tbuckley/cabot-search huggingface dataset:
Correlation of the SOX9 FGFR2b feed forward loop with prognostic variants and survival in resected pancreatic cancer.
Authors: Shereen Rafee, Ray McDermott, Niall Swan, Maire Lavelle, Brianan McGovern, Jean Murphy, Fergal C Kelleher
Journal: Journal of Clinical Oncology (2015)

e15282 Background: Pancreatic progenitor specific ablation of the transcription factor Sox9 in early pancreatic development affects lineage specific cell fate. Sox9, Fgfr2 & Fgf10 form a feed forward expression loop in the early pancreatic organ niche. Fgfr2b or Fgfr10 is required for pancreatic progenitor cell proliferation. Methods: In 59 patients post pancreaticoduodenectomy (PD) immunohistochemistry (IHC) expression of SOX9, FGFR2 & DPC4, clinicopathologic variants of prognostic significance & survival were assessed. SOX9-FGFR2 co-expression (SF+) on IHC correlated with variants in R0 cohort. Eligibility: minimum 2 yrs follow-up post PD for pancreatic ductal adenocarcinoma. Mean duration of follow-up 4.5 yrs Results: Mean age 62.6 yrs (range 38-81 yrs). Male 64.4%, female 35.6%. R0 55 (93%), R1 4 (7%). Average maximum pathological tumor axis 2.98cm. Mean number positive nodes 1.83, mean number negative nodes 9.78. Tumor differentiation: well 8.4%, moderate 64.4%, poor 28.6%. Portal vein involvement: present 3.4%, absent 96.6%. Perineural invasion: present 81.3%. Lymphovascular invasion: present 61%. 33.9% patients alive, 66.1% dead at time of analysis. Cause of death-pancreatic cancer 97.4%, other 3.6%. IHC: FGFR2 positive 91.5%, SOX9 positive 55.9%, DPC4 positive 42.3%, (SF+) 54.2%. Kaplan Meier analysis R0 cohort: median survival 737days (d) (482d-991d); median pancreatic cancer specific survival 541d (429d-653d). Median maximum pathologic axis in cm: (SF+) 3.50, (SF-) 2.35. Mann-Whitney sum of ranks (SF+) 941, (SF-) 599, U test 248, Wilcoxon W599, Z -2.179, asymp. Sig. (2-tailed) .029. Median number of positive nodes (SF+): (SF-) 2:1, median number of negative nodes (SF+): (SF-) 8:10. Mann-Whitney U 354: 248, Wilcoxon W705: 683, Z-.398, -2.182, asymp Sig.(2-tailed). 691, .029.SF status not significantly associated with T stage, differentiation, age, LVI, perineural invasion or DPC4 positivity. Median survival of (SF+) 730d, median survival (SF-) 737d, no significant difference Conclusions: (SF+) is significantly correlated with greater median tumor dimension & median number of positive lymph nodes. NVP-BGJ398 merits preclinical investigation in (SF+) pancreatic cancer.
Behavioural therapy is often more effective than drugs for urinary incontinence in women, finds review
Authors: Susan Mayor
Journal: BMJ (2019)

Behavioural therapy to strengthen the pelvic floor or to change behaviour influencing bladder function, with or without other treatment, is generally more effective than drugs in treating stress or urgency urinary incontinence in women, a review of randomised trials has found.

Urinary incontinence affects nearly one in five (17%) non-pregnant women, and the prevalence increases with age, particularly after the menopause. The most common types are stress or urgency urinary incontinence, or a mix of both types.

A range of non-pharmacological and …
Abstract P164: Walking Pace is Inversely Associated With Heart Failure Risk in the Physicians’ Health Study
Authors: Omar Al-Ramady, Jiaying Chen, John M Gaziano, Luc Djoussé
Journal: Circulation (2019)

