tbuckley/cabot-search huggingface dataset:
The Serendipitous Story of SGLT2 Inhibitors in Heart Failure
Authors: Subodh Verma, John J.V. McMurray
Journal: Circulation (2019)

Diabetes mellitus intersects with cardiovascular disease at every level.Although there has been much focus on understanding atherosclerotic complications, less well appreciated is the relationship between diabetes mellitus and heart failure.In addition to being a key and independent risk factor for the development of heart failure, 1 diabetes mellitus is also one of the most important adverse prognostic factors in those with established heart failure with either reduced or preserved ejection fraction (EF). 1,2Diabetes mellitus is associated with a high prevalence of unrecognized left ventricular diastolic and systolic dysfunction, and it accelerates the development of overt heart failure compared with similar patients without diabetes mellitus. 3In addition to cardiac predictors such as left ventricular dysfunction, hypertrophy, and coronary artery disease, features of diabetes mellitus associated with the development of heart failure include poor glycemic control, longer duration of diabetes mellitus, insulin treatment, and the presence of microvascular complications, such as retinopathy or nephropathy. 2,4Finally, data from randomized trials and registries remind us that heart failure is numerically nearly as common as ischemic complications in patients with type 2 diabetes mellitus and remains one of the leading causes of hospitalizations in this population. 1,2Although conventional risk factor control can reduce ischemic complications, heart failure risk remains a recalcitrant problem in diabetes mellitus for which intensive glycemic control has had little benefit.The serendipitous story of sodium-glucose transporter 2 (SGLT2) inhibitors and heart failure stems from the EMPA-REG OUTCOME trial (Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients), 5 which unexpectedly demonstrated a profound 35% relative risk reduction in hospitalization for heart failure in patients with type 2 diabetes mellitus and established atherosclerotic vascular disease (ASCVD) who were treated with empagliflozin.Two additional SGLT2 inhibitors, canagliflozin and dapagliflozin, have been studied in large cardiovascular outcome trials (the CANVAS [Canagliflozin Cardiovascular Assessment Study] Program 6 and DECLARE-TIMI 58 [Dapagliflozin Effect on Cardiovascular Events: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial to Evaluate the Effect of Dapagliflozin 10 mg Once Daily on the Incidence of Cardiovascular Death, Myocardial Infarction or Ischemic Stroke in Patients With Type 2 Diabetes], 7 respectively).Both confirmed the benefit of SGLT2 inhibitors on hospitalization for heart failure (HHF), the composite of HHF or cardiovascular death (HHF/CV death), and renal composite outcomes.Importantly, these latter studies included people with type 2 diabetes mellitus with and without established ASCVD.
Abstract 18391: The Effect of Targeted Temperature Management on the Neurologic Outcome of In-hospital Cardiac Arrest Survivors
Authors: Justin Lundbye, Kelly N Sawyer, Leah Bergman, Sanjeev Nair, Antonio Fernandez
Journal: Circulation (2015)

