研究者詳細 - 橋口　明典

論文 - 橋口　明典

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Urinary Biomarkers Associated With Pathogenic Pathways Reflecting Histologic Findings in Lupus Nephritis

Hiramoto K., Saito S., Hanaoka H., Kikuchi J., Fukui H., Hashiguchi A., Suzuki K., Takeuchi T., Kaneko Y.

Arthritis and Rheumatology 77 （ 3 ） 298 - 310 2025年03月

共著, ISSN 23265191

Objective: There is a pressing need to understand the pathogenesis of histologic findings and identify the biomarkers for predicting the histologic severity in lupus nephritis (LN). This study aimed to identify the pathogenic signal pathway and elucidate urinary biomarkers for predicting the presence or severity of histologic findings in LN. Methods: Urine samples from patients with biopsy-proven active LN were screened for 1,305 proteins using an aptamer-based proteomic assay. The diversity and expansion of individual renal histologic features in LN were quantified to identify the urinary proteins associated with the histologic findings found in each score. Candidate urinary proteins were validated in a validation cohort. Immunohistochemical staining of the renal tissues was performed to clarify the localization of the candidate proteins. Results: Cluster analysis extracted five histologic subgroups according to their correlations with each histologic finding in LN. Protein groups that correlated with each histologic subgroup revealed a distinct pathogenesis in LN using pathway analyses. Enzyme-linked immunosorbent assay validation revealed that urinary calgranulin B (S100A9), monocyte chemotactic protein 1 (MCP-1), and insulin-like growth factor binding protein 5 (IGFBP-5) levels could specifically predict the presence and severity of active glomerular lesions, interstitial inflammation, and interstitial fibrosis, respectively. Immunohistochemical staining revealed the localization of these proteins in each lesion. Conclusion: Renal histologic findings may reflect the different pathogeneses involved in each lesion, and estimating the urinary calgranulin B, MCP-1, and IGFBP-5 levels may be useful in predicting the presence and severity of histologic findings in LN.

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A Case of Membranous Nephropathy Associated with Syphilis: Correlative Light and Electron Microscopy Revealing the Localization of Neuron-derived Neurotrophic Factor within Subepithelial Electron Dense Deposits.

Minezaki C, Azegami T, Hashiguchi A, Yoshifuji A, Yoshimoto N, Hagiwara A, Hishikawa A, Hayashi K

Internal medicine (Tokyo, Japan) 2024年12月

共著, ISSN 0918-2918

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The proteinuria selectivity index value predicts the remission of IgA nephropathy: a retrospective cohort study.

Mitsuno R, Nakayama T, Ito W, Maruki T, Nakamichi R, Adachi K, Yoshimoto N, Hishikawa A, Hagiwara A, Yamaguchi S, Monkawa T, Yoshino J, Hashiguchi A, Azegami T, Hayashi K

Renal failure 46 （ 2 ） 2423839 2024年12月

共著, ISSN 0886-022X

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Clinical relevance of proteinuria selectivity index and fractional excretion of sodium in patients with nephrotic syndrome.

Nakayama T, Azegami T, Yamaguchi S, Hirano K, Komatsu M, Fujii K, Futatsugi K, Urai H, Kawaguchi T, Itoh T, Yoshimoto N, Hagiwara A, Hishikawa A, Matsuda H, Ando T, Yamaji Y, Murakami M, Hashiguchi A, Kaneko Y, Yokoo T, Hayashi K

Scientific reports 14 （ 1 ） 23755 2024年10月

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Primary breast lymphoma mimicking triple-negative breast cancer: a case report with clinical and pathological implications.

Sawano T, Wada M, Ozaki A, Hashiguchi A, Hirooka S, Tanimoto T

Surgical case reports 10 （ 1 ） 234 2024年10月

共著, ISSN 2198-7793

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機能性表示食品「紅麹コレステヘルプ」およびNSAIDs服用中に発症した完全型Fanconi症候群を伴う急性腎障害の1例

星健太, 村上円人, 佐藤芳紀, 杉浦康平, 船木裕規, 橋口明典

日本腎臓学会誌（(一社)日本腎臓学会） 66 （ 7 ） 1207 - 1214 2024年10月

共著, ISSN 0385-2385

薬剤性腎障害の原因は多岐にわたるが,漢方薬やサプリメントなど医薬品以外の物質の関与も多く,病歴を漏れなく聴取することが重要である。近年,機能性表示食品「紅麹コレステヘルプ」(小林製薬,大阪,日本)による健康被害の報告が多数のぼり,腎機能障害や尿所見異常などを呈し,一部の症例では末期腎不全に至るなどの臨床像が報告されているが,原因物質は未詳である。今回われわれは,以前より軽度の推算糸球体濾過量(estimated glomerular filtration rate:eGFR)低下を指摘されていたところへ同サプリメントを3年間内服継続し,発症2ヵ月前から非ステロイド性抗炎症薬(non-steroidal anti-inflammatory drugs:NSAIDs)を使用していたところに発症した急性腎障害(acute kidney injury:AKI),後天性完全型Fanconi症候群を伴った急性尿細管障害(acute tubular injury:ATI)の1例を経験した。初診時には尿中β2ミクログロブリン(β2 microglobulin:β2MG)および好中球ゼラチナーゼ結合リポカリン(neutrophil gelatinase-associated lipocalin:NGAL)の上昇と,汎アミノ酸尿,尿糖陽性,高カルシウム尿症,高リン尿症,高尿酸尿症,II型尿細管性アシドーシスといった近位尿細管機能異常を認め,Fanconi症候群を呈したATIによるAKIと考えられた。腎生検組織所見では尿細管上皮の傷害像はみられたが,炎症性細胞浸潤は乏しかった。足突起消失(foot process effacement)は部分的であった。ステロイドを含めた免疫抑制治療は行わず保存的治療のみで腎機能障害やFanconi症候群は軽快し,現在経過観察中である。全国的に使用されているサプリメントであり,原因物質の究明が待たれるが,同サプリメントにより惹起される腎機能障害や蛋白尿などの尿所見異常の病態を中心に,文献的考察を踏まえて報告する。(著者抄録)

False-positive Serum Antiglomerular Basement Membrane Antibody due to Bovine Serum Albumin-containing Surgical Adhesive: A Case Report.

Yoshida R, Azegami T, Yamaguchi S, Hagiwara A, Hishikawa A, Yoshimoto N, Hashiguchi A, Hayashi K

Kidney medicine 6 （ 10 ） 100880 2024年10月

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Effective calcineurin inhibitor treatment in adult-onset steroid-resistant nephrotic syndrome with a novel splice donor site variant of TRPC6: a case report.

Nagasaka T, Uchiyama K, Hama EY, Kojima D, Kaneko K, Yoshimoto N, Yasuda I, Yamada M, Miya F, Suzuki H, Tajima T, Yamaguchi S, Hayashi K, Kanda T, Hashiguchi A, Kosaki K, Itoh H

CEN case reports 2024年09月

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Complement Receptor 1 Enhancement in Recurrent Membranous Nephropathy Following Kidney Transplantation: A Case Report.

Kounoue N, Oguchi H, Hashiguchi A, Honda K, Kang D, Mikami T, Tochigi N, Kawamura T, Itabashi Y, Yonekura T, Sakurabayashi K, Sakai K

Kidney medicine 6 （ 9 ） 100876 2024年09月

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多発病変の中の小さな最高grade病変は,MRIで検出できるのか

松本一宏, 秋田大宇, 橋口明典, 武田利和, 小坂威雄, 福本桂資郎, 安水洋太, 田中伸之, 森田伸也, 水野隆一, 浅沼宏, 大家基嗣, 陣崎雅弘

泌尿器外科（医学図書出版(株)） 37 （ 8 ） 942 - 944 2024年08月

共著, ISSN 0914-6180

Intestinal epithelium dysfunctions cause IgA deposition in the kidney glomeruli of intestine-specific Ap1m2-deficient mice

Kinashi Y., Tanaka K., Kimura S., Hirota M., Komiyama S., Shindo T., Hashiguchi A., Takahashi D., Shibata S., Karaki S.I., Ohno H., Hase K.

eBioMedicine 106 105256 2024年08月

共著

Background: Intestinal epithelial cells (IECs) serve as robust barriers against potentially hostile luminal antigens and commensal microbiota. Epithelial barrier dysfunction enhances intestinal permeability, leading to leaky gut syndrome (LGS) associated with autoimmune and chronic inflammatory disorders. However, a causal relationship between LGS and systemic disorders remains unclear. Ap1m2 encodes clathrin adaptor protein complex 1 subunit mu 2, which facilitates polarized protein trafficking toward the basolateral membrane and contributes to the establishment of epithelial barrier functions. Methods: We generated IEC-specific Ap1m2-deficient (Ap1m2ΔIEC) mice with low intestinal barrier integrity as an LSG model and examined the systemic impact. Findings: Ap1m2ΔIEC mice spontaneously developed IgA nephropathy (IgAN)-like features characterized by the deposition of IgA–IgG immune complexes and complement factors in the kidney glomeruli. Ap1m2 deficiency markedly enhanced aberrantly glycosylated IgA in the serum owing to downregulation and mis-sorting of polymeric immunoglobulin receptors in IECs. Furthermore, Ap1m2 deficiency caused intestinal dysbiosis by attenuating IL-22-STAT3 signaling. Intestinal dysbiosis contributed to the pathogenesis of IgAN because antibiotic treatment reduced aberrantly glycosylated IgA production and renal IgA deposition in Ap1m2ΔIEC mice. Interpretation: IEC barrier dysfunction and subsequent dysbiosis by AP-1B deficiency provoke IgA deposition in the mouse kidney. Our findings provide experimental evidence of a pathological link between LGS and IgAN. Funding: AMED, AMED-CREST, JSPS Grants-in-Aid for Scientific Research, JST CREST, Fuji Foundation for Protein Research, and Keio University Program for the Advancement of Next Generation Research Projects.

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Detection of the Highest-Grade Lesion in Multifocal Discordant Prostate Cancer by Multiparametric Magnetic Resonance Imaging

Matsumoto K., Akita H., Hashiguchi A., Takeda T., Kosaka T., Fukumoto K., Yasumizu Y., Tanaka N., Morita S., Mizuno R., Asanuma H., Oya M., Jinzaki M.

Clinical Genitourinary Cancer （Clinical Genitourinary Cancer） 22 （ 3 ） 102084 - 102084 2024年06月

共著, ISSN 15587673

Purpose: Prostate cancer generally occurs multifocally. The lesions of the largest size and highest-grade are often concordant, and defined as an index tumor. However, these factors sometimes do not coincide within one lesion. In such discordant cases, not the largest size lesion but the highest-grade lesion is known to determine the prognosis. We focused on the multiparametric magnetic resonance imaging (mpMRI) detectability of the highest-grade tumors in discordant cases. Materials and Methods: We investigated the detectability of the highest-grade tumor using preoperative mpMRI in 50 discordant patients who underwent radical prostatectomy. The radiologist was informed of the tumor location on the pathological tumor map, and mpMRI interpretation for each tumor was performed. Results: Prostate Imaging-Reporting and Data System (PI-RADS) scores of 1, 2, 3, 4, and 5 on preoperative mpMRI were assigned to 13, 1, 9, 16, and 11 of the largest tumors, respectively. On the other hand, scores of 1, 2, 3, 4, and 5 were assigned to 23, 0, 7, 19, and 1 of the highest-grade tumors, respectively. The difference between them was statistically significant (p=0.007). We also found that the largest anterior tumor frequently hid the ipsilateral posterior highest-grade tumor; the detection rate of the highest-grade tumor in this pattern was 42.1% (8 of 19 cases) Conclusion: We found that mpMRI detectability of the highest-grade tumor in discordant cases was inferior to that of the largest tumor with low malignant potential. Our results suggest that the risk of high-grade tumors which determine patient prognosis being overlooked.

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慢性腎臓病患者における腎洞脂肪量と腎血行動態の関連の検証

金子賢司, 満野竜之介, 児島大輝, 畔上達彦, 小杉将太郎, 中村俊文, 橋口明典, 山田祥岳, 陣崎雅弘, 山口慎太郎, 伊藤裕, 吉野純, 林香

日本腎臓学会誌（(一社)日本腎臓学会） 66 （ 4 ） 586 - 586 2024年06月

共著, ISSN 0385-2385

Establishment of artificial intelligence model for precise histological subtyping of lung adenocarcinoma and its application to quantitative and spatial analysis.

Miura E, Emoto K, Abe T, Hashiguchi A, Hishida T, Asakura K, Sakamoto M

Japanese journal of clinical oncology 54 （ 9 ） 1009 - 1023 2024年05月

共著, ISSN 0368-2811

Background: The histological subtype of lung adenocarcinoma is a major prognostic factor. We developed a new artificial intelligence model to classify lung adenocarcinoma images into seven histological subtypes and adopted the model for whole-slide images to investigate the relationship between the distribution of histological subtypes and clinicopathological factors. Methods: Using histological subtype images, which are typical for pathologists, we trained and validated an artificial intelligence model. Then, the model was applied to whole-slide images of resected lung adenocarcinoma specimens from 147 cases. Result: The model achieved an accuracy of 99.7% in training sets and 90.4% in validation sets consisting of typical tiles of histological subtyping for pathologists. When the model was applied to whole-slide images, the predominant subtype according to the artificial intelligence model classification matched that determined by pathologists in 75.5% of cases. The predominant subtype and tumor grade (using the WHO fourth and fifth classifications) determined by the artificial intelligence model resulted in similar recurrence-free survival curves to those determined by pathologists. Furthermore, we stratified the recurrence-free survival curves for patients with different proportions of high-grade components (solid, micropapillary and cribriform) according to the physical distribution of the high-grade component. The results suggested that tumors with centrally located high-grade components had a higher malignant potential (P < 0.001 for 5-20% high-grade component). Conclusion: The new artificial intelligence model for histological subtyping of lung adenocarcinoma achieved high accuracy, and subtype quantification and subtype distribution analyses could be achieved. Artificial intelligence model therefore has potential for clinical application for both quantification and spatial analysis.

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慢性腎臓病患者における腎洞脂肪量と腎血行動態の関連の検証

金子賢司, 満野竜ノ介, 児島大輝, 畔上達彦, 中村俊文, 橋口明典, 山田祥岳, 陣崎雅弘, 山口慎太郎, 伊藤裕, 吉野純, 林香

日本内分泌学会雑誌（(一社)日本内分泌学会） 100 （ 1 ） 348 - 348 2024年05月

共著, ISSN 0029-0661

慢性腎臓病患者における腎洞脂肪量と腎血行動態の関連の検証

金子賢司, 満野竜ノ介, 児島大輝, 畔上達彦, 中村俊文, 橋口明典, 山田祥岳, 陣崎雅弘, 山口慎太郎, 伊藤裕, 吉野純, 林香

日本内分泌学会雑誌（(一社)日本内分泌学会） 100 （ 1 ） 348 - 348 2024年05月

共著, ISSN 0029-0661

Renal sinus fat is associated with intrarenal hemodynamic abnormalities independent of visceral fat in patients with chronic kidney disease

Kaneko K., Mitsuno R., Kojima D., Azegami T., Kosugi S., Nakamura T., Hashiguchi A., Yamada Y., Jinzaki M., Yamaguchi S., Itoh H., Yoshino J., Hayashi K.

Obesity Research and Clinical Practice （Obesity Research and Clinical Practice） 18 （ 2 ） 118 - 123 2024年03月

共著, ISSN 1871403X

Objective: Obesity is a risk factor of chronic kidney disease (CKD), contributing to the rising incidence of cardiometabolic diseases. Renal sinus fat (RSF) is an ectopic fat depot located at the renal cavity that could impair renal function and hemodynamic through compression of renal structures. The major purpose of this study was to explore the relationship between RSF accumulation and renal dysfunction in CKD patients. Methods: We evaluated the associations between computed tomography measured RSF volume and key clinical and histologic parameters involved in renal function and hemodynamics in 132 well-characterized CKD patients who underwent renal biopsy (median age: 62 years; 63.6% men). Results: RSF volume normalized by renal volume (RSF%) positively correlated with obesity-related traits such body mass index and visceral fat volume (VFV) (all P < 0.001) whereas it negatively correlated with estimated glomerular filtration rate (eGFR) (ρ = −0.42, P < 0.001) and 24-h urinary creatinine clearance (CCr) (ρ = −0.34, P < 0.001). Notably, we found robust positive correlations between RSF% and renal resistive index (RRI) measured by the Doppler ultrasound (ρ = 0.40, P < 0.001), and the histological severity of global glomerular sclerosis (ρ = 0.48, P < 0.001) and interstitial fibrosis and tubular atrophy (IFTA) (ρ = 0.35, P < 0.001). In the multivariate linear regression models, after accounting for potential confounders including VFV, RSF% remained significantly associated with CCr (β = −0.26, P < 0.001), RRI (β = 0.17, P = 0.022), global glomerular sclerosis (β = 0.21, P = 0.002), and IFTA (β = 0.17, P = 0.012). Conclusion: RSF accumulation is associated with renal dysfunction and hemodynamic abnormalities independent of visceral adiposity. Our results suggest that RSF may have a potential unique role in the pathogenesis of CKD.

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Morphological and etiological analyses of C3 and non-C3 glomerulonephritis in primary membranoproliferative glomerulonephritis using periodic acid-methenamine silver stain electron microscopy: a retrospective multicentered study

Honma S., Sato N., Sakaguchi R., Hashiguchi A., Uesugi N., Nakamura Y., Sasano H., Joh K.

Medical Molecular Morphology （Medical Molecular Morphology） 57 （ 1 ） 23 - 34 2024年03月

共著, ISSN 18601480

This study elucidated the etiology of C3 glomerulonephritis (C3GN) and non-C3GN with primary membranoproliferative glomerulonephritis (MPGN) using transmission electron microscopy (TEM) and periodic acid-methenamine silver stain (PAM-EM). Thirty-one primary MPGN cases were analyzed by TEM and PAM-EM to distinguish among MPGN I, MPGN II, MPGN III Burkholder subtype (MPGN IIIB), and Anders and Strife subtype (MPGN IIIA/S). Each case was also classified into C3GN or non-C3GN according to the standard C3GN definition using immunostaining. Four cases of MPGN II met C3 glomerulopathy; whereas, four cases of MPGN IIIB did not meet C3 glomerulopathy. Seven of 11 cases (64%) of MPGN I without GBM disruption and 7 of 12 cases (58%) of MPGN IIIA/S with GBM disruption met the non-C3GN criteria with significant immunoglobulins’ deposition. Regardless of the C3GN or non-C3GN diagnosis, the deposits in primary MPGN I and MPGN IIIA/S exhibited ill-defined, amorphous, and foggy characteristics similar to those found in postinfectious GN but were different from immune complex (IC) deposits seen in MPGN IIIB. Not only C3GN but also non-C3GN was due to mechanisms other than IC deposition as found in postinfectious GN. Consequently, GBM disruption of MPGN IIIA/S was not due to IC deposition.

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Clinicopathological prognostic stratification for proteinuria and kidney survival in IgA nephropathy: a Japanese prospective cohort study

Koike K., Kawamura T., Hirano K., Nishikawa M., Shimizu A., Joh K., Katafuchi R., Hashiguchi A., Yano Y., Matsuzaki K., Matsushima M., Tsuboi N., Maruyama S., Narita I., Yokoo T., Suzuki Y.

Clinical Kidney Journal （Clinical Kidney Journal） 17 （ 1 ） sfad294 2024年01月

共著, ISSN 20488505

Background. We require a clinicopathological risk stratification method for immunoglobulin A nephropathy (IgAN) to predict kidney outcomes. We examined a renal failure risk group (RF-RG) classification system created following a prior multicentre, retrospective study to determine if RF-RG could predict kidney outcomes. Methods. We collected data from Japanese patients with IgAN registered between 1 April 2005 and 31 August 2015. The primary outcome was a composite 50% increase in serum creatinine from baseline or dialysis induction. The secondary outcomes were times to proteinuria remission (ProR) and haematuria remission (HemR). Results. The enrolled 991 patients from 44 facilities were followed for a median of 5.5 years (interquartile range 2.5-7.5), during which 87 composite events (8.8%) occurred. RF-RG was significantly associated with the primary outcome {hazard ratio [HR] II 2.78 [95% confidence interval (CI) 1.12-6.93], III 7.15 (2.90-17.6), IV 33.4 (14.1-79.0), I as a reference, P < .001}. The discrimination performance was good [C-statistic 0.81 (95% CI 0.76-0.86)] and the time-dependent C-statistics exceeded 0.8 over 10 years. Among the 764 patients with proteinuria and 879 patients with haematuria at baseline, 515 and 645 patients showed ProR and HemR, respectively. ProR was significantly less frequent in patients with advanced disease [subdistribution HR: II 0.79 (95% CI 0.67-0.94), III 0.53 (0.41-0.66), IV 0.15 (0.09-0.23), I as a reference, P < .001]. We also observed an association between HemR and RF-RG. Conclusions. RF-RG demonstrated good predictive ability for kidney outcomes.

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Associations of corticosteroid therapy and tonsillectomy with kidney survival in a multicenter prospective study for IgA nephropathy

Kawamura T., Hirano K., Koike K., Nishikawa M., Shimizu A., Joh K., Katafuchi R., Hashiguchi A., Matsuzaki K., Maruyama S., Tsuboi N., Narita I., Yano Y., Yokoo T., Suzuki Y.

Scientific Reports （Scientific Reports） 13 （ 1 ） 18455 - 18455 2023年12月

共著

Efficacy of systemic corticosteroid therapy (CS) for long-term kidney survival in patients with IgA nephropathy (IgAN) is controversial. Therefore, prospective studies evaluating targeted therapies to lymphatic tissues in mucosal immune system responsible for production of nephritogenic IgA have been desired worldwide. Here, we aimed to evaluate the associations of CS and combination therapy of CS and tonsillectomy (CS + Tx) with kidney survival, using database from a nationwide multicenter prospective cohort study on IgAN. Primary outcome was a 50% increase in serum creatinine from baseline or dialysis induction. The analysis included 941 patients (CS/CS + Tx/non-CS 239/364/338), 85 (9.0%) of whom reached outcomes during median follow-up of 5.5 (interquartile range 2.0–8.0) years. On overlap weighting analysis with balanced baseline characteristics, CS and CS + Tx were associated with lower risk of kidney events when compared with non-CS (hazard ratio [HR] 0.51, 95% confidence interval [CI] 0.29–0.88 and HR 0.20, 95%CI 0.09–0.44, respectively). Notably, when compared with the CS, CS + Tx was associated with a lower risk of kidney events (HR 0.40, 95%CI 0.18–0.91). Present study demonstrated, keeping with favorable association of systemic CS with kidney survival, concurrent tonsillectomy as one of targeted interventions to lymphatic tissues may provide additional improvement to kidney survival in patients with IgAN.

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維持透析後のリツキシマブ寛解維持療法継続により血液透析を離脱した重症難治型ANCA関連血管炎の1例

星健太, 村上英人, 小野田怜依, 熊谷光祐, 佐藤由佳, 渡部統, 中村彰良, 橋口明典, 浦井秀徳

日本透析医学会雑誌（(一社)日本透析医学会） 56 （ 10 ） 377 - 384 2023年10月

共著, ISSN 1340-3451

当院において,コントロール不良の2型糖尿病および間質性肺炎を併存する高齢男性に生じた急速進行性糸球体腎炎(rapidly progressive glomerulonephritis:RPGN)で腎生検組織所見から感染後糸球体腎炎合併ANCA関連糸球体腎炎と診断した症例を経験した.プレドニゾロン(prednisolone:PSL)およびリツキシマブ(rituximab:RTX)で寛解導入療法を行うも腎機能が改善せず,維持血液透析療法導入となった.その後の寛解維持療法の継続により重篤な感染症を呈することなくステロイドを投与終了し残存腎機能の回復を認め,RTXの寛解維持治療中に透析導入後11ヵ月で透析離脱となった.高齢かつ合併症の多いANCA関連血管炎におけるRPGNにおいても,腎予後良好な徴候がみられた場合には適切な感染症予防を行ったうえでRTX療法を継続することで透析離脱が可能となる場合がある.(著者抄録)

当院における腎移植後5年の移植腎生検病理組織の検討

坂巻裕介, 香野日高, 橋口明典, 環聡, 桝田司, 高橋遼平, 萩生田純, 徳山博文, 中川健

移植（(一社)日本移植学会） 58 （総会臨時） 336 - 336 2023年09月

共著, ISSN 0578-7947

慢性糸球体腎炎の臨床経過で腎生検によりmasked IgG kappa depositsを伴う膜性腎症と診断し保存的加療を行った一例

満野竜ノ介, 吉本憲史, 橋口明典, 内山清貴, 山口慎太郎, 林香

日本腎臓学会誌（(一社)日本腎臓学会） 65 （ 6-E ） 638 - 638 2023年09月

共著, ISSN 0385-2385

Hepatitis B Virus-related Membranous Nephropathy with Crescentic Formation in an Inactive Carrier of Positive Hepatitis B Surface Antigen with Undetectable DNA under Anti-viral Treatment: A Case Report.

Kounoue N, Oguchi H, Mikami T, Yamaguchi Y, Hashiguchi A, Nagai H, Watanabe K, Furukawa S, Hisamatsu K, Sakai K

Internal medicine (Tokyo, Japan) 63 （ 1 ） 101 - 106 2023年05月

共著, ISSN 0918-2918

A man who was an inactive hepatitis B virus (HBV) carrier with positive hepatitis B surface antigen (HBs antigen) and undetectable HBV-DNA under anti-viral treatment developed nephrotic syndrome at 52 years old, and a renal biopsy revealed advanced membranous nephropathy (MN) with focal cellular crescents, interstitial hemorrhaging, and peritubular capillaritis. Immunofluorescence studies demonstrated granular IgG deposition and HBs antigen-positivity along the capillaries. Glomeruli were negative for phospholipase A2 receptor 1. There were no clinical findings of systemic vasculitis. We considered MN combined with small-vessel vasculitis due to HBV infection. These results suggest that HBV-related kidney disease should be considered even in patients with an inactive HBV carrier status under treatment.

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J-IGACSを用いたIgA腎症Oxford分類を構成する病変の組み合わせと治療反応性との関連の検討

坂口涼子, 城謙輔, 小此木英男, 中里毅, 橋口明典, 片渕律子, 清水章, 小池健太郎, 平野景太, 坪井伸夫, 川村哲也, 横尾隆, 成田一衛, 鈴木祐介

日本腎臓学会誌（(一社)日本腎臓学会） 65 （ 3 ） 320 - 320 2023年05月

共著, ISSN 0385-2385

J-IGACSを用いたIgA腎症Oxford分類を構成する病変の組み合わせと治療反応性との関連の検討

坂口涼子, 城謙輔, 小此木英男, 中里毅, 橋口明典, 片渕律子, 清水章, 小池健太郎, 平野景太, 坪井伸夫, 川村哲也, 横尾隆, 成田一衛, 鈴木祐介

日本腎臓学会誌（(一社)日本腎臓学会） 65 （ 3 ） 320 - 320 2023年05月

共著, ISSN 0385-2385

IgA腎症におけるステロイド療法,扁摘と腎予後の関連性

平野景太, 川村哲也, 小池健太郎, 西川正子, 清水章, 城謙輔, 片渕律子, 橋口明典, 松崎慶一, 丸山彰一, 坪井伸夫, 成田一衛, 矢野裕一朗, 横尾隆, 鈴木祐介

日本腎臓学会誌（(一社)日本腎臓学会） 65 （ 3 ） 272 - 272 2023年05月

共著, ISSN 0385-2385

IgA腎症におけるステロイド療法,扁摘と腎予後の関連性

日本腎臓学会誌（(一社)日本腎臓学会） 65 （ 3 ） 272 - 272 2023年05月

共著, ISSN 0385-2385

Immunohistochemistry May Not Replace Immunofluorescence in Paraffin-embedded Tissue for Detecting Masked Monoclonal Immunoglobulin Deposits: A Case Report.

Oda Y, Ikeda Y, Abe H, Hashiguchi A, Hatanaka K, Sawai T, Ushiku T, Nangaku M

Internal medicine (Tokyo, Japan) 62 （ 24 ） 3657 - 3661 2023年04月

共著, ISSN 0918-2918

An 84-year-old man developed a membranoproliferative glomerulonephritis pattern of injury, and the most likely cause detected during a workup was monoclonal IgG-λ in the urine and serum. Predominant IgG and λ light chain deposition was confirmed only by immunofluorescence using formalin-fixed, paraffin-embedded tissue and not by immunohistochemistry. A smaller and non-linear dynamic range of immunohistochemistry makes it less quantitative than immunofluorescence staining and may explain why immunohistochemistry failed to detect the light chain restriction. This case suggests that immunohistochemistry may not serve as a substitute for immunofluorescence on formalin-fixed, paraffin-embedded tissue in detecting masked monoclonal immunoglobulin deposits, although further research is warranted.

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DNA-damaged podocyte-CD8 T cell crosstalk exacerbates kidney injury by altering DNA methylation

Nakamichi R., Hishikawa A., Chikuma S., Yoshimura A., Sasaki T., Hashiguchi A., Abe T., Tokuhara T., Yoshimoto N., Nishimura E.S., Hama E.Y., Azegami T., Nakayama T., Hayashi K., Itoh H.

Cell Reports （Cell Reports） 42 （ 4 ） 112302 - 112302 2023年04月

共著

Recent epigenome-wide studies suggest an association between blood DNA methylation and kidney function. However, the pathological importance remains unclear. Here, we show that the homing endonuclease I-PpoI-induced DNA double-strand breaks in kidney glomerular podocytes cause proteinuria, glomerulosclerosis, and tubulointerstitial fibrosis with DNA methylation changes in blood cells as well as in podocytes. Single-cell RNA-sequencing analysis reveals an increase in cytotoxic CD8+ T cells with the activating/costimulatory receptor NKG2D in the kidneys, which exhibit a memory precursor effector cell phenotype, and the CD44high memory CD8+ T cells are also increased in the peripheral circulation. NKG2D blockade attenuates the renal phenotype caused by podocyte DNA damage. Blood methylome shows increased DNA methylation in binding sites for STAT1, a transcription factor contributing to CD8+ T cell homeostasis. Collectively, podocyte DNA damage alters the blood methylome, leading to changes in CD8+ T cells, which contribute to sustained renal injury in chronic kidney disease.

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Significance of podocyte DNA damage and glomerular DNA methylation in CKD patients with proteinuria

Yoshimoto N., Hayashi K., Hishikawa A., Hashiguchi A., Nakamichi R., Sugita-Nishimura E., Yoshida-Hama E., Azegami T., Nakayama T., Itoh H.

