bluuebunny/crossref_metadata_2025_split huggingface dataset:
DIPG-36. DRD2 ANTAGONISM RESCUES IMMUNE-TUMOR SURVEILLANCE, WARMING THE TUMOR IMMUNE MICROENVIRONMENT OF DIFFUSE MIDLINE GLIOMA MODELS
Authors: Persson Mika L , Jackson Evangeline R , Duchatel Ryan J , de la Nava Daniel , Thomas Bryce C , Savary Clara , McEwen Holly P , Beitaki Tyrone S , Kearney Padraic S , Findlay Izac J , Douglas Alicia M , Larsen Martin R , Faridi Pouya , Holst Jeff , Mayall Jemma , Hondermarck Hubert , Horvat Jay , Nixon Brett , Cartaxo Rodrigo T , Nazarian Javad , Hulleman Esther , Mueller Sabine , Vitanza Nicholas A , Koshmann Carl , Alonso Marta M , Carvalheiro Tiago , van der Lugt Jasper , Dun Matthew D 
Published: June 2024

Abstract

BACKGROUND
Less than 10% of patients with diffuse midline glioma (DMG) survive 2-years post-diagnosis, with no approved treatments other than palliative radiotherapy. Immune-checkpoint inhibition has failed in the clinic, likely due to a lack of tumor infiltrating lymphocytes (TILs) and limited/no expression of immune checkpoint proteins or proinflammatory cytokines in the tumor immune microenvironment (TIME). Similarly, glioblastoma patients suffer from a ‘cold’ TIME, linked to the sequestration of T cells in the bone marrow (BM) through β-arrestin-induced internalization of S1PR1. β-arrestin is activated by Dopamine receptors (DRD2); therefore, we hypothesized that systemic DRD2 antagonism using the antagonist ONC201, might reverse lymphopenia, increasing TIL populations.

METHODS
Flow cytometry analysis was performed on bloods from DMG patients at diagnosis. Circulating immune cells and BM from the immunocompetent PPK model +/-ONC201 and tumor-naïve mice were analyzed by a hematology analyzer and flow cytometry. Immunocompromised SU-DIPG-VI and HSJD-DIPG-007 and immunocompetent XFM murine models were treated +/-ONC201 and tumors analyzed by immunoblotting, immunohistochemistry, and flow cytometry. scRNAseq and scATACseq analysis was performed on tumors from immunocompetent PPK models +/-ONC201.

RESULTS
DMG patients displayed low levels of total lymphocytes, including CD4+, CD8+ and NK subsets (n=9). Similarly, DMG-bearing mice displayed lower levels of lymphocytes (CD45+, CD4+, CD8+ subsets, n=3) compared to sham-engrafted mice. ONC201 treated mice showed lymphocyte levels comparative to sham-engrafted mice, reversing tumor-induced lymphopenia. A significant increase of T cells expressing S1PR1+ was seen in the BM following ONC201. Tumor immune cell infiltration following ONC201 was confirmed in both immunocompromised and immunocompetent models. Multiomics analysis identified ONC201 to promote pro-inflammatory polarization of microglia/macrophages (MHC II and CD86) and increase expression of immune checkpoints (VISTA and PD-L1).

CONCLUSIONS
DMG patients suffer from low peripheral lymphocytes, likely contributing to cold TIME. ONC201 reversed tumor-induced lymphopenia, promoting TIL recruitment within the tumor, warming the TIME.
DIPG-41. CONVECTION ENHANCED DELIVERY-MEDIATED RADIOSENSITIZATION FOR DIFFUSE MIDLINE GLIOMA
Authors: Gallitto Matthew , De Santos Genesis Los , Wei Hong-Jian , Zhang Xu , Zhang Zhiguo , Wu Cheng-Chia 
Published: June 2024

Abstract

BACKGROUND
Diffuse midline glioma (DMG) is the most aggressive primary brain tumor in children. The only approved standard of care is radiation therapy (RT). Studies examining the role of other systemic agents have failed to demonstrate a survival benefit, partially due to tumor extension to areas of the brain where the blood-brain barrier (BBB) remains intact. As our laboratory has recently determined active NAD(P)H Quinone Dehydrogenase 1 (NQO1) expression in patient-derived DMG tumor samples, we sought to investigate NQO1 bioactivatable agent Napabucasin to augment reactive oxygen species (ROS) production and overcome radioresistance in DMG. Furthermore, we explore the safety and feasibility of convection-enhanced deliver (CED) to overcome limitations of the BBB.

