tbuckley/cabot-search huggingface dataset:
Olezarsen, Acute Pancreatitis, and Familial Chylomicronemia Syndrome
Authors: Erik S G Stroes, Veronica J Alexander, Ewa Karwatowska-Prokopczuk, Robert A Hegele, Marcello Arca, Christie M Ballantyne, Handrean Soran, Thomas A Prohaska, Shuting Xia, Henry N Ginsberg, Joseph L Witztum, Sotirios Tsimikas
Journal: New England Journal of Medicine (2024)

BackgroundFamilial chylomicronemia syndrome is a genetic disorder associated with severe hypertriglyceridemia and severe acute pancreatitis. Olezarsen reduces the plasma triglyceride level by reducing hepatic synthesis of apolipoprotein C-III.MethodsIn a phase 3, double-blind, placebo-controlled trial, we randomly assigned patients with genetically identified familial chylomicronemia syndrome to receive olezarsen at a dose of 80 mg or 50 mg or placebo subcutaneously every 4 weeks for 53 weeks. There were two primary end points: the difference between the 80-mg olezarsen group and the placebo group in the percent change in the fasting triglyceride level from baseline to 6 months, and (to be assessed if the first was significant) the difference between the 50-mg olezarsen group and the placebo group. Secondary end points included the mean percent change from baseline in the apolipoprotein C-III level and an independently adjudicated episode of acute pancreatitis.ResultsA total of 66 patients underwent randomization; 22 were assigned to the 80-mg olezarsen group, 21 to the 50-mg olezarsen group, and 23 to the placebo group. At baseline, the mean (±SD) triglyceride level among the patients was 2630±1315 mg per deciliter, and 71% had a history of acute pancreatitis within the previous 10 years. Triglyceride levels at 6 months were significantly reduced with the 80-mg dose of olezarsen (−43.5%; 95% confidence interval [CI], −69.1 to −17.9; P<0.001) but not with the 50-mg dose (−22.4%; 95% CI, −47.2 to 2.5; P=0.08). The difference in the mean percent change in the apolipoprotein C-III level from baseline to 6 months in the 80-mg group as compared with the placebo group was −73.7% (95% CI, −94.6 to −52.8) and between the 50-mg group as compared with the placebo group was −65.5% (95% CI, −82.6 to −48.3). By 53 weeks, 11 episodes of acute pancreatitis had occurred in the placebo group, and 1 episode had occurred in each olezarsen group (rate ratio [pooled olezarsen groups vs. placebo], 0.12; 95% CI, 0.02 to 0.66). Adverse events of moderate severity that were considered by a trial investigator at the site to be related to the trial drug or placebo occurred in 4 patients in the 80-mg olezarsen group.ConclusionsIn patients with familial chylomicronemia syndrome, olezarsen may represent a new therapy to reduce plasma triglyceride levels. (Funded by Ionis Pharmaceuticals; Balance ClinicalTrials.gov number, NCT04568434.)
Influenza Vaccine Immune Response in Patients With High-Risk Cardiovascular Disease
Authors: Alexander Peikert, Brian L. Claggett, Jacob A. Udell, Jacob Joseph, Sheila M. Hegde, KyungMann Kim, Lu Mao, Tuo Wang, Thomas C. Havighurst, Michael E. Farkouh, Deepak L. Bhatt, Matthew C. Tattersall, Lawton S. Cooper, Scott D. Solomon, Orly Vardeny
Journal: JAMA Cardiology (2024)

High-dose trivalent compared with standard-dose quadrivalent influenza vaccine did not significantly reduce all-cause mortality or cardiopulmonary hospitalizations in patients with high-risk cardiovascular disease in the INVESTED trial. Whether humoral immune response to influenza vaccine is associated with clinical outcomes is unknown.
Plozasiran (ARO-APOC3) for Severe Hypertriglyceridemia
Authors: Daniel Gaudet, Denes Pall, Gerald F. Watts, Stephen J. Nicholls, Robert S. Rosenson, Karen Modesto, Javier San Martin, Jennifer Hellawell, Christie M. Ballantyne
Journal: JAMA Cardiology (2024)

