tbuckley/cabot-search huggingface dataset:
Symptom burden at the end of life for neuroendocrine tumors: A population-based analysis of patient-reported outcomes.
Authors: Julie I. Hallet, Laura Davis, Alyson L. Mahar, Calvin Law, Lev Bubis, Elie Isenberg-Grzeda, Simron Singh, Sten Myrehaug, Haoyu Zhao, Kaitlyn Beyfuss, Lesley Moody, Natalie G. Coburn
Journal: Journal of Clinical Oncology (2019)

297 Background: How to best support neuroendocrine tumor (NET) patients remains unclear. While the peri-diagnostic period has been investigated, there is no data regarding symptoms at the end of life, when suboptimal symptom control may be particularly burdensome. This study examined symptom trajectories and factors associated with high symptom burden in NET at the end of life. Methods: We conducted a population-based retrospective cohort study of NET diagnosed from 2004-2015, who died between 2007-2016. Prospectively collected patient-reported Edmonton Symptom Assessment System scores were linked to provincial administrative datasets. Moderate-to-severe symptom scores in the 6 months prior to death were presented by 2-week intervals. Multivariable Poisson regression identified factors associated with moderate-to-severe symptoms scores. Results: Among 677 decedents, 2,579 symptom assessments prior to death were analyzed. Overall, moderate-to-severe scores were most commonly reported for tiredness (86%), wellbeing (81%), lack of appetite (75%), and drowsiness (68%) at any time. This proportion changed over time, progressively increasing closer to death: 56.8% to 83.9% tiredness, 50.5% to 73.1% wellbeing, 40.9% to 80.6% lack of appetite, and 41.5% to 68.8% drowsiness. The increase was steeper in the 8 weeks before death for lack of appetite, drowsiness, and shortness of breath. On multivariate analyses, the risk of moderate-to-severe symptoms was significantly higher in the last 2 months prior to death and with shorter survival from diagnosis (&lt; 6 months). Women reported a higher burden of anxiety, nausea, and pain than men. There was no association between symptom burden and age or primary tumor site. Conclusions: NET patients suffer a high symptom burden at the end of life, not previously described. The proportion of moderate-to-severe symptoms increases steeply as death nears, highlighting an opportunity for improved management. Combined with identified factors associated with moderate-to-severe symptom, this information is important to improve patient-centred and personalized supportive care for NET at the end of life.
Insurance status and hepatocellular carcinoma: A NCDB analysis.
Authors: Hibah Ahmed, Aabra Ahmed, Katrina Wolfe, Peter T. Silberstein
Journal: Journal of Clinical Oncology (2019)

240 Background: Typically occurring in patients with chronic liver disease, hepatocellular carcinoma is the most common liver cancer. Our goal was to compare survival of patients with differing insurance types diagnosed with hepatocellular carcinoma identified in the National Cancer Database (NCDB). Methods: We identified 113,159 patients with hepatocellular carcinoma in the NCDB diagnosed between 2004-2014. Patients included were categorized as having no insurance, private insurance, Medicaid, or Medicare were included. Between-insurance survival differences were estimated by the Kaplan-Meier method and associated log-rank tests; Tukey-Kramer adjusted p &lt; .05 indicated statistical significance. Results: Statistically significant survival differences were indicated between all insurance groups (all adjusted p &lt; 0.05), such that privately insured patients had the highest median survival. The discrepancy in survival between uninsured and privately insured patients was the largest (4.6 months vs. 16.9 months, respectively). Medicaid patients on average had a survival of 9.8 months, while Medicare patients had a median survival of 10.0 months. 19% of uninsured patients presented with stage I hepatocellular carcinoma, whereas 30.3% of privately insured patients presented with stage I hepatocellular carcinoma. More uninsured patients did not have surgery of the primary site compared to privately insured patients (87.7% vs. 70.0%, respectively). Likewise, more privately insured patients had a transplant compared to those with Medicaid, Medicare, or those who were uninsured (13.0% vs. 5.7% vs. 5.0% vs. 1.6%, respectively). Conclusions: Our study shows the discrepancies in survival between patients with differing insurance statuses. Of all insurances, those privately insured had the largest median survival. Median survival and percentage surviving. [Table: see text]
FOENIX-101: A phase II trial of TAS-120 in patients with intrahepatic cholangiocarcinoma harboring <i>FGFR2</i> gene rearrangements.
Authors: Lipika Goyal, Rastilav Bahleda, Junji Furuse, Juan W. Valle, Markus Hermann Moehler, Do-Youn Oh, Heung-Moon Chang, Robin Kate Kelley, Milind M. Javle, Mitesh J. Borad, Li-Tzong Chen, Nataliya Volodymyrivna Uboha, Heinz-Josef Klumpen, Peter J. O'Dwyer, Daneng Li, Chigusa Morizane, Jerry Huang, John A. Bridgewater
Journal: Journal of Clinical Oncology (2019)

