IDH-mutant Gliomas Research Articles

Suppression of antitumor immune signatures and upregulation of VEGFA as IDH-mutant gliomas progress to higher grade.

Several studies have compared the immune microenvironment of isocitrate dehydrogenase (IDH)-wildtype glioma versus IDH-mutant glioma. The authors sought to determine whether histological tumor progression in a subset of IDH-mutant glioma was associated with concomitant alterations in the intratumoral immune microenvironment. The authors performed bulk RNA sequencing on paired and unpaired samples from patients with IDH-mutant glioma who underwent surgery for tumor progression across multiple timepoints. They compared patterns of differential gene expression, overall inflammatory signatures, and transcriptomic measures of relative immune cell proportions. A total of 55 unique IDH-mutant glioma samples were included in the analysis. The authors identified multiple genes associated with progression and higher grade across IDH-mutant oligodendrogliomas and astrocytomas. Compared with lower-grade paired samples, grade 4 IDH-mutant astrocytomas uniquely demonstrated upregulation of VEGFA in addition to counterproductive alterations in inflammatory score reflective of a more hostile immune microenvironment. Here, the authors have provided a transcriptomic analysis of a progression cohort for IDH-mutant glioma. Compared with lower-grade tumors, grade 4 astrocytomas displayed alterations that may inform the timing of antiangiogenic and immune-based therapy as these tumors progress.

GlioPredictor: a deep learning model for identification of high-risk adult IDH-mutant glioma towards adjuvant treatment planning

Identification of isocitrate dehydrogenase (IDH)-mutant glioma patients at high risk of early progression is critical for radiotherapy treatment planning. Currently tools to stratify risk of early progression are lacking. We sought to identify a combination of molecular markers that could be used to identify patients who may have a greater need for adjuvant radiation therapy machine learning technology. 507 WHO Grade 2 and 3 glioma cases from The Cancer Genome Atlas, and 1309 cases from AACR GENIE v13.0 datasets were studied for genetic disparities between IDH1-wildtype and IDH1-mutant cohorts, and between different age groups. Genetic features such as mutations and copy number variations (CNVs) correlated with IDH1 mutation status were selected as potential inputs to train artificial neural networks (ANNs) to predict IDH1 mutation status. Grade 2 and 3 glioma cases from the Memorial Sloan Kettering dataset (n = 404) and Grade 3 glioma cases with subtotal resection (STR) from Northwestern University (NU) (n = 21) were used to further evaluate the best performing ANN model as independent datasets. IDH1 mutation is associated with decreased CNVs of EGFR (21% vs. 3%), CDKN2A (20% vs. 6%), PTEN (14% vs. 1.7%), and increased percentage of mutations for TP53 (15% vs. 63%), and ATRX (10% vs. 54%), which were all statistically significant (p < 0.001). Age > 40 was unable to identify high-risk IDH1-mutant with early progression. A glioma early progression risk prediction (GlioPredictor) score generated from the best performing ANN model (6/6/6/6/2/1) with 6 inputs, including CNVs of EGFR, PTEN and CDKN2A, mutation status of TP53 and ATRX, patient’s age can predict IDH1 mutation status with over 90% accuracy. The GlioPredictor score identified a subgroup of high-risk IDH1-mutant in TCGA and NU datasets with early disease progression (p = 0.0019, 0.0238, respectively). The GlioPredictor that integrates age at diagnosis, CNVs of EGFR, CDKN2A, PTEN and mutation status of TP53, and ATRX can identify a small cohort of IDH-mutant with high risk of early progression. The current version of GlioPredictor mainly incorporated clinically often tested genetic biomarkers. Considering complexity of clinical and genetic features that correlate with glioma progression, future derivatives of GlioPredictor incorporating more inputs can be a potential supplement for adjuvant radiotherapy patient selection of IDH-mutant glioma patients.

EZH2 Inhibition Sensitizes IDH1R132H-Mutant Gliomas to Histone Deacetylase Inhibitor.

