tbuckley/cabot-search huggingface dataset:
Young patients with cancer related to modifiable behaviors in the United States: What can we learn from them?
Authors: John Chan, Michelle Ann P. Caesar, Chloe Chan, Michael Richardson, Daniel Stuart Kapp, Alex Andrea Francoeur, Cheng-I Liao
Journal: Journal of Clinical Oncology (2021)

10560 Background: We proposed to examine trends in modifiable behaviorally related cancers among younger men and women in the United States. Methods: Alcohol-associated cancers, HPV-associated, obesity-associated, physical inactivity-associated, and tobacco-associated were defined using ICD-O-3 site codes. From 2001 and 2017, registry data were obtained from the United States Cancer Statistics database. SEER*Stat 8.3.8 and Joinpoint regression program 4.8.0.1 were used to calculate the trends of associated cancers expressed per 100,000. Results: Of the young women (ages 20-49 years) the incidence of cancers in 2017 associated with alcohol, smoking and obesity were 89/100,000, 43/100,000 and 64/100,000 respectively. Based on analysis of trends of women from 2001 to 2017, obesity, physical inactivity and alcohol related cancers increased with an annual percent change (APC 2.31%, 1.67%, 0.46%, p &lt; 0.001). Using a projection model, in Hispanic women, obesity related cancers will become the highest incidence cancers by 2035, surpassing alcohol and physical inactivity. Of the young men (ages 20-49 years) the incidence of cancers in 2017 associated with alcohol, obesity, and tobacco were 23/100,000, 36/100,000 and 44/100,000 respectively. On trends analysis, obesity, physical inactivity, and alcohol related cancers have increased (APC 2.0%, 1.65%, 0.17%, p &lt; 0.001, p &lt; 0.001, p = 0.044), whereas tobacco-related cancers are decreasing with an APC of -0.44% (p &lt; 0.001). When examining different regions, the highest APC for obesity and physical inactivity related cancers was 2.43% in the Midwest (p &lt; 0.001). Using a prediction model, obesity is predicted to surpass alcohol and physical inactivity related cancers for men 20-49 years old by 2035. Conclusions: In women, most modifiable factors associated with cancer are increasing except in HPV related cancers. In men, these rates of cancer are increasing except in tobacco related cancers. However, rates of obesity related cancers are on the rise in Hispanic women and younger men in southern U.S. regions. Obesity is projected to become the major modifiable factor for many associated cancers.
FIREFLY-1: A phase 2 study of the pan-RAF inhibitor DAY101 in pediatric patients with low-grade glioma.
Authors: Lindsay Baker Kilburn, Nada Jabado, Andrea Franson, Susan N. Chi, Michael J. Fisher, Darren R. Hargrave, Jordan R. Hansford, David S. Ziegler, Daniel Landi, Hyoung Jin Kang, Nicolas U. Gerber, Michal Yalon-Oren, Izzy Cornelio, Samuel C. Blackman, Michael Craig Cox, Olaf Witt, Michael Prados, Sabine Mueller
Journal: Journal of Clinical Oncology (2021)

