tbuckley/cabot-search huggingface dataset:
Cetuximab biweekly plus mFOLFOX6 as first-line therapy in patients (pts) with KRAS wild-type (wt) (exon 2) metastatic colorectal cancer (mCRC): Primary endpoint and subgroup analysis of the CEBIFOX trial.
Authors: Stefan Kasper, Johannes Meiler, Heike Knipp, Thomas Hoehler, Peter Reimer, Tilman Steinmetz, Winfried Berger, Gabriele Linden, Saskia Ting, Peter Markus, Andreas Paul, Alexander Dechene, Brigitte Schumacher, Karina Kosbade, Karl Worm, Kurt Werner Schmid, Thomas Herold, Martin H. Schuler, Tanja Trarbach
Journal: Journal of Clinical Oncology (2015)

3568 Background: The multicenter, single-arm, phase II CEBIFOX trial (Simon`s two stage minimax design) evaluated the efficacy of mFOLFOX6 + biweekly cetuximab (500 mg/m2) as 1st line therapy in KRAS wt (exon 2) mCRC. Final efficacy data as well as extended molecular and clinical subgroup analyses are presented. Methods: Primary endpoint was objective response rate (ORR) per RECIST 1.0, secondary endpoints were safety, metastasectomy rate, quality of life, progression-free (PFS) and overall survival (OS). Extended molecular profiling was performed using NGS-based panel sequencing including NRAS (exon 2-4), KRAS (exon 2-4), BRAF (exon 15) and PI3KCA (exon 10 and 21). Clinical parameters included: tumor localisation (right sided vs. left sided-LCRC), liver-limited disease (LLD), early tumor-shrinkage (ETS), depth of response (DPR), metastasectomy and inflammation markers (neutrophil/lymphocyte ratio-NLR). Differences in ORR, PFS and OS were calculated for subgroups using chi-square and logrank tests. Hazard ratios were calculated by Cox regression analysis. Results: Among 57 pts of the ITT, 50 pts were evaluable for response with an ORR of 72%, and a disease control rate of 90%. Median PFS and OS (ITT) were 9.5 (7.4-11.6) and 29.4 (16.7-42.0) months. Metastasectomy was achieved in 33.3%; grade 3/4 adverse events occurred in 52% of the ITT population, including leukocytopenia, rash and GI-toxicity. New RAS and BRAF mutations were detected in 17.4% and 13.3%, respectively with a negative impact on treatment efficacy. Pts with LCRC (75%), ETS (59.2%), secondary metastasectomy and LLD (49.1%) had significantly prolonged OS, whereas pts with high NLR ( > 5; 28.6%) had inferior OS (all p-values < 0.05). Median DPR was -46.4%, and correlated significantly with PFS and OS (p < 0.01). Conclusions: This study supports the efficacy and safety of biweekly cetuximab given in combination with mFOLFOX6 in pts with mCRC. Extended mutational analyses of key oncogenes and routinely assessed clinical parameters can help to identify patients with maximum likelihood of benefit from anti-EGFR antibody-based immunochemotherapy. Clinical trial information: NCT01051167.
Prognostic and predictive role of comprehensive geriatric assessment (CGA) in elderly patients with metastatic renal cell cancer (RCC) treated with sunitinib (SUN) or pazopanib (PAZ): A single center experience.
