Impact of MiRNA-181a2 on the Clinical Course of IDH1 Wild Type Glioblastoma

Background: Recently, miRNA-181a2 could be identified as a major regulator of IDH1 expression in fat tissue. The IDH1 gene, its mutation and expression have a major impact on overall survival in patients with glioblastoma. The presented study aimed to investigate the effect of miRNA181a2 on IDH1 expression in glioblastoma and on the prognosis of patients suffering from, for example, a tumor. Methods: A total of 74 glioblastoma specimens were analyzed for the expression of miRNA-181a2, acquired as fold change, using qRT-PCR. IDH1 protein expression was estimated via mRNA quantification. Eight post mortal, non-glioma related brain tissue specimens served as the control group. The results were correlated with relevant demographic and clinical aspects of the cohort. A TCGA dataset was used as an independent reference. Results: MiRNA-181a2 was significantly downregulated in tumor samples compared to the control group (p < 0.001). In the glioblastoma cohort, 63/74 (85.1%) showed an IDH1 wild type, while 11/74 (14.9%) patients harbored an IDH 1 mutation. In patients with IDH1 wild type glioblastoma, low miRNA-181a2 expression correlated with a prolonged overall survival (p = 0.019), also verifiable in an independent TCGA dataset. This correlation could not be identified for patients with an IDH1 mutation. MiRNA-181a2 expression tended to correlate inversely with IDH1 protein expression (p = 0.06). Gross total resection of the tumor was an independent marker for a prolonged survival (p = 0.03). Conclusion: MiRNA181a2 seems to be a promising prognostic marker of selective glioblastoma patients with IDH1 wild type characteristics. This effect may be mediated via direct regulation of IDH1 expression

Prognostic genetic markers in malignant gliomas

Glioblastomas are the most frequent and malignant brain tumors in adults. Surgical cure is virtually impossible and despite of radiation and chemotherapy the clinical course is very poor. Epigenetic silencing of MGMT has been associated with a better response to temozolomide-chemotherapy. We previously showed that temozolomide increases the median survival time of patients with tumors harbouring deletions on 9p within the region for p15(INK4b), p16(INK4a), and 10q (MGMT).&nbsp;The aim of this study was to investigate the methylation status of p15, p16, 14ARF and MGMT in glioblastomas and to correlate the results with the clinical data.Only patients with KPS &gt; 70, radical tumor resection, radiation and temozolomide-chemotherapy after recurrence were included.&nbsp;We observed promoter methylation of MGMT in 56% (15/27) and of p15 in 37% (10/27) of the tumors, whereas methylation of p16 and p14ARF were rare.&nbsp;Interestingly, methylation of p15 emerged as a significant predictor of shorter overall survival (16.9 vs. 23.8 months, p=0.025), whereas MGMT promoter methylation had no significant effect on median overall survival under this treatment regimen (22.5 vs. 22.1 months, p=0.49). In the presence of other clinically relevant factors, p15 methylation remains the only significant predictor (p=0.021; Cox regression).Although these results need to be confirmed in larger series and under different treatment conditions, our retrospective study shows clear evidence that p15 methylation can act as an additional prognostic factor for survival and underlines that this tumor suppressor, involved in cell cycle control, can act as an attractive candidate for therapeutic approaches in glioblastomas

Intracranial Intracerebral Schwannoma: a Case Report and Review of the Literature