Background: Heart Failure (HF) continues to place a large burden on the public health. While previous studies reported a lower risk of HF and coronary heart disease with increased physical activity, limited data is known about the role of intensity and duration of exercise, specifically walking pace in relation to heart failure risk. Objective: The primary objective is to assess whether walking pace is associated with a lower risk of heart failure among male US physicians. Methods: In a prospective cohort study of US male physicians, walking pace was collected through a self-reported questionnaire. Incidence of HF was measured via self-reported annual questionnaires and validated in a subsample. Results: We studied 21,345 men with a mean age of 67.6 ± 8.9 years. After a mean follow-up of 8.2 years, 849 cases of HF occurred. In a multivariable Cox regression adjust for age, exercise, prevalent CHD, history of atrial fibrillation, smoking and alcohol consumption, hazard ratios (95% CI) for HF were 1.08 (0.85-1.36) for walking pace of &lt;2 mph, 0.73 (0.60-0.90) for 2-2.9 mph, and 0.55 (0.43-0.71) for ≥3 mph compared to not walking regularly (p trend &lt;0.0001). Conclusions: Walking Pace was inversely associated with HF in male physicians in a dose-response manner
Incidence of bloodstream infections and predictive value of qualitative and quantitative skin cultures of patients with overlap syndrome or toxic epidermal necrolysis: A retrospective observational cohort study of 98 cases
Authors: Aude Lecadet, Paul-Louis Woerther, Camille Hua, Audrey Colin, Camille Gomart, Jean-Winoc Decousser, Armand Mekontso Dessap, Pierre Wolkenstein, Olivier Chosidow, Nicolas de Prost, Saskia Ingen-Housz-Oro
Journal: Journal of the American Academy of Dermatology (2019)
Abstract P040: Body Mass Index, Sedentary Lifestyle, and Incidence of Coronary Heart Disease
Authors: Xiang Li, Tao Zhou, Dianjianyi Sun, Yoriko Heianza, Lu Qi
Journal: Circulation (2019)

Importance: Obesity has been related to sedentary lifestyle, and an increased risk of coronary heart disease (CHD); however, no study has assessed the causal link between obesity, sedentary lifestyle, and CHD. Objective: To examine whether BMI is causally associated with sedentary lifestyle, and quantify the mediation effects of sedentary lifestyle in the relation between BMI and CHD. Method: Sedentary lifestyle was quantified by hours spent on sedentary behaviors including TV watching, using computer (not at work) and driving. We tested the causality between BMI and sedentary lifestyle by Mendelian randomization (MR) analysis using 77 BMI related single-nucleotide polymorphisms (SNP) as the instrumental variable, among 401,876 white British participants (enrolled from 2006 to 2010) from the UK Biobank. A further mediation analysis was performed to assess the relations between BMI, sedentary lifestyle, and CHD risk among 366,370 participants with 3,816 incident CHD cases (followed up to 2016). Result: The MR analysis showed that there was a causal relation between BMI and sedentary lifestyle. One standard deviation increment in BMI causally resulted in 0.38 increase in the sedentary hour (p&lt;0.001), independent of age, sex, physical activity, alcohol intake, smoking, and the socioeconomic status. In addition, our mediation analysis indicated that 7% and 26% of the effect of high BMI on incident CHD risk were mediated by 4-5 hours (p=0.02), and ≥ 6 hours (p&lt;0.001) of sedentary lifestyle, compared with &lt; 2 sedentary hours, respectively. Conclusion: Our results indicate that high BMI is causally associated with increased hours of sedentary lifestyle, which mediate a significant proportion of the CHD risk associated with high BMI.
Correlation between RECIST-conventional imaging techniques, morphologic response by CT and histopathologic response, in hepatic metastasis secondary to colorectal cancer: The AVAMET study.
Authors: Ruth Vera, Maria Luisa Gomez Dorronsoro, Juan Ramón Ayuso, Joan Figueras, Pilar Garcia Alfonso, Virginia Martínez-Marín, Adelaida La Casta Munoa, Ana Ruiz, Maria Jose Safont, Jorge Aparicio, Juan Manuel Campos, Juan Carlos Camara, Marta Martin-Richard, Clara Montagut Viladot, Carles Pericay, Jose Maria Vieitez de Prado, Esther Falco, Mónica Jorge Fernández, Miguel Marin, Mercedes Salgado Fernández
Journal: Journal of Clinical Oncology (2015)

