tbuckley/cabot-search huggingface dataset:
Individual Variation in the Distribution of Apolipoprotein B Levels Across the Spectrum of LDL-C or Non–HDL-C Levels
Authors: Ahmed Sayed, Eric D. Peterson, Salim S. Virani, Allan D. Sniderman, Ann Marie Navar
Journal: JAMA Cardiology (2024)

Although apolipoprotein B (apoB) is a superior marker of lipid-related risk compared with low-density lipoprotein cholesterol (LDL-C), few data exist to translate the goals and thresholds from LDL-C to their apoB equivalent. In addition, although current American College of Cardiology/American Heart Association guidelines provide a relative indication for apoB measurement among individuals with hypertriglyceridemia, whether discordance is limited to those subgroups is unknown.
Validating Patient-Reported Outcome Measures in Dermatology
Authors: Zachary H. Hopkins, Lourdes Maria Perez-Chada
Journal: JAMA Dermatology (2024)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Dermatology HomeNew OnlineCurrent IssueFor Authors Podcast Journals JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2024 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Dermatology journal
Integrative Modeling of Accelerometry-Derived Sleep, Physical Activity, and Circadian Rhythm Domains With Current or Remitted Major Depression
Authors: Sun Jung Kang, Andrew Leroux, Wei Guo, Debangan Dey, Marie-Pierre F. Strippoli, Junrui Di, Julien Vaucher, Pedro Marques-Vidal, Peter Vollenweider, Martin Preisig, Kathleen R. Merikangas, Vadim Zipunnikov
Journal: JAMA Psychiatry (2024)

Importance Accelerometry has been increasingly used as an objective index of sleep, physical activity, and circadian rhythms in people with mood disorders. However, most prior research has focused on sleep or physical activity alone without consideration of the strong within- and cross-domain intercorrelations; and few studies have distinguished between trait and state profiles of accelerometry domains in major depressive disorder (MDD). Objectives To identify joint and individual components of the domains derived from accelerometry, including sleep, physical activity, and circadian rhythmicity using the Joint and Individual Variation Explained method (JIVE), a novel multimodal integrative dimension-reduction technique; and to examine associations between joint and individual components with current and remitted MDD. Design, Setting, and Participants This cross-sectional study examined data from the second wave of a population cohort study from Lausanne, Switzerland. Participants included 2317 adults (1164 without MDD, 185 with current MDD, and 968 with remitted MDD) with accelerometry for at least 7 days. Statistical analysis was conducted from January 2021 to June 2023. Main Outcomes and Measures Features derived from accelerometry for 14 days; current and remitted MDD. Logistic regression adjusted for age, sex, body mass index, and anxiety and substance use disorders. Results Among 2317 adults included in the study, 1261 (54.42%) were female, and mean (SD) age was 61.79 (9.97) years. JIVE reduced 28 accelerometry features to 3 joint and 6 individual components (1 sleep, 2 physical activity, 3 circadian rhythms). Joint components explained 58.5%, 79.5%, 54.5% of the total variation in sleep, physical activity, and circadian rhythm domains, respectively. Both current and remitted depression were associated with the first 2 joint components that were distinguished by the salience of high-intensity physical activity and amplitude of circadian rhythm and timing of both sleep and physical activity, respectively. MDD had significantly weaker circadian rhythmicity. Conclusions and Relevance Application of a novel multimodal dimension-reduction technique demonstrates the importance of joint influences of physical activity, circadian rhythms, and timing of both sleep and physical activity with MDD; dampened circadian rhythmicity may constitute a trait marker for MDD. This work illustrates the value of accelerometry as a potential biomarker for subtypes of depression and highlights the importance of consideration of the full 24-hour sleep-wake cycle in future studies.
Prevalence and Treatment Patterns in Patients With Lichen Planopilaris
Authors: Natalia Pelet del Toro, Andrew Strunk, Amit Garg, George Han
Journal: JAMA Dermatology (2024)

