Publications (20)45.6 Total impact
-
Article: A Case of IgG4-Related Hypophysitis without Pituitary Insufficiency.
[show abstract] [hide abstract]
ABSTRACT: Context:Immunoglobulin (Ig) G4-related hypophysitis is a novel clinical disease entity, which is typically complicated by hypopituitarism.Objective:To describe a novel case of IgG4-related hypophysitis without pituitary insufficiency and summarize the current relevant literature.Patient and Methods:A 55-year-old Japanese man presented with an enlarged pituitary gland and bitemporal hemianopsia. Endocrine studies revealed normal pituitary function, although his serum IgG4 level was high. The patient underwent a transsphenoidal biopsy of the pituitary gland and the pathological tissues were consistent with IgG4-related hypophysitis. Oral prednisolone therapy was started, and after 6 months, his serum IgG4 level decreased and visual field improved.Conclusion:We described the first case of IgG4-related hypophysitis without pituitary insufficiency. However, further case collection is needed to characterize the pathophysiology of IgG4-related hypophysitis.The Journal of clinical endocrinology and metabolism 03/2013; · 6.50 Impact Factor -
Article: Assessment of pre- and postoperative endocrine function in 94 patients with Rathke's cleft cyst.
[show abstract] [hide abstract]
ABSTRACT: We reviewed 94 patients with Rathke's cleft cyst (RCC) who were surgically treated at Nippon Medical School Hospital between December 1995 and July 2009 to clarify the effect of surgery on their endocrine function. In our statistical analysis we considered their age and sex, the cyst volume, and preoperative MRI findings. Using simple linear- and multiple regression analysis we evaluated the association between these factors and their preoperative hormone baseline levels. To assess pre- and postoperative anterior pituitary function we subjected the results of various hormone loading tests to the Wilcoxon rank sum test. Surgery improved headache and visual impairment in most patients and elevated PRL levels were significantly normalized after surgery (p = 0.004). However, pre- and postoperative anterior pituitary hormone loading tests revealed that the levels of GH, TSH, LH, and FSH were not improved significantly by surgery. Although the ACTH loading test showed postoperative improvement, the change was not statistically significant. We suggest that RCC patients with headache or visual impairment are good candidates for surgery. We also recommend that patients with hyperprolactinemia and those with ACTH deficiency whose MRI findings reveal low- intensity on T1-WI and high-intensity on T2-WI are likely to benefit from surgery. In contrast, RCC patients with other hormone dysfunctions do not appear to benefit from surgical intervention.Endocrine Journal 11/2012; · 2.03 Impact Factor -
Article: [Present conditions and the prospects of the clinical studies of hypothalamus, and the pituitary tumor].
Nippon rinsho. Japanese journal of clinical medicine 03/2011; 69 Suppl 2:221-7. -
Article: Easy slip-knot: a new simple tying technique for deep sutures.
[show abstract] [hide abstract]
ABSTRACT: Knot-tying in the deep operative field is very complicated because of the narrow working space during endoscopic transsphenoidal surgery. We present a novel technique for tying deep knots called the "easy slip-knot," which was developed from a knot used to tie fishing lines. After threading the dura, an easy slip-knot is made outside the nostril. One end of the string is pulled, the knot then naturally slips, and should reach the operative field without needing a knot-pusher. This method is not complicated, is easily applied to the operative field by slipping the knot into position, and is able to tie sutures securely. The easy slip-knot should be useful for endoscopic surgery.Acta Neurochirurgica 03/2011; 153(7):1543-5; discussion 1545. · 1.52 Impact Factor -
Article: ACTH and alpha-subunit are co-expressed in rare human pituitary corticotroph cell adenomas proposed to originate from ACTH-committed early pituitary progenitor cells.
