bluuebunny/crossref_metadata_2025_split huggingface dataset:
DIPG-03. VENTRICULAR CEREBROSPINAL FLUID SAMPLING IN PEDIATRIC DIFFUSE MIDLINE GLIOMA PATIENTS: INSTITUTIONAL EXPERIENCE AND REVIEW OF THE LITERATURE
Authors: Li Daphne , Stellpflug Wendy , Romanski Kathy , Speck Stacy , Saratsis Amanda 
Published: June 2024

Abstract

BACKGROUND
Increasing evidence suggests that circulating biomarkers may serve diagnostic and longitudinal monitoring purposes in pediatric neuro-oncology. Mutant tumor DNA is detectable in the cerebrospinal fluid (CSF) of pediatric diffuse midline glioma (DMG) patients and quantity can reflect disease burden. CSF sampling (“liquid biopsy”) via a CSF access device could therefore play a role in DMG management. Therefore, we set to evaluate the incidence of hydrocephalus (HCP) in DMG patients, and to characterize ventricular reservoir placement and access practices.

METHODS
A single institution retrospective review of DMG patients &lt;21-years-old was performed (1984-2019). MEDLINE searches for reports of ventricular reservoir or shunt placement in DMG, and reservoir access for intraventricular chemotherapy (IVC) were performed.

RESULTS
At our institution, 62.6% of DMG patients (67/108) required intervention for HCP: 19.4% provided transient CSF access (ETV alone n=3, EVD n=8, unspecified n=2), and 80.6% permanent CSF access (ETV + reservoir n=13, shunt n=41). Further, 22/34 patients with initially transient CSF devices required conversion to a permanent device. Five devices were revised for malfunction, one for infection. Seventeen articles cited HCP in 22% to 100% of DMG patients. IVC administration was described in 632 patients (seven articles), with 42 infectious and 63 non-infectious complications.

CONCLUSIONS
Management of HCP is often necessary in children with DMG. Given the low rate of clinical risk associated with VAD placement and access, and the potential utility of longitudinal disease monitoring via CSF analysis, VAD placement could be considered in future clinical trials to guide DMG treatment.
DIPG-09. PROGNOSTIC FACTORS IN REIRRADIATED DIFFUSE INTRINSIC PONTINE GLIOMA: CLINICAL AND RADIOMIC ANALYSIS
Authors: Wawrzuta Dominik , Chojnacka Marzanna , Drogosiewicz Monika , Pędziwiatr Katarzyna , Dembowska-Bagińska Bożenna 
Published: June 2024

Abstract

BACKGROUND
Diffuse Intrinsic Pontine Glioma (DIPG) is a lethal pediatric brain tumor. Radiation therapy (RT) is the standard treatment, with reirradiation considered at progression. However, the prognostic factors for reirradiation remain unclear. This study aims to investigate the outcomes of patients with DIPG undergoing reirradiation and to identify radiomic prognostic factors.

METHODS
We analyzed patients with histopathologically proven DIPG who underwent reirradiation at our institution. We delineated pre-reirradiation tumors using 3D Slicer software and extracted radiomic features from FLAIR MRI sequences using the Python package PyRadiomics. Finally, we used the least absolute shrinkage and selection operator (Lasso) for Cox’s proportional hazard model with leave-one-out cross-validation to select optimal prognostic factors for survival after reirradiation. We have also compared the reirradiated group with our cohort of 22 non-reirradiated DIPG patients eligible for reirradiation but whose parents chose only supportive care at progression.

RESULTS
The study included 15 patients who received reirradiation at the first progression, with a total dose of 20 Gy or 24 Gy in 2 Gy fractions. Reirradiation was well tolerated, without grade &gt;2 toxicity. Neurological improvement was observed in 80% of patients. Median survival from the end of the first RT was significantly (p = 0.01) longer in the reirradiated group (68 weeks) compared to the non-reirradiated group (25 weeks). The Cox model demonstrated a concordance of 0.88 (95% CI: 0.83–0.92), revealing that tumor sphericity and structural gray-level heterogeneity in FLAIR MRI images were associated with more prolonged survival in reirradiated patients.

