tbuckley/cabot-search huggingface dataset:
New Combination Therapy for Cystic Fibrosis
Authors: Anita Slomski
Journal: JAMA (2018)

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Complete molecular testing in AML.
Authors: Travis Grant Williams, Siddhartha Ganguly, Joseph McGuirk, Heather Jean Male, Allan Fleming, Omar Salah Aljitawi, Sunil H. Abhyankar, Tara L. Lin
Journal: Journal of Clinical Oncology (2014)

e18016 Background: Historically, cytogenetics has been the most significant predictor of outcome in Acute Myeloid Leukemia (AML). In 2008, the WHO revised its classification to recognize molecular markers in normal cytogenetics AML (CN-AML), including mutations in FLT3, NPM1 and CEBPα. In 2006, the c-Kit mutation was associated with increased risk of recurrence in core binding factor (CBF) AML. The National Comprehensive Cancer Network incorporate molecular testing into prognosis and treatment recommendations. Given their significance, we studied patterns of complete molecular evaluations in newly diagnosed AML. We hypothesized that rates of molecular testing would be higher in an academic center versus community practice sites. Methods: A retrospective chart review included all de novo AML patients (excluding M3) at Kansas University Medical Center (KUMC) from January, 2008 through April, 2013. Records were evaluated for completeness of molecular testing as indicated by karyotype (FLT3, CEBPα, NPM1 in CN-AML and c-KIT in CBF AML). Data was collected for those diagnosed at KUMC or referred to KUMC for initial chemotherapy or stem cell transplant evaluation. Results: 271 charts were reviewed: 98 with CN-AML and 29 with CBF AML. 70 were diagnosed at KUMC, 57 at a community site. Molecular testing was sent in 76/98 (77%) patients with CN-AML. Patients diagnosed at KUMC had a significantly higher rate of molecular testing (51/55, 93%) as compared to those diagnosed at outside centers (18/43,41%) (p=0.0029). Of 29 patients with CBF AML, c-kit mutational analysis was done more frequently at KUMC (14/15, 93%) than in community sites (8/14, 57%) (p=.26). There was a trend towards increased testing at both KUMC and community sites in later years. Conclusions: In the five years from the WHO revision of AML, rates of molecular testing in CBF and CN-AML were higher in an academic center versus community sites. Although we were unable to review charts of patients treated outside KUMC, it provides information regarding adoption of guidelines for molecular testing in AML. All physicians who diagnose and treat AML must remain up to date on the latest recommendations and controversies in molecular testing in order to appropriately risk stratify patients and determine optimal therapy.
High-dose carmustine (BCNU), etoposide (VP-16), cytarabine (Ara-C), and cyclophosphamide-BVAC with autologous transplant (ASCT) in relapsed and refractory Hodgkin disease (HD): Long-term follow-up of 89 patients
Authors: T. Iyengar, M. Hayashi, C. Leopold, B. J. Smith, R. Gingrich, T. Carter, M. de Magalhaes-Silverman
Journal: Journal of Clinical Oncology (2007)

8068 Background: High dose chemotherapy followed by ASCT has been established as the therapy for refractory and relapsed HD. Relapse remains the primary contributor to an unsuccessful outcome after ASCT. Intensification of the conditioning regimen is one means of decreasing relapse and improving results. We report our experience with an augmented preparative regimen in patients (pts) with relapsed or refractory HD undergoing ASCT. Methods: Retrospective analysis of 89 consecutive pts from October 1984 to October 2004. All pts received high-dose chemotherapy with BCNU 600mg/m 2 IV day -8, Etoposide 400mg/m 2 /day days -7, -6, -5, and -4, Ara-C 3gm/m2 IV every 12 hours for 8 doses starting day -7, and Cyclophosphamide 90mg/kg IV on day-2 followed by bone marrow (40 pts), peripheral blood (43 pts) or both (6 pts) rescue. Ten pts received planned XRT post-transplant. Survival data were estimated using Kaplan-Meier curves. Cox