tbuckley/cabot-search huggingface dataset:
Bevacizumab, atezolizumab and acetylsalicylic acid in recurrent, platinum-resistant ovarian cancer: the EORTC 1508-GCG phase II study
Authors: Susana Banerjee, Eleonora Ghisoni, Anita Wolfer, Petronella Beatrix. Ottevanger, Ronan Le Scodan, Apostolos Sarivalasis, Ana Montes, Judith Kroep, Margarita Romeo Marin, Petr Szturz, Matteo Morotti, Julien Dagher, Lana Kandalaft, Fernanda Herrera, Corneel Coens, Denarda Dangaj Laniti, George Coukos
Journal: Clinical Cancer Research (2025)

Abstract Purpose: Treatment options for platinum-resistant ovarian cancer (PROC) are limited and new therapeutic strategies are urgently needed. This phase II, randomized, multicentre trial evaluated the safety and activity of the anti-PD-L1 antibody atezolizumab (atezo) combined with the VEGF-inhibitor bevacizumab (bev) and the irreversible cyclooxygenase inhibitor aspirin (ASA) in PROC. Patients and Methods: Patients were randomized to bev monotherapy 15 mg/kg (arm 1), atezo 1200 mg plus placebo (pbo)(arm 2), atezo plus ASA 320 mg/daily (arm 3), bev plus atezo plus pbo (arm 4) or bev plus atezo plus ASA (arm 5). Primary endpoint was progression-free survival at 6 months (PFS-6). Secondary objectives included overall survival (OS), PFS, PFS2 and tolerability. Time to first subsequent therapy (TFST) was evaluated in a post-hoc analysis. Results: In arms 1, 4 and 5, there were 7/32 (21.9%, 70% CI, 14.0-32.0), 8/32 (25.0%, 70% CI, 16.6-35.3), and 8/32 (25.0%, 70% CI, 16.6-35.3) patients alive and progression-free at 6 months. The primary objective was not reached in any arm. Median PFS were 2.3 for bev monotherapy, 4.1 for bev-atezo-pbo, and 4.0 months for bev-atezo-ASA. TFST suggested benefit of adding bev to atezo-ASA (p&amp;lt;0.001). Tumour-infiltrating lymphocytes (TILs) increased in the atezo containing arms and increased TILs were associated with longer TFST. Conclusions: The addition of ASA to bev-atezo was well tolerated but did not improve efficacy in PROC. Relative to bev, the bev-atezo combination numerically improved PFS. Exploratory analyses suggest clinical benefit in a subgroup of patients characterised by high TILs infiltration and PD-L1+ tumours at baseline.
Clinical validity of repeated circulating tumor cell enumeration as an early treatment monitoring tool for metastatic breast cancer in the PREDICT global pooled analysis
Authors: Wolfgang Janni, Thomas W.P. Friedl, Tracy C. Yab, Francois-Clément Bidard, Massimo Cristofanilli, Daniel F. Hayes, Michail Ignatiadis, Meredith M. Regan, Catherine Alix-Panabieres, William E. Barlow, Carlos Caldas, Lisa A. Carey, Luc Dirix, Tanja Fehm, Jose A. Garcia-Saenz, Paola Gazzaniga, Daniele Generali, Lorenzo Gerratana, Rafael Gisbert-Criado, William Jacot, Zefei Jiang, Simon A. Joosse, Evi Lianidou, Rafael López López, Mark J.M. Magbanua, Luis Manso, Dimitris Mavroudis, Volkmar Müller, Elisabetta Munzone, Klaus Pantel, Jean-Yves Pierga, Brigitte Rack, Sabine Riethdorf, Hope S. Rugo, Kostandinos Sideras, Stefan Sleijfer, Jeffrey Smerage, Justin Stebbing, Leon W.M.M. Terstappen, Jose Vidal-Martínez, Markus Wallwiener, Karthik V. Giridhar, Minetta C. Liu
Journal: Clinical Cancer Research (2025)

Abstract Purpose: The aim of PREDICT was to confirm clinical validity and the potential for clinical utility of serial circulating tumor cell (CTC) enumeration in metastatic breast cancer (MBC) patients focusing on its prognostic value in different breast cancer subtypes and clinical settings. Experimental design: In total, 4436 individual patient-level data with CTC results from both baseline and one follow-up (CellSearch®; Menarini Silicon Biosystems) were analyzed to evaluate the association between CTC detection and overall survival (OS) in the full patient cohort and separately for tumor and treatment types. Results: Using the cutoff ≥ 1 CTC for CTC positivity, 913 (20.6%) patients had 0 CTCs at both time points (neg/neg), 325 (7.3%) and 1189 (26.8%) patients converted from CTC negative to CTC positive (neg/pos) or vice versa (pos/neg), while 2009 (45.3%) patients had at least one CTC at both time points (pos/pos). Median OS for the neg/neg, neg/pos, pos/neg and pos/pos group was 45.6, 26.1, 32.3, and 17.3 months, respectively (P &amp;lt; 0.0001, global log-rank test). CTC responders (pos/neg) showed a lower risk of death compared to CTC non-responders (pos/pos) (HR 0.48, 95% CI 0.44 – 0.53). Similar results were obtained in subgroup analyses according to hormone receptor and HER2 subtype, treatment type, and with a ≥ 5 CTC cutoff for CTC positivity. Conclusions: Follow-up CTC assessments strongly predict OS independently from tumor subtype and treatment. New randomized trials to define the clinical utility of CTC monitoring for risk stratification and as an early response marker in MBC are urgently needed.
Clinical and Genomic Characterization of Secondary Rectal Cancer After Radiotherapy for Prostate Cancer
Authors: Dana M. Omer, Farheen Shah, Anisha Luthra, Chin-Tung Chen, Christina I. Lee, Hannah Williams, Henry Walch, Floris S. Verheij, Roni Rosen, Janet Alvarez, Canan Firat, Georgios Karagkounis, Martin R. Weiser, Maria Widmar, Iris H. Wei, Emmanouil P. Pappou, Garrett M. Nash, J. Joshua Smith, Walid K. Chatila, Paul B. Romesser, Jinru Shia, Philip B. Paty, Julio Garcia-Aguilar, Francisco Sanchez-Vega
Journal: JAMA Network Open (2025)

Importance Patients treated with radiotherapy (RT) for prostate cancer (PC) have increased risk of secondary rectal cancer (SRC) and more limited treatment options. Objective To assess the tumor molecular profile, clinical characteristics, and oncologic outcomes of SRC after PC and compare them with those of primary rectal cancer (PRC). Design, Setting, and Participants This case-control study included patients with SRC diagnosed 5 or more years after RT for PC and patients with PRC who were treated at Memorial Sloan Kettering Cancer Center in New York between February 1, 1994, and September 31, 2022. Main Outcomes and Measures Clinical information and DNA sequencing data were analyzed. Oncologic outcomes were compared between patients with SRC and clinically matched patients with PRC using log-rank tests and Cox proportional hazards regression models. Numerical and categorical variables were compared using the Wilcoxon rank sum test and Fisher exact test, respectively. Results The analysis included 604 male patients with PRC (71.6%; median age, 55 [IQR, 46-66] years) and 64 male patients with SRC (median age, 78 [IQR, 72-82] years). Patients with SRC had more distal rectum (37 of 63 [58.7%] vs 131 of 581 [22.5%]; P &amp;amp;lt; .001) and anterior rectal wall (20 of 57 [35.1%] vs 67 of 496 [13.5%]; P &amp;amp;lt; .001) tumors, were less likely to receive neoadjuvant treatment (33 of 64 [51.6%] vs 570 of 604 [94.4%]), and had shorter 5-year overall survival (45.7% vs 64.9%; P = .01) and disease-free survival (40.3% vs 71.2%; P = .006) compared with clinically matched patients with PRC. Targeted DNA sequencing data from 31 SRC tumors identified lower mutational burden (median, 4.4 [IQR, 3.2-6.7] per megabase [Mb] vs 5.8 [IQR, 4.4-7.0] per Mb; P = .047), lower frequency of APC alterations (15 [48.4%] vs 432 [79.9%]; P &amp;amp;lt; .001), and higher rates of SMAD4 inactivation (8 [25.8%] vs 54 [10.0%]; P = .01) compared with 541 PRC tumors. Whole-exome sequencing data from 17 SRC tumors identified a higher rate of frameshift deletions compared with 28 PRC tumors (median, 5.0 [IQR, 4.0-9.0] vs 2.5 [IQR, 1.0-4.2] variants; P &amp;amp;lt; .001). Conclusions and Relevance In this case-control study, patients with SRC after RT for PC had worse survival and different molecular profiles than patients with PRC. These findings may help improve the clinical management of SRC.
