tbuckley/cabot-search huggingface dataset:
Do COPD subtypes really exist? COPD heterogeneity and clustering in 10 independent cohorts
Authors: Peter J Castaldi, Marta Benet, Hans Petersen, Nicholas Rafaels, James Finigan, Matteo Paoletti, H Marike Boezen, Judith M Vonk, Russell Bowler, Massimo Pistolesi, Milo A Puhan, Josep Anto, Els Wauters, Diether Lambrechts, Wim Janssens, Francesca Bigazzi, Gianna Camiciottoli, Michael H Cho, Craig P Hersh, Kathleen Barnes, Stephen Rennard, Meher Preethi Boorgula, Jennifer Dy, Nadia N Hansel, James D Crapo, Yohannes Tesfaigzi, Alvar Agusti, Edwin K Silverman, Judith Garcia-Aymerich
Journal: Thorax (2017)

<h3>Background</h3> COPD is a heterogeneous disease, but there is little consensus on specific definitions for COPD subtypes. Unsupervised clustering offers the promise of 'unbiased' data-driven assessment of COPD heterogeneity. Multiple groups have identified COPD subtypes using cluster analysis, but there has been no systematic assessment of the reproducibility of these subtypes. <h3>Objective</h3> We performed clustering analyses across 10 cohorts in North America and Europe in order to assess the reproducibility of (1) correlation patterns of key COPD-related clinical characteristics and (2) clustering results. <h3>Methods</h3> We studied 17 146 individuals with COPD using identical methods and common COPD-related characteristics across cohorts (FEV<sub>1</sub>, FEV<sub>1</sub>/FVC, FVC, body mass index, Modified Medical Research Council score, asthma and cardiovascular comorbid disease). Correlation patterns between these clinical characteristics were assessed by principal components analysis (PCA). Cluster analysis was performed using k-medoids and hierarchical clustering, and concordance of clustering solutions was quantified with normalised mutual information (NMI), a metric that ranges from 0 to 1 with higher values indicating greater concordance. <h3>Results</h3> The reproducibility of COPD clustering subtypes across studies was modest (median NMI range 0.17–0.43). For methods that excluded individuals that did not clearly belong to any cluster, agreement was better but still suboptimal (median NMI range 0.32–0.60). Continuous representations of COPD clinical characteristics derived from PCA were much more consistent across studies. <h3>Conclusions</h3> Identical clustering analyses across multiple COPD cohorts showed modest reproducibility. COPD heterogeneity is better characterised by continuous disease traits coexisting in varying degrees within the same individual, rather than by mutually exclusive COPD subtypes.
Using probiotics in clinical practice: Where are we now? A review of existing meta-analyses
Authors: Mariangela Rondanelli, Milena Anna Faliva, Simone Perna, Attilio Giacosa, Gabriella Peroni, Anna Maria Castellazzi
Journal: Gut Microbes (2017)

The scientific literature has demonstrated that probiotics have a broad spectrum of activity, although often the results are contradictory. This study provides a critical overview of the current meta-analyses that have evaluated the efficacy of probiotics in physiologic and pathological conditions, such as metabolic disease, antibiotic-associated and Clostridium difficile-associated diarrhea, IBS, constipation, IBD, chemotherapy-associated diarrhea, respiratory tract infection, ventilator-associated pneumonia, NAFLD, liver encephalopathy, periodontitis, depression, vaginosis, urinary tract infections, pancreatitis, incidence of ventilator-associated pneumonia, hospital infection and stay in ICU, mortality of post-trauma patients, necrotising enterocolitis in premature infants.Only for antibiotic- and Clostridium difficile-associated diarrhea, and respiratory tract infections the effects of probiotics are considered "evidence-based." Concerning other fields, meta-analyses lacks to define type and biologic effect of probiotic strains, as well as the outcome in a disease state. Therefore, the results presented should be a stimulus for further studies which will provide clinical recommendations.
Open-label phase Ib study of entinostat (E), and lapatinib (L) alone, and in combination with trastuzumab (T) in patients (pts) with HER2+ metastatic (mHER2+) breast cancer after progression on trastuzumab.
