Various types of bioartificial livers (BALs), which are extracorporeal medical devices incorporat... more Various types of bioartificial livers (BALs), which are extracorporeal medical devices incorporating living hepatocytes in cartridges, have been developed. However, it is difficult to compare metabolic functions among BAL types or to know what proportion of the normal liver functions could be replaced by a BAL, because there is not a well-established method for the quantitative evaluation of BAL functions. In our series of studies, we have proposed methods for performing drug-loading tests and procedures to analyze drug concentration changes for the quantitative evaluation and expression of BAL metabolic functions. In this study, constant infusion tests of lidocaine were performed on a BAL device developed in our laboratory, and lidocaine concentration changes in the perfusion medium were analyzed by using pharmacokinetic equations. The lidocaine clearance value of the BAL was precisely determined by a constant infusion test, demonstrating the usefulness of the constant infusion test for quantitative evaluation of BAL functions.
Lymph node dissection is a crucial procedure for curative resection of gastric cancer [1]. To avo... more Lymph node dissection is a crucial procedure for curative resection of gastric cancer [1]. To avoid portal vein injury during laparoscopic extended lymph node dissection for gastric cancer, taping of the common hepatic artery and subsequent confirmation of the portal vein have been recommended [2, 3]. This taping method, however, makes laparoscopic nodal dissection technically complicated. This study introduces a novel procedure for safe and simple laparoscopic suprapancreatic nodal dissection without taping of the common hepatic artery. The authors' novel, simplified method consists of four steps: (1) dissection along the cranial edge of the pancreas from right to left, (2) dissection along the splenic artery with exposure of the left renal fascia, (3) dissection along the left gastric and the common hepatic arteries, and (4) retraction of the lymph nodes surrounding the common and proper hepatic arteries and their complete dissection from the portal vein. This procedure is reversely directed compared with conventional open gastrectomy (i.e., the nodal dissection is from left to right). For this study, the lymph node stations and groups were defined according to the 13th edition of the Japanese Classification for Gastric Carcinoma. The described procedures were performed for 58 consecutive patients with gastric cancer. The indication for this operation is primary T1/T2 gastric cancer without clinical nodal metastasis. In all cases, safely extended suprapancreatic lymph node dissection was successfully accomplished using the described technique. A total of 43.5 +/- 18 lymph nodes were retrieved, including 14.4 +/- 6.3 second-tier lymph nodes. The overall number of retrieved lymph nodes in this study was similar to that reported previously [4]. Postoperative morbidity occurred at a rate of 22.3%, and the mortality rate was 0%. There was no conversion to open surgery. The mean blood loss was 127 ml (range, 0-490 ml), and the mean operative time was 289 min (range, 104-416 min) in the last 20 consecutive cases. To date, no tumor recurrence has been observed. The median postoperative observation period was 1.4 years (range, 0.4-2.4 years). The described novel procedure would be sufficient and convenient for dissection of the suprapancreatic lymph nodes.
A bioartificial liver (BAL) was prepared by simple inoculation of hepatocytes into the inner spac... more A bioartificial liver (BAL) was prepared by simple inoculation of hepatocytes into the inner space of hollow fibers of a hemodialyzer and it was maintained in a closed circuit for in vitro culture. Morphology of hepatocytes in the hollow fibers was studied in detail using transmission electron microscopy (TEM). The hepatocytes formed three-dimensional, rod-shaped aggregates of 200 microm in diameter throughout the whole dimension of the hollow fibers after 1 day of culture. Approximately five hepatocyte layers existed from the surface to the center of the aggregate. The hepatocytes in the aggregate displayed mostly polygonal shapes and were surrounded by five to six cells. Abundant bile canaliculi were formed between the hepatocytes and were sealed by tight junctions. The distance between the adjacent hepatocytes except the bile canaliculus domain was approximately 20 nm, and interdigitation was observed between some hepatocytes. These observations indicate that the hepatocytes formed functionally associated aggregates, that is, organoids. Although the cells facing the inner surface of the hollow fiber lost their polygonal shape and became flattened during the following several-day culture, no drastic change was observed in the morphology of the hepatocytes located inside the aggregate. After 14 days of culture, the number of living cells decreased and most of these had a deformed nucleus, few numbers of organelles, and intermittent lipid droplets.
