tbuckley/cabot-search huggingface dataset:
Plasma Proteomics of Exercise Blood Pressure and Incident Hypertension
Authors: Prashant Rao, Michelle. J. Keyes, Michael Y. Mi, Jacob L. Barber, Usman A. Tahir, Shuliang Deng, Clary B. Clish, Dongxiao Shen, Laurie. A. Farrell, James G. Wilson, Yan Gao, Wondwosen K. Yimer, Lynette Ekunwe, Michael E. Hall, Paul M. Muntner, Xiuqing Guo, Kent D. Taylor, Russell P. Tracy, Stephen S. Rich, Jerome I. Rotter, Vanessa Xanthakis, Ramachandran S. Vasan, Claude Bouchard, Mark A. Sarzynski, Robert E. Gerszten, Jeremy M. Robbins
Journal: JAMA Cardiology (2024)

Blood pressure response during acute exercise (exercise blood pressure [EBP]) is associated with the future risk of hypertension and cardiovascular disease (CVD). Biochemical characterization of EBP could inform disease biology and identify novel biomarkers of future hypertension.
Coronary In-Stent Restenosis Treated With Paclitaxel-Coated Balloon vs Uncoated Balloon—Reply
Authors: Robert W. Yeh, Ajay J. Kirtane
Journal: JAMA (2024)

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Skin Manifestations of VEXAS Syndrome and Associated Genotypes
Authors: Isabella J. Tan, Marcela A. Ferrada, Serene Ahmad, Alice Fike, Kaitlin A. Quinn, Emma M. Groarke, David B. Beck, Jill Allbritton, Leslie Castelo-Soccio, Neal S. Young, Bhavisha A. Patel, Peter C. Grayson, Edward W. Cowen
Journal: JAMA Dermatology (2024)

Importance VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome is a newly defined genetic disease with an estimated prevalence of 1 in 4269 men older than 50 years and is marked by systemic inflammation, progressive bone marrow failure, and inflammatory cutaneous manifestations. Objective To define the spectrum of cutaneous manifestations in VEXAS syndrome and the association of these findings with clinical, genetic, and histological features. Design, Setting, and Participants This observational cohort study included data from 112 patients who were diagnosed with VEXAS-defining genetic variants in UBA1 between 2019 and 2023. Data were collected from medical record review or from patients with VEXAS directly evaluated at the National Institutes of Health in Bethesda, Maryland. Main Outcomes and Measures To define the spectrum of cutaneous manifestations in VEXAS in association with genetic, histological, and other clinical findings. A secondary outcome was cutaneous response to treatment in VEXAS. Results Among the 112 patients (median [range] age, 69 [39-79] years; 111 [99%] male), skin involvement was common (93 [83%]), and the most frequent presenting feature of disease (68 [61%]). Of 64 histopathologic reports available from 60 patients, predominant skin histopathologic findings were leukocytoclastic vasculitis (23 [36%]), neutrophilic dermatosis (22 [34%]), and perivascular dermatitis (19 [30%]). Distinct pathogenic genetic variants were associated with specific cutaneous manifestations. The p.Met41Leu variant was most frequently associated with neutrophilic dermal infiltrates (14 of 17 patients [82%]), often resembling histiocytoid Sweet syndrome. In contrast, the p.Met41Val variant was associated with vasculitic lesions (11 of 20 patients [55%]) with a mixed leukocytic infiltrate (17 of 20 patients [85%]). Oral prednisone improved skin manifestations in 67 of 73 patients (92%). Patients with VEXAS treated with anakinra frequently developed severe injection-site reactions (12 of 16 [75%]), including ulceration (2 of 12 [17%]) and abscess formation (1 of 12 [8%]). Conclusions and Relevance Results of this cohort study show that skin manifestations are a common and early manifestation of VEXAS syndrome. Genetic evaluation for VEXAS should be considered in older male patients with cutaneous vasculitis, neutrophilic dermatoses, or chondritis. Awareness of VEXAS among dermatologists is critical to facilitate early diagnosis.
A Novel Approach to Quantify Heterogeneity of Intrahepatic Cholangiocarcinoma: the Hidden-Genome Classifier
Authors: Yi Song, Thomas Boerner, Esther Drill, Paul Shin, Sandeep Kumar, Carlie Sigel, Andrea Cercek, Nancy Kemeny, Ghassan Abou-Alfa, Christine Iacobuzio-Donahue, Darren Cowzer, Nikolaus Schultz, Henry Walch, Vinod Balachandran, Bas Groot Koerkamp, Peter Kingham, Kevin Soares, Alice Wei, Michael D’Angelica, Jeffrey Drebin, Rohit Chandwani, James J. Harding, William Jarnagin
Journal: Clinical Cancer Research (2024)