Intracranial schwannomas are relatively uncommon, accounting for approximately 8% of all intracranial tumors, while intracerebral schwannomas represent an even rarer entity, responsible for roughly 1% of all intracranial schwannomas. After reviewing the relevant literature, we discussed the clinical journey of a 74-year-old woman who presented with a 3-week history of dizziness and nausea. Magnetic resonance imaging revealed a right temporal mass lesion with perifocal edema. The initial suspicion was the diagnosis of a glioblastoma or metastasis, prompting surgical intervention. During the surgery, a gross total resection of a noninvasive tumor was successfully performed. The patient’s postoperative recovery was uneventful. Histopathological examination and confrmatory immunohistochemistry played a crucial role in reaching the fnal diagnosis of an intracerebral temporal schwannoma, highlighting the diagnostic challenges posed by radiologically indistinguishable features from metastasis and gliomas. Despite these challenges, complete surgical removal remains the most preferred treatment option, resulting in a favorable long-term prognosis without the need for adjuvant or neoadjuvant chemotherapy. Intracerebral schwannomas are exceedingly rare brain tumors, often found on the brain’s surface or adjacent ventricles. Early and accurate diagnosis can be challenging due to radiological features overlapping with other intracranial pathologies. Nonetheless, histopathological examination and immunohistochemistry remain indispensable tools in establishing a defnitive diagnosis and guiding efective treatment strategies. With complete surgical excision, patients with intracerebral schwannomas can expect a positive outcome and a promising long-term prognosis. Further research and case studies are warranted to enhance our understanding of these rare tumors and improve patient outcomes

MicroRNA 200a as a histologically independent marker for meningioma recurrence : Results of a four microRNA panel analysis in meningiomas

Introduction: Meningiomas are mostly benign neoplasms of the central nervous system. Nevertheless there are recurrences in about 20% after surgical resection. Previous studies could reveal several predictors of meningioma recurrence. Tumor progression often is associated with a specific pattern of chromosome losses. Our study investigated the potential function of selected microRNAs as markers of tumor progression. Methods: By real-time polymerase chain reaction the expressions of microRNA 21-3p, 34a-3p, 200a-3p, and 409-3p were analyzed in solid tumor and in blood samples of 51 meningioma patients as well as in blood samples of 20 healthy individuals. Additionally, aberrations of parts of chromosomes 1, 14, 18, and 22 were analyzed by FISH. Tumor and blood samples were statistically analyzed, using Spearman's rank correlation coefficient as well as Mann–Whitney U- and Kruskal–Wallis-Test. Results: MicroRNA 200a showed significantly lower expressions in recurrent meningiomas than in newly diagnosed ones. MicroRNA 409 in meningiomas was correlated significantly with tumor volume and showed a significant negative correlation with patient age. Significance was found between the expression patterns of microRNAs 34a and 200a with the respective aberrations of chromosome 1p and the microRNA 409 with aberration of chromosome 14. In the male cohort the expression of microRNA 200a in blood was significantly upregulated in patients compared to healthy volunteers. By our research the function of microRNA 200a was proved to detect meningioma patients by liquid biopsy. Conclusion: We detected microRNA 200a as a new biomarker to indicate meningioma recurrences. Future transferability to blood could be important for patient follow-up

Increased Seroreactivity to Glioma-Expressed Antigen 2 in Brain Tumor Patients under Radiation

Background: Surgery and radiation are the mainstays of therapy for human gliomas that are the most common primary brain tumors. Most recently, cell culture and animal studies provided the first convincing evidence that radiation not only eliminates tumor cells, but also modulates the immune response and likely improves anti-tumor immunotherapy. Methology/Pricipal Findings: We present an in vivo study that analyzes the effects of radiation on the immune response in tumor patients. As readout system, we utilized the reactivity of glioma patients ’ sera against antigen GLEA2 as the most frequent antigen immunogenic in glioblastoma patients. We established an ELISA assay to analyze reactivity of 24 glioblastoma patients over a period of several months. As control we used 30 sera from healthy donors as well as 30 sera from lung cancer patients. We compared the course of GLEA2 seroreactivity at different times prior, during and after radiation. The GLEA2 seroreactivity was increased by the time of surgery, decreased after surgery, increased again under radiation, and slightly decreased after radiation. Conclusions/Significance: Our results provide in vivo evidence for an increased antibody response against tumor antigens under radiation. Antigens that become immunogenic with an increased antibody response as result of radiation can serv

