bluuebunny/crossref_metadata_2025 huggingface dataset:
INNV-05. DEVELOPMENT OF A LABEL-FREE PLASMONIC OPTICAL BIOSENSOR FOR INTRAOPERATIVE DETECTION OF TUMOR TISSUE IN GLIOBLASTOMA
Authors: García-Milán Víctor , Franco Alfredo , Zvezdanova Margarita Estreya , Marcos Sara , Martín-Láez Rubén , Moreno Fernando , Fernández-Luna José L , Velásquez Carlos
Published: November 2024

Safe maximal resection of patients with glioblastoma remains a surgical challenge due to the invasive nature of the tumor and the difficulty in distinguishing tumor margins during resection. Several tools are currently used for this purpose, such as, confocal laser endomicroscopy and fluorescence-guided surgery. In this context, biosensors based on plasmonic technology using the extraordinary optical transmission (EOT) phenomenon can help to distinguish between tumor and surrounding tissue based on their optical properties. We developed a biosensor utilizing EOT through a nanostructured gold matrix with 220 nm diameter holes and conducted a prospective study in 35 GBM patients. Paired samples of tumor and peritumoral tissue were collected during surgery. Each sample’s optical imprint was analyzed, revealing significant differences in refractive indices (RI). Tumor tissue showed higher RI values (1.350, IQR 1.344–1.363) compared to peritumoral tissue (1.341, IQR 1.339–1.349) with a p-value of 0.0047. The receiver operating characteristic (ROC) curve indicated the biosensor’s ability to differentiate the tissues (AUC = 0.8779, p < 0.0001). An optimal RI cut-off point of 0.003 was determined, with the biosensor achieving 81% sensitivity and 80% specificity. Our results indicate that this plasmonic technology-based biosensor could have a significant impact on the surgical treatment of glioblastoma by providing a label-free tool for tumor margin discrimination and improving the accuracy of glioblastoma surgery. Future research will focus on optimizing the nanoarchitecture of the biosensor to further improve its sensitivity and specificity, as well as exploring its applicability to other cancer types by analyzing the biomarkers responsible for the different RIs of the footprints.
INNV-16. ONCOPATH: OPTIMIZED TREATMENT GUIDELINE CONCORDANT PATHWAY PRESENTED ON A VISUAL-INTERACTIVE DASHBOARD FOR CLINICAL DECISION SUPPORT COMPUTED BY OVERLAYING PATIENT LONGITUDINAL DATA ON A KNOWLEDGE GRAPH
Authors: Snyder James , Alford Sharon Hensley , Kumar Tarun , Pindolia Kirit , Poisson Laila , Mahatma Shilpa , Mikkelsen Tom
Published: November 2024

BACKGROUND

OncoPath provides a visual analysis of a brain tumor patient’s longitudinal clinical data overlayed on disease specific pathways with the goal of reducing knowledge discordant care and insurance authorization burden. By ingesting, curating and visually presenting the patient experience on guidelines, OncoPath aims to streamline clinical decision making and related processes. Understanding the patient’s journey compared to treatment guidelines is of value in addressing health equity and guideline adoption in real world settings.

METHODS

Data from 44 glioma patients diagnosed and treated between 2016-2021 were uploaded to OncoPath using natural language processing and other tools to capture abstractable data elements. The data was overlayed on guidelines using recursive graph modeling. Using the knowledge graph of a patient’s history, the model also recommends treatment options in an interactive visual dashboard representing NCCN guidelines. The dashboard includes the guidelines in graphical format with associated references and notation.

RESULTS

28 males and 16 females age 21-38 years at diagnosis were abstracted. Cases represented 4 oligodendrogliomas, 13 astrocytomas, and 27 glioblastomas. Data was available through second line therapy, discharge to hospice or death. Cases were matched to the NCCN 2021 guidelines which was used for treatment decisions until November 2022. The patient data matched OncoPath except in 3 cases where KPS was not available resulting in premature pathway truncation. For these cases we inferred KPS based on subsequent treatment received to optimize the historic data.

CONCLUSION

To our knowledge, this is a first-of-a-kind technology in neuro-oncology that may improve time to treatment, reduce health utilization resources and can serve as a benchmarking tool for care delivery. The feasibility of clinically implementing such tools for decision support was demonstrated. This type of tool could be particularly useful in low-resource areas where disease specific expertise may not be available or to illuminate care discrepancies.
INNV-20. FLUORESCEIN GUIDED SURGERY FOR ATYPICAL BRAIN LESIONS: IS IT USEFULL? CASE SERIES USING A LOW-COST DEVICE
Authors: Campos Paiva Aline Lariessy , Araujo João Luiz Vitorino , Lovato Renan Maximillian , de Oliveira Jean Gonçalves , Veiga José Carlos Esteves
Published: November 2024

INTRODUCTION

Sodium Fluorescein (SF) enhances in areas in the brain with a disrupted Blood brain barrier (BBB). In neurosurgery, SF is extensive used for malignant brain tumors. Solitary brain abscesses (BA) are characterized by the pathognomonic finding of BBB disruption. Consequently, FL may have the potential to improve the intra-operative visualization of BA. Other infections also disrupt BBB and SF may guide these surgeries.

CASE SERIES

A 32-year old male patient, previously diagnosed with HIV presented with headache and during investigation MRI disclosure an extensive leptomeningeal commitment. Leptomeningeal biopsy guided by fluorescein and using Varioguide system was performed and the diagnosis was primary central nervous system lymphoma (Diffuse large B-cell). During surgery, it was observed increased fluorescence in arachnoid. A 72-year old woman presented with headache, impairment of mental status and epilepsy and a KPS of 60. Her initial hypothesis was metastasis but patient did not have a primary situs diagnosis. An open biopsy was performed through temporal posterior craniotomy. During surgery no visible well delimited tumor was found, even with ultrasound use. Fluorescein guided biopsy was performed. Histological evaluation showed an Epstein-Barr virus infection causing encephalitis. This is an extremely rare presentation of this type of infection and SF was extremely helpful to guide the procedure.

