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Koji Iida, Kaoru Kurisu, Kazunori Arita and Minako Ohtani

Object. The goal of this study was to elucidate the optimal time for rewarming of patients who have been treated with hypothermia for severe head injury.

Methods. Eleven patients with severe head injuries who had been treated by hypothermia underwent transcranial Doppler (TCD) ultrasonography examinations. The patients were divided into two groups: Group A consisted of three patients in whom acute brain swelling occurred during the rewarming period and Group B was composed of eight patients who displayed no significant intracranial hypertension during or after hypothermia therapy. In all patients, the mean flow velocity of the middle cerebral artery (FVMCA) recorded transcranially and the mean flow velocity of the internal carotid artery (FVICA), recorded high in the neck, were monitored at 24-hour intervals after the patient was admitted to the hospital. In Group A, the FVMCA was normal at 48 hours (maintenance state of hypothermia) in each patient, and abnormal increases and peak values (> 100 cm/second) occurred from 96 to 144 hours postinjury (rewarming period). The FVICA, which was monitored concurrently also varied as the FVMCA increased. The pulsatility indices in the arteries decreased at the time of the peak FVMCA. The enhanced FVMCA was consistent with hyperemia because of the low FVMCA/FVICA ratios (< 3). Two patients in whom jugular venous oxygen saturation was monitored were found to have high values (> 80%), representing hyperemia. All intracranial pressures (ICPs) that lay within the normal range at 48 hours postinjury elevated acutely after the peak FVMCA. In Group B, both FVMCA and FVICA values were normal at 48 hours postinjury and remained stable throughout the rewarming period. Values of ICP were also maintained within the normal range until the patients were weaned from hypothermia therapy.

Conclusions. Hyperemia, detectable by TCD ultrasonography, may serve as an index in the prediction of acute brain swelling, and rewarming should be terminated when such a hemodynamic phenomenon is observed.

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Yasuhiro Matsuda, Keiichi Kawamoto, Katsuzo Kiya, Kaoru Kurisu, Kazuhiko Sugiyama and Tohru Uozumi

✓ The presence of the progesterone receptor (PR) in meningioma tissue has been confirmed by previous investigations. Studies have shown that the antiprogesterone drug, mifepristone, is a potent agent that inhibits the growth of cultured meningioma cells and reduces the size of meningiomas in experimental animal models and humans. However, these studies have not fully examined the relationship between the antitumor effects of an antiprogesterone agent and the expression of the PR.

The present study examined the antitumor effects of mifepristone and a new potent antiprogesterone agent, onapristone; a correlation between the antitumor effects of these antiprogesterones and the presence of PR's in meningiomas in vitro and in vivo was also investigated. Meningioma tissue surgically removed from 13 patients was used in this study. In the in vitro arm of the study, mifepristone and onapristone exhibited cytostatic and cytocidal effects against cultured meningioma cells, regardless of the presence or absence of PR's; however, three PR-negative meningiomas showed no response to any dose of mifepristone and/or onapristone. In the in vivo arm, meningioma cells, embedded in a collagen gel, were implanted into the renal capsules of nude mice. Antiprogesterone treatment resulted in a marked reduction of the tumor volume regardless of the presence or absence of PR's. No histological changes in the meningioma cells suggestive of necrosis or apoptosis were detected in any of the mice treated with antiprogesterones. These findings suggest that mifepristone and onapristone have an antitumor effect against meningioma cells via the PR's and/or another receptor, such as the glucocorticoid receptor.

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Satoshi Yamaguchi, Kuniki Eguchi, Yoshihiro Kiura, Masaaki Takeda and Kaoru Kurisu

Object

The vertebral artery (VA) often takes a protrusive course posterolaterally over the posterior arch of the atlas. In this study, the authors attempted to quantify this posterolateral protrusion of the VA.

Methods

Three-dimensional CT angiography images obtained for various cranial or cervical diseases in 140 patients were reviewed and evaluated. Seven patients were excluded for various reasons. To quantify the protrusive course of the VA, the diameter of the VA and 4 parameters were measured in images of the C1–VA complex obtained in the remaining 133 patients. The authors also checked for anomalies and anatomical variations.

