tbuckley/cabot-search huggingface dataset:
First-Line Nivolumab in Stage IV or Recurrent Non–Small-Cell Lung Cancer
Authors: David P. Carbone, Martin Reck, Luis Paz-Ares, Benjamin Creelan, Leora Horn, Martin Steins, Enriqueta Felip, Michel M. van den Heuvel, Tudor-Eliade Ciuleanu, Firas Badin, Neal Ready, T. Jeroen N. Hiltermann, Suresh Nair, Rosalyn Juergens, Solange Peters, Elisa Minenza, John M. Wrangle, Delvys Rodriguez-Abreu, Hossein Borghaei, George R. Blumenschein, Liza C. Villaruz, Libor Havel, Jana Krejci, Jesus Corral Jaime, Han Chang, William J. Geese, Prabhu Bhagavatheeswaran, Allen C. Chen, Mark A. Socinski
Journal: New England Journal of Medicine (2017)

Nivolumab has been associated with longer overall survival than docetaxel among patients with previously treated non-small-cell lung cancer (NSCLC). In an open-label phase 3 trial, we compared first-line nivolumab with chemotherapy in patients with programmed death ligand 1 (PD-L1)-positive NSCLC.We randomly assigned, in a 1:1 ratio, patients with untreated stage IV or recurrent NSCLC and a PD-L1 tumor-expression level of 1% or more to receive nivolumab (administered intravenously at a dose of 3 mg per kilogram of body weight once every 2 weeks) or platinum-based chemotherapy (administered once every 3 weeks for up to six cycles). Patients receiving chemotherapy could cross over to receive nivolumab at the time of disease progression. The primary end point was progression-free survival, as assessed by means of blinded independent central review, among patients with a PD-L1 expression level of 5% or more.Among the 423 patients with a PD-L1 expression level of 5% or more, the median progression-free survival was 4.2 months with nivolumab versus 5.9 months with chemotherapy (hazard ratio for disease progression or death, 1.15; 95% confidence interval [CI], 0.91 to 1.45; P=0.25), and the median overall survival was 14.4 months versus 13.2 months (hazard ratio for death, 1.02; 95% CI, 0.80 to 1.30). A total of 128 of 212 patients (60%) in the chemotherapy group received nivolumab as subsequent therapy. Treatment-related adverse events of any grade occurred in 71% of the patients who received nivolumab and in 92% of those who received chemotherapy. Treatment-related adverse events of grade 3 or 4 occurred in 18% of the patients who received nivolumab and in 51% of those who received chemotherapy.Nivolumab was not associated with significantly longer progression-free survival than chemotherapy among patients with previously untreated stage IV or recurrent NSCLC with a PD-L1 expression level of 5% or more. Overall survival was similar between groups. Nivolumab had a favorable safety profile, as compared with chemotherapy, with no new or unexpected safety signals. (Funded by Bristol-Myers Squibb and others; CheckMate 026 ClinicalTrials.gov number, NCT02041533 .).
Lung cancer screening patient navigation for current smokers in community health centers: A randomized controlled trial.
Authors: Sanja Percac-Lima, Jeffrey M Ashburner, Nancy Rigotti, Elyse R. Park, Yuchiao Chang, Steven J Atlas
Journal: Journal of Clinical Oncology (2017)