Isocitrate Dehydrogenase-1 (IDH1) is commonly mutated in lower-grade diffuse gliomas. The IDH1R132H mutation is an important diagnostic tool for tumor diagnosis and prognosis; however, its role in glioma development, and its impact on response to therapy, is not fully understood. We developed a murine model of proneural IDH1R132H-mutated glioma that shows elevated production of 2-hydroxyglutarate (2-HG) and increased trimethylation of lysine residue K27 on histone H3 (H3K27me3) compared to IDH1 wild-type tumors. We found that using Tazemetostat to inhibit the methyltransferase for H3K27, Enhancer of Zeste 2 (EZH2), reduced H3K27me3 levels and increased acetylation on H3K27. We also found that, although the histone deacetylase inhibitor (HDACi) Panobinostat was less cytotoxic in IDH1R132H-mutated cells (either isolated from murine glioma or oligodendrocyte progenitor cells infected in vitro with a retrovirus expressing IDH1R132H) compared to IDH1-wild-type cells, combination treatment with Tazemetostat is synergistic in both mutant and wild-type models. These findings indicate a novel therapeutic strategy for IDH1-mutated gliomas that targets the specific epigenetic alteration in these tumors.

IDH1 mutation inhibits differentiation of astrocytes and glioma cells with low oxoglutarate dehydrogenase expression by disturbing α-ketoglutarate-related metabolism and epigenetic modification

Abstract Isocitrate dehydrogenase (IDH) mutations frequently occur in lower-grade gliomas and secondary glioblastomas. Mutant IDHs exhibit a gain-of-function activity, leading to the production of D-2-hydroxyglutarate (D-2HG) by reducing α-ketoglutarate (α-KG), a central player in metabolism and epigenetic modifications. However, the role of α-KG homeostasis in IDH-mutated gliomagenesis remains elusive. In this study, we found that low expression of oxoglutarate dehydrogenase (OGDH) was a common feature in IDH-mutated gliomas, as well as in astrocytes. This low expression of OGDH resulted in the accumulation of α-KG and promoted astrocyte maturation. However, IDH1 mutation significantly reduced α-KG levels and increased glutaminolysis and DNA/histone methylation in astrocytes. These metabolic and epigenetic alterations inhibited astrocyte maturation and led to cortical dysplasia in mice. Moreover, our results also indicated that reduced OGDH expression can promote the differentiation of glioma cells, while IDH1 mutations impeded the differentiation of glioma cells with low OGDH by reducing the accumulation of α-KG and increasing glutaminolysis. Finally, we found that l-glutamine increased α-KG levels and augmented the differentiation-promoting effects of AGI5198, an IDH1-mutant inhibitor, in IDH1-mutant glioma cells. Collectively, this study reveals that low OGDH expression is a crucial metabolic characteristic of IDH-mutant gliomas, providing a potential strategy for the treatment of IDH-mutant gliomas by targeting α-KG homeostasis.

Hemizygous deletion of cyclin-dependent kinase inhibitor 2A/B with p16 immuno-negative and methylthioadenosine phosphorylase retention predicts poor prognosis in IDH-mutant adult glioma.

