Cytomegalovirus is highly prevalent in glioblastomas. In 2006, we initiated a randomized, double-blind, placebo-controlled, hypothesis-generating study to examine the safety and potential efficacy of Valganciclovir as an add-on therapy for glioblastoma. Forty-two glioblastoma patients were randomized in double-blind fashion to receive Valganciclovir or placebo in addition to standard therapy for 6 months. Magnetic resonance images were obtained before and immediately and 3 and 6 months after surgery to evaluate treatment efficacy by measuring contrast enhancing tumor volume (primary end point). Survival data were analyzed for patients and controls in explorative analyses to aid the design of future randomized trials. Trends but no significant differences were observed in tumor volumes in Valganciclovir and placebo patients at 3 (3.58 vs. 7.44 cm 3 , respectively, p 5 0.2881) and 6 (3.31 vs. 13.75 cm 3 , p 5 0.2120) months. Median overall survival (OS) was similar in both groups (17.9 vs. 17.4 months, p 5 0.430). Patients could take Valganciclovir for compassionate use after the study phase. Explorative analyses showed an OS of 24.1 months (95% CI, 17.4-40.3) in patients receiving >6 months of Valganciclovir (Val > 6M) versus 13.1 months (95% CI, 7.9-17.7, p < 0.0001) in patients receiving Valganciclovir for 0 or <6 months, and 13.7 months (95% CI, 6.9-17.3, p 5 0.0031) in contemporary controls. OS at 4 years was 27.3% in Val>6M patients versus 5.9% in controls (p 5 0.0466). Prolonged OS in Val>6M patients suggest that future randomized trials are warranted and should evaluate whether continuous antiviral treatment can improve outcome in glioblastoma patients.Glioblastoma is the most aggressive malignant primary brain tumor and is not curable. With current standard therapy, median overall survival (OS) is <15 months. 1,2 The 2-year survival rate in patients treated with combined radiotherapy and temozolomide after maximal surgery may reach only 26.5%, 3 and 5-year survival is <10%. 1,4 New strategies Key words: cytomegalovirus, glioblastoma, valganciclovir Additional Supporting Information may be found in the online version of this article. Authors' disclosure of potential conflicts of interest: Over 4 years ago, CSN received speaker's fees and sponsored travel costs for presentations of her own research group's basic science data on the indirect molecular effects of HCMV at scientific meetings.

$These authors share senior authorship.Keywords: cytomegalovirus, glioblastoma, immunosenescence, survival, T cells Abbreviations: GBM, glioblastoma multiforme; HCMV, human cytomegalovirus; PBMC, peripheral blood mononuclear cell; Valcyte, valganciclovir; WBC, white blood cell countPatients with glioblastoma multiforme (GBM) are immunosuppressed and have a broad range of immunological defects in both innate and adaptive immune responses. GBMs are frequently infected with human cytomegalovirus (HCMV), a virus capable of causing immunosuppression. In 42 HCMV-positive GBM patients in a clinical trial (VIGAS), we investigated T-cell phenotypes in the blood and assessed their relation to survival. Blood was collected before and 3, 12, and 24 weeks after surgery, and the frequency of T-cell subsets was compared with that in 26 age-matched healthy controls. GBM patients had lower levels of CD3 cells than the controls, but had significantly higher levels of CD4 C CD28 ¡ T cells before and 3 and 12 weeks after surgery and increased levels of CD4 C CD57 C and CD4 C CD57 C CD28 C T cells at all-time points. These T-cell subsets were associated with both immunosenescence and HCMV infection. GBM patients also had higher levels of gd T cells at all-times after surgery and lower levels of CD4 C CD25 C cells before and 3 weeks after surgery than healthy controls. Overall survival was significantly shorter in patients with higher levels of CD4 C CD28 ¡ T cells (p D 0.025), CD4 C CD57 C T (p D 0.025) cells, and CD4 C CD28 ¡ CD57 C CD28 ¡ T cells (p < 0.0004) at 3 weeks after surgery. Our findings indicate that signs of immunosenescence in the CD4 C compartment are associated with poor prognosis in patients with HCMV-positive GBMs and may reflect the HCMV activity in their tumors.

Submit your article to this journal Background. Glioblastoma (GBM) is the most common malignant brain tumor in adults and is nearly always fatal. Emerging evidence suggests that human Cytomegalovirus (HCMV) is present in 90-100% of GBMs and that add-on antiviral treatment for HCMV show promise to improve survival.Methods. In a randomized, placebo-controlled trial of valganciclovir in 42 GBM patients, blood samples were collected for analyses of HCMV DNA, RNA, reactivity against HCMV peptides, IgG, and IgM at baseline and at 3, 12, and 24 weeks of treatment.Results. All 42 tumors were positive for HCMV protein. All patients examined had at least one blood sample positive for HCMV DNA, 63% were HCMV RNA positive, and 21% were IgM positive. However, 29% of GBM patients were IgG negative for HCMV. Five of these samples were positive in an enzyme-linked immunosorbent assay (ELISA) that used antigens derived from a clinical isolate. Blood T cells from 11 of 13 (85%) HCMV IgG-negative GBM patients reacted against HCMV peptides. Valganciclovir did not affect IgG titers, DNA, or RNA levels of the HCMV immediate early (HCMV IE) gene in blood.Conclusion. In GBM patients, HCMV activity is higher than in healthy controls and serology is a poor test to define previous or active HCMV infection in these patients.