bluuebunny/crossref_metadata_2025 huggingface dataset:
DIPG-58. Therapeutic HDAC targeting in hypermutant CNS tumors
Authors: Myers Carrie , Noll Alyssa , Biery Matthew , Meechan Michael , Tahiri Sophie , Foster Jessica , Dun Matthew , Olson James , Vitanza Nicholas
Published: June 2022

Diffuse intrinsic pontine glioma (DIPG) is a universally fatal tumor of the pons, most often characterized by mutations in genes encoding histone 3, that led to the classification diffuse midline glioma, H3 K27M-mutant (DMG). However, 15% of DIPG are histone wildtype (H3WT) and can have a hypermutant phenotype, characterized by mutations in DNA mismatch repair that also occur in pediatric high-grade glioma (pHGG). We previously published the preclinical efficacy of quisinostat in DMG. As hypermutant CNS tumors share transcriptional disruption with DMG, we investigated if HDAC inhibition was also therapeutic against hypermutant DIPG and pHGG. We tested PBT-24, a PMS2 mutant, treatment-naïve, patient-derived hypermutant DIPG model, and found similar quisinostat sensitivity compared to other DMG cultures in vitro (IC50 = ~30 nM), as well as significant efficacy in a xenograft flank model (60 day mean tumor size of 1109mm3 [vehicle] vs. 19mm3 [quisinostat-treated]). This in vivo effect was greater than the anti-tumor effect observed in a xenograft flank non-hypermutant DMG model PBT-09 (60 day mean tumor size of 1006mm3 [vehicle] vs. 244mm3 [quisinostat-treated]). To validate the effect of hypermutation on sensitivity to quisinostat, we generated PMS2 knock-out (KO) and MSH2 KO isogenic cell lines using the H3WT model VUMC-DIPG-10. In a xenograft flank model, we observed increased quisinostat sensitivity in the KO models (20 day mean tumor volume of 547mm3 [parental], 396mm3 [PMS2 KO], and 150mm3 [MSH2 KO]). RNA sequencing of quisinostat-treated PBT-24 revealed an increase in acute inflammatory response genes which we are investigating as a mechanism of action for HDACi against hypermutant tumors. Ultimately, we demonstrate the in vivo efficacy of quisinostat against hypermutant DIPG that supports the investigation of HDAC inhibition as a treatment strategy across hypermutant CNS tumors.
DDEL-02. Intra-arterial Delivery for Novel Combinatorial Chemotherapies in Choroid Plexus Carcinoma
Authors: Martin Brice , Garman Tyler , Laramee Madeline , Wang Amy , Hagen Natalie , Dahmane Nadia , Thomas Craig , Souweidane Mark
Published: June 2022

Choroid plexus carcinoma (CPC) is a rare infantile brain tumor with an aggressive clinical course that often leaves children with debilitating side effects due to aggressive and toxic chemotherapies. New delivery routes such as intra-arterial (IA) route are being explored to limit toxicity and improve efficacy. To identify novel compounds that may be used in this context, we conducted a high-throughput screen (HTS) informing on the cytotoxicity of 2454 compounds, including some currently approved for IA in other brain tumors, that identified multiple active drugs on a human primary CPC cell line. Key molecular targets previously identified in CPC literature such as mTOR, PDGFR, ATR, CDK, FGFR1 and PI3K were enriched relative to other targets in the screen. Importantly, a combination screen with a wide variety of targets revealed multiple synergistic combinations. We examined two key combinations (topotecan/elimusertib and melphalan/elimusertib) based on mechanistic alignment and translational potential through extended in vitro validation and transcriptome analyses. Pharmacokinetic assays established increased drug brain penetrance with IA delivery when compared with intravenous delivery. Ultimately, a single intra-arterial administration of melphalan combined with systemic administration of elimusertib led to a significant increased survival in a CPC genetic mouse model. This study underscores the efficacy of IA delivery and identifies a promising therapeutic option for the treatment of CPC.
DDEL-04. Pharmacokinetic/Pharmacodynamic analysis of the DNA methyltransferase inhibitor 5-azacytidine shows adequate brain tissue penetration with intravenous administration in a DIPG mouse patient-derived xenograft model.
Authors: Groves Andrew , Jones Kristen , Cameron Amy , Panditharatna Eshini , Morrow Murry , Mozarsky Brett , McCully Cynthia , Peer Cody , De Nguyen Quang- , Filbin Mariella , Warren Katherine
Published: June 2022

One of the biggest obstacles in developing effective therapies for CNS tumors is drug delivery due to the enigmatic challenge of penetrating the blood-brain barrier. 5-azacytidine is a DNA methyltransferase inhibitor which was the first epigenetic targeting chemotherapeutic approved by the FDA. Altered DNA methylation is a hallmark of many cancers, including diffuse intrinsic pontine glioma (DIPG). 5-azacytidine has been shown to be active in DIPG cell lines, with only modest in-vivo activity. We have previously shown in a non-human primate model that intravenous (IV) administration of 5-azacitidine does not result in measurable CSF penetration, while intrathecal (IT) administration does and is well tolerated. To follow up these studies in a tumor-bearing mouse model (HSJD DIPG007), we performed pharmacokinetic (PK) and pharmacodynamic (PD) analysis following IV vs. IT administration. Forty mice were randomized to receive four weekly doses of IV 5-azacytidine (25 mg/kg), IT 5-azacytidine (40 μg), or corresponding vehicle controls. Four mice from each arm were sacrificed 30 minutes after the last dose and brain tissue was collected for PK/PD analysis. Drug concentration was quantified using ultra-high-performance liquid chromatography with tandem mass spectrometric detection, while pharmacodynamic methylation profiling was performed using the Infinium MethylationEPIC BeadChip (850K). Brain tissue concentrations were comparable between IV (7.6-58.0 pg/mg) and IT (6.9-63.9 pg/mg) dosing. Methylation profiling unexpectedly showed a significantly more pronounced pharmacodynamic effect with IV dosing vs. IT, with a mean decrease of 13.6% vs. 2.6% in global DNA methylation score (GDMS = percentage of highly methylated (beta ≥ 0.7) genomic loci) compared to vehicle controls. For the remaining mice, there was no significant difference in survival. Our results are encouraging that phenotypically relevant demethylating effects can be achieved in the CNS with IV 5-azacytidine administration; however, further research is needed to develop promising combination strategies in DIPG.
DDEL-06. Drug Delivery to the Pons Using Short-Pulse Focused Ultrasound and Microbubble Exposure for the Treatment of Diffuse Midline Glioma
Authors: Chattenton Dani , Rivens Ian , Jiang Zheng , Carvalho Diana M , Sujarittam Krit , Boult Jessica K R , Robinson Simon P , Jones Chris , ter Haar Gail , Choi James
Published: June 2022

