bluuebunny/crossref_metadata_2025_split huggingface dataset:
DIPG-77. TREATMENT EXTENT AND THE EFFECT ON SURVIVAL IN DIFFUSE INTRINSIC PONTINE GLIOMA
Authors: Baugh Joshua , Colditz Niclas , Janssens Geert , Dietzsch Stefan , Hargrave Darren , von Bueren André , Kortmann Rolf-Dieter , Bison Brigitte , van Vuurden Dannis , van Zanten Sophie Veldhuijzen , Kramm Christof 
Published: December 2020

Abstract

BACKGROUND
Front line radiotherapy for diffuse intrinsic pontine glioma (DIPG) remains the only standard of care. Is this still appropriate?

PATIENTS AND METHODS
We examined survival outcomes across six treatment modalities including I) no treatment (n=19), II) radiotherapy alone (n=38), III) radio-chemotherapy (n=101), IV) radiotherapy and relapse chemotherapy (n=35), V) radio-chemotherapy and relapse chemotherapy (n=163), and VI) radio-chemotherapy and relapse chemotherapy, plus reirradiation (n=54). Data were collected retrospectively using the Society of Pediatric Oncology and Hematology (GPOH) and the SIOPE DIPG Registry. 410 patients were included with radiologically centrally reviewed DIPG, mostly unbiopsied. Of note, the untreated patients and radiotherapy only cohorts chose limited treatment voluntarily.

RESULTS
Median overall survival (MOS) of the whole cohort was 11 months and progression free survival (PFS) 7 months. PFS was not significantly different between the treatment groups. OS and post-progression survival (PPS) were significantly different between cohorts. For the respective treatment groups, median OS was 3 months (I), 7 months (II), 8 months (III), 13 months (IV), 13 months (V), and 15 months (VI). For only front line vs at least one second line therapy, MOS was 8 months vs 14 months and PPS 2 months vs 5 months.

CONCLUSIONS
Although subject to biases to some extent, it seems that additional therapies beyond radiation therapy are of benefit to extending survival in DIPG patients. This is at least partially caused by the introduction of reirradiation regimens. To what extent other therapies contribute to survival and quality of life is subject to further investigation.
DIPG-80. CLINICAL AND RADIOGRAPHIC RESPONSE TO ONC201 IN A PEDIATRIC PATIENT WITH A THALAMIC H3K27M AND BRAFV600E MUTANT DIFFUSE MIDLINE HIGH GRADE GLIOMA
Authors: Duke Elizabeth , Murnick Jonathan , Tarapore Rohinton , Allen Joshua , Kilburn Lindsay 
Published: December 2020

Abstract
Recent improved understanding of the molecular markers of high grade glioma has shifted the approach to these aggressive CNS tumors to increasingly use molecularly guided targeted therapies. Treatment of patients with BRAFV600E mutant high grade gliomas with BRAF inhibitors has shown efficacy, however the impact of concomitant H3K27M mutation is unknown. ONC201 targets dopamine receptor D2 (DRD2), which is shown to be broadly overexpressed in the thalamus as well as multiple tumor types; its antagonism has demonstrated anti-tumor efficacy and immunomodulatory properties in preclinical studies. ONC201 has also demonstrated clinical efficacy in patients with H3K27M mutant gliomas. We present the case of a 9-year-old male with a right thalamic H3.3K27M mutant diffuse midline glioma with a concomitant BRAFV600E mutation with an ongoing partial response to ONC201 treatment. The patient was diagnosed in May 2018. He underwent biopsy, followed by standard focal proton radiation therapy (54Gy) and subsequent treatment with dasatinib, bevacizumab and everolimus over the course of five months. After continued radiographic progression on serial imaging, in April 2019 he started ONC201 375mg orally once per week through an expanded access trial. He has tolerated the medication well with grade 1 nausea and fatigue. Over the next nine months, he demonstrated clinical and radiographic improvement with modest increased use of his left side and MRIs showing progressive decrease in size of the thalamic lesion with a 70 % decrease in the target lesion (measuring 53x62mm prior to treatment, decreased to 38x26mm in January 2020).
DIPG-82. CLINICAL EXPERIENCE OF CONVECTION ENHANCED DELIVERY (CED) OF CARBOPLATIN AND SODIUM VALPROATE INTO THE PONS FOR THE TREATMENT OF DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG) IN CHILDREN AND YOUNG ADULTS AFTER RADIOTHERAPY
Authors: Szychot Elwira , Walker David , Collins Peter , Hyare Harpreet , Shankar Ananth , Bienemann Alison , Hollingworth Milo , Gill Steven 
Published: December 2020

