tbuckley/cabot-search huggingface dataset:
Regorafenib in patients with unresectable hepatocellular carcinoma (uHCC) in routine clinical practice: Exploratory analysis of overall survival (OS) in the prospective, observational REFINE study.
Authors: Richard S. Finn, Masatoshi Kudo, Heinz-Josef Klümpen, Ho Yeong Lim, Philippe Merle, Masafumi Ikeda, Gianluca Masi, Catherine T. Frenette, Yoon Jun Kim, René Gerolami, Masayuki Kurosaki, Kazushi Numata, Julia Pisarenko, Kirhan Ozgurdal, Shukui Qin
Journal: Journal of Clinical Oncology (2022)

433 Background: Regorafenib improved OS versus placebo in patients with uHCC who progressed on prior sorafenib in the RESORCE trial (Bruix J, 2017). An interim analysis of the observational REFINE study supported the safety and effectiveness of regorafenib in patients with uHCC in real-world clinical practice (Lim HY, 2021). Here we present an exploratory analysis of OS in REFINE by prior treatment. Methods: REFINE is a multicenter study that enrolled patients with uHCC for whom a decision to treat with regorafenib is made by the treating physician prior to enrollment according to the local health authority approved label. The primary objective of this study is safety, including the incidences of treatment-emergent adverse events (TEAEs) and dose modifications due to TEAEs (NCI-CTCAE v4.03). The secondary endpoints include OS, progression-free survival, and treatment duration. Results: Of the 1,031 patients enrolled, 1,008 were evaluable for interim analysis. At baseline, median age was 66 years (range 21–94); 62% of patients were Barcelona Clinic Liver Cancer stage C; 62% had Child–Pugh A disease; and 83% had an Eastern Cooperative Oncology Group performance status of 0 or 1. In total, 99% of patients received prior treatment: 96% had prior sorafenib, 9% had ≥1 prior immunotherapy (most common: nivolumab [50%] and pembrolizumab [21%]), and 6% had a multikinase inhibitor other than sorafenib (lenvatinib [62%]). The majority of patients experienced TEAEs (91%) and drug-related TEAEs (73%). Median OS was 12.9 months (95% confidence interval [CI] 11.4, 14.6). Subgroup analyses of OS by prior treatment are shown (Table). Conclusions: REFINE reflects the changing treatment landscape and supports the safety and effectiveness of regorafenib in real-world patients with uHCC who had prior systemic treatment other than sorafenib, including immunotherapy. This interim analysis suggests that patients who received regorafenib in the second line had longer OS than patients who received regorafenib in the third line and beyond. Clinical trial information: NCT03289273. [Table: see text]
Abstract 130: Developing Optogenetic Tools for Mitochondria and sarco/endoplasmic Reticulum Interactions
Authors: Masayuki Yazawa, Fan Shi
Journal: Circulation Research (2017)

Interaction between mitochondria and sarco/endoplasmic reticulum (SR/ER) is essential for cardiac calcium handling, metabolism and autophagy. Here we present novel light-induced systems to control the interaction between mitochondria and SR/ER in mammalian cardiomyocytes. To develop this system, first we have tested and optimized multiple light-induced hetero dimer domains in mammalian cell lines, HEK 293T and NIH 3T3 cells. Using electron and confocal microscopes with an optimized system, next we confirm that blue light (~450-470nm, shot illumination ~1sec) could induce coupling of SR/ER with mitochondria. In addition, we developed reversible and non-reversible types of light-induced coupling of mitochondria and SR/ER for further applications in human and mouse cardiomyocytes with viral transduction. The new optogenetic tools will help us study the molecular mechanisms underlying cardiac calcium signaling, metabolism and autophagy.
A Phase I Study of Single-Agent Inotuzumab Ozogamicin in Pediatric CD22-Positive Relapsed/Refractory Acute Lymphoblastic Leukemia: Preliminary Results of the ITCC-059 Study
Authors: Erica Brivio, Marta Lopez-Yurda, Cormac Ownes, Cristina Díaz de Heredia, Bella Bielorai, Claudia Rossig, Vincent van der Velden, Anneke C.J. Ammerlaan, Inge M. van der Sluis, Monique L. Den Boer, Ying Chen, Barbara Sleight, Benoit Brethon, Karsten Nysom, Jan Stary, Ingrid Øra, Christiane Chen-Santel, Luciana Vinti, Franco Locatelli, Christian Michel Zwaan
Journal: Blood (2019)
Abstract MP022: Cost-effectiveness of the Non-laboratory Based Framingham Algorithm in Primary Prevention of Cardiovascular Disease: a Simulated Analysis of a Cohort of African American Adults
Authors: Jacob Kariuki, Susan Leveille, Philimon Gona, Eileen Stuart-Shor, Jerry Cromwell
Journal: Circulation (2017)

