tbuckley/cabot-search huggingface dataset:
MBCL-51. RETROSPECTIVE ANALYSIS OF VICTORIAN PATIENTS DIAGNOSED WITH MEDULLOBLASTOMA BETWEEN 1990-2017
Authors: S Khan, C White, P A Downie, J Hansford, C R Cochrane, A Szczepny, P Siswara, A Sexton-Oates, D McGregor, T B Phung, E Algar, J E Cain
Journal: Neuro-Oncology (2018)

Medulloblastoma is the most common yet challenging paediatric brain tumour. No longer considered a single disease entity, medulloblastoma is comprised of at least four distinct genetically and molecularly defined subgroups. Retrospectively assess the performance and outcomes of all patients diagnosed with medulloblastoma between 1990-2017 according to molecular subgroups. After obtaining ethical approval, confirming sample adequacy, 76 samples (FFPE and Fresh Frozen) were retrieved from the two Victorian children’s oncology providers, Monash Children’s Hospital and The Royal Children’s Hospital. Blinded review of histology and immunohistochemistry using subgroups specific antibodies (INI1, CTNNB1, GAB, YAP, DKK1, SFRP1), is performed by a neuropathologist. For molecular determination of the subgroups, DNA extraction and restoration (FFPE samples only), and bisulphite modification is performed prior to analysis on the Infinium MethylationEPIC BeadChip, containing >850k methylation sites, performed at the Australian Genome Research Facility. Whilst several methods exist, Methylation Array is the current gold standard for subgroup analysis. Data analysis is performed using the Heidelberg groups (MolecularNeuropathology) algorithm and locally using R-studio. Molecular information is paired with clinical variables and international data (where available). 24 samples analysed to date show no discrepancy with regards to incidence amongst subgroups, gender distribution, outcomes and international data. Further analysis will examine trends in mutational burden within subgroups, change in population trends with respect to incidence, relapse and survival. Acknowledgements: CCF, Australian Lions, Baileys Day.
LGG-46. TRAMETINIB THERAPY IN PEDIATRIC PATIENTS WITH LOW-GRADE GLIOMAS (LGG) WITH BRAF GENE FUSION; A DISEASE-SPECIFIC COHORT IN THE FIRST PEDIATRIC TESTING OF TRAMETINIB
Authors: Eric Bouffet, Mark Kieran, Darren Hargrave, Stephen Roberts, Isabelle Aerts, Alberto Broniscer, Birgit Geoerger, Kohinoor Dasgupta, Lillian Tseng, Mark Russo, Bijoyesh Mookerjee, Christopher Moertel
Journal: Neuro-Oncology (2018)

LGG is the most prevalent childhood brain tumor. BRAF fusions drive constitutive activation of BRAF and tumorigenesis. We report results of trametinib, a MEK1/2 inhibitor, in pediatric patients with LGG with BRAF fusion. This phase 1/2 trial (NCT02124772) enrolled pediatric patients (≤18 y) with refractory/recurrent tumors. We report results from interim analysis of pediatric patients with LGG harboring BRAF fusion. Trametinib was dosed at 4 dose levels in part A (0.0125, 0.025, 0.04, and 0.032 mg/kg/d) and at 0.025 mg/kg/day in the expansion cohort. Tumor assessments were performed every 8 weeks by MRI, including T2-FLAIR sequences, using RANO criteria. Twenty-three patients were enrolled across cohorts. Median age of patients was 8 y (range, 2-18) and 13 of 23 were male. At data cutoff, 15 patients were ongoing. One patient discontinued with progressive disease (PD) at 35 weeks, 4 due to adverse events (AEs), 2 per investigator discretion, and 1 per consent withdrawal. The most common treatment-related AEs were diarrhea (14), rash (13), paronychia (9), and maculopapular rash (8). There were no deaths on study. Confirmed partial responses were observed in 3 patients by investigator and 1 patient by independent review. No patients had best response of PD. All responses were ongoing at the data cutoff (all >1 y), and 12 patients had ongoing stable disease (49-121 weeks). In pediatric patients with pretreated LGG and BRAF fusion, trametinib was well tolerated, with 1 independently confirmed RANO response, and most patients were without PD >1 y.
RADI-12. CORRELATION BETWEEN F-DOPA PET AND MRI IN BRAIN TUMOURS
Authors: Francesco Fraioli, Ananth Shankar, Harpreet Hyare, Marilena Rega, Kshitij Mankad, Vincenzo Militano, Stefan Voo, Valentina Ferrazzoli, Anna Barnes
Journal: Neuro-Oncology (2018)

