tbuckley/cabot-search huggingface dataset:
Pertuzumab Retreatment for Human Epidermal Growth Factor Receptor 2–Positive Locally Advanced/Metastatic Breast Cancer (PRECIOUS Study): Final Overall Survival Analysis
Authors: Yutaka Yamamoto, Hiroji Iwata, Shigehira Saji, Masato Takahashi, Tetsuhiro Yoshinami, Takayuki Ueno, Tatsuya Toyama, Takashi Yamanaka, Toshimi Takano, Masahiro Kashiwaba, Koichiro Tsugawa, Yoshie Hasegawa, Kenji Tamura, Hiroshi Tada, Fumikata Hara, Tomomi Fujisawa, Naoki Niikura, Naruto Taira, Satoshi Morita, Masakazu Toi, Shinji Ohno, Norikazu Masuda
Journal: Journal of Clinical Oncology (2025)

In the primary analysis of the open-label phase III PRECIOUS study, pertuzumab retreatment combined with trastuzumab plus chemotherapy of physician's choice (PTC) significantly improved investigator-assessed progression-free survival (PFS) compared with trastuzumab plus physician's choice chemotherapy (TC) in patients with human epidermal growth factor receptor 2 (HER2)-positive locally advanced/metastatic breast cancer (LA/mBC). Here, we report final overall survival (OS) at the median follow-up of 25.8 months. Patients who have previously received pertuzumab-containing regimens as first-/second-line treatment for LA/mBC were randomly assigned 1:1 to two groups, PTC group (n = 110) and TC group (n = 109). Median OS was longer in the PTC group (median OS 36.2 v 26.5 months; hazard ratio [HR], 0.73 [one side 95% CI upper limit, 0.97]). Updated median investigator-assessed PFS (5.5 v 4.2 months; HR, 0.81 [one side 95% CI upper limit, 1.02]) were also better in the PTC group. Median PFS by independent review did not show the difference between the two groups (4.4 v 4.4 months; HR, 1.03 [one side 95% CI upper limit, 1.36]). These findings suggest that dual HER2 blockade with pertuzumab plus trastuzumab could contribute to improving OS in patients who have previously been treated with pertuzumab-containing regimens for HER2-positive LA/mBC.
Machine Learning to Predict Mortality in Older Patients With Cancer: Development and External Validation of the Geriatric Cancer Scoring System Using Two Large French Cohorts
Authors: Etienne Audureau, Pierre Soubeyran, Claudia Martinez-Tapia, Carine Bellera, Sylvie Bastuji-Garin, Pascaline Boudou-Rouquette, Anne Chahwakilian, Thomas Grellety, Olivier Hanon, Simone Mathoulin-Pélissier, Elena Paillaud, Florence Canouï-Poitrine
Journal: Journal of Clinical Oncology (2025)

PURPOSE Establishing an accurate prognosis remains challenging in older patients with cancer because of the population's heterogeneity and the current predictive models' reduced ability to capture the complex interactions between oncologic and geriatric predictors. We aim to develop and externally validate a new predictive score (the Geriatric Cancer Scoring System [GCSS]) to refine individualized prognosis for older patients with cancer during the first year after a geriatric assessment (GA). MATERIALS AND METHODS Data were collected from two French prospective multicenter cohorts of patients with cancer 70 years and older, referred for GA: ELCAPA (training set January 2007-March 2016) and ONCODAGE (validation set August 2008-March 2010). Candidate predictors included baseline oncologic and geriatric factors and routine biomarkers. We built predictive models using Cox regression, single decision tree (DT), and random survival forest (RSF) methods, comparing their predictive performance for 3-, 6-, and 12-month mortalities by computing time-dependent area under the receiver operator curve (tAUC). RESULTS A total of 2,012 and 1,397 patients were included in the training and validation set, respectively (mean age: 81 ± 6 years/78 ± 5 years; women: 47%/70%; metastatic cancer: 50%/34%; 12-month mortality: 43%/16%). Tumor site/metastatic status, cancer treatment, weight loss, ≥five prescription drugs, impaired functional status and mobility, abnormal G-8 score, low creatinine clearance, and elevated C-reactive protein (CRP)/albumin were identified as relevant predictors in the Cox model. DT and RSF identified more complex combinations of features, with G-8 score, tumor site/metastatic status, and CRP/albumin ratio contributing most to the predictions. The RSF approach gave the highest tAUC (12 months: 0.87 [RSF], 0.82 [Cox], 0.82 [DT]) and was retained as the final model. CONCLUSION The GCSS on the basis of a machine learning approach applied to two large French cohorts gave an accurate externally validated mortality prediction. The GCSS might improve decision making and counseling in older patients with cancer referred for pretherapeutic GA. GCSS's generalizability must now be confirmed in an international setting.
A Very Atypical Meckel Diverticulum on 99mTcO4− Scintigraphy
Authors: Ann Foran, Pensiree Attaseth, Frederick D. Grant, Hongming Zhuang
Journal: Clinical Nuclear Medicine (2025)

