tbuckley/cabot-search huggingface dataset:
Abstract P061: Incidence of Major Cardiovascular Disease and Subsequent Risk of End-stage Renal Disease: the Atherosclerosis Risk in Communities (ARIC) Study
Authors: Junichi Ishigami, Logan Cowan, Ryan Demmer, Pamela Lutsey, Morgan Grams, Josef Coresh, Kunihiro Matsushita
Journal: Circulation (2019)

Background: Cardiorenal syndrome is a well-known concept. However, in contrast to extensive investigations of chronic kidney disease (CKD) as a risk factor of cardiovascular disease (CVD), whether CVD increases long-term risk of end-stage renal disease (ESRD) is much less studied. Methods: In 8,881 participants of the Atherosclerosis Risk in Communities Study who attended visit 4 (1996-1998), we assessed the association of incident hospitalization with major CVD (heart failure, atrial fibrillation, coronary heart disease, and stroke) with subsequent risk of ESRD. Hospitalization with CVD was entered into multivariable Cox models as a time-varying exposure to estimate hazard ratios (HRs) and 95% confidence intervals (CI). Results: Baseline mean age was 62 years, 59% were female, 22% were black, and 5.5% had eGFR 15-60 ml/min/1.73m 2 . During a median follow-up of 15.9 years, there were 141 cases of ESRD. In multivariable Cox analysis, each incident CVD subtype was independently associated with increased risk of ESRD, with the highest HR for heart failure (HR, 16.9 [95%CI, 11.6-24.7]), followed by coronary heart disease, atrial fibrillation, and stroke (Model 2 in Table ). The association remained significant across CVD subtypes except for atrial fibrillation, when all CVD subtypes were simultaneously entered into a Cox model as time-varying exposures (Model 3 in Table ). The results were similar when modeling death as a competing risk, and consistent across subgroups of age, sex, race, diabetes, and CKD. When analyzing confirmed events of heart failure with preserved ejection fraction (HFpEF) (n=205) and reduced ejection fraction (HFrEF) (n=190), the association was particularly evident for HFpEF (10.8 [5.9-19.7]) compared to HFrEF (4.9 [2.0-11.7]). Conclusions: These findings support CVD as a potent risk factor of ESRD. Patients with CVD, particularly heart failure, should be recognized as a high risk population for ESRD. Distinct contribution of HFpEF vs. HFrEF to ESRD deserves future investigations.
The Association of Coronary Artery Calcification With Subsequent Incidence of Cardiovascular Disease in Type 1 Diabetes
Authors: Matthew Budoff, Jye-Yu C. Backlund, David A. Bluemke, Joseph Polak, Ionut Bebu, David Schade, Suzanne Strowig, Philip Raskin, John M. Lachin
Journal: JACC. Cardiovascular imaging (2019)
MRI Imaging of the Hemodynamic Vasculature of Neuroblastoma Predicts Response to Antiangiogenic Treatment
Authors: Konstantinos Zormpas-Petridis, Neil P. Jerome, Matthew D. Blackledge, Fernando Carceller, Evon Poon, Matthew Clarke, Ciara M. McErlean, Giuseppe Barone, Alexander Koers, Sucheta J. Vaidya, Lynley V. Marshall, Andrew D.J. Pearson, Lucas Moreno, John Anderson, Neil Sebire, Kieran McHugh, Dow-Mu Koh, Yinyin Yuan, Louis Chesler, Simon P. Robinson, Yann Jamin
Journal: Cancer Research (2019)

