tbuckley/cabot-search huggingface dataset:
Abstract 18410: Gastrointestinal Bleeding in Recipients of the HeartWare Ventricular Assist System
Authors: Daniel J Goldstein, Keith D Aaronson, Antoine Tatooles, Scott C Silvestry, Valluvan Jeevanandam, Robert A Gordon, David R Hathaway, Kevin B Najarian, Mark S Slaughter
Journal: Circulation (2013)

Purpose: Gastrointestinal bleeding (GIB) is a significant problem with continuous flow left ventricular assist devices. The HeartWare HVAD was recently approved for bridge to transplantation (BTT). GIB in patients supported with the HVAD as part of the pivotal BTT trial and the Continued Access Protocol (CAP) is reviewed. Methods: GIB events from 332 HeartWare recipients (140 BTT, 192 CAP patients) having at least 6 months of follow up (306 patient-years) were analyzed. Post implant anticoagulation consisted of heparin followed by Coumadin at a target INR of 2-3. Aspirin was recommended at 81-325 mg. Statistical analysis was performed using Fisher’s exact test for the comparison of proportions and Poisson regression for the comparison of event rates. Results: Forty-two (12.7%) patients (78.6% men) age 55.3 ± 11.4 yrs experienced a GIB. Overall, the 42 patients had 82 GIB events that resulted in 0.27 events PPY (range 1-7 events) with 38% experiencing a recurrent GIB. Median time to first GIB was 89 days. GIB was more frequent in patients receiving 81mg aspirin vs. 325mg (0.14 vs. 0.09 PPY, P=0.018). Patients with GIB were more likely to have ischemic CHF etiology (54.8% vs. 34.1% P =0.016), and diabetes (47.6% vs. 33.1%, P=0.083). Most GIB events (71/82, 86.6%) occurred &gt;30 days post implant and 94% required transfusions. Seventeen percent of events occurred in setting of INR &gt;3. GIB resulted in 65 rehospitalizations in 32 patients with a median length of stay of 8 days. Source of bleeding was ascribed to a definite or suspected AVM in 28% of patients while in 29% of patients, no source was identified. Location was 22% upper GI, 32% small bowel, 11% lower GI and 33% unknown. Forty-six percent of patients with GIB had an intervention such as cautery or clipping. None required surgery. There were no deaths related to GIB. Conclusion: GIB occurred in 12.7% of HVAD recipients followed for at least 6 months postop. GIB events were often recurrent, led to transfusions and were rarely associated with supratherapeutic INRs. Most occurred outside the perioperative window and AVMs were the predominant culprit lesion. Rehospitalizations were frequent and prolonged. Efforts to reduce the incidence of and readmissions for GIB are warranted.
A descriptive analysis of clinician input and feedback into the CADTH pan-Canadian Oncology Drug Review process.
Authors: Maureen E. Trudeau, Susan Mirabi, Kendra Christiansen, Kelvin K. Chan, Alexandra Chambers, Adam E. Haynes, Sohail Mulla
Journal: Journal of Clinical Oncology (2018)

42 Background: In Canada, through the pan-Canadian Oncology Drug Review (pCODR) process, CADTH conducts evaluations of clinical, economic, and patient evidence on cancer drugs to provide public reimbursement recommendations. The pCODR Expert Review Committee (pERC) makes these recommendations based on a drug’s overall clinical benefit, alignment with patient values, cost-effectiveness, and feasibility of adoption into the health system. Methods: In February 2016, pCODR launched a pilot process that allowed eligible clinicians (individually or as groups) not directly involved in the reviews to participate in the pCODR process, to provide: (1) input at the outset of a review; and, (2) feedback on the Initial Recommendation made by the pERC. Eligible clinicians are those who: (1) are actively practising physicians; (2) are members of a provincial cancer agency or similar body or a national cancer organization; and, (3) submit a declaration of conflict of interest. Results: As of March 31, 2018, 177 oncologists have registered to participate in the pCODR process. Of 43 submissions, 38 (88%) included clinician input. Fifteen submissions received individual input, and 33 received group input, the latter involving three to 13 clinicians or groups. Between April 2016 and March 2018, clinician input by tumour type was as follows: lung (n = 8), leukemia (n = 5), lymphoma (n = 5), gastrointestinal (n = 5), myeloma (n = 4), breast (n = 3), melanoma (n = 2), gynecological (n = 2), endocrine (n = 2), sarcoma (n = 1), and genitourinary (n = 1). Clinician input has answered several key questions, including current treatments, eligible patient populations, relevance to clinical practice, sequencing and priority of treatments, and companion diagnostic testing. Conclusions: Clinician engagement has provided value-added information on local issues from a practice perspective and insights into areas of unmet need. Continuous process improvement is important, however, and the pCODR program completed consultations in April 2018 to enhance clinician participation, proposing to: (1) customize the template that clinicians complete; and, (2) broaden the eligibility of clinicians to oncology pharmacists and oncology nurses.
Abstract 15013: The Regulation of miRNAs in rHDL-Induced Rescue of Diabetes-Impaired Angiogenesis
Authors: Samuel T Hourigan, Anisyah Ridiandries, Edward R Tepper, Jennifer Q Zhang, Rodney Henriquez, Tania Tsatralis, Zoë E Clayton, Laura Z Vanags, Stacy Robertson, Stephen J Nicholls, Martin K Ng, Christina A Bursill, Joanne T Tan
Journal: Circulation (2017)

