tbuckley/cabot-search huggingface dataset:
Vemurafenib for Refractory Multisystem Langerhans Cell Histiocytosis in Children: An International Observational Study
Authors: Jean Donadieu, Islam Amine Larabi, Mathilde Tardieu, Johannes Visser, Caroline Hutter, Elena Sieni, Nabil Kabbara, Mohamed Barkaoui, Jean Miron, François Chalard, Paul Milne, Julien Haroche, Fleur Cohen, Zofia Hélias-Rodzewicz, Nicolas Simon, Mathilde Jehanne, Alexandra Kolenova, Anne Pagnier, Nathalie Aladjidi, Pascale Schneider, Geneviève Plat, Anne Lutun, Anne Sonntagbauer, Thomas Lehrnbecher, Alina Ferster, Viktoria Efremova, Martina Ahlmann, Laurence Blanc, James Nicholson, Anne Lambilliote, Houda Boudiaf, Andrej Lissat, Karel Svojgr, Fanette Bernard, Sarah Elitzur, Michal Golan, Dmitriy Evseev, Michael Maschan, Ahmed Idbaih, Olga Slater, Milen Minkov, Valerie Taly, Matthew Collin, Jean-Claude Alvarez, Jean-François Emile, Sébastien Héritier
Journal: Journal of Clinical Oncology (2019)

PURPOSE Off-label use of vemurafenib (VMF) to treat BRAF V600E mutation–positive, refractory, childhood Langerhans cell histiocytosis (LCH) was evaluated. PATIENTS AND METHODS Fifty-four patients from 12 countries took VMF 20 mg/kg/d. They were classified according to risk organ involvement: liver, spleen, and/or blood cytopenia. The main evaluation criteria were adverse events (Common Terminology Criteria for Adverse Events [version 4.3]) and therapeutic responses according to Disease Activity Score. RESULTS LCH extent was distributed as follows: 44 with positive and 10 with negative risk organ involvement. Median age at diagnosis was 0.9 years (range, 0.1 to 6.5 years). Median age at VMF initiation was 1.8 years (range, 0.18 to 14 years), with a median follow-up of 22 months (range, 4.3 to 57 months), whereas median treatment duration was 13.9 months (for 855 patient-months). At 8 weeks, 38 complete responses and 16 partial responses had been achieved, with the median Disease Activity Score decreasing from 7 at diagnosis to 0 ( P &lt; .001). Skin rash, the most frequent adverse event, affected 74% of patients. No secondary skin cancer was observed. Therapeutic plasma VMF concentrations (range, 10 to 20 mg/L) seemed to be safe and effective. VMF discontinuation for 30 patients led to 24 LCH reactivations. The blood BRAF V600E allele load, assessed as circulating cell-free DNA, decreased after starting VMF but remained positive (median, 3.6% at diagnosis, and 1.6% during VMF treatment; P &lt; .001) and was associated with a higher risk of reactivation at VMF discontinuation. None of the various empirical therapies (hematopoietic stem-cell transplantation, cladribine and cytarabine, anti-MEK agent, vinblastine, etc) used for maintenance could eradicate the BRAF V600E clone. CONCLUSION VMF seemed safe and effective in children with refractory BRAF V600E -positive LCH. Additional studies are needed to find effective maintenance therapy approaches.
Features of Fecal and Colon Microbiomes Associate With Responses to Biologic Therapies for Inflammatory Bowel Diseases: A Systematic Review
Authors: Maria Manuela Estevinho, Cátia Rocha, Luís Correia, Paula Lago, Paula Ministro, Francisco Portela, Eunice Trindade, Joana Afonso, Laurent Peyrin-Biroulet, Fernando Magro
Journal: Clinical Gastroenterology and Hepatology (2019)
Early Identification of People Who Would Benefit From a Palliative Approach—Moving From Surprise to Routine
Authors: James Downar, Pete Wegier, Peter Tanuseputro
Journal: JAMA Network Open (2019)