e14656 Background: The RECIST criteria may be limited in assessing response to biologic agents such as bevacizumab (BVZ). Retrospective studies of patients (pts) with colorectal liver metastases (CLM) receiving BVZ have shown association of computed tomography-based morphologic criteria (CTMC) with pathologic response (pR). Methods: Pts with ≤ 4 resectable CLM with no prior chemotherapy for metastatic disease received 3 cycles of capecitabine/oxaliplatin (XELOX)+BV. Response was evaluated using RECIST criteria and CTMC. For CTMC, metastasis was assigned to 1 of 3 groups (Table): CTMC were defined as optimal (metastasis changed from a group 3 or 2 to a 1), incomplete (group changed from 3 to 2), and none (the group had not changed or increased). Those pts without progression, received other cycle of XELOX prior to surgery. Pathologic response was scored as minor (≥50% of residual tumor cells), major (1-49% residual tumor cells), and complete (no residual tumor cells detected). The main objective was correlate response determined using CTMC and RECIST, with pR (Chi square). Results: 83 pts were recruited. 68 pts were evaluated by RECIST; 67 of them were also evaluated using CTMC, 60 pts underwent surgery and 51 pts had their resected CLM anatomopathologically analyzed. 33 of 68 pts reached partial response RECIST (49%, 95%CI 37-60%) and 58 pts had optimal (26) or incomplete (32) response by CTMC (85%, 95%CI 75-92%). Complete (12) or major (30) pR was achieved in 42 of 51 pts (82%, 95%CI 70-90%). Morphologic response (optimal/incomplete) was more specific for predicting pR (complete/major) than RECIST response (36 of 42, CTMC vs. 24 of 42, RECIST, p=.0038). Conclusions: Among pts with CLM treated with BVZ-containing chemotherapy an outstanding complete or major pR was reached. Morphologic criteria seem to be a better surrogate marker of pR than RECIST. Clinical trial information: NCT01493713.CTM groups. CTMC Morphology Group Overall Attenuation Tumor-Liver Interface Peripheral Rim of enhancement 3 Heterogeneous Ill defined May be present 2 Mixed Variable If initially present, partially resolved 1 Homogeneous & hypoattenuating Sharp If initially present, completely resolved
Abstract P225: Hyperhomocysteinemia Mediates the Association of Food Deserts With Recurrent Heart Failure Hospitalizations
Authors: Aditi Nayak, Siyi Geng, Andreas Kalogeropoulos, Arshed A Quyyumi, Javed Butler, Alanna A Morris
Journal: Circulation (2019)

Background: Food deserts (FD) are low-income areas with low access to healthful foods. Prior studies have shown that a diet rich in fruits, vegetables and dairy products substantially lowers homocysteine (Hcy) levels by supplementing folate, vitamin B 12 , B 6 and choline intake. Since Hcy is an independent risk factor for cardiovascular disease, and may be abnormal in subjects living in a FD, we examined the impact of living in a FD on serum Hcy levels and the risk of recurrent heart failure hospitalizations (HFH). Methods: FD status was assessed using the USDA FD Research Atlas in 173 HF patients (mean age 57 ± 12 yrs, 63% male, 38% black), prospectively enrolled in the Atlanta Cardiomyopathy Consortium from 2007 to 2011. Hcy values were log-transformed (log 2 Hcy) for analysis. Linear regression was used to determine the association of FD with log 2 Hcy, and Poisson regression to examine the association of FD with risk of repeat HFH. Models were adjusted for age, gender, race, HF etiology, NYHA class, smoking status, EF, DM, hyperlipidemia, mean arterial pressure, BMI and serum creatinine. Results: Patients who lived in a FD (n=29) were younger (p=0.08) and more likely to be black (p&lt;0.001). After adjusting for covariates, FD status was associated with higher log 2 Hcy levels (adjusted β estimate: 0.32, 95% CI: 0.11- 0.52, p=0.003). During a median follow-up of 827 (IQR 506, 1379) days, 60 (34.7%) subjects had at least 1 HFH. The overall frequency of HFH (40.9 vs. 29.2 per 100 patient-years) was higher in patients who lived in a FD. In a fully adjusted model, for each unit increase in log 2 Hcy, there were 1.98 (adjusted, 95% CI: 1.38-2.82, p&lt;0.001) times more HFH. Living in a FD was associated with 1.46 (adjusted, 95% CI: 1.1-1.94, p=0.009) times more HFH. Addition of log 2 Hcy to the Poisson model eliminated the association of FD with recurrent HFH (adjusted HR: 1.14, 95% CI: 0.74- 1.76, p=0.54). Conclusions: Living in a FD is associated with higher serum Hcy. These results provide insights into the mechanisms by which FD status influences the risk of recurrent HFH.
Abstract P263: Gestational Diabetes and Patterns of Cardiometabolic Risk Factors Before and After Childbearing: Coronary Artery Risk Development in Young Adults Study
Authors: Baiyang Sun, Marnie Bertolet, Cora E Lewis, Janet M Catov, Erica P Gunderson
Journal: Circulation (2019)

