bluuebunny/crossref_metadata_2025 huggingface dataset:
INNV-36. ULTRA-FAST DEEP-LEARNED CNS TUMOR CLASSIFICATION USING NANOPORE-SEQUENCING DURING SURGERY
Authors: Wesseling Pieter , Vermeulen Carlo , Pages-Gallego Marc , Kester Lennart , Kranendonk Mariëtte , Verburg Niels , Hamer Philip de Witt , Kooi Evert-Jan , Dankmeijer Luuk , van der Lugt Jasper , Van Baarsen Kirsten , Hoving Eelco , Tops Bastiaan , De Ridder Jeroen
Published: November 2023

BACKGROUND

Preoperative imaging and intraoperative histological analysis provide important guidance during CNS tumor surgery but are not always precise enough. Also, the diagnosis of CNS tumors increasingly requires a combination of morphological and molecular analysis. Illumina DNA methylation array analysis provides information on hundreds of thousands of methylation sites genome-wide but is relatively time-consuming and expensive. Nanopore sequencing enables real-time generation of an increasingly precise methylation profile. AIM: To exploit the potential of nanopore sequencing as a tool for intraoperative molecular diagnostics of CNS tumors.

METHODS

We developed Sturgeon, a patient-agnostic, transfer-learned neural network approach. Sturgeon leverages publicly available Illumina 450K DNA methylation profiles to simulate millions of nanopore sequencing experiments, which were used to train and validate classifier models. Subsequently, snap-frozen archival samples of 50 CNS tumors were analyzed, as well as fresh tumor samples of an additional 25 CNS tumors intraoperatively.

RESULTS

Sturgeon delivers models capable of classifying 81 different CNS tumor types based on relatively sparse, randomly distributed nanopore sequencing data. Sturgeon was able to suggest within 40 minutes after the start of sequencing the correct diagnosis with high confidence in 45 out of 50 archival CNS tumor samples; in the remaining cases Sturgeon abstained from a diagnosis. In the real-life scenario, in 18 out of 25 cases (72%) the suggested diagnosis was correct, and in 7 cases the required confidence threshold was not reached (mostly because of low tumor cell percentage). Importantly, the Sturgeon models are portable, work across patients and sequence depths, and require less than a minute of computation on a laptop CPU.

CONCLUSIONS

Intraoperative nanopore sequencing can assist neurosurgical decision making and opens avenues for starting tumor-specific therapy already during operation. Furthermore, this diagnostic approach has the potential to reduce the costs of methylation profiling analysis and speed-up the multidisciplinary decision-making process.
INNV-42. INTRA-ARTERIAL MELPHALAN FOR HISTIOCYTIC NEOPLASMS INVOLVING NEUROLOGIC, OCULAR, AND HEAD AND NECK STRUCTURES
Authors: Diamond Eli , Ramos Alexander , Knopman Jared , Reilly Julia , Canestaro Julia , Hatzoglou Vaios , Pierre Gobin Y , Garton Andrew , Abramson David , Francis Jasmine
Published: November 2023

BACKGROUND

Histiocytic neoplasms are clonal hematopoietic disorders of myeloid lineage. Involvement of neurologic structures by histiocytic infiltration or disease-associated neurodegeneration (ND) represents a severe disease phenotype associated with morbidity and mortality. Despite recent advances with BRAF and MEK inhibitors, patients with neurohistiocytic involvement continue to demonstrate suboptimal outcomes. Intra-arterial chemotherapy (IAC) may represent an effective therapy for this disease manifestation.

METHODS

Patients with biopsy-proven histiocytic neoplasms involving neurologic, ocular, or head and neck structures were treated with intra-arterial melphalan delivered via selective catheterization of tumor arterial vasculature. Patients treated had refractory/persistent tumorous disease or progressive functional decline despite BRAF/MEK inhibition, or had limited disease appropriate for local therapy. Patients were evaluated for radiologic (PET or CT/MRI) response and functional neurologic response with quantified ataxia and dysarthria scales, or change in visual acuity (VA), as appropriate. Procedure-related adverse events as well as clinical and laboratory toxicities were captured.

RESULTS

74 IAC treatments were administered to 17 patients, 12 with tumorous disease (6 Rosai-Dorfman disease; 3 xanthogranuloma; 3 Langerhans cell histiocytosis[LCH]; 1 Erdheim-Chester disease [ECD]), 5 with ND-LCH/ECD, and ten with disease-related impairment of VA. Patients received a range of 2-12 IAC doses. 9/12 (75%) patients with tumorous disease had complete or partial radiologic response. 4/5 patients with ND had measurable improvement in dysarthria and 2/5 had measurable improvement in ataxia. 4/10 patients had improved VA. Of all patients with clinical or radiologic response, three have experienced disease recurrence since IAC in long-term follow-up. No procedural adverse events were observed, 1 patient had neutropenia and 1 patient melphalan hypersensitivity.

CONCLUSIONS

IA melphalan is a safe and robustly effective treatment option for tumorous and ND histiocytic neoplasms of neurologic, ocular, and head and neck structures.
PATH-14. MSI GENETIC FINDINGS IN FAMILIAL TURCOT SYNDROME 1 ASSOCIATED TO REPRODUCTION FAILURE
Authors: Abdelmoula Nouha Bouayed , Abdelmoula Balkiss
Published: November 2023