Lichen planopilaris (LPP) is a form of scarring alopecia associated with progressive, permanent hair loss. Symptoms range from burning pain to itching, also carrying substantial psychological morbidity. Yet, disease characteristics, pathophysiology, and effective treatment data are limited, making treatment a challenge.
Updated Estimate of the Number of Extreme Risk Protection Orders Needed to Prevent 1 Suicide
Authors: Matthew Miller, Yifan Zhang, David M. Studdert, Sonja Swanson
Journal: JAMA Network Open (2024)

Importance Extreme risk protection orders (ERPOs)—also known as red flag, risk warrant, and gun violence restraining orders—authorize law enforcement, family members, and sometimes others to petition a court to remove firearms from and prevent the acquisition of new firearms by a person judged to pose an immediate danger to themselves or others. Previous estimates suggest that 1 suicide is prevented for every 10 ERPOs issued, a number needed to treat that depends critically on the counterfactual estimate of the proportion of suicidal acts by ERPO respondents that would have involved firearms in the absence of ERPOs. Objective To empirically inform updated estimates of the number of ERPOs needed to prevent 1 suicide. Design, Setting, and Participants This cohort study used data from California for method-specific suicides by handgun ownership (October 18, 2004, to December 31, 2015). Handgun-owning suicide decedents in California were identified using individual-level registry data about lawful handgun ownership linked to cause-specific mortality for a cohort of more than 25 million adults. The study also used data from Connecticut for method-specific suicides among ERPO respondents who died by suicide, extracted from published data (October 1999 to June 2013). Data analysis was performed in December 2023. Exposure Handgun ownership. Main Outcomes and Measures The primary outcomes were the number and distribution of suicidal acts by handgun owners in California, estimated using method-specific suicide mortality data and published case fatality ratios, and the counterfactual number and distribution of suicidal acts and deaths among ERPO respondents in Connecticut had no ERPOs been issued. Results A total of 1216 handgun owners (mean [SD] age, 50 [18] years; 1019 male [83.8%]) died by suicide during the study period. Among male handgun owners in California, 28% of suicidal acts involved firearms, 54% involved drug poisoning, 9% involved cutting or piercing, 3% involved hanging or suffocation, 2% involved poisoning with solids and/or liquids, and the remaining 4% involved other methods. Assuming this distribution approximates the counterfactual distribution among ERPO respondents in Connecticut in the absence of ERPOs, 1 suicide death was prevented for every 22 ERPOs issued. Conclusions and Relevance The estimates produced by this cohort study of California handgun owners suggest that ERPOs can play an important role in averting deaths among high-risk individuals.
Aspects of Area Deprivation Index in Relation to Hippocampal Volume Among Children
Authors: Benson S. Ku, Katrina Aberizk, Cope Feurer, Qingyue Yuan, Benjamin G. Druss, Dilip V. Jeste, Elaine F. Walker
Journal: JAMA Network Open (2024)

Area deprivation index (ADI) has been shown to be associated with reduced hippocampal volume (HV) among youths. The social environment may interact with the association between ADI and HV.
A PDE3A-SLFN12 Molecular Glue Exhibits Significant Antitumor Activity in TKI-Resistant Gastrointestinal Stromal Tumors
Authors: Emiri O. Takaki, Kunihiko Kiyono, Yutaka Obuchi, Takeshi Yamauchi, Takashi Watanabe, Hideki Matsumoto, Miho Karimine, Yuki Kuniyoshi, Shingo Nishikori, Fumiharu Yokoyama, Hikaru Nishimori, Hiroshi Nabeshima, Kazuhide Nakamura
Journal: Clinical Cancer Research (2024)

