Application of Time-Driven Activity-Based Costing for Head and Neck Microvascular Free Flap Reconstruction.

OBJECTIVE: Traditional hospital accounting fails to provide an accurate cost of complex surgical care. Here we describe the application of time-driven activity-based costing (TDABC) to characterize costs of head and neck oncologic procedures involving free tissue transfer. STUDY DESIGN: Retrospective cohort study. SETTING: Single tertiary academic medical center. METHODS: An analysis of head and neck oncologic procedures involving microvascular free flap reconstruction from 2018 to 2020 (n = 485) was performed using TDABC methodology to measure cost across operative case and postoperative admission, using quantity of time and cost per unit of each resource to characterize resource utilization. Univariate and generalized linear mixed models were used to examine associations between patient and hospital characteristics and cost of care delivery. RESULTS: The total cost of care delivery was $41,905.77 ± 21,870.27 with operating room (OR) supplies accounting for only 10% of the total cost. Multivariable analyses identified significant cost drivers including operative time, postoperative length of stay, number of return trips to the OR, postoperative complication, number of free flaps performed, and patient transfer from another hospital or via emergency department admission (P < .05). CONCLUSION: Operative time and postoperative length of stay, but not operative supplies, were primary drivers of cost of care for head and neck oncology cases involving free tissue transfer. TDABC offers granular cost characterization to inform cost optimization through unused capacity identification and postoperative admission efficiencies.

Upfront neck dissection for treatment selection and improvement in quality of life as a novel treatment paradigm for deintensification in HPV+ OPSCC.

PURPOSE: Locoregionally advanced HPV+ oropharyngeal squamous cell carcinoma (OPSCC) has excellent cure rates, although current treatment regimens are accompanied by acute and long-term toxicities. We designed a phase II de-escalation trial for patients with HPV+OPSCC to evaluate the feasibility of an upfront neck dissection to individualize definitive treatment selection to improve quality of life without compromising survival. METHODS: Patients with T1-3, N0-2 HPV+ OPSCC underwent an upfront neck dissection with primary tumor biopsy. Patients with a single lymph node less than six centimeters, with no extracapsular spread(ECS), and no primary site adverse features underwent transoral surgery (Arm A). Patients who had two or more positive lymph nodes with no ECS, or those with primary site adverse features were treated with radiation alone (Arm B). Patients who had ECS in any lymph node were treated with chemoradiation (Arm C). The primary endpoint was quality of life at 1 year compared to a matched historical control. RESULTS: Thirty-four patients were enrolled and underwent selective neck dissection. Based on pathologic characteristics, 14 patients were assigned to arm A, 10 patients to arm B, and 9 to arm C. A significant improvement was observed in HNQOL compared to historical controls (-2.6 vs -11.9, p=0.034). With a median follow-up of 37 months, the 3-year overall survival was 100% and estimated 3-year estimated progression free survival was 96% (95% CI: 76-99%). CONCLUSION: A neck dissection driven treatment paradigm warrants further research as a de-intensification strategy.

ctDNA transiting into urine is ultrashort and facilitates noninvasive liquid biopsy of HPV+ oropharyngeal cancer.

BACKGROUNDTransrenal cell-free tumor DNA (TR-ctDNA), which transits from the bloodstream into urine, has the potential to enable noninvasive cancer detection for a wide variety of nonurologic cancer types.MethodsUsing whole-genome sequencing, we discovered that urine TR-ctDNA fragments across multiple cancer types are predominantly ultrashort (<50 bp) and, therefore, likely to be missed by conventional ctDNA assays. We developed an ultrashort droplet digital PCR assay to detect TR-ctDNA originating from HPV-associated oropharyngeal squamous cell carcinoma (HPV+ OPSCC) and confirmed that assaying ultrashort DNA is critical for sensitive cancer detection from urine samples.ResultsTR-ctDNA was concordant with plasma ctDNA for cancer detection in patients with HPV+ OPSCC. As proof of concept for using urine TR-ctDNA for posttreatment surveillance, in a small longitudinal case series, TR-ctDNA showed promise for noninvasive detection of recurrence of HPV+ OPSCC.ConclusionOur data indicate that focusing on ultrashort fragments of TR-ctDNA will be important for realizing the full potential of urine-based cancer diagnostics. This has implications for urine-based detection of a wide variety of cancer types and for facilitating access to care through at-home specimen collections.FundingNIH grants R33 CA229023, R21 CA225493; NIH/National Cancer Institute grants U01 CA183848, R01 CA184153, and P30CA046592; American Cancer Society RSG-18-062-01-TBG; American Cancer Society Mission Boost grant MBGI-22-056-01-MBG; and the A. Alfred Taubman Medical Research Institute.

