Use of metformin and outcome of patients with newly diagnosed glioblastoma: Pooled analysis

Metformin has been linked to improve survival of patients with various cancers. There is little information on survival of glioblastoma patients after use of metformin. We assessed the association between metformin use and survival in a pooled analysis of patient data from 1,731 individuals from the randomized AVAglio, CENTRIC and CORE trials. We performed multivariate Cox analyses for overall survival (OS) and progression-free survival (PFS) comparing patients' use of metformin at baseline and/or during concomitant radiochemotherapy (TMZ/RT). Further exploratory analyses investigated the effect of metformin with a history of diabetes and nonfasting glucose levels in relation to OS or PFS of glioblastoma patients. Metformin alone or in any combination was not significantly associated with OS or PFS (at baseline, hazard ratio [HR] for OS = 0.87; 95% confidence interval [CI] = 0.65-1.16; HR for PFS = 0.84; 95% CI = 0.64-1.10; during TMZ/RT HR for OS = 0.97; 95% CI = 0.68-1.38; HR for PFS = 1.02; 95% CI = 0.74-1.41). We found a statistically nonsignificant association of metformin monotherapy with glioblastoma survival at baseline (HR for OS = 0.68; 95% CI = 0.42-1.10; HR for PFS = 0.57; 95% CI = 0.36-0.91), but not during the TMZ/RT period (HR for OS = 0.90; 95% CI = 0.51-1.56; HR for PFS = 1.05; 95% CI = 0.64-1.73). Diabetes mellitus or increased nonfasting glucose levels were not associated with a difference in OS or PFS in our selected study population. Metformin did not prolong survival of patients with newly diagnosed glioblastoma in our analysis. Additional studies may identify patients with specific tumor characteristics that are associated with potential benefit from treatment with metformin, possibly due to metabolic vulnerabilities

Targeting integrins in malignant glioma

The integrin family of cell adhesion receptors is emerging as a promising target of anticancer therapy. AlphaVbeta3 and alphaVbeta5 integrins are overexpressed on both glioma cells and tumor vasculature. Cilengitide, the most advanced specific integrin inhibitor in oncology, has shown antitumor activity against glioma in early clinical trials. Durable remissions have been observed in phase I and phase II trials for recurrent glioblastoma (GBM) with both lower and higher doses of cilengitide. Pilot trials in newly diagnosed glioblastoma in conjunction with standard chemoradiotherapy have been encouraging. Preclinical data suggest synergy with concomitant chemo- and radiation therapy. A pivotal phase III study (CENTRIC) in newly diagnosed GBM patients is currently recruiting. This paper summarizes the current understanding of the role of integrins and their inhibition in gliomagenesis. The background and design of ongoing trials are outline

Glioblastoma Mimicking Viral Encephalitis Responds to Acyclovir: A Case Series and Literature Review

Viral encephalitis and glioblastoma are both relatively rare conditions with poor prognoses. While the clinical and radiographic presentations of these diseases are often distinctly different, viral encephalitis can sometimes masquerade as glioblastoma. Rarely, glioblastoma can also be misdiagnosed as viral encephalitis. In some cases where a high-grade glioma was initially diagnosed as viral encephalitis, antiviral administration has proven effective for relieving early symptoms. We present three cases in which patients presented with symptoms and radiographic findings suggestive of viral encephalitis and experienced dramatic clinical improvement following treatment with acyclovir, only to later be diagnosed with glioblastoma in the region of suspected encephalitis and ultimately succumb to tumor progression

The ELAV RNA-stability factor HuR binds the 5′-untranslated region of the human IGF-IR transcript and differentially represses cap-dependent and IRES-mediated translation

The type I insulin-like growth factor receptor (IGF-IR) is an integral component in the control of cell proliferation, differentiation and apoptosis. The IGF-IR mRNA contains an extraordinarily long (1038 nt) 5′-untranslated region (5′-UTR), and we have characterized a diverse series of proteins interacting with this RNA sequence which may provide for intricate regulation of IGF-IR gene expression at the translational level. Here, we report the purification and identification of one of these IGF-IR 5′-UTR-binding proteins as HuR, using a novel RNA crosslinking/RNase elution strategy. Because HuR has been predominantly characterized as a 3′-UTR-binding protein, enhancing mRNA stability and generally increasing gene expression, we sought to determine whether HuR might serve a different function in the context of its binding the IGF-IR 5′-UTR. We found that HuR consistently repressed translation initiation through the IGF-IR 5′-UTR. The inhibition of translation by HuR was concentration dependent, and could be reversed in trans by addition of a fragment of the IGF-IR 5′-UTR containing the HuR binding sites as a specific competitor, or abrogated by deletion of the third RNA recognition motif of HuR. We determined that HuR repressed translation initiation through the IGF-IR 5′-UTR in cells as well, and that siRNA knockdown of HuR markedly increased IGF-IR protein levels. Interestingly, we also found that HuR potently inhibited IGF-IR translation mediated through internal ribosome entry. Kinetic assays were performed to investigate the mechanism of translation repression by HuR and the dynamic interplay between HuR and the translation apparatus. We found that HuR, occupying a cap-distal position, significantly delayed translation initiation mediated by cap-dependent scanning, but was eventually displaced from its binding site, directly or indirectly, as a consequence of ribosomal scanning. However, HuR perpetually blocked the activity of the IGF-IR IRES, apparently arresting the IRES-associated translation pre-initiation complex in an inactive state. This function of HuR as a 5′-UTR-binding protein and dual-purpose translation repressor may be critical for the precise regulation of IGF-IR expression essential to normal cellular homeostasis