Introduction: Diabetic vascular complications are associated with impaired hypoxia-driven angiogenesis. We recently found that reconstituted high-density lipoproteins (rHDL) rescue diabetes-impaire...
Liquid biopsies to track trastuzumab resistance in metastatic HER2-positive gastric cancer
Authors: De-Shen Wang, Ze-Xian Liu, Yun-Xin Lu, Hua Bao, Xue Wu, Zhao-Lei Zeng, Zekun Liu, Qi Zhao, Cai-Yun He, Jia-Huan Lu, Zhi-Qiang Wang, Miao-Zhen Qiu, Feng Wang, Feng-Hua Wang, Yu-Hong Li, Xiao-Nan Wang, Dan Xie, Wei-Hua Jia, Yang W Shao, Rui-Hua Xu
Journal: Gut (2018)

Objective To monitor trastuzumab resistance and determine the underlying mechanisms for the limited response rate and rapid emergence of resistance of HER2+ metastatic gastric cancer (mGC). Design Targeted sequencing of 416 clinically relevant genes was performed in 78 paired plasma and tissue biopsy samples to determine plasma-tissue concordance. Then, we performed longitudinal analyses of 97 serial plasma samples collected from 24 patients who were HER2+ to track the resistance during trastuzumab treatment and validated the identified candidate resistance genes. Results The results from targeted sequencing-based detection of somatic copy number alterations (SCNA) of HER2 gene were highly consistent with fluorescence in situ hybridisation data, and the detected HER2 SCNA was better than plasma carcinoembryonic antigen levels at predicting tumour shrinkage and progression. Furthermore, most patients with innate trastuzumab resistance presented high HER2 SCNA during progression compared with baseline, while HER2 SCNA decreased in patients with acquired resistance. PIK3CA mutations were significantly enriched in patients with innate resistance, and ERBB2/4 genes were the most mutated genes, accounting for trastuzumab resistance in six (35.3%) and five (29.4%) patients in baseline and progression plasma, respectively. Patients with PIK3CA/R1/C3 or ERBB2/4 mutations in the baseline plasma had significantly worse progression-free survival. Additionally, mutations in NF1 contributed to trastuzumab resistance, which was further confirmed through in vitro and in vivo studies, while combined HER2 and MEK/ERK blockade overcame trastuzumab resistance. Conclusion Longitudinal circulating tumour DNA sequencing provides novel insights into gene alterations underlying trastuzumab resistance in HER2+mGC.
Clinical exome sequencing for fetuses with ultrasound abnormalities and a suspected Mendelian disorder
Authors: Elizabeth A. Normand, Alicia Braxton, Salma Nassef, Patricia A. Ward, Francesco Vetrini, Weimin He, Vipulkumar Patel, Chunjing Qu, Lauren E. Westerfield, Samantha Stover, Avinash V. Dharmadhikari, Donna M. Muzny, Richard A. Gibbs, Hongzheng Dai, Linyan Meng, Xia Wang, Rui Xiao, Pengfei Liu, Weimin Bi, Fan Xia, Magdalena Walkiewicz, Ignatia B. Van den Veyver, Christine M. Eng, Yaping Yang
Journal: Genome Medicine (2018)

