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Acta Neuropathologica Communications Nov 2023MGMT promoter methylation testing is required for prognosis and predicting temozolomide response in gliomas. Accurate results depend on sufficient tumor cellularity, but...
MGMT promoter methylation testing is required for prognosis and predicting temozolomide response in gliomas. Accurate results depend on sufficient tumor cellularity, but histologic estimates of cellularity are subjective. We sought to determine whether driver mutation variant allelic frequency (VAF) could serve as a more objective metric for cellularity and identify possible false-negative MGMT samples. Among 691 adult-type diffuse gliomas, MGMT promoter methylation was assessed by pyrosequencing (N = 445) or DNA methylation array (N = 246); VAFs of TERT and IDH driver mutations were assessed by next generation sequencing. MGMT results were analyzed in relation to VAF. By pyrosequencing, 56% of all gliomas with driver mutation VAF ≥ 0.325 had MGMT promoter methylation, versus only 37% with VAF < 0.325 (p < 0.0001). The mean MGMT promoter pyrosequencing score was 19.3% for samples with VAF VAF ≥ 0.325, versus 12.7% for samples with VAF < 0.325 (p < 0.0001). Optimal VAF cutoffs differed among glioma subtypes (IDH wildtype glioblastoma: 0.12-0.18, IDH mutant astrocytoma: ~0.33, IDH mutant and 1p/19q co-deleted oligodendroglioma: 0.3-0.4). Methylation array was more sensitive for MGMT promoter methylation at lower VAFs than pyrosequencing. Microscopic examination tended to overestimate tumor cellularity when VAF was low. Re-testing low-VAF cases with methylation array and droplet digital PCR (ddPCR) confirmed that a subset of them had originally been false-negative. We conclude that driver mutation VAF is a useful quality assurance metric when evaluating MGMT promoter methylation tests, as it can help identify possible false-negative cases.
Topics: Adult; Humans; Brain Neoplasms; Tumor Suppressor Proteins; Mutation; DNA Methylation; DNA Modification Methylases; DNA Repair Enzymes; Glioma; Isocitrate Dehydrogenase
PubMed: 37919784
DOI: 10.1186/s40478-023-01680-0 -
Neuro-oncology Advances 2023Telomere maintenance by telomerase reverse transcriptase (TERT) is essential for immortality in most cancers, including oligodendrogliomas. Agents that disrupt telomere...
BACKGROUND
Telomere maintenance by telomerase reverse transcriptase (TERT) is essential for immortality in most cancers, including oligodendrogliomas. Agents that disrupt telomere maintenance such as the telomere uncapping agent 6-thio-2'-deoxyguanosine (6-thio-dG) are in clinical trials. We previously showed that TERT expression in oligodendrogliomas is associated with upregulation of glucose-6-phosphate dehydrogenase (G6PD), the rate-limiting enzyme of the pentose phosphate pathway (PPP). We also showed that hyperpolarized δ-[1-C]-gluconolactone metabolism to 6-phosphogluconate (6-PG) can be used to probe the PPP in glioblastomas. The goal of this study was to determine whether hyperpolarized C imaging using δ-[1-C]-gluconolactone can monitor TERT expression and response to 6-thio-dG in oligodendrogliomas.
METHODS
We examined patient-derived oligodendroglioma cells and orthotopic tumors to assess the link between TERT and hyperpolarized δ-[1-C]-gluconolactone metabolism. We performed in vivo imaging to assess the ability of hyperpolarized δ-[1-C]-gluconolactone to report on TERT and response to 6-thio-dG in rats bearing orthotopic oligodendrogliomas in vivo.
RESULTS
Doxycycline-inducible TERT silencing abrogated 6-PG production from hyperpolarized δ-[1-C]-gluconolactone in oligodendroglioma cells, consistent with the loss of G6PD activity. Rescuing TERT expression by doxycycline removal restored G6PD activity and, concomitantly, 6-PG production. 6-PG production from hyperpolarized δ-[1-C]-gluconolactone demarcated TERT-expressing tumor from surrounding TERT-negative normal brain in vivo. Importantly, 6-thio-dG abrogated 6-PG production at an early timepoint preceding MRI-detectable alterations in rats bearing orthotopic oligodendrogliomas in vivo.
CONCLUSIONS
These results indicate that hyperpolarized δ-[1-C]-gluconolactone reports on TERT expression and early response to therapy in oligodendrogliomas. Our studies identify a novel agent for imaging tumor proliferation and treatment response in oligodendroglioma patients.
