研究者詳細 - 水口　徹

論文 - 水口　徹

分割表示 >> ／全件表示 156 件中 1 - 156 件目

ロボット支援肝切除の導入と初期成績

村上武志, 永山稔, 今村将史, 加藤透, 久木田和晴, 水口徹, 木村康利, 竹政伊知朗

日本臨床外科学会雑誌 ( 日本臨床外科学会 ) 85 ( 2 ) 295 - 295 2024年02月

ePROによる手術部位感染症が肝胆膵外科手術後の総医療費へ与える評価

水口徹, 石貫智裕, 加藤透, 合田恵理香, 進士誠一, 吉田寛, 渡邉学, 横尾英樹, 柴田英貴, 青木武士, 問山裕二, 西森英史, 秦史壯

日本外科感染症学会雑誌 ( (一社)日本外科感染症学会 ) 20 ( 3 ) 474 - 474 2023年11月

オンラインPRO情報システムによるがん手術患者の術創部感染症の危険因子と予後の検証

石貫智裕, 久冨五郎, 島宏彰, 和田朝香, 青木武士, 吉田寛, 渡邉学, 長田拓哉, 横尾英樹, 問山裕二, 大西浩文, 林宏至, 森脇健介, 大柳俊夫, 水口徹

日本癌治療学会学術集会抄録集 ( (一社)日本癌治療学会 ) 61回 P61 - 5 2023年10月

【周術期感染管理マニュアル】肝臓手術における周術期感染管理

永山稔, 石貫智裕, 水口徹

日本外科感染症学会雑誌 ( (一社)日本外科感染症学会 ) 20 ( 2 ) 113 - 116 2023年09月

Synergistic antitumor effect of histone deacetylase class IIa inhibitor with lenvatinib in hepatocellular carcinoma.

Ryo Ito, Koji Miyanishi, Tomohiro Kubo, Kota Hamaguchi, Takahiro Osuga, Shingo Tanaka, Hiroyuki Ohnuma, Kazuyuki Murase, Kohichi Takada, Minoru Nagayama, Yasutoshi Kimura, Toru Mizuguchi, Ichiro Takemasa, Junji Kato

Hepatology international 17 ( 3 ) 735 - 744 2023年06月 [国際誌]

BACKGROUND: Histone deacetylase (HDAC) class I and IIa are highly expressed in hepatocellular carcinoma (HCC) and associated with decreased survival. However, clinically used pan and class I inhibitors have serious adverse events. In this study, we assessed the antitumor effects and tolerability of class IIa HDAC inhibitor (HDACI) with lenvatinib, which is a standard therapy for HCC. METHODS AND RESULT: Combination therapy with class IIa HDACI and lenvatinib exerted synergistic antitumor effect in human HCC cell lines. In mouse models, this therapy showed significant antitumor effects, and few adverse events occurred. In immunoblotting, the expression of fibroblast growth factor receptor 4 (FGFR4) and fibroblast growth factor 19 (FGF19) was high in cell lines that showed a high antitumor effect. In addition, class IIa HDACI administration decreased the expression of FGFR4. In the small interfering RNA (siRNA) analysis, knockdown of HDAC9, which is an isoform of HDAC class IIa, reduced the expression of FGFR4 and induced apoptosis. Immunohistochemistry of human clinical specimens showed a positivity rate of 32% for FGFR4 and 84% for HDAC9 in HCC, and all FGFR4-positive patients were HDAC9 positive. CONCLUSION: Class IIa HDACI and lenvatinib combination therapy induces apoptosis by downregulating FGFR4 and blocking the FGFR signaling in FGFR4-positive HCC cell lines and has demonstrated synergistic antitumor effects and safety. This combination therapy overcomes the problems of conventional therapies and will be beneficial for FGFR4-positive HCC patients.

DOI PubMed

肝がん患者のSSI発生に関連する要因の検討

石貫智裕, 合田恵理香, 巽博臣, 加藤透, 原田敬介, 升田好樹, 大西浩文, 秦史壯, 大柳俊夫, 水口徹

日本外科系連合学会誌 ( 日本外科系連合学会 ) 48 ( 3 ) 409 - 409 2023年05月

肝がん患者のSSI発生に関連する要因の検討

石貫智裕, 合田恵理香, 巽博臣, 加藤透, 原田敬介, 升田好樹, 大西浩文, 秦史壯, 大柳俊夫, 水口徹

日本外科系連合学会誌 ( 日本外科系連合学会 ) 48 ( 3 ) 409 - 409 2023年05月

Positional advantages of supine MRI for diagnosis prior to breast‑conserving surgery.

Goro Kutomi, Hiroaki Shima, Daisuke Kyuno, Fukino Satomi, Asaka Wada, Yoko Kuga, Minoru Okazaki, Akira Okazaki, Hideji Masuoka, Toshihiko Mikami, Yuichi Yuyama, Takashi Matsuno, Tosei Ohmura, Hidekazu Kameshima, Toru Mizuguchi, Ichiro Takemasa

Molecular and clinical oncology 18 ( 5 ) 44 - 44 2023年05月 [国際誌]

The present study aimed to evaluate the rate of positive surgical margins for magnetic resonance imaging (MRI) performed in the supine position prior to breast-conserving surgery (BCS). The rate of positive surgical margins and the clinicopathological factors were examined in consecutive patients with BCS who underwent preoperative MRI performed in the supine position at Sapporo Medical University Hospital (Sapporo, Japan) and related hospitals and clinics between January 2012 and December 2013. Of 1,175 eligible patients, 1,150 were included after excluding 25 patients with either bilateral breast cancer or stage IV disease. Positive margin was defined as no cancer seen on the resected margin. The primary endpoint was the rate of positive surgical margins when preoperative MRI was performed in the supine position and the secondary endpoint was identification of the factors that predict positive margins. Of the 1,150 female patients (median age, 55 years; range, 29-97 years) who underwent BCS for breast cancer following MRI performed in the supine position, 215 (18.8%) had positive margins, which is similar to the rate with MRI in the prone position, and 930 (81.2%) had negative margins. The rate of positive surgical margins in patients of the human epidermal growth factor receptor 2 (HER2) type was significantly higher than that in the non-HER2 type group (6.5 and 2.9%; χ2 P=0.0103). There was no increase in the rate of positive margins in breast cancers with a diameter of >T2. The rate of positive surgical margins following MRI performed in the supine position was 18.8%. Supine MRI appears to be suitable for informing on the extent of resection of breast cancer.

DOI PubMed

一次縫合創に対するNPWTの最適な適応とは SSI予防ガイドラインの次期改定に必要な予防的NPWTに関する有効性の再考

水口徹, 石貫智裕, 張苓, 巽博臣, 久野芳佳, 原田敬介, 大西浩文, 加藤透, 沖田憲司, 川本雅樹, 目黒誠, 秦史壯, 大柳俊夫

日本外科感染症学会雑誌 ( (一社)日本外科感染症学会 ) 19 ( 1 ) 185 - 185 2022年10月

肝臓

水口徹, 石貫智裕, 張苓, 巽博臣, 久野芳佳, 原田敬介, 大西浩文, 加藤透, 沖田憲司, 川本雅樹, 永山稔, 竹政伊知朗, 大柳俊夫

日本外科感染症学会雑誌 ( (一社)日本外科感染症学会 ) 19 ( 1 ) 230 - 230 2022年10月

肝胆膵外科における周術期感染対策肝切除後の腹腔内合併症に対する治療方法の検討

永山稔, 木村康利, 加藤透, 村上武志, 久木田和晴, 今村将史, 水口徹, 竹政伊知朗

日本外科感染症学会雑誌 ( (一社)日本外科感染症学会 ) 19 ( 1 ) 153 - 153 2022年10月

当科における肝硬変合併肝細胞癌に対する腹腔鏡下肝切除術と周術期成績

永山稔, 加藤透, 村上武志, 久木田和晴, 今村将史, 水口徹, 伊東竜哉, 信岡隆幸, 木村康利, 竹政伊知朗

日本消化器外科学会雑誌 ( (一社)日本消化器外科学会 ) 55 ( Suppl.2 ) 328 - 328 2022年10月

当科における腹腔鏡下肝葉切除の手技と成績

加藤透, 永山稔, 木村康利, 今村将史, 久木田和晴, 村上武志, 水口徹, 竹政伊知朗

日本臨床外科学会雑誌 ( 日本臨床外科学会 ) 83 ( 増刊 ) S458 - S458 2022年10月

一次縫合創に対するNPWTの最適な適応とは SSI予防ガイドラインの次期改定に必要な予防的NPWTに関する有効性の再考

水口徹, 石貫智裕, 張苓, 巽博臣, 久野芳佳, 原田敬介, 大西浩文, 加藤透, 沖田憲司, 川本雅樹, 目黒誠, 秦史壯, 大柳俊夫

日本外科感染症学会雑誌 ( (一社)日本外科感染症学会 ) 19 ( 1 ) 185 - 185 2022年10月

肝臓

水口徹, 石貫智裕, 張苓, 巽博臣, 久野芳佳, 原田敬介, 大西浩文, 加藤透, 沖田憲司, 川本雅樹, 永山稔, 竹政伊知朗, 大柳俊夫

日本外科感染症学会雑誌 ( (一社)日本外科感染症学会 ) 19 ( 1 ) 230 - 230 2022年10月

【ここまで進んだERAS】肝外科

石貫智裕, 太田盛道, 小野崎由香, 加藤透, 川本雅樹, 目黒誠, 永山稔, 竹政伊知朗, 大柳俊夫, 水口徹

消化器外科 ( (株)へるす出版 ) 45 ( 9 ) 1003 - 1010 2022年09月

Current standard values of health utility scores for evaluating cost-effectiveness in liver disease: A meta-analysis

Tomohiro Ishinuki, Shigenori Ota, Kohei Harada, Masaki Kawamoto, Makoto Meguro, Goro Kutomi, Hiroomi Tatsumi, Keisuke Harada, Koji Miyanishi, Toru Kato, Toshio Ohyanagi, Thomas T Hui, Toru Mizuguchi

World Journal of Gastroenterology ( Baishideng Publishing Group Inc. ) 28 ( 31 ) 4442 - 4455 2022年08月

DOI

Association between Hepatic Oxidative Stress Related Factors and Activation of Wnt/β-Catenin Signaling in NAFLD-Induced Hepatocellular Carcinoma.

Kota Hamaguchi, Koji Miyanishi, Takahiro Osuga, Shingo Tanaka, Ryo Ito, Hiroki Sakamoto, Tomohiro Kubo, Hiroyuki Ohnuma, Kazuyuki Murase, Kohichi Takada, Minoru Nagayama, Yasutoshi Kimura, Toru Mizuguchi, Ichiro Takemasa, Junji Kato

Cancers 14 ( 9 ) 2022年04月 [国際誌]

We investigated the association between iron overload, oxidative stress (8-oxo-7,8-dihydroguanine: 8-oxo-dG scores), Wnt/β-catenin pathway activation (expression of glutamine synthetase: GS), and tumor hyperintensity in the Gd-EOB-DTPA-enhanced MRI hepatobiliary phase (relative enhancement ratio: RER). This was a retrospective analysis of 94 hepatocellular carcinoma (HCC) patients who underwent surgical resection. In HBV-, HCV-, and alcohol-associated HCC, serum ferritin levels in the high and low RER groups were equivalent. In contrast, ferritin levels were elevated in the 'high RER' group of patients with nonalcoholic fatty liver disease (NAFLD)-HCC. As predictors of GS positivity, high RER had a sensitivity of 57.2% and a specificity of 100%. High serum ferritin had a sensitivity of 85.7% and a specificity of 85.7%. All cases with serum ferritin ≥275.5 ng/mL and high RER were 8-oxo-dG- and iron staining-positive. Additionally, GS positivity was seen in all cases with "serum ferritin levels above the upper limits or iron staining-positive" and '8-oxo-dG high' cases. Therefore, combining serum ferritin levels with RER may increase the accuracy with which activated Wnt/β-catenin signaling is predicted in NAFLD-HCC. We suggest that 8-oxo-dG accumulates following increased oxidative stress due to hepatic tissue iron deposition; this may activate Wnt/β-catenin signaling and trigger carcinogenesis.

DOI PubMed

高齢者におけるMajor hepatectomyに伴う術後合併症にGeriatric Nutritional Risk Index(GNRI)で評価した栄養状態が及ぼす影響

加藤透, 永山稔, 木村康利, 今村将史, 久木田和晴, 村上武志, 水口徹, 竹政伊知朗

日本臨床外科学会雑誌 ( 日本臨床外科学会 ) 83 ( 3 ) 599 - 600 2022年03月

回腸瘻閉鎖術と腹腔鏡下肝切除術を同時施行した2例

永山稔, 木村康利, 今村将史, 村上武志, 加藤透, 久木田和晴, 伊東竜哉, 水口徹, 竹政伊知朗

日本外科感染症学会雑誌 ( (一社)日本外科感染症学会 ) 18 ( 1 ) 252 - 252 2021年11月

An Optimal Timing for Removing a Drain After Breast Surgery: A Systematic Review and Meta-Analysis.

Hiroaki Shima, Goro Kutomi, Kiminori Sato, Yoko Kuga, Asaka Wada, Fukino Satomi, Satoko Uno, Noriko Nisikawa, Hidekazu Kameshima, Tosei Ohmura, Toru Mizuguchi, Ichiro Takemasa

The Journal of surgical research 267 267 - 273 2021年11月 [国際誌]

BACKGROUND: In clinical practice, drains had been routinely used for reducing seroma formation after breast surgery. However, an optimal timing to remove drains does not identify yet. METHODS: This study aimed to compare the clinical outcome, such as seroma formation, surgical site infection (SSI), and a length of hospital stay between early removal and late removal. A systematic review was performed using PubMed, MEDLINE, and the Cochrane Library. Breast cancer patients who received surgery using drains were eligible. Those parameters were compared between early vs late removal. RESULTS: Eleven studies included in this meta-analysis. Seroma formation in the early removal group was significantly higher than the one in the late removal group (RR = 1.58: 95%CI [1.25-2.01], P = 0.0001), meanwhile no significant difference was found among the groups for SSI (RR = 0.82: 95%CI [0.51-1.31], P= 0.40). A length of hospital stay in the early removal group was also significantly shorter than late removal (RR -3.31: 95%CI [-5.13-1.49], P = 0.0004). CONCLUSIONS: Seroma formation was significantly higher in patients who had early drain removal. Conversely, SSI incidence was low, and early removal did not increase SSI incidence. In conclusion, early drain removal has no proved clinical benefit in these settings besides reduction of hospital stays.

DOI PubMed

Maturation of robotic liver resection during the last decade: A systematic review and meta-analysis

Tomohiro Ishinuki, Shigenori Ota, Kohei Harada, Makoto Meguro, Masaki Kawamoto, Goro Kutomi, Hiroomi Tatsumi, Keisuke Harada, Koji Miyanishi, Ichiro Takemasa, Toshio Ohyanagi, Thomas T Hui, Toru Mizuguchi

World Journal of Meta-Analysis ( Baishideng Publishing Group Inc. ) 9 ( 5 ) 462 - 473 2021年10月

DOI

Major hepatectomyにおけるGeriatric Nutritional Risk Index(GNRI)で評価した栄養状態と短期予後との関連に関する検討

永山稔, 木村康利, 今村将史, 久木田和晴, 村上武志, 加藤透, 伊東竜哉, 信岡隆幸, 水口徹, 竹政伊知朗

日本臨床外科学会雑誌 ( 日本臨床外科学会 ) 82 ( 増刊 ) S773 - S773 2021年10月

Extracellular vesicles containing miR-146a-5p secreted by bone marrow mesenchymal cells activate hepatocytic progenitors in regenerating rat livers.

Norihisa Ichinohe, Masayuki Ishii, Naoki Tanimizu, Toru Mizuguchi, Yusuke Yoshioka, Takahiro Ochiya, Hiromu Suzuki, Toshihiro Mitaka

Stem cell research & therapy 12 ( 1 ) 312 - 312 2021年05月 [国際誌]

BACKGROUND: Small hepatocyte-like progenitor cells (SHPCs) appear to form transient clusters in rat livers treated with retrorsine (Ret) and 70% partial hepatectomy (PH). We previously reported that the expansion of SHPCs was amplified in Ret/PH-treated rat livers transplanted with Thy1+ cells derived from D-galactosamine-treated injured livers. Extracellular vesicles (EVs) produced by hepatic Thy1+ donor cells activated SHPCs via interleukin (IL)-17 receptor B signaling. As bone marrow-derived mesenchymal cells (BM-MCs) also express Thy1, we aimed to determine whether BM-MCs could also promote the growth of SHPCs. METHODS: BM-MCs were isolated from dipeptidyl-peptidase IV (DPPIV)-positive rats. BM-MCs or BM-MC-derived EVs were administered to DPPIV-negative Ret/PH rat livers, and the growth and the characteristics of SHPC clusters were evaluated 14 days post-treatment. miRNA microarrays and cytokine arrays examined soluble factors within EVs. Small hepatocytes (SHs) isolated from an adult rat liver were used to identify factors enhancing hepatocytic progenitor cells growth. RESULTS: The recipient's livers were enlarged at 2 weeks post-BM-MC transplantation. The number and the size of SHPCs increased remarkably in livers transplanted with BM-MCs. BM-MC-derived EVs also stimulated SHPC growth. Comprehensive analyses revealed that BM-MC-derived EVs contained miR-146a-5p, interleukin-6, and stem cell factor, which could enhance SHs' proliferation. Administration of EVs derived from the miR-146a-5p-transfected BM-MCs to Ret/PH rat livers remarkably enhanced the expansion of SHPCs. CONCLUSIONS: miR-146a-5p involved in EVs produced by BM-MCs may play a major role in accelerating liver regeneration by activating the intrinsic hepatocytic progenitor cells.

DOI PubMed

外科周術期感染予防に関するガイドライン SSI予防の周術期管理ガイドライン発表から2年経過して

水口徹, 石貫智裕, 太田盛道, 沖田憲司, 西舘敏彦, 久野芳佳, 首藤英里香, 城丸瑞恵, 堀口雅美, 秦史壮, 角隆臣, 大柳俊夫, 久冨五郎, 永山稔, 竹政伊知朗

日本外科系連合学会誌 ( 日本外科系連合学会 ) 46 ( 3 ) 323 - 323 2021年05月

Tomohiro Ishinuki, Shigenori Ota, Kohei Harada, Hiroomi Tatsumi, Keisuke Harada, Koji Miyanishi, Minoru Nagayama, Ichiro Takemasa, Toshio Ohyanagi, Thomas T Hui, Toru Mizuguchi

World Journal of Meta-Analysis ( Baishideng Publishing Group Inc. ) 9 ( 1 ) 88 - 100 2021年02月

DOI

Surgical advantage of ultrasonically activated devices during axillary lymph node dissection for breast cancer

Goro Kutomi, Hiroaki Shima, Hideki Maeda, Fukino Satomi, Asaka Wada, Kiminori Sato, Toru Mizuguchi, Ichiro Takemasa

International Surgery ( International College of Surgeons ) 105 ( 1-3 ) 623 - 627 2021年

Purposes: Axillary dissection is the gold standard for axillary lymph node metastasis in breast cancer patients. We compared surgical outcomes between ultrasonically activated devices (USADs) and thermal scalpel (TS) during axillary lymph node dissection in breast cancer patients. Methods:We conducted a retrospective analysis for 73 patients using TS between June 2012 to May 2016 and 63 patients using USADs between June 2016 to January 2019 in the breast cancer patients who received axillary dissection. Surgical outcomes were compared among the groups statistically. Results: Median operative time in the USAD group was significantly shorter than in the TS group (136 versus 182 minutes, P , 0.001). Intraoperative blood loss in the USAD group was also significantly lower than in the TS group (35 versus 120 mL, P , 0.001). Furthermore, the total drainage discharge in the USAD group was also significantly lower than in the TS group (570 versus 700 mL, P 0.016). The lymphedema frequency in the USAD group was significantly less than in the TS groups (1 of 63 versus 7 of 73, P 0.0296). Conclusion: The USADs could improve surgical outcomes, such as lymphedema, for axillary dissection of the breast cancer surgery compared with TS.

DOI

Nature of the liver volume depending on the gender and age assessing volumetry from a reconstruction of the computed tomography.

Kohei Harada, Tomohiro Ishinuki, Yoshiya Ohashi, Takeo Tanaka, Ayaka Chiba, Kanako Numasawa, Tatsuya Imai, Shun Hayasaka, Takahito Tsugiki, Koji Miyanishi, Minoru Nagayama, Ichiro Takemasa, Junji Kato, Toru Mizuguchi

PloS one 16 ( 12 ) e0261094 2021年 [査読有り] [国際誌]

Although the liver is a regenerating organ, excessive loss of liver volume (LV) can cause fatal liver failure. It is unclear whether LV is correlated with age; however, it is known that liver function decreases with age. In addition, the gender-related role of LV remains unclear. This study aimed to investigate the changes in LV by age and gender. Between January and December 2018, 374 consecutive patients who underwent abdominal multidetector computed tomography (MDCT) for any abdominal examinations were enrolled. LV was evaluated using MDCT. The relationship between the LV and body mass index (BMI), body surface area (BSA), age, and gender was investigated. The modified LV (mLV) was calculated by a formula measured LV × 1.5/BSA. LV correlated to BSA more than to BMI in both the males (R: 0.559 vs. 0.416) and females (R: 0.479 vs. 0.300) in our study. Age was negatively correlated to LV and BSA, and correlated to LV more than to BSA in males (R: 0.546 vs. 0.393) and females (R: 0.506 vs. 0.385). In addition, the absolute slope between age and LV in the males was higher than that in the females (14.1 vs. 10.2, respectively). Furthermore, the absolute slope of age and mLV in the males was slightly higher than in the females (9.1 vs. 7.3, respectively). In conclusion, LV in the normal liver is correlated to age rather than the one in the diseased liver. Liver volume in the males decreased more with age than LV in the females.

DOI PubMed

Effect of Rikkunshito, a Traditional Japanese Herbal Medicine, on Delayed Gastric Emptying and Oral Dietary Intake After Pancreaticoduodenectomy: A Prospective, Randomized, Single-Center, Open-Labeled Study.

Hiroshi Yamaguchi, Yasutoshi Kimura, Masafumi Imamura, Minoru Nagayama, Tatsuya Ito, Daisuke Kyuno, Tsuyoshi Kono, Akina Kimura, Emi Akizuki, Toshihiko Nishidate, Kenji Okita, Takayuki Nobuoka, Toru Mizuguchi, Koichi Hirata, Ichiro Takemasa

Clinical and experimental gastroenterology 13 577 - 587 2020年12月 [国際誌]

Introduction: Delayed gastric emptying (DGE) remains an important problem after pancreaticoduodenectomy (PD). There is a lack of effective treatments for early recovery of oral dietary intake. Rikkunshito (RKT), a Japanese herbal medicine, has been gaining attention as a facilitator of gastric emptying. We evaluated the effects of RKT on DGE after PD. Methods: In this prospective, randomized, open-labeled study, patients were randomly allocated before PD in a 1:1 ratio to the RKT group or the control group that received no additional treatment. The RKT group received 2.5 g of RKT three times daily (7.5 g/day) from postoperative day (POD) 1 to POD 21. The primary endpoint was the incidence of DGE. Secondary endpoints were short-term postoperative outcomes including oral dietary intake volume and perioperative changes in levels of the hormones ghrelin and leptin. Patients were observed until hospital discharge. Results: Twenty-six patients in each group (n = 52) completed the protocol treatment and were included in the analysis set. There were no statistically significant differences in basic characteristics and operative factors. The overall incidence of DGE was not statistically different between the RKT and control groups (30.8% vs 30.8%, p>0.9999). There were no statistically significant differences in the amount of postoperative oral dietary intake represented by total dietary intake (TDI) up to POD 14 and POD 21, complications, and length of hospital stay. No adverse events related to this study were observed. In the RKT group, total ghrelin and acyl-ghrelin were significantly upregulated and leptin was significantly downregulated earlier than in the control group. Conclusion: RKT treatment from POD 1 to 21 did not reduce the incidence of DGE and had no clinically beneficial effect on short-term postoperative outcomes irrespective of changes in hormone levels.