We assessed DOPA PET for staging (5) or progression (10) in adolescent patients (age 17 ± 4) with brain tumour in comparison with contrast MRI. 15 patients underwent 18 DOPA PET/MRI (2 had repeated follow up) (2 germinoma and 13 gliomas, 7 high grade [HGG] and 6 low grade glioma[LGG]). Two NM physicians recorded quantitative PET parameters. Two neuroradiologists recorded tumour characteristics. The Gold Standard was either surgery or clinical follow-up. The readers drew the volume of tumour on a dedicated platform (ITK-SNAP) on PET or on MR. The association of PET and MRI parameters was evaluated by non-parametric correlation analysis. Intermodality variability on the PET and MRI volumes, their ratios and percentage of overlapping were assessed. 16 lesions were established as tumour persistence/recurrence by histological and clinical criteria. Three LGG and 1 HGG were positive on MR and negative on PET, all non-enhancing on post contrast MR. GS demonstrated disease. With a cut-off value of SUVmax 2.20, TBR 1.30 and TSR 0.90, a sensitivity of 87% was achieved in tumour assessment/ progression on DOPA PET. In most of the patients there was excellent overlapping between PET and MRI volumes (average 59%). In 3 patients there were mismatch of volumes (0 to 23%) with different areas of uptake/enhancement in the 2 modalities. Our preliminary results showed that DOPA PET is accurate for primary assessment/recurrence. In few cases there was a volume mismatch on uptake/enhancement/signal change, which might reflect different biological behaviors of the tumours.
LGG-18. GANGLIOGLIOMAS IN CHILDREN - MD ANDERSON CANCER CENTER EXPERIENCE
Authors: Muhammad Baig, David McCall, Sana Mohiuddin, Shekhar Patil, Minjeong Park, Wafik Zaky, Soumen Khatua
Journal: Neuro-Oncology (2018)

Ganglioglioma (GG) is a rare mixed glial-neuronal neoplasm accounting for 0.5-5% of all pediatric brain tumors. Optimal therapeutic strategy remains unknown. This retrospective study evaluates the prognostic factors and outcomes of this rare neoplasm. 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 and treatment data were collected and analyzed. Kaplan-Meier survival and Cox-regression analyses were performed to assess the overall survival (OS) and progression-free survival (PFS). The mean age at diagnosis was 11.8 years (range 1-21 years) with a median follow-up period of 9.5 years (95% CI: 5.7–11.5). Fifty three patients had low grade GG and 2 patients had anaplastic GG. Twenty five patients had tumor progression, whose median progression free survival time was 12 years. Six patients with low grade GG progressed to a higher grade, with median survival of 9.1 month after transformation. The 5 and 10 years PFS and OS were 65%, 57%, 96% and 86% respectively. Tumor location and extent of resection were significant factors for PFS and presence of metastasis attained significance for OS. We present one of the largest retrospective to-date studies in pediatric GG. Notably the extent of tumor, can further stratify GG into low- and high-risk groups among children. Considering the rarity of these tumors, prospective collaborative multi-institutional studies are warranted to delineate treatment consensus and investigate prognostic factors to improve the outcome.
MBRS-21. EXTRACELLULAR VESICLES FROM METASTATIC MEDULLOBLASTOMA CELL LINES CARRY mRNAs KNOWN TO CORRELATE WITH METASTATIC DISEASE
Authors: Hannah K Jackson, Franziska Linke, Ian D Kerr, Beth Coyle
Journal: Neuro-Oncology (2018)

