bluuebunny/crossref_metadata_2025_split huggingface dataset:
GCT-27. Β-HCG STIMULATION WITH RAPIDLY PROGRESSIVE PUBERTY (PP) IN INTRACRANIAL NON-GERMINOMATOUS GCT (NGGCT): CASE REPORT
Authors: Yilmaz Yasin , Salhah Hiba , Mattera Emily , Damilano Cecilia , Bakjaji Shadi , Mamilly Leena , Thomas Diana , Shaikhouni Ammar , Khan Sara 
Published: June 2024

Abstract

BACKGROUND
Intracranial non-germinomatous are rare heterogenous group of Central Nervous System (CNS) tumors that consist of embryonal carcinomas, yolk sac tumors, choriocarcinomas, and teratomas (mature, immature), with or without malignant transformation, as well as mixed types. Presentation frequently includes endocrinopathies, visual changes and signs of raised intracranial pressure.

CASE
We present a 9-year-old boy with history of headaches, voice changes, increased height and muscle mass, and new onset pubic hair for one month. Examination showed mild papilledema with no cranial nerve palsies, advanced linear growth with height velocity of 15.8 cm/yr with height and weight at 94th and 85th percentile respectively for age. Tanner 2 pubic hair, muscular body habitus and testicles volume of 10-12mLs bilaterally. MRI brain showed a localized pineal region mass with obstructive hydrocephalus. Tumor markers were elevated in serum (β-hCG;69 IU/l and AFP;36.8 ng/ml) with high CSF β-hCG of 41 IU/l with AFP &lt;10ng/ml. Work up for advanced puberty showed bone age of 11.3yrs. Markedly elevated testosterone levels at 929 ng/dl with free testosterone of 135 pg/m. Both LH and FSH were undetectable supporting the diagnosis of peripheral non-gonadotropic puberty (PP). Diagnosis of NGGCT was established on biopsy. He received therapy with chemotherapy, second look surgery and radiation. He remains in remission (negative tumors markers and MRI). Interestingly initiation of therapy resulted in age-appropriate testosterone level and slowing down of rapidly progressive puberty clinically.

CONCLUSION
We herein present a rare association of β-hCG secreted by NGGCT that cross-reacts with testicular and adrenal LH receptors resulting in increased testosterone levels and rapidly progressive or precocious puberty in males. The incidence of PP in pineal NGGCT remains unknown with very few cases reported in the literature however these are an important consideration in children with advanced puberty in the absence of exogenous hormone exposure and or non-CNS etiologies.
HGG-05. GLUCOSE CONJUGATION FOR THE SPECIFIC TARGETING AND TREATMENT OF GLIOBLASTOMA
Authors: Iorio Anna Lisa , Lenci Elena , Marzano Chiara , Tirinnanzi Bianca , Giunti Laura , Fonte Carla , Guidi Milena , Tellini Marco , Castelli Barbara , Nicola Marco Di , Trabocchi Andrea , Sardi Iacopo 
Published: June 2024

Abstract

BACKGROUND
Malignant brain tumors, such as Glioblastoma (GBM), are a major challenge in oncology with a dismal prognosis. This can be in part explained by the inability to deliver more effective drugs, as Doxorubicin (DOX), into the brain because of resistance mechanisms. Malignant tumors as GBM also show an elevated glycolytic rate through glucose transporters and GLUT1 is reported to be the main mediator of BBB glucose uptake. For these reasons, we have developed an innovative approach able to increase drug efficiency and selectivity, by conjugating the anticancer agents DOX to glucose.

METHODS
Two glycoconjugates (EB73 and EB74) were synthesized, using an oxime-based linkers between position 6 of glucose and carbonyl group of DOX, and characterized for absorbance, fluorescence and binding affinity to ctDNA. The cytotoxic effect of EB73 and EB74 was evaluated in two GBM cell lines (A172 and T98G). These cells were also used to study the effect of glucose deprivation on GLUT1 and breast cancer resistance protein (BCRP) expression. Moreover, cellular uptake of the glicoconjugates was evaluate in an in vitro BBB model and by immunofluorescence (IF) in GBM cells.

