tbuckley/cabot-search huggingface dataset:
NIMG-34. QUANTITATIVE MR PARAMETERS FOR THE PREDICTION OF EGFR AMPLIFICATION AND THE TERT PROMOTER MUTATION STATUS OF IDH-WILDTYPE LOWER-GRADE GLIOMAS
Authors: Yae Won Park, Sung Soo Ahn, Eui Hyun Kim, Seok-Gu Kang, Jong Hee Chang, Se Hoon Kim, Seung-Koo Lee
Journal: Neuro-Oncology (2020)

Abstract OBJECTIVES To assess the predictive role of quantitative MRI parameters from DTI, dynamic susceptibility contrast (DSC), and dynamic contrast-enhanced (DCE) imaging in determining the epidermal growth factor receptor (EGFR) amplification and telomerase reverse transcriptase promoter (TERTp) mutation status of isocitrate dehydrogenase-wildtype (IDHwt) lower-grade gliomas (LGGs). METHODS A total of 49 patients with IDHwt LGGs with either known EGFR amplification (39 EGFR non-amplified, 10 EGFR-amplified) or TERTp mutation (19 TERTp wildtype, 21 TERTp mutant) statuses underwent preoperative MRI. The mean apparent diffusion coefficient (ADC), fractional anisotropy (FA), normalized cerebral blood volume (nCBV), normalized cerebral blood flow (nCBF), volume transfer constant (Ktrans), rate transfer coefficient (Kep), extravascular extracellular volume fraction (Ve), and plasma volume fraction (Vp) values were assessed. Univariate and multivariate logistic regression models were constructed to predict EGFR amplification and TERTp status. RESULTS EGFR-amplified tumors showed lower mean ADC values than EGFR non-amplified tumors (p = 0.019). Mean ADC was an independent predictor of EGFR amplification, with an AUC of 0.75. TERTp mutant tumors showed higher mean nCBV (p = 0.020), higher mean nCBF (p = 0.017), and higher mean Vp (p = 0.002) than TERTp wildtype tumors. With multivariate logistic regression, mean Vp was the only independent predictor of TERTp mutation status, with an AUC of 0.85. CONCLUSION Lower ADC values may be a useful marker for the prediction of EGFR amplification, whereas higher Vp values may be a useful marker for the prediction of the TERTp mutation status of IDHwt LGGs.
RARE-39. MOLECULARLY CONFIRMED ATYPICAL CHOROID PLEXUS PAPILLOMA WITH INTRACRANIAL DISSEMINATION
Authors: Masato Yanagi, Kohei Fukuoka, Yuko Matsushita, Yuko Hibiya, Satoko Honda, Makiko Mori, Yuki Arakawa, Koichi Ichimura, Yutaka Tanami, Atsuko Nakazawa, Jun Kurihara, Katsuyoshi Ko
Journal: Neuro-Oncology (2020)

Abstract INTRODUCTION Among choroid plexus tumors (CPTs), metastasis occurs more frequently as pathological grading increases. There could be an underestimation of pathological diagnosis if disseminated CPTs are diagnosed with lower grade tumors such as choroid plexus papilloma (CPP) or atypical choroid plexus papilloma (aCPP). Thus, molecular diagnosis using genome-wide DNA methylation profiling may be useful to clarify malignant potential among thetumor entity. Here, we report about a case of aCPP with intracranial dissemination that was molecularly diagnosed by methylation profiling. CASE DESCRIPTION: A 2-year-old girl presented with a history of vomiting. Brain magnetic resonance imaging showed a large tumor mass in the right lateral ventricle and diffuse enhancement surrounding her brainstem, which suggested dissemination. Gross total resection of the mass was performed. Intraoperative findings revealed multiple spot metastatic lesions on the inner wall of lateral ventricle. The pathological diagnosis was aCPP owing to the presence of a glandular structure with a papillary pattern suggesting a neoplasm of epithelial origin, increased cellularity, several necrotic areas, and an intermediate number of mitoses. The CPT-SIOP-2000 treatment protocol was followed without radiation therapy, and the disseminated lesion was disappeared during the chemotherapy. Methylation data of the current case was entered into a recently published classifier, and the tumor was classified as methylation class “plexus tumor, subclass pediatric A” with high confidence (calibrated score 0.96), which includes cases diagnosed as CPP and aCPPs. CONCLUSION Our case indicates the clinical significance of molecular confirmation of diagnosis among CPTs, particularly lower grade tumors with dissemination.
