tbuckley/cabot-search huggingface dataset:
RNA-Seq analyses of immune cell-type enrichments in 158 Asian colorectal cancers (CRCs).
Authors: Iain BeeHuat Tan, Andrew Nguyen, Charles Joseph Vaske, Christopher Szeto, Yulia Newton, Etienne Becht, Joe Poh Sheng Yeong, Stephen Charles Benz, Saranya Thangaraju, Bram Lim, Danliang Ho, Kiat Hon Tony Lim, Clarinda Wei Ling Chua, Ronnie Mathew, Choong Leong Tang, Evan Newell, Jonathan Göke, Anders Skanderup, Shahrooz Rabizadeh, Si-Lin Koo
Journal: Journal of Clinical Oncology (2018)

e15597 Background: Responses to anti-PD1 is ~35% in microsatellite unstable (MSI-h) and near 0% in microsatellite stable (MSS) Colorectal cancer (CRC). Understanding the composition of immune cell populations in the tumor microenvironment of CRC is crucial to developing effective immunotherapeutic strategies in CRC. Methods: We performed whole genome sequencing (WGS) (60x tumor, 30x normal) and deep whole transcriptomic sequencing (RNA-Seq) (∼200x106 reads per tumor) on 158 fresh frozen (FF) colorectal cancers tumors, of which 32 are microsatellite instability high (MSI-H) tumours and 126 are microsatellite stable (MSS). We evaluated immune cell composition with 2 computational algorithms, MCP-counter (Becht et al., 2016) relying on counts of cell-type specific transcriptomic markers and an RNA deconvolution method based on immune-signature enrichment, tumor purity and a comparison with a pan-tumor transcriptomic database. We also performed RNA-Seq on FFPE tissue from amongst 20 patients (9 MSI-H, 11 MSS). Results: Immune cell enrichment scores by both methods correlated well with each other (R2 values for T cells: 0.81 NK: 0.43 B cells: 0.83monocytes: 0.59, neutrophils: 0.45). MSI-H & POLE mutant tumors had increased CD8, macrophage, NK, Th1,Th2, Tmem & aDC immune cell enrichment compared with MSS tumors. Amongst MSS tumors, immune cell enrichment patterns were not found to be clearly associated with mutational burden nor tumor sidedness. A subset of tumors were found to exhibit T-helper & in particular T-h2 immune cell enrichment. With RNASeq from FFPE, tumor enrichment scores were found to correlate with scores derived from matched FF-RNASeq. Conclusions: We evaluated immune cell compositions with computational cell type enrichment/deconvolution methodologies in RNASeq of a large cohort of Asian CRCs. Subset of tumors with distinct immune cell composition patterns were identified. These analyses could be reproduced using FFPE RNA-Seq potentially being extendible to large retrospective clinical trial cohorts.
Pollen Genetic Markers for Detection of Mutagens in the Environment
Authors: R. A. Nilan, J. L. Rosichan, P. Arenaz, A. L. Hodgdon, A. Kleinhofs
Journal: Environmental Health Perspectives (1981)

To utilize and exploit pollen for in situ mutagen monitoring, screening and toxicology, the range of genetic traits in pollen must be identified and analyzed. Traits that can be considered include ornamentation, shape and form, male sterility viability, intraspecific incompatibility, proteins and starch deposition. To be useful for the development of mutagen detection systems proteins should be: (1) activity stainable or immunologically identifiable in the pollen, (2) the products of one to three loci, and (3) gametophytic and nuclear in origin. Several proteins including alcohol dehydrogenase in maize, which meet those criteria will be discussed. The waxy locus in barley and maize which controls starch deposition has been characterized genetically and methods have been developed for pollen screening and mutant detection. At Washington State University a waxy pollen system is being developed in barley for in situ mutagen monitoring. The basis is an improved method for staining and scoring waxy pollen mutants. Specific base substitution, frameshift, and deletion mutant lines are being developed to provide information about the nature of the mutations induced by environmental mutagens. Thirty waxy mutant lines, induced by sodium azide and gamma-rays have been selected and are being characterized for spontaneous and induced reversion frequencies, allelism, karyotype, amylose content, and UDP glucose glucosyltransferase (waxy gene product) activity. Twelve mutant alleles are being mapped by recombinant frequencies.
Symptom burden and hospital length of stay among patients with curable cancer.
Authors: Sara D'Arpino, Areej El-Jawahri, Samantha M.C. Moran, Connor Johnson, Daniel Lage, Risa Wong, Yian Xiao, Margaret Ruddy, Brandon Temel, William F. Pirl, Lara Traeger, Inga Tolin Lennes, Barbara J. Cashavelly, Holly S Martinson, Vicki A. Jackson, Joseph A. Greer, David P. Ryan, Ephraim P. Hochberg, Jennifer S. Temel, Ryan David Nipp
Journal: Journal of Clinical Oncology (2017)

