tbuckley/cabot-search huggingface dataset:
Forward-viewing echoendoscope versus standard echoendoscope for endoscopic ultrasound-guided tissue acquisition of solid lesions: a randomized, multicenter study
Authors: Alberto Larghi, Mostafa Ibrahim, Lorenzo Fuccio, Selma Lekkerkerker, Pierre Eisendrath, Leonardo Frazzoni, Paul Fockens, Marina La Marca, Jeanin E. van Hooft, Jacques Deviere, Guido Costamagna
Journal: Endoscopy (2018)

Abstract Background A forward-viewing linear (FVL) echoendoscope has been developed with the aim of overcoming some of the limitations of standard curved linear-array (CLA) echoendoscopes. There are no existing studies comparing the performance of the two echoendoscopes for endoscopic ultrasound-guided tissue acquisition (EUS-TA) of solid lesions other than subepithelial lesions. Methods This was a prospective, multicenter, randomized trial with a noninferiority design comparing FVL vs. CLA echoendoscopes in patients with solid lesions of the gastrointestinal tract or adjacent organs. Primary outcomes were successful identification of the lesion and success of EUS-TA. Secondary outcomes were safety, sensitivity, specificity, and diagnostic accuracy of the two different scopes for EUS-TA. Results 126 patients with solid lesions were randomly assigned to the CLA group (63 patients) or the FVL group (63 patients). The two groups were homogeneous with no differences in terms of needle type used, mean number of passes, and site of EUS-TA. No differences were observed between the FVL vs. CLA scopes in identification of the lesion (96.8 % vs. 98.4 %; P &gt; 0.99) and technical success of EUS-TA (92.1 % vs. 96.8 %; P = 0.44). No adverse events occurred. Overall, diagnostic accuracy (77.8 % vs. 84.1 %), sensitivity (76.6 % vs. 84.1 %), and specificity (81.3 % vs. 84.2 %) did not differ between the two groups. Conclusions Our results strongly suggest that the FVL echoendoscope is noninferior to the CLA scope for the detection and performance of EUS-TA in patients with solid lesions of the gastrointestinal tract and adjacent organs. In addition, the FVL scope has the same diagnostic yield, accuracy, and safety as the CLA scope.
Efficacy and safety of rasagiline in Chinese patients with early Parkinson’s disease: a randomized, double-blind, parallel, placebo-controlled, fixed-dose study
Authors: Zhenxin Zhang, Jian Wang, Shengdi Chen, Chunfeng Liu, Baorong Zhang, Rong Peng, Shenggang Sun, Xiangru Sun, Gang Zhao, Qiumin Qu, Yansheng Li, Suiqiang Zhu, Xiaoping Pan, Ming Shao, Yanping Wang
Journal: Translational Neurodegeneration (2018)

