tbuckley/cabot-search huggingface dataset:
An Individual Participant Data Meta-Analysis of 13 Randomized Trials to Evaluate the Impact of Prophylactic Use of Heparin in Oncological Patients
Authors: Holger Schünemann, Matthew Ventresca, Mark Crowther, Marcello Di Nisio, Matthias Briel, Qi Zhou, Simon Noble, Fergus Macbeth, Gareth Griffiths, David A Garcia, Gary H. Lyman, Alfonso Iorio, Lawrence Mbuagbaw, Ignacio Neumann, Nick Van Es, Jan Brozek, Gordon Guyatt, Michael B. Streiff, Melissa Brouwers, Tejan Baldeh, Maura Marcucci, Ivan Florez, Ziad Solh, Walter Ageno, Suzanne Bleker, George Bozas, Harry Büller, Clara Klerk, Bernard Lebeau, Ramon Lecumberri, Robert D. McBane, Kostandinos Sideras, Anthony Maraveyas, Uwe Pelzer, Charles Loprinzi, Patrick Bossuyt, Lara Kahale, Elie A Akl, Gilbert Zulian
Journal: Blood (2017)
Abstract 024: The Timing of Cardiovascular Health Decline and Its Association With Subclinical Atherosclerosis in Adulthood
Authors: Lindsay R Pool, Amy E Krefman, Darwin Labarthe, Philip Greenland, Markus Juonala, Mika Kähönen, Terho Lehtimäki, Rena S Day, Lydia Bazzano, Linda Van Horn, Lei Liu, Camilo F Alonso, Larry S Webber, Katja Pahkala, Tomi T Laitinen, Olli Raitakari, Donald M Lloyd-Jones, Norrina B Allen
Journal: Circulation (2019)

Introduction: Declines in CVH beginning as early as childhood have been linked to development of subclinical atherosclerosis and CVD in adulthood; however, less is known about the timing and sequence. The objective of this study was to determine patterns for the loss of the health factors that comprise CVH and the associations with cIMT. Methods: We pooled data from five childhood/young adult cardiovascular cohorts including BHS, CARDIA, Young Finns, Project HB!, and STRIP. Available data allowed analysis of 4 of the 7 metrics that define CVH: BMI, blood pressure, total cholesterol, and blood glucose, categorized as ideal or non-ideal. We built a multi-trajectory model which fitted trajectory groups based on the simultaneous modeling of the loss of ideal CVH (defined as the probability of being ideal for a given health factor dropping below 50%), from childhood (ages 0-19) through early adulthood (ages 20-39) to middle adulthood (ages 40-59). Logistic regression was used to examine association of the trajectories and high cIMT. Results: There were 9,388 individuals included (55% female, 66% white), and 5 distinct trajectory groups were formed (Figure). As compared to those who maintained ideal levels of all four health factors, those who had a childhood loss of a single ideal health factor were about two times as likely to have high cIMT (cholesterol OR: 1.99; 95% CI 1.49-2.65; BMI OR: 1.91; 95% CI 1.45-2.53), while those with loss of more than one ideal health factors in childhood were 2.89 times more likely to have high cIMT (95% CI 2.21-3.78). The loss of ideal BMI and cholesterol during early adulthood was also associated with a higher likelihood of high cIMT than when ideal levels were retained to this age (OR: 1.47; 95% CI 1.10-1.97). Conclusions: Loss of multiple CVH factors in childhood was associated with the highest probability of developing subclinical atherosclerosis compared with retention of ideal levels into middle adulthood. These data add evidence of the importance of preserving ideal CVH beginning in childhood.
Are tumor size changes predictive of survival for checkpoint blockade based immunotherapy in metastatic melanoma?
Authors: Meihua Wang, Cong Chen, Thomas Jemielita, James Anderson, Xiaoyun Li, Chen Hu, S. Peter Kang, Nageatte Ibrahim, Scot Ebbinghaus
Journal: Journal for ImmunoTherapy of Cancer (2019)

