tbuckley/cabot-search huggingface dataset:
Letter to the Editor: Beta‐Blockers Are Preferable to Banding Ligation for Primary Prophylaxis of Variceal Bleeding?
Authors: Gin‐Ho Lo
Journal: Hepatology (2019)

Potential conflict of interest: Nothing to report. SEE ARTICLE ON PAGE XXXX. To the Editor: I read with interest regarding the comparison of therapies for primary prophylaxis of esophageal variceal bleeding.1 This systematic review provides important updated knowledge for clinicians when deciding on whether to perform prophylaxis of first esophageal variceal bleeding. The study revealed that nonselective beta‐blockers may decrease all‐cause mortality and that it had a lower risk of serious complications compared with banding ligation. The authors concluded that nonselective beta‐blockers may be the initial approach for primary prophylaxis of variceal bleeding. In actuality, the choices between beta‐blockers and banding ligation merit further consideration. It is well demonstrated that nonselective beta‐blockers are associated with a higher incidence of adverse events. This may lead to discontinuation of therapy. A hemodynamic study showed that up to 43% of patients with cirrhosis were not responsive to nonselective beta‐blockers.2 Banding ligation may be associated with serious adverse events such as ulcer bleeding or perforation; however, the incidence is appreciably low.3 The incidence of postbanding ulcers could be reduced by a longer interval of ligation.4 Banding ligation instead of beta‐blockers is prone to result in variceal obliteration. The achievement of variceal obliteration could create a long period of freedom from worry of hemorrhage for high‐risk patients. These facts may explain why a slight majority of patients and physicians prefer banding ligation over beta‐blockers.5 It appears that both nonselective beta‐blockers and banding ligation could be the initial approach for primary prophylaxis of variceal bleeding. Apart from patients with intolerance and contraindications, shared decision making may be the most practical approach for patients with high‐risk esophageal varices nowadays.
III. The Diverse Effects of Normal Human Serum
Authors: J. F. Mccall, J. R. E. Fraser
Journal: Annals of the Rheumatic Diseases (1966)

Derived from analysis of variance after angular trans- formation (Fisher and Yates, 1953).Note: The residual error was identical in both synovial and skin cell series.trasts with the effect of heat-inactivated serum which shows a simple positive relationship to concentration.In this series of experiments, the last-mentioned effect dominates the aggregate effect of concen- tration as shown in the interaction table.With passage of time there was a highly significant increase in spreading, chiefly in the higher titre.53
HDAC6 Inhibition Synergizes with Anti-PD-L1 Therapy in ARID1A-Inactivated Ovarian Cancer
Authors: Takeshi Fukumoto, Nail Fatkhutdinov, Joseph A. Zundell, Evgenii N. Tcyganov, Timothy Nacarelli, Sergey Karakashev, Shuai Wu, Qin Liu, Dmitry I. Gabrilovich, Rugang Zhang
Journal: Cancer Research (2019)

Abstract ARID1A, encoding a subunit of the SWI/SNF complex, is the most frequently mutated epigenetic regulator in human cancers and is mutated in more than 50% of ovarian clear cell carcinomas (OCCC), a disease that currently has no effective therapy. Inhibition of histone deacetylase 6 (HDAC6) suppresses the growth of ARID1A-mutated tumors and modulates tumor immune microenvironment. Here, we show that inhibition of HDAC6 synergizes with anti-PD-L1 immune checkpoint blockade in ARID1A-inactivated ovarian cancer. ARID1A directly repressed transcription of CD274, the gene encoding PD-L1. Reduced tumor burden and improved survival were observed in ARID1Aflox/flox/PIK3CAH1047R OCCC mice treated with the HDAC6 inhibitor ACY1215 and anti-PD-L1 immune checkpoint blockade as a result of activation and increased presence of IFNγ-positive CD8 T cells. We confirmed that the combined treatment limited tumor progression in a cytotoxic T-cell–dependent manner, as depletion of CD8+ T cells abrogated these antitumor effects. Together, these findings indicate that combined HDAC6 inhibition and immune checkpoint blockade represents a potential treatment strategy for ARID1A-mutated cancers. Significance: These findings offer a mechanistic rationale for combining epigenetic modulators and existing immunotherapeutic interventions against a disease that has been so far resistant to checkpoint blockade as a monotherapy. See related commentary by Prokunina-Olsson, p. 5476
A Case of Muscle Twitching With Psoriasis
Authors: Min Qian, Lan Qin, Hongzhi Guan
Journal: JAMA Neurology (2019)