Rasagiline is a monoamine oxidase-B inhibitor used for Parkinson's disease (PD) treatment, but its effectiveness on Chinese patients is unclear. This study aimed to evaluate the efficacy and safety of rasagiline monotherapy in Chinese patients with early PD.A 26-weeks, randomized, double-blind, placebo-controlled study has been performed at 15 sites in China and enrolled outpatients (≥35 years old) with idiopathic PD without a history of using any dopaminergic drugs. Participants were randomized 1:1 to receive rasagiline 1 mg once daily or placebo. The primary endpoint was the change of the Unified Parkinson's Disease Rating Scale (UPDRS) total score from baseline to 26 weeks treatment. Secondary endpoints included changes in UPDRS subscale scores from part I to III. Health status was assessed with the PD Questionnaire (PDQ)-39 and EuroQol-Five-Dimension (EQ-5D) questionnaire. Safety profile was collected until 30 weeks after randomization.A total of 130 patients (n = 65/group) were recruited, and 127 (rasagiline, n = 64; placebo, n = 63) were included in the full analysis set. Baseline characteristics were comparable between the two groups. The decrease in the mean UPDRS total score was greater in the rasagiline group than in the placebo group (- 3.18 ± 0.95 vs. - 0.18 ± 0.98, P = 0.025), and the mean UPDRS part I non-motor symptoms score (- 0.54 ± 0.15 vs. -0.08 ± 0.15, P = 0.003) were significantly decreased in the rasagiline group compared with placebo treated patients. An improvement trend was observed in the active treatment group for the subscales evaluation with parts II and III, while the difference to placebo was not statistically significant. Life quality assessed by the EQ-5D visual analog scale improved in the rasagiline group but worsened in placebo treated patients. The overall incidence of treatment-emergent adverse events (AEs) was slightly lower in the rasagiline group (41.5%) than in the placebo group (46.2%).Rasagiline is effective, safe, and well tolerated as monotherapy for the treatment of Chinese PD patients.Clinicaltrials.gov: NCT01556165. Registered 13 Mar 2012.
Development of a multicomponent psychological mobile application (app) for patients with acute myeloid leukemia (AML).
Authors: Areej El-Jawahri, Joseph Greer, Emily M. Wright, Olivia Vanbenschoten, Lauren Waldman, Jennifer S. Temel
Journal: Journal of Clinical Oncology (2018)

166 Background: Patients newly diagnosed with AML experience substantial psychological distress as they confront a life-threatening diagnosis requiring an urgent 4-6 week hospitalization to initiate chemotherapy. Interventions to address psychological distress in this population are lacking. Methods: We used a five-step app development process to create a psychological intervention app targeting patients’ needs during the initial hospitalization following a new diagnosis of AML. Patients, caregivers, oncologists, psychologists, and nurses served as stakeholders and were involved in 1) developing a conceptual framework for the intervention; 2) creating an intervention manual that incorporates medical information, psychoeducation, and psychosocial skill-building corresponding to the illness trajectory; 3) translating the intervention manual into a storyline with gamification to enhance patient engagement; 4) creating initial wireframes of the app modules; and 5) refining the app through iterative testing. Results: The app consists of five 20-minute modules which the patient will complete weekly over a 5-week period. The modules consist of 1) supportive psychotherapy to address the initial shock of diagnosis; 2) psychoeducation to manage expectations and mobilize social supports; 3) psychosocial skill-building to promote effective coping; 4) self-care to promote positive health behaviors; and 4) a summary module to reinforce learning points from prior modules. Two bonus modules are available for patients who wish to engage in additional cognitive-based restructuring strategies. We utilized gamification strategies to enhance patient engagement including a) creating an app storyline focused on the patient’s journey during hospitalization; 2) creating a guide character doctor that accompanies the patient through their journey; 3) incorporating videos of AML survivors; and 4) developing a point reward system for completing the modules. Conclusions: We developed a novel psychological intervention app for patients with AML using an iterative development process. Future studies should assess the efficacy of the app in improving outcomes for patients with AML.
Safety of guselkumab in patients with moderate‐to‐severe psoriasis treated through 100 weeks: a pooled analysis from the randomized <scp>VOYAGE</scp> 1 and <scp>VOYAGE</scp> 2 studies
Authors: K. Reich, K.A. Papp, A.W. Armstrong, Y. Wasfi, S. Li, Y.K. Shen, B. Randazzo, M. Song, A.B. Kimball
Journal: British Journal of Dermatology (2018)

