Papers - NAKASE Hiroshi

MEFV Gene-Related Enterocolitis Account for Some Cases Diagnosed as Inflammatory Bowel Disease Unclassified.

Daisuke Saito, Noritaka Hibi, Ryo Ozaki, Oki Kikuchi, Taro Sato, Sotaro Tokunaga, Shintaro Minowa, Osamu Ikezaki, Tatsuya Mitsui, Miki Miura, Akihito Sakuraba, Mari Hayashida, Jun Miyoshi, Minoru Matsuura, Hiroshi Nakase, Tadakazu Hisamatsu

Digestion     1 - 9  2019.09  [Refereed]  [International journal]

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BACKGROUND AND AIMS: Familial mediterranean fever (FMF), an autoinflammatory disease, is characterized by periodic fever and serositis. An MEFV gene mutation has been identified as the cause of FMF. Recently, patients with MEFV gene mutations and chronic gastrointestinal mucosal inflammation mimicking inflammatory bowel disease (IBD) have been reported. In this retrospective study, we analyzed the clinical characteristics of patients with IBD unclassified (IBDU) with MEFV gene mutations. METHODS: MEFV gene analysis was performed on 8 patients with IBDU among 710 patients with IBD who had been treated at Kyorin University Hospital from April 2016 to December 2018. Clinical manifestations, endoscopic findings, and serological markers were also analyzed. RESULTS: The average of the 8 patients with IBDU (3 men, 5 women) was 32.7 ± 6.4 years (range 26-76 years). Their symptoms comprised diarrhea (n = 8, 100%), hematochezia (n = 3, 37.5%), abdominal pain (n = 3, 37.5%), high fever (n = 2, 16.5%), and other periodic symptoms (n = 2, 16.5%). MEFV gene mutation was confirmed in 4/8 of these patients. Colonoscopy showed various mucosal lesions, rectal sparing, right side dominant colitis, pseudopolyposis, and granular protrusions. Colchicine was administered to 5 of the 8 patients (4 with and 1 without MEFV mutation) who were resistant to conventional treatment for ulcerative colitis. Clinical and endoscopic improvement was observed in all of 5 patients treated with colchicine. CONCLUSIONS: Some patients diagnosed as having IBDU have enterocolitis related to MEFV gene mutation and respond to colchicine therapy.

DOI PubMed

Gastric Hamartomatous Inverted Polyp Causing Ball Valve Syndrome.

Gota Sudo, Tokuma Tanuma, Hiroshi Nakase

Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association   17 ( 10 ) e119-e120  2019.09  [Refereed]  [International journal]

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Interleukin 5-producing ST2+ memory Th2 cells in IgG4-related dacryoadenitis and sialadenitis.

Motohisa Yamamoto, Ken-Ichi Takano, Ryuta Kamekura, Satsuki Aochi, Chisako Suzuki, Shingo Ichimiya, Hiroshi Nakase, Tetsuo Himi, Hiroki Takahashi

Modern rheumatology   29 ( 5 ) 856 - 860  2019.09  [Refereed]  [International journal]

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Objectives: Immunoglobulin (Ig) G4-related disease (IgG4-RD) is often complicated by allergic disorders. This study was conducted to investigate the mechanism of type 2 helper T-inflammation (Th2-inflammation) in IgG4-related dacryoadenitis and sialadenitis (IgG4-DS). Methods: We separated and analyzed the proportion of growth stimulation expressed gene 2 (ST2)+ memory Th2 cells among the peripheral blood mononuclear cells by flow cytometry in cases with IgG4-DS and healthy individuals. Finally, we identified the role of ST2+ memory Th2 cells in the involved tissues. Results: The proportion of circulating ST2+ memory Th2 cells was much higher in the patients with IgG4-DS than in the healthy controls. Abundant infiltration of ST2+ memory Th2 cells was detected in the involved salivary glands and lymph nodes, and these cells produced interleukin-5. Conclusion: We demonstrated that there is an increase of interleukin-5 producing ST2+ memory Th2 cells in the involved tissues in IgG4-DS. This subset of cells is considered to be an important player in inducing the inflammatory Th2 environment characteristic of IgG4-DS.

