tbuckley/cabot-search huggingface dataset:
KEYNOTE-164: Phase II study of pembrolizumab (MK-3475) for patients with previously treated, microsatellite instability-high advanced colorectal carcinoma.
Authors: Dung T. Le, Takayuki Yoshino, Dirk Jäger, Thierry Andre, Johanna C. Bendell, Ruixue Wang, SoonMo Peter Kang, Minori Koshiji, Luis A. Diaz
Journal: Journal of Clinical Oncology (2016)

TPS787 Background: A subset of advanced colorectal cancers (CRC) is characterized by mismatch repair (MMR) deficiency leading to a microsatellite instability-high (MSI-H) phenotype, which is characterized by a high mutational burden and lymphocytic infiltrates. Pembrolizumab is a monoclonal anti–PD-1 antibody designed to block the interaction between PD-1 and its ligands PD-L1 and PD-L2. In the phase II KEYNOTE-016 study, pembrolizumab provided an ORR of 62% in patients (pts) with progressive MMR-deficient metastatic CRC vs 0% in pts with MMR-proficient CRC. The multicenter, phase II KEYNOTE-164 trial (NCT02460198) will evaluate the efficacy and safety of pembrolizumab in pts with previously treated, advanced MSI-H CRC. Methods: Key eligibility criteria include age ≥ 18 y; advanced CRC; MSI-H phenotype evidenced by ≥ 2 allelic shifts using a PCR-based assay or lack of expression of ≥ 1 MMR protein (MLH1, MSH2, MSH6, PMS2) by IHC; prior treatment with a fluoropyrimidine, oxaliplatin, irinotecan, bevacizumab, and, if KRAS and NRAS wild type, cetuximab or panitumumab; ECOG PS 0-1; no active autoimmune disease or brain metastases; and no prior anticancer therapy within 2 wk of study treatment. Pembrolizumab 200 mg Q3W will be administered for 35 cycles or until disease progression, unacceptable toxicity, pt withdrawal, or investigator decision. Clinically stable pts with RECIST-defined progression may continue pembrolizumab until a scan performed ≥ 4 wk later confirms progression. Pts who complete all 35 cycles or who discontinue pembrolizumab following a complete response and experience progression may be eligible for 1 y of pembrolizumab retreatment. Response will be evaluated every 9 wk per RECIST v1.1 by central review and per RECIST adapted for immunotherapy response patterns. AEs will be assessed throughout treatment and for 30 d thereafter (up to 90 d for serious AEs) and graded per NCI CTCAE v4.0. Pts will be followed for survival every 2 mo. ORR per RECIST v1.1 by central review is the primary end point; secondary end points include PFS, OS, disease control rate, and duration of response. Enrollment is ongoing and will continue until ~60 pts have enrolled. Clinical trial information: NCT02460198.
Ki-67 labeling index in breast carcinoma: An immunohistochemical study with correlation to molecular subtypes
Authors: R. Bharagva, J. Striebel, A. Onisko, K. McManus, D. J. Dabbs
Journal: Journal of Clinical Oncology (2008)