CONCLUSIONS
Reirradiation is a safe and effective approach for patients with DIPG. MRI-based radiomic models could help predict survival after treatment. Our results revealed that tumors with low sphericity and high homogeneity of gray levels are associated with a worse prognosis after reirradiation.
DIPG-11. PRECLINICAL EFFICACY OF B7-H3 CAR T CELLS IN COMBINATION WITH ONC206
Authors: Timpanaro Andrea , Song Edward , Biery Matthew C , Lau Davina , Meechan Michael , Elena-Sanchez Leonel , Vo Linh Thuy , Gustafson Joshua , Koschmann Carl , Dun Matthew D , Foster Jessica B , Jensen Michael C , Vitanza Nicholas A 
Published: June 2024

Abstract
Diffuse intrinsic pontine glioma (DIPG) is a fatal pediatric tumor of the pons affecting over 300 children in the U.S. each year. Chimeric antigen receptor (CAR) T cells are a targeted immunotherapy with remarkable clinical success against hematological malignancies and now are being investigated against central nervous system (CNS) tumors. B7-H3 is a surface antigen specifically expressed on nearly all DIPG but not on normal brain providing an attractive therapeutic window. Therefore, Seattle Children’s opened BrainChild-03 (NCT04185038), a first-in-human phase 1 trial of repeatedly dosed intracranial B7-H3 CAR T cells for children with DIPG. We found the highest planned dose (10x107 cells) to be tolerable and observed preliminary signals of efficacy. ONC206 is a small molecule ClpP-agonist and DRD2-antagonist derivative of ONC201 that is currently being evaluated on PNOC-023 (NCT04732065). Here, we set out to evaluate the combinatorial potential of these modalities. ONC206 effectively reduced DIPG tumor cell viability (IC50 = ~300 nM compared to ONC201 ~1400 nM) against four treatment-naïve patient-deriving DIPG models representing a range of molecular subtypes. Using multiple orthogonal systems, apoptosis of DIPG cells was confirmed. We found that ONC206 drives tumor cell mitochondrial dysfunction and upregulation of DR5, a cell-death receptor involved in the TRAIL pathway, whereas levels of B7-H3, DRD2, and ClpP remain constant. We previously published the efficacy of B7-H3 CAR T cells against DIPG, but here - using low effector:tumor (E:T) ratios (e.g. 0.5:1) of activated B7-H3 CAR T cells and low-dose ONC206 (e.g. 200 nM) - we found a significant in vitro combinatorial benefit against DIPG (p&lt;0.01). Supportive biologic studies suggest this could be an additive benefit and in vivo studies are currently ongoing. Based on the clinical translation of B7-H3 CAR T cells and ONC206, we aim to further validate this combinatorial benefit to help future patients.
DIPG-12. ASSESSING THE EFFICACY OF BAY2402234 IN COMBINATION WITH ONC201 IN IMMUNE-COMPETENT MURINE MODELS OF DIFFUSE MIDLINE GLIOMA
Authors: Mizoguchi Sean , Kritzer Bettina , Cerna Steven J , Packer Roger , Yadavilli Sridevi , Phoenix Tim , Nazarian Javad 
Published: June 2024

Abstract

BACKGROUND
Radiation therapy remains the sole standard-of-care treatment for Diffuse Midline Glioma (DMG), an aggressive and lethal brain tumor. Despite numerous clinical trials, median overall survival has not improved. Therefore, precise preclinical modeling is essential to guide clinical trials toward positive patient outcomes. ONC201, a ClpP antagonist, has demonstrated efficacy in treating DMG (NCT05580562, NCT05476939). However, efficacy is short-term and acquired resistance necessitates combination therapies. Therefore, we assessed the efficacy of BAY2402234, a potent and selective Dihydroorotate Dehydrogenase (DHODH) inhibitor, in combination with ONC201 in a murine model of DMG.

