Detection of Lymph Nodes Metastasis in Biliary Carcinomas:Morphological Criteria by MDCT and the Clinical Impact of DEI-MRI

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.


The relationship of CD133, histone deacetylase 1 and thrombospondin-1 in gastric cancer.

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.


Effective use of a vessel-sealing system for laparoscopic unroofing of liver cysts.

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.


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).

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.

International Journal of Clinical Oncology


Duodenal-jejunal bypass improves diabetes and liver steatosis via enhanced glucagon-like peptide-1 elicited by bile acids.

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.

Journal of Gastroenterology and Hepatology


Impact of newly developed, next-generation artificial endocrine pancreas

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.

The Journal of Medical Investigation : JMI


再発抑制のための抗ウイルス療法

再発抑制のための抗ウイルス療法


Dysfunction of liver regeneration in aged liver after partial hepatectomy.

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.


Clinical role of Notch signaling pathway in intraductal papillary mucinous neoplasm of the pancreas.

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.


Recovery of nutritional metabolism after liver transplantation

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.


膵癌・胆道癌 ─基礎・臨床の最新研究動向─

膵癌・胆道癌 ─基礎・臨床の最新研究動向─

Nihon Rinsho. Japanese Journal of Clinical Medicine


外科の立場からのキャリアアップ支援

外科の立場からのキャリアアップ支援


New ports placement in laparoscopic central lymph nodes dissection with left colic artery preservation for sigmoid colon and rectal cancer.

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.


Clinical role of Foxp3+ regulatory T cell in Living donor related liver transplantation for prediction of life-threatening complications.

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.


Usefulness of artificial endocrine pancreas during resection of insulinoma.

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.


Hypomethylation of Long Interspersed Nuclear Element-1 (LINE-1) is Associated with Poor Prognosis via Activation of c-MET in Hepatocellular Carcinoma.

LINE-1 hypomethylation is significantly associated with poor prognosis in patients with HCC, possibly due to activation of c-MET expression.

LINE-1 was significantly hypomethylated in tumor tissues compared with nontumor tissues (48.3 ± 12.2 % vs. 68.2 ± 2.0 %, respectively, p < 0.0001). LINE-1 hypomethylation was not associated with any clinicopathological factors in HCC patients, except sex (p < 0.05). However, patients with LINE-1 hypomethylation exhibited significantly poorer outcome, and multivariate analysis revealed that LINE-1 hypomethylation was an independent risk factor for overall survival (hazard ratio (HR) = 6.1, p = 0.031) and disease-free survival (HR = 2.34, p = 0.045). L1-MET expression was significantly higher in tumor tissues (p <0.01). L1-MET expression levels were inversely correlated with LINE-1 methylation levels, and positively correlated with c-MET expression (p < 0.05). Furthermore, higher c-MET protein expression was observed in the LINE-1 hypomethylated tumor tissues compared with hypermethylated tumor tissues (p = 0.032).


Recovery pattern of non-protein respiratory quotient and non-esterified fatty acid after liver resection

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.


Abrogation of Rbpj attenuates experimental autoimmune uveoretinitis by inhibiting IL-22-producing CD4+ T cells.

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.


Comparison of measured and predicted energy expenditure in patients with liver cirrhosis

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.

Asia Pacific Journal of Clinical Nutrition


Blood vessel-based liver segmentation using the portal phase of an abdominal CT dataset

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.


Beneficial effects of green tea catechin on massive hepatectomy model in rats.

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.


Molecular features of triple negative breast cancer cells by genome-wide gene expression profiling analysis.

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.


Beneficial effects of enteral nutrition containing with hydrolyzed whey peptide on warm ischemia/reperfusion injury in the rat liver.

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.


Usefulness of continuous blood glucose monitoring and control for patients undergoing liver transplantation.

The STG-22 closed-loop system is effective for maintaining strict blood glucose control during liver transplantation with minimal variability in blood glucose concentration.

The Journal of Medical Investigation : JMI


手術手技 前区域枝門脈灌流領域が上右肝静脈を包含する症例に対する，下右肝静脈温存，上右肝静脈とドレナージ領域を含む


肝切除支援ソフトによる術前シミュレーション，術中ナビゲーション，部分肝臓機能解析


[達人こだわりの手術テクニック] II. 肝胆膵領域 3. 肝癌に対する区域切除


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

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.


