tbuckley/cabot-search huggingface dataset:
Monoclonal antibody therapy for the treatment of asthma and chronic obstructive pulmonary disease with eosinophilic inflammation
Authors: John Nixon, Paul Newbold, Tomas Mustelin, Gary P. Anderson, Roland Kolbeck
Journal: Pharmacology & Therapeutics (2016)

Eosinophils have been linked with asthma for more than a century, but their role has been unclear. This review discusses the roles of eosinophils in asthma and chronic obstructive pulmonary disease (COPD) and describes therapeutic antibodies that affect eosinophilia. The aims of pharmacologic treatments for pulmonary conditions are to reduce symptoms, slow decline or improve lung function, and reduce the frequency and severity of exacerbations. Inhaled corticosteroids (ICS) are important in managing symptoms and exacerbations in asthma and COPD. However, control with these agents is often suboptimal, especially for patients with severe disease. Recently, new biologics that target eosinophilic inflammation, used as adjunctive therapy to corticosteroids, have proven beneficial and support a pivotal role for eosinophils in the pathology of asthma. Nucala® (mepolizumab; anti-interleukin [IL]-5) and Cinquair® (reslizumab; anti-IL-5), the second and third biologics approved, respectively, for the treatment of asthma, exemplifies these new treatment options. Emerging evidence suggests that eosinophils may contribute to exacerbations and possibly to lung function decline for a subset of patients with COPD. Here we describe the pharmacology of therapeutic antibodies inhibiting IL-5 or targeting the IL-5 receptor, as well as other cytokines contributing to eosinophilic inflammation. We discuss their roles as adjuncts to conventional therapeutic approaches, especially ICS therapy, when disease is suboptimally controlled. These agents have achieved a place in the therapeutic armamentarium for asthma and COPD and will deepen our understanding of the pathogenic role of eosinophils.
GW26-e1478 Pridictive Value of Soluble Urokinase-type Plasminogen Activator Receptor in Patients with Acute Coronary Syndrome Undergoing Percutaneous Coronary Intervention
Authors: Zhenda Zheng, Cailian Cheng, Caihong Qu, Ruimin Dong, Min Wang, Lin Chen, Xiaoxian Qian
Journal: Journal of the American College of Cardiology (2015)
Relationship between Autoimmune Phenomena and Disease Stage and Therapy in B-Cell Chronic Lymphocytic Leukaemia.
Authors: Wilma Barcellini, Silvana Capalbo, Rosa M. Agostinelli, Francesca R. Mauro, Achille Ambrosetti, Rossella Calori, Agostino Cortelezzi, Luca Laurenti, Enrico M. Pogliani, Paola Pedotti, Vincenzo Liso, Franco Mandelli, Alberto Zanella
Journal: Blood (2006)
Staphylococcal Superantigen-Like 5 Activates Platelets, and Supports Platelet Adhesion Under Flow Conditions, Which Is Mediated by GPIb- Alpha and Alpha-IIb-Beta-3
Authors: Cees Weeterings, Carla JC de Haas, Mignon M Vughs, Philip G de Groot, Jos van Strijp, Ton Lisman
Journal: Blood (2008)
Long-Term Follow-up of TBI
Authors: Jordan Grafman
Journal: New England Journal of Medicine (2016)

To the Editor: An article by Okie (July 14 issue)1 on traumatic brain injury (TBI) focused on the personal paths to recovery taken by combat veterans with TBI. The article, however, gave an erroneous impression that previous research on the long-term effects of TBI has been scarce. In fact, there is considerable published literature on this topic that could guide present and future research and clinical management of both closed (including blast-related2) and penetrating TBI. Even if it is difficult to predict with absolute certainty a precise outcome after TBI in any individual patient, there are key preinjury and . . .
The influence of procedural volume and proficiency gain on mortality from upper GI endoscopic mucosal resection
Authors: Sheraz R Markar, Hugh Mackenzie, Melody Ni, Jeremy R Huddy, Alan Askari, Omar Faiz, S Michael Griffin, Laurence Lovat, George B Hanna
Journal: Gut (2016)