PubMed: 37600229
DOI: 10.1093/noajnl/vdad092 -
Oncology Letters Aug 2023Glioma is the most common intracranial tumor of the central nervous system in adults; however, the diagnosis of glioma, and its grading and histological subtyping, is...
Glioma is the most common intracranial tumor of the central nervous system in adults; however, the diagnosis of glioma, and its grading and histological subtyping, is challenging for pathologists. The present study assessed serine and arginine rich splicing factor 1 (SRSF1) expression in 224 glioma cases in the Chinese Glioma Genome Atlas (CGGA) database, and verified its expression by immunohistochemical analysis of specimens from 70 clinical patients. In addition, the prognostic potential of SRSF1 concerning the survival status of patients was evaluated. , the biological role of SRSF1 was assessed using MTT, colony formation, wound healing and Transwell assays. The results revealed that SRSF1 expression was significantly associated with the grading and the histopathological subtype of glioma. As determined using a receiver operating characteristic curve analysis, the specificity of SRSF1 for glioblastoma (GBM) and World Health Organization (WHO) grade 3 astrocytoma was 40 and 48%, respectively, whereas the sensitivity was 100 and 85%. By contrast, pilocytic astrocytoma tumors exhibited negative immunoexpression of SRSF1. Additionally, Kaplan-Meier survival analysis indicated that high SRSF1 expression predicted a worse prognosis for patients with glioma in both the CGGA and clinical cohorts. , the results demonstrated that SRSF1 promoted the proliferation, invasion and migration of U87MG and U251 cells. These data suggested that immunohistochemical analysis of SRSF1 expression is highly sensitive and specific in the diagnosis of GBM and WHO grade 3 astrocytoma, and may have an important role in glioma grading. Furthermore, the lack of SRSF1 is a potential diagnostic biomarker for pilocytic astrocytoma. However, neither in oligodendroglioma and astrocytoma, nor in GBM was an association detected between SRSF1 expression and mutations or co-deletion. These findings indicated that SRSF1 may serve as a prognostic factor in glioma cases and could have an active role in promoting glioma progression.
PubMed: 37427339
DOI: 10.3892/ol.2023.13934 -
Journal of Veterinary Internal Medicine 2023In humans, the T2-weighted (T2W)-fluid-attenuated inversion recovery (FLAIR) mismatch sign (T2FMM) is a specific imaging biomarker for the isocitrate dehydrogenase 1...
BACKGROUND
In humans, the T2-weighted (T2W)-fluid-attenuated inversion recovery (FLAIR) mismatch sign (T2FMM) is a specific imaging biomarker for the isocitrate dehydrogenase 1 (IDH1)-mutated, 1p/19q non-codeleted low-grade astrocytomas (LGA). The T2FMM is characterized by a homogeneous hyperintense T2W signal and a hypointense signal with a hyperintense peripheral rim on FLAIR sequences. In gliomas in dogs, the T2FMM has not been described.
HYPOTHESES/OBJECTIVES
In dogs with focal intra-axial brain lesions, T2FMM will discriminate gliomas from other lesions. The T2FMM will be associated with the LGA phenotype and presence of microcysts on histopathology. Interobserver agreement for T2FMM magnetic resonance imaging (MRI) features will be high.
ANIMALS
One hundred eighty-six dogs with histopathologically diagnosed focal intra-axial lesions on brain MRI including oligodendrogliomas (n = 90), astrocytomas (n = 47), undefined gliomas (n = 9), cerebrovascular accidents (n = 33), and inflammatory lesions (n = 7).
METHODS
Two blinded raters evaluated the 186 MRI studies and identified cases with the T2FMM. Histopathologic and immunohistochemical slides of T2FMM cases were evaluated for morphologic features and IDH1-mutations and compared to cases without the T2FMM. Gene expression analyses were performed on a subset of oligodendrogliomas (n = 10) with and without T2FMM.
RESULTS
The T2FMM was identified in 14/186 (8%) of MRI studies, and all dogs with T2FMM had oligodendrogliomas (n = 12 low-grade [LGO], n = 2 high-grade [HGO]; P < .001). Microcystic change was significantly associated with the T2FMM (P < .00001). In oligodendrogliomas with T2FMM, IDH1-mutations or specific differentially expressed genes were not identified.
CONCLUSION AND CLINICAL IMPORTANCE
The T2FMM can be readily identified on routinely obtained MRI sequences. It is a specific biomarker for oligodendroglioma in dogs, and was significantly associated with non-enhancing LGO.
