tbuckley/cabot-search huggingface dataset:
Clinical and Genetic Characteristics of East Asian Patients with Occult Macular Dystrophy (Miyake Disease)
Authors: Kaoru Fujinami, Lizhu Yang, Kwangsic Joo, Kazushige Tsunoda, Shuhei Kameya, Gen Hanazono, Yu Fujinami-Yokokawa, Gavin Arno, Mineo Kondo, Natsuko Nakamura, Toshihide Kurihara, Kazuo Tsubota, Xuan Zou, Hui Li, Kyu Hyung Park, Takeshi Iwata, Yozo Miyake, Se Joon Woo, Ruifang Sui
Journal: Ophthalmology (2019)
Endoscopic examination of the papilla: to cap or swap the scope?
Authors: Marianna Arvanitakis
Journal: Endoscopy (2019)

Standard esophagogastroduodenoscopy (S-EGD) with a forward-viewing endoscope has become an established, highly efficient procedure for examining the upper digestive tract. However, S-EGD has a limited role in offering a complete assessment of the major duodenal papilla (MDP), which is due to the tangential position of the MDP and the presence of duodenal folds, as well as occasionally to a periampullary diverticulum [1]. On the other hand, a thorough examination of the MDP is essential for the early detection of ampullary and periampullary lesions in high risk patients (for example, those with familial polyposis syndromes) and for surveillance after previous endoscopic resection of an ampullary tumor, as well as in patients who have a dilatation of the common bile duct or the main pancreatic duct, or recurrent acute pancreatitis of unclear etiology [2]. In these cases, a side-viewing endoscope is recommended [1]; nevertheless, side-viewing endoscopes are not widely available and their use requires specific experience [2].
DIPG-06. RAPID, ULTRA-DEEP SEQUENCING OF PEDIATRIC DIPG FROM CEREBROSPINAL FLUID USING A NOVEL HAND-HELD ELECTRONIC DNA ANALYSIS PLATFORM
Authors: Amy K Bruzek, Leo Tunkle, Stefanie Stallard, Veena Thamilselvan, Tingting Qin, Ian Wolfe, Rajen Mody, Karin L Muraszko, Patricia L Robertson, Cormac O Maher, Hugh J L Garton, Carl Koschmann
Journal: Neuro-Oncology (2019)

INTRODUCTION: Brain tumors release tumor DNA (tDNA) into cerebrospinal fluid (CSF), allowing for detection and serial monitoring of tumor-associated genetic mutations by CSF sampling. For midline and brainstem tumors such as diffuse intrinsic pontine glioma (DIPG), surgical biopsy poses possible severe neurological deficits. As such, liquid biopsy is needed. Current platforms for CSF tDNA analysis are limited by their requirement for assay development for each mutation (digital droplet PCR), or cost and timeliness (Illumina sequencing). We hypothesized that direct, electronic analysis of DNA with a novel hand-held platform (Oxford Nanopore) could provide real-time, ultra-deep (>1,000x reads) sequencing of DIPG CSF tDNA. METHODS: We performed amplicon-based PCR on DNA from normal brain (n=6), normal CSF (n=13), tumor brain (n=3), and tumor CSF (n=10) to amplify wildtype and mutant H3F3A K27M, HIST1H3B K27M, and ACVR1 G328E genes from normal controls and pediatric patients with DIPG. We performed parallel barcoded sequencing of multiple samples run in duplicate or triplicate using NanoPore MinION technology and determined variant allele fraction (VAF) of each amplicon via an expeditious pipeline using MinKNOW, Albacore, MiniMap2, and Integrated Genome Browser. RESULTS: NanoPore sequenced 30 amplicons with average depth of 17,244 reads per amplicon in under 80 minutes. H3F3A K27M VAF was 49.14% (S.D. 0.49) in tumor tissue and 13.63% (S.D. 0.35) in CSF. VAF was 10.42% (S. D. 1.11) for HIST1H3B K27M and 7% (S.D. 0.46) for ACVR1 G328E in CSF. VAF were comparable to biopsy results by Illumina. Sensitivity and specificity of NanoPore were 100% and 98.8%, respectively, with p-values of < 0.05 for normal versus tumor samples. CONCLUSIONS: NanoPore MinION technology rapidly, reliably, and efficiently sequences tumor mutations in pooled tissue and CSF from patients with DIPG with outstanding sensitivity and specificity. NanoPore is more efficient, and cost and time effective than digital droplet PCR and Illumina.
