David Fortin

Safety and efficacy of a multicenter study using intraarterial chemotherapy in conjunction with osmotic opening of the blood-brain barrier for the treatment of patients with malignant brain tumors.

The aim of this study was to determine the safety and efficacy of intraarterial chemotherapy with osmotic opening of the blood‐brain barrier (BBB) for the treatment of malignant brain tumors when administered across multiple centers.

Tumor bed radiosurgery after resection of cerebral metastases.

OBJECTVEAdjuvant irradiation after resection of brain metastases reduces the risk of local recurrence. Whole-brain radiation therapy can be associated with significant neurotoxicity in long-term survivors of brain metastases. This retrospective study evaluates the role of tumor bed stereotactic radiosurgery as an alternative method of irradiation after initial resection of brain metastases to prevent local recurrence. METHODSForty patients underwent tumor bed radiosurgery after resection of brain metastases at two separate academic medical centers. The median age was 59.5 years. Twenty patients (67.5%) had single metastases. Resection was complete in 80% and partial in 20% of the patients. At the time of radiosurgery, systemic disease was active in 57.5%, inactive in 32.5%, and in remission in 10% of the patients. The median Karnofsky Performance Scale score was 80% (range, 60–100%). Radiosurgery was performed a median of 4 weeks after tumor resection. The median cavity radiosurgery volume was 9.1 ml (range, 0.6–39.9 ml). The median margin and maximum radiation dose were 16 and 32 Gy, respectively. RESULTSLocal control at the resection site was achieved in 73% of patients at a median follow-up period of 13 months. No variable significantly affected local control. New remote brain metastases occurred in 54% of the patients. Symptomatic radiation effect was seen in 5.4% of the patients. The median survival was 13 months after radiosurgery (range, 2–56 mo). CONCLUSIONTumor bed radiosurgery provides effective local control of the tumor after resection in most patients. These preliminary data support radiosurgery after resection rather than traditional radiation therapy.

Recent Advances in Blood-Brain Barrier Disruption as a CNS Delivery Strategy

The blood–brain barrier (BBB) is a complex functional barrier composed of endothelial cells, pericytes, astrocytic endfeets and neuronal cells. This highly organized complex express a selective permeability for molecules that bear, amongst other parameters, adequate molecular weight and sufficient liposolubility. Unfortunately, very few therapeutic agents currently available do cross the BBB and enters the CNS. As the BBB limitation is more and more acknowledged, many innovative surgical and pharmacological strategies have been developed to circumvent it. This review focuses particularly on the osmotic opening of the BBB, a well-documented approach intended to breach the BBB. Since its inception by Rapoport in 1972, pre-clinical studies have provided important information on the extent of BBB permeation. Thanks to Neuwelt and colleagues, the osmotic opening of the BBB made its way to the clinic. However, many questions remain as to the detailed physiology of the procedure, and its best application to the clinic. Using different tools, amongst which MRI as a real-time in vivo characterization of the BBB permeability and CNS delivery, we attempt to better define the osmotic BBB permeabilization physiology. These ongoing studies are described, and data related to spatial and temporal distribution of a molecule after osmotic BBB breaching, as well as the window of BBB permeabilization, are discussed. We also summarize recent clinical series highlighting promising results in the application of this procedure to maximize delivery of chemotherapy in the treatment of brain tumor patients.

Ki-67: A prognostic factor for low-grade glioma?