In oncology clinical development, objective response rate, disease control rate and early tumor size changes are commonly used as efficacy metrics for early decision-making. However, for immunotherapy trials, it is unclear whether these early efficacy metrics are still predictive of long-term clinical benefit such as overall survival. The goal of this paper is to identify appropriate early efficacy metrics predictive of overall survival for immunotherapy trials.Based on several checkpoint blockade based immunotherapy studies in metastatic melanoma, we evaluated the predictive value of early tumor size changes and RECIST-based efficacy metrics at various time points on overall survival. The cut-off values for tumor size changes to predict survival were explored via tree based recursive partitioning and validated by external data. Sensitivity analyses were performed for the cut-offs.The continuous tumor size change metric and RECIST-based trichotomized response metric at different landmark time points were found to be statistically significantly associated with overall survival. The predictive values were higher at Week 12 and 18 than those at Week 24. The percentage of tumor size changes appeared to have comparable or lower predictive values than the RECIST-based trichotomized metric, and a cut-off of approximately 10% tumor reduction appeared to be reasonable for predicting survival.An approximate 10% tumor reduction may be a reasonable cut-off for early decision-making while the RECIST-based efficacy metric remains the primary tool. Early landmark analysis is especially useful for decision making when accrual is fast. Composite response rate (utilizing different weights for PR/CR and SD) may be worth further investigation.Clinical trials gov, NCT01295827 , Registered February 15, 2011; NCT01704287 , Registered October 11, 2012; NCT01866319 , Registered May 31, 2013.
Abstract P219: Central Obesity and All-cause and Cause Specific Mortality: a Systematic Review and Dose-response Meta-analysis of Prospective Studies
Authors: Tao Huang, Tingting Geng
Journal: Circulation (2019)

Background: The association of central obesity and mortality risk has not been systematically investigated. The strength and shape of dose-response relationship between central obesity and all-cause and cause specific mortality still remains unclear. Therefore, we conducted a systematic review and meta-analysis to clarify the associations. Methods: Categorical and dose-response meta-analysis was conducted involving of prospective studies. PubMed and Embase were searched up to April 1st, 2017 for eligible studies of waist circumference, waist-to-hip ratio and all-cause and cause specific mortality. Random-effects models were used to derive the summary relative risks (RRs) and corresponding 95% CI for specific categories of central obesity and a continuous association using generalized least-squares trend estimation. Results: A total of 1 760 947 participants in 50 studies were included in the meta-analysis. The pooled RRs for a 10 cm increase in waist circumference were 1.06 (95% CI, 1.04-1.08; I 2 =92.9%), 1.06 (95% CI, 1.03-1.08; I 2 =90.9%), 1.21 (95% CI, 1.06-1.35; I 2 =88.1%) and 1.05 (95% CI, 1.02-1.08; I 2 =86.5%) for all-cause, cardiovascular disease (CVD), coronary heart disease (CHD), and cancer mortality, respectively. We found a nonlinear relationship between waist circumference and all-cause mortality among both women (p&lt;0.001) and men (p=0.011). The summary RRs for a 0.1 unit in waist-to-hip ratio were 1.17 (95% CI, 1.12-1.21; I 2 =88.2%), 1.26 (95% CI, 1.17-1.34; I 2 =66.3%), 1.25 (95% CI, 1.10-1.40; I 2 =67.8%) and 1.13 (95% CI, 1.09-1.16; I 2 =0.0%) for all-cause, CVD, CHD, and cancer mortality, respectively. There was evidence of a nonlinear relationship between waist-to-hip ratio and all-cause mortality among women (p=0.016) rather than men (p=0.424). The dose-response relationship between central obesity and cause specific mortality were linear, except the association of waist circumference and CVD mortality (p=0.037), and waist-to-hip ratio and cancer mortality (p=0.039). Conclusions: Higher waist circumference and waist-to-hip ratio measured continuously and categorically, increase the risk of all-cause mortality among men and women and are associated with increased risk of CVD, CHD and cancer mortality.
Human Genetics and Drug Development
Authors: Michael V. Holmes
Journal: New England Journal of Medicine (2019)

Current tools in the field of human genetics can reliably estimate both the intended and the adverse effects of modifying a therapeutic target to guide the clinical development of medicines.1 The distinction between an adverse effect of a drug that is target-mediated, and thus a characteristic of all drugs in the same class, and an adverse effect that is off-target, affecting typically an individual drug (rather than a drug class), is critical to decision making in drug development. Although relevant studies of human genetics cannot characterize off-target effects (), extrapolations may be feasible in certain limited circumstances. For example, . . .
Cancer screening in the United States, 2019: A review of current American Cancer Society guidelines and current issues in cancer screening
Authors: Robert A. Smith, Kimberly S. Andrews, Durado Brooks, Stacey A. Fedewa, Deana Manassaram‐Baptiste, Debbie Saslow, Richard C. Wender
Journal: CA A Cancer Journal for Clinicians (2019)

