tbuckley/cabot-search huggingface dataset:
Letter to the Editor: Can Colder Weather and Fewer Sunlight Hours Truly Increase Alcohol Consumption and Alcoholic Cirrhosis?
Authors: Gin‐Ho Lo
Journal: Hepatology (2019)

Potential conflict of interest: Nothing to report. To the Editor: I read with interest regarding the influence of colder weather and fewer sunlight hours on the increase in alcohol consumption and alcoholic cirrhosis.1 The study of a global cohort including 193 countries showed that colder climates may play a causal role on alcohol‐attributable fraction (AAF) of cirrhosis mediated by alcohol consumption. Although it may hold true in many countries, the situation in Taiwan appears to be opposite to this conclusion. Taipei and Kaohsiung cities are located at northern and southern Taiwan, respectively. Colder weather, fewer sunlight hours, and high rainfall are noted in Taipei, whereas hot weather and more sunlight hours are a feature of Kaohsiung. Several studies of variceal bleeding among patients with cirrhosis in Taiwan revealed that alcoholism accounting for about 10% of cirrhosis in Taipei, whereas alcoholism accounting for 30% in Kaohsiung.2 Although not a cross‐sectional survey, it disclosed that cold weather and fewer sunlight hours in Taipei do not evoke more interest in alcohol drinking as compared with Kaohsiung. Thus, it can be assumed that sociocultural factors appear to be more important than cold weather in eliciting the habit of alcohol drinking and AAF of cirrhosis in different locations such as Taiwan and Ireland.4
Ocular melanoma liver metastases treated by percutaneous hepatic perfusion with melphalan followed by ipilimumab: A case report.
Authors: Ahmad Fitri Idris, Michael John Martin, Ian R Davidson, Gerard J O'Sullivan, Ahmad A Jamaludin, Paul P. Donnellan
Journal: Journal of Clinical Oncology (2013)

e20008 Background: Patients with unresectable liver metastases from ocular melanoma have a poor prognosis with just 10% surviving 1 year with standard treatments. High-dose melphalan via percutaneous hepatic perfusion (PHP) and filtration system (ChemoSat, Delcath Inc.) is licensed in Europe for treatment of liver-only metastases from ocular melanoma and neuroendocrine tumours. Ipilimumab (Ipi), anti-CTLA4 immunotherapy is licensed in US and Europe for treatment of metastatic malignant melanoma. A 32-year-old man was referred to our unit with unresectable liver metastases from primary ocular melanoma treated 8 years earlier. Here we describe the first report of sequential ChemoSat and Ipi in this setting. Methods: With assistance of an international proctoring team, and following on-site training, we treated this patient with ChemoSat according to manufacturer’s instructions (details at meeting). There were no immediate complications or subsequent hematological or other systemic chemotherapy side-effects. On day 4, the patient developed acute epigastric pain, pyrexia, ST elevation, and elevated troponin. Cardiac ECHO, coronary angiogram, CT pulmonary angiogram, abdominal USS and gastroscopy were normal. Blood cultures were repeatedly negative. He developed acute kidney injury secondary to intravenous contrast and NSAIDs. Repeat abdominal USS showed a thickened wall of gall bladder. A diagnosis of acute chemical cholecystitis was made. His symptoms settled, kidney function improved and he was discharged on day 23 of procedure. 10 weeks post ChemoSat the patient underwent treatment with Ipi 3mg/kg i.v. day 1, q 3/52 x 4 cycles which he received without significant side-effects. Results: MRI scan of liver 8 weeks post-ChemoSat (pre-Ipi) showed the liver lesions to be unchanged. CT scan 6 weeks post-Ipi treatment showed significant improvement. Conclusions: ChemoSat treatment is feasible and safe but can cause unexpected gall-bladder toxicity. Subsequent treatment with ipilimumab seems to be effective in this single case with short-term follow up.
Modulation of Respiration and Mitochondrial Dynamics by SMAC-Mimetics for Combination Therapy in Chemoresistant Cancer
Authors: Judith Hagenbuchner, Herbert Oberacher, Kathrin Arnhard, Ursula Kiechl-Kohlendorfer, Michael J. Ausserlechner
Journal: Theranostics (2019)

