bluuebunny/crossref_metadata_2025 huggingface dataset:
HGG-26. MLH1, MSH2, MSH6, AND PMS2 IMMUNOHISTOCHEMISTRY REPRESENTS A HIGHLY SENSITIVE SCREENING METHOD FOR MISMATCH REPAIR DEFICIENCY SYNDROMES IN PEDIATRIC HIGH-GRADE GLIOMA
Authors: Friker Lea L , Perwein Thomas , Waha Andreas , Dörner Evelyn , Klein Rebecca , Blattner-Johnson Mirjam , Layer Julian P , Sturm Dominik , Nussbaumer Gunther , Kerl Kornelius , Hennewig Ulrike , Rohde Marius , Karow Axel , Bluemcke Ingmar , Schmitz Ann Kristin , Reinhard Harald , Herz Nina A , Driever Pablo Hernáiz , Wendt Susanne , Weiser Annette , Guerreiro Stücklin Ana S , Gerber Nicolas U , von Bueren André O , Khurana Claudia , Jorch Norbert , Kratz Christian P , Eyrich Matthias , Karremann Michael , Hölzel Michael , Jones David T W , Pietsch Torsten , Gielen Gerrit H , Kramm Christof M
Published: June 2024

BACKGROUND

Pediatric central nervous system (CNS) tumors can occur as first manifestations of cancer predisposition syndromes (CPS) resulting from pathogenic variants in DNA mismatch repair (MMR) genes MLH1, MSH2, MSH6, and PMS2. Early detection of MMR deficiencies (MMRD) may warrant the therapeutic use of checkpoint inhibitors and enable genetic consulting for the patient’s families.

METHODS

We prospectively screened 128 pediatric high-grade gliomas (pedHGG) for MMR protein expression by immunohistochemistry (IHC) as part of the HIT-HGG-2013 clinical trial. We compared IHC results to independently collected patient information on CPS including MMRD to test the method’s efficiency in screening for Lynch syndrome and Constitutional MMRD syndrome CMMRD.

RESULTS

From 128 successfully tested tumors, ten cases (10/128, 7.8%), showed loss of expression of at least one of the MMR proteins. In seven of the ten affected patients (7/128, 5.5%), genetic testing uncovered heterozygous (6/10) or homozygous (1/10) pathogenic germline variants in MMR genes (MLH1, MSH2 or MSH6) confirming the diagnosis of Lynch syndrome respectively CMMRD. In three cases (3/128 2.3%), MMR alterations were restricted to tumor tissue. The group of diffuse midline gliomas, H3 K27-altered, (67/128, 52.3%) did not show MMR alterations, while either somatic or germline MMR mutations were detected in two of eight patients with diffuse hemispheric glioma, H3 G34-mutant. In 88 patients (88/128, 68.8%) either clinical or molecular-genetic information on CPS could be provided. All ten patients with signs of MMRD were successfully detected by IHC from tumor tissue.

CONCLUSIONS

IHC for MMR proteins represents a highly sensitive screening method for MMRD in pedHGG. Considering the occurrence of at least 11.5% (7/61) of MMRD in pediatric patients with diffuse high-grade glioma excluding DMG, MMRD IHC should be part of routine diagnostics as cost-effective, broadly available and robust screening method.
HGG-28. THE IMPACT OF CMMRD IN HIGH-GRADE GLIOMA PATIENTS, A RETROSPECTIVE ANALYSIS OF 7 YEARS IN LMIC; AN IRRDC STUDY
Authors: Mushtaq Naureen , Minhas Khurram Minhas Khurram , Bashir Farrah , Zahid Soha , Das Anirban , Hawkins Cynthia , Tabori Uri , Bouffet Eric
Published: June 2024

BACKGROUND

Constitutional mismatch repair (MMR) deficiency (CMMRD) is a genetic cancer predisposition syndrome presenting among children and young adults. This study is the first to evaluate CMMRD prevalence among high-grade glioma patients in Pakistan, a country with high consanguinity rates.

METHODS

We reviewed data of patients younger than 18 diagnosed with pediatric high-grade glioma, anaplastic astrocytoma, and diffuse midline glioma with CMMRD testing between 2016 and 2023. Tumor slides of all included cases were prepared and sent to Sick Kids Toronto to review the MMR protein stains via multi-gene panels.

RESULTS

Forty-five patients were identified (62.3% females); median age of 11. Headache (88.9%) was the most common symptom, followed by vomiting (60%) and seizures (37.8%); median duration of symptoms was two months. Histopathology revealed 73.3% pediatric high-grade glioma, 22.2% Anaplastic Astrocytoma, and 4.4% Diffuse Midline Glioma. Thirty-six patients (80%) had a cerebral tumor, 13.3%, and 6.7% had a posterior fossa and midline tumor, respectively. CMMRD was positive in 15 of 45 patients (33.3%). Eight patients (53.4%) had CMMRD with loss of PMS 2, two (13.3%) had loss of PMS 2 and MLH 1, two (13.3%) had loss of MSH 2, two (13.3%) had loss of MSH 6, and only one patient had loss of MSH 6 and MSH 2. Consanguinity correlated with CMMRD (P=0.045), but family history of malignancy was not significant (P=0.202). One-year overall survival of all patients, with a median follow-up of 4.8 months, was 44.4 %, whereas 1-year overall survival compared to CMMRD was 33.3%, with a median follow-up of 7.2 months (P=0.616)

CONCLUSION

We found high prevalence of CMMRD among pediatric high-grade glioma patients and patients with consanguinity. The findings of our study emphasize the importance of genetic testing and counseling. Timely accurate diagnosis is essential as decreased response to conventional treatment regimens may increase disease burden.
HGG-34. EFFICACY AND SAFETY OF DOXORUBICIN PLUS STANDARD THERAPY IN PEDIATRIC HIGH GRADE GLIOMAS: AN OPEN-LABEL MONOCENTRIC NOT-RANDOMIZED PHASE II STUDY
Authors: Castelli Barbara , Tellini Marco , Fonte Carla , Censullo Maria Luigia , Guidi Milena , Nicola Marco Di , Giunti Laura , Buccoliero Anna Maria , Caporalini Chiara , Giordano Flavio , Desideri Isacco , Greto Daniela , D’Incerti Ludovico , Balducci Federico , Pugi Alessandra , Tortora Katia , Scagnet Mirko , Genitori Lorenzo , Sardi Iacopo
Published: June 2024

BACKGROUND

Pediatric high-grade gliomas (pHGGs) comprise a very poor prognosis. Current treatment consists of maximal surgical resection followed by radiotherapy plus concomitant and adjuvant temozolomide (Stupp’s regimen). Despite innovative approaches, outcome remains dismal. Based on the results of previous in vitro and in vivo assays, also considering the wide experience in other pediatric tumors, we aimed to introduce doxorubicin (DOX) as add-on therapy to the standard of care.

