tbuckley/cabot-search huggingface dataset:
Prediction of the Optimal Dosing Regimen Using a Mathematical Model of Tumor Uptake for Immunocytokine-Based Cancer Immunotherapy
Authors: Benjamin Ribba, Christophe Boetsch, Tapan Nayak, Hans Peter Grimm, Jehad Charo, Stefan Evers, Christian Klein, Jean Tessier, Jean Eric Charoin, Alex Phipps, Pavel Pisa, Volker Teichgräber
Journal: Clinical Cancer Research (2018)

Purpose: Optimal dosing is critical for immunocytokine-based cancer immunotherapy to maximize efficacy and minimize toxicity. Cergutuzumab amunaleukin (CEA-IL2v) is a novel CEA-targeted immunocytokine. We set out to develop a mathematical model to predict intratumoral CEA-IL2v concentrations following various systemic dosing intensities.Experimental Design: Sequential measurements of CEA-IL2v plasma concentrations in 74 patients with solid tumors were applied in a series of differential equations to devise a model that also incorporates the peripheral concentrations of IL2 receptor-positive cell populations (i.e., CD8+, CD4+, NK, and B cells), which affect tumor bioavailability of CEA-IL2v. Imaging data from a subset of 14 patients were subsequently utilized to additionally predict antibody uptake in tumor tissues.Results: We created a pharmacokinetic/pharmacodynamic mathematical model that incorporates the expansion of IL2R-positive target cells at multiple dose levels and different schedules of CEA-IL2v. Model-based prediction of drug levels correlated with the concentration of IL2R-positive cells in the peripheral blood of patients. The pharmacokinetic model was further refined and extended by adding a model of antibody uptake, which is based on drug dose and the biological properties of the tumor. In silico predictions of our model correlated with imaging data and demonstrated that a dose-dense schedule comprising escalating doses and shortened intervals of drug administration can improve intratumoral drug uptake and overcome consumption of CEA-IL2v by the expanding population of IL2R-positive cells.Conclusions: The model presented here allows simulation of individualized treatment plans for optimal dosing and scheduling of immunocytokines for anticancer immunotherapy. Clin Cancer Res; 24(14); 3325-33. ©2018 AACRSee related commentary by Ruiz-Cerdá et al., p. 3236.
Government is to publish performance data on all general practices in England
Authors: Michael Cross
Journal: BMJ (2011)

Comparative data on clinical outcomes and general practices’ prescribing are among six datasets from the NHS to be made public from December 2011 under an initiative to make public services more transparent.

Bruce Keogh, the NHS’s medical director, said last week that publishing the data would allow patients to evaluate their local doctors objectively. “Rumour and word of mouth are no longer good enough,” he said.

The proposals met a mixed reception from professional bodies. The BMA warned against creating “simplistic league tables,” whereas the Royal College of General Practitioners said that GPs “have …
Report on suicides of doctors under GMC investigation will trigger review of procedures
Authors: Abi Rimmer
Journal: BMJ (2014)

Thank you for your interest in spreading the word about The BMJ.NOTE: We only request your email address so that the person you are recommending the page to knows that you wanted them to see it, and that it is not junk mail. We do not capture any email address. Username * Your Email * Send To * You are going to email the following Report on suicides of doctors under GMC investigation will trigger review of procedures Your Personal Message CAPTCHA This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Low Transvalvular Flow Rate Predicts Mortality in Patients With Low-Gradient Aortic Stenosis Following Aortic Valve Intervention
Authors: Anastasia Vamvakidou, Wenying Jin, Oleksandr Danylenko, Navtej Chahal, Rajdeep Khattar, Roxy Senior
Journal: JACC. Cardiovascular imaging (2018)
Hypertrophy Regression With N-Acetylcysteine in Hypertrophic Cardiomyopathy (HALT-HCM)
Authors: Ali J. Marian, Yanli Tan, Lili Li, Jeffrey Chang, Petros Syrris, Manouchehr Hessabi, Mohammad H. Rahbar, James T. Willerson, Benjamin Y. Cheong, Chia-Ying Liu, Neal S. Kleiman, David A. Bluemke, Sherif F. Nagueh
Journal: Circulation Research (2018)

