tbuckley/cabot-search huggingface dataset:
CRAN-12. PERIOSTIN CONCENTRATIONS IN CHILDHOOD-ONSET CRANIOPHARYNGIOMA PATIENTS
Authors: Kerstin Heinks, Caroline De Schutter-Nüsse, Svenja Boekhoff, Anika Hoffmann, Jinzhou Zhu, Junxiang Peng, Hermann L Müller
Journal: Neuro-Oncology (2018)

The expression of the extracellular matrix protein periostin has been found to be increased in adamantinomatous craniopharyngioma-associated fibroblasts. It has been further identified as a novel marker for Non-Alcoholic Fatty Liver Disease (NAFLD). Half of childhood-onset craniopharyngioma (CP) patients with hypothalamic involvement develop a NAFLD. We hypothesized that periostin concentration is elevated in CP patients with pathological hepatic parameters. We analyzed 35 patients with childhood-onset CP, 3 patients with isolated growth hormone deficiency (GHD), 5 patients with low insulin-like growth factor (IGF)-1 (IGF-1D) and 7 healthy controls. Periostin concentration was determined in serum (34 CP, 3 GHD, 5 IGF-1D and 7 healthy controls), urine (27 CP, 3 GHD, 5 IGF-1D and 7 healthy controls) and salvia (18 CP, 3 GHD, 3 IGF-1D and 7 healthy controls). Periostin serum, urine and salvia concentrations in CP patients were similar to concentrations of the other groups. Hypothalamic involvement as well as hepatic enzymes were not associated with elevated periostin concentrations. However, due to low patient numbers with pathological hepatic parameters (8 of 35 CP showed increased hepatic enzymes) no conclusions can be drawn from measured periostin concentrations in serum. Interestingly, the subgroup of patients with low IGF-1 levels showed elevated concentrations of serum periostin when compared with other groups. Periostin does not seem to be a suitable marker for NAFLD in childhood-onset CP. However, the association between low IGF-1 levels and periostin should be part of further investigations.
EPEN-01. OUTCOME OF YOUNG CHILDREN WITH SUPRATENTORIAL EPENDYMOMA TREATED WITH RADICAL SURGICAL RESECTION AND INTENSIVE CHEMOTHERAPY: FINAL REPORT OF THE HEAD START I-III TRIALS, 1991–2009
Authors: Mohamed AbdelBaki, Rajkumar Venkatramini, Stergios Zacharoulis, Sharon Gardner, Girish Dhall, Jonathan Finlay
Journal: Neuro-Oncology (2018)

The optimal management of young children with newly-diagnosed supratentorial ependymomas remains poorly-defined. We report outcomes of young children under 7 years old at diagnosis prospectively treated on three sequential multi-center trials of intensive chemotherapy with intent of avoiding irradiation. Between 1991 and 2009, 14 children (median/mean ages of 34 months, range 3–74 months) were enrolled on “Head Start” (HS) trials (3 on HS-I, 3 on HS-II and 8 on HS-III). Induction chemotherapy was identical on HS-I and HS-II; on HS-III, this regimen was supplemented with high-dose systemic methotrexate in each cycle. Consolidation was uniform with a single cycle of marrow-ablative thiotepa/etoposide/carboplatin followed by autologous hematopoietic cell rescue. Irradiation was reserved for children >72 months old or with residual disease following Induction. Tumor pathology underwent central review. Ten children achieved initial gross total resections (GTRx) of tumor and 4 subtotal resections 2 of whom achieved GTRx following chemotherapy. Pathology revealed cellular ependymoma in 6 and anaplastic ependymoma in 8. There was 1 toxic death in Induction, on HS-I. Four children relapsed (3 on HS-II, 1 on HS-III), all locally, 3 expiring of disease despite focal irradiation, 20–72 months from initial diagnosis; the fourth continues recurrence-free after GTRx and focal irradiation. Seven patients survive without irradiation. Young children with supratentorial ependymomas have a good survival outcome when treated with irradiation-avoiding chemotherapy incorporating high-dose systemic methotrexate. However, it remains unclear if similar results could have been achieved with GTRx alone. The prognostic significance of molecular subtype is under evaluation.
CRAN-09. CHOROID PLEXUS CARCINOMA IN INFANCY: FAVORABLE OUTCOME IN THREE PATIENTS TREATED WITH CHEMOTHERAPY
Authors: Reuben Antony, James Boggan, Arzu Ozturk, Theo Nicolaides, Lee-Way Jin, Marike Zwienenberg-Lee
Journal: Neuro-Oncology (2018)

