Administration Of Temozolomide Research Articles

Hepatitis B virus reactivation during temozolomide administration for malignant glioma.

The purpose of this study is to clarify the clinical features of temozolomide (TMZ)-related hepatitis B virus (HBV) reactivation and to identify HBV reactivation predictive factors. We retrospectively reviewed the clinical course of 145 patients newly diagnosed or with recurrent malignant glioma treated with TMZ. Before treatment, we screened patients for HB surface antigen (HBsAg) positivity (HBV carrier) and HBsAg negativity. Patients were also screened for antibody for HB core antigen (anti-HBc) positivity and/or for HB surface antigen positivity (resolved HBV infection). The patients were monitored by HBV DNA, alanine, and aspartate aminotransaminase during and after the completion of TMZ. HBV carriers and those with resolved HBV infections with HBV reactivation received preemptive entecavir treatment. In those with resolved HBV infections, we analyzed clinical characters for the predictive factors for HBV reactivation. In one of two HBV carriers, HBV DNA turned positive 8months after the completion of TMZ and entecavir. In four (16.7%) of 24 resolved HBV infections, HBV DNA turned detectable at completion of concomitant radiation and TMZ or during monthly TMZ. HBV DNA turned negative with entecavir in all patients without liver dysfunction. In resolved HBV infections, those with a high anti-HBc titer had significantly higher incidence of HBV reactivation than those with low anti-HBc titers (60% vs. 5.3%: p = 0.018). Screenings, monitoring, and preemptive entecavir were important for preventing TMZ-related HBV reactivations. Anti-HBc titers could be the predictive markers for HBV reactivation in the those with resolved HBV infections.

Synthetic High-density Lipoprotein Nanodiscs for Personalized Immunotherapy Against Gliomas.

Gliomas are brain tumors with dismal prognoses. The standard-of-care treatments for gliomas include surgical resection, radiation, and temozolomide administration; however, they have been ineffective in providing significant increases in median survival. Antigen-specific cancer vaccines and immune checkpoint blockade may provide promising immunotherapeutic approaches for gliomas. We have developed immunotherapy delivery vehicles based on synthetic high-density lipoprotein (sHDL) loaded with CpG, a Toll-like receptor-9 agonist, and tumor-specific neoantigens to target gliomas and elicit immune-mediated tumor regression. We demonstrate that vaccination with neoantigen peptide-sHDL/CpG cocktail in combination with anti-PD-L1 immune checkpoint blocker elicits robust neoantigen-specific T-cell responses against GL261 cells and eliminated established orthotopic GL261 glioma in 33% of mice. Mice remained tumor free upon tumor cell rechallenge in the contralateral hemisphere, indicating the development of immunologic memory. Moreover, in a genetically engineered murine model of orthotopic mutant IDH1 (mIDH1) glioma, sHDL vaccination with mIDH1 neoantigen eliminated glioma in 30% of animals and significantly extended the animal survival, demonstrating the versatility of our approach in multiple glioma models. Overall, our strategy provides a general roadmap for combination immunotherapy against gliomas and other cancer types.

Effect of temozolomide chronotherapy in patients with high-grade glioma.

