tbuckley/cabot-search huggingface dataset:
DIPG-16. APPLYING THE SIOPE DIPG REGISTRY SURVIVAL PREDICTION TOOL TO SELECT A SURVIVAL EXTENSION TARGET FOR A POWER CALCULATION FOR A NEW TRIAL OF CONVECTION ENHANCED DRUG DELIVERY (CED) OF CARBOPLATIN AND SODIUM VALPROATE IN DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG)
Authors: Elwira Szychot, Peter Collins, Hanna Cassidy, Mohammed Desai, Harpreet Hyare, Ananth Shankar, Steven Gill, Dannis van Vuurden, Sophie Veldhuijzen van Zanten, David Walker
Journal: Neuro-Oncology (2019)

INTRODUCTION: In diffuse intrinsic pontine glioma (DIPG) drug resistance is in part due to inadequate penetration of the blood-brain barrier (BBB) by systemically administered drugs. Convection enhanced drug delivery (CED) techniques have been established to bypass the BBB. Trial design to measure efficacy requires evidence to justify a power calculation. AIMS: To apply the SIOPe DIPG registry survival prediction tool (1) to a pilot cohort of children with DIPG treated with CED of carboplatin and sodium valproate. METHODS: Case note and imaging review of 9 children with typical DIPG on imaging, treated on a compassionate basis with CED intra-tumoural infusions of carboplatin (0.12 mg/ml) and sodium valproate (14.4 mg/ml), given after radiotherapy (n=9) and chemotherapy (n=4). Each had a skull-based Renishaw device placed with 4 micro-catheters located within the tumour mass. Up to 8 treatment cycles of CED infusions delivered through 2 pairs of catheters on 2 days to encompass the pontine tumour volume. Survival prediction was performed using clinical criteria: age, sex, duration of symptoms, prior chemotherapy; radiological criteria: absence of distant metastases; disease involving more than 50% of, and confined to, the pons, ring enhancement at diagnosis. RESULTS: Cases were categorized as intermediate or high-risk using SIOPe risk scoring with predicted median overall survival (OS) of 9.7, and 7.0 months, respectively. Four cases, who were categorized as high-risk, had median OS of 14.2 months. Five children, categorized as standard-risk, had median OS of 16.0 months. CONCLUSIONS: OS of CED treated cases compared favourably with the SIOPe DIPG registry survival prediction tool. This supports the justification of phase 2 trial of CED carboplatin and sodium valproate powered to detect at least a 4 month prolongation of survival.
ATRT-13. LATE RECURRENCES O​​F ATYPICAL TERATOID/RHABDOID TUMOR (AT/RT) AND BENEFIT OF SALVAGE TREATMENT WITH CRANIOSPINAL IRRADIATION
Authors: Matthew Miller, Adekunle Adesina, Robert Dauser, Arnold Paulino, Murali Chintagumpala, Holly Lindsay
Journal: Neuro-Oncology (2019)

BACKGROUND: Atypical teratoid/rhabdoid tumor (AT/RT) is an aggressive pediatric brain tumor. The majority of patients recur within 2–3 years of completion of therapy. We report the outcomes of 2 patients with late relapses occurring more than 4 years after completion of initial therapy who are long-term survivors. PATIENT COHORT: Patient #1 at 2 years of age was treated with focal irradiation and chemotherapy. He developed a distant recurrence 4 years later and was treated with craniospinal irradiation (CSI) and chemotherapy. He is disease-free at 10 years. Patient #2 at 3 years of age was treated with whole brain irradiation and chemotherapy. This patient developed a new distant AT/RT 11 years later and was treated with CSI and high-dose chemotherapy with autologous stem cell rescue. She is alive without disease at 4 years. Testing for germline SMARCB1 loss was performed in patient #2 and showed the patient to have rhabdoid predisposition syndrome type 1. Consequently, it is possible that the recurrence 11 years after her initial diagnosis was a second primary. We compared the outcomes of these late recurrences with all 20/32 patients with ATRT who recurred after initial therapy since 2007. All but 2 patients recurred within 3 years of completion of therapy, and all 18 died of disease. The 2 remaining patients are undergoing active salvage treatment. CONCLUSION: Late recurrences more than 4 years from completion of therapy in AT/RT are infrequent. In the 2 patients presented above, however, salvage treatment including CSI was successful in controlling these late relapses. We hypothesize that unlike early recurrences, late recurrences of AT/RT may be successfully controlled with salvage treatment that includes CSI.
Patrolling monocytes promote the pathogenesis of early lupus-like glomerulonephritis
Authors: Jeeba Kuriakose, Vanessa Redecke, Cliff Guy, Jingran Zhou, Ruiqiong Wu, Sirish K. Ippagunta, Heather Tillman, Patrick D. Walker, Peter Vogel, Hans Häcker
Journal: Journal of Clinical Investigation (2019)

