tbuckley/cabot-search huggingface dataset:
Cost benefit analysis of laboratory directed chemotherapy for advanced pancreatic cancer in U.S. and Brazilian patients.
Authors: Robert Alan Nagourney, Rene Claudio Gansl, Gilberto Lopes, Antonio C. Buzaid, Fernando C. Maluf, Paulo D'Amora, Nise Hitomi Yamaguchi, Fabricio Colacino Silva, Andre Nebel De Mello
Journal: Journal of Clinical Oncology (2015)

e17782 Background: Precision medicine offers improved response rates (RR) & cost containment. Pancreatic cancer (PC) with Stage IV 5-yr survival of 1-2% is ideal for strategies that pre-select responsive patients (pts) yet actionable molecular targets are few. Phenotypic assays, with the capacity to examine cytotoxic & targeted agents, the subject of prior meta-analysis (Apfel, Proc. ASCO, 2013), provided a 2.04 fold improvement in (RR) (p < 0.001) & 1.44 fold improvement in 1-yr survival (P = 0.02) in 2581 pts. Methods: We applied Ex Vivo Analysis of Programmed Cell Death (EVA/PCD) (Nagourney, Anticancer Res, 2012) in 23 US & Brazilian pt. tumors to identify the most active drugs, then used literature (RR) of standard PC regimens & hospital pharmacy charges/2 cycles ($ or $R/mg) @ 1.7 m2 (BSA) for predictions. Results: Drug selection frequency (N/%), RR (post-test) & cost/2-cycles reveal: CDDP + Gemcitabine 4/23 (17.9%); RR = 40.8%; $534/R$ 5748; FOLFIRINOX 8/23(37.7%) RR = 63.4%, $2988/R$27,592; GTX 2/23(8.6%) RR = 40.8%; $6538/R$31,776; nab-Paclitaxel + Gemcitabine 3(13%) RR = 46.9%, $13,480/$R 239,548; CDDP + Gemcitabine + Capecitabine 4/23 (17.9%) RR = 40.8% $2838/R$31,948; 5-FU 2(8.6%) RR = 20% $306/R$10,448. Costs include EVA/PCD @$4000/pt. ($92,000/23) but no growth factors, anti-emetics, infusion pumps or hospital stays. As nab-Paclitaxel use in Brazil is off label, skewing costs, the cost/response analyses use only US $ in final comparisons. Weighted RR for EVA/PCD selected drugs = 47.6% at aggregate 2-cycle costs for all 23 (+ EVA/PCD) = $184,096 ($16,736/response), compared with FOLFIRINOX, RR = 31% aggregate 2-cycle cost $68,724 ($9817/response) and nab-Paclitaxel + Gemcitabine, RR = 23%, aggregate 2-cycle cost $310,040 ($62,008/response). Conclusions: Clinically validated drug selection methods can provide superior RR in PC at comparable or lower costs/response. As a non-recurring cost, EVA/PCD savings improve over successive cycles. Including growth factors & toxicity of intensive regimens enhances EVA/PCD savings. Finally, phenotypic platforms like EVA/PCD have the potential to improve pt. selection, contain costs, reduce futile care & streamline drug discovery.
The Use of Biomarkers in Early Clinical Trials at the NCI
Authors: Joseph Tomaszewski
Journal: Clinical Cancer Research (2007)

