Shinji Tanaka, Mitsuo Shimada, Ken Shirabe, Shin-ichiro Maehara, Eiji Tsujita, Akinobu Taketomi and Yoshihiko Maehara : Surgical outcome of patients with hepatocellular carcinoma originating in the caudate lobe, Sep. 2005.
(Summary)
Hepatocellular carcinoma (HCC) originating in the caudate lobe is rare, and the treatment for this type of carcinoma is difficult because of its unique anatomic location. This retrospective study assessed the surgical outcome of patients with caudate lobe HCC. There were 20 cases of HCC originating in the caudate lobe among 435 patients with primary HCC who underwent hepatic resection in our department from 1990 to 2002. The caudate tumors were located in the Spiegel lobe in 3 patients, the paracaval portion in 15 patients, and the caudate process in 2 patients. Surgical procedures consisted of limited resection of the caudate lobe in 6 patients and extended caudate lobectomy in 14 patients. Recurrence was recognized in 12 patients, including 8 patients with multiple intrahepatic recurrences, 1 with peritoneal dissemination, and 1 with lymph node metastasis. There was no significant difference in postoperative survival rate between patients who underwent limited resection of the caudate lobe and those who underwent extended caudate lobectomy. Compared with 415 patients with HCC originating in other locations, the 20 patients with caudate lobe HCC showed significantly more intraoperative blood loss (P<.05), longer operation time (P<.0001), and more postoperative complications (P<.005). Intrahepatic recurrence was more frequent in the caudate lobe HCC compared with HCC originating in other locations (40% vs 17.6%; P<.05). There was a significantly poor survival rate in the postoperative patients with caudate HCC (25.9% vs 54.1% for five-year survival; P=.01). Intrahepatic multiple recurrences were frequently recognized in the patients with caudate lobe HCC, indicating no significance for extended caudate lobectomy. Because of the relatively poor prognosis in patients with caudate lobe HCC, adjuvant therapy combined with surgical operation should be considered.
K Nomoto, Takashi Nishizaki, Mitsuo Shimada, S Okano, Ryosuke Minagawa and Keizo Sugimachi : Extended lobectomy for procurement of the left lobe with caudate lobe for living-related liver transplantation, Jul. 2005.
(Summary)
Liver transplantation from living-related donors has been established for end-stage liver disease. In adult cases, the left lobe with a caudate lobe was transplanted in order to increase the graft volume. However, the procurement operation should be less invasive for the donor. In this article, we represent our technique by which the blood loss can be reduced during the harvesting operation. The technique was used to improve the extended left lobectomy for the procurement in 27 patients between May 1997 and December 1999 at Kyushu University Hospital. The groups included the following: 1) Procurement operation of the extended left lobe with caudate (n=9), 2) without caudate (n=18). The detailed record during the operation showed that the mean blood loss and the amount for the group with caudate was significantly smaller than that in the group without caudate. To reduce the blood loss during the procurement operation, we continue to use this technique in the living-related donors for adult recipients.
Shinji Tanaka, Mitsuo Shimada, Ken Shirabe, Shin-ichiro Maehara, Norifumi Harimoto, Eiji Tsujita, Keizo Sugimachi and Yoshihiko Maehara : A novel intrahepatic arterial chemotherapy after radical resection for advanced hepatocellular carcinoma, May 2005.
(Summary)
Advanced hepatocellular carcinoma (HCC) with portal vein invasion and/or intrahepatic metastasis has an unfavorable prognosis even after radical hepatic resection. The aim of this study was to evaluate the effectiveness of a novel postoperative adjuvant chemotherapy given through the hepatic artery and based on biochemical modulation using cisplatin (CDDP) and 5-fluorouracil (5-FU). Fifteen patients with advanced HCC with portal vein invasion into the main trunk and/or intrahepatic metastases of more than 3 segments were included in this study. After radical hepatic resection, the patients were divided to two groups: the adjuvant chemotherapy group (n=7) given the novel arterial infusion regimen with CDDP and 5-FU, and the control group (n=8) given no adjuvant chemotherapy. Three-year survival rate of the adjuvant chemotherapy group tended to be significantly longer compared to that for the control group (p < 0.05). Most of the tumor recurrence was in the remnant liver, 5 cases in both of the groups. Significant difference of the recurrence patterns was recognized, rather than difference of the disease-free survival rate between the two groups. All of the intrahepatic recurrences are multiple in the control group, but in the adjuvant chemotherapy group, 2 cases of the recurrences showed a localized tumor surgically resected. It is noteworthy that the occurrence of multiple recurrence was significantly later in the adjuvant chemotherapy group compared to the control group (18.9 months vs. 6.5 months; p<0.05). Our data suggest that this novel adjuvant chemotherapy can improve the postoperative prognosis of patients with the advanced HCC.
Akihiro Nishie, Kengo Yoshimitsu, Yoshiki Asayama, Hiroyuki Irie, Hitoshi Aibe, Tsuyoshi Tajima, Kenji Shinozaki, Tomohiro Nakayama, Daisuke Kakihara, Mitsuo Shimada, Shin-ichi Aishima, Kisaku Yoshida and Hiroshi Honda : Detection of combined hepatocellular and cholangiocarcinomas on enhanced CT: comparison with histologic findings, American Roentgen Ray Society, Apr. 2005.
12.
Norifumi Harimoto, Akinobu Taketomi, Dai Kitagawa, Yousuke Kuroda, Shinji Itoh, Tomonobu Gion, Shinji Tanaka, Ken Shirabe, Mitsuo Shimada and Yoshihiko Maehara : The newly established human hepatocyte cell line: application for the bioartificial liver, European Association for the Study of the Liver, Apr. 2005.
(Summary)
Human hepatocyte cell lines are reported to lose many of their biochemical functions in a hybrid artificial liver support system (HALSS). Differentiation therapy is useful to up-regulate liver function. The human hepatoblastoma cell line HepG2 was transfected with HSV/tk gene. Albumin synthesis and ammonia removal activity were evaluated when HepG2/tk was cultured with histone deacetylase inhibitor (FR228) and peroxisome proliferator activated receptor-gamma ligand (pioglitazone). To investigate the function of HepG2/tk in vivo, cell transplantation for 90% hepatectonized rats was conducted. We established stable cell lines which expressed HSV/tk and were sensitive to gancyclovir in vitro and in vivo. Both albumin synthesis rate and ammonia removal rate improved for HepG2/tk incubated with FR228 and pioglitazone for 3 days, which induced nuclear transport of p21. Rats with intrasplenic injection of HepG2/tk precultured for 3 days with FR228 and pioglitazone survived significantly longer than the control rats. The ammonia and total bilirubin concentrations were significantly lower in the test group than in the control group. The injection of gancyclovir inhibited the prolonged survival of the rats with precultured HepG2/tk. HepG2/tk is safe as well as enhancing high levels of liver function. It will be a potential cell source for HALLS in the future.
Takashi Maeda, Mitsuo Shimada, Norifumi Harimoto, Eiji Tsujita, Shin-ichiro Maehara, Tatsuya Rikimaru, Shinji Tanaka, Ken Shirabe and Yoshihiko Maehara : Role of tissue trace elements in liver cancers and non-cancerous liver parenchyma, H.G.E. Update Medical Publishing, Jan. 2005.
(Summary)
The role of trace elements in liver fibrosis, carcinogenesis and progression of hepatocellular carcinoma (HCC) has not yet been clarified. The aim of this study is to analyze the characteristics of trace elements in liver cancers and non-cancerous liver and to discuss their role in hepatic fibrosis, hepatocarcinogenesis and progression of HCC. The amount of zinc (Zn), iron (Fe), and copper (Cu) in 20 HCCs, 2 cholangiocellular carcinomas (CCC), 7 metastatic liver cancers (Meta) and their non-tumorous liver parenchyma were measured using an atomic absorption spectrophotometer. The amounts of Zn and Fe in non-tumorous liver parenchyma were reduced by liver fibrosis, and the amounts were lower in HCC tissue compared to non-tumorous liver parenchyma. The amounts of Zn and Cu were higher in HCC than the amounts found in CCC and Meta. The amount of Zn in HCC tissue decreased, but the amount of Fe increased in tumors more than 4cm in diameter. These results suggest that the decrease in the amount of Zn and Fe found in non-tumorous liver parenchyma correlates with liver fibrosis leading to cirrhosis and hepatocarcinogenesis. Also that decreases in Zn and increases of Fe in HCC tissue correlates with HCC tumor progression.
Tsuyoshi Tajima, Kengo Yoshimitsu, Hiroyuki Irie, Hitoshi Aibe, Kenji Shinozaki, Akihiro Nishie, Hiroshi Honda and Mitsuo Shimada : Detecting postsurgical recurrent hepatocellular carcinoma with multiphasic helical computed tomography: intrahepatic metastasis or multicentric occurrence?, Lippincott Williams & Wilkins, Jan. 2005.
(Summary)
The aim of this study was to assess the computed tomography (CT) patterns of postoperative recurrent hepatocellular carcinoma (HCC). Of 84 patients with histologically proven HCC by hepatectomies, multiphasic helical CT demonstrated 54 HCC lesions of intrahepatic recurrence in 31 (37%) patients. The initial and final appearances of HCC on hepatic arterial phase images were retrospectively determined by the serial CT scans, which were compared with appearances of primary HCC. The initial appearances of 54 recurrent HCCs were identical to the appearances of primary HCC in 41 (76%) lesions. Serial changes from the initial appearance to the final appearance of recurrent HCC were observed in 10 (42%) of 24 lesions. The 13 discordant lesions and the 10 lesions with altered lesion vascularity in our series implied that at least 43% were of multicentric occurrence. More than 40% of postoperative recurrent HCCs show intranodular hemodynamic changes. The incompatibility between CT findings of primary and recurrent HCCs implies that these tumors contain nodules of multicentric occurrence.
Shin-ichiro Maehara, Shinji Tanaka, Mitsuo Shimada, Ken Shirabe, Yoshiro Saito, Kazuhiko Takahashi and Yoshihiko Maehara : Selenoprotein P, as a predictor for evaluating gemcitabine resistance in human pancreatic cancer cells, John Wiley & Sons, Inc., Nov. 2004.
(Summary)
Gemcitabine is a new standard chemotherapeutic agent used in the treatment of pancreatic cancer, but the mechanisms of gemcitabine sensitivity are still controversial. In our study to determine a mechanism that regulates gemcitabine sensitivity, we carried out molecular analysis on the susceptibility of the pancreatic cancer cells. Using a gemcitabine-sensitive pancreatic cancer cell line KLM1, we established a resistant cell line KLM1-R exhibiting a 20-fold IC50-value (the concentration of gemcitabine causing 50% growth inhibition). Microarray analysis of genes showed specific expression of selenoprotein P, one of the anti-oxidants, in the KLM1-R cell line but not in the KLM1 cell line. Administration of selenoprotein P inhibited the gemcitabine-induced cytotoxicity in the pancreatic cell lines. The levels of intracellular reactive oxygen species (ROS) were increased in the KLM1 cells by gemcitabine, but selenoprotein P suppressed the gemcitabine-induced ROS levels. Furthermore interferon-gamma suppressed the expression of selenoprotein P mRNA and increased intracellular ROS level, leading to the recovery of the gemcitabine sensitivity in KLM1-R. These results suggest a novel mechanism that selenoprotein P reduces the intracellular ROS levels, resulting in the insusceptibility to gemcitabine.
Taketoshi Suehiro, Takashi Matsumata, Yasunori Shikada, Mitsuo Shimada, Ken Shirabe and Keizo Sugimachi : Change in alpha glutathione s-transferase levels during liver resection, H.G.E. Update Medical Publishing, Nov. 2004.
(Summary)
Alpha-glutathione s-transferase (GST) is a 50,000-kDa cytosol protein of the hepatocytes. It comprises 5% of the soluble protein of hepatocytes and is readily released in response to injury. Its half-life time is 60 minutes (AST: 47 hrs, ALT: 22 hrs). The aim of this study is to clarify the usefulness of GST measurement during liver resection. We obtained data from 26 patients undergoing liver resection and compared GST levels with AST and ALT levels. Patients included 15 hepatocellular carcinoma, 5 cholangiocellular carcinoma and 6 metastatic cancers (4: colon, 2: stomach). We performed lobectomy for 11, segmentectomy for 5 and partial resection for 10 patients. From these patients, blood samples were collected before surgery, beginning of resection, end of resection, 15, 30, 60 min after resection, end of surgery, 1, 3, 6, 12, 24 hr after operation and 2, 3, 4, 5, 6, 7, 10, 14 postoperative days (POD). GST (Biotrin, Ireland) levels in the serum samples were determined by an ELISA. We also measured AST, ALT levels from the same set of samples. At the end of resection, GST showed highest level and quickly decreased at 1 hr after operation. On the other hand, AST and ALT showed peak levels at 12 hr after operation. Our findings suggest that perioperative GST measurement may be a sensitive and useful marker to evaluate liver function after liver resection.
Taketoshi Suehiro, Takashi Matsumata, Yasunori Shikada, Mitsuo Shimada, Ken Shirabe and Keizo Sugimachi : Preoperative hyaluronic acid measurement to assess the hepatic functional reserve, H.G.E. Update Medical Publishing, Nov. 2004.
(Summary)
With liver surgery, preoperative assessment of the hepatic functional reserve is important for estimating the extent of hepatectomy. Hyaluronic acid (HA) is specifically cleared and metabolized by endothelial cells in the liver. Its half-life time is 2-5 min and HA might be a sensitive liver function marker. We obtained data from 44 patients with liver tumor undergoing liver resection. We studied 44 liver resected patients. Blood samples were obtained before surgery and HA levels and other liver function markers [type IV collagen (IV), procollagen-III-peptide (PIIIP), lecithin-cholesterol acyltransferase (LCAT), cholinesterase (ChE), albumin (Alb), platelets (Plt), prothrombin time (PT%)] levels in the samples were measured. We also performed indocyanine green retention test and calculate R15% (ICG). HA showed strong positive correlation with ICG, IV and PIIIP, negative correlation with LCAT, ChE, Alb, Plt and PT%. ICG was not correlated with ChE, Plt and PT%. The HA levels and ICG of the patients who had more than 2 segments of the liver resected were below 100 ng/mL and 20%, respectively. In the patients with obstructive jaundice HA levels of the 3 patients with obstructive jaundice who underwent bisegmentectomy were below 100 ng/mL. Our findings suggest that HA is a useful preoperative liver function test as well as ICGR15%. Preoperative HA levels <100 ng/mL and ICGR15% <20% might be helpful indicators for major liver resection. We also recommend that HA measurement for evaluating liver function in the patients with obstructive jaundice ICG is not helpful.
(Keyword)
Adult / Aged / Aged, 80 and over / Biomarkers, Tumor / Cohort Studies / Female / Hepatectomy / Humans / Hyaluronic Acid / Liver Function Tests / Liver Neoplasms / Liver Regeneration / Male / Middle Aged / Neoplasm Staging / Postoperative Complications / Preoperative Care / Probability / Prognosis / Risk Assessment / Sensitivity and Specificity / Statistics, Nonparametric / Survival Analysis / Treatment Outcome
(Link to Search Site for Scientific Articles)
● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 15532824
Ryosuke Minagawa, Shinji Okano, Yukihiro Tomita, Kenji Kishihara, Hisakata Yamada, Kenichi Nomoto, Mitsuo Shimada, Yoshihiko Maehara, Keizo Sugimachi, Yasunobu Yoshikai and Kikuo Nomoto : The critical role of Fas-Fas ligand interaction in donor-specific transfusion-induced tolerance to H-Y antigen, Lippincott Williams & Wilkins, Sep. 2004.
(Summary)
Donor-specific transfusion (DST) has been clinically used to enhance the survival of transplanted organs, and it has been shown in mice to induce tolerance to male (H-Y) antigen (Ag). Although the biologic mechanisms that initiate and maintain DST-induced tolerance involve clonal deletion, induction of anergy, and generation of regulatory cells, the molecules essential to tolerance induction are still unclear. In this study, we investigated the role of Fas-FasL interaction in DST-induced tolerance to H-Y Ag. C57BL/6 (B6) or B6-Fas(lpr) (lpr) female mice were intravenously injected with B6, lpr, or B6-FasL(gld) (gld) male spleen cells (SC). B6 male skin grafts, mixed lymphocyte reaction (MLR) assay, and cytotoxicity assay (CTL) were performed 7 days after DST. In some experiments, purified B-cells were used as transfused cells. B6 female mice treated with B6 male SC permanently accepted B6 male skins, whereas untreated B6 or lpr female mice rejected B6 male skins. On the other hand, B6 female mice treated with gld male SC acceleratingly rejected male skin, as did lpr female mice treated with B6 or gld male SC. The recipient mice in the experimental groups, in which DST resulted in the accelerated rejection of the skin grafts, had strong allo-responses to H-Y Ag in MLR and CTL. Further, B6 female mice treated with gld male B-cells acceleratingly rejected male skins, whereas B6 female mice treated with B6 or lpr male B-cells from mice accepted male skins. These findings suggest that the interaction between FasL upon infused SC, especially upon B-cells and Fas in a recipient, is essential in DST-induced tolerance to H-Y Ag.
Takashi Maeda, Ken-ichi Taguchi, Shin-ichi Aishima, Mitsuo Shimada, Deborah Hintz, Nicholas Larusso, Gores Gores, Masazumi Tsuneyoshi, Keigo Sugimachi, Jack R. Wands and Suzanne M. de la Monte : Clinicopathological correlates of aspartyl (asparaginyl) beta-hydroxylase over-expression in cholangiocarcinoma, International Society for Preventive Oncology (ISPO), Sep. 2004.
(Summary)
Aspartyl (asparaginyl) beta-hydroxylase (AAH) expression in surgically resected intrahepatic cholangiocarcinoma significantly correlated with tumor size, growth type, differentiation, vascular invasion, and prognosis after surgery. AAH may have a role in regulating invasive or metastatic tumor cell growth of human intrahepatic cholangiocarcinoma. Recent studies demonstrated increased expression of the AAH gene in the majority of cholangiocarcinomas. The present study was undertaken to determine the relationship between high or low levels of AAH expression and the clinical course of intrahepatic cholangiocarcinoma (ICC). AAH expression was examined in 50 surgically resected primary ICCs, 12 samples of normal liver, and 12 cases of primary sclerosing cholangitis (PSC). The sections were evaluated by immunohistochemical staining with the FB-50 monoclonal antibody to human AAH protein. The sections were examined under code and graded for relative levels of AAH immunoreactivity. The results were analyzed with respect to multiple clinical and histopathological variables to determine correlates of AAH expression in ICCs. Forty-six of the 50 (92%) ICCs had AAH immunoreactivity, whereas the 12 normal liver and 12 PSC specimens were AAH negative. In the ICC specimens, the highest levels of AAH immunoreactivity were detected at the infiltrating margins that interfaced with uninvolved liver tissue, and the lowest levels occurred in the central portions of the tumors. Multivariate analysis demonstrated that high levels of AAH expression were correlated with tumor size (P < 0.05), infiltrative growth pattern (P < 0.01), aggressive histological grade (P < 0.01), vascular invasion (P < 0.05), and poor prognosis (P < 0.05). These findings suggest that AAH has an important role in regulating invasive or metastatic tumor cell growth of human ICC, and that high levels of AAH expression correlate with poor prognosis.
Kenji Shinozaki, Kengo Yoshimitsu, Hiroyuki Irie, Hitoshi Aibe, Tsuyoshi Tajima, Akihiro Nishie, Tomohiro Nakayama, Daisuke Kakihara, Mitsuo Shimada and Hiroshi Honda : Comparison of test-injection method and fixed-time method for depiction of hepatocellular carcinoma using dynamic steady-state free precession magnetic resonance imaging, Lippincott Williams & Wilkins, Sep. 2004.
(Summary)
The purpose of this study was to clarify the usefulness of the test-injection method as compared with the fixed-time method in dynamic magnetic resonance (MR) imaging of hepatocellular carcinoma (HCC). Ninety-seven patients with a total of 118 hepatocellular carcinomas underwent 3-dimensional fast imaging with steady-state free precession (3D-FISP) for dynamic study of the liver as well as catheter-assisted computed tomography hepatic angiography (CTHA) for preoperative evaluation. In 42 cases, the fixed-time method (30-second scan time delay in the hepatic arterial phase [HAP]) was performed (group 1), and in 55 cases, the test-injection method was performed (group 2). The following parameters were evaluated: 1) the adequacy of the HAP, 2) tumor vascularity using CTHA findings as a gold standard, and 3) the contrast-to-noise ratio (CNR) of the HCC during the HAP of dynamic MR imaging. In group 1, 79% (33 of 42) of the cases were obtained at the optimal HAP; the percentage in group 2 was 98% (54 of 55) of the cases. This difference was statistically significant (P < 0.05). The vascularity of 82% of the tumors in group 1 and 89% of those in group 2 was diagnosed correctly. Regarding hypervascular tumors, correct evaluation of tumor vascularity was made in 87% of group 1 cases and 95% of group 2 cases. No significant difference was present between the 2 groups (total: P = 0.43, hypervascular HCC: P = 0.29). 3) The CNR calculated for all HCCs in group 2 (mean +/- SD: 8.66 +/- 11.0) was significantly higher than that for HCCs in group 1 (4.29 +/- 9.44; P < 0.05). As for the hypervascular tumors, the CNR calculated for group 2 (mean +/- SD: 9.89 +/- 10.6) was also significantly higher than that for group 1 (5.52 +/- 9.81; P < 0.05). The 3D-FISP dynamic MR imaging using the test-injection method resulted in better demonstration of HCC than the 3D-FISP using the fixed-time method.
Yo-ichi Yamashita, Mitsuo Shimada, Ryosuke Minagawa, Eiji Tsujita, Norifumi Harimoto, Shinji Tanaka, Ken Shirabe, Jun-ichi Miyazaki and Yoshihiko Maehara : Muscle-targeted interleukin-12 gene therapy of orthotopic hepatocellular carcinoma in mice using in vivo electrosonoporation, American Association for Cancer Research, Sep. 2004.
(Summary)
We developed a new potent nonviral gene transfer method into mouse muscles in vivo named "electrosonoporation." We tried in this report to treat murine orthotopic hepatocellular carcinoma (HCC) by muscle-targeted mouse interleukin-12 (mIL-12) gene transfer using in vivo electrosonoporation. I.m. administration of the mIL-12 gene with electrosonoporation elevated serum IL-12 and IFN-gamma and significantly prolonged the survival periods with both growth inhibition of orthotopic HCC and inhibition of spontaneous lung metastasis. The IL-12 gene therapy reduced the number of microvessels and induced more Mac-1-positive cells into HCC. These results show that muscle-targeted mIL-12 gene therapy for orthotopic HCC using in vivo electrosonoporation is very efficient and is thus promising for further clinical trial.
Shinichi Aishima, Shuji Matsuura, Takahiro Terashi, Kenichi Taguchi, Mitsuo Shimada, Yoshihiko Maehara and Masazumi Tsuneyoshi : Aberrant expression of laminin gamma 2 chain and its prognostic significance in intrahepatic cholangiocarcinoma according to growth morphology, United States and Canadian Academy of Pathology, Aug. 2004.
(Summary)
Laminin gamma 2 chain is an extracellular matrix protein that plays an important role in cell migration and tumor invasion. We report altered expression and characteristic localization of this chain in a series of 105 cases of intrahepatic cholangiocarcinomas examined immunohistochemically. All tumors were grossly classified into the following three types: intraductal growth type (n=9), periductal infiltrating type (n=8) and mass-forming type (n=88). The tumors exhibited three distinct staining types: basement membrane staining, cytoplasmic staining and stromal staining. The basement membranous staining of laminin gamma 2 chain was more frequent in biliary dysplasia, intraductal growth and periductal infiltrating type than in mass-forming type. The cytoplasmic staining of carcinoma cells was observed especially at the cancer-stromal interface or at the invasive front of tumors. Stromal staining of laminin gamma 2 chain was essentially localized in the stroma around cancer cells at the invasive area, and the expression was significantly correlated with tumor aggressive factors and a poor prognosis in patients with intrahepatic cholangiocarcinoma. We conclude that laminin gamma 2 chain exhibits aberrant expression in a stepwise manner through different aggressive stages of tumor progression.
Norifumi Harimoto, Mitsuo Shimada, Shin-ichi Aishima, Dai Kitagawa, Shinji Itoh, Eiji Tsujita, Shin-ichiro Maehara, Akinobu Taketomi, Shinji Tanaka, Ken Shirabe and Yoshihiko Maehara : The role of heat shock protein 27 expression in hepatocellular carcinoma in Japan: special reference to the difference between hepatitis B and C, International Association for the Study of the Liver, Aug. 2004.
(Summary)
A recent report showed that heat shock protein (HSP)-27 expression was related to histological grade and survival of patients with hepatocellular carcinoma (HCC). The aim of this study was to examine the effect of expression of HSP-27 on clinicopathological variables in Japanese patients with HCC. An immunohistochemical study for HSP-27 was performed on 60 HCC cases using a monoclonal anti-HSP-27 antibody. We divided 60 patients into two groups, patients with a low expression of HSP-27 (n = 34) and those with a high expression of HSP-27 (n = 26). Forty patients tested positive for the hepatitis C virus (HCV) antibody and 20 tested positive for the hepatitis B surface antigen. There appeared to be no relationship between HSP expression and clinicopathologic factors and no differences were observed between the high expression group and the low expression group. In the hepatitis B virus (HBV) group (n = 20), HSP-27 expression correlated significantly with prognosis, disease-free survival (DFS) and overall survival. High expression was significantly associated with poor prognosis in the HBV group. In contrast, patients with a high expression tended to have a good prognosis in the HCV group (n = 40): DFS and overall survival. This study showed the possibility that HSP-27 plays different roles in HBV- and HCV-associated HCCs.
(Keyword)
heat shock protein 27 / hepatitis virus / hepatocellular carcinoma
Akira Hirao, Masao Yamasaki, Hitomi Chujo, Nami Koyanagi, Hiroaki Kanouchi, Shin Yasuda, Aya Matsuo, Eri Nishida, Tatsuya Rikimaru, Eiji Tsujita, Mitsuo Shimada, Yoshihiko Maehara, Hirofumi Tachibana and Koji Yamada : Effect of dietary conjugated linoleic acid on liver regeneration after a partial hepatectomy in rats, The Vitamin Society of Japan, Feb. 2004.
(Summary)
We examined the effect of dietary conjugated linoleic acid (CLA) on liver regeneration after a partial hepatectomy (PH) in Sprague-Dawley rats. PH was performed on rats fed a 0 or 1 wt.% CLA diet for 3 wk. Average liver weight in the CLA fed rat population was heavier than the control rat population at the time of PH and 1-d after PH. Conversely. CLA fed rats' liver weight was significantly lower than control rats at 7-d after PH. This suggests that dietary CLA reduced liver weight gain after PH. Dietary CLA did not affect serum aspartate aminotransferase (AST) or alanine aminotransferase (ALT) activities. However. CLA significantly reduced serum albumin levels at 1-d but not at 7-d after PH. 5-Bromo- and 5-iododeoxyuridine incorporation into hepatocytes 1-d post PH was lower in the CLA group. In conclusion, the data suggests that dietary CLA inhibits DNA synthesis after PH, which results in hepatocyte proliferation inhibition.
Takahiro Terashi, Shinichi Aishima, Kenichi Taguchi, Yoshiki Asayama, Keishi Sugimachi, Shuji Matsuura, Mitsuo Shimada, Shinichiro Maehara, Yoshihiko Maehara and Masazumi Tsuneyoshi : Decreased expression of osteopontin is related to tumor aggressiveness and clinical outcome of intrahepatic cholangiocarcinoma, International Association for the Study of the Liver, Feb. 2004.
Mitsuo Shimada : コンセンサス2004 肝疾患 治療, Arcmedium, Tokyo, Feb. 2004.
27.
Mitsuo Shimada, Yo-ichi Yamashita, Shinji Tanaka, Ken Shirabe, Kohji Nakazawa, Hiroyuki Ijima, Ryoichi Sakiyama, Junji Fukuda, Kazumori Funatsu and Keizo Sugimachi : Characteristic Gene Expression Induced by Polyurethane Foam/Spheroid Culture of Hepatoma Cell Line, Hep G2 as A Promising Cell Source for Bioartificial Liver, 2004.
28.
Yo-ichi Yamashita, Mitsuo Shimada, Norifumi Harimoto, Shinji Tanaka, Ken Shirabe, Hiroyuki Ijima, Kohji Nakazawa, Junji Fukuda, Kazumori Funatsu and Yoshihiko Maehara : cDNA microarray analysis in hepatocyte differentiation in Huh 7 cells, Cognizant Communication Corporation, 2004.
(Summary)
The risk of xenozoonosis infections poses the greatest obstacle against the clinical application of a hybrid artificial liver support system (HALSS). Primary human hepatocytes are an ideal source for HALSS, but the shortage of human livers available for hepatocyte isolation limits this modality. To resolve this issue, we previously demonstrated the upregulation of hepatocyte-specific function by spheroid formation in polyurethane foam and by culturing with the histone deacetylase inhibitor, trichostatin A (TSA), in a human hepatoma cell line (Huh 7). In this article we analyze the gene expression profile using cDNA microarray (1281 genes) in spheroid formation or culturing with TSA in Huh 7 to determine the target genes in hepatocyte differentiation. In both the spheroid formation and in the culture with TSA, the Oct-3/4 transcription factor was upregulated more thantwofold, while the early growth response-1 (EGR-1) transactivator was downregulated less than 0.5-fold. These results indicate that expressions of Oct-3/4 and EGR-1 may be key factors in the induction of hepatocyte differentiation in Huh 7.
(Keyword)
cDNA microarray / Hepatocyte differentiation / Hybrid artificial liver support system (HALSS)
Shunji Taniguchi, Yasushi Mochida, Takeshi Uchiumi, Tomoko Tahira, Kenshi Hayashi, Koichi Takagi, Mitsuo Shimada, Yoshihiko Maehara, Hiroyuki Kuwano, Suminori Kono, Hitoo Nakano, Michihiko Kuwano and Morimasa Wada : Genetic polymorphism at the 5' regulatory region of multidrug resistance 1 (MDR1) and its association with interindividual variation of expression level in the colon, American Association for Cancer Research, Dec. 2003.
(Summary)
The multidrug resistance 1 (MDR1) is a key molecule in determining not only the resistance of cancer cells to anticancer agents but also the disposition of a variety of drugs in intestinal and other tissues. However, the mechanism underlying interindividual variations in levels of MDR1 activity and expression in various tissues remains unclear. We analyzed the nucleotide sequence polymorphisms in the 5' upstream regulatory region of the gene spanning 4 kb from the transcriptional start site of MDR1 and tried to identify any associations between polymorphisms and MDR1 expression. Within that region, we identified eight single nucleotide polymorphisms (SNPs) in the region in the Japanese population. Of the SNPs identified, -2410T>C, -1910T>C, and 692T>C were in perfect linkage disequilibrium. In normal colorectal mucosa, diplotypes at the region showed more significant association with the expression level of MDR1 mRNA than each SNP did. In an in vitro reporter assay, transcription activity of the minor-type construct carrying haplotypes 2 and 3 was significantly lower than that of the major-type construct carrying haplotype 1. We next identified two DNA binding proteins: one protein bound to the nucleotide sequence carrying -692T but not to that carrying -692C and another bound to the nucleotide sequence carrying -2352G but three times weaker than that carrying -2352A. This suggested the significance of SNP at -692 and -2352 of MDR1 in variable expression in the colon interindividually. This is the first report connecting SNPs and interindividual variety of MDR1 expression rationally.
Keizo Sugimachi, Shinji Tanaka, Kenichi Taguchi, Shinichi Aishima, Mitsuo Shimada and Masazumi Tsuneyoshi : Angiopoietin switching regulates angiogenesis and progression of human hepatocellular carcinoma, BMJ Publishing Group Ltd & Association of Clinical Pathologists, Nov. 2003.
(Summary)
Aim: Angiopoietin 1 (Ang-1) and its antagonist, angiopoietin 2 (Ang-2), are novel ligands that regulate the Tie2 receptor. The Ang-2 gene is upregulated in the hypervascular type of human hepatocellular carcinoma (HCC). To gain a better understanding of the role of the Ang-Tie2 system in HCC the expression of these genes was investigated in a series of human HCCs. The expression of the angiopoietin and Tie2 proteins was investigated in nine normal liver tissues and 52 surgically resected HCCs. In addition, the effects of hypoxic stimuli on Ang-1, Ang-2, vascular endothelial growth factor (VEGF), and erythropoietin (EPO) expression was investigated in Hep3B cells. Ang-1, rather than Ang-2, was more frequently expressed in the normal liver. Ang-1 was expressed in 68% of HCCs, whereas Ang-2 was expressed in 81%, and was significantly higher in poorly differentiated HCCs characterised by high vascularity (p = 0.02), and in tumours with a peliotic change (p = 0.02). Strong expression of Tie2 was seen in tumour vessels in accordance with Ang-2 expression. In Hep3B cells, hypoxic stimuli upregulated VEGF and EPO, but not Ang-1 or Ang-2. These data support the evidence that the reversal of Ang-1 and Ang-2 expression plays an important role in the angiogenic and dedifferentiation processes in HCC. The hypoxic stimuli were not responsible for Ang-2 upregulation, unlike that of VEGF, in human HCC cells.
Mizuki Ninomiya, Noboru Harada, Satoko Shiotani, Shoji Hiroshige, Ryosuke Minagawa, Yuji Soejima, Taketoshi Suehiro, Takashi Nishizaki, Mitsuo Shimada and Keizo Sugimachi : Hepatocyte growth factor and transforming growth factor beta1 contribute to regeneration of small-for-size liver graft immediately after transplantation, Springer-Verlag, Berlin, Nov. 2003.
(Summary)
Although the ability of the liver to regenerate to a predetermined size after resection made adult-to-adult living donor liver transplantation (LDLT) possible, there is little information regarding the growth regulatory mechanism for a small-for-size graft. Forty-one cases of LDLT were divided into two groups by graft volume to standard liver volume ratio (GV/SLV); small graft group (Group S, GV/SLV<40%, n=16) and non-small graft group (Group NS, GV/SLV>40%, n=25). The regeneration rate (GV at 1 week/harvested GV) and serum levels of hepatocyte growth factor (HGF), transforming growth factor-alpha (TGF-alpha) and transforming growth factor-beta1 (TGF-beta1) were compared between two groups. The regeneration rates in Group S were significantly higher than that of Group NS (217+/-12% and 178+/-10%, respectively, P<0.01). The serum HGF levels of Group S were significantly higher than those of Group NS on POD 1. The TGF-beta1 levels of Group S were significantly higher than those of Group NS on POD 3 and 5. The TGF-alpha levels were not different at any time points studied. These results indicate that a small-for-size graft retains the capacity to regenerate faster by modulation of expression pattern of HGF and TGF-beta1 immediately after LDLT. After the acceleration of the regenerative response by HGF, subsequent elevation of TGF-beta1 synergistically controls graft size, regulating uncontrolled proliferation of hepatocytes.
Shin-ichi Aishima, Ken-ichi Taguchi, Takahiro Terashi, Shuji Matsuura, Mitsuo Shimada and Masazumi Tsuneyoshi : Tenascin expression at the invasive front is associated with poor prognosis in intrahepatic cholangiocarcinoma, United States and Canadian Academy of Pathology, Oct. 2003.
(Summary)
Tenascin and decorin are components of the extracellular matrix (ECM) that are implicated in cell proliferation in tumors. Here, we propose that abnormal expression of stromal ECM may play an important role in the progression of intrahepatic cholangiocarcinoma, which is characterized by desmoplastic reaction. To explore this hypothesis, we performed immunohistochemical analysis in order to examine the expression and distribution of tenascin and decorin in 75 cases of intrahepatic cholangiocarcinoma. In the intratumoral stroma, positive staining for tenascin was observed in 51 (68%) cases, and positive staining for decorin was observed in 61 (81%) cases. However, at the invasive front, positive staining for tenascin was found in 23 (31%) cases, and positive staining for decorin was found in 6 (8%) cases. Decorin staining was not correlated with aggressive behavior of intrahepatic cholangiocarcinoma, whereas intratumoral tenascin staining was correlated with lymphatic permeation and proliferative activity measured by Ki67. Tenascin staining at the invasive front was associated with tumor size, lymphatic permeation, lymph node metastasis, and proliferative activity and appeared to be a useful prognostic factor by univariate analysis, although it was not an independent prognostic factor. These results indicate that tenascin plays a role in tumor progression in cases of intrahepatic cholangiocarcinoma and that tenascin expression, especially at the invasive front, may be a useful marker in evaluating an unfavorable prognosis in patients with intrahepatic cholangiocarcinoma.
Tohru Utsunomiya, Mitsuo Shimada, Tatsuya Rikimaru, Hirofumi Hasegawa, Yoichi Yamashita, Takayuki Hamatsu, Masao Yamasaki, Shihoko Kaku, Koji Yamada and Keizo Sugimachi : Antioxidant and anti-inflammatory effects of a diet supplemented with sesamin on hepatic ischemia-reperfusion injury in rats, Thieme, Stuttgart, ALLEMAGNE, Sep. 2003.
34.
Ken Shirabe, Mitsuo Shimada, Takashi Matsumata, Hidefumi Higashi, Yohichi Yakeishi, Shigeki Wakiyama, Yasuharu Ikeda, Takuhiro Ezaki, Shingo Fukuzawa, Kenji Takenaka, Keishi Kishikawa, Tetsuo Ikeda, Ken-ichi Taguchi, Yoshihiko Maehara and Keizo Sugimachi : Analysis of the prognostic factors for liver metastasis of gastric cancer after hepatic resection: a multi-institutional study of the indications for resection, Thieme, Stuttgart, ALLEMAGNE, Sep. 2003.
35.
Kosei Moriyama, Kazuhiro Hayashida, Mitsuo Shimada, Shuji Nakano, Yoshiyuki Nakashima and Yasuyuki Fukumaki : Antisense RNAs transcribed from the upstream region of the precore/core promoter of hepatitis B virus, Society for General Microbiology, Jul. 2003.
(Summary)
The bidirectional activity of the precore/core promoter of hepatitis B virus (HBV) has been demonstrated in cultured cell lines. However, HBV antisense transcripts (asRNAs) have not been demonstrated in vivo. In the present study using liver tissue from patients with chronic hepatitis, an anchored 5'RACE mapping the 5' ends at position 1680/1681, 1655 or 1609/1602 was carried out. In limited cases, RLM-3'RACE detected asRNAs to terminate at four or five consecutive dT residues in the 0.7 kb downstream region. PCR of oligo(dT)-primed cDNA did not amplify a typical polyadenylated asRNA. RT-PCR using various primers did not detect any spliced forms. Competitive RT-PCR estimated the copy numbers of the asRNAs to be 0.05-0.4 % of total sense RNAs. All sequenced asRNAs had ORF6 but, in one patient, the asRNA initiating at position 1680/1681 had additional initiation and termination codons in front of ORF6. Therefore, asRNAs are transcribed by RNA polymerase III at a low level, encompass a dispensable ORF6 gene and might be retained in the nucleus. The endogenous asRNAs complementary to the common ends of all sense RNAs suggest antisense-mediated self-regulation of hepadnavirus.
(Keyword)
Base Sequence / Gene Expression Regulation, Viral / Hepatitis B Core Antigens / Hepatitis B virus / Hepatitis B, Chronic / Humans / Liver / Molecular Sequence Data / Promoter Regions, Genetic / Protein Precursors / RNA, Antisense / Trans-Activators / Transcription, Genetic / Viral Regulatory and Accessory Proteins
Takayuki Hamatsu, Tatsuya Rikimaru, Yo-ichi Yamashita, Shinichi Aishima, Shinji Tanaka, Ken Shirabe, Mitsuo Shimada, Yasushi Toh and Keizo Sugimachi : The role of MTA1 gene expression in human hepatocellular carcinoma, May 2003.
(Summary)
The MTA1 gene has been identified as metastasis-associated gene and has been seen to correlate with the degree of invasion and lymphatic metastasis in gastric, colorectal, and esophageal carcinomas. We investigated the possible role of MTA1 gene expression in hepatocellular carcinoma (HCC). The mRNA expression level of the MTA1 gene was examined using reverse transcription polymerase chain reaction (RT-PCR) in HCC and paired non-tumor liver tissues which were obtained from 33 patients who underwent curative hepatectomy. The expression level of each case was calculated as tumor/non-tumor (T/N) ratios. To clarify the clinical significance of MTA1 gene expression in HCC, patient disease-free survival rate after hepatectomy were univariately analyzed using 25 clinicopathological variables, including MTA1 expression level. High expression (T/N > or =1) of the MTA1 gene in HCC as compared to the paired non-tumor tissues was recognized in 14 of 33 (42%) samples. With regard to the differentiation of HCC, the high expression of MTA1 gene in well or moderately differentiated HCC and poorly differentiated HCC were observed in 9 of 27 (33%) and 5 of 6 (83%) samples, respectively. There was no relation between expression levels of the MTA1 gene and cancer invasion to the portal vein or intrahepatic metastasis. However, the disease-free survival rate of the MTA1-high expression group (T/N > or =1) was significantly lower than that of the MTA1-low expression group (T/N <1) (p<0.05). High expression of the MTA1 gene is suggested to be a new prognostic indicator after curative hepatectomy for HCC.
Yo-ichi Yamashita, Mitsuo Shimada, Norifumi Harimoto, Tatsuya Rikimaru, Ken Shirabe, Shinji Tanaka and Keizo Sugimachi : Histone deacetylase inhibitor trichostatin A induces cell-cycle arrest/apoptosis and hepatocyte differentiation in human hepatoma cells, Wiley-Liss, Inc., Feb. 2003.
(Summary)
Remodeling of the chromatin template by inhibition of HDAC activities represents a potential transcriptional therapy for neoplastic disease. A number of HDAC inhibitors that modulate in vitro cell growth and differentiation have been developed. We analyzed the effects of TSA, a specific and potent HDAC inhibitor, on the human hepatoma cell lines HepG2 and Huh-7. TSA increased levels of acetylated histones H3 and H4 in both HepG2 and Huh-7. It inhibited cell proliferation in vitro and induced G(0)/G(1) arrest in HepG2 and apoptosis in Huh-7. Gene expression of liver-specific functions and liver-enriched transcription factors was upregulated by TSA. TSA upregulated the ammonia removal rate and the albumin synthesis rate of HepG2 and Huh-7. Our results indicate that TSA can induce cell-cycle arrest/apoptosis and hepatocyte differentiation in human liver cancer cell lines.
Takashi Maeda, Hidetoshi Itasaka, Kenji Takenaka, Takashi Matsumata, Mitsuo Shimada, Toshihiko Ikeda and Keizo Sugimachi : Low-dose cisplatin plis oral tegafur and uracil for the treatment of lung metastases of hepatocellular carcinoma, 2003.
41.
Junji Fukuda, Ken Okamura, Kohji Nakazawa, Hiroyuki Ijima, Yo-ichi Yamashita, Mitsuo Shimada, Ken Shirabe, Eiji Tsujita, Keizo Sugimachi and Kazumori Funatsu : Efficacy of a polyurethane foam/spheroid artificial liver by using human hepatoblastoma cell line (Hep G2), Cognizant Communication Corporation, 2003.
(Keyword)
Hybrid artificial liver / Spheroids / Polyurethane foam / Hep G2 / Human primary hepatocytes / Porcine primary hepatocytes
42.
Mitsuo Shimada and 杉町 圭蔵 : A.肝 17. 肝細胞眼ー外科手術と集学的治療, Nankodo, Tokyo, 2003.
43.
Masao Yamasaki, Hitomi Chujo, Yasuko Koga, Ayana Oishi, Tatsuya Rikimaru, Mitsuo Shimada, Keizo Sugimachi, Hirofumi Tachibana and Koji Yamada : Potent cytotoxic effect of the trans10, cis12 isomer of conjugated linoleic acid on rat hepatoma dRLh-84 cells, Elsevier Science, Ireland, Dec. 2002.
Masao Yamasaki, Atsushi Ikeda, Akira Hirao, Yoko Tanaka, Tatsuya Rikimaru, Mitsuo Shimada, Keizo Sugimachi, Hirofumi Tachibana and Koji Yamada : Dose-dependent effect of dietary conjugated linoleic acid on the growth of rat hepatoma dRLh-84 cells in vivo, The Japanese Society of Food & Nutrition and the Vitamin Society of Japan, Dec. 2002.
(Summary)
In this study, the effect of varying doses of conjugated linoleic acid (CLA) on the growth of transplanted hepatoma dRLh-84 cells and the relationship between tumor growth and prostaglandin (PG) E2 production or cyclooxygenase (COX)-2 expression were examined. Donryu rats were fed an experimental diet containing 0, 0.1, 0.5, or 2 wt.% CLA for 3 wk, and then dRLh-84 cells were transplanted into the liver. Results show that dietary CLA (0.5 and 2 wt.%) significantly enhanced the growth of the transplanted hepatoma cells compared to the non-CLA diet group at 20 d after cell transplantation. Tumor weight at 10 d after transplantation was also significantly higher in the 2 wt.% CLA group than in non-CLA fed rats. Ten days after transplantation, the PGE2 level in the tumor tissue was shown to be depressed in a CLA dose-dependent manner. Cyclooxygenase-2 (COX-2) mRNA expression in the tumor also tended to be lower in the CLA group than in the non-CLA diet group 10 d after transplantation. Dietary CLA did not affect the tumor phospholipid arachidonic acid level, which is a substrate for PG synthesis. These results indicate that dietary CLA of at least 0.5 wt.% enhances the growth of transplanted dRLh-84 cells in vivo. It is believed that growth promotion of dRLh-84 cells in vivo by CLA cannot be clarified by the PG synthesis dependent mechanism.
