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Yosuke Akamatsu, Hiroaki Shimizu, Atsushi Saito, Miki Fujimura and Teiji Tominaga

Object

In the intraluminal suture model of middle cerebral artery occlusion (MCAO) in the mouse, disturbance of blood flow from the internal carotid artery to the posterior cerebral artery (PCA) may affect the size of the infarction. In this study, PCA involvement in the model was investigated and modified for consistent MCAO without involving the PCA territory.

Methods

Thirty-seven C57Bl/6 mice were randomly divided into 4 groups according to the length of coating over the tip of the suture (1, 2, 3, or 4 mm) and subjected to transient MCAO for 2 hours. Real-time topographical cerebral blood flow was monitored over both hemispheres by laser speckle flowmetry. After 24 hours of reperfusion, the infarct territories and volumes were evaluated.

Results

The 1- and 2-mm coating groups showed all lesions in the MCA territory. In the 3- and 4-mm coating groups, 62.5% and 75% of mice, respectively, showed lesions in both the MCA and the PCA territories and other lesions in the MCA territory. Mice in the 1- and 2-mm coating groups had significantly smaller infarct volumes than the 3- and 4-mm groups. Laser speckle flowmetry was useful to distinguish whether the PCA territory would undergo infarction.

Conclusions

Small changes in the coating length of the intraluminal suture may be critical, and 1–2 mm of coating appeared to be optimal to produce consistent MCAO without involving the PCA territory. Laser speckle flowmetry could predict the territory of infarction and improve the consistency of the infarct size.

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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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Takashi Inoue, Hiroaki Shimizu, Miki Fujimura, Atsushi Saito and Teiji Tominaga

Object

In this paper, the authors' goals were to clarify the characteristics of growing unruptured cerebral aneurysms detected by serial MR angiography and to establish the recommended follow-up interval.

Methods

A total of 1002 patients with 1325 unruptured cerebral aneurysms were retrospectively identified. These patients had undergone follow-up evaluation at least twice. Aneurysm growth was defined as an increase in maximum aneurysm diameter by 1.5 times or the appearance of a bleb.

Results

Aneurysm growth was observed in 18 patients during the period of this study (1.8%/person-year). The annual rupture risk after growth was 18.5%/person-year. The proportion of females among patients with growing aneurysms was significantly larger than those without growing aneurysms (p = 0.0281). The aneurysm wall was reddish, thin, and fragile on intraoperative findings. Frequent follow-up examination is recommended to detect aneurysm growth before rupture.

Conclusions

Despite the relatively short period, the annual rupture risk of growing unruptured cerebral aneurysms detected by MR angiography was not as low as previously reported. Surgical or endovascular treatment can be considered if aneurysm growth is detected during the follow-up period.

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Kazunori Arita, Kaoru Kurisu, Atsushi Tominaga, Fusao Ikawa, Koji Iida, Selji Hama and Haruyuki Watanabe

✓ A size-adjustable plate constructed of pure titanium is proposed for use in the reconstruction of the sella turcica. The plate is composed of two semicircular pieces that are connected by a hinge located at the top of the plate. Using an applicator, the plate is inserted into the sella turcica in a closed position. The same applicator is then used to open and secure the plate. The titanium causes minimal ferromagnetic artifacts on postoperative magnetic resonance imaging.

Preliminary findings indicate a possibie clinical use for this plate in the reconstruction of the sella turcica when no suitable piece of bone is available.

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Atsushi Kanoke, Masayuki Kanamori, Toshihiro Kumabe, Ryuta Saito, Mika Watanabe and Teiji Tominaga

This patient presented with a rare case of metachronous, multicentric gliomas first manifesting as headache and nausea in 1983 when he was an 8-year-old boy. Computed tomography revealed a cerebellar tumor and the tumor was subtotally resected. The histological diagnosis was pilocytic astrocytoma, and radiation therapy to the posterior fossa and chemotherapy consisting of nimustine hydrochloride and fluorouracil were performed. In 1989, at age 14 years, the patient presented with local recurrence. He underwent gross-total resection of the tumor, and histological examination revealed that the tumor consisted of classic pilocytic astrocytoma with a biphasic pattern and a small oligodendroglioma-like component. In 2011, at age 36 years, he presented with seizure. Magnetic resonance imaging revealed a mass lesion in the right middle frontal gyrus. Gross-total resection of the tumor was performed, and the histological diagnosis was oligodendroglioma. Genetic analyses revealed amplification of the BRAF gene in both the primary cerebellar pilocytic astrocytoma and the recurrent tumor with biphasic features, as well as a BRAF V600E missense mutation in the oligodendroglioma-like component. On the other hand, the IDH1 R132H mutation, instead of aberrations of the BRAF gene, was identified in the oligodendroglioma arising in the right frontal lobe. Different types of aberrations of the BRAF gene in the classic and oligodendroglioma-like component in the recurrent pilocytic astrocytoma suggest that they had different cell origins or that amplification of BRAF was negatively selected under the de novo BRAF V600E mutation. In addition, the aberration profiles of IDH1 and BRAF suggest that the oligodendroglioma arose independent of cerebellar pilocytic astrocytoma.

