tbuckley/cabot-search huggingface dataset:
Abstract P301: Obesity and Mortality: the Jackson Heart Study
Authors: Yuan-I Min, Karen A Valle, Pramod Anugu, Yan Gao, Anshul Anugu, Arnita F Norwood, Adolfo Correa
Journal: Circulation (2019)

Background: Mortality has been reported to be lower among individuals classified as overweight/obese (based on body mass index (BMI, kg/m 2 )) when compared with their normal weight counterparts (“obesity paradox”). One possible reason for this apparent paradox is that BMI includes the weight of lean muscle and fat mass, both of which vary with age, sex, and race/ethnicity, and variations in these individual mass measures may not be reflected by the BMI. We compared associations between all-cause mortality and BMI and other obesity measures that may better reflect central adiposity, including waist circumference (WC, cm), waist-to-height ratio (WHtR) and waist-to-hip ratio (WHR) in the Jackson Heart Study (JHS), a prospective cohort study of cardiovascular disease in African Americans. Methods: Data from 3,976 JHS participants (441 deaths) who attended Exam 2 (2005-2008) where various measures of obesity were collected, were analyzed. Cox regression models were used to evaluate the associations between obesity and all-cause mortality. “Time 0” for the survival analysis was the date of Exam 2 and the administrative censoring date was 12/31/2015. Obesity measures were analyzed as categories based on standard cut-points defining obesity and as quintiles. Covariates include age, sex and smoking. The predictive abilities of these obesity measures were assessed using c-index. Results: The age-sex-smoking adjusted mortality rates were the lowest among participants who were overweight (BMI 25-&lt;30) or with class I obesity (BMI 30-&lt;35). However, compared to normal weight participants (BMI 18.5-&lt;25), only participants with class III obesity (BMI ≥40) had a significantly higher mortality (adjusted HR [aHR] 1.92 [95% CI 1.34-2.75]). In addition, higher mortality was associated with obesity defined by WC (&gt;102 in men/&gt;88 in women vs. ≤102 in men/≤88 in women; aHR 1.45 [1.16-1.82]) and by WHR (≥0.9 in men/≥0.85 in women vs. &lt;0.9 in men/&lt;0.85 in women; aHR 1.54 [1.21-1.95]); but not by BMI (≥30 vs. &lt;25; aHR 1.04 [0.79-1.37]) or WHtR (≥0.5 vs. &lt;0.5; aHR 1.03 [0.72-1.49]). Sex-stratified analyses suggest the stronger predictor for mortality was WC-defined obesity in men and WHR-defined obesity in women; however, test for interactions were not statistically significant. The associations were not found to vary by age (&gt;65 vs. ≤65 years). Analyses using quintiles showed that the 5 th quintiles were associated with a significant increase in mortality compared with the 1 st quintiles for all obesity measures. The c-indexes were comparable for all obesity measures. Conclusions: The “obesity paradox” was suggested in the JHS based on BMI. However, only morbidly obese participants had a significantly higher mortality than normal weight participants. The recommended cut-points for defining obesity based on WC and WHR were significantly associated with increased mortality in this large cohort of African Americans.
Tumor mutational burden (TMB) and BCG responsiveness in high-risk non-muscle invasive bladder cancer (NMIBC).
