tbuckley/cabot-search huggingface dataset:
PATH-04. MDM2/4 AMPLIFICATION AND RISK OF HYPERPROGRESSION IN HIGH-GRADE GLIOMAS TREATED WITH CHECKPOINT INHIBITORS
Authors: Laura Donovan, Jessica Schulte, Teri Kreisl, Mary Welch, Andrew B. Lassman, Fabio Iwamoto
Journal: Neuro-Oncology (2018)

Checkpoint inhibitors are revolutionizing cancer treatment. However, there are recent reports of systemic cancer patients treated with checkpoint inhibitors with associated hyperprogressive disease (HPD), a ≥2-fold increase in tumor growth rate at first post-treatment imaging, and worse outcomes. Some reports have suggested that MDM 2/4 amplification in advanced cancer may correlate with higher risk for HPD. MDM2/4 amplifications are relatively common and are reported in up to 20% of glioblastomas. We performed a retrospective review to assess the association between MDM2/4 amplification and HPD in patients with high grade gliomas (HGG) treated with immune checkpoint inhibitors. Of 102 patients with HGG at our institution receiving PD1 inhibitors, 13 patients were identified to have MDM2/4 amplification. 5 were treated upfront and 8 at recurrence with PD1 inhibitors. 7/8 patients at recurrence received concurrent bevacizumab. MRIs, prior to and following initiation of checkpoint inhibitor therapy, were evaluated for evidence of HPD. 6/13 patients had radiographic progression on the first MRI after initiation of treatment. Of these, 1 met criteria for HPD in the setting of a trial with nivolumab and vorinostat. She later resumed nivolumab and avastin with significant radiographic improvement; however, continued to clinically deteriorate and died 6 weeks later. 4/6 patients had radiographic pseudo-progression with subsequent response or stabilization of disease, 1 with pathologic confirmation after re-resection. 1 continued to progress at a similar rate prior to starting immunotherapy. In this small retrospective cohort, 1 patient with MDM2/4 amplification had evidence of HPD after starting treatment with Nivolumab. However, concurrent treatment with vorinostat limits the ability to draw conclusions. Preliminarily, it does not seem that these patients need to be excluded from checkpoint inhibitors trials. After final collection of progression and survival data, we will compare the rate of progression of MDM2/4 amplified HGG to non-amplified MDM2/4 tumors.
Joint Contributions of Rare Copy Number Variants and Common SNPs to Risk for Schizophrenia
Authors: Sarah E. Bergen, Alexander Ploner, Daniel Howrigan, Michael C. O’Donovan, Jordan W. Smoller, Patrick F. Sullivan, Jonathan Sebat, Benjamin Neale, Kenneth S. Kendler
Journal: American Journal of Psychiatry (2018)

Objective: Both rare copy number variants (CNVs) and common single-nucleotide polymorphisms (SNPs) contribute to liability to schizophrenia, but their etiological relationship has not been fully elucidated. The authors evaluated an additive model whereby risk of schizophrenia requires less contribution from common SNPs in the presence of a rare CNV, and tested for interactions. Method: Genetic data from 21,094 case subjects with schizophrenia and 20,227 control subjects from the Psychiatric Genomics Consortium were examined. Three classes of rare CNVs were assessed: CNVs previously associated with schizophrenia, CNVs with large deletions ≥500 kb, and total CNV burden. The mean polygenic risk scores (PRSs) between study subjects with and without rare CNVs were compared, and joint effects of PRS and CNVs on schizophrenia liability were modeled by using logistic regression. Results: Schizophrenia case subjects carrying risk CNVs had a lower polygenic risk than case subjects without risk CNVs but a higher risk than control subjects. For case subjects carrying known risk CNVs, the PRS was diminished in proportion to the effect size of the CNV. The strongly associated 22q11.2 deletion required little added PRS to produce schizophrenia. Large deletions and increased CNV burden were also associated with lower polygenic risk in schizophrenia case subjects but not in control subjects or after removal of known risk CNV carriers. Conclusions: The authors found evidence for interactive effects of PRS and previously associated CNVs for risk for schizophrenia, and the results for large deletions and total CNV burden support an additive model. These findings offer insights into the genetic architecture of schizophrenia by illuminating how different established genetic risk factors act and interact to influence liability to schizophrenia.
HOUT-03. SCREENING FOR MOOD DISTURBANCE IN LONG-TERM CENTRAL NERVOUS SYSTEM (CNS) TUMOR SURVIVORS USING PATIENT REPORTED OUTCOMES MEASUREMENT INFORMATION SYSTEM (PROMIS): A NEURO-ONCOLOGY BRANCH NATURAL HISTORY STUDY (NOB-NHS) REPORT
Authors: María Fletcher Ruiz, Elizabeth Vera, Alvina Acquaye, Lisa Boris, Miranda Brown, Sonja Crandon, Nancy Garren, Ming Ji, Jason Levine, Jennifer Reyes, Christine Siegel, Jing Wu, Mark Gilbert, Terri Armstrong
Journal: Neuro-Oncology (2018)

