Rationale and Design of a Phase 1 Clinical Trial to Evaluate HSV G207 Alone or with a Single Radiation Dose in Children with Progressive or Recurrent Malignant Supratentorial Brain Tumors.

Primary central nervous system tumors are the most common solid neoplasm of childhood and the leading cause of cancer-related death in pediatric patients. Survival rates for children with malignant supratentorial brain tumors are poor despite aggressive treatment with combinations of surgery, radiation, and chemotherapy, and survivors often suffer from damaging lifelong sequelae from current therapies. Novel innovative treatments are greatly needed. One promising new approach is the use of a genetically engineered, conditionally replicating herpes simplex virus (HSV) that has shown tumor-specific tropism and potential efficacy in the treatment of malignant brain tumors. G207 is a genetically engineered HSV-1 lacking genes essential for replication in normal brain cells. Safety has been established in preclinical investigations involving intracranial inoculation in the highly HSV-sensitive owl monkey (Aotus nancymai), and in three adult phase 1 trials in recurrent/progressive high-grade gliomas. No dose-limiting toxicities were seen in the adult studies and a maximum tolerated dose was not reached. Approximately half of the 35 treated adults had radiographic or neuropathologic evidence of response at a minimum of one time point. Preclinical studies in pediatric brain tumor models indicate that a variety of pediatric tumor types are highly sensitive to killing by G207. This clinical protocol outlines a first in human children study of intratumoral inoculation of an oncolytic virus via catheters placed directly into recurrent or progressive supratentorial malignant tumors.

Detection of JC virus DNA sequences in brain tumors in pediatric patients.

OBJECT: The JC virus is a human neurotropic polyomavirus that causes progressive multifocal leukoencephalopathy and is closely related to simian virus 40. Several recent reports have indicated a possible association between the JC virus and the development of various human brain tumors. The authors examined the presence of JC virus DNA sequences in primary brain tumors in pediatric patients to evaluate the hypothesis that particular brain tumors can arise in the pediatric population as a consequence of infection with the JC virus. METHODS: Genomic DNA sequences were isolated from 62 brain tumors (32 medulloblastomas, 18 ependymomas, five choroid plexus papillomas, and seven pilocytic astrocytomas) and analyzed for the presence of JC virus DNA by Southern blot hybridization and direct sequencing. The JC virus DNA sequence was detected in five ependymomas and one choroid plexus papilloma. Immunohistochemical studies revealed nuclear expression of the large T-antigen in a choroid plexus papilloma. None of the medulloblastomas or pilocytic astrocytomas contained JC virus DNA. CONCLUSIONS: The results of this study provide molecular evidence of the association between JC virus and the development of certain ependymomas and choroid plexus papillomas.

Increased p53 immunopositivity in anaplastic medulloblastoma and supratentorial PNET is not caused by JC virus.

BACKGROUND: p53 mutations are relatively uncommon in medulloblastoma, but abnormalities in this cell cycle pathway have been associated with anaplasia and worse clinical outcomes. We correlated p53 protein expression with pathological subtype and clinical outcome in 75 embryonal brain tumors. The presence of JC virus, which results in p53 protein accumulation, was also examined. METHODS: p53 protein levels were evaluated semi-quantitatively in 64 medulloblastomas, 3 atypical teratoid rhabdoid tumors (ATRT), and 8 supratentorial primitive neuroectodermal tumors (sPNET) using immunohistochemistry. JC viral sequences were analyzed in DNA extracted from 33 frozen medulloblastoma and PNET samples using quantitative polymerase chain reaction. RESULTS: p53 expression was detected in 18% of non-anaplastic medulloblastomas, 45% of anaplastic medulloblastomas, 67% of ATRT, and 88% of sPNET. The increased p53 immunoreactivity in anaplastic medulloblastoma, ATRT, and sPNET was statistically significant. Log rank analysis of clinical outcome revealed significantly shorter survival in patients with p53 immunopositive embryonal tumors. No JC virus was identified in the embryonal brain tumor samples, while an endogenous human retrovirus (ERV-3) was readily detected. CONCLUSION: Immunoreactivity for p53 protein is more common in anaplastic medulloblastomas, ATRT and sPNET than in non-anaplastic tumors, and is associated with worse clinical outcomes. However, JC virus infection is not responsible for increased levels of p53 protein.

[Primary central nervous system lymphomas in AIDS patients]. / Linfomas primarios del sistema nervioso central en pacientes con sida.

INTRODUCTION: Primary lymphoma is the most common neoplasm of the central nervous system (CNS) in AIDS patients. METHODS: We retrospectively reviewed the clinical manifestations, neuroimaging findings, diagnostic methods used, histological characteristics, detection of Epstein-Barr virus (EBV) DNA by PCR in cerebrospinal fluid (CSF) and brain smears, and outcome of 18 HIV/AIDS patients with primary CNS lymphoma. RESULTS: The overall incidence of primary CNS lymphoma was 2.6%. Fifteen were men and mean age was 33.6 years. The most frequent clinical findings were focal neurological deficits and seizures. The mean CD4 T cell count at the time of diagnosis was 44 cells/microl. Primary CNS lymphoma presented as single, large (> 2.5 cm) lesions in 14 patients (77.8%). All the lesions were associated with a mass effect and surrounding edema. EBV DNA was detected in nine brain smears. In seven of these nine cases, EBV DNA was also found in CSF by PCR. Median survival after specific diagnosis was 75 days. CONCLUSIONS: This study upholds a link between EBV and these tumors. Primary CNS lymphoma was associated with a poor prognosis and short survival in this cohort of patients.