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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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Atsushi Saito, Hiroaki Shimizu, Yusuke Doi, Tatsuhiro Ishida, Miki Fujimura, Takashi Inoue, Hiroshi Kiwada and Teiji Tominaga

Object

Targeted drug delivery with immunoliposomes has been applied to various in vivo animal models and is newly focused as a novel therapeutic target. Lectin-like oxidized low-density lipoprotein receptor–1 (LOX1) is a potent regulator of systemic atherosclerosis, and the authors focused on its effect on carotid plaques. The authors developed a LOX1-targeted liposomal rho-kinase inhibitor and examined the therapeutic effect on carotid intimal hypertrophy in rats.

Methods

LOX1-targeted rho-kinase inhibitor fasudil-containing liposomes, composed of hydrogenated soy phosphatidylcholine/cholesterol/PEG2000-DSPE, were prepared by conjugating anti-LOX1 antibodies on the surface and by remote loading of fasudil. Carotid intimal hypertrophy was induced by balloon injury, and the drugs were intravenously administered on Day 3 postinjury. The rats were divided into 4 groups: nontreatment, treatment with intravenous fasudil (2 mg), treatment with liposomal fasudil (2 mg), and treatment with LOX1-targeted liposomal fasudil (2 mg). The authors compared intimal hypertrophy, atherosclerotic factor, and matrix metalloproteinase-9 expression among groups.

Results

DiI–labeled LOX1-targeted liposomes were prominently observed in the lesions on Day 7 after the surgery. The intimal thickness was significantly reduced in the LOX1-targeted liposomal fasudil–treated group (mean 81.6 ± 13.9 μm) compared with the other groups (no treatment 105.4 ± 16.8 μm; fasudil treatment 102.4 ± 20.0 μm; and liposomal fasudil treatment 102.8 ± 22.2 μm; p = 0.046). Matrix metalloproteinase-9 expression was also significantly reduced in the LOX1-targeted liposomal fasudil group.

Conclusions

Liposomes conjugated with anti-LOX1 antibody effectively reached carotid artery lesions, and liposomal rho-kinase significantly inhibited intimal hypertrophy. The new liposomal drug delivery system targeting LOX1 may become a therapeutic strategy for atherosclerotic diseases.

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Seiji Hama, Kazunori Arita, Takashi Nishisaka, Toshiyuki Fukuhara, Atsushi Tominaga, Kazuhiko Sugiyama, Hiroyuki Yoshioka, Kuniki Eguchi, Masayuki Sumida, Yuji Heike and Kaoru Kurisu

Object. Rathke cleft cysts (RCCs) are composed of tall, well-differentiated, ciliated columnar epithelia. Their structures are altered by hyperplasia or squamous metaplasia, but their cause remains unknown.

Methods. The authors studied pathological findings and anterior pituitary function in 20 patients harboring RCCs. They classified RCC epithelium as either single (a single ciliated columnar cell lining or a flattened cuboidal cell lining) or stratified (a stratified ciliated columnar cell lining, basal cell hyperplasia, columnar cell hyperplasia, or squamous metaplasia). Inflammation was classified as acute, subacute, chronic, or end stage.

The epithelial cell lining was observed in 13 specimens obtained during surgery (six specimens contained single and seven contained stratified epithelia). Inflammation had penetrated the cyst epithelium or subjacent stroma in 10 patients, and the stage of inflammation correlated well with the type of epithelia group: early stages of inflammation in the single epithelium group and chronic or end-stage inflammation in the stratified epithelia (p = 0.0027). The adenohypophysis was identified in 21 surgical specimens. Postoperatively, growth hormone (p = 0.019), cortisol (p = 0.027), and thyroid-stimulating hormone (p = 0.039) responses significantly worsened as the inflammation progressed. The presence of diabetes insipidus correlated well with advanced stages of neurohypophysitis (p = 0.025).