Despite advances in understanding diffuse midline glioma (DMG-H3K27), including DIPG, there are still no effective treatments available, and the dismal clinical prognosis remains. This is partly because of tumour spread behind an intact blood brain barrier (BBB), preventing drug delivery and the reason for many drugs failing in the clinic. The use of focused ultrasound and intravenous microbubbles enables temporary increases in BBB permeability, allowing drugs to enter the targeted brain region. Building on recent research demonstrating that short pulses (<5 µs) of ultrasound can deliver drugs safely and uniformly to the hippocampus, we evaluated whether a similar result was achievable in the pons of mice. Mice were exposed to ultrasound (peak-negative pressure: 0.4 MPa, pulse length: 5 cycles, centre frequency 1 MHz) emitted in bursts of 38 pulses. During exposure mice received an intravenous injection of SonoVue(R) microbubbles and a fluorescently-tagged tracer (dextran, 3 kDa), acting as a drug mimic. Dextran was successfully delivered to the pons of non-tumour-bearing mice assessed by fluorescence microscopy immediately post-treatment. Dextran delivery was repeatable and confined to the targeted pons region with a homogenous distribution, typical of short pulse ultrasound, and important for treating DMG to ensure all tumour cells receive an equal drug dose. No damage to the brain was observed after H&E staining. Panobinostat has shown promise in vitro but tolerated doses have not shown therapeutic benefit in vivo as it does not cross the BBB. The in vitro toxicity of panobinostat was confirmed in a Nestin-Tv-a/p53fl/fl, RCAS-ACVR1R206H + RCAS-H3.1K27M murine cell line, with a GI50 of 15.56 nM. The ability of focused ultrasound to deliver panobinostat across the BBB to these tumours grown orthotopically will be assessed. Overall, we hope to develop a drug delivery system, that enables therapeutics to cross the BBB, expanding treatment options for DMG.
EPCT-02. A Phase 1 Study of Mebendazole with Bevacizumab and Irinotecan in High Grade Gliomas
Authors: Krystal Julie , Hanson Derek , Donnelly Danielle , Atlas Mark
Published: June 2022

BACKGROUND: High grade gliomas (HGG) have a dismal prognosis despite multimodal therapy. Mebendazole (MBZ) is an anti-helminthic benzimidazole. In vitro, MBZ has efficacy in numerous cancer models and is able to cross the blood brain barrier. We conducted a phase 1 trial (NCT01837862) to evaluate the safety of MBZ in combination with bevacizumab (BVCZ) and irinotecan (CPT-11). OBJECTIVE: To determine the maximally tolerated dose of MBZ when given in combination with BVCZ and CPT-11 in children with high-grade gliomas; to describe the progression-free survival (PFS) and overall survival (OS) for this group. METHODS: Patients between 1 and 21 years of age with HGG were enrolled in a 3 + 3 design to escalating doses of MBZ in combination with BVCZ 10mg/kg/dose and CPT-11 150mg/m2/dose. Subjects were eligible upfront after completion of radiation or at the time of progression. MBZ was taken orally twice per day continuously and BVCZ and CPT-11 were given intravenously on days 1 and 15 of 28-day cycles. RESULTS: Between 2015 and 2020, 10 subjects were enrolled at MBZ 50mg/kg/day (n=3), 100mg/kg/day (n=4), and 200mg/kg/day (n=3). One subject assigned to 100mg/kg/day was not evaluable. Seven subjects had a diagnosis of diffuse midline glioma, 1 subject had anaplastic astrocytoma, and 1 subject had a spinal HGG. All subjects received radiation. There were no dose limiting toxicities. The most frequent G3/G4 adverse events were neutropenia (n=3), and lymphopenia (n= 4). The overall response rate was 33% with 2 subjects achieving a partial response and 1 subject achieving a complete response sustained for 10 months. The PFS and OS from the start of study treatment were 4.7 months and 11.4 months, respectively. CONCLUSION: MBZ was safe and well tolerated when administered with BVCZ and CPT-11 at doses up to 200mg/kg/day. Further studies are needed to determine the efficacy of this treatment.
EPCT-04. Stereotactic biopsy split-course radiation therapy for diffuse midline glioma of the pons (SPORT-DMG): Early phase II enrolling clinical trial
Authors: Cunningham Danielle , Schwartz Jonathan , Guerin Julie , Johnson Derek , Khatua Soumen , Laack Nadia , Ahmed Safia , Silvera Victoria Michelle , Brinkmann Debra , Pafundi Deanna , Keating Gesina , Raghunathan Aditya , Giannini Caterina , Daniels David , Mahajan Anita
Published: June 2022