Authors: Bora Lim, Rashmi Krishna Murthy, Summer Jackson, Jie S. Willey, Jangsoon Lee, Ricardo H. Alvarez, Carlos Hernando Barcenas, Meghan Sri Karuturi, Nuhad K. Ibrahim, Daniel J. Booser, Stacy L. Moulder, Sharon Hermes Giordano, Abenaa M. Brewster, Ronald Stewart Walters, Powel Brown, Debu Tripathy, Vicente Valero, Naoto T. Ueno
Journal: Journal of Clinical Oncology (2016)

609 Background: Entinostat (E) an HDAC inhibitor, and Lapatinib (L) given in combination induces FOXO3a and mediates Bim1 expression in HER2+ cell lines resulting in apoptosis [Lee et al. BCRT 2014], providing rationale for this NCI/CTEP sponsored phase 1b trial of E and L +/- T in mHER2+ breast cancer. Methods: A 3+3 phase 1b design was used to determine MTD. Group 1 received E and L. Group 2 received E, L and T. MTD was E 15mg q 2 wks, L 1250mg q 28 days (Group 1), E 12mg q 2 wks, L 1000 mg q 28 days and T 8mg/kg -> 6mg/kg q 3 wks (Group 2); 11 pts received E, L and T at MTD in an expansion cohort. Results: 37 pts were enrolled (15 Group 1, 11 Group 2, and 11 dose expansion); 18 had evaluable circulating tumor cells (isolated using ApoCell’s ApoStream technology) with Akt, HER2, EGFR for further correlative analysis. Median age was 52 (26-72 yo), received 3 (1-15 lines) previous therapies; 13 pts in Group 1, and 19 pts in Group 2/expansion had evaluable response to date. Total 9(24%) pts had clinical benefit (CB=CR, PR, SD at 6mo), 7(54%) pts with prior lapatinib had CB. CBR in metastatic IBC was 23%. Efficacy and toxicity summarized in table 1. Final clinical and correlative results will be reported at presentation. Conclusions: The entinostat, lapatinib and trastuzumab (ELT) regimen was safe and effective in pts who progressed on trastuzumab, even in those with prior lapatinib exposure. These results justify further evaluation of entinostat in combination with HER2 targeted therapy to overcome resistance. Clinical trial information: NCT01434303.Clinical efficacy and toxicity. IBC Prior L Response Grade 3 toxicity Grade 4 toxicity Group 1 6/15 7/15 CR (1), SD (4) CB (1) Rash (2) Abdominal pain + dyspnea (1) Neutropenia (1 each at 12mg and 15mg) Group 2 + expansion 7/22 6/22 CR (2), PR(3), SD (6) CB (6) 2pts ongoing Diarrhea (1 each at 10mg and 12mg) Neutropenia (2 at 12 mg) Leukopenia (1 at 12mg) Anemia (1 at 12mg) Thrombocytopenia (1 at 12mg) Hypokalemia (1 at 12mg) Thrombocytopenia (1 each at 12mg and 15mg) CR: complete response, PR: partial response, SD: stable disease at 4 mo, (*):* number of pts; L: lapatinib
Value of breast cancer molecular subtypes and Ki67 expression for the prediction of efficacy and prognosis of neoadjuvant chemotherapy in a Chinese population.