Shin-ichi Aishima, Yoshiki Asayama, Ken-ichi Taguchi, Keishi Sugimachi, Ken Shirabe, Mitsuo Shimada, Keizo Sugimachi and Masazumi Tsuneyoshi : The utility of keratin 903 as a new prognostic marker in mass-forming-type intrahepatic cholangiocarcinoma, the United States and Canadian Academy of Pathology,Inc, Nov. 2002.
Ichiro Yoshino, Makoto Hashizume, Mitsuo Shimada, Morimasa Tomikawa and Keizo Sugimachi : Video-assisted thoracoscopic extirpation of a posterior mediastinal mass using the da Vinci computer enhanced surgical system, The Society of Thoracic Surgeons, Oct. 2002.
(Summary)
A 28-year-old woman presented a left posterior mediastinal mass surrounded by the intercostal vein, hemiazygos vein, sympathetic nerve, and descending aorta. We successfully resected the mass, that was revealed to be a bronchogenic cyst, by a totally thoracoscopic procedure using the da Vinci computer-enhanced system (Intutive Surgical, Mountain View, CA) without injuring the neighboring structures or the capsule of the mass.
Mitsuo Shimada, 辻田 英司 and 杉町 圭蔵 : 最新消化器内視鏡治療 第2部 第14章, 先端医療技術研究所, Tokyo, Jul. 2002.
48.
Ken-ichi Taguchi, Yoshiki Asayama, Shin-ichi Aishima, Hidehiro Nishi, Keishi Sugimachi, Shuji Matsuura, Takahiro Terashi, Takeharu Yamanaka, Mitsuo Shimada, Keizo Sugimachi and Masazumi Tsuneyoshi : Morphologic approach to hepatocellular carcinoma development in man: de novo or the so-called 'dysplastic nodule-carcinoma' sequence?, D.A. Spandidos, Athens, Jul. 2002.
(Summary)
The so-called dysplastic nodule-carcinoma sequence in the liver is generally accepted because hepatocellular carcinoma is not an uncommon finding in precancerous lesions. In order to evaluate the existence and frequency of de novo hepatocarcinogenesis we studied 112 surgically resected early well-differentiated hepatocellular carcinomas showing replacing growth without less differentiated component in themselves. They were divided into two groups: carcinoma in dysplastic area (type A) and carcinoma without dysplastic area (type B) and were analyzed clinicopathologically. We encountered 77 cases of type A (68.8%) and 35 of type B (31.2%). The frequency of type A in cirrhotic group (74.7%) is statistically higher than that of non-cirrhotic group (54.5%) (p=0.0453). Using multivariate analysis, the occurrence of type A was related with higher age, the presence of cirrhosis and hepatitis B surface antigen positive. The tumor size and the presence of fatty change in the tumor tended to relate with type A. We propose two pathways morphologically in early hepatocarcinogenesis, one of which has a close relation to hepatitis B virus and/or cirrhosis.
Kenji Shinozaki, Hiroshi Honda, Kengo Yoshimitsu, Ken-ichi Taguchi, Toshiro Kuroiwa, Hiroyuki Irie, Hitoshi Aibe, Akihiro Nishie, Tomohiro Nakayama, Mitsuo Shimada and Kouji Masuda : Optimal multi-phase three-dimensional fast imaging with steady-state free precession dynamic MRI and its clinical application to the diagnosis of hepatocellular carcinoma, Medical Tribune Inc., May 2002.
(Summary)
To determine the appropriate acquisition parameters for three-dimensional fast imaging with steady-state free precession (3D-FISP), to clarify the superiority of 3D-FISP to two-dimensional fast low-angle shot (2D-FLASH) on phantom study, and to clarify the clinical usefulness of 3D-FISP in diagnosing hepatocellular carcinoma (HCC). 3D-FISP images with varying flip angles were compared by using a phantom. Signal-to-noise ratios (SNRs) and contrast-enhancement ratios (CERs) were compared for the four two-dimensional fast low-angle shot (2D-FLASH) sequences and 3D-FISP sequences in a phantom. The optimal 3D-FISP dynamic study was compared with plain, postcontrast MR sequences used to study 78 HCC cases and analyzed according to histological grade. The 3D-FISP image obtained 30 sec after gadopentetate dimeglumine (Gd) administration was also compared with CT hepatic angiography (CTHA). A 25 degrees flip angle and double-dose Gd administration were appropriate for 3D-FISP dynamic study. CER was the highest with 3D-FISP, and SNR was higher in 3D-FISP than in 2D-FLASH images in a phantom with high Gd concentration. Among the 105 lesions, 103 (98%) were depicted on 3D-FISP images. The detection rate of HCC on 3D-FISP was higher than 95% for each histological grade. The vascularity of the tumors as determined by CTHA findings was correctly diagnosed on 3D-FISP in 80% of cases. In phantom study, 3D-FISP with double-dose Gd injection showed higher contrast than 2D-FLASH as a sequence for liver dynamic study. In clinical study, 3D-FISP is useful in the detection of HCC, regardless of tumor vascularity and histological grade.
Tsuyoshi Tajima, Hiroshi Honda, Ken-ichi Taguchi, Yoshiki Asayama, Toshirou Kuroiwa, Kengo Yoshimitsu, Hiroyuki Irie, Hitoshi Aibe, Mitsuo Shimada and Kouji Masuda : Sequential hemodynamic change in hepatocellular carcinoma and dysplastic nodules: CT angiography and pathologic correlation, American Roentgen Ray Society, Apr. 2002.
51.
Shinichi Aishima, Ken-ichi Taguchi, Keishi Sugimachi, Mitsuo Shimada, Keizo Sugimachi and Masazumi Tsuneyoshi : c-erbB-2 and c-Met expression relates to cholangiocarcinogenesis and progression of intrahepatic cholangiocarcinoma, the British Division of the International Academy of Pathology, Mar. 2002.
(Summary)
The c-erbB-2 and c-Met proto-oncogenes are important for tumour invasiveness and metastasis in many types of malignant tumours. Previous studies have indicated that these proteins are associated with carcinogenesis in intrahepatic cholangiocarcinoma. In this study, we examined c-erbB-2 and c-Met expression by immunohistochemistry in hepatolithiasis, intrahepatic cholangiocarcinoma and metastatic lymph node, in order to clarify whether these proteins play a role in carcinogenesis and tumour metastasis in intrahepatic cholangiocarcinoma. In hepatolithiasis, the staining for c-erbB-2 was positive in 14 of the 23 (61%) cases, while staining for c-Met was positive in eight of the 23 (35%) cases. In intrahepatic cholangiocarcinoma, staining for c-erbB-2 was positive in 45 of the 81 (55%) cases, while staining for c-Met was positive in 28 (35%) cases. The positivity of c-Met staining in intrahepatic cholangiocarcinoma was significantly higher in the differentiated type of cholangiocarcinoma than in the undifferentiated type. In addition, c-Met-positive staining had an inverted correlation with tumour size, the presence of perineural invasion and the presence of lymph node metastasis. c-Met staining had a significantly higher positivity in cases at an early stage of intrahepatic cholangiocarcinoma. In contrast, the positivity of c-erbB-2 staining in intrahepatic cholangiocarcinoma was significantly higher in cases with lymph node metastasis than in cases without. In metastatic lymph nodes, the staining for c-erbB-2 was positive in 20 of the 25 (80%) cases, while staining for c-Met was positive in six of the 25 (24%) cases. There was no difference in survival between c-erbB-2-positive and negative patients. However, the patients with c-Met-positive tumours had a significantly longer survival than those with c-Met-negative tumours in the medium survival term. The multivariate analysis showed the presence of lymph node metastasis, lymphatic permeation and histological differentiation to be independent prognostic factors. These results indicate that increased c-Met expression participates in cholangiocarcinogenesis and in the early developmental stages of intrahepatic cholangiocarcinoma, while increased c-erbB-2 expression contributes to the development of cholangiocarcinogenesis into an advanced stage associated with tumour metastasis.
K Kanoh, Ken-ichi Nomoto, T Shimura, Mitsuo Shimada, Keizo Sugimachi and Hiroyuki Kuwano : A comparison of right-lobe and left-lobe graft for living-donor liver transplantation, Jan. 2002.
53.
Yuh Fujiwara, Mitsuo Shimada, Kenji Takenaka, Kiyoshi Kajiyama, Ken Shirabe and Keizo Sugimachi : The Sialyl Lewis X expression in hepatocarcinogenesis: Potential predictor for the emergence of hepatocellular carcinoma, Thieme, Stuttgart, ALLEMAGNE, Jan. 2002.
54.
Shinichi Aishima, Kenichi Taguchi, Keishi Sugimachi, Yoshiki Asayama, Hidehiro Nishi, Mitsuo Shimada, Keizo Sugimachi and Masazumi Tsuneyoshi : The role of thymidine phosphorylase and thrombospondin-1 in angiogenesis and progression of intrahepatic cholangiocarcinoma, Westminster Publications, Jan. 2002.
55.
Kohji Nakazawa, Hiroyuki Ijima, Junji Fukuda, Ryo-ichi Sakiyama, Yo-ichi Yamashita, Mitsuo Shimada, Ken Shirabe, Eiji Tsujita, Keizo Sugimachi and Kazumori Funatsu : Development of a hybrid artificial liver using polyurethane foam/hepatocyte spheroid culture in a preclinical pig experiment, Wichtig Editore, Milano,Italy, Jan. 2002.
(Summary)
We describe a preclinical study of our original hybrid artificial liver support system (HALSS) for a clinical trial. We designed a HALSS comprising a multi-capillary polyurethane foam packed-bed module (MC-PUF module) containing a total 200 g (2 x 10(10) cells) porcine hepatocytes, and an extracorporeal circulation device. Almost all porcine hepatocytes in the MC-PUF module formed many spherical multicellular aggregates (spheroids). This extracorporeal circulation device was improved to promote solute exchange between a living body and a MC-PUF module by including a plasma bypass line in the circulation loop. The efficacy of the HALSS was evaluated using a 25-kg pig with warm ischemic liver failure by portocaval shunt and ligation of hepatic artery (HALSS group, n=3). As a control experiment, the same system without hepatocytes in the module was used with the same kind of liver failure pig (Control group, n=3). The blood ammonia in the control group was 143 N-microg/dl at the start of circulation, and rapidly increased to 351 N-microg/dl at 2 hours and to 704 N-microg/dl at 6 hours. But the blood ammonia in the HALSS group was completely suppressed, and remained less than the hepatic coma level (over 200 N-microg/dl) during the circulation time. The blood glucose in the control group gradually decreased, and became less than 40 mg/dl within 6 hours of circulation. But the blood glucose in the HALSS group was maintained well, and remained the normal glucose level (50 - 105 mg/dl) for more than 20 hours of circulation. Improvement in blood creatinine and lactate, and the stabilization of vital signs and urinary excretion, were observed in the HALSS group. The survival time of the pigs in the HALSS group was 19.3 hours compared with 8.9 hours in the control group. In conclusion, our HALSS was effective to stabilize the general conditions of the body in addition to supporting various liver functions. These results suggest that our HALSS has a strong possibility to be used in treating liver failure patients. We have applied for approval of the clinical trial of our HALSS to our institutional ethics committee.
Yo-ichi Yamashita, Mitsuo Shimada, Eiji Tsujita, Ken Shirabe, Hiroyuki Ijima, Kohji Nakazawa, Ryoichi Sakiyama, Junji Fukuda, Kazumori Funatsu and Keizo Sugimachi : High metabolic function of primary human and porcine hepatocytes in a polyurethane foam/spheroid culture system in plasma from patients with fulminant hepatic failure, Cognizant Communication Corporation, 2002.
(Keyword)
Fulminant hepatic failure / Human hepatocytes / Porcine hepatocytes / Polyurethane foam/spheroid culture system
59.
Junji Fukuda, Ryoichi Sakiyama, Kohji Nakazawa, Hiroyuki Ijima, Yo-ichi Yamashita, Mitsuo Shimada, Ken Shirabe, Eiji Tsujita, Keizo Sugimachi and Kazumori Funatsu : Mass preparation of primary porcine hepatocytes and the design of a hybrid artificial liver module using spheroid culture for a clinical trial, European Society for Artificial Organs, Milano, Nov. 2001.
(Summary)
To isolate a large number of porcine hepatocytes, we originally developed a mass preparation method that combined the usual collagenase perfusion method of a whole liver with a collagenase redigestion method of tissue fragments after liver perfusion. Using a pig of 10kg, collagenase perfusion only resulted in a yield of 63+/-78 x 10(8) total cells with a viability of 69.2+/-25.3 %, but our combined method had a yield of 167+/-31 x 10(8) total cells with a viability of 87.9+/-4.4% (mean +/- SD). Also, the combined method was applied to two pigs of 10kg body weight at the same time, and isolated 387+/-89 x 10(8) hepatocytes with a viability of 87.1+/-6.9% and a purity of 93.6+/-2.8 % in 11 experiments. We designed a large multi-capillary polyurethane foam (MC-PUF) packed-bed module containing 1 x 10(10) porcine hepatocytes on a clinical trial scale. The porcine hepatocytes in the module formed spherical multicellular aggregates (spheroids) of 200 - 500 microm diameter. Most hepatocytes forming spheroids were viable judged by fluorescein diacetate and ethidium bromide staining. The activities of ammonia removal, albumin secretion and oxygen consumption of the large MC-PUF module were the same as for a small MC-PUF module containing 2 x 10(8) porcine hepatocytes, and were maintained for at least 9 days of culture. These results show that a large MC-PUF module is successfully scaled up 50 times. In conclusion, we succeeded in developing a mass preparation method of porcine hepatocytes and a large hybrid artificial liver module on a clinical trial scale.
Ichiro Yoshino, Makoto Hashizume, Mitsuo Shimada, Morimasa Tomikawa, Makiko Tomiyasu, Ryuichi Suemitsu and Keizo Sugimachi : Thoracoscopic thymomectomy with the da Vinci computer-enhanced surgical system, The American Association for Thoracic Surgery, Oct. 2001.
Keishi Sugimachi, Ken-ichi Taguchi, Shin-ichi Aishima, Shinji Tanaka, Mitsuo Shimada, Kiyoshi Kajiyama, Keizo Sugimachi and Masazumi Tsuneyoshi : Altered expression of beta-catenin without genetic mutation in intrahepatic cholangiocarcinoma, the United States and Canadian Academy of Pathology,Inc, Sep. 2001.
RCAS1 has been reported as a tumor-associated antigen in uterine and ovarian carcinomas. In vitro studies on RCAS1 indicated that it might function as an apoptosis-inducing factor since binding between RCAS1 and its receptor induced apoptosis in receptor-expressing cells. In this study, 68 surgically resected samples of hepatocellular carcinoma (HCC) were prepared and RCAS1 expression was examined immunohistochemically, because RCAS1 was also positive in all HCC cell lines tested. Clinical and pathological parameters were then compared between RCAS1-positive and -negative HCC cases. As a result, RCAS1 is expressed in 26.5% of HCC cases and vascular invasion is observed at a much higher rate in the RCAS1-positive cases (72.2%) than in RCAS1-negative cases (24.0%). RCAS1 is not an antigen specific for gynecological cancers. In HCC cases, the RCAS1-positive percentage is not high, however, RCAS1-positive HCCs exhibited a trend towards invasive character.
Ken Shirabe, Mitsuo Shimada, Eiji Tsujita, Shin-ichiro Maehara, Yo-ichi Yamashita, Tatsuya Rikimaru, Shinji Tanaka and Keizo Sugimachi : Thrombectomy before hepatic resection for hepatocellular carcinoma with a tumor thrombus extending to the inferior vena cava, Minerva Medica, Turin,Italy, Jul. 2001.
64.
Kengo Yoshimitsu, Hiroshi Honda, Toshiro Kuroiwa, Hiroyuki Irie, Hitoshi Aibe, Tsuyoshi Tajima, Kazuo Chijiiwa, Mitsuo Shimada and Kouji Masuda : Liver metastasis from gallbladder carcinoma: anatomic correlation with cholecystic venous drainage demonstrated by helical computed tomography during injection of contrast medium in the cholecystic artery, American Cancer Society, Jul. 2001.
Tohru Utsunomiya, Mitsuo Shimada, Ken Shirabe, Kiyoshi Kajiyama, Tomonobu Gion, Kenji Takenaka and Keizo Sugimachi : Clinicopathological characteristics of patients with extrahepatic recurrence following a hepatectomy for hepatocellular carcinoma, H.G.E. Update Medical Publishing, Jul. 2001.
(Summary)
None of the previous studies have compared the prognosis or clinicopathological factors between the patients with extrahepatic recurrence and those with intrahepatic recurrence of hepatocellular carcinoma after a hepatic resection. The clinicopathological features and prognoses of patients with extrahepatic recurrence after a curative hepatectomy for hepatocellular carcinoma were investigated. Twenty-three patients with extrahepatic recurrence had more advanced-stage hepatocellular carcinoma at the primary operation compared to 186 patients with intrahepatic recurrence. After adjusting for tumor size, the prognosis of the 2 groups were comparable. However, among the patients with hepatocellular carcinoma exceeding 5 cm in diameter, the number of patients whose plasma levels of des-gamma-carboxy prothrombin was higher than 2.0 AU/mL in the patients with extrahepatic recurrence (62.5%) was significantly more (P < 0.05) than that in the patients with intrahepatic recurrence (20.0%). On the other hand, the prognosis of the 13 patients with extrahepatic recurrence alone was significantly better than in the 10 patients with both intrahepatic and extrahepatic recurrences. The prognoses of the 3 patients who underwent a surgical resection for isolated extrahepatic recurrence were markedly better than that of the remaining 10 patients only treated palliatively. If patients have tumors exceeding 5 cm in diameter and their plasma levels of des-gamma-carboxy prothrombin are higher than 2.0 AU/mL, more careful follow-up examinations than usual may thus be necessary in order to detect extrahepatic recurrence as early as possible. Furthermore, a surgical resection for the isolated extrahepatic recurrence of hepatocellular carcinoma is also recommended to produce long-term survivors.
Mitsuo Shimada, Takayuki Hamatsu, Yo-ichi Yamashita, Tatsuya Rikimaru, Ken-ichi Taguchi, Tohru Utsunomiya, Ken Shirabe and Keizo Sugimachi : Characteristics of multicentric hepatocellular carcinomas: comparison with intrahepatic metastasis, Springer-Verlag, Tokyo, Jul. 2001.
(Summary)
Characteristics of multicentric hepatocellular carcinomas (HCCs) remain obscure. We therefore aimed to clarify them and compare them with HCC with intrahepatic metastases. A series of 118 patients who had definite hepatitis C viral status and multinodular HCC were divided into two groups: a multicentric occurrence (MO) group (n = 38), with multicentric HCCs; and an intrahepatic metastasis (IM) group (n = 80), with HCC having intrahepatic metastases. Clinicopathologic variables, including the patient's survival and disease-free survival rates, were compared between the MO and IM groups. Univariate analysis revealed the presence of esophageal varices, the presence of hepatitis C virus infection, a platelet count of less than 10 x 10(4)/microliter, hepaplastin test, gamma-globulin, the histologically active hepatitis, tumor size, des-gamma-carboxy prothrombin > 0.1 AU/ml, positive portal vein invasion, and histologic grade as discriminating factors. The MO score to differentiate multicentric HCCs from intrahepatic metastatic HCCs was determined using the following four independent factors selected by a stepwise regression analysis: the presence of hepatitis C virus infection, a platelet count of less than 10 x 10(4)/microliter, tumor size, and histologic grade. The sensitivity and specificity of the MO scores using those factors were 84% and 70%, respectively, when the cutoff value was 0.4. The disease-free survival rate in the MO group was similar to that in the IM group, whereas the survival rate in the MO group was significantly better than that in the IM group. The multivariate analysis revealed the multicentric occurrence of HCC as one of the independent prognostic factors. Clinicopathologic factors differentiating multicentric HCCs from intrahepatic metastatic HCCs were the presence of hepatitis C virus infection, a platelet count of less than 10 x 10(4)/microliter, small tumor size, and low histologic grade.
Tohru Utsunomiya, Yasunori Emi, Koji Ikejiri, Minoru Suzuki, Hideki Saitsu, Shigeru Yakabe, Michiyasu Nonaka, Motonori Saku, Koji Yoshida, Mitsuo Shimada and Keizo Sugimachi : Retrospective study on the effects of lipiodolization before a potentially curative hepatectomy for colorectal liver metastases: long-term results of a pilot study, Thieme, Stuttgart, ALLEMAGNE, May 2001.
68.
Takashi Nishizaki, Toru Ikegami, Shoji Hiroshige, Koji Hashimoto, Hideaki Uchiyama, Tomoharu Yoshizumi, Keishi Kishikawa, Mitsuo Shimada and Keizo Sugimachi : Small graft for living donor liver transplantation, Lippincott Williams & Wilkins, Apr. 2001.
(Summary)
To evaluate the impact of graft size on recipients in living donor liver transplantation (LDLT) to establish a clinical guideline for the minimum requirement. Although the minimum graft size required for LDLT has been reported to be 30% to 40% of graft volume (GV)/standard liver volume (SLV), the safety limit of the graft size was unknown. A total of 33 cases of LDLT, excluding auxiliary transplantation, were reviewed with a minimum observation period of 4 months. The 33 patients were divided into three groups according to GV/SLV: medium-size graft group, small-size graft group, and extra-small graft group. The effect of GV/SLV on graft function, graft regeneration, and survival was evaluated. The overall patient survival rate was 94% at a mean follow-up of 15 months with a minimum observation period of 4 months. There were no statistically significant differences in postoperative bilirubin clearance, alanine aminotransferase, prothrombin time, and frequency of postoperative complications among the three groups. One week after transplantation, the regeneration rate (GV at 1 week/harvested GV) in the extra-small and small groups was significantly higher than that of the medium group. The graft and patient survival rates were both 100% in the extra-small group, 75% and 88% in the small group, and 90% and 95% in the medium group. Small-for-size grafts less than 30% of SLV can be used with careful intraoperative and postoperative management until the grafts regenerate.
(Keyword)
Adult / Case-Control Studies / Female / Follow-Up Studies / Graft Survival / Humans / Liver / Liver Regeneration / Liver Transplantation / Living Donors / Male / Time Factors
(Link to Search Site for Scientific Articles)
● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 11303141
Makoto Nakamuta, Seiya Tada, Koutaro Uchimura, Munechika Enjoji, Naoko Kinukawa, Hiroaki Iwamoto, Rie Sugimoto, Mitsuo Shimada, Masao Ohashi, Keizo Sugimachi and Hajime Nawata : Serum leptin levels in patients with nonalcoholic chronic liver disease, Thieme, Stuttgart, ALLEMAGNE, Mar. 2001.
70.
Kazumori Funatsu, Hiroyuki Ijima, Kohji Nakazawa, Yo-ichi Yamashita, Mitsuo Shimada and Keizo Sugimachi : Hybrid artificial liver using hepatocyte organoid culture, The International Federation for Artificial Organs, Mar. 2001.
(Summary)
We developed 2 types of hybrid artificial liver modules using hepatocyte organoid culture. One was a polyurethane foam (PUF)/hepatocyte spheroid packed-bed module. Hepatocytes spontaneously formed spheroids in the PUF pores, and they maintained liver-specific functions well for at least 2 weeks in vitro. As a preclinical experiment, a hybrid artificial liver with 200 g porcine hepatocytes was applied to a pig (25 kg) with liver failure and showed that the hybrid artificial liver was effective in support of liver functions and stabilization of general conditions. We established a new technique of hepatocyte organoid formation using centrifugal force. A hepatocyte organoid formed by centrifugation in hollow fibers maintained functions for more than 4 months in vitro. We developed a new sinusoid-like structure module having hollow fibers arranged by spacers in a micro-regular arrangement. Inoculated hepatocytes in the extra-fiber space of the module formed the organoid by centrifugation, and they maintained the functions for at least 1 month in vitro. The results indicated that this module seems to be promising as a hybrid artificial liver.
(Keyword)
Hybrid artificial liver support system / Polyurethane foam / Spheroid / Hollow fiber / Hepatocyte organoid / Preclinical experiment
Kengo Yoshimitsu, Hiroshi Honda, Makiko Jimi, Toshiro Kuroiwa, Hiroyuki Irie, Hitoshi Aibe, Kenji Shinozaki, Yoshiki Asayama, Mitsuo Shimada and Kouji Masuda : Correlation of three-dimensional gradient echo dynamic MR imaging with CT during hepatic arteriography in patients with hypervascular hepatocellular carcinomas: preliminary clinical experience, International Society for Magnetic Resonance in Medicine, Feb. 2001.
(Summary)
The purpose of this study is to elucidate the usefulness of dynamic MR study of the whole liver using 3DFISP with double dose gadolinium (Gd) enhancement in detecting enhancing lesions in 20 patients. Twenty patients with hepatocellular carcinoma (HCC) underwent 3DFISP dynamic study with double dose Gd. The demonstration of enhancing hypervascular lesions regardless of etiology was evaluated on a segment-by-segment basis with receiver operating characteristic (ROC) analysis, using findings on CT during hepatic arteriography as a gold standard. Diagnostic accuracy of 3DFISP in the detection of HCC was also evaluated. As to the demonstration of enhancing lesions, the Az value of the ROC curve was 88%. The detection rate of HCC with 3DFISP was 98%. 57% of enhancing pseudolesions were not detected on 3DFISP. We concluded that Dynamic MR study of the whole liver using 3DFISP with double dose Gd enhancement is a useful method to demonstrate hypervascular HCC.
(Keyword)
magnetic resonance / contrast enhancement / liver neoplasm / three-dimensional image / dynamic study
Hiroyuki Irie, Hiroshi Honda, Hitoshi Aibe, Toshiro Kuroiwa, Kenzo Yoshimitsu, Kenji Shinozaki, Koji Yamaguchi, Mitsuo Shimada and Kouji Masuda : Efficacy of three-dimensional fast imaging with steady precession dynamic MR imaging in evaluating pancreatic ductal adenocarcinoma, Elsevier Science, Jan. 2001.
(Summary)
To compare the diagnostic efficacy of three-dimensional fast imaging with steady precession (3D-FISP) dynamic MR imaging in assessing pancreatic ductal adenocarcinoma with conventional MR imaging and helical CT, 15 patients with surgically proven pancreatic ductal adenocarcinoma were studied. Contrast-to-noise ratio (CNR) of the tumor, tumor detectability, local tumor extension, and vascular involvement were evaluated for all techniques. The results indicate that 3D-FISP dynamic MR imaging may improve the imaging assessment of pancreatic ductal adenocarcinoma.
Masao Yamasaki, Atsushi Ikeda, Akira Hirao, Yoko Tanaka, Yoshiyuki Miyazaki, Tatsuya Rikimaru, Mitsuo Shimada, Keizo Sugimachi, Hirofumi Tachibana and Koji Yamada : Effect of dietary conjugated linoleic acid on the in vivo growth of rat hepatoma dRLh-84, Lawrence Erlbaum Associates, 2001.
(Summary)
We examined the effect of dietary conjugated linoleic acid (CLA) on the growth of injected hepatoma dRLh-84 in Donryu rats. After experimental diets containing 0% or 2% CLA were given to male Donryu rats for 3 wk, dRLh-84 cells were injected into the left lobe of the hepatic capsule, and the experimental diet was continued. The cells formed a solid tumor > or = 1 wk after the injection, and thereafter the tumor grew with feeding duration. In a morphological study, this tumor appeared to be a low-differentiated hepatoma, and there was no remarkable difference in the morphology of the tumor between 0% and 2% CLA groups. Tumor weight was significantly higher in the 2% CLA group than in the 0% CLA group throughout the feeding period after the injection. Serum glutamic-oxaloacetic transaminase and glutamic-pyruvic transaminase activities were significantly higher in 2% CLA-injected rats than in 0% CLA-injected rats at 3 wk after the injection. CLA upregulated acyl-CoA oxidase activity, especially 1 wk after the injection. However, dietary CLA did not activate carnitine palmitoyl transferase II, which is a rate-limiting enzyme in the mitochondrial beta-oxidation pathway. Natural killer cell activity in the spleen tended to be higher in injected rats, but a significant effect of dietary CLA was not recognized. Serum interferon-gamma and tumor necrosis factor-alpha levels were higher in injected than in sham rats. Moreover, these levels were higher in 2% CLA groups than in the respective 0% CLA groups.
Hiroyuki Ijima, Kohji Nakazawa, Mitsuru Kaneko, Junji Fukuda, Mitsuo Shimada, Yo-ichi Yamashita, Tomonobu Gion, Ken Shirabe, Keizo Sugimachi and Kazumori Funatsu : Development of a Hybrid Artificial Liver Support System and Preclinical Animal Experiments, Springer, Sep. 2000.
Shinji Tanaka, Keishi Sugimachi, Ken Shirabe, Mitsuo Shimada, Jack R. Wands and Keizo Sugimachi : Expression and antitumor effects of TRAIL in human cholangiocarcinoma, American Association for the Study of Liver Diseases, Sep. 2000.
79.
Hiroyuki Ijima, Kohji Nakazawa, Shingo Koyama, Mitsuru Kaneko, Taku Matsushita, Tomonobu Gion, Ken Shirabe, Mitsuo Shimada, Kenji Takenaka, Keizo Sugimachi and Kazumori Funatsu : Conditions required for a hybrid artificial liver support system using a PUF/hepatocyte-spheroid packed-bed module and it's use in dogs with liver failure, Wichtig Editore, Milano,Italy, Jul. 2000.
(Summary)
We studied the effects of a hybrid artificial liver support system we developed on dogs with hepatic failure. The system consisted of a multi-channel polyurethane foam packed-bed culture module, including primary dog hepatocyte spheroids. Blood ammonia was well metabolized by 20 g hepatocytes, but the other functions such as glucose concentration, total bile acid concentration, and survival time required 30 g hepatocytes to improve conditions. We found that we should use a culture substratum that easily forms spheroids, and that an artificial liver module should be used as soon as possible after spheroid formation by hepatocytes in the module.
Takashi Maeda, Kenji Takenaka, Kenichi Taguchi, Kiyoshi Kajiyama, Ken Shirabe, Mitsuo Shimada, Hiroshi Honda and Keizo Sugimachi : Small hepatocellular carcinoma with minute satellite nodules, Thieme, Stuttgart, ALLEMAGNE, Jul. 2000.
81.
Mitsuo Shimada, Yo-ichi Yamashita, Takayuki Hamatsu, Tatsuya Rikimaru, Hirofumi Hasegawa, Tomonobu Gion, Ken Shirabe, Kenji Takenaka and Keizo Sugimachi : Surgical indications for advanced hepatocellular carcinoma, H.G.E. Update Medical Publishing, Jul. 2000.
82.
Mitsuo Shimada, Kenji Takenaka, Tatsuya Rikimaru, Takayuki Hamatsu, Yo-ichi Yamashita, Kiyoshi Kajiyama, Ken-ichi Taguchi, Ken Shirabe and Keizo Sugimachi : Characteristics of sarcomatous cholangiocarcinoma of the liver, H.G.E. Update Medical Publishing, Jul. 2000.
(Summary)
The aim of this study was to clarify the clinicopathological characteristics of intrahepatic cholangiocarcinoma with sarcomatous changes. Four cases of cholangiocarcinoma with sarcomatous change were identified and investigated. The clinicopathological findings, including the results of immunohistochemical staining, were investigated in comparison with those of ordinary cholangiocarcinoma. Two of them exhibited pyrexia as the initial symptom. The serum alkaline phosphatase level in sarcomatous cholangiocarcinoma was significantly lower than that in ordinary cholangiocarcinoma. Both the serum carcinoembryonic antigen and carbohydrate 19-9 level in sarcomatous cholangiocarcinoma also tended to be lower than those in ordinary cholangiocarcinoma. The carcinomatous component of all tumors was mostly poorly differentiated adenocarcinoma. The associated microscopic findings were as follows: lymphocyte infiltration in the tumor, accompanied by both necrosis and extensive lymph node metastases. Three of them predominantly exhibited spindle-shaped sarcomatous changes, whereas the other case predominantly demonstrated pleomorphic-type sarcomatous changes. The sarcomatous area was positive for both vimentin, a mesenchymal marker, and for epithelial markers, furthermore, in 3 of 4 cases, the carcinoma portions were also positive for vimentin. The overall survival curves were not significantly different between the 2 groups, however, no long-term survivor was found in sarcomatous cholangiocarcinoma. The main characteristics of cholangiocarcinoma with sarcomatous changes are considered to be as follows: 1) often demonstrating pyrexia as a symptom; 2) not always demonstrating remarkable abnormal findings in the laboratory data including tumor markers; 3) histologically showing poorly differentiated adenocarcinoma; and 4) showing a very poor prognosis (especially, in a pleomorphic-type).
(Keyword)
Aged / Bile Duct Neoplasms / Bile Ducts, Intrahepatic / Chi-Square Distribution / Cholangiocarcinoma / Female / Humans / Immunohistochemistry / Liver Function Tests / Male / Middle Aged / Sarcoma / Statistics, Nonparametric / Treatment Outcome
(Link to Search Site for Scientific Articles)
● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 11020857
Hiroshi Honda, Tsuyoshi Tajima, Ken-ichi Taguchi, Toshiro Kuroiwa, Kengo Yoshimitsu, Hiroyuki Irie, Hitoshi Aibe, Kenji Shinozaki, Yoshiki Asayama, Mitsuo Shimada and Kouji Masuda : Recent developments in imaging diagnostics for HCC: CT arteriography and CT arterioportography evaluation of vascular changes in premalignant and malignant hepatic nodules, Springer-Verlag, Tokyo, Jun. 2000.
84.
Hiroyuki Ijima, Kohji Nakazawa, Shingo Koyama, Mitsuru Kaneko, Taku Matsushita, Tomonobu Gion, Ken Shirabe, Mitsuo Shimada, Kenji Takenaka, Keizo Sugimachi and Kazumori Funatsu : Development of a hybrid artificial liver using a polyurethane foam/hepatocyte-spheroid packed-bed module, Wichtig Editore, milano, Jun. 2000.
(Summary)
Primary dog hepatocytes spontaneously formed spheroids in the pores of polyurethane foam (PUF) within 1-2 days of stationary culture. The spheroids, about 100-150 microm in diameter, partly attached to the surface and immobilized inside these pores. The lidocaine disappearance rate decreased to about 4 microg/10(5) viable cells/day for 10 days, while in the PUF/spheroid culture the rate was maintained at almost the initial level of 8 microg/10(5) viable cells/day for 10 days. Then, two scales of PUF packed-bed modules were designed. A small module (PUF volume; 14.5 cm3) was used for in vitro culture to investigate optimum culture conditions, and a large module (PUF volume; 300 cm3) was designed for dog experiments. Hepatocytes inoculated in these modules also formed spheroids and maintained almost the same activity of albumin secretion rate (111 microg/cm3 PUF/day in the small module and 87.7 microg/cm3 PUF/day in the large module). These results indicate that the PUF packed-bed module containing hepatocyte-spheroids is promising as a hybrid artificial liver.
Hiroyuki Irie, Hiroshi Honda, Hitoshi Aibe, Toshiro Kuroiwa, Kengo Yoshimitsu, Kenji Shinozaki, Koji Yamaguchi, Mitsuo Shimada and Kouji Masuda : MR cholangiopancreatographic differentiation of benign and malignant intraductal mucin-producing tumors of the pancreas, American Roentgen Ray Society, May 2000.
86.
Takashi Maeda, Kenji Takenaka, Kenichi Taguchi, Kiyoshi Kajiyama, Ken Shirabe, Mitsuo Shimada, Masazumi Tsuneyoshi and Keizo Sugimachi : Clinicopathological characteristics of surgically resected minute hepatocellular carcinomas, H.G.E. Update Medical Publishing, Mar. 2000.
Mitsuo Shimada, Takayuki Hamatsu, Tatsuya Rikimaru, Yo-ichi Yamashita, Shinji Tanaka, Ken Shirabe, Hiroshi Honda, Makoto Hashizume and Keizo Sugimachi : Impact of combined preoperative three-dimensional computed tomography and intraoperative real-time three dimensional ultrasonography on liver surgery, Springer-Verlag, London, 2000.
90.
Hiroshi Honda, Tsuyoshi Tajima, Kiyoshi Kajiyama, Toshiro Kuroiwa, Kengo Yoshimitsu, Hiroyuki Irie, Hitoshi Aibe, Mitsuo Shimada and Kouji Masuda : Vascular changes in hepatocellular carcinoma: correlation of radiologic and pathologic findings, American Roentgen Ray Society, Nov. 1999.
91.
Tsuyoshi Tajima, Hiroshi Honda, Toshirou Kuroiwa, Kengo Yoshimitsu, Hiroyuki Irie, Hitoshi Aibe, Ken-ichi Taguchi, Mitsuo Shimada and Kouji Masuda : Radiologic features of intrahepatic bile duct adenoma: a look at the surface of the liver, Lippincott Williams & Wilkins, Sep. 1999.
(Summary)
We report the radiological features of intrahepatic bile duct adenoma (BDA) in three patients. BDA was shown as a small mass located in the peripheral region of the liver with each imaging modality: a hypervascular mass on angiography and a mass appearing as early nodular enhancement found disproportionately evident compared with their small size and distinct delayed or prolonged enhancement on CT. BDA should be included in the diseases to be differentiated from hypervascular hepatic tumors.
Kohji Nakazawa, Hiroshi Mizumoto, Mitsuru Kaneko, Hiroyuki Ijima, Tomonobu Gion, Mitsuo Shimada, Ken Shirabe, Kenji Takenaka, Keizo Sugimachi and Kazumori Funatsu : Formation of porcine hepatocyte spheriacal multicellular aggregates (spheroid) and analysis of drug metabolic functions, Springer-Verlag, Netherlands, Sep. 1999.
93.
Mitsuo Shimada, Hirofumi Hasegawa, Tomonobu Gion, Ken Shirabe, Ken-ichi Taguchi, Kenji Takenaka, Shinji Tanaka and Keizo Sugimachi : Risk factors of the recurrence of hepatocellular carcinoma originating from residual cancer cells after hepatectomy, H.G.E. Update Medical Publishing, Jul. 1999.
(Summary)
Little has been documented to differentiate between recurrence originating from microscopic residual tumor cells and recurrence due to metachronous multicentric origin of hepatocellular carcinoma (HCC). The aim of this study was to clarify the risk factors of HCC recurrence closely related to residual tumor cells. A retrospective review of hepatic resections for HCC during the period between April 1985 and April 1997 was undertaken at a University Hospital with a long history of hepatectomy for HCC. Three hundred and thirteen HCC patients without any definite multicentric recurrence, who underwent hepatectomy, were retrospectively investigated. Main outcome measures were: (Study 1) Risk factors for recurrence were univariately and multivariately investigated among various clinicopathological variables, including the vi factor as a new indicator of the potential malignancy of HCC (i.e., the presence of both microscopic portal vein invasion and intrahepatic metastasis). (Study 2). The risk factors for recurrence were then analyzed according to the period of recurrence. (Study 1) Independent risk factors were: (tumor factors) a positive vi factor, alpha-fetoprotein > 100 ng/ml, and poorly differentiated histology; (host factors) albumin < 3.8 g/dl, the presence of diabetes mellitus, platelet count < 14 x 10(4)/microliter, Y-globulin fraction > 20%. In those risk factors, the relative risk of the vi factor (2.6) was the largest. (Study 2) Within 1 year after hepatectomy, only tumor factors, including the vi factor and poorly differentiated histology, were significant risk factors, tumor factors were significant only up to 2 years after hepatectomy, and thereafter only host factors were significant. The risk factors for non-multicentric recurrence of HCC are considered to be a positive vi factor, alpha-fetoprotein, and poorly differentiated histology, and the vi factor is considered to be a new prognostic indicator expressing the potential malignancy of HCC such as invasion and metastasis.
Kazuharu Yamamoto, Kenji Takenaka, Takashi Matsumata, Mitsuo Shimada and Keizo Sugimachi : The effect of octreotide on morphological hepatic regeneration and hepatic functional recovery after a two-thirds hepatectomy in rats, H.G.E. Update Medical Publishing, May 1999.
(Summary)
The aim of this study was to clarify the effect of octreotide on either morphological hepatic regeneration or hepatic function after a two-thirds hepatectomy in rats. The rats were separated into two groups as follows: group 1 received 100 microg of octreotide acetate subcutaneously every 6 hours from 24 hours before hepatic resection until sacrifice; group 2 received 0.9% saline solution instead of octreotide as a control. Morphological hepatic regeneration, protein synthesis and mitochondrial function were all studied. The regenerative rate in liver volume and the BrdU labeling index in group 1 were significantly lower than those in group 2. The levels of glutamic acid dehydrogenase were significantly lower in group 1 than those in group 2 at 24 (64.2+/-14.6 and 77.8+/-8.3 IU/l, respectively), 36 (46.1+/-14.4 and 60.6+/-5.9 IU/l, respectively) and 48 hours (39.7+/-13.7 and 51.0+/-11.8 IU/l, respectively) after hepatectomy. At 24 hours after hepatectomy, the levels of arterial ketone body ratio was higher in group 1 than in group 2 (0.67+/-0.05 and 0.51+/-0.07, respectively), and the energy charge of the liver was also higher in group 1 than in group 2 (0.662+/-0.031 and 0.605+/-0.053, respectively). Our results suggest that morphological hepatic regeneration is not necessarily synchronized with hepatic functional recovery. In addition, hepatic functional recovery was preserved by keeping the energy metabolism in hepatocytes, even when the use of octreotide suppressed morphological hepatic regeneration.
Hidetoshi Itasaka, Taketoshi Suehiro, Shigeki Wakiyama, Katsuhiko Yanaga, Mitsuo Shimada and Keizo Sugimachi : The mechanism of hepatic graft protection against reperfusion injury by prostaglandin E1, Springer-Verlag, Tokyo, May 1999.
96.
Kazuharu Yamamoto, Kenji Takenaka, Kiyoshi Kajiyama, Mitsuo Shimada, Ken Shirabe, Akinobu Taketomi, Takashi Maeda and Keizo Sugimachi : Cell proliferation and cell loss in nodule-in-nodule hepatocellular carcinoma, H.G.E. Update Medical Publishing, Athens, Mar. 1999.
(Summary)
In order to clarify the significance of the balance between cell proliferation and cell loss during the progression of hepatocellular carcinoma, 16 operative specimens of nodule-in-nodule hepatocellular carcinoma were investigated. In 16 specimens, cell proliferation was evaluated by the expression of Ki-67 nuclear antigen, and cell loss was also examined by the method of terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL). The expressions of p53 protein, bcl-2 protein and Fas antigen were also investigated to clarify the relationship between their expression and cell kinetics. The Ki-67 labeling index of the inner nodules was higher than that for the outer nodules (18.9% vs. 7.2%; p < 0.05) and the TUNEL labeling index of the inner nodules was also higher than that for the outer nodules (12.8% vs. 6.6%; p < 0.05). The increasing rate of the Ki-67 labeling index from Edmondson's grade I to II was 3.9 +/- 3.0, that from grade II to III was 3.9 +/- 2.4, while the increasing rate of the TUNEL labeling index from grade I to II was 2.7 +/- 0.3 and that from grade II to III was 1.7 +/- 0.2 (p < 0.05). p53 Protein was observed in 5 cases, while bcl-2 protein was found in 4 cases in the border area of the inner nodule. However, Fas antigen was found in none of the examined cases. Regarding the Ki-67 positive rate in the inner nodule, the Ki-67 positive rate in the p53 protein positive cases was significantly higher than that in the negative cases (30.3 +/- 15.4 vs. 11.9 +/- 9.2; p < 0.05). However, the TUNEL labeling index was not affected by the expression of those proteins. This study suggested that tumor progression depends on a disturbance in the cell kinetic balance caused not by a decrease in the absolute amount of cell loss but in the chaotic balance between cell loss and cell proliferation.
Mitsuo Shimada, Tomonobu Gion, Takayuki Hamatsu, Yo-ichi Yamashita, Hirofumi Hasegawa, Tohru Utsunomiya, Kenji Takenaka and Keizo Sugimachi : Evaluation of major hepatic resection for small hepatocellular carcinoma, H.G.E. Update Medical Publishing, Jan. 1999.