In Vivo Microstructure Imaging in Oropharyngeal Squamous Cell Carcinoma Using the Random Walk With Barriers Model.

BACKGROUND: Apparent diffusion coefficient is not specifically sensitive to tumor microstructure and therapy-induced cellular changes. PURPOSE: To investigate time-dependent diffusion imaging with the short-time-limit random walk with barriers model (STL-RWBM) for quantifying microstructure parameters and early cancer cellular response to therapy. STUDY TYPE: Prospective. POPULATION: Twenty-seven patients (median age of 58 years and 7.4% of females) with p16+/p16- oropharyngeal/oral cavity squamous cell carcinomas (OPSCC/OCSCC) underwent MRI scans before therapy, of which 16 patients had second scans at 2 weeks of the 7-weeks chemoradiation therapy (CRT). FIELD STRENGTH/SEQUENCE: 3-T, diffusion sequence with oscillating gradient spine echo (OGSE) and pulse gradient spin echo (PGSE). ASSESSMENT: Diffusion weighted images were acquired using OGSE and PGSE. Effective diffusion times were derived for the STL-RWBM to estimate free diffusion coefficient D0 , volume-to-surface area ratio of cellular membranes V/S, and cell membrane permeability κ. Mean values of these parameters were calculated in tumor volumes. STATISTICAL TESTS: Tumor microstructure parameters were compared with clinical stages of p16+ I-II OPSCC, p16+ III OPSCC, and p16- IV OCSCC by Spearman's rank correlation and with digital pathological analysis of a resected tissue sample. Tumor microstructure parameter responses during CRT in the 16 patients were assessed by paired t-tests. A P-value of <0.05 was considered statistically significant. RESULTS: The derived effective diffusion times affected estimated values of V/S and κ by 40%. The tumor V/S values were significantly correlated with clinical stages (r = 0.47) as an increase from low to high clinical stages. The in vivo estimated cell size agreed with one from pathological analysis of a tissue sample. Early tumor cellular responses showed a significant increase in D0 (14%, P = 0.03) and non-significant increases in κ (56%, P = 0.6) and V/S (10%, P = 0.1). DATA CONCLUSION: Effective diffusion time estimation might impact microstructure parameter estimation. The tumor V/S was correlated with OPSCC/OCSCC clinical stages. LEVEL OF EVIDENCE: 1 TECHNICAL EFFICACY STAGE: 1.

Team-Based Surgical Approach to Head and Neck Microvascular Free Flap Reconstruction.

Importance: Because microvascular free flap reconstruction is increasingly used to restore function in patients with head and neck cancer, there is a growing need for evidence-based perioperative care. Objective: To assess the association of different team-based surgical approaches with intraoperative and postoperative outcomes for patients undergoing head and neck free flap reconstruction. Design, Setting, and Participants: This retrospective cohort study of 733 patients was conducted at an academic tertiary care medical center. Head and neck oncologic procedures involving microvascular free flap reconstruction with available intraoperative data collected from January 1, 2000, to December 31, 2021, were included. Main Outcomes and Measures: Patient characteristics including demographic characteristics and comorbid conditions, operative variables, length of stay, and postoperative outcomes were measured. Descriptive statistics and effect size measures were performed to compare the 3 intraoperative surgical team approaches, specifically single surgeon, separate 2-team approach, and integrated 2-team approach; 1:1 nearest neighbor matching without caliper was performed to compare single- vs 2-team and separate and integrated 2-team approaches. Effect size measures including Cramer V for dichotomous variables, the Kendall W coefficient of concordance for ordinal variables, and η2 for continuous variables were reported with 95% CIs to describe precision. Results: Among 733 cases, there were no clinically significant differences in patient demographic characteristics, clinicopathologic characteristics, and choice of free flap reconstruction based on intraoperative surgical team approach. The mean (SD) age was 58.7 (12.4) years, and 514 were male (70.1%). In terms of operative and postoperative variables, there was a difference in operative times and intraoperative fluid requirements among the 3 different techniques, with the integrated 2-team approach demonstrating a mean reduction in operative time of approximately 2 hours (η2 = 0.871; 95% CI, 0.852-0.887; mean [SD] operative time = 541 [191] minutes for the single-surgeon approach, 399 [175] minutes for the integrated 2-team approach, and 537 [200] minutes for the separate 2-team approach) and lower fluid requirements of greater than 1 L (η2 = 0.790; 95% CI, 0.762-0.817). In both unadjusted analyses and propensity score matching, there were no clinically significant differences in terms of ischemia time, use of pressors, postoperative complications (including free flap failure, number of return trips to the operating room, length of stay, or 30-day readmission) based on intraoperative team approach. Conclusions and Relevance: Findings suggest that the integrated 2-team surgical approach for complex head and neck microvascular reconstruction can be used to safely decrease operative time, with no difference in postoperative outcomes.

