Language：English   Publisher：Gastric Cancer  

Background: Hepatoid adenocarcinoma of the stomach (HAS), a subtype of gastric cancer (GC), includes multiple tumor components, such as enteroblastic and tubular adenocarcinoma components. However, which component mostly contributes to the aggressive behavior of HAS remains unclear. Moreover, the role of tumor-associated macrophages (TAMs) has not been explored in HAS. This study evaluated the clinical significance of the proportion of the hepatoid component within the tumor, CD163 + macrophages, and macrophage colony-stimulating factor-1 (CSF-1) in HAS. Methods: In total, 56 cases of primary HAS were analyzed. In each case, hepatoid (HC), enteroblastic (EC), and tubular (TC) components were identified, and the ratio of HC to the entire tumor (hepatoid component ratio, HCR) was assessed to examine the correlation between HCR and clinicopathological features. Immunohistochemical staining for CD163 and CSF-1 was performed, and differences in immunohistochemical results among the three tumor components were analyzed. In each tumor component, the prognostic impact of CD163 and CSF-1 was examined. Results: A high HCR was associated with worse overall survival (OS). CD163 + TAMs and CSF-1 immunoreactivity score in HC were significantly higher than those in the other components. High infiltration of CD163 + TAMs and a high CSF-1 immunoreactivity score in HC were associated with an aggressive course and worse OS. Multivariate analysis revealed the proportion of HC in HAS as an independent prognostic factor (HR = 3.176, p = 0.006). Conclusions: The HCR and CD163 + TAMs may be useful prognostic predictors, and TAMs may be novel therapeutic targets of HAS.

DOI： 10.1007/s10120-024-01562-x

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Digestive and Liver Disease  

DOI： 10.1016/j.dld.2024.07.003

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Digestive and Liver Disease  

DOI： 10.1016/j.dld.2024.07.003

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Language：English  

DOI： 10.14309/ajg.0000000000003094

PubMed

Language：English  

DOI： 10.14309/ajg.0000000000003094

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Language：English   Publisher：シュプリンガー・ジャパン(株)  

Language：English   Publisher：シュプリンガー・ジャパン(株)  

Publisher：株式会社医学書院  

DOI： 10.11477/mf.1403203667

CiNii Research

Publisher：株式会社医学書院  

DOI： 10.11477/mf.1403203674

CiNii Research

Publisher：株式会社医学書院  

DOI： 10.11477/mf.1403203673

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Publisher：金原出版  

DOI： 10.18888/rp.0000002708

CiNii Research

Language：Japanese   Publisher：(株)医学書院  

＜文献概要＞患者は60歳代,男性.20XX-2年に気管支喘息を発症.20XX-1年に近医呼吸器内科で好酸球性肺炎と診断され,ステロイド内服加療中であった.20XX年に心窩部痛と血便が出現し当科を受診した.大腸内視鏡検査で遠位S状結腸～直腸に周囲を縁取るような発赤を伴う地図状潰瘍の多発を認めた.カプセル小腸内視鏡検査では上部～下部小腸にわたり大腸病変に相似する潰瘍性病変の散在を認めた.皮膚病変を検索したところ体幹と四肢に網状紫斑の多発を認め,臀部の網状紫斑より採取した皮膚生検組織で壊死性血管炎の所見を認め,好酸球性多発血管炎性肉芽腫症と確定診断した.心病変,神経炎の合併を認めシクロホスファミド大量静注療法を施行した.特徴的な小腸病変と大腸病変の内視鏡所見から本症を疑って皮膚病変を検索し,紫斑を皮膚生検した結果,本症の確定診断に至った症例であった.

Language：Japanese   Publisher：(株)医学書院  

＜文献概要＞消化管に虚血による病変を生じるまれな疾患として,クリオグロブリン血症性血管炎を提示する.患者は40歳代,男性.HCV陽性患者で直接作用型抗ウイルス薬による治療中に腹痛を生じ,消化管検査を行った.十二指腸に不整形の潰瘍を複数認め,大腸にはびらんが散見された.小腸には潰瘍や潰瘍瘢痕が観察された.クリオグロブリン弱陽性であり,クリオフィルトレーションと直接作用型抗ウイルス薬による治療を行った.経過中,横行結腸の瘢痕部から血管炎の所見が得られ,クリオグロブリン血症性血管炎と診断した.報告が少ないため消化管病変の特徴は明らかではないが,治療に結び付けるため鑑別診断として考えることは重要である.

Language：Japanese   Publisher：(株)医学書院  

＜文献概要＞消化管に虚血による病変を生じるまれな疾患として,クリオグロブリン血症性血管炎を提示する.患者は40歳代,男性.HCV陽性患者で直接作用型抗ウイルス薬による治療中に腹痛を生じ,消化管検査を行った.十二指腸に不整形の潰瘍を複数認め,大腸にはびらんが散見された.小腸には潰瘍や潰瘍瘢痕が観察された.クリオグロブリン弱陽性であり,クリオフィルトレーションと直接作用型抗ウイルス薬による治療を行った.経過中,横行結腸の瘢痕部から血管炎の所見が得られ,クリオグロブリン血症性血管炎と診断した.報告が少ないため消化管病変の特徴は明らかではないが,治療に結び付けるため鑑別診断として考えることは重要である.

Language：Japanese   Publisher：(株)医学書院  

＜文献概要＞患者は60歳代,男性.20XX-2年に気管支喘息を発症.20XX-1年に近医呼吸器内科で好酸球性肺炎と診断され,ステロイド内服加療中であった.20XX年に心窩部痛と血便が出現し当科を受診した.大腸内視鏡検査で遠位S状結腸～直腸に周囲を縁取るような発赤を伴う地図状潰瘍の多発を認めた.カプセル小腸内視鏡検査では上部～下部小腸にわたり大腸病変に相似する潰瘍性病変の散在を認めた.皮膚病変を検索したところ体幹と四肢に網状紫斑の多発を認め,臀部の網状紫斑より採取した皮膚生検組織で壊死性血管炎の所見を認め,好酸球性多発血管炎性肉芽腫症と確定診断した.心病変,神経炎の合併を認めシクロホスファミド大量静注療法を施行した.特徴的な小腸病変と大腸病変の内視鏡所見から本症を疑って皮膚病変を検索し,紫斑を皮膚生検した結果,本症の確定診断に至った症例であった.

Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：The Japanese Society of Gastroenterology  

<p>A 66-year-old male patient with a thyroid and nasopharyngeal cancer history visited our hospital because of a positive fecal occult blood test. Total colonoscopy detected sessile or subpedunculated polyps in the ascending colon, sigmoid colon, and rectum. These polyps were endoscopically resected, and the rectal polyp was pathologically diagnosed as adenocarcinoma in adenoma and the others as adenomas. Additionally, multiple sessile lesions were revealed in the sigmoid colon and rectum. A complete gastrointestinal tract examination revealed multiple foci of glycogenic acanthosis in the esophagus, multiple sessile lesions in the stomach, multiple sessile lesions, clubbings (rod-shaped lesions), and venous malformations in the small bowel. Mucocutaneous examination indicated hemangiomas on the body trunk, patchy pigmentation on the glans penis, and keratotic papules in the inguinal region. The National Comprehensive Cancer Network diagnostic criteria for Cowden syndrome were used in this case. The patient met four major and two minor criteria;thus, Cowden syndrome was diagnosed. Moreover, the patient was had phosphatase and tensin homolog deleted on chromosome 10 gene mutation. This is the first reported case of metachronal triple cancers in a male patient with Cowden syndrome, and our results indicate the importance of cancer surveillance.</p>

DOI： 10.11405/nisshoshi.121.489

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：The Japanese Society of Gastroenterology  

<p>A 66-year-old male patient with a thyroid and nasopharyngeal cancer history visited our hospital because of a positive fecal occult blood test. Total colonoscopy detected sessile or subpedunculated polyps in the ascending colon, sigmoid colon, and rectum. These polyps were endoscopically resected, and the rectal polyp was pathologically diagnosed as adenocarcinoma in adenoma and the others as adenomas. Additionally, multiple sessile lesions were revealed in the sigmoid colon and rectum. A complete gastrointestinal tract examination revealed multiple foci of glycogenic acanthosis in the esophagus, multiple sessile lesions in the stomach, multiple sessile lesions, clubbings (rod-shaped lesions), and venous malformations in the small bowel. Mucocutaneous examination indicated hemangiomas on the body trunk, patchy pigmentation on the glans penis, and keratotic papules in the inguinal region. The National Comprehensive Cancer Network diagnostic criteria for Cowden syndrome were used in this case. The patient met four major and two minor criteria;thus, Cowden syndrome was diagnosed. Moreover, the patient was had phosphatase and tensin homolog deleted on chromosome 10 gene mutation. This is the first reported case of metachronal triple cancers in a male patient with Cowden syndrome, and our results indicate the importance of cancer surveillance.</p>

DOI： 10.11405/nisshoshi.121.489

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Language：Japanese   Publisher：(一財)日本消化器病学会  

66歳男性.検診異常のため下部消化管内視鏡検査を施行し,S状結腸・直腸に過形成性ポリープの多発を認めた.また直腸の隆起病変を内視鏡的に切除し,腺腫内癌と診断した.他に,食道の白色扁平隆起,胃・小腸の無茎性隆起,小腸の静脈奇形,特徴的な皮膚所見もあり,Cowden症候群と診断しPTEN遺伝子変異も確認した.甲状腺癌,上咽頭癌の既往があり,本症候群の男性に直腸腺腫内癌を含めた3重複癌はまれであり報告する.(著者抄録)

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Language：Japanese   Publisher：(一財)日本消化器病学会  

66歳男性.検診異常のため下部消化管内視鏡検査を施行し,S状結腸・直腸に過形成性ポリープの多発を認めた.また直腸の隆起病変を内視鏡的に切除し,腺腫内癌と診断した.他に,食道の白色扁平隆起,胃・小腸の無茎性隆起,小腸の静脈奇形,特徴的な皮膚所見もあり,Cowden症候群と診断しPTEN遺伝子変異も確認した.甲状腺癌,上咽頭癌の既往があり,本症候群の男性に直腸腺腫内癌を含めた3重複癌はまれであり報告する.(著者抄録)

Publisher：株式会社医学書院  

DOI： 10.11477/mf.1403203624

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Publisher：株式会社医学書院  

DOI： 10.11477/mf.1403203629

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Publisher：株式会社医学書院  

DOI： 10.11477/mf.1403203631

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Language：Japanese   Publisher：(株)医学書院  

＜文献概要＞患者は80歳代,男性.検診目的に施行されたEGDで十二指腸病変を指摘され,生検で腺癌と診断されたことから,精査目的に当科へ紹介され受診となった.低緊張性十二指腸X線造影検査で病変は下行部の乳頭対側に径15mm弱のIIa+IIc様病変として描出され,側面像では弧状変形相当の変形を認めた.EGDで病変部は厚みを伴っており,送気で伸展不良所見を認めた.周囲隆起の立ち上がりは粘膜下腫瘍様を呈しており,上皮性の変化は認めなかった.陥凹底には白苔が付着していたが,NBI拡大観察で周囲隆起の陥凹辺縁部では絨毛構造が消失し,走行異常を伴う微小血管構築像を認め,腫瘍の露出が疑われた.SM massiveに浸潤した癌を疑い,亜全胃温存膵頭十二指腸切除術を施行した.切除標本では周囲隆起部に腺癌成分を伴う内分泌細胞癌で,病変全体で粘膜下層に浸潤しており,陥凹内中央の一部でわずかに筋層へ浸潤している所見を認め,neuroendocrine carcinoma(NEC),large cell type(NEC 80%,adenocarcinoma 20%),pT2N1M0と診断された(WHO分類第5版).本邦の胃癌取扱い規約/大腸癌取扱い規約では内分泌細胞癌に該当した.併存する腺癌領域の免疫組織化学的検討の結果,Brunner腺分化を示す腺癌(MUC6陽性)を起源とする内分泌細胞癌の症例と考えられた.

Language：Japanese   Publisher：(株)医学書院  

＜文献概要＞患者は80歳代,男性.検診目的に施行されたEGDで十二指腸病変を指摘され,生検で腺癌と診断されたことから,精査目的に当科へ紹介され受診となった.低緊張性十二指腸X線造影検査で病変は下行部の乳頭対側に径15mm弱のIIa+IIc様病変として描出され,側面像では弧状変形相当の変形を認めた.EGDで病変部は厚みを伴っており,送気で伸展不良所見を認めた.周囲隆起の立ち上がりは粘膜下腫瘍様を呈しており,上皮性の変化は認めなかった.陥凹底には白苔が付着していたが,NBI拡大観察で周囲隆起の陥凹辺縁部では絨毛構造が消失し,走行異常を伴う微小血管構築像を認め,腫瘍の露出が疑われた.SM massiveに浸潤した癌を疑い,亜全胃温存膵頭十二指腸切除術を施行した.切除標本では周囲隆起部に腺癌成分を伴う内分泌細胞癌で,病変全体で粘膜下層に浸潤しており,陥凹内中央の一部でわずかに筋層へ浸潤している所見を認め,neuroendocrine carcinoma(NEC),large cell type(NEC 80%,adenocarcinoma 20%),pT2N1M0と診断された(WHO分類第5版).本邦の胃癌取扱い規約/大腸癌取扱い規約では内分泌細胞癌に該当した.併存する腺癌領域の免疫組織化学的検討の結果,Brunner腺分化を示す腺癌(MUC6陽性)を起源とする内分泌細胞癌の症例と考えられた.

Language：Japanese   Publisher：(株)医学書院  

＜文献概要＞非乳頭部十二指腸神経内分泌腫瘍(NEN)のX線造影所見・内視鏡所見を明らかにすることを目的として,当科において病理組織学的に非乳頭部十二指腸NENと診断した症例を対象に抽出し,遡及的にその臨床所見とX線造影所見・内視鏡所見を検討した.その結果,最近10年間に計14例15病変がNENと確定診断されており,NET 13例14病変(全病変G1)とNEC1例1病変に分類された.NET 14病変は全病変が十二指腸球部に位置し,内視鏡所見としては頂部にdelleを伴う黄白色調のSMT様隆起の形態が特徴的で,表面には白色観察およびNBI拡大観察で高率に血管拡張像と窩間部の開大を認めた.X線造影検査は7例に施行し,6例が透亮像として描出され,半数例でバリウム斑を伴っていた.切除標本を検討すると,13病変中2病変で病変表面に胃腺窩上皮化生を認めた.NECは下行部に位置し,IIa+IIc様の形態を呈していた.

Language：Japanese   Publisher：(株)医学書院  

＜文献概要＞患者は50歳代,女性.上部消化管内視鏡検査で胃底腺領域内に10個前後の発赤調の粘膜下腫瘍(SMT)様隆起があり,背景粘膜は肥厚様であった.SMT様隆起の生検病理検査は神経内分泌腫瘍(NET)の所見であった.血清ガストリンは著増していたが,抗胃壁細胞抗体および抗内因子抗体は陰性,胃以外に内分泌腫瘍を認めなかった.1cm大の2病変に対し,内視鏡的粘膜切除術を施行し,腫瘍部はNET G1であり,病理組織学的に背景粘膜の胃底腺に過形成性変化を認めた.後日,プロトンポンプのαサブユニットをコードするATP4A遺伝子に病的バリアントを認めることが判明し,胃壁細胞機能不全を原因とするIV型胃NETと診断した.

Language：Japanese   Publisher：(株)医学書院  

＜文献概要＞患者は50歳代,女性.上部消化管内視鏡検査で胃底腺領域内に10個前後の発赤調の粘膜下腫瘍(SMT)様隆起があり,背景粘膜は肥厚様であった.SMT様隆起の生検病理検査は神経内分泌腫瘍(NET)の所見であった.血清ガストリンは著増していたが,抗胃壁細胞抗体および抗内因子抗体は陰性,胃以外に内分泌腫瘍を認めなかった.1cm大の2病変に対し,内視鏡的粘膜切除術を施行し,腫瘍部はNET G1であり,病理組織学的に背景粘膜の胃底腺に過形成性変化を認めた.後日,プロトンポンプのαサブユニットをコードするATP4A遺伝子に病的バリアントを認めることが判明し,胃壁細胞機能不全を原因とするIV型胃NETと診断した.

Language：English   Publisher：シュプリンガー・ジャパン(株)  

日本において、その希少性から十二指腸癌以外の原発性小腸腺癌(PSBA)の臨床病理学的特徴と予後は明らかでない。日本大腸肛門病学会に登録された44施設における、2008年1月から2017年12月までのPSBA358症例を解析した。年齢の中央値は67歳(男性218例、61.6%)であった。平均腫瘍径は49.9(7～100)mmであった。PSBAの部位は空腸が66.2%、回腸が30.4%であった。219例(61.9%)で診断目的の小腸内視鏡検査(シングルバルーン内視鏡、ダブルバルーン内視鏡、カプセル内視鏡)が施行された。19例(5.4%)がリンチ症候群で、272例(76.8%)が初回診断時に有症状であった。病期0、I、II、III、IVの症例はそれぞれ5.4%、2.5%、27.1%、26.0%、35.6%であった。それぞれの病期の5年生存率は92.3%、60.0%、75.9%、61.4%、25.5%、疾患特異的5年生存率(DSS)は100%、75.0%、84.1%、59.3%、25.6%であった。空腸原発、初回診断時有症状、および進行臨床病期の症例の予後は不良であった。Coxハザードモデルを用いた多変量解析の結果、臨床病期のみがPSBA症例のDSSの有意な予知因子であった。PSBA症例のうち76.8%が初回診断時に有症状であり、その多くは進行した病期で診断されていた。以上より、良好な予後のためにはPSBAを早期病期の段階で発見することが重要である。

Language：Japanese   Publisher：(株)医学書院  

＜文献概要＞非乳頭部十二指腸神経内分泌腫瘍(NEN)のX線造影所見・内視鏡所見を明らかにすることを目的として,当科において病理組織学的に非乳頭部十二指腸NENと診断した症例を対象に抽出し,遡及的にその臨床所見とX線造影所見・内視鏡所見を検討した.その結果,最近10年間に計14例15病変がNENと確定診断されており,NET 13例14病変(全病変G1)とNEC1例1病変に分類された.NET 14病変は全病変が十二指腸球部に位置し,内視鏡所見としては頂部にdelleを伴う黄白色調のSMT様隆起の形態が特徴的で,表面には白色観察およびNBI拡大観察で高率に血管拡張像と窩間部の開大を認めた.X線造影検査は7例に施行し,6例が透亮像として描出され,半数例でバリウム斑を伴っていた.切除標本を検討すると,13病変中2病変で病変表面に胃腺窩上皮化生を認めた.NECは下行部に位置し,IIa+IIc様の形態を呈していた.

Publisher：株式会社医学書院  

DOI： 10.11477/mf.1403203560

CiNii Research

Publisher：東京医学社  

DOI： 10.24479/endo.0000001383

CiNii Research

Publisher：東京医学社  

DOI： 10.24479/endo.0000001352

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Publisher：東京医学社  

DOI： 10.24479/endo.0000001354

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Language：English   Publisher：DEN Open  

We herein describe a 49-year-old man with severe heart failure due to fulminant myocarditis who underwent left ventricular assist device implantation and received clopidogrel and warfarin as antithrombotic agents. The patient developed anemia secondary to chronic bleeding gastric hyperplastic polyps, necessitating endoscopic mucosal resection. Despite attempts to manage post-endoscopic mucosal resection bleeding from a gastric ulcer by endoscopic hemostasis using hemostatic forceps, local hemostatic agents, and polyglycolic acid sheets, the bleeding persisted. Hemostasis of the refractory bleeding was finally achieved by endoscopic hand-suturing of the ulcer. One month later, the ulcer was almost completely scarred. This case has important clinical value in that it demonstrates the efficacy of endoscopic hand-suturing even in challenging cases such as refractory bleeding gastric ulcers in patients with left ventricular assist devices.

DOI： 10.1002/deo2.369

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Clinical and Experimental Nephrology  

BACKGROUND: The intestinal microbiome is involved in the pathogenesis of chronic kidney disease (CKD). Despite its importance, the microbiome of the small intestinal mucosa has been little studied due to sampling difficulties, and previous studies have mainly focused on fecal sources for microbiome studies. We aimed to characterize the small intestinal microbiome of CKD patients by studying the microbiome collected from duodenal and fecal samples of CKD patients and healthy controls. METHODS: Overall, 28 stage 5 CKD patients and 21 healthy participants were enrolled. Mucosal samples were collected from the deep duodenum during esophagogastroduodenoscopy and fecal samples were also collected. The 16S ribosomal RNA gene sequencing using Qiime2 was used to investigate and compare the microbial structure and metagenomic function of the duodenal and fecal microbiomes. RESULTS: The duodenal flora of CKD patients had decreased alpha diversity compared with the control group. On the basis of taxonomic composition, Veillonella and Prevotella were significantly reduced in the duodenal flora of CKD patients. The tyrosine and tryptophan metabolic pathways were enhanced in the urea toxin-related metabolic pathways based on the Kyoto Encyclopedia of Genes and Genomes database. CONCLUSION: The small intestinal microbiome in CKD patients is significantly altered, indicating that increased intestinal permeability and production of uremic toxin may occur in the upper small intestine of CKD patients.

DOI： 10.1007/s10157-023-02434-x

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Language：English   Publisher：John Wiley & Sons Australia, Ltd  

Language：English   Publisher：(一社)日本腎臓学会  

Language：English   Publisher：John Wiley & Sons Australia, Ltd  

Language：English   Publisher：(一社)日本腎臓学会  

Language：English   Publisher：John Wiley & Sons Australia, Ltd  

小腸カプセル内視鏡(CE)画像読影を補助するためのモデリング問題について検討するデータセットおよび対象検出CE人工知能(AI)モデルの作成を試みた。2014年9月から2021年6月までの間に施行した523回の小腸CEから18481枚の画像を抽出した。23033病変の12320枚の画像に対して注解を行い、6161枚の正常画像と組み合わせてデータセットとして、その特徴を解析した。このデータセットに基づいてYOLO v5を用いた対象検出AIモデルを作成し、その検証を行った。データセットで用いた注解項目は12種類で、同一画像に対して複数の注解項目を適用した。1396枚の画像を用いてAIモデルを検証し、全12種類の注解項目の感度は91%で、1375画像が真陽性、659画像が偽陽性、120画像が偽陰性であった。各注解項目のうち、最も感度が高かったのは97%で、受信者動作特性曲線下面積は0.98であったが、注解項目により診断能は異なっていた。以上より、YOLO v5を用いた小腸CEにおける対象検出AIモデルは効果的かつ理解が容易な読影補助となる可能性があることが示唆された。

Publisher：診断と治療社  

DOI： 10.34433/dt.0000000620

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Publisher：株式会社医学書院  

DOI： 10.11477/mf.1403203469

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Publisher：東京医学社  

DOI： 10.24479/endo.0000001234

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Publisher：株式会社医学書院  

DOI： 10.11477/mf.1403203479

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：JCO Global Oncology  

PURPOSE: Limited information is available regarding the characteristics and outcomes of stage IV small bowel adenocarcinoma (SBA) in Japan. This study examined the clinical and pathological characteristics and outcomes according to the treatment strategies in patients with stage IV SBA. METHODS: This retrospective observational study used the data of patients with jejunal or ileal adenocarcinoma collected by the Small Bowel Malignant Tumor Project of the Japanese Society for Cancer of the Colon and Rectum. Descriptive statistics were expressed as the mean (standard deviation) or median (range). Survival analysis was performed using Kaplan-Meier curves and pairwise log-rank tests. RESULTS: Data from 128 patients were analyzed. The treatment strategies were chemotherapy alone (26 of 128, 20.3%), surgery alone (including palliative surgery; 21 of 128, 16.4%), surgery + chemotherapy (74 of 128, 57.8%), and best supportive care (7 of 128, 5.5%). The median (range) overall survival was 16 (0-125) months overall, and 11 (1-38) months, 8 (0-80) months, 18 (0-125) months, and 0 (0-1) months for the chemotherapy, surgery, surgery + chemotherapy, and best supportive care groups, respectively. Three main categories of chemotherapeutic regimen were used: a combination of fluoropyrimidine and oxaliplatin (F + Ox), fluoropyrimidine and irinotecan (F + Iri), and single-agent fluoropyrimidine. Among patients treated with chemotherapy, the median (range) OS was 16 (1-106) months overall, and 17 (1-87) months, 29 (7-39) months, and 16 (1-106) months in patients treated with fluoropyrimidine, F + Iri, and F + Ox, respectively. CONCLUSION: Patients treated with surgery, chemotherapy, or both had a better prognosis than those who received best supportive care. Among patients who received chemotherapy, survival did not differ according to the chemotherapeutic regimen.

