tbuckley/cabot-search huggingface dataset:
Pharmacokinetics and pharmacodynamics of MEDI4736, a fully human anti-programmed death ligand 1 (PD-L1) monoclonal antibody, in patients with advanced solid tumors.
Authors: Xuyang Song, Min Pak, Carlos Chavez, Meina Liang, Hong Lu, Martin Schwickart, John A. Blake-Haskins, Paul B. Robbins, Xiaoping Jin, Ashok Kumar Gupta, Lorin Roskos, Rajesh Narwal
Journal: Journal of Clinical Oncology (2015)

e14009 Background: MEDI4736 is a human IgG1 mAb that blocks PD-L1 binding to PD-1 and CD-80 with high affinity and selectivity. The primary objectives of this analysis were to assess the pharmacokinetics (PK), pharmacodynamics (PD), and immunogenicity of MEDI4736 in patients with advanced solid tumors. Methods: Data were collected from a Phase 1 study (NCT01693562) designed to evaluate safety, tolerability, and PK following 0.1, 0.3, 1.0, 3.0, and 10 mg/kg every 2 weeks (Q2W) and 15 mg/kg every 3 weeks (Q3W) intravenous doses of MEDI4736. A total of 377 patients provided evaluable PK and soluble PD-L1 (sPD-L1) data. ADA data were available from 386 subjects. PK, sPD-L1, and ADA were measured using validated electrochemiluminescence assays in human serum. Data analysis was performed using Phoenix WinNonlin and GraphPad Prism software. Results: Area under the curve (AUC) increased more than dose proportionally over the dose range of 0.1 to 10 mg/kg Q2W or 15 mg/kg Q3W and approached linearity at ≥ 3 mg/kg Q2W. Accumulation in PK exposure was observed following repeated dosing. No major differences in PK of MEDI4736 were observed among many tumor types evaluated during expansion phase of the study. Soluble PD-L1 was fully suppressed in the majority of patients over the entire dosing interval with doses ≥ 0.3 mg/kg Q2W. Eight of 388 patients (1 patient each in 0.1, 1, 3 and 15 mg/kg and 4 patients in 10 mg/kg) were ADA positive post treatment with an impact on PK and PD in 1 subject (3 mg/kg). Based on preclinical/clinical PK, PD, and safety data, a dose of 10 mg/kg Q2W was selected for the Phase 2/3 studies. Conclusions: MEDI4736 exhibited non-linear (dose-dependent) PK and yielded dose-dependent sPD-L1 suppression. Low incidence (2%) of ADA was observed. A monotherapy dose of 10 mg/kg Q2W is currently being evaluated in multiple tumor types in the expansion phase and Phase 2/3 studies. Clinical trial information: NCT01693562.
The lymphocyte-to-monocyte ratio as a predictor of overall survival in comparison to established systemic markers of inflammation in resectable colorectal cancer.
Authors: Joseph Chan, Connie Irene Diakos, David Chan, Anthony J Gill, Alexander Engel, Stephen John Clarke
Journal: Journal of Clinical Oncology (2016)

593 Background: The prognostic significance of systemic inflammatory markers in colorectal cancer (CRC) such as the neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR) and modified Glasgow prognostic score (mGPS) have been well defined in literature. In addition, commonly utilized genetic markers such as combined BRAF-MMR status have also been found to be prognostic. Recent evidence suggests that the lymphocyte-to-monocyte ratio (LMR) may hold prognostic utility in CRC. However the LMR has still not been clearly defined in either its clinical utility or in comparsion to other established biomarkers. Methods: Consecutive patients from the Northern Sydney Local Health District undergoing curative surgical resection for colorectal cancer from January 1998 to December 2012 were collated. Of the 3281 patients identified, 1623 patients with complete pre-operative blood counts, BRAF-MMR IHC and clinicopathologic data were further analysed. Variables were analysed in univariate and then a multivariate cox regression model using forwards conditional method looking for association with overall survival (OS). Results: In multivariate analysis of 1623 patients, elevated LMR was associated with better overall survival (OS) (HR 0.565, 95% CI: 0.475-0.672, P &lt; 0.001) independent of age (P &lt; 0.001), T stage (P &lt; 0.001), N stage (P &lt; 0.001) and grade (P = 0.049). Other biomarkers such as NLR, PLR and combined BRAF-MMR status were not significantly associated with OS. In multivariate subgroup analysis of 389 patients with available mGPS data, LMR remained the only independently prognostic biomarker (HR 0.620, 95% CI: 0.437-0.880, p = 0.007). Conclusions: The LMR is an independent predictor of OS in CRC patients undergoing curative resection. Furthermore, the LMR appears to be superior to previously established biomarkers.
Quality Health Care
Authors: G L Laffel, D M Berwick
Journal: JAMA (1993)

