tbuckley/cabot-search huggingface dataset:
An independently validated survival nomogram for lower-grade glioma
Authors: Haley Gittleman, Andrew E Sloan, Jill S Barnholtz-Sloan
Journal: Neuro-Oncology (2019)

Abstract Background Gliomas are the most common primary malignant brain tumor. Diffuse low-grade and intermediate-grade gliomas, which together compose the lower-grade gliomas (LGGs; World Health Organization [WHO] grades II and III), present a therapeutic challenge to physicians due to the heterogeneity of their clinical behavior. Nomograms are useful tools for individualized estimation of survival. This study aimed to develop and independently validate a survival nomogram for patients with newly diagnosed LGG. Methods Data were obtained for newly diagnosed LGG patients from The Cancer Genome Atlas (TCGA) and the Ohio Brain Tumor Study (OBTS) with the following variables: tumor grade (II or III), age at diagnosis, sex, Karnofsky performance status (KPS), and molecular subtype (IDH mutant with 1p/19q codeletion [IDHmut-codel], IDH mutant without 1p/19q codeletion, and IDH wild-type). Survival was assessed using Cox proportional hazards regression, random survival forests, and recursive partitioning analysis, with adjustment for known prognostic factors. The models were developed using TCGA data and independently validated using the OBTS data. Models were internally validated using 10-fold cross-validation and externally validated with calibration curves. Results A final nomogram was validated for newly diagnosed LGG. Factors that increased the probability of survival included grade II tumor, younger age at diagnosis, having a high KPS, and the IDHmut-codel molecular subtype. Conclusions A nomogram that calculates individualized survival probabilities for patients with newly diagnosed LGG could be useful to health care providers for counseling patients regarding treatment decisions and optimizing therapeutic approaches. Free online software for implementing this nomogram is provided: https://hgittleman.shinyapps.io/LGG_Nomogram_H_Gittleman/. Key Points 1. A survival nomogram for lower-grade glioma patients has been developed and externally validated. 2. Free online software for implementing this nomogram is provided allowing for ease of use by practicing health care providers.
Frequency and Determinants of Thrombotic and Bleeding Complications in Ph Negative Myeloproliferative Neoplasms (MPN): The Role of Adamts-13 and VWF Activities in an Italian Cohort 0f 88 Well Characterized Patients
Authors: Augusto B. Federici, Maria C Carraro, Antonella Lattuada, Chiara Vanelli, Veronica Sciumbata, Valentina Rossi, Daniela Intini, Sarah Birindelli, Sara Munizza, Elisabetta Sacchi, Umberto Russo, Ulrich Budde
Journal: Blood (2012)
Azacitidine Plus Lenalidomide for Untreated AML Patients Ineligible for Conventional Chemotherapy
Authors: Daniel A Pollyea, James L. Zehnder, Steven Coutre, Jason Gotlib, Leonel Gallegos, Peter Greenberg, Bing Zhang, Michaela Liedtke, Ross L. Levine, Bruno C. Medeiros
Journal: Blood (2012)
Abstract 138: A Novel Cellular and Genetic Approach to Investigate the Cardioprotective Role Played by Endothelial Nitric Oxide Synthase in Myocardial Infarction
Authors: Carmine Gentile, Scott Kesteven, Jianxin Wu, Christina Bursill, Michael J Davies, Gemma Figtree
Journal: Circulation Research (2019)

The loss of regenerative properties in adult cardiomyocytes (CMs) is directly linked to their inability to proliferate. Following an extensive ischaemic event in an aged heart, fibrotic scar formation is the only repair process and eventually heart failure develops. However, molecular and cellular cues in the neonatal heart support that cardiac regeneration is possible in presence of proliferating CMs. Based on previous studies demonstrating that endothelial nitric oxide synthase (eNOS) regulates proliferation in both endothelial cells (ECs) and CMs, we hypothesized that eNOS signaling could play a cardioprotective role. To test our hypothesis, we injected different combinations of co-cultured ECs and CMs in the LV muscle wall of MI mice (permanent LAD ligation). First, injected cells were isolated from either WT or KO eNOS neonatal mice and then co-cultured to form 3D vascularized cardiac spheroids (VCSs), which were eventually transplanted in adult MI mice on the day of the procedure. Control infarcted animals received media-only (vehicle). Other mice received a suspension of co-cultured VCSs in media as follows: i ) WT CMs and ECs; ii ) WT CMs and KO ECs; iii ) KO CMs and WT ECs. Following 28 days, injection of WT cells increased the ejection fraction (EF%) by 20% compared with control animals (61%±4% and 41%±11%, respectively). When eNOS was absent in either CMs or ECs, the EF% was 40%±5% and 46%±2%, respectively, suggesting that the eNOS-mediated protection is dependent on its presence in both cells. Histological analyses confirmed the presence of WT VCSs in MI mice, contributing to a thicker wall thickness compared to vehicle MI mice. No VCSs were observed in the LV wall when KO cells were injected. Therefore, our results strongly suggest that eNOS may play a major role via both an autocrine (CMs) and paracrine (ECs) mechanism. Current studies are focusing on further evaluating the mechanism(s) for this eNOS-mediated protective role. To our knowledge, this is the first study combining cellular and genetic approaches to evaluate the cardioprotective role of eNOS in the heart. A better understanding of this mechanisms may have significant impact for the development of improved molecular and cell therapeutics (including stem cells) for heart failure patients.
