tbuckley/cabot-search huggingface dataset:
Targeting <i>HER2</i> Aberrations in Non–Small Cell Lung Cancer with Osimertinib
Authors: Shengwu Liu, Shuai Li, Josephine Hai, Xiaoen Wang, Ting Chen, Max M. Quinn, Peng Gao, Yanxi Zhang, Hongbin Ji, Darren A.E. Cross, Kwok-Kin Wong
Journal: Clinical Cancer Research (2018)

Abstract Purpose: HER2 (or ERBB2) aberrations, including both amplification and mutations, have been classified as oncogenic drivers that contribute to 2% to 6% of lung adenocarcinomas. HER2 amplification is also an important mechanism for acquired resistance to EGFR tyrosine kinase inhibitors (TKI). However, due to limited preclinical studies and clinical trials, currently there is still no available standard of care for lung cancer patients with HER2 aberrations. To fulfill the clinical need for targeting HER2 in patients with non–small cell lung cancer (NSCLC), we performed a comprehensive preclinical study to evaluate the efficacy of a third-generation TKI, osimertinib (AZD9291). Experimental Design: Three genetically modified mouse models (GEMM) mimicking individual HER2 alterations in NSCLC were generated, and osimertinib was tested for its efficacy against these HER2 aberrations in vivo. Results: Osimertinib treatment showed robust efficacy in HER2wt overexpression and EGFR del19/HER2 models, but not in HER2 exon 20 insertion tumors. Interestingly, we further identified that combined treatment with osimertinib and the BET inhibitor JQ1 significantly increased the response rate in HER2-mutant NSCLC, whereas JQ1 single treatment did not show efficacy. Conclusions: Overall, our data indicated robust antitumor efficacy of osimertinib against multiple HER2 aberrations in lung cancer, either as a single agent or in combination with JQ1. Our study provides a strong rationale for future clinical trials using osimertinib either alone or in combination with epigenetic drugs to target aberrant HER2 in patients with NSCLC. Clin Cancer Res; 24(11); 2594–604. ©2018 AACR. See related commentary by Cappuzzo and Landi, p. 2470
Insulin exits skeletal muscle capillaries by fluid-phase transport
Authors: Ian M. Williams, Francisco A. Valenzuela, Steven D. Kahl, Doraiswami Ramkrishna, Adam R. Mezo, Jamey D. Young, K. Sam Wells, David H. Wasserman
Journal: Journal of Clinical Investigation (2018)

Before insulin can stimulate myocytes to take up glucose, it must first move from the circulation to the interstitial space. The continuous endothelium of skeletal muscle (SkM) capillaries restricts insulin's access to myocytes. The mechanism by which insulin crosses this continuous endothelium is critical to understand insulin action and insulin resistance; however, methodological obstacles have limited understanding of endothelial insulin transport in vivo. Here, we present an intravital microscopy technique to measure the rate of insulin efflux across the endothelium of SkM capillaries. This method involves development of a fully bioactive, fluorescent insulin probe, a gastrocnemius preparation for intravital microscopy, an automated vascular segmentation algorithm, and the use of mathematical models to estimate endothelial transport parameters. We combined direct visualization of insulin efflux from SkM capillaries with modeling of insulin efflux kinetics to identify fluid-phase transport as the major mode of transendothelial insulin efflux in mice. Model-independent experiments demonstrating that insulin movement is neither saturable nor affected by insulin receptor antagonism supported this result. Our finding that insulin enters the SkM interstitium by fluid-phase transport may have implications in the pathophysiology of SkM insulin resistance as well as in the treatment of diabetes with various insulin analogs.
Risk factors for recurrent venous thromboembolism after unprovoked pulmonary embolism: the PADIS-PE randomised trial
Authors: Cécile Tromeur, Olivier Sanchez, Emilie Presles, Gilles Pernod, Laurent Bertoletti, Patrick Jego, Elisabeth Duhamel, Karine Provost, Florence Parent, Philippe Robin, Lucile Deloire, Florent Leven, Fanny Mingant, Luc Bressollette, Pierre-Yves Le Roux, Pierre-Yves Salaun, Michel Nonent, Brigitte Pan-Petesch, Benjamin Planquette, Philippe Girard, Karine Lacut, Solen Melac, Patrick Mismetti, Silvy Laporte, Guy Meyer, Dominique Mottier, Christophe Leroyer, Francis Couturaud
Journal: European Respiratory Journal (2018)