RESULTS
Our results indicated that EB73 and EB74 maintained Ka binding constants comparable to DOX, confirming that functionalization with glucose did not alter DOX intercalation capability and fluorescence. The cytotoxicity results demonstrated that EB74 has the major effect in A172 and T98G DOX-resistant cells starting from 24h of treatment. Moreover, glucose deprivation showed a GLUT1 overexpression and BCRP downregulation in both cell lines improving EB74 efficacy. BBB in vitro model and IF experiments revealed that only EB74 is able to accumulate in cells nuclei as conventional DOX

CONCLUSION
In conclusion, these results indicated that glycoconjugation of DOX and glucose deprivation may be helpful instruments to increase drugs uptake and effectiveness in aggressive and chemoresistant tumor cells.
HGG-21. DISTRIBUTION AND MUTATIONAL PATTERNS OF TP53 ALTERATIONS ACROSS SUBTYPES OF PEDIATRIC HIGH-GRADE GLIOMAS
Authors: Blattner-Johnson Mirjam , Sturm Dominik , Hirsch Steffen , Jones Barbara , Schramm Kathrin , Balasubramanian Gnana Prakash , Sill Martin , Autry Robert , Previti Christopher , van Tilburg Cornelis M , Milde Till , Pajtler Kristian W , Sahm Felix , Kramm Christof M , Witt Olaf , Pfister Stefan M , Jones David T W 
Published: June 2024

Abstract
Inactivating alterations of tumor suppressor gene TP53 are a hallmark of tumor progression in various cancer entities. Unfortunately, TP53 inactivation has not yet provided an actionable vulnerability. To investigate distribution, mutational pattern and impact of TP53 alterations in pediatric high-grade gliomas (pedHGG), we investigated TP53 alterations in 407 pedHGG by analyzing genomic sequencing and survival data collected through the INFORM and MNP molecular diagnostic pipelines. Nearly half of pedHGG (47%) showed signs of genomic TP53 inactivation. A second hit suggesting complete loss of function was observed in 84% of tumors, with loss of heterozygosity as the most common mechanism (70%). The frequency of TP53 alterations ranged from 97% in H3 G34-mutated tumors, 70% in IDH-mutated tumors and 61% in H3 K27-mutated tumors down to 40% in H3-/IDH-wildtype subtypes and none in infant-type hemispheric gliomas. Alterations in TP53 were associated with significantly shorter mean overall survival of 11 vs. 15 months in patients diagnosed with H3 K27-mutated tumors. Previously described TP53 hotspot mutations, such as amino acid substitutions at position 17, 248, 273, 282 and 342 were also prominent in the studied cohort (NM_000546). Mutations at position 342 were enriched in H3 G34-mutated tumors, with one-third carrying a stopgain mutation at this position rarely seen in other pedHGG. G34-mutated tumors also showed an abundance of nonsense, splicing or frameshift mutations in contrast to the predominance of missense mutations in other subtypes. The functional impact of these differences is currently under investigation. Lastly, we observed potential evidence for a genotype-phenotype link with Li-Fraumeni syndrome (LFS)-associated (constitutional) TP53 mutations in pedHGG, including an absence of the R248 hotspot mutation in 15 LFS-associated tumors.
HGG-23. MAPPING GENETIC DEPENDENCIES IN PAEDIATRIC HIGH GRADE GLIOMAS AT GENOME-SCALE
Authors: Tsui Vanessa , Liang Yuqing , Lee Hanbyeol , Zhou Yichen , Sun Claire , Daniel Paul , Firestein Ron 
Published: June 2024

Abstract

BACKGROUND
Pediatric high-grade gliomas (HGGs) present a therapeutic challenge due to their aggressive behavior and limited treatment options. Traditional treatments often fall short in addressing the genetic complexity and aggressiveness of pediatric HGGs, urging the search for and validation of novel genetic dependencies as potential therapeutic targets.

METHODS
Loss of function CRISPR screens enable the systematic investigation of gene function by selectively disrupting gene expression, offering invaluable insights into the genetic dependencies fuelling tumor growth and survival. Herein, we conducted genome-scale, loss of function CRISPR/Cas12 screens across genetically-defined subtypes of pediatric HGG, including diffuse midline gliomas (n=30 cell lines).