22107 Background: Given the uncertain significance of Ki-67 labeling index (LI) in the published literature and new insight provided by expression profiling, we comprehensively examined 205 cases of consecutive breast carcinoma at our institution. Methods: The tumors were classified as follows: Luminal A (LUMA; ER score 200 or higher, HER2 negative), Triple Negative (TN; ER and PR H-score 10 or less, HER2 negative), ERBB2 (ER and PR H-score 10 or less, HER2 positive), Luminal A-HER2 Hybrid (LAHH; ER H-score 200 or higher, HER2 positive), Luminal Unclassified HER2 Positive (LUHP; ER H-score 11–199, HER2 positive), Luminal Unclassified HER2 Negative (LUHN; ER H-score 11–199, HER2 negative). Tissue microarrays (TMAs) were constructed. TMAs were stained with anti-Ki-67 antibody. Ki-67 LI was calculated using an image analysis system. Results: Of the 205 tumors, 113 (55%) were classified as LUMA, 32 (15%) as TN, 8 (4%) as ERBB2, 10 (5%) as LAHH, 34 (17%) as LUHN, and 8 (4%) as LUHP. Although some luminal A tumors showed increased Ki-67 LI (generally accompanied by high mitotic activity), the average Ki-67 LI was lowest in ductal-type LUMA (average LI of 15.8%) and other receptor positive and HER2 negative tumors. Ki-67 LI was highest for TN tumors with almost all tumors showing LI above 50%. The ERBB2 tumors showed an average LI of 27.8%. Ki-67 LI alone was sufficient in differentiating among LUMA, ERBB2 and TN molecular subclasses (p value <0.01). A higher Ki-67 LI predicted lymph node metastasis in non-triple negative tumors (p value = 0.018). Table shows the relationship between Ki-67 LI and lymph node status irrespective of tumor size and molecular classes. Conclusions: Ki- 67 LI is an important prognostic factor in breast carcinoma. There is correlation between Ki-67 LI and molecular classes; however, intra-class differences in proliferation activity of receptor positive tumors likely account for individual differences in prognosis and response to chemotherapeutic agents. Ki-67 LI and lymph node status (n = 171) LN Negative LN Positive Total LI: 1–10% 41 (71%) 17 (29%) 58 LI: 11–25% 36 (68%) 17 (32%) 53 LI: 26–50% 18 (49%) 19 (51%) 37 LI: 51% or more 19a (83%) 4 (17%) 23 a : Of these 19 cases, 14 were triple negative; LI: Labeling Index; LN: Lymph Node No significant financial relationships to disclose.
Seasonal Influenza Vaccination in Patients With Chronic Lymphocytic Leukemia Treated With Ibrutinib
Authors: Clare Sun, Jin Gao, Laura Couzens, Xin Tian, Mohammed Z. Farooqui, Maryna C. Eichelberger, Adrian Wiestner
Journal: JAMA Oncology (2016)

are warranted to evaluate whether ibrutinib impairs or improves vaccine response relative to other treatments.Limitations of the study include a small sample size and incomplete laboratory confirmation of influenza infection.Furthermore, defining an appropriate control group may prove challenging; treatment-naive patients often have immune impairment related to their disease while patients in remission after chemoimmunotherapy may experience the immunosuppressive effects of treatment. 7Conclusions | Our data show that an antibody response to influenza vaccination is permissible in patients receiving singleagent ibrutinib.Up to 74% of patients achieved seroprotective titers against common influenza viruses after vaccination.Consequently, routine immunization against influenza should be considered in accordance with the Centers for Disease Control and Prevention recommendations for immunocompromised patients.
Comparing the Health Effects of Ambient Particulate Matter Estimated Using Ground-Based versus Remote Sensing Exposure Estimates
Authors: Michael Jerrett, Michelle C. Turner, Bernardo S. Beckerman, C. Arden Pope, Aaron van Donkelaar, Randall V. Martin, Marc Serre, Dan Crouse, Susan M. Gapstur, Daniel Krewski, W. Ryan Diver, Patricia F. Coogan, George D. Thurston, Richard T. Burnett
Journal: Environmental Health Perspectives (2016)

Background:Remote sensing (RS) is increasingly used for exposure assessment in epidemiological and burden of disease studies, including those investigating whether chronic exposure to ambient fine particulate matter (PM2.5) is associated with mortality.Objectives:We compared relative risk estimates of mortality from diseases of the circulatory system for PM2.5 modeled from RS with that for PM2.5 modeled using ground-level information.Methods:We geocoded the baseline residence of 668,629 American Cancer Society Cancer Prevention Study II (CPS-II) cohort participants followed from 1982 to 2004 and assigned PM2.5 levels to all participants using seven different exposure models. Most of the exposure models were averaged for the years 2002–2004, and one RS estimate was for a longer, contemporaneous period. We used Cox proportional hazards regression to estimate relative risks (RRs) for the association of PM2.5 with circulatory mortality and ischemic heart disease.Results:Estimates of mortality risk differed among exposure models. The smallest relative risk was observed for the RS estimates that excluded ground-based monitors for circulatory deaths [RR = 1.02, 95% confidence interval (CI): 1.00, 1.04 per 10 μg/m3 increment in PM2.5]. The largest relative risk was observed for the land-use regression model that included traffic information (RR = 1.14, 95% CI: 1.11, 1.17 per 10 μg/m3 increment in PM2.5).Conclusions:We found significant associations between PM2.5 and mortality in every model; however, relative risks estimated from exposure models using ground-based information were generally larger than those estimated using RS alone.Citation:Jerrett M, Turner MC, Beckerman BS, Pope CA III, van Donkelaar A, Martin RV, Serre M, Crouse D, Gapstur SM, Krewski D, Diver WR, Coogan PF, Thurston GD, Burnett RT. 2017. Comparing the health effects of ambient particulate matter estimated using ground-based versus remote sensing exposure estimates. Environ Health Perspect 125:552–559; http://dx.doi.org/10.1289/EHP575
Transpulmonary Pressure: The Importance of Precise Definitions and Limiting Assumptions
Authors: Stephen H. Loring, George P. Topulos, Rolf D. Hubmayr
Journal: American Journal of Respiratory and Critical Care Medicine (2016)

