tbuckley/cabot-search huggingface dataset:
Treatment-free survival (TFS) after discontinuation of first-line nivolumab (NIVO) plus ipilimumab (IPI) or sunitinib (SUN) in intention-to-treat (ITT) and IMDC favorable-risk patients (pts) with advanced renal cell carcinoma (aRCC) from CheckMate 214.
Authors: David F. McDermott, Brian I. Rini, Robert J. Motzer, Nizar M. Tannir, Bernard Escudier, Christian K. Kollmannsberger, Hans J. Hammers, Camillo Porta, Saby George, Frede Donskov, Howard Gurney, Marc-Oliver Grimm, Michael Roger Harrison, Thomas E. Hutson, Shuo Yang, Jennifer Johansen, Sumati Rao, Sabeen Fatima Mekan, Michael Rael, Thomas Powles
Journal: Journal of Clinical Oncology (2019)

564 Background: TFS characterizes the antitumor activity of immuno-oncology agents after treatment discontinuation. In CheckMate 214, pts with IMDC intermediate/poor-risk aRCC who discontinued first-line NIVO+IPI experienced significantly longer TFS than those who discontinued SUN (McDermott et al, ESMO 2018). Here, we continue the analysis of TFS from CheckMate 214 in ITT and IMDC favorable-risk pts. Methods: Pts with previously untreated, predominantly clear cell aRCC were randomized 1:1 to intravenous NIVO 3 mg/kg + IPI 1 mg/kg every 3 weeks for 4 doses followed by NIVO 3 mg/kg every 2 weeks, or oral SUN 50 mg daily for 4 weeks on, 2 weeks off (6-week cycles). TFS was defined as the time from protocol therapy cessation to the start of subsequent systemic anticancer therapy or death, whichever occurred first. TFS in pts who discontinued NIVO+IPI or SUN was compared using Kaplan–Meier methods and log-rank tests. This analysis was conducted for all ITT (NIVO+IPI, 550; SUN, 546) and IMDC favorable-risk (NIVO+IPI, 125; SUN, 124) pts in CheckMate 214. Results: Among 463 NIVO+IPI and 477 SUN ITT pts who discontinued protocol therapy, the median TFS was 3.0 months with NIVO+IPI vs 1.3 months with SUN (HR [95% CI]; 0.54 [0.46–0.62]; P&lt;0.0001); the TFS rates 2 years post-discontinuation were 21% vs 7%, respectively. In IMDC favorable-risk pts, 111 and 94 pts discontinued from NIVO+IPI and SUN, respectively. TFS in IMDC favorable-risk pts was also significantly longer with NIVO+IPI vs SUN (median, 6.3 vs 1.1 months; HR [95% CI]; 0.47 [0.34–0.65]; P&lt;0.0001). The TFS rates 2 years post-discontinuation in favorable-risk pts were 29% for NIVO+IPI vs 13% for SUN. Conclusions: Similar to the TFS benefit seen in intermediate/poor-risk pts with aRCC, first-line therapy with NIVO+IPI resulted in reduced need for second-line therapy in ITT and IMDC favorable-risk pts compared with SUN. The durable TFS benefit across risk groups despite discontinuation of therapy provides further evidence of the encouraging benefit-risk profile of NIVO+IPI over SUN in pts with previously untreated aRCC. Clinical trial information: NCT02231749.
Abstract P190: Association of Hypertension According to New ACC/AHA Blood Pressure Guidelines with Incident Dementia in the Atherosclerosis Risk in Communities Cohort
Authors: Jeffrey D Hodis, Rebecca F Gottesman, B G Windham, David S Knopman, Pamela L Lutsey, Keenan A Walker, Alvaro Alonso
Journal: Circulation (2019)

