tbuckley/cabot-search huggingface dataset:
Genomic predictors of neoadjuvant chemotherapy (NACT) response in breast cancer (BC).
Authors: Andrea Li Ann Wong, Kar Tong Tan, Raghav Sundar, Samuel Ow, Angela Pang, Hui-Ling Yap, Ching-Wan Chan, Mikael Hartman, Philip Iau, Shaik Ahmad Buhari, Maria Jannet Mogro, Iain BeeHuat Tan, Ling-Zhi Wang, Henry Yang, Boon C. Goh, Soo-Chin Lee
Journal: Journal of Clinical Oncology (2017)

e12122 Background: We assessed effects of NACT on BC mutational landscape. Methods: Baseline (BL) and post-NACT tumor / matched normal DNA from 12 newly diagnosed BC patients on NACT (4 x doxorubicin/cyclophosphamide + low dose sunitinib; NCT01176799) were subject to whole exome sequencing. Nonsynonymous somatic single nucleotide variants from 34 genes in known BC signaling pathways were evaluated for changes in mutant variant allele frequency (VAF) according to clinical outcome. Poor outcome was defined as &lt;50% target lesion reduction after NACT or BC relapse / progression (PD) within 2 years; significant change was defined as &gt; 0.2 difference in BL vs post-NACT mutant VAF. Results: Mean tumor size was 6.4 + 2.9cm; 50% were N+; 8% were M1; 7/12 patients had poor outcomes. Tumors harbored mutations in PI3K (58%), NOTCH (42%), Wnt (42%), TP53 (33%) and FOXA (17%) pathways. Change in no. of somatic mutations post-NACT correlated with outcome (mean percent change +14% vs -30% in patients with poor vs good outcome, p=0.04). 11 patients had &gt;1 of 23 putative driver mutations identified ( Table 1). Mutant VAF declined significantly in those with good outcomes, except for a new NOTCH2 mutation in A2 and rise in mutant VAF in A4. In patients with poor outcomes, mutant VAF persisted or rose, and emergent mutations (AKT1, PIK3CA) occurred in 2 patients. Conclusions: Chemoresistance and emergent mutations were revealed by tracking mutant VAF in BC patients on NACT. Clinical trial information: NCT01176799. [Table: see text]
Amino Acid Transporter Slc38a5 Controls Glucagon Receptor Inhibition-Induced Pancreatic α Cell Hyperplasia in Mice
Authors: Jinrang Kim, Haruka Okamoto, ZhiJiang Huang, Guillermo Anguiano, Shiuhwei Chen, Qing Liu, Katie Cavino, Yurong Xin, Erqian Na, Rachid Hamid, Joseph Lee, Brian Zambrowicz, Roger Unger, Andrew J. Murphy, Yan Xu, George D. Yancopoulos, Wen-hong Li, Jesper Gromada
Journal: Cell Metabolism (2017)
Non-Coding Transcripts from Enhancers: New Insights into Enhancer Activity and Gene Expression Regulation
Authors: Hongjun Chen, Guangshi Du, Xu Song, Ling Li
Journal: Genomics Proteomics & Bioinformatics (2017)

Long non-coding RNAs (lncRNAs) have gained widespread interest in the past decade owing to their enormous amount and surprising functions implicated in a variety of biological processes. Some lncRNAs exert function as enhancers, i.e., activating gene transcription by serving as the cis-regulatory molecules. Furthermore, recent studies have demonstrated that many enhancer elements can be transcribed and produce RNA molecules, which are termed as enhancer RNAs (eRNAs). The eRNAs are not merely the by-product of the enhancer transcription. In fact, many of them directly exert or regulate enhancer activity in gene activation through diverse mechanisms. Here, we provide an overview of enhancer activity, transcription of enhancer itself, characteristics of eRNAs, as well as their roles in regulating enhancer activity and gene expression.
PTU-120 Quantitative Magnetic Resonance Imaging (MRI) in the Evaluation of the Degree of Steatosis, Iron Accumulation and Fibrosis in Chronic Liver Diseases (Mrker Study): Abstract PTU-120 Table 1
Authors: C L Hoad, N Palaniyappan, P Kaye, S Bawden, M Stephenson, G Dolman, M W James, C Costigan, A Austin, Y Chernova-Chernaya, P A Gowland, I N Guha, S T Francis, G P Aithal
Journal: Gut (2013)