METHODS

For testing safety and efficacy of add-on doxorubicin treatment in newly-diagnosed pHGGs, two open-label monocentric not-randomized phase II studies were consequently opened at our institution: GBM TMZ/DOX 2015 (EudraCT 2015-002307-28) and pGBM-WBRT/DOX2020 (EudraCT 2020-005131-74). GBM TMZ/DOX 2015 consisted of DOX 100 mg/mq in 96 hours infusion for 1-3 cycles at 8 week after radiotherapy. pGBM-WBRT/DOX2020 study introduced pan-encephalic radiotherapy followed by DOX 75 mg/mq in 48 hours for 4 cycles starting at week 12 after irradiation, to reduce metastatic relapse rate and to facilitate radiotherapy-induced blood brain barrier opening. Concomitant and adjuvant temozolomide were preserved.

RESULTS

Twenty-one heterogeneous malignant glioma patients (12 hystological diagnosis, 12 males and 8 females, mean age 9.1 ± 4.2 years, age range 2-22 years) were enrolled in the first study. However, for study exiting or for no clinical permissiveness at the time of DOX treatment, only 12 patients were treated with DOX: 2 received three DOX courses and 10 a single course, reducing hematological toxicities. DOX-group showed a longer progression free survival (PFS) compared to standard of care group (median PFS 9 versus 6 months respectively), although this trend was not statistically significative. The second study is on course.

CONCLUSIONS

The adjuvant DOX use in addition to the standard treatment in pHHGs is a practicable option, although to be consolidated, in terms of effectiveness on outcome.
HGG-36. ASSESSMENT OF CHROMOSOMAL ABERRATIONS IN DIFFUSE ASTROCYTOMAS OF CHILDHOOD USING THE ARRAY COMPARATIVE GENOMIC HYBRIDIZATION (ACGH+SNP) TECHNIQUE – PRELIMINARY STUDY
Authors: Maryńczak Laura , Szewczyk Katarzyna , Kwiatkowski Stanisław , Adamek Dariusz , Bik-Multanowski Mirosław
Published: June 2024

BACKGROUND

Comprehensive knowledge of the genomic changes underlying cancer is a key basis for diagnosis, prognosis and targeted therapies. With recent advances, the technique of comparative genomic hybridization (aCGH+SNP) facilitates genome-wide screening for genome copy number changes and rapid examination of numerical and structural chromosomal changes, as well as loss of heterozygosity at high resolution down to several tens of kilobases.

METHODS

The study included 12 patients aged 6 months to 15 years, operated on at the Department of Pediatric Neurosurgery in Krakow due to paediatric-type diffuse gliomas (according to WHO classification 5th Ed). Tumor tissue samples were collected from all included participants as remnants of routine examination. Pangenomic profiling of diffuse astrocytomas was performed with using SurePrint G3 Cancer CGH+SNP Kit 4x180K (Agilent, Santa Clara USA) at the Molecular Genetics Laboratory of the University Children’s Hospital in Krakow. Genomic DNA was extracted automatically from deep-frozen tumor tissue. Descriptive statistics were used to describe the basic characteristics of the data included in the study due to the small number of participants.

RESULTS

Of the 12 tumors examined by microarray, 5 patients had abnormalities in the form of diffuse high grade gliomas. In 1 patient, only numerical changes in chromosomes were observed, in 1 case only structural chromosomal abnormalities were detected. Combined numerical and structural aberrations were presented in 3 samples. Additionally, we detected 1 case of triploidy and 1 case of loss of heterozygosity.

CONCLUSIONS

Significant changes were observed in paediatric-type diffuse high-grade gliomas. Interestingly, we detected new undescribed alterations that were not only of a chromosomal nature, but also concerned individual genes. This may constitute the basis for further research aimed at establishing new diagnostic and prognostic markers, as well as effective therapy. A limitation of this study is the small patient sample, and further research is recommended.
HGG-39. CLINICAL CHARACTERISTICS AND SURVIVAL OUTCOMES OF DIFFUSE HEMISPHERIC GLIOMA, H3 G34-MUTANT: INTERIM RESULTS OF A MULTICENTRE INTERNATIONAL STUDY
Authors: Crowell Cameron , Bennett Julie , Bandopadhayay Pratiti , Sturm Dominik , Green Adam L , MacNeil Mary , Vanan Magimairajan Issai , Larouche Valérie , Renzi Samuele , Imber Brandon , Jones Jacquelyn , Perreault Sébastien , Mata-Mbemba Daddy , Feddersen Charlotte , Vizzini Olivia , Zápotocký Michal , Cheng Sylvia , Harrison Rebecca , Popovacki Aimee , Klawinski Darren , Hansford Jordan R , Lapointe Sarah , Cayrol Romain , Mankuzhy Nikhil , Coleman Christina , Wright-Nadkarni Mariah , Salloum Ralph , Karajannis Matthias , Hawkins Cynthia , Jones David T W , Ligon Keith L , Jabado Nada , Erker Craig
Published: June 2024

BACKGROUND

Diffuse hemispheric glioma, H3 G34-mutant (G34-DHG) is generally associated with very poor outcome. Little is known, however, regarding long-term survivors and associated prognostic factors.

METHODS

This retrospective, multicentre study was designed to investigate clinical, molecular, and imaging variables that may impact the survival of patients with G34-DHG. Patients of any age diagnosed with G34-DHG after January 1, 1995, with at least one measure of survival or progression were eligible.

