Prevention and Management of Osteoradionecrosis in Patients With Head and Neck Cancer Treated With Radiation Therapy: ISOO-MASCC-ASCO Guideline.

PURPOSE: To provide evidence-based recommendations for prevention and management of osteoradionecrosis (ORN) of the jaw secondary to head and neck radiation therapy in patients with cancer. METHODS: The International Society of Oral Oncology-Multinational Association for Supportive Care in Cancer (ISOO-MASCC) and ASCO convened a multidisciplinary Expert Panel to evaluate the evidence and formulate recommendations. PubMed, EMBASE, and Cochrane Library databases were searched for randomized controlled trials and observational studies, published between January 1, 2009, and December 1, 2023. The guideline also incorporated systematic reviews conducted by ISOO-MASCC, which included studies published from January 1, 1990, through December 31, 2008. RESULTS: A total of 1,539 publications were initially identified. There were 487 duplicate publications, resulting in 1,052 studies screened by abstract, 104 screened by full text, and 80 included for systematic review evaluation. RECOMMENDATIONS: Due to limitations of available evidence, the guideline relied on informal consensus for some recommendations. Recommendations that were deemed evidence-based with strong evidence by the Expert Panel were those pertaining to best practices in prevention of ORN and surgical management. No recommendation was possible for the utilization of leukocyte- and platelet-rich fibrin or photobiomodulation for prevention of ORN. The use of hyperbaric oxygen in prevention and management of ORN remains largely unjustified, with limited evidence to support its practice.Additional information is available at www.asco.org/head-neck-cancer-guidelines.

Health Care Cost Reductions with Machine Learning-Directed Evaluations during Radiation Therapy - An Economic Analysis of a Randomized Controlled Study.

BACKGROUND: Machine learning (ML) may cost-effectively direct health care by identifying patients most likely to benefit from preventative interventions to avoid negative and expensive outcomes. System for High-Intensity Evaluation During Radiation Therapy (SHIELD-RT; NCT04277650) was a single-institution, randomized controlled study in which electronic health record-based ML accurately identified patients at high risk for acute care (emergency visit or hospitalization) during radiotherapy (RT) and targeted them for supplemental clinical evaluations. This ML-directed intervention resulted in decreased acute care utilization. Given the limited prospective data showing the ability of ML to direct interventions cost-efficiently, an economic analysis was performed. METHODS: A post hoc economic analysis was conducted of SHIELD-RT that included RT courses from January 7, 2019, to June 30, 2019. ML-identified high-risk courses (≥10% risk of acute care during RT) were randomized to receive standard of care weekly clinical evaluations with ad hoc supplemental evaluations per clinician discretion versus mandatory twice-weekly evaluations. The primary outcome was difference in mean total medical costs during and 15 days after RT. Acute care costs were obtained via institutional cost accounting. Physician and intervention costs were estimated via Medicare and Medicaid data. Negative binomial regression was used to estimate cost outcomes after adjustment for patient and disease factors. RESULTS: A total of 311 high-risk RT courses among 305 patients were randomized to the standard (n=157) or the intervention (n=154) group. Unadjusted mean intervention group supplemental visit costs were $155 per course (95% confidence interval, $142 to $168). The intervention group had fewer acute care visits per course (standard, 0.47; intervention, 0.31; P=0.04). Total mean adjusted costs were $3110 per course for the standard group and $1494 for the intervention group (difference in means, $1616 [95% confidence interval, $1450 to $1783]; P=0.03). CONCLUSIONS: In this economic analysis of a randomized controlled, health care ML study, mandatory supplemental evaluations for ML-identified high-risk patients were associated with both reduced total medical costs and improved clinical outcomes. Further study is needed to determine whether economic results are generalizable. (Funded in part by The Duke Endowment, The Conquer Cancer Foundation, the Duke Department of Radiation Oncology, and the National Cancer Institute of the National Institutes of Health [R01CA277782]; ClinicalTrials.gov number, NCT04277650.).

Prognostic value of different discretization parameters in 18fluorodeoxyglucose positron emission tomography radiomics of oropharyngeal squamous cell carcinoma.

