Oligodendroglioma, IDH-mutant and 1p/19q-codeleted-prognostic factors, standard of care and chemotherapy, and future perspectives with neoadjuvant strategy.

Oligodendroglioma, IDH-mutant and 1p/19q-codeleted is known for their relative chemosensitivity and indolent clinical course among diffuse gliomas of adult type. Based on the data from phase 3 clinical trials, the standard of post-surgical care for those tumors is considered to be initial chemoradiotherapy regardless of histopathological grade, particularly with PCV. However, partly due to its renewed definition in late years, prognostic factors in patients with those tumors are not well established. Moreover, the survival rate declines over 15 years, with only a 37% OS rate at 20 years for grade 3 tumors, even with the current standard of care. Given that most of this disease occurs in young or middle-aged adults, further improvements in treatment and management are necessary. Here, we discuss prognostic factors, standard of care and chemotherapy, and future perspectives with neoadjuvant strategy in those tumors.

Mutant IDH inhibitors induce lineage differentiation in IDH-mutant oligodendroglioma.

A subset of patients with IDH-mutant glioma respond to inhibitors of mutant IDH (IDHi), yet the molecular underpinnings of such responses are not understood. Here, we profiled by single-cell or single-nucleus RNA-sequencing three IDH-mutant oligodendrogliomas from patients who derived clinical benefit from IDHi. Importantly, the tissues were sampled on-drug, four weeks from treatment initiation. We further integrate our findings with analysis of single-cell and bulk transcriptomes from independent cohorts and experimental models. We find that IDHi treatment induces a robust differentiation toward the astrocytic lineage, accompanied by a depletion of stem-like cells and a reduction of cell proliferation. Furthermore, mutations in NOTCH1 are associated with decreased astrocytic differentiation and may limit the response to IDHi. Our study highlights the differentiating potential of IDHi on the cellular hierarchies that drive oligodendrogliomas and suggests a genetic modifier that may improve patient stratification.

Association of Clinical, Tumor, and Treatment Characteristics With Seizure Control in Patients With IDH1/2-Mutant Lower-Grade Glioma.

BACKGROUND AND OBJECTIVES: Patients with IDH1/2-mutant lower-grade glioma have a high frequency of seizures. We aimed to investigate the correlations between seizures and tumor/patient characteristics and the impact of surgery and adjuvant treatments (AT) on seizure control along the disease trajectory. METHODS: We retrospectively included patients with IDH1/2-mutant lower-grade glioma who underwent surgery at the neurosurgery divisions of the University of Turin and Milan and were treated at the Division of Neuro-Oncology of Turin. Inclusion criteria were a diagnosis according to the 2021 WHO Classification and presentation with seizures; exclusion criteria were presence of CDKN2A/B homozygous deletion, intense/ring contrast enhancement on MRI at presentation, and small tissue biopsy. We evaluated seizure freedom for 2 months after surgery, 6 months from starting observation or AT, at recurrence, and for 6 months after treatments of recurrence. RESULTS: We included 150 patients. There were 77 (51%) and 31 (21%) patients with IDH-mutant/1p19q-codeleted grade 2 and 3 oligodendroglioma and 30 (20%) and 12 (8%) with IDH-mutant grade 2 and 3 astrocytoma, respectively. Total resection was accomplished in 68 (45%). Seventy-five patients (50%) received AT while the remaining 75 were observed with MRI. After 6 months after AT, 28 of 29 patients (96.5%) displayed seizure reduction, 5 of 28 (18%) being seizure-free. 66 of 124 patients (53%) had seizures at recurrence. After 6 months after second-line treatments, 60 of 66 patients (91%) had seizure reduction, 11 (17%) being seizure-free. In multivariable analyses, grade 3 histology positively correlated with seizure freedom at 2 months after surgery (OR 3.5, 1.4-8.9, p = 0.008), 6 months after AT (OR 9.0, 1.5-54.9, p = 0.017), and 6 months after treatment of recurrence (OR 4.9, 1.5-16.5, p = 0.009). Adjuvant radiotherapy reduced seizures at recurrence in a univariate analysis (OR 0.14, 0.03-0.7, p = 0.020). Patients with seizure freedom after surgery and AT displayed longer progression-free survival (PFS) (65, 24.5-105, vs 48 months, 32-63.5, p = 0.037). DISCUSSION: This study analyzed seizure control in patients with IDH1/2-mutant lower-grade glioma across multiple time points. Grade 3 correlated with better seizure control throughout the entire disease trajectory, and seizure freedom after surgery and AT correlated with a longer PFS regardless of tumor grade. These results could serve as an external control arm in clinical trials evaluating the efficacy on seizures of antitumor agents in patients with IDH-mutant lower-grade glioma.