Children diagnosed with Choroid Plexus Carcinoma (CPC) in the first year of life usually have a very poor outcome partly because radiotherapy cannot be used as a part of treatment. We report 3 infants diagnosed with CPC in the first year of life including one patient who has Li-Fraumeni Syndrome who were successfully treated solely with chemotherapy. CASE Patient 1: diagnosed at age 1.5 months with a non-metastatic CPC in the 3rd ventricle. Following gross total tumor resection (GTR) he was treated on COG protocol POG 9923/34 using Vincristine, Etoposide, Cyclophosphamide and Cisplatin (VECC). He remains disease free 4 years post completion of therapy. Patient 2: diagnosed at age 8 months with a non-metastatic left lateral ventricle CPC. Following GTR he was treated on protocol POG 9932/34. He remains disease free 6 years post completion of therapy. Patient 3: Patient had a strong family history of cancer and was diagnosed with an adrenocortical neoplasm at birth. She was diagnosed at age 6 months with a right lateral ventricle CPC disseminated through the brainstem and spinal cord. After a GTR of the intracranial tumor she was treated as per the Head Start 2 (Regimen A) protocol using VECC and High Dose Methotrexate followed by triple autologous stem cell transplant (Carboplatin/Thiotepa conditioning). She remains disease free 8 months post completion of therapy. All patients experienced significant bacterial sepsis episodes, malnutrition and ototoxicity. Long term tumor control of CPC is possible using chemotherapy only protocols in very young infants.
MBCL-20. MGMT PROTEIN EXPRESSION AND MGMT GENE PROMOTER METHYLATION AS MARKERS OF DRUG SENSITIVITY TO EPIGENETIC THERAPY IN CHILDHOOD MEDULLOBLASTOMA
Authors: Andrey Levashov, Dmitry Khochenkov, Anna Stroganova, Marina Ryzhova, Sergey Gorelyshev, Stepan Babelyan, Natalya Subbotina, Vidmante Daylidite, Igor Dolgopolov, Svetlana Zagidullina, Georgy Seregin, Georgy Mentkevich
Journal: Neuro-Oncology (2018)