METHODS
Forty 6-week-old C57/B6 mice underwent pontine orthotopic injection with isogenic DMG cells via stereotactic surgery. The cell line used, 24B-7, has a mutational profile (PDGFRA+p53+H3.3K27M) and growth morphology representative of pontine DMGs. In our previous work, untreated mice injected with these cells had a median survival of 58 days. Upon confirmation of tumor growth using IVIS, mice were assigned to treatment groups based on BLI signal, and treatment was initiated. When mice showed signs of tumor burden or &gt;20% weight loss they were euthanized. At euthanasia, the brain was collected, sectioned sagittally, and divided between fixation and freezing. These samples will evaluate tumor growth, morphology, and characterization compared between treatment groups by both immunohistochemistry and western blot.

RESULTS
As expected, ONC201 treated mice demonstrated an increase in median survival compared to the untreated group. While well-tolerated, neither BAY2402234 nor the combination of BAY2402234 and ONC201 exhibited a statistically significant increase in median survival after statistical correction. (Vehicle: 55 days, ONC201: 62 days, p=0.0026; BAY2402234: 58.5 days, p=0.0403; Combination: 57 days, p=0.1491). Ongoing efforts include target validation and tumor analysis through western blot and immunohistochemistry. ONC201 treatment will be evaluated by investigating ATF4, DR5, and CHOP. BAY2402234 treatment will be evaluated by investigating phosphor-gH2AX and gH2AX.

CONCLUSIONS
Pending tumor analysis.
DIPG-14. METABOLIC REPROGRAMMING AS A RESISTANCE MECHANISM IN DIFFUSE MIDLINE GLIOMA
Authors: Neyazi Sina , Gowda Pruthvi , Frederico Stephen C , Nguyen Cuong M , Trissal Maria C , Portero Erika P , Haley-Read John-Paul , Anderson Emily P , Thomas Craig J , Danial Nika N , Filbin Mariella G 
Published: June 2024

Abstract

BACKGROUND
Diffuse midline gliomas (DMG) are uniformly fatal pediatric brain cancers, refractory to current standards of care. Based on genomic and transcriptomic profiling data, we previously proposed that platelet-derived growth factor receptor alpha (PDGFRA) is crucial to the tumorigenic potential and maintenance of stem-like DMG cells and that targeting PDGFRA is an important therapeutic avenue in DMG. In comprehensive pre-clinical studies, we identified avapritinib, an FDA-approved PDGFRA inhibitor, to be highly effective in patient-derived xenograft (PDX) DMG models. We further reported the first clinical experience using avapritinib in recurrent DMG and demonstrated preliminary safety, tolerability, and efficacy of the drug in this population. While a subset of patients experienced a strong clinical response from avapritinib, tumor progression was eventually observed in all patients.

METHODS
Here, we investigated the molecular mechanisms that DMG cells upregulate following avapritinib treatment, with the aim to exploit them therapeutically. To uncover these mechanisms, we performed transcriptomic, metabolic and functional assays along with a combinatorial drug screening.

RESULTS
Transcriptional analysis of patient-derived DMG cell lines revealed an upregulation of genes associated with fatty acid metabolism and oxidative phosphorylation (OXPHOS) following treatment with avapritinib. Functional assays confirmed elevated OXPHOS in avapritinib-treated cells with significant (i) increase in mitochondrial energy transduction, (ii) increase in palmitate- (a product of fatty acid metabolism) driven oxygen consumption rate and (iii) greater incorporation of palmitate-derived carbons into the tricarboxylic acid cycle. To determine which therapies could target this dependency on OXPHOS and fatty acid metabolism, we performed a metabolic drug screening in patient-derived DMG cell lines and identified two metabolic drugs to have synergistic cytotoxic effects with avapritinib.

