IDH Wildtype Research Articles

JS05.6.A CONTINUOUS DYNAMIC MAPPING OF LANGUAGE FUNCTION AND COGNITIVE CONTROL AND SPATIAL CORRELATION TO WHITE MATTER TRACTS USING INTRAOPERATIVE MRI TRACTOGRAPHY

Abstract BACKGROUND Subcortical mapping of white matter tracts (WMTs) subserving complex processes as movement, language and cognition is critical in glioma surgery. Continuous dynamic mapping (CDM) is an indispensable tool for mapping of the corticospinal tract (CST). There is, however, no widespread method for CDM of more advanced brain functions. MATERIAL AND METHODS Patients undergoing awake craniotomy for diffuse gliomas at the Oslo University Hospital with the use of neuronavigation, diffusion tensor imaging (DTI) and CDM coupled with structured evaluation as well as intraoperative magnetic resonance imaging (iMRI) were included in a retrospective analysis. Subcortical CDM was conducted when resection became close to the arcuate fasciculus (AF) and the frontal aslant tract (FAT) with clinical testing using language paradigms and Stroop task. The current was delivered through a monopolar suction probe applying a modified Taniguchi technique with short train of pulses. The spatial relationship between the stimulation response and the examined tracts was determined by measuring the shortest distance between the resection cavity and the relevant white matter tracts (WMTs) using iMRI DTI. RESULTS Twenty IDH-mutant and eight IDH wild type gliomas operated 2021-2023 were included in the analysis. Subcortical CDM of the AF and the FAT proved to be amenable as both language function and the ability to perform Stroop test were affected when the stimulation site gradually became close (< 1 cm) to the examined tracts. Positive stimulation response was verified by repeat challenge. The stimulation intensity was thereafter reduced in a stepwise fashion when there was a consistent hesitation in the patient’s response. Resection was continued until the tumor border was reached and not beyond the threshold of 3mA. The threshold of stimulation intensity correlated to the minimal distance from the resection cavity to the delineated WMTs. We did not observe any seizure activity induced by CDM. CONCLUSION We have experienced subcortical CDM to be a safe and reliable method, where distance to identified WMT appear to be correlated to the applied stimulation intensity.

OS09.2.A REGORAFENIB IN COMBINATION WITH TEMOZOLOMIDE WITH OR WITHOUT RADIOTHERAPY IN PATIENTS WITH NEWLY DIAGNOSED MGMT-METHYLATED, IDH WILDTYPE GLIOBLASTOMA: A PHASE I DOSE-FINDING STUDY (REGOMA-2, EUDRA CT N° 2021-001604-15)

Abstract BACKGROUND Glioblastoma (GBM) is associated with the activation of multiple signaling pathways, including the receptor tyrosine kinases, VEGFR, FGFR and PDGFR. The potential response to anti-angiogenic agents makes GBM an attractive target for regorafenib (REG). Antitumor activity of REG in recurrent GBM patients was shown in the phase II REGOMA trial. Interestingly, in “in vivo” studies, beneficial effects were observed with the combination of REG and temozolomide (TMZ) in subcutaneous xenografts. MATERIAL AND METHODS This phase I open-label multicentric study in progress is evaluating the addition of REG to standard of care treatment with TMZ as adjuvant therapy (cohort A), and in combination with TMZ + radiotherapy (RT) as concomitant therapy (cohort B), in newly diagnosed MGMT-methylated, IDH wildtype GBM patients. Primary objectives are: to determine the safety and tolerability of REG and to establish the maximum tolerated dose (MTD) of REG in these two cohorts. Secondary objectives are: the assessment of pharmacokinetics of REG, TMZ, and possible pharmacokinetic interactions between TMZ and REG in cohort A; the assessment of preliminary antitumor activity; the evaluation of quality of life during the treatment. The dose escalation is being explored according to a “3 + 3” design, starting from cohort A and following 3 dose levels of REG [80 mg, 120 mg and 160 mg]. After finding the MTD in cohort A, the cohort B dose escalation will start, exploring escalating oral doses of REG in combination with concomitant TMZ + RT (60 Gy/30 fractions). In the adjuvant phase of cohort B, REG will be given with TMZ at MTD shown in the prior adjuvant phase dose escalation.The DLT (dose-limiting toxicity) evaluation period will be two cycles from the start of cycle 1 of adjuvant phase (in cohort A) and from day 1 to the last day of the concomitant phase (in cohort B). Recruitment started in May 2022; Level 1 in cohort A (3 patients) has been completed without DLT. Approximately 36 subjects will be enrolled.

