tbuckley/cabot-search huggingface dataset:
Clinical Activity and Safety of Cabozantinib for Brain Metastases in Patients With Renal Cell Carcinoma
Authors: Laure Hirsch, Nieves Martinez Chanza, Subrina Farah, Wanling Xie, Ronan Flippot, David A. Braun, Nityam Rathi, Jonathan Thouvenin, Katharine A. Collier, Emmanuel Seront, Guillermo de Velasco, Hannah Dzimitrowicz, Benoit Beuselinck, Wenxin Xu, I. Alex Bowman, Elaine T. Lam, Bashar Abuqayas, Mehmet Asim Bilen, Andreas Varkaris, Yousef Zakharia, Michael R. Harrison, Amir Mortazavi, Philippe Barthélémy, Neeraj Agarwal, Rana R. McKay, Priscilla K. Brastianos, Katherine M. Krajewski, Laurence Albigès, Lauren C. Harshman, Toni K. Choueiri
Journal: JAMA Oncology (2021)

Patients with brain metastases from renal cell carcinoma (RCC) have been underrepresented in clinical trials, and effective systemic therapy is lacking. Cabozantinib shows robust clinical activity in metastatic RCC, but its effect on brain metastases remains unclear.To assess the clinical activity and toxic effects of cabozantinib to treat brain metastases in patients with metastatic RCC.This retrospective cohort study included patients with metastatic RCC and brain metastases treated in 15 international institutions (US, Belgium, France, and Spain) between January 2014 and October 2020. Cohort A comprised patients with progressing brain metastases without concomitant brain-directed local therapy, and cohort B comprised patients with stable or progressing brain metastases concomitantly treated by brain-directed local therapy.Receipt of cabozantinib monotherapy at any line of treatment.Intracranial radiological response rate by modified Response Evaluation Criteria in Solid Tumors, version 1.1, and toxic effects of cabozantinib.Of the 88 patients with brain metastases from RCC included in the study, 33 (38%) were in cohort A and 55 (62%) were in cohort B; the majority of patients were men (n = 69; 78%), and the median age at cabozantinib initiation was 61 years (range, 34-81 years). Median follow-up was 17 months (range, 2-74 months). The intracranial response rate was 55% (95% CI, 36%-73%) and 47% (95% CI, 33%-61%) in cohorts A and B, respectively. In cohort A, the extracranial response rate was 48% (95% CI, 31%-66%), median time to treatment failure was 8.9 months (95% CI, 5.9-12.3 months), and median overall survival was 15 months (95% CI, 9.0-30.0 months). In cohort B, the extracranial response rate was 38% (95% CI, 25%-52%), time to treatment failure was 9.7 months (95% CI, 6.0-13.2 months), and median overall survival was 16 months (95% CI, 12.0-21.9 months). Cabozantinib was well tolerated, with no unexpected toxic effects or neurological adverse events reported. No treatment-related deaths were observed.In this cohort study, cabozantinib showed considerable intracranial activity and an acceptable safety profile in patients with RCC and brain metastases. Support of prospective studies evaluating the efficacy of cabozantinib for brain metastases in patients with RCC is critical.
Overcoming Therapeutic Inertia in Type 2 Diabetes Care—Timing, Context, and Appropriateness of Treatment Intensification
Authors: Rozalina G. McCoy, Patrick J. O’Connor
Journal: JAMA Network Open (2021)

Timothy S. Anderson, MD, MAS; Alexandra K. Lee, PhD, MSPH; Bocheng Jing, MS; Sei Lee, MD; Shoshana J. Herzig, MD, MPH; W. John Boscardin, PhD; Kathy Fung, MS; Anael Rizzo, BA; Michael A. Steinman, MD
Clinical and Preclinical Evidence for Roles of Soluble Epoxide Hydrolase in Osteoarthritis Knee Pain
Authors: Peter R. W. Gowler, James Turnbull, Mohsen Shahtaheri, Sameer Gohir, Tony Kelly, Cindy McReynolds, Jun Yang, Rakesh R. Jha, Gwen S. Fernandes, Weiya Zhang, Michael Doherty, David A. Walsh, Bruce D. Hammock, Ana M. Valdes, David A. Barrett, Victoria Chapman
Journal: Arthritis & Rheumatology (2021)