Authors: Jiayu Wang, Binghe Xu, Die Sang, Pin Zhang, Qing LI, Peng Yuan, Fei Ma, Yang Luo, Ying Fan, Ruigang Cai, Shanshan Chen, Qiao LI
Journal: Journal of Clinical Oncology (2016)

e12512 Background: To determine the predictive role of breast cancer subtypes in the efficacy and prognosis of neoadjuvant chemotherapy (NCT) regimens combining taxanes and anthracyclines. Methods: Data from 240 patients with breast cancer who received surgery after 4-6 weeks of NCT were retrospectively analyzed. The patients were classified into luminal A, luminal B, HER2 overexpression and triple negative breast cancer (TNBC) as well as low Ki67 ( ≤ 40%) and high Ki67 ( > 40%) expression groups using immunohistochemistry. NCT outcome parameters were pathological complete response (pCR), clinical complete response (CR), partial response (PR), stable disease (SD) and progressive disease (PD) 4 weeks after surgery. Long-term outcome parameters were disease free survival (DFS) with a follow up time of 3-56 months. Results: pCR rates were 1.6%, 13.4%, 22.6% and 23.8% in patients with luminal A, luminal B, HER2 and TNBC cancers, respectively. High pCR rates correlated with high Ki67 expression ( > 40%) (P < 0.001, HR = 0.17, 95% CI: 0.074-0.37) and negative estrogen receptor (ER) status (P< 0.001, HR = 3.74, 95% CI: 1.71-8.12) in a multivariate analysis. However, the DFS rate of luminal A breast cancer was highest compared to all other groups, but only significantly higher compared to luminal B (P = 0.035, HR = 1.480, 95% CI: 1.060-1.967) patients and correlated with Ki67 expression > 40% (P= 0.005). Conclusions: Luminal A type patients derived the least benefit from neoadjuvant chemotherapy but had better long-term prognoses. ER status and Ki67 expression served as efficacy predictors for NCT, whereas only Ki67 expression > 40% correlated with long-term treatment outcomes.
Abstract 128: Network-based Approaches to Identify Novel Regulators of Heart Failure
Authors: Christoph D Rau, Milagros C Romay, Jessica Wang, Shuxun Ren, Yibin Wang, Aldons J Lusis
Journal: Circulation Research (2015)

Heart failure is a highly heterogeneous disorder characterized by the interactions of multiple environmental and genetic factors. While reductionistic approaches have made significant inroads into characterizing the pathophysiology of the syndrome, they are unable to properly dissect the complex interactions between sets of genes and pathways which result in the emergent phenotypes . Systems genetics offers a means by which these interactions may be identified and explored. We have developed a resource, the Hybrid Mouse Diversity Panel (HMDP) to perform systems-level analyses in mice. Nine week old female mice from 93 unique inbred lines of the HMDP were give 30 ug/g/day of isoproterenol through an abdominally implanted Alzet micropump. After three weeks, mice were sacrificed along with age-matched controls. A portion of the left ventricle was arrayed on an Illumina Mouse Ref 8.0 platform. Maximal Information Component Analysis was used to construct gene networks, and a module of 41 genes was identified which shows strong correlation to a number of important phenotypic traits, including heart weight and cardiac fibrosis. This module contains a number of genes of interest, including Lgals3, a diagnostic marker for heart failure. Through the use of structural equation modeling, we identified several key genes within the module for further analysis, the most important of which is the metalloprotease Adamts2. We have performed a series of in vitro analyses demonstrating the important role of Adamts2 in this module using neonatal rat ventricular myocytes. Knockout of Adamts2 results in an amelioration of the hypertrophic response to catecholamine stimulation as well as a reduction of hypertrophic markers such as Nppa and Nppb. Furthermore, we observe that other genes in the module no longer respond to catecholamine stimulation after knockdown of Adamts2.