Survivorship is an important area of cancer care and research. There are limited studies exploring the experience of long term survivors of CNS tumors. A recent review of quality of life in adults with CNS tumors underscored the need for studies exploring patient outcomes, including mood disturbance. This report explores mood disturbance in CNS tumor patients living greater than 5 years from diagnosis. Patients enrolled on the NOB-NHS were included. PROMIS depression/anxiety measures were completed at study entry. T-scores >60 were considered significant. Independent sample t-tests, chi-square and Fishers Exact tests were used to identify associations with mood disturbance. Significance level was set at 0.05. 132 patients, primarily white (84%), males (58%), with median age 49 (22–81), were included with 59% having low grade tumors; oligodendroglioma (19%) was the most common diagnosis, 30% underwent gross total resection, 33% had had a recurrence and 27% had a poor KPS (80). Five percent were on corticosteroids and 20% on psychotropic medications. Overall, 14% and 18% reported significant depression and anxiety respectively, with 10% reporting both. More non-white [29% vs 11%; X2 (1) = 4.4, p<0.04] reported significant depressive symptoms, as did those with poor KPS [25% vs. 10%; X2 (1) = 4.2, p<0.04] and those on psychotropic medications [27% vs 11%; X2 (1) = 4.5, p<0.04]. Anxiety was only associated with the use of psychotropic medications [38% vs. 13%; X2 (1) = 9.3, p<0.01]. Symptoms of depression and anxiety occurred in 20% of long-term brain tumor survivors on screening. Depressive symptoms were associated with race, lower KPS, and use of psychotropic medications. Additionally, use of psychotropic medications was associated with anxiety. Assessment of depression and anxiety as part of survivorship care is warranted. Future studies exploring phenotypes at risk and targeted interventions are needed to mitigate these symptoms.
PDTM-14. MiR-1253 IS A NOVEL TUMOR SUPPRESSOR GENE IN MEDULLOBLASTOMA
Authors: Ranjana Kanchan, Naveen Perumal, Pranita Atri, Ishwor Thapa, Mohd Nasser, Deborah Perry, Surinder Batra, Sidharth Mahapatra
Journal: Neuro-Oncology (2018)

Medulloblastoma (MB), the most common malignant pediatric brain tumor, is a leading cause of childhood related morbidity and mortality. Large-scale transcriptional profiling and mutational analyses have facilitated the stratification of medulloblastoma into four primary subgroups, i.e. SHH (sonic hedgehog), WNT (wingless), and non-SHH/WNT groups 3 and 4. The most frequent cytogenetic abnormality in medulloblastoma, i.e. i17q, distinguishes the non-SHH/WNT subgroup. Haploinsufficiency of 17p13.3 is reported in up to 50% of human MB cases. Included within this locus is miR-1253, which is exclusively expressed in the brain and an important regulator of bone morphogenic proteins that play a critical role in cerebellar development. Recently, two oncogenic targets of miR-1253, i.e. TGIF2 and ALX4, were identified in SHH medulloblastoma. Based upon these observations, we hypothesized that miR-1253 may be a putative tumor suppressor gene that undergoes epigenetic silencing in pediatric medulloblastoma. We first discovered reduced expression of miR-1253 in 24 pediatric medulloblastoma specimens and in 7 medulloblastoma cell lines. We then learned that miR-1253 silencing is accomplished via hypermethylation; expectedly, de-methylation of miR-1253, resulted in the recovery of expression with a subsequent decline in MB cell proliferation. MiR-1253 restoration was further concomitant with activation of apoptotic pathways and cell cycle arrest at G0/G1 phase. Moreover, miR-1253 overexpression led to a reduction in cell proliferation, colony formation, migration and invasive potential of MB tumor cell lines. Using high throughput RNA sequencing analysis and luciferase reporter assay, we further identified several oncogenic targets of miR-1253, including CDK-6 and CD276. Taken together, these data strongly support a tumor suppressive role for miR-1253. This would be the first time such an effect has been attributed to miR-1253 in the context of medulloblastoma.
COMP-12. TOWARDS BIG DATA IN DIGITAL NEUROPATHOLOGY WITH THE DIGITAL BRAIN TUMOR ATLAS
Authors: Thomas Roetzer, Anna-Christina Moser, Petra Mercea, Romana Prihoda, Baran Atli, Johannes Hainfellner, Bernhard Baumann, Georg Langs, Adelheid Woehrer
Journal: Neuro-Oncology (2018)