Abstract Typical Meckel diverticulum on 99m TcO 4− scintigraphy usually appears early in the dynamic imaging in the right lower quadrant of the abdomen, without change of location during the study. We report a case of pathology-proven Meckel diverticulum a 7-year-old boy, which appeared only on the later part of the 99m TcO 4− study in the midline upper pelvis which gradually changed location during the study.
Coordinated immune networks in leukemia bone marrow microenvironments distinguish response to cellular therapy
Authors: Katie Maurer, Cameron Y. Park, Shouvik Mani, Mehdi Borji, Florian Raths, Kenneth H. Gouin, Livius Penter, Yinuo Jin, Jia Yi Zhang, Crystal Shin, James R. Brenner, Jackson Southard, Sachi Krishna, Wesley Lu, Haoxiang Lyu, Domenic Abbondanza, Chanell Mangum, Lars Rønn Olsen, Michael J. Lawson, Martin Fabani, Donna S. Neuberg, Pavan Bachireddy, Eli N. Glezer, Samouil L. Farhi, Shuqiang Li, Kenneth J. Livak, Jerome Ritz, Robert J. Soiffer, Catherine J. Wu, Elham Azizi
Journal: Science Immunology (2025)

Understanding how intratumoral immune populations coordinate antitumor responses after therapy can guide treatment prioritization. We systematically analyzed an established immunotherapy, donor lymphocyte infusion (DLI), by assessing 348,905 single-cell transcriptomes from 74 longitudinal bone marrow samples of 25 patients with relapsed leukemia; a subset was evaluated by both protein- and transcriptome-based spatial analysis. In acute myeloid leukemia (AML) DLI responders, we identified clonally expanded ZNF683 + CD8 + cytotoxic T lymphocytes with in vitro specificity for patient-matched AML. These cells originated primarily from the DLI product and appeared to coordinate antitumor immune responses through interaction with diverse immune cell types within the marrow microenvironment. Nonresponders lacked this cross-talk and had cytotoxic T lymphocytes with elevated TIGIT expression. Our study identifies recipient bone marrow microenvironment differences as a determinant of an effective antileukemia response and opens opportunities to modulate cellular therapy.
Human naïve B cells recognize prepandemic influenza virus hemagglutinins
Authors: Jared Feldman, Ana Sofia Ferreira Ramos, Mya Vu, Daniel P. Maurer, Victoria C. Rosado, Daniel Lingwood, Goran Bajic, Aaron G. Schmidt
Journal: Science Immunology (2025)

Understanding the naïve B cell repertoire and its specificity for potential zoonotic threats, such as the highly pathogenic avian influenza (HPAI) H5Nx viruses, may allow prediction of infection- or vaccine-specific responses. However, this naïve repertoire and the possibility to respond to emerging, prepandemic viruses are largely undetermined. Here, we profiled naïve B cell reactivity against a prototypical HPAI H5 hemagglutinin (HA), the major target of antibody responses. We found that the frequency of H5-specific human naïve B cells targeting the HA “head” domain was increased relative to cross-reactive B cells to a circulating seasonal H1N1 strain. We classified the isolated monoclonal antibodies (mAbs) by the HA epitopes engaged and found that selected mAbs neutralized H5N1 at germline. We determined a cryo–electron microscopic structure of one mAb in complex with H5 HA to define its epitope. Our study defines the naïve human B cell repertoire recognizing a potentially zoonotic HPAI.
Skin cancer risk in over 200.000 patients with haematologic malignancies in 30 years; a nationwide population-based study in the Netherlands
Authors: Celeste J Eggermont, Andrya Hollatz, Marlies Wakkee, Marieke Louwman, Avinash G Dinmohamed, Eduardus F M Posthuma, Tamar Nijsten, Loes Hollestein
Journal: British Journal of Dermatology (2025)