The aim of this study was to report MSI genetic findings in a three-generation Tunisian pedigree of Turcot syndrome 1 (TS1), characterized by an uncommon association with infertility and child mortality. Microsatellite instability testing and genetic counseling were offered to affected members and their young relatives, to provide optimal clinical and preventive care. The index case of our Tunisian pedigree was a 38-year-old female, in whom histologic assessment of endoscopic specimens through a colorectal adenoma resection during screening colonoscopy, showed a tubular adenoma of the lower rectum with low-grade intraepithelial neoplasia. The screening procedure was conducted because her two brothers, 58 and 60 years old, harbored respectively glioblastoma multiforme and colon adenocarcinoma. The first brother exhibited an intracranial hypertension syndrome and a left hemiplegia leading to the diagnosis of a brain tumor. Whereas the second brother manifested diarrhea and intestinal colic that were investigated by colonoscopy. Histologic assessment of endoscopic specimens through a right preangular budding formation showed a well-differentiated liberkhunian adenocarcinoma that was treated by a right hemicolectomy. Genetic assessment at the germinal and somatic levels was conducted for the three affected patients using conventional microsatellite instability (MSI) testing methods. Molecular analysis determined MSI status of the tumors and classified them into stable types (MSS) without any mutation or aberrant expression of MLH1, MSH2, MSH6, and PMS2 genes. Familial history revealed, at the first generation, a consanguineous couple who lost several children at a young age. This couple gave birth to eight children, three of whom were infertile, three affected by MMS TS1 and two healthy. The third generation consists of 15 children, so far, without any tumors. Genetic counselling for TS remains difficult because of the rarity of the condition, its shifting definition over the years, and its genetic and phenotypic heterogeneity.
PATH-15. GLIOBLASTOMA, IDH-WILDTYPE WITHOUT KEY MOLECULAR FEATURES.
Authors: Saito Ryuta , Motomura Kazuya , Ohka Fumiharu , Yamaguchi Junya , Maeda Sachi , Nishikawa Tomohide , Mizutani Kosuke , Kibe Yuji , Shimizu Hiroki , Takido Yuhei
Published: November 2023

Molecular alterations that predict aggressive behavior of astrocytic tumors include EGFR amplification, TERT promoter (pTERT) mutations, gain of chromosome 7 and loss of chromosome 10. During January 2020 and February 2023, we encountered 21 cases of pathologically diagnosed glioblastoma, IDH-wildtype without the above-mentioned molecular characteristics. In this study, we tried to characterize these tumors. For all cases, genomic DNA was extracted from fresh frozen tissue. Using extracted DNA, to analyze the status of IDH mutation, 1p/19q codeletion, pTERT mutation, EGFR gene amplification, combined gain of entire chromosome 7, and loss of entire chromosome 10 (+7/− 10), whole exome sequencing, Sanger sequencing and Multiplex Ligation-dependent Probe Amplification (MLPA) was performed. In addition, gene panel testing was performed for suspected familial cases. Among 21 cases, 2 harbored histone G34 mutation and was diagnosed as diffuse hemispheric gliomas, H3 G34-mutant. Among the rest 19 patients, CDKN2A/B homozygous deletions were detected in 7. Three of the rest 12 patients were diagnosed as patients with Li Fraumeni syndrome. Glioblastoma IDH-wildtype CNS WHO grade 4 typically presents necrosis and/or microvascular proliferation. Molecular alterations including EGFR amplification, pTERT mutations, gain of chromosome 7 and loss of chromosome 10 are key features that characterize GBM IDH-wildtype. However, some of the pathologically diagnosed GBM, do not carry these gene alterations. Among those, there existed cases harboring CDKN2A/B homozygous deletions or H3 G34 mutations, and cases suffering Li Fraumeni syndrome.
PATH-16. SURVIVAL ANALYSIS OF ADULT MIDLINE-LOCATED GLIOMAS: DOES THE H3K27 ALTERATION IN ADULT MIDLINE-LOCATED GLIOMAS ACTUALLY INDICATE A POOR PROGNOSIS?
Authors: Chang Jong Hee , Jung In-Ho , Yoo Jihwan , Park Hun Ho , Lim Jaejoon , Moon Ju Hyung , Kim Eui-Hyun , Kang Seok-Gu , Yoon Hong In , Kim Se Hoon
Published: November 2023

OBJECTIVE

Although pediatric midline-located gliomas (MGs) with H3K27 alteration have been widely known to have a poor prognosis, few researchers have assessed adult MGs with H3K27 alteration. We aimed to determine the effect of H3K27 alteration on the prognosis of adult MGs. And we tried to identify the factors affecting the prognosis of diffuse midline glioma (DMG). This is the first study to investigate the prognosis of adult DMGs according to histological grade and is the largest study to investigate the survival of adult patients with DMGs.

METHODS

We reviewed the charts of adult patients diagnosed with MG after undergoing resection or biopsy at our institution between 2010 and 2020. The Gehan–Breslow–Wilcoxon test was used for univariate survival analysis, and the Cox regression proportional hazard model was used for multivariate survival analysis.

RESULTS

Among the 125 adult MGs identified, 45 (36.0%) showed H3K27 alterations. Surprisingly, the H3K27 alteration group showed significantly better median survival than the wildtype group in patients of all ages (23.1 vs. 15.9 months, p=0.040). However, after adjusting for age, the difference in survival between the H3K27-alteration and wildtype groups was not significant (p=0.121). In the survival analysis of 45 patients with DMG, low histological grade, KPS ≥ 80, total resection, and concurrent chemoradiation therapy were associated with significantly better survival.

CONCLUSION

Adult MGs did not show a poor prognosis due to H3K27 alterations, unlike pediatric cases. The prognosis of adult DMGs is based on the histological grade, KPS, adjuvant treatment, and extent of tumor resection.
PATH-17. PILOCYTIC ASTROCYTOMA EXHIBITING DIFFUSE LEPTOMENINGEAL DISSEMINATION: EXTREMELY RARE FORM OF LOW-GRADE GLIOMA WITH DICHOTOMOUS (CHILDREN VERSUS ADULTS) AND UNCHARACTERISTICALLY AGGRESSIVE BEHAVIOR
Authors: Brown Nolan , Kuo Cathleen , Mehkri Yusuf , Gendreau Julian
Published: November 2023

OBJECTIVE

To identify all prior reports of pilocytic astrocytoma (PA) exhibiting diffuse leptomeningeal dissemination (LMD) (WHO Grade I) in an effort to comprehensively characterize this anomalous, predominantly pediatric pathology.

