bluuebunny/crossref_metadata_2025_split huggingface dataset:
INNV-22. TEMOZOLOMIDE DESENSITIZATION AND CONSIDERATIONS FOR IMPLEMENTATION IN AN ACADEMIC MEDICAL CENTER: A CASE REPORT
Authors: Wojkowski Jenna , Palazis Aphrodite , Ogbogu Princess , Wessell Kathryn Ruda , Roberts Patricia , Newton Herbert 
Published: November 2023

Abstract
Temozolomide is an alkylating agent commonly used in the treatment of central nervous system (CNS) malignancies, including glioblastoma multiforme (GBM). Rashes have been noted to occur in about 19% of patients receiving temozolomide, with severe rashes ( &gt; grade 3) only noted in about 1% of patients. Here we report the case of a 42-year-old female patient diagnosed with GBM who presented with widespread, progressive urticaria on her chest, abdomen, back, legs, and arms during her first adjuvant cycle of temozolomide. With temozolomide being a standard of care in the treatment of GBM, our team decided to attempt a second adjuvant cycle via desensitization prior to exploring alternative treatment options. There is currently no standard for temozolomide desensitization; however, there are a few published case reports. Based on existing literature, a protocol was developed and utilized for a total of four additional cycles. During the second, third, and fourth desensitization cycles, which were completed in the outpatient setting, the patient experienced headache, urticaria, and nausea/vomiting. A steroid taper was prescribed and the patient completed the desensitization protocol and the remainder of each of the aforementioned cycles without further issues. Our case report provides a review of the current literature and discusses operational considerations and limitations related to temozolomide desensitization protocol development and execution. This case illustrates the need for additional data to determine efficacy of desensitization compared to standard dosing regimens.
INNV-25. PROLONGED FOLLOW-UP OF AN OLIGODENDROGLIOMA PATIENT WITH HISTORY OF TUMOR TREATING FIELDS (TTF) AS POST CHEMO-RADIATION MAINTENANCE THERAPY
Authors: Ko Uvin , Fu Beverly Dan , Myung Joon , Kong Xiao-Tang 
Published: November 2023

Abstract
INTRODUCTION: Recurrence of low and high-grade gliomas are common after radiation and chemotherapy. Despite continued research on glioma’s management, there is limited knowledge regarding the role of maintenance treatment after standard radiation and chemotherapy therapy. Tumor Treating Fields as maintenance therapy after radiation and chemotherapy may potentially help prevent recurrence of oligodendroglioma. Case Report: A 35-year-old male developed headaches and a non-enhancing mass was detected on his brain MRI in 2011. Observation was advised by his surgeon. The patient presented with seizures in early 2014, and his brain MRI found the mass developed new enhancement. In late 2014, the patient had multiple seizures, and significant progression of the tumor was discovered. The patient underwent craniotomy and biopsy in the middle cerebral artery distribution area in early 2015. Pathology reported grade II oligodendroglioma; however, a biopsy might have missed the high-grade glioma region. His brain MRI showed a significant enhancing lesion, which was clinically also consistent with grade III oligodendroglioma due to rapid growth. Radiation was conducted followed by 6 cycles of PCV chemotherapy throughout 11 months. Post-radiation-chemotherapy brain MRI was stable with a moderate size residue tumor at the right insula region. Following patient wishes, NovoTTF-100A, or Optune, was administered 6 weeks after completion of chemotherapy as maintenance therapy for 2 years to prevent tumor progression. Now, after 5 years being off Optune, the patient is full-functional, and his brain MRI is stable without tumor progression. Discussion: Our case highlights the potential effect of Tumor Treating Fields as maintenance therapy after initial radiation and chemotherapy for lower and higher grade oligodendrogliomas. The patient had rapid tumor progression on brain MRI prior to treatment and only underwent a biopsy without resection, yet uncommonly, remains survival and full functional since initial image diagnosis 12 years ago and tissue diagnosis 8 years ago.
INNV-26. THE CHALLENGE OF TREATING ADULTS WITH MEDULLOBLASTOMA – THE CANON EXPERIENCE
Authors: Bennett Julie , Lim-Fat Mary-Jane , Roberto Katrina , Massey Natalie , Ramaswamy Vijay , Sahgal Arjun , Mason Warren , Morgan Erin , Ironside Sarah , Ahmed Osama , Tsang Derek , Das Sunit , Tabori Uri , Hawkins Cynthia , Climans Seth 
Published: November 2023

Abstract

INTRODUCTION
Medulloblastoma (MB) is the most common malignant brain tumor in children, but relatively rare in adults. Pediatric treatment paradigms may be applied to young adults despite a paucity of data in this population. Here we aim to describe the characteristics of adults with MB presented at the Canadian Adolescent and Young Adult Neuro-Oncology Network (CANON) multi-disciplinary national rounds along with provider’s current practices in treating these patients.