Hospital Security Searches Among Patients With Substance-Related Encounters
Authors: Sarah J. Nessen, Ashish Thakrar, Jeanmarie Perrone, Lin Xu, Rachel McFadden, Margaret Lowenstein
Journal: JAMA Network Open (2025)

Importance Hospital clinicians may request that security personnel search patients’ rooms and belongings in response to suspected possession or use of illicit substances. Although searches are intended to protect patient and employee safety, little is known about search outcomes or consequences for clinical care. Objective To investigate the clinical context and outcomes of room searches among patients with substance-related hospital encounters. Design, Setting, and Participants Retrospective cohort study of security incident reports and electronic health record data for patients with substance-related hospital encounters between July 2021 and July 2023 at an urban, academic hospital with approximately 1000 beds in Philadelphia, Pennsylvania. Participants were adults with International Statistical Classification of Diseases and Related Health Problems, Tenth Revision codes consistent with substance use disorders, chief concerns of drug overdose or withdrawal, and/or positive verbal screenings for opioid use who had emergency department visits or inpatient hospitalizations. Main Outcomes and Measures Primary outcomes were search requests, items confiscated, and patient-directed discharges (PDDs). Secondary measures centered on the clinical context of searches, including location and receipt of medications for opioid use disorder. Results There were 13 827 total substance-related hospital encounters over the study period involving 6985 unique patients (median [IQR] age, 47 [34-58] years; 3863 [55.3%] male; 3688 [52.7%] Black; 302 [4.3%] Hispanic; 2597 [37.2%] White). Over this time, security reported 576 room search requests, among which 457 (79.3%) were requests for searches among patients with substance-related hospital encounters. Nurses requested most searches (376 searches [82.3%]), and 195 searches (43.6%) resulted in no items confiscated. Confiscated items included syringes and unspecified paraphernalia (129 searches [28.9%]), confirmed or suspected drugs and alcohol (102 searches [22.8%]), tobacco products (54 searches [12.1%]), and pipes and smoking materials (53 searches [11.9%]). Patients who had 1 or more search requests during a substance-related hospital encounter had a statistically significant odds ratio (OR) of having a PDD compared with patients who did not undergo searches (OR, 2.99; 95% CI, 2.32-3.86). Conclusions and Relevance In this cohort study of patients with substance-related hospital encounters, most searches did not result in the confiscation of illicit substances, and searches were associated with PDDs. There is an overall need for clear, patient-centered hospital search protocols that support both staff and patient well-being.