<h3>Introduction</h3> Half of all the liver biopsies performed are to assess the severity of pathology including grading of fat, iron accumulation as well as fibrosis. Liver biopsies are invasive tests associated with sampling errors; the coefficient of variation for fibrosis measurement is 45% even with 25mm long specimens. We aimed to develop and validate non-contrast, non-breath-holding, quantitative MRI methodology to estimate the amout of fibrosis, fat and iron accumulation within the whole liver. <h3>Methods</h3> MRI relaxation time data (T1, T2and T2*) were acquired (over 15–20 minutes) using a novel Echo Planar Imaging technique with a respiratory-triggered (r.t.) acquisition method. 1H MR spectra were acquired (r.t.) using a multiple echo PRESS acquisition which allowed for individual T2correction to the spectrum for accurate quantification of the fat fraction in a 30x30x30mm3voxel. <h3>Results</h3> 115 patients (67 Training; 48 Validation cohort) with suspected chronic liver disease aged 19 to 72 years [alcoholic (13%), non-alcoholic (56%) fatty liver disease, chronic viral hepatitis (21%) and haemochromatosis (3%)] who had a liver biopsy ≥25 mm were included in the study. The diagnostic accuracy of the T1 parameter in the detection of different histological stages of fibrosis, using receiver operator curves and areas under the curve (AUC), in the training and validation cohort are summarised in Table 1. There were also significant correlations between MR measures of fat fraction and staging of steatosis with a Spearman’s correlation coefficient of 0.760 (p &lt; 0.001) and T2* with hepatic iron staging with Spearman’s correlation coefficient of –0.588 (p &lt; 0.001). The T1 relaxation time of the liver correlated with the percentage of fibrosis measured as a continous variable on morphometry within the entire study population (Pearson correlation coefficient of 0.712, p &lt; 0.001). <h3>Conclusion</h3> Across a range of chronic liver diseases, MR measures of fat fraction, hepatic iron content and fibrosis of the whole liver correlate well with related histological measures. <h3>Disclosure of Interest</h3> None Declared
Fecal microbiota transplant from a rational stool donor improves hepatic encephalopathy: A randomized clinical trial
Authors: Jasmohan S. Bajaj, Zain Kassam, Andrew Fagan, Edith A. Gavis, Eric Liu, I. Jane Cox, Raffi Kheradman, Douglas Heuman, Jessica Wang, Thomas Gurry, Roger Williams, Masoumeh Sikaroodi, Michael Fuchs, Eric Alm, Binu John, Leroy R. Thacker, Antonio Riva, Mark Smith, Simon D. Taylor‐Robinson, Patrick M Gillevet
Journal: Hepatology (2017)

Recurrent hepatic encephalopathy (HE) is a leading cause of readmission despite standard of care (SOC) associated with microbial dysbiosis. Fecal microbiota transplantation (FMT) may improve dysbiosis; however, it has not been studied in HE. We aimed to define whether FMT using a rationally derived stool donor is safe in recurrent HE compared to SOC alone. An open-label, randomized clinical trial with a 5-month follow-up in outpatient men with cirrhosis with recurrent HE on SOC was conducted with 1:1 randomization. FMT-randomized patients received 5 days of broad-spectrum antibiotic pretreatment, then a single FMT enema from the same donor with the optimal microbiota deficient in HE. Follow-up occurred on days 5, 6, 12, 35, and 150 postrandomization. The primary outcome was safety of FMT compared to SOC using FMT-related serious adverse events (SAEs). Secondary outcomes were adverse events, cognition, microbiota, and metabolomic changes. Participants in both arms were similar on all baseline criteria and were followed until study end. FMT with antibiotic pretreatment was well tolerated. Eight (80%) SOC participants had a total of 11 SAEs compared to 2 (20%) FMT participants with SAEs (both FMT unrelated; P = 0.02). Five SOC and no FMT participants developed further HE (P = 0.03). Cognition improved in the FMT, but not the SOC, group. Model for End-Stage Liver Disease (MELD) score transiently worsened postantibiotics, but reverted to baseline post-FMT. Postantibiotics, beneficial taxa, and microbial diversity reduction occurred with Proteobacteria expansion. However, FMT increased diversity and beneficial taxa. SOC microbiota and MELD score remained similar throughout.FMT from a rationally selected donor reduced hospitalizations, improved cognition, and dysbiosis in cirrhosis with recurrent HE. (Hepatology 2017;66:1727-1738).
Bisphenol A substitutes and obesity in US adults: analysis of a population-based, cross-sectional study
Authors: Buyun Liu, Hans-Joachim Lehmler, Yangbo Sun, Guifeng Xu, Yuewei Liu, Geng Zong, Qi Sun, Frank B Hu, Robert B Wallace, Wei Bao
Journal: The Lancet Planetary Health (2017)