[show abstract] [hide abstract]
ABSTRACT: The functional differentiation of pituitary cells and adenomas follows the combination of transcription factors and co-factors in three cell lineages [growth hormone-prolactin-thyroid-stimulating hormone lineage, adrenocorticotrophic hormone (ACTH)/pro-opiomelanocortin (POMC) lineage, and follicular stimulating hormone (FSH)/luteinizing hormone (LH) lineage], which include Pit-1, GATA-2, SF-1, NeuroD1/beta2, Tpit, ERalpha, and others. Only rarely are hormones from different lineages co-expressed in the same adenoma cells. Most corticotroph cell adenomas belonging to the ACTH/POMC lineage are mono-hormonal. In our study of 89 corticotroph cell adenomas, 5 cases expressed both ACTH and alpha-subunit; these adenomas did not express any other anterior pituitary hormones or subunits. To clarify the mechanism involved, we studied the transcription factors that regulate pituitary cell differentiation. NeuroD1 and T-pit, markers of the ACTH/POMC lineage, and SF-1 and DAX-1, related to the LH/FSH cell lineage were expressed in all cases. GATA2, a synergistic factor in the gonadotroph cell lineage with SF-1, was also expressed in three of five cases. As ACTH and alpha-subunit are the earliest hormones to appear during development, we speculate that these particular adenomas are derived from committed ACTH progenitor cells. The molecular process governing functional differentiation of these adenomas requires further investigation.Endocrine Pathology 02/2008; 19(1):17-26. · 1.36 Impact Factor -
Article: Immunohistochemical detection of somatostatin receptor (SSTR) subtypes 2A and 5 in pituitary adenoma from acromegalic patients: good correlation with preoperative response to octreotide.
[show abstract] [hide abstract]
ABSTRACT: The aim of this study was to determine the correlation between the expression of somatostatin receptors by immunohistochemistry and the percent suppression of GH levels in the octreotide suppression test. Twenty-two patients with acromegaly who underwent an octreotide suppression test before surgery were studied. We performed immunohistochemistry for Somatostatin receptor 2A (SSTR2A) and Somatostatin receptor 5 (SSTR5) on the surgical specimens from all patients, which we scored according to the number of tumor cells staining positive at the surface membrane (3+: >50%, 2+: 25-50%, 1+: <25%). We sought correlations of percent suppression in the octreotide suppression test with these immunohistochemistry scores. Somatostatin receptor 2A (SSTR2A) showed the highest frequency of score 3+ (13 of 22, 59.1%) by immunohistochemistry. Subtype 5 showed the highest frequency for score 2+ (9 of 22, 40.9%), and one (4.5%) was immunonegative. For subtype 2A, there was a significant correlation with percent decrease (P = 0.002 < 0.01). In contrast, there was no significant correlation for SSTR5. Immunohistochemistry for SSTR2A in pathology specimens from acromegalic patients enabled selection of those experiencing clinical benefit from octreotide. Therefore, performing immunohistochemistry for detection of SSTR2A is recommended for all specimens obtained by surgery.Endocrine Pathology 01/2007; 18(4):208-16. · 1.36 Impact Factor -
Article: Expression of proliferation markers in human pituitary incidentalomas.
[show abstract] [hide abstract]
ABSTRACT: This study aimed to immunohistochemically assess the proliferation activity of pituitary incidentalomas. A series of 52 incidentalomas studied included 22 gonadotroph cell adenomas, 21 null cell adenomas, and 9 clinically silent adenomas (identified as functioning by immunohistochemistry). We also analyzed the differences in proliferation activity between 43 non-functioning pituitary incidentalomas (not including 9 silent adenomas), and 43 symptomatic non-functioning adenomas (NFAs) that caused visual disturbance. Cell proliferation markers were immunostained using monoclonal Ki-67 (MIB-1) antibody and monoclonal anti-topoisomerase II alpha (Topo-II alpha) antibody. The average of MIB-1 labeling indices in pituitary incidentalomas was 0.61% +/- 0.06%. Overall, both MIB-1 and Topo-II alpha labeling indices of the incidentalomas were significantly lower than those of symptomatic NFAs. There were no significant differences in immunopositivity between the two groups based on gender, age, or subtype. The MIB-1 index of the smallest adenoma group in pituitary incidentalomas was significantly lower than in symptomatic NFAs, while the Topo-II alpha incidentaloma was significantly lower than in symptomatic NFAs. Our findings suggest that small or less invasive pituitary incidentalomas should be observed with follow-up MRI. Large or invasive incidentalomas should be surgically treated if the patients show visual disturbances, hypopituitarism, or pituitary apoplexy during the follow-up period.Endocrine Pathology 02/2006; 17(3):263-75. · 1.36 Impact Factor -
Article: [Pituitary adenoma].