Background: The non-laboratory based (non-LB) Framingham algorithm, which substitutes body mass index for lipids, has been validated for screening cardiovascular disease (CVD) risk among African Americans (AA). However, its marginal cost and benefit tradeoffs have not been contrasted with the established laboratory based (LB) Framingham algorithm. This study examines the incremental cost-effectiveness ratio (ICER) of a simulated CVD prevention program guided by the non-LB versus LB Framingham algorithm. Methods: We simulated the World Health Organization CVD prevention guidelines on AA participants of the Atherosclerosis Risk in Communities (ARIC) cohort. Treatment intensity was tailored according to absolute CVD risk scores calculated by non-LB and LB Framingham algorithms. Costs were estimated using Medicare fee schedules (diagnostic tests, drugs and visits), Bureau of Labor Statistics (RN wages), and Chapman’s estimates for initial and follow-up costs of managing incident CVD events. Outcomes were assumed to be true positive cases detected at the treatment threshold. ICER was calculated using Drummond’s framework. Results: Among 2690 AA (mean age 53.3 ± 5.8 yrs, 59% female) the simulation under the non-LB vs LB Framingham algorithm had an ICER of -$46,240 per true positive case detected. The average 12-year discounted costs under the LB Framingham algorithm were 18.3% higher ($29,991 vs $25,357) and identified 6.5% fewer cases (309 vs 329) compared to the non-LB Framingham algorithm. Conclusion: The approach guided by the non-LB Framingham algorithm dominated the LB Framingham strategy with respect to both costs and predictive ability. Consequently, the non-LB Framingham algorithm could potentially provide a lower cost but a highly effective tool to address the high burden of CVD in AA and other resource constrained settings.
Low density lipoprotein reduction is associated with C-reactive protein decline in patients with stable coronary disease: The vascular basis study Tracy A. Timms, Scott Kinlay, Paul Ridker, Maureen Clark, M. Carolina Karam, Michael T. Johnstone, William D. Carlson, Alberto Ramirez, Don Lloyd-Jones, Sidney Alexander, Joel Rubenstein, Peter H. Stone. Brigham and Women's Hospital Cardiovascular Division, Boston, MA
Journal: Journal of the American College of Cardiology (2001)
Comprehensive genomic profiling (CGP) of fibrolamellar oncocytic hepatoma (FLO) and conventional hepatocellular carcinomas (HCC): An observational study.
Authors: Aditya V. Shreenivas, Ben George, James P. Thomas, Lindsay Puckett, Sakti Chakrabarti, Musaddiq Awan, Michael Wayne Straza, William A. Hall, Veronica Loy, William S. Rilling, Johnny Hong, Mandana Kamgar, Susan Tsai, T. Clark Gamblin, Amanda Smolock, Kathleen K. Christians, Kali Dougherty, Natalie Danziger, Francisco Durazo, Jeffrey S. Ross
Journal: Journal of Clinical Oncology (2022)

