tbuckley/cabot-search huggingface dataset:
Abstract 14267: Ncx 6560, a Novel Nitric Oxyde Donating Atorvastatin With a Promising Safety and Efficacy Profile: A Randomised, Double Blind Placebo and Active Control Study
Authors: Jacques P Djian, Raffaela Maucci, Liliane Guilmin, Thierry Ferreira, Pascal Pfister
Journal: Circulation (2010)

Introduction: Evidence suggests that statins exert pleiotropic actions beyond lipid-lowering effects. Nonclinical studies have shown that NCX 6560, a nitric oxide (NO)-donating of atorvastatin was as effective as an equimolar dose of atorvastatin (ATV) on lipid lowering while exerting greater effects on anti thrombotic, anti inflammatory properties and endothelial function. The objectives of this FIM study were to assess the safety, tolerability, pharmacokinetics of NCX 6560 and to provide a proof of principle on its pharmacodynamic effects on lipids. Design: Single and multiple ascending doses (MAD) of NCX 6560 were evaluated using an interwoven design in male healthy volunteers. In the MAD part, 48 subjects with high LDL- C ( between 130-180 mg/dL inclusive) were randomly assigned to 4 cohorts of 12 subjects, each receiving either NCX 6560 24, 48, 96 or 144 mg (n=8), ATV 40 mg (n=2) or placebo (n=2) for 2 weeks. Results: A dose-related decrease from baseline in LDL-C (up to 57 %), total cholesterol (up ...
Molecular profiling of aggressive variant urothelial carcinoma.
Authors: Chethan Ramamurthy, David Arguello, Fern Anari, Pooja Ghatalia, Matthew R. Zibelman, Elizabeth R. Plimack, Earle Frederick Burgess, Thomas F. Hogan, Nancy Ann Dawson, Ralph J. Hauke, Jeanny B. Aragon-Ching, Daniel A. Vaena, Elisabeth I. Heath, Daniel M. Geynisman
Journal: Journal of Clinical Oncology (2019)

378 Background: The WHO recognizes multiple variant histologies of urothelial carcinoma (vUC), many of which have been associated with poor outcomes compared with urothelial carcinoma (UC). We aimed to explore molecular differences between aggressive vUC and UC. Methods: 23 micropapillary (MP), 16 plasmacytoid (P), 23 sarcomatoid (S), 7 nested (N), 6 clear cell (CC), and 2 giant cell (GC) vUC specimens were tested between 2012 to 2018 via a multiplatform profiling service (Caris Life Sciences, Phoenix, AZ) consisting of gene sequencing (next generation sequencing [NGS]), gene amplification (CISH or NGS), and protein expression (immunohistochemistry [IHC]). Findings were compared to 435 control UC specimens using the Chi-square test. Results: 84% of samples were from primary tumor. Alterations identified are summarized in Table 1, and are notable for high rates of TP53 mutations across histologic subtypes, varying rates of RB1, ERBB2 and FGFR mutations, and overall low rates of DNA damage repair (DDR) mutations (29 genes reported) except in S. There were more ARID1A mutations detected in MP than UC (100% [3 specimens] v. 41.3%, p=0.044), and more CDH1 mutations in P than UC (50% [4 specimens] v. 2%, p&lt;0.001). CISH ERBB2 (HER2) amplification was seen in 27.3% MP compared with only 10.4% in UC (p=0.005). Compared to UC, PD-L1 IHC (SP142 assay) was positive (&gt;5%) in a high proportion of S (55.6%, p=0.002) but in a lower proportion of other vUC (e.g. absent in P). Tumor mutational burden (TMB) was high in a lower proportion of vUC: 18.4% UC vs. 14.3% MP, 0% P, 16.7% S. Conclusions: Aggressive variant histology UCs have a differential profile of molecular aberrations compared to UC, with notable differences in potential targets such as HER2 and DDR genes as well as immunotherapy biomarkers. Further studies are needed to confirm these findings, and may support therapy development for these rare, aggressive UC subtypes. Aberrations (%) in Variant Histology UC. [Table: see text]
mRNA: A Novel Avenue to Antibody Therapy?
Authors: Thomas Schlake, Moritz Thran, Katja Fiedler, Regina Heidenreich, Benjamin Petsch, Mariola Fotin-Mleczek
Journal: Molecular Therapy (2019)