Kei Ouchi, MD, MPH; Tania Strout, PhD, RN, MS; Samir Haydar, DO, MPH; Olesya Baker, PhD; Wei Wang, PhD; Rachelle Bernacki, MD, MS; Rebecca Sudore, MD; Jeremiah D. Schuur, MD, MHS; Mara A. Schonberg, MD, MPH; Susan D. Block, MD; James A. Tulsky, MD
The impact of weight loss beyond lung function: benefit with respect to asthma outcomes
Authors: Lília Maia Santos, Bárbara Ramos, João Almeida, Cláudia Chaves Loureiro, Carlos Robalo Cordeiro
Journal: Pulmonology (2019)

We evaluated the effect of weight loss (WL) on lung function (LF) in obese individuals who underwent bariatric surgery, and on asthma control, quality of life, LF, and controller medication in a sub-group of obese asthma (OA) patients. Obese individuals who underwent bariatric surgery between July 2015 and July 2017 were included in this prospective longitudinal study. They were classified as OA or obese non-asthmatics (O-NA). LF was assessed preoperatively and 6–9 months postoperatively. In OA patients, asthma control, quality of life, and treatment step were evaluated. P < 0.05 was considered significant. Twenty-six patients (OA: n = 8; O-NA: n = 18), 84.6% with class III obesity were enrolled. Preoperatively, OA patients showed worse values of LF parameters, with upper and lower airway CARAT scores of 6.1 ± 3.1 and 13.4 ± 4.1, respectively, and 75% were in step 4 of treatment. After WL, improvements in dynamic volumes, lung capacities, and total resistance were observed in both groups. Despite greater increases in OA patients, no significant differences were observed between groups. In OA patients, improvements in CARAT score of upper (3.9 ± 1.9, p = 0.017) and lower (4.2 ± 4.4, p = 0.027) airways, and in Asthma Life Quality scores (8.1 ± 5.6, p = 0.017) were observed along with a decrease (−1.8 ± 1.0, p = 0.017) in treatment step. All LF parameters improved after WL. Although the improvement was greater in OA patients, the difference between groups was not significant. Significant improvement from baseline in uncontrolled symptoms of OA patients and quality of life was observed after WL, along with a significant decrease in treatment step.
Targeted COX-2 and EGFR TK inhibition in advanced non-small cell lung cancer
Authors: K. L. Reckamp, J. Czernin, W. A. Weber, S. M. Dubinett, R. A. Figlin
Journal: Journal of Clinical Oncology (2006)

7179 Background: Prostaglandin E2 (PGE2) activates Erk/MAPK signaling pathway in an epidermal growth factor receptor (EGFR) tyrosine kinase (TK)-resistant manner as a result of cyclooxygenase-2 (COX-2) overexpressed in lung cancer. Because 10% of patients respond to this class of drugs, evaluating agents that may overcome resistance and determining the population of patients most likely to respond is crucial. Imaging tumor metabolism by positron emission tomography with the glucose analog fluorodeoxyglucose (FDG-PET) is an innovative approach for assessing the efficacy of targeted agents. We studied the combination of COX-2 inhibition (celecoxib) and EGFR inhibition (erlotinib) in a phase I trial in advanced non-small cell lung cancer (NSCLC) and added FDG-PET imaging as a potential method for evaluation of early response. Methods: A phase I, dose escalation trial to investigate the optimal biologic dose (OBD) of the combination of celecoxib and erlotinib in pts with refractory stage IIIB/IV NSCLC. FDG-PET was evaluated in selected patients at baseline, week 2 and week 8 of study treatment. Tumor metabolic activity was quantitatively assessed by standardized uptake values (SUV). Changes in SUV were compared to CT imaging at week 8 with response defined by RECIST criteria. Results: Twenty-two subjects were enrolled and 21 were evaluable for the determination of the OBD, toxicity assessment and response. Rash and skin-related effects were the most commonly reported toxicities. Seven patients demonstrated partial responses and five patients developed stable disease. Responses were seen in patients both with and without EGFR activating mutations. The duration of partial response was 24–93 wks. TTP was 83 weeks in one patient with stable disease. A patient evaluated by FDG-PET had a significant decrease in SUV (-45%) at week 2 which corresponded to partial responses by RECIST at week 8. Conclusions: FDG-PET as a measure of tumor glucose utilization appears to be a promising tool for assessing early response to targeted therapies. A randomized Phase II trial is planned comparing erlotinib and celecoxib with erlotinib plus placebo in advanced NSCLC, and evaluating FDG-PET response as a marker of early efficacy. Supported by UCLA Lung Cancer SPORE NCI P50 CA 90388, GLAVAHS CDA and STOP Cancer Award. [Table: see text]
Fitness scale-4 item (FS4) to predict six-month postoperative mortality of cancer patients aged 75.
Authors: Armin Shahrokni, Saman Sarraf, Robert J. Downey, Koshy Alexander, Beatriz Korc-Grodzicki
Journal: Journal of Clinical Oncology (2019)