There is a fragile connection between the new knowledge generated by medical research and the care given to patients at the bedside. Physicians may not hear about or accept new findings; they may not know how or when to use them; and the health systems in which they practice may not support the implementation of new knowledge. In the past year, several research groups confirmed the existence of this gap. For example, Listernick's group<sup>1</sup>reported the cases of 10 children who presented to the emergency department of a tertiary care pediatric hospital with clinical manifestations of a disease (three had 21-hydroxylase deficiency and seven had hemoglobinopathy) for which their mothers had received proper antenatal screening and for whom the state screening laboratory had notified physicians about the abnormality. Delays in treatment were caused not by the lack of medical knowledge, but by breakdowns in the follow-up process. Classen and
Detection of Multiple Double-Stranded DNA Viruses after Cord Blood Transplantation Is Frequent and Persistent
Authors: Joshua A Hill, Bryan T Mayer, Hu Xie, Wendy M Leisenring, Filippo Milano, Colleen Delaney, Meei-Li Huang, Terry L Stevens-Ayers, Keith R Jerome, Garrett Nichols, Danielle M Zerr, Joshua T Schiffer, Michael Boeckh
Journal: Blood (2015)
Abstract 13122: Hax1 Mediates Hippo Pathway to Enhance Therapeutic Effect of Sca1+ Cardiac Stem Cell Against Myocardial Ischemia
Authors: Wenfeng Cai, Lei Wang, Wei Huang, Christian Paul, Meifeng Xu, Ronald W Millard, Yigang Wang
Journal: Circulation (2015)

Background: The Hippo pathway can regulate the fate and metabolic function of stem/progenitor cells through a kinase cascade that impinges on the transcription of growth-regulatory genes. This stud...
Physicians Advising Investment Firms
Authors: Lindsay A Hampson, Ezekiel J Emanuel
Journal: JAMA (2005)

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 Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More 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) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2022 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
Response to Letter Regarding Article, “Intracoronary Versus Intravenous Administration of Abciximab in Patients With ST-Segment Elevation Myocardial Infarction Undergoing Primary Percutaneous Coronary Intervention With Thrombus Aspiration: The Comparison of Intracoronary Versus Intravenous Abciximab Administration During Emergency Reperfusion of ST-Segment Elevation Myocardial Infarction (CICERO) Trial”
Authors: Youlan L. Gu, Marthe A. Kampinga, Wouter G. Wieringa, Marieke L. Fokkema, Hans L. Hillege, Ad F.M. van den Heuvel, Eng-Shiong Tan, Gabija Pundziute, Rik van der Werf, Siyrous Hoseyni Guyomi, Iwan C.C. van der Horst, Bart J.G.L. de Smet, Maarten W. Nijsten, Felix Zijlstra
Journal: Circulation (2011)
Folate receptor targeted three-layered micelles and hydrogels for gene delivery to activated macrophages
Authors: Mariam Mohammadi, Ying Li, Daniel G. Abebe, Yuran Xie, Rima Kandil, Teresa Kraus, Nardhy Gomez-Lopez, Tomoko Fujiwara, Olivia M. Merkel
Journal: Journal of Controlled Release (2016)
Molecular predictors of response in patients with myeloid neoplasms treated with lenalidomide
Authors: E Negoro, T Radivoyevitch, C Polprasert, V Adema, N Hosono, H Makishima, B Przychodzen, C Hirsch, M J Clemente, A Nazha, V Santini, K L McGraw, A F List, F Sole, M A Sekeres, J P Maciejewski
Journal: Leukemia (2016)
Metastatic Melanoma: Insights Into the Evolution of the Treatments and Future Challenges
Authors: Antoine Millet, Anthony R. Martin, Cyril Ronco, Stéphane Rocchi, Rachid Benhida
Journal: Medicinal Research Reviews (2016)

