bluuebunny/crossref_metadata_2025_split huggingface dataset:
DDEL-07. A PHASE I STUDY EXAMINING THE FEASIBILITY OF INTERMITTENT CONVECTION-ENHANCED DELIVERY (CED) OF MTX110 FOR THE TREATMENT OF CHILDREN WITH NEWLY DIAGNOSED DIFFUSE MIDLINE GLIOMAS
Authors: Zacharoulis Stergios , Szalontay Luca , Higgins Dominic , Englander Zachary , Jin ZhenZhen , Garvin James , Zylber Rebecca , Stark Eileen , Maddocks Alexis , Sethi Chankrit , Canoll Peter , Dammnett Steve , Cook Craig , Feldstein Neil , Bruce Jeffrey 
Published: December 2020

Abstract
Convection-enhanced delivery (CED, the infusion of drugs under controlled pressure to the brain parenchyma via targeted micro-catheters, allows accurate anatomical targeting and delivery of higher (therapeutic) drug concentrations through clinically relevant volumes of brain tissue or tumor. Histone deacetylase inhibitors have been found in vitro to be the most active agents against Diffuse Midline Gliomas (DMGs) Using a novel device (implantable subcutaneous pump connected with catheter directly implanted into the pons/thalamus) we are performing a Phase I safety study of repeated infusions of MTX110 (MTX110, Midatech) in a dose escalation manner. Eligible patients include 3–18 years of age with newly diagnosed DMGs following radiation therapy without evidence of hemorrhage or cysts with intact organ function. Patients undergo a tumor biopsy and a single catheter (Spetzler lumbar shunt catheter, Integra, Plainsboro, NJ) is placed stereotactically into the geometric center of the tumor. A second catheter is inserted subcutaneously with the distal tubing connected to the infusion pump, (SynchroMed II (Medtronic)), also inserted subcutaneously. The infusion pump is prefilled with MTX110 and administered using wireless N’Vison Clinical programmer into two 24-hour infusions, consisting of 20 hours of drug infusions at 0.2mL/hr. The pulse is completed 7 days later. This is a dose escalation study with the infusate consisting of gadolinium and MTX110 (30, 60, or 90 microM). The study describing the first use in children of this device for direct-to-tumor drug delivery is open to recruitment (January 2020) and the preliminary data will be available for presentation by June 2020.
DDEL-08. CONVECTION-ENHANCED DELIVERY OF NIMUSTINE HYDROCHLORIDE (ACNU) AGAINST PEDIATRIC DIFFUSE INTRINSIC PONTINE GLIOMAS
Authors: Saito Ryuta , Kanamori Masayuki , Tominaga Teiji 
Published: December 2020

Abstract
Diffuse intrinsic pontine gliomas (DIPGs) are amongst the most challenging tumors to treat. Surgery is not an option, the effects of radiation therapy are temporary, and no chemotherapeutic agent has demonstrated significant efficacy. Intracerebral infusion technique of convection-enhanced delivery (CED) for patients with brain tumors could offer a novel approach for effective chemotherapy. We have been working to develop an effective chemotherapy using nimustine hydrochloride (ACNU) with this drug delivery method. After several studies targeting supratentorial recurrent malignant gliomas and recurrent gliomas affecting brainstem, we conducted phase 1 study to evaluate the safety of combination of convection-enhanced delivery of nimustine hydrochloride and systemic temozolomide against recurrent gliomas affecting brainstem. In this study, we demonstrated the safety and feasibility of CED of ACNU as well as real time monitoring of drug distribution by mixing ACNU with contrast agent; Gd-DOTA. We also defined the maximum tolerable concentration in this study and proceeded to phase 2 trial against recurrent gliomas affecting brain stem. However, these trials revealed the difficulty of treating pediatric DIPG at the time of recurrence. Therefore, we decided to treat pediatric DIPG cases at their initial diagnosis in the subsequent study. Aiming at obtaining Shonin approval both for intraparenchymal infusion catheter and drug to infuse into brain parenchyma, we are now conducting Phase II physician-led trial against initially diagnosed pediatric DIPG cases.
DDEL-10. A NANOPARTICLE PLATFORM FOR INTRATHECAL DELIVERY OF THE HISTONE DEACETYLASE INHIBITOR (HDACi) PANOBINOSTAT IN METASTATIC OR RECURRENT MEDULLOBLASTOMA
Authors: Chaudhuri Sauradip , Mohammad Afroz S , Zhang Wenqui , Baker Cassandra , Broughton Colton W , Fowler Martha J , Stabenfeldt Sarah E , Wechsler-Reya Robert J , Sandberg David I , Elmquist William F , Sirianni Rachael W 
Published: December 2020