TPS10056 Background: The mitogen-activated protein kinase (MAPK) signaling pathway is an essential pathway that regulates key cell functions such as growth, survival, and differentiation. Genomic alterations and dysregulation of the MAPK pathway including BRAF fusions, point mutations (e.g. BRAF V600) and in-frame deletions have been described in many different types of malignancies, including pediatric low-grade glioma (pLGG) and other pediatric cancers. The identification of the KIAA1549:BRAF fusion in 2008 led to deeper understanding of the genomic events driving growth of pLGG (Jones, Cancer Res 2008). Despite the low-grade histology and excellent long-term survival, pLGGs are often associated with tumor- and treatment-associated morbidity and significant late-effects that persist throughout the lifespan of the patient. DAY101 is an oral, highly selective, CNS-penetrant small-molecule, Type II pan-RAF kinase inhibitor that is being developed for patients with pLGG harboring an activating BRAF-alteration. DAY101 has demonstrated tumor inhibition in preclinical models and has achieved clinically meaningful and durable responses in 7/8 patients with RAF-altered LGG in a pediatric phase 1 trial, including 2 complete responses, 3 partial responses, 2 stable disease and 1 progressive disease with a median time to response of 10.5 weeks. Patients have been treated for up to two years with no discontinuations due to toxicity or disease progression (Wright, SNO 2020). Methods: FIREFLY-1 is an open-label, multi-center, international Phase 2 study with DAY101 in pediatric and young adult patients between the ages of 6 months and 25 years with LGG harboring a documented BRAF-alteration as determined by local laboratory testing. DAY101 is administered orally once a week on a continuous 28-day schedule. Patients who respond will be treated for a minimum of two years after which they may at any point, opt to enter a “drug holiday” discontinuation period. Dosing is based on body surface area. DAY101 is available in a pediatric-friendly oral liquid formulation and tablets. The primary endpoint is objective response rate based on Response Assessment for Neuro-Oncology (RANO) as determined by an independent review committee. Secondary endpoints include objective response rate based on Response Assessment in Pediatric Neuro-Oncology (RAPNO) working group criteria, duration of response and safety. Exploratory endpoints include quality-of-life measurements as well as functional outcomes. Molecular abnormalities will be characterized through the analysis of archival tissue. Enrollment began in February 2021 and is ongoing. Clinical trial information: NCT03429804.
EU drugs agency admits that it misses UK data and expertise
Authors: Rory Watson
Journal: BMJ (2021)

Alexis Goosdeel, director of the European Monitoring Centre for Drugs and Drug Addiction, has admitted that Brexit has affected the work of the Lisbon based agency.

Introducing the centre’s annual report on 9 June,1 Goosdeel explained that the UK’s departure from the European Union was depriving his team of valuable British expertise and data for the centre, which provides policy makers with scientific, evidence based, and comparable information of the evolving drug problem.

“This is a very painful point for us,” he said. “Because of Brexit, we have lost a broad range of excellent and fantastic experts and colleagues, including the …
First-in-human dose escalation of ALPN-202, a conditional CD28 costimulator and dual checkpoint inhibitor, in advanced malignancies.
Authors: Justin C Moser, Mark Voskoboynik, Nehal J. Lakhani, Michael Millward, Diwakar Davar, Wael A. Harb, Jing Yang, Gary Means, Kristi Manjarrez, Almudena Tercero, Hany Zayed, Jan Hillson, Christine Dela Cruz, Graciela Noemi Perez, Stanford L. Peng
Journal: Journal of Clinical Oncology (2021)