Digital methods are increasingly applied to enhance disease classification, tissue segmentation, and prognostic profiling in virtually all medical specialties. They are recognized also for informing precision diagnostics in neuropathology. However, most computational algorithms depend on large training data sets, which are not yet readily available for tissue slides. Regarding brain tumors, only single histological repositories are freely available, which cover only few tumor types and are limited by poor tissue morphology. Thus, in order to fill this gap, we are in the process of establishing the ‘Digital Brain Tumor Atlas’, which will span the full diagnostic spectrum of brain tumors according to the latest WHO classification. The repository will be based on digitized slides from MedUni Vienna’s neurobiobank, which is one of the largest in Europe containing well over 500,000 surgical samples from 1882 to 2018. We are currently scanning a total of 10,000 diagnostic H&E-stained brain tumor slides at high resolution using a Hamamatsu NanoZoomer XR scanner. To date, roughly 2,700 whole slide images that cover 102 different brain tumor types have already been digitized. All slides will be annotated with tumor type (including molecular subtype where applicable) and location as well as patient age and sex. We will put special focus on the group of diffuse gliomas, for which we have already scanned 500 slides, each providing expert segmentations for compact tumor, necrosis, hemorrhage, and pre-existing brain tissue. In the future, this unique brain tumor slide repository will be made freely available online to enhance further research in digital neuropathology by 1, providing all data necessary for training meaningful machine learning algorithms and 2, comprising an independent dataset for external validation purposes.
Engineering of structural variants of the major peanut allergens Ara h 2 and Ara h 6 for allergen-specific immunotherapy
Authors: Merima Bublin, Maria Kostadinova, Christian Radauer, Eva-Maria Varga, Christine Hafner, Klara Schmidthaler, Aziza Saidova, Soheila J. Maleki, Zsolt Szépfalusi, Thomas Eiwegger, Heimo Breiteneder
Journal: Journal of Allergy and Clinical Immunology (2018)
NIMG-39. THE EVALUATION OF DIFFUSION TENSOR TRACTOGRAPHY USING MIXED REALITY INTEGRATED VIRTUAL SPACE AND REAL SPACE
Authors: Tsukasa Koike, Taichi Kin, Taketo Shiode, Shunsaku Takayanagi, Shota Tanaka, Akitake Mukasa, Nobuhito Saito
Journal: Neuro-Oncology (2018)

PURPOSE: Diffusion tensor tractography (DTT) is a method to estimate the direction of white matter fibers, but it is not easy to verify the relationship with brain functions accurately. We developed mixed reality computer graphics (MRCG) which integrates real space (brain surface image) and preoperative 3DCG (3-dimentional computer graphics). In our previous study, this method allowed high precision registration even after brain shift caused by craniotomy, and target registration error was 0.5 ± 0.04mm (mean±SE). We devised a method to investigate the spatial error of DTT and direct cortical stimulation (DCS) using MRCG. We examine its accuracy and clinical application. We covered 4 patients with glioma who were underwent awake surgery. The sex of all the patients was male, and the average age was 40. MRCG was constructed by fusing 3DCG prepared before surgery and brain surface photograph (JPEG format) just after craniotomy using our original method, which is called thin plate spline method with some landmarks. Brain function mapping results by DCS were plotted on MRCG. In the surface photograph, we provided grids of 1cm square, then we jagged the site where positive symptoms appeared by DCS was true, and the negative site was false. The spatial error between the cortical cortex and brain function mapping estimated by arcuate fiber of DTT was measured. In 4 cases, DCS was performed in 36 places (average 9 places / case). The sensitivity and specificity of DTT were 0.21 and 0.68, false positive rate and false negative rate were 0.31 and 0.79, respectively. In surgery, the tumor resection was performed with reference to MRCG reflecting the brain function mapping result. The proposed method investigated at real space and virtual space suggests DTT does not necessarily match the results of DCS.
PDCT-07. FEASIBILITY TRIAL OF TTFIELDS (TUMOR TREATING FIELDS) FOR CHILDREN WITH RECURRENT OR PROGRESSIVE SUPRATENTORIAL HIGH-GRADE GLIOMA (HGG) AND EPENDYMOMA: A PEDIATRIC BRAIN TUMOR CONSORTIUM STUDY: PBTC-048
Authors: Stewart Goldman, Eugene Hwang, Jin-Shei Lai, Mehmet Kocak, Rishi Lulla, Girish Dhall, Nathan Robison, Arzu Onar-Thomas, Ira J. Dunkel
Journal: Neuro-Oncology (2018)