Rationale: Hypertrophic cardiomyopathy (HCM) is a genetic paradigm of cardiac hypertrophy. Cardiac hypertrophy and interstitial fibrosis are important risk factors for sudden death and morbidity in HCM. Oxidative stress is implicated in the pathogenesis of cardiac hypertrophy and fibrosis. Treatment with antioxidant N-acetylcysteine (NAC) reverses cardiac hypertrophy and fibrosis in animal models of HCM. Objective: To determine effect sizes of NAC on indices of cardiac hypertrophy and fibrosis in patients with established HCM. Methods and Results: HALT-HCM (Hypertrophy Regression With N-Acetylcysteine in Hypertrophic Cardiomyopathy) is a double-blind, randomized, sex-matched, placebo-controlled single-center pilot study in patients with HCM. Patients with HCM, who had a left ventricular wall thickness of ≥15 mm, were randomized either to a placebo or to NAC (1:2 ratio, respectively). NAC was titrated ≤2.4 g per day. Clinical evaluation, blood chemistry, and 6-minute walk test were performed every 3 months, and electrocardiography, echocardiography, and cardiac magnetic resonance imaging, the latter whenever not contraindicated, before and after 12 months of treatment. Eighty-five of 232 screened patients met the eligibility criteria, 42 agreed to participate; 29 were randomized to NAC and 13 to placebo groups. Demographic, echocardiographic, and cardiac magnetic resonance imaging phenotypes at the baseline between the 2 groups were similar. WSE in 38 patients identified a spectrum of 42 pathogenic variants in genes implicated in HCM in 26 participants. Twenty-four patients in the NAC group and 11 in the placebo group completed the study. Six severe adverse events occurred in the NAC group but were considered unrelated to NAC. The effect sizes of NAC on the clinical phenotype, echocardiographic, and cardiac magnetic resonance imaging indices of cardiac hypertrophy, function, and extent of late gadolinium enhancement—a surrogate for fibrosis—were small. Conclusions: Treatment with NAC for 12 months had small effect sizes on indices of cardiac hypertrophy or fibrosis. The small sample size of the HALT-HCM study hinders from making firm conclusions about efficacy of NAC in HCM. Clinical Trial Registration: URL: http://www.clinicaltrials.gov . Unique identifier: NCT01537926.
BBB permeability as a magnetic resonance imaging biomarker for low glioblastoma infiltration
Authors: Antoine Vallatos, Joanna Birch, Haitham Al-Mubarak, Lindsay Gallagher, Lesley Gilmour, Anthony Chalmers, William Holmes
Journal: Neuro-Oncology (2018)

Detecting and measuring invasion of the normal brain is crucial for the successful treatment of glioblastoma (GBM) as it allows increasing the accuracy of target volume delineation for radiotherapy planning. Probing the integrity of the peritumoral Blood-Brain Barrier (BBB) could substantially facilitate drug delivery planning. While magnetic resonance imaging (MRI) is a valuable tool for clinicians treating GBM, standard imaging techniques fail to detect regions of low tumour cell density and provide poor information about subtle BBB permeability changes caused by GBM invasion. However, invading tumour cells often progress along blood vessels and recent results indicate that even individual cells can disrupt the normal BBB function, providing an opportunity to detect tumour invasion at its earliest stages. Our research focuses on the development of MRI techniques probing brain perfusion and BBB permeability, and their assessment as biomarkers for detecting low tumour infiltration regions in mouse GBM models presenting highly invasive tumour margins. A high SNR multiple boli Arterial Spin Labelling (mbASL) technique was optimised for rodent brain perfusion imaging and a diffusion-weighted ASL (DWASL) method was implemented for probing the molecular mobility of perfused blood water. Introducing diffusion gradients into the ASL sequence allows minimising the signal contribution of the fast motion “vascular component” providing with perfusion images dominated by the slower motion “tissue component”. The ratio of the “tissue component” perfusion images to the overall perfusion ones obtained by ASL was expected to produce BBB permeability-weighed maps. The resulting maps were compared with histological sections stained (FITC)-dextrans to assess BBB disruption. The ability of perfusion and BBB permeability techniques to characterise tumour invasion was evaluated by comparison with standard MRI techniques (T2W and DW) and immunohistochemistry sections cut in the MRI plane. Both techniques were shown to detect low tumour regions not detected by standard MRI techniques.
Primary Hepatic Malignant Fibrous Histiocytoma on PET/CT
Authors: Yachao Liu, Baixuan Xu
Journal: Clinical Nuclear Medicine (2018)