Purpose: We aim to interrogate the role of positron emission tomography (PET) image discretization parameters on the prognostic value of radiomic features in patients with oropharyngeal cancer. Approach: A prospective clinical trial (NCT01908504) enrolled patients with oropharyngeal squamous cell carcinoma (N=69; mixed HPV status) undergoing definitive radiotherapy and evaluated intra-treatment 18fluorodeoxyglucose PET as a potential imaging biomarker of early metabolic response. The primary tumor volume was manually segmented by a radiation oncologist on PET/CT images acquired two weeks into treatment (20 Gy). From this, 54 radiomic texture features were extracted. Two image discretization techniques-fixed bin number (FBN) and fixed bin size (FBS)-were considered to evaluate systematic changes in the bin number ({32, 64, 128, 256} gray levels) and bin size ({0.10, 0.15, 0.22, 0.25} bin-widths). For each discretization-specific radiomic feature space, an LASSO-regularized logistic regression model was independently trained to predict residual and/or recurrent disease. The model training was based on Monte Carlo cross-validation with a 20% testing hold-out, 50 permutations, and minor-class up-sampling to account for imbalanced outcomes data. Performance differences among the discretization-specific models were quantified via receiver operating characteristic curve analysis. A final parameter-optimized logistic regression model was developed by incorporating different settings parameterizations into the same model. Results: FBN outperformed FBS in predicting residual and/or recurrent disease. The four FBN models achieved AUC values of 0.63, 0.61, 0.65, and 0.62 for 32, 64, 128, and 256 gray levels, respectively. By contrast, the average AUC of the four FBS models was 0.53. The parameter-optimized model, comprising features joint entropy (FBN = 64) and information measure correlation 1 (FBN = 128), achieved an AUC of 0.70. Kaplan-Meier analyses identified these features to be associated with disease-free survival (p=0.0158 and p=0.0180, respectively; log-rank test). Conclusions: Our findings suggest that the prognostic value of individual radiomic features may depend on feature-specific discretization parameter settings.

Radiomics on spatial-temporal manifolds via Fokker-Planck dynamics.

BACKGROUND: Delta radiomics is a high-throughput computational technique used to describe quantitative changes in serial, time-series imaging by considering the relative change in radiomic features of images extracted at two distinct time points. Recent work has demonstrated a lack of prognostic signal of radiomic features extracted using this technique. We hypothesize that this lack of signal is due to the fundamental assumptions made when extracting features via delta radiomics, and that other methods should be investigated. PURPOSE: The purpose of this work was to show a proof-of-concept of a new radiomics paradigm for sparse, time-series imaging data, where features are extracted from a spatial-temporal manifold modeling the time evolution between images, and to assess the prognostic value on patients with oropharyngeal cancer (OPC). METHODS: To accomplish this, we developed an algorithm to mathematically describe the relationship between two images acquired at time t = 0 $t = 0$ and t > 0 $t > 0$ . These images serve as boundary conditions of a partial differential equation describing the transition from one image to the other. To solve this equation, we propagate the position and momentum of each voxel according to Fokker-Planck dynamics (i.e., a technique common in statistical mechanics). This transformation is driven by an underlying potential force uniquely determined by the equilibrium image. The solution generates a spatial-temporal manifold (3 spatial dimensions + time) from which we define dynamic radiomic features. First, our approach was numerically verified by stochastically sampling dynamic Gaussian processes of monotonically decreasing noise. The transformation from high to low noise was compared between our Fokker-Planck estimation and simulated ground-truth. To demonstrate feasibility and clinical impact, we applied our approach to 18F-FDG-PET images to estimate early metabolic response of patients (n = 57) undergoing definitive (chemo)radiation for OPC. Images were acquired pre-treatment and 2-weeks intra-treatment (after 20 Gy). Dynamic radiomic features capturing changes in texture and morphology were then extracted. Patients were partitioned into two groups based on similar dynamic radiomic feature expression via k-means clustering and compared by Kaplan-Meier analyses with log-rank tests (p < 0.05). These results were compared to conventional delta radiomics to test the added value of our approach. RESULTS: Numerical results confirmed our technique can recover image noise characteristics given sparse input data as boundary conditions. Our technique was able to model tumor shrinkage and metabolic response. While no delta radiomics features proved prognostic, Kaplan-Meier analyses identified nine significant dynamic radiomic features. The most significant feature was Gray-Level-Size-Zone-Matrix gray-level variance (p = 0.011), which demonstrated prognostic improvement over its corresponding delta radiomic feature (p = 0.722). CONCLUSIONS: We developed, verified, and demonstrated the prognostic value of a novel, physics-based radiomics approach over conventional delta radiomics via data assimilation of quantitative imaging and differential equations.