Abstract

PURPOSE
Effective treatment of diffuse intrinsic pontine glioma (DIPG) remains a formidable challenge due to inadequate penetration of the blood-brain barrier (BBB) by systemically administered chemotherapies. The BBB can be overcome by directly infusing drugs into pons using method of convection-enhanced delivery (CED). We describe our clinical experience and what we have learned about the safety and feasibility of treating DIPG with intermittent CED of carboplatin and sodium valproate to the pons through the Renishaw Drug Delivery System (RDDS).

METHODS
Retrospective review (2017–2020) of children with DIPG, who following radiotherapy, received compassionate treatment commencing 3.3–10 months post diagnosis (median 4.9 months). They received up to 7 cycles of 3–6 weekly pontine infusions of carboplatin (0.12-0.18mg/ml) and sodium valproate (14.4- 28.8mg/ml).

RESULTS
13 children 3–19 years (mean 6.9 years) were treated. There were no surgical complications. With the exception of infusion channels blocking in one device there were no adverse device effects. Two patients developed persistent 6th nerve palsies, which led to drug concentration reduction in the combination therapy. Subsequently infusion/ drug related toxicities were transient. Tumour was controlled in pons in 11/13 patients. Median progression free survival (PFS) was 13.0 months, while median overall survival (OS) was 15.3 months.

CONCLUSIONS
Use of the RDDS was safe and well tolerated in all 13 patients. Treatment improved control of pontine disease resulting in longer PFS and OS than reported for conventional therapy and merits further evaluation in a clinical trial.
DIPG-84. COMPLEMENTARY AND ALTERNATIVE MEDICINE IN DIFFUSE INTRINSIC PONTINE GLIOMA
Authors: El-Khouly Fatma , Adil Syed , Hendrikse Harry , Kaspers Gertjan , Kramm Christof , van Zanten Sophie Veldhuijzen , van Vuurden Dannis 
Published: December 2020

Abstract

INTRODUCTION
Diffuse intrinsic pontine glioma (DIPG) is a rare and aggressive childhood brainstem malignancy with a two-year survival rate of ≤10%. In this international survey study we aim to evaluate the use of complementary and alternative medicine (CAM) in this patient population.

METHODS
Parents of-, and physicians treating DIPG patients were asked to participate in a retrospective online survey with questions regarding CAM use during time of illness.

RESULTS
120 parents and 75 physicians contributed to the online survey between January and May 2020. Physicians estimated that &lt;50% of their patients used CAM, whereas 69% of the parents reported to have used CAM to treat their child during time of illness. Cannabis was the most widely used form of CAM, followed by vitamins and minerals, melatonin, curcumin and boswellic acid. CAM was mainly used to actively treat the tumor. Other motivations were to treat side effects of chemotherapy, or to comfort the child. Children diagnosed ≥2016 were more likely to use CAM (χ2=6.08, p=0.014). No significant difference was found between CAM users and non-users based on ethnicity (χ2=4.18, p=0.382) and country of residence (χ2=9.37, p=0.154). Almost 50% of the physicians do not frequently ask their patients about possible CAM use.