e14525 Background: High grade gliomas (HGG) (the most common being glioblastoma) are the most common primary CNS malignancy in adults. Mainstay of therapy is surgical resection followed by concurrent radiation and temozolomide (TMZ) followed by adjuvant TMZ. Unfortunately, prognosis remains poor and optimization of current therapy is critical. Chronotherapy is defined as improvement in treatment outcomes by maximizing treatment efficacy and minimizing toxicity by administering medications in accordance with biological rhythms of the patient. In a mouse model, there was greater anti-tumor efficacy during morning administration of TMZ. This trial was designed to determine the feasibility and potential clinical impact of chrono-therapeutically administering TMZ in patients with HGG. Methods: Adult patients ( > 18 years) with HGG (WHO Grade III/IV) were eligible. Patients were screened and consented prior to initiation of monthly TMZ therapy. Eligible patients were randomized to TMZ in the morning (AM) before 10AM or in the evening (PM) after 8PM. Pill diaries were recorded for drug administration time and compliance. Fact-Br Quality of Life (QoL) surveys were administered to patients at the time of enrollment in the trial and at the end of treatment to measure differences in QoL in both groups. Circadian rhythm was recorded by Actiwatch. Adverse events (AE), overall survival (OS) and progression free survival (PFS) were measured for each group. Results: At the time of submission, a total of 28 patients were evaluated. 15 patients were in AM group and 13 in PM group. It is feasible for participants to take TMZ per study assignment. There was no significant difference in the QoL based on the Fact-Br dataset in the four main categories of physical well-being, social/family well-being, functional well-being and emotional well-being. The Friedman’s two-way nonparametric ANOVA tests were used to analyze the differences across time points. Cytopenias are a known adverse effect of TMZ. There was a trend towards worsening lymphocyte counts in the AM group compared to PM group, although not statistically significant. There was no statistical significance in PFS or OS in patients with newly diagnosed glioblastoma. Conclusions: Chronotherapy with TMZ is feasible. A trend of worsening lymphocyte counts is noted in AM treatment group compared to PM group but was not statistically significant. No difference in OS or PFS was noted, although sample size was too small to effectively assess this. A larger study will need to be conducted to effectively assess the effect of chronotherapy on survival. Clinical trial information: NCT02781792.

Differential roles of pyramidal and fast-spiking, GABAergic neurons in the control of glioma cell proliferation

Recent studies have demonstrated an active role for neurons in glioma progression. Specifically, peritumoral neurons establish functional excitatory synapses with glioma cells, and optogenetic stimulation of cortical pyramidal neurons drives tumor progression. However, the specific role of different subsets of cortical neurons, such as GABAergic interneurons, remains unexplored. Here, we directly compared the effects of optogenetic stimulation of pyramidal cells vs. fast-spiking, GABAergic neurons. In mice inoculated with GL261 cells into the motor cortex, we show that optogenetic stimulation of pyramidal neurons enhances glioma cell proliferation. In contrast, optogenetic stimulation of fast-spiking, parvalbumin-positive interneurons reduces proliferation as measured by BrdU incorporation and Ki67 immunolabelling. Since both principal cells and fast-spiking interneurons are directly activated by sensory afferent input, we next placed tumors in the occipital cortex to test the impact of visual stimulation/deprivation. We report that total lack of visual input via dark rearing enhances the density of proliferating glioma cells, while daily visual stimulation by gratings of different spatial frequencies and contrast reduces tumor growth. The effects of sensory input are region-specific, as visual deprivation has no significant effect on tumor proliferation in mice with gliomas in the motor cortex. We also report that sensory stimulation combined with temozolomide administration delays the loss of visual responses in peritumoral neurons. Altogether, these data demonstrate complex effects of different neuronal subtypes in the control of glioma proliferation.

Entry and exit of chemotherapeutically-promoted cellular dormancy in glioblastoma cells is differentially affected by the chemokines CXCL12, CXCL16, and CX3CL1

Glioblastoma multiforme (GBM) is a malignant brain tumor that evades therapy regimens. Since cellular dormancy is one strategy for surviving, and since chemokines determine the environmental conditions in which dormancy occurs, we investigated how chemokines affect temozolomide (TMZ)-promoted cellular dormancy entry and exit in GBM cells. TMZ administration over ten days promoted cellular dormancy entry, whereas discontinuing TMZ for a further 15 days resulted in resumption of proliferation. Co-administration of a chemokine cocktail containing CXCL12, CXCL16, and CX3CL1 resulted in both delayed entry and exit from cellular dormancy. A microarray-based transcriptome analysis in LN229 GBM cells revealed that cellular dormancy entry was characterized by an increased expression of CCL2 and SAA2, while THSD4, FSTL3, and VEGFC were upregulated during dormancy exit. Co-stimulation with the chemokine cocktail reduced upregulation of identified genes. After verifying the appearance of identified genes in human GBM primary cultures and ex vivo samples, we clarified whether each chemokine alone impacts cellular dormancy mechanisms using specific antagonists and selective CRISPR/Cas9 clones. While expression of CCL2 and SAA2 in LN229 cells was altered by the CXCL12-CXCR4-CXCR7 axis, CXCL16 and CX3CL1 contributed to reduced upregulation of THSD4 and, to a weaker extent, of VEGFC. The influence on FSTL3 expression depended on the entire chemokine cocktail. Effects of chemokines on dormancy entry and exit-associated genes were detectable in human GBM primary cells, too, even if in a more complex, cell-specific manner. Thus, chemokines play a significant role in the regulation of TMZ-promoted cellular dormancy in GBMs.