CONCLUSION

This paper reported atypical uses of SF for brain mass lesions surgeries. One of our cases is a unique presentation of a virus encephalitis which mimicked metastasis and other of increased fluorescence in Lymphoma. These atypical use of SF are relevant for further neurosurgical plannings Keywords: Fluorescein, Lymphoma, Biopsy
PATH-27. MOLECULAR, IMAGING, AND SURVIVAL MANIFESTATIONS IN MOLECULAR GLIOBLASTOMAS: INSIGHTS FROM A MULTI-NATIONAL STUDY
Authors: Park Yae Won , Youssef Gilbert , Freeman Nicolas , Teske Nico , Karschnia Philipp , Foltyn-Dumitru Martha , Banan Rouzbeh , Lee Matthew , Singh Kanwar , Park Ji Eun , Choi Kyu Sung , Wongsawaeng Doonyaporn , Chang Jong Hee , Kim Se Hoon , Lee Seung-Koo , Wen Patrick Y , Barajas Jr Ramon Francisco , Choi Seung Hong , Kim Ho Sung , Jain Rajan , Sahm Felix , Wick Wolfgang , Bendszus Martin , Vollmuth Philipp , Thon Niklas , Huang Raymond , Ahn Sung Soo
Published: November 2024

Apart from the traditional definition of IDH-wildtype GBM based on histological characteristics, IDH-wildtype diffuse gliomas previously assigned to histological grade 2 or 3 are now defined as IDH-wildtype GBM in the presence of qualifying molecular markers (TERTp mutation, EGFR amplification, or chromosome +7/-10) (“molecular GBM”) in the 2021 WHO classification. However, the clinical significance of molecular GBM is unrevealed. This collaboration aims to comprehensively evaluate the clinical, molecular, imaging characteristics, and prognosis of molecular GBMs in a multi-national dataset and stratify survival. Retrospective chart and imaging review was performed in 258 molecular GBM patients from eight centers across three continents. Clinical, molecular, imaging, and survival characteristics were analyzed. The median age of molecular GBM patients was 58 years (range: 23-83) with 139 males, with TERTp mutation (83 of 214 [38.8%]), EGFR amplification (160 of 204 [78.4%]), and chromosome +7/-10 (82 of 143 patients [57.3%]). The majority of tumors were located at the frontal and temporal lobes (48.4%) and exhibited non-contrast-enhancing (CE) tumors (73.7%). Gliomatosis cerebri pattern was shown with 27 patients (12.4%). The median OS was 28.1 months (95% confidence interval 22.1-34.1). There was significantly shorter survival in patients with high Ki-67 index (> 20) compared to those with low Ki-67 index (median OS 19.3 vs. 31.5 months, log-rank test P = 0.002), while no survival differences were found according to histological grade or molecular diagnostics. Survival was significantly shorter in patients with infiltrative imaging appearance compared to those without (median OS 24.7 vs 41.0 months, log-rank test P = 0.014). In conclusion, survival within molecular GBM patients may be heterogeneous and associated with Ki-67 index and infiltrative imaging appearance.
PATH-28. KI-67 INDEX AS A PREDICTIVE MARKER OF MENINGIOMA RECURRENCE FOLLOWING SURGICAL RESECTION
Authors: Mizrachi Mark , Hartley Benjamin , Saleem Shahzaib , Hintz Eric , Ziemba Yonah , Li Jianyi , Goenka Anuj , Schulder Michael
Published: November 2024

BACKGROUND

Meningiomas are the most common primary intracranial tumors in adults. Although benign in a majority of cases, they have a variable clinical course and may recur even after a thorough surgical resection. Ki-67, a nuclear protein involved in cell cycle regulation, has been widely studied as a marker of cellular proliferation in various cancers. Here, we investigate the Ki-67 index, as a predictive marker of meningioma recurrence following resection.

METHODS

The medical records of 451 patients with previously untreated cranial meningiomas who underwent resections from January 2011 to January 2021 at North Shore University Hospital (NSUH) were reviewed. Collected data included WHO grade, Ki-67 proliferative index, degree of resection - gross (GTR) vs subtotal (STR) - as judged by the surgeon, tumor location, and meningioma recurrence. This study was approved by the NSUH Institutional Review Board IRB 21-1107.

RESULTS

There were 290 patients with grade I, 154 with grade II, and 7 with grade III meningiomas. Higher WHO grades were associated with higher rates of recurrence, with rates of 11.4 %, 27.9 %, and 71.4 % for grades 1, 2, and 3, respectively, and subtotal resection corresponded to a higher rate of recurrence than total resection (34.3 % and 13.4 %, respectively). Higher WHO grades also correlated with higher Ki-67 scores (2.59, 10.01, and 20.71) for grades 1, 2, and 3, respectively. A multivariate logistic regression model identified Ki-67 and degree of resection as independent predictive variables for meningioma recurrence, with Ki-67 specifically predicting recurrence in the WHO grade II subset when analyzed separately for WHO grades I and II.

CONCLUSION

Our 10-year retrospective study suggests that the Ki-67 index is an important predictive marker for recurrence of intracranial meningiomas following surgical resection, particularly among patients with WHO grade II tumors. Our findings add to a growing body of data that support inclusion of Ki-67 index in the WHO grading criteria for patients with meningiomas.
PATH-32. THE PROGNOSTIC IMPACT OF CDKN2A/B HETEROZYGOUS DELETIONS IN IDH-MUTANT GLIOMA
Authors: Ippen Franziska Maria , Hielscher Thomas , Friedel Dennis , Göbel Kirsten , Reuss David , Herold-Mende Christel , Krieg Sandro , von Deimling Andreas , Wick Wolfgang , Sahm Felix , Suwala Abigail
Published: November 2024

BACKGROUND

Homozygous deletions of CDKN2A/B have been shown to be a prognosticator for an unfavorable prognosis in gliomas, but the role of heterozygous CDKN2A/B deletions remains less well understood. The aim of this study was to assess the prognostic impact of CDKN2A/B heterozygous deletions in IDH-mutant low-grade astrocytoma and oligodendroglioma.

