Bulk flow and diffusion revisited, and clinical applications

The first Klatzo-Lecture pays homage to an exceptional academician, scientist and teacher. The author spent nearly 1 year in Klatzo's laboratory at the NHI in Bethesda, and the first part of results presented here originate directly from this collaboration. It was shown that following cortical injury, movement of edema fluid into the tissue occurs by bulk flow, and that the driving force is a small tissue pressure gradient. Resolution of edema fluid is achieved by clearance into the ventricular and subarachnoid CSF, is enhanced in the presence of pressure gradients and is supported by re-absorption into capillaries. Using appropriate techniques, the formation rate as well as clearance of edema into CSF and tissue resorption could be determined in human brain metastases and malignant gliomas. Three examples of clinical applications based on the discussed mechanisms are presented: a. Fluorescence-guided surgery of gliomas is based on the accumulation of 5-ALA in tumour cells; there being enzymatically converted to PP-IX, a compound with deep red fluorescence. This fluorescence is used for the more accurate surgical removal of gliomas. b. Radioimmunotherapy of gliomas uses an anti-tenascin antibody, coupled with a nuclide, administered postoperatively into the tumour cavity, from where it diffuses into tissue, couples to the receptor at the glioma cells. Then the isotope destroys the tumour cells. c. Convection-enhanced delivery is based on the interstitial infusion of an appropriate cytotoxic drug into the white matter at low pressure. Thus, the method employs bulk flow, distributes a drug in a larger tissue volume and eventually achieves drug concentrations greater than systemic levels. Experimental studies and clinical results are presented for all three clinical applications.I am very grateful to Z. Czernicki and the organizing group for being offered the great honour of presenting the first Igor Klatzo Lecture. In this report first previous results of bulk flow and diffusion in the development and resolution of brain edema will be revisited, then some recent examples will be shown as to how this knowledge of diffusion and bulk flow can be transferred into clinical applications.A great part of the work on bulk flow and diffusion was done during a stay in I. Klatzo's laboratory in Bethesda in 1973/1974 (Fig. 1). Since then a long collaboration developed with I. Klatzo and M. Spatz. Due to given limits, I will concentrate on the studies of our group. Unfortunately it will not be possible to mention all the important groups who have contributed by essential studies.