Abstract Purpose: Intrahepatic cholangiocarcinoma (IHC) is a heterogeneous tumor. The hidden-genome classifier, a supervised machine learning–based algorithm, was used to quantify tumor heterogeneity and improve classification. Experimental Design: A retrospective review of 1,370 patients with IHC, extrahepatic cholangiocarcinoma (EHC), gallbladder cancer (GBC), hepatocellular carcinoma (HCC), or biphenotypic tumors was conducted. A hidden-genome model classified 527 IHC based on genetic similarity to EHC/GBC or HCC. Genetic, histologic, and clinical data were correlated. Results: In this study, 410 IHC (78%) had &amp;gt;50% genetic homology with EHC/GBC; 122 (23%) had &amp;gt;90% homology (“biliary class”), characterized by alterations of KRAS, SMAD4, and CDKN2A loss; 117 IHC (22%) had &amp;gt;50% genetic homology with HCC; and 30 (5.7%) had &amp;gt;90% homology (“HCC class”), characterized by TERT alterations. Patients with biliary- versus non-biliary-class IHC had median overall survival (OS) of 1 year (95% CI, 0.77, 1.5) versus 1.8 years (95% CI, 1.6, 2.0) for unresectable disease and 2.4 years (95% CI, 2.1, NR) versus 5.1 years (95% CI, 4.8, 6.9) for resectable disease. Large-duct IHC (n = 28) was more common in the biliary class (n = 27); the HCC class was composed mostly of small-duct IHC (64%, P = 0.02). The hidden genomic classifier predicted OS independent of FGFR2 and IDH1 alterations. By contrast, the histology subtype did not predict OS. Conclusions: IHC genetics form a spectrum with worse OS for tumors genetically aligned with EHC/GBC. The classifier proved superior to histologic subtypes for predicting OS independent of FGFR2 and IDH1 alterations. These results may explain the differential treatment responses seen in IHC and may direct therapy by helping stratify patients in future clinical trials.
A phase 3 global study of telisotuzumab vedotin versus docetaxel in previously treated patients with c-Met 0verexpressing, <i>EGFR</i> wildtype, locally advanced/metastatic nonsquamous NSCLC (TeliMET NSCLC-01).
Authors: Shun Lu, Jonathan W. Goldman, JUNKO TANIZAKI, Hiroaki Akamatsu, Summer Xia, Christine Ratajczak, Martha Li, Ellen Bolotin, Jabed Seraj, Antonio Lugini
Journal: Journal of Clinical Oncology (2024)

TPS8656 Background: Non-small cell lung cancer (NSCLC) encompasses over two-thirds of lung cancer diagnoses, most presenting as advanced disease. c-Met (MET protein) is overexpressed in NSCLC. In this study, we investigate telisotuzumab vedotin (Teliso-V), a first-in-class antibody-drug conjugate composed of a c-Met–targeting antibody (telisotuzumab) and a microtubule polymerization inhibitor (cytotoxin monomethyl auristatin E). Interim efficacy analysis of the Phase 2 LUMINOSITY study (NCT03539536) of Teliso-V monotherapy showed an objective response rate (ORR) of 37% (95% CI: 24–51) in previously treated patients (pts) with c-Met overexpressing epidermal growth factor receptor (EGFR) wildtype (WT) nonsquamous NSCLC and 52% (95% CI: 31–73) in the high c-Met overexpressing group (Camidge DR et al. J Clin Oncol. 2022;40(16_suppl):9016). Methods: This randomized, open-label, global Phase 3 study (NCT04928846) evaluates the efficacy, safety, pharmacokinetics, and pharmacodynamics of Teliso-V monotherapy compared with docetaxel in pts with locally advanced/metastatic c-Met overexpressing EGFR WT nonsquamous NSCLC who have progressed on prior therapy. Enrollment began in May 2022. To be eligible across global sites, pts must be ≥18 years old with c-Met overexpressing (ie, ≥25% tumor cells at 3+ intensity by IHC assay [anti-MET clone SP44; Roche Tissue Diagnostics]) locally advanced/metastatic EGFR WT NSCLC, with ECOG score ≤1. Pts must have progressed on at least one prior line of therapy, which can include no more than one line of prior chemotherapy, and must be naïve to c-Met–targeted antibodies and docetaxel. Target enrollment is 698 pts. Pts will be randomized 1:1 to Teliso-V (1.9 mg/kg every 2 weeks) and docetaxel (control, 75 mg/m 2 every 3 weeks). Treatment continues until disease progression or discontinuation criteria are met. Co-primary endpoints are progression-free survival by independent central review and overall survival. Secondary endpoints include ORR, duration of response, and patient-reported outcomes. Safety, adverse events (AEs), drug discontinuation or dosing modification due to AEs, and tolerability will be assessed. Previously presented at the 2023 ESMO Congress, Final Publication Number: 1501TiP, Antonio Lugini et al. - Reused with permission. Clinical trial information: NCT04928846 .
Novel RNA-nanoparticle vaccine for the treatment of early melanoma recurrence following adjuvant anti-PD-1 antibody therapy.
Authors: Bently Patrick Doonan, Christiana M. Shaw, Ji-Hyun Lee, Eugenio Simon Manso, Hector Mendez-Gomez, Christina Von Roemeling, Duane Anthony Mitchell, Elias Sayour, Thomas J. George
Journal: Journal of Clinical Oncology (2024)

