bluuebunny/crossref_metadata_2025_split huggingface dataset:
ATRT-24. CDK7 Inhibition in AT/RT
Authors: Morin Andrew , Wodetzki Darya , Veo Bethany , Pierce Angela , Zahedi Shadi , Crespo Michele , Venkataraman Sujatha , Vibhakar Rajeev , Mulcahy-Levy Jean 
Published: June 2022

Abstract
Atypical teratoid/rhabdoid tumors (AT/RT) are CNS tumors with a 5-year survival of ~35%. AT/RT is characterized by loss-of-function mutations in the SMARCB1 component of the SWI/SNF (SWItch/Sucrose Non-Fermentable) complex. Based on preliminary CRISPR-Cas9 gene essentiality screen results identifying AT/RT vulnerabilities, we hypothesized that interaction between CDK7 and the SWI/SNF complex via SMARCB1 provides a potential target to improve clinical survival of patients. CDK7 expression was identified by microarray in AT/RT, medulloblastoma, glioblastoma and normal brain. Established cell lines (BT12, BT16, CHLA06), patient derived lines (MAF-737, MAF-1298, MAF-1337), normal human astrocytes (NHA) and NIH3T3 mouse embryonic fibroblast cells were utilized for in vitro response to CDK7 inhibition. Murine cerebellar xenografts of MAF-737 were utilized to evaluate genetic and pharmacologic response to CDK7 inhibition. The NCI Approved Oncology Drugs (AOD-9) Panel was evaluated with an IC25 dose of CDK7 inhibitor THZ2 to identify potential synergistic combinations. CDK7 is up-regulated in AT/RT compared to other brain tumors or normal brain. In vitro, AT/RT cells are highly susceptible to CDK7 pharmacologic inhibition with nM IC50 levels. AT/RT cells with shRNA against CDK7 implanted in vivo show significantly reduced growth. Evaluation of in vivo tumors treated with THZ2 demonstrate decreased Ki-67 and reduced pRBP1 demonstrating effective inhibition of the target as well as a decrease in cell proliferation. Combination therapy of THZ2 with the AOD-9 Panel found significant synergy with antimetabolite therapies, specifically pemetrexed, pralatrexate, and methotrexate. There was no synergy with other standard chemotherapy. Our findings demonstrate that CDK7 is highly expressed in AT/RT and necessary for proliferation of AT/RT cells, suggesting it as a potential therapeutic target. Antimetabolites, which are currently used in several AT/RT protocols, synergized with CDK7 inhibition offers a potential future combination therapy for patients.
RARE-01. Cerebral infarction in childhood-onset craniopharyngioma patients: results of KRANIOPHARYNGEOM 2007
Authors: Boekhoff Svenja , Bison Brigitte , Eveslage Maria , Friedrich Carsten , Flitsch Jörg , Müller Hermann L 
Published: June 2022

Abstract
BACKGROUND: Cerebral infarction (CI) is a known vascular complication following treatment of suprasellar tumors. Risk factors for CI, incidence rate, and long-term prognosis are unknown for patients with childhood-onset craniopharyngioma (CP). METHODS: MRI of 244 CP patients, recruited between 2007 and 2019 in KRANIOPHA-RYNGEOM 2007, were reviewed for CI. Risk factors for CI and outcome after CI were analyzed. RESULTS: Twenty-eight of 244 patients (11%) presented with CI based on reference assessment of MRI. One CI occurred before initial surgery and one case of CI occurred after release of intracystic pressure by a cyst catheter. 26 of 28 CI were detected after surgical tumor resection at a median postoperative interval of one day (range: 0.5 - 53 days). Vascular lesions during surgical procedures were documented in 7 cases with CI. No relevant differences with regard to surgical approaches were found. In all 12 irradiated patients, CI occurred before irradiation. Multivariable analyses showed that hydrocephalus and gross-total resection at the time of primary diagnosis / surgery both were risk factors for CI. After CI, quality of life (PEDQOL) and functional capacity (FMH) were impaired. CONCLUSIONS: CI occurs in 11% of surgically-treated CP cases. Degree of resection and increased intracranial pressure are risk factors, which should be considered in the planning of surgical procedures for prevention of CI.
RARE-12. Pineoblastoma of children and young adults in a national population: An analysis of the HIT-MED study cohort
Authors: Yuan Mathias , Mynarek Martin , Goschzik Tobias , Pfaff Elke , Kortmann Rolf , Bison Brigitte , Warmuth-Metz Monika , Schiller Ulrich , Hagel Christian , Obrecht Denise , Benesch Martin , Pfister Stefan M , Pietsch Torsten , Rutkowski Stefan 
Published: June 2022