DOI： 10.1200/GO.23.00392

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Journal of Gastroenterology  

BACKGROUND: The clinicopathological features and prognosis of primary small bowel adenocarcinoma (PSBA), excluding duodenal cancer, remain undetermined due to its rarity in Japan. METHODS: We analyzed 354 patients with 358 PSBAs, between January 2008 and December 2017, at 44 institutions affiliated with the Japanese Society for Cancer of the Colon and Rectum. RESULTS: The median age was 67 years (218 males, 61.6%). The average tumor size was 49.9 (7-100) mm. PSBA sites consisted of jejunum (66.2%) and ileum (30.4%). A total of 219 patients (61.9%) underwent diagnostic small bowel endoscopy, including single-balloon endoscopy, double-balloon endoscopy, and capsule endoscopy before treatment. Nineteen patients (5.4%) had Lynch syndrome, and 272 patients (76.8%) had symptoms at the initial diagnosis. The rates for stages 0, I, II, III, and IV were 5.4%, 2.5%, 27.1%, 26.0%, and 35.6%, respectively. The 5-year overall survival rates at each stage were 92.3%, 60.0%, 75.9%, 61.4%, and 25.5%, respectively, and the 5-year disease-specific survival (DSS) rates were 100%, 75.0%, 84.1%, 59.3%, and 25.6%, respectively. Patients with the PSBA located in the jejunum, with symptoms at the initial diagnosis or advanced clinical stage had a worse prognosis. However, multivariate analysis using Cox-hazard model revealed that clinical stage was the only significant predictor of DSS for patients with PSBA. CONCLUSIONS: Of the patients with PSBA, 76.8% had symptoms at the initial diagnosis, which were often detected at an advanced stage. Detection during the early stages of PSBA is important to ensure a good prognosis.

DOI： 10.1007/s00535-024-02081-3

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Language：Japanese   Publisher：(株)医学書院  

＜文献概要＞過去23年間に当科および関連施設にて診断された大腸の孤立性若年性ポリープ(JP)101例,孤立性PJP(Peutz-Jeghers type polyp)29例,IMGP(inflammatory myoglandular polyp)18例を対象とし,その臨床像,内視鏡像,病理組織像を遡及的に検討した.その結果,JPは平均年齢が低かった.内視鏡所見では,JPはびらん,白苔,白斑,NBI拡大観察下の開大した腺管開口部や疎に分布した腺窩辺縁上皮,細かい血管の増生,色素拡大観察下の星芒状,疎に分布したpitの,PJPは分葉状,NBIや色素拡大観察下の樹枝状構造の,IMGPは白斑,NBI拡大観察下の開大した腺管開口部,細かい血管の増生,色素拡大観察下の星芒状pitの頻度がそれぞれ高かった.以上よりJP,IMGPとPJPは異なる内視鏡像を呈していたが,JPとIMGPの内視鏡像は比較的類似していた.しかしながら,JPはIMGPに比べ,白苔,NBIや色素拡大観察下の疎に分布する腺窩辺縁上皮やpitの頻度が高いことを加味すると鑑別できる可能性があるものと推察する.

Language：Japanese   Publisher：(株)医学書院  

＜文献概要＞過去23年間に当科および関連施設にて診断された大腸の孤立性若年性ポリープ(JP)101例,孤立性PJP(Peutz-Jeghers type polyp)29例,IMGP(inflammatory myoglandular polyp)18例を対象とし,その臨床像,内視鏡像,病理組織像を遡及的に検討した.その結果,JPは平均年齢が低かった.内視鏡所見では,JPはびらん,白苔,白斑,NBI拡大観察下の開大した腺管開口部や疎に分布した腺窩辺縁上皮,細かい血管の増生,色素拡大観察下の星芒状,疎に分布したpitの,PJPは分葉状,NBIや色素拡大観察下の樹枝状構造の,IMGPは白斑,NBI拡大観察下の開大した腺管開口部,細かい血管の増生,色素拡大観察下の星芒状pitの頻度がそれぞれ高かった.以上よりJP,IMGPとPJPは異なる内視鏡像を呈していたが,JPとIMGPの内視鏡像は比較的類似していた.しかしながら,JPはIMGPに比べ,白苔,NBIや色素拡大観察下の疎に分布する腺窩辺縁上皮やpitの頻度が高いことを加味すると鑑別できる可能性があるものと推察する.

Language：English   Publishing type：Research paper (scientific journal)   Publisher：The Japanese Society of Internal Medicine  

<p><b>Objective </b>T helper (Th) cells play a central role in the pathogenesis of ulcerative colitis (UC). The present study analyzed the changes in circulating T cells by administration of ustekinumab (UST), an interleukin-12/23p40 antibody. </p><p><b>Methods </b>CD4 T cells were isolated from peripheral blood at 0 and 8 weeks after UST treatment, and we analyzed the proportion of CD4 T cells by flow cytometry. Clinical information and laboratory data were obtained at 0, 8, and 16 weeks. </p><p><b>Patients </b>We evaluated 13 patients with UC who received UST for the induction of remission between July 2020 and August 2021. </p><p><b>Results </b>The median partial Mayo score improved from 4 (1-7) to 0 (0-6) (p<0.001) with UST. Among serological parameters, albumin concentrations, C-reactive protein concentrations, the sedimentation rate, and leucine-rich alpha 2 glycoprotein concentrations showed significant improvement with UST. A flow cytometric analysis of circulating CD4 T cells showed that the percentage of Th17 cells was significantly decreased by UST treatment in all patients (1.85% to 0.98%, p<0.0001). Th1 cells were significantly increased by UST treatment (9.52% to 10.4%, p<0.05), but Th2 and regulatory T cells were not significantly different. The high-Th17 subgroup had a significantly better partial Mayo score than the low-Th17 subgroup at 16 weeks after UST treatment (0 vs. 1, p=0.028). </p><p><b>Conclusion </b>Treatment with UST decreases circulating Th17 cells, suggesting that this change may be related to the anti-inflammatory effect of UC. </p>

DOI： 10.2169/internalmedicine.1724-23

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：The Japanese Society of Internal Medicine  

<p><b>Objective </b>T helper (Th) cells play a central role in the pathogenesis of ulcerative colitis (UC). The present study analyzed the changes in circulating T cells by administration of ustekinumab (UST), an interleukin-12/23p40 antibody. </p><p><b>Methods </b>CD4 T cells were isolated from peripheral blood at 0 and 8 weeks after UST treatment, and we analyzed the proportion of CD4 T cells by flow cytometry. Clinical information and laboratory data were obtained at 0, 8, and 16 weeks. </p><p><b>Patients </b>We evaluated 13 patients with UC who received UST for the induction of remission between July 2020 and August 2021. </p><p><b>Results </b>The median partial Mayo score improved from 4 (1-7) to 0 (0-6) (p<0.001) with UST. Among serological parameters, albumin concentrations, C-reactive protein concentrations, the sedimentation rate, and leucine-rich alpha 2 glycoprotein concentrations showed significant improvement with UST. A flow cytometric analysis of circulating CD4 T cells showed that the percentage of Th17 cells was significantly decreased by UST treatment in all patients (1.85% to 0.98%, p<0.0001). Th1 cells were significantly increased by UST treatment (9.52% to 10.4%, p<0.05), but Th2 and regulatory T cells were not significantly different. The high-Th17 subgroup had a significantly better partial Mayo score than the low-Th17 subgroup at 16 weeks after UST treatment (0 vs. 1, p=0.028). </p><p><b>Conclusion </b>Treatment with UST decreases circulating Th17 cells, suggesting that this change may be related to the anti-inflammatory effect of UC. </p>

DOI： 10.2169/internalmedicine.1724-23

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Language：English   Publisher：Journal of Gastroenterology and Hepatology (Australia)  

DOI： 10.1111/jgh.16347

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Language：English   Publisher：Journal of Gastroenterology and Hepatology (Australia)  

DOI： 10.1111/jgh.16347

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Language：English   Publisher：(一社)日本内科学会  

2020年7月～2021年8月に寛解導入目的でウステキヌマブ(UST)が投与された潰瘍性大腸炎(UC)患者13例(男性3例、女性10例、中央値42歳)を対象に、循環T細胞分画の変化を評価した。UST治療の0週目と8週目に末梢血からCD4 T細胞を分離し、フローサイトメトリーによりCD4 T細胞率を解析した。UST治療により、部分的Mayoスコア中央値が有意に改善し(4→0)、血清パラメータのうちアルブミン値、C反応性タンパク質値、沈降速度、ロイシンリッチα2グリコプロテイン値が有意に改善した。循環CD4 T細胞のフローサイトメトリー解析では、全患者でUST治療によりヘルパーT(Th)17細胞率が有意に低下し、Th1細胞率が有意に上昇したが、Th2細胞率と制御性T細胞率には有意な変化を認めなかった。治療開始前のTh17細胞率が2%超の患者は2%未満の患者に比べて16週時の部分的Mayoスコアが有意に良好であった(0 vs 1)。UC患者において、UST治療により循環Th17細胞が減少することが示された。

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Society for Clinical Epidemiology  

<p><b>BACKGROUND</b></p><p>This registry aims to allow for a prospective non-interventional observational study of ulcerative colitis. This will facilitate monitoring of the current state of ulcerative colitis in Japan and improving the long-term disease course and adverse events associated with current treatment options.</p><p><b>METHODS</b></p><p>Inclusion of patients from five centres in Japan is planned. The study is expected to take place from July 15, 2020, to November 30, 2024. Background, demographics, and medical history/information will be collected from electronic medical records at enrolment. Medical information including medications, laboratory data, and disease activity will be collected automatically from electronic medical records throughout the study. Patient-reported quality of life data will be collected directly from patients via smartphone. Efficacy endpoints (clinical remission rate, clinical improvement rate, and endoscopic healing rate) and safety endpoints (incidence of adverse events and specific ulcerative colitis-related events) will be collected according to treatment administered. Treatment categories include no treatment, 5-aminosalicylic acids, corticosteroids, immunomodulators, immunosuppressants, anti-tumour necrosis alpha agents, cytapheresis, Janus kinase inhibitors, anti-integrin antibodies, and anti-interleukin-12/23 antibodies.</p><p><b>CONCLUSIONS</b></p><p>The dataset will include cross-sectional and longitudinal data and is expected to capture the state of ulcerative colitis in Japan. Patients will be included on a large scale, and the registry will be established automatically from electronic medical records and direct patient input, facilitating the accurate recording of medical information for patients with ulcerative colitis in Japan and minimizing limitations intrinsic to databases that require manual data entry, such as the burden on participating investigators and entry of data with errors/typos.</p>

DOI： 10.37737/ace.24010

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Society for Clinical Epidemiology  

<p><b>BACKGROUND</b></p><p>This registry aims to allow for a prospective non-interventional observational study of ulcerative colitis. This will facilitate monitoring of the current state of ulcerative colitis in Japan and improving the long-term disease course and adverse events associated with current treatment options.</p><p><b>METHODS</b></p><p>Inclusion of patients from five centres in Japan is planned. The study is expected to take place from July 15, 2020, to November 30, 2024. Background, demographics, and medical history/information will be collected from electronic medical records at enrolment. Medical information including medications, laboratory data, and disease activity will be collected automatically from electronic medical records throughout the study. Patient-reported quality of life data will be collected directly from patients via smartphone. Efficacy endpoints (clinical remission rate, clinical improvement rate, and endoscopic healing rate) and safety endpoints (incidence of adverse events and specific ulcerative colitis-related events) will be collected according to treatment administered. Treatment categories include no treatment, 5-aminosalicylic acids, corticosteroids, immunomodulators, immunosuppressants, anti-tumour necrosis alpha agents, cytapheresis, Janus kinase inhibitors, anti-integrin antibodies, and anti-interleukin-12/23 antibodies.</p><p><b>CONCLUSIONS</b></p><p>The dataset will include cross-sectional and longitudinal data and is expected to capture the state of ulcerative colitis in Japan. Patients will be included on a large scale, and the registry will be established automatically from electronic medical records and direct patient input, facilitating the accurate recording of medical information for patients with ulcerative colitis in Japan and minimizing limitations intrinsic to databases that require manual data entry, such as the burden on participating investigators and entry of data with errors/typos.</p>

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Publisher：株式会社医学書院  

DOI： 10.11477/mf.1403203432

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：American Journal of Gastroenterology  

DOI： 10.14309/ajg.0000000000002366

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Language：Japanese   Publisher：(株)医学書院  

＜文献概要＞●胃神経内分泌腫瘍(NET)は発生環境の違いによりI～III型の3つの亜型に分類される.近年,いずれの亜型とも異なる胃壁細胞の機能不全によるIV型胃NETの症例が報告されている.今回,その臨床的特徴を明らかにすることを目的とした.当科でIV型胃NETと診断した1例とI型胃NETと診断した13例を対象とし,臨床背景,画像所見,採血データおよび内視鏡治療後標本の病理組織学的所見を比較した.IV型胃NET症例では,プロトンポンプのαサブユニットをコードするATP4A遺伝子に複合ヘテロ接合体の病的変異が確認された.IV型胃NET症例では胃底腺領域内に10個程度の発赤調の粘膜下腫瘍様隆起を認めていた.背景粘膜は肥厚様であり,I型胃NETでみられるA型胃炎とは明らかに異なっていた.I型胃NETとの臨床徴候の比較では,発症時年齢やガストリン値はほぼ同等であったが,抗胃壁細胞抗体と抗内因子抗体は陰性であることと,MCVと血清ビタミンB12は正常であることが異なっていた.IV型胃NETは,プロトンポンプの機能不全に起因する遺伝性疾患と考えられ,新規の疾患概念である.

Language：English   Publishing type：Research paper (scientific journal)   Publisher：American Journal of Gastroenterology  

DOI： 10.14309/ajg.0000000000002366

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Language：Japanese   Publisher：(株)医学書院  

＜文献概要＞●胃神経内分泌腫瘍(NET)は発生環境の違いによりI～III型の3つの亜型に分類される.近年,いずれの亜型とも異なる胃壁細胞の機能不全によるIV型胃NETの症例が報告されている.今回,その臨床的特徴を明らかにすることを目的とした.当科でIV型胃NETと診断した1例とI型胃NETと診断した13例を対象とし,臨床背景,画像所見,採血データおよび内視鏡治療後標本の病理組織学的所見を比較した.IV型胃NET症例では,プロトンポンプのαサブユニットをコードするATP4A遺伝子に複合ヘテロ接合体の病的変異が確認された.IV型胃NET症例では胃底腺領域内に10個程度の発赤調の粘膜下腫瘍様隆起を認めていた.背景粘膜は肥厚様であり,I型胃NETでみられるA型胃炎とは明らかに異なっていた.I型胃NETとの臨床徴候の比較では,発症時年齢やガストリン値はほぼ同等であったが,抗胃壁細胞抗体と抗内因子抗体は陰性であることと,MCVと血清ビタミンB12は正常であることが異なっていた.IV型胃NETは,プロトンポンプの機能不全に起因する遺伝性疾患と考えられ,新規の疾患概念である.

Language：English   Publisher：(一社)日本内科学会  

2021年10月～2022年2月、単一施設の炎症性腸疾患(IBD)患者411例を対象に、COVID-19ワクチン接種状況を調査し、臨床的寛解期に1回以上のワクチン接種を行った潰瘍性大腸炎(UC)患者188例とクローン病(CD)患者119例のワクチン接種後の経過を評価した。30日の追跡期間中、UC患者8例(4.3%)とCD患者1例(0.8%)でワクチン接種後の再燃を認めた。再燃を認めた計9例(男性3例、女性6例、中央値62歳)のうち、6例(UC患者5例、CD患者1例)は初回ワクチン接種後の再燃、3例(すべてUC患者)は2回目のワクチン接種後の再燃であった。8例(88.9%)ではワクチン接種後1週以内に再燃が認められ、2例(22.2%)は入院を要した。CD患者1例は、腹腔内膿瘍のために手術を要した。UC患者のうち、再燃を認めた患者と再燃を認めなかった患者で、ベースライン特性に有意差はなかった。COVID-19ワクチン接種後のIBD再燃は稀であることが示された。

Publisher：株式会社医学書院  

DOI： 10.11477/mf.1403203400

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DOI： 10.11477/mf.1403203397

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：The Japanese Society of Internal Medicine  

DOI： 10.2169/internalmedicine.1830-23

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DOI： 10.2169/internalmedicine.1830-23

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Language：English   Publisher：Digestive Endoscopy  

DOI： 10.1111/den.14664

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DOI： 10.1111/den.14664

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DOI： 10.11477/mf.1403203358

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Inflammatory Intestinal Diseases  

INTRODUCTION: Although the importance of mucosal healing has been suggested in Crohn's disease, it is difficult to repeat endoscopy, especially for the entire small bowel. Recently, serum leucine-rich alpha-2 glycoprotein (LRG) has been used as a surrogate marker of endoscopy. However, few studies have investigated a correlation between LRG and mucosal injury of the entire small bowel. METHODS: We retrospectively analyzed the clinical data of 30 patients with Crohn's disease from June 2020 to August 2022 at Yamaguchi Red Cross Hospital. All the patients were surveyed through the gastrointestinal tract by esophagogastroduodenoscopy, total colonoscopy, and capsule endoscopy (CE). Subjects with mucosal injury only in the small bowel were selected. Then, we assessed the relationship between serum biomarkers (LRG, C-reactive protein [CRP], hemoglobin, albumin) and small bowel mucosal injury scores (Lewis score [LS], Capsule Endoscopy Crohn's Disease Activity Index [CECDAI], and Crohn's Disease Activity in Capsule Endoscopy [CDACE]) calculated by CE. RESULTS: LRG and CRP were significantly correlated with small bowel mucosal injury scores (LS, CECDAI, CDACE) (p < 0.05, Spearman's rank correlation coefficient). The degree of correlation was greater for LRG than for CRP. CONCLUSIONS: LRG is a useful surrogate marker that closely reflects small bowel mucosal injury in the entire small bowel.

DOI： 10.1159/000531622

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Publisher：Journal of Gastroenterology  

Background: Evidence of small-bowel capsule endoscopy (SBCE) for evaluating lesions in Crohn’s disease (CD) is lacking. We aimed to clarify the effectiveness and safety of SBCE in a large sample of patients with CD. Methods: This multicenter prospective registration study recorded the clinical information and SBCE results of patients with definitive CD (d-CD) or suspected CD (s-CD). The primary outcomes were the rates of successful assessment of disease activity using SBCE, definitive diagnosis of CD, and adverse events. Secondary outcomes were the assessment of SBCE findings in patients with d-CD and s-CD and factors affecting SBCE incompletion and retention; and tertiary outcomes included the association between clinical disease activity or blood examination, endoscopic disease activity, ileal CD, and the questionnaire assessment of patient acceptance of SBCE. Results: Of 544 patients analyzed, 541 underwent SBCE with 7 (1.3%) retention cases. Of 468 patients with d-CD, 97.6% could be evaluated for endoscopic activity. Of 76 patients with s-CD, 15.8% were diagnosed with ‘confirmed CD’. CD lesions were more frequently observed in the ileum and were only seen in the jejunum in 3.4% of the patients. Male sex and stenosis were risk factors for incomplete SBCE, and high C-reactive protein levels and stenosis were risk factors for capsule retention. In L1 (Montreal classification) patients, clinical remission was associated with endoscopic remission but showed low specificity and accuracy. The answers to the acceptability questionnaire showed the minimal invasiveness and tolerability of SBCE. Conclusion: SBCE is practical and safe in patients with CD.

DOI： 10.1007/s00535-023-02017-3

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Publisher：Journal of Gastroenterology  

Background: Evidence of small-bowel capsule endoscopy (SBCE) for evaluating lesions in Crohn’s disease (CD) is lacking. We aimed to clarify the effectiveness and safety of SBCE in a large sample of patients with CD. Methods: This multicenter prospective registration study recorded the clinical information and SBCE results of patients with definitive CD (d-CD) or suspected CD (s-CD). The primary outcomes were the rates of successful assessment of disease activity using SBCE, definitive diagnosis of CD, and adverse events. Secondary outcomes were the assessment of SBCE findings in patients with d-CD and s-CD and factors affecting SBCE incompletion and retention; and tertiary outcomes included the association between clinical disease activity or blood examination, endoscopic disease activity, ileal CD, and the questionnaire assessment of patient acceptance of SBCE. Results: Of 544 patients analyzed, 541 underwent SBCE with 7 (1.3%) retention cases. Of 468 patients with d-CD, 97.6% could be evaluated for endoscopic activity. Of 76 patients with s-CD, 15.8% were diagnosed with ‘confirmed CD’. CD lesions were more frequently observed in the ileum and were only seen in the jejunum in 3.4% of the patients. Male sex and stenosis were risk factors for incomplete SBCE, and high C-reactive protein levels and stenosis were risk factors for capsule retention. In L1 (Montreal classification) patients, clinical remission was associated with endoscopic remission but showed low specificity and accuracy. The answers to the acceptability questionnaire showed the minimal invasiveness and tolerability of SBCE. Conclusion: SBCE is practical and safe in patients with CD.