6579 Background: Prolonged hospital admissions are often inconsistent with patients’ preferences and incur significant costs. While patients’ symptoms may result in hospitalizations, the relationship between patients’ symptom burden and their hospital length-of-stay (LOS) has not been fully explored in patients with curable cancers. Methods: We prospectively enrolled patients with curable cancer and unplanned hospital admissions between 8/2015 and 12/2016. Within the first 5 days of admission, we assessed patients’ physical (Edmonton Symptom Assessment System [ESAS]; scored 0-10 with higher scores indicating greater symptom burden) and psychological symptoms (Patient Health Questionnaire 4 [PHQ-4]; scored categorically and continuous with higher scores indicating greater distress). We created summated ESAS total and physical symptom variables. To assess the relationship between patients’ symptom burden and their hospital LOS, we used separate linear regression models adjusted for age, sex, marital status, education level, time since cancer diagnosis, and cancer type. Results: We enrolled 452 of 497 (91%) approached patients (mean age = 61.9 years; 188 [42%] female). Over half had hematologic cancers (n = 249, 55%). Mean hospital LOS was 8.3 days. Over one-tenth of patients screened positive for PHQ-4 depression (n = 74, 16%) and anxiety (n = 60, 13%) symptoms. Mean ESAS symptom scores were highest for fatigue (6.6), drowsiness (5.4), pain (4.9), and lack of appetite (4.8). In multivariable regression analysis, patients’ physical and psychological symptoms were associated with longer hospital LOS (table). Conclusions: Patients with curable cancer and unplanned hospital admissions experience a substantial symptom burden, which predicts for prolonged hospitalizations. Importantly, patients’ symptoms are modifiable risk factors that, if properly addressed, can improve care delivery and may have the potential to help decrease prolonged hospitalizations. [Table: see text]
Abstract 11382: Should We Close Left Atrial Appendage in Cardiac Surgery ? : Meta-analysis of 7466 Patients Who Underwent Open-heart Surgery
Authors: Masahiko Ando, Masaki Funamoto, Thoralf M Sundt
Journal: Circulation (2016)

