Citations

Abstract PARP inhibitors (PARPis) are now a standard of care for high-grade serous ovarian cancer (HGSOC), but resistance to these drugs poses a significant concern, necessitating the exploration of novel treatment strategies. Here we investigated the mechanism underlying enhanced PARPi activity in HGSOC cells following treatment with brigatinib—a second-generation anaplastic lymphoma kinase (ALK) inhibitor approved for treating lung cancer. Our previous work has shown that brigatinib is a dual inhibitor of tyrosine kinases FAK and EPHA2 with subsequent additive reduction in downstream PI3K/AKT and MAPK/ERK cell survival signaling. Suppression of these pathways conferred PARPi sensitivity to HGSOC cell lines and patient-derived xenograft (PDX) models, particularly in those with high FAK and EPHA2. To dissect the mechanism linking the FAK/EPHA2 – AKT/ERK pathway to PARPi synergy, we focused on proteomics approaches which revealed that FRA1—an Activator Protein 1 (AP-1) transcription factor known to be downstream of AKT/ERK—and its targets were decreased by brigatinib treatment. In subsequent phosphoproteomics approaches and cell-based confirmatory studies, a phosphorylation crucial for FRA1 stability was found to be disrupted, leading to reduction in total FRA1 protein levels and synergy with PARPis. To explore how FRA1 mediates response to PARPis, immunoblotting analysis revealed that PARPis increased the abundance of FRA1 in HGSOC cells at early timepoints, indicating potential involvement in an adaptive survival response. Follow-up pharmacologic and gene silencing techniques demonstrated that brigatinib still reduces FRA1 in PARPi-treated cells, and FRA1 depletion induces apoptosis when combined with PARPi to levels comparable to brigatinib treatment. Overall, our studies unveil a beneficial ALK-independent effect of brigatinib that may offer new avenues for considering its repurposing as a HGSOC therapy through disruption of a PARPi-induced adaptive survival mechanism. Citation Format: Julie R. Duffield, Xiaonan Hou, Benjamin W. Wilson, Anjali Prasad, Iman K. McKeon-Makki, Amelia M. Huehls, Xinyan Wu, Cristina Correia, Melissa C. Larson, Fergus J. Couch, Ann L. Oberg, Scott H. Kaufmann, Larry M. Karnitz, Arun Kanakkanthara. A PARP-inhibitor-induced early adaptive survival response is tackled through depletion of FRA1 by brigatinib in high-grade serous ovarian carcinoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Ovarian Cancer Research; 2025 Sep 19-21; Denver, CO. Philadelphia (PA): AACR; Cancer Res 2025;85(18_Suppl):Abstract nr A024.

Importance The Implantable Neurostimulator for the Treatment of Parkinson’s Disease (INTREPID) trial was a randomized, double-blind, sham-controlled study of subthalamic nucleus (STN) deep brain stimulation (DBS) for the treatment of Parkinson disease (PD). Objective To evaluate the long-term (5-year) outcomes and safety of STN-DBS for PD. Design, Setting, and Participants This was a prospective, randomized (3:1), 12-week double-blind sham-controlled study at 23 movement disorder centers across the US with an open-label 5-year follow-up. Patients were implanted and followed up with the Vercise DBS system from May 2013 to December 2022. Eligibility required diagnosis of bilateral idiopathic PD with more than 5 years of motor symptoms, more than 6 hours per day of poor motor function, modified Hoehn and Yahr Scale scores higher than 2, Unified Parkinson’s Disease Rating Scale (UPDRS-III) score of 30 or higher (medication-off state), and 33% or higher improvement in UPDRS-III medication-on score. Intervention Bilateral STN-DBS for moderate to advanced PD. Main Outcomes and Measures Primary outcomes included changes in UPDRS and dyskinesia scores, quality-of-life measures, and safety assessments. Exploratory analyses included medication reduction and DBS association with motor signs. Results A total of 313 patients were enrolled with 191 receiving the DBS system, and 137 participants (72%) completed the study. The study population had a mean (SD) age of 60 (7.9) years, with 139 (73%) male participants. Motor function without medication as measured by UPDRS-III improved from a mean (SD) of 42.8 (9.4) to 21.1 (10.6) at year 1 (51%; 95% CI, 49%-53%; P < .001) and 27.6 (11.6) at year 5 (36%; 95% CI, 33%-38%; P < .001). Activities of daily living without medication as measured by UPDRS-II improved from a mean (SD) of 20.6 (6.0) to 12.4 (6.1) at year 1 (41%; 95% CI, 38%-42%; P < .001) and 16.4 (6.5) at year 5 (22%; 95% CI, 18%-23%; P < .001). Dyskinesia scores decreased from 4.0 (5.1) to 1.0 (2.1) at year 1 (75%; 95% CI, 73%-75%; P < .001) and to 1.2 (2.1) at year 5 (70%; 95% CI, 63%-75%; P < .001). The levodopa equivalent dose was reduced by 28% at year 1, remaining stable at year 5 (28%; 95% CI, 26%-31%; P < .001). The most common serious adverse event was infection (9 participants). Ten deaths were reported, none related to the study. Conclusions and Relevance Although STN-DBS outcomes declined slightly, possibly due to the progressive nature of the disease, patients with PD sustained significant improvement in motor and activities of daily living scores, along with a stable reduction in anti-parkinsonian medication over the 5-year follow-up period.