Authors: Diogo Assed Bastos, Mariana Lima, Romulo Loss Mattedi, Filipe Ferreira dos Santos, Vanessa Buzatto, Rodrigo Barreiro, Leopoldo Ribeiro-Filho, Mauricio Cordeiro, Mariane Amano, Jussara Michaloski Souza, Fabiana Bettoni, Pedro Alexandre Favoretto Galante, Carlos Dzik, William Carlos Nahas, Anamaria Aranha Camargo
Journal: Journal of Clinical Oncology (2019)

442 Background: Despite optimal management of NMIBC with transurethral resection of bladder tumor (TURBT) and intravesical BCG therapy, a significant proportion of patients (pts) will eventually present with disease recurrence or progression. To date, there is no validated predictive biomarker to guide patient selection for the most appropriate therapy in this setting. Methods: We retrospectively identified pts with high-risk NMIBC treated with TURBT, repeat TUR and intravesical BCG (≥ 6 instillations) from 2009 to 2016. Patients were classified as BCG-responsive (BCG-R) and BCG-unresponsive (BCG-UR) based on the International Bladder Cancer Group criteria. Whole exome sequencing was performed using archival FFPE tumor tissue from pre-BCG TURBT samples. Association of genomic variables and outcomes was evaluated by Cox proportional hazards survival analysis and likelihood ratio tests. Results: Thirty-five patients were included (BCG-R = 17, BCG-UR = 18). Median follow-up was 46 months for BCG-R and 52 months for BCG-UR pts. The majority of pts was male (91.4%), former smoker (60%), and presented with high-grade urothelial carcinoma (85.7%) and/or T1 staging (71.4%). Median time for relapse and progression was 10.5 and 19 months, respectively, in the BCG-UR group. In this cohort, TMB was significantly different in BCG-R and BCG-UR groups, with a median TMB of 5.53 +- 4.60 and 3.17 +- 1.82 mutations/Mb, respectively ( P= 0.045). TMB was also associated with relapse-free survival (RFS), with a median RFS of 38 and 15 months in high versus low TMB groups, respectively ( P= 0.0092). Intratumoral genetic heterogeneity assessed by mutant-allele tumor heterogeneity (MATH) was not statistically different between the groups, with a median MATH score of 31.8 and 21.9 for BCG-R and BCG-UR ( P= 0.14), respectively. On multivariate analysis, age and TMB were independently associated with RFS. Conclusions: In this exploratory biomarker study, high TMB was associated with benefit from immunotherapy with BCG for NMIBC. The identification of predictive biomarkers in this setting is an important unmet need and integrative analysis of TMB with other potential predictive biomarkers should be assessed in larger datasets.
A pilot study of oxaliplatin, irinotecan and PK-adjusted 5-fluorouracil within a neoadjuvant multidisciplinary approach in locally advanced pancreatic cancer patients.
Authors: Patricia Martin Romano, Azucena Aldaz, Ana Chopitea, Fernando Pardo, Leire Arbea, Jose Carlos Subtil, Fernando Rotellar, Laura Zufia, Jose Luis Solorzano, Juan Pablo Fusco, Eduardo Castanon Alvarez, Javier Rodriguez
Journal: Journal of Clinical Oncology (2015)

e15220 Background: The aim of this study was to evaluate the feasibility and efficacy of FOLFOXIRI induction chemotherapy (ICT) with pharmacokinetic (PK) dose adjustment of 5-FU followed by chemo-radiotherapy (CRT) and surgery (S) in Locally Advanced Pancreatic Cancer patients (pts) Methods: Borderline resectable and unresectableLAPC pts with EUS stages T3-4/N+ were included. ICT consisted of 4 cycles of Oxalipatin (85mg/m²), Leucovorin (400mg/m²), Irinotecan (150mg/m²) and 5-FU [initial dose of 3200mg/m² in 46h; subsequent doses based on PK-guided dose adjustments (therapeutic AUC of 20-30 mg∙h∙L-1)]. 5-FU concentrations were analyzed by High-performanced Liquid Chromatography. PK parameters were estimated by Bayesian Methodology with Multiple Dose Software. Pts with no progressive disease after ICT were planned to receive CRT. Surgery (S) was planned 4 to 6 weeks after completion of CRT. Toxicity was recorded according to the NCI-CTCAE 4.0 Results:From November 2011 to August 2014, 23 LAPC treatment-naïve pts [M/F: 15/8; median age 65; T4/N+: 30%/52%; borderline resectable (10 pts), unresectable due to celiac abutment (4 pts), SMA and celiac encasement (3 pts), unreconstructible SMV and portal occlusion (6 pts)] were enrolled. Grade 3-4 ICT-related toxicities were neutropenia (12 pts) and diarrhea (3 pts). Grade 3 CRT-related toxicity included neutropenia (2 pts), thrombocytopenia (3 pts), diarrhea (1 pt), anorexia (1 pt) and mucositis (1 pt); 3 pts required hospital admission. 22 pts completed the neoadjuvant program. 16 pts underwent S (R0 resection rate 94%), whereas unresectability criteria remained in 7 pts. Pathological response (CAP classification) was 0 (no viable cells) and 1 (small groups of cancer cells) in 13% and 50% of pts, respectively; ypN0 rate was 81%. After a median follow-up of 24 months, the 2-year actuarial PFS and OS were 62% and 72%, respectively Conclusions: Incorporation of PK-guided dose adjustment of 5-FU within the FOLFOXIRI schedule is feasible, providing an acceptable toxicity profile. A longer follow-up is required to rule out whether 5-FU PK adjustment may contribute to a better therapeutic index in LAPC pts
Effectiveness and tolerability of maintenance capecitabine administrated to patients with metastatic pancreatic cancer treated with first line FOLFIRINOX.