DOI： 10.1007/s00535-023-02017-3

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：The Japanese Society of Internal Medicine  

DOI： 10.2169/internalmedicine.1177-22

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：The Japanese Society of Internal Medicine  

DOI： 10.2169/internalmedicine.1177-22

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：The Japanese Society of Internal Medicine  

<p><b>Objective </b>Flares of inflammatory bowel disease (IBD) can occur infrequently after vaccination for coronavirus disease 2019 (COVID-19), although the details of this phenomenon are poorly understood. To clarify the possibility of an unfavorable response in patients with IBD, we investigated IBD-related symptoms during the COVID-19 vaccination. </p><p><b>Methods </b>Between October 2021 and February 2022, we obtained the COVID-19 vaccination status of 411 IBD patients who were being treated at our institution. The disease course of IBD after vaccination was investigated in 188 patients with ulcerative colitis (UC) and 119 patients with Crohn's disease (CD) who had received at least one dose of the vaccine during the clinical remission phase. The baseline characteristics before vaccination were compared between the patients with UC with or without disease flares. </p><p><b>Results </b>During the 30-day follow-up period, eight patients with UC (4.3%) and one patient with CD (0.8%) experienced disease flares following vaccination. Disease flares occurred after the first vaccination in six patients and after the second vaccination in three patients. As for the timing of onset of disease flares, eight events (88.9%) occurred within one week of vaccination. Two patients required hospitalization, and one patient with CD required surgery for an intra-abdominal abscess. The baseline characteristics did not significantly differ between patients with UC who experienced flares and those who did not. </p><p><b>Conclusion </b>IBD flares following COVID-19 vaccination are rare and vaccination should therefore be recommended for patients with IBD. However, the possibility of disease flares should be considered for approximately one week after each vaccination, especially in patients with UC. </p>

DOI： 10.2169/internalmedicine.2335-23

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Language：English   Publisher：シュプリンガー・ジャパン(株)  

青黛の潰瘍性大腸炎への効果から、フェロトーシスと潰瘍性大腸炎発症との関連について解析した。遺伝子解析では、青黛治療により潰瘍性大腸炎患者の粘膜における抗酸化遺伝子の上昇が観察された。in vitro分析では、NRF2関連遺伝子発現が青黛によって上方制御された。青黛処理によって細胞のフェロトーシスに対する耐性が得られた。メタボロミクス分析では、青黛によって還元型グルタチオンの上昇が示唆された。青黛による治療により、直腸でCYP1A1とGPX4の蛋白質発現が上昇した。青黛の主成分のインジルビンとインディゴはフェロトーシスを阻害した。青黛で治療している潰瘍性大腸炎患者の直腸粘膜で、インジルビンが検出された。青黛による腸管上皮でのフェロトーシス抑制が潰瘍性大腸炎の治療の標的であり、青黛の主要な活性成分はインジルビンと考えられた。

Publisher：株式会社医学書院  

DOI： 10.11477/mf.1403203293

CiNii Research

Language：Japanese   Publisher：(株)医学書院  

＜文献概要＞非乳頭部十二指腸腫瘍様病変の内視鏡所見/拡大内視鏡所見を明らかにすることを目的として,当科において内視鏡的切除標本の検討により病理組織学的に腫瘍様病変(異所性胃粘膜,Brunner腺過形成,胃腺窩上皮型過形成性ポリープ,Peutz-Jeghers型ポリープ)と診断した症例を対象として抽出し,遡及的にその臨床所見と内視鏡所見/拡大内視鏡所見を検討した.内視鏡的切除により異所性胃粘膜5例,Brunner腺過形成・過誤腫13例,胃腺窩上皮型過形成性ポリープ12例,Peutz-Jeghers型ポリープ6例が診断されていた.拡大観察所見はdemarcation lineを胃腺窩上皮型過形成性ポリープで全例に認めたが,異所性胃粘膜60.0%,Brunner腺過形成では22.2%にとどまった.dense patternは異所性胃粘膜40.0%,胃腺窩上皮型過形成性ポリープ50.0%にみられたが,Brunner腺過形成では22.2%であった.腫瘍様病変の中で,胃腺窩上皮型過形成性ポリープ,異所性胃粘膜とBrunner腺過形成は表面全体ないし一部が胃腺窩型上皮に被覆されるため,NBI観察では背景粘膜に比してbrownishに見える.特に胃腺窩上皮型過形成性ポリープ,異所性胃粘膜は拡大観察でdense patternを呈する頻度が高く,NBI拡大観察が腫瘍様病変の診断に有用と考えられた.

Language：Japanese   Publisher：(株)医学書院  

＜文献概要＞非乳頭部十二指腸腫瘍様病変の内視鏡所見/拡大内視鏡所見を明らかにすることを目的として,当科において内視鏡的切除標本の検討により病理組織学的に腫瘍様病変(異所性胃粘膜,Brunner腺過形成,胃腺窩上皮型過形成性ポリープ,Peutz-Jeghers型ポリープ)と診断した症例を対象として抽出し,遡及的にその臨床所見と内視鏡所見/拡大内視鏡所見を検討した.内視鏡的切除により異所性胃粘膜5例,Brunner腺過形成・過誤腫13例,胃腺窩上皮型過形成性ポリープ12例,Peutz-Jeghers型ポリープ6例が診断されていた.拡大観察所見はdemarcation lineを胃腺窩上皮型過形成性ポリープで全例に認めたが,異所性胃粘膜60.0%,Brunner腺過形成では22.2%にとどまった.dense patternは異所性胃粘膜40.0%,胃腺窩上皮型過形成性ポリープ50.0%にみられたが,Brunner腺過形成では22.2%であった.腫瘍様病変の中で,胃腺窩上皮型過形成性ポリープ,異所性胃粘膜とBrunner腺過形成は表面全体ないし一部が胃腺窩型上皮に被覆されるため,NBI観察では背景粘膜に比してbrownishに見える.特に胃腺窩上皮型過形成性ポリープ,異所性胃粘膜は拡大観察でdense patternを呈する頻度が高く,NBI拡大観察が腫瘍様病変の診断に有用と考えられた.

Language：Others   Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

Background: Ferroptosis, a type of programmed cell death triggered by oxidative stress, was suspected to play a role in ulcerative colitis. Indigo naturalis is highly effective against ulcerative colitis, but its mechanism is unclear. This study found that indigo naturalis treatment suppressed ferroptosis. Methods: We analyzed 770 mRNA expressions of patients with ulcerative colitis. Suppression of ferroptosis by indigo naturalis treatment was shown using a cell death assay. Malondialdehyde levels and reactive oxygen species were analyzed in CaCo-2 cells treated with indigo naturalis. Glutathione metabolism was shown by metabolomic analysis. Extraction of the ingredients indigo naturalis from the rectal mucosa was performed using liquid chromatograph—mass spectrometry. Results: Gene expression profiling showed that indigo naturalis treatment increased antioxidant genes in the mucosa of patients with ulcerative colitis. In vitro analysis showed that nuclear factor erythroid-2-related factor 2-related antioxidant gene expression was upregulated by indigo naturalis. Indigo naturalis treatment rendered cells resistant to ferroptosis. Metabolomic analysis suggested that an increase in reduced glutathione by indigo naturalis. The protein expression of CYP1A1 and GPX4 was increased in the rectum by treatment with indigo naturalis. The main ingredients of indigo naturalis, indirubin and indigo inhibited ferroptosis. Indirubin was detected in the rectal mucosa of patients with ulcerative colitis who were treated with indigo naturalis. Conclusions: Suppression of ferroptosis by indigo naturalis in the intestinal epithelium could be therapeutic target for ulcerative colitis. The main active ingredient of indigo naturalis may be indirubin.

DOI： 10.1007/s00535-023-02016-4

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Other Link： https://link.springer.com/article/10.1007/s00535-023-02016-4/fulltext.html

Publisher：株式会社医学書院  

DOI： 10.11477/mf.1403203252

CiNii Research

Publisher：株式会社医学書院  

DOI： 10.11477/mf.1403203249

CiNii Research

Language：Others   Publishing type：Research paper (scientific journal)   Publisher：Wiley  

Abstract

Objectives

Artificial intelligence (AI) may be practical for image classification of small bowel capsule endoscopy (CE). However, creating a functional AI model is challenging. We attempted to create a dataset and an object detection CE AI model to explore modeling problems to assist in reading small bowel CE.

Methods

We extracted 18,481 images from 523 small bowel CE procedures performed at Kyushu University Hospital from September 2014 to June 2021. We annotated 12,320 images with 23,033 disease lesions, combined them with 6161 normal images as the dataset, and examined the characteristics. Based on the dataset, we created an object detection AI model using YOLO v5 and we tested validation.

Results

We annotated the dataset with 12 types of annotations, and multiple annotation types were observed in the same image. We test validated our AI model with 1396 images, and sensitivity for all 12 types of annotations was about 91%, with 1375 true positives, 659 false positives, and 120 false negatives detected. The highest sensitivity for individual annotations was 97%, and the highest area under the receiver operating characteristic curve was 0.98, but the quality of detection varied depending on the specific annotation.

Conclusions

Object detection AI model in small bowel CE using YOLO v5 may provide effective and easy‐to‐understand reading assistance. In this SEE‐AI project, we open our dataset, the weights of the AI model, and a demonstration to experience our AI. We look forward to further improving the AI model in the future.

DOI： 10.1002/deo2.258

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Language：English   Publisher：Journal of Gastroenterology  

In the original publication, ‘‘iCREST-CD Study Group’’ was not included in the author list. The correct author list is included in this Correction. Also, an Appendix listing iCREST-CD Study Group collaborators is included in this correction.

DOI： 10.1007/s00535-023-01998-5

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Language：Japanese   Publisher：(株)医学書院  

＜文献概要＞非特異性多発性小腸潰瘍症(CEAS)は持続的な出血に起因する慢性の貧血と低蛋白血症を特徴とする比較的まれな遺伝性疾患である.小腸に多発潰瘍を来すためCrohn病(CD)との鑑別が必要であるが,全例で遺伝学的検査を行うことは現実的でないため,簡便かつ非侵襲的なスクリーニング検査法が必要とされている.今回筆者らは,CEASとCDの鑑別における尿中プロスタグランジンE主要代謝産物(PGE-MUM)濃度の有用性について検討した.CEAS 20例とCD 98例を対象とした.PGE-MUM濃度はCD患者と比較しCEAS患者において有意に高値であった(中央値102.7 vs 27.9μg/g×Cre,p<0.0001).ROC解析では至適カットオフ値は48.9μg/g×Creと算出され,その際の感度は95.0%,特異度は79.6%であった.PGE-MUMは,CEASとCDの鑑別において有用な検査であると考えられた.

Language：Japanese   Publisher：(株)医学書院  

＜文献概要＞患者は10歳代,男性.主訴は腹痛,下痢.大腸内視鏡検査で上行結腸から下行結腸にかけて粘膜浮腫と縦走潰瘍を,S状結腸には小潰瘍から不整形潰瘍を認めた.Crohn病と診断しインフリキシマブを導入し,アザチオプリンの投与を行うものの寛解維持が困難であり,経過観察の大腸内視鏡検査では終末回腸はやや粗そうで,また直腸から連続性に全大腸に粗そう粘膜,びらん,血管透見像の消失を認めた.回腸からの生検では非乾酪性類上皮細胞肉芽腫を,大腸からの生検では炎症細胞浸潤,陰窩炎,陰窩膿瘍および杯細胞の減少を認めた.異時性にCrohn病,潰瘍性大腸炎両者の内視鏡所見を,同時性に両者の病理組織像を認めたことから,IBDUと診断した.青黛の内服投与で寛解導入され,3年後の大腸内視鏡検査では粘膜治癒が確認された.

Language：English   Publisher：Journal of Gastroenterology and Hepatology (Australia)  

DOI： 10.1111/jgh.16027

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Language：Japanese   Publisher：(株)医学書院  

＜文献概要＞非特異性多発性小腸潰瘍症(CEAS)は持続的な出血に起因する慢性の貧血と低蛋白血症を特徴とする比較的まれな遺伝性疾患である.小腸に多発潰瘍を来すためCrohn病(CD)との鑑別が必要であるが,全例で遺伝学的検査を行うことは現実的でないため,簡便かつ非侵襲的なスクリーニング検査法が必要とされている.今回筆者らは,CEASとCDの鑑別における尿中プロスタグランジンE主要代謝産物(PGE-MUM)濃度の有用性について検討した.CEAS 20例とCD 98例を対象とした.PGE-MUM濃度はCD患者と比較しCEAS患者において有意に高値であった(中央値102.7 vs 27.9μg/g×Cre,p<0.0001).ROC解析では至適カットオフ値は48.9μg/g×Creと算出され,その際の感度は95.0%,特異度は79.6%であった.PGE-MUMは,CEASとCDの鑑別において有用な検査であると考えられた.

Language：Japanese   Publisher：(株)医学書院  

＜文献概要＞患者は10歳代,男性.主訴は腹痛,下痢.大腸内視鏡検査で上行結腸から下行結腸にかけて粘膜浮腫と縦走潰瘍を,S状結腸には小潰瘍から不整形潰瘍を認めた.Crohn病と診断しインフリキシマブを導入し,アザチオプリンの投与を行うものの寛解維持が困難であり,経過観察の大腸内視鏡検査では終末回腸はやや粗そうで,また直腸から連続性に全大腸に粗そう粘膜,びらん,血管透見像の消失を認めた.回腸からの生検では非乾酪性類上皮細胞肉芽腫を,大腸からの生検では炎症細胞浸潤,陰窩炎,陰窩膿瘍および杯細胞の減少を認めた.異時性にCrohn病,潰瘍性大腸炎両者の内視鏡所見を,同時性に両者の病理組織像を認めたことから,IBDUと診断した.青黛の内服投与で寛解導入され,3年後の大腸内視鏡検査では粘膜治癒が確認された.

Language：English   Publisher：Journal of Gastroenterology and Hepatology (Australia)  

DOI： 10.1111/jgh.16027

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Gastrointestinal Endoscopy  

DOI： 10.1016/j.gie.2023.04.2086

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：The American journal of gastroenterology  

DOI： 10.14309/ajg.0000000000002175

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：The American journal of gastroenterology  

DOI： 10.14309/ajg.0000000000002175

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Publisher：株式会社医学書院  

DOI： 10.11477/mf.1403203197

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：iScience  

Although chemotherapy has been an essential treatment for cancer, the development of immune checkpoint blockade therapy was revolutionary, and a comprehensive understanding of the immunological tumor microenvironment (TME) has become crucial. Here, we investigated the impact of neoadjuvant chemotherapy (NAC) on immune cells in the TME of human esophageal squamous cell carcinoma using single cell RNA-sequencing. Analysis of 30 fresh samples revealed that CD8+/CD4+ T cells, dendritic cells (DCs), and macrophages in the TME of human esophageal squamous cell carcinoma showed higher levels of an anti-tumor immune response in the NAC(+) group than in the NAC(-) group. Furthermore, the immune cells of the NAC(+) group interacted with each other resulting in enhanced anti-tumor immune response via various cytokines, including IFNG in CD8+/CD4+ T cells, EBI3 in DCs, and NAMPT in macrophages. Our results suggest that NAC potentially enhances the anti-tumor immune response of immune cells in the TME.

DOI： 10.1016/j.isci.2023.106480

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：The Japanese Society of Internal Medicine  

<p><b>Objective </b>The risk of developing peptic ulcers and gastrointestinal bleeding is high in patients with chronic kidney disease (CKD). Whether or not kidney transplant patients, who are treated with multiple medications, including immunosuppressive drugs, are at an increased risk of developing peptic ulcers is unclear. </p><p><b>Methods </b>In this retrospective study, we compared the clinical and endoscopic features of gastroduodenal ulcers between kidney transplant patients and CKD patients. The subjects underwent upper gastrointestinal endoscopy between January 2015 and March 2021. </p><p><b>Results </b>Gastroduodenal ulcers were observed more frequently (6.5%) in kidney transplant patients than in CKD patients (2.1%) (p=0.026). Due in part to the lower median age in the kidney transplant ulcer group than in the CKD ulcer group (59 vs. 70 years old, p=0.016), the rates of atrophic gastritis and <i>Helicobacter pylori</i> infection were also lower in the kidney transplant ulcer group than in the CKD ulcer group. Significantly more kidney transplant patients were treated with acid secretion inhibitors than CKD ulcer patients (100% vs. 34.8%, p=0.0005). Peptic ulcers were observed frequently in kidney transplant patients, even though common risk factors for gastroduodenal ulcers other than immunosuppressive drugs were few. All kidney transplant patients were taking immunosuppressive medications, and tacrolimus, mycophenolate mofetil, and methylprednisolone were taken more frequently than others. </p><p><b>Conclusion </b>Kidney transplant patients have a high risk of developing gastroduodenal ulcers. All kidney transplant patients take immunosuppressive medications, so there may be an association between immunosuppressive medications and gastroduodenal ulcer development. </p>

DOI： 10.2169/internalmedicine.1508-22

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Digestive Diseases  

Introduction The proportion of gastroduodenal ulcers caused by drugs is increasing. However, the risk of gastroduodenal ulcer from drugs other than non-steroidal anti-inflammatory drugs (NSAIDs) and low-dose aspirin (LDA) is unclear. An association between immunosuppressive drugs and gastroduodenal ulcers has been suggested. We aimed to identify the immunosuppressive drugs and clinical characteristics associated with gastroduodenal ulcers in post-liver transplant patients. Methods The study investigated 119 patients who underwent esophagogastroduodenoscopy after liver transplantation and two patients were excluded. Clinical characteristics, medications, and endoscopic images were retrospectively reviewed. Results Among 117 post-living donor liver transplant recipients, gastroduodenal ulcers were found in 10 (9.2%) patients. The ulcer group had endoscopically gastritis more frequently (40%) compared with the non-ulcer group (10%). Logistic regression analysis revealed gastritis, NSAIDs use and mycophenolate mofetil were risk factors in the post-liver transplant patients. Among 103 patients not on NSAIDs, eight (7.8%) had peptic ulcer. The most common ulcer site and ulcer shape were the gastric antrum and a circular shape, respectively. All patients in the ulcer group were taking mycophenolate mofetil, which was the only immunosuppressive drug that showed a significant difference between the two groups. Five out of eight ulcer patients (63%) were taking gastric acid suppressants, and gastroduodenal ulcers in post-liver transplant recipients were suggested to be refractory. Conclusion Patients treated with immunosuppressive drugs after liver transplantation can develop gastroduodenal ulcers, even with gastric acid suppressant medication. Mycophenolate mofetil may increase the risk of gastroduodenal ulcers compared with other immunosuppressive drugs.

DOI： 10.1159/000530472

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Language：Japanese   Publisher：大道学館出版部  

72歳男性。前立腺癌の術後再発に対するホルモン療法中に肺、肝臓の多発腫瘤が認められ、当科へ紹介となった。上部消化管内視鏡では胃体下部前後壁に粘膜下腫瘍状隆起を伴う潰瘍性病変が認められた。経過中に高熱と全身倦怠感が著明となり、緊急入院となり、画像所見から悪性リンパ腫が疑われた。病歴を再確認した結果、関節リウマチに対するメトトレキサート(MTX)の内服歴が判明し、泌尿器科の精査結果を総合して、本症例は胃MTX関連リンパ増殖性疾患と診断された。治療としてMTXの休薬を行い、胃病変や多臓器の多発腫瘤は自然寛解した。2年経過現在、無再発生存中である。

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Journal of Crohn's and Colitis  

BACKGROUND AND AIMS: Perianal lesion is a refractory phenotype of Crohn's disease (CD) with significantly diminished quality of life. We evaluated the clinical characteristics of perianal lesions in newly diagnosed CD patients and the impact of perianal lesions on the quality of life in Japanese patients with CD. METHODS: Patients newly diagnosed with CD after June 2016 were included between December 2018 and June 2020 from the Inception Cohort Registry Study of Patients with CD (iCREST-CD). RESULTS: Perianal lesions were present in 324 (48.2%) of 672 patients with newly diagnosed CD. 71.9% (233/324) were male. The prevalence of perianal lesions was higher in patients aged <40 years versus ≥40 years, and it decreased with age. Perianal fistula (59.9%) and abscess (30.6%) were the most common perianal lesions. In multivariate analyses, male sex, age <40 years, and ileocolonic disease location were significantly associated with a high prevalence of perianal lesions, whereas stricturing behaviour and alcohol intake were associated with low prevalence. Fatigue was more frequent (33.3% vs 21.6%) and, work productivity and activity impairment-work time missed (36.3% vs 29.5%) and activity impairment (51.9% vs 41.1%) were numerically higher in patients with than those without perianal lesions. CONCLUSIONS: At the time of CD diagnosis, approximately half of the patients had perianal lesions; perianal abscesses and perianal fistulas were the most common. Young age, male sex, disease location, and behaviour are significantly associated with the presence of perianal lesions. The presence of perianal lesion was associated with fatigue and impairment of daily activities.

DOI： 10.1093/ecco-jcc/jjad038

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：International Journal of Colorectal Disease  

PURPOSE: Therapeutic efficacy of ustekinumab in the real-world data is limited in patients with refractory Crohn's disease (CD). In addition, factors predictive of better therapeutic efficacy of ustekinumab remains unsolved in CD. We aimed to evaluate therapeutic efficacy of ustekinumab in patients with refractory CD and to identify the factors associated with the efficacy of ustekinumab. METHODS: We retrospectively analyzed the clinical data of 72 patients treated with ustekinumab for refractory CD. Therapeutic efficacy was assessed at weeks 8, 26, 52, and 104 on the basis of dual remission, defined as the combination of Crohn's Disease Activity Index < 150 and CRP < 0.3 mg/dL, and factors predictive of the induction and maintenance of dual remission were investigated. The cumulative continuation rates and safety of ustekinumab were assessed. RESULTS: The dual remission rates at weeks 8, 26, 52, and 104 were 31.9%, 37.9%, 47.5%, and 42.6%, respectively. A short disease duration (≤ 2 years) and higher baseline serum albumin levels (≥ 3.1 g/dL) were positively associated with dual remission at weeks 8 and 52. Meanwhile, higher serum CRP levels (≥ 1.19 mg/dL) were negatively associated with dual remission at week 8. The cumulative ustekinumab continuation rate was favorable, and no severe adverse events were found. CONCLUSION: A short disease duration and higher baseline serum albumin levels might be predictive of favorable therapeutic efficacy of ustekinumab in refractory CD. Induction efficacy appears to be lower in patients with higher serum CRP levels.

DOI： 10.1007/s00384-023-04359-z

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Gastrointestinal Endoscopy  

DOI： 10.1016/j.gie.2022.10.030

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Gastrointestinal Endoscopy  

DOI： 10.1016/j.gie.2022.10.030

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Publisher：株式会社医学書院  

DOI： 10.11477/mf.1403203108

CiNii Research

Publisher：株式会社医学書院  

DOI： 10.11477/mf.1403203120

CiNii Research

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Journal of Gastroenterology and Hepatology (Australia)  

BACKGROUND AND AIM: The aim of this study was to elucidate the continuous use of antithrombotic medications during the peri-colorectal endoscopic submucosal dissection (ESD) period. METHODS: This study included 468 patients with colorectal epithelial neoplasms treated by ESD, consisting of 82 under antithrombotic medications and 386 patients without the medications. Among patients taking antithrombotic medications, antithrombotic agents were continued during the peri-ESD period. Clinical characteristics and adverse events were compared after propensity score matching. RESULTS: Before and after propensity score matching, post-colorectal ESD bleeding rate was higher in patients continuing antithrombotic medications (19.5% and 21.6%, respectively) than in those not taking antithrombotic medications (2.9% and 5.4%, respectively). In the Cox regression analysis, continuation of antithrombotic medications was associated with post-ESD bleeding risk (hazard ratio, 3.73; 95% confidence interval, 1.2-11.6; P < 0.05) compared with patients without antithrombotic therapy. All patients who experienced post-ESD bleeding were successfully treated by endoscopic hemostasis procedure or conservative therapy. CONCLUSIONS: Continuation of antithrombotic medications during the peri-colorectal ESD period increases the risk of bleeding. However, the continuation may be acceptable under careful monitoring for post-ESD bleeding.

DOI： 10.1111/jgh.16149

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Language：Japanese   Publisher：(株)医学書院  

＜文献概要＞過去13年間に当科および関連施設にて診断された癌併存大腸SSL 17例を対象とし,病理組織学的所見と対比可能であったSSLと癌の領域の内視鏡所見を遡及的に比較検討した.その結果,癌領域はSSL領域に比べ,発赤(癌領域64.7%/SSL領域0%,p<0.05),結節・顆粒状隆起(癌領域64.7%/SSL領域5.9%,p<0.05)が多くみられた.一方でSSL領域の色調は全例で同色調,ないし褪色調を呈した(癌領域35.3%/SSL領域100%,p<0.05).以上より発赤,結節・顆粒状隆起の存在が癌併存SSLにおける癌領域の特徴的な所見であり,癌併存大腸SSLは通常内視鏡で診断できる可能性が示唆された.

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Language：Japanese   Publisher：(株)医学書院  

＜文献概要＞過去13年間に当科および関連施設にて診断された癌併存大腸SSL 17例を対象とし,病理組織学的所見と対比可能であったSSLと癌の領域の内視鏡所見を遡及的に比較検討した.その結果,癌領域はSSL領域に比べ,発赤(癌領域64.7%/SSL領域0%,p<0.05),結節・顆粒状隆起(癌領域64.7%/SSL領域5.9%,p<0.05)が多くみられた.一方でSSL領域の色調は全例で同色調,ないし褪色調を呈した(癌領域35.3%/SSL領域100%,p<0.05).以上より発赤,結節・顆粒状隆起の存在が癌併存SSLにおける癌領域の特徴的な所見であり,癌併存大腸SSLは通常内視鏡で診断できる可能性が示唆された.