Monitoring Adverse Effects of Radiation Therapy in Patients With Head and Neck Cancer: The FACT-HN-RAD Patient-Reported Outcome Measure.

Importance: Patients undergoing radiation therapy (RT) for head and neck squamous cell carcinoma (HNSCC) experience a range of debilitating adverse effects (AEs). Patient-reported outcome (PRO) measures to quantify these AEs are a necessary and important component of health care; however, currently available PRO options often measure only disease-related symptoms or AEs of non-RT treatments. Objective: To develop a brief PRO measure of the most common AEs associated with RT for HNSCC. Design, Setting, and Participants: This was a qualitative study that followed the US Food and Drug Administration guidelines to develop a brief measure of patient-reported RT-related AEs (the Functional Assessment of Cancer Therapy-Head and Neck Radiotherapy [FACT-HN-RAD] measure). The study included (1) a literature review of clinical trials; (2) secondary analysis of retrospective concept elicitation interviews (CEIs); (3) electronic surveys of practicing radiation oncologists; (4) mapping of existing items to inform the development of the draft version of the measure; and (5) validation of content and face validity via patient cognitive interviews. Analysis was performed of CEI data and interviews with practicing radiation oncologists. Data analysis was conducted from July 1, 2022, to April 21, 2023. Exposures: Surveys and qualitative interviews. Main Outcomes and Measures: The most common patient-reported RT-related AEs among patients with HNSCC. Results: Of 19 CEI participants, 14 (mean [range] age, 67 [49-86] years; 12 [86%] men and 2 [14%] women) described RT-related AEs and were included in the secondary analysis. Eleven (79%) patients reported difficulty swallowing; 8 (57%), oral pain; 7 (50%), dry mouth; 7 (50%), weight loss; 6 (43%), skin burning; 5 (36%), loss of taste; 5 (36%), voice changes (36%); and 5 (36%), fatigue. Nine radiation oncologists (mean [range] time in practice, 8 [1-42] years; 5 [56%] men and 4 [44%] women) reported the most common AEs: 9 (100%) reported dysgeusia; 7 (78%), xerostomia; 7 (78%), mucositis or oral pain; 8 (89%), dysphagia or odynophagia; 6 (67%), dermatitis; and 3 (33%), fatigue. Together these data informed the development of an 8-item AE-focused measure of pain, dysphagia, xerostomia, dysgeusia, voice changes, dermatitis, fatigue, and weight loss. Cognitive interviews with 10 patients (mean [range] age, 61 [29-84] years; 8 [80%] men and 2 [20%] women) demonstrated strong face validity; all (100%) reported that the measure reflected their experience with RT and stated that the length of the questionnaire was "just right." Conclusions and Relevance: The 8-item FACT-HN-RAD measure captures the most common patient- and physician-reported AEs related to RT for HNSCC. This measure offers a means to serially monitor patient-reported treatment-related AEs and recovery over time in both clinical and research settings. Future work will evaluate the psychometric validity of the measure.

Use of neuromuscular blockade for neck dissection and association with iatrogenic nerve injury.