Homozygous deletion of the tumor suppression genes cyclin-dependent kinase inhibitor 2A/B (CDKN2A/B) is a strong adverse prognostic factor in IDH-mutant gliomas, particularly astrocytoma. However, the impact of hemizygous deletion of CDKN2A/B is unknown. Furthermore, the influence of CDKN2A/B status in IDH-mutant and 1p/19q-codeleted oligodendroglioma remains controversial. We examined the impact of CDKN2A/B status classification, including hemizygous deletions, on the prognosis of IDH-mutant gliomas. We enrolled 101 adults with IDH-mutant glioma between December 2002 and November 2021. CDKN2A/B deletion was evaluated with multiplex ligation-dependent probe amplification (MLPA). Immunohistochemical analysis of p16/MTAP and promoter methylation analysis with methylation-specific MLPA was performed for cases with CDKN2A/B deletion. Kaplan - Meier plots and Cox proportion hazards model analyses were performed to evaluate the impact on overall (OS) and progression-free survival. Of 101 cases, 12 and 4 were classified as hemizygous and homozygous deletion, respectively. Immunohistochemistry revealed p16-negative and MTAP retention in cases with hemizygous deletion, whereas homozygous deletions had p16-negative and MTAP loss. In astrocytoma, OS was shorter in the order of homozygous deletion, hemizygous deletion, and copy-neutral groups (median OS: 38.5, 59.5, and 93.1 months, respectively). Multivariate analysis revealed hazard ratios of 9.30 (P = .0191) and 2.44 (P = .0943) for homozygous and hemizygous deletions, respectively. CDKN2A/B hemizygous deletions exerted a negative impact on OS in astrocytoma. Immunohistochemistry of p16/MTAP can be utilized to validate hemizygous or homozygous deletions in combination with conventional molecular diagnosis.

Chromothripsis is rare in IDH-mutant gliomas compared to IDH-wild-type glioblastomas whereas whole-genome duplication is equally frequent in both tumor types.

Adult-type diffuse gliomas comprise IDH (isocitrate dehydrogenase)-mutant astrocytomas, IDH-mutant 1p/19q-codeleted oligodendrogliomas (ODG), and IDH-wild-type glioblastomas (GBM). GBM displays genome instability, which may result from 2 genetic events leading to massive chromosome alterations: Chromothripsis (CT) and whole-genome duplication (WGD). These events are scarcely described in IDH-mutant gliomas. The better prognosis of the latter may be related to their genome stability compared to GBM. Pangenomic profiles of 297 adult diffuse gliomas were analyzed at initial diagnosis using SNP arrays, including 192 GBM and 105 IDH-mutant gliomas (61 astrocytomas and 44 ODG). Tumor ploidy was assessed with Genome Alteration Print and CT events with CTLPScanner and through manual screening. Survival data were compared using the Kaplan-Meier method. At initial diagnosis, 37 GBM (18.7%) displayed CT versus 5 IDH-mutant gliomas (4.7%; P = .0008), the latter were all high-grade (grade 3 or 4) astrocytomas. WGD was detected at initial diagnosis in 18 GBM (9.3%) and 9 IDH-mutant gliomas (5 astrocytomas and 4 oligodendrogliomas, either low- or high-grade; 8.5%). Neither CT nor WGD was associated with overall survival in GBM or in IDH-mutant gliomas. CT is less frequent in IDH-mutant gliomas compared to GBM. The absence of CT in ODG and grade 2 astrocytomas might, in part, explain their genome stability and better prognosis, while CT might underlie aggressive biological behavior in some high-grade astrocytomas. WGD is a rare and early event occurring equally in IDH-mutant gliomas and GBM.

Intraoperative mapping of epileptogenic foci and tumor infiltration in neuro-oncology patients with epilepsy.

Epileptogenesis and glioma growth have a bidirectional relationship. We hypothesized people with gliomas can benefit from the removal of epileptic tissue and that tumor-related epileptic activity may signify tumor infiltration in peritumoral regions. We investigated whether intraoperative electrocorticography (ioECoG) could improve seizure outcomes in oncological glioma surgery, and vice versa, what epileptic activity (EA) tells about tumor infiltration. We prospectively included patients who underwent (awake) ioECoG-assisted diffuse-glioma resection through the oncological trajectory. The IoECoG-tailoring strategy relied on ictal and interictal EA (spikes and sharp waves). Brain tissue, where EA was recorded, was assigned for histopathological examination separate from the rest of the tumor. Weibull regression was performed to assess how residual EA and extent of resection (EOR) related to the time-to-seizure recurrence, and we investigated which type of EA predicted tumor infiltration. Fifty-two patients were included. Residual spikes after resection were associated with seizure recurrence in patients with isocitrate dehydrogenase (IDH) mutant astrocytoma or oligodendroglioma (HR = 7.6[1.4-40.0], P-value = .01), independent from the EOR. This was not observed in IDH-wildtype tumors. All tissue samples resected based on interictal spikes were infiltrated by tumor, even if the MRI did not show abnormalities. Complete resection of epileptogenic foci in ioECoG may promote seizure control in IDH-mutant gliomas. The cohort size of IDH-wildtype tumors was too limited to draw definitive conclusions. Interictal spikes may indicate tumor infiltration even when this area appears normal on MRI. Integrating electrophysiology guidance into oncological tumor surgery could contribute to improved seizure outcomes and precise guidance for radical tumor resection.