Abstract

INTRODUCTION
Panobinostat is a histone deacetylase inhibitor (HDACi) that is a clinical candidate for treatment of pediatric medulloblastoma and diffuse intrinsic pontine glioma. Panobinostat is poorly water-soluble and experiences a number of barriers to effective delivery. Here, we developed a novel drug delivery system consisting of β-cyclodextrin-poly(β-amino ester). These cyclodextrin-networks (CDNs) self-assemble into nanoparticles encapsulating a high quantity of HDACi for slow release. We sought to test the hypothesis that panobinostat-loaded CDNs would demonstrate a differentiated pharmacokinetic profile compared to free panobinostat in mice after direct administration to cerebrospinal fluid.

METHODS
CDNs were synthesized via Michael addition and engineered to encapsulate a library of HDACi drugs. Nanoparticles were characterized for size, surface charge, loading, controlled release, and stability. CDNs or fluorescent surrogate nanoparticles were administered to the cisterna magna of mice. Tissues were collected for LC-MS/MS (pharmacokinetics [PK]: 1, 4, 8, 24, and 48 hrs) or microscopy (localization: 2, 6, 24, and 48 hrs, 1 and 3 wks).

RESULTS
Intravital and confocal microscopy demonstrate that nanoparticles distribute rapidly in subarachnoid space and can localize with metastases, persisting for &gt; 3 weeks. Nanoparticle panobinostat is released over weeks and is better tolerated than free drug. CDN-panobinostat delivery tended to be higher in the cerebellum and lower in the spinal cord at both early and late time points compared to freely administered drug.

CONCLUSIONS
We present a nanoparticle platform for HDACi delivery with a differentiated PK profile in the CSF compared to free drug. Additional PK and therapeutic studies are ongoing.
DDEL-14. SAFETY OF INTERVENTRICULAR METHOTREXATE ADMINISTRATION FOLLOWING RADIATION IN PEDIATRIC PATIENTS WITH MALIGNANT BRAIN TUMORS
Authors: Rosales Kristofer , Maher Ossama , Fader Maggie , Gallegos Natalie , Niazi Toba , Ragheb John , Khatib Ziad 
Published: December 2020

Abstract

BACKGROUND
Methotrexate has been used for intrathecal administration in leukemia as well as embryonal CNS tumors in children. Concerns about neurologic side effects including leukoencephalopathy, demyelination, and seizures have limited the use of methotrexate following exposure to focal radiation.

OBJECTIVE
To evaluate and determine safety of Intraventricular administration of Methotrexate in pediatric patients with recurrent malignant brain tumors along with systemic Topotecan and Cyclophosphamide after exposure to prior radiation therapy. DESIGN/METHOD: Patients with recurrent cerebellar embryonal tumors after standard treatment that included radiation were enrolled on this IRB approved phase 2 study. An Ommaya reservoir was inserted in the lateral ventricle and used to administer 4 daily doses of methotrexate (2 mg/dose) along with (Topotecan [0.75mg/m2/day] and Cyclophosphamide [250 mg/m2/day]). A neurological evaluation was performed at baseline and daily during the intraventricular administration of the Methotrexate, this evaluation was repeated prior to each subsequent cycle and at completion of the protocol.