Hypertension Research （Hypertension Research） 46 （ 4 ） 1000 - 1008 2023年04月

共著, ISSN 09169636

The number of chronic kidney disease (CKD) patients is increasing worldwide, and it is necessary to diagnose CKD patients in earlier stages to improve their prognosis. Previously, in a study using human samples, we reported that DNA methylation and DNA damage in podocytes are potential markers for kidney function decline in IgA nephropathy; however, these candidate markers have not been adequately investigated in other glomerular diseases. Here, we report that the association of podocyte DNA damage and DNA methylation with eGFR decline and proteinuria differs depending on the type of glomerular disease. Patients diagnosed with minor glomerular abnormality (MGA, n = 33), membranous nephropathy (MN, n = 9) or diabetic nephropathy (DN, n = 10) following kidney biopsy at Keio University Hospital from 2015 to 2017 were included. In MGA patients, both podocyte DNA damage and glomerular DNA methylation were associated with the severity of proteinuria. In DN patients, podocyte DNA double-strand breaks (DSBs) and glomerular DNA methylation were associated with an eGFR decline. When patients with urinary protein levels of more than 1 g/gCr were examined, fewer podocyte DNA DSBs were detected in MN patients than in MGA patients, and the level of glomerular DNA methylation was lower in MN patients than in MGA or DN patients. These results indicate that investigating podocyte DNA DSBs and DNA methylation changes may be useful for understanding the pathogenesis of CKD with proteinuria in humans. [Figure not available: see fulltext.].

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Case report: Importance of early and continuous tocilizumab therapy in nephrotic syndrome associated with idiopathic multicentric Castleman disease: A case series

Kojima D., Yamaguchi S., Hashiguchi A., Hayashi K., Uchiyama K., Yoshimoto N., Adachi K., Nakayama T., Nishioka K., Tajima T., Morimoto K., Yoshino J., Yoshida T., Monkawa T., Kanda T., Itoh H.

Frontiers in Medicine （Frontiers in Medicine） 9 1037032 - 1037032 2023年01月

共著, ISSN 2296-858X

Idiopathic multicentric Castleman disease (iMCD) is a systemic and polyclonal lymphoproliferative disease involving multiple organs, including the kidneys, due to the overproduction of interleukin-6 (IL-6). Recently, several reports have suggested that excessive IL-6 actions in iMCD could have a causal relationship with the development of diverse histopathological renal manifestations that cause nephrotic syndrome. However, the treatment for such cases remains unclear. We report a series of three cases of nephrotic syndrome due to iMCD that helps to delineate the importance of early and continuous therapy with the anti-interleukin-6 receptor antibody tocilizumab. First, treatment was suspended for infectious control, and the patient presented with nephrotic syndrome due to diffuse mesangial and endocapillary hypercellularity without immune deposits complicating acute kidney injury. Second, iMCD was treated with prednisolone alone. The patient suddenly developed nephrotic syndrome due to immune-complex glomerulonephritis, not otherwise specified, complicated with acute kidney injury. In the third case, nephrotic syndrome secondary to membranous glomerulonephritis was diagnosed, with a skin rash and IgE antibodies to tocilizumab, and was therefore treated with prednisolone alone. In contrast to the first two cases, the third progressed to end-stage renal disease on hemodialysis. Taken together, this series suggests that clinicians should maintain clinical vigilance for iMCD as a possible underlying component of nephrotic syndrome, since iMCD presents with a variety of renal pathologies. Prompt initiation and continuous administration of tocilizumab are likely key determinants of renal outcomes in such cases. In particular, when tocilizumab is suspended due to infection or in the perioperative period, consideration of its expeditious resumption should be made, taking into account both the withdrawal period and systemic conditions.

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Antineutrophil cytoplasmic antibody-associated vasculitis predominantly manifesting tubulointerstitial nephritis: A case report

Nishioka K., Yamaguchi S., Hashiguchi A., Yoshimoto N., Tajima T., Yasuda I., Uchiyama K., Kaneko K., Aso M., Yoshino J., Monkawa T., Kanda T., Hayashi K., Itoh H.

SAGE Open Medical Case Reports （SAGE Open Medical Case Reports） 11 2050313X231197324 2023年01月

共著, ISSN 2050-313X

The common histopathology of antineutrophil cytoplasmic antibody-associated vasculitis comprises pauci-immune crescentic glomerulonephritis with concomitant tubulointerstitial nephritis. Tubulointerstitial nephritis in the absence of glomerular involvement in patients with antineutrophil cytoplasmic antibody-associated vasculitis is uncommon. We report a case of antineutrophil cytoplasmic antibody-associated vasculitis-associated acute kidney injury manifesting as tubulointerstitial nephritis without glomerulonephritis. A 75-year-old woman with fever, cough, and myalgia developed kidney dysfunction with inflammatory reactions and tubular-type proteinuria, without glomerular hematuria. A kidney biopsy revealed tubulointerstitial nephritis with arteritis. We ruled out important underlying etiologies of tubulointerstitial nephritis, including infection, drug reactions, and autoimmune diseases. Since chest high-resolution computed tomography demonstrated mild interstitial pneumonia in bilateral lower lung fields, myeloperoxidase antineutrophil cytoplasmic antibody was measured and found to be positive. Therefore, we diagnosed the patient with antineutrophil cytoplasmic antibody-associated vasculitis-associated tubulointerstitial nephritis but not glomerulonephritis, and interstitial pneumonia. The patient’s kidney function and symptoms markedly improved with prednisolone treatment. Clinicians should maintain high-level vigilance for antineutrophil cytoplasmic antibody-associated vasculitis as a possible underlying component of tubulointerstitial nephritis, particularly when kidney function deteriorates with tubulointerstitial injuries without glomerular features.

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Granulomatous interstitial nephritis with CTLA-4 haploinsufficiency: a case report

Kohatsu K., Suzuki T., Takimoto M., Matsui K., Hashiguchi A., Koike J., Shirai S.

BMC Nephrology （BMC Nephrology） 23 （ 1 ） 367 2022年12月

共著

Background: Cytotoxic T lymphocyte antigen-4 (CTLA-4) is an essential inhibitory regulator of immune activation. CTLA-4 haploinsufficiency is known to be associated with dysregulation of FOXP3+ regulatory T cells, hyperactivation of effector T cells, and lymphocytic infiltration of multiple organs. However, there have only been a few reports of renal involvement with CTLA-4. Herein, we present a case of acute granulomatous tubulointerstitial nephritis (TIN) in a patient with CTLA-4 haploinsufficiency. Case presentation: A 44-year-old man presented with a 3-week history of fever and malaise, and subsequently developed acute kidney injury (AKI) a few days after treatment with levofloxacin (LVFX). A kidney biopsy and immunohistochemical staining revealed granulomatous TIN with dominantly infiltrating CD4+ T cells. General symptoms and renal impairment showed improvement after discontinuation of LVFX and initiation of oral steroids. However, they worsened following steroid tapering. Further, a colon biopsy analysis showed similar findings to the renal tissue analysis. We suspected that granulomatous TIN was possibly associated with CTLA-4 haploinsufficiency. Therefore, the patient was transferred to another hospital for further treatment of CTLA-4 haploinsufficiency using immunosuppressive agents. Conclusions: There have been few reports regarding renal involvement of CTLA-4 haploinsufficiency. In the present case, granulomatous TIN could have arisen due to instability of immune regulatory functions, such as CTLA-4 haploinsufficiency, and treatment with LVFX could have triggered immunologic activation and severe inflammation as well as renal dysfunction.

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尿細管・間質病変主体のANCA関連血管炎の一例

西岡謙, 山口慎太郎, 安田格, 吉本憲史, 田島敬也, 林香, 吉野純, 橋口明典, 神田武志, 伊藤裕

日本腎臓学会誌（(一社)日本腎臓学会） 64 （ 6-E ） 549 - 549 2022年10月

共著, ISSN 0385-2385

A girl with membranous nephropathy associated with ventriculoperitoneal shunt infection.

Awazu M, Miyahara M, Chiga M, Hashiguchi A, Takahashi H

CEN case reports （CEN case reports） 12 （ 1 ） 130 - 134 2022年09月

共著

Glomerulopathy associated with shunt infection is commonly membranoproliferative glomerulonephritis, whereas the causative organisms of secondary membranous nephropathy are usually viruses. We report a case of membranous nephropathy associated with shunt infection. The patient was born at 29-week gestation with a birth weight of 1178 g. Ventriculoperitoneal shunt surgery had been performed for congenital hydrocephalus. Thereafter, she had experienced seven shunt infections. At the age 13 years, proteinuria was detected in a school urinary screening. Urinalysis at our hospital demonstrated 3 + protein and 3 + blood. Laboratory testing demonstrated a serum creatinine 0.5 m/dl, albumin 2.5 g/dl, C-reactive protein (CRP) 13.7 mg/dl, and C3 182 mg/dl. Prior to repeat urinalysis, the patient developed vomiting and was admitted with suspected shunt infection. On admission, her body temperature was 36.0 ºC. Physical examination was unremarkable other than small stature and a palpable mass in the left upper quadrant. Urinalysis demonstrated 2 + protein and 1 + blood with no cells or casts. The urinary protein excretion was 3 g/day. Abnormal laboratory tests included erythrocyte sedimentation rate 102 mm/hr, CRP 11.67 mg/dl, IgG 2442 mg/dl, C3 177 mg/dl, and C4 44 mg/dl. Antibiotic therapy was initiated for a presumptive diagnosis of shunt infection and the shunt catheter was removed. Cultures obtained after antibiotic administration were negative. Proteinuria persisted after control of the shunt infection. Histology of a renal biopsy demonstrated membranous nephropathy with diffuse granular IgG staining and subepithelial deposits. Three possible pathomechanisms for her membranous nephropathy were considered.

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Structural modeling for Oxford histological classifications of immunoglobulin A nephropathy

Joh K., Nakazato T., Hashiguchi A., Shimizu A., Katafuchi R., Okonogi H., Koike K., Hirano K., Tsuboi N., Kawamura T., Yokoo T., Narita I., Suzuki Y.

PLoS ONE （PLoS ONE） 17 （ 9 September ） e0268731 2022年09月

共著

In immunoglobulin A nephropathy (IgAN), Cox regression analysis can select independent prognostic variables for renal functional decline (RFD). However, the correlation of the selected histological variables with clinical and/or treatment variables is unknown, thereby making histology-based treatment decisions unreliable. We prospectively followed 946 Japanese patients with IgAN for a median of 66 mo. and applied structural equation modeling (SEM) to identify direct and indirect effects of histological variables on RFD as a regression line of estimated glomerular filtration rate (eGFR) via clinical variables including amount of proteinuria, eGFR, mean arterial pressure (MAP) at biopsy, and treatment variables such as steroid therapy with/without tonsillectomy (ST) and renin-angiotensin system blocker (RASB). Multi-layered correlations between the variables and RFD were identified by multivariate linear regression analysis and the model's goodness of fit was confirmed. Only tubular atrophy/interstitial fibrosis (T) had an accelerative direct effect on RFD, while endocapillary hypercellularity and active crescent (C) had an attenuating indirect effect via ST. Segmental sclerosis (S) had an attenuating indirect effect via eGFR and mesangial hypercellularity (M) had accelerative indirect effect for RFD via proteinuria. Moreover, M and C had accelerative indirect effect via proteinuria, which can be controlled by ST. However, both T and S had additional indirect accelerative effects via eGFR or MAP at biopsy, which cannot be controlled by ST. SEM identified a systemic path links between histological variables and RFD via dependent clinical and/or treatment variables. These findings lead to clinically applicable novel methodologies that can contribute to predict treatment outcomes using the Oxford classifications.

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Diagnosis of monoclonal immunotactoid glomerulopathy with positive λ chain by immunoelectron microscopy.

Sugita E, Sonoda H, Ryuzaki M, Hashiguchi A, Tokuyama H, Wakino S, Kanda T, Itoh H

CEN case reports （CEN case reports） 12 （ 1 ） 7 - 13 2022年06月

共著

We report the case of a 73-year-old-man who developed immunotactoid glomerulopathy (ITG). ITG is a rare disease characterized by proliferative glomerulonephritis and capillary wall deposits with a 10-60 nm diameter microtubular substructure. In monoclonal ITG, immunofluorescence analysis typically exhibits IgG with light chain restriction. Recent reviews recommend distinguishing monoclonal ITG from polyclonal ITG because monoclonal ITG is associated with a higher incidence of hematological disorders and better responsiveness to clone-directed therapy and renal prognosis. In our case, IgG, IgA, and IgM were negative by routine immunofluorescence; however, immunoelectron microscopy revealed positive λ chain. At 6 months after renal biopsy, the IgG λ chain was detected in the serum and urine, reflecting possible monoclonality. Therefore, it is useful to perform immunoelectron microscopy and follow-up with serum and urine protein electrophoresis and immunofixation to diagnose monoclonal ITG, even when routine immunofluorescence shows negative or nonspecific findings.

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MPO-ANCA、抗GBM抗体共陽性かつ膜性腎症を合併した急速進行性糸球体腎炎に対して選択的血漿交換(SePE)を行った一例

星健太, 浦井秀徳, 渡部統, 中村彰良, 橋口明典, 村上円人

日本急性血液浄化学会雑誌（(NPO)日本急性血液浄化学会） 13 （ 1 ） 48 - 51 2022年06月

共著, ISSN 2185-1085

当院において、半月体形成性糸球体腎炎を呈したMPO-ANCA、抗糸球体基底膜(glomerular basement membrane:GBM)抗体共陽性かつ膜性腎症を合併した急速進行性糸球体腎炎(rapidly progressive glomerulonephritis:RPGN)を経験した。血清Crの上昇がみられた早期に副腎皮質ステロイド、静注シクロホスファミドパルス療法(intravenous cyclophosphamide:IVCY)に加え選択的血漿交換(selective plasma exchange:SePE)を行ったところ、2抗体の陰性化を得られ肺障害を生じることなく腎機能障害も改善した。発症早期に、免疫抑制療法に加えて凝固因子補充不要なSePEを行うことが新規抗体産生抑制および抗体除去に有用であると考えられた。(著者抄録)

Clinical and pathological characteristics of patients with acute kidney injury in Japan in whom kidney biopsy was performed: a cross-sectional analysis of the Japan Renal Biopsy Registry (J‑RBR).

Moniwa N, Tanaka M, Sato H, Shimizu A, Sugiyama H, Yokoyama H, Tsuruya K, Hashiguchi A, Committee for Renal Biopsy and Disease Registry of the Japanese Society of Nephrology.

Clinical and experimental nephrology （Clinical and Experimental Nephrology） 26 （ 10 ） 963 - 973 2022年05月

共著, ISSN 1342-1751

Introduction: Acute kidney injury (AKI) is a worldwide concern and it leads to a poor prognosis or end-stage kidney disease. The purpose of this study was to clarify the characteristics of patients with AKI in whom kidney biopsy was performed using data of the Japan Renal Biopsy Registry (J-RBR). Methods: We screened 38,351 cases that were registered in the J-RBR from 2007 to 2018. We obtained data for 383 patients with AKI based on clinical diagnosis for analysis 1 and data for 714 patients with acute interstitial nephritis (AIN) or acute tubular necrosis (ATN) based on pathological diagnosis for analysis 2. Results: Of the cases screened, 383 patients with AKI (1.0%) were included in analysis 1. The main pathological diagnoses of AKI were AIN, ATN, chronic interstitial nephritis, nephro-sclerosis and crescentic glomerulonephritis. Of the cases screened, 589 patients with AIN (1.5%) and 110 patients with ATN (0.3%) were included in analysis 2. The main clinical diagnoses of AIN were AKI, rapidly progressive glomerulonephritis (RPGN), chronic nephritic syndrome (CNS) and drug-induced nephropathy (DIN), whereas those of ATN were AKI, RPGN, DIN and CNS. ATN patients had a higher serum creatinine level than that of AIN patients. Conclusion: Our results revealed that cases in the J-RBR included 1.0% of AKI cases based on clinical diagnosis and 1.5% and 0.3% of AIN and ATN cases, respectively, based on pathological diagnosis. In patients with suspected intrinsic AKI, kidney biopsy should be performed for diagnosis of the precise etiology and selection of appropriate treatment.

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異なる撮像機のデジタルスライドに対して抗酸菌検出AIの再現性を得るための検討

江本桂, 松田紘典, 阿部時也, 橋口明典, 坂元亨宇

日本病理学会会誌（(一社)日本病理学会） 111 （ 1 ） 240 - 240 2022年03月

共著, ISSN 0300-9181

当院で施行した移植腎生検病理組織の検討

坂巻裕介, 香野日高, 橋口明典, 環聡, 萩生田純, 桝田司, 宍戸偉海, 井上博之, 徳山博文, 中川健

日本臨床腎移植学会プログラム・抄録集（(一社)日本臨床腎移植学会） 55回 288 - 288 2022年02月

共著

Quantitative evaluation of color difference between actual specimens and whole-slide imaging-scanned images calibrated with commercial color charts

Murayama Y., Sugiyama T., Ogino Y., Furuta H., Kambara T., Kamisono K., Abe T., Emoto K., Hashiguchi A., Kajimura Y., Sakamoto M.

Progress in Biomedical Optics and Imaging - Proceedings of SPIE （Progress in Biomedical Optics and Imaging - Proceedings of SPIE） 12039 2022年

共著, ISSN 16057422

When using different cameras and displays in the shot and display of one subject, different color images are often showed. To solve this problem, we have developed a color chart in which the constituent colors dyed with dyes are evenly distributed in the color space. We have also developed a tool that creates an International Color Consortium (ICC) profile from the captured image of this color chart. In this report, we will describe the color difference correction accuracy when our method is applied to actual stained pathological specimens taken with multiple whole-slide imaging (WSI). We confirmed color correction accuracy of Lab values in major parts such as the cell nucleus. The Lab value of the specimen itself measured by a spectrocolorimeter was compared with that of the captured image. As a result, the color difference ?E in H&E-stained cell nucleus was improved from 32.2 to 6.4 for Nanozoomer and from 13.5 to 7.2 for ultra-fast scanner (UFS) by our color correction. The results of the evaluations for other areas and other stain methods (PAS, EVG, MT, and PAM) were good. In the future, high-accuracy color correction of teacher data/evaluation data in AI diagnosis using pathological images will be important.

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DNA repair factor KAT5 prevents ischemic acute kidney injury through glomerular filtration regulation

Hishikawa A., Hayashi K., Kubo A., Miyashita K., Hashiguchi A., Kinouchi K., Yoshimoto N., Nakamichi R., Akashio R., Sugita E., Azegami T., Monkawa T., Suematsu M., Itoh H.

iScience （iScience） 24 （ 12 ） 103436 - 103436 2021年12月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 2589-0042

The “preconditioning effect” in AKI is a phenomenon in which an episode of ischemia-reperfusion results in tolerance to subsequent ischemia-reperfusion injury. However, its relationship between DNA damage repair has not been elucidated. Here, we show the role of KAT5 in the preconditioning effect. Preconditioning attenuated DNA damage in proximal tubular cells with elevated KAT5 expression. Ischemia-reperfusion (IR) injuries were exacerbated, and preconditioning effect vanished in proximal tubular-cell-specific KAT5 knockout mice. Investigation of tubuloglomerular feedback (TGF) by MALDI-IMS and urinary adenosine revealed that preconditioning caused attenuated TGF at least in part via KAT5. In addition, K-Cl cotransporter 3 (KCC3) expression decreased in damaged proximal tubular cells, which may be involved in accelerated TGF following IR. Furthermore, KAT5 induced KCC3 expression by maintaining chromatin accessibility and binding to the KCC3 promoter. These results suggest a novel mechanism of the preconditioning effect mediated by the promotion of DNA repair and attenuation of TGF through KAT5.

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A Case of Fibronectin Glomerulopathy Confused with Glomerular Endothelial Injury in a Patient with Takotsubo Cardiomyopathy.

Azegami T, Hashiguchi A, Nakayama T, Hayashi K, Kanda T, Itoh H

Internal medicine (Tokyo, Japan) （Internal Medicine） 61 （ 13 ） 2027 - 2032 2021年12月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0918-2918

A 46-year-old woman developed takotsubo cardiomyopathy and nephrotic syndrome. The first kidney biopsy suggested non-immune-complex-mediated membranoproliferative glomerulonephritis (MPGN), and she was diagnosed with glomerular endothelial injury associated with takotsubo cardiomyopathy. A second biopsy was performed two years later because of persistent proteinuria despite renin-angiotensin system inhibition. This biopsy indicated non-immune-complex-mediated MPGN, but a mesangial and subendothelial substance of a higher electron density than that in the first biopsy was detected, suggesting the possibility of glomerular disease with non-immune deposits rather than endothelial injury. Finally, she was diagnosed with fibronectin nephropathy. Although rare, fibronectin glomerulopathy should be considered in non-immune-complex-mediated MPGN.

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Diabetic condition induces hypertrophy and vacuolization in glomerular parietal epithelial cells

Kawaguchi T., Hasegawa K., Yasuda I., Muraoka H., Umino H., Tokuyama H., Hashiguchi A., Wakino S., Itoh H.

Scientific Reports （Scientific Reports） 11 （ 1 ） 1515 - 1515 2021年12月

研究論文（学術雑誌）, 共著, 査読有り

Diabetic nephropathy (DN) is accompanied by characteristic changes in the glomerulus, but little is known about the effect of diabetes on parietal epithelial cells (PECs). In this study, a descriptive analysis of PECs was undertaken in diabetic db/db mice and in diabetic patients. PEC hypertrophy was significantly more prominent in diabetic mice than in nondiabetic mice, and this was evident even at the early stage. Additionally, the number of vacuoles in PECs was markedly increased in diabetic mice, suggesting the presence of cellular injury in PECs in DN. Although rare, binuclear cells were observed in mice with early diabetes. In cultured PECs, a high glucose condition, compared with normal glucose condition, induced cellular hypertrophy and apoptosis. Flow cytometry showed that some PECs in the G0 phase reentered the cell cycle but got arrested in the S phase. Finally, in human diabetic subjects, hypertrophy and vacuolization were observed in the PECs. Our data showed that PECs undergo substantial changes in DN and may participate in rearrangement for differentiation into podocytes.

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手術標本および生検標本のH&E染色組織画像を用いた畳み込みニューラルネットワークによる肝細胞癌の識別

高木弦, 山口雅浩, 阿部時也, 橋口明典, 坂元亨宇

日本医用画像工学会大会予稿集（(一社)日本医用画像工学会） 40回 133 - 137 2021年10月

研究論文（学術雑誌）, 共著, 査読有り

本研究では,H&E染色病理標本のデジタルスライド画像に対して畳み込みニューラルネットワーク(CNN)による肝細胞癌と非癌の識別を行った.CNNとしてEfficientNetB3を採用し,高解像度の病理画像を分割して学習させ,その結果を統合する方法について検討するとともに,学習率などについて改善行い精度向上を図った.2048×2048画素の手術標本及び生検標本の画像それぞれ約1,000枚に対して5-foldの交差検証を行った結果,先行研究において特徴量ベースのSVMで約90%の精度であったデータに対して,正解率約97%と極めて高い精度を得ることかができた.このとき,生検標本と手術標本の両者の画像を合わせて教師データとした際に,高精度でロバストな識別器が作成できることが示された.さらに,生検標本と手術標本の両方を学習させた際に,CNNが両者に共通する特徴を抽出しているのかについても考察を行った.(著者抄録)

Fabry disease associated with multiple myeloma: a case report.

Keika Adachi, Hirobumi Tokuyama, Yoichi Oshima, Tomoaki Itoh, Akinori Hashiguchi, Hiroyuki Yamakawa, Tadayasu Togawa, Hitoshi Sakuraba, Shu Wakino, Hiroshi Itoh

CEN case reports （CEN case reports） 11 （ 1 ） 146 - 153 2021年09月

研究論文（学術雑誌）, 共著, 査読有り

Fabry disease (FD) is an X-linked genetic lysosomal disorder caused by alpha-galactosidase A (GLA) deficiency. Multiple myeloma (MM) predominately affects older adults, which ranks as the second commonest hematological malignancy. Their overlap has rarely been reported. We present a case of the coexistence of FD and MM in a patient. We report the case of a 68-year-old woman who was referred to our hospital for the evaluation of thoracic spine tumor with bone destruction. On admission, her serum creatinine (Cr) level was elevated to 12.70 mg/dL from the baseline value of 0.91 mg/dL. Bone marrow aspiration revealed MM. Renal biopsy showed myeloma cast nephropathy, which was the primary cause of acute kidney injury. Renal pathology also showed podocyte swelling and tubule myeloid bodies in a mosaic pattern compatible with female FD. Consequently, the patient was diagnosed as FD based on the germ line mutation in GLA. The patient was treated with bortezomib and dexamethasone therapy, which significantly improved the renal function. This is the second case demonstrating a potential pathogenic relationship between FD and MM. Since FD is one of the few genetic diseases for which there are therapeutic agents with fewer side effects, diagnostic value of FD is high. If an MM patient has multiple organ abnormalities or any familial history, the physician should suspect FD.

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Undifferentiated carcinoma of the mandible detected simultaneously with the liver: A case report

Asoda S., Morita M., Soma T., Sato H., Hasegawa T., Nakagawa T., Hashiguchi A., Kawana H.

Oral and Maxillofacial Surgery Cases （Oral and Maxillofacial Surgery Cases） 7 （ 3 ） 100228 - 100228 2021年09月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 2214-5419

We herein report a rare case of undifferentiated carcinoma that originated in the mandible with the same pathological findings as seen in the liver. A 64-year-old man underwent surgery for a hepatic tumor in October 2006, and the pathological diagnosis was undifferentiated carcinoma. The patient was referred to our department in January 2007, when whole-body positron emission tomography/computed tomography showed the uptake of fluorodeoxyglucose in the right mandibular ramus. The patient underwent right hemimandibulectomy in April 2007. The resected tumor was also undifferentiated carcinoma. In May 2014, seven years after the lower mandibular operation, the tumor recurred at the site corresponding to the right mandibular ramus after resection, and tumor resection and right neck dissection were performed. As a result of the histopathological examination, the undifferentiated carcinoma findings were the same as before. There have been no signs of local recurrence or metastases for over six years since the second mandibular surgery.

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MPGN様の病理像を呈したλ鎖単独陽性イムノタクトイド腎症の一例

杉田絵里那, 神田武志, 竜崎正毅, 橋口明典, 林香, 徳山博文, 脇野修, 伊藤裕

日本腎臓学会誌（(一社)日本腎臓学会） 63 （ 6-E ） 739 - 739 2021年09月

共著, ISSN 0385-2385

A girl with a mutation of the ciliary gene CC2D2A presenting with FSGS and nephronophthisis.

Awazu M, Yamada M, Asada N, Hashiguchi A, Kosaki K, Matsumura K

CEN case reports （CEN case reports） 11 （ 1 ） 116 - 119 2021年08月

研究論文（学術雑誌）, 共著, 査読有り

Mutations in the ciliary gene TTC21B, NPHP4, and CRB2 cause familial focal and segmental glomerulosclerosis (FSGS). We report a girl with a mutation of the ciliary gene CC2D2A presenting with FSGS and nephronophthisis. The patient had mental retardation, postaxial polydactyly, and ataxic breathing, and was diagnosed as having compound heterozygous CC2D2A missense mutations at age 5. Retrospectively, azotemia at 1 year and proteinuria at 5 years were recorded but not investigated. At age 6, she was referred to the pediatric nephrology service because of hypertension, pretibial pitting edema, heavy proteinuria, and hematuria. eGFR was 66 ml/min/1.73 m2, total protein 5.3 g/dl, albumin 2.4 g/dl, and cholesterol 317 mg/dl. Ultrasonography showed normal-sized kidneys with a cyst in the right. Losartan was started. On renal biopsy, 8 out of 24 glomeruli were globally sclerosed, and three showed segmental sclerosis and/or hyalinosis with no immune deposits. Mild tubular dilatation, tubular atrophy, and interstitial fibrosis were observed. On electron microscopy, glomeruli showed focal foot process effacement with no electron dense deposits. Since losartan did not exert an obvious effect, treatment with prednisolone was tried. Urine protein decreased from 6.6 to 3.7 g/gCr. Prednisolone was discontinued after 10 days, however, because she developed duodenal ulcer perforation that necessitated omentoplasty. Subsequently, she was treated with losartan only. Her renal function deteriorated and peritoneal dialysis was initiated 8 months later. FSGS in this patient could be primary glomerular associated with CC2D2A mutation, rather than the consequences of tubulointerstitial fibrosis.

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Grading of Multifocal Prostate Cancer Cases in which the Largest Volume and the Highest Grade Do Not Coincide within One Lesion

Matsumoto K., Omura M., Takeda T., Kosaka T., Hashiguchi A., Takamatsu K., Yasumizu Y., Tanaka N., Morita S., Mizuno R., Asanuma H., Oya M.

The Journal of urology （The Journal of urology） 206 （ 2 ） 338 - 345 2021年08月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0022-5347

PURPOSE: In general, the index lesion of prostate cancer has the largest tumor volume, the highest Grade Group (GG), and the highest stage (concordant cases). However, these factors sometimes do not coincide within one lesion (discordant cases). In such discordant cases, the largest tumor may not be of biological significance and the secondary tumor may more greatly impact the prognosis. MATERIALS AND METHODS: We retrospectively reviewed the medical records of patients who underwent radical prostatectomy, and we identified 580 (85.3%) concordant cases and 100 (14.7%) discordant cases. The end point of this study was biochemical recurrence, and median followup was 4.2 years. RESULTS: Among discordant cases in which GGs of the largest tumor and the highest GG tumor differed, the majority (67 patients) had the largest tumor of GG 2, and we set them as the study cohort. On the other hand, we regarded 212 concordant cases with an index tumor of GG 2 as the control cohort. The study cohort comprised 48 (71.6%) patients with a secondary tumor of GG 3 and 19 (28.4%) with a secondary tumor of GG 4/5. Kaplan-Meier curves revealed that the 5-year biochemical recurrence-free survival rates were 76%, and 67%, respectively. The 5-year biochemical recurrence-free survival rate of the control cohort was 91%, which was significantly better than that of the study cohort (p=0.013 and p=0.014, respectively). CONCLUSIONS: Our study suggests that the prognosis of discordant cases is better determined by the secondary cancer lesion with the highest GG instead of the largest lesion.

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Development of nephropathy in an adult patient after Fontan palliation for cyanotic congenital heart disease

Hayashi K., Hashiguchi A., Ikemiyagi M., Tokuyama H., Wakino S., Itoh H.

CEN case reports （CEN case reports） 10 （ 3 ） 354 - 358 2021年08月

研究論文（学術雑誌）, 共著, 査読有り

Cyanotic congenital heart disease is occasionally associated with kidney dysfunction, which is known as cyanotic nephropathy or cyanotic glomerulopathy. The clinical presentation of cyanotic nephropathy includes proteinuria, decreased estimated glomerular filtration rate, hyperuricemia, thrombocytopenia, or polycythemia. Although advances in surgical procedures have improved the prognosis of cyanotic congenital heart diseases, adult cases of cyanotic nephropathy are still rare, and there are few reports of kidney biopsy in adults with cyanotic nephropathy. Here, we present the case of a 41-year-old patient with Fontan palliation who developed nephrotic range proteinuria and had a kidney biopsy, which showed glomerular hypertrophy with segmental glomerulosclerosis around vascular poles, suggesting adaptive focal segmental glomerulosclerosis. This case provides further understanding of kidney dysfunction due to cyanotic congenital heart disease and shows the need for attention in the management for prevention of progression to end-stage renal disease and in the selection of renal replacement therapy.