DOI PubMed

The Unique Mental Impacts of Breast-Conserving Surgery and Mastectomy According to a Multi-Centered Cross Sectional Survey Conducted in Japan

Yuri Hazawa, Goro Kutomi, Hiroaki Shima, Toshio Honma, Tosei Ohmura, Asaka Wada, Toshihiko Mikami, Miki Hotta, Momoka Narumi, Tomohiro Ishinuki, Yoshika Kuno, Makoto Meguro, Ichiro Takemasa, Minoru Okazaki, Hideji Masuoka, Kazuaki Asaishi, Toshio Ohyanagi, Thomas T. Hui, Toru Mizuguchi

Archives of Breast Cancer ( Archives of Breast Cancer ) 119 - 126 2020年08月

Background: Improving health-related quality of life (HRQOL) has become a fundamental goal of breast cancer management. This study aimed to examine the differences between the QOL outcomes of breast-conserving surgery (BCS) and mastectomy. We also established structural equation models for BCS and mastectomy to elucidate their unique effects on QOL.Methods: Between July 2019 and November 2019, 254 patients, who were scheduled to visit one of four clinics, were recruited for this study. We evaluated HRQOL using various questionnaires, such as the BREAST-Q, EQ-5D-5L, and Hospital Anxiety and Depression Scale (HADS). The relationships among the examined clinical indicators were evaluated using structural equation modeling (SEM). Results: The QOL scores of the BCS group were better than those of the mastectomy group (0.85±0.129 vs. 0.81±0.12, P=0.020). Also, anxiety (2.94±2.95 vs. 3.81±3.08, P=0.025) and depression (2.55±2.77 vs. 3.74±3.19, P=0.002) were less severe in the BCS group than in the mastectomy group. Furthermore, the relationships among QOL status and mental health status were more complex in the BCS group than in the mastectomy group (Chi-square minimization p-value: 0.231 vs. 0.469, respectively). Also, depression directly affected QOL in the mastectomy group (R=-0.47), but not in the BCS group.Conclusions: There were differences in QOL and mental health between the BCS and mastectomy groups. SEM is useful for identifying such differences, which can be used to develop strategies for improving QOL.

DOI

【外科栄養-最新のアプローチ】肝臓外科手術の周術期栄養管理

水口徹, 永山稔, 山口洋志, 石貫智裕, 久野芳佳, 今村将史, 竹政伊知朗, 木村康利

外科 ( (株)南江堂 ) 82 ( 4 ) 357 - 363 2020年04月

＜文献概要＞肝切除術周術期における栄養介入について,新たなメタ解析を追加し概説する.ERAS推奨のガイドラインでは,対象患者に術前7日間の栄養介入がすすめられている.免疫調整栄養剤は周術期の全合併症を減少させ(p<0.001),在院日数を短縮する(p=0.007).BCAA製剤も全合併症を低下させる(p=0.03).ERAS導入は周術期の全合併症を減少させる(p<0.001).技術的な課題解決に加えて,肝切除術周術期の栄養介入は臨床成績を改善させる可能性がある.

Self‐Renewal Capability of Hepatocytic Parental Progenitor Cells Derived From Adult Rat Liver Is Maintained Long Term When Cultured on Laminin 111 in Serum‐Free Medium

Junichi Kino, Norihisa Ichinohe, Masayuki Ishii, Hiromu Suzuki, Toru Mizuguchi, Naoki Tanimizu, Toshihiro Mitaka

Hepatology Communications ( Wiley ) 4 ( 1 ) 21 - 37 2020年01月

DOI

Central pancreatectomy in portal annular pancreas for metastatic renal cell carcinoma: a case report

Hiroshi Yamaguchi, Yasutoshi Kimura, Minoru Nagayama, Masafumi Imamura, Shingo Tanaka, Makoto Yoshida, Eiji Yoshida, Hiroki Fujino, Takashi Machiki, Koji Miyanishi, Toru Mizuguchi, Junji Kato, Ichiro Takemasa

World Journal of Surgical Oncology ( Springer Science and Business Media LLC ) 17 ( 1 ) 2019年12月

DOI

Immunohistological analysis of pancreatic carcinoma after vaccination with survivin 2B peptide: Analysis of an autopsy series.

Terufumi Kubo, Giichiro Tsurita, Yoshihiko Hirohashi, Hiroshi Yasui, Yasunori Ota, Kazue Watanabe, Aiko Murai, Kazuhiko Matsuo, Hiroko Asanuma, Hiroaki Shima, Satoshi Wada, Munehide Nakatsugawa, Takayuki Kanaseki, Tomohide Tsukahara, Toru Mizuguchi, Koichi Hirata, Ichiro Takemasa, Kohzoh Imai, Noriyuki Sato, Toshihiko Torigoe

Cancer science 110 ( 8 ) 2386 - 2395 2019年08月 [国際誌]

Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of cancer by providing new options in addition to existing therapies. However, peptide vaccination therapies still represent an attractive approach, because of the antigen specificity. We identified survivin 2B peptide (SVN-2B), a 9-mer antigenic peptide encoded by survivin, and an SVN-2B peptide vaccine-based phase II randomized clinical trial targeting unresectable and refractory pancreatic carcinoma was undertaken. The SVN-2B peptide vaccine did not have any statistically significant clinical benefits in that study. Therefore, we undertook an autopsy study to analyze the immune status of the pancreatic cancer lesions at the histological level. Autopsies were carried out in 13 patients who had died of pancreatic cancer, including 7 who had received SVN-2B peptide vaccination and 6 who had not, as negative controls. The expression of immune-related molecules was analyzed by immunohistochemical staining. Cytotoxic T lymphocytes were analyzed by tetramer staining and enzyme-linked immunospot assay. Histological analysis revealed dense infiltration of CD8+ T cells in some lesions in patients who had received the SVN-2B peptide vaccine. A high rate of programmed cell death ligand 1 expression in cancer cells was observed in these cases, indicating that CTLs were induced by SVN-2B peptide vaccination and had infiltrated the lesions. The lack of a significant antitumor effect was most likely attributable to the expression of immune checkpoint molecules. These findings suggest that the combination of a tumor-specific peptide vaccine and an ICI might be a promising approach to the treatment of pancreatic carcinoma in the future.

DOI PubMed

Randomized phase II trial of survivin 2B peptide vaccination for patients with HLA-A24-positive pancreatic adenocarcinoma

Hiroaki Shima, Giichiro Tsurita, Satoshi Wada, Yoshihiko Hirohashi, Hiroshi Yasui, Hiroshi Hayashi, Takashi Miyakoshi, Kazue Watanabe, Aiko Murai, Hiroko Asanuma, Serina Tokita, Terufumi Kubo, Munehide Nakatsugawa, Takayuki Kanaseki, Tomohide Tsukahara, Yutaka Nakae, Osamu Sugita, Yoichi M. Ito, Yasunori Ota, Yasutoshi Kimura, Goro Kutomi, Koichi Hirata, Toru Mizuguchi, Kohzoh Imai, Ichiro Takemasa, Noriyuki Sato, Toshihiko Torigoe

CANCER SCIENCE ( WILEY ) 110 ( 8 ) 2378 - 2385 2019年08月

The prognosis of advanced pancreatic adenocarcinoma is still extremely poor. This study sought to determine the efficacy of, and immunological response to, peptide vaccination therapy in patients with this disease. In this multicenter randomized phase II study, patients with advanced pancreatic adenocarcinoma after gemcitabine and/or tegafur/gimeracil/oteracil were randomly assigned to 3 groups that each received a 2-step treatment course. In Step 1, the groups received treatments of: (i) survivin 2B peptide (SVN-2B) plus interferon-beta (IFN beta); (ii) SVN-2B only; or (iii) placebo until the patients show progression. In Step 2, all patients who consented to participate received 4 treatments with SVN-2B plus IFN beta. The primary endpoint was progression-free survival (PFS) after initiation of Step 1 treatment. Secondary endpoints included immunological effects assessed by analysis of PBMCs after Step 1. Eighty-three patients were randomly assigned to receive SVN-2B plus IFN beta (n = 30), SVN-2B (n = 34), or placebo (n = 19). No significant improvement in PFS was observed. Survivin 2B-specific CTLs were found to be increased in the SVN-2B plus IFN beta group by tetramer assay. Among patients who participated in Step 2, those who had received SVN-2B plus IFN beta in Step 1 showed better overall survival compared with those who had received placebo in Step 1. Patients vaccinated with SVN-2B plus IFN beta did not have improved PFS, but showed significant immunological reaction after vaccination. Subgroup analysis suggested that a longer SVN-2B plus IFN beta vaccination protocol might confer survival benefit. (Clinical trial registration number: UMIN 000012146).

DOI

Scoring criteria for determining the safety of liver resection for malignant liver tumors

Harada K, Nagayama M, Ohashi Y, Chiba A, Numasawa K, Meguro M, Kimura Y, Yamaguchi H, Kobayashi M, Miyanishi K, Kato J, Mizuguchi T

World J Meta-Anal ( Baishideng Publishing Group Inc. ) 7 ( 5 ) 234 - 248 2019年05月 [査読有り]

DOI

Case report: Long-term survival of a pancreatic cancer patient immunized with an SVN-2B peptide vaccine.

Hiroaki Shima, Goro Kutomi, Fukino Satomi, Masafumi Imamura, Yasutoshi Kimura, Toru Mizuguchi, Kazue Watanabe, Akari Takahashi, Aiko Murai, Tomohide Tsukahara, Takayuki Kanaseki, Yoshihiko Hirohashi, Yuji Iwayama, Tetsuhiro Tsuruma, Hidekazu Kameshima, Noriyuki Sato, Toshihiko Torigoe, Ichiro Takemasa

Cancer immunology, immunotherapy : CII 67 ( 10 ) 1603 - 1609 2018年10月 [国際誌]

A 62-year-old woman who underwent surgery to treat pancreatic cancer provided written, informed consent to undergo adjuvant therapy with gemcitabine, tegafur, and uracil. However, this was stopped after only 14 days due to Grade 4 neutropenia. She was then started on vaccine therapy with Survivin 2B peptide (SVN-2B) including IFA and INF-α. Although metastatic lung tumors were identified and resected at 82 months after surgery, the patient has remained free of new or relapsed disease for 12 years thereafter. Tetramer and ELISPOT assays revealed the continuous circulation of SVN-2B-restricted cytotoxic T-lymphocytes (CTLs) in her peripheral blood, and CTL clones had specific activity for SVN-2B at 12 years after surgery. The adverse effects of the peptide vaccination were tolerable and comprised low-grade headache, nausea, and fatigue. A prognosis beyond 10 years in the face of pancreatic cancer with distant metastasis is extremely rare. This experience might indicate the value of cancer vaccination therapy.

DOI PubMed

外科医のための癌免疫療法進行膵臓がんを対象とした複合型CTLワクチン療法第2相試験

水口徹, 島宏彰, 九冨五郎, 木村康利, 竹政伊知朗, 鳥越俊彦, 廣橋良彦, 塚原智英, 金関貴幸, 釣田義一郎, 安井寛, 和田聡, 林宏至, 宮腰崇

日本臨床外科学会雑誌 ( 日本臨床外科学会 ) 78 ( 増刊 ) 419 - 419 2017年10月

Hepatocytic parental progenitor cells of rat small hepatocytes maintain self-renewal capability after long-term culture

Masayuki Ishii, Junichi Kino, Norihisa Ichinohe, Naoki Tanimizu, Takafumi Ninomiya, Hiromu Suzuki, Toru Mizuguchi, Koichi Hirata, Toshihiro Mitaka

SCIENTIFIC REPORTS ( NATURE PUBLISHING GROUP ) 7 46177 2017年04月 [査読有り]

The liver has a variety of functions for maintaining homeostasis, and hepatocytes play a major role. In contrast with the high regenerative capacity of mature hepatocytes (MHs) in vivo, they have not been successfully expanded ex vivo. Here we demonstrate that CD44-positive cells sorted from small hepatocyte (SH) colonies derived from a healthy adult rat liver can proliferate on a Matrigel-coated dish in serum-free chemically defined medium; in addition, a subpopulation of the cells can divide more than 50 times in a period of 17 weeks every 4-week-passage. The passage cells retained the capability to recover highly differentiated functions, such as glycogen storage, CYP activity and bile secretion. When Matrigel-treated cells from the third passage were transplanted into retrorsine/partial hepatectomytreated rat livers, the cells engrafted to differentiate into MHs and cholangiocytes. These results suggest that long-term cultured CD44(+) SHs retain hepatocytic characteristics in vitro and the capability to differentiate into hepatocytes and cholangiocytes in vivo. Thus, a newly identified subpopulation of MHs possessing the attributes of hepatocytic stem/progenitor cells can be passaged several times without losing hepatocytic characteristics.

DOI PubMed

Transplantation of Thy1(+) Cells Accelerates Liver Regeneration by Enhancing the Growth of Small Hepatocyte-Like Progenitor Cells via IL17RB Signaling

Norihisa Ichinohe, Masayuki Ishii, Naoki Tanimizu, Junko Kon, Yusuke Yoshioka, Takahiro Ochiya, Toru Mizuguchi, Koichi Hirata, Toshihiro Mitaka

STEM CELLS ( WILEY ) 35 ( 4 ) 920 - 931 2017年04月 [査読有り]

Small hepatocyte-like progenitor cells (SHPCs) transiently form clusters in rat livers treated with retrorsine (Ret)/ 70% partial hepatectomy (PH). When Thy1(+) cells isolated from D-galactosamine-treated rat livers were transplanted into the livers of Ret/ PH-treated rats, the mass of the recipient liver transiently increased during the first 30 days after transplantation, suggesting that liver regeneration was enhanced. Here we addressed how Thy1(+) cell transplantation stimulates liver regeneration. We found that the number and size of SHPC clusters increased in the liver at 14 days after transplantation. GeneChip analysis revealed that interleukin 17 receptor b (IL17rb) expression significantly increased in SHPCs from livers transplanted with Thy1(+) cells. We subsequently searched for ligand-expressing cells and found that sinusoidal endothelial cells (SECs) and Kupffer cells expressed Il17b and Il25, respectively. Moreover, extracellular vesicles (EVs) separated from the conditioned medium of Thy1(+) cell culture induced IL17b and IL25 expression in SECs and Kupffer cells, respectively. Furthermore, EVs enhanced IL17rb expression in small hepatocytes (SHs), which are hepatocytic progenitor cells; in culture, IL17B stimulated the growth of SHs. These results suggest that Thy1-EVs coordinate IL17RB signaling to enhance liver regeneration by targeting SECs, Kupffer cells, and SHPCs. Indeed, the administration of Thy1-EVs increased the number and size of SHPC clusters in Ret/ PH-treated rat livers. Sixty days post-transplantation, most expanded SHPCs entered cellular senescence, and the enlarged liver returned to its normal size. In conclusion, Thy1(+) cell transplantation enhanced liver regeneration by promoting the proliferation of intrinsic hepatic progenitor cells via IL17RB signaling.

DOI PubMed

ST6GALNAC1 plays important roles in enhancing cancer stem phenotypes of colorectal cancer via the Akt pathway

Tadashi Ogawa, Yoshihiko Hirohashi, Aiko Murai, Toshihiko Nishidate, Kenji Okita, Liming Wang, Yuzuru Ikehara, Tetsuta Satoyoshi, Akihiro Usui, Terufumi Kubo, Munehide Nakastugawa, Takayuki Kanaseki, Tomohide Tsukahara, Goro Kutomi, Tomohisa Furuhata, Koichi Hirata, Noriyuki Sato, Toru Mizuguchi, Ichiro Takemasa, Toshihiko Torigoe

Oncotarget ( Impact Journals LLC ) 8 ( 68 ) 112550 - 112564 2017年 [査読有り]

Colorectal cancer (CRC) is a mortal disease due to treatment resistance, recurrence and distant metastasis. Emerging evidence has revealed that a small subpopulation of cancer cells termed cancer stem cells (CSCs)/ cancer-initiating cells (CICs) is endowed with high levels of tumor-initiating ability, self-renewal ability and differentiation ability and is responsible for treatment resistance, recurrence and distant metastasis. Eradication of CSCs/CICs is essential to improve current treatments. However, the molecular mechanisms by which CSCs/CICs are maintained are still elusive. In this study, we aimed to determine the molecular mechanisms by which colorectal (CR)-CSCs/CICs in are maintained human primary CRC cells. CR-CSCs/CICs were isolated by sphere-culture and the ALDEFLUOR assay, and transcriptome analysis revealed that the gene ST6 N-Acetylgalactosaminide Alpha- 2,6-Sialyltransferase 1 (ST6GALNAC1) was expressed at high levels in CR-CSCs/CICs. Overexpression of ST6GALNAC1 enhanced the expression of sialyl-Tn (STn) antigen, which is carried by the CSC marker CD44, and increased the sphere-forming ability and resistance to a chemotherapeutic reagent. The opposite phenomena were observed by gene knockdown using siRNA. Furthermore, the Akt pathway was activated in ST6GANAC1-overexpressed cells, and activation of the pathway was cancelled by gene knockdown of galectin-3. The results indicate that ST6GALNAC1 has a role in the maintenance of CR-CSCs/CICs by activating the Akt pathway in cooperation with galectin-3 and that ST6GalNAC1 (or STn antigen) might be a reasonable molecule for CSC/CIC-targeting therapy.

DOI

Liver Progenitors Isolated from Adult Healthy Mouse Liver Efficiently Differentiate to Functional Hepatocytes In Vitro and Repopulate Liver Tissue

Naoki Tanimizu, Norihisa Ichinohe, Masayuki Ishii, Junichi Kino, Toru Mizuguchi, Koichi Hirata, Toshihiro Mitaka

STEM CELLS ( WILEY-BLACKWELL ) 34 ( 12 ) 2889 - 2901 2016年12月 [査読有り]

It has been proposed that tissue stem cells supply multiple epithelial cells in mature tissues and organs. However, it is unclear whether tissue stem cells generally contribute to cellular turnover in normal healthy organs. Here, we show that liver progenitors distinct from bipotent liver stem/progenitor cells (LPCs) persistently exist in mouse livers and potentially contribute to tissue maintenance. We found that, in addition to LPCs isolated as EpCAM(+) cells, liver progenitors were enriched in CD45(-)TER119(-)CD31(-)EpCAM(-)ICAM-1(+) fraction isolated from late-fetal and postnatal livers. ICAM-1(+) liver progenitors were abundant by 4 weeks (4W) after birth. Although their number decreased with age, ICAM-1(+) liver progenitors existed in livers beyond that stage. We established liver progenitor clones derived from ICAM-1(+) cells between 1 and 20W and found that those clones efficiently differentiated into mature hepatocytes (MHs), which secreted albumin, eliminated ammonium ion, stored glycogen, and showed cytochrome P450 activity. Even after long-term culture, those clones kept potential to differentiate to MHs. When ICAM-1(+) clones were transplanted into nude mice after retrorsine treatment and 70% partial hepatectomy, donor cells were incorporated into liver plates and expressed hepatocyte nuclear factor 4 alpha, CCAAT/enhancer binding protein alpha, and carbamoylphosphate synthetase I. Moreover, after short-term treatment with oncostatin M, ICAM-1(+) clones could efficiently repopulate the recipient liver tissues. Our results indicate that liver progenitors that can efficiently differentiate to MHs exist in normal adult livers. Those liver progenitors could be an important source of new MHs for tissue maintenance and repair in vivo, and for regenerative medicine ex vivo.

DOI

Involvement of Pancreatic Stellate Cells in Regeneration of Remnant Pancreas after Partial Pancreatectomy

Shigenori Ota, Miyuki Nishimura, Yuya Murakami, Naoko Kubo Birukawa, Akihiro Yoneda, Hiroki Nishita, Ryosuke Fujita, Yasushi Sato, Kenjiro Minomi, Keiko Kajiwara, Miyono Miyazaki, Maki Uchiumi, Shintaro Mikuni, Yasuaki Tamura, Toru Mizuguchi, Masafumi Imamura, Makoto Meguro, Yasutoshi Kimura, Koichi Hirata, Yoshiro Niitsu

PLOS ONE ( PUBLIC LIBRARY SCIENCE ) 11 ( 12 ) e0165747 2016年12月 [査読有り]

Background and objectives Mechanism of regeneration of remnant pancreas after partial pancreatectomy (PX) is still unknown. In this study, effect of siRNA against the collagen specific chaperone, HSP47, which inhibits collagen secretion from activated pancreas stellate cells (aPSCs), and induces their apoptosis, on regeneration of remnant pancreas was determined. Methods Pancreatectomy was performed according to established methods. Proliferation of cells was assessed by BrdU incorporation. Immunostaining of HSP47 was employed to identify PSCs. Progenitor cells were identified by SOX9 staining. Acinar cells were immunostained for amylase. Co-culture of acinar cells with aPSCs were carried out in a double chamber with a cell culture insert. siRNA HSP47 encapsulated in vitamin A-coupled liposome (VA-lip siRNA HSP47) was delivered to aPSCs by iv injection. Results In remnant pancreas of 90% PX rat, new areas of foci were located separately from duodenal areas with normal pancreatic features. After PX, BrdU uptake of acinar cells and islet cells significantly increased, but was suppressed by treatment with VA-lip siRNA HSP47. BrdU uptake by acinar cells was augmented by co-culturing with aPSCs and the augmentation was nullified by siRNA HSP47. BrdU uptake by progenitor cells in foci area was slightly enhanced by the same treatment. New area which exhibited intermediate features between those of duodenal and area of foci, emerged after the treatment. Conclusion aPSCs play a crucial role in regeneration of remnant pancreas, proliferation of acinar and islet cells after PX through the activity of secreted collagen. Characterization of new area emerged by siRNA HSP47 treatment as to its origin is a future task.

DOI PubMed

Flap revascularization in patients following immediate reconstruction using an autologous free dermal fat graft for breast cancer: a report of two cases.

Hiroaki Shima, Goro Kutomi, Takuro Kyuno, Fukino Satomi, Satoko Uno, Hideki Maeda, Hidekazu Kameshima, Tosei Omura, Yasutoshi Kimura, Toru Mizuguchi, Koichi Hirata, Ichiro Takemasa

Surgical case reports 2 ( 1 ) 54 - 54 2016年12月 [国際誌]

It has been reported that use of the free dermal fat graft (FDFG) technique produces a good cosmetic outcome for breast cancer. An FDFG is harvested from the lower abdomen as a columnar-shaped specimen and implanted into the defect of the breast after a partial mastectomy as a volume replacement technique. In this report, two patients who underwent breast-conserving surgery with immediate reconstruction using an autologous FDFG are described in order to show the difference in status between one case with and one without blood flow in the graft. To assess the benefit of this technique using FDFGs, their cosmetic satisfaction was evaluated using a questionnaire, graft shrinkage was measured by CT, and blood flow was assessed using contrast-enhanced ultrasound (CEUS). Both patients scored 10 of 12 points on the questionnaire. After 2 years, shrinkage of the grafts was 21.6 and 25.2 %, respectively. Although one patient had no blood flow in the center of the graft, the other had blood flow from the pectoralis major muscle to the center of the graft. While satisfaction and graft shrinkage were similar in the two patients, one case showed blood flow and had a somewhat softer graft than the other. The graft status was maintained with a good cosmetic outcome for 3 years after breast-conserving surgery with immediate reconstruction using an autologous FDFG, despite mild shrinkage and hardness of the graft. It is notable that blood flow was observed into the graft on CEUS, and more distinct perfusion was seen in the softer graft case after more than 3 years.

DOI PubMed

Olfactory Receptor Family 7 Subfamily C Member 1 Is a Novel Marker of Colon Cancer-Initiating Cells and Is a Potent Target of Immunotherapy.

