bluuebunny/crossref_metadata_2025_split huggingface dataset:
DIPG-11. DIPGs show robust MHC class I expression but low lymphoid and high myeloid infiltration partly reversible by DNA methyltransferase inhibition
Authors: Mishra Deepak , Wang Jie , Chen Chun-Yu , Zhu Xiaoting , Kumar Shiva Senthil , McHugh Todd , Cripe Timothy , Fouladi Maryam , Drissi Rachid 
Published: June 2022

Abstract
Diffuse intrinsic pontine gliomas (DIPGs) are the most aggressive tumors of the central nervous system in children. Median survival of patients is less than one year post-diagnosis. Radiotherapy remains the only standard treatment but is rarely curative. Immunotherapy is an emerging and promising treatment strategy for children with DIPG. However, general immunotherapy has not lived up to its promise to treat many cancers, including DIPGs, in part due to incomplete understanding of the barriers posed by the tumor microenvironment. We therefore evaluated the immune cell infiltration in a syngeneic mouse model of DIPG and in DIPG tumors collected from patients. We evaluated the expression profiles of T lymphocytes and myeloid cell markers in a cohort of 28 DIPG tumors compared to matched normal tissue specimens. Our data indicate that the expression of MHC I components in DIPG tumors is similar to that of matched normal tissue. Moreover, the well-known immune checkpoint, PD-L1, was not overexpressed in DIPG tumors. Using immunohistochemistry, we demonstrated only rare infiltration of lymphocytes but high enrichment of myeloid cells in tumor tissue. We found similar results in a syngeneic mouse model of DIPG. Collectively, our results indicate that DIPG tumors harbor rare lymphocytes and are enriched in myeloid cells. Recent studies have demonstrated that DNA methyltransferase inhibitors prime some tumors for more effective checkpoint blockade by activating expression of human endogenous retroviruses and sparking a T-cell mediated immune response through a process called “viral mimicry.” We tested the effect of decitabine in a syngeneic mouse model of DIPG. Decitabine reduced the tumor growth kinetics compared to vehicle but was unable to induce the recruitment of lymphoid cells in DIPG tumors. Importantly, we observed a noticeable reduction in the myeloid component of the DIPG microenvironment suggesting a possible role of myeloid cells in tumor growth and progression.
DIPG-14. Neogenin Knockout Stops the Invasion and Dissemination of Diffuse Intrinsic Pontine Gliomasin vivo.
Authors: Sesen Julie , Ghalali Aram , Martinez Tyra , Driscoll Jessica , Fehnel Katie Pricola , Smith Edward 
Published: June 2022

Abstract
INTRODUCTION: Diffuse Intrinsic Pontine Glioma (DIPG) is a devastating high-grade glioma localized in the brainstem that occurs almost exclusively in children. The significant mortality rates of DIPG stem largely from its capacity to invade adjacent normal brain. We have previously published studies identifying the axon guidance factor, neogenin as a key driver regulating brain tumor cell invasion in medulloblastoma, glioblastoma and DIPG in vitro. Here we expand this work with an in vivo model to validate neogenin as promising inducer of DIPG invasion. METHODS: CRISPR-Cas9 system was used to knock-out the neogenin gene in DIPG cells. After validation of the knockout (KO) in vitro by RTqPCR, Western blot, and immunofluroresence, the cells were orthotopically implanted in the pons of nude mice (n=8/group) with a stereotactic frame. Tumor growth and dissemination were monitored using the In Vivo Imaging System (IVIS). Then, brains and spinal cords were collected, and H&E staining was performed. RESULTS:In vitro studies confirmed the KO of neogenin in DIPG cells. In vivo studies revealed that the neogenin total KO group had no progression of the tumor without any dissemination after 4-6 weeks, in marked contrast to the WT group, which exhibited steady growth and widespread dissemination into the spine. Immunohistochemistry confirmed the IVIS results. CONCLUSION: Expanding on previous work, this data suggests that neogenin is a major contributor of DIPG cell invasion and dissemination. The blockade of neogenin in DIPG cells demonstrates the potential utility of neogenin as potential therapeutic target, capable of reducing tumor growth and stopping tumor cell dissemination.
DIPG-23. Artificial intelligence for detecting ACVR1 mutations in patients with DIPG using MRI and clinical data
Authors: Khalid Fahad , Escobar Thibault , Goya-Outi Jessica , Frouin Vincent , Boddaert Nathalie , Grill Jacques , Frouin Frederique 
Published: June 2022

