The brain is highly accessible for nutrients and oxygen, however delivery of drugs to malignant brain tumors is a very challenging task. Convection-enhanced delivery (CED) has been designed to overcome some of the difficulties so that pharmacological agents that would not normally cross the BBB can be used for treatment. Drugs are delivered through one to several catheters placed stereotactically directly within the tumor mass or around the tumor or the resection cavity. Several classes of drugs are amenable to this technology including standard chemotherapeutics or novel experimental targeted drugs. The first Phase III trial for CED-delivered, molecularly targeted cytotoxin in the treatment of recurrent glioblastoma multiforme has been accomplished and demonstrated objective clinical efficacy. The lessons learned from more than a decade of attempts at exploiting CED for brain cancer treatment weigh critically for its future clinical applications. The main issues center around the type of catheters used, number of catheters and their exact placement; pharmacological formulation of drugs, prescreening patients undergoing treatment and monitoring the distribution of drugs in tumors and the tumor-infiltrated brain. It is expected that optimizing CED will make this technology a permanent addition to clinical management of brain malignancies.

The authors describe a method of harvesting autologous pericranium for duraplasty in patients with Chiari malformation Type I (CM-I) that avoids excessive exposure or a second incision. Nonautologous dural grafts have been associated with numerous complications including hemorrhage, bacteria and virus transmission, fatal Creutzfeldt-Jakob disease transmission, foreign body reaction, systemic immune response, excessive scarring, slower healing, premature graft dissolution, and wound dehiscence. Autogenous tissues have the advantage of being nonimmunogenic, nontoxic, readily available, and inexpensive. Pericranium is a preferred substrate because it is flexible, strong, and easily sutured for a watertight closure. Current literature supports the use of autogenous pericranium for dural grafting in CM-I procedures, but has heretofore failed to provide a method of harvest that avoids the complications associated with a larger exposure or second incision. The authors offer a simple alternative technique for using local pericranium in duraplasty for CM-I or other posterior fossa abnormalities.

Corticotrophs in the fetal sheep become increasingly responsive to arginine vasopressin (AVP) in late gestation. We have previously reported that this may be due in part to corresponding increases in signal transduction (inositol trisphosphate, IP3). These ontogenic changes are prevented by hypothalamo-pituitary disconnection (HPD), which also prevents fetal plasma cortisol concentrations from increasing in late gestation. This led us to hypothesize that cortisol is involved in mediating the changes in pituitary responsiveness. HPD was performed on fetal sheep at 120 days of gestation (dGA). Half of the HPD fetuses were infused with cortisol for 3 days beginning on 135-137 dGA (HPD+C). The remaining HPD fetuses and a group of sham operated controls were infused with saline. Pituitary cells were isolated and cultured. After 48h, a subset of cells was stimulated with 100nM AVP for 2h, and the medium collected for ACTH analysis. Another subset of cells was stimulated with 100nM AVP for 30mins and the formation of IP3 determined. Plasma cortisol concentrations increased rapidly within the first 6h following infusion (5.2+/-1.9 to 29.7+/-4.9 ng/ml), but did not increase thereafter. Cells from HPD+C and sham fetuses secreted significantly more ACTH than those from HPD fetuses (% increases from control were 33.0+/-8.8, 47.9+/-10.6 and 11.9+/-2.4). IP3 formation was significantly increased in cells from HPD+C and sham compared to HPD fetuses (% increases from control were 17.7+/-4.4, 18.9+/-4.3 and 4.6+/-1.5). These findings support the idea that cortisol plays a role in mediating the increase in pituitary responsiveness to AVP in the late gestation fetal sheep. Key words: AVP, IP3, pituitary, cortisol replacement.