proportional hazards regression was used to assess the impact of variables on disease-free survival (DFS) and overall survival (OS). Results: A total of 89 pts were identified. Median age was 31 (range 16–62); 51 pts (57.3%) had received one prior therapy at the time of transplant. At transplant only 28 pts (34.6%) were in CR; 79.8% had sensitive disease (CR plus PR).Time to transplant was &lt; 1 year for 17% of pts. With a median follow-up of 811 days, the 5 and 10-year DFS rates were 63.3% and 60.4%, respectively. The estimated 5 and 10- year OS rates were 47.3% and 33.7%. The rate of secondary malignancies at 10 years was 7.8%. Lack of B symptoms and stage at transplant were associated with improved DFS (p= 0.01 and p= 0.0005, respectively) and OS (p=0.002 and p=0.02, respectively). Patients with primary induction failure and resistant relapse did as well as patients with sensitive disease. Conclusions: Though ASCT has been beneficial in prolonging DFS and OS in pts with chemosensitive HD, there has been conflicting data regarding refractory disease. We propose that an intensified regimen, i.e. BVAC, may be of benefit in that setting. Only a large randomized trial can determine whether intensification of the preparative regimen can improve OS for such a population. No significant financial relationships to disclose.
Frontal fibrosing alopecia and cutaneous comorbidities: A potential relationship with rosacea
Authors: Cristina Pindado-Ortega, David Saceda-Corralo, Diego Buendía-Castaño, Pablo Fernández-González, Óscar M. Monero-Arrones, Pablo Fonda-Pascual, Ana R. Rodrigues-Barata, Pedro Jaén-Olasolo, Sergio Vañó-Galván
Journal: Journal of the American Academy of Dermatology (2018)
Hypermetabolic macrophages in rheumatoid arthritis and coronary artery disease due to glycogen synthase kinase 3b inactivation
Authors: Markus Zeisbrich, Rolando E Yanes, Hui Zhang, Ryu Watanabe, Yinyin Li, Lukas Brosig, Jison Hong, Barbara B Wallis, John C Giacomini, Themistocles L Assimes, Jörg J Goronzy, Cornelia M Weyand
Journal: Annals of the Rheumatic Diseases (2018)

Accelerated atherosclerotic disease typically complicates rheumatoid arthritis (RA), leading to premature cardiovascular death. Inflammatory macrophages are key effector cells in both rheumatoid synovitis and the plaques of coronary artery disease (CAD). Whether both diseases share macrophage-dependent pathogenic mechanisms is unknown.Patients with RA or CAD (at least one myocardial infarction) and healthy age-matched controls were recruited into the study. Peripheral blood CD14+ monocytes were differentiated into macrophages. Metabolic profiles were assessed by Seahorse Analyzer, intracellular ATP concentrations were quantified and mitochondrial protein localisation was determined by confocal image analysis.In macrophages from patients with RA or CAD, mitochondria consumed more oxygen, generated more ATP and built tight interorganelle connections with the endoplasmic reticulum, forming mitochondria-associated membranes (MAM). Calcium transfer through MAM sites sustained mitochondrial hyperactivity and was dependent on inactivation of glycogen synthase kinase 3b (GSK3b), a serine/threonine kinase functioning as a metabolic switch. In patient-derived macrophages, inactivated pGSK3b-Ser9 co-precipitated with the mitochondrial fraction. Immunostaining of atherosclerotic plaques and synovial lesions confirmed that most macrophages had inactivated GSK3b. MAM formation and GSK3b inactivation sustained production of the collagenase cathepsin K, a macrophage effector function closely correlated with clinical disease activity in RA and CAD.Re-organisation of the macrophage metabolism in patients with RA and CAD drives unopposed oxygen consumption and ultimately, excessive production of tissue-destructive enzymes. The underlying molecular defect relates to the deactivation of GSK3b, which controls mitochondrial fuel influx and as such represents a potential therapeutic target for anti-inflammatory therapy.
