School of Medicine

Introduction: There is increasing appreciation of the challenges of providing safe and appropriate care to cancer patients in the emergency department (ED). Our goal here was to assess which patient characteristics are associated with more frequent ED revisits.

Methods: This was a retrospective cohort study of all ED visits in California during the 2016 calendar year using data from the California Office of Statewide Health Planning and Development. We defined revisits as a return visit to an ED within seven days of the index visit. For both index and return visits, we assessed various patient characteristics, including age, cancer type, medical comorbidities, and ED disposition.

Results: Among 12.9 million ED visits, we identified 73,465 adult cancer patients comprising 103,523 visits that met our inclusion criteria. Cancer patients had a 7-day revisit rate of 17.9% vs 13.2% for non-cancer patients. Cancer patients had a higher rate of admission upon 7-day revisit (36.7% vs 15.6%). Patients with cancers of the small intestine, stomach, and pancreas had the highest rate of 7-day revisits (22-24%). Cancer patients younger than 65 had a higher 7-day revisit rate than the elderly (20.0% vs 16.2%).

Conclusion: In a review of all cancer-related ED visits in the state of California, we found a variety of characteristics associated with a higher rate of 7-day ED revisits. Our goal in this study was to inform future research to identify interventions on the index visit that may improve patient outcomes.

BACKGROUND: Salivary duct carcinoma (SDC) is a rare and aggressive malignancy with limited population-based data. METHODS: Incidence trends and survival outcomes were analyzed using the Surveillance, Epidemiology, and End Results database. RESULTS: A total of 955 cases were identified. The age-adjusted incidence rate increased from 0.158 in 2000 to 1.18 in 2022 (average annual percent change, 10.38%; p < 0.001), accelerating after 2012. Increases were more pronounced among females, older patients, regional-stage disease, and tumors > 2 cm. The 5-year disease-specific survival (DSS) and overall survival were 60.6% and 51.2%, respectively. Advanced age, non-parotid site, larger tumor size, lymph node metastasis, advanced stage, and non-surgical management were independent predictors of worse DSS. Patients diagnosed in 2013-2022 showed better DSS compared with those in 2004-2012 (64.7% vs. 52.0%, p = 0.048). CONCLUSION: SDC incidence has increased rapidly, possibly reflecting improved diagnostic recognition and reclassification, with only modest survival improvement over the past decade.

Purpose Xerostomia remains a common toxicity following head and neck radiotherapy (RT) that significantly impacts patients' quality of life (QOL). Although intensity-modulated RT reduces the dose to the salivary glands, many patients still experience salivary gland toxicity. Methods and Materials This study examined the association between radiation-induced volume changes in the parotid and submandibular glands, mean dose to the salivary glands, and intra-gland dose distribution, as well as its relationship to QOL scores, over a median follow-up period of 47 months. Results Analysis of 329 patients using a linear mixed-effects model revealed distinct volume change patterns. The parotid glands initially underwent significant volume reduction but subsequently showed dose-dependent recovery, increasing in volume by an average rate of 2.4% per doubling of time. This recovery was negatively impacted by higher age and poor performance status. Conversely, the submandibular glands gradually reduced in volume over time by 5.3% per doubling of time without evidence of recovery, even at low doses. Voxel-wise analysis of the parotid glands indicated that dose constraints targeting the cranial-ventral-lateral portion were critical for accurately predicting volume recovery. No regional dose effects were found for the submandibular gland. Persistent associations were found between salivary gland volumes and chronic xerostomia symptoms, including dry mouth and sticky saliva. Conclusions Objective measurement of salivary gland volume can be used as an indicator of damage and recovery. The observed differential longitudinal patterns suggest that distinct dosing strategies and regenerative approaches may be necessary for the parotid and submandibular glands.