Language：Japanese   Publisher：(株)医学書院  

＜文献概要＞患者は50歳代,男性.20XX年8月より心窩部痛,嘔気,体重減少が出現し,当院へ紹介となった.上部消化管X線造影検査では前庭部から胃体部に辺縁の毛羽立ちと粗そうな粘膜像を認め,EGDでは前庭部から胃体部に不整形のびらんや潰瘍が多発していた.当初は胃MALTリンパ腫を疑ったが,風俗店の利用歴と梅毒血清反応陽性であったため胃生検組織の抗T. pallidum抗体染色を行い,胃梅毒と診断した.ペニシリン,アモキシシリンによる駆梅療法を行った結果,速やかに軽快した.近年,梅毒感染症の増加が報告されており,消化器領域の日常診療でも胃梅毒に注意すべきである.

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Gastrointestinal Endoscopy  

DOI： 10.1016/j.gie.2023.01.032

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BACKGROUND: Tumour immune microenvironment is related with carcinogenesis and efficacy of immunotherapy. B cells play major roles in humoral immunity, but detailed functions of tumour-infiltrating B lymphocytes (TIL-Bs) are unknown. Therefore, our aim was to investigate the functional heterogeneity of TIL-Bs in oesophageal squamous cell carcinoma (ESCC) and lymph nodes (LNs) during chemotherapy. METHODS: Single-cell transcriptome analysis was performed on 23 specimens. We also performed immunohistochemical analysis of immunoglobulin κ C (IGKC), an antibody-secreting cell (ASC) marker, in 166 ESCC samples and evaluated the implication of IGKC in 2-year recurrence free survival (RFS) and 3-year overall survival (OS). RESULTS: A total of 81,246 cells were grouped into 24 clusters. We extracted B cell clusters based on canonical markers and identified 12 TIL-B subtypes in ESCC. We found that several functions, such as co-stimulation and CD40 signalling, were enhanced in TIL-Bs after chemotherapy. The proportion of naive B cells (NBCs) decreased and B cell activation genes were up-regulated in NBCs after chemotherapy. The proportion of ASCs in tumours increased with the loss of migratory abilities and antibody production in ASCs was promoted after chemotherapy. Differentially expressed genes up-regulated with chemotherapy in ASCs correlated with prolonged survival with oesophageal cancer (p = .028). In a metastatic LN, the ASC proportion increased and B cell differentiation was enhanced. In immunohistochemical analysis, RFS and OS of high IGKC expression cases were significantly better than those of low IGKC expression cases (RFS: p < .0001, OS: p < .0001). And in multivariable analysis, the expression of IGKC was an independent favourable prognostic factor for RFS (hazard ratio (HR): 0.23, 95% confidence interval (CI): 0.12-0.45, p < .0001) and OS (HR: 0.20, 95% CI: 0.086-0.47, p = .0002) in ESCC. CONCLUSIONS: Our findings provide novel insights for the heterogeneity of TIL-Bs during chemotherapy and will be useful to understand the clinical importance of TIL-Bs.

DOI： 10.1002/ctm2.1181

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Digestive and Liver Disease  

DOI： 10.1016/j.dld.2022.08.024

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Digestive and Liver Disease  

DOI： 10.1016/j.dld.2022.08.024

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Publisher：株式会社医学書院  

DOI： 10.11477/mf.1403203050

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Journal of Gastroenterology  

BACKGROUND: The Inception Cohort Registry Study of Patients with Crohn's Disease aimed to clarify clinical characteristics and disease course of newly diagnosed Crohn's disease patients in Japan throughout a 4-year period. Results from an interim analysis of the largest nation-wide registry study that covers approximately 1% of Crohn's disease patient population in Japan are reported. METHODS: This prospective, observational registry study was conducted at 19 tertiary centers in Japan. Patients newly diagnosed with Crohn's disease after June 2016 (age ≥ 16 years at informed consent) were enrolled between December 17, 2018 and June 30, 2020. Patient demographics, diagnostic procedures and categories, disease location and lesion behavior (Montreal classification) at the time of diagnosis were recorded. RESULTS: Of 673 patients enrolled, 672 (99.9%) were analyzed (458: men, 214: women), male-to-female ratio: 2.1, median age at diagnosis 25 (range 13-86) years; peak age of disease diagnosis: 20-24 years. Most common disease location was L3 (ileocolonic; 60.1%). Non-stricturing, non-penetrating (B1) disease was most common behavior (62.8%); 48.9% reported perianal lesions. Notably, age-wise analysis revealed disease phenotypes varied between patients aged < 40 and ≥ 40 years in terms of male-to-female ratio (2.5/1.3)/disease location (L3: 66.3%/37.0%)/disease behavior (B1: 66.4%/50.0%)/perianal lesion: (55.7%/20.5%) at Crohn's disease diagnosis, respectively. CONCLUSIONS: Interim analysis of this nation-wide Inception Cohort Registry Study of Patients with Crohn's Disease revealed the demographics and disease characteristics of newly diagnosed Crohn's disease patients in Japan and demonstrated that disease phenotype varied between patients aged < 40 and ≥ 40 years, serving as important information for management of individual patients.

DOI： 10.1007/s00535-022-01907-2

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Language：Japanese   Publisher：(株)医学書院  

＜文献概要＞当科で内視鏡的ないし外科的切除により病理組織学的に非乳頭部十二指腸腺腫・癌と確定診断された85例94病変のうち胃型形質と診断された32例35病変を対象とし,その臨床病理学的特徴を遡及的に検討した.32例35病変の平均年齢は72.2歳で,男性25例,女性7例であった.35病変は十二指腸球部25病変(71.4%),下行部乳頭口側6病変(17.1%)と乳頭より近位側の十二指腸に好発し.肉眼型はSMT様隆起が20病変(57.1%),0-I型が14病変(40.0%)と丈の高い病変がほとんどであった.白色化は35病変中6病変(17.1%)に認めるのみであった.術前に生検を施行した26病変のなかで評価可能であった25病変中22病変(88.0%)で病理組織学的に胃型腫瘍の可能性が示唆されていた.切除標本を検討すると病理組織学的に病変表面には胃腺窩上皮への分化を示す細胞から成る領域を35病変中34病変(97.1%)に認めた.35病変は病理組織学的に腺腫26病変,NUMP(neoplasms of uncertain malignant potential)3病変,腺癌6病変に分類された.NBI併用拡大観察では,NUMPと癌は,腺腫と比較してirregular MS pattern, irregular MV patternをそれぞれより高頻度に認めた.腺癌は全例,高分化管状腺癌で,M癌2例,SM癌4例であった.35病変は優位形質から分類すると,MUC5AC優位型(foveolar type)15病変(腺腫13病変,NUMP 2病変),MUC6優位型(pyloric gland type)18病変(腺腫13病変,NUMP 1病変,腺癌4病変)と分類不能型2病変(腺癌2病変)に分類された.MUC6優位型でより高頻度にSMT様の形態を呈していた.

Language：Japanese   Publisher：(株)医学書院  

＜文献概要＞当科で内視鏡的ないし外科的切除により病理組織学的に非乳頭部十二指腸腺腫・癌と確定診断された85例94病変のうち胃型形質と診断された32例35病変を対象とし,その臨床病理学的特徴を遡及的に検討した.32例35病変の平均年齢は72.2歳で,男性25例,女性7例であった.35病変は十二指腸球部25病変(71.4%),下行部乳頭口側6病変(17.1%)と乳頭より近位側の十二指腸に好発し.肉眼型はSMT様隆起が20病変(57.1%),0-I型が14病変(40.0%)と丈の高い病変がほとんどであった.白色化は35病変中6病変(17.1%)に認めるのみであった.術前に生検を施行した26病変のなかで評価可能であった25病変中22病変(88.0%)で病理組織学的に胃型腫瘍の可能性が示唆されていた.切除標本を検討すると病理組織学的に病変表面には胃腺窩上皮への分化を示す細胞から成る領域を35病変中34病変(97.1%)に認めた.35病変は病理組織学的に腺腫26病変,NUMP(neoplasms of uncertain malignant potential)3病変,腺癌6病変に分類された.NBI併用拡大観察では,NUMPと癌は,腺腫と比較してirregular MS pattern, irregular MV patternをそれぞれより高頻度に認めた.腺癌は全例,高分化管状腺癌で,M癌2例,SM癌4例であった.35病変は優位形質から分類すると,MUC5AC優位型(foveolar type)15病変(腺腫13病変,NUMP 2病変),MUC6優位型(pyloric gland type)18病変(腺腫13病変,NUMP 1病変,腺癌4病変)と分類不能型2病変(腺癌2病変)に分類された.MUC6優位型でより高頻度にSMT様の形態を呈していた.

Language：English   Publisher：シュプリンガー・ジャパン(株)  

全国クローン病患者診断時登録コホート研究の目的は、4年間に日本で新たに診断されたクローン病患者の臨床的特徴と疾患の経過を明らかにすることである。日本におけるクローン病患者の約1%を網羅する国内最大の登録研究の中間解析結果を報告した。日本の第三次医療機関19ヶ所で、前向き観察登録研究を施行した。2016年6月以降に新たに診断された症例(同意取得時の年齢≧16歳)を2018年12月17日から2020年6月30日までの間に登録した。診断時における人口統計学的データ、診断方法および分類、疾患部位と病巣の状態(モントリオール分類)を記録した。673例が登録され、672例(99.9%)を対象とした(男性458例、女性214例)。男女比は2.1で診断時の年齢の中央値は25歳(範囲13～86)であった。診断時の年齢で最も多かったのは20～24歳であった。罹患部位が最も多かったのはL3(回盲部、60.1%)であった。非狭窄性、非穿通性病変(B1)が最も多い病態であった(62.8%)。48.9%に肛門周囲病変が認められた。年齢別の解析の結果、40歳未満と40歳以上との間で、診断時疾患の表現型のうち、男女比(2.5/1.3)、病変部位(L3、66.3%/37.0%)、病態(B1、66.4%/50.0%)、肛門周囲病変の合併(55.7%/20.5%)が異なっていた。全国クローン病患者診断時登録コホート研究の中間解析により、クローン病診断時の人口統計学的データおよび疾患特性が明らかになった。疾患表現型が40歳未満と40歳以上で異なることが見出された。

Publisher：東京医学社  

DOI： 10.24479/endo.0000000381

CiNii Research

Publisher：東京医学社  

DOI： 10.24479/endo.0000000474

CiNii Research

Publisher：株式会社医学書院  

DOI： 10.11477/mf.1403202993

CiNii Research

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Pathology Research and Practice  

Solid-type poorly differentiated adenocarcinoma (solid-type-PDA) of the stomach is a unique histological subtype of "tubular adenocarcinoma", but little is known about its clinicopathological features, molecular pathological characteristics and immunoregulatory tumor microenvironment. Herein, we examined the immunohistochemical expressions of mismatch repair (MMR) proteins (MLH1, PMS2, MSH2, MSH6) in 57 cases of solid-type-PDA and classified them as either MMR-deficient or -proficient (dMMR, N = 23; pMMR, N = 34), and additionally identified 18 dMMR-well-differentiated adenocarcinoma (WDA) and 34 pMMR-WDA as control groups. We analyzed and compared solid-type-PDA with WDA by evaluating the immunoexpressions of key immune pathway proteins (programmed death ligand 1 (PD-L1) and indoleamine 2,3-dioxygenase 1 (IDO1)) and tumor-infiltrating lymphocytes (TILs) (CD8, Foxp3 and PD-1). The results reveled IDO1 was significantly more frequent in dMMR-solid-type-PDA than in dMMR-WDA (P = 0.0046). Moreover, dMMR-solid-type-PDA tended to have higher mean CD8+ and Foxp3+ TILs compared with dMMR-WDA [P = 0.0006 (CD8+) and P = 0.1061 (Foxp3+)], and IDO1-positive tended to be associated with a large number of CD8+, Foxp3+ or PD-1+ TILs in almost all tumor subtypes. PD-L1 was significantly observed in 44 % (15/34) of pMMR-solid-type-PDA compared with 18 % (6/34) of pMMR-WDA (P = 0.0344). Although they are molecularly and morphologically classified as the same chromosomal instability subtype, overall survival (OS) and disease-free-survival (DFS) in pMMR-solid-type-PDA were significantly worse than those in pMMR-WDA [P = 0.0216 (OS) and P = 0.0160 (DFS)]. Our study demonstrates that immunoexpressions of several immunoregulatory proteins and TILs are more prevalent in dMMR-solid-type-PDA, potentially a useful discovery for designing tumor treatments with immune checkpoint inhibitors or combination therapies with a PD-1/PD-L1-inhibitor and IDO1-inhibitor.

DOI： 10.1016/j.prp.2022.154124

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Language：English   Publisher：シュプリンガー・ジャパン(株)  

E-カドヘリン欠損胃印環細胞癌(SRCC)における新規治療標的を同定することを目的とした。E-カドヘリンをコードするCDH1遺伝子をノックアウト(KO)したヒト胃オルガノイド(hGO)を用いて、in vitroのE-カドヘリン欠損胃癌モデルを作製し、新規治療標的を探索した。CDH1 KO hGO細胞は、SRCCに類似した特徴的な形態変化と高い細胞運動性を示した。RNA配列解析の結果、CDH1 KO hGO細胞では、野生型と比較して、マトリックスメタロプロテアーゼ(MMP)遺伝子の発現が増加していた。MMP阻害剤は、in vitroでCDH1 KO hGO細胞およびSRCC細胞株の細胞運動を抑制した。95例の臨床胃癌組織を用いた免疫蛍光分析により、MMP-3はE-カドヘリン異常のSRCCに特異的に多く存在することが示された。また、CDH1 KO後、CXCR4分子が細胞膜上に移行した。CXCR4のリガンドであるCXCL12を培養液に添加すると、CDH1 KO hGO細胞の細胞生存率が延長し、CXCR4アンタゴニストであるAMD3100によってその効果が消失した。SRCCの臨床サンプルでは、CXCL12を分泌する線維芽細胞が癌領域に著しく浸潤していることを確認した。以上より、MMPとCXCL12/CXCR4軸は、E-カドヘリン欠損SRCCの新規治療標的として有望な候補であると考えられた。

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Gastric Cancer  

BACKGROUND: Loss of E-cadherin expression is frequently observed in signet ring carcinoma (SRCC). People with germline mutations in CDH1, which encodes E-cadherin, develop diffuse gastric cancer at a higher rate. Loss of E-cadherin expression is thus assumed to trigger oncogenic development. METHODS: To investigate novel therapeutic targets for gastric SRCC, we engineered an E-cadherin-deficient SRCC model in vitro using a human gastric organoid (hGO) with CDH1 knockout (KO). RESULTS: CDH1 KO hGO cells demonstrated distinctive morphological changes similar to SRCC and high cell motility. RNA-sequencing revealed up-regulation of matrix metalloproteinase (MMP) genes in CDH1 KO hGO cells compared to wild type. MMP inhibitors suppressed cell motility of CDH1 KO hGO cells and SRCC cell lines in vitro. Immunofluorescent analysis with 95 clinical gastric cancer tissues revealed that MMP-3 was specifically abundant in E-cadherin-aberrant SRCC. In addition, CXCR4 molecules translocated onto the cell membrane after CDH1 KO. Addition of CXCL12, a ligand of CXCR4, to the culture medium prolonged cell survival of CDH1 KO hGO cells and was abolished by the inhibitor, AMD3100. In clinical SRCC samples, CXCL12-secreting fibroblasts showed marked infiltration into the cancer area. CONCLUSIONS: E-cadherin deficient SRCCs might gain cell motility through upregulation of MMPs. CXCL12-positive cancer-associated fibroblasts could serve to maintain cancer-cell survival as a niche. MMPs and the CXCL12/CXCR4 axis represent promising candidates as novel therapeutic targets for E-cadherin-deficient SRCC.

DOI： 10.1007/s10120-022-01307-8

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Language：English   Publisher：シュプリンガー・ジャパン(株)  

E-カドヘリン欠損胃印環細胞癌(SRCC)における新規治療標的を同定することを目的とした。E-カドヘリンをコードするCDH1遺伝子をノックアウト(KO)したヒト胃オルガノイド(hGO)を用いて、in vitroのE-カドヘリン欠損胃癌モデルを作製し、新規治療標的を探索した。CDH1 KO hGO細胞は、SRCCに類似した特徴的な形態変化と高い細胞運動性を示した。RNA配列解析の結果、CDH1 KO hGO細胞では、野生型と比較して、マトリックスメタロプロテアーゼ(MMP)遺伝子の発現が増加していた。MMP阻害剤は、in vitroでCDH1 KO hGO細胞およびSRCC細胞株の細胞運動を抑制した。95例の臨床胃癌組織を用いた免疫蛍光分析により、MMP-3はE-カドヘリン異常のSRCCに特異的に多く存在することが示された。また、CDH1 KO後、CXCR4分子が細胞膜上に移行した。CXCR4のリガンドであるCXCL12を培養液に添加すると、CDH1 KO hGO細胞の細胞生存率が延長し、CXCR4アンタゴニストであるAMD3100によってその効果が消失した。SRCCの臨床サンプルでは、CXCL12を分泌する線維芽細胞が癌領域に著しく浸潤していることを確認した。以上より、MMPとCXCL12/CXCR4軸は、E-カドヘリン欠損SRCCの新規治療標的として有望な候補であると考えられた。

Language：Japanese   Publisher：(一社)日本消化器内視鏡学会  

クエン酸マグネシウム(Mg)製剤による大腸内視鏡前処置後に著明な高Mg血症を生じた2例を経験した.両症例とも前処置前には腎障害を認めず,大腸癌による腸管切除歴を有していた.発症時,症例1は直腸吻合部付近の便塊貯留による糞便性腸閉塞を,症例2はS状結腸に吻合部狭窄による通過障害を認めていた.それぞれ全身管理のもとで用手摘便とバルーン拡張にて閉塞を解除することで病状の改善が得られた.潜在的に腸管通過障害を有する被験者では,腎機能に関わらずMg製剤を用いた前処置による高Mg血症の出現に十分注意する必要があると考えられた.(著者抄録)

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Other Link： https://search.jamas.or.jp/default/link?pub_year=2022&ichushi_jid=J00192&link_issn=&doc_id=20220926340005&doc_link_id=10.11280%2Fgee.64.1564&url=https%3A%2F%2Fdoi.org%2F10.11280%2Fgee.64.1564&type=J-STAGE&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00007_2.gif

Language：Japanese   Publisher：(一社)日本消化器内視鏡学会  

クエン酸マグネシウム(Mg)製剤による大腸内視鏡前処置後に著明な高Mg血症を生じた2例を経験した.両症例とも前処置前には腎障害を認めず,大腸癌による腸管切除歴を有していた.発症時,症例1は直腸吻合部付近の便塊貯留による糞便性腸閉塞を,症例2はS状結腸に吻合部狭窄による通過障害を認めていた.それぞれ全身管理のもとで用手摘便とバルーン拡張にて閉塞を解除することで病状の改善が得られた.潜在的に腸管通過障害を有する被験者では,腎機能に関わらずMg製剤を用いた前処置による高Mg血症の出現に十分注意する必要があると考えられた.(著者抄録)

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Gastric Cancer  

BACKGROUND: Loss of E-cadherin expression is frequently observed in signet ring carcinoma (SRCC). People with germline mutations in CDH1, which encodes E-cadherin, develop diffuse gastric cancer at a higher rate. Loss of E-cadherin expression is thus assumed to trigger oncogenic development. METHODS: To investigate novel therapeutic targets for gastric SRCC, we engineered an E-cadherin-deficient SRCC model in vitro using a human gastric organoid (hGO) with CDH1 knockout (KO). RESULTS: CDH1 KO hGO cells demonstrated distinctive morphological changes similar to SRCC and high cell motility. RNA-sequencing revealed up-regulation of matrix metalloproteinase (MMP) genes in CDH1 KO hGO cells compared to wild type. MMP inhibitors suppressed cell motility of CDH1 KO hGO cells and SRCC cell lines in vitro. Immunofluorescent analysis with 95 clinical gastric cancer tissues revealed that MMP-3 was specifically abundant in E-cadherin-aberrant SRCC. In addition, CXCR4 molecules translocated onto the cell membrane after CDH1 KO. Addition of CXCL12, a ligand of CXCR4, to the culture medium prolonged cell survival of CDH1 KO hGO cells and was abolished by the inhibitor, AMD3100. In clinical SRCC samples, CXCL12-secreting fibroblasts showed marked infiltration into the cancer area. CONCLUSIONS: E-cadherin deficient SRCCs might gain cell motility through upregulation of MMPs. CXCL12-positive cancer-associated fibroblasts could serve to maintain cancer-cell survival as a niche. MMPs and the CXCL12/CXCR4 axis represent promising candidates as novel therapeutic targets for E-cadherin-deficient SRCC.

DOI： 10.1007/s10120-022-01307-8

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Language：Japanese   Publisher：(一社)日本消化器内視鏡学会  

クエン酸マグネシウム(Mg)製剤による大腸内視鏡前処置後に著明な高Mg血症を生じた2例を経験した.両症例とも前処置前には腎障害を認めず,大腸癌による腸管切除歴を有していた.発症時,症例1は直腸吻合部付近の便塊貯留による糞便性腸閉塞を,症例2はS状結腸に吻合部狭窄による通過障害を認めていた.それぞれ全身管理のもとで用手摘便とバルーン拡張にて閉塞を解除することで病状の改善が得られた.潜在的に腸管通過障害を有する被験者では,腎機能に関わらずMg製剤を用いた前処置による高Mg血症の出現に十分注意する必要があると考えられた.(著者抄録)

Language：Japanese   Publisher：(一社)日本消化器内視鏡学会  

クエン酸マグネシウム(Mg)製剤による大腸内視鏡前処置後に著明な高Mg血症を生じた2例を経験した.両症例とも前処置前には腎障害を認めず,大腸癌による腸管切除歴を有していた.発症時,症例1は直腸吻合部付近の便塊貯留による糞便性腸閉塞を,症例2はS状結腸に吻合部狭窄による通過障害を認めていた.それぞれ全身管理のもとで用手摘便とバルーン拡張にて閉塞を解除することで病状の改善が得られた.潜在的に腸管通過障害を有する被験者では,腎機能に関わらずMg製剤を用いた前処置による高Mg血症の出現に十分注意する必要があると考えられた.(著者抄録)

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Other Link： https://search.jamas.or.jp/default/link?pub_year=2022&ichushi_jid=J00192&link_issn=&doc_id=20220926340005&doc_link_id=10.11280%2Fgee.64.1564&url=https%3A%2F%2Fdoi.org%2F10.11280%2Fgee.64.1564&type=J-STAGE&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00007_2.gif

Publisher：東京医学社  

DOI： 10.24479/endo.0000000301

CiNii Research

Publisher：東京医学社  

DOI： 10.24479/endo.0000000300

CiNii Research

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Clinical Journal of Gastroenterology  

A 71-year-old man was admitted to our institution complaining of abdominal pain and constipation. Barium enema examination revealed narrowing, cobble stoning, and longitudinal ulcerations in the sigmoid colon and upper rectum. Conventional colonoscopy, magnifying narrow-band imaging endoscopy, and magnifying chromoendoscopy revealed edematous mucosa, longitudinal ulcerations with luminal narrowing, and multiple pseudopolyps. The histologic examination of the biopsy specimens showed thick-walled (arterialized) capillaries and subendothelial fibrin deposits in the mucosa and submucosa. Based on a preoperative diagnosis of idiopathic myointimal hyperplasia of mesenteric veins (IMHMV), he underwent a laparoscopic resection of the sigmoid colon and upper rectum. The histologic examination of the resected specimens showed marked proliferation of venous walls with marked myointimal thickening and luminal occlusion from the submucosa to the mesentery throughout the entire resected tissue section. The final diagnosis was IMHMV.