Abstract Malignant fibrous histiocytoma is mainly presented in extremities, less commonly in posterior peritoneum, but primary presented in liver is very rare and often with a poor prognosis because of its high aggression. The features of clinical presentations and images are variable and the pre-operative diagnosis is difficult. Here, we report a primary hepatic malignant fibrous histiocytoma patient with no distant metastasis showed on pre-operative 18 F-FDG PET/CT, however with many metastases showed on the post-operative 18 F-FDG PET/CT.
Long-term Mortality in NFL Professional Football Players
Authors: Steven T. DeKosky, Michael Jaffee, Russell Bauer
Journal: JAMA (2018)

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The short-term and long-term prognostic risk stratification of patients with resectable gastric cancer.
Authors: En Amada, Hirofumi Kawakubo, Shuhei Mayanagi, Kazumasa Fukuda, Rieko Nakamura, Koichi Suda, Norihito Wada, Yuko Kitagawa
Journal: Journal of Clinical Oncology (2018)

23 Background: Some studies suggest anastomotic leakage (AL) may adversely affect long-term survival in patients undergoing radical gastrectomy (RG) for gastric cancer (GC). Therefore, we assume that common risk evaluation system for short-term and long-term prognosis can be devised in patients with GC that have undergone RG. Methods: Five hundred and twenty patients undergone RG against GC during May 2012 to March 2017 were enrolled. Patients’ characteristics, preoperative laboratory data, operative information and pathological factors were analyzed. Also AL with Clavien-Dindo classification Grade≥III (AL≥III), disease free survival (DFS) and disease specific survival (DSS) were examined. Results: By bringing patients under classification of “with or without relapse” and “with or without AL≥III”, we identified preoperative body weight (BW), serum C-reactive protein (CRP) and albumin (Alb) level were independent risk factors of both relapse and AL≥III. Stratifying patients with recurrence, we obtained crude hazard ratio (HR) of 1.04 (95% CI: 1.02-1.06) for 1kg-increase of BW, 1.51 (95% CI: 1.08-1.40) for 1mg/dl-increase of CRP and 1.23 (95% CI: 1.34-1.64) for 1g/dl-decrease of Alb. With these HR and median value of each parameters of none-relapse group, we defined ABC score (ABCs) is calculated by following formula; ABCs = (4.1-Alb)*51+(58.5-BW)*4+(CRP-0.05)*23. AL≥III were observed in 3.1% of the cases and ABCs of patients with AL≥III was significantly low (with AL≥III; -22.4, without AL≥III; 9.03, p = 0.045). We determine a cut off value of ABCs to -7 on the basis of the ROC curve. Patients with ABCs≤-7 had significantly high risk of AL≥III and we found ABCs≤-7 is an independent risk factor of AL≥III (HR 1.775, p = 0.003). Also, we stratified patients as Low group (L), Mid group (M), High group (H), by approximate tertile value of ABCs, -20 and 30. We found significant shortening of DFS and DSS in order of L, M and H (DFS; L vs M p = 0.006, Mid vs High p = 0.03, DSS; L vs M p = 0.002, L vs H p &lt; 0.001). Moreover, HR for disease specific death for ABCs≥-20 was 4.2 (p = 0.003) in multivariate analysis. Conclusions: ABCs can be a risk evaluation system for short-term and long-term prognosis in patients with GC that have undergone RG.
Targeting bacteroides in the stool microbiome and response to treatment (Rx) with first-line VEGFTKI in metastatic renal cell carcinoma (mRCC).
Authors: Sidney VanAlstine, Camryn Froerer, Andrew W Hahn, Jeffrey Gilreath, Neeraj Agarwal, David D. Stenehjem, Erin B. Bailey
Journal: Journal of Clinical Oncology (2018)