Topics: Humans; Dogs; Animals; Oligodendroglioma; Brain Neoplasms; Retrospective Studies; Isocitrate Dehydrogenase; Magnetic Resonance Imaging; Glioma; Astrocytoma; Mutation; Biomarkers; Dog Diseases
PubMed: 37246729
DOI: 10.1111/jvim.16749 -
Quantitative Imaging in Medicine and... Nov 2023In 2018, a new system was proposed for classifying and reporting post-treatment adult brain tumor on magnetic resonance imaging, named as Brain Tumor Reporting and Data...
BACKGROUND
In 2018, a new system was proposed for classifying and reporting post-treatment adult brain tumor on magnetic resonance imaging, named as Brain Tumor Reporting and Data System (BT-RADS), that needs a validation by means of agreement studies.
METHODS
A retrospective study was designed with the aim of identifying contrast-enhanced magnetic resonance imaging (MRI) of adult patients on follow-up for primary brain tumor at Fondazione Policlinico Campus Bio-Medico. Four radiologists (2 radiology residents, 1 general radiologist, 1 neuroradiologist) read and scored each study using the BT-RADS scoring tool, blinded to the MRI original report. Interobserver agreement and Fleiss' k were calculated to assess the level of diagnostic agreement. It was assessed how many times the assignment of different scoring of BT-RADS would have led to a different patient management.
RESULTS
The total number of patients included in the study was 23 with 147 MRIs and a total of 588 BT-RADS scores retrospectively evaluated. The two most frequent tumor types were astrocytoma grade 4 (62%) and oligodendroglioma grade 3 (21%). The overall agreement rate for all 4 radiologists was 82% with a Fleiss' k of 0.70. The overall agreement rate between general radiologist and neuroradiologist was 91% with a Fleiss' k of 0.86. The overall agreement rate between 2 radiology residents and neuroradiologist was 80% with a Fleiss' k of 0.66. Astrocytoma grade 3 (k: 0.51) and oligodendroglioma grade 2 (k: 0.32) showed a poor agreement while higher values of agreement were found for astrocytoma grade 4 (k: 0.70), astrocytoma grade 2 (k: 0.78) and oligodendroglioma grade 3 (k: 0.78). All the radiologists agreed on BT-RADS assignment in 70% patients, three radiologists agreed in 17% and two radiologists agree in 13%. In no cases there was a complete disagreement among the readers. In 18% of cases the discrepancy in the estimated BT-RADS would have led to a different follow-up management.
CONCLUSIONS
BT-RADS can be considered a valid tool for neuroradiologists and radiologists even with little experience in the interpretation of patients' images during follow-up for adult primary brain tumors supporting standardized interpretation, reporting and clinical management.
PubMed: 37969622
DOI: 10.21037/qims-22-850 -
European Journal of Nuclear Medicine... Jan 2024The primary aim was to evaluate whether anti-3-[F]FACBC PET combined with conventional MRI correlated better with histomolecular diagnosis (reference standard) than MRI...
PURPOSE
The primary aim was to evaluate whether anti-3-[F]FACBC PET combined with conventional MRI correlated better with histomolecular diagnosis (reference standard) than MRI alone in glioma diagnostics. The ability of anti-3-[F]FACBC to differentiate between molecular and histopathological entities in gliomas was also evaluated.
METHODS
In this prospective study, patients with suspected primary or recurrent gliomas were recruited from two sites in Norway and examined with PET/MRI prior to surgery. Anti-3-[F]FACBC uptake (TBR) was compared to histomolecular features in 36 patients. PET results were then added to clinical MRI readings (performed by two neuroradiologists, blinded for histomolecular results and PET data) to assess the predicted tumor characteristics with and without PET.
RESULTS
Histomolecular analyses revealed two CNS WHO grade 1, nine grade 2, eight grade 3, and 17 grade 4 gliomas. All tumors were visible on MRI FLAIR. The sensitivity of contrast-enhanced MRI and anti-3-[F]FACBC PET was 61% (95%CI [45, 77]) and 72% (95%CI [58, 87]), respectively, in the detection of gliomas. Median TBR was 7.1 (range: 1.4-19.2) for PET positive tumors. All CNS WHO grade 1 pilocytic astrocytomas/gangliogliomas, grade 3 oligodendrogliomas, and grade 4 glioblastomas/astrocytomas were PET positive, while 25% of grade 2-3 astrocytomas and 56% of grade 2-3 oligodendrogliomas were PET positive. Generally, TBR increased with malignancy grade for diffuse gliomas. A significant difference in PET uptake between CNS WHO grade 2 and 4 gliomas (p < 0.001) and between grade 3 and 4 gliomas (p = 0.002) was observed. Diffuse IDH wildtype gliomas had significantly higher TBR compared to IDH1/2 mutated gliomas (p < 0.001). Adding anti-3-[F]FACBC PET to MRI improved the accuracy of predicted glioma grades, types, and IDH status, and yielded 13.9 and 16.7 percentage point improvement in the overall diagnoses for both readers, respectively.
