tbuckley/cabot-search huggingface dataset:
Genome-wide association study for germline prognostic markers in colorectal cancer.
Authors: A. Walther, E. Domingo, D. Mesher, E. Johnstone, T. Orntoft, P. Sasieni, M. Dunlop, S. Tejpar, D. J. Kerr, I. Tomlinson
Journal: Journal of Clinical Oncology (2010)

3514 Background: Individual variation in colorectal cancer (CRC) survival may in part be explained by germline determinants. To date, the literature investigating such effects is sparse, and the few associations described weak. We performed a genome-wide association study (GWAS) to determine the impact of germline variation on CRC survival. Methods: 947 patients in the VICTOR trial with stage 2 or 3 CRC were typed at autosomal 309,200 SNPs on Illumina Hap300 BeadChips (Illumina Inc., San Diego). Survival analysis was performed using Cox regression. After excluding noninformative SNPs and those with a minor allele frequency (MAF) <0.12, 25 SNPs with the lowest p value (range 9.19e-08 to 1.46e-05) and 15 SNPs with p<1e-04 and a suggestive functional relevance based on the nearest gene were typed in 3 further patients sets: 561 Scottish population-based patients (S, 33 SNPs) and 1,251 patients enrolled in PETACC 2 (P, 33 SNPs), 401 Danish population-based patients (D, 10 SNPs); all had stage 2 and 3 CRC. The replication HR were stage adjusted and meta-analyzed using a fixed effects model. The significance threshold was p<0.01. This study had 80% power to detect HR=1.5. Results: One SNP reached statistical significance at the prespecified level in meta-analysis of the replication sets with p = 8.54e-03, HR = 1.46 (95% CI 1.10-1.94), and no evidence of statistical heterogeneity (I2 = 0%, p=0.856). This SNP was not significant in any of the individual replication sets, but effect size and direction was similar in all three cohorts: HR = 1.27 (S), HR = 1.55 (P), HR = 1.41 (D). The data are most consistent with a multiplicative model with a detrimental interaction in the minor allele homozygotes (MAF = 25.9%). It lies on chromosome 2, near ACTR2 involved in cell shape and motility, and the process of invasion. No previously described germline determinants were replicated. Conclusions: This GWAS for prognosis in stage II and III CRC is the first in CRC and largest in any tumour type. It supports an effect of germline genetic variation on prognosis in this setting, but very large effects (HR ≥ 2.0) seem unlikely. The study was underpowered to detect lesser effects and further work will explore these in larger cohorts. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Pfizer
Percutaneous Device Closure of Paravalvular Leak
Authors: Patrick A. Calvert, David B. Northridge, Iqbal S. Malik, Leonard Shapiro, Peter Ludman, Shakeel A. Qureshi, Michael Mullen, Robert Henderson, Mark Turner, Martin Been, Kevin P. Walsh, Ivan Casserly, Lindsay Morrison, Nicola L. Walker, John Thomson, Mark S. Spence, Vaikom S. Mahadevan, Angela Hoye, Philip A. MacCarthy, Matthew J. Daniels, Paul Clift, William R. Davies, Philip D. Adamson, Gareth Morgan, Suneil K. Aggarwal, Yasmin Ismail, Julian O. M. Ormerod, Habib R. Khan, Sujay Subash Chandran, Joseph de Giovanni, Bushra S. Rana, Oliver Ormerod, David Hildick-Smith
Journal: Circulation (2016)

