tbuckley/cabot-search huggingface dataset:
Final analysis of phase III LATITUDE study in patients (pts) with newly diagnosed high-risk metastatic castration-naïve prostate cancer (NDx-HR mCNPC) treated with abiraterone acetate + prednisone (AA+P) added to androgen deprivation therapy (ADT).
Authors: Karim Fizazi, Namphuong Tran, Luis Enrique Fein, Nobuaki Matsubara, Alfredo Rodríguez Antolín, Mustafa Ozguroglu, Dingwei Ye, Susan Feyerabend, Andrew Protheroe, Giri Sulur, Yesenia Luna, Susan Li, Suneel Mundle, Kim N. Chi
Journal: Journal of Clinical Oncology (2019)

141 Background: The first and second interim analyses (IA1 and IA2) of the LATITUDE study in NDx-HR mCNPC pts with addition of AA+P to ADT vs placebo (PBO)+ADT showed significant benefit in the coprimary endpoints of overall survival (OS) and radiographic progression free survival (rPFS), and secondary endpoints. Final OS analysis and updated safety results are presented. Methods: 1,199 pts were randomized (1:1) to AA (1 g QD) + P (5 mg QD) + ADT or PBO + ADT. Primary endpoint of OS and secondary endpoints were assessed (stratified proportional hazards model), and adverse events (AEs) were summarized from final analysis, which was planned for around 852 total death events. Results: Final analysis was conducted after a median follow-up of 51.8 mo (~22 mo from IA1) and 618 deaths were observed (275 [46%] in AA+P and 343 [57%] in PBO). Treatment was ongoing for 157 (26.3%) pts in AA+P; 72 (12.0%) crossed over from PBO to AA+P, of which 59 (81.9%) remained on treatment. AA+P treatment continued to show significant OS benefits vs PBO (HR: 0.7, 95% CI: 0.6-0.8; p&lt;0.0001), along with significant improvements in secondary endpoints (table). Serious AEs were reported in 32.2% pts in AA+P and 25.1% in PBO. Grade 3/4 AEs of special interest (AA+P vs PBO; %) were hypertension (21.9 vs 10.5), hypokalemia (11.7 vs 1.7), hepatotoxicity (8.9 vs 3.5), cardiac disorders (3.9 vs 1) and fluid retention (0.8 vs 1). Conclusions: The final analysis continues to demonstrate a significant OS advantage of combining AA+P to ADT in NDx-HR mCNPC pts. These efficacy findings and AE profiles are consistent with IA1 and IA2 and reinforce AA+P as a standard of care in NDx-HR mCNPC pts. Clinical trial information: NCT01715285. [Table: see text]
Spermidine Confers Liver Protection by Enhancing NRF2 Signaling Through a MAP1S‐Mediated Noncanonical Mechanism
Authors: Pengfei Liu, Montserrat Rojo de la Vega, Matthew Dodson, Fei Yue, Boyun Shi, Deyu Fang, Eli Chapman, Leyuan Liu, Donna D. Zhang
Journal: Hepatology (2019)

Spermidine (SPD), a naturally occurring polyamine, has been recognized as a caloric restriction mimetic that confers health benefits, presumably by inducing autophagy. Recent studies have reported that oral administration of SPD protects against liver fibrosis and hepatocarcinogenesis through activation of microtubule associated protein 1S (MAP1S)-mediated autophagy. Nuclear factor (erythroid-derived 2)-like 2 (NRF2) is a transcription factor that mediates cellular protection by maintaining the cell's redox, metabolic, and proteostatic balance. In this study, we demonstrate that SPD is a noncanonical NRF2 inducer, and that MAP1S is a component of this noncanonical pathway of NRF2 activation. Mechanistically, MAP1S induces NRF2 signaling through two parallel mechanisms, both resulting in NRF2 stabilization: (1) MAP1S competes with Kelch-like ECH-associated protein 1 (KEAP1) for NRF2 binding through an ETGE motif, and (2) MAP1S accelerates p62-dependent degradation of KEAP1 by the autophagy pathway. We further demonstrate that SPD confers liver protection by enhancing NRF2 signaling. The importance of both NRF2 and p62-dependent autophagy in SPD-mediated liver protection was confirmed using a carbon tetrachloride-induced liver fibrosis model in wild-type, Nrf2-/- , p62-/- and Nrf2-/- ;p62-/- mice, as the protective effect of SPD was significantly reduced in NRF2 or p62 single knockout mice, and completely abolished in the double knockout mice. Conclusion: Our results demonstrate the pivotal role of NRF2 in mediating the health benefit of SPD, particularly in the context of liver pathologies.