1506 Background: Annual chest computed tomography (CT) can decrease lung cancer mortality in high risk individuals. Patient navigation (PN) has been shown to improve cancer screening rates in underserved populations. We evaluated the impact of PN on lung cancer screening (LCS) in current smokers in community health centers (CHC). Methods: Current smokers aged 55-77 receiving care in five CHC affiliated with an academic medical center were randomized to intervention (n = 400) or control (n = 800) groups. In the intervention arm, patient navigators (PNs) determined eligibility for LCS, provided brief smoking cessation counseling, introduced shared decision making about LCS, scheduled appointments with the primary care provider (PCP), reminded patients about appointments and PCPs to order CTs, and helped patients attend testing and follow-up any abnormal results. Control patients received usual care. The primary outcome was the proportion of patients in each group who had any chest CT during the study period. Secondary outcomes included proportion of patients receiving lung screening CTs and the number of lung cancers diagnosed in each group. Results: Baseline patient characteristics were similar between randomized groups. From March 2016-January 2017, PNs contacted 332 (83%) of intervention patients; 76 refused further participation. Of participating patients, 130 (51%) were eligible for LCS. Exclusions included insufficient smoking history (n = 117), competing comorbidities (n = 5), moved (n = 2), and died (n = 2). In intention-to-treat analyses, 124 intervention patients (31%) had chest CT vs. 138 control patients (17.3%, p &lt; 0.01). Lung cancer screening CTs were performed in 94 intervention patients (23.5%) vs. 69 control patients (8.6%, p &lt; 0.01). Eight lung cancers were diagnosed in intervention patients (2%) vs. 4 in controls (0.5%). Conclusions: A patient navigation program implemented in community health centers significantly increased lung cancer screening among current smokers. PNs may help underserved low-income current smokers complete LCS and improve equity in care while decreasing lung cancer mortality. Clinical trial information: 2015P002239.
Abstract 232: Bendavia, a Novel Mitochondria Targeting Peptide, Improves Mitochondrial Function in Circulating Blood Monocytes From Dogs With Chronic Heart Failure
Authors: Hani N Sabbah, Vinita Sing-Gupta, Ramesh C Gupta
Journal: Circulation Research (2015)

Background: Mitochondrial (MITO) function is abnormal in heart failure (HF) as evidenced by reduced MITO respiration and rate of ATP synthesis. We showed that MITO dysfunction can be normalized in HF dogs after therapy with Bendavia (BEN), a novel MITO targeting peptide. This study tested the hypothesis that BEN will also reverse abnormalities of MITO function present in blood monocytes (MCs) of HF dogs. Methods: Blood samples obtained from 6 normal (NL) dogs and 6 dogs with coronary microembolizations-induced HF (LV ejection fraction ~30%) were used to isolate MCs by sequential Ficoll and Percoll density gradients. An XFe/XF96 analyzer (Seahorse Bioscience) was used to measure oxygen consumption rates (OCR) in MCs in the presence and absence of 1 μM oligomycin, 0.5 μM FCCP, or 1 μM each rotenone and antimycin. MITO proton leak, maximal respiration (MAXresp) and spare respiratory capacity (SRC) were measure in the presence and absence of 0.1, 1.0 and 10 μM concentrations of BEN and results expressed in pmols OCR/min/μg protein. Results: Proton leak, MAXresp and SRC were abnormal in MCs of HF dogs compared to NL. Incubation with BEN had no effect on measures of MCs MITO function of NL dogs but nearly normalized MITO function of MCs of HF dogs as evidenced by a dose-dependent increase MAXresp and SRC and dose-dependent decrease in proton leak (Table). Conclusions: MITO function is abnormal in blood MCs of HF dogs. BEN had no effect on MITO function of MCS from NL dogs but normalized MITO function in MCs from HF dogs. These findings support the use of circulating blood MCs as means of assessing MITO dysfunction in HF and as a marker of potential benefits derived from treatment with MITO targeted therapies.
Exercise-induced asthma.
Authors: A Bundgaard
Journal: BMJ (1980)

All asthmatics have exercise-induced asthma (EIA). In periods where the asthma spontaneously deteriorate, there will be more exercise-induced asthma. About 3/4 of the asthmatics will have a positive exercise test on the first challenge. Exercise is not the best test to obtain the diagnosis of asthma, as other tests, e.g. inhalation of histamine, is more sensitive and specific. The best pretreatment of EIA is inhaled beta 2-agonists. Inhaled, nebulized SCG seem to offer better protection against EIA than inhalation of SCG as a powder and is most effective in children. EIA should today primarily be used in studies concerning the pathogenesis of asthma and in the evaluation of medication against asthma.
Can 8 week <sup>18</sup>F-FDG PET/CT predict clinical response in evaluation of bone metastases in breast cancer?
Authors: Gurdip Kaur Azad, Francois Cousin, Angela Swampillai, Benjamin P Taylor, Ines Sandri, Mark Harries, Janine Mansi, Gary J. R. Cook
Journal: Journal of Clinical Oncology (2017)