METHODS

A systematic review of the literature was performed using the PubMed, Scopus, and Web of Science databases.

RESULTS

Twenty-nine studies featuring 60 patients (54 pediatric,6 adult) were identified.The mean age at initial diagnosis was 10.2 ± 10.6 years (range, 0.3 to 55 years), and most of the patients were male (n=39,65.0%). The most common primary tumor locations were the hypothalamus (n=18,30.0%), cerebellum (n=16,26.7%), and optic chiasm (n=8,13.3%). Signs/symptoms at presentation included paralysis, cerebellar findings, and symptomatic, obstructive hydrocephalus. Most patients underwent surgery alone (n=26,43.4%) or in combination with radiotherapy (n=10,16.7%) or chemotherapy (n=8,13.3%). Of 43 patients who underwent surgery, subtotal resection (STR) was achieved in 26. STR appeared to be a risk factor for future LMD and poor prognosis. Additionally, adjuvant therapy did not seem to reduce the odds of subsequent LMD. Twenty-two patients (36.7%) were found to have LMD at presentation. Time to dissemination for the remaining patients ranged from between 3.6 - 206 months. Among all the included patients, 24 (40%) exhibited LMD within the brain only, 22 (36.7%) within the spine only, and 14 (23.3%) within both locations. Multi-agent chemotherapy alone (n=20, 33.3%) was the most commonly utilized treatment modality, followed by radiotherapy alone (n=13,21.7%), surgery with radiotherapy (n=10,16.7%), and surgery alone (n=5,8.3%). The mean follow-up duration was 44.2 ± 47.7 months (range, 0 to 221 months). Mortality occurred in 18 out of the 58 patients who had follow-up information available, with a mean time from LMD diagnosis to death of 19.9 ± 23.6 months.

CONCLUSION

Given its truly anomalous behavior, future concerted efforts to analyze the genetic profile of all identified tissue samples of PA with LMD is warranted.
PATH-19. PROGNOSTIC FACTORS, RESPONSE TO TREATMENT, AND OUTCOME OF PATIENTS WITH ISOCITRATE DEHYDROGENASE (IDH)-MUTANT ASTROCYTOMA, CNS WHO GRADE 4
Authors: Weller Michael , Felsberg Jörg , Hentschel Bettina , Gramatzki Dorothee , Kubon Nadezhda , Wolter Marietta , Roth Patrick , Krex Dietmar , Herrlinger Ulrich , Westphal Manfred , Tonn Joerg-Christian , Regli Luca , Maurage Claude-Alain , von Deimling Andreas , Pietsch Torsten , Rhun Emilie Le , Reifenberger Guido
Published: November 2023

PURPOSE

To study disease characteristics, prognostic markers and outcome in patients with isocitrate dehydrogenase (IDH)-mutant astrocytoma by CNS WHO grade.

EXPERIMENTAL DESIGN

We determined molecular biomarkers and assembled clinical and outcome data in a cohort of 258 patients with IDH-mutant astrocytomas (114 CNS WHO grade 2, 73 CNS WHO grade 3, 71 CNS WHO grade 4) confirmed by central pathology review.

RESULTS

The median age for astrocytoma, IDH mutant, CNS WHO grade 4, was 37 (range: 23-79 years) and similar to patients with CNS WHO grade 2 or 3 tumors. Karnofsky performance status at diagnosis inversely correlated with CNS WHO grade (p< 0.001). Despite more intensive treatment upfront with higher grade, CNS WHO grade was strongly prognostic: median overall survival was 22.2 years (95% n.a.) for grade 2, 8.1 years (95% 5.4-10.8) for grade 3 and 4.7 years (95% 3.4-6.0) for grade 4. Among patients with CNS WHO grade 4 astrocytoma, median overall survival was 5.5 years (95% 4.3-6.7) without (n=58) versus 1.8 years (95% 0-4.1) with (n=12) homozygous CDKN2A homozygous deletion. Reduced global DNA methylation as indicated by LINE-1 methylation levels was strongly associated with CNS WHO grade 4 (p< 0.001) and poor outcome among IDH-mutant astrocytoma patients. MGMT promoter methylation status was not prognostic for overall survival.

CONCLUSIONS

The CNS WHO grade is prognostic in patients with IDH-mutant astrocytoma. CDKN2A homozygous deletion and reduced LINE-1 methylation levels are linked to CNS WHO grade 4 and associate with shorter survival. These data serve to inform on clinical trial designs, e.g., using IDH inhibitors, in this patient population.
PATH-30. GLIOMAS WITH FGFR ONCOGENIC ALTERATIONS: CLINICO-PATHOLOGICAL FEATURES, MANAGEMENT AND OUTCOMES IN PEDIATRIC, ADOLESCENT AND YOUNG ADULT PATIENTS.
Authors: Vanan Magimairajan Issai , Kakumanu Saranya , Pitz Marshall , Harlos Craig , Kazina Colin , McDonald Patrick , Drapeau Annie , Kaufmann Anthony , O'Carroll Aoife , Xu Qi , Drimes Tina , Bourne Cathy , Streilein Jessica , Sinha Namita
Published: November 2023

INTRODUCTION

Fibroblast growth factor receptor (FGFR1-4) pathway alterations are rare in pediatric cancers (1-3%) but are enriched in certain specific subtypes of difficult to treat pediatric and AYA brain tumors. Some of the common oncogenic alterations include structural variants (fusions, duplications), mutations and amplifications.

METHODS

We describe here the clinico-pathological features and therapeutic outcomes of pediatric and AYA patients (ages 0-39yrs) with FGFR pathway altered gliomas diagnosed in the past 10yrs (2013-2023). Data was collected from review of patient charts.