METHODS

Tissue samples diagnosed as astrocytoma, IDH-mutant and oligodendroglioma, IDH-mutant, 1p/19q co-deleted CNS WHO grade 2 and 3 were collected from the archive of the Institute of Neuropathology in Heidelberg. DNA methylation analysis was performed on formalin-fixed paraffin-embedded (FFPE) samples. Evaluation of the CDKN2A/B locus was performed by visual inspection of copy-number plots derived from methylation-array data for each case. Heterozygous and homozygous losses were assessed in relation to whole chromosomal or larger segmental losses and gains in the chromosomal profile. Survival probabilities were assessed using the Kaplan–Meier method.

RESULTS

A total of 334 low-grade glioma cases were identified. Those cases included 173 astrocytomas and 161 oligodendrogliomas. Heterozygous deletions in CDKN2A/B (37/173 in astrocytomas, 15/161 in oligodendrogliomas) did not confer worse survival outcomes compared to CDKN2A/B wildtype cases in neither low grade astrocytoma (p= 0.2556) nor oligodendroglioma (p= 0.2760), regardless of CNS WHO grade, which was further validated on a subgroup of astrocytoma, IDH mutant CNS WHO 4 cases (p= 0.1680).

CONCLUSION

In summary, our study suggests that heterozygous CDKN2A/B deletions do not confer worse survival rates with respect to OS and PFS in astrocytoma, IDH-mutant and oligodendroglioma, IDH-mutant, 1p/19q co-deleted CNS WHO grade 2 and 3.
PATH-33. THE IMPACT OF THE MOLECULAR CLASSIFICATION IN HISTOLOGICALLY DIAGNOSED GLIOBLASTOMAS
Authors: Arakawa Yoshiki , Kawauchi Takeshi , Makino Yasuhide , Katsuma Asako , Yoshioka Ema , Shofuda Tomoko , Kanematsu Daisuke , Yamamoto Etsuko , Takada Shigeki , Sano Noritaka , Tanji Masahiro , Mineharu Yohei , Kanemura Yonehiro
Published: November 2024

OBJECTIVE

Glioblastomas have been diagnosed based on traditional histological findings (necrosis, microvascular proliferation) and molecular genetic findings (IDH-wildtype, H3-wildtype, TERT promoter mutation, EGFR amplification, +7/−10 chromosome copy-number changes). Thus, IDH-wildtype and H3-wildtype glioblastomas can be classified into those with molecular genetic findings (defined as molecular glioblastoma) and those with only histological findings (defined as non-molecular glioblastoma). We re-evaluated the molecular genetics of patients diagnosed histologically with glioblastoma at our institution and examined their characteristics.

METHODS

A total of 275 cases diagnosed histologically as glioblastoma between December 2000 and March 2022 were included. Sanger sequencing (IDH1/2, Histone H3, TERTp) and MLPA for copy number analysis (PDGFRA, EGFR, CDKN2A, PTEN, MDM2, CDK4, TP53) were performed. The genetic analysis results and survival periods were analyzed.

RESULTS

Among the 275 cases, 151 initial glioblastomas met the criteria of IDH wild-type and H3 wild-type. Genetic analysis results that could be evaluated were obtained in 89 of these cases. TERT promoter mutation was present in 43 cases (48%), with 37% (16 cases) showing EGFR amplification and 19% (8 cases) showing EGFR gain/PTEN loss (+7/-10) simultaneously. On the other hand, TERT promoter wild-type was found in 45 cases (51%), with EGFR amplification in only 1 case (2%) and EGFR ain/PTEN loss in 4 cases (9%), and these 5 cases were judged to correspond to molecular glioblastoma. Adding one case with TERT promoter evaluation failure but EGFR amplification, the integrated molecular/non-molecular glioblastoma cases were 49 (55%)/40 (45%), revealing that both tumor types exist in nearly equal proportions. Survival curve analysis showed that median overall survivals of molecular and non-molecular glioblastoma were 17 and 29 months, respectively, showing a two-fold difference, and non-molecular glioblastoma had significantly better prognosis (P=0.0136).

CONCLUSION

It was revealed that tumors diagnosed as glioblastoma based on conventional histological findings can be broadly classified into molecular and non-molecular glioblastoma, with significant differences in prognosis.
PATH-36. DO GENE EXPRESSION PROFILES BETTER PREDICT OLIGODENDROGLIOMA SURVIVAL?
Authors: Roy Vijaylaxmi , Lath Devraj , Sreegiriraju Vijay , Sadasivam Subhashini , Ghanekar Yashoda , Goel Pallavi , Kumari Neha , Pawar Vikas , Madiraju Surya , Ray Amit
Published: November 2024