The aim of this study was to estimate MGMT protein expression and MGMT gene promoter methylation in medulloblastoma specimens and their prognostic significance. Fifty four patients were treated according to like-SJMB03, MTX-OPEC-based, thiophosphamide/carboplatin-based chemotherapy regimens combined with radiation therapy (average risk group - 22, high risk group - 32). MGMT protein expression and molecular subgroups were assessed by immunohistochemical method. MGMT positive specimen was defined as weak (1+), moderate (2+), strong (3+) colouring of the tumor nuclei and cytoplasm with number of positive tumor cells above 25%. MGMT gene promoter methylation was detected by methylation-specific PCR (MSP) method. MGMT positive tumor cells were revealed in 31 out of (/) 54 specimens (57.4%), 2/10 (20%) - for infants, 29/44 (65.9%) - for children (p = 0.08); MGMT2,3+ - in 13/54 (24%), 0/10 (0%) – for infants, 13/44 (29.5%) – for children (p = 0.049), MGMT gene promoter methylation - in 1/15 (6.7%). MGMT positive endotheliocytes were observed in 25/42 (59.5%). MGMT positive tumor cells and endotheliocytes were revealed in 21/27 (77.8%), in 10/12 (83.3% - for MGMT2,3+). MGMT2,3+ positive tumor cells were detected in 1/12 (8.3% - SHH), 5/12 (41.7% - Group 3), 4/10 (40% - Group 4), p = 0.137. There was not determined any significant correlation between MGMT expression and M0/M+ status, overall survival, event-free survival. These data suggest that the presence of MGMT expression in tumor cells and endotheliocytes opens the way for using demethylating therapeutic agents in patients with Group 3 and Group 4 medulloblastoma.
RSV prevention in infancy and asthma in later life – Authors' reply
Authors: Nienke M Scheltema, Elisabeth E Nibbelke, Juliëtte Pouw, Maarten O Blanken, Maroeska M Rovers, Christiana A Naaktgeboren, Natalie I Mazur, Joanne G Wildenbeest, Cornelis K van der Ent, Louis J Bont
Journal: The Lancet Respiratory Medicine (2018)
Small volume resuscitation with 20% albumin in intensive care: physiological effects
Authors: Johan Mårtensson, Shailesh Bihari, Jonathan Bannard-Smith, Neil J. Glassford, Patryck Lloyd-Donald, Luca Cioccari, Nora Luethi, Aiko Tanaka, Marco Crisman, Nicolas Rey de Castro, Marcus Ottochian, Agnes Huang, Maria Cronhjort, Andrew D. Bersten, Shivesh Prakash, Michael Bailey, Glenn M. Eastwood, Rinaldo Bellomo
Journal: Intensive Care Medicine (2018)
Motivation to Participate in PTSD Research—Reply
Authors: Edna B. Foa, Carmen P. McLean, Alan L. Peterson
Journal: JAMA (2018)

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Characteristics of patients ≥10 years of age with diffuse intrinsic pontine glioma: a report from the International DIPG/DMG Registry
Authors: Craig Erker, Adam Lane, Brooklyn Chaney, Sarah Leary, Jane E Minturn, Ute Bartels, Roger J Packer, Kathleen Dorris, Nicholas G Gottardo, Katherine E Warren, Alberto Broniscer, Mark W Kieran, Xiaoting Zhu, Peter White, Phillip J Dexheimer, Katie Black, Anthony Asher, Mariko DeWire, Jordan R Hansford, Sridharan Gururangan, Javad Nazarian, David S Ziegler, Eric Sandler, Allison Bartlett, Stewart Goldman, Chie-Schin Shih, Tim Hassall, Hetal Dholaria, Pratiti Bandopadhayay, Yvan Samson, Michelle Monje, Paul G Fisher, Andrew Dodgshun, Sarah Parkin, Murali Chintagumpala, Karen Tsui, David Gass, Valerie Larouche, Emmett Broxson, Mercedes Garcia Lombardi, Stacie Shiqi Wang, Jie Ma, Cynthia Hawkins, Dima Hamideh, Lars Wagner, Carl Koschmann, Christine Fuller, Rachid Drissi, Blaise V Jones, James Leach, Maryam Fouladi
Journal: Neuro-Oncology (2021)

Diffuse intrinsic pontine gliomas (DIPG) generally occur in young school-age children, although can occur in adolescents and young adults. The purpose of this study was to describe clinical, radiological, pathologic, and molecular characteristics in patients ≥10 years of age with DIPG enrolled in the International DIPG Registry (IDIPGR).Patients ≥10 years of age at diagnosis enrolled in the IDIPGR with imaging confirmed DIPG diagnosis were included. The primary outcome was overall survival (OS) categorized as long-term survivors (LTS) (≥24 months) or short-term survivors (STS) (<24 months).Among 1010 patients, 208 (21%) were ≥10 years of age at diagnosis; 152 were eligible with a median age of 12 years (range 10-26.8). Median OS was 13 (2-82) months. The 1-, 3-, and 5-year OS was 59.2%, 5.3%, and 3.3%, respectively. The 18/152 (11.8%) LTS were more likely to be older (P < .01) and present with longer symptom duration (P < .01). Biopsy and/or autopsy were performed in 50 (33%) patients; 77%, 61%, 33%, and 6% of patients tested had H3K27M (H3F3A or HIST1H3B), TP53, ATRX, and ACVR1 mutations/genome alterations, respectively. Two of 18 patients with IDH1 testing were IDH1-mutant and 1 was a LTS. The presence or absence of H3 alterations did not affect survival.Patients ≥10 years old with DIPG have a median survival of 13 months. LTS present with longer symptom duration and are likely to be older at presentation compared to STS. ATRX mutation rates were higher in this population than the general DIPG population.
MBRS-57. TARGETING METABOLIC ADAPTATION IN MYC/MYCN AMPLIFIED PEDIATRIC MEDULLOBLASTOMA AND NEUROBLASTOMA
Authors: Alberto Delaidelli, Gian Luca Negri, Simran Sidhu, Jordan Cran, Marc Remke, Stefan Pfister, Marcel Kool, Michael Taylor, John Maris, Gabriel Leprivier, Poul Sorensen
Journal: Neuro-Oncology (2018)