Desmopressin and the risk of hyponatremia: A population-based cohort study
Authors: Michael Fralick, Sebastian Schneeweiss, Christopher J. D. Wallis, Emily H. Jung, Aaron S. Kesselheim
Journal: PLoS Medicine (2019)

Background Desmopressin was approved by the Food and Drug Administration (FDA) in 1978 for use in diabetes insipidus and bleeding disorders, but it is also prescribed off-label for patients with nocturia. Quantifying the potential risks facing adult patients taking desmopressin has taken on added importance because a new intranasal formulation of desmopressin was approved by the FDA in 2017. Like the old formulation, the main active ingredient is desmopressin acetate, but the new formulation also contains an excipient designed to enhance absorption. Our objective was to quantify the rate of hyponatremia in routine clinical care for patients prescribed the older formulation of desmopressin. Methods and findings We conducted a population-based new-user cohort study from 1 February 2006 to 1 February 2017 using a nationwide commercial health plan database. Patients newly prescribed the older formulation of desmopressin were propensity-score (PS)–matched to patients newly prescribed oxybutynin. As a sensitivity analysis, tamsulosin was used as the comparator rather than oxybutynin. The primary outcome was a primary position diagnosis of hyponatremia. Proportional hazard models after 1:1 PS matching were used to estimate hazard ratios (HRs) and 95% confidence intervals (CI). We identified 3,137 adults who were newly prescribed desmopressin and matched them to 3,137 adults who were newly prescribed oxybutynin. Mean age was 70, 55% were male, 13% filled a prescription for a diuretic during the baseline time period, and the mean baseline sodium prior to receiving either study drug was 140 mmol/L (normal: 135–145). The rate of hyponatremia was 146 per 1,000 person-years for adults prescribed desmopressin compared to 11 per 1,000 person-years for adults prescribed oxybutynin, corresponding to a 13-fold higher rate (HR 13.19; 95% CI 6.69, 26.01; p < 0.01). When follow-up was truncated at 30 days, a similar increased rate was observed (HR 19.41; 95% CI 7.11, 52.99; p < 0.01). A higher rate of hyponatremia was also observed with desmopressin when tamsulosin was the comparator (HR 12.10; 95% CI 6.54, 22.37; p < 0.01). Important limitations of our study include unmeasured confounding (for example, over-the-counter medication use, dietary intake), missing data (i.e., only 20% of patients had a baseline serum sodium), and a lack of data on the newer formulation of desmopressin. Conclusions Use of an older formulation of desmopressin was associated with a marked increased rate of subsequent hyponatremia compared to use of other medications indicated for lower urinary tract symptoms. Such risks should be clearly communicated to patients prescribed this formulation of desmopressin.