縦隔腫瘍と鑑別を要した左肺葉外肺分画症の1例

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


腹腔鏡補助下肝部分切除術を施行した肝芽腫の1例

腹腔鏡補助下肝部分切除術を施行した肝芽腫の1例


「内視鏡外科医のための微細局所解剖アトラス」肝胆膵 肝外側区域切除-脈管処理のコツ


【必読 イレウスの診断から治療まで】機械的イレウス 複雑性または絞扼性イレウス ヘルニア嵌頓


Treatment of rapid weight loss in a donor with hepatic steatosis in a living donor liver transplantation: a case report

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.


A case of small intestinal mesenteric liposarcoma

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.


血流障害，遊走脾を伴った急性胃軸捻転症の1例

血流障害，遊走脾を伴った急性胃軸捻転症の1例


Possible utility of MRI using Gd-EOB-DTPA for estimating liver functional reserve

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.


癌治療に求められる漢方の意義 臨床現場にどのように活かすか"牛車腎気丸"によるFOLFOX関連末梢神経障害の軽減

産婦人科漢方研究のあゆみ

産婦人科漢方研究のあゆみ


[達人が教える肝胆膵高度技能専門医手術-コツとピットフォール] 肝葉切除(右肝・左肝切除)非手割法


II-4 抗癌剤 「肝胆膵」

II-4 抗癌剤 「肝胆膵」


Bevacizumab併用化学療法中に大腸穿孔・穿通をきたした症例の検討

Bevacizumab併用化学療法中に大腸穿孔・穿通をきたした症例の検討


Notch2 regulates the development of marginal zone B cells through Fos.

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.

Biochemical and Biophysical Research Communications


Hepatic and pancreatic regenerative medicine using Adipose tissue-derived mesenchymal stem cell

【脂肪由来幹細胞の臨床応用への展開】脂肪由来幹細胞を用いた肝および膵再生医療

Journal of Clinical and Experimental Medicine


ALTA療法の効果判定としての経肛門超音波パワードップラー法の可能性

ALTA療法の効果判定としての経肛門超音波パワードップラー法の可能性


Effects of indole-3-carbinol and phenethyl isothiocyanate on bile and pancreatic juice excretion in rats.

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.

The Journal of Medical Investigation : JMI


Torsion of an accessory spleen with situs inversus in a child.

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.


Evaluation of the usefulness of Roux-en-Y reconstruction with jejunal pouch by radioisotope scintigraphy and 13C breath test

【胃癌術後QOL向上に役立つ手技・再建法とその機能的評価】13Cを用いた空腸吸収能検査・Radioisotope(RI)法による排出能検査からみた胃全摘術後空腸嚢付加Roux-en-Y再建の意義


Nutritional Assessment of Pre- and Post- Liver Resection by Energy Metabolism and Laboratory Data

エネルギー代謝と血液生化学検査からみた肝切除前後の栄養評価

Journal of Japanese Society of Clinical Nutrition


【内視鏡外科手術をめぐる最近のトピックス】 新たな領域への手術適応 保険収載後の腹腔鏡下肝切除術の展開


薬物治療学の進歩-この30年-，IX. 肝移植 1)ネオーラル(ノバルティス)

薬物治療学の進歩-この30年-，IX. 肝移植 1)ネオーラル(ノバルティス)


術後障害に対する漢方治療.

術後障害に対する漢方治療.


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.

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.


New stepwise cooling system for short-term porcine islet preservation.

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.


【特集】大腸がん鏡視下手術の標準化

【特集】大腸がん鏡視下手術の標準化


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∼.

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


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

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


Impact of splenectomy in patients with liver cirrhosis: Results from 18 patients in a single center experience.

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.


ステロイド長期投与患者における周術期ステロイドカバー.

ステロイド長期投与患者における周術期ステロイドカバー.

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.


手術機器の使い方-基本と応用- 鏡視下手術用機器 5.リトラクター

手術機器の使い方-基本と応用- 鏡視下手術用機器 5.リトラクター


特集/必読 最新の肝切除—その2 2.Liver hanging maneuver


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


Effect of long-term late-evening snack on health-related quality of life in cirrhotic patients.

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.