RESULTS
Three patients (age range 3–20) received 2–3 cycles of intra-Ommaya Methotrexate and Topotecan/Cyclophosphamide. No MRI demyelination or white matter changes were seen after completion of the intraventricular Methotrexate therapy. None of the patients enrolled on this trial had adverse effects related to the therapy regimen received. Clinical neurological status was unchanged during the entire course of the treatment and upon completion of the scheduled therapy.

CONCLUSION
Intraventricular administration of daily low dose Methotrexate is well tolerated in children with recurrent embryonal CNS tumors who had prior exposure to radiation.
DIPG-02. USEFULNESS OF BEVACIZUMAB IN MAINTAINING QUALITY OF LIFE AT THE TIME OF DIFFUSE INTRINSIC PONTINE GLIOMA RELAPSE
Authors: Gomi Akira , Uchiyama Taku , Oguma Hirofumi , Yamaguchi Takashi , Kawai Kensuke 
Published: December 2020

Abstract

INTRODUCTION
Even in the age of molecular diagnosis, diffuse intrinsic pontine glioma (DIPG) is still a dismal disease. The usefulness of bevacizumab for DIPG relapse is reported.

SUBJECTS AND METHODS
The treatment and outcomes of 10 patients with DIPG who were treated at our institute since 2001 were retrospectively reviewed. All patients were diagnosed with DIPG by MRI imaging and underwent radiation therapy first. Three cases did not receive chemotherapy at the time of relapse (Untreated Group). In 7 cases, chemotherapy was performed at the time of relapse with ACNU/vincristine or interferon beta (Other Treatment Group), and 2 cases with bevacizumab (Bv Group). The change in the Karnofsky Performance Status Scale (KPS) from the time of relapse was compared.

RESULTS
The average overall survival (OS) for all 10 cases was 10.0 months. No prolongation of OS by bevacizumab was observed. However, it was only in the Bv Group that the KPS increased from the time of relapse. Comparison of the KPS at the time of relapse and the KPS after 4 months showed that the Bv Group remained unchanged or increased, while the Untreated Group and the Other Treatment Group decreased. In the Other Treatment Group, hospitalization was required for treatment, and side effects of bone marrow suppression were observed. However, in the Bv Group, outpatient treatment was possible, there were no side effects, and all could be observed at home.

CONCLUSION
From the above results, bevacizumab appears useful for palliative treatment for maintaining quality of life after DIPG relapse.
DIPG-03. THERAPEUTIC TARGETING OF TRANSCRIPTIONAL ELONGATION IN DIFFUSE INTRINSIC PONTINE GLIOMA
Authors: Katagi Hiroaki , Takata Nozomu , Aoi Yuki , Zhang Yongzhan , Rendleman Emily J , Blyth Gavin T , Eckerdt Frank D , Tomita Yusuke , Sasaki Takahiro , Saratsis Amanda M , Kondo Akihide , Goldman Stewart , Becher Oren J , Smith Edwin , Zou Lihua , Shilatifard Ali , Hashizume Rintaro 
Published: December 2020

Abstract
Diffuse intrinsic pontine glioma (DIPG) is highly aggressive brain stem tumor and needed to develop novel therapeutic agents for the treatment. The super elongation complex (SEC) is essential for transcription elongation through release of RNA polymerase II (Pol II). We found that AFF4, a scaffold protein of the SEC, is required for the growth of H3K27M-mutant DIPG cells. In addition, the small molecule SEC inhibitor, KL-1, increased promoter-proximal pausing of Pol II, and reduced transcription elongation, resulting in down-regulate cell cycle, transcription and DNA repair genes. KL-1 treatment decreased cell growth and increased apoptosis in H3K27M-mutant DIPG cells, and prolonged animal survival in our human H3K27M-mutant DIPG xenograft model. Our results demonstrate that the SEC disruption by KL-1 is a novel therapeutic strategy for H3K27M-mutant DIPG.
DIPG-04. THERAPEUTIC STRATEGY FOR DIFFUSE MIDLINE GLIOMAS. A SINGLE CENTER EXPERIENCE
Authors: Yamanaka Takumi , Takahashi Yoshinobu , Morisako Tamaki , Nagai Toshiki , Tanigawa Seisuke , Umebayashi Daisuke , Takeuchi Hayato , Tatsuzawa Kazunori , Miyachi Mitsuru , Yagyu Shigeki , Iehara Tomoko , Hosoi Hajime , Hashimoto Naoya 
Published: December 2020

Abstract

INTRODUCTION
Diffuse midline gliomas have unfavorable prognoses due to the difficulty of surgery and chemo-radiation resistances. The purpose of this study is to overview our surgical experiences and prognoses of this challenging neoplasm.