Distal advanced gastric cancer (AGC) occasionally causes gastric outlet obstruction (GOO). We dev... more Distal advanced gastric cancer (AGC) occasionally causes gastric outlet obstruction (GOO). We developed a laparoscopic stomach-partitioning gastrojejunostomy (LSPGJ) to restore the ability of food intake. This was a retrospective study performed at a single institution. Of consecutive 78 patients with GOO caused by AGC between 2006 and 2012, 43 patients who underwent LSPGJ were enrolled. The procedure was performed in an antiperistaltic Billroth II fashion, and the afferent loop was elevated and fixed along the staple line of the proximal partitioned stomach. Then, patients for whom R0 resection was planned received chemotherapy prior to laparoscopic gastrectomy. The primary end point was food intake at the time of discharge, which was evaluated using the GOO scoring system (GOOSS). Short- and long-term outcomes were assessed as secondary end points. Overall survival was estimated and compared between the groups who received neoadjuvant chemotherapy followed by surgery (NAC group), definitive chemotherapy followed by curative resection (Conversion group), and best supportive care (BSC group). The median operative time was 92 min, blood loss did not exceed 30 g in any patient, and postoperative complications (Clavien-Dindo grade ≥2) were only seen in four patients (9.3 %). The median time to food intake was 3 days, and GOOSS scores were significantly improved in 41 patients (95.3 %). Chemotherapy was administered to 38 patients (88.4 %), of whom 11 later underwent radical resection, and 4 of 11 patients underwent conversion surgery following definitive chemotherapy. Median survival times were significantly superior in the NAC (n = 7; 46.8 months) and Conversion (n = 4; 35.9 months) groups than in the BSC group (n = 26; 12.2 months); however, the difference was not significant between the Conversion and NAC groups. LSPGJ is a feasible and safe minimally invasive induction surgery for patients with GOO from surgical and oncological perspectives.
Background: The aim of this study was to analyze the oncological aspects of gastric cancer follow... more Background: The aim of this study was to analyze the oncological aspects of gastric cancer following laparoscopic gastrectomy with D2 lymphadenectomy (LG-D2). Methods: We retrospectively evaluated the long-term outcomes of 354 patients who underwent LG-D2 for primary gastric cancer. Recurrence patterns and predictors of peritoneal metastasis were analyzed. Results: Median follow-up time was 43.8 months. Five-year overall survival rates for yp/pStages I, II, and III gastric cancer were 93.7, 78.5, and 42.2 %, respectively. Recurrence was observed in 86 patients. Peritoneal metastasis was the most frequent recurrence pattern (n = 51), followed by hepatic metastasis (n = 17). Lymphatic recurrence at distant sites was observed in 10 patients. No locoregional lymph node metastasis or local recurrence was seen. Nine of 51 cases of peritoneal recurrence were detected by probe laparoscopy. Peritoneal recurrence rates were significantly higher in yp/pT4 and yp/pN3 diseases compared with yp/pT ≤ 3 and yp/pN ≤ 2 diseases. Multivariate analyses demonstrated that yp/pT4, yp/pN3, tumor size ≥70 mm, vascular invasion, and undifferentiated tumors were predictors of peritoneal recurrence following LG-D2. Conclusion: Long-term outcomes of gastric cancer following LG-D2, including recurrence patterns and predictors of peritoneal metastasis, were comparable to those following open D2 gastrectomy. LG-D2 showed good local control. Probe laparoscopy after LG may be effective in detecting peritoneal recurrence, which is not determined with less invasive examinations, including a CT scan. Future large-scale prospective studies are desirable to evaluate not only surgical but also oncological benefits and safety of LG-D2 for advanced gastric cancer.