Authors: Francesco Pierantoni, Umberto Basso, Marco Maruzzo, Antonella Brunello, Giuseppe Anile, Annunziata Lettiero, Giuseppina Tierno, Evelina Lamberti, Vittorina Zagonel
Journal: Journal of Clinical Oncology (2019)

647 Background: Few data are available concerning the prognostic and predictive role of CGA in elderly pts ≥70 years with metastatic RCC treated with either Sun or Paz. Materials and Methods: We retrospectively reviewed the charts of all elderly pts with advanced RCC treated at our Institute with either Sun or Paz, with at least 6 months follow-up after starting treatment. Every pt received at baseline a CGA and was classified as fit, vulnerable or frail according to Balducci’s Criteria. Results: We identified 73 pts who started therapy from January 2006 to March 2018, median age 76 years (range 70-89), 63% males; 42.5% fit and 57.5% unfit pts (38.3% vulnerable, 19.2% frail). Sun to Paz ratio was 40 to 33 pts with a median duration of treatment of 10.8 months; incidence of G1/2 toxicities was 85% vs 93.9% (p = 0.28), G3/4 was 37.5% vs 30.3% (p = 0.63), dose reduction was necessary in 77.5% vs 78.8% of pts (p = 0.9), respectively. Median PFS and OS with Sun or Paz were 13.6 vs 9.4 months (p = 0.152) and 27 vs 22.3 months (p = 0.641), respectively. CGA fit category predicted longer PFS (p = 0.039) and OS (p = 0.001) in the whole cohort. We found no significant differences between fit and unfit pts according to incidence of G1/2 adverse events, incidence of dose reduction or necessity to early suspend treatment due to toxicity, while the incidence of G3/4 events was lower in the fit subgroup (p = 0.026). Out of 67 pts progressing after first line therapy, 27 (40.3%) received a second line consisting in Nivolumab (22.4%), Everolimus (13.4%) and Sorafenib (4.5%), while 40 (59.7%) received only palliative treatments. CGA fit category significantly correlated with a higher chance of receiving a second line treatment (p = 0.004). Conclusions: In our retrospective single-center experience, CGA has a strong prognostic value in terms of OS and has the ability to discriminate pts at higher risk of experiencing G3/4 toxicities with Sun or Paz, with shorter PFS and lower chance of receiving a second line treatment. There were no striking differences in terms of toxicity rates between Sun or Paz, although different in type and possibly biased by patient selection.
Urologic malignancies: A comparison of outcomes after index surgery between academic and community hospitals.
Authors: Jamil Syed, Alejandro Abello, Juan Javier-Desloges, Michael Leapman, Patrick Aloysius Kenney
Journal: Journal of Clinical Oncology (2019)

489 Background: To compare the rate of hospital based outcomes in patients with urologic malignancies who underwent surgery as part of treatment in academic and community hospitals. Methods: We reviewed the Vizient Clinical Database from September 2014 to December 2017. Vizient is a member-driven health services organization that includes ~99% of academic hospitals (AH) and more than 40 community hospitals (CH). This is a comparative database comprised of administrative billing. Data include patient demographics, readmission rates, costs, LOS, case mix index (CMI) and mortality. Patients aged ≥ 18 were included and ICD-9 and ICD-10 codes were used to identify patients with urologic malignancies who underwent surgical treatment. Chi square and student t-tests were used to compare categorical and continuous variables, respectively. Results: We identified a total of 37,628 cases. There were 33,290 (88%) procedures performed in AH and 4,330 (12%) in CH. These included radical prostatectomy (RP) 18,540, radical nephrectomy (rNx) 8,059, partial nephrectomy (pNx) (5,287), radical cystectomy (4,421), radical nephroureterectomy (rNu) (1,006), and partial cystectomy (321). There were no significant differences in 30-day readmission rates or mortality for any procedure between AH and CH. LOS was significantly lower (P&lt;0.01) for radical cystectomy (8.83 vs 11.43 days) and RP (1.63 days vs 1.77 days) in AH, and lower in CH for rNx (4.93 vs 4.51, P: 0.03). AH had a significantly lower amount of partial cystectomies performed when compared to community centers (6.2% vs 16.2% P&lt;0.001), and a similar number of partial nephrectomies performed (39.8% vs 38.0%, P=0.2). The mean direct cost for index admission was significantly higher in AH for rNx, pNx, rNu, and RP. Case complexity using the CMI was similar between CH and AH. Conclusions: The Vizient clinical database provides a novel resource for observational data at US hospitals. Despite academic and community hospitals having similar case complexity, direct costs were lower in community hospitals without an associated increase in readmission rates or deaths. The only clinically significant difference in length of stay was shorter stays for cystectomy in academic centers.
Pembrolizumab for metastatic castration-resistant prostate cancer (mCRPC) previously treated with docetaxel: Updated analysis of KEYNOTE-199.
