Koichiro Matsukado

Enhanced tumor uptake of carboplatin and survival in glioma-bearing rats by intracarotid infusion of bradykinin analog, RMP-7.

OBJECTIVE Intracarotid infusion of the bradykinin analog, RMP-7, can increase permeability in brain tumor capillaries. This study sought to determine the following: 1) the unidirectional transport, Ki, of radiolabeled [14C]carboplatin into brain tumors with either intravenous or intracarotid RMP-7 infusions; 2) the duration and extent of increased permeability in tumor capillaries during continuous RMP-7 infusions; and 3) the effect on survival of carboplatin combined with RMP-7 treatment in rats with gliomas. METHODS Wistar rats with RG2 gliomas were used, and a unidirectional transfer constant, Ki, was determined using quantitative autoradiography. In the survival study, the rats were treated with intra-arterial carboplatin and RMP-7 at Days 5 and 7 after tumor implantation. RESULTS Intracarotid infusion of RMP-7 for 15 minutes increased the transport of [14C]carboplatin to tumors by 2.7-fold, as compared with saline infusion alone (P < 0.001). The transports of [14C]dextran and [14C]carboplatin into tumors were significantly higher with 15 minutes of intracarotid infusion of RMP-7 (0.1 microgram/kg/min), compared to those with 10-, 30-, or 60-minute infusions (P < 0.01). Rats treated at Days 5 and 7 after tumor implantation with carboplatin alone (10 mg/kg) exhibited a modest increase in survival at 31 days (37%, compared to < 10% of controls), while those given the combination of carboplatin with RMP-7 exhibited a significantly higher survival rate (74%). CONCLUSION Intracarotid infusion of RMP-7 can selectively increase transport of carboplatin into brain tumors and results in higher survival in rats with gliomas. These findings support the use of intracarotid infusion of RMP-7 to enhance the delivery of carboplatin to patients with malignant brain tumors.

Unilaterally symptomatic moyamoya disease in children: long-term follow-up of 20 patients.

OBJECTIVE:In unilaterally symptomatic moyamoya disease in children, it remains controversial whether bypass surgery should be performed on the asymptomatic side along with on the symptomatic side. We aimed to verify the validity of our strategy of only performing bypass surgery on the symptomatic side. METHODS:Among 91 pediatric patients with moyamoya disease who underwent bypass surgery in our department between 1980 and 2004, 20 with unilateral ischemic symptoms who were followed for more than 60 months were analyzed in the present study. Initially, we only performed bypass surgery on the symptomatic side for all 20 patients. Among these 20 patients, five developed frequent transient ischemic attacks in the initially asymptomatic side and underwent a second bypass surgery on that side (Group A), eight developed sporadic transient ischemic attacks and were followed up without surgery (Group B), and seven did not experience any ischemic symptoms on the asymptomatic side (Group C). RESULTS:In total, 18 patients progressed well without cerebral infarctions after their last surgery, although some showed deterioration of angiographic stenosis and a transient decrease in the regional cerebral blood flow or cerebral perfusion reserve. One patient in Group A had an intraventricular hemorrhage 5 years after the second operation, and one in Group B had a minor stroke on the initially asymptomatic side. CONCLUSION:In unilaterally symptomatic moyamoya disease, bypass surgery for the asymptomatic side can be delayed until the development of ischemic symptoms, such as frequent transient ischemic attacks.

Selective Transvascular Delivery of Oligodeoxynucleotides to Experimental Brain Tumors

Optimal therapeutic strategy for malignant brain tumors is controversial. Recent studies of viral or nonviral gene therapy in rats emphasize the need for a selective delivery system. We examined whether phosphorothioate oligodeoxynucleotides (lacZ 2157, 5′-GTGGCGTCTGGCGGAAAACC-3′) could be selectively delivered transvascularly into experimental brain tumors following intracarotid infusion of bradykinin, a specific blood–tumor barrier opener. The specificity of 32P-labeled complementary antisense lacZ 2157 and the stability of lacZ 2157 in vivo were confirmed using slot-blotting hybridization method and polyacrylamide gel electrophoresis. Concentrations of lacZ 2157 after intracarotid injection (2 mg/kg, 10μg/kg/min) with or without bradykinin were determined in the brain, tumor tissue, liver, kidney, and plasma. The transfer ratio of lacZ 2157 from the plasma to the tissues was calculated and expressed as tissue content relative to plasma content of lacZ 2157 per mg tissue (Do, µl/mg). Delivery of lacZ 2157 to tumor tissue increased 3.24 times with bradykinin over delivery in controls (0.0243±0.0176 vs. 0.00750±0.00389; p<0.05). Delivery of lacZ 2157 to ipsilateral and contralateral cerebral cortex to the tumor, and delivery to the contralateral basal ganglia, did not increase significantly with bradykinin. These results indicate that such transvascular delivery with bradykinin can deliver a relatively large amount of oligodeoxynucleotide selectively to brain tumors without affecting normal brain.