Genetically Distinct Oligosarcoma Arising from Oligodendroglioma: Systematic Review & Illustrative Case Example.

BACKGROUND: Oligosarcoma is a rare central nervous system (CNS) neoplasm that may arise following oligodendroglioma resection, which demonstrates a unique genetic profile and aggressive clinical phenotype. We present a systematic review and illustrative case example emphasizing the clinical and prognostic features of this unusual and unfavorable neuro-oncologic disease. METHODS: Systematic literature review and illustrative case report. RESULTS: A 41-year-old man who had undergone 2 neurosurgical resections for a World Health Organization grade II oligodendroglioma (Ki-67 = 5-10%, 1p/19q codeleted, IDH2 mutated), without adjuvant chemoradiation, presented with seizures seven years after resection. An extra-axial mass was identified adjacent to the resection cavity, in which gross total resection was achieved. Pathology confirmed World Health Organization grade IV oligosarcoma (Ki-67 = 20%). Adjuvant chemoradiation was initiated, with disease control observed over 6 months of follow-up. Seven publications met inclusion criteria. Oligosarcoma has been confirmed in 36 lesions, arising in 35 patients; 5 were primary oligosarcoma, while 31 occurred in the setting of prior resected oligodendroglioma or oligoastrocytoma. Features shared by these lesions include regain of H3K27me3 expression, 1p/19q codeletion, homozygous deletion of CDKN2A/B, loss of 6q, loss of NF1 and YAP1, and attenuation of CpG island methylator. Median survival after oligosarcoma diagnosis was 1.3 years (range, 0-5.2; n = 35). CONCLUSIONS: Oligosarcoma is a prognostically unfavorable CNS neoplasm with characteristic imaging and pathologic features, and a strong association with previously resected oligodendroglioma. Aggressive treatment is recommended, including gross total resection and adjuvant chemoradiation. Further study is required to define optimal treatment protocol for this CNS malignancy.

Rise of oligodendroglioma hypermutator phenotype from a subclone harboring TP53 mutation after TMZ treatment.

Oligodendrogliomas characterized and defined by 1p/19q co-deletion are slowly growing tumors showing better prognosis than astrocytomas. TP53 mutation is rare in oligodendrogliomas while the vast majority of astrocytomas harbor the mutation, making TP53 mutation mutually exclusive with 1p/19q codeletion in lower grade gliomas virtually. We report a case of 51-year-old woman with a left fronto-temporal oligodendroglioma that contained a small portion with a TP53 mutation, R248Q, at the initial surgery. On a first, slow-growing recurrence 29 months after radiation and nitrosourea-based chemotherapy, the patient underwent TMZ chemotherapy. The recurrent tumor responded well to TMZ but developed a rapid progression after 6 cycles as a malignant hypermutator tumor with a MSH6 mutation. Most of the recurrent tumor lacked typical oligodendroglioma morphology that was observed in the primary tumor, while it retained the IDH1 mutation and 1p/19q co-deletion. The identical TP53 mutation observed in the small portion of the primary tumor was universal in the recurrence. This case embodied the theoretically understandable clonal expansion of the TP53 mutation with additional mismatch repair gene dysfunction leading to hypermutator phenotype. It thus indicated that TP53 mutation in oligodendroglioma, although not common, may play a critical role in the development of hypermutator after TMZ treatment.

Comparison of diagnostic performance of radiologist- and AI-based assessments of T2-FLAIR mismatch sign and quantitative assessment using synthetic MRI in the differential diagnosis between astrocytoma, IDH-mutant and oligodendroglioma, IDH-mutant and 1p/19q-codeleted.