Potential for additional government spending on HIV/AIDS in 137 low-income and middle-income countries: an economic modelling study
Authors: Annie Haakenstad, Mark W Moses, Tianchan Tao, Golsum Tsakalos, Bianca Zlavog, Jennifer Kates, Adam Wexler, Christopher J L Murray, Joseph L Dieleman
Journal: The Lancet HIV (2019)

Between 2012 and 2016, development assistance for HIV/AIDS decreased by 20·0%; domestic financing is therefore critical to sustaining the response to HIV/AIDS. To understand whether domestic resources could fill the financing gaps created by declines in development assistance, we aimed to track spending on HIV/AIDS and estimated the potential for governments to devote additional domestic funds to HIV/AIDS.We extracted 8589 datapoints reporting spending on HIV/AIDS. We used spatiotemporal Gaussian process regression to estimate a complete time series of spending by domestic sources (government, prepaid private, and out-of-pocket) and spending category (prevention, and care and treatment) from 2000 to 2016 for 137 low-income and middle-income countries (LMICs). Development assistance data for HIV/AIDS were from Financing Global Health 2018, and HIV/AIDS prevalence, incidence, and mortality were from the Global Burden of Disease study 2017. We used stochastic frontier analysis to estimate potential additional government spending on HIV/AIDS, which was conditional on the current government health budget and other finance, economic, and contextual factors associated with HIV/AIDS spending. All spending estimates were reported in 2018 US$.Between 2000 and 2016, total spending on HIV/AIDS in LMICs increased from $4·0 billion (95% uncertainty interval 2·9-6·0) to $19·9 billion (15·8-26·3), spending on HIV/AIDS prevention increased from $596 million (258 million to 1·3 billion) to $3·0 billion (1·5-5·8), and spending on HIV/AIDS care and treatment increased from $1·1 billion (458·1 million to 2·2 billion) to $7·2 billion (4·3-11·8). Over this time period, the share of resources sourced from development assistance increased from 33·2% (21·3-45·0) to 46·0% (34·2-57·0). Care and treatment spending per year on antiretroviral therapy varied across countries, with an IQR of $284-2915. An additional $12·1 billion (8·4-17·5) globally could be mobilised by governments of LMICs to finance the response to HIV/AIDS. Most of these potential resources are concentrated in ten middle-income countries (Argentina, China, Colombia, India, Indonesia, Mexico, Nigeria, Russia, South Africa, and Vietnam).Some governments could mobilise more domestic resources to fight HIV/AIDS, which could free up additional development assistance for many countries without this ability, including many low-income, high-prevalence countries. However, a large gap exists between available financing and the funding needed to achieve global HIV/AIDS goals, and sustained and coordinated effort across international and domestic development partners is required to end AIDS by 2030.The Bill & Melinda Gates Foundation.