CD133 expression is a potential prognostic indicator in intrahepatic cholangiocarcinoma.

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.


Pseudostenosis of the Common Hepatic Duct caused by Compression of the Cystic Artery

胆嚢動脈による偽性総肝管狭窄の1例

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.

胆道狭窄は悪性疾患を疑う所見である.胆道は直接的診断が困難であり,間接的な画像診断が行われるため,偽性胆管狭窄の報告がみられる.症例は74歳の女性で,診断は胆嚢腫瘍および総肝管狭窄であった.超音波内視鏡検査では胆嚢腫瘍は最大径12mmであり,また総肝管狭窄は胆嚢癌の総肝管浸潤や胆管癌による可能性が否定できなかったため開腹胆嚢摘出術および術中胆道造影検査を施行した.術中所見では総肝管は胆嚢動脈に圧排されており,狭窄の原因と考えられた.胆嚢動脈の切離後,総胆管を切開し狭窄部を確認するも病変は認められなかった.胆道造影検査でも狭窄像は認められなかった.胆嚢内には12mm大の隆起性病変を認め,深達度mpの早期胆嚢癌であった.今回,我々は胆嚢動脈の圧排によって画像上偽性総肝管狭窄を生じた胆嚢癌の1例を経験したので文献的考察を加えて報告する.

The Japanese Journal of Gastroenterological Surgery


High expression of Toll-like receptor 4/myeloid differentiation factor 88 signals correlates with poor prognosis in colorectal cancer.

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.


Two Cases of Emergency Operations in Patients Undergoing Bevacizumab Treatment

Bevasizumab併用化学療法中に緊急手術をした2例.

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>

Bevacizumab使用中の手術は創傷治癒遅延のため投与後4∼6週間以降に施行することが推奨されているが，消化管穿孔などでは緊急手術が必要となる．今回，Bevacizumab使用中に緊急手術行った2例を報告する．症例1,50歳代男性.下行結腸癌同時性肝転移肺転移と診断され，腫瘍によるイレウスに対して人工肛門造設術を施行，その後，腫瘍の後腹膜への穿通に対して結腸左半切除術を施行．8日後に腸腰筋膿瘍に対して洗浄ドレナージ術を施行．症例2,70歳代男性.虫垂粘液嚢胞腺癌,腹膜播種と診断され治療を行っていた．消化管穿孔に対して緊急手術を施行．横行結腸に穿孔部が認められたが高度の癌性腹膜炎の状態であり洗浄ドレナージ術を施行し治療した．Bevacizumab使用時において消化管吻合が可能な場合においても吻合を行わず，人工肛門造設による2期的手術を行い，人工肛門閉鎖については，十分なBevacizumab休薬期間と原疾患の進行状況に合わせてその時期を検討する必要がある．<br>

Journal of the Japan Society of Coloproctology


Expression of hypoxia-inducible factor-1 alpha (HIF-1alpha) in patients with the gallbladder carcinoma.

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.

International Journal of Clinical Oncology


Ⅰ.消化管 20. 肛門癌

Ⅰ.消化管 20. 肛門癌


肝癌ステージングと予後推定.

肝癌ステージングと予後推定.


S上結腸SM癌に対するS状結腸切除 D2郭清.

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

腹腔鏡下大腸手術の基本手術手技


Predictive factors of peritoneal metastasis in gastric cancer.

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.


脂肪肝グラフトを用いた肝移植における移植後グラフト機能不全の機序解明.

脂肪肝グラフトを用いた肝移植における移植後グラフト機能不全の機序解明.

上原記念生命化学財団研究報告集

上原記念生命化学財団研究報告集


特集/消化器外科データベースの構築とその展開4. 高度技能医制度を包括するデータベース.


全国集計からみた先天性胆道拡張症, 膵・胆管合流異常の胆道癌発生率とその特徴

全国集計からみた先天性胆道拡張症, 膵・胆管合流異常の胆道癌発生率とその特徴


肝移植の画像診断ー生体ドナーの安全とレシピエントの予後向上をめざしてー

肝移植の画像診断ー生体ドナーの安全とレシピエントの予後向上をめざしてー


メタボリックシンドロームと肝細胞癌

メタボリックシンドロームと肝細胞癌


腹腔鏡下肝切除:腹腔鏡下肝切除術における最近の話題 ∼気腹とガス塞栓∼.