TPS9609 Background: Melanoma is a major public health concern with an anticipated increase in prevalence and incidence in the coming years. Early detection and surgical management remain the mainstay of treatment of early-stage disease and use of adjuvant immunotherapy has improved outcomes for patients with more aggressive (IIB-IIC) local disease or those with lymph node involvement (IIIA-IIID). Based on the tolerability and efficacy across subjects with both BRAF mutated and wildtype melanoma anti-PD1 (aPD1) therapy with either nivolumab or pembrolizumab are considered first line treatment in this setting. Adjuvant aPD1 therapy has significant improvement in relapse free survival (RFS) yet 25-30% of subjects will have disease recurrence within 1 year of surgery. When disease recurs, the response rate to immunotherapy is significantly reduced, re-challenged with aPD1 therapy has shown an Objective Response Rate (ORR) of zero and a marginally better response to CTLA-4 blockade. Novel strategies are needed for this at-risk population with early aPD1 resistance. To address this need we have developed a novel multi-lamellar lipid-nanoparticle complexed with total-tumor derived mRNA administered intravenously to restore responsiveness to aPD1 through reprogramming the tumor microenvironment (TME) bridging an innate and adaptive immune response. We have designed a clinical trial in which patients who progress on while on aPD1 therapy or within 6 months of therapy will have tumor sampled and a personalized lipid-nanoparticle vaccine generated. This vaccine is then administered IV for a total of 3 doses spanning 6 weeks to reprogram the TME and restore response to aPD1 which will be resumed on completion of vaccine series. This phase I study will assess initial feasibility and safety of vaccine generation, utilize ctDNA surveillance as early detection of adjuvant failure, and provide essential biologic information on immunotherapy resistance to aPD1 therapy. Methods: We have designed a modified 3+3 phase I clinical trial that will enroll subjects who have evidence of progressive disease (PD) by ctDNA and/or RECIST 1.1 criteria while receiving adjuvant aPD1 therapy, or those who progress within 6 months of completion of treatment for stage IIB-IIID melanoma. The goal of this study is to assess safety, tolerability, and feasibility of tumor specific RNA-LPs. Important biological correlates will also be collected and analyzed including tumor tissue sampling at initial time of checkpoint resistance and following vaccination series to identify key changes to the TME and tumor induced by lipid-nanoparticle vaccine administration. Clinical trial information: NCT05264974 .
FURTHER: A global study to evaluate furmonertinib in patients with EGFR mutant NSCLC including uncommon EGFR mutations (FURMO-002).
Authors: Xiuning Le, Alexander I. Spira, Shirish M. Gadgeel, Jonathan W. Riess, Yan Yu, Yanqiu Zhao, Ying Cheng, Oscar Juan-Vidal, Bo Gao, Kiyotaka Yoh, Martin Forster, Satoru Kitazono, Hidetoshi Hayashi, David Planchard, Yong Jiang, Nichole Baio, Marcin Kowanetz, William Leung, Jerry Y. Hsu, Jie Wang
Journal: Journal of Clinical Oncology (2024)

