tbuckley/cabot-search huggingface dataset:
The contribution of child, family and health service factors to respiratory syncytial virus (RSV) hospital admissions in the first 3 years of life: birth cohort study in Scotland, 2009 to 2015
Authors: Pia Hardelid, Maximiliane Verfuerden, Jim McMenamin, Rosalind L Smyth, Ruth Gilbert
Journal: Eurosurveillance (2019)

Introduction Several vaccines for respiratory syncytial virus (RSV) are under development. Designing an effective vaccination programme for RSV requires information about the relative contribution of risk factors for severe RSV symptoms. Aim To inform preventive strategies in Europe by quantifying the contribution of key child, family and health service risk factors to the burden of RSV hospital admissions in young children. Methods We constructed a birth cohort study of all singleton children born in Scotland between October 2009 and September 2012 using linkage between birth registration, maternity, vaccination and hospital admission records, with follow-up until the age of 3 years. RSV-confirmed hospital admissions were defined using linkage to national laboratory surveillance data. We estimated hospital admission rates per 1,000 child years and length of stay according to each risk factor. Cox proportional hazard regression models were used to estimate adjusted hazard ratios. Results There were 5,185 RSV admissions among the 169,726 children in the cohort: 48.6% of admissions occurred before the age of 6 months, and 29.6% after the age of 1 year. Children born prematurely, small for gestational age, between July and December, with chronic conditions, older siblings, mothers &lt; 30 years old or delayed infant vaccination had a significantly increased risk of admission. Minimising the risk posed by older siblings could reduce RSV admissions by up to 34%. Conclusion Future RSV vaccination programmes must protect children throughout early childhood. Vaccination and/or interventions to reduce transmission by older siblings could substantially reduce RSV hospital admissions.
Comprehensive Transcriptome Profiling of Cryptic CBFA2T3-GLIS2 Fusion-Positive AML Defines Novel Therapeutic Options — a COG and Target Pediatric AML Study
Authors: Jenny L. Smith, Rhonda E. Ries, Marianne T. Santaguida, Christos Gekas, Todd A Alonzo, Robert B Gerbing, Alan S Gamis, Richard Aplenc, E. Anders Kolb, Tiffany Hylkema, Lisa Eidenschink Brodersen, Michael R. Loken, Hamid Bolouri, Soheil Meshinchi
Journal: Blood (2018)
Prevention of irinotecan-induced diarrhea by probiotics: Randomized double-blind, placebo-controlled phase III study.
Authors: Michal Mego, Jozef Chovanec, Iveta Andrezalova, Peter Konkolovsky, Milada Mikulova, Maria Reckova, Vera Miskovska, Branislav Bystricky, Lenka Medvecova, Dagmar Mikusova, Adela Lagin, Daniela Svetlovska, Stanislav Spanik, Jozef Mardiak, Vladimir Zajac, Lubos Drgona
Journal: Journal of Clinical Oncology (2014)

9611 Background: Diarrhea is one of the dose limiting toxicity of irinotecan. SN-38 is main irinotecan metabolite responsible for diarrhea development. SN-38 is excreted in glucuronidated form into the intestine. Due to the bacterial enzyme beta-D-glucuronidase in intestinal lumen it is deconjugated and in this form causes direct damage to the intestinal mucosa associated with the development of diarrhea. This study aimed to determine the effectiveness of the probiotics in the prevention of irinotecan induced diarrhea due to reduction of intestinal beta-D-glucuronidase activity. Methods: Between January 2011 and December 2013, 46 patients with colorectal cancer starting a new line of irinotecan based therapy were included. 5-flurouracil/capecitabine along with irinotecan was administered to 26 (56.5%) patients and 22 (47.8%) patients received biological therapy as well. Patients were randomized 1:1 to probiotics (PRO) or placebo (PLA). Probiotic formula Colon Dophilus, was administered at a dose of 10x 109CFU of bacteria tid, orally for 12 weeks of chemotherapy. Primary endpoint was incidence of grade 3/4 diarrhea. The study was prematurely terminated due to slow accrual, when 46 of 220 planned patients were accrued. Herein, we report final analysis of the study. Results: 23 patients were randomized to PRO and 23 patients to PLA. Administration of probiotics compared to placebo led to a reduction in the incidence of severe diarrhea of grade 3 or 4 (0% for PRO vs. 17.4% for PLA, p = 0.11), as well as reduction of the overall incidence of diarrhea (39.1% for PRO vs. 60.9% for PLA, p = 0.24) and incidence of enterocolitis (0% for PRO vs. 8.7% for PLA). Patients on PRO used less loperamid compared to PLA (mean duration of loperamid use: 4.5 days for PRO vs. 10.4 days for PLA, p = 0.45; mean number of loperamid tablets: 5.9 for PRO vs. 37.7 for PLA, p = 0.49). There was no infection caused by probiotic strains recorded. Conclusions: Administration of probiotics in patients with colorectal cancer treated with irinotecan-based chemotherapy is safe and could lead to a reduction in the incidence and severity of gastrointestinal toxicity. Phase III clinical trials with adequate sample size are warranted. Clinical trial information: NCT01410955.
<i>TP53</i> and Prognosis in mCRPC Survival: Biology or Coincidence?
Authors: Richard J. Rebello, Christoph Oing, Silke Gillessen, Robert G. Bristow
Journal: Clinical Cancer Research (2019)