RESULTS

We identified 13 patients with gliomas harboring an oncogenic FGFR alteration. Median age at diagnosis was 16yrs (range, 6-30yrs) and was more common in males (M: F-3:1). Seizures were the most common presenting symptom (N=5/13, 38%); all of these patients had cortical tumors, which were resected and seizures were adequately controlled. A biopsy only approach was done in more than half (N=7/13, 54%) of the patients. Pathological diagnosis included low grade glio-neuronal tumors in all but one of the patients, who had a high-grade glioma (Pilocytic astrocytoma N=6, Diffuse astrocytoma N=2, glio-neuronal tumors N=2, PLNTY N=2). FGFR alterations included oncogenic fusions (FGFR1-TACC1=1, FGFR2-TACC1=1, FGFR2-CTNNA3=2, FGFR3-TACC3=1), tandem duplications (FGFR1-TKD-ITD=3) and mutations (FGFR1- N546K=2, K654E=1, K656E=2). Co-occurring mutations were seen in 4 patients (H3.3-K27M=1, PIK3CA-E545K=1, PTPN11-G503V=1, PTPN11-E69K=1). Patients with symptomatic residual tumors (N=6, 46%) were treated with targeted therapies (Erdafitinib=3, Trametinib=1, Ponatinib / Everolimus=1, Dasatinib=1) and two patients received Radiation therapy. Erdafitinib was discontinued in one patient due to intra-tumoral bleed. Rest of the patients are tolerating the targeted therapy well and all of the patients are alive.

CONCLUSION

In summary, cortical tumors bearing FGFR alterations present with refractory seizures and are eminently treatable with surgical resection. Targeted therapy with FGFR specific inhibitors is tolerated well and updated response assessment of our patients will be presented in the meeting.
PATH-35. SHIFTS IN GLIOMA PROGNOSTIC MOLECULAR FEATURES ACROSS THE LIFESPAN
Authors: Patel Ruchit , Ghosh Hia , Antonio Chiocca E , Reardon David , Wen Patrick , Santagata Sandro , Ligon Keith , Beroukhim Rameen , Bi Wenya Linda
Published: November 2023

INTRODUCTION

Epidemiological studies examining glioma prognostic features have consistently identified older age as a negative predictor of survival. Accumulation and co-occurrence of favorable or deleterious molecular alterations across the lifespan likely plays a role in the age-dependent variability seen in glioma patient outcomes.

METHODS

We assembled 4,297 molecularly and clinically annotated glioma patients from multi-institutional datasets and TCGA, with IDH1/2-mutation, MGMT-methylation, and chromosome 1p19q codeletion status assayed. Patient age was stratified: pediatric (< 20 years), young adult (20-39 years), middle aged (40-64 years), and older adults ( >65 years). Pairwise proportions were tested to study distribution of alterations across age as well as variability in assaying for MGMT-methylation.

RESULTS

4,297 patients with glioma were identified with molecular annotation of IDH1/2-mutation status (40.1% IDH1/2-mutant). Of assayed gliomas, 44.3% were MGMT-methylated and 13.9% had chromosome 1p19q codeletion. IDH1/2-mutation incidence decreased with age across all gliomas (85% in young adults, 35% middle aged, and 8% older adults) and in grade 4 gliomas (64% IDH1/2-mutation in young adults, 9% middle aged, and 2% older adults). 1p19q codeletion also decreased in incidence with increasing age (young adult 22%, middle aged 15%, older adults 6%). MGMT-methylation remained consistent across adult patients, between 43-50% across all gliomas. Interestingly, amongst the few patients >65 years old with IDH1/2-mutation or 1p19q codeletion, 87% possessed co-occurring MGMT-methylation, significantly greater than young adults (54%, p< 0.001). Consistent with this, 82% of patients >65yrs with grade 4 IDH1/2-mutant gliomas had co-occurring MGMT-methylation. Despite the treatment response implication of MGMT-methylation, 72.2% of low-grade gliomas were not assayed for MGMT.

CONCLUSIONS

There is an age-dependent pattern of molecular alterations in gliomas, with the incidence of certain favorable prognostic signatures decreasing over time. Given the stability of MGMT-methylation across the age spectrum and grade, more widespread MGMT profiling may be beneficial to guide treatment decisions.
PATH-38. MOLECULAR CHARACTERIZATION OF GLIOMA TISSUE AFTER TTFIELDS TREATMENT
Authors: Mawrin Christian , Luchtmann Michael , Kirches Elmar
Published: November 2023

INTRODUCTION

This study aims to investigate the molecular characterization of glioma tissue after treatment with Tumor Treating Fields (TTFields). TTFields therapy utilizes low-intensity alternating electric fields to disrupt cancer cell division and is approved for treatment of glioblastoma as well as mesothelioma. Understanding the histological, cellular, and epigenetic changes induced by TTFields treatment can help identify biomarkers for TTFields response and elucidate potential resistance mechanisms. MATERIAL AND

METHODS

Tumor tissue samples (FFPE) were collected from newly diagnosed glioblastoma patients treated with TTFields, including both the primary tumor and matching recurrent tumor samples. Molecular analyses using a glioma-targeted next-generation sequencing (NGS) panel sequencing were performed to assess genetic alterations in both primary and recurrent tumors.

RESULTS

Genomic analysis of paired samples from 5 patients (4 glioblastoma, one astrocytoma, IDH-mutated WHO grade 4) revealed an identical molecular pattern (TERT mutation) in 2 patients, one patient with a gain of an ATRX mutation in the recurrent tumor, one patient with gain of two EGFR mutations, and the IDH1-mutated astrocytoma showing a loss of a TP53 mutation in the recurrent tumor.