First attempts to use exogenous mRNA for protein expression in vivo were made more than 25 years ago. However, widespread appreciation of in vitro transcribed mRNA as a powerful technology for supplying therapeutic proteins to the body has evolved only during the past few years. Various approaches to turning mRNA into a potent therapeutic have been developed. All of them share utilization of specifically designed, rather than endogenous, sequences and thorough purification protocols. Apart from this, there are two fundamental philosophies, one promoting the use of chemically modified nucleotides, the other advocating restriction to unmodified building blocks. Meanwhile, both strategies have received broad support by successful mRNA-based protein treatments in animal models. For such in vivo use, specifically optimized mRNA had to be combined with potent formulations to enable efficient in vivo delivery. The present review analyzes the applicability of mRNA technology to antibody therapy in all main fields: antitoxins, infectious diseases, and oncology.
Which is ISS or R-ISS?
Authors: Kubilay Ekiz, Sude Hatun Aktimur, Nevin Alayvaz, Engin Kelkitli, Memis Hilmi Atay, Mehmet Turgut
Journal: Journal of Clinical Oncology (2015)

e18084 Background: Multiple myeloma (MM) is characterized by the neoplastic proliferation of plasma cells producing a monoclonal immunoglobulin. The staging of the illness at the moment of diagnosis determines both the approach to the patient and treatment strategy. D.Salmon and ISS staging systems, which have been used for a long time, don’t contain some important risk factors. In this context, the comparison of ISS staging system to R-ISS staging system which is identified in 2014 with addition of genetic classification made with FISH and serum LDH level is the main aim of our study. Methods: In our study, 84 MM patients who were newly diagnosed were evaluated retrospectively in hematology clinic of Ondokuz Mayıs University Hospital between January2009 and December2013. All the patients were the ones followed with similar treatment strategies. According to ISS and R-ISS systems, their stagings were made at the moment of diagnosis. According to genetic results made with FISH and serum LDH level, survival analyses were made. Overall survival and progression free survival durations were calculated. The similar and different aspects of both two stagings were evaluated. Results: The median age of the patients was 61,5. 11 patients (%13) had high LDH level. But in terms of survival, LDH couldn’t be found as an important risk factor. 13 patients (%15,4) who have high risk genetics had 15-month overall survival while 27 month in standard risky group. In the comparison of staging systems, staging systems were significantly different (p < 0,001). Coefficient of concordance kappa was calculated as 0,63. When there is no significant difference in terms of stage-1, fewer people were evaluated as stage-III in R-ISS system and those patients stood for the patients with the worst diagnosis among all the groups. In stage III in ISS, there were 32 patients and median overall survival was 19 months while there were 12 patients and median overall survival was 14,5 months in stage III in R-ISS. Conclusions: It is a correct approach to add genetic factor, which is an important prognostic marker, to the staging system. Much more clinical study is needed for LDH. R-ISS staging system is more effective than ISS staging system as it includes genetic factors. Yet, much more clinical experience is needed to substitute for ISS staging system.
Abstract P325: Effectiveness of the First Outpatient Pritikin Intensive Cardiac Rehabilitation (ICR) Program
Authors: Dominique Williams, Vinaya Mulkareddy, Kristin Montgomery, Taylor Carpenter, Andrea Soares, Christopher Graham, Kristin McKenzie, Serene Rashdi, Lisa de las Fuentes, Mike Rich, Susan Racette, Linda Peterson
Journal: Circulation (2019)

Introduction: ICR has been used for the treatment of patients recovering from a myocardial infarction, cardiac surgery, percutaneous intervention, and/or stable angina. Pritikin ICR is a comprehensive program whereby patients follow a structured diet and exercise program. The first outpatient Pritikin ICR program was implemented at Barnes-Jewish Hospital/Washington University School of Medicine. While patients domiciled at the Pritikin Longevity Center show marked improvements in several cardiovascular disease (CVD) risk factors, the effects of the outpatient Pritikin ICR program are unknown. Hypothesis: Patients who complete 24 sessions of the outpatient Pritikin ICR program will have improvements in several clinically important CVD risk factors, including body mass index (BMI, primary endpoint), adiposity, lipid profiles, and cardiorespiratory fitness. Methods: This observational study of the outpatient Pritikin ICR program was conducted as part of routine clinical care. Patients referred for ICR since 1/1/2017 were invited to participate in assessments at baseline and after completing 24 sessions. ICR was comprised of monitored exercise sessions plus Pritikin education sessions focusing on dietary changes (low-fat, low-sodium, high-fiber foods) and stress management through a series of videos, cooking classes, and workshops. Body composition was assessed using bioelectrical impedance. Fitness was estimated with the 6-minute walk test. Hand grip strength was assessed by dynamometry. Results: 140 ICR patients (28% women; age 68 ± 9 y, mean ± SD) completed baseline and visit 24 assessments over an average of 9.9 weeks. Significant improvements ( P &lt;0.001) were observed for BMI (pre 31.0 ± 6.2, post 30.5 ± 6.0 kg/m 2 ), weight (mean ± SD, -1.6 ± 3.0 kg), whole-body fat % (-1.2 ± 2.5), trunk fat % (-1.7 ± 3.3), 6-min walk distance (+37.6 ± 53.6 m), and hand grip strength (+1.22 ± 3.42 kg). Improvements also were observed for waist circumference, total cholesterol, and LDL cholesterol ( P &lt;0.05). Conclusion: An outpatient Pritikin ICR program results in significant cardiovascular benefits by reducing adiposity, improving lipid profiles, and enhancing exercise capacity. These favorable results should lead to fewer cardiovascular events.
Drug-drug interaction (DDI) of darolutamide with cytochrome P450 (CYP) and P-glycoprotein (P-gp) substrates: Results from clinical and <i>in vitro</i> studies.
Authors: Christian Zurth, Kristina Graudenz, Karsten Denner, Timo Korjamo, Robert Fricke, Gary Wilkinson, Friedeborg Seitz, Olaf Prien
Journal: Journal of Clinical Oncology (2019)