Through a genome-wide cDNA microarray, we identified that the paternally expressed gene 10 (PEG10... more Through a genome-wide cDNA microarray, we identified that the paternally expressed gene 10 (PEG10) was highly expressed in a great majority of hepatocellular carcinomas, although its expression was absent in normal liver cells. Exogenous expression of PEG10 conferred oncogenic activity and transfection of hepatoma cells with antisense S-oligonucleotides suppressing PEG10 resulted in their growth inhibition. Additional experiments revealed that PEG10 protein associated with SIAH1, a mediator of apoptosis, and that overexpression of PEG10 decreased the cell death mediated by SIAH1. These findings suggested that development of drug(s) inhibiting PEG10 activity could be a novel approach for the treatment of hepatocellular carcinomas.
To shed light on mechanisms that underlie development and/or progression of intestinal-type gastr... more To shed light on mechanisms that underlie development and/or progression of intestinal-type gastric cancer, we compared expression profiles of cancer cells obtained by laser-capture microdissection of 20 intestinaltype gastric tumors with expression of genes in corresponding noncancerous mucosae, by a cDNA microarray consisting of 23,040 genes. We identified 61 genes that were commonly up-regulated and 63 that were commonly down-regulated in the cancer tissues. Altered expression of 12 of those genes was associated with lymph node metastasis. A "predictive score," based on expression profiles of five of the genes that were able to distinguish tumors with metastasis from node-negative tumors in our panel, correctly diagnosed the lymph node status of nine additional gastric cancers. This genome-wide information contributes to an improved understanding of molecular changes during the development of intestinaltype gastric cancers. It may help clinicians predict metastasis to lymph nodes and assist researchers in identifying novel therapeutic targets for this type of cancer.
Background. The influence of xenogeneic humoral immunoreaction on hepatic nonparenchymal cells (N... more Background. The influence of xenogeneic humoral immunoreaction on hepatic nonparenchymal cells (NPCs) was evaluated ex situ in xenoperfused rat livers. Methods. Isolated rat livers were perfused via the portal vein (PV) for 240 min. The perfusates consisted of fresh rat blood (group 1), fresh human blood (group 2), and fresh human blood containing 5 g/mL soluble complement receptor type 1 (Group 3). Results. Deposition of human IgM and C 5b-9 complement was observed in group 2, although only human IgM deposition was detected in group 3. Portal vein pressure in group 2 rose drastically during the first 10 min. Creatine kinase BB component gradually increased in all groups, followed by an elevation in alanine aminotransferase and both parameters were significantly higher in group 2 than in groups 1 and 3. In group 2, platelet thrombi in the peripheral PVs and periportal hemorrhage were observed after 10 min, and massive necrosis around the central veins after 240 min; these changes were not observed in group 1 or 3. Production of tumor necrosis factor ␣ and ␣ interferon and expression of intercellular adhesion molecule 1 (ICAM-1) were lower in group 2 than in groups 1 and 3. In group 2, there were negative areas for ICAM-1 and tumor necrosis factor ␣ staining around the central veins after 240 min, which were consistent with necrotic areas. Conclusions. In xenoperfused rat livers, humoral mediators initially caused the disturbance of microcirculation, which would induce long ischemia in the pericentral areas, resulting in massive necrosis. NPC necrosis may be responsible for less production of cytokines and adhesion molecules in the xenoperfused livers.