Abstract Purpose: Gastrointestinal stromal tumor (GIST), the most common mesenchymal tumor with KIT or PDGFRA driver mutations, is typically treated with tyrosine kinase inhibitors (TKI). However, resistance to TKIs due to secondary mutations is a common challenge in advanced GISTs. In addition, there are currently no effective therapies for several other molecular subtypes, such as succinate dehydrogenase–deficient GISTs. Therefore, novel therapeutic strategies are needed. Experimental Design: To address this need, we tested the efficacy of a novel non-TKI compound, OPB-171775, using patient-derived xenograft models of GISTs. In parallel, we sought to elucidate the mechanism of action of the compound. Results: Our study revealed that OPB-171775 exhibited significant efficacy against GISTs regardless of their KIT mutation status by inducing complex formation between phosphodiesterase 3A (PDE3A) and Schlafen family member 12 (SLFN12), which are highly expressed in GISTs, leading to SLFN12 RNase-mediated cell death. Furthermore, we identified the activation of general control non-derepressible 2 and its downstream response as an effector pathway of SLFN12 in mediating anticancer activity and revealed potential pharmacodynamic markers. Conclusions: These findings suggest that OPB-171775, with its significant efficacy, could potentially serve as a novel and effective treatment option for advanced GISTs, particularly those resistant to TKIs.
Targeting GPC2 on intraocular and CNS metastatic retinoblastomas with local and systemic delivery of CAR T-cells
Authors: Guillem Pascual-Pasto, Brendan McIntyre, Anna M. Giudice, Fatemeh Alikarami, Amanda Morrissey, Stephanie Matlaga, Ted J. Hofmann, Victor Burgueño, Kyra Harvey, Daniel Martinez, Amish C. Shah, Jessica B. Foster, Jennifer Pogoriler, Ralph C. Eagle, Angel M. Carcaboso, Carol L. Shields, Ann-Marie Leahey, Kristopher R. Bosse
Journal: Clinical Cancer Research (2024)

Abstract Purpose: Retinoblastoma is the most common intraocular malignancy in children. Although new chemotherapeutic approaches have improved ocular salvage rates, novel therapies are required for patients with refractory intraocular and metastatic disease. Chimeric antigen receptor (CAR) T cells targeting glypican-2 (GPC2) are a potential new therapeutic strategy. Experimental Design: GPC2 expression and its regulation by the E2F1 transcription factor were studied in retinoblastoma patient samples and cellular models. In vitro, we performed functional studies comparing GPC2 CAR T cells with different costimulatory domains (4-1BB and CD28). In vivo, the efficacy of local and systemic administration of GPC2 CAR T cells was evaluated in intraocular and leptomeningeal human retinoblastoma xenograft models. Results: Retinoblastoma tumors, but not healthy retinal tissues, expressed cell surface GPC2, and this tumor-specific expression was driven by E2F1. GPC2-directed CARs with 4-1BB costimulation (GPC2.BBz) were superior to CARs with CD28 stimulatory domains (GPC2.28z), efficiently inducing retinoblastoma cell cytotoxicity and enhancing T-cell proliferation and polyfunctionality. In vivo, GPC2.BBz CARs had enhanced persistence, which led to significant tumor regression compared with either control CD19 or GPC2.28z CARs. In intraocular models, GPC2.BBz CAR T cells efficiently trafficked to tumor-bearing eyes after intravitreal or systemic infusions, significantly prolonging ocular survival. In central nervous system (CNS) retinoblastoma models, intraventricular or systemically administered GPC2.BBz CAR T cells were activated in retinoblastoma-involved CNS tissues, resulting in robust tumor regression with substantially extended overall mouse survival. Conclusions: GPC2-directed CAR T cells are effective against intraocular and CNS metastatic retinoblastomas.
Tissue-free liquid biopsies combining genomic and methylation signals for minimal residual disease detection in patients with early colorectal cancer from the UK TRACC Part B study
Authors: Susanna Slater, Annette Bryant, Maria Aresu, Ruwaida Begum, Hsiang-Chi Chen, Clare Peckitt, Retchel Lazaro-Alcausi, Paul Carter, Gayathri Anandappa, Shelize Khakoo, Lucinda Melcher, Vanessa Potter, Francisca Marti Marti, Joseph Huang, Graham Branagan, Nicol George, Muti Abulafi, Sarah Duff, Ashraf Raja, Ashish Gupta, Nicholas West, Leslie Bucheit, Thereasa Rich, Ian Chau, David Cunningham, Naureen Starling
Journal: Clinical Cancer Research (2024)