First-line (1L) immuno-oncology (IO) combination therapies in metastatic renal cell carcinoma (mRCC): Preliminary results from the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC).
Authors: Shaan Dudani, Jeffrey Graham, Connor Wells, Sumanta K. Pal, Nazli Dizman, Frede Donskov, Georg A. Bjarnason, Aaron Richard Hansen, Marco Adelmo James Iafolla, Ulka N. Vaishampayan, Camillo Porta, Benoit Beuselinck, Flora Yan, Lori Wood, Elizabeth Chien Hern Liow, Christian K. Kollmannsberger, Takeshi Yuasa, Chiyuan A Zhang, Toni K. Choueiri, Daniel Yick Chin Heng
Journal: Journal of Clinical Oncology (2019)

584 Background: In mRCC, ipilimumab and nivolumab (ipi-nivo) is a 1L treatment option. Recent data have also shown efficacy of 1L PD(L)1-VEGF (PV) inhibitor combinations. The efficacy of these two strategies has not been compared. Methods: Using the IMDC dataset, patients (pts) treated with any 1L PV combination were compared to those treated with ipi-nivo. Multivariable Cox regression analysis was performed to control for imbalances in IMDC risk factors. Results: 164 pts received 1L IO combination therapy: 104 treated with PV combinations and 60 with ipi-nivo. Baseline characteristics and IMDC risk factors were comparable between groups (Table). When comparing PV combinations vs ipi-nivo, 1L response rates (RR) were 30% vs 39% (p = 0.29), time to treatment failure (TTF) was 13.2 (95% CI 8.3-16.1) vs 8.5 months (95% CI 5.7-14.0, p = 0.31), and median overall survival (OS) was not reached (NR) (95% CI 19.7-NR) vs NR (95% CI 27.6-NR, p = 0.39). When adjusted for IMDC risk factors, the hazard ratio (HR) for TTF was 0.77 (95% CI 0.44-1.35, p = 0.36) and the HR for death was 0.94 (95% CI 0.33-2.71, p = 0.91). Similar results were seen when restricting the cohort to IMDC intermediate/poor risk pts only. In pts receiving subsequent VEGF TKI monotherapy, second-line (2L) RR (13% vs 45%, p = 0.07) and TTF (5.5 vs 5.4 months, p = 0.80) for PV combinations (n = 15) vs ipi-nivo (n = 20) were not significantly different. Conclusions: There does not appear to be a superior 1L IO combination strategy in mRCC, as PV combinations and ipi-nivo have comparable RR, TTF and OS. Although there is a trend towards differences in RR, there does not appear to be a significant difference in TTF for patients receiving 2L VEGF TKI therapy. [Table: see text]
Abstract P379: Atherosclerotic Abdominal Aortic Plaque and All-Cause Mortality: The Framingham Heart Study
Authors: Philimon N Gona, Farouc A Jaffer, Connie W Tsao, Saadia Qazi, Christopher J O’Donnell, Warren J Manning, Michael L Chuang
Journal: Circulation (2019)

Introduction: Atherosclerotic abdominal aortic plaque (AAP) is often seen incidentally on magnetic resonance (MR) scans. Prevalence and burden of AAP are associated with cardiovascular disease (CVD) risk factors, but the relationship between AAP and all-cause mortality (“Death”) is not well characterized. We sought to determine whether AAP predicts Death among community-dwelling adults initially without clinically overt CVD. Methods: 318 Framingham Offspring cohort members (age 60±9 yrs, 51% women) underwent noncontrast abdominal MR at 1.5 Tesla in 1998-1999. Participants were recruited from equal strata of age, sex and quintile of Framingham Risk Score (FRS), with double sampling of the top quintile. MR used ECG-triggered black-blood T2W turbo spin-echo with 1.03 x 0.64 