tbuckley/cabot-search huggingface dataset:
Continuity of transcriptomes among colorectal cancer subtypes based on meta-analysis
Authors: Siyuan Ma, Shuji Ogino, Princy Parsana, Reiko Nishihara, Zhirong Qian, Jeanne Shen, Kosuke Mima, Yohei Masugi, Yin Cao, Jonathan A. Nowak, Kaori Shima, Yujin Hoshida, Edward L. Giovannucci, Manish K. Gala, Andrew T. Chan, Charles S. Fuchs, Giovanni Parmigiani, Curtis Huttenhower, Levi Waldron
Journal: Genome biology (2018)

Previous approaches to defining subtypes of colorectal carcinoma (CRC) and other cancers based on transcriptomes have assumed the existence of discrete subtypes. We analyze gene expression patterns of colorectal tumors from a large number of patients to test this assumption and propose an approach to identify potentially a continuum of subtypes that are present across independent studies and cohorts. We examine the assumption of discrete CRC subtypes by integrating 18 published gene expression datasets and > 3700 patients, and contrary to previous reports, find no evidence to support the existence of discrete transcriptional subtypes. Using a meta-analysis approach to identify co-expression patterns present in multiple datasets, we identify and define robust, continuously varying subtype scores to represent CRC transcriptomes. The subtype scores are consistent with established subtypes (including microsatellite instability and previously proposed discrete transcriptome subtypes), but better represent overall transcriptional activity than do discrete subtypes. The scores are also better predictors of tumor location, stage, grade, and times of disease-free survival than discrete subtypes. Gene set enrichment analysis reveals that the subtype scores characterize T-cell function, inflammation response, and cyclin-dependent kinase regulation of DNA replication. We find no evidence to support discrete subtypes of the CRC transcriptome and instead propose two validated scores to better characterize a continuity of CRC transcriptomes.
Abstract 17572: Single-beat 3D Transthoracic Echocardiography Applied to Carcinoid Heart Disease and Pulmonary Arterial Hypertension is Feasible and Accurate for Right Ventricular Volumetric Quantification Compared With MRI, With Incremental Value Over 2D Echocardiography
Authors: Daniel S Knight, Agata Grasso, Vivek Muthurangu, Andrew M Taylor, John G Coghlan, Joseph Davar
Journal: Circulation (2013)

Introduction: The right ventricle (RV) is a clinically important, complex structure that is challenging to quantify by 2D echocardiography (2DE). Single-beat full volume 3D echocardiography (SB3DE) can acquire large volumes at high volume rates in one cardiac cycle, without stitching artefact. We evaluated the accuracy and reproducibility of SB3DE for quantifying RV volumes in large adult populations of acquired RV pressure- or volume-overload, namely pulmonary arterial hypertension (PAH) and carcinoid heart disease (CHD) respectively. Methods: One-hundred individuals underwent 2DE, SB3DE and cardiac magnetic resonance imaging (CMRI): 49 patients with PAH, 20 with CHD, 11 with metastatic carcinoid tumor but without CHD, and 20 healthy volunteers. Two operators performed test-retest acquisition and post-processing for inter- and intraobserver variability in 21 subjects. Results: RV SB3DE was attainable in 96% of cases. Average volume rates were 33 volumes per second (vps) for disease groups and 42 vps for ...
Modifying Rap1-signalling by targeting Pde6δ is neuroprotective in models of Alzheimer’s disease
Authors: Michael Dumbacher, Tom Van Dooren, Katrien Princen, Koen De Witte, Mélissa Farinelli, Sam Lievens, Jan Tavernier, Wim Dehaen, Stefaan Wera, Joris Winderickx, Sara Allasia, Amuri Kilonda, Stéphane Spieser, Arnaud Marchand, Patrick Chaltin, Casper C. Hoogenraad, Gerard Griffioen
Journal: Molecular Neurodegeneration (2018)