Inhibitor of apoptosis proteins (IAP) are cell death regulators that bind caspases and interfere with apoptotic signalling via death receptors or intrinsic cell death pathways.BIRC4/XIAP is the most potent anti-apoptotic IAP-member and it physically interacts with caspases via its BIR2 and its BIR3 domain.These domains are also critical for the interaction with mitochondria-derived SMAC/Diablo and with the IAP protein survivin.Survivin is frequently overexpressed in neuroblastoma due to a gain of 17q and we have demonstrated that survivin confers resistance to chemotherapeutic agents and reprograms metabolism of neuroblastoma cells towards glycolysis.As regulator of mitochondrial fission and autophagy survivin acts at the crossroads of mitochondrial architecture, autophagy and cellular energy metabolism.Methods: We tested the effect of SMAC-mimetics on the XIAP/survivin axis as modulator of cellular metabolism analysing mitochondrial morphology, metabolic intermediates and cellular survival.Finally, the impact of the combined treatment was evaluated in a xenograft neuroblastoma mouse model assessing the therapy effect on tumour size and volume.Results: Here we demonstrated that XIAP sequesters significant amounts of survivin within the cell that can be mobilized by so called SMAC-mimetics.SMAC-mimetics are drugs that are designed to bind with high affinity to XIAP-BIR2 / BIR3 domains to release caspases and re-sensitize XIAP-overexpressing tumors for chemotherapy.However, SMAC-mimetic treatment releases also survivin from XIAP and thereby induces mitochondrial fragmentation, prevents ROS accumulation and leads to the Warburg effect, an unwanted side effect of this therapy.Importantly, cells that drift into a highly glycolytic state due to SMAC-mimetic treatment become also highly sensitive to non-genotoxic treatment with glycolysis inhibitors such as 2-Deoxy-D-glucose (2DG) in vitro and in vivo. Conclusion:A combinational therapy of non-genotoxic SMAC-mimetics and glycolysis-inhibitors overcomes IAP-mediated cell survival in cancer and provides therefore an attractive usage of SMAC-mimetics.
The prognostic impact of high MET gene copy number on non-small cell lung cancer: A meta-analysis of eight studies.
Authors: Anastasios Dimou, Lemuel Non, Kostas N Syrigos
Journal: Journal of Clinical Oncology (2013)

e22049 Background: The risk stratification of NSCLC on the basis of molecular information is a key approach in the clinical management of patients with the disease. MET is the receptor for HGF and is present in the membrane of NSCLC cells. The most common genetic alteration associated with MET is the gene amplification. Methods: Two independent investigators applied parallel search strategies with the terms "MET" AND "lung cancer", "MET" AND "NSCLC", "met gene copy number" AND "prognosis" in PubMed through November 2012. We selected the studies that investigated the association of MET gene copy number with prognosis. A quality score that assessed the lab methods, the generalizability and the analysis, was assigned to each study that was finally included in the analysis. Results: Among 791 studies that were identified in the initial search, we retrieved 8 cross sectional studies on retrospective cohorts with adequate data regarding the prognostic impact of MET gene copy number on the survival of patients with NSCLC. Among the studies, 5 used FISH and the remaining 3 used RT PCR to assess the MET gene copy number in the primary tumor. All 8 studies used tissue from surgically resected specimens. MET gene copy number predicted worse overall survival when all studies were combined in a fixed effects model (HR=1.35, 95% CI 1.17-1.57). We calculated the I 2 statistic to assess heterogeneity (I 2 =44%, p=0.09). There were four studies where a higher gene copy number predicted a better outcome and four in which the opposite was true. The Egger’s regression intercept showed no significant publication bias (p=0.38). Conclusions: Higher MET gene copy number in the primary tumor at the time of diagnosis predicts worse outcome in patients with NSCLC.
Abstract 1096: Predictors Of Carotid Intimal-medial Thickness In Subjects With Hyperalphalipoproteinemia
Authors: Michael West, Bela Asztalos, Toni Pollin, Wendy Post, Annabelle Rodriguez
Journal: Circulation (2007)