METHODS
Using two DMG cell lines, we performed clonogenic survival assays with increasing doses of RT with and without Napabucasin. We then created subcutaneous xenograft mouse models, treating with (1) vehicle control, (2) Napabucasin, (3) 2 Gy of RT daily, or (4) combination treatment with RT and Napabucasin. Using a syngeneic orthotopic DMG mouse model, we implanted 7-day osmotic infusion pumps containing either vehicle control or 80uM Napabucasin. Mice then underwent a second randomization with or without daily RT for 5 days.

RESULTS
We identified a robust radiosensitizing effect with Napabucasin using in vitro clonogenic survival assays. In subcutaneous flank models, combination treatment led to a statistically significant smaller tumor volume post-treatment completion when compared to any monotherapy. In our syngeneic orthotopic DMG mouse model, RT after CED pump implantation in the brainstem did not lead to significant morbidity or mortality. Combination RT and CED of Napabucasin led to a significant survival benefit when compared to monotherapy.

CONCLUSIONS
In this study, we show Napabucasin as a promising radiosensitizer in DMG. Furthermore, this is the first preclinical study showing safety/efficacy of CED with concurrent RT in DMG.
DIPG-51. DIFFUSE MIDLINE GLIOMAS HIJACK MYELOID CELL POPULATIONS TO INITIATE AN ANTI-INFLAMMATORY TUMOR IMMUNE MICROENVIRONMENT
Authors: Metselaar Dennis Serge , du Chatinier Aimée , Verbaan Annemieke , Gamas-Vis Susanne , Waranecki Piotr , Ruiz-Moreno Cristian , Kranendonk Mariette , Stunnenberg Hendrik , Phoenix Timothy , Hoving Eelco Wieger , Kool Marcel , Meel Michael Hananja , Hulleman Esther 
Published: June 2024

Abstract

BACKGROUND
Diffuse midline gliomas (DMG) are universally fatal pediatric brain tumors, for which no effective treatment exists. These tumors are known for their “cold” non-inflammatory tumor-immune microenvironment (TIME), which is thought to be a major hurdle for immunotherapy efficacy.

METHODS/RESULTS
To further investigate the mechanisms that drive this cold environment, we allografted immunocompetent mice with Histone 3.3 Lysine 27 (H3.3K27M) and 3.1 Lysine 27 (H3.1K27M) mutant murine DMG tumors, created through intra uterine electroporation, and performed single-cell analyses on the tumors that developed. Using Cellular Indexing of Transcriptomes and Epitopes by Sequencing (CITEseq) we mapped the single-cell RNA and protein expression profiles of the TIME of these tumors and healthy pontine regions, with a dominant focus on the myeloid cell populations. Through differential expression and pathway enrichment analyses, we found that DMG-microglia populations upregulate anti-inflammatory pathways and, over time, are pushed out by infiltrating anti-inflammatory macrophages. We confirmed these findings in single-cell sequencing data from DMG patients, taken at diagnosis and at late stage disease. Next, we established microglia cultures in vitro, by differentiating monocytes from healthy donors into microglia. We discovered that treatment of these microglia with tumor-conditioned medium, taken from primary DMG cultures, diminished their pro-inflammatory potential after stimulation with lipopolysaccharides (LPS), as observed by cytokine release arrays that showed a strong downregulation of IL-6 and TNF-alpha release, amongst others. Subsequently, using a Seahorse metabolic analyzer, we found that glycoATP potential was diminished in DMG-primed microglia after LPS stimulation, further suggesting that DMG-excreted factors are responsible for blocking the pro-inflammatory potential of microglia.