There is no curative treatment for patients with metastatic medulloblastoma, which is underdiagnosed by current techniques. To improve diagnosis and treatment a greater understanding of the mechanisms of metastasis is required, as is the development of novel diagnostic methods. Extracellular vesicles (EVs) are a heterogeneous population of nano-sized, cell derived vesicles. EVs have been shown to transfer oncogenic proteins and nucleic acid cargo to recipient cells, which modulates their activity and plays a decisive role in tumorigenesis. We hypothesised that EVs play a role in medulloblastoma metastasis. An ultracentrifugation isolation method was optimised to selectively isolate EVs from medulloblastoma cell lines (DAOY, UW228-3, CHLA-01-MED, CHLA-01R-MED, HD-MB03 and D283). Validation was by nanoparticle tracking analysis, transmission electron microscopy and western blotting. The RNA cargo of the isolated EVs was analysed for the expression of metastasis-associated genes c-Met, ABCB1, MMP2, BSG and ITG-A9 by qRT-PCR. Immunofluorescence is also being used to localise MMP2 and EMMPRIN (BSG) encoded proteins. Our data demonstrates that medulloblastoma cells secrete two distinct populations of EVs, exosomes and microvesicles, with unique size, morphology and cargo. We have shown that metastatic cell lines produce significantly higher quantities of exosomes compared with non-metastatic cell lines. Finally, we have identified that candidate metastatic mRNAs; c-Met, ABCB1, MMP2, BSG, and ITG-A9 are present in EVs. This study provides new insights on medulloblastoma EVs. Our results indicate that mRNA of metastasis-associated genes is passed from the parent cells to EVs. Thus, EVs are potential diagnostic and therapeutic biomarkers for medulloblastoma patients.
DIPG-40. PRE-TREATMENT MONOCYTE-TO-LYMPHOCYTE RATIO IN PEDIATRIC GLIOMAS WITH HISTONE H3 K27M MUTATION
Authors: Seema Patel, Shiyang Wang, Jonathan Serrano, Sharon Gardner, Matija Snuderl
Journal: Neuro-Oncology (2018)

We previously reported an increased prevalence of pre-treatment lymphopenia in pediatric patients with medulloblastoma, the most common childhood malignant brain tumor, suggesting tumor-induced systemic immune suppression present at the time of diagnosis. Tumor-induced systemic immune suppression, including lymphopenia, has been recognized in adult high-grade gliomas for several decades. Pediatric midline gliomas express distinct epigenetic and genetic alterations, such as the histone H3 K27M mutation. Patients with this mutation often experience a more aggressive clinical course and poor outcome. We confirmed the K27M mutation from tumor biopsies in 10 pediatric midline glioma patients by whole genome DNA methylation array analysis, and analyzed complete blood counts (CBC) at the time of diagnosis prior to surgery and chemotherapy. Compared to a control group of pilocytic astrocytoma, patients with K27M-mutated gliomas have higher monocyte-to-lymphocyte ratios (MLR) and absolute monocyte counts (AMC), reaching statistical significance (p<0.05). Furthermore, the prevalence of monocytosis, characterized by AMC above normal age-adjusted means, was statistically significantly higher (p<0.05) in the study group (80%) than the control group (33%). High pre-operative MLR has previously been reported in various solid tumors in association with worse prognosis and poor overall survival. This is the first study to our knowledge that identifies MLR as a potential valuable biomarker in pediatric gliomas. Our findings suggest monocytosis and overall tumor-induced systemic immune suppression present at the time of diagnosis in K27M mutant tumors. Aberrant circulating immune cell ratios may affect the development of immune therapies for malignant pediatric midline gliomas with the histone H3 K27M mutation.
NSRG-07. TURCOT SYNDROME: A SYNCHRONOUS CLINICAL PRESENTATION OF MEDULLOBLASTOMA AND LOWER RECTAL TUMOR
Authors: Mehdi Borni, Fatma Kolsi, Anis Abdelhedi, Firas Jarraya, Mohammed Zaher Boudawara
Journal: Neuro-Oncology (2018)

