Advances in the understanding of the blood-brain barrier in neuro-oncology.

The blood-brain barrier (BBB) is a paradox. On one hand, it protects the brain from what would otherwise be a constant systemic barrage of noxious substances. On the other hand, it prevents, in large measure, the delivery of therapeutic agents to patients with brain tumors. In an ongoing effort to improve the understanding and clinical consequences of the BBB and its disruption, a 3-day meeting was held under the direction of Drs. Edward A. Neuwelt and Nancy Doolittle of Oregon Health and Science University. Nearly 100 experts from various clinical and basic science disciplines participated in the Eighth Annual Meeting of the Blood-Brain Barrier Disruption Consortium (April 25 through April 27, 2002, at Skamania Lodge in Stevenson, WA). The meeting, “Importance of the Blood-Brain Barrier and Imaging in Future Neuro-Oncology Therapeutics,” was partially funded by an R13 meeting grant from the National Institutes of Health. It was presented after an afternoon symposium titled “Mechanisms and Therapeutics of Neurologic Disease: Impact of the Blood-Brain Barrier” that took place in Portland, Oregon, on April 24. At the April 25–27 meeting, a full range of clinical topics in neuro-oncology was presented, extending from funding opportunities through clinical management and new directions in therapeutics and imaging, which allowed for lively exchanges between the presenters and the audience. The balanced mixture of state-of-the-art clinical protocols and future directions for patient care enabled practicing physicians (neurologic surgeons, neurologists, medical oncologists, radiation oncologists, diagnostic radiologists) to appreciate the ongoing translational efforts bringing new concepts to clinical fruition. The initial evening of the consortium, opened by Archie Bleyer (MD Anderson Cancer Center), concentrated on pediatric and adolescent brain tumors and provided an introduction to case presentations the next day by Gregory Hornig (Children’s Mercy Hospital), Nate Selden (Oregon Health and Science University), and Kenneth Stevens (Oregon Health and Science University), who demonstrated combination therapy (surgery, chemotherapy) and BBB disruption for high grade glioma and primitive neuroectodermal tumors in children. Dr. Hornig discussed the importance of chemotherapy delivery as a means to decrease the need for radiation. He illustrated this concept by presenting a 2-year-old child enrolled in the Oregon Health and Science University Blood-Brain Barrier Disruption Program who, after completion of a bone marrow transplant, had recurrence of the primative neuroectodermal tumor but subsequently had a dramatic response to intra-arterial delivery of chemotherapy after BBB disruption (Fig 1, A–D). This permitted up to a 100-fold increase in drug delivery to the brain and CSF compared with the same dose when IV administered. Thus, only very focused radiosurgery and not cranial spinal radiation was subsequently administered. The child remained healthy and without recurrence 24 months later. Raymond Mulhern (St. Jude Children’s Hospital) continued the discussion of efficacy versus toxicity with a focus on radiation therapy and neuropsychological testing. He documented a continual decline of patients’ intelligence quotient over time after radiation therapy. This decline correlated with diminution of white matter volume, as determined by volumetric measurements based on serial MR images. Altering therapeutic chemotherapy and radiation therapy strategies to diminish these deleterious effects was discussed. It is anticipated that functional MR imaging (cortical activation by using the blood oxygen level dependent technique) will have a role in assessing the effects of these treatment protocols. Gigi McMillan (Director, We Can Pediatric Brain Tumor Network) presented information from the patient advocate perspective. As the mother of a child with a brain tumor, she brought attention to the significance of the emotional health of the family. She noted that treating physicians and health care providers can ensure continued participation in treatment studies, especially during collection of crucial follow-up data. Clinical trials involving chemotherapy with a focus on dose intensity was the concentration of the next session. The challenges and problems of conducting randomized clinical trials in brain tumors were discussed from the perspective of a statistician, Dale Kraemer (Oregon Health and Science University). The rare occurrence of some tumors, difficulties with patient recruitment, and biases in selection and referrals were all mentioned as problems in designing randomized clinical trials. The need for a standardized tumor response definition was discussed. Leslie Muldoon (Oregon Health and Science University) emphasized work on preclinical chemo-protection studies in which increased chemo-protection could allow for a greater dose and therefore result in increased cytotoxicity to a tumor. For example, Nancy Doolittle described the potential use of sodium thiosulfate infusion 4 hours after BBB disruption, when BBB permeability has returned to baseline, as a protective agent for carboplatin-based high frequency hearing loss and possibly as a prevention of thrombocytopenia when administered in high doses, 4 or 8 Meeting Summary