腹腔鏡下肝切除:腹腔鏡下肝切除術における最近の話題 ∼気腹とガス塞栓∼.


肝・胆道系症候群(Ⅱ)— その他の肝・胆道系疾患を含めて - 肝臓編(下)第2版 XIV 肝細胞癌以外の肝腫瘍 「原発性肝肉腫(Primary hepatic sarcoma)」


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


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

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


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

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.


Dual hepatic artery reconstruction in living donor liver transplantation using a left hepatic graft with 2 hepatic arterial stumps.

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).


② 意外に難しいスライディング・スケール法による血糖管理 --- 人工膵臓を用いた外科手術周術期血糖管理法


The novel hypoxic cell radiosensitizer, TX-1877 has antitumor activity through suppression of angiogenesis and inhibits liver metastasis on xenograft model of pancreatic cancer.

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.


Geranylgeranylacetone prevents acute liver damage after massive hepatectomy in rats through suppression of a CXC chemokine GRO1 and induction of heat shock proteins.

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.


Dendritic cell-mediated NK cell activation is controlled by Jagged2-Notch interaction.

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.

Proceedings of the National Academy of Sciences of the United States of America


The effect of transgenic expression of TGF-beta1 on transplanted islet graft survival.

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.


Relationship between mucin expression and preoperatie bile juice cytology in biliary tract carcinoma

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.

The Journal of Medical Investigation : JMI


Effect of late evening snack with rice ball on energy metabolism in liver cirrhosis.

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.


Reconstruction of the middle hepatic vein tributaries using the recipient's recanalized umbilical vein in right-lobe living-donor liver transplantation

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.


Prevention of lethal hepatic injury in Long-Evans Cinnamon(LEC) rats by D-galactosamine hydrochloride

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.


肝硬変患者における就寝前夜食療法継続指導の健康関連QOLに対する効果

肝硬変患者における就寝前夜食療法継続指導の健康関連QOLに対する効果


Short-term intensive treatment for donors with hepatic steatosis in living-donor liver transplantation

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.


Effect of intraportal infusion to improve small for size graft injury in living donor adult liver transplantation

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.


Overexpression of a novel superoxide-producing enzyme,NADPH oxidase 1,in adenoma and well differentiated adenocarcinoma of the human colon

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.


Living donor liver transplantation for hepatocellular carcinoma: a special reference to a preoperative des-gamma-carboxy prothrombin value

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.


Rab13 Mediates the Continuous Endocytic Recycling of Occludin to the Cell Surface

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.


Evaluation of Acute Hepatic Failure Treated at the Department of Medicine III, Kyushu University Hospital : Indications for Living-donor Liver Transplantation --- 生体肝移植への適応検討

九州大学病院第三内科における急性肝不全の治療 --- 生体肝移植への適応検討

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.


IL-12 gene therapy is an effective therapeutic strategy for hepatocellular carcinoma in immunosuppressed mice

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.


S100beta protein: The preoperative new clinical indicator of brain damage in patients with fulminant hepatic failure

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.


Involvement of Rho-kinase in cold ischemia-reperfusion injury after liver transplantation in rats

Reperfusion of ischemic tissues is known to cause the generation of reactive oxygen species (ROS) with resultant tissue damage. However, the sources of ROS in reperfused tissues are not fully characterized. We hypothesized that the small GTPase Rho and its target effector Rho-kinase/ROK/ROCK are involved in the oxidative burst in reperfused tissue with resultant reperfusion injury. In an in vivo rat model of liver transplantation using cold ischemia for 12 hr followed by reperfusion, a specific Rho-kinase inhibitor, fasudil (30 mg/kg), was administered orally 1 hr before the transplantation. Fasudil suppressed the ischemia-reperfusion (I/R)-induced generation of ROS after reperfusion (P<0.01) and also suppressed the release of inflammatory cytokines (tumor necrosis factor-alpha, interleukin-1beta) 3 hr after reperfusion, resulting in a significant reduction of I/R-induced hepatocellular injury (P<0.05), necrosis, apoptosis (P<0.01), and neutrophil infiltration (P<0.0001) 12 hr after reperfusion. All animals receiving a graft without fasudil died within 3 days, whereas 40% of those receiving fasudil survived (P<0.001). The present study demonstrates that Rho-kinase-mediated production of ROS and inflammatory cytokines are substantially involved in the pathogenesis of hepatocellular necrosis and apoptosis induced by cold I/R in vivo and that Rho-kinase may be regarded as a novel therapeutic target for the disorder.