Abstract Background Patients with haematologic malignancies are at increased risk of developing skin cancer and often experience worse skin cancer-related outcomes. However, there is a lack of nationwide, population-based data with long-term follow-up on the incidence and risks of different skin cancer types across all haematologic malignancies. Objectives To assess population-based risk estimates for cutaneous squamous cell carcinoma (CSCC), malignant melanoma (MM), Merkel cell carcinoma (MCC), and basal cell carcinoma (BCC) among patients with haematologic malignancies, stratified by skin cancer type and haematologic malignancy subgroup. These estimates can serve as a base for surveillance guidelines and patient education. Methods This nationwide population-based epidemiologic cohort study used data on 210,794 patients diagnosed with a haematologic malignancy between 1989 and 2020 from the Netherlands Cancer Registry (NCR). In addition, data on each type of histopathologically confirmed skin cancer per patient after haematologic malignancy diagnosis was retrieved from the NCR. Patients with a history of skin cancer prior to their haematologic malignancy were excluded. Cumulative incidences, standardized incidence ratio’s (SIRs), and absolute excess risks for each of the four skin cancers were calculated and stratified by haematologic malignancy subgroup, age, sex, follow-up, and primary treatment. Results The overall 10-year cumulative incidence of developing a first skin cancer was 2.6% for CSCC, 0.5% for MM, 0.05% for MCC, and 4.8% for BCC. Compared to the general population, nearly all haematologic malignancy subgroups showed more than a twofold increased risk of CSCC, MM, MCC and BCC. Patients with chronic lymphocytic leukemia (CLL) showed the highest risks for each of the four skin cancers, with SIRs of 4.4 for CSCC, 2.7 for MM, 9.3 for MCC, and 2.6 for BCC. These elevated risks persisted for more than 30 years after haematologic malignancy diagnosis. Conclusions Patients with all types of haematologic malignancies, and especially those with CLL, have a lifetime increased risk of developing different types of skin cancer. These findings highlight the importance of creating awareness among patients and care providers about this increased risk and promoting sun-protective measures and regular skin self-examinations in this high-risk population.
Targeting TUT1 Depletes Tri-snRNP Pools to Suppress Splicing and Inhibit Pancreatic Cancer Cell Survival
Authors: Ziwei Guo, Junran Huang, Zhi J. Lu, Yongsheng Shi, Charles J. David, Mo Chen
Journal: Cancer Research (2025)

Abstract Pancreatic ductal adenocarcinoma (PDAC) is highly aggressive and lacks effective therapeutic options. Cancer cells frequently become more dependent on splicing factors than normal cells due to increased rates of transcription. Terminal uridylyltransferase 1 (TUT1) is a specific terminal uridylyltransferase for U6 small nuclear RNA (snRNA), which plays a catalytic role in the spliceosome. Here, we found that TUT1 was required for the survival of PDAC cells but not for normal pancreatic cells. In PDAC cells, the uridylylation activity of TUT1 promoted tri-snRNP assembly by facilitating the binding of LSM proteins to U6 snRNA and subsequent tri-snRNP assembly. PDAC cells required higher amounts of tri-snRNP to efficiently splice pre-mRNA with weak splice sites to support the high transcriptional output. Depletion of TUT1 in PDAC cells resulted in inefficient splicing of exons in a group of highly expressed RNAs containing weak splice sites, thereby resulting in the collapse of an mRNA processing circuit and consequently dysregulating splicing required by PDAC cells. Overall, this study unveiled an interesting function of TUT1 in regulating splicing by modulating tri-snRNP levels and demonstrated a distinct mechanism underlying splicing addiction in pancreatic cancer cells.
Phase Ib study of PRT543, an oral protein arginine methyltransferase 5 (PRMT5) inhibitor, in patients with advanced splicing factor-mutant myeloid malignancies
Authors: Jan Philipp Bewersdorf, Xiaoli Mi, Bin Lu, Andrew Kuykendall, David Sallman, Manish Patel, Don Stevens, Alexander Philipovskiy, Grerk Sutamtewagul, Lucia Masarova, Gina Keiffer, Amit Verma, Neha Bhagwat, Min Wang, Andrew Moore, Joseph Rager, Diane Heiser, Sunhee Ro, Wan-Jen Hong, Omar Abdel-Wahab, Eytan M. Stein
Journal: Leukemia (2025)