A 42-year-old man presents with a 2-month history of persistent muscle twitching in his abdomen and bilateral calves during wakefulness and sleep accompanied with excessive sweating, as well as mild bilateral lower extremity weakness after prolonged walking. What is your diagnosis?
Transcriptomic Profiling of the Developing Cardiac Conduction System at Single-Cell Resolution
Authors: William R. Goodyer, Benjamin M. Beyersdorf, David T. Paik, Lei Tian, Guang Li, Jan W. Buikema, Orlando Chirikian, Shannon Choi, Sneha Venkatraman, Eliza L. Adams, Marc Tessier-Lavigne, Joseph C. Wu, Sean M. Wu
Journal: Circulation Research (2019)

Rationale: The cardiac conduction system (CCS) consists of distinct components including the sinoatrial node, atrioventricular node, His bundle, bundle branches, and Purkinje fibers. Despite an essential role for the CCS in heart development and function, the CCS has remained challenging to interrogate because of inherent obstacles including small cell numbers, large cell-type heterogeneity, complex anatomy, and difficulty in isolation. Single-cell RNA-sequencing allows for genome-wide analysis of gene expression at single-cell resolution. Objective: Assess the transcriptional landscape of the entire CCS at single-cell resolution by single-cell RNA-sequencing within the developing mouse heart. Methods and Results: Wild-type, embryonic day 16.5 mouse hearts (n=6 per zone) were harvested and 3 zones of microdissection were isolated, including: Zone I—sinoatrial node region; Zone II—atrioventricular node/His region; and Zone III—bundle branch/Purkinje fiber region. Tissue was digested into single-cell suspensions, cells isolated, mRNA reverse transcribed, and barcoded before high-throughput sequencing and bioinformatics analyses. Single-cell RNA-sequencing was performed on over 22 000 cells, and all major cell types of the murine heart were successfully captured including bona fide clusters of cells consistent with each major component of the CCS. Unsupervised weighted gene coexpression network analysis led to the discovery of a host of novel CCS genes, a subset of which were validated using fluorescent in situ hybridization as well as whole-mount immunolabeling with volume imaging (iDISCO+) in 3 dimensions on intact mouse hearts. Further, subcluster analysis unveiled isolation of distinct CCS cell subtypes, including the clinically relevant but poorly characterized transitional cells that bridge the CCS and surrounding myocardium. Conclusions: Our study represents the first comprehensive assessment of the transcriptional profiles from the entire CCS at single-cell resolution and provides a characterization in the context of development and disease.
Multimodality Imaging of Left Ventricular Apical Pouch With Midventricular Cavity Obliteration
Authors: M. Fuad Jan, Timothy E. Paterick, Khawaja Afzal Ammar, Ahmad Khraisat, Bijoy K. Khandheria, A. Jamil Tajik
Journal: Journal of the American College of Cardiology (2012)
Ibrutinib in combination with nab-paclitaxel and gemcitabine as first-line treatment for patients with metastatic pancreatic adenocarcinoma: results from the phase 3 RESOLVE study
Authors: M. Tempero, D. Oh, T. Macarulla, M. Reni, E. Van Cutsem, A. Hendifar, D. Waldschmidt, N. Starling, J. Bachet, H. Chang, J. Maurel, S. Lonardi, L. Coussens, L. Fong, L. Tsao, G. Cole, D. James, J. Tabernero
Journal: Annals of Oncology (2019)
Abstract 275: A Randomized Controlled Trial of Compression Rates (COMPRATE trial) During Cardiopulmonary Resuscitation
Authors: Sung-oh Hwang, Kyoung Chul Cha, Kyuseok Kim, You Hwan Cho, Jonghwan Shin, Huijai Lee, Sung Phil Chung, Je Sung You, Yoo Seok Park, Seunghwang Kim, Sang-Cheon Choi, Won Young Kim, Dong Woo Seo, Sungwoo Moon, Gapsu Han, Han Sung Choi, Hyung Goo Kang, Seung Min Park, Woon Yong Kwon, Eun Jung Park
Journal: Circulation (2013)