Exome sequencing is now being incorporated into clinical care for pediatric and adult populations, but its integration into prenatal diagnosis has been more limited. One reason for this is the paucity of information about the clinical utility of exome sequencing in the prenatal setting.We retrospectively reviewed indications, results, time to results (turnaround time, TAT), and impact of exome results for 146 consecutive "fetal exomes" performed in a clinical diagnostic laboratory between March 2012 and November 2017. We define a fetal exome as one performed on a sample obtained from a fetus or a product of conception with at least one structural anomaly detected by prenatal imaging or autopsy. Statistical comparisons were performed using Fisher's exact test.Prenatal exome yielded an overall molecular diagnostic rate of 32% (n = 46/146). Of the 46 molecular diagnoses, 50% were autosomal dominant disorders (n = 23/46), 41% were autosomal recessive disorders (n = 19/46), and 9% were X-linked disorders (n = 4/46). The molecular diagnostic rate was highest for fetuses with anomalies affecting multiple organ systems and for fetuses with craniofacial anomalies. Out of 146 cases, a prenatal trio exome option designed for ongoing pregnancies was performed on 62 fetal specimens, resulting in a diagnostic yield of 35% with an average TAT of 14 days for initial reporting (excluding tissue culture time). The molecular diagnoses led to refined recurrence risk estimates, altered medical management, and informed reproductive planning for families.Exome sequencing is a useful diagnostic tool when fetal structural anomalies suggest a genetic etiology, but other standard prenatal genetic tests did not provide a diagnosis.
Tiers of service: Outpatient medical oncology services for British Columbia, Canada.
Authors: Shallen Letwin, Astra Pereira, Tammy Currie, Gary K. Pansegrau, Marie Hawkins
Journal: Journal of Clinical Oncology (2018)

40 Background: The vision is for cancer care in British Columbia to be delivered in a coordinated, efficient manner, governed through effective partnerships between the Regional Health Authorities and BC Cancer. Systemic Therapy is delivered throughout BC by several providers, however service provision standards do not exist. BC Cancer and Fraser Health embarked on a process to develop a provincial Tiers of Service that outlines the responsibilities and requirements for the delivery of systemic therapy. Methods: From October 2017-April 2018, a working group drafted a Tiers of Service framework to be further approved by a Provincial Working Group. A scan of the literature and review of other jurisdiction's frameworks were evaluated. BC Cancer in partnership with the Regional Health Authorities have identified that the increased need for outpatient medical oncology services, combined with human resource and healthcare facility constraints requires a framework for organizing and delivering cancer care services in British Columbia. Therefore, a need to update the framework and shift nomenclature from the current “Levels of Service” to “Tiers of Service” was identified. Results: A survey of the working group was utilized to understand their level of confidence with regards to the development and utilization of the framework. Overall the working group increased their level of confidence from 33% to 100%. Conclusions: Tiers of Service: Outpatient Medical Oncology Services provides a practical framework which will be used to define and plan medical oncology services in British Columbia utilizing a common language and methodology. It describes the minimum responsibilities and requirements of each tier in providing a safe, sustainable and appropriate level of service. Tiers of Service will set standards and provide clarity for service provision, help build a capacity plan, plan where resources should be located, measure and monitor performance and improve the quality of the patient experience.
Abstract 14562: Association Between Cardiovascular Health and Depression Among U.S. Adults: Nhanes 2007-2014
Authors: Zefeng Zhang, Cathleen Gillespie, Robert Merritt, Quanhe Yang
Journal: Circulation (2017)

Introduction: Studies suggest that depression and related conditions are associated with increased risk for cardiovascular disease. The American Heart Association’s “Life’s Simple 7” includes 7 cardiovascular (CV) health metrics (body mass index, smoking, physical activity, dietary intake, total cholesterol, blood pressure and fasting glucose). A few studies examined the association between CV health metrics and depression, but none used nationally representative sample. The present study examines the association between CV health metrics and depressive symptoms among U.S. adults. Hypothesis: Adults with poor CV health have an increased association with depression compared to those with optimum CV health. Methods: We used data on 14,561 adults aged ≥20 years from the National Health and Nutrition Examination Survey 2007-2014. Depressive symptoms were assessed using the Patient Health Questionnaire; a score of 0-4, 5-9, and ≥10 represented no/minimal, mild, moderate/severe depressive symptoms, respectively...
Emerging biology of persistent mucous cell hyperplasia in COPD
Authors: Renat Shaykhiev
Journal: Thorax (2018)

Secretion of mucus into the airway lumen is a fundamental host defense mechanism that enables trapping of pathogens and other inhaled particles and their subsequent removal from the airways via mucociliary escalator. The numbers of mucus-producing goblet cells are tightly controlled to secure the baseline mucin levels on the airway surface, while preventing mucus plugging of small bronchioles, where these cells are rare or absent.1 Maintaining a proper number of mucus-producing cells in the airways is a function of tissue-resident basal stem cells, which, under control of physiological or injury-associated signals, regenerate airway epithelium with a distinct proportion of basal, ciliated and secretory cells.