Paravalvular leak (PVL) occurs in 5% to 17% of patients following surgical valve replacement. Percutaneous device closure represents an alternative to repeat surgery.All UK and Ireland centers undertaking percutaneous PVL closure submitted data to the UK PVL Registry. Data were analyzed for association with death and major adverse cardiovascular events (MACE) at follow-up.Three hundred eight PVL closure procedures were attempted in 259 patients in 20 centers (2004-2015). Patient age was 67±13 years; 28% were female. The main indications for closure were heart failure (80%) and hemolysis (16%). Devices were successfully implanted in 91% of patients, via radial (7%), femoral arterial (52%), femoral venous (33%), and apical (7%) approaches. Nineteen percent of patients required repeat procedures. The target valve was mitral (44%), aortic (48%), both (2%), pulmonic (0.4%), or transcatheter aortic valve replacement (5%). Preprocedural leak was severe (61%), moderate (34%), or mild (5.7%) and was multiple in 37%. PVL improved postprocedure (P<0.001) and was none (33.3%), mild (41.4%), moderate (18.6%), or severe (6.7%) at last follow-up. Mean New York Heart Association class improved from 2.7±0.8 preprocedure to 1.6±0.8 (P<0.001) after a median follow-up of 110 (7-452) days. Hospital mortality was 2.9% (elective), 6.8% (in-hospital urgent), and 50% (emergency) (P<0.001). MACE during follow-up included death (16%), valve surgery (6%), late device embolization (0.4%), and new hemolysis requiring transfusion (1.6%). Mitral PVL was associated with higher MACE (hazard ratio [HR], 1.83; P=0.011). Factors independently associated with death were the degree of persisting leak (HR, 2.87; P=0.037), New York Heart Association class (HR, 2.00; P=0.015) at follow-up and baseline creatinine (HR, 8.19; P=0.001). The only factor independently associated with MACE was the degree of persisting leak at follow-up (HR, 3.01; P=0.002).Percutaneous closure of PVL is an effective procedure that improves PVL severity and symptoms. Severity of persisting leak at follow-up is independently associated with both MACE and death. Percutaneous closure should be considered as an alternative to repeat surgery.
A novel 3D human glioblastoma cell culture system for modeling drug and radiation responses
Authors: Natividad Gomez-Roman, Katrina Stevenson, Lesley Gilmour, Graham Hamilton, Anthony J Chalmers
Journal: Neuro-Oncology (2016)

Glioblastoma (GBM) is the most common primary brain tumor, with dismal prognosis. The failure of drug–radiation combinations with promising preclinical data to translate into effective clinical treatments may relate to the use of simplified 2-dimensional in vitro GBM cultures. We developed a customized 3D GBM culture system based on a polystyrene scaffold (Alvetex) that recapitulates key histological features of GBM and compared it with conventional 2D cultures with respect to their response to radiation and to molecular targeted agents for which clinical data are available. In 3 patient-derived GBM lines, no difference in radiation sensitivity was observed between 2D and 3D cultures, as measured by clonogenic survival. Three different molecular targeted agents, for which robust clinical data are available were evaluated in 2D and 3D conditions: (i) temozolomide, which improves overall survival and is standard of care for GBM, exhibited statistically significant effects on clonogenic survival in both patient-derived cell lines when evaluated in the 3D model compared with only one cell line in 2D cells; (ii) bevacizumab, which has been shown to increase progression-free survival when added to standard chemoradiation in phase III clinical trials, exhibited marked radiosensitizing activity in our 3D model but had no effect on 2D cells; and (iii) erlotinib, which had no efficacy in clinical trials, displayed no activity in our 3D GBM model, but radiosensitized 2D cells. Our 3D model reliably predicted clinical efficacy, strongly supporting its clinical relevance and potential value in preclinical evaluation of drug–radiation combinations for GBM.
Determinants of predicted efficacy of antiarrhythmic drugs in the electrophysiologic study versus electrocardiographic monitoring trial. The ESVEM Investigators.
Journal: Circulation (1993)