Nippon rinsho. Japanese journal of clinical medicine 10/2005; 63 Suppl 9:145-50. -
Article: Management of pituitary incidentalomas: according to a survey of pituitary incidentalomas in Japan.
[show abstract] [hide abstract]
ABSTRACT: The development of computed tomography (CT) and magnetic resonance imaging (MRI) has resulted in the discovery of unsuspected endocrinologically silent pituitary masses (pituitary incidentalomas). The aim of this study was to clarify the natural history of pituitary incidentalomas in order to establish an appropriate approach to them. Five hundred fifty patients with pituitary incidentalomas were analyzed in this study; 261 patients (47.4%) underwent surgery (surgical group; SG), whereas 289 patients (52.6%) were followed up conservatively (nonsurgical group; NSG) for a mean period of 27.3 months (range, 6-173 months). Clinical and biochemical assessment, CT or MRI of the pituitary, and visual field testing were assessed at baseline and at 6 months and yearly thereafter. A total of 261 tumors in the SG group consisted of 211 (80.8%) nonfunctioning pituitary adenomas and 42 (16.1%) Rathke's cysts. During a follow-up period, of 289 tumors in the NSG group, 209 (72.3%) tumors stayed the same size as before, 35 tumors (12.1 %) increased in size, and 41 tumors (14.2%) decreased in size. The estimated diagnoses of the tumors that increased consist of 28 nonfunctioning pituitary adenomas, 5 Rathke's cyst, and 2 others. The decreased tumors consist of 11 nonfunctioning adenomas, 21 Rathke's cysts, and 3 others. Pituitary incidentalomas usually follow a benign course. We recommend transsphenoidal adenomectomy for a solid mass attached to the optic chiasma estimated to be a pituitary adenoma by MRI. Other patients should be followed up by MRI and biochemical assessment. Especially asymptomatic cystic masses (including Rathke's cleft cysts) could be followed up without surgical intervention because they tend to stay the same size or sometimes be cured spontaneously.Seminars in Ultrasound CT and MRI 03/2005; 26(1):47-50. · 1.24 Impact Factor -
Article: Pathological study of thyrotropin-secreting pituitary adenoma: plurihormonality and medical treatment.
[show abstract] [hide abstract]
ABSTRACT: Thyrotropin (TSH)-secreting adenomas are rare and, as most adenomas are large, invasive and difficult to cure by surgery only, many require additional medical treatment. Many TSH-secreting adenomas cosecrete growth hormone (GH) and/or prolactin (PRL). We evaluated the relationship between pathology and the effect of dopamine agonist bromocriptine and somatostatin analogue octreotide in 20 operated patients with TSH-secreting adenomas. The four men and 16 women ranged in age from 23 to 62 years; three had clinically overt acromegaly; two manifested galactorrhea-amenorrhea. Endocrinologically, elevated serum GH, and/or IGF-1 were observed in six patients and elevated serum PRL was observed in eight. Immunohistochemically, 16 of the 20 adenomas were positive for GH and/or PRL (GH-positive, n=13; PRL-positive, n=9). Pituitary-specific transcription factor Pit-1 was demonstrated in the nuclei of all adenoma cells. Octreotide tests showed suppression of serum TSH (<50%) in ten of 14 patients. Preoperative octreotide treatment effectively reduced serum TSH and tumor size in two patients. Electron micrographs of octreotide-treated TSH-secreting adenomas showed shrinkage of the cytoplasm and diffuse distribution of secretory granules. Our study suggests that cosecretion of GH and/or PRL from TSH-secreting adenoma has no correlation with response of tumor cells to medical treatment.Acta Neuropathologica 08/2004; 108(2):147-53. · 9.32 Impact Factor -
Article: [Clinical aspects of pituitary incidentalomas].