Neuronal Ca2+ dyshomeostasis and hyperactivity play a central role in Alzheimer's disease pathology and progression. Amyloid-beta together with non-genetic risk-factors of Alzheimer's disease contributes to increased Ca2+ influx and aberrant neuronal activity, which accelerates neurodegeneration in a feed-forward fashion. As such, identifying new targets and drugs to modulate excessive Ca2+ signalling and neuronal hyperactivity, without overly suppressing them, has promising therapeutic potential.Here we show, using biochemical, electrophysiological, imaging, and behavioural tools, that pharmacological modulation of Rap1 signalling by inhibiting its interaction with Pde6δ normalises disease associated Ca2+ aberrations and neuronal activity, conferring neuroprotection in models of Alzheimer's disease.The newly identified inhibitors of the Rap1-Pde6δ interaction counteract AD phenotypes, by reconfiguring Rap1 signalling underlying synaptic efficacy, Ca2+ influx, and neuronal repolarisation, without adverse effects in-cellulo or in-vivo. Thus, modulation of Rap1 by Pde6δ accommodates key mechanisms underlying neuronal activity, and therefore represents a promising new drug target for early or late intervention in neurodegenerative disorders.Targeting the Pde6δ-Rap1 interaction has promising therapeutic potential for disorders characterised by neuronal hyperactivity, such as Alzheimer's disease.
Methods for alerting clinicians to concerning symptom questionnaire responses during cancer care: Approaches from two randomized trials (STAR, AFT-39 PRO-TECT).
Authors: Angela M. Stover, Sydney Henson, Allison Mary Deal, Carrie Tompkins Stricker, Karen Joan Hammelef, Antonia Vickery Bennett, Philip M Carr, Jennifer Jansen, Lisa A. Kottschade, Amylou C. Dueck, Ethan M. Basch
Journal: Journal of Clinical Oncology (2018)

158 Background: There is limited research on methods for alerting clinicians to concerning patient-reported outcome (PRO) responses and how often PROs trigger alerts to nurses during cancer care. Methods: In two randomized trials, adults with advanced cancer receiving chemotherapy were enrolled. Participants were randomized to usual care vs. weekly PROs completed between visits (with automated feedback to nurses). PRO responses in the intervention arm triggered automated email alerts to nurses for frequent, severe, or worsening symptoms in the last 7 days. Alert thresholds for PROs were chosen a priori but were unique to each study. The “Symptom Tracking and Reporting” (STAR) trial was conducted at one academic medical center. The “PROs to Enhance Cancer Treatment” (PRO-TECT [AFT-39]) cluster-randomized trial is being conducted in &gt; 30 community practices. Results: In STAR, 766 patients participated (58% female, 38% ages ≥65, 17% minority, 28% ≤high school). 441 participants were randomized to the intervention arm, where 1,431/84,212 items (2%) triggered a concerning symptom alert, during 1,070/8,498 weeks (13%). Frequent alerts were for fatigue (62%), pain (32%), and appetite (16%). In PRO-TECT (AFT-39), 300 patients have been enrolled (58% female, 49% ages ≥65, 8% minority, 47% ≤high school) out of 1,000. 146 participants have been randomized to the intervention arm, where 1,422/24,739 items (6%) triggered an alert, during 824/2249 weeks (37%). Common alerts were for pain (48%), physical function (35%), and diarrhea (15%). PRO-TECT provided clinical decision support with alerts. Conclusions: In two randomized trials in advanced cancer, PROs collected during care delivery enabled tailored treatment based on issues identified on PROs. Pain, physical function, appetite, and diarrhea commonly triggered alerts for concerning symptoms. Early PRO-TECT results are showing a trend for higher weekly alert rates for concerning symptoms (37% vs. 13% in STAR), which may indicate that the PRO intervention will be even more effective in community practices. Results assist in addressing logistical considerations for implementing PROs into routine care. Clinical trial information: NCT03249090.
Abstract 14502: Risk of Ischemic Stroke in Newly Diagnosed Heart Failure Patients
Authors: Jeffrey S Berger, Eric Peterson, François Laliberté, Guillaume Germain, Dominique Lejeune, Jeff Schein, Patrick Lefebvre, Qi Zhao, Matthew Weir
Journal: Circulation (2016)