Systemic lupus erythematosus (SLE) is a complex autoimmune disease with genetic and environmental contributions. Hallmarks of the disease are the appearance of immune complexes (IC) containing autoreactive Abs and TLR-activating nucleic acids, whose deposition in kidney glomeruli is suspected to promote tissue injury and glomerulonephritis (GN). Here, using a mouse model based on the human SLE susceptibility locus TNFAIP3-interacting protein 1 (TNIP1, also known as ABIN1), we investigated the pathogenesis of GN. We found that GN was driven by TLRs but, remarkably, proceeded independently of ICs. Rather, disease in 3 different mouse models and patients with SLE was characterized by glomerular accumulation of patrolling monocytes (PMos), a cell type with an emerging key function in vascular inflammation. Consistent with such function in GN, monocyte-specific deletion of ABIN1 promoted kidney disease, whereas selective elimination of PMos provided protection. In contrast to GN, PMo elimination did not protect from reduced survival or disease symptoms such as IC generation and splenomegaly, suggesting that GN and other inflammatory processes are governed by distinct pathogenic mechanisms. These data identify TLR-activated PMos as the principal component of an intravascular process that contributes to glomerular inflammation and kidney injury.
Abstract 16701: Provision of Free Cell Phone Adapters as a Mechanism to Mitigate Disparities in Implantable Cardioverter Defibrillator (ICD) Remote Monitoring
Authors: Nicholas Mantini, Ryan T Borne, Michael Brunnquell, Matthew Zipse, Ryan Aleong, Lucas Marzec, William H Sauer, Duy T Nguyen
Journal: Circulation (2017)

Introduction: A retrospective review of the National Cardiovascular Disease Registry (NCDR) ICD RegistryTM from 2006 to 2010 identified African American and Hispanic race as risk factors for failur...
MEDU-43. GLOBAL AND REGIONAL EFFECTS OF RADIATION THERAPY ON CEREBRAL MICROVASCULATURE IN PEDIATRIC BRAIN TUMOR SURVIVORS
Authors: Sivakami Avadiappan, Melanie Morrison, Angela Jakary, Erin Felton, Schuyler Stoller, Christopher Hess, Sabine Mueller, Steve Braunstein, Janine Lupo
Journal: Neuro-Oncology (2019)

INTRODUCTION: Although cranial radiation therapy (RT) is a common treatment for pediatric brain tumors, it can have long-term effects such as cognitive decline and vascular injury in the form of cerebral microbleeds (CMBs). As pediatric brain tumor patients’ survival is now extending into adulthood, it is increasingly important to understand the impact of vascular injury due to RT on their cognitive function. METHODS: 15 patients (ages 10–24) treated with whole-brain or whole-ventricular RT for infratentorial pediatric brain tumors (Medulloblastoma, Germinoma, Anaplastic Ganglioglioma) 2 months to 16 years prior, and 3 non-irradiated control patients (ages 14–26) were scanned on a 7 Tesla MRI scanner using a novel simultaneous MRA-SWI acquisition that enabled visualization of arteries, veins, and CMBs on one image. Arteries were segmented from the MRA and the resulting distribution of vessels in different brain lobes and white matter was correlated with cognitive performance and compared among the two RT treatment groups and the non-irradiated control group. RESULTS: Global arterial volume, normalized by brain volume, was significantly reduced with increasing RT treatment volume (p<0.02) and decreased with the number of CMBs and over time. The executive function score from Cogstate test was significantly lower in patients with smaller arterial vessel volume than average (p<0.02). Local vessel volume (normalized by regional brain volume) reduced uniformly across all brain lobes for patients who received whole-brain RT compared to the non-irradiated control patients. Patients who received whole-ventricular RT had reduced vessel volume only in the occipital and temporal lobes, which were within the treatment field. Although CMBs were located closer to veins than arteries, their size increased with distance from the nearest vessel. CONCLUSIONS: Our findings suggest that spatial variations in vascular morphology are related to the presence and size of CMBs, depend on the RT treatment volume, and may affect cognitive function.
LGG-07. CLINICAL FEATURES OF NON-CANONICAL MOLECULAR DRIVERS IN PLGG; AN UPDATE FORM THE INTERNATIONAL PLGG TASKFORCE
Authors: Scott Ryall, Michal Zapotocky, Kohei Fukuoka, Ana Guerreiro-Stucklin, Julie Bennett, Anthony Arnoldo, Paul Kowalski, Monique Johnson, Liana Figueiredo Nobre, Alvaro Lassaletta, Eric Bouffet, Ute Bartels, David Ellison, Ruth Tatevossian, Wilda Orisme, Ibrahim Qaddoumi, Mariarita Santi, Lea Surrey, Angela Waanders, Marilyn Li, Matthias Karajannis, Stephen Gilheeney, Marc Rosenblum, Tejus Bale, Uri Tabori, Cynthia Hawkins
Journal: Neuro-Oncology (2019)