[show abstract] [hide abstract]
ABSTRACT: The development of computed tomography(CT) and magnetic resonance imaging (MRI) has resulted in the discovery of unsuspected endocrinologically silent pituitary masses(pituitary incidentalomas). The management of these pituitary incidentalomas is controversial. Some lesions may increase in size, compress optic chiasm while others will remain unchanged in size. Five hundred and six patients with pituitary incidentalomas were obtained by questionnaire from March 1999 to May 2000 under the auspices of the Ministry of Health, Labor and Welfare in Japan. In thirty-three patients with pituitary incidentalomas (13.3%) developed tumor enlargement during the mean follow-up period of 45.5 months. Of 115 estimated non-functioning adenomas, 23(20.0%) tumor increased during mean follow up period of 50.7 months (range 10 to 173 months), while 5(5.4%) of 94 estimated Rathke's cysts increased in size during follow up. Pituitary apoplexy was occurred in one patient of 248 patients (0.4%). Pituitary incidentalomas usually follow a benign course. Transsphenoidal adenectomy is indicated for a solid mass attached to optic chiasma. For other patients, MRI every 6 months for the first 2 years, and then yearly may be recommended.Nippon rinsho. Japanese journal of clinical medicine 06/2004; 62(5):946-50. -
Article: Anti-alpha-enolase antibodies in pituitary disease.
[show abstract] [hide abstract]
ABSTRACT: A previous study reported a high prevalence of autoantibodies to alpha-enolase in lymphocytic hypophysitis and these antibodies efficiently distinguished lymphocytic hypophysitis from pituitary tumors. To confirm this, we examined autoantibodies to alpha-enolase in patients with lymphocytic hypophysitis (n = 17), pituitary non-functioning adenoma (n = 13), other pituitary diseases (n = 17) and other autoimmune diseases (n = 30), and compared to healthy controls (n = 46). Autoantibodies were found in 41.2%, 46.2%, 23.5%, 20.0% and 4.3%, respectively. Our findings indicate that detection of anti-alpha-enolase antibodies is not suitable for specific diagnosis of lymphocytic hypophysitis.Endocrine Journal 01/2004; 50(6):697-702. · 2.03 Impact Factor -
Article: Frequent appearance of autoantibodies against prohormone convertase 1/3 and neuroendocrine protein 7B2 in patients with nonfunctioning pituitary macroadenoma.
[show abstract] [hide abstract]
ABSTRACT: Among pituitary disorders having mass effect of the pituitary gland, nonfunctioning pituitary macroadenoma and lymphocytic hypophysitis are difficult to differentiate without histological examination. In order to efficiently distinguish lymphocytic hypophysitis and pituitary tumors, we studied the presence of autoantibodies against prohormone-processing enzymes, prohormone convertase (PC) 1/3, PC2, carboxypeptidase E (CPE), and PC2 regulatory protein, 7B2, by radioligand assay using recombinant human 35S-labeled protein in patients with clinically nonfunctioning pituitary macroadenoma, lymphocytic hypophysitis, and other pituitary diseases. The indexes for anti-PC1/3 antibodies (Ab) were significantly higher in patients with nonfunctioning pituitary macroadenoma than in patients with lymphocytic hypophysitis. Patients positive for either anti-PC1/3 or anti-7B2 Ab were significantly frequent among patients with nonfunctioning pituitary macroadenoma than in other pituitary diseases and healthy controls. None of the patients was positive for anti-PC2 Ab or anti-CPE Ab. These results suggest that autoantibodies against PC1/3 and 7B2 are novel tumor-associated autoantibodies and can be helpful in the diagnosis of clinically nonfunctioning pituitary macroadenoma.Endocrine 01/2004; 22(3):335-40. · 1.42 Impact Factor -
Article: [Spontaneous remission of acromegaly after meningitis: a case report].
[show abstract] [hide abstract]
ABSTRACT: There have been several reports describing the cases of acromegaly, which show reduction in size of tumor in due to pituitary apoplexy or lymphocytic hypophysitis. We have encountered a patient of acromegaly, who developed panhypopituitarism after suffering from meningitis and showed the reduction of tumor in size. The results of imaging examination suggested the presence of pituitary apoplexy and lymphocytic hypophysitis. The patient was a 27-year-old woman, who visited a local physician with complains of headache and fever. After performing lumbar puncture, she was diagnosed as viral meningitis, and conservative therapy was initiated. The results of biochemical test of blood revealed hyponatremia. Because facial appearance of the patient was similar to that of acromegaly, endocrine dysfunction was suspected. The result of pituitary hormone tests showed high levels of growth hormone (GH) and somatomedin C (IGF-1) and low levels of the other hormones. At the same time, sign of diabetes insipidus was noted, and the patient was referred to our hospital. In the examination at the admission, GH and IGF-1 showed the trends to decrease, and the reduction in size of tumor was also detected. From the results of imaging examination, pituitary apoplexy and lymphocytic hypophysitis were suspected. Operation was performed, and pathological examination revealed inflammation of pituitary adenoma.Nō to shinkei = Brain and nerve 12/2003; 55(11):967-71. -
Article: A survey of pituitary incidentaloma in Japan.
