EGFR as a therapeutic target in glioblastoma

The tyrosine kinase receptor epidermal growth factor receptor (EGFR) can be activated by several ligands, thus triggering downstream pathways regulating cell growth and survival. Its dysregula­tion is particularly important for the development and progression of astrocytomas. After the description of its role in glioblastomas (WHO grade IV astrocytomas), an overview on the therapeutic strategies target­ing EGFR is provided. It analyzes the past and ongoing trials concerning the small molecule tyro­sine kinase inhibitors, i.e. gefitinib, erlotinib and the combination therapies, the EGFR vaccina­tion strategies, the antibodies directed against EGFR and finally the intracranially administered EGFR-targeted therapies. As our understanding of the underlying molecular aberrancies in glioblastoma grows, our ability to better target specific subtypes of glioblastoma should improve. Molecular biomarker enriched clinical trials may lead to improved patient outcomes

Survival and complications of stereotactic radiosurgery

Background: Utilization of stereotactic radiosurgery (SRS) for treatment of high-grade gliomas (HGGs) has been slowly increasing with variable reported success rates. Objective: Systematic review of the available data to evaluate the efficacy of SRS as a treatment for HGG with regards to median overall survival (OS) and progression-free survival (PFS), in addition to ascertaining the rate of radiation necrosis and other SRS-related major neurological complications. Methods: Literature searches were performed for publications from 1992 to 2016. The pooled estimates of median PFS and median OS were calculated as a weighted estimate of population medians. Meta-analyses of published rates of radiation necrosis and other major neurological complications were also performed. Results: Twenty-nine studies reported the use of SRS for recurrent HGG, and 16 studies reported the use of SRS for newly diagnosed HGG. For recurrent HGG, the pooled estimates of median PFS and median OS were 5.42 months (3–16 months) and 20.19 months (9–65 months), respectively; the pooled radiation necrosis rate was 5.9% (0–44%); and the pooled estimates of major neurological complications rate was 3.3% (0–23%). For newly diagnosed HGG, the pooled estimates of median PFS and median OS were 7.89 months (5.5–11 months) and 16.87 months (9.5–33 months) respectively; the pooled radiation necrosis rate was 6.5% (0–33%); and the pooled estimates of other major neurological complications rate was 1.5% (0–25%). Conclusion: Our results suggest that SRS holds promise as a relatively safe treatment option for HGG. In terms of efficacy at this time, there are inadequate data to support routine utilization of SRS as the standard of care for newly diagnosed or recurrent HGG. Further studies should be pursued to define more clearly the therapeutic role of SRS

Clinical management of supratentorial non-skull sase meningiomas

Supratentorial non-skull base meningiomas are the most common primary central nervous system tumor subtype. An understanding of their pathophysiology, imaging characteristics, and clinical management options will prove of substantial value to the multi-disciplinary team which may be involved in their care. Extensive review of the broad literature on the topic is conducted. Narrowing the scope to meningiomas located in the supratentorial non-skull base anatomic location highlights nuances specific to this tumor subtype. Advances in our understanding of the natural history of the disease and how findings from both molecular pathology and neuroimaging have impacted our understanding are discussed. Clinical management and the rationale underlying specific approaches including observation, surgery, radiation, and investigational systemic therapies is covered in detail. Future directions for probable advances in the near and intermediate term are reviewed

The Coincidence Between Increasing Age, Immunosuppression, and the Incidence of Patients With Glioblastoma