Background: Although associations between hypertension in mid-life and the development of dementia and cognitive decline have been established, the impact of the new 2017 ACC/AHA guidelines on dementia risk at the population level has not been evaluated. Objectives: To assess the association of hypertension categories with the risk of incident dementia and to calculate the population attributable fraction (PAF) for dementia from hypertension categories according to the 2017 ACC/AHA guidelines, and compare these associations with hypertension defined according to JNC7. Methods: We studied dementia-free participants recruited to the Atherosclerosis Risk in Communities (ARIC) cohort in 1987-89. Hypertension was defined by 2003 JNC7 and 2017 ACC/AHA guidelines using blood pressure measured at baseline; participants using antihypertensive medication were included in hypertension stage 2 for both sets of guidelines. Dementia was defined using adjudicated consensus diagnoses at visit 5 (2011-13), informant telephone interviews, and ICD-9 codes from hospitalizations and death certificates through 2013. Cox proportional hazards regression models estimated hazard ratios (HR) and 95% confidence intervals (CI) by hypertension categories, adjusting for potential confounders, including sociodemographic, lifestyle and clinical variables. PAF of dementia by hypertension category was calculated using rate ratios from Poisson regression and the prevalence of the risk factor in the population. Results: Among 13,971 participants followed for a median of 23.0 years, 1381 cases of dementia were identified. Prevalence of elevated BP (systolic BP [SBP] 120-129 and diastolic BP [DBP] &lt;80), hypertension stage 1 (SBP 130-139 or DBP 80-89) and hypertension stage 2 (SBP ≥140 or DPB ≥90) according to 2017 ACC/AHA categories was 13%, 15% and 44%, respectively. Corresponding HR (95%CI) compared to normal BP were 1.35 (95%CI 1.12, 1.61), 1.28 (1.07, 1.52) and 1.36 (1.18, 1.57), respectively. PAF (95%CI) of dementia from hypertension categories were 3% (1%, 5%), 3% (1%, 5%) and 9% (4%, 14%). PAF using JNC7 categories were similar to 2017 ACC/AHA: 6% (3%, 9%) for prehypertension (SBP 120-129 or DBP 80-89), 0% (-2%, 2%) for hypertension stage 1 (SBP 140-159 or DBP 90-99), and 9% (5%, 13%) for hypertension stage 2 (SBP ≥160 or DBP ≥100). Conclusions: Risk of dementia was increased across categories defined by the new ACC/AHA hypertension guidelines. However, the population impact on dementia incidence using 2017 ACC/AHA was similar to the impact of JNC7. These results suggest that the new criteria for diagnosis of hypertension will not increase the number of persons in whom hypertension could be reasonably labeled as a risk for dementia.
Incidence and survival of gallbladder cancer over three decades: A SEER database study.
Authors: Adnan Ali, Swati Pendhakar, Rizwan Ali, Akanksha Chichra, Dinesh Pendharkar
Journal: Journal of Clinical Oncology (2015)

e17651 Background: Gallbladder cancer (GBC) is relatively a rare malignancy with dreary long term survival. There is a dearth of literature on the incidence and survival of primary GBC in the most recent decade especially with respect to socioeconomic status (SES). Methods: We queried the SEER database for primary GBC patients diagnosed over three decades between 1980 and 2009 using ICD-O-3 C23.9 from the 9 original registry sites. Data obtained included the demographics, SES status, treatment, age adjusted incidence, cause specific survival (CSS) and relative survival rates (RSR) of primary GBC. Results: A total of 6,943 patients with primary GBC were reported between 1980-2009. The incidence of GBC/100,000 decreased from 1.3 in 1980s to 1.0 in 1990s to 0.8 in 2000s. Females showed a higher incidence of GBC/100,000 as compared to Males in all three decades (1.6 vs 0.9 in 1980s; 1.2 vs 0.6 in 1990s and 1.0 vs 0.6 in 2000s). When stratified by SES, the high poverty group showed highest incidence of GBC/100,000 in all the three decades (2.6, 1.9 and 1.5 in 1980s, 1990s and 2000s respectively) as compared to low and medium poverty groups. The median CSS improved with each successive decade from 4.5 months in 1980s to 6.2 months in 1990s to 8.3 months in 2000s. Overall 5- year RSR increased from 10.4% for 1980s to 11.8% for 1990s to 15.6% for 2000s (all p < 0.0001). The 5-year RSR in 2000s was higher in females (16.7%) than males (12.8%) (p = 0.004). The low-poverty group consistently showed higher RSR compared to high-poverty group at 6-months and 12-months intervals over three decades. However, this difference wasn’t significant. On multivariate cox regression analysis for GBC specific survival, age (RR: 1.019 95% CI 1.017-1.021; p < 0.001) and sex (Female vs Male: RR: 0.943 95% CI 0.917-0.969; p < 0.001) were found to be significant predictors of survival. Conclusions: Our analysis shows that, over the three decades, overall RSRs and median CSS have improved each successive decade, while the incidence has decreased by 38.5%. Females have higher incidence of GBC throughout all decades, but showed a significantly increased survival rates than males in the most recent decade. Also, the incidence was found to be higher in high poverty group consistently.
Loss of Microbial Topography between Oral and Nasopharyngeal Microbiota and Development of Respiratory Infections Early in Life
Authors: Wing Ho Man, Melanie Clerc, Wouter A. A. de Steenhuijsen Piters, Marlies A. van Houten, Mei Ling J. N. Chu, Jolanda Kool, Bart J. F. Keijser, Elisabeth A. M. Sanders, Debby Bogaert
Journal: American Journal of Respiratory and Critical Care Medicine (2019)