Purposes: This prospective, randomized, multicenter-, controlled trial was conducted to compare the efficacy of CPR with compression rate of 100/min to CPR with compression rate of 120/min in patients with cardiac arrest. Methods: Patients with non-traumatic out-of-hospital cardiac arrest whose age is equal and over 19 years old were randomized into two groups when the patient arrived at emergency department. The patients received manual CPR either a compression rate of 100 /min (CPR-100 group) or a compression rate of 120/min (CPR-120 group). Chest compressions were performed by pre-trained AHA certified healthcare providers according to guidance of metronome and a real-time CPR measurement feedback system. Quality of chest compression was assessed by reviewing the depth and rate of compressions recorded in the high quality electronic monitoring system of the defibrillator. The case was excluded if the accuracy of the depth and rate of chest compressions could not be maintained over 90%. The primary outcome measure was sustained return of spontaneous circulation (ROSC). The secondary outcome measures were survival discharge from the hospital, 1-month survival, and 1-month survival with good functional status, categorized as a score of 2 or less on the cerebral performance category. Results: 470 patients were enrolled in the study. 221 patients were assigned to CPR-100 group and 249 patients assigned to CPR-120 group. A total of 136 patients (61.5 %) in the CPR-100 group and 156 patients (62.7 %) in the CPR-120 group were included in the analysis. In comparison of primary outcome, 69 patients (50.7%) in CPR-100 group and 67 patients (42.9%) in CPR-120 group had ROSC (p=0.183). In secondary outcome measures, the rates of survival discharge from the hospital, 1-month survival, and 1-month survival with good functional status were not different between two groups (16.9% vs. 12.8%, p=0.375; 12.5% vs. 6.4%, p=0.073; 5.9% vs. 2.6%, p=0.154). Conclusions: In patients with out-of-hospital non-traumatic cardiac arrest resuscitated in emergency department, no differences in the resuscitation outcomes were found between those who received CPR with a compression rate of 100/min and those who received CPR with a compression rate of 120/min.
Outcomes Associated With Overlapping Surgery
Authors: John W. Urwin, Ezekiel J. Emanuel
Journal: JAMA (2019)

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Overexpression of CD36, Driven By STAT3, Mediates Free Fatty Acid Uptake in CLL Cells
Authors: Uri Rozovski, David M. Harris, Ping Li, Zhiming Liu, Preetesh Jain, Alessandra Ferrajoli, Jan A. Burger, Prithviraj Bose, Philip A Thompson, Nitin Jain, William G Wierda, Michael J. Keating, Zeev Estrov
Journal: Blood (2017)
Incidence of posttransplantation lymphoproliferative disorder (PTLD) following allogeneic blood or marrow transplantation (alloBMT) using post-transplantation cyclophosphamide (PT-Cy) for graft-versus-host disease (GVHD) prophylaxis.
Authors: Jennifer Ann Kanakry, Yvette L. Kasamon, Lode J. Swinnen, Javier Bolanos-Meade, Douglas Gladstone, Heather J. Symons, Huzefa J. Mogri, Christopher George Kanakry, Christopher D Gocke, Leo Luznik, Ephraim Joseph Fuchs, Richard J. Jones, Richard F. Ambinder
Journal: Journal of Clinical Oncology (2013)

7009 Background: Immunosuppression to prevent graft rejection and GVHD is associated with an increased incidence of PTLD in the first year after alloBMT. AlloBMTs using partially HLA-mismatched or unrelated donor grafts, particularly when coupled with selective T-cell depletion approaches and/or anti-thymocyte globulin therapy, are associated with PTLD rates of 4-8%. The incidence of PTLD after umbilical cord blood alloBMT ranges from 2-7%. We evaluated the incidence of PTLD associated with the use of PT-Cy as GVHD prophylaxis at Johns Hopkins Hospital. Methods: After IRB approval, the Blood and Marrow Transplant Research database was queried for adult patients (age &gt; 18) who received PT-Cy as GVHD prophylaxis. Medical records from the first year after alloBMT, including clinical notes, pathology reports, and laboratory assays for Epstein-Barr virus (EBV), were reviewed. Results: From 2000-2011, 765 alloBMT patients received PT-Cy (50 mg/kg/day on days 3 and 4 after alloBMT) as GVHD prophylaxis. Of these, 734 patients had 1-year follow-up or death. In patients receiving myeloablative conditioning and HLA-matched grafts (n=289, 117 unrelated donors), PT-Cy was the sole GVHD prophylaxis. Other patients undergoing alloBMT received mycophenolate mofetil and tacrolimus in addition to PT-Cy. These included recipients of HLA-matched (n=63) or haploidentical (n=352) grafts who were conditioned with reduced intensity regimens, as well as recipients of HLA-haploidentical grafts who received myeloablative regimens (n=30). Forty-one patients with CD20(+) tumors received rituximab after alloBMT as part of a clinical protocol. There were no cases of PTLD. Conclusions: The absence of PTLD in this series, even among high-risk recipients of haploidentical or unrelated donor grafts, suggests that PT-Cy is less associated with PTLD than other GVHD prophylaxis strategies. We hypothesize that multiple mechanisms may account for the lack of PTLD with PT-Cy, including destruction of B cells that harbor EBV, sparing of EBV-specific memory T cells, and rapid immune reconstitution.
Bayesian network meta-analysis (NMA) of complete remission without or with incomplete hematologic recovery (CR/CRi) to CPX-351, FLAG, and standard 7+3 (7+3) chemotherapy in the treatment of newly diagnosed secondary acute myeloid leukemia (sAML).
Authors: Mok Oh, Bernard Marini, Anthony Perissinotti, Lydia Benitez, Patrick William Burke, Dale L. Bixby, Kristen Marie Pettit, Ivo Abraham, Ali McBride
Journal: Journal of Clinical Oncology (2019)