474 Background: FLO is a rare variant of liver cancer that disproportionately affects young adults and is frequently progressive and fatal as it is often detected in a clinically advanced stage. It is seldom associated with cirrhosis of liver, viral hepatitis or other risk factors associated with conventional HCC. Treatment options are largely limited to surgical resection, and there is dearth of effective targeted therapies for FLO. Methods: Comprehensive genomic profiling (CGP) was performed using the Foundation Medicine Inc. (FMI) data base on 63 FLO and 1,793 HCC clinically advanced cases between 6/2013-12/2020 using a hybrid capture-based assay of up to 324 genes a to detect genomic alterations (GA), tumor mutational burden (TMB) and microsatellite instability (MSI). PD-L1 expression in tumor cells (Dako 22C3) was measured by IHC and scored using the tumor proportion score (TPS) method. Results: The FLO patients (pts) were significantly younger than HCC pts (median age 20 vs. 64, respectively) and the male preponderance was similar. The HCC group featured significantly more GA/tumor than FLO group (3.74 vs 1.31 p&lt;.0001). In the currently untargetable GA group, CTNNB1, TERT and TP53 GA were significantly more frequent in HCC than FLO. GA in potentially targetable genes were extremely uncommon in both FLO and HCC with HCC featuring slightly more MTOR pathway targets ( PTEN, TSC2, NF1). GA in DNA damage and repair (DDR) pathway including BRCA2 were infrequent in both groups. GA in targetable kinases including EGFR, ERBB2, ALK, RET and PIK3CA were extremely uncommon in both groups. GA associated with intrahepatic cholangiocarcinoma (IDH1, FGFR2) were extremely uncommon in these tumors. Although the mean TMB was significantly higher in HCC than FLO, overall TMB was low with very few cases having TMB &gt; 10 mutations/Mb. PD-L1 expression was relatively low in both groups. GA in genes associated with immune checkpoint inhibitors (ICPI) drug response like PBRM1, CD274, MDM2, STK11 were rarely identified in both groups. Additional details are illustrated in the table. Conclusions: Comparison of CGP of FLO with HCC illustrates the multifarious nature of these cancers. In HCC, there is a high prevalence of GA in TERT, CTNNB1 and TP53. CGP identified certain targetable GA in the MTOR and DDR pathways and TMB was higher in HCC. These findings warrant further evaluation of clinically advanced FLO and HCC pts by CGP to identify possible targetable genomic pathways. [Table: see text]
Toppling the HAT to Treat Lethal Prostate Cancer
Authors: Reyaz ur Rasool, Ramakrishnan Natesan, Irfan A. Asangani
Journal: Cancer Discovery (2021)

In this issue of Cancer Discovery, Welti and colleagues demonstrate a positive correlation between the expression of the histone acetyltransferase paralogs CBP and p300 with increased androgen receptor (AR) signaling and androgen deprivation therapy resistance in advanced prostate cancer. CCS1477, a selective inhibitor of p300/CBP bromodomain, disrupts AR- and MYC-regulated gene expression, suppresses tumor growth in vivo in multiple castration-resistant prostate cancer xenograft models, and modulates biomarker expression in early clinical evaluation, providing a novel therapeutic approach for AR-addicted advanced prostate cancer.See related article by Welti et al., p. 1118.
Abstract 17385: Endothelium Specific Reduction in Mitochondrial ROS Reverses the Deleterious Effects on Coronary Endothelium Caused by Prolonged Increase in NADPH Oxidase Derived ROS
Authors: Isabella McCormack, Bonnie Colantuono, Melissa Stanley, Frank Sellke, Ruhul Abid
Journal: Circulation (2018)

Introduction: Recent findings from our lab demnstrated that prolonged increase in NADPH oxidase (NOX)-derived ROS results in increased mitochondrial (mito) ROS levels, reduced aspartate/dNTP synthesis, reduced coronary endothelial cell (EC) proliferation, and decreased recovery of post-MI cardiac function. Hypothesis: We hypothesized that endothelium-specific reduction in mitochondrial ROS will reverse the deleterious effects of prolonged NOX-ROS increase by improving mitochondrial function and aspartate/dNTP synthesis. Methods: Tetracycline (Tet)-ON/Tet-OFF binary transgenic mice, Tet-Nox2:VE-Cad-tTA (NOX-OE), were used as a model for endothelium-specific increase in the expression of the catalytic subunit of NADPH oxidase resulting in increased ROS. Mouse heart EC (MHEC) were isolated from Tet-ON and Tet-OFF Tg-Nox2 mice that were exposed to &gt;16 weeks of increased EC-ROS. MHECs were then subject to mitochondrial antioxidants nitroxide (XJB-131) and nanoparticle (CeTiO2) followed by determination of mito-ROS, aspartate/dNTP synthesis, and EC proliferation. NOX-OE was crossbred with SOD-OE to generate a double-transgenic mice with EC-specific overexpression of mitochondrial antioxidant MnSOD (Sod2), Tet-Sod2:Tet-Nox2:VE-Cad-tTA ( SOD-OE ). Both NOX-OE and SOD-OE were subject to myocardial infarction (MI) LAD ligation experiments. Results: Mito-ROS levels were significantly reduced (by &gt;2-fold) in MHEC from SOD-OE compared to NOX-OE. Both dNTP and proliferation were increased in SOD-OE, and also in NOX-EC treated with XJB-131 and CeTiO2. Together, these data suggest that reduction in mito-ROS abrogated negative effects of NOX-ROS in EC. Preliminary data demonstrate that there was an increase in capillary density (by 34± 5.8 %; p&lt;0.05) and angiogenesis (by 2-fold) in SOD-OE post-MI myocardium compared to that of NOX-OE. Infarct sizes and cardiac function between NOX-OE and SOD-OE will be presented. Conclusion: These results suggest that reduction in mito-ROS can abrogate deleterious effects coronary endothelium caused by prolonged exposure to NOX-ROS. EC-specific modulation of mito-ROS may thus help develop therapeutic modalities to improve cardiovascular health and myocardial preservation in the post-MI heart.
Abstract P178: Cost-Effectiveness of Intensive versus Standard Blood Pressure Goals by Baseline Systolic Blood Pressure Levels in SPRINT-Eligible US Adults
Authors: Brandon K Bellows, Adam P Bress, Jordan B King, Natalia Ruiz-Negrón, Rachel Hess, Srinivasan Beddhu, Zugui Zhang, Dan R Berlowitz, William S Weintraub, Andrew E Moran
Journal: Circulation (2017)

