tbuckley/cabot-search huggingface dataset:
When not to start antibiotics: avoiding antibiotic overuse in the intensive care unit
Authors: K.J. Denny, J. De Wale, K.B. Laupland, P.N.A. Harris, J. Lipman
Journal: Clinical Microbiology and Infection (2019)

BackgroundMost intensive care unit (ICU) patients receive broad-spectrum antibiotics. While lifesaving in some, in others these treatments may be unnecessary and place patients at risk of antibiotic-associated harms.ObjectivesTo review the literature exploring how we diagnose infection in patients in the ICU and address the safety and utility of a 'watchful waiting' approach to antibiotic initiation with selected patients in the ICU.SourcesA semi-structured search of PubMed and Cochrane Library databases for articles published in English during the past 15 years was conducted.ContentDistinguishing infection from non-infectious mimics in ICU patients is uniquely challenging. At present, we do not have access to a rapid point-of-care test that reliably differentiates between individuals who need antibiotics and those who do not. A small number of studies have attempted to compare early aggressive versus conservative antimicrobial strategies in the ICU. However, this body of literature is small and not robust enough to guide practice.ImplicationsThis issue will not likely be resolved until there are diagnostic tests that rapidly and reliably identify the presence or absence of infection in the ICU population. In the meantime, prospective trials that identify clinical situations wherein it is safe to delay or withhold antibiotic initiation in the ICU until the presence of an infection is proven are warranted.
Entrectinib in NTRK-fusion positive gastrointestinal cancers: integrated analysis of patients enrolled in three trials (STARTRK-2, STARTRK-1, and ALKA-372-001)
Authors: S. Siena, G. Demetri, R. Doebele, Y. Chae, P. Conkling, I. Garrido-Laguna, P. Garrido, C. Rolfo, D. Sigal, S. Eng, B. Simmons, C. Ye, F. Ciardiello
Journal: Annals of Oncology (2019)
Toward Accelerated Authorization and Access to New Medicines for Juvenile Idiopathic Arthritis
Authors: Laura E. Schanberg, Athimalaipet V. Ramanan, Fabrizio De Benedetti, Timothy Beukelman, Guy S. Eakin, Vincent Del Gaizo, Sarah Ringold, Richard Vesely, Suzanne Schrandt, Thomas Jaki, Androniki Bili, James B. Chung, Stephanie De Bono, Wendy Douglass, Jeffrey V. Enejosa, Keith S. Kanik, Karin Knobe, Rebecca Kunder, Juliana C. Leite‐Schnell, Ricardo Maisse Suehiro, Robert L. Wong, Kelly L. Mieszkalski, Laura C. Marrow, Kristin Siebenaler, Elizabeth Fraulo, Yukiko Kimura
Journal: Arthritis & Rheumatology (2019)

A meeting was organized to bring together multiple stakeholders involved in the testing and authorization of new medications for juvenile idiopathic arthritis ( JIA ) to discuss current issues surrounding clinical trials and access to new medications for children and adolescents with JIA . The Childhood Arthritis and Rheumatology Research Alliance invited representatives of regulatory agencies (Food and Drug Administration and European Medicines Agency), and major pharmaceutical companies with JIA ‐approved products or products in development, patient and parent representatives, representatives of an advocacy organization (Arthritis Foundation), and pediatric rheumatology clinicians/investigators to a 1‐day meeting in April 2018. The participants engaged in discussion regarding issues in clinical trials. As the pharmacologic options to treat inflammatory arthritis rapidly expand, registration trial designs to test medications in JIA patients must adapt. Many methodologies successfully used in the recent past are no longer feasible. The pool of patients meeting entry criteria who are willing to participate is shrinking while the number of medications to be tested is growing. Suggested solutions included proposing innovative clinical trial methods to regulatory agencies, as well as open discussions among stakeholders. Ensuring that new medications are authorized in a timely manner to meet the needs of JIA patients worldwide is critical. Approaches should include open dialog between regulatory agencies, pharmaceutical companies, and other stakeholders to develop and implement novel study designs, including patient and clinician perspectives to define meaningful trial outcomes, and changing existing study plans.
Microvascular Disease in Patients With Diabetes With Heart Failure and Reduced Ejection Versus Preserved Ejection Fraction
Authors: Jasper Tromp, Shir Lynn Lim, Wan Ting Tay, Tiew-Hwa Katherine Teng, Chanchal Chandramouli, Wouter Ouwerkerk, Gupreet S. Wander, Jitendra P.S. Sawhney, Jonathan Yap, Michael R. MacDonald, Lieng Hsi Ling, Naveed Sattar, John J.V. McMurray, A. Mark Richards, Inder Anand, Carolyn S.P. Lam, Mark Richards, Carolyn S.P. Lam, Inder Anand, Chung-Lieh Hung, Lieng His Ling, Houng Bang Liew, Calambur Narasimhan, Tachapong Ngarmukos, Sang Weon Park, Eugenio Reyes, Bambang B. Siswanto, Wataru Shimizu, Shu Zhang
Journal: Diabetes Care (2019)

