks x 6 doses) was administered with weekly cisplatin (40mg/m2 X 6) and radiation (60-66Gy) for those with high-risk features and radiation alone for patients with intermediate-risk features. The primary endpoint was DFS, which was compared by log-rank test to historical controls (RTOG 9501). Evidence of pathological response to neoadjuvant pembrolizumab was evaluated by comparing pre- and post-surgical tumor specimens for treatment effect (TE) defined as tumor necrosis and/or histiocytic inflammation and giant cell reaction to keratinaceous debris. Response was classified as none (NPR, Results Sixty-six of 84 enrolled patients had received adjuvant pembrolizumab and therefore were evaluable for DFS at the time of interim analysis. Patient characteristics included: median age 59 (range of 27 – 76) years; 30% female; 85% oral cavity, 11% larynx, and 2% human papillomavirus negative oropharynx; 85% clinical T3/4 and 68% ≥2N; 41(51%) high-risk (positive margins, 49%; ECE, 80%). At a median follow-up of 16 months, 1-year DFS was 66% (95%CI 0.48-0.84) in the high-risk group (p=1) and 91% (95%CI 0.79-1) in the intermediate-risk group (versus 69% in RTOG 9501, p=0.05) (figure 1). Among 70 patients evaluable for pathological response, TE was scored as NPR in 40, PPR in 27, and MPR in 3 patients. Patients with pathological response that were also evaluable for DFS (PPR + MPR) had significantly improved 1-year DFS when compared with those with NPR (100% versus 57%, p=0.0033; HR = 0.18 [95%CI 0.05-0.64]) (figure 2). PPR/MPR was associated with robust macrophage infiltration via Nanostring. Conclusions Neoadjuvant and adjuvant pembrolizumab led to high DFS in intermediate-risk, but not high-risk, resected HNSCC patients. Pathological response to neoadjuvant pembrolizumab was associated with high 1-year DFS. Acknowledgements We’d like to acknowledge the UCCC clinical trials office for their hard work on this study as well as our patients. We’d also like to acknowledge Merck & Co, Inc as they partially funded the clinical trial. Trial Registration NCT02641093 Ethics Approval This study was approved by the University of Cincinnati IRB with approval number 2015-6798 References Cooper JS, Pajak TF, Forastiere AA, et al. Postoperative concurrent radiotherapy and chemotherapy for high-risk squamous-cell carcinoma of the head and neck. N Engl J Med 2004;350(19):1937-1944. doi:10.1056/NEJMoa032646 Oweida A, Lennon S, Calame D, et al. Ionizing radiation sensitizes tumors to PD-L1 immune checkpoint blockade in orthotopic murine head and neck squamous cell carcinoma. Oncoimmunology2017;6(10):e1356153. Published 2017 Aug 3. doi:10.1080/2162402X.2017.1356153

The efficacy of ionizing radiation (IR) for head and neck cancer squamous cell carcinoma (HNSCC) is limited by poorly understood mechanisms of adaptive radioresistance. Elevated glutaminase gene expression is linked to significantly reduced survival (p < 0.03). The glutaminase inhibitor, telaglenastat (CB-839), has been tested in Phase I/II cancer trials and is well tolerated by patients. This study investigated if telaglenastat enhances the cellular response to IR in HNSCC models. Using three human HNSCC cell lines and two xenograft mouse models, we examined telaglenastat’s effects on radiation sensitivity. IR and telaglenastat combinatorial treatment reduced cell survival (p ≤ 0.05), spheroid size (p ≤ 0.0001) and tumor growth in CAL-27 xenograft bearing mice relative to vehicle (p ≤ 0.01), telaglenastat (p ≤ 0.05) or IR (p ≤ 0.01) monotherapy. Telaglenastat significantly reduced the Oxygen Consumption Rate/Extracellular Acidification Rate ratio in CAL-27 and HN5 cells in the presence of glucose and glutamine (p ≤ 0.0001). Telaglenastat increased oxidative stress and DNA damage in irradiated CAL-27 cells. These data suggest that combination treatment with IR and telaglenastat leads to an enhanced anti-tumor response. This pre-clinical data, combined with the established safety of telaglenastat justifies further investigation for the combination in HNSCC patients.

Background Patients with the heritable disease, Fanconi anemia (FA), have a 500-fold risk of developing head and neck squamous cell carcinomas (HNSCC). However, the use of conventional cytotoxic agents including radiation therapy and cisplatin-based chemotherapy is contraindicated in patients with FA due to underlying DNA repair defects. Methods/results We present a young FA patient with recurrent HNSCC and high-risk pathologic features treated with a therapeutic trial of chemoradiation. This novel strategy employs a gentle radiation dose and volume escalation with concurrent pembrolizumab. The patient completed the entire course of therapy with no treatment delays or interruptions. Conclusions The FA patient population has a clear need for adjuvant treatment regimens given their predilection for HNSCC. A therapeutic trial may allow FA and other radiosensitive patients to trial radiation with the option to terminate treatment before any severe side effects occur and for some to complete a full course of treatment.

This study evaluates the prognostic significance of MST1R (RON) expression in breast cancer with respect to disease progression, long-term survival, subtype, and association with conventional prognostic factors. The approach includes interrogation of survival and tumor staging with paired MST1R RNA expression from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) datasets. Protein expression evaluation was performed using immunohistochemistry (IHC) staining of MST1R on breast cancer tissue samples from the Cancer Diagnosis Program Breast Cancer Progression tissue microarray and locally obtained breast tumor tissue samples analyzed with paired survival, metastasis, and subtype. Data from TCGA (n = 774) show poorer relapse-free survival (RFS) in patients with high MST1R expression (P = 0.32) and no difference in MST1R expression based on tumor stage (P = 0.77) or nodal status (P = 0.94). Patients in the GEO-derived Kaplan–Meier Plotter microarray dataset demonstrate the association of MST1R and poorer overall survival (n = 1402, P = 0.018) and RFS in patients receiving chemotherapy (n = 798, P = 0.041). Patients with high MST1R expression display worse overall survival (P = 0.01) and receiver operator characteristic (ROC) analysis demonstrate the predictive capacity of increased MST1R with early death (P = 0.0017) in IHC-stained samples. Paired IHC-stained breast tumor samples from the primary versus metastatic site show MST1R expression is associated with metastatic progression (P = 0.032), and ROC analysis supports the predictive capacity of MST1R in metastatic progression (P = 0.031). No associations of MST1R with estrogen receptor (ER), progesterone receptor (PR), both ER and PR, HER2 positivity, or triple-negativity were found (P = 0.386, P = 0.766, P = 0.746, P = 0.457, P = 0.947, respectively). MST1R expression has prognostic value in breast cancer with respect to survival and metastatic progression. MST1R expression is not associated with tumor stage, nodal status, or subtype.