Long‐term evaluation is required to confirm the safety profile of newer biologic agents. To report on pooled safety data from the ongoing VOYAGE 1 (NCT02207231) and VOYAGE 2 (NCT02207244) trials through 100 weeks of follow‐up. Patients were randomized to either guselkumab 100 mg at weeks 0 and 4 and every 8 weeks thereafter; placebo at weeks 0, 4, 12 followed by guselkumab 100 mg at weeks 16 and 20 and every 8 weeks thereafter; or adalimumab 80 mg at week 0, 40 mg at week 1, and 40 mg every 2 weeks thereafter. Patients who received adalimumab crossed over to guselkumab at week 52 (VOYAGE 1) and at/after week 28 based on clinical response (VOYAGE 2). Open‐label extensions, in which all patients received guselkumab, started at week 52 (VOYAGE 1) and week 76 (VOYAGE 2). Rates of adverse events (AEs) per 100 patient‐years (PYs) are presented through 100 weeks of follow‐up. Through week 52, observed rates for guselkumab‐ and adalimumab‐treated patients, respectively, were 262·45 per 100 PYs and 328·28 per 100 PYs for AEs, 6·20 per 100 PYs and 7·77 per 100 PYs for serious AEs (SAEs), 1·22 per 100 PYs and 1·79 per 100 PYs for serious infections (SIs), 0·28 per 100 PYs and 0·40 per 100 PYs for malignancies other than nonmelanoma skin cancers (NMSCs), 0·56 per 100 PYs and 0·40 per 100 PYs for NMSCs, and 0·47 per 100 PYs and 0·40 per 100 PYs for major adverse cardiovascular events (MACEs). Rates among patients treated with guselkumab through week 52 and week 100, respectively, were 262·45 per 100 PYs and 210·41 per 100 PYs for AEs, 6·20 and 6·29 per 100 PYs, for SAEs, 1·22 per 100 PYs and 1·06 per 100 PYs for SIs, 0·28 per 100 PYs and 0·38 per 100 PYs for malignancies, 0·56 per 100 PYs and 0·39 per 100 PYs for NMSCs, and 0·47 per 100 PYs and 0·38 per 100 PYs for MACEs. Among patients treated with adalimumab, rates of AEs, SAEs, SIs, malignancies, NMSCs, and MACEs showed some variability before and after crossover to guselkumab, although no new safety signals were noted after crossover. The safety profile for guselkumab remains favourable through 100 weeks of treatment in patients with moderate‐to‐severe psoriasis.
Evaluation of Digital Breast Tomosynthesis as Replacement of Full-Field Digital Mammography Using an In Silico Imaging Trial
Authors: Aldo Badano, Christian G. Graff, Andreu Badal, Diksha Sharma, Rongping Zeng, Frank W. Samuelson, Stephen J. Glick, Kyle J. Myers
Journal: JAMA Network Open (2018)

<h3>Importance</h3> Expensive and lengthy clinical trials can delay regulatory evaluation of innovative technologies, affecting patient access to high-quality medical products. Simulation is increasingly being used in product development but rarely in regulatory applications. <h3>Objectives</h3> To conduct a computer-simulated imaging trial evaluating digital breast tomosynthesis (DBT) as a replacement for digital mammography (DM) and to compare the results with a comparative clinical trial. <h3>Design, Setting, and Participants</h3> The simulated Virtual Imaging Clinical Trial for Regulatory Evaluation (VICTRE) trial was designed to replicate a clinical trial that used human patients and radiologists. Images obtained with in silico versions of DM and DBT systems via fast Monte Carlo x-ray transport were interpreted by a computational reader detecting the presence of lesions. A total of 2986 synthetic image–based virtual patients with breast sizes and radiographic densities representative of a screening population and compressed thicknesses from 3.5 to 6 cm were generated using an analytic approach in which anatomical structures are randomly created within a predefined breast volume and compressed in the craniocaudal orientation. A positive cohort contained a digitally inserted microcalcification cluster or spiculated mass. <h3>Main Outcomes and Measures</h3> The trial end point was the difference in area under the receiver operating characteristic curve between modalities for lesion detection. The trial was sized for an SE of 0.01 in the change in area under the curve (AUC), half the uncertainty in the comparative clinical trial. <h3>Results</h3> In this trial, computational readers analyzed 31 055 DM and 27 960 DBT cases from 2986 virtual patients with the following Breast Imaging Reporting and Data System densities: 286 (9.6%) extremely dense, 1200 (40.2%) heterogeneously dense, 1200 (40.2%) scattered fibroglandular densities, and 300 (10.0%) almost entirely fat. The mean (SE) change in AUC was 0.0587 (0.0062) (<i>P</i> &lt; .001) in favor of DBT. The change in AUC was larger for masses (mean [SE], 0.0903 [0.008]) than for calcifications (mean [SE], 0.0268 [0.004]), which was consistent with the findings of the comparative trial (mean [SE], 0.065 [0.017] for masses and −0.047 [0.032] for calcifications). <h3>Conclusions and Relevance</h3> The results of the simulated VICTRE trial are consistent with the performance seen in the comparative trial. While further research is needed to assess the generalizability of these findings, in silico imaging trials represent a viable source of regulatory evidence for imaging devices.
Risk of Suicide After Cancer Diagnosis in England
Authors: Katherine E. Henson, Rachael Brock, James Charnock, Bethany Wickramasinghe, Olivia Will, Alexandra Pitman
Journal: JAMA Psychiatry (2018)

