tbuckley/cabot-search huggingface dataset:
Prevalent Homozygous Deletions of Type I Interferon and Defensin Genes in Human Cancers Associate with Immunotherapy Resistance
Authors: Zhenqing Ye, Haidong Dong, Ying Li, Tao Ma, Haojie Huang, Hon Sing Leong, Jeanette Eckel-Passow, Jean-Pierre A. Kocher, Han Liang, Liguo Wang
Journal: Clinical Cancer Research (2018)

Purpose: Homozygous deletions play important roles in carcinogenesis. The genome-wide screening for homozygously deleted genes in many different cancer types with a large number of patient specimens representing the tumor heterogeneity has not been done.Experimental Design: We performed integrative analyses of the copy-number profiles of 10,759 patients across 31 cancer types from The Cancer Genome Atlas project.Results: We found that the type-I interferon, α-, and β-defensin genes were homozygously deleted in 19 cancer types with high frequencies (7%-31%, median = 12%; interquartile range = 10%-16.5%). Patients with homozygous deletion of interferons exhibited significantly shortened overall or disease-free survival time in a number of cancer types, whereas patients with homozygous deletion of defensins did not significantly associate with worse overall or disease-free survival. Gene expression analyses suggested that homozygous deletion of interferon and defensin genes could activate genes involved in oncogenic and cell-cycle pathways but repress other genes involved in immune response pathways, suggesting their roles in promoting tumorigenesis and helping cancer cells evade immune surveillance. Further analysis of the whole exomes of 109 patients with melanoma demonstrated that the homozygous deletion of interferon (P = 0.0029, OR = 11.8) and defensin (P = 0.06, OR = 2.79) genes are significantly associated with resistance to anti-CTLA4 immunotherapy.Conclusions: Our analysis reveals that the homozygous deletion of interferon and defensin genes is prevalent in human cancers, and importantly this feature can be used as a novel prognostic biomarker for immunotherapy resistance. Clin Cancer Res; 24(14); 3299-308. ©2018 AACR.
Abstract 10908: Bare Metal Stents, Durable Polymer Drug Eluting Stents or Biodegradable Polymer Stents for Coronary Artery Disease: A Mixed Treatment Comparison Analysis of 254 361 Patient-Years of Follow-up From Randomized Trials
Authors: Bora Toklu, Nicholas Amoroso, Mario Fusaro, Sunil Kumar, Edward L. Hannan, David P. Faxon, Frederick Feit, Sripal Bangalore
Journal: Circulation (2013)

Background:  Biodegradable polymer DES preserve the safety of BMS while maintaining the efficacy (restenosis reduction) of DES. However, the efficacy and safety of biodegradable polymer DES when compared with newer generation DES is not known.   Methods:  PUBMED, EMBASE, and CENTRAL were searched for RCTs, comparing any of the FDA approved durable polymer DES (SES, PES, CoCr EES, PtCr EES, ZES and ZES-R) or biodegradable polymer stent (BPS), with each other or against BMS. Long-term efficacy [target vessel revascularization (TVR)] and safety [death, myocardial infarction (MI), stent thrombosis] outcomes were evaluated. Landmark analysis at >1-year time point was evaluated to assess the potential late benefit of biodegradable polymer stents.   Findings:  From 124 randomized trials and 254 361 patient-years of follow-up, in terms of efficacy (TVR), BPS was superior to PES [Rate ratio (RR) 0.66; 95% credibility interval (CrI) 0.57, 0.78] and ZES (RR 0.69; 95% CrI 0.56, 0.84) but not to newer generation DES (e.g.: vs. CoCr EES Rate ratio RR 1.03; 95% CrI 0.89, 1.21). Similarly, BPS was superior to PES (RR 0.61; 95% CrI 0.37, 0.89) but inferior to CoCr EES (RR 2.04; 95% CrI 1.27, 3.35) for safety (definite stent thrombosis). In the landmark analysis after 1 year, BPS was superior to SES for TVR (RR 0.29; 95% CrI 0.10, 0.82) but was associated with increased mortality compared with CoCr EES (RR 1.52; 95% CrI 1.02, 2.22). Overall, among all stent types, the newer generation DES (ZES-R, CoCr EES and PtCr EES) were the most efficacious (lowest TVR rate) stents, while CoCr EES was the safest with significant reduction in definite stent thrombosis (RR 0.35; 95% CrI 0.21, 0.53), myocardial infarction (RR 0.65; 95% CrI 0.55, 0.75) and death (RR 0.72; 95% CrI 0.58, 0.90) when compared with BMS.   Interpretation:  Biodegradable polymer stents, are superior in reducing TVR compared to 1 st  generation DES, but not to newer generation stents. Newer generation DES and especially CoCr EES have the best combination of efficacy and safety. The utility of biodegradable polymer stents in the context of excellent clinical outcomes with newer generation durable polymer DES needs to be proven.
Bias Amplification in Epidemiologic Analysis of Exposure to Mixtures
Authors: Marc G. Weisskopf, Ryan M. Seals, Thomas F. Webster
Journal: Environmental Health Perspectives (2018)