Diffuse midline glioma (DMG) of the pons remains the leading cause of death among pediatric patients with brain tumors, despite numerous attempts to intensify treatment. While standard treatment includes 54Gy in 30 fractions of radiation over six weeks of time, nearly all patients progress within the treatment field, and many experience symptomatic radionecrosis with steroid dependence. Symptom improvement typically begins after 20Gy to the tumor. Both hypofractionation and reirradiation after recurrence have been found to be safe for patients with DMG. Our study aims to enroll patients with newly diagnosed pontine DMG aged >1 year (no maximum age), and collect molecular information about DMG via stereotactic biopsy, followed by a short 2 week course of 25Gy in 10 fractions of radiation, with volumes guided by MRI with tractography reconstruction and FDOPA PET radiotracer uptake. Patients are followed closely and can complete the 25Gy in 10 fraction radiation course up to 3 times total for meeting radiographic and clinical progression criteria. Our primary endpoint is to estimate the time to progression from diagnosis to after receiving the second 25Gy course, and to compare this to the historical 7 month standard from diagnosis to progression after one 54Gy course. We aim to improve the time interval where patients are asymptomatic at home while minimizing time receiving daily treatments. Other endpoints will include the patient quality of life, caregiver quality of life, PFS intervals after each course, overall survival, and toxicity.
EPCT-08. Disease-specific working groups within the Pacific Pediatric Neuro-Oncology Consortium (PNOC) and Children’s Brain Tumor Network (CBTN) facilitate multi-disciplinary collaboration and translation of innovative strategies in pediatric neuro-oncology
Authors: Kline Cassie , Resnick Adam , Prados Michael , Mueller Sabine
Published: June 2022

BACKGROUND: In Summer 2019, PNOC leadership developed working groups to align basic scientists, clinical researchers, and foundations for rapid translation of novel therapies for children and young adults with central nervous system tumors. Soon after, PNOC partnered with the Children’s Brain Tumor Network (CBTN) to grow collaborations and augment preclinical resources. Since their inception, working groups have advanced translation of new therapies and biomarkers, developed pipelines for preclinical and clinical research, and expanded global collaborations. DESIGN: Each working group is led by 2 to 3 experts in a disease, such as medulloblastoma, diffuse midline glioma, or craniopharyngioma, or subject matter, like imaging, nursing, or diversity, equity, and inclusion. A project manager coordinates regular multidisciplinary meetings to share new findings from research laboratories, provide updates on clinical trial development (with real-time feedback and incorporation of trial endpoints and biomarkers), and invite speakers to share advancements in the disease or subject of interest. RESULTS: Eleven working groups have been created with over 200 members across the United States, Europe, Australia. More than 20 foundations, led predominantly by families, provide support and insight to guide working group efforts. Working groups have developed 4 clinical trials (n=2, diffuse midline glioma; n=1, craniopharyngioma; n=1, medulloblastoma) and completed 3 international surveys, investigating experiences of patients/families affected by craniopharyngioma, evaluating diversity and inclusion throughout the consortia, and assessing nursing and advanced practice provider needs. Additional accomplishments include a registry for atypical teratoid rhabdoid tumors, a population dataset evaluating diversity in clinical research participation across consortia, incorporation of nursing members for review and refinement of clinical trial protocols, and updated imaging case report forms for application across clinical trials. CONCLUSION: Multidisciplinary working groups within international consortia facilitate efficient translation of multi-pronged strategies to improve the care of children and young adults with central nervous system tumors.
EPEN-04. Refinement of molecular and clinical characteristics in a cohort of 1,801 ependymomas
Authors: Pohl Lara , Obrecht Denise , Schweizer Leonille , Wefers Annika , Rutkowski Stefan , Bockmayr Michael , Schüller Ulrich
Published: June 2022

DNA methylation profiling led to the definition of ten molecular types of ependymomas with distinct biological and clinical features. The largest published reference cohort consists of 500 ependymomas encompassing nine molecular types that were known at this point. Our study aimed to confirm and refine molecular and clinical characteristics of ependymoma types and subtypes based on a considerably larger, well-annotated cohort of ependymal tumors. Here, we analyzed previously published and newly generated DNA methylation profiles, generated on the Illumina 450k and EPIC arrays, from a total of n=1,801 ependymomas. We looked at both global DNA methylation as well as inferred copy number profiles and correlated these data with clinical parameters. Patients with EPN-PFA, EPN-RELA, and EPN-MYCN tumors showed the worst outcome with 10 year-overall survival rates of 56%, 64%, and a 5 year-overall survival rate of 73%, respectively. EPN-PFA, the most frequent tumor type in our series, occurred in children in >98% of cases, epigenetically split into two major subtypes, and harbored chromosome 1q gains and 6q losses as markers for worse survival (p<0.0001 and p=0.042, respectively). In supratentorial EPN-RELA, a combined loss of CDKN2A/B indicated a worse survival compared to the wildtype (p=0.0004), but the loss of only CDKN2A or CDKN2B did not. Ten out of 169 EPN-RELA were located in the posterior fossa, and Kaplan Meier estimators showed that these tumors relapsed or progressed even earlier than supratentorial cases with a combined loss of CDKN2A/B (p=0.0062). SP-MPE and PF-SE, which are generally regarded as non-aggressive tumors, only had a 10-year progression-free survival of 60% and 63%, respectively, in our series. In ongoing analyses, we are training machine learning algorithms to more accurately predict survival and response to treatments. These methods shall help clinicians make informed decisions regarding treatment options on new patients.
EPEN-20. PDL1 expression and tumor-infiltrating immune cell subpopulations: The role of immune-checkpoint molecules in the prognosis of patients with supratentorial ependymoma and its correlation to survival
Authors: Malik Rafat , Sharma Agrima , Kumar Amandeep , Singh Manmohan , Suri Vaishali , Sharma Mehar Chand
Published: June 2022