A diagnosis of cancer carries a substantial risk of psychological distress. There has not yet been a national population-based study in England of the risk of suicide after cancer diagnosis.To quantify suicide risk in patients with cancers in England and identify risk factors that may assist in needs-based psychological assessment.Population-based study using data from the National Cancer Registration and Analysis Service in England linked to death certification data of 4 722 099 individuals (22 million person-years at risk). Patients (aged 18-99 years) with cancer diagnosed from January 1, 1995, to December 31, 2015, with follow-up until August 31, 2017, were included.Diagnosis of malignant tumors, excluding nonmelanoma skin cancer.All deaths in patients that received a verdict of suicide or an open verdict at the inquest. Standardized mortality ratios (SMRs) and absolute excess risks (AERs) were calculated.Of the 4 722 099 patients with cancer, 50.3% were men and 49.7% were women. A total of 3 509 392 patients in the cohort (74.3%) were aged 60 years or older when the diagnosis was made. A total of 2491 patients (1719 men and 772 women) with cancer died by suicide, representing 0.08% of all deaths during the follow-up period. The overall SMR for suicide was 1.20 (95% CI, 1.16-1.25) and the AER per 10 000 person-years was 0.19 (95% CI, 0.15-0.23). The risk was highest among patients with mesothelioma, with a 4.51-fold risk corresponding to 4.20 extra deaths per 10 000 person-years. This risk was followed by pancreatic (3.89-fold), esophageal (2.65-fold), lung (2.57-fold), and stomach (2.20-fold) cancer. Suicide risk was highest in the first 6 months following cancer diagnosis (SMR, 2.74; 95% CI, 2.52-2.98).Despite low absolute numbers, the elevated risk of suicide in patients with certain cancers is a concern, representing potentially preventable deaths. The increased risk in the first 6 months after diagnosis may indicate an unmet need for psychological support. The findings of this study suggest a need for improved psychological support for all patients with cancer, and attention to modifiable risk factors, such as pain, particularly in specific cancer groups.
Polycomb repressors controlling stem cell fate: Implications for cancer and development
Authors: Maarten Lohuizen
Journal: Cancer Research (2008)