11542 Background: We have been prospectively collecting Geriatric Assessment (GA) data on patients aged 75+ undergoing oncologic surgery at a single institution. We aimed to to determine if a fitness scale based on a limited number of easily captured datafields can be developed, validated, and associated with 6 month postoperative mortality. Methods: From patients referred to Memorial Sloan Kettering (MSK) Geriatrics Service for preoperative GA since 2015, we have selected patients who were aged 75+, had elective surgery, with hospital length of stay (LOS) of ≥1 day, and had at least 6-month follow up. The Fitness Scale-4 item (FS4) is composed of 3 variables from the GA; Karnofsky Performance Scale (KPS), ability to walk outside, ability to perform housekeeping, and additional variable of preoperative albumin level. The FS4 total score ranges from 0-8 (frail = 0-2, vulnerable = 3-5, and fit = 6+). We validated this scale against prevalence of geriatric syndromes in each fitness category. We performed multivariable regression (MVR) analysis to assess the odds of six-month postoperative mortality among vulnerable and frail patients vs. fit patients. Results: Out of 1270 patients (median age 79, IQR 77-83), 792 (61.4%), 327 (25.7%) and 151 (11.9%) were fit, vulnerable, and frail, respectively. All of the geriatric syndromes were more prevalent among frail and vulnerable patients than fit patients. Six-month mortality rate was 4.7%, 12.5%, and 21.2% for fit, vulnerable, and frail patients, respectively. In the MVR analysis, and after adjustment for age, gender, ASA PS, LOS, operation time, KPS, and preoperative albumin, the odds of six-month mortality among frail (OR = 4.58, p = 0.004) and vulnerable patients (OR = 2.63, p = 0.004) vs. fit patients were much higher. Conclusions: Frail and vulnerable patients based on FS4 are at significantly higher risk for six-month postoperative mortality vs. fit patients. Future studies should assess the external validation of FS4, and its impact on surgical decision making, and perioperative care of older cancer patients.
Extracellular RNA released due to shear stress controls natural bypass growth by mediating mechanotransduction in mice
Authors: Manuel Lasch, Eike Christian Kleinert, Sarah Meister, Konda Kumaraswami, Judith-Irina Buchheim, Tobias Grantzow, Thomas Lautz, Sofia Salpisti, Silvia Fischer, Kerstin Troidl, Ingrid Fleming, Anna M. Randi, Markus Sperandio, Klaus T. Preissner, Elisabeth Deindl
Journal: Blood (2019)
Global Variation in Opioid Use in Prostate Cancer Trials
Authors: Jessica K. Roydhouse, Daniel L. Suzman, Laurel A. Menapace, Pallavi S. Mishra-Kalyani, Rajeshwari Sridhara, Gideon M. Blumenthal, Julia A. Beaver, Richard Pazdur, Paul G. Kluetz
Journal: JAMA Oncology (2019)