HDL cholesterol (HDL-C) is inversely associated with risk for CVD in the general population. However, the metabolic pathways leading to high HDL (hyperalphalipoproteinemia) are complex, and some patients with high HDL-C are not protected against atherosclerotic disease. The purpose of this study was to determine the associations between CVD risk factors, especially HDL subpopulations, and subclinical vascular disease in patients with high HDL-C. Community-dwelling adult subjects with and without CAD between the ages of 18 – 80 years with HDL-C levels above 60 mg/dl were recruited for this study (n=46, 34 women and 12 men, mean age 58.7 ± 9.7 years). After an overnight fast, blood was obtained for measurement of lipids, inflammatory markers and lipoproteins by NMR spectroscopy (Liposcience, NC) and 2D-gel analysis. Far wall common carotid artery intimal-medial thickness (IMT) was measured using carotid ultrasonography. None of the subjects were taking statins. The lipid levels (mean ± SD) were total cholesterol 225.6 ± 37.9 mg/dl, triglycerides 77.9 ± 29.4 mg/dl, HDL 90.4 ± 22.5 mg/dl and LDL 119.6 ± 33.4 mg/dl. Carotid IMT values were normally distributed, with a range of 0.46 –1.1 mm. Unadjusted pairwise-correlations showed that carotid IMT was significantly associated with LDL particle number ( p&lt; 0.03), HDL subpopulations by 2D-gel analysis [α-3: p&lt; 0.005; α-4: p&lt; 0.04; and preα-1: p&lt; 0.03], C-reactive protein ( p&lt; 0.03), sVCAM-1 ( p&lt; 0.02), age ( p&lt; 0.0008), systolic blood pressure ( p&lt; 0.02), heart rate ( p&lt; 0.02) and corneal arcus ( p&lt; 0.04). Carotid IMT was not associated with any traditional lipid level, gender or history of CAD. In a multiple regression model, age ( p =0.0007), α-3 ( p&lt; 0.008) and CRP ( p&lt; 0.03) were significant independent predictors of carotid IMT in this population. Thus, in subjects with hyperalphalipoproteinemia, increased small, dense HDL (α-3) and CRP levels were associated with increasing carotid IMT, suggesting heterogeneity in the role of HDL particles on subclinical atherosclerosis.
Efficacy endpoints (EEPs) in melanoma randomized controlled adjuvant trials (RCATs).
Authors: Jose Gerard Monzon, Teresa M. Petrella, Janet Dancey
Journal: Journal of Clinical Oncology (2012)

e13049 Background: Inconsistencies in RCAT EEPs definitions and reporting complicate the evaluation of EEPs as adequate surrogates for overall survival (OS) and the comparison of the EEPs between trials. We aimed to identify issues in reporting and defining of EEPs used in melanoma RCATs. Methods: To identify phase 3 melanoma RCATs published in English language journals from 1994- 2011, a Pubmed database search and systematic review of published meta-analyses were performed. RCAT characteristics and endpoint definitions were obtained. Original protocols were requested. Results: A total of 34 RCATs met the criteria for review. Interferon alone or in combination with another agent was the most commonly tested treatment. Node positive disease was included in 24 studies with 1 including resected metastatic disease. The eligibility criteria in regards to age, previous treatment, and performance status were not reported in 26%, 32%, and 53% of studies respectively. The baseline and follow-up radiological tests were not specified in 35% and 26% of studies respectively. Eight time-to-event (TTE) EEPs were identified, with most studies using more than one (See Table). The primary EEP was not specified 23% of the time. Clear definitions of TTE EEPs start and end time criteria were absent in 58% and 44% of studies, respectively. Conclusions: The inconsistencies in the reporting of EEPs in melanoma RCATs is due to a lack of standardization in their definition and measurement. Standardizing EEPs will reduce resource consumption and enhance the comparison of agents across studies in melanoma RCATs. [Table: see text]
Do Outcomes in Elective Colon and Rectal Cancer Surgery Differ by Weekday? An Observational Study Using Data From the Dutch ColoRectal Audit
Authors: Daniëlle D. Huijts, Onno R. Guicherit, Jan Willem T. Dekker, Julia T. van Groningen, Leti van Bodegom-Vos, Esther Bastiaannet, Johannes A. Govaert, Michel W. Wouters, Perla J. Marang-van de Mheen
Journal: Journal of the National Comprehensive Cancer Network (2019)