TPS8666 Background: Furmonertinib (AST2818) is an oral, highly brain-penetrant, and broadly active mutation-selective epidermal growth factor receptor ( EGFR) inhibitor engineered for broad activity and selectivity across EGFRmutations (mts) (1). Furmonertinib is approved in China for first-line advanced NSCLC with EGFR Ex19del or L858R mts based on the progression-free survival benefit observed in the Phase 3 study versus gefitinib (FURLONG). Furmonertinib has also demonstrated promising interim efficacy and safety in patients (pts) with NSCLC harboring EGFR exon 20 insertion (ex20ins) mts with a confirmed overall response rate (ORR) of 78.6% (n=28) by blinded independent central review (BICR) and a preliminary median duration of response (DoR) of 15.2 months in the front-line setting (FAVOUR study; see Han et al., WCLC 2023). Furmonertinib recently obtained FDA Breakthrough Therapy Designation for the treatment of pts with advanced NSCLC with EGFR ex20ins mts. P-loop and αC-helix Compressing (PACC) mts represent another subset of uncommon EGFR mts (2) that are similar to ex20ins mts in narrowing the drug-binding pocket; including G719X, S768I, E709X, L747X, V774M. Preclinical data indicating that furmonertinib is potent in models harboring EGFR PACC mts Developing efficacious, well-tolerated, and CNS-penetrant medicines for NSCLC pts with EGFR ex20ins mts and PACC mts remains an unmet need. Methods: FURTHER (FURMO-002) is the first global trial evaluating furmonertinib in NSCLC pts with EGFR and HER2 mts in North America, Europe, and the Asia-Pacific. FURTHER is a phase 1b, open-label, multicenter study in which pts will be treated orally with furmonertinib daily. For Stage 1 dose-escalation, the primary endpoint is incidence and severity of adverse events, including dose limiting toxicities and has been completed. For Stage 2 dose expansion, approximately 120 pts will be enrolled across 4 expansion cohorts. Stage 2 Cohorts 1-3 dose expansion cohorts will enroll pts with previously treated, locally advanced or metastatic NSCLC pts with either EGFR ex20ins mts, HER2 ex20ins mts, or EGFR activating mts, respectively. Cohorts 1-3 allow enrollment of pts with prior EGFR or HER2-directed therapy. Stage 2 Cohort 4 will enroll EGFR TKI-naïve NSCLC pts with EGFR PACC mts. Key inclusion criteria include documented EGFR or HER2 mts by local testing and measurable disease per RECIST v1.1. Stage 2 primary endpoint is ORR using RECIST v1.1. Key secondary endpoints include progression-free survival and overall survival. Stage 2 enrollment is ongoing. 1. Musib et al., NACLC 2022. 2. Robichaux et al., 2021. Clinical trial information: NCT05364073 .
REZILIENT3: Phase 3 study of zipalertinib plus chemotherapy in patients with previously untreated, advanced nonsquamous non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (<i>EGFR</i>) exon 20 insertions (ex20ins) mutations.
Authors: Helena Alexandra Yu, Benjamin Besse, Makoto Nishio, Ying Cheng, Li Wei, Volker Wacheck, John Heymach
Journal: Journal of Clinical Oncology (2024)

TPS8671 Background: Despite recent advances, tolerable and effective treatments for patients with NSCLC harboring EGFR ex20ins mutations are needed, particularly in the first-line setting, where platinum-based chemotherapy remains the standard of care. Zipalertinib (CLN-081/TAS6417), an oral tyrosine kinase inhibitor (TKI) of EGFR with broad activity against EGFR mutations, showed encouraging antitumor activity in heavily pretreated patients with EGFR ex20ins–mutant NSCLC, leading to ‘Breakthrough Therapy’ designation by the U.S. Food and Drug Administration in January 2022. Data suggest that combining EGFR TKIs with chemotherapy can improve antitumor efficacy versus chemotherapy or TKI treatment alone in patients with EGFR-mutated nonsquamous NSCLC. REZILIENT3 is a pivotal phase 3 study designed to compare the efficacy and safety of zipalertinib plus first-line standard-of-care platinum-based chemotherapy versus chemotherapy alone in previously untreated patients with nonsquamous NSCLC harboring EGFR ex20ins mutations. Methods: This randomized, controlled, open-label, phase 3 study (NCT05973773) will be conducted in two parts. Part A (safety lead-in) will confirm the safety of zipalertinib 100 mg twice daily as the recommended dose in combination with chemotherapy in patients with locally advanced or metastatic nonsquamous NSCLC harboring uncommon EGFRmutations. In Part B (randomized part), patients with EGFR ex20ins mutations and at least one measurable lesion (per Response Evaluation Criteria in Solid Tumours, version 1.1) will be randomized 1:1 to zipalertinib plus chemotherapy or chemotherapy alone, stratified by Eastern Cooperative Oncology Group performance status (0/1), brain metastases (yes/no), and geography (Asia/rest of world). Zipalertinib will be administered orally at a starting dose of 100 mg twice daily (pending confirmation in Part A). Chemotherapy (pemetrexed 500 mg/m² plus cisplatin 75 mg/m² or carboplatin area under the curve 5 mg/mL/min) will be administered intravenously on Day 1 of each cycle (carboplatin/cisplatin for four cycles). The primary objective in Part A is safety and tolerability. In Part B, the primary objective is efficacy; progression-free survival assessed by blinded independent central review is the primary endpoint. Secondary endpoints include overall survival, investigator-assessed progression-free survival, objective response rate, duration of response, disease control rate, safety, intracranial efficacy endpoints, and quality of life. Part A is anticipated to enroll between 6 and 12 patients, while Part B is estimated to enroll approximately 300 patients. Enrollment commenced in June 2023. Clinical trial information: NCT05973773 .
TRICK-MCC: A proof-of-concept, investigator-initiated study of combination therapy with anti–PD-1, anti–LAG-3, and anti–TIM-3 in participants with advanced or metastatic PD-(L)1 refractory Merkel cell carcinoma.
Authors: Natalie J. Miller, Grete Ambrazeviciute, Wenwen Chen, Sumia N Dakhil, Erica Gaylord, Evan Thomas Hall, Julia Majovski, Zachary Herrin, Samantha Kiriluk, Paul Nghiem, Vivian Nguyen, Andrea Perdue, Thomas Pulliam, Lisa May Ling Tachiki, Joshua Veatch, Shailender Bhatia
Journal: Journal of Clinical Oncology (2024)