Melanoma is the deadliest form of skin cancer. While associated survival prognosis is good when diagnosed early, it dramatically drops when melanoma progresses into its metastatic form. Prior to 2011, the favored therapies include interleukin-2 and chemotherapies, regardless of their low efficiency and their toxicity. Following key biological findings, two new types of therapy have been approved. First, there are the targeted therapies, which rely on small molecule B-Raf and MEK inhibitors and allow the treatment of patients with B-Raf mutated melanoma. Second, there are the immunotherapies, with anti-CTLA-4 and anti-PD-1 antibodies that are used for patients harboring a B-Raf wild-type status. Both approaches have significantly improved patient survival, compared with alkylating agents, in the treatment of unresectable melanoma. Herein, we review the evolution of the treatment of melanoma starting from early discoveries to current therapies. A focus will be provided on drug discovery, synthesis, and mode of action of relevant drugs and the future directions of the domain to overcome the emergence of the resistance events.
Differential Antigenic Targets of Anti-Tumor Immune Response and Selective Immunity to Stem Cell Associated Group B SOX Proteins in Preneoplastic Versus Malignant Gammopathy.
Authors: Radek Spisek, Lyn-Chi Chen, Matthew Scanlan, Andrew Simpson, Gerd Ritter, Erik Rasmussen, Jason McCoy, Anne Murray, Joseph Krasovsky, Brian Durie, John Crowley, Amitabha Mazumder, Sundar Jagannath, Bart Barlogie, Ali Gure, Madhav Dhodapkar
Journal: Blood (2005)
Response to: Preventing penalty corner injuries and head trauma in field hockey—time to consider the power play?
Authors: Udo Rolle, Peter Wefers Bettink
Journal: British Journal of Sports Medicine (2016)

In their recent editorial, Batten et al 1 discuss the high risk of injury during penalty corners in field hockey. The authors note the potential risk of head injuries caused by the frequently used drag flicks during penalty corners in field hockey and recommend the removal of the penalty corner and a change involving the use of a specialised power play. The authors consequently recommend further injury research on field hockey penalty corners.

We do not entirely agree with this editorial and especially with its strong conclusion. …
Influence of Chronic Kidney Disease on Warfarin Therapy for Atrial Fibrillation
Authors: Muthiah Vaduganathan, Stephen J. Greene
Journal: JAMA (2014)

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
Confirmation of high prevalence of BAP1 inactivation in mesothelioma.
Authors: Andrea Cercek, Marjorie Glass Zauderer, Andreas Rimner, Valerie W. Rusch, Prasad S. Adusumili, Garrett Michael Nash, Julija Hmeljak, Marc Ladanyi, Lee M. Krug
Journal: Journal of Clinical Oncology (2015)

7564 Background: Efforts to elucidate tumorigenic mutations in mesothelioma are essential to advance therapy. Prior efforts to characterize the molecular heterogeneity of this disease have been limited by sample condition and testing platforms. Herein, we describe efforts to prospectively test patients using next-generation sequencing with matched patient germline controls. Methods: Sequential mesothelioma patients were approached for consent to our IRB protocol NCT01775072 to perform MSK-IMPACT (Integrated Mutation Profiling of Actionable Cancer Targets), a comprehensive molecular profiling platform based on solution-phase exon capture and next generation sequencing to detect somatic genetic alterations in FFPE tumor specimens. MSK-IMPACT involves hybridization capture and deep sequencing of all protein-coding exons of 341 key cancer-associated genes, including all genes that are druggable by approved therapies or are targets of experimental therapies being investigated in clinical trials at MSKCC. Results: 40 patients with mesothelioma underwent MSK-IMPACT testing (see Table 1). 6 samples had low tumor content and in 3 of those no alterations were identified. In 2 samples with sufficient tumor content, no alterations were identified. Among 37 samples with results, BAP1 was the most common alteration (57%). Conclusions: Using MSK-IMPACT, BAP1 inactivation is the most common alteration. Other aberrations previously reported at high frequency were identified but albeit at lower frequencies (NF2 and p16, previously reported as 40% and 75% respectively). For multiple samples with deep coverage, no alterations were identified. The high incidence of BAP1 mutations in this systematic testing makes this pathway ideal for developing and testing targeted therapies.
How Many Lymph Nodes Are Enough? Assessing the Adequacy of Lymph Node Yield for Papillary Thyroid Cancer
Authors: Timothy J. Robinson, Samantha Thomas, Michaela A. Dinan, Sanziana Roman, Julie Ann Sosa, Terry Hyslop
Journal: Journal of Clinical Oncology (2016)