CONCLUSION
We revealed distinct metabolic reprogramming in avapritinib-treated DMG cells and showed that targeting these metabolic vulnerabilities might further increase the clinical benefit of PDGFRA inhibitor avapritinib.
DIPG-16. THE BIG AND SMALL OF PROTEIN POST-TRANSLATIONAL MODIFICATIONS: TARGETING SUMOYLATION AND CITRULLINATION IN DIFFUSE MIDLINE GLIOMA
Authors: Rayner Benjamin S , Samadder Arjayeeta , Holliday Holly , Chen Yongjuan , Nguyen Hieu , Lee Alvin , Liu Jie , Hayden Elisha , Ogunmodede Oluwaseyi S , Rye Kerry-Anne , Tsoli Maria , Bertoldo Jean B , Ziegler David S 
Published: June 2024

Abstract

BACKGROUND
Protein post-translational modifications (PTMs) alter the properties of protein through proteolytic cleavage, or the addition of modifying groups to one or more amino acids. Histones are major targets of PTMs, including through SUMOylation of lysine residues and citrullination of arginine residues, with both processes able to regulate gene transcription. We aimed to delineate the potential role of SUMOylation and citrullination in the epigenetic dysregulation that drives Diffuse Midline Glioma (DMG) tumorigenicity.

METHODS AND RESULTS
DMG tumours demonstrated an upregulation of SUMOylation machinery pathway components and increased expression of peptidylarginine deiminases (PADs), the enzymes responsible for citrullination. Nanomolar doses of the SUMOylation inhibitor TAK-981 blocks DMG cell cycle G2/M transition and results in potent decreases in cell viability and clonogenic potential, triggering ‘viral mimicry’ in DMG cells, resulting in increased expression of interferon stimulated genes and inflammatory mediators including IL-1β, IL-6 and TNFα, whilst also causing a pro-inflammatory M1 macrophage response. These data suggest that SUMOylation inhibition may lead to a double-punch effect against DMG by inhibiting tumorgenicity and stimulating an immune response. In further studies, we have shown that pharmacological inhibition of PAD activity in DMG decreases histone citrullination and restores histone methylation – considered the Achilles heel of DMG. This was accompanied by induction of reactive oxygen species and an unfolded protein response, resulting in DMG cell death in a dose dependent manner. In addition to fully characterising the epigenetic and global changes within DMG initiated through SUMOylation or PAD inhibition, we are currently performing preliminary drug efficacy studies in orthotopic DMG models, providing the necessary pre-clinical research pipeline towards an effective treatment for DMG.

CONCLUSIONS
Protein SUMOylation and citrullination are previously unrecognised therapeutic targets in DMG and potentially play key roles in tumour initiation and pathogenesis. Our data suggests a novel therapeutic approach for children with DMG.
DIPG-17. DYSREGULATED PURINE METABOLISM IN A LETHAL CHILDHOOD BRAINSTEM TUMOR REVEALS NEW TREATMENT STRATEGIES WITH OLD DRUGS
Authors: Mersich Ian , Congrove Sunny , Horchar Matthew , Caceres Roman , Desai Janki , Desai Pankaj , Sallans Larry , Haines Julie , Menon Ranjith , Stevenson Charles , de Blank Peter , Pillay-Smiley Natasha , Hummel Trent , Tavassoli Ali , D’Alessandro Angelo , Phoenix Timothy , Dasgupta Biplab 
Published: June 2024