BACKGROUND: Cranial nerve injury is an uncommon but significant complication of neck dissection. We examined the association between the use of intraoperative neuromuscular blockade and iatrogenic cranial nerve injury during neck dissection. METHODS: This was a single-center, retrospective, electronic health record review. Study inclusion criteria stipulated patients > 18 years who had ≥ 2 neck lymphatic levels dissected for malignancy under general anesthesia with a surgery date between 2008 - 2018. Use of neuromuscular blockade during neck dissection was the primary independent variable. This was defined as any use of rocuronium, cisatracurium, or vecuronium upon anesthesia induction without reversal with sugammadex prior to surgical incision. Univariate tests were used to compare variables between those patients with, and those without, iatrogenic cranial nerve injury. Multivariable logistic regression determined predictors of cranial nerve injury and was performed incorporating Firth's estimation given low prevalence of the primary outcome. RESULTS: Our cohort consisted of 925 distinct neck dissections performed in 897 patients. Neuromuscular blockade was used during 285 (30.8%) neck dissections. Fourteen instances (1.5% of surgical cases) of nerve injury were identified. On univariate logistic regression, use of neuromuscular blockade was not associated with iatrogenic cranial nerve injury (OR: 1.73, 95% CI: 0.62 - 4.86, p = 0.30). There remained no significant association on multivariable logistic regression controlling for patient age, sex, weight, ASA class, paralytic dose, history of diabetes, stroke, coronary artery disease, carotid atherosclerosis, myocardial infarction, and cardiac arrythmia (OR: 1.87, 95% CI: 0.63 - 5.51, p = 0.26). CONCLUSIONS: In this study, use of neuromuscular blockade intraoperatively during neck dissection was not associated with increased rates of iatrogenic cranial nerve injury. While this investigation provides early support for safe use of neuromuscular blockade during neck dissection, future investigation with greater power remains necessary.

Color Match Following Free Flap Surgery in Head and Neck Reconstruction: A Colorimetric and Aesthetic Analysis.

BACKGROUND: Many options for free tissue transfer have been described for head and neck reconstruction. While functional outcomes remain paramount, aesthetic considerations like color match can be equally consequential for patient quality of life. It is important to understand differences in color match based on flap donor site for head and neck reconstruction. METHODS: A retrospective review was performed of patients who underwent head and neck reconstruction with free tissue transfer at a tertiary care academic medical center between November 2012 and November 2020. Patients with documented pictures of their reconstruction and external skin paddles were considered. Patient demographics and surgery specific factors were recorded. Objective differences in color match were obtained by calculating the International Commission on Illumination Delta E 2000 (dE2000) score. Standard univariate descriptive statistics and multivariable statistical analyses were performed. RESULTS: Lateral arm, parascapular, and medial sural artery perforator (MSAP) free tissue transfer performed favorably compared to other donor sites, whereas anterolateral thigh flaps had the highest average dE2000 scores. Differences in dE2000 scores were mitigated by post-operative radiation to the flap site and with increasing time beyond 6 months post-operatively. CONCLUSIONS: We provide an objective assessment of external skin color match in patients undergoing free tissue transfer for head and neck cancer by donor site. MSAP, lateral arm, and parascapular free flaps performed well compared to traditional donor sites. These differences are more significant at the face and mandible when compared to the neck, but diminish 6 months after surgery and with post-operative radiation to the free flap skin paddle.

Development of a high-performance multi-probe droplet digital PCR assay for high-sensitivity detection of human papillomavirus circulating tumor DNA from plasma.