DOI PubMed

多発性骨髄腫における新規エピジェネティック併用療法の開発(Development of a new combinational epigenetic therapy of multiple myeloma)

石黒 一也, 北嶋 洋志, 新沼 猛, 石田 禎夫, 丸山 玲緒, 池田 博, 山本 英一郎, 甲斐 正広, 佐々木 泰史, 時野 隆至, 仲瀬 裕志, 鈴木 拓

日本癌学会総会記事 ( (一社)日本癌学会 )  78回   P - 2241  2019.09

SMOC1の大腸腫瘍診断マーカーとしての臨床的有用性の検討(Clinical usefulness of SMOC1 as a diagnostic marker of colorectal precancerous lesions)

青木 敬則, 山本 英一郎, 高澤 啓, 新沼 猛, 山野 泰穂, 萬 顕, 北嶋 洋志, 甲斐 正広, 小山内 誠, 仲瀬 裕志, 菅井 有, 鈴木 拓

日本癌学会総会記事 ( 日本癌学会 )  78回   P - 1323  2019.09

新規大腸がん線維芽細胞関連遺伝子の同定(Identification of a novel cancer associated fibroblast-related gene in colorectal cancer)

須藤 豪太, 山本 英一郎, 萬 顕, 新沼 猛, 杉本 亮, 北嶋 洋志, 久保 俊之, 畠中 柚衣, 甲斐 正広, 時野 隆至, 仲瀬 裕志, 菅井 有, 鈴木 拓

日本癌学会総会記事 ( 日本癌学会 )  78回   P - 3102  2019.09

正常大腸粘膜のヒストン修飾異常とCIMP大腸腫瘍の発がんリスクの関連(Repressive histone mark in normal colon is associated with the risk of CRC with CpG island methylator phenotype)

山本 英一郎, 須藤 豪太, 久保 俊之, 萬 顕, 原田 拓, 青木 敬則, 北嶋 洋志, 新沼 猛, 甲斐 正広, 菅井 有, 仲瀬 裕志, 鈴木 拓

日本癌学会総会記事 ( 日本癌学会 )  78回   J - 2035  2019.09

術後早期に腹腔内播種再発をきたしたnon-invasive IPMCの一例

中村 友哉, 柾木 喜晴, 大和田 紗恵, 平野 雄大, 川上 裕次郎, 石上 敬介, 伊東 文子, 阿久津 典之, 本谷 雅代, 佐々木 茂, 今村 将史, 木村 康利, 竹政 伊知朗, 仲瀬 裕志

日本消化器病学会北海道支部例会・日本消化器内視鏡学会北海道支部例会プログラム・抄録集 ( 日本消化器病学会-北海道支部 )  125回・119回   39 - 39  2019.09

肝血管腫として11年間経過観察中に診断された混合型肝癌の1例

平野 雄大, 阿久津 典之, 大和田 紗恵, 柾木 喜晴, 石上 敬介, 伊東 文子, 本谷 雅代, 佐々木 茂, 仲瀬 裕志

日本消化器病学会北海道支部例会・日本消化器内視鏡学会北海道支部例会プログラム・抄録集 ( 日本消化器病学会-北海道支部 )  125回・119回   58 - 58  2019.09

消化器内視鏡治療におけるトラブルシューティング 当科におけるEST後出血の現状と対処法

柾木 喜晴, 本谷 雅代, 仲瀬 裕志

日本消化器病学会北海道支部例会・日本消化器内視鏡学会北海道支部例会プログラム・抄録集 ( 日本消化器病学会-北海道支部 )  125回・119回   54 - 54  2019.09

Diversity of Gut Microbiota Affecting Serum Level of Undercarboxylated Osteocalcin in Patients with Crohn's Disease.