CONCLUSION
This survey demonstrates that worldwide a considerable number of DIPG patients use CAM. Physicians should be more aware of potential CAM use and more actively discuss the topic. More research is needed to gain knowledge about possible anticancer effects of CAM and their interactions with conventional therapies.
EPCT-06. A PHASE I STUDY OF MULTI-TARGETED THERAPY IN NEWLY DIAGNOSED OR PROGRESSIVE DIFFUSE INTRINSIC PONTINE GLIOMA
Authors: Baig Muhammad , Johnson Jason , Gupta Sumit , Sadighi Zsila , Zaky Wafik , Khatua Soumen 
Published: December 2020

Abstract

BACKGROUND
Diffuse intrinsic pontine glioma (DIPG) constitutes 80% of pediatric brain stem tumors with a median survival of 12 months. The PI3K/AKT/mTOR pathway is a key oncogenic driver of this tumor. Targeting the chromatin dysregulation through HDAC inhibition, demonstrated benefit in vivo and vitro studies. We completed the first study as a multi-targeted therapy using SAHA and temsirolimus in pediatric DIPG.

METHODS
After receiving institutional IRB approval, we enrolled 6 patients on this phase I study using a 3 + 3 statistical design. Patients were divided into stratum 1 and stratum 2, based on newly diagnosed or relapsed DIPG respectively. Stratum I patients received radiation therapy concurrently with vorinostat, followed by maintenance therapy with vorinostat and temsirolimus for 10 cycles (28 day cycle), while in stratum II patients received vorinostat and temsirolimus for 12 cycles. Neuroimaging including diffusion tensor imaging were evaluated where feasible.

RESULTS
Three patients were enrolled in each of the stratum. One patient in stratum 1 completed therapy, 2 other demonstrated progressive disease (PD) after 4th and 1st cycle of maintenance therapy respectively. In stratum 2 all patients progressed 2 months after the start of therapy. However no dose-limiting toxicity (DLT) was noted. The patient in stratum 1 who completed therapy, remained free of PD 21 months after diagnosis with continued improvements in the volume of enhancing and T2 hyperintense disease.

CONCLUSION
Although no significant benefit was seen as compared to historical controls during this study, no dose limiting toxicity was noticed with this treatment.
EPCT-15. THE REMIND TRIAL: MULTI-ANTIGEN TARGETED T CELLS FOR PEDIATRIC CNS TUMORS
Authors: Grant Melanie , Fortiz Maria Fernanda , Wang Lu , Lang Haili , Datar Anushree , Reynolds Emily , Terpilowski Madeline , Lazarski Chris , Tanna Jay , Pitino Adriana , Zhang Nan , Hoq Fahmida , Hanley Patrick , Kilburn Lindsay , Packer Roger , Rood Brian , Bollard Catherine , Hwang Eugene 
Published: December 2020

Abstract

BACKGROUND
Patients with relapsed CNS malignancies or DIPG face terrible prognoses. We hypothesized that T cells specific for 3 tumor-associated antigens (TAA), WT1, PRAME and survivin, would be safe and elicit anti-tumor immunity.

METHODS
Patients (n=9) have received autologous tumor antigen-associated T cells (TAAT) (up to 4x107/m2) for newly diagnosed DIPG (Group A) or recurrent CNS malignancies (Group B) on a Phase I dose-escalation study (NCT03652545) and were monitored for safety and response. RESULTS/

DISCUSSION
9/9 patients who received TAAT completed the 45-day safety monitoring phase with no dose-limiting toxicities. Infused cells were predominantly CD3+ T cells (median 96%; range: 87–99%), with CD4+ and CD8+ comprising 16% (range: 5–87%) and 40% (range: 4–67%) of the CD3+ cells, respectively. TAAT with specificity for 1–3 TAAs, at varying frequencies, was demonstrated in 8/9 TAAT by anti-IFN-γ ELISPOT. Plasma cytokine profiles demonstrated infusion-related immune cytokine responses. In summary, TAAT are safe and may elicit anti-tumor responses in vivo. To confirm TAAT-driven effects, we are evaluating plasma proteomic profiles for immune-response signatures and assessing unique T cell receptor rearrangements of infused TAAT. Response assessment and dose escalation are ongoing.
EPCT-16. A PHASE IB STUDY OF PTC596 IN CHILDREN WITH NEWLY DIAGNOSED DIFFUSE INTRINSIC PONTINE GLIOMA AND HIGH GRADE GLIOMA
Authors: Smiley Natasha Pillay , Baxter Patricia , Kumar Shiva , Hwang Eugene , Breneman John , Lane Adam , Doughman Renee , Deutsch Michelle , Stevenson Charles , Stewart Clinton , Leach Jim , Li Xiao-Nan , Romero Sonia , Maliakal Pius , Gao Lan , Fouladi Maryam , Drissi Rachid 
Published: December 2020