Molecular characterization of pediatric low-grade gliomas (pLGG) have identified recurrent alterations, most commonly involving BRAF and NF1, which have been exploited to aid in diagnosis and treatment decisions. However, a significant portion do not have these canonical alterations, and the genetics and clinical course of these tumors remains unknown. We molecularly characterized a cohort of 986 patients diagnosed at SickKids from 1990–2017 with comprehensive long-term clinical data. For the rare non-canonical alterations uncovered, data was supplemented with cases from the Taskforce. Within the SickKids cohort, 72% were driven by canonical alterations in either BRAF (38% fusions, 16% V600E) or NF1 (18%). 11.5% were driven via recurrent non-canonical events involving FGFR1 (6%), FGFR2 (1%), MYB (1%), MYBL1 (1%), H3F3A (2%) or IDH1 (0.5%). The Taskforce supplemented cohort revealed that most FGFR1/2 fusions (n=51) were hemispheric and benign, with no deaths observed. In contrast, FGFR1 activating mutations (n=29) were commonly observed as a second hit, occurred throughout the neuraxis, and at an older age. These tumors were more aggressive, having a poor response to therapy and resulting in death. MYB/MYBL1 alterations (n=19) were seen exclusively in angiocentric gliomas and diffuse astrocytomas, respectively. Both are primarily hemispheric and often occur as massive lesions in childhood, yet have excellent long-term outcome. IDH1 (n=8) was seen mostly in adolescents (15–18 years). Importantly, several had a long history of seizures and presented with small lesions years prior to surgery. While all tumours eventually progressed, some (n=6) are alive up to 13 years post diagnosis. H3F3A driven pLGGs (n=12) progressed early, (median 11 months) and all patients succumbed to their disease. The work here represents the largest cohort of non-canonical pLGGs assembled. Our work supports a diagnostic workflow which includes these alterations, and we provide preliminary clinical features of these tumors to better equip practicing clinicians.
The optimal oral biopsy site for diagnosis of mucous membrane pemphigoid and pemphigus vulgaris
Authors: B. Carey, S. Joshi, A. Abdelghani, J. Mee, M. Andiappan, J. Setterfield
Journal: British Journal of Dermatology (2019)

BackgroundAccepted 'standard practice' for the diagnosis of immunobullous disease is a perilesional sample for direct immunofluorescence (DIF).
Treatment of Patients With Psychogenic Nonepileptic Attacks
Authors: Benjamin Tolchin, Steve Martino, Lawrence J. Hirsch
Journal: JAMA (2019)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Estimation of the Required Lipoprotein(a)-Lowering Therapeutic Effect Size for Reduction in Coronary Heart Disease Outcomes
Authors: Claudia Lamina, Florian Kronenberg
Journal: JAMA Cardiology (2019)