Results

When there was no dominant side, mean distances from the most protrusive part of the VA to the posterior arch of the atlas were 6.73 ± 2.35 mm (right) and 6.8 ± 2.15 mm (left). When the left side of the VA was dominant, the distance on the left side (8.46 ± 2.00 mm) was significantly larger than that of the right side (6.64 ± 2.0 mm). When compared by age group (≤ 30 years, 31–60 years, and ≥ 61 years), there were no significant differences in the extent of the protrusion. When there was no dominant side, the mean distances from the most protrusive part of the VA to the midline were 30.73 ± 2.51 mm (right side) and 30.79 ± 2.47 mm (left side). When the left side of the VA was dominant, the distance on the left side (32.68 ± 2.03 mm) was significantly larger than that on the right side (29.87 ± 2.53 mm). The distance from the midline to the intersection of the VA and inner cortex of the posterior arch of the atlas was ~ 12 mm, irrespective of the side of VA dominance. The distance from the midline to the intersection of the VA and outer cortex of the posterior arch was ~ 20 mm on both sides. Anatomical variations and anomalies were found as follows: bony bridge formation over the groove for the VA on the posterior arch of C-1 (9.3%), an extracranial origin of the posterior inferior cerebellar artery (8.2%), and a VA passing beneath the posterior arch of the atlas (1.8%).

Conclusions

There may be significant variation in the location and branches of the VA that may place the vessel at risk during surgical intervention. If concern is noted about the vulnerability of the VA or its branches during surgery, preoperative evaluation by CT angiography should be considered.

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Kazunori Arita, Kaoru Kurisu, Koji Iida, Ryosuke Hanaya, Tomohide Akimitsu, Seiichiro Hibino, Basant Pant, Masatake Hamasaki and Shoji Shinagawa

✓ The authors report on a patient who exhibited intractable epilepsy due to an inaccessible hypothalamic hamartoma and subsequently underwent stereotactic radiosurgery. This 25-year-old man had a 24-year history of intractable gelastic and tonic—clonic seizures. Magnetic resonance (MR) imaging performed at examination as well as that performed 30 months earlier demonstrated a nonenhancing and nonprogressive spherical mass, approximately 10 mm in diameter, located on the patient's right side at the floor of the third ventricle. Focal radiation treatment performed with a gamma knife unit administered 36 Gy to the center and 18 Gy to the periphery of the lesion. This treatment resulted in an improvement in seizure control. Before the patient underwent radiosurgery, he suffered from three to six generalized seizures per month in spite of attentive compliance with an anticonvulsant medication regimen. After irradiation of the harmatoma, the frequency of the seizures transiently increased and then subsided 3 months posttreatment. The patient has been free of seizures for the last 21 months, with no neurological or endocrinological complications. Magnetic resonance imaging performed 12 months posttreatment demonstrated complete disappearance of the lesion.

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Kazunori Arita, Atsushi Tominaga, Kazuhiko Sugiyama, Kuniki Eguchi, Koji Iida, Masayuki Sumida, Keisuke Migita and Kaoru Kurisu

Object

The increase in the incidental detection of asymptomatic pituitary adenomas, known as “pituitary inciden-talomas,” led the authors to conduct a survey of the natural course of these lesions.

Methods

Forty-two patients with clinically nonfunctioning pituitary adenomas who had manifested no neurological or endocrinological disorders were monitored with magnetic resonance imaging studies. The follow-up period ranged from 10.8 to 168.2 months (mean ± standard deviation, 61.9 ± 38.2 months). The mean initial tumor size was 18.3 ± 7 mm.

In 21 patients, the tumor increased by at least 10% of its measured size on detection. This increase was first detected between 8.4 and 58.8 months (mean 31.8 ± 17.6 months) after diagnosis. There was no correlation between the original tumor size, patient age, or the presence of intratumoral cysts and tumor growth. Symptoms were noted in 10 patients during follow up; in four, extensive tumor necrosis accompanied hemorrhage, leading to severe headache, acute ophthalmological symptoms, and panhypopituitarism, which was indicative of pituitary apoplexy. Transsphenoidal surgery was performed in 12 patients with enlarged tumors, including three with apoplexy. With the exception of one apoplectic patient, visual function was recovered in all who underwent surgery. All apoplectic patients continue to manifest hypopituitarism.

Conclusions

In the course of 4 years, the size of the incidentalomas increased in 40% of 42 patients and became symptomatic in 20%. During the 5-year follow up, pituitary apoplexy developed in 9.5%. These findings may justify early intervention, especially in young individuals with incidentally found macroadenoma.

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Kiyoharu Shimizu, Masaaki Takeda, Takafumi Mitsuhara, Shunichi Tanaka, Yushi Nagano, Hitoshi Yamahata, Kaoru Kurisu and Satoshi Yamaguchi

OBJECTIVE

Spinal dural arteriovenous fistulas (SDAVFs) commonly present with symptoms of myelopathy due to venous congestion in the spinal cord; asymptomatic SDAVFs are rarely encountered. To elucidate the clinical characteristics of asymptomatic SDAVFs, the authors present 5 new cases of asymptomatic SDAVF and report the results of their systematical review of the associated literature.