x 5-mm 3 voxels. AAP was hand-traced and comprised discrete protrusions of ≥1mm into the aortic lumen. Participants were stratified into three levels of AAP: zero (AAP0); then among those with nonzero-AAP, subdivided into below median (AAP1) and above median (AAP2). FRS was calculated for each participant (using age, sex, systolic blood pressure, total and HDL cholesterol, diabetes, smoking); A Cox proportional hazards model adjusted for standardized, log-transformed FRS (zFRS) was used to determine hazard ratio (HR) for Death with AAP0 as the referent. The log-rank test was used to compare event-free survival. Results: AAP by MR was present in 40.4% of women and 42.1% of men. Over a median 14.8 years of follow up, there were 52 Deaths (5 CVD, 22 cancer, 25 other causes). AAP2 had HR=2.08 (95% CI 1.07 - 4.08, p=0.03); AAP1 was HR=1.37 (CI=0.65 - 2.92, p=0.4). The figure shows the Kaplan-Meier plot for survival; log-rank p=0.034. Conclusions: Among adults initially free of clinically overt CVD, above median burden of AAP was associated with 2-fold greater hazard of all-cause mortality. Although the majority of deaths were not principally due to CVD, excess AAP was a predictor of mortality over nearly 15 year follow up.
During weight-loss maintenance, energy expenditure was higher with lower-carbohydrate diets
Authors: Scott Kahan
Journal: Annals of Internal Medicine (2019)

ACP Journal Club19 March 2019During weight-loss maintenance, energy expenditure was higher with lower-carbohydrate dietsScott Kahan, MD, MPHScott Kahan, MD, MPHJohns Hopkins Bloomberg School of Public Health, Washington, DC, USA (S.K.)Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/ACPJ201903190-031 SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail Source CitationEbbeling CB, Feldman HA, Klein GL, et al. Effects of a low carbohydrate diet on energy expenditure during weight loss maintenance: randomized trial. BMJ. 2018;363:k4583. https://pubmed.ncbi.nlm.nih.gov/30429127Clinical Impact RatingsGIM/FP/GP: Public Health: References1 Hall KD, Kahan S. Maintenance of lost weight and long-term management of obesity. Med Clin North Am. 2018;102:183-97. [PMID: 29156185] Google Scholar2 Hall KD, Guo J. Obesity energetics: body weight regulation and the effects of diet composition. Gastroenterology. 2017;152:1718-27.e3. [PMID: 28193517] Google Scholar3 Jensen MD, Ryan DH, Apovian CM, et al; American College of Cardiology/American Heart Association Task Force on Practice Guidelines. 2013 AHA/ACC/TOS guideline for the management of overweight and obesity in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and The Obesity Society. Circulation. 2014;129:S102-38. [PMID: 24222017] Google Scholar4 Hall KD, Guo J. Carbs versus fat: does it really matter for maintaining lost weight? BioRxiv. 2018. doi.org/10.1101/476655 (accessed 2 Jan 2019). Google Scholar Author, Article, and Disclosure InformationAffiliations: Johns Hopkins Bloomberg School of Public Health, Washington, DC, USA (S.K.)This article was published at Annals.org on 5 March 2019. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics 19 March 2019Volume 170, Issue 6Page: JC31KeywordsBioenergeticsBody weightCarbohydratesDietExerciseFatsProteinsSodiumWeight gainWeight loss ePublished: 19 March 2019 Issue Published: 19 March 2019 Copyright & PermissionsCopyright © 2019 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...