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C3腎症を基準とした一次性MPGNの再分類:電顕PAMを用いたType 3 Anders-Strife型の鑑別のもとに

本間志功, 佐藤直実, 橋口明典, 上杉憲子, 中村保宏, 城謙輔

日本腎臓学会誌（(一社)日本腎臓学会） 63 （ 4 ） 436 - 436 2021年06月

共著, ISSN 0385-2385

DNA修復因子KAT5を介した尿細管糸球体フィードバック制御

菱川彰人, 林香, 久保亜紀子, 宮下和季, 橋口明典, 吉本憲史, 中道蘭, 杉田絵里那, 赤塩理起, 門川俊明, 末松誠, 伊藤裕

日本腎臓学会誌（(一社)日本腎臓学会） 63 （ 4 ） 488 - 488 2021年06月

共著, ISSN 0385-2385

Malignancy-associated membranous nephropathy with PLA2R double-positive for glomeruli and carcinoma

Yasuda I., Tokuyama H., Hashiguchi A., Hasegawa K., Uchiyama K., Ryuzaki M., Yasuda M., Mizuno R., Ishidoya S., Wakino S., Itoh H.

CEN case reports （CEN case reports） 10 （ 2 ） 281 - 286 2021年05月

研究論文（学術雑誌）, 共著, 査読有り

Phospholipase A2 receptor (PLA2R) is the most common primary target antigen of idiopathic membranous nephropathy (MN) although PLA2R antibodies are also reported to be present in malignancy-associated MN. However, a case of PLA2R-positive MN secondary to PLA2R-positive carcinoma has not been reported. A 26-year-old Japanese woman presented with general fatigue, fever, and nonproductive cough. Computed tomography demonstrated a left kidney mass with pathologic diagnosis of Xp11.2 translocation renal cell carcinoma (RCC). After the second time of administration with Sunitinib, the patients exhibited significant proteinuria and hypoalbuminemia. Renal biopsy revealed a diagnosis of diffuse MN secondary to RCC. Immunofluorescence staining showed granular patterns positive for immunoglobulin (Ig) G, IgA, and C3c. PLA2R and IgG1-3 were positive, while IgG4 was negative. For the treatment of severe nephrotic syndrome, we attempted steroid therapy without any clinical improvement. Open nephrectomy was performed and surprisingly, RCC was stained for PLA2R with polarity for the basal side. At outpatient follow-up, 4 months after the operation, urinary protein had still persisted, although serum albumin was slightly increased. We report a case of PLA2R-positive MN secondary to PLA2R-positive RCC.

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デジタル画像解析を用いたIgA腎症糸球体病変定量化

橋口明典, 石川雅浩, 城謙輔, 坂本直樹, 山内暁, 大塚武, 福西宗憲, 清水章, 片渕律子, 川村哲也

日本病理学会会誌（(一社)日本病理学会） 110 （ 1 ） 327 - 327 2021年03月

共著, ISSN 0300-9181

A cross-sectional study in patients with IgA nephropathy of correlations between clinical data and pathological findings at the time of renal biopsy: a Japanese prospective cohort study

Kamano C., Shimizu A., Joh K., Hashiguchi A., Hisano S., Katafuchi R., Kawamura T.

Clinical and Experimental Nephrology （Clinical and Experimental Nephrology） 25 （ 5 ） 509 - 521 2021年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 13421751

Background: The correlations between clinical data and pathological findings at the time of renal biopsy were investigated in IgA nephropathy patients. Methods: 771 patients diagnosed with IgA nephropathy by renal biopsy were enrolled. The correlations between clinical variables including eGFR, daily proteinuria, mean arterial pressure (MAP), serum uric acid (UA) values, and pathological parameters were examined. These patients were further divided into three groups: children (< 19 years old), young adults (19–60 years), and elderly patients (> 60 years). Results: Daily proteinuria was moderately correlated with all pathological parameters (Rs = 0.23–0.49). The mesangial score, the percentage of glomeruli that contained endocapillary hypercellularity, cellular/fibrocellular crescents or tuft necrosis, and segmental glomerulosclerosis (GS) affected daily proteinuria most on multiple linear regression analysis (MLRA). eGFR, MAP, and serum UA levels were mainly correlated with the degree of GS and interstitial lesions. In children, the degree of cellular/fibrocellular crescents or tuft necrosis was correlated with not only daily proteinuria, but also decreased eGFR (Rs = 0.51, − 0.24). Endocapillary hypercellularity was the only independent variable related to daily proteinuria on MLRA. Conclusion: In all age cohorts of IgA nephropathy patients, daily proteinuria was correlated with all histological parameters, including both acute and chronic glomerular lesions, and the mesangial score. Independent variables for daily proteinuria were the meangial score, acute histological lesions, and segmental GS on MLRA, whereas the remaining independent variable in the pediatric group was endocapillary hypercellurality. The clinical pathological correlation at the time of biopsy varied depending on the age group.

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Glomerulonephritis caused by bartonella spp. infective endocarditis: The difficulty and importance of differentiation from anti-neutrophil cytoplasmic antibody-related rapidly progressive glomerulonephritis

Yoshifuji A., Hibino Y., Komatsu M., Yasuda S., Hosoya K., Kobayashi E., Baba Y., Hirose S., Hashiguchi A., Kanno Y., Ryuzaki M.

Internal Medicine （Internal Medicine） 60 （ 12 ） 1899 - 1906 2021年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 09182918

A 65-year-old man with valvular disorder presented to his physician because of widespread purpura in both lower extremities. Blood tests showed elevated serum creatinine levels and proteinase 3-anti-neutrophil cytoplasmic antibody (ANCA) with hematuria, suggesting ANCA-related rapidly progressive glomerulonephritis (RPGN). Although multiple blood cultures were negative, transthoracic echocardiography revealed warts in the valves, and a renal biopsy also showed findings of glomerular infiltration by mononuclear leukocytes and C3 deposition in the glomeruli, suggesting infection-related glomerulonephritis. Later, Bartonella antibody turned positive. Antimicrobial treatment improved the purpura and renal function without any recurrence. ANCA-positive RPGN requires the exclusion of infective endocarditis, especially that induced by Bartonella spp.

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Association of glomerular DNA damage and DNA methylation with one-year eGFR decline in IgA nephropathy

Hayashi K., Hishikawa A., Hashiguchi A., Azegami T., Yoshimoto N., Nakamichi R., Tokuyama H., Itoh H.

Scientific Reports （Scientific Reports） 10 （ 1 ） 237 - 237 2020年12月

研究論文（学術雑誌）, 共著, 査読有り

© 2020, The Author(s). Accumulation of DNA double-strand breaks (DSBs) is linked to aging and age-related diseases. We recently reported the possible association of DNA DSBs with altered DNA methylation in murine models of kidney disease. However, DSBs and DNA methylation in human kidneys was not adequately investigated. This study was a cross-sectional observational study to evaluate the glomerular DNA DSB marker γH2AX and phosphorylated Ataxia Telangiectasia Mutated (pATM), and the DNA methylation marker 5-methyl cytosine (5mC) by immunostaining, and investigated the association with pathological features and clinical parameters in 29 patients with IgA nephropathy. To evaluate podocyte DSBs, quantitative long-distance PCR of the nephrin gene using laser-microdissected glomerular samples and immunofluorescent double-staining with WT1 and γH2AX were performed. Glomerular γH2AX level was associated with glomerular DNA methylation level in IgA nephropathy. Podocytopathic features were associated with increased number of WT1(+)γH2AX(+) cells and reduced amount of PCR product of the nephrin gene, which indicate podocyte DNA DSBs. Glomerular γH2AX and 5mC levels were significantly associated with the slope of eGFR decline over one year in IgA nephropathy patients using multiple regression analysis adjusted for age, baseline eGFR, amount of proteinuria at biopsy and immunosuppressive therapy after biopsy. Glomerular γH2AX level was associated with DNA methylation level, both of which may be a good predictor of renal outcome in IgA nephropathy.

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最大病変が最高Gleason scoreでないmultifocal前立腺癌症例へのGleason scoreの付け方

松本一宏, 橋口明典, 武田利和, 小坂威雄, 高松公晴, 安水洋太, 田中伸之, 森田伸也, 水野隆一, 浅沼宏, 大家基嗣

日本癌治療学会学術集会抄録集（(一社)日本癌治療学会） 58回 P - 353 2020年10月

研究論文（学術雑誌）, 共著, 査読有り

多彩な臨床症状を示した顕微鏡的多発血管炎に続発した血栓性微小血管症の1例

坂巻裕介, 小西孝之助, 橋口明典, 松崎達, 香野日高, 中川健, 寺嶋毅, 林晃一

日本腎臓学会誌（(一社)日本腎臓学会） 62 （ 5 ） 465 - 476 2020年07月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0385-2385

症例は70歳代、女性。微熱、頭重感、両大腿のだるさを契機に他院を受診、腎機能障害を指摘され、精査目的で当院を紹介された。血液検査でミエロペルオキシダーゼ抗好中球細胞質抗体(myeloperoxidase anti-neutrophil cytoplasmic antibody:MPO-ANCA)陽性が判明し、腎生検病理所見の結果、血栓性微小血管症(thrombotic microangiopathy:TMA)を合併した顕微鏡的多発血管炎(microscopic polyangiitis:MPA)と診断した。プレドニゾロン(40mg/日)の投与を開始し、ステロイドパルス療法を2クール、静注シクロホスファミドパルス療法(intravenous cyclophosphamide:IVCY)を1クール行った。また、中等度の高血圧を認めたため、ニフェジピンを投与し、血圧コントロールを行った。その後、両下腿浮腫と両側胸水貯留を認めたため、フロセミドを投与した。患者の病状は安定し、入院37日目に退院した。しかし、退院後に、痙攣と夜間に増悪する呼吸困難を認め、うっ血性心不全の診断で再度入院した。入院後、フロセミドを投与したが、尿量の増加は得られず、急速に呼吸状態の悪化を認めたため、気管内挿管後、人工呼吸器を装着した。14時間にわたる持続低効率血液透析(sustained low efficiency dialysis:SLED)を行い、患者の呼吸状態は著明に改善した。抜管後、意識レベルの低下を伴う痙攣を認め、頭部単純CTでは、両側後頭葉に低吸収域を認めたことから、可逆性後頭葉白質脳症(posterior reversible encephalopathy syndrome:PRES)の関与が示唆された。12誘導心電図検査では、経時的にT波の陰転化を認め、心臓超音波検査では、心尖部に限局した壁運動の低下を認めた。冠動脈造影CTでは、血管病変は認めず、たこつぼ心筋症と診断した。本症例は、重篤で多彩な臨床症状を示した、TMAを合併したMPAの1例である。ANCA関連血管炎に続発したTMA症例では免疫抑制療法開始後も注意深い経過観察が必要である。(著者抄録)

デジタル画像解析を用いたIgA腎症腎生検糸球体病変定量化

橋口明典, 石川雅浩, 城謙輔, 坂本直樹, 山内暁, 大塚武, 福西宗憲, 清水章, 久野敏, 片渕律子, 川村哲也

日本腎臓学会誌（(一社)日本腎臓学会） 62 （ 4 ） 317 - 317 2020年07月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0385-2385

IgA腎症の組織分類の治療選択における有用性の検証

城謙輔, 中里毅, 橋口明典, 清水章, 片渕律子, 川村哲也

日本腎臓学会誌（(一社)日本腎臓学会） 62 （ 4 ） 265 - 265 2020年07月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0385-2385

IgA腎症の組織学的重症度分類に関する亜型分類(A/C)のエヴィデンスに関する前向き多施設共同研究

城謙輔, 橋口明典, 久野敏, 清水章

日本病理学会会誌（(一社)日本病理学会） 109 （ 1 ） 291 - 291 2020年03月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0300-9181

腎生検糸球体病変定量化の試み

橋口明典, 石川雅浩, 城謙輔, 清水章, 久野敏, 片渕律子, 川村哲也

日本病理学会会誌（(一社)日本病理学会） 109 （ 1 ） 435 - 435 2020年03月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0300-9181

T細胞性悪性リンパ腫の腎浸潤により尿蛋白をきたした一例

押田卓磨, 徳山博文, 橋口明典, 大島洋一, 内山清貴, 脇野修, 伊藤裕

日本内科学会雑誌（(一社)日本内科学会） 109 （ Suppl. ） 206 - 206 2020年02月

共著, ISSN 0021-5384

Evaluation of Gleason Grade Group 5 in a Contemporary Prostate Cancer Grading System and Literature Review

Kamitani R., Matsumoto K., Kosaka T., Takeda T., Hashiguchi A., Tanaka N., Morita S., Mizuno R., Shinojima T., Asanuma H., Oya M.

Clinical Genitourinary Cancer （Clinical Genitourinary Cancer） 19 （ 1 ） 69 - 75.e5 2020年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 15587673

© 2020 Elsevier Inc. Introduction: The aim of this study was to validate contemporary grading systems, in particular, the Gleason grade group (GGG) 5. Patients and Methods: We retrospectively reviewed the clinicopathologic data of 176 patients who underwent radical prostatectomy and whose pathologic results were GGG 4 or 5. The endpoints were biochemical recurrence (BCR) and castration-resistant prostate cancer (CRPC). Results: The GGG 4 group was composed of 69 patients. The GGG 5 group consisted of 78 patients with GS 4+5 and 29 patients with GS 5+4 or higher. The 5-year BCR-free survival rates for men with GGG 4, GS 4+5, and GS 5+4 or higher were 59%, 54%, and 20%, respectively, and the 5-year CRPC-free survival rates were 98%, 100%, and 88%, respectively. Both the BCR- and CRPC-free survival rates were significantly higher in GS 4+5 than in GS 5+4 or higher (P < .001 and P = .002, respectively), but there were no significant differences between GGG 4 and GS 4+5 (P = .702 and P = .803, respectively). The multivariate analysis demonstrated that GS 5+4 or higher (hazard ratio, 3.4; P = .002) and lymphovascular invasion (hazard ratio, 3.4; P < .001) greatly affected BCR. Conclusion: Our follow-up study revealed that men with GS 4+5 and those with GGG 4 had a similar prognosis. However, there was a significant discrepancy in prognosis between GS 4+5 and GS 5+4 or higher. This suggested that GGG 4 and 5 in the contemporary prostate cancer grading system should be reviewed. Furthermore, lymphovascular invasion may be useful to subgroup these pathologically high-risk patients.

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Maternal undernutrition aggravates renal tubular necrosis and interstitial fibrosis after unilateral ureteral obstruction in male rat offspring

Awazu M., Abe T., Hashiguchi A., Hida M.

PLoS ONE （PLoS ONE） 14 （ 9 ） e0221686 2019年09月

研究論文（学術雑誌）, 共著, 査読有り

© 2019 Awazu et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Maternal undernutrition is known to reduce glomerular number but it may also affect tubulointerstitium, capillary density, and response to oxidative stress. To investigate whether the latter elements are affected, we examined the response to unilateral ureteral obstruction (UUO), an established model of renal tubulointerstitial fibrosis, in the kidney of offspring from control and nutrient restricted rats. Six-week old male offspring from rats given food ad libitum (CON) and those subjected to 50% food restriction throughout pregnancy (NR) were subjected to UUO for 7 days. Body weight was significantly lower in NR. Systolic blood pressure and blood urea nitrogen increased similarly in CON and NR after UUO. Tubular necrosis in the obstructed kidney, on the other hand, was more extensive in NR. Also, the collagen area, a marker of fibrosis, of the obstructed kidney was significantly increased compared with the contralateral kidney only in NR. Capillary density was decreased similarly in the obstructed kidney of CON and NR compared with the contralateral kidney. Urine nitrate/ nitrite, a marker of nitric oxide production, from the obstructed kidney was significantly increased in NR compared with CON. Nitrotyrosine, a marker of nitric oxide-mediated free radical injury, was increased in the obstructed kidney compared with the contralateral kidney in both CON and NR, but the extent was significantly greater in NR. In conclusion, more severe tubular necrosis and fibrosis after UUO was observed in NR, which was thought to be due to increased nitrosative stress.

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Acute Interstitial Nephritis With Karyomegalic Epithelial Cells After Nivolumab Treatment—Two Case Reports

Ryuzaki M., Tokuyama H., Uchiyama K., Nakaya H., Hasegawa K., Miyashita K., Konishi K., Hashiguchi A., Wakino S., Itoh H.

Clinical Medicine Insights: Case Reports （Clinical Medicine Insights: Case Reports） 12 1179547619853647 - 1179547619853647 2019年06月

研究論文（学術雑誌）, 共著, 査読有り

© The Author(s) 2019. Clinical application of immune checkpoint inhibitors (CPIs) including nivolumab is expanding in the field of oncology treatment. Nivolumab is an anti-programmed death 1 protein (PD-1) antibody designed to augment an immunologic reaction against cancer cells. On the contrary, CPIs are known to cause a unique variety of side effects termed as immune-related adverse events, which can affect any organ including kidney. However, the characteristics of renal disorders by nivolumab treatment are poorly described. We describe two cases of acute kidney injury that were treated with nivolumab. Two patients, one with renal-cell carcinoma and the other with lung cancer, exhibited progressive renal dysfunction after the initiation of nivolumab treatment. By kidney biopsy, each case was diagnosed as acute interstitial nephritis (AIN). Of note, tubular epithelial cells enlarged with hyperchromatic nuclei were focally observed, and this finding was consistent with karyomegalic tubular epithelial cells. In immunostaining, most of the enlarged tubular epithelial cells were positive for Ki-67, which suggested regeneration of tubular epithelial cells. Clinically, in one case, renal function was partially recovered with the discontinuation of nivolumab, while in another case renal function was fully recovered with additional corticosteroid treatment. We presented nivolumab-induced AIN with karyomegalic changes of tubular epithelia. We propose that immunosuppressive therapy may be necessary for the full recovery from renal impairment.

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完全寛解後3ヵ月の経過で血液透析導入となった微小変化型ネフローゼ症候群の1例

山口慎太郎, 徳山博文, 橋口明典, 小西孝之助, 林晃一, 脇野修, 伊藤裕

日本抗加齢医学会総会プログラム・抄録集（(一社)日本抗加齢医学会） 19回 251 - 251 2019年06月

共著

IgA腎症の生検時の臨床データと病理所見の関連性

鎌野千佐子, 清水章, 城謙輔, 橋口明典, 久野敏, 片渕律子, 川村哲也

日本腎臓学会誌（(一社)日本腎臓学会） 61 （ 3 ） 395 - 395 2019年05月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0385-2385

IgA腎症のOxford分類と日本分類(組織学的重症度分類)の腎機能予後予測に関する比較

城謙輔, 中里毅, 橋口明典, 清水章, 久野敏, 片渕律子, 川村哲也

日本腎臓学会誌（(一社)日本腎臓学会） 61 （ 3 ） 394 - 394 2019年05月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0385-2385

IgA腎症のOxford分類と日本分類(組織学的重症度分類)の腎機能予後予測に関する比較

城謙輔, 橋口明典, 久野敏, 清水章

日本病理学会会誌（(一社)日本病理学会） 108 （ 1 ） 297 - 297 2019年04月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0300-9181

Effectiveness of color correction on the quantitative analysis of histopathological images acquired by different whole-slide scanners

Aziz M., Nakamura T., Yamaguchi M., Kiyuna T., Yamashita Y., Abe T., Hashiguchi A., Sakamoto M.

Artificial Life and Robotics （Artificial Life and Robotics） 24 （ 1 ） 28 - 37 2019年03月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 14335298

© 2018, ISAROB. Advances in whole-slide scanning have led to research on digital pathology, including monitor-based diagnosis, feature quantification, and computer-aided diagnosis. The color variations due to the staining process and scanning device are a serious issue that should be solved in whole-slide imaging applications, and methods for color correction have been studied. Nevertheless, the effectiveness of color-correction methods in the quantitative analysis of histopathological images acquired by different whole-slide scanners (WSSs) has not been confirmed. In this work, several liver tissue samples were scanned by different WSSs, and a color-correction method for whole-slide images was applied to the digitized tissue specimens. A set of histological features were extracted from the histopathological images, both without and with color correction, to analyze the effectiveness of the color-correction method in feature quantification and cancer identification.

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経腋窩的豊胸術後の早期乳癌に対してセンチネルリンパ節生検を施行した1例

和田真弘, 橋口明典

日本外科系連合学会誌（日本外科系連合学会） 44 （ 1 ） 13 - 20 2019年02月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0385-7883

症例は48歳,女性.右乳房腫瘤を主訴に当院を受診した.既往歴として,25歳時に両側経腋窩的豊胸術(大胸筋下に生理食塩水バッグを挿入)を施行した.触診上,右乳頭直下に2cm大の腫瘤を触知した.画像検査では,乳癌が示唆された.確定診断のために針生検を提示するも,患者は拒否した.そこで,われわれは一期的な診断・手術治療を提示した.すなわち,全身麻酔下で切開生検・術中迅速病理組織検査を施行し,乳癌の場合には乳房切除+センチネルリンパ節生検+生理食塩水バッグ抜去+Tissue Expander挿入である.その方針に同意が得られた.結果は乳癌であった.センチネルリンパ節生検では転移陰性のため,腋窩リンパ節郭清は省略した.現在無再発生存中である.今後本邦では豊胸術施後の乳癌症例が増加してくることが予想される.その際のセンチネルリンパ節生検について若干の文献的考察を加えて報告する.(著者抄録)

A grading system that predicts the risk of dialysis induction in IgA nephropathy patients based on the combination of the clinical and histological severity

Okonogi H., Kawamura T., Joh K., Koike K., Miyazaki Y., Ogura M., Tsuboi N., Hirano K., Matsushima M., Yokoo T., Horikoshi S., Suzuki Y., Yasuda T., Shirai S., Shibata T., Hattori M., Akioka Y., Katafuchi R., Hashiguchi A., Hisano S., Shimizu A., Kimura K., Maruyama S., Matsuo S., Tomino Y.

Clinical and Experimental Nephrology （Clinical and Experimental Nephrology） 23 （ 1 ） 16 - 25 2019年01月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 13421751

© 2018, The Author(s). Histological classification is essential in the clinical management of immunoglobulin A nephropathy (IgAN). However, there are limitations in predicting the prognosis of IgAN based on histological information alone, which suggests the need for better prognostic models. Therefore, we defined a prognostic model by combining the grade of clinical severity with the histological grading system by the following processes. We included 270 patients and explored the clinical variables associated with progression to end-stage renal disease (ESRD). Then, we created a predictive clinical grading system and defined the risk grades for dialysis induction by a combination of the clinical grade (CG) and the histological grade (HG). A logistic regression analysis revealed that the 24-h urinary protein excretion (UPE) and the estimated glomerular filtration rate (eGFR) were significant independent variables. We selected UPE of 0.5 g/day and eGFR of 60 ml/min/1.73 m 2 as the threshold values for the classification of CG. The risk of progression to ESRD of patients with CG II and III was significantly higher than that of patients with CG I. The patients were then re-classified into nine compartments based on the combination of CG and HG. Furthermore, the nine compartments were grouped into four risk groups. The risk of ESRD in the moderate, high, and super-high-risk groups was significantly higher than that in the low-risk group. Herein, we are giving a detailed description of our grading system for IgA nephropathy that predicted the risk of dialysis based on the combination of CG and HG.

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Non-invasive liver fibrosis assessment correlates with collagen and elastic fiber quantity in patients with hepatitis C virus infection

Yasui Y., Abe T., Kurosaki M., Matsunaga K., Higuchi M., Tamaki N., Watakabe K., Okada M., Wang W., Shimizu T., Takaura K., Masugi Y., Nakanishi H., Tsuchiya K., Takahashi Y., Itakura J., Sakurai U., Hashiguchi A., Sakamoto M., Izumi N.

Hepatology Research （Hepatology Research） 49 （ 1 ） 33 - 41 2019年01月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 13866346

© 2018 The Japan Society of Hepatology Aim: Elastic fiber deposition is a cause of irreversibility of liver fibrosis. However, to date, its relevance to clinical features has not yet been clarified. This study aimed to clarify the correlation between non-invasive markers of fibrosis and fiber quantity, including elastic fiber, obtained from computational analysis. Methods: This retrospective study included 270 patients evaluated by non-invasive liver fibrosis assessment prior to liver biopsy. Of these patients, 95 underwent magnetic resonance elastography (MRE) and 244 were assessed with Wisteria floribunda agglutinin-positive Mac-2 binding protein (WFA + -M2BP). Using whole-slide imaging of Elastica van Gieson-stained liver biopsy sections, the quantity of collagen, elastin, and total fiber (elastin + collagen) was determined. Results: The total fiber quantity showed significant linear correlation with fibrosis stage F0–F4. Collagen fiber quantity increased from stage F0 to F4, whereas elastic fiber quantity increased significantly only from stage F2 to F3. Spearman's rank correlation test revealed that non-invasive liver fibrosis assessment significantly correlates with each fiber quantity, including correlation between total fiber quantity and the Fibrosis-4 (FIB-4) index (r = 0.361, P < 0.001), WFA + -M2BP values (r = 0.404, P < 0.001), and liver stiffness value by MRE (r = 0.615, P < 0.001). Receiver operating characteristic (ROC) curve analyses revealed that the area under ROC for predicting higher elastic fiber (>3.6%) is 0.731 by FIB-4 index, 0.716 by WFA + -M2BP, and 0.822 by liver stiffness by MRE. Conclusion: Liver fibrosis correlates with fiber quantity through non-invasive assessment regardless of fiber type, including elastic fiber. Moreover, MRE is useful for predicting high amounts of elastic fiber.

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Prediction of extraprostatic extension by MRI tumor contact length: difference between anterior and posterior prostate cancer

Matsumoto K., Akita H., Narita K., Hashiguchi A., Takamatsu K., Takeda T., Kosaka T., Mizuno R., Kikuchi E., Oya M., Jinzaki M.

Prostate Cancer and Prostatic Diseases （Prostate Cancer and Prostatic Diseases） 22 （ 4 ） 539 - 545 2019年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 13657852

© 2019, Springer Nature America, Inc. Background: Tumor contact length (TCL) is defined as the extent of contact between prostate cancer and the prostatic capsule, and its predictive value for microscopic extraprostatic extension (EPE) has been reported. However, the impact of the zonal origin (anterior or posterior tumor) of the tumor on the diagnosis of EPE is controversial. Methods: We retrospectively analyzed the records of 233 consecutive patients who underwent preoperative MRI and radical prostatectomy. We designated their tumors as anterior or posterior, and evaluated the correlation between the TCL measured by MRI and microscopic EPE in the radical prostatectomy specimen. Then, we created the predicted probability curves for EPE versus TCL for anterior and posterior prostate cancer. Results: There were 109 patients (47%) with an anterior tumor and 124 patients (53%) with a posterior tumor. Postoperative pathological analysis confirmed pT3 in 18 patients (17%) with an anterior tumor and in 53 patients (43%) with a posterior tumor. Multivariate analysis demonstrated that the zonal origin of the tumor was an independent predictive factor for EPE. We developed separate probability curves of EPE versus TCL for anterior and posterior prostate cancer, which revealed that anterior tumors were less likely to invade the extraprostatic tissues. Among patients whose TCL was 10–20 mm, 9/32 patients (28%) with an anterior tumor had EPE compared with 24/45 patients (53%) with a posterior tumor (p = 0.036). The decision curve of this EPE predictive model had high clinical efficacy. Conclusions: Our results indicate that anterior tumors have more favorable pathological characteristics than posterior tumors with the same TCL measured by MRI. We constructed two separate predicted probability curves for EPE after discriminating anterior and posterior tumors, which will be useful for decision making in clinical practice.

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高度の尿細管萎縮・間質線維化とともに,尿細管基底膜(TBM)にPolyclonalなimmunoglobulin Gの沈着を認めた一例

日鼻瑛, 坂巻裕介, 小西孝之助, 林晃一, 萩原正幸, 萩生田純, 香野日高, 中川健, 橋口明典

日本腎臓学会誌（(一社)日本腎臓学会） 60 （ 6 ） 933 - 933 2018年08月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0385-2385

Mesenchymal–epithelial transition of pancreatic cancer cells at perineural invasion sites is induced by Schwann cells

Fujii-Nishimura Y., Yamazaki K., Masugi Y., Douguchi J., Kurebayashi Y., Kubota N., Ojima H., Kitago M., Shinoda M., Hashiguchi A., Sakamoto M.

Pathology International （Pathology International） 68 （ 4 ） 214 - 223 2018年04月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1440-1827

© 2018 Japanese Society of Pathology and John Wiley & Sons Australia, Ltd Epithelial–mesenchymal transition (EMT) promotes invasion and metastasis of pancreatic ductal adenocarcinoma (PDAC). However, the importance of its reverse process, mesenchymal–epithelial transition (MET), for PDAC remains unclear. We aimed to characterize the histological finding “focal differentiation” in PDAC at perineural invasion sites in the context of MET and to investigate the role of Schwann cells in inducing tumor MET. Tumor differentiation and immunohistochemical expressions of E-cadherin, SMAD3, and vimentin at perineural invasion sites were examined in 168 PDAC tissues. Four PDAC cell lines were co-cultured with Schwann cells to investigate cell morphology, motility, or EMT-related markers using immunocytochemistry and quantitative PCR. Of 168 tumors, 124 (74%) showed focal differentiation with enhanced E-cadherin membrane expression (P < 0.001) and decreased nuclear accumulation of SMAD3 (P < 0.001). Among 115 PDACs harboring grade 1/2 tumor, tumors with focal differentiation showed worse survival compared to those without focal differentiation (P = 0.019). PDAC cells co-cultured with Schwann cells demonstrated a sheet-like appearance, increased E-cadherin expression, decreased expressions of SMAD3 and vimentin, and reduced cell motility. In conclusion, MET-like change is induced by Schwann cells, suggesting that Schwann cells contribute to PDAC colonization in pancreatic nerves through activating the MET machinery inside tumor cells in the pancreatic tumor microenvironment.

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IgA腎症組織学的重症度分類A/C亜型の有用性の検証厚労省分科会前向き研究847症例の解析

城謙輔, 橋口明典, 清水章, 久野敏, 片渕律子, 中里毅, 川村哲也

日本腎臓学会誌（(一社)日本腎臓学会） 60 （ 3 ） 364 - 364 2018年04月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0385-2385

C3腎症の視点から膜性増殖性糸球体腎炎(MPGN)の再検討 MPGN I型とIII型-2nd formは同一疾患か?

佐藤直実, 城謙輔, 中村保宏, 谷内真司, 橋口明典, 高木孝士, 笹野公伸

日本病理学会会誌（(一社)日本病理学会） 107 （ 1 ） 448 - 448 2018年04月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0300-9181

IgA腎症における病理所見と治療反応性の検討 IgA腎症の腎病理所見と予後の関連に関する前向き多施設共同研究

片渕律子, 川村哲也, 橋口明典, 久野敏, 清水章, 城謙輔

日本腎臓学会誌（(一社)日本腎臓学会） 60 （ 3 ） 364 - 364 2018年04月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0385-2385

【病理診断の新潮流】発症機序を考慮した糸球体疾患の分類

橋口, 明典

腎臓内科・泌尿器科（(有)科学評論社） 7 （ 3 ） 201 - 205 2018年03月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 2188-9147

Quantitative assessment of liver fibrosis reveals a nonlinear association with fibrosis stage in nonalcoholic fatty liver disease.