e12539 Background: 18 F-FDG (fluorodeoxyglucose) PET/CT scan is widely used for staging and response assessment of metastatic breast cancer. However, the role of early treatment response assessment of bone metastases remains undefined and the optimal method not yet determined. Our hypothesis was that early 18 F-FDG PET/CT can predict subsequent clinical response and our aim was to compare early 8 week 18 F-FDG PET/CT with clinical response assessment up to 12 weeks in bone metastases following endocrine treatment. Methods: Eighteen patients starting endocrine treatment for de novo or progressive bone metastases were prospectively recruited. 18 F-FDG PET/CT scans were performed before and 8 weeks after treatment. Percentage change in maximum SUV (SUVmax) from the same ≤ 5 index lesions was measured. Clinical response up to 12 weeks, (combination of CT/bone scintigraphy, patient symptoms, Ca-15.3), assessed by an oncologist blinded to PET imaging findings was used as a reference standard. Results: In the 4 patients with progressive disease (PD); SUVmax increased ( &gt; 25%) in 2/20 (10%) and was stable in 15/20 (75%) lesions. Clinically, 2/4 (50%) patients had stable symptoms and 2/4 (50%) worsening bone pain at 8 and 12 weeks. Ca-153 increased ( &gt; 40%) in 3/4 (75%) patients. Conventional imaging at 12 weeks showed PD in all 4 patients. In the 7 patients with clinical partial response (PR); SUVmax decreased ( &lt; 25%) in 23/35 (66%) and remained stable in 10/35 (29%) lesions. Ca-153 decreased ( &gt; 80%) in 4/7 (57%) patients. Clinically, symptoms remained stable or improved in 6/7 (86%) patients at 8 and 12 weeks. Conventional scanning at 3 months showed either PR (n = 3) or SD (n = 4). In the 7 patients with stable disease (SD); SUVmax remained unchanged in 15/27 (56%) and decreased in 12/27 (44%) lesions. Ca-153 showed minimal changes in 6/7 (86%) patients. Conventional scans showed SD in all 7 patients. Conclusions: Our data show that although 18 F-FDG PET/CT is reliable at predicting PR or SD, it has poorer predictive ability for clinical PD in bone metastases at 8 weeks. Intra-patient heterogeneity of response between lesions is a common observation. Clinical trial information: 12/LO/1801.
Evaluation of the analytical performance of the Breast Cancer Index (BCI) assay.
Authors: Ranelle C. Salunga, Tristan G. Harris, Yi Zhang, Jose Ramirez, Dennis Sgroi, Adam Brufsky, Catherine A. Schnabel
Journal: Journal of Clinical Oncology (2016)