TPS468 Background: Intrahepatic cholangiocarcinoma (iCCA) is a cancer arising from the intrahepatic bile duct. Standard treatment of unresectable, recurrent, or metastatic iCCA is with cytotoxic chemotherapy. FGFR2 gene fusions have been identified as oncogenic drivers in 10–20% of iCCA tumors, but no targeted agents have been established to date. TAS-120 is an investigational irreversible FGFR1–4 inhibitor in development as a once-daily oral treatment for iCCA. Based on initial studies in multiple tumor types expressing FGFR abnormalities, iCCA was identified as a tumor type with potential susceptibility to FGFR inhibition and high unmet need. A phase I portion of the trial with an iCCA expansion cohort demonstrated tolerability and preliminary evidence of clinical efficacy with TAS-120 as a continuous, once-daily oral treatment in patients with iCCA. The most common AEs in the phase I portion of the trial were hyperphosphatemia, a mechanism-based on-target side effect, cutaneous AEs, and gastrointestinal AEs. The phase I portion of the study is continuing to enroll, and final results are anticipated in early 2019. Based on preliminary findings, a phase II portion of the study (FOENIX-101; clinicaltrials.gov registration NCT02052778) has been initiated. Methods: The phase II portion of the trial is a global, single-arm study of TAS-120 in patients with iCCA harboring FGFR2 gene rearrangements. The study will enroll approximately 100 adult patients with locally advanced or metastatic iCCA that progressed after ≥ 1 systemic therapies and with an ECOG PS of 0 or 1. Prior systemic therapy must include gemcitabine plus platinum-based chemotherapy. Screening for FGFR2 gene rearrangements will be performed at a central laboratory. The primary endpoint is objective response rate based on RECIST v1.1. Secondary endpoints include duration of response, disease control rate, overall survival, progression-free survival, safety, and health-related quality of life. Clinical trial information: NCT02052778.
Outcomes Among 196 Patients With Noninfectious Proximal Aortitis
Authors: Alison H. Clifford, Amr Arafat, Jay J. Idrees, Eric E. Roselli, Carmela D. Tan, E. Rene Rodriguez, Lars G. Svensson, Eugene Blackstone, Douglas Johnston, Gosta Pettersson, Edward Soltesz, Gary S. Hoffman
Journal: Arthritis & Rheumatology (2019)

Noninfectious aortitis may occur in the context of a recognized systemic disease or as a topographically limited lesion without systemic features, which is called clinically isolated aortitis (CIA). This study was undertaken to better define and stress the limitations of this diagnostic category in a large population of patients in a single center dedicated to aortic diseases and to suggest recommendations for care.Records of patients undergoing thoracic aortic surgery (1996-2012) at the Cleveland Clinic were reviewed to identify 196 patients with histopathologically proven aortitis. Clinical diagnoses (giant cell arteritis [GCA], Takayasu arteritis [TAK], CIA, or Other) were determined at the time of surgery. Clinical features, laboratory findings, and imaging results were recorded throughout the follow-up period. At least 6 months of follow-up data were available for 73 CIA patients.The mean age of the patients at time of surgery was 65.6 years (range 15-88 years); 67% of patients were female, and 90.3% were white. At the time of surgery, 129 patients (65.8%) met criteria for CIA, 42 (21.4%) for GCA, 14 (7.1%) for TAK, and 11 (5.6%) met criteria for other systemic inflammatory diseases. During a mean follow-up period of 56.2 months, 19% of CIA patients developed new symptoms, 45% developed new radiographic vascular lesions, 40% underwent additional vascular surgery, and 12% died (n = 9). Eleven of 73 patients (15%) initially classified as having CIA developed features of a systemic disease, most often GCA.The majority of patients (66%) with histopathologically proven aortitis have CIA at the time of surgery. CIA patients infrequently report new symptoms over time, but new vascular lesions requiring surgery commonly occur. Serial follow-up including large vessel imaging is strongly advised for all aortitis patients.
Abstract 24073: Need of Treating Residual Inflammatory Activity in Coronary Heart Disease: the value of high sensitive CRP and LDL in a Real World Cohort.
Authors: Alexander Peikert, Klaus Kaier, Julian Merz, Ibrahim Ahmed Fadel Ali Hassanin, Dennis Wolf, Ingo Hilgendorf, Florian Willecke, Peter Stachon, Andreas Zirlik
Journal: Circulation (2017)