Increase in goblet cell numbers or mucous cell hyperplasia (MCH) occurs in response to pathogens, oxidants, toxins, particles and cigarette smoke, leading to a transient mucus hypersecretion that normally disappears after the stimuli are no longer present. In chronic lung diseases, such as asthma and chronic obstructive pulmonary disease (COPD), overproduction of mucus persists over time contributing to clinical symptoms. Long-term maintenance of MCH, a morphological basis of chronic mucus hypersecretion in these conditions, can result from sustained activation of airway basal cells or their progenies by disease-associated signals that promote their excessive differentiation toward mucus-producing cells.

Several pathways are known to promote MCH by modifying the fate of airway basal cells. Airway inflammation driven by T helper (Th)2 cells, characteristic for asthma, promotes MCH via interleukin (IL)-13 that shifts the fate of airway basal cell-derived progenitors to the goblet cell lineage by activating Notch signalling required for differentiation of airway basal cells into secretory cells.2 3 Th17-derived IL-17 associated with neutrophilic airway inflammation in severe asthma and COPD exacerbations can promote MCH via Notch2-dependent signalling in airway basal cells.3 

Cigarette smoking, the major risk factor for COPD, can promote MCH independent of inflammation, by …
Bioselection Reveals miR-99b and miR-485 as Enhancers of Adenoviral Oncolysis in Pancreatic Cancer
Authors: Maria Rovira-Rigau, Giulia Raimondi, Miguel Ángel Marín, Meritxell Gironella, Ramon Alemany, Cristina Fillat
Journal: Molecular Therapy (2018)

Oncolytic viruses are designed for cancer treatment. Cell-virus interactions are key determinants for successful viral replication. Therefore, the extensive reprogramming of gene expression that occurs in tumor cells might create a hurdle for viral propagation. We used a replication-based approach of a microRNA (miRNA) adenoviral library encoding up to 243 human miRNAs as a bioselection strategy to identify miRNAs that facilitate adenoviral oncolytic activity in pancreatic ductal adenocarcinoma. We identify two miRNAs, miR-99b and miR-485, that function as enhancers of adenoviral oncolysis by improving the intra- and extracellular yield of mature virions. An increased adenoviral activity is the consequence of enhanced E1A and late viral protein expression, which is probably mediated by the downregulation of the transcriptional repressors ELF4, MDM2, and KLF8, which we identify as miR-99b or miR-485 target genes. Arming the oncolytic adenovirus ICOVIR15 with miR-99b or miR-485 enhances its fitness and its antitumoral activity. Our results demonstrate the potential of this strategy to improve oncolytic adenovirus potency, and they highlight miR-99b and miR-485 as sensitizers of adenoviral replication. Oncolytic viruses are designed for cancer treatment. Cell-virus interactions are key determinants for successful viral replication. Therefore, the extensive reprogramming of gene expression that occurs in tumor cells might create a hurdle for viral propagation. We used a replication-based approach of a microRNA (miRNA) adenoviral library encoding up to 243 human miRNAs as a bioselection strategy to identify miRNAs that facilitate adenoviral oncolytic activity in pancreatic ductal adenocarcinoma. We identify two miRNAs, miR-99b and miR-485, that function as enhancers of adenoviral oncolysis by improving the intra- and extracellular yield of mature virions. An increased adenoviral activity is the consequence of enhanced E1A and late viral protein expression, which is probably mediated by the downregulation of the transcriptional repressors ELF4, MDM2, and KLF8, which we identify as miR-99b or miR-485 target genes. Arming the oncolytic adenovirus ICOVIR15 with miR-99b or miR-485 enhances its fitness and its antitumoral activity. Our results demonstrate the potential of this strategy to improve oncolytic adenovirus potency, and they highlight miR-99b and miR-485 as sensitizers of adenoviral replication.
Abstract 15695: Late Systolic Myocardial Loading is Strongly Related to Left Atrial Dysfunction in Hypertension
Authors: Julio A Chirinos, Amer Ahmed Syed, Zeba Hashmath, Timothy S Phan, Maheswara R Koppula, Uzma Kewan, Zoubair Ahmed, Ravikantha Chandamuri, Swapna Varakantam, Ejaz Shah, Ryan Gorz, Scott R Akers
Journal: Circulation (2016)