Objective Endoscopic mucosal resection (EMR) is established for the management of benign and early malignant upper GI disease. The aim of this observational study was to establish the effect of endoscopist procedural volume on mortality. Design Patients undergoing upper GI EMR between 1997 and 2012 were identified from the Hospital Episode Statistics database. The primary outcome was 30-day mortality and secondary outcomes were 90-day mortality, requirement for emergency intervention and elective cancer re-intervention. Risk-adjusted cumulative sum (RA-CUSUM) analysis was used to assess patient mortality risk during initial stage of endoscopist proficiency gain and the effect of endoscopist and hospital volume. Mortality was compared before and after the change point or threshold in the RA-CUSUM curve. Results 11 051 patients underwent upper GI EMR. Endoscopist procedure volume was an independent predictor of 30-day mortality. Fifty-eight per cent of EMR procedures were performed by endoscopists with annual volume of 2 cases or less, and had a higher 30-day and 90-day mortality rate for patients with cancer, 6.1% vs 0.4% (p&lt;0.001) and 12% vs 2.1% (p&lt;0.001), respectively. The requirement for emergency intervention after EMR for cancer was also greater with low volume endoscopists (1.8% vs 0.1%, p=0.002). In patients with cancer, the RA-CUSUM curve change points for 30-day mortality and elective re-intervention were 4 cases and 43 cases, respectively. Conclusions EMR performed by high volume endoscopists is associated with reduced adverse outcomes. In order to reach proficiency, appropriate training and procedural volume accreditation training programmes are needed nationally.
Медики-подвижники на ниві земської медицини
Authors: Z. Shevtsovа, V. Gaponov, M. Chaban
Journal: GASTROENTEROLOGY (2016)

Земська медицина як форма медичного обслуговування сільського населення виникла у другій половині ХІХ століття. На земство була покладена турбота про охорону здоров’я людей, медицина стала соціальною службою. Розвиток земської медицини сприяв збільшенню кількості медичних працівників на селі. Наданi життєвий шлях і професійна діяльність медиків Івана Лешко-Попеля, Василя Смирнова, Миколи Моцакова, Всеволода Малиновського. Їх долі, без залишку віддані людям, є взірцем кращих традицій земської медицини.
Carcinogenicity of pentachlorophenol and some related compounds
Authors: Kathryn Z Guyton, Dana Loomis, Yann Grosse, Fatiha El Ghissassi, Véronique Bouvard, Lamia Benbrahim-Tallaa, Neela Guha, Heidi Mattock, Kurt Straif
Journal: The Lancet Oncology (2016)
Advances in the management of castration resistant prostate cancer
Authors: Chad R Ritch, Michael S Cookson
Journal: BMJ (2016)

Docetaxel based chemotherapy showed survival benefit and emerged as the mainstay of treatment for castration resistant prostate cancer (CRPC) in 2004. However, therapeutic options have expanded rapidly since 2011. The spectrum of new agents is broad and includes drugs that target the androgen axis (enzalutamide, abiraterone), immunotherapy (sipuleucel-T), bone seeking radionuclides (radium-223), and second line chemotherapy (cabazitaxel). In addition, new agents have been developed to reduce skeletal related events (denosumab). Given that docetaxel was the standard first line treatment for metastatic CRPC, the newer oral agents that affect the androgen axis were initially approved in the post-docetaxel setting. However, subsequent randomized trials have led to their approval in the pre-chemotherapy setting as well. Patients with CRPC are clinically heterogeneous, ranging from patients who are asymptomatic and do not have metastases to those with substantial symptoms and both bony and visceral metastases. CRPC is a clinically challenging disease entity, therefore, with a wide array of treatment options and multiple possible sequencing combinations depending on the individual patient. This review will summarize the findings of the randomized trials that led to the approval of the therapies for CRPC. It will also discuss recent guidelines and provide suggestions for sequencing of drugs based on the best available evidence.
Molecular classification of non-small cell lung cancer using a four protein quantitative assay.
Authors: V. K. Anagnostou, T. Botsis, E. Killiam, V. Zolota, D. Dougenis, L. Tanoue, F. C. Detterbeck, K. N. Syrigos, G. Bepler, D. Rimm
Journal: Journal of Clinical Oncology (2010)