CONCLUSIONS
Taken together, these findings increase our understanding on how DMG cells reprogram tumor-associated myeloid cells to generate an immune-cold TIME, which will aid the scientific community to find therapeutic solutions to reverse this phenomenon and improve the efficacy of immunotherapy in these devastating malignancies.
DIPG-59. RADIATION-INDUCED DIPG IN A CHILD PREVIOUSLY IRRADIATED FOR CRANIOPHARYNGIOMA: CASE REPORT AND LITERATURE REVIEW
Authors: Ain Rahat Ul , Rehman Laeeq Ur , Qaiser Rabia Aqeel , Goraya Amber , Salman Zeena , Qaddoumi Ibrahim , Mushtaq Naureen , Bouffet Eric 
Published: June 2024

Abstract

BACKGROUND
Radiation-induced second malignancies occur in a subset of patients following cranial radiation therapy (RT). In Craniopharyngioma (CP), adjuvant RT is commonly recommended for residual tumor or recurrence, and radiation-induced malignant gliomas (RIMGs) are rarely reported.

METHODS
We report a case of radiation-induced diffuse intrinsic pontine glioma (DIPG) in pediatric Craniopharyngioma and conducted a review of previously reported cases.

RESULTS
A 14-year-old boy presented with complaints of headaches and vomiting for 1 month; difficulty in walking, and slurred speech for 1 week, with Lansky Performance Score (LPS) of 20. Eight years before this admission, he underwent surgical excision and 3D-conformal RT for Craniopharyngioma. His recent MRI brain was suggestive of DIPG and after a multidisciplinary discussion re-irradiation (30Gy in 10 fractions) was given. He has been alive for 5 months since diagnosis with improved symptoms and LPS (70). Including the index case, 19 cases of RIMGs in CP were identified. All except one were reported from high-income countries. Only 4 involved the pons/brainstem. The median age at CP diagnosis was 7.0 years (2.0-22.0 years), and with RIMG was 18 (6.8-41.0 years). Median latency period was 10.0 years (4.5-25.0 years). The female-to-male ratio was 1.8:1. The median previous RT dose was 54.8 Gy (49.3-60.1 Gy) with 37% cases treated with 3D conformal and 37% with conventional RT (not specified in 26%). Cerebral cortex (66.6%) was the most common site for the RIMG with temporal lobe predisposition. Chemotherapy was given in 56%, surgical excision in 50% and repeat RT in 31% cases with a median survival of 4 months (0-13 months).

CONCLUSION
We report the first case of radiation-induced DIPG in pediatric Craniopharyngioma in an LMIC. RIMG appears to be a rare occurrence in CP and doesn’t seem to be associated with the RT type. The overall prognosis is extremely poor.
DIPG-73. FOCUSED ULTRASOUND FOR TREATMENT OF CHILDREN DIAGNOSED WITH DIFFUSE MIDLINE GLIOMAS
Authors: Woldegerima Ayda , Wei Hong-Jian , Zhang Chunchao , Yadavillli Sridevi , Packer Roger , Wu Cheng-Chia , Nazarian Javad 
Published: June 2024

Abstract

BACKGROUND
Diffuse midline glioma (DMG) is a highly aggressive and fatal brain tumor that predominantly impacts children and young adults. The infiltrative pattern and rapid growth characteristics of DMG causes a significant challenge in finding an effective treatment. Additionally, the blood-brain barrier (BBB) poses a significant challenge by restricting the passage of therapeutic drugs to tumor bed. Currently the established standard of care is radiotherapy (RT), which is transitory. Thus there is a need for improved treatment options.