Severe hypertriglyceridemia (sHTG) confers increased risk of atherosclerotic cardiovascular disease (ASCVD), nonalcoholic steatohepatitis, and acute pancreatitis. Despite available treatments, persistent ASCVD and acute pancreatitis-associated morbidity from sHTG remains.
History of smallpox vaccination and marked clinical expression of mpox among cases notified in France from May to July 2022
Authors: Catarina Krug, Emilie Chazelle, Arnaud Tarantola, Harold Noël, Guillaume Spaccaferri, Isabelle Parent du Châtelet, Laura Zanetti, Hana Lahbib, Myriam Fayad, Florence Lot, Henriette De Valk, Didier Che, Bruno Coignard, Alexandra Mailles, Anne-Sophie Barret, Abdoul Djamal Moukaila, Ami Yamada, Amina Ahamadi, Anne Bernadou, Anne Guinard, Anne Laporte, Asma Saidouni Oulebsir, Audrey Diavolo, Aurélien Zhu-Soubise, Axel Grellier, Brigitte Demma, Carine Grenier, Carole Dagorne, Catherine Aventini, Catherine Bec, Céline Erieau, Christine Meffre, Christine Pere, Clara Leyendecker, Damien Ott, Diane François, Elise Brottet, Elsa Balleydier, Erica Fougere, Florence Didier, Florence Lot, Frédérique Dorleans, Gabriel Yubero, Jacques El Kouri, Jean-Loup Chappert, Jean-Paul Guyonnet, Julien Berra, Laetitia Ali-Oicheih, Laure Petit-Made, Laura Reques, Laurence Marais, Lazare Agbahoungba, Leila Beikheira, Louise Luan, Lucie Sautron, Marie Barba-Vasseur, Marion Louault, Nathalie Bonnet, Nathalie Mathevet, Ndeye Fatou Sow, Olivier Glass, Patrick Baguet, Patrick Calen, Patrick Rolland, Philippe Reboud, Robin Le Barreau, Ronan Ollivier, Sander De Souza, Sabrina Fournier, Sophie Grellet, Ulviyya Alizada, Valerie Henry, Valérie Pontiès, Victorien Dachary, Yassoungo Silue, Yoann Mallet, Yvan Souares
Journal: Clinical Microbiology and Infection (2024)
Tissue fibroblasts are versatile immune regulators: An evaluation of their impact on the aging process
Authors: Antero Salminen, Kai Kaarniranta, Anu Kauppinen
Journal: Ageing Research Reviews (2024)

Fibroblasts are abundant stromal cells which not only control the integrity of extracellular matrix (ECM) but also act as immune regulators. It is known that the structural cells within tissues can establish an organ-specific immunity expressing many immune-related genes and closely interact with immune cells. In fact, fibroblasts can modify their immune properties to display both pro-inflammatory and immunosuppressive activities in a context-dependent manner. After acute insults, fibroblasts promote tissue inflammation although they concurrently recruit immunosuppressive cells to enhance the resolution of inflammation. In chronic pathological states, tissue fibroblasts, especially senescent fibroblasts, can display many pro-inflammatory and immunosuppressive properties and stimulate the activities of different immunosuppressive cells. In return, immunosuppressive cells, such as M2 macrophages and myeloid-derived suppressor cells (MDSC), evoke an excessive conversion of fibroblasts into myofibroblasts, thus aggravating the severity of tissue fibrosis. Single-cell transcriptome studies on fibroblasts isolated from aged tissues have confirmed that tissue fibroblasts express many genes coding for cytokines, chemokines, and complement factors, whereas they lose some fibrogenic properties. The versatile immune properties of fibroblasts and their close cooperation with immune cells indicate that tissue fibroblasts have a crucial role in the aging process and age-related diseases.
Comparative effectiveness of sacubitril/valsartan versus angiotensin‐converting enzyme inhibitors/angiotensin receptor blockers in patients with de novo heart failure with mildly reduced and preserved ejection fraction
Authors: Ankeet S. Bhatt, Muthiah Vaduganathan, Barada Prasad Jena, Sylwia Suminska, Carlos Eid, Rahul Khairnar, Gabriella Farries, Michele Senni
Journal: European Journal of Heart Failure (2024)
Real-World Experience and 36-Week Outcomes of Patients With Symptomatic Obstructive Hypertrophic Cardiomyopathy Treated With Mavacamten
Authors: Nosheen Reza, Anandkumar Dubey, Thomas Carattini, Amy Marzolf, Nicole Hornsby, Alejandro de Feria, Nadim Mahmud, Patricia Schuler, Anjali Tiku Owens
Journal: JACC Heart Failure (2024)
Personalized neoantigen vaccine and pembrolizumab in advanced hepatocellular carcinoma: a phase 1/2 trial
Authors: Mark Yarchoan, Edward J. Gane, Thomas U. Marron, Renzo Perales-Linares, Jian Yan, Neil Cooch, Daniel H. Shu, Elana J. Fertig, Luciane T. Kagohara, Gabor Bartha, Josette Northcott, John Lyle, Sarah Rochestie, Joann Peters, Jason T. Connor, Elizabeth M. Jaffee, Ildiko Csiki, David B. Weiner, Alfredo Perales-Puchalt, Niranjan Y. Sardesai
Journal: Nature Medicine (2024)