10528 Background: The importance of definitive histologic subclassification has significantly increased as drug trials have shown benefit or adverse effects associated with histology in non-small cell lung cancer (NSCLC). The acuity of this problem is further exacerbated by the use of minimally invasive, biopsy and cytology samples with misclassification rates as high as 25%. Despite the unmet need for a standardized assay to adequately classify NSCLC patients by histology there is no routinely used molecular tool to distinguish between different NSCLC subtypes. Here we describe the development and validation of a 4-protein classifier that differentiates primary lung adenocarcinomas (AC) from squamous cell carcinomas (SCC). Methods: Quantitative immunofluorescence (AQUA) was employed to measure and identify proteins differentially expressed between AC and SCC; 8 out of the 24 proteins studied were further analyzed in a logistic regression model following stepwise selection. An objective 4-protein classifier was generated to define likelihood of AC in a training set of 343 NSCLC patients followed by validation in 2 independent cohorts (n = 197 and n = 235). Results: Statistical modeling on 1000 bootstrap samples selected TTF1, CK5, CK13 and EGFR to generate a weighted classifier in the training set and to identify the optimal cutpoint for differentiating AC from SCC tumors. Using the pathologist's final diagnosis as ground truth, the molecular test showed a sensitivity of 96% and specificity of 93%. The classifier was then validated in a blinded analysis in a retrospectively collected cohort of 197 NSCLC patients yielding a sensitivity of 92%,specificity of 97% and area under the curve (AUC) equal to 0.984. We further validated our test in a prospectively collected cohort of 235 patients that revealed a sensitivity and specificity of 96% and 97% and an AUC of 0.989. Interestingly adenosquamous tumors (n = 14) were classified either as AC or SCC whereas our test was unable to accurately classify large cell or giant cell tumors. Conclusions: Molecular classification of NSCLC using an objective quantitative test can be highly accurate and could be translated into a robust diagnostic platform for broad clinical application. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration HistoRx HistoRx
Impact of <i>TP53</i> Mutations on Outcome in <i>EGFR</i>-Mutated Patients Treated with First-Line Tyrosine Kinase Inhibitors
Authors: Matteo Canale, Elisabetta Petracci, Angelo Delmonte, Elisa Chiadini, Claudio Dazzi, Maximilian Papi, Laura Capelli, Claudia Casanova, Nicoletta De Luigi, Marita Mariotti, Alessandro Gamboni, Rita Chiari, Chiara Bennati, Daniele Calistri, Vienna Ludovini, Lucio Crinò, Dino Amadori, Paola Ulivi
Journal: Clinical Cancer Research (2016)

Abstract Purpose: To analyze the impact of TP53 mutations on response to first-line tyrosine kinase inhibitors (TKI) in patients with EGFR-mutated non–small cell lung cancer (NSCLC). Experimental Design: 136 EGFR-mutated NSCLC patients receiving first-line TKIs were analyzed. TP53 mutations were evaluated in 123 patients in relation to disease control rate (DCR), objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). Results: TP53 mutations were observed in 37 (30.1%), 10 (27.0%), 6 (16.2%), 9 (24.3%), and 12 (32.4%) patients in exons 5, 6, 7, and 8, respectively. DCR was 70% in TP53-mutated patients compared with 88% in TP53-wild type (wt) patients [relative risk, RR, of disease progression: 3.17 (95% CI, 1.21–8.48), P = 0.019]. In particular, a 42% DCR was observed in patients with TP53 exon 8 mutation versus 87% in exon 8 wt patients [RR of disease progression 9.6 (2.71–36.63), P &amp;lt; 0.001]. Shorter median PFS and OS were observed in patients with TP53 exon 8 mutations compared with others (4.2 vs. 12.5, P = 0.058, and 16.2 vs. 32.3, P = 0.114, respectively); these differences became significant in the subgroup with EGFR exon 19 deletion (4.2 vs. 16.8, P &amp;lt; 0.001, and 7.6 vs. not reached, P = 0.006, respectively), HR 6.99 (95% CI, 2.34–20.87, P &amp;lt; 0.001) and HR 4.75 (95% CI, 1.38–16.29, P = 0.013), respectively. Conclusions: TP53 mutations, especially exon 8 mutations, reduce responsiveness to TKIs and worsen prognosis in EGFR-mutated NSCLC patients, mainly those carrying exon 19 deletions. Clin Cancer Res; 23(9); 2195–202. ©2016 AACR.
<sup>11</sup>C-PD153035 PET/CT molecular imaging of EGFR for evaluation of advanced non-small cell lung cancer (NSCLC) to EGFR-targeted therapy
Authors: X. Meng, J. M. Yu, G. R. Yang, S. Q. Zhao, X. D. Sun
Journal: Journal of Clinical Oncology (2009)