Purpose Proton pencil beam scanning (PBS) treatment planning for head & neck (H&N) cancers involves numerous conflicting objectives, requiring iterative objective parameter adjustments to balance multiple clinical goals. We propose a learning-driven inverse optimizer and integrate it into a proximal policy optimization (PPO)-based planning framework to automatically generate high-quality plans for patients with diverse treatment requirements. Methods and Materials The inverse optimizer is a learning-to-optimize (L2O) method that predicts update steps by learning from task-specific data distributions. For the first time, long-context processing techniques developed for large language models (LLMs) are utilized to address the scalability limitations of existing L2O methods, enabling simultaneous optimization over a substantially large set of variables. The PPO framework functions as an outer-loop virtual planner, autonomously adjusting objective parameters through a policy network, and the inner-loop L2O inverse optimizer computes machine-deliverable spot monitor unit (MU) values based on the PPO-refined objectives. Moreover, a Swin UnetR dose predictor is trained with prescription- and beam-specific information to estimate the initial objective parameters. In our experiments, total 97 patients with bilateral or ipsilateral H&N cancers are collected for training and testing. Results Compared with the second-order gradient-based methods, our L2O optimizer improves the effectiveness and efficiency of the time-consuming inverse optimization by 22.97 % and 36.41 % , respectively, and in conjunction with the PPO-based virtual planner, plans are generated within clinically acceptable times, i.e. 2.55 hours in average, and shows improved or comparable organs-at-risk sparing with superior target coverage compared with humangenerated plans. Conclusions The proposed inverse optimizer is the first L 2 O model applied to radiotherapy treatment planning and achieves promising performance. The high-quality plans generated for patients with variable prescription dose levels, multiple target volumes and patient-specific beam angles highlight the strong potential of the proposed automatic planning framework for practical clinical use.

Head and neck squamous cell carcinoma (HNSCC) is a significant cause of morbidity and mortality worldwide, with limited treatment options for patients with locally advanced disease. CD47 immune checkpoint inhibitors have been used to block the CD47/SIRPa interaction that inhibits antigen-presenting cell phagocytosis, thereby enhancing antigen presentation to cytotoxic T-cells, and have shown promise in combination with anti-PD1 immunotherapy in tumors, including recurrent/metastatic HNSCC. We found that CD47 expression is associated with poor prognosis in HNSCC and explored the anti-tumor activity of an anti-CD47 fusion protein in combination with anti-PD1 and lymphatic-sparing radiotherapy in a locally advanced HNSCC model. In the 4MOSC1 syngeneic HPV-negative HNSCC mouse model, ALX301 (an engineered CD47-blocking SIRPα fusion for murine models) induced complete tumor regression when combined with anti-PD-1, and produced a partial tumor response as a monotherapy. An anti-PD1 immune checkpoint inhibitor in a CD47-null tumor background led to complete tumor regression confirming a key role for CD47 in tumor immunity. ALX301 treated mice demonstrated increased MHC-II expression on dendritic cells within the tumor and upregulation of CD86 co-stimulatory molecule on dendritic cells within the tumor, sentinel lymph nodes, and contralateral lymph nodes. Combination ALX301 and anti-PD1 treatment in an anti-PD1 resistant 4MOSC2 model demonstrated significant tumor regression, enhanced survivability, improved response with neoadjuvant radiotherapy, and greater retention of CD8 + T-cells within the tumor microenvironment. Notably, T-cell receptor sequencing revealed increased shared clonality between the tumor and sentinel lymph nodes of ALX301 treated mice. These data demonstrate that a combination of CD47 blockade and anti-PD1 therapy enhances tumor antigen presentation and immune cell infiltration, while further improving anti-tumor responses in combination with tumor-targeted radiotherapy. This study provides support for the rational design of combinatorial immunoradiotherapy, using anti-CD47 inhibitors and anti-PD1 therapy, in a clinical trial targeting locally advanced HPV-negative HNSCC.