RESULTS

69 patients with G34-DHG (62 G34R, 5 G34V, 2 diagnosed by methylation profiling only) have been included to date. Median age at diagnosis was 16.0 years (range: 2–38). 75% of patients were under the age of 18. 52% of patients were male. 8% of patients had multifocal/disseminated disease at diagnosis. Upfront therapy included gross/near total resection in 47% of patients, radiation therapy in 88% (89% focal, 6% CSI), and maintenance chemotherapy in 85% (62% TMZ-based, 33% TMZ/CCNU, 5% non-TMZ). Median follow-up time was 20.0 months (IQR=12.0–30.0). 86% of patients had progressive disease with a median time-to-progression of 14.0 months (IQR=6.6-22.5). At last follow-up, 70% of patients had died from disease, 23% were alive with disease, and 7% were alive without disease. Median overall survival was 24.7 months (IQR=18.8–30.6). Median time from progression to death was 6.0 months (IQR=2.0–10.8). Six patients were found to be long-term survivors > 5 years (four dead of disease, one alive with disease, one alive without disease). Log-rank assessment revealed improved survival to be associated with upfront gross/near-total resection (p=0.002) and age at diagnosis ≥ 18 years (p=0.012).

CONCLUSIONS

Surprisingly, we found that nearly 10% of G34-DHG patients survive 5 years or longer. Radical surgical resection and older age at diagnosis appear to be associated with longer survival. Imaging and molecular prognostic factors are being further investigated.
HGG-52. MULTI-INTEGRIN TARGETING EFFECTIVELY SUPPRESSES DIFFUSE MIDLINE GLIOMA MIGRATION
Authors: Cartaxo Rodrigo , Nieblas-Bedolla Edwin , Niculcea Michael , Miclea Madeline , Siada Ruby ` , Schwark Kallen , Ji Sunjong , Gera Ananya , Doherty Robert , Galban Stefanie , Nuechterlein Nicholas , Hara Toshiro , Parent Jack , Filbin Mariella , Koschmann Carl
Published: June 2024

Diffuse midline gliomas (DMGs) are aggressive tumors characterized by infiltration into normal midline brain tissue, hindering surgical resection and contributing to overall morbidity and mortality. We established a novel two-step pooled whole genome CRISPR-Migration screen by using serum-free conditions and laminin-dependent cell attachment, mimicking cell migration on brain vasculature scaffolds, a common feature in glioblastoma (GBM). Comparing DMG and GBM primary cell lines (n=5), genes involved in focal adhesion (ITGB1, CRKL, PARVA, PTK2, FERMT2) were identified as significantly restricting migration in all cell lines. Multi-institutional transcriptomic data revealed an association of expression of these focal adhesion genes with survival primarily in K27M-DMG and pediatric high-grade glioma compared to lower-grade brain tumors, and ITGB1 expression increased with glioma grade. Single-cell RNA-seq and spatial transcriptomic data demonstrated higher expression of ITGB1 in OPC-like/Mesenchymal cells associated with leading edge and microvasculature in both K27M-DMG and GBM tumors. Unexpectedly, knockout of ITGB1 (ITGB1-KO), primarily responsible for cell adhesion to laminin, led to the decreased expression of multiple mitochondrial NADH dehydrogenase genes, and reduced levels of glycolysis and oxidative phosphorylation (OXPHOS) activity. Preliminary mechanistic data linked this phenotype to impaired mitochondrial fusion. Orthotopic implantation of control and ITGB1-KO models of H3K27M-DMG and adult GBM in mouse brains revealed two distinct phenotypes: (1) ITGB1-KO reducing proliferation and significantly increasing survival; and (2) ITGB1-KO leading to upregulation of ITGB3 and ITGB5 in vivo without impacting survival. Cilengitide (αvβ3 and αvβ5 inhibitor) ablated migration of all ITGB1-KO models on vitronectin (secreted by pericytes surrounding blood vessels) in vitro. Ongoing combinatorial therapy with an experimental anti-Integrin Beta 1 antibody (AIIB2, CNS delivered) and Cilengitide is underway with promising early results. In summary, multi-integrin inhibition provides a feasible avenue to curb glioma spread in the brain through impaired focal adhesion as well as blunting mitochondrial glucose metabolism.
IMG-01. LONGITUDINAL SIGNAL CHANGES IN THE DENTATE AND INFERIOR OLIVARY NUCLEI IN PATIENTS WITH CEREBELLAR MUTISM SYNDROME
Authors: Pinto Soniya N , Scoggnis Matthew , Liang Jia , Li Yimei , Khan Raja B , Robinson Giles W , Klimo Paul , Wheeler Charles A , McAfee Samuel S
Published: June 2024

BACKGROUND

Cerebellar mutism syndrome (CMS) is a complication of posterior fossa surgery with an acute impairment in speech, and long-term neurocognitive deficits. Lesion mapping studies suggest the cognitive symptoms are associated with dentatorubrolivary damage1. We hypothesize that CMS patients will demonstrate more longitudinal MRI signal abnormalities in the dentate and inferior olivary nuclei as compared to non-CMS patients.

METHODS

MRI brains on 40 pediatric medulloblastoma patients between 2013-2015 were retrospectively reviewed by a neuroradiologist blinded to the diagnosis at pre-operative and immediate, 6-month, 12 month and most recent post-operative time points. The dentate and inferior olivary nuclei were scored for restricted diffusion, T1 and T2 hypo-and hyperintensity. A linear regression with different scores on CMS status (YES vs NO) was applied, after adjusting for age.

RESULTS

In the dentate nuclei, there was significantly higher T2 hypointensity in the CMS group on immediate (difference is 0.4084, p=0.0467) and most recent (difference is 0.7190, p=0.0386) post-operative MRIs. The CMS group had significantly higher T1 hyperintensity on the 1-year (difference is 0.9254, p=0.0108) and most recent (difference is 1.3291, p<0.001) post-operative MRIs. In the inferior olivary nuclei, there was significantly higher T2 hyperintensity on the 6-month (difference is 0.71, p=0.0045) and 1-year (difference is 0.6356, p=0.0162) post-operative MRIs.