Authors: Juliette Reure, Philippe Follana, Jocelyn Gal, Ludovic Evesque, Gerard Cavaglione, Angelique Saint, Eric Francois
Journal: Journal of Clinical Oncology (2015)

4120 Background: Treating metastatic pancreatic cancer (MPC) remains a challenging issue. Significant improvement was achieved recently by combining 4 drugs with Folfirinox regimen at the cost of increased toxicities compared to Gemcitabine. Maintenance therapy is a growing concept used in many different types of cancer. Our retrospective analysis aims to evaluate effectiveness and tolerability of early maintenance capecitabine administrated to patients with MPC treated with first line Folfirinox. Methods: 103 patients treated for MPC between November 2009 and July 2014 were retrospectively identified. Among them, 31 patients initially treated with a minimum of 4 cycles of Folfirinox, without sign of progression, received maintenance therapy with capecitabine until progression. Upon first progression (PFS1), patients were retreated with Folfirinox until second progression (PFS2). Survival was estimated with Kaplan Meier method. Results: Median numbers of cycles achieved for Folfirinox and capecitabine were respectively 6 and 4.5. Initial median dose of capecitabine was 2000mg/m2, we recorded dose reduction in 11 cases (35,4%), mostly due to cutaneous and digestive toxicities. Median overall survival (OS) was 19 months. Survival rates were 74% at 1 year (95% CI [0.59 to 0.91]) and 24% at 2 years (95% CI [0.12 to 0.47]). Median PFS1 was 11 months (95% CI [0.22 to 0.58]). 30 patients have relapsed during capecitabine treatment (96,7%). After disease progression, Folfirinox could be reintroduced in 14 cases. Other patients received FOLFIRI, Gemcitabine and Folfox due mainly to persistence of neuropathy and asthenia. Median PFS 2 was 16 months (95% CI [0.22 to 0.65]). Conclusions: Maintenance with capecitabine seems effective and safe without compromising Folfirinox efficacy and allows obtaining very promising overall and progression free survival. Role of maintenance therapy in MPC will soon be addressed in a French multicenter phaseII/III study. PANOPTIMOX/PRODIGE 35.
CT-Guided Biopsies Should Not Replace the Bedside Approach: Clinico-Pathologic Features Associated with Optimal Bone Marrow Procedures
Authors: Ana Acuna Villaorduna, Devika Rao, Yanan Fang, Joshua Heisler, Shirin Attarian, Todd Miller, Louis Juden Reed, Yanhua Wang, Ellen W. Friedman
Journal: Blood (2018)
Targeting DNA Methylation and EZH2 Activity to Overcome Melanoma Resistance to Immunotherapy
Authors: Abdullah Al Emran, Aniruddha Chatterjee, Euan J. Rodger, Jessamy C. Tiffen, Stuart J. Gallagher, Michael R. Eccles, Peter Hersey
Journal: Trends in Immunology (2019)

Methylation of DNA at CpG sites is the most common and stable of epigenetic changes in cancer. Hypermethylation acts to limit immune checkpoint blockade immunotherapy by inhibiting endogenous interferon responses needed for recognition of cancer cells. By contrast, global hypomethylation results in the expression of programmed death ligand 1 (PD-L1) and inhibitory cytokines, accompanied by epithelial-mesenchymal changes that can contribute to immunosuppression. The drivers of these contrasting methylation states are not well understood. DNA methylation also plays a key role in cytotoxic T cell 'exhaustion' associated with tumor progression. We present an updated exploratory analysis of how DNA methylation may define patient subgroups and can be targeted to develop tailored treatment combinations to help improve patient outcomes.