Despite the discovery of multiple TAAs, only a limited number is available for clinical applicati... more Despite the discovery of multiple TAAs, only a limited number is available for clinical application, particularly against epithelial malignancies. In this study we searched for novel TAAs using expression profiles of gastric cancer examined with cDNA microarray, and identified the SCRN1 gene as a candidate. SCRN1 was confirmed to be expressed in five out of seven gastric cancers with semiquantitative RT-PCR. With Northern blot analysis, it was detected abundantly in the testis and ovary, but it was barely detectable in 14 other normal human adult organs. Colony formation assay revealed that its augmented expression is associated with promoted cell growth. As these expression profiles and functional features of SCRN1 appeared to be compatible with the characteristics of the hypothesized ideal TAAs, we examined whether SCRN1 protein contains antigenic epitope peptides restricted to HLA-A*0201. We synthesized the candidate peptides derived from SCRN1, and tried to induce CTLs with each peptide. The CTL clones were successfully induced with a peptide SCRN1-196 (KMDAEHPEL), and they lyzed not only the peptide-pulsed targets but also the tumor cells expressing both SCRN1 and HLA-A*0201 endogenously. These results strongly suggest that SCRN1-196 is an epitope peptide restricted to HLA-A*0201. Furthermore, we synthesized an anchor-modified peptide SCRN1-9 V (KMDAEHPEV), in which leucine at position 9 was substituted for valine to increase the binding affinity to the HLA-A*0201 molecules. The CTL clones induced by SCRN1-9 V also recognized tumor cells expressing its natural SCRN1 protein endogenously. These results strongly suggest that SCRN1 is a novel TAA and these peptides, both native and modified, may be applicable for cancer vaccines to treat gastric cancer.
To shed light on mechanisms that underlie development and/or progression of intestinal-type gastr... more To shed light on mechanisms that underlie development and/or progression of intestinal-type gastric cancer, we compared expression profiles of cancer cells obtained by laser-capture microdissection of 20 intestinaltype gastric tumors with expression of genes in corresponding noncancerous mucosae, by a cDNA microarray consisting of 23,040 genes. We identified 61 genes that were commonly up-regulated and 63 that were commonly down-regulated in the cancer tissues. Altered expression of 12 of those genes was associated with lymph node metastasis. A "predictive score," based on expression profiles of five of the genes that were able to distinguish tumors with metastasis from node-negative tumors in our panel, correctly diagnosed the lymph node status of nine additional gastric cancers. This genome-wide information contributes to an improved understanding of molecular changes during the development of intestinaltype gastric cancers. It may help clinicians predict metastasis to lymph nodes and assist researchers in identifying novel therapeutic targets for this type of cancer.
To elucidate the molecular mechanism of colorectal carcinogenesis, we have been attempting to iso... more To elucidate the molecular mechanism of colorectal carcinogenesis, we have been attempting to isolate genes involved in the -catenin/T-cell factor pathway. In the experiments reported here, analysis by cDNA microarray indicated that AF17, a fusion partner of the MLL gene in acute leukemias with t(11;17)(q23;q21), was transactivated according to accumulation of -catenin. Expression of AF17 was significantly enhanced in 8 of the 12 colorectal cancer tissues examined. Introduction of a plasmid designed to express AF17 stimulated growth of NIH3T3 cells, and fluorescence-activated cell sorter analysis indicated that the AF17 regulation of cell-cycle progression was occurring mainly at the G 2-M transition. Our results suggest that the AF17 gene product is likely to be involved in the -catenin-T-cell factor/lymphoid enhancer factor signaling pathway and to function as a growth-promoting, oncogenic protein. These findings should aid development of new strategies for diagnosis, treatment, and prevention of colon cancers and acute leukemias by clarifying the pathogenesis of these conditions.