Abstract Background: Previous studies showing higher mortality after elective surgery performed on a Friday were based on administrative data, known for insufficient case-mix adjustment. The goal of this study was to investigate the risk of adverse events for patients with colon and rectal cancer by day of elective surgery using clinical data from the Dutch ColoRectal Audit. Patients and Methods : Prospectively collected data from the 2012–2015 Dutch ColoRectal Audit (n=36,616) were used to examine differences in mortality, severe complications, and failure to rescue by day of elective surgery (Monday through Friday). Monday was used as a reference, analyses were stratified for colon and rectal cancer, and case-mix adjustments were made for previously identified variables. Results: For both colon and rectal cancer, crude mortality, severe complications, and failure-to-rescue rates varied by day of elective surgery. After case-mix adjustment, lower severe complication risk was found for rectal cancer surgery performed on a Friday (odds ratio, 0.84; 95% CI, 0.72–0.97) versus Monday. No significant differences were found for colon cancer surgery performed on different weekdays. Conclusions: No weekday effect was found for elective colon and rectal cancer surgery in the Netherlands. Lower severe complication risk for elective rectal cancer surgery performed on a Friday may be caused by patient selection.
Abstract 17140: Altered Epigenetic Signaling in the Coronary Arteries of Patients With Pulmonary Arterial Hypertension: the Role for BRD4 in the Development of Comorbidities
Authors: Valerie Nadeau, Jolyane Meloche, Eve Tremblay, Marie-Claude Lampron, Francois Potus, Olivier Boucherat, Roxane Paulin, Eric Charbonneau, Steeve Provencher, Sebastien Bonnet
Journal: Circulation (2016)

Rationale: Pulmonary arterial hypertension (PAH) is a devastating vasculopathy. Recent progress in understanding its pathogenesis led to an increase in patient’s quality of life but also to the occ...
Creating clinical target validation groups via quality assured transfer of robust clinical pharmacodynamic (PD) assays from the NCI: Clinical implementation of a PAR immunoassay in tumor biopsies.
Authors: Ralph E. Parchment, Robert J. Kinders, Jiuping Jay Ji, Apurva K. Srivastava, Katherine V. Ferry-Galow, Joseph E. Tomaszewski, James H. Doroshow
Journal: Journal of Clinical Oncology (2013)

e22080 Background: Early phase clinical trials of investigational agents benefit from laboratory assays that quantify intended mechanism of action on molecular target (1° PD effects), desired changes in mechanistic biomarkers (2° PD effects), and 3° PD effects on cell survival. Robust PD assay results are valuable for informing go/no‐go decisions about continued development of new agents and for identifying combinations of targeted agents that cover the multiple molecular defects underlying many malignancies. Methods: Readying PD assays for clinical use involves validating analytical performance, identifying and qualifying critical reagents, demonstrating fit‐for‐purpose for the clinical protocol, and finalizing companion SOPs specifying specimen handling and processing. Because clinical PD questions often demand assay performance that meets or even exceeds clinical diagnostic assay standards, but key assay reagents are usually R and D‐rather than GMP‐grade, stringent reagent Quality Control is critical for preventing assay failures due to lot-to-lot variability. Results: The poly(ADP-ribose) (PAR) Immunoassay was the first qualified assay developed by NCI for implementation in early phase clinical trials. Development of stringent production and internal Quality Control specifications for accepting/rejecting new lots of critical reagents and a defined Quality Assurance Plan allowed a network of users to achieve consistent results and quality using R&amp;D-grade source materials. Conclusions: The NCI’s Division of Cancer Treatment and Diagnosis is developing a clinical PD assay portfolio capable of quantifying 1°, 2°, and 3° PD effects. Proven clinical assays are formally transferred from the NCI to requesting sites in academia and industry via laboratory‐based certification and training, centralized access to SOPs, assistance with assay transfer, and participation in the assay’s Quality Assurance Plan. Funded by NCI Contract No HHSN261200800001E.
Abstract 14337: Venous Thromboembolism (VTE) Mortality Trends in Hispanics: Analysis of the National Inpatient Sample (NIS) Database
Authors: Guillermo H Tafur, Iva Golemi, Harry Fuentes, Kaushal Majmudar, Luis Diaz, Juan P Salazar, Luis H Paz, Christian Torres, Oscar J Garza, Alfonso Tafur
Journal: Circulation (2018)