Reinforcement learning for optimal scheduling of Glioblastoma treatment with Temozolomide

Background: Glioblastoma multiforme (GBM) is the most frequent primary brain tumor in adults and Temozolomide (TMZ) is an effective chemotherapeutic agent for its treatment. In Silico models of GBM growth provide an appropriate foundation for analysis and comparison of different regimens. We propose a mathematical frame for patient specific design of optimal chemotherapy regimens for GBM patients. Methods: The proposed frame includes online interaction of a virtual GBM with an optimizing agent. Spatiotemporal dynamics of GBM growth and its response to TMZ are simulated with a three dimensional hybrid cellular automaton. Q learning is tailored to the virtual GBM for treatment optimization aimed at minimizing tumor size at the end of treatment course. Q learning consists of a learning agent that interacts with the virtual GBM. System state is affected by the agent decisions and the obtained rewards guide Q learning to the optimal schedule. Results: Computational results confirm that the optimal chemotherapy schedule depends on some patient specific parameters including body weight, tumor size and its position in the brain. Furthermore, the algorithm is used for scheduling 2100 mg of TMZ on a virtual GBM and the obtained schedule is to administer150 mg of TMZ every other day. The obtained schedule is compared to the standard 7/14 regimen and the results show that it is superior to the 7/14 regimen in minimizing tumor size. Conclusion: The proposed frame is an appropriate decision support system for patient specific design of TMZ administration regimens on GBM patients. Also, since the obtained optimal schedule outperforms the standard 7/14 regimen, it is worthy of further clinical testing.

Temozolomide therapy for aggressive pituitary tumours - current understanding and future perspectives.

The use of temozolomide (TMZ) for the management of aggressive pituitary tumours (APT) has revolutionised clinical practice in this field with significantly improved clinical outcomes and long-term survival. Its use is now well established however a large number of patients do not respond to treatment and recurrence after cessation of TMZ is common. A number of challenges remain for clinicians such as appropriate patient selection, treatment duration and the role of combination therapy. This review will examine the use of TMZ to treat APT including mechanism of action, treatment regimen and duration; biomarkers predicting response to treatment and patient selection; and current evidence for administration of TMZ in combination with other agents.

Survival analysis of patients with glioblastoma treated by long-term administration of temozolomide.

This analysis aimed to investigate whether the long-term administration of temozolomide (TMZ) claimed a survival advantage for patients with glioblastoma in China.A total of 75 patients with newly diagnosed glioblastoma at the Department of Radiation Oncology, Shenzhen People's Hospital between August 2008 and August 2016 were retrospectively evaluated during analysis. A propensity-matched analysis was performed to balance the basic characteristics of patients between compared groups. Kaplan–Meier method and Cox proportional hazards model were used to assess progression-free survival (PFS) and overall survival (OS) of patients receiving 6 adjuvant TMZ cycles compared with patients treated with more than 6 cycles.Twenty of 75 patients received more than 6 cycles of TMZ, and the other 55 patients were treated with a median of 6 cycles ranging from 1 to 6. The patients with long-term administration of TMZ had better OS (47.0 months, 95% CI 20.0–73.9 vs 20.6 months, 95% CI 17.9–23.2, P = .014) but not PFS (17.0 months, 95% CI 10.1–24.5 vs 14.2 months, 95% CI 11.8–16.6, P = .133). Balancing the clinical factors with a propensity-matched analysis also showed the significant advantage of prolonged TMZ application in terms of OS but not PFS.Prolonged administration of TMZ beyond 6 cycles did demonstrate survival benefits for patients with initially diagnosed glioblastoma.

