tbuckley/cabot-search huggingface dataset:
Epacadostat plus pembrolizumab in patients with advanced urothelial carcinoma: Preliminary phase I/II results of ECHO-202/KEYNOTE-037.
Authors: David C. Smith, Thomas Gajewski, Omid Hamid, Jeffrey S. Wasser, Anthony J. Olszanski, Sandip P. Patel, Ronac Mamtani, Emmett V. Schmidt, Yufan Zhao, Janet E. Maleski, Tara C. Gangadhar
Journal: Journal of Clinical Oncology (2017)

4503 Background: Pembrolizumab (P), a PD-1 inhibitor, is active and well tolerated in platinum-treated, advanced urothelial carcinoma (UC). Epacadostat (E) potently and selectively inhibits indoleamine 2,3-dioxygenase 1 (IDO1), a tryptophan-catabolizing enzyme that suppresses T-cell–mediated immune surveillance. IDO1 overexpression is associated with tumor progression and shortened patient (pt) survival. ECHO-202/KEYNOTE-037 is an open-label, phase I/II study of E + P in pts with advanced tumors. We report phase I/II efficacy and safety outcomes for the UC cohort at an October 29, 2016 data cutoff. Methods: Adult pts with advanced UC, prior platinum therapy (adjuvant or advanced disease setting) or alternative therapy (if platinum was not appropriate), and no prior checkpoint inhibitor therapy were eligible to participate. In phase I, pts received E (25, 50, 100, or 300 mg PO BID) + P (2 mg/kg or 200 mg IV Q3W); MTD was not exceeded. E (100 mg BID) + P (200 mg Q3W) dosing was selected for phase II. Response was assessed in RECIST 1.1–evaluable pts. Safety was assessed in pts receiving ≥1 E + P dose. Results: A total of 40 pts (phase I, n = 5; phase II, n = 35) were evaluated. Median age was 67 years, 75% were men, 88% were white, 100% had prior platinum therapy, and 75% had 0–1 prior line of therapy for advanced disease. Preliminary ORR (CR+PR) and DCR (CR+PR+SD) for all efficacy-evaluable pts were 35% (13/37; all PR) and 57% (21/37; 13 PR, 8 SD), respectively; for pts with 0–1 prior line of therapy for advanced disease, ORR and DCR were 37% (10/27) and 63% (17/27). At data cutoff, 12/13 responses were ongoing (range, 1+ to 652+ days). PFS and biomarker analyses are ongoing. The most common TRAEs (≥10% of 40 pts) were fatigue (28%), rash (18%), and increased amylase (10%; asymptomatic). Grade ≥3 TRAEs occurred in 20% of pts (rash was the only grade ≥3 TRAE to occur in &gt; 1 pt [n = 3]). Three pts discontinued due to TRAEs (grade 3 rash [n = 1]; grade 3 COPD exacerbation [n = 1], grade 2 diarrhea [n = 1]). Conclusions: E + P was generally well tolerated and associated with increased response compared with previously reported PD-1 inhibitor monotherapy in pts with advanced UC. A phase III UC study is planned. Clinical trial information: NCT02178722.
Natural History of Subclinical Neovascularization in Nonexudative Age-Related Macular Degeneration Using Swept-Source OCT Angiography
Authors: João R. de Oliveira Dias, Qinqin Zhang, José M.B. Garcia, Fang Zheng, Elie H. Motulsky, Luiz Roisman, Andrew Miller, Chieh-Li Chen, Sophie Kubach, Luis de Sisternes, Mary K. Durbin, William Feuer, Ruikang K. Wang, Giovanni Gregori, Philip J. Rosenfeld
Journal: Ophthalmology (2017)
Endocrine Disruptors and Health Effects in Africa: A Call for Action
Authors: Maria S. Bornman, Natalie H. Aneck-Hahn, Christiaan de Jager, Gesina M. Wagenaar, Hindrik Bouwman, Irene E.J. Barnhoorn, Sean M. Patrick, Laura N. Vandenberg, Andreas Kortenkamp, Bruce Blumberg, Sarah Kimmins, Bernard Jegou, Jacques Auger, Joseph DiGangi, Jerrold J. Heindel
Journal: Environmental Health Perspectives (2017)

