tbuckley/cabot-search huggingface dataset:
RARE-20. BRAF MUTATIONS IN PEDIATRIC GANGLIOGLIOMAS AND THE CLINICAL SIGNIFICANCE AN MD ANDERSON CANCER CENTER EXPERIENCE
Authors: Sheetal Phadnis, Shekhar Patil, MInjeong Park, Diane Liu, Wei-Lien Wang, Khalida Wani, Susana Calle, Heather Meador, Leena Ketonen, Wafik Zaky, Soumen Khatua
Journal: Neuro-Oncology (2018)

Ganglioglioma (GG) is a rare mixed glioneuronal neoplasm accounting for 0.5–5% of all pediatric central nervous system tumors. BRAF V600E mutation has been previously reported in GG but its incidence and impact remain unknown. This retrospective study evaluates the incidence of BRAF mutation in GG and its prognostic implication. PATIENTS AND Retrospective review of 55 patients under the age of 21 years diagnosed with GG at our institution from 1992 to 2012 was performed. Patient demographics, clinical history, radiological features, treatment data and molecular analysis data were collected and analyzed. Molecular testing using next generation gene sequencing and /or immunohistochemistry (IHC) to identify BRAFV600E mutation was performed in available tumor specimens. Kaplan-Meier survival and Cox-regression analyses were performed to assess the overall survival (OS) and progression-free survival (PFS). 55 patients with GG were identified; tumor tissue was available for 21 patients for molecular analysis. Two specimens were inadequate for analysis, 19 patients specimens were tested for BRAF mutation, 3 using sequencing and 16 using IHC. BRAF V600E was detected in nine patients specimens (47%). BRAF mutation was equally distributed among both genders. No association was found with tumor location, size, metastatic status or imaging characteristics. There was no difference in outcome between patients with BRAF mutated tumors versus non mutated tumors, with the 10 years PFS and OS 77.8% versus 51.4% and 88.9% versus 100% (p=0.26, p= 0.29), respectively. Unfortunately, the study number is small to draw statistical conclusion. We present one of the largest retrospective studies in pediatric GG. Though limited sample numbers were probed for BRAF mutation in our study, our data suggests similar incidence as reported in the literature. Prospective studies should continue to evaluate this molecular event, and newer generation of BRAF inhibitors should be profiled which could improve clinical outcome.
ACTR-15. SAFETY AND PRELIMINARY ACTIVITY OF PT2385, A FIRST-IN-CLASS HIF2-ALPHA INHIBITOR, PLANNED INTERIM ANALYSIS OF AN OPEN LABEL, SINGLE-ARM PHASE II STUDY IN PATIENTS WITH RECURRENT GLIOBLASTOMA
Authors: Roy Strowd, Benjamin Ellingson, Patrick Wen, Manmeet Ahluwalia, Anna Piotrowski, Arati Desai, Jennifer Clarke, Frank Lieberman, Serena Desideri, L Burt Nabors, Stuart Grossman
Journal: Neuro-Oncology (2018)

Hypoxia inducible factor 2-alpha (HIF2a) is a stress response transcription factor that mediates the cellular response to hypoxia. HIF2a is an underexplored target in glioma. PT2385 is a first-in-class oral HIF2a inhibitor with favorable blood-brain barrier penetrating properties and in vivo single-agent activity against glioblastoma (GBM). A single-arm open-label phase II study of adults with bevacizumab-naïve first recurrence of GBM following chemoradiation with measurable disease was conducted within the Adult Brain Tumor Consortium. PT2385 was administered at the recommended phase II dose (800 mg b.i.d.). The primary study outcome is objective radiographic response (CR+PR). Secondary objectives are safety, overall survival, and progression-free survival. Patients at selected study sites underwent pH-weighted amine-CEST MRI imaging to quantify tumor acidity at baseline and explore associations with drug response. Results of planned interim analysis are presented. 24 patients were enrolled; mean age 61 ± 11 years, 63% male, 92% white, median KPS 80. MGMT promoter was methylated in 46%, unmethylated in 50%, and indeterminate in 1 patient. Prior surgery included biopsy (8%), subtotal (38%) and gross total resection (54%). To date, 21 patients have progressed at a median of 7.7 weeks (95%CI 4.66–12.3 weeks). No objective radiographic responses have been observed. Three patients continue on treatment at a median of 19 weeks (95%CI 12–19.1). The drug was well tolerated with expected side effect profile. Common Grade 1–2 drug-related adverse events were anemia, dyspnea, and thrombocytopenia. Grade 3–4 drug-related adverse events included hypoxia (n=2, 8%), anemia (n=1, 4%), and hypophosphatemia (n=1, 4%). At baseline, pH-weighted MRI showed high levels of acidity and intratumoral heterogeneity. PK and PD data are forthcoming. Results of this planned interim analysis suggest that single-agent PT2385 has acceptable safety but minimal activity in glioblastoma patients after first recurrence. Ongoing analysis will explore patterns of progression and correlate these with tumor acidity measurements.
ATIM-22. PROGNOSTIC VALUE OF PTEN LOSS IN NEWLY DIAGNOSED GBM PATIENTS TREATED WITH AUTOLOGOUS HEAT SHOCK PROTEIN VACCINE
Authors: Paula Alcaide Leon, Tracy Luks, Marisa Lafontaine, Jennifer Clarke, Susan Chang, Sarah Nelson, Orin Bloch, Javier Villanueva-Meyer
Journal: Neuro-Oncology (2018)