Kohei Wagatsuma, Satoshi Yamada, Misora Ao, Minoru Matsuura, Hidemi Tsuji, Tomoya Iida, Kentaro Miyamoto, Kentaro Oka, Motomichi Takahashi, Kiyoshi Tanaka, Hiroshi Nakase

Nutrients ( MDPI AG )  11 ( 7 ) 1541 - 1541  2019.07  [Refereed]  [International journal]

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Several reports have indicated a possible link between decreasing plasma levels of vitamin K and bone mineral density. It has been suggested that intestinal bacteria contribute to maintenance of vitamin K. Several factors are involved in the reduction of vitamin K in patients with Crohn's disease (CD). We aimed to assess the relationship between gut microbiota and alternative indicators of vitamin K deficiency in patients with CD. We collected the feces of 26 patients with clinically inactive CD. We extracted 16S rRNA from the intestinal bacteria in the feces and amplified it by polymerase chain reaction. The generated polymerase chain reaction product was analyzed using a 16S metagenomic approach by Illumina Miseq platform. Serum undercarboxylated osteocalcin concentration was used as an alternative indicator of vitamin K deficiency. There was a significant negative correlation between serum undercarboxylated osteocalcin and mean Chao1 index in cases of low activity. The diversity of the gut microbiota was significantly lower, and Ruminococcaceae and Lachnospiraceae were significantly decreased in the vitamin K-deficient group in comparison to the vitamin K-normal group. Taken together, these data suggested the significance of investigating the gut microbiota even in patients with clinically inactive CD for improving patients' vitamin K status.

DOI PubMed

The Etiology of Pancreatic Manifestations in Patients with Inflammatory Bowel Disease.

Tomoya Iida, Kohei Wagatsuma, Daisuke Hirayama, Yoshihiro Yokoyama, Hiroshi Nakase

Journal of clinical medicine   8 ( 7 )  2019.06  [Refereed]  [International journal]

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Inflammatory bowel disease (IBD) is an idiopathic chronic and recurrent condition that comprises Crohn's disease and ulcerative colitis. A pancreatic lesion is one of the extraintestinal lesions in patients with IBD. Acute pancreatitis is the representative manifestation, and various causes of pancreatitis have been reported, including those involving adverse effects of drug therapies such as 5-aminosalicylic acid and thiopurines, gall stones, gastrointestinal lesions on the duodenum, iatrogenic harm accompanying endoscopic procedures such as balloon endoscopy, and autoimmunity. Of these potential causes, autoimmune pancreatitis (AIP) is a relatively newly recognized disease and is being increasingly diagnosed in IBD. AIP cases can be divided into type 1 cases involving lymphocytes and IgG4-positive plasma cells, and type 2 cases primarily involving neutrophils; the majority of AIP cases complicating IBD are type 2. The association between IBD and chronic pancreatitis, exocrine pancreatic insufficiency, pancreatic cancer, etc. has also been suggested; however, studies with high-quality level evidence are limited, and much remains unknown. In this review, we provide an overview of the etiology of pancreatic manifestation in patients with IBD.

DOI PubMed

膵癌に対するGemcitabine+nab-Paclitaxel療法・FOLFIRINOX療法における原発巣縮小効果

仲地 耕平, 本谷 雅代, 阿久津 典之, 石上 敬介, 伊東 文子, 柾木 喜晴, 佐々木 茂, 金戸 宏之, 矢和田 敦, 岡 俊洲, 仲瀬 裕志

膵臓 ( (一社)日本膵臓学会 )  34 ( 3 ) A160 - A160  2019.06

UHRF1 depletion and HDAC inhibition reactivate epigenetically silenced genes in colorectal cancer cells.

Takeshi Niinuma, Hiroshi Kitajima, Masahiro Kai, Eiichiro Yamamoto, Akira Yorozu, Kazuya Ishiguro, Hajime Sasaki, Gota Sudo, Mutsumi Toyota, Tomo Hatahira, Reo Maruyama, Takashi Tokino, Hiroshi Nakase, Tamotsu Sugai, Hiromu Suzuki

Clinical epigenetics   11 ( 1 ) 70 - 70  2019.05  [Refereed]  [International journal]