Background: Africa faces a number of unique environmental challenges. Unfortunately, it lacks the infrastructure needed to support the comprehensive environmental studies that could provide the scientific basis to inform environmental policies. There are a number of known sources of endocrine-disrupting chemicals (EDCs) and other hazardous chemicals in Africa. However, a coordinated approach to identify and monitor these contaminants and to develop strategies for public health interventions has not yet been made. Objectives: This commentary summarizes the scientific evidence presented by experts at the First African Endocrine Disruptors meeting. We describe a “call to action” to utilize the available scientific knowledge to address the impact of EDCs on human and wildlife health in Africa. Discussion: We identify existing knowledge gaps about exposures to EDCs in Africa and describe how well-designed research strategies are needed to address these gaps. A lack of resources for research and a lag in policy implementation slows down intervention strategies and poses a challenge to advancing future health in Africa. Conclusion: To address the many challenges posed by EDCs, we argue that Africans should take the lead in prioritization and evaluation of environmental hazards, including EDCs. We recommend the institution of education and training programs for chemical users, adoption of the precautionary principle, establishment of biomonitoring programs, and funding of community-based epidemiology and wildlife research programs led and funded by African institutes and private companies. https://doi.org/10.1289/EHP1774
Ancestry-based differences in hereditary cancer genetic testing.
Authors: Olufunmilayo I. Olopade, Sarah Nielsen, Shengfeng Wang, Ryan Bernhisel, Krystal Brown, Hannah C Cox, Shelly Cummings, Eric Thomas Rosenthal, Jennifer Saam, Johnathan M. Lancaster, Dezheng Huo
Journal: Journal of Clinical Oncology (2017)

e13107 Background: Ancestry-based disparities in genetic testing for the hereditary breast and ovarian cancer (HBOC) genes BRCA1/2 have been well documented, but it is unclear whether this extends to other cancer-risk genes. Given reduced costs and broader access to multi-gene panels, we evaluated ancestry-based differences in the utilization and outcomes of HBOC and pan-cancer panel testing. Methods: Individuals who had genetic testing for BRCA1/2only (2006-2016) or with a multi-gene pan-cancer panel (2013-2016) were assessed. Clinical information was obtained from provider-completed test request forms. The most commonly reported ancestries [European (EU), Latin American/Caribbean (LA/C), African (AF), Asian (AS)] were evaluated. Individuals of Ashkenazi Jewish ancestry were not included in the EU group. Results: The relative utilization of HBOC testing in 2013-2016 increased in AF and LA/C individuals (vs 2006-2013) and was similar to panel testing in all ancestries (Table). The positive mutation rate for panel testing was 6.7%; AF (6.4%), LA/C (6.6%), AS (7.1%), EU (7.1%). The positive rate for HBOC testing from 2006-2013 was 5.7%. Of significance, the HBOC positive rate from 2013-2016 dropped to 4.1% and ancestry-specific positive rates were much lower relative to panel testing (Table). Gene-specific mutation prevalence differed by ancestry, but mutations were identified in a wide range of genes for all ancestries. Possible founder mutations were identified in BRCA1/2 and other genes. Conclusions: In this cohort, broader access to genetic testing has reduced disparities in recent years and panel testing shows improved clinical utility relative to HBOC testing in all ancestries. [Table: see text]
SMYD5 Controls Heterochromatin and Chromosome Integrity during Embryonic Stem Cell Differentiation
Authors: Benjamin L. Kidder, Runsheng He, Darawalee Wangsa, Hesed M. Padilla-Nash, M. Margarida Bernardo, Shijie Sheng, Thomas Ried, Keji Zhao
Journal: Cancer Research (2017)