Rena Morita, Yoshihiko Hirohashi, Toshihiko Torigoe, Satoko Ito-Inoda, Akari Takahashi, Tasuku Mariya, Hiroko Asanuma, Yasuaki Tamura, Tomohide Tsukahara, Takayuki Kanaseki, Terufumi Kubo, Goro Kutomi, Toru Mizuguchi, Takeshi Terui, Kunihiko Ishitani, Satoshi Hashino, Toru Kondo, Nozomi Minagawa, Norihiko Takahashi, Akinobu Taketomi, Satoru Todo, Masahiro Asaka, Noriyuki Sato

Clinical cancer research : an official journal of the American Association for Cancer Research 22 ( 13 ) 3298 - 309 2016年07月 [国際誌]

PURPOSE: Cancer-initiating cells (CICs) are thought to be essential for tumor maintenance, recurrence, and distant metastasis, and they are therefore reasonable targets for cancer therapy. Cancer immunotherapy is a novel approach to target cancer. In this study, we aimed to establish novel CIC-targeting immunotherapy. EXPERIMENTAL DESIGN: Colorectal cancer (CRC) CICs were isolated as side population (SP) cells. The gene expression profile of CRC CICs was analyzed by cDNA microarray and RT-PCR. Protein expression of olfactory receptor family 7 subfamily C member 1 (OR7C1) were analyzed by Western blot and immunohistochemical staining. The functions of OR7C1 were analyzed by gene overexpression and gene knockdown using siRNAs. OR7C1-positive cells were isolated by a flow cytometer and analyzed. CTLs specific for OR7C1 peptide were generated, and the antitumor effect was addressed by mice adoptive transfer model. RESULTS: OR7C1 has essential roles in the maintenance of colon CICs, and the OR7C1-positive population showed higher tumorigenicity than that of the OR7C1-negative population, indicating that OR7C1 is a novel functional marker for colon CIC. Immunohistochemical staining revealed that OR7C1 high expression was correlated with poorer prognosis in CRC patients. OR7C1-derived antigenic peptide-specific CTLs showed specific cytotoxicity for CICs, and an OR7C1-specific CTL clone showed a greater antitumor effect than did a CTL clone targeting all cancer cells in a CTL adoptive transfer mouse model. CONCLUSIONS: OR7C1 is a novel marker for colon CICs and can be a target of potent CIC-targeting immunotherapy. Clin Cancer Res; 22(13); 3298-309. ©2016 AACR.

DOI PubMed

Intrahepatic Bile Ducts Are Developed Through Formation of Homogeneous Continuous Luminal Network and Its Dynamic Rearrangement in Mice

Naoki Tanimizu, Kota Kaneko, Tohru Itoh, Norihisa Ichinohe, Masayuki Ishii, Toru Mizuguchi, Koichi Hirata, Atsushi Miyajima, Toshihiro Mitaka

HEPATOLOGY ( WILEY-BLACKWELL ) 64 ( 1 ) 175 - 188 2016年07月 [査読有り]

The intrahepatic bile duct (IHBD) is a highly organized tubular structure consisting of cholangiocytes, biliary epithelial cells, which drains bile produced by hepatocytes into the duodenum. Although several models have been proposed, it remains unclear how the three-dimensional (3D) IHBD network develops during liver organogenesis. Using 3D imaging techniques, we demonstrate that the continuous luminal network of IHBDs is established by 1 week after birth. Beyond this stage, the IHBD network consists of large ducts running along portal veins (PVs) and small ductules forming a mesh-like network around PVs. By analyzing embryonic and neonatal livers, we found that newly differentiated cholangiocytes progressively form a continuous and homogeneous luminal network. Elongation of this continuous network toward the liver periphery was attenuated by a potent Notch-signaling inhibitor N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester. Subsequent to this first step, the fine homogenous network is reorganized into the mature hierarchical network consisting of large ducts and small ductules. Between E17 and E18, when the homogenous network is radically reorganized into the mature hierarchical network, bile canaliculi rapidly extend and bile flow into IHBDs may increase. When formation of bile canaliculi was blocked between E16 and E18 by a multidrug resistance protein 2 inhibitor (benzbromarone), the structural rearrangement of IHBDs was significantly suppressed. Conclusion: Establishment of the mature IHBD network consists of two sequential events: (1) formation of the continuous luminal network regulated by the Notch-signaling pathway and (2) dynamic rearrangement of the homogeneous network into the hierarchical network induced by increased bile flow resulting from the establishment of hepatobiliary connections.

DOI PubMed

Pancreatic regeneration: basic research and gene regulation

Kenji Okita, Toru Mizuguchi, Ota Shigenori, Masayuki Ishii, Toshihiko Nishidate, Tomomi Ueki, Makoto Meguro, Yasutoshi Kimura, Naoki Tanimizu, Norihisa Ichinohe, Toshihiko Torigoe, Takashi Kojima, Toshihiro Mitaka, Noriyuki Sato, Norimasa Sawada, Koichi Hirata

SURGERY TODAY ( SPRINGER ) 46 ( 6 ) 633 - 640 2016年06月 [査読有り]

Pancreatic regeneration (PR) is an interesting phenomenon that could provide clues as to how the control of diabetes mellitus might be achieved. Due to the different regenerative abilities of the pancreas and liver, the molecular mechanism responsible for PR is largely unknown. In this review, we describe five representative murine models of PR and thirteen humoral mitogens that stimulate beta-cell proliferation. We also describe pancreatic ontogenesis, including the molecular transcriptional differences between alpha-cells and beta-cells. Furthermore, we review 14 murine models which carry defects in genes related to key transcription factors for pancreatic ontogenesis to gain further insight into pancreatic development.

DOI PubMed

Multiple hepatocellular adenomas: A case report

Fumito Tamura, Yutaka Kawano, Koji Miyanishi, Tomohiro Kubo, Yusuke Kamihara, Yutaka Okagawa, Kazuma Ishikawa, Kohichi Takada, Tsuyoshi Hayashi, Tsutomu Sato, Yasushi Sato, Masayoshi Kobune, Rishu Takimoto, Masaki Kawamoto, Makoto Meguro, Toru Mizuguchi, Ziro Ogino, Tadashi Hasegawa, Norihide Yoneda, Motoko Sasaki, Junji Kato

Acta Hepatologica Japonica ( Japan Society of Hepatology ) 56 ( 11 ) 584 - 595 2015年12月

We report a rare case of multiple hepatocellular adenomas difficulty in ruling out well-differentiated hepatocellular carcinomas prior to resection. A 40s female was admitted to the hospital for examination of multiple liver tumors. CT and Gd-EOB-MRI showed that tumors were located in segment 2 and 5. We conducted a percutaneous tumor biopsy and tumor showed low atypical cells containing fat deposit. As the possibility of multiple hepatocellular carcinomas could not be denied, partial hepatectomy and RFA were done. All resected tumors showed a decreased expression of the liver fatty acid binding protein (L-FABP), and were finally diagnosed as multiple HNF1α-inactivated type hepatocellular adenomas Multiple hepatocellular adenomas are rare tumors, so we report this case with review of the literatures.

DOI

Surgical and oncological impact of main pancreatic duct spread in invasive ductal adenocarcinoma: A clinicopathological study of 184 resected cases

Masayuki Ishii, Yasutoshi Kimura, Shintaro Sugita, Masafumi Imamura, Tatsuya Ito, Takayuki Nobuoka, Makoto Meguro, Tadashi Hasegawa, Toru Mizuguchi, Koichi Hirata

PANCREATOLOGY ( KARGER ) 15 ( 6 ) 681 - 687 2015年11月 [査読有り]

Background/Objectives: This study examined main pancreatic ductal spread in invasive ductal adenocarcinoma (IDC) of the pancreas. Methods: Data from IDC patients who underwent radical surgery from 1990 to 2013 in our hospital were examined retrospectively. Incidence of intraductal spread of pancreatic cancer (IS), distance from the tumor edge, direction of IS and clinicopathological factors associated with the presence of IS were retrospectively examined with data from IDC patients who underwent radical surgery. Results: Among 260 IDC patients who underwent surgery, 184 eligible cases, IS was identified in 42 patients (22.8%) and mean length of IS was 18.7 +/- 21.6 mm. Mean distances on the ampullary and distal sides of IS were 11.1 mm and 11.6 mm. IS was significantly more frequent in localized tumors (UICC T1-2 vs. 3-4, p = 0.007), with tumor diameter <= 2 cm (p = 0.034) and in cases with scarce microscopic perineural invasion (p = 0.047). Among patients who underwent pancreaticoduodenectomy and distal pancreatectomy, IS presence (11.6 vs. 21.8%), mean distance to the contralateral side (11.4 vs. 11.6 mm), and IS >= 2 cm (3.3 vs. 4.7%) showed no significant differences. Overall survival did not differ significantly between IS-positive and -negative patients in the full analysis set or propensity score-matched patients (42 matched pairs). Conclusions: In setting resectional margins at 2 cm, a small proportion of cases (3.8%) showed positive surgical margins. Localized tumor (UICC: T1-2, or <2 cm in diameter) requires more care with surgical margins, warranting intraoperative frozen sections. Copyright (C) 2015, IAP and EPC. Published by Elsevier India, a division of Reed Elsevier India Pvt. Ltd. All rights reserved.

DOI

Long-term and perioperative outcomes of laparoscopic versus open liver resection for colorectal liver metastases with propensity score matching: a multi-institutional Japanese study

Toru Beppu, Go Wakabayashi, Kiyoshi Hasegawa, Naoto Gotohda, Toru Mizuguchi, Yutaka Takahashi, Fumitoshi Hirokawa, Nobuhiko Taniai, Manabu Watanabe, Masato Katou, Hiroaki Nagano, Goro Honda, Hideo Baba, Norihiro Kokudo, Masaru Konishi, Koichi Hirata, Masakazu Yamamoto, Kazuhisa Uchiyama, Eiji Uchida, Shinya Kusachi, Keiichi Kubota, Masaki Mori, Keiichi Takahashi, Ken Kikuchi, Hiroaki Miyata, Takeshi Takahara, Masafumi Nakamura, Hironori Kaneko, Hiroki Yamaue, Masaru Miyazaki, Tadahiro Takada

JOURNAL OF HEPATO-BILIARY-PANCREATIC SCIENCES ( WILEY ) 22 ( 10 ) 711 - 720 2015年10月 [査読有り]

Background The aim of the present study was to clarify the surgical outcome and long-term prognosis of laparoscopic liver resection (LLR) compared with conventional open liver resection (OLR) in patients with colorectal liver metastases (CRLM). Methods A one-to-two propensity score matching (PSM) analysis was applied. Covariates (P<0.2) used for PSM estimation included preoperative levels of CEA and CA19-9; primary tumor differentiation; primary pathological lymph node metastasis; number, size, location, and distribution of CRLM; existence of extrahepatic metastasis; extent of hepatic resection; total bilirubin and prothrombin activity levels; and preoperative chemotherapy. Perioperative data and long-term survival were compared. Results From 2005 to 2010, 1,331 patients with hepatic resection for CRLM were enrolled. By PSM, 171 LLR and 342 OLR patients showed similar preoperative clinical characteristics. Median estimated blood loss (163 g vs 415 g, P<0.001) and median postoperative hospital stay (12 days vs 14 days; P<0.001) were significantly reduced in the LLR group. Morbidity and mortality were similar. Five-year rates of recurrence-free, overall, and disease-specific survival did not differ significantly. The R0 resection rate was similar. Conclusions In selected CRLM patients, LLR is strongly associated with lower blood loss and shorter hospital stay and has equivalent long-term survival comparable with OLR.

DOI PubMed

バイオマーカーをめぐるQ&A(Question 16) hERO1-Lα発現による乳癌予後予測は可能か?

九冨五郎, 久木田和晴, 里見蕗乃, 前田豪樹, 島宏彰, 水口徹, 平田公一

Surgery Frontier ( (株)メディカルレビュー社 ) 22 ( 3 ) 283 - 285 2015年09月

Clinical comparison of laparoscopic and open liver resection after propensity matching selection

Makoto Meguro, Toru Mizuguchi, Masaki Kawamoto, Shigenori Ota, Masayuki Ishii, Toshihiko Nishidate, Kenji Okita, Yasutoshi Kimura, Koichi Hirata

SURGERY ( MOSBY-ELSEVIER ) 158 ( 3 ) 573 - 587 2015年09月 [査読有り]

Background. This study aimed to compare the radicality for and clinical advantages of laparoscopic liver resection, which is increasingly used, and the corresponding open procedure by propensity score matching analysis. Methods. We analyzed 260 hepatocellular carcinoma patients who underwent initial liver resection at our department between January 2003 and June 2011, including 60 laparoscopic (the Lap group) and 200 open cases (the Open group). Propensity scores were calculated for each patient via the use of various clinicopathologic features as covariates, and patients' survival was compared. Results. The Lap group had more women and patients of advanced age (n = 60) than the Open group (n = 200). Tumor size (2.3 cm vs 3.5 cm median), multiple tumors (18.3% vs 41.0%), vascular invasion (15.0% vs 36.5%), poor differentiation status (11.2% vs 24.5%), intraoperative bleeding (110 mL vs 420 mL; median), and operative time (277 minutes vs 312 minutes; median) were significantly more favorable in the Lap group than in the Open group because of a selection bias of the patients (Lap vs Open). The postoperative recurrence-free and overall survival rates were greater in the Lap group than in the Open group; however, when 35 patients from each group were analyzed after propensity scare matching of clinicopathologic characteristics of the patients, intraoperative bleeding was lesser in the Lap group. The recurrence-free survival rates at 1, 3, and 5 years were 75.0%, 43.8%, and 43.8%, respectively, in the Lap group and 73.6%, 49.3%, and 37.2%, respectively, in the Open group, which indicated no significant differences (P = .954). Similarly, the overall survival rates at 1, 3, and 5 years were 93.9%, 82.1%, and 82.1%, respectively, in the Lap group and 94.3%, 85.2%, and 61.8%, respectively, in the Open group, indicating no significant differences between the 2 groups (P = .672). Conclusion. Our results indicate that laparoscopic liver resection is comparable with the corresponding open procedure in clinical safety and prognostic efficacy.

DOI

Effects of antecolic versus retrocolic reconstruction for gastro/duodenojejunostomy on delayed gastric emptying after pancreatoduodenectomy: A systematic review and meta-analysis

Masafumi Imamura, Yasutoshi Kimura, Tatsuya Ito, Takuro Kyuno, Takayuki Nobuoka, Toru Mizuguchi, Koichi Hirata

Journal of Surgical Research ( Academic Press Inc. ) 200 ( 1 ) 147 - 157 2015年05月

Background Delayed gastric emptying (DGE) is a relatively common complication after pancreatoduodenectomy (PD). The aim of this study was to determine whether DGE is affected by antecolic or retrocolic reconstruction for gastro/duodenojejunostomy after PD. Methods A literature search was performed of the MEDLINE (PubMed), Ovid SP, ISI Web of Knowledge, EMBASE, and Cochrane databases to identify randomized controlled trials (RCTs) and clinical observational studies related to this topic from January 1995 to November 2014. Pooled odds ratios (ORs) with 95% confidence intervals (CIs) were calculated for categorical outcomes, and mean differences (MD) using fixed-effect and random-effects models were calculated for the meta-analysis. Results Fourteen studies including 1969 patients met the inclusion criteria. Six studies were RCTs, and eight studies were clinical observational studies. DGE was less common in the antecolic reconstruction group than in the retrocolic reconstruction group (OR = 0.24 [0.12-0.48], P < 0.0001). Postoperative days to start solid foods (MD = -3.67 d [-5.10 to -2.33], P < 0.00001) and length of hospital stay (MD = -2.90 d [-5.36 to -2.33], P < 0.00001) were also significantly in favor of the antecolic reconstruction group. There was no difference in the incidence of pancreatic fistula, intra-abdominal fluid collection or abscess, biliary fistula, or mortality. However, in the subgroup analyses, using the data of six RCTs or seven studies according to the International Study Group of Pancreatic Surgery definition, there was no significant difference in the incidence of DGE. Conclusions Antecolic reconstruction for gastro/duodenojejunostomy does not seem to offer an advantage over retrocolic reconstruction with respect to DGE after PD.

DOI PubMed

Prognostic roles of preoperative α-fetoprotein and des-γ-carboxy prothrombin in hepatocellular carcinoma patients

Makoto Meguro, Toru Mizuguchi, Toshihiko Nishidate, Kenji Okita, Masayuki Ishii, Shigenori Ota, Tomomi Ueki, Emi Akizuki, Koichi Hirata

World Journal of Gastroenterology ( WJG Press ) 21 ( 16 ) 4933 - 4945 2015年04月

AIM: To clarify the utility of using des-γ-carboxy prothrombin (DCP) and α-fetoprotein (AFP) levels to predict the prognosis of hepatocellular carcinoma (HCC) in patients with hepatitis B virus (HBV) and the hepatitis C virus (HCV) infections. METHODS: A total of 205 patients with HCC (105 patients with HBV infection 100 patients with HCV infection) who underwent primary hepatectomy between January 2004 and May 2012 were enrolled retrospectively. Preoperative AFP and DCP levels were used to create interactive dot diagrams to predict recurrence within 2 years after hepatectomy, and cutoff levels were calculated. Patients in the HBV and HCV groups were classifed into three groups: a group with low AFP and DCP levels (LL group), a group in which one of the two parameters was high and the other was low (HL group), and a group with high AFP and DCP levels (HH group). Liver function parameters, the postoperative recurrence-free survival rate, and postoperative overall survival were compared between groups. The survival curves were compared by logrank test using the Kaplan-Meier method. Multivariate analysis using a Cox forward stepwise logistic regression model was conducted for a prognosis. RESULTS: The preoperative AFP cutoff levels for recurrence within 2 years after hepatectomy in the HBV and HCV groups were 529.8 ng/mL and 60 mAU/mL, respectively for preoperative DCP levels, the cutoff levels were 21.0 ng/mL in the HBV group and 67 mAU/mL in the HCV group. The HBV group was significantly different from the other groups in terms of vascular invasion, major hepatectomy, volume of intraoperative blood loss, and surgical duration. Significant differences were found between the LL group, the HL group, and the HH group in terms of both mean disease-free survival time (MDFST) and mean overall survival time (MOST):64.81 ± 7.47 vs 36.63 ± 7.62 vs 18.98 ± 6.17 mo (P = 0.001) and 85.30 ± 6.55 vs 59.44 ± 7.87 vs 46.57 ± 11.20 mo (P = 0.018). In contrast, the HCV group exhibited a significant difference in tumor size, vascular invasion, volume of intraoperative blood loss, and surgical duration however, no significant difference was observed between the three groups in liver function parameters except for albumin levels. In the LL group, the HL group, and the HH group, the MDFST was 50.09 ± 5.90, 31.01 ± 7.21, and 14.81 ± 3.08 mo (log-rank test, P < 0.001), respectively, and the MOST was 79.45 ± 8.30, 58.82 ± 7.56, and 32.87 ± 6.31 mo (log-rank test, P < 0.001), respectively. CONCLUSION: In the HBV group, the prognosis was poor when either AFP or DCP levels were high. In the HCV group, the prognosis was good when either or both levels were low however, the prognosis was poor when both levels were high. High levels of both AFP and DCP were an independent risk factor associated with tumor recurrence in the HBV and HCV groups. The relationship between tumor marker levels and prognosis was characteristic to the type of viral hepatitis.

DOI PubMed

Clinical feasibility of laparoscopic lateral pelvic lymph node dissection following total mesorectal excision for advanced rectal cancer

Tomohisa Furuhata, Kenji Okita, Toshihiko Nishidate, Tatsuya Ito, Hiroshi Yamaguchi, Tomomi Ueki, Emi Akizuki, Makoto Meguro, Tadashi Ogawa, Kazuharu Kukita, Yasutoshi Kimura, Toru Mizuguchi, Koichi Hirata

SURGERY TODAY ( SPRINGER ) 45 ( 3 ) 310 - 314 2015年03月 [査読有り]

Purpose To evaluate the technical feasibility, safety and oncological outcomes of laparoscopic lateral pelvic lymph node dissection in patients with advanced low rectal cancer. Methods Laparoscopic lateral pelvic lymph node dissection was performed in 18 patients from November 2009 to September 2012. The data regarding the patient demographics, surgical outcomes and short-term oncological outcomes were analyzed. Results In all 18 patients, the procedures were completed without conversion to open surgery. The mean length of the operation was 603.7 min (473-746 min). The mean number of harvested lateral pelvic lymph nodes was 16.9 (7-27), and five patients (27.8 %) had lymph node metastases. The postoperative mortality and morbidity rates were 0 and 16.7 %, respectively. Three patients developed Grade 2 urinary retention. No local recurrence had developed after a mean follow-up period of 23.6 months. Conclusion Laparoscopic lateral pelvic lymph node dissection is technically feasible, safe and oncologically acceptable within the limitations of the short-term follow-up period.

DOI

An immunohistochemical marker panel including claudin-18, maspin, and p53 improves diagnostic accuracy of bile duct neoplasms in surgical and presurgical biopsy specimens.

Yoshiko Keira, Akira Takasawa, Masaki Murata, Masanori Nojima, Kumi Takasawa, Jiro Ogino, Yukimura Higashiura, Ayaka Sasaki, Yasutoshi Kimura, Toru Mizuguchi, Satoshi Tanaka, Koichi Hirata, Norimasa Sawada, Tadashi Hasegawa

Virchows Archiv : an international journal of pathology 466 ( 3 ) 265 - 77 2015年03月 [国際誌]

Biliary tract cancers have an extremely poor outcome, and specific diagnostic markers and effective treatments are needed urgently. In this study, we assessed the capacity of panel of immunohistochemical markers including claudin-18, maspin, and p53 to distinguish biliary tract carcinoma and biliary intraepithelial neoplasia (BilIN) from non-neoplastic epithelium. We performed a retrospective study of 66 biliary tract cancer specimens and 63 specimens with non-neoplastic lesions. Of the surgical specimens, 96.7 % with adenocarcinoma/BilIN were detected as neoplastic, and all 63 specimens histologically diagnosed as non-neoplastic lesion were detected as non-neoplastic with high sensitivity (91.1 %) and specificity (100 %). Of presurgical endobiliary forceps biopsy specimens, all with adenocarcinoma/BilIN and only 1 of the 19 with a non-neoplastic lesion were distinguished as neoplastic with high sensitivity (100 %) and specificity (94.7 %). Moreover, this panel provided good separation of neoplasm from malignancy-undetermined atypical epithelium (18/21, 85.7 %). This panel achieves a more reliable distinction of biliary tract cancers and BilINs from non-neoplastic epithelia in both surgical and biopsy specimens than immunohistochemical analysis with single antibodies and is useful in supporting a diagnosis of adenocarcinoma and BilIN.

DOI PubMed

A dose-escalation study of oxaliplatin/capecitabine/irinotecan (XELOXIRI) and bevacizumab as a first-line therapy for patients with metastatic colorectal cancer

Yasushi Sato, Hiroyuki Ohnuma, Masahiro Hirakawa, Minoru Takahashi, Takahiro Osuga, Yutaka Okagawa, Kazuyuki Murase, Kohichi Takada, Yutaka Kawano, Satoshi Iyama, Tsuyoshi Hayashi, Tsutomu Sato, Koji Miyanishi, Rishu Takimoto, Masayoshi Kobune, Kenji Okita, Toru Mizuguchi, Tomohisa Furuhata, Koichi Hirata, Junji Kato

CANCER CHEMOTHERAPY AND PHARMACOLOGY ( SPRINGER ) 75 ( 3 ) 587 - 594 2015年03月 [査読有り]

The aim of this study was to determine the recommended dose (RD) of a triweekly capecitabine, oxaliplatin, irinotecan, and bevacizumab (XELOXIRI/bevacizumab) regimen that was easier to administer than FOLFOXIRI/bevacizumab, using capecitabine instead of 5-fuorouracil (5-FU), in patients with metastatic colorectal cancer (mCRC). Patients received oxaliplatin (100 mg/m(2), day 1), capecitabine (1,700 mg/m(2) per day from day 2 to 15), irinotecan (100, 120, 150 mg/m(2) for dose levels 1, 2, 3, day 1), and bevacizumab (7.5 mg/kg, day 1), repeated every 3 weeks. Dose-limiting toxicities (DLTs) were assessed in the first two cycles to determine the maximum tolerated dose (MTD). Twelve patients received a median of 6.5 cycles of therapy (range 2-12). The DLT was grade 4 neutropenia, observed in one of six patients at dose level 2. The MTD was not reached at dose level 3. Therefore, the RD of irinotecan was defined as 150 mg/m(2). The most common grade a parts per thousand yen3 toxicities were neutropenia (41 %), anemia (17 %), diarrhea (8 %), and febrile neutropenia (8 %). The response rate and median progression-free survival were 83 % and 15 months, respectively. XELOXIRI/bevacizumab is a feasible regimen for patients with mCRC, neutropenia was the DLT, and the RD of irinotecan is 150 mg/m(2). The response rate observed is very promising and warrants further investigation.