(Summary)
The aim of this study is to clarify the significance of a major hepatectomy for small hepatocellular carcinomas (HCCs). Seventy-eight patients with solitary HCC measuring less than 3 cm in diameter, whose liver function was considered sufficient to tolerate a right hepatic lobectomy, were classified into 2 groups consisting of: a major group (n = 18), who underwent a major hepatectomy (2 segments or more); and, a minor group (n = 60), who underwent a hepatectomy including one segment or less. The early post-operative outcome and the long-term outcomes, comprising patient survival as well as disease-free survival, were compared. In addition, the post-operative long-term changes in liver function tests and esophageal variceal occurrence were also compared. In the post-operative mortality and morbidity, no significant differences were found between the 2 groups. However, 1 patient in the major group unexpectedly died of liver failure 6 months after operation. No significant difference was observed in patient survival and disease-free survival. The platelet count in the major group tended to decline more rapidly than that in the minor group. Furthermore, 1 patient in the major group demonstrated risky esophageal varices 29 months after operation, which had to be treated by endoscopic injection sclerotherapy. Based on the above findings, a major hepatectomy is therefore not recommended for patients with solitary small HCC measuring 3 cm or less in diameter.
(Keyword)
Aged / Carcinoma, Hepatocellular / Evaluation Studies as Topic / Female / Hepatectomy / Humans / Liver Function Tests / Liver Neoplasms / Male / Middle Aged / Recurrence / Time Factors / Treatment Outcome
(Link to Search Site for Scientific Articles)
● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 10228830
Mitsuru Kaneko, T Ito, Kohji Nakazawa, Hiroyuki Ijima, Taku Matsushita, Tomonobu Gion, Mitsuo Shimada, Ken Shirabe, Hirofumi Hasegawa, Kenji Takenaka, Keizo Sugimachi and Kazumori Funatsu : Development of a Hybrid Artificial Liver Support System with Porcine Hepatocyte Spheroids for Preclinical Use, 1999.
99.
Kohji Nakazawa, Hiroyuki Ijima, Mitsuru Kaneko, Junji Fukuda, Tomonobu Gion, Mitsuo Shimada, Ken Shirabe, Kenji Takenaka, Keizo Sugimachi and Kazumori Funatsu : Development of a hybrid artificial liver support system and its application to hepatic failure animals, 1999.
100.
Hiroyuki Ijima, Kohji Nakazawa, Mitsuru Kaneko, Hiroshi Mizumoto, Taku Matsushita, Tomonobu Gion, Mitsuo Shimada, Ken Shirabe, Kenji Takenaka, Keizo Sugimachi and Kazumori Funatsu : The formation of a spheroid of primary hepatocytes and the expression of liver-specific functions depend on the characteristics of polyurethane foam, Springer Japan, Sep. 1998.
101.
Mitsuo Shimada, Tomonobu Gion, Yuh Fujiwara, Ken Shirabe, Kenji Takenaka, T Kano and Keizo Sugimachi : A branched chain amino acid-enriched solution does not induce any beneficial effect on the postoperative intestinal functions., May 1998.
102.
Mitsuo Shimada, Kenji Takenaka, Yuh Fujiwara, Tomonobu Gion, Hirofumi Hasegawa, Ken Shirabe and Keizo Sugimachi : Significance of the peroral phenolsulfonphthalein test in hepatic resection: a possible predictor of bacterial translocation, H.G.E. Update Medical Publishing, Mar. 1998.
(Summary)
The aim of this study was to evaluate the perioperative changes in intestinal permeability by using the phenolsulfonphthalein (PSP) test and to also to clarify the significance of the peroral PSP test in hepatic resection. Fifty patients, all of whom underwent hepatic resection, were prospectively studied. Postoperative complications occurred in 16 patients, and 10 of these complications were infectious. A peroral PSP test, which was scheduled before operation and on postoperative days 3, 7, and 14, was performed as follows: after the administration of 30 mg of PSP, a 24-hour urine was collected, and the urinary PSP was measured by colorimetric assay. The correlation between the preoperative PSP value and various clinical variables, such as perioperative changes in urinary PSP excretion, and the relationship between the postoperative PSP value and postoperative complications, were investigated. Preoperative urinary PSP excretion was found to increase in proportion to the degree of liver dysfunction. In contrast, urinary PSP excretion did not significantly change during the perioperative period. However, urinary PSP excretion on postoperative day 3 in patients with postoperative infectious complications (27.3%) was significantly greater than that in those without infectious complications (17.4%; p < 0.05). Furthermore, PSP excretion on postoperative day 3 in those with infectious complications was also significantly greater as compared to the preoperative level. The patients with a urinary PSP excretion level on postoperative day 3 of greater than 25%, exhibited infectious complications more frequently than patients with a level under 25% (60% versus 10.3%, respectively; p < 0.05). The peroral PSP test is thus suggested to be a possible predictor of bacterial translocation after hepatic resection.
Mitsuo Shimada, T Kano, Y Matsuzaki, N Miyazaki and K Ninomiya : Gastroenterological surgery for patients with chronic respiratory insufficiency, Mar. 1998.
104.
Kenji Takenaka, Yuh Fujiwara, Tomonobu Gion, Takashi Maeda, Ken Shirabe, Mitsuo Shimada, Katsuhiko Yanaga and Keizo Sugimachi : A thoracoabdominal hepatectomy and a transdiaphragmatic hepatectomy for patients with cirrhosis and hepatocellular carcinoma, American Medical Association, Jan. 1998.
105.
Mitsuo Shimada, Takashi Matsumata, Kazuharu Yamamoto, Akinobu Taketomi, Ken Shirabe, Kenji Takenaka and Keizo Sugimachi : The role of growth hormone, somatostatin and glucagon in hepatic resection, Jan. 1998.
(Summary)
The aim of this study was to clarify the roles of growth hormone, somatostatin, and glucagon in vital reactions against surgical stress as well as in hepatic regeneration. Eleven consecutive patients, who underwent hepatic resection, were included in this study. Changes in intrinsic hormones, specifically growth hormone, somatostatin, and glucagon, were investigated. Furthermore, a comparison was made between major (more than 2 segments) and minor (less than 1 segment) hepatectomies. Growth hormone was observed to increase four-fold during hepatectomy and thereafter remained at relatively high levels. Somatostatin reached its lowest level on postoperative day 1 and then returned to near the preoperative level on postoperative day 7, while glucagon gradually increased and reached a peak around postoperative day 3. The concentrations of both somatostatin and glucagon in the portal vein were higher than those in the peripheral vein. No significant differences between major and minor hepatectomies were found throughout the perioperative course. Growth hormone is considered to be a sensitive parameter in terms of surgical stress and can also act as a trigger as well as a promoter of hepatic regeneration, while a dissociation between somatostatin and glucagon in the early postoperative period indicates the promotion of hepatic regeneration. Furthermore, portal blood, which contains higher concentrations of these substances, plays an important role in regulating hepatic regeneration. However, the absence of a correlation between the extent of the hepatectomy and these parameters suggests that some other, as yet unidentified mechanism, may also be related to the regulation of hepatic regeneration.
Takashi Maeda, Kenji Takenaka, Ken-ichi Taguchi, Kiyoshi Kajiyama, Ken Shirabe, Mitsuo Shimada, Masazumi Tsuneyoshi and Keizo Sugimachi : Adenosquamous carcinoma of the liver: clinicopathologic characteristics and cytokeratin profile, American Cancer Society, Aug. 1997.
Takashi Matsumata, Kazuharu Yamamoto, Ken Shirabe, Mitsuo Shimada, Keizo Sugimachi, F Takesue, Yoichi Muto and Tetsuo Ikeda : Urinary excretion of prostaglandins and renal function after hepatic resection, May 1997.
109.
Akinobu Taketomi, Kenji Takenaka, Takashi Matsumata, Mitsuo Shimada, Hidefumi Higashi, Ken Shirabe, Hidetoshi Itasaka, Eesuke Adachi, Takashi Maeda and Keizo Sugimachi : Circulating intercellular adhesion molecule-1 in patients with hepatocellular carcinoma before and after hepatic resection, Mar. 1997.
110.
Ken Shirabe, Kenji Takenaka, Tomonobu Gion, Mitsuo Shimada, Yuh Fujiwara and Keizo Sugimachi : Significance of alpha-fetoprotein levels for detection of early recurrence of hepatocellular carcinoma after hepatic resection, John Wiley & Sons, Inc., Feb. 1997.
Ken Shirabe, Takashi Matsumata, Mitsuo Shimada, Kenji Takenaka, Naoyuki Kawahara, Kazuharu Yamamoto, Takashi Nishizaki and Keizo Sugimachi : A comparison of parenteral hyperalimentation and early enteral feeding regarding systemic immunity after major hepatic resection--the results of a randomized prospective study, Jan. 1997.
(Summary)
To compare the nutritional efficacy, especially regarding the systemic immunity of early enteral (EEN) and total parenteral nutrition (TPN) in major hepatic resection. A randomized, prospective controlled study was performed in the Second Department of Surgery, Faculty of Medicine, Kyushu University, Fukuoka, Japan. Twenty-six patients who underwent a major hepatic resection were divided into 2 groups: EEN (n = 13), and TPN (n = 13). There was no significant difference between the two groups in regard to either clinical backgrounds, nutritional parameters. There was no significant difference in the nutritional parameters after hepatectomy, such as the serum levels of retinol binding protein, transierrin, pre-albumin, and 3-methylhistidine between the two groups. Among the immunologic parameters, NK activity and changes in the lymphocyte number, the PHA response and the NK activity, which was expressed as a percentage of the preoperative values, was significantly higher in the EEN group than in the TPN group (p < 0.05). The incidence of infectious complications in the TPN group was 4 of 13 patients (31%), although the same incidence in the EEN group was only 1 of 13 (8%). In one case of TPN, a bacterial strain of gut origin was isolated from the intra-abdominal abscess, which suggested that bacterial translocation occurred. No significant difference was observed in the nutritional parameters between the EEN and TPN groups. Early enteral feeding maintained immunocompetence, and thus such feeding possibly reduced the rate of infectious complications after major hepatic resection.
Mitsuo Shimada, Kenji Takenaka, Naoyuki Kawahara, Ken Shirabe, Takashi Nishizaki, Katsuhiko Yanaga, T Kano and Keizo Sugimachi : Hepatic resection for interic type hepatocellular carcinoma, 1997.
114.
Katsuhiko Yanaga, Kenji Takenaka, Kazuharu Yamamoto, Takashi Nishizaki, Ken Shirabe, Mitsuo Shimada, Naoyuki Kawahara, A Chishaki and Keizo Sugimachi : Cardiac complications after hepatic resection, British Journal of Surgery Society Ltd., Oct. 1996.
115.
Kenji Takenaka, Tomonobu Gion, Yuh Fujiwara, Ken Shirabe, Takashi Nisizaki, Mitsuo Shimada, Katsuhiko Yanaga and Keizo Sugimachi : Evaluation of indications for the surgical treatment of cavernous hemangioma of the liver, Springer Japan, Tokyo, Jun. 1996.
116.
Ken Shirabe, Kenji Takenaka, Kazuharu Yamamoto, M Kitamura, Hidetoshi Itasaka, Takashi Matsumata, Mitsuo Shimada and Keizo Sugimachi : The role of prostanoid in hepatic damage during hepatectomy, May 1996.
(Summary)
The aim of this study in hepatectomy is to investigate whether or not hepatic ischemia elevates the serum prostanoid levels, and whether or not thromboxane A2 (TXA2) synthetase inhibitor (OKY 046) improves hepatic damage. The prostanoid levels were measured in 22 hepatectomy cases. The beneficial effects of thromboxane A2 synthetase inhibitor were examined in cases who underwent hepatectomy under hemihepatic vascular control. The total prostanoid levels (6-keto PG Fla+ PGE2 + TXB2) were measured in 22 cases before and after hepatectomy. The hepatic ischemic time (HIT) was defined as the time required to perform a hepatic mobilization plus the right hemihepatic vascular control technique. The total prostanoid levels increased after hepatectomy (P < 0.01). The changes in the total prostanoid levels positively correlated with the HIT (P < 0.01). The 17 cases who underwent hepatectomy with the HIT were randomly divided into 2 groups; the OKY group (n = 9), OKY 046 (0.2 mg/kg/hr), the control group (n = 8); no drug was given. The OKY 046 administration reduced the TXB2 levels (P < 0.01), without any changes in the PGE2, or 6-keto PGF1a levels. The serum glutamic oxaloacetic transaminase levels after operation were lower, and the hepaplastin tests were higher in the OKY group than those of the control (P < 0.05). These results demonstrated that hepatectomy under ischemia elevated the prostanoid levels. OKY 046 significantly reduced the TXB2 levels and the degree of hepatic damage in hepatectomy under ischemia.
Takashi Nishizaki, Kenji Takenaka, Katsuhiko Yanaga, Mitsuo Shimada, Ken Shirabe, Takashi Matsumata and Keizo Sugimachi : Nutritional support after hepatic resection: a randomized prospective study, May 1996.
(Summary)
A consensus as to whether hypertonic dextrose should be given to patients with chronic liver diseases such as cirrhosis or chronic hepatitis after major hepatectomy has not been reached, mostly because metabolism in the remnant liver switches from utilization of blood glucose to utilization predominantly of fatty acid as an energy source. We investigated whether nutritional support would have beneficial effects for such patients. Among 19 patients, 10 were given peripheral dextrose (10 kcal/kg/day) for seven days following hepatectomy and the other 9 were given hypertonic glucose. Twenty and 30 kcal/kg/day was the average non-protein caloric intake, including free oral intake during the first one week following hepatectomy, respectively. The groups were comparable with regard to laboratory data and operative stress. There were no untoward effects related to this support. In patients given nutritional support, retinol binding protein and prealbumin improved (p < 0.05 and p < 0.05, respectively), urinary 3-methylhistidine excretion decreased (p < 0.01) and the nitrogen balance normalized earlier (p < 0.05), as compared to findings with the conventional method. The remnant liver can utilize dextrose and nutritional support improves the nutritional status and may even preserve muscle protein mass.
Takashi Matsumata, Akinobu Taketomi, Yuh Fujiwara, Mitsuo Shimada, Kenji Takenaka and Keizo Sugimachi : Renal function after elective hepatic resection, May 1996.
(Summary)
Although morbidity and mortality associated with liver surgery has declined, in particular operative death from liver failure, accumulation of fluid in the peritoneal or pleural cavities after hepatic resection is still the most common post-operative complication and it often decreases the patient's quality of life. The purpose of this retrospective review is to discuss the effect of renal dysfunction following hepatic resection on ascites formation in patients who underwent hepatic resection. The patients who underwent hepatectomy were assigned to two groups; Group A patients (n = 119) had some form of ascites or pleural effusion, either intractable or easily controlled, while Group B patients (n = 178) had neither ascites nor pleural effusion. We compared the clinical and laboratory data, operative risk factors, and the post-operative renal as well as hepatic functions of the two groups. In addition to ordinary risk factors associated with ascites formation such as decreased plasma oncotic pressure due to hypoalbuminemia along with increased hydrostatic pressure in the portal circulation, renal dysfunction after hepatic resection might be the primary cause of fluid accumulation in the peritoneal cavity. As one of the mechanisms of ascites formation following hepatic resection, we must consider the presence of renal dysfunction and protect against ascites formation and treat refractory ascites after hepatic resection not only by such traditional methods such as water and salt restriction, the use of diuretics, and the infusion of albumin products, but also by preserving the renal function after hepatectomy.
Mitsuo Shimada, Kenji Takenaka, Naoyuki Kawahara, Kazuharu Yamamoto, Ken Shirabe, Yoshihiko Maehara and Keizo Sugimachi : Chemosensitivity in primary liver cancers: evaluation of the correlation between chemosensitivity and clinicopathological factors, 1996.
123.
Hidetoshi Itasaka, Taketoshi Suehiro, Shigeki Wakiyama, Katsuhiko Yanaga, Mitsuo Shimada and Keizo Sugimachi : Significance of hyaluronic acid for evaluation of hepatic endothelial cell damage after cold preservation/reperfusion, Academic Press, Nov. 1995.
Ken Shirabe, Takashi Matsumata, Eisuke Adachi, Takashi Maeda, Mitsuo Shimada, Akinobu Taketomi and Keizo Sugimachi : Prognosis of well differentiated small hepatocellular carcinoma--is well differentiated hepatocellular carcinoma clinically early cancer?, Nov. 1995.
(Summary)
The purpose of this study is to examine whether or not well differentiated (w-d) hepatocellular carcinoma (HCC) is indeed clinically early cancer. Seventy six patients with solitary small HCCs up to 3 cm in diameter, who underwent hepatectomy, were observed for at least 2 years for possible recurrence. These patients were divided into two groups: 10 patients with w-d HCCs (Edmondson and Steiner's grade I) and 66 patients with less differentiated (l-d) HCCs (Edmondson and Steiner's grade I-II, II-III, and III). The histological analysis revealed that w-d HCCs had lower incidences of fibrous capsule formation (P<0.01), when compared to l-d HCCs. There were no significant differences in the incidence of intrahepatic metastasis, or portal vein invasion. In a resected specimen of w-d HCC, barium sulfate and gelatin were injected into portal vein and a transparent specimen was made. The transparent specimen showed that the portal vein in the tumor seemed to be intact. Microscopically, cancer cell infiltration into the fibrous frame of the portal tract was present. There were no significant differences in the disease free survival between the two groups. An analysis of tumor volume doubling time in recurrent foci suggested that minute cancerous foci had been present at the time of operation. W-d HCCs were clinically demonstrated not to be early cancer, because there was no significant difference in disease free survival between the patients with w-d and l-d HCCs.
Ysuharu Ikeda, Kiyoshi Kajiyama, Eisuke Adachi, M Yamagata, Mitsuo Shimada and Katsuhiko Yanaga : Early recurrence after surgery of hepatocellular carcinoma, Sep. 1995.
(Summary)
In 231 patients with hepatocellular carcinoma who underwent liver resection from 1986 to 1992 to determine the significance of alpha-fetoprotein (AFP) levels. There were 13 patients (5.6 per cent) with early recurrence within six months after hepatectomy. Preoperative serum alpha-fetoprotein (AFP) levels were significantly higher in patients with early recurrence (p < 0.01). Postoperative histological examination revealed that there were significant correlations between patients with early recurrence and intrahepatic metastasis (p < 0.01), and portal vein infiltration (p < 0.01). There were significant correlations between patients with early recurrence and preoperative diagnosis of intrahepatic metastasis (p < 0.01), however, preoperative diagnosis of portal vein infiltration could not be detected enough. Eight (73%) of 11 patients with over 1000 ng/ml of AFP and preoperative diagnosis of intrahepatic metastasis had early recurrence (p < 0.01). We found that patients of hepatocellular carcinoma with over 1000 ng/ml of AFP and preoperative diagnosis of intrahepatic metastasis are the most important factors in the preoperative clinical data linked to early recurrence type of HCC after hepatectomy.
Mitsuo Shimada, Naoyuki Kawahara, Kiyoshi Kajiyama, Ken Shirabe, Takashi Nishizaki and Katsuhiko Yanaga : A refined method of trans-thoracoabdominal hepatectomy for cirrhotic patients with hepatocellular carcinoma, Sep. 1995.
(Summary)
A hepatectomy in cirrhotic patients with hepatocellular carcinoma, located in either the posterior or superior part of the right lobe, inevitably requires a forced mobilization of the right lobe. Such a forced procedure causes a decreased hepatic blood flow resulting in postoperative morbidity and mortality, as well as an increased risk of the intrahepatic dissemination of cancer cells during the operation. We have thus refined the method of trans-thoracoabdominal hepatectomy to minimize those demerits of conventional transabdominal hepatectomies. The main characteristics of our refinements are as follows; (1) an optimal incision for the best short-cut to the hepatocellular carcinoma is determined by a three-dimensional imaging of either helical computed tomography and/or magnetic resonance imaging before operation; (2) a complete view of the operative field is obtained by the pertinent use of rotating the operation table, on which the patient is placed in a left semi-lateral position; (3) this method is suitable for resecting a tumor located in the posterior segment such as a posterior segmentectomy. This refined method is considered to decrease the postoperative morbidity including post-operative hepatic dysfunction and is also useful for cirrhotic patients with hepatocellular carcinoma.
Takashi Matsumata, Katsuhiko Yanaga, Mitsuo Shimada, Ken Shirabe, Akinobu Taketomi and Keizo Sugimachi : Occurrence of intraperitoneal septic complications after hepatic resections between 1985 and 1990, Springer-Verlag, Tokyo, Jan. 1995.
Hiroshi Hayashi, Takashi Maeda, Eisuke Adachi, Mitsuo Shimada, Takashi Matsumata and Kenji Takenaka : Argyrophilic nuclear organizer regions (AgNOR) of resected intrahepatic cholangio cellular carcinoma, 1995.
130.
Mitsuo Shimada, Takashi Matsumata, Akinobu Taketomi, Ken Shirabe, Kazuharu Yamamoto, Kenji Takenaka and Keizo Sugimachi : The role of interleukin-6, interleukin-1β, tumor necrosis factor-α, and endotoxin in hepatic resection, 1995.
131.
Mitsuo Shimada, A Saitoh and T Kano : Oral administration of vancomycin in preventing postoperative methicillin-resistant staphylococcus aureus enterocolitis, Adis International, 1995.
Hidefumi Higashi, Takashi Matsumata, J Hayashi, Katsuhiko Yanaga, Mitsuo Shimada, Ken Shirabe, Akinobu Taketomi, S Kashiwagi and Keizo Sugimachi : Detection of hepatitis C virus RNA in the ultrasonic dissector irrigating solution used in liver surgery, British Journal of Surgery Society Ltd., Sep. 1994.
134.
Mitsuo Shimada, Takashi Matsumata, Kazuharu Yamamoto, Hidetoshi Itasaka, Akinobu Taketomi and Keizo Sugimachi : Initiation of a fibrinolytic system in hepatic resection: the roles of tissue-type plasminogen activator and plasminogen activator inhibitor-1, Springer-Verlag, Tokyo, Sep. 1994.
Mitsuo Shimada, Kenji Takenaka and Keizo Sugimachi : A comprehensive multi-institutional study of empiric therapy with flomoxef in surgical infections of the digestive organs. The Kyushu Research Group for Surgical Infection, Aug. 1994.
(Summary)
The effect of flomoxef as empiric therapy for surgical infections of the digestive organs was analyzed in 103 patients, most of whom (94.2%) had intra-abdominal infections. Surgical procedures were performed on 73 patients contemporaneously with the flomoxef therapy. Flomoxef is an oxacephem and has a potent and broad bactericidal spectrum against aerobes and anaerobes. It provokes fewer adverse reactions than latamoxef such as vitamin K deficiency and platelet dysfunction. Flomoxef was administered intravenously at a dose 1-4g/day for more than 3 days without any other antimicrobial agent. The clinical response was classified into 3 groups; cured, improved and failed, and both the cured and improved responses were defined as satisfactory. A satisfactory response was obtained in 99 patients (96.1%). Regarding bacteriological response, the overall eradication rate was 81.3%. Adverse reactions including abnormal laboratory data occurred in only two patients. One had abdominal pain, and the other had a mild elevation of transaminases, and both were mild and easily reversible. Therefore, flomoxef is considered to have the potential of becoming one of the most effective agents in empiric therapy for surgical infections of the digestive organs.
(Keyword)
Adolescent / Adult / Aged / Aged, 80 and over / Bacterial Infections / Cephalosporins / Child / Digestive System Surgical Procedures / Female / Humans / Male / Middle Aged / Postoperative Complications
(Link to Search Site for Scientific Articles)
● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 7830103
Mitsuo Shimada, Takashi Matsumata, Takashi Nishizaki, Akinobu Taketomi, Hidetoshi Itasaka and Keizo Sugimachi : Major hepatic resection in patients with a prosthetic heart valve receiving anticoagulation treatment, Jun. 1994.
(Summary)
We experienced two patients with a prosthetic heart valve, who underwent hepatic resection for hepatoma while on anticoagulation therapy. Patients with a prosthetic heart valve have the following characteristics; an increased risk of thromboembolism due to diminished anticoagulation in the perioperative period, a greater risk of endocarditis due to the artificial material in the heart, and impaired cardiopulmonary function including possible arrhythmia and heart failure. Furthermore, when such patients also have liver cirrhosis with a hepatoma, there is an increased risk of perioperative bleeding while on anticoagulation due to coagulopathy and also a risk of infection due to decreased cellular immunity. Patients with a prosthetic heart valve therefore require special care and attention whenever they have to undergo hepatic resection. With respect to anticoagulation, a minimal level is required to prevent bleeding and thromboembolism. Warfarin being administered preoperatively may be switched to heparin while closely monitoring the activated clotting time (biomaterial valve: 130-150 sec, non-biomaterial valve: 150-180 sec); the heparin should then be changed back to warfarin immediately after starting oral intake following operation. For the prevention of infection, a broad spectrum antibiotic should be used prophylactically both intra-operatively and postoperatively. The cardiopulmonary function must also be carefully monitored. For the assessment of postoperative liver function, lecithin: cholesterol acyltransferase, serum bilirubin and albumin are useful because there is no relevance of coagulation parameters such as prothrombin time under anticoagulation.
Takashi Matsumata, Hidefumi Higashi, Mitsuo Shimada, Eisuke Adachi, Ken Shirabe and Keizo Sugimachi : Indications for major hepatectomy in cirrhotic liver, Apr. 1994.
(Summary)
In an investigation of the indications for major hepatic resection of the cirrhotic liver, the records of 152 consecutive patients who had undergone a right hepatic resection between April 1985 and January 1991 were reviewed. A comparison of right hepatic lobectomy and right partial hepatectomy of the liver with no cirrhotic changes, revealed that postoperative values of serum glutamic pyruvic transaminase were significantly higher after right partial hepatectomy than after right lobectomy, despite the fact that there were no significant differences with respect to preoperative laboratory data, and there was a greater blood loss and total weight of the resected liver in patients receiving a right lobectomy as compared with those undergoing partial hepatectomy. These results suggest that in order to enable a more favorable recovery from hepatic resection, it is essential to avoid both mechanical damage and ischemic injury to the residual liver during hepatic surgery. A total of 77 patients underwent a partial hepatectomy of a cirrhotic liver, and among these patients, 16 patients had values of the indocyanine green test of less than 20%, as well as a portal pressure of less than 200 mm saline. Compared with these 16 cirrhotic patients and those patients who underwent right lobectomy, there were no significant differences with regard to the pre-operative laboratory data and portal pressure. These results therefore suggest that major hepatic lobectomy could be performed on selected patients with cirrhotic livers.
Mitsuo Shimada, Takashi Matsumata, Eisuke Adachi, Hidetoshi Itasaka, Shigeki Wakiyama and Keizo Sugimachi : Estimation of degree of liver cirrhosis using a fibrosis score; a multivariate analysis of clinical parameters and resected specimens, Apr. 1994.
(Summary)
We designed this study to estimate the degree of liver cirrhosis using clinical parameters and surgically resected specimens. One hundred and twenty-nine cases who underwent hepatic resection in the Department of Surgery II, Kyushu University Hospital during the period between April 1985 and July 1991 for whom data for all 29 variables evaluated were available, were admitted to this study. On the basis of the histological findings of fibrosis of the liver, the non-neoplastic part of the resected specimens were classified into 3 groups; Z0, no cirrhosis (n = 63), Z1, mild cirrhosis (n = 38), and Z2, severe cirrhosis (n = 28). A univariate analysis revealed 14 significant variables. After multiple logistic regression analysis of these, five independent variables (low platelet count, female, low value of hepaplastin test, a high Pugh's score and a high value of ICG) were identified. We obtained a fibrosis score using the coefficient of each above-mentioned variable. This score increased the discriminative power. The fibrosis score is therefore considered useful for estimating the severity of liver cirrhosis.
Mitsuo Shimada, Takashi Matsumata, Hidetoshi Itasaka, Ken Shirabe, Akinobu Taketomi and Keizo Sugimachi : The prediction of portal pressure: a multivariate analysis of clinical data and intraoperative portal pressure, Springer-Verlag, Tokyo, Apr. 1994.
(Summary)
Portal pressures were estimated non-invasively in 100 patients who underwent hepatic resection and completely fulfilled the 21 variables evaluated. Ten variables were selected from among all those in the univariate analysis, and a stepwise discriminant analysis revealed four independent significant variables, namely: The indocyanine green dye retention test at 15 min (ICGR15); the prothrombin time index; the platelet count; and the globulin fraction. An equation to estimate the portal pressure was made using the coefficients in the analysis, the reliability of which was confirmed (r = 0.70484, P = 0.0001). The univariate analysis revealed ten significant variables to discriminate portal hypertension, defined as a portal pressure of over 200 mmH2O. A multiple logistic regression analysis of these variables revealed two independent variables, being ICGR15 and the platelet count. Thus, we consider that our equation for estimating portal pressure is potentially useful, and that the platelet count and ICGR15 are the most significant parameters in discriminating between the presence or absence of portal hypertension. Moreover, a platelet count of less than 120 x 10(3)/mm3 and an ICGR15 value of more than 15% correlated well with portal hypertension.
(Keyword)
Adult / Aged / Analysis of Variance / Discriminant Analysis / Female / Hepatectomy / Humans / Hypertension, Portal / Indocyanine Green / Male / Middle Aged / Monitoring, Intraoperative / Multivariate Analysis / Platelet Count / Portal Pressure / Predictive Value of Tests / Prothrombin Time / Regression Analysis
(Link to Search Site for Scientific Articles)
● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 8038504
Mitsuo Shimada, Takashi Matsumata, Tatsuro Kamakura, Taketoshi Suehiro, Hidetoshi Itasaka and Keizo Sugimachi : Changes in regulating blood coagulation in hepatic resection with special references to soluble thrombomodulin and protein C, Jan. 1994.
(Summary)
The protein C anticoagulant pathway in hepatic resection was studied. The patients were divided into two groups--group 1 consisted of patients with a normal liver and group 2 consisted of patients with either hepatitic or a cirrhotic liver. Plasma protein C activity and soluble thrombomodulin were then sequentially measured during hepatectomy and in the early postoperative period. The protein C activity in group 1 decreased during hepatectomy and reached a low immediately after operation, and thereafter, recovered to near preoperative levels. However, the preoperative value in group 2 was lower than that in group 1 and the postoperative values were significantly lower than those in group 1 (p < 0.05). The level of soluble thrombomodulin in group 1 decreased during hepatectomy but later returned to preoperative levels. However, in group 2, the preoperative value was higher than that in group 1 and the postoperative values were greater than that of the preoperative values, while the values were significantly higher than those in group 1 (p < 0.05). During hepatectomy, hypercoagulability may contribute to the low levels of protein C and soluble thrombomodulin. The postoperative significant increase of soluble thrombomodulin may, thus, indicate the occurrence of endothelial injury in the remnant liver. The sequential measurements of both parameters can, therefore, be useful in detecting coagulopathy and endothelial injury in hepatic resection.
(Keyword)
Aged / Blood Coagulation / Female / Hepatectomy / Hepatitis / Humans / Liver Cirrhosis / Male / Middle Aged / Protein C / Thrombomodulin
(Link to Search Site for Scientific Articles)
● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 8156121
Takashi Matsumata, Hidetoshi Itasaka, Ken Shirabe, Mitsuo Shimada, Katsuhiko Yanaga and Keizo Sugimachi : Strategies for reducing blood transfusions in hepatic resection, 1994.
(Summary)
A comparison of 60 blood transfused and 71 nonblood transfused hepatic resection patients was done to evaluate strategies for reducing blood transfusions during hepatic surgery. There were no significant differences between the two groups with regard to preoperative laboratory data, except for prothrombin time and hematocrit value. The mean operative blood loss was 1990 ml and 760 ml in the blood transfused and nonblood transfused groups, respectively. A multivariate analysis suggested that the patient's body weight, preoperative prothrombin time, and operative blood loss independently predicted the need for intraoperative blood transfusion. Major postoperative complications developed more frequently in the blood transfused group than in the nonblood transfused group (31.7 vs. 11.3%, p < 0.005). These results suggest that the difference in operative blood loss between the two groups was related to the prolonged prothrombin time and a susceptibility for blood transfusion was found to exist particularly in patients with a lower hematocrit value as well as a lower body weight. Thus, the improvement of these preoperative laboratory data combined with avoiding the use of the hematocrit value as a determining factor for intraoperative transfusion could correspond to a reduction in operative blood loss, while curtailing the demands on blood bank facilities, and lowering the risk of postoperative complications.
(Keyword)
Adult / Aged / Blood Loss, Surgical / Blood Transfusion / Body Weight / Carcinoma, Hepatocellular / Combined Modality Therapy / Female / Hematocrit / Hepatectomy / Humans / Intraoperative Care / Liver Neoplasms / Male / Middle Aged / Multivariate Analysis / Postoperative Complications / Predictive Value of Tests / Preoperative Care / Prothrombin Time / Risk Factors / Time Factors / Treatment Outcome
(Link to Search Site for Scientific Articles)
● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 7993858
Ken Shirabe, Takashi Matsumata, Mitsuo Shimada, Akinobu Taketomi, Takashi Nishizaki and Keizo Sugimachi : The effects of pirenzepine and famotidine on hepatic resection. a randomized prospective study, 1994.
146.
Takashi Nishizaki, Takashi Matsumata, Katsuhiko Yanaga, Mitsuo Shimada, Hideshi Higashi and Keizo Sugimachi : Open and closed suction drainage after hepatic resection, Springer-Verlag, Tokyo, Oct. 1993.
Mitsuo Shimada, Tatsuro Kamakura, Hidetoshi Itasaka, Takashi Matsumata, Makoto Hashizume and Keizo Sugimachi : The significance of methicillin-resistant Staphylococcus aureus infection in general surgery: a multivariate analysis of risk factors and preventive approaches, Springer-Verlag, Tokyo, Oct. 1993.
Katsuhiko Yanaga, Takashi Matsumata, Hiroshi Hayashi, Mitsuo Shimada, Keiko Urata, Taketoshi Suehiro and Keizo Sugimachi : Effect of diabetes mellitus on hepatic resection, American Medical Association, Apr. 1993.
150.
Katsuhiko Yanaga, Takashi Matsumata, Takashi Nishizaki, Mitsuo Shimada and Keizo Sugimachi : Alternate hemihepatic vascular control technique for hepatic resection, Elsevier Science, Mar. 1993.
(Summary)
This report describes a simple and improved inflow control technique for resection of a hepatic tumor that lies across the right and left hepatic lobes. With alternate hemihepatic inflow control by en masse occlusion of Glisson's sheath of each hemipedicle at the bifurcation, hepatic resection across the two hepatic lobes is completed. Compared with Pringle's maneuver, this technique eliminates splanchnic congestion and reduces warm ischemia of the remnant liver, while maintaining a comparable hemostatic effect.
Yasuharu Ikeda, Takayuki Kanematsu, Takashi Matsumata, Mitsuo Shimada, M Yamagata and Keizo Sugimachi : Liver resection and intractable postoperative ascites, Feb. 1993.
(Summary)
Among 211 patients who, between 1985 and 1990, underwent liver resection in Kyushu University Hospital, uncontrollable ascites occurred in 53 (25%). A univariate analysis revealed that postoperative death with liver failure occurred more frequently in patients with intractable ascites (p < 0.05). Alanine amino transferase levels were significantly higher in patients with intractable ascites (p < 0.05), but serum bilirubin, alkaline phosphatase and serum albumin levels did not differ significantly. Portal pressure (p < 0.05), the operation time (p < 0.01) and blood loss (p < 0.01) were significantly higher in patients with intractable postoperative ascites. A multiple analysis showed a correlation between the operation time, portal hypertension and postoperative intractable ascites. Postoperative histology revealed that a larger number of patients with cirrhosis had intractable ascites (p < 0.05). We conclude that cirrhosis, portal pressure and operating time are the most important factors related to intractable ascites in the case of hepatectomy. Areas of the liver to be resected should be limited in cirrhotic patients with portal hypertension.
Mitsuo Shimada, Takashi Matsumata, Shigeki Wakiyama, Takashi Maeda, Takayuki Kanematsu and Keizo Sugimachi : A safe and simple technique for exchanging central venous catheters, The Fellowship of Postgraduate Medicine, Feb. 1993.
Mitsuo Shimada, Makoto Hashizume, M Ohta, Kouhei Akazawa, Tatsuro Kamakura, Keizo Sugimachi and Yoshiaki Nose : Prediction of survival of patients with esophageal varices treated by endoscopic injection sclerotherapy in Japan, 1993.
Mitsuo Shimada, Katsuhiko Yanaga, Hidefumi Higashi, Leonard Makowka, Saburo Kakizoe and Thomas E. Starzl : Pretransplant assessment of human liver grafts by plasma lecithin: cholesterol acyltransferase (LCAT) activity in multiple organ donors, Springer-Verlag, Berlin, Mar. 1992.
(Summary)
In spite of the improved outcome of orthotopic liver transplantation (OLTx), primary graft nonfunction remains one of the life-threatening problems following OLTx. The purpose of this study was to evaluate plasma lecithin: cholesterol acyltransferase (LCAT) activity in multiple organ donors as a predictor of liver allograft viability prior to OLTx. Thirty-nine donors were studied during a 5-month period between April and August 1988. Allograft hepatectomy was performed using a rapid technique or its minor modification with hilar dissections, and the allografts were stored cold (4 degrees C) in University of Wisconsin (UW) solution. Early post-transplant allograft function was classified as good, fair, or poor, according to the highest SGOT, SGPT, and prothrombin time within 5 days following OLTx. Procurement records were reviewed to identify donor data, which included conventional liver function tests, duration of hospital stay, history of cardiac arrest, and graft ischemic time. Blood samples from the donors were drawn immediately prior to aortic crossclamp, and from these plasma LCAT activity was determined. Plasma LCAT activity of all donors was significantly lower than that of healthy controls (12.4 +/- 8.0 vs 39.2 +/- 13.3 micrograms/ml per hour, P less than 0.01). LCAT activity (16.4 +/- 8.3 micrograms/ml per hour) in donors of grafts with good function was significantly higher than that in those with fair (8.6 +/- 4.5 micrograms/ml per hour, P less than 0.01) or poor (7.3 +/- 2.4 micrograms/ml per hour, P less than 0.01) function.(ABSTRACT TRUNCATED AT 250 WORDS)
Kenji Takenaka, Mitsuo Shimada, Kengo Fukuzawa, Tetsuo Ikeda, Hidetoshi Itasaka, Hidefumi Higashi and Keizo Sugimachi : Viability of porcine transplanted liver graft determinable by serum lecithin:cholesterol acyltransferase (LCAT) activity, 1992.
161.
Katsuhiko Yanaga, Mitsuo Shimada, Robert D Gordon, Andreas G Tzakis, Leonard Makowka, J Wallis Marsh, Andrei C Stieber, Satoru Todo, Shunzaburo Iwatsuki and Thomas E Starzl : Pancreatic complications following orthotopic liver transplantation, 1992.
162.
Kouhei Akazawa, Mitsuo Shimada, Sunao Moriguchi, K Fujisawa, Tomohiro Odaka and Yoshiaki Nose : Interactive statistical analysis system for clinical investigators, Taylor & Francis, London, Oct. 1991.
(Summary)
We have developed an interactive statistical analysis system (ISAS-Q) with which clinical investigators with little experience in computers and programming can easily perform statistical analyses. ISAS-Q can perform most of the frequently used statistical methods, including multivariate analysis, in an interactive mode. Furthermore, ISAS-Q has self-consistent and extensive help functions.
(Keyword)
Data Interpretation, Statistical / Hospital Information Systems / Hospitals, University / Japan / Multivariate Analysis / Online Systems / Research / Software / User-Computer Interface
(Link to Search Site for Scientific Articles)
● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 1762470
Kouhei Akazawa, Tomohiro Odaka, Maki Sakamoto, Shigeaki Ohtsuki, Mitsuo Shimada, Tatsuro Kamakura and Yoshiaki Nose : A random allocation system with the minimization method for multi-institutional clinical trials, Springer-Verlag, Netherlands, Aug. 1991.
(Summary)
This paper describes the random allocation system used to perform precise and rapid treatment assignments in multi-institutional clinical trials. This system is based on sophisticated randomization procedures, according to Pocock and Simon's minimization method and Zelen's method for institution balancing. The major advantage of randomized treatment assignments with this system is to balance treatment numbers for each level of various prognostic factors over the entire trial and at the same time balance the allocation of treatments within an institution. Therefore, the randomized treatment assignments by this system can prevent degrading of the statistical power of a particular treatment factor. This system is designed to run on a small-sized notebook computer and therefore can be set up beside a telephone for registration, without occupying a large space. At present, this system is conveniently being used in two clinical trials.
Kouhei Akazawa, Tsuyoshi Nakamura, Sunao Moriguchi, Mitsuo Shimada and Yoshiaki Nose : Simulation program for estimating statistical power of Cox's proportional hazards model assuming no specific distribution for the survival time, Elsevier Science, Ireland, Jul. 1991.
K Fujisawa, Kouhei Akazawa, Y Hayashi, Mitsuo Shimada, Hidefumi Higashi, Yoshiaki Watanabe, Sunao Moriguchi and Yoshiaki Nose : A 24-hour ordering system for clinical examinations, Jul. 1991.
(Summary)
We have developed a 24-hour ordering system for clinical examinations, making use of the features of multi-function workstation (IBM5550) which performs two functions both in an on-line terminal and in a personal computer. It is used as an on-line terminal for the host computer (IBM4381) in day time. At night or on holiday, it is used as a stand-alone type personal computer to order clinical examinations. For this purpose, basic information of the inpatients (patient number, name, sex, date of birth, clinic, ward) are transferred from the host computer to the disket in the workstation in the evening when host computer finished on-line service. A physician can input the patient number followed by examination items using the touch panel according to the dialogue type guides written in Chinese character. Then, specimen label, list of ordered tests and an order form are printed out instantly. The date (patient number, examination items, identification number of the specimen, etc.) stored in the disket in the workstation at night are transferred from workstation to the host computer next morning. The host computer merges the information ordered in day time and at night and supplies working documents for examination (worksheets, master log, etc.) to technicians. Thus physicians can order examinations all day long using workstation, which make it possible to spare the time.
(Keyword)
Clinical Laboratory Information Systems / Computer Communication Networks / Hospital Information Systems / Japan / Laboratory Techniques and Procedures / Medical Records Systems, Computerized / Time Factors
(Link to Search Site for Scientific Articles)
● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 10170754
Mitsuo Shimada, Kouhei Akazawa, Sunao Moriguchi, Tomohiro Odaka and Yoshiaki Nose : A personal computer network system for equitable allocation of cadaver organs, Taylor & Francis, London, Jul. 1991.
(Summary)
We developed a personal computer network system for the equitable allocation of cadaveric organs. This network consists of a host computer (IBM PS55 model 5570 T) and various kinds of personal computers manufactured by many different computer makers in Japan. The merits of our personal computer network include lower cost and an easy access to the host computer from all the centres participating in this network while using their own favourite personal computers. Among the programs made for allocating cadaveric organs, we present in this paper the program for livers. This program was developed with a modified version of the logic developed by Starzl et al. The grade modification for the United Network for Organ Sharing (UNOS) in the United States was used as the basis for classification of medical urgency. Our program weighed the factors of medical urgency, compatibility of blood group and waiting time. Distance factors were omitted because of the smaller area of the network compared to that of UNOS. This computer network would be linked to other computer networks in creating a national organ procurement and transplant network in Japan, in order to help them to catch up with other advanced transplant countries. Such an equal and objective computer system should allow organ transplantation to become more widely accepted.
(Keyword)
Computer Communication Networks / Histocompatibility Testing / Humans / Japan / Microcomputers / Organ Transplantation / Regional Medical Programs / Software / Software Design / Tissue and Organ Procurement
(Link to Search Site for Scientific Articles)
● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 1758219
Tomohiro Odaka, Yoshiaki Watanabe, Sunao Moriguchi, Kouhei Akazawa, Mitsuo Shimada, Maki Sakamoto, Taturo Kamakura and Yoshiaki Nose : Micro-mainframe-like personal clinical research system, Springer-Verlag, Netherlands, Jun. 1991.
168.
Kengo Fukuzawa, Mitsuo Shimada, Hidetoshi Itasaka, Kenji Takenaka and Keizo Sugimachi : Ammonia elimination as a rapid index of viability in liver grafts in dogs, Elsevier Science Inc. USA, USA, Jan. 1991.
Katsuhiko Yanaga, Leonard Makowka, Mitsuo Shimada, G Lebeau, D Kahn, A L Mieles, L Sher, P Chapchap, G L Podesta and Thomas E Starzl : Improved method of porcine renal allografting for transplantation research, 1991.
(Summary)
This study presents a refined, reproducible, and clinically appropriate animal model of renal transplantation. A pair of kidneys are harvested from a donor pig and preserved in Euro-Collins' solution (4 degrees C). After a set period of preservation, the allografts are transplanted to two recipient pigs. The abdomen is entered through a midline incision. The right common iliac artery and vein are dissected and bilateral native nephrectomy is performed. Each allograft is then randomly assigned and transplanted to the recipients. Three minutes before unclamping, 100 mg of furosemide and 10 g of mannitol are given IV. Immediately after reperfusion, urine output is measured for 1 h. The allograft is biopsied and ureteroneocystostomy is created. Cystostomy is then placed using a 16F Foley catheter. The bladder neck is ligated to secure complete diversion of urine, and the abdomen is closed in layers. This kidney transplant model allows an absolutely paired study of the kidney allograft function from the same donor and also collection of pure urine at any time postoperatively, obviating the need for metabolic cages or sedation for urinary collection. This model and its unique modifications allow various transplant studies, including organ preservation, immunosuppressive protocol, and the prevention of reperfusion injury from oxygen free radicals.