Children with recurrent or progressive pediatric CNS tumors have poor prognoses. Optune delivers TTFields, an anti-mitotic FDA-approved cancer therapy, for adult patients with newly diagnosed and recurrent supratentorial GBM. This multicenter trial [NCT03033992] examines the feasibility and device-related toxicity of TTFields in 20 children aged 5–21 years with recurrent supratentorial HGG and ependymoma. Secondary objectives include: response rate, event-free survival, compliance and QoL. Feasibility in this trial is defined as the ability of pediatric subjects to wear Optune ≥18 hours/day for at least 23/28 days of cycle one following a 7-day learning period. Treatment may continue up to 26 cycles based on observed benefit and safety. QOL instruments include PROMIS and Neuro-QOL. Following enrollment of the 11th evaluable subject, the study will be temporarily suspended to share interim feasibility and safety data with the FDA. This planned interim analysis included 11 patients (7 males/4 females) with supratentorial tumors: ten HGG and one ependymoma. Median age was 14.2 (6.4–21.3) years. Ten patients were evaluable (1 Progressive Disease) during the feasibility period) and 4 remained on study through 4 cycles and one patient is currently on Cycle 14. One grade 5 intracranial hemorrhage not associated with the device and no grade IV toxicities occurred, 3 patients had seizures (grade 1–3), fatigue, scalp pain, localized rash, and headache (none greater than grade 3). Of the 10 evaluable patients, 7 satisfied the feasibility criteria for the Optune therapy, which is above the prespecified threshold of at least 6/11. This is the first prospective safety and feasibility trial for Optune in children with recurrent supratentorial HGG and ependymoma. Preliminary results indicate feasibility with minimal toxicity. Accrual to the study is ongoing. An amendment is in progress adding a stratum for newly diagnosed diffuse intrinsic pontine glioma (DIPG) patients.
ATIM-39. IMPROVED SURVIVAL NOTED IN GLIOBLASTOMA PATIENTS TREATED WITH ADJUVANT TLR-3 AGONIST IN SETTING OF AUTOLOGOUS LYSATE-PULSED DC VACCINATION
Authors: Joseph Antonios, Richard Everson, Horacio Soto, Sara Khattab, Jacob Bethel, Matthew Sun, Aaron Mochizuki, Alexander Lee, Sylvia Odesa, Emma Billingslea-Yoon, Diana Moughon, Anthony Wang, Tim Cloughesy, Robert Prins, Linda Liau
Journal: Neuro-Oncology (2018)

Despite advances in the understanding of glioblastoma multiforme (GBM) molecular biology, genomics, and tumor microenvironment, prognosis for patients diagnosed with this disease remains dismal with standard therapies. We and others have shown utility in dendritic cell (DC) vaccination as an active immunotherapeutic treatment for these patients. In this study, we evaluated the use of autologous tumor lysate puled DC vaccine with and without adjuvant toll-like receptor (TLR) agonists. TLRs are present on dendritic cells and serve to modulate immune responses. Twenty-three patients with WHO Grade III or IV glioma were treated with three intradermal injections of autologous tumor lysate-pulsed DC on days 0, 14, and 28 followed by adjuvant placebo treatment, resiquimod (TLR-7 agonist), or poly ICLC (TLR-3 agonist). Gene expression profiling, immunohistochemistry, and mass cytometry (cyTOF) were performed on patient tumors and peripheral blood mononuclear cells. Patients that received adjuvant poly ICLC had a significantly improved median survival of 54 months over placebo (11 months) and adjuvant resiquimod (17 months) groups. Within each treatment cohort, patients with Grade III tumors had increased overall survival over Grade IV tumors. Overall, patients with MGMT methylated tumors on pathology had a median survival of 57 months, while patients with MGMT unmethylated tumors had a median survival of 19 months. Our findings suggest that adjuvant TLR-3 agonist improves outcomes with autologous lysate-pulsed DC vaccine treatment.
Beyond Autoantibodies: Biologic Roles of Human Autoreactive B Cells in Rheumatoid Arthritis Revealed by RNA‐Sequencing
Authors: Ankit Mahendra, Xingyu Yang, Shaza Abnouf, Jay R. T. Adolacion, Daechan Park, Sanam Soomro, Jason Roszik, Cristian Coarfa, Gabrielle Romain, Keith Wanzeck, S. Louis Bridges, Amita Aggarwal, Peng Qiu, Sandeep K. Agarwal, Chandra Mohan, Navin Varadarajan
Journal: Arthritis & Rheumatology (2018)