The MYC oncogenes contribute to more than 50% of all human cancers, but their therapeutic targeting has proven challenging. MYC/MYCN amplification in childhood medulloblastoma (MB) and neuroblastoma (NB) determine aggressive disease and high mortality, underlying the need for novel and effective therapies. MYC-driven transformation is energy demanding and impairs cell survival under nutrient deprivation (ND), a characteristic stress condition within the tumor microenvironment. We recently identified eukaryotic Elongation Factor 2 Kinase (eEF2K) as a pivotal mediator of the adaptive response of tumor cells to ND. We therefore hypothesized that eEF2K facilitates the adaptation of MYC/MYCN amplified MB/NB to ND, and that inhibiting this pathway can impair tumor progression. Analyzing publicly available genomic databases and tissue microarrays, we found that high eEF2K expression and activity are strongly predictive of poor outcome in MB and NB (p<0.001), and correlate with MYC/MYCN amplification (p<0.001). Inhibition of eEF2K significantly decreases survival of MYC/MYCN amplified MB/NB cell lines in vitro under ND. Combination of eEF2K knockdown and caloric restriction determines a twofold growth decrease of MYCN amplified NB mouse xenografts. Finally, eEF2K inactivation significantly attenuated the ability of tumor cells to engage fatty acid oxidation under ND, suggesting a link between eEF2K, MYC transformation and lipid metabolism. eEF2K represents a critical mediator for the adaptive response of MYC/MYCN amplified tumors to acute metabolic stress, and is therefore a promising therapeutic target. Future studies will combine eEF2K pharmacological inhibition with caloric restriction mimetics, as eEF2K activity appears to be critical under ND.
MBRS-18. ALK EXPRESSION AT THE PROTEIN LEVEL IS A MARKER FOR THE DIFFERENTIATION DIAGNOSIS OF THE WNT-ACTIVATED TYPE OF PEDIATRIC MEDULLOBLASTOMA
Authors: Maria Lastowska, Joanna Trubicka, Magdalena Niemira, Magdalena Paczkowska-Abdulsalam, Agnieszka Karkucinska-Wieckowska, Magdalena Kaleta, Monika Drogosiewicz, Magdalena Tarasinska, Marta Perek-Polnik, Adam Kretowski, Bozenna Dembowska-Baginska, Wieslawa Grajkowska, Maciej Pronicki, Ewa Matyja
Journal: Neuro-Oncology (2018)

