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.

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.

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.

Mammalian α-arrestins are members of the same arrestin family as the ubiquitously expressed and extensively studied β-arrestins. Arrestins share common structural elements, including the conserved N- and C-arrestin-fold domains, polar core, finger loop, and C-terminal tail, all of which mediate protein-protein interactions. In β-arrestins, these domains enable the control of G protein-coupled receptor (GPCR) signaling and scaffolding interactions with various signaling proteins including c-Src. By contrast, the repertoire of α-arrestin scaffolding partners and regulatory mechanisms that control their interactions are not well-understood. α-arrestins differ considerably from β-arrestins in the C-terminal region; β-arrestins contain clathrin adaptor β-adaptin-binding sites, whereas α-arrestins harbor PPxY motifs, demonstrated to interact with WW domains of E3 ubiquitin ligases such as WWP2. Here we report the identification of a novel phosphorylation site, tyrosine (Y) 394, embedded in the C-terminal PPxY motif of α-arrestin ARRDC3. The Y394 site functions as a phospho-regulatory switch to enable distinct ARRDC3 binding partners and scaffolding functions. We found that ARRDC3 Y394 phosphorylation promotes interaction with c-Src via its SH2 domain, whereas the non-phosphorylated form binds to WWP2. Our results further show that ARRDC3 Y394 phosphorylation and c-Src SH2 domain-dependent interaction enables regulation of c-Src activity, whereas ARRDC3 Y394 phosphorylation disrupts WWP2 interaction and perturbs ARRDC3-dependent lysosomal trafficking of the GPCR, protease-activated receptor-1. Together, these findings indicate that ARRDC3 Y394 functions as a phospho-regulatory switch to enable selective binding to different partners that impact distinct scaffolding functions.

BACKGROUND: Breast cancer screening with dynamic contrast-enhanced MRI (DCE-MRI) is recommended for high-risk women but has limitations, including variable specificity and difficulty in distinguishing cancerous (CL) and high-risk benign lesions (HRBL) from average-risk benign lesions (ARBL). Complementary non-invasive imaging techniques would be useful to improve specificity. PURPOSE: To evaluate the performance of a previously-developed breast-specific diffusion-weighted MRI (DW-MRI) model (BS-RSI3C) to improve discrimination between CL, HRBL, and ARBL in an enriched screening population. STUDY TYPE: Prospective. SUBJECTS: Exactly 187 women, either with mammography screening recommending additional imaging (N = 49) or high-risk individuals undergoing routine breast MRI (N = 138), before the biopsy. FIELD STRENGTH/SEQUENCE: Multishell DW-MRI echo planar imaging sequence with a reduced field of view at 3.0 T. ASSESSMENT: A total of 72 women had at least one biopsied lesion, with 89 lesions categorized into ARBL, HRBL, CL, and combined CLs and HRBLs (CHRLs). DW-MRI data were processed to produce apparent diffusion coefficient (ADC) maps, and estimate signal contributions (C₁, C₂, and C₃-restricted, hindered, and free diffusion, respectively) from the BS-RSI3C model. Lesion regions of interest (ROIs) were delineated on DW images based on suspicious DCE-MRI findings by two radiologists; control ROIs were drawn in the contralateral breast. STATISTICAL TESTS: One-way ANOVA and two-sided t-tests were used to assess differences in signal contributions and ADC values among groups. P-values were adjusted using the Bonferroni method for multiple testing, P = 0.05 was used for the significance level. Receiver operating characteristics (ROC) curves and intra-class correlations (ICC) were also evaluated. RESULTS: C₁, √C₁C₂, and were significantly different in HRBLs compared with ARBLs (P-values < 0.05). The had the highest AUC (0.821) in differentiating CHRLs from ARBLs, performing better than ADC (0.696), especially in non-mass enhancement (0.776 vs. 0.517). DATA CONCLUSION: This study demonstrated the BS-RSI3C could differentiate HRBLs from ARBLs in a screening population, and separate CHRLs from ARBLs better than ADC. LEVEL OF EVIDENCE: 1: TECHNICAL EFFICACY STAGE: 2.

Objective: This mixed methods study explores gender differences in, and reasons for, toothbrushing and flossing among Mexican-origin adults. Methods: Interviews and surveys about oral hygiene behaviors were collected from 72 adults (ages 21-40) living on the California-Mexico border. Interviews were audio-recorded, transcribed in their original language (English/Spanish), then coded. Survey responses were linked to coded transcripts in Dedoose. Qualitative reports were thematically analyzed for each behavior, stratified into four groups by gender and whether or not participants met American Dental Association (ADA) weekly guidelines (brushing ≥ 14/week; flossing ≥ 7/week). Self-reported weekly frequencies of brushing and flossing were collected continuously, and then dichotomized as meeting guidelines or not. Kruskal-Wallis and chi-square tests assessed differences in hygiene behavior frequency by gender. Negative binomial and logistic regressions were performed, accounting for socio-demographic characteristics. Results: Overall, 76% and 40% of adults met ADA guidelines for brushing and flossing, respectively. There were no differences in meeting ADA guidelines by gender. When brushing was examined continuously, women brushed 1.24 (1.05-1.47; p = 0.0099) times the rate of weekly brushing than men in the full model; flossing frequency differences were not found. Men and women, whether ADA guidelines were met or not, identified similar brushing and flossing facilitators (health concerns, aesthetics), and barriers (lack of time, not being home). Some women (mothers) were motivated to brush to be role models for their children. Self-efficacy, or confidence in ability to brush or floss, was described differently by adults who met ADA guidelines (high self-efficacy) compared to the adults not meeting guidelines (low self-efficacy). Conclusions: Integrating quantitative and qualitative data obtained from Mexican-origin adults identified few differences in both oral hygiene behaviors and the factors that influence their enactment.