Abstract P063: Cigarette Smoking and Neuroimaging Indices of Cerebrovascular Health in a Population-based Cohort of Middle-aged Adults
Authors: Martine Elbejjani, David R Jacobs, Reto Auer, Nick R Bryan, Lenore J Launer
Journal: Circulation (2016)

Introduction: Several studies report an association between cigarette smoking and dementia. One proposed hypothesis is that smoking leads to adverse cognitive and brain changes through vascular pathways. To date, few data exist on the link between smoking and vascular brain measures. We examined, in a population-based middle-aged cohort, the association of history of cigarette smoking with three indicators of cerebrovascular health: (i) white matter (WM) integrity measured using WM-fractional anisotropy, (ii) abnormal WM volume, and (iii) cerebral blood flow (CBF) in the gray matter. We focused on lobar measures of these indicators to detect whether specific regional cerebrovascular indicators are differently related to smoking. Hypothesis: We assessed the hypothesis that smoking history is associated with more adverse cerebrovascular measures (lower fractional anisotropy, larger abnormal WM volumes, and lower CBF). Methods: Data come from the Coronary Artery Risk Development in Young Adults CARDIA-brain magnetic resonance imaging sub-study (n=538). Brain measures and self-reported smoking history were obtained at the 25th year follow-up (mean age=50). We used linear (for CBF and WM-fractional anisotropy) and multinomial logistic (for abnormal WM volume) regression models, adjusted for potential confounders (including vascular and lifestyle risk factors and medical conditions). Results: Compared to never-smokers, current smokers had lower WM-fractional anisotropy in all brain lobes (-0.005 lower fractional anisotropy in the occipital lobe and -0.006 in the other lobes; p&lt;0.05). Smoking history was also associated with larger abnormal WM volumes: Compared to never-smokers, smokers and/or former-smokers had patterns of larger abnormal WM volumes in all lobes, with pronounced associations observed in the frontal lobe wherein smokers and former-smokers had up to twice the risk of having larger abnormal frontal WM volumes as never-smokers (p&lt;0.05). Smoking history was associated with lower CBF in the occipital (-2.89 ml/100g/min (95%CI=-5.43, -0.36); p=0.03) and parietal lobes (-3.31 (95%CI=-5.91, -0.71); p=0.01). Conclusions: In this cohort of middle-aged adults, associations between smoking and adverse WM measures were observed in all brain lobes, whereas associations of smoking with CBF were localized in the occipital and parietal lobes. This localization may reflect a link between smoking and blood flow processes related to sensory-cognitive networks. In conclusion, results suggest that smoking is associated with three early-indicators of cerebrovascular burden (WM-fractional anisotropy, WM abnormal volume, and CBF) across the brain and that it may be differentially related to different regional cerebrovascular indicators.