Purpose Although a standard cutoff value of less than 35 mm in the maximum mouth opening (MMO) has been used to diagnose trismus, this value does not account for natural demographic variations. The present cross-sectional study investigated the effects of age, weight, height, body mass index (BMI), and gender on the MMO in a healthy, heterogeneous population. Materials and Methods A volunteer sample from multiple sites in Cincinnati, Ohio, without any reported head and neck pathologies or current dental prostheses and with intact natural incisors were included. The main outcome measure was the average MMO. Key demographic information was collected from each participant. Multivariate regression analysis was completed on the factors of age, gender, weight, and height. One-way analysis of variance was completed for binned categories of BMI. Results Data from 330 participants (age range, 18 to 86 years; mean, 42.13 ± 18.53 years; 171 men, 159 women) were collected. The range of MMO was 31 to 71 mm. Age, height, and weight were significant predictors of the MMO, and the final model accounted for ∼20% of the variation in the MMO [adjusted r2, 0.208; F(3,326) = 29.731; P = .001]. On average, individuals with a greater BMI had a greater MMO (BMI, ≤25 kg/m2, 50.57 ± 7.16 mm; BMI >25 but ≤30 kg/m2, 51.58 ± 7.13 mm; BMI >30 kg/m2, 53.53 ± 9.84 mm). Conclusions In a heterogeneous population of healthy adults, natural variations in age, height, and weight significantly affected the MMO.

Head and neck cancers (HNC) are associated with significant morbidity. Quality-of-life (QoL) analyses can assist with understanding subjective factors shaping the patient experience. Here, we assess for patient and/or tumor factors associated with increased pain reporting at the time of initial radiation oncology consultation at a single institution in 2015.Prospective cross-sectional questionnaire research.All new patient consultations in 2015 were offered the European Organization for Research and Treatment of Cancer Quality-of-Life Questionnaire Core-30 (EORTC QLQ-C30) survey. HNC patients were also offered the EORTC QLQ-HN35 module. Retrospective chart review was performed on patients who completed the surveys. Patient demographics, tumor characteristics, and QoL responses were analyzed for potential associations. Statistical analyses were conducted using SAS v9.4 (SAS Institute, Cary, NC), with P .05 considered significant.Of 771 new patient consultations, 137 consultations were for HNC patients. Of those, 62 patients completed both surveys. HNC patients reported greater pain relative to all other disease sites (odds ratio [OR]: 2.05; P .01). On univariate analysis of the EORTC QLQ-C30 data, increased pain was found to be associated with tumor size 4 cm (OR: 3.05; P ≤ .05). The EORTC QLQ-HN35 data revealed lymph node involvement to be independently associated with pain (OR: 3.12; P ≤ .05). On multivariate analysis, increased pain was associated with lack of pain medication prescription at the time of consultation (P ≤ .05) and age ≥ 65 years (P ≤ .05).Patients with HNC reported significantly more pain at consultation than patients with other primary malignancies. Understanding factors contributing to subjective pain may allow providers to potentially address these symptoms proactively to improve patients' QoL.2c - Outcomes research. Laryngoscope, 131:326-332, 2021.

OBJECTIVES/HYPOTHESIS This study evaluates the existence and nature of maternity and paternity leave policies for residents during otolaryngology training. The study sought to survey program directors (PDs) on the impact of parental leave. STUDY DESIGN Cross-sectional survey. METHODS An electronic survey was sent to 103 otolaryngology residency PDs. A link to a 10-page, 30-question survey was provided. Descriptive statistics and comments were collected. RESULTS Forty-one respondents (39.8%) completed the survey, all of whom were from university-based programs. Programs from the Midwest (n = 11, 26.8%), Northeast (n = 12, 29.3%), South (n = 12, 29.3%) and West (n = 6, 14.6%) were represented. Sixteen (42%) programs reported having a written formal maternity leave policy for trainees, and 13 (32%) programs had a paternity-specific policy. Four programs reported using short-term disability, whereas 11 programs reported using the Family Medical Leave Act to accommodate parental leave. Policies primarily followed the Accreditation Council for Graduate Medical Education and American Board of Otolaryngology guidelines, with factors such as clinical duties and call schedules left to the programs' discretion. Although the majority of PDs (56%) reported support of residents who planned to become pregnant during training, many expressed concerns regarding the burden on co-residents and the difficulty of fulfilling training obligations for the resident taking leave. CONCLUSIONS Many institutions do not have parental leave policies and logistics regarding leave are left to the discretion of individual programs. Surveyed PDs addressed the challenges of becoming a parent during training and the potential burden placed on the program when trainees take leave. LEVEL OF EVIDENCE 4 Laryngoscope, 129:1093-1099, 2019.

Head and neck cancer (HNC) remains the sixth most common malignancy worldwide and survival upon recurrence and/or metastasis remains poor. HNSCC has traditionally been associated with alcohol and nicotine use, but more recently the Human Papilloma Virus (HPV) has emerged as a favorable prognostic risk factor for oropharyngeal HNSCC. However, further stratification with additional biomarkers to predict patient outcome continues to be essential. One candidate biomarker is the DEK oncogenic protein, which was previously detected in the urine of patients with bladder cancer and is known to be secreted by immune cells such as macrophages. Here, we investigated if DEK could be detected in human plasma and if DEK levels correlated with clinical and pathological variables of HNSCC. Plasma was separated from the peripheral blood of newly diagnosed, untreated HNSCC patients or age-matched normal healthy controls and analyzed for DEK protein using ELISA. Plasma concentrations of DEK protein were lower in p16-negative tumors compared to both normal controls and patients with p16-positive tumors. Patients with lower plasma concentrations of DEK were also more likely to have late stage tumors and a lower white blood cell count. Contrary to previously published work demonstrating a poor prognosis with high intratumoral DEK levels, we show for the first time that decreased concentrations of DEK in patient plasma correlates with poor prognostic factors, including HPV-negative status as determined by negative p16 expression and advanced tumor stage.