CONCLUSION

The immediate post-operative findings are suggestive of a hemorrhagic, rather than an ischemic process in the dentate nuclei. On long-term follow up, the signal changes in the dentate and the inferior olivary nuclei represent dystrophic mineralization and hypertrophic degeneration, due to inflammation and axonal degeneration within the dentatorubroolivary tract2 References: 1. Albazron, Fatimah M., et al. “Pediatric postoperative cerebellar cognitive affective syndrome follows outflow pathway lesions.” Neurology 93.16 (2019). 2. Perreault, Sebastien, et al. “Time-dependent structural changes of the dentatothalamic pathway in children treated for posterior fossa tumor.” American journal of neuroradiology 35.4 (2014).
IMG-04. ASSOCIATION BETWEEN MICROSTRUCTURAL INTEGRITY OF BRAIN SUBSTRUCTURES AND NEUROCOGNITIVE OUTCOMES: A MULTI-TRAJECTORY ANALYSIS IN CHILDHOOD BRAIN TUMOR SURVIVORS
Authors: Oglesby Ryan , Pathiravasan Chathurangi , Peterson Rachel , Acharya Sahaja
Published: June 2024

BACKGROUND

The relationship between the brain’s microstructural integrity and neurocognitive outcomes is not well characterized in childhood brain tumor survivors. In healthy children, mean diffusivity (MD) generally decreases and fractional anisotropy (FA) increases with age as the brain progressively myelinates and develops. Increasing MD and decreasing FA is suggestive of microstructural injury. We investigate the association between longitudinal neurocognitive outcomes and change in MD and FA in childhood brain tumor survivors.

METHODS

Patients diagnosed with a brain tumor at < 20 years of age with ≥ 2 neurocognitive assessments and paired DTI at each neurocognitive timepoint were retrospectively identified and eligible for inclusion. Multi-trajectory modeling was applied to cluster patients into distinct neurocognitive trajectories based on intelligent quotient, processing speed and working memory. Linear mixed models were used to determine whether the clusters were associated with change in MD and FA over time.

RESULTS

A total of 61 patients were eligible with 151 neurocognitive assessments paired with DTI. Mean follow-up was 4.8 years. Multi-trajectory modeling identified two clusters of patients with distinct neurocognitive trajectories. Compared to the low-performance group, the high-performance group (45.5%) had higher baseline neurocognitive scores with less decline in all neurocognitive outcomes. The high-performance group was also associated with a greater decrease in MD and greater increase in FA of the hippocampus and several white matter tracts such as the corpus callosum, pontine crossing tract, anterior limb of the internal capsule and inferior cerebellar peduncle, after adjusting for age and sex (all p<0.05). Additionally, the high-performance group was associated with a greater increase in FA in the superior, middle and inferior frontal gyri (all p<0.05).

CONCLUSIONS

The high-performance neurocognitive group was associated with greater microstructural integrity over time in multiple brain substructures compared to the low-performance group, as measured by change in fractional anisotropy and mean diffusivity.
IMG-05. USING CONVOLUTIONAL NEURAL NETWORKS TO IDENTIFY COMMON MOLECULAR ALTERATIONS IN PEDIATRIC BRAIN TUMORS
Authors: Free Taylor , Moore Jonathon , Taras Michael , Ganapathy Shankar , Sreedher Gayathri , Wright Erin
Published: June 2024

BACKGROUND

Artificial intelligence (AI) and deep learning have had increased uses in healthcare. Initial studies have shown it is possible to predict multiple tumor types in adults and children using convolutional neural networks (CNN), a form of deep learning, using MRIs. In pediatric CNS tumors, molecular alterations are used in both diagnosis and treatment decisions. This project aims to verify that we can use deep learning to help diagnose and molecularly classify primary pediatric CNS tumors. Previously, we used Recurrent Health’s platform to predict high vs. low grade CNS lesions to >95% recall and 85% precision in pediatric patients. The objective of this study is to validate the AI’s ability to predict common genetic alterations with 90% accuracy.

METHODS

This retrospective study evaluated patients (ages 0-21) with histologically confirmed primary CNS tumors that underwent BRAF molecular analysis. We collected demographic data: age, tumor location, and presence of BRAF mutations/fusions. The data was divided into a training and validation set (80%/20% split). To determine the viability of models, we will measure specificity, sensitivity, and F1 Score (Sorenson-Dice coefficient) for predicting genetic alterations. Model score confidence was achieved through K-fold cross-validation and statistical power analysis with a finite population coefficient to determine the appropriate sample size.

RESULTS

Our retrospective test included 136 patients with multiple scans for training, model validation and testing. The CNN was able to predict presence of BRAF fusions with >95% recall/sensitivity, >76% precision/specificity and F1/accuracy >87% while predicting BRAFV600 mutations with >75% recall/sensitivity, >95% precision/specificity and F1/accuracy >85%. These metrics indicate strong discrimination in classification.

CONCLUSIONS

Preliminary data suggests the accuracy of the model in identifying the presence of BRAF mutations, providing a potential opportunity for a non-invasive tool to help aid in diagnosis and help guide initiation of targeted therapy.
IMG-07. PEDIATRIC CRANIAL INCIDENTALOMAS: A SYSTEMATIC REVIEW UTILIZING MACHINE LEARNING
Authors: Cochrane Anne M , Abdelbaki Mohamed S
Published: June 2024

BACKGROUND

The use of diagnostic neuroimaging in the care of pediatric patients continues to increase, leading to a rise in incidentally discovered lesions. The understanding of appropriate assessment and management of these findings is critical to providing comprehensive and timely care. This review aims to analyze the current literature to characterize diagnostic and prognostic characteristics of incidentally found brain tumors in pediatric patients.

METHODS

Using the guidelines under the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA), Pubmed and Medline (NCBI) databases were searched using selected keyword combinations and machine learning-assisted software. Case reports, case series, and retrospective cohort studies published up to December 2023 were included.

