tbuckley/cabot-search huggingface dataset:
Preventing disease relapses in autoimmune pancreatitis with maintenance steroids: are we there yet?
Authors: Phil A Hart, Suresh T Chari
Journal: Gut (2016)

Autoimmune pancreatitis (AIP) is a fibro-inflammatory disease, which has defining histopathology and is characterised by a dramatic response to steroid treatment.1 Type 1 AIP describes the pancreatic manifestation of a multiorgan syndrome, currently referred to as IgG4-related disease and is frequently associated with an elevated serum IgG4 antibody level.2 This is a chronic disease with relapses occurring in 30–50% of patients within 3 years of disease onset.3 ,4 Published data suggest that low-dose maintenance steroids may decrease the risk for future disease relapse; however, this has not been demonstrated in a prospective clinical trial.5 In the present study, Masamune et al 6 present their findings from a randomised controlled trial (RCT) examining the efficacy of low-dose steroids for maintenance of disease remission. We discuss this article in the context of the existing literature and identify future opportunities to improve the management of type 1 AIP.

In the present study, the authors present their findings from a multicenter, double-blind RCT using low-dose steroids for maintenance of disease remission. A total of 49 subjects were enrolled with a diagnosis of AIP based on the Japanese Pancreas Society diagnostic criteria, with all but two also meeting the International Consensus Diagnostic Criteria for AIP. Treatment naive subjects were randomised at the time of diagnosis to one of two strategies for maintenance therapy. Both groups received similar treatment over the initial 26 weeks, which consisted of high-dose steroids (prednisolone 0.6 mg/kg/day) with a taper over 12 weeks, then intermediate-term exposure to a low steroid dose (prednisolone 5–7.5 mg/day) over the next 14 weeks. At the end of 26 weeks, subjects randomised to the maintenance therapy arm continued their low steroid dose for the remainder of the 3 year study period, whereas those in the steroid cessation arm discontinued steroid use.

The …
Excess medical costs in patients with asthma and the role of comorbidity
Authors: Wenjia Chen, Larry D. Lynd, J. Mark FitzGerald, Carlo A. Marra, Robert Balshaw, Teresa To, Hamid Tavakoli, Mohsen Sadatsafavi
Journal: European Respiratory Journal (2016)

Asthmatic patients frequently have comorbidities, but the role of comorbidities in the economic burden of asthma is unclear. We examined the excess direct medical costs, including asthma- and comorbidity-related costs, in patients with asthma. We created a propensity score-matched cohort of patients newly diagnosed with asthma and non-asthmatic comparison subjects, both aged 5–55 years, from health administrative data (1997–2012) in British Columbia, Canada. Health services use records were categorised into 16 major disease categories based on International Classification of Diseases codes. Excess costs (in 2013 Canadian dollars ($)) were estimated as the adjusted difference in direct medical costs between the two groups. Average overall excess costs were estimated at $1058/person-year (95% CI 1006–1110), of which $134 (95% CI 132–136) was attributable to asthma and $689 (95% CI 649–730) to major comorbidity classes. Psychiatric disorders were the largest component of excess comorbidity costs, followed by digestive disorders, diseases of the nervous system, and respiratory diseases other than asthma. Comorbidity-attributable excess costs greatly increased with age but did not increase over the time course of asthma. These findings suggest that both asthma and comorbidity-related outcomes should be considered in formulating evidence-based policies and guidelines for asthma management.
NICE recommends first drug through “managed access” model of the Cancer Drugs Fund
Authors: Susan Mayor
Journal: BMJ (2016)

The National Institute for Health and Care Excellence (NICE) has recommended the first drug to be provided through the new “managed access” system of the Cancer Drugs Fund. Interim guidance published in September said that osimertinib should be provided through the fund to patients with a particularly aggressive form of lung cancer for the next two years, while further data on efficacy and cost effectiveness were collected and evaluated.1