MATERIALS AND METHODS
Five patients of diffuse midline gliomas who were treated between 2016 and 2019 were enrolled. Tumor locations, surgical procedures, molecular diagnoses, and prognoses were retrospectively reviewed.

RESULTS
There were 3 male and 2 female patients, and the median age was 15 years ranged from 7 to 21 years. Tumors were located at the basal ganglia in 1 patient, thalamus in 1, brain stem in 2, and cervical spine in 1. Mutations of H3 K27M genes were detected in 4 surgically treated patients, except for 1 patient, who were radiologically diagnosed as diffuse intrinsic pontine glioma (DIPG). Focal irradiation of ranged 35 to 54Gy were administered in all cases along with temozolomide in 2 cases and bevacizumab in 2 cases. The median survival time was 13 months ranged from 4 to 18 months.

DISCUSSION
Supratentorial tumors were maximumly resected, whereas just biopsies were performed in cases of exophytic brain stem and spinal tumors. Diagnosis of DIPG was made without using surgical specimens. Therapeutic strategies should be discussed with a concern to the patients’ qualities of life for this tumor entity with dismal prognosis.
DIPG-05. HISTONE H3.3 K27M IMPAIRS SER31 PHOSPHORYLATION, RESULTING IN CHROMOSOMAL INSTABILITY, LOSS OF CELL CYCLE CHECKPOINT CONTROL, AND TUMOR FORMATION
Authors: Day Charles , Langfald Alyssa , Grigore Florina , Fadness Sela , Sepaniac Leslie , Stumpff Jason , Vaughan Kevin , Robinson James , Hinchcliffe Edward 
Published: December 2020

Abstract
Diffuse midline gliomas with the H3.3 K27M mutation are lethal brain tumors in children. H3 K27M causes global loss of Lys27 triple methylation (Lys27me3), inducing epigenetic reprograming. Here we show that H3.3 K27M also causes decreased H3.3 Ser31 phosphorylation on mitotic chromosomes. We show that H3.3 K27M DIPG cells have reduced pericentromeric phospho-Ser31 and increased rates of chromosome missegregation compared to normal, diploid human cells. CRISPR-editing K27M to M27K restored phospho-Ser31 to WT levels and dramatically decreased the rate of chromosome missegregation. We confirm that Chk1 is the H3.3 Ser31 kinase: K27M mutant H3.3 protein exhibits ~60% reduced Chk1 phosphorylation of Ser31 in vitro. Chk1 knockdown completely abolishes phospho-Ser31 in cells and these have increased rates of chromosome missegregation. In normal, diploid cells, expression of K27M or an S31A non-phosphorylatable mutant increased chromosome missegregation; this is suppressed by expressing a phosphomimetic double mutant (K27M/S31E) that restores phospho-Ser31. WT cells arrest following chromosome missegregation. However, cells expressing H3.3 K27M or S31A fail to arrest - despite having WT p53. Finally, we expressed H3F3AS31A and PDGFb in an RCAS/TVA mouse model of DIPG and ~80% developed diffuse high-grade brain tumors and show significantly decreased survival. Our results suggest that loss of phospho-Ser31 alone is oncogenic because H3.3 S31A-expressing cells are WT for K27me3. Our results demonstrate that H3.3 K27M inhibits Ser31 phosphorylation both in vitro and in vivo, leading to both chromosome missegregation and loss of subsequent G1 arrest – thus creating diffuse midline gliomas with both dynamic, complex karyotypes and epigenetic reprogramming.
DIPG-08. ELECTRONIC SEQUENCING PROVIDES OPTIMIZED QUANTIFICATION OF SERIAL, MULTI-GENE MOLECULAR RESPONSE IN THE CSF OF CHILDREN WITH HIGH-GRADE GLIOMA
Authors: Bruzek Amy , Muruganand Ashwath , Ravi Karthik , Wadden Jack , Babila Clarissa , Tunkle Leo , Wierzbicki Kyle , Stallard Stefanie , Cantor Evan , Qin Tingting , Wolfe Ian , Mody Rajen , Muraszko Karin , Franson Andrea , Robertson Patrica , Maher Cormac , Garton Hugh , Koschmann Carl 
Published: December 2020