Abstract Childhood neuroblastoma is a hypervascular tumor of neural origin, for which antiangiogenic drugs are currently being evaluated; however, predictive biomarkers of treatment response, crucial for successful delivery of precision therapeutics, are lacking. We describe an MRI-pathologic cross-correlative approach using intrinsic susceptibility (IS) and susceptibility contrast (SC) MRI to noninvasively map the vascular phenotype in neuroblastoma Th-MYCN transgenic mice treated with the vascular endothelial growth factor receptor inhibitor cediranib. We showed that the transverse MRI relaxation rate R2* (second−1) and fractional blood volume (fBV, %) were sensitive imaging biomarkers of hemorrhage and vascular density, respectively, and were also predictive biomarkers of response to cediranib. Comparison with MRI and pathology from patients with MYCN-amplified neuroblastoma confirmed the high degree to which the Th-MYCN model vascular phenotype recapitulated that of the clinical phenotype, thereby supporting further evaluation of IS- and SC-MRI in the clinic. This study reinforces the potential role of functional MRI in delivering precision medicine to children with neuroblastoma. Significance: This study shows that functional MRI predicts response to vascular-targeted therapy in a genetically engineered murine model of neuroblastoma.
Germline DNA repair mutations in men with prostate cancer are less frequent in African Americans as compared with Caucasians.
Authors: Piper L.W. Nicolosi, Elisa Ledet, Shan Yang, Scott T. Michalski, James Vu, A. Oliver Sartor
Journal: Journal of Clinical Oncology (2019)

258 Background: Pathogenic DNA repair defects are well described in Caucasian (C) men with prostate cancer (PCa) but comparative data on African-American (AA) men are sparse. Methods: Germline testing for DNA repair defects were assayed by Invitae (Invitae.com). Pathogenic variants in 14 genes were compared between AA and C men with PCa; these particular genes were also assessed by Pritchard et al NEJM 375:443, 2016. Identical gene panels were not used in all men, thus variations in assay numbers from gene to gene are noted. Chi square was used to compare proportions. Results: In the 14 genes, there were 16/214 (7.5%) AA men and 347/2488 (13.9%) C men with pathogenic findings (p=0.008). As shown in the Table, the most common pathogenic variants in AA men were BRCA2 (6/214, 2.8%), BRCA1 (3/213, 1.4%), PALB2 (2/182, 1.1%), ATM (2/206, 1.0%), RAD51C (1/148, 0.68%), CHEK2 (1/207, 0.48%), and PMS2 (1/212, 0.47%). In contrast to C men in this series, no AA men had pathogenic mutations in BARD1, BRIP1, MLH1, MSH2, MSH6, NBN, or RAD51D. Pathogenic CHEK2 was less commonly detected in AA as compared to C (p=0.03) in this dataset. Comparing our C men revealed no differences in the proportion of men with pathogenic findings compared to Pritchard et al (13.9% here vs 11.8%, P=0.15). Conclusions: AA men with PCa are less likely to have pathogenic DNA repair mutations among these 14 assayed DNA repair genes compared to C men. Limitations regarding lack of stage, Gleason scores, and FH are notable. Details on gene assays and comparison to Pritchard et al NEJM 375:443, 2016 [Table: see text]
IFNγ, a Double-Edged Sword in Cancer Immunity and Metastasis
Authors: Chengfei Liu, Allen C. Gao
Journal: Cancer Research (2019)

Abstract IFNγ has antitumorigenic effects; however, the findings of IFNγ in promoting the tumor cell survival and inducing adaptive immune resistance via CD4+ T-cell loss and programmed death ligand 1 (PD-L1) upregulation challenge this concept. Lo and colleagues determined that IFNγ induces epithelial–mesenchymal transition (EMT) by regulating the turnover of miRNA in prostate cancer, emphasizing the duplicitous effects of IFNγ. IFIT5, an IFN-induced tetratricopeptide repeat (IFIT) family member, was found to form a complex with the exoribonuclease-XRN1 to process miRNA maturation. These findings unveil a new IFNγ–STAT1–IFIT5–miRNA–EMT pathway in prostate cancer progression. The biphasic effects of IFNγ in prostate cancer raise concerns about its therapeutic application, which need to be evaluated in future studies. See related article by Lo et al., p. 1098
Graphical Depiction of Longitudinal Study Designs in Health Care Databases
Authors: Sebastian Schneeweiss, Jeremy A. Rassen, Jeffrey S. Brown, Kenneth J. Rothman, Laura Happe, Peter Arlett, Gerald Dal Pan, Wim Goettsch, William Murk, Shirley V. Wang
Journal: Annals of Internal Medicine (2019)