Background: In high-risk adults, intensive systolic blood pressure (SBP) goals (&lt;120 mmHg) reduced cardiovascular disease (CVD) events and mortality, when compared to standard SBP goals (&lt;140 mmHg), in the Systolic Blood Pressure Intervention Trial (SPRINT). While average benefit of reduced CVD risk with intensive SBP goals outweighs the average risk of serious adverse events (SAEs) and treatment costs, net intensive SBP goal benefits may vary by baseline SBP. We hypothesized that intensive SBP goals would be cost-effective vs. standard SBP goals when stratified by baseline SBP level in SPRINT-eligible US adults from the payer’s perspective. Methods: Using CVD event, death, and SAE risks, a microsimulation model compared direct healthcare costs and quality-adjusted life-years (QALYs) in the SPRINT intensive and standard SBP goal arms over patients’ remaining lifetimes. Published literature and national estimates were used for model parameters. The model assumed that, after the planned duration of SPRINT, adherence to treatment goals decayed over time. To estimate the effect of baseline SBP on the cost-effectiveness of intensive SBP goals, baseline SBP was stratified into the following groups: 130-139 mmHg, 140-149 mmHg, 150-159 mmHg, 160-169 mmHg, and 170-180 mmHg. Results: With higher baseline SBP, patients in both arms experienced higher rates of CVD events or CVD deaths and accrued higher costs compared with patients starting with lower baseline SBP. However, with higher baseline SBP, there were slightly more incremental QALYs gained with intensive SBP treatment, from 0.29 to 0.31. This led to a modestly better incremental cost-effectiveness ratio (ICER) for intensive vs. standard SBP goals, decreasing from approximately $50,000 to $43,000 per QALY gained as baseline SBP increased. If SPRINT treatment effects and in-trial adherence persisted for the remaining lifetime, the ICER for intensive SBP goals decreased to approximately $25,000-$26,000 per QALY gained across baseline SBP groups. Conclusions: Treatment of all SPRINT-eligible patients led to lifetime cost-effectiveness below accepted willingness-to-pay thresholds and lifetime net benefit and cost-effectiveness varied only modestly by baseline SBP. However, this analysis was based on summary data and did not account for individual patient risks. Multiple predictors, in addition to baseline SBP, may be needed to identify which SPRINT-eligible patients derive maximal benefit from intensive SBP treatment.
Erratum for the Research Article: “Selectins impair regulatory T cell function and contribute to systemic lupus erythematosus pathogenesis” by M. Scherlinger, V. Guillotin, I. Douchet, P. Vacher, A. Boizard-Moracchini, J.-P. Guegan, A. Garreau, N. Merillon, A. Vermorel, E. Ribeiro, I. Machelart, E. Lazaro, L. Couzi, P. Duffau, T. Barnetche, J.-L. Pellegrin, J.-F. Viallard, M. Saleh, T. Schaeverbeke, P. Legembre, M.-E. Truchetet, H. Dumortier, C. Contin-Bordes, V. Sisirak, C. Richez, P. Blanco
Journal: Science Translational Medicine (2021)