OBJECTIVE
Focused ultrasound (FUS) is an advancing non-invasive technology that has been used to open BBB and enhance drug delivery. We hypothesize that a combination therapy of FUS with pharmacological agents will be an effective and non-invasive treatment option for children diagnosed with DMG.

METHOD
Syngeneic DMG murine models were used to study the combination therapy of FUS with ONC201, FUS with anti-PD1 and FUS with RT. FUS mediated BBB opening was monitored with contrast-enhanced T1-weighted MRI. FUS-mediated drug delivery was validated with western blot, assessment of ROS, and optical label imaging. Kaplan Meier analysis was used to assess survival benefits. Single cell RNA-sequencing (scRNA-Seq) analysis is being done to assess the treatment effects of FUS and RT combination therapy.

RESULTS/CONCLUSION
We found that FUS and ONC201 combination therapy resulted in a decrease in NDUFA12 protein (a biomarker of ONC201 response) and an increase in ROS production compared to ONC201 monotherapy. For FUS and anti-PD1 combination therapy, an increased anti-PD1 delivery to the brainstem was detected. The overall survival of mice treated with FUS and anti-PD1 combination therapy increased when compared to anti-PD1 alone. Our preliminary scRNA-Seq analysis showed that combination therapy of FUS and RT induces innate immune response compared to the untreated group. Combination therapy with focused ultrasound shows a promising outcome by increasing the efficacy of therapeutic drugs and immunotherapy.
DIPG-80. IMAGING CHARACTERISTICS IN PEDIATRIC PATIENTS WITH DIFFUSE INTRINSIC PONTINE GLIOMA AND OUTCOME: THE MD ANDERSON CANCER CENTER EXPERIENCE
Authors: Stitzlein Lea M , Baig Muhammad , He Jiasen , Paulino Arnold , Yeboa Debra N , Calle Susana , Majd Nazanin , McGovern Susan , Zaky Wafik 
Published: June 2024

Abstract

BACKGROUND
Diffuse intrinsic pontine glioma (DIPG) occurs exclusively in children and, although rare, carries a poor prognosis with a median survival of approximately 10 months. Diagnosis is made on clinical and radiological appearance of the tumor. The treatment for DIPG is radiation therapy, but it is inadequate as most patients experience rapid progression and succumb to the disease. Our study sought to review radiological characteristics and survival outcomes in pediatric DIPG patients at MD Anderson Cancer Center to better understand imaging and improve current DIPG management.

METHODS
We performed a retrospective review of demographic and clinical data of patients with radiographic diagnosis of DIPG from 2006-2019, with IRB approval. The patients included in this study were treated at The University of Texas MD Anderson Cancer Center. Imaging findings upon diagnosis of DIPG, including the presence of hydrocephalus, intratumoral bleeding, contrast enhancement, and necrosis, were correlated with survival using Kaplan-Meier methods

RESULTS
This study included 25 patients diagnosed with DIPG via MRI imaging. The median OS was 13.7 months and median PFS was 10 months for this cohort. At diagnosis, if the patient had hydrocephalus or intratumoral bleeding, the median PFS were shorter compared with those who did not (8.5 and 5.4 months vs 12.2 and 10.8 months; Log-rank, P=0.019 and P=0.029, respectively). Other imaging findings, including contrast enhancement (CE) or presence of necrosis, are trending toward worse outcomes (CE vs no CE: PFS 7.9 vs 11.1 months, P=0.10; necrosis vs no necrosis: PFS 5.2 vs 10.5 months, P=0.78, respectively)