OBJECTIVES: To develop a high-performance droplet digital PCR (ddPCR) assay capable of enhancing the detection of human papillomavirus (HPV) circulating tumor DNA (ctDNA) in plasma from patients with HPV-associated oropharyngeal squamous cell carcinoma (HPV+ OPSCC). MATERIALS AND METHODS: Plasma samples from subjects with HPV+ OPSCC were collected. We developed a high-performance ddPCR assay designed to simultaneously target nine regions of the HPV16 genome. RESULTS: The new assay termed 'ctDNA HPV16 Assessment using Multiple Probes' (CHAMP- 16) yielded significantly higher HPV16 counts compared to our previously validated 'Single-Probe' (SP) assay and a commercially available NavDx® assay. Analytical validation demonstrated that the CHAMP-16 assay had a limit of detection (LoD) of 4.1 copies per reaction, corresponding to < 1 genome equivalent (GE) of HPV16. When tested on plasma ctDNA from 21 patients with early-stage HPV+ OPSCC and known HPV16 ctDNA using the SP assay, all patients were positive for HPV16 ctDNA in both assays and the CHAMP-16 assay displayed 6.6-fold higher HPV16 signal on average. Finally, in a longitudinal analysis of samples from a patient with recurrent disease, the CHAMP-16 assay detected HPV16 ctDNA signal âˆ¼ 20 months prior to the conventional SP assay. CONCLUSION: Increased HPV16 signal detection using the CHAMP-16 assay suggests the potential for detection of recurrences significantly earlier than with conventional ddPCR assays in patients with HPV16+ OPSCC. Critically, this multi-probe approach maintains the cost-benefit advantage of ddPCR over next generation sequencing (NGS) approaches, supporting the cost-effectiveness of this assay for both large population screening and routine post-treatment surveillance.

Patterns of recurrence in head and neck squamous cell carcinoma to inform personalized surveillance protocols.

BACKGROUND: Development of evidence-based post-treatment surveillance guidelines in recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC) is limited by comprehensive documentation of patterns of recurrence and metastatic spread. METHODS: A retrospective analysis of patients diagnosed with R/M HNSCC at a National Cancer Institute-designated cancer center between 1998- 2019 was performed (n = 447). Univariate and multivariate analysis identified patterns of recurrence and predictors of survival. RESULTS: Median overall survival (mOS) improved over time (6.7 months in 1998-2007 to 11.8 months in 2008-2019, p = .006). Predictors of worse mOS included human papillomavirus (HPV) negativity (hazard ratio [HR], 1.8; 95% confidence interval [CI], 1.2-2.6), high neutrophil/lymphocyte ratio (HR, 2.1 [1.4-3.0], disease-free interval (DFI) ≤6 months (HR, 1.4 [1.02-2.0]), and poor performance status (Eastern Cooperative Oncology Group, ≥2; HR, 1.91.1-3.4). In this cohort, 50.6% of recurrences occurred within 6 months of treatment completion, 72.5% occurred within 1 year, and 88.6% occurred within 2 years. Metachronous distant metastases were more likely to occur in patients with HPV-positive disease (odds ratio [OR], 2.3 [1.4-4.0]), DFI >6 months (OR, 2.4 [1.5-4.0]), and body mass index ≥30 (OR, 2.3 [1.1-4.8]). Oligometastatic disease treated with local ablative therapy was associated with improved survival over polymetastatic disease (HR, 0.36; 95% CI, 0.24-0.55). CONCLUSION: These data regarding patterns of distant metastasis in HNSCC support the clinical utility of early detection of recurrence. Patterns of recurrence in this population can be used to inform individualized surveillance programs as well as to risk-stratify eligible patients for clinical trials. PLAIN LANGUAGE SUMMARY: After treatment for head and neck cancer (HNC), patients are at risk of recurrence at prior sites of disease or at distant sites in the body. This study includes a large group of patients with recurrent or metastatic HNC and examines factors associated with survival outcomes and recurrence patterns. Patients with human papillomavirus (HPV)-positive HNC have good survival outcomes, but if they recur, this may be in distant regions of the body and may occur later than HPV-negative patients. These data argue for personalized follow-up schedules for patients with HNC, perhaps incorporating imaging studies or novel blood tests.

Increased Nerve Density Adversely Affects Outcome in Oral Cancer.