Evaluation of Pharmaceutical Company Payments and Conflict of Interest Disclosures Among Oncology Clinical Practice Guideline Authors in Japan
Authors: Hiroaki Saito, Akihiko Ozaki, Toyoaki Sawano, Yuki Shimada, Tetsuya Tanimoto
Journal: JAMA Network Open (2019)

<h3>Importance</h3> Clinical practice guidelines (CPGs) are important in advancing the quality of medical care. Financial relationships between physicians and pharmaceutical companies may influence clinical practice. In accordance with the Japan Pharmaceutical Manufacturers Association guidelines for transparency, pharmaceutical company payments to physicians have been disclosed since 2013. The distribution of pharmaceutical company payments among CPG authors in Japan has not been studied. <h3>Objectives</h3> To determine the characteristics and distribution of payments made by pharmaceutical companies to authors of oncologic CPGs in Japan and to assess the transparency of policies associated with conflict of interest (COI) disclosures in CPGs. <h3>Design, Setting, and Participants</h3> This retrospective cross-sectional study of 326 authors from 6 prominent oncologic CPGs from Japan included annual payment data for 2016 from 78 pharmaceutical companies during varying times from January 1, 2016, through September 30, 2017. <h3>Main Outcomes and Measures</h3> Amount and proportion of payments made by pharmaceutical companies to the authors; amount and proportion of payments made to the authors of each guideline; and information on policies for disclosing COIs in CPGs (Japanese yen were converted to US dollars based on the February 20, 2019 exchange rate of 110 yen per 1 US dollar). <h3>Results</h3> Of 326 eligible authors, 255 (78.2%) received payments from pharmaceutical companies in 2016. The total number of payments was 3947, and the total amount was $3 444 193 (¥378 861 220), including $2 696 777 for speaking, $181 944 for writing, $554 381 for consulting, and $11 091 for unclear fees. The median payment amount was $3233 (interquartile range [IQR], $506-$10 873), and the mean (SD) payment amount was $10 565 ($20 059); 84 authors (25.8%) received more than $10 000. The largest proportions of CPG authors receiving at least 1 payment were those for gastric carcinoma (92%) and colorectal carcinoma (92%). The median payment was highest for authors of colorectal carcinoma guidelines ($7781; IQR, $2506-$18 633), whereas it was lowest for authors of pancreatic carcinoma guidelines ($2207; IQR, $304-$9240). Only breast carcinoma CPGs published the authors' individual COI disclosure in an identifiable matter; guidelines for lung, colorectal, pancreatic, and hepatocellular carcinomas disclosed the financial relationships between the authors and companies anonymously; and the gastric carcinoma CPGs did not have a COI disclosure section. <h3>Conclusions and Relevance</h3> Most oncologic CPG authors received payments from pharmaceutical companies, and COI disclosure methods appeared to be insufficient. Given the possibility of bias in guideline content if authors have any financial relationships with pharmaceutical companies, CPGs from Japan may require improved transparency.
MEDU-11. MOLECULAR CHARACTERIZATION OF ETMRs REVEALS A ROLE FOR R-LOOP MEDIATED CHROMOSOMAL INSTABILITY
Authors: Sander Lambo, Susanne Gröbner, Tobias Rausch, Sebastian Waszak, Christin Schmidt, Aparna Gorthi, Carolina Romero, Monika Mauermann, Sebastian Brabetz, Sonja Krausert, Emmanuelle Uro-Coste, Franck Bourdeaut, Annie Huang, Alexander Bishop, Stefan Pfister, Andrey Korshunov, Marcel Kool
Journal: Neuro-Oncology (2019)

ETMRs are aggressive embryonal brain tumors with a very poor prognosis, having a median overall survival of ~12 months after diagnosis. ETMRs harbour in ~90% of all cases amplification of a miRNA cluster on chromosome 19 (C19MC) that is thought to be the driver of the disease. However, current treatment options are lacking as (a) the mechanisms downstream of C19MC are poorly understood and (b) the drivers in cases lacking the C19MC aberration are unknown. To investigate the genomic landscape of ETMR, we collected 186 ETMR samples and 23 matched relapses. Interestingly, among the 18 tumors without C19MC amplification, we identified five cases with truncating DICER1 germline mutations in one allele and somatic missense mutations in the RNASE III domain in the other allele. In addition, SVs affecting C19MC were found in three other cases and amplification of the miR-17–92 cluster in another two cases. However, despite the presence of different genetic aberrations, based on DNA methylation profiling no molecular subgrouping was observed within our cohort. Whole-genome sequencing revealed an overall low recurrence and conservation of SNVs but strong conservation of SVs from primary tumors to relapses especially surrounding C19MC. SVs detected in ETMRs significantly co-localized with R-loops, structures that form upon a collision of replication and transcription and are associated to increased levels of chromosomal instability, which is frequently observed in ETMRs. Using a DICER1 KO model we found that global deregulation of miRNAs led to increased levels of R-loops and R-loop associated chromosomal instability. Finally, we show that treating ETMR cells with topoisomerase and PARP inhibitors strongly increased the levels of both R-loops and DNA damage and effectively killed the cells. Our results show that genomically instable ETMR cells are vulnerable to further increases in chromosomal instability, knowledge that may lead to new treatment strategies in the future.