Background: Heart failure (HF) is a major cause of hospitalization and may increase the risk of stroke. Atrial fibrillation (AF) is frequently diagnosed in HF patients and could lead to an even higher risk of stroke. Ongoing trials will provide insights how to best protect HF patients against stroke and other adverse events. Objective: To quantify the incremental risk of ischemic stroke among newly diagnosed patients with HF, and the risk of stroke among HF patients with and without AF. Methods: A retrospective study was conducted using the Truven Health Analytics MarketScan Databases (01/2010-04/2015). HF patients with ≥18 months of enrollment prior to the index HF were matched 1:1 with non-HF patients based on propensity score method. Ischemic stroke was identified as a primary diagnosis in a hospitalization. Incidence rate (IR) and Kaplan-Meier (KM) rates for strokes were evaluated. A sensitivity analysis was performed excluding patients whose HF was diagnosed near a stroke evaluation (i.e., within 14 ...
Current and Future Management of Malignant Mesothelioma: A Consensus Report from the National Cancer Institute Thoracic Malignancy Steering Committee, International Association for the Study of Lung Cancer, and Mesothelioma Applied Research Foundation
Authors: Anne S. Tsao, O. Wolf Lindwasser, Alex A. Adjei, Prasad S. Adusumilli, Matthew L. Beyers, Gideon M. Blumenthal, Raphael Bueno, Bryan M. Burt, Michele Carbone, Suzanne E. Dahlberg, Marc de Perrot, Dean A. Fennell, Joseph Friedberg, Ritu R. Gill, Daniel R. Gomez, David H. Harpole, Raffit Hassan, Mary Hesdorffer, Fred R. Hirsch, Julija Hmeljak, Hedy L. Kindler, Edward L. Korn, Geoffrey Liu, Aaron S. Mansfield, Anna K. Nowak, Harvey I. Pass, Tobias Peikert, Andreas Rimner, Bruce W.S. Robinson, Kenneth E. Rosenzweig, Valerie W. Rusch, Ravi Salgia, Boris Sepesi, Charles B. Simone, Rajeshwari Sridhara, Peter Szlosarek, Emanuela Taioli, Ming-Sound Tsao, Haining Yang, Marjorie G. Zauderer, Shakun M. Malik
Journal: Journal of Thoracic Oncology (2018)
Efficacy of an antiemetic therapeutic interchange protocol driven by a medically integrated pharmacy.
Authors: Lalan S. Wilfong, Debra A. Patt, Kathryn Wallace, Sabrina Q. Mikan, Carla Portnoy, Leigh Kipley, Neal Dave, Jim R. Schwartz, J. Russell Hoverman
Journal: Journal of Clinical Oncology (2018)

133 Background: Control of chemotherapy induced nausea and vomiting (CINV) remains an unmet need. An antiemetic therapeutic interchange protocol was developed to enhance control of CINV. This abstract reports the efficacy results of patients treated with highly emetogenic regimens as defined by NCCN guidelines. Methods: Medically integrated pharmacists imbedded within 2 centers of a community oncology practice evaluated each new chemotherapy order and adjusted antiemetics including a 5HT3 antagonist, steroids, olanzapine and an NK1 inhibitor using an NCCN based protocol. Exact medications depended on insurance coverage and copays. Medications were adjusted for patient comorbidities, drug interactions and patient refusal. All patients were given prochlorperazine and ondansetron for breakthrough nausea and vomiting. Medication education to increase adherence was provided by the pharmacist, nurse and advance practice provider. Patients were evaluated by nursing or pharmacist calls on day 2 and 3 and as needed to characterize CINV using the Multinational Association of Supportive Care in Cancer (MASCC) antiemesis tool that scores CINV on a Likert scale. Based on review of the literature, a score of 3 or higher reflected symptom management failure. Additionally, due to drowsiness as the most commonly reported side effect of olanzapine, each center sought to characterize the risk of drowsiness. Results: 367 consecutive patients treated with highly emetogenic chemotherapy regimens were identified at two centers by pharmacists and followed by nursing or pharmacy calls over a 9-month timeframe: November 2016 to August 2017. 89% of patients had complete control of nausea with only 11% reporting nausea greater than a 3. Additionally, 11% of patients reported drowsiness greater than a 3. Conclusions: Administering a pharmacist driven antiemetic protocol is an effective way to control CINV. While CINV did occur, evaluation shows CINV was mild. We have shown that utilizing an antiemetic therapeutic interchange protocol with a collaborative care team including medically integrated pharmacists facilitates excellent control of CINV.
A Small Molecule, Shikonin, Dually Functions As a Proteasome Inhibitor and a Necroptosis Inducer In Multiple Myeloma Cells
Authors: Naoko Wada, Yawara Kawano, Shiho Fujiwara, Yoshitaka Kikukawa, Yutaka Okuno, Hiroaki Mitsuya, Hiroyuki Hata
Journal: Blood (2013)
Making Sense of the Genome Remains a Work in Progress
Authors: Wylie Burke
Journal: JAMA (2018)

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Nationwide utilization and costs of targeted anti-cancer drugs for elderly patients with solid tumors in the United States, 2004-2015.
Authors: Lauren E Wilson, Melissa Greiner, Ivy Altomare, Jason Rotter, Michaela Ann Dinan
Journal: Journal of Clinical Oncology (2018)