Abstract Epigenetic regulation of chromatin states is thought to control gene expression programs during lineage specification. However, the roles of repressive histone modifications, such as trimethylated histone lysine 20 (H4K20me3), in development and genome stability are largely unknown. Here, we show that depletion of SET and MYND domain–containing protein 5 (SMYD5), which mediates H4K20me3, leads to genome-wide decreases in H4K20me3 and H3K9me3 levels and derepression of endogenous LTR- and LINE-repetitive DNA elements during differentiation of mouse embryonic stem cells. SMYD5 depletion resulted in chromosomal aberrations and the formation of transformed cells that exhibited decreased H4K20me3 and H3K9me3 levels and an expression signature consistent with multiple human cancers. Moreover, dysregulated gene expression in SMYD5 cancer cells was associated with LTR and endogenous retrovirus elements and decreased H4K20me3. In addition, depletion of SMYD5 in human colon and lung cancer cells results in increased tumor growth and upregulation of genes overexpressed in colon and lung cancers, respectively. These findings implicate an important role for SMYD5 in maintaining chromosome integrity by regulating heterochromatin and repressing endogenous repetitive DNA elements during differentiation. Cancer Res; 77(23); 6729–45. ©2017 AACR.
An open-label study of rovalpituzumab tesirine in patients with DLL3-expressing advanced solid tumors.
Authors: Edward Kavalerchik, Satwant Lally, Tae H. Han, Laura R. Saunders, Sheila Bheddah, Scott J. Dylla
Journal: Journal of Clinical Oncology (2017)

TPS2597 Background: Delta-like protein 3 (DLL3) is an inhibitory ligand of the Notch receptor family. It is highly expressed in high-grade neuroendocrine carcinoma (NEC), such as small cell lung cancer (SCLC) and large cell NEC (LCNEC), but is not expressed in normal tissue. DLL3 is expressed in melanoma, glioblastoma (GBM), neuroendocrine prostate, medullary thyroid carcinoma (MTC), and other solid cancers. Rovalpituzumab tesirine (Rova-T™) is an antibody-drug conjugate targeting DLL3, composed of a DLL3-specific IgG1 monoclonal antibody joined to a toxic DNA cross-linking agent by a cleavable linker. Rova-T binds to DLL3 on target-expressing cells, is internalized and cleaved, releasing the toxin to induce cell death. A Phase 1 study of Rova-T in SCLC showed encouraging antitumor activity in DLL3-high patients (pts), and was well-tolerated (Rudin et al., Lancet Oncol, 2016). As novel therapies are needed for multiple cancers that express DLL3, Rova-T may be effective in these tumors. Methods: This is a Phase 1/2, open-label, multicenter study (NCT02709889) with 8 cohorts of pts (up to ~318 total, 14 pts enrolled as of 20 January 2017) with melanoma, MTC, GBM, LCNEC, neuroendocrine prostate cancer, gastroenteropancreatic NEC, other NEC, or other solid tumor. In Part A, a 3+3 dose escalation will be used. Rova-T 0.2, 0.3, or 0.4 mg/kg will be given on Day 1 of each 42-day cycle. Dose-limiting toxicities (DLTs) will be assessed over a 21-day period. Dose escalation will proceed within cohort until a maximum tolerated dose is reached. Part B expansion, Stage 1, will explore the recommended dose in 7 pts in disease specific cohorts. Stage 2 will use an adaptive 2-stage design to determine sample size. Pt eligibility: ≥ 18 years; histologically confirmed, measurable, advanced solid tumor; relapsed/refractory to prior standard therapy; ECOG 0-1; no prior exposure to a pyrrolobenzodiazepine-based drug. Primary objective: assess safety and tolerability of Rova-T. Secondary objectives: explore Rova-T antitumor activity, pharmacokinetics, and incidence of anti-therapeutic antibodies. Exploratory objectives: explore the relationship between DLL3 and clinical outcome, and effects on biomarkers and pharmacodynamics. Clinical trial information: NCT02709889.
CONCEPT provides robust evidence that chondroitin sulfate is superior to placebo and similar to celecoxib in the symptomatic management of osteoarthritis
Authors: Jean-Yves L Reginster
Journal: Annals of the Rheumatic Diseases (2017)