Abstract Purpose: The absence of postoperative circulating tumor DNA (ctDNA) identifies patients with resected colorectal cancer (CRC) with low recurrence risk for adjuvant chemotherapy (ACT) de-escalation. Our study presents the largest resected CRC cohort to date with tissue-free minimal residual disease (MRD) detection. Experimental Design: TRACC (tracking mutations in cell-free tumor DNA to predict relapse in early colorectal cancer) included patients with stage I to III resectable CRC. Prospective longitudinal plasma collection for ctDNA occurred pre- and postsurgery, post-ACT, every 3 months for year 1 and every 6 months in years 2 and 3 with imaging annually. The Guardant Reveal assay evaluated genomic and methylation signals. The primary endpoint was 2-year recurrence-free survival (RFS) by postoperative ctDNA detection (NCT04050345). Results: Between December 2016 and August 2022, 1,203 were patients enrolled. Plasma samples (n = 997) from 214 patients were analyzed. One hundred forty-three patients were evaluable for the primary endpoint; 92 (64.3%) colon, 51 (35.7%) rectal; two (1.4%) stage I, 64 (44.8%) stage II, and 77 (53.8%) stage III. Median follow-up was 30.3 months (95% CI, 29.5–31.3). Two-year RFS was 91.1% in patients with ctDNA not detected postoperatively and 50.4% in those with ctDNA detected [HR, 6.5 (2.96–14.5); P &amp;lt; 0.0001]. Landmark negative predictive value (NPV) was 91.2% (95% CI, 83.9–95.9). Longitudinal sensitivity and specificity were 62.1% (95% CI, 42.2–79.3) and 85.9% (95% CI, 78.9–91.3), respectively. The median lead time from ctDNA detection to radiological recurrence was 7.3 months (IQR, 3.3–12.5; n = 9). Conclusions: Tissue-free MRD detection with longitudinal sampling predicts recurrence in patients with stage I to III CRC without the need for tissue sequencing. The UK TRACC Part C study is currently investigating the potential for ACT de-escalation in patients with undetectable postoperative ctDNA, given the high NPV indicating a low likelihood of residual disease.
A phase 3 trial of fixed dose combinations of fianlimab (anti–LAG-3) + cemiplimab (anti–PD-1) versus relatlimab + nivolumab in patients with unresectable or metastatic melanoma.
Authors: Nikhil I. Khushalani, Jayakumar Mani, Jocelyn Booth, Zoe Zhang, Mark Salvati, Israel Lowy, Matthew G. Fury, Karl Lewis, Garen Manvelian, Hussein A. Tawbi
Journal: Journal of Clinical Oncology (2024)