Mitsuo Shimada, Kengo Fukuzawa, Hidetoshi Itasaka, Kenji Takenaka and Keizo Sugimachi : A simple and reliable assessment of liver allograft quality by analysis of effluent flushed from the grafts before liver transplantation in dogs, 1991.
171.
Kouhei Akazawa, Mitsuo Shimada, Y Hayashi, Yoshiaki Watanabe, Hidefumi Higashi, Sunao Moriguchi, K Fujisawa and Yoshiaki Nose : A disposable patient identification card made of a paper, Japan Hospital Association, Jul. 1990.
(Summary)
This paper describes a patient identification system with a disposable paper card. In general, total costs of cards themselves, equipments and personnel are remarkable, not negligible for the hospital management. Therefore, a disposable identification cards made of a paper were issued to out-patients in our hospital. Many order forms were integrated into only one sheet. Patient identification data were printed on this sheet by a computer system when a patient came to the reception desk, and quickly transmitted to physicians. We could save the hospital costs and printing works by physicians, and also shorten the waiting time of patients at reception desks.
(Keyword)
Ambulatory Care Information Systems / Disposable Equipment / Evaluation Studies as Topic / Japan / Medical Records Systems, Computerized / Outpatient Clinics, Hospital / Paper / Patient Identification Systems
(Link to Search Site for Scientific Articles)
● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 10108043
Mitsuo Shimada, Kouhei Akazawa, Hidefumi Higashi, Yoshiaki Watanabe, Y Hayashi, Sunao Moriguchi, K Fujisawa and Yoshiaki Nose : Development of an automatic medical summary report system, Japan Hospital Association, Jul. 1990.
(Summary)
We developed a medical summary report system. In this system, each department can specify the predetermined conditions for issuing the summary report. The summary is made through a hierarchical database in the integrated hospital information system according to the predetermined conditions. The summary automatically issued after reception of the outpatient, or also issued by on-line summary report program with the patient number if requested by doctors. The report is sent to the proper consulting room from the reception desk using an air-shooter. The report contains the patient information such as a patient name, age, sex, birthday, a clinic name, a chart number, a patient number, diagnoses and examinations. The doctors can refer to the points of the clinical history of the patient in his own and other departments, and make a correct diagnoses and avoid the overlaps of the examinations and medications. This system has contributed to the quality-up of the patient care by availability of patient information even in other departments without the medical chart.
(Keyword)
Hospital Information Systems / Japan / Medical Records / Medical Records Department, Hospital / Models, Theoretical / Outpatient Clinics, Hospital
(Link to Search Site for Scientific Articles)
● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 10108042
Hidefumi Higashi, Katsuhiko Yanaga, Mitsuo Shimada, Leonard Makowka, DH Thiel Van and Thomas E Starzl : Plasma lecithin/cholesterol acyltransferase (LCAT) activity in multiple-organ donors: a predictor of allograft viability in clinical liver transplantation, Apr. 1990.
Kengo Fukuzawa, Mitsuo Shimada, Kenji Takenaka and Keizo Sugimachi : Ex vivo perfusion for accurate assessment of liver graft viability in dogs, Taylor & Francis, 1990.
(Summary)
A new type of ex vivo liver perfusion model (EVPM) was developed. The system includes a physiological porto-portal connection, using a centrifugal pump and an aorto-aortal connection, through a heparin-coated tube. Ten pairs of mongrel dogs, weighing 13-20 kg, were used. Grafts of the liver procured from donors were perfused on the EVPM for 3 h. These grafts were divided into two groups: group A (n = 5), nonpreserved graft; group B (n = 5), 8-h graft preserved with lactated Ringer's solution (4 degrees C). The orthotopic liver transplantation (OLTx) series with the nonpreserved graft was reviewed, and dogs surviving for over 7 days following OLTx, group C (n = 5), were selected for liver grafts in the actual OLTx. In comparison with groups A and C, no difference was noted among enzyme levels (sGOT, sGPT, LDH) or in the recovery rate of ATP content in the graft liver tissue after revascularization. There were significant differences between group A and group B after revascularization. This simple and physiological EVPM accurately reflects graft function and hemodynamics in the actual OLTx. Graft viability, as a substitute for OLTx, in large animals can be reliably assessed. This EVPM is expected to contribute to research on events related to liver transplantation.
Katsuhiko Yanaga, Leonard Makowka, G Lebeau, R R Hwang, Mitsuo Shimada, Saburo Kakizoe, J A Demetris and Thomas E Starzl : A new liver perfusion and preservation system for transplantation research in large animals, Taylor & Francis, 1990.
(Summary)
A kidney perfusion machine, model MOX-100 (Waters Instruments, Ltd, Rochester, MN) was modified to allow continuous perfusion of the portal vein and pulsatile perfusion of the hepatic artery of the liver. Additional apparatus consists of a cooling system, a membrane oxygenator, a filter for foreign bodies, and bubble traps. This system not only allows hypothermic perfusion preservation of the liver graft, but furthermore enables investigation of ex vivo simulation of various circulatory circumstances in which physiological perfusion of the liver is studied. We have used this system to evaluate the viability of liver allografts preserved by cold storage. The liver was placed on the perfusion system and perfused with blood with a hematocrit of approximately 20%, and maintained at 37 degrees C for 3 h. The flows of the hepatic artery and portal vein were adjusted to 0.33 mL and 0.67 mL/g of liver tissue, respectively. Parameters of viability consisted of hourly bile output, oxygen consumption, liver enzymes, electrolytes, vascular resistance, and liver histology. This method of liver assessment in large animals will allow the objective evaluation of organ viability for transplantation and thereby improve the outcome of organ transplantation. Furthermore, this pump enables investigation into the pathophysiology of liver ischemia and preservation.
Katsuhiko Yanaga, Andreas G Tzakis, Mitsuo Shimada, William E Campbell, J Wallis Marsh, Andrei C Stieber, Leonard Makowka, Satoru Todo, Robert D Gordon, Shunzaburo Iwatsuki and Thomas E Starzl : Reversal of hypersplenism following orthotopic liver transplantation, Aug. 1989.
177.
Katsuhiko Yanaga, Mitsuo Shimada, Leonard Makowka, Hidefumi Higashi, Satoru Todo and Thomas E Starzl : The effect of preservation fluid on the blood flow of pediatric liver allografts, Aug. 1989.
Kenji Takenaka, Takashi Kanematsu, Mitsuo Shimada and Keizo Sugimachi : Low dose 1-hexylcarbamoyl-5-fluorouracil (HCFU) recommended for cirrhotic patients with hepatocellular carcinoma, Elsevier Science, Aug. 1989.
(Summary)
The metabolism of 1-hexylcarbamoyl-5-fluorouracil (HCFU), a drug prescribed for treating patients with hepatocellular carcinoma (HCC), was studied in relation to liver function, with the objective of clarifying the occurrence of any adverse side-effects on the central nervous system. Twenty-five HCC patients were administered 3.4 mg/kg HCFU once orally, after which the blood levels of HCFU and its derivatives (5-FU, CPEFU, CPRFU, HHCFU, OHCFU and F-beta-alanine) were serially measured using high performance liquid chromatography. The area under the concentration curve (AUC) of HCFU in the group of ICG R15 greater than or equal to 30% (group 2) was 5.35 +/- 1.73 h.micrograms/ml, a value which was significantly higher than the 2.60 +/- 1.19 h.micrograms/ml recorded for the group of ICG R15 less than 30% (group 1) (P less than 0.001). The AUC of HCFU had a significant positive correlation with the value of ICG R15 (P = 0.002) or the serum total bilirubin (P = 0.0005). The AUC of 5-FU showed no difference between the two groups. The AUC of CPRFU in group 2 was 0.16 +/- 0.25 h.micrograms/ml, a value significantly lower than the 0.48 +/- 0.39 h.micrograms/ml in group 1 (P = 0.023). There was no correlation between the AUC of other derivatives and the markers of liver function. These data suggest that, in patients with advanced cirrhosis, the accumulation of HCFU is related to the occurrence of side-effects from the administered drug, ingested over a long-term period. Therefore, when HCFU is given to cirrhotic patients with both HCC and 30% or more ICG R15, a careful monitoring for side-effects is required.
Katsuhiko Yanaga, Mitsuo Shimada, Leonard Makowka, O C Esquivel, Andreas G Tzakis and Thomas E Starzl : Significance of blood flow measurement in clinical liver transplantation, Feb. 1989.
Kenichiro Okadome, Hiroshi Eguchi, Takashi Yukizane, Yoichi Muto, Mitsuo Shimada and Keizo Sugimachi : Long-term results of arterial reconstruction of lower extremities determined by flow waveform analysis, Torino(Italy), Jan. 1989.
(Summary)
Arterial reconstructions of the lower extremities were reviewed to assess the usefulness of flow waveform analysis. Six hundred and thirty-four arterial reconstructions were divided into two groups: a former (1965-1973) group of 218 reconstructions not assessed by flow waveform analysis and a recent (1974-1985) group of 416 reconstructions analyzed according to flow waveform. The cumulative patency rates of the former and the recent group at 5 years were as follows: aorto-femoral, 75.2% and 86.7% (P less than 0.05); femoral-distal, 34.6% and 61.5% (P less than 0.001); extra-anatomical, 63.6% and 80.2% (P = 0.06), respectively. Based on the various flow waveforms evidenced intraoperatively, the cumulative patency rate of cases in the recent group with type 0 and I flow waveform was compared to the rate of those with type II flow waveform. The cumulative patency rates at 5 years were as follows: aorto-femoral, 92% and 82.7% (P = 0.15); femoral-distal, 77.7% and 49.3% (P less than 0.001); extra-anatomical, 91.8% and 68.9% (P less than 0.05), respectively. These results indicate that intraoperative flow waveform analysis is a simple and useful indicator for predicting the long-term results of arterial reconstruction.
Katsuhiko Yanaga, Leonard Makowka, Mitsuo Shimada, O C Esquivel, S J Bowman, Satoru Todo, Andreas G Tzakis and Thomas E Starzl : Hepatic artery thrombosis following pediatric liver transplantation:assessment of blood flow measurement in allografts, 1989.
Koichi Okamoto, Tomoyuki Kawaguchi, Kaizo Kagemoto, Yoshifumi Kida, Yasuhiro Mitsui, Fumika Nakamura, Kouzou Yoshikawa, Masahiro Sogabe, Yasushi Sato, Joji Shunto, Yoshimi Bando, Mitsuo Shimada and Tetsuji Takayama : Gastric fundic gland polyposis and cancer development after eradication of Helicobacter pylori in patient with gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS)., Gastric Cancer, Vol.27, No.3, 635-640, 2024.
(Summary)
A 44-year-old woman with gastric cancer (GC) and fundic gland polyposis (FGPs) was referred to our hospital for further diagnosis and treatment. She successfully underwent eradication therapy for Helicobacter pylori (HP) 6 years ago, but did not exhibit FGPs at that time. When she underwent an esophagogastroduodenoscopy 2, 4, and 5 years after the eradication of HP, her imaging results revealed the existence of FGPs which gradually increased in her gastric fundus and body. Gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS) was suspected and a mutational analysis was performed, revealing an APC promoter 1B variant c.-191T > C. A robotic total gastrectomy with lymphadenectomy was performed. Histopathological analysis of the surgical specimens revealed GC with no lymph node metastasis. GAPPS is characterized by GC and FGPs. However, our case shows different gastric phenotypes that are dependent on the status of HP infection.
Chie Takasu, Shuhai Chen, Luping Gao, Yu Saitou, Yuji Morine, Tetsuya Ikemoto, Shin-ichiro Yamada and Mitsuo Shimada : Role of Nrf2 signaling in development of hepatocyte-like cells, The Journal of Medical Investigation : JMI, Vol.70, No.3,4, 343-349, 2023.
(Summary)
Generation of hepatocytes from human adipose-derived mesenchymal stem cells (hADSCs) could be a promising alternative source of human hepatocytes. However, mechanisms to differentiate hepatocytes from hADSCs are not fully elucidated. We have previously demonstrated that our three-step differentiation protocol with glycogen synthase kinase (GSK) 3 inhibitor was effective to improve hepatocyte functions. In this study, we investigated the activation of the nuclear factor erythroid-2 related factor 2 (Nrf2) on hADSCs undergoing differentiation to HLC (hepatocyte-like cells). Our three-step differentiation protocol was applied for 21 days (Step 1:day 1-6, Step2:day 6-11, Step3:day 11-21). Our results show that significant nuclear translocation of Nrf2 occurred from day 11 until the end of HLC differentiation. Nuclear translocation of Nrf2 and CYP3A4 activity in the GSK3 inhibitor-treated group was obviously higher than that in Activin A-treated groups at day 11. The maturation of HLCs was delayed in Nrf2-siRNA group compared to control group. Furthermore, CYP3A4 activity in Nrf2-siRNA group was decreased at the almost same level in Activin A-treated group. Nrf2 translocation might enhance the function of HLC and be a target for developing highly functional HLC. J. Med. Invest. 70 : 343-349, August, 2023.
Shoko Yamashita, Chie Takasu, Yuji Morine, Hiroki Ishibashi, Tetsuya Ikemoto, Hiroki Mori, Shin-ichiro Yamada, Takeshi Oya, Koichi Tsuneyama and Mitsuo Shimada : Characteristic submucosal alteration in biliary carcinogenesis of pancreaticobiliary maljunction with a focus on inflammasome activation., Journal of Hepato-Biliary-Pancreatic Sciences, Vol.30, No.4, 462-472, 2023.
(Summary)
Activated fibroblasts and M2 macrophages in the GB lamina propria may be associated with biliary carcinogenesis of PBM, possibly through inflammasome activation.
Shohei Okikawa, Hideya Kashihara, Mitsuo Shimada, Kouzou Yoshikawa, Takuya Tokunaga, Masaaki Nishi, Chie Takasu, Yuuma Wada and Toshiaki Yoshimoto : Effect of duodenal-jejunal bypass on diabetes in the early postoperative period, Scientific Reports, Vol.13, No.1, 1856-1856, 2023.
(Summary)
<jats:title>Abstract</jats:title><jats:p>Metabolic surgery is an effective treatment for patients with type 2 diabetes mellitus (T2DM). The aim of this study was to investigate the effect of duodenal-jejunal bypass (DJB) in a rat model of T2DM during the early postoperative period. A rat model of non-obese T2DM was allocated to two groups: a sham group and a DJB group. On postoperative day 1 (1POD), oral glucose tolerance testing (OGTT) was performed and the changes of glucose transporter expressions in the small intestine was evaluated. [18F]-fluorodeoxyglucose ([18]-FDG) uptake was measured in sham- and DJB-operated rats using positron emission tomography-computed tomography (PET-CT). DJB improved the glucose tolerance of the rats on 1POD. The expression of sodium-glucose cotransporter 1 (SGLT1) and glucose transporter 1 (GLUT1) was high, and that of GLUT2 was low in the alimentary limb (AL) of rats in the DJB group. PET-CT showed that [18F]-FDG uptake was high in the proximal jejunum of DJB-operated rats. These results may show that DJB improve glucose tolerance in very early postoperative period as the result of glucose accumulation in the AL because of changes in glucose transporter expression.</jats:p>
Shohei Okikawa, Hideya Kashihara, Mitsuo Shimada, Kouzou Yoshikawa, Takuya Tokunaga, Masaaki Nishi, Chie Takasu, Yuuma Wada and Toshiaki Yoshimoto : Effect of duodenal-jejunal bypass on diabetes in the early postoperative period., Scientific Reports, Vol.13, No.1, 1856, 2023.
(Summary)
Metabolic surgery is an effective treatment for patients with type 2 diabetes mellitus (T2DM). The aim of this study was to investigate the effect of duodenal-jejunal bypass (DJB) in a rat model of T2DM during the early postoperative period. A rat model of non-obese T2DM was allocated to two groups: a sham group and a DJB group. On postoperative day 1 (1POD), oral glucose tolerance testing (OGTT) was performed and the changes of glucose transporter expressions in the small intestine was evaluated. [18F]-fluorodeoxyglucose ([18]-FDG) uptake was measured in sham- and DJB-operated rats using positron emission tomography-computed tomography (PET-CT). DJB improved the glucose tolerance of the rats on 1POD. The expression of sodium-glucose cotransporter 1 (SGLT1) and glucose transporter 1 (GLUT1) was high, and that of GLUT2 was low in the alimentary limb (AL) of rats in the DJB group. PET-CT showed that [18F]-FDG uptake was high in the proximal jejunum of DJB-operated rats. These results may show that DJB improve glucose tolerance in very early postoperative period as the result of glucose accumulation in the AL because of changes in glucose transporter expression.
Shin-ichiro Yamada, Yuji Morine, Satoru Imura, Tetsuya Ikemoto, Yu Saitou, Mayuko Shimizu, Koichi Tsuneyama, Mitsue Nishiyama, Shiori Ishizawa and Mitsuo Shimada : Effect of daikenchuto (TU-100) on carcinogenesis in non-alcoholic steatohepatitis., The Journal of Medical Investigation : JMI, Vol.70, No.1.2, 66-73, 2023.
(Summary)
TU-100 regulates the intestinal microbiome and may suppress subsequent hepatocarcinogenesis in the NASH model. J. Med. Invest. 70 : 66-73, February, 2023.
Shin-ichiro Yamada, Yuji Morine, Tetsuya Ikemoto, Yu Saitou, Katsuki Miyazaki, Mayuko Shimizu, Koichi Tsuneyama and Mitsuo Shimada : Inhibitory effect of non-alcoholic steatohepatitis on colon cancer liver metastasis., EJSO - European Journal of Surgical Oncology, Vol.49, No.2, 410-415, 2023.
(Summary)
The WD-fed NASH mouse model showed an inhibitory effect on CLM. Suppressed interleukin-6/signal transducer and activator of transcription 3 signaling and serum amyloid A/matrix metalloproteinase 9 expression may affect this phenomenon.
Satoshi Sumida, Mayuko Shimizu, Yuko Miyakami, Takumi Kakimoto, Tomoko Kobayashi, Yasuyo Saijo, Minoru Matsumoto, Hirohisa Ogawa, Takeshi Oya, Yoshimi Bando, Hisanori Uehara, Shu Taira, Mitsuo Shimada and Koichi Tsuneyama : Histological and immunohistochemical analysis of epithelial cells in epidermoid cysts in intrapancreatic accessory spleen., The Journal of Medical Investigation : JMI, Vol.70, No.1.2, 251-259, 2023.
(Summary)
Novel histological features of epithelial cells of ECIPAS were indicated. Although more cases need to be evaluated, we propose that the cause of ECIPAS may be different from that of pancreatic ductal origin. J. Med. Invest. 70 : 251-259, February, 2023.
Shinji Nagasaka, Yoshiro Abe, Yutaro Yamashita, Hiroyuki Yamasaki, Kazuhide Mineda, Mitsuo Shimada and Ichiro Hashimoto : Radiographic Study Evaluating Perforator Vessels in the Ischiorectal Fossa for Safe Elevation of Island Flaps, Plastic and Reconstructive Surgery. Global Open, Vol.10, No.10, e4561, 2022.
(Summary)
Perforator flaps based on the ischiorectal fossa (IRF) (ie, internal pudendal artery perforator flaps) are useful for perineal reconstruction. The three-dimensional characterization of perforator arteries in the IRF remains unclear, as the IRF contains thick adipose tissue as well as organs, such as the rectum, vagina, and urethra. This study aimed to evaluate perforators in the IRF to guide the safe elevation of skin flaps designed based on the IRF. IRF vessels were examined in 200 bilateral computed tomography angiography scans performed in 100 patients. We examined branching patterns arising from the internal iliac artery and the origins of the skin perforators in the IRF. The branching patterns of the internal iliac artery were divided into three groups: perforators derived exclusively from the internal pudendal artery (78%), perforators derived from the internal pudendal artery and the inferior gluteal artery (18%), and perforators derived exclusively from the inferior gluteal artery (4%). The average number of perforators in the IRF was 1.5 ± 0.7. The number of perforators was significantly higher in women than in men. The perforator arteries were found exclusively around the medial and dorsal sides of the ischial tuberosity. We found that perforators in the IRF were stable. All cases had more than one skin perforator, which was mainly derived from the internal pudendal artery. Although perforators cannot be identified during flap elevation because the fatty tissue in the IRF is very thick, physicians must focus on preserving the perforator-containing fatty tissue around the ischial tuberosity.
Beibei Ma, Hiroyuki Ueda, Koichi Okamoto, Masahiro Bando, Shota Fujimoto, Yasuyuki Okada, Tomoyuki Kawaguchi, Hironori Wada, Hiroshi Miyamoto, Mitsuo Shimada, Yasushi Sato and Tetsuji Takayama : TIMP1 promotes cell proliferation and invasion capability of right-sided colon cancers via the FAK/Akt signaling pathway., Cancer Science, Vol.113, No.12, 4244-4257, 2022.
(Summary)
Although right-sided colorectal cancer (CRC) shows a worse prognosis than left-sided CRC, the underlying mechanism remains unclear. We established patient-derived organoids (PDOs) from left- and right-sided CRCs and directly compared cell proliferation and invasion capability between them. We then analyzed the expression of numerous genes in signal transduction pathways to clarify the mechanism of the differential prognosis. Cell proliferation activity and invasion capability in right-sided cancer PDOs were significantly higher than in left-sided cancer PDOs and normal PDOs, as revealed by Cell Titer Glo and transwell assays, respectively. We then used quantitative RT-PCR to compare 184 genes in 30 pathways among right-sided and left-sided cancer and normal PDOs and found that the TIMP1 mRNA level was highest in right-sided PDOs. TIMP1 protein levels were upregulated in right-sided PDOs compared with normal PDOs but was downregulated in left-sided PDOs. TIMP1 knockdown with shRNA significantly decreased cell proliferation activity and invasion capability in right-sided PDOs but not in left-sided PDOs. Moreover, TIMP1 knockdown significantly decreased pFAK and pAkt expression levels in right-sided PDOs but not in left-sided PDOs. A database analysis of The Cancer Genome Atlas revealed that TIMP1 expression in right-sided CRCs was significantly higher than in left-sided CRCs. Kaplan-Meier survival analysis showed significantly shorter overall survival in high-TIMP1 patients versus low-TIMP1 patients with right-sided CRCs but not left-sided CRCs. Our data suggest that TIMP1 is overexpressed in right-sided CRCs and promotes cell proliferation and invasion capability through the TIMP1/FAK/Akt pathway, leading to a poor prognosis. The TIMP1/FAK/Akt pathway can be a target for therapeutic agents in right-sided CRCs.
(Keyword)
Humans / Prognosis / Signal Transduction / Colorectal Neoplasms / Colonic Neoplasms / Cell Proliferation / Tissue Inhibitor of Metalloproteinase-1
Nanami Nasu, Sonoko Yasui-Yamada, Natsumi Kagiya, Mami Takimoto, Yumiko Kurokawa, Yoshiko Suzuki, Hideya Kashihara, Yu Saitou, Masaaki Nishi, Mitsuo Shimada and Yasuhiro Hamada : Muscle strength is a stronger prognostic factor than muscle mass in patients with gastrointestinal and hepatobiliary-pancreatic cancers., Nutrition, Vol.103-104, 111826, 2022.
(Summary)
Sarcopenia has been reported as a prognostic risk factor in patients with gastrointestinal (GI) and hepatobiliary pancreatic (HBP) cancers. This study aimed to investigate whether the loss of muscle mass or strength is a stronger prognostic factor, and explore the cutoff values of skeletal muscle mass index (SMI) and handgrip strength (HGS) based on the survival outcome in patients with GI and HBP cancers. A total of 480 elderly patients with primary GI and HBP cancers who underwent their first resection surgery were analyzed retrospectively. Patients were divided into four groups: Appropriate SMI and HGS, low SMI alone, low HGS alone, and low SMI and HGS. Low SMI was derived from a bioelectrical impedance analysis, and low HGS was defined according to the Asian Working Group for Sarcopenia 2019 criteria. The multivariate analysis showed that low SMI was a significant risk factor for mortality in men only, but low HGS was significant in both sexes. From the multivariate analysis of the four groups, low HGS alone and low SMI and HGS showed a significantly higher hazard ratio than appropriate SMI and HGS in both sexes. An SMI of 7.21 kg/m and HGS of 28 kg were obtained as cutoff values based on the 3-y survival outcomes in men. Low muscle strength was a stronger prognostic factor than low muscle mass. Therefore, measuring muscle strength in all patients is essential.
Yosuke Iwakawa, Kouzou Yoshikawa, Koichi Okamoto, Tetsuji Takayama, Takuya Tokunaga, Toshihiro Nakao, Masaaki Nishi, Chie Takasu, Hideya Kashihara, Yuuma Wada, Toshiaki Yoshimoto, Shoko Yamashita and Mitsuo Shimada : Four cases of gastric adenocarcinoma and proximal polyposis of the stomach treated by robotic total gastrectomy, Surgical Case Reports, Vol.8, No.1, 70, 2022.
(Summary)
Gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS) is a rare disease and characterized by a unique point mutation in the promoter 1B region of the adenomatous polyposis coli (APC) gene. There are two aims in surgery for GAPPS; the first is prophylactic gastrectomy, and the second is excising concurrent cancer. We performed robotic total gastrectomy (RTG) for four cases of GAPPS. Case 1 was a woman in her 40 s whose sister had died from gastric cancer. Mutational analysis revealed mutation of APC exon 1B. We performed prophylactic gastrectomy. Case 2 was a woman in her 30 s who had a mutation of APC exon 1B, and preoperative biopsy revealed suspected adenocarcinoma. Case 3 was a woman in her 40 s who was diagnosed with gastric cancer with multiple polyps in the stomach and a mutation of APC exon 1B. Case 4 was a woman in her 20 s in whom biopsy revealed low-grade dysplasia of a raised lesion. She had a mutation in APC exon 1B. We performed RTG with D1 + lymphadenectomy in all patients, and there were no intraoperative complications. Patients with GAPPS are mainly followed regularly with repeat biopsy, and tumors are detected in an early stage. As the safety of robotic surgery for the early gastric cancer is reported, RTG is an option for these patients. This is the first report of RTG for GAPPS patients.
Shoko Yamashita, Masaaki Nishi, Kozo Yoshikawa, Toshihiro Nakao, Takuya Tokunaga, Chie Takasu, Hideya Kashihara, Yuma Wada, Toshiaki Yoshimoto, Yosuke Iwakawa, Takeshi Oya, Koichi Tsuneyama and Mitsuo Shimada : Gastric carcinoma with lymphoid stroma derived from hamartomatous inverted polyp with osteoclast-like giant cells: a case report., International Cancer Conference Journal, Vol.11, No.3, 196-200, 2022.
(Summary)
Gastric carcinomas with lymphoid stroma (GCLS) are characterized by prominent stromal infiltration of lymphocyte and account for 1-4% of gastric cancers. Although, osteoclast-like giant cells (OGC) have been reported in some GCLS, OGCs in gastric tumors is exceedingly rare. A 60-year-old woman presented to our hospital after the finding of a positive fecal blood test during a routine medical check. Esophagogastroduodenoscopy revealed a Type 0-III + IIc tumor in the middle part of the gastric body. Biopsy revealed a poorly differentiated tumor and she was referred to our department. Early phase computed tomography showed thickening of the wall in the middle of the gastric body and enlargement of nearby lymph nodes. Laparoscopic total gastrectomy was performed. Pathological examination revealed a hamartomatous inverted polyp (HIP) in the submucosal layer with tub2-por1 tumor in the HIP. Prominent lymphocytic infiltration and OGCs were found around the tumor. Immunohistochemical analysis showed that the tumor cells were negative for EBER, MLH-1, and MSH2, 6. These findings suggest that this tumor was a non-microsatellite instability (MSI)-high GCLS without Epstein-Barr virus (EBV) infection. The patient's postoperative course was uneventful and she was discharged 11 days after surgery. She remains well 3 years after surgery.
Hiroki Mori, Hiroki Ishibashi, Noriko Yokota and Mitsuo Shimada : Risk factors for metachronous contralateral inguinal hernia after laparoscopic percutaneous extraperitoneal closure for unilateral inguinal hernia in children., Surgery Today, Vol.52, No.10, 1491-1496, 2022.
(Summary)
We use the laparoscopic percutaneous extraperitoneal closure (LPEC) method as the standard procedure for pediatric inguinal hernia. Despite judging there to be no contralateral patent processus vaginalis (PPV) at the time of the first LPEC, we experienced five cases in which metachronous contralateral inguinal hernia (MCH) developed, so we report the characteristics, including the predictors. For pediatric inguinal hernia, the LPEC method was used in 1277 cases from 2005 to 2019 in our department. Of these, 374 patients underwent unilateral LPEC, and we compared the 5 patients with MCH onset and the 369 without MCH onset. The items to be examined were the gender, age, presence of a low birth weight, initial-onset side, and contralateral internal inguinal ring classification. There was no significant difference in the gender, age, initial-onset side, or contralateral internal inguinal ring classification between the two groups. Low-birth-weight infants were significantly more common among those with MCH than among those without MCH. The only predictor of a contralateral onset after LPEC for pediatric inguinal hernia was a low birth weight. Therefore, for the above-mentioned unilateral LPEC cases, the possibility of a contralateral onset after LPEC due to acquired factors rather than congenital factors should be considered.
Mami Takimoto, Sonoko Yasui-Yamada, Nanami Nasu, Natsumi Kagiya, Nozomi Aotani, Yumiko Kurokawa, Yoshiko Suzuki, Hideya Kashihara, Yu Saitou, Masaaki Nishi, Mitsuo Shimada and Yasuhiro Hamada : Development and Validation of Cutoff Value for Reduced Muscle Mass for GLIM Criteria in Patients with Gastrointestinal and HepatobiliaryPancreatic Cancers, Nutrients, Vol.14, No.943, 1-10, 2022.
(Summary)
The Global Leadership Initiative on Malnutrition (GLIM) criteria recommends using race- and sex-adjusted cutoff values for reduced muscle mass (RMM), but the only cutoff values available for Asians are the skeletal muscle mass index (SMI) established by the Asian Working Group for Sarcopenia (AWGS). This retrospective study aimed to develop and validate cutoff values for the fat-free mass index (FFMI) and arm circumference (AC) of Asians, and to investigate the association between GLIM malnutrition and prognosis. A total of 660 patients with primary gastrointestinal (GI) and hepatobiliary-pancreatic (HBP) cancers who underwent their first resection surgery were recruited and randomly divided into development and validation groups. The FFMI and AC cutoff values were calculated by receiver operating characteristic curve analysis for the AWGS SMI as the gold standard. The cutoff values for each RMM were used to diagnose malnutrition on the basis of GLIM criteria, and the survival rates were compared. The optimal FFMI cutoff values for RMM were 17 kg/m for men and 15 kg/m for women, and for AC were 27 cm for men and 25 cm for women. In the validation group, the accuracy of the FFMI and AC cutoff values to discriminate RMM were 85.2% and 68.8%, respectively. Using any of the three measures of RMM, overall survival rates were significantly lower in the GLIM malnutrition group. In conclusion, the cutoff values for the FFMI and AC in this study could discriminate RMM, and GLIM malnutrition using these cutoff values was associated with decreased survival.
Hiroki Ishibashi, Noriko Yokota, Hiroki Mori and Mitsuo Shimada : 【小児外科疾患の家族内発生】側頸瘻, Japanese Journal of Pediatric Surgery, Vol.53, No.12, 1243-1247, 2021.
Yu Saitou, Mitsuo Shimada, Yuji Morine, Shin-ichiro Yamada and Maki Sugimoto : Essential updates 2020/2021: Current topics of simulation and navigation in hepatectomy., Annals of Gastroenterological Surgery, Vol.6, No.2, 190-196, 2021.
(Summary)
With the development of three-dimensional (3D) simulation software, preoperative simulation technology is almost completely established. The remaining issue is how to recognize anatomy three-dimensionally. Extended reality is a newly developed technology with several merits for surgical application: no requirement for a sterilized display monitor, better spatial awareness, and the ability to share 3D images among all surgeons. Various technology or devices for intraoperative navigation have also been developed to support the safety and certainty of liver surgery. Consensus recommendations regarding indocyanine green fluorescence were determined in 2021. Extended reality has also been applied to intraoperative navigation, and artificial intelligence (AI) is one of the topics of real-time navigation. AI might overcome the problem of liver deformity with automatic registration. Including the issues described above, this article focuses on recent advances in simulation and navigation in liver surgery from 2020 to 2021.
Masaki Kaibori, Kosuke Matsui, Mitsuo Shimada, Shoji Kubo and Kiyoshi Hasegawa : Update on perioperative management of patients undergoing surgery for liver cancer., Annals of Gastroenterological Surgery, Vol.6, No.3, 344-354, 2021.
(Summary)
Hepatocellular carcinoma is often accompanied by chronic hepatitis or cirrhosis. Preoperative evaluation of liver function and postoperative nutritional management are critical in patients with hepatocellular carcinoma who undergo liver surgery. Although the incidence of postoperative complications and death has declined in Japan over the last 10 years, postoperative complications have not been fully overcome. Therefore, surgical procedures and perioperative management must be improved. Accurate preoperative evaluations of liver function, nutrition, inflammation, and body skeletal muscle are required. Determination of the optimal surgical procedure should consider not only tumor characteristics but also the physical reserve of the patient. Nutritional management of chronic liver disorders, especially maintaining protein synthesis for postoperative protein/energy, is important. Prophylactic antibiotics are recommended for short-term use within 24 hours after surgery. Abdominal drainage is recommended for patients with cirrhosis who may develop large amounts of ascites, who are at risk of postoperative bleeding, or who may have bile leakage due to a large resection area. Postoperative exercise therapy may improve insulin resistance in patients with chronic liver damage. Implementation of an early/enhanced recovery after surgery program is recommended to reduce biological invasive responses and achieve early independence of physical activity and nutrition intake. We review the latest information on the perioperative management of patients undergoing liver resection for hepatocellular carcinoma.
Jun Uemura, Keiichi Okano, Minoru Oshima, Hironobu Suto, Yasuhisa Ando, Kensuke Kumamoto, Kyuichi Kadota, Shuji Ichihara, Yasutaka Kokudo, Takashi Maeba, Yoshihide Nanno, Hirochika Toyama, Yasutsugu Takada, Mitsuo Shimada, Kazuhiro Hanazaki, Tsutomu Masaki and Yasuyuki Suzuki : Immunohistochemically Detected Expression of ATRX, TSC2, and PTEN Predicts Clinical Outcomes in Patients With Grade 1 and 2 Pancreatic Neuroendocrine Tumors., Annals of Surgery, Vol.274, No.6, e949-e956, 2021.
(Summary)
The goal of this retrospective study was to clarify the clinical implications of immunohistochemically detected protein expression for genes that are frequently mutated in pancreatic neuroendocrine tumors (PNETs). The clinical management of PNETs is hindered by their heterogenous biological behavior. Whole-exome sequencing recently showed that 5 genes (DAXX/ATRX, MEN1, TSC2, and PTEN) are frequently mutated in PNETs. However, the clinical implications of the associated alterations in protein expression remain unclear. We collected Grade 1 and 2 (World Health Organization 2017 Classification) primary PNETs samples from 100 patients who underwent surgical resection. ATRX, DAXX, MEN1, TSC2, and PTEN expression were determined immunohistochemically to clarify their relationships with prognosis and clinicopathological findings. Kaplan-Meier analysis indicated that loss of TSC2 (n = 58) or PTEN (n = 37) was associated with significantly shorter overall survival, and that loss of TSC2 or ATRX (n = 41) was associated with significantly shorter recurrence-free survival. Additionally, loss of ATRX or TSC2 was significantly associated with nodal metastasis. In a multivariate analysis, combined loss of TSC2 and ATRX (n = 31) was an independent prognostic factor for shorter recurrence-free survival (hazard ratio 10.1, 95% confidence interval 2.1-66.9, P = 0.003) in G2 PNETs. Loss of ATRX, TSC2, and PTEN expression might be useful as a method of clarifying the behavior and clinical outcomes of Grade 1 and 2 PNETs in routine clinical practice. Combined loss of TSC2 and ATRX had an especially strong, independent association with shorter recurrence-free survival in patients with G2 PNETs. Loss of pairs in ATRX, TSC2, or PTEN would be useful for selecting the candidate for postoperative adjuvant therapy.
Katsuki Miyazaki, Yuji Morine, Shin-ichiro Yamada, Yu Saitou, Kazunori Tokuda, Shohei Okikawa, Shoko Yamashita, Takeshi Oya, Tetsuya Ikemoto, Satoru Imura, Haun Hu, Hisayoshi Morioka, Koichi Tsuneyama and Mitsuo Shimada : Stromal tumor-infiltrating lymphocytes level as a prognostic factor for resected intrahepatic cholangiocarcinoma and its prediction by apparent diffusion coefficient., International Journal of Clinical Oncology, Vol.26, No.12, 2265-2274, 2021.
(Summary)
Tumor-infiltrating lymphocytes (TILs) are a prognostic factor or an indicator of chemotherapy response for various malignancies. The aim of this study was to investigate the prognostic impact of TILs in resected intrahepatic cholangiocarcinoma (IHCC). We also investigated the usefulness of the apparent diffusion coefficient (ADC) in diffusion-weighted magnetic resonance imaging (DW-MRI) to predict TILs. We enrolled 23 patients with IHCC who underwent initial hepatic resection in Tokushima University Hospital from 2006 to 2017. We evaluated stromal TILs in the tumor marginal area and central area in surgical specimens. Patients were divided into low vs high stromal TILs groups. We analyzed the patients' clinicopathological factors, including prognosis, according to the degree of stromal TILs. We also analyzed the correlation between stromal TILs and the minimum ADC value. Stromal TILs in the marginal area reflected overall survival more accurately than that in the central area. Additionally, marginal low TILs was significantly associated with lymph node metastasis and portal vein invasion. Both overall- and disease-free survival rates in the marginal low TILs group were significantly worse than those in the marginal high TILs group (P < 0.05). In the multivariate analysis, marginal low TILs were an independent prognostic factor for both overall- and disease-free survival (P < 0.05), and marginal low TILs were significantly associated with lower minimum ADC values (P < 0.02). Stromal TILs, especially in the marginal area, might demonstrate prognostic impact in patients with IHCC. Moreover, the ADC values from MRI may predict TILs in IHCC tumor tissue.
(Keyword)
Bile Duct Neoplasms / Bile Ducts, Intrahepatic / Cholangiocarcinoma / Diffusion Magnetic Resonance Imaging / Humans / Lymphocytes, Tumor-Infiltrating / Prognosis
Hiroki Ishibashi, Noriko Yokota, Hiroki Mori and Mitsuo Shimada : 【消化管重複症のすべて】腹部食道, Japanese Journal of Pediatric Surgery, Vol.53, No.9, 924-929, 2021.
Yu Saitou, Tetsuya Ikemoto, Kazunori Tokuda, Katsuki Miyazaki, Shin-ichiro Yamada, Satoru Imura, Masato Miyake, Yuji Morine, Seiichi Oyadomari and Mitsuo Shimada : Effective three-dimensional culture of hepatocyte-like cells generated from human adipose-derived mesenchymal stem cells., Journal of Hepato-Biliary-Pancreatic Sciences, Vol.28, No.9, 705-715, 2021.
(Summary)
The aim of this study was to clarify the effectiveness of a new three-dimensional (3D) culture system for hepatocyte-like cells (HLCs) generated from human adipose-derived mesenchymal stem cells (ADSCs). Human ADSCs (2 × 10 ) with or without 0.1 mg/mL human recombinant peptide μ-piece per well were seeded in a 96-well U-bottom plate and then our three-step differentiation protocol was applied for 21 days. At each step, cell morphology and gene expression were investigated. Mature hepatocyte functions were evaluated after HLC differentiation. These parameters were compared between 2D- and 3D-cultured HLCs, and, DNA microarray analysis was also performed. Finally, HLCs were transplanted in to CCl induced acute liver failure model mice. Two-dimensional-cultured HLCs at day 21 did not have a spindle shape and had formed spheroids after day 6, which gradually increased in size for 3D-cultured HLCs. Definitive endoderm, hepatoblast, and hepatocyte genes showed significantly higher expression in the 3D culture group. Three-dimensional-cultured HLCs also had higher albumin expression, CYP3A4 activity, urea synthesis, and ammonium metabolism, and much higher expression of ion transporter, blood coagulation, and cell communication genes. HLC transplantation improved serum liver function, especially in T-Bil levels, and engrafted into immunodeficient mice with HLA class I positive staining. Our new 3D culture protocol is effective to improve hepatocyte functions. Our HLCs might be promising for clinical cell transplantation to treat metabolic disease.
Masaaki Nishi, Ryosuke Miyamoto, Kasane Shima, Hirokazu Miki, Hideo Terasawa, Chie Takasu, Kouzou Yoshikawa, Takuro Oyama, Katsuya Tanaka, Yuishin Izumi and Mitsuo Shimada : Robot-assisted total gastrectomy for gastric cancer in a patient with amyotrophic lateral sclerosis receiving long-term tracheostomy invasive ventilation, International Cancer Conference Journal, Vol.10, No.4, 318-323, 2021.
(Summary)
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease. Although affected patients may develop cancers, major surgical intervention has been hampered by its questionable overall benefit due to limited prognosis and risk of postoperative respiratory collapse. A recent study, however, showed that tracheostomy invasive ventilation (TIV) prolonged median survival to 11.3 years; thus, patients with ALS receiving TIV might benefit from major surgery. A 66-year-old man with ALS, who had received TIV and enteral tube feeding for 8 years, presented with bloody stool. The patient also had type 2 diabetes mellitus, stage 4 chronic kidney disease, abdominal aortic aneurysm, and anti-phospholipid syndrome, as well as multiple episodes of pneumonia and catheter-related urinary tract infection treated by antibiotics. Medical examination and esophagogastroduodenoscopy revealed a type 3 tumor in the middle part of the stomach. The patient's preoperative diagnosis was gastric cancer (GC), MU, type3, Less-Post, T3(SS), N1, H0, P0, M0, cStage III. The estimated mortality rate was 30.5%, according to the Japanese National Clinical Database. The patient and his family were fully informed of the risk of surgery; the patient clearly requested curative surgery by eye movement. Thus, robot-assisted total gastrectomy (RATG) was performed. The tissues were extremely fragile and hemorrhagic. The surgical time was 7 h 0 min; intraoperative blood loss was 324 ml. Pathological examination revealed GC, MU, type3, T4a(SE), N2, H0, CY0, P0, M0 fStage IIIB. The postoperative course was uneventful. He has remained in stable condition for 3 months. Our findings suggest that patients with ALS who achieve longer survival with TIV can undergo major cancer surgery, including robot-assisted surgery, which may facilitate a better mid-long-term prognosis. The online version contains supplementary material available at 10.1007/s13691-021-00499-7.
Yuji Morine, Hiroki Ishibashi and Mitsuo Shimada : 【胆管損傷と(医原性)術後胆管狭窄:回避とリカバリー法】先天性胆道拡張症手術における胆道再建と術後胆管狭窄へのリカバリーショット, Journal of Biliary Tract & Pancreas, Vol.42, No.7, 631-637, 2021.
26.
Hiroki Ishibashi, Noriko Yokota, Hiroki Mori and Mitsuo Shimada : 【シミュレーションとナビゲーション】胸腔鏡下肺葉切除術, Japanese Journal of Pediatric Surgery, Vol.53, No.5, 520-524, 2021.
The Clinical Practice Manual for Hepatocellular Carcinoma was published based on evidence confirmed by the Evidence-based Clinical Practice Guidelines for Hepatocellular Carcinoma along with consensus opinion among a Japan Society of Hepatology (JSH) expert panel on hepatocellular carcinoma (HCC). Since the JSH Clinical Practice Guidelines are based on original articles with extremely high levels of evidence, expert opinions on HCC management in clinical practice or consensus on newly developed treatments are not included. However, the practice manual incorporates the literature based on clinical data, expert opinion, and real-world clinical practice currently conducted in Japan to facilitate its use by clinicians. Alongside each revision of the JSH Guidelines, we issued an update to the manual, with the first edition of the manual published in 2007, the second edition in 2010, the third edition in 2015, and the fourth edition in 2020, which includes the 2017 edition of the JSH Guideline. This article is an excerpt from the fourth edition of the HCC Clinical Practice Manual focusing on pathology, diagnosis, and treatment of HCC. It is designed as a practical manual different from the latest version of the JSH Clinical Practice Guidelines. This practice manual was written by an expert panel from the JSH, with emphasis on the consensus statements and recommendations for the management of HCC proposed by the JSH expert panel. In this article, we included newly developed clinical practices that are relatively common among Japanese experts in this field, although all of their statements are not associated with a high level of evidence, but these practices are likely to be incorporated into guidelines in the future. To write this article, coauthors from different institutions drafted the content and then critically reviewed each other's work. The revised content was then critically reviewed by the Board of Directors and the Planning and Public Relations Committee of JSH before publication to confirm the consensus statements and recommendations. The consensus statements and recommendations presented in this report represent measures actually being conducted at the highest-level HCC treatment centers in Japan. We hope this article provides insight into the actual situation of HCC practice in Japan, thereby affecting the global practice pattern in the management of HCC.