Previous analyses indicated that expression of ALK at the RNA level is correlated with the WNT-activated type of medulloblastoma. Therefore, we investigated if ALK expression at the protein level may serve as an useful marker for identification of this type of medulloblastoma. Tumors from 134 patients were studied at diagnosis by immunohistochemistry using antibody ALK clone D5F3 #3633 (Cell Signaling). Consensus scoring was applied as the following: 0 (negative) for 0-10%, 1+ for >10-50%, 2+ for >50-100% of positive tumor cells. Transcriptional subtypes of medulloblastoma tumors were established in all cases. Thirty infratentorial ependymal tumors were also investigated to determine if ALK protein expression may serve as a marker for differential diagnosis. All 19 WNT tumors were positive for ALK expression and in all but one positive reaction was present in >50% of tumor cells (score 2+). Only four ALK positive tumors were detected among the remaining 85 tumors: one tumor with a score 2+ in Group 4 and three tumors with a score 1+ (one in Group 3 and two in SHH group). Therefore, expression of ALK is strongly associated with the WNT type of disease (p<0.0001). By contrast, none of the analyzed ependymal tumors displayed positive ALK reaction. The results indicate that ALK expression at the protein level may serve as a marker for differential diagnosis for the WNT-activated type of medulloblastoma. Funded by National Science Centre, Poland (2016/21/B/NZ2/01785 and 2016/23/B/NZ2/03064).
LGG-31. SUSTAINED OBJECTIVE RESPONSE TO DABRAFENIB THERAPY ACROSS DIFFERENT BRAIN HISTOLOGIES HARBOURING BRAF V600E ACTIVATING MUTATION
Authors: David Sumerauer, Lenka Krskova, Martin Kyncl, Michal Zapotocky, Adela Kuklova, Josef Zamecnik, Barbora Ondrova, Jan Stary
Journal: Neuro-Oncology (2018)

Paediatric low-grade gliomas are the most common brain tumours in children. They are characterized by alterations of the Ras/MAPK pathway. Gliomas harbouring BRAF activating mutations were repeatedly shown to respond to BRAF inhibition. We present our experience with dabrafenib monotherapy in four patients with low grade gliomas harbouring activating V600E BRAF mutation. Two patients were treated at the time of disease diagnosis, two at the time of disease progression. Although various histologies (PA, PXA, GG), age (6 months, 13 months, 27 months and 8 years) and primary locations (OPG, thalamus, brainstem) were encountered, in all cases dabrafenib treatment at the dose 5.25 mg/kg/day resulted in rapid and profound radiologic response with clinical improvement. All patients are on therapy for 15, 11, 11 and 9 months without any documented toxicity to date. Dabrafenib is active and well tolerated among patients with BRAF V600E mutation positive paediatric low-grade gliomas. Rapid responses of tumours to BRAF inhibition may have input on some of their feared sequelae (i.e. visual impairment), not prevented with other therapies to date.
NSRG-22. ENDOSCOPIC APPROACH TO PINEAL REGION LESIONS WITH SPLITTING OF THE CHOROID FISSURE AND MASSA INTERMEDIA
Authors: Charlotte Burford, Cristina Bleil, Jose Lavrador, Ahilan Kailaya-Vasan, Bassel Zebian
Journal: Neuro-Oncology (2018)

In patients presenting with obstructive hydrocephalus secondary to pineal region lesions, a combined endoscopic third ventriculostomy (ETV) and tumour biopsy is an increasingly common procedure. Performing it through a monoportal approach with a rigid scope is especially challenging given the anatomy of the third ventricle. Here we report our experience of the monoportal endoscopic combined approach made possible by splitting the choroid fissure (CF) and massa intermedia (MI). A 13-year-old male was referred to our unit having presented with a 2-day history of headache, blurred vision, diplopia and vomiting. An MRI revealed a pineal region lesion causing obstructive hydrocephalus. An ETV was performed. Access to the pineal region was then gained by splitting of the CF and subsequent division of a small MI. A biopsy was taken and limited debulking performed (tumour was large and hard making complete resection difficult). Histopathology confirmed an immature teratoma. Post-operatively the patient made an excellent recovery. The endoscopic transchoroidal approach with splitting of the MI allows management of hydrocephalus and access to pineal tumours for biopsy/debulking via a single burr hole and using a solid scope. In the future complete resection of pineal lesions via this approach may become commonplace with improved instrumentation and equipment.
MBRS-24. INVESTIGATING THE ROLE OF THE RNA BINDING PROTEIN, MUSASHI 1 IN PEDIATRIC GROUP 3 MEDULLOBLASTOMA
Authors: Michelle Kameda-Smith, Chitra Venugopal, David Bakhshinyan, Branavan Manoranjan, Ashley Adile, Minomi Subapanditha, Adam Fleming, Kristen Hope, Sheila Singh
Journal: Neuro-Oncology (2018)