Abstract

BACKGROUND
For pediatric high-grade glioma (pHGG), non-invasive methods for diagnosis and surveillance are needed. Tumors release DNA (tDNA) into cerebrospinal fluid (CSF), allowing for detection of tumor-associated mutations by CSF sampling. We hypothesized that direct, electronic analysis of tDNA with a novel, hand-held platform (Oxford Nanopore MinION) could quantify patient-specific CSF tDNA variant allele fraction (VAF) with improved speed and limit of detection compared to established methods.

METHODS
We integrated required multi-timepoint (0, 2, and 6 months) correlate lumbar punctures (LP) in two ongoing pHGG clinical trials. Using Nanopore technology, we performed amplicon-based PCR on CSF tDNA for recurrent mutations from patient samples (n=19) and normal controls. VAF were determined via MinKNOW, Guppy, MiniMap2, and Integrated Genome Browser.

RESULTS
Nanopore CSF tDNA demonstrated improved sensitivity (91%) when compare to NGS sequencing (50%). Nanopore analysis of serially diluted CSF sample demonstrated significantly lower limit of detection (attomolar) than typical NGS sample requirement (nanomolar). H3K27M mutation was reliably detected with 1,000x depth sequencing, which was achieved in less than 15 minutes of sequencing after amplification. Multiplexed Nanopore analysis of H3F3A and HIST1H3B was employed when H3 status was unknown. Serial CSF tDNA analysis confirmed multi-gene (H3F3A K27M, PIK3CA, and TP53) molecular remission in a 17-year-old with thalamic diffuse midline glioma that correlated with sustained clinical response to ONC201 (14 months and ongoing).

CONCLUSIONS
Use of a hand-held, electronic DNA analysis platform allows quantification of multi-gene molecular response with improved speed and limit of detection in the CSF of children with high-grade glioma.
DIPG-11. A PHASE I DOSE ESCALATION STUDY OF BXQ-350 IN CHILDREN AND YOUNG ADULTS WITH RELAPSED SOLID TUMORS
Authors: Setty Bhuvana , Cripe Timothy , Schottmiller Mariko DeWire- , Curry Richard , AdelBaki Mohamed 
Published: December 2020

Abstract
BXQ-350 is a novel agent composed of the multifunctional, lysosomal activator protein Saposin C (SapC) and dioleoyl- phosphatidylserine (DOPS). BXQ-350 demonstrated antitumor effects in vitro and in vivo. Many tumors, including diffuse intrinsic pontine glioma (DIPG), and cells of tumor vasculature have aberrantly-exposed PS-rich domains on the cell surface. BXQ-350 is an anti-tumor agent in development from Bexion Pharmaceuticals, Inc. that selectively targets tumor cell PS, particularly those translocated to the outer leaflet of the plasma membrane in tumor cells. BXQ-350 activates and participates in various cellular processes, including apoptosis and necrosis, and may also exhibit novel mechanisms leading to cell death that require further investigation. An adult Phase I trial with BXQ-350 completed enrollment in 2019 having dosed 86 recurrent solid tumor patients, including glioblastoma, with only one serious infusion-related reaction. The highest planned dose of 2.4 mg/kg was achieved and seven patients remain on study with multiple cases demonstrating an objective response. A Phase I pediatric dose escalation trial in recurrent solid tumors, including central nervous system (CNS) tumors, also completed enrollment in 2019. The highest planned dose of 3.2 mg/kg was achieved and there have been no BXQ-350 related serious adverse events. Eight patients (7 CNS and 1 non-CNS) completed at least one cycle with one DIPG patient completing cycle five. A pediatric Phase I trial in newly diagnosed DIPG and diffuse midline glioma (DMG) is planned for 2nd quarter 2020.
DIPG-12. TARGETING EPIGENETIC MODIFIERS TO INDUCE IMMUNE SIGNALING IN DIPG
Authors: Tetens Ashley , Martin Allison , Arnold Antje , Novak Orlandi , Eberhart Charles , Feinberg Andrew , Raabe Eric , Koldobskiy Michael 
Published: December 2020