Introduction: While percutaneous closure of left atrial appendage (LAA) can be a potential alternative to life-long anticoagulation in patients with atrial fibrillation (AF), comprehensive evidence on surgical LAA closure (LAAC) is scant. Hypothesis: Surgical LAAC is associated with reduced risk of mortality and stroke. Methods: We conducted a meta-analysis on the studies comparing the patients who underwent open-heart surgery with or without LAAC. Literature search was performed on PubMed, Embase, and Cochrane Trials databases. Outcomes of interest were 30-day/in-hospital mortality and morbidity, and late mortality and stroke. I-square statistics were used to evaluate heterogeneity and publication bias was evaluated by Begg’s and Egger’s tests. Results: We reviewed 821 articles and 12 articles including 7466 patients (3039 in LAAC group and 4427 in Non-LAAC group) were selected for the analysis. Among 12 studies, 3 were randomized-controlled, 2 were propensity-matched, and others were cohort study. There was no significant heterogeneity or publication bias. At 30-day/in-hospital follow-up, LAAC was not associated with risk of mortality or stroke (Risk ratio (RR) 0.67, 95% confidence interval (CI) 0.42-1.06 for mortality, and RR 0.83, 95%CI 0.54-1.26 for stroke). LAAC was not associated with risk of postoperative AF or re-exploration for bleeding. At the latest follow-up, LAAC was significantly associated with decreased risk of mortality (Risk ratio (RR) 0.64, 95%CI 0.44-0.94, p-value 0.024). This association showed similar tendency in stratified meta-analysis by age, sex, study design, type of surgery, and preoperative AF status. Conclusions: LAAC was associated with decreased risk of late mortality, but not late stroke. Better survival in LAAC group would be based on baseline differences or postoperative anticoagulation management. Further prospective investigation is needed to clarify these findings.
P1.28 Dusp4 Expression as A Marker of Heterogeneous Signaling in Colorectal Cancer Patients
Authors: V. de Vriendt, W. de Roock, A.F. di Narzo, S. Tian, B. Biesmans, B. Jacobs, J. de Schutter, E. Budzinska, X. Sagaert, M. Delorenzi, I. Simon, S. Tejpar
Journal: Annals of Oncology (2012)
Fractional Flow Reserve Measurement for the Physiological Assessment of Coronary Artery Stenosis Severity
Authors: Deepak L. Bhatt
Journal: JAMA (2018)

This Clinical Update explains the uses and interpretation of fractional flow reserve (FFR) measures that quantify the pressure gradient proximal and distal to intracoronary lesions and determine the clinical significance of angiographically detected coronary artery stenoses.
Out-of-Pocket Costs for Infliximab and Its Biosimilar for Rheumatoid Arthritis Under Medicare Part D
Authors: Jinoos Yazdany, R. Adams Dudley, Grace A. Lin, Randi Chen, Chien-Wen Tseng
Journal: JAMA (2018)

Therapeutic Drug Monitoring in Infliximab Induction and Remission of Immune-Mediated Inflammatory Diseases
KI67 expression and uPA/PAI-1 level: adjuvant chemotherapy markers in intermediate risk early breast cancer.
Authors: Elise Deluche, Laurence Venat-Bouvet, Sophie Leobon, Veronique Fermeaux, Yves Aubard, Nadira Saidi, Isabelle Jammet, Nicole Tubiana-Mathieu
Journal: Journal of Clinical Oncology (2016)

e23234 Background: Adjuvant chemotherapy decisions are relatively simple using clinicopathological parameters (Goldhirsch et al. 2007), some cases require the addition of biomarkers as in patients with node negative or micrometastatic (N0), grade II (GII) breast cancer. The objective of this study was to evaluate the impact of uPA/PAI-1 and Ki67 compared to classical criteria in adjuvant treatment decision in this population. Methods: This retrospective study included patients, treated from December 2007 to October 2015 in the Department of Medical Oncology at Limoges University Hospital (France). Ki67 and uPA/PAI-1 were analysed on the initial specimen tumor. Optimal cut-off of Ki67 was defined at 20% (Coates et al. 2015). The positivity thresholds of uPA and PAI-1 were 3 ng/mg and 14 ng/mg respectively (Look et al. 2002). All clinicopathological parameters were recorded prospectively. Results: 2300 patients with breast cancer were screened. Among these patients, 227 N0, GII breast cancer patients were included with a median age of 61 years (33-87). Ki67 expression was significantly lower in low uPA/PAI-1 tumors (p = 0.04) than in high uPA/PAI-1 tumors, but discordance was observed between the two markers in 58% of tumors. Ki67 was not correlated to uPA/PAI-1 expression in luminal B, GII, breast cancer (p = 0.1). Considering Ki67 status, the indication to perform adjuvant chemotherapy was increased by 21% compared to clinicopathological parameters (p < 0.001). Using uPA/PAI-1 level, indication to perform adjuvant chemotherapy was increased by 48% whatever Ki67 status (p < 0.001). Considering uPA/PAI-1 level and Ki67 status, the indication to perform adjuvant chemotherapy based on clinicopathological markers increased by 49% (p < 0.001). In current practice, the final decision of chemotherapy by the multidisciplinary board was increased by 8% compared to St Gallen criteria (p = 0.03). Conclusions: This study highlighted that uPA/PAI-1 and Ki67 assessment provides additional information for adjuvant chemotherapy decision making. The use of uPA/PAI-1 combined to Ki67 was feasible, cost-effective in N0, GII breast cancer’s patients.
Abstract 10434: Non-Typical Angina and Mortality in Women With Obstructive Coronary Artery Disease: Results From the Women's Ischemia Syndrome Evaluation Study (WISE)
Authors: Erika Jones, B. Delia Johnson, Leslee Shaw, May Bakir, Janet Wei, Margo Minissian, Puja K Mehta, Carl Pepine, Steven Reis, Sheryl F Kelsey, Sopko George, Eileen Handberg, Vera Bittner, C. Noel Bairey-Merz
Journal: Circulation (2015)