2547 Background: Strong preclinical rationale has emerged for combining checkpoint inhibition (CPI) with T cell costimulatory agonists, particularly CD28, a critical T cell costimulatory molecule recently recognized as a key target of checkpoint inhibition. ALPN-202 is a variant CD80 vIgD-Fc fusion that mediates PD-L1-dependent CD28 costimulation and inhibits the PD-L1 and CTLA-4 checkpoints. It has demonstrated superiority to CPI-only therapies in tumor models, while demonstrating favorable safety in preclinical toxicology studies. Methods: This is a cohort-based, open-label dose escalation and expansion study of ALPN-202 in adults with advanced solid tumors or lymphoma (NCT04186637). Subjects with cancers refractory to standard therapies (including approved CPIs), or cancers without available standard or curative therapy are eligible. After two planned single-subject cohorts, a standard 3+3 dose escalation has been implemented with two dose schedules in parallel, Q1W and Q3W. Objectives include evaluation of safety and tolerability, PK, PD and preliminary anticancer activity of ALPN-202. Disease assessments are evaluated by RECIST v1.1 for solid tumors or by Lugano Classification for lymphoma. Results: As of January 2021, 20 subjects with advanced malignancies have received ALPN-202. Dose-dependent PK and target saturation have been preliminarily observed. So far, ALPN-202 has been well tolerated at dose levels ranging from 0.001 to 1 mg/kg weekly, with no DLTs. Low-grade skin toxicities (grade 1-2 rash) have been observed in 4 subjects (20%). Among 11 evaluable subjects, an unconfirmed partial response has been observed in one subject with colorectal carcinoma, while stable disease has been observed in 5 subjects with colorectal carcinoma, mesothelioma (2), cholangiocarcinoma, and renal cell carcinoma -- for a preliminary clinical benefit (PR+SD) rate of 100% (4/4) at dose levels of 0.3 mg/kg and higher, or 54% (5/11) overall (table). The meeting presentation will update this data, which is expected to include the conclusion of Q1W dose escalation, as well as immune correlates. Conclusions: First-in-human dose escalation with ALPN-202 has been well tolerated at doses capable of engaging CD28 costimulation in vivo in association with dual PD-L1/CTLA-4 checkpoint inhibition, with early signs of anti-tumor activity. These findings suggest that CD28 agonism can be safely achieved in humans, and further suggest that dose expansion with ALPN-202 is warranted to assess the relevance of controlled CD28 costimulation as a novel approach to cancer immunotherapy. Clinical trial information: NCT04186637. [Table: see text]
In-hospital outcomes of CAR T-cell therapy in United States in 2018: A nationwide analysis.
Authors: Manoj P. Rai, Prabhjot Singh Bedi, Anup Kasi, Kathan Mehta
Journal: Journal of Clinical Oncology (2021)

6556 Background: CAR T-cell therapy is a type of adoptive cell transfer (ACT). In 2017 CAR T-cell therapy was approved by the Food and Drug Administration (FDA) for management of diffuse large B-cell lymphoma refractory to at least two prior lines of therapy (DLBCL) including primary mediastinal large B-cell lymphoma (PMBCL), and B cell precursor acute lymphoblastic leukemia (ALL) up to 25 years of age that is refractory or in second or later relapse. Since its inception, several patients underwent CAR T-cell therapy but data on real world outcome is limited. In this study we aim to evaluate the in-hospital outcomes of CAR T-cell therapy in the United States in 2018. Methods: This is a cross-sectional study using National Inpatient Sample 2018 database. Discharges with the ICD-10-PCS code for CAR T-cell therapy and ICD-10-CM code of ALL, DLBCL or PMBCL were included in the study. We analyzed their in-hospital outcomes (Total discharges, length of stay in days, hospitalization cost, and mortality - number of deaths). We applied the cost to charge ratio to hospitalization charges to estimate the mean hospitalization cost. The weighted sample represents national estimates. Results: We identified 785 discharges with CAR T cell therapy and diagnosis of ALL, DLBCL or PMBCL. 155 (19.75 %) were ALL, 620 (78.98%) DLBCL, and 10 (1.27%) PMBCL. Mean length of stay for the study cohort was 23.26 days. Specifically, for ALL mean LOS was 33.67 days, DLBCL 20.76 days, and PMBCL 17 days. Mean hospitalization cost for the study cohort was $285,989, specifically for ALL it was $342,228, DLBCL $274,102, PMBCL $179,431. There were a total of 60 (7.6%) deaths in the study cohort. Diagnosis specific mortality was 20 (12.9%) in ALL, 40 (6.4%) in DLBCL and none in PMBCL. Conclusions: Majority of discharges who underwent CAR T-cell therapy were DLBCL followed by ALL and PMBCL. CAR-T Cell hospitalizations have high costs and long length of stays. Mean length of stay was highest in ALL discharges, least in PMBCL. Mean hospitalization cost was higher in DLBCL discharges compared to ALL and was least in PMBCL discharges. The in-hospital mortality with the CAR-T cell therapy appears to be higher than reported in clinical trials, especially for ALL. [Table: see text]
Spread of Misinformation About Face Masks and COVID-19 by Automated Software on Facebook
Authors: John W. Ayers, Brian Chu, Zechariah Zhu, Eric C. Leas, Davey M. Smith, Mark Dredze, David A. Broniatowski
Journal: JAMA Internal Medicine (2021)