Conclusions. Epithelial stratification in the RCC is caused by inflammation that may extend into the adjacent adenohypophysis or neurohypophysis and overwhelm the hypophysis, resulting in panhypopituitarism. Transsphenoidal excision may represent the best choice for treatment, at least for cases of RCC in which there is partial impairment of hypophysial function.

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Fumiyuki Yamasaki, Takeshi Takayasu, Ryo Nosaka, Vishwa Jeet Amatya, Aidos Doskaliyev, Yuji Akiyama, Atsushi Tominaga, Yukio Takeshima, Kazuhiko Sugiyama and Kaoru Kurisu

OBJECT

The differentiation of malignant lymphomas from gliomas or malignant gliomas by conventional MRI can be difficult. The authors studied Gd-enhanced MR images to obtain a differential diagnosis between malignant lymphomas and gliomas without central necrosis or cystic changes and investigated the diagnostic value of single-voxel proton MR spectroscopy (1H-MRS) using different parameters, including lipid levels.

METHODS

This was a retrospective study of patients with primary malignant CNS lymphoma (n = 17) and glioma (n = 122 [Grades I, II, III, and IV in 10, 30, 33, and 49 patients, respectively]) who were treated between 2007 and 2013. The authors focused on 15 patients with homogeneously enhanced primary malignant CNS lymphomas and 7 homogeneously enhanced gliomas. Images of all the included tumors were acquired with 1H-MRS at 3 T, and the diagnoses were histologically confirmed.

RESULTS

Using a short echo time 1H-MRS, large lipid peaks were observed in all 17 patients with a malignant lymphoma, in 39 patients (79.6%) with a Grade IV glioma, and in 10 patients (30.3%) with a Grade III glioma. A focus on homogeneously enhanced tumors revealed large lipid peaks in 15 malignant lymphomas that were free of central necrosis on Gd-enhanced T1-weighted images. Conversely, in the 7 homogeneously enhanced gliomas (glioblastoma and anaplastic astrocytoma, n = 2 each; anaplastic oligodendroglioma, diffuse astrocytoma, and pilomyxoid astrocytoma, n = 1 each), lipid peaks were small or absent.

CONCLUSIONS

Large lipid peaks on 1H-MRS images of tumors without central necrosis were characteristic of malignant lymphomas. Conversely, small or absent lipid peaks in intraaxial tumors without central necrosis were strongly suggestive of glioma.

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Kenji Oki, Kiminori Yamane, Yoshiaki Oda, Nozomu Kamei, Hiroshi Watanabe, Atsushi Tominaga, Vishwa Jeet Amatya, Yutaka Oki and Nobuoki Kohno

A 36-year-old man with a 1-year history of diabetes mellitus was referred to the authors' hospital for further endocrinological evaluation of acromegaly. On physical examination, typical acromegalic features but no typical cushingoid features were observed. The clinical diagnosis of growth hormone (GH)–producing pituitary adenoma was confirmed by MR imaging findings, nonsuppression of serum GH levels during a 75-g oral glucose tolerance test (trough GH 6.33 ng/ml), and elevated serum insulin-like growth factor—I levels (1361.3 ng/ml). Moreover, autonomic adrenocorticotropic hormone (ACTH) secretion was suspected, based on inadequate suppression of ACTH or cortisol levels by an 0.5-mg overnight dexamethasone suppression test. Analysis of the patient's plasma by using the gel filtration method revealed the presence of a high-molecular-weight (HMW) form of ACTH known to exhibit low biological activity. Transsphenoidal adenomectomy was performed for the pituitary tumor. Immunohistochemical investigation of the resected specimen showed strong and diffuse immunoreactivity to GH and focal immunoreactivity to ACTH. Although there have been a few cases of pituitary adenoma that produced GH and ACTH concomitantly, this is the first report of the detection of HMW ACTH in patients with GH- and ACTH-producing adenomas. Furthermore, the previous cases also did not exhibit typical cushingoid features. It is suggested that the secretion of ACTH in patients with concurrent GH- and ACTH-secreting adenomas might consist of the HMW form and that the HMW ACTH is consequently associated with a subclinical Cushing state.