Background: Women frequently present with non-typical angina (NTA) making ischemia diagnosis and treatment challenging. We hypothesized that mortality would be higher in women with obstructive coronary artery disease (CAD) and NTA vs typical angina (TA). Methods: We studied 364 Women’s Ischemia Syndrome Evaluation (WISE) participants with signs and symptoms of ischemia and obstructive CAD, defined as ≥50% stenosis by WISE angiography core laboratory. TA was defined as sub-sternal chest pain precipitated by physical exertion or emotional stress and relieved with rest or nitroglycerin, while NTA was defined as symptoms not meeting criteria for TA. Death was confirmed by National Death Index. Time to death was analyzed and plotted using Kaplan-Meier survival analyses. The analyses were adjusted by age using a Cox Proportional Hazards regression, and reported with a hazard ratio (HR) and 95% confidence interval (CI). Results: Overall, 249 (68%) NTA and 115 (32%) TA women had a mean age of 63 ± 12yrs and 21% were non-white. Women with NTA were more hypertensive (72% vs. 60%, p=0.03) and more often on angiotensin-converting enzyme inhibitor (37% vs 25%, p= 0.03) than women with TA. There was no difference in mean cholesterol level, CAD severity or body mass index between the two groups. Over a median of 8.8 years, 122 (34%) women died including 92 NTA and 30 TA (HR 1.5, 95% CI 1.006, 2.30) (Figure). Conclusions: Among WISE women with signs and symptoms of ischemia and obstructive CAD, NTA has a higher mortality compared to TA. These findings extend prior evidence that chest pain, including NTA, identifies higher risk in women with obstructive CAD. These data support intensive management and clinical follow up of women with obstructive CAD and NTA. Further evaluation regarding ischemic burden and treatment is ongoing to further understand the elevated NTA mortality.
Outcomes of embedded palliative care outpatients consults on timing of palliative care access, symptoms, and end-of-life quality indicators among advanced non-small cell lung cancer patients.
Authors: Sriram Yennu, Bernard Lobato Prado, Zhanni Lu, Syed Naqvi, Janet L. Williams, Taekyu Lim, Eduardo Bruera
Journal: Journal of Clinical Oncology (2018)