CTNI-42. FIRST-IN-HUMAN FLUORESCENCE GUIDED SURGERY OF HIGH-GRADE GLIOMAS USING PANITUMUMAB-IRDYE800
Authors: Quan Zhou, Nynke van den Berg, Naoki Nishio, Guolan Lu, Stefania Chirita, Roan Raymundo, Grace Yi, Hannes Vogel, Romain Cayrol, Eben Rosenthal, Gordon Li
Journal: Neuro-Oncology (2020)

Abstract INTRODUCTION High-grade gliomas (HGGs) are malignant brain tumors with devastating prognosis. Extent of resection predicts survival in patients, but current neuroimaging approaches lack tumor specificity. The epidermal growth factor receptor (EGFR) is a biomarker heterogeneously expressed in HGGs. We assessed the feasibility of imaging HGGs using a near-infrared fluorescent anti-EGFR antibody. METHODS Nine patients with contrast enhancing HGGs on presurgical MRI scan were systemically infused with a flat dose of either 50mg (n = 4) or 100mg (n = 5) panitumumab-IRDye800, 1–5 days before surgery. Near-infrared fluorescence imaging of tumor and histologically normal brain tissues was performed intraoperatively and ex vivo. Fluorescence was measured as mean fluorescence intensity (MFI), and tumor-to-background ratio (TBR) were calculated by comparing MFIs of tumor and histologically uninvolved tissue. Immunohistopathological staining of EGFR was performed on formalin fixed paraffin embedded tissue sections. RESULTS Both MFI and TBR were positively correlated to panitumumab-IRDye800 dose per body weight (R2 = 0.59 and 0.07, P &amp;lt; 0.0001 and P = 0.046 respectively). The TBR was higher at a 100 mg dose than at 50 mg (2.1 vs. 1.5). The smallest detectable tumor volume in a closed-field setting was 21 mg with 50 mg of dye and 12 mg with 100 mg. On sections of paraffin embedded tissues, positive EGFR protein expression was observed in 88.9% ± 12.4% of tumor tissues and positively correlated with fluorescence. Sensitivity and specificity of tumor fluorescence for viable tumor detection was calculated and fluorescence was found to be highly sensitive (93%) and specific (81%) for viable tumor tissues while normal brain tissues showed minimal fluorescence. No adverse events related to the imaging probe was observed. CONCLUSION This first-in-human study demonstrates the feasibility and safety of antibody based imaging for contrast enhancing high-grade gliomas.
SURG-10. PROGNOSTIC IMPORTANCE OF THE EXTENT OF RESECTION IN IDH-WILD TYPE GRADE II ASTROCYTOMAS ACCORDING TO PTERT MUTATION
Authors: Alessia Pellerino, Francesco Bruno, Antonio Silvani, Tamara Ius, Lorenzo Bello, Giuseppe Minniti, Andrea Pace, Giuseppe Lombardi, Riccardo Soffietti, Roberta Rudà
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND IDH-wild type diffuse astrocytomas with pTERT mutation have been suggested by cIMPACT-NOW update 3 to share a poor prognosis with glioblastoma (GBM). In a previous series of the Italian Association of Neuro-Oncology, we reported that IDH-wild type grade II astrocytomas benefit from gross total resection. However, the impact of surgery in the pTERT-mutated subgroup has not been addressed so far. Here, we present our preliminary data about the impact of the extent surgery according to pTERT status. MATERIAL AND METHODS We re-analysed a national database of 122 patients with grade II IDH-wild type astrocytoma. P-TERT mutation was evaluated by gene sequencing. Kaplan-Meier curves were used for the analysis of progression-free and overall survival (PFS and OS). RESULTS Median follow-up was 33.0 months. P-TERT status was available in 40 cases and the mutation was found in 27 cases (67.5%). Patients with pTERT mutation had a significantly shorter PFS (9.4 vs 147.7 months, P &amp;lt; 0.001) and OS (NR vs 36.6 months, P = 0.012). Furthermore, the OS of patients with pTERT mutation, who underwent gross total resection, was significantly longer than in patients with subtotal / partial resection (37.0 vs 32.0 months, P = 0.018). Thus far, the OS of patients without pTERT mutation was not reached with either subtotal / partial or gross total resection. CONCLUSIONS IDH-wild type astrocytomas may be stratified into classes with different outcome based on the pTERT mutation. As far as we know, this is the first study that specifically investigated the importance of a gross total resection according to pTERT status in IDH-wild type grade II astrocytomas.