23 Background: Studies of patients age &lt; 65 suggest large increases in utilization and costs of targeted anti-cancer drugs (TADs). However, use and costs of TADs in patients age 65+ have not been examined in a national sample. Methods: We conducted a retrospective analysis of patients ≥ 65 years with invasive lung (LC), breast (BC), or colorectal (CC) cancer using Medicare 5% claims from 2004-2015. We identified the yearly proportion of cancer patients receiving an intravenous TAD and the proportion of Part D enrolled Medicare patients receiving an oral TAD. We examined yearly costs of TADs as a proportion of total Medicare cancer and all-cause spending. Using generalized linear models, we estimated yearly trends in mean cost per beneficiary for TADs, all cancer spending, and total Medicare cost with adjustment for age, sex, region and comorbidities. Costs were adjusted to 2015 dollars using the CPI medical cost index. Results: We observed higher uptake of IV TADs in the 65+ patient population for each of the three cancers compared to oral TADs. IV TAD utilization reached 9.8% in CC patients, 5.0% in lung cancer patients, and 3.7% of BC patients. Use of oral TADs remained lower than use of IV TADs (≤ 1% of patients across all three cancers). From 2005-2015, total and cancer-specific Medicare spending per beneficiary decreased slightly for CC and LC patients and remained stable for BC patients. However, adjusted mean IV TAD spending per beneficiary increased from $139 in 2005 to $897 in 2015 for LC, from $96 to $550 for BC, and from $384 to $455 for CC. For Part D patients, the combined contribution of IV and oral TADs to total yearly cancer spending increased significantly from 2006 to 2015 for LC (2 to 5%), BC (4 to 18%), and CC (6 to 12%) cancers. Conclusions: Use of IV TADs in the US elderly lung, breast, and colorectal cancer populations grew rapidly in the years following FDA approval and stabilized. Use of oral TADs remained low compared to IV agents. Against the backdrop of largely stable Medicare spending, TADs are increasingly responsible for a growing proportion of that spending, particularly in breast cancer patients where TADs accounted for nearly a fifth of all 2015 cancer spending for Part D patients.
Screen time: two hour daily limit would improve children’s cognition, study finds
Authors: Jacqui Wise
Journal: BMJ (2018)

Limiting children’s time spent watching screens to less than two hours a day—including phones, tablets, video consoles, and television—would improve their cognition, say researchers.1

Canada’s 24 Hour Movement Guidelines for Children and Youth recommend at least 60 minutes of physical activity a day, two hours or less of recreational screen time a day, and 9-11 hours of sleep a night.2

A study published in the Lancet Child and Adolescent Health journal examined the relation between sticking to these three recommendations and children’s cognitive development. Data were collected …
Mobile device access to electronic patient portals in oncology: Potential implications for patient and practice experiences.
Authors: Kelvin Ky-Minh Pho, Rong Lu, Samantha Gates, Jennifer Cai, Donglu Xie, Yang Xie, Simon Craddock Lee, David E. Gerber
Journal: Journal of Clinical Oncology (2018)

179 Background: Mobile devices provide individuals with rapid and frequent access to electronic patient portals. How patients use this growing and widespread technology to review test results and communicate with providers is not known. Methods: Retrospective study of patients enrolled in the MyChart electronic health portal associated with the EPIC electronic medical record in the Harold C. Simmons Comprehensive Cancer Center. We recorded type of portal access according to year and patient characteristics. Associations between patient characteristics and type of portal access were tested using Mann-Whitney test, Chi-square test, and linear Gaussian regression models. Results: Since the availability of mobile access in 2012, 2,524 patients accessed MyChart from a mobile device at least once, accounting for 291,526 mobile logins. The proportion of patients with mobile MyChart logins increased from 4% in 2012 to 13% in 2017 ( P= 0.004). Among these patients, the proportion of logins from mobile devices increased from 22% to 72% ( P&lt; 0.001). Mobile access occurred more frequently among younger ( P&lt; 0.001), black ( P= 0.002), and Hispanic ( P= 0.004) patients. In 2017, among patients who accessed MyChart from mobile devices at least once, those under age 40 years used the mobile application for over 90% of logins; those over age 60 years used the mobile application for 65% of logins. Black and Hispanic patients who used mobile MyChart access did so for approximately 80% of logins, compared to 70% of logins for non-Hispanic white patients. Before 2012, patients who went on to use mobile access averaged about five more logins per year than did mobile application never-users. While login frequency increased for both groups, the change was far greater for mobile application users. After 2012, total portal login frequency increased approximately 110% among patients who used mobile access, compared to 25% among non-users ( P&lt; 0.001). Conclusions: Mobile access to electronic health portals has increased patient portal use, particularly among traditionally underserved populations. How this widely and immediately available technology impacts patient and practice experiences warrants further study.
Aberrant phenotypic expression of MUC17 is associated with aggressive behavior of colorectal adenocarcinomas
Authors: Chandrakumar Shanmugam, Nirag Jhala, Sreelatha Meleth, Wade Junker, Surinder Batra, William Grizzle, Upender Manne
Journal: Cancer Research (2008)