Regional variation in opioid use may be attenuated when pharmaceutical-sponsored trials include care that is often standardized by protocols. Understanding such variation is important for global trials that sometimes include time to opioid use as an end point.To identify whether regional and country-level variation in opioid use exists among prostate cancer clinical trials across the world.International phase 3 randomized clinical trials with patients with metastatic prostate cancer and initiation from January 1, 2008, or later were identified through internal databases of the US Food and Drug Administration. Data of patients in the intention-to-treat population from each trial were pooled. Descriptive and regression analyses of the collected data were conducted from September 2018 to February 2019.Cancer therapy.Opioid use data were from concomitant medications reported in the database for each trial. Logistic regression models, descriptive statistics, and χ2 tests were used to compare opioid use across world regions while adjusting for patient age, presence of visceral disease, bony disease, and baseline Eastern Cooperative Oncology Group Performance Status score and pain score.In total, 9670 patients (mean [SD] age of 69.2 [8.3] years) from 8 prostate cancer clinical trials in 46 countries were included. Patients in Eastern Europe (adjusted odds ratio [AOR], 0.19; 95% CI, 0.16-0.22) and Asia (AOR, 0.31; 95% CI, 0.25-0.38) were less likely to use opioids compared with patients in North America. These findings held even when the analysis was restricted to patients who reported moderate to high pain levels at baseline (Eastern Europe: AOR, 0.16 [95% CI, 0.12-0.22]; Asia: AOR, 0.47 [95% CI, 0.29-0.79]). Within North America, rates of opioid use were similar between the United States and Canada (AOR, 1.13; 95% CI, 0.93-1.37).This study found that, despite the clinical trial setting, opioid use appeared to vary by world regions, suggesting that this variability should be considered in international clinical trials.
Body Mass Index Drives Changes in DNA Methylation
Authors: Dianjianyi Sun, Tao Zhang, Shaoyong Su, Guang Hao, Tao Chen, Quan-Zhen Li, Lydia Bazzano, Jiang He, Xiaoling Wang, Shengxu Li, Wei Chen
Journal: Circulation Research (2019)

Previous EWASs (Epigenome-Wide Association Studies) suggest that obesity may be the cause, not a consequence, of changes in DNA methylation (DNAm). However, longitudinal observations are lacking.To identify 5'-cytosine-phosphate-guanine-3' in DNA (CpG) sites associated with body mass index (BMI) and examine the temporal relationship between dynamic changes in DNAm and BMI in a longitudinal cohort.Race-specific EWASs were performed in 995 whites and 490 blacks from the Bogalusa Heart Study. Suggestive CpG sites were further replicated in 252 whites and 228 blacks from the Georgia Stress and Heart Study. Cross-lagged panel analysis was used to examine the temporal relationship between DNAm and BMI in 439 whites and 201 blacks who were examined twice 6.2 years apart. In discovery and replication samples, 349 CpG sites (266 novel) in whites and 36 (21 novel) in blacks were identified to be robustly associated with BMI, with 8 (1 novel) CpG sites overlapping between the 2 races. Cross-lagged panel analyses showed significant unidirectional paths (PFDR <0.05) from baseline BMI to follow-up DNAm at 18 CpG sites in whites and 7 in blacks; no CpG sites showed significant paths from DNAm at baseline to BMI at follow-up. Baseline BMI was associated with a DNAm score (calculated from DNAm levels at the associated CpG sites) at follow-up (P<0.001 both in blacks and in whites).The findings provide strong evidence that obesity is the cause, not a consequence, of changes in DNAm over time.
Establishing the Prevalence and Prevalence at Birth of Hemophilia in Males
Authors: Alfonso Iorio, Jeffrey S. Stonebraker, Hervé Chambost, Michael Makris, Donna Coffin, Christine Herr, Federico Germini
Journal: Annals of Internal Medicine (2019)