Cell-free circulating tumor DNA (ctDNA) or circulating tumor cell (CTC) assays are potentially powerful in the treatment of metastatic castration-resistant prostate cancer (mCRPC). A new study suggests that mutation of TP53 supersedes AR in predicting mCRPC survival. A role for TP53 mutation as a driver for mCRPC remains unexplored.See related article by De Laere et al., p. 1766.
Probiotics for Children With Recurrent Abdominal Pain
Authors: Tamsin Newlove-Delgado, Rebecca A. Abbott, Alice E. Martin
Journal: JAMA Pediatrics (2018)

Do dietary interventions, such as probiotics, improve pain in children with recurrent abdominal pain?Compared with placebo, children who were treated with probiotic preparations were more likely to experience improvement in pain in the short term (odds ratio, 1.63; 95% CI, 1.07-2.47), suggesting that clinicians could consider probiotics as part of a holistic management strategy in recurrent abdominal pain.
Usefulness of l-[3-<sup>18</sup>f]-α-methyl tyrosine (<sup>18</sup>F-FAMT) PET as therapeutic monitoring for patients with advanced lung cancer.
Authors: Kyoichi Kaira, Tetsuya Higuchi, Noboru Oriuchi, Noriaki Sunaga, Takeshi Hisada, Takayuki Asao, Yoshihito Tsushima, Masanobu Yamada
Journal: Journal of Clinical Oncology (2014)

11096 Background: L-[3-18F]-α-methyl tyrosine (18F-FAMT) PET has a high specificity for detecting malignant lesions, and the high uptake of 18F-FAMT within tumor cells could be a useful marker for predicting worse outcome. However, it remains unknown whether 18F-FAMT PET has a potential of therapeutic monitoring after chemotherapy. Thus, we evaluated 18F-FAMT PET for therapy response and survival in patients with advanced lung cancer, as compared with 18F-FDG PET. Methods: 18F-FAMT PET and 18F-FDG PET were performed before and 4 weeks after chemotherapy in patients with untreated advanced lung cancer. Uptake of tracers was measured by standardized uptake value (SUV) in the primary tumor. The maximum SUV (SUVmax) on pre-treatment and post-treatment, and metabolic response (MR) were correlated with the survival time estimated by Kaplan-Meier method. Results: Of 111 enrolled patients, 95 patients eligible for post-treatment SUVmax analyses on both 18F-FAMT PET and 18F-FDG PET. Seventy patients received systemic chemotherapy alone as first-line treatment, and 25 patients were treated with concurrent thoracic chemoradiotherapy. The histological type included 87 non-small cell lung cancers and 8 small-cell lung cancers. Post-treatment SUVmax and MR on 18F-FAMT PET were significantly correlated with tumor response by Response evaluation criteria in solid tumor (RESCIST), but pre-treatment SUVmax was not. In all patients (n=95), post-treatment SUVmax on 18F-FDG and 18F-FAMT PET, and MR on 18F-FAMT PET were significant prognostic marker for predicting poor outcome by univariate analysis. Multivariate analysis confirmed that MR on 18F-FAMT PET was a significant independent prognostic factor. MR on 18F-FAMT PET was also an independent prognostic predictor in 70 patients who received chemotherapy alone. Conclusions: MR on 18F-FAMT PET may be a potential parameter to predict the prognosis after first-line chemotherapy in patients with advanced lung cancer.
Abstract 053: Genome-wide <i>Tcea3</i> -SNP Interaction Study Identifies Novel QT Interval Loci
Authors: Christy L Avery, Dan E Arking, Antoine Baldassari, Steve Buyske, Maria P Concas, Charles Kooperberg, Henry Lin, Ching-Ti Lin, Martina Müller-Nurasyid, Raymond Noordam, Kari E North, Katharina Schramm, Elsayed Soliman, Nona Sotoodehnia, Stella Trompet, Christopher Newton-Cheh
Journal: Circulation (2018)