Head and neck squamous cell carcinoma (HNSCC) is an aggressive and often fatal disease. Cisplatin is the most common chemotherapeutic drug in the treatment of HNSCC, but intrinsic and acquired resistance are frequent, and severe side effects occur at high doses. The second messenger cyclic GMP (cGMP) is produced by soluble guanylate cyclase (sGC). We previously reported that activation of the cGMP signaling cascade caused apoptosis in HNSCC cells, while others found that this pathway enhances cisplatin efficacy in some cell types. Here we found that sGC stimulators reduced HNSCC cell viability synergistically with cisplatin, and enhanced apoptosis by cisplatin. Moreover, the sGC stimulators effectively reduced viability in cells with acquired cisplatin resistance, and were synergistic with cisplatin. The sGC stimulator BAY 41-2272 reduced expression of the survival proteins EGFR and β-catenin, and increased pro-apoptotic Bax, suggesting a potential mechanism for the anti-tumorigenic effects of these drugs. The sGC stimulator Riociguat is FDA-approved to treat pulmonary hypertension, and others are being studied for therapeutic use in several diseases. These drugs could provide valuable addition or alternative to cisplatin in the treatment of HNSCC.

Cancer patients infected with the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have a higher mortality rate compared to non-cancer patients. Recent anticancer treatment, including immunotherapy, is associated with severe infection including development of acute respiratory distress syndrome (ARDS) and high levels of cytokine release resulting in cytokine storm. Immune checkpoint inhibitors (ICIs) are approved for use in multiple cancer types and function by blocking the interaction between PD-1 and its ligand PD-L1, activating antitumor cytotoxic immune cells. However, ICIs can also increase inflammatory cytokine secretion, which may predispose to the development of cytokine storm. In fact, we have shown via single-cell cytokine secretion analysis that pembrolizumab (anti-PD-1 antibody) increases cytokine secretion by polyfunctional strength index, a measure of the percentage of cells secreting multiple functional cytokines. Therefore, we hypothesize that ICIs may worsen inflammatory cytokine secretion and potentiate cytokine storm and downstream complications in COVID-19 patients. Peripheral blood mononuclear cells (PBMCs) were isolated via Ficoll density gradient centrifugation from healthy donors, head and neck cancer (HNC) patients, and COVID-19-infected cancer patients. Flow cytometry was performed on patient PBMCs, after staining for viability and immune cell markers including CD3, CD8, CD19, and CD45. PBMCs were also activated overnight with low-dose IL-2, cocultured with Cal27 or HN5 cell lines, and subjected to various treatment conditions. For non-COVID-19 patients, PBMCs were exposed to 25 nM SARS-CoV-2 recombinant spike (S) protein, a virulent protein associated with cytokine storm, or control prior to drug treatments. Preliminary flow cytometry analysis showed that a COVID-19-positive patient with thyroid cancer had an increased proportion of CD8+ cells compared with a COVID-negative ovarian cancer patient and healthy donor. Recombinant SARS-CoV-2 S protein caused increased secretion of IL-6, IL-2, perforin, and MIP-1b from PBMCs isolated from both healthy donors and HNC patients, which was measured by IsoLight Codeplex bulk cytokine analysis or ELISA. We have previously shown that metformin, a commonly prescribed antidiabetes drug, decreases the proportion of cells that secrete inflammatory cytokines such as IL-6, which is thought to be an important cytokine for cytokine storm. Interestingly, we observed that metformin treatment resulted in decreased IL-6 secretion from PBMCs isolated from a COVID-19-positive patient. Results from this project suggest that ICIs may potentiate cytokine storm, and ongoing investigation will be informative to oncologists as to whether ICI treatment should be postponed in severe COVID-19 infections. In addition, metformin may be a novel potential treatment for COVID-19 patients to prevent and treat cytokine storm. Citation Format: Layne Weatherford, Maria Lehn, McKenzie Crist, Chelsea Wendling, Kristin Hudock, Vinita Takiar, Trisha Wise-Draper. SARS-CoV-2 induces inflammatory cytokine release, which may be exacerbated by immune checkpoint blockade [abstract]. In: Proceedings of the AACR Virtual Meeting: COVID-19 and Cancer; 2020 Jul 20-22. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(18_Suppl):Abstract nr S02-03.

6031 Background: Salvage surgery for locally recurrent head and neck squamous cell carcinoma (rHNSCC) results in local control rates of 33-50% but only 20-40% of patients achieve long-term survival necessitating additional therapy (Haque et al., Oral Oncol. 2019). Many patients are ineligible for re-irradiation and chemotherapy alone after salvage surgeryhas shown no survival benefit. The clinical activity and tolerability of immune checkpoint inhibitors has been demonstrated in metastatic HNSCC, but the benefit after salvage surgery (SS) has not been studied. Here we report the results of a multi-center phase II investigation of nivolumab, a PD-1 inhibitor, after SS in recurrent HNSCC (NCT03355560). Methods: HNSCC patients undergoing curative-intent SS were enrolled to receive 6 months of nivolumab beginning 4-11 weeks after surgery. All received radiation with or without chemotherapy as prior definitive therapy and had no other curative treatment options at the time of surgery. Key exclusion criteria included: distant metastatic disease, gross residual disease, or a history of immunodeficiency, autoimmunity, or pneumonitis. The primary endpoint was 2-year disease-free survival (DFS) measured by Kaplan Meier curves. Safety was evaluated by CTCAE v5.0. Results: 39 patients were enrolled. Median age was 68 years (range, 49-85). 12/39 (31%) were female. 34/39 (87%) were white. Disease sites included oropharynx 9/39 (23%), oral cavity 14/39 (36%), and larynx 16/39 (41%). P16 status was 26% (+), 48% (-), and 26% (unknown). 17/39 (44%) had high risk pathologic features (positive margins or extranodal spread) at time of SS. 28/39 (72%) patients experienced treatment-related adverse events (TRAE), the most common of which were fatigue (26%), hypothyroidism (10%) and acneiform rash (13%). Grade 3-4 TRAEs were rare, occurring in 3/39 (8%) patients and included diarrhea, oral pain, neck pain, productive cough, stridor, and COPD exacerbation. 3/39 (8%) required treatment discontinuation and there were no grade 5 events. The 2-year DFS was 60% (95%CI 0.39-0.91). 2-year overall survival was 74% (95% CI 0.54-1). In single-cell multiplex cytokine analysis, patients who relapsed following adjuvant nivolumab had a significantly higher proportion of peripheral blood CD8 T cells which displayed a polyfunctional cytokine profile. IFN-γ and Granzyme were the dominant CD8 cytokines in both responders and non-responders, however CD8 expression of MIP1a and TNF-α were significantly higher in patients who ultimately relapsed. Conclusions: Nivolumab after salvage surgery in rHNSCC is well tolerated and shows promising antitumor activity in this high-risk patient population with unmet need. Immunotherapy after salvage surgery should be studied in randomized clinical trials. Clinical trial information: NCT03355560.