DOI

New technique of extracorporeal hepatic inflow control for pure laparoscopic liver resection

Toru Mizuguchi, Masaki Kawamoto, Yukio Nakamura, Makoto Meguro, Thomas T. Hui, Koichi Hirata

Surgical Laparoscopy, Endoscopy and Percutaneous Techniques ( Lippincott Williams and Wilkins ) 25 ( 1 ) e16 - e20 2015年02月

We have developed a new technique of the Pringle maneuver by clamping outside the abdominal wall for pure laparoscopic liver resection (pure Lap). Our technique successfully controls bleeding and enables pure Lap to be completed without any events, even for a large tumor. Between 2008 and 2010, we compared consecutive patients who received pure Lap with (n=11) and without (n=7) this Pringle maneuver. Although tumor size in the Pringle group was significantly larger than in the no-Pringle group (3.35±1.64 vs. 1.11±0.29 cm, respectively), intraoperative bleeding was not significantly different (165.5±188.5 vs. 177.9±364.4 mL, respectively). In contrast, operation time in the Pringle group was significantly longer than in the no-Pringle group (343.1±99.5 vs. 199.6±63.2 min, respectively). Pure Lap for large tumors is feasible when employing a new Pringle maneuver outside the abdominal wall.

DOI PubMed

Prognostic value of HLA class I expression in patients with colorectal cancer

Yuji Iwayama, Tetsuhiro Tsuruma, Toru Mizuguchi, Tomohisa Furuhata, Nobuhiko Toyota, Masayuki Matsumura, Toshihiko Torigoe, Noriyuki Sato, Koichi Hirata

WORLD JOURNAL OF SURGICAL ONCOLOGY ( BIOMED CENTRAL LTD ) 13 2015年02月 [査読有り]

Background: Prognostic factors are useful for determination of the therapeutic strategy and follow-up examination after curative operation in cancer treatment. The immunological state of the host can influence the prognosis for cancer patients as well as the features of the cancer. Human lymphocyte antigen (HLA) class I molecules have a central role in the anti-cancer immune system. Therefore, we focused on the HLA class I expression level in cancer cells to investigate its prognostic value in patients with colorectal cancer. Methods: We reviewed the clinical pathology archives of 97 consecutive patients with stage II colorectal cancer who underwent curative operation at the Sapporo Medical University, Japan, from February 1994 to January 2005. Fifty-six high-risk patients had adjuvant chemotherapy. The cancer cell membrane immunoreactivity level for HLA class I expressed by EMR8-5 was classified into three categories (positive, dull, and negative). In this study, the cases were divided into two groups: "positive" and "dull/negative". HLA class I expression level and clinicopathological parameters were evaluated with the Pearson chi(2) test. Survival analysis was assessed by the Kaplan-Meier methods, and the differences between survival curves were analyzed using the log-rank test. Results: Immunohistochemical study of HLA class I revealed the following. There were 51 cases that were positive, 40 were dull, and six negative. The HLA class I expression level had no significant correlation with other clinicopathological parameters, except for gender. Univariate and multivariate analyses related to disease-free survival (DFS) revealed that tumor location, HLA expression level, and venous invasion were significant independent prognostic factors (P < 0.05). The 5-year DFS rates in HLA class I positive group and in the dull/negative group were 89% and 70%, respectively. For high-risk patients with adjuvant chemotherapy, the 5-year DFS rates in the HLA class I positive group and in the dull/negative group were 84% and 68%, respectively. For low-risk patients without the chemotherapy, the 5-year DFS rates in the HLA class I positive group and in the dull/negative group were 100% and 71%, respectively. Conclusions: Our study concluded that the HLA class I expression level might be a very sensitive prognostic factor in colorectal cancer patients with stage II disease.

DOI

Remnant Pancreas Reconstruction with Duct-To-Duct Anastomosis after Middle Pancreatectomy: A Report of Two Cases

Masayuki Ishii, Yasutoshi Kimura, Masafumi Imamura, Daisuke Kyuno, Tomomi Ueki, Motonobu Uchiyama, Toru Mizuguchi, Mitsuhiro Mukaiya, Koichi Hirata

HEPATO-GASTROENTEROLOGY ( H G E UPDATE MEDICAL PUBLISHING S A ) 62 ( 137 ) 190 - 194 2015年01月 [査読有り]

Reconstruction of a remnant pancreas after middle pancreatectomy has generally been performed with. a pancreaticoenterostomy. We report here two cases in which physiological reconstructive procedures were performed. The reconstructive procedures included pancreatic duct-to-duct anastomosis and parenchymal sutures with absorbable monofilament interrupted stitches. A pancreatic tube was inserted for decompression at the anastomotic site in both cases. The patients comprised one with pancreatic metastasis from renal cell carcinoma and another with a non-malignant insulinoma. The tumors were located in the pancreatic body. Although an International Study Group on Pancreatic Fistula classification grade B-pancreatic fistula was observed in each patient, they both resolved with conservative therapy. The pancreatic duct at the anastomosis site was patent in both cases, and no atrophic changes developed in the remnant pancreas in either patient. These outcomes confirmed that, in selected cases, this reconstructive procedure is safe and feasible for physiological reconstruction without involvement of the digestive tract.

DOI

Soluble Lutheran/basal cell adhesion molecule is detectable in plasma of hepatocellular carcinoma patients and modulates cellular interaction with laminin-511 in vitro

Yamato Kikkawa, Takahiro Miwa, Naoki Tanimizu, Yuichi Kadoya, Takaho Ogawa, Fumihiko Katagiri, Kentaro Hozumi, Motoyoshi Nomizu, Toru Mizuguchi, Koichi Hirata, Toshihiro Mitaka

Experimental Cell Research ( Academic Press Inc. ) 328 ( 1 ) 197 - 206 2014年10月

Lutheran (Lu), an immunoglobulin superfamily transmembrane receptor, is also known as basal cell adhesion molecule (B-CAM). Lu/B-CAM is a specific receptor for laminin α5, a subunit of laminin-511 (LM-511) that is a major component of basement membranes in various tissues. Our previous study showed that Lu/B-CAM was cleaved by MT1-MMP and released from cell surfaces. In this study we examined the soluble Lu/B-CAM in culture media and in plasma of mice bearing HuH-7 hepatocellular carcinoma (HCC) cells and patients with HCC. Two HCC cell lines, HepG2 and HuH-7, released Lu/B-CAM into the culture media. Although Lu/B-CAM was cleaved by MT1-MMP in HuH-7 cells, HepG2 cells released Lu/B-CAM in a MMP-independent manner. The concentration of Lu/B-CAM released into mouse plasma correlated with tumor size. Moreover the soluble Lu/B-CAM in plasma of HCC patients was significantly decreased after resection of the tumor. Immunohistochemical studies showed that although the expression of Lu/B-CAM was observed in most HCCs, MT1-MMP was not always expressed in tumor tissues, suggesting that a part of Lu/B-CAM in plasma of HCC patients was also released in a MMP-independent manner. In vitro studies showed that the soluble Lu/B-CAM released from HCC cells bound to LM-511. Moreover the soluble Lu/B-CAM influenced cell migration on LM-511. These results suggest that soluble Lu/B-CAM serves as not only a novel marker for HCC but also a modulator in tumor progression.

DOI PubMed

プロペンシティ解析を用いた膵頭十二指腸切除術後アウトカムの比較研究

安田尚美, 木村康利, 今村将史, 伊東竜哉, 沖田憲司, 水口徹, 古畑智久, 平田公一

日本臨床外科学会雑誌 ( 日本臨床外科学会 ) 75 ( 9 ) 2643 - 2643 2014年09月

Saline Injection Method for Facilitating the Liver Hanging Maneuver During Hepatectomy for a Large Right Liver Tumor

Toru Mizuguchi, Masaki Kawamoto, Makoto Meguro, Kenji Okita, Toshihiko Nishidate, Tomohisa Furuhata, Thomas T. Hui, Koichi Hirata

JOURNAL OF THE AMERICAN COLLEGE OF SURGEONS ( ELSEVIER SCIENCE INC ) 219 ( 2 ) E11 - E14 2014年08月 [査読有り]

DOI

Highest intraoperative lactate level could predict postoperative infectious complications after hepatectomy, reflecting the Pringle maneuver especially in chronic liver disease

Makoto Meguro, Toru Mizuguchi, Masaki Kawamoto, Toshihiko Nishidate, Masayuki Ishii, Hiroomi Tatsumi, Yasutoshi Kimura, Tomohisa Furuhata, Koichi Hirata

JOURNAL OF HEPATO-BILIARY-PANCREATIC SCIENCES ( SPRINGER JAPAN KK ) 21 ( 7 ) 489 - 498 2014年07月 [査読有り]

Background The Pringle maneuver is used to minimize blood loss during liver transection; however, it may cause reperfusion injury, which can cause increased intraoperative lactate levels and an immune compromised state. This may further lead to infectious complications. Methods Here, we divided 77 patients who underwent hepatectomy between December 2007 and August 2010 into two groups: the chronic hepatitis and liver cirrhosis (CH + LC) group and normal liver (NL) group. We investigated the effect of the highest intraoperative lactate level on occurrence of infectious complications after hepatectomy by assessing the correlations of the highest intraoperative lactate level with total Pringle time, operative factors, and various parameters in serum after surgery. Parameters showing significant correlations with postoperative complications of Clavien-Dindo grade III or higher, with a wound or intra-abdominal infection, were analyzed by using interactive dot diagrams to determine cut-off values with the highest sensitivity and specificity. Results We noted that, to prevent postoperative infectious complications, the highest lactate level during liver resection should be maintained at <44.0mg/dL in the NL group and <29.0mg/dL in the CH + LC group. Conclusions Minimizing the highest intraoperative lactate level may be important to prevent increase in postoperative infectious complications after hepatectomy, reflecting the Pringle maneuver especially in chronic liver disease.

DOI

Propensity score analysis demonstrated the prognostic advantage of anatomical liver resection in hepatocellular carcinoma

Masayuki Ishii, Toru Mizuguchi, Masaki Kawamoto, Makoto Meguro, Shigenori Ota, Toshihiko Nishidate, Kenji Okita, Yasutohsi Kimura, Thomas T. Hui, Koichi Hirata

World Journal of Gastroenterology ( Baishideng Publishing Group Co ) 20 ( 12 ) 3335 - 3342 2014年

AIM: To compare the prognoses of hepatocellular carcinoma (HCC) patients that underwent anatomic liver resection (AR) or non-anatomic liver resection (NAR) using propensity score-matched populations. METHODS: Between January 2002 and December 2010, 268 consecutive HCC patients, including 110 and 158 patients that underwent AR and NAR, respectively, were retrospectively enrolled in this study. Forty-four patients from each group were selected and matched using logistic multivariate analysis followed by propensity score analysis. RESULTS: In the whole analysis set, the histologi-cal background of the liver, liver function, and tumor marker levels differed significantly among the groups. Although the overall survival (OS) and recurrence-free survival rates of the two groups did not differ significantly in the whole analysis set, the OS of the AR group was significantly longer than that of the NAR group after propensity matching (76.2 ± 6.3 mo vs 58.9 ± 6.3 mo P = 0.0039). Although AR (HR = 0.456, P = 0.039) was found to be a prognostic factor in the univariate analysis, only vascular invasion (HR = 0.228, P = 0.002) and the hepatocyte growth factor level (HR = 52.366, P = 0.035) were subsequently found to be independent prognostic factors. CONCLUSION: AR conveys a survival advantage over NAR in specific subpopulations of HCC patients with tumors of less than 5 cm in diameter, single tumor, and good liver function. © 2014 Baishideng Publishing Group Co., Limited. All rights reserved.

DOI PubMed

Preoperative hepatocyte transplantation improves the survival of rats with nonalcoholic steatohepatitis-related cirrhosis after partial hepatectomy

Yukio Nakamura, Toru Mizuguchi, Naoki Tanimizu, Norihisa Ichinohe, Hidekazu Ooe, Masaki Kawamoto, Makoto Meguro, Koichi Hirata, Toshihiro Mitaka

Cell Transplantation ( Cognizant Communication Corporation ) 23 ( 10 ) 1243 - 1254 2014年

Liver failure after liver resection for cirrhosis is a critical problem, and no effective therapy except liver transplantation is currently available. The objective of this study was to examine whether hepatocyte transplantation (HT) reduces the poststandard liver resection mortality rate of rats with nonalcoholic steatohepatitis (NASH)- related cirrhosis. Liver resection for hepatocellular carcinoma (HCC) combined with NASH-related cirrhosis has become increasingly common. We developed a rat model of acute liver failure after two-thirds partial hepatectomy (PH) for NASH-related cirrhosis. The mechanism by which HT improved the survival of the model rats was examined in short- and long-term investigations. Female DPPIV- recipient F344 rats were fed the cholinedeficient l-amino acid (CDAA)-defined diet for 12 weeks. Some of the rats were transplanted with male F344 DPPIV + rat hepatocytes 24 h before undergoing PH. The overall post-PH survival of each group was evaluated, and short- and long-term pathological and molecular biological evaluations were also performed. Overall survival was significantly longer in the HT group than the non-HT group (7-day survival rates: 46.7% and 7.7%, respectively). Compared with the recipient livers of the non-HT group, numerous Ki-67 + hepatocytes and few TUNEL + hepatocytes were observed in the livers of the HT group. At 6 months after the HT, the DPPIV + hepatocytes had partially replaced the recipient liver and formed hepatocyte clusters in the spleen. Preoperative HT might improve the survival of rats with NASH-related cirrhosis after PH by preventing the host hepatocytes from accelerating their growth and falling into apoptosis.

DOI PubMed

Pancreaticoduodenectomy for biliary tract carcinoma with situs inversus totalis: difficulties and technical notes based on two cases.

Kyuno Daisuke, Kimura Yasutoshi, Imamura Masafumi, Uchiyama Motonobu, Ishii Masayuki, Meguro Makoto, Kawamoto Masaki, Mizuguchi Toru, Hirata Koichi

World journal of surgical oncology 11 312 - 312 2013年12月 [査読有り] [国際誌]

Situs inversus totalis (SIT) denotes complete right-left inversion of the thoracic and abdominal viscera. Diagnosis and surgical procedures for abdominal pathology in patients with SIT are technically more complicated because of mirror-image transposition of the visceral organs. Moreover, SIT is commonly associated with cardiovascular and hepatobiliary malformations, which make hepatobiliary-pancreatic surgery difficult. Two cases of pancreaticoduodenectomy for biliary tract carcinoma in patients with SIT are presented. Both patients had an anomaly of the hepatic artery. Advanced diagnostic imaging techniques were very important for careful preoperative planning and to prevent misunderstanding of the arrangement of the abdominal viscera. This facilitated the surgical team's adaptation to the mirror image of the standard procedure and helped avoid intraoperative complications due to cardiovascular and hepatobiliary malformations associated with SIT. Pancreaticoduodenectomy in patients with SIT can be performed successfully with detailed preoperative assessment, use of effective techniques by the surgeon, and appropriate support by assistants.

DOI PubMed

腹腔鏡補助下腹会陰式直腸切断術後の会陰ヘルニアの1例

及能拓朗, 古畑智久, 植木知身, 沖田憲司, 秋月恵美, 川本雅樹, 西舘敏彦, 目黒誠, 信岡隆幸, 木村康利, 水口徹, 平田公一, 久木田和晴

北海道外科雑誌 ( 北海道外科学会 ) 58 ( 2 ) 177 - 178 2013年12月

Hepatic biliary epithelial cells acquire epithelial integrity but lose plasticity to differentiate into hepatocytes in vitro during development

Naoki Tanimizu, Yukio Nakamura, Norihisa Ichinohe, Toru Mizuguchi, Koichi Hirata, Toshihiro Mitaka

JOURNAL OF CELL SCIENCE ( COMPANY OF BIOLOGISTS LTD ) 126 ( 22 ) 5239 - + 2013年11月 [査読有り]

In developing organs, epithelial tissue structures are mostly developed by the perinatal period. However, it is unknown whether epithelial cells are already functionally mature and whether they are fixed in their lineage. Here we show that epithelial cells alter their plasticity during postnatal development by examining the differentiation potential of epithelial cell adhesion molecule (EpCAM)(+) cholangiocytes (biliary epithelial cells) isolated from neonatal and adult mouse livers. We found that neonatal cholangiocytes isolated from 1-week-old liver converted into functional hepatocytes in the presence of oncostatin M and Matrigel (R). In contrast, neither morphological changes nor expression of hepatocyte markers were induced in adult cholangiocytes. The transcription factors hepatocyte nuclear factor 4 alpha and CCAAT/enhancer binding protein alpha (C/EBP alpha), which are necessary for hepatocytic differentiation, were induced in neonatal cholangiocytes but not in adult cells, whereas grainyhead-like 2 (Grhl2) and hairy-enhance of slit 1 (Hes1), which are implicated in cholangiocyte differentiation, were continuously expressed in adult cells. Overexpression of C/EBPa and Grhl2 promoted and inhibited hepatocytic differentiation, respectively. Furthermore, adult cholangiocytes formed a monolayer with higher barrier function than neonatal ones did, suggesting that cholangiocytes are still in the process of epithelial maturation even after forming tubular structures during the neonatal period. Taken together, these results suggest that cholangiocytes lose plasticity to convert into hepatocytes during epithelial maturation. They lose competency to upregulate hepatocytic transcription factors and downregulate cholagiocytic ones under conditions inducing hepatocytic differentiation. Our results suggest that a molecular machinery augmenting epithelial integrity limits lineage plasticity of epithelial cells.

DOI PubMed

大腸癌転移性肝転移の術前化学療法症例の検討

西舘敏彦, 古畑智久, 沖田憲司, 植木知身, 秋月恵美, 久木田和晴, 小川宰司, 目黒誠, 川本雅樹, 信岡隆幸, 木村康利, 水口徹, 秦史壮, 佐々木一晃, 平田公一

日本消化器外科学会雑誌 ( (一社)日本消化器外科学会 ) 46 ( Suppl.2 ) 250 - 250 2013年10月

Continuous monitoring of central venous oxygen saturation predicts postoperative liver dysfunction after liver resection

Makoto Meguro, Toru Mizuguchi, Masaki Kawamoto, Yukio Nakamura, Shigenori Ota, Kazuharu Kukita, Masayuki Ishii, Hiroomi Tatsumi, Koichi Hirata

SURGERY ( MOSBY-ELSEVIER ) 154 ( 2 ) 351 - 362 2013年08月 [査読有り]

Background. We examined whether the data obtained by monitoring central venous oxygen saturation (ScvO(2)) and/or stroke volume variation (SVV) during hepatectomy, as measured with the FloTrac/Vigileo system, can predict postoperative liver dysfunction. Methods. This study included 33 patients with normal liver function who underwent hepatectomy between December 2007 and August 2010. Baseline ScvO(2) and baseline SVV, as control values, were defined as the mean of ScvO(2) and SVV, respectively, measured with the FloTrac/Vigileo system before hepatectomy. ScvO(2) decrease (Delta ScvO(2)) was defined as the difference between the baseline ScvO(2) and the lowest intraoperative ScvO(2) and SVV increase (Delta SVV) was defined as the difference between the baseline SVV and the highest intraoperative SVV Moreover, mean ScvO(2) and mean SVV were defined as the means of all ScvO(2) and SVV values measured during surgery, respectively. We examined correlations of the new parameters with the highest postoperative values of total bilirubin (T. Bil). Results. The cutoff values for Delta ScvO(2) and mean SVV for predicting the highest postoperative T. Bil level to be >= 3.0 mg/dL with the highest sensitivity and specificity were found to be 10.2% and 13.6%, respectively. The areas under curve in receiver-operating-characteristic analysis of Delta ScvO(2) and mean SVV were 0.797 and 0.757, respectively, showing significant differences. Conclusion. Our results suggest that Delta ScvO(2) and mean SVV can predict postoperative liver dysfunction. When Delta ScvO(2) and mean SVV exceed 10.2% and 13.6%, respectively, we advocate that adequate attention be paid to postoperative liver dysfunction, and that early intraoperative general circulatory management measures be implemented as needed.

DOI

下部直腸癌における腹腔鏡下側方リンパ節郭清術

古畑智久, 沖田憲司, 西舘敏彦, 植木知身, 秋月恵美, 久木田和晴, 信岡隆幸, 木村康利, 水口徹, 平田公一

日本消化器外科学会総会 ( (一社)日本消化器外科学会 ) 68回 RV - 1 2013年07月

Asialoglycoprotein receptor scintigraphy with Tc-99m-galactosyl human serum albumin (Tc-99m-GSA) as an early predictor of survival in acute liver failure

H. Tatsumi, Y. Masuda, H. Imaizumi, S. Yoshida, K. Goto, N. Yama, T. Mizuguchi, K. Hirata

ANAESTHESIA AND INTENSIVE CARE ( AUSTRALIAN SOC ANAESTHETISTS ) 41 ( 4 ) 523 - 528 2013年07月 [査読有り]

This study evaluated the usefulness of asialoglycoprotein receptor scintigraphy with Tc-99m-galactosyl human serum albumin (Tc-99m-GSA scintigraphy) as an early predictor for prognosis of acute liver failure. Forty-eight patients with acute liver failure and without a past history of chronic liver disease were enrolled. Patients were divided into survival and non-survival groups by 28-day mortality. Tc-99m-GSA scintigraphy to detect uptake ratio of the heart at 15 minutes to that at three minutes (HH15) and uptake ratio of the liver at 15 minutes to the liver plus the heart at 15 minutes (LHL15), and measurements of serum total bilirubin, hepatocyte growth factor and prothrombin time were performed immediately after the diagnosis of acute liver failure. Areas under the receiver operating characteristic curves were used to compare the prognostic ability of total bilirubin, hepatocyte growth factor, prothrombin time, HH15 ratio, LHL15 ratio and the model for end-stage liver disease score. Clinical characteristics of patients in the survival group (n=20) and in the non-survival group (n=28) Were not significantly different. HH15 and LHL15 uptake ratios in the survival group were 0.670 and 0.875 and they were significantly lower and higher than those in the non-survival group, respectively. All patients with LHL15 <0.760 died, and the area under the receiver operating characteristic curve for LHL15 were significantly larger than the areas under the receiver operating characteristic curves of serum variables and model for end-stage liver disease score. In summary, in patients with acute liver failure without chronic liver disease, HH15 and LHL15 of Tc-99m-GSA scintigraphy are more useful variables in predicting prognosis than serum variables and model for end-stage liver disease score.

Prognosis and Predictors of Surgical Complications in Hepatocellular Carcinoma Patients With or Without Cirrhosis after Hepatectomy

Toru Mizuguchi, Masaki Kawamoto, Makoto Meguro, Yukio Nakamura, Shigenori Ota, Thomas T. Hui, Koichi Hirata

WORLD JOURNAL OF SURGERY ( SPRINGER ) 37 ( 6 ) 1379 - 1387 2013年06月 [査読有り]

Although poor liver function is associated with a high morbidity rate and poor prognosis in hepatocellular carcinoma (HCC) patients, the exact effects of liver pathology on the surgical outcomes of HCC patients are poorly understood. The purpose of this study was to assess how the liver pathology of HCC patients affects their prognosis and complications rate after liver resection. Between January 2006 and November 2010, 149 consecutive hepatocellular carcinoma patients, including 79 noncirrhosis patients and 70 cirrhosis patients, were enrolled in this study. Among the noncirrhotic patients, operative time, fresh frozen plasma (FFP) transfusion requirement, tumor size, and serum retinol binding protein (RBP) levels were significantly higher in the complications group than in the complications-free groups. On the other hand, in the cirrhotic patients the prothrombin time (PT) and indocyanine green retention value at 15 min (ICGR(15)) of the complications group were significantly lower and higher, respectively, than those of the complications-free group. In the noncirrhotic patients, recurrence-free survival and overall survival did not differ between the complications and complications-free groups. On the other hand, in the cirrhotic patients, the recurrence-free survival and overall survival of the complications-free group were significantly longer than those of the complications group. In the noncirrhotic patients, surgical complications had no prognostic effect, whereas they had a significant survival impact in the cirrhotic patients. The surgical strategy for HCC should be based on the patient's pathological background.