We aimed to identify risk factors for recurrent venous thromboembolism (VTE) after unprovoked pulmonary embolism. Analyses were based on the double-blind randomised PADIS-PE trial, which included 371 patients with a first unprovoked pulmonary embolism initially treated during 6 months who were randomised to receive an additional 18 months of warfarin or placebo and followed up for 2 years after study treatment discontinuation. All patients had ventilation/perfusion lung scan at inclusion ( i.e. at 6 months of anticoagulation). During a median follow-up of 41 months, recurrent VTE occurred in 67 out of 371 patients (6.8 events per 100 person-years). In main multivariate analysis, the hazard ratio for recurrence was 3.65 (95% CI 1.33–9.99) for age 50–65 years, 4.70 (95% CI 1.78–12.40) for age &gt;65 years, 2.06 (95% CI 1.14–3.72) for patients with pulmonary vascular obstruction index (PVOI) ≥5% at 6 months and 2.38 (95% CI 1.15–4.89) for patients with antiphospholipid antibodies. When considering that PVOI at 6 months would not be available in practice, PVOI ≥40% at pulmonary embolism diagnosis (present in 40% of patients) was also associated with a 2-fold increased risk of recurrence. After a first unprovoked pulmonary embolism, age, PVOI at pulmonary embolism diagnosis or after 6 months of anticoagulation and antiphospholipid antibodies were found to be independent predictors for recurrence.
Immunotherapy and pulmonary toxicities: can concomitant immune-checkpoint inhibitors with radiotherapy increase the risk of radiation pneumonitis?
Authors: Guillaume Louvel, Rastislav Bahleda, Samy Ammari, Cécile Le Péchoux, Antonin Levy, Christophe Massard, Jérôme Le Pavec, Stéphane Champiat, Eric Deutsch
Journal: European Respiratory Journal (2018)

Delaunay et al . [1] presented the results of a retrospective study of 1826 cancer patients treated with immune-checkpoint inhibitors (ICIs). 3.5% of the patients developed interstitial lung diseases (ILDs). The mechanisms of this toxicity remain largely unknown [2]. The cohort was mainly composed of lung cancer patients (75%). This explains why a significant proportion of the patients (40%) with ILD had received thoracic radiotherapy. However, patients with ILD features within the initial volumes of radiotherapy were excluded from the study to dissociate cases related to radiation pneumonitis. This study is important and brings to the light key data regarding the emerging field of clinical management of adverse ICI events. Cases of radiation pneumonitis developed after concomitant checkpoint inhibitors and lung SBRT: a matter of concern? <http://ow.ly/k78q30g1qDJ>
From the authors:
Authors: I. Bergdahl, K. Torén, T. Nillson, K. Eriksson, U. Hedlund, R. Flodin, B. Järvholm
Journal: European Respiratory Journal (2004)

We are grateful for the valuable comments by D.M. Bernstein. We fully agree with him that the papers we cited do not corroborate our findings. The cited papers do …
Hepatitis B virus–specific T cells associate with viral control upon nucleos(t)ide-analogue therapy discontinuation
Authors: Laura Rivino, Nina Le Bert, Upkar S Gill, Kamini Kunasegaran, Yang Cheng, Damien Zm Tan, Etienne Becht, Navjyot K Hansi, Graham R Foster, Tung-Hung Su, Tai-Chung Tseng, Seng Gee Lim, Jia-Horng Kao, Evan W Newell, Patrick Tf Kennedy, Antonio Bertoletti
Journal: Journal of Clinical Investigation (2018)

The clinical management of chronic hepatitis B virus (HBV) patients is based exclusively on virological parameters that cannot independently determine in which patients nucleos(t)ide-analogue (NUC) therapy can be safely discontinued. NUCs efficiently suppress viral replication, but do not eliminate HBV. Thus, therapy discontinuation can be associated with virological and biochemical relapse and, consequently, therapy in the majority is life-long.
NHS cancels planned surgery and outpatient appointments in response to winter crisis
Authors: Gareth Iacobucci
Journal: BMJ (2018)

Hospitals have been advised by NHS England to defer outpatient appointments and day case surgery and extend an existing deferral on non-urgent surgery until the end of January in a bid to ease mounting pressure on services this winter.