PURPOSE: This study aimed to compare assessments by radiologists, artificial intelligence (AI), and quantitative measurement using synthetic MRI (SyMRI) for differential diagnosis between astrocytoma, IDH-mutant and oligodendroglioma, and IDH-mutant and 1p/19q-codeleted and to identify the superior method. METHODS: Thirty-three cases (men, 14; women, 19) comprising 19 astrocytomas and 14 oligodendrogliomas were evaluated. Four radiologists independently evaluated the presence of the T2-FLAIR mismatch sign. A 3D convolutional neural network (CNN) model was trained using 50 patients outside the test group (28 astrocytomas and 22 oligodendrogliomas) and transferred to evaluate the T2-FLAIR mismatch lesions in the test group. If the CNN labeled more than 50% of the T2-prolonged lesion area, the result was considered positive. The T1/T2-relaxation times and proton density (PD) derived from SyMRI were measured in both gliomas. Each quantitative parameter (T1, T2, and PD) was compared between gliomas using the Mann-Whitney U-test. Receiver-operating characteristic analysis was used to evaluate the diagnostic performance. RESULTS: The mean sensitivity, specificity, and area under the curve (AUC) of radiologists vs. AI were 76.3% vs. 94.7%; 100% vs. 92.9%; and 0.880 vs. 0.938, respectively. The two types of diffuse gliomas could be differentiated using a cutoff value of 2290/128 ms for a combined 90th percentile of T1 and 10th percentile of T2 relaxation times with 94.4/100% sensitivity/specificity with an AUC of 0.981. CONCLUSION: Compared to the radiologists' assessment using the T2-FLAIR mismatch sign, the AI and the SyMRI assessments increased both sensitivity and objectivity, resulting in improved diagnostic performance in differentiating gliomas.

Reliable detection of genetic alterations in cyst fluid DNA for the diagnosis of brain tumors.

PURPOSE: Liquid biopsy of cyst fluid in brain tumors has not been extensively studied to date. The present study was performed to see whether diagnostic genetic alterations found in brain tumor tissue DNA could also be detected in cell-free DNA (cfDNA) of cyst fluid in cystic brain tumors. METHODS: Cyst fluid was obtained from 22 patients undergoing surgery for a cystic brain tumor with confirmed genetic alterations in tumor DNA. Pathological diagnoses based on WHO 2021 classification and diagnostic alterations in the tumor DNA, such as IDH1 R132H and TERT promoter mutation for oligodendrogliomas, were detected by Sanger sequencing. The same alterations were analyzed by both droplet digital PCR (ddPCR) and Sanger sequencing in cyst fluid cfDNA. Additionally, multiplex ligation-dependent probe amplification (MLPA) assays were performed to assess 1p/19q status, presence of CDKN2A loss, PTEN loss and EGFR amplification, to assess whether differentiating between astrocytomas and oligodendrogliomas and grading is possible from cyst fluid cfDNA. RESULTS: Twenty-five genetic alterations were found in 22 tumor samples. All (100%) alterations were detected in cyst fluid cfDNA by ddPCR. Twenty of the 25 (80%) alterations were also detected by Sanger sequencing of cyst fluid cfDNA. Variant allele frequency (VAF) in cyst fluid cfDNA was comparable to that of tumor DNA (R = 0.62, Pearson's correlation). MLPA was feasible in 11 out of 17 (65%) diffuse gliomas, with close correlation of results between tumor DNA and cyst fluid cfDNA. CONCLUSION: Cell-free DNA obtained from cyst fluid in cystic brain tumors is a reliable alternative to tumor DNA when diagnosing brain tumors.

Exploiting nanopore sequencing for characterization and grading of IDH-mutant gliomas.