PURPOSE: Perineural invasion (PNI) in oral cavity squamous cell carcinoma (OSCC) is associated with poor survival. Because of the risk of recurrence, patients with PNI receive additional therapies after surgical resection. Mechanistic studies have shown that nerves in the tumor microenvironment promote aggressive tumor growth. Therefore, in this study, we evaluated whether nerve density (ND) influences tumor growth and patient survival. Moreover, we assessed the reliability of artificial intelligence (AI) in evaluating ND. EXPERIMENTAL DESIGN: To investigate whether increased ND in OSCC influences patient outcome, we performed survival analyses. Tissue sections of OSCC from 142 patients were stained with hematoxylin and eosin and IHC stains to detect nerves and tumor. ND within the tumor bulk and in the adjacent 2 mm was quantified; normalized ND (NND; bulk ND/adjacent ND) was calculated. The impact of ND on tumor growth was evaluated in chick chorioallantoic-dorsal root ganglia (CAM-DRG) and murine surgical denervation models. Cancer cells were grafted and tumor size quantified. Automated nerve detection, applying the Halo AI platform, was compared with manual assessment. RESULTS: Disease-specific survival decreased with higher intratumoral ND and NND in tongue SCC. Moreover, NND was associated with worst pattern-of-invasion and PNI. Increasing the number of DRG, in the CAM-DRG model, increased tumor size. Reduction of ND by denervation in a murine model decreased tumor growth. Automated and manual detection of nerves showed high concordance, with an F1 score of 0.977. CONCLUSIONS: High ND enhances tumor growth, and NND is an important prognostic factor that could influence treatment selection for aggressive OSCC. See related commentary by Hondermarck and Jiang, p. 2342.

Initial Feasibility and Acute Toxicity Outcomes From a Phase 2 Trial of 18F-Fluorodeoxyglucose Positron Emission Tomography Response-Based De-escalated Definitive Chemoradiotherapy for p16+ Oropharynx Cancer: A Planned Interim Analysis.

PURPOSE: 18F-Fluorodeoxyglucose positron emission tomography (FDG-PET) parameters are prognostic of oncologic outcomes in human papillomavirus-associated oropharyngeal squamous cell carcinoma (OPSCC). We used FDG-PET imaging biomarkers to select patients for de-escalated chemoradiotherapy (CRT), hypothesizing that acute toxicity will be improved with de-escalation. METHODS AND MATERIALS: This is a planned interim initial feasibility and acute toxicity report from a phase 2, prospective, nonrandomized study, which enrolled patients with stage I-II p16+ OPSCC. All patients started definitive CRT to 70 Gy in 35 fractions, and those who met de-escalation criteria on midtreatment FDG-PET at fraction 10 completed treatment at 54 Gy in 27 fractions. We report the acute toxicity and patient-reported outcomes for 59 patients with a minimum follow-up of 3 months. RESULTS: There were no statistically significant differences between baseline patient characteristics in the standard and de-escalated cohorts. There were 28 of 59 (47.5%) patients who met FDG-PET de-escalation criteria and collectively received 20% to 30% less dose to critical organs at risk known to affect toxicity. At 3 months posttreatment, patients who received de-escalated CRT lost significantly less weight (median, 5.8% vs 13.0%; P < .001), had significantly less change from baseline in penetration-aspiration scale score (median, 0 vs 1; P = .018), and had significantly fewer aspiration events on repeat swallow study (8.0% vs 33.3%, P = .037) compared with patients receiving standard CRT. CONCLUSIONS: Approximately half of patients with early-stage p16+ OPSCC are selected for de-escalation of definitive CRT using midtreatment FDG-PET biomarkers, which resulted in significantly improved rates of observed acute toxicity. Further follow-up is ongoing and will be required to determine whether this de-escalation approach preserves the favorable oncologic outcomes for patients with p16+ OPSCC before adoption.

Tumor immune microenvironment alterations using induction cetuximab in a phase II trial of deintensified therapy for p16-positive oropharynx cancer.

BACKGROUND: We sought to characterize early changes in CD8+ tumor-infiltrating lymphocytes and tumor transcriptomes after induction cetuximab in a cohort with p16-positive oropharyngeal cancer on a phase II clinical de-escalation trial. METHODS: Tumor biopsies were obtained before and 1 week after a single cetuximab loading dose in eight patients enrolled in a phase II trial of cetuximab and radiotherapy. Changes in CD8+ tumor-infiltrating lymphocytes and transcriptomes were assessed. RESULTS: One week after cetuximab, five patients (62.5%) had an increase in CD8+ cell infiltration with a median (range) fold change of +5.8 (2.5-15.8). Three (37.5%) had unchanged CD8+ cells (median [range] fold change of -0.85 [0.8-1.1]). In two patients with evaluable RNA, cetuximab induced rapid tumor transcriptome changes in cellular type 1 interferon signaling and keratinization pathways. CONCLUSIONS: Within 1 week, cetuximab induced measurable changes in pro-cytotoxic T-cell signaling and immune content.