Molecular Aberrations Associated with Seizure Control in Diffuse Astrocytic and Oligodendroglial Tumors.

Diffuse astrocytic and oligodendroglial tumors are frequently associated with symptomatic epilepsy, and predictive seizure control is important for the improvement of patient quality of life. To elucidate the factors related to drug resistance of brain tumor-associated epilepsy from a pathological perspective. From January 2012 to October 2017, 36 patients diagnosed with diffuse astrocytic or oligodendroglial tumors were included. Assessment for seizure control was performed according to the Engel classification of seizures. Patient clinical, radiological, and pathological data were stratified based on the following 16 variables: age, sex, location of tumor, existence of the preoperative seizure, extent of resection, administration of temozolomide, radiation therapy, recurrence, Karnofsky performance scale, isocitrate dehydrogenase 1, 1p/19q co-deletion, Olig2, platelet-derived growth factor receptor alpha, p53, ATRX, and Ki67. These factors were compared between the well-controlled group and drug-resistant seizure group. Twenty-seven patients experienced seizures; of these, 14 cases were well-controlled, and 13 cases were drug-resistant. Neither clinical nor radiological characteristics were significantly different between these two groups, though p53 immunodetection levels were significantly higher, and the frequency of 1p/19q co-deletion was significantly lower in the group with drug-resistant seizures than in the well-controlled group. In the multivariate analysis, only one item was selected according to stepwise methods, and a significant difference was observed for p53 (OR, 21.600; 95% CI, 2.135–218.579; P = 0.009). Upregulation of p53 may be a molecular mechanism underlying drug resistant epilepsy associated with diffuse astrocytic and oligodendroglial tumors.

COT-06 HBV REACTIVATION DURING AND AFTER THE TREATMENT OF MALIGNANT GLIOMA WITH TEMOZOLOMIDE

BACKGROUNDIt has been reported that temozolomide treatment for malignant glioma can lead to the reactivation of Hepatitis B virus (HBV) and fulminant hepatitis. However, the frequency of HBV reactivation and the preventative effect of entecavir remains unclear. In this study, we retrospectively reviewed clinical features of the cases treated by temozolomide for malignant glioma, focusing on the reactivation of HBV and the effect of entecavir.METHODSWe screened 129 cases with newly diagnosed and recurrent malignant glioma for HBs antigen, HBs antibody and HBc antibody before the administration of temozolomide. HBV-DNA were quantified by real-time PCR in the HBV carrier and the cases with occult HBV infection. HBV- DNA were monitored every 1–3 months by real-time PCR during temozolomide treatment and 12 months after completion of temozolomide. Entecavir were started before temozolomide treatment to the HB carrier, and if HBV-DNA became detectable at follow-up to the cases with occult HBV infection. Results 2 (1.5%) and 20 (15%) of 129 cases were HB carrier and had occult HBV infection, respectively. HBV- DNA in both of HB carrier turned negative after administration of entecavir, but transiently turned positive again during temozolomide treatment. In the cases with occult HBV infection, 4 (20%) patients had HBV reactivation. HBV- DNA turned negative after starting entecavir without liver dysfunction.CONCLUSIONHBV carrier and the cases with occult HBV infection were not rare in Japan, and HBV reactivation developed frequently during temozolomide treatment. Because pharmacological prevention of HBV reactivation with entecavir was effective, the screening and monitoring is indispensable in the treatment of malignant glioma with temozolomide.