This meant that osimertinib could be used for treating locally advanced or metastatic non-small cell lung cancer expressing the epidermal growth factor receptor (EGFR) T790M …
QOL at 3 years after diagnosis in aggressive lymphoma survivors.
Authors: Carrie A. Thompson, Matthew J. Maurer, Cristine Allmer, Stephen Maxted Ansell, Raina Mahajan Ferzoco, Thomas Matthew Habermann, David James Inwards, Patrick B. Johnston, Robin Klebig, William R Macon, Ivana N. M. Micallef, Kathleen J. Yost, Umar Farooq, Brian K. Link, James Robert Cerhan
Journal: Journal of Clinical Oncology (2015)

9586 Background: Patients with aggressive lymphoma are potentially curable, but longer-term effects of treatment may adversely impact quality of life (QOL). We examined QOL scores at baseline enrollment and 3 year follow-up in survivors of aggressive lymphoma. Methods: Newly diagnosed lymphoma patients were prospectively enrolled within 9 months of diagnosis in the University of Iowa/Mayo Clinic SPORE Molecular Epidemiology Resource (MER) and systematically followed. We measured baseline QOL at time of enrollment and at 3 years after diagnosis with the Functional Assessment of Cancer Therapy-General (FACT-G) scale. This scale measures well-being (WB) in 4 QOL domains—physical (PWB), social/family (SWB), emotional (EWB), functional (FWB)—along with a total FACT-G score (TOT). For this study, we defined “survivor” as alive at 3 year follow-up with no active disease or treatment within the previous year. Results: From 2002-2009, 1902 patients with aggressive lymphoma were prospectively enrolled. Of these, 477 completed QOL questionnaires at both baseline and 3 years and met the study definition of survivor. Median age at diagnosis was 62 years (range 18-87) and 58% were male. Distribution of NHL subtypes were 61% DLBCL, 12% mantle cell, 10% FL grade III, 9% T cell, and 8% other. Each FACT-G subscale was significantly higher than assessment at diagnosis with the exception of SWB, which was significantly lower (all p < 0.0001), with mean changes ranging from -1.8 (SWB) to 7.0 (TOT) points. After adjusting for baseline QOL, there was a modest association between older age and smaller change from baseline QOL for TOT (p = 0.021), PWB (p = 0.012), and FWB (p = 0.001); otherwise there were no other clinical associations between change in TOT from diagnosis to 3 years (all p > 0.11). Compared to the US general population, 3-year survivors have significantly higher QOL (EWB p = 0.039, all other p < 0.0001), while their QOL at baseline was similar to the general population for FWB (p = 0.59), higher for SWB (p < 0.0001) and TOT (p = 0.0033), and lower for PWB (p = 0.0003) and EWB (p < 0.0001). Conclusions: In survivors of aggressive lymphoma, QOL improves over time and is higher than the QOL for the US general population at 3 years post-diagnosis.
The Irish Programme for Stratified Prostate Cancer Therapy (iPROSPECT).
Authors: John Patrick Greene, Orla Casey, Karen O'Leary, Ciara Fahey, Suzanne Bracken, Sharon A. Glynn, Antoinette Perry, William Watson, Stephen Finn, Ray McDermott
Journal: Journal of Clinical Oncology (2016)

