tbuckley/cabot-search huggingface dataset:
Correlates of cervical cancer screening from four Sub-Saharan African (SSA) countries: Results from the Demographic Health Survey (DHS)—2013-2015.
Authors: Manoj Menon, Elizabeth Krantz, Corey Casper
Journal: Journal of Clinical Oncology (2017)

e18006 Background: Widespread cervical cancer screening has led to a dramatic reduction in cervical-cancer related mortality in resource-rich regions. However, cervical cancer remains a leading cause of cancer-related death in SSA due in part to a lack of accessible screening and treatment options. Methods: The DHS is a nationally representative household survey designed by ICF International and typically implemented every 5 years. In addition to demographic characteristics, select surveys collect data on cervical cancer awareness and screening. We included women aged ≥21 years from Côte d'Ivoire, Kenya, Namibia, and Zimbabwe who participated in the DHS. After sample weights were applied, we used logistic regression to examine associations of demographics and national cervical cancer incidence (as per the International Agency on Research on Cancer) with cervical cancer screening. Factors with p &lt; 0.20 in bivariate analyses were included in a multivariate model. Results: We analyzed data from 45,947 women aged 21 to 49 years (mean = 32.2); 69% were married with an average of 3 children. Nearly half had completed secondary education (47%), 73% were literate, and 48% belonged to the highest two wealth quintiles. Over 70% of women were aware of cervical cancer; 24% of all women reported a previous screening exam with variation by country. Namibia, with the highest rates of screening (46%), had the lowest incidence. In multivariate analyses, cervical cancer screening was associated with increasing age (OR = 1.06; CI = 1.05, 1.07), education (OR = 1.48; CI = 1.30, 1.69), literacy (OR = 1.80; CI = 1.53, 2.13), and wealth (OR = 1.14; CI = 1.09, 1.20). Higher cervical cancer incidence at the national level (OR = .980; CI = .976, .983) and rural residence (OR = .839; CI = .738, .953) were inversely associated with odds of cervical cancer screening. Conclusions: Based on DHS data from four SSA countries, awareness of cervical cancer is high, but receipt of cervical cancer screening is low and may be associated with reductions in cervical cancer incidence. Targeted efforts to increase utilization of cervical cancer screening in SSA are warranted to reduce the preventable burden of cervical cancer.
PEMBROSARC combination of MK3475 and metronomic cyclophosphamide (mCP) in patients (pts) with advanced sarcomas a multicentre phase II trial with 3 new combination strategies.
Authors: Maud Toulmonde, Thomas Grellety, Jean-Yves Blay, Axel Le Cesne, Nicolas Penel, Sophie Piperno-Neumann, Francois Bertucci, Christine Chevreau, Emmanuelle Bompas, Sophie Cousin, Sabrina Sellan-Albert, Marina Pulido, Carine A. Bellera, Barbara Lortal, Simone Mathoulin-Pélissier, Antoine Italiano
Journal: Journal of Clinical Oncology (2018)