Introduction: Cardiometabolic risk factor levels before pregnancy affect risk of gestational diabetes mellitus (GDM), and unfavorable risk factors have been found after pregnancy. However, changes in risk factors during both the pre- and post-childbearing periods have not been evaluated longitudinally in prospective studies. Hypothesis: Women who develop GDM pregnancy exhibit less favorable patterns of CVD risk factors during both pre- and post-childbearing eras. Methods: We used data from CARDIA, a multi-center, longitudinal cohort of black and white young adults initially aged 18-30 with serial in-person exams across 30 years (9 exams, 1985-2016). Women with ≥1 births after baseline (n=1288) self-reported GDM and were classified as “ever” GDM (n=148, at least one GDM pregnancy) and as non-GDM (all non-GDM births; n=1140). Piecewise linear mixed-models, which allowed differing intercepts and slopes for pre- and post-childbearing eras, compared GDM group to non-GDM group on annual changes in CVD risk factor (BMI, waist circumference [WC], lipids, and blood pressure) during pre-childbearing period (before the first post-baseline birth) and post-childbearing period (after the last post-baseline birth). Models adjusted for baseline socioeconomics, length of childbearing period (from the first to the last post-baseline birth), parity, time-varying lifestyle habits and medication use. Results: Annual BMI increase before initiation of childbearing was higher in GDM group than non-GDM group (0.35 vs 0.23 kg/m 2 /year; p=0.03). Similarly, WC showed marked pre-childbearing increase for GDM group compared to non-GDM group (0.82 vs. 0.54 cm/year; p=0.04). In contrast, the annual increase in BMI and WC after childbearing did not differ by GDM history. No differences were detected for the other CVD risk factors. Conclusions: Accelerated gains in overall and central adiposity before the childbearing period was associated with elevated risk of GDM, but risk factor changes do not show differences after childbearing.
PRODIGE 20: Bevacizumab + chemotherapy (BEV-CT) versus chemotherapy alone (CT) in elderly patients (pts) with untreated metastatic colorectal cancer (mCRC)—A randomized phase II trial.
Authors: Thomas Aparicio, Olivier Bouche, Eric Francois, Emilie Maillard, Sylvie Kirscher, Julien Taïeb, Pierre-Luc Etienne, Roger Faroux, Faiza Khemissa, Farid El Hajbi, Christophe Locher, Yves Rinaldi, Thierry Lecomte, Sandrine Lavau-Denes, Mathieu Baconnier, Alice Oden-Gangloff, Dominique Genet, Elena Paillaud, Frederic Retornaz, Laurent Bedenne
Journal: Journal of Clinical Oncology (2015)