CONCLUSION

This pilot study provides valuable insights into the molecular characterization of glioma tissue after TTFields treatment. It appears that the spectrum of mutations may vary in a substantial number of TTF-treated tumors. Further validation and larger-scale studies are needed to confirm and expand upon these preliminary results.
PATH-40. “DE NOVO REPLICATION REPAIR DEFICIENT GLIOBLASTOMA, IDH-WILDTYPE” IS A DISTINCT GLIOBLASTOMA SUBTYPE IN ADULTS THAT MAY BENEFIT FROM IMMUNE CHECKPOINT BLOCKADE
Authors: Hadad Sara , Bush Nancy Ann Oberheim , Clarke Jennifer , Taylor Jennie , Young Jacob , Villanueva-Meyer Javier , Zhang Yalan , Gupta Rohit , Wu Jasper , Ravindranathan Ajay , Hervey-Jumper Shawn , Chang Susan , Berger Mitchel , Molinaro Annette , Solomon David
Published: November 2023

Glioblastoma is clinically and molecularly heterogeneous, and new predictive biomarkers are needed to identify those patients most likely to respond to specific treatments. Through prospective genomic profiling of 459 primary treatment-naïve IDH-wildtype glioblastomas in adults, we identified a subgroup (2%, 8/459) defined by somatic hypermutation and DNA replication repair deficiency due to mismatch repair gene inactivation and/or proofreading domain mutation in the DNA polymerase POLE. The deleterious mutations in mismatch repair genes were often present in the germline in the heterozygous state with somatic inactivation of the remaining wildtype allele, consistent Lynch syndrome-associated glioblastomas. All tumors were hypermutated ( >20 somatic nonsynonymous mutations/Mb), while the three tumors with POLE mutations were “ultrahypermutated” with >150 mutations/Mb. The median age at diagnosis was 52 years (range 27-78), compared with median age of 63 years for the other 451 patients with conventional glioblastoma. All tumors were diffuse astrocytic gliomas of the giant cell histologic subtype. They lacked EGFR amplification and only rarely had TERT promoter mutation (1/8), CDKN2A homozygous deletion (1/8), or the combination of trisomy 7 and monosomy 10 (1/8). Instead, they harbored frequent inactivating mutations in the TP53, NF1, PTEN, ATRX, and SETD2 genes ( >50% each) and recurrent activating mutations in PDGFRA (4/8). DNA methylation profiling revealed they did not align with known glioblastoma methylation classes, but instead mostly classified as “Diffuse pediatric-type high grade glioma, RTK1 subtype, subclass A (novel)”. Some patients were treated with immune checkpoint blockade (nivolumab or pembrolizumab) and survived over three years. The median overall survival for the cohort was 37.4 months (95% CI: 22-not reached), compared to 15.4 months (95% CI: 14.7-17.9) for the other 451 patients. We speculate that “de novo replication repair deficient glioblastoma, IDH-wildtype” represents a biologically distinct subtype that may benefit from prospective identification and treatment with immune checkpoint blockade.
PATH-41. INTEGRATED MOLECULAR ANALYSIS REVEALS HYPERMETHYLATION AND OVEREXPRESSION OF HOX GENES TO BE POOR PROGNOSTICATORS IN IDH MUTANT GLIOMA
Authors: Mamatjan Yasin , Voisin Mathew , Nassiri Farshad , Bunda Severa , von Deimling Andreas , Aldape Kenneth , Zadeh Gelareh
Published: November 2023

BACKGROUND

Diffuse gliomas represent over 80% of malignant brain tumors ranging from low-grade to aggressive high-grade lesions. Within IDH-mutant gliomas there is a high variability in survival and a need to more accurately predict outcome.

METHODS

To identify and characterize a predictive signature of outcome in gliomas, we utilized an integrative molecular analysis (using methylation, mRNA, copy number variation (CNV) and mutation data), analyzing a total of 729 IDH-mutant samples including a test set of 99 from University Health Network (UHN) and two validation cohorts including the German Cancer Research Center (DKFZ) and The Cancer Genome Atlas (TCGA).

RESULTS

Cox regression analysis of methylation data from the UHN cohort identified CpG-based signatures that split the glioma cohort into two prognostic groups strongly predicting survival that were validated using two independent cohorts from TCGA and DKFZ (all p-values< 0.0001). The methylation signatures that predicted poor outcome also exhibited high CNV instability and hypermethylation of HOX gene probes. Integrated multi-platform analyses using mRNA and methylation (iRM) showed that parallel HOX gene overexpression and simultaneous hypermethylation were significantly associated with increased mutational load, high aneuploidy and worse survival (p-value< 0.0001). A 7-HOX gene signature was developed and validated using the most significantly associated HOX genes with patient outcome in both 1p/19q codeleted and non-codeleted IDHmut gliomas.

CONCLUSIONS

HOX gene methylation and expression provide important prognostic information in IDH-mutant gliomas that are not captured by current molecular diagnostics. A 7-HOX gene signature of outcome shows significant survival differences in both 1p/19q codeleted and non-codeleted IDH-mutant gliomas.
PATH-42. UNCOVERING AN ASSOCIATION BETWEEN OLIGODENDROGLIOMA AND THE HUMAN PAPILLOMAVIRUS (HPV) THROUGH MOLECULAR SUBPOPULATION ANALYSIS USING NETRAAI
Authors: Qorri Bessi , Tsay Mike , Spiegel Josh , Cook Douglas , Geraci Joseph
Published: November 2023