Objective Chronic pain due to osteoarthritis (OA) is a major clinical problem, and existing analgesics often have limited beneficial effects and/or adverse effects, necessitating the development of novel therapies. Epoxyeicosatrienoic acids (EETs) are endogenous antiinflammatory mediators, rapidly metabolized by soluble epoxide hydrolase (EH) to dihydroxyeicosatrienoic acids (DHETs). We undertook this study to assess whether soluble EH–driven metabolism of EETs to DHETs plays a critical role in chronic joint pain associated with OA and provides a new target for treatment. Methods Potential associations of chronic knee pain with single‐nucleotide polymorphisms (SNPs) in the gene‐encoding soluble EH and with circulating levels of EETs and DHETs were investigated in human subjects. A surgically induced murine model of OA was used to determine the effects of both acute and chronic selective inhibition of soluble EH by N‐[1‐(1‐oxopropy)‐4‐piperidinyl]‐N′‐(trifluoromethoxy)phenyl]‐urea (TPPU) on weight‐bearing asymmetry, hind paw withdrawal thresholds, joint histology, and circulating concentrations of EETs and DHETs. Results In human subjects with chronic knee pain, 3 pain measures were associated with SNPs of the soluble EH gene EPHX2 , and in 2 separate cohorts of subjects, circulating levels of EETs and DHETs were also associated with 3 pain measures. In the murine OA model, systemic administration of TPPU both acutely and chronically reversed established pain behaviors and decreased circulating levels of 8,9‐DHET and 14,15‐DHET. EET levels were unchanged by TPPU administration. Conclusion Our novel findings support a role of soluble EH in OA pain and suggest that inhibition of soluble EH and protection of endogenous EETs from catabolism represents a potential new therapeutic target for OA pain.
Cumulative incidence and disease-specific survival of metastatic cutaneous squamous cell carcinoma: A nationwide cancer registry study
Authors: Selin Tokez, Marlies Wakkee, Wilner Kan, Zoe C. Venables, Antien L. Mooyaart, Marieke Louwman, Tamar Nijsten, Loes M. Hollestein
Journal: Journal of the American Academy of Dermatology (2021)

Cutaneous squamous cell carcinoma (cSCC) represents the most serious form of keratinocyte cancers because of its metastatic potential. Studies on nationwide incidence and disease-specific survival rates of metastatic cSCC (mcSCC) are lacking.To investigate the cumulative incidence and disease-specific survival of patients with mcSCC in the Dutch population and assess patient-based risk factors.We conducted a nationwide cancer registry study including all patients with the first cSCC in 2007 or 2008, using data from the Netherlands Cancer Registry, the nationwide network and registry of histopathology and cytopathology, and Statistics Netherlands. Cumulative incidence and Kaplan-Meier curves were calculated, and time-dependent Cox proportional hazards regression analyses were used.Of the 11,137 patients, metastases developed in 1.9% (n = 217). The median time to metastasis was 1.5 years (interquartile range 0.6-3.8 years). The risk factors were age (adjusted hazard ratio [aHR] 1.03, 95% CI 1.02-1.05), male sex (aHR 1.7, 95% CI 1.3-2.3), and immunosuppression (aHR [organ transplant recipient] 5.0, 95% CI 2.5-10.0; aHR [hematologic malignancy] 2.7, 95% CI 1.6-4.6). The 5-year disease-specific survival for patients with mcSCC was 79.1%.Only histopathologically confirmed mcSCCs were included.About 2% of cSCCs metastasize, with higher risk for men, increasing age, and immunocompromised patients. Disease-specific survival for patients with mcSCC is high.
P69.01 The Role of the Pregnancy Associated Protein Glycodelin and Its Influence on the Immune System in Non-Small-Cell Lung Cancer
Authors: S. Richtmann, T. Muley, P. Christopoulos, M. Thomas, H. Winter, U. Klingmüller, M. Meister, M. Schneider
Journal: Journal of Thoracic Oncology (2021)
Electronic Outpatient Referral System for Liver Transplant Improves Appropriateness and Allows First Visit Triage
Authors: Flaminia Ferri, Martina Milana, Aurelio Abbatecola, Alessandro Pintore, Ilaria Lenci, Simona Parisse, Alessandro Vitale, Gianluca Di Croce, Gianluca Mennini, Quirino Lai, Massimo Rossi, Roberta Angelico, Giuseppe Tisone, Alessandro Anselmo, Mario Angelico, Stefano Ginanni Corradini
Journal: Clinical Gastroenterology and Hepatology (2021)