We are very grateful to our distinguished colleague for his constructive comments.1 However it seems that some keypoints of our study were grossly misunderstood.2 As clearly stated, the objective of the CONCEPT study was to confirm that chondroitin sulfate (CS) is superior to placebo (PLB) in the symptomatic treatment of osteoarthritis, with the addition of a Celebrex (CLB) arm, as requested by the European Medicines Agency, to provide an external validation and to better assess the relevance of the difference in pain relief observed between the CS and PLB arms. There was no intent to demonstrate a non-inferiority of CS versus Celebrex. In such a case, a non-inferiority margin for the comparison would be mentioned in the protocol, and the power calculation would be substantially different. The use of the word similar in describing Visual Analogue Scale (VAS) and Lequesne scoring …
Abstract P196: The Impact of MicroRNA195 on the Lkb1/AMPK Signaling Axis and Hypertrophic Cardiomyopathy
Authors: Hao Chen, Laurel Mckee, Gustavo Untiveros, Jessica Perez, John Konhilas
Journal: Circulation Research (2011)

Objectives: MicroRNAs (miRs) have been identified as chief post-transcriptional regulators of cardiac disease progression. In addition, a critical role of the adenosine monophosphate-activated kinase (AMPK) pathway in the development of myocardial hypertrophy has been revealed. Yet, regulation of the AMPK pathway by miRs in the heart has not been addressed. We hypothesized that components of the AMPK pathway are targeted by miRs and alter AMPK signaling in a mouse model of hypertrophic cardiomyopathy (HCM). Methods and results: Using real-time PCR, a candidate miR screen that included 22 miRs implicated in pathological cardiac disease and/or metabolic dysregulation was performed on hearts from 60-, 120-, and 240-day-old transgenic HCM male mice harboring an R403Q mutation in the myosin heavy gene. Among early (60 day) elevated miRs were miR-195 and -451. Both miR-195 and -451 have conserved target sites in the 3′ UTR of CAB39 (MO25), a central component of the MO25/STRAD/LKB1 complex that acts as an upstream kinase for AMPK and its subsequent activation. We further confirmed the elevation of miR-195 and -451 by Northern blotting. Next, we demonstrated specific expression and a similar distribution pattern of miR-195 and -451 in cardiomyocytes of R403Q HCM hearts by in situ hybridization. To determine whether the conserved sites in MO25 3′ UTR acted as functional targets, either the miR-195 or miR-451 target sequence was cloned into a luciferase expression vector. MiR-195 but not miR-451 suppressed luciferase activity compared to the missense sequence control vector in C2C12 cells. In addition, over-expression of miR195 in C2C12 cells knocked down MO25 expression levels and downstream AMPK signaling (phosphorylation of Acetyl CoA carboxylase). Finally, parallel changes were measured in 60 day R403Q HCM male hearts that included reduced MO25 expression and lowered phosphorlation of AMPK and Acetyl CoA carboxylase. Conclusion: Our findings indicate that miR-195 targets the LKB1/AMPK signaling axis and suggest a functional role for miR-195 elevation in R403Q HCM disease progression.
Downregulation of DNMT3A by miR-708-5p Inhibits Lung Cancer Stem Cell–like Phenotypes through Repressing Wnt/β-catenin Signaling
Authors: Tianchi Liu, Xiaoping Wu, Tong Chen, Zewei Luo, Xiaohua Hu
Journal: Clinical Cancer Research (2017)