[show abstract] [hide abstract]
ABSTRACT: The development of computed tomography (CT) and magnetic resonance imaging (MRI) has resulted in the discovery of unsuspected endocrinologically silent pituitary masses (pituitary incidentalomas). The aim of this study was to perform a national survey on pituitary incidentalomas in order to establish an appropriate approach to them. Five hundred and six patients with pituitary incidentalomas were obtained by questionnaire from March 1999 to May 2000 under the auspices of the Ministry of Health, Labor and Welfare in Japan. Two hundred and fifty-eight patients underwent surgery (surgical group), while 248 patients were followed up conservatively for a mean period of 26.9 Months (range 6-173 Months) (non-surgical group). Clinical and biochemical assessment, CT or MRI of the pituitary, and visual field testing by Goldman perimetry were assessed at baseline and 6 Months and Yearly thereafter. Thirty-three patients with pituitary incidentalomas (13.3%) developed tumor enlargement during the mean follow-up period of 45.5 Months. Of 115 estimated non-functioning adenomas, 23 tumors (20.0%) increased during a mean follow-up period of 50.7 Months (range 10-173 Months), while 5 of 94 (5.3%) estimated Rathke's cysts increased in size during follow-up. Pituitary apoplexy occurred in one of 248 patients (0.4%). Pituitary incidentalomas usually follow a benign course. We recommend transsphenoidal adenectomy for a solid mass attached to the optic chiasma estimated to be a pituitary adenoma by MRI. Other patients should be followed up by MRI every 6 Months for the first 2 Years, and then Yearly.European Journal of Endocrinology 09/2003; 149(2):123-7. · 3.42 Impact Factor -
Article: [Endoscopic pituitary tumor surgery].
Nō to shinkei = Brain and nerve 07/2003; 55(6):487-96. -
Article: A case of Cushing's disease caused by pituitary adenoma producing adrenocorticotropic hormone and growth hormone concomitantly: aberrant expression of transcription factors NeuroD1 and Pit-1 as a proposed mechanism.
[show abstract] [hide abstract]
ABSTRACT: A 53-year-old Japanese woman was diagnosed with Cushing's disease caused by a adrenocorticotropic hormone (ACTH)-secreting pituitary adenoma on the basis of clinical an imaging data. The surgically resected tumor tissue was investigated histopathologically using immunohistochemical analysis of pituitary hormones. Our study revealed that the adenoma expressed not only ACTH but growth hormone (GH) in the tumor cells. Furthermore, immunohistochemical double staining showed that some adenoma cells were positive for both ACTH and GH. In situ hybridization for GH mRNA revealed that the adenoma cells produced GH as opposed to simply storing it. Although many pituitary adenomas produce multiple pituitary hormones, pituitary adenoma producing both ACTH and GH in the same adenoma cells, such as seen in this case, is extremely rare. To elucidate the molecular mechanism involved, we investigated the expression of transcription factors NeuroD1 and Pit-1 and found that both transcription factors were expressed in many tumor cells. This case report describes a very rare case of pituitary adenoma that produced both ACTH and GH. We propose a hitherto undescribed translineage expression of transcription factors as the basic mechanism of this unique functional differentiation.Modern Pathology 11/2002; 15(10):1102-5. · 4.79 Impact Factor -
Article: Immunohistochemical analysis of p27 (Kip1) in human pituitary glands and in various types of pituitary adenomas
[show abstract] [hide abstract]
ABSTRACT: p27 (Kip1) plays regulatory roles in the cell cycle by inhibiting the activity of cyclin dependent kinases (CDKs). This immunohistochemical study is aimed at elucidating the expression of p27 in human pituitary and in various types of pituitary adenomas in order to clarify its role in the regulation of proliferation. Sixteen normal pituitary glands and 179 human pituitary adenomas were used for immunohistochemical studies. The tissues were fixed in 10% formalin and embedded in paraffin. Indirect peroxidase method was performed after heat-induced antigen retrieval using a monoclonal antibody against p27 protein. p27 protein was expressed in the nuclei