INTRODUCTION: The safety and efficacy of a heat shock protein peptide complex- 96 vaccine (HSPPC-96, Prophage) has been previously studied in phase II single-arm trials for the treatment of newly diagnosed and recurrent glioblastoma (GBM). These studies demonstrated modest improvements in survival compared with historical standards. PTEN loss has been recently associated with immunoresistance in GBM patients, mediated in part by B7-H1. PTEN status has not shown clear prognostic value in GBM patients treated with standard of care therapies. The aim of this study is to evaluate the prognostic significance of PTEN status in newly diagnosed GBM patients treated with autologous HSP vaccine and standard chemoradiation. Our institutional cohort of patients enrolled in a single arm, phase II study of adult GBM patients treated with autologous HSP vaccine and standard chemoradiation (n=27) was analyzed. Differences in overall survival (OS) by PTEN status were evaluated via Kaplan-Meier curves and Log-rank test. Median overall survival (n=27) was 26 months. 23 patients had PTEN status available. PTEN loss was found in 16 patients (69.6%) whereas retained PTEN was present in 7 patients (30.4%). Median OS was 59 months (95% CI, 0–120 months) in patients with retained PTEN and 23 months (95% CI, 15–30 months) in patients with PTEN loss. The difference in OS was statistically significant (p=0.037). CONCLUSION: Retained PTEN expression was associated with extended survival in GBM patients treated with HSP vaccine. This finding suggests that PTEN loss may be associated with resistance to vaccine treatment and emphasizes the need for subgroup analysis in further immunotherapy studies.
Diagnostic vs Management Reasoning
Authors: Jayshil J. Patel, Paul A. Bergl
Journal: JAMA (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 HomeNew OnlineCurrent IssueFor Authors 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) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More 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
Risk factors for MI are more potent in women, finds study
Authors: Zosia Kmietowicz
Journal: BMJ (2018)

High blood pressure, smoking, and diabetes increase the risk of myocardial infarction in both sexes but have more of an impact in women than they do in men, shows a study in The BMJ .1

The findings emphasise that women should have the same access to treatments for these risk factors as men do, said the researchers.

Overall, men are at greater risk of myocardial infarction than women, but several studies have indicated that certain risk factors …
Expression and regulation of various tumor suppressor genes in gastrointestinal stromal tumor
Authors: Keun Hur, Hyuk-Joon Lee, Han-Kwang Yang
Journal: Cancer Research (2006)

1608  Gastrointestinal stromal tumors (GISTs) are Kit/CD117 expressing mesenchymal tumors. Aberrant hypermethylation of promoter CpG islands is an important mechanism for the inactivation of tumor suppressor genes. CpG island hypermethylation occurs in relation to tumorigenesis in many human tumors. Moreover, we have previously reported that transcriptional repression of Cox-2 is caused by hyper-methylation of the Cox-2 promoter region CpG island in human gastric carcinoma (BBRC., 310(3), 844-851, 2003). The pathogenesis of GISTs involves a gain-of-function mutation in the KIT proto-oncogene, leading to ligand-independent constitutive activation of the KIT receptor. KIT-wild-type GISTs have shown mutually exclusive platelet-derived growth factor receptor (PDGFR) mutation and activation. However, the data on the methylation status of various tumor suppressor genes and mutation status of KIT and PDGFR in GISTs has been very limited. We attempted to determine the methylation status of 12 genes (APC, COX-2, GSTP1, MGMT, p14, p16, RUNX-3, THBS-1, TIMP-3, DAP-kinase, E-cadherin, RASSF1A), in 30 human gastrointestinal stromal tumor tissues. In addition, we confirmed the mutation status of KIT and PDGFR genes in 30 human gastrointestinal stromal tumor tissues. Thirty c-kit-positive Gastrointestinal stromal tumors were selected for this study. Genomic DNAs and RNAs from human Gastrointestinal stromal tumors were analyzed for the relationship between expression and methylation status by cDNA microarray and methylation specific PCR (MSP). CpG island hyper-methylation was found in 40% for APC, 46% for COX-2, 16% for GSTP1, 26% for MGMT, 60% for p14, 30% for p16, 16% for RUNX-3, 23% for THBS-1, 10% for TIMP-3, 20% for DAP-kinase, 36% for E-cadherin, 10% for RASSF1A. Our results suggest that the DNA methylation-mediated transcriptional silencing of various tumor suppressor genes is a predominant mechanism for the down-regulation of various tumor suppressor genes expression in human gastrointestinal stromal tumors.
INNV-24. SAFETY OF TUMOR TREATING FIELDS IN GLIOBLASTOMA PATIENTS WITH IMPLANTED NON-PROGRAMMABLE AND PROGRAMMABLE SHUNTS, AND PACEMAKERS/DEFIBRILLATORS: 6.5-YEAR UPDATED RETROSPECTIVE ANALYSIS
Authors: Yvonne Kew, Nancy Ann Oberheim Bush
Journal: Neuro-Oncology (2018)