Olaparib in recurrent isocitrate dehydrogenase mutant high-grade glioma: A phase 2 multicenter study of the POLA Network

Abstract Background Based on preclinical studies showing that IDH-mutant (IDHm) gliomas could be vulnerable to PARP inhibition we launched a multicenter phase 2 study to test the efficacy of olaparib monotherapy in this population. Methods Adults with recurrent IDHm high-grade gliomas (HGGs) after radiotherapy and at least one line of alkylating chemotherapy were enrolled. The primary endpoint was a 6-month progression-free survival rate (PFS-6) according to response assessment in neuro-oncology criteria. Pre-defined threshold for study success was a PFS-6 of at least 50%. Results Thirty-five patients with recurrent IDHm HGGs were enrolled, 77% at ≥ 2nd recurrence. Median time since diagnosis and radiotherapy were 7.5 years and 33 months, respectively. PFS-6 was 31.4% (95% CI [16.9; 49.3%]). Two patients (6%) had an objective response and 14 patients (40%) had a stable disease as their best response. Median PFS and median overall survival were 2.05 and 15.9 months, respectively. Oligodendrogliomas (1p/19q codeleted) had a higher PFS-6 (53.4% vs. 15.7%, P = .05) than astrocytomas while an initial diagnosis of grade 4 astrocytoma tended to be associated with a lower PFS-6 compared to grade 2/3 gliomas (0% vs 31.4%, P = .16). A grade 2 or 3 treatment-related adverse event was observed in 15 patients (43%) and 5 patients (14%), respectively. No patient definitively discontinued treatment due to side effects. Conclusions Although it did not meet its primary endpoint, the present study shows that in this heavily pretreated population, olaparib monotherapy was well tolerated and resulted in some activity, supporting further PARP inhibitors evaluation in IDHm HGGs, especially in oligodendrogliomas.

Malignant glioma in L-2-Hydroxyglutaric Aciduria: thorough molecular characterization of a case and literature review.

L-2-hydroxyglutaric aciduria (L-2-HGA) is a rare neurometabolic disorder characterized by accumulation of L2-hydroxyglutarate (L-2-HG) due to mutations in the L2HGDH gene. L-2-HGA patients have a significantly increased lifetime risk of central nervous system (CNS) tumors. Here, we present a 16-year-old girl with L-2-HGA who developed a tumor in the right cerebral hemisphere, which was discovered after left-sided neurological deficits of the patient. Histologically, the tumor had a high-grade diffuse glioma phenotype. DNA sequencing revealed the inactivating homozygous germline L2HGDH mutation as well as inactivating mutations in TP53, BCOR and NF1. Genome-wide DNA-methylation analysis was unable to classify the tumor with high confidence. More detailed analysis revealed that this tumor clustered amongst IDH-wildtype gliomas by methylation profiling and did not show the glioma CpG island methylator phenotype (G-CIMP) in contrast to IDH-mutant diffuse gliomas with accumulated levels of D-2-HG, the stereoisomer of L-2-HD. These findings were against all our expectations given the inhibitory potential of 2-HG on DNA-demethylation enzymes. Our final integrated histomolecular diagnosis of the tumor was diffuse pediatric-type high-grade glioma, H3-wildtype and IDH-wildtype. Due to rapid tumor progression the patient died nine months after initial diagnosis. In this manuscript, we provide extensive molecular characterization of the tumor as well as a literature review focusing on oncogenetic considerations of L-2-HGA-associated CNS tumors.