Introduction: Cooling patients that have been resuscitated from out-of-hospital cardiac arrest (OHCA) using targeted temperature management (TTM) is standard of care. However the role of TTM in patients after in-hospital cardiac arrest (IHCA) is presently unclear. Hypothesis: We evaluated the effect of TTM on neurologic outcome of patients after successful resuscitation from IHCA Methods: A retrospective analysis was performed on prospectively collected data from 112 consecutive, adult IHCA patients admitted to a tertiary cardiac intensive care unit between January 1, 2004, and June 1, 2013. Patients were categorized into the hypothermia group (underwent TTM) and the control group (did not undergo TTM). Univariable as well as multivariable analyses by binomial logistic regression were performed on the collected data. The primary outcome was defined as neurologic outcome at hospital discharge using the cerebral performance categories (CPC) (Good= CPC 1-2 and Bad= CPC 3-5 respectively). Results: Of the 112 patients who formed the study cohort, 84 patients formed the hypothermia group and 28 patients formed the control group. The two groups were similar with respect to age, gender, ethnicity, past medical history, smoking, rate of witnessed cardiac arrest, and time to return of spontaneous circulation(P&gt;0.05). On univariable analysis 34(41%) patients in the hypothermia group had good neurologic outcome as compared to 5 (18%) patients in the control group (p=0.03). On multivariable analysis the use of TTM was the only independent predictor of good neurologic outcome (OR=3.79, 95 % CI: 1.18-12.79, P=0.024).(Figure) Conclusions: The use of TTM in patients resuscitated from IHCA is associated with significantly better neurologic outcome as compared to similar patients who did not undergo TTM. Larger studies are required to corroborate this finding.
Abstract P398: Mexican Mothers’ Experiences With Food Insecurity in Childhood, and Associations With Mothers’ and Children’s Cardiovascular Health
Authors: Liliana Aguayo, Lindsay Pool, Matthew M Davis, Craig Gundersen, Andiara Schwingel, Mercedes Carnethon
Journal: Circulation (2019)

Introduction: Food insecurity (FI) is disproportionately experienced by Mexican families. While associations between FI and cardiovascular health (CVH) factors have been recognized, less is known about how fluctuations in FI experiences throughout life relate to CVH or whether FI experiences have intergenerational effects. This study examines the associations between Mexican mothers’ FI experiences in childhood and currently, with their own and their 4-6 year old child’s odds of having optimal CVH. Methods: Mexican mother-child dyads were recruited in central Mexico, and central IL, US. Mothers were asked about their experiences with food insecurity “in the last 12 months”, and “when they were children” using an adapted version of the USDA-Food Insecurity and Hunger Module. Optimal CVH was defined as having desirable measurements of six CVH factors: BMI/BMI-Percentile, blood glucose, triglycerides, total cholesterol, HDL, and LDL cholesterol. FI experiences were categorized based upon whether mothers (1) never experienced FI, (2) experienced FI only in childhood, (3) experienced FI currently, but not in childhood, or (4) experienced FI in childhood and currently. Logistic regression was used to determine associations between FI and optimal CVH (6 factors vs. ≤5), adjusted for age, years of education, country of residence, and child sex. Results: Overall 28% mothers and 49% children had optimal CVH. FI was experienced by 19% of mothers in childhood only, by 14% currently, but not in childhood, and by 35% in childhood and currently. FI experiences were not associated with optimal CVH among the mothers. Compared to children of mothers who never experienced FI, children born to women who experienced FI only in childhood, but not currently were less likely to have optimal CVH (OR=0.15; 95% CI: 0.03, 0.91). Discussion: Mexican mothers who experienced FI during childhood, but not currently were less likely to have children with optimal CVH. Feeding patterns of mothers who experienced FI as children merit further investigation.
Inhibition of SYK or BTK augments venetoclax sensitivity in SHP1-negative/BCL-2-positive diffuse large B-cell lymphoma
Authors: Binu K. Sasi, Claudio Martines, Elena Xerxa, Fabiola Porro, Hilal Kalkan, Rosa Fazio, Sven Turkalj, Engin Bojnik, Beata Pyrzynska, Joanna Stachura, Abdessamad Zerrouqi, Małgorzata Bobrowicz, Magdalena Winiarska, Valdemar Priebe, Francesco Bertoni, Larry Mansouri, Richard Rosenquist, Dimitar G. Efremov
Journal: Leukemia (2019)
Initial results from a phase II study of nivolumab (NIVO) plus ipilimumab (IPI) for the treatment of metastatic castration-resistant prostate cancer (mCRPC; CheckMate 650).
Authors: Padmanee Sharma, Russell Kent Pachynski, Vivek Narayan, Aude Flechon, Gwenaelle Gravis, Matt D. Galsky, Hakim Mahammedi, Akash Patnaik, Sumit Kumar Subudhi, Marika Ciprotti, Tao Duan, Abdel Saci, Sarah Hu, G. Celine Han, Karim Fizazi
Journal: Journal of Clinical Oncology (2019)