The 2021 WHO Classification of Central Nervous System Tumors recommended evaluation of cyclin-dependent kinase inhibitor 2A/B (CDKN2A/B) deletion in addition to codeletion of 1p/19q to characterize IDH-mutant gliomas. Here, we demonstrated the use of a nanopore-based copy-number variation sequencing (nCNV-seq) approach to simultaneously identify deletions of CDKN2A/B and 1p/19q. The nCNV-seq approach was initially evaluated on three distinct glioma cell lines and then applied to 19 IDH-mutant gliomas (8 astrocytomas and 11 oligodendrogliomas) from patients. The whole-arm 1p/19q codeletion was detected in all oligodendrogliomas with high concordance among nCNV-seq, FISH, DNA methylation profiling, and whole-genome sequencing. For the CDKN2A/B deletion, nCNV-seq detected the loss in both astrocytoma and oligodendroglioma, with strong correlation with the CNV profiles derived from whole-genome sequencing (Pearson correlation (r) = 0.95, P < 2.2 × 10-16 to r = 0.99, P < 2.2 × 10-16 ) and methylome profiling. Furthermore, nCNV-seq can differentiate between homozygous and hemizygous deletions of CDKN2A/B. Taken together, nCNV-seq holds promise as a new, alternative approach for a rapid and simultaneous detection of the molecular signatures of IDH-mutant gliomas without capital expenditure for a sequencer.

Whole tumor analysis reveals early origin of the TERT promoter mutation and intercellular heterogeneity in TERT expression.

BACKGROUND: The TERT promoter mutation (TPM) is acquired in most IDH-wildtype glioblastomas (GBM) and IDH-mutant oligodendrogliomas (OD) enabling tumor cell immortality. Previous studies on TPM clonality show conflicting results. This study was performed to determine whether TPM is clonal on a tumor-wide scale. METHODS: We investigated TPM clonality in relation to presumed early events in 19 IDH-wildtype GBM and 10 IDH-mutant OD using 3-dimensional comprehensive tumor sampling. We performed Sanger sequencing on 264 tumor samples and deep amplicon sequencing on 187 tumor samples. We obtained tumor purity and copy number estimates from whole exome sequencing. TERT expression was assessed by RNA-seq and RNAscope. RESULTS: We detected TPM in 100% of tumor samples with quantifiable tumor purity (219 samples). Variant allele frequencies (VAF) of TPM correlate positively with chromosome 10 loss in GBM (R = 0.85), IDH1 mutation in OD (R = 0.87), and with tumor purity (R = 0.91 for GBM; R = 0.90 for OD). In comparison, oncogene amplification was tumor-wide for MDM4- and most EGFR-amplified cases but heterogeneous for MYCN and PDGFRA, and strikingly high in low-purity samples. TPM VAF was moderately correlated with TERT expression (R = 0.52 for GBM; R = 0.65 for OD). TERT expression was detected in a subset of cells, solely in TPM-positive samples, including samples equivocal for tumor. CONCLUSIONS: On a tumor-wide scale, TPM is among the earliest events in glioma evolution. Intercellular heterogeneity of TERT expression, however, suggests dynamic regulation during tumor growth. TERT expression may be a tumor cell-specific biomarker.

The cortical high-flow sign of oligodendroglioma, IDH-mutant and 1p/19q-codeleted: comparison between arterial spin labeling and dynamic susceptibility contrast methods.

PURPOSE: The cortical high-flow sign with the non-enhancing area was reportedly found to be more frequent with oligodendroglioma, IDH-mutant and 1p/19q codeleted (ODG IDHm-codel) than with IDH-wildtype or astrocytoma, IDH-mutant on arterial spin labeling (ASL) in diffuse gliomas. This study aimed to compare the identification rate of the cortical high-flow sign on ASL in patients with ODG IDHm-codel to that on dynamic susceptibility contrast-enhanced perfusion-weighted imaging (DSC-PWI). METHODS: Participants consisted of 32 adult ODG IDHm-codel patients with pathologically confirmed. Subtraction images were generated from paired control and label images on ASL. For DSC, dynamic T2*-weighted perfusion weighted images were obtained after pre-bolus of gadolinium-based contrast agent. Regional cerebral blood flow/volume maps were generated based on the concentration-time curve and arterial input function. Tumor-affecting cortices without contrast enhancement on conventional MR imaging were targeted. The identification rate of the cortical high-flow sign was compared between ASL and DSC using the Pearson's Chi-Square test. RESULTS: Frequency of the cortical high-flow sign was significantly higher on ASL (18/32, 56.3%; p < 0.001) than on DSC (5/32, 15.6%). All cases with the positive cortical high-flow sign on DSC were identified on ASL. CONCLUSION: ASL effectively identifies the cortical high-flow sign in ODG IDHm-codel, surpassing DSC in identification rates.