TMOD-36. THE DEVELOPMENT OF A NOVEL MOUSE MODEL TO STUDY THE ROLE OF HISTONE MUTATIONS AND MODIFICATIONS IN PEDIATRIC HIGH-GRADE GLIOMA
Authors: Florina Grigore, Charles Day, Nicholas Hanson, Alyssa Langfald, Jann Sarkaria, David Daniels, Edward Hinchcliffe, James Robinson
Journal: Neuro-Oncology (2020)

Abstract Pediatric glioblastoma and diffuse intrinsic pontine glioma are high-grade gliomas of children (pHGG) with a median overall survival of under 15 months and among the most lethal cancers. Mutations in histone H3.3 and H3.1 occur as an early event in pHGG. H3.3G34R/V-mutations occur in pHGG of cerebral hemispheres, and H3.3K27M mutations occur in midline pHGGs. Post-translational histone modifications (PTMs) serve to regulate gene expression by relaxing or compacting chromatin and by recruiting proteins, with subsequent silencing or activating effects. H3.3 Serine 31 (S31) shows reduced phosphorylation during mitosis in H3.3G34R/V and H3.3K27M mutant cell. Phosphorylation at S31 is restored in wildtype H3.3K27 CRISPR revertants. Serine to alanine (A) mutant H3.3 S31A are nonphosphorylatable in vitro. To study the influence of histone mutations and the role of altered PTM and including the loss of methylation and phosphorylation on tumorigenesis, we have developed an innovative model based on the RCAS/N-TVA mouse model. In this system, the expression of an oncogenic driver is linked to mutant histone expression using a self-cleaving peptide, and tumors develop following viral delivery to neural stem cells in newborn mice. This approach is necessary, as otherwise, clonal selection could prevent tumors from forming with mutations detrimental to growth. To establish the model, N-TVA mice were injected with RCAS H3.3K27M-P2A-PDGFB, RCAS H3.3G34R-P2A-PDGFB, or H3.3WT-P2A-PDGFB. The mean survival of mice injected with H3.3K27M and H3.3S31A was 81 and 68 days, respectively, and 100% of S31A mice developed HGG. In contrast, H3.3WT caused only low-grade tumors in 46% of the mice, and all mice survived until 100 days. In ongoing experiments with H3.3G34R, 23% of mice succumb to tumors by 80 days. These results provide mechanistic insights into the early establishment of pHGGs and established a new mouse model to study the role of histone mutation and PTMs in tumor development.