Background: The analysis of health effects of exposure to mixtures is a critically important issue in human epidemiology, and increasing effort is being devoted to developing methods for this problem. A key feature of environmental mixtures is that some components can be highly correlated, raising the issues of confounding by coexposure and colinearity. A relatively unexplored topic in epidemiologic analysis of mixtures is the impact of residual confounding bias due to unmeasured or unknown variables. Objectives: This paper examines the potential amplification of such biases when correlated exposure variables are included in regression models. Methods: We use directed acyclic graphs (DAGs) to describe different simple scenarios involving residual confounding. We derive expressions for the expected value of the resulting bias using linear models and multiple linear regression. Results: Approaches to the analysis of mixtures that involve regressing the outcome on several exposures simultaneously can in some cases amplify rather than reduce confounding bias. Discussions: The problem of bias amplification can worsen with stronger correlation between mixture components or when more mixture components are included in the model. Conclusions: Investigators must consider steps to minimize possible bias amplification in the design and analysis of epidemiologic studies of multiple correlated exposures. This may be particularly important when biomarkers of exposure are used. https://doi.org/10.1289/EHP2450
Deep and Durable Responses in Patients (Pts) with Relapsed/Refractory Multiple Myeloma (MM) Treated with Monotherapy GSK2857916, an Antibody Drug Conjugate Against B-Cell Maturation Antigen (BCMA): Preliminary Results from Part 2 of Study BMA117159
Authors: Suzanne Trudel, Nikoletta Lendvai, Rakesh Popat, Peter M. Voorhees, Brandi Reeves, Edward N. Libby, Paul G Richardson, Larry Anderson, Heather Sutherland, Kwee Yong, Axel Hoos, Michele Gorczyca, Soumi Lahiri, Zangdong He, Roxanne C Jewell, Joanna B. Opalinska, Adam D. Cohen
Journal: Blood (2017)
Impact of various demographic variables and different insurances on chemotherapy in stage IV non-small cell lung cancer patients (NSCLC) using NCDB (2000-2011).
Authors: Vamsi Krishna Chilluru, Lakshmi Manogna Chintalacheruvu, Sri Harsha Tella, Peter T. Silberstein
Journal: Journal of Clinical Oncology (2014)

e12524 Background: Lung cancer is the leading cause of cancer death in United States. Chemotherapy is the main stay of treatment in Stage IV NSCLC patients. Various demographic variables and insurance types can influence treatment in these patients and data corresponding to this is lacking. In this study, we evaluated the relationship of various demographic variables and different insurances on chemotherapy in Stage 4 NSCLC. Methods: Retrospective analysis of 484,247 Stage IV NSCLC patients from 2000-2011 has been done using national cancer database (NCDB) which is a nationwide oncology outcomes database for ~70% of newly diagnosed cases from more than 1,500 commission-accredited cancer programs in the United States and Puerto Rico. Various demographic variables such as age, sex, race, household income, education, number of comorbidities and different insurances are studied in patients who are receiving chemotherapy. Chi square test is used for statistical analysis. Results: Patients who are younger (<60 years age) undergo chemotherapy twice as often as those of the older age group (>60 years age) (p<0.001). High chemotherapy rates are seen in patients with private insurance, higher educational status, higher income and without any co-morbid conditions (all p<0.001). Gender and race are shown not to play any significant role in receiving chemotherapy (p=0.20). Conclusions: This is the largest retrospective analysis to our knowledge that evaluates the impact of various demographic variables in treatment of Stage IV NSCLC. Younger ages (<60 years), higher income, higher education, individuals with no comorbidities and those with private insurance have higher rates of chemotherapy. Gender and race has no impact on chemotherapy. Age, education, income, comorbid conditions and insurance effect whether patients receive chemotherapy. Chemotherapy % Age (year) >60 24 <60 52 Race Black 47 Hispanic 48 White 49 Education % with HS deg <69% 45 69-87.9% 48 >88% 53 Household income (per year) <$28,000 44 $28,000-$48,999 47 >$49,000 53 Insurance status Medicare 44 Uninsured 45 Medicaid 51 Private/managed 62
Airway epithelial phosphoinositide 3-kinase-δ contributes to the modulation of fungi-induced innate immune response
Authors: Jae Seok Jeong, Kyung Bae Lee, So Ri Kim, Dong Im Kim, Hae Jin Park, Hern-Ku Lee, Hyung Jin Kim, Seong Ho Cho, Narasaiah Kolliputi, Soon Ha Kim, Yong Chul Lee
Journal: Thorax (2018)