AMPK is necessary for Treg functional adaptation to microenvironmental stress during malignancy and viral pneumonia
Authors: Manuel A. Torres Acosta, Jonathan K. Gurkan, Qianli Liu, Nurbek Mambetsariev, Carla Reyes Flores, Kathryn A. Helmin, Anthony M. Joudi, Luisa Morales-Nebreda, Kathleen Cheng, Hiam Abdala-Valencia, Samuel E. Weinberg, Benjamin D. Singer
Journal: Journal of Clinical Investigation (2025)

CD4+FOXP3+ regulatory T (Treg) cells maintain self-tolerance, suppress the immune response to cancer, and protect against tissue injury during acute inflammation. Treg cells require mitochondrial metabolism to function, but how Treg cells adapt their metabolic programs to optimize their function during an immune response occurring in a metabolically stressed microenvironment remains unclear. Here, we tested whether Treg cells require the energy homeostasis-maintaining enzyme AMPK to adapt to metabolically aberrant microenvironments caused by malignancy or lung injury, finding that AMPK is dispensable for Treg cell immune-homeostatic function but is necessary for full Treg cell function in B16 melanoma tumors and during influenza virus pneumonia. AMPK-deficient Treg cells had lower mitochondrial mass and exhibited an impaired ability to maximize aerobic respiration. Mechanistically, we found that AMPK regulates DNA methyltransferase 1 to promote transcriptional programs associated with mitochondrial function in the tumor microenvironment. During viral pneumonia, we found that AMPK sustains metabolic homeostasis and mitochondrial activity. Induction of DNA hypomethylation was sufficient to rescue mitochondrial mass in AMPK-deficient Treg cells, linking AMPK function to mitochondrial metabolism via DNA methylation. These results define AMPK as a determinant of Treg cell adaptation to metabolic stress and offer potential therapeutic targets in cancer and tissue injury.
Bioengineering the metabolic network of CAR T cells with GLP-1 and Urolithin A increases persistence and long-term anti-tumor activity
Authors: Areej Akhtar, Md Shakir, Mohammad Sufyan Ansari, None Divya, Md Imam Faizan, Varnit Chauhan, Aashi Singh, Ruquaiya Alam, Iqbal Azmi, Sheetal Sharma, Mehak Pracha, Insha Mohi Uddin, Uzma Bashir, Syeda Najidah Shahni, Rituparna Chaudhuri, Sarah Albogami, Rik Ganguly, Shakti Sagar, Vijay Pal Singh, Gaurav Kharya, Amit Kumar Srivastava, Ulaganathan Mabalirajan, Soumya Sinha Roy, Irfan Rahman, Tanveer Ahmad
Journal: Cell Reports Medicine (2025)

Constant tumor antigen exposure disrupts chimeric antigen receptor (CAR) T cell metabolism, limiting their persistence and anti-tumor efficacy. To address this, we develop metabolically reprogrammed CAR (MCAR) T cells with enhanced autophagy and mitophagy. A compound screening identifies a synergy between GLP-1R agonist (semaglutide [SG]) and Urolithin A (UrA), which activate autophagy through mTOR (mechanistic target of rapamycin) inhibition and mitophagy via Atg4b activation, maintaining mitochondrial metabolism in CAR T cells (MCAR T-1). These changes increase CD8+ T memory cells (Tm), enhancing persistence and anti-tumor activity in vitro and in xenograft models. GLP-1R knockdown in CAR T cells diminishes autophagy/mitophagy induction, confirming its critical role. We further engineer GLP-1-secreting cells (MCAR T-2), which exhibited sustained memory, stemness, and long-term persistence, even under tumor re-challenge. MCAR T-2 cells also reduce cytokine release syndrome (CRS) risks while demonstrating potent anti-tumor effects. This strategy highlights the potential of metabolic reprogramming via targeting autophagy/mitophagy pathways to improve CAR T cell therapy outcomes, ensuring durability and efficacy.
Histamine 2 receptor: Emerging target for the treatment of attention-deficit/hyperactivity disorder
Authors: Ling Shan, Dick F Swaab
Journal: Cell Reports Medicine (2025)

A study by An et al. sheds a novel light on the potential role of histamine 2 receptor (H2R) deficiency in attention-deficit/hyperactivity disorder (ADHD), which could be a future therapeutic target of ADHD. This spotlight provides an overview of the current knowledge of the histaminergic system and proposes future directions.