Abstract Each year, the American Cancer Society publishes a summary of its guidelines for early cancer detection, data and trends in cancer screening rates, and select issues related to cancer screening. In this issue of the journal, the current American Cancer Society cancer screening guidelines are summarized, and the most current data from the National Health Interview Survey are provided on the utilization of cancer screening for men and women and on the adherence of men and women to multiple recommended screening tests.
High Glucose Triggers Nucleotide Imbalance through O-GlcNAcylation of Key Enzymes and Induces KRAS Mutation in Pancreatic Cells
Authors: Chun-Mei Hu, Sui-Chih Tien, Ping-Kun Hsieh, Yung-Ming Jeng, Ming-Chu Chang, Yu-Ting Chang, Yi-Ju Chen, Yu-Ju Chen, Eva Y.-H.P. Lee, Wen-Hwa Lee
Journal: Cell Metabolism (2019)
Abstract P084: Neighborhood Deprivation is Associated With Diabetes Complications: Results From the UCSF Population Health Data Initiative
Authors: Mary E Lacy, Courtney R Lyles, Mahasin S Mujahid, Kirsten Bibbins-Domingo, Mark J Pletcher
Journal: Circulation (2019)

Introduction: Although neighborhood-level factors influence diabetes and diabetes complications, these determinants are often ignored in clinical practice. The widespread use of electronic medical records (EMR) represents a unique opportunity to incorporate these factors into clinical decision making through geocoding of a patient’s residential address. However, despite increasing interest, few examples exist of how to leverage geospatial data within a clinical care system to inform patient care. The objective of this study is to examine the association between neighborhood deprivation and diabetes complications using geocoded address and clinical data extracted from patients’ EMR. Methods: Using retrospective EMR data from UCSF Health (01/01/2015-06/30/2018), we identified a cohort of patients with diabetes using a combination of labs, diagnosis codes and medications (n=9,876). Patients’ residential addresses were extracted from EMR, geocoded, and assigned to census block/track. Area deprivation index (ADI) was calculated for each census block/track, categorized as high neighborhood-level deprivation (ADI ≥80 th percentile) or not (ADI &lt;80 th percentile), and linked to patient-level data. ADI includes 17 measures of education, employment, housing-quality, and poverty and incorporates information from the Census and American Community Survey. We used logistic regression models to examine the association between ADI and the following diabetes-related outcomes: poor glycemic control (HbA1c ≥9%), severe hypoglycemia (ICD-9/10 codes for hypoglycemia-related ED visit or hospitalization), and retinopathy (ICD-9/10 codes). Models were adjusted for age, sex, race/ethnicity, and insurance coverage. Hypoglycemia and retinopathy models were additionally adjusted for last available HbA1c measure. Results: In fully-adjusted models, high neighborhood-level deprivation was associated with increased risk of poor glycemic control (OR: 1.18, 95% CI: 1.01, 1.40) and severe hypoglycemia (OR: 1.35, 95% CI: 1.04, 1.76). Conversely, high neighborhood-level deprivation was associated with decreased risk of retinopathy (OR: 0.78, 95% CI: 0.63, 0.96). Conclusions: Using EMR data, after controlling for several patient-level factors, neighborhood-level deprivation was associated with increased risk of poor glycemic control and severe hypoglycemia and decreased risk retinopathy. Understanding the patient’s broader social context could help inform risk stratification and tailoring of diabetes management. Future analyses will more fully characterize patients’ clinical and utilization-related characteristics and will include additional diabetes complications such as nephropathy, neuropathy and chronic kidney disease. This study represents an example of how neighborhood-level data obtained through patient’s EMR could be used to inform clinical practice.
Clinicopathological implications of newly defined immune checkpoints in extra-hepatic cholangiocarcinoma.
Authors: Satoshi Wada
Journal: Journal of Clinical Oncology (2015)