DOI： 10.1007/s12328-022-01647-z

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Clinical Journal of Gastroenterology  

A 71-year-old man was admitted to our institution complaining of abdominal pain and constipation. Barium enema examination revealed narrowing, cobble stoning, and longitudinal ulcerations in the sigmoid colon and upper rectum. Conventional colonoscopy, magnifying narrow-band imaging endoscopy, and magnifying chromoendoscopy revealed edematous mucosa, longitudinal ulcerations with luminal narrowing, and multiple pseudopolyps. The histologic examination of the biopsy specimens showed thick-walled (arterialized) capillaries and subendothelial fibrin deposits in the mucosa and submucosa. Based on a preoperative diagnosis of idiopathic myointimal hyperplasia of mesenteric veins (IMHMV), he underwent a laparoscopic resection of the sigmoid colon and upper rectum. The histologic examination of the resected specimens showed marked proliferation of venous walls with marked myointimal thickening and luminal occlusion from the submucosa to the mesentery throughout the entire resected tissue section. The final diagnosis was IMHMV.

DOI： 10.1007/s12328-022-01647-z

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Language：English   Publisher：シュプリンガー・ジャパン(株)  

症例は71歳男性で、4ヵ月前からの間欠性腹痛と便秘を訴えて入院した。バリウム注腸検査で、S状結腸と上部直腸の狭窄、cobble stoning、縦断的潰瘍形成が認められた。従来型結腸鏡検査と拡大狭帯域光観察、拡大色素内視鏡検査では、浮腫性粘膜、内腔狭窄と皺襞集中像を伴う縦断的潰瘍形成、多発性ポリープ様病変が認められた。生検標本の組織学的所見は、厚壁(動脈化)毛細管、粘膜および粘膜下層の内皮下フィブリン沈着であった。直腸S状結腸の特発性腸間膜静脈筋内膜過形成(IMHMV)と術前診断し、S状結腸と上部直腸の腹腔鏡下切除術を行った。切除標本の組織学的所見は、著明な筋内膜肥厚を伴う静脈壁の著明な増殖、粘膜下層から腸間膜への内腔閉塞であった。IMHMVと最終診断した。術後8ヵ月の時点で、再発の徴候は認めていない。

Language：English   Publisher：The Japanese Society of Internal Medicine  

DOI： 10.2169/internalmedicine.8475-21

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Language：English   Publisher：The Japanese Society of Internal Medicine  

DOI： 10.2169/internalmedicine.8475-21

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Publisher：株式会社医学書院  

DOI： 10.11477/mf.1403202916

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Publisher：株式会社医学書院  

DOI： 10.11477/mf.1403202910

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Publisher：株式会社医学書院  

DOI： 10.11477/mf.1403202757

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Publisher：株式会社医学書院  

DOI： 10.11477/mf.1403202793

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Publisher：株式会社医学書院  

DOI： 10.11477/mf.1403202850

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Publisher：株式会社医学書院  

DOI： 10.11477/mf.1403202844

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Publisher：株式会社医学書院  

DOI： 10.11477/mf.1403202819

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Publisher：株式会社医学書院  

DOI： 10.11477/mf.1403202830

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Publisher：株式会社医学書院  

DOI： 10.11477/mf.1403202762

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Language：English   Publisher：Digestive and Liver Disease  

DOI： 10.1016/j.dld.2020.11.014

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Language：Japanese   Publisher：(株)医学書院  

＜文献概要＞過去15年間に当科および関連施設にて診断された原発性空・回腸癌19例を対象とし,臨床像,小腸X線造影所見を検討した.平均腫瘍径は43.4mmで,病変部位は空腸12例,回腸7例であった.肉眼型は潰瘍型が14例と最多で,すべて輪状狭窄型であった.TNM分類Stage IVの割合が高く(32%),5年後のOS(overall survival)は58%,TNM分類Stage IVはOS,EFS(event-free survival)の,空腸,潰瘍型はEFSの予後不良因子であった.小腸X線造影所見では輪状狭窄型の全例,および全周性の隆起型病変でnapkin-ring sign,口側腸管の拡張像を,輪状狭窄型はさらに全例でoverhanging edgeを認めた.以上より,原発性空・回腸癌の予後不良因子はTNM分類Stage IVであり,輪状狭窄型および全周性の隆起型病変は特徴的な小腸X線造影検査所見を有していた.

Language：English   Publisher：Digestive and Liver Disease  

DOI： 10.1016/j.dld.2020.11.014

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Language：Japanese   Publisher：(株)医学書院  

＜文献概要＞過去15年間に当科および関連施設にて診断された原発性空・回腸癌19例を対象とし,臨床像,小腸X線造影所見を検討した.平均腫瘍径は43.4mmで,病変部位は空腸12例,回腸7例であった.肉眼型は潰瘍型が14例と最多で,すべて輪状狭窄型であった.TNM分類Stage IVの割合が高く(32%),5年後のOS(overall survival)は58%,TNM分類Stage IVはOS,EFS(event-free survival)の,空腸,潰瘍型はEFSの予後不良因子であった.小腸X線造影所見では輪状狭窄型の全例,および全周性の隆起型病変でnapkin-ring sign,口側腸管の拡張像を,輪状狭窄型はさらに全例でoverhanging edgeを認めた.以上より,原発性空・回腸癌の予後不良因子はTNM分類Stage IVであり,輪状狭窄型および全周性の隆起型病変は特徴的な小腸X線造影検査所見を有していた.

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Digestion  

INTRODUCTION: An association has been found between human-gut microbiota and various diseases (e.g., metabolic disease) by analyzing fecal or colonic microbiota. Despite the importance of the small intestinal microbiota, sampling difficulties prevent its full analysis. We investigated the composition and metagenomic functions of microbiota along the small intestine and compared them with the microbiota from feces and from other gastrointestinal (GI) sites. METHODS: Mucosal samples from the six GI sites (stomach, duodenum, distal jejunum, proximal ileum, terminal ileum, and rectum) were collected under balloon-assisted enteroscopy. Fecal samples were collected from all participants. The microbial structures and metagenomic functions of the small intestinal mucosal microbiota were compared with those from feces and other GI sites using 16S ribosomal RNA gene sequencing. RESULTS: We analyzed 133 samples from 29 participants. Microbial beta diversity analysis showed that the jejunum and ileum differed significantly from the lower GI tract and the feces (p < 0.001). Jejunal and duodenal microbiotas formed similar clusters. Wide clusters spanning the upper and lower GI tracts were observed with the ileal microbiota, which differed significantly from the jejunal microbiota (p < 0.001). Veillonella and Streptococcus were abundant in the jejunum but less so in the lower GI tract and feces. The metagenomic functions associated with nutrient metabolism differed significantly between the small intestine and the feces. CONCLUSIONS: The fact that the compositional structures of small intestinal microbiota differed from those of fecal and other GI microbiotas reveals that analyzing the small intestinal microbiota is necessary for association studies on metabolic diseases and gut microbiota.

DOI： 10.1159/000524023

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Intestinal Research  

BACKGROUND/AIMS: Recent studies suggested a favorable effect of indigo naturalis (IN) in inducing remission for refractory ulcerative colitis (UC), however, the maintenance effect of IN for patients with UC remains unknown. Therefore, we conducted a prospective uncontrolled open-label study to analyze the efficacy and safety of IN for patients with UC. METHODS: Patients with moderate to severe active UC (clinical activity index [CAI] ≥ 8) took 2 g/day of IN for 52 weeks. CAI at weeks 0, 4, 8, and 52 and Mayo endoscopic subscore (MES) and Geboes score (GS) at weeks 0, 4, and 52 were assessed. Clinical remission (CAI ≤ 4), mucosal healing (MES ≤ 1), and histological healing (GS ≤ 1) rates at each assessment were evaluated. Overall adverse events (AEs) during study period were also evaluated. The impact of IN on mucosal microbial composition was assessed using 16S ribosomal RNA gene sequences. RESULTS: Thirty-three patients were enrolled. The rates of clinical remission at weeks 4, 8, and 52 were 67%, 76%, and 73%, respectively. The rates of mucosal healing at weeks 4 and 52 were 48% and 70%, respectively. AEs occurred in 17 patients (51.5%) during follow-up. Four patients (12.1%) showed severe AEs, among whom 3 manifested acute colitis. No significant alteration in the mucosal microbial composition was observed with IN treatment. CONCLUSIONS: One-year treatment of moderate to severe UC with IN was effective. IN might be a promising therapeutic option for maintaining remission in UC, although the relatively high rate of AEs should be considered.

DOI： 10.5217/ir.2021.00124

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Intestinal Research  

BACKGROUND/AIMS: Recent studies suggested a favorable effect of indigo naturalis (IN) in inducing remission for refractory ulcerative colitis (UC), however, the maintenance effect of IN for patients with UC remains unknown. Therefore, we conducted a prospective uncontrolled open-label study to analyze the efficacy and safety of IN for patients with UC. METHODS: Patients with moderate to severe active UC (clinical activity index [CAI] ≥ 8) took 2 g/day of IN for 52 weeks. CAI at weeks 0, 4, 8, and 52 and Mayo endoscopic subscore (MES) and Geboes score (GS) at weeks 0, 4, and 52 were assessed. Clinical remission (CAI ≤ 4), mucosal healing (MES ≤ 1), and histological healing (GS ≤ 1) rates at each assessment were evaluated. Overall adverse events (AEs) during study period were also evaluated. The impact of IN on mucosal microbial composition was assessed using 16S ribosomal RNA gene sequences. RESULTS: Thirty-three patients were enrolled. The rates of clinical remission at weeks 4, 8, and 52 were 67%, 76%, and 73%, respectively. The rates of mucosal healing at weeks 4 and 52 were 48% and 70%, respectively. AEs occurred in 17 patients (51.5%) during follow-up. Four patients (12.1%) showed severe AEs, among whom 3 manifested acute colitis. No significant alteration in the mucosal microbial composition was observed with IN treatment. CONCLUSIONS: One-year treatment of moderate to severe UC with IN was effective. IN might be a promising therapeutic option for maintaining remission in UC, although the relatively high rate of AEs should be considered.

DOI： 10.5217/ir.2021.00124

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Language：English   Publisher：Gastrointestinal Endoscopy  

DOI： 10.1016/j.gie.2021.09.032

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Language：English   Publisher：Gastrointestinal Endoscopy  

DOI： 10.1016/j.gie.2021.09.032

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Human Pathology  

Lymphoproliferative disorder (LPD) can occur in patients with inflammatory bowel disease (IBD) such as ulcerative colitis (UC) and Crohn's disease (CD). On rare occasion, patients with IBD develop myeloid neoplasms; however, the frequency and clinicopathological features of IBD-associated lymphoid and myeloid proliferative disorder (LMPD) in Japanese patients is still unclear. In this study, we reviewed 2474 Japanese patients with IBD, and found that LMPD occurred in 12 (0.5%) patients with UC (n=7) or CD (n=5). Together with an additional 3 cases, we analyzed a total of 15 cases of LMPD for clinicopathological and histological features. Based on the status of using immunosuppressants such as biologics and immunomodulators, Epstein-Barr virus (EBV) infection, and histopathology, the 15 cases were classified into the Group I (high-grade LPD; n=7), Group II (low-grade LPD; n=5), and Group III (myeloid neoplasms; n=3). Most patients in Group I were undergoing strong immunosuppressive therapy, and the LPD lesions corresponded to high-grade B-cell or T/NK-cell lymphoma often with EBV infection. Discontinuation of immunosuppressive drugs alone did not resolve these LPDs; Group I patients required chemotherapy, and eventually 4 of them (57%) died of the tumor. Most cases in Group II were low-grade B-cell lymphoma without EBV infection and had an indolent clinical course with excellent prognosis. All patients in Group III developed acute myeloid leukemia (AML) during the course of CD. Two (67%) of these patients died of AML. Our study suggests that IBD-associated LMPD is very rare, but can follow an aggressive clinical course.

DOI： 10.1016/j.humpath.2021.12.010

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Language：Japanese   Publisher：Japan Gastroenterological Endoscopy Society  

<p>Two cases of extreme hypermagnesemia occurred after administration of bowel preparation with magnesium citrate for colonoscopy. Neither patient had renal dysfunction but both had a history of bowel resection for treatment of colorectal cancer. Each patient presented with bowel obstruction secondary to fecal impaction at the rectal anastomosis or severe anastomotic stricture at the sigmoid colon. The hypermagnesemia improved in each with the successful release of the bowel obstruction by digital disimpaction or balloon dilation under systemic management. In a patient with a possible intestinal obstruction, the risk of hypermagnesemia incidence with bowel preparation with magnesium products should be considered regardless of renal function.</p>

DOI： 10.11280/gee.64.1564

Scopus

CiNii Research

Language：Japanese   Publisher：Japan Gastroenterological Endoscopy Society  

<p>Two cases of extreme hypermagnesemia occurred after administration of bowel preparation with magnesium citrate for colonoscopy. Neither patient had renal dysfunction but both had a history of bowel resection for treatment of colorectal cancer. Each patient presented with bowel obstruction secondary to fecal impaction at the rectal anastomosis or severe anastomotic stricture at the sigmoid colon. The hypermagnesemia improved in each with the successful release of the bowel obstruction by digital disimpaction or balloon dilation under systemic management. In a patient with a possible intestinal obstruction, the risk of hypermagnesemia incidence with bowel preparation with magnesium products should be considered regardless of renal function.</p>

DOI： 10.11280/gee.64.1564

Scopus

CiNii Research

Language：Japanese   Publisher：The Japanese Society of Small Intestinal Disease  

<p>【背景】</p><p>　クローン病（CD）は小腸診療において多く遭遇する疾患の一つである。炎症性腸疾患において、1〜3%程度の頻度でCOVID-19ワクチン接種後に病勢が増悪することが報告されているが、潰瘍性大腸炎と統合された頻度であり、個々の病態の変化に関する詳細な報告は少ない。そこで我々は、CDにおけるCOVID-19ワクチン接種後の病勢変化を明らかにすることを目的とし、本研究を行なった。</p><p>【方法】</p><p>　2021年10月から2022年2月の期間に、当科通院中のCD患者を対象にワクチン接種状況および接種前後のCDに関連する症状について後方視的観察研究を行った。</p><p>　詳細な臨床情報が得られた179例中、ワクチン接種を受けていた患者は148例であった。非ストーマ患者では接種前後のHarvey-Bradshaw index（HBI）を、ストーマ患者ではInternational organization for the study of IBD score（IOIBD）を算出した。</p><p>　接種前のHBI≦３もしくはIOIBD≦1を寛解期、HBI≧4もしくはIOIBD≧2を活動期と定義し、⊿HBI≧2あるいは⊿IOIBD≧2を増悪と定義した。接種後の発熱や倦怠感は4日以上持続するものを全身状態の悪化と判定した。</p><p>【結果】</p><p>　ワクチンを接種したCD症例148例の平均年齢は44.3歳であり、男性104例、女性44例で、病型は小腸大腸型が87例、小腸型が43例、大腸型が18例であった。</p><p>　接種前のHBIおよびIOIBDの平均値はそれぞれ0.51および0.2であり、寛解期が119例、活動期が29例であった。病勢が増悪した症例を2例認めた。寛解期に増悪を認めた症例は1例（0.8%）で、初回接種の7日後から増悪し、腹腔内膿瘍のため手術を要した。活動期に増悪を認めた症例も１例（3.4%）であり、2回の接種期間を通じて徐々に増悪したため、ステロイドおよびアザチオプリン内服を追加した。</p><p>【結語】</p><p>　CDにおいて、ワクチン接種後に病勢が増悪した症例を２例（1.4％）認めたものの、頻度は極めて少なく、ウィズコロナ時代において、CD患者へのワクチン接種は推奨されるべきと考えられた。</p>

DOI： 10.32264/shocho.6.0_56

CiNii Research

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: The mortality and risk factors of severe disease and death due to arterial and venous thromboembolism (ATE and VTE, respectively) in patients with inflammatory bowel disease (IBD) remain unclear, especially in Asia. AIMS: This study aimed to reveal the mortality and risk factors of TE in IBD patients in Japan. METHODS: In the primary surveillance, responses to questionnaires regarding the number of cases of severe TE and TE-associated death in IBD patients in a span of over the past 10 years were obtained from 32 institutions in Japan. In the secondary surveillance, detailed data about IBD patients with TE were collected. The characteristics, laboratory data, therapy status, and situation at the time of TE development were retrospectively collected, and the data were compared between the patients with and without severe TE and TE-associated death. RESULTS: The incidence of TE was 1.89% among 31,940 IBD patients. The frequencies of severe TE and TE-associated mortality were 10.7% and 1.0% among the total IBD and TE with IBD patients, respectively. The only risk factor for severe ATE and ATE-associated death was ischemic heart disease. The independent risk factors for severe VTE and VTE-associated death were age (≤ 45 years old), the site of VTE, and disease severity, with anti-TNF therapy as a potential negative risk factor. Patients with severe VTE had a high risk of developing persistent VTE and sequelae. CONCLUSION: Unlike ATE, the incidence of VTE was comparable in Asian and Western countries. Therapeutic and prophylactic strategies for managing IBD-associated TE in Asia are urgently needed.

DOI： 10.1007/s00535-021-01829-5

Language：English   Publishing type：Research paper (scientific journal)  

ABSTRACT: To investigate the mucosal microbiota in the stomach of patients with Helicobacter pylori-negative mucosa-associated lymphoid tissue (MALT) lymphoma by means of metagenomic analysis.Although some gastric MALT lymphomas are associated with the presence of H. pylori, other gastric MALT lymphomas occur independently of H. pylori infection. The pathogenesis of H. pylori-negative MALT lymphoma remains unclear.Mucosal biopsy specimens were collected from the gastric body from 33 MALT lymphoma patients with gastric lesions, including both H. pylori-infection naïve patients and posteradication patients, as well as 27 control participants without H. pylori infection or cancer. Subsequently, the samples were subjected to 16S rRNA gene sequencing. Quantitative insights into microbial ecology, linear discriminant analysis effect size, and phylogenetic investigation of communities by reconstruction of unobserved states softwares were used to analyze the participants' microbiota.H. pylori-negative MALT lymphoma patients had significantly lower alpha diversity (P = .04), compared with control participants. Significant differences were evident in the microbial composition (P = .04), as determined by comparison of beta diversity between the 2 groups. Taxonomic composition analysis indicated that the genera Burkholderia and Sphingomonas were significantly more abundant in MALT lymphoma patients, while the genera Prevotella and Veillonella were less abundant. Functional microbiota prediction showed that the predicted gene pathways "replication and repair," "translation," and "nucleotide metabolism" were downregulated in MALT lymphoma patients.H. pylori-negative MALT lymphoma patients exhibited altered gastric mucosal microbial compositions, suggesting that altered microbiota might be involved in the pathogenesis of H. pylori-negative MALT lymphoma.

DOI： 10.1097/MD.0000000000027287

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Ustekinumab (UST), an antibody targeting the p40 subunit of interleukin (IL)-12 and IL-23, is effective in treating Crohn's disease (CD). To clarify the mechanism of UST, we investigated T-cell differentiation in CD patients treated with UST. METHODS: Twenty-seven patients with active CD were enrolled in this study. Seventeen patients were treated with UST, and 10 patients were treated with anti-tumor necrosis factor (TNF)-alpha therapy. The changes in the proportions of T-cell subsets after these therapies were analyzed by flow cytometry. Comprehensive gene expression changes in the colonic mucosa were also evaluated. RESULTS: The frequency of T helper (Th) 17 cells was significantly decreased in the peripheral blood of patients with active CD after UST therapy. Anti-TNF therapy had a minimal effect on Th17 cells but increased the proportion of regulatory T cells. Enrichment analysis showed the expression of genes involved in the Th17 differentiation pathway was downregulated in the colonic mucosa after UST but not anti-TNF therapy. There were no common differentially expressed genes between CD patients treated with UST and anti-TNF therapy, suggesting a clear difference in their mechanism of action. CONCLUSION: In patients with active CD, UST therapy suppressed Th17 cell differentiation both in the peripheral blood and colonic tissues.

DOI： 10.1159/000518103

Language：English   Publishing type：Research paper (scientific journal)  

Background With recent advances in endoscopic modalities, small bowel vascular lesions (SBVLs) are often now detected in patients with gastrointestinal bleeding. Given the high invasiveness of endoscopic treatment, it is important to select patients at high risk for bleeding. Aim To assess the risk of rebleeding in patients with SBVLs as a systemic disease rather than a gastrointestinal disease in relation to their general health. Methods We retrospectively analyzed the clinical data of 55 patients with SBVLs among patients with obscure gastrointestinal bleeding. The possible association between the clinical findings and the updated Charlson comorbidity index with rebleeding was evaluated. Results Gastrointestinal rebleeding occurred in 20 patients (36.4%) during the follow-up period. The presence of multiple comorbidities as indicated by an updated Charlson comorbidity index of ≥4 was a risk factor for rebleeding (hazard ratio, 3.64; P = 0.004). Other risk factors were arteriosclerosis of the superior mesenteric artery and multiple SBVLs. Endoscopic hemostasis and the discontinuation of antithrombotic medications were not significantly associated with rebleeding. Patients with a high updated Charlson comorbidity index had a high risk of death of causes other than gastrointestinal rebleeding. Conclusions Gastrointestinal rebleeding is not a rare condition among patients with SBVLs. Patients with poor general health may therefore have a higher risk of rebleeding.

DOI： 10.2169/internalmedicine.6341-20

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: This multicenter prospective study (UMIN000019958) aimed to evaluate the usefulness of serum leucin-rich alpha-2 glycoprotein (LRG) levels in monitoring disease activity in inflammatory bowel disease (IBD). METHODS: Patients with moderate-to-severe IBD initiated on adalimumab therapy were enrolled herein. Serum LRG, C-reactive protein (CRP), and fecal calprotectin (fCal) levels were measured at week 0, 12, 24, and 52. Colonoscopy was performed at week 0, 12, and 52 for ulcerative colitis (UC), and at week 0, 24, and 52 for Crohn's disease (CD). Endoscopic activity was assessed using the Simple Endoscopic Score for Crohn's Disease (SES-CD) for CD and the Mayo endoscopic subscore (MES) for UC. RESULTS: A total of 81 patients was enrolled. Serum LRG levels decreased along with improvements in clinical and endoscopic outcomes upon adalimumab treatment (27.4 ± 12.6 μg/ml at week 0, 15.5 ± 7.7 μg/ml at week 12, 15.7 ± 9.6 μg/ml at week 24, and 14.5 ± 6.8 μg/ml at week 52), being correlated with endoscopic activity at each time point (SES-CD: r = 0.391 at week 0, r = 0.563 at week 24, r = 0.697 at week 52; MES: r = 0.534 at week 0, r = 0.429 at week 12, r = 0.335 at week 52). Endoscopic activity better correlated with LRG compared to CRP and fCal on pooled analysis at all time points (SES-CD: LRG: r = 0.636, CRP: r = 0.402, fCal: r = 0.435; MES: LRG: r = 0.568, CRP: 0.389, fCal: r = 0.426). CONCLUSIONS: Serum LRG is a useful biomarker of endoscopic activity both in CD and UC during the adalimumab treatment.

DOI： 10.1007/s00535-021-01793-0

Language：English   Publishing type：Research paper (scientific journal)  

PURPOSE: The aim of this investigation was to evaluate the clinical value of barium enema (BE) examination for the management of colorectal epithelial neoplasms. METHODS: We reviewed the colonoscopy records at our institution from 2014 to 2019 and identified cases of endoscopically or surgically resected colorectal epithelial neoplasms evaluated by BE, conventional colonoscopy, magnifying narrow-band imaging colonoscopy (M-NBI), and magnifying chromoendoscopy (MCE). The yield of each modality for the diagnosis of massively submucosal invasive (mSM) colorectal cancer was evaluated by a receiver-operating characteristic analysis including the area under the curve (AUC). RESULTS: We analyzed the records of 105 patients (17 adenomas, 53 high-grade dysplasias (HGDs), and 35 cancers). Smooth surface, irregularity in depression, and eccentric deformity on the profile view with BE were observed more frequently in mSM cancers than adenomas/HGDs/slightly submucosal invasive cancers (p < 0.01). The AUC of BE was 0.8355, the value of which was not different from the other three modalities (conventional colonoscopy 0.7678; M-NBI 0.7835; MCE 0.8376). Although the specificity, PPV, and accuracy of BE were lower than those of M-NBI and MCE, the sensitivity and NPV of BE were the highest among the four types of examinations. CONCLUSION: BE is still available and may serve as a supplementary modality for the diagnosis of mSM cancers.

