bluuebunny/crossref_metadata_2025 huggingface dataset:
MBCL-21. GERMLINE ELONGATOR MUTATIONS IN SONIC HEDGEHOG MEDULLOBLASTOMA
Authors: Robinson Giles W , Waszak Sebastian M , Gudenas Brian L , Smith Kyle S , Forget Antoine , Kojic Marija , Jesus Garcia-Lopez , Hadley Jennifer , Hamilton Kayla V , Indersie Emilie , Buchhalter Ivo , Jager Natalie , Sharma Tanvi , Rausch Tobias , Kool Marcel , Sturm Dominic , Jones David T W , Tatevossian Ruth , Lombard Berangere , Loew Damarys , Bowers Daniel , Bendel Anne , Partap Sonia , Chintagumpala Murali , Crawford John , Gottardo Nicholas G , Smith Amy , Dufour Christelle , Rutkowski Stefan , Grotzer Michael , Remke Mark , Puget Stephanie , Pajtler Kristian W , Milde Till , Witt Olaf , Ryzhova Marina , Korshunov Andrey , Orr Brent A , Ellison David W , Brugieres Laurence , Lichter Peter , Nichols Kim E , Gajjar Amar , Wainwright Brandon J , Ayrault Olivier , Korbel Jan O , Northcott Paul A , Pfister Stefan M
Published: December 2020

BACKGROUND

Our previous analysis of established cancer predisposition genes in medulloblastoma (MB) identified pathogenic germline variants in ~5% of all patients. Here, we extended our analysis to include all protein-coding genes.

METHODS

Case-control analysis performed on 795 MB patients against >118,000 cancer-free children and adults was performed to identify an association between rare germline variants and MB.

RESULTS

Germline loss-of-function variants of Elongator Complex Protein 1 (ELP1; 9q31.3) were strongly associated with SHH subgroup (MBSHH). ELP1-associated-MBs accounted for ~15% (29/202) of pediatric MBSHH cases and were restricted to the SHHα subtype. ELP1-associated-MBs demonstrated biallelic inactivation of ELP1 due to somatic chromosome 9q loss and most tumors exhibited co-occurring somatic PTCH1 (9q22.32) alterations. Inheritance was verified by parent-offspring sequencing (n=3) and pedigree analysis identified two families with a history of pediatric MB. ELP1-associated-MBSHH were characterized by desmoplastic/nodular histology (76%; 13/17) and demonstrated a favorable clinical outcome when compared to TP53-associated-MBSHH (5-yr OS 92% vs 20%; p-value=1.3e-6) despite both belonging to the SHHα subtype. ELP1 is a subunit of the Elongator complex, that promotes efficient translational elongation through tRNA modifications at the wobble (U34) position. Biochemical, transcriptional, and proteomic analyses revealed ELP1-associated-MBs exhibit destabilization of the core Elongator complex, loss of tRNA wobble modifications, codon-dependent translational reprogramming, and induction of the unfolded protein response.

CONCLUSIONS

We identified ELP1 as the most common MB predisposition gene, increasing the total genetic predisposition for pediatric MBSHH to 40%. These results mark MBSHH as an overwhelmingly genetically-predisposed disease and implicate disruption of protein homeostasis in MBSHH development.
MBCL-22. EFFICACY OF DOUBLE-CONDITIONING REGIMEN COMPRISING THIOTEPA AND MELPHALAN FOR RELAPSED MEDULLOBLASTOMA – A SINGLE INSTITUTION EXPERIENCE
Authors: Yamasaki Kai , Tanimura Kazuki , Okuhiro Yuki , Hira Kota , Nitani Chika , Okada Keiko , Fujisaki Hiroyuki , Kunihiro Noritsugu , Matsusaka Yasuhiro , Sakamoto Hiroaki , Hara Junichi
Published: December 2020

BACKGROUND

The prognosis of relapsed medulloblastoma was dismal. Recently, we published the promising outcome of metastatic medulloblastomas treated with a double-conditioning regimen comprising high-dose thiotepa and melphalan (HD-TM). Here, we report a single-center study of HD-TM for relapsed medulloblastomas.

MATERIALS AND METHODS

From April 2006 to January 2019, 17 consecutive medulloblastoma patients with the first relapse were identified, and of which 10 received HD-TM were retrospectively reviewed.

RESULTS

The median age at first relapse was 11.9 years (range 1.8–31.7). The median follow-up period was 23.5 months after 1st relapse. Four localized relapses at the posterior fossa and 6 metastatic relapses including 3 with multiple sites were observed. Surgical resection and re-irradiation were administered in 5 and 9 patients, respectively. Two-year PFS and OS after relapse were 21±18.1% and 60±21.9%, respectively, and significantly better than in patients who did not receive HD-TM. Among 7 evaluable patients, tumor shrinkage was observed in 6 after HD-TM administration including 3 patients who were resistant to prior chemotherapy. At the present time, 5 patients are alive with no evidence of disease (NED). The last 5 patients received re-irradiation including 12 Gy craniospinal irradiation (CSI), and 4 are alive with NED. In multivariate analysis for all patients, both HD-TM and re-irradiation were associated with improved OS and PFS, but disseminated relapse had no prognostic value (p=0.56).

