Quantitative evaluation of white matter tract DTI parameter changes in gliomas using nonlinear registration.

Diffusion tensor imaging (DTI) has been used extensively to investigate white matter architecture in the brain. In the context of neurological disease, quantification of DTI data sets enables objective characterisation of the associated pathological changes. The aim of this study is to propose a method of evaluating DTI parameter changes in gliomas in the internal capsule using nonlinear registration to delineate the white matter and enable quantitative assessment of DTI derived parameters. 20 patients selected pre-operatively with probable grade 2 or grade 3 glioma on structural MRI along with ten normal volunteers were included in this study. DTI fractional anisotropy (FA) maps were used to define a common segmented FA skeleton that was projected back onto the original individual FA maps. Objective segment classification as normal or abnormal was achieved by comparison to prediction intervals of FA and mean diffusivity (MD) defined in normal subjects. The internal capsules of each patient were segmented into 10 regions of interest (ROI) with 20 and 16 segments across the group having significantly increased or decreased FA and MD values respectively. Seven glioma patients had abnormal DTI parameters in the internal capsule. We show that the classification of tract segments was consistent with disruption, oedema or compression. The results suggest that this method could be used to detect changes in eloquent white matter tracts in individual patients.

Imaging biomarkers of angiogenesis and the microvascular environment in cerebral tumours.

Conventional contrast-enhanced CT and MRI are now in routine clinical use for the diagnosis, treatment and monitoring of diseases in the brain. The presence of contrast enhancement is a proxy for the pathological changes that occur in the normally highly regulated brain vasculature and blood-brain barrier. With recognition of the limitations of these techniques, and a greater appreciation for the nuanced mechanisms of microvascular change in a variety of pathological processes, novel techniques are under investigation for their utility in further interrogating the microvasculature of the brain. This is particularly important in tumours, where the reliance on angiogenesis (new vessel formation) is crucial for tumour growth, and the resulting microvascular configuration and derangement has profound implications for diagnosis, treatment and monitoring. In addition, novel therapeutic approaches that seek to directly modify the microvasculature require more sensitive and specific biological markers of baseline tumour behaviour and response. The currently used imaging biomarkers of angiogenesis and brain tumour microvascular environment are reviewed.

Diffuse brainstem gliomas in children: should we or shouldn't we biopsy?

The decision to biopsy diffuse pontine gliomas in children remains controversial. There have been many publications over the last 30 years aiming to address this issue. The prognosis for these patients remains extremely poor regardless of treatment and many authors advocate that biopsy carries significant risk for little or no clinical benefit. However, with an increasing knowledge of tumour biology and genetics there is the potential for specific treatments tailored for individual tumours based on their biological or genetic characteristics. The progress of such science in the first instance requires histological diagnosis as part of well conducted clinical trials, then, when treatments have been developed, biopsy samples will be needed to identify the tumours that may respond to such treatments. The authors believe that there is an increasing need for performing a biopsy of these lesions.

Lymphoma in cotton-top marmosets after inoculation with Epstein-Barr virus: tumor incidence, histologic spectrum antibody responses, demonstration of viral DNA, and characterization of viruses.

6 of 20 cotton-top tamarins (Saguinus oedipus) inoculated with Epstein-Barr virus (EBV) developed diffuse malignant lymphoma resembling reticulum cell or immunoblastic sarcoma of man. Hyperplastic lymphoreticular lesions were induced in three additional animals; in two instances the hyperplastic lesions regressed. Inapparent infection with development of antibody occured in eight animals. In two animals there was no evidence of EBV infection. One animal died in the first week after inoculation of parasitic infection. 10 animals uninoculated or mock-inoculated developed neither lymphoproliferative disease nor antibody. The malignant lymphoma appeared to arise from a cell with an uncleaved vesicular nucleus found in the center of the germinal follicle. The prominent cytologic features of this cell were extensive formation or rough endoplasmic reticulum and elaboration of the cytoplasmic membrane with microvilli. Cell lines derived from these tumors did not have receptors for complement. IgFc, or sheep erythrocytes, and the cell lines adhered to glass and plastic. EB nuclear antigen was found in imprints of two lymph nodes, one with lymphoma and one with hyperplasia. EB virus DNA was detected directly in the tumors of three animals and in cell lines from two lymphomas. Typical herpes virus particles were found in supernatant fluids from cell lines obtained from lymph nodes with tumors and hyperplasia, as well as in lines derived from blood leukocytes of marmosets with inapparent infection. These virus preparations had the biologic property characteristic of EBV, namely, stimulation of cellular DNA synthesis and immortalization of human lymphocytes. The virus derived from two cell lines was neutralized by reference human sera with EBV antibody and not by antibody-negative human sera. The virus derived from the experimental lesions is thus indistinghishable from human EBV. The marmoset has enhanced susceptibility to oncogenesis by EB virus. Among identified factors which may play a role in the heightened tumorigenicity of EB virus in this species are the increased production of virus by transformed cells and the absence of membrane receptors for complement or IgFc on transformed cells.

Biological properties and viral surface antigens of Burkitt lymphoma- and mononucleosis- derived strains of Epstein-Barr virus released from transformed marmoset cells.

Three strains of Epstein-Barr virus (EBV), two from Burkitt lymphoma (BL) and one from infectious mononucleosis (IM) were used to transform separate cultures of the same batch of primary marmoset leukocytes, and the viruses released from the transformants were compared. The three viruses shared properties of the transforming biotype of EBV, namely, stimulation of DNA synthesis and immortalization of cord blood leukocytes, and failure to induce "early antigen" in lymphoblast lines. All viruses produced more virus in transformed marmoset cells than in transformed human cells, as measured by the number of EBV genomes detected by complementary RNA/DNA hybridization, by virus capsid antigen expression, or by released virions and biologically active virus. Reference human sera and sera from primary EBV infections were used to compare the three virus strains in a virus neutralization test based on inhibition of stimulation of DNA synthesis. Specimens taken late in convalescence from patients with mononucleosis and sera from marmosets experimentally infected with virus from a patient with mononucleosis neutralized the homologous virus, as well as the two virus strains isolated from patients with BL. This finding indicates that viral antigens that elicit neutralizing antibodies are shared among the strains. However, in certain sera the neutralizing-antibody titer against one strain was consistently higher than against another strain. Furthermore, sera taken early after onset of IM contained low levels of neutralizing antibody against IM-derived virus, but failed to neutralize BL-derived virus. These latter findings suggest the existence of heterogeneity among surface antigens of EBVs. The results emphasize the biological and antigenic similarity of EBV isolates from BL and IM and do not suggest major subtype variations. It remains to be determined whether antigenic diversity such as described or virus genome variation detectable by other means is epidemiologically significant.