Introduction: Inflammation drives atherosclerosis and its complications. Thus, CANTOS as the first anti-inflammatory outcome trial in this population produced positive results. However, it is unclear how many patients qualify for an anti-inflammatory therapy in everyday practice. Hypothesis: This study analyzes how many patients with coronary heart disease (CHD) on guideline conform therapy show an increased residual inflammatory as opposed to an increased residual lipid risk in order to define the need for an anti-inflammatory treatment in a real world setting. Methods: High sensitive C-reactive protein (hsCRP) and low density lipoprotein (LDL) levels were determined in 700 all comer patients between June 2016 and June 2017 in our center. Patients lacking CHD, such with chronic-inflammatory diseases, acute inflammation, and on immunosuppressive medication were excluded. Patients were divided in the following groups: elevated hsCRP (≥2mg/dl), normal hsCRP (&lt;2mg/dl), off target LDL-cholesterol (≥70mg/dl), on target LDL-cholesterol (&lt;70mg/dl). Univariate logistic regression and backward selection was performed in order to define factors influencing hsCRP. Results: From 700 patients 221 fulfilled the inclusion and exclusion criteria. HsCRP was increased in 45% of these patients. Patients with on target LDL Levels showed lower hsCRP concentrations than those with off target values of LDL confirming a positive association between both (1,92mg/dl vs. 3,15mg/dl, p=0.005). However, despite guideline-conform LDL-control 34% of patients with a LDL-cholesterol &lt;70mg/dl had elevated levels of hsCRP (≥2mg/dl) suggestive of residual inflammation. After logistic univariate regression LDL-cholesterol ≥70mg/dl (OR 2.15, p=0.014), heart failure (OR 3.07, p&lt;0.001) and diabetes mellitus (OR 2.22, p=0.021) independently predicted elevated levels of hsCRP. Heart failure (OR 4.56, p&lt;0.001) and diabetes together (OR 3.04, p=0.012) identified as co-predictors increased hsCRP following backward selection. Conclusions: A substantial part of patients with CHD shares a residual inflammatory risk defining a need for an anti-inflammatory therapy. Residual inflammation is particularly prevalent in patients with heart failure and diabetes.
Abstract 18029: Dietary Oxydized Lipids Induce Pulmonary Hypertension
Authors: Gregoire Ruffenach, Ellen I O'Connor, Mylène vaillancourt, Victor Grijalva, Shervin Sarji, Christine Cunningham, Abbas Ardehali, Aman Mahajan, Soban Umar, Srinivasa T Reddy, Mansoureh Eghbali
Journal: Circulation (2017)

Background: Pulmonary arterial hypertension (PAH) is a deadly disease characterized by increased pulmonary arterial pressure, vascular occlusion and inflammation. Recently, a robust increase in oxidized lipids have been demonstrated, including 15-hydroxyeicosatetraenoic acids (15HETE), in the lungs and plasma of PAH patients and animal models. We hypothesized that diets rich in 15HETE is sufficient to cause PH in wild type mice. We also examined whether 15HETE or its metabolites are required to cause PH by comparing the effect of 15HETE with 15HETE methyl ester (15HETE-ME), a stable form of 15HETE that is not easily metabolized. Methods: C57BL/6 male mice were fed for 3 weeks (5μg/day) with 15HETE, 15HETE-ME, or regular chow diet (n=8-21 mice/group). PH development was followed via weekly echocardiography. Right ventricular systolic pressure (RVSP) via direct heart catheterization and RV hypertrophy index were measured. Lung morphology, lipid deposit and inflammation were assessed using H&E, Oil red O sta...
Novel genetic and epigenetic factors of importance for inter-individual differences in drug disposition, response and toxicity
Authors: Volker M. Lauschke, Yitian Zhou, Magnus Ingelman-Sundberg
Journal: Pharmacology & Therapeutics (2019)