Yohei Masugi, Tokiya Abe, Hanako Tsujikawa, Kathryn Effendi, Akinori Hashiguchi, Masanori Abe, Yasuharu Imai, Keisuke Hino, Shuhei Hige, Miwa Kawanaka, Gotaro Yamada, Masayoshi Kage, Masaaki Korenaga, Yoichi Hiasa, Masashi Mizokami, Michiie Sakamoto

Hepatology communications （Hepatology Communications） 2 （ 1 ） 58 - 68 2018年01月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 2471-254X

Accurate staging of liver fibrosis is crucial to guide therapeutic decisions for patients with nonalcoholic fatty liver disease (NAFLD). Digital image analysis has emerged as a promising tool for quantitative assessment of fibrosis in chronic liver diseases. We sought to determine the relationship of histologic fibrosis stage with fiber amounts quantified in liver biopsy specimens for the better understanding of NAFLD progression. We measured area ratios of collagen and elastin fibers in Elastica van Gieson-stained biopsy tissues from 289 patients with NAFLD from four hospitals using an automated computational method and examined their correlations with Brunt's fibrosis stage. As a secondary analysis, we performed multivariable logistic regression analysis to assess the associations of the combined area ratios of collagen and elastin with noninvasive fibrosis markers. The combined fiber area ratios correlated strongly with Brunt's stage (Spearman correlation coefficient, 0.78; P < 0.0001), but this relationship was nonlinear (P = 0.007) with striking differences between stage 4 (median area ratios, 12.3%) and stages 0-3 (2.1%, 2.8%, 4.3%, and 4.8%, respectively). Elastin accumulation was common in areas of thick bridging fibrosis and thickened venous walls but not in areas of perisinusoidal fibrosis. The highest tertile of the combined fiber area ratios was associated with the fibrosis-4 index and serum type IV collagen 7s domain (7s collagen) levels, whereas the upper two tertiles of the fiber amounts significantly associated with body mass index, aspartate aminotransferase, and 7s collagen in the multivariable analysis. Conclusion: Quantitative fibrosis assessment reveals a nonlinear relationship between fibrosis stage and fiber amount, with a marked difference between stage 4 and stage 3 and much smaller differences among stages 0-3, suggesting a heterogeneity in disease severity within NAFLD-related cirrhosis. (Hepatology Communications 2018;2:58-68).

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生体腎移植後に持続血糖測定器による血糖変動の評価が有用であった2型糖尿病の3例

坂巻, 裕介, 香野, 日高, 橋口, 明典, 萩生田, 純, 萩原, 正幸, 高橋, 遼平, 與那嶺, 智子, 森田, 伸也, 篠田, 和伸, 林, 晃一 and 中川, 健

腎移植・血管外科（腎移植・血管外科研究会） 28 （ 1 ） 45 - 51 2017年10月

共著, ISSN 0915-9118

今回われわれは、生体腎移植後1年以内に、持続血糖測定(Continuous glucose monitoring;CGM)を行った2型糖尿病の3例を経験したので報告する。1例目は60歳代の男性、混合型インスリンで治療中に、随時血糖の上昇を認めCGMを施行、昼食後の血糖上昇と血糖変動幅の増大が認められ、超速効型インスリンを追加した。2例目は50歳代の女性、強化インスリン療法中に、食後の低血糖症状を認めCGMを施行、超速効型インスリンの投与時間を食前から食後へと変更する方針となった。3例目は40歳代の男性、BOT(Basal Supported Oral Therapy)治療中に、HbA1cの上昇を認めCGMを施行、食後の血糖上昇に伴う血糖変動幅の増大に対して、超速効型インスリンを開始する方針となった。このように、腎移植後の血糖変動パターンをCGMで評価することで腎移植後糖尿病のより良い治療が行える可能性が示唆された。(著者抄録)

Polycythemia, capillary rarefaction, and focal glomerulosclerosis in two adolescents born extremely low birth weight and premature

Asada, N., Tsukahara, T., Furuhata, M., Matsuoka, D., Noda, S., Naganuma, K., Hashiguchi, A. and Awazu, M.

Pediatr Nephrol （Springer Verlag） 32 （ 7 ） 1275 - 1278 2017年07月

共著, ISSN 1432-198X

BACKGROUND: Low birthweight infants have a reduced number of nephrons and are at high risk of chronic kidney disease. Preterm birth and/or intrauterine growth restriction (IUGR) may also affect peritubular capillary development, as has been shown in other organs. CASE-DIAGNOSIS/TREATMENT: We report two patients with a history of preterm birth and extremely low birthweight who showed polycythemia and renal capillary rarefaction. Patient 1 and 2, born at 25 weeks of gestation with a birthweight of 728 and 466 g, showed mild proteinuria at age 8 and 6 years, respectively. In addition to increasing proteinuria, hemoglobin levels became elevated towards adolescence and their serum erythropoietin (EPO) was high despite polycythemia. Light microscopic examination of renal biopsy specimens showed glomerular hypertrophy, focal segmental glomerulosclerosis, and only mild tubulointerstitial fibrosis. A decrease in the immunohistochemical staining of CD31 and CD34 endothelial cells in renal biopsy specimens was consistent with peritubular capillary rarefaction. CONCLUSIONS: Since kidney function was almost normal and fibrosis was not severe, we consider that the capillary rarefaction and polycythemia associated with elevated EPO levels were largely attributable to preterm birth and/or IUGR.

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【腎生検・病理診断-臨床と病理の架け橋】 (第2章)臨床医が知っておくべき腎生検標本の作製と観察の実際　光顕の標本の作製と観察　光顕所見を観察するうえでの基本と注意点

橋口, 明典

腎と透析 82 （増刊） 77 - 84 2017年05月

共著, ISSN 0385-2156

母体低栄養は片側尿管結紮による腎障害を増悪する　ラットモデルを用いた検討

飛彈, 麻里子, 阿部, 時也, 橋口, 明典 and 粟津, 緑

発達腎研究会誌 25 （ 1 ） 30 - 33 2017年04月

共著, ISSN 0919-7532

子宮内劣悪環境によりネフロン数は減少する。尿細管、間質、微小血管密度、血管内皮機能も影響を受けている可能性がある。これらの変化が二次侵襲により明らかになるかを、成熟後の母体低栄養ラット仔に片側尿管結紮を行い検討した。胎生1日から出産まで飼料を対照の50%に制限した母体の仔ラット(NR)を6週齢で左尿管結紮し、7日後に体重、血圧を測定、血液、結紮側腎の尿を採取し、その後サクリファイス、病理学的検討を行った。結紮前のNRの体重は対照に比し有意に低く、収縮期血圧は高かった。結紮後、両者の体重の有意差はなくなったが、NRのみ血圧が有意に上昇した。閉塞腎の尿の生化学パラメーターは対照、NR間で差はみられなかった。BUNは結紮前後で対照では変化しなかったが、NRでは有意に増加した。結紮腎では尿細管壊死がNRにおいて著明に認められ、尿細管壊死面積の占有率は対照に比し有意に高値であった。また健側腎のcollagen面積の占有率は対照、NR間で差がなかったが、閉塞腎ではNRが有意に高値であった。CD31の染色性はNRと対照で差がなかった。閉塞腎の尿中nitric oxideはNR結紮腎の尿中で対照の1/10以下であった。eNOS発現は健側腎に比し閉塞腎で増加していたがその程度はNRでは対照に比し少なかった。以上、NRは尿管結紮による尿細管壊死、線維化の程度が強く、その原因として腎NO産生低下に起因する血管収縮による低酸素が考えられた。(著者抄録)

【IgA腎症update】組織学的予後分類　日本分類とオックスフォード分類の比較

橋口, 明典

腎と透析 82 （ 4 ） 549 - 553 2017年04月

共著, ISSN 0385-2156

【計量(デジタル)病理学:画像の数値化から補助診断まで】定量的病理診断と病理形態学ルネサンス

橋口, 明典 and 坂元, 亨宇

病理と臨床 35 （ 1 ） 32 - 40 2017年01月

共著, ISSN 0287-3745

Extraction of glomeruli in whole slide imaging of kidney biopsy specimens

Masahiro Ishikawa, Sumire Watanabe, Natsuki Honda, Naoki Kobayashi, Tokiya Abe, Akinori Hashiguchi, Michiie Sakamoto

Progress in Biomedical Optics and Imaging - Proceedings of SPIE （SPIE） 10140 2017年

共著, 査読有り, ISSN 1605-7422

The pathological diagnosis of a transplanted kidney is made on Banff Classification in order to gain an accurate understanding of the condition of the kidney. This type of diagnosis is extremely difficult and, thus, a variety of methods for diagnosis, including diagnosis by electron microscope, are being considered at present. Quantification of the diagnostic information derived by image processing is required for such purposes. This study proposes an automatic extraction method for normal glomeruli for the purpose of quantifying Elastica Van Gieson(EVG)-stained pathology specimens. In addition, we provide a report on the package of methods that we have created for the extraction of the glomerulus in the cortex.

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肝線維化の定量と発癌リスク　肝線維化定量技術

阿部, 時也, 波多野, まみ, 橋口, 明典 and 坂元, 亨宇

The Liver Cancer Journal （メディカルレビュー社） 8 （ 2 ） 102 - 105 2016年12月

共著, ISSN 1883-9347

【新規技術が創り出す肝疾患診療のスペクタクル】診断への応用　デジタル画像解析技術を用いた肝病理組織の定量的評価

橋口, 明典 and 坂元, 亨宇

肝・胆・膵 73 （ 5 ） 703 - 711 2016年11月

共著, ISSN 0389-4991

画像診断と病理　肝線維化を診断　肝線維化を病理学的に定量する

阿部, 時也, 波多野, まみ, 橋口, 明典 and 坂元, 亨宇

肝臓クリニカルアップデート（医学図書出版） 2 （ 2 ） 203 - 207 2016年10月

共著, ISSN 2189-4469

CD4+ T cell-dominant insulitis in acute-onset Type 1 diabetes mellitus associated with intraductal papillary mucinous adenoma.

Yajima K, Oikawa Y, Ogata K, Hashiguchi A, Shimada A

Endocrine journal （Japan Endocrine Society） 63 （ 9 ） 841 - 847 2016年09月

共著, ISSN 1348-4540

The loss of insulin-producing pancreatic beta-cells in Type 1 diabetes mellitus (DM) is presumably the result of a T cell-mediated process. In general, CD8+ T cells are the predominant lymphocytes in the insulitis lesions, and CD4+ T cell-dominant insulitis is very rare. We present a case of a 72-year-old woman presented with excessive thirst and a 3-month history of weight loss. She was in a state of ketosis, and her plasma glucose concentration and HbA1c value were elevated. Moreover, anti-islet autoantibodies were positive, thus acute-onset Type 1 DM was diagnosed. At the time of diagnosis, a tumour was detected in the pancreas; total pancreatectomy was carried out 2 months later. The pathological diagnosis was intraductal papillary mucinous adenoma. Immunohistochemical staining of a sample of non-tumorous pancreatic tissue revealed 13 insulitis lesions infiltrated by both CD4+ and CD8+ T cells, and interestingly there were more CD4+ T cells than CD8+ T cells in the lesions. Moreover, B cells and macrophages had also infiltrated the lesions, and these two cell frequencies were both positively correlated with CD4+ as well as CD8+ T cell frequencies. This was a rare case with acute-onset Type 1 DM characterized by CD4+ T cell-dominant insulitis. Proinflammatory cytokines that can promote beta-cell apoptosis or CD8+ T cell function are reported to be secreted from CD4+ T cells. Thus, together with B cells and macrophages, CD4+ T cell-associated immune responses may have, directly and/or indirectly, played a role in the pathogenesis of the Type 1 DM in this patient.

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腎移植1年後のeGFRとwhole slide imageを用いた移植腎生検組織における線維化定量値の比較検討

坂巻裕介, 阿部時也, 橋口明典, 香野日高, 篠田和伸, 森田伸也, 小西孝之助, 林晃一, 中川健

移植（(一社)日本移植学会） 51 （総会臨時） 298 - 298 2016年09月

共著, ISSN 0578-7947

ステロイド治療が良好な結果をもたらしたIgA-dominant感染後糸球体腎炎の一例

菱川彰人, 徳山博文, 川口隆久, 橋口明典, 脇野修, 伊藤裕

日本腎臓学会誌（(一社)日本腎臓学会） 58 （ 6 ） 813 - 813 2016年08月

共著, ISSN 0385-2385

【腎と透析診療指針2016】 (第11章)全身疾患に伴う腎疾患　骨髄腫に伴う腎障害

坂巻, 裕介, 橋口, 明典, 香野, 日高, 中川, 健 and 林, 晃一

腎と透析 80 （増刊） 366 - 369 2016年06月

共著, ISSN 0385-2156

【CKDの臨床検査と腎病理診断】 CKDの病理

橋口, 明典

臨床検査（医学書院） 60 （ 6 ） 642 - 648 2016年06月

共著, ISSN 0485-1420

たこつぼ型心筋症を合併した顕微鏡的多発血管炎の一例

坂巻裕介, 橋口明典, 香野日高, 林晃一, 中川健

日本透析医学会雑誌（(一社)日本透析医学会） 49 （ Suppl.1 ） 584 - 584 2016年05月

共著, 査読有り, ISSN 1340-3451

Pathological sub-analysis of a multicenter randomized controlled trial of tonsillectomy combined with steroid pulse therapy versus steroid pulse monotherapy in patients with immunoglobulin A nephropathy.

Katafuchi R, Kawamura T, Joh K, Hashiguchi A, Hisano S, Shimizu A, Miyazaki Y, Nagata M, Matsuo S, IgA nephropathy Study Group in Japan

Clinical and experimental nephrology （Springer Tokyo） 20 （ 2 ） 244 - 52 2016年04月

共著, ISSN 1437-7799

BACKGROUND: The IgA nephropathy (IgAN) Study Group in Japan conducted a multicenter, randomized, controlled trial of tonsillectomy with steroid pulse therapy (TSP) versus steroid pulse monotherapy in patients with IgAN (UMIN Clinical Trial Registry Number; C000000384). The effects of therapies in relation to pathological severity were analyzed in this study. METHODS: The patients with IgAN, urinary protein 1.0-3.5 g/day, serum creatinine of 1.5 mg/dl or less were randomly assigned to receiving TSP (Group A) or steroid pulses alone (Group B). The primary endpoint was the disappearance of proteinuria and/or hematuria. Twenty-six biopsies in Group A and 33 in Group B were available. The histological grades (HG) according to the percentage of glomeruli with crescent or sclerosis and the Oxford classification were analyzed. RESULTS: The patients in Group A had a 4.32- to 12.1-fold greater benefit of disappearance of proteinuria and 3.61- to 8.17-fold greater benefit of clinical remission (disappearance of proteinuria and hematuria) than those in Group B in patients with HG2-3, acute lesions (cellular or fibrocellular crescent) affecting more than 5 % of glomeruli, chronic lesions (fibrous crescents or sclerosis) affecting more than 20 % and S1. In contrast, odds ratios for disappearance of proteinuria or clinical remission in Group A to Group B were not significant in patients with HG 1, acute lesion in 5 % or less of glomeruli, chronic lesion in 20 % or less and S0. The disappearance of hematuria showed no relation to pathological severity. CONCLUSION: TSP might be better employed according to the pathological severity.

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Automatic quantification of morphological features for hepatic trabeculae analysis in stained liver specimens

Ishikawa, M., Murakami, Y., Ahi, S. T., Yamaguchi, M., Kobayashi, N., Kiyuna, T., Yamashita, Y., Saito, A., Abe, T., Hashiguchi, A. and Sakamoto, M.

J Med Imaging (Bellingham) （SPIE） 3 （ 2 ） 027502 2016年04月

共著, ISSN 2329-4302

This paper proposes a digital image analysis method to support quantitative pathology by automatically segmenting the hepatocyte structure and quantifying its morphological features. To structurally analyze histopathological hepatic images, we isolate the trabeculae by extracting the sinusoids, fat droplets, and stromata. We then measure the morphological features of the extracted trabeculae, divide the image into cords, and calculate the feature values of the local cords. We propose a method of calculating the nuclear-cytoplasmic ratio, nuclear density, and number of layers using the local cords. Furthermore, we evaluate the effectiveness of the proposed method using surgical specimens. The proposed method was found to be an effective method for the quantification of the Edmondson grade.

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血栓性微小血管症と抗リン脂質抗体症候群を合併したループス腎炎の1例

坂巻, 裕介, 小西, 孝之助, 橋口, 明典, 冨田, 茂樹, 久保田, 英司, 伊藤, 裕 and 林, 晃一

日本腎臓学会誌 58 （ 1 ） 45 - 54 2016年01月

共著, ISSN 0385-2385

症例は48歳、女性。21歳時に、顔面、四肢の紅斑および発熱を認め、全身性エリテマトーデス(systemic lupus erythematosus:SLE)と診断され、副腎皮質ステロイド(プレドニゾロン)が開始された。当院入院の13日前にかかりつけ医を受診し、SLEの再燃が疑われて当科紹介となった。当院入院時の血液検査では、汎血球減少症、低補体血症、腎機能障害、ループス抗凝固因子の陽性、検尿では血尿と高度の蛋白尿が認められた。ループス腎炎の活動性評価目的で腎生検を施行後、プレドニゾロンによる免疫抑制療法に加え、抗血小板療法、抗凝固療法を開始した。第22病日には、破砕赤血球の出現を伴う溶血性貧血、血小板減少、腎機能障害の進行が認められた。新鮮凍結血漿を置換液とした血漿交換療法を計10回施行し全身状態や血小板減少は改善したが、腎機能の改善はなく、第36病日には血液透析を導入した。腎生検病理所見は、半月体形成と管内増殖を呈する高度の増殖性腎炎に加え、糸球体係蹄腔内には粗大な血栓を認め、細動脈内腔には閉塞性の硝子様沈着が認められた。蛍光抗体法による染色では、係蹄壁に免疫グロブリンと補体の顆粒状沈着を認め、電子顕微鏡では、分節性に上皮下と基底膜内の高電子密度沈着物を認めたものの、明らかな内皮下沈着物はみられなかった。ループス腎炎では、ステロイドを中心とした免疫抑制療法が治療の主体となるが、APSや血栓性微小血管症を合併した場合、免疫抑制療法に加え、抗血小板療法、抗凝固療法、血漿交換療法を含めた集学的治療が必要となる。ループス腎炎の病態は不明な点が多いが、今回われわれは、TMAが腎障害の進行に関与した可能性が示唆されたループス腎炎の1例を経験したので報告する。(著者抄録)

Elastin Fiber Accumulation in Liver Correlates with the Development of Hepatocellular Carcinoma

Yasui, Y., Abe, T., Kurosaki, M., Higuchi, M., Komiyama, Y., Yoshida, T., Hayashi, T., Kuwabara, K., Takaura, K., Nakakuki, N., Takada, H., Tamaki, N., Suzuki, S., Nakanishi, H., Tsuchiya, K., Itakura, J., Takahashi, Y., Hashiguchi, A., Sakamoto, M. and Izumi, N.

PLoS One （PUBLIC LIBRARY SCIENCE） 11 （ 4 ） e0154558 2016年

共著, ISSN 1932-6203

BACKGROUND & AIMS: The fibrosis stage, which is evaluated by the distribution pattern of collagen fibers, is a major predictor for the development of hepatocellular carcinoma (HCC) for patients with hepatitis C. Meanwhile, the role of elastin fibers has not yet been elucidated. The present study was conducted to determine the significance of quantifying both collagen and elastin fibers. METHODS: We enrolled 189 consecutive patients with hepatitis C and advanced fibrosis. Using Elastica van Gieson-stained whole-slide images of pretreatment liver biopsies, collagen and elastin fibers were evaluated pixel by pixel (0.46 mum/pixel) using an automated computational method. Consequently, fiber amount and cumulative incidences of HCC within 3 years were analyzed. RESULTS: There was a significant correlation between collagen and elastin fibers, whereas variation in elastin fiber was greater than in collagen fiber. Both collagen fiber (p = 0.008) and elastin fiber (p < 0.001) were significantly correlated with F stage. In total, 30 patients developed HCC during follow-up. Patients who have higher elastin fiber (p = 0.002) in addition to higher collagen fiber (p = 0.05) showed significantly higher incidences of HCC. With regard to elastin fiber, this difference remained significant in F3 patients. Furthermore, for patients with a higher collagen fiber amount, higher elastin was a significant predictor for HCC development (p = 0.02). CONCLUSIONS: Computational analysis is a novel technique for quantification of fibers with the added value of conventional staging. Elastin fiber is a predictor for the development of HCC independently of collagen fiber and F stage.

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[Renal thrombotic microangiopathy and antiphospholipid syndrome nephropathy in a patient with lupus nephritis]

Sakamaki, Y., Konishi, K., Hashiguchi, A., Tomita, S., Kubota, E., Itoh, H. and Hayashi, K.

Nihon Jinzo Gakkai Shi 58 （ 1 ） 45 - 54 2016年

ISSN 0385-2385

The patient was a 48-year-old Japanese woman diagnosed as having systemic lupus erythematosus at the age of 21 years when she presented with fever and an erythematous skin rash on her face and extremities. Prednisolone was initiated at that time. Thirteen days before admission to our hospital, she was referred to us by her family physician. Upon admission, blood tests showed pancytopenia, hypocomplementemia, and renal dysfunction, as well as the presence of lupus anticoagulant. Urinalysis showed abundant proteinuria and heavy microscopic hematuria. After performing a renal biopsy, we initiated immunosuppressive therapy and an anticoagulant. On the 22nd hospital day, microangiopathic hemolytic anemia appeared with the progression of thrombocytopenia and renal failure, and the patient subsequently underwent ten sessions of plasma exchange. After the commencement of the plasma exchange, her general condition improved. Her renal dysfunction, however, continued to progress, and hemodialysis was started on the 36th hospital day. The light microscopy showed severe endo- and extra-capillary proliferative glomerulonephritis with abundant crescents, and massive thrombi in the capillary lumen of the glomeruli. The arterioles contained occlusive hyaline materials. An immunofluorescence study showed granular staining of immunoglobulins and complements along the glomerular capillary wall. An electron microscopy examination revealed the presence of electron-dense deposits in the subepithelial and intramembranous areas of the glomeruli, but subendothelial deposits were absent. For cases with lupus nephritis (LN), immunosuppressive therapy based on corticosteroid remains the mainstay of treatment. However, immunosuppression alone may be insufficient when antiphospholipid antibody syndrome and thrombotic microangiopathy (TMA) are also present, and other treatment modalities including antiplatelet therapy, anticoagulation, and plasma exchange are likely to be necessary, as illustrated by the present case. Although the mechanism responsible for LN remains uncertain, we report a case of LN suggesting that TMA is associated with renal dysfunction.

Correction: Elastin Fiber Accumulation in Liver Correlates with the Development of Hepatocellular Carcinoma

PLoS One 11 （ 8 ） e0160133 2016年

ISSN 1932-6203

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Renal thrombotic microangiopathy and antiphospholipid syndrome nephropathy in a patient with lupus nephritis

Yusuke Sakamaki, Konosuke Konishi, Akinori Hashiguchi, Shigeki Tomita, Eiji Kubota, Hiroshi Itoh, Koichi Hayashi

Japanese Journal of Nephrology （Japanese Society of Nephrology） 58 （ 1 ） 45 - 54 2016年

共著, ISSN 0385-2385

The patient was a 48-year-old Japanese woman diagnosed as having systemic lupus erythematosus at the age of 21 years when she presented with fever and an erythematous skin rash on her face and extremities. Prednisolonewas initiated at that time. Thirteen days before admission to our hospital, she was referred to us by her family physician. Upon admission, blood tests showed pancytopenia, hypocomplementemia, and renal dysfunction, as well as the presence of lupus anticoagulant. Urinalysis showed abundant proteinuria and heavy microscopic hematuria. After performing a renal biopsy, we initiated immunosuppressive therapy and an anticoagulant. On the 22nd hospital day, microangiopathic hemolytic anemia appeared with the progression of thrombocytopenia and renal failure, and the patient subsequently underwent ten sessions of plasma exchange. After the commencement of the plasma exchange, her general condition improved. Her renal dysfunction, however, continued to progress, and hemodialysis was started on the 36th hospital day. The light microscopy showed severe endo- And extra-capillary proliferative glomerulonephritis with abundant crescents, and massive thrombi in the capillary lumen of the glomeruli. The arterioles contained occlusive hyaline materials. An immunofluorescence study showed granular staining of immunoglobulins and complements along the glomerular capillary wall. An electron microscopy examination revealed the presence of electron-dense deposits in the subepithelial and intramembranous areas of the glomeruli, but subendo- Thelial deposits were absent. For cases with lupus nephritis (LN), immunosuppressive therapy based on corticosteroid remains the mainstay of treatment. However, immunosuppression alone may be insufficient when antiphos- pholipid antibody syndrome and thrombotic microangiopathy (TMA) are also present, and other treatment modalities including antiplatelet therapy, anticoagulation, and plasma exchange are likely to be necessary, as illustrated by the present case. Although the mechanism responsible for LN remains uncertain, we report a case of LN suggesting that TMA is associated with renal dysfunction.

腎生検所見から何を学ぶか(No.57)　全身性浮腫で発症し血小板減少を伴った管内増殖性腎炎の1例

野田, 翔子, 住田, 圭一, 関根, 章成, 上野, 智敏, 今福, 礼, 川田, 真宏, 平松, 里佳子, 早見, 典子, 長谷川, 詠子, 諏訪部, 達也, 星野, 純一, 澤, 直樹, 高市, 憲明, 西田, 彩, 藤井, 晶子, 大橋, 健一, 藤井, 丈士, 乳原, 善文 and 橋口, 明典

腎と透析 79 （ 6 ） 984 - 996 2015年12月

共著, ISSN 0385-2156

Feature analyses of trabecular pattern of hepatocellular carcinoma using graph structure

Hideki Komagata, Masahiro Ishikawa, Naoki Kobayashi, Kazuma Shinoda, Masahiro Yamaguchi, Tokiya Abe, Akinori Hashiguchi, Michiie Sakamoto

IIEEJ Transactions on Image Electronics and Visual Computing （The Institute of Image Electronics Engineers of Japan） 3 （ 2 ） 80 - 91 2015年12月

共著, 査読有り, ISSN 2188-191X

A case of severe osteomalacia caused by Tubulointerstitial nephritis with Fanconi syndrome in asymptomotic primary biliary cirrhosis

Yamaguchi, S, Maruyama, T, Wakino, S, Tokuyama, H, Hashiguchi, A, Tada, S, Homma, K, Monkawa, T, Thomas, J, Miyashita, K, Kurihara, I, Yoshida, T, Konishi, K, Hayashi, K, Hayashi, M, Itoh, H

BMC Nephrol 16 187 - 187 2015年11月

共著, ISSN 1471-2369

BACKGROUND: Primary biliary cirrhosis (PBC) is an immune-mediated chronic cholestatic liver disease, characterized by increased concentrations of serum IgM and the presence of circulating anti-mitochondrial antibodies. Although bone diseases such as osteoporosis or osteodystrophy are commonly associated with PBC, osteomalacia which is caused by abnormal vitamin D metabolism, mineralization defects, and phosphate deficiency has not been recognized as a complication of PBC. CASE PRESENTATION: We report the case of a 49-year-old Japanese woman who complained of multiple fractures. Hypophosphatemic osteomalacia was diagnosed from a low serum phosphorus level, 1,25-dihydroxyvitamin D3 level, high levels of bone specific alkaline phosphatase and the findings of bone scintigraphy, although a bone biopsy was not performed. Twenty four hour urine demonstrated a low renal fractional tubular reabsorption of phosphate, increased fractional excretion of uric acid and generalized aminoaciduria. An intravenous bicarbonate loading test suggested the presence of proximal renal tubular acidosis (RTA). These biochemical data indicated Fanconi syndrome with proximal RTA. A kidney biopsy demonstrated t

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Visualization of acetaminophen-induced liver injury by time-of-flight secondary ion mass spectrometry

橋口明典

ANALYTICAL BIOCHEMISTRY （ACADEMIC PRESS INC ELSEVIER SCIENCE） 488 51 - 58 2015年11月

研究論文（学術雑誌）, 共著, ISSN 0003-2697

Time-of-flight secondary ion mass spectrometry (MS) provides secondary ion images that reflect distributions of substances with sub-micrometer spatial resolution. To evaluate the use of time-of-flight secondary ion MS to capture subcellular chemical changes in a tissue specimen, we visualized cellular damage showing a three-zone distribution in mouse liver tissue injured by acetaminophen overdose. First, we selected two types of ion peaks related to the hepatocyte nucleus and cytoplasm using control mouse liver. Acetaminophen-overdosed mouse liver was then classified into three areas using the time-of-flight secondary ion MS image of the two types of peaks, which roughly corresponded to established histopathological features. The ion peaks related to the cytoplasm decreased as the injury became more severe, and their origin was assumed to be mostly glycogen based on comparison with periodic acid Schiff staining images and reference compound spectra. This indicated that the time-of-flight secondary ion MS image of the acetaminophen-overdosed mouse liver represented the chemical changes mainly corresponding to glycogen depletion on a subcellular scale. In addition, this technique also provided information on lipid species related to the injury. These results suggest that time-of-flight secondary ion MS has potential utility in histopathological applications. (C) 2015 Elsevier Inc. All rights reserved.