BET inhibitor in combination with BCG vaccine enhances antitumor efficacy and orchestrates T cell reprogramming for melanoma
Authors: Wenhua Wang, Xin Li, Rui Hu, Liang Dong, Shiyao Pei, Liping Jin, Qian Gao, Xiang Chen, Mingzhu Yin
Journal: Cell Reports Medicine (2025)

Immunotherapy shows remarkable benefits in treating melanoma, yet existing approaches achieve limited overall responses. Here, we show that a combination of bromodomain and extra-terminal protein family inhibitor, NHWD-870, and Bacillus Calmette-Guérin vaccine is a promising therapeutic strategy for melanomas. Single-cell transcriptome analyses and functional experiments show that the combination therapy significantly inhibited tumor growth by reprogramming T cells toward an immune-activated state, enhancing their cytotoxicity, preventing their exhaustion, and increasing the recruitment of them into the tumor microenvironment. We identify the molecule, MT1, as a direct downstream target of BRD4, which is effectively suppressed by NHWD-870. Furthermore, our findings are reinforced by a humanized patient-derived xenograft (PDX) model, which exhibits notable antitumor effects in humanized tumor-bearing mice treated with the combination therapy. Our study underscores the immense potential of this therapeutic approach for clinical practice, offering promising prospects in overcoming the limitations of current treatments.
Single-cell atlas of endothelial and mural cells across primary and metastatic brain tumors
Authors: Leire Bejarano, Joao Lourenco, Annamaria Kauzlaric, Eleni Lamprou, Catia F Costa, Sabine Galland, Roeltje R Maas, Paola Guerrero Aruffo, Nadine Fournier, Jean-Philippe Brouland, Andreas F Hottinger, Roy T Daniel, Monika E Hegi, Johanna A Joyce
Journal: Immunity (2025)
Changes in Adrenal Function and Insufficiency Symptoms After Cessation of Prednisolone
Authors: Simon Bøggild Hansen, Anja Fenger Dreyer, Nanna Thurmann Jørgensen, Hajir Al-Jorani, Lise Sofie Bislev, Victor Brun Boesen, Stina Willemoes Borresen, Louise Lehmann Christensen, Dorte Glintborg, Ellen Margrethe Hauge, Merete Lund Hetland, Richard Christian Jensen, Søren Andreas Just, Kresten Krarup Keller, Marianne Klose, Kristina Laugesen, Henning Locht, Marie Louise Lund, Jelena Stankovic, Paul M. Stewart, Randi Maria Hanghøj Tei, Anne Voss, Ulla Feldt-Rasmussen, Jens Otto L. Jørgensen, Marianne Skovsager Andersen
Journal: JAMA Network Open (2025)

Importance The widespread use of glucocorticoid (GC) therapy may result in GC-induced adrenal insufficiency (GIAI), but the prevalence and clinical implications remain uncertain. Objective To ascertain the prevalence and symptoms of GIAI. Design, Setting, and Participants Cross-sectional multicenter study at 3 Danish hospitals. Baseline data were collected March 2021 to March 2024 from an ongoing randomized clinical trial. Participants were patients with polymyalgia rheumatica and/or giant cell arteritis who were investigated a median (IQR) of 39 (25-62) days after planned cessation of prednisolone treatment. Exposure Prednisolone treatment a median (IQR) of 13 (10-20) months in duration. Main outcomes and measures Primary outcome GIAI was defined as a stimulated plasma cortisol level less than 420 nmol/L in response to a short 250 μg corticotropin test (SST). Secondary outcomes were adrenal insufficiency symptoms assessed by the Addison disease-specific quality of life questionnaire (AddiQoL-30), body composition, and muscle function. Results Of 267 patients included (145 female [55%]; median [IQR] age 73 [68-78] years), 5 (1.9%; 95% CI, 0.8%-4.3%) had GIAI, whereas 75 (34%; 95% CI, 28%-41%) had symptoms compatible with adrenal insufficiency defined by an AddiQoL-30 score 85 or lower (symptomatic group). The symptomatic group had lower basal cortisol levels compared with the asymptomatic group (263 nmol/L; 95% CI, 242-283 nmol/L vs 309 nmol/L; 95% CI, 295-324 nmol/L; P &amp;amp;lt; .001). Factors associated with a low AddiQoL-30 score included female sex (prevalence ratio [PR], 1.68; 95% CI, 1.13-2.51), increased body fat percentage (PR, 2.33; 95% CI, 1.21-4.50), reduced handgrip strength (PR, 2.71; 95% CI, 1.44-5.10) and low Short Physical Performance Battery score (PR, 2.78; 95% CI, 1.42-5.42). Conclusions and Relevance This cross-sectional study of 267 patients with polymyalgia rheumatica or giant cell arteritis found a GIAI prevalence of 1.9% after cessation of prednisolone. This is much lower than previously reported and speaks against routine screening, which should be restricted to patients with overt symptoms. The high prevalence of symptoms of adrenal insufficiency in association with lower basal cortisol levels substantiate the clinical challenges of steroid withdrawal and merit future research.