297 Background: Maintaining quality of survival, by delaying disease progression and minimizing therapy burden, is critical for patients and has been evaluated in the pivotal phase III ARAMIS study in patients with non-metastatic castration-resistant prostate cancer. Due to comorbidity, elderly men often receive multiple comedications, including CYP and P-gp substrates, eg, simvastatin and digoxin. Enzalutamide and apalutamide, approved androgen receptor (AR) inhibitors, are strong CYP3A4 inducers and thus have potential for CYP-mediated DDIs. The effect of darolutamide, a structurally unique AR antagonist, on CYP activity ( in vitro and in vivo) and P-gp activity ( in vivo) was assessed. Methods: Inhibition of CYP isoforms by Daro was investigated in human liver microsomes using standard substrates. In addition, CYP and P-gp activity during darolutamide treatment was studied in a phase I trial of 15 healthy men who received 75 mg dabigatran etexilate (DABE, P-gp substrate) + 1 mg midazolam (MDZ, CYP3A4 substrate) once followed by 600 mg darolutamide (two 300 mg tablets) twice daily (BID) given with food for 9 days. On day 9, darolutamide was concomitantly administered with a single dose of 75 mg DABE + 1 mg MDZ. Results: Based on in vitro data, no clinically relevant inhibition of CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, or 3A4 by darolutamide is expected. In 13 evaluable subjects in the phase I study, concomitant darolutamide reduced MDZ C max by ~32% and AUC by ~29% vs MDZ alone. Concomitant darolutamide reduced non-conjugated dabigatran C max by 16% and AUC by 9% vs DABE alone. The observed treatment-emergent adverse events were consistent with the known safety profile of darolutamide. No new safety risks were revealed by co-administration of darolutamide and DABE or MDZ. Safety data for patients in ARAMIS who received darolutamide, including those with concomitant CYP or P-gp substrates, will be presented. Conclusions: Darolutamide showed only weak effects or none on P-gp, CYP3A4, or any other relevant CYP enzyme. Thus, darolutamide is not expected to cause any clinically relevant DDI with CYP or P-gp substrates, minimizing complications of polypharmacy. Clinical trial information: NCT03237416.
Harmonized outcome measures for use in asthma patient registries and clinical practice
Authors: Richard E. Gliklich, Mario Castro, Michelle B. Leavy, Valerie G. Press, Amisha Barochia, Christopher L. Carroll, Julie Harris, Sarah S. Rittner, Robert Freishtat, Reynold A. Panettieri, Giselle S. Mosnaim
Journal: Journal of Allergy and Clinical Immunology (2019)
Abstract P212: Higher Rates of Breastfeeding Mediate the Association Between the 2009 Wic Food Package Change and BMI Z-score at Age 4
Authors: M. Pia Chaparro, Christopher Anderson, Catherine M Crespi, May C Wang, Shannon E Whaley
Journal: Circulation (2019)