Tumor Treating Fields (TTFields) are a noninvasive, loco-regional, anti-mitotic cancer treatment approved in the U.S. for adults with recurrent and newly diagnosed glioblastoma (GBM). TTFields (low intensity, intermediate frequency, alternating electric fields) are delivered by a portable medical device (Optune®). GBM patients may develop hydrocephalus and benefit from subsequent shunt placement. Safety information on concomitant use of TTFields with implanted devices in GBM patients will identify potential interference with the functioning of these devices. A review of the clinical information for GBM patients treated with TTFields in the U.S. between November 2011 and May 2018 identified 79 patients with non-programmable shunts (NPS), 11 with programmable shunts (PS), and 14 with pacemakers/defibrillators (PM/DF). The safety data obtained from post-market surveillance in all 104 patients were analyzed to identify implantable device-related adverse events. Adverse events (AEs) reported for these 104 patients did not reveal any new safety concerns on concurrent use of Optune with implanted devices. Infections or infestations (bronchitis, diverticulitis, infection NOS, meningitis, sepsis, shunt infection, upper respiratory and urinary tract infections, wound infection) were reported in 13/79 (15.2%) of NPS patients and in 4/11 (36.4%) of PS patients. No arrhythmia or other cardiac adverse events were reported in the 14 patients with PM/DF. Skin irritations were seen in 4/79 (5.1%) of NPS patients. Neurological symptoms (35.4%), which included convulsions (15.2%) in the NPS patients were related to the underlying tumor rather than TTFields treatment. Hydrocephalus was seen in 6/79 (7.6%) NPS and 2/11(18.2%) PS patients but were not related to shunt malfunction. No unexpected safety issues were observed in the 104 patients analyzed in this updated report. Further evaluation of the concurrent use of TTFields with programmable shunts and pacemaker/defibrillators should include bench testing of the compatibility of these devices to TTFields.
NIMG-11. DIFFERENTIATING TREATMENT-INDUCED EFFECTS FROM TRUE RECURRENT HIGH GRADE GLIOMA USING MULTIPARAMETRIC MRI TECHNIQUES
Authors: Julia Cluceru, Sarah Nelson, Annette Molinaro, Joanna J Phillips, Beck Olson, Marisa Lafontaine, Angela Jakary, Devika Nair, Susan Chang, Paula Alcaide-Leon, Mitchel Berger, Janine Lupo
Journal: Neuro-Oncology (2018)