Placebo Response and Practice Effects in Schizophrenia Cognition Trials
Authors: Richard S. E. Keefe, Vicki G. Davis, Philip D. Harvey, Alexandra S. Atkins, George M. Haig, Owen Hagino, Stephen Marder, Dana C. Hilt, Daniel Umbricht
Journal: JAMA Psychiatry (2017)

<h3>Importance</h3> Patients' previous experience with performance-based cognitive tests in clinical trials for cognitive impairment associated with schizophrenia can create practice-related improvements. Placebo-controlled trials for cognitive impairment associated with schizophrenia are at risk for these practice effects, which can be difficult to distinguish from placebo effects. <h3>Objectives</h3> To conduct a systematic evaluation of the magnitude of practice effects on the Measurement and Treatment Research to Improve Cognition in Schizophrenia Consensus Cognitive Battery (MCCB) in cognitive impairment associated with schizophrenia and to examine which demographic, clinical, and cognitive characteristics were associated with improvement in placebo conditions. <h3>Design, Setting, and Participants</h3> A blinded review was conducted of data from 813 patients with schizophrenia who were treated with placebo in 12 randomized placebo-controlled clinical trials conducted mostly in outpatient clinics in North America, Europe, Asia, and Latin America from February 22, 2007, to March 1, 2014. A total of 779 patients provided data for the primary outcome measure at baseline and at least 1 follow-up. Seven trials had prebaseline assessments wherein the patients knew that they were not receiving treatment, allowing a comparison of practice and placebo effects in the same patients. <h3>Interventions</h3> Placebo compared with various experimental drug treatments. <h3>Main Outcomes and Measures</h3> Composite score on the MCCB. <h3>Results</h3> Of the 813 patients in the study (260 women and 553 men; mean [SD] age, 41.2 [11.5] years), the mean MCCB composite score at baseline was 22.8 points below the normative mean, and the mean (SEM) total change in the MCCB during receipt of placebo was 1.8 (0.2) T-score points (95% CI, 1.40-2.18), equivalent to a change of 0.18 SD. Practice effects in the 7 studies in which there was a prebaseline assessment were essentially identical to the postbaseline placebo changes. Baseline factors associated with greater improvements in the MCCB during receipt of placebo included more depression/anxiety (<i>F</i><sub>1,438</sub> = 5.41;<i>P</i> = .02), more motivation (<i>F</i><sub>1,272</sub> = 4.63;<i>P</i> = .03), and less improvement from screening to baseline (<i>F</i><sub>1,421</sub> = 59.32;<i>P</i> &lt; .001). <h3>Conclusions and Relevance</h3> Placebo effects were minimal and associated with the number of postbaseline assessments and several patient characteristics. Given that the patients performed 2.28 SDs below normative standards on average at baseline, a mean placebo-associated improvement of less than 0.2 SD provides evidence that ceiling effects do not occur in these trials. These minimal changes in the MCCB could not be responsible for effective active treatments failing to separate from placebo.
A prospective study of stress, anxiety and depression response to undergoing genetic assessment at the time of ovarian cancer diagnosis.
Authors: Melissa Kristen Frey, Sarah S. Lee, Zachary Schwartz, Deanna Gerber, Jessica Martineau, Kathleen Lutz, Erin Reese, Emily Dalton, Bhavana Pothuri, John P Curtin, Stephanie V. Blank
Journal: Journal of Clinical Oncology (2017)

e13024 Background: Genetic assessment (GA) is recommended for all women with ovarian cancer however little is known about the psychological implications of this intervention. We sought to evaluate the psychological response to GA in newly diagnosed ovarian cancer patients as part of our facilitated genetics referral pathway. Methods: English-speaking patients with ovarian cancer undergoing GA at the time of cancer diagnosis completed three validated anxiety, stress and depression survey instruments immediately prior to and following GA and again 6-9 months after GA. Results: Forty-eight English-speaking patients underwent GA; 43 (90%) completed the pre-GA survey, 32 (67%) post-GA survey and 11 (23%) 6-9 months follow-up survey. Eight patients (17%) had documented psychiatric diagnoses (5 anxiety, 2 depression, 1 anxiety+depression) prior to cancer diagnosis. Overall, patients demonstrated mild to moderate stress, clinically significant anxiety and borderline depression (Table 1). There was no change in depression, anxiety or stress scores when comparing pre- to post-GA surveys. Age, stage, method of treatment, performance status at enrollment and history of psychiatric disorders were not associated with anxiety, stress or depression. Conclusions: A genetic testing pathway whereby GA is encouraged and facilitated at the time of diagnosis has not increased patient depression, anxiety or stress in our cohort. Concern about causing additional emotional distress should not deter clinicians from early genetics referral. [Table: see text]
The clinical impact of early immunological responses in human HER2-positive breast cancers on responsiveness to trastuzumab-based therapy.