TPS9611 Background: Fianlimab (anti–lymphocyte activation gene 3 [LAG-3]) and cemiplimab (anti–programmed cell death-1 [PD-1]) are high-affinity, fully human, immunoglobulin G4 monoclonal antibodies. Concurrent LAG-3 blockade may enhance the efficacy of anti–PD-1 therapies. Relatlimab (anti–LAG-3) + nivolumab (anti–PD-1) monoclonal antibodies demonstrated benefit in progression-free survival (PFS) in advanced melanoma (Mel) patients compared with nivolumab alone in the RELATIVITY-047 study. In a multicohort Phase 1 study (NCT03005782), fianlimab + cemiplimab demonstrated reproducibly high clinical activity (objective response rate [ORR]: 61%, N=98) in three independent cohorts of advanced PD-(L)1–naïve metastatic Mel patients with an acceptable safety profile. Methods: This is a randomized, open-label, multicenter Phase 3 study (NCT06246916) comparing the fixed dose combination (FDC) of fianlimab + cemiplimab to the FDC of relatlimab + nivolumab in patients with unresectable or metastatic Mel. The primary objective is to demonstrate superiority of fianlimab + cemiplimab compared with relatlimab + nivolumab as measured by ORR assessed by blinded independent central review (BICR). This study will be conducted at approximately 80 sites across North America. Key inclusion criteria are: (1) aged ≥18 years; (2) histologically confirmed unresectable stage III or IV (metastatic) Mel; (3) no prior systemic therapy for unresectable or metastatic Mel; patients with adjuvant and/or neoadjuvant systemic therapies are eligible with a treatment-free and disease-free interval of &gt;6 months; (4) measurable disease per Response Evaluation Criteria in Solid Tumors version 1.1; (5) Eastern Cooperative Oncology Group performance status of ≤1; (6) adequate bone marrow, hepatic, and kidney function. Approximately 560 patients will be randomized in a 1:1 ratio to two treatment arms: Arm A: FDC of fianlimab (Dose 1) + cemiplimab (Dose 2) every 3 weeks intravenously (IV); Arm B: FDC of relatlimab 160 mg + nivolumab 480 mg every 4 weeks IV. All patients will be stratified based on metastatic stage (stage III vs M1a–b vs M1c–d), baseline lactate dehydrogenase level (≤ vs &gt; upper limit of normal), and prior adjuvant and/or neoadjuvant systemic therapy. Patients will receive treatment until disease progression, unacceptable toxicity, withdrawal of consent, a study withdrawal criterion is met, or the sponsor terminates the study. The primary endpoint is ORR and key secondary endpoints are PFS and overall survival. Additional secondary endpoints are duration of response, disease control rate, investigator-assessed ORR and PFS, safety, pharmacokinetics, and immunogenicity. Clinical trial information: NCT06246916 .
The MARIANE-trial: Multicenter phase 1b/2 trial testing safety and efficacy of neoadjuvant intradermal ipilimumab and nivolumab in high-risk stage II melanoma.
Authors: Lotte L. Hoeijmakers, Anke M.J. Kuijpers, Bart A. van de Wiel, Marta I. Lopez-Yurda, Elsemieke I Plasmeijer, Charlotte L. Zuur, Hanna C. van der Pol, Minke W. Lucas, Jurriaan Romano, Judith Lijnsvelt, Alfonsus Johannes Maria van den Eertwegh, Mathilde Jalving, Ellen Kapiteijn, Karijn Suijkerbuijk, Astrid Aplonia Maria Van Der Veldt, Bart Jacobs, Tanja D de Gruijl, Christian U. Blank
Journal: Journal of Clinical Oncology (2024)