Background: Glioblastoma (GBM) is the most aggressive primary brain tumor in adults and is associated with a median overall survival (mOS) of 16–21 months. Our previous work found a negative association between advanced aging and the survival benefit after treatment with immunotherapy in an experimental brain tumor model. Given the recent phase III clinical success of immunotherapy in patients with many types of cancer, but not for patients with GBM, we hypothesize that aging enhances immunosuppression in the brain and contributes to the lack of efficacy for immunotherapy to improve mOS in patients with malignant glioma. Herein, we compare epidemiological data for the incidence and mortality of patients with central nervous system (CNS) cancers, in addition to immune-related gene expression in the normal human brain, as well as peripheral blood immunological changes across the adult lifespan.Methods: Data were extracted from the National Cancer Institute’s surveillance, epidemiology, and end results (SEER)-, the Broad Institute’s Genotype Tissue Expression project (GTEx)-, and the University of California San Francisco’s 10k Immunomes-databases and analyzed for associations with aging.Results: The proportion of elderly individuals, defined as ≥65 years of age, has predominantly increased for more than 100 years in the United States. Over time, the rise in elderly United States citizens has correlated with an increased incidence and mortality rate associated with primary brain and other CNS cancer. With advanced aging, human mRNA expression for factors associated with immunoregulation including immunosuppressive indoleamine 2,3 dioxygenase 1 (IDO) and programmed death-ligand 1 (PD-L1), as well as the dendritic cell surface marker, CD11c, increase in the brain of normal human subjects, coincident with increased circulating immunosuppressive Tregs and decreased cytolytic CD8+ T cells in the peripheral blood. Strikingly, these changes are maximally pronounced in the 60–69 year old group; consistent with the median age of a diagnosis for GBM.Conclusion: These data demonstrate a significant association between normal human aging and increased immunosuppression in the circulation and CNS; particularly late in life. Our data raise several hypotheses including that, aging: (i) progressively suppresses normal immunosurveillance and thereby contributes to GBM cell initiation and/or outgrowth; (ii) decreases immunotherapeutic efficacy against malignant glioma

A randomized controlled phase III study of VB-111 combined with bevacizumab vs bevacizumab monotherapy in patients with recurrent glioblastoma (GLOBE).

BackgroundOfranergene obadenovec (VB-111) is an anticancer viral therapy that demonstrated in a phase II study a survival benefit for patients with recurrent glioblastoma (rGBM) who were primed with VB-111 monotherapy that was continued after progression with concomitant bevacizumab.MethodsThis pivotal phase III randomized, controlled trial compared the efficacy and safety of upfront combination of VB-111 and bevacizumab versus bevacizumab monotherapy. Patients were randomized 1:1 to receive VB-111 1013 viral particles every 8 weeks in combination with bevacizumab 10 mg/kg every 2 weeks (combination arm) or bevacizumab monotherapy (control arm). The primary endpoint was overall survival (OS), and secondary endpoints were objective response rate (ORR) by Response Assessment in Neuro-Oncology (RANO) criteria and progression-free survival (PFS).ResultsEnrolled were 256 patients at 57 sites. Median exposure to VB-111 was 4 months. The study did not meet its primary or secondary goals. Median OS was 6.8 versus 7.9 months in the combination versus control arm (hazard ratio, 1.20; 95% CI: 0.91-1.59; P = 0.19) and ORR was 27.3% versus 21.9% (P = 0.26). A higher rate of grades 3-5 adverse events was reported in the combination arm (67% vs 40%), mainly attributed to a higher rate of CNS and flu-like/fever events. Trends for improved survival with combination treatment were seen in the subgroup of patients with smaller tumors and in patients who had a posttreatment febrile reaction.ConclusionsIn this study, upfront concomitant administration of VB-111 and bevacizumab failed to improve outcomes in rGBM. Change of treatment regimen, with the lack of VB-111 monotherapy priming, may explain the differences from the favorable phase II results.Clinical trials registrationNCT02511405

Central nervous system blastomycosis presenting as a year-long chronic headache

This case describes a posterior fossa mass due to blastomycotic infection in a non-immunocompromised 41-year-old male presenting with a chronic headache for over one year. Given the risk of herniation, no lumbar puncture could be performed. A full work-up found no evidence of systemic infection. Surgical resection helped identify the mass as a blastomycotic abscess. Magnetic resonance imaging characteristics of the mass were helpful in the identification of the mass as a fungal abscess