DOI

Differentiation capacity of hepatic stem/progenitor cells isolated from D-galactosamine-treated rat livers.

Norihisa Ichinohe, Naoki Tanimizu, Hidekazu Ooe, Yukio Nakamura, Toru Mizuguchi, Junko Kon, Koichi Hirata, Toshihiro Mitaka

Hepatology (Baltimore, Md.) 57 ( 3 ) 1192 - 202 2013年03月 [国際誌]

UNLABELLED: Oval cells and small hepatocytes (SHs) are known to be hepatic stem and progenitor cells. Although oval cells are believed to differentiate into mature hepatocytes (MHs) through SHs, the details of their differentiation process are not well understood. Furthermore, it is not certain whether the induced cells possess fully mature functions as MHs. In the present experiment, we used Thy1 and CD44 to isolate oval and progenitor cells, respectively, from D-galactosamine-treated rat livers. Epidermal growth factor, basic fibroblast growth factor, or hepatocyte growth factor could trigger the hepatocytic differentiation of sorted Thy1(+) cells to form epithelial cell colonies, and the combination of the factors stimulated the emergence and expansion of the colonies. Cells in the Thy1(+) -derived colonies grew more slowly than those in the CD44(+) -derived ones in vitro and in vivo and the degree of their hepatocytic differentiation increased with CD44 expression. Although the induced hepatocytes derived from Thy1(+) and CD44(+) cells showed similar morphology to MHs and formed organoids from the colonies similar to those from SHs, many hepatic differentiated functions of the induced hepatocytes were less well performed than those of mature SHs derived from the healthy liver. The gene expression of cytochrome P450 1A2, tryptophan 2,3-dioxygenase, and carbamoylphosphate synthetase I was lower in the induced hepatocytes than in mature SHs. In addition, the protein expression of CCAAT/enhancer-binding protein alpha and bile canalicular formation could not reach the levels of production of mature SHs. CONCLUSION: The results suggest that, although Thy1(+) and CD44(+) cells are able to differentiate into hepatocytes, the degree of maturation of the induced hepatocytes may not be equal to that of healthy resident hepatocytes. (HEPATOLOGY 2013).

DOI PubMed

Soluble form of luthern/B-CAM in plasma as a potential maker for hepatocellular carcinoma

Kikkawa Yamato, Tanimizu Naoki, Miwa Takahiro, Mizuguchi Toru, Hirata Koichi, Nomizu Motoyoshi, Mitaka Toshihiro

GLYCOBIOLOGY 22 ( 11 ) 1601 2012年11月 [査読有り]

Area between the hepatic and heart curves of Tc-99m-galactosyl-human serum albumin scintigraphy represents liver function and disease progression for preoperative evaluation in hepatocellular carcinoma patients

Kohei Harada, Toru Mizuguchi, Yoshimi Katagiri, Masaki Kawamoto, Yukio Nakamura, Makoto Meguro, Shigenori Ota, Shigeru Sasaki, Koji Miyanishi, Tomoko Sonoda, Mitsuru Mori, Yasuhisa Shinomura, Junji Kato, Koichi Hirata

JOURNAL OF HEPATO-BILIARY-PANCREATIC SCIENCES ( SPRINGER JAPAN KK ) 19 ( 6 ) 667 - 673 2012年11月 [査読有り]

Background/purpose We developed software to calculate the pixels of interest in the area between the hepatic and heart curves (ABC) of Tc-99m-galactosyl human serum albumin (GSA) scintigraphy. The aim of this study was to examine the accuracy of the ABC to evaluate liver function before hepatectomy. Methods Between January 2005 and December 2010, 205 consecutive patients who underwent initial hepatectomy were enrolled in this study. The ABC was calculated using original computer software. The area under the receiver operating characteristic curve (AUC) was calculated for evaluation of Child-Pugh score grade B (Child B), pathological chronic hepatitis (CH), and liver cirrhosis (LC). Results The AUC of any indicator for Child B was more than 0.900 except bilirubin. The AUC of ABC for CH and LC (AUC 0.734 each) was comparable to those of HH15 (clearance index; AUC 0.704 and 0.700, respectively) and LHL15 (receptor index; AUC 0.703 and 0.706, respectively) in multiple receiver operating characteristic comparison. Conclusions We have developed a novel liver function indicator, the ABC, to count radioactivity in sequence. The ABC reflects liver function according to pathological deterioration of the liver. Although the ABC gave no significant advantage compared to HH15 and LHL15, it improved the AUC evaluation by 0.028-0.034.

DOI PubMed

【Oncologic emergency】胆道閉塞

孫誠一, 木村康利, 今村将史, 今野愛, 鶴間哲弘, 目黒誠, 水口徹, 平田公一

消化器外科 ( (株)へるす出版 ) 35 ( 3 ) 301 - 309 2012年03月

Low-dose steroid pretreatment ameliorates the transient impairment of liver regeneration

Toshihito Shibata, Toru Mizuguchi, Yukio Nakamura, Masaki Kawamoto, Makoto Meguro, Shigenori Ota, Koichi Hirata, Hidekazu Ooe, Toshihiro Mitaka

WORLD JOURNAL OF GASTROENTEROLOGY ( BAISHIDENG PUBL GRP CO LTD ) 18 ( 9 ) 905 - 914 2012年03月 [査読有り]

AIM: To determine if liver regeneration (LR) could be disturbed following radiofrequency (RF) ablation and whether modification of LR by steroid administration occurs. METHODS: Sham operation, partial hepatectomy (PH), and partial hepatectomy with radiofrequency ablation (PHA) were performed on adult Fisher 344 rats. We investigated the recovery of liver volume, DNA synthetic activities, serum cytokine/chemokine levels and signal transducers and activators of transcription 3 DNA-binding activities in the nucleus after the operations. Additionally, the effects of steroid (dexamethasone) pretreatment in the PH group (S-PH) and the PHA group (S-PHA) were compared. RESULTS: The LR after PHA was impaired, with high serum cytokine/chemokine induction compared to PH, although the ratio of the residual liver weight to body weight was not significantly different. Steroid pretreatment disturbed LR in the S-PH group. On the other hand, low-dose steroid pretreatment improved LR and suppressed tumor necrosis factor (TNF)-alpha elevation in the S-PHA group, with recovery of STAT3 DNA-binding activity. On the other hand, low-dose steroid pretreatment improved LR and suppressed TNF-alpha elevation in the S-PHA group, with recovery of STAT3 DNA-binding activity. CONCLUSION: LR is disturbed after RF ablation, with high serum cytokine/chemokine induction. Low-dose steroid administration can improve LR after RF ablation with TNF-alpha suppression. (C) 2012 Baishideng. All rights reserved.

DOI PubMed

Serum Antithrombin III Level is Well Correlated with Multiple Indicators for Assessment of Liver Function and Diagnostic Accuracy for Predicting Postoperative Liver Failure in Hepatocellular Carcinoma Patients

Toru Mizuguchi, Masaki Kawamoto, Makoto Meguro, Seiichi Son, Yukio Nakamura, Kohei Harada, Toshihito Shibata, Shigenori Ota, Koichi Hirata

HEPATO-GASTROENTEROLOGY ( H G E UPDATE MEDICAL PUBLISHING S A ) 59 ( 114 ) 551 - 557 2012年03月 [査読有り]

Background/Aims: Evaluation of preoperative hepatic reserve is critical to avoid a fatal clinical course such as liver failure. We retrospectively evaluated 158 consecutive hepatocellular carcinoma (HCC) patients who underwent initial hepatectomy. The aim of this study was to determine the correlations of multiple indicators for assessment of liver function before hepatectomy. Furthermore, diagnostic probability for the pathological background and prediction of postoperative liver failure/dysfunction was compared between the antithrombin (AT) III level and indocyanine green retention] rate at 15 minutes (ICGR(15)). Methodology: Between January 2001 and March 2008, 158 HCC patients who underwent initial hepatectomy were enrolled in this study. Spearman's correlation coefficients (r values] were obtained for 15 clinical laboratory tests including ATIII and ICGR(15). Receiver operating characteristic (ROC) curve analysis was used for calculating the probability and predictive ability of the tests. Results: All 158 consecutive HCC patients were eligible for hepatectomy based on the Japanese guideline. ATIII is correlated with 13 of 14 other clinical tests, including albumin, bilirubin, prothrombin time, rapid turnover proteins, HGF, ICGR(15) and others. The diagnostic probabilities to distinguish between normal liver and other pathological backgrounds of ATIII and ICGR(15) were significantly different. The specificity of ATIII to predict postoperative liver failure/dysfunction was higher than that of ICGR(15). Conclusions: The serum ATIII level before hepatectomy is valuable to estimate the pathological background and predict postoperative liver failure/dysfunction. It should be possible to use ATIII as an additional indicator for liver function and substitute for ICGR(15) in the future.

DOI

Vascular endothelial growth factor 165b expression in stromal cells and colorectal cancer

Makoto Tayama, Tomohisa Furuhata, Yoshiko Inafuku, Kenji Okita, Toshihiko Nishidate, Toru Mizuguchi, Yasutoshi Kimura, Koichi Hirata

WORLD JOURNAL OF GASTROENTEROLOGY ( BAISHIDENG PUBL GRP CO LTD ) 17 ( 44 ) 4867 - 4874 2011年11月 [査読有り]

AIM: To characterize the implications of vascular endothelial growth factor (VEGF)-A in stromal cells and colorectal cancer and the expression of VEGF-A splice variants. METHODS: VEGF-A expression in tumor and stromal cells from 165 consecutive patients with colorectal cancer was examined by immunohistochemistry. The association between VEGF-A expression status and clinicopathological factors was investigated. Twenty fresh-frozen samples were obtained for laser capture microdissection to analyze the splice variants of VEGF-A. RESULTS: VEGF-A was expressed in 53.9% and 42.4% of tumor and stromal cells, respectively. VEGF-A expression in tumor cells (t-VEGF-A) was associated with advanced clinical stage (stage 0, 1/9; stage 1, 2/16; stage 2, 32/55; stage 3, 38/66; stage 4, 16/19, P < 0.0001). VEGF-A expression in stromal cells (s-VEGF-A) increased in the earlier clinical stage (stage 0, 7/9; stage 1, 6/16; stage 2, 33/55; stage 3, 22/66; stage 4, 5/19; P = 0.004). Multivariate analyses for risk factors of recurrence showed that only s-VEGF-A expression was an independent risk factor for recurrence (relative risk 0.309, 95% confidence interval 0.141-0.676, P = 0.0033). The five-year disease-free survival (DFS) rates of t-VEGF-A-positive and -negative cases were 51.4% and 62.9%, respectively. There was no significant difference in t-VEGF-A expression status. The five-year DFS rates of s-VEGF-A-positive and -negative cases were 73.8% and 39.9%, respectively. s-VEGF-A-positive cases had significantly better survival than s-VEGF-A-negative cases (P = 0.0005). Splice variant analysis revealed that t-VEGF-A was mainly composed of VEGF165 and that s-VEGF-A included both VEGF165 and VEGF165b. In cases with no venous invasion (v0), the level of VEGF165b mRNA was significantly higher (v0 204.5 +/- 122.7, v1 32.5 +/- 36.7, v2 2.1 +/- 1.7, P = 0.03). The microvessel density tended to be lower in cases with higher VEGF165b mRNA levels. CONCLUSION: s-VEGF-A appears be a good prognostic factor for colorectal cancer and includes VEGF165 and VEGF165b. (C) 2011 Baishideng. All rights reserved.

DOI

Prognostic Impact of Preoperative the Branched-Chain Amino Acid to the Tyrosine Ratio in Hepatocellular Carcinoma Patients after Initial Hepatectomy

Toru Mizuguchi, Masaki Kawamoto, Makoto Meguro, Yukio Nakamura, Kohei Harada, Kazuharu Kukita, Koichi Hirata

JOURNAL OF GASTROINTESTINAL SURGERY ( SPRINGER ) 15 ( 8 ) 1433 - 1439 2011年08月 [査読有り]

The branched-chain amino acid/tyrosine ratio (BTR) reflects the amino acid balance and the severity of liver disease. The aim of the present study was to determine the relationship between BTR and liver function in patients with hepatocellular carcinoma (HCC). Furthermore, we evaluated the clinical usefulness of BTR as a prognostic indicator of disease-free and overall patient survival after initial hepatectomy. Between January 2004 and December 2008, 105 consecutive HCC patients who underwent initial hepatectomy were enrolled in this study. The correlation between BTR and preoperative liver functional indicators was evaluated. The cutoff levels of BTR for 2-year survival prediction were evaluated using a dot blot diagram. The patients were divided into high BTR (4.5 or higher) and low BTR (4.4 or lower) groups and these were compared in terms of clinical variables such as liver functional indicators, operative variables, and tumor characteristics. The preoperative BTR level decreased according to the severity of liver disease. BTR was correlated with the albumin, bilirubin, and prealbumin levels, as well as the prothrombin time. Although the preoperative liver function was significantly different between the high BTR and low BTR groups, the operative variables and tumor-related variables were not found to be significantly different. Postoperative complications in the high BTR group were significantly less frequent than in the low BTR group (p = 0.003). Disease-free and overall patient survival in the high BTR group were significantly longer than in the low BTR group (p < 0.001 and p = 0.021, respectively). BTR reflected the pathological liver background with a high correlation to the other liver functional indicators. BTR is thus considered to be a useful marker to predict postoperative complications, disease-free survival, and overall survival of HCC patients after initial hepatectomy. It is, therefore, a useful indicator of liver function and a predictor for the risk of cancer recurrence and overall survival in HCC patients.

DOI

Cluster analysis of indicators of liver functional and preoperative low branched-chain amino acid tyrosine ration indicate a high risk of early recurrence in analysis of 165 hepatocellular carcinoma patients after initial hepatectomy

Yukio Nakamura, Toru Mizuguchi, Masaki Kawamoto, Makoto Meguro, Kohei Harada, Shigenori Ota, Koichi Hirata

SURGERY ( MOSBY-ELSEVIER ) 150 ( 2 ) 250 - 262 2011年08月 [査読有り]

Background. Cluster analysis is used for dividing many prognostic indicators, including liver function, tumor progression, and operative variables, into specific clusters. The albumin (ALB), hepatocyte growth factor (HGF), and branched chain amino-acid to tyrosine ratio (BTR) may represent the severity of liver disease and function of the hepatic reserve. We developed the ALB-BTR and HGF-BTR classifications depending on each level to find specific unique subgroups. Our aim was to identify specific subgroups destined for favorable and poor prognoses after initial hepatectomy. Methods. Between 2002 and 2008, 165 patients were analyzed retrospectively. Liver function indicators, including BTR, tumor-related factors, and operative variables, were evaluated by cluster analysis with Ward's criterion. The ALB-BTR classification, was divided into 4 groups depending on ALB (cutoff value, 4.0 g/dL) and BTR (cutoff value, 6.0). The HGF-BTR classification was also divided into 4 groups depending on Tiff (cutoff value, 0.35 ng/mL) and BTR (cutoff value, 6.0). The prognoses of the subgroups were compared by the log-rank test. Results. Cluster analysis divided multiple indicators into 5 different clusters. In each cluster, we further analyzed subgroups using the ALB-BTR and HGF-BTR classification. Mean recurrence-free survival times in ALB-GI (19.1 +/- 2.4 months) and HGF-GIII (29.4 +/- 3.8 months) were less than their mean overall survival times. Conclusion. Cluster analysis is useful to find similar and different indicators. Even though liver function, was well preserved, low BTR could identify early recurrence in hepatocellular carcinoma patients after resection. (Surgery 2011;150:250-62.)

DOI

フォンダパリヌクスナトリウム使用による下部消化管手術後の静脈血栓塞栓症予防対策

山口洋志, 古畑智久, 久木田和晴, 西舘敏彦, 沖田憲司, 信岡隆幸, 木村康利, 水口徹, 平田公一

日本消化器外科学会総会 ( (一社)日本消化器外科学会 ) 66回 546 - 546 2011年07月

当科での下部消化管手術におけるフォンダパリヌクスナトリウムの使用経験

山口洋志, 古畑智久, 久木田和晴, 西舘敏彦, 沖田憲司, 信岡隆幸, 木村康利, 水口徹, 平田公一

日本大腸肛門病学会雑誌 ( (一社)日本大腸肛門病学会 ) 64 ( 2 ) 102 - 102 2011年02月

【肝・胆・膵外科における感染症に対する治療戦略】肝切除術創部管理に関する検討真皮埋没縫合と皮下持続吸引ドレナージの有用性について

川本雅樹, 水口徹, 目黒誠, 久木田和晴, 中村幸雄, 信岡隆幸, 木村康利, 古畑智久, 平田公一

日本外科感染症学会雑誌 ( (一社)日本外科感染症学会 ) 8 ( 1 ) 21 - 25 2011年02月

開腹肝臓手術では、大きな手術創と長時間の手術のため、創感染が生じ易いことが問題となる。そこでその防止対策が課題となっている。【目的】肝切除術における皮下持続吸引ドレーン設置の意義や閉創縫合法の関与を検討した。【対象】2004年1月から2009年3月までの間に行われた肝切除症例135例について、スキンステイプラーによる皮膚縫合、皮下ドレーンなしで行った前期(2004年1月から2007年12月)103例と皮下埋没縫合、皮下ブレイクシリコンドレーン留置によるドレーン管理を行った後期(2008年1月から2009年3月まで)32例について検討を行った。【結果】患者背景はBMIを除いて有意差を認めなかった。創感染は前期群で8例(7.8%)発生、後期群は認めなかった。肝機能不良例に限定すると創感染率で有意差を認めないものの後期群で減少する傾向であった。これらより肝切除術創閉鎖においては真皮埋没縫合とともに皮下持続吸引ドレナージを用いることで創感染防止に有用であることが示唆された。(著者抄録)

ローカルSSIサーベイランス2007 最新の報告を10年分と比較して

水口徹, 川本雅樹, 目黒誠, 久木田和晴, 中村幸雄, 木村康利, 信岡隆幸, 古畑智久, 平田公一

日本外科感染症学会雑誌 ( (一社)日本外科感染症学会 ) 7 ( 6 ) 589 - 594 2010年12月

【はじめに】外科周術期における感染症のサーベイランスは、各病院レベルや国レベルで施行されており、検出細菌には一定の傾向が認められる。われわれは北海道内の医育病院より検体を収集し、一括して薬剤感受性試験を施行した結果を含めて外科周術期感染症サーベイランスを継続して行ってきた。2007年度に検出された細菌と薬剤感受性を過去10年間で検出されたものと比較し、最近の周術期感染症の動向を明らかにすることを目的とした。【方法】北海道の10医育関連病院にて、外科手術後の周術期に観察された外科周術期感染症に対して毎年9月から3月までの半年間で検体を収集し、検出細菌ごとの感受性を比較検討した。【結果】2007年の検出細菌は、Escherichia coli、Enterococcus faecalis、Bacteroides thetaiotaomicron、Bacteroides wadsworthia、Bacteroides fragilis、Staphylococcus aureusが上位の検出細菌だった。E.coliに対してはAmpicillin(以下、ABPC)の感受性が65%と低下していた。E.faecalisに対してはニューキノロンが55.6%でカルバペネム系ではImipenem(以下、IPM)が88.9%の感受性であった。B.thetaiotaomicron、Bacteroides coacae、B.fragilisに対してはカルバペネム系が良好な感受性を示したものの、Clindamycin(以下、CLDM)では50%、4.4%、80%と低下していた。B.wadsworthiaに対しては、CLDMで良好な感受性を示した。Methicillin-resistant S.aureus(以下、MRSA)の感受性は、Arbekacin(以下、ABK)以外で良好に保たれていた。【結語】われわれの結果は欧米や国内のサーベイランス結果とも同様の傾向を示すものもあり、この実績を考慮してこれまでの感染対策を継続し医育病院グループとしてのサーベイランスを継続すべきと思われた。(著者抄録)

大腸癌における血清抗p53抗体測定の有用性に関する検討

久木田和晴, 古畑智久, 沖田憲司, 西舘敏彦, 信岡隆幸, 木村康利, 水口徹, 秦史壮, 佐々木一晃, 平田公一

日本消化器外科学会総会 ( (一社)日本消化器外科学会 ) 65回 491 - 491 2010年07月

当科における腹腔鏡補助下肝切除術出血量の抑制と手術時間の短縮を目指して

川本雅樹, 水口徹, 目黒誠, 久木田和晴, 永山稔, 信岡隆幸, 木村康利, 古畑智久, 平田公一

日本消化器外科学会総会 ( (一社)日本消化器外科学会 ) 65回 81 - 81 2010年07月

直腸周囲膿瘍で発症し門脈気腫を認めた直腸GISTの1例

久木田和晴, 古畑智久, 沖田憲司, 西舘敏彦, 信岡隆幸, 木村康利, 水口徹, 平田公一

北海道外科雑誌 ( 北海道外科学会 ) 55 ( 1 ) 65 - 65 2010年06月

原発巣切除versus非切除根治切除不能Stage IV大腸癌に対する治療方針

古畑智久, 沖田憲司, 西舘敏彦, 久木田和晴, 山口洋志, 木村康利, 水口徹, 平田公一

北海道外科雑誌 ( 北海道外科学会 ) 55 ( 1 ) 12 - 16 2010年06月

これまで、根治切除不能StageIV大腸癌に対する治療方針は、まず原発巣の切除を行い、その後に切除不能な病変を対象に化学療法を行うことが標準的とされてきた。しかし、最近の大腸癌に対する薬物療法の著しい進歩により、その治療方針は徐々に変化してきている。原発巣による症状を有している症例においては、現在においても原発巣切除が必要と考えられるが、無症状の症例においては、最新の化学療法を施行可能であれば、多くの場合、経過中に原発巣に対する処置を必要としないとの報告がある。5-FU、イリノテカン、オキサリプラチンの細胞障害性薬剤にベバシズマブ、セツキシマブといった分子標的治療薬を加えることにより転移巣のみならず、原発巣のコントロールも可能と考えられてきており、さらに著効例では根治切除可能となる場合もある。今後、切除不能StageIV大腸癌に対する原発巣切除の意義について、論議されていくことが予測される。(著者抄録)

腹腔鏡(補助)下肝切除術における肝離断方法の工夫症例によるdeviceの選択

川本雅樹, 水口徹, 目黒誠, 久木田和晴, 永山稔, 信岡隆幸, 木村康利, 古畑智久, 平田公一

日本肝胆膵外科学会・学術集会プログラム・抄録集 ( (一社)日本肝胆膵外科学会 ) 22回 262 - 262 2010年05月

完全腹腔鏡下外側区域部分切除術を施行した一例

庄司哲明, 水口徹, 川本雅樹, 目黒誠, 久木田和晴, 永山稔, 信岡隆幸, 木村康利, 古畑智久, 平田公一

日本臨床外科学会雑誌 ( 日本臨床外科学会 ) 71 ( 5 ) 1375 - 1375 2010年05月

イレウスに対する診断と外科治療下部大腸癌イレウスに対する治療戦略

沖田憲司, 古畑智久, 西舘敏彦, 久木田和晴, 原田敬介, 川本雅樹, 今村将史, 目黒誠, 永山稔, 信岡隆幸, 木村康利, 水口徹, 秦史壮, 佐々木一晃, 平田公一

日本外科系連合学会誌 ( 日本外科系連合学会 ) 35 ( 3 ) 452 - 452 2010年05月

肝細胞癌患者における分枝鎖アミノ酸/チロシンモル比(BTR)値の術前肝機能評価および予後予測因子としての有用性に関する検討

久木田和晴, 水口徹, 川本雅樹, 目黒誠, 中村幸雄, 信岡隆幸, 木村康利, 古畑智久, 平田公一

日本外科学会雑誌 ( (一社)日本外科学会 ) 111 ( 臨増2 ) 729 - 729 2010年03月

当科における腹腔鏡補助下肝切除術

久木田和晴, 水口徹, 川本雅樹, 目黒誠, 永山稔, 信岡隆幸, 木村康利, 古畑智久, 平田公一, 孫誠一

日本臨床外科学会雑誌 ( 日本臨床外科学会 ) 71 ( 3 ) 869 - 870 2010年03月

肝機能指標としてのATIIIの有用性とICGとの相関性と互換性に関する検討

水口徹, 川本雅樹, 目黒誠, 久木田和晴, 中村幸雄, 永山稔, 今村将史, 木村康利, 信岡隆幸, 古畑智久, 平田公一

日本外科学会雑誌 ( (一社)日本外科学会 ) 111 ( 臨増2 ) 729 - 729 2010年03月

肝硬変ラットモデルにおける肝細胞移植の肝機能改善効果についての検討

中村幸雄, 水口徹, 目黒誠, 川本雅樹, 柴田稔人, 久木田和晴, 古畑智久, 木村康利, 信岡隆幸, 平田公一, 三高俊広

日本外科学会雑誌 ( (一社)日本外科学会 ) 111 ( 臨増2 ) 526 - 526 2010年03月

進行直腸癌からの出血にたいして、緊急骨盤内臓全摘術を施行した1例

西舘敏彦, 古畑智久, 沖田憲司, 久木田和晴, 目黒誠, 原田敬介, 川本正樹, 今村将史, 永山稔, 信岡隆幸, 木村康利, 水口徹, 平田公一

日本腹部救急医学会雑誌 ( (一社)日本腹部救急医学会 ) 30 ( 2 ) 249 - 249 2010年02月

[Present status and future prospects of nutritional support teams].