RESULTS

A total of 20 studies encompassing 627 patients were included in the review. The most common indications for imaging were headache (204; 33%), seizures (96; 15%), and trauma (78; 12%). Of studies providing information regarding localization, lesions were found in the supratentorial region in 327 (52%) cases and infratentorial region in 190 (30%). Of studies reporting imaging characteristics, T1 hypointensity (183/302; 61%), T2 hyperintensity (410/497; 82%), and no contrast enhancement (58/97; 60%) were the most common findings. Four hundred and thirty (68%) patients were observed after diagnosis, 83 (13%) patients underwent surgical intervention at diagnosis, and 40 (6%) patients underwent surgery after observation. Of 91 patients with histopathology data available, pilocytic astrocytoma (19; 21%) was most commonly reported.

CONCLUSION

In this study, we provide a review of diagnostic characteristics of incidentally discovered brain tumors in the pediatric population. Management of such lesions has changed greatly over the past several decades, and risks of surgical intervention should be weighed against a more conservative management and interval monitoring approach. These results may help guide discussions regarding disclosure of findings and recommendations for additional clinical management.
IMG-09. A DEEP LEARNING-BASED APPROACH FOR BRAIN TISSUE EXTRACTION USING MULTI- AND SINGLE-PARAMETRIC MRI IN PEDIATRICS
Authors: Gandhi Deep B , Gottipati Anurag , Tu Wenxin , Familiar Ariana , Haldar Shuvanjan , Khalili Neda , Jain Paarth , Viswanathan Karthik , Storm Phillip B , Resnick Adam C , Ware Jeffrey B , Vossough Arastoo , Nabavizadeh Ali , Kazerooni Anahita Fathi
Published: June 2024

BACKGROUND

Skull-stripping, the process of extracting brain tissue from MR images, is an important step for tumor segmentation and downstream imaging-based analytics such as AI-powered radiomic feature extraction. Existing skull-stripping models, designed for pediatric or adult patients, show limitations in accurately segmenting tumors in sellar/suprasellar regions. This limitation hinders their reliable application across different histologies of pediatric brain tumors. We propose a deep learning approach for fully automated skull-stripping, compatible with both single- or multi-parametric MRI sequences.

METHODS

We developed 3D nnU-Net models trained on preprocessed MRI sequences (including pre- and post-contrast T1w, T2w, and FLAIR) from 336 patients with brain tumors across multiple tumor histologies such as low-grade, high-grade and brainstem gliomas, medulloblastoma, ependymoma, etc., aged between 3 months and 20 years (median age, 8.5 years). The training utilized manually generated brain masks, including the sellar/suprasellar region, from 153 patients and employed 5-fold cross-validation to split the data into inner training-validation sets. The models were then tested on a withheld set of 183 subjects. Additionally, we trained a single-parametric model on individual images, resulting in 612 training and 732 testing cases. Model performance was evaluated using the Dice similarity metric for segmenting both the entire brain and slices specifically containing the sella turcica.

RESULTS

The multi-parametric and single-parametric models achieved mean±sd Dice scores of 0.981±0.008 (median=0.983) and 0.979±0.009 (median=0.981), respectively. For the sellar/suprasellar slices, the scores were 0.983±0.009 (median=0.986) and 0.981±0.012 (median=0.984), respectively. These results indicate a high precision in segmenting not only the entire brain volume, but also the sellar/suprasellar region.

CONCLUSION

Our proposed deep learning-based skull-stripping approach, leveraging both multi-parametric and single-parametric MRI inputs, demonstrates excellent accuracy. These models, made publicly available, have potential for improving auto-processing pipelines in pediatric brain tumors.
IMG-12. CBTN BRAIN TUMOR SEGMENTATION INITIATIVE: UPDATES ON MODEL RELEASE, HGG SEGMENTATION, AND SURVIVAL ANALYSIS
Authors: Kazerooni Anahita Fathi
Published: June 2024

BACKGROUND

Assessment of treatment responses in pediatric brain tumors requires accurate tumor segmentation, particularly important for nonresectable tumors like diffuse midline glioma (DMG), including diffuse intrinsic pontine glioma (DIPGs). Evaluating tumor progression in these tumors relies on monitoring tumor size changes in longitudinal MRI exams which is challenged by their infiltrative growth patterns. Our team developed a comprehensive multi-institutional, multi-histology autosegmentation deep learning (DL) model leveraging data from the Children’s Brain Tumor Network (CBTN), involving continuous enhancements and enriched by an expanding dataset including post-surgical/post-treatment studies.

METHODS

Recently, we trained and validated this DL model (publicly available) on a multi-institutional dataset of 644 PBTs, including 273 pediatric-type diffuse high-grade gliomas (HGGs, including DMG/DIPGs), using pre-operative and post-operative/post-treatment multiparametric MRI scans. We tested the model in 23 longitudinal MRI exams of 8 DMGs from the PNOC003 and PNOC007 clinical trials and applied Cox regression for predicting overall survival (OS) using tumor volume, computed with our autosegmentation model, as a time-varying variable in 18 patients.

RESULTS

For HGGs in treatment-naïve sessions, our model demonstrated strong performance with median Dice scores of 0.89 for whole tumor and tumor core (encompassing all regions, except for edema), and 0.73 for enhancing tumor segmentation. In longitudinal MRI exams of DMGs from the aforementioned clinical trials, the model achieved median Dice scores of 0.79 for whole tumor, and 0.78 for enhancing tumor and tumor core segmentation. Cox regression showed the significance of longitudinal volumetric measurements (p=0.08) for predicting OS in DMGs.

CONCLUSIONS

Our approach provides reliable tumor segmentation in HGGs across diverse datasets, crucial for treatment response assessment. Looking ahead, we plan to validate our model on a larger set of longitudinal exams and use volumetric measurements to predict tumor progression. This ongoing effort aims to improve model performance, extend its generalizability, and mitigate potential model decay.
IMG-14. DIAGNOSTIC UTILITY OF THE T2-FLAIR MISMATCH SIGN FOR DNETS AND ITS ASSOCIATION WITH FGFR1 ALTERATIONS
Authors: Wheeler Charles A , Liang Jia , Li Yimei , Chiang Jason , Bag Asim K
Published: June 2024

BACKGROUND

The T2-FLAIR mismatch sign, hyperintense T2-weighted signals with corresponding hypointensity on FLAIR sequence, has emerged as a potential diagnostic tool for identifying specific brain tumor subtypes. We tested the diagnostic utility of the sign in dysembryoplastic neuroepithelial tumors (DNETs) with and without FGFR1 alterations.

