In vivo isolated kidney perfusion with tumour necrosis factor α (TNF-α) in tumour-bearing rats

Isolated perfusion of the extremities with high-dose tumour necrosis factor α (TNF-α) plus melphalan leads to dramatic tumour response in patients with irresectable soft tissue sarcoma or multiple melanoma in transit metastases. We developed in vivo isolated organ perfusion models to determine whether similar tumour responses in solid organ tumours can be obtained with this regimen. Here, we describe the technique of isolated kidney perfusion. We studied the feasibility of a perfusion with TNF-α and assessed its anti-tumour effects in tumour models differing in tumour vasculature. The maximal tolerated dose (MTD) proved to be only 1 μg TNF-α. Higher doses appeared to induce renal failure and a secondary cytokine release with fatal respiratory and septic shock-like symptoms. In vitro, the combination of TNF-α and melphalan did not result in a synergistic growth-inhibiting effect on CC 531 colon adenocarcinoma cells, whereas an additive effect was observed on osteosarcoma ROS-1 cells. In vivo isolated kidney perfusion, with TNF-α alone or in combination with melphalan, did not result in a significant anti-tumour response in either tumour model in a subrenal capsule assay. We conclude that, because of the susceptibility of the kidney to perfusion with TNF-α, the minimal threshold concentration of TNF-α to exert its anti-tumour effects was not reached. The applicability of TNF-α in isolated kidney perfusion for human tumours seems, therefore, questionable. © 1999 Cancer Research Campaig

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Clinical perspectives on secular trends of intervertebral foramen diameters in an industrialized European society

Low back pain origins have been a matter of great controversy. While spinal stenosis is now radiologically traceable, the alteration of intervertebral foramen is less clear. The aim of this study was to assess "secular trends"-alterations occurring from one generation to the next-in osseous intervertebral foramina of the major vertebral segments in an industrialized society, and to discuss their possible clinical implication. The macerated "maximum intervertebral foramen width" and "intervertebral foramen height" of all major vertebral levels in 71 non-pathologic Swiss adult skeletons from the nineteenth and early twentieth century, with known individual age and sex and similar geographic and socio-economic background, were measured by sliding caliper at validated landmarks. A secular trend of the increase in "maximum intervertebral foramen width" is found for most levels, with females showing a more prominent alteration. Additionally, the non-pathologic "maximum intervertebral foramen width" does not change with respect to individual age, nor is a significant side difference detectable. "Intervertebral foramen height," hereby defined as the difference of the dorsal vertebral body height minus pedicle height, demonstrates for most levels, and either sex, an insignificant negative secular trend. Neither stature nor skeletal robustness vary significantly through time within this particular sample. The results of this study, despite obvious inadequacies of methods used, exclude secular narrowing of the "maximum intervertebral foramen width" as the only cause of radiculopathy or spinal stenosis. Furthermore, we found a mild insignificant decrease of the clinically more relevant "intervertebral foramen height." Nevertheless, the detected short-time variability of the bony intervertebral foramen, independent of individual stature, skeletal robustness or age, argues for an enhanced focus on the understanding of clinically relevant changes of spinal morphology from generation to generation