Beyond T2-FLAIR mismatch sign in isocitrate dehydrogenase mutant 1p19q non-codeleted astrocytoma: Analysis of tumor core and evolution with multiparametric magnetic resonance imaging.

The T2-FLAIR mismatch sign is an imaging correlate for isocitrate dehydrogenase (IDH)-mutant 1p19q non-codeleted astrocytomas. However, it is only seen in a part of the cases at certain stages. Many of the tumors likely lose T2 homogeneity as they grow in size, and become heterogenous. The aim of this study was to investigate the timecourse of T2-FLAIR mismatch sign, and assess intratumoral heterogeneity using multiparametric magnetic resonance imaging techniques. A total of 128 IDH-mutant gliomas were retrospectively analyzed. Observers blinded to molecular status used strict criteria to select T2-FLAIR mismatch astrocytomas. Pre-biopsy and follow-up standard structural sequences of T2, FLAIR and apparent diffusion coefficient, MR spectroscopy (both single- and multi-voxel techniques), and DSC perfusion were observed. Nine T2-FLAIR mismatch astrocytomas were identified. 7 had MR spectroscopy and perfusion data. The smallest astrocytomas began as rounded T2 homogeneous lesions without FLAIR suppression, and developed T2-FLAIR mismatch during follow-up with falls in NAA and raised Cho/Cr ratio. Larger tumors at baseline with T2-FLAIR mismatch signs developed intratumoral heterogeneity, and showed elevated Cho/Cr ratio and raised relative cerebral blood volume (rCBV). The highest levels of intratumoral Cho/Cr and rCBV changes were located within the tumor core, and this area signifies the progression of the tumors toward high grade. T2-FLAIR mismatch sign is seen at a specific stage in the development of astrocytoma. By assessing the subsequent heterogeneity, MR spectroscopy and perfusion imaging are able to predict the progression of the tumor towards high grade, thereby can assist targeting for biopsy and selective debulking.

The Epigenetic Evolution of Glioma Is Determined by the IDH1 Mutation Status and Treatment Regimen.

Standard treatments are related to loss of DNA methylation in IDHmut glioma, resulting in epigenetic activation of genes associated with tumor progression and alterations in the microenvironment that resemble treatment-naïve IDHwt glioma.

Reliability assessment of methylthioadenosine phosphorylase immunohistochemistry as a surrogate biomarker for CDKN2A homozygous deletion in adult-type IDH-mutant diffuse gliomas.

According to the 2021 World Health Organization classification of brain tumors, astrocytomas containing a CDKN2A/B homozygous deletion (HD) are designated as grade 4 even when no microvascular proliferation and/or necrosis is present. In this study, we aimed to investigate the relationship between CDKN2A HD and loss of methylthioadenosine phosphorylase (MTAP) expression in adult-type IDH-mutant gliomas and to assess the sensitivity and specificity of MTAP immunohistochemistry (IHC) along with interobserver agreement as a surrogate biomarker for CDKN2A HD. Eighty-eight astrocytomas and 71 oligodendrogliomas cases that were diagnosed between 2014 and 2021 at Hacettepe University were selected and tissue microarrays were conducted to perform CDKN2A fluorescence in situ hybridization and MTAP IHC. Twenty-five (15.7%) cases harbored CDKN2A HD. MTAP loss was detected in 28 (15.7%) cases by the first observer and 27 (17%) cases by the second observer. The sensitivity and specificity of MTAP were calculated as 88% and 95.52%-96.27% for 2 observers. A very good/perfect agreement was noted between the observers (Cohen kappa coefficient = 0.938). Intratumoral heterogeneity was observed in 4 cases. MTAP IHC was found to be a reliable surrogate biomarker as a possible alternative to CDKN2A HD identification with a high sensitivity and specificity along with high interobserver agreement.