PURPOSE Immunohistochemical techniques were used to detect the expression of Ki-67, a nuclear proliferation marker, in 180 low-grade glioma tumor specimens to determine whether Ki-67 is a prognostic predictor of survival or tumor recurrence. MATERIALS AND METHODS A clinical database of 180 low-grade glioma patients (35 children aged </=18 years and 145 adults) was compiled. Eighty patients had received postoperative radiotherapy (RT) and 100 patients had had RT deferred until the time of tumor progression/recurrence. Ki-67 indexes were evaluated retrospectively on tumor specimens from these patients using a semiautomated computer analysis technique. Ten observations were averaged per patient. The maximal Ki-67 value was recorded. RESULTS The correlation between the Ki-67 index and survival was much higher for the averaged Ki-67 value than for the maximal value. Of the tumor specimens, 29% had a negative Ki-67 index (i.e., zero Ki-67 positive cells) and 7.7% had an average Ki-67 index of >/=5%. An average Ki-67 value of >/=5% was prognostically significant for reduced cause-specific survival (CSS, p = 0.05) and a Ki-67 level >/=10% was strongly significant of a poor survival outcome (p = 0.009). Ki-67 was not prognostically significant for progression-free survival. Other prognostically significant factors for CSS included age (p = 0.05), Karnofsky performance status (p = 0.0001), radiation dose (p = 0.02), extent of surgical resection (biopsy vs. others, p = 0.004), and timing of radiation (p = 0.0005). Ki-67 did not remain an independent statistically significant factor for CSS on multivariate analysis. Age and Ki-67 positivity (both maximal and average values) directly correlated (i.e., advancing age was associated with a higher Ki-67 index). When the patient group was further subdivided by age and timing of RT (postoperative vs. deferred), the prognostic significance of Ki-67 for CSS was lost. Within the deferred RT subgroup, a maximal Ki-67 >2% was associated with a worsened CSS. Within the pediatric population, Ki-67-negative patients had a 5-year CSS and progression-free survival of 100%. The 5-year CSS and progression-free survival declined significantly to 84% and 67% for patients with tumors demonstrating any degree of Ki-67 positivity (p = 0.005 and p = 0.006, respectively). CONCLUSION Ki-67 is a useful predictor of CSS in low-grade gliomas; however, it is not independent of other prognostic factors, particularly age. Although Ki-67 was not helpful in predicting which adult patients were likely to benefit from postoperative RT, the results of the present study indicate a possible utility in the selection of pediatric patients for RT and in the selection of poorer prognosis patients for clinical trials.

Association of total dose intensity of chemotherapy in primary central nervous system lymphoma (human non-acquired immunodeficiency syndrome) and survival

OBJECTIVE The importance of enhanced drug delivery in patients with central nervous system (CNS) malignancies has not yet been demonstrated conclusively. Intra-arterial chemotherapy in combination with osmotic blood-brain barrier disruption (BBBD) increases drug delivery to tumor by 2- to 5-fold and to surrounding brain tissue by 10- to 100-fold as compared with intravenous administration of chemotherapy. Primary CNS lymphoma (PCNSL) is an excellent model for studying dose intensity because PCNSL is a highly infiltrative, chemosensitive, primary CNS malignancy in which the integrity of the blood-brain barrier is highly variable. METHODS Survival time was assessed in 74 non-acquired immunodeficiency syndrome patients with PCNSL who underwent a total of 1047 BBBD procedures. Total dose intensity is estimated by using the number of intra-arterial infusions or a cumulative degree of BBBD score. RESULTS Using proportional hazards multivariable analyses to adjust for baseline characteristics, survival was significantly associated with the total intensity of BBBD (P < 0.05). Additional statistical analyses demonstrate that survival bias does not fully explain these associations. Even when only patients who attained a complete response are considered, increased dose intensity resulted in increased survival. CONCLUSION In patients with PCNSL, a chemotherapy-responsive tumor type, survival time is highly associated with total drug dose delivered, even in analyses designed to control for potential survival biases. These results probably constitute the strongest evidence to date of the importance of total dose intensity in treating CNS malignancies.

Enhanced chemotherapy delivery by intraarterial infusion and blood‐brain barrier disruption in the treatment of cerebral metastasis

Cerebral metastases are clinically significant in 10% to 30% of patients with neoplasia. Multiple cerebral metastases are typically treated with palliative radiotherapy. There is no consensus on the role of enhanced chemotherapy delivery as an adjuvant treatment modality in this disease. In this report, the authors detailed their experience with intraarterial (IA) chemotherapy infusion with and without blood‐brain barrier disruption (BBBD) in patients with multiple cerebral metastases.

Standardization and detailed characterization of the syngeneic Fischer/F98 glioma model.