ED03-01   The NCI has embarked on a new program utilizing the FDA’s Exploratory IND (X-IND) Guidance to develop molecularly targeted oncology drugs in a more comprehensive fashion than is typically performed in most preclinical drug development programs. The fundamental principles of this program are defined in a paper by Kummar et al. (1). The concept is to use the X-IND guidance using pharmacologically active doses (not micro-doses) to more fully evaluate potential therapeutics at an earlier time point in clinical development to determine if continued development is warranted. Thus, selection of appropriate pharmacodynamic (PD) marker(s) and mouse tumor models is key to this process and requires a more complete understanding of the pathways involved and how inhibiting them contributes to the efficacy of the compound in various tumor models. The NCI has created an early drug development program (Phase  and where required, Phase I) in which the development of qualified, SOP-driven PD assays are a requirement and are key to the success of the program.  In preclinical studies, the development of appropriate assays, both pharmacokinetics (PK) and PD, takes place at an earlier time point and are used to define the preclinical studies and the clinical trial design. The preclinical efficacy studies that are performed in this program do not simply measure tumor size and body weight loss, but are intricately designed efficacy/PK/PD studies with multiple dose levels, time points and end points. The objective of these studies is to interrogate the target and determine what linkage exists between efficacy and plasma or tumor drug levels and the selected PD end points. The data derived from these studies permit a greater understanding of these relationships using assays that are highly reliable with a small coefficient of variation. As a result, more defined questions can be asked and ultimately answered in a relatively small clinical trail with data that is obtained in real time.  In our first Phase  with Abbott’s PARP inhibitor, ABT-888, we developed an ELISA to measure the inhibition of PAR in both tumor and PBMCs as a surrogate for tumor. This assay was standardized so that it consistently produced a low LLQ and coefficient of variation over a 4-log concentration range. With as few as six patients, we were able to determine that we could achieve our targeted plasma concentration that was previously linked to a statistically significant PD endpoint in animal studies; and achieve our target of 50% or greater inhibition of PAR in both tumor biopsies and the surrogate compartment, PBMCs. As a result, this data was used to more intelligently design more comprehensive Phase I combination trials in which additional PD end points will be evaluated. The conduct of this trial prior to Phase I did not cause any delay in the Phase I program.  References  1. Kummar S. Compressing drug development timelines in oncology using phase 0 trials. Nature Rev Cancer 2007;( 7): 131-9.
A Phase 2a dose‐escalation study of the safety, tolerability, pharmacokinetics and haemodynamic effects of <scp>BMS</scp>‐986231 in hospitalized patients with heart failure with reduced ejection fraction
Authors: Cristina Tita, Edward M. Gilbert, Adrian B. Van Bakel, Jacek Grzybowski, Garrie J. Haas, Mohammad Jarrah, Stephanie H. Dunlap, Stephen S. Gottlieb, Marc Klapholz, Parag C. Patel, Roman Pfister, Tim Seidler, Keyur B. Shah, Tomasz Zieliński, Robert P. Venuti, Douglas Cowart, Shi Yin Foo, Alexander Vishnevsky, Veselin Mitrovic
Journal: European Journal of Heart Failure (2017)

Abstract Aims This study was designed to evaluate the safety, tolerability and haemodynamic effects of BMS ‐986231, a novel second‐generation nitroxyl donor with potential inotropic, lusitropic and vasodilatory effects in patients hospitalized with decompensated heart failure and reduced ejection fraction ( HFrEF ). Methods and results Forty‐six patients hospitalized with decompensated HFrEF were enrolled into four sequential dose‐escalation cohorts in this double‐blind, randomized, placebo‐controlled Phase 2a study. Patients with baseline pulmonary capillary wedge pressure ( PCWP ) of ≥20 mmHg and a cardiac index of ≤2.5 L/min/m 2 received one 6‐h i.v. infusion of BMS ‐986231 (at 3, 5, 7 or 12 µg/kg/min) or placebo. BMS ‐986231 produced rapid and sustained reductions in PCWP , as well as consistent reductions in time‐averaged pulmonary arterial systolic pressure, pulmonary arterial diastolic pressure and right atrial pressure. BMS ‐986231 increased non‐invasively measured time‐averaged stroke volume index, cardiac index and cardiac power index values, and decreased total peripheral vascular resistance. There was no evidence of increased heart rate, drug‐related arrhythmia or symptomatic hypotension with BMS ‐986231. Analyses of adverse events throughout the 30‐day follow‐up did not identify any toxicities specific to BMS ‐986231, with the potential exception of infrequent mild‐to‐moderate headaches during infusion. There were no treatment‐related serious adverse events. Conclusions BMS ‐986231 demonstrated a favourable safety and haemodynamic profile in patients hospitalized with advanced heart failure. Based on preclinical data and these study's findings, it is possible that the haemodynamic benefits may be mediated by inotropic and/or lusitropic as well as vasodilatory effects. The therapeutic potential of BMS ‐986231 should be further assessed in patients with heart failure.
A Comparison of Fibroscan (Transient Ultrasound Elastography) and Liver Biopsy Results in the Assessment of Fibrosis and Cirrhosis in Patients with Chronic Liver Disease
Authors: D McEnroy, F MacCarthy, J Lee
Journal: Endoscopy (2006)

Aims: An accurate and reproducible non-invasive measurement of liver fibrosis would be clinically helpful. This study compares the FibroScan (transient ultrasound elastography) and liver biopsy results for the assessment of fibrosis and cirrhosis in chronic liver disease.
Maternal Obesity and Cerebral Palsy in Offspring
Authors: Yong-Jiang Li, Ya-Min Li
Journal: JAMA (2017)

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 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
Effects of high-intensity strength training on multiple risk factors for osteoporotic fractures. A randomized controlled trial
Authors: M. E. Nelson
Journal: JAMA (1994)