Pediatric brain tumours are the leading cause of solid cancer mortality with medulloblastoma (MB) representing the most frequent malignant solid central nervous system (CNS) tumour. To date, most experimental efforts to understand the biological mechanism of solid cancers have been directed towards transcriptional regulatory mechanisms that modulate fate determination in stem and progenitor cells. However, little is known regarding post-transcriptional pathways that contribute to mRNA stability, translation into protein, and functional effects on cell fate. The mRNA binding protein, Musashi (Msi) has been observed to play a crucial role in promoting stem cell self–renewal and is implicated in CNS tumours including glioma and MB with associated poor clinical prognosis. METHODS AND Since increasing brain tumour stem cell or brain tumour-initiating cell (BTIC) frequency is associated with tumor aggressiveness and poor patient outcome, we probed for Msi1 within 251 primary human MBs from four transcriptional databases and 74 NanoString-subgrouped MBs, and found it was enriched in aggressive MB subgroups. Applying gene knockdown and overexpression of Msi1 in Group 3 MB, we have performed in vitro and in vivo assays elucidating how these RNA-binding proteins help to maintain the BTIC state promote an aggressive tumour phenotype. Though transcriptional manipulation has uncovered novel druggable targets to treat MB, bench-to-bedside clinical translation of these targets has yet to yield significant patient benefit. For the first time, Msi analysis in MB provides a novel paradigm for treatment of MB through targeting post-transcriptional pathways and regulators.
IMMU-06. PEMBROLIZUMAB AS SALVAGE TREATMENT IN CHILDREN WITH RECURRENT DIFFUSE MIDLINE GLIOMA: REPORT OF THREE CASES
Authors: Yi-Yen Lee, Hsin-Hung Chen, Yi-Wei Chen, Feng-Chi Chang, Shih-Chieh Lin, Muh-Lii Liang
Journal: Neuro-Oncology (2018)
MBRS-31. GERMLINE MICROSATELLITE SIGNATURE RELIABLY DIFFERENTIATES CHILDREN WITH MEDULLOBLASTOMA
Authors: Samuel Rivero-Hinojosa, Nicholas Kinney, Harold Garner, Brian Rood
Journal: Neuro-Oncology (2018)

The genetic events leading to medulloblastoma initiation, and therefore the ability to determine who is at risk and why, are still unknown. Microsatellites are short tandem repeated sequences that comprise ~3% of the genome. The number of repeats varies between individuals and are often non-randomly associated with disease, including several cancers such as breast, glioma, lung and ovarian. We have developed a novel approach for identifying and validating a microsatellite signature set for medulloblastoma tumors using germline DNA. Analyzing germline DNA sequence from a training set of 120 medulloblastoma subjects and 425 healthy controls, we have identified a set of 139 microsatellite loci whose genotype are significantly different between medulloblastoma subjects and controls. Using an iterative classification algorithm, we found a subset of 43 microsatellites able to distinguish medulloblastoma subjects from controls with a sensitivity and specificity of 0.88 and 0.92, respectively. This signature set was validated in an independent dataset with greater sensitivity and specificity. Analysis of the minor alleles of those 139 informative loci demonstrates that these loci are more mutable in medulloblastoma patients than controls. Finally, a downstream analysis of the genes harboring these microsatellite loci revealed significantly enriched pathways (Autophagy and mTOR signaling) and genes associated with cell cycle and DNA replication, recombination, and repair. Interestedly, we identified two exonic microsatellites in the transcription factors RAI1 and BCL6B associated with medulloblastoma. This study demonstrates that medulloblastoma-specific microsatellite variations in the germline DNA can distinguish individuals with medulloblastoma as well as provide insight into mechanisms of predisposition.