A Genome-wide association study of metastatic prostate cancer.
Authors: Craig Teerlink, Andrew W Hahn, John Esther, Nityam Rathi, James M Farnham, Neeraj Agarwal, Lisa Cannon-Albright
Journal: Journal of Clinical Oncology (2019)

160 Background: There are no biomarkers currently used in clinical practice that can predict which men will develop metastatic prostate cancer (mPrCa). Germline genetic variants that are highly associated with metastatic disease could be used for such prediction and may be identifiable from genome-wide association analyses (GWAS) conducted in appropriately scaled mPrCa case-control datasets. Methods: 451 mPrCa cases sequentially sampled from University of Utah/Huntsman Cancer Institute clinics were genotyped on the Illumina OmniExpress SNP platform and population-matched via principal components analysis to 1043 controls from dbGaP study phs000733 genotyped on the Illumina 5M SNP platform. The mPrCa cases and controls were analyzed via genome-wide association to identify SNPs highly associated with mPrCa. The dataset was then merged and re-analyzed with 176 lethal prostate cancer cases (identified in the Utah SEER Tumor Registry with a linked Utah death certificate including prostate cancer as a cause of death) in an attempt to identify a larger number of potential candidate SNPs associated with metastatic or lethal prostate disease. Results: The GWAS of mPrCa cases identified 4 significant SNPs at the 8q24.21 locus (p &lt; 5e-8), as well as 9 SNPs in 6 previously unreported regions (5q14.1, 6p24.1, 8q21.3, 15q13.3, 15q22.2, and 17q25.1) with suggestive evidence for association (p &lt; 1e-6). In addition, 30 SNPs with nominal evidence (p &lt; 0.001) in the mPrCa-only GWAS appeared with more extreme p-values when the 176 lethal subjects were included in the analysis, and may be appropriate candidate variants to test in external datasets. Conclusions: In this case-control GWAS study of 627 men with mPrCa or lethal PrCa, germline SNPs at the 8q24.21 locus and 6 previously unreported regions may be associated with mPrCa. These findings should be validated in external datasets of men with mPrCa.
Abstract P014: Aortic Stiffness and Late-life Depression: the Atherosclerosis Risk in Communities Neurocognitive Study (ARIC-NCS)
Authors: Jingkai Wei, Priya Palta, Kenneth R Butler, Mariana Lazo, Benjamin D Capistrant, Thomas H Mosley, Gerardo Heiss
Journal: Circulation (2019)

Introduction: Late-life depression, which occurs at the age of 65 years or older, is a heterogeneous syndrome associated with cognitive decline and dementia. Aortic stiffness increases pulsatility, which damages microvascular circulation, resulting in poor vasoreactivity and cerebral hypoperfusion that is related to late-life depression. However, only few studies that relate aortic stiffness to late-life depression. Hypothesis: Higher aortic stiffness is associated with greater depressive symptoms and a higher prevalence of late-life depression. Methods: A total of 4,392 ARIC-NCS participants (mean age: 75.2±5.0 years; 40% male; 21% Black) with measurements of aortic stiffness and depressive symptoms in 2011-2013 were included in this cross-sectional analysis. Aortic stiffness was assessed as carotid-femoral pulse wave velocity (cfPWV) using the VP-1000 plus system (Omron Co., Ltd., Japan). cfPWV was dichotomized based on the upper 25th percentile. The 11-item short form of the Center for Epidemiological Studies Depression Scale (CES-D) was used to assess depressive symptoms. Depressive symptoms were calculated as the sum of scores obtained from the 11 items addressing appetite, depressed feelings, sense of effort, restless sleep, feeling happy, sad, or lonely, perceiving others as unfriendly, enjoying life, feeling disliked, and not able to get going (score range:0 to 22). The CES-D score was quantified as both a binary and a continuous variable. Individuals were categorized as depressed if CES-D score≥8. The total CES-D was log-transformed due to right skewed distribution (mean: 3.1; median: 2.0). Multivariable linear regression was used to estimate the association between high cfPWV and CES-D score, and multivariable logistic regression was used to estimate the association between high cfPWV and odds of depression. All models were adjusted for age, sex, race-center, education, self-reported financial situation, smoking, alcohol use, body mass index, LDL cholesterol, prevalent hypertension, diabetes and coronary heart disease. Race and sex were tested as potential effect measure modifiers. Results: A total of 412 (9.4%) participants were depressed. Compared to participants with less stiff aortas (cfPWV&lt;13.11 m/s), those with stiffer aortas (cfPWV≥13.11m/s) had higher average CES-D scores (3.5 vs. 2.9, respectively) and a higher prevalence of depression (12.9% vs 8.2%, respectively). High cfPWV was associated with 6% higher depressive symptoms (beta (β): 0.06, 95% confidence interval (CI): 0.002, 0.13), and greater odds of depression (odds ratio (OR): 1.32, 95% CI: 1.03, 1.69). No significant interactions were found by race or sex. Conclusion: Aortic stiffness is associated with late-life depression. These results suggest a role for age-related hemodynamic properties as targets for the study of late-life depression and the mitigation of its burden.