METHODS

Five databases were systematically searched for all relevant English-language articles on SDAVFs published from 1990 to 2018. The clinical features and imaging findings of asymptomatic SDAVFs were collected and compared with those of symptomatic SDAVFs.

RESULTS

Twenty cases, including the 5 cases from the authors’ experience, were found. Asymptomatic SDAVFs were more prevalent in the cervical region (35.0%); cervical lesions account for only 2% of all symptomatic SDAVFs. The affected perimedullary veins tended to drain more cranially (50.0%) than caudally (10.0%). Four cases of asymptomatic SDAVF became symptomatic, 1 case spontaneously disappeared, and the remaining 15 cases were unchanged or surgically treated.

CONCLUSIONS

The higher prevalence of asymptomatic SDAVFs in the cervical spine might be a distinct feature of asymptomatic SDAVFs. Given that venous congestion is the pathophysiology of a symptomatic SDAVF, abundant collateral venous pathways and unique flow dynamics of the CSF in the cervical spine might prevent asymptomatic cervical SDAVFs from becoming symptomatic. In cases in which venous congestion is avoidable, not all asymptomatic SDAVFs will become symptomatic.

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Yuji Saito, Yosihiro Nakada, Takuhiro Hotta, Takasi Mikami, Kaoru Kurisu, Katuzou Kiya, Keiichi Kawamoto and Tohru Uozumi

✓ Cell lines resistant to 1-(4-amino-2-methyl-5-pyrimidinyl)methyl-3-(2-chloroethyl)-3-nitrosourea hydrochloride (ACNU) show a high degree of collateral sensitivity to L-asparaginase. The mechanism for this phenomenon was investigated by comparing the nutritional requirements and asparagine synthetase activity of the resistant sublines to those of parent cells. Nine ACNU-resistant sublines were isolated from rat glioma 9L cells after incubation with various concentrations of ACNU in Ham's F-12 medium. The 9L cells grew independently of asparagine, developing well in asparagine-deficient Dulbecco's modified Eagle's medium. In contrast, the growth rates of all nine ACNU-resistant sublines decreased under the same conditions and required the addition of 10−4 M asparagine for maximum growth. Asparagine synthetase activity in the ACNU-resistant cells was much lower than in the 9L cells, suggesting that the requirement for asparagine in the resistant sublines was due to reduced activity of this enzyme. A growth-inhibition assay showed that the ACNU-resistant sublines were more sensitive to L-asparaginase than 9L cells by up to 2 × 105-fold. These results suggest that L-asparaginase therapy has the potential to become a new approach for treating acquired ACNU resistance.

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Yasuyuki Kinoshita, Atsushi Tominaga, Satoshi Usui, Kazunori Arita, Tetsuhiko Sakoguchi, Kazuhiko Sugiyama and Kaoru Kurisu

OBJECTIVE

Patients with symptomatic Rathke's cleft cysts (RCCs) managed by surgical treatment often experience recurrence. The authors attempted to clarify the outcome of surgically treated RCCs over a long-term follow-up period.

METHODS

Ninety-one consecutive RCC patients with a follow-up period of more than 12 months (mean 80.2 months, range 12–297 months) were retrospectively studied. The authors examined the clinical features and postoperative course of patients who experienced a reaccumulation of cyst contents visible on MRI after the initial surgery, and they investigated data from the patients who underwent reoperation for symptomatic recurrent RCCs.

RESULTS

Reaccumulation of cyst contents occurred in 36 patients (39.6%). In 34 of these patients, a reaccumulation occurred in the first 5 years after surgery. The initial cysts in these patients were most often large, with squamous metaplasia in the cyst walls. Thirteen patients (14.3%) with recurrent symptoms underwent a reoperation, and 10 of the 13 patients had a reaccumulation of RCCs within the 1st year after surgery. The reoperations were performed in the 1st year (61.5%) or several years later (23.1%). Patients were likely to initially have had a visual disturbance and the cyst walls likely included squamous metaplasia. However, no association was observed between the incidence of reaccumulation/reoperation of RCCs and the surgical procedure for RCCs.

CONCLUSIONS

The reaccumulation rate of RCC is high in the long-term period, and it is associated with the histological findings but not with the surgical procedure. Long-term monitoring, for a period of at least 5 years, should therefore be conducted to identify and assess any RCC reaccumulation.