RESULTS
Distinct genetic dependencies exclusive to pediatric high-grade gliomas (pHGG) are uncovered compared to their adult counterparts, particularly within druggable pathways. These dependencies are associated with specific pathways such as cellular metabolism, epigenetics, and tissue development. Notably, histone-altered subtypes of pHGG exhibit dependency on distinct gene sets for growth. Furthermore, machine learning techniques are applied to correlate various -omics features (RNA, DNA, epigenomics, proteomics) with genetic dependencies, facilitating the identification of biomarkers predictive of therapeutic response.

CONCLUSION
Our work provides a comprehensive genetic dependency map of pHGG. We expect this data to serve as a springboard for enriching our biological understanding of pHGG, ultimately improving clinical outcomes and quality of life.
HGG-37. CLINICAL AND MOLECULAR FEATURES OF BITHALAMIC GLIOMAS IN CHILDREN AND ADOLESCENTS: MULTICENTRIC STUDY AND META-ANALYSIS
Authors: Perez-Somarriba Marta , Cherungonath Anoop , Wasti Ajla , Pace Erika , Benjamin Philip , Villacampa Guillermo , Reisz Zita , Al-Sarraj Safa , Bridges Leslie , Jacques Thomas , Lavarino Cinzia , Gene Nagore , Pereira Rita , Grabovska Yura , Mackay Alan , Kessler Ketty , Clarke Matthew , Santa-Maria Vicente , Cruz Ofelia , La Madrid Andres Morales , Llort Anna , Lassaletta Alvaro , Vazquez-Gomez Felisa , Carceller Elena , Garrido Carmen , Solano-Paez Palma , Quiroga Eduardo , Zebian Bassel , Hettige Samantha , Cockle Julia , Mandeville Henry , Angelini Paola , Srivatsa Kavitha , Vaidya Sucheta , Marshall Lynley , Jones Chris , Carceller Fernando 
Published: June 2024

Abstract

BACKGROUND
Bithalamic gliomas (BTG) are rare brain tumors with dismal prognosis. Optimal management and role of novel therapies have not been established yet. This study aimed to improve our understanding of BTG to guide adapted treatments.

METHODS
Retrospective case series across 6 Pediatric Neuro-Oncology Units (United Kingdom, Spain) of ≤18-year-old patients with BTG between 2000-2022. Clinical, pathological, and molecular data were derived and reviewed. A systematic review of the literature, meta-analysis, and survival analysis were performed.

RESULTS
Overall, 148 BTG cases were evaluated (study=25; literature=123). Of those, 97/148 (65%) had individual survival data. Median overall survival (mOS) (95%CI/range) was 13.2 months (12-16.8/0.6-262.2). mOS stratified by histological grading: 21.0 months (low-grade, n=32) versus 12.0 months (high-grade, n=55); hazard ratio (HR) 0.37 (95%CI 0.20-0.68), p-value=0.001. Molecular analyses (n=70) showed EGFR alterations (56%), TP53 mutations (30%), and H3K27M mutations (23%). mOS of EGFR-altered BTG based on targeted therapy was 13.2 months (no EGFR-inhibitors, n=26) versus 21.6 months (EGFR-inhibitors, n=9); HR 0.36 (95CI% 0.11-1.22). Methylation array data was generated for 4 patients and combined with 10 previously available profiles. Integrated MNP12.8 and mutation information classified 57% as DMG_EGFR and 21% as pedHGG_RTK2B. The remaining cases were classified as DMG_K27M (2/14) or pedHGG_A (1/14). Work is underway to establish a patient-derived EGFR-mutated BTG cell culture and further studies.

CONCLUSIONS
BTG have distinct radiological, and molecular features. EGFR alterations are seen in approximately half of BTG and H3K27M mutations are less frequent than in other midline high-grade gliomas (HGG). Low-grade histology is associated with a survival advantage, although still poor compared to pediatric low-grade gliomas. Therefore, treatment as per HGG guidelines should be considered for all BTG regardless of histological grading. EGFR-altered BTG patients can derive survival benefit from EGFR inhibitors, indicating that these should be considered as part of future treatment protocols.
HGG-40. UNRAVELING THE IMMUNOLOGIC VULNERABILITIES OF DIFFUSE HEMISPHERIC GLIOMA, H3 G34-MUTANT
Authors: Galvin Robert T , Sadeghipour Negar , Xiu Joanne , Ashley David M , Ahluwalia Manmeet S , Aulakh Sonikpreet , Huang R Stephanie , Largaespada David A 
Published: June 2024