METHODS
Cases presented at national rounds between April 2021 – June 2023 including young adults with MB were analyzed to describe patient characteristics and themes of the questions posed. In addition, a survey was sent to all Canadian neuro-oncologists asking about current practice patterns and we describe responses.

RESULTS
A total of 15 young adults with MB were discussed in this time frame. There were 13 males and 2 females with a median age of 30 years (range 20-61). Subgrouping was available on 12/15, with 7 (46.7%) SHH-activated, 3 (20%) WNT-activated and 3 (20%) Group 4 MB. Ten of the patients presented were new diagnoses with discussion regarding treatment including dose of radiation and chemotherapy protocol. In addition, 4/10 had an incomplete resection and there was discussion regarding a second look surgery. Three patients were presented at time of recurrence, with 2/3 being extra-cranial recurrence. There were a total of 25 responses to the Canadian survey on medulloblastoma, showing variation in practice. Most patients got craniospinal irradiation with 36 Gy. There was wide variation in terms of chemotherapy regimens offered.

CONCLUSION
There are differences in treatment practices for adults with MB across Canada with many questions regarding what treatment should be offered, specifically related to chemotherapy regimen. This highlights the desperate need to harmonize practice and examine adults as a unique cohort.
PATH-04. TRANSFORMATION OF GRADE 2 OLIGODENDROGLIOMA TO GLIOSARCOMA WITH RAPID AND EXTENSIVE PROGRESSION: CASE REPORT.
Authors: Jani Ronak , Casinelli Eric , Goyal Abhishek , Prabhu Vikram , Chundury Anupama , Borys Ewa , Barton Kevin , Thakkar Jigisha 
Published: November 2023

Abstract
Transition of WHO grade 2 oligodendroglioma to gliosarcoma is rare. We report a case of a 40 year-old gentleman with WHO grade 2 oligodendroglioma, isocitrate dehydrogenase enzyme (IDH)-mutant, 1p/19q co-deletion positive, O6-methylguanine-DNA methyltransferase (MGMT) promoter methylated, tumor mutational burden of 5 mutations/megabase, with microsatellite stability. He underwent rapid and extensive transformation to WHO grade 4 glioblastoma with gliosarcomatous features, mesenchymal subclass on DNA methylation, IDH-wild type, 1p/19q co-deletion negative, MGMT promoter methylated. He was diagnosed with bi-hemispheric multifocal partially enhancing, T2-FLAIR hyperintense lesions. Pathology revealed WHO grade 2 oligodendroglioma. He enrolled on a clinical trial to receive proton radiation (45 Gray in 25 fractions) to the involved tumor sites. Three weeks after initiation of radiation, he developed headache, imbalance, and confusion. MRI brain 3 weeks after completion of radiation revealed worsening enhancement, edema, and a new region of non-enhancing T2-FLAIR hyperintensity. Bevacizumab was added for presumed pseudo-progression; followed by chemotherapy with procarbazine and lomustine (PC). Four cycles of PC were completed with observations of gradual clinical and radiographic worsening after each cycle. Re-resection of multifocal tumor for tissue diagnosis and tumor debulking revealed progression to WHO grade 3 oligodendroglioma with high mitotic activity and regions of palisading necrosis. Two weeks postoperatively, malignant cerebral edema developed, requiring left sided decompressive craniectomy. Despite early introduction of 2nd-line chemotherapy with temozolomide, his disease continued to progress and he succumbed 1.5 years after initial diagnosis. Autopsy revealed extensive bi-hemispheric involvement of WHO grade 4 glioblastoma. Our patient demonstrated unusually rapid clinical and radiographic progression within one month after completion of radiation. Other reported cases in the literature have documented progression at 1 to 5 years after initial treatment. Both IDH mutation and 1p19q co-deletion were lost in the gliosarcomatous transformation. This tumor did not respond to alkylating agents despite the MGMT promoter-methylated status.
PATH-07. GENOMIC AND IMMUNE ANALYSIS OF PRIMARY REPLICATION-REPAIR DEFICIENT (RRD) GLIOMAS REVEALS THREE SUBGROUPS WITH DISTINCT DRIVERS AND RESPONSE TO IMMUNOTHERAPY: AN IRRDC REPORT.
Authors: Fernandez Nicholas , Chang Yuan , Lee Caitlin , Dimayacyac Jose , Levine Adrian , Negm Logine , Aamir Zoya , Nobre Liana Figueiredo , Bianchi Vanessa , Stengs Lucie , Crump Owen , Gattoni Emma , Chung Jiil , Nunes Nuno , Edwards Melissa , Bouffet Eric , Hawkins Cynthia , Das Anirban , Tabori Uri 
Published: November 2023