Abstract
BACKGROUND: Pineoblastoma is a malignant tumor of the pineal gland and accounts for &lt;1% of all pediatric brain tumors. PURPOSE/METHODS: Patients &lt;21 years (y) with pineoblastoma confirmed by central neuropathology review between 2001–2021 and included into the HIT2000 trial, HIT2000interim- or I-HIT-MED-registries were eligible. RESULTS: 88 patients were identified. Age at diagnosis was 0.01–20.71y (median 9.34y), median follow-up was 6.54y (IQR 1.78–12.41y) in 48 patients alive at last follow-up. 20 patients were &lt;4y and received chemotherapy with intent to avoid radiotherapy. Of these, 7 patients were alive at last follow-up, two patients were radiotherapy-naïve and 5 patients had undergone CSI + boost (4 after incomplete response and one after progression). 5-y-PFS/OS in 68 patients &gt;4y differed according to metastatic status (M0 (n=40) 72.7±8.3%/75.0±8.3%; M+ (n=28) 28.7±10.3%/40.8±10.9%, p=0.001/0.001). Therapy escalation in M0 patients by giving SKK chemotherapy before radiotherapy did not improve PFS/OS compared to upfront radiotherapy (5-y-PFS/OS 70.7±14.3%/70.0±14.5% vs 74.2±10.1%/78.9±9.4%, p=0.61/0.73). Applied CSI dosages were 24–50Gy (mean 35.6Gy) with no prognostic value of specific dosages being observed. Similarly, in M0 patients hyperfractionated radiotherapy (2x1.0Gy/d, total dose (TD) 36Gy, n=23) was not superior to conventional radiotherapy (1.6Gy/d, TD 35.2Gy, n=7). In all patients, favorable prognostic factors were age &gt;4y (5-y-PFS/OS 54.1±7.0%/60.0±7.0% vs 30.0 ±10.2%/35.0±10.7%, p=0.012/0.053) and radiotherapy in primary therapy (5-y-PFS/OS 55.8±6.5%/61.4±6.4% vs 14.4±9.4%/21.4±11.0%, p&lt;0.001/=0.003), whereas unfavorable prognosis was associated with metastatic disease (5-y-PFS/OS 33.6±9.0%/45.9±9.3% vs 58.8±7.6%/59.3±7.7%, p=0.028/0.086). CONCLUSION: Survival is poor in pineoblastoma patients &lt;4y treated without radiotherapy. Unfavorable prognosis was associated with metastatic disease, especially in older children. Chemotherapy combined with CSI is effective for non-metastatic patients at age &gt;4y. Further research will consider biological subgroups to enhance risk stratification and identify approaches for therapy improvements.
RARE-20. Retrospective analysis of 9 pineoblastoma
Authors: Ai Ruyu , Li Juan , Lai Mingyao , Cai Linbo 
Published: June 2022