Fludarabine-treosulfan compared to thiotepa-busulfan-fludarabine or FLAMSA as conditioning regimen for patients with primary refractory or relapsed acute myeloid leukemia: a study from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation (EBMT)
Authors: Francesco Saraceni, Myriam Labopin, Arne Brecht, Nicolaus Kröger, Matthias Eder, Johanna Tischer, Hélène Labussière-Wallet, Hermann Einsele, Dietrich Beelen, Donald Bunjes, Dietger Niederwieser, Tilmann Bochtler, Bipin N. Savani, Mohamad Mohty, Arnon Nagler
Journal: Journal of Hematology & Oncology (2019)

Limited data is available to guide the choice of the conditioning regimen for patients with acute myeloid leukemia (AML) undergoing transplant with persistent disease.We retrospectively compared outcome of fludarabine-treosulfan (FT), thiotepa-busulfan-fludarabine (TBF), and sequential fludarabine, intermediate dose Ara-C, amsacrine, total body irradiation/busulfan, cyclophosphamide (FLAMSA) conditioning in patients with refractory or relapsed AML.Complete remission rates at day 100 were 92%, 80%, and 88% for FT, TBF, and FLAMSA, respectively (p = 0.13). Non-relapse mortality, incidence of relapse, acute (a) and chronic (c) graft-versus-host disease (GVHD) rates did not differ between the three groups. Overall survival at 2 years was 37% for FT, 24% for TBF, and 34% for FLAMSA (p = 0.10). Independent prognostic factors for survival were Karnofsky performance score and patient CMV serology (p = 0.01; p = 0.02), while survival was not affected by age at transplant. The use of anti-thymocyte globulin (ATG) was associated with reduced risk of grade III-IV aGVHD (p = 0.02) and cGVHD (p = 0.006), with no influence on relapse.In conclusion, FT, TBF, and FLAMSA regimens provided similar outcome in patients undergoing transplant with active AML. Survival was determined by patient characteristics as Karnofsky performance score and CMV serology, however was not affected by age at transplant. ATG appears able to reduce the incidence of acute and chronic GVHD without influencing relapse risk.
