Yoshio Imahori

Postoperative hemodynamic and metabolic changes in patients with subarachnoid hemorrhage.

Positron emission tomography was performed using an oxygen-15 gas inhalation technique to measure regional cerebral blood flow, metabolic rate for oxygen, oxygen extraction fraction, and cerebral blood volume in 13 patients with subarachnoid hemorrhage during the period of delayed vasospasm after surgery as well as in 10 volunteers as controls. Compared with the controls, the patients showed decreased hemoglobin concentration and decreased total arterial oxygen content due to postoperative hemodilution. Global reductions in the metabolic rate for oxygen and in the tissue oxygen supply were noted even in the apparently normal cortex of the patients in spite of adequate blood flow and adequate oxygen extraction fraction. In addition, regional reductions in blood flow and in perfusion reserve were seen in the cortical territory corresponding to cerebral vasospasm. Our results indicate that two processes are involved in the pathophysiology of cerebral vasospasm: 1) generalized impairment of oxygen metabolism with a reduced tissue oxygen supply, even in the apparently normal cortex, and 2) additional impairment of regional perfusion in the territory of vasospasm.

Effect of hemodilution on cerebral hemodynamics and oxygen metabolism.

Background and Purpose To evaluate the effects of hemodilution on cerebral hemodynamics and oxygen metabolism in the normal human brain, we measured regional cerebral blood flow, oxygen extraction fraction, oxygen metabolic rate, and regional cerebral blood volume in eight normal volunteers before and after hemodilution using positron emission tomography and oxygen-15–labeled gas inhalation technique. Summary of Report Hemodilution was accomplished by phlebotomy of 400 ml and drip infusion of 500 ml low molecular weight dextran, which reduced hematocrit from 42.5% to 37.2% and arterial oxygen content from 19.1 to 16.9 ml/dl (both p < 0.005). It also increased mean cerebral blood flow from 45.2 to 47.7 ml/100 ml/min (p < 0.025), but decreased tissue oxygen delivery from 8.7 to 8.0 ml/100 ml/min (p < 0.05) and cerebral blood volume from 4.9% to 4.6% (p < 0.025) in the overall cortical gray matter. Conclusions Our results indicate that hemodilution in the tested range does not improve oxygen transport or tissue oxygenation in the normal human brain, although it increases cerebral blood flow.

Dopaminergic modulation of LTP induction in the dentate gyrus of intact brain

THE effect of the dopamine system on the induction of long-term potentiation (LTP) in the dentate gyrus was studied in anesthetized rats. A subthreshold tetanic train (seven pulses at 100 Hz) given to the perforant pathway, which usually fails to elicit LTP, potentiated a slope of field excitatory postsynaptic potentiation (fEPSP) measured from the hilus of the dentate gyrus when a precursor for catecholamine, L-3,4-dihydroxyphenylalanine (L-DOPA), was administered orally to rats. The increase in the fEPSP slope persisted for at least 60 min. Intraventricular injection of a specific dopamine D1/D5 agonist, SKF38393, mimicked the effect of L-DOPA, suggesting an involvement of D1/D5 receptors in the induction of dentate gyrus LTP. Consistent with this, intraventricular administration of the D1/D5 antagonist SCH23390 resulted in complete inhibition of LTP induction by a longer tetanus (100 pulses at 100 Hz), which usually elicits a robust LTP. Thus, D1/D5 receptor activation appears to modulate LTP induction in vivo.

Positron emission tomographic studies on cerebral hemodynamics in patients with cerebral contusion.

Positron emission tomography is currently one of the most useful methods for measurements of cerebral hemodynamics and oxygen metabolism, because it facilitates accurate analysis of the local cerebral circulation in three-dimensional quantitative images. In this study, we performed positron emission tomography studies to measure cerebral circulation in a total of 11 patients who sustained head injuries with contusion. Several parameters were measured including regional cerebral blood flow, regional cerebral blood volume, permeability, and regional cerebral metabolic rate for oxygen. Data from brains both with and without contusion were analyzed for chronological changes, in the subacute stage from the 8th to 29th day and in the chronic stage until 360 days after the injury and compared with similar data in a group of normal subjects. It was concluded that in the subacute stage, regional cerebral blood flow decreased (26 +/- 7 and 39 +/- 10 ml/100 g/min) and regional cerebral blood volume increased (5.6 +/- 1.8 and 5.4 +/- 0.9 ml/100 g) both in areas of cerebral contusion and in areas remote from cerebral contusion and that permeability increased in areas of contusion but not in remote brain areas. In the chronic stage, these parameters showed a tendency for recovery.

The Early Successful Treatment of Glioblastoma Patients with Modified boron Neutron Capture Therapy

We very effectively treated two patients with recurrent glioblastoma with modified boron neutron capture therapy (BNCT). In this paper, we describe the effectiveness of this treatment, and discuss the ways in which we modified the treatment. A 61-year-old man had a first operation for a right temporal glioblastoma, followed by full-dose chemo-radiotherapy. One year after the operation a partial removal was performed for the recurrent tumor at the same site. Fifty days after the second surgery, the patient received BNCT. We used an epithermal neutron beam as the neutron source, and used both sodium borocapate and boronophenylalanine as boron compounds with the craniotomy. Forty-eight hours after the BNCT, the follow-up MRI was applied to estimate the early effect of this treatment, which showed a 70% reduction in the contrast enhanced lesion, compared with the pretreatment MRI. In addition, the lesion/normal brain ratio of thallium-SPECT had improved markedly. No serial sequelae appeared after this treatment, and the patient remains healthy 6 months after the treatment.A 29-year-old young lady had a right temporal brain tumor, which was partially resected and followed by stereotactic radiosurgery for the residual mass. Seven months after the radiosurgery, a second operation was performed, which revealed the glioblastoma as diagnosis. We applied BNCT uneventfully for this patient with epithermal beam and two kinds of boron compounds as described above. For the treatment of the patient irradiation was applied without craniotomy with marked reduction of tumor volume immediately after the treatment.