Shoko Yamashita, Yuji Morine, Satoru Imura, Tetsuya Ikemoto, Yu Saitou, Chie Takasu, Shinichiro Yamada, Kazunori Tokuda, Shohei Okikawa, Katsuki Miyazaki, Takeshi Oya, Koichi Tsuneyama and Mitsuo Shimada : A new pathological classification of intrahepatic cholangiocarcinoma according to protein expression of SSTR2 and Bcl2., World Journal of Surgical Oncology, Vol.19, No.1, 142, 2021.
(Summary)
This method could be used to classify IHCC into peripheral and perihilar type by embryological expression patterns of SSTR2 and Bcl2.
(Keyword)
Bile Duct Neoplasms / Bile Ducts, Intrahepatic / Cholangiocarcinoma / Humans / Prognosis / Proto-Oncogene Proteins c-bcl-2 / Receptors, Somatostatin
Nozomi Aotani, Sonoko Yasui-Yamada, Natsumi Kagiya, TAKIMOTO Mami, Yu Ohiwa, Matsubara Atsumi, Sayaka Matsura, Mayu Tanimura, Yoshiko Suzuki, Hideya Kashihara, Yu Saitou, Masaaki Nishi, Mitsuo Shimada and Yasuhiro Hamada : Malnutrition by European Society for Clinical Nutrition and Metabolism criteria predicts prognosis in patients with gastrointestinal and hepatobiliary-pancreatic cancer, Clinical Nutrition ESPEN, Vol.42, 265-271, 2021.
(Summary)
The European Society for Clinical Nutrition and Metabolism (ESPEN) proposed the ESPEN diagnostic criteria (EDC) for malnutrition in 2015. There is no report on the association between the EDC and prognosis in patients with gastrointestinal (GI) and hepatobiliary-pancreatic (HBP) cancer. This study aimed to (1) determine the prevalence of EDC malnutrition, (2) investigate the validity of the EDC as a nutritional and prognostic indicator, and (3) examine which components of the EDC are most related to long-term prognosis in patients with GI and HBP cancers. A total of 634 patients with primary GI and HBP cancers who underwent their first resection surgery between July 2014 and March 2018 were retrospectively recruited. According to the EDC, patients were divided into malnourished and non-malnourished groups. Clinical parameters and survival between these two groups were compared. The prognostic effects of the EDC and the EDC components were analyzed using Cox proportional hazard models. The prevalence of EDC malnutrition was 22%. Anthropometric data and biochemical data were associated with EDC malnutrition. The 5-year survival rate was lower in the malnourished group (72%) than in the non-malnourished group (73%; P = 0.007). The multivariate analysis demonstrated that the malnourished group was an independent risk factor for mortality (hazard ratio = 1.70 in the malnourished group; 95% confidence interval 1.08-2.63; P = 0.024). Among EDC components, body mass index (BMI) of <18.5 kg/m was an independent poor prognostic factor. EDC malnutrition is associated with poor postoperative long-term prognosis. Among the EDC components, BMI of <18.5 kg/m is most associated with prognosis in patients with preoperative GI and HBP cancers.
Yusuke Arakawa, Katsuki Miyazaki, Masato Yoshikawa, Shin-ichiro Yamada, Yu Saitou, Tetsuya Ikemoto, Satoru Imura, Yuji Morine and Mitsuo Shimada : Value of the fibrinogen-platelet ratio in patients with resectable pancreatic cancer., The Journal of Medical Investigation : JMI, Vol.68, No.3.4, 342-346, 2021.
(Summary)
Background : Several prognostic factors were reported in pancreatic cancer. The fibrinogen-platelet ratio (FPR) was reported as a prognostic factor of resectable gastric cancer. In this report, the FPR was evaluated in patients with resectable pancreatic cancer. Methods : Between 2004 and 2019, 163 patients with curative resection for pancreatic cancer were enrolled. Cases of non-curative resection were excluded. The FPR was calculated using the preoperative plasma fibrinogen and the platelet counts and the cut-off value was determined by receiver operating characteristic (ROC) curve analysis. The patients were divided into high and low FPR groups according to this cut-off value. Results : The cut-off value of FPR was 25.2. Among age, sex, body mass index (BMI), and surgical factors including surgery type, volume of blood loss and surgery time, there was no significant difference between the two groups. Patients in the low FPR group had significantly better overall survival (OS) and relapse-free survival (RFS) compared with the high FPR group (P < 0.05). On multivariate analysis, a high FPR, CA19-9 > 300 U /l, and receipt of adjuvant chemotherapy were independent risk factors for OS and DFS. Conclusions : The FPR might be a prognostic factor for patients with resectable pancreatic cancer. J. Med. Invest. 68 : 342-346, August, 2021.
Tetsu Tomonari, Yasushi Sato, Hironori Tanaka, Takahiro Tanaka, Tatsuya Taniguchi, Masahiro Sogabe, Koichi Okamoto, Hiroshi Miyamoto, Naoki Muguruma, Yu Saitou, Satoru Imura, Yoshimi Bando, Mitsuo Shimada and Tetsuji Takayama : Conversion therapy for unresectable hepatocellular carcinoma after lenvatinib Three case reports., Medicine, Vol.99, No.42, e22782, 2020.
(Summary)
Lenvatinib (LEN) is a novel potent multi-tyrosine kinase inhibitor, approved as first-line treatment for unresectable hepatocellular carcinoma (HCC). Considering its high objective response rate, LEN therapy could be expected to achieve downstaging of tumors and lead to conversion therapy with hepatectomy or ablation. However, the feasibility of conversion therapy after LEN treatment in unresectable HCC remains largely unknown. Here, we reported 3 cases of unresectable HCC: case 1, a 69-year-old man diagnosed with ruptured HCC; case 2, a 72-year-old woman with nonalcoholic steatohepatitis-based HCC; and case 3, a 73-year-old man with a history of alcoholic cirrhosis-based HCC. In all cases, cirrhosis was classified as Child-Pugh 5 and modified albumin-bilirubin grade 1 or 2a. HCC was diagnosed as Barcelona Clinic Liver Cancer (BCLC) stage B. In all cases, LEN was initiated after conventional-transcatheter arterial embolization enforcement, while maintaining liver function. In all cases, the main tumor size decreased after 6 months of LEN treatment and no satellite nodes were detected, indicating downstaging of HCC to BCLC stage A. Subsequently, conversion hepatectomy or ablation was performed. After successful conversion therapy, the general condition of the patients was good, without tumor recurrence during the observation period (median 10 months). This study demonstrated that LEN enables downstaging of HCC and thus represents a bridge to successful surgery or ablation therapy. In particular, LEN treatment may facilitate the possibility for conversion therapy of initially unresectable HCC, while maintaining the hepatic functional reserve.
Although pancreatic cancer often invades into peripancreatic adipose tissue, little is known about the cancer-adipocyte interaction. We first investigated the ability of adipocytes to de-differentiate to cancer-associated adipocytes (CAAs) by co-culturing with pancreatic cancer cells. We then examined the effects of CAA-conditioned media (CAA-CM) on the malignant characteristics of cancer cells, the mechanism underlying those effects, and their clinical relevance in pancreatic cancer. When 3T3-L1 adipocytes were co-cultured with pancreatic cancer cells (PANC-1) using Transwell system, adipocytes lost their lipid droplets and morphologically changed to fibroblast-like cells (CAA). Adipocyte-specific marker mRNA levels significantly decreased but those of fibroblast-specific markers appeared, characteristic findings of CAA, as revealed by real-time PCR. When PANC-1 cells were cultured with CAA-CM, significantly higher migration/invasion capability, chemoresistance, and epithelial-mesenchymal transition (EMT) properties were observed compared with control cells. To investigate the mechanism underlying these effects, we performed microarray analysis of PANC-1 cells cultured with CAA-CM, and found 78.5-fold higher expression of SAA1 compared with control cells. When SAA1 gene in PANC-1 cells was knocked down with SAA1 siRNA, migration/invasion capability, chemoresistance, and EMT properties were significantly attenuated compared with control cells. Immunohistochemical analysis on human pancreatic cancer tissues revealed positive SAA1 expression in 46/61 (75.4%). Overall survival in the SAA1-positive group was significantly shorter than in the SAA1-negative group (p=0.013). In conclusion, we demonstrated that pancreatic cancer cells induced de-differentiation in adipocytes toward CAA, and CAA promoted malignant characteristics of pancreatic cancer via SAA1 expression, suggesting that SAA1 is a novel therapeutic target in pancreatic cancer.
Toshiaki Yoshimoto, Kouzou Yoshikawa, Jun Higashijima, Tomohiko Miyatani, Takuya Tokunaga, Masaaki Nishi, Chie Takasu, Hideya Kashihara, Yukako Takehara and Mitsuo Shimada : Bevacizumab-associated intestinal perforation and perioperative complications in patients receiving bevacizumab., Annals of Gastroenterological Surgery, Vol.4, No.2, 151-155, 2020.
(Summary)
The purposes of this study are to present cases of emergency surgery in which gastrointestinal perforation occurred during bevacizumab administration, consider the indications for emergency surgery, and examine the safety of scheduled surgery after a washout period for bevacizumab. (a) We retrospectively investigated seven patients who underwent emergency surgery for bevacizumab-associated intestinal perforation. (b) We investigated 104 patients with advanced colorectal cancer treated with neoadjuvant therapy who underwent surgery from 2008 to 2018, retrospectively. (a) In the seven patients undergoing emergency surgery for gastrointestinal perforation, the median bevacizumab administration and washout periods were 16 weeks and 24 days, respectively. A stoma was created in all patients except in those who were not candidates. Two patients developed postoperative abdominal abscesses, and two patients died from perioperative sepsis and gastrointestinal bleeding, respectively; both of these patients had poor performance status. (b) In patients receiving bevacizumab (n = 45) and patients treated with bevacizumab-free regimens as neoadjuvant therapy (n = 59), 31 and 52 patients received chemoradiotherapy, respectively. We found no correlation with postoperative complications with or without bevacizumab. The surgical indications should be considered carefully in patients with gastrointestinal perforation secondary to bevacizumab administration. Meanwhile, after appropriate cessation time, scheduled surgery following bevacizumab administration is feasible.
Daichi Ishikawa, Kouzou Yoshikawa, Jun Higashijima, Masaaki Nishi, Hideya Kashihara, Chie Takasu and Mitsuo Shimada : Anastomotic recurrence after laparoscopic distal gastrectomy with delta-shaped anastomosis : report of a case., The Journal of Medical Investigation : JMI, Vol.67, No.1.2, 211-213, 2020.
(Summary)
Delta-shaped anastomosis is nowadays an increasingly performed reconstruction method in laparoscopic distal gastrectomy for early gastric cancer. To date, anastomotic recurrence at the delta-shaped anastomotic site has not been reported. Surgery for this disease is more complicated than anastomotic recurrence at the site of conventional Billroth-I anastomosis. A 68-year-old female was referred to our institute with early gastric cancer on the posterior wall of the antrum. She underwent laparoscopic distal gastrectomy with delta-shaped Billroth-I anastomosis. Follow-up gastrofiberscopy 16 months after the operation revealed suspected anastomotic recurrence, and gastric biopsy revealed signet-ring cell carcinoma. Open total gastrectomy with reconstruction with the Roux-en-Y method was performed. At the distal part of the previous anastomosis, an adequate length of the duodenum was dissected from the pancreas. Then, the duodenum was transected 3 cm distal to the anastomosis using a linear stapler. The patient recovered well and was discharged on postoperative day 14. The patient is alive without re-recurrence 3 years postoperatively. We successfully treated a patient with anastomotic recurrence of gastric cancer after delta-shaped anastomosis. Adequate resection of the duodenal stump was performed without any residual tumor or injury to the pancreas. J. Med. Invest. 67 : 211-213, February, 2020.
Shuichi Iwahashi, Feng Rui, Yuji Morine, Shin-ichiro Yamada, Yu Saitou, Tetsuya Ikemoto, Satoru Imura and Mitsuo Shimada : Hepatic Stellate Cells Contribute to the Tumor Malignancy of Hepatocellular Carcinoma Through the IL-6 Pathway., Anticancer Research, Vol.40, No.2, 743-749, 2020.
(Summary)
The hepatic stellate cells (HSCs) have relationship to cancer progression. The aim of this study is to investigate the effect of HSCs and the role of IL-6/Stat3 pathway on hepatocellular carcinoma (HCC) progression. HCCs were co-cultured with HSCs. The viability and migration ability of cancer cells were detected. Epithelial-mesenchymal transition (EMT) marker (E-cadherin), stem cell marker (CD44) and p-signal transducer and activator of transcription 3 (p-STAT3) of cancer cells were evaluated. Finally, interleukin-6 (IL-6) neutralization was performed. Co-culture of HCCs with HSCs increased cancer cell viability and migration ability. EMT and stemness of cancer cells increased with HSCs. Following IL-6 neutralization, phospho-STAT3 activation, cancer cell viability and migration, as well as EMT, and stemness of cancer cells decreased. HSCs promoted HCC progression through the IL-6/STAT3 pathway.
Daichi Ishikawa, Kouzou Yoshikawa, Chie Takasu, Hideya Kashihara, Masaaki Nishi, Takuya Tokunaga, Jun Higashijima and Mitsuo Shimada : Expression Level of MicroRNA-449a Predicts the Prognosis of Patients With Gastric Cancer., Anticancer Research, Vol.40, No.1, 239-244, 2020.
(Summary)
In previous studies, we demonstrated the significant role of microRNA-449a (miR-449a) in colorectal cancer with in vivo and clinical samples. The importance of miR-449a in gastric cancer is still to be elucidated. This study examined the impact of miR-449a expression in tumor tissue and serum and investigated its potential as a prognostic marker in gastric cancer. Sixty-six patients with gastric cancer who underwent surgery were included in the study. miR-449a expression in tumor tissue and serum were investigated by real-time polymerase chain reaction analysis. The association of miR-449a expression with clinicopathological factors and patient prognosis were also investigated. miR-449a expression was lower in tumor tissue than non-tumor tissue. miR-449a in tumor tissue negatively correlated with the malignancy of tumor and clinical stage. Increased carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA19-9) levels were seen at significantly higher frequencies in patients with low miR-449a expression. Patients with low miR-449a expression had poorer cancer-specific survival compared to those with high miR-449a expression. The univariate analysis showed that lymphovascular invasion, increased CEA and CA19-9 and a low expression of miR-449a were associated with a poorer 5-year cancer-specific survival. miR-449a expression level in serum correlated to that in tumor tissue and was also associated with tumor malignancy. The miR-449a level in tumor tissue might be useful as a prognostic indicator for patients with gastric cancer and miR-449a in serum appears to reflect its expression in tumor tissue.
Shuichi Iwahashi, Mitsuo Shimada, Yuji Morine, Satoru Imura, Tetsuya Ikemoto, Yu Saitou, Shin-ichiro Yamada and Toru Utsunomiya : Effect of epigenetic modulation on cancer sphere., The Journal of Medical Investigation : JMI, Vol.67, No.1.2, 70-74, 2020.
(Summary)
Background : Cancer stem cell properties are highly relevant to the biology of treatment-resistant cancers. Epigenetic modification regulates gene expressions by chromatin remodeling during malignant transformation. The aim of this study was to elucidate the possible strategy for cancer stem cells focusing on epigenetic modification. Methods : We made cancer sphere from HepG2 cells, and we added Histone deacetylase (HDAC) inhibitor, valproic acid to cancer sphere. And we compared methylation status and the gene expression between normal HepG2 and cancer sphere groups, and between cancer sphere and sphere with HDAC inhibitor treatment groups. Results : Valproic acid (VPA) cancelled this spheroid formation. In comparison between normal HepG2 and cancer sphere, the number of methylation status changes more than 0.1 of beta level was 826 probes, and we could isolate some epithelial-mesenchymal transition (EMT) related genes. And VPA reduced the expressions of EMT related genes in sphere with RT-PCR. On the other hand, in comparison between cancer sphere and sphere with VPA treatment, we detected 29 probe of methylation status change, and VPA reduced the expressions of Bcl-6 in sphere. Conclusions : HDAC inhibitor affected the methylation status of cancer stem cells. Histone-acetylation might overcome treatmet-resistant cancer through the regulation of cancer stem cell. J. Med. Invest. 67 : 70-74, February, 2020.
Kouzou Yoshikawa, Mitsuo Shimada, Jun Higashijima, Tomohiko Miyatani, Takuya Tokunaga, Masaaki Nishi, Chie Takasu, Hideya Kashihara, Toshiaki Yoshimoto and Takashi Iwata : Establishment of an evaluation system for non-technical skills in surgery : Surgeon and paramedical staff assessments., The Journal of Medical Investigation : JMI, Vol.67, No.1.2, 83-86, 2020.
(Summary)
Purposes : Non-technical skills contribute to safe and efficient team performance. The aim of this study was to clarify the importance of non-technical skills by a questionnaire and the usefulness of feedback to the operator. Method : A questionnaire was administered to the operator and paramedical staff for 404 operations. Total and individual scores were compared, and the effect of feedback was analyzed by comparison between pre-feedback and post-feedback. Results : The total score of the paramedical staff was 100 [full score] [n = 186], 90-99 [n = 133], and 80-89 [n = 47]. In all cases, the score of the paramedical staff was significantly better than that of the operator. After feedback, the rate of a score less than 80 was significantly decreased. In junior doctor cases with laparoscopy, feedback tended to have a positive effect. Conclusions : Questionnaires completed by both surgeons and paramedical staff are useful for identifying problems with non-technical skills. J. Med. Invest. 67 : 83-86, February, 2020.
(Keyword)
Allied Health Personnel / Clinical Competence / Communication / Decision Making / Evaluation Studies as Topic / General Surgery / Humans / Leadership / Patient Care Team / Surgeons / Surveys and Questionnaires
Shogo Ohta, Tetsuya Ikemoto, Yuma Wada, Yu Saitou, Shin-ichiro Yamada, Satoru Imura, Yuji Morine and Mitsuo Shimada : A change in the zinc ion concentration reflects the maturation of insulin-producing cells generated from adipose-derived mesenchymal stem cells., Scientific Reports, Vol.9, No.1, 18731, 2019.
(Summary)
The generation of insulin-producing cells (IPCs) from pluripotent stem cells could be a breakthrough treatment for type 1 diabetes. However, development of new techniques is needed to exclude immature cells for clinical application. Dithizone staining is used to evaluate IPCs by detecting zinc. We hypothesised that zinc ion (Zn) dynamics reflect the IPC maturation status. Human adipose-derived stem cells were differentiated into IPCs by our two-step protocol using two-dimensional (2D) or 3D culture. The stimulation indexes of 2D -and 3D-cultured IPCs on day 21 were 1.21 and 3.64 (P < 0.05), respectively. The 3D-cultured IPCs were stained with dithizone during culture, and its intensity calculated by ImageJ reached the peak on day 17 (P < 0.05). Blood glucose levels of streptozotocin-induced diabetic nude mice were normalised (4/4,100%) after transplantation of 96 3D-cultured IPCs. Zn concentration changes in the medium of 3D cultures had a negative value in the early period and a large positive value in the latter period. This study suggests that Zn dynamics based on our observations and staining of zinc transporters have critical roles in the differentiation of IPCs, and that their measurement might be useful to evaluate IPC maturation as a non-destructive method.
Yuzo FUKUSHIMA, Mitsuo Shimada, Tomonori KAWAI, Ryosuke FUJITA, Rikitoshi UENO, Tae FUNAKOSHI, Junichiro MIAKE and Tokuo SUGIHARA : A Case of Stomachache Successfully Treated with Yokukansankachinpihange, Kampo Medicine, Vol.70, No.4, 361-365, 2019.
(Summary)
<p>We report the case of a 36-year-old male who presented with an abdominal complaint after straightening of irregular teeth. He was examined and treated, however, the cause of the abdominal complaint could not be determined and the treatment was ineffective. He was treated in our clinic with yokukansankachinpihange for obvious pulsation in the supraumbilical region following the oral tradition of Kampo medicine, and the symptom gradually disappeared. We discussed the mechanism of the stomachache in Kampo medicine. After treatment, this case was diagnosed as somatoform autonomic dysfunction in psychiatric medicine. Advanced treatment by a psychiatrist was necessary to treat this disease in psychiatric medicine. In this case it is suggested that treatment following the oral tradition of Kampo medicine was effective.</p>
(Keyword)
supraumbilical region pulsation / yokukansan / yokukansankachinpihange
Hiroki Ishibashi, Hiroki Mori, Noriko Yokota and Mitsuo Shimada : 先天性胆道拡張症と膵・胆管合流異常, Japanese Journal of Pediatric Medicine, Vol.51, No.10, 1516-1520, 2019.
44.
Tetsuya Ikemoto, Rui Feng, Shuichi Iwahashi, Shin-ichiro Yamada, Yu Saitou, Yuji Morine, Satoru Imura, Munehide Matsuhisa and Mitsuo Shimada : In vitro and in vivo effects of insulin-producing cells generated by xeno-antigen free 3D culture with RCP piece., Scientific Reports, Vol.9, No.1, 2019.
(Summary)
To establish widespread cell therapy for type 1 diabetes mellitus, we aimed to develop an effective protocol for generating insulin-producing cells (IPCs) from adipose-derived stem cells (ADSCs). We established a 3D culture using a human recombinant peptide (RCP) petaloid μ-piece with xeno-antigen free reagents. Briefly, we employed our two-step protocol to differentiate ADSCs in 96-well dishes and cultured cells in xeno-antigen free reagents with 0.1 mg/mL RCP μ-piece for 7 days (step 1), followed by addition of histone deacetylase inhibitor for 14 days (step 2). Generated IPCs were strongly stained with dithizone, anti-insulin antibody at day 21, and microstructures resembling insulin secretory granules were detected by electron microscopy. Glucose stimulation index (maximum value, 4.9) and MAFA mRNA expression were significantly higher in 3D cultured cells compared with conventionally cultured cells (P < 0.01 and P < 0.05, respectively). The hyperglycaemic state of streptozotocin-induced diabetic nude mice converted to normoglycaemic state around 14 days after transplantation of 96 IPCs under kidney capsule or intra-mesentery. Histological evaluation revealed that insulin and C-peptide positive structures existed at day 120. Our established xeno-antigen free and RCP petaloid μ-piece 3D culture method for generating IPCs may be suitable for clinical application, due to the proven effectiveness in vitro and in vivo.
Daichi Ishikawa, Chie Takasu, Hideya Kashihara, Masaaki Nishi, Takuya Tokunaga, Jun Higashijima, Kouzou Yoshikawa, Koji Yasutomo and Mitsuo Shimada : The Significance of MicroRNA-449a and Its Potential Target HDAC1 in Patients With Colorectal Cancer., Anticancer Research, Vol.39, No.6, 2855-2860, 2019.
(Summary)
miR-449a level might be a prognostic indicator for colorectal cancer and miR-449a might regulate HDAC1 expression.
Akemi Hara, Yuko Nakagawa, Keiko Nakao, Motoyuki Tamaki, Tetsuya Ikemoto, Mitsuo Shimada, Munehide Matsuhisa, Hiroki Mizukami, Nobuhiro Maruyama, Hirotaka Watada and Yoshio Fujitani : Development of monoclonal mouse antibodies that specifically recognize pancreatic polypeptide., Endocrine Journal, Vol.66, No.5, 459-468, 2019.
(Summary)
Pancreatic polypeptide (PP) is a 36-amino acid peptide encoded by the Ppy gene, which is produced by a small population of cells located in the periphery of the islets of Langerhans. Owing to the high amino acid sequence similarity among neuropeptide Y family members, antibodies against PP that are currently available are not convincingly specific to PP. Here we report the development of mouse monoclonal antibodies that specifically bind to PP. We generated Ppy knockout (Ppy-KO) mice in which the Ppy-coding region was replaced by Cre recombinase. The Ppy-KO mice were immunized with mouse PP peptide, and stable hybridoma cell lines producing anti-PP antibodies were isolated. Firstly, positive clones were selected in an enzyme-linked immunosorbent assay for reactivity with PP coupled to bovine serum albumin. During the screening, hybridoma clones producing antibodies that cross-react to the peptide YY (PYY) were excluded. In the second screening, hybridoma clones in which their culture media produce no signal in Ppy-KO islets but detect specific cells in the peripheral region of wild-type islets, were selected. Further studies demonstrated that the selected monoclonal antibody (23-2D3) specifically recognizes PP-producing cells, not only in mouse, but also in human and rat islets. The monoclonal antibodies with high binding specificity for PP developed in this study will be fundamental for future studies towards elucidating the expression profiles and the physiological roles of PP.
Yu Saitou, Satoru Imura and Mitsuo Shimada : Gastroenterological, Hepatobiliary and Pancreatic Surgery, Journal of Japan Society of Computer Aided Surgery, Vol.21, No.3, 150-152, 2019.
Tumenjin Enkhbat, Masaaki Nishi, Kouzou Yoshikawa, Jun Higashijima, Takuya Tokunaga, Chie Takasu, Hideya Kashihara, Daichi Ishikawa, Masahide Tominaga and Mitsuo Shimada : Epigallocatechin-3-gallate Enhances Radiation Sensitivity in Colorectal Cancer Cells Through Nrf2 Activation and Autophagy., Anticancer Research, Vol.38, No.11, 6247-6252, 2018.
(Summary)
Epigallocatechin-3-gallate (EGCG) is a major polyphenolic component of green tea. EGCG plays a potential role in radio-sensitizing cancer cells. The combined effect of EGCG and radiation was investigated in a colorectal cancer cell line, focusing on nuclear factor (erythroid-derived 2)-like 2 (Nrf2) autophagy signalling. HCT-116 cells were treated with 12.5 μM EGCG for different periods of time, 2 Gy radiation, or both. Cell viability was determined with the WST-8 assay. The number of colonies was determined with the colony formation assay. mRNA expression of LC3 and caspase-9 was analyzed with quantitative real-time polymerase chain reaction. Combination treatment with EGCG and radiation significantly decreased the growth of HCT-116 cells. The number of colonies was reduced to 34.2% compared to the control group. Immunofluorescence microscopy images showed that nuclear translocation of Nrf2 was significantly increased when cells were treated with the combination of EGCG and radiation compared to the control and single-treatment groups. Combined treatment with EGCG and radiation significantly induced LC3 and caspase-9 mRNA expression. EGCG increased the sensitivity of colorectal cancer cells to radiation by inhibiting cell proliferation and inducing Nrf2 nuclear translocation and autophagy.
Rui Feng, Yuji Morine, Tetsuya Ikemoto, Satoru Imura, Shuichi Iwahashi, Yu Saitou and Mitsuo Shimada : Nrf2 activation drive macrophages polarization and cancer cell epithelial-mesenchymal transition during interaction, Cell Communication & Signaling, Vol.16, No.1, 54, 2018.
(Summary)
The M2 phenotype of tumor-associated macrophages (TAM) inhibits the anti-tumor inflammation, increases angiogenesis and promotes tumor progression. The transcription factor Nuclear Factor (erythroid-derived 2)-Like 2 (Nrf2) not only modulates the angiogenesis but also plays the anti-inflammatory role through inhibiting pro-inflammatory cytokines expression; however, the role of Nrf2 in the cancer cell and macrophages interaction is not clear. Hepatocellular carcinoma cells (Hep G2 and Huh 7) and pancreatic cancer cells (SUIT2 and Panc-1) were co-cultured with monocytes cells (THP-1) or peripheral blood monocytes derived macrophages, then the phenotype changes of macrophages and epithelial-mesenchymal transition of cancer cells were detected. Also, the role of Nrf2 in cancer cells and macrophages interaction were investigated. In this study, we found that cancer cells could induce an M2-like macrophage characterized by up-regulation of CD163 and Arg1, and down-regulation of IL-1b and IL-6 through Nrf2 activation. Also, Nrf2 activation of macrophages promoted VEGF expression. The Nrf2 activation of macrophages correlated with the reactive oxygen species induced by cancer cells derived lactate. Cancer cells educated macrophages could activate Nrf2 of the cancer cells, in turn, to increase cancer cells epithelial-mesenchymal transition (EMT) through paracrine VEGF. These findings suggested that Nrf2 played the important role in the cancer cells and macrophages interaction. Macrophage Nrf2 activation by cancer cell-derived lactate skews macrophages polarization towards an M2-like phenotype and educated macrophages activate Nrf2 of the cancer cells to promote EMT of cancer cells. This study provides a new understanding of the role of Nrf2 in the cancer cell and TAM interaction and suggests a potential therapeutic target.
(Keyword)
Cell Communication / Cell Movement / Cell Transformation, Neoplastic / Epithelial-Mesenchymal Transition / Gene Expression Regulation, Neoplastic / Hep G2 Cells / Humans / Lactic Acid / Macrophages / NF-E2-Related Factor 2 / Phenotype / Reactive Oxygen Species / Vascular Endothelial Growth Factor A
Hideya Kashihara, Mitsuo Shimada, Kouzou Yoshikawa, Jun Higashijima, Tomohiko Miyatani, Takuya Tokunaga, Masaaki Nishi and Chie Takasu : The Effect of Roux-en-Y Reconstruction on Type 2 Diabetes in the Early Postoperative Period., Anticancer Research, Vol.38, No.8, 4901-4905, 2018.
(Summary)
The aim of this study was to investigate the effect of Roux-en-Y (RY) reconstruction on type 2 diabetes with gastric cancer in the early postoperative period. A total of 44 patients with gastric cancer with type 2 diabetes who underwent total gastrectomy (TG) or distal gastrectomy (DG) with Roux-en-Y reconstruction or DG with Bilroth I were enrolled. All three groups had their fasting glucose and daily insulin dose recorded preoperatively, on day 2 postoperatively (POD2) and at discharge. The TG group showed low fasting glucose and daily insulin dose on POD2 compared to their preoperative state. On discharge, the fasting glucose and daily insulin dose were significantly lower in both TG and DG Roux-en-Y groups than preoperatively. Roux-en-Y reconstruction showed early improvement of type 2 diabetes regardless of any body weight loss. The effect of Roux-en-Y reconstruction in TG on type 2 diabetes was more remarkable than that of DG.
(Keyword)
Aged / Aged, 80 and over / Anastomosis, Roux-en-Y / Blood Glucose / Diabetes Mellitus, Type 2 / Female / Gastrectomy / Gastroenterostomy / Humans / Insulin / Male / Middle Aged / Postoperative Period / Stomach Neoplasms / Treatment Outcome
Kazumi Kawase, Kyoko Nomura, Ryuji Tominaga, Hirotaka Iwase, Tomoko Ogawa, Ikuko Shibasaki, Mitsuo Shimada, Tomoaki Taguchi, Emiko Takeshita, Yasuko Tomizawa, Sachiyo Nomura, Kazuhiro Hanazaki, Tomoko Hanashi, Hiroko Yamashita, Norihiro Kokudo and Kotaro Maeda : Analysis of gender-based differences among surgeons in Japan: results of a survey conducted by the Japan Surgical Society. Part. 2: personal life., Surgery Today, Vol.48, No.3, 308-319, 2018.
(Summary)
To assess the true conditions and perceptions of the personal lives of men and women working as surgeons in Japan. In 2014, all e-mail subscribed members of the Japan Surgical Society (JSS, n = 29,861) were invited to complete a web-based survey. The questions covered demographic information, work environment, and personal life (including marital status, childcare, and nursing care for adult family members). In total, 6211 surgeons (5586 men and 625 women) returned the questionnaires, representing a response rate of 20.8%. Based on the questionnaire responses, surgeons generally prioritize work and spend most of their time at work, although women with children prioritize their family over work; men spend significantly fewer hours on domestic work/childcare than do their female counterparts (men 0.76 h/day vs. women 2.93 h/day, p < 0.01); and both men and women surgeons, regardless of their age or whether they have children, place more importance on the role of women in the family. The personal lives of Japanese surgeons differed significantly according to gender and whether they have children. The conservative idea that women should bear primary responsibility for the family still pertains for both men and women working as surgeons in Japan.
(Keyword)
Adult / Aged / Family / Female / Gender Identity / General Surgery / Humans / Japan / Life / Male / Middle Aged / Occupational Health / Physicians, Women / Societies, Medical / Surgeons / Surveys and Questionnaires / Work
Ken Shirabe, Susumu Eguchi, Hideaki Okajima, Kiyoshi Hasegawa, Shigeru Marubashi, Koji Umeshita, Seiji Kawasaki, Katsuhiko Yanaga, Mitsuo Shimada, Toshimi Kaido, Naoki Kawagishi, Akinobu Taketomi, Koichi Mizuta, Norihiro Kokudo, Shinji Uemoto and Yoshihiko Maehara : Current Status of Surgical Incisions Used in Donors During Living Related Liver Transplantation-A Nationwide Survey in Japan., Transplantation, Vol.102, No.8, 1293-1299, 2018.
(Summary)
Smaller surgical incisions have recently been introduced in living donor liver procurement. This study used national data from Japan to clarify the present status of surgical incisions in living donor liver procurement. A nationwide, questionnaire-based survey related to 3121 donors and recipients was used. Donors were divided into 2 groups: left lateral segment graft (LLSG) procurement (n = 690) and other types (n = 2431). Incisions were classified into 6 types: type I, upper midline and bilateral subcostal; type II, upper midline and right subcostal; type III, upper midline and right subcostal to the right lateral margin of the abdominal rectus muscle; type IV, upper midline without laparoscopy; type V, upper midline with laparoscopy; and type VI, lower abdominal using the full laparoscopic technique. Types I, II, and III were regarded as standard, and types IV, V, and VI as small incisions. In LLSGs, blood transfusion and postoperative complication rates were significantly less frequent in the small incision group than in the standard group. In other graft types, there were no significant differences in blood transfusion, postoperative complication, and recipients' graft loss rates. The rates of wound extension during surgery were 2.8% and 2.1% in the small incision group in LLSGs and in other graft types, respectively. A small incision was adapted more frequently and postoperative complications were less common in high-volume centers. Various incisions have been adopted in living donor liver procurement. Donor safety and graft integrity appear to have been retained for donors receiving small incisions.
(Keyword)
Blood Transfusion / End Stage Liver Disease / Hepatectomy / Humans / Japan / Laparoscopy / Liver / Liver Transplantation / Living Donors / Multivariate Analysis / Postoperative Complications / Postoperative Period / Surgical Wound / Surveys and Questionnaires / Wound Healing
Rui Feng, Yuji Morine, Tetsuya Ikemoto, Satoru Imura, Shuichi Iwahashi, Yu Saitou and Mitsuo Shimada : Nab-paclitaxel interrupts cancer-stromal interaction through C-X-C motif chemokine 10-mediated interleukin-6 downregulation in vitro., Cancer Science, Vol.109, No.8, 2509-2519, 2018.
(Summary)
Cancer-associated fibroblasts (CAF), derived from stroma of cancer tissues, interact with cancer cells and play an important role in cancer initiation, growth, and metastasis. Nab-paclitaxel (nab-PTX) is a 130 nm albumin-binding paclitaxel and recommended for many types of cancer chemotherapy. The nab-PTX stromal-disrupting effect during pancreatic cancer treatment has been reported. The aim of the present study was to determine the role of nab-PTX in cancer cells and CAF interaction. Cancer cells (MIA PaCa-2 and Panc-1) were cocultured with CAF or treated with CAF conditioned medium, after which their migration and invasion ability, epithelial-mesenchymal transition (EMT)-related marker expression and C-X-C motif chemokine 10 (CXCL10) expression and secretion were detected. Nab-PTX treatment was carried out during the coculture system or during preparation of CAF conditioned medium. Then cancer cell migration and invasion ability, EMT-related marker expression, CXCL10 expression and secretion, and interleukin-6 (IL-6) expression and secretion by CAF were checked After coculture with CAF, migration and invasion ability of cancer cells increased. CAF also downregulated E-cadherin and upregulated N-cadherin and vimentin expression in cancer cells. During coculture or stimulation with cancer cell-cultured medium, CAF significantly increased IL-6 expression and secretion. However, nab-PTX in the coculture system canceled CAF-induced migration and invasion promotion and EMT-related gene changes. Moreover, nab-PTX increased CXCL10 expression of cancer cells which blocked CAF IL-6 expression and secretion. Nab-PTX treatment could increase CXCL10 expression of cancer cells which blocks CAF cancer cell migration and invasion-promoting effect by inhibiting IL-6 expression.
Yu Saitou, Shin-ichiro Yamada, Satoru Imura, Yuji Morine, Tetsuya Ikemoto, Shuichi Iwahashi and Mitsuo Shimada : A learning curve for laparoscopic liver resection: an effective training system and standardization of technique., Translational Gastroenterology and Hepatology, Vol.3, 45, 2018.
(Summary)
The incidence of laparoscopic liver resection (LHx) has been increased in the past decade. There have been some reports about some advantages of LHx, in both short and long-term outcomes after operation. The use of a minor LHx was regarded as a standard surgical practice, and some peri-operative complications hindered worldwide increase of LHx in the Second International Consensus Conference on LHx at Morioka. However, no suggestions were described in terms with how to provide the best teaching and training necessary to shorten the learning curve for inexperienced surgeons using a new surgical technique while continuing to maintain a low rate of morbidity from the very beginning. This study includes a literature review of published research which looked at a learning curve for LHx. As well, it proposes a new step-wise training method for inexperienced surgeons and standardization of a technique for LHx focusing especially on laparoscopic left hepatectomy (LLHx).
Youichiro Kawashita, Yuji Morine, Yu Saitou, Chie Takasu, Tetsuya Ikemoto, Shuichi Iwahashi, Hiroki Teraoku, Masato Yoshikawa, Satoru Imura, Toshiyuki Yagi and Mitsuo Shimada : Role of heat shock factor 1 expression in the microenvironment of intrahepatic cholangiocarcinomas., Journal of Gastroenterology and Hepatology, Vol.33, No.7, 1407-1412, 2018.
(Summary)
Heat shock factor 1 (HSF1), a master regulator of heat shock response, has been shown to play a multifaceted role in cancer progression. However, the clinical significance and biological effect of HSF1 expression in intrahepatic cholangiocarcinoma (IHCC) remain unknown. Forty-nine patients with IHCC who underwent hepatic resection were enrolled in this study. HSF1 expression in tumor tissue was determined by immunohistochemistry, and patients were divided into two groups, those with high (n = 20) and low (n = 29) HSF1 expression. Clinicopathological factors including prognosis were compared in these two groups. HSF1 expression was significantly higher in tumors than in normal tissue. The overall survival rate was significantly lower in patients with high than low HSF1. Multivariate analysis showed that high HSF1 expression was a factor independently prognostic of patient survival. High HSF1 expression in tumor tissues may be a prognostic biomarker in patients with IHCC.
Tumenjin Enkhbat, Masaaki Nishi, Chie Takasu, Kouzou Yoshikawa, Jun Higashijima, Takuya Tokunaga, Hideya Kashihara, Daichi Ishikawa and Mitsuo Shimada : Programmed Cell Death Ligand 1 Expression Is an Independent Prognostic Factor in Colorectal Cancer., Anticancer Research, Vol.38, No.6, 3367-3373, 2018.
(Summary)
Programmed cell death protein 1 (PD-1)/ programmed cell death ligand 1(PD-L1) axis is associated with immune tolerance via inhibition of T cell activation. The aim of this study was to clarify the significance of PD-1 and PD-L1 expressions and analyze the relationships between PD-1, PD-L1, transforming growth factor-β (TGF-β) and Forkhead box P3 (Foxp3) expressions in colorectal cancer (CRC). A total of 116 patients who underwent curative colectomy for stage II/III CRC were included in the study. PD-1, PD-L1, TGF-β, and Foxp3 expressions were examined by immunohistochemistry and related to prognostic factors by Kaplan-Meier. PD-1 expression was correlated with PD-L1, TGF-β, and Foxp3 expressions. Overall survival rates were significantly poorer in the PD-1 and PD-L1-positive groups. Multivariate analysis showed that PD-L1-positive is an independent risk factor. Disease-free survival (DFS) was tended in the PD-L1-positive group. The group with double-positive expression had significantly poorer prognosis. PD-1 and PD-L1 expressions were associated with a poor prognosis and correlated with TGF-β and Foxp3 expressions in patients with CRC.
Masaaki Nishi, Kouzou Yoshikawa, Jun Higashijima, Takuya Tokunaga, Hideya Kashihara, Chie Takasu, Daichi Ishikawa, Yuma Wada and Mitsuo Shimada : The Impact of Indoleamine 2,3-dioxygenase (IDO) Expression on Stage III Gastric Cancer., Anticancer Research, Vol.38, No.6, 3387-3392, 2018.
(Summary)
Indoleamine 2,3-dioxygenase (IDO) down-regulates T cell activation, attenuates regulatory T cell (Treg) activation and is related to immune tolerance. The aim of the study was to clarify the significance of IDO expression and analyze the relationships between the expression of IDO, TGF-β, and Foxp3 in gastric cancer (GC). A total of 60 patients who underwent curative gastrectomy for stage III gastric cancer were included in the study. The expression of IDO, TGF-β, and Foxp3 was examined by immunohistochemistry and the relationship of each expression level to several prognostic factors was examined using univariate and multivariate analyses. IDO expression was not positively correlated with any of the factors examined. IDO expression was positively correlated with TGF-β expression (p<0.05), and TGF-β expression was positively correlated with FoxP3 expression (p<0.05). Overall survival (OS) rates were significantly poorer in the IDO-positive group compared to the IDO-negative group (3-year OS, 78.5% vs. 90%, respectively; p<0.05). Multivariate analysis confirmed IDO expression as independent prognostic factors in OS. Disease-free survival (DFS) was significantly poorer in the IDO-positive group compared to the IDO-negative group (3-year DFS, 59.3% vs. 69.3%, respectively; p<0.05). IDO is associated with poor prognosis and immuno-tolerance through attenuation of Treg activation in Stage III GC.
野村 幸世, 冨澤 康子, 大津 洋, 小川 朋子, 柴崎 郁子, Mitsuo Shimada, 竹下 恵美子, 花崎 和弘, 葉梨 智子, 山下 啓子, 明石 定子, 山内 英子, 岩瀬 弘敬, 田口 智章, 前田 耕太郎 and 中村 清吾 : CURRENT STATUS OF SUPPORT FOR FEMALE DOCTORS IN THE SPECIALIST MEDICAL SOCIETIES OF THE JAPANESE ASSOCIATION OF MEDICAL SCIENCE IN 2015 : RESULTS OF A QUESTIONNAIRE SURVEY, Journal of Japan Surgical Society, Vol.119, No.1, 97-99, 2018.
Kouzou Yoshikawa, Mitsuo Shimada, Jun Higashijima, Takuya Tokunaga, Masaaki Nishi, Chie Takasu, Hideya Kashihara and Daichi Ishikawa : Usefulness of the Transoral Anvil Delivery System for Esophagojejunostomy After Laparoscopic Total Gastrectomy: A Single-institution Comparative Study of Transoral Anvil Delivery System and the Overlap Method., Surgical Laparoscopy, Endoscopy & Percutaneous Techniques, Vol.28, No.2, e40-e43, 2018.
(Summary)
Many reconstruction techniques have been reported after laparoscopic total gastrectomy (LTG), but it is not clear which anastomosis technique is most useful, and no standard methods have been established. This study examined whether LTG using the transoral anvil delivery system (TOADS) is a feasible and safe procedure for gastric cancer. A series of 47 patients underwent the overlap method and 36 underwent the hemi-double-stapling technique with TOADS. Intraoperative and postoperative outcomes were compared between the 2 groups. In the TOADS group, operation time for reconstruction was shorter (16 3 vs. 45 10in, P=0.003), and blood loss was reduced (45 15 vs. 126 13L, P=0.0002). There were no significant differences in intraoperative complications, conversion to open surgery, and intraoperative anastomosis-related complications between the 2 groups. Furthermore, there were no significant differences in the incidence of complications, reoperation, mortality, and postoperative hospital stay. LTG using TOADS for gastric cancer may be a technically feasible surgical procedure with acceptable morbidity.
Tetsuya Ikemoto, Rui Feng, Mitsuo Shimada, Yu Saitou, Shuichi Iwahashi, Yuji Morine and Satoru Imura : A new 2-step acceleration protocol using a histone deacetylase inhibitor to generate insulin-producing cells from adipose-derived mesenchymal stem cells, Pancreas, Vol.47, No.4, 477-481, 2018.
(Summary)
We aimed to develop a simple protocol for deriving insulin-producing cells (IPCs) from adipose-derived mesenchymal stem cells (ADSCs). We established a 2-step creation method and an acceleration strategy with a histone deacetylase inhibitor that promoted a pro-endocrine pancreatic lineage. We seeded ADSCs in 96-well dishes and cultured in Dulbecco's modified Eagle's medium/F12 medium containing 1% fetal bovine serum, 1% B27 supplement, 1% N2 supplement, 50-ng/mL human activin A, and 10-nM exendin-4 for step 1 of differentiation (7 days). Then 10-mM nicotinamide and 50-ng/mL human hepatocyte growth factor, with or without 1 mM histone deacetylase inhibitor, were added for step 2 of differentiation (14 days). After the 2-step differentiation was complete, cell morphology, immunohistochemistry, messenger RNA expression, and function were investigated. Our new differentiation protocol with the histone deacetylase inhibitor significantly accelerated IPC differentiation compared with the conventional protocol without the histone deacetylase inhibitor (median, 21.6 vs 38.8 days; P < 0.05). It also improved the islet morphology score (P < 0.05) and the glucose stimulation index (3.1). By applying our new and easy 2-step protocol using a histone deacetylase inhibitor, ADSCs may be an effective cell source for differentiation of IPCs.