Machine Learning Model of Emergency Department Use for Patients Undergoing Treatment for Head and Neck Cancer Using Comprehensive Multifactor Electronic Health Records.

PURPOSE: To use a hybrid method, combining statistical profiling, machine learning (ML), and clinical evaluation to predict emergency department (ED) visits among patients with head and neck cancer undergoing radiotherapy. MATERIALS AND METHODS: Patients with head and neck cancer treated with radiation therapy from 2015 to 2019 were identified using electronic health record data. Records from 60 days before 90 days after treatment were analyzed. Statistical profiling and ML were used to create a predictive model for ED visits during or after radiation therapy. A comprehensive set of variables were studied. Multiple ML models were developed including extreme gradient-boosted decision tree and generalized logistic regression with comparison of multiple predictive performance metrics. RESULTS: Of the 1,355 patients studied, 13% had an ED visit during or after treatment. Our hybrid methodology enabled evidence-based winnowing of candidate features from 141 to 11 with clinically applicable, evidence-based thresholds. Extreme gradient boosting had the highest area under the curve (0.81 ± 0.06) with a sensitivity of 0.89 ± 0.10 and exceeded generalized logistic regression (area under the curve 0.64 ± 0.02). Significant predictors of ED visits during treatment included increasingly complex opioid use, number of prior ED visits, tumor volume, rate of change of blood urea nitrogen, total bilirubin, body mass index, and distance from hospital. CONCLUSION: Our approach combining bootstrapped statistical profiling and ML importance analysis supported integration of clinician input to identify a distilled set of phenotypical characteristics for developing ML models predicting which patients undergoing head and neck cancer radiation therapy were at risk for ED visits.

Neurotization of the radial forearm free flap improves swallowing outcomes in hemiglossectomy defects.

BACKGROUND: We examined the effect of free tissue neurotization on speech and swallowing outcomes for patients undergoing reconstruction of hemiglossectomy defects with a radial forearm free flap (RFFF). METHODS: A retrospective study was performed in patients with oral cavity squamous cell carcinoma undergoing a hemiglossectomy and reconstruction with a RFFF. Functional outcomes including nutritional mode, range of liquids and solids, and speech understandability were analyzed 1-year post-treatment. RESULTS: Eighty-four patients were included in this analysis, 41 of whom had neurotized flaps (49%). No significant differences in demographic or clinical variables were seen between the neurotized and non-neurotized groups. On multivariate analysis controlling for BMI, flap area, and N-classification, patients with neurotized flaps were significantly more likely to have normal range of liquids and solids and less likely to have a G-tube. CONCLUSIONS: Neurotization of RFFF reconstructing hemiglossectomy defects results in decreased G-tube dependence and improved range of liquids and solids.

Prognostic value of CD103+ tumor-infiltrating lymphocytes and programmed death ligand-1 (PD-L1) combined positive score in recurrent laryngeal squamous cell carcinoma.

OBJECTIVES: In an evolving era of immunotherapeutic options for persistent or recurrent laryngeal squamous cell carcinoma (LSCC), there is a need for improved biomarkers of treatment response and survival to inform optimal treatment selection and prognostication. Herein, our primary objective was to explore correlations between tumor infiltrating lymphocytes (TILs) and PD-L1 Combined Positive Score (CPS). Secondarily, we sought to explore their combined association with survival outcomes in patients with persistent or recurrent LSCC treated with salvage surgery. MATERIALS AND METHODS: This was a retrospective cohort study at a single academic medical center. Immunohistochemistry staining for TILs and PD-L1 was performed on a tissue microarray of persistent or recurrent LSCC pathologic specimens. Correlations between TIL subsets and PD-L1 CPS were examined using Pearson's correlation coefficient and survival outcomes were analyzed with the Kaplan-Meier method and log-rank tests. RESULTS: Only CD103+ TILs showed a statistically significant, weakly-positive correlation with PD-L1 CPS (r2 = 0.264, p < 0.015). No other TIL subsets correlated with PD-L1 CPS in our cohort. The most favorable survival outcomes were seen in patients with pathologic N0 tumors showing high CD103+ TILs and/or high PD-L1 CPS staining. CONCLUSION: Among patients with persistent or recurrent LSCC, CD103+ TILs only modestly correlated with PD-L1 CPS. A combined biomarker score incorporating CD103+ TILs and PD-L1 CPS greatly enhanced survival discrimination. This model may have additional utility in predicting the clinical benefit of immunotherapies in persistent or recurrent LSCC in the future.