Authors: Alex J Eustace, Sinead Toomey, Joanna Fay, Ausra Teiserkiene, Malgorzata Milewska, Elaine Kay, Darran O'Connor, Ailis Fagan, Leonie S Young, Norma O'Donovan, Janice Maria Walshe, Arnold D. Hill, M. John Kennedy, Colm Power, Deirdre Duke, Niamh Hambly, William M. Gallagher, John Crown, Bryan Hennessy
Journal: Journal of Clinical Oncology (2016)

587 Background: ‘TCHL’ an ICORG phase-II neo-adjuvant study in HER2+ve Breast cancer (BC) assessed the impact of TCH (Docetaxel, Carboplatin, Trastuzumab) versus TCHL (Docetaxel, Carboplatin, Trastuzumab, Lapatinib) in 78 patients. In these patients we determined the impact of total infiltrating lymphocytes (stromal and tumoral) (TIL) as a prognostic marker of pathological complete response (pCR). Methods: We determined TIL counts using immunohistochemical staining with Haemotoxalyin+Eosin, AE1/AE3 and CD45 in formalin fixed paraffin embedded (FFPE) baseline biopsy samples (n = 78) and in fresh frozen (FF) biopsies taken 20-days post cycle 1 (Day-20) of TCH/TCHL (n = 24). RNAseq analysis was performed in matched FF tumour biopsies taken pre-treatment and at Day-20 of treatment and analysed using ESTIMATE and CIBERSORT, to determine tumour content and specific immune cell subpopulations in each patient tumour sample. Results: Overall Mean TIL counts in the baseline pre-treatment biopsy samples were 33% higher in those patients who had a pCR relative to those who had either a partial response (PR) or no response (NR) (TIL pCR = 45 ± 7 vs no pCR = 34 ± 7; p = 0.15). We also assessed Mean TIL counts in FF Day-21 biopsies. In 3 patients who had no response, TIL counts (TIL count = 38 ± 16) were lower than those observed in 7 patients who had a PR (TIL count = 57 ± 6) or 3 patient who had a pCR (TIL count = 85 ± 11), with those patients who had a pCR having significantly greater TIL counts than those with a PR (p = 0.033). ESTIMATE analysis demonstrated a good correlation with tumour cell and lymphocyte counts determined by pathological review. CIBERSORT analysis reveals that those with higher plasma cell numbers in the pre-treatment samples are more likely to have a PR/pCR relative to NR patients Conclusions: TIL counts during treatment play an important role in determining the likelihood of pCR in HER2-Positive BC patients who receive neoadjuvant trastuzumab; further analysis of the role of TIL subpopulations may identify key predictive biomarkers.
Referral for genetic counseling in survivors of triple negative breast cancer (TNBC): An ongoing objective.
Authors: Maryam Nemati Shafaee, Arup Kumar Sinha, Babita Saigal, Rashmi Krishna Murthy, Masood Pasha Syed, Ashley Henriksen Woodson, Banu Arun, Carlos Hernando Barcenas
Journal: Journal of Clinical Oncology (2016)

1095 Background: Inherited mutations in the BRCA gene are responsible for 5-10% of breast cancers. These mutations, predominantly BRCA 1, predispose to TNBC. Around 20% of women with TNBC are BRCA mutation carriers. The NCCN guidelines regarding genetic counseling eligibility have changed over time. According to the year 2011 update, all women with TNBC diagnosed at age < 60 are eligible for referral. This means that all TNBC survivors who were younger than age 60 at diagnosis currently meet the referral criteria. This highlights the vital role of survivorship care in addressing this need. We sought to describe referral patterns in our institution. Methods: In a single-institution retrospective analysis of TNBC long-term ( > 5 years) survivors, we evaluated the rate of genetic counseling referral in patients who had been diagnosed with breast cancer during years 1992-2007 and were disease-free at 5 or more years after diagnosis. We only included patients who received treatment and subsequent follow up at MD Anderson. In referred women who were subsequently tested, the rate of for BRCA mutation was noted. Results: Of 606 long-term TNBC female survivors, 505 had received their treatment and follow up at MD Anderson. Most (59%) were diagnosed before age 50, and all met the current guidelines for genetic counseling. A total of 94 patients (19%) had been referred to genetic counseling, 47 (50%) were tested, and 13 (28%) tested positive for BRCA mutation. Among women diagnosed at age < 50 who underwent testing, 12 (36%) tested positive for a deleterious BRCA mutation. In women diagnosed age 50-60, 1 patient (7%) tested positive. 24 patients (25%) declined testing after a referral. Rate of referral was significant for improvement over time; 30% for women with last date of follow up between 2012-2015, versus 10% for year 2011 and earlier. Conclusions: A considerable number of long-term TNBC survivors have a deleterious BRCA mutation. Survivorship care presents a good opportunity to address genetic counseling referral. Areas of opportunity towards increasing utilization of genetic counseling services pertaining to this population will be further explored in the presentation.