Clinical and molecular diagnosis, screening and management of Beckwith–Wiedemann syndrome: an international consensus statement
Authors: Frédéric Brioude, Jennifer M. Kalish, Alessandro Mussa, Alison C. Foster, Jet Bliek, Giovanni Battista Ferrero, Susanne E. Boonen, Trevor Cole, Robert Baker, Monica Bertoletti, Guido Cocchi, Carole Coze, Maurizio De Pellegrin, Khalid Hussain, Abdulla Ibrahim, Mark D. Kilby, Malgorzata Krajewska-Walasek, Christian P. Kratz, Edmund J. Ladusans, Pablo Lapunzina, Yves Le Bouc, Saskia M. Maas, Fiona Macdonald, Katrin Õunap, Licia Peruzzi, Sylvie Rossignol, Silvia Russo, Caroleen Shipster, Agata Skórka, Katrina Tatton-Brown, Jair Tenorio, Chiara Tortora, Karen Grønskov, Irène Netchine, Raoul C. Hennekam, Dirk Prawitt, Zeynep Tümer, Thomas Eggermann, Deborah J. G. Mackay, Andrea Riccio, Eamonn R. Maher
Journal: Nature Reviews Endocrinology (2018)

Beckwith–Wiedemann syndrome is an overgrowth disorder characterized by variable clinical phenotypes and a complex molecular aetiology. This Consensus Statement summarizes recommendations for clinical indications, molecular diagnosis and management of the newly defined Beckwith–Wiedemann spectrum. Beckwith–Wiedemann syndrome (BWS), a human genomic imprinting disorder, is characterized by phenotypic variability that might include overgrowth, macroglossia, abdominal wall defects, neonatal hypoglycaemia, lateralized overgrowth and predisposition to embryonal tumours. Delineation of the molecular defects within the imprinted 11p15.5 region can predict familial recurrence risks and the risk (and type) of embryonal tumour. Despite recent advances in knowledge, there is marked heterogeneity in clinical diagnostic criteria and care. As detailed in this Consensus Statement, an international consensus group agreed upon 72 recommendations for the clinical and molecular diagnosis and management of BWS, including comprehensive protocols for the molecular investigation, care and treatment of patients from the prenatal period to adulthood. The consensus recommendations apply to patients with Beckwith–Wiedemann spectrum (BWSp), covering classical BWS without a molecular diagnosis and BWS-related phenotypes with an 11p15.5 molecular anomaly. Although the consensus group recommends a tumour surveillance programme targeted by molecular subgroups, surveillance might differ according to the local health-care system (for example, in the United States), and the results of targeted and universal surveillance should be evaluated prospectively. International collaboration, including a prospective audit of the results of implementing these consensus recommendations, is required to expand the evidence base for the design of optimum care pathways.
STAT3/p53 pathway activation disrupts IFN-β–induced dormancy in tumor-repopulating cells
Authors: Yuying Liu, Jiadi Lv, Jinyan Liu, Xiaoyu Liang, Xun Jin, Jing Xie, Le Zhang, Degao Chen, Roland Fiskesund, Ke Tang, Jingwei Ma, Huafeng Zhang, Wenqian Dong, Siqi Mo, Tianzhen Zhang, Feiran Cheng, Yabo Zhou, Qingzhu Jia, Bo Zhu, Yan Kong, Jun Guo, Haizeng Zhang, Zhuo-Wei Hu, Xuetao Cao, F. Xiao-Feng Qin, Bo Huang
Journal: Journal of Clinical Investigation (2018)

Dynamic interaction with the immune system profoundly regulates tumor cell dormancy. However, it is unclear how immunological cues trigger cancer cell–intrinsic signaling pathways for entering into dormancy. Here, we show that IFN-β treatment induced tumor-repopulating cells (TRC) to enter dormancy through an indolamine 2,3-dioxygenase/kynurenine/aryl hydrocarbon receptor/p27–dependent (IDO/Kyn/AhR/p27-dependent) pathway. Strategies to block this metabolic circuitry did not relieve dormancy, but led to apoptosis of dormant TRCs in murine and human melanoma models. Specifically, blocking AhR redirected IFN-β signaling to STAT3 phosphorylation through both tyrosine and serine sites, which subsequently facilitated STAT3 nuclear translocation and subsequent binding to the p53 promoter in the nucleus. Upregulation of p53 in turn disrupted the pentose phosphate pathway, leading to excessive ROS production and dormant TRC death. Additionally, in melanoma patients, high expression of IFN-β correlated with tumor cell dormancy. Identification of this mechanism for controlling TRC dormancy by IFN-β provides deeper insights into cancer-immune interaction and potential new cancer immunotherapeutic modalities.