Enhancing radiotherapy response via intratumoral injection of the TLR9 agonist CpG to stimulate CD8 T cells in an autochthonous mouse model of sarcoma.

Radiation therapy is frequently used to treat cancers including soft tissue sarcomas. Prior studies established that the toll-like receptor 9 (TLR9) agonist cytosine-phosphate-guanine oligodeoxynucleotide (CpG) enhances the response to radiation therapy (RT) in transplanted tumors, but the mechanism(s) remain unclear. Here, we used CRISPR/Cas9 and the chemical carcinogen 3-methylcholanthrene (MCA) to generate autochthonous soft tissue sarcomas with high tumor mutation burden. Treatment with a single fraction of 20 Gy RT and two doses of CpG significantly enhanced tumor response, which was abrogated by genetic or immunodepletion of CD8+ T cells. To characterize the immune response to RT + CpG, we performed bulk RNA-seq, single-cell RNA-seq, and mass cytometry. Sarcomas treated with 20 Gy and CpG demonstrated increased CD8 T cells expressing markers associated with activation and proliferation, such as Granzyme B, Ki-67, and interferon-γ. CpG + RT also upregulated antigen presentation pathways on myeloid cells. Furthermore, in sarcomas treated with CpG + RT, TCR clonality analysis suggests an increase in clonal T-cell dominance. Collectively, these findings demonstrate that RT + CpG significantly delays tumor growth in a CD8 T cell-dependent manner. These results provide a strong rationale for clinical trials evaluating CpG or other TLR9 agonists with RT in patients with soft tissue sarcoma.

Clinical outcomes of oropharyngeal squamous cell carcinoma stratified by human papillomavirus subtype: A systematic review and meta-analysis.

PURPOSE: We aim to determine if there is a survival difference between patients with oropharyngeal squamous cell carcinoma (OPSCC) associated with human papillomavirus (HPV) 16 versus HPV-non16 subtypes. PATIENT AND METHODS: Databases were queried for full length, peer-reviewed, English language, articles published between 01/01/1980 and 06/08/2022. Studies reporting clinical outcomes of OPSCC associated with HPV16 and HPV-non16 subtypes with at least 10 patients were included. Primary outcome was the overall survival (OS) of patients with HPV16- versus HPV-non16-associated OPSCC. Secondary outcomes were recurrence-free survival (RFS) and pooled rate of p16 positivity by immunohistochemistry (IHC). RESULTS: A total of 9 studies met inclusion criteria and included 1,310 patients with HPV16 and 219 with HPV-non16 subtypes of OPSCC. The prevalence of HPV-non16 was 14.3 %. The pooled 5-year OS rates for patients with HPV16 and HPV-non16 were 83.4 %(95 % CI 77.8-89.0 %) and 69.3 %(95 % CI 58.5-80.1 %), respectively. OS at 5 years was significantly worse for HPV-non16 subtype, compared to HPV16 (log odds ratio [OR] -0.54, p = 0.008). There was a trend towards worse 5-year RFS with HPV-non16 compared to HPV16 (log OR -0.55, p = 0.063). Patients with HPV-non16 disease were less likely to be p16 positive by IHC (log OR -0.91, p = 0.02). CONCLUSION: Patients with HPV-non16OPSCC may experience worse OS and were less likely to be p16 positive compared to patients with HPV16 disease. While future prospective validation is warranted, routine assessment of both p16 IHC and HPV subtype could be considered prior to pursuing treatment de-escalation for HPV-associated OPSCC.