Abstract Programmed cell death protein 1 (PD-1) inhibitors have modest efficacy as a monotherapy in hepatocellular carcinoma (HCC). A personalized therapeutic cancer vaccine (PTCV) may enhance responses to PD-1 inhibitors through the induction of tumor-specific immunity. We present results from a single-arm, open-label, phase 1/2 study of a DNA plasmid PTCV (GNOS-PV02) encoding up to 40 neoantigens coadministered with plasmid-encoded interleukin-12 plus pembrolizumab in patients with advanced HCC previously treated with a multityrosine kinase inhibitor. Safety and immunogenicity were assessed as primary endpoints, and treatment efficacy and feasibility were evaluated as secondary endpoints. The most common treatment-related adverse events were injection-site reactions, observed in 15 of 36 (41.6%) patients. No dose-limiting toxicities or treatment-related grade ≥3 events were observed. The objective response rate (modified intention-to-treat) per Response Evaluation Criteria in Solid Tumors 1.1 was 30.6% (11 of 36 patients), with 8.3% (3 of 36) of patients achieving a complete response. Clinical responses were associated with the number of neoantigens encoded in the vaccine. Neoantigen-specific T cell responses were confirmed in 19 of 22 (86.4%) evaluable patients by enzyme-linked immunosorbent spot assays. Multiparametric cellular profiling revealed active, proliferative and cytolytic vaccine-specific CD4 + and CD8 + effector T cells. T cell receptor β-chain (TCRβ) bulk sequencing results demonstrated vaccination-enriched T cell clone expansion and tumor infiltration. Single-cell analysis revealed posttreatment T cell clonal expansion of cytotoxic T cell phenotypes. TCR complementarity-determining region cloning of expanded T cell clones in the tumors following vaccination confirmed reactivity against vaccine-encoded neoantigens. Our results support the PTCV’s mechanism of action based on the induction of antitumor T cells and show that a PTCV plus pembrolizumab has clinical activity in advanced HCC. ClinicalTrials.gov identifier: NCT04251117 .
Effect of Gamification, Financial Incentives, or Both to Increase Physical Activity Among Patients at High Risk of Cardiovascular Events: The BE ACTIVE Randomized Controlled Trial
Authors: Alexander C. Fanaroff, Mitesh S. Patel, Neel Chokshi, Samantha Coratti, David Farraday, Laurie Norton, Charles Rareshide, Jingsan Zhu, Tamar Klaiman, Julia E. Szymczak, Louise B. Russell, Dylan S. Small, Kevin G.M. Volpp
Journal: Circulation (2024)