Phase I study of anti-mesothelin antibody drug conjugate anetumab ravtansine (AR).
Authors: George R. Blumenschein, Raffit Hassan, Kathleen N. Moore, Alessandro Santin, Hedy L. Kindler, John J. Nemunaitis, Shelly Marie Seward, Prabhu Rajagopalan, Annette Walter, Nenad Sarapa, Johanna C. Bendell
Journal: Journal of Clinical Oncology (2016)

2509 Background: AR (BAY 94-9343) comprises a novel fully human anti-mesothelin IgG1 antibody conjugated to the maytansinoid tubulin inhibitor DMR. A phase I study was conducted in patients (pts) with advanced solid tumors. Methods: Eligible pts with solid tumors refractory to standard treatment, adequate organ function, and ECOG performance status (PS) ≤ 1 were enrolled. AR was administered IV on 2 schedules: every 21 days (q3w) in 45 pts (21 mesothelioma [Meso], 9 pancreatic, 5 breast, 4 ovarian cancer [OC], 6 other) at doses ranging from 0.15 to 7.5 mg/kg and in an expansion cohort at 6.5 mg/kg (12 Meso and 20 OC); and weekly (qw) in 71 pts (31 Meso and 40 OC) randomized to either 1.8 mg/kg or 2.2 mg/kg. Pts were assessed for AEs weekly C1-C3 and on D1 in subsequent cycles. Tumor response was assessed q6w C1-C8 and q12w thereafter. Mesothelin expression in archival tumor samples was assessed by IHC (SP74, Ventana). Results: A total of 147 pts were evaluable: 64% female, mean age 61 yrs (range 18-88), PS 0/1 29%/71%. The 7.5 mg/kg q3w dose was not tolerated. The maximally tolerated dose (MTD) was 6.5 mg/kg q3w; 15 of 32 (47%) pts in MTD expansion had dose reduction to 5.5 mg/kg q3w. Adverse events (AEs) were similar to the mesothelin-ADC inhibitor class, including reversible keratopathy, asymptomatic liver function test increases, and gastrointestinal disorders. Drug-related (DR) serious AEs were low (11 total; 5 at the q3w MTD) and highly similar to this class of inhibitors. No DR deaths were reported. One patient in each expansion cohort discontinued due to a reversible DRAE. Partial response (PR), stable disease (SD), and disease control rates (DCR) were 18%/47%/65% at the q3w MTD (n = 38), 6%/35%/41% at 1.8 mg/kg qw (n = 34), and 3%/50%/53% at 2.2 mg/kg qw (n = 36). At the q3w MTD, the PR/SD/DCR for OC pts (n = 22) was 9%/50%/59% and for Meso pts (n = 16) was 31%/44%/75%, respectively. Five of 16 (31%) Meso pts treated at the MTD had a durable PR ( > 600 days in 4); the response rate in 2ndline Meso pts was 50% (5/10). Durable responses were also observed in OC pts. Conclusions: Preliminary data with AR at 6.5 mg/kg q3w showed durable PRs in pts with advanced Meso. All DRAEs were reversible. A phase II trial in 2nd-line metastatic pleural Meso is ongoing (NCT02610140). Clinical trial information: NCT01439152.