Drug loading and the efficiency of nanodiamond-anticancer drug complexes in cancer treatment

We retrospectively investigated the prognostic impact of molecular phenotypes in patients with recurrent anaplastic glioma treated with prolonged administration of temozolomide (TMZ). Malignant gliomas have a dismal prognosis despite the available multimodal treatments. We reviewed 87 patients who were diagnosed with recurrent anaplastic gliomas between March 2004 and June 2010, and 58 were enrolled for analysis. In the cohort, 21 patients had anaplastic oligodendrogliomas, 18 anaplastic oligoastrocytomas and 19 anaplastic astrocytomas. All patients were initially treated with surgical resection or biopsy followed by involved-field radiotherapy. At recurrence, patients were treated with 150–200 mg/m2 of TMZ on days 1–5 in 28 day cycles until disease progression. We evaluated the association of molecular phenotypes, including 1p19q deletion, O6-methylguanine DNA methyltransferase (MGMT) promoter methylation status, isocitrate dehydrogenase-1 (IDH1) mutation and other clinico-histopathological findings with treatment outcome. During the mean follow-up period of 34.6 months, 33 patients were still alive (56.9%). Median survival from recurrence was 39.7 months (95% confidence interval [CI] 22.7–56.7). Time to progression from administration of TMZ was 6.4 months (95% CI 5.0–7.8). Univariate analysis demonstrated that the presence of the IDH1 mutation was closely associated with treatment response (8.4 versus 3.8 months; p = 0.015). Oligodendroglial lineage, 1p19q deletion status and MGMT promoter methylation status were not independent variables for determining the TMZ treatment outcome. In recurrent anaplastic gliomas, TMZ treatment is an effective modality regardless of MGMT methylation status or histological type. The IDH1 mutation has the most powerful prognostic impact on overall patient survival.

A Drug‐Eluting 3D‐Printed Mesh (GlioMesh) for Management of Glioblastoma

AbstractCurrent treatment strategies for Glioblastoma (GBM)—including surgery, radiotherapy, and chemotherapy with oral administration of temozolomide (TMZ)—still lead to poor survival rates, making the development of more effective therapeutic methods an urgent need. This study presents a new approach for the treatment of GBM patients using a 3D‐printed hydrogel‐based mesh (GlioMesh), loaded with TMZ‐releasing microparticles, that is capable of delivering TMZ over several weeks at the tumor site. Given the challenges associated with loading the amphiphilic TMZ in polymeric substrates, a novel encapsulation strategy is developed using an oil‐in‐oil emulsion method that improves the encapsulation efficiencies of TMZ in poly(lactic‐co‐glycolic acid) (PLGA) from <7% to about 61%. The cytotoxic effects of GlioMesh on GBM cells are evaluated in vitro by investigating the resultant levels of DNA break, autophagic activity, and mitochondrial damage. It is shown that GlioMesh produces significantly higher susceptibility to the drug in comparison with free TMZ by maintaining the level of autophagic activity and inducing larger degrees of mitochondrial damage. Sustained delivery of TMZ holds promise for suppressing chemoresistance to TMZ that is normally developed in GBM cells in systemic administration of the drug due to the induction of autophagy.

MGMT immunohistochemistry in pituitary tumors: controversies with clinical implications.

Temozolomide (TMZ) is currently considered as a rational therapeutic option for patients with progressively aggressive pituitary adenomas and carcinomas not responding to conventional therapies. Administration of TMZ results in clinical response and improvement in survival of many of these patients depending upon the expression of the DNA repair enzyme O-6 methylguanine DNA transferase (MGMT). Low or negative MGMT immunoreactivity predicts responsiveness to TMZ therapy. Therefore, MGMT serves as a criterion to select candidate patients anticipating response to treatment. The MGMT expression was investigated in 25 pituitary adenomas with Ki-67 labeling index more that 3% and p53 expression, using various antigen retrieval protocols. After direct application of the antibody, only one adenoma yielded positive for MGMT. However, after pretreatment of tissue sections with antigen retrieval protocols, another 3 adenomas, initially negative turned to positive. These findings could explain lack of response to TMZ treatment in patients with false negative MGMT immunohistochemistry. Evaluation of tumor samples for MGMT expression should carefully be carried-out using the optimum immunohistochemical protocol to obtain consistent and reliable results that help to identify patients that could respond to TMZ therapy.