BackgroundBisphenol F (BPF) and bisphenol S (BPS) are increasingly used in consumer products as substitutes for bisphenol A (BPA), a widespread environmental endocrine disruptor and putative obesogen. However, studies on the effects of BPF and BPS on obesity in human beings are scarce. We examined the associations of BPA, BPF, and BPS exposure with obesity in US adults.MethodsWe included participants aged 20 years or older, who had available data on concentrations of BPA, BPF, and BPS (n=1709), from a cross-sectional study, the National Health and Nutrition Examination Survey 2013–14. Participants who were pregnant or had cancer were excluded from the analysis. Urinary BPA, BPF, and BPS concentrations were measured using on-line solid phase extraction coupled to high performance liquid chromatography and tandem mass spectrometry. We used body-mass index to define general obesity and waist circumference to define abdominal obesity. We used logistic regression with sample weights to estimate the odds ratios (ORs) for obesity.Findings1521 participants were included in the analysis. Higher BPA, BPF, and BPS concentrations were observed in adults who were obese than adults who were not obese; median concentration 1·5 ng/mL (IQR 0·7–2·8) versus 1·1 ng/mL (0·5–2·3) for BPA, 0·4 ng/mL (0·1–1·3) versus 0·3 ng/mL (0·1–0·9) for BPF, and 0·4 ng/mL (0·2–1·0) versus 0·3 ng/mL (0·1–0·8) for BPS. After adjustment for demographic, socioeconomic, and lifestyle factors, and urinary creatinine concentrations, BPA, but not BPF or BPS, was significantly associated with obesity. The OR for general obesity was 1·78 (95% CI 1·10–2·89; p=0·04 for trend) comparing the highest with lowest quartile of BPA, 1·02 (0·70–1·47; p=0·81 for trend) for BPF, and 1·22 (0·81–1·83; p=0·30 for trend) for BPS. The corresponding OR for abdominal obesity was 1·55 (1·04–2·32; p=0·02 for trend) for BPA, 1·05 (0·68–1·63; p=0·99 for trend) for BPF, and 1·16 (0·72–1·88; p=0·54 for trend) for BPS.InterpretationWhereas there were significant associations of BPA exposure with general and abdominal obesity, concentrations of BPF or BPS were not significantly associated with obesity in US adults at current exposure levels. Continued biomonitoring of these bisphenols and further investigation into their health effects on human beings are warranted.FundingNational Institutes of Health.
Outcomes related to delayed initiation of anti-HER 2 therapy in pregnant HER2 positive breast cancer patients.
Authors: Oluchi Oke, Carla L. Warneke, Mariana Chavez-Mac Gregor, Andrea Milbourne, Jennifer Keating Litton
Journal: Journal of Clinical Oncology (2017)

e12059 Background: Overexpression of HER2 is associated with aggressive breast cancers. In non-pregnant HER2+ breast cancer patients, anti-HER2 therapy is usually initiated after surgery or in the neoadjuvant setting. However, for pregnant HER2+ breast cancer patients, anti-HER2 therapy must be delayed until after delivery due to fetal toxicity. We describe here the outcomes of pregnant patients with HER2+ breast cancer at a single center. Methods: Twenty-three pregnant HER2+ breast cancer patients were treated between November 1989 to October 2016. Median age at diagnosis was 31.8. (Table 1) We report Kaplan-Meier estimates of OS from diagnosis and PFS from surgery. The effect of time from diagnosis to anti-HER2 therapy (TTH) on OS and PFS from HER2 therapy initiation was assessed using Cox proportional hazards regression models. Results: Seventeen patients received anti-HER2 therapy after delivery, 6 did not – 4 were treated prior to the use of HER2 therapies, and 2 were lost to follow-up. Median TTH was 181 days. All but 3 patients started HER2 treatment within 2 months of delivery. Twenty-one received anthracycline-based chemotherapy during pregnancy. Three patients have died, with all 3 receiving HER2 therapy, but one only at relapse due to diagnosis before routine trastuzumab use. Median follow-up was 3.4 years (range 0.2-16.2 years), and 5-year OS was 80% (95%CI 41-95%). Five patients progressed. Median PFS was 3.1 years (range 0.3-14.2 years), and 5-year PFS was 75% (95%CI 46-90%). Delay of initiation of HER-2 therapy did not appear to be associated with OS or PFS from date of HER-2 therapy initiation (both n = 17, HR 1.01, 95%CI 0.97-1.06, P= 0.52). Conclusions: In this small case series, we did not detect adverse outcomes associated with delaying initiation of anti-HER2 therapy in pregnant patients with HER2+ breast cancer. Larger series are needed to further evaluate this concern. [Table: see text]
Health-related quality of life (HRQoL) of postmenopausal women with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC) treated with ribociclib + letrozole: Results from MONALEESA-2.
Authors: Sunil Verma, Joyce O'Shaughnessy, Howard A. Burris, Mario Campone, Emilio Alba, David Chandiwana, Stephanie Manson, Santosh C. Sutradhar, Mauricio Monaco, Wolfgang Janni
Journal: Journal of Clinical Oncology (2017)