The National Emergency Pressures Panel, chaired by NHS England’s medical director, Bruce Keogh, has also told hospitals to place consultants in emergency units to assess whether patients are presenting with a genuine medical emergency.

The measures were taken as the service struggled to cope with the volume of patients presenting to emergency departments. The panel noted that the NHS has been under “sustained pressure” since Christmas, with early indications of an increase in flu prevalence, high levels of respiratory illness, and limited bed capacity.

To help free up capacity NHS England has told hospitals to defer day case procedures …
Targeting Obsessive-Compulsive Symptoms With rTMS and Perfusion Imaging
Authors: Stephanie Winkelbeiner, Samir Suker, Hanta Bachofner, Sarah Eisenhardt, Sarah Steinau, Sebastian Walther, Andrea Federspiel, Thomas Dierks, Werner Strik, Philipp Homan
Journal: American Journal of Psychiatry (2018)

suggestion, the effect of lithium on the rate of suiciderelated events increased in both bipolar I and bipolar II disorder when patients diagnosed with mixed episodes were excluded (1).However, the association remained nonsignificant for patients with bipolar I disorder.Two points should be noted, however.First, even though the patient register uses ICD-10 codes, many clinicians in Sweden used DSM-IV and translated diagnoses to ICD-10.In addition, DSM-IV requires that the criteria for both depression and mania be met (except the time criterion) in order to diagnose a mixed episode.This means that it is still possible that the bipolar I disorder group contains individuals with mixed features according to DSM-5.Thus, we cannot refute Dr. Terao and colleagues' suggestion.Future studies using DSM-5 criteria are needed to answer their question.Second, because ICD-10 does not distinguish between bipolar I and bipolar II disorder, we used data from a quality register for the subgroup analyses.This quality register contains only one-third of all Swedish patients with bipolar disorder, which decreases the size of the study sample.Thus, the fact that the results in bipolar I disorder do not reach statistical significance might be a power issue.Therefore, we agree with Terao et al. that more efforts are needed to explore the effect of lithium in preventing suicidal behavior in specific subgroups, where not only the subtype of bipolar disorder is taken into account, but also mixed features.
Impact of Financial Incentives on Early and Late Adopters among US Hospitals: observational study
Authors: Igna Bonfrer, Jose F Figueroa, Jie Zheng, E John Orav, Ashish K Jha
Journal: BMJ (2018)

<h3>Abstract</h3> <h3>Objective</h3> To examine how hospitals that volunteered to be under financial incentives for more than a decade as part of the Premier Hospital Quality Incentive Demonstration (early adopters) compared with similar hospitals where these incentives were implemented later under the Hospital Value-Based Purchasing program (late adopters). <h3>Design</h3> Observational study. <h3>Setting</h3> 1189 hospitals in the USA (214 early adopters and 975 matched late adopters), using Hospital Compare data from 2003 through 2013. <h3>Participants</h3> 1 371 364 patients aged 65 years and older, using 100% Medicare claims. <h3>Main outcome measures</h3> Clinical process scores and 30 day mortality. <h3>Results</h3> Early adopters started from a slightly higher baseline of clinical process scores (92) than late adopters (90). Both groups reached a ceiling (98) a decade later. Starting from a similar baseline, just below 13%, early and late adopters did not have significantly (P=0.25) different mortality trends for conditions targeted by the program (0.05% point difference quarterly) or for conditions not targeted by the program (−0.02% point difference quarterly). <h3>Conclusions</h3> No evidence that hospitals that have been operating under pay for performance programs for more than a decade had better process scores or lower mortality than other hospitals was found. These findings suggest that even among hospitals that volunteered to participate in pay for performance programs, having additional time is not likely to turn pay for performance programs into a success in the future.
Abstract 14013: E-selectin-targeted Novel Nano Polymers Stabilize Atherosclerotic Plaque and Improve Cardiac Remodeling
Authors: Olga Tsoref, Uri Amit, Natalie Landa, David Kain, Osnat Rosenboim-Cohen, Dalia Tyomkin, Ayelet David, Jonathan Leor
Journal: Circulation (2016)