Abstract
The median survival of children with Diffuse Intrinsic Pontine Glioma (DIPG), an incurable brainstem cancer is less than 1 year. Radiation therapy is the only treatment that offers a transient benefit. The preclusion of surgery and biopsy due to the anatomical location of the tumor impeded our understanding of tumor biology for a long time. Genomic analysis during the past decade revealed that over 80% of DIPGs harbor an oncogenic histone H3K27M point mutation. However, the pathways altered by the mutation are still poorly understood. Metabolites serve as proxies to the state of biochemical pathways in a tissue. Given that unbiased a priori knowledge about metabolic alterations in DIPG is limited, we set out for the first time to identify metabolic dependencies intrinsic to DIPGs by leveraging untargeted and targeted metabolomics, transcriptomics, ChiP-Seq and ATAC-seq and integrating multi-omics datasets. We discovered that the mutant histone reprograms chromatin landscape causing aberrant misregulation of genes including a family of transcription factors that in turn causes misregulation of purine biosynthesis and folate metabolism. Specifically, the mutation alone is sufficient to upregulate a rate limiting bifunctional enzyme of de novo purine biosynthesis called ATIC, and the reduced folate carrier SLC19A1 to enhance purine synthesis and folate import, respectively, causing antifolate resistance. Genetic or pharmacological inhibition of ATIC greatly reduced tumor burden and extended survival in mice. Finally, folate removal from the microenvironment sensitized DIPGs to the antifolate methotrexate. Our studies identify ATIC as a novel target in DIPG and reveal a potential treatment strategy with antifolates in children with this lethal brain tumor.
DIPG-19. SURGICAL STATUS IN THE ERA OF NEW MOLECULAR DIAGNOSTICS: INSIGHTS FROM A SINGLE-CENTER CASE SERIES REPORT IN CHINA
Authors: Li Juan , Ai Ruyu , Lai Mingyao , Cai Linbo 
Published: June 2024

Abstract
The therapeutic value of surgery for DIPG has been a subject of controversy. Surgical biopsy provides valuable information on molecular markers of brain gliomas, aiding in further personalized treatment. This retrospective study aimed to elucidate the real-world application of surgery in Diffuse Intrinsic Pontine Glioma (DIPG) in the era of new molecular diagnostics. This study from Guangdong Sanjiu Brain Hospital investigates the surgical landscape in the treatment of Diffuse Intrinsic Pontine Glioma (DIPG) amid the new molecular diagnostics era (Jan 2017 to Feb 2023). Among 184 cases, 58.6% underwent surgery. Notably, 97.2% were introduced to surgery, with 65.8% opting for open surgeries and 34.2% utilizing the Rosa robot. Patients aged 18 and above showed a higher surgery rate (78.3%) than those below 18 (49.1%), revealing a significant difference (P&lt;0.05). The median time from surgery to radiotherapy varied between open (19 days) and stereotactic biopsy (7 days). Complications included increased cranial nerve dysfunction in 20 open biopsy cases. All 108 patients received pathological diagnoses, with 79 having diffuse midline gliomas. Targeted therapy based on second-generation sequencing was administered to seven patients, involving drugs like ribociclib and rigosertib. The study concludes that compared to a decade ago, there is an increased willingness among oncologists to perform brainstem surgery, especially in older patients. Stereotactic biopsy, with fewer side effects, allows swift initiation of radiotherapy. Obtaining lesion tissue during surgery holds promise for new treatments and future research.
DIPG-20. SURGICAL INTERVENTION’S CORRELATION WITH SUBSEQUENT METASTASIS DEVELOPMENT IN CHILDREN WITH DIFFUSE INTRINSIC PONTINE GLIOMAS (DIPG)
Authors: BASHIR SHOAIB , Zhou Jiangfen , Lai Mingyao , Cai Linbo 
Published: June 2024

Abstract

BACKGROUND
Diffuse intrinsic pontine glioma (DIPG) is a highly aggressive pediatric brain tumor with a poor prognosis. Currently, there is no curative treatment option available for these patients. These patients often undergo surgery to confirm the diagnosis pathologically. However, the relationship between surgery and dissemination is to be confirmed. This retrospective cohort determines if surgical intervention increases the risk of dissemination and what other factors may also be associated.