CONCLUSION
Anti-3-[F]FACBC PET demonstrated high uptake in the majority of gliomas, especially in IDH wildtype gliomas, and improved the accuracy of preoperatively predicted glioma diagnoses.
CLINICAL TRIAL REGISTRATION
ClinicalTrials.gov ID: NCT04111588, URL: https://clinicaltrials.gov/study/NCT04111588.
Topics: Humans; Brain Neoplasms; Oligodendroglioma; Prospective Studies; Neoplasm Recurrence, Local; Glioma; Positron-Emission Tomography; Glioblastoma; Magnetic Resonance Imaging
PubMed: 37776502
DOI: 10.1007/s00259-023-06437-4 -
Frontiers in Oncology 2024Gliomas are a group of heterogeneous tumors that account for substantial morbidity, mortality, and costs to patients and healthcare systems globally. Survival varies... (Review)
Review
Gliomas are a group of heterogeneous tumors that account for substantial morbidity, mortality, and costs to patients and healthcare systems globally. Survival varies considerably by grade, histology, biomarkers, and genetic alterations such as IDH mutations and promoter methylation, and treatment, but is poor for some grades and histologies, with many patients with glioblastoma surviving less than a year from diagnosis. The present review provides an introduction to glioma, including its classification, epidemiology, economic and humanistic burden, as well as treatment options. Another focus is on treatment recommendations for IDH-mutant astrocytoma, IDH-mutant oligodendroglioma, and glioblastoma, which were synthesized from recent guidelines. While recommendations are nuanced and reflect the complexity of the disease, maximum safe resection is typically the first step in treatment, followed by radiotherapy and/or chemotherapy using temozolomide or procarbazine, lomustine, and vincristine. Immunotherapies and targeted therapies currently have only a limited role due to disappointing clinical trial results, including in recurrent glioblastoma, for which the nitrosourea lomustine remains the standard of care. The lack of treatment options is compounded by frequently suboptimal clinical practice, in which patients do not receive adequate therapy after resection, including delayed, shortened, or discontinued radiotherapy and chemotherapy courses due to treatment side effects. These unmet needs will require significant efforts to address, including a continued search for novel treatment options, increased awareness of clinical guidelines, improved toxicity management for chemotherapy, and the generation of additional and more robust clinical and health economic evidence.
PubMed: 38571509
DOI: 10.3389/fonc.2024.1368606 -
Cureus Dec 2023Oligodendroglioma is an uncommon glial tumor known for its extremely rare tendency to metastasize to extracranial areas, particularly to the spinal region. We present a...
Oligodendroglioma is an uncommon glial tumor known for its extremely rare tendency to metastasize to extracranial areas, particularly to the spinal region. We present a rare case of oligodendroglioma that metastasizes to the spinal cord 14 years after resection of the initial tumor. Furthermore, a systematic review of the relevant literature is conducted following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, encompassing oligodendroglioma cases with extracranial metastases. Our PRISMA-guided systematic review fills a critical knowledge gap in neurosurgery by consolidating scattered data on oligodendroglioma metastases, offering pivotal insights for clinical practice and future research. A 50-year-old male patient exhibited severe headaches and dizziness, with MRI findings revealing a significant brain mass suggestive of oligodendroglioma. Consequently, the patient underwent a craniotomy procedure. After 14 years, the patient presented with weakness in both lower extremities and bladder as well as bowel dysfunction. A lumbosacral MRI of the patient revealed two intradural enhancing masses in the lumbosacral spine. Surgical resection was performed, and the characteristics were identical to those of the primary tumor. The systemic review encompassed 52 articles, covering 67 cases of extracranial metastases from oligodendroglioma. Only three cases in the literature review fulfilled the inclusion criteria, demonstrating the required molecular genetic profiles of isocitrate dehydrogenase (IDH)-mutation and chromosome 1p/19q-codeletion. The inclusion criteria encompassed cases of oligodendroglioma with confirmed extracranial metastases, focusing on those with documented molecular genetic profiles indicating IDH-mutation and 1p/19q-codeletion. Our emphasis was on identifying cases with this specific genetic profile to ensure consistency and relevance in the literature review. Interestingly, our case was the first to exhibit intradural spinal metastases, while the other cases involved metastasis to the spinal bone marrow. Our case and literature review demonstrate that oligodendrogliomas, although exceptionally rare, can metastasize not only to the extracranial area but also to the spinal cord. To improve survival in oligodendroglioma cases, it is recommended to implement regular radiological screening and monitoring to enable early detection and treatment of extracranial metastases.