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BACKGROUND: Ubiquitin-like protein containing PHD and RING finger domains 1 (UHRF1) is a major regulator of epigenetic mechanisms and is overexpressed in various human malignancies. In this study, we examined the involvement of UHRF1 in aberrant DNA methylation and gene silencing in colorectal cancer (CRC). RESULTS: CRC cell lines were transiently transfected with siRNAs targeting UHRF1, after which DNA methylation was analyzed using dot blots, bisulfite pyrosequencing, and Infinium HumanMethylation450 BeadChip assays. Gene expression was analyzed using RT-PCR and gene expression microarrays. Depletion of UHRF1 rapidly induced genome-wide DNA demethylation in CRC cells. Infinium BeadChip assays and bisulfite pyrosequencing revealed significant demethylation across entire genomic regions, including CpG islands, gene bodies, intergenic regions, and repetitive elements. Despite the substantial demethylation, however, UHRF1 depletion only minimally reversed CpG island hypermethylation-associated gene silencing. By contrast, the combination of UHRF1 depletion and histone deacetylase (HDAC) inhibition reactivated the silenced genes and strongly suppressed CRC cell proliferation. The combination of UHRF1 depletion and HDAC inhibition also induced marked changes in the gene expression profiles such that cell cycle-related genes were strikingly downregulated. CONCLUSIONS: Our results suggest that (i) maintenance of DNA methylation in CRC cells is highly dependent on UHRF1; (ii) UHRF1 depletion rapidly induces DNA demethylation, though it is insufficient to fully reactivate the silenced genes; and (iii) dual targeting of UHRF1 and HDAC may be an effective new therapeutic strategy.

DOI PubMed

Chronic intestinal pseudo-obstruction due to al amyloidosis: a case report and literature review.

Tomoya Iida, Daisuke Hirayama, Gota Sudo, Kei Mitsuhashi, Hisayoshi Igarashi, Kentaro Yamashita, Hiroo Yamano, Hiroshi Nakase

Clinical journal of gastroenterology   12 ( 2 ) 176 - 181  2019.04  [Refereed]  [Domestic journal]

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A 59-year-old woman presented to our hospital with a 6-month history of nausea, weight loss, and abdominal distension. Physical examination revealed abdominal distension without tenderness, and edema, numbness, and multiple peripheral neuropathy in the limbs. Blood test results showed anemia, hypoproteinemia, and hypoalbuminemia. Immunoelectrophoresis detected kappa-type Bence-Jones protein in both the serum and urine. Bone marrow examination did not reveal an increase of plasma cells. Computed tomography showed intestinal distension and retention of intestinal contents. No obstructive intestinal lesions were observed. Lower gastrointestinal endoscopy showed a decrease in the vascular visibility of the rectal mucosa. Histological findings showed amyloid deposition, which was positive for amyloid light-chain (AL) κ. Thus, she was diagnosed with chronic intestinal pseudo-obstruction (CIPO) due to gastrointestinal and neurological involvement of AL amyloidosis. Her abdominal symptoms were gradually improved by the insertion of an ileus tube and medication. Although we recommended chemotherapy for stopping her disease progression, she did not want to receive it. She died 1 year later because of her pneumonia. We should keep in mind that amyloidosis is an important cause of CIPO. Histopathological examination by endoscopic biopsy is required for exact diagnosis and appropriate treatment for CIPO due to amyloidosis.

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Pedunculated Upper Esophageal Adenocarcinoma in Lynch Syndrome.

Hajime Sasaki, Kentaro Yamashita, Hiroshi Nakase

Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association   17 ( 5 ) A20  2019.04  [Refereed]  [International journal]

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Gastric Xanthomas and Fundic Gland Polyps as Endoscopic Risk Indicators of Gastric Cancer.

Kentaro Yamashita, Ryo Suzuki, Toshiyuki Kubo, Kei Onodera, Tomoya Iida, Mayuko Saito, Yoshiaki Arimura, Takao Endo, Masanori Nojima, Hiroshi Nakase

Gut and liver   13 ( 4 ) 409 - 414  2019.03  [Refereed]  [International journal]