Abstract

BACKGROUND
BMI-1 is highly expressed in DIPG. Downregulation leads to inhibition of cell proliferation, cell cycle signaling, self-renewal, telomerase expression, activity, and suppression of DIPG cell migration. Targeted inhibition of BMI-1 sensitizes DIPG cells to radiation and drug-induced DNA damage. PTC596 (formulated by PTC Therapeutics, Inc.) is a novel, orally available drug that inhibits microtubule polymerization, resulting in G2/M cell cycle arrest and post-translational modification of BMI-1 protein and reduced BMI-1 protein levels. OBJECTIVES: To estimate the maximum tolerated dose and describe dose limiting toxicities, pharmacokinetics and pharmacodynamics of PTC596 in children 3–21 years of age with newly diagnosed diffuse intrinsic pontine glioma and high-grade gliomas.

METHODS
PTC596 is administered twice per week orally during radiotherapy and as maintenance for up to two years. The starting dose of PTC596 was 200 mg/m2, with a subsequent dose level of 260mg/m2/dose. Pharmacokinetics are performed in Cycles 1 and 2.

RESULTS
This study is currently ongoing. Nine patients (7 with DIPG, 2 with HGG), 8 evaluable, have been enrolled. At dose level 1, 200 mg/m2, three evaluable patients were enrolled and experienced no DLTs. At dose level 2, among 5 evaluable patients, 2 experienced dose-limiting grade 4 neutropenia. PTC596 has been otherwise well tolerated. Five patients remain in Cycles 2–11.

CONCLUSION
This phase I trial is ongoing. PTC596 is tolerable at dose level 1. We are amending the protocol to introduce tablets that can be dissolved in liquid to allow enrollment of younger patients and those unable to swallow whole tablets.
EPEN-02. EVALUATION OF TREATMENT OUTCOMES AND EXPRESSION OF EMT-RELATED TRANSCRIPTION FACTORS AS NOVEL THERAPEUTIC TARGETS IN PEDIATRIC EPENDYMOMA
Authors: Makino Keishi , Kuroda Jun-ichiro , Shinojima Naoki , Fujimoto Kenji , Takada Akira , Mukasa Akitake 
Published: December 2020

Abstract

OBJECTIVE
Intracranial ependymomas are common brain tumors in children. However, prognosis, especially in young children, remains poor because of the chemo- and radioresistant properties of intracranial ependymomas. Furthermore, effective treatments for intracranial ependymomas remain a challenge. The epithelial-to-mesenchymal transition (EMT) is important for invasion and metastasis in many cancers. This study aimed to evaluate and compare treatment outcomes with the expression of EMT-related transcription factors in pediatric ependymomas.

MATERIAL AND METHODS
Medical and radio-imaging data of 22 (11 boys, 11 girls) patients aged &lt;15 years with intracranial ependymomas were reviewed from January 1983 to December 2018. Six cases were subdivided into clinicopathological-molecular subgroups and immunohistochemically analyzed for Slug and ZEB.

RESULTS
The median age at the start of treatment was 5 years (range 8 months–15 years) (9 cases were aged &lt;3 years). The median progression-free survival (PFS) was 25.6 (range, 0.8–383.5) months; the median overall survival (OS) was 81.9 (range, 2.9–383.5) months. Extent of resection and malignant histology were significant prognostic factors for OS and PFS in multivariate analysis. There were 6 cases (2 cases of PFA, 2 of PFB, 1 of ST and 1 case of ST-RELA). Nuclear expression of ZEB1 was found in all tumors; however, that of Slug increased only in PFA and PFB tumors, which were associated with a poor prognosis.