7576 Background: Our previous study suggests that 11 C-PD153035, a specific and potent inhibitor of EGFR tyrosine kinase (EGFR-TKI), is a novel PET radiotracer and 11 C-PD153035 PET/CT is a promising non-invasive method for in vitro and vivo imaging of EGFR in NSCLC. We report a pilot study evaluating the efficacy of 11 C-PD153035 PET/CT imaging as a “molecular fingerprint” to the EGFR-TKI in advanced NSCLC (stage IIIB/IV). Methods: Patients with pathologically proved advanced NSCLC were enrolled. 11 C-PD153035 PET/CT was performed before (PET/CT 1) and 4 weeks after (PET/CT 2) received EGFR-targeted therapy (erlotinib) with assessment of maximum standardized uptake values (SUVmax) for correlation with response. Treatment response was also expressed as CT results on the basis of traditional Response Evaluation Criteria in Solid Tumors (RECIST) criteria. Image fusion and calculation of tumor subvolumes was performed on Xeleris workstation. Radioactivity concentrations, derived from regions of interest, were analyzed to the SUVmax. Results: 12 patients (5 men, 7 women; age range, 60–79 years) have been enrolled in this study from August 2008, including 3 cases of squamous cell carcinoma, 1 case of large cell carcinoma, and the other of adenocarcinoma. Tumor uptake of 11 C-PD153035 before received therapy was observed in 8 patients and SUVmax ranged from 3.1 to 5.9. There was significant difference in SUVmax (p &lt; 0.01) between tumor and normal tissue. Tumor/lung ratio at 20 min was 4.14 ± 1.80. The SUVmax did not correlate with tumor marker before therapy in our limited data. After 4 weeks therapy, a total of 7 patients underwent the 11C-PD153035 PET /CT again and 5 patients only received CT scanning. Tumor responders had a higher baseline pre-therapy SUVmax than nonresponders (p &lt; 0.01). However, there was no significant difference between pre- and post-therapy SUVmax among 7 patients (p &gt; 0.05). Conclusions: Our data indicated that 11C-PD153035 PET/CT before therapy may play a vital role for identification of patients that could be suitable for EGFR targeted therapies. Thus, it offers opportunities to individualize and optimize target therapy for NSCLC patients. No significant financial relationships to disclose.
Final results of a phase Ib study of tivozanib and FOLFOX6 in patients (pts) with advanced gastrointestinal (GI) tumors.
Authors: Ferry Eskens, Corina N. Oldenhuis, Walter J. Loos, Brooke Esteves, Leni van Doorn, Monette M. Cotreau, Pankaj Bhargava, Joshua Zhang, Andrew Louis Strahs, Martha Willemine den Hollander, Jourik A. Gietema
Journal: Journal of Clinical Oncology (2012)