The Electrophysiologic Study Versus Electrocardiographic Monitoring (ESVEM) study was designed to compare the accuracy of predictions of antiarrhythmic drug efficacy made by electrophysiological study (EPS) with those made by Holter monitoring (HM) combined with exercise testing. The present study describes the baseline characteristics and the response to drug efficacy tests of 486 randomized subjects.Patients with ventricular tachyarrhythmias were randomly assigned to undergo serial testing of up to six antiarrhythmic drugs by either EPS (EPS limb) or HM and exercise testing (HM limb). Efficacy predictions were achieved in 108 of 242 patients in the EPS limb (45%) and in 188 of 244 patients (77%) in the HM limb. Left ventricular ejection fraction (LVEF) < 0.25 and presence of coronary artery disease were negative correlates (p < 0.10) of drug efficacy predictions in the EPS limb. In the HM limb, LVEF was the lone univariate correlate of efficacy, although it was only marginally significant (p = 0.107). A multivariate model selected assessment by HM and higher LVEF as independent predictors (p < 0.05) of drug efficacy. The drug evaluation process required an actuarial median time of 25 days in the EPS limb and 10 days in the HM limb (p < 0.0001).1) Drug efficacy predictions are achieved more frequently by HM than by EPS. 2) Assessment by HM and severity of left ventricular dysfunction are independent correlates for a drug efficacy prediction. 3) The duration of drug testing is considerably shorter for the HM method.
Lung cancer screening: improving understanding of the psychological impact
Authors: Samantha L Quaife, Sam M Janes
Journal: Thorax (2016)

The clinical evidence base for low-dose CT (LDCT) lung cancer screening is rapidly advancing and the case for implementing a UK programme building. This is welcome news to the lung cancer community whose patients too often face a bleak prognosis, in part because early diagnosis is so infrequent. Relatively less attention, however, has been paid to the potential psychological responses of high-risk individuals to such a screening programme; something which should inform policy decision-makers and shape healthcare professionals' practice of screening, to maximise patient benefit and well-being.

Previous research on screening for other types of cancer has shown there is potential for patients to experience distress at any point along the screening pathway. An individual's propensity to experience distress in response to cancer screening may be determined in part by the nature of the result they receive and any ensuing tests or surveillance, as well as their psychosocial characteristics.1 In Thorax, Brain et al provide an invaluable contribution to both these aspects and the first from the UK; reporting the long-term psychosocial outcomes of screening among participants in the UK Lung Screening (UKLS) trial.2

The psychological cost of abnormal findings is especially important to understand in the context of LDCT lung cancer screening because they are frequent, with an average pulmonary nodule detection rate of 20% across trials.3 In the US National Lung Screening Trial (NLST), 39% of participants received a positive screening result for one of their three annual screens, of which 96% were false positives.4 Incidental findings (ie, medical conditions other than lung cancer) were also a common outcome for screenees, affecting 10% of NLST participants following their prevalence (first) screen.4 The UKLS investigators made a distinction between false positive and indeterminate results based on their clinical management. Pulmonary nodules …
A Study of Reverse Causation: Examining the Associations of Perfluorooctanoic Acid Serum Levels with Two Outcomes
Authors: Radhika Dhingra, Andrea Winquist, Lyndsey A. Darrow, Mitchel Klein, Kyle Steenland
Journal: Environmental Health Perspectives (2016)