Preclinical Evaluation of the ATR Inhibitor BAY 1895344 as a Radiosensitizer for Head and Neck Squamous Cell Carcinoma.

PURPOSE: Despite aggressive multimodal treatment that typically includes definitive or adjuvant radiation therapy (RT), locoregional recurrence rates approach 50% for patients with locally advanced human papillomavirus (HPV)-negative head and neck squamous cell carcinoma (HNSCC). Thus, more effective therapeutics are needed to improve patient outcomes. We evaluated the radiosensitizing effects of ataxia telangiectasia and RAD3-related (ATR) inhibitor (ATRi) BAY 1895344 in preclinical models of HNSCC. METHODS AND MATERIALS: Murine and human HPV-negative HNSCC cells (MOC2, MOC1, JHU-012) were treated with vehicle or ATRi with or without 4 Gy. Checkpoint kinase 1 phosphorylation and DNA damage (γH2AX) were evaluated by Western blot, and ATRi half-maximal inhibitory concentration was determined by MTT assay for HNSCC cells and immortalized murine oral keratinocytes. In vitro radiosensitization was tested by clonogenic assay. Cell cycle distribution and mitotic catastrophe were evaluated by flow cytometry. Mitotic aberrations were quantified by fluorescent microscopy. Tumor growth delay and survival were assessed in mice bearing MOC2 or JHU-012 transplant tumors treated with vehicle, ATRi, RT (10 Gy × 1 or 8 Gy × 3), or combined ATRi + RT. RESULTS: ATRi caused dose-dependent reduction in checkpoint kinase 1 phosphorylation at 1 hour post-RT (4 Gy) and dose-dependent increase in γH2AX at 18 hours post-RT. Addition of RT to ATRi led to decreased BAY 1895344 half-maximal inhibitory concentration in HNSCC cell lines but not in normal tissue surrogate immortalized murine oral keratinocytes. Clonogenic assays demonstrated radiosensitization in the HNSCC cell lines. ATRi abrogated the RT-induced G2/M checkpoint, leading to mitosis with unrepaired DNA damage and increased mitotic aberrations (multinucleated cells, micronuclei, nuclear buds, nucleoplasmic bridges). ATRi and RT significantly delayed tumor growth in MOC2 and JHU-012 in vivo models, with improved overall survival in the MOC2 model. CONCLUSIONS: These findings demonstrated that BAY 1895344 increased in vitro and in vivo radiosensitivity in HPV-negative HNSCC preclinical models, suggesting therapeutic potential warranting evaluation in clinical trials for patients with locally advanced or recurrent HPV-negative HNSCC.

Temporary Knockdown of p53 During Focal Limb Irradiation Increases the Development of Sarcomas.

Approximately half of patients with cancer receive radiotherapy and, as cancer survivorship increases, the low rate of radiation-associated sarcomas is rising. Pharmacologic inhibition of p53 has been proposed as an approach to ameliorate acute injury of normal tissues from genotoxic therapies, but how this might impact the risk of therapy-induced cancer and normal tissue injuries remains unclear. We utilized mice that express a doxycycline (dox)-inducible p53 short hairpin RNA to reduce Trp53 expression temporarily during irradiation. Mice were placed on a dox diet 10 days prior to receiving 30 or 40 Gy hind limb irradiation in a single fraction and then returned to normal chow. Mice were examined weekly for sarcoma development and scored for radiation-induced normal tissue injuries. Radiation-induced sarcomas were subjected to RNA sequencing. Following single high-dose irradiation, 21% of animals with temporary p53 knockdown during irradiation developed a sarcoma in the radiation field compared with 2% of control animals. Following high-dose irradiation, p53 knockdown preserves muscle stem cells, and increases sarcoma development. Mice with severe acute radiation-induced injuries exhibit an increased risk of developing late persistent wounds, which were associated with sarcomagenesis. RNA sequencing revealed radiation-induced sarcomas upregulate genes related to translation, epithelial-mesenchymal transition (EMT), inflammation, and the cell cycle. Comparison of the transcriptomes of human and mouse sarcomas that arose in irradiated tissues revealed regulation of common gene programs, including elevated EMT pathway gene expression. These results suggest that blocking p53 during radiotherapy could minimize acute toxicity while exacerbating late effects including second cancers. SIGNIFICANCE: Strategies to prevent or mitigate acute radiation toxicities include pharmacologic inhibition of p53 and other cell death pathways. Our data show that temporarily reducing p53 during irradiation increases late effects including sarcomagenesis.