Abstract
BACKGROUND: Pineoblastomas (PBs) are rare, supratentorial, primitive neuroectodermal tumors. Little is known with the clinical features and outcomes of PBs. METHODS: We retrospectively analyzed consecutive patients with PBs who were treated in Guangdong Sanjiu Brain Hospital between December 2006 to May 2020. RESULTS: A total of 9 patients (7 males and 2 females) with PBs were treated in our hospital with a median age of 9 yrs (range: 1-36 yrs) at diagnosis. Total or near-total resection was achieved in 3 patients (33%), partially resection in 4 (44.4%),and biopsy in 2(22.2%). There were 4 patients have spinal cord metastasis at diagnosis. Five patients received craniospinal irradiation (CSI), with concurrent or adjuvant chemotherapy. The average total dose of CSI was 34.80±2.683Gy, and the average dose to local tumor bed was 56.08±6.41Gy. Two patients younger than 3 years old only received chemotherapy, while 1 patient did not receive any postoperative treatment, and 1 patients was unknown. The median followed up time is ? months(range:3-39 months). At the last follow up, 5 patients were died, 3 patients were survived, and 1 was lost to follow-up. The median OS was 31 months (95%CI 1.782-60.281). Disease progression occurred in 5 patients during the follow-up period, and the median PFS was 19 months. CONCLUSION: Pineoblastoma is a rare central nervous system malignancy with a tendency for disseminated disease. Comprehensive therapies such as surgical resection, radiation and chemo therapy are effective therapies for PBs.
RARE-27. Treatment and outcomes in atypical choroid plexus papilloma: a single institution experience
Authors: Cluster Andrew , Cantor Evan , Meyer Ashley , Ogle Andrea , McEvoy Sean , Strahle Jennifer , Brossier Nicole , Shatara Margaret , Limbrick David , Abdelbaki Mohamed 
Published: June 2022

Abstract
BACKGROUND: Atypical choroid plexus papillomas (aCPP) are rare central nervous system (CNS) tumors often occurring in very young children. While surgical resection has been a mainstay of therapy, there is no consensus and limited data on the treatment of relapsed or metastatic tumors. METHODS: Retrospective review of the treatment and outcome of patients diagnosed with aCPP since 2011 was performed. RESULTS: Of the seven patients, 4 were male and 3 were female with a median age of 3 years at diagnosis (range: antenatal to 18 years old). All non-metastatic patients (six) were treated with surgery and all achieved gross total resection. Two patients had diffuse leptomeningeal contrast enhancement on diagnosis MRI that resolved after resection of primary tumor alone. One patient developed local relapse underwent re-resection with a GTR then was treated with 4 cycles of chemotherapy based on CPT-SIOP-2000 protocol (carboplatin, etoposide) and has not had further relapse in 24 months. One patient had metastatic disease at the time of diagnosis. They were treated with adjuvant chemotherapy, which stabilized disease for 36 months until they had progression. Additional four cycles were given and has again stabilized disease now 8 months from completion of that therapy. One non-metastatic patient died of unknown causes 28 months from diagnosis. CONCLUSIONS: Surgical resection remains the standard of care for patients with aCPP. However, chemotherapy based on the SIOP backbone may be useful to reduce the need for or to delay radiation therapy in select patients in the relapsed or metastatic setting.
DIPG-03. Therapeutic targeting of purine biosynthesis in DIPG
Authors: Mersich Ian , Dasgupta Biplab 
Published: June 2022

Abstract
Diffuse intrinsic pontine glioma (DIPG) is an incurable brainstem malignancy in children. Little progress has been made in treating this deadly disease due to its inoperable location and treatments aimed at targets defined in adult gliomas. Currently there are no targeted therapies that significantly improve overall survival in patients with this disease. To this end, we are developing a metabolic profile for this disease by integrating metabolomics and gene expression data from cell lines derived from DIPG patient tumors. Our long-term goal is to significantly improve the overall survival of children with DIPG by identifying novel therapeutic targets. Central to this goal is our investigation into dysregulated purine metabolism in these tumors. We’ve integrated gene expression and metabolomic datasets for DIPG cells and identified a potential therapeutic target in the de novo purine biosynthesis (DNPB) pathway. Genetic knockout experiments confirmed that DIPG cells require the last enzyme in the DNPB pathway, ATIC, for survival. Furthermore, we have identified a compound that disrupts ATIC homo-dimerization, which is required for ATIC catalytic activity. Our preliminary data demonstrates this compound may offer clinical benefits over traditional antifolates that target this same pathway; however, the mechanism leading to selective cytotoxicity was unclear. Antifolates such as methotrexate competitively inhibit folate binding sites in multiple enzymes within this pathway; however, there are known mechanisms of resistance to these drugs. We show that the ATIC dimerization inhibitor differs from the antifolates by disrupting a multi-enzyme complex known as the purinosome, which requires intact, functional ATIC for assembly. Furthermore, targeting ATIC through genetic and pharmacological inhibition in vivo has extended survival in our PDX mouse model of DIPG.
DIPG-08. The development of ACT001 as a novel therapeutic for diffuse intrinsic pontine gliomas
Authors: Upton Dannielle , George Sandra , Liu Jie , Cai Dongpo Doug , Su Steven Yung-Chang , Rayner Benjamin , Tsoli Maria , Ziegler David 
Published: June 2022