Background: QT interval (QT) genome-wide association studies (GWAS) have identified upwards of 35 common variant loci, including SNPs adjacent to putative transcription elongation factor TCEA3. Transcription elongation control has broad effects on gene expression, the misregulation of which is known to influence cardiac conduction system morphogenesis as well as activation or repression of key regulatory genes. Thus, we hypothesized that a genome-wide gene-gene interaction study of TCEA3 lead SNP rs2298632 would identify novel loci that influence QT. Methods: Using 1000 Genomes imputed data (&gt;20 million SNPs) in n=67,445 participants (69% Caucasian; 18% Hispanic/Latino; 11% African American) from 10 studies, we conducted genome-wide meta-analyses to test for the presence of: interaction effect loci by examining rs2298632xSNP interactions on QT; and joint effect loci by simultaneously examining SNP main effects and rs2298632xSNP interactions on QT. Inverse-variance weighted meta-analysis of genomically controlled ancestry- and study-specific summary effects estimated using multivariable adjusted linear models or generalized estimating equations that incorporated robust standard errors was performed using METAL. SNPs demonstrating evidence of heterogeneity (Cochran’s Q P &lt; 0.05) and SNPs that were infrequent or rare (minor allele frequency [MAF] &lt;5%) were excluded. Results: We identified one genome-wide significant interaction effect locus ( P INT &lt;5x10 -8 ) at PVT1 (lead SNP: rs4733591; mean MAF = 32%), a long non-coding RNA gene for which previous GWAS identified suggestive associations with left ventricular systolic dysfunction. We also identified four genome-wide significant joint effect loci ( P JOINT &lt;5x10 -8 ) that mapped within or nearby NUCKS1 (lead SNP: rs823094; MAF = 0.33) , CASR (lead SNP = rs17251221; MAF = 0.13) , ACTBL2 (lead SNP = rs7737409; MAF = 0.22) , and KDM1B (lead SNP = rs34969716; MAF = 0.26) , loci with roles in calcium sensing, regulation of gene expression through histone modification, and tumor suppression. Conclusion: Extension of traditional main effects GWAS to interrogate gene-gene interactions for biologically motivated loci like TCEA3 may help inform the structure and function of genetic pathways underlying complex traits like QT.
Protein network mapping of glucose metabolism in ovarian cancer.
Authors: Maria Isabella Sereni, Elisa Baldelli, Guido Gambara, Laura Zanotti, Elisabetta Bandiera, Eliana Bignotti, Antonella Ravaggi, Francesco Meani, Germana Tognon, Franco Odicino, Roberto Angioli, Lance A. Liotta, Sergio L. Pecorelli, Emanuel Petricoin, Mariaelena Pierobon
Journal: Journal of Clinical Oncology (2014)

5550 Background: Epithelial ovarian carcinoma (EOC) is the fifth leading cause of tumor related death in the female population, with a 5-year survival after diagnosis of only 30% of patients in case of an advanced disease. The aim of the study was to perform broad-scale drug target activation analysis of EOC to determine if the drug target activation architecture was different in early vs late stage EOC tumors, and if so then to identify new druggable targets for personalized therapy in the context of early vs late stage/advanced disease. Methods: 72 ovarian primary lesions collected from chemo-naïve EOC patients were analyzed. Highly enriched tumor epithelial cells were isolated by laser capture microdissection, lysed and subjected to reverse phase protein microarray analysis for multiplexed protein pathway activation mapping. The activation/phosphorylation level of 157 key signaling proteins involved in tumorigenesis and metastatic colonization was analyzed. Based on the FIGO staging at diagnosis, the patients were segregated into early stages (stage I-IIB, 15 patients) and advanced stages (stage IIC-IV, 57 patients). Wilcoxon rank-sum test was used to detect significant differences between the two groups in the drug target activation profile. Results: Activation of canonical AKT/mTOR and AMPK/ACC signaling pathway architecture (i.e.. AMPKalpha1 (S485), AMPKbeta1 (S108), ACC (S79), LKB1 (S428), AKT (S473), AKT (T308), mTOR (S2448); p=0.0007, p=0.0043, p<0.0001, p=0.0473, p=0.0031, p=0.0068, and p=0.0415 respectively) were found to be significantly higher in early stage tumors compared to advanced stage disease. Conclusions: Functional drug target activation mapping uncovered a systemic alteration of drug targets known to play a critical importance in the metabolic rate of tumors. Activation of AMPK-ACC signaling as well as AKT/mTOR networks in early stage EOC may be the result of the central role for pro-survival signaling activation and a compensatory hyperactivation of AMPK pathway in response to the Warburg effect and mTOR activation. These results, confirmed in an independent study set, suggest that the utilization of drugs targeting AMPK, such as metformin, could be very useful in advanced ovarian cancer.
Outcomes of asymptomatic metastatic gastric cancer (MGC) patients when the initiation of systemic therapy is delayed.
Authors: Roopma Wadhwa, Elena Elimova, Kazuki Sudo, Hironori Shiozaki, Rebecca Slack, Hsiang-Chun Chen, Brian D. Badgwell, Aurelio Matamoros, Jeffrey H. Lee, Brian Weston, Manoop S. Bhutani, Mariela A. Blum, Jeannelyn Estrella, Prajnan Das, Jaffer A. Ajani
Journal: Journal of Clinical Oncology (2014)