Tumor heterogeneity and tumor-microglia interactions in primary and recurrent IDH1-mutant gliomas.

The isocitrate dehydrogenase (IDH) gene is recurrently mutated in adult diffuse gliomas. IDH-mutant gliomas are categorized into oligodendrogliomas and astrocytomas, each with unique pathological features. Here, we use single-nucleus RNA and ATAC sequencing to compare the molecular heterogeneity of these glioma subtypes. In addition to astrocyte-like, oligodendrocyte progenitor-like, and cycling tumor subpopulations, a tumor population enriched for ribosomal genes and translation elongation factors is primarily present in oligodendrogliomas. Longitudinal analysis of astrocytomas indicates that the proportion of tumor subpopulations remains stable in recurrent tumors. Analysis of tumor-associated microglia/macrophages (TAMs) reveals significant differences between oligodendrogliomas, with astrocytomas harboring inflammatory TAMs expressing phosphorylated STAT1, as confirmed by immunohistochemistry. Furthermore, inferred receptor-ligand interactions between tumor subpopulations and TAMs may contribute to TAM state diversity. Overall, our study sheds light on distinct tumor populations, TAM heterogeneity, TAM-tumor interactions in IDH-mutant glioma subtypes, and the relative stability of tumor subpopulations in recurrent astrocytomas.

Radiogenomics Provides Insights into Gliomas Demonstrating Single-Arm 1p or 19q Deletion.

BACKGROUND AND PURPOSE: IDH-mutant gliomas are further divided on the basis of 1p/19q status: oligodendroglioma, IDH-mutant and 1p/19q-codeleted, and astrocytoma, IDH-mutant (without codeletion). Occasionally, testing may reveal single-arm 1p or 19q deletion (unideletion), which remains within the diagnosis of astrocytoma. Molecular assessment has some limitations, however, raising the possibility that some unideleted tumors could actually be codeleted. This study assessed whether unideleted tumors had MR imaging features and survival more consistent with astrocytomas or oligodendrogliomas. MATERIALS AND METHODS: One hundred twenty-one IDH-mutant grade 2-3 gliomas with 1p/19q results were identified. Two neuroradiologists assessed the T2-FLAIR mismatch sign and calcifications, as differentiators of astrocytomas and oligodendrogliomas. MR imaging features and survival were compared among the unideleted tumors, codeleted tumors, and those without 1p or 19q deletion. RESULTS: The cohort comprised 65 tumors without 1p or 19q deletion, 12 unideleted tumors, and 44 codeleted. The proportion of unideleted tumors demonstrating the T2-FLAIR mismatch sign (33%) was similar to that in tumors without deletion (49%; P = .39), but significantly higher than codeleted tumors (0%; P = .001). Calcifications were less frequent in unideleted tumors (0%) than in codeleted tumors (25%), but this difference did not reach statistical significance (P = .097). The median survival of patients with unideleted tumors was 7.8 years, which was similar to that in tumors without deletion (8.5 years; P = .72) but significantly shorter than that in codeleted tumors (not reaching median survival after 12 years; P = .013). CONCLUSIONS: IDH-mutant gliomas with single-arm 1p or 19q deletion have MR imaging appearance and survival that are similar to those of astrocytomas without 1p or 19q deletion and significantly different from those of 1p/19q-codeleted oligodendrogliomas.

[Classification and Diagnosis of Adult-Type Diffuse Gliomas].

The Central Nervous System Tumours: WHO Classification of Tumours, 5th ed.(WHO CNS5)incorporates molecular pathogenesis with histopathology to classify brain tumors into more biologically and narrowly defined entities. According to this approach, adult-type diffuse gliomas are classified into three tumor types: astrocytoma, IDH-mutant; oligodendroglioma, IDH-mutant and 1p/19q-codeleted; and glioblastoma, IDH-wildtype. Astrocytoma and oligodendroglioma are clearly defined as IDH-mutant tumors, and glioblastoma as an IDH-wildtype tumor. WHO CNS5 provides clear diagnostic criteria framed as "essential and desirable diagnostic criteria," including histopathological and molecular features. In this article, we summarized the diagnostic and grading criteria of adult-type diffuse gliomas, which include histopathological and molecular features. Further, we presented a clinical diagnostic workflow based on the immunohistopathological studies, molecular tests and their surrogate assays, and histopathological features to establish the diagnosis of adult-type diffuse gliomas. We also discussed the limitations of the clinical diagnostic workflow; for instance, some tumors may not fit within this classification provided by this diagnostic flow. Despite these limitations, we are required to utilize the diagnostic criteria and determine optimal treatment in the clinical setting.