Microvascular complications are common among patients with diabetes mellitus (DM). The presence of heart failure (HF) is presumed to be due to macrovascular disease (typically HF with reduced ejection fraction [HFrEF] following myocardial infarction). We hypothesized that HF with preserved ejection fraction (HFpEF) in patients with DM may be a manifestation of microvascular disease compared with HFrEF. The objective of this study was to examine the prevalence and association with clinical outcome of microvascular complications in patients with HF and DM.We investigated the prevalence, association with clinical outcome, and cardiac structure and function of microvascular (neuropathy, nephropathy, and retinopathy) complications of DM in 2,800 prospectively enrolled participants with HF and DM (561 with HFpEF) from the Asian Sudden Cardiac Death In Heart Failure (ASIAN-HF) registry.A total of 601 (21.5%) participants with DM had microvascular complications. Participants with DM and any (one or more) microvascular complications were more likely to have HFpEF (odds ratio 1.70 [95% CI 1.15-2.50]; P = 0.008). Furthermore, the likelihood of having HFpEF increased with an increasing number of microvascular complications (Ptrend < 0.001). Microvascular complications were associated with more left ventricular (LV) hypertrophy and a greater reduction in quality of life in HFpEF than HFrEF (Pinteraction < 0.001 for all). Compared with participants with DM and without microvascular complications, the adjusted hazard ratio for the composite outcome of all-cause death or HF hospitalization was 1.35 (95% CI 1.04-1.76) for participants with DM and microvascular complications regardless of HF type (Pinteraction = 0.112).Diabetic microvascular disease is more common, and related to greater LV remodeling, more impairment of quality in life, and similar adverse outcomes, in participants with HFpEF compared with HFrEF. HFpEF may be a clinical manifestation of microvascular disease in DM.
Building Trust in Health Care—Why, Where, and How
Authors: Dhruv Khullar
Journal: JAMA (2019)

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Abstract 12957: Prognostic Significance of Elevated Troponin I After Valve Heart Surgery
Authors: Roberto C Aragao, Roney O Sampaio, Marcio S Bittencourt, Antonio S Lopes, Tarso A Accorsi, Vitor E Rosa, João R Fernandes, Guilherme S Spina, Ludhmila A Hajjar, Flavio Tarasoutchi
Journal: Circulation (2015)

Background: Cardiac troponin is associated with adverse events after cardiac surgery. However, the ideal time for its measurement after surgery is unclear. In order to predict its relationship to in-hospital mortality, independent value of troponin I levels, at different time points during the first 72 hours after valvular heart surgery, was evaluated. Methods: All patients, who underwent valvular heart surgery at a single tertiary center from 2011 to 2015, were included. Troponin levels were grouped according to the time after surgery as: within the first 12h, 12 to 24h, 24 to 48h, and 48h to 72h. Univariable and multivariable logistic regression models were built to define the role of troponin measurements during the first 72 hours after surgery as predictors of in hospital mortality. The multivariable models were adjusted for EuroSCORE (ES). Model discrimination was compared using the area under the ROC curve. Results: 1854 patients were included (48% women, mean age 56±15 years), with a mean ES of 4.5±3.6. The mortality was 14% (267 patients). Individuals who died during the admission had higher troponin values during the first 72 hours (p&lt;0.001), the largest difference occurred after 24 hours (figure, left panel). After adjustment for the ES, all troponin measurements remained significantly associated with mortality (OR per 10 unit change in troponin: 1.3 before 12h; 1.4 at 12 to 24 hours, 1.8 at 24 to 48 hours; and 2.0 at 48 to 72 hours (p&lt;0.001 for all). While initial post-operative troponin measurement did not significantly improved the discrimination for mortality (p=0.17 for troponin before 12 hours), the discrimination improved for late troponin measurements (figure, right panel). Conclusion: Postoperative troponin is independently associated with in-hospital mortality in individuals who underwent valvular heart surgery. Among the troponin values, those collected after 24 hours are more accurate independent preditors of in-hospital mortality.
Abstract 18289: Increased Two-year Cardiovascular Event Rate in Patients With Bilateral Carotid Inflammation. Insights From a Multicenter Study
Authors: Georgios Benetos, Konstantinos Toutouzas, Georgios Oikonomou, Fotini Mitropoulou, Iosif Koutagiar, Nikolaos Barampoutis, Periklis Davlouros, Eleftherios Tsiamis, Elias Siores, Dimitris Tousoulis
Journal: Circulation (2017)