METHODS

We evaluated the T2-FLAIR mismatch sign in a cohort of 43 patients with definitive or probable DNET. Low-grade glioma patients with definite non-DNET diagnoses were chosen as control (n=43). Receiver operative curve analysis was performed, and the corresponding odds ratios were calculated.

RESULTS

Of the 43 DNET cases, 35 were definite, and 8 were probable DNETs. FGFR1 alterations were confirmed in 9 definitive DNETs. The area under the curve (AUC) for diagnosing DNET with the T2-FLAIR mismatch sign was 0.884 (DeLong CI: 0.2, 0.95) (Accuracy: 0.88, 95% CI: 0.80, 0.94; Sensitivity: 0.84; Specificity: 0.95); for definite DNET it was 0.891 (DeLong CI: 0.82, 0.96) (Accuracy: 0.90, 95% CI: 0.81, 0.95; Sensitivity: 0.87; Specificity: 0.94); for probable DNET it was 0.852 (DeLong CI: 0.69, 1;) (Accuracy 0.92, 95% CI: 0.81, 0.98; Sensitivity: 0.84; Specificity: 0.75), and for DNET with FGFR1 alterations was 0.977 (DeLong CI: 0.95, 1) (Accuracy 0.96, 95% CI: 0.87, 1; Sensitivity: 1; Specificity: 0.81). The odds of having DNET (definite +probable) if the T2-FLAIR mismatch sign was positive was 81.96 (CI: 16.25, 852.48, P<0.001), and DNET with FGFR1 is 315.4 (CI: 312.3, 318.5, P<0.001).

CONCLUSION

The T2-FLAIR mismatch sign is a reliable radiological biomarker for DNET and strongly predicts FGFR1 alterations in these tumors.
IMG-34. THE UTILITY OF [18F]FET PET IMAGING IN PAEDIATRIC CNS TUMOURS: A SINGLE INSTITUTION EXPERIENCE IN SYDNEY, AUSTRALIA
Authors: Govender Dinisha , Chung David
Published: June 2024

BACKGROUND

MRI remains the standard imaging modality in paediatric CNS tumours. Whilst Positron emission tomography (PET) with O-(2-[18F]fluoroethyl)-L-tyrosine ([18F-FET) is a well-established tool in adult central nervous system (CNS) tumours, established data on its diagnostic utility and impact on clinical management in children and adolescents remain limited.

METHODS

Single centre retrospective review of database of all paediatric and adolescent patients (age 0-19years) who underwent 18F]FET-PET imaging with cross referencing of patient electronic medical records. Conducted at the Children’s Hospital at Westmead in Sydney, Australia.

RESULTS

116 patients underwent 18F-FET PET imaging between October 2012 and January 2024. 28 patients had additional comparative fluorodeoxyglucose (FDG) CNS dedicated PET imaging. Primary indications for FET PET imaging included differentiating between a neoplastic versus non-neoplastic process (23.3%), identifying active residual tumour (14.7%), characterising tumour grade in patients including in those with the known tumour predisposition syndromes (6%), distinguishing between progression pseudo-progression (2.5%) and providing additional localisation or biopsy guidance (8.6%). Malignant transformation, gliomatosis and extent of disease was also noted as indications. 15 patients were able to avoid a biopsy or invasive surgery. Nearly 60% of FET PET imaging was considered clinically useful with the management of 52/112 (46%) patients being supported or changed. Management changes included change second look surgery, change of radiation field, change of treatment and access to a clinical trial. Only 3 scans were reported to have technical challenges in resolution or poor spatial correlation with MRI. Further analysis is currently being conducted, reviewing standard uptake values (SUV’s) of histologically proven low/high grade tumours and T2 enhancing/non-enhancing lesions.

CONCLUSIONS

This small study demonstrated the clinical benefit and utility of 18F-FET PET imaging in paediatric CNS tumours. Our experience has demonstrated significant surgical and diagnostic advantage in tumour localisation as well as avoiding surgery where able.
IMMU-06. CAR DESIGN SHAPES THE BRAIN TUMOR IMMUNE MICROENVIRONMENT: IMPACT ON ACTIVITY AND PERSISTENCE OF ANTI-GLIOMA ADOPTIVE T CELL IMMUNOTHERAPY
Authors: Haydar Dalia , Ibañez-Vega Jorge , Crawford Jeremy , Yi Zhongzhen , DeRenzo Chris , Gottschalk Stephen , Roussel Martine , Thomas Paul , Krenciute Giedre
Published: June 2024

BACKGROUND

B7-H3 CAR T-cells effectively eradicate brain tumors in xenograft models and have proven safe in clinical trials, yet no objective responses were observed in patients. The limited efficacy is partly attributed to the immunosuppressive tumor microenvironment (TME), a characteristic not fully recapitulated in investigations using xenograft models. In this study, we set to optimize B7-H3 CAR structure and examine the effects of CAR design on the brain TME using an immunocompetent glioma model.

METHODS

We generated a panel of fully murine B7-H3 CARs with variations in transmembrane, co-stimulatory, and activation domains. This enabled us to comprehensively investigate their effector functions within the intact immune system. High-dimensional flow cytometry and single-cell RNA sequencing were then used to investigate changes in the brain TME following CAR T-cell therapy.

RESULTS

While five out of six B7-H3 CARs with single co-stimulatory domains exhibited potent functionality in vitro, optimizing co-stimulation and signaling failed to enhance their anti-glioma efficacy in vivo. To further enhance therapeutic effectiveness and persistence, we incorporated 4-1BB and CD28 co-stimulation through transgenic expression of 4-1BBL on CD28-based CAR T-cells. Although this design significantly improved anti-glioma efficacy in vitro, it conferred no additional benefits in vivo. Analysis of the TME revealed that CAR T-cell therapy influenced the immune composition of the brain TME. Successful anti-tumor responses were dictated by the recruitment, activation, and spatial localization of unique inflammatory ‘immune hubs’ containing specific subsets of macrophages and endogenous T-cells. Interestingly, depletion of brain macrophages using CSF1R inhibitor markedly inhibited CAR T-cell anti-tumor activity.