CONCLUSION
Imaging characteristics at diagnosis can be predictive of outcome. Hence, we propose to consider early interventions for these subgroups with worse outcomes to proceed with shunt placement and early enrollment for clinical trials as feasible. To further validate these findings, a large prospective study is required.
DIPG-91. CLINICAL, RADIOGRAPHIC, HISTOPATHOLOGIC, AND MOLECULAR CHARACTERISTICS OF LONG-TERM SURVIVORS OF DIFFUSE INTRINSIC PONTINE GLIOMA-AN UPDATE FROM THE INTERNATIONAL AND EUROPEAN SOCIETY FOR PEDIATRIC ONCOLOGY DIPG REGISTRIES (IDIPGR/SIOPE-DIPGR)
Authors: Pillay-Smiley Natasha , Nussbaumer Gunther , Damen-Corbijn Carin , Baugh Joshua , Webster Aaron , Lane Adam , Godschalk T C , Grill Jacques , Hawkins Cynthia , Leach James , Janssens Geert , Jones Blaise , Massimino Maura , Karremann Michael , van Vuurden Dannis G , Bailey Simon , Das Anirban , Thomale Ulrich-Wilhelm , Goldman Stewart , Perreault Sebastien , Biassoni Veronica , Minturn Jane , Hummel Trent , Kramm Christof , van Zanten Sophie Veldhuijzen , Hoffman Lindsey M 
Published: June 2024

Abstract

BACKGROUND
Diffuse intrinsic pontine glioma (DIPG) is a childhood tumor with median survival of &lt; 1 year. Survival-associated factors for this rare disease are poorly understood.

METHODS
Clinical, radiological, and histo-molecular data were abstracted from databases of the IDIPGR and SIOPE-DIPGR and analyzed using descriptive statistics. Survival was estimated by the Kaplan Meier method. Short term survivors (STS) were defined as overall survival (OS) &lt; 2 years, and long term survivors (LTS) had OS &gt;2 years. We present data from the IDIPGR with additional analyses forthcoming.

RESULTS
Analysis included 1123 patients with DIPG, with 476 undergoing central radiographic review. Median OS for the entire cohort was 11 months (IQR 7-15 months), with 2 yr OS 6.9% (5.6% to 8.6%). Median age at diagnosis was 6.6 years (5-9.7 years) for 1045 STS (93.1%) and 6.8 years (3.7-13 years) for 78 LTS (6.9%). Factors significantly associated with LTS included longer symptom duration (STS 73.7% vs LTS 42%; p&lt;0.001), age &lt; 3 and &gt; 10 years (STS 4.5 and 22.8% vs LTS 17.9 and 35.9%; p&lt;0.0001), and receipt of chemotherapy at any time during therapy (STS 54.7% vs LTS 67.9%; p=0.025). A similar percentage of STS and LTS received EGFR, MTOR, PI3K, HDAC, local delivery and immunotherapy, although more LTS used VEGF inhibition (20.5 % vs 8.6%; p = 0.002). Of 104 patients with molecular data, 69 harbored the H3.3 histone mutations (7 LTS, 62 STS), and 15 had H3.1(3 LTS, 12 STS).

CONCLUSION
Early analysis of factors associated with survival in patients with DIPG reveal similar findings as the prior IDIPGR/SIOPE-DIPGR study in 2018. These findings will be updated for the final presentation to include ~400 more cases and additional radiological and molecular data.
TRLS-11. PNOC005: ONCOLYTIC MEASLES VIRUS FOR THE TREATMENT OF CHILDREN AND YOUNG ADULTS WITH RECURRENT MEDULLOBLASTOMA OR ATYPICAL TERATOID RHABDOID TUMOR
Authors: Kline Cassie , Yu Bohyeon , Knowles Truman , Ranavaya Aeesha , Minturn Jane , Banerjee Anuradha , Leary Sarah , Abdelbaki Mohamed , Whipple Nicholas , Goldman Stewart , Margol Ashley , Dabobo Nour , Rauschecker Andreas , George Elizabeth , Nabavizadeh Ali , Hoare Owen , Jung Jangham , Phillips Joanna , Prados Michael , Molinaro Annette , Gupta Nalin , Raffel Corey , Cole Kristina , Diaz Aaron , Mueller Sabine 
Published: June 2024

Abstract

BACKGROUND
PNOC005 is a phase 1 clinical trial investigating the safety and tolerability of intratumoral or intrathecal administration of oncolytic measles virus (MV-NIS) in children and young adults with recurrent medulloblastoma (MB) or atypical teratoid/rhabdoid tumor (ATRT).