The large observed variability in hemophilia prevalence prevents robust estimation of burden of disease.To estimate the prevalence and prevalence at birth of hemophilia and the associated life expectancy disadvantage.Random-effects meta-analysis of registry data.Australia, Canada, France, Italy, New Zealand, and the United Kingdom.Male patients with hemophilia A or B.Prevalence of hemophilia as a proportion of cases to the male population, prevalence of hemophilia at birth as a proportion of cases to live male births by year of birth, life expectancy disadvantage as a 1 - ratio of prevalence to prevalence at birth, and expected number of patients worldwide based on prevalence in high-income countries and prevalence at birth.Prevalence (per 100 000 males) is 17.1 cases for all severities of hemophilia A, 6.0 cases for severe hemophilia A, 3.8 cases for all severities of hemophilia B, and 1.1 cases for severe hemophilia B. Prevalence at birth (per 100 000 males) is 24.6 cases for all severities of hemophilia A, 9.5 cases for severe hemophilia A, 5.0 cases for all severities of hemophilia B, and 1.5 cases for severe hemophilia B. The life expectancy disadvantage for high-income countries is 30% for hemophilia A, 37% for severe hemophilia A, 24% for hemophilia B, and 27% for severe hemophilia B. The expected number of patients with hemophilia worldwide is 1 125 000, of whom 418 000 should have severe hemophilia.Details were insufficient to adjust for comorbid conditions and ethnicity.The prevalence of hemophilia is higher than previously estimated. Patients with hemophilia still have a life expectancy disadvantage. Establishing prevalence at birth is a milestone toward assessing years of life lost, years of life with disability, and burden of disease.None.
OR21, a New Oral DNA Methyltransferase Inhibitor for Treatment of MDS and AML
Authors: Hiroshi Ureshino, Tatsuro Watanabe, Yuki Kurahashi, Yuki Fukuda Kurahashi, Kaoru Tohyama, Seiji Okada, Toshikazu Ushijima, Hiroshi Ureshino
Journal: Blood (2018)
Chronotype, Social Jet Lag, and Cardiometabolic Risk Factors in Early Adolescence
Authors: Elizabeth M. Cespedes Feliciano, Sheryl L. Rifas-Shiman, Mirja Quante, Susan Redline, Emily Oken, Elsie M. Taveras
Journal: JAMA Pediatrics (2019)

Inadequate sleep duration and quality increase the risk of obesity. Sleep timing, while less studied, is important in adolescents because increasing evening preferences (chronotypes), early school start times, and irregular sleep schedules may cause circadian misalignment.To investigate associations of chronotype and social jet lag with adiposity and cardiometabolic risk in young adolescents.Starting in 1999, Project Viva recruited pregnant women from eastern Massachusetts. Mother-child in-person visits occurred throughout childhood. From January 23, 2012, to October 16, 2016, 804 adolescents aged 12 to 17 years completed 5 days or more of wrist actigraphy, questionnaires, and anthropometric measurements. A cross-sectional analysis using these data was conducted from April 31, 2018, to May 1, 2019.Chronotype, measured via a continuous scale with higher scores indicating greater evening preferences, and social jet lag, measured as the continuous difference in actigraphy sleep midpoint in hours from midnight on weekends vs weekdays, with higher values representing more delayed sleep timing on weekends.Adiposity, measured via anthropometry and dual-energy x-ray absorptiometry. For a subset of 479 adolescents with blood samples, cardiometabolic risk scores were computed as the mean of 5 sex- and cohort-specific z scores for waist circumference, systolic blood pressure, inversely scaled high-density lipoprotein cholesterol, and log-transformed triglycerides and homeostatic model of insulin resistance.Among the 804 adolescents in the study, 418 were girls and 386 were boys, with a mean (SD) age of 13.2 (0.9) years. In multivariable models adjusted for age, puberty, season, and sociodemographics, associations of chronotype and social jet lag with adiposity varied by sex. For girls, greater evening preference was associated with a 0.58-cm (95% CI, 0.12-1.03 cm; P = .04 for interaction) higher waist circumference and 0.16 kg/m2 (95% CI, 0.01-0.31 kg/m2; P = .03 for interaction) higher fat mass index as measured by dual-energy x-ray absorptiometry; each hour of social jet lag was associated with a 1.19-cm (95% CI, 0.04-2.35 cm; P = .21 for interaction) higher waist circumference and 0.45 kg/m2 (95% CI, 0.09-0.82 kg/m2; P = .01 for interaction) higher fat mass index as measured by dual-energy x-ray absorptiometry. Associations of social jet lag and evening chronotypes persisted for many measures of adiposity after adjustment for sleep duration and other lifestyle behaviors. By contrast, no associations were observed in boys. There were no associations with the cardiometabolic risk score for either sex, although statistical power was low for this outcome.Evening chronotypes and social jet lag were associated with greater adiposity in adolescent girls but not adolescent boys. Interventions aimed at improving sleep schedules may be useful for obesity prevention, especially in girls.
Effect of Immersive Virtual Reality Education Before Chest Radiography on Anxiety and Distress Among Pediatric Patients
Authors: Sung-Hee Han, Jin-Woo Park, Sang Il Choi, Ji Young Kim, Hyunju Lee, Hee-Jeong Yoo, Jung-Hee Ryu
Journal: JAMA Pediatrics (2019)