Concurrent gliomas in patients with multiple sclerosis

BackgroundConcurrent malignant brain tumors in patients with multiple sclerosis (MS) constitute a rare but paradigmatic phenomenon for studying neuroimmunological mechanisms from both molecular and clinical perspectives.MethodsA multicenter cohort of 26 patients diagnosed with both primary brain tumors and multiple sclerosis was studied for disease localization, tumor treatment-related MS activity, and molecular characteristics specific for diffuse glioma in MS patients.ResultsMS neither predisposes nor protects from the development of gliomas. Patients with glioblastoma WHO grade 4 without isocitratdehydrogenase (IDH) mutations have a longstanding history of MS, whereas patients diagnosed with IDH-mutant astrocytoma WHO grade 2 receive multiple sclerosis diagnosis mostly at the same time or later. Concurrent MS is associated with a lesser extent of tumor resection and a worse prognosis in IDH-mutant glioma patients (PFS 32 vs. 64 months, p = 0.0206). When assessing tumor-intrinsic differences no distinct subgroup-defining methylation pattern is identified in gliomas of MS patients compared to other glioma samples. However, differential methylation of immune-related genetic loci including human leukocyte antigen locus on 6p21 and interleukin locus on 5q31 is found in MS patients vs. matched non-MS patients. In line, inflammatory disease activity increases in 42% of multiple sclerosis patients after brain tumor radiotherapy suggesting a susceptibility of multiple sclerosis brain tissue to pro-inflammatory stimuli such as ionizing radiation.ConclusionsConcurrent low-grade gliomas should be considered in multiple sclerosis patients with slowly progressive, expansive T2/FLAIR lesions. Our findings of typically reduced extent of resection in MS patients and increased MS activity after radiation may inform future treatment decisions.

10091-COT-12 ELUCIDATING THE PATHOPHYSIOLOGY OF POST-OPERATIVE VENOUS THROMBOEMBOLISM IN IDH-WILDTYPE MALIGNANT GLIOMAS

Abstract BACKGROUND We have previously reported elevated expression of podoplanin and high incidence of post-operative venous thromboembolism (VTE) in IDH-wildtype gliomas (Watanabe et al., World Neurosurgery, 2019). Podoplanin binds to C-type lectin-like receptor-2 (CLEC-2) on the surface of platelets and induces platelet aggregation, potentially leading to the development of VTE. In the present report, we monitor serum podoplanin and CLEC-2 after surgery in malignant glioma patients to directly determine if this is the cause of post-operative VTE. METHODS Fourty-four malignant glioma patients undergoing surgery at the Department of Neurosurgery, Niigata University Hospital between April, 2018 and August, 2020 were assessed. Platelet counts as well as serum D-dimer, podoplanin, soluble CLEC-2, and C2PAC index (soluble CLEC-2 divided by platelet count) were measured within 10 days after surgery. Serum podoplanin and soluble CLEC-2 were assessed by enzyme-linked immunosorbent assay (ELISA). Values for IDH-wildtype glioma patients and IDH-mutant glioma patients were compared to patients undergoing microvascular decompression (MVD) and healthy volunteers (HV). RESULTS Post-operative VTE was observed in 8 out of 35 (23%) IDH-wildtype glioma patients, compared to 1 out of 9 (11%) IDH-mutant glioma patients. Serum soluble CLEC-2 levels (p = 0.0004) and C2PAC index (p = 0.0002) were significantly elevated in IDH-wildtype glioma patients compared to IDH-mutant glioma, MVD and HV groups. A C2PAC index threshold of 3.7 provide an 87.5% sensitivity and 51.9% specificity to predict post-operative VTE in IDH-wildtype gliomas. We serially monitored podoplanin and soluble CLEC-2 in select patients, and found that podoplanin is transiently elevated, followed by soluble CLEC-2 after surgery. CONCLUSION Platelet aggregation due to the activation of podoplanin-CLEC2 axis leads to post-operative VTE in IDH-wildtype malignant glioma patients. The C2PAC index is a potential biomarker for the early detection of VTE after surgery in these patients.