1020 Background: In the MONALEESA-2 trial, ribociclib + letrozole significantly improved progression-free survival (PFS) and showed higher overall response rates vs letrozole alone in HR+, HER2– ABC. To place these clinical results in the context of patient experience, here we present key patient-reported outcomes (PROs) including HRQoL. Methods: 668 patients were randomized (1:1); 334 each to the ribociclib + letrozole and placebo + letrozole arms. PROs were evaluated during treatment and at progression using the EORTC QLQ-C30, QLQ-BR23, and EQ-5D-5L questionnaires. Changes from baseline in all subscales were analyzed using a linear mixed-effect model and time to 10% deterioration was compared between treatment arms using the stratified log-rank test. Results: Questionnaire compliance rates were high (≥90%). During treatment, HRQoL (global health status/QoL score) was maintained and similar in both treatment arms. At progression/end of treatment, HRQoL worsened numerically in both arms. Time to definitive 10% deterioration of HRQoL was similar between treatment groups, slightly favoring the ribociclib + letrozole arm (hazard ratio: 0.89; 95% confidence interval: 0.67–1.18). No statistically or clinically relevant differences were observed for key symptoms using EORTC QLQ-C30 including fatigue, nausea, and vomiting. There was a clinically relevant ( &gt; 5 points) improvement in pain from baseline to post-baseline (up to Cycle 15) in the ribociclib + letrozole arm while there was only mild improvement ( &lt; 5 points) observed in the placebo + letrozole arm. Conclusions: In addition to significantly improving PFS, ribociclib + letrozole maintains HRQoL when compared with letrozole + placebo. A numerical trend was observed favoring ribociclib + letrozole for pain reduction. Clinical trial information: NCT01958021.
Genomic alterations driving breast cancer (BC) metastases and their relationship with the subtype switch in the GEICAM ConvertHER study.
Authors: Joan Albanell, Abel Gonzalez, Ana M. Gonzalez-Angulo, Agda Karina Eterovic, Eduardo Martinez-De Duenas, Xiaofeng Zheng, Angel Guerrero, Shuying Liu, Ramon Pérez-Carrión, Ken Chen, Jose Ignacio Chacon, Gordon B. Mills, Silvia Antolín Novoa, Isabel Blancas, Maria Sanchez-Arago, Eva Maria Carrasco, Rosalia Caballero, Federico Rojo, Funda Meric-Bernstam, Ana Lluch Hernandez
Journal: Journal of Clinical Oncology (2017)

1017 Background: To understand the mechanisms underlying the evolution of tumors in the process of metastasis, we studied 61 paired primary-relapse BC from the GEICAM ConvertHER study. While some of the metastases maintained the clinical (ER/PR and HER2 status) and/or intrinsic subtype (defined by expression arrays) of the original tumor (concordant), others exhibited a subtype shift (discordant). We aimed to identify the genomic alterations driving the metastases and, particularly, their relationship with the subtype switch. Methods: We detected the somatic variants (mutations and copy number alterations (CNAs)) affecting 202 genes across the 61 sample pairs via targeted sequencing. We employed the Cancer Genome Interpreter (cancergenomeinterpreter.org), a bioinformatics approach to identify the alterations most likely driving tumorigenesis, and subsequently identified those whose cancer cell fraction markedly changed in the metastases. We explored the clonal remodeling in metastasis comparing the cell fractions of driver mutations in both concordant and discordant tumors. Results: We found that 156 genes had 747 somatic mutations and 171 genes suffered 1042 somatic CNAs in the 61 studied tumor pairs. We identified a median of 11 and 9 mutations in primaries and metastases, respectively. Several frequent BC mutational drivers, such as TP53, PIK3CA, MLL3, MAP3K1, and NOTCH2 were amongst the more frequently changed their cancer cell fraction in metastases with respect to primaries. We found that driver mutations of discordant tumors exhibited a significantly higher increase of clonal cell fraction. Moreover, whether the clonal status of a driver mutation was conserved in the metastasis was significantly associated to whether the tumor maintains its clinical subtype but not its intrinsic subtype. Conclusions: Our results suggest that a shift in the clinical subtype of BC undergoing metastasis is accompanied by more significant changes at the genomic level than those suffered by tumors that maintain their clinical subtype. This remodeling of the landscape of drivers could open new therapeutic opportunities to specifically target discordant BC.
Predictive modeling of adverse events in chemotherapy.
Authors: Roma Maguire, Cees van Berkel, Julie Cowie, Robert L. Blake, Nora Kearney
Journal: Journal of Clinical Oncology (2012)