Randomized Phase II Study of Physiologic MRI-Directed Adaptive Radiation Boost in Poor Prognosis Head and Neck Cancer.

PURPOSE: We conducted a randomized phase II multicenter clinical trial to test the hypothesis that physiologic MRI-based radiotherapy (RT) dose escalation would improve the outcome of patients with poor prognosis head and neck cancer. PATIENTS AND METHODS: MRI was acquired at baseline and at RT fraction 10 to create low blood volume/apparent diffusion coefficient maps for RT boost subvolume definition in gross tumor volume. Patients were randomized to receive 70 Gy (standard RT) or 80 Gy to the boost subvolume (RT boost) with concurrent weekly platinum. The primary endpoint was disease-free survival (DFS) with significance defined at a one-sided 0.1 level, and secondary endpoints included locoregional failure (LRF), overall survival (OS), comparison of adverse events and patient reported outcomes (PRO). RESULTS: Among 81 randomized patients, neither the primary endpoint of DFS (HR = 0.849, P = 0.31) nor OS (HR = 1.19, P = 0.66) was significantly improved in the RT boost arm. However, the incidence of LRF was significantly improved with the addition of the RT boost (HR = 0.43, P = 0.047). Two-year estimates [90% confidence interval (CI)] of the cumulative incidence of LRF were 40% (27%-53%) in the standard RT arm and 18% (10%-31%) in the RT boost arm. Two-year estimates (90% CI) for DFS were 48% (34%-60%) in the standard RT arm and 57% (43%-69%) in the RT boost arm. There were no significant differences in toxicity or longitudinal differences seen in EORTC QLQ30/HN35 subscales between treatment arms in linear mixed-effects models. CONCLUSIONS: Physiologic MRI-based RT boost decreased LRF without a significant increase in grade 3+ toxicity or longitudinal PRO differences, but did not significantly improve DFS or OS. Additional improvements in systemic therapy are likely necessary to realize improvements in DFS and OS.

Spatial and Transcriptomic Analysis of Perineural Invasion in Oral Cancer.

PURPOSE: Perineural invasion (PNI), a common occurrence in oral squamous cell carcinomas, is associated with poor survival. Consequently, these tumors are treated aggressively. However, diagnostic criteria of PNI vary and its role as an independent predictor of prognosis has not been established. To address these knowledge gaps, we investigated spatial and transcriptomic profiles of PNI-positive and PNI-negative nerves. EXPERIMENTAL DESIGN: Tissue sections from 142 patients were stained with S100 and cytokeratin antibodies. Nerves were identified in two distinct areas: tumor bulk and margin. Nerve diameter and nerve-to-tumor distance were assessed; survival analyses were performed. Spatial transcriptomic analysis of nerves at varying distances from tumor was performed with NanoString GeoMx Digital Spatial Profiler Transcriptomic Atlas. RESULTS: PNI is an independent predictor of poor prognosis among patients with metastasis-free lymph nodes. Patients with close nerve-tumor distance have poor outcomes even if diagnosed as PNI negative using current criteria. Patients with large nerve(s) in the tumor bulk survive poorly, suggesting that even PNI-negative nerves facilitate tumor progression. Diagnostic criteria were supported by spatial transcriptomic analyses of >18,000 genes; nerves in proximity to cancer exhibit stress and growth response changes that diminish with increasing nerve-tumor distance. These findings were validated in vitro and in human tissue. CONCLUSIONS: This is the first study in human cancer with high-throughput gene expression analysis in nerves with striking correlations between transcriptomic profile and clinical outcomes. Our work illuminates nerve-cancer interactions suggesting that cancer-induced injury modulates neuritogenesis, and supports reclassification of PNI based on nerve-tumor distance rather than current subjective criteria.