Impaired kidney function and earlier menopause were associated with perfluorooctanoic acid (PFOA) serum levels in previous cross-sectional studies. Reverse causation, whereby health outcomes increase serum PFOA, may underlie these associations.We compared measured (subject to reverse causation) versus modeled (unaffected by reverse causation) serum PFOA in association with these outcomes to examine the possible role of reverse causation in these associations.In cross-sectional analyses, we analyzed PFOA in relation to self-reported menopause among women (n = 9,192) 30-65 years old and in relation to kidney function among adults > 20 years old (n = 29,499) in a highly exposed Mid-Ohio Valley cohort. Estimated glomerular filtration rate (eGFR, a marker of kidney function) and serum PFOA concentration were measured in blood samples collected during 2005-2006. Retrospective year-specific serum PFOA estimates were modeled independently of measured PFOA based on residential history and plant emissions. Using measured and modeled PFOA in 2005 or 2006 (predictor variables), cross-sectional associations were assessed for eGFR and menopause (yes/no). We also analyzed measured PFOA (dependent variable) in relation to the number of years since menopause.Menopause and eGFR were significantly associated with measured (trend tests: p = 0.013, p = 0.0005, respectively) but not with modeled serum PFOA (p = 0.50, p = 0.76, respectively). Measured PFOA levels increased for the first 7 years after menopause (trend test, p < 0.0001), providing further evidence that the observed association between measured PFOA and menopause is subject to reverse causation for this outcome.Our results support the conjecture that in previous studies, earlier menopause and reduced kidney function are the causes rather than the results of increased measured serum PFOA. These results suggest caution in using biomarkers in cross-sectional studies. Citation: Dhingra R, Winquist A, Darrow LA, Klein M, Steenland K. 2017. A study of reverse causation: examining the associations of perfluorooctanoic acid serum levels with two outcomes. Environ Health Perspect 125:416-421; http://dx.doi.org/10.1289/EHP273.
Deep sequencing shows that HBV basal core promoter and precore variants reduce the likelihood of HBsAg loss following tenofovir disoproxil fumarate therapy in HBeAg-positive chronic hepatitis B
Authors: Julianne Bayliss, Lilly Yuen, Gillian Rosenberg, Darren Wong, Margaret Littlejohn, Kathleen Jackson, Anuj Gaggar, Kathryn M Kitrinos, G Mani Subramanian, Patrick Marcellin, Maria Buti, Harry L A Janssen, Ed Gane, Vitina Sozzi, Danni Colledge, Rachel Hammond, Rosalind Edwards, Stephen Locarnini, Alexander Thompson, Peter A Revill
Journal: Gut (2016)

Hepatitis B e antigen (HBeAg) seroconversion and hepatitis B surface antigen (HBsAg) loss are important clinical outcomes for patients with chronic hepatitis B (CHB) treated with antiviral therapy. To date, there have been few studies that have evaluated viral sequence markers predicting serological response to nucleos(t)ide analogue (NA) treatment.We used next-generation sequencing (NGS) and quantitative HBV serology (HBeAg and HBsAg) to identify viral sequence markers associated with serological response to long-term tenofovir disoproxil fumarate therapy among HBeAg-positive patients. In the GS-US-174-0103 study, approximately half the patients seroconverted to anti-HBe by week 192 and 11% of patients exhibited HBsAg loss, the closest outcome to functional cure. The frequency of HBV variants that have previously been associated with HBV clinical outcomes was evaluated. HBV viral diversity in baseline sequences generated by NGS was calculated using Shannon entropy.NGS analysis of HBV sequences from 157 patients infected with genotypes A to D showed the frequency of variants in the basal core promoter (BCP) and precore (PC) regions varied by genotype and that these mutations were associated with the absence of HBsAg loss. This was the case even when mutations were present at frequencies below the threshold of detection by population sequencing. Increased viral diversity across the HBV genome as determined by NGS was also associated with reduced likelihood of HBsAg loss.Patients with detectable BCP and/or PC variants and higher viral diversity have a lower probability of HBsAg loss during long-term NA therapy. Strategies to achieve functional cure of HBV infection through combination therapy should consider using NGS to stratify patients according to BCP/PC sequence. Consideration should also be given to earlier initiation of therapy prior to the emergence of BCP/PC variants.NCT00116805; Post result.
Ser559 of Glycoprotein Ibα Is Phosphorylated by Protein Kinase A Which Plays Key Roles In Regulating Von Willebrand Factor Binding, Surface Expression and Signaling of Glycoprotein Ib-IX
Authors: Zhang Weilin, Liu Guanglei, Yuan Yanhong, Zhao Lili, Yan Rong, Liao Yi, Changgeng Ruan, Dai Kesheng
Journal: Blood (2010)
Comparison of PBSC Vs Cord Blood (CB) As Stem Cells Source for Reduced-Intensity Conditioning Regimen (RIC) Allogeneic Stem Cell Transplantation (allo-SCT) in Adult Patients with Haematological Diseases: A Single Centre Analysis.
Authors: Amandine Lebourgeois, Marion Loirat, Benoit Tessoulin, Elsa Lestang, Pierre Peterlin, Florent Malard, Catherine Mohr, Cyrille Touzeau, Nicolas Blin, Aline Clavert, Karine Augeul-Meunier, Thierry Guillaume, Jacques Delaunay, Sameh Ayari, Eolia Brissot, Viviane Dubruille, Beatrice Mahe, Virginie Roland, Thomas Gastinne, Steven Le Gouill, Philippe Moreau, Mohamad Mohty, Lucie Planche, Patrice Chevallier
Journal: Blood (2012)
Alternating Courses of 3x CHOP and 3x DHAP Plus Rituximab Followed by a High Dose ARA-C Containing Myeloablative Regimen and Autologous Stem Cell Transplantation (ASCT) Increases Overall Survival When Compared to 6 Courses of CHOP Plus Rituximab Followed by Myeloablative Radiochemotherapy and ASCT in Mantle Cell Lymphoma: Final Analysis of the MCL Younger Trial of the European Mantle Cell Lymphoma Network (MCL net)
Authors: Olivier Hermine, Eva Hoster, Jan Walewski, Vincent Ribrag, Nicole Brousse, Catherine Thieblemont, Reda Bouabdallah, Hartmut Dohner, Pierre Feugier, Roswitha Forspointner, Corinne Haioun, Michael Kneba, Mathias Hänel, Olivier Casasnovas, Roland H. Mertelsmann, Michael Hallek, Andre Bosly, M Nowacki, Wolfram Klapper, Christian Gisselbrecht, Bertrand Coiffier, Michael Unterhalt, Wolfgang Hiddemann, Martin H. Dreyling
Journal: Blood (2012)
Prevalence of Obesity in the United State
Authors: Lawrence Appel
Journal: JAMA (2014)