BACKGROUND: Physical activity is associated with a lower risk of major adverse cardiovascular events, but few individuals achieve guideline-recommended levels of physical activity. Strategies informed by behavioral economics increase physical activity, but their longer-term effectiveness is uncertain. We sought to determine the effect of behaviorally designed gamification, loss-framed financial incentives, or their combination on physical activity compared with attention control over 12-month intervention and 6-month postintervention follow-up periods. METHODS: Between May 2019 and January 2024, participants with clinical atherosclerotic cardiovascular disease or a 10-year risk of myocardial infarction, stroke, or cardiovascular death of ≥7.5% by the Pooled Cohort equation were enrolled in a pragmatic randomized clinical trial. Participants received a wearable device to track daily steps, established a baseline, selected a step goal increase, and were randomly assigned to control (n=151), behaviorally designed gamification (n=304), loss-framed financial incentives (n=302), or gamification+financial incentives (n=305). The primary outcome of the trial was the change in mean daily steps from baseline through the 12-month intervention period. RESULTS: A total of 1062 patients (mean±SD age, 67±8; 61% female; 31% non-White) were enrolled. Compared with control subjects, participants had significantly greater increases in mean daily steps from baseline during the 12-month intervention in the gamification arm (adjusted difference, 538.0 [95% CI, 186.2–889.9]; P =0.0027), financial incentives arm (adjusted difference, 491.8 [95% CI, 139.6–844.1]; P =0.0062), and gamification+financial incentives arm (adjusted difference, 868.0 [95% CI, 516.3–1219.7]; P &lt;0.0001). During the 6-month follow-up, physical activity remained significantly greater in the gamification+financial incentives arm than in the control arm (adjusted difference, 576.2 [95% CI, 198.5–954]; P =0.0028), but it was not significantly greater in the gamification (adjusted difference, 459.8 [95% CI, 82.0–837.6]; P =0.0171) or financial incentives (adjusted difference, 327.9 [95% CI, −50.2 to 706]; P =0.09) arms after adjustment for multiple comparisons. CONCLUSIONS: Behaviorally designed gamification, loss-framed financial incentives, and the combination of both increased physical activity compared with control over a 12-month intervention period, with the largest effect in gamification+financial incentives. These interventions could be a useful component of strategies to reduce cardiovascular risk in high-risk patients. REGISTRATION: URL: https://clinicaltrials.gov ; Unique Identifier: NCT03911141.
Olezarsen for Hypertriglyceridemia in Patients at High Cardiovascular Risk
Authors: Brian A Bergmark, Nicholas A Marston, Thomas A Prohaska, Veronica J Alexander, André Zimerman, Filipe A Moura, Sabina A Murphy, Erica L Goodrich, Shuanglu Zhang, Daniel Gaudet, Ewa Karwatowska-Prokopczuk, Sotirios Tsimikas, Robert P Giugliano, Marc S Sabatine
Journal: New England Journal of Medicine (2024)

Reducing the levels of triglycerides and triglyceride-rich lipoproteins remains an unmet clinical need. Olezarsen is an antisense oligonucleotide targeting messenger RNA for apolipoprotein C-III (APOC3), a genetically validated target for triglyceride lowering.
Clinical Benefit and Regulatory Outcomes of Cancer Drugs Receiving Accelerated Approval
Authors: Ian T. T. Liu, Aaron S. Kesselheim, Edward R. Scheffer Cliff
Journal: JAMA (2024)

The US Food and Drug Administration's (FDA) accelerated approval pathway allows approval of investigational drugs treating unmet medical needs based on changes to surrogate measures considered "reasonably likely" to predict clinical benefit. Postapproval clinical trials are then required to confirm whether these drugs offer clinical benefit.
Randomized Evaluation of a Remote Management Program to Improve Guideline-Directed Medical Therapy: The DRIVE Trial
Authors: Alexander J. Blood, Lee-Shing Chang, Shahzad Hassan, Jacqueline Chasse, Gretchen Stern, Daniel Gabovitch, David Zelle, Caitlin Colling, Samuel J. Aronson, Christian Figueroa, Emma Collins, Ryan Ruggiero, Emily Zacherle, Joshua Noone, Carey Robar, Jorge Plutzky, Thomas A. Gaziano, Christopher P. Cannon, Deborah J. Wexler, Benjamin M. Scirica
Journal: Circulation (2024)

