bluuebunny/crossref_metadata_2025_split huggingface dataset:
COVD-01. VINBLASTINE MONOTHERAPY INDUCTION FOR LOCALISED CNS GERMINOMA DURING THE COVID-19 PANDEMIC
Authors: Moleron Rafael , Stoneham Sara , Ajithkumar Thankamma , Cross Justin , Nicholson James , Murray Matthew 
Published: December 2020

Abstract

INTRODUCTION
Patients with localised CNS-germinoma have excellent survival. More recently, intensive inpatient chemotherapy (carboPEI=carboplatin/etoposide/ifosfamide in Europe) has been effectively employed to reduce radiotherapy fields and/or dose. Current research priorities focus on reducing treatment burden and long-term sequelae. Of note, outpatient-based single-agent carboplatin chemotherapy is associated with excellent outcomes in metastatic testicular seminoma (an identical pathology) [Alifrangis,EJC,2020]. Recently, successful vinblastine monotherapy was reported in localised CNS-germinoma [Murray,Neurooncol-Adv,2020].

METHODS
Due to the COVID-19 pandemic, adapted UK guidelines for germ-cell-tumour management were distributed, including potential non-standard treatment options that would reduce hospital visits/admissions. A 30-year-old patient presented with a 32mmx30mmx35mm diameter solid+multi-cystic localised pineal CNS lesion, consistent radiologically with a germ-cell-tumour with prominent teratoma component. Investigation revealed negative AFP/HCG markers and biopsy-proven pure germinoma. After appropriate consent, the patient commenced 12-week induction with weekly vinblastine monotherapy (low-grade-glioma dosing [Lassaletta,JCO,2016]), with wk6&12 MRI re-assessment prior to definitive radiotherapy.

RESULTS
Vinblastine was well-tolerated. After initial 4mg/m2 test-dosing (wk1), standard 6mg/m2 was delivered for wk2, but resulted in asymptomatic neutropenia (nadir 0.3x10^9/l) and missed dosing at wk3. Subsequent doses were 4mg/m2, with no further neutropenia. As expected, MRI showed moderate 40% tumour volume reduction by wk12. Surgical resection of the residual presumed teratoma component was undertaken prior to radiotherapy.

CONCLUSION
Patients with CNS-germinoma have excellent outcomes and reduction of treatment-effects remains a priority. The exquisite chemosensitivity of germinoma, excellent results from monotherapy for metastatic testicular disease, and early promise of vinblastine monotherapy lend itself to further exploration for CNS-germinoma.
DDEL-06. DRUG INTERACTION BETWEEN EVEROLIMUS AND CANNABIDIOL IN PEDIATRIC PATIENTS WITH SUBEPENDYMAL GIANT CELL ASTROCYTOMAS: A SINGLE INSTITUTION EXPERIENCE
Authors: Sabus Ashley , Winzent Shelby , Hemenway Molly , Levy Jean Mulcahy , Foreman Nicholas 
Published: December 2020

Abstract
Tuberous sclerosis complex (TSC) is an autosomal recessive genetic disorder associated with clinical manifestations including subependymal giant cell astrocytomas (SEGA) and seizures. The combination of everolimus and Epidiolex, a purified form of cannabidiol, has become an increasingly common treatment regimen in this population. Everolimus is primarily metabolized via CYP3A4, which may be inhibited by cannabidiol. We seek to describe our institution’s experience with this drug interaction. METHODS: Investigators conducted a retrospective review of neuro-oncology patients with TSC and SEGA who were treated concurrently with everolimus and cannabidiol. Data collected included demographics, body surface area, everolimus dose, everolimus troughs, date of cannabidiol initiation, documented symptoms, liver and renal function tests, and reason for discontinuing therapy. RESULTS: Three patients (ages 11–17 years) met inclusion criteria. All patients were stable on everolimus doses ranging from 6.5 to 9.5 mg/m2/day and achieving trough goals of 5–10 ng/mL. Two to four weeks after initiating cannabidiol, everolimus trough concentrations rose 200–860% above goal. One patient reported new-onset involuntary movements, but no other toxicities were noted. Cannabidiol was discontinued in all cases due to caregiver concerns regarding drug interactions. All patients were able to achieve goal trough concentrations on previously stable doses of everolimus after discontinuing cannabidiol. CONCLUSIONS: Cannabidiol appears to modulate everolimus metabolism leading to significantly elevated serum concentrations. Additional research is required to determine the need for empiric dose adjustments upon cannabidiol initiation. Patient counseling, frequent trough monitoring, and surveillance for adverse effects are crucial for optimizing outcomes in patients prescribed this regimen.
DIPG-07. HIGH THROUGHPUT DRUG SCREENING IDENTIFIES POTENTIAL NEW THERAPIES FOR DIFFUSE INTRINSIC PONTINE GLIOMAS (DIPGs)
Authors: Upton Dannielle , Valvi Santosh , Liu Jie , Yeung Nicole , George Sandra , Ung Caitlin , Khan Aaminah , Franshaw Laura , Ehteda Anahid , Shen Han , Orienti Isabella , Farruggia Giovanna , Nath Christa , Reynolds Patrick , Tsoli Maria , Ziegler David 
Published: December 2020