of all 16 normal human pituitary glands. p27 protein was also expressed in 128 of 179 cases of pituitary adenomas (71.5%). A marked decrease of p27 expression was noted in ACTH-secreting adenomas, 8/20 (40.0%), compared with other types of pituitary adenomas—GH-secreting adenomas, 35/46 (76.1%); PRL-secreting adenomas, 22/33 (66.7%); TSH-secreting adenomas, 8/11 (72.7%); and nonfunctioning adenomas, 55/69 (79.7%). These results suggest that p27 may play some role in the regulation of proliferation in all types of pituitary adenomas. The lower levels of p27 in ACTH-secreting adenoma is of particular interest with respect to the intermediate lobe-derived pituitary tumor developed in p27 knockout mice.Endocrine Pathology 05/2001; 12(2):181-188. · 1.36 Impact Factor -
Article: Expression of Pituitary Homeo Box 1 (Ptx1) in Human Non-Neoplastic Pituitaries and Pituitary Adenomas
[show abstract] [hide abstract]
ABSTRACT: We investigated the localization of pituitary homeo box 1 (Ptx1) protein in five human non-neoplastic pituitaries and 73 of all types of pituitary adenomas using immunohistochemistry, and the expression of Ptx1 messenger RNA (mRNA) in 18 representative pituitary adenomas using the reverse transcriptase polymerase chain reaction (RT-PCR) technique. By immunohistochemical analysis, Ptx1 protein was extensively detected in the nuclei of normal human pituitary cells. Ptx1 was detected in 10/14 (71.4%) of growth hormone (GH)-secreting adenomas, 12/12 (100%) of prolactin (PRL)-secreting adenomas, 18/20 (90%) of adrenocorticotropic hormone (ACTH)-secreting adenomas, 6/7 (85.7%) of thyroid-stimulating hormone (TSH)-secreting adenomas, and 17/20 (85%) of clinically non-functioning adenomas, including 9/10 (90%) of gonadotropin-subunit-positive adenomas. Thus, there was no relationship between Ptx1 expression and a particular type of pituitary adenomas. By RT-PCR analysis, Ptx1 mRNA was expressed in all 18 cases of pituitary adenomas, including two cases negative for Ptx1 protein by immunohistochemistry. These results suggested that Ptx1 may be an universal transcription factor in both neoplastic and non-neoplastic conditions in human pituitaries. The synergistic action with other transcription factors may be speculated to determine the specific production of the anterior pituitary hormones.Keywords: Immunohistochemistry, Pituitary, Pituitary adenoma, Ptx1, Transcription factorModern Pathology 09/2000; 13(10):1097-1108. · 4.79 Impact Factor -
Article: Expression of Ptx1 in the adult rat pituitary glands and pituitary cell lines: hormone-secreting cells and folliculo-stellate cells
[show abstract] [hide abstract]
ABSTRACT: The pituitary homeobox1 gene (Ptx1) was initially identified as encoding a pituitary-restricted transcription factor for the proopiomelanocortin (POMC) gene. In order to elucidate the expression pattern of the Ptx1 protein, we investigated the localization of the protein in adult rat pituitary gland and in various pituitary cell lines. We produced an antibody specific for Ptx1 protein, and confirmed its specificity by Western blot analysis. Immunohistochemically, many nuclei in the anterior pituitary cells as well as in the intermediate cells were positive for Ptx1 staining with this specific antibody. Immunohistochemical double staining revealed the presence of Ptx1 not only in all types of hormone-secreting cells but also in some folliculo-stellate (FS) cells. Furthermore, the expression of Ptx1 mRNA was confirmed in various pituitary cell lines and in the FS cell line by using the reverse transcriptase-polymerase chain reaction (RT-PCR) method. Our studies indicated that Ptx1 may not only play a role as a basic transcriptional factor for production of various hormones, but may also play some important role(s) in FS cells. Possible synergistic actions with other factors remain to be investigated. The novel finding of Ptx1 in FS cells is of particular interest, and may suggest that FS cells and hormone-secreting cells are derived from a common cellular ancestor.Cell and Tissue Research 08/1999; 298(1):55-61. · 3.11 Impact Factor
Top co-authors
Top Journals
Institutions
-
1999–2012
-
Nippon Medical School
- Department of Neurosurgery
Sendai, Kagoshima-ken, Japan
-