JS09.8.A COMPARATIVE PROGNOSTIC VALUE OF O-(2-[18F]-FLUOROETHYL)-L-TYROSINE PET IMAGING AND DCE MRI BLOOD VOLUME IMAGING IN PATIENTS WITH SUSPECTED RECURRENT IDH-WILDTYPE HIGH-GRADE GLIOMA

Abstract BACKGROUND Quantitative blood volume (BV) imaging using dynamic T1-weighted contrast enhanced (DCE) perfusion MRI may be of diagnostic value in patients with suspected recurrent high-grade glioma, but the association of DCE BV measurements with survival is not known. The aim of the study was to compare the prognostic information of DCE BV measurements with that of O-(2-[18F]-fluoroethyl)-L-tyrosine ([18F]FET) PET imaging in treated IDH wildtype high-grade astrocytoma and glioblastoma (2016 WHO classification). MATERIAL AND METHODS A total of 94 hybrid [18F]FET PET/MRI scans with DCE from unique adult patients were retrospectively analysed. Scans were obtained after surgery/biopsy (n=94) and radiotherapy (n=93) due to variable suspicion of residual or progressive disease. In each scan the visually BV positive (VOLBV), the [18F]FET PET avid (VOLFET) and the contrast-enhancing (VOLCE) volumes were delineated, and fractional tumour volumes (fVOL) within VOLCE, as well as maximal BV (BVmax) and maximal [18F]FET tumour-to-background ratio (TBRmax) were determined. Accuracy for prediction of 6-month progression free survival and 1 year overall survival were assessed by logistics regression. Associations with overall survival were assessed for each parameter by Cox proportional hazard analysis. RESULTS In a univariate analysis, adjusted for age and MGMT, both VOLCE, and all [18F]FET and DCE BV derived metrics were predictive of both 6 month progression free survival, 1 year survival and overall survival. ROC AUC for prediction of 6 month progression free survival and 1 year overall survival tended to be higher for [18F]FET derived metrics, but ROC AUC values were not significantly different between any [18F]FET and DCE BV derived metrics. In Cox models for overall survival (adjusting for age, MGMT and VOLCE) only TBRmax and VOLBV had independent prognostic value among [18F]FET PET and DCE BV derived metrics, respectively. In a final model including both TBRmax and VOLBV, only TBRmax remained significant.. CONCLUSION DCE BV and [18F]FET PET derived metrics provides prognostic information independent of age, MGMT status and contrast enhancing tumour volume in treated glioblastoma, with volume of increased BV and [18F]FET TBRmax providing strongest associations with overall survival. Accounting for functional imaging biomarkers may be important in balancing future randomized clinical trials.

Impact of signal intensity normalization of MRI on the generalizability of radiomic-based prediction of molecular glioma subtypes

ObjectivesRadiomic features have demonstrated encouraging results for non-invasive detection of molecular biomarkers, but the lack of guidelines for pre-processing MRI-data has led to poor generalizability. Here, we assessed the influence of different MRI-intensity normalization techniques on the performance of radiomics-based models for predicting molecular glioma subtypes.MethodsPreoperative MRI-data from n = 615 patients with newly diagnosed glioma and known isocitrate dehydrogenase (IDH) and 1p/19q status were pre-processed using four different methods: no normalization (naive), N4 bias field correction (N4), N4 followed by either WhiteStripe (N4/WS), or z-score normalization (N4/z-score). A total of 377 Image-Biomarker-Standardisation-Initiative-compliant radiomic features were extracted from each normalized data, and 9 different machine-learning algorithms were trained for multiclass prediction of molecular glioma subtypes (IDH-mutant 1p/19q codeleted vs. IDH-mutant 1p/19q non-codeleted vs. IDH wild type). External testing was performed in public glioma datasets from UCSF (n = 410) and TCGA (n = 160).ResultsSupport vector machine yielded the best performance with macro-average AUCs of 0.84 (naive), 0.84 (N4), 0.87 (N4/WS), and 0.87 (N4/z-score) in the internal test set. Both N4/WS and z-score outperformed the other approaches in the external UCSF and TCGA test sets with macro-average AUCs ranging from 0.85 to 0.87, replicating the performance of the internal test set, in contrast to macro-average AUCs ranging from 0.19 to 0.45 for naive and 0.26 to 0.52 for N4 alone.ConclusionIntensity normalization of MRI data is essential for the generalizability of radiomic-based machine-learning models. Specifically, both N4/WS and N4/z-score approaches allow to preserve the high model performance, yielding generalizable performance when applying the developed radiomic-based machine-learning model in an external heterogeneous, multi-institutional setting.Clinical relevance statementIntensity normalization such as N4/WS or N4/z-score can be used to develop reliable radiomics-based machine learning models from heterogeneous multicentre MRI datasets and provide non-invasive prediction of glioma subtypes.Key Points• MRI-intensity normalization increases the stability of radiomics-based models and leads to better generalizability.• Intensity normalization did not appear relevant when the developed model was applied to homogeneous data from the same institution.• Radiomic-based machine learning algorithms are a promising approach for simultaneous classification of IDH and 1p/19q status of glioma.