Background: The Special Supplemental Nutrition Program for Women, Infants and Children (WIC) is a federal nutrition assistance program which provides supplemental food and nutrition services to children 0-5 years and their mothers, living in low-income households. In October of 2009, WIC food packages were changed to be better aligned to the Dietary Guidelines of Americans. Objective: The objective of this study was to evaluate whether observed differences in children’s BMI z-scores (BMIz) at age 4 years between WIC participants enrolled before and after the 2009 policy change could be attributable to changes in the type of infant feeding package they were exposed to. Methods: Our sample is based on children enrolled in WIC in Los Angeles County, CA between 2003 and 2016, from birth to age 5, with infant package issuance data for 11 or more of the first 13 months of life. Infant package exposure was quantified by the number of months receiving the fully breastfeeding infant package (a proxy for exclusive breastfeeding). A mediation analysis was performed in which BMIz at age 4 was the outcome, WIC package (new vs. old) was the exposure, and the number of months receiving the fully breastfeeding infant package was the mediator. Mediation was assessed by a product of coefficients method, and confidence limits for the mediated effect were based on the non-normal distribution of the mediated effect, using the PRODCLIN program in SAS. Models were gender-stratified and adjusted for child race/ethnicity, maternal education and language preference, household poverty status, initial weight status, and whether the child had a sibling in the sample. Results: The sample consisted of 140,204 children. Boys and girls exposed to the new WIC package received the fully breastfeeding infant package for 1.40 and 1.45 months longer than boys and girls exposed to the old WIC package. Among boys, the new WIC package was associated with a 0.12 standard deviation lower BMIz at age 4 (SE 0.01, p &lt;0.0001), whereas the corresponding number for girls was 0.07 (SE 0.01, p&lt;0.0001). Number of months exposed to the fully breastfeeding infant package partially mediated the association between exposure to the new WIC food package (vs. old) and BMIz at age 4, explaining 22.1% of the total effect (95% CI 19.1-25.1) for boys and 34.4% of the total effect (95% CI 29.9-38.9) for girls. Conclusions: Longer exposure to the fully breastfeeding infant package seemed to explain part of the association between BMIz at age 4 and receiving the new (vs. old) WIC food package. The percent of the total effect mediated by months of fully breastfeeding exposure was greater in girls than in boys. Future revisions to the WIC packages that continue to support women to fully breastfeed are likely to have significant effects on childhood obesity.
The role of adjuvant chemotherapy for pT2-4 upper urinary tract urothelial cancer: Exploratory analysis of large multi-institutional study (JCOG1110A).
Authors: Junichi Inokuchi, Kentaro Kuroiwa, Hiroyuki Nishiyama, Takahiro Kojima, Yoshiyuki Kakehi, Mikio Sugimoto, Toshiki Tanikawa, Hiroyuki Fujimoto, Momokazu Gotoh, Naoya Masumori, Osamu Ogawa, Masatoshi Eto, Chikara Ohyama, Akito Yamaguchi, Hideyasu Matsuyama, Tomohiko Ichikawa, Keiichi Ito, Junki Mizusawa, Junko Eba, Seiji Naito
Journal: Journal of Clinical Oncology (2019)

374 Background: Recently, it was presented that adjuvant chemotherapy (AC) after radical nephroureterectomy (RNU) improved metastasis-free survival in pT2-4 upper urinary tract urothelial cancer (UTUC) with a median follow-up of 17.6 months (POUT study). However, the impact of AC on other outcomes remains unclear, especially for pT2 disease. Methods: The large case-series study, JCOG1110A, included 2,744 patients with non-metastatic UTUC who underwent RNU in 30 institutions in Japan between 1995 and 2009. In this analysis, patients with prior history or synchronous bladder cancer, patients who received neoadjuvant chemotherapy were excluded. Patients who received AC except for GC (gemcitabine, cisplatin) or MVAC (methotrexate, vinblastine, doxorubicin, cisplatin) were also excluded. We extracted pT2-4 patients as study subjects from remaining patients, and identified 950 patients. The impact of AC on overall survival (OS) and extravesical recurrence-free survival (RFS) were examined by the multivariable Cox regression model in all patient and pT2, pT3-4 subgroups. Results: Of 244 pT2 and 706 pT3-4 patients with a median follow-up of 41.1 months, AC were performed in 34 (13.9%) and 183 (25.9%). In AC (+) group, high frequency of pT3-4 disease, high grade tumor, pathological node metastasis, lymphovascular invasion, and younger age were seen compared to AC (-) group. The 5-year survival of the AC (+) and AC (-) were 66.0% and 67.4% for OS, 58.0% and 57.8% for RFS, respectively. Multivariable analysis showed the improved outcome in AC (+) group on both OS and RFS in all patients (OS: HR 0.60, 95% CI 0.41-0.89, RFS: HR 0.71, 95% CI 0.51-1.00). Although AC had a great impact on OS in pT3-4 patients (HR 0.56, 95% CI 0.36-0.87), there was no clear impact on either OS or RFS in pT2 patients (OS: HR 0.81, 95% CI 0.32-2.07, RFS: HR 0.69, 95% CI 0.29-1.62). Conclusions: AC after RNU had the significant impacts on OS and RFS in pT2-4 UTUC patients. This tendency was seen strongly in pT3-4 patients, but not in only pT2 patients. The randomized trial is necessary to determine the utility of AC in UTUC patients, especially in pT2 patients. Clinical trial information: NCT01993979.
Predictors of BRCA mutation in male breast cancer.
Authors: Can Ardic, Angelica M. Gutierrez-Barrera, Nisreen Elsayegh, Juhee Song, Jessica Profato, Jennifer Keating Litton, Sharon Hermes Giordano, Debu Tripathy, Banu Arun
Journal: Journal of Clinical Oncology (2015)