Abstract P046: Baseline Insulin Sensitivity From Oral Glucose Tolerance Test Are Associated With Incident Dyslipidemia: The Ansan-Ansung Community Cohort Study
Authors: Ju-mi Lee, kyoung Min Kim, Soo Lim
Journal: Circulation (2019)

Introduction: Insulin resistance and dyslipidemia are often comorbid. Although possible biochemical explanations exist, there is still too small community based longitudinal data to support the theory directly. Objectives: This study aimed to test the association between the baseline of insulin sensitivity from oral glucose tolerance test (OGTT) and the incidence of dyslipidemia in a community cohort. Secondly, we tested which lipidemia profile is associated with tertiles of Matsuda index. Methods: Participants (n=3899; aged 40-69 years, during visit1 to 7, mean follow-up for 12 years) were recruited from the Ansan-Ansung cohort study, a subset of Korean Genome Epidemiology Study. OGTT were measured at baseline examination. Baseline Matsuda index was calculated by the formula 10 4 /((GLU0xINS0xGLU60xINS60) 0.5 ). We then used tertiles of Matsuda index. The associations of Matsuda index tertiles with the incidence of dyslipidemia and each component of the lipid profile during 12 years were assessed by logistic regression. Age, body mass index, alcohol drinking, cigarette smoking, c reactive protein, education level, and income were adjusted at the final model. Results: Tertile groups were divided: low tertile(&lt;6.25, N=1306, 33.50%), tertile 2 (6.25-10.89, N=1277, 32.75%), and tertile 3(≥10.89, N=1316, 33.75%). Low tertile (referent: tertile2) was associated with greater incident dyslipidemia in total before (OR=1.39, 1.13-1.72) and after adjustment (OR=1.26, 1.02-1.57). Low tertile was associated with greater incident triglycerides≥200mg/dl in total (OR=1.33, 1.10-1.62), women (OR=1.35, 1.01-1.81) and men (OR=1.34, 1.03-1.74) before and adjustment. However low tertile was not associated with other dyslipidemia profiles such as HDL, LDL, and total cholesterol. Conclusions: Low tertile of insulin sensitivity at baseline had increased associations with future incidence of dyslipidemia especially with triglycerides component.
Eltrombopag for Moderate Aplastic Anemia and Unilineage Cytopenias: Dosing, Long-Term Follow-up, Clonal Evolution and Somatic Mutation Profiling
Authors: Xing Fan, Thomas Winkler, Ronan Desmond, Bogdan Dumitriu, Danielle M. Townsley, Maria del Pilar Fernandez Ibanez, Fernanda Gutierrez-Rodrigues, Sophia Grasmeder, Ma Evette Barranta, Diane Madey, Jennifer Lotter, Janet Valdez, Katherine R. Calvo, Colin Wu, Neal S. Young, Cynthia E. Dunbar
Journal: Blood (2018)
Assessing Long-Term Survival Benefits of Immune Checkpoint Inhibitors Using the Net Survival Benefit
Authors: Julien Péron, Alexandre Lambert, Stephane Munier, Brice Ozenne, Joris Giai, Pascal Roy, Stéphane Dalle, Abigirl Machingura, Delphine Maucort-Boulch, Marc Buyse
Journal: JNCI Journal of the National Cancer Institute (2019)

The treatment effect in survival analysis is commonly quantified as the hazard ratio, and tested statistically using the standard log-rank test. Modern anticancer immunotherapies are successful in a proportion of patients who remain alive even after a long-term follow-up. This new phenomenon induces a nonproportionality of the underlying hazards of death.The properties of the net survival benefit were illustrated using the dataset from a trial evaluating ipilimumab in metastatic melanoma. The net survival benefit was then investigated through simulated datasets under typical scenarios of proportional hazards, delayed treatment effect, and cure rate. The net survival benefit test was computed according to the value of the minimal survival difference considered clinically relevant. As comparators, the standard and the weighted log-rank tests were also performed.In the illustrative dataset, the net survival benefit favored ipilimumab [Δ(0) = 15.8%, 95% confidence interval = 4.6% to 27.3%, P = .006]. This favorable effect was maintained when the analysis was focused on long-term survival differences (eg, >12 months, Δ(12) = 12.5% (95% confidence interval = 4.4% to 20.6%, P = .002). Under the scenarios of a delayed treatment effect and cure rate, the power of the net survival benefit test compared favorably to the standard log-rank test power and was comparable to the power of the weighted log-rank test for large values of the threshold of clinical relevance.The net long-term survival benefit is a measure of treatment effect that is meaningful whether or not hazards are proportional. The associated statistical test is more powerful than the standard log-rank test when a delayed treatment effect is anticipated.
Development of an imaging approach to detect splice variants of androgen receptor in prostate cancer.