Dynamic contrast-enhanced MRI radiomics model predicts epidermal growth factor receptor amplification in glioblastoma, IDH-wildtype.

To develop and validate a dynamic contrast-enhanced (DCE) MRI-based radiomics model to predict epidermal growth factor receptor (EGFR) amplification in patients with glioblastoma, isocitrate dehydrogenase (IDH) wildtype. Patients with pathologically confirmed glioblastoma, IDH wildtype, from January 2015 to December 2020, with an EGFR amplification status, were included. Patients who did not undergo DCE or conventional brain MRI were excluded. Patients were categorized into training and test sets by a ratio of 7:3. DCE MRI data were used to generate volume transfer constant (Ktrans) and extracellular volume fraction (Ve) maps. Ktrans, Ve, and conventional MRI were then used to extract the radiomics features, from which the prediction models for EGFR amplification status were developed and validated. A total of 190 patients (mean age, 59.9; male, 55.3%), divided into training (n = 133) and test (n = 57) sets, were enrolled. In the test set, the radiomics model using the Ktrans map exhibited the highest area under the receiver operating characteristic curve (AUROC), 0.80 (95% confidence interval [CI], 0.65-0.95). The AUROC for the Ve map-based and conventional MRI-based models were 0.74 (95% CI, 0.58-0.90) and 0.76 (95% CI, 0.61-0.91). The DCE MRI-based radiomics model that predicts EGFR amplification in glioblastoma, IDH wildtype, was developed and validated. The MRI-based radiomics model using the Ktrans map has higher AUROC than conventional MRI.

Outcomes of Isocitrate Dehydrogenase Wild Type Glioblastoma after Re-irradiation.

Glioblastomas (GBM) are the most common malignant primary brain tumors in adults and have a dismal prognosis. Patients frequently suffer from local tumor recurrences, with limited therapeutic options. Re-irradiation represents a possible intervention, but given the recent 5th edition of the World Health Organization classification of central nervous system tumors, studies in isocitrate dehydrogenase wild type (IDH-wt) cohorts undergoing a second course of radiotherapy remain limited. Herein, we sought to describe our institutional experience and outcomes after GBM IDH-wt re-irradiation. GBM patients with confirmed IDH-wt status undergoing re-irradiation were included in this single-center, retrospective analysis. A total of 88 patients were analyzed. The median clinical and radiographic follow-up periods were 4.6months and 4.4months, respectively. Most patients had a Karnofsky performance status of at least 80% (n=57). The median biologically effective dose and 2Gy equivalent dose (EQD2) for re-irradiations, assuming an α/β ratio of 10Gy for GBM, were 51.4 and 42.8Gy, respectively. In total, 71 deaths were recorded. The median overall survival (OS) was 8.0months. Multivariable Cox regression of OS revealed a positive influence of gross total resection vs. biopsy or no resection (hazard ratio: 0.43, p=0.02). The median progression-free survival (PFS) was 5.9months. The multivariable Cox regression for PFS did not detect any significant factors. No clear evidence of radiation necrosis was recorded during the available follow-up. However, only a minority (n=4) of patients underwent surgery after re-irradiation, none showing histopathological proof of radiation necrosis. The prognosis for recurrent IDH-wt GBM after re-irradiation is poor. Patients who are amenable and able to undergo re-resection may have a favorable OS. A second course of radiotherapy with a moderate cumulative EQD2 and small- to medium-sized planning target volumes appeared safe regarding the occurrence of radiation necrosis.

The prognostic power of [11C]methionine PET in IDH-wildtype diffuse gliomas with lower-grade histological features: venturing beyond WHO classification.

IDH-wildtype (IDH-wt) diffuse gliomas with histological features of lower-grade gliomas (LGGs) are rare and heterogeneous primary brain tumours. [11C]Methionine (MET) positron emission tomography (PET) is commonly used to evaluate glial neoplasms at diagnosis. The present study aimed to assess the prognostic value of MET PET in newly diagnosed, treatment naïve IDH-wt gliomas with histological features of LGGs. Patients with a histological diagnosis of IDH-wt LGG who underwent preoperative (< 100days) MET PET/CT and surgery were retrospectively included. Qualitative and semi-quantitative analyses of MET PET images were performed. Progression-free survival (PFS) and overall survival (OS) were analysed by Kaplan-Meier curves. Cox proportional-hazards regression was used to test the association of imaging and clinical data to PFS and OS. We included 48 patients (M:F = 25:23; median age 55). 39 lesions were positive and 9 negative at MET PET. Positive MET PET was significantly associated with shorter median PFS (15.7months vs. not reached, p = 0.0146) and OS time (32.6months vs. not reached, p = 0.0253). Incomplete surgical resection and higher TBRmean values were independent predictors of shorter PFS on multivariate analysis (p < 0.001 for both). Higher tumour grade and incomplete surgical resection were independent predictors of OS at multivariate analysis (p = 0.027 and p = 0.01, respectively). MET PET is useful for the prognostic stratification of patients with IDH-wt glial neoplasms with histological LGGs features. Considering their huge biological heterogeneity, the combination of MET PET and molecular analyses may help to improve the prognostic accuracy in these diffuse gliomas subset and influence therapeutic choices accordingly.