Missed or inappropriate referrals of potential candidates for liver transplantation (LT) are common and traditional referral methods (tRs) do not allow for efficient triage. We investigated the effects of a website developed for electronic outpatient referral to LT (eRW-LT) on these issues.We prospectively collected data on all consecutive outpatient referrals to 2 Italian LT centers from January 2015 to December 2019. In the second half of the study, starting from July 2017, referring physicians had the option of using eRW-LT, quickly obtaining the judgment on the appropriateness and urgency of the visit from a transplant hepatologist.In the second half of the study, there were 99 eRW-LTs and 96 traditional referrals (new tRs), representing a 17.4% increase over the 161 traditional referrals (old tRs) of the first half. With eRW-LT, 11.1% of referrals were judged inappropriate online without booking a visit. Appropriateness, judged at the time of the first visit, was 59.6%, 56.2%, and 94.3% with old tRs, new tRs, and eRW-LT, respectively. Considering the appropriate visits, the median waiting time in days between referral date and first visit appointment was significantly shorter for urgent visits referred with eRW-LT (5.0; 95% CI, 4.8-9.3) compared with nonurgent visits sent with the same system (17.0; 95% CI, 11.5-25.0; P < .0001), those referred with old tRs (14.0; 95% CI, 8.0-23.0; P < .001) and with new tRs (16.0; 95% CI, 10.0-23.0; P < .001).eRW-LT allows an increase in the number of referrals for LT, ensuring effective triage and better appropriateness of visits.
P24.12 Biomarker Testing for Advanced Lung Cancer by Next-Generation Sequencing in Elderly Patients
Authors: L. Basbus, J.N. Minatta, Y. Ferreira, A. Antivero, J. Pandolfi, H. Garcia Rivello, M. Dalurzo, L. Lupinacci, F. Jauk
Journal: Journal of Thoracic Oncology (2021)
TCT-487 DynamX Bioadaptor, a Novel “Uncaging” Platform for Coronary Artery Revascularization: Final 36-Month Clinical Results
Authors: Antonio Colombo, Mathias Vrolix, Matteo Montorfano, Francesco Bedogni, Christophe Dubois, Bernard de Bruyne, Francesco Giannini, Carlo Zivelonghi, Alexandre Abizaid, Ricardo Costa, Jose Costa, Dean Kereiakes, Stefan Verheye
Journal: Journal of the American College of Cardiology (2021)
Roxadustat for the treatment of anemia in patients with <scp>lower‐risk</scp> myelodysplastic syndrome: Open‐label, dose‐selection, lead‐in stage of a phase 3 study
Authors: David H. Henry, John Glaspy, Rosemary Harrup, Moshe Mittelman, Amy Zhou, Hetty E. Carraway, Charles Bradley, Gopal Saha, Katharina Modelska, Pamela Bartels, Robert Leong, Kin‐Hung P. Yu
Journal: American Journal of Hematology (2021)