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C型肝炎関連クリオグロブリン血症に伴う糸球体腎炎の一例

伊藤智章, 脇野修, 徳山博文, 橋口明典, 小西孝之助, 海老沼浩利, 林松彦, 伊藤裕

日本腎臓学会誌（(一社)日本腎臓学会） 57 （ 6 ） 992 - 992 2015年08月

共著, ISSN 0385-2385

菲薄基底膜病の母を有し、Alport症候群が疑われた一症例

田島敬也, 脇野修, 中谷英章, 徳山博文, 橋口明典, 小西孝之助, 林松彦, 伊藤裕

日本腎臓学会誌（(一社)日本腎臓学会） 57 （ 6 ） 961 - 961 2015年08月

共著, ISSN 0385-2385

抗甲状腺薬内服中にMPO-ANCAが陽性となった腎症の一例

盛崎瑞葉, 脇野修, 徳山博文, 中谷英章, 橋口明典, 小西孝之助, 林松彦, 伊藤裕

日本腎臓学会誌（(一社)日本腎臓学会） 57 （ 6 ） 966 - 966 2015年08月

共著, ISSN 0385-2385

両側視力障害を主訴に緊急搬送されRPLSを認めた高血圧合併糖尿病性腎症の1症例

篠塚圭祐, 徳山博文, 橋口明典, 小西孝之助, 脇野修, 伊藤裕

日本腎臓学会誌（(一社)日本腎臓学会） 57 （ 6 ） 960 - 960 2015年08月

共著, ISSN 0385-2385

ポラプレジンクによる薬剤性急性尿細管間質性腎炎の一例

萩原あいか, 徳山博文, 脇野修, 橋口明典, 小西孝之助, 林晃一, 伊藤裕

日本腎臓学会誌（(一社)日本腎臓学会） 57 （ 6 ） 954 - 954 2015年08月

共著, ISSN 0385-2385

びまん性大細胞型B細胞性リンパ腫に合併した治療抵抗性IgA腎症の一例

藤井健太郎, 脇野修, 徳山博文, 橋口明典, 小西孝之助, 林松彦, 伊藤裕

日本腎臓学会誌（(一社)日本腎臓学会） 57 （ 6 ） 1016 - 1016 2015年08月

共著, ISSN 0385-2385

RPGNを呈したPR3-ANCA陽性膜性腎症の一例

村丘寛和, 徳山博文, 橋口明典, 小西孝之助, 林晃一, 脇野修, 伊藤裕

日本腎臓学会誌（(一社)日本腎臓学会） 57 （ 6 ） 966 - 966 2015年08月

共著, ISSN 0385-2385

MGUS(Monoclonal gammopathy of undetermined significance)(IgMκ)が原因の二次性Fanconi症候群にIgA腎症が合併した一例

田島敬也, 脇野修, 中谷英章, 徳山博文, 橋口明典, 小西孝之助, 伊藤裕

日本腎臓学会誌（(一社)日本腎臓学会） 57 （ 6 ） 956 - 956 2015年08月

共著, ISSN 0385-2385

【病理診断クイックリファレンス】 (第9章)腎(非腫瘍)　膜性腎症

橋口, 明典

病理と臨床 33 （臨増） 132 2015年04月

共著, ISSN 0287-3745

An Efficient Wavelet-Based ROI Coding for Multiple Regions

橋口明典

IEICE TRANSACTIONS ON FUNDAMENTALS OF ELECTRONICS COMMUNICATIONS AND COMPUTER SCIENCES （IEICE-INST ELECTRONICS INFORMATION COMMUNICATIONS ENG） E98A （ 4 ） 1006 - 1020 2015年04月

研究論文（学術雑誌）, 共著, ISSN 1745-1337

Region of interest (ROI) coding is a useful function for many applications. JPEG2000 supports ROI coding and can decode ROIs preferentially regardless of the shape and number of the regions. However, if the number of regions is quite large, the ROI coding performance of JPEG2000 declines because the code-stream includes many useless non-ROI codes. This paper proposes a wavelet-based ROI coding method suited for multiple ROIs. The proposed wavelet transform does not access any non-ROIs when transforming the ROIs. Additionally, the proposed method eliminates the need for unnecessary coding of the bits in the higher bit planes of non-ROI regions by adding an ROI map to the code-stream. The experimental results show that the proposed method achieves a higher peak signal-to-noise ratio than the ROI coding of JPEG2000. The proposed method can be applied to both max-shift and scaling-based ROI coding.

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【病理診断クイックリファレンス】 (第9章)腎(非腫瘍)　ループス腎炎

橋口, 明典

病理と臨床 33 （臨増） 134 2015年04月

共著, ISSN 0287-3745

【病理診断クイックリファレンス】 (第9章)腎(非腫瘍)　糖尿病性腎症

橋口, 明典

病理と臨床 33 （臨増） 133 2015年04月

共著, ISSN 0287-3745

NAFLDにおけるDual energy CTを用いた肝脂肪変性定量評価の有用

岡部純弥, 澤井良之, 福田和人, 井倉技, 小来田幸世, 今井康陽, 磯谷圭介, 米澤稔, 藤田典彦, 兵頭朋子, 辻川華子, 阿部時也, 橋口明典, 坂元亨宇, 村上卓道

肝臓（(一社)日本肝臓学会） 56 （ Suppl.1 ） A359 - A359 2015年04月

共著, ISSN 0451-4203

市販の下剤多量内服による薬剤性の関与が疑われた広範な糸球体硬化と肝硬変の一例

高畑尚, 徳山博文, 脇野修, 橋口明典, 小西孝之助, 林晃一, 伊藤裕

日本内分泌学会雑誌（(一社)日本内分泌学会） 91 （ 1 ） 327 - 327 2015年04月

共著, ISSN 0029-0661

An accurate method of extracting fat droplets in liver images for quantitative evaluation

Ishikawa, Masahiro, Kobayashi, Naoki, Komagata, Hideki, Shinoda, Kazuma, Yamaguchi, Masahiro, Abe, Tokiya, Hashiguchi, Akinori, Sakamoto, Michiie

Medical Imaging 2015: Digital Pathology 9420 2015年

共著, 査読有り

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Enhancing automatic classification of hepatocellular carcinoma images through image masking, tissue changes and trabecular features.

Aziz, Maulana Abdul, Kanazawa, Hiroshi, Murakami, Yuri, Kimura, Fumikazu, Yamaguchi, Masahiro, Kiyuna, Tomoharu, Yamashita, Yoshiko, Saito, Akira, Ishikawa, Masahiro, Kobayashi, Naoki, Abe, Tokiya, Hashiguchi, Akinori, Sakamoto, Michiie

Journal of pathology informatics 6 26 - 26 2015年

共著, 査読有り

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Overexpression of CXCR4 on circulating B cells in patients with active systemic lupus erythematosus

Hironari Hanaoka, Yuka Okazaki, Akinori Hashiguchi, Hidekata Yasuoka, Tsutomu Takeuchi, Masataka Kuwana

Clinical and Experimental Rheumatology （Clinical and Experimental Rheumatology S.A.S.） 33 （ 6 ） 863 - 870 2015年

共著, ISSN 1593-098X

Objective: To evaluate the roles of circulating B cells in the pathogenic process of systemic lupus erythematosus (SLE) by measuring the expression of chemokines and their receptors. Methods: Peripheral-blood mononuclear cells were obtained from 17 active, 21 inactive SLE patients, and 13 healthy controls. The expression of CXCR4, CXCR5, and CCR7 on CD19+ B cells was determined by flow cytometry, serum concentration of CXCL12 was measured by enzyme-linked immunosorbent assay, and the chemotactic responsiveness of B cells toward CXCL12 was evaluated. B or plasma cells expressing CXCR4 in renal biopsy specimens were detected using immnofluorescent staining. Results: Flow cytometric analysis revealed that expression level of CXCR4 on circulating B cells was significantly higher in patients with active disease than in those with inactive disease or controls. Serum CXCL12 concentration was not different between these groups. In addition, the migratory ability of B cells toward CXCL12 was enhanced in active SLE patients. Finally, CXCR4-expressing B cells were more frequently observed in the renal biopsy specimens of lupus nephritis. Conclusion: Up-regulated CXCR4 expression on circulating B cells in active SLE may enhance their chemotactic response toward CXCL12, which may promote infiltration of these cells into inflamed renal tissue and contribute to the development of SLE.

Improvement in karyomegalic interstitial nephritis three years after ifosfamide and cisplatin therapy by corticosteroid

Matsuura, T, Wakino, S, Yoshifuji, A, Nakamura, T, Tokuyama, H, Hashiguchi, A, Konishi, K, Iwasa, T, Shoji, M, Hosono, A, Ohashi, K, Chuman, H, Itoh, H

CEN Case Rep 3 （ 2 ） 226 - 231 2014年11月

共著, ISSN 2192-4449

Long-term nephrotoxicity of ifosfamide is occasionally progressive, and, in such case, there has been no specific treatment to prevent progression. It has been reported that the presence of karyomegalic interstitial nephritis, which is rare type of interstitial nephritis, may be related to ifosfamide-induced nephropathy with poor prognosis and resistant to the immunosuppressive therapy. A 15-year-old boy presented with progressive nephrotoxicity 3 years after systemic chemotherapy with ifosfamide and cisplatin for the treatment of osteosarcoma. Renal biopsy revealed the severe tubulointerstitial nephritis with tubular atrophy and focal global and segmental glomerular sclerosis. It also showed tubular epithelial cells with variably sized nuclei, some of which were massively enlarged, abnormal hyperchromatic, irregular shaped, and bizarre-appearing. These morphological changes were suggestive of the histology of karyomegalic interstitial nephritis. Corticosteroid retarded the progression of nephrotoxicity. The present case is the first report, suggesting that corticosteroid was effective against the late-onset renal toxicity by ifosfamide therapy. Our case also suggests that karyomeg

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Rac1 accumulates in the nucleus at the invasive front of colorectal cancer through promoting cell motility

橋口明典

CANCER RESEARCH （AMER ASSOC CANCER RESEARCH） 74 （ 19 ） 865 - 870 2014年10月

研究論文（学術雑誌）, 共著, ISSN 0008-5472

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Up-Regulated Expression of CXCR4 on Circulating B Cells in Patients with Systemic Lupus Erythematosus

橋口明典

ARTHRITIS & RHEUMATOLOGY （WILEY-BLACKWELL） 66 S1177 - S1178 2014年10月

研究論文（学術雑誌）, 共著, ISSN 2326-5191

A rare association between Fabry's disease and granulomatosis with polyangiitis: a potential pathogenic link

Hironari Hanaoka, Akinori Hashiguchi, Konosuke Konishi, Tomohiro Ishii, Masataka Kuwana

BMC NEPHROLOGY （BIOMED CENTRAL LTD） 15 157 2014年10月

共著, 査読有り, ISSN 1471-2369

Background: Fabry's disease is a rare X-linked, hereditary lysosomal storage disease caused by a deficiency of the enzyme alpha-galactosidase A. Granulomatosis with polyangiitis is characterized by the involvement of the respiratory tract and kidneys. Here, we report the first case of the coexistence of these diseases.
Case presentation: We describe a 29-year-old man suffering from fever with maxillary sinusitis, multiple lung nodules, and proteinuria. He was diagnosed with Fabry's disease accompanying granulomatosis with polyangiitis on the basis of the low activity of peripheral leukocyte alpha-galactosidase A and pathological findings in the lung and kidney. Glucocorticoid and cyclophosphamide were administered, followed by enzyme replacement therapy. Progression to end-stage renal disease has not been observed for 6 years until the time of drafting this manuscript.
Conclusion: Because both Fabry's disease and granulomatosis with polyangiitis or crescentic glomerulonephritis are rare diseases, their concurrence in this and related cases suggests there may be a pathogenic link between these two conditions. Fabry's disease may be underdiagnosed, particularly in cases of granulomatosis with polyangiitis or crescentic glomerulonephritis.

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Label-free visualization of acetaminophen-induced liver injury by high-speed stimulated Raman scattering spectral microscopy and multivariate image analysis

Shuya Satoh, Yoichi Otsuka, Yasuyuki Ozeki, Kazuyoshi Itoh, Akinori Hashiguchi, Ken Yamazaki, Hiroyuki Hashimoto, Michiie Sakamoto

PATHOLOGY INTERNATIONAL （WILEY-BLACKWELL） 64 （ 10 ） 518 - 526 2014年10月

共著, 査読有り, ISSN 1320-5463

We recently established a high-speed, label-free, spectral imaging method based on stimulated Raman scattering (SRS). This method enables examination of cellular features within relatively short periods, thus enabling new imaging applications in pathology. Previously, we reported on label-free visualization of mouse tissue using SRS spectral microscopy combined with multivariate image analysis, but the feasibility of applying this approach to diseased tissues with diverse morphology and irregular chemical species has not been examined. We, therefore, assessed acetaminophen-induced liver injury to evaluate the potential use of Raman spectral microscopy for visualizing histopathologic specimens. Acetaminophen-overdosed mouse liver was prepared and the pathologic changes including centrilobular necrosis were confirmed. Multi-colored images were reconstructed through principal component analysis (PCA) of a multi-band SRS dataset, which provided rich information compared with a monochrome single-band SRS dataset. A wide view of the multi-colored principal component (PC) images showed the distribution of cellular constituents, which was similar to that observed by fat staining. In addition, different types of cells in liver parenchyma were also demonstrated. In conclusion, the combination of SRS spectral microscopy and PCA has the potential to reveal both the morphological and chemical features of specimens and therefore has potential utility in diagnostic pathology.

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腎生検所見から何を学ぶか(No.53)　タクロリムスが上皮下沈着物に対して治療効果を示した難治性ループス腎炎の1例

野中, 香苗, 乳原, 善文, 諏訪部, 達也, 住田, 圭一, 平松, 里佳子, 長谷川, 詠子, 豊原, 敬文, 広浜, 大五郎, 山内, 真之, 山内, 淳司, 早見, 典子, 冨永, 直人, 星野, 純一, 澤, 直樹, 竹本, 文美, 黒田, 陽子, 大橋, 健一, 高市, 憲明 and 橋口, 明典

腎と透析 77 （ 3 ） 389 - 398 2014年09月

共著, ISSN 0385-2156

BCG膀胱内注入療法により誘発された腎サルコイドーシスの一例

新井舞, 柏真紀, 徳山博文, 脇野修, 橋口明典, 林松彦, 小西孝之助, 林晃一, 伊藤裕

日本腎臓学会誌（(一社)日本腎臓学会） 56 （ 6 ） 845 - 845 2014年08月

共著, ISSN 0385-2385

急性骨髄性白血病(AML)に対して造血幹細胞移植施行後に微小血管病変(TMA)を発症した一例

浦井秀徳, 徳山博文, 脇野修, 橋口明典, 小西孝之助, 林晃一, 伊藤裕

日本腎臓学会誌（(一社)日本腎臓学会） 56 （ 6 ） 846 - 846 2014年08月

共著, ISSN 0385-2385

ステロイドが著効した間質性腎炎を伴うLight chain tubulopathyの一例

内藤真規子, 脇野修, 橋口明典, 徳山博文, 小西孝之助, 林晃一, 林松彦, 伊藤裕

日本腎臓学会誌（(一社)日本腎臓学会） 56 （ 6 ） 840 - 840 2014年08月

共著, ISSN 0385-2385

HE染色肝病理標本における組織構造定量化によるがん検出精度向上の検討

石川, 雅浩, 藤田, 悠介, Aziz, Maulana Abdul, 村上, 百合, 山口, 雅浩, 小林, 直樹, 喜友名, 朝春, 齋藤, 彰, 阿部, 時也, 橋口, 明典 and 坂元, 亨宇

MEDICAL IMAGING TECHNOLOGY 32 （ Suppl. ） 1 - 9 2014年07月

共著, ISSN 0288-450X

HE染色病理組織標本におけるコンピュータ診断支援の従来研究では、細胞核の形態的特徴を用いる場合が多いが、特に高分化がんあるいは早期がんの検出、診断においては核情報以上に組織構造が重要な役割を持っている。本発表では、肝細胞がんを対象として、これまでに我々が検討を行ってきた組織構造の特徴量をがんの識別に応用した基礎的な結果を報告する。具体的には、肝細胞索の層の厚さ、索構造の乱れ、肝細胞索ごとに算出したN/C比及び核密度などを画像から計測した結果、がんと非がんの間で有意差が認められた。さらに、これらの組織構造の特徴量を従来の細胞核の特徴量に加えることにより、がん識別の精度を向上する可能性が示された。本手法で用いた組織構造の特徴量は、病理組織標本のデジタルスライド画像から自動的に算出できるもので、定量的情報に基づくコンピュータ病理診断支援システムに有用なものと考えられる。(著者抄録)

Effective Color Transform Method for Image Compression of H&E Stained Whole Slide Image Using Subset Pixels

KOBAYASHI Naoki, SHINODA Kazuma, KATOH Ayako, KOMAGATA Hideki, YAMAGUCHI Masahiro, ABE Tokiya, HASHIGUCHI Akinori, SAKAMOTO Michiie

IIEEJ Trans Image Electron Vis Comput (CD-ROM) （The Institute of Image Electronics Engineers of Japan） 2 （ 1 ） 37 - 47 2014年06月

共著, 査読有り, ISSN 2188-191X

抗GBM抗体陽性腎炎発症し、透析導入後にヘノッホ・シェーライン紫斑病(HSP)を併発した一例

小口英世, 徳山博文, 脇野修, 小西孝之助, 橋口明典, 林晃一, 伊藤裕

日本透析医学会雑誌（(一社)日本透析医学会） 47 （ Suppl.1 ） 1012 - 1012 2014年05月

共著, ISSN 1340-3451

肥満関連腎症組織学的変化の新たな知見

徳山博文, 脇野修, 橋口明典, 小西孝之助, 林晃一, 伊藤裕

日本腎臓学会誌（(一社)日本腎臓学会） 56 （ 3 ） 249 - 249 2014年05月

共著, ISSN 0385-2385

Whole slide imageを用いた膠原・弾性線維定量法

阿部, 時也, 橋口, 明典, 山崎, 剣 and 坂元, 亨宇

病理と臨床 32 （ 4 ） 448 - 450 2014年04月

共著, ISSN 0287-3745

Distinct Cell Clusters Touching Islet Cells Induce Islet Cell Replication in Association with Over-Expression of Regenerating Gene (REG) Protein in Fulminant Type 1 Diabetes

橋口明典

PLOS ONE （PUBLIC LIBRARY SCIENCE） 9 （ 4 ） 774 - 779 2014年04月

研究論文（学術雑誌）, 共著, ISSN 1932-6203

Background: Pancreatic islet endocrine cell-supporting architectures, including islet encapsulating basement membranes (BMs), extracellular matrix (ECM), and possible cell clusters, are unclear.
Procedures: The architectures around islet cell clusters, including BMs, ECM, and pancreatic acinar-like cell clusters, were studied in the non-diabetic state and in the inflamed milieu of fulminant type 1 diabetes in humans.
Result: Immunohistochemical and electron microscopy analyses demonstrated that human islet cell clusters and acinar-like cell clusters adhere directly to each other with desmosomal structures and coated-pit-like structures between the two cell clusters. The two cell-clusters are encapsulated by a continuous capsule composed of common BMs/ECM. The acinar-like cell clusters have vesicles containing regenerating (REG) I alpha protein. The vesicles containing REG I alpha protein are directly secreted to islet cells. In the inflamed milieu of fulminant type 1 diabetes, the acinar-like cell clusters over-expressed REG I alpha protein. Islet endocrine cells, including beta-cells and non-beta cells, which were packed with the acinar-like cell clusters, show self-replication with a markedly increased number of Ki67-positive cells.
Conclusion: The acinar-like cell clusters touching islet endocrine cells are distinct, because the cell clusters are packed with pancreatic islet clusters and surrounded by common BMs/ECM. Furthermore, the acinar-like cell clusters express REG I alpha protein and secrete directly to neighboring islet endocrine cells in the non-diabetic state, and the cell clusters over-express REG Ia in the inflamed milieu of fulminant type 1 diabetes with marked self-replication of islet cells.

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Supratentorial neurenteric cyst with spontaneous repetitive intracystic hemorrhage mimicking brain abscess: a case report

橋口明典

NEUROSURGICAL REVIEW （SPRINGER） 37 （ 1 ） 153 - 159 2014年01月

研究論文（学術雑誌）, 共著, ISSN 0344-5607

Neurenteric cyst (NC) is a benign epithelial cyst (BEC) of endodermal origin that mostly occurs in the spinal subdural space or posterior cranial fossa. A 28-year-old male presented with a left frontal lobe NC associated with spontaneous repetitive intracystic hemorrhage, which was initially diagnosed and treated as a brain abscess. He presented with headache and disorientation, without underlying diseases. A cystic tumor was suspected because of a hypointense signal on diffusion-weighted magnetic resonance imaging (MRI). One day after admission, his condition deteriorated rapidly and emergency cyst aspiration was performed. A brown viscous liquid like bloody pus comprising many neutrophils and macrophages was obtained. Although culture was negative, we initially started antibiotic treatment because of cyst content characteristics and rapid clinical course compatible with brain abscess. He was discharged without neurological deficits, but occasionally complained of intense headache. Computed tomography/MRI showed repetitive intracystic hemorrhage and gradual re-enlargement of the lesion. He underwent radical cyst excision by frontal craniotomy 34 months after aspiration. The pathological diagnosis was NC. We believe this is the first report of a supratentorial NC with spontaneous repetitive intracystic hemorrhage. BECs, especially with intracystic hemorrhage, are difficult to be distinguished from brain abscesses. In cases of cystic lesions or presumed brain abscesses refractory to treatment with aspiration and/or antibiotics, BECs should be considered, and radical cyst wall removal should be considered a treatment option.

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Inhibition of Activated Rac1 Signaling Induces Recovery of E-Cadherin Function and Abrogation of Invasive Phenotype of Side Population in Colon Cancer Cells

橋口明典

DIGESTION （KARGER） 89 （ 1 ） 83 - 83 2014年

研究論文（学術雑誌）, 共著, ISSN 0012-2823

Enhancing Automatic Classification of Hepatocellular Carcinoma Images through Image Masking, Tissue Changes, and Trabecular Features

橋口明典

ANALYTICAL CELLULAR PATHOLOGY （Hindawi Limited） 2014 51 - 58 2014年

研究論文（学術雑誌）, 共著, ISSN 2210-7177

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Whole Slide Image Analysis System for Quantification of Liver Fibrosis

橋口明典

ANALYTICAL CELLULAR PATHOLOGY （Hindawi Limited） 2014 774 - 779 2014年

研究論文（学術雑誌）, 共著, ISSN 2210-7177

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Development of a Prototype for Hepatocellular Carcinoma Classification Based on Morphological Features Automatically Measured in Whole Slide Images

橋口明典

ANALYTICAL CELLULAR PATHOLOGY （Hindawi Limited） 2014 774 - 779 2014年

研究論文（学術雑誌）, 共著, ISSN 2210-7177

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Computational hepatocellular carcinoma tumor grading based on cell nuclei classification

Atupelage, C., Nagahashi, H., Kimura, F., Yamaguchi, M., Tokiya, A., Hashiguchi, A., Sakamoto, M.

Journal of Medical Imaging 1 （ 3 ） 034501 - 034501 2014年

共著, 査読有り

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Color processing in pathology image analysis system for liver biopsy

Yuri Murakami, Tokiya Abe, Yoshiko Yamashita, Masahiro Yamaguchi, Masahiro Ishikawa, Akinori Hashiguchi, Kiyuna Tomoharu, Akira Saito, Michiie Sakamoto

Final Program and Proceedings - IS and T/SID Color Imaging Conference （Society for Imaging Science and Technology） 2014- （ January ） 184 - 188 2014年

共著, ISSN 2169-2629

We have been developing a prototype system for the automatic detection of hepatocellular carcinoma (HCC) from whole slide images (WSIs) of liver biopsy based on image analysis techniques. In this paper, we present two color-related topics of this system: color correction and the calculation of color-related features of cytoplasm. A WSI-basis color correction method was implemented for the prototype system. We tested the color correction using more than 300 WISs, and it was confirmed that the color correction works well and stably. In addition, it was found that the success rate of nuclei detection significantly increaseed due to color correction. As for color-related features, we propose a method to calculate the representative color of cytoplasm and the clearness of cytoplasm. It was found that there was slight difference between the distributions of the representative colors of HCC and non-cancer tissues. In addition, there was slight correlation between the clearness of cytoplasm and nuclei density, which implies a promising role of the clearness index in a nuclei-based HCC detection.

Renal thrombotic microangiopathy in a patient with septic disseminated intravascular coagulation

橋口明典

BMC NEPHROLOGY （BIOMED CENTRAL LTD） 14 3037 - 3045 2013年11月

研究論文（学術雑誌）, 共著, ISSN 1471-2369

Background: The mechanism for the development of thrombotic microangiopathy (TMA) during sepsis has only been partially elucidated. TMA is recognized as a disease caused by various factors, and may be involved in the emergence of organ damage in severe sepsis. Here we report a case of TMA that followed disseminated intravascular coagulation (DIC) due to severe infection in a patient with a reduced ADAMTS-13 activity level.
Case presentation: An 86-year-old Japanese woman was admitted to our hospital because of low back pain and fever. A careful evaluation led to a diagnosis of acute obstructive pyelonephritis due to a ureteral stone. Proteus mirabilis was isolated from both blood and urine cultures. The patient developed systemic inflammatory response syndrome and DIC, and was treated with antibiotics and daily continuous hemodiafiltration. Although infection and the coagulation abnormalities due to DIC were successfully controlled, renal failure persisted and her consciousness level deteriorated progressively in association with severe thrombocytopenia and microangiopathic hemolytic anemia. We therefore suspected the presence of TMA and started plasma exchange, which resulted in an impressive improvement in consciousness as well as the laboratory abnormalities. The ADAMTS-13 activity was 44% and the patient tested negative for the ADAMTS-13 inhibitor prior to the initiation of plasma exchange. A renal biopsy was performed to determine the etiology of acute renal injury, which revealed findings that were interpreted to be compatible with the sequelae of TMA. The follow-up studies performed after the successful treatment of TMA showed that her plasma ADAMTS-13 activity level remained persistently low. It is surmised that septic DIC occurring in the presence of preexisting reduced ADAMTS-13 activity have led to the development of secondary TMA in the present case.
Conclusion: The present case suggests that TMA can be superimposed on sepsis-induced DIC, and plasma exchange is expected to be beneficial in such situations. Clinicians should consider the possibility of secondary TMA that follows sepsis-induced DIC in certain indicative clinical settings.

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IgA腎症の寛解基準の提唱

松尾, 清一, 川村, 哲也, 鈴木, 祐介, 城, 謙輔, 富野, 康日己, 堀越, 哲, 西野, 友哉, 吉川, 徳茂, 服部, 元史, 木村, 健二郎, 安田, 隆, 白井, 小百合, 柴田, 孝則, 吉村, 光弘, 宇都宮, 保典, 遠藤, 正之, 坂本, なほ子, 松島, 雅人, 宮崎, 陽一, 安田, 宜成, 横尾, 隆, 香美, 祥二, 幡谷, 浩史, 鈴木, 仁, 松崎, 慶一, 内田, 俊也, 伊藤, 孝史, 清水, 章, 片渕, 律子, 久野, 敏, 橋口, 明典 and 厚生労働科学研究費補助金難治性疾患克服研究事業進行性腎障害に関する調査研究班報告IgA腎症分科会

日本腎臓学会誌（(一社)日本腎臓学会） 55 （ 7 ） 1249 - 1254 2013年10月

共著, ISSN 0385-2385

Clinical significance of quantitative measurement of elastin in liver biopsy

橋口明典

HEPATOLOGY 58 605A - 605A 2013年10月

研究論文（学術雑誌）, 共著, ISSN 0270-9139

HE染色肝病理組織標本における索状構造の配列の乱れ定量化法の提案

石川, 雅浩, 福井, 智也, 藤田, 悠介, 村上, 百合, 山口, 雅浩, 阿部, 時也, 橋口, 明典, 坂元, 亨宇 and 齋藤, 彰

MEDICAL IMAGING TECHNOLOGY 31 （ Suppl. ） 1 - 7 2013年08月

共著, ISSN 0288-450X

HE染色肝病理標本における肝細胞がんの診断では、細胞核や細胞配列など様々な形態学的特徴が用いられる。これらの画像解析に関する研究としては、従来、細胞核に着目した研究が多く報告されているが、がんの診断には、核の情報だけでは不十分である。本研究では、細胞配列に基づく特徴量を定量化することで、がんの検出や、分化度分類等に応用することを提案する。正常な肝組織では、肝細胞は索状に配列し、整然とした小葉構造を形成しているが、がんでは、これらの配列に乱れが生じる。これは小領域で考えた場合、正常では肝細胞索同士が並行に近い関係にあり、一定の方向性を持つのに対し、がんでは、細胞索の方向に規則性が失われると考えられる。そこで本研究では、細胞索同士で相対的な角度を算出し、その分布に基づく特徴量を求めた。提案法により、肝細胞の索状配列の特徴を定量化することで、肝細胞がんの識別に利用できる可能性が得られた。(著者抄録)

Bortezomibにより腎機能が回復した血管型ALアミロイドーシスの一例

中村俊文, 脇野修, 徳山博文, 中谷英章, 橋口明典, 小西孝之助, 林晃一, 伊藤裕

日本腎臓学会誌（(一社)日本腎臓学会） 55 （ 6 ） 1072 - 1072 2013年08月

共著, ISSN 0385-2385

骨髄非破壊的同種末梢血幹細胞移植11年経過後に発症した、著明な高血圧・ネフローゼ症候群の一例

松浦友一, 脇野修, 徳山博文, 篠塚圭祐, 小西孝之助, 橋口明典, 伊藤裕

日本腎臓学会誌（(一社)日本腎臓学会） 55 （ 6 ） 1038 - 1038 2013年08月

共著, ISSN 0385-2385

肺高血圧症を伴ったPOEMS症候群による腎機能障害の一例

篠塚圭祐, 脇野修, 徳山博文, 橋口明典, 小西孝之助, 林晃一, 伊藤裕

日本腎臓学会誌（(一社)日本腎臓学会） 55 （ 6 ） 1075 - 1075 2013年08月

共著, ISSN 0385-2385

Karyomegalic-like interstitial nephritisを呈したイフォスファミド腎症の1例

吉藤歩, 脇野修, 松浦友一, 徳山博文, 中村俊文, 橋口明典, 小西孝之助, 林晃一, 伊藤裕

日本腎臓学会誌（(一社)日本腎臓学会） 55 （ 6 ） 1068 - 1068 2013年08月

共著, ISSN 0385-2385

Suppression of autophagy by CUB domain-containing protein 1 signaling is essential for anchorage-independent survival of lung cancer cells

橋口明典

CANCER SCIENCE （WILEY-BLACKWELL） 104 （ 7 ） 865 - 870 2013年07月

研究論文（学術雑誌）, 共著, ISSN 1349-7006

CUB (C1r/C1s, urchin embryonic growth factor, BMP1) domain-containing protein 1 (CDCP1) has been implicated in promoting metastasis of cancer cells through several mechanisms, including the inhibition of anoikis, which is cell death triggered by the loss of extracellular matrix interactions. However, the mechanism inhibiting cell death regulated by CDCP1 remains elusive. Inhibition of CDCP1 expression using small interfering RNA (siRNA) induced the cell death of suspended cancer cells without cleaving caspase-3, a marker of apoptosis; cell death was not inhibited by a general caspase inhibitor, suggesting that the loss of CDCP1 induces caspase-independent cell death. In contrast, knockdown of CDCP1 as well as protein kinase C (PKC), a downstream effector of CDCP1, in a suspension culture of lung cancer cells resulted in marked induction of membranous microtubule-associated protein 1 light chain 3 (LC3)-II protein, a hallmark of autophagy, and caused the formation of an autophagosome structure visualized using green fluorescent protein-tagged LC3-II. Expression and phosphorylation of exogenous CDCP1 by Fyn kinase reduced the formation of autophagosomes and inhibited phosphorylation of CDCP1 by PP2, a Src kinase inhibitor or inhibited PKC by rottlerin, stimulating autophagosome formation. Moreover, death of suspended lung cancer cells induced by CDCP1 siRNA or by PKC siRNA was reduced by the autophagy inhibitor 3-methyladenine. CDCP1-PKC signaling plays a critical role in inhibiting autophagy, which is responsible for anoikis resistance of lung cancer cells.