First-line treatment of malignant glioma with carmustine implants followed by concomitant radiochemotherapy: a multicenter experience

Randomized phase III trials have shown significant improvement of survival 1, 2, and 3 years after implantation of 1,3-bis (2-chloroethyl)-1-nitrosourea (BCNU) wafers for patients with newly diagnosed malignant glioma. But these studies and subsequent non-phase III studies have also shown risks associated with local chemotherapy within the central nervous system. The introduction of concomitant radiochemotherapy with temozolomide (TMZ) has later demonstrated a survival benefit in a phase III trial and has become the current treatment standard for newly diagnosed malignant glioma patients. Lately, this has resulted in clinical protocols combining local chemotherapy with BCNU wafers and concomitant radiochemotherapy with TMZ although this may carry the risk of increased toxicity. We have compiled the treatment experience of seven neurosurgical centers using implantation of carmustine wafers at primary surgery followed by 6 weeks of radiation therapy (59–60 Gy) and 75 mg/m2/day TMZ in patients with newly diagnosed glioblastoma followed by TMZ monochemotherapy. We have retrospectively analyzed the postoperative clinical course, occurrence and severity of adverse events, progression-free interval, and overall survival in 44 patients with newly diagnosed glioblastoma multiforme. All patients received multimodal treatment including tumor resection, BCNU wafer implantation, and concomitant radiochemotherapy. Of 44 patients (mean age 59 ± 10.8 years) with glioblastoma who received Gliadel wafer at primary surgery, 28 patients (64%) had died, 16 patients (36%) were alive, and 15 patients showed no evidence of clinical or radiographic progression after a median follow-up of 15.6 months. At time of analysis of adverse events in this patient population, the median overall survival was 12.7 months and median progression-free survival was 7.0 months. Surgical, neurological, and medical adverse events were analyzed. Twenty-three patients (52%) experienced adverse events of any kind including complications that did not require treatment. Nineteen patients (43%) experienced grade 3 or grade 4 adverse events. Surgical complications included cerebral edema, healing abnormalities, cerebral spinal fluid leakage, meningitis, intracranial abscess, and hydrocephalus. Neurological adverse events included newly diagnosed seizures, alteration of mental status, and new neurological deficits. Medical complications were thromboembolic events (thrombosis, pulmonary embolism) and hematotoxicity. Combination of both treatment strategies, local chemotherapy with BCNU wafer and concomitant radiochemotherapy, appears attractive in aggressive multimodal treatment schedules and may utilize the sensitizing effect of TMZ and carmustine on MGMT and AGT on their respective drug resistance genes. Our data demonstrate that combination of local chemotherapy and concomitant radiochemotherapy carries a significant risk of toxicity that currently appears underestimated. Adverse events observed in this study appear similar to complication rates published in the phase III trials for BCNU wafer implantation followed by radiation therapy alone, but further add the toxicity of concomitant radiochemotherapy with systemic TMZ. Save use of a combined approach will require specific prevention strategies for multimodal treatments

DNA methylation-based classification of central nervous system tumours.

Accurate pathological diagnosis is crucial for optimal management of patients with cancer. For the approximately 100 known tumour types of the central nervous system, standardization of the diagnostic process has been shown to be particularly challenging-with substantial inter-observer variability in the histopathological diagnosis of many tumour types. Here we present a comprehensive approach for the DNA methylation-based classification of central nervous system tumours across all entities and age groups, and demonstrate its application in a routine diagnostic setting. We show that the availability of this method may have a substantial impact on diagnostic precision compared to standard methods, resulting in a change of diagnosis in up to 12% of prospective cases. For broader accessibility, we have designed a free online classifier tool, the use of which does not require any additional onsite data processing. Our results provide a blueprint for the generation of machine-learning-based tumour classifiers across other cancer entities, with the potential to fundamentally transform tumour pathology