e19617 Background: Patients with cancer receiving chemotherapy are at risk of developing severe or life threatening adverse events (AEs). The aim of this study was to develop and test a risk model for six common toxicities based on a detailed analysis of daily self-reported symptoms. The retrospective study was performed on a data set of 33 breast cancer patients who self reported symptoms over multiple therapy cycles. The monitored symptoms were diarrhoea, hand-foot syndrome, mucositis, nausea, vomiting and fatigue. Methods: The data analysis focused on four toxicity aspects: the occurrence patterns, the severity distributions, the duration and the interrelationship between symptoms. The clustering of symptoms was a key aspect of the modeling. The data analysis was supported and augmented with knowledge from an expert group of clinicians and an advisory group of patients. The final model is a Bayesian network in which the probability of toxicity on a given day, depends on the probability of that toxicity on a previous day and on the probability of others with which it is linked. Personalized predictions are made by feeding patient self reported observations from a particular patient into the model. Results: The different toxicities show quite marked and varied time (day to day) behaviors and there are strong and significant interrelations between fatigue / nausea, vomiting / nausea and fatigue / vomiting. The model provides effective prediction of toxicity over the entire set of symptoms. The Area Under the Curve (AUC) values for personalized prediction over different forecasting periods ranged from one day ahead (AUC=0.89) to 7 days ahead (AUC=0.82). Non personalized prediction gives an AUC of 0.78 for all time periods. Conclusions: Personalized prediction based on real-time self-reported symptoms is effective on timescales up to one week. These predictions may be useful for patient care. If communicated appropriately to patients, they can be used to target information sharing on side effects, support self-care and plan activities of daily living in advance. For clinicians the information can be useful to identify patients who are at greater risk of developing certain AEs, facilitating more efficacious, timely and cost-effective interventions.
Vitamin D and Breast Cancer Survival
Authors: Raffaella Mormile
Journal: JAMA Oncology (2017)

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Temporal trends in the intensity and duration of oncologic care among colorectal cancer (CRC) patients (pts).
Authors: Leo Chen, John Joseph Spinelli, Winson Y. Cheung, Hagen F. Kennecke
Journal: Journal of Clinical Oncology (2017)

6552 Background: Substantial advances in therapy of CRC pts occurred between 2000 and 2012 contributing to a significant increase in overall survival. The objective of this study is to quantify the change in treatment (tx) intensity as measured by clinic and tx visits at a network of medical and radiation oncology clinics. Methods: Electronic scheduling records of stage I-IV CRC patients referred between 2000-2012 to the six oncology centers comprising the British Columbia Cancer Agency were reviewed and stratified by tx phases: I and II (adjuvant first 6 months, continued), III and IV (palliative first 6 months, continued), and V (last 6 months of life). Clinic Visit Intensity (CVI), Chemo Tx Intensity (CTI), number of chemo agents and number of cycles (CC), Radiotherapy (Rx) courses (RC) and fractions (RF) were measured, and trends by referral year were modelled using zero inflated negative binomial regression. Mean duration of visit for chemo tx (CHD) and clinic visits (CVD) were modelled using linear regression. Sex, age at diagnosis, stage, income, and community size were included in models if terms were significant. Results: 15,157 pts were included across 10 cohorts. CTI and CC increased significantly in tx phases II-V with later year of referral, while phase I results were stable or decreased, likely due to the substitution of oral for intravenous regimens. Rx increased only in advanced phases. Mean duration of scheduled time showed significant increases. Conclusions: CRC pts referred in 2012 vs 2000 receive significantly greater intensity and duration of care in tx phases II-V. Results have significant implications for resource allocation and the patient experience. [Table: see text]