DOI： 10.1007/s11604-021-01157-x

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1016/j.jot.2020.12.005

Language：English  

DOI： 10.1002/hon.2816

Language：English  

BACKGROUND:  This study aimed to compare the markers of potential pancreatic injury during antegrade double-balloon endoscopy (DBE) using the newly developed ultrathin EN-580XP system and the conventional EN-580T system. METHODS:  Patients who were scheduled for antegrade DBE during daily clinical practice were enrolled. Clinical background, adverse events, and laboratory data of patients were compared between those who underwent endoscopy using the EN-580XP system and those in whom the EN-580T system was used. The primary end points were pancreatic hyperamylasemia and hyperlipasemia after DBE. RESULTS:  A total of 295 cases were registered. Pancreatic hyperamylasemia occurred in 2 of 92 patients (2.2 %) in the EN-580XP group and in 28 of 147 patients (19.1 %) in the EN-580 T diagnosis group (P < 0.001). Hyperlipasemia was significantly different between the two groups (1.1 % [EN-580XP] vs. 13.6 % [EN-580 T diagnosis]; P < 0.001). Acute pancreatitis occurred in four patients (7.1 %) in the EN-580 T therapy group. Multiple logistic regression analyses revealed that the endoscope type EN-580 T was significantly associated with pancreatic hyperamylasemia (adjusted odds ratio [OR] 8.63, 95 % confidence interval [CI] 1.97 - 37.70; P < 0.01) and hyperlipasemia (adjusted OR 13.10, 95 %CI 1.70 - 100.70; P = 0.01). CONCLUSIONS:  The EN-580XP system seemed less harmful to the pancreas during antegrade DBE.

DOI： 10.1055/a-1243-0226

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Although combining thiopurine with infliximab (IFX) is considered to improve the clinical efficacy of IFX when treating Crohn's disease (CD), it also increases the risk of adverse events (AEs). We compared the efficacy and safety of delayed thiopurine addition after loss of response (LOR) to IFX with the efficacy and safety of an earlier combination of thiopurine and IFX. METHODS: This retrospective study analyzed patients with CD who started IFX as a first-line biologic at Kyushu University Hospital between June 2002 and July 2018. Patients were assigned to either the early-combination (EC) group, who started IFX and thiopurine simultaneously, or the late-combination (LC) group, who were treated with IFX alone until they developed LOR. We compared the cumulative IFX continuation rates and AE incidence between the two groups. RESULTS: One hundred seventy-six patients were enrolled in this study; 49 were enrolled in the EC group, and 127 were enrolled in the LC group. Disease activity at baseline did not significantly differ between the groups, nor did the cumulative IFX continuation rates differ between the groups (P = 0.30); however, the AE rate was significantly higher in the EC group than in the LC group (38.7% vs. 21.2%; P = 0.02). The severe AE rate was also higher in the EC group than in the LC group (18.3% vs 3.1%; P = 0.001). CONCLUSION: Considering the risk-benefit balance, delayed addition of thiopurine after LOR to IFX might be an alternative strategy when using IFX to treat CD.

DOI： 10.1007/s10620-020-06600-z

Language：English   Publishing type：Research paper (scientific journal)  

A 67-year old woman with a history of long-term Chinese herb use was admitted to our institution complaining of abdominal pain. Barium enema disclosed rigidity of throughout the proximal colon and a slightly elevated lesion in the transverse colon. Colonoscopy showed diffuse and bronze mucosa in the proximal colon, which was compatible with mesenteric phlebosclerosis. There was also a reddish, elevated lesion in the transverse colon. Magnifying colonoscopy revealed irregular microsurface and microvessels on the surface of the lesion. Under a diagnosis of intramucosal cancer, the elevated lesion was treated by endoscopic submucosal dissection. Histological examination of the resected specimen showed intramucosal well-differentiated adenocarcinoma, and fibrous thickening of the vascular wall together with collagen deposition in the submucosa. The final diagnosis was an intramucosal cancer occurring in mesenteric phlebosclerosis.

DOI： 10.1007/s12328-020-01205-5

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BACKGROUND: To clarify the genetic background of ulcerative colitis (UC) in the Japanese population, we conducted a genome-wide association study (GWAS) using a population-specific single nucleotide polymorphism (SNP) array. METHODS: We performed a GWAS and replication study including 1676 UC patients and 2381 healthy controls. The probability of colectomy was compared between genotypes of rs117506082, the top hit SNP at HLA loci, by the Kaplan-Meier method. We studied serum expression of miR-622, a newly identified candidate gene, from 32 UC patients and 8 healthy controls by quantitative reverse-transcription polymerase chain reaction. RESULTS: In the GWAS, only the HLA loci showed genome-wide significant associations with UC (rs117506082, P = 6.69E-28). Seven nominally significant regions included 2 known loci, IL23R (rs76418789, P = 6.29E-7) and IRF8 (rs16940202, P = 1.03E-6), and 5 novel loci: MIR622 (rs9560575, P = 8.23E-7), 14q31 (rs117618617, P = 1.53E-6), KAT6B (rs12260609, P = 1.81E-6), PAX3-CCDC140-SGPP2 (rs7589797, P = 2.87E-6), and KCNA2 (rs118020656, P = 4.01E-6). Combined analysis revealed that IL23R p.G149R (rs76418789, P = 9.03E-11; odds ratio [OR], 0.51) had genome-wide significant association with UC. Patients with GG genotype of rs117506082 had a significantly lower probability of total colectomy than those with the GA+AA genotype (P = 1.72E-2). Serum expression of miR-622 in patients with inactive UC tended to be higher than in healthy controls and patients with active UC (inactive UC vs healthy controls, P = 3.03E-02; inactive UC vs active UC, P = 6.44E-02). CONCLUSIONS: IL23R p.G149R is a susceptibility locus for UC in Japanese individuals. The GG genotype of rs117506082 at HLA loci may predict a better clinical course.

DOI： 10.1093/ibd/izaa033

Language：English  

DOI： 10.1111/den.13776

Language：English   Publishing type：Research paper (scientific journal)  

Expression quantitative trait locus (eQTL) analyses have enabled us to predict the function of disease susceptibility SNPs. However, eQTL for the effector memory T cells (TEM) located in the lamina propria mononuclear cells (LPMCs), which play an important role in Crohn's disease (CD), are not yet available. Thus, we conducted RNA sequencing and eQTL analyses of TEM cells located in the LPMCs from IBD patients (n = 20). Genome-wide association study (GWAS) was performed using genotyping data of 713 Japanese CD patients and 2,063 controls. We compared the results of GWAS and eQTL of TEM, and also performed a transcriptome-wide association study using eQTL from Genotype Tissue Expression project. By eQTL analyses of TEM, correlations of possible candidates were confirmed in 22,632 pairs and 2,463 genes. Among these candidates, 19 SNPs which showed significant correlation with tenascin-XA (TNXA) expression were significantly associated with CD in GWAS. By TWAS, TNFSF15 (FDR = 1.35e-13) in whole blood, ERV3-1 (FDR = 2.18e-2) in lymphocytes, and ZNF713 (FDR = 3.04e-2) in the sigmoid colon was significantly associated with CD. By conducting integration analyses using GWAS and eQTL data, we confirmed multiple gene transcripts are involved in the development of CD.

DOI： 10.1038/s41598-020-66951-5

Language：English   Publishing type：Research paper (scientific journal)  

Because the pathogenesis of gastrointestinal follicular lymphoma (GI-FL) remains unclear, no standardized treatment strategy has been established. Of the gastrointestinal lymphomas, gastric mucosa-associated lymphoid tissue lymphomas are strongly associated with Helicobacter pylori; hence, the microbiota may be involved in GI-FL pathogenesis. However, the association between GI-FL and the microbiota remains uninvestigated. Therefore, we compared the mucosal microbiotas of GI-FL patients with those of controls to identify microbiota changes in GI-FL patients. Mucosal biopsy samples were obtained from the second portion of the duodenum from 20 GI-FL patients with duodenal lesions and 20 controls. Subsequent 16S rRNA gene sequencing was performed on these samples. QIIME pipeline and LEfSe software were used to analyze the microbiota. The GI-FL patients had significantly lower alpha diversity (P = .049) than did the controls, with significant differences in the microbial composition (P = .023) evaluated by the beta diversity metrics between the two groups. Comparing the taxonomic compositions indicated that the genera Sporomusa, Rothia, and Prevotella and the family Gemellaceae were significantly less abundant in the GI-FL patients than in the controls. GI-FL patients presented altered duodenal mucosal microbial compositions, suggesting that the microbiota might be involved in the GI-FL pathogenesis.

DOI： 10.1002/hon.2717

Language：English   Publishing type：Research paper (scientific journal)  

Because the pathogenesis of gastrointestinal follicular lymphoma (GI-FL) remains unclear, no standardized treatment strategy has been established. Of the gastrointestinal lymphomas, gastric mucosa-associated lymphoid tissue lymphomas are strongly associated with Helicobacter pylori; hence, the microbiota may be involved in GI-FL pathogenesis. However, the association between GI-FL and the microbiota remains uninvestigated. Therefore, we compared the mucosal microbiotas of GI-FL patients with those of controls to identify microbiota changes in GI-FL patients. Mucosal biopsy samples were obtained from the second portion of the duodenum from 20 GI-FL patients with duodenal lesions and 20 controls. Subsequent 16S rRNA gene sequencing was performed on these samples. QIIME pipeline and LEfSe software were used to analyze the microbiota. The GI-FL patients had significantly lower alpha diversity (P =.049) than did the controls, with significant differences in the microbial composition (P =.023) evaluated by the beta diversity metrics between the two groups. Comparing the taxonomic compositions indicated that the genera Sporomusa, Rothia, and Prevotella and the family Gemellaceae were significantly less abundant in the GI-FL patients than in the controls. GI-FL patients presented altered duodenal mucosal microbial compositions, suggesting that the microbiota might be involved in the GI-FL pathogenesis.

DOI： 10.1002/hon.2717

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND AND AIM: Indigo naturalis (IN) is a traditional Chinese herbal medicine reported to be effective in inducing remission in ulcerative colitis (UC). We conducted a retrospective observational study to investigate the efficacy and safety of IN for induction and maintenance therapy in patients with inflammatory bowel disease. METHODS: Data were collected from the electric medical records of patients with inflammatory bowel disease who had started IN treatment between March 2015 and April 2017 at Kyushu University Hospital. Clinical response and remission rates were assessed based on the clinical activity index determined by Rachmilewitz index or Crohn's disease (CD) activity index. Cumulative IN continuation rates were estimated using the Kaplan-Meier method. Overall adverse events (AEs) during follow-up were also analyzed. RESULTS: Seventeen UC patients and eight CD patients were enrolled. Clinical response and remission rates at week 8 were 94.1% and 88.2% in UC patients and 37.5% and 25.0% in CD patients, respectively. Clinical remission rates, as assessed through non-responders imputation analyses at weeks 52 and 104, were 76.4% and 70.4% in UC patients and 25.0% and 25.0% in CD patients, respectively. Ten patients (40%) experienced AEs during follow-up. Three patients (12%) experienced severe AEs, including acute colitis requiring hospitalization in two patients and acute colitis with intussusception requiring surgery in one patient. CONCLUSIONS: Indigo naturalis showed favorable therapeutic efficacy in UC, whereas its therapeutic efficacy in CD appeared to be modest. The risk of severe AEs should be recognized for IN treatment.

DOI： 10.1111/jgh.14823

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DOI： 10.1111/jgh.14823

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DOI： 10.1111/jgh.14885

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Hypocomplementemic urticarial vasculitis syndrome (HUVS) is a small vessel vasculitis characterized by hypocomplementemia and urticaria-like exanthema. Some cases also display abdominal pain and membranoproliferative glomerulonephritis (MPGN) with immune complex deposits. We treated a case of HUVS with biopsy-proven gastrointestinal vasculitis and atypical histological findings in a kidney biopsy. The 36-year-old Japanese man, who was previously diagnosed with diffuse panbronchiolitis, visited our hospital due to transient urticaria-like exanthema and rapid deterioration of kidney function. On admission, the skin lesion was found to be only pigmentation, showing no vasculitis by skin biopsy. In laboratory findings, renal dysfunction with hematuria and proteinuria and hypocomplementemia were observed. Gastrointestinal vasculitis was proven by endoscopy and biopsy of the mucosa. Kidney biopsy revealed MPGN with crescents. No immune complex deposits were observed by immunofluorescence or electron microscopy. Additional examination revealed high titers of anti-C1q antibody. The patient was diagnosed with HUVS and treated with corticosteroids and plasma exchange. Although renal function and gastrointestinal vasculitis partially improved, infectious pneumonia frequently recurred. His renal dysfunction began to progress again and reached end-stage kidney disease. This is the first case of HUVS with biopsy-proven gastrointestinal vasculitis and MPGN without immune complex deposits. Notably, in some case of HUVS, anti-C1q antibody may activate the alternative complement pathway without immune complex deposits, resulting in renal injury.

DOI： 10.1007/s13730-019-00421-4

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Primary colorectal diffuse large B-cell lymphoma (DLBCL) is rare, and its clinicopathological and genetic features are poorly understood. The aim of our study was to elucidate the frequency and prognostic significance of molecular subgroups in colorectal DLBCL. We examined 25 cases of colorectal lymphoma with DLBCL-like morphology and classified them into germinal center B-cell like (GCB)/non-GCB subgroups by immunohistochemistry (IHC) for CD10, bcl-6 and MUM1, or into double-expressor (DE)/non-DE subgroups by IHC for bcl-2 and c-myc. Translocations involving BCL2, BCL6, MYC, IGH, IGK, IGL, and MALT1 were also investigated using break-apart fluorescence in situ hybridization (FISH). The 25 cases were classified into two entities-DLBCL, not otherwise specified (NOS) (n = 23; 92%) and high grade B-cell lymphoma, double hit (n = 2; 8%)-according to the recent WHO classification. None of them showed histological evidence of Epstein-Barr virus infection or high-grade transformation from low grade B-cell lymphoma. Ten cases were GCB-type and four cases were DE-type, but these subtypes did not contribute to clinicopathological differences. Translocations involving BCL2, BCL6, MYC, IGH, IGK, IGL, and MALT1 were detected in 3 (12%), 3 (12%), 10 (40%), 14 (56%), 3 (12%), 3 (12%), and 0 (0%) of 25 cases, respectively. Of note, the presence of IGH translocation was significantly associated with better overall survival (P = .0053) and progression free survival (P = .0259). Similarly, the translocation involving at least one of the IGs (IGH, IGK, and/or IGL) was associated with more favorable prognosis in DLBCLs or even in DLBCL, NOS. This is the first report to reveal that a small subset of colorectal DLBCL corresponds to double-hit lymphoma. In addition, translocations involving at least one of the IGs may be a favorable prognostic factor in colorectal DLBCL. Testing the translocation involving rearrangement of IGs as well as MYC and BCL2/BCL6 may thus be useful for diagnosis and prognosis.

DOI： 10.1016/j.humpath.2019.09.003

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DOI： 10.1016/j.humpath.2019.09.003

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DOI： 10.1053/j.gastro.2019.07.047

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DOI： 10.1053/j.gastro.2019.07.047

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DOI： 10.1111/jgh.14689

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DOI： 10.1111/jgh.14685

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND/AIMS: It remains uncertain which patients with stricturing-type Crohn's disease (CD) require early small bowel surgery after the initial diagnosis. We aimed to clarify clinical characteristics associated with the intervention in such condition of CD. METHODS: We retrospectively evaluated the clinical course of 53 patients with CD and small bowel strictures who were initially treated with medications after the initial diagnosis. We investigated possible associations between small bowel surgery and the following: clinical factors and radiologic findings at initial diagnosis and the types of medications administered during follow-up. RESULTS: Twenty-eight patients (53%) required small bowel resection during a median follow-up period of 5.0 years (range, 0.5-14.3 years). The cumulative incidence rates of small bowel surgery at 2, 5, and 10 years were 26.4%, 41.0%, and 63.2%, respectively. Univariate analysis indicated that obstructive symptoms (P=0.036), long-segment stricture (P<0.0001), and prestenotic dilation (P<0.0001) on radiography were associated with small bowel surgery, and immunomodulatory (P=0.037) and biological therapy (P=0.008) were significant factors during follow-up. Multivariate analysis revealed that long-segment stricture (hazard ratio [HR], 4.25; 95% confidence interval [CI], 1.78-10.53; P=0.001) and prestenotic dilation (HR, 3.41; 95% CI, 1.24-9.62; P=0.018) on radiography showed a positive correlation with small bowel surgery, and biological therapy (HR, 0.40; 95% CI, 0.15-0.99; P=0.048) showed a negative correlation. CONCLUSIONS: CD patients with long-segment stricture and prestenotic dilation on radiography seem to be at a higher risk of needing small bowel surgery. For such patients, early surgical intervention might be appropriate, even at initial diagnosis.

DOI： 10.5217/ir.2018.00107

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND/AIMS: Gastrointestinal stromal tumor (GIST) is one of the most common types of submucosal tumors (SMTs). Because of GIST's malignant potential, it is crucial to differentiate it from other SMTs. The present study aimed to identify characteristic endoscopic findings of GISTs in the small intestine. METHODS: We reviewed the clinicopathological and endoscopic findings of 38 patients with endoscopically or surgically resected SMTs in the small intestine. SMTs were classified into GIST and non-GIST groups, and clinicopathological and endoscopic findings were compared between the 2 groups. RESULTS: Fifteen patients had GIST and 23 patients had other types of SMTs in the small intestine. Comparison of the endoscopic findings between the 2 groups revealed that dilated vessels in the surrounding mucosa were significantly more in number in the GIST group than in the non-GIST group (P<0.05). However, there were no other differences in endoscopic findings between the 2 groups. Among patients with GISTs, the presence of dilated vessels in the surrounding mucosa was not associated with bleeding risk, tumor size, or metastasis rate at diagnosis. CONCLUSIONS: Dilated vessels in the surrounding mucosa, identified during balloon-assisted endoscopy, may be a diagnostic indicator for GIST in the small intestine. However, its clinical significance should be further analyzed.

DOI： 10.5217/ir.2018.00161

Language：English   Publishing type：Research paper (scientific journal)  

A 57-year-old woman with pre-dialysis chronic kidney disease (CKD) was hospitalized because of fever and fatigue. On admission, increased inflammatory response and pyuria with bacteriuria were observed. Pyelonephritis was successfully treated with antibiotics, whereas her fatigue continued and she developed progressive hypercalcemia and hyponatremia; serum sodium level, 116 mEq/L and corrected serum calcium level, 13.4 mg/dL. Plasma concentrations of adrenocorticotropic hormone and cortisol and serum luteinizing hormone were under the detection level. Although the reaction of other anterior pituitary hormones and the serum antidiuretic hormone (ADH) was preserved, the response of serum luteinizing hormone to administration of luteinizing hormone releasing hormone was impaired. Magnetic resonance imaging showed no structural abnormality in the thalamus, hypothalamus, and pituitary gland. She was diagnosed with adrenal insufficiency caused by partial hypopituitarism in concomitant with pyelonephritis. After starting hydrocortisone replacement, serum levels of sodium and calcium were rapidly normalized. This case highlights the importance of adrenal insufficiency as a differential diagnosis of hypercalcemia in patients with pre-dialysis CKD, especially when hyponatremia was concomitantly observed. Besides, infection should be considered as an important trigger for the development of latent adrenal insufficiency since it could increase the physiological demand of corticosteroid in the body. Also, CKD may enhance the magnitude of hypercalcemia since CKD patients have decreased capacity to increase urinary calcium excretion.

DOI： 10.1007/s13730-018-0371-9

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: We recently reported on a hereditary enteropathy associated with a gene encoding a prostaglandin transporter and referred to as chronic enteropathy associated with SLCO2A1 gene (CEAS). Crohn's disease (CD) is a major differential diagnosis of CEAS, because these diseases share some clinical features. Therefore, there is a need to develop a convenient screening test to distinguish CEAS from CD. AIM: To examine whether prostaglandin E major urinary metabolites (PGE-MUM) can serve as a biomarker to distinguish CEAS from CD. METHODS: This was a transactional study of 20 patients with CEAS and 98 patients with CD. CEAS was diagnosed by the confirmation of homozygous or compound heterozygous mutation of SLCO2A1. We measured the concentration of PGE-MUM in spot urine by radioimmunoassay, and the concentration was compared between the two groups of patients. We also determined the optimal cut-off value of PGE-MUM to distinguish CEAS from CD by receiver operating characteristic (ROC) curve analysis. RESULTS: Twenty Japanese patients with CEAS and 98 patients with CD were enrolled. PGE-MUM concentration in patients with CEAS was significantly higher than that in patients with CD (median 102.7 vs 27.9 μg/g × Cre, P < 0.0001). One log unit increase in PGE-MUM contributed to 7.3 increase in the likelihood for the diagnosis of CEAS [95% confidence interval (CI) 3.2-16.7]. A logistic regression analysis revealed that the association was significant even after adjusting confounding factors (adjusted odds ratio 29.6, 95%CI 4.7-185.7). ROC curve analysis revealed the optimal PGE-MUM cut-off value for the distinction of CEAS from CD to be 48.9 μg/g × Cre with 95.0% sensitivity and 79.6% specificity. CONCLUSION: PGE-MUM measurement is a convenient, non-invasive and useful test for the distinction of CEAS from CD.

DOI： 10.3748/wjg.v25.i14.1753

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Anti-tumor necrosis factor (TNF) therapy induces and maintains clinical remission in patients with Crohn's disease (CD). However, the effect of anti-TNF therapy on the natural course of CD remains controversial. We aimed to investigate the effect of anti-TNF therapy on the initial intestinal surgery for CD. METHODS: In this single-center retrospective cohort study, clinical course of 199 CD patients of inflammatory type at the initial diagnosis (the period between 1973 and 2014) was precisely reviewed until the end of 2016. Patients were divided into TNF and non-TNF groups based on anti-TNF agent use. After comparisons of clinical characteristics and medical treatments, propensity scores were calculated for covariates. Risk of intestinal surgery was compared by a Cox proportional hazards model using the propensity scores. The effect of immunomodulators on initial intestinal surgery was assessed in the TNF group. RESULTS: During the study period, 108 patients received anti-TNF therapy. The patients in the TNF group were diagnosed more recently, and more frequently had isolated colonic involvement, and perianal disease. Immunomodulators were more frequently used in the TNF group. Cumulative probability of initial intestinal surgery was significantly lower in the TNF group (P < 0.0001). The hazard ratio in the TNF group was 0.32 (95% CI 0.13-0.74). Immunomodulators did not decrease the risk of initial intestinal surgery. CONCLUSIONS: Anti-TNF therapy can decrease the risk of intestinal surgery among patients with inflammatory-type CD at the initial diagnosis. Further studies should be necessary to determine the additive effect of immunomodulators on the risk of intestinal surgery.