Authors: Emmanuel S. Antonarakis, Jeffrey C. Goh, Marine Gross-Goupil, Ulka N. Vaishampayan, Josep M. Piulats, Ronald De Wit, Tuomo Alanko, Satoshi Fukasawa, Kenichi Tabata, Susan Feyerabend, Raanan Berger, Haiyan Wu, Jeri Kim, Christian Heinrich Poehlein, Johann S. De Bono
Journal: Journal of Clinical Oncology (2019)

216 Background: Previously presented data from cohorts (C) 1-3 of the phase 2 KEYNOTE-199 study (n = 258; NCT02787005) showed that pembrolizumab monotherapy had antitumor activity and acceptable safety in patients (pts) with mCRPC previously treated with next-generation hormonal agents (NHAs; eg, abiraterone, enzalutamide) and docetaxel. Activity was observed for both PD-L1–positive and negative cohorts and in RECIST-measurable and bone-predominant disease. We present data from KEYNOTE-199 C1, C2, and C3 based on longer-follow-up. Methods: C1 enrolled 133 pts with RECIST-measurable, PD-L1–positive disease, C2 enrolled 66 pts with RECIST-measurable, PD-L1–negative disease, and C3 enrolled 59 pts with nonmeasurable, bone-predominant disease. All pts had ECOG PS 0-2 and received ≥1 NHA and 1-2 prior chemotherapies including docetaxel. Pembrolizumab 200 mg Q3W was given for 35 cycles or until PD or intolerable toxicity. Response was assessed Q9W in yr 1, then Q12W. Primary end point was ORR per RECIST v1.1 by central review. Key secondary end points included DCR (CR + PR + SD ≥6 mo), duration of response (DOR), OS, and safety. Results: Median follow-up as of Aug 21, 2018, was 9.5 mo in C1, 7.9 mo in C2, and 14.1 mo in C3. ORR (95% CI) was 5% (2-11) in C1 and 3% ( &lt; 1-11) in C2. DCR was 10% in C1, 9% in C2, and 22% in C3 per RECIST v1.1. Median (range) DOR was not reached (1.9-21.8+ mo) in C1 and 10.6 mo (4.4-16.8) in C2; KM estimates of DOR ≥12 mo were 71% and 50%. Median (95% CI) OS was 9.5 mo (6.4-11.9) in C1, 7.9 mo (5.9-10.2) in C2, and 14.1 (10.8-17.6) in C3. 12-mo OS rates were 41% in C1, 35% in C2, and 62% in C3; 18-mo rates were 30%, 21%, and 36%. Grade 3-5 drug-related AE rates were 15% in C1, 14% in C2, and 17% in C3. There were 2 drug-related deaths (n = 1 each sepsis and pneumonitis). Conclusions: Pembrolizumab shows antitumor activity and disease control with acceptable safety in RECIST-measurable and bone-predominant mCRPC previously treated with NHAs and docetaxel. Responses are durable, and the observed OS benefit is promising. Clinical trial information: NCT02787005.