Long-term risk of carotid stenosis and cerebrovascular disease after radiation therapy for head and neck cancer.

BACKGROUND: Recipients of radiation therapy (RT) for head and neck cancer (HNC) are at significantly increased risk for carotid artery stenosis (CAS) and cerebrovascular disease (CVD). We sought to determine (1) cumulative incidences of CAS and CVD among HNC survivors after RT and (2) whether CAS is associated with a RT dose response effect. METHODS: This single-institution retrospective cohort study examined patients with nonmetastatic HNC who completed (chemo)RT from January 2000 through October 2020 and subsequently received carotid imaging surveillance ≤2 years following RT completion and, in the absence of CAS, every 3 years thereafter. Exclusion criteria included history of known CAS/CVD. Asymptomatic CAS was defined as ≥50% reduction of luminal diameter, symptomatic CAS as stroke or transient ischemic attack, and composite CAS as asymptomatic or symptomatic CAS. RESULTS: Of 628 patients undergoing curative intent RT for HNC, median follow-up was 4.8 years (interquartile range, 2.6-8.3), with 97 patients followed ≥10 years. Median age was 61 years and 69% of patients received concurrent chemotherapy and 28% were treated postoperatively. Actuarial 10-year incidences of asymptomatic, symptomatic, and composite CAS were 29.6% (95% CI, 23.9-35.5), 10.1% (95% CI, 7.0-13.9), and 27.2% (95% CI, 22.5-32.1), respectively. Multivariable Cox models significant association between asymptomatic CAS and absolute carotid artery volume receiving ≥10 Gy (per mL: hazard ratio, 1.09; 95% CI, 1.02-1.16). CONCLUSIONS: HNC survivors are at high risk for post-RT CAS. A dose response effect was observed for asymptomatic CAS at doses as low as 10 Gy. PLAIN LANGUAGE SUMMARY: Recipients of radiation therapy for head and neck cancer are at significantly increased risk for carotid artery stenosis and cerebrovascular disease. However, carotid artery screening is not routinely performed among head and neck survivors following radiation therapy. In this single-institution retrospective cohort study, patients with head and neck cancer were initially screened for carotid artery stenosis ≤2 years following radiation therapy completion, then every 3 years thereafter. The 10-year actuarial incidence of carotid artery stenosis was >25% and stroke/transient ischemic attack >10%. Multivariable analysis demonstrated significant associations between asymptomatic carotid artery stenosis and artery volumes receiving ≥10 Gy.

Evaluating Tumor Hypoxia Radiosensitization Via Electron Paramagnetic Resonance Oxygen Imaging (EPROI).