Purpose Patients who undergo surgery for papillary thyroid cancer with only a limited lymph node examination are thought to be at risk for potentially harboring occult disease. However, this risk has not been objectively quantified and may have implications for subsequent management and surveillance. Methods Data from the National Cancer Database (1998 to 2012) were used to characterize the distribution of nodal positivity of adult patients diagnosed with localized ≥ 1-cm papillary thyroid cancer who underwent thyroidectomy with one or more lymph nodes (LNs) examined. A β-binomial distribution was used to estimate the probability of occult nodal disease as a function of total number of LNs examined and pathologic tumor stage. Results A total of 78,724 patients met study criteria; 38,653 patients had node-positive disease. The probability of falsely identifying a patient as node negative was estimated to be 53% for patients with a single node examined and decreased to less than 10% when more than six LNs were examined. To rule out occult nodal disease with 90% confidence, six, nine, and 18 nodes would need to be examined for patients with T1b, T2, and T3 disease, respectively. Sensitivity analyses limited to patients likely undergoing prophylactic central neck dissection resulted in three, four, and eight nodes needed to provide comparable adequacy of LN evaluation. Conclusion To our knowledge, our study provides the first empirically based estimates of occult nodal disease risk in patients after surgery for papillary thyroid cancer as a function of primary tumor stage and number of LNs examined. Our estimates provide an objective guideline for evaluating adequacy of LN yield for surgeons and pathologists in the treatment of papillary thyroid cancer, and especially intermediate-risk disease, for which use of adjuvant radioactive iodine and surveillance intensity are not currently standardized.
Change in plasma volume and prognosis in acute decompensated heart failure: an observational cohort study
Authors: Sarah R Hudson, Daniel Chan, Leong L Ng
Journal: Journal of the Royal Society of Medicine (2016)

This study aimed to develop an inexpensive, readily available prognostic indicator in acute decompensated heart failure patients to guide management and improve outcome. Prognostic biomarkers for heart failure exist but are expensive and not routinely performed. Increasing plasma volume has been associated with worse outcomes.UK University Teaching Hospital.Observational Cohort study.967 patients with acute decompensated heart failure.Haemoglobin and haematocrit were measured at admission and discharge and were used to calculate the plasma volume change using the Strauss-Davis-Rosenbaum formula.Endpoints were death and the composite of death and/or heart failure hospitalisation. Change in plasma volume was added to ADHERE scoring to determine predictive value.During follow-up, 536 died and 626 died or were hospitalised with heart failure. Multivariable Cox models showed change in plasma volume was an independent predictor of mortality (hazard ratio (HR) [95% confidence interval (CI)]: 1.150 [1.031-1.283], p = 0.012) and death or heart failure hospitalisation (HR: 1.138 [1.029-1.259], p = 0.012). Kaplan-Meier analysis of change in plasma volume tertiles for outcome measures showed significant difference for the top tertile compared to the lower two. Multivariable analysis of change in plasma volume with ADHERE scoring showed change in plasma volume change remained an independent predictor of death (HR: 1.138 [1.026-1.261], p = 0.015) and death or heart failure hospitalisation (HR: 1.129 [1.025-1.243], p = 0.014).Change in plasma volume over an admission can be used for prognostication and adds value to the ADHERE score. Change in plasma volume can be easily and inexpensively calculated from routine blood tests. Clinically, this may facilitate targeted treatment of acute decompensated heart failure patients at greatest risk.
Cardiovascular Benefits of Wearing Particulate-Filtering Respirators: A Randomized Crossover Trial
Authors: Jingjin Shi, Zhijing Lin, Renjie Chen, Cuicui Wang, Changyuan Yang, Jing Cai, Jingyu Lin, Xiaohui Xu, Jennifer A. Ross, Zhuohui Zhao, Haidong Kan
Journal: Environmental Health Perspectives (2016)