DOI： 10.1007/s00535-018-1511-x

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1007/s00535-018-1511-x

Language：Japanese   Publishing type：Research paper (scientific journal)  

A small rectal cancer manifesting as ischemic colitis caused by a tumor embolus in the inferior mesenteric vein

DOI： 10.11280/gee.61.163

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1159/000496826

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.3748/wjg.v25.i14.1753

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1016/j.dld.2017.12.003

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1016/j.dld.2017.12.003

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND AND AIM: The gut microbiota is suggested to play an important role in the pathogenesis of ulcerative colitis (UC). However, interindividual and spatial variations hamper the identification of UC-related changes. We thus investigated paired mucosa-associated microbiota obtained from both inflamed and non-inflamed sites of UC patients and corresponding sites of non-inflammatory bowel disease (IBD) controls. METHODS: Mucosal biopsies of both inflamed and non-inflamed sites were obtained from 14 patients with active UC of the left-sided or proctitis type. Paired mucosal biopsies of the corresponding sites were obtained from 14 non-IBD controls. The microbial community structure was investigated using 16S ribosomal RNA gene sequences, followed by data analysis using qiime and LEfSe softwares. RESULTS: Microbial alpha diversity in both inflamed and non-inflamed sites was significantly lower in UC patients compared with non-IBD controls. There were more microbes of the genus Cloacibacterium and the Tissierellaceae family, and there were less microbes of the genus Neisseria at the inflamed site when compared with the non-inflamed site in UC patients. Decreased abundance of the genera Prevotella, Eubacterium, Neisseria, Leptotrichia, Bilophila, Desulfovibrio, and Butyricimonas was evident at the inflamed site of UC patients compared with the corresponding site of non-IBD controls. Among these taxa, the genera Prevotella and Butyricimonas were also less abundant at the non-inflamed site of UC patients compared with the corresponding site in non-IBD controls. CONCLUSIONS: Mucosal microbial dysbiosis occurs at both inflamed and non-inflamed sites in UC patients. The taxa showing altered abundance in UC patients might mediate colonic inflammation.

DOI： 10.1111/jgh.14129

Language：English   Publishing type：Research paper (scientific journal)  

Background and Aim: The gut microbiota is suggested to play an important role in the pathogenesis of ulcerative colitis (UC). However, interindividual and spatial variations hamper the identification of UC-related changes. We thus investigated paired mucosa-associated microbiota obtained from both inflamed and non-inflamed sites of UC patients and corresponding sites of non-inflammatory bowel disease (IBD) controls. Methods: Mucosal biopsies of both inflamed and non-inflamed sites were obtained from 14 patients with active UC of the left-sided or proctitis type. Paired mucosal biopsies of the corresponding sites were obtained from 14 non-IBD controls. The microbial community structure was investigated using 16S ribosomal RNA gene sequences, followed by data analysis using qiime and LEfSe softwares. Results: Microbial alpha diversity in both inflamed and non-inflamed sites was significantly lower in UC patients compared with non-IBD controls. There were more microbes of the genus Cloacibacterium and the Tissierellaceae family, and there were less microbes of the genus Neisseria at the inflamed site when compared with the non-inflamed site in UC patients. Decreased abundance of the genera Prevotella, Eubacterium, Neisseria, Leptotrichia, Bilophila, Desulfovibrio, and Butyricimonas was evident at the inflamed site of UC patients compared with the corresponding site of non-IBD controls. Among these taxa, the genera Prevotella and Butyricimonas were also less abundant at the non-inflamed site of UC patients compared with the corresponding site in non-IBD controls. Conclusions: Mucosal microbial dysbiosis occurs at both inflamed and non-inflamed sites in UC patients. The taxa showing altered abundance in UC patients might mediate colonic inflammation.

DOI： 10.1111/jgh.14129

Language：English   Publishing type：Research paper (scientific journal)  

Rationale: Neurogenic shock is generally typified by spinal injury due to bone metastases in cancer patients, but continuous disturbance of the vagus nerve controlling the aortic arch baroreceptor can cause shock by a reflex response through the medulla oblongata. Patient concerns: A 43-year-old woman with dysphagia presented to our hospital. Computed tomography showed a primary tumor adjacent to and surrounding half the circumference of the descending aorta, and multiple cervical lymph node metastases, including a 55 × 35-mm lymph node overlapping the root of the left vagus nerve. Squamous esophageal cancer (T4bN3M1, stage IV) was diagnosed. Whereas shock status initially appeared soon after left cervical pain, suggesting pain-induced neutrally-mediated syncope, sustained bradycardia and hypotension occurred even after alleviation of pain by opioids. Diagnosis: Disturbance of the left vagus nerve associated with the aortic arch baroreceptor by a large left cervical lymph node metastasis was considered as the cause of shock, pathologically mimicking the baroreceptor reflex. Interventions: Systemic steroid administration was performed, and radiotherapy for both the primary site and lymph node metastasis was started 2 days after initiating steroid treatment. Outcomes: Four days after initiating steroid administration, hypotension and bradycardia were improved and stable. Lessons: Disturbance of the vagus nerve controlling the aortic arch baroreceptor should be kept in mind as a potential cause of neurogenic shock in cancer patients, through a pathological reflex mimicking the baroreceptor reflex.

DOI： 10.1097/MD.0000000000008987

Language：English   Publishing type：Research paper (scientific journal)  

RATIONALE: Neurogenic shock is generally typified by spinal injury due to bone metastases in cancer patients, but continuous disturbance of the vagus nerve controlling the aortic arch baroreceptor can cause shock by a reflex response through the medulla oblongata. PATIENT CONCERNS: A 43-year-old woman with dysphagia presented to our hospital. Computed tomography showed a primary tumor adjacent to and surrounding half the circumference of the descending aorta, and multiple cervical lymph node metastases, including a 55 × 35-mm lymph node overlapping the root of the left vagus nerve. Squamous esophageal cancer (T4bN3M1, stage IV) was diagnosed. Whereas shock status initially appeared soon after left cervical pain, suggesting pain-induced neutrally-mediated syncope, sustained bradycardia and hypotension occurred even after alleviation of pain by opioids. DIAGNOSIS: Disturbance of the left vagus nerve associated with the aortic arch baroreceptor by a large left cervical lymph node metastasis was considered as the cause of shock, pathologically mimicking the baroreceptor reflex. INTERVENTIONS: Systemic steroid administration was performed, and radiotherapy for both the primary site and lymph node metastasis was started 2 days after initiating steroid treatment. OUTCOMES: Four days after initiating steroid administration, hypotension and bradycardia were improved and stable. LESSONS: Disturbance of the vagus nerve controlling the aortic arch baroreceptor should be kept in mind as a potential cause of neurogenic shock in cancer patients, through a pathological reflex mimicking the baroreceptor reflex.

DOI： 10.1097/MD.0000000000008987

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1242/bio.027458

Language：English   Publishing type：Research paper (scientific journal)  

Adhesion of cells to the extracellular matrix (ECM) via focal adhesions (FAs) is crucial for cell survival, migration, and differentiation. Although the regulation of FAs, including by integrins and the ECM, is important to cell behavior, how FAs are regulated is not well known. Autophagy is induced by both cell adhesion and cell detachment. Here, we showed that autophagosomes are located close to internalized collagen and paxillin, which is a well-known marker of FAs. Autophagy-deficient cells showed increased levels of internalized collagen compared with control cells. Moreover, paxillin exhibited a more peripheral distribution and the area of paxillin was increased, and adhesion-induced focal adhesion kinase signaling was impaired and adhesion was enhanced, in autophagy-deficient cells. These results suggest that autophagy suppressed cell adhesion by regulating internalized ECM and FAs.

DOI： 10.1242/bio.027458

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 153

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1053/j.gastro.2017.01.020

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1053/j.gastro.2017.01.020

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1111/gtc.12402

Language：English   Publishing type：Research paper (scientific journal)  

Genomewide association studies have shown that a nonsynonymous single nucleotide polymorphism in PRKCH is associated with cerebral infarction and atherosclerosis-related complications. We examined the role of PKCη in lipid metabolism and atherosclerosis using apolipoprotein E-deficient (Apoe-/- ) mice. PKCη expression was augmented in the aortas of mice with atherosclerosis and exclusively detected in MOMA2-positive macrophages within atherosclerotic lesions. Prkch+/+ Apoe-/- and Prkch-/- Apoe-/- mice were fed a high-fat diet (HFD), and the dyslipidemia observed in Prkch+/+ Apoe-/- mice was improved in Prkch-/- Apoe-/- mice, with a particular reduction in serum LDL cholesterol and phospholipids. Liver steatosis, which developed in Prkch+/+ Apoe-/- mice, was improved in Prkch-/- Apoe-/- mice, but glucose tolerance, adipose tissue and body weight, and blood pressure were unchanged. Consistent with improvements in LDL cholesterol, atherosclerotic lesions were decreased in HFD-fed Prkch-/- Apoe-/- mice. Immunoreactivity against 3-nitrotyrosine in atherosclerotic lesions was dramatically decreased in Prkch-/- Apoe-/- mice, accompanied by decreased necrosis and apoptosis in the lesions. ARG2 mRNA and protein levels were significantly increased in Prkch-/- Apoe-/- macrophages. These data show that PKCη deficiency improves dyslipidemia and reduces susceptibility to atherosclerosis in Apoe-/- mice, showing that PKCη plays a role in atherosclerosis development.

DOI： 10.1111/gtc.12402

Language：English   Publishing type：Research paper (scientific journal)  

Language：English  

DOI： 10.1053/j.gastro.2016.06.018

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1053/j.gastro.2016.06.018

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

The physiological role of autophagic flux within the vascular endothelial layer remains poorly understood. Here, we show that in primary endothelial cells, oxidized and native LDL stimulates autophagosome formation. Moreover, by both confocal and electron microscopy, excess native or modified LDL appears to be engulfed within autophagic structures. Transient knockdown of the essential autophagy gene ATG7 resulted in higher levels of intracellular (125) I-LDL and oxidized LDL (OxLDL) accumulation, suggesting that in endothelial cells, autophagy may represent an important mechanism to regulate excess, exogenous lipids. The physiological importance of these observations was assessed using mice containing a conditional deletion of ATG7 within the endothelium. Following acute intravenous infusion of fluorescently labeled OxLDL, mice lacking endothelial expression of ATG7 demonstrated prolonged retention of OxLDL within the retinal pigment epithelium (RPE) and choroidal endothelium of the eye. In a chronic model of lipid excess, we analyzed atherosclerotic burden in ApoE(-/-) mice with or without endothelial autophagic flux. The absence of endothelial autophagy markedly increased atherosclerotic burden. Thus, in both an acute and chronic in vivo model, endothelial autophagy appears critically important in limiting lipid accumulation within the vessel wall. As such, strategies that stimulate autophagy, or prevent the age-dependent decline in autophagic flux, might be particularly beneficial in treating atherosclerotic vascular disease.

DOI： 10.1111/acel.12423

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1111/acel.12423

Language：English   Publishing type：Research paper (scientific journal)  

Endothelial secretion of von Willebrand factor (VWF) from intracellular organelles known as Weibel-Palade bodies (WPBs) is required for platelet adhesion to the injured vessel wall. Here we demonstrate that WPBs are often found near or within autophagosomes and that endothelial autophagosomes contain abundant VWF protein. Pharmacological inhibitors of autophagy or knockdown of the essential autophagy genes Atg5 or Atg7 inhibits the in vitro secretion of VWF. Furthermore, although mice with endothelial-specific deletion of Atg7 have normal vessel architecture and capillary density, they exhibit impaired epinephrine-stimulated VWF release, reduced levels of high-molecular weight VWF multimers and a corresponding prolongation of bleeding times. Endothelial-specific deletion of Atg5 or pharmacological inhibition of autophagic flux results in a similar in vivo alteration of hemostasis. Thus, autophagy regulates endothelial VWF secretion, and transient pharmacological inhibition of autophagic flux may be a useful strategy to prevent thrombotic events.

DOI： 10.1038/nm.3288

Language：English   Publishing type：Research paper (scientific journal)  

Background and aims: The effects of maintenance infliximab for Crohn's disease vary widely among patients. The aim of this study was to examine the cytokine profiles and to identify possible markers predictive of therapeutic effect of maintenance infliximab. Methods: Cytokine profiles of 35 Crohn's disease patients under maintenance infliximab therapy were analyzed prospectively. Blood samples were obtained prior to, and 2 and 6. weeks after infliximab infusion. Circulating cytokine values of interleukin (IL)-23, IL-17A, IL-12, IL-6, interferon gamma (IFN-γ), and tumor necrosis factor alpha (TNF-α) were compared according to the disease activity and therapeutic efficacy. Patients were classified into either the active or quiescent phase according to their disease activity at baseline. Patients were also divided into a sustained response group and non-sustained response group according to therapeutic efficacy of infliximab determined 2 and 6. weeks after infliximab infusion. Results: At baseline, serum levels of IL-23 (p < 0.05), IL-17A (p < 0.01), IFN-γ (p < 0.05), and IL-6 (p < 0.01) were significantly higher in active Crohn's disease than in quiescent disease. These cytokine levels remained unchanged during the follow-up period. When serum cytokine levels were compared between groups classified by therapeutic efficacy of infliximab, patients in the non-sustained response group had a significantly higher level of serum IL-17A than those in the sustained response group (p < 0.05). There were also trends toward higher serum IL-23 and IL-12 in the former than in the latter. Conclusion: Higher levels of IL-17A, IL-23, and IL-12 at baseline may be predictive markers for poor therapeutic response to maintenance infliximab therapy.

DOI： 10.1016/j.crohns.2011.10.010

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND AND AIMS: The effects of maintenance infliximab for Crohn's disease vary widely among patients. The aim of this study was to examine the cytokine profiles and to identify possible markers predictive of therapeutic effect of maintenance infliximab. METHODS: Cytokine profiles of 35 Crohn's disease patients under maintenance infliximab therapy were analyzed prospectively. Blood samples were obtained prior to, and 2 and 6 weeks after infliximab infusion. Circulating cytokine values of interleukin (IL)-23, IL-17A, IL-12, IL-6, interferon gamma (IFN-γ), and tumor necrosis factor alpha (TNF-α) were compared according to the disease activity and therapeutic efficacy. Patients were classified into either the active or quiescent phase according to their disease activity at baseline. Patients were also divided into a sustained response group and non-sustained response group according to therapeutic efficacy of infliximab determined 2 and 6 weeks after infliximab infusion. RESULTS: At baseline, serum levels of IL-23 (p<0.05), IL-17A (p<0.01), IFN-γ (p<0.05), and IL-6 (p<0.01) were significantly higher in active Crohn's disease than in quiescent disease. These cytokine levels remained unchanged during the follow-up period. When serum cytokine levels were compared between groups classified by therapeutic efficacy of infliximab, patients in the non-sustained response group had a significantly higher level of serum IL-17A than those in the sustained response group (p<0.05). There were also trends toward higher serum IL-23 and IL-12 in the former than in the latter. CONCLUSION: Higher levels of IL-17A, IL-23, and IL-12 at baseline may be predictive markers for poor therapeutic response to maintenance infliximab therapy.

DOI： 10.1016/j.crohns.2011.10.010

Language：English   Publishing type：Research paper (scientific journal)  

Background. Findings from several studies suggest associations between tooth loss and health outcomes, including malnutrition, poor quality of life, and mortality, in older individuals. However, limited information is available regarding whether those associations remain true in very elderly subjects after adequately considering confounding factors such as sex and smoking status. Herein, we determined whether the number of teeth in 80-year-old subjects is an independent predictor of mortality. Methods. We initially contacted 1282 80-year-old community-dwelling individuals born in 1917, of whom 697 responded and participated in a baseline study, with follow-up examinations conducted 4 and 5.5 years later. Data from interviews and medical and oral examinations were obtained, and oral health was determined according to the number of teeth remaining in the oral cavity. Results. A total of 108 and 157 subjects died in 4 years and 5.5 years, respectively, after the baseline study. Tooth loss was significantly associated with mortality at age 85.5, but not at age 84, after adjusting for potential confounders. When the analysis was stratified by sex, we found a stronger association in females in follow-up examinations conducted at both 4- and 5.5 years. On the other hand, the effect of tooth loss on mortality was not significantly different between smokers and non-smokers. Conclusion. Tooth loss is a significant predictor of mortality independent of health factors, socio-economic status, and lifestyle in octogenarians, with a stronger association in females.

DOI： 10.1186/1471-2458-10-386

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Findings from several studies suggest associations between tooth loss and health outcomes, including malnutrition, poor quality of life, and mortality, in older individuals. However, limited information is available regarding whether those associations remain true in very elderly subjects after adequately considering confounding factors such as sex and smoking status. Herein, we determined whether the number of teeth in 80-year-old subjects is an independent predictor of mortality. METHODS: We initially contacted 1282 80-year-old community-dwelling individuals born in 1917, of whom 697 responded and participated in a baseline study, with follow-up examinations conducted 4 and 5.5 years later. Data from interviews and medical and oral examinations were obtained, and oral health was determined according to the number of teeth remaining in the oral cavity. RESULTS: A total of 108 and 157 subjects died in 4 years and 5.5 years, respectively, after the baseline study. Tooth loss was significantly associated with mortality at age 85.5, but not at age 84, after adjusting for potential confounders. When the analysis was stratified by sex, we found a stronger association in females in follow-up examinations conducted at both 4- and 5.5 years. On the other hand, the effect of tooth loss on mortality was not significantly different between smokers and non-smokers. CONCLUSION: Tooth loss is a significant predictor of mortality independent of health factors, socio-economic status, and lifestyle in octogenarians, with a stronger association in females.

DOI： 10.1186/1471-2458-10-386

Language：English   Publishing type：Research paper (scientific journal)  

Since little is known about the very elderly population aged 80 years and older, we evaluated the association of quality of life (QoL) in an 85-year-old population with physical fitness measurements assessed at age 80 and 85 years. Two hundred seven individuals (90 males, 117 females) aged 85 years underwent the Short Form-36 (SF-36) questionnaires for QoL assessment and physical fitness measurements (handgrip strength, leg-extensor strength, one-leg standing time, stepping rate of legs, walking speed). In 85-year-olds, significant associations were found, by multiple regression analysis or logistic regression analysis, with adjustment for various influencing factors in QoL assessed by SF-36 with physical fitness measurements examined at the age of 85 and 80 years. Physical scales and scores in SF-36, such as physical functioning (PF), limitation in role functioning for physical reasons (role physical; RP), bodily pain (BP), and the physical component score (PCS) tended to be more tightly associated with fitness measurements than mental scales and scores such as limitation in role functioning for emotional reasons (role emotional; RE), and emotional well-being (mental health; MH), and mental component score (MCS). Three scales the general health perceptions (GH), the vitality (VT), and the social functioning (SF) consisting of both physical and mental components were associated with fitness, the extent being intermediate between physical scales and mental scales. Of the several physical fitness measurements, leg-extensor strength and the walking speed of 85-year-olds, and the stepping rate of 80-year-olds were most closely associated with QoL. In a very elderly population of 85- and 80-year-olds, significant associations were found between QoL by SF-36 and physical fitness measurements, suggesting that increases in the levels of physical fitness, even in the very elderly, can contribute to improvements in QoL.

DOI： 10.1016/j.archger.2009.04.005

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Background and aims: Although serum albumin levels are associated with mortality in non-institutionalized elderly people under 80 years old, as well as in the institutionalized very elderly, little is known about the relationship in community-dwelling very elderly people. We, therefore, examined the association in a Japanese population of 80-year-old community residents. Methods: Serum albumin levels were measured in 672 (267 men, 405 women) out of 1282 80-year-old individuals. Over the following 4 years, the dates and causes of death were recorded from resident registration cards and official death certificates. Results: Of the above individuals, 107 subjects died (58 men, 49 women: 27 due to cancer, 27 cardiovascular disease, and 22 pneumonia). Survival rates were compared among 4 groups (highest ≥45 g/L, higher than 43-44 g/L, lower than 41-42 g/L, lowest ≤40 g/L). After adjustment for confounding factors, total death or cardiovascular death in the lowest albumin group was 3.1 times and 10.7 times more incident than in the highest albumin group, but there were no differences among groups as regards deaths due to cancer or pneumonia. Conclusion: Serum albumin levels are an independent predictor of mortality due to all-cause or cardiovascular disease, but not of mortality due to cancer or pneumonia in very elderly Japanese community residents.

DOI： 10.1007/BF03324812

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND AND AIMS: Although serum albumin levels are associated with mortality in non-institutionalized elderly people under 80 years old, as well as in the institutionalized very elderly, little is known about the relationship in community-dwelling very elderly people. We, therefore, examined the association in a Japanese population of 80-year-old community residents. METHODS: Serum albumin levels were measured in 672 (267 men, 405 women) out of 1282 80-year-old individuals. Over the following 4 years, the dates and causes of death were recorded from resident registration cards and official death certificates. RESULTS: Of the above individuals, 107 subjects died (58 men, 49 women: 27 due to cancer, 27 cardiovascular disease, and 22 pneumonia). Survival rates were compared among 4 groups (highest >or=45 g/L, higher than 43-44 g/L, lower than 41-42 g/L, lowest <or=40 g/L). After adjustment for confounding factors, total death or cardiovascular death in the lowest albumin group was 3.1 times and 10.7 times more incident than in the highest albumin group, but there were no differences among groups as regards deaths due to cancer or pneumonia. CONCLUSION: Serum albumin levels are an independent predictor of mortality due to all-cause or cardiovascular disease, but not of mortality due to cancer or pneumonia in very elderly Japanese community residents.

Language：English   Publishing type：Research paper (scientific journal)  

Hypertension is one of the greatest risk factors for cardiovascular disease, but its contribution to cardiovascular mortality weakens with aging. We have previously demonstrated that at the age of 80, higher systolic blood pressure (SBP) is not correlated with increased mortality in Japan. However, we did not examine in detail whether diastolic blood pressure (DBP) independently affects mortality. In the present study, 639 participants, who were 80 years old in 1997, were enrolled. The subjects were divided by their DBP [below 70 mmHg (group 1, n = 136), from 70 mmHg to 80 mmHg (group 2, n = 200), from 80 mmHg to 90 mmHg (group 3, n = 194), over 90 mmHg (group 4, n = 109)]. During the 4-year follow-up period, 90 individuals died. Cox multivariate regression analysis revealed that group 1 showed a significantly higher mortality rate than group 4 [relative risk (RR) 2.47, confidence interval (CI) 1.0-75.70, p = 0.03)]. The relative risks of deaths from cardiovascular diseases, pneumonia, and cancer tended to be higher in group 1 than in group 4, but the difference did not reach statistical significance. These results suggest that decreased DBP is associated with higher mortality in the Japanese elderly.

DOI： 10.3109/10641960903407009

Language：English   Publishing type：Research paper (scientific journal)  

Hypertension is one of the greatest risk factors for cardiovascular disease, but its contribution to cardiovascular mortality weakens with aging. We have previously demonstrated that at the age of 80, higher systolic blood pressure (SBP) is not correlated with increased mortality in Japan. However, we did not examine in detail whether diastolic blood pressure (DBP) independently affects mortality. In the present study, 639 participants, who were 80 years old in 1997, were enrolled. The subjects were divided by their DBP [below 70 mmHg (group 1, n = 136), from 70 mmHg to 80 mmHg (group 2, n = 200), from 80 mmHg to 90 mmHg (group 3, n = 194), over 90 mmHg (group 4, n = 109)]. During the 4-year follow-up period, 90 individuals died. Cox multivariate regression analysis revealed that group 1 showed a significantly higher mortality rate than group 4 [relative risk (RR) 2.47, confidence interval (CI) 1.07-5.70, p = 0.03)]. The relative risks of deaths from cardiovascular diseases, pneumonia, and cancer tended to be higher in group 1 than in group 4, but the difference did not reach statistical significance. These results suggest that decreased DBP is associated with higher mortality in the Japanese elderly.

DOI： 10.3109/10641960903407009

Language：English   Publishing type：Research paper (scientific journal)  

AIM: Helicobacter pylori (HP) has been implicated as a risk factor for cardiovascular and atherosclerotic diseases. Arterial stiffness determined by pulse wave velocity (PWV) or the cardio-ankle vascular index (CAVI) has been shown to be higher in HP-positive subjects than in HP-negative subjects; however, this result has been observed only in young subjects. The aim of the study was to investigate the possible correlation between HP infection and PWV or CAVI in middle-aged subjects. METHODS: We measured brachial-ankle PWV (baPWV), CAVI, metabolism markers, pepsinogens (PGs) and IgG antibody to HP in 343 individuals aged either 60 or 65 year old. Atrophic gastritis (AG) was diagnosed based on the values of PGs. RESULTS: baPWV and CAVI were significantly higher in the AG-positive group than in the AG-negative group even after adjusting for possible confounding factors (baPWVc; 16.63+/-3.50 vs. 15.59+/-3.47 p=0.010, CAVIc; 8.59+/-1.20 vs. 8.27+/-1.19 p=0.022). baPWV and CAVI values tended to be higher in the HP-positive group than in the HP-negative group. High-density lipoprotein (HDL) cholesterol level and the adiponectin level were lower in the AG-positive group than in the AG-negative group. CONCLUSION: There may be an association between atrophic gastritis and atherosclerosis in middle-aged subjects.