PURPOSE: Tumor hypoxia contributes to aggressive phenotypes and diminished therapeutic responses to radiation therapy (RT) with hypoxic tissue being 3-fold less radiosensitive than normoxic tissue. A major challenge in implementing hypoxic radiosensitizers is the lack of a high-resolution imaging modality that directly quantifies tissue-oxygen. The electron paramagnetic resonance oxygen-imager (EPROI) was used to quantify tumor oxygenation in two murine tumor models: E0771 syngeneic transplant breast cancers and primary p53/MCA soft tissue sarcomas, with the latter autochthonous model better recapitulating the tumor microenvironment in human malignancies. We hypothesized that tumor hypoxia differs between these models. We also aimed to quantify the absolute change in tumor hypoxia induced by the mitochondrial inhibitor papaverine (PPV) and its effect on RT response. PROCEDURES: Tumor oxygenation was characterized in E0771 and primary p53/MCA sarcomas via EPROI, with the former model also being quantified indirectly via diffuse reflectance spectroscopy (DRS). After confirming PPV's effect on hypoxic fraction (via EPROI), we compared the effect of 0 versus 2 mg/kg PPV prior to 20 Gy on tumor growth delay and survival. RESULTS: Hypoxic sarcomas were more radioresistant than normoxic sarcomas (p=0.0057, 2-way ANOVA), and high baseline hypoxic fraction was a significant (p=0.0063, Cox Regression Model) hazard in survivability regardless of treatment. Pre-treatment with PPV before RT did not radiosensitize tumors in the sarcoma or E0771 model. In the sarcoma model, EPROI successfully identified baseline hypoxic tumors. DRS quantification of total hemoglobin, saturated hemoglobin, changes in mitochondrial potential and glucose uptake showed no significant difference in E0771 tumors pre- and post-PPV. CONCLUSION: EPROI provides 3D high-resolution pO2 quantification; EPR is better suited than DRS to characterize tumor hypoxia. PPV did not radiosensitize E0771 tumors nor p53/MCA sarcomas, which may be related to the complex pattern of vasculature in each tumor. Additionally, understanding model-dependent tumor hypoxia will provide a much-needed foundation for future therapeutic studies with hypoxic radiosensitizers.

Both CD8 and CD4 T cells contribute to immunosurveillance preventing the development of neoantigen-expressing autochthonous sarcomas.

The adaptive immune system plays an essential anti-tumor role through immunosurveillance and response to immunotherapies. Characterizing phenotypic features and mechanisms of dysfunction of tumor-specific T cell populations may uncover novel immunotherapeutic targets and biomarkers of response. To study tumor-specific T cell responses in vivo, a tumor model must express a known neoantigen. While transplant models with known neoantigen expression are widely available, autochthonous tumor models in which the tumor coevolves with the immune system are limited. In this study, we combined CRISPR/Cas9 and sleeping beauty transposase technology to develop an autochthonous orthotopic murine sarcoma model with oncogenic KrasG12D, functionally impaired p53, and expression of known MHCI and MHCII sarcoma neoantigens. Using MHC tetramer flow cytometry, we identified a tumor-specific immune response in the peripheral blood as early as 10 days after tumor induction leading to tumor clearance. Tumors developed at high penetrance after co-depletion of CD8 and CD4 T cells, but depletion of either CD8 or CD4 T cells alone was insufficient to permit tumor growth. These results suggest that CD8 and CD4 T cells can independently contribute to immunosurveillance leading to clearance of sarcomas expressing MHCI and MHCII neoantigens.

Low contralateral neck recurrence risk with ipsilateral neck radiotherapy in N2b tonsillar squamous cell carcinoma.

OBJECTIVES: To characterize factors including nodal burden, pre-treatment imaging, and other patient factors which may influence the role of ipsilateral neck radiotherapy (IRT) in tonsillar squamous cell carcinoma (SCC) with multiple involved ipsilateral nodes. METHODS: Patients with cT1-2N0-2bM0 (AJCC 7th edition) tonsillar SCC treated with definitive radiation therapy (RT) at Duke University Medical Center from 1/1/1990-10/1/2019 were identified. Patient, tumor, and treatment characteristics were compared between those that received bilateral neck RT (BRT) versus IRT. Recurrence-free survival (RFS) was estimated with Kaplan-Meier method. A subset analysis of patients with N2b disease was performed. Patterns of recurrence were analyzed. RESULTS: 120 patients with cT1-2N0-2b tonsillar SCC were identified, including 71 with N2b disease (BRT: n = 30; IRT: n = 41). Median follow-up was 80 months (range: 7-209). No N2b patients who received IRT had > 1 cm of soft palate/base of tongue extension. N2b patients treated with IRT had a median of 3 (range 2-9) involved lymph nodes, with median largest nodal dimension of 2.8 cm (range 1.3-4.8 cm). 93 % of N2b patients who received IRT had staging by PET/CT, and 100 % received IMRT. For N2b patients treated with IRT, there were no contralateral neck recurrences, and 10 year RFS was 95 % (95 % CI 82 %-98 %). CONCLUSIONS: For patients treated with IRT for well-lateralized N2b tonsillar SCC, we observed high rates of local control with no observed contralateral neck recurrence. These data suggest that BRT is not universally necessary for patients with multiple involved ipsilateral nodes, particularly in the setting of baseline staging with PET/CT.