6006 Background: Patients with resected HNSCC, with high-risk (positive margins, extracapsular spread [ECE]) or intermediate-risk pathological features have an estimated 1-year DFS of 65% and 69%, respectively. Immune checkpoint blockade improved survival of patients with recurrent/metastatic HNSCC, and preclinical models indicate radiotherapy (RT) synergizes with anti-PD-1. Therefore, we administered the PD-1 inhibitor pembrolizumab (pembro) pre- and post-surgery with adjuvant RT +/- cisplatin in patients with resectable, locoregionally advanced (clinical T3/4 and/or ≥2 nodal metastases) HNSCC (NCT02641093). Methods: Eligible patients received pembro (200 mg I.V. x 1) 1-3 weeks before resection. Adjuvant pembro (q3 wks x 6 doses) was administered with RT (60-66Gy) with or without weekly cisplatin (40mg/m2 X 6) for patients with high-risk and intermediate-risk features, respectively. The primary endpoint was 1-year DFS estimated by Kaplan Meier curves. Safety was evaluated by CTCAE v5.0. Pathological response (PR) to neoadjuvant pembro was evaluated by comparing pre- and post-surgical tumor specimens for treatment effect (TE), defined as tumor necrosis and/or histiocytic inflammation and giant cell reaction to keratinaceous debris. PR was classified as no (NPR, < 20%), partial (PPR, ≥20% and < 90%) and major (MPR, ≥90%). Tumor PD-L1 immunohistochemistry was performed with 22c3 antibody and reported as combined positive score (CPS). Results: Ninety-two patients were enrolled. Seventy-six patients received adjuvant pembro and were evaluable for DFS. Patient characteristics included: median age 58 (range 27 – 80) years; 32% female; 88% oral cavity, 8% larynx, and 3% human papillomavirus negative oropharynx; 86% clinical T3/4 and 65% ≥2N; 49 (53%) high-risk (positive margins, 45%; ECE, 78%); 64% (44/69 available) had PD-L1 CPS ≥1. At a median follow-up of 20 months, 1-year DFS was 67% (95%CI 0.52-0.85) in the high-risk group and 93% (95%CI 0.84-1) in the intermediate-risk group. Among 80 patients evaluable for PR, TE scoring resulted in 48 NPR, 26 PPR and 6 MPR. Patients with PPR/MPR had significantly improved 1-year DFS when compared with those with NPR (100% versus 68%, p = 0.01; HR = 0.23). PD-L1 CPS ≥ 1 was not independently associated with 1-year DFS, but was highly associated with MPR/PPR (p = 0.0007). PPR/MPR in PD-L1 CPS < 1, ≥1 and ≥20, were estimated as 20, 55 and 90%, respectively. Grade ≥ 3 adverse events occurred in 62% patients with most common including dysphagia (15%), neutropenia (15%), skin/wound infections (10%), and mucositis (9%). Conclusions: PR to neoadjuvant pembro is associated with PD-L1 CPS≥1 and high DFS in patients with resectable, local-regionally advanced, HNSCC. Clinical trial information: NCT02641093.

Background The prognostic value of pretreatment complete blood count (CBC) data, including absolute lymphocyte count (ALC) and the neutrophil-to-lymphocyte ratio (NLR), has been reported for many diseases with decreased ALC and increased absolute neutrophil count (ANC) and NLR values correlating with worse outcomes. There is minimal data relating these hematologic parameters to oropharyngeal squamous cell carcinoma (OPSCC) prognosis. This study evaluates the prognostic value of pretreatment CBC data in OPSCC on overall survival (OS) and progression-free survival (PFS) in relation to HPV status. Methods A single-institutional retrospective review of patients with pretreatment hematologic data who received radiation for OPSCC was performed. Univariate and multivariate (UVA/MVA) Cox proportional hazard regression analyses were performed to identify prognostic variables. Translational studies related outcomes to the degree of tumor-infiltrating lymphocytes (TILs) in histologic specimens. Results From 2007 to 2018, 201 patients were treated for OPSCC. Median follow-up was 40 months. 3-year OS was 86.2% in the HPV-positive cohort, 46.3% for HPV-negative. Median NLR was 3.04. NLR ≥ 3 was associated with worse PFS (HR 1.67, p = 0.044. In the subset of 158 HPV + patients, MVA revealed increasing ALC to be associated with improved OS (HR 0.53; p = 0.040) and PFS (HR = 0.48; p = 0.0075). On UVA, high-TIL infiltration at diagnosis was associated with improved OS. Conclusion In a cohort of HPV + OPSCC patients, increasing ALC is associated with improved OS and PFS. Our study is the first to identify pre-treatment ALC as an independent prognostic factor in HPV-associated OPSCC.

Purpose Reirradiation of head and neck (H&N) cancer is a clinical challenge. Proton radiation therapy (PRT) offers dosimetric advantages for normal tissue sparing and may benefit previously irradiated patients. Here, we report our initial experience with the use of PRT for H&N reirradiation, with focus on clinical outcomes and toxicity. Methods and Materials We retrospectively reviewed the records of patients who received H&N reirradiation with PRT from April 2011 through June 2015. Patients reirradiated with palliative intent or without prior documentation of H&N radiation therapy were excluded. Radiation-related toxicities were recorded according to the Common Terminology Criteria for Adverse Events Version 4.0. Results The conditions of 60 patients were evaluated, with a median follow-up time of 13.6 months. Fifteen patients (25%) received passive scatter proton therapy (PSPT), and 45 (75%) received intensity modulated proton therapy (IMPT). Thirty-five patients (58%) received upfront surgery, and 44 (73%) received concurrent chemotherapy. The 1-year rates of locoregional failure–free survival, overall survival, progression-free survival, and distant metastasis–free survival were 68.4%, 83.8%, 60.1%, and 74.9%, respectively. Eighteen patients (30%) experienced acute grade 3 (G3) toxicity, and 13 (22%) required a feeding tube at the end of PRT. The 1-year rates of late G3 toxicity and feeding tube independence were 16.7% and 2.0%, respectively. Three patients may have died of reirradiation-related effects (1 acute and 2 late). Conclusions Proton beam therapy can be a safe and effective curative reirradiation strategy, with acceptable rates of toxicity and durable disease control.