Kouzou Yoshikawa, Mitsuo Shimada, Jun Higashijima, Toshihiro Nakao, Masaaki Nishi, Chie Takasu, Hideya Kashihara, Syohei Eto and Yoshimi Bando : Ki-67 and Survivin as Predictive Factors for Rectal Cancer Treated with Preoperative Chemoradiotherapy., Anticancer Research, Vol.38, No.3, 1735-1739, 2018.
(Summary)
To evaluate the usefulness of Ki-67 index and survivin as predictive prognostic factors for rectal cancer treated with preoperative chemoradiotherapy. The Ki-67 index and survivin expression were examined in patients with stage II/III rectal cancer (n=46) by immunohistochemistry. Patients were divided into a high-group and a low-group for the Ki-67 index, and positive and negative groups for survivin expression. Overall and disease-free survival were compared between the groups, and the correlation between Ki-67 index and survivin expression was assessed. The 5-year disease-free survival rate of the group with high Ki-67 index was significantly lower than that of the group with low Ki-67 index (53% and 88%, p=0.03), as was the 5-year overall survival rate (68% and 100%, p=0.03). Findings for survivin were not significant. Ki-67 index and survivin may be useful biomarkers for rectal cancer with preoperative CRT.
Mureo Kasahara, Koji Umeshita, Seisuke Sakamoto, Akinari Fukuda, Hiroyuki Furukawa, Shotaro Sakisaka, Eiji Kobayashi, Eiji Tanaka, Yukihiro Inomata, Seiji Kawasaki, Mitsuo Shimada, Norihiro Kokudo, Hiroto Egawa, Hideki Ohdan and Shinji Uemoto : Living donor liver transplantation for biliary atresia: An analysis of 2085 cases in the registry of the Japanese Liver Transplantation Society., American Journal of Transplantation, Vol.18, No.3, 659-668, 2018.
(Summary)
Biliary atresia (BA) is the most common indication for liver transplantation (LT) in pediatric population. This study analyzed the comprehensive factors that might influence the outcomes of patients with BA who undergo living donor LT by evaluating the largest cohort with the longest follow-up in the world. Between November 1989 and December 2015, 2,085 BA patients underwent LDLT in Japan. There were 763 male and 1,322 female recipients with a mean age of 5.9 years and body weight of 18.6 kg. The 1-, 5-, 10-, 15-, and 20-year graft survival rates for the BA patients undergoing LDLT were 90.5%, 90.4%, 84.6%, 82.0%, and 79.9%, respectively. The donor body mass index, ABO incompatibility, graft type, recipient age, center experience, and transplant era were found to be significant predictors of the overall graft survival. Adolescent age (12 to <18 years) was associated with a significantly worse long-term graft survival rate than younger or older ages. We conclude that LDLT for BA is a safe and effective treatment modality that does not compromise living donors. The optimum timing for LT is crucial for a successful outcome, and early referral to transplantation center can improve the short-term outcomes of LT for BA. Further investigation of the major cause of death in liver transplanted recipients with BA in the long-term is essential, especially among adolescents.
Satoru Imura, Hiroki Teraoku, Masato Yoshikawa, Daichi Ishikawa, Shin-ichiro Yamada, Yu Saitou, Shuichi Iwahashi, Tetsuya Ikemoto, Yuji Morine and Mitsuo Shimada : Potential predictive factors for microvascular invasion in hepatocellular carcinoma classified within the Milan criteria., International Journal of Clinical Oncology, Vol.23, No.1, 98-103, 2018.
(Summary)
Microvascular invasion (mvi) is an important risk factor for recurrent hepatocellular carcinoma (HCC), even after curative liver resection or orthotopic liver transplantation. However, mvi is difficult to detect preoperatively. The aim of this study was to clarify the risk factors of postoperative recurrence and investigate predictive factors of mvi before hepatectomy for HCC classified within the Milan criteria. One hundred fifty-nine patients with hepatocellular carcinoma (HCC) classified within the Milan criteria, who underwent hepatectomy, were enrolled in this study. We investigated the risk factors of recurrence. In addition, we divided them into two groups: mvi-negative group and mvi-positive group, based on pathological findings after surgery. We compared the clinicopathological factors between the two groups and determined the risk factors for mvi. Overall survival rate at 1, 3, and 5 years were 91.6%, 80.5%, and 74.9%, and the recurrence-free survival rate at 1, 3, and 5-years were 72.3%, 51.6%, and 37.2%. Risk factor analysis for tumor recurrence revealed that total bilirubin, albumin, ICGR15, AFP-L3, tumor number, mvi, and tumor stage had a significant predictive value. Multivariate analysis revealed that tumor number and mvi were significant independent risk factors for tumor recurrence. Predictive analysis for risk factors of mvi revealed that multiple tumors and AFP-L3 > 10% were significant independent risk factors for mvi in HCC classified within the Milan criteria. The mvi was one of the independent risk factors for tumor recurrence in HCC classified within the Milan criteria. Multiple tumors and high AFP-L3 value were independent predictive factors for mvi.
Toshiaki Yoshimoto, Satoru Imura, Yuji Morine, Tetsuya Ikemoto, Yusuke Arakawa, Shuichi Iwahashi, Yu Saitou, Chie Takasu, Daichi Ishikawa, Hiroki Teraoku, Yoshimi Bando and Mitsuo Shimada : The Outcome of Sorafenib Therapy on Unresectable Hepatocellular Carcinoma: Experience of Conversion and Salvage Hepatectomy., Anticancer Research, Vol.38, No.1, 501-507, 2018.
(Summary)
We report the outcomes of sorafenib therapy for advanced hepatocellular carcinoma (HCC) in our Department. Thirty-eight patients with unresectable HCC who were administrated sorafenib from 2009 to 2015 were investigated retrospectively. The 1-year overall survival rate was 59.3%. The macroscopic vascular invasion and response rate were independent prognostic factors of survival. Surgical resection after sorafenib achieved long-term survival in two cases. Case 1: A patient with locally unresectable HCC showed significant response induced by sorafenib, which allowed complete surgical resection. This tumor tested positive for FGF4. Case 2: A patient with a history of hepatectomy for HCC had multiple distant metastases. Most lesions were reduced in size after sorafenib therapy and new lesions in the remnant liver and residual lung metastases were resected. The sorafenib-resistant lesions were negative for FGF4. Sorafenib combined with surgical resection is a feasible option in advanced HCC patients, if sorafenib has been effective.
Hiroki Ishibashi, Mitsuo Shimada, Hiroki Mori, Yuji Morine and 安藤 久實 : 【慢性炎症から肝胆膵癌にいたるランドスケープ】膵・胆管合流異常と胆道癌, KAN TAN SUI, Vol.77, No.3, 659-667, 2018.
(Keyword)
和文論文
71.
Keigo Yada, Yuji Morine, Hiroki Ishibashi, Hiroki Mori and Mitsuo Shimada : Treatment strategy for successful hepatic resection of icteric liver., The Journal of Medical Investigation : JMI, Vol.65, No.1.2, 37-42, 2018.
(Summary)
The treatment strategy for jaundiced patients with hilar cholangiocarcinoma (HC) is not well established. In this study, we evaluate the feasibility of our perioperative protocol for jaundiced patients with HC. Twenty patients with HC who underwent hepatic resection at our institute were enrolled, and patients were divided into icteric(n=6) and normal(n=14) group. As a perioperative protocol, Oral administration of Inchinkoto(ICKT), steroid and nafamostat mesilate were introduced. The evaluation of functional future remnant liver(FRL) by asiaroscintigraphy, and postoperative outcomes were retrospectively compared. Indocyanine green dye retention rate at 15 minutes was higher, and LHL15 values was lower in icteric group. However, in the functional evaluation of FRL, which was the sum of GSA uptake of the future FRL, there was no significant difference of LHL15 values of the remnant liver functional reserve between the two groups. As results, according to the difference of liver function, serum AST level was not different between two groups. The number of patients with postoperative morbidity in the two groups was comparable. Even in HC patients with icteric liver, accurate assessment of liver functional reserve and effective perioperative treatment may attribute to successful hepatectomy and favorable post-operative outcomes. J. Med. Invest. 65:37-42, February, 2018.
(Keyword)
Aged / Aged, 80 and over / Bile Duct Neoplasms / Cholangiocarcinoma / Female / Hepatectomy / Humans / Jaundice, Obstructive / Male / Postoperative Complications / Retrospective Studies
MicroRNAs have broad roles in tumorigenesis and cell differentiation through regulation of target genes. Notch signaling also controls cell differentiation and tumorigenesis. However, the mechanisms through which Notch mediates microRNA expression are still unclear. In this study, we aimed to identify microRNAs regulated by Notch signaling. Our analysis found that microRNA-449a (miR-449a) was indirectly regulated by Notch signaling. Although miR-449a-deficient mice did not show any Notch-dependent defects in immune cell development, treatment of miR-449a-deficient mice with azoxymethane (AOM) or dextran sodium sulfate (DSS) increased the numbers and sizes of colon tumors. These effects were associated with an increase in intestinal epithelial cell proliferation following AOM/DSS treatment. In patients with colon cancer, miR-449a expression was inversely correlated with disease-free survival and histological scores and was positively correlated with the expression of MLH1 for which loss-of function mutations have been shown to be involved in colon cancer. Colon tissues of miR-449a-deficient mice showed reduced Mlh1 expression compared with those of wild-type mice. Thus, these data suggested that miR-449a acted as a key regulator of colon tumorigenesis by controlling the proliferation of intestinal epithelial cells. Additionally, activation of miR-449a may represent an effective therapeutic strategy and prognostic marker in colon cancer.
Naoki Muguruma, Koichi Okamoto, Tadahiko Nakagawa, Katsutaka Sannomiya, Shota Fujimoto, Yasuhiro Mitsui, Tetsuo Kimura, Hiroshi Miyamoto, Jun Higashijima, Mitsuo Shimada, Yoko Horino, Shinya Matsumoto, Kenjiro Hanaoka, Tetsuo Nagano, Makoto Shibutani and Tetsuji Takayama : Molecular imaging of aberrant crypt foci in the human colon targeting glutathione S-transferase P1-1., Scientific Reports, Vol.7, No.1, 6536, 2017.
(Summary)
Aberrant crypt foci (ACF), the earliest precursor lesion of colorectal cancers (CRCs), are a good surrogate marker for CRC risk stratification and chemoprevention. However, the conventional ACF detection method with dye-spraying by magnifying colonoscopy is labor- and skill-intensive. We sought to identify rat and human ACF using a fluorescent imaging technique that targets a molecule specific for ACF. We found that glutathione S-transferase (GST) P1-1 was overexpressed in ACF tissues in a screening experiment. We then synthesized the fluorogenic probe, DNAT-Me, which is fluorescently quenched but is activated by GSTP1-1. A CRC cell line incubated with DNAT-Me showed strong fluorescence in the cytosol. Fluorescence intensities correlated significantly with GST activities in cancer cell lines. When we sprayed DNAT-Me onto colorectal mucosa excised from azoxymethane-treated rats and surgically resected from CRC patients, ACF with strong fluorescent signals were clearly observed. The ACF number determined by postoperative DNAT-Me imaging was almost identical to that determined by preoperative methylene blue staining. The signal-to-noise ratio for ACF in DNAT-Me images was significantly higher than that in methylene blue staining. Thus, we sensitively visualized ACF on rat and human colorectal mucosa by using a GST-activated fluorogenic probe without dye-spraying and magnifying colonoscopy.
Conversion therapy is an option for unresectable metastatic gastric cancer when distant metastases are controlled by chemotherapy; however, the feasibility and efficacy remain unclear. This study aimed to assess the feasibility and efficacy of conversion therapy in patients with initially unresectable gastric cancer treated with docetaxel, cisplatin, and S-1 (DCS) chemotherapy by evaluating clinical outcomes. One hundred unresectable metastatic gastric cancer patients, enrolled in three DCS chemotherapy clinical trials, were retrospectively evaluated. The patients received oral S-1 (40 mg/m2 b.i.d.) on days 1-14 and intravenous cisplatin (60 mg/m2) and docetaxel (50-60 mg/m2) on day 8 every 3 weeks. Conversion therapy was defined when the patients could undergo R0 resection post-DCS chemotherapy and were able to tolerate curative surgery. Conversion therapy was achieved in 33/100 patients, with no perioperative mortality. Twenty-eight of the 33 patients (84.8 %) achieved R0 resection, and 78.8 % were defined as histological chemotherapeutic responders. The median overall survival (OS) of patients who underwent conversion therapy was 47.8 months (95 % CI 28.0-88.5 months). Patients who underwent R0 resection had significantly longer OS than those who underwent R1 and R2 resections (P = 0.0002). Of the patients with primarily unresectable metastases, 10 % lived >5 years. Among patients who underwent conversion therapy, multivariate analysis showed that the pathological response was a significant independent predictor for OS. DCS safely induced a high conversion rate, with very high R0 and pathological response rates, and was associated with a good prognosis; these findings warrant further prospective investigations.
Yuri Matsumoto, Hiroshi Miyamoto, Akira Fukuya, Fumika Nakamura, Takahiro Goji, Shinji Kitamura, Tetsuo Kimura, Koichi Okamoto, Masahiro Sogabe, Naoki Muguruma, Mitsuo Shimada, Yoshimi Bando and Tetsuji Takayama : Hemosuccus pancreaticus caused by a mucinous cystic neoplasm of the pancreas., Clinical Journal of Gastroenterology, Vol.10, No.2, 185-190, 2017.
(Summary)
Hemosuccus pancreaticus is a gastrointestinal hemorrhage through the main pancreatic duct. Here, we report a rare case of hemosuccus pancreaticus due to a mucinous cystic neoplasm of the pancreas. A 62-year-old woman who had been followed for a branch duct intraductal papillary mucinous neoplasm visited our emergency room due to severe abdominal pain and bloody discharge. Computed tomography revealed that the pancreatic cyst increased the tension of the wall and a high-density area indicative of bleeding into the cyst was observed. Endoscopy showed opening of and hemorrhaging from the papilla of Vater. The patient was diagnosed with hemosuccus pancreaticus caused by hemorrhaging into the cyst from the branch duct intraductal papillary mucinous neoplasm. Based on this diagnosis, elective distal pancreatectomy was performed. The histopathological diagnosis was a mucinous cystic neoplasm with intermediate-grade dysplasia based upon the pathological findings that fibrous ovarian-type stroma existed abundantly and the stroma cells were positive for progesterone receptor and inhibin. Hemosuccus pancreaticus caused by a mucinous cystic neoplasm is extremely rare and there has been only one case reported to date. In conclusion, it should be recognized that pancreatic cystic neoplasms including mucinous cystic neoplasms may cause hemosuccus pancreaticus.
(Keyword)
Ampulla of Vater / female / Gastrointestinal Hemorrhage / Humans / magnetic resonance imaging / Middle Aged / Neoplasms, Cystic, Mucinous, and Serous / Pancreatic Cyst / Pancreatic Ducts / Pancreatic Neoplasms / Tomography, X-Ray Computed
Naoji Mita, Shinji Kawahito, Tomohiro Soga, Kazumi Takaishi, Hiroshi Kitahata, Munehide Matsuhisa, Mitsuo Shimada, Kinoshita Hiroyuki, Yasuo Tsutsumi and Katsuya Tanaka : Strict blood glucose control by an artificial endocrine pancreas during hepatectomy may prevent postoperative acute kidney injury, Journal of Artificial Organs, Vol.20, No.1, 76-83, 2017.
(Summary)
The aim of the present study was to evaluate the usefulness of a closed-loop system (STG-55; Nikkiso, Tokyo, Japan), a type of artificial endocrine pancreas for the continuous monitoring and control of intraoperative blood glucose, for preventing postoperative acute kidney injury (AKI) in patients undergoing hepatectomy. Thirty-eight patients were enrolled in this study. Glucose concentrations were controlled with either a manual injection of insulin based on a commonly used sliding scale (manual insulin group, n = 19) or the programmed infusion of insulin determined by the control algorithm of the artificial endocrine pancreas (programmed insulin group, n = 19). After the induction of anesthesia, a 20-G intravenous catheter was inserted into the peripheral forearm vein of patients in the programmed insulin group and connected to an artificial endocrine pancreas (STG-55). The target range for glucose concentrations was set to 100-150 mg/dL. The mean serum creatinine concentrations of preoperative, postoperative 24 and 48 h were 0.72, 0.78, and 0.79 mg/dL in the programmed insulin group, and 0.81, 0.95, and 1.03 mg/dL in the manual insulin group, respectively. Elevations in serum creatinine concentrations postoperative 48 h were significantly suppressed in the programmed insulin group. The STG-55 closed-loop system was effective for maintaining strict blood glucose control during hepatectomy with minimal variability in blood glucose concentrations and for suppressing elevations in serum creatinine concentrations. Strict blood glucose control by an artificial endocrine pancreas during hepatectomy may prevent postoperative AKI.
(Keyword)
Acute Kidney Injury / Aged / Aged, 80 and over / Blood Glucose / Creatinine / Female / Hepatectomy / Humans / Insulin / Insulin Infusion Systems / Japan / Male / Middle Aged / Pancreas, Artificial / Postoperative Complications / Treatment Outcome
Yasuteru Fujino, Shunsaku Takeishi, Kensei Nishida, Koichi Okamoto, Naoki Muguruma, Tetsuo Kimura, Shinji Kitamura, Hiroshi Miyamoto, Akiko Fujimoto, Jun Higashijima, Mitsuo Shimada, Kazuhito Rokutan and Tetsuji Takayama : Downregulation of miR-100/miR-125b is associated with lymph node metastasis in early colorectal cancer with submucosal invasion., Cancer Science, Vol.108, No.3, 390-397, 2017.
(Summary)
A majority of early colorectal cancers (CRCs) with submucosal invasion undergo surgical operation, despite a very low incidence of lymph node metastasis. Our study aimed to identify microRNAs (miRNAs) specifically responsible for lymph node metastasis in submucosal CRCs. MicroRNA microarray analysis revealed that miR-100 and miR-125b expression levels were significantly lower in CRC tissues with lymph node metastases than in those without metastases. These results were validated by quantitative real-time PCR in a larger set of clinical samples. The transfection of a miR-100 or miR-125b inhibitor into colon cancer HCT116 cells significantly increased cell invasion, migration, and MMP activity. Conversely, overexpression of miR-100 or miR-125b mimics significantly attenuated all these activities but did not affect cell growth. To identify target mRNAs, we undertook a gene expression array analysis of miR-100-silenced HCT116 cells as well as negative control cells. The Ingenuity Pathway Analysis, TargetScan software analyses, and subsequent verification of mRNA expression by real-time PCR identified mammalian target of rapamycin (mTOR) and insulin-like growth factor 1 receptor (IGF1R) as direct, and Fas and X-linked inhibitor-of-apoptosis protein (XIAP) as indirect candidate targets for miR-100 involved in lymph node metastasis. Knockdown of each gene by siRNA significantly reduced the invasiveness of HCT116 cells. These data clearly show that downregulation of miR-100 and miR-125b is closely associated with lymph node metastasis in submucosal CRC through enhancement of invasion, motility, and MMP activity. In particular, miR-100 may promote metastasis by upregulating mTOR, IGF1R, Fas, and XIAP as targets. Thus, miR-100 and miR-125b may be novel biomarkers for lymph node metastasis of early CRCs with submucosal invasion.
Hiroki Ishibashi, Mitsuo Shimada and Keigo Yada : Japanese clinical practice guidelines for congenital biliary dilatation, The Japanese Journal of Gastro-enterology, Vol.113, No.12, 2004-2015, 2016.
Toshihiro Nakao, Mitsuo Shimada, Kouzou Yoshikawa, Jun Higashijima, Takuya Tokunaga, Masaaki Nishi, Chie Takasu, Hideya Kashihara, Ichio Suzuka, Takashi Nishizaki, Hiroshi Okitsu, Toshiyuki Yagi, Hidenori Miyake, Murato Miura, Mitsutoshi Fukuyama, Daisuke Wada and Yoshiaki Bando : Propensity score-matched study of laparoscopic and open surgery for colorectal cancer in rural hospitals., Journal of Gastroenterology and Hepatology, Vol.31, No.10, 1700-1704, 2016.
(Summary)
Various randomized clinical studies have suggested that short- and long-term outcomes of laparoscopic surgery (LAP) for colorectal cancer are comparable with those of open surgery (OP). However, these studies were performed in high-volume hospitals. The aim of the present study was to compare the outcomes of LAP versus OP for colorectal cancer in rural hospitals. This was a multicenter retrospective propensity score-matched case-control study of patients who underwent colorectal surgery from January 2004 to April 2009 in 10 hospitals in Japan. All patients underwent curative surgery for pathologically diagnosed stage II or III colorectal cancer. The primary end point was 5-year overall survival (OS). The secondary end points were disease-free survival (DFS) and postoperative complications. In total, 319 patients who underwent LAP and 1020 patients who underwent OP were balanced to 261 pairs. There was no significant difference in the OS and DFS between two groups. The operation time was significantly shorter for OP than for LAP. Blood loss was significantly lower in LAP than in OP. There was no difference in intraoperative morbidity between the two groups. The postoperative morbidity was significantly lower in LAP than in OP. The hospital stay was significantly shorter in LAP than in OP. There was no significant difference in 90-day postoperative mortality. Laparoscopic surgery may be a feasible option for colorectal cancer in rural hospitals.
Tetsuo Kimura, Hiroshi Miyamoto, Akira Fukuya, Shinji Kitamura, Koichi Okamoto, Masako Kimura, Naoki Muguruma, Tetsuya Ikemoto, Mitsuo Shimada, Akiko Yoneda, Yoshimi Bando, Makoto Takishita and Tetsuji Takayama : Neuroendocrine carcinoma of the pancreas with similar genetic alterations to invasive ductal adenocarcinoma., Clinical Journal of Gastroenterology, Vol.9, No.4, 261-265, 2016.
(Summary)
Neuroendocrine carcinoma (NEC) of the pancreas is very rare, and its origin is not fully elucidated. Here, we present a case of a small-size NEC of the pancreas that is genetically similar to invasive ductal adenocarcinoma (IDA). A 65-year-old man was referred to our hospital due to obstructive jaundice and found to have a 12-mm solid tumor in the pancreas head. The tumor exhibited low vascularity on enhanced computed tomography, and endoscopic retrograde pancreatographic imaging revealed an irregular obstruction in a branch duct of the pancreas. The patient was thereby diagnosed with a pancreatic ductal cancer, and stomach-preserving pancreaticoduodenectomy with regional lymph node resection was performed. Histochemical analysis of the resected tumor showed that the neoplastic cells with scanty cytoplasm and hyperchromatic nuclei strongly expressed chromogranin A and synaptophysin. The Ki-67 index was 40 % in the most proliferative tumor regions, and the tumor was diagnosed as a NEC of the pancreas. However, in the analysis of genetic alterations of the tumor tissue, the neoplastic cells showed altered KRAS, TP53, and SMAD4/DPC4, suggesting that the NEC in our case is genetically related to IDA. Our data suggest that poorly differentiated IDAs may transform into NECs.
Kouzou Yoshikawa, Mitsuo Shimada, Jun Higashijima, Toshihiro Nakao, Masaaki Nishi, Chie Takasu, Hideya Kashihara and Syohei Eto : Combined liver mobilization and retraction: A novel technique to obtain the optimal surgical field during laparoscopic total gastrectomy., Asian Journal of Endoscopic Surgery, Vol.9, No.2, 111-115, 2016.
(Summary)
During laparoscopic gastrectomy, it is important to establish a good operative field and ensure an adequate working space. The combined liver mobilization and retraction method is used to get a safe and optimal view. We retrospectively analyzed 32 consecutive patients who underwent laparoscopic total gastrectomy for gastric cancer. The patients were divided into two groups: the mobilization (+) group (n = 12) and the mobilization (-) group (n = 20). Hepatic function tests were performed in all patients. Mobilization provided a satisfactory view of the working field, especially the gastroesophageal junction and the angle of His during laparoscopic total gastrectomy, and no complications were observed during liver retraction. On postoperative hepatic function testing, there was no significant difference between the two groups on any day. Combined liver mobilization and retraction may be helpful in laparoscopic total gastrectomy.
Keigo Yada, Hiroki Ishibashi, Hiroki Mori and Mitsuo Shimada : Intrascrotal lipoblastoma: report of a case and the review of literature., Surgical Case Reports, Vol.2, No.1, 34, 2016.
(Summary)
Intrascrotal lipoblastoma is a rare pediatric benign soft tissue neoplasm, and only 11 cases have been reported. The accurate preoperative diagnosis is difficult because of its rarelity and the similarity with the other soft tissue tumors. Among them, accurate preoperative diagnosis had been made in only one case. Thus, almost all of the cases had required inguinal mass excision (and orchidectomy in one case). In this paper, we discuss the accurate preoperative diagnosis of intrascrotal lipoblastoma and subsequent simple tumorectomy via minimal invasive scrotal skin incision, in 1-year-old boy. On physical examination, intrascrotal extra-testicular lobulated mass was palpated on the right scrotum. An ultrasonography revealed the well-circumscribed, iso-echoic, scant blood-flow, and lobulated tumors with each lobules of 1 to 4 cm in diameter, and the tumor located outside of the tunica vaginalis testis. The serum values of alpha-fetoprotein (AFP) and beta-human chorionic gonadotropin (b-hCG) were within normal limit. The preoperative diagnosis of intrascrotal lipoblastoma was made, and the mass was excised via minimal scrotal incision. The right testicle and epididymis were normal. The lesion consisted of the distinct two lobulated tumors, and microscopic examination confirmed the diagnosis of intrascrotal lipoblastoma. The postoperative course was uneventful without evidence of recurrence. A rare intrascrotal lipoblastoma is seldom made accurate preoperative diagnosis; however, the accurate preoperative suspicion of this tumor leads to the minimal invasive tumorectomy via scrotal skin incision and favorable postoperative recovery without recurrence.
Keigo Yada, Hiroki Ishibashi, Hiroki Mori, Yuji Morine, Chengzhan Zhu, Rui Feng, Toru Kono and Mitsuo Shimada : The Kampo medicine "Daikenchuto (TU-100)" prevents bacterial translocation and hepatic fibrosis in a rat model of biliary atresia., Surgery, Vol.159, No.6, 1600-1611, 2016.
(Summary)
Biliary atresia is the most common cause of end-stage liver disease in children. It is known that bile duct ligation contributes to liver fibrosis via bacterial translocation (BT) and toll-like receptor 4 (TLR4) signaling of hepatic stellate cells (HSCs). We have reported previously that the traditional Japanese medicine, "Dai-kenchu-to (TU-100)," a form of "Kampo medicine" prevents BT in rats exposed to the stress of fasting. The aim of this study was to clarify the effect of TU-100 on a rat model of biliary atresia using bile duct ligation. Bile duct ligation and subsequent daily oral administration of TU-100 was performed in 6-week-old rats. The rats were killed at 3, 7, or 14 days after bile duct ligation to evaluate the liver injury, occurrence of BT, and hepatic fibrosis. As an in vitro experiment, we isolated fresh HSCs from the rats undergoing bile duct ligation. After cell attachment, TU-100 and its 3 component herbs (eg, processed ginger, ginseng radix, and Japanese pepper) were added, and the expressions of Alpha actin2 (acta2), Alpha-1 type I collagen (colIa1), and tissue inhibitor of metalloproteinase 1 (timp1) were analyzed. In vivo experiments demonstrated that oral administration of TU-100 decreased liver injury and atrophy of intestinal mucosa BT, hepatic fibrosis, and hepatic expression of alpha smooth muscle actin ( SMA) and TLR4, compared with rats that underwent bile duct ligation only. In vitro experiments showed that administration of TU-100 or the component herbs inhibited the expressions of acta2, colIa1, and timp1 in the HSCs. TU-100 prevented BT, activation of HSCs, and subsequent hepatic fibrosis. TU-100 may prevent progression of hepatic fibrosis in children with biliary atresia and improve prognosis.
Tomohiro Nishina, Toshikazu Moriwaki, Mitsuo Shimada, Jun Higashijima, Yoshinori Sakai, Toshiki Masuishi, Mitsuharu Ozeki, Kenji Amagai, Yuji Negoro, Shunju Indo, Tadamichi Denda, Mikio Sato, Yuji Yamamoto, Go Nakajima, Minoru Mizuta, Ikuo Takahashi, Yoshinori Hiroshima, Hiroyasu Ishida, Takashi Maeba and Ichinosuke Hyodo : Uracil-Tegafur and Oral Leucovorin Combined With Bevacizumab in Elderly Patients (Aged · 75 Years) With Metastatic Colorectal Cancer: A Multicenter, Phase II Trial (Joint Study of Bevacizumab, Oral Leucovorin, and Uracil-Tegafur in Elderly Patients [J-BLUE] Study)., Clinical Colorectal Cancer, Vol.15, No.3, 236-242, 2015.
(Summary)
We previously reported that uracil-tegafur with oral leucovorin (UFT/LV) treatment for elderly patients (aged · 75 years) was well-tolerated in a phase II study. In the present study, the efficacy and safety of a modified (1-week shorter administration period) UFT/LV schedule combined with bevacizumab for a similar population are reported. The present study was a single-arm, open-label, multicenter, cooperative group clinical trial. The key eligibility criteria included age · 75 years, Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1, first-line chemotherapy, measurable lesions, and preserved organ function. Patients received UFT 300 mg/m(2)/d and LV 75 mg/d on days 1 to 21 and intravenous bevacizumab 5 mg/kg on days 1 and 15. Treatment was repeated every 28 days. The primary endpoint was progression-free survival (PFS), and the secondary endpoints were the objective response rate (ORR), overall survival (OS), and safety. Of the 55 patients enrolled from 15 Japanese institutions, 52 eligible patients were evaluated. Their median age was 80 years (range, 75-87 years), and 73% had an ECOG performance status of 0. The median PFS was 8.2 months (95% confidence interval [CI], 6.2-10 months). The ORR was 40% (95% CI, 27%-55%). The median OS was 23 months (95% CI, 12-33 months). The most common grade 3 and 4 treatment-related adverse events were hypertension (12%), fatigue (8%), anemia (8%), nausea (6%), and diarrhea (6%). Treatment-related death occurred in 2 patients. UFT/LV (3 weeks of therapy and 1 week without) combined with biweekly bevacizumab is a tolerable and effective treatment option for elderly patients (aged · 75 years) with metastatic colorectal cancer.
Yuji Morine and Mitsuo Shimada : The value of systematic lymph node dissection for intrahepatic cholangiocarcinoma from the viewpoint of liver lymphatics., Journal of Gastroenterology, Vol.50, No.9, 913-927, 2015.
(Summary)
Lymph node (LN) metastasis from intrahepatic cholangiocarcinoma (IHCC) might be one of the most important indicators of aggressive surgical resection, yet the value of LN dissection is still controversial. To address this clinical problem, we need to better understand the multidirectional lymphatic outflow from the liver. Although most hepatic lymph flows into the hilar LNs along portal triads, there are also several lymphatic outflows directly communicating with distant areas or the general lymphatic system. Moreover, it has been revealed that LN metastasis spreads to more distal LNs through the hepatoduodenal ligament or other multidirectional lymphatic pathways connected to the general lymphatic system. Therefore, systematic LN dissection might merely be LN sampling in IHCC with LN metastasis. A multidisciplinary strategy focusing on adjuvant treatment after surgery is immediately necessary in these cases. In IHCC without LN metastasis, the accuracy of preoperative imaging assessment of LN metastasis is unsatisfactory and useless for detecting metastatic LNs in clinical settings. Therefore, prophylactic systematic LN dissection for IHCC without preoperative LN swelling is recommended for accurate LN status assessment and reduction of local recurrences. However, this procedure might not offer any clinical benefit according to the results of retrospective comparative studies. In this review, we summarize previous reports regarding lymphatic outflow of the liver and discuss LN dissection for IHCC.
Toshihiro Nakao, Takashi Iwata, Masanori Hotchi, Kouzou Yoshikawa, Jun Higashijima, Masaaki Nishi, Chie Takasu, Shohei Eto, Hiroki Teraoku and Mitsuo Shimada : Prediction of response to preoperative chemoradiotherapy and establishment of individualized therapy in advanced rectal cancer., Oncology Reports, Vol.34, No.4, 1961-1967, 2015.
(Summary)
Preoperative chemoradiotherapy (CRT) has become the standard treatment for patients with locally advanced rectal cancer. However, no specific biomarker has been identified to predict a response to preoperative CRT. The aim of the present study was to assess the gene expression patterns of patients with advanced rectal cancer to predict their responses to preoperative CRT. Fifty-nine rectal cancer patients were subjected to preoperative CRT. Patients were randomly assigned to receive CRT with tegafur/gimeracil/oteracil (S-1 group, n=30) or tegafur-uracil (UFT group, n=29). Gene expression changes were studied with cDNA and miRNA microarray. The association between gene expression and response to CRT was evaluated. cDNA microarray showed that 184 genes were significantly differentially expressed between the responders and the non-responders in the S-1 group. Comparatively, 193 genes were significantly differentially expressed in the responders in the UFT group. TBX18 upregulation was common to both groups whereas BTNL8, LOC375010, ADH1B, HRASLS2, LOC284232, GCNT3 and ALDH1A2 were significantly differentially lower in both groups when compared with the non-responders. Using miRNA microarray, we found that 7 and 16 genes were significantly differentially expressed between the responders and non-responders in the S-1 and UFT groups, respectively. miR-223 was significantly higher in the responders in the S-1 group and tended to be higher in the responders in the UFT group. The present study identified several genes likely to be useful for establishing individualized therapies for patients with rectal cancer.
Nobuhiro Kurita, Hiroaki Miyata, Mitsukazu Gotoh, Mitsuo Shimada, Satoru Imura, Wataru Kimura, Naohiro Tomita, Hideo Baba, Yukou Kitagawa, Kenichi Sugihara and Masaki Mori : Risk Model for Distal Gastrectomy When Treating Gastric Cancer on the Basis of Data From 33,917 Japanese Patients Collected Using a Nationwide Web-based Data Entry System., Annals of Surgery, Vol.262, No.2, 295-303, 2015.
(Summary)
To establish a risk model for distal gastrectomy in Japanese patients with gastric cancer. Risk stratification for distal gastrectomy in Japanese patients with gastric cancer improves surgical outcomes. The National Clinical Database was constructed for risk determination in gastric cancer-related gastrectomy among Japanese individuals. Data from 33,917 gastric cancer cases (1737 hospitals) were used. The primary outcomes were 30-day and operative mortalities. Data were randomly assigned to risk model development (27,220 cases) and test validation (6697 cases) subsets. Stepwise selection was used for constructing 30-day and operative mortality logistic models. The 30-day, in-hospital, and operative mortality rates were 0.52%, 1.16%, and 1.2%, respectively. The morbidity was 18.3%. The 30-day and operative mortality models included 17 and 21 risk factors, respectively. Thirteen variables overlapped: age, need for total assistance in activities of daily living preoperatively or within 30 days after surgery, cerebrovascular disease history, more than 10% weight loss, uncontrolled ascites, American Society of Anesthesiologists score (≥ class 3), white blood cell count more than 12,000/μL or 11,000/μL, anemia (hemoglobin: males, <13.5 g/dL; females, <12.5 g/dL; or hematocrit: males, <37%; females <32%), serum albumin less than 3.5 or 3.8 g/dL, alkaline phosphatase more than 340 IU/L, serum creatinine more than 1.2 mg/dL, serum Na less than 135 mEq/L, and prothrombin time-international normalized ratio more than 1.25 or 1.1. The C-indices for the 30-day and operative mortalities were 0.785 (95% confidence interval, 0.705-0.865; P < 0.001) and 0.798 (95% confidence interval, 0.746-0.851; P < 0.001), respectively. The risk model developed using nationwide Japanese data on distal gastrectomy in gastric cancer can predict surgical outcomes.
(Keyword)
Aged / Aged, 80 and over / Female / Gastrectomy / Hospital Mortality / Humans / internet / Japan / Laparoscopy / Logistic Models / Male / Middle Aged / Odds Ratio / Quality Indicators, Health Care / Risk Factors / Sensitivity and Specificity / Stomach Neoplasms / Survival Rate / Treatment Outcome / 欧文論文
Chie Takasu and Mitsuo Shimada : 外科の立場からのキャリアアップ支援と問題点, 第40回日本外科系連合学会学術集会, 2015.
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Yuji Morine, Mitsuo Shimada, Satoru Imura, Tetsuya Ikemoto, Jun Hanaoka, Mami Kanamoto, Hiroki Ishibashi and Toru Utsunomiya : Detection of Lymph Nodes Metastasis in Biliary Carcinomas:Morphological Criteria by MDCT and the Clinical Impact of DEI-MRI, Hepato-Gastroenterology, Vol.62, No.140, 777-781, 2015.
(Summary)
This study was conducted to assess the usefulness of multi-slice CT (MDCT) and diffusion weighted MR images (DWI-MRI) for diagnosis of metastatic lymph nodes (LNs) in biliary carcinomas. Eighteen patients with biliary carcinomas (total 121 LNs) underwent surgical resection were included. In MDCT, the following criteria were measured: the maximum diameter, the enhanced value and the long and short axis (L/S) ratio. In DWI-MRI, the apparent diffusion coefficients (ADCs) were measured from ADC maps. In ROC analysis, the maximum diameter has the highest diagnostic power with area under curves of 0.903. And when the maximum diameter 8 mm and L/S ratio is less than 2, the accuracy was improved with a sensitivity of 81%, positive predictive value (PPV) of 45%. In DWI-MRI, ADCs values of metastatic LNs significantly lower than that of non-metastatic LNs (mean: 1.65 vs. 2.11 x10 3mm2/s). When the ADC value of 1.8 x10(-3) was used as a cut-off value, the best results were obtained with sensitivity of 75%, PPV of 82%. Using MDCT, diagnosis of LNs metastasis should be more than 8mm diameter and less than 2 of L/S ratio. In addition, DWI-MRI is more useful modality for diagnosis of LNs metastasis.
(Keyword)
欧文論文
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● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 26901999
Shohei Eto, Kouzou Yoshikawa, Mitsuo Shimada, Jun Higashijima, Takuya Tokunaga, Toshihiro Nakao, Masaaki Nishi, Chie Takasu, Horohiko Sato and Nobuhiro Kurita : The relationship of CD133, histone deacetylase 1 and thrombospondin-1 in gastric cancer., Anticancer Research, Vol.35, No.4, 2071-2076, 2015.
(Summary)
Gastric cancer is one of the most common types of cancer. Cancer stem cells (CSCs) have been reported to play important roles in multiple cancer types. This study investigated the correlation between cluster of differentiation 133 (CD133), histone deacetylase 1 (HDAC1) and thrombospondin-1 (THBS1) expression in advanced gastric cancer. The study included 65 patients with gastric cancer with recurrence after surgery. Expression of CD133, HDAC1 and THBS1 was examined by immunohistochemistry. Prognostic factors were investigated by multivariate analysis using Cox's proportional hazard model. Clinicopathological variables, including survival, of patients positive for CD133 expression (n=6, 23%), were compared with those without CD133 expression (n=20, 77%). Positive HDAC1 expression and THBS1 expression were observed in 34 (52%) and 17 (26%) patients, respectively. Using univariate analysis, positive expression of CD133 and negative expression of THBS1 predicted significantly worse prognosis. Multivariate analysis revealed CD133-positive and THBS1-negative expression were independent prognostic indicators. CD133 expression and THBS1 expression were prognostic factors, and a negative relationship between HDAC and THBS1 was observed in advanced gastric cancer. These biomarkers may help determine postoperative treatment in patients with gastric cancer.
Mami Kanamoto, Satoru Imura, Yuji Morine, Tohru Utsunomiya, Hiroki Mori, Yusuke Arakawa, Chie Takasu and Mitsuo Shimada : Effective use of a vessel-sealing system for laparoscopic unroofing of liver cysts., Asian Journal of Endoscopic Surgery, Vol.8, No.1, 91-94, 2015.
(Summary)
Liver cysts that present with symptoms such as jaundice, abdominal pain, and intra-cystic infection require treatment. In laparoscopic unroofing of liver cysts, appropriate treatment is needed in cases where the cystic walls contain vessels or bile ducts. A vessel-sealing system can seal not only vessels, but also bile ducts. We experienced four cases in which laparoscopic unroofing of liver cysts was performed with a vessel-sealing system. Case 1 was a woman in her 70s who presented at our hospital with abdominal pressure. Abdominal CT showed liver cysts with a maximum diameter of 13 cm. Laparoscopic unroofing was performed with LigaSure Impact. Case 2 was a woman in her 50s with abdominal discomfort. CT showed a cyst 15 cm in diameter situated in the right lobe. We performed SILS using a LigaSure Blunt Tip to unroof the cyst. Case 3 was a man in his 80s with abdominal pain. CT showed a huge cyst 25 cm in diameter in the right lobe. We performed hybrid SILS with a LigaSure Blunt Tip to unroof the cysts. Case 4 was a woman in her 70s with upper abdominal pain. CT showed multiple cysts with a maximum diameter of 15 cm in the bilateral lobes. We performed hybrid SILS to successfully unroof her cysts. None of the cases experienced postoperative complications, such as bleeding or bile leakage, and none experienced recurrence of cysts. A laparoscopic unroofing using a vessel-sealing system can be a minimally invasive and safe treatment for liver cysts.
Mitsuo Shimada, Yuji Morine, Hiroaki Nagano, Etsuro Hatano, Takashi Kaiho, Masaru Miyazaki, Toru Kono, Toshiya Kamiyama, Satoshi Morita, Junichi Sakamoto, Mitsuo Kusano, Shigetoyo Saji, Takashi Kanematsu and Masaki Kitajima : Effect of TU-100, a traditional Japanese medicine, administered after hepatic resection in patients with liver cancer: a multi-center, phase III trial (JFMC40-1001)., International Journal of Clinical Oncology, Vol.20, No.1, 95-104, 2015.
(Summary)
This multi-center, phase III trial assesses the efficacy of daikenchuto (TU-100) on gastrointestinal disorders after hepatic resection (UMIN Registration No. 000003103). A total of 231 patients, who underwent hepatic resection at 26 Japanese centers, were enrolled. Patients were randomly assigned to receive either oral doses (15 g/day, three times a day) of TU-100 or placebo control from preoperative day 3 to postoperative day 10, except on the day of surgery. Primary end points were the time from extubation until the first postoperative bowel movement (FBM-T), serum C-reactive protein (CRP) and ammonia levels. Finally, 209 patients (TU-100: n = 108, placebo: n = 101) were included in the statistical analysis. The median FBM-T was 88.2 h (95 % CI 74.0-94.1) in the TU-100 group and 93.1 h (95 % CI 83.3-99.4) in the placebo group, demonstrating that TU-100 accelerated the time to first bowel movement significantly more than placebo control. Serum CRP levels did not differ significantly during the study period, although serum CRP levels in the TU-100 group tended to be lower than those in the placebo group in patients with grade B liver damage. Meanwhile, the two groups had similar serum ammonia levels. TU-100-related serious adverse events did not occur during the study. TU-100 appears to improve gastrointestinal dysmotility and reduce serum CRP levels in patients with grade B liver damage after hepatectomy. TU-100 is an effective treatment option after hepatic resection in patients with liver cancer.
(Keyword)
Aged / Aged, 80 and over / Ammonia / Asian Continental Ancestry Group / C-Reactive Protein / Female / Gastrointestinal Diseases / Hepatectomy / Humans / Liver / Liver Neoplasms / Male / Medicine, East Asian Traditional / Middle Aged / Naphthoquinones / 欧文論文
Hideya Kashihara, Mitsuo Shimada, Nobuhiro Kurita, Hirohiko Sato, Kouzou Yoshikawa, Jun Higashijima, Motoya Chikakiyo, Masaaki Nishi and Chie Takasu : Duodenal-jejunal bypass improves diabetes and liver steatosis via enhanced glucagon-like peptide-1 elicited by bile acids., Journal of Gastroenterology and Hepatology, Vol.30, No.2, 308-315, 2015.
(Summary)
Bariatric surgery not only elicits weight loss but also rapidly resolves diabetes. However, the mechanisms remain unclear. The present study investigates how diabetes and liver steatosis are improved after duodenal-jejunal bypass (DJB) compared with a glucagon-like peptide-1 (GLP-1) analog and correlations between bile acids and GLP-1 secretion. We initially determined the effects of bile acids on GLP-1 in vitro and then assigned 12 male 16-week-old Otsuka Long-Evans Tokushima Fatty rats to groups that underwent DJB, a sham operation, or were treated with the GLP-1 receptor agonist, liraglutide (n = 4 each). Blood glucose, insulin, GLP-1, serum bile acids, liver steatosis, and the number of GLP-1 positive cells (L cells) in the small intestine and colon were investigated in the three groups at eight weeks postoperatively. Levels of GLP-1mRNA were upregulated and GLP-1 secretion increased in cells incubated with bile acids in vitro. Weight gain was suppressed more in the DJB than in the sham group in vivo. Diabetes was more improved and GLP-1 levels were significantly higher in the DJB than in the sham group. Serum bile acids were significantly increased, the number of L cells in the ileum was upregulated compared with the sham group, and liver steatosis was significantly improved in the DJB compared with the other two groups. Duodenal-jejunal bypass might improve diabetes and liver steatosis by enhancing GLP-1 secretion through increasing serum bile acids and the proliferation of L cells in the ileum, compared with liraglutide.