Is graft size a major risk factor in living-donor adult liver transplantation?

Graft size is known to be a major risk factor in living donor adult liver transplantation (LDALT). The aim of this study is to reassess whether graft size is a critical factor in LDALT or not. A series of 75 LDALTs excluding auxiliary transplantation and ABO blood-type incompatible transplantation were analyzed. The patients were divided into two groups, according to graft volume (GV) and standard liver volume (SLV): group 1 (small-size group) (GV/SLV: <40%), and group 2 (non-small-size group) (> or =40%). Perioperative clinical data were compared between the two groups, including graft survival and postoperative complications. These parameters were also compared under the conditions of cirrhotic recipients. No difference in graft survival was found between the two groups. No difference was found in incidence of postoperative complications, such as intractable ascites and persistent hyperbilirubinemia. Even in cirrhotic patients with Child-Pugh's class C, there was no difference in graft survival between the two groups. Risk factors related to graft loss were a preoperative urgent status due to chronic liver disease, pre-operative hyperbilirubinemia of over 10 mg/dl, and ABO blood type of not identical but compatible combination between donor and recipient. Graft size is not always considered to be a major risk factor in LDALT, although the number of patients was small in this study. Therefore, a left-lobe graft, even a "small-for-size" graft for adult recipients, remains a feasible option in LDALT.


A simple and accurate formula to estimate left hepatic graft volume in living-donor adult liver transplantation

In the field of living-donor adult liver transplantation, a small-for-size graft often occurs, particularly when using left-lobe grafts. This is because of the limited volumes associated with left-lobe grafts. The accurate preoperative evaluation of graft volumes is crucial to avoid this complication. The aim of this study is to clarify the usefulness of a new formula to estimate the left-lobe graft volume. In 61 left-lobe grafts, a new formula was created with stepwise regression analysis using the following variables: height, weight, the thoracic and abdominal distance from anterior to posterior side (A-P), and distance from left to right side (L-R) of the initial 20 donors. With another 41 donors, the difference between the actual and estimated graft volume using the formula and two- and three-dimensional computed tomography was prospectively evaluated. On the basis of the results of the stepwise regression analysis, a new formula was created as follows: graft volume (ml) = 313.4 + 7.7 x weight (kg)-12.6 x thoracic L-R (cm). The difference between the actual and estimated graft volumes using the formula was significantly better (10.8 +/- 9.5%) than that of the volumetry using two-dimensional computed tomography (16.3 +/- 10.1%) (P < 0.05). In conclusion, the new formula can estimate the actual graft volume more accurately than conventional volumetry with two-dimensional computed tomography. The formula is useful to estimate the volume of left-lobe graft in living-donor adult liver transplantation.


The impact of splenectomy or splenic artery ligation on the outcome of a living donor adult liver transplantation using a left lobe graft

The aim of this study was to clarify the impact of splenectomy or splenic artery ligation on the outcome in living donor adult liver transplantation (LDALT) using a left lobe graft. Forty-eight LDALT cases using a left lobe graft were enrolled in this study. The patients were classified into two groups: Group A (n=40), in which neither a splenectomy nor a splenic artery ligation was performed, and Group B (n=8), in which a splenectomy (n=6) or a splenic artery ligation (n=2) was performed. Indications for splenectomy were as follows: 1) demonstrating a hypersplenism and/or 2) having splenic aneurysms. None of the patients receiving a splenectomy or a splenic artery ligation experienced any septic complication in this series. The graft-recipient weight ratio in group B tended to be smaller than in group A. In group B, all patients were classified into Child's class C or B. The incidence of esophageal varices in group B was significantly higher than in group A. Moreover, the platelet count and the white blood cell count in group B were significantly lower than in group A. No statistical difference was found in postoperative functional cholestasis and intractable ascites. None of the participants in group B experienced both postoperative hyperbilirubinemia and intractable ascites, which were characterized as a small-for-size graft after LDALT. The patient survival rate in group B seems to be better than in group A. In a majority of the cases the portal pressure as well as the portal vein flow after a splenectomy decreased in comparison to that before the splenectomy. Splenectomy or splenic artery ligation is considered to be beneficial for improving the outcome in LDALT using a left lobe graft.


