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Chemotherapy of brain tumors

Uptake of tritiated methotrexate by a transplantable intracerebral ependymoblastoma in mice

Charles H. Tator

✓ The uptake and distribution in brain tumors of a parenterally administered chemotherapeutic agent were studied in mice bearing intracerebral implants of a transplantable ependymoblastoma. Tritiated methotrexate (3H-MTX) was injected intravenously, and autoradiographs of the tumors and adjacent brain were prepared at 2, 10, and 60 min after injection using a technique suitable for soluble compounds. In the tumors at 2 min the drug was mainly intravascular and interstitial while at 60 min the drug was mainly intracellular. This is the first demonstration of cellular uptake of a chemotherapeutic agent by neoplastic cells within the brain. At 60 min, almost all the cells in the central mass of the intracerebral tumors were heavily labeled. However, cells at the periphery of the mass and those infiltrating into adjacent brain showed scanty labeling. Uptake in normal brain was very low, while uptake in edematous brain adjacent to the tumors was much higher although not as high as in the tumors. The study shows that this chemotherapeutic agent is capable of penetrating into the neoplastic cells of an intracerebral tumor following parenteral administration, but that the degree of penetration varies considerably depending on the location of the cells within the brain.

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Michael G. Fehlings and Charles H. Tator

Object. The authors conducted an evidence-based review of the literature to evaluate critically the rationale and indications for and the timing of decompressive surgery for the treatment of acute, nonpenetrating spinal cord injury (SCI).

Methods. The experimental and clinical literature concerning the role of, and the biological rationale for, surgical decompression for acute SCI was reviewed. Clinical studies of nonoperative management of SCI were also examined for comparative purposes. Evidence from clinical trials was categorized as Class I (well-conducted randomized prospective trials), Class II (well-designed comparative clinical studies), or Class III (retrospective studies).

Examination of studies in which animal models of SCI were used consistently demonstrated a beneficial effect of early decompressive surgery, although it is difficult to apply these data directly to the clinical setting. The clinical studies provided suggestive (Class III and limited Class II) evidence that decompressive procedures improve neurological recovery after SCI. However, no clear consensus can be inferred from the literature as to the optimum timing for decompressive surgery. Many authors have advocated delayed treatment to avoid medical complications, although good evidence from recent Class II trials indicates that early decompressive surgery can be performed safely without causing added morbidity or mortality.

Conclusions. There is biological evidence from experimental studies in animals that early decompressive surgery may improve neurological recovery after SCI, although the relevant interventional timing in humans remains unclear. To date, the role of surgical decompression in patients with SCI is only supported by Class III and limited Class II evidence. Accordingly, decompressive surgery for SCI can only be considered a practice option. Furthermore, analysis of the literature does not allow definite conclusions to be drawn regarding appropriate timing of intervention. Hence, there is a need to conduct well-designed experimental and clinical studies of the timing and neurological results of decompressive surgery for the treatment of acute SCI.

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Willem Wassenaar, Charles H. Tator, and Wei Sum So

✓ The authors describe a brain tumor model for chemotherapy studies. The tumor is an intracerebral ependymoblastoma that kills the host in a short time (median survival, 27.5 days) and yields consistent, uniform survival curves. A suspension of tumor cells is injected into the right frontal lobe of the mouse by means of a stereotaxic frame, and produces a highly invasive, almost entirely intracranial brain tumor. The use of mice permits extensive chemotherapeutic trials for brain tumors at low cost. It is felt that this model will prove to be very useful for studies of brain tumor chemotherapy.

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Charles H. Tator and Dr. Med. Lüder Deecke

✓ Investigations were performed to determine the relative therapeutic value of local hypothermic perfusion, local normothermic perfusion, and durotomy in monkeys injured by circumferential compression of the spinal cord at T9–10. A new method of cord compression was used consisting of an inflatable Silastic cuff which was passed around the cord extradurally and inflated to either 350 or 400 mm Hg. At the lower compression force, both hypothermic and normothermic perfusion improved the neurological recovery compared to that in control animals. However, at the higher degree of compression only normothermic perfusion produced significantly better recovery. Durotomy was excluded as a contributing factor. The results indicate that normothermic perfusion is a better method of treatment and that the beneficial effect of hypothermic perfusion is probably due to the perfusion rather than the hypothermia. The mechanism by which perfusion exerts its beneficial effect is unknown, but it is suggested that dialysis of noxious substances from the injured cord may play a role.

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Dr. Med. Lüder Deecke and Charles H. Tator

✓ Controlled compression of the spinal cord at a given pressure using the circumferential cuff technique has yielded consistent, reproducible cord injury in primates. To test the constancy of the mechanical factors involved, functional tests were performed to study spinal cord conduction before, immediately after, and up to 3 hours after the injury. Two long fiber tracts were tested, the dorsal funiculus and the pyramidal tract. Afferent conduction testing was carried out extradurally recording the afferent volley in the posterior column following sciatic nerve stimulation. The normal triphasic volley before injury changed after injury into a large monophasic positive “killed end potential” at the site of the lesion; an iso-electric line rostral to the lesion site indicated a complete afferent conduction block up to the end of the experiment (3 hours after injury). Efferent conduction was tested by stimulating the pyramidal tract in the cord above the injury site with a special extradural electrode and observing the most distal hind limb movements (flexion of the hallux). The neurophysiology of this type of spinal cord recording and stimulation is discussed as well as its possible importance in establishing the severity of a spinal cord injury, the response to treatment, and the prognosis in patients with spinal cord injuries.