Introduction: Inflammation is a recognized characteristic of vulnerable atherosclerotic plaque. Microwave radiometry (MWR) allows the noninvasive assessment of the internal temperature of carotid a...
The presence of bone marrow fibrosis is associated with poorer prognosis in newly diagnosed multiple myeloma treated with immunomodulatory agents and/or proteasome inhibitors.
Authors: Barry Paul, Gavin Loitsch, Daniel Feinberg, Ian Barak, Zhiguo Li, Endi Wang, Yue Zhao, Megan Dupuis, Yubin Kang
Journal: Journal of Clinical Oncology (2019)

e19514 Background: The treatment of newly diagnosed multiple myeloma (NDMM) has evolved significantly with the advent of the immunomodulatory agents (IMiDs) and proteasome inhibitors (PIs). While the presence of bone marrow fibrosis (BMF) has previously been associated with poor prognosis in multiple myeloma (MM), these studies were small and conducted prior to the widespread use of IMiDs and PIs. Here, we determined the incidence of BMF in NDMM patients and correlated the degree of BMF with prognosis in a population enriched for IMiD and/or PI exposure. Methods: Bone marrow biopsies from 306 MM patients seen at Duke between 2003 and 2013 were screened for BMF using a reticulin stain. Samples were scored as absent, mild, moderate, or severe fibrosis based on the degree and intensity of staining. The association between presence and degree of BMF to progression free survival (PFS) and overall survival (OS) was calculated using Kaplan-Meier analysis. Results: Of the 306 patients evaluated, 248 (81.0%) were treated with an IMiD, 241 (78.8%) were treated with a PI, and 217 (70.9%) received both. Additionally, 160 (52.3%) patients went on to receive an autologous stem cell transplant (HSCT). A total of 193 patients (63.1%) were evaluable for BMF. Of these, 96 (49.7%) had detectable BMF, while 97 (50.3%) had no BMF. The degree of BMF was mild in 60 patients (62.5%), and moderate or severe in 34 patients (35.4%). Median PFS in patients without BMF was 30.4 months, and 21.8 months in patients with BMF present (log-rank p = 0.02). Median OS was 61.1 months in patients without BMF, and 46.3 months in patients with BMF (log-rank p = 0.048). Patients with moderate or severe BMF had a particularly poor prognosis with a PFS of only 18.8 months and an OS of 32.7 months. Conclusions: Our study represents the largest dataset to date examining the incidence of BMF in MM patients, and is the only one to examine the association of BMF with prognosis in the era of novel therapies and widespread use of HSCT. Our data suggests that BMF is common in NDMM, and MM patients with BMF (particularly those with more extensive BMF) have a poorer prognosis even when treated with IMiDs and PIs. These data emphasize the importance of determining the presence and degree of BMF at time of MM diagnosis, and suggest a role for adjunctive therapies that target BMF in MM patients with co-existing BMF.
Donor Lymphocyte Infusions for Relapsed Hematological Malignancies after Allogeneic Hematopoietic Stem Cell Transplantation: Single Center Experience
Authors: Gunhan Gurman, Guldane Cengiz Seval, Sinem Civriz Bozdag, Selami Kocak Toprak, Meltem Kurt Yuksel, Pervin Topcuoglu, Onder Arslan, Muhit Özcan, Taner Demirer, Osman Ilhan, Meral Beksac, Hamdi Akan
Journal: Blood (2018)
Ibrutinib Plus Venetoclax in Relapsed/Refractory Chronic Lymphocytic Leukemia: The CLARITY Study
Authors: Peter Hillmen, Andy C. Rawstron, Kristian Brock, Samuel Muñoz-Vicente, Francesca J. Yates, Rebecca Bishop, Rebecca Boucher, Donald MacDonald, Christopher Fegan, Alison McCaig, Anna Schuh, Andrew Pettitt, John G. Gribben, Piers E.M. Patten, Stephen Devereux, Adrian Bloor, Christopher P. Fox, Francesco Forconi, Talha Munir
Journal: Journal of Clinical Oncology (2019)