CONCLUSION
Expression of EMT-related transcription factors was increased in pediatric ependymomas. These data suggest that EMT is a novel therapeutic target for treating pediatric intracranial ependymomas.
EPEN-06. CHEMOTHERAPY OF RECURRENT EPENDYMOMA: LONG-TERM RESPONSE ONLY IN FEW CASES
Authors: Adolph Jonas , Tippelt Stephan , Mikasch Ruth , Pfister Stefan , Pajtler Kristian , Witt Hendrik , Witt Olaf , Bison Brigitte , Warmuth-Metz Monika , Kortmann Rolf-Dieter , Dietzsch Stefan , Pietsch Torsten , Timmermann Beate , Fleischhack Gudrun 
Published: December 2020

Abstract

INTRODUCTION
The efficacy of chemotherapy in recurrent ependymoma is unclear. We present results from the German HIT-REZ-studies.

METHODS
137 patients were analyzed regarding the treatment with chemotherapy at first recurrence, the time from first relapse to progression (PFS) and to either time-point of death or last follow-up (OS). Tumor response evaluation was based on MRI and clinically; molecular data was available in 80.

RESULTS
In our cohort, 96 patients (20 supratentorial, 73 infratentorial, 3 spinal) received chemotherapy during first recurrence: 49 (51.0%) temozolomide (TMZ) monotherapy, 12 (12.5%) HIT-SKK regime, 9 (9.4%) carboplatin/etoposide (CE) and 26 (27.1%) other combinations. In 19.8% (26.5% in TMZ), chemotherapy was administered prior to surgery (neoadjuvant), which resulted in tumor progression in 78% (85% in TMZ). Gross-total resection was achieved in 86% without neoadjuvant chemotherapy and in 74% (69% in TMZ) with neoadjuvant treatment. Switching to trofosfamide/etoposide (TE) after surgery and unresponsiveness to TMZ showed further progression in all cases of tumor-residuum after surgery. Regarding 1-year-PFS, treatment with HIT-SKK (50.0%±14.4%) or CE (55.6%±16.6%) was advantageous over TMZ (30.2%±6.7%). However, 5-y-OS was lower in CE (19.0% ±16.8%) than in TMZ (39.8%±7.7%) and HIT-SKK (42.9%±8.7%). Long-term control was seen in individual cases of TMZ, HIT-SKK and CE, with TMZ providing longest response of 72 months.

CONCLUSION
Neoadjuvant TMZ has no significant advantage regarding PFS. However, in few cases chemotherapy prevented progression after incomplete resection. Difficulties in response evaluation and variability in therapies hinder conclusions. Supported by the German Children’s Cancer Foundation
EPEN-10. SPINAL MYXOPAPILLARY EPENDYMOMA AND METHYLATION-PROFILING: THE MD ANDERSON CANCER CENTER (MDACC) EXPERIENCE
Authors: Gupta Sumit , Tian Xiangjun , Wang Jing , Huse Jason , Rhines Laurence , Zaky Wafik , Tatsui Claudio , Khatua Soumen 
Published: December 2020

Abstract

INTRODUCTION
Spinal myxopapillary ependymoma (MPE) is a rare histological variant of ependymoma, classified as WHO grade I tumor. Further interrogation of the molecular and clinical profile is warranted, to better understand the biology and clinical phenotype. We summarize our institutional experience with spinal MPE including methylation-profiling.

METHODS
A retrospective analysis of charts during the period of 2001 to 2019 of histologically proven MPE was done. We performed methylation profiling for 12 patients by Infinium MethylationEPIC Kit.

RESULTS
26 patients with spinal MPE were identified, median age of diagnosis was 34.2 years with a range of 11 to 59.9 years. Ten patients were below 30 years of age, lumbar spine location was commonest and 6 had leptomeningeal spread at diagnosis. All the patients underwent surgery and 11 received radiation following surgery. Eight patients below the age of 30 received radiation due to residual disease or metastases. Methylation profiling revealed 11,752 CpGs differentially methylated between the younger and older patients (p &lt; 0.05), however only one CpG cg22496254 associated with gene NCAPG/DCAF16 (role in promoting mitosis) was detectable with FDR &lt; 0.25 that overly methylated in the younger age group. This is a new finding in MPE.