Several SGLT2i (sodium-glucose transport protein 2 inhibitors) and GLP1-RA (glucagon-like peptide-1 receptor agonists) reduce cardiovascular events and improve kidney outcomes in patients with type 2 diabetes; however, utilization remains low despite guideline recommendations.
Clinical Impact of Routine Assessment of Patient-Reported Health Status in Heart Failure Clinic
Authors: Alexander T. Sandhu, Jamie Calma, Megan Skye, Neil Kalwani, Jimmy Zheng, Jessica Schirmer, Natasha Din, Cati Brown Johnson, Anshal Gupta, Roy Lan, Brian Yu, John A. Spertus, Paul A. Heidenreich
Journal: Circulation (2024)

BACKGROUND: The impact of routine clinic use of patient-reported outcome (PRO) measures on clinical outcomes in patients with heart failure (HF) has not been well-characterized. We tested if clinic-based use of a disease-specific PRO improves patient-reported quality of life at 1 year. METHODS: The PRO-HF trial (Patient-Reported Outcome Measurement in Heart Failure Clinic) was an open-label, parallel, patient-level randomized clinical trial of routine PRO assessment or usual care at an academic HF clinic between August 30, 2021, and June 30, 2022, with 1 year of follow-up. In the PRO assessment arm, participants completed the Kansas City Cardiomyopathy Questionnaire-12 (KCCQ-12) at each HF clinic visit, and results were shared with their treating clinician. The usual care arm completed the KCCQ-12 at randomization and 1 year later, which was not shared with the treating clinician. The primary outcome was the KCCQ-12 overall summary score (OSS) between 12 and 15 months after randomization. Secondary outcomes included domains of the KCCQ-12, hospitalization and emergency department visit rates, HF medication therapy, clinic visit frequency, and testing rates. RESULTS: Across 17 clinicians, 1248 participants were enrolled and randomized to PRO assessment (n=624) or usual care (n=624). The median age was 63.9 years (interquartile range [IQR], 51.8–72.8), 38.9% were women, and the median baseline KCCQ-12 OSS was 82.3 (IQR, 58.3–94.8). Final KCCQ-12 (available in 87.9% of the PRO arm and 85.1% in usual care; P =0.16) median OSS were 87.5 (IQR, 68.8–96.9) in the PRO arm and 87.6 (IQR, 69.7–96.9) in the usual care arm with a baseline-adjusted mean difference of 0.2 ([95% CI, −1.7 to 2.0]; P =0.85). The results were consistent across prespecified subgroups. A post hoc analysis demonstrated a significant interaction with greater benefit among participants with a baseline KCCQ-12 OSS of 60 to 80 but not in less or more symptomatic participants. No significant differences were found in 1-year mortality, hospitalizations, emergency department visits, medication therapy, clinic follow-up, or testing rates between arms. CONCLUSIONS: Routine PRO assessment in HF clinic visits did not impact patient-reported quality of life or other clinical outcomes. Alternate strategies and settings for embedding PROs into routine clinical care should be tested. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT04164004.
Radical surgical resection with molecular margins is associated with improved survival in IDH wild-type glioblastoma
Authors: Elie Massaad, William J Smith, Joseph Bradley, Eric Esposito, Mihir Gupta, Evan Burns, Ryan Burns, José K Velarde, Inka K Berglar, Rajiv Gupta, Maria Martinez-Lage, Jorg Dietrich, Jochen K Lennerz, Gavin P Dunn, Pamela S Jones, Bryan D Choi, Albert E Kim, Matthew Frosch, Fred G Barker, William T Curry, Bob S Carter, Brian V Nahed, Daniel P Cahill, Ganesh M Shankar
Journal: Neuro-Oncology (2024)