<h3>Objective.</h3> —To determine how multiple risk factors for osteoporotic fractures could be modified by high-intensity strength training exercises in postmenopausal women. <h3>Design.</h3> —Randomized controlled trial of 1-year duration. <h3>Setting.</h3> —Exercise laboratory at Tufts University, Boston, Mass. <h3>Population.</h3> —Forty postmenopausal white women, 50 to 70 years of age, participated in the study; 39 women completed the study. The subjects were sedentary and estrogen-deplete. <h3>Interventions.</h3> —High-intensity strength training exercises 2 days per week using five different exercises (n=20) vs untreated controls (n=19). <h3>Main Outcome Measures.</h3> —Dual energy x-ray absorptiometry for bone status, one repetition maximum for muscle strength, 24-hour urinary creatinine for muscle mass, and backward tandem walk for dynamic balance. <h3>Results.</h3> —Femoral neck bone mineral density and lumbar spine bone mineral density increased by 0.005±0.039 g/cm<sup>2</sup>(0.9%±4.5%) (mean±SD) and 0.009±0.033 g/cm<sup>2</sup>(10%±3.6%), respectively, in the strength-trained women and decreased by -0.022±0.035 g/cm<sup>2</sup>(-2.5%±3.8%) and -0.019±0.035 g/cm<sup>2</sup>(-1.8%±3.5%), respectively, in the controls (<i>P</i>=.02 and.04). Total body bone mineral content was preserved in the strength-trained women (+2.0±68 g; 0.0%±3.0%) and tended to decrease in the controls (-33+77 g; -1.2%±3.4%,<i>P</i>=.12). Muscle mass, muscle strength, and dynamic balance increased in the strength-trained women and decreased in the controls (<i>P</i>=.03 to &lt;.001). <h3>Conclusions.</h3> —High-intensity strength training exercises are an effective and feasible means to preserve bone density while improving muscle mass, strength, and balance in postmenopausal women. (<i>JAMA</i>. 1994;272:1909-1914)
Erratum: Corrigendum: Opportunities and challenges in modeling human brain disorders in transgenic primates
Authors: Charles Jennings, Rogier Landman, Yang Zhou, Jitendra Sharma, Julia Hyman, J Anthony Movshon, Zilong Qiu, Angela Roberts, Anna Wang Roe, Xiaoqin Wang, Huihui Zhou, Liping Wang, Feng Zhang, Robert Desimone, Guoping Feng
Journal: Nature Neuroscience (2017)
Low-Fat Dietary Pattern and Breast Cancer Mortality in the Women’s Health Initiative Randomized Controlled Trial
Authors: Rowan T. Chlebowski, Aaron K. Aragaki, Garnet L. Anderson, Cynthia A. Thomson, JoAnn E. Manson, Michael S. Simon, Barbara V. Howard, Thomas E. Rohan, Linda Snetselar, Dorothy Lane, Wendy Barrington, Mara Z. Vitolins, Catherine Womack, Lihong Qi, Lifang Hou, Fridtjof Thomas, Ross L. Prentice
Journal: Journal of Clinical Oncology (2017)

Purpose Earlier Women's Health Initiative Dietary Modification trial findings suggested that a low-fat eating pattern may reduce breast cancers with greater mortality. Therefore, as a primary outcome-related analysis from a randomized prevention trial, we examined the long-term influence of this intervention on deaths as a result of and after breast cancer during 8.5 years (median) of dietary intervention and cumulatively for all breast cancers diagnosed during 16.1 years (median) of follow-up. Patients and Methods The trial randomly assigned 48,835 postmenopausal women with normal mammograms and without prior breast cancer from 1993 to 1998 at 40 US clinical centers to a dietary intervention with goals of a reduction of fat intake to 20% of energy and an increased intake of fruits, vegetables, and grains (40%; n = 19,541) or to a usual diet comparison (60%; n = 29,294). Results In the dietary group, fat intake and body weight decreased (all P < .001). During the 8.5-year dietary intervention, with 1,764 incident breast cancers, fewer deaths occurred as a result of breast cancer in the dietary group, which was not statistically significant (27 deaths [0.016% per year] v 61 deaths [0.024% per year]; hazard ratio [HR], 0.67; 95% CI, 0.43 to 1.06; P = .08). During the same period, deaths after breast cancer (n = 134) were significantly reduced (40 deaths [0.025% per year] v 94 deaths [0.038% per year]; HR, 0.65; 95% CI, 0.45 to 0.94; P = .02) by the dietary intervention. During the 16.1-year follow-up, with 3,030 incident breast cancers, deaths after breast cancer also were significantly reduced (234 deaths [0.085% per year] v 443 deaths [0.11% per year]; HR, 0.82; 95% CI, 0.70 to 0.96; P = .01) in the dietary group. Conclusion Compared with a usual diet comparison group, a low-fat dietary pattern led to a lower incidence of deaths after breast cancer.
Hemopoietic stem cell allogeneic transplantation (HSCT)using a reduced conditioning regimen: A single centre experience
Authors: Rosanna Scimè, Anna M. Cavallaro, Alessandra Santoro, Stefania Tringali, Alessandro Indovina, Raimondo Marcenö, Maria Pagano, Daniela Polizzi, Ignazio Majolino
Journal: Blood (2000)
Occurrence of ALK fusions in cancers other than non-small cell lung cancer in a wide variety of tumor types and response to anti-ALK targeted therapy.
Authors: Jeffrey S. Ross, Siraj Mahamed Ali, Julia Andrea Elvin, Alexa Betzig Schrock, James Suh, Jo-Anne Vergilio, Shakti Ramkissoon, Eric Allan Severson, Sugganth Daniel, David Fabrizio, Garrett Michael Frampton, Vincent A. Miller, Philip J. Stephens, Laurie M. Gay
Journal: Journal of Clinical Oncology (2017)