Koichi Hirata, Kieko Kawasaki, Hiroomi Tatsumi, Toru Mizuguchi, Makoto Meguro, Itaru Hasegawa, Ken-ichi Sasaki, Eri Ishizaka, Ayumi Fujita, Takayuki Nobuoka

Nippon Geka Gakkai zasshi 111 ( 6 ) 341 - 347 2010年

Academic interest in nutritional support teams (NSTs) has increased rapidly in Japan since 1999, when they were first planned by the Japanese Society for Parenteral and Enteral Nutrition (JSPEN). The JSPEN promoted their use extensively after 2006 when extra medical fees were approved for medical management by NSTs under the national health insurance system. The purpose of NSTs is to provide the best nutritional support to patients who are malnourished or at high risk of developing malnutrition, without causing conflict among different medical staff. NSTs offer appropriate medical support and help prevent the deterioration of patients' health. The teams are comprised of specialized medical staff with nutritional expertise who work at the bedside and are committed to establishing good medical practice. The main targets of NSTs are patients who undergo surgery or are being treated in a geriatric or internal medicine unit, including those with lifestyle-related diseases. Therefore, most targets of NSTs are patients with common conditions. A package medical system based on the diagnostic-procedure combination was established, and regional medical centers were integrated to ensure high-quality medical care throughout Japan. Under this system, NSTs are expected to resolve individual patients' dietary issues. In addition, improvement of medical care quality and the training of reliable medical staff are necessary to provide nutritional management in the clinical setting. It will be necessary to the revise the assessment of NSTs as proposed by a committee of the Japanese Nutritional Support Promotion Group or to carry out surveillance to evaluate the outcomes of NST activity.

PubMed

当科における肝切除術における手術創およびドレーン管理

久木田和晴, 水口徹, 川本雅樹, 目黒誠, 永山稔, 信岡隆幸, 木村康利, 古畑智久, 平田公一

北海道外科雑誌 ( 北海道外科学会 ) 54 ( 2 ) 159 - 159 2009年12月

当科における腹腔鏡(補助)下肝切除術の現状と標準化に向けて

目黒誠, 水口徹, 川本雅樹, 久木田和晴, 永山稔, 西舘敏彦, 沖田憲司, 信岡隆幸, 木村康利, 古畑智久, 平田公一

日本内視鏡外科学会雑誌 ( (一社)日本内視鏡外科学会 ) 14 ( 7 ) 598 - 598 2009年12月

当科の肝切除術における創管理法の工夫と術後創感染の検討

目黒誠, 水口徹, 川本雅樹, 久木田和晴, 西舘敏彦, 沖田憲司, 永山稔, 信岡隆幸, 木村康利, 古畑智久, 平田公一

北海道外科雑誌 ( 北海道外科学会 ) 54 ( 2 ) 119 - 123 2009年12月

肝切除術の開腹創は良好な視野を得るために比較的大きく、体壁破壊による術後疼痛持続・残存や創感染機会が他の術創に比し高い。当科で施行してきたHCCに対する肝切除時の皮膚切開方法やドレーン管理法を前期群62例(2001年1月から2003年12月)(上腹部正中+八字切開、絹糸使用、ソフトプリーツドレーン留置)と後期群50例(2004年1月から2006年7月)(逆T字or逆L字切開、吸収糸使用、皮下にも閉鎖吸引式BLAKEドレーン(Johnson & Johnson,Co.,Ltd.)留置)に分けて検討し、肝切除後の創感染(漿液腫を含む)に与える影響について検討した。その結果、前期群で13例(11.6%)、後期群で5例(4.5%)、に創感染を生じたが有意差はなかった(p=0.116)ものの、後期群で頻度が半減した。全期間において、創感染群(18例)と非感染群(94例)に分けて単変量解析を施行したところ、肝予備能の低い症例で有意に創感染の頻度が高かった。多変量解析では、ICG15分値において有意差を認め[RR=1.084(1.009-1.165)、p=0.027]、ICG15分値が16.8%以上の症例でとくに創感染のリスクが高かった(感度66.7%、特異度74.5%)。肝切除術後の創感染発生予防には適切な閉鎖吸引式ドレーン管理と閉腹・閉創方法が重要であり、肝予備能が低い症例では、とくに有用であると思われた。(著者抄録)

Effects of a low-fat meal on the oral bioavailability of UFT and leucovorin in patients with colorectal cancer

Tomohisa Furuhata, Makoto Meguro, Toshihiko Nishidate, Kenji Okita, Gentarou Ishiyama, Yuuji Iwayama, Yuuichi Hosokawa, Tetsuhiko Tsuruma, Yasutoshi Kimura, Toru Mizuguchi, Kazuaki Sasaki

International Journal of Clinical Oncology 14 ( 6 ) 529 - 533 2009年12月

Background: UFT is composed of tegafur, a prodrug of 5-fluorouracil, and uracil, at a fixed ratio of 1: 4. UFT is widely used with leucovorin as adjuvant chemotherapy in patients with colon cancer. As reported, UFT/leucovorin should not be taken simultaneously with food because a high fat content will reduce the systemic exposure to the active cytotoxic moiety of UFT. In this single-dose, randomized, two-way crossover study, we investigated the effects of a low-fat Japanese meal on the pharmacokinetics and oral bioavailability of UFT (2 × 100-mg capsules dose in terms of tegafur) and leucovorin (1 × 25-mg tablet). Methods: Patients (n = 12) were randomly assigned to receive both drugs after an overnight fast or 5 min after eating a standard Japanese breakfast (641 kcal), with a 3-day washout period between treatments. Pharmacokinetics (n = 12) were determined for tegafur, 5-fluorouracil, uracil, leucovorin, and 5-methyltetrahydrofolate (an active metabolite of leucovorin). Results: For 5-fluorouracil pharmacokinetics, the maximum plasma concentration and the area under the curve were reduced by 73.7% and 47.4%, respectively, when UFT was taken postprandially, and the maximum plasma concentration and the area under the curve for uracil were reduced by 84.1% and 68.9%, respectively, compared with dosing on an empty stomach. These decreases in the systemic exposure to 5-fluorouracil were quite marked and may have an impact on its antitumor effect. Conclusion: A low-fat meal affects the pharmacokinetics of UFT similarly to a high-fat meal. © 2009 Japan Society of Clinical Oncology.

DOI PubMed

ローカルサーベイランス2007 最新の報告を10年分と比較して

水口徹, 川本雅樹, 目黒誠, 久木田和晴, 永山稔, 今村将史, 木村康利, 信岡隆幸, 古畑智久, 平田公一

日本外科感染症学会雑誌 ( (一社)日本外科感染症学会 ) 6 ( 5 ) 520 - 520 2009年11月

当科における肝切除術における手術創およびドレーン管理

川本雅樹, 水口徹, 久木田和晴, 目黒誠, 永山稔, 信岡隆幸, 木村康利, 古畑智久, 平田公一

日本外科感染症学会雑誌 ( (一社)日本外科感染症学会 ) 6 ( 5 ) 528 - 528 2009年11月

How I do it?肝切除ラウンドチップCUSAによる高度癒着剥離術と新規肝切離法

水口徹, 川本雅樹, 久木田和晴, 目黒誠, 木村康利, 古畑智久, 信岡隆幸, 平田公一

日本臨床外科学会雑誌 ( 日本臨床外科学会 ) 70 ( 増刊 ) 343 - 343 2009年10月

Clinical compliance with an oral uracil/tegafur (UFT) plus leucovorin (LV) regimen as adjuvant chemotherapy in Japanese colorectal cancer patients

Makoto Meguro, Tomohisa Furuhata, Kenji Okita, Toshihiko Nishidate, Gentaro Ishiyama, Yuji Iwayama, Yasutoshi Kimura, Toru Mizuguchi, Koichi Hirata

INTERNATIONAL JOURNAL OF CLINICAL ONCOLOGY ( SPRINGER TOKYO ) 14 ( 5 ) 402 - 407 2009年10月 [査読有り]

The combination of oral uracil/tegafur (UFT) plus leucovorin (LV) is widely accepted as adjuvant chemotherapy for stages II and III of colorectal cancer. However, the clinical compliance of Japanese patients with this regimen has not been clearly elucidated to date. A total of 40 Japanese outpatients were treated with oral UFT plus LV as adjuvant chemotherapy following colorectal cancer surgery between January 2005 and June 2007. UFT capsules (300-500 mg/body per day) and LV tablets (75 mg/body per day, administered with each dose of UFT) were to be taken for 28 days, followed by 7 days of rest, with this cycle repeated every 35 days for 6 months or until recurrence. The patients were classified into the following three groups based on compliance: the completed group (n = 21), the modified group (n = 12), and the discontinued group (n = 7). The UFT doses (mean +/- SD) were 267 +/- 35 mg/m(2) in the completed group, 276 +/- 50 mg/m(2) in the modified group, and 288 +/- 22 mg/m(2) in the discontinued group. The UFT dose in the discontinued group tended to be higher than that in the completed group (P = 0.12). The most frequent symptoms of nonhematologic toxicity were appetite loss (45%) and fatigue (45%). There were no hematologic or nonhematologic toxicities of grade 3 or 4. The regimen of oral UFT plus LV produced only low-grade toxicity and was convenient for outpatients. It appears that the initial UFT dose might be associated with the development of toxicity in the oral UFT plus LV regimen.

DOI

同時多発性に発症し異なった組織型を呈した混合型肝癌の1切除例

久木田和晴, 水口徹, 川本雅樹, 目黒誠, 孫誠一, 西舘敏彦, 原田敬介, 沖田憲司, 今村将史, 永山稔, 信岡隆幸, 木村康利, 古畑智久, 平田公一

日本臨床外科学会雑誌 ( 日本臨床外科学会 ) 70 ( 増刊 ) 680 - 680 2009年10月

当科における腹腔鏡(補助)下肝切除術の工夫

目黒誠, 水口徹, 川本雅樹, 久木田和晴, 中村幸雄, 西舘敏彦, 沖田憲司, 永山稔, 信岡隆幸, 木村康利, 古畑智久, 平田公一

日本臨床外科学会雑誌 ( 日本臨床外科学会 ) 70 ( 増刊 ) 481 - 481 2009年10月

当科における高齢者肝切除症例の検討

川本雅樹, 水口徹, 目黒誠, 久木田和晴, 孫誠一, 永山稔, 西舘敏彦, 沖田憲司, 今村将史, 信岡隆幸, 木村康利, 古畑智久, 平田公一

日本臨床外科学会雑誌 ( 日本臨床外科学会 ) 70 ( 増刊 ) 683 - 683 2009年10月

Impaired liver regeneration with humoral and genetic disturbances in urinary trypsin inhibitor-deficient mice

Takayuki Nobuoka, Toru Mizuguchi, Hideki Oshima, Toshihito Shibata, Shinsuke Kaji, Minoru Nagayama, Makoto Meguro, Toshihiro Mitaka, Koichi Hirata

LIVER INTERNATIONAL ( WILEY-BLACKWELL PUBLISHING, INC ) 29 ( 7 ) 979 - 987 2009年08月 [査読有り]

Background/Aims Urinary trypsin inhibitor (UTI) is an innate anti-inflammatory regulator. It can block the release of inflammatory factors, prevent the cascade reaction of cytokines and inhibit excessive activation of leukocytes. Liver regeneration (LR) is a dynamic molecular phenomenon without inflammation. Many cytokines, including tumour necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6), have been implicated in regulating LR. However, the role of UTI in LR is totally unknown. The aim of this study was to elucidate the role of UTI in LR using genetically UTI-deficient mice. Methods We performed 68% hepatectomy, comparing UTI (-/-) and UTI (+/+) mice. Recovery of liver weight was recorded and we calculated labelling indices after 5-bromo-2'-deoxyuridine (BrdU) immunohistochemistry. A DNA microarray was used to examine gene expression followed by real-time polymerase chain reaction. Serum IL-6, IL-10, monocyte chemoattractant protein-1 (MCP-1) and macrophage inflammatory protein-1 beta (MIP-1 beta) were measured. Results LR in UTI (-/-) mice was delayed at 36 h after hepatectomy, at which time the DNA profile was different. One hundred and fourteen genes were upregulated and 100 genes were downregulated in UTI (-/-) mice at 36 h after hepatectomy among the 21, 977 mRNAs examined. Furthermore, serum IL-6, IL-10, MCP-1 and MIP-1 beta levels at 36 h after hepatectomy in the UTI (-/-) mice were significantly higher than in the UTI (+/+) mice. Conclusion UTI appears to important cytokine and chemokine regulation in normal liver regeneration.

DOI PubMed

Matrix metalloproteinase-2 expression in stromal tissues is a consistent prognostic factor in stage II colon cancer

Yoshiko Inafuku, Tomohisa Furuhata, Makoto Tayama, Kenji Okita, Toshihiko Nishidate, Toru Mizuguchi, Yasutoshi Kimura, Koichi Hirata

CANCER SCIENCE ( WILEY-BLACKWELL PUBLISHING, INC ) 100 ( 5 ) 852 - 858 2009年05月 [査読有り]

For patients with stage II colon cancer, the usefulness of adjuvant chemotherapy remains controversial. Therefore, it is important to identify high-risk indicators. The biological prognostic factors for recurrence might allow further insight into the optimal treatment strategy for patients with node-negative disease. Matrix metalloproteinase-2 seems to be one of the essential factors for tumor invasion and lymph node metastasis. In this study, we analyzed the expression of cyclooxygenase-2 and matrix metalloproteinase-2 by immunohistochemical staining in 109 patients with stage II colon cancer. A positive correlation was observed between tumor cyclooxygenase-2 and tumor matrix metalloproteinase-2 expression (P = 0.0006) and between tumor cyclooxygenase-2 and stromal matrix metalloproteinase-2 expression (P < 0.0001). Stromal matrix metalloproteinase-2 expression was associated with disease-free survival (P = 0.0095) and was shown to be an independent risk factor for recurrence by multivariate analysis. In addition, we carried out an invasion assay in vitro to investigate whether cyclooxygenase-2 and matrix metalloproteinase-2 affected the tumor-invasive potential of colon cancer cell lines. The invasion assay showed that every cancer cell line acquired invasive potential in coculture with stromal cell lines and the cyclooxygenase-2 inhibitor suppressed this phenomenon by downregulating the matrix metalloproteinase-2 expression of stromal cells. In conclusion, these findings suggest that matrix metalloproteinase-2 expression in stromal cells can be a high-risk indicator for recurrence in patients with stage II colon cancer. (Cancer Sci 2009; 100: 852-858).

DOI

Prognostic Impact of Surgical Complications and Preoperative Serum Hepatocyte Growth Factor in Hepatocellular Carcinoma Patients After Initial Hepatectomy

Toru Mizuguchi, Minoru Nagayama, Makoto Meguro, Toshihito Shibata, Shinsuke Kaji, Takayuki Nobuoka, Yasutoshi Kimura, Tomohisa Furuhata, Koichi Hirata

JOURNAL OF GASTROINTESTINAL SURGERY ( SPRINGER ) 13 ( 2 ) 325 - 333 2009年02月 [査読有り]

The relationship between postoperative complications and survival after hepatectomy is not completely understood. The purpose of this study was to determine if surgical complications would have a prognostic impact and to identify any difference of the prognostic factors between a complication group and complication-free group for hepatocellular carcinoma (HCC) patients after initial hepatectomy. One hundred consecutive HCC patients were analyzed in this study. Operative variables and liver functional markers were compared between the complication group and complication-free group. The diagnostic accuracy for predicting complications was evaluated by the receiver operating characteristic (ROC) curve. The Kaplan-Meier method with log-rank test was employed for survival analysis. Univariate and multivariate analyses were performed to identify the prognostic factors in each group. A total of 45 complications in 32 patients were observed according to the modified Clavien classification. The albumin, gamma-glutamyl transferase, choline esterase, indocyanine green retention rate at 15 min (ICGR(15)), hyaluronic acid, prealbumin, hepatocyte growth factor (HGF), HH15, and LHL15 levels before hepatectomy, operative time, and blood loss were significantly different between the two groups. Multivariate analysis revealed that gamma-glutamyl transferase, ICGR(15), and HGF were independent risk factors for postoperative complications. The values of the areas under the ROC curve for predicting complications proved the significance of the predictions. Although the recurrence-free survival rates were not significantly different, the overall survival rates were significantly different between the two groups. Univariate and multivariate analyses for the overall survival rate showed that the stage of the HCC and HGF for the complication group and tumor size for the complication-free group were independent prognostic factors for overall survival. Postoperative surgical complications could have a prognostic impact on overall survival in HCC patients after initial hepatectomy. Serum HGF could be a factor connected to complications and survival in this group.

DOI

Rapid recovery of postoperative liver function after major hepatectomy using saline-linked electric cautery

Toru Mizuguchi, Tadashi Katsuramaki, Minoru Nagayama, Makoto Meguro, Toshihito Shibata, Shinsuke Kaji, Koichi Hirata

Hepato-Gastroenterology 55 ( 88 ) 2188 - 2192 2008年11月

Background/Aims: The exact effect of heat injury in the residual liver on postoperative liver function is not totally understood. The purpose of this study was to compare postoperative liver function after major liver resection using an argon laser beam coagulator (AR) and that using saline-linked electric cautery (SLC) for vessels and bile duct sealing. Methodology: Between January 2001 and December 2005, thirty patients were analyzed in this study retrospectively. The inclusion criteria were that the patients received hemihepatectomy without vascular and biliary reconstruction in a non-cirrhotic liver. Operative variables and liver functions were compared between the AR method and the SLC method. Results: The clinical profiles of the two groups were almost identical, including preoperative hepatic function. Although there was no difference in most of the intraoperative variables between them, warm ischemic time in the SLC group was shorter than in the AR group (46.53 + 25.42 min vs. 70.47±11.48 min: p=0.003). Albumin and hulirubin levels at 7 days after hepatectomy were not significantly different between the two groups, but low-density lipoprotein (LDL) and apolipoprotein B (ApoB) levels in the SLC group at 7 days after hepatectomy were significantly higher than in the AR group (84.27 ± 14.38 mg/dl vs. 60.21 ± 14.27 mg/dl: p=0.001 69.53 ± 17.18 mg/dl vs. 55.87 ± 9.56 mg/dl: p=0.012, respectively). Conclusion: SLC reduces warm ischemic time during hepatectomy. Furthermore, the rapid recovery of LDL and ApoB levels in the SLC group indicates that the SLC method has potential benefits for postoperative hepatic function. © H.G.E. Update Medical Publishing S.A., Athens-Stuttgart.

PubMed

Laminin α5 mediates ectopic adhesion of hepatocellular carcinoma through integrins and/or Lutheran/basal cell adhesion molecule

Yamato Kikkawa, Ryo Sudo, Junko Kon, Toru Mizuguchi, Motoyoshi Nomizu, Koichi Hirata, Toshihiro Mitaka

Experimental Cell Research ( ELSEVIER INC ) 314 ( 14 ) 2579 - 2590 2008年08月 [査読有り]

Laminins are a diverse group of alpha/beta/gamma heterotrimers formed from five alpha, three beta and three gamma chains; they are major components of all basal laminae (BLs). One laminin chain that has garnered particular interest due to its widespread expression pattern and importance during development is laminin alpha 5. Little is known, however, about the expression and function of laminins containing the alpha 5 chain in human hepatocellular carcinoma (HCC). Here, using a specific antibody, we examined the expression of laminin alpha 5 in normal liver and in HCCs. In normal liver, although laminin alpha 5 was observed in hepatic BLS underlying blood vessels and bile ducts, it was absent from the parenchyma, which may be the origin of HCC. Oil the other hand, laminin alpha 5 deposition was observed throughout all HCCs tested, regardless of tumor grade. in well-differentiated HCCs, it localized along the trabecules of the tumor. In poorly-differentiated HCCs, it was present in surrounding tumor nodules. In HCC cell lilies, laminin alpha 5 heterotrimerized with beta and gamma chains and was secreted into the culture media. To attempt to understand the function of laminins containing alpha 5, the expression of its receptors in HCCs was also determined. In this regard, alpha 3 beta 1/alpha 6 beta 1 integrins and Lutheran/basal cell adhesion molecule (Lu/B-CAM) were expressed in HCC cells. In vitro studies showed that HCC cells readily attached to laminin containing the alpha 5 chain, more so than did primary hepatocytes. in addition to alpha 3 beta 1/alpha 6 beta 1 integrins and Lu/B-CAM, laminin alpha 5 was recognized by integrin alpha 1 beta 1, which also was expressed in HCC cells. These results suggest that laminins containing alpha 5 serve as functional substrates regulating progression of HCC. (C) 2008 Elsevier Inc. All rights reserved.

DOI

Prospective nonrandomized comparison between pylorus-preserving and subtotal stomach-preserving pancreaticoduodenectomy from the perspectives of DGE occurrence and postoperative digestive functions

Emi Akizuki, Yasutoshi Kimura, Takayuki Nobuoka, Masafumi Imamura, Toshihiko Nishidate, Toru Mizuguchi, Tomohisa Furuhata, Koichi Hirata

Journal of Gastrointestinal Surgery 12 ( 7 ) 1185 - 1192 2008年07月

Background: To determine the influence of pylorus preservation after pancreaticoduodenectomy, we compared the postoperative course of subtotal stomach-preserving pancreaticoduodenectomy (SSPPD) and pylorus-preserving pancreaticoduodenectomy (PPPD). Methods: A prospective, nonrandomized comparison of 77 consecutive patients undergoing PPPD (n=37) or SSPPD (n=40) between January 2003 and March 2007 was planned. The early postoperative course, dietary intake, and the incidence of delayed gastric emptying (DGE) were evaluated. Results: SSPPD included significantly more cases of regional lymph node dissection (D2, PPPD 53% vs. SSPPD 80%) and portal vein resection. The median duration of surgery (457 vs. 520 min) was significantly shorter, and blood loss (619 vs. 1,235 ml) was significantly less in PPPD. Regarding postoperative clinical factors, the duration of nasogastric tube intubation (1 vs.1 day), days until solid diet (7 vs. 7 days), and the incidence of DGE (9% vs.10%) were similar in PPPD and SSPPD. However, the postoperative/preoperative body weight ratio (95% vs. 93%) was significantly higher, and the postoperative hospital stay (31 vs. 38 days) was significantly shorter in PPPD (p< 0.05). Conclusions: Despite the bias of the operative factors, the incidence of DGE and postoperative dietary intake after SSPPD was comparable with PPPD, and therefore, pylorus preservation seemed to have no impact on postoperative dietary intake or DGE. © 2008 The Society for Surgery of the Alimentary Tract.