Abstract

BACKGROUND
Insights into the pathogenesis of diffuse hemispheric glioma, H3 G34-mutant (DHG-G34), an incurable high-grade glioma, have opened new therapeutic possibilities. The DHG-G34 oncohistone mutation impairs the epigenetic regulator SETD2, which normally orchestrates DNA-mismatch-repair and negatively regulates Polycomb Repressive Complex 2 (PRC2). In DHG-G34, a mismatch-repair-deficiency phenotype is predicted, but an anti-tumor immune response is notably absent, which we hypothesize is linked to the aberrant transcriptional repression by PRC2. Here, we investigate DHG-G34 immunosuppression mechanisms in a real-world multi-omics cohort and cell line model.

METHODS
Clinical, molecular, and immunologic characteristics of a DHG-G34 cohort, sequenced at Caris Life Sciences, are contrasted against diffuse midline glioma (DMG) and pediatric low-grade glioma (LGG). KNS-42 DHG-G34 cell line was exposed to valemetostat (a EZH1/2 inhibitor) or DMSO in-vitro. Flow cytometry and RNA-sequencing were utilized to determine differential immunologic characteristics.

RESULTS
29 DHG-G34, 51 DMG, and 52 LGG were identified. DHG-G34 median OS was 15.4 mo., like DMG (HR=1.1, p=0.686). Common DHG-G34 alterations were TP53 (93.1%), ATRX (69.0%), PDGFRA (31.0%). Tumor mutational burden (TMB) was high, &gt;=10mt/MB, in 10% of DHG-G34, with 0 DMG or LGG events (p&lt;0.01, q&gt;0.05), but innate and adaptive immune fractions and antigen-presenting genes were decreased (fold-change: 0.19–0.83, q&lt;0.05). In KNS-42, PRC2 inhibition upregulated MHC class 1 (p&lt;0.001). Of 402 missense variants, 43 were upregulated following EHZ2 inhibition, and 4 were downregulated (q&lt;0.05). Among immunostimulatory genes, P2RX7, which engages T-cells, was downregulated in patient samples (q&lt;0.001) and upregulated in EZH2 inhibited KNS-42 (q&lt;0.001).

CONCLUSIONS
DHG-G34 has a propensity for high TMB but remains immunologically cold. Our pilot experiment suggests inhibiting PRC2’s unique role in DHG-G34 may sensitize DHG-G34 to an immune response by inducing MHC class 1 expression and transcriptional read-through of mutated transcripts. Understanding whether treatment induces TMB in DHG-G34 may affect timing of an immunotherapeutic intervention.
HGG-42. COMBINED PRECLINICAL AND CLINICAL INVESTIGATION OF WHICH PEDIATRIC HIGH-GRADE GLIOMA SUBTYPES BENEFIT FROM CCNU/TEMOZOLOMIDE
Authors: Haase Rebecca D , Kilburn Lindsay , Filbin Mariella , Green Adam L 
Published: June 2024

Abstract

BACKGROUND
The only chemotherapy regimen that has shown a clear survival benefit in pediatric high-grade glioma (pHGG) is combining temozolomide (TMZ) and lomustine (CCNU) with RT per COG ACNS0423. However, which pHGG subgroups benefit from this treatment is unknown.

METHODS
Through the Children’s Brain Tumor Network (CBTN) database, we found 20 pHGG patients treated with RT-TMZ-CCNU, along with 95 control patients who received other treatment. We compared overall (OS) and event-free survival (EFS) using the Log-rank test for the respective pHGG subtype. We used a patient-derived xenograft (PDX) model, representing newly diagnosed hemispheric pHGG (diffuse hemispheric glioma, G34R-mutant (DHG), to test the effects of combining TMZ-CCNU.