CONCLUSION

HD-TM contributes to prolonged survival when combined with re-irradiation. HD-TM might become a curative approach for relapsed medulloblastoma, especially when combined with CSI.
MBRS-44. TIME, PATTERN AND OUTCOME OF MEDULLOBLASTOMA RELAPSE ARE ASSOCIATED WITH TUMOUR BIOLOGY AT DIAGNOSIS AND UPFRONT THERAPY: A COHORT STUDY
Authors: Hill Rebecca , Richardson Stacey , Schwalbe Edward , Hicks Debbie , Lindsey Janet , Crosier Stephen , Rafiee Gholamreza , Grabovska Yura , Wharton Stephen , Jacques Thomas , Michalski Anthony , Joshi Abhijit , Pizer Barry , Williamson Daniel , Bailey Simon , Clifford Steven
Published: December 2020

Disease relapse occurs in ~30% of children with medulloblastoma, and is fatal in the majority. We sought to establish whether clinico-molecular characteristics at diagnosis are associated with the nature of relapse, subsequent disease-course, and whether these associations could inform clinical management. We surveyed the clinical features of medulloblastoma relapse (time-to-relapse, pattern-of-relapse, time-to-death and overall outcome) in 247 centrally-reviewed patients who relapsed following standard-upfront-therapies. We related these to clinico-molecular features at diagnosis, prognostic factors, and first-line/relapse treatment. Patients who received upfront craniospinal irradiation (CSI-treated) displayed prolonged time-to-relapse compared to CSI naïve patients (p<0.001). Similarly, in CSI naïve patients, CSI at relapse, alongside re-resection and desmoplastic/nodular histology, were associated with long-term survival. In CSI-treated patients, the nature of relapse was subgroup-dependent. Local-nodular relapse patterns were enriched in relapsed-MBSHH patients (p<0.001), but a notable proportion (65%) also acquired distant-diffuse disease (p=0.010). MBGroup3 relapsed quickly (median 1.3 years), MBGroup4 slowly (median 2.1 years). Distant-disease was prevalent in MBGroup3 and MBGroup4 relapses (90%) but, in contrast to relapsed-MBSHH, nodular and diffuse patterns of distant-disease were observed. Furthermore, nodular disease was associated with a prolonged time-to-death post-relapse (p=0.006). Investigation of second-generation MBGroup3/4 subtypes refined our understanding of heterogeneous relapse characteristics. Subtype VIII had prolonged time-to-relapse; subtype II a rapid time-to-death. Subtypes II/III/VIII developed a significantly higher incidence of distant-disease at relapse, whereas subtypes V/VII did not. The nature of medulloblastoma relapse are biology and therapy-dependent, providing immediate translational opportunities for improved disease management through biology-directed surveillance, post-relapse prognostication and risk-stratified selection of second-line treatment.
MODL-12. DEVELOPMENT OF A NOVEL IMMUNOCOMPETENT MOUSE MODEL FOR DIFFUSE INTRINSIC PONTINE GLIOMA
Authors: Seblani Maggie , Zannikou Markella , Pituch Katarzyna , Ilut Liliana , Becher Oren , Balyasnikova Irina
Published: December 2020

Diffuse intrinsic pontine glioma (DIPG) is a devastating brain tumor affecting young children. Immunotherapies hold promise however the lack of immunocompetent models recreating a faithful tumor microenvironment (TME) remains a challenge for development of targeted immunotherapeutics. We propose to generate an immunocompetent DIPG mouse model through induced overexpression of interleukin 13 receptor alpha 2 (IL13Rα2), a tumor-associated antigen overexpressed by glioma cells. A model with an intact TME permits comprehensive preclinical assessment of IL13Rα2-targeted immunotherapeutics. Our novel model uses the retroviral avian leucosis and sarcoma virus (RCAS) for in vivo gene delivery leading to IL13Rα2 expression in proliferating progenitor cells. Transfected cells expressing IL13Rα2 and PDGFB, a ligand for platelet derived growth factor receptor, alongside induced p53 loss via the Cre-Lox system are injected in the fourth ventricle in postnatal pups. We validated the expression of PDGFB and IL13Rα2 transgenes in vitro and in vivo and will characterize the TME through evaluation of the peripheral and tumor immunologic compartments using immunohistochemistry and flow cytometry. We confirmed expression of transgenes via flow cytometry and western blotting. Comparison of survival dynamics in mice inoculated with PDGFB alone with PDGFB+IL13Rα2 demonstrated that co-expression of IL13Rα2 did not significantly affect mice survival compared to the PDGFB model. At time of application, we initiated experiments to characterize the TME. Preliminary data demonstrate establishment of tumors within and adjacent to the brainstem and expression of target transgenes. Preclinical findings in a model recapitulating the TME may provide better insight into outcomes upon translation to clinical application.
NFB-08. PHASE II STUDY OF AXITINIB IN PATIENTS WITH NEUROFIBROMATOSIS TYPE 2 AND PROGRESSIVE VESTIBULAR SCHWANNOMAS
Authors: Phadnis Sheetal , Hagiwara Mari , Yaffe Anna , Mitchell Carole , Nicolaides Theodore , Akshintala Srivandana , Hochman Tsivia , Goldberg Judith , Allen Jeffrey , Karajannis Matthias
Published: December 2020

INTRODUCTION

Vascular endothelial growth factor receptor (VEGFR), platelet derived growth factor receptor (PDGFR), and c-KIT represent clinically and/or preclinically validated molecular targets in vestibular schwannomas. We conducted a single institution, prospective, open-label, two-stage phase II study (ClinicalTrials.gov identifier NCT02129647) to estimate the response rate to axitinib, an oral multi-receptor tyrosine kinase inhibitor targeting VEGFR, PDGFR and c-KIT, in neurofibromatosis type 2 (NF2) patients with progressive vestibular schwannomas (VS).