Abstract Anemia is the predominant cytopenia in myelodysplastic syndromes (MDS) and treatment options are limited. Roxadustat is a hypoxia‐inducible factor prolyl hydroxylase inhibitor approved for the treatment of anemia of chronic kidney disease in the UK, EU, China, Japan, South Korea, and Chile. MATTERHORN is a phase 3, randomized, double‐blind, placebo‐controlled study to assess the efficacy and safety of roxadustat in anemia of lower risk‐MDS. Eligible patients had baseline serum erythropoietin ≤ 400 mIU/mL, and a low packed RBC transfusion burden. In this open‐label (OL), dose‐selection, lead‐in phase, enrolled patients were assigned to 1 of 3 roxadustat starting doses ( n = 8 each): 1.5, 2.0, and 2.5 mg/kg. The primary efficacy endpoint of the OL phase was the proportion of patients with transfusion independence (TI) for ≥ 8 consecutive weeks in the first 28 treatment weeks. A secondary efficacy endpoint was the proportion of patients with a ≥ 50% reduction in RBC transfusions over an 8‐week period compared with baseline. Adverse events were monitored. Patients were followed for 52 weeks. Of the 24 treated patients, TI was achieved in 9 patients (37.5%) at 28 and 52 weeks; 7 of these patients were receiving 2.5 mg/kg dose when TI was achieved. A ≥ 50% reduction in RBC transfusions was achieved in 54.2% and 58.3% of patients at 28 and 52 weeks, respectively. Oral roxadustat dosed thrice weekly was well tolerated. There were no fatalities or progression to acute myeloid leukemia. Based on these outcomes, 2.5 mg/kg was the chosen starting roxadustat dose for the ongoing double‐blind study phase.
X-ray dark-field chest imaging for detection and quantification of emphysema in patients with chronic obstructive pulmonary disease: a diagnostic accuracy study
Authors: Konstantin Willer, Alexander A Fingerle, Wolfgang Noichl, Fabio De Marco, Manuela Frank, Theresa Urban, Rafael Schick, Alex Gustschin, Bernhard Gleich, Julia Herzen, Thomas Koehler, Andre Yaroshenko, Thomas Pralow, Gregor S Zimmermann, Bernhard Renger, Andreas P Sauter, Daniela Pfeiffer, Marcus R Makowski, Ernst J Rummeny, Philippe A Grenier, Franz Pfeiffer
Journal: The Lancet Digital Health (2021)

Although advanced medical imaging technologies give detailed diagnostic information, a low-dose, fast, and inexpensive option for early detection of respiratory diseases and follow-ups is still lacking. The novel method of x-ray dark-field chest imaging might fill this gap but has not yet been studied in living humans. Enabling the assessment of microstructural changes in lung parenchyma, this technique presents a more sensitive alternative to conventional chest x-rays, and yet requires only a fraction of the dose applied in CT. We studied the application of this technique to assess pulmonary emphysema in patients with chronic obstructive pulmonary disease (COPD).
Replication stress response defects are associated with response to immune checkpoint blockade in nonhypermutated cancers
Authors: Daniel J. McGrail, Patrick G. Pilié, Hui Dai, Truong Nguyen Anh Lam, Yulong Liang, Leonie Voorwerk, Marleen Kok, Xiang H.-F. Zhang, Jeffrey M. Rosen, Amy B. Heimberger, Christine B. Peterson, Eric Jonasch, Shiaw-Yih Lin
Journal: Science Translational Medicine (2021)

Treatment with immune checkpoint blockade (ICB) has resulted in durable responses for a subset of patients with cancer, with predictive biomarkers for ICB response originally identified largely in the context of hypermutated cancers. Although recent clinical data have demonstrated clinical responses to ICB in certain patients with nonhypermutated cancers, previously established ICB response biomarkers have failed to accurately identify which of these patients may benefit from ICB. Here, we demonstrated that a replication stress response (RSR) defect gene expression signature, but not other proposed biomarkers, is associated with ICB response in 12 independent cohorts of patients with nonhypermutated cancer across seven tumor types, including those of the breast, prostate, kidney, and brain. Induction or suppression of RSR deficiencies was sufficient to modulate response to ICB in preclinical models of breast and renal cancers. Mechanistically, we found that despite robust activation of checkpoint kinase 1 signaling in RSR-deficient cancer cells, aberrant replication origin firing caused exhaustion of replication protein A, resulting in accumulation of immunostimulatory cytosolic DNA. We further found that deficient RSR coincided with increased intratumoral dendritic cells in both mouse cancer models and human tumors. Together, this work demonstrates that the RSR defect gene signature can accurately identify patients who may benefit from ICB across numerous nonhypermutated tumor types, and pharmacological induction of RSR defects may further expand the benefits of ICB to more patients.
Update of the Blood Lead Reference Value — United States, 2021
Authors: Perri Zeitz Ruckart, Robert L. Jones, Joseph G. Courtney, Tanya Telfair LeBlanc, Wilma Jackson, Mateusz P. Karwowski, Po-Yung Cheng, Paul Allwood, Erik R. Svendsen, Patrick N. Breysse
Journal: MMWR Morbidity and Mortality Weekly Report (2021)