Evaluate the Safety and Effectiveness of Intranasal Administration of Temozolomide in Patients With Glioblastoma

Evaluate the Safety and Effectiveness of Intranasal Administration of Temozolomide in Patients With Glioblastoma

Temozolomide has anti-tumor effects through the phosphorylation of cPLA2 on glioblastoma cells

Temozolomide is an alkylating agent used as the first line of treatment for glioblastoma. However, chemoresistance to temozolomide is common in glioma patients. In addition, there are likely many unknown mechanisms for the anti-tumor effects of temozolomide. It is known that an alkylating agent, sulfur mustard, activates cytosolic phospholipase A2 (cPLA₂) releasing arachidonic acid to suppress tumors. The present study was performed to elucidate the involvement of cPLA2 in the anti-tumor mechanisms of temozolomide.In three glioblastoma cell lines (GL261, U251MG and T98G), we performed several evaluations including cell viability, cell migration and apoptosis, to study temozolomide-induced anti-tumor effects. Further, we evaluated tumor size in the murine orthotropic glioblastoma model after oral administration of temozolomide. Finally, we investigated the phosphorylation of cPLA2 in GL261 cells treated with temozolomide, and clarified whether phosphorylation of cPLA2 affects cell growth.Temozolomide suppressed cell growth and cell migration in glioblastoma cells in vitro and showed anti-tumor effect in the murine orthotopic glioblastoma model in vivo. Furthermore, temozolomide increased phosphorylation of cPLA2, which was associated with suppression of cell growth. However, in MGMT high-expressing glioblastoma T98G cells, temozolomide could not suppress cell growth or cause phosphorylation of cPLA2.These findings indicate that temozolomide suppressed cell growth partly by phosphorylation of cPLA2 in glioblastoma cells. In addition, because temozolomide did not cause phosphorylation of cPLA2 in MGMT high-expressing glioblastoma T98G cells, phosphorylation of cPLA2 may be caused by DNA alkylation of temozolomide.

Personalized oncology with artificial intelligence: The case of temozolomide.

Using artificial intelligence techniques, we compute optimal personalized protocols for temozolomide administration in a population of patients with variability. Our optimizations are based on a Pharmacokinetics/Pharmacodynamics (PK/PD) model with population variability for temozolomide, inspired by Faivre et al. [10] and Panetta et al. [25,26]. The patient pharmacokinetic parameters can only be partially observed at admission and are progressively learned by Bayesian inference during treatment. For every patient, we seek to minimize tumor size while avoiding severe toxicity, i.e. maintaining an acceptable toxicity level. The optimization algorithm we rely on borrows from the field of artificial intelligence. Optimal personalized protocols (OPP) achieve a sizable decrease in tumor size at the population level but also patient-wise. The tumor size is on average 67.2 g lighter than with the standard maximum-tolerated dose protocol (MTD) after 336 days (12 MTD cycles). The corresponding 90% confidence interval for average tumor size reduction amounts to 58.6-82.7 g. When treated with OPP, less patients experience severe toxicity in comparison to MTD. We quantify in-silico the benefits offered by personalized oncology in the case of temozolomide administration. To do so, we compute optimal personalized protocols for a population of heterogeneous patients using artificial intelligence techniques. At each treatment day, the protocol is updated by taking into account the feedback obtained from patient's reaction to the drug administration. Personalized protocols greatly differ from each other, and from the standard MTD protocol. Benefits of personalization are very sizable: tumor sizes are much smaller on average and also patient-wise, while severe toxicity is made less frequent.

To treat or not to treat? A retrospective multicenter assessment of survival in patients with IDH-mutant low-grade glioma based on adjuvant treatment.