METHODS

NF2 patients older than 5 years with at least one volumetrically measurable, progressive VS were eligible. The primary endpoint was to estimate the objective volumetric response rates to axitinib. Axitinib was given continuously in 28-day cycles for up to of 12 cycles. Response was assessed every 3 months with MRI using 3-D volumetric tumor analysis and audiograms. Volumetric response and progression were defined as ≥20% decrease or increase in VS volume, respectively.

RESULTS

Twelve eligible patients (ages: 14–56 years) were enrolled on this study. Seven of twelve patients completed 12 cycles (range: 2 to 12 cycles). We observed two imaging and three hearing responses. Best volumetric response was -53.9% after nine months on axitinib. All patients experienced drug-related toxicities, the most common adverse events were diarrhea, hematuria and skin toxicity, not exceeding grade 2 and hypertension, not exceeding grade 3.

CONCLUSIONS

While axitinib has modest anti-tumor activity in NF2 patients, it is more toxic and appears to be less effective compared to bevacizumab. Based on these findings, further clinical development of axitinib for this indication does not appear warranted.
PATH-13. PLEOMORPHIC XANTHOASTROCYTOMA INTEGRATED GENOMIC CHARACTERIZATION - WHAT HAVE WE LEARNED?
Authors: Vaubel Rachael , Zschernack Valentina , Caron Alissa , Milosevic Dragana , Jenkins Robert , Kipp Benjamin , Rodriguez Fausto , Tran Quynh , Orr Brent , Pietsch Torsten , Giannini Caterina
Published: December 2020

Pleomorphic xanthoastrocytoma (PXA) is a rare astrocytoma occurring predominantly in children and young adults. It is characterized histologically by large pleomorphic, spindled and lipidized cells with frequent eosinophilic granular bodies and pericellular reticulin deposition. BRAF p.V600E mutation and CKDN2A/B deletion are the most common genetic alterations. We report the integrated genomic characterization of a cohort of 67 patients (37 F, 30 M; median age 20.3 years (interquartile 13.4–32.9) with histologically defined PXA (52, 78%) or anaplastic PXA (A-PXA) (15, 22%), using genome-wide cytogenetic (ThermoFisher Oncoscan, n=67), methylation profiling (Illumina EPIC array, n=43), and targeted next generation sequencing (n=32). BRAF p.V600E mutation (n=51, 76.1%) and CDKN2A/B deletion (n=63; 94%) were the most frequent alterations. Of 16 BRAF p.V600E negative cases, 7 showed an alternative BRAF activating mutation (n=2), NF1 (n=3) mutation or ATG7-RAF1 fusion (n=2). Targeted TERT analysis found promoter mutations in 3 (of 58) cases, but TERT amplification was absent. Supervised and unsupervised methylation profiling against a comprehensive reference cohort demonstrated consensus grouping with the PXA class in 36 of 43 cases; while the minority grouped with a ganglioglioma class (n=3), with reactive brain or had no resolvable subgroup (n=4). Follow-up was available in 61 patients (91.0%) (median 63 months). Overall survival was significantly different between PXA and A-PXA (5-year:80.4% vs. 55.1%; p=0.001), but not progression-free survival (5-year:61.7% vs. 39.8%; p=0.128). Our data confirm the high frequency of MAP-K abnormalities and CDKN2A/B deletion in PXA. WHO grade remains a strong predictor of patient overall survival.
QOL-26. I’VE GOT FRIENDS NOW: PAEDIATRIC PATIENTS’ EXPERIENCES OF METHYLPHENIDATE TREATMENT FOR NEUROCOGNITIVE LATE-EFFECTS ASSOCIATED WITH BRAIN TUMOUR
Authors: Verity Sarah , Hill Rebecca , Halliday Gail , Ryles Jade , Bailey Simon
Published: December 2020

BACKGROUND

Whilst rates of survival following paediatric brain tumour have increased, quality of survival continues to present a significant challenge to children and their families. The neurocognitive impact of cranial radiotherapy (CRT) in childhood upon future intellectual development is well established. Both CRT and chemotherapy are associated with medium-term slowed speed of cognitive processing, attention, and memory impairment, and with longer-term failure to achieve pre-morbid intellectual potential and low Health-Related Quality of Life (HRQoL).Methylphenidate is a psychostimulant drug shown to be effective in alleviating some of the neurocognitive symptoms of cancer treatment, however the subjective experience of paediatric participants is not reported. AIM: The current study aimed to explore the subjective experience of HRQoL in paediatric neuro-oncology patients currently receiving methylphenidate.

METHODS

A retrospective audit was conducted on 12 paediatric neuro-oncology patients in receipt of methylphenidate. Both standardised and novel measures were used to assess aspects of HRQoL, specifically; social life, perceived independence, mood, confidence, school life, self-esteem, interpersonal relationships and fatigue levels. Data collected were analysed using Thematic Analysis.

RESULTS

Five key themes were identified; physical, emotional, social, academic and neuropsychological impact.