3541 Background: AVEX study has demonstrated increased progression-free survival (PFS) with capecitabine + bevacizumab compared to capecitabine alone in pts aged over 70 with mCRC. The treatment with bevacizumab has so far not been evaluated in combination with other standard chemotherapy regimens for elderly pts. Methods: Pts aged 75 and over were randomly assigned in a 1:1 ratio to BEV-CT versus CT. Following regimens were authorized: LV5FU2, FOLFOX and FOLFIRI, chosen by the investigators. The primary endpoint, assessed 4 months after randomization was composite, based on efficacy: tumor control (stable disease or objective tumor response) and absence of decrease of the Spitzer QoL index and safety: absence of severe cardiovascular toxicities and unexpected hospitalization. The decision rules for the experimental arm were: if >15 pts met the efficacy criterion and if >25 pts met the safety criterion, the BEV-CT treatment is considered efficient and well tolerated. Results: 102 pts were randomized (51 BEV-CT and 51 CT arm), median age was 80 (range 75-91), men (55%), ECOG 0: 27%, 1: 53% and 2: 20%. CT was LV5FU2 in 53 pts (27 BEV-CT and 26 CT) and a doublet regimen in 49 pts (24 BEV-CT and 25 CT) including 23 FOLFOX and 26 FOLFIRI. Primary tumor was resected in 31 pts in BEV-CT and 30 pts in CT. Of the 46 pts evaluable in the BEV-CT arm, 23 pts (50% [90% CI: 37.1-62.9]) responded to the efficacy criterion and 28 pts (61% [90% CI: 47.7-73.0]) to the safety criterion. Multivariate analysis show that primary tumor resected and normal independent activity of daily living are predictive for the composite criterion. Conclusions: BEV-CT arm responded to the efficacy and safety criterion. Addition of bevacizumab to 1st line chemotherapy in pts aged over 75 years with a mCRC is efficient and well tolerated. Clinical trial information: NCT01417494.Preliminary follow-up results. CT BEV + CT Grade 3-5 toxicities 65% 80% Median time to autonomy failure in months (m) 5.5 [95% CI: 3.8-NA] 5.9 [95% CI: 3.8-14.8] Median time to QoL deterioration (m) 13.6 [95% CI: 11.6-NA] Not achieved Median PFS (m) 7.8 [95% CI: 6.6-10.6] 10.7 [95% CI: 8.2-13.8] Median overall survival (m) 19.7 [95% CI: 13.4-21.9] 21.7 [95% CI: 14.6-NA]
Methylation of SSTR2 in gastroenteropancreatic tumours.
Authors: Christina Simoglou Karali, Nicolas Marco Arino, Eric Aboagye, Rohini Sharma
Journal: Journal of Clinical Oncology (2015)

e13559 Background: DNA methylation in promoter regions of tumor suppressor genes alters gene expression and tumour phenotype in all subtypes of NETs. High expression of SSTR2 is a hallmark of NETs. Methods: We constructed a quantitative epigenotype employing pyrosequencing of 35bp in the upstream promoter of SSTR2, immunohistochemistry and analysis of clinicopathological parameters in 84 GEP-NETs. We conducted in vitro demethylation and uptake assays by administration of demethylating agents and/or somatostatin analogue (SSA) in clinically relevant concentrations in 6 human gastrointestinal cancer cell lines followed by pyrosequencing, western blot, qPCR and immunofluorescence in order to reexpress SSTR2. Results: Promoter methylation was observed in 86% of GEP-NET. Hypermethylation frequency varied considerably ; somatostatinomas - 30%, insulinomas - 18%, non-functional pNETs - 25%, GI-NETs -17%. Distant hepatic metastases exhibited low SSTR2 methylation density. 5-year survival correlated with methylation in the promoter region of SSTR2 (p = 0.012). Administration of demethylating agents resulted in the reversibility of the gene-specific methylation pattern and concomitant restoration of SSTR2 expression. Combination treatment with SSA resulted in increased transcriptional expression and internalization of the receptor. Conclusions: This is the most extensive panel of GEP-NETs screened for epigenetic aberrations of SSTR2. Methylation of SSTR2 in normal, tumour-surrounding tissue suggests the presence of a field defect of widespread pre-neoplastic alterations within the gastrointestinal tract. Our in vitro experiments confirm the causal role of DNA methylation in the transcriptional silencing of SSTR2. Combination therapy with SSAs and demethylating agents represents a promising scenario that could take advantage of the key regulatory role of methylation, in order to facilitate the upregulation of SSTRs and to target non-responders populations.
Abstract P052: Not Only Velocity but Also Variability in Body Mass Index in Childhood Are Associated With HOMA-IR at Adulthood: 30 Years Follow-up Kangwha
Authors: Su Jin Lee, Jung Hyun Lee, Hyeon Chang Kim, Il Suh
Journal: Circulation (2019)