335 Background: iPROSPECT is a prospective longitudinal translational study, funded through the Irish Cancer Society in partnership with Movember that is examining blood and tissue markers that might correlate with treatment response and survival and aid future stratification of metastatic prostate cancer (mPCa) patients with regard to optimal personalised treatment regimens. Methods: Patients with metastatic prostate cancer who are beginning or changing treatment are eligible for inclusion. Nine hospital sites supported by four research laboratories are open to recruitment. Cohort 1 (n = 15) includes patients with newly diagnosed mPCa who are beginning treatment with androgen deprivation therapy (ADT). Cohort 2 (n = 45) includes patients with CRPC who are beginning or changing treatment. All enrolled patients have blood drawn for plasma, serum and CTC analysis at baseline and thereafter every 4 months. All eligible patients with metastatic bone disease are offered an optional substudy of bone marrow biopsy performed prior to starting treatment. Any patient with visceral or nodal disease is offered a targeted CT guided biopsy. All patients are offered the PCa Research Consortium questionnaire, FACT-P and the Brief Pain inventory short form. Results: Between March and August 2015, 15 patients within cohort 1 (100%) have been enrolled and 22 patients in cohort 2 (48.8%). In cohort 1, the median age of patients was 66, median PSA at entry was 9.2 with an average Gleason score of 8. In cohort 2, the median age of patients was 68, median PSA at entry was 236.4 with an average Gleason score of 8. Eight patients underwent bone marrow biopsy, and 2 patients underwent CT guided biopsies. All patients had archival FFPE tissue collected. Questionnaires were collected from all eligible patients. Conclusions: The recruitment rate to date has indicated successful implementation of this study. Results will identify how clinical and biological patterns change over time and relate to each individual’s treatment response and progression of disease. [Table: see text]
Mortality due to C difficile colitis in elderly people has been underestimated
Authors: M Lesna, D M Parham
Journal: BMJ (1996)

tutes.We found that all the general practitioners offered counselling about hepatitis, screening, and hepatitis B vaccinations.The audit showed that, of 120 injecting drug users, 30 had been vaccinated against hepatitis B, 30 were immune, and 14 had chosen not to be screened.The hepatitis B status was not known in 42 users, two were carriers, and two had yielded negative results on testing but had not yet been vaccinated.
Abstract 9926: Molecular Imaging of the Pro-angiogenic Paracrine Effects of Stem Cell Therapy
Authors: Jae Choon Ryu, Qi Yue, Chard Carr, Todd Belcik, Aris Xie, Brian Davidson, Yan Zhao, Juliana M Woda, Anthony E Ting, Jonathan R Lindner
Journal: Circulation (2011)

Background: Pro-angiogenic stem cells are a promising therapy for patients with severe coronary or peripheral vascular disease. Mechanisms by which cell therapy promotes vascular remodeling remain unclear. We applied contrast-enhanced ultrasound (CEU) molecular imaging to test whether cell therapy acts in a paracrine fashion by promoting recruitment of pro-angiogenic (CX3CR-1 hi ) monocytes. Methods: Unilateral hindlimb ischemia was produced in 52 mice by iliac artery ligation. One day later, the proximal hindlimb received either: (1) IM injection of 1×10 6 multipotent adult progenitor cells (MAPC), (2) sham saline injection, or (3) no therapy. At Day3, 7, and 21 CEU perfusion imaging and molecular imaging of CX3CR-1 and P-selectin were performed. In 8 separate mice, intravital microscopy of TNF-a-treated cremaster muscle was performed 3 days after injection of either 5×10 5 MAPCs or saline. Results: Arterial ligation resulted in a 70% reduction in limb muscle blood flow to 0.20±0.06 ml/min/g. MAPC therapy produced a more rapid and complete recovery of flow (0.61±0.06 ml/min/g at day 21, ≈25% higher than both control groups, p&lt;0.05). Signal for CX3CR-1 was significantly (p&lt;0.05) higher vs control groups at all 3 study intervals (Figure),corroborated by a marked increase in tissue monocytes on Mac-2 immunohistology. P-selectin signal was also significantly higher in the MAPC-treated mice at days 3 and 7 (Figure). Intravital microscopy which showed that MAPCs migrated to a perivascular location and produced a 50% increase in leukocyte rolling flux fraction. Conclusions: In chronic limb ischemia, MAPCs migrate to a perivascular location and promote the sustained recruitment of pro-angiogenic monocytes, in part through effects on endothelial adhesion molecule expression. These results suggest that cell therapy can act to promote vascular remodeling through inflammatory pathways
The Structure of the Gene for miR-223 in Humans, a MicroRNA Highly Expressed in Hematopoietic Tissues.
Authors: Wilson A. Silva, Kelson R. Kodama, Greice A. Molfetta, Dalila L. Zanette, Valeria Valente, Amelia G. Araujo, Eduardo M. Rego, Marco A. Zago
Journal: Blood (2005)
State-Specific Prevalence of Current Cigarette Smoking and Smokeless Tobacco Use Among Adults — United States, 2014
Authors: Kimberly H. Nguyen, LaTisha Marshall, Susan Brown, Linda Neff
Journal: MMWR Morbidity and Mortality Weekly Report (2016)