Abstract
INTRODUCTION: ACVR1 mutations are found in about 25% of patients with diffuse intrinsic pontine glioma (DIPG). Recent work has identified the combination of vandetanib and everolimus as a promising therapeutic approach for these patients. We investigate the predictive power of an AI model integrating clinical and radiomic information to predict ACVR1 mutation. METHODS: This retrospective monocentric study includes 65 patients with known ACVR1 status. Patients were scanned at the diagnosis time with at least one of the four structural MRI modalities (pre- and post-contrast T1, T2, FLAIR) and basic clinical information (age and sex) was collected. Radiomic features were extracted within the tumor region from each modality. For each modality, a recursive feature elimination method was used to select the most relevant features. Inside a leave-one-out framework, up to five logistic regression models were built: one per MRI modality and one for the clinical information. The final prediction for each patient was computed as the mean of the probabilities of ACVR1 mutation for the up to 5 different models. Assigning a different weight to clinical data according to age, (more or less than 10 years old) was also tested. RESULTS: Out of the 65 patients (mean age 7.9±3.7, 15 patients older then 10 years), ACVR1 mutations were identified with a 78% accuracy (sensitivity = 92% and specificity = 75%) in the leave-out-out process. Accounting for the clinical data in the model increase the accuracy to 82% (resp. sensitivity = 86% and specificity = 80%). CONCLUSION: The proposed multi model approach compensates for missing MR modalities while taking advantage of all the available information. Our first results suggest that a dedicated model could be developed for younger patients to improve the prediction. The different models will now be tested using additional data coming from the ongoing multi-centric BIOMEDE trials.
DIPG-29. Highly multiplexed digital spatial profiling of the tumor immune environment of pediatric and adultH3 K27M-mutant diffuse midline gliomas
Authors: Damodharan Sudarshawn , Helgager Jeffrey , Dey Mahua 
Published: June 2022

Abstract
BACKGROUND: H3 K27M-mutant diffuse midline gliomas (DMGs) are highly aggressive malignancies of the central nervous system that affect both pediatric and adult populations. The immune layout and genetic changes within the tumor microenvironment associated with these high-grade malignancies are thought to play an integral role in the phenotypic differences in tumor presentation and clinical course between both populations. Comparative immune landscape between pediatric and adult DMGs is not known. METHODS: The NanoString GeoMxTM Digital Spatial Profiler platform was used to determine the immune marker and genetic layout in a cohort of both pediatric and adult H3 K27M-mutant DMG tissue samples. Three fluorescently labeled antibodies targeting immune cells (CD45), epithelial cells (PanCK), tumor cells (H3 K27M) and a nucleic acid stain (SYTO-13) were used to identify and separate out the various components within the tumor tissues from selected regions of interest. The resultant information was then pooled into libraries that were run through the Illumina sequencing system to assess gene expression and proteomics for both cohorts of samples. RESULTS: Our data revealed that there were immune and genetic marker changes that were seen within both populations across multiple regions of interest within the tumor tissues. A number of immune cell types and protein markers exhibited significant difference between the pediatric and adult tissue cohorts. CONCLUSION: The digital spatial analysis of pediatric and adult H3 K27M-mutant DMGs show different immune and genetic profiles which are proposed to contribute to the clinical differences between both populations. These observed differences may play a role in future treatments for H3 K27M-mutant DMGs and further research is needed to explore this.
DIPG-30. A Phase 1, Safety and Dose Escalation Study of BXQ-350 in Combination with Radiation in Pediatric Patients with Diffuse Midline Glioma or Diffuse Intrinsic Pontine Glioma
Authors: O'Toole Dorris Kathleen McCarthy , Fouladi Maryam , Hummel Trent , Takigiku Ray , Tapolsky Gilles , Curry III Richard 
Published: June 2022