10109-COT-13 LONG-TERM FOLLOW-UP OF FLAIR HIGH LESION IN THE BRAIN

Abstract AIM Incidental FLAIR (Fluid Attenuated Inversion Recovery) high-intensity lesion in the brain can be considered as IDH-mutant low-grade glioma (LGG). Differential diagnosis includes trauma, ischemic changes, demyelinating diseases, and other inflammatory diseases. The biopsy is sometimes high risk for a young patient or an asymptomatic patient with a lesion in the brain stem, motor or language area. Imaging intervals vary among hospitals and the method for regular follow-up for these cases has not been established. METHODS We have studied 26 patients with FLAIR high lesion from 2012 to 2022. In cases of suspected LGG, the biopsy was performed, when necessary, after consultation with the patient and family. Our neurosurgery team protocol was to perform PET-MRI at the first consultation, and if there was negative, we have scheduled MRI examination at the next visit in one month. Then, MRI was performed every 2-3 months for the first year and every 3-6 months thereafter. The clinical features of these FLAIR high lesion and their differentiations from LGG in our cases are examined. RESULTS Biopsy was performed in 5 cases, but no tumor was found. The male-to-female ratio was 7:19, which was more common in female. The median age at onset was 44 years (15-47 years), showing a bimodal distribution with peaks in younger and older individuals. Among 26 cases, 14 cases had been unchanged for more than 5 years. The median maximum lesion diameter was 17 mm (8-47 mm). An annual average increase of LGG has been reported to be 3-5 mm in (Pallud, 2010). There were no cases diagnosed as glioma in cases where no expansion was seen after 5 years or more. CONCLUSION In this study, the possibility of glioma was considered to be low for cases in which no expansion on MRI was seen after 5 years or more.

The potential of amino acid PET imaging for prediction and monitoring of vorasidenib response in IDH-mutant gliomas.

The potential of amino acid PET imaging for prediction and monitoring of vorasidenib response in IDH-mutant gliomas.

Adolescents and Young Adults With Cancer: CNS Tumors.

Tumors of CNS are common in adolescents and young adults (AYAs). As the second leading cause of cancer-related death, CNS tumors in AYAs require improved clinical management. In this review, we discussed the current diagnostic approaches and recommended management strategies for malignant tumors in adult-type (IDH-mutant gliomas) and pediatric-type gliomas (pediatric high-grade gliomas), ependymoma and medulloblastoma, which commonly occur in AYAs. The impact of advanced molecular diagnostic approaches on the understanding of tumor biology of AYA CNS tumors is emphasized. To enhance participation in clinical trials, which poses a unique challenge in AYAs with CNS tumors, we propose encouraging referrals to neuro-oncology specialty care and improving collaboration between oncologists who care for both pediatric and adult patients. This will ensure better representation of AYA patients in research studies. Finally, we discussed the importance of considering neurocognitive and psychological function in AYAs with CNS tumor.

Multiparametric MRI and T2/FLAIR mismatch complements the World Health Organization 2021 classification for the diagnosis of IDH-mutant 1p/19q non-co-deleted/ATRX-mutant astrocytoma