Abstract P5-05-10: Estrogen receptor β suppresses metastasis of inflammatory breast cancer by regulating cell cytoskeleton and cytokine signaling
Authors: C Thomas, I Karagounis, RK Srivastava, S Kumar, J Karar, H-H Chao, A Kazimierczak, I Bado, F Nikolos, N Leli, C Koumenis, S Krishnamurthy, NT Ueno, R Chakrabarti, A Maity
Journal: Cancer Research (2019)

Abstract Inflammatory breast cancer (IBC) is the most lethal form of breast cancer that accounts for about 10% of breast cancer mortality annually in US. Poor prognosis is largely due to the high propensity of IBC tumors to develop distant metastasis that occurs directly from the gland epithelium and through lymphatic invasion in which dermal lymphatics are filled with tumor emboli. Owing to the complex metastatic process, the molecular basis of IBC aggressiveness is poorly understood, and no specific therapeutic target has been identified. Despite the lack of estrogen receptor α (ERα) in the majority of IBC tumors, estrogen may still play a role in these cancers through pathways that involve ERβ. Our tissue staining reveals expression of ERβ in more than 50% of IBCs that is reproduced in IBC cell lines. Furthermore, analysis of IBC datasets indicates correlation of receptor expression with good prognosis. We studied this association in preclinical models of IBC by knocking out ERβ in IBC cells. This promotes migration and invasion through cytoskeleton remodeling whereas re-expression of the receptor in knockout cells restores the cytoskeletal structure and migration to the levels of control cells. Consistent with increased migration, deletion of ERβ activates large gene networks of cell de-differentiation and cytokine synthesis that trigger tumor microenvironment responses to promote the motile phenotype of IBC cells. In contrast, ligands that activate the receptor inhibit signaling that contributes to metastasis in IBC. Analysis of an orthotopic xenograft model shows that IBC tumors lacking ERβ have higher propensity for metastasis compared with the ERβ-proficient tumors supporting the anti-metastatic activity of the receptor. Our findings point towards a role of ERβ in preventing distant metastases by inhibiting dissemination of IBC cells and maintaining the integrity of emboli. This function combined with distinct expression indicates the potential of ERβ to represent a unique prognostic marker and therapeutic target that can be utilized to repress IBC metastasis and eliminate its associated mortality. Citation Format: Thomas C, Karagounis I, Srivastava RK, Kumar S, Karar J, Chao H-H, Kazimierczak A, Bado I, Nikolos F, Leli N, Koumenis C, Krishnamurthy S, Ueno NT, Chakrabarti R, Maity A. Estrogen receptor β suppresses metastasis of inflammatory breast cancer by regulating cell cytoskeleton and cytokine signaling [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P5-05-10.
[Protocol Review] The CLASS Study: Comparison of LAser, Surgery and foam Sclerotherapy as a treatment for varicose veins
Authors: L Ternent, L Vale, J Brittenden, J Burr, M Campbell, I Chetter, S Cotton, J Earnshaw, J Francis, M Gough, A McDonald, McPherson, , G, C Ramsay
Journal: The Lancet (2009)
DIPG-27. OPTIMIZING CLINICAL TRIAL DESIGN: PHARMACOKINETICS OF MARIZOMIB AND PANOBINOSTAT IN A NON-HUMAN PRIMATE MODEL
Authors: Katherine Warren, Priya Shankarappa, Cody Peer, Rafael Cruz Garcia, Michelle Monje-Deisseroth, W Doug Figg, Cynthia Lester McCully
Journal: Neuro-Oncology (2019)

BACKGROUND: Pre-clinical determination of disease-specific activity, effective dosing, safety, pharmacokinetics, and CNS delivery can optimize clinical trial designs. The proteasome inhibitor, marizomib, together with the HDAC inhibitor, panobinostat, is active and synergistic in pre-clinical DIPG studies, with target concentrations of 20 and 100 nM, respectively. The adult maximum tolerated dose (MTD) for marizomib is 0.8 mg/m2. We evaluated the safety, tolerability and pharmacokinetics in a non-human primate model, predictive of pediatric patients. METHODS: Marizomib was administered (10-minute intravenous infusion) at three dose levels: 0.02 (n=4), 0.04 (n=5), and 0.06 mg/kg (n=1), equivalent to human doses (HED) of 0.4, 0.8, and 1.1 mg/m2, respectively. Marizomib (dose 0.04 mg/kg) was subsequently administered (n=4) 1-hr post-panobinostat (dose 1 mg/kg, HED 20 mg/m2, p.o.). Drug concentrations were determined by LC-MS/MS using validated assays and PK parameters calculated via noncompartmental methods. RESULTS: Marizomib +/- panobinostat was tolerable with the exception of one animal (single agent marizomib, dose 0.06 mg/kg, HED= 1.2 mg/m2) that expired 12–20 hr post administration; no clear etiology was found at necropsy. Remaining adverse events were Gr 1, 2 with the exception of lymphocytopenia, Gr 3 (n=2). Marizomib demonstrated rapid plasma clearance (1.22–10.25 L/min), short plasma half-life (4.45–8.24 min), non-linear increase in AUCinf, and no significant difference across dose levels. Conversely, in CSF, there was a trend toward increasing exposure with increasing dose. T1/2 was longer in CSF than blood (18–25 min vs. 4–7 min, respectively). Comparing marizomib PK before and after panobinostat, t1/2 and clearance were similar (mean 7.80 vs. 9.49 min, and 6.04 vs. 4.24 L/min, respectively); CSF AUCinf increased, 65.69 vs. 121.68 min*nM, respectively. CONCLUSIONS: Marizomib penetrates into the CNS and CSF exposure was higher after panobinostat. This combination warrants clinical evaluation in DIPG; correlation of results with preclinical findings is planned.