Animal Models and Their Role in Imaging-Assisted Co-Clinical Trials.

The availability of high-fidelity animal models for oncology research has grown enormously in recent years, enabling preclinical studies relevant to prevention, diagnosis, and treatment of cancer to be undertaken. This has led to increased opportunities to conduct co-clinical trials, which are studies on patients that are carried out parallel to or sequentially with animal models of cancer that mirror the biology of the patients' tumors. Patient-derived xenografts (PDX) and genetically engineered mouse models (GEMM) are considered to be the models that best represent human disease and have high translational value. Notably, one element of co-clinical trials that still needs significant optimization is quantitative imaging. The National Cancer Institute has organized a Co-Clinical Imaging Resource Program (CIRP) network to establish best practices for co-clinical imaging and to optimize translational quantitative imaging methodologies. This overview describes the ten co-clinical trials of investigators from eleven institutions who are currently supported by the CIRP initiative and are members of the Animal Models and Co-clinical Trials (AMCT) Working Group. Each team describes their corresponding clinical trial, type of cancer targeted, rationale for choice of animal models, therapy, and imaging modalities. The strengths and weaknesses of the co-clinical trial design and the challenges encountered are considered. The rich research resources generated by the members of the AMCT Working Group will benefit the broad research community and improve the quality and translational impact of imaging in co-clinical trials.

Healthcare provider evaluation of machine learning-directed care: reactions to deployment on a randomised controlled study.

OBJECTIVES: Clinical artificial intelligence and machine learning (ML) face barriers related to implementation and trust. There have been few prospective opportunities to evaluate these concerns. System for High Intensity EvaLuation During Radiotherapy (NCT03775265) was a randomised controlled study demonstrating that ML accurately directed clinical evaluations to reduce acute care during cancer radiotherapy. We characterised subsequent perceptions and barriers to implementation. METHODS: An anonymous 7-question Likert-type scale survey with optional free text was administered to multidisciplinary staff focused on workflow, agreement with ML and patient experience. RESULTS: 59/71 (83%) responded. 81% disagreed/strongly disagreed their workflow was disrupted. 67% agreed/strongly agreed patients undergoing intervention were high risk. 75% agreed/strongly agreed they would implement the ML approach routinely if the study was positive. Free-text feedback focused on patient education and ML predictions. CONCLUSIONS: Randomised data and firsthand experience support positive reception of clinical ML. Providers highlighted future priorities, including patient counselling and workflow optimisation.

Insurance Coverage and Forgoing Medical Appointments Because of Cost Among Cancer Survivors After 2016.

PURPOSE: The uninsured rate began rising after 2016, which some have attributed to health policies undermining aspects of the Affordable Care Act. Our primary objectives were to assess the changes in insurance coverage and forgoing medical care because of cost in cancer survivors from pre-enactment (2016) through postenactment of those policies (2019) and determine whether there were subgroups that were disproportionately affected. METHODS: The 2016-2019 Behavioral Risk Factor Surveillance System surveys were queried for 18- to 64-year-old cancer survivors. Survey-weighted logistic regression was used to assess temporal changes in (1) insurance coverage and (2) forgoing medical appointments because of cost in the preceding 12 months. RESULTS: A total of 62,669 cancer survivors were identified. The percentage of insured cancer survivors decreased from 92.4% in 2016 to 90.4% in 2019 (odds ratio for change in insurance coverage or affordability per one-year increase [ORyear], 0.92; 95% CI, 0.86 to 0.98; P = .01), translating to 161,000 fewer cancer survivors in the United States with insurance coverage. There were decreases in employer-sponsored insurance coverage (ORyear, 0.89) but increases in Medicaid coverage (ORyear, 1.17) from 2016 to 2019. Forgoing medical appointments because of cost increased from 17.9% in 2016 to 20.0% in 2019 (ORyear, 1.05; 95% CI, 1.01 to 1.1; P = .025), affecting an estimated 169,000 cancer survivors. The greatest changes were observed among individuals with low income, particularly those residing in nonexpansion states. CONCLUSION: Between 2016 and 2019, there were 161,000 fewer cancer survivors in the United States with insurance coverage, and 169,000 forwent medical care because of cost.