This case series describes the use of pelvic radiotherapy (RT) and MRI-based intracavitary brachytherapy (ICBT) for patients with small volume, early-stage, primary vaginal cancer. A customized pelvic MRI protocol with a vaginal cylinder in place (MRVC) was used to measure disease extent and tumor thickness (defined as distance from lateral/apical margin of tumor to cylinder surface) at time of diagnosis. Non-bulky tumors with initial (pre-RT) thickness ≤ 2 cm from the cylinder surface received pelvic RT followed by ICBT. Ten patients with FIGO stage I–II primary vaginal cancer treated with pelvic RT +/− cisplatin and ICBT at our institution between 1998 and 2008 were included. Initial tumor thickness measured on MRVC ranged from 0 to 2 cm. Initial tumor volume ranged from 0 to 9.8 cm3. Mean pelvic RT dose was 45 Gy. At the time of ICBT, 60% of patients had a complete response (cR) and 40% had a partial response (pR). No patients with a cR had a recurrence whereas one patient with a pR had a local recurrence following ICBT. For the entire cohort, the median follow-up time was 59.9 months (range: 15–153). The estimated 5-year overall survival, disease-specific survival, and local failure-free survival were 67%, 80%, and 90%, respectively. Among survivors, there were no late grade 3–4 toxicities. In this series of patients with small primary early-stage vaginal tumors, long term clinical outcomes were acceptable following RT and MRI-based ICBT, especially among those with a cR at time of brachytherapy., Highlights • Brachytherapy for vaginal cancer is highly individualized. • This small case series included stage I–II patients with limited tumor volume. • A pelvic MRI with vaginal cylinder in place (MRVC) documented tumor extent at diagnosis. • Patients with initial tumor thickness on MRVC ≤ 2 cm received EBRT + intra-cavitary boost. • Best results were among those with no residual disease at time of brachytherapy.

Purpose To review our 15-year institutional experience using intensity modulated radiation therapy (IMRT) to reirradiate patients with head and neck squamous cell carcinomas (HNSCC) and identify predictors of outcomes and toxicity. Methods and Materials We retrospectively reviewed the records of 227 patients who received head and neck reirradiation using IMRT from 1999 to 2014. Patients treated with noncurative intent were excluded. Radiation-related acute and late toxicities were recorded. Prognostic variables included performance status, disease site, disease-free interval, chemotherapy, and RT dose and volume. Correlative analyses were performed separately for surgery and nonsurgery patients. Results Two hundred six patients (91%) were retreated with curative intent, and 173 had HNSCC histology; 104 (50%) underwent salvage resection, and 135 (66%) received chemotherapy. Median follow-up after reirradiation was 24.7 months. Clinical outcomes were worse for HNSCC patients, with 5-year locoregional control, progression-free survival, and overall survival rates of 53%, 22%, and 32%, respectively, compared with 74%, 59%, and 79%, respectively, for non-HNSCC patients. On multivariate analysis, concurrent chemotherapy and retreatment site were associated with tumor control, whereas performance status was associated with survival. Favorable prognostic factors specific to surgery patients were neck retreatment and lack of extracapsular extension, whereas for nonsurgery patients, these were a nasopharynx subsite and complete response to induction chemotherapy. Actuarial rates of grade ≥3 toxicity were 32% at 2 years and 48% at 5 years, with dysphagia or odynophagia being most common. Increased grade ≥3 toxicity was associated with retreatment volume >50 cm 3 and concurrent chemotherapy. Conclusions Reirradiation with IMRT either definitively or after salvage surgery can produce promising local control and survival in selected patients with head and neck cancers. Treatment-related toxicity remains significant. Prognostic factors are emerging to guide multidisciplinary treatment approaches and clinical trial design.

// Shreya Mitra 1 , Lorenzo Federico 1 , Wei Zhao 1 , Jennifer Dennison 1 , Tapasree Roy Sarkar 2 , Fan Zhang 1 , Vinita Takiar 3 , Kwai W. Cheng 4 , Sendurai Mani 5 , Ju Seog Lee 1 , Gordon B. Mills 1 1 Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA 2 Center for Statistical Bioinformatics, Texas A&M University, College Station, TX, USA 3 Department of Radiation Oncology, University of Cincinnati, Cincinnati, OH, USA 4 Cardiac Catheterization Laboratory, Michael and DeBakey Medical Center, Houston, TX, USA 5 Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA Correspondence to: Shreya Mitra, email: smitra@mdanderson.org Keywords: Rab25, Rab coupling protein, breast cancer, luminal B, claudin low Received: March 30, 2016 Accepted: May 10, 2016 Published: May 31, 2016 ABSTRACT The Rab GTPases regulate vesicular trafficking machinery that transports and delivers a diverse pool of cargo, including growth factor receptors, integrins, nutrient receptors and junction proteins to specific intracellular sites. The trafficking machinery is indeed a major posttranslational modifier and is critical for cellular homeostasis. Deregulation of this stringently controlled system leads to a wide spectrum of disorders including cancer. Herein we demonstrate that Rab25, a key GTPase, mostly decorating the apical recycling endosome, is a dichotomous variable in breast cancer cell lines with higher mRNA and protein expression in Estrogen Receptor positive (ER+ve) lines. Rab25 and its effector, Rab Coupling Protein (RCP) are frequently coamplified and coordinately elevated in ER+ve breast cancers. In contrast, Rab25 levels are decreased in basal-like and almost completely lost in claudin-low tumors. This dichotomy exists despite the presence of the 1q amplicon that hosts Rab25 across breast cancer subtypes and is likely due to differential methylation of the Rab25 promoter. Functionally, elevated levels of Rab25 drive major hallmarks of cancer including indefinite growth and metastasis but in case of luminal B breast cancer only. Importantly, in such ER+ve tumors, coexpression of Rab25 and its effector, RCP is significantly associated with a markedly worsened clinical outcome. Importantly, in claudin-low cell lines, exogenous Rab25 markedly inhibits cell migration. Similarly, during Snail-induced epithelial to mesenchymal transition (EMT) exogenous Rab25 potently reverses Snail-driven invasion. Overall, this study substantiates a striking context dependent role of Rab25 in breast cancer where Rab25 is amplified and enhances aggressiveness in luminal B cancers while in claudin-low tumors, Rab25 is lost indicating possible anti-tumor functions.