Abstract
DIPG is a universally fatal pediatric brainstem tumor with no effective therapy. Recent work has shown that over 80% of DIPG cases harbor the H3K27M mutation leading to global loss of the repressive H3K27 trimethylation mark, global DNA hypomethylation, and a distinct gene expression signature. We sought to exploit epigenetic vulnerabilities in DIPG through the use of DNA methyltransferase inhibitors and histone deacetylase (HDAC) inhibitors. We find that treatment with low-dose 5-aza-2’-deoxycytidine (decitabine), alone and in combination with HDAC inhibitors, elicits profound genome-wide demethylation in DIPG patient-derived neurosphere cell lines, impairs proliferation, and induces apoptosis. We show that this treatment induces immune activation, with induction of type I interferon signaling, increased expression of major histocompatibility complexes, and expression of tumor antigens. These results suggest that the immunogenicity of DIPG may be modulated by epigenetic therapies, suggesting the possibility of novel combination approaches to immunotherapy of DIPG in the future.
DIPG-13. TARGETING HYPOXIA AND MITOCHONDRIA WITH REPURPOSED METABOLIC DRUGS AS AN APPROACH TO RADIOSENSITIZATION FOR DIFFUSE INTRINSIC PONTINE GLIOMAS (DIPG)
Authors: Shen Han , Chang Cecilia , Gee Harriet , McKelvey Kelly , O’Neill Geraldine , Prior Victoria , Blackburn Anneke , Hau Eric 
Published: December 2020

Abstract
DIPG is the leading cause of brain tumor-related death in children. Currently, radiation is the only treatment that offers transient benefit. Compared to normal brain tissue, DIPGs are hypoperfused with tumors being exposed to hypoxia, a potent barrier to effective radiotherapy. Biguanides are hypoglycemic agents that can reduce the oxygen consumption rate (OCR) in mitochondria, thereby reducing hypoxia. Our previous study has shown that metformin significantly improves the radiosensitivity of DIPG and extends survival in a patient-derived xenograft (PDX) model. In the present study, phenformin, a second biguanide derivative, demonstrated even greater anti-DIPG activity and radiosensitising effect in vitro. As a single agent, phenformin dose-dependently inhibited OCR and increased extracellular acidification rate (ECAR). Low-dose phenformin reduced mitoATP/glycoATP ratio, whereas high doses significantly suppressed net ATP production. To attenuate the phenformin-induced ECAR, phenformin was combined with dichloroacetate (DCA), a clinically relevant pyruvate dehydrogenase kinase inhibitor that can suppress the elevated glycolytic rate of cancers. This combination significantly blocked the phenformin-induced ECAR and killed DIPG cells synergistically by inducing apoptosis, DNA damage and metabolic catastrophe. Moreover, protein expression of HIF-1α and c-Myc, two master regulators that collaboratively enhance the metabolic capacity of tumor cells through increased glycolysis thereby contributing to radioresistance, were also suppressed by phenformin-DCA treatment in vitro. This combination therapy upregulated genes inhibiting cell proliferation while downregulating genes for DNA repair. The triple combination of phenformin, DCA and irradiation demonstrated the most potent efficacy in vitro and is currently being tested in our PDX cohort in vivo.