EPCT-19. A PHASE I STUDY OF RIBOCICLIB AND EVEROLIMUS FOLLOWING RADIATION THERAPY IN CHILDREN WITH NEWLY DIAGNOSED NON-BIOPSIED DIFFUSE PONTINE GLIOMAS (DIPG) AND RB+ BIOPSIED DIPG AND HIGH GRADE GLIOMAS (HGG)
Authors: Mariko DeWire, James Leach, Christine Fuller, Peter de Blank, Trent Hummel, Natasha Pillay-Smiley, Ralph Salloum, Charles Stevenson, Rachid Drissi, Shiva Senthil Kumar, Patricia Baxter, David Gass, Stewart Goldman, Sarah Leary, Adam Lane, Olivia Campagne, Clinton Stewart, Maryam Fouladi
Journal: Neuro-Oncology (2020)

Abstract Genomic aberrations in the cell cycle and mTOR pathways have been reported in diffuse pontine gliomas (DIPG) and high-grade gliomas (HGG). Dual inhibition of CDK4/6 (ribociclib) and mTOR (everolimus) has strong biologic rationale, non-overlapping single-agent toxicities, and adult clinical experience. The maximum tolerated dose (MTD) and/or recommended phase two dose (RP2D) of ribociclib and everolimus administered during maintenance therapy following radiotherapy was determined in the phase I study as a rolling 6 design. Ribociclib and everolimus were administered once daily for 21 days and 28 days, respectively starting two-four weeks post completion of radiotherapy. All HGG patients and any DIPG patient who had undergone biopsy were screened for RB protein by immunohistochemistry. Eighteen eligible patients enrolled (median age 8 years; range: 2–18). Six patients enrolled at dose levels 1,2, and 3 without dose limiting toxicities (DLT). Currently, five patients are enrolled at dose level 3 expansion cohort. The median number of cycles are 4.5 (range: 1–20+). Among the expansion cohort, one dose limiting toxicity included a grade 3 infection and one patient required a dose reduction in course 3 due to grade 3 ALT and grade 4 hypokalemia. The most common grade 3/4 adverse events included neutropenia. Preliminary pharmacokinetic studies on 12 patients suggest an impact of ribociclib on everolimus pharmacokinetics. The MTD/RP2D of ribociclib and everolimus following radiotherapy in newly diagnosed DIPG and HGG is anticipated to be 170 mg/m2/day x 21 days and 1.5 mg/ m2/day every 28 days which is equivalent to the adult RP2D.
SWK-10. TELEHEALTH IN OUTPATIENT PEDIATRIC NEURO-ONCOLOGY CARE
Authors: Shannon Raber, Carly Hoffman, Carol Yarbrough, Linda Branagan, Neela Penumarthy, Jami Manning, Alyssa Reddy, Anuradha Banerjee, Cassie Kline, Sabine Mueller
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Telehealth is an emerging modality that can include patient evaluation, review of test results, and clinical decision-making. Access to care and quality of life are challenges for patients with pediatric brain tumors and their families. Herein we describe the introduction of video visits within our outpatient services led by nurse practitioners and nurse coordinators. METHODS The pediatric neuro-oncology program at University of California, San Francisco - Benioff Children’s Hospital (UCSF) established a robust telehealth practice to improve access to care for children and young adults with brain and spine tumors. Our nursing team identifies appropriate time points to offer video visits in lieu of in-person visits. Families are guided to connect through secure video conferencing. Data was collected retrospectively through electronic medical record schedules, billing records, and UCSF patient satisfaction surveys. RESULTS Since 2015 we have utilized telehealth for over 400 encounters. The service was limited to patients located in California. Introduction of telehealth resulted in savings of 2300 hours of travel by car, over $22,000 in gas, and over 127,000 miles traveled. Surveys indicate patient satisfaction is equal to or better than in-person experiences. Anecdotally, this service allows for face-to-face contact with patients who have significant barriers to travel. Challenges have included technology platforms, native language, provider and patient acceptance, and billing. CONCLUSION Overall, telehealth is feasible as a tool to deliver outpatient care in pediatric neuro-oncology. Implementation of video visits in clinical practice increases access to neuro-oncologic care and improves quality of life for patients and families.
