Citations

Background Acute kidney injury (AKI) is associated with high morbidity and mortality in critically ill patients. Multicenter analyses describing the epidemiology of AKI in the cardiac intensive care unit (CICU) are scarce. Here, we describe the prevalence, predictors, and outcomes associated with AKI in a contemporary multicenter CICU population. Methods The Critical Care Cardiology Trials Network (CCCTN) is a collaboration of CICUs in North America coordinated by the TIMI Study Group (Boston, MA). We evaluated patient and hospital-level outcomes as a function of creatinine-only Kidney Disease: Improving Global Outcomes (KDIGO) AKI stage within the CCCTN registry. Logistic regression was used to assess associations with in-hospital mortality. Results Among 21 603 admissions, the overall prevalence of AKI was 23.7%, which was composed of KDIGO stage 1: 12.7%, stage 2: 1.7%, and stage 3: 9.2%. A higher prevalence and severity of AKI were seen in patients with baseline kidney disease, hypertension, or diabetes and in admissions with heart failure, cardiogenic shock, and cardiac arrest ( P < .001 for all). There was a stepwise increase in hospital mortality across AKI stages (stage 1: 23%, stage 2: 39%, stage 3: 42%; P < .0001). The increased risk of death associated with progressive AKI stage persisted after multivariate adjustment (adjusted OR: stage 1: 2.1, stage 2: 3.7, stage 3: 3.4). Conclusions AKI occurs in 1 in 4 admissions to the CICU, and a higher AKI stage is incrementally associated with in-hospital mortality, highlighting a need to develop strategies to mitigate AKI and its complications.

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Non-Small Cell Lung Cancer (NSCLC) provide recommendations for the treatment of patients with NSCLC, including diagnosis, primary disease management, surveillance, and subsequent treatment. The panel has updated the list of recommended targeted therapies based on recent FDA approvals and clinical data. This selection from the NCCN Guidelines for NSCLC focuses on treatment recommendations for advanced or metastatic NSCLC with actionable biomarkers.

Abstract Different MRI image contrasts are designed to highlight various tissue properties and combining them allows extension of probabilistic segmentation beyond the commonly used “gray-white-CSF” models. This work describes a fully automated method that combines T1-weighted, T2-FLAIR, and conventional T2-weighted images to provide internal consistency across prediction of tissue segmentations including segmentation of superficial and deep gray matter, white matter hyperintensities, and MR-visible perivascular spaces. Results from 773 imaging datasets from 403 participants in the Mayo Clinic Study of Aging and Mayo Clinic Alzheimer’s Disease Research Center (ADRC) are presented.

Background Reductions in blood pressure (BP) control among patients with hypertension were observed early in the COVID‐19 pandemic. The degree to which BP control may have returned to prepandemic levels is unknown. Methods Individuals aged 18 to 85 years with hypertension from 17 health systems participating in the National Patient‐Centered Clinical Research Network were identified using electronic health record data collected as part of routine care. BP control (percentage of patients whose most recent BP measurement was <140/<90 mm Hg) was estimated in a series of 12‐month rolling measurement periods from 2017 through 2022 (January 1, 2017 through December 31, 2017; April 1, 2017 through March 31, 2018; … January 1, 2022 through December 31, 2022). Differences in average BP control between 2022 (January 1, 2022 through December 31, 2022) and 2019 (January 1, 2019 through December 31, 2019) were estimated overall (adjusted for age, sex, and race and ethnicity) and by race and ethnicity (adjusted for age and sex). Results Our sample included 1 193 314 persons with hypertension in 2019 (48.9% aged 65–85 years, 52.9% men, 66.2% non‐Hispanic White) and 1 499 418 individuals in 2022 (50.6% aged 65–85 years, 47.1% men, 62.7% non‐Hispanic White). The weighted average BP control dropped from 65.3% in 2019 to 61.8% in 2020 and then partially recovered to 62.6% in 2022 (adjusted mean difference, −2.6 percentage points [95% CI, −5.0 to −0.2]). Non‐Hispanic Asian individuals experienced the largest temporal drop in BP control, declining from 68.4% in 2019 to 63.9% in 2022. Conclusions BP control was disrupted during the COVID‐19 pandemic and had not fully rebounded to prepandemic levels by the end of 2022. Continued surveillance is needed to determine whether the decline in BP control will persist and will result in future adverse cardiovascular events.