Rationale: The respiratory microbiota is increasingly being appreciated as an important mediator in the susceptibility to childhood respiratory tract infections (RTIs). Pathogens are presumed to originate from the nasopharyngeal ecosystem.Objectives: To investigate the association between early life respiratory microbiota and development of childhood RTIs.Methods: In a prospective birth cohort (Microbiome Utrecht Infant Study: MUIS), we characterized the oral microbiota longitudinally from birth until 6 months of age of 112 infants (nine regular samples/subject) and compared them with nasopharyngeal microbiota using 16S-rRNA-based sequencing. We also characterized oral and nasopharynx samples during RTI episodes in the first half year of life.Measurements and Main Results: Oral microbiota were driven mostly by feeding type, followed by age, mode of delivery, and season of sampling. In contrast to our previously published associations between nasopharyngeal microbiota development and susceptibility to RTIs, oral microbiota development was not directly associated with susceptibility to RTI development. However, we did observe an influx of oral taxa, such as Neisseria lactamica, Streptococcus, Prevotella nanceiensis, Fusobacterium, and Janthinobacterium lividum, in the nasopharyngeal microbiota before and during RTIs, which was accompanied by reduced presence and abundance of Corynebacterium, Dolosigranulum, and Moraxella spp. Moreover, this phenomenon was accompanied by reduced niche differentiation indicating loss of ecological topography preceding confirmed RTIs. This loss of ecological topography was further augmented by start of daycare, and linked to consecutive development of symptomatic infections.Conclusions: Together, our results link the loss of topography to subsequent development of RTI episodes. This may lead to new insights for prevention of RTIs and antibiotic use in childhood.
Abstract P051: College Students’ Perception and Beliefs Regarding Cardiovascular Risk Factors: A Mixed-Methods Study
Authors: Dieu-My T Tran, Catherine Dingley, Rogelio Arenas
Journal: Circulation (2019)

Background: Many college students underestimate their cardiovascular risk while engaging in high-risk behaviors such as consumption of high-fat foods, smoking, alcohol abuse, and sedentary lifestyle. Objective: To explore the perceptions and beliefs regarding cardiovascular risk factors and lifestyle modifications among college students who have been identified as high risk for cardiovascular disease (CVD). Methods: Using a mixed-methods design, quantitative data was collected to identify participants with high CVD risk. Participants with a Framingham 30-year CVD risk of 10% or higher were invited to participate in the qualitative interviews. Of 148 college students who completed the quantitative portion, 16 were high risk and invited to participate in qualitative interviews. A conventional content analysis was used to analyze interview data. Results: Ten participants completed the interviews (mean 30-year CVD risk was 19.0% (ranges 10% to 39%). All participants were overweight or obese, 70% consumed alcohol, 60% had elevated blood pressure, 50% had a family history of heart disease, and 20% were current smokers while none had diabetes or hyperlipidemia. Analysis of the in-depth interviews revealed a thematic structure consisting of five primary categories: 1) recognizing risk, 2) lifestyle trajectories, 3) factors influencing lifestyles, 4) ideal healthy lifestyle modifications, and 5) perceived benefits of healthy lifestyles. Recognizing risk, participants had varied responses to the news that they were at risk for CVD, some were not surprised to learn of their cardiovascular risk status while others found this information to be unexpected. Lifestyle trajectory, participants often used their previous lifestyle and behaviors as a context for their current lifestyles. The influencing factors, both facilitators and barriers, are categorized as environmental, relational, financial, work/life/school balance, and internal/intrinsic motivation. Participants described their conceptualizations of an ideal healthy lifestyle modification program and the necessary components for success. The benefits and results of a healthy lifestyle were clearly described as feeling better and experiencing improved physical tolerance, looking better, reaping the rewards of experiencing results, positive feedback from others, and social acceptance and validation. Conclusions: Understanding high-risk college students’ beliefs and perceptions regarding CVD risk factors, barriers, facilitators, and strategies for implementing a healthy lifestyle, is the first step to assessing the problem facilitating early intervention which may result in improved long-term cardiovascular health outcomes in the young population.
Contrasting requirements during disease evolution identify EZH2 as a therapeutic target in AML
Authors: Faisal Basheer, George Giotopoulos, Eshwar Meduri, Haiyang Yun, Milena Mazan, Daniel Sasca, Paolo Gallipoli, Ludovica Marando, Malgorzata Gozdecka, Ryan Asby, Olivia Sheppard, Monika Dudek, Lars Bullinger, Hartmut Döhner, Richard Dillon, Sylvie Freeman, Oliver Ottmann, Alan Burnett, Nigel Russell, Elli Papaemmanuil, Robert Hills, Peter Campbell, George S. Vassiliou, Brian J.P. Huntly
Journal: The Journal of Experimental Medicine (2019)