[Oligodendroglioma, IDH Mutation and 1p/19q Codeletion].

Oligodendrogliomas were clearly defined as tumors with IDH mutations and 1p/19q codeletion by the World Health Organization(WHO)in 2016. Their prognosis is better than that of morphologic oligodendrogliomas, which might include some other gliomas according to WHO in 2016 and 2021. The term "low-grade gliomas" does not exist in the WHO classification and has changed in meaning over time; prior to WHO 2016, it meant grade I and II gliomas; subsequently, it changed to "lower-grade gliomas," including grade II and III gliomas, with the same molecular features. In the current classification, IDH wild-type grade II and III gliomas have been eliminated, and "lower-grade gliomas" now only include gliomas with IDH mutations. Maximal safe resection is necessary for a proper molecular diagnosis and survival, and awake craniotomy should be aggressively considered to prevent permanent postoperative neurologic deficits for tumors in the eloquent region. Supramarginal resection is an attractive approach for neurosurgeons to improve survival outcomes, but the evidence is still lacking. Chemoradiotherapy with procarbazine, CCNU, and vincristine is recommended for both grade 2 and 3 oligodendrogliomas. However, the risk of radiation-induced neurotoxicity is a concern in long-term survivors, and several clinical trials have tested the efficacy of chemotherapy alone in terms of cognitive function. Since CCNU is not approved in Japan, ACNU-containing regimen as PAV, or temozolomide are commonly used for the tumor.

Intraventricular central neurocytoma molecularly defined as extraventricular neurocytoma: a case representing the discrepancy between clinicopathological and molecular classifications.

Central neurocytoma (CN) is classically defined by its intraventricular location, neuronal/neurocytic differentiation, and histological resemblance to oligodendroglioma. Extraventricular neurocytoma (EVN) shares similar histological features with CN, while it distributes any site without contact with the ventricular system. CN and EVN have distinct methylation landscapes, and EVN has a signature fusion gene, FGFR1-TACC1. These characteristics distinguish between CN and EVN. A 30-year-old female underwent craniotomy and resection of a left intraventricular tumor at our institution. The histopathology demonstrated the classical findings of CN. Adjuvant irradiation with 60 Gy followed. No recurrence has been recorded for 25 years postoperatively. RNA sequencing revealed FGFR1-TACC1 fusion and methylation profile was discrepant with CN but compatible with EVN. We experienced a case of anatomically and histologically proven CN in the lateral ventricle. However, the FGFR1-TACC1 fusion gene and methylation profiling suggested the molecular diagnosis of EVN. The representative case was an "intraventricular" neurocytoma displaying molecular features of an "extraventricular" neurocytoma. Clinicopathological and molecular definitions have collided in our case and raised questions about the current definition of CN and EVN.

Long-term follow up of patients with WHO grade 2 oligodendroglioma.

PURPOSE: Since the introduction of the molecular definition of oligodendrogliomas based on isocitrate dehydrogenase (IDH)-status and the 1p19q-codeletion, it has become increasingly evident how this glioma entity differs much from other diffuse lower grade gliomas and stands out with longer survival and often better responsiveness to adjuvant therapy. Therefore, apart from using a molecular oligodendroglioma definition, an extended follow-up time is necessary to understand the nature of this slow growing, yet malignant condition. The aim of this study was to describe the long-term course of the oligodendroglioma disease in a population-based setting and to determine which factors affect outcome in terms of survival. METHODS: All adults with WHO-grade 2 oligodendrogliomas with known 1p19q-codeletion from five Scandinavian neurosurgical centers and with a follow-up time exceeding 5 years, were analyzed regarding survival and factors potentially affecting survival. RESULTS: 126 patients diagnosed between 1998 and 2016 were identified. The median follow-up was 12.0 years, and the median survival was 17.8 years (95% CI 16.0-19.6). Factors associated with shorter survival in multivariable analysis were age (HR 1.05 per year; CI 1.02-1.08, p < 0.001), tumor diameter (HR 1.05 per millimeter; CI 1.02-1.08, p < 0.001) and poor preoperative functional status (KPS < 80) (HR 4.47; CI 1.70-11.78, p = 0.002). In our material, surgical strategy was not associated with survival. CONCLUSION: Individuals with molecularly defined oligodendrogliomas demonstrate long survival, also in a population-based setting. This is important to consider for optimal timing of therapies that may cause long-term side effects. Advanced age, large tumors and poor function before surgery are predictors of shorter survival.