ABSTRACT Background The assessment of gastrointestinal (GI) motility disorders is limited by the invasive, resource‐intensive, and subjective nature of current testing. Artificial Intelligence (AI) is being applied to address these challenges. This review aimed to comprehensively identify, appraise, and synthesize the spectrum of AI applications in GI motility diagnostics. Methods A systematic search of PubMed, Embase, Scopus, Web of Science, and Medline for original studies was conducted in March 2025. Results were narratively synthesized and grouped by anatomic region. Key Results Of 1383 articles, 90 primary studies met the inclusion criteria. In the esophagus ( n = 31), the primary focus was automation of High‐Resolution Esophageal Manometry (HREM), pH impedance, and Functional Luminal Imaging Probe (FLIP) panometry analysis. In the gastroduodenum ( n = 21), studies looked to improve diagnostic accuracy and interpretability of legacy electrogastrography (EGG). In the small and large intestine ( n = 19), AI was used to determine transit time and predict post‐operative ileus. In the anorectum ( n = 9), tools focused on standardizing manometry interpretation. Review of pan‐GI applications ( n = 10) highlighted AI's application to wireless capsule endoscopy and bowel sounds analysis. While promising, all areas need more rigorous research and external validation before widespread deployment. Conclusions and Inferences AI will play an essential role in improving and automating the interpretation of GI motility diagnostics. However, even the most promising models require large‐scale prospective validation before clinical implementation. Trial Registration PROSPERO (ID: 1128662)

Abstract INTRODUCTION: Cholangiocarcinoma (CCA) is a deadly cancer of the hepatic bile duct epithelial cells. Loss-of-function mutations of epigenetic regulator ubiquitin C-terminal hydrolase deubiquitinase BRCA1-associated protein 1 (BAP1) occur in 26-32% of human CCA and are associated with worse prognosis and resistance to cytotoxic therapy. The goal of this study is to identify how BAP1 loss promotes cell death evasion through metabolic rewiring. MATERIALS & METHODS: Isogenic wild-type and BAP1-deficient human and murine CCA cell lines were generated with shRNA/siRNA or CRISPR/Cas9 and were used to assess ferroptosis sensitivity by treatment with ferroptosis inducers. In vitro, ferroptosis was assessed by phospholipid peroxidation (C-11BODIPY), mitochondrial phospholipid peroxidation (MitoPeDPP, MitoCLox), iron oeverload (MitoFerro green) and cell death (CellTiter-Glo). Phospholipidomics and proteomics were performed in isogenic cells by LC-MS/MS. Isogenic liver orthotopic CCA murine models were used for in vivo pre-clinical studies. RESULTS: Our findings indicate that BAP1 loss confers CCA ferroptosis resistance. BAP1 loss protects CCA against mitochondrial iron overload, ROS accumulation, and phospholipid peroxidation. Strikingly, BAP1 loss protects from mitochondrial phospholipid peroxidation and cardiolipin oxidation. Unbiased phospholipidomic profiling revealed that BAP1 loss remodels membrane phospholipid composition, enriching for ferroptosis-blocking monounsaturated phospholipids (MUFA-PLs) at the expense of ferroptosis-inducing polyunsaturated (PUFA-PLs). We found that BAP1 loss upregulates TLCD1, a phosphatidylethanolamine acyltransferase that incorporates MUFAs into membrane phospholipids, thereby stabilizing membranes against peroxidation. TLCD1 knockdown in BAP1-deficient CCA cells, restored ferroptosis sensitivity Notably, TLCD1 is significantly upregulated in human BAP1-mutant CCA as compared to WT tumors. We identified TLCD1 in the endoplasmic reticulum, Golgi and by mitochondrial outer membrane. In syngeneic liver orthotopic CCA murine models, engineered EpCAM-aptamer-coated lactosomes carrying GPX4 siRNA selectively targeted CCA cells, inducing ferroptosis and robustly suppressing tumor growth without systemic toxicity. Lastly, BAP1-mutant patient-derived xenografts (PDXs) and organoids were resistant to ferroptosis inducers, as compared to WT controls. CONCLUSIONS: Our findings reveal that BAP1 loss rewires mitochondrial phospholipid metabolism thus conferring CCA resistance to ferroptosis, identifying TLCD1 as a targetable metabolic vulnerability in BAP1-mutant CCA. Citation Format: Yu Zhao, Peyton Classon, Danielle Marie Carlson, Jayla Millender, Irene K. Yan, Sumera Ilyas, Rory L. Smoot, Gregory J. Gores, TUSHAR PATEL, Davide Povero. BAP1 loss confers ferroptosis resistance to cholangiocarcinoma via TLCD1-mediated membrane phospholipid remodeling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 2433.