The level of evidence for adjuvant treatment of diffuse WHO grade II glioma (low-grade glioma, LGG) is low. In so-called "high-risk" patients most centers currently apply an early aggressive adjuvant treatment after surgery. The aim of this assessment was to compare progression-free survival (PFS) and overall survival (OS) in patients receiving radiation therapy (RT) alone, chemotherapy (CT) alone, or a combined/consecutive RT+CT, with patients receiving no primary adjuvant treatment after surgery. Based on a retrospective multicenter cohort of 288 patients (≥ 18 years old) with diffuse WHO grade II gliomas, a subgroup analysis of patients with a confirmed isocitrate dehydrogenase (IDH) mutation was performed. The influence of primary adjuvant treatment after surgery on PFS and OS was assessed using Kaplan-Meier estimates and multivariate Cox regression models, including age (≥ 40 years), complete tumor resection (CTR), recurrent surgery, and astrocytoma versus oligodendroglioma. One hundred forty-four patients matched the inclusion criteria. Forty patients (27.8%) received adjuvant treatment. The median follow-up duration was 6 years (95% confidence interval 4.8-6.3 years). The median overall PFS was 3.9 years and OS 16.1 years. PFS and OS were significantly longer without adjuvant treatment (p = 0.003). A significant difference in favor of no adjuvant therapy was observed even in high-risk patients (age ≥ 40 years or residual tumor, 3.9 vs 3.1 years, p = 0.025). In the multivariate model (controlled for age, CTR, oligodendroglial diagnosis, and recurrent surgery), patients who received no adjuvant therapy showed a significantly positive influence on PFS (p = 0.030) and OS (p = 0.009) compared to any other adjuvant treatment regimen. This effect was most pronounced if RT+CT was applied (p = 0.004, hazard ratio [HR] 2.7 for PFS, and p = 0.001, HR 20.2 for OS). CTR was independently associated with longer PFS (p = 0.019). Age ≥ 40 years, histopathological diagnosis, and recurrence did not achieve statistical significance. In this series of IDH-mutated LGGs, adjuvant treatment with RT, CT with temozolomide (TMZ), or the combination of both showed no significant advantage in terms of PFS and OS. Even in high-risk patients, the authors observed a similar significantly negative impact of adjuvant treatment on PFS and OS. These results underscore the importance of a CTR in LGG. Whether patients ≥ 40 years old should receive adjuvant treatment despite a CTR should be a matter of debate. A potential tumor dedifferentiation by administration of early TMZ, RT, or RT+CT in IDH-mutated LGG should be considered. However, these data are limited by the retrospective study design and the potentially heterogeneous indication for adjuvant treatment.

Impact of extremely low-frequency electromagnetic field (100 Hz, 100 G) exposure on human glioblastoma U87 cells during Temozolomide administration

ABSTRACTGlioblastoma multiforme (GBM) is a highly malignant brain tumor with an extremely dismal prognosis, a median survival is12 months. Temozolomide (TMZ) is an alkylating agent widely used to treat cancer, resistance to this drug is often found. One unexplored possibility for overcoming this resistance is a treatment based on concomitant exposure to electromagnetic fields (EMF) and TMZ. Indeed, many evidences show that EMF affects cancer cells and drug performance. Therefore, the present study was carried out to evaluate the potential synergistic effect of 100 µM TMZ and EMF (100 Hz, 100 G) on human glioma cell line U87 U87 cells with four experimental groups (I–IV) were exposed to ELF-EMF and TMZ for 120 and 144 h, as follows: (I) control; (II) ELF-EMF; (III) TMZ; (IV) ELF-PEMFs / TMZ. mRNA expression of genes such as (Nestin,CD133, Notch4 and GFAP) were investigated by Real-time PCR and western blot. We also evaluated, SOD activity, MDA and calcium concentration by ELISA assay. Co-treatment synergistically decreased the expression of Nestin,CD133, and Notch4 and increased the GFAP genes. We also observed an increase in Superoxide dismutase (SOD) activity, Malondialdehyde (MDA) and Ca2+concentration in comparison to controls.TMZ prevents cancer progression not only through the induction of cell death, but also by inducing differentiation in cancer cells. In addition, our data demonstrate ELF-EMF (100 Hz, 100 G) can significantly enhance the effects of TMZ on human glioblastoma U87 cell. These findings may open new window for future studies.