Abstract
Diffuse Intrinsic Pontine Gliomas (DIPG) are a subset of Diffuse Midline Gliomas (DMG) and are the most devastating of all brain tumours. There are currently no effective treatments. ACT001 is a novel anti-cancer agent in clinical development that is blood-brain-barrier permeable. Previous studies undertaken in adult glioblastoma suggest that ACT001 exerts an anti-tumour effect via induction of oxidative stress and inhibition of NF-kB and STAT3 pathways. In DIPG, we have found that ACT001 demonstrated potent cytotoxic activity against a panel of DIPG neurospheres and also inhibited colony formation. Flow cytometric analysis confirmed the induction of apoptosis in vitro. Interestingly, we also observed increased expression of some markers of the ROS-dependant NRF2 endogenous antioxidant pathway within DIPG neurospheres suggesting an alternative mechanism of inhibition of DIPG cell proliferation involving ROS generation. In vivo testing of ACT001 in a highly aggressive DIPG-orthotopic model showed that ACT001 was well tolerated and significantly improved survival. ACT001 treatment of HSJD-DIPG007 tumour-bearing animals extended median survival from 59 to 78 days (p=0.0005). ACT001 treated mice had significantly decreased proliferating DIPG cells, analysed by Ki67 staining (p=0.01), and significantly increased H3K27me3 staining (p=0.0479). Given the significant effects on H3K27me3 we evaluated two potential drug combinations with known, clinically available epigenetic modifers. Combination of ACT001 with the FACT inhibitor CBL0137 or the HDAC inhibitor SAHA each significantly and synergistically decreased colony formation. These combinations are currently being evaluated in vivo in orthotopic models of DIPG. ACT001 is currently in a Phase 1 paediatric trial for children with DIPG/DMG. Clinical activity has been demonstrated in DIPG/DMG patients, including a reduction in tumour burden and clinical response. These combined preclinical and clinical results suggest that ACT001 is a viable therapy for patients with DIPG/DMG and preclinical combination therapy testing may guide further clinical trials.
DIPG-17. CD155 regulates cell growth and immune evasion in diffuse intrinsic pontine glioma
Authors: Tzaridis Theophilos , Eisemann Tanja , Andrade Augusto F , Hope Jennifer L , Romero Megan M , Becher Oren J , Jabado Nada , Bradley Linda M , Wechsler-Reya Robert J 
Published: June 2022