Turcot syndrome (TS) is a rare hereditary disorder with genetic susceptibility to cancer which is characterized by the occurrence of colorectal and central nervous system (CNS) tumors. CLINICAL Here we report the case of a 16-year-old patient who was operated for medulloblastoma with simple operative follow-up after radio and chemotherapy. Two years later, she was admitted, in a state of cachexia, for abdominal pain and rectorrhagia. The explorations found an infected lower rectal tumor. The patient underwent an urgent surgery. Immediate consequences were marked by the installation of a severe septic shock causing the patient’s death. Turcot syndrome is a rare but quite serious disease characterized by clinical polymorphism and often late diagnosis. It must be searched in front of evocative personal or family history. Molecular genetic allows early selection of subjects at risk and access to early stages treatment.
NFM-01. NF105: A PHASE II PROSPECTIVE STUDY OF CABOZANTINIB (XL184) FOR PLEXIFORM NEUROFIBROMAS IN SUBJECTS WITH NEUROFIBROMATOSIS TYPE 1: A NEUROFIBROMATOSIS CLINICAL TRIAL CONSORTIUM (NFCTC) STUDY
Authors: Chie-Schin Shih, Jaishri Blakely, Wade Clapp, Pam Wolters, Eva Dombi, Gary Cutter, Nichole Ullrich, Jeffrey Allen, Roger Packer, Stewart Goldman, David Gutmann, Scott Plotkin, Tena Rosser, Kent Robertson, Brigitte Widemann, Bruce Korf, Michael Fisher
Journal: Neuro-Oncology (2018)

BACKGROUNDPlexiform neurofibromas (PNs) are histologically complex peripheral nerve sheath tumors composed of Schwann cells and fibrocytes. Pre-clinical models have demonstrated that altering the microenvironment with molecular targeting therapy may lead to the shrinkage of PN. Here we test the activity of Cabozantinib, a tyrosine kinase inhibitor of KIT, MET, VEGF, and AXL, in adolescents and adults with NF1-associated PN.
Gemcitabine/nabpaclitaxel efficacy in elderly patients with metastatic or locally advanced pancreatic adenocarcinoma
Authors: V. Michalaki, A. Poydorou, G. Frangulidis, A. Vezakis, E. Karvouni, C. Papadimitriou
Journal: Annals of Oncology (2018)

Introduction: Pancreatic cancer is a major health concern worldwide and, despite the attempts at management, the prognosis of patients remains poor, with a median survival of a few months. Gemcitabine/nabpaclitaxel is an active regimen currently used as first-line treatment of patients with metastatic pancreatic adenocarcinoma and a good performance status (PS). but few data are available in elderly patients. Aim of this analysis is to evaluate outcomes and toxicities of gemcitabine/nabpaclitaxel in a cohort of elderly patients. Methods: Clinical records of advanced pancreatic cancer patients receiving nabpaclitaxel 125 mg/m2 and gemcitabine 1000 mg/m2on days 1,8 and 15 of a 28 day cycle as first line chemotherapy were reviewed, investigating activity, efficacy (Progression Free Survival, PFS and Overall Survival, OS) and safety. Analysis was then performed in ≥ 70 years group of pts. OS and PFS were estimated with Kaplan-Meyer method with 95% CI. Cox-regression model was applied to the data with univariate and multivariate approach. Results: Twenty eight patients with a median age of 72 years (range: 70-78) were included in this analysis: PS2: 5 (18%); primary location: head 15 (54%); biliary stent:10 (35%). Overall response rate (ORR) was 35.2%; median progression-free survival (PFS) was 7.4 months (95% CI 5.54-9.26) and median overall survival (OS) was 12.8 mo (95% CI 10.9-15.24). Treatment was well tolerated. No grade 4 toxicity was reported. Grade 3 toxicity included neutropenia in 3 pts (11%), peripheral neuropathy in 1 pts (3.5%), thrombocytopenia in 2 pts (7%), diarrhea in 3 pts (11%), nausea and vomiting in 1 pt (3.5%), and fatigue in 3 pts (11%). Finally, pain control was achieved in 21 of 28 patients (75%) with a performance status improvement of 15% according to the Karnofsky scale. Conclusion: These data suggest that patients aged ≥ 70 may benefit of first-line gemcitabine plus nab-paclitaxel combination, as well as younger ones, both in terms of response and survival experiencing a tolerable, toxicity profile. Identifying elderly patients who will benefit from combination chemotherapy for pancreatic cancer remains a significant clinical challenge.
dropEst: pipeline for accurate estimation of molecular counts in droplet-based single-cell RNA-seq experiments
Authors: Viktor Petukhov, Jimin Guo, Ninib Baryawno, Nicolas Severe, David T. Scadden, Maria G. Samsonova, Peter V. Kharchenko
Journal: Genome biology (2018)