Dr Ogden and colleagues1 concluded that there have been no significant changes in the prevalence of obesity over the past decade. The authors also reported that the prevalence of obesity in children ages 2 through 5 years declined significantly. However, the data on the prevalence of obesity in this age group were unstable (13.9% in 2003-2004, 10.7% in 2005-2006, 10.1% in 2007-2008, 12.1% in 2009-2010, and 8.4% in 2011-2012, from Table 6 in the article).
Randomized phase II study of axitinib alone or combined with lomustine in patients with recurrent glioblastoma.
Authors: Johnny Duerinck, Stephanie Du Four, Frank Bouttens, Vincent Verschaeve, Chantal Andre, Frank Van fraeyenhove, Cristo Chaskis, Nicky D'Haene, Marie Le Mercier, Isabelle Salmon, Bart Neyns
Journal: Journal of Clinical Oncology (2016)

2038 Background: vascular endothelial growth factor receptor (VEGFR) signal transduction mediates glioblastoma (GB) associated neo-angiogenesis. Axitinib, a small molecule TKI with high affinity and specificity for the VEGFRs, has demonstrated anti-tumor activity in patients with recurrent GB (J Clin Oncol 32:5s, 2014 [suppl; abstr 2018]). We investigated whether the combination of axitinib with lomustine (LOM) improves the outcome of pts with rGB as opposed to axitinib monotherapy. Methods: pts with rGB were randomized between single agent axitinib (AXI) vs. axitinib in combination with LOM (AXILOM) in an open label, randomized, phase II clinical trial. Pts in the AXI arm were allowed to cross over to AXILOM at progression. Six-month PFS served as the primary endpoint. Results: between February 2014 and July 2015, 56 pts were randomized 1:1 to AXI and AXILOM. Baseline characteristics were well balanced between both study arms (median age 56y [range 18-75]; 35M/21F; 15, 19, 11 and 11 pts had a WHO-PS of 0, 1, 2 and 3 respectively; MGMT promoter methylation: 11 pts methylated, 35- unmethylated, 10- unknown). All pts had failed prior therapy with RT and temozolomide. Six-mth PFS% did not differ between both study arms (AXI: 21% (95% CI 7-37] vs. AXILOM: 17% [95% CI 2-32]; neither did OS differ between both study arms (6-mths OS AXI 57% [95% CI 38-76] vs. AXILOM 53% [95% CI 34-73]). Pts with a methylated MGMT-promoter had a superior PFS and OS on the AXIG-arm but not in the AXILOM-arm. The best response (by RANO criteria) was 0 CR/ 6 PR/ 8 SD in the AXI arm (BORR 21%) vs. 1 CR/ 9 PR/ 3 SD in the AXILOM arm (BORR 38%). Among the 12 pts in the AXI arm who crossed-over at the time of progression, BORR was 0%, following cross-over SD was documented in 8 pts, median PFS 14wks (range 11 to 34). AXILOM pts were at higher risk for grade 3/4 adverse events (most frequent gr3/4 AE on AXILOM vs AXI were: thrombocytopenia 3- vs 0 pts, hypertension 2 vs 2 pts, anorexia 3 vs 3 pts). Conclusions: combination of axitinib and lomustine does not improve the outcome of pts with rGB as compared to axitinib monotherapy, regardless of the MGMT promoter methylation status. The previously reported activity and safety profile of axitinib monotherapy in pts with rGB was confirmed. Clinical trial information: NCT01562197.
E7080, an oral multitargeted tyrosine kinase inhibitor, has direct anti-tumor efficacy via inhibition of KIT signaling in gastrointestinal stromal tumor (GIST)
Authors: Yuji Yamamoto, Tatsuo Watanabe, Akihiko Tsuruoka, Toshiaki Wakabayashi, Makoto Asada
Journal: Cancer Research (2006)