Epigenetic regulators, such as EZH2, are frequently mutated in cancer, and loss-of-function EZH2 mutations are common in myeloid malignancies. We have examined the importance of cellular context for Ezh2 loss during the evolution of acute myeloid leukemia (AML), where we observed stage-specific and diametrically opposite functions for Ezh2 at the early and late stages of disease. During disease maintenance, WT Ezh2 exerts an oncogenic function that may be therapeutically targeted. In contrast, Ezh2 acts as a tumor suppressor during AML induction. Transcriptional analysis explains this apparent paradox, demonstrating that loss of Ezh2 derepresses different expression programs during disease induction and maintenance. During disease induction, Ezh2 loss derepresses a subset of bivalent promoters that resolve toward gene activation, inducing a feto-oncogenic program that includes genes such as Plag1, whose overexpression phenocopies Ezh2 loss to accelerate AML induction in mouse models. Our data highlight the importance of cellular context and disease phase for the function of Ezh2 and its potential therapeutic implications.
Seasonal malaria chemoprevention combined with community case management of malaria in children under 10 years of age, over 5 months, in south-east Senegal: A cluster-randomised trial
Authors: Jean Louis A. Ndiaye, Youssoupha Ndiaye, Mamadou S. Ba, Babacar Faye, Maguette Ndiaye, Amadou Seck, Roger Tine, Pape Moussa Thior, Sharanjeet Atwal, Khalid Beshir, Colin Sutherland, Oumar Gaye, Paul Milligan
Journal: PLoS Medicine (2019)

Seasonal malaria chemoprevention (SMC) is recommended in the Sahel region of Africa for children under 5 years of age, for up to 4 months of the year. It may be appropriate to include older children, and to provide protection for more than 4 months. We evaluated the effectiveness of SMC using sulfadoxine-pyrimethamine plus amodiaquine given over 5 months to children under 10 years of age in Saraya district in south-east Senegal in 2011.
A laboratory demonstration of transmission and prevention of hereditary tumors in hybrid rats
Authors: Morris Pollard
Journal: Clinical Cancer Research (2007)

A42   Hereditary tumors develop spontaneously through endogenous mechanisms that are not preventable and rarely curable. Herditary tumors were originally identified by familial clustering (multiple cases per family), by onset at early age, by aggressive growth patterns, and by speculations that they were transmitted in dominant mode from fathers to sons by inheritance. However benign tumors also express hereditary characteristics. Two disparate strains of inbred rats were selected, each developing spontaneously up to age 24 months, differences in tumor type, in organ site, and in optimal level of endogenous testosterone for tumor development. Male Fischer (F344) rats that develop benign interstitial testicular (Leydig cell) tumors (ITT) linked to low physiological levels of endogenous testosterone (T) and prevented by high levels of T, were mated with female Lobund-Wistar (LW) rats, a strain that develops prostate cancer (PC) linked to abnormally high levels of endogenous T and prevented by early T-deprivation. Low physiological levels of T are ~ 250 pg/ml serum and abnormal high levels of T are >1800 pg/ml serum. At age 24 months, the male hybrids carried low levels of T, and 50% of the F1 hybrids developed overt ITT, a pattern that was repeated in F2 and F3 hybrids. Hybrids were free of overt and of microscopic biomarkers of PC, however a) a subset of hybrids (37%) developed overt PC following IV inoculation of mutagenic methylnitrosourea plus implants of exogenous testosterone propionate ,and b) like LW control rats, hybrids were susceptible to the unique hormone refractory PC (PAIII) transplanted cell, that was rejected by control Fischer rats. This innovative experiment a) confirms the speculations of male to male transmission of ITT in hybrids linked to low levels of T and b) revealed the inherited genomic potential in hybrids derived from both of their parents.
Mapping Portuguese Research on Respiratory Diseases in Primary Care: A systematic review
Authors: B. Malheiro, P.M. Teixeira, L. Alves, J. Yaphe, J. Correia de Sousa
Journal: Pulmonology (2019)