Improvement of the Treatment Results in Childhood Acute Myeloid Leukemia in Poland from 1983 to 2017
Authors: Walentyna Balwierz, Malgorzata Czogala, Katarzyna Pawinska-Wasikowska, Jacek Wachowiak, Jolanta Skalska-Sadowska, Michal Matysiak, Tomasz Szczepanski, Renata Tomaszewska, Maryna Krawczuk-Rybak, Katarzyna Muszynska-Roslan, Jerzy R. Kowalczyk, Hanna Wisniewska-Slusarz, Wojciech Mlynarski, Alicja Chybicka, Anna Rodziewicz, Tomasz Urasinski, Elzbieta Adamkiewicz-Drozynska, Lucyna Maciejka-Kemblowska, Grazyna Karolczyk, Irena Karpinska-Derda, Borys Przybyszewski, Agnieszka Malarz-Mizia, Sylwia Koltan, Radoslaw Chaber
Journal: Blood (2017)
Reversal of castrate resistant prostate cancer by extracellular vesicle therapy.
Authors: Anthony E. Mega, Joseph F. Renzulli, Peter J. Quesenberry, Devasis Chatterjee
Journal: Journal of Clinical Oncology (2015)

e16111 Background: Castrate resistant prostate cancer (CRPC) is the second leading cause of cancer-related death and nearly all men develop castrate resistance. Several new therapies, including enzalutamide- and taxane-based chemotherapy have improved outcomes for CRPC. However, resistance to both therapies develops in over 40% of patients. Tumor cells release extracellular vesicles (EV), which can alter the tumor microenvironment and promote disease progression. We examined the ability of EV isolated from non-malignant cells and human mesenchymal stem cells (hMSC EV) to inhibit the malignant phenotype and reverse drug resistance. Methods: EV were isolated from hMSC EV, non-malignant, malignant prostate cells and from biopsied tissue from patients with high grade prostate cancer (PCa). EV were co-cultured with recipient non- or malignant prostate cells and/or paclitaxel and enzalutamide sensitive or resistant cells after which: the induction or transfer of proteins was determined via mass spectrometry and Western blot analysis; and anchorage independent and tumor xenograft growth were assessed and sensitivity to enzalutamide and paclitaxel was monitored via MTT assay. Results: High Gleason grade PCa patient EV significantly induced anchorage independent growth and cell migration and the malignant phenotype of non-malignant prostate cells. Antibody analysis and mass spectrometry determined proteins that may be responsible for EV-mediated phenotypic changes. We identified increased protein levels of putative mediators of the EV-induced changes including 14-3-3 zeta in (log p value < 0.05 as determined by the Comparison Analysis Tool in the IPA software) in non-malignant cells co-cultured with PCa patient EV. Knockdown of 14-3-3 zeta lead to partial reversal of soft agar growth, indicating that it is a potential candidate for targeted therapy. Co-culture of malignant PCa cells with non-malignant prostate EV or EV isolated from hMSC significantly inhibited tumor xenograft growth and reversed enzalutamide and taxane resistance. Conclusions: Our study provides a rational basis to evaluate the therapeutic use of non malignant-derived EV or hMSC EV to inhibit CRPC progression and reverse enzalutamide or taxane resistance.
