Differences in methylation profiles between long-term survivors and short-term survivors of IDH-wild-type glioblastoma.

Background: Patients with glioblastoma (GBM) have a median overall survival (OS) of approximately 16 months. However, approximately 5% of patients survive >5 years. This study examines the differences in methylation profiles between long-term survivors (>5 years, LTS) and short-term survivors (<1 year, STS) with isocitrate dehydrogenase (IDH)-wild-type GBMs. Methods: In a multicenter retrospective analysis, we identified 25 LTS with a histologically confirmed GBM. They were age- and sex-matched to an STS. The methylation profiles of all 50 samples were analyzed with EPIC 850k, classified according to the DKFZ methylation classifier, and the methylation profiles of LTS versus STS were compared. Results: After methylation profiling, 16/25 LTS and 23/25 STS were confirmed to be IDH-wild-type GBMs, all with +7/-10 signature. LTS had significantly increased O6-methylguanine methyltransferase (MGMT) promoter methylation and higher prevalence of FGFR3-TACC3 fusion (P = .03). STS were more likely to exhibit CDKN2A/B loss (P = .01) and higher frequency of NF1 (P = .02) mutation. There were no significant CpGs identified between LTS versus STS at an adjusted P-value of .05. Unadjusted analyses identified key pathways involved in both LTS and STS. The most common pathways were the Hippo signaling pathway and the Wnt pathway in LTS, and GPCR ligand binding and cell-cell signaling in STS. Conclusions: A small group of patients with IDH-wild-type GBM survive more than 5 years. While there are few differences in the global methylation profiles of LTS compared to STS, our study highlights potential pathways involved in GBMs with a good or poor prognosis.

Bevacizumab for Cerebral Radionecrosis: A Single-Center Experience.

BACKGROUND: Cerebral radionecrosis, a subacute or late effect of radiotherapy, can be debilitating and difficult to treat. Steroids can reduce symptoms, but have significant long-term side effects. Bevacizumab has been shown to reduce edema and other radiologic features associated with radionecrosis and improve patient symptoms. We report our experience using bevacizumab for cerebral radionecrosis. METHODS: We retrospectively reviewed the charts of all patients treated at our institution with bevacizumab for non-glioma-associated cerebral radionecrosis. We recorded change in symptoms, change in steroids, change in performance status, time to tumor progression, and time to death. We delineated the volume of necrosis pre- and post-bevacizumab on T1-post-gadolinium and fluid-attenuated inversion recovery (FLAIR) MRI scans. RESULTS: We identified 15 patients, 8 with brain metastases, 6 with meningioma, and 1 with nasopharyngeal carcinoma. Most received four doses of bevacizumab, 7.5 mg/kg q 3 weeks × 4 doses. Neuroimaging demonstrated a reduced T1 gadolinium-enhancing volume and edema in 14/15 patients (the average reduction in T1-post-gadolinium volume was 3.0 cm3, and average reduction in FLAIR volume was 27.9 cm3). There was no appreciable change in patient performance status. Steroid doses decreased in five of nine patients. There was a high rate (26%) of adverse events, including pulmonary embolism, stroke, and wound dehiscence. The median progression-free survival was 6.5 months. CONCLUSION: Although bevacizumab is commonly prescribed for cerebral radionecrosis, in our retrospective cohort, the clinical benefits were modest and there was significant toxicity.

Opinion & Special Article: Glioma Classification: How to Interpret Molecular Markers in a Diffuse Glioma Pathology Report.