142 Background: Immune checkpoint inhibitor monotherapy has shown limited clinical benefit in patients (pts) with prostate cancer, likely due to an immunologically “cold” tumor microenvironment. We report preplanned interim efficacy/safety for NIVO + IPI in pts with mCRPC from CheckMate 650. Methods: Asymptomatic/minimally symptomatic pts who progressed after 2nd-generation hormone therapy and have not received chemotherapy for mCRPC (cohort 1) and pts who progressed after taxane-based chemotherapy (cohort 2) were included. Treatment was NIVO 1 mg/kg + IPI 3 mg/kg Q3W for 4 doses, then NIVO 480 mg every 4 weeks. Coprimary endpoints: objective response rate (ORR) and radiographic PFS per PCWG2. Safety is a secondary endpoint. Exploratory endpoints include correlation of biomarkers with efficacy. Results: 78 pts had a minimum follow-up of 6 months; among pts with baseline measurable disease, ORR was 26% and 10% in cohorts 1 and 2 (Table). In both cohorts, ORR was higher in pts with PD-L1 ≥1%, DNA damage repair (DDR), homologous recombination deficiency (HRD), or above-median tumor mutational burden (TMB). Of all PSA responding pts (Table), 4 had PSA &lt;0.2 ng/mL. Grade 3–4 treatment-related adverse events occurred in 39% and 51% of pts in cohorts 1 and 2; one grade 5 event occurred in each cohort. Conclusions: In a malignancy where immune checkpoint inhibitor monotherapy has previously shown limited success, NIVO + IPI demonstrated activity in pretreated pts with mCRPC, particularly in a biomarker-enriched population, with a safety profile consistent with this dosing schedule. Further study is warranted. Clinical trial information: NCT02985957. [Table: see text]
Abstract 17592: Coronary Revascularization in Patients With Chronic Kidney Disease and Stable Ischemic Heart Disease: Utilization and Association With Long-term Survival
Authors: Jay Shavadia, Matthew James, Danielle Southern, Robert Welsh, Kevin Bainey
Journal: Circulation (2016)

Introduction: Clinical trials of revascularization versus medical management in stable ischemic heart disease (SIHD) support a conservative approach. However, chronic kidney disease (CKD) patients ...
Gender and racial variations in palliative care utilization among patients hospitalized with metastatic gastrointestinal malignancies.
Authors: Philip N. Okafor, Derrick J Stobaugh, Jayant A. Talwalkar
Journal: Journal of Clinical Oncology (2015)

e17565 Background: Increased healthcare resource utilization has been demonstrated among patients with advanced malignancies. We sought to explore patient and hospital level determinants of inpatient palliative care (IPC) utilization among patients with metastatic gastrointestinal cancers (colorectal, gastric, pancreatic and esophageal) using a national database. Methods: An analysis of the 2012 National Inpatient Sample was performed. International Classification of Diseases, 9th revision codes were used to identify discharges associated with metastatic digestive tract cancers and patient/hospital covariates for inclusion in a logistic regression model. Total charges and length of stay (LOS) were analyzed in a linear regression model. Results: Compared to males, females were more likely to receive IPC [adjusted odds ratio (OR) 1.12, p = 0.002]. No difference was seen between White, and Asian patients (OR 1.2, p = 0.11) or Native-Americans patients (OR 1.4, p = 0.22). However, relative to White patients, African-Americans (AA) (OR 1.13, p = 0.02) and Hispanics (OR 1.25, p = 0.001) had significantly higher odds of IPC. Medicare patients were least likely to receive IPC compared to Medicaid and commercial payers. Patient's zip-code median household income and county population were not predictive of IPC. However, patients admitted to larger hospitals were more likely to receive IPC during their hospitalizations than those in smaller hospitals (OR 1.3, p = 0.0001). IPC was most utilized in urban teaching hospitals compared to rural nonteaching hospitals (OR 1.2, p = 0.02). LOS during these hospitalizations was longer in AA (p = 0.0001), Asians (p = 0.0001) and Native-Americans (p = 0.03) compared to White patients. No difference was seen when total charges were compared between White and AA patients (p = 0.08). Conversely, total charges were higher in Hispanics (p = 0.005) and Asians (p = 0.001) relative to White patients. Conclusions: IPC utilization among patients hospitalized with metastatic gastrointestinal cancers appears to be higher among females compared to males. AA are more likely to receive IPC compared to Whites, even though LOS is significantly longer in AA.
Brain networks for emotion and cognition: Implications and tools for understanding mental disorders and pathophysiology
Authors: Luiz Pessoa
Journal: Behavioral and Brain Sciences (2019)