Evaluation of fluoride-labeled boronophenylalanine-PET imaging for the study of radiation effects in patients with glioblastomas

Here we demonstrate that differentiation between glioblastoma (GB) tumor progression (TP) and radiation necrosis (RN) can be achieved with fluoride-labeled boronoalanine positron emission tomography (F-BPA-PET). F-BPA-PET images were obtained from histologically verified 38 GB, 8 complete RN, and 5 RN cases with partial residual tumors. The lesion/normal (L/N) ratios for these groups were 4.2 ± 1.4, 1.5 ± 0.3, and 2.0 ± 0.3, respectively. Ten GB patients underwent F-BPA-PET twice (once before and once after radiation treatment) due to enlargement of the original lesion or the development of new lesions post radiation. The L/N ratios of ten original site lesions had decreased by the second PET, and these lesions were revealed to be RN. In contrast, the L/N ratios of two lesions distant from the original site increased, and these lesions were revealed as cases of TP. Repeat PET imaging was found to be useful for evaluating changes in GB-associated tumor activity with respect to the treatment received.

Visualization of mRNA expression in CNS using 11C-labeled phosphorothioate oligodeoxynucleotide

Antisense phosphorothioate oligodeoxynucleotide for mRNA of glial fibrillary acidic protein (GFAP) was labeled with the positron emitter 11C and administered i.v. to rats bearing glioma, which were expected to exhibit active expression of GFAP. Antisense oligodeoxynucleotide was retained in tumor cells, yielding clear images of tumors, while the control 20% mismatch oligodeoxynucleotide and sense-strand oligodeoxynucleotide were not retained in tumor cells. Findings revealed sequence-specific binding of the antisense oligodeoxynucleotide to the GFAP mRNA. Our methods can be used directly for non-invasive imaging of human gene expression using PET, a frequently used method of clinical examination.

Survival benefit from boron neutron capture therapy for the newly diagnosed glioblastoma patients.

OBJECTIVE Since 2002-2007, we applied boron neutron capture therapy (BNCT) to >50 cases of malignant gliomas (MGs) with epithermal neutron irradiations. Recently, we showed the early radiographical improvement of malignant glioma patients by our modified BNCT, with simultaneous use of BPA (borono-phenylalanine) and BSH (sodium borocaptate). In this time, we focused on the survival benefit from BNCT for the newly diagnosed glioblastoma patients. METHODS BNCT group including 21 newly histological confirmed glioblastoma patients treated with surgical removal followed by BNCT in Osaka Medical College during 2002-2006 period. Ten patients were treated with BNCT only, and in the other 11 patients, 20-30 Gy fractionated external beam X-ray irradiation therapy (XRT) was performed after BNCT. No chemotherapy was administered until tumor progression was observed. RESULTS Treatments were well tolerated. Any kind of acute systemic or local severe toxicity were not demonstrated. Mean over all survival of the patients treated by BNCT was 20.7 and the median was 15.6 months with 2-years survival of 25%. Stratification by RPA criteria showed 6, 6, 8 and 1 patients, respectively, in classes III-VI. Three patients out of six in class III and one out of eight in class V are alive at the end point of this study. All the patients in classes IV and VI died. Median survival time for the BNCT group compared to the RTOG database was as follows: 20.6 months vs. 17.9 months for class III; 16.9 months vs. 11.1 months for class IV; 13.2 months vs. 8.9 months for class V. CONCLUSION The RTOG RPA prognostic criteria were helpful in establishing which class of glioma patients could potentially benefit from BNCT. BNCT showed a survival benefit in all of the RPA classes of the RTOG database not only for the good prognosis group.

Chronological Positron Emission Tomographic Study of Severe Diffuse Brain Injury in the Chronic Stage

Cerebral blood flow and metabolism were investigated in five patients with severe diffuse brain injury in the chronic stage, using positron emission tomography (PET). Regional cerebral blood flow, regional oxygen extraction fraction, regional cerebral blood volume, regional cerebral metabolic rate for oxygen, and regional cerebral metabolic rate for glucose were measured bilaterally in the frontal, temporal, occipital, and parietal gray matter, as well as the white matter of the centrum semiovale. In 4 of 5 patients, a follow-up PET study was also performed. In three cases, below-normal regional cerebral blood flow and regional cerebral metabolic rate for oxygen values accompanied by above-normal regional oxygen extraction fraction values, as well as low metabolism, were demonstrated in the initial PET studies. In two of three cases, clinical improvements were observed, and follow-up PET data also improved. These findings suggest that chronological PET studies may be able to assess quantitatively clinical improvements in patients with diffuse brain injury.

Treatment results of boron neutron capture therapy using intra-arterial administration of boron compounds for recurrent head and neck cancer

The effect of boron neutron capture therapy (BNCT) is correlated with the density of boron in the tumour. BNCT using intra-arterial administration of boron compounds was performed for recurrent head and neck cancer. Of the five patients treated, one achieved a complete response and four achieved a partial response. There was one case of transient headache but no severe adverse effects were observed. The advantages of using an intra-arterial administration route for BNCT, which causes the selective killing of tumour cells, might offer a new option in the treatment of recurrent head and neck malignancies. These promising results require further verification and optimization of the BNCT schedule; however, dose escalation would appear to be justified because the toxicity appears to be very low.