Abstract Purpose: Lung cancer is the leading cause of cancer-related death in the world, and emerging evidences suggest that lung cancer stem cells (CSC) are associated with its poor prognosis, tumor recurrence, and therapy resistance. Here we reveal a novel role for miR-708-5p in inhibiting lung CSC–like features. Experimental Design: Phenotypic effects of miR-708-5p on the lung CSC–like properties were examined by in vitro sphere formation assay and in xenografted animal models. Immunoblotting, dual luciferase reporter, and immunocytochemistry were performed to determine the target of miR-708-5p. DNA methylation of CDH1 promoter region was tested using bisulfate sequencing. Genome-wide miRNA sequencing data of 990 patients from The Cancer Genome Atlas (TCGA) dataset and 148 patients from China cohort were analyzed to excavate the pathogenic implications of miR-708-5p. Results: Expression of miR-708-5p inhibits the CSC traits of NSCLC cells in vitro while antagonizing miR-708-5p promotes tumorigenesis in vivo. miR-708-5p directly suppresses the translation of DNMT3A, which results in a substantial reduction of global DNA methylation and the upregulated expression of tumor suppressor CDH1. The upregulation of CDH1 decreased the activity of Wnt/β-catenin signaling and then impaired the stemness characteristics of NSCLC cells. Clinically, patients with high miR-708-5p expression show significantly better survival and lower recurrence. Furthermore, miR-708-5p has a promising potential to apply to differentiating histologic subtypes in NSCLC. Conclusions: Our findings support that miR-708-5p suppresses NSCLC initiation, development, and stemness through interfering DNMT3A-dependent DNA methylation. miR-708-5p may function as a novel diagnostic and prognostic biomarker in NSCLC. Clin Cancer Res; 24(7); 1748–60. ©2017 AACR.
PD-1 Expression in Head and Neck Squamous Cell Carcinomas Derives Primarily from Functionally Anergic CD4+ TILs in the Presence of PD-L1+ TAMs
Authors: Austin K. Mattox, Jina Lee, William H. Westra, Robert H. Pierce, Ronald Ghossein, William C. Faquin, Thomas J. Diefenbach, Luc G. Morris, Derrick T. Lin, Lori J. Wirth, Armida Lefranc-Torres, Eiichi Ishida, Patrick D. Chakravarty, Lauren Johnson, Yang C. Zeng, Huabiao Chen, Mark C. Poznansky, Neil M. Iyengar, Sara I. Pai
Journal: Cancer Research (2017)

Oral tongue squamous cell carcinoma (OTSCC) is the most common oral cavity tumor. In this study, we examined the basis for the activity of programmed cell death protein (PD-1)-based immune checkpoint therapy that is being explored widely in head and neck cancers. Using multispectral imaging, we systematically investigated the OTSCC tumor microenvironment (TME) by evaluating the frequency of PD-1 expression in CD8+, CD4+, and FoxP3+ tumor-infiltrating lymphocytes (TIL). We also defined the cellular sources of PD-1 ligand (PD-L1) to evaluate the utility of PD-1:PD-L1 blocking antibody therapy in this patient population. PD-L1 was expressed in 79% of the OTSCC specimens examined within the TME. Expression of PD-L1 was associated with moderate to high levels of CD4+ and CD8+ TILs. We found that CD4+ TILs were present in equal or greater frequencies than CD8+ TILs in 94% of OTSCC and that CD4+FOXP3neg TILs were colocalized with PD-1/PD-L1/CD68 more frequently than CD8+ TILs. Both CD4+PD1+ and CD8+PD1+ TILs were anergic in the setting of PD-L1 expression. Overall, our results highlight the importance of CD4+ TILs as pivotal regulators of PD-L1 levels and in determining the responsiveness of OTSCC to PD1-based immune checkpoint therapy. Cancer Res; 77(22); 6365-74. ©2017 AACR.
PTH-135 Patients’ perceptions of constipation differ strikingly from those of both general practitioners and gastroenterology specialists, and there is no consistent agreement with the rome iv criteria
Authors: E Dimidi, A Hovanov, C Cox, S Neville, R Grant, SM Scott, K Whelan
Journal: Gut (2017)

Introduction  Although constipation is a prevalent condition, it is unclear whether patients’ and doctors’ perceptions of the definition of constipation agree with each other or with formal diagnostic criteria.  Method  A survey was conducted to compare the perceptions of constipation diagnosis within the adult general population (with and without constipation), gastroenterology specialists (gastroenterologists, coloproctologists) and General Practitioners (GPs). Symptoms considered important in diagnosing constipation, together with 10 case studies based on the Rome IV criteria were investigated.  Results  2257 members of the general population (1623 self-reported constipation, 934 without), 365 gastroenterology specialists and 411 GPs completed the survey. Only a minority of the general population considered the Rome IV symptoms important for diagnosing constipation (Table 1). Infrequent bowel movements were most frequently reported as important by GI specialists (65%), compared with less than half of GPs (41%) and less than a third of the constipated general population (26%) (p  In the 10 case studies, correct diagnoses were made by doctors (GPs and GI specialists) on 79%–80% of occasions. However, on average, the absence of constipation was correctly identified by doctors in 85%–92% of the cases without constipation, whereas the presence of constipation was correctly identified in only 60%–70% of the cases with constipation.  Conclusion  There are striking differences in the symptoms consistent with constipation between the general population, gastroenterology specialists and GPs, and variable agreement with the Rome IV criteria. These differences have major implications for patient care and satisfaction with treatment. The findings reinforce the need to re-evaluate current diagnostic criteria for constipation and to ensure these are communicated widely.  Disclosure of Interest  None Declared
A Novel Breast Cancer Index for Prediction of Distant Recurrence in HR+ Early-Stage Breast Cancer with One to Three Positive Nodes
Authors: Yi Zhang, Brock E. Schroeder, Piiha-Lotta Jerevall, Amy Ly, Hannah Nolan, Catherine A. Schnabel, Dennis C. Sgroi
Journal: Clinical Cancer Research (2017)