Immune checkpoint blockade of the programmed cell death ligand-1 (PD-L1)/programmed death-1 (PD-1) axis has shifted the way advanced cancers are treated. The 'ST-RELA fusion positive' and 'PF-A' molecular subgroups of ependymomas (EPN) have a dismal prognosis. AIMS: This study is undertaken to look for immunological microenvironment in ependymomas. Based on L1CAM protein expression and/or the presence of RELA/YAP1 fusion transcripts by RT-PCR, all supratentorial (ST) Grade-II/III EPNs were classified as ST-RELA, ST-YAP, and ST-not otherwise specified (NOS). Based on H3K27me3 protein expression and chromosome 1q gain, all posterior fossa (PF) EPNs were classified as PF-A or PF-B. PD-L1 (SP263, Ventana) and CD8 immunohistochemistry was performed. The enrichment of RelA protein at the PDL1 promoter site was investigated using chromatin immunoprecipitation-qPCR (ChIP-qPCR) in three ST-RELA samples. A total of 83 intracranial EPNs were included in our preliminary data, and we discovered that PD-L1 expression correlates with increasing cytotoxic T-lymphocyte infiltrates in intracranial ependymomas using PD-L1 and CD8 IHC. The majority of PD-L1-positive intracranial EPNs are members of the ST-RELA subset, which also has the highest CTL density. Our findings suggest that ST-RELA EPNs could be used in immunotherapy to target immune checkpoint modulators. To further this research, we are looking into the presence of tumour infiltrating cells such as CD3, CD8, CD163, FOXP3, and others, which can aid in characterising the tumour microenvironment in cell types expressing PD-L1.This study will also be used to predict the prognostic significance of PD-L1/PD1 and other tumour cell infiltrating biomarkers in ependymomas and correlate it with survival outcomes.
EPEN-26. Chemokine receptor blockade reverses CCL2 mediated immunosuppression and restores CAR-T cell function in posterior fossa ependymoma
Authors: Cole Allison P , Donson Andrew M , Pierce Angela M , Grimaldo Enrique , Calhoun Jacob D , Griesinger Andrea M , Sublett Caroline , Kaplan Rosandra N , Fry Terry J , Foreman Nicholas K , Nellan Anandani
Published: June 2022

Trastuzumab-based HER2 CAR-T constructs have demonstrated preclinical efficacy in medulloblastoma and are being evaluated for use in children and young adults with recurrent or refractory CNS tumors. Preliminary results demonstrate immune activation but no objective tumor response in three patients, including two patients with posterior fossa (PF)-EPN. A key finding in the serum and CSF of all three patients was very high levels of the inflammatory chemokine CCL2 following treatment with CAR-T cells. Preclinical studies suggest that high levels of CCL2 may impede T cell mediated anti-tumor activity in CNS tumors. The role of CCL2 to enhance or diminish CAR-T cell efficacy for CNS tumors is unknown. We evaluated a second generation trastuzumab-based HER2 CAR construct with a 4-1BB co-stimulatory domain in two ultra-high-risk patient-derived xenograft (PDX) models that faithfully recapitulate PFA-EPN. In contrast to preclinical studies in other cancers, treatment with trastuzumab-based HER2 CAR-T cell alone causes only partial regression of tumors and robust infiltration of immunosuppressive monocytes in PFA-EPN PDX mouse models. We studied constitutive NF-kB activation because it is a hallmark of PFA-EPN that drives dysregulation of inflammatory genes and forms an immunosuppressive tumor microenvironment. Upon tumor recognition, CAR-T cells produce high amounts of the cytokine tumor necrosis factor-alpha, which is an extracellular stimulus that propagates NF-kB activation in PFA-EPN. We show that HER2 CAR-T cell treatment causes increased nuclear translocation of the RELA NF-kB subunit, which induces CCL2 gene transcription and chemokine release. This results in CCL2-CCR2 ligand/receptor mediated influx of inflammatory monocytes and regulatory T cells, impairing CAR-T cell effector function. Inhibition of CCR2 restores anti-tumor CAR-T cytotoxicity against bulky orthotopic tumors by decreasing the infiltration of inflammatory monocytes and regulatory T cells. Combinatorial strategies addressing tumor mediated immunosuppression should be evaluated in upcoming CAR-T cell trials for patients with high-risk CNS tumors.
EPID-04. PREDCAP, the French registry of predisposition to pediatric cancers
Authors: Guerrini-Rousseau Lea , Hoarau Pauline , Bougeard Gaelle , Golmard Lisa , Colas Chrystelle , Gauthier-Villars Marion , Houdayer Claude , Frebourg Thierry , Bourdeaut Franck , Brugieres Laurence
Published: June 2022