DOI PubMed

膵癌に対する膵頭十二指腸切除術の各種手術手技膵周囲剥離面陰性化を目指した神経叢郭清と門脈合併切除・再建

木村康利, 永山稔, 今野愛, 信岡隆幸, 今村将史, 水口徹, 古畑智久, 平田公一

日本消化器外科学会雑誌 ( (一社)日本消化器外科学会 ) 41 ( 7 ) 1013 - 1013 2008年07月

膵と胆管で乳頭粘液性腫瘍が同時重複した一例

永山稔, 木村康利, 今野愛, 信岡隆幸, 古畑智久, 水口徹, 平田公一, 廣川直樹

膵臓 ( (一社)日本膵臓学会 ) 23 ( 3 ) 432 - 432 2008年06月

膵IPMCと胆管IPMNが並存した1例

永山稔, 木村康利, 今野愛, 信岡隆幸, 水口徹, 古畑智久, 平田公一

北海道外科雑誌 ( 北海道外科学会 ) 53 ( 1 ) 96 - 96 2008年06月

術前に腫瘤を指摘しえなかった膵癌の1例

今野愛, 木村康利, 永山稔, 信岡隆幸, 古畑智久, 水口徹, 石渡裕俊, 林毅, 新津洋司郎, 平田公一

北海道外科雑誌 ( 北海道外科学会 ) 53 ( 1 ) 94 - 94 2008年06月

【膵切除術の術式選択と手術手技】膵頭部浸潤性膵管癌に対する外科治療

永山稔, 木村康利, 今野愛, 信岡隆幸, 水口徹, 古畑智久, 平田公一

消化器外科 ( (株)へるす出版 ) 31 ( 7 ) 1123 - 1131 2008年06月

教室における小膵癌(ts1)症例の検討

木村康利, 永山稔, 今野愛, 信岡隆幸, 西館敏彦, 水口徹, 古畑智久, 平田公一

膵臓 ( (一社)日本膵臓学会 ) 23 ( 3 ) 443 - 443 2008年06月

腫瘍性病変疑診例に対する腹腔鏡下膵切除

今野愛, 木村康利, 永山稔, 信岡隆幸, 今村将史, 秋月恵美, 水口徹, 古畑智久, 平田公一

日本臨床外科学会雑誌 ( 日本臨床外科学会 ) 69 ( 3 ) 714 - 714 2008年03月

腹腔鏡下脾臓摘出術の有用性開腹術との比較による臨床的検討

永山稔, 木村康利, 今野愛, 信岡隆幸, 西舘敏彦, 水口徹, 古畑智久, 平田公一

日本臨床外科学会雑誌 ( 日本臨床外科学会 ) 69 ( 3 ) 709 - 709 2008年03月

Short- and midterm outcomes of laparoscopy-assisted colectomy for colon and rectosigmoid cancer

Toshihiko Nishidate, Tomohisa Furuhata, Kenji Okita, Makoto Meguro, Gentaro Ishiyama, Takayuki Nobuoka, Koji Yamaguchi, Yasutoshi Kimura, Toru Mizuguchi, Fumitake Hata, Koichi Hirata

Tumor Research 43 31 - 37 2008年

Background: Laparoscopy-assisted colectomy (LAC) has gained acceptance for the treatment of colon cancer. Objective: To evaluate the use and outcomes of LAC. Patients: Patients who underwent LAC (n = 176) for colon and rectosigmoid cancer (2001-2008). Results: There were 97 men (55.1%) and 79 women(44.9%), whose median age was 67.5 years (range, 33-99 years). The median operating time for patients who underwent LAC was 216 minutes (range, 70-440). The median blood loss was 60 ml (range 10-610 ml). Intra- and postoperative complications occurred in 3 (1.7%) and 16 patients (9.1%) respectively. The morbidity rate of patient was 0%. The overall survival rates for 3 years were 100.0%, 97.5%, 95.9%, 90.1% and 77.9% for stages 0 I, II, IIIa and IIIb, respectively. The relapse-free survival rates for 3 years were 100.0%, 100.0% 90.1%, 65.7% and 62.3% for stages 0, I, II, IIIa and IIIb, respectively. Conclusion: This study confirmed the favorable short- and midterm operative results in patients who underwent LAC.

Proliferation of Hepatocyte Progenitor Cells Isolated From Adult Human Livers in Serum-Free Medium

Kazunori Sasaki, Rtnko Kon, Toru Mizuguchi, Qijie Chen, Hidekazu Ooe, Hideki Oshima, Koichi Hirata, Toshihiro Mitaka

CELL TRANSPLANTATION ( COGNIZANT COMMUNICATION CORP ) 17 ( 10-11 ) 1221 - 1230 2008年 [査読有り]

Rat small hepatocytes (SHs) are committed progenitor cells that can differentiate into mature hepatocytes and can selectively proliferate in serum-free medium when they are cultured on hyaluronic acid (HA)-coated dishes. In this study we examined the separation of human SHs from adult human livers. We obtained liver tissues from the resected liver of 16 patients who underwent hepatic resections. Extracted liver specimens were clearly separate from the tumor regions with sufficient margins. Hepatic cells were isolated using the modified method of two-step collagenase perfusion. A low-speed centrifugation was performed and cells in the supernatant were finally cultured on HA-coated dishes in serum-free DMEM/F12 medium including nicotinamide, EGF, and HGF. Small-sized hepatocytes selectively proliferated to form colonies and many colonies continued growing for more than 3 weeks. The average number of cells in a colony was 38.6 +/- 18.0, 79.0 +/- 54.0, and 101.5 +/- 115.7 at day 7, 14, and 21, respectively. About 0.04% of plated cells could form an SH colony. Immunocytochemistry showed that the cells forming a colony were positive for albumin, transferrin, keratin 8, and CD44. The results of RT-PCR showed that colony-forming cells expressed albumin, transferrin, alpha(1)-antitrypsin, fibrinogen, glutamine synthetase, many cytochrome P450s, and liver-enriched transcription factors (HNF3 alpha, HNF4 alpha, C/EBP alpha, and C/EBP beta. Furthermore, the cells expressed not only the genes of hepatic differentiated functions but also those of both hepatic stein cell marker (Thy1.1, EpCAM, AFP) and SH marker (CD44, D6.1A, BRI3). Albumin secretion into culture medium was also observed. Our results demonstrate the existence of hepatocyte progenitor cells in human adult livers, and the cells can grow in a serum-free medium on HA-coated dishes. Human SHs may be a useful source for cell transplantation as well as pharmaceutical and toxicological investigations.

PubMed

Efficient transformation of small hepatocytes into insulin-expressing cells by forced expression of Pdx1.

Kawasaki H, Mizuguchi T, Oshima H, Nobuoka T, Shibata T, Kaji S, Kokai Y, Katsuramaki T, Mitaka T, Hirata K

Journal of hepato-biliary-pancreatic surgery ( 4 ) 15 403 - 409 2008年 [査読有り]

DOI PubMed

In vitro transformation of adult rat hepatic progenitor cells into pancreatic endocrine hormone-producing cells.

Kawasaki H, Mizuguchi T, Kikkawa Y, Oshima H, Sasaki Y, Tokino T, Kokai Y, Miyazaki J, Katsuramaki T, Mitaka T, Hirata K

Journal of hepato-biliary-pancreatic surgery 15 ( 3 ) 310 - 7 2008年 [査読有り] [国内誌]

BACKGROUND/PURPOSE: Pancreatic and duodenal homeobox factor 1 (Pdx-1) plays an important role in initiating differentiation toward pancreatic endocrine cells. The transdifferentiation or transformation of hepatocytes into pancreatic endocrine cells could be feasible, due to their similar cellular origins. Our goal in this study was to see if small hepatocytes (SHs) could give rise to pancreatic endocrine cells via exogenous Pdx-1 gene expression. METHODS: SHs were cultured for 10 days before adenovirus (Adt)-mediated Pdx-1 gene transfection. We performed western blot analysis for pancreatic transcription factors in the nuclei and reverse-transcription polymerase chain reaction (RT-PCR) for the gene expression of pancreatic endocrine hormones. Confocal laser microscanning analysis was used to observe the transformation of SHs. RESULTS: Pancreatic transcription factors such as Pdx-1, Ngn3, NeuroD, Nkx2.2, and Pax6 were induced after Adt-Pdx-1 gene transfection. The mRNA expression of pancreatic endocrine hormones (insulin, glucagon, and somatostatin) was induced after the gene transfection. Pdx-1 was expressed in the nucleus, where the cells were positive for one or more of the hormones and cytokeratin (CK) 8. Some cells were positive for multiple hormones. The insulin level increased while the glucagon level decreased after the glucose loading test, depending on the glucose concentration. CONCLUSIONS: SHs are transformed into functional pancreatic endocrine cells after Pdx-1 gene transfection.

DOI PubMed

漿膜下層浸潤胆嚢癌に対する至適術式の検討

信岡隆幸, 木村康利, 大野敬祐, 西舘敏彦, 秋月恵美, 水口徹, 向谷充宏, 平田公一

胆道 = Journal of Japan Biliary Association ( 日本胆道学会 ) 21 ( 5 ) 630 - 636 2007年12月

教室で経験した漿膜下層(ss)浸潤胆嚢癌(以下ss胆嚢癌)44症例について解析し,術式の在り方について検討した. 5生率は50. 2%であった. 肝切除付加群で有意に予後が良好であったが,肝切除範囲の多少では有意差を認めなかった.膵頭十二指腸切除術(以下PD)群の3生率は83.3%と良好であったが,胆管切除群との間に有意差は無かった.郭清度D1以下群に比しD2以上群で予後は有意に良好で,とくに頸部,胆嚢管癌でその意義が伺われる傾向にあった.
予防的系統的肝切除, 予防的リンパ節郭清としての胆管切除・PD付加の意義は不明瞭であった.D2以上のリンパ節郭清と肝切除を伴う根治的手術がss胆嚢癌の至適術式と考えられた.

DOI CiNii

腹腔鏡下脾臓摘出術の有用性開腹術との比較による臨床的検討

永山稔, 木村康利, 今野愛, 信岡隆幸, 水口徹, 古畑智久, 平田公一

北海道外科雑誌 ( 北海道外科学会 ) 52 ( 2 ) 144 - 147 2007年12月

教室で施行した脾臓摘出術症例を、鏡視下手術(LS群)と開腹手術(OS群)にわけ、術後回復過程での鏡視下手術の有用性について検討した。1994年8月から2007年8月までに、教室で施行した脾臓摘出術症例27例を対象とした。LS群は21例(うち、用手補助腹腔鏡下手術3例)、OS群は6例であった。疾患は、LS群では特発性血小板減少性紫斑病、肝硬変に伴う脾機能亢進症、脾腫瘍が(それぞれ6例)、OS群では特発性血小板減少性紫斑病が3例で最も多かった。手術因子として、平均手術時間と出血量において両群間に差はなかった。一方、周術期因子として頓用鎮痛薬使用期間(LS群:1.9日、OS群:6.4日)と術後在院期間(LS群:9.2日、OS群:17.5日)で有意にLS群が短かった(p<0.05)。腹腔鏡下脾臓摘出術は、低侵襲かつ安全に施行されており、今後ますますその需要が増えると考えられた。(著者抄録)

New strategy for the antifibrotic therapy with oral administration of FR260330 (a selective inducible nitric oxide synthase inhibitor) in rat experimental liver cirrhosis

Hitoshi Kikuchi, Tadashi Katsuramaki, Kazuma Kukita, Sonofu Taketani, Makoto Meguro, Minoru Nagayama, Masato Isobe, Toru Mizuguchi, Koichi Hirata

Wound Repair and Regeneration 15 ( 6 ) 881 - 888 2007年11月

Inducible nitric oxide synthase (iNOS) activity is significantly elevated in viral hepatitis, alcoholic cirrhosis, and cholestasis. However, there are few reports on the relationship between iNOS and cirrhosis. Here, we investigated the effects of a new iNOS inhibitor that has been developed for oral administration in an experimental rat liver cirrhosis model. A cirrhotic rat model was developed by long-term administration of thioacetamide injections. FR260330 is a new, rationally designed, selective iNOS inhibitor that can be administered orally. After 12 weeks of treatment with FR260330, the rats showed inhibition of progressions of cirrhosis, ascites, and splenomegaly as well as a significant reduction in the proportions of connective tissue in the liver. The expression of nitrotyrosine, which indicates the existence of peroxynitrite and nuclear factor-κB activation, was remarkably decreased in the FR260330 treatment group. In addition, immunohistochemical and Western blot analyses showed that the expression of transforming growth factor-β1 was remarkably decreased in this group. The present study demonstrates that FR260330 reduces liver fibrosis by the inhibition of transforming growth factor-β1 and retards the development of cirrhosis. This oral iNOS inhibitor will be a new strategy for the treatment of cirrhosis. © 2007 by the Wound Healing Society.

DOI PubMed

Current status of surgery for pancreatic cancer.

Hirata Koichi, Egawa Shinichi, Kimura Yasutoshi, Nobuoka Takayuki, Oshima Hidenori, Katsuramaki Tadashi, Mizuguchi Toru, Furuhata Tomohisa

Dig Surg 24 ( 2 ) 137 - 147 2007年04月 [査読有り]

DOI PubMed

Assessment of nutritional status and prediction of postoperative liver function from serum apolioprotein A-1 levels with hepatectomy

Tadashi Katsuramaki, Toru Mizuguchi, Masaki Kawamoto, Kouji Yamaguchi, Makoto Meguro, Minoru Nagayama, Takayuki Nobuoka, Yasutoshi Kimura, Tomohisa Furuhata, Koichi Hirata

WORLD JOURNAL OF SURGERY ( SPRINGER ) 30 ( 10 ) 1886 - 1891 2006年10月 [査読有り]

Background: We investigated the usefulness-of apolipoprotein A-1 (apoA) as an indicator of nutritional status, and the correlation of the preoperative apoA level with changes in postoperative liver function following hepatectomy. Methods: One hundred patients underwent hepatectomy. Serum levels of apoA, prealbumin (prealb), retinol-binding protein (RBP), lectin-cholesterol acyltransferase (LCAT), hyarulonate (HA), indocyanine green dye retention at 15 minutes (ICG), and the receptor index of Tc-GSA scintigraphy (LHL15) were measured at preoperation and on postoperative days (POD) 7 and 14. Partial resection was carried out in 62 cases, segmentectomy in nine cases, and bisegmentectomy in 29 cases. Co-existent liver conditions were normal liver (NL) in 43 cases, chronic hepatitis (CH) in 29 cases, and liver cirrhosis (LC), in 28 cases. Results: In most cases the serum apoA level had decreased on POD 7, and recovered on POD 14. There were no significant differences in the changes of apoA between the individual operative procedures. Although preoperative apoA had almost the same value in the NL, CH, and LC cases, apoA in LC cases on POD 114 was the lowest of all cases. The apoA level showed significant correlations with prealb, LCAT, and HA on POD 14. All cases were divided into two groups (group N: apoA over 91 mg/dl; group L: apoA under 90 mg/dl) based on the preoperative serum apoA level. On POD 14, the ICG, LHL15, and HA of group L were significantly deteriorated compared with those of group L. Conclusion: The serum level of apoA reflects the changes in hepatic protein synthetic ability after hepatectomy; therefore, it may be possible to estimate recovery of nutritional status after hepatectomy from serum apoA. Moreover, we can predict postoperative deterioration of liver function from the preoperative apoA level.

DOI

In situ graft-trimming method using polyester vascular prosthesis for inferior vena cava reconstruction after hepatectomy

Toru Mizuguchi, Tadashi Katsuramaki, Kiyofumi Morishita, Masaki Kawamoto, Takayuki Nobuoka, Masato Imamura, Yasutoshi Kimura, Koichi Hirata

Digestive Surgery 23 ( 1-2 ) 115 - 118 2006年08月

Hepatectomy for secondary liver cancer that has invaded the inferior vena cava (IVC) can be the only way to achieve long-term survival. We describe a method for hepatectomy combined with partial IVC resection without venous bypass circulation and an in situ graft-trimming method to avoid graft size mismatch after reconstruction. We carried out left hepatectomy extended to segment 1 with partial IVC resection first. During resection and reconstruction of the IVC, it was clamped below the right hepatic vein and above the inferior right hepatic vein to maintain systemic circulation. The graft was trimmed in situ, after a half running suture of the graft was finished to ensure the correct size. Preservation of both inferior right hepatic vein and right hepatic vein helps to maintain systemic circulation during reconstruction of the IVC. The in situ graft-trimming method is an easy and safe method to ensure the correct graft size after IVC reconstruction. Copyright © 2006 S. Karger AG.

DOI PubMed

Assessment of liver fibrosis by a noninvasive method of transient elastography and biochemical markers

Masaki Kawamoto, Toru Mizuguchi, Tadashi Katsuramaki, Minoru Nagayama, Hideki Oshima, Hiroyuki Kawasaki, Takayuki Nobuoka, Tasutoshi Kimura, Koichi Hirata

World Journal of Gastroenterology ( Baishideng Publishing Group Co ) 12 ( 27 ) 4325 - 4330 2006年07月

Aim: To assess the correlation between the fibrotic area (FA) as calculated by a digital image analysis (DIA), and to compare the diagnostic accuracy of FibroScan to the other existing Liver fibrosis (LF) markers using the receiver operating curve analysis. Methods: We recruited 30 patients who underwent a liver resection for three different etiologies including normal liver, hepatitis B, and hepatitis C. Liver stiffness was measured by using a FibroScan. The FA was then calculated by DIA to evaluate LF in order to avoid any sampling bias. Results: The FA negatively correlated with Prothrombin time (PT), platelet count, lecithin-cholesterol acyltransferase (LCAT), and pre-albumin (ALB). On the other hand, the findings of FibroScan correlated with similar markers. The FA positively correlated with FibroScan, serum hyaluronate level, and type IV collagen level, and aspartate transaminase to platelet ratio index (APRI). The area under the receiver operating curve for FibroScan was higher than that for the other markers, even though the statistical significance was minimal. Conclusion: Our findings suggest that FibroScan can initially be used to assess LF as an alternative to a liver biopsy (LB) and serum diagnosis, because it is a safe method with comparable diagnostic accuracy regarding the existing LF markers. © 2006 The WJG Press. All rights reserved.

DOI PubMed

Serum lipid and lipoprotein alterations represent recovery of liver function after hepatectomy

M Kawamoto, T Mizuguchi, M Nagayama, T Nobuoka, H Kawasaki, T Sato, K Koito, S Parker, T Katsuramaki, K Hirata

LIVER INTERNATIONAL ( BLACKWELL PUBLISHING ) 26 ( 2 ) 203 - 210 2006年03月 [査読有り]

Background: The assessment of liver function during human liver regeneration is necessary to prevent unexpected liver failure and to prepare for further treatment. We selected patients prospectively and measured serum lipid and lipoprotein levels to identify which lipids and lipoproteins could represent recovery of liver function in human liver regeneration. Methods: Thirty selected patients who underwent hepatectomy were divided into three groups depending on the serum hyaluronate (HA) level and the type of liver resection. Results: We found three patterns of lipid and lipoprotein alterations after hepatectomy. Among the lipids and lipoproteins examined, the serum beta-lipoprotein and low-density lipoprotein (LDL) levels were significantly different among the groups at 7 days after hepatectomy. The alteration of the apolipoprotein (Apo) B level was similar to that of LDL. The LDL level was correlated with both beta-lipoprotein and Apo B before hepatectomy (r=0.653 and 0.894, respectively) and at 7 days after hepatectomy (r=0.841 and 0.943, respectively). Conclusion: Serum HA before hepatectomy can reflect postoperative liver function depending on the type of liver resection. Recovery of the beta-lipoprotein and LDL levels can reflect the recovery of liver function in human liver regeneration within the early period in association with the Apo B level.

DOI

Liver repopulation and long-term function of rat small hepatocyte transplantation as an alternative cell source for hepatocyte transplantation

C Shibata, T Mizuguchi, Y Kikkawa, T Nobuoka, H Oshima, H Kawasaki, M Kawamoto, T Katsuramaki, T Mitaka, K Hirata

LIVER TRANSPLANTATION ( JOHN WILEY & SONS INC ) 12 ( 1 ) 78 - 87 2006年01月 [査読有り]

Hepatocyte transplantation (HT) is an attractive therapeutic modality for liver disease as an alternative for liver organ transplantation. Primary fresh hepatocytes (FHs) are the exclusive cell source that has been used for clinical HT, However, the use of FHs is limited due to a shortage of donor cells. Small hepatocytes (SHs) are hepatic progenitor cells and can be isolated not only from rodents but also from humans. SHs can proliferate in vitro and express liver functions, although conventional hepatocytes lose them within a short period after culture. SH functions in vivo have never been studied. We therefore investigated HT using SHs to evaluate cell engraftment and function compared to HT using FHs. The donor cell number in the SH group was smaller than that in the FH group at HT. The cell engraftment in the SH group was smaller in the liver and larger in the spleen than in the FH group. The cell engraftment in the liver increased after HT; however, that in the spleen decreased after HT in both groups. HT using SHs supported the serum albumin level in the NAR experiment as well as that using FH, and albumin mRNA was detectable in the recipients' tissues at 12 weeks after HT. In conclusion, HT using SHs showed hepatic repopulation similar to that using FHs. This suggests that both SHs and FHs can repopulate the liver as if they were hepatic stem cells. In addition, HT using SHs supported liver functions such as albumin correction at the same level as that using FHs. These observations strongly support the idea that SHs could be an alternative to primary FHs as a novel cell source for future HT.

DOI PubMed

Portal blood flow regulates volume recovery of the rat liver after partial hepatectomy: Molecular evaluation

T. Nobuoka, T. Mizuguchi, H. Oshima, T. Shibata, Y. Kimura, T. Mitaka, T. Katsuramaki, K. Hirata

EUROPEAN SURGICAL RESEARCH ( KARGER ) 38 ( 6 ) 522 - 532 2006年 [査読有り]

Background/Aim: Liver regeneration is a finely tuned process that is closely regulated by multiple cell cycle steps. Although the portal blood flow affects liver regeneration, the molecular mechanism by which the blood flow regulates gene expression and liver function is largely unknown. The aim of this study was to investigate the molecular effect of portal blood flow on hepatocyte proliferation and gene regulation during liver regeneration. Materials and Methods: We developed a simple surgical rat model to investigate the relation between portal blood flow and liver regeneration by partially ligating the portal trunk with 8-0 Proline sutures under microscopy to reduce the blood flow by 40%. We investigated recovery of liver volume, DNA synthesis, and gene expression associated with cell cycle regulators, comparing partially hepatectomized (PH) rats without (PH group; n = 30) and with partial portal ligation (PHPL group; n = 30) for 7 days after the operation. Results: The hepatic tissue blood flow and the recovery ratio between liver weight and body weight in the PHPL group were significantly lower than in the PH group after hepatectomy. The peak 5-bromo-2'-deoxyuridine labeling index in the PHPL group was delayed and weak compared with the PH group. The expression of CT-1 and cyclin D, E, and B mRNAs indicated that the liver regeneration in the PHPL group was delayed and weak. In addition, there was reciprocal expression of C/EBP alpha and C/EBP beta mRNAs, an observation supported by their nuclear protein levels. Furthermore, the cytochrome P-450 protein level in the PHPL group was higher than that in the PH group 1 day after hepatectomy. Conclusion: The portal blood flow regulates the activity of liver regeneration and the gene expression associated with cell cycle regulators, while the functions are maintained. Copyright (c) 2006 S. Karger AG, Basel.

DOI

Successful management of locally advanced hilar cholangiocarcinoma : Surgical procedure for extended left hepatic lobectomy coupled by resection/ reconstruction of the right hepatic artery

Akizuki Shindo Emi, Kimura Yasutoshi, Mukaiya Mitsuhiro, Honnma Toshio, Mizuguchi Toru, Furuhata Tomohisa, Koito Kazumitsu, Katsuramaki Tadashi, Hirata Koichi

Tumor Research ( Sapporo Medical University ) 41 77 - 81 2006年

Recently, the methods for hepatic lobectomy, which require highly qualified and experienced surgeons and include difficult post-operative management, have improved markedly, and, moreover, there are very few patient deaths resulting from hepatic artery reconstruction. Now, as an overall trend, the focus of discussion has shifted to whether there is any positive value in radical resection. A few reports have described success in such operations.Extended left hepatectomy with right hepatic artery resection in a case of advanced hilar cholangiocarcinoma with suspected right hepatic artery invasion is reported. The surgery absolutely required reconstruction of the hepatic artery. During the postoperative course, in which the patient was at high risk for complications, temporary bleeding was observed from a pseudo aneurysm in the anastomotic site. Fortunately, no severe problems were caused by transarterial embolization in the right hepatic artery. The patient completed the planned chemotherapy regimen and was discharged.