Abstract 614: Using Intact Trabeculae to Determine the Effect of Myosin-Modifying Drugs on Work, Power, and Mechanical Control of Relaxation
Authors: Brianna M Schick, Melissa J Bukowski, Charles S Chung
Journal: Circulation Research (2019)

Background: Heart failure and especially heart failure with preserved ejection fraction are significant burdens on health. Intact cardiac trabeculae may reveal functional changes that cannot be seen in other ex vivo (skinned, single molecule) preparations. For example, using intact trabeculae, we have shown that relaxation is mechanically controlled by the lengthening strain rate at end systole, not afterload. Objective: We sought to evaluate the effect of myosin activator Omecamtiv Mercarbil (OM) and inhibitor Mavacamten (Mav) on physiologic function in intact trabeculae. Methods/Results: Afterload-clamp protocols were applied to intact cardiac trabeculae from Sprague Dawley rats to simulate physiologic work-loops and evaluate mechanical control of relaxation. Both OM and Mav reduced stroke work (force x length) by &gt;50% and power (force x velocity) by ~50% at doses reducing developed force by 50%. These were mediated by dose-dependent reductions in both force and shortening length. We have recently reported preliminary results that OM improves contraction-relaxation coupling and makes the relaxation rate more sensitive to strain rate in a dose-dependent manner. Mav does not lead to significant changes in contraction-relaxation coupling at any dose; Mav alters the sensitivity of relaxation rate to strain rate only at doses that reduce developed force by 50%. Summary/Perspective: Intact rat cardiac trabeculae reveal function mimicking physiology. OM and Mav show remarkable similarities in force, work, and power, which may be due to the high expression of alpha-myosin heavy chain. OM treatment not only modified contractility but increased sensitivity of the relaxation rate to strain rate in a dose dependent manner, which may explain why diastolic dysfunction is not more prevalent in clinical studies. Mav appears to only modify the attachment of crossbridges as expected.
Abstract 260: The ER Unfolded Protein Response Effector, ATF6, Reduces Fibrosis and Moderates Activation of Cardiac Fibroblasts
Authors: Winston T Stauffer, Erik A Blackwood, Khalid Azizi, Haley N Stephens, Shirin Doroudgar, Christopher C Glembotski
Journal: Circulation Research (2019)

Fibroblasts in the heart respond to myocardial injury by infiltrating the affected area and differentiating into new cell types called myofibroblasts. These cells are characterized both by the induction of contractile proteins and the secretion of extracellular matrix proteins which form fibrotic scar tissue. Investigating the factors governing fibroblast activation is key to understanding how these cells function in the heart and may be key to future therapeutic strategies. Activating transcription factor 6 (ATF6), an effector of the endoplasmic reticulum unfolded protein response, plays critical roles in development, as well as in the differentiation of certain cell types, though it has not been studied in this regard in the heart. Our lab has demonstrated that ATF6 in cardiac myocytes is cardioprotective in vivo during heart disease. However, ATF6 has not been studied in cardiac fibroblasts and its effect on fibrosis in the heart is unknown. We hypothesized that ATF6 in fibroblasts is an important regulator of their function. Fibroblast activation markers including αSMA were increased in infarcted hearts with global ATF6 deletion. Additionally, hearts with pressure overload showed increased fibrosis staining in global ATF6-null mice relative to WT hearts. In isolated adult murine ventricular fibroblasts (AMVF), loss of ATF6 induced myofibroblast markers with and without the activation stimulus TGFβ. ATF6 loss of function also enhanced the effect of TGFβ on fibroblast contraction. These effects were associated with an increase in Smad phosphorylation, a crucial step in the TGFβ pathway. Interestingly, the effect of ATF6 loss of function in AMVF was erased when treated with a TGFβ receptor inhibitor. Additionally, when ATF6 was overexpressed or when endogenous ATF6 was chemically activated, myofibroblast markers were reduced and activation by TGFβ was blunted. ATF6 activation was associated with induction of several TGFβ/Smad pathway negative regulators including SMURF1, SMURF2, and PMEPA1, though none of these are known to be ATF6 target genes. These data suggest that ATF6 plays an important role in moderating fibroblast activation and this may contribute to previously reported roles for ATF6 in preserving cardiac function post-injury.