The proneural subtype is not associated with survival benefit from bevacizumab in newly diagnosed glioblastoma: a secondary analysis of the GLARIUS trial

PurposeThe AVAglio trial reported a significant survival benefit for first line bevacizumab treatment in patients with IDH wildtype glioblastoma of the proneural gene expression subtype. We here aim to replicate these findings in an independent trial cohort.MethodsWe evaluate the treatment benefit of bevacizumab according to gene expression subtypes of pretreatment tumor samples (n = 123) in the GLARIUS trial (NCT00967330) for MGMT unmethylated glioblastoma patients with Kaplan-Meier analyses, log-rank tests and Cox regression models.ResultsEmploying the Phillips classifier, bevacizumab conferred a significant PFS advantage in patients with proneural IDH wild-type tumors (10.4 vs. 6.0 months, p = 0.002), but no OS advantage (16.4 vs. 17.4 months, p = 0.6). Multivariable analysis adjusting for prognostic covariates confirmed the absence of a significant OS advantage from bevacizumab (hazard ratio, 1.05, 95% CI, 0.42 to 2.64; p = 0.14). Further, there was no interaction between the proneural subtype and treatment arm (p = 0.15). These results were confirmed in analyses of tumor subgroups according to the Verhaak classifier.ConclusionIn contrast to AVAglio, glioblastoma gene expression subgroups were not associated with a differential OS benefit from first-line bevacizumab in the GLARIUS trial.

The role of cytoreductive surgery in multifocal/multicentric glioblastomas

PurposeMultifocal/multicentric glioblastomas (mGBM) account for up to 20% of all newly diagnosed glioblastomas. The present study investigates the impact of cytoreductive surgery on survival and functional outcomes in patients with mGBM.MethodsWe retrospectively reviewed clinical and imaging data of 71 patients with newly diagnosed primary (IDH1 wildtype) mGBM who underwent operative treatment in 2015–2020 at the authors’ institution. Multicentric/multifocal growth was defined by the presence of ≥ 2 contrast enhancing lesions ≥ 1 cm apart from each other.Results36 (50.7%) patients had a resection and 35 (49.3%) a biopsy procedure. MGMT status, age, preoperative KPI and NANO scores as well as the postoperative KPI and NANO scores did not differ significantly between resected and biopsied cases. Median overall survival was 6.4 months and varied significantly with the extent of resection (complete resection of contrast enhancing tumor: 13.6, STR: 6.4, biopsy: 3.4 months; P = 0.043). 21 (58.3%) of resected vs. only 12 (34.3%) of biopsied cases had radiochemotherapy (p = 0.022). Multivariate analysis revealed chemo- and radiotherapy and also (albeit with smaller hazard ratios) extent of resection (resection vs. biopsy) and multicentric growth as independent predictors of patient survival. Involvement of eleoquent brain regions, as well as neurodeficit rates and functional outcomes did not vary significantly between the biopsy and the resection cohorts.ConclusionResective surgery in mGBM is associated with better survival. This benefit seems to relate prominently to an increased number of patients being able to tolerate effective adjuvant therapies after tumor resections. In addition, cytoreductive surgery may have a survival impact per se.

Expression and clinical significance of RBBP4 gene in lower-grade glioma: An integrative analysis

This study investigated the expression pattern of retinoblastoma binding protein 4 (RBBP4) gene in glioma and explored its associations with clinicopathologic characteristics and prognosis of patients. Data retrieved from the GEPIA, CGGA, HPA and TIMER databases were processed to analyze RBBP4 expression in glioma and investigate its relationship with clinicopathologic characteristics, tumor immune infiltration and prognosis in glioma patients. Immunohistochemistry was applied to determine the expression of RBBP4 protein in glioma tissue. Additionally, the Coexpedia database was visited to identify co-expressed genes for RBBP4 gene, while the Cytoscape software was run to visualize the enriched GO entries and KEGG pathways of these co-expressed genes. The expression levels of RBBP4 in lower-grade glioma (LGG) and glioblastoma (GBM) tissues were markedly elevated when compared to normal tissues (both p < 0.05). The up-regulation of RBBP4 expression was associated with an increase in WHO grade (II-IV), wild-type IDH, and 1p/19q non-codeletion (all p < 0.05). Multi-variate Cox regression analysis showed that both increased abundance of infiltrating macrophages and up-regulated RBBP4 expression independently predicted poor survival outcomes in LGG patients (both p < 0.05). Furthermore, RBBP4 expression exhibited significant positive correlations with the abundance of infiltrating B cell, CD8+ T cell, CD4+ T cell, macrophage, neutrophil, and dendritic cell in LGG (all p < 0.05). Functional enrichment analyses indicated that the co-expressed genes associated with RBBP4 were highly involved in pathways such as the p53 signaling pathway, cell cycle, DNA replication, glutathione metabolism, as well as biological processes including cell cycle process, DNA replication, and DNA repair. High levels of RBBP4 are predictive for the poor survival outcome of LGG patients. RBBP4 gene, therefore, is expected to be a potential biomarker for prognosis of LGG and a target for immunotherapy.