A pathogenic or likely pathogenic variant (PV) in a major cancer predisposition gene is identified in almost 10% of children or young adults who developed a cancer, regardless of their family history. This incidence may increase by the development of wide tumor sequencing programs leading to identify germline PVs in cancer patients and new cancer predisposition syndromes (CPS) associated with childhood cancers. Due to the rarity of each CPS, we still lack information about phenotype associated with most CPS especially cancer risks according to age as well as tumor characteristics and response to treatment. Within the French genetic multidisciplinary network involving pediatric oncologists, oncogeneticists and researchers, we have created a clinico-molecular registry for pediatric-CPS according to data protection regulation. The PREDCAP database collects clinical, genetic and molecular data from patients who developed pediatric tumors associated with a CPS, both retrospectively and prospectively. It includes a mandatory set of data on clinical phenotype, tumor characteristics (including treatment and outcome), family data and results of genetic analyses, with annual data updates. Interoperability with existing databases is planned, allowing for pooling of data collection and management. Aims of PREDCAP registry are to obtain reliable clinical and molecular data on pediatric CPS with a simplified and effective access. By collecting all available data on a large number of patients thanks to international collaborations, we hope to improve the knowledge on rare CPS, in particular, to better define the tumor spectrum and the penetrance of PVs, to analyze the specificity of tumors associated with these germline PVs. With this tool, we wish to facilitate future projects using structured and centralized data, associated with a virtual bank of available tumor and constitutional DNA, to evaluate and improve the relevance of management recommendations established for each syndrome.
EPID-10. Creation, use, and effectiveness of a primary provider education tool for timely pediatric CNS tumor diagnosis based on HeadSmart
Authors: Pacheco Daniel , Fraley Claire , Walker David , Green Adam
Published: June 2022

BACKGROUND: Patients of minority race and ethnicity and lower socioeconomic status experience poorer survival of pediatric CNS tumors in the US. These disparities arise in part from differences in stage of disease at diagnosis, suggesting they could be mitigated by earlier diagnosis. HeadSmart is a campaign in the UK to increase awareness of pediatric CNS tumor symptoms among primary care practitioners and the public that has led to a significant decrease in time to diagnosis. METHODS: We created a 30-minute workshop, based on HeadSmart, to educate primary care providers on the presentation, common symptoms, work-up, and diagnosis of pediatric CNS tumors. We publicized the workshop throughout Colorado and delivered it via live webinar or online video recording. We collected demographic, specialty, and practice setting data from participants via optional survey. Participants could also take a 10-question, multiple-choice assessment of their knowledge on pediatric CNS tumor symptoms, work-up, and diagnosis before and after the workshop. RESULTS: We have now delivered the workshop to more than 400 providers in Colorado and the US. 39 providers participated in the survey; 19 completed both the pre- and post-workshop assessments. The mean pre-workshop score was 4.5 correct out of 10 (range 0-7); the mean post-workshop score was 5.4 (range 3-7) (unpaired t-test p=0.04). The mean improvement was 1.1 (paired t-test p=0.007). The majority of participants who completed the survey were pediatricians (n=30). Family practice (FP) physicians and pediatric/FP advance practice practitioners also participated. There was no significant difference in improvement for pediatricians vs. other providers. CONCLUSIONS: An educational tool based on the HeadSmart campaign was widely disseminated and is effective at increasing understanding of the timely diagnosis of pediatric CNS tumors among primary providers in Colorado. Further study, refinement, and dissemination have the potential to help mitigate disparities in pediatric CNS tumor outcomes.
ETMR-04. Embryonal tumor with multi-layered rosettes (ETMR) located in the brainstem: a case report on clinical decision-making and a multimodal, interdisciplinary treatment approach including interstitial brachytherapy
Authors: Jünger Stephanie T , Rueß Daniel , Goldbrunner Roland , Gielen Gerrit H , Peitsch Torsten , Johann Pascal , Landgraf Pablo , Simon Thorsten , Ruge Maximilian I
Published: June 2022

OBJECTIVE: Embryonal tumors with multi-layered rosettes (ETMR) (CNS WHO grade 4) comprise a rare and malignant tumor type affecting predominantly infants below 3 years of age. The treatment consists of maximal safe surgical resection, irradiation, and intensive medulloblastoma type chemotherapy. Despite aggressive treatment, the prognosis of these patients remains poor, especially for brainstem tumors. We present the case of a male infant diagnosed with a brainstem ETMR, successfully treated with an interdisciplinary multimodal approach, including stereotactic interstitial brachytherapy. RESULTS: A 19 month old boy first presented with hemiparesis, intermittent bradycardia and reduced consciousness. Initial imaging showed a brainstem lesion with characteristic features of a diffuse intrinsic pontine glioma (DIPG). We performed stereotactic biopsy to confirm the diagnosis and initiated temozolomide treatment. While the pathology result was still pending, the boy’s clinical condition deteriorated to a soporic state with stretch synergisms. By emergency open surgery, partial resection was achieved. Eventually, the patient recovered rapidly. After the diagnosis of ETMR was established, medulloblastoma type chemotherapy (systemic carboplatin/etoposide; intrathecal methotrexate) was administered. After two cycles, the patient showed only residual right-sided hemiparesis. However, imaging demonstrated only a minimal reduction of the tumor size. Therefore, stereotactic interstitial brachytherapy using 125iodine seeds and subsequent high-dose chemotherapy (HDCT) with autologous stem cell transplantation (ASCT) was performed and overall tolerated well. After two months of brachytherapy and two additional cycles of chemotherapy, the MRI showed ≥ 50% reduction in tumor volume and no neurological deficit can be clinically detected. CONCLUSION: This case indicates that stereotactic interstitial brachytherapy during intensive systemic chemotherapy is feasible. It may provide a suitable treatment for malignant infant brain tumors. Furthermore, it shows that paediatric patients are capable of recovery even after devastating neurological symptoms. Lastly, it emphasizes the importance of multidisciplinary and multimodal treatment for rare diseases.
ETMR-05. Single-cell transcriptomics of ETMR reveals developmental cellular programs and tumor-pericyte communications in the microenvironment
Authors: de Faria Flavia W , Walter Carolin , Interlandi Marta , Melcher Viktoria , Riedel Nicole , Graf Monika , Moreno Natalia , Schoof Melanie , Holdhof Dörthe , Thomas Christian , Frühwald Michael C , Maerkl Bruno , Ho Ben , Sandmann Sarah , Varghese Julian , Ebinger Martin , Schuhmann Martin , Canak Aysegül , Huang Annie , Schüller Ulrich , Albert Thomas K , Kerl Kornelius
Published: June 2022