Recent studies applying the principles of respiratory mechanics to respiratory disease have used inconsistent and mutually exclusive definitions of the term "transpulmonary pressure." By the traditional definition, transpulmonary pressure is the pressure across the whole lung, including the intrapulmonary airways, (i.e., the pressure difference between the opening to the pulmonary airway and the pleural surface). However, more recently transpulmonary pressure has also been defined as the pressure across only the lung tissue (i.e., the pressure difference between the alveolar space and the pleural surface), traditionally known as the "elastic recoil pressure of the lung." Multiple definitions of the same term, and failure to recognize their underlying assumptions, have led to different interpretations of lung physiology and conclusions about appropriate therapy for patients. It is our view that many current controversies in the physiological interpretation of disease are caused by the lack of consistency in the definitions of these common physiological terms. In this article, we discuss the historical uses of these terms and recent misconceptions that may have resulted when these terms were confused. These misconceptions include assertions that normal pleural pressure must be negative (subatmospheric) and that a pressure in the pleural space may not be substantially positive when a subject is relaxed with an open airway. We urge specificity and uniformity when using physiological terms to define the physical state of the lungs, the chest wall, and the integrated respiratory system.
First international external quality assessment for hepatitis delta virus RNA quantification in plasma
Authors: Frédéric Le Gal, Ségolène Brichler, Roland Sahli, Sylvie Chevret, Emmanuel Gordien
Journal: Hepatology (2016)

Infection by the hepatitis delta virus (HDV), a satellite of the hepatitis B virus (HBV), increases viral liver disease severity. Its diagnosis is thus vital for HBV-infected patients. HDV-RNA load (HDVL) should be assessed and monitored in plasma using real-time reverse-transcriptase polymerase chain reaction assays. Taking advantage of the recently-developed World Health Organization (WHO) HDV international standard (WHO-HDV-IS), the first international external quality control for HDVL quantification was performed. Two panels of samples were sent to 28 laboratories in 17 countries worldwide. Panel A comprised 20 clinical samples of various genotypes (1, 2, and 5-8) and viral loads, including two negative controls. Panel B, composed of dilutions of the WHO-HDV-IS, allowed the conversion of results from copies/mL into IU/mL for HDVL standardization and interlaboratory comparisons. Comprehensive analysis revealed a very high heterogeneity of assay characteristics, including their technical steps and technologies. Thirteen labs (46.3%) properly quantified all 18 positive samples; 16 (57.1%) failed to detect one to up to 10 samples, and several others underestimated (>3 log IU/mL) HDVL of African genotype strains (1 and 5-8). Discrepancies were mainly attributed to either primers or probe mismatches related to the high genetic variability of HDV and, possibly, to the complex secondary structure of the target genomic RNA. The labs were grouped in four clusters by the statistical analysis of their performances. The best clusters comprised the 17 labs that obtained the expected HDVL values, including five that otherwise failed to quantify one or two samples.The results of this international quality-control study underline the urgent need to improve methods used to monitor HDV viremia and will be instrumental in achieving that goal. (Hepatology 2016;64:1483-1494).
Cognitive Therapy and Preventing Suicide Attempts
Authors: Kristian B Filion, J A C Delaney
Journal: JAMA (2005)