Abstract
There is an unmet need for more effective treatment strategies for diffuse intrinsic pontine glioma (DIPG), a devastating brain tumour arising in children and young adults. While immunotherapy is emerging as a powerful approach to treatment of other cancers, clinical trials with immune checkpoint inhibitors have failed to show a survival benefit for DIPG patients. In this study, we analysed the expression of immune checkpoint molecules on the surface of human and murine DIPG cells by flow cytometry and identified CD155 and B7-H3 as the most highly expressed checkpoint molecules, with minimal expression of PD-L1, PD-L2, Galectin-9, CEACAM-1, CD86, CD252 and CD137. These findings were confirmed in primary patient samples from pediatric brain tumours, including high-grade gliomas, medulloblastomas and ependymomas. To test whether CD155 inhibition increases susceptibility to CD8+ T cell killing in vitro, we cultured DIPG cells expressing ovalbumin (OVA) with CD8+ T cells from OT-I mice, which express T cell receptors specific for OVA. Addition of CD155 blocking antibodies to these cultures increased expression of T cell activation markers (CD25, CD44 and CD69) as well as T cell-mediated tumour killing, supporting the notion that CD155 can function as an immune checkpoint in DIPG. In addition to its effects on T cells, CD155 also exerted direct effects on tumour cells: treatment with anti-CD155 antibodies led to impaired cell viability, and shRNA-mediated knockdown of CD155 resulted in reduced cell proliferation in vitro. Strikingly, knockdown of CD155 also led to reduced growth of DIPG cells in vivo, and mice transplanted with the CD155-deficient cells had a clear survival benefit compared to mice transplanted with wild type cells. These studies demonstrate that CD155 functions as an immune checkpoint and as a regulator of tumor growth in DIPG, and suggest that targeting CD155 could be a valuable therapeutic strategy for this devastating disease.
DIPG-27. Behavioral disturbances as underestimated presenting symptoms in children with Diffuse Intrinsic Pontine Glioma (DIPG)
Authors: Milanaccio Claudia , Profio Sonia Di , De Giuseppe Sara , Ramaglia Antonia , Verrico Antonio , Crocco Marco , Piccolo Gianluca , Satragno Camilla , Biassoni Veronica , Garrè Maria Luisa 
Published: June 2022

Abstract
PURPOSE: to describe how often behavioral and emotional changes occur at diagnosis in children with DIPG, or precede it. METHODS: the anamnesis, clinical history, psychological evaluation, and onset symptoms of all cases of DIPG diagnosed at Gaslini Institute between January 2010 and December 2020 were reviewed. RESULTS: 20 DIPGs were diagnosed, 7 males, with a median age of 7,6 years (range 2,4-16,2). All patients presented typical neurological symptoms: 16 had cranial nerves palsy, 12 ataxia, 8 dysarthria, 5 dysphagia, 5 hemiparesis, 5 headache, and 2 obstructive hydrocephalus. Behavioral disorders were found in 14 cases, with several manifestations and in various association: irritability and aggressive behavior in 6, ideomotor slowdown and apathy in 5, emotional dysregulation in 4, mood deflection in 3, sleep disturbances (i.e. nightmares, insomnia, and somniloquy) in 3, marked behavioral changes, school phobia and separation anxiety in 2, depersonalization crisis and phobia of waterdrops in the eyes in 2 patients each. In 6 cases behavioral disturbances were the presenting symptom, appearing one to twelve months earlier than the classic neurological deficits. In all patients, behavioral symptoms improved during Radiotherapy. CONCLUSIONS: behavioral disturbances, although well-known and described in the literature, are not commonly reported among the onset symptoms of DIPG, thus being probably underestimated. Their pathogenesis can be explained by neurophysiology: the brainstem contains reciprocal cerebro-ponto-cerebellar connections whose disruption compromises their modulatory function on affective and cognitive behavior. Furthermore, the reticular formation contains aggregates of neurons regulating several complex functions including the state of alertness (e.g. sleep and wakefulness), the perception of pain, and cognitive functions (e.g. attention, mood, and memory). A careful anamnestic and medical history together with a detailed psychological assessment should be always performed in all DIPGs at diagnosis, in order to bring out those underlying behavioral disorders which could benefit from early neuropsycological support.
DIPG-33. Treating Pediatric Diffuse Intrinsic Pontine Glioma with Brain Radiation and Temozolomide: A Case Report
Authors: Ramadhan Diko Anugrah , Gautami Wanda , Rahmartani Ludi Dhyani , Rafli Achmad , Handoko Handoko , Nuryadi Endang , Amal Mohamad Yanuar 
Published: June 2022