Effects of a Household Air Pollution Intervention with Liquefied Petroleum Gas on Cardiopulmonary Outcomes in Peru. A Randomized Controlled Trial
Authors: William Checkley, Kendra N. Williams, Josiah L. Kephart, Magdalena Fandiño-Del-Rio, N. Kyle Steenland, Gustavo F. Gonzales, Luke P. Naeher, Steven A. Harvey, Lawrence H. Moulton, Victor G. Davila-Roman, Dina Goodman, Carla Tarazona-Meza, Catherine H. Miele, Suzanne Simkovich, Marilu Chiang, Ryan T. Chartier, Kirsten Koehler
Journal: American Journal of Respiratory and Critical Care Medicine (2020)

Rationale: Approximately 40% of people worldwide are exposed to household air pollution (HAP) from the burning of biomass fuels. Previous efforts to document health benefits of HAP mitigation have been stymied by an inability to lower emissions to target levels. Objectives: We sought to determine if a household air pollution intervention with liquefied petroleum gas (LPG) improved cardiopulmonary health outcomes in adult women living in a resource-poor setting in Peru. Methods: We conducted a randomized controlled field trial in 180 women aged 25–64 years living in rural Puno, Peru. Intervention women received an LPG stove, continuous fuel delivery for 1 year, education, and behavioral messaging, whereas control women were asked to continue their usual cooking practices. We assessed for stove use adherence using temperature loggers installed in both LPG and biomass stoves of intervention households. Measurements and Main Results: We measured blood pressure, peak expiratory flow (PEF), and respiratory symptoms using the St. George's Respiratory Questionnaire at baseline and at 3–4 visits after randomization. Intervention women used their LPG stove exclusively for 98% of days. We did not find differences in average postrandomization systolic blood pressure (intervention – control 0.7 mm Hg; 95% confidence interval, −2.1 to 3.4), diastolic blood pressure (0.3 mm Hg; −1.5 to 2.0), prebronchodilator peak expiratory flow/height2 (0.14 L/s/m2; −0.02 to 0.29), postbronchodilator peak expiratory flow/height2 (0.11 L/s/m2; −0.05 to 0.27), or St. George's Respiratory Questionnaire total score (−1.4; −3.9 to 1.2) over 1 year in intention-to-treat analysis. There were no reported harms related to the intervention. Conclusions: We did not find evidence of a difference in blood pressure, lung function, or respiratory symptoms during the year-long intervention with LPG. Clinical trial registered with www.clinicaltrials.gov (NCT02994680).
Blocking NHE1 stimulates glioma tumor immunity by restoring OXPHOS function of myeloid cells
Authors: Md Nabiul Hasan, Lanxin Luo, Dawei Ding, Shanshan Song, Mohammad Iqbal H. Bhuiyan, Ruijia Liu, Lesley M. Foley, Xiudong Guan, Gary Kohanbash, T. Kevin Hitchens, Maria G. Castro, Zhongling Zhang, Dandan Sun
Journal: Theranostics (2020)

Background: Immunosuppressive tumor microenvironment (TME) in glioblastoma (GBM) is one of the contributing factors for failed immunotherapies. Therefore, there is an urgent need to better understand TME and to identify novel modulators of TME for more effective GBM therapies. We hypothesized that H+ extrusion protein Na/H exchanger 1 (NHE1) plays a role in dysregulation of glucose metabolism and immunosuppression of GBM. We investigated the efficacy of blockade of NHE1 activity in combination with temozolomide (TMZ) therapy in increasing anti-tumor immunity. Methods: Mouse syngeneic intracranial glioma model was used to test four treatment regimens: DMSO (Vehicle-control), TMZ, NHE1 specific inhibitor HOE642, or TMZ+HOE642 (T+H) combination. Ex vivo1H/19Fluorine magnetic resonance imaging (MRI) with cell tracking agent Vsense was performed to monitor the infiltration of glioma-associated microglia/myeloid cells (GAMs). Glucose metabolism and transcriptome profiles were analyzed by Seahorse analyzer and bulk RNA-sequencing. The impact of selective Nhe1 deletion in GAMs on sensitivity to anti-PD-1 therapy was evaluated in transgenic NHE1 knockout (KO) mice. Results: Among the tested treatment regimens, the T+H combination therapy significantly stimulated the infiltration of GAMs and T-cells; up-regulated Th1 activation, and mitochondrial oxidative phosphorylation (OXPHOS) pathway genes, increased glucose uptake and mitochondrial mass, and decreased aerobic glycolysis in GAMs. Selective deletion of Nhe1 in Cx3cr1+Nhe1 KO mice increased anti-tumor immunity and sensitivity to TMZ plus anti-PD-1 combinatorial therapy. Conclusions: NHE1 plays a role in developing glioma immunosuppressive TME in part by dysregulating glucose metabolism of GAMs and emerges as a therapeutic target for improving glioma immunity.