The WHO 2021 classification of oligodendroglioma grade 2 (G2) and grade 3 (G3), is separated by histopathology alone and does not universally reflect survival outcome. DNA methylation-based profiling also fails to separate oligodendroglioma grades. Our aim was to define transcriptome-based molecular subgroups that predict survival of oligodendroglioma (IDH-mutant and 1p/19q-codeleted) patients. Clinical and whole-transcriptome data for oligodendroglioma were obtained from TCGA (n=132), CGGA (n=53), and the Exsegen Genomics Research Biobank (n=16) (CTRI/2021/09/036861); while that of control brain samples (n=9) were obtained from CPTAC. Overall survival (OS) was significantly different in TCGA samples between WHO CNS G2 and G3 oligodendrogliomas (log-rank test, p=0.0001); but, not in CGGA (p=0.1833) or Exsegen (p>0.06) samples. Genes with highly variable expression (Median Absolute Deviation, i.e. MAD>1; 1645 genes) across TCGA oligodendroglioma and CPTAC control brain samples were used to exclude 9 oligodendroglioma samples with Pearson’s correlation>0.75 with control brain samples. Consensus clustering (K-means and spectral) of remaining 124 TCGA oligodendroglioma samples identified three significantly different (SigClust, p<0.05) transcriptomic classes using 1347 highly variable genes (MAD>1) in these samples. Principal component analysis (PCA) on expression of 1347 genes in TCGA samples revealed partial overlap of G2 and G3 tumours; but transcriptomic classes with distinct OS could be identified at both extremes of survival. Gene expression signatures for each transcriptomic class were developed using core TCGA samples from each class. For further validation, gene signatures were used to predict the transcriptomic classes of CGGA and Exsegen samples based on highest cosine similarity between sample gene expression and gene signature of each transcriptomic class. OS was significantly different between the transcriptomic classes in TCGA samples and predicted ones in CGGA samples. Transcriptome profiling separated oligodendrogliomas into distinct classes which can predict survival and potentially augment grading and refine prognostication and treatment options.
PATH-38. INTRACRANIAL SARCOMA WITH DICER1 MUTATION IN A PATIENT WITH NEUROFIBROMATOSIS TYPE 1
Authors: Weisnicht Allison , Pytel Nicholas
Published: November 2024

A 16-year-old male with neurofibromatosis type 1 (NF1) and a history of low-grade gliomas presented for resection of a progressively enlarging, known low-grade glioma. On follow-up imaging for surgical planning of the low-grade glioma, a new area of concern was detected of a leptomeningeal-based lesion over the left frontal lobe. A biopsy of the frontal lobe lesion subsequently showed a primary intracranial sarcoma with DICER1 mutations, DICER1 p.Q1552 and p.D1709G. An important histology finding was that of prominent eosinophilic cytoplasmic globules, which are associated with intracranial sarcomas with DICER1 mutations. Additional molecular findings of this tumor included NF1 p.K1986fs and TP53 p.G279E mutations in the setting of this patient’s known history of NF1. A DICER mutation was not detected in the concurrent low-grade glioma at the time of his intracranial sarcoma diagnosis, thus thought not to be a germline-derived mutation. He went on to have a surgical resection with subsequent photon radiation therapy followed by consolidation chemotherapy. A Ewing sarcoma based regimen as per COG protocol AEWS1031 was selected for his therapy consisting of vincristine, doxorubicin, cyclophosphamide alternating with ifosfamide, etoposide (VDC-IE). This was chosen based on prior cases showing response to anthracycline-based regimens. This patient has overall shown improvement without signs of progression now 7 months out from his initial diagnosis. This case highlights the importance of recognizing the association of patients with NF1 being at an increased risk for the development of intracranial sarcomas with DICER1 mutations and correlation with histologic findings of eosinophilic cytoplasmic globules. It also points to the need for reporting these rare cases for optimization of therapy selection to provide a more standardized and evidence-based approach in the care for these patients.
PATH-45. TREATMENT OF FGFR1 – ALTERED WHO GRADE 1 GLIONEURONAL TUMORS WITH FGFR INHIBITOR ERDAFITINIB
Authors: Kushnirsky Marina , Gampel Bradley , Gultekin Sakir Humayun , Ivan Michael E , Komotar Ricardo J , Capo Hilda , Williams Basil , de la Fuente Macarena I
Published: November 2024

INTRODUCTION

Low-grade mitogen-activated protein kinase (MAPK) pathway-altered glioneuronal tumors carry distinct molecular alterations, which may represent therapeutic opportunities to avoid or delay toxic treatments like radiation. Erdafitinib is a pan-FGFR tyrosine kinase inhibitor, regulatorily approved in recurrent urothelial carcinoma, and is under clinical investigation for recurrent FGFR-altered gliomas (NCT05859334).

METHODS

We report two patients with FGFR1-altered rosette-forming glioneuronal tumors (RGNT) treated with erdafitinib.

RESULTS

Patient 1 is a 32-year-old woman who presented with obstructive hydrocephalus and a non-enhancing pineal tumor. She underwent a subtotal resection, with histopathology initially consistent with a low grade dysembryoplastic neuroepithelial tumor. She was under observant management for 7 years, and developed worsening symptoms with slow non-enhancing growth, although stable per RANO low grade criteria. The initial tissue was sent for next-generation sequencing (NGS) and DNA methylation profiling, revealing an FGFR1 pathogenic variant with DNA methylation profiling matching with RGNT. Patient began Erdafitinib 8 mg daily, and had stable disease per RANO at 6 months. She developed CTCAE grade 1 toxicities of subretinal fluid, fatigue, dry skin, and paronychia. Patient 2 is a 34-year-old man diagnosed 1 year prior with a tectal tumor, who underwent biopsy due to non-measurable/ non-enhancing progression. Histopathology was consistent with RGNT. NGS revealed FGFR1 mutation, PIK3CA mutation, and NF1 pathogenic variant, described in the literature as characteristic of RGNT. There was insufficient tissue for DNA methylation profiling. Patient started erdafitinib 8 mg daily and remains clinically stable for 1 month. He developed asymptomatic hyperphosphatemia (CTCAE grade 1). Both patients have tolerated treatment without interruptions or dose reductions.