BACKGROUND: Embryonal tumors with multilayered rosettes (ETMR) are pediatric brain tumors bearing a grim prognosis, despite intensive multimodal therapeutic approaches. Insights into cellular heterogeneity and cellular communication of tumor cells with cells of the tumor microenvironment (TME), by applying single-cell (sc) techniques, potentially identify mechanisms of therapy resistance and target-directed treatment approaches. MATERIAL AND METHODS: To explore ETMR cell diversity, we used single-cell RNA sequencing (scRNA-seq) in human (n=2) and murine ETMR (transgenic mode; n=4) samples, spatial transcriptomics, 2D and 3D cultures (including co-cultures with TME cells), multiplex immunohistochemistry and drug screens. RESULTS: ETMR microenvironment is composed of tumor and non-tumor cell types. The ETMR malignant compartment harbour cells representing distinct transcriptional metaprograms, (NSC-like, NProg-like and Neuroblast-like), mirroring embryonic neurogenic cell states and fuelled by neurogenic pathways (WNT, SHH, Hippo). The ETMR TME is composed of oligodendrocyte and neuronal progenitor cells, neuroblasts, microglia, and pericytes. Tumor-specific ligand-receptor interaction analysis showed enrichment of intercellular communication between NProg-like ETMR cells and pericytes (PC). Functional network analyses reveal ETMR-PC interactions related to stem-cell signalling and extracellular matrix (ECM) organization, involving factors of the WNT, BMP, and CxCl12 networks. Results from ETMR-PC co-culture and spatial transcriptomics pointed to a pivotal role of pericytes in keeping ETMR in a germinal neurogenic state, enriched in stem-cell signalling. Drug screening considering cellular heterogeneity and cellular communication suggested novel therapeutic approaches. CONCLUSION: ETMR demonstrated diversity in the microenvironment, with enrichment of cell-cell communications with pericytes, supporting stem-cell signalling and interfering in the organization of the tumor extracellular matrix. Targeting ETMR-PC interactions might bring new opportunities for target-directed therapy.
ETMR-06. Molecular and clinical characteristics of CNS tumors withBCOR(L1) fusion/internal tandem duplication
Authors: Gojo Johannes , Schmitt-Hoffner Felix , Mauermann Monika , von Hoff Katja , Sill Martin , Korshunov Andrey , Stichel Damian , Capper David , Tauziede-Espariat Arnault , Varlet Pascale , Aldape Kenneth , Abdullaev Zied , Donson Andrew , Pahnke Jens , Schüller Ulrich , Tran Ivy , Galbraith Kristyn , Snuderl Matija , Alexandrescu Sanda , Brandner Sebastian , Łastowska Maria , Miele Evelina , Lugt Jasper v , Meijer Lisethe , Bunt Jens , Kramm Christof , Hansford Jordan R , Krskova Lenka , Zapotocky Michal , Nobusawa Sumihito , Solomon David , Haberler Christine , Jones Barbara , Sturm Dominik , Sahm Felix , Jäger Natalie , Pfister Stefan M , Kool Marcel
Published: June 2022

Central nervous system (CNS) tumor with BCOR internal tandem duplication (BCOR-ITD) have recently been introduced in the 5th edition of the WHO classification of CNS tumors, however, their molecular makeup and clinical characteristics remain widely enigmatic. This is further complicated by the recent discovery of tumors characterized by gene fusions involving BCOR or its homologue BCORL1. We identified a cohort of 206 BCOR altered CNS tumors via DNA methylation profiling and conducted in-depth molecular and clinical characterization in an international effort. By performing t-SNE clustering analysis we found that BCOR-fusion tumors form a distinct cluster (n=61), adjacent to BCOR-ITD cases (n=145). The identified fusion partners of BCOR(L1) included EP300 (n=20), CREBBP (n=5), and NUTM2HP (n=1). Notably, three cases within the BCOR-ITD cluster harbored a c-terminal intragenic deletion within BCOR. With respect to clinical characteristics gender ratio was balanced in BCOR-fusion cases (m/f, 1.1), whereas predominance of male patients was observed in the BCOR-ITD group (m/f, 1.5). Moreover, age at diagnosis of BCOR-fusion patients was higher as compared to BCOR-ITD cases (15 vs 4.5 years). Interestingly, BCOR-fusion tumors were exclusively found in the supratentorial region being originally diagnosed as ependymomas or gliomas whereas BCOR-ITD emerged across the entire CNS with diverse original diagnoses. 8% of BCOR-ITD and none of BCOR-fusion cases were disseminated at diagnosis. In line with this observation, 40% of first relapses within the BCOR-ITD group were metastatic which was less frequent in BCOR-fusion tumors. Survival estimates demonstrated no differences, generally showing short median PFS (BCOR-fusion, 2 years, n=15; BCOR-ITD, 1.8 years, n=55) and intermediate OS rates (BCOR-fusion, 6.8 years, n=18; BCOR-ITD 6.3 years, n=60). Further molecular and clinical characterization is ongoing potentially revealing first therapeutic leads for these highly aggressive CNS tumor types.
ETMR-13. Embryonal Tumor with Multilayered Rosettes in an Infant: Case Report
Authors: Yu Llarx Saundt , Palabyab Eric Paolo , Baticulon Ronnie
Published: June 2022