Pharmacoepidemiologic and pharmacoeconomic analysis of health care databases has become a vital source of evidence to support health care decision making and efficient management of health care organizations. However, decision makers often consider studies done in nonrandomized health care databases more difficult to review than randomized trials because many design choices need to be considered. This is perceived as an important barrier to decision making about the effectiveness and safety of medical products. Design flaws in longitudinal database studies are avoidable but can be unintentionally obscured in the convoluted prose of methods sections, which often lack specificity. We propose a simple framework of graphical representation that visualizes study design implementations in a comprehensive, unambiguous, and intuitive way; contains a level of detail that enables reproduction of key study design variables; and uses standardized structure and terminology to simplify review and communication to a broad audience of decision makers. Visualization of design details will make database studies more reproducible, quicker to review, and easier to communicate to a broad audience of decision makers.
Cellular Senescence as a Mechanism and Target in Chronic Lung Diseases
Authors: Peter J. Barnes, Jonathan Baker, Louise E. Donnelly
Journal: American Journal of Respiratory and Critical Care Medicine (2019)

Section:ChooseTop of pageAbstract <<Normal Lung AgingCellular SenescenceSenescence-associated Sec...Phosphoinositide-3-Kinase...Reduced Antiaging Molecul...Key Role of MicroRNAExtracellular Vesicles as...Implications for TherapyConclusionsReferencesCITING ARTICLES
Abstract P4-10-02: Impact of raloxifene adherence in breast cancer risk
Authors: M Chavez-MacGregor, X Lei, H Zhao, TB Bevers, A Brewster, SH Giordano
Journal: Cancer Research (2019)

Abstract BACKGROUND: Raloxifene is a selective estrogen receptor modulator that has demonstrated to reduce breast cancer risk and reduce the incidence of vertebral fractures. Based on these effects, raloxifene is used as a risk reduction agent and to prevent osteoporosis in postmenopausal women. Little is known about the raloxifene adherence rates or the relationship between adherence and breast cancer incidence. METHODS: Women 60 years or older without a breast cancer history were identified in the MarketScan database (2008-2015). We identified women who received raloxifene by searching for prescription claims. Proportion of days covered (PDC) were calculated, adherence was defined as a PDC &amp;gt;80% in the first year after initial prescription claim. We identified factors associated with adherence. ICD-9 codes were used to identify incident cases of invasive breast cancer and cumulative incidence rates were calculated. A multivariable Cox model with propensity score method (matching variables included year of claim, age, comorbidities and family history of breast cancer) was used to evaluate the association between raloxifene adherence and breast cancer risk. All statistical tests were two-sided. RESULTS: A total of 16,179 women were included in the analysis. We identified that during the first year of treatment 6,716 (40.2%) women had a PDC &amp;gt;80% and thus were considered to be adherent. Factors associated with increased adherence included the use of generic drug, mail order of 90 days supply and family history of breast cancer (all p&amp;lt;0.001). Using propensity score matching, the 5 year-cumulative incidence of invasive breast cancer was 1.5% among those not adherent and 0.9% among those adherent to raloxifene (p=0.01). Similarly, the 9 year-cumulative rates were 3.6% and 1.9% respectively (p=0.01). After adjusting for potential confounders, patients that were adherent to raloxifene during the first year of treatment had a lower risk of invasive breast cancer compared to those that were non-adherent (HR=0.64; 95%CI 0.04-0.9). CONCLUSIONS: Among women 60 years of age or older receiving raloxifene, adherence to therapy was associated with lower risk of invasive breast cancer. Efforts to ensure adherence and compliance are crucial so patients can receive full benefit from this therapy. Citation Format: Chavez-MacGregor M, Lei X, Zhao H, Bevers TB, Brewster A, Giordano SH. Impact of raloxifene adherence in breast cancer risk [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P4-10-02.
Translational research on molecular markers in gastric cancer patients treated with adjuvant therapy (Italian Intergroup Adjuvant Chemotherapy of Adenocarcinoma of the Stomach-ITACA-S Trial).
Authors: Maria Di Bartolomeo, Luigi Mariani, Alessandro Pellegrinelli, Rosalba Miceli, Filippo Pietrantonio, Antonio Martinetti, Maria Grazia Daidone, Vittoria Disciglio, Emilio Bajetta, Roberto Buzzoni, Marta Caporale, Claudia Maggi, Filippo G. De Braud
Journal: Journal of Clinical Oncology (2015)