Mutations in RNA splicing factor genes are common in patients with myelodysplastic neoplasms (MDS) and secondary acute myeloid leukemia (AML) [1][2][3].Cells bearing these mutations have been shown to be preferentially sensitive to pharmacologic modulation of splicing compared to wild-type (WT) cells [4,5].Protein arginine methyltransferase 5 (PRMT5) is an arginine methyltransferase which utilizes the methyl donor S-adenosylmethionine (SAM) to symmetrically methylate arginine residues on a variety of proteins [6,7].PRMT5-dependent symmetric di-methyl arginine (SDMA) mark is essential for spliceosome assembly and normal splicing [8].Several preclinical studies have demonstrated that PRMT5 inhibition results in synthetic lethality with splicing factor mutant leukemia cells [1,8].Here we describe the discovery and characterization of PRT543, an oral potent, selective inhibitor of PRMT5, in preclinical studies as well as a phase I dose-escalation/expansion trial in patients with relapsed/refractory (R/R) myeloid neoplasms (NCT03886831).This was a multicenter, open-label, sequential cohort, doseescalation/expansion phase I study of PRT543 monotherapy in patients with advanced solid and hematologic malignancies.Only data from patients with AML, MDS, and MDS/MPN (myeloproliferative neoplasm) overlap are reported here.Data from the doseescalation part leading to the identification of the recommended phase 2 dose (RP2D) of PRT543 35 mg daily 5x/week have been presented previously [9,10].Full details on study design are in Supplementary Methods.The primary endpoint of the dose escalation phase was to characterize dose-limiting toxicities (DLTs) and determine the RP2D of PRT543 monotherapy.In the dose expansion phase, the primary endpoint was best overall response rate (ORR) during first three response assessments.ORR was
Diabetes Risk After Treatment for Childhood and Young Adult Cancer
Authors: Kirsten J. Cromie, Robert D. Murray, Ramzi A. Ajjan, Nicola F. Hughes, Richard G. Feltbower, Adam W. Glaser
Journal: Diabetes Care (2025)

OBJECTIVE Diabetes is a potential late consequence of childhood and young adult cancer (CYAC) treatment. Causative treatments associated with diabetes have been identified in retrospective cohort studies but have not been validated in population-based cohorts. Our aim was to define the extent of diabetes risk and explore contributory factors for its development in survivors of CYAC in the United Kingdom. RESEARCH DESIGN AND METHODS Cancer registration data (n = 4,238) were linked to electronic health care databases to identify cases of diabetes through clinical coding or HbA1c values. Total effect of prespecified treatment exposures on diabetes risk was estimated using flexible parametric modeling and standardized cause-specific cumulative incidence functions (CIFs). RESULTS After median follow-up of 14.4 years, 163 individuals (3.8%) were identified with diabetes. Total body irradiation (TBI) increases diabetes risk over time, with a 40-year CIF reaching 21.0% (95% CI 13.8–31.9) compared with 8.4% (95% CI 6.1–11.5) without TBI. Survivors treated with corticosteroids had a 7.7% increased risk at 40 years after cancer diagnosis. Hematopoietic stem cell transplant (HSCT) survivors had markedly higher risk, with a 40-year CIF of 19.6% (95% CI 13.4–28.6) versus 8.2% (95% CI 6.0–11.3) for patients who had not undergone HSCT. Among patients who received allogeneic HSCT, the 40-year CIF of diabetes was 25.7% (95% CI 17.4–38.0), compared with 7.9% (95% CI 3.3–19.1) in patients who received autologous transplants. CONCLUSIONS This evaluation of a hospital-based cohort of patients with CYAC identifies these patients’ increased long-term risk of developing diabetes and how this varies temporally according to treatment modalities. Notable contrasts in risk by treatment were detected as early as 10 years after cancer diagnosis. Findings should inform the development of risk-stratified evidence-based screening.
Long COVID and gut microbiome: insights into pathogenesis and therapeutics
Authors: Raphaela I. Lau, Qi Su, Siew C. Ng
Journal: Gut Microbes (2025)