Tobacco use is the leading cause of preventable disease and death in the United States, resulting in approximately 480,000 premature deaths and more than $300 billion in direct health care expenditures and productivity losses each year (1). In recent years, cigarette smoking prevalence has declined in many states; however, there has been relatively little change in the prevalence of current smokeless tobacco use or concurrent use of cigarettes and smokeless tobacco in most states, and in some states prevalence has increased (2). CDC analyzed data from the 2014 Behavioral Risk Factor Surveillance System (BRFSS) to assess state-specific prevalence estimates of current use of cigarettes, smokeless tobacco, and cigarette and/or smokeless tobacco (any cigarette/smokeless tobacco use) among U.S. adults. Current cigarette smoking ranged from 9.7% (Utah) to 26.7% (West Virginia); current smokeless tobacco use ranged from 1.4% (Hawaii) to 8.8% (Wyoming); current use of any cigarette and/or smokeless tobacco product ranged from 11.3% (Utah) to 32.2% (West Virginia). Disparities in tobacco use by sex and race/ethnicity were observed; any cigarette and/or smokeless tobacco use was higher among males than females in all 50 states. By race/ethnicity, non-Hispanic whites had the highest prevalence of any cigarette and/or smokeless tobacco use in eight states, followed by non-Hispanic other races in six states, non-Hispanic blacks in five states, and Hispanics in two states (p<0.05); the remaining states did not differ significantly by race/ethnicity. Evidence-based interventions, such as increasing tobacco prices, implementing comprehensive smoke-free policies, conducting mass media anti-tobacco use campaigns, and promoting accessible smoking cessation assistance, are important to reduce tobacco use and tobacco-related disease and death among U.S. adults, particularly among subpopulations with the highest use prevalence (3).
TNFα-Induced Mucin 4 Expression Elicits Trastuzumab Resistance in HER2-Positive Breast Cancer
Authors: María F. Mercogliano, Mara De Martino, Leandro Venturutti, Martín A. Rivas, Cecilia J. Proietti, Gloria Inurrigarro, Isabel Frahm, Daniel H. Allemand, Ernesto Gil Deza, Sandra Ares, Felipe G. Gercovich, Pablo Guzmán, Juan C. Roa, Patricia V. Elizalde, Roxana Schillaci
Journal: Clinical Cancer Research (2016)