A Dual-Aware deep learning framework for identification of glioma isocitrate dehydrogenase genotype using magnetic resonance amide proton transfer modalities

To propose a Dual-Aware deep learning framework for genotyping of isocitrate dehydrogenase (IDH) in gliomas based on magnetic resonance amide proton transfer (APT) modality data as a means to assist non-invasive diagnosis of gliomas. We collected multimodal magnetic resonance imaging (MRI) imaging data of the brain from 118 cases of gliomas, including 68 wild-type and 50 mutant type cases. The delineation of the ROI of brain glioma was completed in all the cases. APT modality imaging does not require contrast agents, and its signal intensity on tumors is positively correlated with tumor malignancy, and the signal intensity on wild-type IDH is higher than that on mutant IDH. For APT modalities, tumor imaging and derived areas are morphologically variable and lack prominent edge contour characteristics compared with other modalities. Based on these characteristics, we propose the Dual-Aware framework, which introduces the Multi-Aware framework to mine multi-scale features, and the Edge Aware module mines the edge features for automatic genotype identification. The introduction of two types of Aware mechanisms effectively improved the identification rate of the model for glioma IDH genotyping. The accuracy and AUC for each modality data were enhanced, and the best performance was achieved on the APT modality with a prediction accuracy of 83.1% and an AUC of 0.822, suggesting its advantages and effectiveness for identifying glioma IDH genotypes. The proposed deep learning algorithm model constructed based on the image characteristics of the APT modality is effective for glioma IDH genotyping and identification task and may potentially replace the commonly used T1CE modality to avoid contrast agent injection and achieve non- invasive IDH genotyping.

Platinum Sensitivity in IDH1/2 Mutated Intrahepatic Cholangiocarcinoma: Not All “BRCAness” Is Created Equal

Preclinical data suggest that IDH1/2 mutations result in defective homologous recombination repair (HRR). We hypothesized that patients with IDH1/2mt intrahepatic cholangiocarcinoma (IHCC) would benefit more from 1 L platinum chemotherapy than patients with wildtype (WT) tumors. We performed a multicenter retrospective study of 81 patients with unresectable IHCC treated with 1 L platinum with a primary endpoint of clinical benefit rate (CBR). Patients with IDH1/2mt tumors had a similar CBR and objective response rate compared to those with IDH WT disease (59 versus 54%; p = 0.803), suggesting that a relationship between platinum sensitivity and HRR gene defects may be specific to tumor context.

MYEF2: an immune infiltration-related prognostic factor in IDH-wild-type glioblastoma.

Glioblastoma (GBM) is the most malignant and prevalent primary brain tumor. In this study, weighted gene coexpression network analysis (WGCNA) was performed to analyze RNA binding protein (RBP) expression data from The Cancer Genome Atlas (TCGA) for the IDH-wild type GBM cohort. The CIBERSORT algorithm quantified the cellular composition of immune cells and was used to identify key modules associated with CD8+ T cell infiltration. Coexpression networks analysis and protein-protein interaction (PPI) network analysis was used to filter out central RBP genes. Eleven RBP genes, including MYEF2, MAPT, NOVA1, MAP2, TUBB2B, CDH10, TTYH1, PTPRZ1, SOX2, NOVA2 and SCG3, were identified as candidate CD8+ T cell infiltration-associated central genes. A Cox proportional hazards regression model and Kaplan-Meier analysis were applied to identify candidate biomarkers. MYEF2 was selected as a prognostic biomarker based on the results of prognostic analysis. Flow Cytometric Analysis indicated that MYEF2 expression was negatively correlated with dysfunctional CD8+ T cell markers. Kaplan-Meier survival analysis (based on IHC staining) revealed that GBM patients with elevated MYEF2 expression have a better prognosis. Knockdown of MYEF2 in GBM cells via in vitro assays was observed to promote cell proliferation and migration. Our study suggests that MYEF2 expression negatively correlates with T cell exhaustion and tumor progression, rendering it a potentially valuable prognostic biomarker for GBM.