4075 Background: Despite many investigations, the median survival of MGC patients remains well below 12 months. The purpose of this analysis was to assess if the onset (instant or delayed) of systemic chemotherapy affected patient survival. Methods: We retrospectively compared the outcome of MGC patients who received first line systemic treatment based on symptoms (symptomatic versus asymptomatic) and treatment timing (instant or delayed). The OS was calculated from time of initiation of chemotherapy. Results: 125 patients with MGC were analyzed. Patients were mostly men (65%) with good PS (0-1) but most (70%) were symptomatic. In all asymptomatic patients, the median time to start of chemotherapy was 7 weeks (95% CI: 5, 10). More treated asymptomatic patients were alive at 1 year (71%) post-therapy compared to symptomatic patients (45%; p=0.03). Patients were also grouped based on treatment delay of >4 weeks or no delay. Patients with >4-week delay were more likely to be alive 1 year after treatment (61%) compared to those treated within ≤4 weeks (34%; p =0.01). Asymptomatic patients in whom chemotherapy was delayed >4 weeks had 78% 1-year survival after treatment versus 53% in patients who started treatment ≤4 weeks but this was not significant (p=0.06). Conclusions: Acknowledging that asymptomatic MGC patients are likely to have a lower tumor burden than those with symptoms, our data suggest that we need not rush to initiate systemic treatment in asymptomatic MGC patients, thus allowing them time without chemotherapy toxicities. Frequent patient evaluations (q 8-10 weeks) are routine.
Abstract 20351: Transient Receptor Potential Ankyrin-1 Deficiency in Mice Protected Against Myocardial Ischemia-Reperfusion Injury
Authors: Daniel J Conklin, Yiru Guo, Ganapathy Jagatheesan, Peter Kilfoil, Matthew Nystoriak, Detlef Obal, Roberto Bolli, Aruni Bhatnagar
Journal: Circulation (2017)

Introduction: Myocardial ischemia-reperfusion (I/R) results in the generation of oxygen-derived free radicals, the accumulation of lipid peroxidation-derived unsaturated aldehydes, variable angina ...
Personalized cancer therapy for ovarian cancer patients.
Authors: Alfredo Aguilar, Priscila I. Valdiviezo, Carolina Ibañez, Maria L Bravo, Pamela Gonzales, Sumi Kato, Marcelo Garrido, Jorge Brañes, Javier Pizarro, Maria I Barriga, Hector Leon, EVA Bustamante, Catalina Alonso, Erasmo Bravo, Clemente Arab, Alejandro Barra, Nicanor Barrena, Paula Jimenez, Mauricio A Cuello, Gareth I Owen
Journal: Journal of Clinical Oncology (2014)