Genetic and epidemiologic data suggest that lipoprotein(a) (Lp[a]) is one of the strongest genetically determined risk factors for coronary heart disease (CHD). Specific therapies to lower Lp(a) are on the horizon, but the required reduction of Lp(a) to translate into clinically relevant lowering of CHD outcomes is a matter of debate.To estimate the required Lp(a)-lowering effect size that may be associated with a reduction of CHD outcomes compared with the effect size of low-density lipoprotein cholesterol (LDL-C)-lowering therapies.Genetic epidemiologic study using a mendelian randomization analysis to estimate the required Lp(a)-lowering effect size for a clinically meaningful effect on outcomes. We used the effect estimates for Lp(a) from a genome-wide association study (GWAS) and meta-analysis on Lp(a) published in 2017 of 5 different primarily population-based studies of European ancestry. All Lp(a) measurements were performed in 1 laboratory. Genetic estimates for 27 single-nucleotide polymorphisms on Lp(a) concentrations were used. Odds ratios for these 27 single-nucleotide polymorphisms associated with CHD risk were retrieved from a subsample of the CHD Exome+ consortium.Genetic LPA score, plasma Lp(a) concentrations, and observations of statin therapies on CHD outcomes.Coronary heart disease.The study included 13 781 individuals from the Lp(a)-GWAS-Consortium from 5 primarily population-based studies and 20 793 CHD cases and 27 540 controls from a subsample of the CHD Exome+ consortium. Four of the studies were similar in age distribution (means between 51 and 59 years), and 1 cohort was younger; mean age, 32 years. The frequency of women was similar between 51% and 55%. We estimated that the required reduction in Lp(a) effect size would be 65.7 mg/dL (95% CI, 46.3-88.3) to reach the same potential effect on clinical outcomes that can be reached by lowering LDL-C by 38.67 mg/dL (to convert to millimoles per liter, multiply by 0.0259).This mendelian randomization analysis estimated a required Lp(a)-lowering effect size of 65.7 mg/dL to reach the same effect as a 38.67-mg/dL lowering of LDL-C. However, this estimate is determined by the observed effect estimates of single-nucleotide polymorphisms on Lp(a) concentrations and is therefore influenced by the standardization of the Lp(a) assay used. As a consequence, calculations of the required Lp(a)-lowering potential of a drug to be clinically effective might have been overestimated in the past.
Abstract 107: Comparison Between Cerebral Microcirculatory Blood Flow Following Epinephrine and Vasopressin During CPR
Authors: Giuseppe Ristagno, Shijie Sun, Lei Huang, Yun-Te Chang, Wanchun Tang, Max H Weil
Journal: Circulation (2006)

Introduction. Both epinephrine and vasopressin increase cerebral cortical large vessel pressure when administered during CPR. However, we recently demonstrated that epinephrine reduces cerebral cortical microcirculatory blood flow (MBF). Accordingly, we explored the effects of non-adrenergic vasopressin on cerebral cortical perfusion. Methods. Ten domestic male pigs weighing 40 ± 2 kg were intubated and mechanically ventilated. A fronto-parietal bilateral craniotomy was created. MBF was measured with the Orthogonal Polarization Spectral imaging method using the CYTOSCAN A/R (Cytometrics Inc., Philadelphia, PA). Tissue carbon dioxide tension (PbCO2) was measured with a miniature carbon dioxide tissue electrode (CO2-O2-PH ABG Module, Optical Sensors Inc, MN). Blood flow velocity in pial and penetrating vessels < 20 μm was graded from 0 (no flow) to 3 (normal). Ventricular fibrillation (VF) was induced by an AC current delivered to the right ventricular endocardium. VF was untreated for 3 min. Animals were r...
Mutation in bone morphogenesis protein receptor 1A (BMPR1A) initiates tumorigenesis via ‘mixed polyposis - carcinoma’ sequence in colorectal cancers.
Authors: Peh Yean Cheah, Yu Hui Wong, Xia Cao, Carol Loi, Kong Weng Eu
Journal: Cancer Research (2007)

5259  Background: Accumulating evidence has indicated that most colorectal cancer (CRC) is initiated by the inactivation of adenomatous polyposis coli (APC) via the multi-step ‘adenomatous polyps-carcinoma’ sequence. The initiating event for the ‘mixed polyposis-carcinoma’ sequence remains unclear. Hereditary Mixed Polyposis Syndrome is characterized by colonic polyps of mixed histological types that are autosomal dominantly inherited and eventually lead to cancer. In previous study, we have identified an 11-bp deletion in exon 2 of the bone morphogenesis protein receptor 1A (BMPR1A) gene as the underlying germline defect in one such family. Methods/Results: In the present study, we screened for BMPR1A mutation by RT-PCR, long-range PCR and cDNA sequencing in six Singapore Chinese HMPS families and one sporadic CRC patient. All patients have colonic polyps of mixed hyperplastic, adenomatous, and occasional juvenile types. Five out of six of the families have patients with CRC. All cases were found to be APC and MYH mutation negative. Exon 4-5 deletion of BMPR1A was found in four out of six of the familial cases, suggesting that this could be the mutational hot spot. This germline mutation deletes the transmembrane domain that anchors the protein to the membrane and hence renders the protein non-functional. The sporadic patient was found to harbor a somatic exon 1-11 deletion in BMPR1A, effectively deleting all the functional domains of the protein, in his inflammed mucosa. Conclusion: Our results suggest that inactivating BMPR1A of the BMP pathway can initiate colorectal tumorigenesis via the ‘mixed polyposis-carcinoma’ sequence in both hereditary and sporadic CRC.
Efficacy of Integrated Exposure Therapy vs Integrated Coping Skills Therapy for Comorbid Posttraumatic Stress Disorder and Alcohol Use Disorder
Authors: Sonya B. Norman, Ryan Trim, Moira Haller, Brittany C. Davis, Ursula S. Myers, Peter J. Colvonen, Erika Blanes, Robert Lyons, Emma Y. Siegel, Abigail C. Angkaw, Gregory J. Norman, Tina Mayes
Journal: JAMA Psychiatry (2019)