6536 Background: There are no studies comparing the outcomes of embedded consults (EPC) as compared to independent outpatient palliative care consults (PC).Our aim was to determine the timing of palliative care access, symptoms and EOL outcomes of advanced non-small cell lung cancer patients referred to EPC as compared to those referred to PC. Methods: We retrospectively reviewed a random sample of EPC (Aug, 2012 - Jun, 2013) and PC consults (Jan, 2009 –Jul, 2012) at MD Anderson Cancer Center. Baseline features, symptoms (ESAS), EOL quality outcomes (intensive care unit deaths, admissions, emergency center visits , and hospitalizations and length of stay in the last 30 days before death; cancer treatments 14 days before death; hospice discussions and referrals; do not resuscitate order at first follow-up; advanced care planning (ACP) discussions, and completion of advanced directives), time from referral to first consult, ACP date to death, and overall survival from consult to death were retrieved. Results: 340 were evaluable (EPC = 147). At baseline, mean ECOG (2.2 vs 1.9, p < .001), and median pain (6 vs 5, p = .038) were higher in EPC. Time from referral to first consult was shorter (median 0 vs 7 days, p < .001) and dyspnea was better in EPC at follow-up (-1 vs 0, p = .039). A higher proportion in EPC (77% vs 58%, p < .001) had ACP discussions and these occurred earlier (median 4 vs 1 month before death, p < .001). No other significant differences in symptoms or EOL outcomes were found. Conclusions: EPC consults at referral had earlier access and worse pain and performance status. EPC was not associated with significant improvement in symptoms or EOL outcomes except for better dyspnea control, and more frequent as well as earlier ACP discussions. Further research is needed.
Abstract 18417: Clinical Presentation, Cardiac Phenotype and Long Term Prognosis of Patients With Late Onset Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy
Authors: Aditya Bhonsale, Anneline S te Riele, Abhishek Sawant, Judith Groeneweg, Cynthia A James, Brittney Murray, Crystal Tichnel, Dennis Dooijes, Jeroen v Heijden, Harikrishna Tandri, Peter v Tintelen, Daniel P Judge, Richard Hauer, Hugh Calkins
Journal: Circulation (2015)

Introduction: The phenotypic features and clinical course of elderly Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy (ARVD/C) patients (age&gt; 50 years at diagnosis) is unknown. Methods: Demographic, phenotypic and genotypic data of 502 patients with ARVC diagnosis (2010 Task Force Criteria) from Johns Hopkins and Utrecht (NL) ARVD/C registries was obtained and long term clinical outcomes ascertained. Results: Late presentation was seen in 104 (21%) patients (38% with PKP2 mutation; no DSP or DSG2 mutation carrier) with 3% being ≥ 65 years at diagnosis. Sustained ventricular tachycardia (VT) is the major (43%) mode of presentation in the elderly while cardiac syncope is infrequent (p&lt;0.001). The elderly are significantly less likely to harbor a pathogenic mutation (53%; p=0.005), have precordial T wave repolarization changes (p&lt;0.001) and have lower ventricular ectopy burden (median count 1503 vs 2497; p=0.026) compared to younger patients. In the elderly, over 7±5 years of follow up, 68(65%) patients experienced sustained ventricular arrhythmias with similar (p=0.08) arrhythmia free survival at 5 years of follow up (73% vs.60% in younger). LV dysfunction and heart failure was seen in 24(32%) and 15(14%) patients respectively without need for cardiac transplantation. Male gender (OR 2.12, 95%CI (1.3-3.45); p=0.002), absence of a pathogenic mutation (OR 1.94, 95%CI (1.20, 3.12); p=0.006) and family member status (OR 2.09, 95%CI (1.24, 3.51); P=0.006) were independently associated with late presentation. In the elderly, EP study inducibility (&lt;0.001), major RV structural disease (p=0.022), absent family history (p&lt;0.001), male gender (p=0.002) and pathogenic mutation (p=0.001) were associated with increased risk of ventricular arrhythmias while ECG abnormalities and ventricular ectopy (p=0.489) were not. Conclusion: One fifth of all ARVD/C patients present after 50 years of age, often with sustained VT and are less likely to have prior syncope or identifiable pathogenic mutation. In ARVD/C, late presentation does not confer a benign prognosis and is associated with high arrhythmic risk. Electrocardiographic changes and ventricular ectopy are significantly less common in the elderly and are not associated with arrhythmic events.
Long-term survival in metastatic uveal melanoma (MUM).
Authors: Sophie Piperno Neumann, Sylvain Dureau, Manuel Jorge Rodrigues, Laurence Desjardins, Gaëlle Pierron, Christine Levy-gabriel, Livia Lumbroso, Vincent Servois, Marie Najean, Alexia Savignoni, Nathalie Cassoux, Pascale Mariani
Journal: Journal of Clinical Oncology (2018)