In their study of suicide prevention, Dr Brown and colleagues conclude that cognitive therapy reduces the risk for subsequent suicide attempts. We have some methodological concerns that we believe affect this conclusion. First, 15 (25%) of the participants in the cognitive therapy group and 20 (33%) of the participants in the control group were lost to follow-up. With these relatively large numbers of unknown outcomes, it is difficult to assess whether the study results are accurate estimates of the true effect. As the authors suggest in the Comment section of their article, given a small number of patients in each group and a small number of outcome events, a few misclassified or unknown outcomes could have substantial impact on the comparison between the 2 groups. It would be helpful for the authors to provide the results of their sensitivity analysis.
Real world COPD study may be better way to evaluate drug treatments
Authors: Susan Mayor
Journal: BMJ (2016)

A real world controlled effectiveness study carried out in unselected patients from UK general practices provides a better way of evaluating drug treatments for use in routine clinical care than standard randomised controlled trials, say the authors of a study in chronic obstructive pulmonary disease (COPD).1

The Salford Lung Study randomly assigned 2799 patients with COPD to a once daily inhaled combination of fluticasone-furoate and vilanterol or to usual care. The patients were recruited from 75 general practices in Salford …
IL-1β is an innate immune sensor of microbial proteolysis
Authors: Christopher N. LaRock, Jordan Todd, Doris L. LaRock, Joshua Olson, Anthony J. O’Donoghue, Avril A. B. Robertson, Matthew A. Cooper, Hal M. Hoffman, Victor Nizet
Journal: Science Immunology (2016)

Interleukin-1β (IL-1β) is a key proinflammatory cytokine that drives antimicrobial immune responses. IL-1β is aberrantly activated in autoimmune diseases, and IL-1β inhibitors are used as therapeutic agents to treat patients with certain autoimmune disorders. Review of postmarketing surveillance of patients receiving IL-1β inhibitors found a disproportionate reporting of invasive infections by group A Streptococcus (GAS). IL-1β inhibition increased mouse susceptibility to GAS infection, but IL-1β was produced independent of canonical inflammasomes. Newly synthesized IL-1β has an amino-terminal prodomain that blocks signaling activity, which is usually proteolytically removed by caspase-1, a protease activated within the inflammasome structure. In place of host caspases, the secreted GAS cysteine protease SpeB generated mature IL-1β. During invasive infection, GAS isolates may acquire pathoadaptive mutations eliminating SpeB expression to evade detection by IL-1β. Pharmacological IL-1β inhibition alleviates this selective pressure, allowing invasive infection by nonpathoadapted GAS. Thus, IL-1β is a sensor that directly detects pathogen-associated proteolysis through an independent pathway operating in parallel with host inflammasomes. Because IL-1β function is maintained across species, yet cleavage by caspases does not appear to be, detection of microbial proteases may represent an ancestral system of innate immune regulation.
A Cyst Misinterpreted on Airport Scan as Security Threat
Authors: Warren R. Heymann
Journal: JAMA Dermatology (2016)

an ongoing partial response (Figure, B).However, tumor biopsies were declined by the patient.Furthermore, the creatinine level remained stable at 5.25 mg/dL.Vismodegib treatment was tolerated without any clinically relevant adverse effects.Interestingly, the common adverse effects such as muscle cramps of the lower leg, fatigue, weight loss, or dysgeusia were not reported.Only alopecia developed within the first 4 weeks of treatment.The patient's quality of life was significantly improved by reepithelialization of ulcerated and bleeding areas of the tumor.In particular, the formation of an epiphysis of the right midface contributed to an improvement of the patient's quality of life.At last follow-up, treatment with vismodegib was being continued at the same dose.Discussion | To our knowledge, this is the first case report that describes vismodegib use and its tolerability in a patient with chronic stage 4 kidney disease receiving dialysis treatment.This case indicates good efficacy and tolerability of vismodegib in a patient with advanced BCC.Based on this patient's response and tolerability, we suggest that vismodegib may offer a safe treatment option to be considered in the setting of adequate medical monitoring for patients with renal insufficiency receiving dialysis therapy.However, further observations are needed to evaluate the safety profile of vismodegib in patients with renal impairment.
Development of a Conceptual Model for Surgical Quality Improvement Collaboratives
Authors: Michael W. Wandling, Christina A. Minami, Julie K. Johnson, Kevin J. O’Leary, Anthony D. Yang, Jane L. Holl, Karl Y. Bilimoria
Journal: JAMA Surgery (2016)