The purpose of this study was to investigate the setup and positioning uncertainty of a custom cushion/mask/bite‐block (CMB) immobilization system and determine PTV margin for image‐guided head and neck stereotactic ablative radiotherapy (HN‐SABR). We analyzed 105 treatment sessions among 21 patients treated with HN‐SABR for recurrent head and neck cancers using a custom CMB immobilization system. Initial patient setup was performed using the ExacTrac infrared (IR) tracking system and initial setup errors were based on comparison of ExacTrac IR tracking system to corrected online ExacTrac X‐rays images registered to treatment plans. Residual setup errors were determined using repeat verification X‐ray. The online ExacTrac corrections were compared to cone‐beam CT (CBCT) before treatment to assess agreement. Intrafractional positioning errors were determined using prebeam X‐rays. The systematic and random errors were analyzed. The initial translational setup errors were −0.8±1.3 mm, −0.8±1.6 mm, and 0.3±1.9 mm in AP, CC, and LR directions, respectively, with a three‐dimensional (3D) vector of 2.7±1.4 mm. The initial rotational errors were up to 2.4° if 6D couch is not available. CBCT agreed with ExacTrac X‐ray images to within 2 mm and 2.5°. The intrafractional uncertainties were 0.1±0.6 mm, 0.1±0.6 mm, and 0.2±0.5 mm in AP, CC, and LR directions, respectively, and 0.0∘±0.5°, 0.0∘±0.6°, and −0.1∘±0.4∘ in yaw, roll, and pitch direction, respectively. The translational vector was 0.9±0.6 mm. The calculated PTV margins mPTV(90,95) were within 1.6 mm when using image guidance for online setup correction. The use of image guidance for online setup correction, in combination with our customized CMB device, highly restricted target motion during treatments and provided robust immobilization to ensure minimum dose of 95% to target volume with 2.0 mm PTV margin for HN‐SABR. PACS number(s): 87.55.ne

Background This study assessed outcomes of patients with hypopharyngeal carcinoma treated with organ-preservation therapy utilizing intensity-modulated radiation therapy (IMRT). Methods The medical records of 98 patients treated with definitive IMRT +/- chemotherapy from 2001 to 2013 for nonmetastatic hypopharyngeal cancer were retrospectively reviewed. Results Patients were treated to doses of 66 to 72 Gy. Eighty-three patients (85%) received chemotherapy. With median follow-up of 35 months, 2-year overall survival (OS), locoregional control, progression-free survival (PFS), and laryngectomy-free survival rates were 74%, 77%, 67%, and 65%, respectively. Functional laryngeal preservation rate was 76% at 2 years. N3 disease correlated with worse OS (p < .01). Concurrent chemotherapy correlated with improved locoregional control (p = .03) and complete response to induction chemotherapy correlated with improved OS and PFS (p = .02). Actuarial 2-year and 5-year grade 3 treatment toxicities were 17% and 21%, respectively. Conclusion Favorable disease outcomes and functional laryngeal preservation rates can be achieved with IMRT for patients with hypopharyngeal cancer. © 2016 Wiley Periodicals, Inc. Head Neck, 2016

OBJECTIVES: Recurrence rates for head and neck squamous cell carcinoma (HNSCC) approach 50% at 5 years. Current staging fails to identify patients with a worse prognosis who might benefit from intensified treatment, which warrants improved prognostic biomarkers. The purpose of this retrospective case study is to identify potential prognostic biomarkers in patients with HNSCC including APE1 (DNA repair/redox gene regulator), NRF2 and PPARGC1A (redox gene regulators), SOD3 and DCN (antioxidant proteins). MATERIALS AND METHODS: Differential protein expression between benign, carcinoma in situ (CIS), and invasive HNSCC tissue specimens from 77 patients was assessed using immunohistochemistry. Protein expression was analyzed with multivariate, pair-wise, and Kaplan-Meier survival analyses to identify potential prognostic biomarkers. Utilizing The Cancer Genome Atlas’s transcriptome database, pair-wise and survival analysis was performed to identify potential prognostic biomarkers. RESULTS: APE1, NRF2, PPARGC1A, SOD3, and DCN expression in HNSCC in relation to, lymph node invasion, and patient survival were examined. Elevated APE1 protein expression in CIS corresponded with reduced survival (p=0.0243). Increased APE1 gene expression in stage T4a HNSCC was associated with reduced patient survival (p

Head and neck cancer is the 6th most common cancer worldwide. Ionizing radiation (IR) is an important aspect of cancer treatment. However, its efficacy is limited by radioresistance, resulting in locoregional failure rates as high as 50%. The pathways used by cells to evade the cellular damage caused by IR are poorly understood. Initial Reverse Phase Protein Array analyses in our laboratory demonstrated that IR induced metabolic pathways, including those involving the Krebs cycle. Glutamate is a key substrate of the Krebs cycle, and essential for the production of biomolecules necessary for tumor proliferation. Glutaminase is the enzyme that converts glutamine to glutamate. Analysis of The Cancer Genome Atlas's transcriptome database revealed that glutaminase overexpression (upper 25%) in patients with HNSCC was associated with significantly reduced patient survival (p In this study, we aimed to identify whether glutaminase inhibition with CB-839 could enhance cellular response to IR. To do this, we used three representative human-derived HNSCC cell lines: CAL-27, FaDu, and HN5. We first established that proliferation of all 3 HNSCC cell lines was glutamine dependent (20-50% increase, n=3 per line, p3). Combination of CB-839 with IR significantly inhibited tumor growth in Cal-27 xenograft mice relative to vehicle (p In summary, adaptive resistance to IR and locoregional failure is a major hurdle in the successful treatment of HNSCC. Overall, these data suggest that combinatorial treatment with IR and the glutaminase inhibitor, CB-839, lead to an enhanced response over either treatment alone and provide pre-clinical data to justify further investigation for clinical use in patients with HNSCC. Citation Format: Christina A. Wicker, Brian G. Hunt, Sarah Palackdharry, William R. Elaban, Gordon B. Mills, Trisha Wise-Draper, Susan Waltz, Vinita Takiar. Glutaminase inhibition in combination with ionizing radiation improves treatment response in head and neck squamous cell carcinoma models [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6278.