e21501 Background: Prognosis of MUM is poor, with a median overall survival (OS) of 12 months (mo) and a 80% mortality rate within the first year. Rare patients (pts) achieve long-term survival, variables associated with prolonged survival are not well understood. Methods: Going through our UM database, we collected retrospectively clinical, pathological and genomic data from the primary tumor and metastases, therapeutic and outcome information from 109 long survivors with MUM. We defined long-term survivors as those alive for 3 years or more after the first metastatic event. Survival rates were estimated according to the Kaplan-Meier method and compared using the log-rank test. A Cox proportional hazard model was performed for multivariate analysis and build a prognostic score. Results: Among 4457 consecutive UM pts, 1122 developed a first metastasis between 2000 and 2014, and 109 were long-term survivors. The median follow-up for metastatic pts was 15.7 yrs (range, 0.3-33.4) from the primary and 5.1 yrs (range, 0.1-14.9) from metastasis. The median time to metastasis was 28.2 mo (CI 95% = 26.3 - 31.2). The median OS from metastasis was 12 mo (CI 95% = 11-13), 3-y and 5-y OS rates were 13.6% (CI 95% = 11.6 - 15.9) and 7.2% (CI 95% = 5.6- 9.2) respectively. In the subset of 109 long survivors, the median time to metastasis was 64 mo (CI 95% = 59-76). The median OS from metastasis was 61 mo (CI 95% = 53 – 76), and the 5-y OS was 53% (CI 95% = 44-64). Liver surgery was performed as the first metastatic treatment in 66 long-term survivors, being R0 in 51 (77%). The multivariate analysis identified predictors of long-term survival: absence of ciliary body extension, time to metastasis > 24 mo, Performance Status ≤1, liver metastasis only and a number of metastases ≤4. According to these parameters, a prognostic score was built in order to estimate survival. Conclusions: Long-term survivors with MUM represent 10% of the metastatic population; translational research is ongoing to assess the genetic and immunological profile of such unusual pts. The prognostic score should be validated prospectively and may be helpful to select pts candidates for liver surgery or clinical trials.
The Injurious Effects of Elevated or Nonelevated Respiratory Rate during Mechanical Ventilation
Authors: Evangelia Akoumianaki, Katerina Vaporidi, Dimitris Georgopoulos
Journal: American Journal of Respiratory and Critical Care Medicine (2018)

Respiratory rate is one of the key variables that is set and monitored during mechanical ventilation. As part of increasing efforts to optimize mechanical ventilation, it is prudent to expand understanding of the potential harmful effects of not only volume and pressures but also respiratory rate. The mechanisms by which respiratory rate may become injurious during mechanical ventilation can be distinguished in two broad categories. In the first, well-recognized category, concerning both controlled and assisted ventilation, the respiratory rate per se may promote ventilator-induced lung injury, dynamic hyperinflation, ineffective efforts, and respiratory alkalosis. It may also be misinterpreted as distress delaying the weaning process. In the second category, which concerns only assisted ventilation, the respiratory rate may induce injury in a less apparent way by remaining relatively quiescent while being challenged by chemical feedback. By responding minimally to chemical feedback, respiratory rate leaves the control of V. e almost exclusively to inspiratory effort. In such cases, when assist is high, weak inspiratory efforts promote ineffective triggering, periodic breathing, and diaphragmatic atrophy. Conversely, when assist is low, diaphragmatic efforts are intense and increase the risk for respiratory distress, asynchronies, ventilator-induced lung injury, diaphragmatic injury, and cardiovascular complications. This review thoroughly presents the multiple mechanisms by which respiratory rate may induce injury during mechanical ventilation, drawing the attention of critical care physicians to the potential injurious effects of respiratory rate insensitivity to chemical feedback during assisted ventilation.