Venous thromboembolism (VTE) is the third leading cardiovascular diagnosis, and it is a major cause of mortality among patients in the United States. Hispanic is the largest minority group in the U...
Achieving Improved Survival Outcomes in Advanced Breast Cancer
Authors: Hope S. Rugo
Journal: New England Journal of Medicine (2019)

Breast cancer is the most common cancer diagnosis in young women.1 In the United States, the incidence of breast cancer among women under the age of 50 is increasing by 0.2% per year, and the incidence of distant disease at the time of diagnosis among patients with hormone-receptor–positive breast cancer increased by about 2% per year between 1976 and 2009.2 A young age at diagnosis has been associated with worse outcomes and less sensitivity to endocrine therapy. Small-molecule inhibitors of cyclin-dependent kinases 4 and 6 (CDK4/6) have changed the standard of care for patients with advanced hormone-receptor–positive breast cancer. The . . .
Characteristics of gastrointestinal stromal tumor (GIST) patients receiving short-term versus long-term imatinib (IM) adjuvant therapy: A chart review analysis.
Authors: Annie Guerin, Anthony Paul Conley, Medha Sasane, Genevieve Gauthier, Frances Schwiep, Christopher Hunt Keir, Eric Q. Wu
Journal: Journal of Clinical Oncology (2012)

10094 Background: In clinical practice, significant variability is seen in duration of adjuvant IM use. The objective of this study is to compare characteristics of GIST pts receiving adjuvant IM for a short (6-12 months) vs extended period (≥24 months) to better understand factors that may influence treatment (trt) duration decisions. Methods: Physician prescribing patterns and clinical information on adult pts with primary resectable Kit positive GIST initiating IM ≤84 days post-surgery was collected from 248 U.S. oncologists using online data collection forms. In addition to physicians’ perception of short- vs long-term use, pts’ risk assessment, trt, demographics, and comorbidities were collected for 246 short-term and 395 long-term IM pts. Characteristics were compared using Wilcoxon and Chi-square tests. Results: While pts were similar in age [59.0 vs. 58.1, P =.23], ethnicity, and region of residence, the short-term group included fewer males (57.7% vs 69.6%, P &lt;.01) and had a higher prevalence of cardiovascular (11.4% vs 5.8%, P = .01) and ischemic heart diseases (5.3% vs 1.5%, P&lt;.01). Differences were also observed in indicators of pre-treatment risk profile (tumor size, location, and rupture during surgery, mitotic count, and Miettinen score) (Table). Findings were consistent with main reasons reported by physicians for prescribing adjuvant IM over longer duration; in addition to pt risk profile (76.6%), tolerability (70.6%), younger pts (59.7%), safety (39.1%), trt response (29.8%), and economic reasons (26.2%) were other reasons impacting trt decisions. Conclusions: Pt risk is an important factor in physicians’ decisions to prescribe adjuvant IM for extended duration. However, age, tolerability, and comorbidities, also play an important role. [Table: see text]
Abstract 975: Heat Shock Protein 90 Inhibitors Protect And Restore Pulmonary Endothelial Barrier Function.
Authors: Alexander Antonov, Connie Snead, Boris Gorshkov, Alexander D Verin, John D Catravas
Journal: Circulation (2007)

Heat shock protein 90 (hsp 90) inhibitors inactivate and/or degrade various client proteins, including many involved in inflammation. Disruption of endothelial barrier and increased vascular permea...
Private Equity and Dermatology—First, Do No Harm
Authors: Joshua M. Sharfstein, Jamar Slocum
Journal: JAMA Dermatology (2019)

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