Ceritinib plus Nivolumab in Patients with Advanced ALK-Rearranged Non–Small Cell Lung Cancer: Results of an Open-Label, Multicenter, Phase 1B Study
Authors: Enriqueta Felip, Filippo G. de Braud, Michela Maur, Herbert H. Loong, Alice Tsang Shaw, Johan F. Vansteenkiste, Thomas John, Geoffrey Liu, Martijn P. Lolkema, Giovanni Selvaggi, Vanessa Giannone, Pilar Cazorla, Jason Baum, O. Alejandro Balbin, Luojun (Victor) Wang, Yvonne Y. Lau, Jeffrey W. Scott, Daniel Shao-Weng Tan
Journal: Journal of Thoracic Oncology (2019)

IntroductionInduction of programmed death ligand 1 (PD-L1) expression due to constitutive oncogenic signaling has been reported in NSCLC models harboring echinoderm microtubule associated protein like 4 gene (EML4)–ALK receptor tyrosine kinase gene (ALK) rearrangements. We assessed the safety and activity of ceritinib plus nivolumab in these patients.MethodsIn this open-label, phase 1B, multicenter, dose escalation and expansion study, previously treated (with ALK receptor tyrosine kinase [ALK] inhibitor [ALKI]/chemotherapy) or treatment-naive patients with stage IIIB or IV ALK-rearranged NSCLC received nivolumab, 3 mg/kg intravenously every 2 weeks, plus ceritinib, 450 mg/300 mg daily, with a low-fat meal.ResultsIn total, 36 patients were treated (a 450-mg cohort [n=14] and a 300-mg cohort [n=22]). In the 450-mg cohort, four patients experienced dose-limiting toxicities. In the 300-mg cohort, two patients experienced dose-limiting toxicities. Among ALKI-naive patients, the overall response rate (ORR) was 83% (95% confidence interval [CI]: 35.9–99.6) in the 450-mg cohort and 60% (95% CI: 26.2–87.8) in the 300-mg cohort. Among ALKI-pretreated patients, the ORR was 50% (95% CI: 15.7–84.3) in the 450-mg cohort and 25% (95% CI: 5.5–57.2) in the 300-mg cohort. The ORR point estimate was observed to be greater in patients who were positive for PD-L1 than in those who were negative for PD-L1, with overlapping CIs (e.g., at a cutoff ≥1% PD-L1, 64% of patients [95% CI: 35.1–87.2] had confirmed responses as compared with those with negative PD-L1 staining (31% [95% CI: 11.0–58.7]). The most frequently reported grade 3 or 4 adverse events were increased alanine aminotransferase level (25%), increased gamma-glutamyl transferase level (22%), increased amylase level (14%), increased lipase level (11%), and maculopapular rash (11%). The incidence of all-grade rash (grouped term) was 64% in both cohorts; grade 3 rash was reported in 29% and 14% of patients in the 450-mg and 300-mg cohorts, respectively; no grade 4 rash was reported.ConclusionCeritinib plus nivolumab has activity; ORR appears to correlate with PD-L1 at baseline. Toxicity, especially rash, is more common than with either single agent.
High-Dose Chemotherapy Followed By Autologous Stem Cell Transplantation As a Salvage Treatment in Patients with Relapsed or Refractory Primary Central Nervous System Lymphoma
Authors: Jaewon Hyung, Jung Yong Hong, Dok Hyun Yoon, Shin Kim, Jung Sun Park, Chan-Sik Park, Sang Wook Lee, Jin-Sook Ryu, Jooryung Huh, Cheolwon Suh
Journal: Blood (2018)
Primary care comprehensive medication reviews in cancer patients with comorbid conditions.
Authors: Emily R. Mackler, Amy Thompson, Michelle Azar, Karen B. Farris
Journal: Journal of Clinical Oncology (2019)

48 Background: Management of comorbidities is an important component of cancer care and may impact treatment toxicities, effectiveness, and survival. The purpose of this pilot study was to explore patient characteristics and interventions from a comprehensive medication review (CMR) in cancer patients with select comorbidities. Methods: Adult patients who received both active cancer treatment and primary care at Michigan Medicine with comorbid conditions of diabetes (DM), hypertension, chronic (HTN), heart failure (HF), depression, and/or anxiety, completed an intake survey and had a CMR done by primary care clinical pharmacists. Medication recommendations were reviewed with PCPs, implemented in follow-up visits, and documented in the electronic medical record. When needed, patients were referred to pharmacists for DM and/or HTN management using collaborative practice agreements. Results: Of the 96 eligible patients, 81% had solid tumor cancers (31% metastatic) while 19% had a hematologic cancer. Patients were 39% male, 34% ≥70 years, and 70% Caucasian. Comorbid conditions included DM (20%), HTN (61%), HF (6%), and depression/anxiety (45%). To date, pharmacists have seen 31 patients, and changes to medication profiles were made in 84% of patients. Almost 1 in 4 patients (23%) were referred for disease management. Patient intake surveys were obtained for 28 of the 31 patients. Over 1 in 5 (21%) reported their most bothersome symptom to be pain or neuropathy. Of the 2 patients reporting low social support, they also reported low confidence in symptom self-management. When asked to rate the hassle with frequent doctor appointments, 1 patient indicated a value of 4 or higher (5-point scale, where 5 = high) with the majority selecting no or little hassle. Conclusions: Primary care pharmacists have an opportunity to improve the coordination of care and enhance clinical outcomes in patients with cancer and comorbid conditions, as 23% of patients required additional chronic disease management. Furthermore, patients having lower social support may require additional services to ensure their needs are met.