Understanding how structure maps to function in the brain in terms of large-scale networks is critical to elucidating the brain basis of mental phenomena and mental disorders. Given that this mapping is many-to-many, I argue that researchers need to shift to a multivariate brain and behavior characterization to fully unravel the contributions of brain processes to typical and atypical function.
20 Years of Transplant Program in Multiple Myeloma - a Single Centre Experience
Authors: Jiri Minarik, Edgar Faber, Ludek Raida, Tomas Szotkowski, Jaroslav Bacovsky, Tomas Pika, Ivana Skoumalova, Petra Krhovska, Jana Zapletalova, Tomas Papajik, Vlastimil Scudla
Journal: Blood (2018)
Tolerability of neo-adjuvant chemoradiotherapy (nCRT) with capecitabine and surgical outcomes in patients aged 70 years or older with locally advanced rectal cancer (LARC).
Authors: Lotte Jacobs, Ellen van der Vlies, Daan ten Bokkel Huinink, Haiko Bloemendal, Anke B. Smits, Peter. D. Siersema, Bas L.A.M. Weusten, Niels van Lelyveld, Maartje Los
Journal: Journal of Clinical Oncology (2015)

e14600 Background: In studies on colorectal cancer, elderly are frequently underrepresented since comorbid conditions and functional status often lead to study exclusion. In older patients with an indication for nCRT based on T/N stage, physicians decide on clinical grounds whether nCRT should be offered. Aim: to assess the proportion of patients aged ≥ 70 years with (LARC) undergoing nCRT, and to evaluate safety and efficacy of nCRT and subsequent surgery in a selected group of elderly. Methods: We used data from the Dutch Comprehensive Cancer Centre (IKNL) on 1704 rectal cancer patients in 4 Dutch hospitals over the last 10 years. Patient characteristics included clinical TNM stage, pathological staging, preoperative, surgical, adjuvant and palliative treatment and vital statistics. Patients aged ≥ 70 years were included if treated with nCRT according to the ESMO Guidelines, introduced in 2006, and analyzed for treatment deviations, postoperative morbidity, mortality and survival. Data were stratified for patient age into 3 groups: 70-74, 75-79, ≥ 80 years. Results: Between 2006 and 2012 a total of 447 rectal cancer patients aged ≥ 70 were identified. Of these, 42 patients (9%), median age 74 (IQR 72-78), with LARC were treated with nCRT. Overall, 37 patients (88%) completed the planned nCRT. Radiation dermatitis, fatigue and diarrhea was reported in resp. 62%, 57% and 43%. Forty patients (95%) were treated with surgery; 1 patient refused a resection, 1 patient died because of severe mucositis due to DPD-deficiency during nCRT. Postoperative complications were observed in 11 patients (28%) and the 30-day mortality rate was 0%. Two- and five year overall survival rates were 82% (95% CI 70-94) and 49% (95% CI 23-75). Treatment deviations, postoperative morbidity and treatment efficacy were not different in the 3 age groups. Conclusions: This multicenter study shows that only a minority of older patients with LARC are treated with nCRT. However, if selected on clinical grounds, nCRT is safe, well tolerated and leads to a favorable surgical outcome even in older age groups. The results show that elderly should not be excluded from nCRT based exclusively on age.
Proposal of a new staging system for intrahepatic cholangiocarcinoma: Analysis of surgical patients from a nationwide survey of Liver Cancer Study Group of Japan.
Authors: Yoshihiro Sakamoto, Norihiro Kokudo, Yutaka Matsuyama, Michiie Sakamoto, Masumi Kadoya, Shuichi Kaneko, Yonson Ku, Masatoshi Kudo, Tadatoshi Takayama, Osamu Nakashima
Journal: Journal of Clinical Oncology (2015)