The negative impact of lead exposure on young children and those who become pregnant is well documented but is not well known by those at highest risk from this hazard. Scientific evidence suggests that there is no known safe blood lead level (BLL), because even small amounts of lead can be harmful to a child's developing brain (1). In 2012, CDC introduced the population-based blood lead reference value (BLRV) to identify children exposed to more lead than most other children in the United States. The BLRV should be used as a guide to 1) help determine whether medical or environmental follow-up actions should be initiated for an individual child and 2) prioritize communities with the most need for primary prevention of exposure and evaluate the effectiveness of prevention efforts. The BLRV is based on the 97.5th percentile of the blood lead distribution in U.S. children aged 1-5 years from National Health and Nutrition Examination Survey (NHANES) data. NHANES is a complex, multistage survey designed to provide a nationally representative assessment of health and nutritional status of the noninstitutionalized civilian adult and child populations in the United States (2). The initial BLRV of 5 μg/dL, established in 2012, was based on data from the 2007-2008 and 2009-2010 NHANES cycles. Consistent with recommendations from a former advisory committee, this report updates CDC's BLRV in children to 3.5 μg/dL using NHANES data derived from the 2015-2016 and 2017-2018 cycles and provides helpful information to support adoption by state and local health departments, health care providers (HCPs), clinical laboratories, and others and serves as an opportunity to advance health equity and environmental justice related to preventable lead exposure. CDC recommends that public health and clinical professionals focus screening efforts on populations at high risk based on age of housing and sociodemographic risk factors. Public health and clinical professionals should collaborate to develop screening plans responsive to local conditions using local data. In the absence of such plans, universal BLL testing is recommended. In addition, jurisdictions should follow the Centers for Medicare & Medicaid Services requirement that all Medicaid-enrolled children be tested at ages 12 and 24 months or at age 24-72 months if they have not previously been screened (3).
Effect of CRTH2 antagonism on the response to experimental rhinovirus infection in asthma: a pilot randomised controlled trial
Authors: Hugo Farne, Nicholas Glanville, Nicholas Johnson, Tata Kebadze, Julia Aniscenko, Eteri Regis, Jie Zhu, Maria-Belen Trujillo-Torralbo, Onn Min Kon, Patrick Mallia, A Toby Prevost, Michael R Edwards, Sebastian L Johnston, Aran Singanayagam, David J Jackson
Journal: Thorax (2021)

Background and aims The chemoattractant receptor-homologous molecule expressed on T helper type 2 cells (CRTH2) antagonist timapiprant improved lung function and asthma control in a phase 2 study, with evidence suggesting reduced exacerbations. We aimed to assess whether timapiprant attenuated or prevented asthma exacerbations induced by experimental rhinovirus (RV) infection. We furthermore hypothesised that timapiprant would dampen RV-induced type 2 inflammation and consequently improve antiviral immune responses. Methods Atopic patients with partially controlled asthma on maintenance inhaled corticosteroids were randomised to timapiprant (n=22) or placebo (n=22) and challenged with RV-A16 3 weeks later. The primary endpoint was the cumulative lower respiratory symptom score over the 14 days post infection. Upper respiratory symptoms, spirometry, airway hyperresponsiveness, exhaled nitric oxide, RV-A16 virus load and soluble mediators in upper and lower airways samples, and CRTH2 staining in bronchial biopsies were additionally assessed before and during RV-A16 infection. Results Six subjects discontinued the study and eight were not infected; outcomes were assessed in 16 timapiprant-treated and 14 placebo-treated, successfully infected subjects. There were no differences between treatment groups in clinical exacerbation severity including cumulative lower respiratory symptom score day 0–14 (difference 3.0 (95% CI −29.0 to 17.0), p=0.78), virus load, antiviral immune responses, or RV-A16-induced airway inflammation other than in the bronchial biopsies, where CRTH2 staining was increased during RV-A16 infection in the placebo-treated but not the timapiprant-treated group. Timapiprant had a favourable safety profile, with no deaths, serious adverse events or drug-related withdrawals. Conclusion Timapiprant treatment had little impact on the clinicopathological changes induced by RV-A16 infection in partially controlled asthma.
Adolescents’ Concerns About School Violence or Shootings and Association With Depressive, Anxiety, and Panic Symptoms
Authors: Kira E. Riehm, Ramin Mojtabai, Leslie B. Adams, Evan A. Krueger, Delvon T. Mattingly, Paul S. Nestadt, Adam M. Leventhal
Journal: JAMA Network Open (2021)