BACKGROUND: Prostate-specific membrane antigen (PSMA; FOLH1) is a cell-surface target for diagnostics and treatment in prostate cancer. We utilized a database of molecularly-profiled prostate tumors to evaluate clinical, genomic, and immunologic correlates of high FOLH1 RNA expression. PATIENTS AND METHODS: Prostate cancer specimens (N = 7,082) underwent DNA/RNA sequencing and immunohistochemistry at Caris Life Sciences. FOLH1-High/Low expression was defined by upper/lower quartiles or median transcripts per million (TPM). Overall survival (OS) was calculated from insurance claims. RESULTS: Prostate adenocarcinoma had 2.97-fold higher FOLH1 expression compared to high grade neuroendocrine prostate cancer (q < 0.0001). Of 7,020 adenocarcinomas, 4,464 were primary prostate samples, 828 were lymph node metastases, and 1,686 were distant metastases. FOLH1 expression varied across metastatic sites (highest in lymph node and lowest in liver; 1.2-fold difference, q < 0.05). FOLH1-High tumors were enriched in AR-V7 variants (10.1% vs. 4.5%, q < 0.05) and associated with higher androgen receptor (AR) signaling (0.82 vs 0.78, q < 0.05). Conversely, FOLH1-Low tumors were enriched with FOXA1 (12.2% vs. 6.4%), APC (11.4% vs. 3.0%), PIK3CA (5.8% vs. 2.7%) and PIK3R1 (2.6% vs. 0.48%) mutations (q < 0.05). FOLH1-High tumors had a lower M1: M2 ratio, fewer Tregs and CD8+ T cells, higher immune checkpoint expression, and lower interferon signature scores. FOLH1-High primary tumors were more frequently microsatellite instability (MSI)-High, tumor mutational burden (TMB)-High, and PD-L1-positive. Among patients with metastatic tumors, median OS was improved in the FOLH1-High group (31.9 vs 23.3 months, p < 0.001). CONCLUSIONS: This enhanced understanding of the distinct molecular and clinical profiles of FOLH1-expressing prostate cancers may inform optimization of PSMA-directed treatments.

Colorectal cancer (CRC) remains a substantial public health challenge globally and is the second leading cause of cancer-related death in the USA. Despite advances in screening and treatment, disparities in CRC outcomes persist, especially among Black individuals in the USA, who face higher CRC incidence and mortality and lower survival compared with White individuals. Inequities are largely attributed to social determinants of health (SDOH), such as access to health care, socioeconomic conditions and systemic inequities. In this Review, we examine Black–White disparities in CRC outcomes across the CRC care continuum in the USA, highlighting contributing modifiable (non-biological) and non-modifiable (biological) risk factors. We also discuss successful interventions that have reduced or eliminated disparities. Existing evidence suggests that Black–White differences in CRC screening participation, CRC incidence and CRC mortality can be resolved. Future efforts must emphasize improving access to screening and guideline-concordant treatment to achieve progress in the near term while addressing the underlying and historical SDOH that drive inequities to eliminate disparities in the long term. The Review underscores the need for sustained investment in addressing both immediate and systemic barriers to CRC screening and care in Black communities to eliminate disparities in CRC outcomes and improve the overall health of the nation.

Surgical ablation or broad radiation of tumor-draining lymph nodes can eliminate the primary tumor response to immunotherapy, highlighting the crucial role of these nodes in mediating the primary tumor response. Here, we show that immunoradiotherapy efficacy is dependent on treatment sequence and migration of modulated dendritic cells from tumor to sentinel lymph nodes. Using a tamoxifen-inducible reporter paired with CITE-sequencing in a murine model of oral cancer, we comprehensively characterize tumor immune cellular migration through lymphatic channels to sentinel lymph nodes at single-cell resolution, revealing a unique immunologic niche defined by distinct cellular phenotypic and transcriptional profiles. Through a structured approach of sequential immunomodulatory radiotherapy and checkpoint inhibition, we show that sequenced, lymphatic-sparing, tumor-directed radiotherapy followed by PD-1 inhibition achieves complete and durable tumor responses. Mechanistically, this treatment approach enhances migration of activated CCR7+ dendritic cell surveillance across the tumor-sentinel lymph node axis, revealing a shift from their canonical role in promoting tolerance to driving antitumor immunity. Overall, this work supports rationally sequencing immune-sensitizing, lymphatic-preserving, tumor-directed radiotherapy followed by immune checkpoint inhibition to optimize tumor response to immunoradiotherapy by driving activated dendritic cells to draining sentinel lymph nodes.