e16521 Background: The treatment of ovarian cancer consists principally in radical surgery followed by chemotherapy. Patients generally respond well to first line chemotherapy (70%) but consistently relapse within 18 months, with successive rounds of chemotherapy offering low patient benefit. Despite every cancer being unique, all cancer patients are generally treated by the same chemotherapy regimes. An approach used in the past has been to use chemosensitivity assays based on cells isolated from solid tumors to predict chemotherapy response. However, recent advances have demonstrated that the metastatic cancer cell is distinct to that found in the primary tumor and is thus the true target of chemotherapy. Methods: We have developed in-house techniques to expand and enrich in stem cell markers, cancer cells isolated from ascitic fluid. Our objective was to isolate these potential ovarian metastatic cells from patients and coorelate their in vitro response to the chemotherapy observed in the patient. Primary cultures of ovarian cancer cells (peritoneal fluid) were obtained with signed informed consent from a network of Chilean and Peruvian hospitals. Chemotherapy response was assessed by MTS and data correlated with medical follow-up. Results: Analysis of 62 assays for ovarian cancer patients with clinical follow-up demonstrated showed a marked separation of the curves of progression free survival (PFS) according to the classification of our in vitro assay. Analysis of only first line patients (32 assays) demonstrated a median progression free survival (PFS) of 17 months for patients predicted to respond to treatment in our assay, but only an average of 2 months PFS in patients where our assay predicted treatment failure. In second line therapies (upon relapse) the correlation with our assay and treatment failure was 92.3%. Conclusions: When using exclusively cancer cells extracted from ascites and an in-house expansion and enrichment technique, we demonstrate a clear distinction in time to relapse between patients we predict or do not predict to respond to treatment. Our results demonstrate the requirement of the medical community to consider reevaluating this procedure and to expand this assay to the stage of randomized clinical trials.
A Phase II Study of Pegylated Asparaginase, Cyclophosphamide, Rituximab, and Dasatinib Added to the UCSF 8707 (Linker 4-drug) Regimen with Liposomal Cytarabine CNS Prophylaxis for Adults with Newly Diagnosed Acute Lymphoblastic Leukemia (ALL) or Lymphoblastic Lymphoma (LBL): University of California Hematologic Malignancies Consortium Study (UCHMC) 1401
Authors: Matthew J. Wieduwilt, Brian A. Jonas, Gary J. Schiller, Lin Liu, Carolyn Mulroney, Gabriel N. Mannis, Dimitrios Tzachanis, Januario E. Castro, Edward D Ball, Peter T. Curtin, Charalambos Andreadis, Aaron C. Logan, Jesika Reiner, Lloyd E. Damon
Journal: Blood (2018)
Whole-body diffusion-weighted MRI (DWMR) compared with [68Ga] DOTATOC-PET/CT (68Ga) and OctreoScan (OCT) for staging neuroendocrine tumors (NET).
Authors: Regis Bezerra, Brenda Pires Gumz, Elba Etchebehere, Allan OLIVEIRA Santos, Recidia Rayane Reboucas Fernandes, Paulo Marcelo Hoff, Ralph Strecker, Marcos Menezes, Frederico Costa
Journal: Journal of Clinical Oncology (2014)

e15167 Background: G1/G2 NET can be indolent neoplasms usually diagnosed with distant metastasis. 68Ga and OCT are commonly used methods for NET staging. Both use somatostatin analog affinity for tumor localization. DWMR is a promising staging method for NET, that can study the whole body. Accuracy for DWMR in comparison with 68Ga and OCT is unknown. Methods: Data from 19 patients with pathology proven G1/G2 stage IV NET underwent Ga68, OCT and DWMR with < 90 days apart. Primary site was pancreas 37%, lung 21%, small bowel 21%, unknown 10% and others 11%. DWMR used the same 1.5-T whole-body imager without intravenous (IV) contrast. For every scan, whole body examination was obtained in coronal plane using a set of head and neck, two-body matrix and a spine array coil in three sequences (T1, STIR-short tau inversion recovery and diffusion). Staging methods were blind read using a pre-planned report schema by three independent investigators, one for each modality. Results from all studies were compared for accuracy determination. Results: Using OCT as gold-standard, DWMR had 11% higher accuracy (ACR) (p=0.003), 16% higher sensitivity (SEN) (p=0.008), similar specificity (SPE), similar positive predictive value (PPV) and 27% higher negative predictive value (NPV) (p=0.047) than 68Ga. Using 68Ga as gold-standard, DWMR had 5% higher accuracy (ACR) (p=0.023) and similar SEN, SPE, PPV and NPV than OCT. The Table shows DWMR analysis by body site and 68Ga concordance using OCT as gold-standard. Conclusions: DWMR has similar accuracy in comparison with 68Ga or OCT in the staging of G1/G2 NET. DWMR seems complementary to these two functional studies. The world wide availability of MRI machines, the lack of radiation and IV contrast make this staging method attractive and deserve further validation studies. Body site ACR SEN SPE PPV NPV Kappa (DWMR -68Ga) Lung 0.89 0.88 1.0 1.0 0.5 0.61 Liver 0.95 0.88 1.0 1.0 0.92 0.89 Pancreas 1.0 1.0 1.0 1.0 1.0 1.0 GI tract 1.0 1.0 1.0 1.0 1.0 1.0 LN 0.95 0.88 1.0 1.0 0.92 0.89 MSS 0.84 0.85 0.83 0.92 0.71 0.65 Abbreviations: GI tract, gastrointestinal tract; LN, lymph nodes; MSS, muscle-skeleton system. Concordance: kappa: 0.61-0.80 good; 0.81-0.99 excellent; 1.0 perfect.