Abstract

BACKGROUND
Replication-repair deficiency (RRD) caused by germline/somatic defects in mismatch repair (MMRD) and/or polymerase-proofreading genes (PPD) drives 5-10% of high-grade gliomas in children, adolescents, and young adults (CAYA). Despite harbouring high mutation-burden (TMB), the basis of their heterogenous responses to immune-checkpoint inhibitors (ICI) is unknown.

METHODS
We performed multi-omic and immune analyses on human RRD-glioma specimens and developed murine models to investigate their differential responses to ICI.

RESULTS
RRD-gliomas in 202 CAYA-patients uniformly harbored high genomic microsatellite-instability and hypermutation (median TMB: 302-mutations/megabase), with specific MMRD mutational signatures contributing to frequent mutations in TP53 (88%), ATRX (83%), RAS/MAPK (77%) and IDH1/2 (17%). Strikingly, common pediatric mutations (K27M, G34R/V and BRAF;p.V600E) unrelated to MMRD signatures were absent, and a unique methylation profile distinct from non-RRD gliomas was observed. Molecularly, RRD-gliomas segregated into three genomic subgroups: RRD1 (MMRD+PPD; 56%), RRD2 (MMRD-only; 27%), and RRD3 (MMRD+IDH1/2; 17%). RRD1 included glioblastomas that developed early in germline CMMRD patients across the cerebral hemispheres and posterior-fossa, harbored extreme TMB (median: 420-mutations/megabase), balanced copy-number profiles, and immunogenic PPD signatures. RRD3 predominated in Lynch syndrome, presented in older children, were located in the forebrain, harbored lower TMB (median: 31-mutations/megabase) and demonstrated specific chromosomal gains/losses. Enrichment for immune-resistant JAK-STAT signalling in the RRD2/RRD3 transcriptome, and presence of high CD8+ T-cells in RRD1-glioma microenvironment, correlated with significantly improved 24-month post-ICI survival of 75% in RRD1 versus 43% and 33% for RRD2/3, respectively (p &lt; 0.0001). Genetically engineered mouse models recapitulated the immuno-genomic phenotype and ICI-responses of the human RRD-subgroups, allowing successful preclinical testing of combinatorial checkpoint-inhibition strategies. Significant temporal and spatial heterogeneity linked to genomic instability and post-therapy immune-escape were observed.

CONCLUSION
Our data emphasizes an immediate need to distinguish RRD-glioma subgroups in clinical practice and translate our preclinical discoveries to subgroup-specific ICI-based combinatorial clinical trials.
PATH-11. POOLED IN VIVO ASSAY TO CHARACTERIZE GLIOBLASTOMA INVASION AT THE SINGLE-CELL RESOLUTION
Authors: Hara Toshiro , Chanoch-Myers Rony , Bussema Lillian , Greenwald Alissa , Behnan Jinan , Wakimoto Hiroaki , Galli Rossella , Tirosh Itay , Suva Mario 
Published: November 2023