TPS11587 Background: PD-L1 is expressed in soft tissue sarcomas (STS) but PD-1 inhibition alone has limited activity. This primary resistance may partly be explained by IDO pathway activation. Epigenetics modifications have also been recognized as mechanisms of resistance to PD-1 inhibition. We hypothesized that the association of MK3475 (PZ) + mCP, either alone or with IDO inhibitor Epacadostat (EP), TLR4 agonist G100 or EZH2 inhibitor Tazemetostat (TZ) could have a synergistic activity with good safety in pts with advanced STS, with a focus on Undifferentiated Pleomorphic Sarcoma (UPS). Methods: This is a multicenter, prospective open-labeled single-arm phase II trial with ten independent strata assessing: PZ 200 mg IV on day 8 of a 3 weeks cycle, mCP 50 mg b.i.d. orally one week on /one week off: - in leiomyosarcoma (stratum 1), UPS (stratum 2), other STS (stratum 3), osteosarcoma (stratum 4) and GIST (stratum 5) - + EP orally 100 mg b.i.d. in UPS (stratum 6) and other STS (stratum 7) - + G100 intratumor at 20 µg once weekly for 6 weeks in STS (stratum 8) - + TZ orally 800 mg b.i.d. in UPS (stratum 9) and other STS (stratum 10) Main eligibility criteria are - adult pts with metastatic or unresectable locally advanced, histologically confirmed sarcoma by central review, - measurable progressive disease (RECIST v1.1) – no more than 2 previous lines of systemic treatment – PDL1 and/or IDO expression on immune cells > 1% on < 3 months old tumor sample (strata 6 and 7) Primary endpoint is 6-month non progression as per RECIST v1.1. Secondary endpoints encompass toxicity according to NC-CTCAE v4.03, best overall response RECIST v1.1, 1-year progression-free survival and overall survival, growth modulationi, pharmacodynamics on mandatory collection of blood and tumor samples at baseline and on treatment. Each strategy will follow a 2-stage Simon's design. PZ+mCP + either EP, G100 or TZ will be considered promising if at least 8 non-progressions at 6 months are observed among 29 evaluable pts. In this regards, 32 pts will be recruited in each stratum. Strata 1-3, 5 have been reported. Stratum 4 is on hold for intermediate analysis. Opening of strata 6-10 is awaited by June 2018. Clinical trial information: NCT02406781.
TCT-280 Usefulness of White Blood Cell Count to Mean Platelet Volume Ratio for Predicting Long-Term Prognosis After Primary Percutaneous Coronary Intervention in Patients with Acute Coronary Syndrome
Authors: Na Xu, Xiao-Fang Tang, Yi Yao, Jing-jing Xu, Ying Song, Ru Liu, Ping Jiang, Lin Jiang, Huan-Huan Wang, Yuejin Yang, Runlin Gao, Bo Xu, Jin-qing Yuan
Journal: Journal of the American College of Cardiology (2018)
Discovery of novel, PD-L1-independent immune checkpoints using JEDI GFP-specific CD8 T cells.
Authors: Ranjan Upadhyay, Judith Agudo, Alessia Baccarini, Brian D. Brown, Joshua Brody
Journal: Journal of Clinical Oncology (2016)

3076 Background: Checkpoint blockade has emerged as an effective strategy for enhancing the endogenous T cell response against tumor-associated antigens. Its clinical benefit is maximized when combined with other immunomodulators or therapeutic maneuvers that induce immunogenic cell death. In order to find additional targetable suppressors of T cell activity, we have created an easily manipulable model of cancer immunoediting. Use of previous transgenic CD8 T cell models (e.g. OT-1) are confounded by difficulty in assessing tumor antigen (e.g. OVA) levels independent of MHC expression. Methods: Balb/c-derived A20 lymphoma cells expressing EGFP (A20-GFP-R0) were cultured with JEDI T cells that recognize the EGFP200-208 peptide epitope presented on H-2Kd (Agudo et al., Nat Biotech 2015). This novel system permitted the flow sorting of rare ( < 0.1%) surviving cells based on antigen and MHC class I expression.Five iterations of this T-cell selective pressure allowed for the enrichment of JEDI-resistant clones (A20-GFP-R5) that exclude antigen-loss and antigen presentation-deficient variants, two common mechanisms of immune escape. Results: A20-GFP-R5 exhibit marked (~100-fold) resistance to killing by JEDI T cells, despite at-least-equivalent levels of MHC-I and GFP expression compared to A20-GFP-R0. T cell activation, as measured by surface expression of CD25 and CD69 as well as proliferation, is nearly identical in response to either R0 or R5, suggesting that there is no impairment of the TCR-peptide-MHC complex. However, we observe a severe deficiency in the production of effector cytokines TNFα and INFγ in T cells cultured with R5. This effect seems to be independent of the PD-1 signaling pathway, since R5 has similar levels of PD-L1 expression, and treatment with PD-1 blocking antibodies cannot rescue the exhausted T cell phenotype. Conclusions: By naturally selecting for a rare subpopulation of cancer cells that are resistant to killing by CD8 T cells, we have found a PD-L1-independentcheckpoint pathway utilized by cancer to evade the immune response. Whole exome and RNA-seq studies are ongoing in order to identify the resistance mechanism(s) and to assess their use as potential immunotherapy targets.
P05.51 Prognostic impact of genetic alterations and methylation class in meningioma
Authors: A S Berghoff, G Ricken, U Rajky, C Marosi, J A Hainfellner, A von Deimling, F Sahm, M Preusser
Journal: Neuro-Oncology (2018)