Abstract P331: Unfavorable Social Factors Increased the Risk of Future Disability Subsequent to Heart Failure in Elderly Japanese Community Dwellers: The Iwate KENCO Study Group
Authors: Shuko Takahashi, Kozo Tanno, Yuki Yonekura, Fumitaka Tanaka, Masaki Ohsawa, Motoyuki Nakamura, Toru Kuribayashi, Toshiyuki Onoda, Kiyomi Sakata, Makoto Koshiyama, Kazuyoshi Itai, Akira Okayama
Journal: Circulation (2019)

Introduction: The risk factors that contribute to future disability after heart failure (HF) are poorly understood. The aim of this study was to determine the risk factors of future disability subsequent to HF in the general elderly population in Japan. Hypothesis: We assessed the hypothesis that unfavorable social factors after than traditional cardiovascular risk factors contribute to an increased risk for disability after HF. Methods: The subjects were community-dwelling elderly individuals aged 65 years or older without a history of cardiovascular diseases. We defined disabled subjects as individuals who had been newly certified by the long-term care insurance (LTCI) system during the observation period. HF was diagnosed according to the Framingham diagnostic criteria. After excluding subjects who received LTCI without HF (n= 2,305) and subjects who had already received LTCI prior to HF onset (n=33), we classified the remaining subjects (n= 4,644) into 3 groups: event-free (no LTCI and no HF; n= 4,548, mean age = 70.1 years at the baseline survey), no LTCI after HF (n= 52, mean age = 72.3 years) and LTCI after HF (n= 44, mean age =74.6 years). We determined the multivariate-adjusted odds ratio (OR) for having each risk factor (male gender, age (increment of years), unmarried status, less educational years (&lt;7 years), no job status, smoking, drinking, hypertension, diabetes mellitus and dyslipidemia) in the latter two groups (reference: event-free) using polytomous logistic regression analysis. Results: The median follow-up period was 10.6 years (49,133 person-years), and the median period [interquartile range] from the incidence of HF to the certification for LTCI was 1.3 [0.3- 4.7] years. Significantly associated risk factors were more advanced age (OR [95% confidence intervals]:1.18 [1.10-1.25]), unmarried status (2.29 [1.14- 4.63]), less educational years (3.36 [1.72-6.55]) and regular drinking (2.58 [1.13- 5.88]) in the group of LTC after HF, while the risk factor was more advanced age (1.08 [1.02-1.15]) in the group of no LTCI after HF. Conclusion: The results suggested that unfavorable social risk factors such as unmarried status, shorter education period and regular drinking strongly contributed to the higher risk of disability subsequent to HF, while those unfavorable risk factors did not contribute to the risk of incident HF without LTCI. Preventive measures must be taken to protect elderly individuals with unfavorable social factors from disability after HF via a multidisciplinary approach.
Abstract 014: Race and Sex-Based Disparities Associated With Carotid Endarterectomy in the Atherosclerosis Risk in Communities (ARIC) Study
Authors: Caitlin W Hicks, Natalie Daya, James H Black, Kunihiro Matsushita, Elizabeth Selvin
Journal: Circulation (2019)

Introduction: The indications and risks associated with carotid endarterectomy (CEA) are well established. We sought to investigate sex and race-based disparities in the incidence of CEA after adjusting for carotid artery stenosis risk factors. Methods: We conducted a prospective cohort analysis of 14,754 black and white participants in the Atherosclerosis Risk in Communities (ARIC) study who did not have a diagnosis of carotid artery stenosis at baseline (1987-1989). We estimated the cumulative incidence of CEA by sex and race using the Kaplan-Meier method. We used Cox proportional hazards models with adjustment for sociodemographic, cardiovascular, and disease severity risk factors to quantify the association of sex and race with incident CEA. Cardiovascular risk factors (hypertension, coronary heart disease, chronic kidney disease, diabetes), carotid intima media thickness(IMT), and symptomatic status (stroke or symptomatic carotid artery stenosis based on hospital diagnosis codes) were adjusted as time-varying exposures. Results: CEA was performed in 345 of 14,754 ARIC participants over a median of 27 years follow-up [incidence rate 1.04 (95%CI 0.93-1.15) per 1,000 persons-years]. The crude incidence of CEA varied significantly by sex [female vs. male: HR 0.58 (95%CI 0.47-0.72)] and race [black vs. white: HR 0.63 (95%CI 0.48-0.84)]. Adjustment for sociodemographic and cardiovascular risk factors, carotid IMT, and symptomatic status attenuated the association of sex with CEA [females vs. males HR 0.82 (95%CI 0.65-1.03)], but black participants had a persistently lower risk of incident CEA despite adjustment [HR 0.64 (95%CI 0.45-0.89)]( Figure ). Conclusions: While there are known sex and race-based differences in the prevalence of carotid artery stenosis, we found significant variation in the incidence of CEA based on race that is independent of traditional risk factors and carotid IMT. Whether this disparity is a reflection of differences in disease presentation or access to care deserves investigation.