Introduction: Inflammation is implicated in the initiation and progression of cardiovascular disease. Endothelial activation with up-regulation of E-selectin adhesion molecules stimulates leukocyte infiltration leading to atherosclerotic plaque growth, plaque vulnerability and acute myocardial infarction. Hypothesis: Novel E-selectin-targeted polymers, with or without dexamethasone, can prevent plaque progression and adverse cardiac remodeling in atherosclerosis prone ApoE deficient ApoE (-/-) mice. Methods and Results: To target and modulate cardiovascular inflammation we used novel N-(2-hydroxypropyl)-meth-acrylamide polymers conjugated with peptides that bind E-selectin with high affinity, with and without dexamethasone 1mg/kg (P-ESBP-Dex, P-ESBP). Five-month-old ApoE (-/-) mice were fed a high-fat diet (HFD) for 8 weeks. Plaque growth was assessed by vascular ultrasound (US) 4 and 8 weeks after onset of HFD. We used a novel software application designed to measure in-vivo vessel wall anatomy and motion in small-animal models. Following the baseline vascular US, mice were randomized to 4 treatment groups: P-ESBP-Dex, P-ESBP, free dexamethasone or saline, delivered by 4 weekly intraperitoneal injections. Left ventricular remodeling and function were assessed by echocardiography in parallel to the vascular US. We found that both P-ESBP and P-ESBP-Dex selectively targeted atherosclerotic lesions, and reduced wall thickness of the ascending aorta. Furthermore, compared with saline controls, P-ESBP significantly decreased the area of necrotic core in the aortic plaques (74.2±5.9 mm2 vs. 34.7±15.5 mm2, p&lt;0.05). Notably, the addition of dexamethasone to P-ESBP did not improve their therapeutic effect. Finally, P-ESBP attenuated left ventricular diastolic and systolic dilatation, compared with controls. Conclusion: E-selectin binding polymers reduce the growth of atherosclerotic lesions, contribute to plaque stability and prevent adverse cardiac remodeling in ApoE (-/-) mice. We suggest a novel nanomedicine-based therapy for atherosclerosis, unstable plaque, and to prevent adverse cardiac remodeling.
Associations of General and Central Adiposity With Incident Diabetes in Chinese Men and Women
Authors: Fiona Bragg, Kun Tang, Yu Guo, Andri Iona, Huaidong Du, Michael V. Holmes, Zheng Bian, Christiana Kartsonaki, Yiping Chen, Ling Yang, Qiang Sun, Caixia Dong, Junshi Chen, Rory Collins, Richard Peto, Liming Li, Zhengming Chen
Journal: Diabetes Care (2018)