CONCLUSION

The current findings evidence the perception of patients that methylphenidate supported them to regain previously lost functionality. Methylphenidate has the potential to increase HRQoL in this population and to provide children with the opportunity to regain a sense of normality in their lives.
QOL-41. CARDIAC DYSFUNCTION IN MEDULLOBLASTOMA SURVIVORS TREATED WITH PHOTON IRRADIATION
Authors: Cacciotti Chantel , Chordas Christine , Valentino Kate , Allen Rudy , Manley Peter , Pillay-Smiley Natasha
Published: December 2020

BACKGROUND

Medulloblastoma is an aggressive central nervous system (CNS) tumor that occurs mostly in the pediatric population. Treatment includes surgical resection, craniospinal radiation (CSI) and chemotherapy. Children who receive standard photon radiation (RT) are at risk for cardiac toxicities. Potential late effects include coronary artery disease, left ventricular scarring and dysfunction, valvular damage and atherosclerosis. Current survivorship guidelines recommend routine ECHO surveillance for these patients but this comes at significant health care costs over a lifetime. We describe the experience of cardiac dysfunction in medulloblastoma survivors in a multi-institution study.

METHODS

A retrospective chart review of medulloblastoma patients treated between 1980 and 2010 with radiation at Lurie Children’s Hospital and Dana-Farber/ Boston Children’s Hospital who had an echocardiogram done following completion of therapy.

RESULTS

168 patients were treated for medulloblastoma during the study time. Of whom, 80 patients had echocardiogram follow up and 76 received photon irradiation. The latter were included in the study. The mean age at CSI was 8.6 years (range 2.9- 20), and mean number of years post RT at echocardiogram 7.4 years (range 2–16). Mean ejection fraction (EF) was 60.03% and shortening fraction (SF) 33.8%. Four patients (5%) had abnormal results, all of which had EF<50%.

CONCLUSION

Patients who received craniospinal irradiation for medulloblastoma therapy have relatively normal echocardiograms post treatment. Although RT may result in cardiac risks, echocardiograms may not be the most cost effective or efficacious mode to evaluate the risk in these survivors long term.
RARE-12. VASCULOPATHY IN PEDIATRIC CRANIOPHARYNGIOMA PATIENTS TREATED WITH SURGERY AND RADIOTHERAPY
Authors: Lucas John , LeVine David , Ismael Yousef , Hsu Chi-Yang , Darrow Kaleb , Faught Austin , Moskvin Vadim , Pilepesov Fakhriddin , Sabin Noah , Boop Frederick , Klimo Paul , Elijovich Lucas , Merchant Thomas
Published: December 2020

PURPOSE

As much as 40% of pediatric brain tumor patients will experience varied levels of Vasculopathy (VS), however few predictive factors have been described. Here we describe the type and timing of VS and explore the relationship between treatment modality and the timing, location, and distribution of VS.

METHODS

94 pediatric Craniopharyngioma patients underwent surgery and proton radiotherapy. Pre- and post-treatment imaging, cumulative physical and biological proton dose maps, clinical characteristics, and measures of dyslipidemia were evaluated. MR and MRAs were evaluated for pre- and post-radiotherapy VS (type, workup, location, and severity). VS events were segmented and described according to their normal brain region, and vascular territory.

RESULTS

47 patients were found to have 154 confirmed VS of varying severity with a median time to event of 3.41 years 95% CI 3.08–3.88. 22% (N=21) of patients had ≥1 pre-existing instances of VS and 26.6% (N=25) had a dyslipidemia at diagnosis. Forty-six (48.9%) patients had evidence of VS post-RT with 9.5% (N=9) being clinically significant. Aspirin was recommended in 10.6% (N=10) patients. Only 4 (4.2%) patients required revascularization. Clinical characteristics were not predictive of VS. An increased frequency of VS were observed along the operative corridor and high-dose radiotherapy field.

CONCLUSIONS

VS often precedes radiotherapy necessitating appropriate baseline imaging. Surgery type and extent are interrelated to the risk for radiotherapy-induced VS. While the spatial radiotherapy dose distribution approximated most vascular injury events, it was not all-inclusive. Spatial modeling of biological and physical dose may offer insights into therapy related vascular injury.
RARE-39. MOLECULARLY CONFIRMED ATYPICAL CHOROID PLEXUS PAPILLOMA WITH INTRACRANIAL DISSEMINATION
Authors: Yanagi Masato , Fukuoka Kohei , Matsushita Yuko , Hibiya Yuko , Honda Satoko , Mori Makiko , Arakawa Yuki , Ichimura Koichi , Tanami Yutaka , Nakazawa Atsuko , Kurihara Jun , Ko Katsuyoshi
Published: December 2020

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.
RONC-03. NEUROCOGNITIVE CHANGES AFTER RADIATION FOR PEDIATRIC BRAIN TUMOURS: WHICH BRAIN SUBSTRUCTURES ARE MOST IMPORTANT?
Authors: Tsang Derek S , Kim Laurence , Mabbott Donald , Khandwala Mohammad , Liu Zhihui Amy , Laperriere Normand , Janzen Lauran , Dama Hitesh , Ramaswamy Vijay , Keilty Dana , Bouffet Eric , Hodgson David C
Published: December 2020

INTRODUCTION

The contribution of different intracranial structures on neurocognitive decline after radiation therapy (RT) in children is unclear.

METHODS

This was a retrospective study of children with brain tumours treated from 2005 to 2017. Patients with longitudinal neurocognitive assessments and photon dosimetric data (if RT given) were included. Full scale intelligence quotient (FSIQ) was the primary endpoint; sub-indices of neurocognition were modelled separately (perceptual reasoning [PRI], processing speed [PSI], verbal comprehension [VCI] and working memory [WMI]). Multivariable linear mixed effects models were used to model endpoints, with age at diagnosis & dose to different brain regions as fixed effects and patient-specific random intercepts.