This cross-sectional study examines the spread of misinformation regarding the Danish Study to Assess Face Masks for the Protection Against COVID-19 Infection on Facebook.
Chronic Pelvic Pain in Women
Authors: Georgine Lamvu, Jorge Carrillo, Chensi Ouyang, Andrea Rapkin
Journal: JAMA (2021)

Chronic pelvic pain (CPP) is a challenging condition that affects an estimated 26% of the world's female population. Chronic pelvic pain accounts for 40% of laparoscopies and 12% of hysterectomies in the US annually even though the origin of CPP is not gynecologic in 80% of patients. Both patients and clinicians are often frustrated by a perceived lack of treatments. This review summarizes the evaluation and management of CPP using recommendations from consensus guidelines to facilitate clinical evaluation, treatment, improved care, and more positive patient-clinician interactions.Chronic pelvic pain conditions often overlap with nonpelvic pain disorders (eg, fibromyalgia, migraines) and nonpain comorbidities (eg, sleep, mood, cognitive impairment) to contribute to pain severity and disability. Musculoskeletal pain and dysfunction are found in 50% to 90% of patients with CPP. Traumatic experiences and distress have important roles in pain modulation. Complete assessment of the biopsychosocial factors that contribute to CPP requires obtaining a thorough history, educating the patient about pain mechanisms, and extending visit times. Training in trauma-informed care and pelvic musculoskeletal examination are essential to reduce patient anxiety associated with the examination and to avoid missing the origin of myofascial pain. Recommended treatments are usually multimodal and require an interdisciplinary team of clinicians. A single-organ pathological examination should be avoided. Patient involvement, shared decision-making, functional goal setting, and a discussion of expectations for long-term care are important parts of the evaluation process.Chronic pelvic pain is like other chronic pain syndromes in that biopsychosocial factors interact to contribute and influence pain. To manage this type of pain, clinicians must consider centrally mediated pain factors as well as pelvic and nonpelvic visceral and somatic structures that can generate or contribute to pain.
Abstract 12543: Acacetin is a Promising New Pharmacologic Agent for Suppression of Life-threatening Arrhythmias Associated With the Brugada and Early Repolarization Syndromes
Authors: Hector Barajas, Jose Di Diego, Bence Patocskai, Virág Borbáth, Gui-Rong Li, Dan Hu, Alexander Burashnikov, Charles N Antzelevitch
Journal: Circulation (2019)

Introduction: Brugada (BrS) and Early Repolarization (ERS) Syndromes, referred to as J wave syndromes (JWS), are channelopathies associated with the development of life-threatening VT/VF. At presen...
A phase I clinical trial investigating the telomerase vaccine UV1 in combination with pembrolizumab in patients with advanced melanoma.
Authors: Yousef Zakharia, Steven O'Day, Wenche Rasch, Mohammed M. Milhem
Journal: Journal of Clinical Oncology (2021)