Individuals differ substantially in their response to pharmacological treatment. Personalized medicine aspires to embrace these inter-individual differences and customize therapy by taking a wealth of patient-specific data into account. Pharmacogenomic constitutes a cornerstone of personalized medicine that provides therapeutic guidance based on the genomic profile of a given patient. Pharmacogenomics already has applications in the clinics, particularly in oncology, whereas future development in this area is needed in order to establish pharmacogenomic biomarkers as useful clinical tools. In this review we present an updated overview of current and emerging pharmacogenomic biomarkers in different therapeutic areas and critically discuss their potential to transform clinical care. Furthermore, we discuss opportunities of technological, methodological and institutional advances to improve biomarker discovery. We also summarize recent progress in our understanding of epigenetic effects on drug disposition and response, including a discussion of the only few pharmacogenomic biomarkers implemented into routine care. We anticipate, in part due to exciting rapid developments in Next Generation Sequencing technologies, machine learning methods and national biobanks, that the field will make great advances in the upcoming years towards unlocking the full potential of genomic data.
Abstract 17380: Genetic Variation in PCSK9 and Protection From Peripheral Artery Disease
Authors: Derek Klarin, Aeron Small, Jie Huang, Julie Lynch, Shipra Arya, Themistocles L Assimes, Pradeep Natarajan, Sekar Kathiresan, Daniel J Rader, John Concato, J. M Gaziano, Yan Sun, Kelly Cho, Peter W Wilson, Kyong-Mi Chang, Christopher J O’Donnell, Philip S Tsao, Scott M Damrauer
Journal: Circulation (2017)

Introduction: In the recently published FOURIER trial, an inhibitor of PCSK9 reduced LDL cholesterol levels by 56 mg/dl, and also reduced the risk of the primary outcome (a composite of cardiovascular death, stroke, myocardial infarction, hospitalization for unstable angina or revascularization) by 15%. Whereas symptomatic peripheral artery disease (PAD) was an inclusion criteria for this trial, PAD outcomes were not reported, and questions about the role of PCSK9 in PAD remain unanswered. Hypothesis: DNA sequence variants leading to loss of PCSK9 function are associated with reduced risk of PAD. Methods: We analyzed the electronic health records from 230,080 white and 60,386 black U.S. veterans with available genetic data from the VA Million Veteran Program (MVP). We studied three DNA sequence variants in PCSK9 that lead to loss of PCSK9 function and as such, represent a model of pharmacologic inhibition. We performed logistic regression adjusting for age, sex, and 10 principal components of ancestry, to...
Ubiquitin-activating enzyme inhibition induces an unfolded protein response and overcomes drug resistance in myeloma
Authors: Junling Zhuang, Fazal Shirazi, Ram Kumar Singh, Isere Kuiatse, Hua Wang, Hans C. Lee, Zuzana Berkova, Allison Berger, Marc Hyer, Nibedita Chattopadhyay, Sakeena Syed, Judy Qiuju Shi, Jie Yu, Vaishali Shinde, Stephen Tirrell, Richard Julian Jones, Zhiqiang Wang, R. Eric Davis, Robert Z. Orlowski
Journal: Blood (2019)
How common is imaging for low back pain in primary and emergency care? Systematic review and meta-analysis of over 4 million imaging requests across 21 years
Authors: Aron Downie, Mark Hancock, Hazel Jenkins, Rachelle Buchbinder, Ian Harris, Martin Underwood, Stacy Goergen, Chris G Maher
Journal: British Journal of Sports Medicine (2019)