Abstract
DIPGs are the most devastating of all brain tumors. There are no effective treatments, hence almost all children will die of their tumor within 12 months. There is an urgent need for novel effective therapies for this aggressive tumor. We performed a high-throughput drug screen with over 3,500 biologically active, clinically approved compounds against a panel of neurosphere-forming DIPG cells. We identified 7 compounds- auranofin, fenretinide, ivermectin, lanatoside, parthenolide, SAHA and mefloquine- that were confirmed to have potent anti-tumor activity against a panel of DIPG-neurospheres, with minimal effect on normal cells. Using cytotoxicity and clonogenic assays, we found that these drugs were able to inhibit DIPG-neurosphere proliferation and colony formation in-vitro. To determine whether the in-vitro efficacy could be replicated in-vivo, we tested the activity of each of these compounds in an orthotopic DIPG model. Of the agents tested, fenretinide and SAHA were the most active anti-tumor agents, significantly enhancing the survival of tumor bearing animals. Mechanistic studies showed fenretinide enhancing apoptotic cell death of DIPG cells via inhibition of PDGFRa transcription and downregulation of the PI3K/AKT/MTOR pathway. We therefore examined the therapeutic efficacy of fenretinide using a second orthotopic model with PDGFRa amplification. We used two different Fenretinide formulations (LYM-X-Sorb and NanoMicelle) which were found to enhance survival. Fenretinide is clinically available with safety data in children. Validation of the activity of Fenretinide in PDGFRa-amplified or overexpressed DIPGs will lead to the development of a clinical trial, allowing the advancement of fenretinide as potentially the first active therapy for DIPG.
DIPG-17. BIOPSY-PROVEN DIFFUSE MIDLINE GLIOMA IN ADOLESCENTS AND YOUNG ADULTS
Authors: Tanaka Shota , Takayanagi Shunsaku , Shinya Yuki , Kawashima Mariko , Shin Masahiro , Nakatomi Hirofumi , Saito Nobuhito 
Published: December 2020

Abstract

INTRODUCTION
Diffuse midline glioma (DMG) mostly affects young children. The newly-introduced disease entity DMG, H3K27M-mutant uniformly portends poor prognosis, and therefore that in the pons is usually treated based upon radiological diagnosis without histological confirmation. DMG is rarer in adolescents and young adults (AYA), and remains poorly characterized. In this study, we sought to investigate the clinical, pathological, and molecular profiles of DMG in AYA generation.

METHODS
Patients of age between 16 and 39 undergoing biopsy at the University of Tokyo Hospital between 2003 and 2019 were included in the study. Clinical data and images were retrospectively reviewed. Genetic analyses were performed in cases with abundant tissues.

RESULTS
Ten patients included 8 brainstem and 2 thalamic DMG. The median age was 25 years (range, 19–38). Pathological diagnosis was DMG, H3K27M-mutant in 3 patients, glioblastoma, IDH-mutant in 1, anaplastic astrocytoma, IDH-wildtype in 4, diffuse astrocytoma, IDH-mutant in 1, and diffuse astrocytoma, IDH-wildtype in 1. Genetic analyses detected H3F3A-K27M mutation in 2, HIST1H3B-K27M mutation in 1, IDH1-R132H mutation in 1, and IDH1-R132S mutation in 1. With a median follow-up of 23 months (range, 2–61), only 3 patients died 29–61 months after diagnosis, and the remaining 7 patients survived for 2–59 months. Neither IDH1 mutation nor H3K27M mutation was associated with survival in this series.