540 Background: BCI is an 11-gene RT-PCR based assay that predicts risk of overall (0-10y) and late ( > 5y) distant recurrence, and is predictive of extended endocrine benefit in patients with early-stage, ER+ breast cancer. The objective of the current study was to evaluate the analytical performance characteristics of the BCI assay. Methods: Studies were conducted using primary resected formalin-fixed paraffin-embedded breast tumor samples. Repeatability, reproducibility, and RNA input range were assessed, and PCR linearity studies for each gene were performed. Total standard deviation (SD) was calculated as the sum of between-subject and within-subject variability estimated by linear mixed models. Assay interference studies included tumor specimens combined with patient-matched, non-tumor elements: normal tissue, activated stroma and inflammatory cells. Assay success rate due to specimen age was examined on consecutive clinical cases (N = 2667). Receiver Operating Characteristic (ROC) analysis was performed using a multi-institutional clinical validation cohort. BCI scores and risk groups based on the pre-specified cut-points were calculated. Results: In repeatability studies, SD on individual gene measurements ranged from 0.05 to 0.59 CTs (threshold cycle) with CVs of 1-2%. In reproducibility studies, total SD for individual genes ranged from 0.23 to 0.45 CTs with CVs ≤ 3%. Total SD of the BCI score ranged from 0.17 to 0.62 units across three operators on a 10-unit scale, resulting in 96% concordance in risk group categorization. RNA input was optimal between 1 to 1000 ng, wherein linearity was demonstrated for all genes tested. BCI scores were stable (change of < 1 unit) when non-tumor elements were mixed up to 60% per unit area. Analytical success rate was 99.3%, 99.9%, 99.7%, and 100% (p = 0.3) from specimens of varying age 0-2 y, > 2-5 y, > 5-8 y, and > 8 y, respectively. ROC analysis showed an AUC (area under the curve) of 0.76. Conclusions: Results demonstrate robust performance characteristics for the BCI assay including high precision, reproducibility, specificity, dynamic range, accuracy, and analytical success, supporting its reliable use as a prognostic and predictive tool in patients with ER+, early-stage breast cancer.
A model for predicting individualized absolute risk of contralateral breast cancer.
Authors: Marzana Chowdhury, David Euhus, Tracy Onega, Swati Biswas, Pankaj K Choudhary
Journal: Journal of Clinical Oncology (2016)

1567 Background: The rate of contralateral prophylactic mastectomy has been rising alarmingly in recent years even though the risk of developing Contralateral Breast Cancer (CBC) is relatively low for most women with unilateral breast cancer. Thus, there is a pressing need for educating patients on their individualized risk of CBC. For this, physicians need a prediction model to provide a quantitative risk of CBC. Methods: To address this need, we develop a CBC risk prediction model using data from the Breast Cancer Surveillance Consortium. We include women aged 18 - 89 with 1st diagnosis of ductal carcinoma in situ (DCIS) and/or invasive cancer and undergoing mammography screening between 1995 and 2010. The cases are matched with controls in 1:3 ratio on year of 1st diagnosis, race, and length of follow-up. A total of 1921 cases and 5763 controls meet the eligibility criteria. The modeling steps are similar to those used in developing Gail (BCRAT) model, a popular model for estimating the risk of 1st breast cancer. Specifically, first we use logistic regression to identify risk factors associated with CBC and build a relative risk model. Then we combine this model with estimates of age-specific baseline CBC incidence rates and mortal hazard rates from non-CBC causes to predict absolute CBC risk. Results: We found 8 risk factors to be significantly associated with CBC (p-value of overall model < 0.001). These are presented in the table below as column headers. The table also shows examples of 3 women with various combinations of risk factors and their predicted CBC risks at 5 and 15 years from their diagnoses of 1st breast cancer. Conclusions: Our model provides individualized absolute risk estimates of CBC. We believe it can potentially fulfill a real need of effective tools for educating breast cancer patients. Age at 1st Diagnosis Family History 1st Can cer Type BI-RADS Density ER Status Hormone Therapy High Risk Pre- neoplasia Age at 1st Birth 5-year CBC Risk (%) 15-year CBC Risk (%) 30-39 yes DCIS extreme dense negative no unknown 30-39 7.5 20.0 40+ no invasive almost entirely fat positive yes yes < 30 1.0 2.9 40+ no DCIS scattered positive unknown unknown 30-39 2.5 7.2
Paradoxical Suppression of Atherosclerosis in the Absence of microRNA-146a
Authors: Henry S. Cheng, Rickvinder Besla, Angela Li, Zhiqi Chen, Eric A. Shikatani, Maliheh Nazari-Jahantigh, Adel Hammoutène, My-Anh Nguyen, Michele Geoffrion, Lei Cai, Nadiya Khyzha, Tong Li, Sonya A. MacParland, Mansoor Husain, Myron I. Cybulsky, Chantal M. Boulanger, Ryan E. Temel, Andreas Schober, Katey J. Rayner, Clinton S. Robbins, Jason E. Fish
Journal: Circulation Research (2017)