Authors: Yusuke Imamura, Amy H Tien, Jian Kunzhong, Jinhe Pan, Kuo-Shyan Lin, Raymond J Andersen, Marianne Sadar
Journal: Journal of Clinical Oncology (2015)

5058 Background: Resistance to therapies that target androgen receptor (AR) ligand-binding domain (LBD) in prostate cancer patients may be due to expression of constitutively active AR splice variants that lack LBD. EPI small molecules bind to activation function-1 (AF-1) in the AR amino-terminal domain (NTD). Development of a radiolabeled analogue, 123I-EPI, may be useful for imaging prostate cancer using single-photon emission computed tomography (SPECT). Currently AR is imaged with positron emission tomography with 16β-[18F]-fluoro-5α dihydrotestosterone (18F-FDHT) that binds to AR LBD. 18F-FDHT cannot detect AR splice variants lacking LBD. Our approach would employ sequential imaging with 18F-FDHT to detect solely full-length (fl)-AR and 123I-EPI to detect NTD of both fl-AR and variant AR. Discordant distribution or level of uptake between 18F-FDHT and 123I-EPI may reveal expression of AR splice variants lacking LBD. Methods: Specific activity against AR by I-EPI was confirmed in cells using reporter gene constructs for AR and related steroid hormone receptors. Binding experiments were done using 123I-EPI with recombinant AF-1 and fl-AR proteins, as well as to endogenous fl-AR and variant AR in cells. Evaluation of 123I-EPI in whole-body distribution included dosimetry in xenografts by small animal SPECT imaging; and temporal evaluation of 123I-EPI uptake and clearance by quantifying 123I in harvested organs. Results: In cell-based assays, I-EPI was specific for AR and blocked the activity of an AR-driven reporter, while having no effect on transcriptional activities of other steroid hormone receptors. 123I-EPI covalently binds specifically to AR in living cells and to recombinant fl-AR and AR AF-1. Whole body SPECT imaging showed preferential uptake in LNCaP95 human prostate cancer xenografts that express AR while negligible uptake was observed in PC3 xenografts that lack functional AR. Conclusions: An AR NTD-targeted molecular imaging probe such as 123I-EPI may be useful to select patients for subsequent antiandrogen therapies, monitor treatment response, and provide insight into the role of all AR species in resistance mechanisms.
Anti-commensal IgG Drives Intestinal Inflammation and Type 17 Immunity in Ulcerative Colitis
Authors: Tomas Castro-Dopico, Thomas W. Dennison, John R. Ferdinand, Rebeccah J. Mathews, Aaron Fleming, Dean Clift, Benjamin J. Stewart, Chenzhi Jing, Konstantina Strongili, Larisa I. Labzin, Edward J.M. Monk, Kourosh Saeb-Parsy, Clare E. Bryant, Simon Clare, Miles Parkes, Menna R. Clatworthy
Journal: Immunity (2019)
Outcomes of the miltuximab first in human trial and proposed study design for a phase I trial <sup>89</sup>Zr/<sup>177</sup>Lu theranostic trial.
Authors: Douglas Campbell, Dhanusha Sabanathan, Howard Gurney, David Gillatt, Marko Trifunovic, Pirooz Poursoultan, Kevin Ho Shon, Tiffany Mackay, Dale L Bailey, Paul Roach, Brad Walsh
Journal: Journal of Clinical Oncology (2019)

261 Background: Miltuximab is a chimeric antibody targeting Glypican-1 which is overexpressed in prostate cancer. Miltuximab has shown promising safety and efficacy in radioimmunotherapy models of prostate cancer. Methods: Metastatic patients (prostate, pancreatic and bladder) were dosed with unlabelled Miltuximab followed by the infusion of 1 mg/250MBq 67 Ga-Miltuximab. Patients underwent whole body gamma and SPECT/CT scans up to 144 hours post-infusion. Standard of care imaging was performed at least 14 days before and after participation. Safety was evaluated by an external monitoring committee. Total organ exposure was determined by dosimetry of whole-body gamma scans. Antibody pharmacokinetics were also determined. Results: 12 patients were enrolled into the trial. Miltuximab was well tolerated and did not elicit any drug-related adverse reactions. Liver and spleen uptake of 67 Ga-Miltuximabwas observed from 30 min to 72 hours post dose. Pre-infusion of unlabelled Miltuximab resulted in reduced liver accumulation and increased distribution in the rest of the body. Miltuximab targeting to sites of active progressive disease was observed in certain prostate cancer patients who had failed enzalutamide treatment. Dosimetry analysis combined with antibody pharmacokinetic data was used to establish safe dose limits for a Phase 1 study. Conclusions: This study is the first in human for Miltuximab and demonstrates its potential for further clinical evaluation as a theranostic in prostate cancers and formed the basis for a Phase I imaging and therapy study planned for 2019. This study will use 89 Zr-labelled Miltuximab to screen eligible patients and confirm tumour localisation, followed by treatment with 177 Lu-labelled Miltuximab. Clinical trial information: ACTRN12616000787482.