Effect of histamine on the blood-tumor barrier in transplanted rat brain tumors.

We studied the effect of intracarotid administration of histamine on the blood-tumor barrier permeability and also on the blood-brain barrier permeability in transplanted rat C6 glioma. There was no definite Evans blue (EB) extravasation either in normal or tumor tissue after intracarotid saline infusion. In contrast, histamine at doses of 1 and 10 micrograms/kg/min produced slight to moderate EB extravasation in the tumor without any significant extravasation in the normal brain tissue. Intravenously administered H1 and H2 receptor antagonists (5 mg/kg each) reduced the histamine (10 micrograms/kg/min) induced extravasation of EB in the tumor tissue. These results indicated that brain tumor vessels responded to histamine in a different fashion from normal brain capillaries. Histamine could thus be utilized for selective drug delivery to brain tumors without affecting normal brain tissue.

Selective Increase in Blood-Tumor Barrier Permeability by Calcium Antagonists in Transplanted Rat Brain Tumors

To clarify the altered response of calcium antagonists on pathological vessels, we investigated the effect of intracarotid infusion of nifedipine on the blood-brain barrier (BBB) permeability using a rat glioma model. Animals were treated with 0, 0.1, 1, 5, and 10 micrograms/kg/min of intracarotid continuous infusion of nifedipine. 2% Evans blue (EB, 2 ml/kg) was injected intravenously immediately after nifedipine infusion. BBB and blood-tumor barrier (BTB) permeability were evaluated by direct visual and histological observation. During the entire experiment, systemic parameters such as arterial blood pressure and blood analysis were not changed significantly. There was a dose-dependent increase of EB permeability selectively in the tumor tissue without affecting the normal brain. These results indicate that tumor vessels may show an altered response to calcium antagonists. Intracarotid administration of calcium antagonists contribute to a selective enhancement of drug delivery to malignant brain tumors without affecting the normal brain.

The transventricular preforniceal approach for exophytic chiasmatic/hypothalamic astrocytomas extending into the anterior third ventricle

BackgroundSurgical treatment of large exophytic chiasmatic/hypothalamic astrocytomas extending into the anterior third ventricle remains a challenging task for neurosurgeons. In particular, when the tumor extends from the chiasmatic region upward to the foramen of Monro, damage to the fornix and other neurovascular structures is a major concern.ObjectiveTo describe the technique used in the transventricular preforniceal surgical approach to remove the superior and superoposterior part of the tumor in the third ventricle for treatment of exophytic chiasmatic/hypothalamic astrocytoma.MethodsThe transventricular preforniceal approach was used in two cases of exophytic chiasmatic/hypothalamic astrocytoma. The approach is summarized in 4 procedures: 1) exposure of the anterior horn of the lateral ventricle by the transcallosal approach, 2) identification of the foramen of Monro and the fornix, 3) incision of the septum pellucidum or the wall of the lateral ventricle, in front of the columns of the fornix, and 4) removal of the tumor through the space between the anterior commissure and the columns of the fornix.ResultsBecause the tumor compressed the foramen of Monro posteriorly and stretched the space between the anterior commissure and the columns of the fornix, the posterosuperior part of the tumor in the third ventricle was successfully removed through the surgical corridor in front of the columns of the fornix. In both cases, tumors were successfully removed using this approach without damaging the fornix and the anterior commissure. Residual tumor was removed using an anterior interhemispheric translamina terminalis approach in a two-stage surgery.ConclusionsThe transventricular preforniceal approach can be applied for removing the superior part of exophytic chiasmatic/hypothalamic astrocytomas, because the space between the anterior commissure and the fornix is stretched by the tumor, providing an appropriate surgical corridor.