Purpose: Model interpretability is a critical requirement for deploying artificial intelligence (AI) applications in clinical speech settings, yet existing evaluation methods often overlook this aspect. The complex nature of speech features and the opaque decision-making processes of AI models underscore the need for a tailored framework to assess interpretability in speech-based clinical AI systems. This article proposes an initial framework composed of eight key factors to consider when evaluating the interpretability of clinical speech AI models. These factors are categorized into two groups: functional factors and clinician-centered factors. The functional factors, which can be assessed independently without user involvement, include faithfulness and computational efficiency. The clinician-centered factors include four established ones from existing literature (cognitive load, human–AI task performance, mental model, and user trust) and two new factors tailored to the unique demands of clinical speech applications: clinical understandability and decision relevance. We further suggest evaluation methods for each of the identified factors and propose modifying existing instruments such as the System Usability Scale and the Healthcare Systems Usability Scale to evaluate the two newly introduced factors. Conclusions: Our identified factors form an initial framework for evaluating the interpretability of speech-based clinical AI systems, supporting the effective integration of AI into clinical workflows. Future works include conducting an evaluation experiment using the proposed framework and refining it further based on the findings from the experiment.

Abstract Objective Gastrointestinal (GI) symptoms are common in systemic mastocytosis (SM). We hereby report the clinicopathologic and molecular features of GI mastocytosis. Methods The study includes 104 patients with suspected SM. Of 258 GI biopsy ­specimens, 33 (20 patients, 19%) were mastocytosis-positive, with 19 (16 patients) initially missed. Results Tryptase (n = 29) was weakly positive/negative in two-thirds of the mastocytosis-positive GI biopsy specimens. Additional immunohistochemistry (n = 23) showed positive mast cell expression for CD30 (n = 2), CD123 (n = 7), and PD-L1 (n = 12), as well as increased PD-1–positive cells (n = 4). Sixty patients had positive bone marrow (BM) for SM (SM-BM+), including 19 with positive GI biopsy specimens (SM-GI+). Almost all (43/44) SM-BM– patients were SM-GI–. The SM-GI vs SM-BM status showed high positive predictive value (95%) and specificity (98%). Patients with SM with mastocytosis-positive vs mastocytosis-negative GI biopsy specimens had higher serum tryptase levels (P = .04). KIT D816V mutation was detected in 7 of 13 and 12 of 13 mastocytosis-positive GI biopsy specimens using allele-specific polymerase chain reaction and droplet digital polymerase chain reaction (ddPCR), respectively. Conclusions GI mastocytosis is highly predictive of SM in BM; however, most SM-BM+ patients are SM-GI–. The SM-BM– patients are very unlikely to be SM-GI+. Because GI neoplastic mast cells are often tryptase negative, diagnostic evaluation should include CD117 and CD25 immunohistochemistry, as well as KIT D816V mutation analysis by ddPCR as needed.