PubMed: 38264380
DOI: 10.7759/cureus.51035 -
Clinical Oncology (Royal College of... Feb 2024The National Health Service strategy for the delivery of proton beam therapy (PBT) in the UK provides a unique opportunity to deliver high-quality evidence for PBT... (Review)
Review
The National Health Service strategy for the delivery of proton beam therapy (PBT) in the UK provides a unique opportunity to deliver high-quality evidence for PBT through randomised controlled trials (RCTs). We present a summary of three UK PBT RCTs in progress, including consideration of their key design characteristics and outcome assessments, to inform and support future PBT trial development. The first three UK multicentre phase III PBT RCTs (TORPEdO, PARABLE and APPROACH), will compare PBT with photon radiotherapy for oropharyngeal squamous cell carcinoma, breast cancer and oligodendroglioma, respectively. All three studies were designed by multidisciplinary teams, which combined expertise from clinicians, clinical trialists and scientists with strong patient advocacy and guidance from national radiotherapy research networks and international collaborators. Consistent across all three studies is a focus on the reduction of long-term radiotherapy-related toxicities and an evaluation of patient-reported outcomes and health-related quality of life, which will address key uncertainties regarding the clinical benefits of PBT. Innovative translational components will provide insights into mechanisms of toxicity and help to frame the key future research questions regarding PBT. The UK radiotherapy research community is developing and delivering an internationally impactful PBT research portfolio. The combination of data from RCTs with prospectively collected data from a national PBT outcomes registry will provide an innovative, high-quality repository for PBT research and the platform to design and deliver future trials of PBT.
Topics: Female; Humans; Breast Neoplasms; Proton Therapy; Randomized Controlled Trials as Topic
PubMed: 38042671
DOI: 10.1016/j.clon.2023.11.027 -
Neuro-oncology Practice Apr 2024Isocitrate dehydrogenase (IDH) is commonly mutated (mIDH) in gliomas, and this mutant enzyme produces the oncometabolite 2-hydroxyglutarate (2HG). 2HG promotes...
BACKGROUND
Isocitrate dehydrogenase (IDH) is commonly mutated (mIDH) in gliomas, and this mutant enzyme produces the oncometabolite 2-hydroxyglutarate (2HG). 2HG promotes gliomagenesis and is implicated in epileptogenesis. Ivosidenib (IVO), a small molecule oral mIDH1 inhibitor, is FDA-approved for mIDH1 newly diagnosed and relapsed/refractory acute myeloid leukemia. Moreover, IVO has efficacy in clinical trials for recurrent mIDH1 gliomas. Given the lack of targeted treatments for gliomas, we initiated off-label IVO for mIDH glioma patients in October 2020.
METHODS
Retrospectively, we sought to assess early outcomes in our patients and describe their experience on IVO from October 2020 through February 2022. Our objective was to report on the following variables of off-label use of IVO: radiographic response, seizure control, tolerability, and access to the medication. All patients initially received single-agent IVO dosed at 500 mg orally once daily.
RESULTS
The cohort age range was 21-74 years. Tumor types included astrocytoma ( = 14) and oligodendroglioma ( = 16), with most being grade 2 ( = 21). The best radiographic response in nonenhancing disease ( = 22) was 12 stable diseases, 5 minor responses, 3 partial responses, and 2 progressive diseases. Seizure frequency was stable to improved for most patients (70%, = 21). IVO was well-tolerated, with the most common toxicities being diarrhea, elevated creatine kinase, and QTc interval prolongation. Most patients (66.7%, = 20) received drugs via the patient assistance program, with insurance initially covering a third of patients and with ongoing use, later covering 60%.
CONCLUSIONS
Targeted therapies like IVO are options for mIDH glioma patients and can provide positive oncologic and neurological outcomes.
PubMed: 38496920
DOI: 10.1093/nop/npad068