Meningioma is a heterogenous disease in terms of prognosis and precise molecular characterization may support clinical decision-making. Several recurring gene mutations as well as prognostic relevant subgroups using DNA-methylation based information were recently identified in meningioma. We aimed to validate the recent findings in an independent cohort. Formalin fixed and paraffin emended samples of 127 meningioma patients (Grade I 40.9%; Grade II: 37.8%; Grade III: 21.3%) were retrieved from the Neuro-Biobank, Institute of Neurology, Medical University of Vienna. Methylation was analyzed using 850k EPIC (Illumina, San Diego, CA, USA) and methylation class (MC) were scored as previously published. Panel sequencing for genes reported to impact meningioma, namely NF2, TRAF7, KLF4, ARID, SMO, AKT, TERT, PIK3CAand SUFUwas performed as previously outlined. The TRAKLS mutation type was characterized by presence of TRAF7, AKT1, KLF4or/and SMO mutation. Survival data including progression free survival was retrieved from chart review. Target mutations were evident in 96/127 (75.5%) specimens with mutations in NF2(42/127; 33.1%), TRAF7(40/127; 31.5%), KLF4(27/127; 21.3%) and ARID (25/127; 19.7%) being the most frequently ones. Two or more mutations were observed in 51/127 (40.2%) specimens. MC correlated with presence of target mutations as well as clinical characteristics (p<0.05; Chi Square test). TRAF7, KLF4and TERTmutations as well as TRAKLS mutation type associated with progression free survival in univariate analysis (<0.05; log rank test), however in multivariable analysis only MC (HR 1.9; 95% CI 1.3–2.8; p=0.001; cox regression model) and TERTmutation HR 24.9; 95% CI 3.9–159.8; p=0.001; cox regression model) remained statically significant. Molecular profiling including mutational analysis and DNA methylation classification may facilitate more precise prognostic assessment and identification of potential targets for targeted therapy in meningioma patients.
Association of folate and vitamins involved in the one-carbon cycle with polymorphisms in the methylenetetrahydrofolate reductase (MTHFR) gene and global DNA methylation in patients with colorectal cancer.
Authors: Samuel Aguiar Junior, Ariana Ferrari, Dirce Maria Carraro, Fabio Oliveira Ferreira, Ademar Lopes, Celso Lopes Mello
Journal: Journal of Clinical Oncology (2016)

e15097 Background: Folate, vitamin B2, vitamin B6, vitamin B12, choline and betaine are nutrients involved in the one-carbon cycle that can alter the levels of DNA methylation and influence the carcinogenesis and/or tumor progression. The main objective of this study was toevaluate the association between folate and other vitamins involved in the one-carbon cycle with MTHFR polymorphisms and with global DNA methylation in patients with colorectal cancer. Methods: between May, 2011 and May, 2012, 189 consecutive and untreated patients with colorectal adenocarcinoma answered a Food Frequency Questionnaire (FFQ) previously validated in Portuguese for patients with colon and rectal cancer. Blood samples were collected for serum folate quantification and determination of MTHFR gene polymorphisms (C677T and A1298C); global DNA methylation was determined in blood and tumor samples. Results: no association was found between serum folate leves or dietary folate intake and MTHFR gene polymorphisms C677T or A1298C; no association was found between intake of the other vitamins and MTHFR gene polymorphisms; the values for serum folate were positively associated with the equivalent total dietary folate (total DFE) (rho = 0.51, p = 0.03); high serum levels of folate were also significantly associated with the global DNA methylation in paired blood samples (rho = 0.20, p = 0.03). Patients aged over 61 years (p = 0.01); tumor stages III and IV (P = 0.01); and with wild type homozygous genotypes for the MTHFR A1298C gene polymorphism (p = 0.04) had higher levels of global DNA methylation. In a covariance analyisis, the association between dietary intake of folate, serum folate, and tumor stage were predictive of global DNA methylation in patients' blood. Conclusions: high serum levels and high dietary folate intake can influence the status of blood total DNA methylation and tumor staging.
Age-Related Changes in Glucose Metabolism, Hyperglycemia, and Cardiovascular Risk
Authors: Chee W. Chia, Josephine M. Egan, Luigi Ferrucci
Journal: Circulation Research (2018)

Aging and diabetes mellitus are 2 well-known risk factors for cardiovascular disease (CVD). During the past 50 years, there has been an dramatic increase in life expectancy with a simultaneous increase in the prevalence of diabetes mellitus in the older population. This large number of older individuals with diabetes mellitus is problematic given that CVD risk associated with aging and diabetes mellitus. In this review, we summarize epidemiological data relating to diabetes mellitus and CVD, with an emphasis on the aging population. We then present data on hyperglycemia as a risk factor for CVD and review the current knowledge of age-related changes in glucose metabolism. Next, we review the role of obesity in the pathogenesis of age-related glucose dysregulation, followed by a summary of the results from major randomized controlled trials that focus on cardiovascular risk reduction through glycemic control, with a special emphasis on older adults. We then conclude with our proposed model of aging that body composition changes and insulin resistance link possible dysregulation of physiological pathways leading to obesity and diabetes mellitus—both forms of accelerated aging—and risks for CVD.
Abstract 19290: The Mitochondrial Derived Peptide Humanin Protects the Heart From Age-Related Fibrosis
Authors: Silvia Delrio, Kelvin Yen, Hemal H Mehta, Pinchas Cohen, Lilach O Lerman, Amir Lerman
Journal: Circulation (2016)