CONCLUSION

Our study highlights the critical role of CAR structural design and its modulation of the TME in mediating the efficacy of CAR T-cell therapy in brain tumors. Yet, more specific targeting and/or reprogramming of the TME is warranted for the successful design of effective adoptive immunotherapies for high-grade glioma.
IMMU-11. CLINICAL EXPERIENCE WITH THE CONCEPT OF MULTIPHASE COMBINED TREATMENT FOR ADULTS WITH GBM
Authors: Van Gool Stefaan W , Kosmal Jennifer , Van de Vliet Peter , Kampers Linde F C , Stuecker Wilfried
Published: June 2024

BACKGROUND

We published survival data of 50 adults with GBM treated with individualized multimodal immunotherapy (IMI) as part of a multiphase combined treatment (Van Gool et al, https://doi:org/10.1016/bs.mcb.2023.06.001). Analysis was repeated with new observation data.

METHODS

Patient definition for retrospective analysis: start IMI between 27/05/2015 and 31/10/2023, >18y, newly diagnosed, IDH1 wild-type, MGMT promoter-methylation status documented, survival known, no second malignancy.

RESULTS

Forty (14 female, 26 male) GBM patients were MGMT-promoter-unmethylated (unmeth), while 31 (15 female, 16 male) were MGMT-promoter-methylated (meth). Comparing the molecular subgroups, both respective median age; 48 years (range 18-65) and 54 years (range 26-72), and respective Karnofsky performance index; 70 (range 50-100) and 80 (range 60-100), were equal. Patient distribution (< complete resection, complete resection, not documented) was equal: 17/15/8 (unmeth) versus 17/11/3 (meth). Both groups were treated similarly: in median 37 (range 0-147) sessions of modulated electrohyperthermia, in median 37 (range 5-147) bolus injections of Newcastle Disease Virus, in median 2 (range 0-6) IO-Vac® vaccines with a median total number of 30.7x10e6 DCs (range 0-158x10e6). The median overall survival (mOS) for the total group was 27 months. The 2-year overall survival (OS) was 57.9 % and the 3-year OS 37.1 %. The mOS for unmeth patients was 22.1 month, with a 2-year OS of 42.7%. The mOS for meth patients was 37.7 months, with a 2-year OS of 75.5%. Sampling five control arms of contemporary RCTs as external control arm (Liau et al, JAMA Oncol 2023) showed for unmeth and meth patients a mOS of 14.6 resp. 21.3 months with a 2-year OS of 21% resp. 42%, which reflects the current prognosis for these patients.

CONCLUSIONS

Our analysis confirms that the integration of IMI during and after standard of care improves the OS. Similar multiphase combined treatment strategy, including IMI, should be considered to treat childhood GBM.
LGG-04. TRAMETINIB COMBINED WITH CHEMOTHERAPY FOR INFANT BRAF-FUSED CHIASMATIC GLIOMA
Authors: Toledano Helen , Michaeli Orli , Kaadan Walid , Caduri Shlomi , Friedland Rivka , Dotan Gad , Konen Osnat
Published: June 2024

BACKGROUND

Infant chiasmatic gliomas present a major therapeutic challenge due to large size, threat to vision and progressive nature. Infants <1 year respond poorly to Vincristine/Carboplatinum chemotherapy (SIOP-LGG2). BRAF fusion is common, so MEK inhibitors have been used second line in older children, but time to response is slow (median ~20 months). Data on the use of these drugs in infants is limited as is data on the safety and efficacy of combining chemotherapy with MEK inhibitors.

METHODS

We report two infants treated successfully for BRAF fused chiasmatic glioma - both presented age 5 months with nystagmus and diencephalic syndrome. Both had significant tumor progression within 6 weeks of starting Vincristine/ Carboplatin which responded rapidly to the addition of Trametinib.

RESULTS

Case 1 required tumor debulking at week 6 of chemotherapy due to progressive hyponatremia, hydrocephalus and brainstem compression. Surgery caused diabetes insipidus, hemianopia and hemiparesis. Tumor growth continued despite reinstating chemotherapy. Addition of trametinib caused tumor shrinkage by 75% within 12 weeks and 90% by 1 year. Minirin doses were reduced by 80% on Trametinib. After 1.3 years, chemotherapy was stopped & Trametinib continued alone. Case 2 - tumor growth and severe hyponatremia by week 6 of chemotherapy prompted addition of Trametinib without surgery. There was tumor reduction of 50% over 6 months and improvement of severe failure to thrive. Hyponatremia, requiring sodium and urea supplementation, stabilized. Bilateral vision and age-appropriate development are maintained. Hypertension developed early, but resolved completely after stopping and then gradually reintroducing Trametinib. Recurrent diarrhea required dose reduction.

CONCLUSIONS

We show the safety and efficacy of combined treatment with chemotherapy and MEK inhibition in infants and postulate that both the combination and the young age at initiation of therapy may have contributed to the excellent outcome. We urge for clinical trials of combination therapy in this age group.
LGG-09. REBOUND GROWTH AFTER MAPKI WITHDRAWAL INVOLVES RAPID MAPK REACTIVATION AND CYTOKINE-MEDIATED MICROGLIA RECRUITMENT IN PEDIATRIC LOW-GRADE GLIOMA MODEL
Authors: Kocher Daniela , Cao Lei , Guiho Romain , Langhammer Melanie , Lai Yun-Lu , Becker Pauline , Friedel Dennis , Selt Florian , Vonhören David , Zaman Julia , Valinciute Gintvile , Herter Sonja , Rettenmeier Johanna , Maass Kendra K , Pajtler Kristian W , von Deimling Andreas , Pusch Stefan , Pfister Stefan M , Oehme Ina , Jones David T W , Halbach Sebastian , Brummer Tilman , Martinez-Barbera Juan Pedro , Witt Olaf , Milde Till , Sigaud Romain
Published: June 2024