4132 Background: Tivozanib is a potent, selective, oral small-molecule tyrosine kinase inhibitor of vascular endothelial growth factor receptors 1, 2 and 3 with a long half-life. A Phase I study found tivozanib's maximum tolerated dose (MTD) to be 1.5 mg/d and responses were observed in pts with colorectal cancer (CRC) and other tumors. Tivozanib has shown additive anti-tumor activity with 5-fluorouracil in a preclinical breast tumor model. FOLFOX6 is a standard chemotherapy for GI cancers. This open-label, Phase Ib study (NCT00660153) sought to determine the MTD, dose-limiting toxicities (DLTs), pharmacokinetics (PK), and anti-tumor activity of escalating doses of tivozanib combined with a modified (m) FOLFOX6 regimen (85 mg/kg 2 oxaliplatin) in pts with advanced GI tumors. Methods: Tivozanib was administered once daily in 4-week cycles (3 weeks on, 1 week off) with mFOLFOX6 administered on Days 1 and 15 of each cycle. Pts also received a single dose of tivozanib on day -5 for PK analysis. Pts were allowed to continue tivozanib following discontinuation of mFOLFOX6. Results: Twenty two pts (14:8 male:female; median age 58 years; 91% Caucasian) received tivozanib 0.5 mg (n=9), 1.0 mg (n=3), or 1.5 mg (n=10) and mFOLFOX6. Pts received a median of 5.2 (range 0.0 to 25.1) months of treatment. DLTs were observed in 2 pts on tivozanib 0.5 mg (reversible Grade [Gr] 3 diarrhea and Gr 3/4 transaminase elevations) and in 2 pts on tivozanib 1.5 mg (Gr 3 seizure and reversible Gr 3 vertigo). Other Gr 3/4 drug-related adverse events (AEs) included neutropenia, fatigue, and hypertension (n=2 each). Eight pts discontinued treatment due to AEs. The MTD for tivozanib with mFOLFOX6 was 1.5 mg. The disease control rate was 63% (&lt;1% complete response, 27% partial response, 36% stable disease). Preliminary PK data showed no interaction between tivozanib and mFOLFOX6. Eight additional pts enrolled at the 1.5 mg dose level are currently being evaluated. Final results will be presented. Conclusions: Tivozanib can be combined at its recommended dose of 1.5 mg/day with mFOLFOX6 for pts with advanced GI tumors. The combination was tolerable and showed encouraging anti-tumor activity. A Phase II study of this combination for mCRC is ongoing.
Cost-effectiveness of influenza vaccination of adult cancer patients
Authors: E. B. Avritscher, C. D. Cooksley, J. M. Geraci, B. N. Bekele, S. B. Cantor, K. V. Rolston, L. S. Elting
Journal: Journal of Clinical Oncology (2006)

6079 Background: Despite recommendations to immunize all patients at increased risk from underlying immunosuppressive disease against influenza, many insurance plans do not cover the vaccine. We analyzed the cost-effectiveness of vaccinating adult cancer patients against influenza from the perspective of a third-party payer. Methods: We developed a decision-analytic model using epidemiological, vaccine effectiveness, resource utilization, cost, and utility data from published sources, supplemented with data collected from our institutional accounting system. Two strategies were compared: vaccination of adult cancer patients against influenza, and no vaccination. The cost-effectiveness analysis included charges (inflated to 2005 US$) for vaccination, influenza-related hospitalizations, physician and emergency visits, and the average wholesale price for prescription drugs and influenza vaccine. The base-case patient for the model was assumed to be a 67-year-old cancer patient (the median age at initial cancer diagnosis - all sites - for the 1998–2002 SEER population) with active disease. Results: The effectiveness of the no vaccination strategy was 4.665 QALYs at a cost of $95.23. The effectiveness of the influenza vaccine was 4.672 QALYs at a cost of $70.73. Thus, the vaccination strategy provided an incremental effectiveness of 0.007 QALYs over the no vaccination strategy at a reduction in cost of $24.50. Based on these gains, we estimate that vaccination of all adult cancer patients could potentially save third-party payers over $87 million in addition to gains in clinical benefits. The model was not sensitive to plausible changes in cancer survival, incidence of influenza, vaccine effectiveness, vaccine price, and risk of influenza-related hospitalization. Conclusions: Influenza vaccine is cost-effective for adult cancer patients. Health plans should expand their coverage to include the vaccine for adult patients with cancer. No significant financial relationships to disclose.
GW26-e2193 Renal insufficiency and mortality in coronary artery disease with reduced ejection fraction
Authors: Yong Peng, Tianli Xia, Wei Liu, Baotao Huang, Zhengang Zhao, Fangyang Huang, Chen Zhang, Yanbiao Liao, Hua Chai, Xiaolin Luo, Qiao Li, Yuanning Xu, Chi Chen, Qingtao Meng, Mao Chen, Dejia Huang
Journal: Journal of the American College of Cardiology (2015)
The cyclin-dependent kinase inhibitor AT7519 accelerates neutrophil apoptosis in sepsis-related acute respiratory distress syndrome
Authors: David A Dorward, Jennifer M Felton, Calum T Robb, Thomas Craven, Tiina Kipari, Timothy S Walsh, Christopher Haslett, Kallirroi Kefala, Adriano G Rossi, Christopher D Lucas
Journal: Thorax (2016)