Background Respiratory fungal exposure is known to be associated with severe allergic lung inflammation. Airway epithelium is an essential controller of allergic inflammation. An innate immune recognition receptor, nucleotide-binding domain, leucine-rich-containing family, pyrin-domain-containing-3 (NLRP3) inflammasome, and phosphoinositide 3 kinase (PI3K)-δ in airway epithelium are involved in various inflammatory processes. Objectives We investigated the role of NLRP3 inflammasome in fungi-induced allergic lung inflammation and examined the regulatory mechanism of NLRP3 inflammasome, focusing on PI3K-δ in airway epithelium. Methods We used two in vivo models induced by exposure to Aspergillus fumigatus ( Af ) and Alternaria alternata ( Aa ), as well as an Af -exposed in vitro system. We also checked NLRP3 expression in lung tissues from patients with allergic bronchopulmonary aspergillosis (ABPA). Results Assembly/activation of NLRP3 inflammasome was increased in the lung of Af -exposed mice. Elevation of NLRP3 inflammasome assembly/activation was observed in Af -stimulated murine and human epithelial cells. Similarly, pulmonary expression of NLRP3 in patients with ABPA was increased. Importantly, neutralisation of NLRP3 inflammasome derived IL-1β alleviated pathophysiological features of Af -induced allergic inflammation. Furthermore, PI3K-δ blockade improved Af -induced allergic inflammation through modulation of NLRP3 inflammasome, especially in epithelial cells. This modulatory role of PI3K-δ was mediated through the regulation of mitochondrial reactive oxygen species (mtROS) generation. NLRP3 inflammasome was also implicated in Aa -induced eosinophilic allergic inflammation, which was improved by PI3K-δ blockade. Conclusion These findings demonstrate that fungi-induced assembly/activation of NLRP3 inflammasome in airway epithelium may be modulated by PI3K-δ, which is mediated partly through the regulation of mtROS generation. Inhibition of PI3K-δ may have potential for treating fungi-induced severe allergic lung inflammation.
Sidedness, mutations, and survival in stage IV colon cancer: A U.S. population-based study.
Authors: Albert Y. Lin, Amanda Kahl, Irena Gribovskaja-Rupp, Michele West, Charles F Lynch, Mary E. Charlton
Journal: Journal of Clinical Oncology (2018)

742 Background: Despite recent diagnostic and therapeutic advances in colon cancer (CC), it remains one of the leading causes for cancer-related deaths worldwide. At time of diagnosis, 20% of CC patients (PTS) present with de novo stage IV. In recent years, clinical trials have identified sidedness and several molecular biomarkers (MBM), such as microsatellite instability high (MSI-H), KRAS and BRAF mutations, as prognostic and predictive factors for treatment response in stage IV CC. However, their impact and interactions in the population-based setting remain elusive. Methods: The National Cancer Institute’s 2014 Patterns of Care study included a sample of 1,444 stage IV CC PTS from Surveillance, Epidemiology, and End Results registries, and captured MSI, BRAF and detailed chemotherapy information not available in the public-use dataset. Demographic, tumor, molecular and treatment data were compared using chi-square tests. Cox proportional hazards models were used to compare overall survival (OS) across subgroups of demographic, tumor, MBM and treatment characteristics. Results: Compared to left-sided (L) CC, PTS diagnosed with right-sided (R) CC tend to be older (median age: 65 vs 60, respectively; p &lt; 0.001), more females (54% vs 44%, p = 0.001), African Americans (25% vs 22%, p = 0.001), have poorly or undifferentiated tumors (27% vs 15%, p = 0.001), and harbor MSI-H (14% vs 7%, p = 0.018), KRAS (52% vs 36%, p &lt; 0.001) or BRAF (29% vs 11%, p = 0.001) mutations. FOLFOX, with or without bevacizumab, accounted for &gt; 50% of the first-line regimens. Multivariable Cox proportional hazards models revealed the following poor risk factors: right-sidedness, poorly or undifferentiated tumor, no surgery, no chemotherapy, no cetuximab/panitumumab or no bevacizumab therapy. In separate models for LCC and RCC among those tested for KRAS (n = 689), treatment with bevacizumab was associated with lower odds of death in both models (p &lt; 0.05). Cetuximab/panitumumab were nearly significantly associated with lower odds of death in LCC (p = 0.06) but not RCC (0.35). Conclusions: Right-sidedness is a poor prognostic factor in stage IV CC. Regardless of sidedness, stage IV CC PTS can benefit from surgery, chemotherapy, or bevacizumab.
Clinical Trials in Medical Center Advertising
Authors: Alex John London, Jonathan Kimmelman
Journal: JAMA Oncology (2018)