Abstract
Tumor cell invasion is the main characteristic of glioblastoma and one of the obstacles to successful treatments. Nonetheless, molecular features of invading glioblastoma cells remain elusive and poorly characterized, such as their gene expression states and microenvironmental influences. Recently, we described cell state heterogeneity in glioblastoma by single-cell RNA-sequencing (scRNA-seq) and uncovered the contribution of immune cells to the heterogeneity. However, it is unclear whether the cell states observed in clinical specimens are implicated in invading glioblastoma cells in the surgically inaccessible brain parenchyma. It is also unclear whether the cell states are correlated to the non-immune microenvironment. As a tool for probing these questions, we developed an in vivo approach with mixtures of human glioblastoma spheroid lines for mouse intracranial xenografts. We validated this with 20 patient-derived models and identified, by scRNA-seq, in vivo models capable of infiltrating along the periphery of either neurons or blood vessels. We profiled and characterized programs, states, and clonality of invading glioblastoma cells by comparing cells from the contralateral invasive edge to their counterparts at the original bulk tumor. This comparative analysis showed evidence of a bi-directional transitioning model for cells residing in different spatial niches. Importantly, presence of an OPC-like state was significantly associated with invasion phenotype regardless of the infiltration routes. Our results suggest that cellular plasticity may be a prerequisite for the invasive phenotypes, urging further assessment to identify critical regulators of the cell states. In conclusion, this work describes pooled in vivo assays for the rapid interrogation of patient-derived xenografts, coupling the gene expression phenotypes with cellular functions such as invasion.
PATH-26. A RARE CASE OF EXOPHYTIC PILOCYTIC ASTROCYTOMA DIAGNOSED VIA MOLECULAR TESTING
Authors: Chee Michelle , McGranahan Tresa 
Published: November 2023

Abstract

INTRODUCTION
Pilocytic astrocytoma (PA) is a WHO grade 1 neoplasm that can share histological and radiological features with more malignant entities, including high grade astrocytoma with piloid features. In cases where the differential remains broad after histopathological examination, DNA methylation analysis and next generation sequencing can contribute significantly to making an accurate diagnosis. Machine learning has also played a role in developing multiple classifying algorithms which group tumors by their methylation status.

CASE
We report a case of an exophytic left frontal mass with adjacent bone erosion that preoperatively was favored to be a meningioma. Intraoperatively, the mass was found to be cortically based. With histopathologic review at two centers, the diagnosis remained IDH wildtype low-grade glioma not otherwise specified. The clinical treatment team interpreted the post-operative increase in T2 signal as radiographic progression consistent with high grade glioma and planned to proceed with chemoradiation. Patient elected for further evaluation; methylation array profiling and next generation sequencing identified a KIAA1549::BRAF fusion, consistent with a final diagnosis of pilocytic astrocytoma, a WHO Grade 1 Glioma. Given the favorable prognosis following gross total resection, the patient was recommended active surveillance and radiation and chemotherapy treatment planning was stopped.

DISCUSSION
This is a rare case of an exophytic pilocytic astrocytoma in which the tumor’s atypical histologic and radiographic appearance increased the likelihood of diagnostic errors. This case illustrates the clinical importance of utilizing methylation array profiling and next-generation sequencing to confirm a diagnosis.
PATH-39. INTERPRETABLE IDH CLASSIFICATION FROM H&E-STAINED HISTOLOGY SLIDES
Authors: Innani Shubham , Baheti Bhakti , Nasrallah MacLean P , Bakas Spyridon 
Published: November 2023

Abstract

BACKGROUND
Infiltrating gliomas are the most common primary adult brain tumors. Isocitrate dehydrogenase (IDH) mutation is a key driver of gliomagenesis in 25–30% of infiltrating gliomas and correlates with favorable prognosis when compared with the histologically-similar but biologically-distinct IDH-wildtype glioblastoma. We sought an interpretable computational pipeline to predict IDH status from digitized histopathology glioma sections (Whole Slide Images - WSI) and identify associated cell-level morphology. Materials and

METHODS
We identify 799/1122 TCGA-GBM and TCGA-LGG tumors (1534 WSIs) with available IDH status. 379 of these tumors (756 WSI) are IDH-wildtype and 420 tumors (778 WSI) are IDH-mutant. Each H&E-stained WSI undergoes comprehensive curation to remove artifactual content before classification. Our interpretability mechanism is based on weakly-supervised attention-based multiple-instance-learning. IDH-associated morphology in each WSI is evaluated by a HoverNet model from the 50 highest-attention tiles. Classification performance was assessed using 10-fold cross-validation, with training (80%), validation (10%), and test (10%) sets stratified on the patient/tumor level, without controlling for grade. An additional out-of-sample hold-out test set of 82 IDH-wildtype and 32 IDH-mutant tumors from the University of Pennsylvania Health System was further used for independent evaluation.

RESULTS
Quantitative performance evaluation revealed AUC=0.92 and Balanced Accuracy=0.84 on the TCGA test set, and AUC=0.88 and Balanced Accuracy=0.80 on the independent hold-out UPenn set. When comparing identified IDH-wildtype with IDH-mutant tumors (and while excluding glioblastoma with lower-grade histology), the former shows significantly (p&lt; 0.00005) higher distribution of neoplastic and necrotic cells and significantly (p&lt; 0.00003) lower distribution of inflammatory and connective cell type tissue.

