Von Hippel-Lindau disease. To determine the origin of the neoplastic cell in CNS hemangioblastomas in vHL and its role in tumor formation and distribution, we characterized and differentiated neoplastic cells from hemangioblastomas removed from VHL patients. CNS hemangioblastomas from VHL patients were resected and analyzed. Tumor cells from the hemangioblastomas were characterized, grown and differentiated into multiple lineages. Consistent with an embryologically-derived hemangioblast, the neoplastic cells demonstrated co-expression of mesodermal markers brachyury, Flk-1 and Scl. The neoplastic cells also expressed hematopoietic stem cell antigens and receptors including CD133, CD34, c-kit, Scl, erythropoietin and erythropoietin receptor. Under specific microenvironments, neoplastic cells (hemangioblasts) were expanded and differentiated into erythrocytic, granulocytic, and endothelial progenitors. Deletion of the wild-type VHL allele in the hematopoietic and endothelial progeny confirmed their neoplastic origin. These findings indicate that the neoplastic cell of origin for CNS hemangioblastomas in VHL patients is the mesoderm-derived, embryologically-arrested hemangioblast. The hematopoietic and endothelial differentiation potential of these cells can be reactivated under suitable conditions. These findings help explain the unique tissue distribution of tumor involvement and may provide for new therapeutic opportunities.? ? To identify features predictive of symptom development that might permit earlier treatment of smaller presymptomatic hemangioblastomas in von Hippel-Lindau disease, we analyzed the serial clinical and imaging findings in VHL patients who were followed more than 10 years. Features predictive of symptom formation were determined by recursive partition and regression analyses. Hemangioblastomas grew in a stuttering pattern (mean growth period 13+15 months, mean quiescent period 25+19 months). Twenty-six (45%) of the hemangioblastomas that eventually produced symptoms were not among the tumors that were apparent on the initial MR-imaging. Depending on location, hemangioblastoma size and/or tumor/cyst growth rate predicted symptom development and the need for treatment (P, < 0.05). Because hemangioblastomas exhibit a stuttering growth pattern and frequently remain asymptomatic not requiring treatment for long intervals, unqualified radiographic progression is not an indication for treatment. Basing the decision to intervene in individual tumors solely on radiographic progression would have resulted in about 4 additional procedures per patient during a 10-year period. Threshold values for tumor size and/or tumor/cyst growth rate that predict symptom formation and future need for treatment were determined.? ? Endolymphatic sac tumors (ELSTs) are rare, locally invasive, neoplasms that are associated with hearing loss, tinnitus, vertigo, aural fullness, and/or facial nerve dysfunction. In vHL, ELSTs frequently occur bilaterally and result in significant neurologic disability, including deafness. To determine the natural history, the mechanisms of early symptom formation, the precise histologic origin, and the optimal timing of treatment of ELSTs, we analyzed the imaging, clinical and surgical findings in vHL patients with ELSTs. We discovered that: morbid hearing loss in vHL patients without imaging evidence of ELSTs may result from a microscopic tumor in the endolymphatic sac or duct; hemorrhage and endolymphatic hydrops underlie the initial symptoms associated with ELSTs; the site of origin of ELSTs is the endolymphatic duct or sac; and the molecular biology of ELSTs, loss of heterozygosity of the vHL gene, supports their clinical association with vHL; early detection permits resection of small ELSTs with functional hearing, which can reduce the incidence and severity of neurologic dysfunction associated with these tumors.? ? The blood-brain barrier (BBB) breakdown that occurs with malignant brain tumors causes brain tumor-associated edema, a major source of morbidity and mortality. Acting through the glucocorticoid receptor (GR), dexamethasone partially restores BBB function, reducing brain tumor-associated edema (BTAE). Although steroids are effective, high doses are required, and their use is associated with debilitating receptor-mediated side effects. We initiated research designed to understand the mechanisms by which dexamethasone interacts with the BBB. (1) The interaction of dexamethasone with the P-glycoprotein (Pgp) pump. The Pgp pump is the product of the multidrug resistance (MDR1) gene and is a normal BBB component, acting to restrict entry of many drugs into the CNS. Dexamethasone is a substrate for, and potential regulator of, the membrane-bound Pgp pump. The brains of tumor-bearing rats were examined for Pgp expression in control and dexamethasone-treated rats. In control tumors, vessels staining positively for Pgp were diminished in intensity and in number compared to normal brain, whereas in dexamethasone-treated animals Pgp remained detectable in tumor vessels, suggesting induced expression of Pgp in the tumor vessels by dexamethasone. In the brain tumor setting, this could reduce the efficacy of dexamethasone and other therapeutic drugs that are Pgp substrates. Thus, interaction of dexamethasone and Pgp in the brain tumor setting may complicate treatment of this disease. (2) AQP-1 and the BBB in gliomas. Aquaporins (AQP) function as a water-selective transport mechanism in cells. We observed that AQP-1 is absent from normal brain, but markedly and selectively upregulated perivascularly in human glioblastomas. In glioma cells in vitro, AQP-1 is upregulated by dexamethasone and increased availability of glucose. This suggests that AQP-1 in gliomas may regulate the fluid movement and microenvironment of tumor-associated blood vessels. The specific upregulation of AQP-1 in glioma cells may provide a novel therapeutic target, both as a cell surface marker and as a functional intervention. ? ? A clinical study was completed (Protocol #96-N-0093) that evaluated the functional activity and regional blood flow in cerebral cortex exposed during awake craniotomy to treat brain tumors and medically intractable epilepsy. This study demonstrated that primary brain tumors are hypoperfused compared to normal brain and that metastatic tumors are hyperperfused compared to normal brain. Brain surrounding tumors was hypoperfused due to the tumors compressing the surrounding brain tissue. Tumor removal resulted in improved perfusion of the brain tissue that was in proximity to the tumor.
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