TPS9615 Background: Adjuvant anti-PD1 (nivolumab or pembrolizumab) has been shown to improve relapse free survival for patients with high-risk stage II melanoma (IIB-C). However, this therapy probably won’t be reimbursed as standard of care in most European countries due to high costs, and the benefit-risk-ratio. For macroscopic stage III melanoma, neoadjuvant ipilimumab (IPI; anti-CTLA4) plus nivolumab (NIVO; anti-PD1) has been shown to induce high pathologic response rates in the resected lymph nodes, long-term event free survival, and this schedule is currently being compared to adjuvant NIVO in a phase 3 study (NCT04949113). This combination schedule, however, is unsuitable for earlier disease stages, due to high costs and clinical toxicity. In preclinical models, a local tumor draining lymph node directed delivery of anti-PD-1 plus anti-CTLA-4 has been demonstrated to outperform systemic administration on induction of T-cell proliferation and tumor control. In patients, local delivery of anti-PD-1 or anti-CTLA-4 has been suggested to be equally effective in tumor control with a reduction of adverse events. These data have formed the rationale for testing intradermal injections at the excision site of the primary tumor with IPI and NIVO prior to the re-excision and sentinel node procedure in high-risk stage II melanoma patients. Methods: This multicenter, dose-escalating phase Ib/II trial, using a Simon’s two-stage design, is the first trial to test feasibility and efficacy of intradermal IPI plus NIVO in high-risk stage II melanoma patients. In total 21 to 80 patients, diagnosed with a stage T3-4 cutaneous melanoma with ≥ 50% chance of positive sentinel node, naïve for re-excision, sentinel node surgery and immunotherapy, will be included in this trial. Patients will receive 2 cycles of intradermal IPI 0.5 mg + NIVO 1 mg at the excision site of the primary melanoma (every 3 weeks; arm A); 6 cycles intradermal IPI 0.5 mg + NIVO 1 mg (every week; arm B); 2 cycles intradermal IPI 10 mg + NIVO 20 mg (every 3 weeks, arm C); or 2 cycles of intravenous nivolumab 240 mg every 3 weeks combined with the most optimal intradermal regimen of IPI + NIVO (based on the results of arm A, B or C) in arm D. In week 6, patients will undergo sentinel node surgery, whereafter only patients with a non-MPR (&gt;10% vital tumor) will be treated with adjuvant anti-PD1 according to current standard of care. We expect the first patient to be enrolled in March 2024and to be accruing for 1-1.5 years. Clinical trial information: NCT06240143 .
Intralesional administration of L19IL2/L19TNF in high-risk locally advanced basal cell carcinoma or cutaneous squamous cell carcinoma.
Authors: Lukas Flatz, Ulrike M. Leiter, Francisco Meraz Torres, Frederik Carlos Wolfsperger, Andreas Meiwes, Nikolaus Wagner, Lisa Nadal, Emanuele Puca, Derya Durak, Alfredo Covelli, Giuliano Elia, Antonio Cozzio, Dario Neri, Teresa Amaral
Journal: Journal of Clinical Oncology (2024)

TPS9617 Background: Basal cell carcinoma (BCC) and cutaneous squamous cell carcinoma (cSCC) account for 99% of skin neoplasms, with a rising incidence due to increased sun exposure and growing life expectancy. Approximately 0.8-5% of patients (pts) develop high-risk locally advanced (LA) disease, which is treated with surgery, radiotherapy, sonic hedgehog inhibitors, PD1-based immune checkpoint blockade, or chemotherapy. While surgery offers high cure rates, factors such as location, functional and cosmetic impairment, or patient factors including age, comorbidities, and personal preferences may preclude surgery. Intralesional treatment with immunostimulatory drugs represents an attractive therapeutic approach to treat LA BCC and LA cSCC. Here, we investigate a combination of two immunocytokines (Bifikafusp alfa (L19IL2) and Onfekafusp alfa (L19TNF)) targeting the extradomain B of fibronectin (EDB) for the treatment of high-risk locally advanced BCC and cSCC. EDB is an oncofetal antigen that is undetectable in virtually all healthy adult tissues but becomes highly expressed in tumors, including BCC and cSCC. Methods: In a single-arm phase II study (NCT04362722), pts with locally advanced, non-metastatic, node-negative, single, or multifocal BCC or cSCC not eligible for surgery or radiotherapy are treated with four weekly intratumoral administrations of L19IL2/L19TNF. The study is divided into two parts: a first exploratory part with a total of 40 pts with laBCC or lacSCC, and a second part where the laBCC cohort has been expanded to up to 72 pts not eligible for surgery or radiotherapy. The first part of the trial has been completed with 28 laBCC pts and 12 lacSCC pts evaluable for safety and efficacy. The pre-specified activity goal for the first stage of accrual was met, and the second stage of accrual began in September 2023, with a total of 39 BCC and 18 cSCC pts enrolled so far. Clinical trial information: NCT04362722 .