RESULTS

Sixty-nine patients were included; ten patients did not receive any RT (i.e. low-grade glioma). Median neurocognitive follow-up was 3.2 years. Right hippocampus mean dose was a strong predictor of declines in FSIQ (p < .001), VCI (p = 0.002) and PRI (p = 0.049). Dose to 50% of the supratentorial brain (D50) was the strongest predictor for WMI (p < .001) and PSI (p < .001). Each gray increase in mean right hippocampus dose resulted in a decrease of 0.038 FSIQ points/year. After adjusting for dose to brain substructures, younger age & presence of a ventriculoperitoneal shunt were also associated with decreased FSIQ.

CONCLUSIONS

Mean dose to the right hippocampus was associated with declines in FSIQ, VCI and PRI, while supratentorial brain D50 was associated with WMI and PSI. Efforts should be made to reduce unnecessary dose to these brain structures.
SURG-15. THE SURGERY OF THALAMIC LESIONS IN PEDIATRIC BRAIN TUMORS
Authors: Shimizu Yuzaburo , Akiyama Osamu , Kondo Akihide
Published: December 2020

BACKGROUND

Pediatric brain tumors are occurred in the center of central nervous system. Since mid-line glioma has defined in the new classification, thalamus has attracted attention as a site that requires surgical intervention. However, the surgery for thalamus is a challenging procedure for neurosurgeons. In this study, we studied our surgical cases of patients suffering from pediatric brain tumors in thalamus and/or thalamic regions to evaluate the safety of surgeries and the consideration of appropriate surgical approaches.

METHODS

We reviewed neuroradiological images, medical record, and, surgical videos for the assessment of surgical fields in patients under the age of 15 who had surgical treatments at our institution.

RESULTS

We had six cases that could be analyzed. The lesions in the posterior parts of the thalamus had been operated by the occipital transtentorial approach. The lesions in the superior parts of thalamus were treated with transcortical transventricle approach. It was possible to achieve sufficient removal of tumors and have good surgical view. The monitoring of motor function and visual function was used in all cases. After removal, we could have a nice view of the important structures around thalamus.

CONCLUSIONS

The surgeries for thalamus and thalamic regions were safety with enough considerations for neurological examinations and radiological imaging. The intra operative monitoring for motor and visual function should be used.
TBIO-17. INTEGRATIVE ANALYSES OF BRAFv600e MUTATED GLIOMAS: FROM MOLECULAR BIOLOGY TO RADIOLOGY AND TREATMENTS
Authors: Lhermitte Benoit , Guerin Eric , Ruhland Elisa , Sebastia Consuelo , Chammas Agathe , Fuchs Quentin , Bund Caroline , Namer Izzie Jacques , Dontenwill Monique , Entz-Werle Natacha
Published: December 2020

BRAFv600e mutation is encountered mostly in low-grade pediatric gliomas (LGG) and epileptogenic glioneuronal tumors, such as gangliogliomas (GG). Less frequently this mutation is present in high-grade glial (HGG) or glioneuronal tumors. Recent publications were highlighting BRAF mutation and CDKN2A deletion, as independent prognostic factors linked to a worst outcome in LGGs. We studied retrospectively a monocentric cohort of 12 LGGs (9 GG and 3 pilocytic astrocytomas) and 9 HGG (5 “de novo” tumors and 4 with a long past of LGG evolution) with BRAFv600e positivity. The patients were aged from 1 to 47 years. LGGs were under 20 years and only 3 patients with HGGs had less than 18 years. We focused on extended tumors’ biology assessment by DNA single-cell analyses, RNAsequencing, NGS, metabolomics, radiology (MRI, PET-scanning and spectroscopy) and correlated them to tumor’s data. One LGG had a CDKN2A deletion. Six had a complete surgical resection, 2 had a minimal residue and 4 had chemotherapies after partial surgery and relapsed. All HGGs had a surgical resection followed by chemotherapy and radiotherapy and additional CDKN2A deletion. Two pediatric HGGs relapsed rapidly. Only one benefited positively from targeted therapy. Specific radiological and spectroscopic signs were linked to the BRAF mutation itself and those different groups (LGGs, HGGs and LGGs with long term evolution of HGG), where specific molecular pathways and metabolomic profiles are associated. Currently, we are going further in the correlations to be able to predict in LGG their potential long-term evolution, where MAPK pathway modulations might be involved.
TBIO-19. INTEGRATED GENOMIC, PROTEOMIC AND PHOSPHOPROTEOMIC ANALYSIS OF SEVEN TYPES OF PEDIATRIC BRAIN CANCER
Authors: Petralia Francesca , Tignor Nicole , Rykunov Dmitri , Revas Boris , Chowdhury Shrabanti , Krek Azra , Raman Pichae , Ji Jiayi , Zhu Yuankun , Ma Weiping , Song Xiaoyu , Fenyo David , Gygi Steven , Ivey Richard , Iavarone Antonio , Whiteaker Jeffrey , Colaprico Antonio , Nesvizhskii Alexey , Rodriguez Henry , Paulovich Amanda , Hiltke Tara , Resnick Adam , Wang Pei , Rood Brian
Published: December 2020