584 Background: Diarrhea occurs in ~50% patients with mRCC receiving VEGFTKIs, and is a common cause of VEGFTKI Rx dose reductions/delays/interruptions. Stool bacteroides level directly correlates with diarrhea in these patients on Rx with VEGFTKI (Pal SK, Clinical Cancer Research 2015, PMID:26152743). Hypothesis was that mRCC patients on incidental antibiotics (ABX) which also target stool bacteroides will have less diarrhea, leading to improved Rx compliance, and improved outcomes on VEGFTKI. Methods: A retrospective study of mRCC patients with MSKCC intermediate or poor risk mRCC on 1 st line VEGFRTKIs between 2005-2017. ABX usage was categorized by ABX bacteroides sensitivity at anytime during Rx with 1 st line VEGFTKI along with the total number of days on ABX. 1 st line VEGFRTKI progression free survival (PFS) was assessed by Kaplan-Meier and Cox proportional hazard models. Results: 145 patients with intermediate (n = 123, 85%) or poor risk (n = 22, 15%) mRCC on a VEGFTKI were identified. ABX were prescribed incidentally in 50 (34%) patients. 18 patients were prescribed ABX with bacteroides coverage of which 13 had ABX with high sensitivity for bacteroides. The median number of days supplied of all ABX was 7 (IQR 1-15 days). The median number of days supplied of ABX with bacteroides coverage was 6 (IQR 1.5-15.5 days). The median PFS in those prescribed ABX with bacteroides sensitivity was 18 months versus 8 months in those prescribed no ABX (p = 0.067), and 9 months in those prescribed ABX without bacteroides sensitivity. Duration of bacteroides ABX coverage resulted in a hazard ratio of 0.92 (95% CI 0.83-0.99, p = 0.043) for each additional day an ABX with bacteroides coverage was prescribed compared to those with no ABX. Conclusions: In these hypothesis generating data, incidental targeting of stool bacteroides with ABX correlated with improved PFS in mRCC patients on 1 st line VEGFTKIs. Data need validation. Equal contribution: SAV, CDF, AWH
Phase II trial of BC-819 intravesical gene therapy in combination with BCG in patients with non-muscle invasive bladder cancer (NMIBC).
Authors: Sarel Halachmi, Ilan Leibovitch, Amnon Zisman, Avi Stein, Shalva Benjamin, Ami Sidi, Ron Knickerbocker, Michal Limor, Yan Moore
Journal: Journal of Clinical Oncology (2018)

499 Background: BC-819 is an intravesical gene therapy consisting of a recombinant DNA construct which delivers a lethal cellular toxin, engineered from diphtheria, specifically to malignant cells in the bladder. In this study we tested the feasibility of administering BC-819 in combination with BCG with the goal of improving outcomes for patients with NMIBC. Methods: This phase II multi-center trial assessed 3 intravesical combination induction schedules of BC-819 and BCG; alternating (A), sequential (S), and twice weekly (TW) for 6-12 weeks. The population included adult patients for whom BCG was indicated. All patients underwent transurethral resection of the bladder tumor (TURBT) prior to study entry. The primary endpoint was safety; recurrence was assessed as a secondary endpoint. Results: 38 Caucasian patients were included in the intent-to-treat population; 16 in A, 6 in S, and 16 in TW cohorts. The median follow-up is 18-mo. The mean age was 69 years (±11.3), 92% were males. 29% had prior BCG. 16% of patients had CIS lesions, and 47% had multiple recurrences prior to participation. In 86% the resected tumor size ≥1.0cm. The overall median time to recurrence (mTTR) was not reached. The 24-months rates of recurrence and progression were 46% and 24%, respectively. The longest median time to recurrence among the three schedules was in the alternating group, but due to the small numbers of patients in each group the best schedule could not be determined. Therapy was associated with 5 AEs (in 5 patients; 13%) related to BC-819 (2 UTIs – 1 mild/1 moderate, 2 hematurias – both mild, 1 dysuria - mild) and 29 related to BCG. 3 SAEs were reported, none related to BC-819. Conclusions: These data demonstrate that administration of BC-819 in combination with BCG is feasible and exhibits clinically meaningful activity in all three induction schedules. The safety profile suggests that BC-819 is well tolerated and does not add substantial toxicity to intravesical therapy. A phase 3 randomized trial of BC-819 and BCG in patients with NMIBC is planned. NCT01878188. Clinical trial information: NCT01878188. [Table: see text]
Driver Oncogenes but Not as We Know Them: Targetable Fusion Genes in Breast Cancer
Authors: Rachael Natrajan, Andrew N.J. Tutt, Christopher J. Lord
Journal: Cancer Discovery (2018)