Microcatheter shaping using intravascular placement during intracranial aneurysm coiling

Background The selection of a pre-shaped microcatheter or a shaping method must be carefully considered for successful aneurysm coiling. The objective of this report is to verify the use of intravascular placement to establish an appropriate microcatheter shape. Methods Fifteen patients (15 aneurysms) were included in this study because of the predicted difficulty of microcatheter insertion and stabilisation. The SL-10 straight microcatheter was inserted into the parent artery until the tip of the catheter passed through the neck of the aneurysm. After 5 minutes, the microcatheter was pulled out and the shape acquired from intravascular placement was confirmed and compared with the three-dimensional rotational angiography. In addition, the microcatheter tip was steam-shaped for coiling and coil embolisation was performed. A silicone flow model was also used to confirm our findings. The first experiment compared the bend angle in four different microcatheters placed in the model for 5 minutes. In the second experiment, the SL-10 straight microcatheter was placed in the model, and the bend angle was measured at 2.5, 5, 7.5 and 10 minutes to observe the changes in bend angle over time. Results The SL-10 straight microcatheter, in place for 5 minutes, acquired a shape similar to the patient’s own vessel. Among the 15 patients included, 13 were treated using an intravascular shaped microcatheter. In the flow model experiments, the SL-10 most easily acquired the vessel shape, and the shape change stabilised after 5 minutes. Conclusion Shaping the SL-10 straight microcatheter using intravascular placement is an effective shaping method for aneurysm coil embolisation.

Effect of calcium antagonists on regional cerebral blood flow in transplanted rat brain tumors

We studied the effect of intracarotid infusion of various calcium antagonists on regional CBF (rCBF) in the C6 rat glioma by a hydrogen clearance method. Nimodipine at doses of 0.1, 0.5 and 1 μg/kg/min was found to produce tumor-specific increases in the rCBF (40.2 ± 18.4%, p < 0.01, 67.8 ±32.6%, p < 0.001 and 37.3 ±37.2%, p < 0.05, respectively) without affecting systemic blood pressure. Regarding the time course of the nimodipine effects, at a dose of 0.5 μg/kg/min, rCBF in the tumor showed maximum value at fifteen minutes after the start of the intracarotid infusion. Diltiazem at doses of 5, 20, and 40 μg/kg/min also increased tumor rCBF in a dose-dependent manner (27.9 ± 12.5%, p < 0.001, 52.0 ± 21.8%, p -AN 0.001 and 54.5 ± 18.4%, p < 0.001, respectively). Both nifedipine and flunarizine significantly increased the rCBF in the tumor, while they did not cause a higher percent increase of the rCBF when compared with those of nimodipine and diltiazem. No significant percent increase of the rCBF in the tumor was observed in verapamil treated rats. These results indicate that tumor vessels may have an altered response to calcium antagonists, especially to nimodipine and diltiazem, when compared to normal brain capillaries. The varied responses to calcium antagonists could be explained by their differences in tissue selectivity and affinity to calcium channels.

Effect of intracarotid bradykinin infusion on cerebral blood flow in dogs.

We examined whether intracarotid infusion of bradykinin altered circulation in the normal canine brain. Twenty-four anesthetized dogs were divided into four groups receiving different doses of bradykinin (1, 2.5, 5, and 10 micrograms kg-1 min-1). Regional cerebral blood flow (rCBF) was measured continuously using laser Doppler flowmetry through a burr hole in the frontal bone. Systemic blood pressure (SBP) and heart rate (HR) were monitored simultaneously. Higher doses of bradykinin significantly but temporarily decreased rCBF and SBP immediately after the start of infusion; these parameters rapidly recovered and then were stable through the rest of the infusion. During this period, percent change in rCBF and SBP was small, and differences between groups were not significant. On the other hand, HR increased during infusion and remained high. SBP, rCBF, and HR returned to pre-infusion levels after bradykinin was stopped. The results suggest that intracarotid infusion of bradykinin for treatment of brain tumors would be safe in terms of circulation to the uninvolved brain.