We performed a comprehensive proteogenomic analysis across seven childhood brain tumors for a deeper understanding of their functional biology. Whole genome sequencing, RNAseq, quantitative proteomic profiling and phosphoproteomics were performed on 219 fresh frozen tumor samples representing the histologic diagnoses of: low grade astrocytoma (93), ependymoma (32), high grade astrocytoma (26), medulloblastoma (22), ganglioglioma (18), craniopharyngioma (16) and atypical teratoid rhabdoid tumor (12). Unsupervised clustering analysis based on proteomics data reveals eight clusters with distinct protein profiles and pathway activities. While some clusters coincide with histologic diagnoses, a couple of clusters appear to be a mixture of different diagnoses, including one cluster consisting of “aggressive” tumors characterized by poor survival and high stemness scores. By integrating proteomic data with RNAseq and WGS data, we characterize the impact of mutations (H3K27M, BRAFV600E, BRAF fusion) and CNVs upon the proteome across various diagnoses. Multiomics based kinase-substrate association analysis and co-expression network analysis reveal targetable active kinase networks within these tumors. Proteomic data reveals unique biology associated with H3K27M mutation status in HGG and BRAF aberrations in LGG. Characterization of the tumor microenvironment through deconvolution analyses based on multi-omics data reveals 5 distinct tumor clusters associated with different populations of infiltrating immune cells and the relative activity of the immune system based upon the expression of pro-inflammation or immunosuppressive markers. This study reports the first large-scale deep comprehensive proteogenomic analysis crossing traditional histologic boundaries to uncover foundational pediatric brain tumor biology including functional insight that helps drive translational efforts.
THER-03. IN VITRO EVALUATION OF THE EFFECT OF CANNABIDIOL ON PAEDIATRIC BRAIN TUMOUR CELL LINES USING A PULSED TREATMENT REGIME
Authors: Faulkes Sophie , Lockwood George , O’Sullivan Saoirse E , Grundy Richard G , Storer Lisa C D
Published: December 2020

Paediatric brain tumours are the second most common cancer after haematological malignancies. Intermittent dosing regimens are typical for chemotherapy drugs in order to avoid excessive damage to organs and avoid the onset of late effects. Cannabidiol (CBD) has been shown to have cytotoxic properties on paediatric brain tumour cell lines. Although CBD is far less toxic and damaging than the classical chemotherapy options which are currently available to children suffering with brain tumours, there are some possible side effects. Given that the half-life of the drug is 24 hours, it was important to establish the nature of the effect of cumulative dosing on top of the remaining drug in the system. The pHGG cell line, SF188 was cultured in different concentrations of CBD with either 1, 2 or 3 doses being given on consecutive days. 24 hours after the last dose the cells were analysed using the resazurin assay. It was observed that the amount of drug required for an EC50 to be obtained decreased; 17.6µM (1 dose), 8µM (2 doses), 5µM (3 doses) and that cell survival was reduced to nearly 0% in those cells which received multiple does of CBD at 17.6µM. In order to mimic the intermittent dosing regime, the cells were returned to the incubator for 4 days before the resazurin assay was repeated. The decrease in viability was maintained over the extended culture period meaning that the ability of even the apparent “healthy” cells to proliferate had been permanently affected.
Management of recurrent or progressive spinal metastases: reirradiation techniques and surgical principles
Authors: Kotecha Rupesh , Dea Nicolas , Detsky Jay S , Sahgal Arjun
Published: December 2020

With the growing incidence of new cases and the increasing prevalence of patients living longer with spine metastasis, a methodological approach to the management of patients with recurrent or progressive disease is increasing in relevance and importance in clinical practice. As a result, disease management has evolved in these patients using advanced surgical and radiotherapy technologies. Five key goals in the management of patients with spine metastases include providing pain relief, controlling metastatic disease at the treated site, improving neurologic deficits, maintaining or improving functional status, and minimizing further mechanical instability. The focus of this review is on advanced reirradiation techniques, given that the majority of patients will be treated with upfront conventional radiotherapy and further treatment on progression is often limited by the cumulative tolerance of nearby organs at risk. This review will also discuss novel surgical approaches such as separation surgery, minimally invasive percutaneous instrumentation, and laser interstitial thermal therapy, which is increasingly being coupled with spine reirradiation to maximize outcomes in this patient population. Lastly, given the complexities of managing recurrent spinal disease, this review emphasizes the importance of multidisciplinary care from neurosurgery, radiation oncology, medical oncology, neuro-oncology, rehabilitation medicine, and palliative care.
Neuro-Oncology Practice resources for optimizing care and practice in spinal oncology
Authors: Chakravarthy Vikram B , Grabowski Matthew M , Benzel Edward C , Benzil Deborah L
Published: December 2020

As the diagnosis and treatment of systemic cancers continues to improve, increased patient survival has resulted in a rise in the number of patients who develop spinal metastases (SM). Within many areas of oncology, utilization of multidisciplinary care models in the management and decision making of SM patients has proven effective for optimizing care and improving patient safety. Three main goals of an effective clinical pathway include improving outcomes and quality, improving the patient experience, and lowering cost. This paper outlines the strategies employed to optimally establish such a collaborative program for the management of patients with SM, as well as direct providers in and out of the field, patients and caregivers, and practice managers to the appropriate resources.
The importance of multidisciplinary care for spine metastases: initial tumor management
Authors: Newman William Christopher , Patel Ankur , Goldberg Jacob L , Bilsky Mark H
Published: December 2020

