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Minoru Fujiki, Hidenori Kobayashi, Tatsuya Abe, and Tohru Kamida

Object. Data in the present study demonstrate that repetitive transcranial magnetic stimulation (rTMS) induces ischemic tolerance against delayed neuronal death (DND) of hippocampal neurons following an otherwise lethal ischemic insult.

Methods. Various regimens of rTMS were delivered to adult gerbils at various times prior to an episode of ischemia induced by transient (5-minute) bilateral common carotid artery (CCA) occlusion. The extent of DND in the CA1 region of the hippocampus was assessed quantitatively 7 days after the transient ischemic episode.

When rTMS was delivered 2 to 5 days prior to bilateral CCA occlusion, DND was substantially attenuated; delivery of rTMS 12 to 24 hours prior to occlusion induced partial tolerance. In the group of animals that had received stimulation 2 days prior to occlusion, neuron density in the CA1 sector was significantly higher (three gerbils, 210.33, 86.01% of normal) than in the group that experienced ischemia only (three gerbils, 10.66, 4.36% of normal). A similar degree of neuron sparing occurred when stimulation was delivered 3, 4, or 5 days prior to occlusion. Note that rTMS was effective when it was delivered at frequencies of 25 and 50 Hz. Stimulation at 25 Hz for 128 seconds (3200 pulses) was more effective than stimulation at 50 Hz for 64 seconds (3200 pulses) or 128 seconds (6400 pulses), however.

Conclusions. Noninvasive rTMS represents an important tool for exploring the mechanisms of ischemic tolerance and preventing ischemic neuronal damage.

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Yoshimasa Mori, Tatsuya Kobayashi, and Yuta Shibamoto


Metastases to the pituitary gland and cavernous sinus occasionally occur. Metastases of this nature are problematic because they are adjacent to eloquent structures such as cranial nerves, including the optic pathways and nerves for extraocular movement and facial sensation. Stereotactic radiosurgery has been reported to be safe and effective for metastases in various sites of brain parenchyma, providing the tumors are not large. Radiosurgery can be performed to treat a precisely defined target, and the risk of radiation side effects on the surrounding structures is reduced. The results of Gamma Knife surgery (GKS) for the treatment of metastases in the pituitary gland and the cavernous sinus are evaluated.


Among 623 patients with brain metastases treated by GKS, 13 patients (2.1%) had pituitary and/or cavernous metastases. The primary malignancies included lung cancer (five cases), breast cancer (two cases), parotid cancer (two cases), renal cell carcinoma, thyroid cancer, nasal cancer, and gastrointestinal stromal tumor (one case each). The location of the tumors was the pituitary gland (Type 1) in four patients, the cavernous sinus (Type 2) in five patients, and both the cavernous sinus and the sellar region (Type 3) in four patients. The patients' symptoms included dysfunction of the pituitary gland (two patients), visual disturbance (four patients), oculomotor palsy (one patient), abducent palsy (five patients), and trigeminal dysfunction (five patients). A margin dose of 12 to 12.3 Gy was delivered to pituitary metastases. A margin dose of 14.4 to 20 Gy was delivered to cavernous lesions. The dose selection depended on the spatial relationship between tumors and the cranial nerves. Imaging and clinical follow-up data have been obtained in nine of 13 patients for 2 to 12 months (median 4 months) after GKS. Three pituitary and/or cavernous tumors are stable in size, and six tumors have disappeared or decreased in size; full or partial improvement of visual function, extraocular movement, and facial sensation have been achieved in these six patients.


These preliminary results seem to indicate that GKS is a safe and effective treatment for pituitary and cavernous metastases, as it is effective for parenchymal metastases and promptly improved some patients' symptoms.

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Tatsuya Kobayashi, Naoki Kageyama, and Ken Ohara

✓ The authors report the results of internal irradiation with labeled chromic phosphate (32P) and gold-198 (198Au) colloid in eight cases of cystic craniopharyngiomas. They used a newly developed dosimetric formula, by which the radiation dose at the cyst wall and at any point far from the radioactive source can be calculated. Ten courses of irradiation in eight patients were carried out by injection of either 32P or 198Au colloid into the cyst through an Ommaya drainage system that had been placed at craniotomy. Follow-up studies ranging from 13 to 156 months revealed that all cysts were effectively treated, with elimination of fluid or collapse of the cyst. This was confirmed by Conray cystography and/or computerized tomography.