Noriko Kambe, Shinji Kawahito, Naoji Mita, Kazumi Takaishi, Tosiko Katayama, Yoko Sakai, Tomohiro Soga, Hiroaki Kawano, Munehide Matsuhisa, Mitsuo Shimada, Tetsuya Kitagawa and Hiroshi Kitahata : Impact of newly developed, next-generation artificial endocrine pancreas, The Journal of Medical Investigation : JMI, Vol.62, No.1-2, 41-44, 2015.
(Summary)
Recent studies have shown that strict perioperative blood glucose management may reduce mortality and morbidity in critically ill adult patients. The purpose of this study was to assess the accuracy and efficacy of the intraoperative application of a newly developed, next-generation artificial endocrine pancreas (STG-55, Nikkiso Co., Ltd., Tokyo, Japan). Twenty patients scheduled to undergo surgery were enrolled in this study. The STG-55 is designed to be more user-friendly than its conventional counterpart (STG-22) while maintaining the latter's fundamental functions, such as a closed-loop system using algorithms for insulin and glucose infusion. After anesthetic induction, a 20G intravenous catheter was inserted into a peripheral forearm vein and connected to a continuous blood glucose monitor. The resultant 105 scores for paired blood glucose values were compared by Bland-Altman analysis. Stable blood glucose values were maintained automatically, and there were no complications related to use of the STG-55. A close correlation (r=0.96) was observed between continuous glucose measurements using the STG-55 and conventional intermittent glucose measurements. The difficulty of manipulation using this system was decreased by improved preparation procedures. The glycemic control system using the STG-55 could provide an alternative way to achieve effective and safe perioperative glycemic control.
Chinbold Enkhbold, Yuji Morine, Tohru Utsunomiya, Satoru Imura, Tetsuya Ikemoto, Yusuke Arakawa, Yu Saitou, Shinichiro Yamada, Daichi Ishikawa and Mitsuo Shimada : Dysfunction of liver regeneration in aged liver after partial hepatectomy., Journal of Gastroenterology and Hepatology, Vol.30, No.7, 1217-1224, 2015.
(Summary)
A remarkable feature of the liver is its regenerative capacity following partial hepatectomy. However, the regenerative capacity of many organs and tissues loses its natural ability to divide with aging. In this study, we investigated the association of aging with endoplasmic reticulum stress, the cell cycle, autophagy, and apoptosis-related genes during liver regeneration after hepatectomy. Balb/c 4-week and 40-week-old male mice were subjected to 70% hepatectomy. Animals were sacrificed at 24, 48, and 72 h after hepatectomy. Immunohistochemical stainings for proliferating cell nuclear antigen, LC3, Atg5, and caspase-3 were used to quantify protein expression. Real-time reverse transcription-polymerase chain reaction was used to detect p16, CHOP, LC3, Atg5, hepatocyte growth factor, cMet, cyclin D1, cyclin A2, and caspase-3 expression. After hepatectomy, old group showed a lower survival rate and significantly lower expression of hepatocyte growth factor, cMet, cyclin D1, cyclin A2, proliferating cell nuclear antigen labeling index, and SMP30 compared with young group. The liver weight/body weight ratio was significantly lower at 48 h and 72 h after hepatectomy and was accompanied by markedly elevated levels of the liver cell injury markers, LC3 and caspase-3. Immunohistochemical results showed that LC3, Atg5, and caspase-3 protein expression were higher in old group than in young group. These results revealed that impaired liver regeneration was due to aging, which was expressed by decreased cell cycle and increased autophagy and apoptosis. Therefore, understanding the molecular basis for aged liver regeneration might provide a new therapeutic option for old patients.
Tetsuya Ikemoto, Koji Sugimoto, Mitsuo Shimada, Tohru Utsunomiya, Yuji Morine, Satoru Imura, Yusuke Arakawa, Mami Kanamoto, Shuichi Iwahashi, Yu Saitou and Shinichiro Yamada : Clinical role of Notch signaling pathway in intraductal papillary mucinous neoplasm of the pancreas., Journal of Gastroenterology and Hepatology, Vol.30, No.1, 217-222, 2015.
(Summary)
This study was performed to elucidate the expression of the Notch signaling pathway and its correlations to clinicopathological factors of intraductal papillary mucinous neoplasms (IPMNs). It is incontrovertible that regulatory T cells (Tregs) play an important role in tumor immunity. However, the whole mechanism of control of peripheral Tregs remains unclear. It is also known that the Notch signaling pathway is involved in Treg suppressor function. Moreover, IPMNs have a high malignant potential. Peripheral blood samples and resected specimens from 18 patients with IPMN were evaluated. All patients were pathologically diagnosed with IPMN. Resected specimens were immunohistochemically evaluated (anti-Notch1, anti-Notch2, and anti-Notch2-intracellular domain antibody staining) and compared in terms of clinicopathological factors. Peripheral Treg populations were analyzed with an automated flow cytometer. Disease-free survival was significantly worse in the Notch1 high-expression group (P = 0.023). Notch2 family expressions were higher in intraductal papillary mucinous carcinoma (IPMC) than in intraductal papillary mucinous adenoma (IPMA) (Notch2, P = 0.012; Notch2-intracellular domain, P = 0.036). Jagged1 expression was significantly higher in IPMC than in IPMA (P < 0.05) and was significantly related to recurrence. The Treg population in peripheral blood was higher in patients with IPMC than in those with IPMA (P < 0.01). Notch signaling, especially Jagged1 expression, reflects IPMN aggressiveness. Our data may suggest that the Notch signaling pathway is a key pathway that determines IPMN pathological aggressiveness and reflects the peripheral Treg population.
Satoru Imura, Mitsuo Shimada and Toru Utsunomiya : Recent advances in estimating hepatic functional reserve in patients with chronic liver damage., Hepatology Research, Vol.45, No.1, 10-19, 2015.
(Summary)
Preoperative estimation of liver functional reserve is important in liver surgery to prevent postoperative liver failure. Although the hepatic functional reserve of patients with chronic liver disease is generally evaluated by measuring indocyanine green dye retention at 15 min, no standard method of estimating regional liver function has been established to date. Several recently introduced imaging modalities, such as hepatobiliary scintigraphy and magnetic resonance imaging with gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid, may be used to evaluate liver function. Here, we review recent advances in estimating hepatic functional reserve, mainly by radiological modalities, in patients with chronic liver damage.
Kohei Sugihara, Hisami Okumura, Arisa Teramoto, Eri Urano, Takafumi Katayama, Yuji Morine, Satoru Imura, Tohru Utsunomiya, Mitsuo Shimada and Eiji Takeda : Recovery of nutritional metabolism after liver transplantation, Nutrition, Vol.31, No.1, 105-110, 2015.
(Summary)
Perioperative nutritional assessment is critically important to reflect nutritional management because liver transplantation (LTx) often is undertaken in patients with poor nutritional status. The aim of this study was to evaluate nutritional status, including the non-protein respiratory quotient (npRQ), resting energy expenditure (REE), nitrogen balance, and blood biochemical parameters in patients before and after LTx. Fourteen patients undergoing LTx and 10 healthy controls were enrolled in this study. The npRQ and REE were measured using indirect calorimetry before LTx and at 2, 3, and 4 wk after the procedure. Blood biochemistry and nitrogen balance calculated by 24-h urine collection were performed concurrently with indirect calorimetric measurement; the results were compared between the two groups. Before LTx, npRQ was significantly lower and serum non-esterified fatty acid levels were significantly higher in the patients than in the controls. Furthermore, a negative nitrogen balance was observed in the patients. These, however, improved significantly at 4 wk after LTx. REE did not significantly increase compared with the preoperative values in recipients. Blood biochemistry showed gradually increasing levels of serum cholinesterase and albumin. These failed to reach to normal levels by 4 wk post-transplant. The findings revealed that improvement of nutritional metabolism after LTx may require 4 wk. Additional nutritional strategies, therefore, may be needed to minimize catabolic state during the early post-transplant period. Adequate, individualized nutritional guidance before and after LTx should be performed in these patients.
(Keyword)
Body Mass Index / Body Weight / Calorimetry, Indirect / Case-Control Studies / Cholinesterases / energy metabolism / Fatty Acids, Nonesterified / Female / Humans / Liver Transplantation / Male / Middle Aged / Nitrogen / Nutrition Assessment / Nutritional Status / Perioperative Care / Serum Albumin
Jun Higashijima, Mitsuo Shimada, Takashi Iwata, Kouzou Yoshikawa, Toshihiro Nakao, Masaaki Nishi, Hideya Kashihara and Chie Takasu : New ports placement in laparoscopic central lymph nodes dissection with left colic artery preservation for sigmoid colon and rectal cancer., The Journal of Medical Investigation : JMI, Vol.62, No.3-4, 223-227, 2015.
(Summary)
Lymph nodes (LNs) dissection around inferior mesenteric artery (IMA) with left colic artery (LCA) preservation is difficult due to the anatomical feature of IMA. The aim of this study is to evaluate the usefulness of new ports placement inserted from a suprapubic region in laparoscopic LNs dissection around IMA with LCA preservation for sigmoid colon and ractal cancer. Twenty-two patients who underwent laparoscopic colectomy for sigmoid colon and recal cancer were included. The new ports placement group (n=15, new group) was compared with the basic ports placement group (n=7, basic group). Average number of harvested LNs, total operation time, central LNs dissection time, intraoperative blood loss were compared. There was no significant difference in the average number of harvested LNs. The mean of intraoperative blood loss of new group was significantly lower than that of the basic group (40.0±39.8 ml vs 95.7±81.0 ml, p<0.05). In addition, the mean of operation time of the new group was significantly shorter than that of the basic group (250.0±55.7 min vs 353.4±80.2 min, p<0.05). The new ports placement is useful in laparoscopic LNs dissection around IMA with LCA preservation for sigmoid colon and rectal cancer.
Michihito Asanoma, Hiroki Mori, Tetsuya Ikemoto, Toru Utsunomiya, Satoru Imura, Yuji Morine, Jun Hanaoka, Mami Kanamoto, Yu Saitou, Shinichiro Yamada and Mitsuo Shimada : Clinical role of Foxp3+ regulatory T cell in Living donor related liver transplantation for prediction of life-threatening complications., The Journal of Medical Investigation : JMI, Vol.62, No.1-2, 37-40, 2015.
(Summary)
It is no doubt that regulatory T cells (Foxp3(+)CD4(+)CD25(+)T cells: Treg) play important roles in transplant immunity. We investigated the significance of Treg expression in acute stage of living donorrelated liver transplantation (LDLT) for the possibility of the sensitive marker for immunological state and homeostatic stress after liver transplantation. Peripheral blood was drawn from 5 recipients of LDLT preoperatively and on post operative 1, 4, 7, and 14 days. The peripheral blood mononuclear cells (PBMCs) were stained with CD4, CD25, Foxp3, and were analyzed with FACScan. This data was compared with clinical output of LDLT. The populations of Treg were significantly decreased in all patients on day 1 after LDLT and significantly increased in patients who had early postoperative complications compared with patients who had no complications. The population of Treg in peripheral blood may reflect the surgical stress such as life-threatening complications after LDLT.
Kayo Hirose, Shinji Kawahito, Naoji Mita, Kazumi Takaishi, Tomiya Kawahara, Tomohiro Soga, Toshiko Katayama, Satoru Imura, Yuji Morine, Tetsuya Ikemoto, Mitsuo Shimada, Munehide Matsuhisa and Hiroshi Kitahata : Usefulness of artificial endocrine pancreas during resection of insulinoma., The Journal of Medical Investigation : JMI, Vol.61, No.3-4, 421-425, 2014.
(Summary)
A 71-year-old woman had an episode of syncope due to hypoglycemia of 27 mg/dl. She was diagnosed with insulinoma and scheduled for laparoscopic enucleation along with the use of an artificial endocrine pancreas (STG-22, Nikkiso Co., Ltd., Tokyo, Japan). Anesthesia was maintained with sevoflurane and remifentanil. Her blood glucose level was controlled using the artificial endocrine pancreas, which enabled continuous blood glucose monitoring and computer-operated glucose and insulin infusion to maintain the blood glucose level at a steady state. The target concentration of blood glucose was set at 80-120 mg/dl during surgery. Until removal of the tumor, the blood glucose level was kept at around 80-100 mg/dl. After removal of the tumor, the blood glucose level gradually increased, but it was kept in the normal range by the artificial endocrine pancreas. The artificial endocrine pancreas was useful to monitor and maintain blood glucose levels during and after the removal of insulinoma, without any hyper- or hypoglycemia. J. Med. Invest. 61: 421-425, August, 2014.
KKohei Sugihara, Hisami Okumura, Arisa Teramoto, Eri Urano, Takafumi Katayama, Hiroki Mori, Toru Utsunomiya, Mitsuo Shimada and Eiji Takeda : Recovery pattern of non-protein respiratory quotient and non-esterified fatty acid after liver resection, Nutrition, Vol.30, No.4, 443-448, 2014.
(Summary)
Perioperative nutritional care is important to maintain preoperative and postoperative nutritional status. However, few reports have investigated energy metabolism after hepatectomy. The aim of this study was to determine differences in energy metabolism, blood biochemistry, and nutritional status before and after liver resection in patients with hepatocellular carcinoma (HCC) and healthy living donors for liver transplantation. Eighteen hospitalized patients with HCC group and 13 living donors for liver transplantation (donor group) were enrolled in this study. The donor group was divided into two groups on the basis of age; Y-donor group (age < 40 y, n = 7), and O-donor group (age ≥ 40 y, n = 6). Energy metabolism was measured by indirect calorimetry at preoperative day and postoperative day (POD) 7 and 14, and blood biochemistry was also examined. Recovery of non-protein respiratory quotient (npRQ) and blood biochemical data such as total bilirubin, aspartate aminotransferase and alanine aminotransferase levels were observed in Y-donor group on POD 14. However, although biochemical data improved in the HCC and O-donor group, npRQ remained unchanged on POD 14. Improvement of npRQ took longer than blood biochemical data in patients with HCC and older donors. Because the recovery of npRQ is associated with donor age, careful nutritional management may be required for a longer time depending on the pathophysiological condition of each patient after hepatectomy.
(Keyword)
Adult / Age Factors / Aged / Alanine Transaminase / Aspartate Aminotransferases / Bilirubin / Calorimetry, Indirect / Carcinoma, Hepatocellular / energy metabolism / Fatty Acids, Nonesterified / Female / Hepatectomy / Hospitalization / Humans / Liver / Liver Neoplasms / Liver Transplantation / Living Donors / Male / Middle Aged / Nutritional Status / Postoperative Care / Postoperative Period / Young Adult
Ahmed Zaied Bhuyan, Michihito Asanoma, Akiko Iwata, Chieko Ishifune, Yoichi Maekawa, Mitsuo Shimada and Koji Yasutomo : Abrogation of Rbpj attenuates experimental autoimmune uveoretinitis by inhibiting IL-22-producing CD4+ T cells., PLoS ONE, Vol.9, No.2, e89266, 2014.
(Summary)
Experimental autoimmune uveoretinitis (EAU) is an organ-specific T cell-mediated disease induced by immunizing mice with interphotoreceptor retinoid binding protein (IRBP). Autoaggressive CD4(+) T cells are the major pathogenic population for EAU. We investigated the contribution of Notch signaling in T cells to EAU pathogenesis because Notch signaling regulates various aspects of CD4(+) T cell functions. Rbpj is required for Notch signaling, and Rbpj deficiency in T cells inhibited EAU disease severity. The amelioration of EAU in T cell-specific Rbpj-deficient mice correlated with low levels of IL-22 production from CD4(+) T cells, although IRBP-specific CD4(+) T cell proliferation and Th17 differentiation were unaffected. Administration of recombinant IL-22 during the late phase, but not the early phase, of EAU increased EAU clinical scores in T cell-specific Rbpj-deficient mice. Notch inhibition in mice immunized with IRBP with a -secretase inhibitor (GSI) suppressed EAU progression, even when GSI was administered as late as 13 days after IRBP immunization. Our data demonstrate that Rbpj/Notch-mediated IL-22 production in T cells has a key pathological role in the late phase of EAU, and suggest that Notch blockade might be a useful therapeutic approach for treating EAU.
A Teramoto, Hisami Okumura, E Urano, T Nakamura-Kutsuzawa, K Sugihara, Takafumi Katayama, Hidenori Miyake, Satoru Imura, Toru Utsunomiya, Mitsuo Shimada and Eiji Takeda : Comparison of measured and predicted energy expenditure in patients with liver cirrhosis, Asia Pacific Journal of Clinical Nutrition, Vol.23, No.2, 197-204, 2014.
(Summary)
Obesity is a risk factor for the onset of liver cancer in patients with cirrhosis. To prevent overfeeding and obesity, estimation of energy requirement is important, but energy expenditure in patients with liver cirrhosis has not been fully elucidated. This study aimed to investigate resting energy expenditure (REE) and energy intake in patients with cirrhosis and determine adequate energy intake criteria. In this cross-sectional study, indirect calorimetry measurement was conducted in 488 Japanese inpatients with cirrhosis. We compared REE measured by indirect calorimetry (M-REE) with basal energy expenditure (BEE) predicted by the Harris-Benedict equation (H-BEE) and Dietary Reference Intakes (DRI) for Japanese (D-BEE). Mean M-REE (1256 kcal) was significantly lower than H-BEE (1279 kcal); however, it was not significantly different from D-BEE (1254 kcal). Mean M-REE expressed in relation to body weight (BW; REE/kg BW) was 21.7 kcal/kg BW. H-BEE was significantly higher than M-REE in patients in the first and second quartiles of BMI, and D-BEE was significantly different from MREE in patients in the highest and lowest quartiles of BMI. Average energy intake was 30.5 kcal/kg BW, which was 1.4 times greater than REE/kg BW. Although DRI is a useful tool for the estimation of REE in patients in the second and third quartiles of BMI, M-REE is recommended to ensure the provision of adequate nutritional care to patients with cirrhosis, including those in the highest and lowest quartiles of BMI.
(Keyword)
Basal Metabolism / Body Mass Index / Calorimetry, Indirect / Cross-Sectional Studies / Energy Metabolism / Female / Humans / Japan / Liver Cirrhosis / Male / Middle Aged
Ahmed Shawky Maklad, Mikio Matsuhiro, Hidenobu Suzuki, Yoshiki Kawata, Noboru Niki, Satake Mitsuo, Moriyama Noriyuki, Toru Utsunomiya and Mitsuo Shimada : Blood vessel-based liver segmentation using the portal phase of an abdominal CT dataset, Medical Physics, Vol.40, No.11, 113501(17pp.), 2013.
(Summary)
Blood vessel (BV) information can be used to guide body organ segmentation on computed tomography (CT) imaging. The proposed method uses abdominal BVs (ABVs) to segment the liver through the portal phase of an abdominal CT dataset. This method aims to address the wide variability in liver shape and size, separate liver from other organs of similar intensity, and segment hepatic low-intensity tumors (LITs). Thin ABVs are enhanced using three-dimensional (3D) opening. ABVs are extracted and classified into hepatic BVs (HBVs) and nonhepatic BVs (non-HBVs) with a small number of interactions, and HBVs and non-HBVs are used for constraining automatic liver segmentation. HBVs are used to individually segment the core region of the liver. To separate the liver from other organs, this core region and non-HBVs are used to construct an initial 3D boundary surface. To segment LITs, the core region is classified into non-LIT- and LIT-parts by fitting the histogram of the core region using a variational Bayesian Gaussian mixture model. Each part of the core region is extended based on its corresponding component of the mixture, and extension is completed when it reaches a variation in intensity or the constructed boundary surface, which is reconfirmed to fit robustly between the liver and neighboring organs of similar intensity. A solid-angle technique is used to refine main BVs at the entrances to the inferior vena cava and the portal vein. The proposed method was applied to 80 datasets: 30 Medical Image Computing and Computer Assisted Intervention (MICCAI) and 50 non-MICCAI; 30 datasets of non-MICCAI data include tumors. Our results for MICCAI-test data were evaluated by sliver07 (http://www.sliver07.org/) organizers with an overall score of 85.7, which ranks best on the site as of July 2013. These results (average ± standard deviation) include the five error measures of the 2007 MICCAI workshop for liver segmentation as follows. Results for volume overlap error, relative volume difference, average symmetric surface distance, root mean square symmetric surface distance, and maximum symmetric surface distance were 4.33 ± 0.73, 0.28 ± 0.87, 0.63 ± 0.16, 1.19 ± 0.28, and 14.01 ± 2.88, respectively; and when applying our method to non-MICCAI data, results were 3.21 ± 0.75, 0.06 ± 1.29, 0.45 ± 0.17, 0.98 ± 0.26, and 12.69 ± 3.89, respectively. These results demonstrate high performance of the method when applied to different CT datasets. BVs can be used to address the wide variability in liver shape and size, as BVs provide unique details for the structure of each studied liver. Constructing a boundary surface using HBVs and non-HBVs can separate liver from its neighboring organs of similar intensity. By fitting the histogram of the core region using a variational Bayesian Gaussian mixture model, LITs are segmented and measuring the volumetry of non-LIT- and LIT-parts becomes possible. Further examination of the proposed method on a large number of datasets is required for clinical applications, and development of the method for full automation may be possible and useful in the clinic.
Yu Saitou, Hiroki Mori, Chie Takasu, Masato Komatsu, Jun Hanaoka, Shin-ichiro Yamada, 淺野間 理仁, Tetsuya Ikemoto, Satoru Imura, Yuji Morine, Toru Utsunomiya and Mitsuo Shimada : Beneficial effects of green tea catechin on massive hepatectomy model in rats., Journal of Gastroenterology, 2013.
(Summary)
BACKGROUND: Green tea catechin, especially epigallocatechin gallate (EGCG), is a well-known scavenger of reactive oxygen species and it may also function as an antioxidant through modulation of transcriptional factors and enzyme activities. METHODS: Green tea extract (GTE(®)) which contained numerous EGCG was used. Wistar rats were performed 90 % hepatectomy and classified into 2 groups with (GTEHx, n = 25) or without GTE treatment (Hx, n = 25) and sacrificed at 1, 3, 7 and 14 days after operations. All rats had free access to drinking water supplemented with or without GTE from the 7th pre-operative day. Liver regeneration, hepatic inducible nitric oxide synthase (iNOS), anti-oxidative enzymes [superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-Px)] and inflammatory markers [cyclooxygenase-2 (COX-2), nuclear factor kappa B (NFκB), tumor necrosis factor-α (TNF-α)] were investigated. RESULTS: The liver weight to body weight ratio (p < 0.01), proliferating cell nuclear antigen labeling index (p < 0.05) and phosphorylated extracellular signal-regulated kinase 1/2 (p < 0.05) at day 1 in the GTEHx group significantly increased compared to the Hx group. Hepatic iNOS levels at day 1 significantly decreased (p < 0.01) in the GTEHx group. Hepatic SOD, CAT and GSH-Px levels at day 1 significantly increased (SOD: p < 0.01, CAT and GSH-Px: p < 0.05) in the GTEHx group. In contrast, COX-2, NFκB and TNF-α levels at day 1 significantly decreased (COX-2: p < 0.01, NFκB and TNF-α: p < 0.05) in the GTEHx group. CONCLUSIONS: GTE pretreatment stimulated liver regeneration and improved liver damage after massive hepatectomy through anti-oxidative and anti-inflammatory effects. Green tea catechin might have the potential to attenuate liver dysfunction in early stage after massive hepatectomy.
Masato Komatsu, Tetsuro Yoshimaru, Taisuke Matsuo, Kazuma Kiyotani, Yasuo Miyoshi, Toshihito Tanahashi, Kazuhito Rokutan, Rui Yamaguchi, Ayumu Saito, Seiya Imoto, Satoru Miyano, Yusuke Nakamura, Mitsunori Sasa, Mitsuo Shimada and Toyomasa Katagiri : Molecular features of triple negative breast cancer cells by genome-wide gene expression profiling analysis., International Journal of Oncology, Vol.42, No.2, 478-506, 2013.
(Summary)
Triple negative breast cancer (TNBC) has a poor outcome due to the lack of beneficial therapeutic targets. To clarify the molecular mechanisms involved in the carcinogenesis of TNBC and to identify target molecules for novel anticancer drugs, we analyzed the gene expression profiles of 30 TNBCs as well as 13 normal epithelial ductal cells that were purified by laser-microbeam microdissection. We identified 301 and 321 transcripts that were significantly upregulated and downregulated in TNBC, respectively. In particular, gene expression profile analyses of normal human vital organs allowed us to identify 104 cancer-specific genes, including those involved in breast carcinogenesis such as NEK2, PBK and MELK. Moreover, gene annotation enrichment analysis revealed prominent gene subsets involved in the cell cycle, especially mitosis. Therefore, we focused on cell cycle regulators, asp (abnormal spindle) homolog, microcephaly-associated (Drosophila) (ASPM) and centromere protein K (CENPK) as novel therapeutic targets for TNBC. Small-interfering RNA-mediated knockdown of their expression significantly attenuated TNBC cell viability due to G1 and G2/M cell cycle arrest. Our data will provide a better understanding of the carcinogenesis of TNBC and could contribute to the development of molecular targets as a treatment for TNBC patients.
Jun Hanaoka, Mitsuo Shimada, Toru Utsunomiya, Yuji Morine, Satoru Imura, Tetsuya Ikemoto, Hiroki Mori, Koji Sugimoto, Yu Saitou, Shinichiro Yamada and Michihito Asanoma : Beneficial effects of enteral nutrition containing with hydrolyzed whey peptide on warm ischemia/reperfusion injury in the rat liver., Hepatology Research, Vol.44, No.1, 114-121, 2013.
(Summary)
This study examined the efficacy of enteral nutrition containing hydrolyzed whey peptide (HWP) on warm ischemia/reperfusion (I/R) injury in the rat liver. Male Wistar rats were subjected to 30 min of warm hepatic ischemia followed by immediate p.o. intake of enteral nutrition with WHP (HWP group) or 20% glucose solution (control group) (0.025 mL/g). The animals were killed at 6 or 12 h after reperfusion. The serum aspartate aminotransferase (AST) and alanine aminotransferase alt (ALT) levels were measured. The necrotic areas were assessed histologically. Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining and caspase-3 activation were assessed to evaluate apoptosis. The expressions of hepatic tumor necrosis factor (TNF)-α, interleukin (IL)-6 and nuclear factor (NF)-κB in the liver tissue were assessed by real time reverse transcription polymerase chain reaction. Significant reductions in the serum AST and ALT levels were seen in the HWP group compared with the control group at both 6 and 12 h after reperfusion. The necrotic areas and numbers of TUNEL positive cells were significantly decreased in the HWP group at 6 and 12 h after reperfusion. The caspase-3/7 activities were significantly decreased in HWP group at 6 and 12 h after reperfusion. The mRNA expressions of TNF-α and IL-6 were significantly reduced in the HWP group at 12 h after reperfusion. NF-κB mRNA expression was significantly increased in the HWP group at 6 and 12 h after reperfusion. Enteral nutrition containing HWP ameliorated the hepatic warm I/R injury possibly through the suppression of pro-inflammatory cytokine expressions and the induction of NF-κB in the rat liver.
Tsuyoshi Okada, Shinji Kawahito, Naoji Mita, Munehide Matsuhisa, Hiroshi Kitahata, Mitsuo Shimada and Shuzo Oshita : Usefulness of continuous blood glucose monitoring and control for patients undergoing liver transplantation., The Journal of Medical Investigation : JMI, Vol.60, No.3-4, 205-212, 2013.
(Summary)
The STG-22 closed-loop system is effective for maintaining strict blood glucose control during liver transplantation with minimal variability in blood glucose concentration.
Kotaro Miyake, Masanori Nishioka, Satoru Imura, Erdenebulgan Batmunkh, Yoshihiro Uto, Hideko Nagasawa, Hitoshi Hori and Mitsuo Shimada : The novel hypoxic cytotoxin, TX-2098 has antitumor effect in pancreatic cancer; possible mechanism through inhibiting VEGF and hypoxia inducible factor-1 targeted gene expression, Experimental Cell Research, Vol.318, No.13, 1554-1563, 2012.
(Summary)
Tumor hypoxia has been considered to be a potential therapeutic target, because hypoxia is a common feature of solid tumors and is associated with their malignant phenotype. In the present study, we investigated the antitumor effect of a novel hypoxic cytotoxin, 3-[2-hydroxyethyl(methyl)amino]-2-quinoxalinecarbonitrile 1,4-dioxide (TX-2098) in inhibiting the expression of hypoxia inducible factor-1α (HIF-1α), and consequently vascular endothelial cell growth factor (VEGF) expression in pancreatic cancer. The antitumor effects of TX-2098 under hypoxia were tested against various human pancreatic cancer cell lines using WST-8 assay. VEGF protein induced pancreatic cancer was determined on cell-free supernatant by ELISA. Moreover, nude mice bearing subcutaneously (s.c.) or orthotopically implanted human SUIT-2 were treated with TX-2098. Tumor volume, survival and expression of HIF-1 and associated molecules were evaluated in treatment versus control groups. In vitro, TX-2098 inhibited the proliferation of various pancreatic cancer cell lines. In s.c model, tumors from nude mice injected with pancreatic cancer cells and treated with TX-2098 showed significant reductions in volume (P<0.01 versus control). Quantitative real-time reverse transcription-PCR analysis revealed that TX-2098 significantly inhibited mRNA expression of the HIF-1 associated molecules, VEGF, glucose transporter 1 and Aldolase A (P<0.01 versus control). These treatments also prolong the survival in orthotopic models. These results suggest that the effect of TX-2098 in pancreatic cancer might be correlated with the expression of VEGF and HIF-1 targeted molecules.
矢田 圭吾, Mitsuo Shimada, Hiroki Ishibashi, Horohiko Sato, Hiroki Mori and 淺野間 理仁 : 縦隔腫瘍と鑑別を要した左肺葉外肺分画症の1例, Journal of the Japanese Society of Pediatric Surgeons, Vol.48, No.3, 592, 2012.
Hiroki Ishibashi, Hiroki Mori, 矢田 圭吾, 淺野間 理仁, Horohiko Sato and Mitsuo Shimada : 腹腔鏡補助下肝部分切除術を施行した肝芽腫の1例, Journal of the Japanese Society of Pediatric Surgeons, Vol.48, No.3, 450, 2012.
Hisami Okumura, Akihiko Kawaura, Satoru Imura, Toru Utsunomiya, Mitsuo Shimada and Eiji Takeda : Treatment of rapid weight loss in a donor with hepatic steatosis in a living donor liver transplantation: a case report, Hepato-Gastroenterology, Vol.59, No.115, 869-871, 2012.
(Summary)
The use of steatotic livers for transplantation is often associated with increased primary non-function. To reduce the risk of liver injury, steatosis of the donor liver in living donor liver transplantation (LDLT) was treated with restricted diet and exercise. A 21-year-old male donor, 167cm in height and 87kg in body weight, initially received a 1800kcal/day diet for 9 days which was then gradually reduced using a 1600kcal/day diet for 43 days, followed by a 1500kcal/day diet for one day and was finally maintained on a 1400kcal/day diet for 52 days. Daily exercise consumed 500kcal/day. The non-protein respiratory quotient (npRQ) gradually increased while the non-esterified fatty acids (NEFA) decreased during the course of the 105-day treatment. Consequently, the initial 80% steatosis was reduced to 10% and was accompanied by 13% weight loss for 81 days. The npRQ values and NEFA concentrations in the later period of dietary and exercise treatment were higher and lower, respectively, than in the early treatment period, indicating compensation through long-term treatment. Therefore, energy metabolism and NEFA levels represent important biomarkers for short-term intensive treatment by restricted diet and exercise in donors with hepatic steatosis.
(Keyword)
Biological Markers / Caloric Restriction / Donor Selection / energy metabolism / Exercise / Fatty Acids, Nonesterified / Fatty Liver / Hepatectomy / Humans / Liver Transplantation / Living Donors / Male / Severity of Illness Index / Time Factors / Treatment Outcome / Weight Loss / Young Adult
Horohiko Sato, Mitsuo Shimada, 小笠原 卓, 大塚 敏弘, Tsutomu Ando and 長堀 順二 : A case of small intestinal mesenteric liposarcoma, Shikoku Acta Medica, Vol.68, No.1-2, 41-44, 2012.
(Summary)
We report a case of small intestinal mesenteric liposarcoma. An 84-year-old woman wasadmitted to our hospital with a chief complaint of abdominal distension and pointing out a tumor inher abdomen. On physical examination an adult's head-sized tumor was palpated from the leftupper portion of the pelvis. Abdominal computed tomography(CT)revealed the mass24×18×13cm in size which had clear borderline and smooth surface. Multi-detector-CT scan revealed aheterogeneously enhanced mass fed by the Superior mesenteric artery. With a clinical diagnosisof liposarcoma arisen from the small intestinal mesentery, the patient was operated on. The tumorwas present in the mesentery of the small intestine and a removal of the tumor with associatedresection of the small intestine was perfomed. The histological diagnosis was well-differentiatedliposarcoma. The patient has been followed for nine months after the operation without evidenceof local recurrence.
(Keyword)
mesenteric liposarcoma / well-differentiated liposarcoma / small intestine
Hiroki Ishibashi, Horohiko Sato, Hiroki Mori and Mitsuo Shimada : 血流障害，遊走脾を伴った急性胃軸捻転症の1例, Journal of the Japanese Society of Pediatric Surgeons, Vol.48, No.2, 274, 2012.
Toru Utsunomiya, Mitsuo Shimada, Jun Hanaoka, Mami Kanamoto, Tetsuya Ikemoto, Yuji Morine, Satoru Imura and Masafumi Harada : Possible utility of MRI using Gd-EOB-DTPA for estimating liver functional reserve, Journal of Gastroenterology, Vol.47, No.4, 470-476, 2012.
(Summary)
Preoperative estimation of the liver functional reserve is important in liver surgery. We evaluated the role of dynamic magnetic resonance (MR) imaging with gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid (Gd-EOB-DTPA), i.e., EOB-MRI, for determining liver functional reserve. Fifty patients who underwent EOB-MRI to examine their liver tumors were included in this study. We first performed a pixel-by-pixel comparison of registered MR images and activity images with Tc-99m galactosyl human serum albumin (GSA) on each slice, and the correlation coefficient was calculated for 8 patients. We also determined the correlation coefficient between the relative signal intensity (SI) values of EOB-MRI and preoperative liver function, such as the GSA, indocyanine green dye retention at 15 min (ICGR15), and prothrombin time. The mean of the correlation coefficients for 512 × 512 matrices between the EOB-MRI and the GSA was 0.83 ± 0.05 (ranging from 0.73 to 0.87). The correlation coefficient between the relative SI of the EOB-MRI and the receptor index (LHL15) of GSA was 0.56 (P < 0.01). Better correlation coefficients were observed between the relative SI and the liver function test, including ICGR15 (r = -0.67, P < 0.01) and prothrombin time (r = 0.59, P < 0.01). In a patient with hilar cholangiocarcinoma whose right hepatic duct was obstructed, the relative SI in the right lobe (2.4 ± 0.3) was significantly lower than that in the left lobe (3.1 ± 0.1). EOB-MRI represents a practical and reliable imaging technique that may be used to estimate regional liver functional reserve in the clinical setting.
(Keyword)
Adult / Aged / Aged, 80 and over / Contrast Media / Female / Gadolinium DTPA / Humans / Liver / Liver Function Tests / magnetic resonance imaging / Male / Middle Aged
Shuichi Iwahashi, Yoichi Maekawa, Jun Nishida, Chieko Ishifune, Akiko Kitamura, Hideki Arimochi, Keiko Kataoka, Shigeru Chiba, Mitsuo Shimada and Koji Yasutomo : Notch2 regulates the development of marginal zone B cells through Fos., Biochemical and Biophysical Research Communications, Vol.418, No.4, 701-707, 2012.
(Summary)
B cells are classified into several subsets depending on their functions, marker expression pattern and localization. Marginal zone B (MZB) cells are a distinct lineage from follicular B cells, and regulate host defenses against blood-borne pathogens. Notch2/RBP-J signaling regulates the development of MZB cells by interacting with delta-like 1 ligand, although the target genes for Notch2 signaling remain unclear. We identified Fos as an upregulated gene in LPS-stimulated B cells that received Notch2 signaling. Fos is expressed in CD21(high)CD23(low) MZB cells at a higher level compared to CD21(Int)CD23(high) follicular B cells. Deleting the Notch2 gene in CD19(+) B cells decreased Fos expression in B cells. Overexpression of Fos in Notch2-deficient B cells or bone marrow cells partially restored MZB development. Fos promoter activity was upregulated by Notch2 signaling, indicating that Notch2 directly controls Fos transcription associated with MZB development. These data identify Fos as one of the target genes for Notch2 signaling that is crucial for MZB development.
Yuji Morine and Mitsuo Shimada : Hepatic and pancreatic regenerative medicine using Adipose tissue-derived mesenchymal stem cell, Journal of Clinical and Experimental Medicine, Vol.42, No.(4), 303-308, 2012.
Hiroki Ishibashi, Tomomi Kuwahara, H Nakayama-Imaohji, Y Ohnishi, Hiroki Mori and Mitsuo Shimada : Effects of indole-3-carbinol and phenethyl isothiocyanate on bile and pancreatic juice excretion in rats., The Journal of Medical Investigation : JMI, Vol.59, No.3-4, 246-252, 2012.
(Summary)
Bile and pancreatic juice contain a number of parameters for cancer chemoprevention. Indole-3-carbinol (I3C) and phenethyl isothiocyanate (PEITC), which are hydrolytic products of brassica plants, have been established to be anti-cancer agents. Here, we developed a method for the continuous and selective sampling of bile and pancreatic juice, and the effects of I3C and PEITC on bile and pancreatic excretion and γ-glutamyl transpeptidase (γ-GTP) activity in the samples were investigated. Male Fisher 344 rats (eight weeks of age) were challenged intragastrically with I3C (150 mg/kg) or PEITC (160 mg/kg) for five days. Twenty-four hours after the final administration, cannulation was undertaken into the rats' bile and pancreatic ducts, and the bile and pancreatic juice were separately collected for 48 h. In this rat model, bile was stably excreted, and the bile and pancreatic excretion of the control rats was 21.9 ± 1.4 ml/48 h and 12.8 ± 1.7 ml/48 h, respectively. Bile excretion for the first 24 h significantly increased in the I3C- or PEITC-treated rats compared with the control rats. In the case of pancreatic juice, excretion during the first 24 h significantly increased in the PEITC-treated rats. In bile, γ-GTP activity was significantly increased for the first 24 h in the I3C- and PEITC-treated rats, but no difference was observed in the pancreatic juice. Increases of bile excretion and γ-GTP activity in bile might be a factor involved in the anti-cancer effect of I3C and PEITC. Our rat model described here is a useful tool for the study of cancer chemoprevention.
Hiroki Ishibashi, Takehito Oshio, Tomoko Sogami, Akira Nii, Hiroki Mori and Mitsuo Shimada : Torsion of an accessory spleen with situs inversus in a child., The Journal of Medical Investigation : JMI, Vol.59, No.1-2, 220-223, 2012.
(Summary)
We present an unusual case of acute abdomen caused by torsion of an accessory spleen with situs inversus in a child. A three-year-old girl was admitted to our hospital with an 11-day history of right flank pain with fever. Her medical history revealed an operation of coarctation of the aorta with situs inversus at one month of age. Physical examination revealed a right flank mass and tenderness. A contrast-enhanced CT scan showed a normally enhanced small spleen in the right upper quadrant and a 7.0×6.0×3.5 cm, hypodense, marginal enhancing mass in the right midabdomen adjacent to the intestine. An emergency laparotomy was decided upon with a preoperative diagnosis as an acute abdomen. During surgery, a mass was found under the greater omentum and two accessory spleens of 1.5 cm in diameter were found surrounding the main spleen. Several loops of bowel were adherent to the mass. The loops of bowel were dissected away. A pediculated congested mass was observed as an accessory spleen emerging from the greater omentum. The mass was twisted on its vascular pedicle and strangulated. The necrotic mass was removed and the postoperative recovery was uneventful. Though torsion of an accessory spleen is extremely rare, it should be considered in the differential diagnosis of acute abdomen in childhood.
Jun Higashijima, Mitsuo Shimada, Nobuhiro Kurita, Takashi Iwata, Masanori Nishioka, Shinya Morimoto, Kouzou Yoshikawa, Tomohiko Miyatani, 柏原 秀也 and Chie Mikami : Evaluation of the usefulness of Roux-en-Y reconstruction with jejunal pouch by radioisotope scintigraphy and 13C breath test, Japanese Journal of Cancer Clinics, Vol.56, No.5, 377-382, 2011.
(Keyword)
Total gastrectomy / Roux-en-Y reconstruction / Jejunal pouch / Radioscintigraphy
Hisami Okumura, 浦野 恵利, 板東 友美, 山内 利香, Satoru Imura, Toru Utsunomiya, Mitsuo Shimada and Eiji Takeda : Nutritional Assessment of Pre- and Post- Liver Resection by Energy Metabolism and Laboratory Data, Journal of Japanese Society of Clinical Nutrition, Vol.32, No.3, 133-140, 2011.
Kotaro Miyake, Satoru Imura, Masanori Nishioka, Erdenebulgan Batmunkh, Koji Sugimoto, Yasukazu Ohmoto and Mitsuo Shimada : Serum evaluation of soluble interferon-alpha/beta receptor and high-sensitivity C-reactive protein for diagnosis of the patients with gastrointestinal and hepatobiliary-pancreatic cancer., Cytokine, Vol.49, No.3, 251-255, 2010.
(Summary)
Serum soluble interferon-alpha/beta receptor (sIFN-alpha/betaR) and high-sensitivity C-reactive protein (hs-CRP) levels were evaluated in the patients with gastrointestinal and hepatobiliary-pancreatic cancer. We compared the sensitivity and specificity of serum sIFN-alpha/betaR with that of serum hs-CRP and evaluated the two diagnostic parameters in combination. Serum sIFN-alpha/betaR levels were measured in 92 patients and 25 healthy individuals by enzyme-linked immunosorbent assay. The diagnoses were 37 cases of hepatocellular carcinoma, 17 cases of pancreatic cancer, 15 cases of colon cancer, 13 cases of biliary tract cancer, and 10 cases of gastric cancer. Serum levels of sIFN-alpha/betaR and hs-CRP were significantly higher in the patients than in healthy individuals (p<0.05). The optimal cut-off values of sIFN-alpha/betaR and hs-CRP were 3600pg/ml and 0.5microg/ml, respectively. The sensitivity and specificity for these thresholds were 94.6% and 88.0%, whereas positive predictive and negative predictive values were 96.7% and 81.5%. These results suggest that a combination of serum sIFN-alpha/betaR and hs-CRP thresholds may be more reliable diagnostic parameter for gastrointestinal and hepatobiliary-pancreatic cancer.
(Keyword)
欧文論文 / Aged / Aged, 80 and over / Biliary Tract Neoplasms / C-Reactive Protein / Female / Gastrointestinal Neoplasms / Humans / Liver Neoplasms / Male / Middle Aged / Pancreatic Neoplasms / Predictive Value of Tests / Receptor, Interferon alpha-beta / Sensitivity and Specificity / Young Adult
Tetsuya Ikemoto, Hirofumi Noguchi, Yasutaka Fujita, Morihito Takita, Masayuki Shimoda, Koji Sugimoto, Andrew Jackson, Bashoo Naziruddin, Mitsuo Shimada, Marlon F. Levy and Shinichi Matsumoto : New stepwise cooling system for short-term porcine islet preservation., Pancreas, Vol.39, No.7, 960-963, 2010.
(Summary)
Porcine islets are the most suitable for xeno-islet transplantation. However, it is necessary to establish an effective preservation method against its fragility. Recently, we developed a new cooling and preservation (Keep and Fresh [KFC]; FUJIYA Co, Tokushima, Japan) system, which can maintain viability of hepatocyte. In this study, we examined the KFC for porcine islet preservation.
(Keyword)
欧文論文 / Cell Survival / Islets of Langerhans / Islets of Langerhans Transplantation / Organ Preservation / Swine
Toru Utsunomiya, Mitsuo Shimada, Satoru Imura, Yuji Morine, Tetsuya Ikemoto, Jun Hanaoka, Hiroki Mori, 岩橋 衆一, 川田 祐子 and 斎藤 裕 : 問題を有するドナーからの生体肝移植 ∼胃癌術後ドナーおよび喘息罹患ドナー∼., The Japanese journal of clinical and experimental medicine, Vol.87, No.9, 1282-1283, 2010.