Effect of temozolomide on neurogenesis and anxiety in the adult mouse brain.

e23082 Background: The hippocampus is one of two regions in the adult brain where new neurons are generated well into adulthood. Newborn neurons develop from neural stem cells, and are consequently integrated into the hippocampal circuitry to function in learning and memory. Temozolomide (TMZ) is a commonly used alkylating agent for treatment of malignant gliomas. In this study, we examine the effects of TMZ on adult neurogenesis and cognitive function in the murine model. Methods: Adult male mice (8-week-old) were injected daily with TMZ (25 mg/kg, i.p.) for 2, 2.5 and 3.5 weeks to estimate progenitor proliferation, neuronal maturation and animal behavior respectively. For progenitor proliferation, a single dose of BrdU (50mg/kg, i.p.) was injected at 2 weeks and the mice sacrificed 2 hours later. For maturation analysis, five separate doses of EdU (41.1 mg/kg, i.p.) were injected over five days starting at 2 weeks. Three weeks after first EdU injection mice were sacrificed. Both BrdU and EdU are novel thymidine analogues that label dividing cells. Immunostaining was performed on hippocampal brain slices to label progenitors at different stages of development. For behavioral analysis, daily tests measuring anxiety, memory and motor activity were started at 2 weeks into TMZ administration. Results: TMZ significantly reduced the resident radial glia-like and non-radial glia-like population (MCM2+Nestin+), as well as the overall proliferating progenitor pool (n = 2, p < 0.05). In addition, it significantly reduced the population of Type-3 neuroblasts (EdU+DCX+NeuN-) (n = 4, p < 0.05). During neuronal maturation, immature new neurons (EdU+DCX+NeuN+) and mature new neurons (EdU+DCX-NeuN+) were also reduced by TMZ (n = 4, p < 0.05). These effects of TMZ coincided with specific behavioral deficits. While TMZ had no effect on working memory and locomotor activity, mice that underwent TMZ administration showed significantly increased anxiety on the open field test (n = 7, p < 0.05). Conclusions: Our findings demonstrate TMZ significantly impairs cellular proliferation of neural stem cells and fate-committed neuroblasts, and increases anxiety with sparing of non-hippocampal-dependent memory. TMZ may thus be associated with specific deficits in hippocampal function in the adult brain, providing mechanistic insight into adverse effects that may be observed with TMZ treatment.

Targeting NFE2L2, a transcription factor upstream of MMP-2: A potential therapeutic strategy for temozolomide resistant glioblastoma

Glioblastoma (GBM) is the most malignant form of brain tumor posing a major threat to cancer amelioration. Temozolomide (TMZ) resistance is one of the major hurdles towards GBM prognosis. Oxidative stress and ECM remodeling are the two important processes involved in gaining chemo-resistance. Here, we established NFE2L2, an important member of oxidative stress regulation elevated in resistant cells, to be playing a transcriptional regulatory role on MMP-2, an ECM remodeling marker. This link led us to further explore targeted molecules to inhibit NFE2L2, thus affecting MMP-2, an important member promoting chemo-resistance. Thus, diosgenin was proposed as a novel NFE2L2 inhibitor acting as an alternative strategy to prevent the high dose administration of TMZ. Combinatorial therapy of diosgenin and TMZ significantly reduced the dosage regimen of TMZ and also showed affectivity in hitherto TMZ resistant GBM cells. GBM cells underwent apoptosis and early cell cycle arrest with significant reduction in MMP-2 levels. Thus preclinical validation of molecular interaction between diosgenin and NFE2L2 down-regulating MMP-2, EMT markers and promoting apoptosis, offers rationale for new therapeutic horizons in the field of glioblastoma management.