Recurrent high grade gliomas (rHGG) are difficult to diagnose accurately as they are often confounded with treatment-induced effects (TxE) because on conventional T1w and T2w anatomical MR imaging these two phenomena appear identical. This could result in removing a patient from an effective second-line therapy, confound the results of a clinical trial of a new therapeutic, and expose a patient to unnecessary surgical intervention. Advanced MR imaging modalities have shown promise in distinguishing between TxE and rHGG, but prior studies are unable to account for heterogeneity within the same lesion and often lack pathological confirmation. The goal of this study was to identify imaging parameters that could spatially map directly to pathology to account for heterogeneity within lesions. 1–8 tissue samples were collected upon surgical resection of suspected rHGG. A total of 484 samples were collected from 183 patients; 332 of these (163 patients) were labeled as either pathologically confirmed treatment effect or having no tumor cells (tumor score=0) within the imaging abnormality (TxE; 80/51 samples/patients) or rHGG (tumor score=2–3; 252/118 samples/patients) by a pathologist. Preoperative 3T MRI scans included T1w-Gd and T2w FLAIR; diffusion tensor imaging (b=1000s/mm2); 3D MRSI; and dynamic susceptibility-contrast perfusion MRI. Univariate models were created using generalized estimating equations to evaluate each variable’s ability to distinguish TxE from rHGG tissue samples. Normalized choline (median=1.1 TxE & 1.2 rHGG), choline-to-NAA index (CNI, median=2.4 TxE & 3.5 rHGG), and normalized cerebral blood volume (nCBV, median=1.2 TxE & 1.4 rHGG) were significantly associated with biopsy-level classification (p=0.034, 0.015, 0.017). These results are being consolidated into a multiparametric algorithm for predicting TxE or rHGG, which could be of clinical importance in managing patients with recurrent rHGG. Downstream analysis will create a spatial map of rHGG to help guide future surgical sampling.
NIMG-38. QUANTITATIVE IMAGING PREDICTORS OF OVERALL SURVIVAL IN GLIOBLASTOMA PATIENTS ROBUST IN THE PRESENCE OF INTER-SCANNER VARIATIONS
Authors: Saima Rathore, Spyridon Bakas, Hamed Akbari, Martin Rozycki, Christos Davatzikos
Journal: Neuro-Oncology (2018)

Glioblastoma is the most aggressive primary adult brain tumor with median overall survival (OS) of ~14 months following treatment. Although associations have been shown between multi-parametric magnetic resonance imaging (mpMRI) signatures and OS in glioblastoma patients, there is no sufficient validation across different institutions/scanners. This study explores appropriate normalization approaches and multivariate machine learning (ML) to identify robust and reproducible imaging predictors of OS across scanners/institutions. We identified a retrospective cohort of 208 patients, who underwent surgery with gross total resection status, and had available mpMRI (T1,T1-Gd,T2,T2-FLAIR,DTI,DSC) data from three different scanners in the Hospital of the University of Pennsylvania. Median OS was used as a cut-off between long- and short-survivors. Inter-scanner harmonization of mpMRI was conducted by normalizing the tumor intensity profile, with that of the contralateral healthy tissue. Intensity distributions, morphological, statistical, and texture descriptors extracted from intensity-normalized tumor sub-regions (enhancing, non-enhancing, edematous), were multivariately integrated via ML to derive predictors of patient OS. The predictors generalizability on unseen patient data was evaluated under two configurations: i) pooled/scanner-agnostic using 10-fold cross-validation, and ii) across scanners (training in multiple scanners and testing in one). The accuracy for predicting long- versus short-survivors was 80.64% (sensitivity=82.82%, specificity=78.16%, area under the curve [AUC]=0.79) and 75.26% (sensitivity=80.80%, specificity=68.97%, AUC=0.75) for pooled/scanner-agnostic and across-scanner configuration, respectively. The short-survivors, compared to long-survivors, showed relatively large and irregular infiltrating tumor, increased and compromised tumor microvascularity (DSC, T1-Gd), lower water concentration (T2), and higher cell density (DTI). Our findings suggest that quantitative analysis of appropriately normalized clinically-acquired mpMRI, coupled with ML, yields non-invasive robust predictors of OS for glioblastoma patients in presence of inter-scanner variations. Further validation of our predictors in more extensive multi-institutional datasets, can facilitate their potential incorporation into clinical practice, influencing surgical decision-making, treatment planning, and assisting patient management.
COMP-14. TUMOR EVOLUTION DIRECTED GRAPHS IMPLY THERAPIES AGAINST MOVING TARGETS IN PAN-GLIOMAS
Authors: Jiguang Wang
Journal: Neuro-Oncology (2018)