Introduction: Recent studies have reported that childhood obesity increased the risk of adult metabolic disorders. Moreover, the variability and rapid increase in body mass index (BMI) during childhood have been revealed as risk factors for adult obesity. Although obesity increases metabolic disorders through induction of insulin resistance, it has not been studied whether the rate of change and variability of BMI during childhood are independently associated with insulin resistance at adulthood. Hypothesis: We assessed the hypothesis that rate of change and variability of BMI during childhood would affect insulin resistance at adulthood. Method: The study cohort consisted of 284 Kangwha study participants (aged 25 - 38 years at follow-up) who had been screened at least four times during childhood (aged 6 - 19 years) and also had no diabetes at adulthood. The average follow-up period was 21.5 years. BMI Z-score was measured by considering the growth curve in Korea, and rate of change (velocity) in BMI during childhood for each individual was assessed by mixed models; BMI residual standard deviation (RSD) during childhood was calculated as a measure of variability. Outcome variable was homeostatic model assessment of insulin resistance (HOMA-IR) at adulthood follow-up. Results: The mean age of the participants 13.3 (SD 1.4) years and mean BMI was 18.6 (SD 2.3) at childhood. One SD increase in rate of change in BMI z-score ( β = 0.32, p -value &lt;0.001) and in RSD of BMI ( β = 0.31, p -value &lt;0.001) during childhood were positively and independently associated with HOMA-IR. Stratified by sex, adult HOMA-IR was also positively associated with the velocity ( β = 0.36, p = 0.001 in men, and β = 0.38, p = 0.001 in women) and variability ( β = 0.25, p = 0.03 in men; β = 0.27, p = 0.002 in women) of BMI during childhood. Conclusions: BMI velocity and variability during childhood appear to be independent risk factors for adult HOMA-IR. Our findings suggest prevention of rapid weight gain and body weight regulation during childhood would be important factors to reduce insulin resistance at adulthood related with metabolic disorders.
Generation of specific polyclonal and polyfunctional CD4<sup>+</sup> T-helper1 cells against WT-1, MAGE-A3, Survivin and ROR-1 for adoptive T-cell immunotherapy.
Authors: Simone Kayser, Cristina Boß, Christina Kyzirakos, Stefan Stevanovic, Martin Röcken, Rupert Handgretinger, Tobias Feuchtinger
Journal: Journal of Clinical Oncology (2015)

e14025 Background: Adoptive T cell therapy (ACT) is a promising option to treat cancer. Th1 cells have been shown effective against viremia and cancer and are mediators of senescence in tumor cells. T cells against tumor associated antigens like cancer testis antigens can be used for adoptive T-cell transfer approaches. Methods: According to these considerations, we developed a protocol according to good manufacturing practice (GMP) to generate Th1 cells against WT-1, MAGE-A3, Survivin and ROR-1. The protocol starts with a presensitization of T cells with antigen. T cells were then enriched based on IFN-γ capture technique and expanded using autologous feeder and IL-2, IL-7 and IL-15. T-cell specificity and function was analyzed by flow cytometry. Results: Large scale generation of T cells specific to the tumor antigens was performed. The T-cell lines showed high numbers of specific IFN-γ+ and TNF-α+ CD4+ T cells but no IL-10. Both, CD4+ and CD8+T cells had an effector memory phenotype and proliferated in response to the tumor antigens. Adding PD-1 antibody to the T cells resulted in an improved proliferation in response to the antigens. Treatment of a WT-1+ leukemia patient with stem cell donor derived WT-1 specific T cells in combination with WT-1 vaccine was accompanied with WT-1 CD4+ and CD8+T cell responses and ongoing remission. Conclusions: Protocols for the generation of Survivin, WT-1-, MAGE-A3- and ROR-1-specific T cells were successfully established. T cell products mainly consisted of CD4+ T-cells with secretion of the cytokines IFN-γ and TNF. This cytokine profile enables the induction of senescence in tumor cells. Although tumor associated antigens are potential self antigens, it is possible to induce a functional Th1 response in T cells from healthy donors making T-cell transfer feasible in an allogeneic settings post stem cell transplantation. Further improvements could be achieved by combination of T-cell therapy with antibodies to PD-1.