CONCLUSIONS
Spinal MPE is a rare spinal tumor. Our study though limited by numbers, showed younger patients had aggressive phenotype, most requiring radiation. Methylation profiling reaffirmed this finding and trend in the younger patients. Prospective studies in a larger cohort of patients with methylation profiling are needed to identify prognostic variables and new targets for treatment.
EPEN-13. PRIMARY EXTRADURAL SACROCOCCYGEAL SUBCUTANEOUS MYXOPAPILAR EPENDYMOMA MISDIAGNOSED AS PILONIDAL CYST IN A 7 YEAR-OLD BOY: A CASE REPORT
Authors: del Campo Regina M Navarro-Martin , Tavares-Macias Geronimo M , Pozos-Ochoa Luis Ivan , Orozco-Alvarado Ana L , Sanchez-Zubieta Fernando , Arredondo-Navarro Luis Angel 
Published: December 2020

Abstract

BACKGROUND
Ependymomas occur in the brain or spinal cord and rarely as an extraspinal variety at the sacrococcygeal region, separated from the spinal cord. This rare presentation is thought to originate from a group of heterotopic ependymal cells called the coccygeal medullary vestige. There are few reports of this occurrence in children. CLINICAL CASE: A 7-year-old male presented with a history of a soft mass arising in the sacrococcygeal area 3 years earlier, diagnosed as pilonidal cyst at primary level and treated with surgery twice, as this mass recurred the boy was sent to our hospital, a 3rd surgery was performed, all tumoral tissue was removed, no attachment with dural space was founded, pathology revealed myxopapilar ependymoma with positivity for PS100, EMA and Vimentin. After surgery a Follow up MRI of cranium and spine showed absence of disease, no radiotherapy neither chemotherapy was implemented. He has been on surveillance from 3 years now without recurrence.

CONCLUSION
This report highlights the fact that pediatric ependymoma can have an extradural presentation and can be confounded with pilonidal cyst, total resection is needed to control the disease. Potential for recurrence or metastatic disease can continue 20 years from the time of primary tumor, so prolonged surveillance is important.
EPEN-20. EZHIP/CATACOMB COOPERATES WITH PDGF-A AND p53 LOSS TO GENERATE A GENETICALLY ENGINEERED MOUSE MODEL FOR POSTERIOR FOSSA A EPENDYMOMA
Authors: Kagan Emily , Brat Daniel , Shilatifard Ali , Piunti Andrea , Becher Oren 
Published: December 2020

Abstract

BACKGROUND
PFA ependymoma is a pediatric brain tumor with only 30% long-term survival. Recently a gene called CXORF67/EZHIP/CATACOMB (henceforward: CATACOMB) was found to be overexpressed in PFA ependymoma. CATACOMB’s mechanism of action has been found to be analogous to that of the H3K27M mutation as its expression reduces H3K27me3 via inhibition of PRC2 catalytic activity.

METHODS
We infected NESTIN- or GFAP-expressing neonatal hindbrain progenitors with wild-type CATACOMB or a loss of function (LOF) point mutant (M406K), alone, with PDGFA, and with and without p53 deletion.

RESULTS
CATACOMB overexpression alone or with p53 loss was insufficient to induce tumorigenesis. CATACOMB overexpression with PDGFA and p53 loss was sufficient to induce tumorigenesis using either the LOF mutant (M406K) or the wild-type CATACOMB in both cells-of-origin. The histology appeared more ependymoma-like when CATACOMB was expressed in GFAP-expressing progenitors. Median survival for the model initiated in NESTIN progenitors was 99.5 days for the CATACOMB mutant (n=26) group and 61 days for the CATACOMB wild-type (n=28; log-rank test p=0.0033). Median survival for the model initiated in GFAP progenitors were 144 days for the CATACOMB mutant (n=19) group and 65 days for the CATACOMB wild-type (n=21; log-rank test is P&lt;0.0013). Immunohistochemistry for H3K27me3 demonstrated that CATACOMB wild-type tumors had reduced H3K27me3 compared to CATACOMB mutant tumors.

CONCLUSIONS
Disrupting CATACOMB inhibitory activity toward PRC2 significantly increases survival in mice in both models, suggesting this activity plays a critical role in accelerating tumorigenesis. Ependymoma-like histology was more commonly observed in the model initiated in the GFAP-expressing progenitors.