Rates of Extreme Neonatal Hyperbilirubinemia and Kernicterus in Children and Adherence to National Guidelines for Screening, Diagnosis, and Treatment in Sweden
Authors: Jenny Alkén, Stellan Håkansson, Cecilia Ekéus, Pelle Gustafson, Mikael Norman
Journal: JAMA Network Open (2019)

<h3>Importance</h3> Neonatal hyperbilirubinemia can cause lifelong neurodevelopmental impairment (kernicterus) even in high-resource settings. A better understanding of the incidence and processes leading to kernicterus may help in the design of preventive measures. <h3>Objectives</h3> To determine incidence rates of hazardous hyperbilirubinemia and kernicterus among near-term to term newborns and to evaluate health care professional adherence to best practices. <h3>Design, Setting, and Participants</h3> This population-based nationwide cohort study used prospectively collected data on the highest serum bilirubin level for all infants born alive at 35 weeks' gestation or longer and admitted to neonatal care at all 46 delivery and 37 neonatal units in Sweden from 2008 to 2016. Medical records for newborns with hazardous hyperbilirubinemia were evaluated for best neonatal practices and for a diagnosis of kernicterus up to 2 years of age. Data analyses were performed between September 2017 and February 2018. <h3>Exposures</h3> Extreme (serum bilirubin levels, 25.0-29.9 mg/dL [425-509 μmol/L]) and hazardous (serum bilirubin levels, ≥30.0 mg/dL [≥510 μmol/L]) neonatal hyperbilirubinemia. <h3>Main Outcomes and Measures</h3> The primary outcome was kernicterus, defined as hazardous neonatal hyperbilirubinemia followed by cerebral palsy, sensorineural hearing loss, gaze paralysis, or neurodevelopmental retardation. Secondary outcomes were health care professional adherence to national guidelines using a predefined protocol with 10 key performance indicators for diagnosis and treatment as well as assessment of whether bilirubin-associated brain damage might have been avoidable. <h3>Results</h3> Among 992 378 live-born infants (958 051 term births and 34 327 near-term births), 494 (320 boys; mean [SD] birth weight, 3505 [527] g) developed extreme hyperbilirubinemia (50 per 100 000 infants), 6.8 per 100 000 infants developed hazardous hyperbilirubinemia, and 1.3 per 100 000 infants developed kernicterus. Among 13 children developing kernicterus, brain injury was assessed as potentially avoidable for 11 children based on the presence of 1 or several of the following possible causes: untimely or lack of predischarge bilirubin screening (n = 6), misinterpretation of bilirubin values (n = 2), untimely or delayed initiation of treatment with intensive phototherapy (n = 1), untimely or no treatment with exchange transfusion (n = 6), or lack of repeated exchange transfusions despite indication (n = 1). <h3>Conclusions and Relevance</h3> Hazardous hyperbilirubinemia in near-term or term newborns still occurs in Sweden and was associated with disabling brain damage in 13 per million births. For most of these cases, health care professional noncompliance with best practices was identified, suggesting that a substantial proportion of these cases might have been avoided.