Financial support for this work was provided by FEDER funds through the Operational Programme Competitiveness Factors-COMPETE and National Funds through FCT-Foundation for Science and Technology under the project POCI-01-0145-FEDER-007038, and by the project NORTE-01-0145-FEDER-000013, supported by Norte Portugal Regional Operational Programme (NORTE 2020), under the PORTUGAL 2020 Partnership Agreement, through the European Regional Development Fund (ERDF).
Prediction and monitoring of relapse in stage III melanoma using circulating tumor DNA
Authors: L. Tan, S. Sandhu, R.J. Lee, J. Li, J. Callahan, S. Ftouni, N. Dhomen, P. Middlehurst, A. Wallace, J. Raleigh, A. Hatzimihalis, M.A. Henderson, M. Shackleton, A. Haydon, V. Mar, D.E. Gyorki, D. Oudit, M.A. Dawson, R.J. Hicks, P. Lorigan, G.A. McArthur, R. Marais, S.Q. Wong, S.-J. Dawson
Journal: Annals of Oncology (2019)

The advent of effective adjuvant therapies for patients with resected melanoma has highlighted the need to stratify patients based on risk of relapse given the cost and toxicities associated with treatment. Here we assessed circulating tumor DNA (ctDNA) to predict and monitor relapse in resected stage III melanoma.
Abstract MP54: Sex-Related Differences in the Association of Social Isolation With Plasma Leptin Concentration
Authors: Todd R Sponholtz, Ramachandran S Vasan
Journal: Circulation (2019)

Introduction: Studies have reported a positive associations of depression and psychosocial stress and plasma leptin concentration. Social isolation has been linked to increased leptin signaling in male rats, but this association has not been investigated in humans. Methods: We investigated the cross-sectional association of social isolation and plasma leptin concentration among 2,729 Framingham Offspring Cohort participants at the 7 th examination (1999-2001, mean age = 60.1 years, 42% men). Social isolation was measured using the Berkman-Syme Social Network Index: we assigned 1 point for being married, 1 point each for &gt;2 close friends and &gt;2 close relatives, 1 point for participation is social groups, and 1 point for participation in religious meetings ≥1-2 times per month. Social isolation was defined as a total of 0 points. Non-fasting plasma leptin levels were measured using a commercial immunoassay. The primary outcome was plasma leptin concentration. Secondary outcomes included caloric intake, measured by food frequency questionnaire, and volumes of abdominal subcutaneous adipose tissue (SAT), and visceral adipose tissue (VAT), measured by CT among 1,210 of the subjects between 2002 and 2005. Leptin concentration and adipose tissue volume were log-transformed due to skewed distributions. We estimated the associations of social isolation with all outcomes using linear regression. Models included age, body mass index, years of education, smoking status, physical activity index, hypertension, high blood glucose, and CES-D score as covariates. Because leptin levels and responses to social stress may vary among men and women, analyses were stratified by sex. Results: Socially isolated participants were younger and had higher CES-D scores than those who were not. Other characteristics were similar between the two groups. Plasma leptin concentration was 20% lower among socially isolated men (95% CI: -31, -6%) compared with men who were not isolated. Social isolation was also associated with lower caloric intake as well (β = -144.5 kcal, 95% CI: -287.1, -1.87 kcal). Among the subset of men for whom we had adipose tissue depot volume measurements (n=552), VAT volume appeared to be 10% lower among socially isolated men compared with non-isolated men (95% CI: -19, 1%), but this was not true of SAT (β = 1%, 95% C: -9, 10%). We did not observe differences in leptin concentration (β = -1%, 95% CI: -10, 15%), caloric intake (β = -39.1 kcal, 95% CI: -136.0, 57.7 kcal) or SAT β=4%, 95% CI: -3, 14%) according to social isolation among women. Socially isolated women appeared to have higher VAT (β = 10, 95% CI: -1, 10%) Conclusions: In our population of middle-aged and older adults, social isolation was associated with lower leptin levels among men, but not women. The lower leptin concentration observed among isolated men may reflect decreased caloric intake in response to social stress.