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PURPOSE:To assess the safety and efficacy of upfront treatment using bortezomib combined with standard radiation therapy (RT) and temozolomide (TMZ), followed by adjuvant bortezomib and TMZ for ≤24 cycles, in patients with newly diagnosed glioblastoma multiforme (GBM). METHODS AND MATERIALS:Twenty-four patients with newly diagnosed GBM were enrolled. The patients received standard external beam regional RT with concurrent TMZ beginning 3 to 6weeks after surgery, followed by adjuvant TMZ and bortezomib for ≤24 cycles or until tumor progression. During RT, bortezomib was given at 1.3mg/m2 on days 1, 4, 8, 11, 29, 32, 36, and 39. After RT, bortezomib was given at 1.3mg/m2 on days 1, 4, 8, and 11 every 4weeks. RESULTS:No unexpected adverse events occurred from the addition of bortezomib. The efficacy analysis showed a median progression-free survival (PFS) of 6.2months (95% confidence interval [CI] 3.7-8.8), with promising PFS rates at ≥18months compared with historical norms (25.0% at 18 and 24months; 16.7% at 30months). In terms of overall survival (OS), the median OS was 19.1months (95% CI 6.7-31.4), with improved OS rates at ≥12months (87.5% at 12, 50.0% at 24, 34.1% at 36-60months) compared with the historical norms. The median PFS was 24.7months (95% CI 8.5-41.0) in 10 MGMT methylated and 5.1months (95% CI 3.9-6.2) in 13 unmethylated patients. The estimated median OS was 61months (95% CI upper bound not reached) in the methylated and 16.4months (95% CI 11.8-21.0) in the unmethylated patients. CONCLUSIONS:The addition of bortezomib to current standard radiochemotherapy in newly diagnosed GBM patients was tolerable. The PFS and OS rates appeared promising, with more benefit to MGMT methylated patients. Further clinical investigation is warranted in a larger cohort of patients.

Purpose: To perform a Phase I study to determine the safety and feasibility of using external beam radiotherapy to prevent neointimal hyperplasia in patients after surgical bypass of occluded infrainguinal arteries. Methods and Materials: All patients undergoing operative infrainguinal bypass for chronic ischemia were eligible for enrollment, although those requiring a prosthetic graft were preferentially considered. Immediately after bypass, the distal anastomosis was marked with clips, and the baseline anatomy of the anastomosis was documented with an intraoperative angiogram. The distal anastomotic site and 2 cm of surrounding tissues were irradiated to a total dose of 30 Gy, delivered in 10 fractions. The first dose was given within 48 h of surgery. Results: Twenty-one patients were enrolled in this study. No anastomotic or wound problems or any other short-term complications of the treatment developed. However, at a mean follow-up of 10 months (range 3–18), 12 (57%) of the 21 grafts had occluded. Angiography was performed in 2 patients after successful thrombolysis and demonstrated normal anastomoses without residual stenosis. Evidence of stenosis at the irradiated anastomosis was seen in only 1 of the 21 patients by ongoing ultrasound surveillance. Conclusion: Fractionated external irradiation to a total dose of 30 Gy delivered to the distal surgical anastomosis immediately after operative bypass has no short-term complications and was associated with an apparently low rate of intimal hyperplasia. However, any possible gains made by reducing the neointimal hyperplasia at the site of anastomosis were significantly diminished by the high frequency of thrombotic events.

Purpose: The major radiobiological issue in determining the rationale for the use of radiation to inhibit vascular restenosis is the identification of the target cell(s) and/or cytokine(s) responsible for neointimal hyperplasia and vascular remodeling. The central hypothesis of this report is that the macrophage/monocyte and PDGF are key elements in the process of neointimal hyperplasia seen following angioplasty, similar to their role in lesion formation and progression found in atherosclerotic thickening. Specific immunohistochemical and cytochemical stains were applied to a rat carotid model in a temporal series after balloon angioplasty to determine macrophage activity vs. smooth muscle cell proliferation, the latter being classically thought to be the cell responsible for restenosis. Methods and Materials: Neointimal hyperplasia was created in an established rat carotid artery model by a balloon catheter technique. Immediately following injury, treatment groups received irradiation via high dose rate (HDR) brachytherapy, the 192Ir source being placed externally to the vessel. Radiation was delivered to a length of 2 cm of the injured vessel at doses of 5, 10, and 15 Gy, and the animals were sacrificed at various time points following treatment (24 h to 6 months). Serial sections of tissue were stained immunohistochemically with the primary antibodies CD11b, mac-1, anti-PDGF, and α-smooth muscle actin. Results: Immediately (24 h) postinjury, there is an apparent migration of macrophages seen in the adventitia; after 1 week, proliferation and migration of macrophages could be seen clearly within all the vessel layers, especially in the intima; by 3 weeks, when there was evidence of neointimal hyperplasia, macrophages could still be seen, mainly in the intima scattered among the smooth muscle cells and myofibroblasts, and to a lesser degree at 6 months. There was corresponding expression of PDGF, whenever and wherever there were zones of activation/neointimal hyperplasia. α-Smooth muscle actin staining identified the smooth muscle cells distinct from the macrophages, and these SMCs exhibited activation in the neointimal hyperplasia zones at all later time points. Furthermore, we showed that radiation significantly reduced the macrophage population, while the onset of neointimal hyperplasia was accompanied by a return of the macrophage population. Conclusion: Our results suggest that the activated adventitial macrophage/monocyte are the key cells responsible for initiating the arterial neointimal hyperplasia and vascular remodeling developing postangioplasty as they are in the initiation and perpetuation of atheromatous thickening. Irradiation delivered immediately postinjury is, therefore, highly effective, because the macrophage population is exquisitely radiosensitive.