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Background/Aims: Fundic gland polyps (FGPs), hyperplastic polyps (HPs), and xanthomas (XTs) are common benign gastric lesions that can be diagnosed by endoscopic appearance alone in most cases. The aim of this study was to evaluate associations between gastric cancer and these benign lesions. Methods: Two expert endoscopists reviewed a series of gastroscopy images. FGPs, HPs, and XTs were diagnosed by endoscopic appearance, whereas all gastric cancers were confirmed pathologically. Results: Of the 1,227 patients reviewed, 114 (9.3%) had a concurrent or past history of gastric cancer. The overall prevalences of FGPs, HPs and XTs were 9.4%, 6.3% and 14.2%, respectively. HPs and XTs coexisted in 1.6% of patients, whereas other combinations were rarer. XTs were observed in 39.3% and 11.5% of patients with and without gastric cancer, respectively (p<0.001). In contrast, no gastric cancer patients had FGPs, whereas 10.4% of patients without cancer had FGPs (p<0.001). The prevalence of HPs was similar between the two groups (8.8% and 6.0% of patients with and without cancer, respectively, p=0.29). Multivariate and Mantel-Haenszel analyses demonstrated that XTs were positively associated and FGPs were negatively associated with gastric cancer. Conclusions: XTs and FGPs might be useful as endoscopic risk indicators for monitoring gastric cancer.

DOI PubMed

Tumor recognition of peanut agglutinin-immobilized fluorescent nanospheres in biopsied human tissues.

Hironori Kumagai, Kosuke Yamada, Kanako Nakai, Tokio Kitamura, Kohta Mohri, Masami Ukawa, Takumi Tomono, Takaaki Eguchi, Testuya Yoshizaki, Takumi Fukuchi, Takuya Yoshino, Minoru Matsuura, Etsuo Tobita, Wellington Pham, Hiroshi Nakase, Shinji Sakuma

European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V ( Elsevier )  136   29 - 37  2019.03  [Refereed]  [International journal]

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We are investigating an imaging agent for early detection of colorectal cancer. The agent, named the nanobeacon, is coumarin 6-encapsulated polystyrene nanospheres whose surfaces are covered with poly(N-vinylacetamide) and peanut agglutinin that reduces non-specific interactions with the normal mucosa and exhibits high affinity for terminal sugars of the Thomsen-Friedenreich antigen, which is expressed cancer-specifically on the mucosa, respectively. We expect that cancer can be diagnosed by detecting illumination of intracolonically administered nanobeacon on the mucosal surface. In the present study, biopsied human tissues were used to evaluate the potential use of the nanobeacon in the clinic. Prior to the clinical study, diagnostic capabilities of the nanobeacon for detection of colorectal cancer were validated using 20 production batches whose characteristics were fine-tuned chemically for the purpose. Ex vivo imaging studies on 66 normal and 69 cancer tissues removed from the colons of normal and orthotopic mouse models of human colorectal cancer, respectively, demonstrated that the nanobeacon detected colorectal cancer with excellent capabilities whose rates of true and false positives were 91% and 5%, respectively. In the clinical study, normal and tumor tissues on the large intestinal mucosa were biopsied endoscopically from 11 patients with colorectal tumors. Histological evaluation revealed that 9 patients suffered from cancer and the rest had adenoma. Mean fluorescence intensities of tumor tissues treated with the nanobeacon were significantly higher than those of the corresponding normal tissues. Correlation of magnitude relation of the intensity in individuals was observed in cancer patients with a high probability (89%); however, the probability reduced to 50% in adenoma patients. There was a reasonable likelihood for diagnosis of colorectal cancer by the nanobeacon applied to the mucosa of the large intestine.

DOI PubMed

当初潰瘍性大腸炎と診断された家族性地中海熱の一例

柴田 泰洋, 山下 健太郎, 上野 あかり, 斎藤 潤信, 守谷 洋, 風間 友江, 須藤 豪太, 三橋 慧, 能正 勝彦, 山野 泰穂, 菊地 剛史, 遠藤 高夫, 仲瀬 裕志

日本消化器病学会北海道支部例会プログラム・抄録集 ( 日本消化器病学会-北海道支部 )  124回   80 - 80  2019.03

術前診断が困難であった低異型度分化型胃癌(超高分化型胃癌)の2例

風間 友江, 上野 あかり, 柴田 泰洋, 須藤 豪太, 五十嵐 央祥, 久保 俊之, 三橋 慧, 能正 勝彦, 山下 健太郎, 山野 泰穂, 市原 真, 杉田 真太朗, 長谷川 匡, 信岡 隆幸, 竹政 伊知朗, 仲瀬 裕志

日本消化器病学会北海道支部例会プログラム・抄録集 ( 日本消化器病学会-北海道支部 )  124回   67 - 67  2019.03