Acute respiratory distress syndrome (ARDS) is a neutrophil-dominant disorder with no effective pharmacological therapies. While the cyclin-dependent kinase inhibitor AT7519 induces neutrophil apoptosis to promote inflammation resolution in preclinical models of lung inflammation, its potential efficacy in ARDS has not been examined. Untreated peripheral blood sepsis-related ARDS neutrophils demonstrated prolonged survival after 20 hours <i>in vitro</i> culture. AT7519 was able to override this phenotype to induce apoptosis in ARDS neutrophils with reduced expression of the pro-survival protein Mcl-1. We demonstrate the first pharmacological compound to induce neutrophil apoptosis in sepsis-related ARDS, highlighting cyclin-dependent kinase inhibitors as potential novel therapeutic agents.
Coronary Artery Bypass Graft Versus Percutaneous Coronary Intervention
Authors: Paul Kurlansky, Morley Herbert, Syma Prince, Michael Mack
Journal: Circulation (2016)

Multiple studies have compared coronary artery bypass graft (CABG) with percutaneous coronary interventions (PCI) for coronary revascularization. There is considerable evidence that adherence to medical therapy can affect the outcomes of therapeutic interventions. However, the long-term influence of compliance with recommended medical therapy on the comparative outcomes of CABG versus PCI remains to be defined.All non-ST-segment-elevation myocardial infarction patients undergoing coronary revascularization in an 8-hospital network were followed for up to 8 years to determine medication history and major adverse cardiac events: all-cause mortality, nonfatal myocardial infarction, and reintervention. All mortalities were checked against the Social Security Death Index. Survival curves were derived with Kaplan-Meier methods; hazard ratios were calculated with the Cox proportional hazard model; and propensity score matching was used to account for differences in patient selection.Among the 973 CABG and 2255 PCI patients, Kaplan-Meier major adverse cardiac event-free survival curves demonstrated a significant benefit for antiplatelet, lipid-lowering, and β-blocker therapy in both the CABG and PCI groups (P=0.001 for all 3 medications). Cox regression identified compliance with optimal medical therapy as a more powerful predictor of major adverse cardiac event-free survival than choice of therapy (hazard ratio for noncompliance=2.79; 95% confidence limits, 2.19-3.54; P<0.001; hazard ratio for PCI versus CABG=1.68, 95% confidence limits, 138-2.04; P<0.001). In propensity-matched patients, CABG outcomes were superior to PCI outcomes in patients nonadherent to optimal medical therapy (P=0.001) but were not different in patients adherent to optimal medical therapy (P=0.574).Regardless of coronary revascularization strategy, medication adherence has a dramatic effect on long-term outcome. Among comparable patients who adhere to optimal medical therapy, outcomes of PCI and CABG may not differ; however, among nonadherent patients, CABG affords better major adverse cardiac event-free survival. Therefore, patient compliance with medical therapy may inform clinical decision making and should be incorporated into all future comparative studies of comparative coronary revascularization strategies.