Precision cancer medicine aims at defining targeted treatments based on personalized mutations. While this approach has been successfully applied to a few cancers, there are several obstacles in the adoption of these approaches in complex tumors such as the gliomas. Among the main challenges that preclude the efficacy of targeted therapies are clonal heterogeneity (different cancer cells within a tumor can present diverse genetic make-up), and the dynamic nature of tumors (tumors evolve to explore niches and escape therapies). To address this challenge and to predict the evolution of gliomas, we have applied the tumor evolution direct graph framework [1] to a longitudinal cohort of genomic data from 260 glioma patients. Since cancer is a dynamic process, the optimal treatment should not only consider present characteristics of cancer cells but also the evolutionary trends, which might eventually determine the clinical outcome. To this end, our framework assembles existing computational pipelines and machine-learning approaches to learn the patterns of tumor evolution and to assign the sequential order of key driving somatic alterations in glioma progression. In addition to our previous observations [2–3], this study found that TERT promotor mutations, chromosome 1p and 19q co-deletion, PDGFA amplification, and FGFR3-TACC3 fusion are all significantly early events. Meanwhile, not limited to hypermutation and mismatch repair protein alterations, a remarkable number of cases harbor tyrosine kinase mutations (such as EGFR and MET) at the late stage, highlighting the importance of targeting moving targets in treating recurrent gliomas. More importantly, the order of somatic mutations inferred from this longitudinal cohort was also used to preclude tumor behaviors based on early alterations, which provides the possibility of early-stage intervention based on moving targets. [1] Wang, et al. eLife, 3:e02869 (2014). [2] Wang, et al. Nature Genetics, 48:768–776 (2016). [3] Lee, Wang, et al. Nature Genetics, 49:594–599 (2017).
PATH-43. RETROSPECTIVE RECLASSIFICATION OF ADULT GLIOMAS FROM A MANITOBA PATIENT COHORT ACCORDING TO THE WHO 2016 GUIDELINES
Authors: Amy Norquay, Marshall Pitz, Pascal Lambert, Katie Galloway, Sherry Krawitz
Journal: Neuro-Oncology (2018)

The new WHO 2016 classification of CNS tumours classifies adult gliomas based on the presence or absence of two key molecular markers, IDH mutation and 1p/19q co-deletion. We applied the new criteria to Manitoba glioma patients diagnosed between 2013–2016 with the objective of assessing the distribution of molecular markers among the entire population of glioma patients, assess the prognostic power of the molecular markers, and evaluate the impact of the new classification system on patients. In total, 203 patients were included, and the majority of gliomas were IDH wild type (81.8%). Among the IDH mutant tumours, 9.9% were 1p/19q intact and/or ATRX loss, and 8.4% were 1p/19q co-deleted. The WHO 2016 was impactful on patients such that roughly one third were reclassified into 2016 diagnostic categories with different prognoses. Molecular markers were marginally better than grade at predicting progression free survival, however, the predictive power of the model was improved when molecular markers and grade were included in the same model.
NIMG-59. VALIDATION OF QUANTITATIVE VESSEL SIZE IMAGING (VSI) IN HUMAN GLIOMAS USING IMAGE-GUIDED STEREOTACTIC BIOPSIES
Authors: Ararat Chakhoyan, Kevin Leu, Robert Harris, Whitney Pope, Noriko Salamon, William Yong, Albert Lai, Linda Liau, Phioanh Nghiemphu, Timothy Cloughesy, Benjamin Ellingson
Journal: Neuro-Oncology (2018)

Angiogenesis is critical for brain tumor development and malignant transformation1, influencing both prognosis and response to therapy. The vessel size imaging (VSI) 2 is a quantitative technique that estimates the mean diameter of vessels by using multi-echo spin-and-gradient-echo (SAGE) dynamic susceptibility contrast (DSC) perfusion MRI. In the current study, we compared rCBV and VSI maps to histology-equivalent estimates of vessel density and vessel diameter in high grade glioma patients, using stereotactic image-guided biopsies. A total of 26 image-guided biopsies were obtained in 11 glioma patients (7 grade III and 4 glioblastoma). MRI examinations were acquired prior to surgery on a 3T MRI, including multi-echo SAGE DSC perfusion (2x gradient echo, 1x asymmetric echo, and 1x spin-echo). One to three biopsy targets (5mm radius) were defined and stereotactically biopsied. Relative cerebral blood volume (rCBV) was calculated3 using DSC data from a single gradient echo. VSI was quantified as VSIm= 0.867(ADC.rCBV)^(1/2)((R_2^*)/R_2^(3/2)) where ADC is the apparent diffusion coefficient (mm2/s), R2* and R2 are transverse relaxation rates. Histologically estimates of VSIHisto. were obtained as previously modelized.4 Our results suggest that no differences exist in vessel density and VSI from histology between grade III and IV. Indeed, ADC, rCBV and VSI are similar within targets for those grades. We observed a significant correlation between rCBV and vessel density (r=0.42, p=0.032) but not between rCBV and VSIHisto.. Interestingly, VSIMRI was independent of vessel density but highly correlated with VSIHisto. MR measures of VSI exhibit a strong relationship to histological measures of vessel diameter in high grade glioma and that independently of blood volume and vessel density. References: 1 Digernes et al. JCBFM 2017. DOI: 10.1177/0271678X17694187 2 Kiselev et al. MRM 2005. DOI: 10.1002/mrm.20383 3 Leu et al. JMRI 2016. DOI: 10.1002/jmri.25227 4 Tropres et al. MRI 2004 DOI: 10.1002/mrm.20017