Co-occurrence of posttraumatic stress disorder (PTSD) and alcohol use disorder (AUD) is common and associated with psychiatric and functional problems. Understanding whether exposure therapy is tolerable and efficacious for treating PTSD and AUD is critical to ensure that best practice treatments are available.
Financial Incentives for At-home Colorectal Cancer Screening Tests
Authors: Liam Rose
Journal: JAMA Network Open (2019)

Shivan J. Mehta, MD, MBA, MSHP; Rebecca S. Pepe, MPH; Nicole B. Gabler, PhD, MPH, MHA; Mounika Kanneganti, BA; Catherine Reitz, MPH; Chelsea Saia, MPH; Joseph Teel, MD; David A. Asch, MD, MBA; Kevin G. Volpp, MD, PhD; Chyke A. Doubeni, MD, MPH
HGG-22. CHARACTERIZING THE ROLE H3.3G34R MUTATION IN PEDIATRIC HIGH GRADE ASTROCYTOMA
Authors: Byungjin Kim, Robert Siddaway, Scott Milos, Sanja Pajovic, Cynthia Hawkins
Journal: Neuro-Oncology (2019)

PURPOSE: Approximately 20% of hemispheric pHGA have a mutation in the histone H3.3 encoding H3F3A gene, leading to a glycine-arginine substitution (H3.3G34R). However, our understanding of the biological consequences of this mutation remain poor. Here we use a novel proteomics-based strategy to investigate the H3.3G34R-associated changes in the histone interactome. METHOD: We utilized BioID to map the interactome of wildtype (WT) and G34R mutant Histone H3.3. The histones were expressed with an N-terminally tagged BirA* protein that ligates biotin to juxtaposed proteins. Biotinylated proteins were identified through mass spectrometry post biotin affinity capture. RESULTS: Through BioID we identified 343 proteins that had altered interaction with H3.3G34R vs WT H3.3 including histone modifiers/readers. Additionally, DNA repair protein involved in double stranded break (DSB) repair such as BRCA1 and RAD18 lost interaction with H3.3G34R. These findings were validated using Western blot of streptavidin pull downs and proximity ligation assay. To test for H3.3G34R-dependent defects in DSB repair, we generated immortalized normal human astrocytes (iNHAs) expressing H3.3G34R, empty vector (EV) or H3WT. H3.3G34R iNHAs had approximately double the number of yH2AX foci 1 and 24 hours post radiation compared to empty vector and WT control. H3.3G34R cells also had a larger olive tail moment based on the neutral comet assay suggesting a delay in DSB repair kinetics. Furthermore, cells expressing H3.3G34R accumulated 4216 more mutations including 342 indel events over six passages without the presence of an exogenous DNA damaging agent as determined by whole genome sequencing. CONCLUSION: H3.3G34R mutations leads to changes in interactome that suggest an altered function at the chromatin level. Our data suggest that H3.3G34R mutation is inducing genomic instability through loss of function in the DSB repair pathway and may provide a novel avenue of therapeutic vulnerability.
Abstract 19711: Dual-phase Snapshot 320-detector Computed Tomography for the Improvement of Left Atrial Appendage Thrombus Detection
Authors: Keiichiro Kuronuma, Yasuyuki Suzuki, Ayano Makita, Tadashi Ashida, Katsuaki Yokoyama, Eizo Tachibana, Satoshi Kunimoto, Naoya Matsumoto, Atsushi Hirayama
Journal: Circulation (2017)

Introduction: Detection of thrombus in left atrial appendage (LAA) is important for the safe pulmonary vein isolation(PVI) in atrial fibrillation. Although transesophageal echocardiography (TEE) would be rarely associated with fatal complication, TEE is considered as a gold standard device for detecting LAA thrombus. Cardiac computed tomography (CCT) contributes to a safe PVI as a tool of integrated electroanatomic mapping and detection of LAA thrombus. However, diagnostic performance of 320-detector CCT for the detection of LAA thrombus in patients undergoing PVI has not been evaluated. Objectives: Assessing the diagnostic performance of 320-row CCT for the detection of LAA thrombus using TEE as the gold standard. Methods: Consecutive 125 patients (93 men, 32 women, median age 69 years, range 60-76) who performed CCT and TEE between August 2016 and May 2017 at Nihon University Hospital were enrolled. The median interval between CCT and TEE was 2 days (range 1-15 days). All CCT scanning were performed wit...