Abstract P110: Early-Life Exposure to Severe Famine is Associated With Higher Methylation Level in the IGF2 Gene and Higher Total Cholesterol in Late Adulthood: The Genomic Research of the Chinese Great Famine (GRECF) Study
Authors: Luqi Shen, Changwei Li, Zhenghe Wang, Ruiyuan Zhang, Ye Shen, Toni Miles, Jingkai Wei, Zhiyong Zou
Journal: Circulation (2019)

Objective: To evaluate association of early-life exposure to the Chinese Great Famine (1959-1961) with DNA methylation in IGF2 , a gene involved in growth and development, and its subsequent influence on blood lipid levels in late adulthood among participants of the Genomic Research of the Chinese Great Famine (GRECF) study. Methods: The GRECF study recruited 790 participants born between 1956 and 1964 from two neighbor provinces, Anhui and Jiangxi, in China through a multistage, clustered, random sampling. Historically, famine was severe in Anhui and moderate in Jiangxi. Besides individuals born in Anhui province, those who were born during or before the Chinese Great Famine in Jiangxi province and reported having siblings starved to death were also categorized as having severe famine exposure; All other participants born in Jiangxi province were considered as having moderate famine exposure. DNA methylation within the IGF2 gene locus were assayed using the Sequenom’s MassARRAY system among a random sample of 188 participants. Total cholesterol (TC), low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol were assayed using enzymatic colormetric tests. Triglycerides was calculated using the Friedman formula and was logarithmically transformed for analyses. Multivariate linear regressions were used to evaluate associations of famine severity with lipids, famine severity with DNA methylation in the IGF2 , and DNA methylation in the IGF2 with lipids, respectively, controlling for sex in the base model and additionally controlling for age, education, smoking, and drinking in the fully adjusted model. Mediation analysis was applied to assess the mediation effect of DNA methylation at the IGF2 gene on the association between early-life exposure to severe famine and adult lipids levels. Results: DNA methylation was quantified at 8 cytosine-phosphate-guanine dinucleotides (CpG) sites in the IGF2 gene. Exposure to severe famine was associated with higher methylation level at one site of the IGF2 gene (CpG1: β =0.07, P =5.00х10 -4 ) and increased levels of TC ( β =0.85; P =9.30х10 -7 ). Furthermore, per unit increase in methylation of the CpG1 site was associated with 1.13-unit increase in TC ( P =0.02). After further adjustment for all covariates, these associations were still significant ( P famine-CpG1 =0.03; P famine-TC =7.55х10 -6 ; P CpG1-TC = 0.05). Methylation of the CpG1 site mediated 6% ( P =0.18) of the association between exposure to the severe Chinese Great Famine and adult TC. Conclusion: Increased methylation level in the IGF2 gene may be a consequence of early-life exposure to severe famine during the Chinese Great Famine and this change was also positively associated with TC in late adulthood.
A Comparison of Prognostic Indices in Diffuse Large B-Cell Lymphoma within the UK NCRI R-CHOP 14 Versus 21 Phase III Trial
Authors: Mary Gleeson, Nicholas Counsell, David Cunningham, Eliza Hawkes, Anthony Lawrie, Andrew Jack, Paul Smith, Christopher Pocock, Kirit M. Ardeshna, John Radford, Andrew McMillan, John Davies, Deborah Turner, Anton Kruger, Peter Johnson, David C. Linch
Journal: Blood (2018)
Role of cyclic adenosine monophosphate (cAMP) in modulation of antitumor effect of cytostatic chemotherapy (CT) in experiment.