PURPOSE: Patients with neurofibromatosis (NF) develop tumors of the central nervous system (CNS). Radiation therapy (RT) is used to treat these lesions. To better define the efficacy of RT in these patients, we reviewed our 20-year experience. METHODS AND MATERIALS: Eighteen patients with NF with CNS tumors were treated from 1986 to 2007. Median follow-up was 48 months. Progression was defined as growth or recurrence of an irradiated tumor on serial imaging. Progression-free survival (PFS) was measured from the date of RT completion to the date of last follow-up imaging study. Actuarial rates of overall survival (OS) and PFS were calculated according to the Kaplan-Meier method. RESULTS: Eighty-two tumors in 18 patients were irradiated, with an average of five tumors/patient. Median age at treatment was 25 years (range, 4.3-64 years). Tumor types included acoustic neuroma (16%), ependymoma (6%), low-grade glioma (11%), meningioma (60%), and schwanomma/neurofibroma (7%). The most common indication for treatment was growth on serial imaging. Most patients (67%) received stereotactic radiosurgery (median dose, 1,200 cGy; range, 1,000-2,400 cGy). The OS rate at 5 years was 94%. Five-year PFS rates were 75%(acoustic neuroma), 100%(ependymoma), 75%(low-grade glioma), 86%(meningioma), and 100%(schwanomma/neurofibroma). Thirteen acoustic neuromas had a local control rate of 94% with a 50% hearing preservation rate. CONCLUSIONS: RT provided local control, OS, and PFS rates similar to or better than published data for tumors in non-NF patients. Radiation therapy should be considered in NF patients with imaging progression of CNS tumors.

OBJECT: Salvage treatment of large, symptomatic brain metastases after failure of whole-brain radiotherapy (WBRT) remains challenging. When these lesions require resection, there are few options to lower expected rates of local recurrence at the resection cavity margin. The authors describe their experience in using Gamma Knife surgery (GKS) to target the resection cavity in patients whose tumors had progressed after WBRT. METHODS: The authors retrospectively identified 143 patients in whom GKS had been used to target a brain metastasis resection cavity between 2000 and 2005. Seventy-nine of these patients had undergone WBRT prior to resection and GKS. The median patient age was 53 years, and the median prescribed dose was 18 Gy (range 8-24 Gy), with resection cavities of relatively larger volume (> 15 cm3). The GKS dose was prescribed at the 40 to 95% isodose contour (mode 50%). Local recurrence within 1 cm of the treatment volume occurred in four (5.1%) of 79 cases. The median duration of time to local recurrence was 6.1 months (range 2-13 months). The median duration of time to occurrence of distant metastases following GKS of the resection cavity was 10.8 months (range 2-86 months). Carcinomatous meningitis developed in four (5.1%) of 79 cases. Symptomatic radionecrosis requiring surgical treatment occurred in three (3.8%) of 79 cases. The median duration of survival following GKS of the resection cavity was 69.6 weeks. The median 2- and 5-year survival rates were 20.2 and 6.3%, respectively. CONCLUSIONS: When metastases progress after WBRT and require resection, GKS targeting the resection cavity is a viable strategy. In 75 (94.9%) of 79 cases, GKS of the resection cavity in patients in whom WBRT had failed appears to have achieved its goal of local disease control.

Stieber, V. W., Robbins, M., Balamucki, C., DeGuzman, A., Tatter, S. B., Ekstrand, K. E., McMullen, K. P., Branch, C., Shaw, E. G., Bourland, J. D., Lovato, J., Munley, M. T. and Ellis, T. L. Determination of a Clinical Value for the Repair Half-Time (T(1/2)) of the Trigeminal Nerve Based on Outcome Data from Gamma Knife Radiosurgery for Facial Pain. Radiat. Res. 168, 143-148 (2007).Stereotactic radiosurgery (GKRS) using the Leksell Gamma Knife is a treatment option for patients with trigeminal pain. We analyzed a database of 326 GKRS procedures performed over 4.6 years at three discrete dose levels commonly described in the published literature. Logistic regression was used to model the logit of response as a function of treatment time. The resulting coefficient was converted to an estimated probability of response for the shortest and longest treatment times in clinical practice. The two estimated probabilities were then compared to yield the estimated difference in the biologically effective dose (BED) between the two doses, using a modified linear-quadratic model for stereotactic radiosurgery. This difference was used to back-calculate a clinical value for T(1/2), resulting in a range of 1.28-1.77 h for T(1/2). The biological model appeared to accurately predict that, given the doses and treatment times used in general clinical practice, there would be no significant difference in clinical outcome.