Proc Amer Assoc Cancer Res, Volume 47, 2006

4038 

Most gastrointestinal stromal tumors (GIST) express constitutively active forms of the receptor tyrosine kinase KIT, derived from oncogenic mutation in the extracullular, juxtamembrane, or kinase domains. Constitutively activated KIT signaling induces tumor growth and the tumor malignant phenotype of GIST. Glivec (Imatinib mesylate, STI571) which inhibits the kinase activity of KIT, has been therapeutically effective in patients with GIST. E7080 is an oral multitargeted tyrosine kinase inhibitor against KDR (VEGFR-2), Flt-1 (VEGFR-1), FGFR1 and PDGFRbeta with IC50 values of 5 - 50 nM in cell free kinase assays. E7080 also inhibits KIT with an IC50 value of 100 nM. We evaluated the effect of E7080 on KIT activity in GIST cell line. Treatment of GIST882 with E7080 resulted in dose-dependent inhibition of cell proliferation, with an IC50 value of 35 nM. E7080 inhibited KIT tyrosine phosphorylation in GIST882 in a dose-dependent manner, with an IC50 values of ∼ 200 nM. E7080 also inhibited downstream events following KIT activation including ERK1/2 and Akt phosphorylation in a dose-dependent manner, with IC50 values consistent with that observed for the inhibition of KIT phosphorylation. Anti-tumor efficacy of E7080 in a GIST882 xenograft model also was evaluated. Oral administration of E7080 at doses of 30 or 100 mg/kg (BID, QD×28) caused tumor dormancy. E7080 at a dose of 100 mg/kg resulted in tumor shrinkage that measured approximately 40%, even when treatment was initiated following significant tumor growth. The status of KIT activation was examined in GIST882 tumors resected after 2 h treatment with E7080. E7080 clearly reduced phospho-KIT levels in GIST882 tumors. Soluble KIT (s-KIT) was evaluated as a potential biomarker of E7080 in the GIST882 xenograft model, because it has been reported that s-KIT in plasma samples could be used as a biomarker for therapeutic efficacy in patients with GIST in clinical trials. Detectable level of s-KIT (ng/ml) existed in the plasma of mice implanted with GIST882, although it was not detected in normal mice. The level of s-KIT was correlated with tumor weight in mice implanted with GIST882 (r=0.90 ∼ 0.95). Moreover treatment with E7080 at a dose of 100 mg/kg (BID, QD × 14) clearly reduced s-KIT level in plasma, compared with the plasma from mice after treatment with vehicle control. Our results suggested that E7080 has therapeutic potential in GIST mediated by direct anti-tumor efficacy via inhibition of KIT signaling, and s-KIT might be useful as a biomarker in patients with GIST.