Evaluation of chromosome 1p/19q deletion by Fluorescence in Situ Hybridization (FISH) as prognostic factors in malignant glioma patients on treatment with alkylating chemotherapy.

BACKGROUND: Either deletion or co-deletion of chromosomal arms 1p or 19q is a characteristic and early genetic event in oligodendroglial tumors that is associated with a better prognosis and enhanced response to therapy. Information of 1p/19q status is now regarded as the standard of care when managing oligodendroglial tumors for therapeutic options in anticipation of the increased survival and progression-free survival times associated with it. Keeping this in view, we first time attempted to establish the FISH based detection of 1p/19q deletion in glioma tissue samples to evaluate its role and involvement in the disease. METHOD: Overall 39 glioma cases of different histologies were evaluated by fluorescence in situ hybridization (FISH) technique using specific FISH probes with Olympus BX43 fluorescent microscope to detect chromosomes 1p and 19q or co-deletions therein. RESULTS: Of the 39 glioma samples, overall 27 (69.2%) were found to have deletion either in 1p, 19q or both. Deletions were observed in 23.0%, 7.6% and 38.4% in 1p, 19q and 1p/19q co-deletions respectively. Overall oligidendrioglioma presented with 53.8% (21 of 39) deletions, astrocytoma group showed 12.8% and GBM accounted for 2.5% deletions. Overall survival and disease free survival was seen significantly better in oligidendrioglioma and astrocytoma with deleted tumors as compared to non-deleted ones (p<0.05). CONCLUSION: Allelic losses on 1p and 19q, either discretely or shared, were more frequent in classic oligodendrogliomas than in either astrocytoma or Glioblastoma with better survival and response to therapy.

Genomic alterations of oligodendrogliomas at distant recurrence.

BACKGROUND: Oligodendroglioma is known for its relatively better prognosis and responsiveness to radiotherapy and chemotherapy. However, little is known about the evolution of genetic changes as oligodendroglioma progresses. METHODS: In this study, we evaluated gene evolution invivo during tumor progression based on deep whole-genome sequencing data (ctDNA). We analyzed longitudinal genomic data from six patients during tumor evolution, of which five patients developed distant recurrence. RESULTS: Whole-exome sequencing demonstrated that the rate of shared mutations between the primary and recurrent samples was relatively low. In two cases, even well-known major driver mutations in CIC and FUBP1 that were detected in primary tumors were not detected in the relapse samples. Among these cases, two patients had a conversion from the IDH mutation in the originating state to the IDH1 wild state during the process of gene evolution under chemotherapy treatment, indicating that the cell phenotype and genetic characteristics of oligodendroglioma may change during tumor evolution. Two patients received long-term temozolomide (TMZ) treatment before the operation, and we found that recurrence tumors harbored mutations in the PI3K/AKT and Sonic hedgehog (SHh) signaling pathways. Hypermutation occurred with mutations in MMR genes in one patient, contributing to the rapid progression of the tumor. CONCLUSION: Oligodendroglioma displayed great spatial and temporal heterogeneity during tumor evolution. The PI3K/AKT and SHh signaling pathways may play an important role in promoting treatment resistance and distant relapse during oligodendroglioma evolution. In addition, there was a tendency to increase the degree of tumor malignancy during evolution. Distant recurrence may be a later event duringoligodendroglioma progression. CLINICALTRIALS: gov, Identifier: NCT05512325.