Epigenetic preconditioning with decitabine sensitizes glioblastoma to temozolomide via induction of MLH1.

INTRODUCTION: To improve the standard treatment paradigm for glioblastoma (GBM), efforts have been made to explore the efficacy of epigenetic agents as chemosensitizers. Recent data suggest possible synergy between decitabine (DAC), a DNA hypomethylating agent, and temozolomide (TMZ) in GBM, but the mechanism remains unclear. The objective of this study was to determine the effects of DAC on TMZ sensitization in a consecutively derived set of primary GBM cultures, with a focus on mismatch repair (MMR) proteins. METHODS: Half maximal inhibitory concentrations (IC50) of TMZ were calculated in eleven consecutive patient-derived GBM cell lines before and after preconditioning with DAC. MMR protein expression changes were determined by quantitative immunoblots and qPCR arrays. Single-molecule real-time (SMRT) sequencing of bisulfite (BS)-converted PCR amplicons of the MLH1 promoter was performed to determine methylation status. RESULTS: TMZ IC50 significantly changed in 6 of 11 GBM lines of varying MGMT promoter methylation status in response to DAC preconditioning. Knockdown of MLH1 after preconditioning reversed TMZ sensitization. SMRT-BS sequencing of the MLH1 promoter region revealed higher levels of baseline methylation at proximal CpGs in desensitized lines compared to sensitized lines. CONCLUSIONS: DAC enhances TMZ cytotoxicity in a subset of GBM cell lines, comprising lines both MGMT methylated and unmethylated tumors. This effect may be driven by levels of MLH1 via E2F1 transcription factor binding. Using unbiased long-range next-generation bisulfite-sequencing, we identified a region of the proximal MLH1 promoter with differential methylation patterns that has potential utility as a clinical biomarker for TMZ sensitization.

Emerging applications of hypomethylating agents in the treatment of glioblastoma (Review).

DNA hypomethylating agents (HMAs) such as decitabine and 5-azacytidine have established roles in the treatment paradigms for myelodysplastic syndrome and acute myelogenous leukemia, where they are considered to exert their anticancer effects by restoring the expression of tumor suppressor genes. Due to their relatively favorable adverse effect profile and known ability to pass through the blood-brain barrier, applications in the treatment of glioblastoma (GBM) and other central nervous system malignancies are under active investigation. The present review examines the types of HMAs currently available, their known and less-understood antineoplastic mechanisms, and the evidence to date of their preclinical and clinical efficacy in glioblastoma and other solid malignancies. The present review discusses the potential synergies HMAs may have with established and emerging GBM treatments, including temozolomide, immune checkpoint inhibitors and cancer vaccines. Recent successes and setbacks in clinical trials for newly diagnosed and recurrent GBM are summarized in order to highlight opportunities for HMAs to improve therapeutic responses. Challenges for future clinical trials are also assessed.

The incidence of venous thromboembolism following surgical resection of intracranial and intraspinal meningioma. A systematic review and retrospective study.

INTRODUCTION: Historically, the development of venous thromboembolism (VTE) including deep venous thrombosis (DVT) and pulmonary thromboembolism (PE) was cited as a higher post-operative risk for patients harboring meningiomas. However, recent literature has suggested that there may be no elevated risk for VTE among these patients. The authors perform both a retrospective review of their own cases as well as a systematic review of the literature in order to determine the frequency of the VTE and rate of post-operative hemorrhage in this patient population. METHODOLOGY: Patients undergoing surgery for intracranial and spinal meningioma from 2012 to 2019 were retrospectively reviewed for patient demographics, clinical characteristics, and post-operative complications. Logistic regression was used to determine risk factors for the development of VTE. Additionally, a PubMed search was performed to identify patients addressing this topic. RESULTS: Our retrospective review included 189 patients who underwent 197 operations. The rate of VTE for patients receiving LMWH was 3.55 % vs. 4.06 % for those not receiving LMWH. There were no observed hemorrhages after initiation of LMWH. Multivariate analysis found tumor volume, history of DVT, and length of hospital stay as independent risk factors for VTE. In the systematic review, 11 papers describing 28,954 patients were included. The risk of developing a VTE with or without LMWH was 2.71 % versus 4.07 %, respectively. The hemorrhage risk was 2.23 % on LMWH versus 4.20 % not on LMWH. DISCUSSION: In several heterogeneous series of all types of neurosurgical procedures, the reported rate of VTE was 11.1 %. In our review of the literature, the VTE rate of 2.71 % was similar to our cohort's rate of 3.55 %, for patients administered LMWH postoperatively. Higher rates of VTE with meningiomas may not be the case as once thought. Regular use of LMWH appears to be a safe, but it also did not necessarily lower the rates of VTE in our cohort. The use of routine lower-extremity duplex ultrasound, mechanical prophylaxis, and early mobilization, may have contributed to these lower rates of VTEs in patients with meningiomas.