Patients with pediatric low-grade gliomas (pLGG), the most common primary brain tumor in children, can often benefit from MAPK inhibitor (MAPKi) treatment. However, rapid tumor regrowth, also referred to as rebound growth, may occur once treatment is stopped, constituting a significant clinical challenge. Four patient-derived pLGG models were investigated to model rebound growth in vitro based on viable cell counts in response to MAPKi treatment and withdrawal. A multi-omics dataset of the rebound model encompassing different MAPKi withdrawal timepoints was generated using RNA sequencing and LC-MS/MS based phospho-/proteomics to investigate possible driving mechanisms of rebound growth. Following in vitro validation, putative rebound driving mechanisms were validated in vivo using the BT-40 orthotopic xenograft model. Of the tested models, BT-40 (BRAFV600E, CDKN2A/Bdel) showed rebound growth upon MAPKi withdrawal, characterized by faster cell regrowth after MAPKi withdrawal compared to standard-of-care chemotherapy. Using this model, we observed MAPK pathway reactivation within hours after withdrawal, associated with a transient overactivation of key MAPK molecules at transcriptional (e.g. FOS) and phosphorylation (e.g. pMEK) levels. Additionally, we observed increased expression and secretion of cytokines (in particular CCL2, CX3CL1, CXCL10 and CCL7) upon MAPKi treatment, maintained during early withdrawal (at least until 24 h). While increased cytokine expression did not affect response to MAPKi or rebound growth upon withdrawal in an autocrine manner, increased attraction of microglia cells mediated by these cytokines was observed. MAPK pathway reactivation during rebound growth and increased expression of CX3CL1 and CXCL10 induced by MAPKi treatment could further be confirmed in vivo. Taken together, these data indicate a rapid MAPK reactivation upon MAPKi withdrawal as a tumor cell intrinsic rebound driving mechanism. Furthermore, increased microglia recruitment during MAPKi treatment and withdrawal, mediated by cytokines, may play a role in response to MAPKi treatment and rebound growth upon withdrawal, warranting further evaluation.
LGG-25. ADVANCING RESPONSE ASSESSMENT OF LOW-GRADE GLIOMAS: IDENTIFYING VOLUME CORRELATIONS OF BI-PERPENDICULAR DIAMETER CHANGES WITH MACHINE LEARNING
Authors: Dumbrille Gabe , Zhang Silu , Robinson Giles W , Merchant Thomas E , Bag Asim K
Published: June 2024

BACKGROUND

Assessing brain tumor response is key for effective management and clinical trial benchmarks. Traditionally, bi-perpendicular diameter (BPD) measurements have been used to estimate tumor size. However, recent studies suggest volumetric assessment yields a more accurate measure of response and estimate of tumor burden. Advances in technology enable rapid volume assessments. Integrating volumetric analysis into clinical settings is challenged by the absence of volume-based standards aligned with traditional RAPNO bi-dimensional criteria. Our goal was to correlate volume change percentages with bi-perpendicular diameter changes using machine learning.

METHODS

In this project, we compared 2 machine learning models to establish a correlation between percentage change of sum of products of BPD and percent change in volume using a generalized linear model (GLM) and an artificial neural network (ANN). We analyzed 49 patients with low grade glioma, treated with focal irradiation (NCT04065776) (n=27) or mirdametinib (NCT04923126) (n=22). We trained and validated the models at train-test split ratios of 80/20, 75/25, and 70/30, incorporating a proportionate split of tumors from each group. The models were compared on the validation data set using mean-squared error (MSE).

RESULTS

At percentage changes of +25%, -25%, -50%, and -75% in the sum of BPDs, the GLM predicts changes in volume to be +33%, -31%, -59%, and -83%, respectively. For the ANN, the predicted changes are +20%, -29%, -53%, and -78%. The ANN demonstrated a lower MSE compared to the GLM. The two models showed higher concordance in their volume predictions at negative percentage changes in the sum of BPDs: -25% (p=0.15), -50% (p=0.03), and 75% (p=.08)

CONCLUSION

We identified volume percentage changes matching BPD changes per RAPNO criteria using two machine learning methods, both agreeing on negative values. Further testing with a larger dataset is needed to reliably correlate percentage changes.
LGG-28. THE ROLE OF REOPERATION IN PEDIATRIC CEREBELLAR PILOCYTIC ASTROCYTOMA
Authors: Kameda-Smith Michelle Masayo , Green Katherine , Hutton Dana Louise , Jeelani Owase , Thompson Dominic , Hargrave Darren , Aquilina Kristian
Published: June 2024

BACKGROUND

Cerebellar pilocytic astrocytomas (cPAs) in childhood have long been recognized to have a good prognosis after total resection but the outcome after incomplete resective surgery remains largely unpredictable with the incidence of radiological progressive disease ranging from 18-100%. Traditionally thought that GTR was required for long-term survival, small residuals were classically resected in a subsequent operation.

METHODS

We analyzed our Pediatric Low-Grade Glioma (PLGG) database, between 1985 and 2020, and filtered for intracranial pilocytic astrocytomas to determine what clinical or radiological factors precipitated revisional resective surgery in our single quaternary center cohort.

RESULTS

Using our Pediatric Low-Grade Glioma (PLGG) database, 283 patients were identified to have a histopathological diagnosis of intracranial pilocytic astrocytoma between 1985-2020 of which 202 were within the cerebellum (68.2%). The majority of patients with cerebellar PA were between 1-10 years of age (n=147, 73.5%) without gender predominance (M:F=99:101), usually presenting with 1 lesion (n=197, 98.5%). Gross total resection (GTR) was achieved in 74.5% (n=149) of initial surgeries for cerebellar PA. In patients with NTR or STR, the mean largest diameter of the post-operative residual was 1.1cm (0.2-3.7cm). Seven patients with STR did not require a second resective intervention. In 31 patients the neuro-oncology multidisciplinary team (MDT) recommended a second surgical resection at a mean time interval of 22.9 months (0.13-81.6 months) from the initial surgery. Proportionally, the children who underwent multiple resections were also more likely to receive adjuvant chemo/radiotherapy. Functionally, the children in the multiple operation cohort experienced more complications of therapy including ongoing endocrinopathy, treatment-associated hearing deficit, and neurocognitive deficits.

CONCLUSION

Residual disease in cPA should be maintained under clinocoradiological surveillance post-operatively with adoption of a more conservative approach when residual disease is not significantly changing over time.