Abstract
Diffuse Intrinsic Pontine Gliomas (DIPG) is a rare and highly aggressive central nervous system tumour arising from glial cells which occur mostly in children. It remains a potentially deadly cancer despite treatment, with the highest mortality rate, in which most children die within 1-year of diagnosis. Radiation therapy might improve the clinical symptoms, but the results are temporary, with tumor progression typically occurring months post radiation, whereas chemotherapy remains controversial. Here we present a case report of a patient with DIPG Indonesia and how we diagnose and currently treat it. An eight years-old boy presented with decrease level of consciousness with headache, limb weakness, slurred speech, double vision, hemifacial weakness, paraplegia, and disequilibrium which worsened two weeks prior to admission. He was initially noted to have a medially inverted left eye two months prior to admission. On physical examination, there was a N.VI and N.VII palsy, hyperreflexia, paraplegia, and nystagmus. Head MRI demonstrated a solid with minimal enhancement after contrast administration in the left pons region extending into mesencephalon with cystic component and flat floor of fourth ventricle sign, causing hydrocephalus, suggestive diffuse intrinsic pontine glioma. He was given fractionated focal intensity modulated radiation therapy (IMRT) to the tumor along with 5 mm margins with a total dose of 54 Gy. 1.8 Gy fractions, given once daily for 5 days per week over a period of 6 weeks. Supportive care in the form of corticosteroids is used to treat the peri-tumoral edema. There was a short period of motoric improvement. But then the disease progressed with the latest head CT showed hydrocephalus formation with increased size of mass. He is treated with chemotherapy using Temozolomide, and currently alive after 3 months post diagnosis.
Keywords: childhood brain tumour, Diffuse Intrinsic Pontine Glioma, radiation therapy
DIPG-35. Personalized treatment for molecularly heterogeneous Diffuse midline glioma, H3 k27-altered Paediatric case
Authors: Mobark Nahla Ali , Alharbi Musa , Bayoumi Yasser S , Albanyan Aymn , Balbaid Ali Abdullah O , Aljabarat Wael abdel Rahman , Abedalthagafi Malak 
Published: June 2022

Abstract
Diffuse midline glioma, H3 k27-altered (DMG) is a type of Paediatric- type diffuse high grade gliomas according to the 2021 WHO CNS tumors Classification. Diffuse intrinsic pontine glioma (DIPG) is another acceptable related term when it located in the pons with fatal prognosis. The combination of H3K27M with BRAF V600 mutations rarely reported in DMG although more commonly in Paediatric-type low grade gliomas (Diffuse low-grade glioma, MAPK pathway-altered). We present a twenty-month-old boy, previously healthy, presented with 2 weeks history of unsteady gait, drooling, cranial nerves palsy MRI imaging showed diffuse pontine mass with classic radiological features of DIPG. 2.6 x 1.6 x 3.2 (AP x TV x CC) with no evidence for spinal metastases. Patient underwent right retro sigmoid approach and open biopsy of lesion he received focal Radiation Therapy 54GY/30fx as stander of care of DIPG with mild neurogical improvement Pathological & molecular Diagnosis was Diffuse midline glioma, H3 k27-altered with Co-occurrence BRAF V600E mutation. Two months after end of radiation, he presented with vomiting, and neurological deterioration with new right-side hemiplegia. Imaging studies showed interval increase in the pontine lesion with increased edema causing narrowing of the fourth ventricle, no active hydrocephalus. He was started on combination therapy BRAF inhibitor Dabrafenib and MEK Inhibitor Trametinib as maintenance therapy the patient gradually showed Marked neurological and clinical improvement. A 6-month MRI after start of targeted therapy showed favorable treatment response with complete resolution of the previous diffusion restriction, reduced tumor volume on MR perfusion ,reduced perilesional edema otherwise almost stabilization of nonenhancing pontine lesion. The poor prognosis of recurrent DIPG is well known but our patient is clinically and radiologically stable with excellent quality of life and well tolerating the therapy . Our case show that personalized treatment approach that address molecular heterogeneity of H3K27M glioma are safe and feasible