To (1) estimate the proportion of patients seeking care for low back pain (LBP) who are imaged and (2) explore trends in the proportion of patients who received diagnostic imaging over time. We also examined the effect of study-level factors on estimates of imaging proportion.Electronic searches of MEDLINE, Embase and CINAHL databases from January 1995 to December 2017.Observational designs and controlled trials that reported imaging for patients presenting to primary care or emergency care for LBP. We assessed study quality and calculated pooled proportions by care setting and imaging type, with strength of evidence assessed using the GRADE system.45 studies were included. They represented 19 451 749 consultations for LBP that had resulted in 4 343 919 imaging requests/events over 21 years. Primary care: moderate quality evidence that simple imaging proportion was 16.3% (95% CI 12.6% to 21.1%) and complex imaging was 9.2% (95% CI 6.2% to 13.5%). For any imaging, the pooled proportion was 24.8% (95% CI 19.3%to 31.1%). Emergency care: moderate quality evidence that simple imaging proportion was 26.1% (95% CI 18.2% to 35.8%) and high-quality evidence that complex imaging proportion was 8.2% (95% CI 4.4% to 15.6%). For any imaging, the pooled proportion was 35.6% (95% CI 29.8% to 41.8%). Complex imaging increased from 7.4% (95% CI 5.7% to 9.6%) for imaging requested in 1995 to 11.4% (95% CI 9.6% to 13.5%) in 2015 (relative increase of 53.5%). Between-study variability in imaging proportions was only partially explained by study-level characteristics; there were insufficient data to comment on some prespecified study-level factors.One in four patients who presented to primary care with LBP received imaging as did one in three who presented to the emergency department. The rate of complex imaging appears to have increased over 21 years despite guideline advice and education campaigns.CRD42016041987.
Proteomic analysis to identify markers for response to treatment in esophageal cancer.
Authors: Oran Zlotnik, Tal Goshen-Lago, Baruch Brenner, Yulia Kundel, Nikolai Menasherov, Hanoch Kashtan, Irit Ben-Aharon
Journal: Journal of Clinical Oncology (2019)

61 Background: Neoadjuvant chemoradiotherapy (NCRT) followed by surgery represents a key therapeutic strategy for locally advanced esophageal cancer (LAEC). Former studies addressed the clinicopathological patterns of patients who demonstrated good response to NCRT compared with inferior response. Nevertheless, there is paucity of data regarding potentially involved cellular pathways that account for tumor response to NCRT. We performed a comprehensive proteomic analysis to identify the key differences in protein function and pathway activation between patients with a poor response and those with a favourable response to treatment. Methods: Patients diagnosed with LAEC who were treated with NCRT and operated at our institution were included in the study. Patients were defined as good responders (GR) upon the tumor regression grade (TRG) in the pathological specimen: GR defined as TRG 0/1 and no evidence of recurrence at 1-year post surgery. Bad responders (BR) were defined as TRG 2/3 and recurrence &lt; 1year. Tumor was isolated from the surgical specimen and proteins were extracted and processed for mass spectrometry-based analysis. Clinical data of demographics, response to treatment, and survival was retrieved from electronic medical records. Difference in protein expression between GR and BR were analysed using validated gene expression pathways tools and correlated to clinical data. Results: Forty-four patients were included in the cohort. Mean age was 66.7 years, male predominance (33/44). Thirty-five patients had adenocarcinoma – 17 GR and 18 BR. Nine patients had squamous cell carcinoma – 6 GR and 3 BR. Protein expression patterns significantly differed between GR and BR regardless of histology, mainly in cellular pathways account for nucleic acid metabolism (p &lt; 10 -9 ), whereas BR had overexpression of these genes. Conclusions: Our study indicate that lack of response to NCRT may derive from overexpression of unique cellular pathways. Former studies imply these cellular pathways may play a role in resistance to cisplatin. Larger transcriptomic studies are warranted for future analysis to extend these observations.
Abstract 17918: Mineralocorticoid Receptor Antagonist Use Following Acute Heart Failure Hospitalization: An Analysis of Drug Adherence and Effects on Patient Outcomes
Authors: Jason M Duran, Shady Gad, Barry Greenberg
Journal: Circulation (2017)

Introduction: Patients hospitalized for heart failure (HF) have increased risk for events post-discharge. Mineralocorticoid receptor antagonists (MRAs) have mortality benefits in patients with systolic HF. We assessed MRA use in high-risk patients identified by a HF hospitalization. Methods: Patients admitted to UCSD Hospitals from 2011-2013 for systolic HF exacerbation were enrolled retrospectively through automated search of electronic medical records for appropriate ICD 9 and 10 codes. Of the 1250 patients identified, 444 had >1 year follow up in our clinics. Of these, 286 patients (65%) met inclusion criteria of LVEF<40% with NYHA class III-IV symptoms. Results: At index hospital admission, 22.7% (65/286) were taking MRAs and 16.4% (47/286) had MRA initiated prior to discharge. Of the 176 patients not started on MRAs, 2 had hyperkalemia and 8 had CKD precluding MRA use per guideline recommendations. Patients taking MRAs (n = 112) did not have significantly different baseline characteristics than patie...