Purpose: The study objective was to characterize the prognostic performance of a novel Breast Cancer Index model (BCIN+), an integration of BCI gene expression, tumor size, and grade, specifically developed for assessment of distant recurrence (DR) risk in HR+ breast cancer patients with one to three positive lymph nodes (pN1).Experimental Design: Analysis was conducted in a well-annotated retrospective series of pN1 patients (N = 402) treated with adjuvant endocrine therapy with or without chemotherapy using a prespecified model. The primary endpoint was time-to-DR. Results were determined blinded to clinical outcome. Kaplan-Meier estimates of overall (0-15 years) and late (≥5 years) DR, HRs, and 95% confidence interval (CIs) were estimated. Likelihood ratio statistics assessed relative contributions of prognostic information.Results: BCIN+ classified 81 patients (20%) as low risk with a 15-year DR rate of 1.3% (95% CI, 0.0%-3.7%) versus 321 patients as high risk with a DR rate of 29.0% (95% CI, 23.2%-34.4%). In patients DR-free for ≥5 years (n = 349), the late DR rate was 1.3% (95% CI, 0.0%-3.7%) and 16.1% (95% CI, 10.6%-21.3%) in low- and high-risk groups, respectively. BCI gene expression alone was significantly prognostic (ΔLR-χ2 = 20.12; P < 0.0001). Addition of tumor size (ΔLR-χ2 = 13.29, P = 0.0003) and grade (ΔLR-χ2 = 12.72; P = 0.0004) significantly improved prognostic performance. BCI added significant prognostic information to tumor size (ΔLR-χ2 = 17.55; P < 0.0001); addition to tumor grade was incremental (ΔLR-χ2 = 2.38; P = 0.1) with considerable overlap between prognostic values (ΔLR-χ2 = 17.74).Conclusions: The integrated BCIN+ identified 20% of pN1 patients with limited risk of recurrence over 15 years, in whom extended endocrine treatment may be spared. Ongoing studies will characterize combined clinical-genomic risk assessment in node-positive patients. Clin Cancer Res; 23(23); 7217-24. ©2017 AACR.
Abstract 101: Coronary Anatomy, Culprit Vessels, and Survival Following Out-of-Hospital Cardiac Arrest
Authors: Karl B Kern, Kapildeo Lotun, John A McPherson, Nainesh C Patel, Paul McMullan, Barbara Unger, David B Seder, Michael Mooney
Journal: Circulation (2013)

Background: Aggressive post cardiac arrest (PCA) care improves long-term survival among those successfully resuscitated. The most promising post resuscitation treatments are therapeutic hypothermia...
GPs in an “invidious” position to prescribe ADHD drugs without specialist support
Authors: Gareth Iacobucci
Journal: BMJ (2017)

GPs have warned that they are being placed in an “invidious position” to prescribe drugs to adults with attention-deficit/hyperactivity disorder (ADHD) without specialist support, after a treatment service led by an NHS mental health trust stopped taking new patients because of high demand.

Norfolk and Waveney Local Medical Committee (LMC) raised concerns with five clinical commissioning groups (CCGs) after NHS England wrote to GPs notifying them that the trust was implementing an immediate pause in new referrals because of capacity pressures. The letter was drafted on behalf of the CCGs and Norfolk and Suffolk NHS Foundation …