PURPOSE: This phase I trial was designed to (1) establish the dose of O6-benzylguanine (O6-BG) administered intravenously as a continuous infusion that suppresses O6-alkylguanine-DNA alkyltransferase (AGT) levels in brain tumors,(2) evaluate the safety of extending continuous-infusion O6-BG at the optimal dose with intracranially implanted carmustine wafers, and (3) measure the pharmacokinetics of O6-BG and its metabolite. PATIENTS AND METHODS: The first patient cohort (group A) received 120 mg/m2 of O6-BG over 1 hour followed by a continuous infusion for 2 days at escalating doses presurgery. Tumor samples were evaluated for AGT levels. The continuous-infusion dose that resulted in undetectable AGT levels in 11 or more of 14 patients was used in the second patient cohort. Group B received the optimal dose of O6-BG for 2, 4, 7, or 14 days after surgical implantation of the carmustine wafers. The study end point was dose-limiting toxicity (DLT). RESULTS: Thirty-eight patients were accrued. In group A, 12 of 13 patients had AGT activity levels of less than 10 fmol/mg protein with a continuous-infusion O6-BG dose of 30 mg/m2/d. Group B patients were enrolled onto 2-, 4-, 7-, and 14-day continuous-infusion cohorts. One DLT of grade 3 elevation in ALT was seen. Other non-DLTs included ataxia and headache. For up to 14 days, steady-state levels of O6-BG were 0.1 to 0.4 micromol/L, and levels for O6-benzyl-8-oxoguanine were 0.7 to 1.3 micromol/L. CONCLUSION: Systemically administered O6-BG can be coadministered with intracranially implanted carmustine wafers, without added toxicity. Future trials are required to determine if the inhibition of tumor AGT levels results in increased efficacy.

In late gestation fetal sheep the pituitary becomes increasingly responsive to stimulation by arginine vasopressin (AVP). This change appears to be one important factor mediating the plasma cortisol surge, a critical developmental event. It is not known precisely why pituitary corticotropes become more responsive at this time. In this study we examined the possibility that changes in second messenger generation (inositol trisphosphate, IP3) are responsible. Two studies were undertaken. The first was an ontogeny study where pituitaries were isolated from 100, 120, and 140 days gestational age (dGA) fetal sheep. Cells were cultured, stimulated with arginine vasopressin (AVP) and the formation of IP3 assessed. The amount of IP3 generated increased with gestational age (% increases from unstimulated controls were 4.6, 11.5 and 21.5 for 100, 120 and 140 dGA respectively), with significant differences between the 140 dGA group and both earlier groups apparent. The second study examined the impact of 120 dGA hypothalamo-pituitary disconnection (HPD- which prevents corticotrope maturation) on responsiveness of pituitary cells isolated from 140 dGA fetuses. Cells were stimulated with AVP, and the formation of IP3 and secretion of ACTH were assessed. Significantly less IP3 was formed and ACTH secreted in cells from HPD compared with control fetuses (IP3 and ACTH levels were 50% and 35% lower respectively). Results from the HPD study demonstrate that the ontogenic changes in IP3 following AVP require an intact hypothalamic-pituitary adrenal axis. These findings suggest that heightened second messenger generation may be a key reason for increased ACTH secretory responsiveness to AVP in the late gestation sheep fetus.

OBJECT: Gamma Knife surgery (GKS) is a treatment option for patients with refractory typical trigeminal neuralgia (TN), TN with atypical features, and atypical types of facial pain. The Gamma Knife's 201 60Co sources decay with a half-life of 5.26 years. The authors examined whether the decrease in dose rate over 4.6 years between Co source replacements affected the control rates of facial pain in patients undergoing GKS. METHODS: The authors collected complete follow-up data on 239 of 326 GKS procedures performed in patients with facial pain. Patients were classified by their type of pain. The isocenter of a 4-mm collimator helmet was targeted at the proximal trigeminal nerve root, and the dose (80-90 Gy) was prescribed at the 100% isodose line. Patients reported the amount of pain control following radiosurgery by answering a standardized questionnaire. Eighty percent of patients experienced greater than 50% pain relief, and 56% of patients experienced complete pain relief after GKS. Neither dose rate nor treatment time was significantly associated with either the control rate or degree of pain relief. A significant association between the type of facial pain and the pain control rate after GKS was observed (p < 0.001; Pearson chi-square test). In their statistical analysis, the authors accounted for changes in prescription dose over time to prevent the dose rate from being a confounding variable. There was no observable effect of the dose rate or of the treatment duration within the typical period to source replacement. CONCLUSIONS: Patients with facial pain appear to receive consistent treatment with GKS at any time during the first half-life of the Co sources.