INTRODUCTION Adequate animal glioma models are mandatory for the pursuit of preclinical research in neuro-oncology. Many implantation models have been described, but none perfectly emulate human malignant gliomas. This work reports our experience in standardizing, optimizing and characterizing the Fischer/F98 glioma model on the clinical, pathological, radiological and metabolic aspects. MATERIALS AND METHODS F98 cells were implanted in 70 Fischer rats, varying the quantity of cells and volume of implantation solution, and using a micro-infusion pump to minimize implantation trauma, after adequate coordinates were established. Pathological analysis consisted in hematoxylin and eosin (H&E) staining and immunohistochemistry for GFAP, vimentin, albumin, TGF-bl, TGF-b2, CD3 and CD45. Twelve animals were used for MR imaging at 5, 10, 15 and 20 days. Corresponding MR images were compared with pathological slides. Two animals underwent 18F-FDG and 11C-acetate PET studies for metabolic characterization of the tumors. RESULTS Implantation with 1 x 10(4) cells produced a median survival of 26 days and a tumor take of 100%. Large infiltrative neoplasms with a necrotic core were seen on H&E. Numerous mitosis, peritumoral infiltrative behavior, and neovascular proliferation were also obvious. GFAP and vimentin staining was positive inside the tumor cells. Albumin staining was observed in the extracellular space around the tumors. CD3 staining was negligible. The MR images correlated the pathologic findings. 18F-FDG uptake was strong in the tumors. CONCLUSION The standardized model described in this study behaves in a predictable and reproducible fashion, and could be considered for future pre-clinical studies. It adequately mimics the behavior of human malignant astrocytomas.

Intraarterial chemotherapy and osmotic blood-brain barrier disruption for patients with embryonal and germ cell tumors of the central nervous system

The rate of durable responses in embryonal and certain germ cell tumors of the central nervous system (CNS) is unsatisfactory. Intraarterial chemotherapy and osmotic blood‐brain barrier disruption (IA/BBBD) increases drug delivery to the CNS.

Real-time multi-peak tractography for instantaneous connectivity display

The computerized process of reconstructing white matter tracts from diffusion MRI (dMRI) data is often referred to as tractography. Tractography is nowadays central in structural connectivity since it is the only non-invasive technique to obtain information about brain wiring. Most publicly available tractography techniques and most studies are based on a fixed set of tractography parameters. However, the scale and curvature of fiber bundles can vary from region to region in the brain. Therefore, depending on the area of interest or subject (e.g., healthy control vs. tumor patient), optimal tracking parameters can be dramatically different. As a result, a slight change in tracking parameters may return different connectivity profiles and complicate the interpretation of the results. Having access to tractography parameters can thus be advantageous, as it will help in better isolating those which are sensitive to certain streamline features and potentially converge on optimal settings which are area-specific. In this work, we propose a real-time fiber tracking (RTT) tool which can instantaneously compute and display streamlines. To achieve such real-time performance, we propose a novel evolution equation based on the upsampled principal directions, also called peaks, extracted at each voxel of the dMRI dataset. The technique runs on a single Computer Processing Unit (CPU) without the need for Graphical Unit Processing (GPU) programming. We qualitatively illustrate and quantitatively evaluate our novel multi-peak RTT technique on phantom and human datasets in comparison with the state of the art offline tractography from MRtrix, which is robust to fiber crossings. Finally, we show how our RTT tool facilitates neurosurgical planning and allows one to find fibers that infiltrate tumor areas, otherwise missing when using the standard default tracking parameters.

Blood-brain barrier disruption in the treatment of brain tumors.

Standard chemotherapy administered systemically has a limited efficacy in the treatment of brain tumors. One of the major obstacles in the treatment of brain neoplasias is the impediment to delivery across the intact blood-brain barrier (BBB). Many innovative approaches have been developed to circumvent this obstacle. One such strategy is BBB disruption (BBBD), which successfully increases the delivery of antineoplastic agents to the central nervous system (CNS). This chapter describes the application of the BBBD technique in rats. Different methods to evaluate and measure BBB permeability following hyperosmolar mannitol infusion including Evans blue staining, albumin immunohistochemistry, and dynamic magnetic resonance imaging are also described.