Objective To obtain the comprehensive transcriptome profile of human citrulline‐specific B cells from patients with rheumatoid arthritis ( RA ). Methods Citrulline‐ and hemagglutinin‐specific B cells were sorted by flow cytometry using peptide–streptavidin conjugates from the peripheral blood of RA patients and healthy individuals. The transcriptome profile of the sorted cells was obtained by RNA ‐sequencing, and expression of key protein molecules was evaluated by aptamer‐based SOMA scan assay and flow cytometry. The ability of these proteins to effect differentiation of osteoclasts and proliferation and migration of synoviocytes was examined by in vitro functional assays. Results Citrulline‐specific B cells, in comparison to citrulline‐negative B cells, from patients with RA differentially expressed the interleukin‐15 receptor α ( IL ‐15Rα) gene as well as genes related to protein citrullination and cyclic AMP signaling. In analyses of an independent cohort of cyclic citrullinated peptide–seropositive RA patients, the expression of IL ‐15Rα protein was enriched in citrulline‐specific B cells from the patients’ peripheral blood, and surprisingly, all B cells from RA patients were capable of producing the epidermal growth factor ligand amphiregulin ( AREG ). Production of AREG directly led to increased migration and proliferation of fibroblast‐like synoviocytes, and, in combination with anti–citrullinated protein antibodies, led to the increased differentiation of osteoclasts. Conclusion To the best of our knowledge, this is the first study to document the whole transcriptome profile of autoreactive B cells in any autoimmune disease. These data identify several genes and pathways that may be targeted by repurposing several US Food and Drug Administration–approved drugs, and could serve as the foundation for the comparative assessment of B cell profiles in other autoimmune diseases.
RARE-13. CHARACTERIZATION OF ADULT MEDULLOBLASTOMA PATIENTS AT RECURRENCE: RETROSPECTIVE REVIEW OF THE MD ANDERSON CANCER CENTER EXPERIENCE
Authors: Maximilian Mastall, Nazanin Majd, Gregory Fuller, Maria Gule-Monroe, Jason T Huse, Soumen Khatua, Ganesh Rao, David Sandberg, Jeffrey Wefel, Debra Yeboa, Wafik Zaky, Anita Mahajan, Vinay Puduvalli, Dima Suki, Kristin Alfaro, Shiao-Pei Weathers, Rebecca Harrison, John de Groot, Marta Penas-Prado
Journal: Neuro-Oncology (2018)

Adult medulloblastoma (MB) is rare, accounting for 150–300 new cases in the US annually. Given the low incidence, prospective studies are challenging, and treatment guidelines and recurrence characteristic are derived from pediatrics. However, adult MB is a distinct entity, and further studies are warranted. Surgery followed by radiation and chemotherapy are accepted treatment modalities, but there is limited information on characteristics and outcomes of adult MB at recurrence. 136 adult MB patients (≥18 years at diagnosis) were identified at MD Anderson from January 1978 to April 2017. Median progression-free survival (PFS) and overall survival (mOS) were estimated using the Kaplan-Meier method. Median age 28 (18–63); 53.7% standard risk (SR) (minimal residual disease and no metastasis) and 32.4% high risk (HR) (indeterminate in 19). Median PFS and mOS for the entire cohort were 98 and 133 months, respectively. No residual tumor after initial surgery and use of adjuvant chemotherapy were associated with improved survival, but M status was not. 44.9% had developed recurrence at median follow-up of 59.5 months (34.4% were SR and 42.6% were HR); median time to 1st recurrence was 34 months; mOS after first recurrence was 23 months. Local recurrence was associated with improved survival compared to distant recurrence. To our knowledge, this is the largest series of adult MB from a single institution. Extent of surgery was associated with improved survival, which is an established positive prognostic indicator in pediatric MB but has been controversial in adults. Adjuvant chemotherapy was associated with improved survival in patients without residual tumor after first surgery. Late recurrences were more common than in the pediatric population, highlighting the need for long term follow-up. Adult MB patients have a poor mOS of 23 months after recurrence, and optimizing treatments at recurrence is an unmet need.
Notice of Duplicate Publication: Performance of the Simplified American Academy of Pediatrics Table to Screen Elevated Blood Pressure in Children
Authors: Bo Xi
Journal: JAMA Pediatrics (2018)

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 Pediatrics HomeNew OnlineCurrent IssueFor Authors Podcast 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 Pediatrics journal