SY06-04  Repressive Polycomb-group (Pc-G) protein complexes and the counteracting Trithorax-group (Trx-G) of nucleosome remodeling factors are involved in the dynamic maintenance of proper gene expression patterns during development, acting at the level of chromatin structure. As such, they are important controllers of cell fate. When deregulated, these master switches of gene expression are strongly implicated in formation of a diverse set of cancers. An example is the Pc-G gene Bmi1 which is overexpressed in medulloblastoma, Non small cell lung cancer, hepatocellular carcinoma and breast cancer and Glioma and is causally implicated in leukemia. We and others have recently implicated Bmi1/Pc-G as a critical regulator of stem cell fate in hemapoietic stem cells, neural stem cells, mammary epithelial precursor cells and ES cells. In addition, we have shown that Bmi1 is regulated by the Shh pathway and that the Ink4a/ARF tumors suppressors are critical Bmi1 target genes in stem cells and in cancer formation. However our recent work on brain cancer (Glioma) points to important ink4a/ARF-independent Bmi1 targets involved in adhesion and motility. Comprehensive profiling of Polycomb target genes in Drosophila revealed its crucial conserved role in repressing lineage differentiation pathways and morphogens, including Wg, Hh, Delta and Notch. Furthermore, we have characterized in detail an essential E3-ubiquitin ligase activity in the PRC1 Polycomb complex that consists of a functional Ring1B-Bmi1 heterodimer. This E3 ligase activity is required for maintenance of Polycomb repression in normal- and cancer stem cells and hence offers potential novel ways to target cancer stem cells or tumor re-initiating cells in which the activity of this E3 ligase is hyperactivated. This is further substantiated by a novel way by which the activity of the Ring1B.Bmi1 E3 ligase is controlled. The implications of these findings for stem cell biology, development and cancer will be discussed.
miR-200c/141 Regulates Breast Cancer Stem Cell Heterogeneity via Targeting HIPK1/β-Catenin Axis
Authors: Bingjie Liu, Ruikai Du, Lei Zhou, Jiahui Xu, Song Chen, Ji Chen, Xiaoli Yang, Dong-xu Liu, Zhi-ming Shao, Lixing Zhang, Zuoren Yu, Ni Xie, Jun-lin Guan, Suling Liu
Journal: Theranostics (2018)

Increasing evidence demonstrates the existence of two inter-convertible states of breast cancer stem cells (BCSCs) with distinct behaviors in proliferation and mobility, and the BCSC heterogeneity is accurately regulated by sophisticated mechanisms including microRNAs.The microRNA-200 family including miR-200c/141 cluster was reported to affect cancer cell invasion and metastasis by regulating epithelial to mesenchymal transition (EMT).However, the effect of miR-200 family on BCSC heterogeneity is uncertain.Thus, we investigated whether the miR-200c/141 cluster had different effects on breast tumor growth and metastasis by switching the two states of BCSC.Methods: The spontaneous mammary tumor mouse model with miR-200c/141 conditional knockout was utilized for analyzing the role of miR-200c/141 cluster in vivo.The effect of miR-200c/141 cluster on BCSCs was performed by CD24/CD29 staining and ALDEFLUOR assay.miR-200c/141 target expression and EMT-related marker expression were verified in tumor sections, primary cells and breast cancer cell lines by qRT-PCR or western blotting.Statistical analysis was determined using two-way ANOVA and Student's t-test.All values were presented as the mean ± s.e.m.Results: The deletion of miR-200c/141 cluster regulated BCSC heterogeneity and promoted the EMT-like BCSC generation, which resulted in increased tumor metastasis and inhibited tumor growth by directly upregulating the target gene homeodomain-interacting protein kinase 1 (HIPK1) and sequential β-catenin activation.Conclusions: Our results indicated that miR-200c/141 played biphasic roles in breast tumor progression via affecting the BCSC heterogeneity, suggesting targeting BCSC heterogeneity to simultaneously restrict breast cancer initiation and metastasis could be a promising therapeutic strategy for breast cancer.
Abstract 16810: Identification of a New Class of Small Molecule Antagonists for Protease Proprotein Convertase Subtilisin-Like Kexin Type 9
Authors: Nabil A Elshourbagy, Harold V Meyers, Shaker A Mousa, Sherin S Abdel-Meguid
Journal: Circulation (2017)

Intervention with drugs to reduce low density lipoprotein-cholesterol (LDL-C) has proven to decrease mortality. Here, we report the development of small molecules that lower LDL-C by targeting the ...
Biosimilar Filgrastim Use in the United States vs the European Union and Japan—Why Does It Lag Behind and What Can Be Done?
Authors: Zaina P. Qureshi, Sumimasa Nagai, Charles L. Bennett
Journal: JAMA Oncology (2018)