Recent single-cell RNA-seq protocols based on droplet microfluidics use massively multiplexed barcoding to enable simultaneous measurements of transcriptomes for thousands of individual cells. The increasing complexity of such data creates challenges for subsequent computational processing and troubleshooting of these experiments, with few software options currently available. Here, we describe a flexible pipeline for processing droplet-based transcriptome data that implements barcode corrections, classification of cell quality, and diagnostic information about the droplet libraries. We introduce advanced methods for correcting composition bias and sequencing errors affecting cellular and molecular barcodes to provide more accurate estimates of molecular counts in individual cells.
PHRM-04. COMPARISON OF PHARMACOKINETIC PARAMETERS BETWEEN NON-HUMAN PRIMATES AND HUMAN PATIENTS
Authors: Ethan Baratz, Cynthia McCully, Joanna Shih, Katherine Warren
Journal: Neuro-Oncology (2018)

Chemotherapeutic agents are evaluated in at least two animal species prior to evaluation in humans. In children with CNS tumors, the plasma and CSF pharmacokinetics of these agents are derived from models like non-human primates (NHP) to predict CNS penetration. However, the extent to which these NHP parameters accurately predict those observed in clinical trials has not been thoroughly evaluated. The objective of this study was to compare the pharmacokinetics of cytotoxic and cytostatic agents in NHPs and patients to assess the degree of correlation between species. A list of known anti-neoplastic agents within the National Cancer Institute’s (NCI) database was compiled, and a literature search for each drug was performed on Scopus, Pubmed, and PsycINFO using keyword combinations “pharmacokinetics,” “non-human primates,” “clinical testing,” and others. The pharmacokinetic parameters AUC, clearance, half-life, peak time (Tmax) and maximum concentration (Cmax) were compared between species using Spearman’s rank correlations. Plasma pharmacokinetic data were obtained for 17 cytotoxic and 6 cytostatic compounds. Rank correlation coefficients (ρ=cytotoxic; cytostatic) were: AUC (0.662; 0.500); Clearance (0.857; 1.000); Half-life (0.632; 0.600); Tmax (0.232; 0.530); and Cmax (0.447; 0.200). Interspecies correlations were moderate-to-strongly positive (ρ > 0.50) for AUC, clearance, and half-life, and weak-to-moderate (ρ >0.20 >0.50) for Tmax and Cmax. Interspecies data were only available for a limited number of cytostatic compounds, and no data were available for CSF pharmacokinetic parameters. These findings support the use of NHPs as relevant pharmacokinetic models for chemotherapy agents. Additional studies to assess CSF pharmacokinetics are indicated.
The impact of combining Selective Internal Radiation Therapy (SIRT) with sorafenib on overall survival in patients with advanced hepatocellular carcinoma: The SORAMIC trial palliative cohort
Authors: J. Ricke, B. Sangro, H. Amthauer, I. Bargellini, P. Bartenstein, E. De Toni, A. Gasbarrini, H J Klumpen, M. Peck, P. Popovic, O. Rosmorduc, E. Schott, C. Verslype, P. Malfertheiner
Journal: Annals of Oncology (2018)