2620 Background: UV1, a telomerase peptide-based vaccine, consists of 3 long peptides (15-30 aa) representing a 54 aa sequence in the catalytic unit of the reverse transcriptase subunit of telomerase (hTERT). UV1 contains both CD4 and CD8 epitopes, and immunogenicity is shown in 78% of HLA unselected patients (pts.) in prior studies. UV1 induced expansion of hTERT specific CD4+ T cells that might be relevant in tumors expressing telomerase, theoretically enabling enhanced checkpoint efficacy in pts. with insufficient spontaneously primed T cells. Reciprocally, checkpoint inhibitor may support the UV1-induced T cells and provide increased effector activity, as these cells may be restricted by intrinsic and tumor-induced suppressor mechanisms. Methods: UV1 was combined with standard of care pembrolizumab in pts. with advanced melanoma. The primary objective of this phase I, multicenter study (NCT03538314), was to evaluate safety and tolerability of UV1 in combination with standard pembrolizumab. Secondary objective was evaluation of response rate (RR) according to iRECIST. Pts. received, in a serial manner, adjuvant GM-CSF and UV1 (300μg) intradermally followed by pembrolizumab. The first 3 UV1/GM-CSF doses were given during week 1, and from week 2 in combination with pembrolizumab (Q3W). Two different doses of GM-CSF were investigated: 37.5μg (20 pts. cohort 1) and 75μg (10 pts. cohort 2). Totally 8 UV1/GM-CSF vaccinations per pt. were planned (14 weeks). Results: In total 30 pts. were enrolled; cohort 1 (N = 20); cohort 2 (N = 10). The abstract reports cohort 1 results. The majority of adverse events (AEs) reported was grade 1 or 2 (48%, 41%). Main AEs were fatigue (8%), injection site reaction (5%), diarrhea (4%) and pyrexia (3%). 18% and 30% of AEs were possibly/definitely related to UV1 or pembrolizumab, respectively. Three patients experienced SAE, one (inflammatory arthritis) was considered possibly related to UV1. No severe allergic reactions were observed. Pembrolizumab was continued after completion of UV1 treatment in 14 pts. for a mean of 8.2 months (range 3-21). Four pts. discontinued pembrolizumab due to PD, one for irAE and one for unknown reason. The RR was 60%, with 5 CRs, and the 1-year survival rate 85 %. Conclusions: Results from cohort 1 (N = 20) show that the treatment of UV1 together with pembrolizumab was safe and well tolerated in patients with advanced melanoma. Updated data with minimum 18 months follow-up will be presented at the conference. Cohort 2 results will be presented at a later stage. Clinical trial information: NCT03538314. [Table: see text]
Lenvatinib plus toripalimab as first-line treatment for advanced intrahepatic cholangiocarcinoma: A single-arm, phase 2 trial.
Authors: Zhou Jian, Jia Fan, Guo-Ming Shi, Xiao-Yong Huang, Dong Wu, Fei Liang, Guo-Huan Yang, Jia-Cheng Lu, Yi Chen, Ning-Ling Ge, Yuan Ji, YY Hou, Hui-Chuan Sun, Shuang-Jian Qiu, Qing-Hai Ye, Xiao-Wu Huang, Ying-Hong Shi, Qiang Gao, Xin-Rong Yang, Xiao-Ying Wang
Journal: Journal of Clinical Oncology (2021)

4099 Background: Lenvatinib monotherapy and lenvatinib plus PD-1 antibody have shown some clinical benefit for advanced intrahepatic cholangiocarcinoma (ICC) in the second-line setting. Our study assesses the role of lenvatinib plus toripalimab (PD-1 antibody) for advanced ICC patients as the first line therapy. Methods: Patients (pts) with locally advanced or metastatic ICC received 12 mg/day (Body Weight ≥60 kg) or 8 mg/day (Body Weight &lt;60 kg) oral lenvatinib daily plus 240 mg intravenous toripalimab every 3 weeks. The primary endpoint was objective response rate (ORR) and evaluated according to Response Evaluation Criteria In Solid Tumors version 1.1 (RECIST v1.1). Secondary endpoints included safety, progression-free survival (PFS) and overall survival (OS). Treatment continued until confirmed disease progression, unacceptable toxicity, or voluntary withdrawal. This trial is registered with ClinicalTrials.gov (NCT04361331). Results: From March 2020 to Sep. 2020, 31 pathologically confirmed advanced ICC pts with a mean age of 58.4 (range, 25-73) years, including 18 women (58.0%), were enrolled at Zhongshan Hospital, Fudan University. At the end of last follow-up (February 10, 2021), the ORR was 32.3% (10/31; 95% CI: 16.7%-51.4%) and the disease control rate (DCR) was 74.2% (23/31; 95% CI: 55.4%-88.1%). Median follow-up was 6.9 months. Two pts with locally advanced disease were down-staged and then underwent resection. They remained disease-free survival at the end of last follow-up. 11 pts exerted disease progression and 7 pts died. The median PFS and OS have not been reached. Median duration of response (DOR) has not been reached and responses were ongoing in 9/10 (90.0%) pts at data cutoff. 6-months OS rate was 87.1%. No grade 5 adverse event (AE) was observed in present study. 32.3% (10/31) of pts experienced Grade 3 or higher AEs and 1 pts discontinued the treatment owing to severe fatigue. Conclusions: As the first-line therapy, lenvatinib plus toripalimab provided promising efficacy with reasonable safety profile in advanced ICC patients. It offered an alternative treatment for advanced ICC who cannot tolerate gemcitabine-based chemotherapy. Clinical trial information: NCT04361331.
Prevalence of <i>NTRK1/3</i> fusions in mismatch repair-deficient (dMMR)/microsatellite instable (MSI) tumors of patients with metastatic colorectal cancer (mCRC).
Authors: Magali Svrcek, Raphael Colle, Anne Cayre, Pierre Bourgoin, Romain Cohen, Thierry Andre, Frederique Madeleine Penault-Llorca, Nina Radosevic-Robin
Journal: Journal of Clinical Oncology (2021)

