Higher Human Cytomegalovirus (HCMV) Specific IgG Antibody Levels in Plasma Samples from Patients with Metastatic Brain Tumors Are Associated with Longer Survival.

Background: Human cytomegalovirus (HCMV) has been detected in tissue samples from patients with glioblastoma but little is known about the systemic immunological response to HCMV in these patients. Objectives: To investigate the presence and clinical significance of HCMV antibodies levels in plasma samples obtained from patients with brain tumors. Materials and Methods: HCMV-specific IgG and IgM antibody levels were determined in 59 plasma samples collected from brain tumor patients included in a prospective study and in 114 healthy individuals. We examined if the levels of HCMV specific antibodies varied in patients with different brain tumor diagnoses compared to healthy individuals, and if antibody levels were predictive for survival time. Results: HCMV specific IgG antibodies were detected by ELISA in 80% and 89% of patients with GBM and astrocytoma grades II-III, respectively, in all samples (100%) from patients with secondary GBM and brain metastases, as well as in 80% of healthy donors (n = 114). All plasma samples were negative for HCMV-IgM. Patients with brain metastases who had higher plasma HCMV-IgG titers had longer survival times (p = 0.03). Conclusions: HCMV specific IgG titers were higher among all brain tumor patient groups compared with healthy donors, except for patients with secondary GBM. Higher HCMV specific IgG levels in patients with brain metastases but not in patients with primary brain tumors were associated with prolonged survival time.

Epstein-Barr virus- and cytomegalovirus-specific immune response in patients with brain cancer.

BACKGROUND: Patients with brain tumor or pancreatic cancer exhibit the poorest prognosis, while immune fitness and cellular immune exhaustion impacts their survival immensely. This work identifies differences in the immune reactivity to the common human pathogens cytomegalovirus (CMV) and Epstein-Barr virus (EBV) between patients with brain tumor in comparison to those with pancreatic cancer and healthy individuals. METHODS: We characterized the humoral and cellular immune responses of patients with brain tumor or pancreatic cancer to cytomegalovirus structural protein pp65 (CMV-pp65) as well as Epstein-Barr nuclear antigen-1 (EBNA-1) by whole-blood assay and ELISA. RESULTS: Anti-CMV-pp65 plasma immunoglobulin gamma (IgG) titers were significantly lower in patients with brain tumor compared to healthy donors and patients with pancreatic cancer. Among the responding patients with GBM, those with a weak anti-CMV IgG response also had a decreased median overall survival (p = 0.017, 667 vs 419 days) while patients with brain tumor showed a generally suppressed anti-CMV immune-reactivity. Patients with brain tumor exhibited a significantly lower interferon gamma (IFNγ) response to EBNA-1 and CMV-pp65 compared to patients with pancreatic cancer or healthy donors. This antigen-specific response was further amplified in patients with brain tumor upon conditioning of whole blood with IL-2/IL-15/IL-21. Exclusively in this setting, among the responding patients with GBM, those exhibiting a EBV-specific cellular immune response above the median also displayed an increased median overall survival pattern compared to weak responders (753 vs 370 days, p < 0.001). CONCLUSIONS: This report provides (i) a fast and easy assay using common viral antigens and cytokine stimulation to screen for immune fitness/exhaustion of patients with brain tumor in comparison to pancreatic cancer and healthy individuals and (ii) EBV/CMV-induced IFNγ production as a potential marker of survival in patients with brain tumor.

Post-craniotomy neuronavigation based purely on intraoperative ultrasound imaging without preoperative neuronavigational planning.

Neuronavigation has become an established technology which provides objective data for localization in 3D space and thus decreases uncertainties regarding tumor localization, relation to vasculature, safe trajectories, and craniotomy design during surgery. We have evaluated whether neuronavigation based purely on 3D ultrasound without any preoperative navigational imaging can provide necessary information for navigation and resection control. This application is a new way of utilizing ultrasound-guided neuronavigation. Eighteen patients were operated on with ultrasound-based navigation only; they represented 16% of all the 131 navigation-assisted procedures during our 1-year study period. Of the procedures, 2 were planned as diagnostic biopsies, 1 was resection of an abscess, and 15 were tumor resections. Pre- and postoperative radiological images were evaluated to assess volumes and volume reduction following surgery. Pathology results were recorded. For patients undergoing resections, the resection radicality was >99% in 12 patients and 95-99% in 4 patients undergoing resections. In the latter patients, additional radicality was avoided intentionally because of concern for sensitive central structures. The two biopsies yielded representative material. It was possible to use operative neuronavigation based on intraoperative ultrasound without relying on preoperative navigational imaging. Neuronavigation based solely on intraoperative ultrasound was feasible and may increase surgical safety when preoperative neuronavigational image is not feasible or unavailable.

Presence of the Human Cytomegalovirus in Glioblastomas-A Systematic Review.

Glioblastoma is a malignant brain tumor with a dismal prognosis. The standard treatment has not changed in the past 15 years as clinical trials of new treatment protocols have failed. A high prevalence of the human cytomegalovirus (HCMV) in glioblastomas was first reported in 2002. The virus was found only in the tumor and not in the surrounding healthy brain tissue. Many groups have confirmed the presence of the HCMV in glioblastomas, but others could not. To resolve this discrepancy, we systematically reviewed 645 articles identified in different databases. Of these, 81 studies included results from 247 analyses of 9444 clinical samples (7024 tumor samples and 2420 blood samples) by different techniques, and 81 articles included 191 studies that identified the HCMV in 2529 tumor samples (36% of all tumor samples). HCMV proteins were often detected, whereas HCMV nucleic acids were not reliably detected by PCR methods. Optimized immunohistochemical techniques identified the virus in 1391 (84,2%) of 1653 samples. These data suggest that the HCMV is highly prevalent in glioblastomas and that optimized immunohistochemistry techniques are required to detect it.