Embryonal tumor with multilayered rosettes (ETMR) is a highly malignant tumor (WHO grade 4) seen predominantly in infants. It includes morphologically distinct embryonal tumors namely, embryonal tumor with abundant neuropil and true rosettes, ependymoblastoma, and medulloepithelioma. The presence of multilayered rosettes and C19MC amplification at chromosome 19q13.42 confirms the diagnosis. The median overall survival is less than a year and the prognosis is generally poor. We report the case of a 1-year-old girl who presented with vomiting, lethargy, and increasing head circumference over a period of six months. On admission, she was drowsy and irritable. Verbal output was limited to moans and motor response was localizing. She was macrocephalic with a head circumference of 51 cm. MRI showed a large 5 x 5 x 6.5cm contrast-enhancing cerebellar vermian tumor with obstructive hydrocephalus. There was no evidence of leptomeningeal disease or spinal metastasis at this time. She underwent a right frontal ventriculoperitoneal shunt insertion, followed by suboccipital craniotomy and subtotal tumor resection one week later. Her shunt was ligated two days after tumor excision, due to development of bilateral subdural hygromas. The patient regained full consciousness, but still had spastic lower extremities and inability to swallow at the time of discharge. Histopathology and immunostains were consistent with an embryonal tumor, possibly ETMR, and the patient was for advised chemotherapy. Before initation of chemotherapy, the patient was admitted in another instution because of alteration in sensorium. Repeat imaging showed progression of the patient’s subdural hygromas, requiring insertion of a subduroperitoneal shunt. The patient died seven weeks after tumor resection due to progression of her tumor residual. Management options for ETMR are limited, especially in low- and middle-income countries. International linkages may help facilitate the accurate diagnosis and early treatment of these patients with rare but aggressive brain tumors.
ETMR-15. Central Nervous System Embryonal Tumor with EWSR1 translocation: Evolving changes in histology, sequencing, and epigenetics at relapse in 2 patients and potential treatment implications
Authors: Littrell Mary , Bielamowicz Kevin , Gokden Murat , Jayappa Sateesh , Albert Gregory
Published: June 2022

INTRODUCTION: Histologically diagnosed embryonal tumors (ET) of the central nervous system (CNS) in the pediatric population represent a group of aggressive malignancies with historically poor prognoses. Immunohistochemistry (IHC) and cytogenetics refined tumor classification and improved treatment strategies. Modern advancements in molecular methods including methylation profiling provide further delineation of distinct ET subclasses. CASE DESCRIPTION: We present two cases with initial diagnosis of a CNS embryonal tumor with EWSR1 rearrangement. Relapsed tissue in both cases displayed acquisition of INI-1 loss consistent with atypical teratoid/rhabdoid tumor (AT/RT). The first case presented at 14 months of age with vomiting and altered mental status. Imaging revealed right frontal lobe hemorrhagic mass with signs of increased intracranial pressure; pathology returned as a CNS embryonal tumor with EWSR1-PLAGL1 translocation. Patient ultimately experienced multiple relapses with tumor sample each with INI-1 loss. The second case presented at 11 months of age with new onset seizures and was found to have right frontal tumor; pathology returned as CNS embryonal tumor with EWSR1-PLAGL1 translocation. Patient experienced recurrence in original tumor bed and pathology was consistent with malignant recurrence with INI-1 loss. Methylation profiling for diagnostic samples in both patients was consistent with ET not otherwise specified, while methylation profiling of relapsed tissue in both cases was consistent with AT/RT. EWSR1 translocation was persistent from diagnostic to relapsed samples. CONCLUSION/DISCUSSION: These cases illustrate the need for ongoing analysis in patients with CNS primitive neuroectodermal tumors and EWSR1 rearrangements, and the unique role of molecular studies in relapsed tissue. The emergence of treatment resistance in a subpopulation of cells more consistent with AT/RT suggests these patients could benefit from upfront and experimental treatment approaches for AT/RT.
GCT-01. Pediatric intracranial germ cell tumors and primary polyuria-polydipsia syndrome: a 13-year single institutional experience
Authors: Pavone Rossana , Fonte Carla , Ricci Franco , Varriale Gaia , Enrico Giorgia , Censullo Maria Luigia , Gori Carlotta Gemma , Guidi Milena , Buccoliero Anna Maria , Caporalini Chiara , Genitori Lorenzo , Sardi Iacopo
Published: June 2022

Intracranial germ cell tumors (IGCTs) represent about 4% of all childhood brain tumors. They are common in both the pineal and pituitary regions and sometimes they can be bifocal. Suprasellar and bifocal IGCTs usually present stereotypical symptoms, including primary polyuria-polydipsia syndrome (PPS). Consolidated IGCTs’ therapy is based on the International Society of Pediatric Oncologic (SIOP) CNS GCT II protocol consisting of primary pre-radiation chemotherapy combining etoposide, carboplatin and/or cisplatin and ifosfamide. PPS management in these patients requires monitoring of electrolytes and fluids during chemotherapy, especially for cisplatin and/or ifosfamide-based cycles, for which hyperhydratation is required. We report the results of our single-center cohort of patients with IGCTs treated between 2008 and 2021, focusing on the clinical presentation, treatment and long-term follow-up. Thirty-one patients were analyzed (median age=13 years, 87% male). Twelve children (39%) presented a PPS and needed desmopressin treatment, maintained at long-term follow-up data update in all. Over these PPS patients, 6 had bifocal germinomas, 4 suprasellar germinomas, 1 metastatic germinoma and 1 non-germinomatous IGCT. Eleven PPS children (92%) received cisplatin and/or ifosfamide-based chemotherapy: all of them had optimal biochemical urine and blood investigations before, during and after chemotherapy. None of them presented serious complications during treatment. After a median follow-up of 5 years, two patients (6.5%) died (1 IGCT-related, 1 non-cancer related) and one had a second malignancy (parotid gland mucoepidermoid carcinoma, 6 years after IGCT diagnosis). Childhood IGCTs have an excellent prognosis, but present a significant risk of long-lasting severe endocrine sequelae which may be worsened by the primary oncological strategy, requiring careful management of complications related to fluid and electrolytes disturbances. In order to avoid post-treatment pituitary insufficiency, guidelines for diabetes insipidus management when cisplatin and/or ifosfamide-based protocols are used should be established and all patients should receive meticulous endocrine follow-up.
GCT-10. Successful Salvage of Relapsed intracranial Non-Germinaoteous Germ Cell Tumors NGGCTs in a Child With Renal Insufficiency with Novel platinum-Free chemotherapy Regimen
Authors: Mobark Nahla Ali , Alharbi Musa , Ballourah Walid , AlSultan Abdulrahman , Manjomi Fahad Al , Alotabi Fahad , Balbaid Ali Abdullah O , Rayis Mohammed , AlNaqib Zaid G , Aljabarat Wael abdel Rahman , Finlay Jonathan L
Published: June 2022