e18514 Background: Patients (pts) sAML have poor outcomes (CR/CRi= 25-35%) with standard 7+3 induction chemotherapy (7+3). CPX-351 (liposomal encapsulated daunorubicin + cytarabine at a synergistic 5:1 molar ratio) was approved recently for sAML based on improvements in CR/CRi and survival but high cost and toxicity has discouraged its use. FLAG (fludarabine + high-dose cytarabine + granulocyte colony stimulating factor) have emerged as a lower cost, safe alternatives; however, outcomes between CPX-351 and FLAG have yet to be compared. In the absence of a direct trial, we aimed to estimate indirectly by Bayesian NMA the comparative efficacy of CPX-351, FLAG, and 7+3 therapy for sAML patients. Methods: Publications that compared FLAG or CPX-351 to 7+3 in newly diagnosed sAML were identified through a search of PubMed. CR/CRi rates were used in a Bayesian NMA to assess the direct (CPX-351 vs 7+3; FLAG vs 7+3) and indirect (CPX-351 vs FLAG) comparative efficacy of these regimens. Fixed (FE) and random effect (RE) analyses were conducted to estimate pooled odds ratios (OR) with 95% credible interval (CrI). Results: Of 169 identified articles, four studies (three RCT and one retrospective cohort) on a total of 781 pts in three treatment arms were retained. NMA showed no significant difference in pooled CR/CRi rates between CPX-351 and FLAG in both FE and RE models. However, pts receiving either FLAG or CPX-351 had significantly higher CR/CRi than those receiving 7+3 in both FE and RE models as shown in the table. Conclusions: This NMA suggests that both CPX-351 and FLAG prevail in CR/CRi efficacy over 7+3. In indirect comparison, CPX-351 and FLAG are equivalent in efficacy. The cost implications of these results remain to be established. [Table: see text]
18F-DCFPyL PET/CT in a Single Large Metastasis With Prostate-Specific Antigen Level of 856 ng/mL
Authors: Maurits Wondergem, Sandra Srbljin, Friso M. van der Zant, Wouter A. M. Broos, Remco J. J. Knol
Journal: Clinical Nuclear Medicine (2019)

Literature shows that prostate-specific membrane antigen (PSMA) PET/CT may detect biochemical recurrence of prostate cancer at low prostate-specific antigen (PSA) levels, including detection of oligometastatic disease and hence direct metastasis-directed therapy. Although it is generally accepted that higher PSA values indicate higher disease burden, few data are available on the relation between PSA levels and number of detected metastases on PSMA PET/CT. This report demonstrates a patient with high PSA levels (856 ng/mL) at time of biochemical recurrence that showed only 1 metastasis on PSMA PET/CT. Combined androgen deprivation therapy and radiation therapy resulted in a complete biochemical response.
Nonclinical safety assessment of AMG 553, an investigational anti-FLT3 CAR-T therapy.
Authors: Christine M Karbowski, Rebecca Goldstein, Brendon Frank, Kei Kim, Chi-Ming Li, Bradford Gibson, Oliver Homann, Kelly Hensley, Ben Brooks, Qinghong Yan, Rocio Hernandez, Gregor Adams, Michael C Boyle, Tara Lynn Arvedson, Herve Lebrec
Journal: Journal of Clinical Oncology (2019)