e15016 Background: Nowadays, no biomarkers are available to drive the treatment decision-making in patients (pts) with radically resected gastric cancer (GC), moreover the role of genes mutations in gastric carcinogenesis and their correlation with clinical outcomes are not fully defined. The aim of this translational study is to evaluate the correlation of Cyclooxygenase-2 (COX-2), E-cadherin (CDH1), B-catenine, osteopontin (OPN) expression and PIK3CA, KRAS/BRAF mutations with pathological disease stage, relapse free survival (RFS) and overall survival (OS) in pts recruited in the ITACA-S trial. The choice of these factors derived from the strong correlation of all the markers with H. Pylori infection. Methods: From 23 ITACA-S study recruiting centers, we collected 346 primary GC samples of pts radically resected for GC stratified by treatment arms and by the presence/absence of disease relapse. Multivariable analyses of RFS and OS were performed using Cox models. Results: Among the immunoistochemichal markers, OPN and E-cadherin expression was significantly associated with RFS and OS (p <0.001; 0.017and p = 0.003 and 0.001 respectively). The expression of ß-catenin showed a trend for association with RFS and a significant correlation with OS (p = 0.054; 0.009). At multivariable Cox model analysis, only OPN was independently associated with outcome. COX-2 not significantly associated with RFS and OS; conversely no mutation of PIK3CA, KRAS and BRAF were observed. HP positivity were documented in 28% of samples. Conclusions: The results suggest that OPN overexpression is an independent prognostic factor for RFS and OS in radically resected GC. The lack PI3K KRAS and BRAF mutation exclude any strong correlation with HP infection. The study was supported in part by AIRC grant
Nonadherence to Insulin Therapy Detected by Bluetooth-Enabled Pen Cap Is Associated With Poor Glycemic Control
Authors: Medha N. Munshi, Christine Slyne, Jordan M. Greenberg, Tori Greaves, Ariel Lee, Sam Carl, Astrid Atakov-Castillo, Elena Toschi
Journal: Diabetes Care (2019)

OBJECTIVE To objectively evaluate adherence to timing and dosing of insulin by using Bluetooth pen caps and examine factors related to adherence. RESEARCH DESIGN AND METHODS Bluetooth-enabled insulin pen caps were used in younger (ages 18–35 years) and older (ages ≥65 years) adults on two or more insulin injections per day. RESULTS We evaluated 75 participants with diabetes, 42 younger (29 ± 4 years) and 33 older (73 ± 7 years). Nonadherence was found in 24% of bolus (Apidra) doses and 36% of basal (Lantus) doses. We divided participants into tertiles on the basis of overall adherence, with the most adherent tertile having 85% dose adherence compared with 49% in the least adherent tertile (P &amp;lt; 0.001). Participants in the most adherent tertile had better glycemic control than those in the least adherent tertile (7.7 ± 1.1% [61 ± 12 mmol/mol] vs. 8.6 ± 1.5% [70 ± 16.4 mmol/mol], P &amp;lt; 0.03). CONCLUSIONS Nonadherence to insulin dosing and timing can be objectively assessed by Bluetooth pen caps and is associated with poor glycemic control.
Pembrolizumab (pembro) and cabozantinib (cabo) in patients (pts) with metastatic renal cell carcinoma (mRCC): Phase I results.
Authors: Molika Emmeline Keeler, Elizabeth Riley Kessler, Brandon Bernard, Sarah Weisdack, Kathryn M. Breaker, Mali Wold, Donna Ertz, David Weitzenkamp, Thomas W. Flaig, Elaine Tat Lam
Journal: Journal of Clinical Oncology (2019)