CONCLUSION
Survival of AYA patients with DMG was seemingly variable with some long survivors. H3K27M mutation was present in a subset of patients. A further study is warranted to correlate molecular profile with clinical pictures including patient survival.
DIPG-22. DISSECTING THE ONCOGENIC ROLE OF FOXR2 IN DIFFUSE INTRINSIC PONTINE GLIOMA
Authors: Tsai Jessica W , Patel Smruti K , Bear Heather , Dubois Frank , Khadka Prasidda , Lu Sophie , Gonzalez Elizabeth , Ligon Keith , Bandopadhayay Pratiti , Phoenix Timothy N 
Published: December 2020

Abstract

BACKGROUND
Diffuse intrinsic pontine gliomas (DIPGs) pose particular challenges for treatment. We recently completed a genomic analysis of close to 200 DIPGs and high-grade gliomas. We identified that nearly 10% of all DIPGs have increased expression of the fork head domain transcription factor FOXR2. We hypothesize that FOXR2 accelerates gliomagenesis in histone mutant DIPGs and represents a previously unexplored therapeutic target.

METHODS
To determine whether FOXR2 is sufficient to mediate gliomagenesis, we applied an integrative genomics approach using both in vitro and in vivo DIPG models: mouse neural stem cell models expressing FOXR2, in vivo mouse models using in utero brainstem electroporation, patient-derived DIPG cell lines, and RNA sequencing analysis of human and mouse tumors expressing FOXR2.

RESULTS
Our data shows that FOXR2 indeed is an oncogene that rapidly accelerates gliomagenesis using an in vivo brainstem in utero electroporation model of DIPG. In human tumors, increased FOXR2 expression is mutually exclusive with MYC amplification suggesting functional redundancy. In vivo, FOXR2 results in large brainstem gliomas and rapid neurologic decline of animals. Transcriptional profiling of these tumors demonstrates activation of MYC signaling pathways. In vitro, we have further identified patient-derived cell lines with increased expression of FOXR2.

CONCLUSION
FOXR2 is sufficient to enhance gliomagenesis and represents a previously understudied therapeutic target for patients with the devastating disease DIPG.
DIPG-25. KETOGENIC DIET IN DIFFUSE INTRINSIC PONTINE GLIOMA IN CHILDREN: A RETROSPECTIVE STUDY INVESTIGATING THE FEASIBILITY
Authors: Perez Alexandre , Nathan Janak , El-Ayadi Moatasem , Korff Christian , Ansari Marc , von Bueren André 
Published: December 2020

Abstract

PURPOSE
Diffuse Intrinsic Pontine Glioma (DIPG) is one of the most devastating diseases amongst children with cancer, thus novel strategies are urgently needed. We aimed to retrospectively evaluate the feasibility of the carbohydrate restricted ketogenic diet (KD) in DIPG patients.

METHODS
Searches of MEDLINE and Embase identified four publications meeting the inclusion criteria (diagnosis of DIPG and exposition to a KD ≥ 3 months). One additional case was identified by contact with experts. The minimal feasibility criteria were defined as the ability to use the KD for ≥ 3 months. Individual patient data were extracted from the publications or obtained from investigators.

RESULTS
Five patients (males, n=3; median age 4.4 years; range, 2.5–17 years) met the inclusion criteria (one patient – identified and not included - was on KD &lt; 3 months due to disease progression). Further feasibility analyses showed a duration of the KD of ≥ 3 months and less than 7 months (n=2), &gt; 7 months and less than 1 year (n= 2), and two years (n=1), respectively.