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A pilot study of ponatinib in cholangiocarcinoma patients with FGFR2 fusions.
Authors: Thomas DeLeon, Steven R. Alberts, Robert R. McWilliams, Joleen Marie Hubbard, Daniel H. Ahn, Tanios S. Bekaii-Saab, Kabir Mody, Lewis R. Roberts, Marcela Salomao, Benjamin Kipp, Thorvardur Ragnar Halfdanarson, Muhammed Murtaza, Ramesh K. Ramanathan, Amylou C. Dueck, Mitesh J. Borad
Journal: Journal of Clinical Oncology (2018)

TPS532 Background: Recent studies have shown that FGFR2 fusions may represent recurrent (prevalence ~10-15% in larger cohorts) driver events amenable to therapeutic targeting in patients with advanced, intrahepatic cholangiocarcinoma. Methods: This single arm pilot study (NCT02265341) is being conducted at 3 centers (Mayo Clinic Arizona, Mayo Clinic Florida and Mayo Clinic Rochester; enrollment initiated December 2014). Next-generation sequencing based assays and a FISH-break apart assay are used to identify tumors with FGFR2 fusions. Patients must additionally have histologically/cytologically confirmed cholangiocarcinoma, ECOG performance score 0-2, measurable disease, preserved hematologic/renal and hepatic function and absence of cardiac events/stroke in the preceding 6 months. Ponatinib is administered at 45 mg once daily. Patients will be treated until disease progression, intolerable toxicity or patient decision to not pursue further therapy. The primary objective of the study is to estimate the clinical benefit rate (defined as composite of partial response rate, complete response rate and stable disease rate ≥ 4 months; as defined by RECIST criteria v1.1). Secondary endpoints include estimation of progression-free survival, overall survival, CA19-9 response rate (defined as &gt; 50% reduction from baseline) and evaluation of the overall adverse event profile of ponatinib in this patient population. Translational objectives include serial circulating DNA (ct-DNA) monitoring, target knockdown assessments in tumor tissue (p-FGFR2, p-FRS2, p-Akt and p-ERK) and evaluation of mechanisms of resistance through comparison of baseline and progression biopsy samples using multi-platform sequencing (exome, RNA-Seq and methyl-Seq). Additionally, quality of life assessments will be evaluated using EORTC-QLQ-C30 and BIL21 tools. A total of 30 patients will be enrolled into the study (12 of 30 patients have been enrolled). The trial is designed using an underlying assumption of clinical benefit rate (CBR) of 5% with significance level of 0.15 and 80% power to detect a 20% CBR. Clinical trial information: NCT02265341.
A study of ramucirumab (LY3009806) versus placebo in patients with hepatocellular carcinoma and elevated baseline alpha-fetoprotein (REACH-2).
Authors: Andrew X. Zhu, Peter R. Galle, Masatoshi Kudo, Richard S. Finn, Shukui Qin, Yihuan Xu, Paolo Abada, Josep Llovet
Journal: Journal of Clinical Oncology (2018)