600 Background: PD-L1- and VEGF-targeted therapies have improved survival for mRCC pts and mechanisms of synergy have been reported. We conducted a phase I/II study to evaluate the safety and efficacy of pembro and cabo in mRCC pts. Phase I data are presented here. Methods: mRCC pts received pembro and cabo in a standard 3+3 dose escalation to determine the dose limiting toxicity (DLT), maximum tolerated dose (MTD), and objective response rate (ORR). Cabo was dosed at 40mg QD and 60mg QD in the first and second cohorts, respectively. Pembro was dosed at 200mg IV Q3W in all cohorts. The DLT window was 21 days. Scans were obtained every 9 weeks. Treatment beyond progression was allowed. Results: Eight pts (6M, 2F) were enrolled in the dose escalation cohort with cabo 40mg (5 pts) or 60mg (3 pts) and pembro 200mg. Two pts were not evaluable for DLT due to missing ≥25% of the planned cabo doses in C1, not related to DLT. Median age was 52.5 yrs (range 40-68). Seven pts had clear cell RCC and 1 pt had non-clear cell RCC. Seven pts had MSKCC intermediate risk and 1 pt had MSKCC poor risk. All pts had prior nephrectomy. Median number of prior therapies was one (range 1-3). No DLTs were observed. Drug-related G1 and G2 adverse effects included fatigue (87.5%), weight loss (75%), anorexia (50%), diarrhea (50%), dysgeusia (50%), and abnormal LFTs (50%). One pt had SAE of G3 reversible posterior leukoencephalopathy syndrome during C4, attributed to cabo. One pt each developed G3 hypertension, G3 anorexia, and G3 confusion, all occurring outside the DLT window. No dose reductions were needed at the 40mg cohort. One pt in the 60mg cohort required dose reduction to 40mg after C5. All patients were evaluable for response: 2 PR (at 60 mg cohort), 5 SD [median duration SD 18 wks (range 9-36+)], 1 PD; ORR 25%; clinical benefit rate 87.5%. No correlation was seen between PD-L1 status (archival tissue) and response. Conclusions: The MTD was determined to be pembro 200 mg Q3W and cabo 60 QD. Enrollment in the phase II dose expansion is ongoing and the MTD may be adjusted based on additional pt experience and long-term tolerability. There was encouraging early efficacy. This is an investigator-initiated study sponsored by Merck. Clinical trial information: NCT03149822.
Meta-analysis of temozolomide treatment of pituitary carcinomas and aggressive adenomas
Authors: Yan Ji, Rachel Isaksson Vogel, Emil Lou
Journal: Journal of Clinical Oncology (2015)