Oligodendrogliomas (OGs) are a rare subset of primary brain tumors, accounting for approximately 5% of all brain tumors. While the etiology of OG has yet to be fully characterized, genomic heterogeneity is linked to clinical heterogeneity with variability in progression and survival. Currently, OGs are stratified into three molecular subtypes based on IDH mutation and 1p/19q co-deletion with additional molecular heterogeneity related to EGFR, PTEN, 10q deletion, and several other markers observed among 1p/19q co-deleted OGs. Using a public OG dataset, we assembled a set consisting of 156 primary OG tumors, 14 primary glioma samples, and 9 normal samples profiled using mRNA expression arrays. Using NetraAI, a novel machine learning platform, we identified three OG patient subpopulations based on survival and differentially expressed genes. Examining low- versus high-grade OG, we identified two subpopulations: (1) 26 low-grade and 21 high-grade OGs characterized by higher RPS6KV1 expression, and (2) 6 low-grade and 61 high-grade OGs characterized by higher LFNG expression. A third subpopulation emerged examining 1p/19p co-deletion, consisting of 60 no co-deletion and 3 co-deletion OGs characterized by higher HDAC1 expression. These driving genes have a common link to human papillomavirus (HPV) infection based on functional genomic analysis. HDAC1 is a histone deacetylase involved in gene expression regulation, LFNG is implicated in the Notch signaling pathway, and RPS6KB1 is a kinase regulating protein synthesis and cell growth. We hypothesize that concomitant HPV infection may negatively impact OG prognosis, warranting further investigation into the precise molecular interactions linking HPV infection to clinical outcomes. Furthermore, exploring the link between HPV infection and vaccination to OG outcomes on a population basis may provide valuable insights. The identification of these subpopulations, not previously described by other groups, demonstrates the utility of the NetraAI approach in uncovering subpopulations with potential implications in developing targeted therapies for OG.
PATH-47. MOLECULAR MARKERS ASSOCIATED WITH SURVIVAL IN GRADE 3 MENINGIOMA
Authors: Tosefsky Kira , Rebchuk Alexander , Wang Justin , Chornenka Karina , Zadeh Gelareh , Makarenko Serge , Yip Stephen
Published: November 2023

Meningiomas have historically been graded using histologic features. However, a subset of meningiomas progress in manners inconsistent with their histologic grading. While TERT promoter (TERTp) mutations and CDKN2A/B homozygous deletion were recently added to the WHO 2021 classification criterion for grade 3 meningioma, the precise prognostic implications of these and other molecular features remain to be fully characterized. In this case series, we explored whether molecular markers were associated with clinical outcomes in a single-center cohort of grade 3 intracranial meningiomas. Demographic, clinical and histopathological information were obtained from the electronic medical records of all grade 3 meningioma cases surgically treated at a tertiary center between 2007-2020. Tissue blocks were reviewed by a neuropathologist and tested for TERTp mutations, BAP1 and CDKN2A/B copy number profiles, and BAP1, p16 and MTAP expression by immunohistochemistry (IHC). Predictors of survival were identified by Cox regression. Fifteen patients (8 female, 7 male) with a median age of 64 (IQR: 48, 74) years were included. Eight (53%) tumors were classified as anaplastic, 6 (40%) as rhabdoid and 1 (6.7%) as papillary. One (7%) rhabdoid tumor exhibited BAP1 loss, while four (27%) tumors harbored TERTp mutations and 3 (20%) demonstrated homozygous CDKN2A/B loss. All three tumors exhibiting homozygous CDKN2A/B loss were MTAP-negative, while two were p16-negative and the third showed focal (< 50%) p16 loss by IHC. TERTp mutations and CDKN2A/B copy number status were associated with significant reductions in RFS (HR = 6.90, 95% CIs: 1.13-42.2 and HR = 12.0, 05% CIs: 1.51-95.4, respectively) and OS (HR = 8.72, 95% CIs: 1.87-40.6 and HR = 6.18, 95% CIs: 1.30-29.4, respectively). The associations between reduced OS and TERTp mutations and CDKN2A/B status remained significant after adjusting for Simpson resection grade. Our findings support using TERT p mutations and CDKN2A/B status for prognostication in grade 3 meningioma.
PATH-56. SUPRATENTORIAL NEUROEPITHELIAL TUMORS WITH NOVEL PLAGL1 FUSIONS: 2 CASE REPORTS
Authors: Helfer Cassandra , McDonald Malcolm , Patel Akash , Sheth Sameer , Rao Ganesh , Jalali Ali , Katlowitz Kalman , Echeverria Alfredo , Ogunbona Oluwaseun , Aldape Kenneth , Abdullaev Zied , Lu Hsiang-Chih , Holloman Ashley , Mandel Jacob
Published: November 2023

Neuroepithelial tumors with pleomorphic adenoma gene-like (PLAGL1) fusions represent a distinct subgroup of neoplasms that have been recently identified. These fusions are quite rare and most commonly associated with fusions in the EWSR1 or FOXO1 genes. Limited reports in literature have indicated a median age of diagnosis of 6.2 years and poor progression-free survival at 35 months. Here we present two cases of patients with neuroepithelial tumors with PLAGL1 fusions. Case 1 was a 49 year old male who underwent resection of a left frontal lobe mass at 2 year old that was reported as a low grade ependymoma. He did not receive radiation or chemotherapy and subsequently developed seizures in childhood. At age 47, he presented with worsening seizures and MRI brain revealed a 4.5 cm mass in the left frontal lobe with serpiginous enhancement. He underwent surgical resection and molecular profiling demonstrated PLAGL1-FOXO1 fusion. Case 2 was an 18 year old female presenting with generalized tonic-clonic seizures. MRI brain demonstrated a 1.4 x 1.2 cm cortical and subcortical lesion in the right parietal lobe. Following surgical resection, pathology reported a low grade neuroepithelial neoplasm with ependymal-like features. Molecular profiling showed PLAGL1-EWSR1 fusion. As PLAGL1 fusions are not yet characterized in the WHO classification system, these cases aid in tumor characterization and highlight the importance of molecular and methylation analysis for accurate tumor classification. Case 2 presents a notable variation from reported age of presentation of 6.2 years with diagnosis at 18 years of age, indicating these tumors may also present in young adulthood. Additionally, Case 1 demonstrated 45 years progression-free survival compared to previously reported median of 35 months, suggesting outcomes may be heterogeneous with potential for prolonged survival. Further research is needed to better elucidate the imaging, clinical course, and prognosis for tumors with this novel fusion.
PATH-57. WHOLE EXOME SEQUENCING OF INTRACRANIAL EPIDERMOID CYSTS (IECS) REVEALS POTENTIAL SOMATIC DRIVERS
Authors: Kondaboina Shruthi , Parada Carolina Da Silva , Ferreira Manuel
Published: November 2023