Not only the dose delivered to the wall but also the thickness of the cyst wall and the location of the cyst are important factors in planning internal irradiation. A safe and adequate dose to the cyst wall could range between 9000 to 30,000 rads for craniopharyngioma. This treatment is suitable for large cysts that are thought to be difficult to remove radically, recurrent cysts resistant to previous treatment, or multiple cysts. Internal irradiation may also be applicable in other cystic intracranial tumors if dosimetry is calculated accurately.

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Tatsuya Kobayashi, Louis Bakay, and Joseph C. Lee

✓ The deposition of Hg203-chlormerodrin was studied in intracranial tumors in mice induced by implantation of 20-methyl cholanthrene by tissue assay, as well as light microscopic and electron microscopic autoradiography. The investigations were carried out in astrocytomas, glioblastomas, and meningeal tumors. The chlormerodrin content of the tumors exceeded that of normal brain with a significant tumor/brain ratio ranging from 5.8 to 22.5. It was found that the chlormerodrin molecule becomes rapidly incorporated in the tumor cells, with a preference for that portion of the cytoplasm associated with the vacuolar system.

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Symptomatic Rathke's cleft cyst

Morphological study with light and electron microscopy and tissue culture

Jun Yoshida, Tatsuya Kobayashi, Naoki Kageyama, and Masaki Kanzaki

✓ A rare case is reported in which a symptomatic Rathke's cleft cyst was studied by light and electron microscopy and tissue culture. The findings are compared with those of a craniopharyngioma studied in the same way. The patient was a 26-year-old woman presenting with headache, chiasmatic syndrome, and hypopituitarism. A cyst containing a mural nodule was partially removed and an Ommaya reservoir placed in the operative site for further treatment. The cyst wall was composed of connective tissue and three kinds of epithelial cells: non-ciliated squamous, ciliated columnar, and mucous-secreting cells. The morphology of these cells in vitro was similar to prickle cells seen in craniopharyngioma and the epidermis. It is concluded that both Rathke's left cyst and craniopharyngioma originate in remnants of Rathke's pouch, but at times may show some histological differences.

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Tatsuya Kobayashi, Yoshihisa Kida, and Toshinori Hasegawa


One hundred seven cases of craniopharyngiomas were treated using gamma knife surgery (GKS) at Komaki City Hospital during the past 12 years. The authors report the long-term results obtained in 100 patients who were followed for 6 to 148 months (mean 65.5 months).


All patients underwent GKS. The mean tumor diameter and volume were 18.8 mm and 5.8 ml, respectively; lesions were treated with a maximum dose of 21.8 Gy and marginal dose of 11.5 Gy (mean isocenters 4.5). Overall tumor responses were complete in 19, partial in 44, no change in 14, and disease progression in 23, yielding a complete response rate of 19%, overall response rate of 63%, control rate of 77%, and progression rate of 23%. Considering factors such as patient age, nature of the tumor (solid, mixed, cystic), frequency of previous treatments, and tumor size, the age and nature of the tumor were significant prognostic factors.

Changes in neurological and pituitary–hypothalamic symptoms after GKS were evaluated in 91 patients. Overall improvement was demonstrated in 17 (18.7%), no change in 59 (64.8%), and deterioration in 15 (16.5%). Outcome was documented in 93 cases: excellent in 42, good in 23, fair in seven, poor in three, and dead in 18 patients.


Stereotactic GKS is a safe and effective treatment as an adjuvant or boost therapy for postresection residual and/or recurrent craniopharyngiomas; the effects are durable and side effects acceptable.

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Yoshihisa Kida, Tatsuya Kobayashi, and Yoshimasa Mori

Object. The purpose of this paper is to report the long-term results of gamma knife radiosurgery (GKS) for low-grade astrocytomas.