To investigate whether T2-weighted imaging-fluid-attenuated inversion recovery (T2/FLAIR) mismatch, T2∗ dynamic susceptibility contrast (DSC) perfusion, and magnetic resonance spectroscopy (MRS) correlated with the histological diagnosis and grading of IDH (isocitrate dehydrogenase)-mutant, 1p/19q non-co-deleted/ATRX (alpha-thalassemia mental retardation X-linked)-mutant astrocytoma. Imaging of 101 IDH-mutant diffuse glioma cases of histological grades 2-3 (2019-2021) were analysed retrospectively by two neuroradiologists blinded to the molecular diagnosis. T2/FLAIR mismatch sign is used for radio-phenotyping, and pre-biopsy multiparametric MRI images were assessed for grading purposes. Cut-off values pre-determined for radiologically high-grade lesions were relative cerebral blood volume (rCBV) ≥2, choline/creatine ratio (Cho/Cr) ≥1.5 (30 ms echo time [TE]), Cho/Cr ≥1.8 (135 ms TE). Sixteen of the 101 cases showed T2/FLAIR mismatch, all of which were histogenetically confirmed IDH-mutant 1p/19q non-co-deleted/ATRX mutant astrocytomas; 50% were grade 3 (8/16) and 50% grade 2 (8/16). None showed contrast enhancement. Nine of the 16 had adequate multiparametric MRI for analysis. Any positive value by combining rCBV ≥2 with Cho/Cr ≥1.5 (30 ms TE) or Cho/Cr ≥1.8 (135 ms TE) predicted grade 3 histology with sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of 100%. The T2/FLAIR mismatch sign detected diffuse astrocytomas with 100% specificity. When combined with high Cho/Cr and raised rCBV, this predicted histological grading with high accuracy. The future direction for imaging should explore a similar integrated layered approach of 2021 classification of central nervous system (CNS) tumours combining radio-phenotyping and grading from structural and multiparametric imaging.

2021 World Health Organization Classification of Brain Tumors.

The classification of brain tumors is a rapidly evolving field that requires extensive integration of molecular diagnostic findings from an expanding set of platforms and assays. This article summarizes the schema presented in the 5th edition of the World Health Organization (WHO) classification of central nervous system (CNS) tumors while highlighting diagnostic molecular findings and discussing the strengths and weaknesses of commonly available testing modalities. Several major changes in practice were introduced with the 5th edition of the CNS WHO classification, including molecular grading of adult diffuse gliomas, the introduction of many new entities within the spectrum of pediatric gliomas and glioneuronal tumors, and the widespread adoption of methylation classes as useful or even necessary diagnostic criteria. Additionally, several revisions to nomenclature (eg, IDH-mutant gliomas) were introduced for simplicity and to disambiguate from other tumor types. The classification of brain tumors continues to grow in complexity alongside our improved understanding of their nuanced molecular underpinnings.

Individualized discrimination of tumor progression from treatment-related changes in different types of adult-type diffuse gliomas using [11C]methionine PET.

This study aimed to assess the ability of [11C]methionine (MET) PET in distinguishing between tumor progression (TP) and treatment-related changes (TRCs) among different types of adult-type diffuse gliomas according to the 2021 World Health Organization classification and predict overall survival (OS). We retrospectively selected 113 patients with adult-type diffuse gliomas with suspected TP who underwent MET PET imaging. Maximum and mean tumor-to-background ratios (TBRmax, TBRmean) and metabolic tumor volume (MTV) were calculated. Diagnoses were verified by histopathology (n = 50) or by clinical/radiological follow-up (n = 63). The diagnostic performance of MET PET parameters was evaluated through receiver operating characteristic (ROC) analysis and area under the curve (AUC) calculation. Survival analysis employed the Kaplan-Meier method and Cox proportional-hazards regression. TP and TRCs were diagnosed in 76 (67%) and 37 (33%) patients, respectively. ROC analysis revealed TBRmax had the best performance in differentiating TP from TRCs with a cut-off of 1.96 in IDH-mutant astrocytoma (AUC, 0.87; sensitivity, 93%; specificity 69%), 1.80 in IDH-mutant and 1p/19q-codeleted oligodendroglioma (AUC, 0.96; sensitivity, 100%; specificity, 89%), and 2.13 in IDH wild-type glioblastoma (AUC, 0.89; sensitivity, 89%; specificity, 78%), respectively. On multivariate analysis, higher TBRmean and MTV were significantly correlated with shorter OS in all IDH-mutant gliomas, as well as in IDH-mutant astrocytoma subgroup. This work confirms that MET PET has varying diagnostic performances in distinguishing TP from TRCs within three types of adult-type diffuse gliomas, and highlights its high diagnostic accuracy in IDH-mutant and 1p/19q-codeleted oligodendroglioma and potential prognostic value for IDH-mutant gliomas, particularly IDH-mutant astrocytoma.