Introduction: Aging is associated with myocardial fibrosis and reduced performance. The mitochondrial derived peptide (MDP) humanin (HN) has been previously demonstrated to have myocardial protection properties. Endogenous HN levels, and consequently its protective effects, fall with age. HN analogs, such as HNG, have beneficial effects on the cardiovascular system, but their role in protecting the heart from age-induced fibrosis has not yet been demonstrated. The current study was designed to test the hypothesis that chronic replenishment of HN by administration of HNG can attenuate the development of age-induced cardiac fibrosis in mice. Methods: Thirteen C57Bl/6 female mice were divided into 3 groups. Young mice (n=5) were euthanized at 20 weeks old. Additional 18-months old mice were randomized to untreated (Old, n=3) or treated with HNG (Old + HNG, n=5, 4mg/kg/Bw IP) for 14 months. Old mice were euthanized at 32 months of age and hearts harvested to evaluate tissue collagen content with Picrosirius R...
Safety and efficacy of durvalumab following multimodality therapy for locally advanced esophageal and GEJ adenocarcinoma: Two-year follow-up results from Big Ten Cancer Research Consortium study.
Authors: Hirva Mamdani, Bryan J. Schneider, Pashtoon Murtaza Kasi, Laith I. Abushahin, Thomas J. Birdas, Kenneth Kesler, Heather Burney, Susan Perkins, Shadia Ibrahim Jalal
Journal: Journal of Clinical Oncology (2020)

404 Background: Concurrent chemoradiation(CRT) followed by esophagectomy is a standard of care for locally advanced esophageal(LA-EAC) and GEJ adenocarcinoma. Approximately 50% of patients(pts) experience disease relapse within the 1 st yr after treatment(tx) completion. No adjuvant tx has been shown to improve survival in these pts. Immune checkpoint inhibitors have activity in metastatic PD-L1 positive EAC. Preclinical studies have shown radiation +/- chemotherapy upregulate PD-1/PD-L1 pathway. Methods: We conducted a phase II trial evaluating safety and efficacy of durvalumab(durva) in pts with LA-EAC and GEJ adenocarcinoma who have residual disease in surgical specimen after neoadjuvant CRT and R0 resection. Pts received durva 1500mg IV every 4 weeks for up to 1yr. Results: 24 pts were enrolled from 4/2016-1/2018(median age: 60yrs (range, 43-70). 18 received carbo/paclitaxel and 6 received cis/5-FU concurrently with radiation. Staging at diagnosis: T2N0(n = 3, 12.5%), T2N2(n = 3, 12.5%),T3N0(n = 6, 25%), T3N1(n = 6, 25%), T3N2(n = 4, 17%), T3N3(n = 1, 4%), T3Nx(n = 1, 4%).19 pts(79%) had positive lymph nodes(LNs) at the time of surgery following CRT. 12 pts completed 1yr of tx, 12 came off tx because of relapse(6), AEs(5), and consent withdrawal(1). Most common AEs were fatigue(n = 8, 33.3%) and nausea(n = 6, 25%). 3pts (12.5%) developed grade 3 irAEs: pneumonitis(1), hepatitis(1), colitis(1). At median follow up of 21.9mo(range, 1.7-23.9mo), 11 pts have relapsed: 9 distant and 2 locoregional. Two of 3 pts with grade 3 irAEs are alive and disease free at 17 and 23 mo respectively. 1-yr RFS and OS were 79.2% and 95.5%, respectively. RFS at 26 mo was 20.6%. Overall mOS and mOS after relapse were 28.1mo(range, 22.9-28.1) and 11.1 mo(range, 0.1-11.3mo) respectively. The study was expanded to enroll 14 additional pts who are currently undergoing tx. Conclusions: Adjuvant durvalumab following trimodality therapy for LA-EAC and GEJ adenocarcinoma is safe with improvement in 1-yr RFS to 79.2% compared to historical rate of 50%. RFS was 20.6% at 26 months. Evaluation of predictive biomarkers of RFS with durva is underway. Clinical trial information: NCT02639065.
OS1.7 Genomic attributes of tumor evolution and treatment response in diffuse glioma
Authors: A L Lin, P Jonsson, S Ogilvie, S Chavan, C Nolan, I Gavrilovic, T Kaley, C Grommes, E Pentsova, E Diamond, M Daras, J Stone, L DeAngelis, V Tabar, C Brennan, R J Young, M Rosenblum, B S Taylor, I K Mellinghoff
Journal: Neuro-Oncology (2018)