Delta-Like Notch Ligands Expressed By Host Non-Hematopoietic Radioresistant Cells Regulate Graft-Versus-Host Disease and Extrathymic T Cell Development After Bone Marrow Transplantation
Authors: Christen L Ebens, Jooho Chung, Ute Koch, Ivy T Tran, Ashley R Sandy-Sloat, Ann Friedman, Bruce R Blazar, Pavan Reddy, Minhong Yan, Christian W Siebel, Freddy Radtke, Ivan Maillard
Journal: Blood (2013)
High Dose Intravenous Busulfan and Melphalan Followed By Bortezomib (BuMelVel) As Conditioning With Autologous Stem Cell Transplantation (ASCT) For Patients With Multiple Myeloma (MM)
Authors: Danielle Sterrenberg, Patrick J Stiff, Mala Parthasarathy, Aileen Go, Scott E. Smith, Tulio E. Rodriguez
Journal: Blood (2013)
Revisiting Early Stages of Chronic Myeloid Leukemia (CML): Evidence That Leukemic Progenitors Appear First in Peripheral Blood during Molecular Recurrence
Authors: Ali G Turhan, Patricia Hugues, Nathalie Sorel, Christophe Desterke, Annelise Bennaceur-Griscelli, Jean-Claude Chomel
Journal: Blood (2018)
Can we keep patients home? Decreasing hospitalizations in the oral chemotherapy patient.
Authors: Michelle Rene Karlin, Sabrina Q. Mikan, Lalan S. Wilfong, Holly Books
Journal: Journal of Clinical Oncology (2019)

294 Background: The Oncology Care Model (OCM) pilot includes all types of cancer with an aim to test whether additional funding for enhanced services and financial incentives to improve quality and efficiency, could reduce Medicare spending while maintaining or improving quality for a broad array of cancer types. Patients taking oral chemotherapy are included in the OCM. Often these patients require hospitalization due to side effects,decreased access and ability to communicate with providers. Limited documented strategies exist showing how to decrease hospitalizations in patients with cancer. The aim of this study was to decrease the hospitalization rate of oral chemotherapy patients at five sites by improving access to care and communication via establishment of phone triage nursing management. Methods: The aim of this project was to reduce hospitalizations for oral chemotherapy patients being treated at home over an eight month period. The Model for Improvement served as the research framework and design for this improvement project. The model includes identifying, defining and diagnosing a problem, before developing solutions and implementing interventions that are anticipated to solve the identified issues. Plan, Do, Study, Act (PDSA) cycles were utilized to develop and test changes in support of the oral chemotherapy patients. Five clinical sites affiliated with a community oncology practice in Texas collaborated with a Patient Support Service (PSS) nursing call center. Results: Implementing the PSS center resulted in a lowered number of monthly hospitalizations over eight months in patients receiving outpatient oral chemotherapy as compared to monthly volume of hospitalizations over eight months before implementation while demonstrating positive patient satisfaction with the oral regimen. Conclusions: This quality initiative found that OCM patients receiving oral chemotherapy can be supported to remain in their homes while decreasing unnecessary hospitalizations through the establishment of a PSS center. Through support systems for out-patient oncology patients, outcomes can be improved, unnecessary hospitalizations decreased, patient satisfaction sustained, and overall cost of care reduced.