Abstract
The significance of sphingolipid metabolism in brain cancers has been demonstrated and enzymes involved in sphingolipid metabolism are being investigated as novel therapeutic targets for adult and pediatric brain cancers. Saposin C is a human protein encoded by the Psap gene and is an allosteric activator of enzymes involved in sphingolipid/ceramide metabolism. BXQ-350 is a nanovesicle of Saposin C that has broad anticancer activity, inducing apoptosis of cancer cells and an anti-tumoral immune response by lowering Sphingosine-1-Phosphate and increasing ceramides concentrations. Also, BXQ-350 is synergistic with radiation therapy. BXQ-350 was investigated in a Phase 1 dose-escalation safety study in pediatric brain cancer patients (NCT03967093); results showed that it was well-tolerated, a MTD was not established, and the safety profile warranted the investigation of combination studies at the highest dose tested (3.4 mg/kg). Additionally, results from a Phase 1 safety and dose escalation study in adult patients with advanced solid malignancies (NCT02859857) indicated that BXQ-350 was well tolerated and showed single agent activity with evidence of modulating sphingolipid metabolism and impacting the immune system positively. The primary objective of this dose-escalation study is to describe the safety profile and to determine the maximum tolerated dose of BXQ-350 in combination with radiation. BXQ-350 is administered intravenously in a modified Fibonacci cohort-based dose escalation design starting at 2.4mg/kg. Multiple secondary parameters are included to characterize BXQ-350’s pharmacokinetic parameters, efficacy profile and investigate potential biomarkers. This trial is currently enrolling at 3 US sites; as of January 2022, enrollment of cohort 1 (2.4 mg/kg and 54 Gy) has been completed while enrollment in cohort 2 (3.2 mg/kg and 54 Gy) is on-going. To this date, no dose-limiting toxicity has been observed and the combination BXQ-350 plus radiation has been well tolerated. Current results will be presented.
DIPG-42. Diffuse midline gliomas, H3K27-altered as an interdisciplinary challenge
Authors: Kammler Gertrud , Fritzsche Friederike , Kordes Uwe , Schüller Ulrich , Westphal Manfred 
Published: June 2022

Abstract
INTRODUCTION: Diffuse midline gliomas represent a particular challenge in treatment. DIPG behave like highly malignant glioma with extremely poor prognosis due to location and inoperability. Molecular genetic studies, complementary to classical histopathology, have found an entity for midline gliomas, newly described ten years ago and entered the WHO classification in 2016. This group of childhood tumor with DMG’s, H3K27-altered will be demonstrated in the following with 14 case reports from our clinic. METHODS: Clinical data of four patients with tectum/thalamic gliomas, six with diffuse intrinsic brainstem glioma, two with cerebellar, one with suprasellar, one with spinal glioma were retrospectively studied. MRI data, volume increase, contrast behavior was also analyzed. Tumor tissue was obtained by various surgical procedures and diagnostic workup included histopathology as well as genetics and epigenetics. RESULTS: 14 pediatric patients were treated from 2012 to 2021, median age 7,5 years. Leading symptoms were hydrocephalus, movement disorders, cranial nerve disorders. Four patients (29%) were partially resected, two (14%) received extended biopsy, seven (50%) were (stereo tactically) biopsied, one diagnosed by liquid biopsy (7%). Histological results revealed the presence of GBM in four cases (29 %). Subsequent methylome analyses confirmed that the tumors belonged to the group of diffuse midline gliomas, H3K27-altered. The other ten tumors (71%) were primarily assigned to this H3K27 group. CONCLUSION: The pediatric tumors of the brainstem, the further midline structures, including intraspinal manifestation show different MRI findings, histology, and clinical course. Complementary molecular genetic diagnosis is essential and a meaningful addition to the histological assignment. It is considered proven that the exclusivity of H3K27 – altered tumors of children and adolescents differs from that of IDH mutated gliomas and glioblastomas by their localization of hemispheric processes. Possible therapeutic approaches using targeted therapy require understanding of these oncological mechanisms.
DIPG-45. Radiation induces a robust interferon response in Diffuse Midline Glioma (DMG), improving the potential for combination immunotherapy
Authors: Minns Hanna E , Padilla Oscar , Wei Hong-Jian , Webster-Carrion Andrea , Tazhibi Masih , McQuillan Nicholas , Zhang Xu , Yeh Rebecca , Zhang Zhiguo , Szalontay Luca , Pavisic Jovana , Garty Guy , Garvin James , Zacharoulis Stergios , Canoll Peter , Vanpouille-Box Claire I , Menon Vilas , Olah Marta , Rabadan Raul , Wu Cheng-Chia , Gartrell Robyn D 
Published: June 2022