Epidemiologic studies and meta-analyses have indicated that metformin is associated with a lower incidence of tumorigenesis among type 2 diabetic patients, including those with head and neck squamous cell carcinoma (HNSCC). HNSCC patients are often treated with concurrent cisplatin-based chemotherapy and radiation (CRT). However, the cure rate remains low at 50% in HPV-negative smokers. Metformin has been shown to inhibit tumor growth and progression, both in vitro and in mouse models, in a wide variety of cancers including HNSCC. The mechanism through which this occurs is thought to be via the inhibition of the mammalian target of rapamycin (mTOR) pathway directly and indirectly through activation of AMPK. Recent studies indicate that increasing the activity of AMPK reduces the expression of PD-L1 found on the surface of cancer cells, thus allowing a greater influx of CD8+ T cells and further activity of NKT cells correlated with increased tumor cell killing. Given the potential antitumorigenic activity of metformin in HNSCC and that biguanide is generally well tolerated compared to other mTOR inhibitors, we hypothesized that the addition of metformin to CRT would be safe and would result in enhanced antitumor responses through activation of AMPK and the immune system. Therefore, in accordance with the phase I open-label, single-site, dose-escalation study combining metformin and CRT in LAHNSCC (NCT02325401), we investigated the effects of metformin on T cells, NK cells, and cytokines from patient PBMCs. Using flow cytometry and cytokine magnetic bead assays (Luminex), we evaluated the immune cell phenotypes and cytokine profiles of peripheral blood in patients before and after metformin treatment on trial. Cytokine profiles were further studied in coculture experiments combining PBMCs, HNSCC cell lines, and metformin. Following metformin treatment, patients developed an increase in activated NK cell populations, determined via NKG2D expression, as well as a shift in their CD8+ T-cell memory phenotypes. Patient serum ELISA examination revealed alterations in cytokine profiles, which were recapitulated in ex vivo experiments. Metformin treatment of HNSCC cell lines in vitro as well as HNSCC PBMCs ex vivo resulted in downregulation of STAT3 compared to healthy controls. Downregulation of STAT3 may be a potential mechanism in which metformin activates NK cells. Here we show evidence that metformin treatment has a direct effect on the innate immune system in patients with LAHNSCC, inducing an antitumorigenic immune response. Our study thus demonstrates that metformin continues to be a good candidate in combination with other therapeutic agents to yield improved clinical outcomes in patients with advanced-stage HNSCC. Citation Format: Sarah M. Palackdharry, Benyamin Yaniv, Melissa Orr-Asman, Nooshin Hashemi, Vinita Takiar, Trisha Wise-Draper. Metformin treatment in LAHNSCC induces an antitumorigenic immune response [abstract]. In: Proceedings of the AACR-AHNS Head and Neck Cancer Conference: Optimizing Survival and Quality of Life through Basic, Clinical, and Translational Research; 2019 Apr 29-30; Austin, TX. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(12_Suppl_2):Abstract nr A12.

Despite advances in clinical detection, molecular subtyping, and targeted therapeutics, breast cancer (BC) is the second leading cause of cancer-related death in women. Recurrent and metastatic disease is the underlying cause of BC mortality. Due to fear of recurrence, BC is the most overtreated cancer, creating significant ethical and financial burdens. Through a discovery-based genomics approach, the RON receptor tyrosine kinase was identified as a predictor of BC recurrence. We and others have shown that RON overexpression occurs in more than half of all BCs and that RON levels are a predictor of metastasis and poor survival. Through evaluation of human breast tumor tissue, we provide the first line of evidence that RON overexpression occurs independent of molecular subtype and provide prognostic evidence of RON expression as a biomarker of BC recurrence. Further, we identified glycolysis and cholesterol biosynthesis, two potentially therapeutically targetable processes, as being significantly upregulated by RON. To test the efficacy of reducing cholesterol as a therapy for BC with RON expression, we treated two independent, spontaneous murine breast cancer models with inhibitors directed at RON and/or cholesterol biosynthesis (atorvastatin). Our studies show that either RON or cholesterol inhibition reduced BC progression and that combination treatments blocked progression further. Current studies are under way to determine the mechanisms by which RON promotes metabolic pathway dependency and to directly test in a novel murine model of BC recurrence if targeting these pathways provides a survival benefit. We anticipate that our studies will serve as the scientific underpinnings for rationally designed new combinatorial therapeutic strategies to decrease the morbidity and mortality associated with advanced breast cancer. Citation Format: Brian G. Hunt, Christina A. Wicker, Jennifer Bourn, Elyse Lower, Vinita Takiar, Susan E. Waltz. Targeting RON-mediated metabolic vulnerabilities in recurrent/progressive breast cancer [abstract]. In: Proceedings of the AACR Special Conference on the Evolving Landscape of Cancer Modeling; 2020 Mar 2-5; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2020;80(11 Suppl):Abstract nr A32.

e18551 Background: Treatment for locally advanced head and neck squamous cell carcinoma (HNSCC) involves a combination of surgery, chemotherapy, and radiotherapy (RT). RT for HNSCC is a known risk factor for the development of hypothyroidism. Recently, anti-PD1 therapies have been approved for recurrent and metastatic HNSCC and are moving to the forefront of HNSCC care. Similarly, thyroid dysfunction is a common immune-related adverse event following anti-PD1 therapy. Whether the addition of anti-PD1 to RT increases the likelihood of developing hypothyroidism remains unknown. Methods: The rate of hypothyroidism in HNSCC patients receiving RT (+/- chemotherapy and surgery) was compared to HNSCC patients receiving RT + anti-PD1 therapy either concurrently or after RT. Exclusion criteria were preexisting thyroid dysfunction, RT dose < 45 Gy and patients with incomplete treatment records. We defined clinical hypothyroidism as an elevation of TSH with low T3, T4 or elevation of TSH with symptoms requiring levothyroxine initiation. Hypothyroidism incidence was compared using Fisher’s exact test. Results: 153 patients were evaluated. In the RT group (N = 103), patients received RT +/- surgery or chemotherapy. 82/103 (80%) were male, median age was 57 and primary tumor groups included oropharynx 62/103 (60%), larynx 29/103 (28%), oral cavity 9/103 (9%) and other 3/103 (3%). In the RT + anti-PD1 group (N = 50), 36/50 (72%) were males, median age was 57 and primary tumor groups included oral cavity 19/50 (38%), oropharynx 17/50 (34%), larynx 8/50 (16%), and other 6/50 (12%). In the RT group, median follow up after RT was 801 days. In the RT+ anti-PD1 group, median follow up was 595 days from RT and 388 days from anti-PD1. The rate of hypothyroidism was significantly higher in the RT group 22.3% (23/103) versus 6% (3/50)after anti-PD1 therapy (p = 0.011). Multinomial logistical regression found no significant difference in hypothyroidism based on age, sex, or BMI. Larynx as primary tumor location was an independent risk factor for development of hypothyroidism (OR 4.74, p = 0.002). Conclusions: The addition of anti-PD1 therapy to standard HNSCC treatments does not significantly increase the risk of developing hypothyroidism. In fact, this study finds a lower incidence of hypothyroidism in HNSCC patient receiving RT + PD1 therapy which may be due to shorter duration of follow up and lower proportion of laryngeal cancer patients who are at relatively higher risk for surgical hypothyroidism.