RESULTS
From our clinical (CBTN) data, we found that median OS for the RT-TMZ-CCNU group was significantly greater compared to the control cohort (990 days (d) vs. 427d, p=0.011), as was EFS (510 vs. 215d, p=0.0041). For patients with hemispheric tumors, median OS and EFS were significantly increased for the RT-TMZ-CCNU group (n=8) vs. controls (n=47) (OS 5,274 vs. 496d, p=0.018; EFS 903 vs. 271d, p=0.018). For patients with midline pHGG, median OS and EFS were not significantly different between the RT-TMZ-CCNU group (n=11) and controls (n=43). In our PDX model, we found that TMZ-CCNU led to long-term survival compared to vehicle control and single-agent treatment (p&lt;0.001). DISCUSSION: Patients with hemispheric pHGG had a significant survival benefit from RT-TMZ-CCNU treatment, while those with midline pHGG did not. Hemispheric pHGG, which are enriched for H3G34 and IDH mutations, may be more likely to respond to RT-TMZ-CCNU. These findings are supported by preclinical data showing that mice with DHG, G34R-mutant were cured after TMZ-CCNU treatment. Given our results and those from ACNS0423, RT-TMZ-CCNU should be strongly considered for treatment of patients with hemispheric pHGG and as a backbone for future clinical trials in this population.
HGG-46. PEDIATRIC RADIATION-INDUCED GLIOMA PATIENT SAMPLES AND NOVEL PATIENT-DERIVED MODELS REVEAL TRANSLATIONALLY RELEVANT TREATMENT SUSCEPTIBILITIES AND POTENTIAL GERMLINE RISK FACTORS
Authors: DeSisto John , Knox Aaron , Slade Mathew , Link Gabrielle , Zhuang Yonghua , Donson Andrew , Miller Kristen , Barsh Elinor , Arnold Michael , Armstrong Gregory T , Bhatia Smita , Karam Sana D , Serkova Natalie , Vibhakar Rajeev , Foreman Nicholas , Green Adam L 
Published: June 2024

Abstract

BACKGROUND
Pediatric radiation-induced glioma (RIG) is an incurable secondary high-grade glioma (HGG) afflicting up to 4% of children who previously received cranial radiotherapy (RT) for other malignancies. RIG accounts for up to 10% of pediatric brain tumor deaths. It has no known genetic risk factors nor effective treatment and is uniformly fatal, partly due to extremely limited available models. Our recent molecular characterization of patient samples showed that while RIG and primary pediatric HGG share histological similarities, their genetic alterations and gene expression profiles differ.

METHODS
We obtained germline DNA sequencing from 28 RIG patients and 112 matched controls who received RT but did not develop RIG. In addition, we developed cell culture and murine orthotopic patient-derived xenograft (PDX) models from four RIGs. We conducted single-cell RNA-seq (scRNA-seq), drug screening/validation, and CRISPR functional screening on our novel models.

RESULTS
Germline mutations in TP53, PARP10, POLI, DCLRE1A, and MLH3 were more common in RIG patients than controls (p&lt;0.002). Our matched cell culture and PDX models of RIG represent the genetic diversity of the disease. The PDX models form tumors in 30-120 days and closely recapitulate human RIG by histology and scRNA-seq. They show susceptibility across models to DNA-damaging treatments (etoposide, irinotecan, radiation), as well as MEK, PARP, and proteasome inhibition, with orthogonal supporting findings via CRISPR screening. Several two-treatment combinations also show efficacy and synergy across models, including radiation and trametinib in vivo (logrank p=0.029). Discussion: RIG is an understudied but major cause of pediatric CNS tumor mortality that differs genetically from primary pediatric HGG. Our findings suggest specific germline alterations in DNA repair pathways may put some patients at higher risk of developing RIG after cranial RT. We also introduce the first set of patient-derived RIG models in order to advance translational RIG research, with characterization of translationally relevant treatment susceptibilities.
HGG-51. INTRANASAL DELIVERY OF PDGFRA-IMMUNOLIPOSOMAL SN-38 FOR THE TREATMENT OF PEDIATRIC HIGH-GRADE GLIOMAS
Authors: Kaur Savneet , Watanabe Jun , Uchida Eita , Zhang Peng , Hashizume Rintaro 
Published: June 2024