Inflammation is a key contributor to atherosclerosis. MicroRNA-146a (miR-146a) has been identified as a critical brake on proinflammatory nuclear factor κ light chain enhancer of activated B cells signaling in several cell types, including endothelial cells and bone marrow (BM)-derived cells. Importantly, miR-146a expression is elevated in human atherosclerotic plaques, and polymorphisms in the miR-146a precursor have been associated with risk of coronary artery disease.To define the role of endogenous miR-146a during atherogenesis.Paradoxically, Ldlr-/- (low-density lipoprotein receptor null) mice deficient in miR-146a develop less atherosclerosis, despite having highly elevated levels of circulating proinflammatory cytokines. In contrast, cytokine levels are normalized in Ldlr-/-;miR-146a-/- mice receiving wild-type BM transplantation, and these mice have enhanced endothelial cell activation and elevated atherosclerotic plaque burden compared with Ldlr-/- mice receiving wild-type BM, demonstrating the atheroprotective role of miR-146a in the endothelium. We find that deficiency of miR-146a in BM-derived cells precipitates defects in hematopoietic stem cell function, contributing to extramedullary hematopoiesis, splenomegaly, BM failure, and decreased levels of circulating proatherogenic cells in mice fed an atherogenic diet. These hematopoietic phenotypes seem to be driven by unrestrained inflammatory signaling that leads to the expansion and eventual exhaustion of hematopoietic cells, and this occurs in the face of lower levels of circulating low-density lipoprotein cholesterol in mice lacking miR-146a in BM-derived cells. Furthermore, we identify sortilin-1(Sort1), a known regulator of circulating low-density lipoprotein levels in humans, as a novel target of miR-146a.Our study reveals that miR-146a regulates cholesterol metabolism and tempers chronic inflammatory responses to atherogenic diet by restraining proinflammatory signaling in endothelial cells and BM-derived cells.
Abstract 359: Human CD34+ Cell-Derived Exosomes Target Endothelial Cells to Deliver MiR-126 Promoting Revascularization and Myocardial Repair
Authors: Susmita Sahoo, Sol Misener, David Kim, Tina Thorne, Christine Kamide, Douglas W Losordo, Douglas E Vaughan
Journal: Circulation Research (2013)

Introduction: Locally transplanted human CD34 + stem cells have been shown to improve exercise tolerance in patients with myocardial ischemia and promote angiogenesis in animal models. Recently we have demonstrated that CD34 + cells secrete exosomes, membrane bound nano-vesicles, as a major component of their paracrine secretion which induces angiogenesis. We hypothesize that cell-free exosomes from CD34 + cells (CD34 Exo) mimic the beneficial effects of cells, and promote myocardial revascularization and repair via transfer of pro-angiogenic microRNAs, possibly to endothelial cells. Methods and Results: Therapeutic potential of CD34 Exo isolated from equal number of adult human peripheral blood-derived CD34 + cells was evaluated in a murine model of myocardial ischemia (MI). Similar to cells, treatment with CD34 Exo resulted in significant improvement in ischemia compared to treatment with PBS (ejection fraction, 42±4 v 22±6%; capillary density, 113±7 v 66±6/HPF; fibrosis 27±2 v 48±7%, p&lt;0.05, n=7-12). Interestingly, confocal imaging and flow cytometry analyses revealed that CD34 Exo was selectively internalized by endothelial cells when injected in to ischemic tissue. MicroRNA expression profiling and confirmatory tests indicated that CD34 Exo is significantly enriched with pro-angiogenic miRNAs such as miR126. Treatment of CD34 Exo increased miR126 expression specifically in endothelial cells of ischemic tissue; treatment of CD34 Exo lacking miR126 abolished that increase and diminished its pro-angiogenic function. This, and studies using fluorescent miR126 confirm that miR126 was directly transferred from CD34 Exo to endothelial cells, and that indirect increase of miR126 by other components of CD34 Exo was minimal. This data also suggests that miR126 is important for CD34 Exo function. Ongoing studies will test the role of transferred miR126 on modulation of proangiogenic gene expression pathways in endothelial cells lacking miR126 either by dicer, or, Egfl-7 knockdown. Conclusion: CD34 + exosomes transfer miR126 to endothelial cells to induce angiogenesis and myocardial repair. The functional benefits associated with CD34 + cell therapy may be mediated by exosomes-mediated transfer of angiogenic microRNAs to endothelial cells.
IND safety reporting: final results and best practices, from the Clinical Trials Transformation Initiative IND Safety Advancement Project.
Authors: Raymond P. Perez, Patrick Archdeacon, Robert Goodwin, Nancy Roach, Jonathan Jarow, Marsha Millikan
Journal: Journal of Clinical Oncology (2016)