Whole-Slide Cytometric Feature Mapping for Distinguishing Tumor Genomic Subtypes in Head and Neck Squamous Cell Carcinoma Whole-Slide Images.

Head and neck squamous cell carcinoma (HNSCC) is a heterogeneous disease where, in advanced stages, clinical and pathologic stages do not correlate with outcome. Molecular and genomic biomarkers for HNSCC classification have shown promise for prognostic and therapeutic applications. This study utilized automated image analysis techniques in whole-slide images of HNSCC tumors to identify relationships between cytometric features and genomic phenotypes. Hematoxylin and eosin-stained slides of HNSCC tumors (N = 49) were obtained from The Cancer Imaging Archive, along with accompanying clinical, pathologic, genomic, and proteomic reports. Automated nuclear detection was performed across the entirety of slides, and cytometric feature maps were generated. Forty-one cytometric features were evaluated for associations with tumor grade, tumor stage, tumor subsite, and integrated genomic subtype. Thirty-two features demonstrated significant association with integrated genomic subtype when corrected for multiple comparisons. In particular, the basal subtype was visually distinguishable from the chromosomal instability and immune subtypes based on cytometric feature measurements. No features were significantly associated with tumor grade, stage, or subsite. This study provides preliminary evidence that features derived from tissue pathology slides could provide insights into genomic phenotypes of HNSCC.

Immunogenetic Determinants of Susceptibility to Head and Neck Cancer in the Million Veteran Program Cohort.

Increasing rates of human papillomavirus (HPV)-driven oropharyngeal cancer (OPC) have largely offset declines in tobacco-associated head and neck squamous cell carcinoma (HNSCC) at non-OPC sites. Host immunity is an important modulator of HPV infection, persistence, and clearance, and also of immune evasion in both virally- and nonvirally-driven cancers. However, the association between collective known cancer-related immune gene variants and HNSCC susceptibility has not been fully characterized. Here, we conducted a genetic association study in the multiethnic Veterans Affairs Million Veteran Program cohort, evaluating 16,050 variants in 1,576 immune genes in 4,012 HNSCC cases (OPC = 1,823; non-OPC = 2,189) and 16,048 matched controls. Significant polymorphisms were further examined in a non-Hispanic white (NHW) validation cohort (OPC = 1,206; non-OPC = 955; controls = 4,507). For overall HNSCC susceptibility in NHWs, we discovered and validated a novel 9q31.1 SMC2 association and replicated the known 6p21.32 HLA-DQ-DR association. Six loci/genes for overall HNSCC susceptibility were selectively enriched in African-Americans (6p21.32 HLA-G, 9q21.33 GAS1, 11q12.2 CD6, 11q23.2 NCAM1/CD56, 17p13.1 CD68, 18q22.2 SOCS6); all 6 genes function in antigen-presenting regulation and T-cell activation. Two additional loci (10q26 DMBT1, 15q22.2 TPM1) were uncovered for non-OPC susceptibility, and three loci (11q24 CRTAM, 16q21 CDH5, 18q12.1 CDH2) were identified for HPV-positive OPC susceptibility. This study underscores the role of immune gene variants in modulating susceptibility for both HPV-driven and non-HPV-driven HNSCC. Additional large studies, particularly in racially diverse populations, are needed to further validate the associations and to help elucidate other potential immune factors and mechanisms that may underlie HNSCC risk. SIGNIFICANCE: Several inherited variations in immune system genes are significantly associated with susceptibility to head and neck cancer, which could help improve personalized cancer risk estimates.