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二期的根治手術を行った両側頸動脈小体腫瘍の1例

奥井, 文子, 冨田, 俊樹, 今西, 順久, 羽生, 昇, 佐藤, 陽一郎, 大塚, 邦憲, 小川, 郁, 橋口, 明典 and 杜, ぶん林

頭頸部外科（JAPAN SOCIETY FOR HEAD AND NECK SURGERY） 23 （ 1 ） 77 - 82 2013年06月

共著, ISSN 1349-581X

30歳男性の両側頸動脈小体腫瘍(左Shamblin I型、右Shamblin III型)に対し、二期的に根治手術を施行した。近医にてCT、MRIにより両側頸動脈小体腫瘍が疑われ、当院を紹介受診した。血管造影検査にて確定診断し、balloon Matas testは陰性であった。まずShamblin I型と思われた左側の手術を行い、頸動脈を温存し腫瘍を摘出した。5ヵ月後に行った右側の手術では、頸動脈分岐部を全周性に取り囲むShamblin III型であった。頸動脈分岐部を合併切除し、大伏在静脈により血行再建した。いずれも術前に栄養血管塞栓術を行った。血管造影検査と塞栓術を脳神経外科が、頸動脈再建術を血管外科が担当した。3科による集学的アプローチのもと、二期的に安全に両側腫瘍を摘出し得た症例を経験した。(著者抄録)

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Quantification of collagen and elastic fibers using whole-slide images of liver biopsy specimens

橋口明典

PATHOLOGY INTERNATIONAL （WILEY-BLACKWELL） 63 （ 6 ） 305 - 310 2013年06月

研究論文（学術雑誌）, 共著, ISSN 1320-5463

Histological evaluation of fibrosis after a liver biopsy is crucial for evaluating the pathology of patients with chronic liver disease. Previous studies have reported quantitative analyses of fibrosis using images of collagen-stained sections. However, analysis of these studies requires manual selection of the region of interest. In addition, the quantification of elastic fibers is not considered. The present study was conducted in order to measure both the collagen and elastic fiber area ratios using Elastica van Gieson-stained whole-slide images (WSIs) of liver biopsy specimens. High-resolution WSIs provide precise color classification, enabling accurate detection of even fine collagen and elastic fibers. To minimize the influence of pre-existing fibrous tissue, median area ratios of the collagen and elastic fibers were independently calculated from the image tiles of the WSIs. These median area ratios were highly concordant with area ratios after the pre-existing fibrous tissues were manually trimmed from the WSI. Further, these median area ratios were correlated with liver stiffness as measured by transient elastography (collagen: r=0.73 [P<0.01], elastic: r=0.53 [P<0.01]). Our approach to quantifying liver fibrosis will serve as an effective tool to evaluate liver diseases in routine practice.

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Leukemia kidney infiltration can cause secondary polycythemia by activating hypoxia-inducible factor (HIF) pathway

橋口明典

EUROPEAN JOURNAL OF PEDIATRICS （SPRINGER） 172 （ 6 ） 829 - 832 2013年06月

研究論文（学術雑誌）, 共著, ISSN 0340-6199

Secondary polycythemia with increased production of erythropoietin (EPO) is known to occur in kidney diseases such as hydronephrosis and cystic disease, but the mechanism remains unclear. We report an 18-year-old female with isolated renal relapse of acute lymphoblastic leukemia accompanied by polycythemia. At the relapse, she presented with bilateral nephromegaly, mild renal dysfunction, and erythrocytosis with increased serum EPO levels up to 52.1 mIU/mL (9.1-32.8). Renal biopsy demonstrated diffuse lymphoblastic infiltration. The expression of hypoxia-inducible factor (HIF)-1 alpha, which is undetectable in normal kidney, was observed in the renal tubule epithelium compressed by lymphoblastic cells. These findings suggest that erythrocytosis was caused by renal ischemia due to leukemic infiltration. Polycythemia probably became apparent because of the lack of leukemic involvement of the bone marrow. With chemotherapy, the serum EPO level rapidly decreased to normal range accompanied by the normalization of kidney size and function. Renal leukemic infiltration may enhance EPO production, although not recognized in the majority of cases because of bone marrow involvement. C onclusion: Our case has clarified the mechanism of previously reported polycythemia associated with renal diseases as renal ischemia. Furthermore, we have added renal ischemia resulting from tumor infiltration to the list of causes of secondary polycythemia.

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CTガイド下腎生検にて診断し得た無症候性IgG4関連疾患の一例

寺西悠, 矢澤聰, 小坂威雄, 水野隆一, 菊地栄次, 長田浩彦, 浅沼宏, 宮嶋哲, 中川健, 中塚誠之, 橋口明典, 向井万起男, 大家基嗣

泌尿器外科（医学図書出版(株)） 26 （臨増） 761 - 761 2013年05月

共著, ISSN 0914-6180

定量的病理診断に向けた病理画像解析技術

山口, 雅浩, 長橋, 宏, 坂元, 亨宇, 橋口, 明典, 齋藤, 彰 and 小林, 直樹

電子情報通信学会論文誌D: 情報・システム（一般社団法人電子情報通信学会） 96 （ 4 ） 782 - 789 2013年04月

共著, ISSN 1880-4535

ディジタルスライド(バーチャルスライド、Whole Slide Imagingとも呼ばれる)技術の進歩に伴い、病理診断のディジタル化が期待されている。ディジタル技術の導入により、従来の病理医の視覚に頼る定性的/半定量的な診断から、画像計測・認識技術に基づいた定量的病理診断が可能になる。本論文では、筆者らが研究・開発に取り組んでいる病理画像認識、高精度画像解析、色補正などの技術を例示し、定量的病理診断の確立に向けた課題などについて議論を行う。(著者抄録)

病理学　病理デジタル画像技術の進歩　デジタル病理学、パソロジー・インフォマティクス

橋口, 明典

医学のあゆみ 244 （ 6 ） 560 - 562 2013年02月

共著, ISSN 0039-2359

A histologic classification of IgA nephropathy for predicting long-term prognosis: emphasis on end-stage renal disease

橋口明典

JOURNAL OF NEPHROLOGY 26 （ 2 ） 350 - 357 2013年01月

研究論文（学術雑誌）, 共著, ISSN 1121-8428

A multicenter case-control study on IgA nephropathy (IgAN) was conducted to develop an evidence-based clinicopathologic classification of IgAN for predicting long-term renal outcome. Methods: Two hundred and eighty-seven patients including those with isolated hematuria or very mild proteinuria were enrolled. During a median follow-up of 9.3 years after biopsy, 49 patients (17%) progressed to end stage renal disease (ESRD). The associations between pathological variables and the need for chronic dialysis was examined by multivariate logistic regression analysis separately in patients who required dialysis earlier than 5 years (Early Progressors) and those who required dialysis within 5 to 10 years (Late Progressors) after biopsy. Results: Independent pathological variables predicting progression to ESRD were global sclerosis, segmental sclerosis and fibrous crescents for Early Progressors, and global sclerosis and cellular/fibrocellular crescents for Late Progressors. Four histological grades, HG 1, HG 2, HG 3 and HG 4, were established corresponding to &lt
25%, 25-49%, 50-74% and ≥75% of glomeruli exhibiting cellular or fibrocellular crescents, global sclerosis, segmental sclerosis or fibrous crescents. Eleven (7%) patients in HG 1, 12 (16%) in HG 2, 13 (31%) in HG 3 and 13 (68%) in HG 4 progressed to ESRD. Multivariate logistic analysis revealed that the risk of progression to ESRD was significantly higher in HG 2, 3 and 4 than in HG 1 (odds ratio, 2.4, 5.7 and 27.6 vs. 1.0). Conclusions: Our evidence-based histologic classification can identify the magnitude of the risk of progression to ESRD and is useful for predicting longterm renal outcome in IgAN. © 2012 Società Italiana di Nefrologia.

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Second-line chemotherapy for refractory small cell neuroendocrine carcinoma of the esophagus that relapsed after complete remission with irinotecan plus cisplatin therapy: Case report and review of the literature

橋口明典

ONCOLOGY LETTERS （SPANDIDOS PUBL LTD） 5 （ 1 ） 117 - 122 2013年01月

研究論文（学術雑誌）, 共著, ISSN 1792-1074

Small cell esophageal carcinoma is a type of small cell neuroendocrine carcinoma (SCNEC). SCNEC follows an aggressive clinical course and has a poor prognosis despite multidisciplinary therapies. A standard therapeutic strategy, including surgery, radiation and first-/second-line chemotherapy, has not yet been established for SCNEC. We present a case of SCNEC of the esophagus. A 66-year-old male with SCNEC as extensive disease was treated with 60 mg/m(2) cisplatin on day 1 plus 60 mg/m(2) irinotecan on days 1,8 and 15 every 4 weeks (IP) with successful complete remission. After the sixth course of IP, increasing pro-gastrin-releasing peptide (ProGRP) and nonspecific enolase (NSE) levels and intense fluorodeoxyglucose (FDG) avidity in a lymph node around the celiac artery (SUVmax, 8.3) indicated a refractory relapse of the disease. The patient was treated with three courses of amrubicin (AMR, 35 mg/m(2)) administered intravenously for 3 consecutive days every 3 weeks as a second-line chemotherapy. The ProGRP and NSE levels returned to the normal range I month after the initiation of second-line chemotherapy. However, the ProGRP and NSE levels were elevated after the third course of AMR, and PET-CT revealed progressive disease with liver metastasis and extended lymph node metastasis. As the patient remained asymptomatic, paclitaxel (100 mg/m(2)) was started as third-line chemotherapy. Patients with SCNEC of the esophagus with extensive disease should be treated with aggressive chemotherapy rather than surgery or radiation monotherapy. In the present case, tumor markers such as ProGRP and NSE were predictive of relapse and PET-CT was used to detect relapse. Further research is required to identify and exploit promising agents for resistant SCNEC.

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Computational grading of hepatocellular carcinoma using multifractal feature description

橋口明典

COMPUTERIZED MEDICAL IMAGING AND GRAPHICS （PERGAMON-ELSEVIER SCIENCE LTD） 37 （ 1 ） 61 - 71 2013年01月

研究論文（学術雑誌）, 共著, ISSN 0895-6111

Cancer grading has become an important topic in the field of image interpretation-based computer aided diagnosis systems. This paper proposes a novel feature descriptor to observe the characteristics of histopathological textures in a discriminative manner. The proposed feature descriptor utilizes fractal geometric analysis with four multifractal measures to construct an eight dimensional feature space. The proposed method employed a bag-of-feature-based classification model to discriminate a set of hepatocellular carcinoma images into five categories according to Edmondson and Steiner's grading system. Three feature selection methods were utilized to obtain the most discriminative features of codeword dictionary (codebook). Furthermore, we incorporated four other textural feature descriptors: Gabor-filters, LM-filters, local binary patterns, and Haralick, to obtain a benchmark of the accuracy of the classification. Two experiments were performed: (i) classifying non-neoplastic tissues and tumors and (ii) grading the hepatocellular carcinoma images into five classes. Experimental results indicated the significance of the multifractal features for describing the histopathological image texture because it outperformed other four feature descriptors. We graded a given ROI image by defining a threshold-based majority-voting rule and obtained an average correct classification rate around 95% for five classes classification. (c) 2012 Elsevier Ltd. All rights reserved.

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What is the Most Effective Tool for Detecting Prostate Cancer using a Standard MR Scanner?

橋口明典

MAGNETIC RESONANCE IN MEDICAL SCIENCES （JPN SOC MAGNETIC RESONANCE IN MEDICINE） 12 （ 4 ） 271 - 280 2013年

研究論文（学術雑誌）, 共著, ISSN 1347-3182

Purpose: We aimed to determine which of the following magnetic resonance (MR) imaging sequences is most effective for detecting prostate cancer: T-2-weighted (T2W), dynamic contrast-enhanced (DCE) T-1-weighted (TOW), or diffusion-weighted (DWI) imaging or apparent diffusion coefficient (ADC) mapping.
Materials and Methods: We included 37 male patients with prostate cancer who underwent MR imaging before radical prostatectomy in this retrospective study. Sixty-four foci (>5 mm in size; 35 in the peripheral zone [PZ], 29 in the transitional zone [TZ]) were histopathologically determined to be prostate cancer. We determined the capacity of T2W, DCE-T1W, DWI, ADC mapping alone, and the combination of ADC mapping with DWI, and conventional MR sequences to detect prostate cancer, including their sensitivity and positive predictive value (PPV), with reference to the results obtained in histopathological examinations of whole-mount sections.
Results: In the PZ, sensitivities were 31.4% (T2W), 37.1% (DCE-T1W), 51.4% (DWI), and 71.4% (ADC mapping); PPVs were 78.6% (T2W), 92.9% (DCE-T1W), 94.7% (DWI), and 96.0% (ADC mapping). Sensitivity was significantly higher of ADC mapping than other sequences. In the TZ, sensitivities were 55.1% (T2W), 44.8% (DCE-T1W), 82.8% (DWI), and 89.7% (ADC mapping); PPVs were 64.0% (T2W), 46.4% (DCE-T1W), 70.6% (DWI), and 72.2% (ADC mapping). Sensitivity was significantly higher of ADC mapping and DWI than conventional MR imaging, but there was no significant correlation between DWI/ADC mapping and T2W/DCE-T1W with respect to PPVs. Combining sequences did not improve sensitivity; only the PPV in the TZ improved when ADC mapping was combined with DCE-T1W.
Conclusion: ADC mapping is the most effective standard MR imaging tool for detecting prostate cancer. The addition of DCE-T1W may improve the PPV of ADC mapping for diagnosing cancer in the TZ.

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[Proposal of remission criteria for IgA nephropathy].

Matsuo S, Kawamura T, Suzuki Y, Joh K, Tomino Y, Horikoshi S, Nishino T, Yoshikawa N, Hattori M, Kimura K, Yasuda T, Shirai S, Shibata T, Yoshimura M, Utsunomiya Y, Endoh M, Sakamoto N, Matsushima M, Miyazaki Y, Yasuda Y, Yokoo T, Kagami S, Hataya H, Suzuki H, Matsuzaki K, Uchida S, Ito T, Shimizu A, Katafuchi R, Hisano S, Hashiguchi A

Nihon Jinzo Gakkai shi 55 （ 7 ） 1249 - 1254 2013年

共著, 査読有り, ISSN 0385-2385

Computational Cell Classification Methodology for Hepatocellular Carcinoma

Chamidu Atupelage, Hiroshi Nagahashi, Fumikazu Kimura, Masahiro Yamaguchi, Tokiya Abe, Akinori Hashiguchi, Michiie Sakamoto

2013 INTERNATIONAL CONFERENCE ON ADVANCES IN ICT FOR EMERGING REGIONS (ICTER) （IEEE） 21 - 27 2013年

共著, 査読有り, ISSN 2377-6854

Liver cancer is one of the frequent causes of death in the world. Hepatocellular carcinoma (HCC) is the most common histological type of primary liver cancer. HCC can be graded according to the malignancy of the tumors. Generally, a HCC grade is determined based on the characteristics of liver cell nuclei. This paper illustrates a methodology for classifying liver cell nuclei and grading HCC histological images quantitatively. The liver cell nuclei are classified in three consecutive tasks: nuclear segmentation, fibrous region detection, and nuclear classification. Each task utilizes the pixel-based textural features that are obtained through multifractal computation on digital images. First, the system segments every possible type of nuclei and excludes the nuclei within fibrous regions. Then, it classifies the rest of the nuclei to discriminate liver cell nuclei. For tumor grading, this method utilizes the following four categories of nuclear features: inner texture, geometry, spatial distribution, and surrounding texture. The proposed method was employed to classify a set of HCC histological images into five.

Automatic classification of hepatocellular carcinoma images based on nuclear and structural features

Tomoharu Kiyuna, Akira Saito, Atsushi Marugame, Yoshiko Yamashita, Maki Ogura, Eric Cosatto, Tokiya Abe, Akinori Hashiguchi, Michiie Sakamoto

MEDICAL IMAGING 2013: DIGITAL PATHOLOGY （SPIE-INT SOC OPTICAL ENGINEERING） 8676 2013年

共著, 査読有り, ISSN 0277-786X

Diagnosis of hepatocellular carcinoma (HCC) on the basis of digital images is a challenging problem because, unlike gastrointestinal carcinoma, strong structural and morphological features are limited and sometimes absent from HCC images. In this study, we describe the classification of HCC images using statistical distributions of features obtained from image analysis of cell nuclei and hepatic trabeculae. Images of 130 hematoxylin-eosin (HE) stained histologic slides were captured at 20X by a slide scanner (Nanozoomer, Hamamatsu Photonics, Japan) and 1112 regions of interest (ROI) images were extracted for classification (551 negatives and 561 positives, including 113 well-differentiated positives). For a single nucleus, the following features were computed: area, perimeter, circularity, ellipticity, long and short axes of elliptic fit, contour complexity and gray level co-occurrence matrix (GLCM) texture features (angular second moment, contrast, homogeneity and entropy). In addition, distributions of nuclear density and hepatic trabecula thickness within an ROI were also extracted. To represent an ROI, statistical distributions (mean, standard deviation and percentiles) of these features were used. In total, 78 features were extracted for each ROI and a support vector machine (SVM) was trained to classify negative and positive ROIs. Experimental results using 5-fold cross validation show 90% sensitivity for an 87.8% specificity. The use of statistical distributions over a relatively large area makes the HCC classifier robust to occasional failures in the extraction of nuclear or hepatic trabecula features, thus providing stability to the system.

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A role of image processing technology for pathological image - A research project for quantitative pathology

Kobayashi, N., Sakamoto, M., Hashiguchi, A., Yamaguchi, M., Nagahashi, H., Saito, A.

Journal of the Institute of Image Electronics Engineers of Japan 42 （ 2 ） 2013年

共著, 査読有り

An algorithm to evaluate the number of trabecular cell layers using nucleus arrangement applied to hepatocellular carcinoma

Hideki Komagata, Naoki Kobayashi, Ayako Katoh, Yasuka Ohnuki, Masahiro Ishikawa, Kazuma Shinoda, Masahiro Yamaguchi, Tokiya Abe, Akinori Hashiguchi, Michiie Sakamoto

MEDICAL IMAGING 2013: DIGITAL PATHOLOGY （SPIE-INT SOC OPTICAL ENGINEERING） 8676 2013年

共著, 査読有り, ISSN 0277-786X

Recent advances in information technology have improved pathological virtual-slide technology and diagnostic support system studies of pathological images. Diagnostic support systems utilize quantitative indices determined by image processing. In previous studies on diagnostic support systems, carcinomatous areas of breast or lung have been recognized by the feature quantities of nuclear sizes, complexities, and internuclear distances based on graph theory, among other features. Improving recognition accuracy is important for the addition of new feature quantities. We focused on hepatocellular carcinoma (HCC) and investigated new feature quantities of histological images of HCC. One of the most important histological features of HCC is the trabecular pattern. For diagnosing cancer, it is important to recognize the tumor cell trabeculae. We propose a new algorithm for calculating the number of cell layers in histological images of HCC in tissue sections stained by hematoxylin and eosin. For the calculation, we used a Delaunay diagram that was based on the median points of nuclei, deleted the sinusoid and fat droplet regions from the Delaunay diagram, and counted the Delaunay lines while applying a thinning algorithm. Moreover, we experimented with the calculation of the number of cell layers with our method for different histological grades of HCC. The number of cell layers discriminated tumor differentiations and Edmondson grades; therefore, our algorithm may serve as an index of HCC for diagnostic support systems.

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Color correction for automatic fibrosis quantification in liver biopsy specimens.

Yuri Murakami, Tokiya Abe, Akinori Hashiguchi, Masahiro Yamaguchi, Akira Saito, Michiie Sakamoto

Journal of pathology informatics 4 36 - 36 2013年

共著

CONTEXT: For a precise and objective quantification of liver fibrosis, quantitative evaluations through image analysis have been utilized. However, manual operations are required in most cases for extracting fiber areas because of color variation included in digital pathology images. AIMS: The purpose of this research is to propose a color correction method for whole slide images (WSIs) of Elastica van Gieson (EVG) stained liver biopsy tissue specimens and to realize automated operation of image analysis for fibrosis quantification. MATERIALS AND METHODS: Our experimental dataset consisted of 38 WSIs of liver biopsy specimens collected from 38 chronic viral hepatitis patients from multiple medical facilities, stained with EVG and scanned at ×20 using a Nano Zoomer 2.0 HT (Hamamatsu Photonics K.K., Hamamatsu, Japan). Color correction was performed by modifying the color distribution of a target WSI so as to fit to the reference, where the color distribution was modeled by a set of two triangle pyramids. Using color corrected WSIs; fibrosis quantification was performed based on tissue classification analysis. STATISTICAL ANALYSIS USED: Spearman's rank correlation coefficients were calculated between liver stiffness measured by transient elastography and median area ratio of collagen fibers calculated based on tissue classification results. RESULTS: Statistical analysis results showed a significant correlation r = 0.61-0.68 even when tissue classifiers were trained by using a subset of WSIs, while the correlation coefficients were reduced to r = 0.40-0.50 without color correction. CONCLUSIONS: Fibrosis quantification accompanied with the proposed color correction method could provide an objective evaluation tool for liver fibrosis, which complements semi-quantitative histologic evaluation systems.

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Automatic segmentation of hepatocellular structure from HE-stained liver tissue

Masahiro Ishikawa, Sercan Taha Ahi, Yuri Murakami, Fumikazu Kimura, Masahiro Yamaguchi, Tokiya Abe, Akinori Hashiguchi, Michiie Sakamoto

MEDICAL IMAGING 2013: DIGITAL PATHOLOGY （SPIE-INT SOC OPTICAL ENGINEERING） 8676 2013年

共著, 査読有り, ISSN 0277-786X

The analysis of hepatic tissue structure is required for quantitative assessment of liver histology. Especially, a cord-like structure of liver cells, called trabecura, has important information in the diagnosis of hepatocellular carcinoma (HCC). However, the extraction of trabeculae is thought to be difficult because liver cells take on various colors and appearances depending on tissue conditions. In this paper, we propose an approach to extract trabeculae from images of hematoxyline and eosin stained liver tissue slide by extracting the rest of trabeculae: sinusoids and stromal area. The sinusoids are simply extracted based on the color information, where the image is corrected by an orientation selective filtering before segmentaion. The stromal area mainly consists of fiber, and often includes lymphocytes densely. Therefore, in the proposed method, fiber region and lymphocytes are extracted separately, then, stromal region is determined based on the extracted results. The determination of stroma is performed based on superpixels, to obtain precise boundaries. Once the regions of sinusoids and stroma are obtained, trabeculae can be segmented as the remaining region. The proposed method was applied to 10 test images of normal and HCC liver tissues, and the results were evaluated based on the manual segmentation. As a result, we confirmed that both sensitivity and specificity of the extraction of trabeculae reach around 90%.

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Classification of Prostate Histopathology Images Based on Multifractal Analysis

橋口明典

IEICE TRANSACTIONS ON INFORMATION AND SYSTEMS （IEICE-INST ELECTRONICS INFORMATION COMMUNICATIONS ENG） E95D （ 12 ） 3037 - 3045 2012年12月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0916-8532

Histopathology is a microscopic anatomical study of body tissues and widely used as a cancer diagnosing method. Generally, pathologists examine the structural deviation of cellular and sub-cellular components to diagnose the malignancy of body tissues. These judgments may often subjective to pathologists' skills and personal experiences. However, computational diagnosis tools may circumvent these limitations and improve the reliability of the diagnosis decisions. This paper proposes a prostate image classification method by extracting textural behavior using multifractal analysis. Fractal geometry is used to describe the complexity of self-similar structures as a non-integer exponent called fractal dimension. Natural complex structures (or images) are not self-similar, thus a single exponent (the fractal dimension) may not be adequate to describe the complexity of such structures. Multifractal analysis technique has been introduced to describe the complexity as a spectrum of fractal dimensions. Based on multifractal computation of digital imaging, we obtain two textural feature descriptors; i) local irregularity: alpha and ii) global regularity: f(alpha). We exploit these multifractal feature descriptors with a texton dictionary based classification model to discriminate cancer/non-cancer tissues of histopathology images of H&E stained prostate biopsy specimens. Moreover, we examine other three feature descriptors; Gabor filter bank, LM filter bank and Haralick features to benchmark the performance of the proposed method. Experiment results indicated that the performance of the proposed multifractal feature descriptor outperforms the other feature descriptors by achieving over 94% of correct classification accuracy.

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微小変化型ネフローゼ症候群を認めた多発性骨髄腫の1例

吉藤歩, 篠村裕之, 脇野修, 徳山博文, 橋口明典, 鷲田直輝, 林晃一, 伊藤裕

日本腎臓学会誌（(一社)日本腎臓学会） 54 （ 6 ） 732 - 732 2012年08月

共著, ISSN 0385-2385

肉芽腫形成を伴う薬剤性急性間質性腎炎の2症例

二木功治, 徳山博文, 脇野修, 小西孝之助, 橋口明典, 林晃一, 林松彦, 伊藤裕

日本腎臓学会誌（(一社)日本腎臓学会） 54 （ 6 ） 714 - 714 2012年08月

共著, ISSN 0385-2385

抗GBM抗体陽性腎炎にヘノッホ・シェーライン紫斑病(HSP)を合併した一例

小口英世, 徳山博文, 脇野修, 小西孝之助, 橋口明典, 林晃一, 伊藤裕

日本腎臓学会誌（(一社)日本腎臓学会） 54 （ 6 ） 736 - 736 2012年08月

共著, ISSN 0385-2385

全国調査に基づくカルシフィラキシス診断基準の提案

林, 松彦, 高松, 一郎, 吉田, 理, 菅野, 義彦, 佐藤, 裕史, 阿部, 貴之, 橋口, 明典, 細谷, 龍男, 秋葉, 隆, 中元, 秀友, 梅澤, 明弘, 重松, 隆, 深川, 雅史, 川村, 哲也, 田中, 勝, 杉野, 吉則 and 「Calciphylaxisの診断・治療に関する調査・研究」班

日本透析医学会雑誌（The Japanese Society for Dialysis Therapy） 45 （ 7 ） 551 - 557 2012年07月

共著, ISSN 1340-3451

カルシフィラキシスは、末期腎不全により透析療法を受けている患者を中心に発症する、非常に疼痛の強い難治性皮膚潰瘍を主症状とする、時に致死的な疾患である。病理学的所見としては、小動脈の中膜石灰化、内膜の浮腫状増殖を特徴的所見としている。これまで本邦における発症状況などは不明であったが、平成21年度厚生労働省難治性疾患克服事業として、われわれ研究班により初めて全国調査がなされた。その結果、発症率は欧米に比べて極めて低いと推定され、その要因の一つとして、疾患に対する認知度が極めて低いことが考えられた。そこで、疾患概念を明らかとして、その認知度を高めるとともに、診断を容易にするために、全国調査を基として診断基準の作成を行った。この診断基準は、今後の症例の集積に基づく見直しが必要と考えられるが、カルシフィラキシスに対する認知度を高める上では重要な試みと考えている。(著者抄録)

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Insulinoma may mask the existence of Type1 diabetes

Y. Oikawa, T. Katsuki, M. Kawasaki, A. Hashiguchi, K. Mukai, K. Handa, M. Tomita, Y. Kabeya, Y. Asai, K. Iwase, S. Hirose, K. Koyama, Y. Atsumi, A. Shimada

Diabetic Medicine 29 （ 7 ） e138 - e141 2012年07月

共著, 査読有り, ISSN 0742-3071

Background Insulinoma is a tumour of insulin-producing cells of the pancreas and is known to be one of the causes of hypoglycaemia. Usually, appropriate removal of the insulinoma results in normalization of blood glucose levels. However, we found novel cases of insulinoma, in which hyperglycaemia developed soon after resection of the insulinoma. Case report We encountered two patients with repeated hypoglycaemia caused by insulinoma. Following removal of the insulinoma, unanticipated hyperglycaemia was observed in both patients. Thereafter, their blood tests revealed low levels of serum C-peptide and high titres of anti-glutamic acid decarboxylase antibody, indicating concomitant Type1 diabetes. Indeed, histological examination of the resected specimen revealed that one patient showed insulitis in non-tumorous pancreatic tissue in which β-cells had already disappeared. Moreover, inflammatory cells infiltrated the insulinoma, as if it were insulitis of Type1 diabetes, suggesting the existence of anti-islet autoimmunity. Conclusion These are first cases of insulinoma associated with underlying Type1 diabetes. Physicians should be aware of the possibility that insulinoma may mask Type1 diabetes, and measurement of anti-islet autoantibodies may be helpful to find underlying Type1 diabetes, such as in these cases. It is pathologically interesting that the immune cell infiltration into insulinoma may be suggestive of anti-islet autoimmunity. © 2012 The Authors. Diabetic Medicine © 2012 Diabetes UK.

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MPO-ANCA associated crescentic glomerulonephritis with numerous immune complexes: case report

Morizane, R, Konishi, K, Hashiguchi, A, Tokuyama, H, Wakino, S, Kawabe, H, Hayashi, M, Hayashi, K, Itoh, H

BMC Nephrol （Springer Science and Business Media LLC） 13 （ 1 ） 32 2012年06月

共著, ISSN 1471-2369

BACKGROUND: Antineutrophil cytoplasmic antibody (ANCA)-associated crescentic glomerulonephritis (CGN) is a major cause of rapidly progressive glomerulonephritis (RPGN). ANCA-associated CGN is generally classified into pauci-immune RPGN, in which there are few or no immune complexes. CASE PRESENTATION: A 78-year-old man presented with RPGN after a 7-year course of chronic proteinuria and hematuria with stable renal function. A blood examination showed a high titer of myeloperoxidase (MPO)-ANCA. A renal biopsy showed crescentic glomerulonephritis with abundant subepithelial, intramenbranous and subendothelial deposits by electron microscopy, leading to the diagnosis of ANCA-associated CGN superimposed on type 3 membranoproliferative glomerulonephritis (MPGN). CONCLUSIONS: This case is unique in that type 3 MPGN and MPO-ANCA-associated CGN coexisted, and no similar case has been reported to date. Because ANCA-associated CGN has a predilection for elderly individuals and primary type 3 MPGN is rarely seen in this age group, coincidental existence appears less likely. This case may confer valuable information regarding the link between immune complex and ANCA-associated CGN.

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当院における切除断端陽性前立腺癌に関する予後因子の検討

矢澤聰, 水野隆一, 中島淳, 長田浩彦, 向井万起男, 橋口明典, 篠田和伸, 香野日高, 菊地栄次, 浅沼宏, 宮嶋哲, 中川健, 大家基嗣

泌尿器外科（医学図書出版(株)） 25 （臨増） 1085 - 1085 2012年05月

共著, ISSN 0914-6180

Disease of the year IgA腎症班会議分類とOxford分類の対比とこれからの課題

橋口明典, 城謙輔

日本腎臓学会誌（(一社)日本腎臓学会） 54 （ 3 ） 193 - 193 2012年04月

共著, ISSN 0385-2385

微小変化群のネフローゼ症候群に合併した急性腎障害に血漿交換療法を併用した2例

小口, 英世, 村上, 円人, 荒木, 崇志, 目黒, 真理子, 橋口, 明典, 佐藤, 崇, 神戸, 香織 and 重原, 理宏

日本透析医学会雑誌（The Japanese Society for Dialysis Therapy） 45 （ 2 ） 179 - 185 2012年02月

共著, ISSN 1340-3451

微小変化群のネフローゼ症候群に合併した急性腎障害に対して血漿交換が著効した2例を経験したので報告する。症例1は39歳男性、症例2は33歳女性である。2例とも、メチルプレドニゾロンのパルス療法を行ったが、急性腎障害となり血液濾過透析が必要になった。血清アルブミン濃度は、症例1が1.8mg/dL、症例2が1.6mg/dLといずれも低値であった。アルブミンの静脈内投与は急性腎障害に対していずれも無効であった。3回の血液濾過透析を施行したが、急性腎障害が改善しないため5%アルブミン溶液による血漿交換を行った。血漿交換の終了時期には尿量は著増し、その後急速に腎機能は改善し、その後の血液濾過透析は不要となった。腎生検所見は微小変化群の所見であり、著明な足突起の癒合を伴っており、急性尿細管壊死の所見は認めなかった。蛋白尿は血漿交換後に症例1では3日後から、症例2では翌日から減少し始めた。血漿交換の急性腎障害に対する有効性は単に重症の低アルブミン血症の補正のみでは説明は困難であると考えられた。血液中に存在する何らかの病因物質の除去とステロイドパルス療法との相乗効果が関与していた可能性が示唆された。(著者抄録)

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【IgA腎症-明らかになったことと今後の問題点】オックスフォード分類とIgA腎症診療指針　第3版における予後分類の比較、使い分け

橋口, 明典

腎と透析 72 （ 1 ） 81 - 84 2012年01月

共著, ISSN 0385-2156

Multifractal feature descriptor for histopathology

Atupelage, C., Nagahashi, H., Yamaguchi, M., Sakamoto, M., Hashiguchi, A.