Abstract Summary: Two reports in this issue of Cancer Discovery outline how the genomic composition of tumors, including the presence of intragenic gene fusions, could inform the selection of treatment approaches in aggressive forms of the disease. Cancer Discov; 8(3); 272–5. ©2018 AACR. See related article by Matissek et al., p. 336. See related article by Liu et al., p. 354.
Final results of a phase 1b study of the safety and efficacy of the PI3Kδ inhibitor acalisib (GS-9820) in relapsed/refractory lymphoid malignancies
Authors: Arnon P. Kater, Sanne H. Tonino, Marjolein Spiering, Martine E. D. Chamuleau, Roberto Liu, Adeboye Henry Adewoye, Jie Gao, Lyndah Dreiling, Yan Xin, Jeanette K. Doorduijn, Marie José Kersten
Journal: Blood Cancer Journal (2018)
PROVIDER- AND HOSPITAL-LEVEL VARIATION IN ORAL ANTICOAGULANT USE FOR STROKE PREVENTION IN ATRIAL FIBRILLATION
Authors: Sean Pokorney, Elaine Hylek, Christopher Granger, Kevin Anstrom, Eva M. Kline-Rogers, Mark Alberts, Peter Berger, John House, Ujwala Vijapurkar, Roberta James, Bimal Shah, Gerald Naccarelli
Journal: Journal of the American College of Cardiology (2018)
Comparison of Military and Civilian Methods for Determining Potentially Preventable Deaths
Authors: Jud C. Janak, Jonathan A. Sosnov, Joan M. Bares, Zsolt T. Stockinger, Harold R. Montgomery, Russ S. Kotwal, Frank K. Butler, Stacy A. Shackelford, Jennifer M. Gurney, Mary Ann Spott, Louis N. Finelli, Edward L. Mazuchowski, David J. Smith
Journal: JAMA Surgery (2018)

<h3>Importance</h3> Military and civilian trauma experts initiated a collaborative effort to develop an integrated learning trauma system to reduce preventable morbidity and mortality. Because the Department of Defense does not currently have recommended guidelines and standard operating procedures to perform military preventable death reviews in a consistent manner, these performance improvement processes must be developed. <h3>Objectives</h3> To compare military and civilian preventable death determination methods to understand the existing best practices for evaluating preventable death. <h3>Evidence Review</h3> This systematic review followed the PRISMA reporting guidelines. English-language articles were searched from inception to February 15, 2017, using the following databases: MEDLINE (Ovid), Evidence-Based Medicine Reviews (Ovid), PubMed, CINAHL, and Google Scholar. Articles were initially screened for eligibility and excluded based on predetermined criteria. Articles reviewing only prehospital deaths, only inhospital deaths, or both were eligible for inclusion. Information on study characteristics was independently abstracted by 2 investigators. Reported are methodological factors affecting the reliability of preventable death studies and the preventable death rate, defined as the number of potentially preventable deaths divided by the total number of deaths within a specific patient population. <h3>Findings</h3> Fifty studies (8 military and 42 civilian) met the inclusion criteria. In total, 1598 of 6500 military deaths reviewed and 3346 of 19 108 civilian deaths reviewed were classified as potentially preventable. Among military studies, the preventable death rate ranged from 3.1% to 51.4%. Among civilian studies, the preventable death rate ranged from 2.5% to 85.3%. The high level of methodological heterogeneity regarding factors, such as preventable death definitions, review process, and determination criteria, hinders a meaningful quantitative comparison of preventable death rates. <h3>Conclusions and Relevance</h3> The reliability of military and civilian preventable death studies is hindered by inconsistent definitions, incompatible criteria, and the overall heterogeneity in study methods. The complexity, inconsistency, and unpredictability of combat require unique considerations to perform a methodologically sound combat-related preventable death review. As the Department of Defense begins the process of developing recommended guidelines and standard operating procedures for performing military preventable death reviews, consideration must be given to the factors known to increase the risk of bias and poor reliability.