Pediatric patients often encounter anxiety and distress in hospital settings, and virtual reality education, providing a vivid, immersive, and realistic experience, has been introduced to mitigate these anxiety responses.To evaluate whether virtual reality education for pediatric patients before chest radiography could reduce anxiety and distress in children and improve the radiographic process.This prospective randomized clinical trial was conducted in a tertiary academic hospital in Seongnam, Republic of Korea. Participants (n = 112) were children aged 4 to 8 years who underwent chest radiography between July 20, 2018, and September 11, 2018. Analysis was performed from October 2, 2018, to April 23, 2019.Children were randomized to simple verbal instruction (control group) or 3-minute virtual reality education explaining the process of chest radiography in detail and leading to appropriate cooperation (virtual reality group).The primary outcome was anxiety and distress among pediatric patients based on behavioral observations using the amended version of the Observational Scale of Behavioral Distress scale for radiology procedures (total score of 30, with a score <5 indicating less distressed and a score ≥5 indicating more distressed). Secondary outcomes were the need of parental presence, parental satisfaction score, procedure time, number of repeated images, and process difficulty score.Of 99 children included in the final analysis, 50 (50.5%) were allocated to the control group (mean [SD] age, 5.6 [1.2] years; 26 boys [52.0%]) and 49 (49.5%) to the virtual reality group (mean [SD] age, 5.8 [1.3] years; 32 boys [65.3%]). The mean (SD) score for anxiety and distress (2.0 [3.7] vs 5.0 [6.1]; mean difference, 3.0 [95% CI, 1.0-5.0]; P = .004), need for parental presence (8 cases with parents present [16.3%] vs 18 cases with parents present [36.0%]), and mean (SD) procedure time (55.1 [21.6] seconds vs 75.0 [42.0] seconds) were lower in the virtual reality group than in the control group. The mean (SD) score for parental satisfaction (9.4 [1.4] vs 8.6 [2.0]) was higher in the virtual reality group than in the control group.Virtual reality education before chest radiography improved the radiography experience among pediatric patients by reducing anxiety, distress, and procedure time while increasing parents' satisfaction.UMIN Clinical Trials Registry: UMIN000030663.
Kantian indifference about moral reason
Authors: Adam J Roberts
Journal: Behavioral and Brain Sciences (2019)

Abstract The pessimistic arguments May challenges depend on an anti-Kantian philosophical assumption. That assumption is that what I call philosophical optimists about moral reason are also committed to empirical optimism, or what May calls “optimistic rationalism.” I place May's book in the literature by explaining how that assumption is resisted by Christine Korsgaard, one of May's examples of a contemporary Kantian.