CONCLUSION

Erdafitinib is a well-tolerated and potentially efficacious treatment of FGFR1- altered RGNT, and may avoid the need for radiation. Diagnosis of MAPK- altered low-grade glioneuronal tumors, specifically RGNT, is increasingly reliant on molecular data, and can significantly impact treatment options.
PATH-55. RAMAN-BASED MACHINE LEARNING PLATFORM REVEALS UNIQUE METABOLIC DIFFERENCES BETWEEN IDHMUT AND IDHWT GLIOMA
Authors: Lita Adrian , Sjöberg Joel , Păcioianu David , Celiku Orieta , Dowdy Tyrone , Păun Andrei , Gilbert Mark R , Noushmehr Houtan , Petre Ion , Larion Mioara
Published: November 2024

BACKGROUND

Formalin-fixed, paraffin-embedded (FFPE) tissue slides are routinely used in cancer diagnosis, clinical decision-making, and stored in biobanks, but their utilization in Raman spectroscopy-based studies has been limited due to the background coming from embedding media.

METHODS

Spontaneous Raman spectroscopy was used for molecular fingerprinting of FFPE tissue from 46 patient samples with known methylation subtypes. Spectra were used to construct tumor/non-tumor, IDH1WT/IDH1mut, and methylation-subtype classifiers. Support vector machine and random forest were used to identify the most discriminatory Raman frequencies. Stimulated Raman spectroscopy was used to validate the frequencies identified. Mass spectrometry of glioma cell lines and TCGA were used to validate the biological findings.

RESULTS

Here we develop APOLLO (rAman-based PathOLogy of maLignant glioma) – a computational workflow that predicts different subtypes of glioma from spontaneous Raman spectra of FFPE tissue slides. Our novel APOLLO platform distinguishes tumors from nontumor tissue and identifies novel Raman peaks corresponding to DNA and proteins that are more intense in the tumor. APOLLO differentiates isocitrate dehydrogenase 1 mutant (IDH1mut) from wildtype (IDH1WT) tumors and identifies cholesterol ester levels to be highly abundant in IDHmut glioma. Moreover, APOLLO achieves high discriminative power between finer, clinically relevant glioma methylation subtypes, distinguishing between the CpG island hypermethylated phenotype (G-CIMP)-high and G-CIMP-low molecular phenotypes within the IDH1mut types.

CONCLUSIONS

Our results demonstrate the potential of label-free Raman spectroscopy to classify glioma subtypes from FFPE slides and to extract meaningful biological information thus opening the door for future applications on these archived tissues in other cancers.
PATH-59. HISTOLOGIC CORRELATES FOR MOLECULAR FEATURES IN MENINGIOMAS
Authors: Congivaram Harrshavasan , Thirunavu Vineeth , Santana-Santos Lucas , Jamshidi Pouya , Chen William , Nandoliya Khizar , Sukhanova Madina , Smith Heather , McCord Matthew , Steffens Alicia , Walshon Jordain , McCortney Kathleen , Flowers Mariah , Wang Wenxia , Lu Xinyan , Lesniak Maciej , Sonabend Adam , Tate Matthew , Khan Osaama , Heimberger Amy , Brat Daniel , Chandler James , Raleigh David , Magill Stephen , Youngblood Mark , Horbinski Craig
Published: November 2024

Histologic findings are the primary determinant of meningioma prognosis and post-operative management. However, the association of specific pathologic features with molecular alterations has not yet been comprehensively investigated. Here we utilized a large dataset of well-characterized meningiomas to identify correlates between clinically relevant histological and molecular features. Detailed histologic information was collected for 809 resected meningiomas, including cases with DNA methylation (n=380), copy number array (n=252), next-generation sequencing (n=52), RNA risk score (n=394), and/or TERT promoter profiling (n=238). Analyses were conducted on prognostic pathologic features, including WHO Grade, Ki-67, mitotic index (MI), brain invasion, and atypical histologic findings (necrosis, hypercellularity, prominent nucleoli, sheeting, and small cells). Correlation with molecular variables was performed using Fisher’s Exact Tests, including DNA methylation subgroup, RNA risk score, CNV profiles, and TERT promoter mutations. All statistics were corrected for multiple hypothesis testing. Nearly 65% of meningiomas exhibited at least one atypical histologic feature. Among said features, Ki-67/MI, WHO Grade, sheeting, and necrosis were associated with recurrent lesions and known clinical features of aggressive meningiomas. Several histologic features, including hypercellularity, elevated Ki-67/mitotic index, and WHO grade, also correlated with DNA methylation and RNA risk groups. Several chromosomal arm events were related to specific pathologic features (prominent nucleoli, Ki-67, MI, and grade), including chromosomes 1, 4, 10, 14, and 18. Our analysis highlights the continued value in screening for histologic markers of aggressive behavior in meningiomas, as they correlate with the presence of high-risk molecular features and may serve as proxy markers when advanced molecular testing is not available.
PATH-61. GENOMIC SIGNATURE IN NON-SMALL CELL LUNG CANCER PATIENTS METASTATIC TO BRAIN-A SINGLE INSTITUTION EXPERIENCE
Authors: Zafar Maha , Nwankwo Nkolika , Reddy Aswanth
Published: November 2024

BACKGROUND

Lung cancer is leading cause of cancer-related death in US, with 10-30 % of NSCLC patients developing brain metastasis, which challenges curative treatment and life expectancy. Somatic mutations in KRAS and EGFR genes have been commonly implicated with brain metastasis. Other studies have shown higher amplification frequencies in MYC, YAP1, and MMP13 and deletions in CDKN2A/B.

METHODS

We conducted a retrospective study on observational cohort of NSCLC patients from January 2022 to July 2023, using IRB-approved data in patients with confirmed brain metastasis (CBS). Beyond demographic information, data on genomic signatures was obtained from maximum parallel/next-generation sequencing on tumor biopsy samples. Comparative analysis was conducted to predict commonalities in brain metastasis gene signatures.

RESULTS

The study involved 143 newly diagnosed lung cancer patients, with 29 having CBS. Genomic data was available in 24 patients. Most common abnormality was noted in TP53 gene in about 47% of patients, followed by LRP1B (12%). Mutations in KRAS, EGFR, NF1, MET, SMARCA4, KEAP1, and STK11 genes were seen in two patients each. Interestingly, 3 of 4 patients with LRP1B had brain metastasis. Actionable mutations/rearrangements were significantly lower compared to general prevalence of these mutations (KRAS gene 8% and EGFR gene 5%).