11595 Background: Genomic fusions of the anaplastic lymphoma kinase gene ( ALK) are an established therapy target for patients with non-small cell lung cancer (NSCLC), but are not well-characterized in non-NSCLC malignancies. Methods: Comprehensive genomic profiling (CGP) of 92,784 clinically advanced malignancies was performed using a hybrid-capture, adaptor ligation based NGS assay to a mean coverage depth of &gt;600X. Tumor mutational burden (TMB) was calculated from a minimum of 1.1 Mb of sequenced DNA. Results: 17,127/92,784 (18.5%) were NSCLC and 75,657 (81.5%) were non-NSCLC. Of the 697 (0.8%) of cases with ALK fusions, 554 (79%) were identified in NSCLC and 143 (21%) in non-NSCLC including 67 carcinomas; 39 sarcomas including 30 non-uterine and uterine leiomyosarcomas and inflammatory myofibroblastic tumors; 24 in hematolymphoid malignancies including non-Hodgkins lymphomas, myelomas and histiocytic malignancies; 3 in gliomas; 2 each in mesotheliomas, neuroblastomas and undifferentiated malignancies and 1 in melanoma. ALK fusions were significantly more frequently identified in NSCLC (3.2%) than in non-NSCLC (p&lt;0.0001). The non-NSCLC ALK fusion positive patients were significantly older (p&lt;0.0001) and more often female (p&lt;0.0001) than the NSCLC ALK fusion positive patients. At 84%, the more frequent finding of EML4 as the fusion partner in the NSCLC patients versus non-NSCLC patients at 31% was significant (p&lt;0.0001). ALK fusion positive non-NSCLC had significantly lower TMB (mean 5.01 mutations/Mb) than non- ALK altered non-NSCLC (p=0.006). Non-NSCLC ALKfusion positive cases responding to ALK inhibitors will be presented. Conclusions: In non-NSCLC patients ALK fusions are rare and found in both epithelial and mesenchymal malignancies. Initial evidence strongly suggests that anti-ALK therapies can be effective in ALK fusion driven non-NSCLC .
Comparison of Standard Assays (Serum Immunofixation and Protein Electrophoresis) with Hevylite Assay in Patients with Multiple Myeloma
Authors: Hani Hassoun, Rosalynn Ruiz, Murata Kazunori, Kathleen Azzi, Sean Devlin, Brittany Cooper, Nikoletta Lendvai, Heather Landau, Alexander M. Lesokhin, David J Chung, Sham Mailankody, Neha S Korde, Sergio A. Giralt, Ola Landgren
Journal: Blood (2016)
Selecting patients with metastatic colorectal cancer for treatment with temozolomide using proteomic analysis of MGMT
Authors: Sarit Schwartz, Fabiola Cecchi, Yuan Tian, Kerry Scott, Maria Di Bartolomeo, Federica Morano, Giovanni Fucà, Antonia Martinetti, Filippo de Braud, Francesca Dominoni, Massimo Milione, Alessandra Calegari Maria, Armando Orlandi, Carlo Barone, Filippo Pietrantonio, Todd Hembrough
Journal: Annals of Oncology (2017)
Endoscopic and oncologic outcomes of gastroduodenal neuroendocrine tumors: A single center, large scale, retrospective study
Authors: Hoon Kim Do, Hwan Yoon, Kyong Na Hee, Yong Ahn Ji, Wook Jung Kee, Don Choi Kee, June Song Ho, Hyug Lee Gin, Hwoon-Yong Jung
Journal: Annals of Oncology (2017)
Abstract 172: Notch Signaling Induces Endocardial Hematopoiesis And Endocardial Cushion Formation Downstream Of Nkx2-5
Authors: Yasuhiro Nakashima, Haruko Nakano, Xiaoqian Liu, Andrew W Harmon, Atsushi Nakano
Journal: Circulation Research (2013)