This literature review examines the creation of a conceptual model of a surgical quality improvement collaborative to facilitate the development, implementation, and systematic evaluation of the Illinois Surgical Quality Improvement Collaborative.
Evaluating Behavioral Interventions: Need for Randomized Controlled Trials
Authors: A. Russell Gerber
Journal: JAMA (1994)

To the Editor.  —We agree with Drs Peterman and Aral 1 regarding the need for more randomized controlled trials of behavior change interventions for human immunodeficiency virus (HIV) and sexually transmitted disease prevention. However, we would like to clarify a few points.  Randomized controlled trials are not always appropriate for evaluating HIV or acquired immunodeficiency syndrome (AIDS) prevention programs. Although randomized controlled trials offer the most rigorous level of evidence, they are not always scientifically appropriate, logistically feasible, economically practical, or ethically defensible.  Peterman and Aral performed a limited literature search with an algorithm of the key words trial, random, control, behavior, and change, and used only one database of computerized abstracts (AIDSLINE) from international AIDS conferences of 1989 through 1992. This would not be expected to produce all significant references for this complex and dynamic field that cuts across medical and social sciences. Some relatively comprehensive reviews of the
Regenerative medicine in China: main progress in different fields
Authors: Biao Cheng, Shu-liang Lu, Xiao-bing Fu
Journal: Military Medical Research (2016)

Regenerative medicine (RM) is an emerging interdisciplinary field of research and China has developed the research quickly and impressed the world with numerous research findings in stem cells, tissue engineering, active molecules and gene therapy. Important directions are induced differentiation of induced pluripotent stem and embryo stem cells as well as somatic stem cell differentiation potential and their application in trauma, burns, diseases of aging and nerve regeneration. The products ActivSkin and bone repair scaffolds have been approved and are applied in the clinic, and similar products are being studied. About 10 engineered growth-factor drugs for repair and regeneration have been approved and are used in the clinic. Gene therapy, therapeutic cloning and xenotransplantation are some of the strategies being studied. However, China needs to develop standards, regulations and management practices suitable for the healthy development of RM. Aspects that should be strengthened include sound administrative systems, laws, and technical specifications and guidelines; conservation of stem cell resources; emphasis on training and retention of talented stem cell researchers; and reasonable allocation of resources, diversification of investment and breakthroughs in key areas. Finally, broad and deep international cooperation is necessary.
Administration of Most Closely HLA-Matched Multivirus-Specific T Cells for the Treatment of EBV, CMV, AdV, HHV6, and BKV Post Allogeneic Hematopoietic Stem Cell Transplant
Authors: Ifigeneia Tzannou, Anastasia Papadopoulou, Ayumi Watanabe, Manik Kuvalekar, Adrian P. Gee, Swati Naik, Caridad Martinez, Kathryn S. Leung, Ghadir S. Sasa, Robert A. Krance, George Carrum, Carlos A. Ramos, Bambi Grilley, Malcolm K. Brenner, Cliona M. Rooney, Helen E Heslop, Ann M. Leen, Bilal Omer
Journal: Blood (2016)
The Hospice Movement
Authors: S. G. Barber
Journal: JAMA (1979)

<h3>To the Editor.—</h3> The editorial "The Hospice Movement" by John P. Callan, MD (241:600, 1979), was interesting but destructive. By adopting the same philosophical approach as the one that collectively calls the nation's health care programs the "health industry," he assesses the hospice movement's approach to man's "agony of extinction" in monetarist terms. I am relieved by personal knowledge that most Americans seem less dollar oriented. His apparent bias overlooks the fundamental motivation for the medieval and many of the modern hospices—the provision of a loving, caring (and Christian) approach to both the physical and the spiritual distresses of those about to die. In this context, the 20% savings in cost have a low, although satisfactory, relevance. The impotence of much modern technology to cater to spiritual problems reduces the value of bustling, noisy, overcrowded general hospital wards. The degree to which they can provide a restful, relaxed atmosphere is