TPS9618 Background: Merkel cell carcinoma (MCC) is an aggressive and highly immunogenic skin cancer often associated with the Merkel cell polyomavirus (MCPyV). Immune checkpoint inhibition (ICI) via PD-(L)1 blockade can promote durable responses among patients with metastatic MCC, yet &gt;50% of MCC patients experience disease progression. There is an unmet need for effective treatment options for these patients. One possible strategy to overcome primary and secondary resistance in PD-(L)1 refractory MCC is concurrent targeting of multiple immune checkpoints to facilitate reversal of chronic T cell exhaustion. Based on our preliminary data revealing high expression of PD-1, LAG-3 and TIM-3 on MCC-specific CD8 T cells, which appear to increase upon clinical disease progression in the context of treatment with PD-(L)1 blockade, we hypothesize that concurrent blockade of PD-1, LAG-3 and TIM-3 will overcome immune evasion in patients with PD-(L) refractory MCC. Methods: TRICK-MCC (Triple Immune Checkpoint Inhibition in MCC) is an investigator initiated, Phase 2 clinical trial investigating concurrent treatment with anti-PD-1 (retifanlimab), anti-LAG3 (INCAGN02385) and anti-TIM-3 (INCAGN02390) in patients with advanced/metastatic MCC that has progressed after treatment with anti-PD-(L)1. Target enrollment is 20 patients total, with 5 patients enrolled as of Jan 2024. Patients will receive anti-PD-1 q4w and anti-TIM-3 and LAG-3 q2w for up to 24 weeks (Induction Phase) followed by all drugs q6w (Maintenance Phase). Treatment will end 2 years after starting the study drugs, or upon disease progression, unacceptable toxicity, or study withdrawal. Primary objective is objective response rate (ORR). Secondary objectives are duration of response, progression free survival, overall survival, and incidence and severity of adverse events. Interim analysis will be done after 10 patients have been enrolled and followed sufficiently long to assess ORR. An observed ORR of 25%will be considered as clinically meaningful in this population with no reliable standard treatments. Serial tumor biopsies and blood samples will be obtained in all patients, unless deemed unsafe or not feasible. Planned correlative studies aim to better characterize the prevalence and significance of cancer-specific T cell exhaustion (through rigorous study of MCPyV-specific T cells), the immunologic effects of triple ICI, and alternative mechanisms of PD-(L)1 resistance beyond T cell exhaustion in PD-(L)1 resistant tumors. We hope to gain insights that are broadly applicable to solid tumor immunotherapy. Clinical trial information: NCT06056895 .
Author Correction: Impact of a deep learning sepsis prediction model on quality of care and survival
Authors: Aaron Boussina, Supreeth P. Shashikumar, Atul Malhotra, Robert L. Owens, Robert El-Kareh, Christopher A. Longhurst, Kimberly Quintero, Allison Donahue, Theodore C. Chan, Shamim Nemati, Gabriel Wardi
Journal: npj Digital Medicine (2024)