CONCLUSION
Histological prediction of IDH status represented an ideal prototype to interrogate WSI towards identifying clinically-relevant tumor biomarkers. Detailed interpretation of results reveals computational predictions being driven by human-identifiable features at the patch level. This study robustly identifies morpho-IDH correlates and could enable further prognostic refinement of patients.
PATH-54. CDC42BPA::BRAF REPRESENTS A NOVEL FUSION IN DESMOPLASTIC INFANTILE GLIOMA
Authors: Guinle Maria Isabel Barros , Nettnin Ella A , Nasajpour Emon , Nirschl Jeffrey , Garcia Cesar A , Vogel Hannes , Yeom Kristen , Prolo Laura , Petritsch Claudia 
Published: November 2023

Abstract
Desmoplastic infantile ganglioglioma/desmoplastic infantile astrocytomas (DIG/DIA), although rare, are low-grade glioneuronal tumors that typically affect patients &lt; 1 year old, and generally carry a good prognosis. Often successfully cured with surgical excision, DIG/DIA still carry the potential for malignant transformation or recurrence. Whilst pediatric low grade glioma (LGG) survival rates are &gt;95%, tumor grade does not correlate well with outcomes in infant LGG (iLGG), thus highlighting the need for investigation into molecular mechanisms of tumor progression. We describe a novel CDC42BPA-BRAF fusion in a DIA in a three-month old patient, and its detection via Next Generation Sequencing. Future studies will investigate whether this novel fusion can function as a target for BRAF and MAPK pathway inhibitors, which have recently been FDA-approved for pLGG.
PATH-63. NEXT GENERATION SEQUENCING FOR CNS TUMORS IN CHILDREN; DOES IT ADD VALUE IN A MIDDLE-INCOME COUNTRY SETUP?
Authors: Amayiri Nisreen , Al-Hussaini Maysa , Maraqa Bayan , Alzoubi Qasem , Musharbash Awni , Ibrahimi Ahmad , Sarhan Nasim , Obeidat Mouness , Hawkins Cynthia , Bouffet Eric 
Published: November 2023

Abstract

INTRODUCTION
Advances in molecular diagnostics led to improved targeted interventions in the treatment of pediatric CNS tumors. However, the capacity to do these diagnostics is limited in LMICs, and consequently their value is questionable.

METHODS
We reviewed our experience of Next Generation Sequencing (NGS) testing (TruSight RNA Pan-Cancer seq panel) for pediatric CNS tumors at KHCC/Jordan (March/2022- April/2023). Paraffin blocks’ scrolls were shipped to Sickkids laboratory based on local multidisciplinary team recommendations. We reviewed patients’ clinical characteristics, tumor types and the impact on treatment.

RESULTS
There were 16 boys and 16 girls; median age at time of testing was 9.5 years (range, 0.9- 21.9 years). Twenty samples were sent at diagnosis and twelve upon tumor progression. Main diagnoses were Low-grade glioma (15), High-grade glioma (10), and other tumors (7). Reasons for NGS testing were: to find a molecular target (20), and to characterize more tumor/behavior (12). The median time from shipping the samples to receive the NGS result was 22 days (range, 15-49 days) at a cost of US$1000. Twenty (63%) tumors had targetable alterations (MAPK/PI3K inhibitors (16), NTRK inhibitors (2), check point inhibitors (2)). Two rare BRAF mutations were identified (BRAFp.G469A, BRAFp.K601E). One tumor diagnosed initially as undifferentiated round-cell sarcoma found to have NAB2::STAT6 fusion and re-diagnosed as aggressive metastatic solitary fibrous tumor. Eight patients received targeted therapy; Dabrafenib/Trametinib (5), Pembrolizumab (2), Entrectinib (1), while radio-chemotherapy was used in the others. Three patients died from disease progression (one used Entrectinib).

CONCLUSIONS
Sent abroad NGS testing was feasible, however local capacity building is necessary. In this highly selected tumor cohort, high percentage of targetable alterations were identified. NGS was helpful to characterize tumors more and to offer alternative therapies. Nevertheless, interpretation of the significance of NGS results and access to those “new” therapies continues to be a challenge in LMICs