METHODS
Patients with recurrence of MB or ATRT were stratified into Stratum A (local recurrence) or B (disseminated recurrence). Stratum A patients received MV-NIS directly into the tumor bed at time of surgical resection. Stratum B patients received a single dose of MV-NIS via lumbar puncture. After safety was demonstrated in Stratum A and B, Stratum C was added with repeat dosing on Day 0 and 7 for patients with recurrent disseminated MB. Specimens for viral shedding were collected. Blood was collected on days 0, 4, 7, 14, and 28. RNA-sequencing deconvolution and time-series analysis were performed to estimate the composition and phenotypes of peripheral blood mononuclear cells (PBMCs).

RESULTS
Thirty-four patients (median age 8.5, range 2-31) enrolled between February 2017 and April 2021, with 23 evaluable patients with MB and 4 with ATRT. One patient experienced a dose-limiting toxicity (grade 3 alanine aminotransferase increase). There were four MV-NIS-related adverse events grade 3 or greater across all strata. Viral shedding was detected in 5 patients, all of which cleared by end-of-treatment. We found a similar gene-expression program in PMBCs that correlated across patients (n=18), which was upregulated at days 4-7 post treatment and consistent with an antiviral response. Concomitant changes in B, T, and natural-killer cell composition and activation were consistent with this interpretation.

CONCLUSION
This is the first trial investigating intratumoral as well as repeated intrathecal delivery of MV-NIS in children with MB and ATRT. We show that therapy is safe and well-tolerated with minimal adverse effects. Immune markers and biologic correlates preliminarily indicate anti-viral effects in tumors.
ETMR-01. BRAIN STEM TUMORS IN CHILDREN LESS THAN THREE MONTHS: CLINICAL AND RADIOLOGIC FINDINGS OF A RARE DISEASE
Authors: Papangelopoulou Danai , Bison Brigitte , Behrens Lars , Bailey Simon , Ansari Marc , Ehlert Karoline , Martinez Ofelia Cruz , Kramm Christof M , La Madrid Andres Morales , von Bueren Andre O 
Published: June 2024

Abstract

BACKGROUND
Brainstem gliomas account for 10-20% of all central nervous system pediatric neoplasms. Brain stem tumors in children less than three months old at diagnosis are extremely rare. Our aim is to study a retrospective cohort to improve the understanding of the disease course and guide patient management.

METHODS
This is a multicenter retrospective analysis across the European Society for Pediatric Oncology SIOP-E HGG/DIPG Working Group linked centers and included patients with a brainstem tumor diagnosed between 2009 and 2020 and aged less than 3 months at diagnosis. Clinical data was collected, and imaging characteristics were analyzed blindly and independently by two experienced neuroradiologists.

RESULTS
Five cases (female; n=4) were identified of which no patient received any therapy. The epicenter of 2 tumors was in the medulla oblongata alone and in the medulla oblongata and the pons in 3 cases. For patients with tumor in equal parts in the medulla oblongata and the pons (n=3) the extension at diagnosis involved the spinal cord; for the 2 patients with the tumor epicenter in the medulla oblongata alone (n=2) the extension at diagnosis included the pons (n=2) and the spinal cord (n=1). Biopsy was performed in one patient identifying a pilocytic astrocytoma. Two patients died rapidly. In one patient autopsy revealed a high-grade glioma (case 3). Three survivors showed either spontaneous tumor regression (n=2) or stable disease (n=1). The surviving patients were followed-up for 10, 7, and 0.6 years, respectively. One case had the typical imaging characteristics of a dorsal exophytic low-grade glioma.

CONCLUSIONS
No patient fulfilled the radiologic criteria defining a high-grade glioma. Central neuroradiological review and biopsy (if feasible) may provide useful information with regards to the patient’s management.