METHODS
The final analysis included 142 pediatric (age ≤ 12) DIPG patients treated at Sanjiu Brain Hospital between January 2017 and June 2023. The data were retrospectively collected following the initial diagnosis. The diagnosis was established based on imaging studies. Three radiologists analyzed the imaging data. The endpoint was the occurrence of subsequent metastasis. Univariable and multivariable logistic regressions were performed to identify predictors of subsequent dissemination. All statistical assessments were two-tailed; only P &lt; 0.05 was considered statistically significant.

RESULTS
Of 142 patients, 28 (19.7%) developed metastasis, and 114 (80.3%) had no evidence of metastasis. There were 77 (54.2%) males and 65 (45.8%) females. The patients’ median age was 7 years (1-12 yrs.). Patients were followed up for at least 6 months or until they developed subsequent metastasis or died without developing metastasis. Univariate logistic regression analysis demonstrated that surgery (OR 4.277, 95%CI 1.753 - 11.607, P=0.002), adjuvant temozolomide (OR 2.891, 95%CI 1.097 - 9.106, P=0.045), and adjuvant bevacizumab (OR 10.278, 95%CI 3.759 - 9.444, P=0.003) were the potential predictor of metastasis development. Multivariate logistic regression analysis showed that surgery (OR 5.061, 95%CI 1.966 - 14.508, P=0.001) and administration of adjuvant bevacizumab (OR 3.020, 95%CI 1.196 - 8.065, P=0.022) were the independent predictors of dissemination.

CONCLUSION
Surgery and adjuvant bevacizumab may increase the risk of subsequent metastasis in the pediatric DIPG population.
DIPG-21. PRECLINICAL ASSESSMENT OF A MULTIMODAL TREATMENT APPROACH WITH GIVINOSTAT, PAXALISIB, AND RADIOTHERAPY FOR DIFFUSE MIDLINE GLIOMA (DMG)
Authors: du Chatinier Aimée , Meel Michaël H , Waranecki Piotr , Metselaar Dennis S , Hulleman Esther 
Published: June 2024

Abstract

BACKGROUND
Despite an extensive body of clinical research conducted, the prognosis for patients with Diffuse Midline Glioma (DMG) has remained stagnant for the past five decades. Years of investigations underscore the robust resistance of DMG tumors to treatment, rendering monotherapy an improbable route to a cure. Recognizing the need for a multimodal approach, this study evaluated a treatment strategy incorporating radiotherapy and two brain-penetrable compounds with potential immunomodulatory effects, Givinostat and Paxalisib.

METHODS
We selected Givinostat, a pan-HDAC inhibitor undergoing clinical studies in children with Duchenne muscular dystrophy, by comprehensive screening of a panel of HDAC inhibitors for their efficacy in DMG neurosphere cultures, ability to penetrate the blood-brain barrier, and clinical utility. in addition, we selected the PI3K/mTOR inhibitor Paxalisib based on a phase II clinical trial currently undergoing in DMG patients (PNOC DMG Adaptive Combination Trial, PNOC022). The anti-tumor, radio-sensitizing, and immunomodulatory effects of both compounds were assessed in vitro and in immunocompetent mice, using various cytotoxicity and proteomic assays and (single-cell) sequencing techniques.

RESULTS
Our investigations revealed that the combination of Givinostat and Paxalisib exerts a profound cytostatic and cytotoxic effect on DMG cells, by reducing cell viability, enhancing DNA damage, and inducing apoptosis. Moreover, this combination therapy sensitized DMG cells to ionizing radiation, potentially by diminishing DNA repair mechanisms and elevating oxidative stress. Additionally, the combination of Givinostat and Paxalisib considerably reduced tumor growth in vivo and transformed the immune-cold microenvironment of DMG tumors into a pro-inflammatory phenotype.

CONCLUSIONS
This study positions Givinostat as a potential addition to the backbone of Paxalisib in forthcoming clinical trials, either as a radio/chemotherapy combination or as a foundation for immunotherapy.