The biology of radiosurgery and its clinical applications for brain tumors.

Stereotactic radiosurgery (SRS) was developed decades ago but only began to impact brain tumor care when it was coupled with high-resolution brain imaging techniques such as computed tomography and magnetic resonance imaging. The technique has played a key role in the management of virtually all forms of brain tumor. We reviewed the radiobiological principles of SRS on tissue and how they pertain to different brain tumor disorders. We reviewed the clinical outcomes on the most common indications. This review found that outcomes are well documented for safety and efficacy and show increasing long-term outcomes for benign tumors. Brain metastases SRS is common, and its clinical utility remains in evolution. The role of SRS in brain tumor care is established. Together with surgical resection, conventional radiotherapy, and medical therapies, patients have an expanding list of options for their care. Clinicians should be familiar with radiosurgical principles and expected outcomes that may pertain to different brain tumor scenarios.

Aggressive infantile embryonal tumors.

Embryonal tumors are the most common brain tumors in infants less than 36 months. Histologically characterized as undifferentiated small, round cell tumors with divergent patterns of differentiation, these include medulloblastoma, the most common form of embryonal tumor, as well as supratentorial primitive neuroectodermal tumor, medulloepithelioma, ependymoblastoma, medullomyoblastoma, melanotic medulloblastoma, and atypical teratoid/rhabdoid tumor. All are similarly aggressive and have a tendency to disseminate throughout the central nervous system. Because of efforts to avoid craniospinal irradiation in an attempt to lessen treatment-related neurotoxicity, management of these tumors in infants is unique. Outcomes remain similarly poor among all the tumor types and, therefore, identification of specific molecular targets that have prognostic and therapeutic implications is crucial. The molecular and clinical aspects of the 3 most common aggressive infantile embryonal tumors, medulloblastoma, supratentorial primitive neuroectodermal tumor, and atypical teratoid/rhabdoid tumor, are the focus of this review.

The novel mTOR inhibitor RAD001 (everolimus) induces antiproliferative effects in human pancreatic neuroendocrine tumor cells.

BACKGROUND/AIM: Tumors exhibiting constitutively activated PI(3)K/Akt/mTOR signaling are hypersensitive to mTOR inhibitors such as RAD001 (everolimus) which is presently being investigated in clinical phase II trials in various tumor entities, including neuroendocrine tumors (NETs). However, no preclinical data about the effects of RAD001 on NET cells have been published. In this study, we aimed to evaluate the effects of RAD001 on BON cells, a human pancreatic NET cell line that exhibits constitutively activated PI(3)K/Akt/mTOR signaling. METHODS: BON cells were treated with different concentrations of RAD001 to analyze its effect on cell growth using proliferation assays. Apoptosis was examined by Western blot analysis of caspase-3/PARP cleavage and by FACS analysis of DNA fragmentation. RESULTS: RAD001 potently inhibited BON cell growth in a dose-dependent manner which was dependent on the serum concentration in the medium. RAD001-induced growth inhibition involved G0/G1-phase arrest as well as induction of apoptosis. CONCLUSION: In summary, our data demonstrate antiproliferative and apoptotic effects of RAD001 in NET cells in vitro supporting its clinical use in current phase II trials in NET patients.

Advanced neuroimaging of pediatric brain tumors: MR diffusion, MR perfusion, and MR spectroscopy.

This article highlights the MR imaging techniques of MR perfusion, MR diffusion, and MR spectroscopy in the evaluation of the child with a pediatric brain tumor. These techniques are complementary to conventional MR imaging in providing tumor physiologic information useful for diagnosis and therapy.

Expression and functional activity of the ABC-transporter proteins P-glycoprotein and multidrug-resistance protein 1 in human brain tumor cells and astrocytes.

The poor prognosis of glioma patients is partly based on the minor success obtained from chemotherapeutic treatments. Resistance mechanisms at the tumor cell level may be, in addition to the blood-brain barrier, involved in the intrinsic chemo-insensitivity of brain tumors. We investigated the expression of the drug-transporter proteins P-glycoprotein (P-gp) and multidrug-resistance protein 1 (MRP1) in cell lines (N = 24) and primary cell cultures (N = 36) from neuroectodermal tumors, as well as in brain tumor extracts (N = 18) and normal human astrocytes (N = 1). We found that a considerable expression of P-gp was relatively rare in glioma cells, in contrast to MRP1, which was constitutively overexpressed in cells derived from astrocytomas as well as glioblastomas. Also, normal astrocytes cultured in vitro expressed high amounts of MRPI but no detectable P-gp. Meningioma cells frequently co-expressed P-gp and MRP1, while, most of the neuroblastoma cell lines express higher P-gp but lower MRP1 levels as compared to the other tumor types. Both, a drug-exporting and a chemoprotective function of P-gp as well as MRP1 could be demonstrated in selected tumor cells by a significant upregulation of cellular 3H-daunomycin accumulation and daunomycin cytotoxicity via administration of transporter antagonists. Summing up, our data suggest that P-gp contributes to cellular resistance merely in a small subgroup of gliomas, but frequently in neuroblastomas and meningiomas. In contrast, MRP1 is demonstrated to play a constitutive role in the intrinsic chemoresistance of gliomas and their normal cell counterpart.

Clinical correlations of genetic changes by comparative genomic hybridization in Ewing sarcoma and related tumors.

Our previous comparative genomic hybridization (CGH) study of Ewing sarcoma and related tumors showed that DNA sequence copy number increases of 1q21-q22 and of chromosomes 8 and 12 were associated with trends toward poor survival (Armengol et al., Br J Cancer 1997, 75, 1403-1409). These trends were not statistically significant. In the present study, we analyzed 28 primary Ewing sarcomas and related tumors by CGH to study whether these (or other) changes have prognostic value in these tumors. Twenty-one tumors (75%) had changes with a mean of 1.9 changes per tumor. The most frequent aberration was gain of chromosome 8 in 10 tumors (36%). Five tumors (18%) had copy number increases at 1q21-22 and 5 had gain of 7q. Copy number increase of 6p21.1-pter, gain of chromosome 12, and loss of 16q were seen in 11%. Copy number increases of 1q21-q22 and of chromosomes 8 and 12 were associated with trends toward worse outcome, but the differences did not reach statistical significance. A novel finding is the association of copy number increase at 6p with worse distant disease-free (P = 0.04) and overall survival (P = 0.004). To confirm this finding and to see whether copy number increases of 1q21-q22 and of chromosomes 8 and 12 have definite prognostic value, a larger number of cases needs to be studied.

Primitive neuroectodermal tumor in a two-month-old black and white Colobus monkey.

A 2-month-old male black and white Colobus monkey (Colobus guereza kikuyuensis) was euthanatized because of progressive physical deterioration, rear limb paralysis, lymphadenopathy, and the presence of facial and retroperitoneal lumbar masses. At necropsy, soft white masses were present in and around lumbar vertebrae, the subcutis of the face, multiple lymph nodes, and the fourth ventricle of the brain. Histologic and immunohistochemical analysis of these masses revealed a primitive neoplasm with both neuronal and glial differentiation, consistent with a primitive neuroectodermal tumor (PNET) with bipotential differentiation. The extracranial tumors were synaptophysin (SYN)-positive, glial fibrillary acidic protein (GFAP)-negative, and neurofilament protein (NFP)-negative, while the intracranial tumor was SYN-positive, GFAP-positive, and NFP-negative.