Although trastuzumab administration improved the outcome of HER2-positive breast cancer patients, resistance events hamper its clinical benefits. We demonstrated that TNFα stimulation in vitro induces trastuzumab resistance in HER2-positive breast cancer cell lines. Here, we explored the mechanism of TNFα-induced trastuzumab resistance and the therapeutic strategies to overcome it.Trastuzumab-sensitive breast cancer cells, genetically engineered to stably overexpress TNFα, and de novo trastuzumab-resistant tumors, were used to evaluate trastuzumab response and TNFα-blocking antibodies effectiveness respectively. Immunohistochemistry and antibody-dependent cell cytotoxicity (ADCC), together with siRNA strategy, were used to explore TNFα influence on the expression and function of its downstream target, mucin 4 (MUC4). The clinical relevance of MUC4 expression was studied in a cohort of 78 HER2-positive breast cancer patients treated with adjuvant trastuzumab.TNFα overexpression turned trastuzumab-sensitive cells and tumors into resistant ones. Histopathologic findings revealed mucin foci in TNFα-producing tumors. TNFα induced upregulation of MUC4 that reduced trastuzumab binding to its epitope and impaired ADCC. Silencing MUC4 enhanced trastuzumab binding, increased ADCC, and overcame trastuzumab and trastuzumab-emtansine antiproliferative effects in TNFα-overexpressing cells. Accordingly, administration of TNFα-blocking antibodies downregulated MUC4 and sensitized de novo trastuzumab-resistant breast cancer cells and tumors to trastuzumab. In HER2-positive breast cancer samples, MUC4 expression was found to be an independent predictor of poor disease-free survival (P = 0.008).We identified TNFα-induced MUC4 expression as a novel trastuzumab resistance mechanism. We propose MUC4 expression as a predictive biomarker of trastuzumab efficacy and a guide to combination therapy of TNFα-blocking antibodies with trastuzumab. Clin Cancer Res; 23(3); 636-48. ©2016 AACR.
Identifying nonalcoholic fatty liver disease patients with active fibrosis by measuring extracellular matrix remodeling rates in tissue and blood
Authors: Martin L. Decaris, Kelvin W. Li, Claire L. Emson, Michelle Gatmaitan, Shanshan Liu, Yenny Wang, Edna Nyangau, Marc Colangelo, Thomas E. Angel, Carine Beysen, Jeffrey Cui, Carolyn Hernandez, Len Lazaro, David A. Brenner, Scott M. Turner, Marc K. Hellerstein, Rohit Loomba
Journal: Hepatology (2016)

Excess collagen synthesis (fibrogenesis) in the liver plays a causal role in the progression of nonalcoholic fatty liver disease (NAFLD). Methods are needed to identify patients with more rapidly progressing disease and to demonstrate early response to treatment. We describe here a novel method to quantify hepatic fibrogenesis flux rates both directly in liver tissue and noninvasively in blood. Twenty-one patients with suspected NAFLD ingested heavy water (2 H2 O, 50-mL aliquots) two to three times daily for 3-5 weeks prior to a clinically indicated liver biopsy. Liver collagen fractional synthesis rate (FSR) and plasma lumican FSR were measured based on 2 H labeling using tandem mass spectrometry. Patients were classified by histology for fibrosis stage (F0-F4) and as having nonalcoholic fatty liver or nonalcoholic steatohepatitis (NASH). Magnetic resonance elastography measurements of liver stiffness were also performed. Hepatic collagen FSR in NAFLD increased with advancing disease stage (e.g., higher in NASH than nonalcoholic fatty liver, positive correlation with fibrosis score and liver stiffness) and correlated with hemoglobin A1C. In addition, plasma lumican FSR demonstrated a significant correlation with hepatic collagen FSR.Using a well-characterized cohort of patients with biopsy-proven NAFLD, this study demonstrates that hepatic scar in NASH is actively remodeled even in advanced fibrosis, a disease that is generally regarded as static and slowly progressive. Moreover, hepatic collagen FSR correlates with established risks for fibrotic disease progression in NASH, and plasma lumican FSR correlates with hepatic collagen FSR, suggesting applications as direct or surrogate markers, respectively, of hepatic fibrogenesis in humans. (Hepatology 2017;65:78-88).
484PD A multicenter prospective biomarker study in afatinib-treated patients with EGFR-mutation positive non-small cell lung cancer
Authors: E. Iwama, K. Sakai, K. Azuma, K. Nosaki, D. Harada, K. Hotta, F. Ohyanagi, T. Kurata, H. Akamatsu, K. Goto, T. Fukuhara, Y. Nakanishi, K. Nishio, I. Okamoto
Journal: Annals of Oncology (2015)
Brief Report: A Prospective Open‐Label Phase IIa Trial of Tocilizumab in the Treatment of Polymyalgia Rheumatica
Authors: Lindsay Lally, Lindsy Forbess, Christopher Hatzis, Robert Spiera
Journal: Arthritis & Rheumatology (2016)