2531 Background: As clarified in 2010, the FDA IND Safety Reporting Regulation requires sponsors to review safety data across all studies in an IND, analyze data in aggregate, assess causality, and issue reports only when it is reasonably likely that serious, unexpected event(s) were caused by the drug. A 2016 FDA analysis demonstrates that the number of expedited reports per IND per year is increasing and most reports (86%) are uninformative. We sought to understand 1) sponsor challenges to full implementation of the Regulation, 2) sponsor motivation to change safety reporting practice, 3) investigator site safety report management, and 4) best practices for communicating safety reports. Methods: Surveys of sponsors (n = 28) and investigator sites (n = 201) were conducted, followed by interviews. Best practices were shared at a July 2015 Expert Meeting. Results: Surveys of sponsors (n = 28) and investigator sites (n = 201) were conducted, followed by interviews. Best practices were shared at a July 2015 Expert Meeting. Conclusions: Sponsor best practices can improve IND safety reporting. Dissemination of these findings, sponsor/site education, and regulatory clarity offer the potential to further enhance safety in oncology trials.
Routine pharmacogenomic testing of lung cancer in Taiwan.
Authors: Kang-Yi Su, Jau-Tsuen Kao, Hsuan-Yu Chen, Yi-Lin Chen, Chi-Chung Wang, Gee-Chen Chang, Chao-Chi Ho, Sung-Liang Yu
Journal: Journal of Clinical Oncology (2016)

e13126 Background: Molecular diagnostics in cancer pharmacogenomics is indispensable for making therapeutic decisions regarding the using of targeted drugs. With the growing of methodology and the use of molecular diagnostics, it poses a wide range of issues for clinical practice including uniform guidance for method validation and quality management. Methods: We established multiplex EGFR mutation testing by MALDI-TOF MS according to ISO15189 regulation. Method validation including precision, accuracy, analytical sensitivity, analytical specificity, reference range, and limit of detection were addressed based on CLIA recommendation. Results: Totally 8,147 cases from Aug 2011 to Jul 2015 were assayed and statistical characteristics were reported.The intra-run precision of EGFR mutation frequency was CV 2.15% in L858R and CV 2.77% in T790M while the inter-run precision was CV 3.50% in L858R and CV 2.84% in T790M. Accuracy test of EGFR mutation status by consensus reference biomaterials was consistent with public database. Both analytical sensitivity and analytical specificity were 100% while taking Sanger sequencing as gold-standard method for comparison. Mutation frequency of peripheral blood mononuclear cell for reference range determination was 0.002±0.016% (95% CI: 0.000-0.036) in L858R and 0.292±0.289% (95% CI: 0.000-0.871) in T790M and 1.658±0.625% in Del19 (95% CI: 0.000-2.961). Among tested 8,147 cases, the average TAT was 4.5 working days, the test failure rate was 0.1%, and mutation rate was similar to public epidemiological statistics. Conclusions: In conclusion, we reported a comprehensive experience from platform establishment, method validation to clinical routine practice in Taiwan. It may be a reference model for molecular diagnostics in cancer pharmacogenomics.