e15151 Background: Extra-hepatic cholangiocarcinoma (EHCC) has not been improved with the five-year survival rate for more than 10 years, which is a refractory cancer of poor prognosis. Development of novel therapeutic agents has been desired, because the standard chemotherapy has not been established yet. Anti-tumor immunotherapy is expected for less burden on the patient in recent years. However, it is limited by multiple tolerogenic mechanisms related to the tumor, the host immune system, and the tumor microenvironment. Therefore satisfactory results are not obtained in the clinical trials for several vaccinations. In this experiment, we focused on negative co-signaling molecules, especially immune checkpoints. The purpose of the present study was to investigate the relationship between the expression of immune checkpoints and clinicopathological findings, including prognosis in EHCC patients. Methods: We enrolled 81 patients (56 men and 25 women; age range: 36-84 years) with EHCC who underwent curative resection with lymphadenectomy at Gunma University Hospital and Saiseikai Maebashi Hospital (Maebashi, Japan) between 2000 and 2011. Patients who had undergone palliative resection, preoperative chemotherapy and radiation therapy were excluded from this study. Furthermore, none of the patients enrolled in this study had synchronous or metachronous cancer in other organs. Results: Immunohistochemical staining of immune checkpoints in primary EHCC tissue was performed. Patients with high B7-H4 expression had a significantly poorer prognosis than those with low B7-H4 expression. However, it was not seen in B7-H3 expression in this experiment. Furthermore, in analysis for the expression of CD8, IFN-γ and FOXP3, patients with high FOXP3 expression had a significantly poorer prognosis than those with low FOXP3 expression. Conclusions: The B7-H4 is a negative co-stimulatory molecule and a novel prognostic marker related to the T-cell mediated immune response. It’s pathway may be a molecular target for controlling tumor progression in patients with EHCC.
Streptozocin-based treatment in advanced neuroendocrine tumors (NETs): A single institution experience.
Authors: Genevieve Huynh-Trudeau, Francine Aubin, Jean-Pierre M. Ayoub, Richard Letourneau, Harold Olney, Mustapha Ali Tehfe
Journal: Journal of Clinical Oncology (2015)

e15179 Background: NETs represent a rare and miscellaneous group of tumors with a variable clinical activity. Streptozocin (STZ) is widely used in the treatment of advanced NETs, despite its controversial effectiveness and risk of toxicity. The aim of the study is to review Streptozocin-based treatment for advanced/metastatic NETs, its toxicities and its impact on progression free survival (PFS) and overall survival (OS). Methods: This retrospective study includes 22 pts treated with STZ for advanced NETs between 2006 – 2014 at CHUM. Kaplan-Meier analysis were used to evaluate PFS and OS of the entire group and of adrenal NETs vs. others. Results: The group included 12 women and 10 men with a median age of 49 years old. Twelve patients (pts) had the primary tumor coming from adrenals and 8 pts from pancreas. 14 pts presented initially with metastases (met); 50% located in the liver. The median time to develop met was 17 months. All pts had G1/G2 disease. The median number of cycles was 3.5, with concomitant doxorubicin in 46%. 32% started STZ in first intention and 68% received at least 1 previous treatment. Gastrointestinal toxicities were the most frequent ones; nausea and vomiting in 36% and diarrhea or constipation in 23%. There was no grade 3/4 hematologic toxicity. Proteinuria, hyperglycemia and elevated hepatic enzymes were found in < 20% of pts. Only 4 pts had acute renal failure (ARF); 3 of them were mild. One pt with massive hepatic metastases died of a tumor lysis syndrome and ARF. STZ was discontinued for disease progression in 55%, disease stabilisation in 18% and toxicity in 14%. PFS was 59 days overall; 51 days for adrenals NETs and 195 days for pancreatic NETs. Median OS was 41 months. Conclusions: STZ is mainly prescribed for advanced adrenal and pancreatic NETs, with no clear benefit on PFS. The toxicity profile and the presence of alternative agents should supplant its usage.
Screening for High Lipoprotein(a)
Authors: George Thanassoulis
Journal: Circulation (2019)