CONCLUSION
These results – based on a small patient population – suggest that the KD appears to be a feasible treatment option for children with DIPG. The potential duration of the KD is limited by the aggressive clinical behavior of DIPG. The safety analysis is currently being retrospectively assessed. These data should encourage further studies on a larger scale; ideally assessing the impact of the KD in DIPG patients in a randomized controlled trial.
DIPG-26. THERAPEUTIC EFFECTS OF RADIOTHERAPY WITH CONCOMITANT AND ADJUVANT TEMOZOLOMIDE VERSUS RADIOTHERAPY WITH CONCOMITANT TEMOZOLOMIDE ALONE IN CHILDREN WITH DIPG: A SINGLE-CENTER EXPERIENCE WITH 82 CASES
Authors: Lai Mingyao , Li Juan , Hu Qingjun , Zhou Jiangfen , Li Shaoqun , Wen Lei , Zhou Zhaoming , Zhou Cheng , Wang Lichao , Shan Changguo , Zhang Yangqiong , Luo Rishun , Cai Linbo 
Published: December 2020

Abstract

OBJECTIVE
To retrospectively analyze the therapeutic effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy with concomitant temozolomide alone for pediatric diffuse intrinsic pontine glioma (DIPG), and to evaluate the value of temozolomide in the treatment of pediatric DIPG.

METHODS
The clinical data of children with confirmed DIPG in Guangdong Sanjiu Brain Hospital between January 1, 2010 and December 30, 2019 were collected. The inclusive criteria included (1) receiving a total radiotherapy dose of 54 Gy in 27 fractions, (2) treated with concomitant temozolomide chemotherapy, and (3) with or without adjuvant temozolomide chemotherapy.

RESULTS
A total of 82 pediatric patients were eligible for the study, with a median age of 7 years (range 2–16 years). The median follow-up was 8.6 months (range 2–28 months) and the median survival time was 9.4 months. The median survival time of 66 patients treated with radiotherapy with concomitant and adjuvant temozolomide was 9.8 months, longer than 7.5 months of the other 16 patients treated with radiotherapy with concomitant temozolomide alone, with statistical differences (P=0.010). Moreover, bevacizumab and nimotuzumab didn’t bring survival benefits to patients with disease recurrence or progression. Hematological toxicity (Grade IV) was not found.

CONCLUSION
Radiotherapy with concomitant and adjuvant temozolomide prolongs the survival time of children with DIPG.
DIPG-37. PREDICTING OUTCOME IN CHILDHOOD DIFFUSE MIDLINE GLIOMAS USING MAGNETIC RESONANCE IMAGING BASED TEXTURE ANALYSIS
Authors: Szychot Elwira , Youssef Adam , Ganeshan Balaji , Endozo Raymond , Hyare Harpreet , Gains Jenny , Shankar Ananth , Mankad Kshitij 
Published: December 2020

Abstract

BACKGROUND
Diffuse midline gliomas (DMG) are aggressive brain tumours with 10% overall survival (OS) at 18 months. Predicting OS will help refine treatment strategy in this patient group. MRI based texture analysis (MRTA) is a novel technique that provides objective information about spatial arrangement of MRI signal intensity and has potential as an imaging biomarker. OBJECTIVES: To investigate MRTA in predicting OS in childhood DMG.

METHODS
Retrospective study of patients diagnosed with DMG, based on radiological features, treated at our institution 2007–2017. MRIs were accomplished at diagnosis and 6 weeks after radiotherapy (54Gy in 30 fractions). MRTA, performed using TexRAD software, on T2W sequence and Apparent Diffusion Coefficient (ADC) maps encapsulated tumour in the largest single axial plane. MRTA comprised filtration-histogram technique using statistical and histogram metrics for quantification of texture. Kaplan-Meier analysis determined association of MRI texture parameters with OS.

RESULTS
32 children 2–14 years (median 7 years) were included. MRTA was undertaken on T2W (n=32) and ADC (n=22). MRTA on T2W was better at prognosticating than on ADC maps. Children with homogenous tumour texture, at medium scale on baseline T2W MRI, had worse prognosis (mean p=0.0098, SD p=0.0115, entropy p=0.0422, mean of positive pixels (MPP) p=0.0051, kurtosis p=0.0374). MPP was the most significant texture parameter. Median survival in this group as identified by MRTA (medium texture, MPP) was 7.5 months versus 17.5 months.