The prognosis of gliomas with different molecular subtypes in the era of intensity-modulated radiation therapy (IMRT).

This study aimed to evaluate the prognosis of glioma patients with different molecular subtypes of who treated with intensity-modulated radiation therapy (IMRT). We collected 45 glioma patients treated in our hospital between January 2017 and December 2020. All enrolled patients received postoperative IMRT and were divided into two groups based on the Isocitrate dehydrogenase (IDH status). Overall survival (OS) and progression-free survival (PFS) were estimated retrospectively. The median follow-up was 22 months (range 2-108.5 months). The 1-year OS of IDH-mut group and ΙDH-wild group was similar (77.3% vs. 81.5%, p = 0.16). While the 1-year PFS of IDH-mut group was significantly higher than that in ΙDH-wild group (90.4% vs. 39.8%, p = 0.0051). Subgroup analysis revealed that the 1-year PFS of IDH-mut/1p/19q codeletion group and IDH-mut/1p/19q noncodeletion group was significantly higher than in IDH-wild type patients. For patients with IDH-mut/MGMT-methylation, the outcome was no significant difference in OS, but PFS was longer than other subtypes. This retrospective study showed that 1-year PFS of patients with IDH mutated was better than IDH-wild type patients. In subgroups analysis, the outcomes were shown that patients with IDH-mut/ 1p/19q codeletion and patients with IDH-mut/1p/19q noncodeletion had longer 1-year PFS than IDH-wild type patients, but the OS was similar between the subgroups. Patients with IDH-mut/MGMT-methylation had the best prognosis in the whole subgroups. However, these results still need further confirmation of large sample size, prospectively, randomized controlled trails.

CLRM-05 ADAPTATION OF NEW CLASSIFICATION OF ASTROCYTOMA IN LOW AND MIDDLE INCOME COUNTRY- HOW SMOOTH IS THE ROAD AHEAD?

Abstract BACKGROUND The 2021 WHO CNS 5 classification made major changes with integration of immunohistochemistry, molecular profiling and sequencing in addition to histopathology to classify brain tumors. IDH mutation is mainstay for diagnosis of low grade glioma and 1p/19q testing required only to confirm oligodendroglioma but not in all cases. This integrated approach has favored prognosis, and diagnosis of disease as well as prediction of response to therapy. METHODS A retrospective study was conducted to analyze the molecular alterations in patients diagnosed with astrocytoma in 2021 in Kathmandu Cancer Center, Nepal. The demographic data were collected from the patients’ archived files from the medical record department. The patients were categorized as IDH: mutant and wild, and ATRX: retained and lost. RESULTS This study demonstrated IDH and ATRX mutation with 30.3% and 24.23% respectively. In our study, among grade 2 and 3 patients, 8 out of 11 (72.7%) were IDH mutant types. 2 patients of this group were IDH wild type, who ideally required further testing for correct classification but couldn’t be done due to financial constraints. IDH status of one patient in this group was unknown. 72.7% of the Grade 4 gliomas were IDH wild type and classified as Glioblastoma Multiforme. In 6 of the patients IDH status was unknown. Among 8 grade 2 and 3 tumors with IDH mutant, 2 had loss of ATRX and 6 had ATRX retained. Among these 6 patients only one had 1p/19q co-deletion done which was positive. Rests 5 were not properly classified. CONCLUSION In conclusion, higher percentage of IDH wild type was seen in Grade 4 gliomas. Similarly, the IDH mutant type predominated in Grade 2 and 3 gliomas. More pronounced investigations are still not feasible in low- and-middle income countries because of limited resources.

SLC10A3 Is a Prognostic Biomarker and Involved in Immune Infiltration and Programmed Cell Death in Lower Grade Glioma