Intracranial Epidermoid Cysts (IECs) are benign, slow-growing, asymptomatic tumors with an incidence rate of 1% of all intracranial tumors. They are significantly enlarged when discovered and can cause seizures. IECs are suspected to form due to disruptions in neural tube closure. Given their rarity, formation of IECs is under-investigated and surgery is the only treatment option. However, because the cyst lining can be adherent to important brain structures, resection is challenging and can result in post-operative complications, highlighting the need to investigate the pathogenesis of IECs to develop drug therapeutic options. We performed paired-end Whole Exome Sequencing (WES) on DNA from six sporadic IECs. Data processing of raw unmapped reads was performed in tumor-normal and tumor-only mode as appropriate, following GATK best practices for variant calling. We identified 2,850 SNPs and 2,102 indels in this cohort. We identified two common variants, NKX2.5 (p.P214del) and STIM-1 (p.T576del, p.T502del) across all samples, which is a novel finding. We also identified 27 genes and variants shared variably across the samples. Gene enrichment analysis revealed that the Sonic Hedgehog (SHH) pathway is implicated in these gene sets due to activating mutations in the SMO gene (p.L23del). We are using an immunohistochemical stain to validate this finding. The mutant NKX2.5, a transcription factor (TF) responsible for stem-cell differentiation in embryogenesis, strongly indicates that the tumor microenvironment (TME) is disrupted. Deletions in the STIM-1 gene indicate loss of interaction with Orai1 calcium channels, disrupting store operated Ca2+ entry (SOCE) and preventing typical cell migration, resulting in trapped fibroblasts. Digital droplet PCR (ddPCR) of these samples is underway to validate the low tumor allele frequencies (< 4%). The discovery of activating mutations in SMO is significant because it potentiates FDA-approved SMO-inhibitors like Vismodegib and Sonidegib as viable treatment options for patients with IECs.
PATH-65. INTEGRATING DNA METHYLATION AND SEQUENCING TECHNOLOGIES FOR ADVANCED BRAIN TUMOR DIAGNOSIS
Authors: Goebel Kirsten , Schrimpf Daniel , Ippen Franziska Maria , Pfister Stefan M , Jones David , Wick Wolfgang , von Deimling Andreas , Sahm Felix , Suwala Abigail
Published: November 2023

DNA methylation has emerged as an indispensable tool in neuropathological diagnostics, improving the diagnosis of various brain tumor entities. At our institution, methylation arrays as well as DNA and RNA sequencing from Formalin-Fixed Paraffin-Embedded (FFPE) tissue blocks have become routine diagnostic practices for several years. In this study, we present an integration of DNA methylation analyses with targeted gene panel sequencing and RNA sequencing data in an extensive cohort comprising 5749 cases. The cohort encompassing both adult and pediatric patients with central nervous system (CNS) tumors. Only those cases conclusively classified by the Heidelberg brain tumor classifier (v12.5, cutoff > 0.9) and possessing available sequencing data were included in the analyses. The study includes several rare and less characterized brain tumor entities, unveiling frequent mutations and gene fusions that will improve the diagnostic process. Our study offers an unparalleled comprehensive overview of the prevalence of genetic alterations in brain tumors, precisely defined by their unique methylation classes. The profound implications of our results extend far beyond diagnosis alone, significantly augmenting the evaluation of targeted treatment options for patients undergoing DNA methylation analyses.
PATH-67. SHH/GLI3 SIGNALOPATHIES AND NEURO-ONCO-GENETIC COUNSELING : A TUNISIAN PEDIGREE
Authors: Abdelmoula Nouha Bouayed , Abdelmoula Balkiss
Published: November 2023

Here, we present a 3-generation pedigree of a Tunisian non-consanguineous family with six offspring affected by heterogeneous forms of the GLI3-related PHS spectrum. Our aim was to assess the neuro-onco-genetic risks and provide counseling for appropriate clinical follow-up. A non-consanguineous couple was referred to our genetic counseling due to the termination of their first pregnancy, which was diagnosed with multiple congenital anomalies. An autopsy examination, including pathological and radiographic analysis, was conducted. Furthermore, a medical genetic assessment considering a family history spanning over three generations as well as cytogenetic analysis were carried out. The index case was diagnosed with GLI3-related PHS based on facial dysmorphic features, auricular malformations, and unilateral postaxial toe syndactyly, along with brain macro-calcifications. The index case's father and his brother exhibited facial dysmorphic features. Furthermore, two cousins from one of their paternal uncles presented another form, associated respectively with unilateral renal agenesis and unilateral hand agenesis. The remaining three cases, who belong to the first generation, and passed away during infancy, exhibited the same condition, associated to congenital heart defect in one of them. The heterogeneity of GLI3-related overlapping conditions (SHH/GLI3 signalopathies) result from the location of GLI3 mutations in different domains of the gene, as well as the resulting functional balance between activating and repressive forms of GLI3 during development. The report of a late diagnosis of GLI3-related PHS following the discovery of hypothalamic hamartomas as well as the description of a new nonsense germline mutation in a child with Greig syndrome and medulloblastoma, support that neuro-oncological investigation of GLI3 families could be beneficial.
NIMG-03. IMPACT OF CONCURRENT IMMUNOTHERAPY AND STEREOTACTIC RADIOSURGERY ON METASTATIC BRAIN DISEASE: A THREE-DIMENSIONAL MAGNETIC RESONANCE FINGERPRINTING RADIOMIC ANALYSIS
Authors: McClelland III Shearwood , Gongala Sree , Hodges Tiffany , Korakavi Nisha , Flask Chris , Ma Dan , Badve Chaitra
Published: November 2023

BACKGROUND

Unlike traditional chemotherapy (limited by the blood-brain barrier), the central nervous system penetrance of immunotherapy allows for synergy with stereotactic radiosurgery (SRS), the standard-of-care management of limited brain metastases. Magnetic resonance fingerprinting (MRF) is a novel technology allowing for simultaneous imaging quantification of multiple tissue properties. We present the first serial MRF results in concomitant SRS/immunotherapy for metastatic brain disease.