Introduction: SORAMIC is an RCT comprising diagnostic, local ablation and palliative studies. Based on the result of the diagnostic study patients were assigned to either the local ablation or palliative cohort. The palliative cohort (reported here) was designed to determine the efficacy and safety of combining SIRT (Selective Internal Radiation Therapy) with sorafenib in patients with advanced HCC. Methods: In the palliative treatment cohort, patients not eligible for TACE were randomised 11:10 to either SIRT with Y-90 resin microspheres plus sorafenib (target dose 400 mg bid) or sorafenib alone. The primary endpoint was overall survival (OS; Kaplan-Meier analysis) in the intention-to-treat population. Results: In the ITT palliative treatment cohort, 216 patients were randomised to SIRT + sorafenib and 208 to sorafenib alone. Median OS was 12.1 months (95% confidence interval [CI], 10.6–14.6) in the SIRT + sorafenib arm, and 11.5 months (95% CI, 9.8–13.9) in the sorafenib arm (hazard ratio [HR], 1.067; 95% CI, 0.82–1.25; p = 0.951). In the per protocol group, median OS was 14.1 months (95% CI, 10.95–16.40) in the SIRT + sorafenib arm (n = 114), and 11.1 months (95% CI, 9.7–13.9) in the sorafenib arm (n = 174; HR, 0.86; 95% CI, 0.67–1.11; p = 0.25). Subgroup analyses of the per-protocol population suggested a survival benefit for patients receiving SIRT + sorafenib ≤65y (HR, 0.65; 95% CI 0.43, 1.00, p = 0.05); non-cirrhotics (HR, 0.46; 95% CI 0.25, 0.86, p = 0.02); and non-alcoholic etiology (HR, 0.63; 95% CI 0.45, 0.89, p = 0.012). Adverse events (AEs) of Common Terminology Criteria for AE Grade ≥3 were reported in 115/159 (72.3%) patients in the SIRT + sorafenib arm and 135/197 (68.5%) patients in the sorafenib arm, respectively. Conclusion: The addition of SIRT to sorafenib did not result in a significant improvement in overall survival compared to sorafenib alone. Subgroup analyses led to hypothesis generating results for patient groups with potential clinical benefit.
Updated results of biweekly gemcitabine/nab-paclitaxel as first-line treatment for advanced pancreatic cancer
Authors: S. Kokkali, M. Drizou, E. Tripodaki, D. Stefanou, E. Magou, D. Zylis, M. Kapiris, D. Nasi, C. Georganta, A. Ardavanis
Journal: Annals of Oncology (2018)

Introduction: The combination of gemcitabine and nab-paclitaxel for first-line treatment for advanced pancreatic cancer has shown better results in response and survival over gemcitabine monotherapy. The standard administration on days 1, 8 and 15 of a 4-week cycle has some practical disadvantages. We present the updated results of an observational study for which we adopted a biweekly regimen with the same dose density. Methods: Between 30 May 2014 and 02 March 2018, 56 patients with ECOG/PS 0-2 diagnosed with locally advanced or metastatic, histologically or cytologically confirmed pancreatic cancer and no prior treatment, were enrolled in the study. The regimen included 1.5 g/m2 gemcitabine and 175 mg/m2 nab-paclitaxel given every two weeks until disease progression or unacceptable toxicity. All patients were informed and signed a consent form. Study endpoints were PFS, OS and toxicity profile. The survival analysis was performed using Kaplan-Meier method. Results: 56 patients received this treatment. After a median follow-up period of 7.1 months, the median PFS and OS were 5.3 and 10 months respectively. There was no toxic death during the study and the adverse events noted were similar to those of the original regime. Conclusion: Biweekly combination of gemcitabine and nab-paclitaxel seems to be as safe and efficient as the original regimen. It reduced the patients' discomfort as well as the cost of the treatment.