Abstract
Diffuse Midline Glioma (DMG), H3K27M altered, confers a dismal survival of 9-15 months and has a non-inflammatory tumor immune microenvironment (TIME). Radiation therapy (RT) is the mainstay treatment for DMG and has been shown in other cancers to recruit an immune component. However, the effect of RT on the DMG TIME has not been explored. In a syngeneic murine model of pontine DMG (PDGFB+, H3.3K27M, p53−/−), mice were treated with single fraction 15Gy RT or sham control, four mice per group. We performed single cell sequencing after CD45 isolation to evaluate the TIME 4 days post RT and compare to untreated tumor (sham control). Unsupervised clustering of 14,848 CD45+ cells revealed 16 immune cell subsets, most abundantly microglia at 75% of cells, with four subtypes representing a spectrum of homeostatic to activated. Microglia from RT are more concentrated in the activated subtypes with an upregulation of interferon response (i.e. Isg15, Ifit3) compared to untreated tumor with an increase in several interferon pathways using REACTOME. Consistent with RT response, RT treated tumors have increase in cell cycle regulatory genes such as Cdkn1a, across all clusters. In non-resident myeloid cells, compared to untreated tumor, RT is associated with a robust upregulation of interferon response genes in both macrophages (Isg15 Fold Change (FC) 2.30; Ifit1 FC 1.64; Ifit3 FC 2.02; Cxcl10 FC 2.29) and dendritic cells (Isg15 FC 2.67; Ifit1 FC 1.72; Ifit3 FC 2.06; Cxcl10 FC 1.50). We also find differential expression of immune checkpoints in RT-treated versus untreated tumor with decreased expression of Lag3, Tim3 (Havcr2), and Csf1R and increased expression of Cd47, Sirpa and Gitr (Tnfrsf18) post RT. In summary, RT stimulates a pro-inflammatory TIME response and alters immune checkpoints in DMG, highlighting the potential for combining RT and immunotherapy in these tumors.
DIPG-48. MRI volumetric and machine learning based analyses predict survival outcome in pediatric diffuse midline glioma
Authors: Bonner Erin R , Liu Xinyang , Tor-Diez Carlos , Kambhampati Madhuri , Eze Augustine , Packer Roger J , Nazarian Javad , Linguraru Marius George , Bornhorst Miriam 
Published: June 2022

Abstract
INTRODUCTION: Diffuse midline glioma (DMG) is a fatal childhood CNS tumor. Magnetic resonance imaging (MRI) is the gold standard for DMG diagnosis and monitoring of response to therapy. Leveraging novel MRI analytical approaches, including volumetric and machine learning based analyses, may aid in the prediction of patient overall survival (OS) and help to identify high-risk cases. METHODS: T1- and T2-weighted MR images were retrospectively collected from children and young adults diagnosed with DMG (n=43). MRI features, including manually determined 3D tumor volume (T2), T1 contrast-enhancing tumor volume, T1 relative to T2 volume (T1/T2), tumor relative to whole brain volume, tumor average intensity, and tumor heterogeneity (i.e., intensity skewness and kurtosis), were evaluated at upfront diagnosis. MRI features were analyzed to identify significant predictors of OS outcome, which was defined as OS shorter, or longer, than one year from diagnosis. A support vector machine was used to predict OS outcomes using combinations of these features. RESULTS: The presence of T1 contrast-enhancing tumor at diagnosis (p=0.01), and a high T1/T2 ratio (&gt;25%, p=0.009), predicted significantly shorter median OS. Moreover, feature selection identified T2 mean intensity (p&lt;0.001), T2 image intensity skew (p=0.006), T1/T2 ratio (p=0.02), and T1 volume relative to whole brain (p=0.03) as significant predictors of OS outcome (short versus long). Combining T2 mean intensity, T2 image skew, T1 segment kurtosis and patient gender resulted in OS outcome prediction accuracy of 83.3% (sensitivity=85%, specificity=81.8%, n=42 cases).CONCLUSION: We have identified MRI volume and imaging features that significantly predict OS outcome in children diagnosed with DMG. Our findings provide a framework for incorporating MRI volumetric and machine learning analyses into the clinical setting, allowing for the customization of treatment based on tumor risk characteristics.
DIPG-51. Hydrocephalus Treatment and the Effect on Survival in Diffuse Intrinsic Pontine Glioma
Authors: Baugh Joshua , Mohammed Nada Ben , van Zanten Sophie Veldhuijzen , Kramm Christof , Biassoni Veronica , Massimino Maura , van Vuurden Dannis 
Published: June 2022