4075 Background: In the current AJCC/UICC staging system 7thed. for intrahepatic cholangiocarcinoma (ICC), tumor size was excluded and “periductal invasion” was added as a new factor determining T-category. However, prognostic significance of tumor size and periductal invasion remains unclear. Methods: Of a total of 1216 patients who underwent surgical resection for ICC between 2000 and 2005 on Japanese nationwide database by Liver Cancer Study Group of Japan (LCSGJ), 756 patients with histologically confirmed mass-forming dominant ICC were studied. A multivariate analysis of the clinicopathological factors on the survivals of patients were performed using the data of 419 patients with complete set of the valid data. A new staging system was customized based on the results of the multivariate analyses. Results: The overall survivals were best stratified with a cut-off value of 2 cm with the minimal p-value to discriminate the survivals of patients. The 5-year survival rate of the 15 patients with ICC < / = 2cm without nodal metastasis or vascular invasion was 100%, suggesting surgical resection offers cure of the disease and these cohort can be defined as T1. Multivariate analysis of prognostic factors for all 419 patients showed that tumor size (HR = 2.487, CI = 0.912-6.780), tumor number (HR = 2.570, CI = 1.814-3.643), nodal metastasis (HR = 2.818, CI = 1.992-3.987) and distant metastasis (HR = 2.940, CI = 1.258-6.869) were independent and significant prognostic factors. The survival curves of N0M0 patients were well-stratified using a new T classification regulated by the 1) tumor size ( < / = 2cm, > 2cm), 2) tumor number and 3) portal vein, arterial or major biliary invasion. The survivals of patients with T1-3N1M0 were as good as those of T4N0M0 patients, and thereby categorized as Stage IVA, discriminating from Stage IVB, a group of T4N1M0 or M1. Conclusions: Tumor size with a cut-off value of 2cm and major biliary invasion were important prognostic factors for survival. The proposed new staging system would be useful for assigning surgical indication for selected patients even with nodal metastasis.
Rationale for the combination of veliparib with platinum-based chemotherapy.
Authors: David Maag, Larry Solomon, Todd Hopkins, Gail Bukhofzer, Yan Shi, Cherrie Donawho, Gui-Dong Zhu, Luis E Rodriguez, Thomas Penning, Enrico DiGiammarino, Sanjay C Panchal, Eric Feral Johnson
Journal: Journal of Clinical Oncology (2015)