Spine metastases are very common in cancer patients often requiring urgent assessment and the initiation of therapy. Treatment paradigms have changed exponentially over the past decade with the evolution and integration of stereotactic body radiotherapy, minimally invasive spine techniques, and systemic options including biologics and checkpoint inhibitors. These advances necessitate multidisciplinary assessments and interventions to optimize outcomes. The NOMS framework provides a mechanism for all practitioners to evaluate the 4 sentinel assessments required to make decisions in patients with spine metastases: Neurologic, Oncologic, Mechanical Stability, and Systemic disease. The NOMS framework is continuously updated with the integration of newer technologies and evidence-based medicine as they become available. This paper presents the current iteration of NOMS with a focus on the role of medical and neuro-oncologists in the assessment and treatment of metastatic spine tumors.
Late diagnosis of isolated central diabetes insipidus secondary to congenital toxoplasmosis—case report
Authors: Omer Tahir , Khan Mustafa , Western Thomas
Published: December 2020

Congenital toxoplasmosis is an uncommon infection. Hypothalamic/pituitary involvement leading to isolated central diabetes insipidus is extremely rare. Making a correct diagnosis of this condition, albeit challenging, is crucial for adequate management. We present a 54-year-old female who developed central diabetes insipidus as a complication of congenital toxoplasmosis. She had polydipsia and hypernatraemia on presentation and responded to intranasal desmopressin with normalization of above-mentioned findings. Magnetic resonance imaging and cranial X-ray’s showed pronounced intracranial calcifications in both choroid plexuses. Thyroid function tests, serum cortisol level and anterior pituitary function were all normal. To the best of our knowledge, this is the first reported case of isolated diabetes insipidus due to congenital toxoplasmosis in literature diagnosed late in adulthood and gives an insight into the challenges of diagnosing central diabetes insipidus and the hypothalamic/pituitary involvement in cases of congenital toxoplasmosis.
Incidental diagnosis of 17 alpha-hydroxylase deficiency: a case report
Authors: Ammar Rasha , Ramadan Ahmad
Published: December 2020

A 17 alpha-hydroxylase deficiency (17OHD) is a rare form of congenital adrenal hyperplasia (CAH). In this article we discuss a case of 8-year-old girl presented with upper respiratory infection symptoms and a history of hospital admission of fatigue and dehydration. She was incidentally found to have hypertension and hypokalemia. After an endocrine workup her biochemical tests showed: metabolic alkalosis, low levels of cortisol, high levels of adrenocorticotropic hormone (ACTH) and follicle-stimulating hormone (FSH) with normal female phenotype and (46,XY) karyotype. These findings led to the diagnosis of 17OHD confirmed by regression of hypertension and hypokalemia with hydrocortisone prescription. This case shows the importance of vital signs measurement, medical history and commitment to a systematic approach.
Immunization with a heat-killed bacterium,Mycobacterium vaccaeNCTC 11659, prevents the development of cortical hyperarousal and a PTSD-like sleep phenotype after sleep disruption and acute stress in mice
Authors: Bowers Samuel J , Lambert Sophie , He Shannon , Lowry Christopher A , Fleshner Monika , Wright Kenneth P , Turek Fred W , Vitaterna Martha H
Published: December 2020

Study Objectives

Sleep deprivation induces systemic inflammation that may contribute to stress vulnerability and other pathologies. We tested the hypothesis that immunization with heat-killed Mycobacterium vaccae NCTC 11659 (MV), an environmental bacterium with immunoregulatory and anti-inflammatory properties, prevents the negative impacts of 5 days of sleep disruption on stress-induced changes in sleep, behavior, and physiology in mice.

Methods

In a 2 × 2 × 2 experimental design, male C57BL/6N mice were given injections of either MV or vehicle on days –17, –10, and –3. On days 1–5, mice were exposed to intermittent sleep disruption, whereby sleep was disrupted for 20 h per day. Immediately following sleep disruption, mice were exposed to 1-h social defeat stress or novel cage (control) conditions. Object location memory (OLM) testing was conducted 24 h after social defeat, and tissues were collected 6 days later to measure inflammatory markers. Sleep was recorded using electroencephalography (EEG) and electromyography (EMG) throughout the experiment.

Results

In vehicle-treated mice, only the combination of sleep disruption followed by social defeat (double hit): (1) increased brief arousals and NREM beta (15–30 Hz) EEG power in sleep immediately post-social defeat compared to baseline; (2) induced an increase in the proportion of rapid-eye-movement (REM) sleep and number of state shifts for at least 5 days post-social defeat; and (3) induced hyperlocomotion and lack of habituation in the OLM task. Immunization with MV prevented most of these sleep and behavioral changes.

Conclusions

Immunization with MV ameliorates a stress-induced sleep and behavioral phenotype that shares features with human posttraumatic stress disorder.
Finding Resonance Amid Trauma: Moral Injury and the Role of Religion Among Christian Post-9/11 U.S. Veterans
Authors: Suitt Thomas Howard
Published: December 2020

Recent scholarship examines the relationship between moral injury and religion but rarely analyzes social processes at work therein. This article uses data from interviews with 47 post-9/11 veterans who once or currently identified as Christian to explore how religious beliefs and practices preempt, mitigate, or exacerbate moral injury. While many veterans experienced potentially morally injurious events, the differences between those with moral injury and those without depended on whether they could find resonance with meaning-making toolkits amid trauma. Dissonance stirred by incoherence in one’s moral narrative and betrayal of significant relationships spurred manifestations of moral injury. Those who achieved resonance relied on religious moral frames they brought with them or those supplied by military culture, or they engaged in explicit moral deliberation. This study reveals a complex process of belief maintenance during moral crises that extends and challenges previous examinations of culture in action, resonance, and moral injury.
A randomized feasibility pilot trial of a financial incentives intervention for dietary self-monitoring and weight loss in adults with obesity
Authors: Voils Corrine I , Pendergast Jane , Hale Sarah L , Gierisch Jennifer M , Strawbridge Elizabeth M , Levine Erica , McVay Megan A , Reed Shelby D , Yancy William S , Shaw Ryan J
Published: December 2020