Identification of new Wilms tumour predisposition genes: an exome sequencing study
Authors: Shazia Mahamdallie, Shawn Yost, Emma Poyastro-Pearson, Esty Holt, Anna Zachariou, Sheila Seal, Anna Elliott, Matthew Clarke, Margaret Warren-Perry, Sandra Hanks, John Anderson, Simon Bomken, Trevor Cole, Roula Farah, Rhoikos Furtwaengler, Adam Glaser, Richard Grundy, James Hayden, Steve Lowis, Frédéric Millot, James Nicholson, Milind Ronghe, Jane Skeen, Denise Williams, Daniel Yeomanson, Elise Ruark, Nazneen Rahman
Journal: The Lancet Child & Adolescent Health (2019)

Wilms tumour is the most common childhood renal cancer and is genetically heterogeneous. While several Wilms tumour predisposition genes have been identified, there is strong evidence that further predisposition genes are likely to exist. Our study aim was to identify new predisposition genes for Wilms tumour.
Clinical validation of circulating cytokines as markers of prognosis and response to docetaxel in men with metastatic castration-resistant prostate cancer.
Authors: Kate Lynette Mahon, Hui-Ming Lin, Michelle Lee-Ng, Martin R. Stockler, Howard Gurney, Girish Mallesara, Karen P. Briscoe, Gavin M. Marx, Celestia S. Higano, Johann S. De Bono, Kim N. Chi, David Brown, Samuel N. Breit, Lisa Horvath
Journal: Journal of Clinical Oncology (2019)

230 Background: Elevated circulating macrophage inhibitory cytokine -1 /growth differentiation factor 15 (MIC-1/GDF15), interleukins 4 (IL4) and 6 (IL6) levels were associated with poor prognosis and resistance to docetaxel chemotherapy in an exploratory cohort of men with metastatic castration resistant prostate cancer (mCRPC). To establish level 2 evidence of biomarker utility, these cytokines were tested in internal and external validation cohorts. Methods: Internal validation cohort: Plasma samples taken at baseline (BL) and preC2 docetaxel (n = 120). MIC-1/GDF15, IL-4 and IL-6 measured by ELISA assay. External validation cohort: Serum samples taken at BL and/or preC3 docetaxel in 430 men with mCRPC on phase III SYNERGY study (docetaxel +/- custirsen as 1 st line chemotherapy in mCRPC with no OS benefit in the experimental arm). MIC-1/GDF15 measured by ELISA assay. Associations between cytokine levels, PSA response, time to PSA progression and OS were assessed by non-parametric tests and Cox Regression survival analyses. Results: Internal validation: At a median follow-up of 14 months, higher MIC-1/GDF15 levels at BL and preC2 were associated with shorter OS (BL; HR 1.2 95%CI 1.0-1.4; p = 0.03 and preC2; HR 1.3 95%CI 1.1-1.5; p = 0.004). Increase in MIC-1/GDF15 after chemotherapy correlated with lack of PSA response (p &lt; 0.001). IL4 and IL6 did not correlate with survival or demonstrate additional value. External validation: At a median follow-up of 23 months, higher MIC-1/GDF15 levels at BL and preC3 predicted shorter OS (BL; HR 1.4 95%CI 1.2-1.6; p &lt; 0.0001 and preC3; HR 1.6 95%CI 1.3-1.8; p &lt; 0.0001). Higher pre C3 MIC-1/GDF15 levels were also associated with shorter time to PSA progression (HR 1.2 95% CI 1.0-1.4; p = 0.02). Rise in MIC-1/GDF15 from BL to preC3 correlated with lack of 50% PSA fall at 12 weeks (p &lt; 0.001). Conclusions: Adherence to a biomarker development pipeline provides level 2 evidence of the prognostic value of circulating MIC-1/GDF15 in men with mCRPC receiving docetaxel. A prospective biomarker led study is now necessary to establish clinical utility.