In 1994, the landmark 4S trial (Scandinavian Simvastatin Survival Study) reported that lowering low-density lipoprotein (LDL) cholesterol with simvastatin reduced cardiovascular events in patients with coronary artery disease and hypercholesterolemia. 1 This seminal trial crystallized our understanding of the causal role of LDL cholesterol in atherosclerosis and launched the modern era of preventive cardiology.Today, the evidence in favor of LDL cholesterol as a modifiable causal driver of atherosclerosis has never been stronger, and current therapies, such as PCSK9 inhibitors (PCSK9i), can now lower LDL cholesterol to levels never previously seen.But despite achieving very low levels of LDL cholesterol, many patients continue to have recurrent events.Although the residual risk for cardiovascular events is likely multifactorial, in certain patients a key component is a high residual burden of atherogenic lipid particles attributable to high lipoprotein(a) [Lp(a)].Lp(a) is a curious lipoprotein particle, first discovered in 1963, that consists of a lipid-rich apolipoprotein (apo) B lipoprotein covalently linked to an apo(a) moiety. 2 The apo(a) component is encoded by the LPA gene, and levels of Lp(a) are almost entirely explained by genetics.Indeed, elevated Lp(a) is the most common genetic dyslipidemia, with nearly 1 in 5 individuals affected in the United States [ie, based on Lp(a) >50 mg/dL or >120 nmol/L].Epidemiological evidence has linked Lp(a) to several cardiovascular diseases, including myocardial infarction (MI), 3 stroke, 3 and aortic valve stenosis, 4 and genetic evidence, using Mendelian randomization, has provided supportive evidence that these associations are causal. 4,5Causality is a key criterion in evaluating whether circulating biomarkers are possible therapeutic targets, and the evidence in support of Lp(a) appears quite favorable.Several agents are currently in development to specifically lower Lp(a), and these appear highly effective in lowering plasma Lp(a), with an excellent safety profile. 6However, to date, there remains no strong clinical evidence that lowering Lp(a) has any beneficial effects in preventing cardiovascular disease.Lp(a) still waits for its "4S" moment, but that moment appears imminent, with at least 1 trial in the final planning stages for post-acute coronary syndrome patients.In the context of these developments, Lp(a) is experiencing a resurgence in interest by the cardiovascular research community, and with good reason: there remain many unanswered questions about Lp(a) and its role in cardiovascular disease.In this issue of Circulation, 2 articles are presented that provide answers to some of these outstanding questions.In the first, Paré et al, 7 using data from the large, multiethnic INTERHEART study, evaluate the associations between Lp(a) levels and isoform size difference with MI across 7 ethnic groups in 6086 cases of first MI and 6857 control subjects.The authors should be commended for using this rich, multiethnic dataset to examine the role of Lp(a) across ethnicities using state-of-the-
Endothelial FSH receptor expression and vascular remodeling in hormone-refractory prostate cancer.
Authors: Nicolae Ghinea, Blaise Robin, Francois Planeix, Isabel Brito, Christophe Pichon
Journal: Journal of Clinical Oncology (2015)

e16035 Background: Work from our laboratory shows that FSH-receptor (FSHR) is present in the tumor endothelial cells, most frequently at the periphery of the hormone-naïve prostate cancer tissue. However, there is no evidence available for the vascular FSHR expression in hormone-refractory prostate cancer (HRPC). Methods: By using a highly specific monoclonal antibody raised against the human FSHR, we have examined the expression of FSHR in 50 HRPC patients on the tissue sections stained by standard peroxidase-immunohistochemistry. We have also quantified the level of FSHR expression in tumor blood vessels associated with HRPC and analyzed its correlation with the tumor microvascular density (MVD) detected with CD34 monoclonal antibody, the vascular endothelial growth factor receptor 2 (VEGFR2), and with the endothelial cell proliferation factor (detected with Ki67 monoclonal antibody). Results: All 50 patients examined expressed FSHR in endothelial cells (average density: 78.5 ± 10.1 vessels/ mm2). No correlations were obtained between the density of FSHR+ vessels and MVD. Although the MVD in HRPC tissue were significantly different from those of non tumoral, adjacent "normal" prostate tissue (209.2 ± 12.9 vs. 146.3± 10.9 CD34+ vessels /mm2, respectively; p = 0.004), the area occupied by CD34+ endothelial cells was not. In HRPC tissue, 93.7% of blood vessels expressing CD34 were capillaries (diameter ≤ 10µm), 5.9% were venules (10 µm < diameter ≤ 100 µm), and 0.4% arterioles. By contrast, in non tumoral tissue, adjacent to HRPC zones, 89.4% of CD34+vessels were capillaries, 8.9% venules, and 1.7% arterioles. No Ki67 staining was observed in ECs and low to undetectable VEGFR2 protein by immunohistochemistry were noticed to be associated with CD34+ ECs in HRPC. Conclusions: Taken together these results suggest a vascular remodeling in HRPC involving a process of intussusception rather than a vascular sprouting and explain the disappointing efficacy of antiangiogenic agents in prostate cancer. The role of the endothelial FSHR in the vascular remodeling associated with HRPC remains to be determined