Abstract

INTRODUCTION
pHGGs are the most common cause of cancer-related death in children, of which the most malignant and devastating tumors include diffuse midline glioma (DMG). Its anatomical location in the braistem, infiltrative nature, and blood-brain barrier (BBB) limit surgical resection and the distribution of systemically administered drugs. Intranasal delivery (IND) is a noninvasive method that bypasses the BBB, by leveraging the unique anatomic connections of the olfactory and trigeminal nerve pathways with the nasal cavity. We previously demonstrated the efficacy of IND of liposomal (LS) formulation of the active metabolite of the DNA topoisomerase I inhibitor, irinotecan, LS-SN-38, in orthotopic human brainstem xenograft models. The specificity of liposomes can be enhanced by using immunoliposome (iLS) formulation, which are coated with antibodies specific to the tumor cells leading to targeted drug delivery and reduced toxicity to normal cells. Platelet-derived growth factor receptor alpha (PDGFRA) plays a role in DMG oncogenesis and is expressed in as much as 70% of DMG by immunohistochemistry. In this study, we evaluated the specificity of anti-PDGFRA monoclonal antibody conjugated immunoliposome (PDGFRA-iLS) in pHGG cell lines.

METHODS
PDGFRA signals were assessed in pHGG cells using western blotting. Cells with high and low expression of PDGFRA were treated with rhodamine (Rho) labeled PDGFRA-iLS and imaged with fluorescent microscope.

RESULTS
DIPG007, SF7761 and KNS42 expressed high levels of PDGFRA, while SF8628 and DIPG36 cells showed low expression. Fluorescence microscopy revealed high PDGFRA-rhodamine (Rho)-iLS expression in DIPG007 cells (PDGFRA high), relative to SF8628 and DIPG36 cells (PDGFRA low).

CONCLUSION
PDGFRA-Rho-iLS shows increase cellular uptake in DIPG cells. Work is underway to determine the biodistribution, host toxicity, and anti-tumor activity of IND of PDGFRA-iLS-SN- 38 alone and in combination with radiation therapy in pHGG xenograft models.
IMG-06. IMAGING-BASED, TEMPORALIS MUSCLE THICKNESS AS A BIOMARKER IN CHILDREN WITH GLIOMAS
Authors: Zapaishchykova Anna , Tak Divyanshu , Ye Zezhong , Vajapeyam Sridhar , Smith Ceilidh , Liu Kevin X , Aerts Hugo J W L , Chi Susan N , Haas-Kogan Daphne A , Nabavizadeh Ali , Familiar Ariana , Mueller Sabine , Poussaint Tina Y , Kann Benjamin H 
Published: June 2024

Abstract

BACKGROUND
Sarcopenia, or lean muscle loss, causes morbidity and early mortality in pediatric cancer patients and survivors. Sarcopenic patients who are also obese have a particularly morbid metabolic condition that cannot be identified by body mass index (BMI) alone. Temporalis muscle thickness (TMT) on T1-weighted MRI provides a direct assessment of lean muscle mass. In this study, we determined how TMT was associated with nutritional and survival outcomes in children with gliomas using an automated deep-learning pipeline that calculates TMT on MRI and provides age-and sex-specific TMT percentiles (iTMT).

METHODS
We analyzed a cohort of 343 patients and 1,673 scans (244 low-grade gliomas(LGG) and 99 high-grade gliomas (HGG)) diagnosed between 2000-2023 at Boston Children’s Hospital/Dana-Farber Cancer Institute, who had linked longitudinal MRI and clinical data available. We calculated and compared age-adjusted iTMT, BMI, weight percentiles, and serum albumin. Sarcopenic obesity in glioma survivors was defined as sarcopenic iTMT (&lt;5th %tile) and obese BMI (&gt;95th %tile).

RESULTS
iTMT was significantly correlated with BMI (N=1,574 scans, Spearman r=0.34, p=4e-45) and weight (N=1,574 scans, r=0.21, p=1e-17), but not serum albumin (N=84 scans, r=-0.04, p=0.66) at any given time point. Of all patients, 113(36.4%) had sarcopenic obesity during at least one time point. For HGG patients, those with less than the median survival time (550 days) had significantly lower baseline iTMT (median: 6th %tile vs. 33rd %tile, p=0.01). For LGG patients, symptoms of malnutrition at diagnosis were associated with a trend toward lower iTMT (N=244, 19th %tile vs.28th %tile, p=0.07).

CONCLUSION
Our study demonstrates that iTMT is an independent biomarker for malnutrition and survival for pediatric gliomas and can identify patients with sarcopenic obesity. iTMT assessment on routine clinical MRI could be a practical way to monitor muscle status and guide supportive interventions in children with brain tumors.