Immune Profile of Patients (pts) with Relapsed and/or Refractory Multiple Myeloma (RRMM) Treated with Pomalidomide (POM) + Low-Dose Dexamethasone (LoDEX) + Daratumumab (DARA) in the Second Line Immediately after Lenalidomide (LEN)
Authors: Xiaozhong Qian, Kathryn Newhall, Mark Tometsko, Chad Bjorklund, Jianglin Ma, Nizar J. Bahlis, David Siegel, Gary J. Schiller, Christy Samaras, Michael Sebag, Jesus G. Berdeja, Siddhartha Ganguly, Jeffrey V. Matous, Kevin W Song, Christopher S. Seet, Giampaolo Talamo, Shanthi Srinivas, Mirelis Acosta-Rivera, Michael Bar, Donald Quick, Bertrand Anz, Gustavo Fonseca, Donna Reece, Jorge Mouro, Amit Agarwal, Faiza Zafar, Anjan Thakurta
Journal: Blood (2017)
Catheter Ablation for Atrial Fibrillation with Heart Failure
Authors: Nassir F. Marrouche, Johannes Brachmann, Dietrich Andresen, Jürgen Siebels, Lucas Boersma, Luc Jordaens, Béla Merkely, Evgeny Pokushalov, Prashanthan Sanders, Jochen Proff, Heribert Schunkert, Hildegard Christ, Jürgen Vogt, Dietmar Bänsch
Journal: New England Journal of Medicine (2018)

Mortality and morbidity are higher among patients with atrial fibrillation and heart failure than among those with heart failure alone. Catheter ablation for atrial fibrillation has been proposed as a means of improving outcomes among patients with heart failure who are otherwise receiving appropriate treatment.We randomly assigned patients with symptomatic paroxysmal or persistent atrial fibrillation who did not have a response to antiarrhythmic drugs, had unacceptable side effects, or were unwilling to take these drugs to undergo either catheter ablation (179 patients) or medical therapy (rate or rhythm control) (184 patients) for atrial fibrillation in addition to guidelines-based therapy for heart failure. All the patients had New York Heart Association class II, III, or IV heart failure, a left ventricular ejection fraction of 35% or less, and an implanted defibrillator. The primary end point was a composite of death from any cause or hospitalization for worsening heart failure.After a median follow-up of 37.8 months, the primary composite end point occurred in significantly fewer patients in the ablation group than in the medical-therapy group (51 patients [28.5%] vs. 82 patients [44.6%]; hazard ratio, 0.62; 95% confidence interval [CI], 0.43 to 0.87; P=0.007). Significantly fewer patients in the ablation group died from any cause (24 [13.4%] vs. 46 [25.0%]; hazard ratio, 0.53; 95% CI, 0.32 to 0.86; P=0.01), were hospitalized for worsening heart failure (37 [20.7%] vs. 66 [35.9%]; hazard ratio, 0.56; 95% CI, 0.37 to 0.83; P=0.004), or died from cardiovascular causes (20 [11.2%] vs. 41 [22.3%]; hazard ratio, 0.49; 95% CI, 0.29 to 0.84; P=0.009).Catheter ablation for atrial fibrillation in patients with heart failure was associated with a significantly lower rate of a composite end point of death from any cause or hospitalization for worsening heart failure than was medical therapy. (Funded by Biotronik; CASTLE-AF ClinicalTrials.gov number, NCT00643188 .).
An Analysis of Maintenance Therapy and Post-Midostaurin Outcomes in the International Prospective Randomized, Placebo-Controlled, Double-Blind Trial (CALGB 10603/RATIFY [Alliance]) for Newly Diagnosed Acute Myeloid Leukemia (AML) Patients with FLT3 Mutations
Authors: Richard A. Larson, Sumithra J Mandrekar, Ben L. Sanford, Kristine Laumann, Susan M. Geyer, Clara D. Bloomfield, Christian Thiede, Thomas W Prior, Konstanze Dohner, Guido Marcucci, Francesco Lo Coco, Rebecca B. Klisovic, Andrew Wei, Jorge Sierra, Miguel A. Sanz, Joseph M. Brandwein, T. M. M de Witte, Dietger Niederwieser, Frederick R. Appelbaum, Bruno C Medeiros, Martin S. Tallman, Jurgen Krauter, Richard F. Schlenk, Arnold Ganser, Hubert Serve, Gerhard Ehninger, Sergio Amadori, Hartmut Döhner, Richard M. Stone
Journal: Blood (2017)
ESCMID Study Group for Infections in Compromised Hosts (ESGICH) Consensus Document on the safety of targeted and biological therapies: an infectious diseases perspective (Introduction)
Authors: M. Fernández-Ruiz, Y. Meije, O. Manuel, H. Akan, J. Carratalà, J.M. Aguado, J. Delaloye
Journal: Clinical Microbiology and Infection (2018)
Quality of life (QOL) analysis from CHAARTED: Chemohormonal androgen ablation randomized trial in prostate cancer (E3805).