CONCLUSIONS
DMG with more homogeneous texture on diagnostic MRI is associated with worse prognosis. MPP texture parameter is the most predictive of OS in childhood DMG.
DIPG-41. DISSECTING THE MECHANISTIC BASIS FOR ACVR1 AND PIK3CA MUTATION CO-OCCURRENCE IN DIFFUSE MIDLINE GLIOMAS USING GENETICALLY ENGINEERED MOUSE MODELS
Authors: Wu Annette , Mak Tak , Fortin Jerome 
Published: December 2020

Abstract
Diffuse midline gliomas (DMGs) are aggressive childhood brain tumors with a dismal prognosis. Most of these tumors carry K27M mutations in histone H3-encoding genes, particularly H3F3A and HIST1H3B. In addition, activating mutations in ACVR1 and PIK3CA co-occur in a subset of DMGs. To understand how these lesions drive the development of DMGs, we generated genetically engineered mouse models in which Acvr1G328V, Hist1h3bK27M, and Pik3caH1047R are targeted to the OLIG2-expressing cell lineage. Animals carrying Acvr1G328V and Pik3caH1047R, with (“AHPO”) or without (“APO”) Hist1h3bK27M, developed high-grade diffuse gliomas involving midline and forebrain regions. Neither Acvr1G328V nor Pik3caH1047R drove tumorigenesis by themselves, but Acvr1G328V was sufficient to cause oligodendroglial differentiation arrest, pointing to a role in the earliest stages of gliomas formation. Transcriptomic analyses of AHPO and APO tumors indicated a predominantly proneural and oligodendrocyte precursor-like gene expression signature, consistent with the corresponding human pathology. Genes encoding transcription factors (TFs) with dual roles in controlling glial and neuronal differentiation were upregulated in tumors. Some of these genes were mildly induced by Acvr1G328V alone. Functional experiments using CRISPR/Cas9-mediated gene editing in patient-derived cell lines confirmed a role for some of these TFs in controlling DMG cell fitness. Overall, our results suggest that Pik3caH1047R consolidates Acvr1G328V-induced glial differentiation arrest to drive DMG development and progression.
DIPG-52. PHASE I CLINICAL TRIAL OF ONC201 IN PEDIATRIC H3 K27M-MUTANT GLIOMA OR NEWLY DIAGNOSED DIPG
Authors: Gardner Sharon , Tarapore Rohinton , Allen Jeffrey , Zaky Wafik , Odia Yazmin , Hall Matthew , Daghistani Doured , Khatib Ziad , Koschmann Carl , Aguilera Dolly , MacDonald Tobey , Fouladi Maryam , McGovern Susan , Kline Cassie , Vitanza Nicholas , Lu Guangrong , Merdinger Krystal , Oster Wolfgang , Allen Joshua , Khatua Soumen 
Published: December 2020

Abstract
H3 K27M-mutant gliomas often manifest as midline gliomas, have a dismal prognosis, and have no effective treatments. ONC201 efficacy has been shown in high-grade glioma preclinical models and durable responses with single agent ONC201 have been reported in adults with recurrent H3 K27M-mutant gliomas. These observations led to a Phase I pediatric clinical trial of ONC201 dosed by body weight. This multi-center, open-label, 3 + 3 dose-escalation and dose-expansion clinical trial (NCT03416530) for H3 K27M-mutant glioma or non-biopsied DIPG has 6 arms: arms A and E determine the RP2D in pediatric post-radiation (recurrent or not-recurrent) H3 K27M-mutant glioma patients with ONC201 administered as an oral capsule as well as a liquid formulation, respectively. Both arms have completed accrual. The study is currently enrolling newly diagnosed DIPG patients to determine the RP2D for ONC201 in combination with radiation (arm B). Dedicated assessment of intratumoral ONC201 concentrations in midline gliomas patients (arm C) and the effects of ONC201 in H3K27M DNA levels in circulating CSF (arm D) are currently enrolling patients. ONC201 as a single agent in patients with progressive H3K27M mutant tumors following irradiation (excluding DIPG/spinal cord tumors) was recently opened (arm F). Once the RP2D is confirmed, there is a dose-expansion cohort to confirm the safety, radiographic efficacy and survival with ONC201. The primary endpoints of arms A, B, and E have been established with the RP2D of 625mg scaled by body weight as a capsule or liquid formulation administered alone or in combination with radiation without incidence of dose-limiting toxicity.
DIPG-57. TRANSCRIPTOMIC AND PROTEOMIC ANALYSES OF DIPG RESPONSE TO ONC201
Authors: Sridharan Sreepradha , Harmanci Arif , Sharma Ajay , Lai Yanlai , Kennis Bridget , Dobson Tara , Swaminathan Jyothishmathi , Haltom Amanda , Khatua Soumen , Tarapore Rohinton , Allen Joshua , Cheng Donghang , Zaky Wafik , Gopalakrishnan Vidya 
Published: December 2020