OBJECTIVE We assess associations of general and central adiposity in middle age and of young adulthood adiposity with incident diabetes in adult Chinese and estimate the associated population burden of diabetes. RESEARCH DESIGN AND METHODS The prospective China Kadoorie Biobank enrolled 512,891 adults 30–79 years of age from 10 localities across China during 2004–2008. During 9.2 years of follow-up, 13,416 cases of diabetes were recorded among 482,589 participants without diabetes at baseline. Cox regression yielded adjusted hazard ratios (HRs) for incident diabetes associated with measures of general (e.g., BMI and BMI at 25 years) and central (e.g., waist circumference [WC]) adiposity. RESULTS The mean (SD) BMI was 23.6 kg/m2 (3.4 kg/m2), and 3.8% had a BMI ≥30 kg/m2. Throughout the range examined (19–32 kg/m2), BMI showed a positive log-linear relationship with diabetes, with adjusted HRs per SD higher usual BMI greater in men (1.98; 95% CI 1.93–2.04) than in women (1.77; 1.73–1.81) (P for heterogeneity &amp;lt;0.001). For WC, HRs per SD were 2.13 (95% CI 2.07–2.19) in men and 1.91 (1.87–1.95) in women (P for heterogeneity &amp;lt;0.001). Mutual adjustment attenuated these associations, especially those of BMI. BMI at age 25 years was weakly positively associated with diabetes (men HR 1.09 [95% CI 1.05–1.12]; women 1.04 [1.02–1.07] per SD), which was reversed after adjustment for baseline BMI. In China, the increase in adiposity accounted for ∼50% of the increase in diabetes burden since 1980. CONCLUSIONS Among relatively lean Chinese adults, higher adiposity—general and central—was strongly positively associated with the risk of incident diabetes. The predicted continuing increase in adiposity in China foreshadows escalating rates of diabetes.
PTH-097 Cognitive behavioural responses and quality of life in stable patients on biologics: an unmet need in ibd?
Authors: IY Liew, G Chung-Faye, P Dubois, L Medcalf, C Jordan, M Hotopf, B Hayee
Journal: Gut (2017)

Introduction  Physician and patient preferences (particularly for the route of administration; RoA) are central to uptake and adherence of biologic therapy in IBD. While patients reportedly prefer subcutaneous (SC) administration [1], there remains a significant cohort who select intravenous (IV) therapy if offered. This cohort study was conducted to elicit psychosocial factors associated with the route of biologic administration.  Method  Patients offered a free choice of RoA, with quiescent disease were identified from our electronic database: optimised, stable dose of biologic and no use of corticosteroids, for ≥3 months; normal B12, ferritin and vitD serum level; faecal calprotectin   Results  24 patients were on adalimumab (SC group; 13F, 36.0±12.3 years, 5UC), with 25 on Remicade (IV group: 17F, 38.5±13.4 years (IV group). There were no significant differences in demographics, or numbers of patients reporting PHQ-9 or GAD-7 scores>10 (moderate symptoms), but 11 (22%) exceeded this cut-off. MHLC responses were identical, while SC patients report lower IBDC (7 vs 9, p  Conclusion  SC patients were significantly more unhelpfully focused on symptoms (“I think a great deal about my symptoms”) and catastrophising (“I will never feel right again”) as well as reporting engaging in behaviours to avoid embarrassment. Despite quiescent disease, ‘unhelpful’ higher CBRSQ scores correlated with worse disease-related QOL (p  References  . Vavricka SR, et al. Inflamm Bowel Dis2012:18:523–530  . Bodger K, et al. Gut2015;63:1092–1102  Disclosure of Interest  None Declared
Cinryze is Efficacious for Hereditary Angioedema (HAE) Attack Prevention In Pediatric Patients: Final Phase 3 Efficacy And Safety Results
Authors: Emel Aygören-Pürsün, Daniel F. Soteres, Sandra Nieto–Martinez, Jim Christensen, Kraig W. Jacobson, Dumitru Moldovan, Arthur Van Leerberghe, Tom Tang, Peng Lu, Inmaculada Martinez-Saguer
Journal: Journal of Allergy and Clinical Immunology (2018)
Effects of rhinovirus 39 infection on airway hyperresponsiveness to carbachol in human airways precision cut lung slices
Authors: Joshua L. Kennedy, Cynthia J. Koziol-White, Susanne Jeffus, Mallikarjuna R. Rettiganti, Paige Fisher, Megan Kurten, Anthony Eze, Suzanne House, James D. Sikes, Emily Askew, Claire Putt, Reynold A. Panettieri, Stacie M. Jones, Richard C. Kurten
Journal: Journal of Allergy and Clinical Immunology (2018)
Abstract 18168: External Validation of Right Heart Failure Risk Scores Following Left Ventricular Assist Device Implantation and Evaluation of the Role of Emerging Echocardiographic Indices
Authors: Marie Aymami, François Haddad, Matthew Wheeler, Myriam Amsallem, Michael Marques, Jackson Adams, Sanford Zeigler, Karim Sallam, Y. Joseph Woo, Richard-Tien Ha, Dipanjan Banerjee
Journal: Circulation (2016)