Role of expression of focal adhesion kinase in progression of hepatocellular carcinoma

Although hepatocellular carcinoma (HCC) is the most common cancer of the human liver, the mechanisms that regulate HCC development and progression remain unclear. The aim of this study was to investigate whether focal adhesion kinase (FAK) is involved in the progression of human HCC. Western blot analysis for FAK was performed on three HCC cell lines. We reviewed 64 consecutive patients who had undergone initial liver resection for HCC without preoperative treatment. Immunohistochemistry analysis for FAK was performed on paraffin-embedded tissues. FAK expression was confirmed by Western blot analysis in several clinical samples. We investigated the correlation between FAK expression and clinical outcome. FAK proteins were detected in all HCC cell lines. Hepatocytes in the normal liver and chronic hepatitis with or without cirrhosis were negative for immunohistochemical staining for FAK expression. Cytoplasmic FAK expression was observed in 18 of 64 patients (28.1%), and this positive staining was correlated with gender (P < 0.05), a lower level of serum albumin (P < 0.05), and portal venous invasion (P < 0.01). Positive staining for FAK was associated with significantly poorer survival (P < 0.05). In multivariate analysis, FAK overexpression was an independent factor in determining the prognosis of patients. These data suggest that FAK plays an important role in promoting tumor progression, especially vascular invasion, in HCC. FAK could play an important role in HCC progression and would be a novel target for HCC therapeutics as well as a prognostic marker.


Prognosis factors in node-negative intrahepatic cholangiocaecinoma eith special reference to angiogenesis

The aim of this study was to clarify prognostic factors and recurrence patterns in patients with node-negative intrahepatic cholangiocarcinoma (IHCC). A retrospective study was performed to review prognostic factors and recurrence patterns (1) in 22 patients with node-negative IHCC after curative hepatic resection and (2) in 49 patients who underwent resection and lymph node dissection for IHCC. In addition to determining the clinicopathologic factors, the investigators also performed immunohistochemical examination of microvessel counts using antihuman CD-31 and antibody. The significant poor prognostic factors in node-negative IHCC were the presence of intrahepatic metastasis, portal vein invasion of cancer cells, and high microvessel counts. After multivariate analysis was conducted, the independent poor prognostic factors were the presence of intrahepatic metastases and high microvessel counts. Of 9 patients who had postoperative recurrence of their disease, intrahepatic recurrence was observed in 7 (78 %). The factors linked to poor prognosis in IHCC were tumor angiogenesis and the presence of intrahepatic metastasis. Because intrahepatic recurrence was common, regional and adjuvant chemotherapy to the liver may improve the outcome of patients with these risk factors and node-negative IHCC.


Graft-versus-host disease following living donor liver transplantation

Graft-versus-host disease (GVHD) is the most common and well-known cause of morbidity and mortality following allogeneic bone marrow transplantation. Sporadic cases have been reported after cadaveric donor liver transplantation with usually fatal outcomes, however, the actual incidence and the characteristics of GVHD after living donor liver transplantation (LDLT) remain unknown. We herein report a person who developed fatal GVHD following LDLT and discuss the applicability of an HLA-homozygous donor to an HLA-haploidentical recipient. A 48-year-old male underwent LDLT for unresectable hepatocellular carcinoma with alcoholic liver cirrhosis. The donor was his 20-year-old son whose pretransplant HLA typing was homozygous at all loci. GVHD occurred 35 days after LDLT and was characterized by fever, diarrhea, maculopapular rash, and leukopenia, which led to the development of fatal pneumonia. We identified 4 cases of GVHD after LDLT in Japan and 1 in the United States, all associated with the use of an HLA-homozygous donor. The use of an HLA homozygous donor which results in a complete 1-way donor-recipient HLA match carries an extremely high risk of developing GVHD after LDLT. Therefore, it is possible that LDLT should be ruled out for such donors. A pretransplant work-up of the HLA type in both the donors and recipients is therefore imperative before determining the indications for LDLT.