Abstract Background Survival is variable in patients with glioblastoma IDH wild-type (GBM), even after comparable surgical resection of radiographically detectable disease, highlighting the limitations of radiographic assessment of infiltrative tumor anatomy. The majority of postsurgical progressive events are failures within 2 cm of the resection margin, motivating supramaximal resection strategies to improve local control. However, which patients benefit from such radical resections remains unknown. Methods We developed a predictive model to identify which IDH wild-type GBMs are amenable to radiographic gross-total resection (GTR). We then investigated whether GBM survival heterogeneity following GTR is correlated with microscopic tumor burden by analyzing tumor cell content at the surgical margin with a rapid qPCR-based method for detection of TERT promoter mutation. Results Our predictive model for achievable GTR, developed on retrospective radiographic and molecular data of GBM patients undergoing resection, had an area under the curve of 0.83, sensitivity of 62%, and specificity of 90%. Prospective analysis of this model in 44 patients found that 89% of patients were correctly predicted to achieve a residual volume (RV) &amp;lt; 4.9cc. Of the 44 prospective patients undergoing rapid qPCR TERT promoter mutation analysis at the surgical margin, 7 had undetectable TERT mutation, of which 5 also had a GTR (RV &amp;lt; 1cc). In these 5 patients at 30 months follow-up, 75% showed no progression, compared to 0% in the group with TERT mutations detected at the surgical margin (P = .02). Conclusions These findings identify a subset of patients with GBM that may derive local control benefits from radical resection to undetectable molecular margins.
Demonstrated efficacy and mechanisms of sensitivity of ONC201: H3K27M-mutant diffuse midline glioma in the spotlight
Authors: Isabel Arrillaga-Romany, Julie J Miller
Journal: Neuro-Oncology (2024)

Journal Article Corrected proof Demonstrated efficacy and mechanisms of sensitivity of ONC201: H3K27M-mutant diffuse midline glioma in the spotlight Get access Isabel Arrillaga-Romany, Isabel Arrillaga-Romany Center for Neuro-Oncology, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA Corresponding Author: Isabel Arrillaga-Romany, MD, PhD, Center for Neuro-Oncology, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA (iarrillaga@mgh.harvard.edu). https://orcid.org/0000-0001-5951-1225 Search for other works by this author on: Oxford Academic PubMed Google Scholar Julie J Miller Julie J Miller Center for Neuro-Oncology, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USATranslational Neuro-Oncology Laboratory, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA Search for other works by this author on: Oxford Academic PubMed Google Scholar Neuro-Oncology, noae051, https://doi.org/10.1093/neuonc/noae051 Published: 08 April 2024 Article history Corrected and typeset: 08 April 2024 Published: 08 April 2024
Perioperative versus adjuvant S-1 plus oxaliplatin chemotherapy for stage II/III resectable gastric cancer (RESONANCE): a randomized, open-label, phase 3 trial
Authors: Xinxin Wang, Canrong Lu, Bo Wei, Shuo Li, Ziyu Li, Yingwei Xue, Yingjiang Ye, Zhongtao Zhang, Yihong Sun, Han Liang, Kai Li, Linghua Zhu, Zhichao Zheng, Yanbing Zhou, Yulong He, Fei Li, Xin Wang, Pin Liang, Hua Huang, Guoli Li, Xian Shen, Jiafu Ji, Yun Tang, Zekuan Xu, Lin Chen
Journal: Journal of Hematology & Oncology (2024)

Abstract Evidence from Europe shows that perioperative chemotherapy may be beneficial for the treatment of locally advanced gastric cancer, but reliable and robust data is lacking. To rectify this, the phase 3 RESONANCE trial investigated the efficacy and safety of S-1 plus oxaliplatin (SOX) as a perioperative chemotherapy regimen for gastric cancer. This randomized, open-label trial enrolled patients from 19 medical centers with stage II/III resectable gastric cancer who were centrally randomly assigned to either perioperative chemotherapy (PC) arm or adjuvant chemotherapy (AC) arm. Patients in the PC arm received two to four cycles of SOX followed by surgery and four to six cycles of SOX. Patients in the AC arm received upfront surgery and eight cycles of SOX. 386 patients in each group were enrolled and 756 (382 in PC and 374 in AC) were included in the mITT population. The three-year DFS rate was 61.7% in the PC arm and 53.8% in the AC arm (log-rank p = 0.019). The R0 resection rate in the PC arm was significantly higher than that in the AC arm (94.9% vs. 83.7%, p &lt; 0.0001). There was no difference between two arms in surgical outcomes or postoperative complications. Safety-related data were like the known safety profile. In conclusion, from a clinical perspective, this trial indicated a trend towards higher three-year disease-free survival rate with perioperative SOX in stage II/III resectable gastric cancer with well-tolerated toxicity compared to adjuvant SOX, which might provide a theoretical basis for applying perioperative SOX in advanced gastric cancer patients. (ClinicalTrials.gov NCT01583361)