METHODS

A patient with known history of small cell lung cancer (SCLC) presented with a seizure. MRI revealed a solitary 1 cm right occipital metastasis, subsequently receiving SRS rather than whole-brain radiation therapy to optimize cognition preservation. Durvalumab (with carboplatin/etoposide) was given one week before SRS (22 Gy single-fraction). Pre-SRS MRF scans were obtained with the Gamma Knife stereotactic headframe in place. Post-SRS MRF scans were obtained at 1, 3, and 5 months. MRF data was processed and region of interest analysis was performed to measure T1 and T2 values within the lesion using MATLAB.

RESULTS

The mean T1 and T2 values of the solid tumor (ST) in precontrast MRF maps decreased over time with a slight increase at final follow-up. Specifically, the T1 values decreased from 2131 ms (Pre-SRS) to 1018 ms, then 996 ms followed by a slight increase to 1296 ms. Similarly, the T2 values progressively decreased from 143 ms (Pre-SRS) to 45 ms (first follow-up) to 43 ms (3-month follow-up), with an increase (51 ms) at last follow-up.

CONCLUSIONS

In this first report of MRF in concomitant immunotherapy/Gamma Knife SRS (and the first in a SCLC patient). MRF demonstrated serial drop in T1 and T2 over time followed by slight increase at 5 months follow-up. The alterations observed in T1 and T2 MRF are compatible with post-treatment effects in the tumor's tissue characteristics, including decreased cellularity, water content, and presence of paramagnetic substances.
NIMG-04. PRE-RADIATION PROGRESSION PREDICTION IN GLIOBLASTOMA PATIENTS
Authors: Farzana Walia , Basree Mustafa M , Diawara Norou , Shboul Zeina A , Dubey Sagel , Lockhart Marie M , Hamza Mohamed , Palmer Joshua , Iftekharuddin Khan M
Published: November 2023

Pre-Radiation Progression (PRP) has been identified as an increase ( > 25%) in the size of the residual brain tumor or interval development of a new tumor after surgical resection but prior to radiation therapy. Glioblastoma (GB) patients with PRP have worse survival outcome compared to patients without PRP (non-PRP).The standardized approach to identify PRP in GB patients is to manually compare early post-operative MRI to radiation planning MRI. In this study, we investigate the efficacy of traditional radiomics and sophisticated multi-resolution fractal texture features to differentiate PRP from non-PRP. Radiation-planning T1C magnetic resonance imaging (MRI) of 13 PRP and 13 non-PRP patients is analyzed to develop the classification method. For each patient, around 600 conventional radiomics and fractal texture features are obtained from tumor tissue and entire brain areas. We propose a two-step feature selection process followed by ensemble classification. In the first step of feature selection, we apply a beta-mixture based graphical model to identify correlations between the extracted features. The features are the nodes of the graph and the edges of the graph denote the correlations among the features and adjacency to PRP node. After the first step feature selection, the 21 selected features are used in the second step feature selection based on accuracy, similarity, and stability of each feature to yield the final 12 features. Lastly, we utilize the final 12 selected features for ensemble classification of PRP from non-PRP. With leave-one-out cross validation, the predictive model has an area under curve (AUC) of 0.79 and accuracy of 80% which indicates the discriminatory function of imaging features to differentiate PRP patients from non-PRP. The experimental results show the diagnostic ability of radiation planning imaging features to predict PRP from non-PRP.
NIMG-10. A MRI-BASED RADIOMICS MODEL PREDICTING DNA DAMAGE REPAIR GENES EXPRESSION SUBTYPES AND PROGNOSIS IN GLIOBLASTOMA
Authors: Zhang Mingwei , Wu Yufan , Li Xiaoxia , Wang Xuezhen , Li Shan , Hong Jinsheng
Published: November 2023

BACKGROUND

Glioblastoma (GBM) is the most common primary brain tumor, with a dismal prognosis. Some DNA Damage Repair (DDR) pathways are related to progression and worse prognosis in GBM patients. However, the association between overall expression levels of DDR genes and prognosis for GBM has not been reported. Radiomics has become an essential tool for assessment of clinical information in GBM patients, expected to be a noninvasive tool for predicting DDR genes expression and prognosis.

METHODS

The TCGA database was used to obtain the GBM patients imaging, clinical and RNAseq data. We screened DDR genes and clustered them into subgroups based on their expression status, and determined differences between subgroups in prognosis and molecular mechanisms. Radiomics model based on MRI CE-T1 image was investigated to predict DDR subgroups and the output was defined as the radiomics score (RS). Prognosis analysis of RS and traditional clinical indicators was performed in TCGA cohorts, and external validated in 2 medical centers.

RESULTS

A total of 156 individuals with GBM were identified from the TCGA cohorts. 140 genes were screened in DDR gene libraries, which were classified into 2 clusters. Survival analysis showed that overall survival (OS) was significantly higher in DDR suppression subgroup than activation subgroup (21.1 vs 14.9, p=0.001), and differences in immune microenvironment, biologically active pathways were observed in the 2 groups. A model composed of 4 radiomics features were built, which can distinguish 2 DDR subgroups. RS was an independent protective factor for OS (HR=0.630, 95%CI=0.400−0.992, P=0.046). The result was externally validated by two cohorts.