Abstract
BACKGROUND: Diffuse intrinsic pontine glioma (DIPG), can cause hydrocephalus and if symptomatic, leads to rapid changes in consciousness requiring surgical intervention. The effect of cerebrospinal fluid (CSF) diversion on overall survival and the clinical factors influencing outcome remain unclear. The aim of this study was to evaluate the impact of the treatment of hydrocephalus on survival in DIPG patients. METHODS: The study was retrospective in design using data from the SIOPE-European Society of Pediatric Oncology DIPG Registry. Hydrocephalus was determined based on a centrally reviewed diagnostic MRI. The Kaplan-Meier method was used for survival statistics. Clinical prognostic factors including: duration of symptoms, age and cranial nerve palsy at diagnosis were evaluated for confounding and effect modification. The effect of hydrocephalus treatment (CSF diversion) on survival was examined using Cox regression. RESULTS: Among 582 patients from the SIOPE-DIPG Registry, 86 (14%) had hydrocephalus at diagnosis. Median OS for hydrocephalus patients treated with CSF diversion (n=43) was 13 months (95% CI, 10.2-17.7) and 9 months (95% CI, 7.4-10.6) for hydrocephalus patients without a CSF diversion (n=43). Survival rates were not significantly different (p=.41). On adjusted Cox regression, correcting for duration of symptoms, hydrocephalus patients with signs of cranial nerve palsy at diagnosis and a CSF diversion had a hazard ratio 0.476 (p=0.004). CONCLUSION: Survival among DIPG patients presenting with hydrocephalus at diagnosis was not influenced by CSF diversion. Hydrocephalus patients with signs of cranial nerve palsy at diagnosis, had a significantly reduced risk after undergoing CSF diversion. There is an indication this subgroup of DIPG patients may benefit more from CSF diversion, although the relationship between hydrocephalus and cranial nerve palsy requires further investigation.
DIPG-54. p53 pathway reactivation as a therapeutic strategy in diffuse intrinsic pontine glioma
Authors: Lupien Leslie , Rendo Veronica , Morin Eric , Khuu Nicholas , DiGiacomo Jeromy , Khadka Prasidda , Chacon Madison , Lu Sophie , Pelton Kristine , Elcavage Lara , Langhnoja Jaldeep , Ligon Keith , Beroukhim Rameen , Phoenix Timothy , Bandopadhayay Pratiti 
Published: June 2022

Abstract
TP53 is the most frequently mutated tumor suppressor with somatic alterations found in approximately 50% of all human cancers. In the remaining TP53 wild-type (WT) tumors, functional inactivation of the p53 pathway may be achieved through a variety of other mechanisms, including gene deletion, epigenetic silencing, and/or alterations in prominent negative regulators, including MDM2/MDM4 and PPM1D. These alterations block p53 activity and lead to uncontrolled cell proliferation and oncogenesis in a majority of cancers, including the highly aggressive, universally fatal glial cell tumors of childhood, known as Diffuse Intrinsic Pontine Gliomas (DIPGs). DIPGs are inoperable due to their location within the brainstem. Available treatment options, including radiotherapy, have had a palliative effect at best, with almost all children succumbing to the disease within 18 months of diagnosis. Recent advances have led to an improved understanding of the biological underpinnings of this disease and identification of recurrent genetic alterations that represent potential therapeutic targets for these patients. Prominent among these targets in DIPGs with WT p53 status (50%) are MDM2/4 and PPM1D, whose suppression lead to p53 reactivation specifically in the WT p53 context. We have undertaken a combination of approaches to better understand the therapeutic potential of MDM2 and PPM1D inhibition in DIPG, characterizing the genomic, transcriptomic, and cell-state changes that drive resistance, and identifying novel vulnerabilities that can be exploited with combination therapies towards a cure.