Interleukin-6 (IL-6) is a pivotal cytokine in the pathogenesis of polymyalgia rheumatica (PMR), yet the efficacy of IL-6 blockade with tocilizumab (TCZ) for the treatment of PMR is unknown. The aim of this study was to assess the efficacy and safety of TCZ in newly diagnosed PMR.In a single-center open-label study, patients with newly diagnosed PMR who had been treated with glucocorticoids (GCs) for <1 month were treated monthly with intravenous (IV) TCZ 8 mg/kg for 1 year, with a rapid tapering of GCs according to standardized protocol. The primary end point was the proportion of patients in relapse-free remission without GC treatment at 6 months. Secondary outcome measures included duration of GC use and cumulative GC dose. Patients were followed up for 15 months.Ten patients were enrolled in the study. One patient withdrew after 2 months, leaving 9 patients in whom the primary end point was assessed. The primary end point of relapse-free remission without GC treatment at 6 months was achieved by all 9 of these patients. All patients who received TCZ treatment were able to discontinue GCs within 4 months of study entry. The cumulative mean ± SD prednisone dose was 1,085 ± 301 mg and the total duration of GC exposure was 3.9 ± 0.9 months. Remission persisted without relapse, in all 9 patients, throughout the entire 15-month study.Our findings suggest that TCZ may be an effective, safe, and well-tolerated treatment for newly diagnosed patients with PMR, with a robust steroid-sparing effect.
Correlation of cisplatin response and caspase-3 cleavage in human carcinomas.
Authors: D. Wang, L. Sakhamuri, P. Ervin
Journal: Journal of Clinical Oncology (2010)

e21104 Background: Cisplatin is a platinum-based chemotherapeutic drug used for treating a variety of human cancers such as breast, lung, and ovarian. Cisplatin exerts its cytotoxicity via the formation of cisplatin-DNA adducts resulting in cell cycle arrest and the induction of apoptosis. Sequential cleavage/activation of caspase cascades are key steps in triggering apoptosis. Activated caspases, such as caspase-3, target cytoplasmic and nuclear proteins involved in maintaining cellular architecture, DNA repair, replication, and transcription. Methods: A total of eleven immortalized human cancer cell lines (five lung, three breast, and three ovarian), and eight patient-derived human ovarian cancer primary cultures were evaluated for response to cisplatin using ChemoFx Drug Response Marker. Each culture was treated with a ten-dose range of cisplatin for seventy-two hours before DAPI staining of nuclei and counting of remaining cells. AUC (area under curve) values were calculated and additional statistical analysis was performed on the resulting dose-response curves to measure responsiveness. In cell western (ICW) analysis was performed in parallel using anticleaved caspase-3 antibody to evaluate activation of apoptosis pathways in the same primary cultures treated with cisplatin. Results: ChemoFx results revealed that among the eleven cancer cell lines, one breast cancer cell line and one lung cancer cell line are nonresponsive, while the remaining nine are responsive to cisplatin. At the same time, ICW results showed that cleaved caspase-3 level increased significantly in all of the nine responsive cell lines, but not in the two nonresponsive cell lines. Furthermore, among the eight ovarian cancer primary cultures, all of the five ChemoFx-cisplatin-responsive cultures, but none of the three nonresponsive cultures, showed significantly elevated cleaved caspase-3 level. Conclusions: Tumor cells identified as responsive to cisplatin by ChemoFx consistently show increased cleaved caspase-3 expression indicative of apoptosis. These results further validate the accuracy of ChemoFx and suggest a potential role of cleaved caspase-3 as a high throughput protein biomarker for prediction of responsiveness to cisplatin. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Precision Therapeutics