The Making of a PreCancer Atlas: Promises, Challenges, and Opportunities
Authors: Sudhir Srivastava, Sharmistha Ghosh, Jacob Kagan, Richard Mazurchuk, Emily Boja, Rodrigo Chuaqui, Eric Chavarria-Johnson, Tanja Davidsen, Janet Eary, Todd Haim, Sean Hanlon, Stephen Hewitt, Shannon Hughes, Paula Jacobs, Jerry Li, Tracy Lively, Stephen Lockett, Tom Misteli, Stefanie Nelson, Hana Odeh, Miguel Ossandon, Sonia Rosenfield, Goli Samimi, Jack Shern, Rob Star, Naoko Takebe, Norbert Tavares, James Tricoli, Ted Trimble, Asad Umar, Jose Velazquez, Chiayeng Wang, JC Zenklusen, Philipp Oberdoerffer, Jerry Lee, Nicholas Kenney
Journal: Trends in cancer (2019)
Mri and Thallium-201 Spect in the Prediction of Outcome in Glioma Therapy
Authors: M.J. Vos, J. Berkhof, O.S. Hoekstra, I. Bosma, E.M. Sizoo, J.J. Heimans, J.C. Reijneveld, E. Sanchez, F.J. Lagerwaard, J. Buter, D.P. Noske, T.J. Postma
Journal: Neuro-Oncology (2010)
Иммунологическая реактивность у больных хроническими диффузными заболеваниями печени
Authors: O.M. Tatarchuk, V.I. Didenko, S.L. Melanich, V.Ye. Kudryavtseva
Journal: GASTROENTEROLOGY (2019)

Цель: оценить состояние основных показателей клеточного иммунитета и уровень цитокинов у больных хроническими диффузными заболеваниями печени (ХДЗП). Материалы и методы. Обследовано 68 пациентов с ХДЗП, которые были распределены на 4 группы в зависимости от этиологических факторов формирования и прогрессирования стеатоза и фиброза печени: І группа — 36 больных неалкогольной жировой болезнью печени; ІІ группа — 13 больных хроническим вирусным гепатитом, ассоциированным с вирусом С; ІІІ группа — 14 больных алкогольной болезнью печени, ІV группа — 5 больных токсическим гепатитом. Проводили изучение основных показателей клеточного иммунитета и уровня интерлейкина (ИЛ) 6, ИЛ-10 и фактора некроза опухоли альфа. Результаты. У 83,3 % больных I группы, 76,9 % больных II группы и половины больных III группы наблюдали значительное снижение Т-хелперной субпопуляции. Недостаточность клеточного иммунитета у больных с ХДЗП способствует формированию стеатоза. У 69,2 % больных II группы установленные нарушения иммунорегуляции указывают на персистенцию вируса гепатита С и, как следствие, развитие фиброза. Согласно полученным результатам, у больных I, II и IV групп концентрация фактора некроза опухоли альфа достоверно превышает контрольные значения в 6,9, 7,9 и 11,0 раза соответственно (р &lt; 0,05). Уровень ИЛ-6 достоверно выше в 3,9 раза (р &lt; 0,05) у больных I группы по сравнению с IV группой больных. Это указывает на прогрессирование иммунопатологического процесса и является патогенетическим признаком неадекватности функционирования иммунной системы при ХДЗП. Выводы. Установлено, что прогрессирование стеатоза печени сопровождается недостаточностью клеточного звена иммунитета и повышением уровня провоспалительных цитокинов.