Language：English   Publishing type：Research paper (scientific journal)  

Background: Immunoglobulin levels are elevated in the older people. However, it is unknown whether these levels are related to mortality. Object: To evaluate the association between immunoglobulin levels and mortality. Methods: The study population included 697 individuals (277 males and 420 females) of 1,282 eighty-year-old individuals residing in the Fukuoka prefecture, Japan. The participants were followed for 4 years after the baseline examination. Results: The hyper-IgA group, defined as a serum IgA level >400 mg/dl, had high mortality using Kaplan-Meier analysis (log rank, p = 0.037). Multivariate Cox regression analyses revealed a high risk of mortality (hazard rate = 1.233, 95% confidence interval 1.109-1.491, p = 0.031) after adjusting for covariates. The high risk of mortality in the hyper-IgA group was significant in males, but not in females. Moreover, Kaplan-Meier analysis revealed that IgA was related to cancer mortality in males (log rank, p = 0.031), but not to pneumonia or cardiovascular disease. IgM and IgG levels were not related to high risk of mortality. Conclusion: Serum IgA levels appear to be a predictor of mortality, especially cancer mortality in males.

DOI： 10.1159/000162260

Language：English   Publishing type：Research paper (scientific journal)  

Aim: Helicobacter pylori (HP) has been implicated as a risk factor for cardiovascular and atherosclerotic diseases. Arterial stiffness determined by pulse wave velocity (PWV) or the cardio-ankle vascular index (CAVI) has been shown to be higher in HP-positive subjects than in HP-negative subjects; however, this result has been observed only in young subjects. The aim of the study was to investigate the possible correlation between HP infection and PWV or CAVI in middle-aged subjects. Methods: We measured brachial-ankle PWV (baPWV), CAVI, metabolism markers, pepsinogens (PGs) and IgG antibody to HP in 343 individuals aged either 60 or 65 year old. Atrophic gastritis (AG) was diagnosed based on the values of PGs. Results: baPWV and CAVI were significantly higher in the AG-positive group than in the AG-negative group even after adjusting for possible confounding factors (baPWVc; 16.63±3.50 vs. 15.59± 3.47 p = 0.010, CAVIc; 8.59±1.20 vs. 8.27±1.19 p = 0.022). baPWV and CAVI values tended to be higher in the HP-positive group than in the HP-negative group. High-density lipoprotein (HDL) cholesterol level and the adiponectin level were lower in the AG-positive group than in the AG-negative group. Conclusion: There may be an association between atrophic gastritis and atherosclerosis in middleaged subjects.

DOI： 10.5551/jat.943

Language：English   Publishing type：Research paper (scientific journal)  

Background: The relationship between Helicobacter pylori (HP) infection and body mass index (BMI) is controversial. Several reports have indicated that eradication of HP infection induces an increase in BMI. In contrast, epidemiological case-control studies have failed to show an association between HP infection and BMI. Therefore, we investigated whether HP and atrophic gastritis (AG) were associated with BMI. Methods: A total of 617 individuals were recruited for the measurements of BMI, serum leptin, pepsinogens (PGs) I and II, and IgG antibody to HP (HP-IgG). BMI and leptin of the subjects were compared when the subjects were stratified by HP-IgG and PGs. Results: The subjects were divided into AG-positive and AG-negative groups according to PGs (AG-positive: PG I ≤ 70 ng/ml and PG I/II ratio ≤ 3.0). BMI after adjusting for sex and age was significantly lower in the AG-positive group than in the AG-negative group (23.47 ± 3.05 vs. 24.18 ± 3.25, P = 0.010). When the subjects were divided into two groups according to HP-IgG, BMI tended to be lower in the HP-IgG-positive group, though the difference was not large. When the subjects were divided into four groups for different combinations of AG and HP-IgG, BMI was the lowest in the AG-positive and HP-IgG-negative group. Conclusions: BMI was associated with AG, as diagnosed by PGs, but not with HP infection status. These results mean that HP infection affects BMI via atrophic gastritis.

DOI： 10.1007/s00535-008-2219-0

Language：English   Publishing type：Research paper (scientific journal)  

Background: Little is known about the association between physical fitness and cognitive function in very elderly people (over 80 years of age). Objectives: To evaluate that relationship in 85-year-old community-dwelling individuals. Methods: Out of 207 participants (90 males, 117 females) who were 85 years old and community-dwelling, 205 completed the Mini-Mental State Examination (MMSE) for evaluating cognitive function. The numbers of subjects who completed physical fitness measurements such as hand-grip strength, isometric leg extensor strength, one-leg standing time, stepping rate, and walking speed were 198, 159, 169, 168, and 151, respectively. Results: There were significant associations in MMSE with hand-grip strength (right or left hand), isometric leg extensor strength, stepping rate, and walking speed by simple regression analysis. MMSE was still significantly associated with hand-grip strength (β = 0.305, p = 0.005 for right side; β = 0.309, p = 0.004 for left side), stepping rate (β = 0.183, p = 0.046), and walking speed (β = -0.222, p = 0.014) by multiple regression analysis after adjustments for the amount of education, gender, smoking, drinking, complication of stroke, body weight, body height, regular medical care, serum albumin, blood HbA1c, and marital status. By logistic regression analysis, the prevalence of a normal MMSE score (MMSE ≥24) was increased by 9% with each 1-kg increase in hand-grip strength of the left hand (OR 1.087, 95% CI 1.003-1.179, p = 0.042), and was increased by 6% with each step per 10 s in stepping rate (OR 1.060, 95% CI 1.000-1.122, p = 0.048). Conclusion: In a very elderly population of 85-year-olds, cognitive function was associated with some physical fitness measurements, independent of confounding factors.

DOI： 10.1159/000129757

Language：English   Publishing type：Research paper (scientific journal)  

Objectives: To evaluate the association between high-level functional capacity and chewing in a middle-old community-based population. Background: Although basic and instrumental activities of daily living are known to be associated with chewing ability in the elderly, an association between higher levels of competence and chewing ability has not been evaluated in the elderly. Materials and methods: The association between chewing ability using a number of different foods and high-level functional capacity by the Tokyo Metropolitan Institute of Gerontology was evaluated in 694, 80-year-old people residing in Fukuoka Prefecture, Japan. Results: A significant correlation was found, using multiple regression or logistic regression analyses adjusted for various confounding factors, between the number of total chewable foods, hard foods or moderately hard foods, and total functional capacity, instrumental activity, intellectual activity or social role ability. In contrast, the number of slightly hard foods, easily chewable foods and remaining teeth were only partly related to total functional capacity and intellectual activity. Conclusion: High-level functional capacity including intellectual activity and social role in middle-old elderly was associated with the ability to chew hard foods than to chew easily chewable foods. Maintenance of chewing ability in elderly might result in better intellectual activity and social role.

DOI： 10.1111/j.1741-2358.2007.00203.x

Language：English   Publishing type：Research paper (scientific journal)  

OBJECTIVES: To evaluate the association between high-level functional capacity and chewing in a middle-old community-based population. BACKGROUND: Although basic and instrumental activities of daily living are known to be associated with chewing ability in the elderly, an association between higher levels of competence and chewing ability has not been evaluated in the elderly. MATERIALS AND METHODS: The association between chewing ability using a number of different foods and high-level functional capacity by the Tokyo Metropolitan Institute of Gerontology was evaluated in 694, 80-year-old people residing in Fukuoka Prefecture, Japan. RESULTS: A significant correlation was found, using multiple regression or logistic regression analyses adjusted for various confounding factors, between the number of total chewable foods, hard foods or moderately hard foods, and total functional capacity, instrumental activity, intellectual activity or social role ability. In contrast, the number of slightly hard foods, easily chewable foods and remaining teeth were only partly related to total functional capacity and intellectual activity. CONCLUSION: High-level functional capacity including intellectual activity and social role in middle-old elderly was associated with the ability to chew hard foods than to chew easily chewable foods. Maintenance of chewing ability in elderly might result in better intellectual activity and social role.

DOI： 10.1111/j.1741-2358.2007.00203.x

Language：English   Publishing type：Research paper (scientific journal)  

Acute liver failure is associated with significant mortality. However, the underlying pathophysiological mechanism is not yet fully understood. Suppressor of cytokine signaling-1 (SOCS1), which is a negative-feedback molecule for cytokine signaling, has been shown to be rapidly induced during liver injury. Here, using liver-specific SOCS1-conditional-knockout mice, we demonstrated that SOCS1 deletion in hepatocytes enhanced concanavalin A (ConA)-induced hepatitis, which has been shown to be dependent on activated T and natural killer T (NKT) cells. Although serum cytokine level and NKT cell activation were similar in wild-type (WT) and SOCS1-deficient mice after ConA treatment, proapoptotic signals, including signal transducers and activators of transcription 1 (STAT1) and Jun-terminal kinase (JNK) activation, were enhanced in SOCS1-deficient fivers compared with those in WT livers. SOCS1-deficient hepatocytes had higher expression of Fas antigen and were more sensitive to anti-Fas antibody-induced apoptosis than were WT hepatocytes. Furthermore, SOCS1-deficient hepatocytes were more sensitive to tumor necrosis factor (TNF)-α-induced JNK activation and apoptosis. These data indicate that SOCS1 is important to the prevention of hepatocyte apoptosis induced by Fas and TNF-α. In contrast, SOCS1 overexpression in the liver by adenoviral gene transfer prevented ConA-induced fiver injury. Conclusion: These findings indicate that SOCS1 plays important negative roles in fulminant hepatitis and that forced expression of SOCS1 is therapeutic in preventing hepatitis.

DOI： 10.1002/hep.22214

Language：English   Publishing type：Research paper (scientific journal)  

UNLABELLED: Acute liver failure is associated with significant mortality. However, the underlying pathophysiological mechanism is not yet fully understood. Suppressor of cytokine signaling-1 (SOCS1), which is a negative-feedback molecule for cytokine signaling, has been shown to be rapidly induced during liver injury. Here, using liver-specific SOCS1-conditional-knockout mice, we demonstrated that SOCS1 deletion in hepatocytes enhanced concanavalin A (ConA)-induced hepatitis, which has been shown to be dependent on activated T and natural killer T (NKT) cells. Although serum cytokine level and NKT cell activation were similar in wild-type (WT) and SOCS1-deficient mice after ConA treatment, proapoptotic signals, including signal transducers and activators of transcription 1 (STAT1) and Jun-terminal kinase (JNK) activation, were enhanced in SOCS1-deficient livers compared with those in WT livers. SOCS1-deficient hepatocytes had higher expression of Fas antigen and were more sensitive to anti-Fas antibody-induced apoptosis than were WT hepatocytes. Furthermore, SOCS1-deficient hepatocytes were more sensitive to tumor necrosis factor (TNF)-alpha-induced JNK activation and apoptosis. These data indicate that SOCS1 is important to the prevention of hepatocyte apoptosis induced by Fas and TNF-alpha. In contrast, SOCS1 overexpression in the liver by adenoviral gene transfer prevented ConA-induced liver injury. CONCLUSION: These findings indicate that SOCS1 plays important negative roles in fulminant hepatitis and that forced expression of SOCS1 is therapeutic in preventing hepatitis.

DOI： 10.1002/hep.22214

Language：English   Publishing type：Research paper (scientific journal)  

Suppressor of cytokine signaling 1 (SOCS1) is an important negative regulator for cytokines; however, the role of SOCS1 in Th17 differentiation has not been clarified. We generated T cell-specific SOCS1-deficient mice and found that these mice were extremely resistant to a Th17-dependent autoimmune disease model, experimental autoimmune encephalomyelitis. SOCS1-deficient naive CD4 ⁺ T cells were predominantly differentiated into Th1 and poorly into Th17 in vitro. These phenotypes were canceled in IFN-γ^-/- background, suggesting that a large amount of IFN-γ in SOCS1-deficient T cells suppressed Th17 differentiation. IL-6 plus TGF-β enhanced retinoic acid receptor-related orphan receptor (ROR)-γt expression and suppressed IFN-γ production in wild-type T cells, whereas these effects were severely impaired in SOCS1-deficient T cells. These phenotypes can be partly explained by STAT3 suppression by enhanced SOCS3 induction through hyper-STAT1 activation in SOCS1-deficient T cells. In addition, SOCS1-deficient T cells were much less sensitive to TGF-β. Suppression of Th1 differentiation by TGF-β was impaired in SOCS1-deficient T cells. TGF-β-mediated Smad transcriptional activity was severely inhibited in SOCS1-deficient cells in the presence of IFN-γ. Such impairment of TGF-γ functions were not observed in SOCS3-overexpressed cells, indicating that suppression of Smads was independent of SOCS3. Therefore, SOCS1 is necessary for Th17 differentiation by suppressing antagonistic effect of IFN-γ on both STAT3 and Smads. Induction of SOCS3 can partly explain IFN-γ-mediated STAT3 suppression, while other mechanism(s) will be involved in IFN-β-mediated Smad suppression. SOCS1-deficient T cells will be very useful to investigate the molecular mechanism for the STAT1-mediated suppression of Th17 development.

Language：English   Publishing type：Research paper (scientific journal)  

Suppressor of cytokine signaling 1 (SOCS1) is an important negative regulator for cytokines; however, the role of SOCS1 in Th17 differentiation has not been clarified. We generated T cell-specific SOCS1-deficient mice and found that these mice were extremely resistant to a Th17-dependent autoimmune disease model, experimental autoimmune encephalomyelitis. SOCS1-deficient naive CD4(+) T cells were predominantly differentiated into Th1 and poorly into Th17 in vitro. These phenotypes were canceled in IFN-gamma(-/-) background, suggesting that a large amount of IFN-gamma in SOCS1-deficient T cells suppressed Th17 differentiation. IL-6 plus TGF-beta enhanced retinoic acid receptor-related orphan receptor (ROR)-gammat expression and suppressed IFN-gamma production in wild-type T cells, whereas these effects were severely impaired in SOCS1-deficient T cells. These phenotypes can be partly explained by STAT3 suppression by enhanced SOCS3 induction through hyper-STAT1 activation in SOCS1-deficient T cells. In addition, SOCS1-deficient T cells were much less sensitive to TGF-beta. Suppression of Th1 differentiation by TGF-beta was impaired in SOCS1-deficient T cells. TGF-beta-mediated Smad transcriptional activity was severely inhibited in SOCS1-deficient cells in the presence of IFN-gamma. Such impairment of TGF-beta functions were not observed in SOCS3-overexpressed cells, indicating that suppression of Smads was independent of SOCS3. Therefore, SOCS1 is necessary for Th17 differentiation by suppressing antagonistic effect of IFN-gamma on both STAT3 and Smads. Induction of SOCS3 can partly explain IFN-gamma-mediated STAT3 suppression, while other mechanism(s) will be involved in IFN-gamma-mediated Smad suppression. SOCS1-deficient T cells will be very useful to investigate the molecular mechanism for the STAT1-mediated suppression of Th17 development.

Language：English   Publishing type：Research paper (scientific journal)  

Type 1 diabetes results from the selective destruction of insulin-producing pancreatic β-cells during islet inflammation, which involves inflammatory cytokines and free radicals. However, mechanisms for protecting β-cells from destruction have not been clarified. In this study, we define the role of SOCS3 on β-cell destruction using β-cell-specific SOCS3-conditional knockout (cKO) mice. The β-cell-specific SOCS3-deficient mice were resistant to the development of diabetes caused by streptozotocin (STZ), a genotoxic methylating agent, which has been used to trigger β-cell destruction. The islets from cKO mice demonstrated hyperactivation of STAT3 and higher induction of Bcl-xL than did islets from WT mice, and SOCS3-deficient β-cells were more resistant to apoptosis induced by STZ in vitro than were WT β-cells. These results suggest that enhanced STAT3 signaling protects β-cells from destruction induced by a genotoxic stress and that STAT3/SOCS3 can be a potential therapeutic target for the treatment of type 1 diabetes.

DOI： 10.1016/j.bbrc.2007.05.198

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1210/me.2006-0413

Language：English   Publishing type：Research paper (scientific journal)  

Adipocyte differentiation is regulated by insulin and IGF-I, which transmit signals by activating their receptor tyrosine kinase. SH2-B is an adaptor protein containing pleckstrin homology and Src homology 2 (SH2) domains that have been implicated in insulin and IGF-I receptor signaling. In this study, we found a strong link between SH2-B levels and adipogenesis. The fat mass and expression of adipogenic genes including peroxisome proliferator-activated receptor gamma (PPARgamma) were reduced in white adipose tissue of SH2-B-/- mice. Reduced adipocyte differentiation of SH2-B-deficient mouse embryonic fibroblasts (MEFs) was observed in response to insulin and dexamethasone, whereas retroviral SH2-B overexpression enhanced differentiation of 3T3-L1 preadipocytes to adipocytes. SH2-B overexpression enhanced mRNA level of PPARgamma in 3T3-L1 cells, whereas PPARgamma levels were reduced in SH2-B-deficient MEFs in response to insulin. SH2-B-mediated up-regulation of PPARgamma mRNA was blocked by a phosphatidylinositol 3-kinase inhibitor, but not by a MAPK kinase inhibitor. Insulin-induced Akt activation and the phosphorylation of forkhead transcription factor (FKHR/Foxo1), a negative regulator of PPARgamma transcription, were up-regulated by SH2-B overexpression, but reduced in SH2-B-deficient MEFs. These data indicate that SH2-B is a key regulator of adipogenesis both in vivo and in vitro by regulating the insulin/IGF-I receptor-Akt-Foxo1-PPARgamma pathway.

Language：English   Publishing type：Research paper (scientific journal)  

Inflammation associates with insulin resistance, which dysregulates nutrient homeostasis and leads to diabetes. The suppressor of cytokine signaling 3 (SOCS3), which is induced by pro-inflammatory cytokines, such as TNFα and IL-6, has been implicated in inflammation-mediated insulin resistance in the liver and adipocytes. However, no genetic evidence has been provided for the involvement of SOCS3 on insulin resistance. Here, we generated hepatocyte-specific SOCS3-deficient (L-SOCS3 cKO) mice and examined insulin sensitivity. Being consistent with a previous idea, the loss of SOCS3 in the liver apparently improved insulin sensitivity. However, unexpectedly, L-SOCS3 cKO mice exhibited obesity and systemic insulin resistance with age. Insulin signaling was rather suppressed in muscles, suggesting that deletion of the SOCS3 gene in the liver modulates insulin sensitivity in other organs. Anti-inflammatory reagent, sodium salicylate, partial improved insulin resistance of aged L-SOCS3 cKO mice, suggesting that enhanced inflammatory status is associated with the phenotype of these mice. STAT3 was hyperactivated and acute-phase proteins were elevated in L-SOCS3 cKO mice liver, which were reduced by sodium salicylate treatment. We conclude that hepatic SOCS3 is a mediator of insulin resistance in the liver; however, lack of SOCS3 in the liver promotes systemic insulin resistance by mimicking chronic inflammation.

DOI： 10.1111/j.1365-2443.2007.01044.x

Language：Others   Publishing type：Research paper (scientific journal)  

Inflammation associates with insulin resistance, which dysregulates nutrient homeostasis and leads to diabetes. The suppressor of cytokine signaling 3 (SOCS3), which is induced by pro-inflammatory cytokines, such as TNFα and IL-6, has been implicated in inflammation-mediated insulin resistance in the liver and adipocytes. However, no genetic evidence has been provided for the involvement of SOCS3 on insulin resistance. Here, we generated hepatocyte-specific SOCS3-deficient (L-SOCS3 cKO) mice and examined insulin sensitivity. Being consistent with a previous idea, the loss of SOCS3 in the liver apparently improved insulin sensitivity. However, unexpectedly, L-SOCS3 cKO mice exhibited obesity and systemic insulin resistance with age. Insulin signaling was rather suppressed in muscles, suggesting that deletion of the SOCS3 gene in the liver modulates insulin sensitivity in other organs. Anti-inflammatory reagent, sodium salicylate, partial improved insulin resistance of aged L-SOCS3 cKO mice, suggesting that enhanced inflammatory status is associated with the phenotype of these mice. STAT3 was hyperactivated and acute-phase proteins were elevated in L-SOCS3 cKO mice liver, which were reduced by sodium salicylate treatment. We conclude that hepatic SOCS3 is a mediator of insulin resistance in the liver; however, lack of SOCS3 in the liver promotes systemic insulin resistance by mimicking chronic inflammation. © 2007 The Authors Journal compilation © 2007 by the Molecular Biology Society of Japan/Blackwell Publishing Ltd.

DOI： 10.1111/j.1365-2443.2007.01044.x

Language：English   Publishing type：Research paper (scientific journal)  

Leptin is an adipocyte-derived hormone that plays a key role in energy homeostasis, yet resistance to leptin is a feature of most cases of obesity in humans and rodents. In vitro analysis suggested that the suppressor of cytokine signaling-3 (Socs3) is a negative-feedback regulator of leptin signaling involved in leptin resistance. To determine the functional significance of Socs3 in vivo, we generated neural cell-specific SOCS3 conditional knockout mice using the Cre-IoxP system. Compared to their wild-type littermates, Socs3-deficient mice showed enhanced leptin-induced hypothalamic Stat3 tyrosine phosphorylation as well as pro-opiomelanocortin (POMC) induction, and this resulted in a greater body weight loss and suppression of food intake. Moreover, the Socs3-deficient mice were resistant to high fat diet-induced weight gain and hyperleptinemia, and insulin-sensitivity was retained. These data indicate that Socs3 is a key regulator of diet-induced leptin as well as insulin resistance. Our study demonstrates the negative regulatory role of Socs3 in leptin signaling in vivo, and thus suppression of Socs3 in the brain is a potential therapy for leptin-resistance in obesity.

DOI： 10.1038/nm1071

Language：Others   Publishing type：Research paper (scientific journal)  

Leptin is an adipocyte-derived hormone that plays a key role in energy homeostasis, yet resistance to leptin is a feature of most cases of obesity in humans and rodents. In vitro analysis suggested that the suppressor of cytokine signaling-3 (Socs3) is a negative-feedback regulator of leptin signaling involved in leptin resistance. To determine the functional significance of Socs3 in vivo, we generated neural cell-specific SOCS3 conditional knockout mice using the Cre-IoxP system. Compared to their wild-type littermates, Socs3-deficient mice showed enhanced leptin-induced hypothalamic Stat3 tyrosine phosphorylation as well as pro-opiomelanocortin (POMC) induction, and this resulted in a greater body weight loss and suppression of food intake. Moreover, the Socs3-deficient mice were resistant to high fat diet-induced weight gain and hyperleptinemia, and insulin-sensitivity was retained. These data indicate that Socs3 is a key regulator of diet-induced leptin as well as insulin resistance. Our study demonstrates the negative regulatory role of Socs3 in leptin signaling in vivo, and thus suppression of Socs3 in the brain is a potential therapy for leptin-resistance in obesity.

DOI： 10.1038/nm1071

Language：English   Publishing type：Research paper (scientific journal)  

A case of ulcerative colitis complicated by Wilson's disease is described. In this case, ulcerative colitis occurred 12 years after the diagnosis of Wilson's disease, and the colitis was intractable to prednisolone and salazosulfapyridine. Because copper is one of the trace elements necessary for antioxidant defenses during inflammatory process, altered copper metabolism may have contributed to the intractability of the ulcerative colitis in this case.

DOI： 10.1097/00004836-200207000-00010

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