The Outcome for relapsed NGGCT is poor. Salvage therapy usually consist of reinduction platinum-based chemotherapy regimen followed by high-dose-chemotherapy and autologous-stem-cell-rescue (HDC/AuSCR) and re-irradiation with no consensus on optimal management and usually associated with remarkable toxicity. We present a 12-year-old boy diagnosed with a localized pineal Non-Germinaoteous Germ Cell Tumors NGGCTs of mixed origin with elevated AFP he had ETV and biopsy started on COG ACNS0122 protocol after receiving first cycle (carbo/Etoposide) he developed acute renal failure investigation showed small dysplastic kidney to avoid nephrotoxicity of platinum agents chemotherapy changed to VBE (Vinblastine, Bleomycin and Etoposide) post 3rd cycle MRI showed increase in size of the pineal mass with normal tumor markers representing Growing Teratoma Syndrome He had total surgical resection of the tumor Pathology showed predominant teratoma component He received radiation therapy CSI then another 3 cycles of VBE 4 months following treatment completion he presented with elevated AFB and new right anterior temporal lesion Spinal MRI and CSF were negative. He had 2 cycles of Salvage Non-nephrotoxic 4-drug regimens GEMPIV Gemcitabine 800 mg/m2 days 1 and 14. Paclitaxel 80 mg/m2 days 1 and14, Irinotecan 50 mg/m2 daily for 5 days Vinblastine 6 mg/m2 weekly days 1,8,14 MRI after 2 cycles showed remission with undetectable AFP then 2 consolidation cycles of etoposide and thiotepa (HDC/AuSCR) The 3rd consolidation cycles were cancelled due to hematological toxicity During treatment phases chemotherapy was well tolerated doses were adjusted according to his GFR with renal conservative and supportive therapy.post (HDC/AuSCR) he experienced delayed hematological recovery with persistent thrombocytopenia responded to Eltrombopag then he had focal Temporal lobe irradiation Currently patients in remission with chronic stage 3 renal Insufficiency Conclusions: this case showed that relapsed intracranial NGGCT can be successfully salvaged without platinum-based chemotherapy in patients with renal insufficiency.
GCT-11. 24 Gy whole ventricular radiotherapy alone is sufficient for disease control in localised germinoma in CR after initial chemotherapy – final of the SIOP CNS GCT II study
Authors: Calaminus Gabriele , Bison Brigitte , Conter Cecile Faure , Frappaz Didier , Peyrl Andreas , Gerber Nicolas U , Müller Jans-Enno , Ajithkumar Thankamma , Morana Giovanni , Cross Justin , Pietsch Torsten , Smith Colin , Solem Kristin , Devenney Irenne , Garre Maria Luisa , Brisse Herve , Zimmermann Martin , Kortmann Rolf-Dieter , Alapetite Claire , Nicholson James
Published: June 2022

SIOP CNS GCT II aimed to establish if 24 Gy Whole Ventricular Radiotherapy (WVRT) in localised germinoma is sufficient for tumour control. After central review of radiological response after ‘CarboPEI’ chemotherapy, patients in complete remission (CR) were consolidated with 24 Gy WVRT. Between 2/2012 and 7/2018, 194 patients from 8 European countries with histologically-confirmed fully-staged localised germinoma were registered, of whom 167 were protocol pts. CR after chemotherapy was achieved in 65 patients, Of the 102 patients not in CR after chemotherapy 91 had partial remission (PR), 8 stable disease (SD), 3 progressive disease (PD). All 65 patients in CR received 24 Gy WVRT alone; two of these relapsed, both locally, 7 and 12 months after diagnosis. Of the 102 non-CR patients after chemotherapy, 91 with PR and 8 with SD received 24 Gy WVRT and 16 Gy boost, of which five relapsed (four local, one distant) 2 -7 years from diagnosis. One additional patient who remained in CR died of infection in CR, 4 years after Dx. In three patients with PD all received 24 Gy ventricular irradiation with varying tumour boosts. 16-30 Gy, no relapses occurred. Median follow-up of the whole group was 4,2 years. 4- years event-free survival (EFS) for patients in CR treated with WVRT only (n=65) was 97% (standard error 2%). 4-years EFS for patients with non-CR ( WVRT 24 Gy and 16 Gy to 30 Gy tumour boost) (n=102) was 95% (standard error 2%). Localised germinoma in CR after chemotherapy had an excellent outcome with 24 Gy WVRT alone. 24 Gy WVRT is therefore considered the standard consolidation treatment in this group and should be used as the standard for further treatment studies in localised germinoma evaluating the recent international consensus on radiological response criteria ( Lancet Oncology accepted).