PURPOSE The treatment of chronic lymphocytic leukemia (CLL) has been revolutionized by targeted therapies that either inhibit proliferation (ibrutinib) or reactivate apoptosis (venetoclax). Both significantly improve survival in CLL and replace chemoimmunotherapy for many patients. However, individually, they rarely lead to eradication of measurable residual disease (MRD) and usually are taken indefinitely or until progression. We present the CLARITY trial that combined ibrutinib with venetoclax to eradicate detectable CLL with the intention of stopping therapy. PATIENTS AND METHODS CLARITY is a phase II trial that combined ibrutinib with venetoclax in patients with relapsed or refractory CLL. The primary end point was eradication of MRD after 12 months of combined therapy. Key secondary end points were response by International Workshop on CLL criteria, safety, and progression-free and overall survival. RESULTS In 53 patients after 12 months of ibrutinib plus venetoclax, MRD negativity (fewer than one CLL cell in 10,000 leukocytes) was achieved in the blood of 28 (53%) and the marrow of 19 (36%). Forty-seven patients (89%) responded, and 27 (51%) achieved a complete remission. After a median follow-up of 21.1 months, one patient progressed, and all patients were alive. A single case of biochemical tumor lysis syndrome was observed. Other adverse effects were mild and/or manageable and most commonly were neutropenia or GI events. CONCLUSION The combination of ibrutinib plus venetoclax was well tolerated in patients with relapsed or refractory CLL. There was a high rate of MRD eradication that led to the cessation of therapy in some patients. The progression-free and overall survival rates are encouraging for relapsed and refractory CLL.
Survival and signals of response in advanced sarcoma patients enrolled on phase 1 trials in the era of precision oncology and novel immunotherapies.
Authors: Shiraj Sen, Kenneth R. Hess, David S. Hong, Gerald Steven Falchook, Roberto Pestana, Filip Janku, Aung Naing, Robert S. Benjamin, Shreyaskumar Patel, Funda Meric-Bernstam, Vivek Subbiah
Journal: Journal of Clinical Oncology (2019)