2556 Background: Owing to the role of PARPs in DNA damage repair, PARP inhibitors (PARPi) are under clinical investigation as anticancer therapies with a focus on tumors with impaired homologous recombination or regimens containing DNA damaging chemotherapies. Pre-clinical evidence indicates that PARPi potentiate the cytotoxicity of platinums. A recent Phase II study suggested evidence of a benefit in both progression and survival when veliparib was added to carboplatin and paclitaxel in the treatment of advanced NSCLC. Methods: In vitroefficacy was evaluated in GFP-overexpressing cell lines cultured as 3D spheroids. In vivo efficacy was determined in xenograft tumor-bearing SCID mice. PARP1 trapping was evaluated by cellular fractionation and immunoblotting. Bone marrow toxicity was determined with CFU assays. Results: We have developed a method to monitor the growth of 3D spheroids in vitro in real time. In this system, veliparib potentiated the activity of platinums in numerous models. Likewise, veliparib potentiated the activity of platinums in multiple xenograft models in vivo. PARP trapping was undetectable when PARPi were combined with cisplatin. PARPi differed in the extent to which catalytic inhibition and trapping could be resolved. PARPi with more potent trapping activity induced greater cytotoxicity in bone marrow CFU assays than equipotent inhibitors with weaker trapping activity. Conclusions: Veliparib potentiates the activity of platinum agents in vitro and in vivo; however the mechanisms underlying this activity remain unclear. PARP trapping is a recently characterized mechanism central to the synergistic cytotoxicity of PARPi and temozolomide. In contrast, our results suggest that PARP trapping is not required for the combination activity of PARPi and cisplatin. Our observation that potent trapping activity is associated with cytotoxicity towards myeloid and erythroid progenitors suggests that trapping may contribute to the anemia and myelosuppression observed in patients treated with PARPi. As such, PARPi capable of catalytic inhibition at concentrations where trapping is undetectable may be more suitable for combination regimens in which trapping is not required for activity.
Whole exome next-generation sequencing of triple-negative breast cancers and rare tumours to reveal novel molecular pathways and therapeutic targets for personalized therapy.
Authors: Aleksandra Filipovic, Lucio Miele, Justin Stebbing
Journal: Journal of Clinical Oncology (2015)

e12534 Background: Decisions in oncology are often guided by molecular genetics. Next-generation sequencing (NGS) can help clarify underlying molecular mechanism(s) and identifies clinically relevant genetic markers for personalized therapy. Methods: We have performed SmartGen 421 NGS gene panel, on (n = 45) solid tumors including: triple negative breast cancer (n = 15), colon cancer (n = 10), NSCLC (n = 3), as well as on rare tumors (chordoma, adenocarcinoma of the thymus, sarcomas, Krukenberg’s metastases, neuroendocrine-, apendeceal carcinoid -, tumors of the unknown primary (n = 17)). Most biopsies were from the site of progression. DNA was extracted from tumor cells after laser capture microdissection, and sequenced on the Ion Torrent Personal Genome Machine. Coding regions +/-5 base pairs of the introns of 421 genes were sequenced. Sensitivity for SNP calls was 94.1% (69.2%-99.7%, at 95% CI), specificity 100%, for introns and deletions sensitivity was 78.9% (62.2%-89.9%, 95% CI) and specificity 99.994%. Copy number changes and chromosomal rearrangements were not detected by this test. VEP, SIFT and polyphen methods were used to assess SNP effect and severity. Results: We will present: 1) analyses of the mutational landscape for each tumor type as well as cross-tumor type analyses, where one third of detected mutations have been described in cancer in the COSMIC database, while rest are novel and recurrent; 2) functional consequences of these mutations in terms of multiple transcripts, effects on upstream/downstream genes etc.; 3) assessment of effects most likely contributing to disease; 4) Ingenuity Pathway Analysis data which identified most prominent functional pathways as STAT3, Epithelial-Mesenchymal transition, PDGF and PTEN. Approved therapeutic options and a comprehensive outline of clinical trials of novel targeted agents suggested by the molecular profiling will be included. Conclusions: Targeted sequencing platform using NGS technology is cost effective, reliable and feasible for clinical use. It provides comprehensive genetic alteration data which help tailor precision and personalized therapeutic approaches.
The IG/TR Next Generation Marker Screening Developed within Euroclonality-NGS Consortium Is Successful in 94% of Acute Lymphoblastic Leukemia Samples
Authors: Michaela Kotrova, Henrik Knecht, Dietrich Herrmann, Martin Schwarz, Karin Olsen, Heiko Trautmann, Nicola Goekbuget, Christiane Pott, Nikos Darzentas, Monika Brüggemann
Journal: Blood (2018)