CONCLUSIONS

Lung cancer with brain metastasis has an abysmal prognosis due to poor CNS penetration of chemotherapeutic agents. Surgical resection and RT remain cornerstones of treatment, but certain TKI has shown some potential. Our study uncovered a notably higher prevalence of TP53 mutation among patients with brain metastasis. While patient cohort was small, those harboring an LRP1B mutation exhibited significantly higher incidence of brain metastasis. Contrary to prevalent epidemiological data, our patient population demonstrated a lower frequency of targetable mutations (specifically in EGFR and KRAS genes). We hypothesize that this observation is due to a markedly higher smoking prevalence in our region.
NIMG-11. DISCOVERING POSTOPERATIVE APHASIA RECOVERY IN GLIOMA PATIENTS: THE ROLE OF THE RIGHT BROCA’S HOMOLOG AND VERIFICATION
Authors: Weng Shimeng , Wang Peng , Fang Shengyu , Jiang Tao
Published: November 2024

OBJECTIVE

This study aimed to elucidate the neurological mechanisms that support the recovery of postoperative aphasia by examining alterations in language and extended networks in patients with glioma. Additionally, we sought to determine the causal relationship between the right Broca’s homolog and language recovery using neuro-navigated repetitive transcranial magnetic stimulation (nrTMS).

METHODS

Sixty-two patients with left hemisphere gliomas were retrospectively analyzed and categorized into aphasia and non-aphasia groups based on Aphasia Quotient (AQ) scores. Resting-state functional MRI (rs-fMRI) data were collected and analyzed to investigate differences in functional connectivity (FC) and topological properties of language-related networks. Additionally, eight patients with surgery-induced aphasia were prospectively treated with nrTMS, targeting the node identified from the retrospective analysis.

RESULTS

Significant increases in FC between the left auditory cortex and the right inferior frontal gyrus in the Executive Control Network were observed in the non-aphasia group. Nodal properties, such as the nodal efficiency of the right Broca’s homolog, were independently associated with postoperative language function. The nrTMS treatment group demonstrated significant improvements in AQ scores, with correlations between increased nodal efficiency and positive language outcomes.

CONCLUSION

The right hemisphere, specifically the right inferior frontal gyrus, plays a compensatory role in maintaining language function after glioma resection. These findings suggest the therapeutic potential of nrTMS for enhancing postoperative language recovery, offering insights into individualized patient care and rehabilitation strategies for patients with glioma.
NIMG-21. EARLY-STAGE GLIOBLASTOMA AND MOLECULAR ANALYSIS REVEAL THE RADIOLOGICAL INITIATION OF IDH WILDTYPE GLIOBLASTOMA
Authors: Shibahara Ichiyo , Shigeeda Ryota , Orihashi Yasushi , Tanihata Yoko , Fujitani Kazuko , Hyakutake Yuri , Toyoda Mariko , Sato Sumito , Hide Takuichiro , Kumabe Toshihiro
Published: November 2024

Glioblastoma (GB), IDH wildtype, is an aggressive and malignant tumor that necessitate early surgical intervention upon radiological suspicion. Consequently, the natural growth dynamics of GB remain not fully understood. Previous studies have examined GB growth using multiple MRIs between initial radiological diagnosis of GB and preoperative MRI, but these studies have short-term intervals between MRIs (defined as shortGB-cohort). Unless GB growth is a constant phenomenon, shortGB cannot estimate radiological initiation. In this study, we focused on early-stage GB (eGB), characterized by small, nonspecific lesions on MRI that eventually progress to classic GB findings. We compared three cohorts: 49 cases of eGB. 68 cases of shortGBt, and 23 cases of eGB from previous publications (other-eGB). Molecular analyses revealed that TERT promoter mutations, EGFR amplification/gain, CDKN2A hemi/homozygous deletion, and PTEN hemi/homozygous deletion were consistent between eGB and shortGB. Our analysis indicated that the radiological initiation of GB in eGB was -0.84 years (95% confidence interval (CI): -1.09 to -0.68), compared to -0.35 years (95%CI: -0.46 to -0.28) in shortGB. In eGB, factors such as age < 65, MIB1 > 30%, TERTp mutation, and the presence of copy-number alterations (CNA) in EGFR/PTEN/CDKN2A, with or without TERTp mutation, correlated with faster tumor progression. In cases without these alterations, the estimated radiological initiation was -2.31 years (95%CI: -100 to -0.80), indicating slower progression. The ShortGB-cohort did not show any significant changes based on these factors, suggesting it does not actually reflect tumor origin. The other-eGB cohort presented radiological initiation between -0.92 and -0.15 year, consistent with our eGB-cohort. This study investigates the radiological origin of GB using extremely rare cases of eGB, providing insights into the radiological pathophysiology and its association with molecular alterations in IDH-wildtype GB.
NIMG-23. A NOVEL APPROACH TO PERFUSION MRI STUDIES IN BRAIN TUMOR PATIENTS USING ENDOGENOUS DEOXYHEMOGLOBIN AS A CONTRAST AGENT: A PROOF-OF-CONCEPT STUDY
Authors: Stumpo Vittorio , Sayin Ece Su , Bellomo Jacopo , Sobczyk Oliva , van Niftrik Christiaan Hendrik Bas , Sebök Martina , Weller Michael , Regli Luca , Kulcsar Zsolt , Pangalu Athina , Bink Andrea , Duffin James , Mikulis David D , Fisher Joseph A , Fierstra Jorn
Published: November 2024

BACKGROUND

Assessment of resting perfusion in brain tumors is clinically relevant and relies on dynamic susceptibility contrast magnetic resonance imaging using gadolinium contrast. Preliminary studies have introduced the use of controlled hemoglobin desaturation by means of a transient hypoxic stimulus during echo-planar imaging(EPI) as a surrogate for gadolinium for resting perfusion assessment in healthy subjects. In this proof of concept study, we investigated whether this approach is feasible in brain tumors and warrant further validation.