Analytical Cellular Pathology 35 （ 2 ） 2012年

共著, 査読有り

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【炎症とがん-最新の知見-】肝炎と肝細胞がん

橋口, 明典 and 坂元, 亨宇

侵襲と免疫 20 （ 4 ） 157 - 163 2011年12月

共著, ISSN 0917-7175

Renal amyloidosis caused by apolipoprotein A-II without a genetic mutation in the coding sequence

橋口明典

CLINICAL AND EXPERIMENTAL NEPHROLOGY （SPRINGER） 15 （ 5 ） 774 - 779 2011年10月

研究論文（学術雑誌）, 共著, ISSN 1342-1751

Although the majority of renal amyloidosis is caused by either acquired monoclonal immunoglobulin light-chain amyloidosis or reactive systemic amyloid A, some cases are caused by hereditary amyloidosis. Apolipoprotein A-II (apoAII) amyloidosis is a rare form of hereditary amyloidosis and cannot be diagnosed by a routine examination. Thus, the prevalence and etiology of apoAII amyloidosis are uncertain. In humans, a genetic mutation in the stop codon of apoAII is considered to be a cause of amyloid fibril formation. We report on a 68-year-old man who presented with proteinuria by apoAII amyloidosis without family history. His proteinuria gradually increased to 6 g/day within 1 year. A renal biopsy showed amyloid deposition in the glomeruli, however, acquired monoclonal immunoglobulin light-chain amyloidosis and reactive systemic amyloid A were ruled out. Immunohistochemistry revealed apoAII deposition in the glomeruli, but DNA sequencing did not identify any genetic mutation in the coding sequence of apoAII. Here, we report a case of apoAII amyloidosis without a genetic mutation in the coding sequence and discuss the etiology of apoAII amyloidosis.

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病理組織標本のデジタルスライド画像における定量的特徴量の算出

福井, 智也, 山口, 雅浩, 村上, 百合, 木村, 文一, 橋口, 明典, 坂本, 亨宇 and 大山, 永昭

MEDICAL IMAGING TECHNOLOGY 29 （ Suppl. ） 1 - 4 2011年08月

共著, ISSN 0288-450X

HE染色された肝病理組織標本を対象として、バーチャルスライドスキャナーにより20倍で全スライドの画像入力を行い、その領域ごとの特徴量の可視化を試みた。今回、特徴量として細胞核の密度と分散及びリンパ球の密度を対象とし、ヘマトキシリン及びエオジン色素の色を考慮した前処理とテンプレートマッチングを用いて核及びリンパ球の抽出を行った。抽出された核やリンパ球の位置を基にして密度や分散などの値を領域ごとの特徴量として算出した。標本全体の画像に対して特徴量の画像化を行った結果、核の密度でがん領域の特徴が明瞭に可視化された。(著者抄録)

PDGF受容体阻害薬Sunitinibによる急性腎障害が疑われた2型糖尿病患者の一例

唐澤隆明, 脇野修, 徳山博文, 橋口明典, 小西孝之助, 林晃一, 大家基嗣, 伊藤裕

日本腎臓学会誌（(一社)日本腎臓学会） 53 （ 6 ） 955 - 955 2011年08月

共著, ISSN 0385-2385

理学的所見に乏しく腎生検にて診断されたALアミロイドーシスの一例

小松素明, 徳山博文, 脇野修, 橋口明典, 小西孝之助, 林晃一, 伊藤裕

日本腎臓学会誌（(一社)日本腎臓学会） 53 （ 6 ） 947 - 947 2011年08月

共著, ISSN 0385-2385

IgA腎症診療指針(第3版)補追　IgA腎症組織アトラス

松尾, 清一, 川村, 哲也, 城, 謙輔, 片渕, 律子, 久野, 敏, 清水, 章, 橋口, 明典 and 進行性腎障害に関する調査研究班

日本腎臓学会誌（(一社)日本腎臓学会） 53 （ 5 ） 655 - 666 2011年07月

共著, ISSN 0385-2385

稀な経過を辿ったependymal cystの一例

北村洋平, 佐々木光, 橋口明典, 百島祐貴, 吉田一成

Brain Tumor Pathology （日本脳腫瘍病理学会） 28 （ Suppl. ） 111 - 111 2011年05月

共著, ISSN 1433-7398

IgA腎症診療指針(第3版)

松尾, 清一, 川村, 哲也, 安田, 隆, 城, 謙輔, 白井, 小百合, 宇都宮, 保典, 遠藤, 正之, 小此木, 英男, 柴田, 孝則, 宮崎, 陽一, 服部, 元史, 小池, 健太郎, 秋岡, 祐子, 横尾, 隆, 平野, 景太, 松島, 雅人, 片渕, 律子, 吉村, 光弘, 久野, 敏, 小倉, 誠, 清水, 章, 堀越, 哲, 橋口, 明典, 鈴木, 祐介, 吉川, 徳茂, 古巣, 朗, 富野, 康日己, 木村, 健二郎 and 厚生労働科学研究費補助金難治性疾患克服研究事業進行性腎障害に関する調査研究班報告IgA腎症分科会

日本腎臓学会誌（(一社)日本腎臓学会） 53 （ 2 ） 123 - 135 2011年03月

共著, ISSN 0385-2385

根治的前立腺摘除術後のPSA再発と関連する腫瘍サイズマーカーの検討

水野隆一, 中島淳, 向井万起男, 橋口明典, 篠田和伸, 香野日高, 菊地栄次, 長田浩彦, 浅沼宏, 宮嶋哲, 中川健, 大家基嗣

日本泌尿器科学会雑誌（(一社)日本泌尿器科学会） 102 （ 2 ） 418 - 418 2011年03月

共著, ISSN 0021-5287

A Case of Membranous Nephropathy with Primary Biliary Cirrhosis and Cyclosporine-induced Remission

橋口明典

INTERNAL MEDICINE （JAPAN SOC INTERNAL MEDICINE） 50 （ 3 ） 233 - 238 2011年

研究論文（学術雑誌）, 共著, ISSN 0918-2918

We report a case of membranous nephropathy with primary biliary cirrhosis (PBC). A 76-year-old Japanese man had been treated for PBC and was referred to our department because of acute severe proteinuria (10 g/day). Renal biopsy was performed and was compatible with a diagnosis of membranous nephropathy. The patient was treated with cyclosporine A (CsA; Neoral (R)), which was followed by normalization of liver function and partial remission of proteinuria (0.68 g/day) within six months without any significant side effects. This case suggests that CsA monotherapy is effective for the treatment of both liver dysfunction and membranous nephropathy associated with PBC.

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Contrast-enhanced Ultrasonography of the Prostate with Sonazoid

橋口明典

JAPANESE JOURNAL OF CLINICAL ONCOLOGY （OXFORD UNIV PRESS） 40 （ 11 ） 1099 - 1104 2010年11月

研究論文（学術雑誌）, 共著, ISSN 0368-2811

The diagnosis of prostate cancer is based on the results of ultrasonography-guided needle biopsy of the prostate, but cancer foci are often not visible in conventional transrectal ultrasonography. Sonazoid is a new microbubble contrast agent. The purpose of our study was to compare areas of contrast material enhancement in the prostate at ultrasonography with whole-mount radical prostatectomy specimens to determine if the use of Sonazoid improves the detection rate of prostate cancer.
Fifty patients with biopsy-proven cancer of the prostate who were scheduled to undergo radical prostatectomy were recruited for this study. The day before the operation, each patient was evaluated with ultrasonography at baseline and again during intravenous infusion of Sonazoid. A map of ultrasonography findings was created prospectively at the time of imaging. Following radical prostatectomy, independent mapping of the pathologic results was performed and the maps were compared.
Ultrasonography evaluation at baseline demonstrated that at least one focus of cancer was identified in 20 of the 50 subjects (40.0%). Meanwhile at least one cancer focus was enhanced in 31 of the 50 patients (62.0%) when Sonazoid was used. The combination of baseline grayscale imaging and contrast-enhanced imaging allowed identification of at least one focus of cancer in 40 patients (80.0%). Contrast-enhanced ultrasonography can improve sensitivity, especially for the detection of large cancer, peripheral zone cancer and highly malignant cancer.
Our study has demonstrated significantly improved detection of prostate cancer with the combination of baseline grayscale imaging and contrast-enhanced imaging compared with conventional ultrasonography techniques only, and this technique may be applicable to targeted biopsy.

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Acute interstitial nephritis associated with ulcerative colitis

Tokuyama, H, Wakino, S, Konishi, K, Hashiguchi, A, Hayashi, K, Itoh, H

Clin Exp Nephrol 14 （ 5 ） 483 - 6 2010年10月

共著, ISSN 1342-1751

Although drugs used in inflammatory bowel diseases (IBD) cause renal injury, glomerulopathies may also accompany IBD. We report a case with the rare association of ulcerative colitis (UC) and acute progressive interstitial nephritis. Although the kidney is acknowledged as a target organ for injury as a result of drug nephrotoxicity, our findings lend support to the novel recognition that the deranged autoimmune system emerging in UC causes interstitial nephritis as an extraintestinal manifestation. Overt renal failure due to interstitial nephritis has rarely been reported in UC patients. The case presented here therefore provides novel information on UC-associated nephropathy.

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血液透析患者に発症した小脳・脳幹型進行性多巣性白質脳症の1例

武田, 彩乃, 真杉, 洋平, 門川, 俊明, 石黒, 喜美子, 武光, 智子, 原, 義和, 伊東, 大介, 橋口, 明典, 小西, 孝之助, 林, 松彦 and 伊藤, 裕

日本透析医学会雑誌（The Japanese Society for Dialysis Therapy） 43 （ 9 ） 807 - 813 2010年09月

共著, ISSN 1340-3451

症例は55歳、女性。骨髄増殖性疾患に対する治療経過中に腎不全に至り、54歳時に血液透析導入となった。透析導入10ヵ月時に小脳失調症状が出現し、当院に入院となり、頭部MRIにて小脳にT2強調画像で異常信号を認めた。病変部位は小脳のみであり非特異的であったが、脳脊髄液検査にてJCウイルスPCR陽性であったことから、進行性多巣性白質脳症が第一に疑われた。病巣が急速に拡大するにつれて症状は進行し、不随意運動・構音障害・嚥下障害が出現、誤嚥性肺炎を繰り返すようになり、発症後10ヵ月(透析導入後20ヵ月)に死亡された。剖検にて小脳・脳幹部に脱髄を認め、同部位にJCウイルスの存在を確認し、小脳型進行性多巣性白質脳症の確定診断に至った。また本症例の透析導入前の腎生検を再度検討したところ萎縮・変性した尿細管上皮細胞内に一致して免疫組織化学ならびに電子顕微鏡的に多量のJCウイルス蛋白が確認された。一般に進行性多巣性白質脳症の中で小脳・脳幹を侵す病型は稀であるが、本邦の透析患者における進行性多巣性白質脳症では、小脳型の報告が散見されており、透析患者では小脳型が稀でない可能性がある。また、本症例において透析導入に至った腎不全の原因として、JCウイルス腎症が関与した可能性が高いことが示唆された。JCウイルス感染の腎障害における病的意義については不明な点が多く、今後、症例の蓄積による病態の解明が必要である。(著者抄録)

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蛍光定量デジタルスライド技術

橋口, 明典 and 坂元, 亨宇

病理と臨床 28 （ 8 ） 878 - 881 2010年08月

共著, ISSN 0287-3745

Apolipoprotein AII変異による腎アミロイドーシスが疑われた一例

森實隆司, 門川俊明, 徳山博文, 橋口明典, 小西孝之助, 林晃一, 林松彦, 伊藤裕

日本腎臓学会誌（(一社)日本腎臓学会） 52 （ 6 ） 674 - 674 2010年08月

共著, ISSN 0385-2385

膜性増殖性糸球体性腎炎(MPGN)type1にて生体腎移植後に再発した一例

小松素明, 徳山博文, 脇野修, 橋口明典, 小西孝之助, 林晃一, 伊藤裕

日本腎臓学会誌（(一社)日本腎臓学会） 52 （ 6 ） 706 - 706 2010年08月

共著, ISSN 0385-2385

発症に肝切除の影響が疑われたIgA腎症の一例

水口斉, 脇野修, 徳山博文, 小西孝之助, 林晃一, 伊藤裕, 橋口明典

日本腎臓学会誌（(一社)日本腎臓学会） 52 （ 6 ） 677 - 677 2010年08月

共著, ISSN 0385-2385

完全寛解後3ヵ月の経過で急性腎障害を呈し維持透析導入となった微小変化型ネフローゼ症候群の1例

山口慎太郎, 徳山博文, 脇野修, 橋口明典, 小西孝之助, 林松彦, 林晃一, 伊藤裕

日本腎臓学会誌（(一社)日本腎臓学会） 52 （ 6 ） 673 - 673 2010年08月

共著, ISSN 0385-2385

妊娠初期に著明なネフローゼ症候群を呈した症例

丸山達也, 二木功治, 谷口友里, 市原淳弘, 林松彦, 徳山博文, 脇野修, 末岡浩, 峰岸一宏, 橋口明典, 林晃一, 伊藤裕

日本腎臓学会誌（(一社)日本腎臓学会） 52 （ 6 ） 673 - 673 2010年08月

共著, ISSN 0385-2385

B型肝炎ウイルスキャリアーに発症した膜性増殖性糸球体腎炎

坂東和香, 脇野修, 徳山博文, 齋藤英胤, 橋口明典, 小西孝之助, 林晃一, 伊藤裕

日本腎臓学会誌（(一社)日本腎臓学会） 52 （ 6 ） 677 - 677 2010年08月

共著, ISSN 0385-2385

肺血栓塞栓症　慢性化のプロセスへの挑戦慢性血栓塞栓性肺高血圧症(CTEPH)症例における肺動脈血栓と大腿静脈血栓の類似性　心内血栓例と剖検例からの考察

渡辺, 慎太郎, 小室, 哲也, 西村, 芳興, 山口, 佳寿博, 橋口, 明典 and 坂田, 洋一

心臓（Japan Heart Foundation） 42 （ 7 ） 1006 - 1007 2010年07月

共著, ISSN 0586-4488

症例1:77歳男。慢性閉塞性肺疾患(COPD)とされていたが、呼吸機能正常などより慢性血栓塞栓性肺高血圧症(CTEPH)と診断した。下肢静脈には高輝度びまん性血栓のみ認め、下大静脈フィルター(IVCF)は使用しなかった。しかし、その後酸素必要量が上昇して入院し、心エコーで右室内に小血栓像を認めた。永久型IVCFを留置し血栓溶解療法を施行したが、肺炎を併発して死亡した。症例2:84歳男。COPDとされていたが、呼吸困難、低酸素血症で入院し、右室負荷を認めてCTEPHと診断した。下肢静脈エコーで高輝度びまん性血栓を認め、入院2日目に死亡した。剖検所見で、左大腿静脈壁内膜の線維性肥厚を認め、器質化陳旧性血栓の所見がみられた。肺動脈内にも内膜の肥厚を認め、下肢静脈の器質化血栓と類似していた。肥厚が強い狭窄部には、剥離と新鮮血栓が形成されている箇所も認めた。

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腎生検所見から何を学ぶか(No.41)　急速進行性糸球体腎炎を呈した紫斑病性腎炎と思われる1例

林, 香, 橋本, 寿之, 篠村, 裕之, 林, 松彦, 小西, 孝之助, 伊藤, 裕, 橋口, 明典 and 長田, 道夫

腎と透析 68 （ 5 ） 923 - 930 2010年05月

共著, ISSN 0385-2156

橋口, 明典

医学のあゆみ 232 （ 11 ） 1121 - 1126 2010年03月

共著, ISSN 0039-2359

IgA腎症は幅広い臨床像を有し、これらの予後を予測するために、数々の組織学的分類が提唱されてきた。2008年、厚生労働省進行性腎障害研究班IgA腎症分科会があらたな病理組織分類を提案する一方、2009年、国際IgA腎症ネットワーク(International IgA Nephropathy Network)およびRenal Pathology Societyのワーキンググループより、いわゆるオックスフォード分類が発表されるに至り、その相違がわが国において混乱を招く危険性を帯びてきた。本稿ではそれぞれの分類の特徴を述べ、両者を比較検討することにより、双方の組織分類の問題点について考察する。(著者抄録)

根治術が施行された前立腺癌における生検本数と病理組織学的所見の比較検討

古内徹, 水野隆一, 中島淳, 向井万起男, 橋口明典, 香野日高, 菊地栄次, 長田浩彦, 宮嶋哲, 中川健, 大家基嗣

日本泌尿器科学会雑誌（(一社)日本泌尿器科学会） 101 （ 2 ） 438 - 438 2010年02月

共著, ISSN 0021-5287

PSA腫瘍密度による限局性前立腺癌の病理学的病期の予測

水野隆一, 中島淳, 向井万起男, 橋口明典, 香野日高, 菊地栄次, 長田浩彦, 浅沼宏, 宮嶋哲, 中川健, 大家基嗣

日本泌尿器科学会雑誌（(一社)日本泌尿器科学会） 101 （ 2 ） 192 - 192 2010年02月

共著, ISSN 0021-5287

A Case of IgA-related Enteropathy Complicated with Gastrointestinal Bleeding and Progressive IgA Nephropathy: A Possible Variant Henoch-Schonlein Purpura?

橋口明典

INTERNAL MEDICINE 49 （ 16 ） 1755 - 1761 2010年

研究論文（学術雑誌）, ISSN 0918-2918

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A Case of IgA-related Enteropathy Complicated with Gastrointestinal Bleeding and Progressive IgA Nephropathy: A Possible Variant Henoch-Schonlein Purpura?

橋口明典

INTERNAL MEDICINE 49 （ 16 ） 1755 - 1761 2010年

研究論文（学術雑誌）, ISSN 0918-2918

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Are predictive models for cancer volume clinically useful in localized prostate cancer?

橋口明典

INTERNATIONAL JOURNAL OF UROLOGY （WILEY-BLACKWELL PUBLISHING, INC） 16 （ 12 ） 936 - 940 2009年12月

研究論文（学術雑誌）, 共著, ISSN 0919-8172

Objectives:
To evaluate the correlation between preoperatively predicted and pathologically measured prostate cancer volumes and to investigate the clinical use of preoperatively predicted cancer volume in predicting pathological stage.
Methods:
Correlations between pathological findings and various preoperative parameters, including the cancer volumes as predicted by using two methods (Vca and estimated PCvol), were analyzed in 196 patients who underwent radical prostatectomy for clinically localized prostate cancer.
Results:
Pathologically measured prostate cancer volume was significantly correlated with the Vca and estimated PCvol, but the correlation coefficients were respectively only 0.46 and 0.35. Prostate-specific antigen (PSA), PSA density (PSAD), primary Gleason score, Vca, Vca fraction (Vcafx), and estimated PCvol were significantly higher in 82 patients with extraprostatic cancer than in 114 patients with organ-confined cancer. Magnetic resonance imaging (MRI) findings were significantly correlated with pathological stage. Multivariate logistic regression analysis indicated that the Vcafx and MRI findings were significant predictors of extraprostatic cancer, but receiver operating characteristic analysis revealed that the combination of Vcafx and MRI findings had no advantage over the combination of Gleason score, PSAD, and MRI findings.
Conclusions:
Vca and estimated PCvol are significantly correlated with the pathologically measured cancer volume but their ability to accurately predict cancer volume is limited. Vcafx and MRI findings were statistically significant predictors of extraprostatic cancer but their combination was not superior to the combination of Gleason score, PSAD, and MRI findings.

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Construction of human monoclonal single-chain Fv antibodies against small-cell lung cancer by phage display libraries derived from cell-immunized SCID mice engrafted with human peripheral blood lymphocytes

橋口明典

PROTEOMICS CLINICAL APPLICATIONS （WILEY-V C H VERLAG GMBH） 3 （ 11 ） 1265 - 1272 2009年11月

研究論文（学術雑誌）, 共著, ISSN 1862-8346

In this study, we describe a phage display strategy to obtain human monoclonal single-chain Fv (scFv) antibodies binding target cancer cell surface proteins. By developing a cancer cell immunization protocol for SCID mice engrafted with human peripheral blood lymphocytes in combination with an antibody phage display method, we have isolated phage antibodies binding small-cell lung cancer cell line H889 by subtractive selection. One of the isolated scFv antibodies, 12EAb, recognized the E2 component of pyruvate dehydrogenase complex (PDC-E2) by immunoprecipitation according to MALDI-TOF MS analysis. Furthermore, we have confirmed the plasma membrane localization of PDC-E2 in small-cell lung cancer cells by immunocytochemistry and cell surface protein biotinylation, although PDC-E2 is usually located in the mitochondrial matrix. These results, including unique localization of identified antigens, were obtained by proteomic approaches. The present methods can be applied to generate human monoclonal scFv antibodies against tumor cells and to identify new molecular targets for immunotherapy and markers for diagnosis.

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第2世代超音波造影剤(ソナゾイド)の前立腺癌描出に関する有用性の検討

松本, 一宏, 中川, 健, 橋口, 明典, 香野, 日高, 菊地, 栄次, 宮嶋, 哲, 中島, 淳 and 大家, 基嗣

泌尿器外科（医学図書出版(株)） 22 （ 8 ） 1061 - 1062 2009年08月

共著, ISSN 0914-6180

第2世代超音波造影剤(ソナゾイド)の前立腺癌描出に関する有用性につきProspectiveに検討を行った。前立腺全摘術を予定された患者を対象とし、術前に検査を実施し腫瘍局在を同定した。前立腺摘出検体の病理組織結果と比較したところ、高率に癌病巣を描出できていた。Gleason's score高値や被膜浸潤陽性症例においては、正診率はさらに上昇した。前立腺生検時に応用することにより、偽陰性となっていた患者の早期発見に繋がる可能性が示唆された。(著者抄録)

病理最前線　腎臓-腎硬化症の語りかけるもの

橋口, 明典

医と食 1 （ 3 ） 2 - 3 2009年08月

共著, ISSN 1883-6658

CKDの発症からシェーグレン症候群と診断に至った一例

侯金成, 徳山博文, 脇野修, 橋口明典, 小西孝之助, 林晃一, 伊藤裕

日本腎臓学会誌（(一社)日本腎臓学会） 51 （ 6 ） 672 - 672 2009年08月

共著, ISSN 0385-2385

肝硬変および糖尿病の影響が疑われた結節性糸球体硬化症の一例

水口斉, 脇野修, 立松覚, 徳山博文, 小西孝之助, 林晃一, 伊藤裕, 橋口明典

日本腎臓学会誌（(一社)日本腎臓学会） 51 （ 6 ） 664 - 664 2009年08月

共著, ISSN 0385-2385

クローン病に腎および腸管アミロイドーシスを合併した一例

籠尾壽哉, 徳山博文, 脇野修, 橋口明典, 小西孝之助, 林松彦, 林晃一, 伊藤裕

日本腎臓学会誌（(一社)日本腎臓学会） 51 （ 6 ） 650 - 650 2009年08月

共著, ISSN 0385-2385

治療抵抗性を示し15年間低補体血症が持続した後自然軽快した1型MPGNの1症例

上原朋子, 遠海重裕, 五月女友美子, 松山健, 本田雅敬, 粟津緑, 橋口明典

日本小児腎臓病学会雑誌（(一社)日本小児腎臓病学会） 22 （ 1Suppl. ） 123 - 123 2009年06月

共著, 査読有り, ISSN 0915-2245

Synuclein-gamma Is Closely Involved in Perineural Invasion and Distant Metastasis in Mouse Models and Is a Novel Prognostic Factor in Pancreatic Cancer

橋口明典

CLINICAL CANCER RESEARCH （AMER ASSOC CANCER RESEARCH） 15 （ 8 ） 2864 - 2871 2009年04月

研究論文（学術雑誌）, 共著, ISSN 1078-0432

Purpose: Perineural invasion is associated with the high incidence of local recurrence and a dismal prognosis in pancreatic cancer. We previously reported a novel perineural invasion model and distinguished high- and low-perineural invasion groups in pancreatic cancer cell lines. This study aimed to elucidate the molecular mechanism of perineural invasion.
Experimental Design: To identify key biological markers involved in perineural invasion, differentially expressed molecules were investigated by proteomics and transcriptomics. Synuclein-gamma emerged as the only up-regulated molecule in high-perineural invasion group by both analyses. The clinical significance and the biological property of synuclein-gamma were examined in 62 resected cases of pancreatic cancer and mouse models.
Results: Synuclein-gamma overexpression was observed in 38 (61%) cases and correlated with major invasive parameters, including perineural invasion and lymph node metastasis (P < 0.05). Multivariate analyses revealed synuclein-gamma overexpression as the only independent predictor of diminished overall survival [hazard ratio, 3.4 (95% confidence interval, 1.51-7.51)] and the strongest negative indicator of disease-free survival [2.8 (1.26-6.02)]. In mouse perineural invasion and orthotopic transplantation models, stable synuclein-gamma suppression by short hairpin RNA significantly reduced the incidence of perineural invasion (P = 0.009) and liver/lymph node metastasis (P = 0.019 and P = 0.020, respectively) compared with the control.
Conclusions: This is the first study to provide in vivo evidence that synuclein-gamma is closely involved in perineural invasion/distant metastasis and is a significant prognostic factor in pancreatic cancer. Synuclein-gamma may serve as a promising molecular target of early diagnosis and anticancer therapy.

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腹腔鏡下右副腎摘除術、腹腔鏡下左副腎部分切除術を一期的に施行した両側副腎褐色細胞腫の1例

武田利和, 宮嶋哲, 柴田洋孝, 橋口明典, 菊地栄次, 中川健, 伊藤裕, 大家基嗣

日本内分泌外科学会総会プログラム・抄録集（(一社)日本内分泌外科学会） 21回 105 - 105 2009年04月

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DVDバーチャルスライド教材の開発　病理実習教育の効率化に向けて

橋口, 明典, 武市, 光司 and 坂元, 亨宇

病理と臨床 27 （ 3 ） 303 - 305 2009年03月

共著, ISSN 0287-3745

第2世代超音波造影剤(ソナゾイド)による前立腺癌の腫瘍血管描出能に関する検討

松本一宏, 中川健, 橋口明典, 香野日高, 菊地栄次, 長田浩彦, 宮嶋哲, 大家基嗣

日本泌尿器科学会雑誌（(一社)日本泌尿器科学会） 100 （ 2 ） 332 - 332 2009年02月

共著, ISSN 0021-5287

弓状動脈にフィブリノイド血管壊死を呈したMPO-ANCA関連RPGN症候群の1例

伊藤新, 徳山博文, 脇野修, 金子友香, 竹本崇史, 小西孝之助, 林松彦, 橋口明典, 林晃一, 伊藤裕

日本内科学会関東地方会（日本内科学会-関東地方会） 556回 33 - 33 2008年09月

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【進化するバーチャルスライド　現状と展望】バーチャルスライドの学生教育への応用

橋口, 明典, 武市, 光司 and 坂元, 亨宇

Medical Technology 36 （ 8 ） 813 - 817 2008年08月

共著, ISSN 0389-1887

Histopathological features and prognostic significance of the micropapillary pattern in lung adenocarcinoma.

Kazunori Kamiya, Yuichiro Hayashi, Junya Douguchi, Akinori Hashiguchi, Taketo Yamada, Yotaro Izumi, Masazumi Watanabe, Masafumi Kawamura, Hirohisa Horinouchi, Naoki Shimada, Koichi Kobayashi, Michiie Sakamoto

Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc 21 （ 8 ） 992 - 1001 2008年08月

共著

The micropapillary pattern is characterized by small papillary tufts with no fibrovascular core lying in spaces and has been reported as an aggressive variant of carcinoma in several organs. We investigated the histopathobiological properties of the micropapillary pattern with immunohistochemistry, serial sections, and electron microscopy in lung adenocarcinoma. We further analyzed its clinicopathological character and prognosis. The subjects included 383 adenocarcinoma cases, of which 184 (48%) were micropapillary pattern-positive and 199 (52%) were micropapillary pattern-negative. On histology, micropapillary tufts seemed to float in the alveolar space or spaces encased by connective tissues, whereas serial sections revealed that most tufts had continuity with other tufts and even with the main tumor. Positive staining for the adhesion molecules E-cadherin and beta-catenin suggested the preservation of tight adhesion, and electron microscopy showed the existence of intercellular junctions. Negative staining for laminin and loss of basement membrane as determined by electron microscopy suggest a loss of cell-matrix contact. Positive staining for Ki-67 indicates that cells constituting micropapillary tufts retained their proliferation potency. There were no CD34-positive cells in micropapillary tufts, and the loss of the vascular core was confirmed. In micropapillary pattern-positive cases, lymphatic invasion was identified significantly more frequently than in micropapillary pattern-negative cases (P<0.001), even at stageIA (without lymph node metastasis, N=197) (P<0.001). The 5-year and 10-year overall survival rates of the micropapillary pattern-positive stageIA group were 77.6 and 67.6%, respectively, which were significantly less than those of the micropapillary pattern-negative stageIA group (98.1 and 98.1%) (P=0.001). In conclusion, cells constituting the micropapillary pattern are likely to have acquired anchorage-independent growth and a potential for high malignancy.

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Prediction of extraprostatic extension by prostate specific antigen velocity, endorectal MRI, and biopsy Gleason score in clinically localized prostate cancer.

Koshiro Nishimoto, Jun Nakashima, Akinori Hashiguchi, Eiji Kikuchi, Akira Miyajima, Ken Nakagawa, Takashi Ohigashi, Mototsugu Oya, Masaru Murai

International journal of urology : official journal of the Japanese Urological Association （John Wiley & Sons Australia, Ltd） 15 （ 6 ） 520 - 3 2008年06月

共著, 査読有り, ISSN 0919-8172

OBJECTIVES: To investigate the clinical value of prostate specific antigen velocity (PSAV) in predicting the extraprostatic extension of clinically localized prostate cancer. METHODS: One hundred and three patients who underwent radical prostatectomy for clinically localized prostate cancer were included in the analysis. The correlation between preoperative parameters, including PSA-based parameters, clinical stage, and histological biopsy findings, and the pathological findings were analyzed. Logistic regression analysis was performed to identify a significant set of independent predictors for the local extent of the disease. RESULTS: Sixty-four (60.2%) patients had organ confined prostate cancer and 39 (39.8%) patients had extraprostatic cancer. The biopsy Gleason score, PSA, PSA density, PSA density of the transition zone, and PSAV were significantly higher in the patients with extraprostatic cancer than in those with organ confined cancer. Multivariate logistic regression analysis indicated that the biopsy Gleason score, endorectal magnetic resonance imaging findings, and PSAV were significant predictors of extraprostatic cancer (P < 0.01). Probability curves for extraprostatic cancer were generated using these three preoperative parameters. CONCLUSIONS: The combination of PSAV, endorectal magnetic resonance imaging findings, and biopsy Gleason score can provide additional information for selecting appropriate candidates for radical prostatectomy.