7032 Background: FMS-like tyrosine kinase 3 (FLT3) is a tyrosine-protein kinase involved in hematopoiesis. In acute myeloid leukemia (AML), higher FLT3 transcript levels, independent of the presence of FLT3 mutations, correlate with higher leukocyte counts and higher degrees of bone marrow infiltration by leukemic cells. FLT3 protein is detectable on the cell surface of more than 80% of leukemia isolates from adult AML patients whereas FLT3 mutations are present only in approximately one third of patients. AMG 553 is a novel, investigational, adoptive cellular immunotherapy for the treatment of relapsed refractory AML, consisting of autologous T cells genetically modified ex vivo to express a transmembrane chimeric antigen receptor (CAR) to target FLT3 protein on the surface of AML cells irrespective of FLT3 mutational status. Methods: The nonclinical safety evaluation of AMG 553 includes assessment of FLT3 expression in normal tissues; in vitro assessment of cytotoxicity against human cells with or without FLT3 expression; toxicology studies in cynomolgus monkeys administered autologous T-cells transduced with an anti-FLT3 CAR or administered anti-FLT3 bi-specific T-cell engager (BiTE) antibodies. Results: Assessment of FLT3 expression in normal tissues indicates that FLT3 protein is detected on the cell surface of a subpopulation of human bone marrow hematopoietic stem and progenitor cells; expression in other tissues is cytoplasmic and not anticipated to be accessible to AMG 553. AMG 553-induced cytotoxicity was only observed in a percentage of primary bone marrow CD34+ cells. There was no evidence of CAR-T cell-mediated toxicity, expansion, or persistence in cynomolgus monkeys likely due to restricted cell surface FLT3 protein expression in healthy animals which demonstrates the limited value of such studies for this target. All findings in toxicology studies with anti-FLT3 BiTEs were consistent with the targeted killing of cells expressing FLT3 on the plasma membrane. Conclusions: The nonclinical safety data support AMG 553 as a novel therapeutic to target FLT3 protein on AML cells irrespective of FLT3 mutational status, while only affecting a percentage of normal hematopoietic stem and progenitor cells.
Analysis of long-term survival in patients with glioblastoma.
Authors: Elisabetta Melegari, Monia Dall'Agata, Graziano Guiducci, Anna Maria Cremonini, Serenella Cerasoli, Toni Ibrahim, Michele Sintini, Patrizia Cenni, Chiara Bomprezzi, Marina Faedi
Journal: Journal of Clinical Oncology (2013)

e13007 Background: Adult glioblastoma (GBM) is the most common type of malignant primary brain tumor. Despite advances made in treatment, median survival is between 12 and 15 months. Standard care is concomitant radiotherapy (RT)/temozolomide (TMZ) and adjuvant TMZ for 6 cycles (EORTC/NCIC trial 2005). At progression, subsequent treatments are left to the discretion of the treating physician. Methods: We evaluated retrospective data of GBM patients (pts) treated from 2003 to 2010, focusing on the treatment of patients with longer survival (over 24 months). Results: 139 pts with GBM were treated during the period. Thirty of these showed survival &gt; 24 months: 20 were subjected to macroscopically radical neurosurgery, 9 to non-radical surgery and 1 to biopsy. All pts had a KPS 100%. 11 pts were treated in the period pre-EORTC/NCIC trial (Stupp et all) and 19 in the period “post-Stupp”. In the former group 10 pts underwent RT followed by TMZ ( 2-12cycles) and 1 patient received only RT. All pts in the latter group were treated with concomitant radio-chemotherapy followed by TMZ. 3 pts are currently disease stable. After the first documented evidence of disease progression (PD) 21 pts were treated, one with neurosurgery, 4 with neurosurgery plus chemotherapy (CT), 15 with only CT and 1 with CT and tomotherapy. With regard to chemotherapy, 14 pts received TMZ ( 2-21cycles), 3 fotemustine (4-16 cycles), 1 carboplatin and VP16 (2 cycles) and 1 irinotecan plus bevacizumab (2 cycles). Further progression was treated with another line of CT in only 8 pts, fotemustine in 5 (1-3 cycles), TMZ in 2 (2 cycles) and carboplatin plus VP16 In 1 (5 cycles). Median overall survival (mOS) of our long-term survivors was 36.18 months (CI 95% 28.32 – 42.01). Considering the two groups separately (pre- and post- Stupp), we observed a mOS of 36.18 months (CI 95% 26.45 – 42.01) (1 pt alive) for the first group and of 36.15 months (CI 95% 28.26 – 48.52) (7 pts alive) for the second. Conclusions: Our long-term survivors, independently of treatment, showed an mOS of 36.18 months (CI 95% 28.32 – 42.01). There was no significant difference in mOS between the 2 groups (p=0.6963). Further research is needed to identify the biomolecular and genetic pattern that is responsible for the long survival of some patients.
Minimal Residual Disease after Hyper-CVAD and Imatinib Mesylate for Philadelphia Positive Adult Acute Lymphoblastic Leukemia
Authors: D. A. Thomas, J. Cortes, G. Garcia Manero, S. Faderl, O apos, S. brien, S. Pierce, S. Verstovsek, F. J. Giles, M. Andreeff, S. M. Kornblau, L. Letvak, H. M. Kantarjian
Journal: Blood (2002)