A subset of cardiac progenitors display multipotency to give rise to major cardiovascular lineages during cardiogenesis. In addition, we have recently identified Nkx2-5+ endocardial cells in the outflow and atria that contribute to definitive hematopoietic cells in vivo, which represents phylogenetically conserved pathway of cardio-vasculo-hematopoietic differentiation. Here, we have examined the molecular mechanism underlying the endocardial hematopoiesis. Immunostaining and colony assay suggest that Nkx2-5 mutant mice showed significant decrease in CD31+/41+ hemogenic endocardial cells, while lineage tracing on Nkx2-5-null background revealed that Nkx2-5-derived endocardial cells are present. These data indicate that Nkx2-5 is required not for the formation of the Nkx2-5-derived endocardium but for the hemogenic activity of the endocardium. Notch signaling is also active in cushion endocardium and its mutant embryos show a similar defect with Nkx2-5 mutants as previously reported. Inspired by these similarities between the function of Nkx2-5 and Notch signaling during cardiogenesis, we next investigated the impact of Notch activation on the endocardial hematopoiesis. In vivo forced activation of Notch in the developing heart using Nkx2-5-Cre mice led to massive increase in the endocardial hematopoiesis. As Nkx2-5 binding sites are found in the regulatory region of Notch1, RBPjk, and Jag1 genes, we tested whether Notch regulates endocardial hematopoiesis downstream of Nkx2-5. Surprisingly, Notch activation restored the defective endocardial hematopoiesis as well as endocardial cushion formation in Nkx2-5 knockout mice, suggesting that Notch signaling mediates the Nkx2-5-dependent endocardial hematopoiesis and cushion development. Drosophila dorsal vessel and lymph gland are closely related and regulated by tinman and notch. Therefore, Nkx2-5-Notch regulatory pathway represents phylogenetically conserved fundamental mechanism of cardio-vasculo-hematopoietic differentiation pathway.
Authors’ reply to Workman
Authors: Gerd Gigerenzer, Kai Kolpatzik
Journal: BMJ (2017)

Evidence shows that, rather than saving lives, ovarian cancer screening with transvaginal ultrasonography and cancer antigen (CA-125) testing produces large numbers of false alarms. These lead to severe harms for women whose healthy ovaries are removed.1 Given the evidence, the US Food and Drug Administration and the US Preventive Services Task Force recommend against ovarian cancer screening. Doctors and patients can more easily understand this and other risks when they are presented in a fact box.2

Nevertheless, 28% of US doctors have reported non-adherence to this recommendation and screen women at no risk of ovarian cancer, and 65% reported screening women at medium risk.3 Over …
The Use of Anti-Thymocyte Globulin Is Associated with Increased Chance of Survival Free from Relapse and Graft-Versus-Host Disease after Allogeneic Peripheral Blood Stem Cell Transplantation for Adults with Philadelphia-Negative Acute Lymphoblastic Leukemia: An Analysis By the Acute Leukemia Working Party of the EBMT
Authors: Sebastian Giebel, Myriam Labopin, Wlodzimierz Mendrek, Gerard Socie, Liisa Volin, Nathalie Fegueux, Tamas Masszi, Didier Blaise, Sridhar Chaganti, Jan J. Cornelissen, Jakob R Passweg, Johan Maertens, Maija Itälä-Remes, Depei Wu, Mohamad Mohty, Arnon Nagler
Journal: Blood (2016)
A Novel Multiplex NGS-Based Digital MLPA Assay for Copy Number Detection of 700 Target Sequences in Childhood Acute Lymphoblastic Leukemia
Authors: Anne Benard, Ilse Zondervan, Jan Schouten, Karel de Groot, Farzaneh Ghazavi, Virinder Sarhadi, Pieter Van Vlierberghe, Barbara De Moerloose, Christine Harrison, Claire Schwab, Sakari Knuutila, Tim Lammens, Suvi Savola
Journal: Blood (2016)