Association of antidepressant drug use with outcome of patients with glioblastoma

Depressive symptoms are common among patients with glioblastoma, but patients are often not treated with antidepressants. There is only limited evidence on the association of antidepressant drug use with survival in glioblastoma. We performed a pooled analysis of patients treated within the CENTRIC, CORE, AVAglio and ACT‐IV trials to explore the relation of antidepressant drug use with progression‐free (PFS) and overall survival (OS) at baseline, at the start of maintenance therapy and at the start of maintenance cycle 4. We further assessed the association of antidepressant drugs with seizure, cognition, fatigue and a diagnosis of depression. Among more than 1700 patients, we found no significant association between the use of antidepressants at baseline or at the start of maintenance therapy and PFS or OS. However, we found OS, but not PFS, to be significantly worse in patients using antidepressants at the start of maintenance cycle 4. After adjustment for antiepileptic drug use and despite showing a trend for increased risk, seizures were not significantly associated with antidepressant drug use, nor was there a change in mini mental state examination (MMSE) scores or fatigue by antidepressant drug use at baseline. However, there was a significant positive association between antidepressant use at the start of maintenance treatment and fatigue during maintenance treatment. The association of antidepressant use at the start of maintenance cycle 4 with inferior OS of glioblastoma patients requires independent confirmation and further study. Further prospective trials should evaluate efficacy, side effects and associations with outcome of antidepressants in glioblastoma

Associations of levetiracetam use with the safety and tolerability profile of chemoradiotherapy for patients with newly diagnosed glioblastoma

Background Levetiracetam (LEV) is one of the most frequently used antiepileptic drugs (AED) for brain tumor patients with seizures. We hypothesized that toxicity of LEV and temozolomide-based chemoradiotherapy may overlap. Methods Using a pooled cohort of patients with newly diagnosed glioblastoma included in clinical trials prior to chemoradiotherapy (CENTRIC, CORE, AVAglio) or prior to maintenance therapy (ACT-IV), we tested associations of hematologic toxicity, nausea or emesis, fatigue, and psychiatric adverse events during concomitant and maintenance treatment with the use of LEV alone or with other AED versus other AED alone or in combination versus no AED use at the start of chemoradiotherapy and of maintenance treatment. Results Of 1681 and 2020 patients who started concomitant chemoradiotherapy and maintenance temozolomide, respectively, 473 and 714 patients (28.1% and 35.3%) were treated with a LEV-containing regimen, 538 and 475 patients (32.0% and 23.5%) with other AED, and 670 and 831 patients (39.9% and 41.1%) had no AED. LEV was associated with higher risk of psychiatric adverse events during concomitant treatment in univariable and multivariable analyses (RR 1.86 and 1.88, P < .001) while there were no associations with hematologic toxicity, nausea or emesis, or fatigue. LEV was associated with reduced risk of nausea or emesis during maintenance treatment in multivariable analysis (HR = 0.80, P = .017) while there were no associations with hematologic toxicity, fatigue, or psychiatric adverse events. Conclusions LEV is not associated with reduced tolerability of chemoradiotherapy in patients with glioblastoma regarding hematologic toxicity and fatigue. Antiemetic properties of LEV may be beneficial during maintenance temozolomide

MGMT Promoter Methylation Cutoff with Safety Margin for Selecting Glioblastoma Patients into Trials Omitting Temozolomide. A Pooled Analysis of Four Clinical Trials

PURPOSE The methylation status of the O6-methylguanine DNA methyltransferase (MGMT) gene promoter is predictive for benefit from temozolomide in glioblastoma. A clinically optimized cutoff was sought allowing patient selection for therapy without temozolomide, while avoiding to withhold it from patients who may potentially benefit. EXPERIMENTAL DESIGN Quantitative MGMT methylation-specific PCR data were obtained for newly diagnosed glioblastoma patients screened or treated with standard radiotherapy and temozolomide in four randomized trials. The pooled dataset was randomly split into a training and test dataset. The unsupervised cutoff was obtained at a 50% probability to be (un)methylated. Receiver operating characteristics (ROC) analysis identified an optimal cutoff supervised by overall survival (OS). RESULTS For 4041 patients valid MGMT results were obtained, whereof 1725 were randomized. The unsupervised cutoff in the training dataset was 1.27 (log2[1000x(MGMT+1)/ACTB]), separating unmethylated and methylated patients. The optimal supervised cutoff for unmethylated patients was -0.28 (AUC=0.61), classifying "truly unmethylated" (≤-0.28) and "grey zone" patients (>-0.28, ≤1.27), the latter comprising ~10% of cases. In contrast, for MGMT methylated patients (>1.27) more methylation was not related to better outcome. Both methylated and grey zone patients performed significantly better for OS than truly unmethylated patients (HR=0.35, 95% CI: 0.27-0.45, p<0.0001; HR=0.58, 95% CI: 0.43-0.78, p<0.001), validated in the test dataset. The MGMT assay was highly reproducible upon retesting of 218 paired samples (R2=0.94). CONCLUSIONS Low MGMT methylation (grey zone) may confer some sensitivity to temozolomide treatment, hence the lower safety margin should be considered for selecting unmethylated glioblastoma patients into trials omitting temozolomide