Though the genomic landscape of primary gliomas has been well characterized by The Cancer Genome Atlas, the genetic determinants of malignant transformation and response to therapy remains poorly understood. Prospective clinical sequencing was performed on 1,004 gliomas from 923 patients. This dataset includes primary and recurrent tumors and contains detailed clinical annotation, including review of the patients’ imaging. We investigated the germline and somatic attributes of IDH1/2-wildtype and IDH1/2-mutant tumors at the time of diagnosis and recurrence. 13% of patients harbored either a pathogenic or likely pathogenic germline mutation, whereof 29% arose in genes mediating DNA repair. In astrocytomas, agnostic of IDH status, cell cycle alterations were depleted in low-grade tumors. Moreover, mutations in effectors of the cell cycle were associated with the development of enhancing disease in IDH-mutant astrocytomas but not oligodendrogliomas. IDH-mutant astrocytomas with a cell-cycle alteration have a significantly shorter progression-free survival from recurrence compared to tumors without a cell cycle alteration (median 2. 5 vs. 35. 3 months, HR 3. 25, log-rank p-value 0. 00061). Based on our data, hypermutation appears to occur exclusively in the context of pre-existing cell cycle alterations in astrocytic tumors, regardless of IDH status. We next correlated molecular findings with clinical behavior and treatment response and defined subsets of gliomas that are uniquely susceptible to targeted treatment and have a differential prognosis. Cell-cycle alterations are lineage-specific alterations associated with aggressive disease in glioma. Targeted genomic sequencing can identify subsets of tumors with a greater sensitivity to treatment and a better prognosis.
Feasibility and implementation of geriatric assessment measures and patient-reported outcomes in a phase 1 trial for acute myeloid leukemia.
Authors: Heidi D. Klepin, Avrita Campinha-Bacote, Wan-Jen Hong, Patrick Phuong, Jue Wang, Mehrdad Mobasher, Peter Trask
Journal: Journal of Clinical Oncology (2018)

e22040 Background: Novel therapies are needed for older patients (pts) with acute myeloid leukemia (AML). Functional impairments and age-related comorbidities can limit treatment (tx) tolerance. Consequently, few older pts enroll on early phase clinical trials limiting available evidence for evaluating their tx options. We integrated select geriatric assessment (GA) measures and patient-reported outcomes (PRO) in a Phase 1b study in relapsed or refractory (R/R) AML (NCT02670044) to better characterize this pt population and their tx experience. Baseline (BL) characteristics and assessment compliance rates are reported here. Methods: Pts ≥60 yrs with R/R AML ineligible for chemotherapy received venetoclax with cobimetinib (Arm A) or idasanutlin (Arm B). GA measures were Short Physical Performance Battery (SPPB), Hematopoietic Cell Transplant-Comorbidity Index (HCT-CI) and Short Blessed Orientation Test (SBOT). PRO version of the common terminology criteria for adverse event (PRO-CTCAE) was electronically administered. GA and PRO were administered at BL, regularly during tx and at tx discontinuation. BL compliance was calculated as number of assessments completed/available. Results: As of 20 November 2017, 30 (Arm A) and 28 (Arm B) pts were treated. BL characteristics were comparable between Arms A and B, respectively: median age (71.5, 74.5 yrs), ECOG 0–1 (83%, 82%), refractory disease (60%, 68%), median number of prior therapies (2, 1). For Arms A and B, respectively, median BL GA measures were HCT-CI (1, 2), SPPB (8, 9), SBOT (2, 2), and select mean BL PRO-CTCAE items were severity of fatigue (1.32, 1.60), nausea (0.36, 0.67), vomiting (0.18, 0.20), decreased appetite (0.82, 0.87). BL compliance was 87% and 82% for GA, 81% and 83% for PRO-CTCAE, respectively. Conclusions: Based on compliance rates, implementation of GA measures and PRO to capture comprehensive tx data is feasible in a Phase 1 trial of older adults with R/R AML and should be considered for trials in this population. Mature data highlighting impact of tx on daily functioning, tolerability and quality of life are valuable for symptom management for this population and will be updated at the time of presentation. Clinical trial information: NCT02670044.