DOI CiNii

Hyperbaric oxygen stimulates cell proliferation and normalizes multidrug resistance protein-2 protein localization in primary rat hepatocytes

T Mizuguchi, H Oshima, H Imaizumi, H Kohara, M Kawamoto, T Nobuoka, H Kawasaki, K Harada, Y Masuda, Y Kikkawa, T Mitaka, Y Asai, K Hirata

WOUND REPAIR AND REGENERATION ( BLACKWELL PUBLISHING ) 13 ( 6 ) 551 - 557 2005年11月 [査読有り]

Hyperbaric oxygen therapy (HBO) has been used for many clinical treatments, including primary liver nonfunction. However, the cellular mechanism by which HBO treatment ameliorates liver function is not understood. Therefore, the purpose of this study was to elucidate this cellular mechanism using primary cultured rat hepatocytes in in vitro studies. Hepatocytes were treated with HBO at 1 day after plating, and the morphological and functional characteristics of bile canaliculi formed in cultured hepatocytes were observed by time-lapse microscopy. Multidrug resistance protein-2 localization was observed by confocal laser microscopy. In cultured hepatocytes, the labeling index in the HBO group at 2 days after treatment was significantly higher than that in the control group. In addition, the proliferating cellular nuclear antigen level in the HBO group was significantly higher than that in the control group. The contraction of the bile canaliculi in the HBO group was slower than in the control group and the dilatation of bile canaliculi in the HBO group was much larger than in the control group. Multidrug resistance protein-2 in the HBO group was localized at the apical membrane. These results show that HBO stimulates hepatocytes to proliferate and HBO normalizes Multidrug resistance protein-2 localization to the apical membrane, which could dilate bile canaliculi.

DOI PubMed

Hepatic organoid formation in collagen sponge of cells isolated from human liver tissues

S Sugimoto, K Harada, T Shiotani, S Ikeda, N Katsura, Ikai, I, T Mizuguchi, K Hirata, Y Yamaoka, T Mitaka

TISSUE ENGINEERING ( MARY ANN LIEBERT INC ) 11 ( 3-4 ) 626 - 633 2005年03月 [査読有り]

We examined whether small hepatocytes (SHs), which are hepatic progenitor cells, could be isolated from a normal human liver and whether human hepatic cells could form hepatic organoids in a collagen sponge. Normal liver tissues were obtained from resected specimens from nine patients who underwent hepatic resection. Isolated hepatic cells were plated on dishes and a collagen sponge. More than 1 month later, SH-like cells appeared and proliferated on the dishes, whereas cell aggregates were formed in the sponge and showed characteristic tissue architecture: columnar and/or cuboidal epithelial cells lined the surface of the sponge. Clusters of epithelial cells with a large cytoplasm and ductular structures were observed under the lining cells. The lining and ductular cells were positive for cytokeratins 7 and 19, which indicated they were biliary epithelial cells (BECs), and the epithelial cells forming clusters were positive for the anti-human hepatocyte antibody, identifying them as hepatocytes. Some lining cells were positive for both the hepatic marker and the BEC markers. The cells in the collagen sponge actively proliferated and the hepatocytes excreted albumin into the medium. Thus, hepatic organoids could be reconstructed in a collagen sponge by normal human liver cells.

DOI PubMed

Hepatocyte transplantation for total liver repopulation.

Mizuguchi T, Mitaka T, Katsuramaki T, Hirata K

Journal of hepato-biliary-pancreatic surgery ( 5 ) 12 378 - 385 2005年 [査読有り]

DOI PubMed

Biliary tract malignancy and chronic inflammation from the perspective of pancreaticobiliary maljunction

Y Kimura, N Nishikawa, K Okita, T Furuhata, T Mizuguchi, T Nobuoka, H Nishimori, H Zenbutsu, M Satoh, T Katsuramaki, K Hirata

ONCOLOGY ( KARGER ) 69 41 - 45 2005年 [査読有り]

This is a brief review of pancreaticobiliary maljunction. The basic treatment for this condition includes either cholecystectomy or extrahepatic bile duct resection. When the condition is accompanied by malignancies, a radical operation should be the first treatment option. Knowledge on molecular pathogenesis is gradually increasing. However, studies should be expanded to include larger patient cohorts, and other types of molecules should be carefully investigated and analyzed. Copyright (C) 2005 S. Karger AG, Basel.

DOI

動脈合併切除再建, 肝外胆管切除再建にて切除しえた肝エキノコックス症の1例

信岡隆幸, 桂巻正, 水口徹, 島宏彰, 木村康利, 古畑智久, 向谷充宏, 平田公一

胆道 = Journal of Japan Biliary Association ( 日本胆道学会 ) 18 ( 1 ) 81 - 87 2004年03月

肝左葉に発生し,肝動脈・胆管浸潤を認めた肝エキノコックス症に対して,拡大肝左葉切除, 肝外胆管切除, 肝動脈合併切除・再建にて治癒切除できた症例を経験した.症例は58歳女性で,黄疸を主訴に近医受診し,腹部USおよび腹部CTで肝左葉全体に腫瘤を認め,血清学的検査にて肝エキノコックス症と診断された.胆管造影では腫瘤の浸潤により,左肝管閉塞,肝門部胆管狭窄を認め,減黄目的にERBDチューブが挿入された.減黄後,手術目的に当科紹介され拡大左葉切除を行なった.開腹時の腹腔内所見は,肝十二指腸間膜で右肝動脈は胆管に浸潤した腫瘤と一塊となって剥離不能であったため,右肝動脈の一部を合併切除し,右肝動脈と固有肝動脈を端々吻合して再建した.本症は発見時にすでに脈管・胆管浸潤を伴って広範囲に進展し,切除不能な場合もある.本症例は肝門部に高度に浸潤していたものの, 肝外胆管切除, 肝動脈再建にて切除できた, 稀な症例と思われ報告した.

DOI CiNii

A case of giant hepatic hemangioma with spontaneous intratumoral bleeding <Case Report>

Nobuoka Takayuki, Katsuramaki Tadashi, Mizuguchi Toru, Shima Hiroaki, Kimura Yasutoshi, Mukaiya Mitsuhiro, Hirata Koichi

Tumor research : experimental and clinical ( 札幌医科大学 ) 39 1 - 5 2004年

Cavernous hemangioma is the most common benign tumor of the liver, and most of them remain asymptomatic. However, a giant hemangioma may rupture spontaneously and present severe complications such as shock and anemia, and need emergency operation. We report a case that spontaneous intratumoral bleeding of a giant hemangiona of the liver that occurred in a 55-year-old woman. She presented with severe abdominal pain, anemia, and shock at 3 and a half years after a transcatheter arterial embolization (TAE) treatment. Although the bleeding was under control, a surgical procedure was considered to reduce the risk for rerupture. The general outcome of surgical treatment for giant hemangiomas is satisfactory. In contrast, especially in our case. TAE was unable to reduce the risk of rupture over the long term. Therefore, surgery for giant hemangioma of the liver should be considered as the first treatment to avoid the risk of rupture even in "healthy" case.

DOI CiNii

Effects of bone marrow stromal cells on the structural and functional polarity of primary rat hepatocytes

T Mizuguchi, K Palm, T Hui, T Aoki, Y Mochizuki, T Mitaka, AA Demetriou, J Rozga

IN VITRO CELLULAR & DEVELOPMENTAL BIOLOGY-ANIMAL ( SOC IN VITRO BIOLOGY ) 38 ( 2 ) 62 - 65 2002年02月 [査読有り]

DOI PubMed

Regulation of c-Met expression in rats with acute hepatic failure

T Mizuguchi, Y Kamohara, T Hui, T Neuman, T Mitaka, AA Demetriou, J Rozga

JOURNAL OF SURGICAL RESEARCH ( ACADEMIC PRESS INC ) 99 ( 2 ) 385 - 396 2001年08月

Background. Earlier we described a model of fulminant hepatic failure (FHF) in the rat where partial hepatectomy is combined with induction of right liver lobe necrosis. In FHF rats, lack of hepatocyte proliferation was associated with delayed expression of HGF and HGF receptor c-met. Since the c-met promoter region has Sp1 binding sites, we decided to examine whether in FHF rats down-regulation of c-met is associated with decreased Spl function and whether changes in blood HGF, IL-6, and TGF beta1 levels might be responsible for these effects. Materials and methods. Induction of FHF, partial (2/3) hepatectomy (PH), and sham hepatectomy (SH) was performed in adult Sprague-Dawley rats. The levels of c-met mRNA and Spl DNA binding activity were studied in rat liver remnants at different time points after surgery. Blood levels of HGF, IL-6, and TGF beta1 were also measured in these rats. Additionally, the effects of treatment with TGF-beta1, IL-6, or a combination of both on c-met expression and Sp1 DNA binding were studied in HGF-induced rat hepatocyte cultures. Results. Compared to SH rats, in PH rat livers c-met was up-regulated after 6 h and Sp1 DNA binding was at or only slightly lower than levels at all time points studied. In FHF rat livers, c-met expression was markedly reduced after 2 and 6 h, moderate after 12 h, and undetectable after 24 h. At the same time, Sp1 DNA binding was detected at 2 h postinduction only. In FHF rats, blood levels of all three cytokines showed early and sustained elevation. In vitro, IL-6 had no effect on c-met expression, whereas TGF beta1 upregulated c-met. When used alone, none of the cytokines affected Spl DNA binding activity. In contrast, a combination of IL-6 and TGF beta1 down-regulated c-met expression as well as Sp1 DNA binding activity. These effects were dependent on the IL-6 concentration used. This study suggests that following massive loss of hepatocyte mass in rats, early increase in blood IL-6 and TGF beta1 levels may weaken the expression of HGF receptor c-met in surviving hepatocytes through suppression of Spl DNA binding. (C) 2001 Academic Press.

DOI

Effects of nicotinamide-related agents on the growth of primary rat hepatocytes and formation of small hepatocyte colonies

F Sato, T Mitaka, T Mizuguchi, Y Mochizuki, K Hirata

LIVER ( MUNKSGAARD INT PUBL LTD ) 19 ( 6 ) 481 - 488 1999年12月

Aims/Background: We report in this study that, 10 mM nicotinamide can stimulate the proliferation of primary rat hepatocytes in serum-free Dulbecco's modified Eagle's medium supplemented with 10 ng/ml epidermal growth factor and that small hepatocyte colonies appear from 4 to 5 days after plating. We examined the effects of nicotinamide-related agents on the growth and differentiation of primary rat hepatocytes and on the appearance of small hepatocyte colonies. Methods: As nicotinamide is an aqueous vitamin named niacin and known to act as an inhibitor of poly (ADP-ribose) polymerase (PARP), we therefore chose to examine the effects on hepatocytes of three nicotinamide-related agents, nicotinic acid (NA) which is also a niacin, 3-aminobenzamide (3-AB) which is a strong inhibitor of PARP but is not a niacin, and 3-acetylpyridine (3-AP) which is a weak inhibitor of PARP and also not a niacin. To examine their effects on the growth of the cells and on the formation of the colony, immunocytochemistry for BrdU was carried out. Expression of albumin, tryptophan 2,3-dioxygenase (TO), and connexin 32 (Cx32) mRNAs were used as marks of hepatic differentiation. Intracellular NAD(+) content was also measured. Results. At concentration of 10 mM, NA could not enhance the proliferation of mature hepatocytes but induced the appearance of small hepatocyte colonies. At concentration of 5 mM, 3-AB enhanced the proliferation of the hepatocytes but did not induce small hepatocyte colonies. On the other hand, although 10 mM 3-AP remarkably inhibited the DNA synthesis of the cells, the expression not only bf albumin but also of TO and Cx32 mRNAs in the cells was well maintained for more than one week, The intracellular NAD(+) concentration was correlated with the proliferation of the hepatocytes. Conclusion: These results suggest that the intracellular NAD(+) content may be correlated with the proliferation of primary hepatocytes and that the supplementation of niacin in the medium may be important for the appearance of small hepatocyte colonies.

DOI PubMed

Reconstruction of hepatic organoid by rat small hepatocytes and hepatic nonparenchymal cells

T Mitaka, F Sato, T Mizuguchi, T Yokono, Y Mochizuki

HEPATOLOGY ( W B SAUNDERS CO ) 29 ( 1 ) 111 - 125 1999年01月

Hepatic cells isolated from an adult rat Liver, consisting of small hepatocytes (SHs), mature hepatocytes (MHs), liver epithelial cells (LECs), Kupffer cells, sinusoidal endothelial cells, and stellate cells, were cultured in a medium supplemented with 10% fetal bovine serum, 10 mmol/L nicotinamide, 1 mmol/L ascorbic acid 2-phosphate, 10 ng/mL epidermal growth factor, and 1% dimethyl sulfoxide. The SHs rapidly proliferated and formed a colony. About 10% of cytokeratin 8 (CK8)-positive cells formed SH colonies. All SHs at day 10 immunocytochemically showed positivity for albumin, transferrin, CK8, and CK18, which are markers for hepatocytes. In contrast, alpha-fetoprotein (AFP)-, CK14-, OC2-, and glutathione S-transferase placental type (GST-P)positive cells, which are thought to be markers for hepatic immature cells, were rarefy observed. At day 20 some cells in the colonies were positive for AFP, CK7, CK19, and GST-P LECs and stellate cells proliferated and surrounded the colonies. About 2 weeks after plating, piled up cells were often observed on the SH colonies. In those colonies LECs and stellate cells invaded under the colonies, The invasion of the cells and gradual deposits of extracellular matrix (ECM) such as type I collagen, type TV collagen, and laminin induced alteration of the shape of the SHs from relatively flat to cuboidal or rectangular. With the cellular structural changes, the expression of albumin, connexin 32 (Cx32), and tryptophan 2,3-dioxygenase (TO) messenger RNAs increased. In addition, overlapping nonparenchymal cells (NPCs) on the piled up cells induced the formation of duct- or cyst-like structures consisting of MHs. In the present experiment we showed that SHs could differentiate to MI-Is by interacting with NPCs and ECM. Thus, SHs may be "committed progenitor cells" that can further differentiate into MHs.

DOI PubMed CiNii

Growth and maturation of small hepatocytes

T Mitaka, T Mizuguchi, F Sato, C Mochizuki, Y Mochizuki

JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY ( BLACKWELL SCIENCE ) 13 S70 - S77 1998年09月

Proliferation of adult rat hepatocytes is observed in serum-free Dulbecco's modified Eagle's medium (DMEM) supplemented with 10 mmol/L nicotinamide and 10 ng/mL epidermal growth factor (EGF). The proliferating cells are mainly mononucleate and form small cell colonies surrounded by mature hepatocytes. Although these cells in focal colonies have a less-differentiated appearance, immunocytochemically and ultrastructurally they possess hepatic characteristics. The size of small hepatocytes is one-third to half that of mature hepatocytes. Therefore, we call the cells forming a colony, small hepatocytes. The small hepatocytes can be subcultured for several passages. Furthermore, the cells are rich in the supernatant following 50 g centrifugation for 1 min after collagenase liver perfusion. When the cells are cultured in DMEM supplemented with 10% foetal bovine serum, 10 mmol/L nicotinamide, 1 mmol/L ascorbic acid 2-phosphate, 10 ng/mL EGF and 1% dimethyl sulphoxide, each small hepatocyte can clonally proliferate for more than 3 months. A small hepatocyte divides to form a colony and the number of cells reaches more than 100 within 20 days. With time in culture, cells with a large cytoplasm appear within a colony. They have many mitochondria and large peroxisomes with crystalline nucleoids and are typical, mature hepatocytes. Immunoreactivity to connexin 32 and well-developed bile canaliculus structures are often observed in the cell-cell borders. Thus, we suggest that small hepatocytes may be considered to be 'committed progenitor cells' that can further differentiate into mature hepatocytes.

Mechanism of metastasis and tumor invasion in gastric carcinoma

Ryuichi Denno, Koichi Hirata, Takahiro Yasoshima, Takayuki Shishido, Hideki Ura, Koji Yamaguchi, Toru Mizuguchi, Fumihiko Sato

Japanese Journal of Gastroenterological Surgery ( Japanese Society of Gastroenterological Surgery ) 31 ( 4 ) 974 - 978 1998年

Surgery should be a curative and minimally invasive treatment for early gastric cancer. Therefore we need to know the biology of malignancy of gastric carcinoma. We established a new cell line, AZ-H5c, which has a high potential of metastasis to the nude mice liver, from the human gastric carcinoma line AZ521. Experimental studies revealed that, compared with AZ521 cells. AZ-H5c cells moved more actively, had stronger enzymatic activity of MMP-9, and expressed higher levels of integrin alpha 1, alpha 2, alpha 3, slpha 4, alpha 5, integrin beta 1 and CD44v3. Based on the above information, we investigated the clinico-pathologic characteristics of patients with carcinoma of the stomach. There were significant correlations of integrin alpha 2 and lymph node metastasis and integrin alpha 3 and liver metastasis. There was no correlation of clinico-pathologic characteristics and the expression of MMP-9, nor was the MMP-9 staining pattern related to survival. To foster the development of more effective, minimally invasive surgery, we should continue to accumulate data on gastric carcinma so as to improve diagnostic accuracy regarding lymph node metastasis, the pattern of recurrence and other factors.

DOI

Subculture of proliferating adult rat hepatocytes in medium supplemented with nicotinamide and EGF

T Mitaka, T Kojima, T Mizuguchi, Y Mochizuki

IN VITRO CELLULAR & DEVELOPMENTAL BIOLOGY-ANIMAL ( SPRINGER ) 32 ( 8 ) 469 - 477 1996年09月 [査読有り]

To establish parenchymal hepatocyte cell lines, we tried to subculture the primary hepatocytes isolated from adult rats. The hepatocytes were cultured in serum-free modified Dulbecco's modified Eagle's medium supplemented with 10 mM nicotinamide and 10 ng/ml epidermal growth factor. When 6 x 10(5) cells were plated on 35-mm dishes coated with rat tail collagen, the cells proliferated and reached confluence at Day 6 to Day 8. The first subculture was carried out at Day 8 using 0.005% collagenase and gentle pipettings. Most cells were recovered and plated on the new dishes coated with the collagen (first passage). The attached cells could proliferate and reached near confluence when the cells occupied more than two-thirds of the dish surface. About a week after the first subculture, the second one was conducted. Although the number of the recovered cells was smaller than at the first passage, the cells could attach and proliferate to a certain extent. Thereafter, they were maintained for more than 2 mo. but they never overgrew. Albumin secretion into the culture medium was confirmed in the subcultured cells. Ultrastructurally, these subcultured cells possessed hepatic characteristics such as peroxisomes with a crystalline nucleiod and bile-canaliculus structures. When 10% fetal bovine serum and ascorbic acid 2-phosphate were added to the cells of the second passage, they began to proliferate very slowly. These proliferating cells were mainly mononucleate and had a small cytoplasm. In addition, some of them could differentiate into typical mature hepatocytes by forming a three-dimensional structure interacting with nonparenchymal cells. In this experiment, we showed the successful subculturing of parenchymal hepatocytes isolated from adult rats and provided evidence that the subcultured cells still have the potential to proliferate and to differentiate.

Changes in cellular distribution of connexins 32 and 26 during formation of gap junctions in primary cultures of rat hepatocytes

T Kojima, M Yamamoto, H Tobioka, T Mizuguchi, T Mitaka, Y Mochizuki

EXPERIMENTAL CELL RESEARCH ( ACADEMIC PRESS INC JNL-COMP SUBSCRIPTIONS ) 223 ( 2 ) 314 - 326 1996年03月 [査読有り]

In the adult rat hepatocyte, gap junction proteins consist of connexin 32 (Cx32) and connexin 26 (Cx26), Previously, we reported that both Cx32 and Cx26 were markedly induced and maintained in primary cultures of adult rat hepatocytes, The reappearing gap junctions were accompanied by increases in both the proteins and the mRNAs, and they were well maintained together with extensive gap junctional intercellular communication (GJIC) for more than 4 weeks. In the present study, we examined the cellular location of the gap junction proteins and the structures in the hepatocytes cultured in our system, using confocal laser microscopy and immunoelectron microscopy of cells processed for Cx32 and Cx26 immunocytochemistry and freeze-fracture analysis, In immunoelectron microscopy, the size of Cx32-immunoreactive gap junction structures on the plasma membrane increased with time of culture, and some of them were larger than those in liver sections in vivo. Freeze-fracture analysis also showed that the size of gap junction plaques increased and that the larger gap junction plaques were composed of densely packed particles. These results suggest that in this culture system, not only the synthesis of Ox proteins but also the size of the gap junction plaques was increased markedly. In the adluminal lateral membrane of the cells, Cx32-immunoreactive lines were observed and many small gap junction plaques were closely associated with a more developed tight junction network. In the basal region of the cells, small Cx32- and Cx26-immunoreactive dots were observed in the cytoplasm and several annular structures labeled with the antibody to Cx32 were observed in the cytoplasm, These results indicated the formation and degradation of gap junctions in the cultured hepatocytes. (C) 1996 Academic Press, Inc.

Effects of oxygen radical scavengers on connexins 32 and 26 expression in primary cultures of adult rat hepatocytes

T Kojima, T Mitaka, T Mizuguchi, Y Mochizuki

CARCINOGENESIS ( OXFORD UNIV PRESS UNITED KINGDOM ) 17 ( 3 ) 537 - 544 1996年03月 [査読有り]

Although we recently reported our success in inducing and maintaining the gap junction proteins connexin 26 (Cx26) and connexin 32 (Cx32) in adult rat hepatocytes cultured in serum-free L-15 medium supplemented with epidermal growth factor, dimethylsulfoxide (DMSO) and glucagon, the mechanisms by which DMSO induces gap junctions are still not clear, It is known that DMSO is not only a differentiation reagent for various cells but also a powerful scavenger of oxygen radicals, In the present study, by using this culture system and the measurement of oxidative stress by the nitro blue tetrazolium (NBT) formazan assay, we have examined the effect of oxygen radical scavengers such as DMSO, dimethylthiourea (DMTU) and alpha-tocopherol on the expression of both Cxs and on gap junctional intercellular communication (GJIC), as compared to another differentiation reagent, hexamethylene-bis-acetamide (HMBA), DMSO and DMTU clearly inhibited the oxidative stress of the cultured hepatocytes, while alpha-tocopherol and HMBA did not, The expression of Cx26 and Cx32 in the cultured hepatocytes was markedly induced by DMSO and DMTU, Furthermore, extensive GJIC was also observed with DMSO and DMTU, These results suggest that the expression of gap junctions in the hepatocytes may be closely related to oxidative stress and that oxygen radical scavengers may be important substances in inducing this expression.

GROWTH AND MATURATION OF SMALL HEPATOCYTES ISOLATED FROM ADULT-RAT LIVER

T MITAKA, T KOJIMA, T MIZUGUCHI, Y MOCHIZUKI

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS ( ACADEMIC PRESS INC JNL-COMP SUBSCRIPTIONS ) 214 ( 2 ) 310 - 317 1995年09月 [査読有り]

Small hepatocytes existed in the supernatant following low-speed centrifugation of the cell suspension after collagenase liver perfusion. The cells proliferated for more than 2 months and formed colonies in the Dulbecco's modified Eagle's medium supplemented with 10 mM nicotinamide, 10% fetal bovine serum, 1 mM ascorbic 2-phosphate, and 10 ng/ml epidermal growth factor. One small cell finally proliferated to several hundred cells. In addition, some cells in the colonies were shown to differentiate into mature hepatocytes that had a large cytoplasm and sometimes two nuclei. The secretion of albumin in the medium by the hepatocytes increased with time in culture, and the cells possessed connexin 32 in their cell membrane and many peroxisomes. Thus, the small hepatocytes may be ''committed progenitor cells'' which can further differentiate into mature hepatocytes. (C) 1995 Academic Press. Inc.

　前のページ - 次のページ　

<水口 徹>

論文 - 水口 徹

<水口　徹>

論文 - 水口　徹