<h3>Importance</h3> The prevalence of internalizing problems among US adolescents has risen in the past decade. The extent to which concerns about school violence or shootings are associated with risk of internalizing problems is unknown. <h3>Objective</h3> To examine the prospective association of concern, worry, and stress related to school violence or shootings with internalizing problems and to examine sex and racial and ethnic differences in the magnitude of the associations. <h3>Design, Setting, and Participants</h3> This longitudinal cohort study involved 3 surveys administered 6 months apart (fall of grade 11 [prebaseline]; spring of grade 11 [baseline]; and fall of grade 12 [follow-up]) from 2015 to 2016. Participants included 2263 students from 10 high schools in Los Angeles, California. Analyses were performed from April 29, 2020, to April 8, 2021. <h3>Exposures</h3> Baseline self-reported level of concern, worry, and stress about shootings or violence at the student's school or other schools, each rated on 5-point scales (ranging from not at all [0] to extremely [4]) with a mean score calculated as a 3-item composite index rescaled into<i>z</i>-score standard deviation units. <h3>Main Outcomes and Measures</h3> Surpassing clinically significant or borderline significant thresholds for major depressive disorder, generalized anxiety disorder, or panic disorder based on symptom ratings on the Revised Children's Anxiety and Depression Scale at 6-month follow-up. <h3>Results</h3> Of the 2263 students included in the analyses (1250 [55.2%] girls; mean [SD] age, 16.5 [0.4] years), appreciable proportions reported being very or extremely concerned (850 0f 2226 [38.2%]), worried (703 of 2209 [31.8%]), or stressed (332 of 2183 [15.2%]) about shootings or violence at their school or other schools. After adjusting for prebaseline covariates, concerns about school violence or shootings were associated with clinically significant generalized anxiety symptoms (odds ratio [OR], 1.31; 95% CI, 1.15-1.50) and panic symptoms (OR, 1.18; 95% CI, 1.05-1.32), but not depressive symptoms (OR, 1.13; 95% CI, 0.99-1.30) at the 6-month follow-up. There was a significant association between concern with school violence or shootings and depressive symptoms for Black youth (OR, 3.15; 95% CI, 1.38-7.19) and non-Hispanic/Latinx White youth (OR, 1.62 [95% CI, 1.25-2.09]) but not for youth of other races and ethnicities (OR for Asian, 1.26 [95% CI, 0.86-1.85]; OR for Hispanic/Latinx, 0.94 [95% CI, 0.76-1.16]; OR for other, 0.93 [95% CI, 0.54-1.61]). Sex did not moderate these associations. <h3>Conclusions and Relevance</h3> The findings of this study suggest that concern, worry, and stress related to school violence or shootings may be risk factors for internalizing problems among adolescents, with variation in the strength of the association by race/ethnicity.
投影分解光干渉断層血管造影により見た神経叢特異的網膜血管解剖と病理【JST・京大機械翻訳】
Authors: T Hormel Tristan, Jia Yali, Jian Yifan, S Hwang Thomas, T Bailey Steven, E Pennesi Mark, J Wilson David, C Morrison John, Huang David
Journal: Progress in Retinal and Eye Research (2021)