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A case of atypical POEMS syndrome without polyneuropathy

橋口明典

EUROPEAN JOURNAL OF HAEMATOLOGY （BLACKWELL PUBLISHING） 80 （ 5 ） 452 - 455 2008年05月

研究論文（学術雑誌）, 共著, ISSN 0902-4441

POEMS (Polyneuropathy, Organomegaly, Endocrinopathy, M-protein, Skin changes) syndrome is a rare hematological disease associated with overproduction of pro-inflammatory cytokines. Under the current nomenclature and diagnostic criteria for POEMS syndrome, the presence of characteristic polyneuropathy is required for diagnosis. We report a 43-year-old Japanese woman with organomegaly, endocrinopathy, M-protein, skin lesions, as well as typical renal lesions and sclerotic bone lesions. Of note, neurological examinations and peripheral nerve conduction tests were normal in this patient. In view of the overwhelming number of otherwise characteristic signs and symptoms, we made a provisional diagnosis of 'atypical POEMS syndrome without polyneuropathy'. If further similar cases are reported in the future, reconsideration of the nomenclature and/or diagnostic criteria for POEMS syndrome may be required.

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前立腺癌の検出におけるMR拡散強調像の臨床的意義全摘標本との対比

谷本伸弘, 中島淳, 篠田和伸, 橋口明典, 栗林幸夫

泌尿器外科（医学図書出版(株)） 21 （臨増） 379 - 379 2008年03月

共著, ISSN 0914-6180

腹部腫瘤を主訴とする後腹膜原発粘液嚢胞腺癌

伊藤, 祐二郎, 大家, 基嗣, 石田, 勝, 安藤, 利行, 橋口, 明典 and 村井, 勝

臨床泌尿器科 62 （ 1 ） 57 - 59 2008年01月

共著, ISSN 0385-2393

Mutated D4-guanine diphosphate-dissociation inhibitor is found in human leukemic cells and promotes leukemic cell invasion

橋口明典

EXPERIMENTAL HEMATOLOGY （ELSEVIER SCIENCE INC） 36 （ 1 ） 37 - 50 2008年01月

研究論文（学術雑誌）, 共著, ISSN 0301-472X

Objective. Rho GTPase may be involved in human cancer invasion via the augmentation of cell motility and adhesion. We report on two point mutations of the D4-guanine diphosphate (GDP)-dissociation inhibitor (GDI) gene, one of the Rho-GDIs, which were found in a human leukemic cell line, Reh, and the mutated D4-GDI functions as an accelerator of leukemic cell invasion.
Material and Methods. We investigated the altered activity of GDP dissociation by mutated (mt) D4-GDI and the functions of this mt and wild-type (wt) D4-GDI in invasion. The mice inoculated with wt or mt D4-GDI vector-transfected Raji cells were observed and examined pathologically. Adhesiveness and cell motility of wt or mt D4-GDI vector-transfected Raji cells were examined. Finally, it was examined whether Rho activation was changed by mutation of D4-GDI under the condition of Rho-GDI knockdown.
Results. Two point mutations of the D4-GDI gene were found in Reh cells. The region of mutations is conserved among members of the Rho-GDI family at the amino acid level. D4-GDI with two mutations (V68L and V69A) functioned in a dominant negative manner in the inhibition of GDP dissociation from Rho. Severe combined immune-deficient mice inoculated with Raji cells developed hemiparalysis. The Raji cells were present in bone marrow and peripheral blood, and hepatic invasion was observed in 20% of the mice. Mice inoculated with wt D4-GDI vector-transfected Raji cells (wt 134) showed later paralysis and none developed hepatic invasion. Mice inoculated with mt D4-GDI-transfected Raji cells (mt D4) showed a 5-day reduction in the time to paraplegia and death. In addition, hepatic invasion was evident in 80% of mice transplanted with mt D4 cells. There were no differences in growth rates and amounts of guanine triphosphate (GTP)-bound Rho, cdc42, or Rac among all clones, however, GTP-bound Rho in mt D4 clone with short hairpin RNA (shRNA) vector for Rho-GDI knockdown was increased compared with wt D4 clone with shRNA vector for Rho-GDI knockdown. The mt D4 cells showed an augmentation of adhesiveness and cell motility. On the other hand, wt D4 cells showed a decreased ability of cell motility.
Conclusion. These results suggest the mutated D4-GDI functions as a dominant negative molecule against the wt D4-GDI and accelerates invasion via regulation of cytoskeletal machinery. (c) 2008 ISEH - Society for Hematology and Stem Cells. Published by Elsevier Inc.

A case of primary retroperitoneal cystadenocarcinoma

Ito Yujiro, Oya Mototsugu, Ishida Masaru, Ando Toshiyuki, Hashiguchi Akinori, Murai Masaru

Japanese Journal of Clinical Urology 62 （ 1 ） 57 - 59 2008年

共著, ISSN 0385-2393

A 71-year-old woman was admitted to our hospital complaining of right lower abdominal mass. Computed tomography, and magnetic resonance imaging showed a cystic tumor, 14 cm in diameter, located at the right lower abdomen with cyst wall calcification. Immunohistochemical staining was positive for CA19-9, but not for CEA and CA125. A transabdominal tumorectomy was performed. The removed tumor was 17.7 x 14.4 x 11.2 cm in size, weighing 1,870 g, and hisotopathological retroperitoneal cystadenocarcinoma.

腎細胞癌に合併したAL型原発性アミロイドーシスによってネフローゼ症候群を呈した1例

高野, 盛登, 須田, 徳子, 市原, 淳弘, 小西, 孝之助, 篠村, 裕之, 林, 晃一, 橋口, 明典, 宮嶋, 哲, 村井, 勝 and 伊藤, 裕

日本腎臓学会誌（Japanese Society of Nephrology） 49 （ 8 ） 1014 - 1019 2007年11月

共著, ISSN 0385-2385

症例は80歳、男性。2005年5月に食思不振を自覚し来院し、軽度蛋白尿と腹部CTで左腎細胞癌を認め、腹腔鏡下腎尿管摘出術を施行した。術後に蛋白尿がさらに増悪し下腿浮腫が出現したため、同年12月に精査目的で再入院した。蓄尿蛋白4.2g/日、血清TP 5.0g/dL,Alb 2.4g/dL,TC 214mg/dL,Cr 1.4mg/dL、クレアチニンクリアランス39mL/minよりネフローゼ症候群と診断されたが、精査により転移および他の悪性腫瘍の合併は否定された。摘出した左腎の非悪性腫瘍部位のHE染色による検討では、有意な異常所見を認めなかったが、念のためコンゴーレッドによる特殊染色をしたところ、小血管壁および糸球体にアミロイド沈着を認めた。アミロイド沈着は過マンガン酸カリウム処置後も残存しており、AL型原発性アミロイドーシスと診断した。その後、骨髄検査で多発性骨髄腫は否定され、尿蛋白電気泳動でわずかなベンスジョーンズ蛋白と上部消化管内視鏡で胃潰瘍病変部位のアミロイド沈着を認めた。腎細胞癌にAL型原発性アミロイドーシスを合併した症例報告はきわめて少なく、術後にネフローゼ症候群が顕在化したことを契機に摘出腎の詳細な検討を加えた結果、診断し得た貴重な症例と考えられた。(著者抄録)

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A case of nephrotic syndrome due to AL-type primary amyloidosis associated with renal cell carcinoma

Takano Morito, Suda Noriko, Ichihara Atsuhiro, Konishi Konosuke, Sasamura Hiroyuki, Hayashi Koichi, Hashiguchi Akinori, Miyajima Akira, Murai Masaru, Itoh Hiroshi

Japanese Journal of Nephrology 49 （ 8 ） 1014 - 1019 2007年

共著, ISSN 0385-2385

An 80-year-old man was admitted because of appetite loss, mild proteinuria, and leg edema. A computed tomography examination revealed a tumor in his left kidney, and a left nephrectomy was performed. The tumor was histologically diagnosed as a clear cell type renal cell carcinoma, and hematoxylin eosin staining of the non-tumor region of the resected kidney showed an almost normal morphology. Three months later, he was readmitted because of the development of nephrotic syndrome with a urinary protein excretion of 4.2 g/day, a serum total protein concentration of 5.0 g/dL, a serum albumin concentration of 2.4 g/dL, a serum total cholesterol concentration of 214 mg/dL, and generalized edema. A full examination revealed no evidence of metastasis or recurrence of the renal cell carcinoma or any other malignant tumor. Congo red staining and immunohistochemical staining were performed using the non-tumor region of his resected kidney, and the presence of amyloid deposits in the microvascular walls and glomeruli that did not disappear when treated with potassium permanganate was disclosed. In this manner, the patient was diagnosed as having AL-type primary amyloidosis. Bence-Jones prot

【肝がん治療のすべて】肝細胞癌　多中心性発癌

橋口, 明典, 入江, 理恵 and 坂元, 亨宇

肝・胆・膵 53 （ 5 ） 619 - 625 2006年11月

共著, ISSN 0389-4991

パルボウイルスB19感染を契機に発症したSLEの1例

粟津緑, 下郷幸子, 飛彈麻里子, 新庄正宜, 高橋孝雄, 柴田理恵, 橋口明典

日本小児科学会雑誌（(公社)日本小児科学会） 110 （ 6 ） 825 - 825 2006年06月

共著, ISSN 0001-6543

急速に進行し肝不全を呈した原発性アミロイドーシスの1例

山岸, 由幸, 森, 朱夏, 松本, 道長, 中澤, 敦, 栗田, 聡, 多田, 慎一郎, 橋口, 明典, 横森, 弘昭, 齋藤, 英胤, 加藤, 眞三 and 日比, 紀文

肝臓（The Japan Society of Hepatology） 47 （ 1 ） 22 - 29 2006年01月

共著, ISSN 0451-4203

60歳女.患者は全身倦怠感を主訴とした.ALPおよびγGTP高値が指摘され,AL typeの原発性アミロイドーシスと診断された.その後,食欲低下をはじめ倦怠感,黄疸が急速に悪化し,眼球結膜黄染を認めた.末梢血では好中球優位の著明な白血球上昇を認め,軽度の貧血も伴っていた.生化学では胆道系酵素の上昇を伴う肝機能障害と直接型優位の著明な黄疸,電解質異常を伴った腎機能障害が認られた.更にCTでは著明な肝腫大と軽度の脾腫,腹水が確認され,対処療法にて経過観察をしていたが,黄疸と腎機能は悪化し,入院第17病日目に死亡となった.剖検所見では典型的な肝アミロイドーシスの肉眼所見で,肝実質へのアミロイド沈着はより高度となり,腎においても糸球体・小血管に高度のアミロイド沈着がみられた

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慶應義塾大学病院における35年間の腎生検　概略と膜性腎症例の詳細検討

浅井, 昌樹, 小西, 孝之助, 福田, 誠一, 内村, 英輝, 高瀬, 敦, 力石, 昭宏, 林, 松彦, 猿田, 享男 and 橋口, 明典

慶應医学（慶應医学会） 82 （ 3 ） 143 - 155 2005年09月

共著, ISSN 0368-5179

腎生検施行症例と,その病理診断を集計し,特に成人ネフローゼ症候群の主要な原因疾患の一つである膜性腎症に関して詳細を追跡した33例について臨床的,病理的検討を行った.20例のネフローゼ症候群を含む22例にステロイドが投与された.治療開始1年後に1日の尿蛋白が1g以下に改善した症例は,ステロイド非投与群36.4%であったのに対してステロイド投与群54.5%で,プレドニゾロンの有効性が示唆された.治療前の尿蛋白よりも治療1ヵ月後の尿蛋白の方が2年後の尿蛋白と有意に相関が高く,治療1ヵ月後の近接効果を把握することによって2年後の治療効果の予測が可能であることが示唆された.55歳以上の年齢,1日の尿蛋白が5g以上,血清クレアチニンの高値や高血圧症などが予後増悪因子であると予測した

[IgA nephropathy associated with polycythemia vera]

Yaguchi, T, Takimoto, C, Uchimura, H, Konishi, K, Ichihara, A, Hayashi, K, Saruta, T, Hashiguchi, A

Nihon Naika Gakkai Zasshi （The Japanese Society of Internal Medicine） 94 （ 8 ） 1612 - 4 2005年08月

共著, ISSN 0021-5384

真性多血症とIgA腎症の合併報告は稀で,合併例でのlgA腎症は重症のことが多く,両者がお互いの進展を促進している可能性も想定されている.症例は55歳男性.以前より真性多血症を指摘され, 1～2カ月に一度,瀉血を施行していた.経過中,血尿,蛋白尿が出現し,徐々に腎機能増悪を認めるようになった.腎生検でIgA腎症と診断され,プレドニゾロン内服を開始したが治療抵抗性で,急速な腎機能悪化が見られた.

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真性多血症にIgA腎症を合併した1例

谷口, 智憲, 滝本, 千恵, 内村, 英輝, 小西, 孝之助, 市原, 淳弘, 林, 晃一, 猿田, 享男 and 橋口, 明典

日本内科学会雑誌 94 （ 8 ） 1612 - 1614 2005年08月

共著, ISSN 0021-5384

55歳男.真性多血症を指摘され,その後頭痛を自覚,RBC 650万/μl,Hct 60%を認め,1〜2ヵ月に1度,瀉血を施行していた.経過中,血尿,蛋白尿があり,徐々に腎機能増悪を認め,血清クレアチニン 2.5mg/dlまで上昇した.腎生検の結果IgA腎症の診断で,尿蛋白6.9g/日,クレアチニンクリアランス 22ml/minであった.第3病日よりプレドニゾロン(PSL)60mgの内服を開始,弟9病日にはRBC 735万/μl,Hct 58%まで増加したため,瀉血を行った.第24病日にはPSL 40mgまで漸減したが尿蛋白は6.0g/日前後で遷延し,高血圧も認めたため,カンデサルタン 4mgの内服を開始した.弟38病日にはPSL 35mg投与下で,尿蛋白は3.4g/日まで減少し,外来経過観察となった

【病理診断における分子生物学】　必要な基礎知識　抗体・人工抗体

橋口, 明典, 山田, 健人 and 坂元, 亨宇

病理と臨床 22 （増刊） 14 - 18 2004年04月

共著, ISSN 0287-3745

病理学総論実習の電子教材の開発と評価

津村, 宏, 橋口, 明典, 武市, 光司 and 秦, 順一

医療マネジメント学会雑誌（Japan Society for Health Care Management） 4 （ 3 ） 365 - 370 2003年12月

共著, ISSN 1345-6903

病理組織所見の写真300枚を電子画像化し,そのデータをもとに病理学総論実習のパソコン用教材を作成した.作成にあたってはマイクロメディア社のディレクタを用いた.この教材をCD-ROMにして学生に配布し,実習終了後にアンケート調査を行った結果,本教材には次のような利点のあることが明らかになった.何時何処でも利用できることから学習の機会を増やせる.予習・復習に活用することで実習を有意義に行える.実際の顕微鏡像が見られること,及びマーキングなどの補助手段により学習が容易になる

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木村病と抗好中球細胞質抗体(ANCA)関連腎炎を合併した再発性多発軟骨炎の1例

楢林敦, 粟津緑, 棗田とも, 井ノ口美香子, 新庄正宜, 高橋孝雄, 西川武二, 佐藤慎二, 平形道人, 亀山香織, 橋口明典

日本小児科学会雑誌（(公社)日本小児科学会） 107 （ 10 ） 1418 - 1418 2003年10月

共著, ISSN 0001-6543

Giant seminoma in a patient with 5a-reductase-2 deficiency

Sasaki Gen, Nakagawa Ken, Hashiguchi Akinori, Hasegawa Tomonobu, Ogata Tsutomu, Murai Masaru

Journal of urology 169 （ 3 ） 1080-1081 2003年03月

研究論文（学術雑誌）, 共著

性幹細胞（組織幹細胞）の分離，増殖，分化誘導体

橋口明典，坂元亨宇，梅澤明弘

日本臨牀 61 （ 3 ） 390-395 2003年03月

研究論文（学術雑誌）, 共著

【再生医療】　再生医療にかかわる基本的事項　再生医療に利用可能な細胞とその供給源　体性幹細胞(組織幹細胞)の分離,増殖,分化誘導

橋口, 明典, 坂元, 亨宇 and 梅澤, 明弘

日本臨床 61 （ 3 ） 390 - 395 2003年03月

共著, ISSN 0047-1852

原発性皮膚B細胞リンパ腫の1例

斎藤, 昌孝, 村木, 良一, 石橋, 了知, 橋口, 明典, 梅澤, 明弘 and 向井, 清

臨床皮膚科 57 （ 2 ） 193 - 196 2003年02月

ISSN 0021-4973

75歳女.頭部および顔面に生じた原発性皮膚B細胞リンパ腫である.頭部には表面平滑な小結節,顔面には表面に鱗屑を伴う浸潤性紅斑を認めたが,病変は皮膚に限局して皮疹部には病理組織学的に胚中心細胞様細胞やリンパ上皮性病変を認め,免疫グロブリン重鎖遺伝子の再構成が検出された.頭部および顔面皮疹は電子線照射後に消退した.MALTリンパ腫の皮膚での相当病変として,SALTからリンパ腫が発生する可能性が指摘されており,SALT関連B細胞リンパ腫という名称が提唱されている

原発性皮膚B細胞リンパ腫の1例

斎藤昌孝，村木良一，石橋了知，橋口明典，梅澤明弘，向井清

臨床皮膚科 57 （ 2 ） 193-196 2003年02月

研究論文（学術雑誌）, 共著

Giant seminoma in a patient with 5 alpha-reductase type 2 deficiency

Sasaki Goro, Nakagawa Ken, Hashiguchi Akinori, Hasegawa Tomonobu, Ogata Tsutomu, Murai Masaru

Journal of urology 169 （ 3 ） 1080-1081 - 1 2003年

研究論文（学術雑誌）, 共著, ISSN 0022-5347

体性幹細胞（組織幹細胞）の分裂，増殖，分化誘導

橋口明典，坂本亨宇，梅澤明弘

日本臨床 61 （ 3 ） 390-395 2003年

研究論文（学術雑誌）, 共著

Correlation between a specific Wilms tumor suppressor gene (WT1) mutation and the histological findings in Wilms tumor(WT)

Shibata Rie, Hashiguchi Akinori, Sakamoto J, Yamada Taketo, Umezawa Akihiro, Hata Junichi

Journal of medical genetics 39 （ 12 ） 83-83 2002年12月

研究論文（学術雑誌）, 共著

経口糖負荷試験で糖尿病型を示さなかった糖尿病性腎症の一例

城祐輔，市原淳弘，江口高，栗原勲，橋口明典，小西孝之助，林松彦，猿田享男

日本腎臓学会誌 44 （ 7 ） 552-557 2002年10月

研究論文（学術雑誌）, 共著

経口糖負荷試験で糖尿病型を示さなかった糖尿病性腎症の1例

城, 祐輔, 市原, 淳弘, 江口, 高, 栗原, 勲, 橋口, 明典, 小西, 孝之助, 林, 松彦 and 猿田, 享男

日本腎臓学会誌 44 （ 7 ） 738 - 743 2002年10月

共著, ISSN 0385-2385

46歳男.両下腿に浮腫をきたした.以後増悪し,全身に浮腫及び,著明な高血圧と腎機能障害を認めたため入院した.血液検査上,糖尿病を示唆する所見はなかった.高血圧に対しニフェジピン,カンデサルタンシレキセチル,ドキサゾシンにより血圧をコントロールし,浮腫に対してフロセミド,スピロノラクトンを投与した.腎生検後,75g OGTTを施行したが糖尿病型ではなかった.又,糖尿病性変化の精査のため蛍光眼底造影を施行した.両眼底とも網膜動脈狭細化,反射亢進,動静脈交叉部での動脈の途絶があり,網膜動脈硬化所見を呈していた.高血圧性網膜症を合併した両糖尿病網膜症(前増殖型)と診断した.第52病日,血圧130/80台を維持,浮腫も改善したため退院した

Exogenous expression of heat shock protein 90kDa retards the cell cycle and impairs the heat shock response

Zhao Chen, Hashiguchi Akinori, Kondoh Kensuke, Du Wenlin, Hata Jun-ichi, Yamada Taketo

Experimental cell research （ACADEMIC PRESS INC ELSEVIER SCIENCE） 275 （ 2 ） 200-214 - 214 2002年05月

研究論文（学術雑誌）, 共著, ISSN 0014-4827

The 90-kDa heat shock protein, HSP90, is an abundant molecular chaperone which functions in cellular homeostasis in prokaryotes and eukaryotes. It is well known that HSP90 plays a critical and indispensable role in regulating cell growth through modulations of various signal transduction pathways, but its roles in cell cycle control are not so well known. We transferred human HSP90 (wild-type or mutated types) expression vectors into NTH-3T3 cells in order to study certain functions of HSP90 in the cell cycle and cell growth under physiological conditions. We found that the exogenous expression of HSP90 (wild-type) induced a decrease in cell growth via retardation of the G1/S transition. The inhibition of cell growth was caused by reduced expressions of cyclin D3 and cyclin A mRNA and protein. On the other hand, no stable transfectants with the three types of mutated HSP90 were obtained. Unexpectedly, exogenous HSP90 expression impaired the heat shock response by inhibiting both heat shock transcription factor 1 (HSF1) activation and transportation of HSF1 into the nucleus. The HSF1 function was disrupted by the direct association between HSF1 and exogenous HSP90, which was present as a monomer. These results reveal important roles of HSP90 in cell cycle control and in the stress response of nontransformed cells. (C) 2002 Elsevier Science (USA).

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Exogenous expression of heat shock protein 90 retards the cell cycle and impairs the heat shock response

Zhao Chen, Hashiguchi Akinori, Kondoh Kensuke, Du Wenglin, Hata Jun-ich, Yamada Taketo

Experimental cell research 275 （ 2 ） 200-214 2002年05月

研究論文（学術雑誌）, 共著

Exogenous　expression of heat shock protein 90kDa retards the cell cycle and impairs the heat shock resonse

Zhao　Chen, Hashiguchi　Akinori, Kondoh　Kensuke, Du　Wenlin, Hata　Jun-ichi, Yamada　Taketo

Experimental Cellular Research 275 （ 2 ） 200-214 2002年03月

研究論文（学術雑誌）, 共著

Augmentation of megakaryocytopoiesis by hematopoietotic microenviromnment of human granulocyte colony-stimulating factor transgenic mice

Fujita T, Yamada T, Hashiguchi A, Fukushima S, Kondoh K, Fujimoto J, Hata J,

Experimental Hematology 29 （ 8 ） 1010-1018 2001年08月

研究論文（学術雑誌）, 共著

Augmentation of megakaryocytopoiesis within the hematopoietic microenvironment of human granulocyte colony-stimulating factor transgenic mice

T Fujita, T Yamada, A Hashiguchi, S Fukushima, K Kondoh, J Fujimoto, J Hata

EXPERIMENTAL HEMATOLOGY （ELSEVIER SCIENCE INC） 29 （ 8 ） 1010 - 1018 2001年08月

共著, ISSN 0301-472X

Objective. Megakaryocytopoiesis was dramatically augmented in human granulocyte colony-stimulating factor transgenic mice (G-Tg) compared to littermates. We examined the characteristics of megakaryocytes and megakaryocyte progenitor cells in these mice.
Materials and Methods. The numbers of colony-forming unit megakaryocytes (CFU-MK) and megakaryocytes in hematopoietic organs were counted. The megakaryocytes of G-Tg were examined ultrastructurally, and bone marrow transplantation studies using congenic G-Tg (Ly5.2) and C57BL/6 (Ly5.1) were performed. The number of day-14 colony-forming unit spleen (CFU-S) that contained megakaryocytes in [Ly5.1 > G-Tg] and [G-Tg > Ly5.1] mice also was counted.
Results. The number of CFU-MK increased markedly in the spleen, bone marrow, and peripheral blood. The number of megakaryocytes in the spleen and bone marrow also were increased in G-Tg mice. Ultrastructural analyses revealed that megakaryocytes in G-Tg mice were immature. Bone marrow transplantation studies of [Ly5.1 > G-Tg] mice resulted in a significantly increased number of megakaryocytes compared to [G-Tg > Ly5.1] mice. The number of day-14 CFU-S that contained megakaryocytes was increased markedly in [Ly5.1 > G-Tg] mice compared to [G-Tg > Ly5.1] mice. In vitro differentiation of megakaryocytes in [Ly5.1 > G-Tg] mice was induced by interleukin-11 and thrombopoietin.
Conclusion. The results showed that the hematopoietic marrow microenvironment of G-Tg is important in augmenting megakaryocytopoiesis. [Ly5.1 > G-Tg] mice are potentially useful as a source of murine megakaryocytes and their progenitors. (C) 2001 International Society for Experimental Hematology. Published by Elsevier Science Inc.

A case of generalized Hailey-Hailey disease with fatal liver injury

Amagai M, Kobayashi M, Wakabayashi K, Hakuno M, Hashiguchi A, Nishikawa T, Hata J

The Keio Journal of Medicine 50 （ 2 ） 109-116 2001年06月

研究論文（学術雑誌）, 共著

A case of generalized Hailey-Hailey disease with fatal liver injury

Amagai M, Kobayashi M, Wakabayashi K, hakuno M, Hashiguchi A, Nishikawa T, Hata J

Keio Journal of Medicine 50 （ 2 ） 109-116 2001年06月

研究論文（学術雑誌）, 共著

Augmentation of human leukemic cell invasion by activation of a small GTP-binding protein Rho

Fukushima S, Yamada T, Hashiguchi A, Nakata Y, Hata J

Experimental Hematology （ELSEVIER SCIENCE INC） 28 （ 4 ） 391-400 - 400 2000年04月

研究論文（学術雑誌）, 共著, ISSN 0301-472X

Objective. The functions of a small GTP-binding protein, Rho, in human leukemic cell invasion was investigated in vivo and in vitro.
Materials and Methods. Human leukemic KM3 and Reh cells (derived from B-cell-type common acute lymphoid leukemias) were inoculated into severe combined immundeficiency (SCID) mice, Alteration of invasion in SCID mice inoculated with KM3 cells that were introduced with the expression vector for Rho Val14 (Rho V14), an activated mutant form of Rho, was observed.
Results. SCID mice inoculated with KM3 and Reh cells developed paraplegia 21 days after inoculation. All died by day 26-27, The leukemic cells were localized to bone marrow and around the spinal cord, with no infiltration into peripheral blood, spleen, liver, thymus, or lymph nodes. SCID mice inoculated with Rho V14-transfected KM3 cells showed a 5-day reduction in the time to paraplegia and death compared with SCID mice inoculated with hygromycin-resistance gene-transfected KM3 (hyg(r)) cells. In addition, the mice inoculated with Rho V14 cells showed leukemic cell infiltration, not only into bone marrow and around the spinal cord but also into peripheral blood, liver, and spleen. There were no in vitro or in vivo differences in growth rates of Rho V14 and hyg(r) cells. However, the Rho V14 cells showed markedly increased cell adhesion compared to the hygr cells.
Conclusion. Results suggest that Rho activation accelerates human leukemic cell invasion via augmentation of cell adhesion. (C) 2000 International Society for Experimental Hematology, Published by Elsevier Science Inc.

Function of 90 kDa heat shock protein in cellular differentiation of human embryonal carcinoma cells

Yamada T, Hashiguchi A, Fukudshim S, Kakita Y, Umezawa A, Maruyama T, Hata J

In Vitro Cellular and Developmental Biology. Animal （SOC IN VITRO BIOLOGY） 36 （ 2 ） 139-146 - 146 2000年02月

研究論文（学術雑誌）, 共著, ISSN 1071-2690

Heat shock proteins (HSPs) have been recognized as molecules that maintain cellular homeostasis during changes in the environment. Here we report that HSP90 functions not only in stress responses but also in certain aspects of cellular differentiation. We found that HSP90 showed remarkably high expression in undifferentiated human embryonal carcinoma (EC) cells, which Here subsequently dramatically down-regulated during in vitro cellular differentiation, following retinoic acid (RA) treatment, at the protein level. Surprisingly, heat shock treatment also triggered the clown-regulation of HSP90 within 48 h at the protein level. Furthermore, the heat treatment induced cellular differentiation into neural cells. This down-regulation of HSP90 by heat treatment was shifted to an up-regulation pattern after cellular differentiation in response to RA treatment. In order to clarify the functions of HSP90 in cellular differentiation, we conducted various experiments, including overexpression of HSP90 via gene transfer. We showed that the RA-induced differentiation of EC cells into a neural cell lineage was inhibited by overexpression of the HSP90 alpha or -beta isoform via the gene transfer method. On the other hand, the overexpression of HSP90 beta alone impaired cellular differentiation into trophoectoderm. These results show that down-regulation of HSP90 is a physiologically critical event in the differentiation of human EC cells and that specific HSP90 isoforms may be involved in differentiation into specific cell lineages.

Apoptosis of human embryonal carcinoma cells with in vitro differentiation

Yamada T, Suzuki N, Hiraoka N, Matsuoka K, Fukushima S, Hashiguchi A, Hata J

Cell Struct Funct （JAPAN SOC CELL BIOLOGY） 21 （ 1 ） 53-61 - 61 1996年

研究論文（学術雑誌）, 共著, ISSN 0386-7196

An in vitro model of apoptosis and differentiation in human embryonal carcinoma (EC) cells was developed to study the mode of cell death and mechanisms of cell death in early development. Death of these cells was induced by treatment with retinoic acid (RA) under the same conditions as those for induction of differentiation. The manner of this cell death was apoptosis, not necrosis, with the morphological criterion for apoptosis. Serum deprivation likewise caused apoptosis in both undifferentiated and differentiated EC cells. In differentiated EC cells, DNA fragmentation was observed in a smear pattern lacking the ladder pattern typically associated with apoptosis. However, in differentiated EC cells, DNA fragmentation occurred in various sizes.
The expression of a carbohydrate antigen, Le(Y), a reported marker of apoptotic cancer cells, was increased by the treatment with RA. However, two-color analysis by flow cytometry with nick end labelling method revealed that Le(Y) expression was closely correlated with cellular differentiation but not apoptosis after RA treatment in the human EC cell system. Collection of Le(Y) positive cells by the magnetic bead method demonstrated that this expression was not due to apoptosis but rather to differentiation. On the other hand, Le(Y) expression associated with apoptosis was induced by serum deprivation in both undifferentiated and differentiated EC cells. These results show that a subpopulation of undifferentiated EC cells takes the apoptotic pathway by induction of differentiation.
The results also suggest that the population of cells taking an apoptotic pathway differs from a population of cells taking a differentiation pathway. This in vitro system for apoptosis in human EC cells will be useful for studies concerning apoptosis or programmed cell death in human developmental biology.

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