6576 Background: Immune checkpoint inhibitors (ICIs) are FDA approved for use in head and neck squamous cell cancer (HNSCC), however, only ~20% patients achieve a response. Identification of biomarkers of response or toxicity remains a challenge. Polyfunctional T-cells, or T-cells producing multiple cytokines, have been recognized as contributors to durable immunity against various cancers. However, their role has not been studied prospectively in HNSCC patients receiving ICIs. To look for an early predictor of response, we used single-cell functional proteomic profiling (IsoPlexis) on blood samples pre- and post- first dose of nivolumab (nivo) in patients on our phase-II study of locally recurrent HNSCC (NCT03355560). Methods: HNSCC patients who failed definitive radiation +/-chemotherapy and were subsequently treated with curative intent salvage resection were enrolled to receive 6 months of nivo beginning 4 to 11 weeks after surgery. Blood samples were collected before and after the first dose of nivo. Peripheral blood mononuclear cells were isolated, enriched for CD8+ T cells and using the 32-plex IsoCode technology, single-cell cytokine signals were captured and polyfunctional strength of CD8+ T cells was evaluated across four groups (effector, stimulatory, regulatory, inflammatory). A comparison analysis was performed between pre- and post- nivo treatment and between patients who relapsed (non-responders) vs those who did not (responders). Results: Thirty-three of 39 planned patients have been enrolled, of which 28 are evaluable and 5/28 (18%) developed recurrence. Median age is 68 years (range 51-85), 9/28 (32%) patients are female, 26/28 (93%) are white, disease sites include oropharyngeal 6/28 (21%), oral cavity 11/28 (39%) and larynx 11/28 (39%). Samples were evaluated at a median follow up of 5.9 months from enrollment. Single-cell analysis demonstrated a strong upregulation of polyfunctional human CD8+ T cell subsets in responders. Polyfunctional Strength Index (PSI) was enhanced in CD8+ T cells across the responders’ samples, composed largely of effector cytokines (granzyme-β, IFN-γ, MIP-1α, perforin, TNF-α). Conclusions: Single-cell functional proteomic analysis revealed significantly upregulated polyfunctional profiles and an increase in effector cytokines in patients who responded to nivo. This data provides important insights into PD-1 inhibitor triggered T-cell activity and may be used to predict response to ICIs in HNSCC patients using a blood test. Clinical trial information: NCT03355560 .

Background Treatment of T4 nasopharyngeal carcinoma (NPC) is challenging because of the proximity of the tumor to the central nervous system. The purpose of this study was to present our evaluation of disease control and toxicity outcomes for patients with T4 NPC treated with intensity-modulated radiation therapy (IMRT) and chemotherapy. Methods The medical records of 66 patients with T4 NPC treated from 2002 to 2012 with IMRT were reviewed. Endpoints included tumor control and toxicity outcomes (Common Terminology Criteria for Adverse Events [CTCAE v4.0]). Results Median follow-up was 38 months. Five-year rates of locoregional control, distant metastasis-free survival, progression-free survival (PFS), and overall survival (OS) were 80%, 62%, 57%, and 69%, respectively. Nodal involvement was associated with worse PFS (p = .015). Gross target volume (GTV) volume >100 cm and planning target volume (PTV) volume >400 cm were associated with worse OS (p = .038 and p = .004, respectively). Four patients had significant cognitive impairment, and 9 had MRI evidence of brain necrosis. Conclusion For patients with T4 NPC treated with IMRT and chemotherapy, survival and locoregional disease control rates have improved; however, late treatment toxicity remains a concern. © 2015 Wiley Periodicals, Inc. Head Neck 38: E925–E933, 2016

Both iodine-125 ((125)I) Collaborative Ocular Melanoma Study and ruthenium-106 ((106)Ru) eye plaques can achieve excellent tumor control in patients diagnosed with uveal melanoma. We analyzed our single institutional experience in the management of ocular melanoma treated with either (125)I or (106)Ru plaque brachytherapy.The records of 107 patients with uveal melanoma treated with either (106)Ru (n = 40) or (125)I (n = 67) plaque brachytherapy between 2000 and 2008 were retrospectively reviewed. Tumor control parameters and toxicity were assessed.Actuarial 5-year rates of local control, progression-free survival, and overall survival with (106)Ru were 97%, 94%, and 92%, respectively. For (125)I, these values were 83%, 65%, and 80%. In the subset of patients with tumor apex height ≤5 mm (36 (125)I and 40 (106)Ru), there was no difference in overall survival; however, progression-free survival was significantly improved with (106)Ru (P = .02). Enucleation-free survival was significantly different between the 2 subsets, with no enucleations in the (106)Ru cohort (P = .02). Patients treated with (106)Ru experienced reduced retinopathy (P = .03) and cataracts (P.01).Both (125)I and (106)Ru eye plaque brachytherapy treatment result in encouraging tumor control for patients with uveal melanoma. We demonstrate that (106)Ru offers these benefits with reduced toxicity in patients treated for uveal melanomas ≤5 mm in apical height.

In patients with pituitary adenomas (PA) who are unable to undergo complete surgical resection, radiation therapy (RT), specifically stereotactic radiosurgery (SRS), results in excellent local control. However, the utility of radiosurgery may be limited by the proximity of the lesion to the optic chiasm (OC). We evaluate the efficacy of debulking surgery in increasing the PA-OC separation to convert patients into SRS candidates. From 2007 to 2015, 31 patients with PA

To report late toxicity outcomes from a randomized trial comparing conventional and hypofractionated prostate radiation therapy and to identify dosimetric and clinical parameters associated with late toxicity after hypofractionated treatment.Men with localized prostate cancer were enrolled in a trial that randomized men to either conventionally fractionated intensity modulated radiation therapy (CIMRT, 75.6 Gy in 1.8-Gy fractions) or to dose-escalated hypofractionated IMRT (HIMRT, 72 Gy in 2.4-Gy fractions). Late (≥90 days after completion of radiation therapy) genitourinary (GU) and gastrointestinal (GI) toxicity were prospectively evaluated and scored according to modified Radiation Therapy Oncology Group criteria.101 men received CIMRT and 102 men received HIMRT. The median age was 68, and the median follow-up time was 6.0 years. Twenty-eight percent had low-risk, 71% had intermediate-risk, and 1% had high-risk disease. There was no difference in late GU toxicity in men treated with CIMRT and HIMRT. The actuarial 5-year grade ≥2 GU toxicity was 16.5% after CIMRT and 15.8% after HIMRT (P=.97). There was a nonsignificant numeric increase in late GI toxicity in men treated with HIMRT compared with men treated with CIMRT. The actuarial 5-year grade ≥2 GI toxicity was 5.1% after CIMRT and 10.0% after HIMRT (P=.11). In men receiving HIMRT, the proportion of rectum receiving 36.9 Gy, 46.2 Gy, 64.6 Gy, and 73.9 Gy was associated with the development of late GI toxicity (P.05). The 5-year actuarial grade ≥2 GI toxicity was 27.3% in men with R64.6Gy ≥ 20% but only 6.0% in men with R64.6Gy20% (P=.016).Dose-escalated IMRT using a moderate hypofractionation regimen (72 Gy in 2.4-Gy fractions) can be delivered safely with limited grade 2 or 3 late toxicity. Minimizing the proportion of rectum that receives moderate and high dose decreases the risk of late rectal toxicity after this hypofractionation regimen.