Geographic Access to Cancer Care and Treatment and Outcomes of Early-Stage Non–Small Cell Lung Cancer
Authors: Pratibha Shrestha, Ying Liu, James Struthers, Benjamin Kozower, Min Lian
Journal: JAMA Network Open (2025)

Importance Data on the impact of geographic access to cancer care on early-stage non–small cell lung cancer (NSCLC) treatment and outcomes are limited. Objective To examine the associations of geographic access to cancer care with guideline-recommended treatment and outcomes in patients with early-stage NSCLC. Design, Setting, and Participants This population-based cohort study included patients with early-stage NSCLC newly diagnosed between January 1, 2007, and December 31, 2015, followed up through December 31, 2016, and identified from the Surveillance, Epidemiology, and End Results dataset. Data analysis was performed from March to November 2024. Exposures Geographic access to thoracic surgeons and radiation oncologists was quantified using the 2-step floating catchment area algorithm and categorized into quintile 1 (least access) through quintile 5 (greatest access). Main Outcomes and Measures Multilevel logistic regression was performed to estimate odds ratios (ORs) of receipt of surgery and radiotherapy. Hazard ratios (HRs) of lung cancer-specific mortality were estimated using Fine and Gray subdistribution hazard regression. Results Among 65 259 patients, the mean (SD) age was 69.4 (10.1) years; 33 114 patients (50.7%) were female, 1071 (1.6%) were uninsured, and 7541 (11.6%) were enrolled in Medicaid. The least (vs greatest) geographic access to thoracic surgeons (HR, 1.10; 95% CI, 1.03-1.18; P &amp;amp;lt; .001 for trend) and radiation oncologists (HR, 1.11; 95% CI, 1.04-1.18; P &amp;amp;lt; .001 for trend) was associated with higher lung cancer mortality. Patients in counties with the least (vs greatest) access to thoracic surgeons were less likely to undergo surgery (OR, 0.80; 95% CI, 0.69-0.93; P &amp;amp;lt; .001 for trend); this association was much stronger in Asian than non-Hispanic White patients and in Medicaid-insured than non-Medicaid-insured patients. Although there was no significant association overall, geographic access to radiation oncologists was significantly associated with radiotherapy use in older (OR, 0.85; 95% CI, 0.76-0.95), Hispanic (OR, 0.65; 95% CI, 0.49-0.86), and uninsured (OR, 0.63; 95% CI, 0.43-0.94) patients. Conclusions and Relevance In this cohort study, geographic access to cancer care was associated with guideline-recommended treatment for early-stage NSCLC and outcomes, particularly in socially marginalized patients, underscoring the importance of ensuring appropriate geographic allocations of cancer care resources and addressing travel barriers to health care to improve NSCLC treatment, prognosis, and equity.