Post-acute coronavirus disease 2019 syndrome (PACS), following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection or coronavirus disease 2019 (COVID-19), is typically characterized by long-term debilitating symptoms affecting multiple organs and systems. Unfortunately, there is currently a lack of effective treatment strategies. Altered gut microbiome has been proposed as one of the plausible mechanisms involved in the pathogenesis of PACS; extensive studies have emerged to bridge the gap between the persistent symptoms and the dysbiosis of gut microbiome. Recent clinical trials have indicated that gut microbiome modulation using probiotics, prebiotics, and fecal microbiota transplantation (FMT) led to improvements in multiple symptoms related to PACS, including fatigue, memory loss, difficulty in concentration, gastrointestinal upset, and disturbances in sleep and mood. In this review, we highlight the latest evidence on the key microbial alterations observed in PACS, as well as the use of microbiome-based therapeutics in managing PACS symptoms. These novel findings altogether shed light on the treatment of PACS and other chronic conditions.
Low-Dose Initiations of Buprenorphine in the Fentanyl Era—A Search for Evidence-Based Approaches to an Evolving Crisis
Authors: Justin Berk, Michael Rose, Ashish P. Thakrar
Journal: JAMA Network Open (2025)

Leslie W. Suen, MD, MAS; Amy Y. Chiang, PhD; Benjamin L. H. Jones, MD; Christine S. Soran, MD, MPH; Michelle Geier, PharmD; Hannah R. Snyder, MD; John Neuhaus, PhD; Janet J. Myers, PhD; Kelly R. Knight, PhD; Alexander R. Bazazi, MD, PhD; Phillip O. Coffin, MD, MIA
Incidence Rate Trends of Breast Cancer Overall and by Molecular Subtype by Race and Ethnicity and Age
Authors: Noelani H. Y. Li, Christopher I. Li
Journal: JAMA Network Open (2025)

Importance Black and Hispanic women in the US experience higher incidence rates of aggressive molecular subtypes of breast cancer, including triple-negative disease. However, how these rates are changing, particularly across different age groups, has not been well documented. Objective To assess changes in overall and subtype-specific breast cancer incidence rates in the US by age and race and ethnicity. Design, Setting, and Participants This cohort study used Surveillance, Epidemiology, and End Results program cancer registry data from 22 US cancer registries on 1 123 658 females who received a diagnosis of invasive breast cancer from 2010 to 2019. Statistical analysis was conducted from August 2023 to October 2024. Exposures Age and race and ethnicity. Main Outcomes and Measures Age-adjusted incidence rates of invasive breast cancer overall and across the 4 major molecular subtypes by age and by race and ethnicity, as well as their associated annual percentage changes using Joinpoint Trend Analysis software. Results Of the 1 123 658 participants in the study, 219 112 (19.5%) were younger than 50 years, 409 257 (36.4%) were aged 50 to 64 years, and 495 289 (44.1%) were 65 years or older. A total of 141 703 participants (12.6%) were Hispanic, 3253 (0.3%) were non-Hispanic American Indian or Alaska Native, 78 306 (7.0%) were non-Hispanic Asian or Pacific Islander, 124 560 (11.1%) were non-Hispanic Black, 769 043 (68.4%) were non-Hispanic White, and 6793 participants (0.6%) had an unknown race and/or ethnicity. Overall, breast cancer incidence rates increased 0.5% per year from 2010 to 2019. Variation by race and ethnicity was observed, with increases of 1.4% per year among Hispanic females, 1.9% per year among non-Hispanic American Indian or Alaska Native females, and 2.1% per year among non-Hispanic Asian or Pacific Islander females, while rates increased only 0.8% per year among non-Hispanic Black females and 0.5% per year among non-Hispanic White females. In subtype analyses, increases of the greatest magnitude in recent years were observed in the incidence rates of triple-negative breast cancer per year among participants aged 65 years or older (Hispanic females, 2.3%; non-Hispanic Asian or Pacific Islander females, 5.5%; and non-Hispanic Black females, 4.3%), while remaining unchanged among non-Hispanic White females. Conclusions and Relevance In this cohort study of 1 123 658 females with breast cancer over the 10-year period from 2010 to 2019, there were substantial differences in trends in the incidence rates of breast cancer overall and by subtype across different racial and ethnic groups. Further research is needed to understand the factors associated with these trends.