METHODS

A computer controlled gas blender was used to induce transient and standardized hypoxic stimulus in isocapnic conditions during EPI acquisition in a heterogenous cohort of tumor patients. The induced blood-oxygen-level-dependent(BOLD) signal changes determined by transit of a bolus of deoxygenated blood in the brain vasculature were used as a surrogate of gadolinium to calculate cerebral blood volume(CBV), cerebral blood flow(CBF) and mean transit time(MTT) using a global arterial input functions obtained through the BOLD signal measured over the middle cerebral artery as previously described by Poublanc et al. Perfusion parameters were calculated in the whole-brain voxel-by-voxel and in automatically segmented region of interest(ROI) using SPM, AFNI, Verbena softwares and MATLAB in-house written scripts.

RESULTS

Nine patients were included. MTT, rCBV, rCBF were calculated voxel-per-voxel. Obtained maps were overlayed on the co-registered T1 MRI scans and compared to T1CE and FLAIR to identify perfusion patterns in tumor ROIs (contrast enhancement, edema, necrosis). The deoxy-hemoglobin BOLD MRI perfusion were compared to clinical DSC-MRI when available and showed high qualitative agreement.

CONCLUSION

Transient and precise hemoglobin desaturation by controlled hypoxic gas modulation is safe and repeatable in brain tumor patients. The induced BOLD signal change allows measurement of resting perfusion, which qualitatively closely mimic gadolinium perfusion in different brain tumors. Deoxyhemoglobin-based perfusion warrant further quantitative validation against gadolinium in a larger cohort of heterogenous tumor patients.
NIMG-24. PRECISION GLIOBLASTOMA MANAGEMENT USING MET AND FMISO PET SCANS
Authors: Miyake Keisuke , Tatano Masaki , Kanda Takahiro , Suzuki Kenta , Ogawa Daisuke , Hatakeyama Tetsuhiro
Published: November 2024

OBJECTIVE

Positron Emission Tomography (PET) may be useful in diagnosing glioblastoma, determining resection areas, and evaluating therapeutic efficacy. This study evaluated the usefulness of PET scans using 11C-Methionine (MET) to assess amino acid metabolism and 18F-Fluoromisonidazole (FMISO) to assess hypoxic regions in glioblastoma treatment.

METHODS

Thirty glioblastoma patients who underwent MET and FMISO PET studies from July 2013 to March 2024 were included. Patients underwent the Stupp regimen post-tumor resection and were treated with temozolomide (TMZ) and bevacizumab (Bev) upon recurrence. PET scans were performed before and after two courses of Bev treatment. Changes in tumor to normal ratio (TNR) for MET, tumor to blood ratio (TBR) for FMISO, and metabolic tumor volume (MTV) for both MET and FMISO were evaluated. Progression-free survival (PFS) and overall survival (OS) were compared based on the rate of change in MTV for MET and FMISO.

RESULTS

The residual volumes (contrast-enhanced MRI, MET, and FMISO) with a MET removal rate of >90% were 0.08 ml, 0.1 ml, and 0.08 ml, respectively. For FMISO removal rates of >90%, residual volumes were 0.36 ml, 1.54 ml, and 0.05 ml, respectively. Groups with a decreased rate of change in MET MTV had significantly better outcomes: PFS (months) 10.7 vs. 2.8 (p=0.19) and OS (months) 18.6 vs. 4.9 (p=0.09). In the FMISO groups, decreased TBR change rates correlated with better outcomes: PFS (months) 16.6 vs. 2.5 (p<0.01) and OS (months) 22.8 vs. 4.9 (p<0.01). MTV change rates also showed significant differences in outcomes: PFS (months) 10.5 vs. 3.7 (p=0.76) and OS (months) 14.9 vs. 7.0 (p=0.87).

CONCLUSION

Higher MET removal rates correlate with fewer contrast-enhanced MRI and FMISO accumulation areas, suggesting MET as a reliable tumor removal indicator. Both MET and FMISO PET scans are valuable in determining glioblastoma treatment response.
NIMG-27. RADIOMETHYLOMICS FOR NON-INVASIVE PREDICTION OF TUMOR PHENOTYPES AND SURVIVAL IN GLIOBLASTOMA
Authors: Matsumoto Yuji , Singh Omkar , Garcia Jose , Kwak Sunwoo , Abdullaev Zied , Freeburg Nelson , Silverbush Dana , Aldape Kenneth , Davatzikos Christos , Nasrallah MacLean
Published: November 2024

BACKGROUND

DNA methylation profiling has become a pivotal tool in neuro-oncology. However, little is known about the impact of methylation profiling on radiological imaging in IDH-wildtype glioblastoma (GBM). This study explored the potential of radiomics to non-invasively predict molecular characteristics based on the methylation profiling of GBM.

METHODS

This study included a multi-sampling cohort of 32 patients with 113 samples and a single-sampling cohort of 87 patients with 87 samples, which underwent genome-wide methylation analysis and were classified as GBM by the DKFZ/Heidelberg CNS tumor classifier. We performed two different methylation-based deconvolution analyses. Deconvolution 1 estimated the fractions of tumor subtypes (RTK_I, RTK_II, MES_TYP, and MES_ATYP) and cell types in the microenvironment. Deconvolution 2 inferred the abundance of malignant cell states (stem-like and differentiated cell components) and cell types in the microenvironment. We derived 6084 radiomic features from preoperative multi-parametric MRI in each patient.

