Interstitial therapy with targeted protein toxins for malignant brain tumors: We are investigating a new approach for the treatment of brain tumors which utilizes a new delivery approach for distribution of a class of potent, targeted anti-cancer compounds, called targeted protein toxins. Preclinical in vitro and in vivo experiments of toxins targeted to the transferrin receptor and epidermal growth factor (EGF) demonstrated significant antitumor activity against a variety of tumor types, including malignant gliomas. New methods of drug delivery have been developed to deliver these agents to brain tumors, and in vivo imaging methods are being developed to demonstrate drug distribution in patients. We completed a phase I trial of regional therapy with a conjugate of human transferrin (Tf) and malignant brain tumors. The results indicated that therapy with Tf-CRM107 produces tumor responses without severe neurologic or systemic toxicity. A multicenter Phase II study has now been finished. The results suggest similar efficacy and toxicity as was observed in the Phase I trial. A new protocol to investigate the safety of perfusing the region of brain surrounding tumor excision to eliminate infiltrating tumor cells and to examine the potential of protecting the brain, but not tumor, with this approach combined with systemic administration of chloroquine, an agent that inhibits endothelial cell injury by Tf-CRM 107, is being prepared. The blood-brain barrier (BBB) breakdown that occurs in the natural progression of malignant brain tumors contributes to brain tumor-associated edema, a major source of morbidity and mortality. Despite attempts at new therapeutic approaches to the treatment of brain tumor patients, the only effective treatment for this life-threatening complication remains administration of high dose synthetic corticosteroids, in particular dexamethasone, which partially restores BBB function, thus reducing edema. Dexamethasone is also a substrate and potential regulator for a membrane-bound P-glycoprotein (Pgp) pump which actively extrudes many lipophilic substances. The Pgp pump is the product of the multidrug resistance (MDR1) gene and is also a normal BBB component, acting to restrict entry of many drugs and xenobiotics into brain tissue. The MDR1 gene is also often upregulated in tumor cells, conferring resistance in such cells to certain chemotherapeutic agents. We examined the interaction between dexamethasone and Pgp in a rodent brain tumor model. The brains of tumor-bearing rats were examined for Pgp expression (by anti-Pgp antibodies) in control and dexamethasone-treated rats. As expected, strong Pgp expression was observed in all normal brain vessels. In control tumors, Pgp expression was decreased in intensity and in number of positively-staining vessels compared to normal brain. In dexamethasone-treated animals, Pgp remained detectable in tumor vessels. Pgp staining was minimally detectable in tumor cells in vivo regardless of treatment. In cultured brain tumor cells, dexamethasone resulted in a modest (25%) but significant (p<0.05) decrease in uptake of the Pgp substrate digoxin, consistent with activation of the Pgp pump by dexamethasone. Although dexamethasone is beneficial in reducing brain tumor-associated edema by restoring BBB function, dexamethasone may also upregulate Pgp expression or activity in tumor blood vessels or tumor cells, thus further limiting access of the tumor to therapeutic drugs that are Pgp substrates. The interaction of dexamethasone and Pgp in the brain tumor setting may complicate treatment of this disease. Understanding the mechanism by which steroids regulate the BBB may lead to new drugs which are more effective in treating this problem, but with fewer side effects/complications.] To define the natural history and growth pattern of central nervous system (CNS) hemangioblastomas associated with von Hippel-Lindau disease (vHL), and to correlate features of hemangioblastomas that are associated with development of symptoms and need for treatment, we reviewed serial magnetic resonance (MR)-imaging and clinical histories of 160 consecutive vHL patients with CNS hemangioblastomas and serially measured volumes of the tumors and associated cysts. 655 hemangioblastomas were identified in the cerebellum (250), brainstem (64, all in posterior medulla), spinal cord (331, 96% in posterior half of spinal cord), and the supratentorial brain (10). Twenty-one of 29 (72%) symptom-producing cerebellar tumors had an associated cyst, whereas only 28 (13%) of the 221 cerebellar tumors without symptoms had tumor-associated cysts. Nine (75%) of 12 symptomatic brainstem tumors had associated cysts compared to only 4 (8%) of the 52 without symptoms. By the time symptoms occurred and surgery was required the cyst was larger than the tumor causing it; cerebellar and brainstem cysts averaged 34-fold and 19-fold the size of their associated tumors at surgery. Ninety-five percent of symptom-producing spinal hemangioblastomas had associated syringomyelia. The clinical circumstance was dynamic. Among 88 patients serially imaged for >= 6 months (median, 32 months), 164 (44%) of 373 hemangioblastomas and 37 (67%) of 55 tumor-associated cysts enlarged. No tumors or cysts spontaneously diminished in size. Symptomatic tumors grew at approximately 10-fold the rates of asymptomatic tumors and symptomatic cysts grew 3.2-fold and 1.7-fold faster than the hemangioblastomas associated with them. Hemangioblastomas frequently demonstrated a pattern of growth in which they would enlarge for a period of time (growth phase) followed by a period of arrested growth (quiescent phase). Of 69 patients with documented tumor growth 18 (26%) had tumor(s) with at least two growth phases. Of the 160 patients with hemangioblastomas, 34 patients (median follow-up 51 months) developed 115 new hemangioblastomas and 15 new tumor-associated cysts. This study defined the natural history of CNS hemangioblastoma associated with vHL. Not only were cysts commonly associated with cerebellar, brainstem, and spinal hemangioblastomas, the pace of enlargement is much greater for cysts than for hemangioblastomas. By the time symptoms appeared the majority of the mass effect producing symptoms derived from the cyst, rather than the tumor causing the cyst. These tumors often have multiple periods of tumor growth separated by periods of arrested growth and many untreated tumors may remain the same size for several years.
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| Oldfield, Edward H; Vortmeyer, Alexander O (2006) Development of a histological pseudocapsule and its use as a surgical capsule in the excision of pituitary tumors. J Neurosurg 104:7-19 |
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