In the Research Article “Selectins impair regulatory T cell function and contribute to systemic lupus erythematosus pathogenesis,” there were errors in Fig. 5. The data shown in the graph measuring GMPs per μL (Fig. 5C, right panel) is identical to the graph measuring L-selectin+ GMPs per μL (Fig. 5D, right panel). The data of L-selectin+ GMPs were incorrectly reported in the total GMP plot (Fig. 5C, right panel). This discrepancy in Fig. 5 has now been corrected, and the online PDF and HTML (full text) of have been updated. The legend for Fig. 5 remains unchanged. The corrections do not impact the interpretation of the data or the conclusions of the paper.
GIRFT06: Dermatology high‐cost drug management: pharmacists getting it right first time in COVID‐19
Journal: British Journal of Dermatology (2021)

confirming not making a diagnosis.Twenty-four admissions required input from other specialities, and one patient was transferred to another speciality.There were two readmissions within 1 month of discharge for the same complex multicomorbid patient.Twenty-five (61%) patients were followedup after discharge in dermatology clinics.A further 18 paediatric inpatients were under joint care in this period with the dermatology and paediatric teams.Although dermatology inpatient care is now less often required, owing to advances in therapy, it remains essential for some with severe skin disease, particularly those with multiple comorbidities, who are unable to cope in the community.To manage their complex needs, these patients often require a multidisciplinary approach from many specialities.In addition, many inpatients with skin disease are under the care of other specialities, requiring dermatology specialist input to optimize care and efficient discharge for these patients.Therefore, it is important to plan workforce, job plans and keep service structures to support those with skin diseases requiring inpatient care.
Medical News
Journal: JAMA (1906)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Managing snakebite
Authors: Ravikar Ralph, Mohammad Abul Faiz, Sanjib Kumar Sharma, Isabela Ribeiro, François Chappuis
Journal: BMJ (2022)

What you need to know• Bites from venomous snakes can result in bleeding, paralysis, long term disability, and death • Immobilise the bitten limb when transporting the patient to a medical facility; the universal use of pressure immobilisation is controversial, and tourniquets are not recommended • The 20-minute whole blood clotting test is a simple bedside test to screen for and monitor coagulopathy in resource-limited settings • Assess vital parameters and initiate resuscitation measures if the patient is clinically unstable with signs of bleeding, shock, paralysis, or respiratory distress • Intravenous antivenom is recommended in patients with systemic symptoms; the dose and type depend on likely snake species, local guidelines, and availabilitySnakebite affects between 1.8 to 2.7 million people worldwide each year, and it is estimated to cause between 80 000 and 138 000 deaths. 1 2 A mixture of toxins (venom) is injected into the body following bite by a venomous snake. 3 Envenoming can be a highly dynamic clinical event.Symptoms can progressively worsen to a life-threatening emergency.Snakebites can have long term physical sequelae such as amputation, paralysis and disability, and psychological health consequences. 4 -7 Snakebite envenoming is more common in South and South-East Asia (2 million annually), sub-Saharan Africa (420 000) and Latin America (150 000). 1 2 These regions also report a high burden of deaths from snakebite (100 000, 32 000, and 5000 deaths respectively) possibly due to poor access to medical aid. 1 2 Delayed diagnosis and treatment can worsen prognosis. 8 -11 The World Health Organization recognised snakebite as a neglected tropical disease in 2017 and called for concerted global action to reduce deaths and disability. 12 In this clinical update, we present an approach to evaluation and management of snakebites for primary care providers in resource-limited settings in endemic regions.The principles of management are broadly similar, but it is beyond the scope of this article to cover clinical syndromes and management for the varied snake species globally. Sources and selection criteriaWe searched the Cochrane Library, Google, and PubMed, using the MeSH terms: "(snakebite, diagnosis and treatment guidelines) and (snake, scientific names of individual snake species, snakebite, envenoming, venom, and antivenom)".Research papers and case reports from Latin America, South and South-East Asia, and sub-Saharan Africa were retrieved.There were no language restrictions.Additional articles were obtained by citation tracking of review and original articles.Although the search focused on key papers published in the past five years, older publications of importance have been included.The review also drew from the widely established African and South-East Asian regional guidelines on the treatment and prevention of snakebite envenoming.
COVID-19: fighting panic with information
Authors: None The Lancet
Journal: The Lancet (2020)

As governments and health officials worldwide grapple with the epidemic of severe acute respiratory syndrome coronavirus 2, new developments in the accounting of and response to cases are occurring as part of a swiftly evolving crisis. On Feb 11, 2020, WHO announced an official name for the novel coronavirus disease: coronavirus disease 2019 (COVID-19). After a stabilisation in the number of new cases, on Feb 13, 2020, China reported nearly 15 000 new COVID-19 cases and 242 deaths in a single day in Hubei province.