Authors: Alla Ivanovna Shikhlyarova, Liubov Yu Vladimirova, Natalya A Abramova, Inna Arnoldovna Novikova, Elena P. Korobeynikova, Tatiana P. Protasova, Irina A. Ishchenko, Tatiana Anatolevna Kurkina, Anna E Storozhakova
Journal: Journal of Clinical Oncology (2015)

e13521 Background: Different approachesto the regulation of biological processes in the body and tumor are necessary for increasing effectiveness of cancer CT. cAMP involvement in mechanisms of transmembrane regulation of cell methobolom, differentiation, proliferation in malignant growth is promising as protecting the CT and regulating body homeostasis. The purpose of the study was to analyze modifying effect of cAMP in experimental CT for progressing tumors. Methods: The study included 60 white outbres rats weighing 220±30 g with sarcoma 45 (S-45). When tumor was > 3 cm3, cyclophosphamide (CP) was injected intraperitoneally 50 mg/kg 4-5 times with a 5 d. interval. Oral introduction of cAMP (“SIGMA-ALDRICH”, Germany (Prod. Of USA)) – 0.01 mg/ml 3 times with a 2 h. interval daily. Cycle TESTTM PLUS DNA Reagent Kit with disaggregating device BD Medimachine was used for studying DNA cytometric parameters of tumor. The samples were analyzed using flow cytometer BD Facs Cantooll with doublet discrimination module. Blood lymphocytes of experimental animals served as diploid standard. The data were processed with ModFit LT program. Proportion of apoptotic lymphocytes was determined by flow cytometry based on the indication of annexin V+ cells (BD “Biosciences”, USA). Proliferation index was calculated as the total number of cells in S- and (G2+М)- phases. Results: Pronounced weakening of C-45 growth and its regression was observed in cAMP+CP group, as well as increased life expectancy by 30% (p = 0.012). These animals showed transformation of heterogeneous tumor cells into diploid clones in 100% of cases, minimization of proliferation index and rate. Decrease of apoptotic lymphocytes was found in blood, as well as increase of living functioning immunocompetent cells. In CP group, 60% of tumors continued growing 10 days after the treatment. Conclusions: cAMP +CP CT affects pathogenetic mechanisms of tumor growth which is promising for clinical CT.
Development of Liver-Specific Thrombopoietin Targeted Sirnas: Impact on Platelet Count, Megakaryocyte Mass, and Hematopoietic Progenitors in Normal and MPN Murine Models
Authors: Dhruv Desai, Anna Borodovsky, Wendell P Davis, Rohan Degaonkar, Kristina Yucius, Kellie D'Angelo, Paul Gedman, Donna Marie Williams, Ophelia Rogers, Zhizhuang Joe Zhao, Jerry L. Spivak, Alison R. Moliterno
Journal: Blood (2018)
A proposal for community standards in clinical trials descriptions and reporting.
Authors: Susan M. Mockus, Roger Liu, Guruprasad Ananda, Christopher S. Potter, Carol J. Bult, J. Marc Pipas, Gregory J. Tsongalis
Journal: Journal of Clinical Oncology (2015)

e12537 Background: An increasing number of interventional clinical trials have a companion diagnostic component. Trial results provide the clinical evidence required for FDA approval of a therapeutic and companion diagnostic as well as clinical utility data for reimbursement. In order to facilitate this common goal, trial eligibility and outcome data need a more specific and defined reporting structure for biomarkers, which does not currently exist in clinical trial registries nor in scientific journal publications. Methods: ClinicalTrials.gov was analyzed for the lack of consistency in gene naming in over 300 trial records using VEGFR2 and KDR search terms. To assess, the lack of specificity in gene variant nomenclature, “EGFR and mutation” were searched to examine the variability in the biomarker eligibility inclusion/exclusion criteria. Syntax for gene naming and referential integrity using HUGO and NCBI gene Id, respectively, was implemented in an in-house manually curated clinical knowledgebase. Furthermore, a regex system for gene variant nomenclature based on HGVS provided proof of concept for a method to map patient variant calls to curated knowledge. Results: Searching on KDR returned 8.6% (5/58) trials, which were irrelevant to the KDR gene. A differential of 93 trials was identified when searching on KDR, versus the synonym, VEGFR2. In addition, 193 trial records were analyzed for the variability in recruiting patients with EGFR mutations. Lastly, 21 patient samples, with an average of 4500 variant calls each, were successfully mapped to an in-house clinical knowledgebase using a gene variant nomenclature standards paired to a regex system. Conclusions: The systematic implementation of biomarker reporting standards will enable better patient stratification and recruitment as well as comparison of outcomes across multiple studies. We have identified the lack of consistency in gene and variant nomenclature in clinical reporting. We have proposed a community standard for biomarker reporting standards with proof of concept.