1538 Background: Breast cancer is uncommon among men. Male breast cancer accounts for less than 1% of all male tumors. Among affected men, it is estimated that 10% have a genetic predisposition for the disease, most of which are determined by BRCA mutations. According to the NCCN guidelines, diagnosis of male breast cancer is sufficient to recommend BRCA genetic testing. In the present study, we evaluated other potential predictors having a BRCA mutation in male breast cancer patients. Methods: Men with a personal history breast cancer and who were referred for genetic testing were identified from a prospectively maintained database. Patient characteristics included personal history of other cancers, family history of breast and ovarian cancer, tumor type, estrogen (ER)/progesterone (PR) /Her2 receptor expression, nuclear grade, age of diagnosis, currently known risk factors for male breast cancer (liver cirrhosis, gynecomastia, radiation exposure, and Klinefelter’s disease), any hormone replacement therapy, and BRCA results. Univariate and multivariate logistic regression analyses were used to determine predictive factors associated with BRCA mutation. Results: After excluding male breast cancer patients presenting for predictive testing, 67 male breast cancer patients were identified. Nine (13%) patients carried a BRCA mutation, all of which were BRCA2. Risk factors that showed significant associations with BRCA mutation included having 2nd degree relatives with breast cancer (p = 0.0465) and having first degree relatives with ovarian cancer (p = 0.0304). Known risk factors for male breast cancer, previous history of other cancers, tumor markers (ER/PR/Her2, nuclear grade, and tumor type), did not show any significant associations. In multivariate analysis, having first degree relatives with ovarian cancer were more likely to have a BRCA mutation (p = 0.0251). Conclusions: Factors associated with predicting a positive BRCA result in men with breast cancer include a family history of breast and ovarian cancer as well as radiation exposure. Further larger studies should evaluate whether having solely male breast cancer is a strong enough predictor for BRCA mutations in the absence of factors mentioned above.
Abstract P411: Does Age at Natural Menopause Influence Changes in Left Ventricular Structure and Function During the Menopausal Transition? The Coronary Artery Risk Development in Young Adults (CARDIA) Study
Authors: Duke Appiah, Chike C Nwabuo2, Imo Ebong, Henrique D Vasconcellos, Melissa F Wellons, Cora E Lewis, Joao A Lima, Pamela J Schreiner
Journal: Circulation (2019)

Introduction: The association between menopause and incident cardiovascular disease (CVD) is controversial. Cardiac structure and function are important predictors of future CVD events, however, evidence for the long-term association of age at natural menopause (NM) with cardiac remodeling as women transition through menopause is lacking. We assessed the hypothesis that age at NM will be positively associated with changes in echocardiographic parameters of left ventricular (LV) structure and function. Methods: We studied 771 premenopausal women (37% black) from the Coronary Artery Risk Development in Young Adults (CARDIA) Study with echocardiographic data in 1990-1991 (mean age: 32 years) who later reached NM by 2015-2016 and had additional echocardiogram. Results: Mean age at NM was 50 years and the average time from menopause to the last echocardiogram was 7 years. In cross-sectional analyses, no associations were found between age at NM and premenopausal baseline parameters of LV structure and function (Table1). However, a one-year decrement in age at NM was significantly associated with higher postmenopausal levels of LV mass (LVM), LVM indexed to body surface area, LV mass-to-volume ratio, and relative wall thickness. In longitudinal analyses, higher age at NM was inversely associated with pre-to-postmenopausal changes in LV structure parameters. Controlling for baseline echocardiographic parameters, demographics, smoking, systolic blood pressure, BMI, physical activity, reproductive factors, total cholesterol and pre- to postmenopausal changes in systolic blood pressure, BMI and total cholesterol as well as hormone therapy attenuated the association of age at NM with these LV structure parameters. Conclusion: In this study, premenopausal CVD risk factors explained the association of age at NM with changes in LV structure parameters during the menopausal transition. These data suggest that premenopausal CVD risk factors rather than age at NM may predispose women to elevated future CVD risk.