Abstract Introduction: Src Family Kinases (SFKs) have a crucial role in tumor proliferation, survival, and metastasis. NXP900 is a highly selective SFK inhibitor with a novel mechanism of action that locks SFKs in a closed, inhibited conformation, providing sustained suppression of catalytic and non-catalytic functions, which is distinct from other SFK inhibitors like dasatinib. A phase I clinical trial of NXP900 in patients with advanced solid tumors is ongoing. Our preclinical studies showed therapeutic efficacy of NXP900 in cholangiocarcinoma (CCA) through decreased YAP, RAF-MAP and PI3K-AKT signaling. Multiomic profiling (RNA-seq, proteomics, phosphoproteomics) of CCA patient-derived xenografts implicated AKT pathway activation in primary NXP900 resistance. NXP900-resistant CCA cell lines generated via prolonged sublethal dose escalation showed a strong IL13RA2-AKT signature on multiomic analysis. Thus, we hypothesized that IL13RA2-AKT signaling was a mechanism of NXP900 resistance. We aimed to define this mechanism and demonstrate that the combinatorial targeting of IL13RA2 or AKT resensitizes to NXP900 treatment. Methods: HuCCT1 or HuCCT1-Resisant (HuCCT1-R) cells were injected bilaterally into the flanks of NOD/SCID mice and were allowed to grow for 3 months prior to tumor collection and analysis. Tumor engraftment and growth between HuCCT1 and HuCCT1-R groups were compared. To delineate the mechanisms for acquired NXP900 resistance, in-vitro treatment studies were performed using siRNAs targeting IL13RA2 as well as combination treatment with capivasertib, a pan-AKT inhibitor. Results: The HuCCT1-R cell line exhibited a higher rate of tumor engraftment and formed significantly larger tumors compared to the parental HuCCT1 cell line, indicating enhanced tumorigenic potential associated with acquired resistance. Silencing of IL13RA2 in HuCCT1-R cells resulted in pronounced reduction of cell proliferation and partially restored sensitivity to NXP900 treatment. Immunoblot analysis demonstrated a corresponding reduction in phosphorylated AKT (Thr308), consistent with suppression of downstream PI3K-AKT signaling. Furthermore, combination treatment of HuCCT1-R cells with the AKT inhibitor capivasertib, and NXP900 led to a significant increase in cell death and a greater inhibition in cell proliferation compared to either agent alone, indicating enhanced responsiveness and improved therapeutic efficacy. Conclusion: These findings confirm the central role of IL13RA2 signaling and the PI3K-AKT pathway in mediating acquired resistance to NXP900, consistent with our previous multiomics analysis. Importantly, this study identifies combination strategies that may be able to overcome NXP900 resistance, supporting the development of combinatorial approaches to restore therapeutic efficacy in resistant tumors. Citation Format: Shelby K. Yee, Hendrien Kuipers, Danielle M. Carlson, Jack W. Sample, Enis Ozmert, Hidemi Nishi, Erik Jessen, Dong-Gi Mun, Aushinie M. Abeynayake, Jennifer L. Tomlinson, Amro M. Abdelrahman, Nathan W. Werneburg, Binbin Li, Mitesh J. Borad, Mark J. Truty, Sumera I. Ilyas, Gregory J. Gores, Rory L. Smoot. Resistance to the SFK inhibitor NXP900 in cholangiocarcinoma is characterized by IL13RA2-AKT signaling and can be overcome by combination therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 7124.

Abstract Approximately 288,000 men are diagnosed with prostate cancer (PCa) in the United States each year, with cases expected to double by 2040. While metastatic PCa can be treated with androgen deprivation therapy (ADT) and AR pathway inhibitors (ARPI), it inevitably develops into treatment resistant, lethal disease. The most common ARPI resistance mechanism in PCa is the expression of AR splice variant AR-V7 that lacks the ligand binding domain and is constitutively active. Patients with PCa expressing AR-V7 experience inferior overall survival. Speckle-type POZ protein (SPOP) is an adaptor protein of the Cullin3-based E3 ubiquitin ligase that facilitates both degradative and non-degradative polyubiquitination of targets such as AR. Loss-of-function SPOP mutations occur in approximately 10-15% of prostate cancers, and SPOP-mutant PCa is a unique subtype that has been shown to be exquisitely sensitive to ADT and ARPI treatment. This sensitivity is mediated in part by increased androgen availability via upregulation of hydroxysteroid 17-beta dehydrogenase 4 (HSD17B4) and related steroid synthesis pathways, reduced AR degradation, and enhanced AR cofactor activity. The remarkable efficacy of ARPI in ADT-resistant SPOP-mutant prostate cancer is not well understood. We hypothesized a novel mechanism by which wild-type SPOP promotes AR-V7-mediated resistance to ARPI in PCa. This mechanism may explain the exceptional ARPI sensitivity of SPOP-mutant PCa, distinct from its susceptibility to ADT. We further proposed that clinical SPOP inhibition may broaden this enhanced ARPI susceptibility to the 85-90% of PCa expressing wild-type SPOP. Our results show that SPOP drives ARPI resistance in prostate cancer that can be reversed by SPOP inhibitor. Bulk RNA sequencing showed that SPOP inhibitor targets spliceosome machinery and more importantly, abrogated AR-V7 expression both at transcriptional and protein level. Further investigation revealed that wild-type SPOP ubiquitinates spliceosome regulator SFPQ, promoting AR-V7 alternative splicing and ARPI resistance. While SPOP loss is pathogenic in PCa, leveraging the weakness conferred by SPOP mutation in the 85% of patients with SPOP-wild type provides an innovative strategy to sensitize ARPI resistant disease to standard of care treatment and save lives. Citation Format: Joanina K. Gicobi, Susanna M. Gregory, Nicole A. Becker, Elizabeth A. Bering, Jacob J. Orme.. SPOP drives AR-V7-mediated ARPI resistance in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 3904.