11063 Background: Few effective US FDA approved therapies exist for refractory, metastatic sarcomas. Many of these patients therefore enroll onto phase 1 clinical trials. Because tumor-specific outcomes are not always reported in less common cancers such as sarcomas, outcomes of sarcoma patients treated with novel immunotherapy and targeted therapy approaches remains unknown. Methods: We analyzed clinical and next generation sequencing data from all sarcoma patients treated on phase 1 trials at MD Anderson Cancer Center (MDACC) and performed logistic and Cox proportional hazards regression analyses to evaluate response rate (RR), median time to progression (mTTP), clinical benefit rate (CBR; defined as CR, PR, or SD &gt; 6 months), and median overall survival (OS). Results: Among the 406 patients with advanced sarcomas (321 soft tissue sarcoma, 85 bone sarcomas) treated on phase 1 trials at MDACC from May 2006 to May 2018, median age was 53 (range 11-84), 48% were female, with a median 3 prior lines of therapy (range 0-9). The most commonly treated soft tissue sarcoma subtypes included leiomyosarcoma (n = 66; 16%), liposarcoma (n = 52; 13%), GIST (n = 44; 11%), UPS (n = 14; 3%), and synovial sarcoma (n = 11; 3%) and most commonly treated bone sarcomas included osteosarcoma (n = 34; 8%), chondrosarcoma (n = 28; 7%), and Ewing’s sarcoma (n = 25; 6%). RR was 7% (95% CI 5, 10), mTTP was 2.9 months (95%CI 2.6, 3.1), CBR was 24% (95% CI 20, 29), mOS was 17.2 months (95% CI 13.8, 20.8). 2 patients had a CR as best response, 1 chondrosarcoma patient treated with an anti-APO2L/Trail agent and 1 Ewing’s sarcoma patient treated with the combination of an IGF1R inhibitor plus mTOR inhibitor. 26 patients (6%) had a PR as best response using novel immunotherapies targeting PD1, PDL1 plus CCR4, CTLA4 plus KIT, and TLR7/8 and novel targeted therapies against TRK, LRRC15, cMET, mTOR, VEGF, MDM2, KIT/PDGFRA, and FGFR. Responses were seen across sarcoma subtypes - ASPS, UPS, myxoid sarcoma, liposarcoma, GIST, carcinosarcoma, clear cell sarcoma, embryonal rhabdomyosarcoma, epitheliod sarcoma, fibrious histiosarcoma, and Ewing’s sarcoma. Conclusions: Our analysis identifies a reasonable survival in heavily pretreated, metastatic refractory sarcoma patients with responses seen with novel targeted therapies and immunotherapies that are not yet US-FDA approved. Biomarker analysis is ongoing to help identify the subset of responders in our cohort. Advanced sarcoma patients should be considered for molecular profiling and early phase clinical trials.
OC-054 Pain endophenotypes can be accurately predicted by whole brain connectivity during painful oesophageal stimulation
Authors: JK Ruffle, SJ Coen, V Giampietro, Scr Williams, AD Farmer, Q Aziz
Journal: Gut (2017)

Introduction  Visceral pain is a complex experience, and is influenced by an array of physiological, psychological and anatomical factors. Previous research from our group has coalesced many of these factors, demonstrating that two major endophenotypic ‘pain clusters’ (PC) exist with the following features: Pain Cluster 1 (PC1), in comparison to Pain Cluster 2 (PC2), had higher neuroticism and anxiety scores, and the serotonin transporter-linked polymorphic region genotype (5-HTTLPR) short allele was over represented. PC1 had greater baseline sympathetic tone and serum cortisol, but during acute pain had a lower stimulus tolerance and increased parasympathetic tone. Meanwhile, PC2 had the converse profile at baseline and during pain. We hypothesised that these PCs could be predicted by whole brain functional connectivity during either rest or oesophageal pain, irrespective of any physiological, psychophysiological and genetic data.  Method  We used a previous dataset of 21 healthy subjects (10 male and 11 female; mean age 30 years), all of which were previously allocated to PC1 (n=9) or PC2 (n=12). All had additionally undergone fMRI with an event-related design of acute oesophageal pain and rest periods. Blood oxygen level dependant (BOLD) signal during rest and oesophageal balloon distention to pain tolerance threshold was extracted from a whole brain parcellation map of 346 single-voxel regions of interest (Figure 1a, single node example), which were cross-correlated to produce whole brain correlation matrices of 59 685 r values. Using complex decision trees, an aspect of the ‘classification-learner’ machine learning algorithm within Matlab, we investigated whether whole brain connectivity could accurately predict which cluster subjects were allocated to.  Results  Whole brain functional connectivity during oesophageal pain accurately predicted subject PC with 85.7% accuracy: area under curve (AUC) 0.86; true positive rate (TPR) for PC1 and PC2 89% and 83% respectively; false negative rate (FNR) for PC1 and PC2 11% and 17% respectively (Figure 1b, receiver operating characteristic curve). However, PC were only predicted with 58% accuracy during rest: AUC 0.58; TPR for PC1 and PC2 44% and 75% respectively, FNR for PC1 and PC2 56% and 25%.  Conclusion  These data suggest that endophenotypic PCs can be accurately predicted from whole brain functional connectivity during acute oesophageal pain, but not by resting connectivity. Future study should investigate for specific brain region connectivity and network differences between PCs to elucidate key differences.  Disclosure of Interest  J. Ruffle: None Declared, S. Coen: None Declared, V. Giampietro: None Declared, S. Williams: None Declared, A. Farmer Conflict with: Medical Research Council Grant, Q. Aziz Conflict with: Medical Research Council Grant