This Viewpoint discusses obstacles that limit the use of biosimilar filgrastim in the United States compared with countries in the European Union and Japan and discusses strategies that might help biosimilar filgrastim use become more widespread.
Activity of durvalumab plus olaparib in metastatic castration-resistant prostate cancer in men with and without DNA damage repair mutations
Authors: Fatima Karzai, David VanderWeele, Ravi A. Madan, Helen Owens, Lisa M. Cordes, Amy Hankin, Anna Couvillon, Erin Nichols, Marijo Bilusic, Michael L. Beshiri, Kathleen Kelly, Venkatesh Krishnasamy, Sunmin Lee, Min-Jung Lee, Akira Yuno, Jane B. Trepel, Maria J. Merino, Ryan Dittamore, Jennifer Marté, Renee N. Donahue, Jeffrey Schlom, Keith J. Killian, Paul S. Meltzer, Seth M. Steinberg, James L. Gulley, Jung-Min Lee, William L. Dahut
Journal: Journal for ImmunoTherapy of Cancer (2018)

<h3>Background</h3> Checkpoint inhibitors have not been effective for prostate cancer as single agents. Durvalumab is a human IgG1-K monoclonal antibody that targets programmed death ligand 1 and is approved by the U.S. Food and Drug Administration for locally advanced or metastatic urothelial cancer and locally advanced, unresectable stage 3 non-small cell lung cancer. Olaparib, a poly (ADP-ribose) polymerase inhibitor, has demonstrated an improvement in median progression-free survival (PFS) in select patients with metastatic castration-resistant prostate cancer (mCRPC). Data from other trials suggest there may be improved activity in men with DNA damage repair (DDR) mutations treated with checkpoint inhibitors. This trial evaluated durvalumab and olaparib in patients with mCRPC with and without somatic or germline DDR mutations. <h3>Methods</h3> Eligible patients had received prior enzalutamide and/or abiraterone. Patients received durvalumab 1500 mg i.v. every 28 days and olaparib 300 mg tablets p.o. every 12 h until disease progression or unacceptable toxicity. All patients had biopsies of metastatic lesions with an evaluation for both germline and somatic mutations. <h3>Results</h3> Seventeen patients received durvalumab and olaparib. Nausea was the only nonhematologic grade 3 or 4 toxicity occurring in &gt; 1 patient (2/17). No patients were taken off trial for toxicity. Median radiographic progression-free survival (rPFS) for all patients is 16.1 months (95% CI: 4.5–16.1 months) with a 12-month rPFS of 51.5% (95% CI: 25.7–72.3%). Activity is seen in patients with alterations in DDR genes, with a median rPFS of 16.1 months (95% CI: 7.8–18.1 months). Nine of 17 (53%) patients had a radiographic and/or PSA response. Patients with fewer peripheral myeloid-derived suppressor cells and with alterations in DDR genes were more likely to respond. Early changes in circulating tumor cell counts and in both innate and adaptive immune characteristics were associated with response. <h3>Conclusions</h3> Durvalumab plus olaparib has acceptable toxicity, and the combination demonstrates efficacy, particularly in men with DDR abnormalities. <h3>Trial registration</h3> ClinicalTrials.gov identifier: NCT02484404.
Analysis of the Evolving MDS/AML Clones to Identify Resistance Mechanisms and Predict New Therapy Options at Relapse Using Computational Biology Modeling: Case-Studies from iCare1 Clinical Study
Authors: Shireen Vali, Taher Abbasi, Neeraj Kumar Singh, Shahabuddin Usmani, Deepak Anil Lala, Poornachandra G, Saumya Radhakrishnan, Shivgonda C Birajdar, Ganesh Naga, Leylah M. Drusbosky, Christopher R. Cogle
Journal: Blood (2018)