TPS538 Background: Ramucirumab (RAM), a human IgG1 mAb, inhibits ligand activation of VEGFR2. In REACH, while improvement in overall survival (OS) in the overall population was not statistically significant, meaningful improvement was observed in a patient subgroup with baseline alpha-fetoprotein (AFP) ≥400 ng/mL (N = 250) (HR = 0.67, p = 0.006; median OS [months] RAM 7.8 vs placebo [pbo] 4.2). RAM treatment was generally well tolerated in patients with advanced hepatocellular carcinoma (HCC) after prior sorafenib (SOR). Methods: REACH-2 is a randomized, double-blind, pbo-controlled, global phase 3 study of RAM+best supportive care (BSC) vs pbo+BSC in patients with HCC and elevated baseline AFP following therapy with SOR. Eligibility includes Child-Pugh &lt; 7; Barcelona Clinic Liver Cancer Stage C or B disease not amenable/refractory to locoregional therapy; AFP ≥400 ng/mL; ECOG PS 0 or 1; ≥1 measurable lesion; and disease progression during/after SOR, or SOR intolerance. Patients with history of hepatic encephalopathy, clinically meaningful ascites, liver transplant, or hepatic locoregional therapy after SOR are not eligible. Eligible patients will be randomized 2:1 to 8 mg/kg RAM or pbo (14-day cycle) and treated until radiographic/clinical disease progression or discontinuation criteria are met. The primary objective is OS; secondary objectives include progression-free survival (PFS), objective response rate, safety, and patient-focused outcomes. Recognizing expanding treatment options for HCC, a second, single arm, open-label cohort of ~44 patients will be enrolled with the same eligibility and treatment as the main cohort except a requirement for prior treatment other than SOR (eg, mTKIs, immune checkpoint inhibitors) and some exclusions of checkpoint inhibitor-related adverse events. The primary objective is safety; secondary objectives include OS, PFS, and patient-focused outcomes. Additionally, a third randomized cohort of ~65 Chinese patients will be enrolled with the same objectives, eligibility, treatment, and evaluations as the main cohort. Analysis of Open-Label and Chinese cohorts will be independent of the main REACH-2 cohort. Clinical trial information: NCT02435433.
Annals Graphic Medicine - The Cure Is at Hand
Authors: Caroline Shooner
Journal: Annals of Internal Medicine (2018)

Web Exclusives3 April 2018Annals Graphic Medicine - The Cure Is at HandFREECaroline Shooner, MDCaroline Shooner, MDUniversity of British Columbia, Queen Charlotte, British Columbia, Canada (C.S.)Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/G17-0021 SectionsAboutVisual AbstractPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail Take a minute's break and enjoy this month's brief look at a humorous side of medical practice. Download figure Download PowerPoint Download figure Download PowerPoint Comments0 CommentsSign In to Submit A Comment Author, Article, and Disclosure InformationAffiliations: University of British Columbia, Queen Charlotte, British Columbia, Canada (C.S.)Disclosures: The author has disclosed no conflicts of interest. The form can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=G17-0021.Author/Illustrator Information: Caroline Shooner, MD, is a family physician practicing on the remote archipelago of Haida Gwaii, off the northwest coast of British Columbia. Her cartoons (www.theboondocs.org) are inspired by the comic side of small town medicine.Author Contributions: Conception and design: C. Shooner. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics 3 April 2018Volume 168, Issue 7Page: W18-W20KeywordsConflicts of interestDisclosure ePublished: 3 April 2018 Issue Published: 3 April 2018 Copyright & PermissionsCopyright © 2018 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...
Tight regulation of FOXO1 is essential for maintenance of B-cell precursor acute lymphoblastic leukemia
Authors: Fan Wang, Salih Demir, Franziska Gehringer, Clarissa D. Osswald, Felix Seyfried, Stefanie Enzenmüller, Sarah M. Eckhoff, Thomas Maier, Karlheinz Holzmann, Klaus-Michael Debatin, Thomas Wirth, Lüder H. Meyer, Alexey Ushmorov
Journal: Blood (2018)
Medical students report the effect of tuition fees
Authors: Samuel Chun, Angelica Sharma
Journal: BMJ (2018)

Gulland reports the effect of tuition fees on medical students.1

An English, Welsh, Scottish, and international student wait for their lecture. They pay respectively £9250, £3000, £0, and £30 000 a year in tuition fees. The lecture is cancelled because the clinician has been called away. Time is money, and we’re acutely aware of the cost of time. This sounds …
Association Between Early Caffeine Citrate Administration and Risk of Acute Kidney Injury in Preterm Neonates
Authors: Matthew W. Harer, David J. Askenazi, Louis J. Boohaker, J. Bryan Carmody, Russell L. Griffin, Ronnie Guillet, David T. Selewski, Jonathan R. Swanson, Jennifer R. Charlton
Journal: JAMA Pediatrics (2018)

Acute kidney injury (AKI) occurs commonly in preterm neonates and is associated with increased morbidity and mortality.