Diffuse infiltrating gliomas are the most common malignant brain tumors in adults. The 2021 World Health Organization classification for central nervous system tumors (CNS5 WHO) has significantly altered the rules for classification and grading of diffuse gliomas. Clinicians, including neurology residents and neurologists, will have to consider the changes that include the introduction of new tumor types, allotting established tumor types to other groups, and substituting previously essential morphological features for additional molecular markers. For example, in the current classification, glioblastoma is defined as isocitrate dehydrogenase (IDH)-wildtype, grade 4. Whereas, a grade 4 IDH-mutated astrocytic glioma is referred to as astrocytoma, IDH-mutated, grade 4. Additionally, potential targeted treatments, based on the underlying molecular alterations, have become therapeutic options for diffuse gliomas. For clinicians, it is important to know the rationale for why these options are only available for specific tumors. Due to the emphasis of molecular markers in the CNS5 WHO classification, interpretation of a pathology report and understanding of its clinical implications can be challenging. This review describes the most important molecular alterations in glioma, summarizes the recent changes in the CNS5 WHO classification for glioma, and presents a stepwise approach for trainees and neurologist to decipher a glioma pathology report.

Chimeric cells of maternal origin do not appear to be pathogenic in the juvenile idiopathic inflammatory myopathies or muscular dystrophy.

INTRODUCTION: Microchimeric cells have been studied for over a decade, with conflicting reports on their presence and role in autoimmune and other inflammatory diseases. To determine whether microchimeric cells were pathogenic or mediating tissue repair in inflammatory myopathies, we phenotyped and quantified microchimeric cells in juvenile idiopathic inflammatory myopathies (JIIM), muscular dystrophy (MD), and noninflammatory control muscle tissues. METHOD: Fluorescence immunophenotyping for infiltrating cells with sequential fluorescence in situ hybridization was performed on muscle biopsies from ten patients with JIIM, nine with MD and ten controls. RESULTS: Microchimeric cells were significantly increased in MD muscle (0.079 ± 0.024 microchimeric cells/mm(2) tissue) compared to controls (0.019 ± 0.007 cells/mm(2) tissue, p = 0.01), but not elevated in JIIM muscle (0.043 ± 0.015 cells/mm(2)). Significantly more CD4+ and CD8+ microchimeric cells were in the muscle of patients with MD compared with controls (mean 0.053 ± 0.020/mm(2) versus 0 ± 0/mm(2) p = 0.003 and 0.043 ± 0.023/mm(2) versus 0 ± 0/mm(2) p = 0.025, respectively). No differences in microchimeric cells between JIIM, MD, and noninflammatory controls were found for CD3+, Class II+, CD25+, CD45RA+, and CD123+ phenotypes, and no microchimeric cells were detected in CD20, CD83, or CD45RO populations. The locations of microchimeric cells were similar in all three conditions, with MD muscle having more microchimeric cells in perimysial regions than controls, and JIIM having fewer microchimeric muscle nuclei than MD. Microchimeric inflammatory cells were found, in most cases, at significantly lower proportions than autologous cells of the same phenotype. CONCLUSIONS: Microchimeric cells are not specific to autoimmune disease, and may not be important in muscle inflammation or tissue repair in JIIM.

Increased microchimeric CD4+ T lymphocytes in peripheral blood from women with systemic sclerosis.

Recent studies have demonstrated the presence of microchimeric cells in peripheral blood and skin lesions from patients with systemic sclerosis (SSc). In a previous study we found that some peripheral blood CD3+ cells from female patients with SSc contained male DNA. Here, peripheral blood samples from 47 patients with SSc (30 with diffuse cutaneous SSc and 17 with limited cutaneous SSc) and 22 healthy controls were sorted for CD4+ and CD8+ T cells. Both positively and negatively selected populations were analyzed for male DNA by quantitative PCR. Analysis of Y chromosome sequences in the sorted cells demonstrated the presence of microchimerism in 82.9% of SSc patients compared to 63.6% of controls. The numbers of CD4+ and CD8+ T cells were found to be significantly higher in the SSc patients than in controls. Furthermore, patients with dcSSc were observed to have significantly more CD4+ microchimeric T cells than the controls. In the CD8+ T-cell population, there was a trend toward more microchimeric cells in the patients but this did not reach significance. These results support the hypothesis that microchimeric CD4+ T cells may be involved in the pathogenesis of SSc.