The association between SLC10A3 (solute carrier family 10 member 3) and lower grade glioma (LGG) remains unclear. We used public databases and bioinformatics analysis to analyze SLC10A3. These included The Cancer Genome Atlas, Genotype-Tissue Expansion, Chinese Glioma Genome Atlas, Human Protein Atlas, GeneCards, cBioPortal, Search Tool for the Retrieval of Interacting Genes/Proteins, Gene Expression Profiling Interactive Analysis, Tumor Immune Estimation Resource, Tumor-Immune System Interaction Database, receiver operating characteristic curve analysis, Kaplan-Meier analysis, Cox analysis, nomograms, calibration plots, gene ontology/Kyoto Encyclopedia of Genes and Genomes enrichment analysis, gene set enrichment analysis, single-sample gene set enrichment analysis, and Spearman's correlation analysis. SLC10A3 was upregulated in adrenocortical carcinoma, glioblastoma, and LGG and was associated with good overall survival (OS) in adrenocortical carcinoma and poor OS in LGG and glioblastoma. SLC10A3 was increased with increased World Health Organization grade, upregulated in isocitrate dehydrogenase-wild type, 1p/19q (chromosome arms 1p and 19q) non-co-deleted, and higher in astrocytoma. Patients with LGG were grouped by the occurrence of the clinical outcome endpoints (i.e., OS, disease-specific survival [DSS], and progression-free interval events). Genetic alterations in SLC10A3 were associated with poor progression-free survival in LGG. Most of clinical characteristics were associated with the SLC10A3 expression level. SLC10A3 with diagnostic and prognostic value (OS, DSS, and progression-free interval) was an independent prognostic factor in LGG. Moreover, Nomograms (WHO grade, 1p/19q codeletion, age and SLC10A3) had moderately accurate predictive for OS and DSS. Functional analysis showed that SLC10A3 might participate in the transport of multiple substances, neurogenic signaling, immune response, and programmed cell death in LGG. SLC10A3 correlated with immune infiltration in LGG and moderately correlated with the gene signature of pyroptosis, lysosome-dependent cell death, necroptosis, apoptosis, ferroptosis, alkaliptosis, and autophagy-dependent cell death. SLC10A3 is a potential diagnostic and prognostic biomarker for LGG and might be associated with substance transport, neurogenic signaling, immune infiltration, and programmed cell death in LGG.

NEIM-11 DEUTERIUM METABOLIC IMAGING (DMI) DETECTS A LARGER WARBURG EFFECT IN HIGH-GRADE BRAIN TUMORS AND IN IDH WILD TYPE GLIOMAS

Abstract BACKGROUND The Warburg Effect (WE) is a metabolic change in which tumors favor glycolysis over oxidative phosphorylation and has been linked to cancer aggressiveness. Mutations in the isocitrate dehydrogenase (IDH) genes in gliomas are associated with improved outcomes. We deployed a magnetic resonance (MR) spectroscopic imaging technique coined Deuterium Metabolic Imaging (DMI) to measure the WE in multiple brain tumor types. METHODS Twenty-one patients underwent DMI, acquired on a Bruker 4T MR scanner after oral administration of 0.75g/kg of deuterated glucose. The WE was defined as the ratio of deuterated lactate, representing glycolysis, over deuterated glutamate and glutamine, representing oxidative phosphorylation. We devised an interval scale from 0 to 2 for the WE RESULTS The Wilcoxon rank sum test was performed to detect differences between groups. RESULTS The WE measurements for the largest groups, by diagnosis, showed: glioblastoma (n=9, mean=1.67); astrocytoma, IDH-mutant, WHO grade 3 (n=2, mean=0.25); oligodendroglioma, WHO grade 3 (n=3, mean=0.5); low grade glioma, IDH-mutant (n=2, mean=0); and meningioma, WHO grade 2 (n=2, mean=0). The WE for high-grade tumors (n=15, mean=1.27) was significantly different from the WE for low-grade tumors (n=5, mean=0), with a p=0.010. The WE for IDH wild type gliomas (n=9, mean=1.67) was significantly different from the WE for IDH-mutant gliomas (n=9, mean=0.44), with a p=0.007. Analysis is ongoing. CONCLUSIONS DMI successfully and non-invasively detects the WE in many types of brain tumors. The WE was larger in high-grade tumors as compared to low-grade tumors, and the WE was larger in IDH wild type gliomas as compared to IDH-mutant gliomas. If validated with future studies, our results suggest that DMI is a useful tool to measure differences in the metabolism of brain tumors with different clinical behaviors.

SYST-20 TARGETED THERAPY MATCHED TO GENOMIC ALTERATIONS (BRAFV600E, NTRK, FGFR, ROS1, PIK3CA, PTEN) IN PATIENTS WITH RECURRENT IDH WILDTYPE GLIOBLASTOMA: A REAL-LIFE COHORT ANALYSIS FROM VENETO INSTITUTE OF ONCOLOGY, PADUA (ITALY)