Abstract
Diffuse Intrinsic Pontine Glioma (DIPG) is an incurable pediatric brain tumor. Current standard of care has shown no improvements in survival. Here, we report our study of ONC201, a first-in-class small molecule developed by Oncoceutics, Inc., against a panel of DIPG cells in vitro and in mouse orthotopic models. ONC201 inhibits signaling through dopamine receptor D2 (DRD2), a G protein-coupled receptor (GPCR). MTT assays revealed a delayed but more robust response to ONC201, as measured by IC50 values, in DIPGs with histone H3.3-K27M expression compared to cells expressing wildtype (WT) or K27M mutant histone H3.1. Interestingly, transcriptomic profiling identified an association of this response delay with an elevation of genes controlling the cellular unfolded protein response, lysosomal and vacuole organization, and a decline in nucleic acid biosynthetic genes. These cells were also more committed to neuronal and oligodendrocytic lineage specification. By contrast, WT-H3 DIPGs that survived ONC201 treatment were stem-like and exhibited altered expression of genes controlling cell proliferation and apoptosis induction, respectively. Single cell proteomics validated the increase in anti-apoptotic proteins in these cells. Intraperitoneal administration of ONC201 for 7-weeks in mice bearing pontine xenografts of histone H3.1-K27M mutant DIPGs, caused a complete blockade of tumor growth relative to untreated controls. However, identical treatment of animals with forebrain tumors resulted only in a partial reduction in tumor burden, suggesting that the tumor microenvironment may be involved in the differential effect. These data indicate that tumor intrinsic and extrinsic factors may contribute to the response of DIPG tumors to ONC201.
DIPG-72. LONG-TERM SURVIVAL OF A CLASSIC DIFFUSE INTRINSIC PONTINE GLIOMA TREATED WITH NIMOTUZUMAB
Authors: Epelman Sidnei , Ramaswamy Vijay , Gorender Ethel , Sakamoto Luis Henrique 
Published: December 2020

Abstract

BACKGROUND
Long-term survival in diffuse intrinsic pontine glioma is rare, and typically associated with atypical imaging and/or atypical clinical course. Although most patients harbor hotspot mutations in H3.1/3-K27M, a proportion of patients have alternate mutations, despite a typical clinicoradiological course. Herein we describe a long-term survivor with a classical presentation, treated with nimotuzumab, highlighting the challenges associated with such cases. CASE REPORT: A 5 year old male, diagnose in 2012 with a 10 day history multiple cranial neuropathies and a right hemiparesis. Cranial MRI revealed a poorly delimited diffuse pontine tumor and secondary hydrocephalus. Tumor biopsy was not performed due to the classic clinical presentation, and he received 54Gy/30 of radiation plus concomitant weekly nimotuzumab 150mg/m2. Initial tumor dimensions were 43x31x28mm. Nimotuzumab 150mg/m2 was continued every 2 weeks. Image assessment at week 12 of treatment revealed 16.9% volume increase, 4 weeks after radiotherapy completion. Nevertheless, subsequent neuroimaging at 24th, 36th, 60th, 96th and 108th weeks of nimotuzumab therapy showed a sustained and progressive tumor cytoreduction of 47.5%, 59%, 62.2%, 63.8% and 67%, respectively, when compared with post-radiotherapy dimensions. Currently, the patient is 13y old, good school performance, no neurologic disabilities. The last MRI at 394 weeks of nimotuzumab revealed dimensions of 21x19x14mm which corresponds to 70% of reduction compared with initial volume.

CONCLUSIONS
Our case of progressive cytoreduction over two years of a classic DIPG, diagnosed in the era prior to the discovery of the K27M mutation, highlights the challenges associated with long-term survival of this devastating entity.