(Keyword)
和文論文
149.
Hiroki Mori, Mitsuo Shimada, Toru Utsunomiya, Satoru Imura, Yuji Morine, Tetsuya Ikemoto and Jun Hanaoka : 急性肝不全に対する肝移植術施行のタイミングに難渋した症例, The Japanese journal of clinical and experimental medicine, Vol.87, No.9, 118-119, 2010.
(Keyword)
和文論文
150.
Satoru Imura, Mitsuo Shimada, Toru Utsunomiya, Yuji Morine, Tetsuya Ikemoto, Hiroki Mori, Jun Hanaoka, Shuichi Iwahashi, Yu Saito, Hisami Okumura and Eiji Takeda : Impact of splenectomy in patients with liver cirrhosis: Results from 18 patients in a single center experience., Hepatology Research, Vol.40, No.9, 894-900, 2010.
(Summary)
Aim: With the recent advances in medical or surgical treatments in chronic hepatic disorders, the indications for splenectomy in hepatic disorders have greatly expanded. We performed splenectomy for cirrhotic patients and investigated the effects of splenectomy on hepatic functional reserve and nutrition metabolism. Methods: Eighteen patients (Child-Pugh B/C: 12/6; Child-Pugh A: excluded) who underwent splenectomy at our institute between 2005 and 2008 were enrolled. Twelve patients (67%) had hepatocellular carcinoma (HCC), eight of whom met the Milan criteria. Results: Overall survival rate was 83.3% at 1 year and 62.7% at 2 years. The survival rate of six patients with liver cirrhosis classified a Child-Pugh C was 80.0% at 1 year and 60.0% at 2 years. Three patients underwent hepatic resection and nine patients received ablation therapy against hepatocelluar carcinoma. Portal pressure decreased after splenectomy in most patients (mean decrease, 4.7 mmHg). Four weeks after the operation, the markers of hepatic functional reserve, indocyanine green retention rate at 15 min (ICGR15) and Technetium-99m-galactosyl human serum albumin value ((99m)Tc-GSA), improved from 38.5% to 35.1% and from 0.773 to 0.788 (LHL15), respectively. The non-protein respiratory quotient (npRQ) did not change in short period after the operation. Other outcomes, including liver function test in cirrhotic patients with long-term (1 year) follow-up after splenectomy (n = 7), did not improve significantly. Post-operative complications included portal thrombus (n = 2), ascites (n = 2) were observed in six patients (33%). Conclusion: Splenectomy improved hepatic functional reserve and nutritional metabolism in some cases. However, the long-term outcomes should still be evaluated.
In patients receiving chronic corticosteroid therapy, the adrenocortical function has decreased because of suppression of the hypothalamic-pituitary-adrenal axis. Under such a condition, it is easy to fall into a serious acute adrenocortical insufficiency during surgical stress. Corticosteroid supplementation is done as prevention of adrenocortical insufficiency. It is changing from corticosteroid supplementation of high dose into that of low dose that based on extrapolation from what constitutes a normal cortisol response to stress in recent years. On the other hand, some authors reported that patients receiving therapeutic doses of corticosteroids who undergo a surgical procedure do not routinely require corticosteroid supplementation so long as they continue to receive their usual daily dose of corticosteroid. Therefore, furthermore investigation should be necessary.
Toru Utsunomiya, Mitsuo Shimada, Satoru Imura, Yuji Morine, Tetsuya Ikemoto, Jun Hanaoka, Hiroki Mori, 岩橋 衆一 and 斎藤 裕 : 性差による肝胆膵疾患の臨床，病態，治療効果のDiscrepancy I.性差と各種肝疾患 7)肝移植と性差, KAN TAN SUI, Vol.60, No.5, 793-799, 2010.
(Keyword)
和文論文
155.
Hisami Okumura, Taki Nakamura, Hidenori Miyake, Harumi Takeuchi, Takafumi Katayama, Yuji Morine, Satoru Imura, Mitsuo Shimada and Eiji Takeda : Effect of long-term late-evening snack on health-related quality of life in cirrhotic patients., Hepatology Research, Vol.40, No.5, 470-476, 2010.
(Summary)
Aim: In patients with liver cirrhosis, abnormal energy metabolism induces low health-related quality of life (HRQOL) scores. However, late-evening snack (LES) prevents morning starvation in cirrhotic patients. Our aim is to assess the effect of long-term LES on HRQOL in cirrhotic patients, using the 36-item Short Form (SF-36) health survey. Methods: Thirty-nine cirrhotic patients classified as Child-Pugh grade A were recruited. The patients were randomly divided into two groups: 24 were assigned to the non-LES group and 15 to the LES group. SF-36 scores, anthropometric data and serum biochemical parameters were examined in the non-LES and LES groups at 0, 6 and 12 months. Results: Neither anthropometric data nor laboratory data showed significant differences between the non-LES and the LES groups at 0, 6 and 12 months. The role-emotional (RE) HRQOL scores at 6 months and mental health (MH) scores at 6 and 12 months were significantly reduced from the baseline level in the non-LES group. In contrast, these scores remained unchanged in the LES group. General health perception (GH) scores at 12 months, RE at 6 months and MH at 6 and 12 months in the LES group were significantly higher than those of the non-LES group. Conclusion: Long-term LES administration may be helpful in maintaining higher HRQOL in patients with cirrhosis.
Mitsuo Shimada, Koji Sugimoto, Shuichi Iwahashi, Toru Utsunomiya, Yuji Morine, Satoru Imura and Tetsuya Ikemoto : CD133 expression is a potential prognostic indicator in intrahepatic cholangiocarcinoma., Journal of Gastroenterology, Vol.45, No.8, 896-902, 2010.
(Summary)
CD133 is one of the most important cancer-initiating (stem) cell markers and was confirmed to be expressed in solid cancers such as colon cancer. However, no one has investigated the role of CD133 in intrahepatic cholangiocarcinoma (IHCC). The aim of this study was to clarify the clinical role of CD133 expression in IHCC.
荒川 悠佑, Mitsuo Shimada, Hideaki Uchiyama, Satoru Imura, Yuji Morine, 金村 普史, Jun Hanaoka, 金本 真美, 杉本 光司 and 西 正暁 : Pseudostenosis of the Common Hepatic Duct caused by Compression of the Cystic Artery, The Japanese Journal of Gastroenterological Surgery, Vol.43, No.4, 405-410, 2010.
(Summary)
Bile duct way stenosis mimic malignant such as cholangiocellular carcinoma lesions and gall bladder carcinoma invasion. A 74-year-old woman a gallbladder (GB) polyp combined with common hepatic duct (CHD) stenosis was found in admitted for surgery to treat. Preoperative evaluation revealed to have a polypoid tumor 12mm in diameter and relatively smooth CHD stenosis. Because the possibility of malignancy could not be excluded, she underwent open abdominal surgery. We conducted the usual cholecystectomy. The CHD was compressed by the cystic artery, so we thoroughly confirmed the absence of any suspicious CHD lesion by directly inspecting the inner side of the stricture by choledochotomy. The definitive diagnosis of the GB tumor was early GB carcinoma. Although CHD compression by the cystic artery is considered uncommon, we suggest that it should be included in the differential diagnosis of extrahepatic biliary stenosis, especially when biliary stenosis is relatively smooth.
Lu Elaine Wang, Zhi-Rong Qian, Masahiko Nakasono, Toshihito Tanahashi, Katsuhiko Yoshimoto, Yoshimi Bando, Eiji Kudo, Mitsuo Shimada and Toshiaki Sano : High expression of Toll-like receptor 4/myeloid differentiation factor 88 signals correlates with poor prognosis in colorectal cancer., British Journal of Cancer, Vol.102, No.5, 908-915, 2010.
(Summary)
BACKGROUND: The Toll-like receptor (TLR) 4 signalling pathway has been shown to have oncogenic effects in vitro and in vivo. To demonstrate the role of TLR4 signalling in colon tumourigenesis, we examined the expression of TLR4 and myeloid differentiation factor 88 (MyD88) in colorectal cancer (CRC). METHODS: The expression of TLR4 and MyD88 in 108 CRC samples, 15 adenomas, and 15 normal mucosae was evaluated by immunohistochemistry, and the correlations between their immunoscores and clinicopathological variables, including disease-free survival (DFS) and overall survival (OS), were analysed. RESULTS: Compared with normal mucosae and adenomas, 20% cancers displayed high expression of TLR4, and 23% cancers showed high expression of MyD88. The high expression of TLR4 and MyD88 was significantly correlated with liver metastasis (P=0.0001, P=0.0054). In univariate analysis, the high expression of TLR4 was significantly associated with shorter OS (hazard ratio (HR): 2.17; 95% confidence interval (95% CI): 1.15-4.07; P=0.015). The high expression of MyD88 expression was significantly associated with poor DFS and OS (HR: 2.33; 95% CI: 1.31-4.13; P=0.0038 and HR: 3.03; 95% CI: 1.67-5.48; P=0.0002). The high combined expression of TLR4 and MyD88 was also significantly associated with poor DFS and OS (HR: 2.25; 95% CI: 1.27-3.99; P=0.0053 and HR: 2.97; 95% CI: 1.64-5.38; P=0.0003). Multivariate analysis showed that high expressions of TLR4 (OS: adjusted HR: 1.88; 95% CI: 0.99-3.55; P=0.0298) and MyD88 (DFS: adjusted HR: 1.93; 95% CI: 1.01-3.67; P=0.0441; OS: adjusted HR: 2.25; 95% CI: 1.17-4.33; P=0.0112) were independent prognostic factors of OS. Furthermore, high co-expression of TLR4/MyD88 was strongly associated with both poor DFS and OS. CONCLUSION: Our findings suggest that high expression of TLR4 and MyD88 is associated with liver metastasis and is an independent predictor of poor prognosis in patients with CRC.
Kouzou Yoshikawa, Mitsuo Shimada, Nobuhiro Kurita, Masanori Nishioka, Shinya Morimoto, Jun Higashijima, Tomohiko Miyatani, Hidenori Miyamoto and Yoshiyasu Terashima : Two Cases of Emergency Operations in Patients Undergoing Bevacizumab Treatment, Journal of the Japan Society of Coloproctology, Vol.63, No.2, 56-60, 2010.
(Summary)
Bevacizumab has become a widely used intervention in patients with advanced colon cancer. In view that a negative effect of wound healing has been reported, surgery should be performed 4-6 weeks after the last treatment. This study examined the approaches to the management of emergency operations in patients undergoing bevacizumab treatment. In this report, four operations were performed for two patients undergoing bevacizumab treatment. Surgical complications and the postoperative course were examined. Case1: The patient was a male in his 50s with descending colon cancer, multiple liver metastasis and lung metastasis. This patient was suffering from ileus due to descending colon cancer. A transverse colostomy was performed. In addition, a descending colectomy and drainage were conducted for the retroperitoneal abscess formation. Case2: The patient was a male in his 70s with mucinous cystadenocarcinoma of the appendix and carcinomatous peritonitis. This patient was suffering from abdominal pain. As a CT showed free air, an emergency operation was performed. Drainage was also performed. The extent of the surgical procedures should be limited, and construction of a stomy should be preferred to primary anastomosis.<br>
Erdenebulgan Batmunkh, Mitsuo Shimada, Yuji Morine, Satoru Imura, Hirofumi Kanemura, Yusuke Arakawa, Jun Hanaoka, Mami Kanamoto, Koji Sugimoto and Masaaki Nishi : Expression of hypoxia-inducible factor-1 alpha (HIF-1alpha) in patients with the gallbladder carcinoma., International Journal of Clinical Oncology, Vol.15, No.1, 59-64, 2010.
(Summary)
Hypoxia-inducible factor-1 (HIF-1) is a transcription factor that plays a central role in biologic processes under hypoxic conditions, especially concerning tumor angiogenesis. Vascular endothelial growth factor (VEGF) is a potent proangiogenic agent and a multifunctional angiogenic cytokine in many malignant tumors.
(Keyword)
欧文論文 / Aged, 80 and over / Female / Gallbladder Neoplasms / Humans / Hypoxia-Inducible Factor 1, alpha Subunit / Immunohistochemistry / Male / Middle Aged / Neovascularization, Pathologic / Prognosis / Transcription Factors / Vascular Endothelial Growth Factor A
Hideaki Uchiyama, Mitsuo Shimada, Satoru Imura, Yuji Morine, Hirofumi Kanemura, Yusuke Arakawa, Mami Kanamoto, Masaaki Nishi and Jun Hanaoka : Living donor liver transplantation using a left hepatic graft from a donor with a history of gastric cancer operation., Transplant International, Vol.23, No.2, 234-235, 2010.
Masanori Nishioka, Mitsuo Shimada, Jun Higashijima and Tomohiko Miyatani : S上結腸SM癌に対するS状結腸切除 D2郭清., 腹腔鏡下大腸手術の基本手術手技, 1-35, 2010.
(Keyword)
和文論文
166.
Nobuhiro Kurita, Mitsuo Shimada, Toru Utsunomiya, Takashi Iwata, Masanori Nishioka, Kouzou Yoshikawa, Tomohiko Miyatani, Jun Higashijima and Toshihiro Nakao : Predictive factors of peritoneal metastasis in gastric cancer., Hepato-Gastroenterology, Vol.57, No.101, 980-983, 2010.
(Summary)
Preoperative radiological diagnosis of gastric cancer with peritoneal metastasis is still incomplete. Staging laparoscopy is performed for patients who are diagnosed T3 or T4 preoperatively. The aim of this study is to establish a method for predicting peritoneal metastasis.
(Keyword)
欧文論文 / Adult / Aged / Aged, 80 and over / Female / Gastrectomy / Humans / Laparoscopy / Male / Middle Aged / Multivariate Analysis / Peritoneal Neoplasms / Sensitivity and Specificity / Stomach Neoplasms / Young Adult
(Link to Search Site for Scientific Articles)
● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 21033263
Tetsuya Ikemoto, Mitsuo Shimada, Shuichi Iwahashi, 川田 祐子, Yu Saitou, Jun Hanaoka, Hiroki Mori, Satoru Imura, Yuji Morine and Toru Utsunomiya : 乳癌が併存するレシピエント，高度脂肪肝ドナーという組み合わせに施行した生体肝移植., The Japanese journal of clinical and experimental medicine, Vol.87, No.9, 1280-1281, 2010.
(Keyword)
和文論文
176.
Jun Hanaoka, Mitsuo Shimada, Toru Utsunomiya, Satoru Imura, Yuji Morine, Tetsuya Ikemoto and Hiroki Mori : 血液型不適合肝移植後interferon治療に難渋したC型肝炎の1例, The Japanese journal of clinical and experimental medicine, Vol.87, No.9, 1330-1331, 2010.
(Keyword)
和文論文
177.
Kotaro Miyake, Mitsuo Shimada, Masanori Nishioka, Koji Sugimoto, Erdenebulgan Batmunkh, Yoshihiro Uto, Hideko Nagasawa and Hitoshi Hori : Downregulation of matrix metalloprotease-9 and urokinase plasminogen activator by TX-1877 results in decreased tumor growth and metastasis on xenograft model of rectal cancer, Cancer Chemotherapy and Pharmacology, Vol.64, No.5, 885-892, 2009.
(Summary)
Purpose It is well known that hypoxic milieu is the primary cancer environment. Therefore, tumor hypoxia is considered to be a potential therapeutic target. In the present study, we investigated the antitumor and antimetastatic effect of hypoxic cell radiosensitizer, TX-1877 on xenograft model of rectal cancer. Methods Nude mice bearing subcutaneously or orthotopically implanted human colon cancer cell lines HCT-116 and HT-29 were treated with TX-1877, irradiation or TX-1877 with irradiation. Tumor volume, survival, expression of matrix metalloproteinase (MMP)-2, MMP-7, MMP-9 and urokinase-type plasminogen activator (uPA) and incidence of lymph node metastasis were evaluated in treatment versus control group. Results In subcutaneous model, tumor treated with TX-1877 and irradiation showed significant reductions in volume (P < 0.05 vs. control, TX-1877 or irradiation group). Quantitative real-time reverse transcription-PCR and immunohistochemical analysis revealed that TX-1877 significantly inhibited expression of the MMP-9 and uPA. These treatments also inhibited the para-aortic lymph node metastasis, however, did not prolong the survival in orthotopic model. Conclusions These data show that the treatment of TX-1877 with irradiation decreased growth of human rectal cancer and, furthermore, suppressed lymph node metastasis.
Hideaki Uchiyama, Noboru Harada, Kensaku Sanefuji, Hiroto Kayashima, Akinobu Taketomi, Yuji Soejima, Toru Ikegami, Mitsuo Shimada and Yoshihiko Maehara : Dual hepatic artery reconstruction in living donor liver transplantation using a left hepatic graft with 2 hepatic arterial stumps., Surgery, Vol.147, No.6, 878-886, 2009.
(Summary)
A left hepatic graft in living donor liver transplantation (LDLT) often has 2 thin and short hepatic arterial stumps, which makes hepatic artery (HA) reconstructions much more difficult to perform. Consequently, some investigators regard using a left graft as a contraindication to LDLT, whereas others report that the reconstruction of only 1 HA is sufficient for most LDLTs. The aim of this retrospective study was to investigate whether 2 HAs on a left hepatic graft in an LDLT can be reconstructed safely and whether the outcomes of LDLTs are affected by reconstructing both HAs (dual reconstruction).
Kotaro Miyake, Mitsuo Shimada, Masanori Nishioka, Koji Sugimoto, Erdenebulgan Batmunkh, Yoshihiro Uto, Hideko Nagasawa and Hitoshi Hori : The novel hypoxic cell radiosensitizer, TX-1877 has antitumor activity through suppression of angiogenesis and inhibits liver metastasis on xenograft model of pancreatic cancer., Cancer Letters, Vol.272, No.2, 325-335, 2008.
(Summary)
Tumor hypoxia has been considered to be a potential therapeutic target, because hypoxia is a common feature of solid tumors and is associated with their malignant phenotype. In the present study, we investigated the antitumor effect of hypoxic cell radiosensitizer, TX-1877 in inhibiting angiogenesis and liver metastasis on pancreatic cancer xenograft model. The antitumor effects of TX-1877 were tested against various human tumor cell lines using cell proliferation assay. Nude mice bearing s.c. or orthotopically implanted human SUIT-2 were treated with TX-1877 alone, irradiation alone or TX-1877 and irradiation. Tumor volume, survival, expression of angiogenic molecules and liver metastasis were evaluated in treatment versus control groups. In vitro, TX-1877 inhibited the proliferation and potentiated the radiosensitivity of various pancreatic cancer cell lines. In an orthotopic model, tumors from nude mice injected with pancreatic cancer cells and treated with TX-1877 and irradiation showed significant reductions in volume (p<0.05 versus control, TX-1877 alone or irradiation alone). Quantitative real-time reverse transcription-PCR and immunohistochemical analysis revealed that treatment with TX-1877 alone or with TX-1877 and irradiation inhibited expression of the angiogenic molecules, vascular endothelial growth factor; basic fibroblast growth factor, interleukin-8 and matrix metalloproteinase 9 more than control or did treatment with irradiation alone. These treatments also induced apoptosis in cancer cells. These data show that treatment of TX-1877 and irradiation decreased growth of human pancreatic cancer, suppressed angiogenesis and inhibited liver metastasis, leading to prolonged survival.
Hirofumi Kanemura, Kenji Kusumoto, Hidenori Miyake, Seiki Tashiro, Kazuhito Rokutan and Mitsuo Shimada : Geranylgeranylacetone prevents acute liver damage after massive hepatectomy in rats through suppression of a CXC chemokine GRO1 and induction of heat shock proteins., Journal of Gastrointestinal Surgery, Vol.13, No.1, 66-73, 2008.
(Summary)
BACKGROUND AND METHODS: Acute liver failure after massive hepatectomy remains a challenging problem. In this study, using a microarray designed to monitor the side effects of drugs, we examined changes in gene expression in the remnant liver during the 24 h after hepatectomy and the effects of a nontoxic heat shock protein (HSP) 70 inducer, geranylgeranylacetone (GGA), after 90% hepatectomy in rats. RESULTS: A single oral administration of 100 mg/kg GGA significantly suppressed the release of aminotransferases and improved survival compared with vehicle administration. The hepatectomy upregulated 74 genes and downregulated 95. Interestingly, ten cytokine genes were upregulated, while no cytokine-related gene was downregulated. Among the ten cytokine genes, a potent chemoattractant for neutrophils, GRO1, was most rapidly and markedly upregulated after 90% hepatectomy. GGA effectively suppressed the up-regulation of GRO1 messenger ribonucleic acid, and this was validated by Northern hybridization. Microarray and immunoblot analyses showed that, in addition to HSP70 and HSP27, GGA preferentially induced an endoplasmic reticulum chaperone, BIP. CONCLUSION: Considering hemodynamic and metabolic overloading as a primary cause of acute lever failure, the ER stress response enhanced by GGA may also play an important role in the prevention of overload-induced liver damage.
Mika Kijima, Takeshi Yamaguchi, Chieko Ishifune, Yoichi Maekawa, Akemi Koyanagi, HIdeo Yagita, Shigeru Chiba, Kenji Kishihara, Mitsuo Shimada and Koji Yasutomo : Dendritic cell-mediated NK cell activation is controlled by Jagged2-Notch interaction., Proceedings of the National Academy of Sciences of the United States of America, Vol.105, No.19, 7010-7015, 2008.
(Summary)
Natural killer (NK) cells regulate various immune responses by exerting cytotoxic activity or secreting cytokines. The interaction of NK cells with dendritic cells (DC) contributes to NK cell-mediated antitumor or antimicrobial responses. However, the cellular and molecular mechanisms for controlling this interaction are largely unknown. Here, we show an involvement of Jagged2-Notch interaction in augmenting NK cell cytotoxicity mediated by DC. Enforced expression of Jagged2 on A20 cells (Jag2-A20 cells) suppressed their growth in vivo, which was abrogated by depleting NK cells. Moreover, Jag2-A20 cells exerted a suppression on the growth of nonmanipulated A20 cells in SCID mice in an NK-dependent manner. Consistently, coinoculation of A20 cells with DC overexpressing Jagged2 (Jag2-DC) suppressed the growth of A20 cells in mice. Stimulation of NK cells with Jagged2 directly enhanced their cytotoxicity, IFN-gamma production, and proliferation. Ligation of Notch2 on NK cells enhanced their cytotoxic activity, and Jag2-DC or CpG-treated DC-mediated NK cell cytotoxicity was suppressed by a gamma-secretase inhibitor. These results indicate that the Jagged2-Notch axis plays a crucial role in DC-mediated NK cell cytotoxicity. Furthermore, manipulation of this interaction may provide an approach to induce potent tumor immunity or to inhibit certain autoimmune diseases caused by NK cell activation.
S Yamasaki, N Kurita, J Hata, Maki Moritani, Mitsuo Itakura and Mitsuo Shimada : The effect of transgenic expression of TGF-beta1 on transplanted islet graft survival., Hepato-Gastroenterology, Vol.54, No.78, 1617-1621, 2007.
(Summary)
Transgenic mice expressing the active form of porcine TGF-beta1 (NOD- TGF-beta1 Tg) were completely protected from autoimmune diabetes in the NOD genetic background in our previous study. Here, we attempted to determine whether transgenic expression of TGF-beta1 in transplanted islets prevents autoimmune destruction in NOD mice. We transplanted islets to the subcapsular region of the kidney using NOD-TGF-beta1 Tg and NOD mice as donor and recipient or vice versa. Cyclophosphamide was administered twice to streptozocin-induced diabetic females NOD-TGF-beta1 Tg or their female littermates after islet transplantation. All islets grafts of NOD-TGF-beta1 Tg in spontaneously diabetic NOD mice were rejected earlier than those of their littermates. Hyperglycemia was induced in all littermates, but three out of four NOD-TGF-beta1 Tg, which were STZ-induced diabetic female mice, remained normoglycemic in response to the administration of cyclophosphamide after islet transplantation. Our results lack direct evidence for the local paracrine TGF-beta1 to protect the transplanted islet grafts. We observed, however, prolonged survival of NOD islets grafts in diabetic NOD-TGF-beta1 Tg suggesting the protective role of transgenic TGF-beta1 to suppress the autoimmune process in our syngenic transplantation model. We are convinced that this data could help resolve many problems regarding islet transplantation for type 1 diabetes.
Yoshitaka Imoto, Naoki Muguruma, Tetsuo Kimura, Eriko Aoyagi, Koichi Okamoto, Seisuke Okamura, Susumu Ito, Nobuya Sano and Mitsuo Shimada : Relationship between mucin expression and preoperatie bile juice cytology in biliary tract carcinoma, The Journal of Medical Investigation : JMI, Vol.54, No.1-2, 41-47, 2007.
(Summary)
The present study evaluated correlations between preoperative bile juice cytology and mucin expression of surgical specimens in biliary tract carcinoma. Twenty-five patients with biliary tract carcinoma surgically treated at our hospital, whose bile juice cytology had been evaluated before operation, were allocated to this study. Biliary cytology was classified into three categories based on the Papanicolaou classification. Immunohistochemical staining of tissues was performed using MUC1 and MUC2 monoclonal antibodies. Lesions showing MUC1 expression of ++ or higher and MUC2 expression of - were classified as Group A, and the remaining lesions as Group B. According to the epithelial site, preoperative cytology was highly correlated in Group A, while it was negative in Group B (p<0.05). In the advanced site of carcinomas, preoperative cytology tended to highly be positive in Group A, while it tended to be negative in Group B (p<0.05). These results suggest that the bile juice cytology results are affected by characteristics of mucin expression in the tissue. Based on the possibility that mucin expression correlates with the prognosis of each carcinoma, a positive cytological result suggests a poor prognosis for the carcinoma, which may be informative for predicting the post-operative courses and choosing treatments.
Hisami Okumura, Taki Nakamura, Harumi Takeuchi, Hidenori Miyake, Takafumi Katayama, Hidekazu Arai, Yutaka Taketani, Masahiko Fujii, Mitsuo Shimada and Eiji Takeda : Effect of late evening snack with rice ball on energy metabolism in liver cirrhosis., European Journal of Clinical Nutrition, Vol.60, No.9, 1067-1072, 2006.
(Summary)
This study investigates the effects of a late evening snack (LES), of 200 kcal of rice ball, on energy metabolism in cirrhotic patients. Impaired nutritional metabolism has been associated with cirrhosis, and frequent intake of small meals may prevent early-onset starvation, and maintain nourishment in these patients. Twenty-one cirrhotic patients and 26 control subjects (Control) were recruited for this study. Patients were subsequently treated by LES (LC-LES) and by a non-LES regimen (LC-NLES). Resting energy expenditure and respiratory quotient (RQ) were assessed by indirect calorimetry at 0830, 1130 and 1430. Blood glucose and non-esterified fatty acids (NEFA) were measured just before the energy metabolism measurements. The regular diet included three major meals and LES, at 0900, 1200, 1800 and 2100, respectively. The Control and LC-NLES groups received only the major meals, whereas the LC-LES group received three meals plus 200 kcal LES for 7 days. There was no difference in the total energy intake among Control, LC-NLES and LC-LES groups. Respiratory quotient in LC-NLES was significantly lower than that of Control at 0830. Respiratory quotient value in LC-LES significantly elevated from that in LC-NLES. The RQ values did not differ among Control, LC-NLES and LC-LES at 2 h after the meal (1130 and 1430). Non-esterified fatty acids in LC-LES were lower than that in LC-NLES after overnight fasting. The ingestion of a 200 kcal rice ball LES can improve the nutritional metabolism in cirrhotic patients.
Yuji Soejima, Mitsuo Shimada, Taketoshi Suehiro, Tomoharu Yoshizumi, Keiji Kishikawa and Yoshihiko Maehara : Reconstruction of the middle hepatic vein tributaries using the recipient's recanalized umbilical vein in right-lobe living-donor liver transplantation, Surgery, Vol.139, No.3, 442-445, 2006.
(Summary)
Right-lobe grafts without the middle hepatic vein (MHV) can cause severe congestion of the anterior segment in living-donor liver transplantation (LDLT). However, the indications and methods for reconstructing the MHV or its tributaries remain controversial. We herein describe two cases of the successful use of the recipient's recanalized umbilical vein as an interposition graft to drain the major MHV tributaries in right-lobe LDLTs. After surgery, both right-lobe grafts are currently functioning well and all of the reconstructed venous tributaries have been confirmed to be patent by doppler ultrasonography. The histopathological features of the recanalized umbilical vein showed an intact intima with thickened media. The use of the recipient's recanalized umbilical vein is a good option for reconstructing MHV tributaries in right-lobe LDLTs.
Otsuka Toshihiro, Keisuke Izumi, Itsuo Tokunaga, Takako Gotohda, Ipposhi Kaneshige, Yoshiharu Takiguchi, Kaneda Shinya, Nobuo Satake, Takamasa Ohnishi, Seiki Tashiro and Mitsuo Shimada : Prevention of lethal hepatic injury in Long-Evans Cinnamon(LEC) rats by D-galactosamine hydrochloride, The Journal of Medical Investigation : JMI, Vol.53, No.1-2, 81-86, 2006.
(Summary)
Repeated injections of D-galactosamine hydrochloride (GalN) increase the survival rate of Long-Evans Cinnamon (LEC) rats, an animal model of Wilson's disease. The aim of the present study was to investigate the mechanism of GalN for prevention of spontaneous lethal hepatic injury in LEC rats. Male LEC rats were given a single subcutaneous injection of 300 mg/kg of GalN or vehicle (0.9% NaCl) at 14 weeks, and killed at 28 weeks of age. Next, 6-week-old male LEC rats were given weekly subcutaneous injections of 300 mg/kg of GalN or vehicle for 3 or 12 weeks, and their hepatic 8-hydroxydeoxy-2'-guanosine (8-OHdG), glutathione peroxidase (GPX), and catalase activities were measured. None of GalN-treated rats died of hepatic injury (0/12), whereas the mortality rate of control rats given 0.9% NaCl was 17% (2/12). GalN administration for 12 weeks decreased the hepatic 8-OHdG, and GalN administration for either 3 or 12 weeks increased the glutathione peroxidase activity. GalN administration increased the serum level of alanine aminotransferase, and accelerated megalocytic degeneration of the hepatocytes. GalN treatment is effective in preventing lethal hepatitis in LEC rats and decrease of oxidative DNA damage by GalN plays an important role in increase of the survival rate.
The use of steatotic livers is associated with increased primary nonfunction in liver transplantation. To reduce the risk of liver injury, we applied a short-term combination therapy of diet, exercise and drugs for 11 living-donor liver transplantation (LDLT) candidates with steatosis. Subjects were treated with a protein-rich (1000 kcal/day) diet, exercise (600 kcal/day), and bezafibrate (400 mg/day) for 2-8 weeks. The treatment significantly improved macrovesicular steatosis (30+/-4% vs. 12+/-2% [mean +/- SEM], P = 0.0028). Body weight and BMI were significantly reduced (73.7 +/- 3.2 kg vs. 66.9 +/- 2.9 kg, P = 0.0033, 26.4 +/- 0.7 kg/m vs. 24.1 +/- 0.8 kg/m, P = 0.0033). The treatment completely normalized liver function tests and lipid metabolism. Seven treated liver grafts (left lobe) were transplanted to the recipients. We compared transplanted graft function and resected liver function of donors using parameters such as peak total bilirubin, prothrombin time at postoperative day 3, and peak alanine aminotransferase between treated liver (n = 7) and donor liver without hepatic steotosis (n = 37). The transplanted grafts showed good liver functions, and there was no difference between them with respect to functional parameters. The treated donors also showed good liver functions, and no significant differences in functional parameters. The results of this study indicate that our short-term treatment effectively reduced steatosis and contributed to safer LDLT. Our findings also suggest that even severely steatotic livers can be used for LDLT grafting subsequent to our short-term treatment regimen.
(Keyword)
Adult / Bezafibrate / Biopsy / Dietary Proteins / Exercise / Fatty Liver / Female / Humans / Hypolipidemic Agents / Liver Transplantation / Living Donors / Male / Middle Aged / Preoperative Care / Severity of Illness Index / Tissue and Organ Procurement
Taketoshi Suehiro, Mitsuo Shimada, Keiji Kishikawa, Tatsuo Shimura, Yuji Soejima, Tomoharu Yoshizumi, Kohji Hashimoto, Yasushi Mochida, Shinji Hashimoto, Yoshihiko Maehara and Hiroyuki Kuwano : Effect of intraportal infusion to improve small for size graft injury in living donor adult liver transplantation, Transplant International, Vol.18, No.8, 923-928, 2005.
(Summary)
The most important problem in the living donor adult liver transplantation (LDALT) is a small for size graft. Although a right lobe graft is used in many cases in order to avoid small for size graft, for a donor, the risk has few in left lobe graft. We evaluate the effect of an intraportal infusion treatment to the small for size graft. One hundred and twelve patients who underwent LDALT were studied. The graft weight recipient standard liver volume ratio (GV/SLV) of these patients were 50% or less. We divided the patients into following two groups; infusion group (n = 53) and control group (n = 59). For the infusion group, 16 G double lumen catheter was inserted into portal vein and nafamostat mesilate (protease inhibitor which stabilize coagulofibrinolytic state; 200 mg/day), prostaglandin E(1) (vasodilator and hepatoprotective effect; 500 microg/day) and thromboxane A(2) synthetase inhibitor (vasodilator and anticoagulant effect; 160 mg/day) were administrated continuously for 7 days. Small-for-size graft syndrome was defined as bilirubin >10 mg/dl and ascites >1000 cc on postoperative day (POD) 14. Comparison examination of a background factors and postoperative bilirubin and amount of ascites was carried out. The mean GV/SLV did not have the difference at 39.1% of infusion group, and 38.3% of control group (P = 0.58). By the control group, 15 patients (25.4%) were small-for-size graft syndrome, however, there was only two (3.8%) small-for-size graft syndrome in infusion group (P = 0.04). The bilirubin levels of infusion and control group on 7 and 14 POD were 9.9 and 7.8 vs. 9.5 and 10.5 mg/dl, respectively. The amount of ascites of infusion group on 7 and 14 POD were 870 and 430 cc, respectively. On the contrary, in control group, the amount of ascites on 7 and 14 POD were 1290 and 1070 cc, respectively. Bilirubin levels and the amount of ascites on 7 and 14 POD were lower in the patients with infusion group then those with control group. There were no differences between infusion group and control group in age, sex and Child's classification. The intraportal infusion had an effect in prevention of hyperbilirubinemia and loss in quality of excessive ascites in the patients with small for size graft. This was suggested to be what is depended on the improvement of the microcirculation insufficiency considered one of the causes of small-for-size graft syndrome.
(Keyword)
intra-portal infusion / living donor adult liver transplantation / small for size graft injury
Mitsutoshi Fukuyama, Kazuhito Rokutan, Toshiaki Sano, Hidenori Miyake, Mitsuo Shimada and Seiki Tashiro : Overexpression of a novel superoxide-producing enzyme,NADPH oxidase 1,in adenoma and well differentiated adenocarcinoma of the human colon, Cancer Letters, Vol.221, No.1, 97-104, 2005.
(Summary)
A superoxide-producing enzyme, NADPH oxidase 1 (Nox1), dominantly expressed in the colon, is implicated in the pathogenesis of colon cancer. Immunohistochemistry showed that Nox1 was constitutively expressed in surface mucous cells. Adenomas and well differentiated adenocarcinomas up-regulated Nox1 expression. Ki-67-negative, well differentiated tumor cells contained abundant Nox1, whereas Ki-67-positive, proliferating cells did not express it. This differentiation-dependent expression in normal as well as tumor tissues suggests distinct roles of Nox1 besides mitogenic function. Nuclear factor (NF)-kappaB was predominantly activated in adenoma and adenocarcinoma cells expressing abundant Nox1, suggesting that Nox1 may stimulate NF-kappaB-dependent antiapoptotic pathways in colon tumors.
(Keyword)
NADPH oxidase 1 / reactive oxygen species / Colon cancer
Mitsuo Shimada, Yusuke Yonemura, Hideki Ijichi, Noboru Harada, Satoko Shiotani, Mizuki Ninomiya, Takahiro Terashi, Tomoharu Yoshizumi, Yuji Soejima and Yoshihiko Maehara : Living donor liver transplantation for hepatocellular carcinoma: a special reference to a preoperative des-gamma-carboxy prothrombin value, Transplantation Proceedings, Vol.37, No.2, 1177-1179, 2005.
(Summary)
Des-gamma-carboxy prothrombin (DCP) is a sensitive marker related to vascular invasion of hepatocellular carcinoma (HCC). The aim of this study was to clarify the risk factors of HCC recurrence in living donor liver transplantation (LDLT) with special reference to preoperative DCP values. Forty consecutive adult HCC patients who underwent LDLT were examined for a correlation between the DCP value and vascular invasion. Risk factors for recurrence were also investigated using clinicopathological variables including preoperative DCP levels. The incidence of positive histological vascular invasion in patients with DCP values above 300 mAU/mL was higher than that with those with DCP value below 300 mAU/mL. Other significant risk factors for recurrence were over 5 cm tumor diameter, not meeting the Milan criteria, AFP value >400 ng/mL, histological vascular invasion, poorly differentiated histology, and male gender. Among the patients who did not meet the Milan criteria, those with both no more than 5 cm of tumor diameter and no more than 300 mAU/mL DCP exhibited a good prognosis. A high DCP value, namely >300 mAU/mL correlated with histological vascular invasion and was one of the strongest prognostic variables. Therefore, special attention should be paid to HCC patients with high DCP values. No correlation between the number of tumor nodules and recurrence was found; therefore, the Milan criteria may require revision regarding the number of tumor nodules.
Shinya Morimoto, Noriyuki Nishimura, Tomoya Terai, Shinji Manabe, Yasuyo Yamamoto, Wakako Shinahara, Hidenori Miyake, Seiki Tashiro, Mitsuo Shimada and Takuya Sasaki : Rab13 Mediates the Continuous Endocytic Recycling of Occludin to the Cell Surface, The Journal of Biological Chemistry, Vol.280, No.3, 2220-2228, 2005.
(Summary)
During epithelial morphogenesis, adherens junctions (AJs) and tight junctions (TJs) undergo dynamic reorganization, whereas epithelial polarity is transiently lost and reestablished. Although ARF6-mediated endocytic recycling of E-cadherin has been characterized and implicated in the rapid remodeling of AJs, the molecular basis for the dynamic rearrangement of TJs remains elusive. Occludin and claudins are integral membrane proteins comprising TJ strands and are thought to be responsible for establishing and maintaining epithelial polarity. Here we investigated the intracellular transport of occludin and claudins to and from the cell surface. Using cell surface biotinylation and immunofluorescence, we found that a pool of occludin was continuously endocytosed and recycled back to the cell surface in both fibroblastic baby hamster kidney cells and epithelial MTD-1A cells. Biochemical endocytosis and recycling assays revealed that a Rab13 dominant active mutant (Rab13 Q67L) inhibited the postendocytic recycling of occludin, but not that of transferrin receptor and polymeric immunoglobulin receptor in MTD-1A cells. Double immunolabelings showed that a fraction of endocytosed occludin was colocalized with Rab13 in MTD-1A cells. These results suggest that Rab13 specifically mediates the continuous endocytic recycling of occludin to the cell surface in both fibroblastic and epithelial cells.
森園 周祐, 中牟田 誠, 国府島 庸之, 宮城 譲, 吉本 剛志, 有村 英一郎, 古藤 和浩, 遠城寺 宗近, Yuji Soejima, 武冨 紹信, 吉住 朋晴, 内山 秀昭, Mitsuo Shimada, 前原 喜彦 and 名和田 新 : Evaluation of Acute Hepatic Failure Treated at the Department of Medicine III, Kyushu University Hospital : Indications for Living-donor Liver Transplantation, Fukuoka Acta Medica, Vol.95, No.12, 321-331, 2004.
(Summary)
To evaluate indications for living-donor liver transplantation (LDLT), we examined 25 consecutive patients with acute hepatic failure admitted to the Department of Medicine III, Kyushu University Hospital between November 2001 and July 2004. These cases were diagnosed as fluminant hepatitis (n=13), severe-type acute hepatitis (n=11), or late-onset hepatic failure (n=1). Nine patients (36 %) improved with conservative treatment (conservative treatment group), and the other 16 patients (64 %) needed LDLT (LDLT indicated group). In the LDLT indicated group, 11 patients received LDLT, and 4 died because of lack of LDLT donors (n=3), or renal failure (n=1). The LDLT survival rate was 82 % (9/11) ; two patients died due to hepatic infarction and brain edema, respectively. It is very important to predict whether a patient with acute hepatic failure belongs to the conservative treatment group or the LDLT indicated group on admission. Therefore, we analyzed variables that could influence prognosis, including, parameters of hepatic function and platelet counts on admission, and relative hepatic volume (%), which represents the ratio of hepatic volume measured by CT relative to standard hepatic volume calculated with body surface area. Univariate logistic analysis showed that relative hepatic volume, gammaglutamyl transpeptidase (γ-GTP), alkaline phosphatase (ALP), and the ratio of direct bilirubin to total bilirubin (DB/TB) were significant predictors of survival (p < 0.05). Using these factors plus prothrombin time (PT) and total cholesterol, both of which were relatively significant predictors of survival (p < 0.2), we proposed a model for predicting the probability of survival by the stepwise method. Consequently, we proposed a model using four parameters : ALP, GGTP, PT, and relative hepatic volume (Volume) as shown below : P(%) = 1/1+exp { ?(-36 .2375+ALP x 0.0251+ γ-GTP x 0.0102+PT x 0.2558+Volume x 21.2158)} ×100 This model showed a significant correlation between prediction and consequence of survival (r2 = 0.7388, p = 0.0003). In conclusion, LDLT is an effective treatment for acute hepatic failure. The results of this study suggested that our model can adequately predict prognosis in the early phase of acute hepatic failure.
(Keyword)
Adult / Alkaline Phosphatase / Female / Humans / Liver / Liver Failure, Acute / Liver Transplantation / Living Donors / Male / Prothrombin Time / Survival Rate / gamma-Glutamyltransferase
Noboru Harada, Mitsuo Shimada, Shinji Okano, Taketoshi Suehiro, Yuji Soejima, Yukihiro Tomita and Yoshihiko Maehara : IL-12 gene therapy is an effective therapeutic strategy for hepatocellular carcinoma in immunosuppressed mice, The Journal of Immunology, Vol.173, No.11, 6635-6644, 2004.
(Summary)
Immunosuppressive therapy for organ transplantation is essential for controlling rejection. When liver transplantation is performed as a therapy for hepatocellular carcinoma (HCC), recurrent HCC is one of the most fatal complications. In this study, we show that intratumoral murine IL-12 (mIL-12) gene therapy has the potential to be an effective treatment for malignancies under immunosuppression. C3H mice (H-2(k)), injected with FK506 (3 mg/kg) i.p., were s.c. implanted with 2.5 x 10(6) MH134 cells (H-2(k)) and we treated the established HCC with electroporation-mediated gene therapy using mIL-12 plasmid DNA. Intratumoral gene transfer of mIL-12 elevated intratumoral mIL-12, IFN-gamma, and IFN-gamma-inducible protein-10, significantly reduced the number of microvessels and inhibited the growth of HCC, compared with HCC-transferred control pCAGGS plasmid. The inhibition of tumor growth in immunosuppressed mice was comparable with that of mIL-12 gene therapy in immunocompetent mice. Intratumoral mIL-12 gene therapy enhanced lymphocytic infiltration into the tumor and elicited the MH134-specific CTL response even under FK506. The dose of FK506 was sufficient to prevent the rejection of distant allogenic skin grafts (BALB/c mice, H-2(d)) and tumors, B7-p815 (H-2(d)) used as transplants, during mIL-12 gene therapy against MH134. Ab-mediated depletion studies suggested that the inhibition of tumor growth, neovascularization, and spontaneous lung metastasis by mIL-12 was dependent almost entirely on NK cells and partially on T cells. These results suggest that intratumoral mIL-12 gene therapy is a potent effective strategy not only to treat recurrences of HCC in liver transplantation, but also to treat solid malignant tumors in immunosuppressed patients with transplanted organ.
Satoko Shiotani, Mitsuo Shimada, Yuji Soejima, Tomoharu Yoshizumi, Shinji Uemoto, Tetsuya Kiuchi, Koichi Tanaka and Yoshihiko Maehara : S100beta protein: The preoperative new clinical indicator of brain damage in patients with fulminant hepatic failure, Transplantation Proceedings, Vol.36, No.9, 2713-2716, 2004.
(Summary)
The aim of this study was to clarify the role of serum S100 beta on the accurate assessment of reversibility of brain damage after fulminant hepatic failure (FHF). Among the 13 patients with FHF enrolled in this study, 12 underwent living donor liver transplantation; one patient could not the procedure because of volvulus of the sigmoid colon. Serum S100 beta was serially measured using a chemiluminescent immunoassay. Preoperative serum S100 beta in patients with diffuse brain edema was significantly higher than that in patients with localized brain edema (P < 0.05). Patients with preoperative brain death showed serum S100 beta levels over 7.0 microg/L. Serum S100 beta levels correlated with the degree of brain edema of FHF. It has the potential to be a new clinical, noninvasive indicator of brain damage due to FHF.