Abstract Prostate-specific membrane antigen (PSMA) is highly expressed in tumor-associated neovasculature in hepatocellular carcinoma (HCC), highlighting its promise as a theranostic target. This prospective study aimed to evaluate the utility of novel biomarkers derived from PSMA positron emission tomography computed tomography (PET/CT) to assess treatment response in advanced HCC patients (pts) receiving first line immune checkpoint inhibitors (ICI). Methods: This study (NCT05176223) enrolled unresectable, advanced HCC pts eligible for first-line ICI (atezolizumab/bevacizumab [A/B] or durvalumab/tremelimumab [D/T]) with measurable disease according to RECIST criteria. Primary endpoints: progression-free survival (PFS) per RECIST 1.1 and mRECIST; overall survival (OS); and best overall response. The survival distribution was estimated using the Kaplan-Meier method. Observed agreement is defined as the proportion of pts whose responses, as classified by PET/CT or CT, were concordant. Weighted kappa and Cohen’s kappa were used to quantify the strength of agreement between PET/CT and CT. Pts completed up to five 68Ga-PSMA PET/CT scans and blood collections. Results: Twenty-six pts were enrolled (25 evaluable) between Oct 2022 and Nov 2024. Median follow up was 22.1 months (m) (Q1, Q3: 14.5-23.7). Median age 68 yrs, 72% male, 88% White, 68% Child-Pugh [CP] A, 32% CP B, 32% Barcelona Clinic Liver Cancer [BCLC] stage B, 68% BCLC stage C, 36% with microvascular invasion; 56% received A/B and 40% received D/T treatment. PSMA was positive in 96% of pts at baseline with median SUVmax 14.3 (range 5.1-40.5) and median background liver SUVmax 3.9 (range 2.1-6.8). Median (95%CI) PFS was 5.6 m (4.6-12.5) by both RECIST and mRECIST. Median (95%CI) OS was 18.6 m (7.2-not estimable), with 56% deceased. The observed agreement between PET/CT adapted PERCIST criteria compared to RECIST and mRECIST in determining the best response was 46% and 50% and weighted kappa of 0.63 (95% CI: 0.37-0.90) and 0.66 (0.41-0.92), respectively. Observed agreement between PERCIST compared to RECIST and mRECIST for responders’ assessment was 67% and 71% with Cohen’s kappa of 0.36 (0.03-0.68) and 0.43 (0.11-0.76), respectively. Conclusion: In this cohort, PSMA PET/CT avidity was observed in all but one pt with advanced HCC, each demonstrating moderate to high SUVmax values. Median OS and PFS were consistent with outcomes reported in clinical trials. Response assessment using 68Ga-PSMA PET/CT according to PERCIST criteria showed good concordance with both RECIST and mRECIST standards. Analysis of immune biomarkers is ongoing. Citation Format: Nguyen H. Tran, Jacob Hirdler, Ajith Antony, Jacob Teske, Sudhakar K. Venkatesh, Amit Mahipal, Michael S. Torbenson, Scott M. Thompson, Thor R. Halfdanarson, Zhaohui Jin, Lionel Aurelien Kankeu Fonkoua, Leslie A. Washburn, Alexander Revzin, Haidong Dong, Robert R. Mcwilliams, Aminah Jatoi, Hani M. Babiker, Mitesh J. Borad, Tanios Bekaii-Saab, Gregory J. Gores, Lewis R. Roberts, Geoffrey B. Johnson, Ajit H. Goenka. Prospective evaluation of 68Ga-PSMA PET imaging in advanced hepatocellular carcinoma patients undergoing first line immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 2611.