Authors: Linda J. Patrick-Miller, Yu-Hui Chen, Michael Anthony Carducci, David Cella, Robert S. DiPaola, Benjamin Adam Gartrell, Glenn Liu, David Frazier Jarrard, Alicia Katherine Morgans, Yu-Ning Wong, Christopher Sweeney
Journal: Journal of Clinical Oncology (2016)

5004 Background: Androgen deprivation therapy plus docetaxel (ADT+D) for metastatic hormone sensitive prostate cancer (mHSPC) improves overall survival over ADT. However, docetaxel’s adverse event profile that can diminish QOL. Methods: Patients were randomized to ADT+D (6 cycles) or ADT. QOL instruments including Functional Assessment of Cancer Therapy-Prostate (FACT-P), FACT-Taxane, FACIT-Fatigue, and Brief Pain Inventory (BPI) were collected at baseline, 3, 6, 9 & 12 months (mo) post randomization. Wilcoxon signed rank tests examined change over time. Mixed effect models compared QOL between arms at each time point. Results: 790 patients were randomized to ADT+D (N = 397) or ADT alone (N = 393) and completed QOL assessments (90% baseline; 84% 3 mo; 74% 9 mo; 69% 12 mo). ADT+D patients reported significant decline in FACT-P at 3 mo (p < .001), but did not differ significantly from baseline to 12 mo (p = .38). ADT+D was associated with significantly worse FACT-P scores at 3 mo (p = 0.02), yet significantly better scores at 12 mo (p = .04). ADT+D patients reported significantly worse FACIT-F scores at 3 mo (p < .001). ADT+D and ADT patients both reported significantly worse follow-up FACT-Taxane scores at all time points (P < .001) and significantly worse BPI scores at 9 and 12 mo (p < .05). BPI scores did not differ significantly between arms over time. Conclusions: Although ADT+D is associated with decreased QOL at 3 mo, 12 mo QOL was better for ADT+D than ADT patients. While both ADT+D and ADT patients report some increased symptoms over time, this study suggests that ADT+D not only provides a survival benefit, but also preserves a better QOL for mHSPC longer than ADT alone. Clinical trial information: NCT00309985.Mixed effects model FACT-P total score1. Difference between ADT+D & ADT2 Estimate SE p-value Baseline -1.00 1.28 0.43 3 months -3.09 1.32 0.02 6 months 0.90 1.34 0.50 9 months 0.29 1.37 0.84 12 months 2.85 1.39 0.04 1Adjusted for age (≤ 59 v 60-69 v ≥ 70; disease extent (high v low), local therapy (Y/N), ECOG PS (0 v ½), baseline physical well-being (≤ 20 v 20 - ≤ 25 v > 25), baseline pain (0/1 v 2/3 v ≥ 4) 2ADT+D score - ADT score *Sanofi provided study drug and ECOG-ACRIN grant.
Severe asthma is associated with metabolic syndrome in Brazilian adolescents
Authors: Fábio Chigres Kuschnir, Mara Morelo Rocha Felix, Maria Cristina Caetano Kuschnir, Kátia Vergetti Bloch, Erica Azevedo de Oliveira Costa Jordão, Dirceu Solé, Antônio José Ledo Alves da Cunha, Moyses Szklo
Journal: Journal of Allergy and Clinical Immunology (2018)