Abstract We retrospectively analyzed 34 patients (pts) [19 males, 15 females, median age 54] with recurrent IDH wildtype glioblastoma treated with target therapy (TT) based on their next-generation sequencing (NGS) profile, between March2020 and December2022 at Veneto Institute of Oncology, Padua (Italy). ECOG PS was 0-1 in 29 pts. All pts received previous radiotherapy and temozolomide. NGS was obtained with FoundationOne®CDx on formalin-fixed paraffin-embedded samples. We identified 6 druggable genomic alterations, classified according to ESCAT (ESMO Scale for Clinical Actionability of molecular Targets): BRAFV600E mutation (IB), NTRK1-2-3 fusions (IC), FGFR1-2-3 alterations (IIB), ROS1 fusions (IIIA), PIK3CA mutations (IIIA) and PTEN loss/mutations (IIIA). The median line of therapy with TT was 3 (range 2-7). TT was dabrafenib/trametinib (9 pts), larotrectinib (2 pts), erdafitinib (4 pts), entrectinib (1 pt), alpelisib (6 pts), ipatasertib+/-atezolizumab (12 pts). At data cut-off (March2023), 19 patients had died. In the entire cohort, median overall survival and progression-free survival (PFS) after starting TT was 8.72 and 2.14 months, respectively. The dabrafenib/trametinib subgroup had the longest median PFS (5.23 months), a disease control rate (DCR) of 77%, an objective response rate of 22%, and a median duration of response of 22.5 months. 7/9 pt had died and 2 pts are continuing dabrafenib/trametinib. The pt with ROS1-GOCP fusion maintained a complete response for 12 months with entrectinib. Among the others, no complete/partial responses were detected. DCR due to stable disease was 50% in larotrectinib and erdafitinib subgroups and 8.3% in ipatasertib+/-atezolizumab subgroup. No toxicities were reported in dabrafenib/trametinib subgroup. Among all patients, no grade 4 drug-related adverse events were observed and in any case TT was interrupted for toxicity. Our results confirm the activity of dabrafenib/trametinib in BRAFV600E mutant glioblastoma pts and might suggest further explorations in targeting ROS1 and FGFR.

T2-FLAIR mismatch sign correlates with 11C-methionine uptake in lower-grade diffuse gliomas.

The T2-FLAIR mismatch sign is recognized as an imaging finding highly suggestive of IDH-mutant astrocytomas. This study was designed to determine whether the T2-FLAIR mismatch sign correlates with uptake of 11C-methionine in lower-grade gliomas. We included 78 histopathologically verified lower-grade gliomas (grade 2: 31 cases, grade 3: 47 cases) in this study. 78 patients underwent 11C-methionine positron emission tomography (MET-PET) scans and magnetic resonance (MR) imaging scans prior to histological diagnosis. The tumor-to-normal ratio (T/N) of 11C-methionine uptake was calculated by dividing the maximum standardized uptake value (SUV) for the tumor by the mean SUV of the normal brain. MR imaging scans were evaluated for the presence of the T2-FLAIR mismatch sign by three independent reviewers. We compared molecular status, the T2-FLAIR mismatch sign and 11C-methionine uptake among patients with different lower-grade glioma molecular types. The 78 lower-grade gliomas were assigned to one of three molecular groups: Group A (IDH-mutant and 1p/19q non-codeleted, n = 22), Group O (IDH-mutant and 1p/19q codeleted, n = 20), and Group W (IDH wildtype, n = 36). T2-FLAIR mismatch was found in 16 cases (20.5%) that were comprised of 8 (36.4%), 0 (0%), 8 (22.2%) cases in the molecular group A, O and W, respectively. The median T/N ratio of MET-PET in tumors with T2-FLAIR mismatch was 1.50, which was significantly lower than that of tumors without T2-FLAIR mismatch (1.83, p < 0.001, Mann-Whitney U test). In the Groups A and W (excluding Group O), the median T/N ratio on MET-PET in groups A and W (but not group O) with T2-FLAIR mismatch was 1.50, which was significantly lower than that of tumors without T2-FLAIR mismatch (1.81, p = 0.002, Mann-Whitney U test). The T2-FLAIR mismatch sign correlated with lower 11C-methionine uptake in lower grade gliomas.

The curious case of IDH mutant acute myeloid leukaemia: biochemistry and therapeutic approaches.

Of the many genetic alterations that occur in cancer, relatively few have proven to be suitable for the development of targeted therapies. Mutations in isocitrate dehydrogenase (IDH) 1 and -2 increase the capacity of cancer cells to produce a normally scarce metabolite, D-2-hydroxyglutarate (2-HG), by several orders of magnitude. The discovery of the unusual biochemistry of IDH mutations spurred a flurry of activity that revealed 2-HG as an 'oncometabolite' with pleiotropic effects in malignant cells and consequences for anti-tumour immunity. Over the next decade, we learned that 2-HG dysregulates a wide array of molecular pathways, among them a large family of dioxygenases that utilise the closely related metabolite α-ketoglutarate (α-KG) as an essential co-substrate. 2-HG not only contributes to malignant transformation, but some cancer cells become addicted to it and sensitive to inhibitors that block its synthesis. Moreover, high 2-HG levels and loss of wild-type IDH1 or IDH2 activity gives rise to synthetic lethal vulnerabilities. Herein, we review the biology of IDH mutations with a particular focus on acute myeloid leukaemia (AML), an aggressive disease where selective targeting of IDH-mutant cells is showing significant promise.