Practical approaches to protect individuals from ambient particulate matter (PM) are urgently needed in developing countries. Evidence on the health benefits of wearing particulate-filtering respirators is limited.We evaluated the short-term cardiovascular health effects of wearing respirators in China.A randomized crossover trial was performed in 24 healthy young adults in Shanghai, China in 2014. The subjects were randomized into two groups and wore particulate-filtering respirators for 48 hr alternating with a 3-week washout interval. Heart rate variability (HRV) and ambulatory blood pressure (BP) were continuously monitored during the 2nd 24 hr in each intervention. Circulating biomarkers were measured at the end of each intervention. Linear mixed-effect models were applied to evaluate the effects of wearing respirators on health outcomes.During the intervention periods, the mean daily average concentration of PM with an aerodynamic diameter < 2.5 μm (PM2.5) was 74.2 μg/m3. Compared with the absence of respirators, wearing respirators was associated with a decrease of 2.7 mmHg [95% confidence interval (CI): 0.1, 5.2 mmHg] in systolic BP and increases of HRV parameters, including 12.5% (95% CI: 3.8%, 21.2%) in high frequency (HF) power, 10.9% (95% CI: 1.8%, 20.0%) in the root mean square of the successive differences, and 22.1% (95% CI: 3.6%, 40.7%) in the percentage of normal RR intervals with duration > 50 msec different from the previous normal RR interval (pNN50). The presence of respirators was also associated with a decrease of 7.8% (95% CI: 3.5%, 12.1%) in the ratio of low frequency (LF)/HF power.Short-term wearing of particulate-filtering respirators may produce cardiovascular benefits by improving autonomic nervous function and reducing BP. Citation: Shi J, Lin Z, Chen R, Wang C, Yang C, Cai J, Lin J, Xu X, Ross JA, Zhao Z, Kan H. 2017. Cardiovascular benefits of wearing particulate-filtering respirators: a randomized crossover trial. Environ Health Perspect 125:175-180; http://dx.doi.org/10.1289/EHP73.
P0743 : Interleukin-6 is associated with liver fibrosis in HCV-infected patients with alcohol abuse
Authors: L.D. Silva, Y.G.G. Giampietro, B.D.M. Theobaldo, L.R. da Cunha, R. Teixeira, G.A. Rocha, D.M.D.M. Queiroz, O.A. Martins Filho, F.S. Neves
Journal: Journal of Hepatology (2015)
Association of insulin-like growth factor-1 receptor (IGF1R) expression in circulating tumor cells (CTCs) with E-cadherin (E-CAD) expression and improved survival in breast cancer (BC).
Authors: Sofia Agelaki
Journal: Journal of Clinical Oncology (2016)

e23041 Background: Components of the insulin growth factor (IGF) system are deregulated and IGF1R overexpression is common in BC. E-CAD has a prominent role in epithelial differentiation. We investigated the expression of IGF1R in CTCs from patients (pts) with BC and evaluated its correlation with E-CAD expression and survival. Methods: Cytospins of peripheral blood mononuclear cells, obtained from early (n = 62) and metastatic (n = 100) pts before adjuvant and 1st-line chemotherapy, respectively, were analysed. Cytospins were double- or triple- stained with cytokeratin (CK) (A45-B/B3) and IGF1R or with CK, IGF1R and E-CAD antibodies, respectively, and evaluated by immunofluorescent microscopy (Ariol system). Results: CTCs were detected in 20 (32%) early and 45 (45%) metastatic BC pts. IGF1R(+) CTCs were more prominent in early than metastatic BC (84% vs 64% of total CTCs, p = 0.0007) and IGF1R(-) CTCs in metastatic BC (36% vs 16%, p = 0.0001). Among early pts, 80% had exclusively IGF1R(+) CTCs, 20% had both IGF1R(+) and IGF1R(-) and none exclusively IGF1R(-) CTCs. The respective values in metastatic pts were 42%, 33% and 25% (p = 0.005). Early BC pts with exclusively IGF1R(+) CTCs had significantly higher DFS (p = 0.0283) and OS (p = 0.0016) compared to those with both IGF1R(+) and IGF1R(-) CTCs. Triple IF staining revealed that IGF1R(-)/E-CAD(-) CTCs prevailed in metastatic vs early BC (54% vs 6% of total CTCs, p = 0.0167). Among early BC pts, 67% had exclusively IGF1R(+)/E-CAD(+) CTCs, 33% also had IGF1R(-)/E-CAD(-) and none had exclusively IGF1R(-)/E-CAD(-) CTCs. The respective values in metastatic pts were 15%, 77% and 8% (p = 0.03). Conclusions: IGF1R(+) CTCs are detected more frequently in early BC. IGF1R and E-CAD are co-expressed at the single CTC level and progression from early to metastatic disease is associated with loss of expression of both proteins. These results suggest that IGF1R expression on CTCs infers a less aggressive phenotype possibly through E-CAD. Moreover, IGFIR expression in CTCs is associated with improved survival in early BC.