987  Background: Mucins are the major secreted glycoprotein of gastrointestinal tract including the colon and the rectum. Aberrant expression of mucins has been known to play a role in colorectal carcinogenesis. Increased expression of MUC17, a recently identified membrane tethered mucin, was reported in pancreatic tumor tissues and in cancer cell lines of pancreas and colon. Nevertheless, the staining patterns of MUC17 and their clinical significance in colorectal adenocarcinomas (CRCs) have not been studied.  Methods: One hundred and thirty six patients, who underwent surgical resection for CRC and had not received any pre- or -post surgery therapy, were selected for this study. Formalin-fixed paraffin embedded tissue specimens from these patients were evaluated for phenotypic expression of MUC17 using rabbit polyclonal antibody and horse-radish peroxidase detection method. The expression levels and patterns were correlated with different clinicopathologic features and patient outcomes.  Results: In our study, MUC17 was localized to the cytoplasm, specifically in supra-nuclear position (punctate pattern), in all benign colonic epithelial tissues. In contrast, we observed two distinct patterns either punctate (60 of 136, 44%) or diffuse cytoplasmic (76 of 136, 56%) staining in tumor tissues. The cases in which the tumors exhibited diffuse cytoplasmic pattern were considered to be aberrant expressors of MUC17. The aberrant expression of MUC17 was significantly correlated with poor tumor differentiation (χ2, P=0.021) and with larger tumor size (χ2, P=0.011). Also, patients whose tumors demonstrated loss of punctate staining (diffuse cytoplasmic) patterns of MUC17 had a trend towards poor overall patient survival (logrank, P=0.072).Conclusion:These preliminary results suggest that the loss of punctate immunostaining pattern of MUC17 is associated with an aggressive behavior of colorectal adenocarcinomas and poor patient survival. This work is supported by funds from the National Institute of Health/National Cancer Institute (RO1-CA98932-01, 2U54-CA118948-03, U01CA111294, and the Early Detection Research Network, U24-CA086359).
Long-term follow-up after endoscopic resection for superficial esophageal squamous cell carcinoma: a multicenter Western study
Authors: Arthur Berger, Gabriel Rahmi, Guillaume Perrod, Mathieu Pioche, Jean-Marc Canard, Elodie Cesbron-Métivier, Jérôme Boursier, Elia Samaha, Ariane Vienne, Vincent Lépilliez, Christophe Cellier
Journal: Endoscopy (2018)

Abstract Background Endoscopic mucosal resection (EMR) and endoscopic submucosal dissection (ESD) are the first-line treatments for superficial esophageal squamous cell carcinoma (SCC). This study aimed to compare long-term clinical outcome and oncological clearance between EMR and ESD for the treatment of superficial esophageal SCC. Methods We conducted a retrospective multicenter study in five French tertiary care hospitals. Patients treated by EMR or ESD for histologically proven superficial esophageal SCC were included consecutively. Results Resection was performed for 148 tumors (80 EMR, 68 ESD) in 132 patients. The curative resection rate was 21.3 % in the EMR group and 73.5 % in the ESD group (P &lt; 0.001). The recurrence rate was 23.7 % in the EMR group and 2.9 % in the ESD group (P = 0.002). The 5-year recurrence-free survival rate was 73.4 % in the EMR group and 95.2 % in the ESD group (P = 0.002). Independent factors for cancer recurrence were resection by EMR (hazard ratio [HR] 16.89, P = 0.01), tumor infiltration depth ≥ m3 (HR 3.28, P = 0.02), no complementary treatment by chemoradiotherapy (HR 7.04, P = 0.04), and no curative resection (HR 11.75, P = 0.01). Risk of metastasis strongly increased in patients with tumor infiltration depth ≥ m3, and without complementary chemoradiotherapy (P = 0.02). Conclusion Endoscopic resection of superficial esophageal SCC was safe and efficient. Because it was associated with an increased recurrence-free survival rate, ESD should be preferred over EMR. For tumors with infiltration depths ≥ m3, chemoradiotherapy reduced the risk of nodal or distal metastasis.