e15537 Background: Inhibitors of tropomyosin receptor kinase (TRK) have shown promising activity against neurotrophic TRK ( NTRK) fusion-driven cancers, regardless of tumor histotype or cell of origin. NTRK gene fusions are observed in less than 1% of colorectal cancers (CRCs). CRCs harboring wild-type BRAF and KRAS and MisMatch Repair deficiency (dMMR)/MicroSatellite Instability (MSI) due to MLH1 hypermethylation have been associated with NTRK fusions in small cohorts of non-metastatic tumors. We aimed at evaluating the incidence of NTRK fusions among dMMR/MSI metastatic CRCs (mCRC) for which there is a need for innovative therapies, as well as the associated clinical characteristics of these patients (pts) carrying NTRK fusion-positive tumors. Methods: Tumor samples of dMMR/MSI mCRC pts, paired primary and metastasis or primary alone, were obtained from a French multicenter retrospective cohort and from a single-center cohort of patients treated by immune checkpoint inhibitors (ICI) (Saint-Antoine Hospital, Paris). Clinico-pathological data including KRAS and BRAF V600E status, MMR proteins and MLH1 methylation status were available for all pts. All samples were screened for TRK expression by immunohistochemistry (IHC) using a pan-TRK antibody (clone EPR17341, Abcam; positivity: 1% of labeled tumor cells)) and for NTRK1 and NTRK3 gene rearrangements, by fluorescent in situ hybridation (FISH). A threshold of 15% nuclei positive for a break apart signal was considered positive for gene rearrangement. Results: A total of 158 pts with dMMR/MSI mCRCs (paired samples: n=39; primary only: n=119) were screened. Tumor samples of 10 patients (6.3%) harbored NTRK fusion genes by FISH ( NTRK1=8; NTRK3=2). Only four of these 10 patients had TRK immunoreactivity. One patient showed a discordance between metastasis harboring NTRK1 fusion (+) and primary tumor being negative. Eight tumors were sporadic with MLH1 hypermethylation. The remaining 2 cases were related to a MMR gene germline mutation (Lynch syndrome) with concurrent loss of MSH2 and MSH6 expression and isolated loss of MSH6 respectively. One Lynch-related tumor was KRAS mutated, one sporadic MLH1-negative tumor was BRAF V600E mutated. Four patients out of 91 treated by ICI had tumors with NTRK fusions. Three have shown radiological response according to iRECIST criteria (two complete responses, one partial response with 25 to 54 months of follow up) and one had primary resistance to ICI. Conclusions: Frequency of NTRK1/3 fusions is 6.3% in our dMMR/MSI mCRCs population. These fusions are not restricted to sporadic cases. The diagnostic accuracy of pan-TRK IHC is low. Optimal testing algorithms for theragnostics remain to be defined in this setting.