Abstract Next-generation sequencing has transformed cancer care by providing essential insights for diagnosis, prognosis, and treatment. However, variability in testing timing, reporting practices, and interpretation challenges limits its clinical impact. This article highlights key opportunities to optimize somatic reporting, emphasizing the importance of timely testing throughout the cancer care continuum to maximize the diagnostic and therapeutic relevance of findings. Technical factors such as test design, sequencing depth, and the use of liquid biopsy substantially influence result accuracy and interpretation, underscoring the need for careful integration with clinical history. Standardized reporting practices that clearly delineate diagnostic, prognostic, and therapeutic findings can enhance the clinical utility of next-generation sequencing results. Streamlined formats and curated clinical trial data further support actionable decision making. Additionally, direct patient engagement and education are essential for empowering patients to navigate genomic testing and make informed decisions about their care. By leveraging multidisciplinary tumor boards, decision-support tools, and emerging artificial intelligence technologies, clinicians can better navigate the complexities of somatic reports. Standardization and clarity in reporting are critical to advancing precision oncology, empowering providers and patients to make informed treatment decisions and improve outcomes.

Introduction/Objectives: Little is known about the prevalence of patient-reported social risk factors and the use of the HOUSES Index, a simple, reliable method of assessing socioeconomic status (SES) based on publicly available housing data, in a predominantly rural, primary care population. Methods: We conducted a cross-sectional analysis of adult patients paneled to family medicine clinicians in a US Midwest health system as of December 31, 2022. Patients’ listed address determined HOUSES Index as quartile rank (Q1 lowest SES) and rural/urban status. Social risk data including housing, food, transportation, finances, and violence were collected from health record questionnaires. A mixed effect model was used to assess associations between social risk, HOUSES Index, and rurality. Results: Of the 352 355 patients included, rural patients were more likely than urban patients to report all social risk factors and had lower SES as measured by HOUSES quartiles. In the mixed effects analysis, HOUSES quartile was independently predictive of reporting an at-risk social risk factor (Q1 vs Q4 OR = 2.27, 95% CI = 2.19-2.37), but rurality was not (OR = 1.02, 95% CI = 0.97-1.07) after adjusting for HOUSES. Conclusions: The increased prevalence of social risk factors among rural residents is largely explained by individual SES measured by HOUSES Index.

Abstract Background Physical activity (PA) is an established protective factor for colorectal cancer (CRC), but it is unclear if genetic variants modify this effect. To investigate this possibility, we conducted a genome-wide gene–PA interaction analysis. Methods Using logistic regression and two-step and joint tests, we analyzed interactions between common genetic variants across the genome and PA in relation to CRC risk. Self-reported PA levels were categorized as active (≥ 8.75 MET-h/wk) vs. inactive (< 8.75 MET-h/wk) and as study- and sex-specific quartiles of activity. Results PA had an overall protective effect on CRC (OR [active vs. inactive] = 0.85; 95%CI = 0.81–0.90). The two-step GxE method identified an interaction between rs4779584, an intergenic variant near the GREM1 and SCG5 genes, and PA for CRC risk (p-interaction = 2.6×10 − 8 ). Stratification by genotype at this locus showed a significant reduction in CRC risk by 20% in active vs. inactive participants with the CC genotype (OR = 0.80; 95%CI = 0.75–0.85), but no significant PA–CRC association among CT or TT carriers. When PA was modeled as quartiles, the 1-d.f. GxE test identified that rs56906466, an intergenic variant near the KCNG1 gene, modified the association between PA and CRC (p-interaction = 3.5×10 − 8 ). Stratification at this locus showed that increase in PA (highest vs. lowest quartile) was associated with a lower CRC risk solely among TT carriers (OR = 0.77; 95%CI = 0.72–0.82). Conclusions In summary, we identified two genetic variants that modified the association between PA and CRC risk. One of them, related to GREM1 and SCG5 , suggests that the bone morphogenetic protein (BMP)-related, inflammatory, and/or insulin signaling pathways may be associated with the protective influence of PA on colorectal carcinogenesis.