e13014 Background: Most pituitary tumors are benign and cured surgically. Pituitary carcinomas (PC) and aggressive pituitary adenomas (APA) are rare variants, but often recur and respond poorly to current treatment approaches. There is currently no evidence-based standard-of-care chemotherapy treatment for these cases. Response to temozolomide (TMZ) has been reported anecdotally. We hypothesized that TMZ represents an effective option for these patients. The primary goal of this analysis was to describe the overall survival (OS) and progression-free survival (PFS) in PC and APA patients following administration of TMZ. Secondary goals included assessment of response rate. Methods: We performed a comprehensive literature research to identify all published cases of PC and APA treated with TMZ. We identified 56 cases; we were able to obtain updated data on 53 patients and performed a meta-analysis of these cases. Of the 53 cases, 30 were APA and 23 were PC. Results: All patients had been previously treated with surgery; 85% had multiple resections. 95% of patients received radiation prior to TMZ. 72.7% received no additional chemotherapy other than TMZ. TMZ was initiated at median of 7 years (0 – 25 years) after initial diagnosis. The overall response rate (complete plus partial response) to TMZ was 67.8% in APA and 60% in PC. 3 patients in each group (9.7% APA and 12% PC) had stable disease. Neither history nor expression of Ki-67 or MGMT correlated with response. The 5-year PFS and OS were 22.7% (CI 4.6-49%) and 57.2% (CI 29.4-77.5%) for APA, versus 36.1% (CI 13.8-59.2%) and 56.2% (CI 30.2-75.8%) for PC, respectively. There was a statistical trend toward benefit from maintenance TMZ therapy, although the differences for OS and PFS did not reach statistical significance. (5-year OS: TMZ maintenance (91.7%, CI 53.9-98.8%, P = 0.08) vs. no maintenance (54.1%, CI 16.5-81.1%); 5-year PFS: TMZ maintenance (61.3%, CI 30.0-81.9%, P = 0.221) vs. no maintenance (16.3%, CI 1.0-48.9%)). Conclusions: TMZ is effective for treatment of both PC and APA, and can be considered as a maintenance form of treatment for particularly aggressive cases. We provide the most comprehensive study to date providing evidence supporting use of TMZ for treatment of PC and APA.
Genetic variant of TWEAK to predict clinical outcome in mCRC patients (pts) treated with first line FOLFIRI and Bevacizumab (FOLFIRI/BEV) in FIRE-3 and TRIBE cohorts.
Authors: Anish Parekh, Yan Ning, Sebastian Stintzing, Fotios Loupakis, Wu Zhang, Dongyun Yang, Yu Sunakawa, Stefan Stremitzer, Satoshi Matsusaka, Satoshi Okazaki, Rita Elkhoueiry, Angela Mendez, Afsaneh Barzi, Marta Schirripa, Volker Heinemann, Heinz-Josef Lenz
Journal: Journal of Clinical Oncology (2015)

3554 Background: Tumor necrosis factor-like weak inducer of apoptosis (TWEAK), acting via the Fn14 cell surface receptor, is a multifunctional pro-inflammatory/pro-angiogenic cytokine that participates in wound repair and tissue regeneration in different tissues. Studies have shown that TWEAK induces embryonic fibroblast proliferation through Ras/ERK signaling pathway. TWEAK produced in the tumor microenvironment acts on vascular endothelial cells and contributes to inflammatory angiogenesis in mCRC pts. In this study, we tested whether SNPs in TWEAK (rs3803800, rs1128963) and Fn14 (rs8052002, rs13209) predict clinical outcome in mCRC pts treated with first line FOLFIRI/BEV in two independent cohorts. Methods: Genomic DNA was isolated from blood or tissue samples of 525 pts treated with first-line FOLFIRI/BEV in FIRE-3 arm B (n = 295) and TRIBE arm A (n = 230) trials. FIRE-3 arm B served as the training set (Median follow up: 39.6 mos; Median PFS: 11.3 mos. and OS: 25 mos). TRIBE arm A served as the validation set (Median follow up: 45.1 mos; Median PFS and OS: 10.4 and 27.3 mos. PCR-based DNA sequencing was used to determine SNPs, which were selected based on frequency and function. FIRE-3 FOLFIRI/Cet (n = 297) was control arm. Results: In the overall population analysis, the TWEAK rs3803800 was significantly associated with shorter PFS (9.2 mos) compared to carrying the G/G genotype (11.3 mos) in the FIRE-3 trial in both univariate (HR: 1.39 [1.03-1.86]; P = 0.026) and multivariate analyses (HR: 1.50 [1.11-2.03], P = 0.008). For KRAS mutant pts in the TRIBE trial, any A allele of TWEAK rs3803800 was associated with a similar trend toward worse PFS compared to G/G in multivariate analyses (HR: 1.64 [0.94-2.86], p = 0.079), which is confirmed in the FIRE-3 trial (8 v. 12.3 mos, logrank test P = 0.019)(HR: 2.11 [0.97-4.49], Wald test P = 0.058). No significant difference in control arm. Conclusions: This study provides the first evidence that TWEAKrs3803800 could be a predictive marker for PFS in mCRC pts treated with first line FOLFIRI/BEV. It also retained a significant correlation with outcomes related to KRAS mutation, which was confirmed in a validated cohort.