RESULTS

In the multi-sampling cohort, Deconvolution 1 and Deconvolution 2 demonstrated that tumor subclass components and immune components exhibited heterogeneous distribution across samples within patients; however, the stem-like to differentiated cell ratio was preserved across samples within patients. In the entire cohort, patients with tumors exhibiting a high proportion of the stem-like component, defined as stem-like tumors, had significantly shorter overall survival. Stem-like tumors exhibited significantly higher levels of the RTK_I component and lower proportions of the RTK_II component compared to non-stem-like tumors. A machine learning model that utilizes support vector machines to classify stem-like tumors using radiomic features achieved a mean AUC of 0.71 (95% confidence interval: 0.56–0.85) in nested cross-validation.

CONCLUSIONS

We showed that radiomethylomics can be used to predict tumor composition and patient survival from preoperative MRI in GBM. Based on these promising results we will increase our power with additional samples to facilitate a personalized approach to GBM management.
NIMG-28. HYPERPOLARIZED13C IMAGING OF D-2-HYDROXYGLUTARATE-INDUCED DOWNREGULATION OF PYRUVATE DEHYDROGENASE ACTIVITY PROVIDES AN EARLY READOUT OF RESPONSE TO VORASIDENIB IN MUTANT IDH GLIOMAS
Authors: Batsios Georgios , Gillespie Anne Marie , Viswanath Pavithra
Published: November 2024

Mutations in isocitrate dehydrogenase (IDHm) define a distinct class of gliomas. IDHm converts a-ketoglutarate (a-KG) to D-2-hydroxyglutarate (D-2HG), which inhibits a-KG-dependent histone/DNA demethylases and induces epigenetic alterations that drive tumorigenesis. The IDHm inhibitor vorasidenib extends progression-free survival in IDHm glioma patients and is expected to be widely used for this patient population. However, not all patients respond to vorasidenib, and magnetic resonance imaging (MRI) does not assess whether a patient is responding to vorasidenib. Therefore, the goal of this study was to identify metabolic alterations induced by D-2HG that can be leveraged for non-invasive imaging of IDHm gliomas. Using clinically relevant patient-derived models (BT257, BT142, BT54, SF10417, SF10602), we show that D-2HG downregulates the activity of pyruvate dehydrogenase (PDH), the rate-limiting enzyme for oxidation of glucose-derived pyruvate via the tricarboxylic acid cycle, by multiple mechanisms. Drug affinity target stability assays show that D-2HG directly binds to and inhibits PDH activity. D-2HG also inhibits a-KG-dependent prolyl hydroxylases that target hypoxia-inducible factor 1-a (HIF-1a) for degradation. As a result, D-2HG stabilizes HIF-1a and drives expression of pyruvate dehydrogenase kinase 3, which phosphorylates and inhibits PDH activity. Suppressing D-2HG using vorasidenib upregulates PDH activity in IDHm glioma cells and intracranial tumors. Next, we examined whether hyperpolarized 13C-MRS, which is an advanced MRI-based method of imaging metabolic activity, monitors PDH activity in IDHm gliomas. Following administration of hyperpolarized [2-13C]-pyruvate, metabolic conversion to [5-13C]-glutamate provides a readout of PDH activity. Our studies indicate that [5-13C]-glutamate production from hyperpolarized [2-13C]-pyruvate is upregulated in IDHm glioma cells treated with vorasidenib. Importantly, [5-13C]-glutamate production is elevated within 5 days of treatment with vorasidenib in rats bearing intracranial BT257 or BT142 xenografts, when changes cannot be observed by MRI. Collectively, our studies identify hyperpolarized [2-13C]-pyruvate as a unique probe of D-2HG-induced metabolic rewiring and highlight its ability to assess IDHm glioma response to therapy, which is a challenge in the clinic.
NIMG-31. CASE REPORT: DIAGNOSIS OF AN INFILTRATIVE GLIOMA IN A LI-FRAUMENI SYNDROME PATIENT OBSCURED BY LESION RESPONSIVENESS TO NSCLC TREATMENT
Authors: Janatpour Zachary , Gregory Timothy
Published: November 2024

Li-Fraumeni syndrome is a rare, autosomal dominant disorder linked to germline mutations of the TP53 suppressor gene. Patients with this syndrome are predisposed to various malignancies and a variety of brain tumors to include choroid plexus carcinoma, medulloblastoma, and glioma. We present a 46-year-old woman with a history of Li-Fraumeni syndrome which manifested with multiple systemic malignancies including breast cancer, ovarian teratoma, and leiomyosarcoma. The patient had been undergoing MRI brain surveillance since 2018, which was initially notable for a right cerebellar midline focus of enhancement associated with slowly evolving right middle cerebellar peduncle FLAIR signal, with no detectable neurologic symptoms. She underwent systemic therapy for non-small cell lung cancer (NSCLC) with pemetrexed/cisplatin. Her next MRI brain in August 2023 showed resolution of the cerebellar enhancement with small residual FLAIR signal. In April 2024, the patient presented with new neurologic symptoms to include ataxia, dizziness, difficulty swallowing, and memory loss. Repeat MRI brain revealed new infiltrative FLAIR signal throughout the right temporal lobe extending from the posterior fossa, contiguous with the previously seen cerebellar findings and consistent with infiltrative glioma. Due to fragmented records and care in multiple systems, her updated MRI initially created a diagnostic challenge with a radiographic interpretation of likely encephalitis. This is a unique case documenting a middle-aged female with Li-Fraumeni syndrome, followed for multiple cancers, presenting with new neurologic symptoms and progressive infiltrative FLAIR changes spanning from the cerebellum into the right temporal lobe. These findings highlight the natural history of a TP53 deficient tumor that ostensibly responded to a cisplatin-based regimen given for a different indication, thereby delaying time to symptom onset and need for biopsy. Surveillance of low grade lesions in patients with underlying tumor predisposition syndromes must be interpreted in context of systemic disease burden and concurrent treatments for other neoplasms.