Financial incentives could be used to improve adherence to behavioral weight loss interventions, increasing their effectiveness. This Phase IIb randomized pilot study evaluated the feasibility and acceptability of a study protocol for providing financial incentives for dietary self-monitoring and/or weight loss. Community-dwelling adults with obesity were enrolled in a 24 week, group-based weight loss program. Participants were randomized in a 2 × 2 factorial design to receive financial incentives for both dietary self-monitoring and weekly weight loss, just one, or neither. Participants could earn up to $300, evolving from fixed weekly payments to intermittent, variable payments. The notice of reward was provided by text message. The study was conducted in three successive cohorts to evaluate study procedure changes, including dietary approach, recruitment and retention strategies, text messaging, and incentives. Descriptive statistics calculated separately for each cohort described study performance relative to predefined targets for recruitment, including minority representation; retention; adherence; and weight loss. Acceptability was assessed via postintervention qualitative interviews. In Cohort 1 (n = 34), a low-carbohydrate diet was used. Recruitment, retention, adherence, and weight loss were adequate, but minority representation was not. For Cohort 2 (n = 31), employing an additional recruitment method and switching to a reduced-calorie diet yielded adequate recruitment, minority representation, retention, and adherence but less weight loss. Returning to a low-carbohydrate diet in Cohort 3 (n = 28) yielded recruitment, minority representation, retention, adherence, and weight loss similar to Cohort 2. Participant feedback informed changes to text message timing and content and incentive amount. Through successive cohorts, we optimized recruitment and retention strategies and text messaging. An adequately powered trial is warranted to evaluate the efficacy of these incentive structures for reducing weight. The trial registration number is NCT02691260.
The facts about pedophilic disorder
Authors: Kiper Valerie , Gary Annette , Geist Rebecca
Published: December 2020

Pedophilia is a controversial and unpleasant subject for many clinicians. Healthcare professionals need to understand the condition and, whenever possible, attempt to reconcile their feelings so they can provide appropriate care when encountering a patient with this diagnosis.
The Impact of Parental Pain-attending and Non–pain-attending Responses on Child Pain Behavior in the Context of Cancer-related Painful Procedures
Authors: Rheel Emma , Ickmans Kelly , Caes Line , Vervoort Tine
Published: December 2020

Objectives:

Literature has demonstrated inconsistent findings regarding the impact of parental responses on child pain-related outcomes. Yet, research into factors that may underlie inconsistent findings regarding the variable impact of parental responses is lacking. The current study investigated the moderating role of parental distress in understanding the impact of parental pain-attending (eg, reassuring the child) and non–pain-attending (eg, distracting the child with humor) responses on child pain behavior (eg, crying).

Methods:

Children (18 y and younger) with leukemia, undergoing a lumbar puncture (LP) and/or bone marrow aspiration procedure, and one of their parents, were recruited from the Pediatric Ghent University Hospital. Parent–child interactions were videotaped after the procedure allowing coding of parental responses and child pain behavior. Parents self-reported on experienced personal distress.

Results:

Participants consisted of 42 children (24 boys, 18 girls) with leukemia and one of their parents. Children were 0.6 to 15 (7.08±4.39) years old. Findings indicated a positive association between parental pain-attending and child pain behavior, but only when parents reported high levels of distress (β=0.56, P=0.001). No association was observed for parents reporting low levels of distress (β=−0.09, ns). Parental non–pain-attending responses contributed to lower child pain behavior (β=−0.24, P=0.045), independently of parental distress (β=−0.07, ns).

Discussion:

The current findings point to the moderating role of parental distress in understanding the impact of parental responses on child pain behavior and highlight the importance of interventions targeting parental emotion regulation to promote optimal child pain outcomes.
Addressing Competing Risks When Assessing the Impact of Health Services Interventions on Hospital Length of Stay
Authors: Batomen Brice , Moore Lynne , Strumpf Erin , Nandi Arijit
Published: December 2020

Background:

Although hospital length of stay is generally modeled continuously, it is increasingly recommended that length of stay should be considered a time-to-event outcome (i.e., time to discharge). Additionally, in-hospital mortality is a competing risk that makes it impossible for a patient to be discharged alive. We estimated the effect of trauma center accreditation on risk of being discharged alive while considering in-hospital mortality as a competing risk. We also compared these results with those from the “naive” approach, with length of stay modeled continuously.

Methods:

Data include admissions to a level I trauma center in Quebec, Canada, between 2008 and 2017. We computed standardized risk of being discharged alive at specific days by combining inverse probability weighting and the Aalen–Johansen estimator of the cumulative incidence function. We estimated effect of accreditation using pre–post, interrupted time series (ITS) analyses, and the “naive” approach.

Results:

Among 5,300 admissions, 12% died, and 83% were discharged alive within 60 days. Following accreditation, we observed increases in risk of discharge between the 7th day (4.5% [95% CI = 2.3, 6.6]) and 30th day since admission 3.8% (95% CI = 1.5, 6.2). We also observed a stable decrease in hospital mortality, –1.9% (95% CI = –3.6, –0.11) at the 14th day. Although pre–post and ITS produced similar results, we observed contradictory associations with the naive approach.

Conclusions:

Treating length of stay as time to discharge allows for estimation of risk of being discharged alive at specific days after admission while accounting for competing risk of death.