Background: Late systolic load has been shown to cause diastolic dysfunction in animal models. Whereas the systolic loading sequence of the left ventricular myocardium likely affects its coupling w...
Olfactory Ensheathing Cells: A Trojan Horse for Glioma Gene Therapy
Authors: Litia A Carvalho, Jian Teng, Renata L Fleming, Elie I Tabet, Max Zinter, Ricardo A de Melo Reis, Bakhos A Tannous
Journal: JNCI Journal of the National Cancer Institute (2018)

The olfactory ensheathing cells (OECs) migrate from the peripheral nervous system to the central nervous system (CNS), a critical process for the development of the olfactory system and axonal extension after injury in neural regeneration. Because of their ability to migrate to the injury site and anti-inflammatory properties, OECs were tested against different neurological pathologies, but were never studied in the context of cancer. Here, we evaluated OEC tropism to gliomas and their potential as a "Trojan horse" to deliver therapeutic transgenes through the nasal pathway, their natural route to CNS.OECs were purified from the mouse olfactory bulb and engineered to express a fusion protein between cytosine deaminase and uracil phosphoribosyltransferase (CU), which convert the prodrug 5-fluorocytosine (5-FC) into cytotoxic metabolite 5-fluorouracil, leading to a bystander killing of tumor cells. These cells were injected into the nasal cavity of mice bearing glioblastoma tumors and OEC-mediated gene therapy was monitored by bioluminescence imaging and confirmed with survival and ex vivo histological analysis. All statistical tests were two-sided.OECs migrated from the nasal pathway to the primary glioma site, tracked infiltrative glioma stemlike cells, and delivered therapeutic transgene, leading to a slower tumor growth and increased mice survival. At day 28, bioluminescence imaging revealed that mice treated with a single injection of OEC-expressing CU and 5-FC had tumor-associated photons (mean [SD]) of 1.08E + 08 [9.7E + 07] vs 4.1E + 08 [2.3E + 08] for control group (P < .001), with a median survival of 41 days vs 34 days, respectively (ratio = 0.8293, 95% confidence interval = 0.4323 to 1.226, P < .001) (n = 9 mice per group).We show for the first time that autologous transplantation of OECs can target and deliver therapeutic transgenes to brain tumors upon intranasal delivery, the natural route of OECs to the CNS, which could be extended to other types of cancer.
Content evaluation of Watson for Oncology: A feasibility study.
Authors: Lotte Keikes, Stephanie Medlock, Daniel van de Berg, Shuxin X. Zhang, Onno Robert Guicherit, Cornelis J. A. Punt, Martijn G.H. van Oijen
Journal: Journal of Clinical Oncology (2018)

325 Background: Digital decision support tools such as Watson offer a promising opportunity to recommend the best cancer treatment to doctors around the globe. Although concordance studies between Watson's recommendations and routine daily practice or expert opinion were reported; scientific papers demonstrating how Watson affects medical decision-making are scarce. The first step of external validation and localization is content evaluation against national guidelines. Therefore, we present a feasibility study of the content evaluation of Watson for Oncology. Methods: We developed synthetic patient cases exhaustively testing the adjuvant treatment of stage I to stage III colon cancer based on relevant patient, clinical and tumor characteristics, and entered these in Watson. We used cross tabulations and a novel scoring system to compare Dutch and NCCN guideline recommendations with Watson’s treatment advice. Our scoring system allows a range from +12 to -12, reflecting the difference between minor disagreement (possible treatment not mentioned) versus serious error (contraindicated treatment was recommended). Treatment options that were contraindicated according to the national guidelines were labeled with a "red flag" if Watson recommended it, and an "orange flag" if Watson considered it. Results: In total, we developed 190 synthetic patient cases (stage I: n = 8; stage II: n = 110; and stage III: n = 72). Overall concordance scores per case for Watson versus Dutch guidelines ranged from a minimum score of -4 (n = 6) to a maximum score of +12 (n = 17) and from -4 (n = 9) to +12 (n = 24) for Watson versus the NCCN guidelines. In total, 69 cases (36%) were labeled with red flags, 96 cases (51%) with orange flags and 25 cases (13%) without flags. For the comparison of Watson with the NCCN guidelines, no red or orange flags were identified. Conclusions: Evaluation of the content of Watson for Oncology against national guidelines is feasible. Overall concordance scores varied considerably between synthetic patient cases. Non-concordance is partially attributable to guideline differences between the United States and The Netherlands. This implies that further adjustments and localization are required before implementation of Watson outside the United States.