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Satoshi Yamaguchi, Kazutoshi Hida, Masaaki Takeda, Takafumi Mitsuhara, Mizuki Morishige, Naoto Yamada and Kaoru Kurisu

Surgical lysis of the thickened arachnoid membrane is the first choice of treatment in spinal arachnoid pathologies that cause flow disturbances or blockage of CSF. However, it is important to consider that while extensive lysis of the arachnoid may temporarily provide a wide pathway for CSF, an extensive lytic procedure may later cause secondary adhesion. Thus, it is ideal for the proper extent of the arachnoid lysis to be determined after careful analysis of regional CSF flow. The authors report their limited experience with intraoperative visualization of CSF flow in spinal arachnoid pathologies. Two patients with a dorsal arachnoid web (DAW) with cervical syringomyelia and 1 patient with focal adhesive arachnoiditis causing edema of the spinal cord were surgically treated at the authors' institution between 2007 and 2013. In all cases, the presence of a DAW or focal adhesive arachnoiditis was suspected from the findings on MRI, namely 1) an indentation on the upper thoracic spinal cord and 2) syringomyelia and/or edema of the spinal cord above the indentation. Exploratory surgery disclosed a transversely thickened arachnoid septum on the dorsal side of the indented cord. To prove blockage of the CSF by the septum and to decide on the extent of arachnoid lysis, regional CSF flow around the arachnoid septum was visualized by subarachnoid injection of gentian violet solution close to the web. Injected dye stagnated just close to the arachnoid septum in all cases, and these findings documented CSF blockage by the septum. In 2 cases, a 2-minute observation showed that the injected dye stayed close to the web without diffusion. The authors performed not only resection of the web itself but also lysis of the thickened arachnoid on both sides of the spinal cord to make a CSF pathway on the ventral side. In the third case, the dye stagnated close to the web at first but then diffused through the nerve root to the ventral CSF space. The lysis procedure was completed after exclusive removal of the dorsal web. Postoperative MR images confirmed reduction of the syrinx and/or improvement of the edema in all cases, suggesting that the extent of arachnoid lysis was optimal in each case. No adverse effect was observed after subarachnoid injection of gentian violet. The authors believe that their technique of visualizing regional CSF flow will be helpful to decide the optimal extent of lysis in some local arachnoid pathologies.

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Kunyu Harada, Kaoru Kurisu, Hidetoshi Tahara, Eiji Tahara, Toshinori Ide and Eiichi Tahara

Object. Telomerase activity is responsible for cell immortality. To examine the role of telomerase in the carcinogenesis of human glioblastomas multiforme (GBMs), the authors studied telomerase activity, telomerase component expression, and telomere lengths in 42 GBM samples.

Methods. In all samples, EGFR and MDM2 amplifications and overexpressions were examined using Southern and Northern blot analyses. The p53 mutation was analyzed using polymerase chain reaction—single strand conformational polymorphism and by direct sequence analysis. Specimens of tissues were immunostained with p53, EGFR, and MDM2 antibodies. Allelic loss on chromosomes 17p and 10 was assessed by loss of heterozygosity (LOH) assays. Telomerase activity, expression of its components (human telomerase reverse transcriptase [hTERT], human telomerase RNA component [hTERC], and telomerase-associated protein [TEP1]), and telomere lengths were analyzed using the telomeric repeat amplification protocol (TRAP)—hybridization protection assay, reverse transcription—polymerase chain reaction, and Southern blot analysis. According to the results of assessments of EGFR and MDM2 amplifications, p53 mutation, LOHs in chromosomes 17p and 10, and the clinical course of the disease, the 42 samples were classified into 22 primary and 20 secondary glioblastomas.

Twenty-six (61.9%) of all 42 samples demonstrated detectable telomerase activity during the TRAP assay. Secondary GBMs displayed significantly higher levels of telomerase activity and hTERT expression than primary GBMs. Tumors with a p53 gene mutation demonstrated significantly higher telomerase activity than those without a p53 mutation. Four samples with a codon 175 mutation demonstrated an exceptionally high amount of telomerase activity. In secondary GBMs, the increase in telomerase activity and the hTERT expression level correlated with the increased frequency of p53 mutations. There was no significant difference in telomere length between primary and secondary GBMs.

Conclusions. These results suggest that telomerase activity and p53 mutations both play important roles in the multistep carcinogenesis of GBMs. Telomerase activity and hTERT expression may be considered as novel distinctive factors in human GBMs.