Introduction:  Preoperative risk scores for right heart failure (RHF) following left ventricular assist device (LVAD) implantation show a discrimination in outcome prediction in derivation cohorts but have not undergone extensive external validation. The aims of the study were to externally validate previously described RHF risk scores and to determine to which extent novel echocardiographic indices can improve risk stratification.   Methods:  We evaluated five clinical RHF risk scores (Michigan, Kormos et al, Penn, CRITT, and Utah) in 158 patients (age 56.0±12.6; 78.5% men; 36.7% destination therapy) having undergone continuous-flow LVAD implantation between February 2009 and August 2015. Clinical, laboratory, hemodynamic, and echocardiographic data were compared between patients with and without RHF, and risk factors identified. Measures of right heart function included right ventricular free wall longitudinal strain (RVLS), right atrial end-systolic area index (RAAI), and right ventricular fractional area change (RVFAC).   Results:  RHF occurred in 36.7% of patients. Three of the 5 scores were different from the null hypothesis, yet the discriminative performance was modest (CRITT score C=0.66 [0.58-0.74], Michigan score C=0.61 [0.53-0.69], Kormos score C=0.60 [0.51-0.67]). Our multivariate analysis identified INTERMACS profile (OR 2.29 [1.38-3.79, p=0.001]) and bilirubin greater than 1.7mg/dL (OR 2.39 [1.03-5.56], p=0.043), RAAI (OR 2.75 [1.32-5.75], p=0.007) and RVGLS (OR 2.20 [1.01-4.82], p=0.048) as independently associated with RHF. The C-statistic for this model was 0.77 [0.69-0.83].   Conclusions:  Predictive risk scores for post-LVAD RHF perform modestly in external validation cohorts. Novel echocardiographic right heart parameters, such as RA size and RVLS, moderately improve the performance of clinical scores.
Survival impact of postoperative radiotherapy timing in pediatric and adolescent medulloblastoma
Authors: Alexander L Chin, Everett J Moding, Sarah S Donaldson, Iris C Gibbs, Scott G Soltys, Susan M Hiniker, Erqi L Pollom
Journal: Neuro-Oncology (2018)

Radiation therapy (RT) remains a critical component of multimodality treatment for medulloblastoma. Traditionally, clinicians strive to start RT within 4–5 weeks of surgery, but the optimal timing after surgery remains unclear. Using the National Cancer Database, we identified pediatric and adolescent patients with medulloblastoma treated with curative-intent surgery, RT, and chemotherapy. Factors associated with early or delayed RT were identified using Pearson chi-squared tests. Overall survival (OS) differences based on RT timing were compared using the Kaplan–Meier estimator with log-rank tests. Patient, tumor, and treatment characteristics associated with OS were analyzed with univariate and multivariate Cox proportional hazards models. Among the 1338 patients analyzed, early RT (defined as initiation ≤3 wk after surgery) was associated with younger age, M1–3 disease, and subtotal resection. Patients who initiated RT early had decreased 5-year OS compared with patients who initiated RT 3.1–4, 4.1–5, or >5 weeks after surgery (72.5% vs. 80.5%, 79.4%, and 77.8%, respectively; P = 0.019), but there was no significant difference in OS among the latter 3 groups (P = 0.788). On multivariate analysis, early RT versus the 3.1- to 4-week interval was significantly associated with poorer OS (adjusted hazard ratio, 1.72; 95% CI: 1.19–2.48; P = 0.004), while time to RT of >5 weeks but within 90 days of surgery did not adversely impact OS (P = 0.563). In this large national database analysis, delaying RT within 90 days of surgery was not associated with inferior outcomes. Although clinical judgment remains paramount, postoperative RT timing should allow for healing and the development of an optimal treatment plan.