Methods. Fifty-one patients with low-grade astrocytomas treated with GKS and followed for more than 24 months are reported. Of the 51 patients, 12 harbored Grade I astrocytomas in and around the visual pathways and hypothalamus. The remaining 39 harbored Grade II astrocytomas. The mean patient age at time of GKS was 9.8 years for patient with Grade I and 30.9 years for those with Grade II astrocytomas. The mean tumor diameter was 25.4 mm for Grade I and 23.7 mm for Grade II tumors. The mean margin dose was 12.5 Gy for Grade I and 15.7 Gy for Grade II tumors.

In the mean follow-up period of 27.6 months, both Grade I and Grade II astrocytomas responded well to GKS. Grade I astrocytomas had a response rate of 50% and a control rate of 91.7%. Grade II astrocytomas had a 46.2% response rate and an 87.2% control rate. Statistical analyses concerning the efficacy and related factors showed a significantly better response for patients 10 years of age or older with Grade I and those with a follow-up period of more than 24 months. Complications included radiation-induced edema in 18 (35.3%) of 51 cases, cyst formation or enlargement in five (9.8%), and transient tumor enlargement in three (5.9%).

Conclusions. Radiosurgery can play an important role in the treatment of low-grade astrocytomas, and complete cure of these tumors is expected in at least some of the cases.

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Yoshihisa Kida, Tatsuya Kobayashi, Jun Yoshida, Kyouzou Kato, and Naoki Kageyama

✓ Therapeutic results in 17 cases of alpha-fetoprotein (AFP)-secreting tumors of the central nervous system are reported. Twelve of the patients were male and five female. The patients' ages ranged from 5 years to 25 years (mean 13.6 years). The tumors originated in the pineal region in 10 cases, in the suprasellar region in four cases, and in both regions in one case; of the other two tumors, one originated in the basal ganglia and one in the sacrococcygeal region. Extraneural metastases or subarachnoid dissemination occurred in seven cases. Increased AFP titer in the serum or cerebrospinal fluid was verified in 13 cases. The patients were divided into two groups: those treated before (Group A) and those treated after (Group B) the introduction in 1980 of cisplatin as a chemotherapeutic agent. All seven Group A patients died, even after extensive therapy consisting of surgery, radiotherapy, and chemotherapy (ACNU or adriamycin) in some of the cases. The mean survival time following diagnosis for Group A was 23.7 months. Six of the 10 Group B patients died an average of 25.8 months after diagnosis; however, the other four were still alive and well an average of 25.3 months after diagnosis. The tumors responded well to chemotherapy consisting of cisplatin either alone or combined with bleomycin and vinblastine. The initial response rate to treatment in Group B was 100% and five cases had a complete remission, verified by computerized tomography or the serum AFP level. Once the tumor recurred, the response to cisplatin was markedly decreased. It is suggested that an effective therapy must still be sought for recurrent tumors.

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Mario Francesco Fraioli, Filiberto Contratti, and Chiara Fraioli

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Tatsuya Kobayashi, Yoshihisa Kida, and Yoshimasa Mori

Object. The authors sought to analyze the long-term outcome of patients with Cushing disease who underwent gamma knife radiosurgery (GKS) as either an adjuvant or primary treatment.

Methods. Twenty-five patients with Cushing disease were treated by GKS and followed for more than 2.5 years (mean 5.3 years).

The overall results showed a complete response rate of 30%, a response rate of 85%, and a tumor control rate of 100%. Tumor size and radiation dose were the most important factors related to the treatment response. The complete response rate for microadenomas and small adenomas was significantly higher than that for macroadenomas. An 83.2% complete response rate was obtained using a maximum dose of more than 55 Gy and/or a margin dose of more than 40 Gy. Serum adrenocorticotropic hormone and cortisol levels were normalized in 35% of patients, decreased significantly in 60%, and decreased in 85%. Fifty-one of 85 characteristic signs and symptoms of Cushing disease improved without any side effects. The overall outcome was excellent in seven cases, good in six, fair in four, and poor in four cases; one patient died. The initial treatment was GKS in four patients, two of whom had a complete response and two of whom had a partial response. Hormone levels returned to normal in the patients in whom there was a complete response. The results in the six patients in whom Nelson syndrome was present were less favorable; the response rate was only 33%, although the control rate was 100%. Hormone levels decreased in two patients.

Conclusions. Gamma knife radiosurgery is safe and effective for the treatment of Cushing disease as an adjuvant or initial therapy when selective and accurate dose planning is performed.