HGG-34. DETECTION OF ONCOGENIC FUSION EVENTS IN SUPRATENTORIAL GLIOBLASTOMAS OF YOUNG CHILDREN
Authors: Torsten Pietsch, Christian Vokuhl, Gerrit H Gielen, Andre O von Bueren, Everlyn Dörner, Glen Kristiansen, Andreas Waha, Christof Kramm
Journal: Neuro-Oncology (2020)

Abstract INTRODUCTION Glioblastoma in infancy and early childhood is characterized by a more favorable outcome compared to older children, a stable genome, and the occurrence of tyrosine kinase gene fusions that may represent therapeutic targets. METHODS 50 glioblastomas (GBM) with supratentorial location occurring in children younger than four years were retrieved from the archives of the Brain Tumor Reference Center, Institute of Neuropathology, University of Bonn. DNA and RNA were extracted from FFPE tumor samples. Gene fusions were identified by FISH using break-apart probes for ALK, NTRK1, -2, -3, ROS1 and MET, Molecular Inversion Probe (MIP) methodology, and targeted RNA sequencing. RESULTS 37 supratentorial GBM occurred in the first year of life, 13 GBM between one and four years. 18 cases showed fusions of ALK to different fusion partners; all occurred in the first year of life (18/37 cases, 48.6%). Fusions of ROS1 were found in 5, MET in 3, NTRK1, -2, -3 in 10 cases. 12 cases showed no and two novel fusions. The different methods led to comparable results; targeted RNA sequencing was not successful in a fraction of cases. Break-apart FISH led to reliable results on the next day, MIP technology represented the most sensitive method for analysis of FFPE samples. CONCLUSIONS Gene fusions involving the tyrosine kinase genes ALK, MET, ROS1 and NTRK1, -2, -3 occurred in 72% of glioblastomas of children younger than four years; the most frequent were ALK fusions occurring in infant GBM. DNA based MIP technology represented the most robust and sensitive assay.
Beneath a Tough Mother (Dura Mater) — Chronic Subdural Hematoma
Authors: Allan H. Ropper
Journal: New England Journal of Medicine (2020)

The eminent neurologist Dr. Raymond Adams had the unenviable task of examining a prominent colleague who had become confused and dull over several weeks. He found grasp responses and mild weakness on the left side without a Babinski sign; percussed each side of the skull; and, while departing, decreed, “Chronic subdurals — they need to come out.” The residents in attendance swooned (this was just at the beginning of the era of computed tomography). But we pushed back on the basis of a report from Mt. Sinai Hospital: “In New York, they try steroids first.”1 “Well this is Boston, not . . .
Interobserver reliability of methods to determine complete resection of adenomas in colonoscopy
Authors: Erica Park, William Barge, Jason Kramer, Bana Alajati, Shriram Jakate, David Cimbaluk, Deborah Giusto, Ethan Ritz, Faraz Bishehsari, Saline Lee, Shubha Singh, John Losurdo, Michael Brown, Mark DeMeo, Rana Abraham, Karen Ma, Joshua Melson
Journal: Endoscopy (2020)

Forceps margin biopsy and polypectomy specimen margins have both been used to assess for polypectomy resection adequacy. The interobserver reliability of the two methods has not been well described.The interpretability of polypectomy specimens for presence of residual neoplasia at the margin was assessed by two blinded pathologists. Next, the concordance of forceps margin biopsy interpretations between three blinded pathologists was evaluated by calculation of interobserver κ.Rates of polypectomy specimen margin interpretability were low: 24/92 (26 %) for pathologist A, 28/92 (30.4 %) for pathologist B. Concordance of forceps margin biopsy interpretations (n = 129) between pathologists was high. Two internal pathologists showed substantial agreement in margin biopsy interpretations (κ 0.779; 95 %CL 0.543, 0.912). The concordance remained strong after biopsies were reviewed by a third, external pathologist (κ 0.829; 95 %CL 0.658, 0.924). There was complete agreement on 123/129 (95.3 %) between all three pathologists for presence of neoplasia.The majority of polypectomy specimen margins were uninterpretable by pathologists for presence of residual neoplasia. Forceps margin biopsy shows strong interobserver reliability in adenomatous lesions.