-Catenin plays significant roles in cell-to-cell adhesion and the Wnt/Wg signal transduction pat... more -Catenin plays significant roles in cell-to-cell adhesion and the Wnt/Wg signal transduction pathway. Accumulation of this protein in the cytoplasm and nucleus as a result of mutations of the adenomatous polyposis coli tumor suppressor gene or of the -catenin gene itself is often seen in a wide variety of tumors including carcinomas of the colon, liver, uterus, and brain. Interaction of accumulated -catenin with Tcf/Lef transcription factors is known to deregulate expression of some downstream genes, but the precise mechanisms whereby -catenin contributes to carcinogenesis remain to be disclosed. Here we report isolation of a novel murine gene, Drctnnb1a (downregulated by Ctnnb1, a), the expression of which was experimentally down-regulated in response to the activated form of -catenin. To investigate a possible role of DRCTNNB1A in cancers, we also isolated the human homologue, DRCTNNB1A, the deduced product of which was 91% identical to the murine protein. The transcript was expressed in all human tissues examined, and we assigned the genomic location of DRCTNNB1A to chromosomal band 7p15.3 by in situ hybridization. Expression of DRCTNNB1A in SW480 colon cancer cells was significantly increased in response to reduction of intracellular -catenin by adenovirus-mediated transfer of the -cateninbinding domain of the adenomatous polyposis coli gene into the cells. Furthermore, we documented reduced expression of DRCTNNB1A in 12 of 15 primary colorectal cancers examined, compared with corresponding adjacent noncancerous mucosae. Our results implied that DRCTNNB1A is one of the genes involved in the -catenin-Tcf/Lef signaling pathway, and that reduced expression of DRCTNNB1A may have some role in colorectal carcinogenesis.
Gan to Kagaku Ryoho Cancer Chemotherapy, Jul 1, 2012
In Japan, the usefulness of robot-assisted surgery using da Vinci surgical system(DVSS)has rapidl... more In Japan, the usefulness of robot-assisted surgery using da Vinci surgical system(DVSS)has rapidly become widely acknowledged. At Fujita Health University, DVSS was introduced in 2009. Thus far, 347 patients were treated by DVSS at our institute, including 204 gastroenterological operations. In our department, robot-assisted gastrectomy(RAG, n=111)and robot-assisted esophagectomy(REG, n=26)have been technically standardized. Recently, we reported that both RAG and REG are minimally invasive. Moreover, we showed that the incidence of recurrent nerve palsy by lymphadenectomy was significantly reduced by REG, compared with conventional thoracoscopic esophagectomy. Although robot-assisted surgery is a highly expensive treatment, these results prompt the need for further evaluation of the effectiveness of robot-assisted surgery in the gastroenterological field. Development of a more accurate and less invasive robotic surgery system would contribute to a better quality of life patients with gastroenterological malignancies.
We investigated the influence of humoral injury during xenoperfusion of porcine livers by human b... more We investigated the influence of humoral injury during xenoperfusion of porcine livers by human blood. The porcine livers were perfused under physiological conditions for 9 hr. The perfusates consisted of porcine whole blood in group 1, human whole blood in group 2, and human whole blood with soluble complement receptor type 1 (300 microg/ml) in group 3. Liver enzyme release and serum hemoglobin in group 2 increased significantly after 3 hr of xenoperfusion, compared with those in group 1 and group 3 (P<0.05). Severe histological damage with minimal cellular infiltration was observed in group 2 after 6 hr of xenoperfusion, but was present only at trace levels in group 1 and group 3. In group 2, von Willebrand factor, a possible target of natural antibodies, was induced on sinusoidal endothelial cells after 3 hr of xenoperfusion, correlating with diffuse deposition of human IgM and membrane attack complex. In group 3, von Willebrand factor, human IgM, and membrane attack complex staining in the intralobular region were present at trace levels. In group 3, the indocyanine green removal capacity, representing hepatocyte function, was significantly higher than in group 2 (P<0.05). Based on these results, we suggest that humoral injury is a major cause of liver damage during liver xenoperfusion. The pattern of humoral injury in xenoperfused livers may be attributed to anatomical features of the liver and unique responses of sinusoidal endothelial cells to xenoperfusion.
To disclose detailed genetic mechanisms in hepatocellular carcinoma (HCC) with a view toward deve... more To disclose detailed genetic mechanisms in hepatocellular carcinoma (HCC) with a view toward development of novel therapeutic targets, we analyzed expression profiles of 20 primary HCCs and their corresponding noncancerous tissues by means of cDNA microarrays consisting of 23,040 genes. Up-regulation of mitosis-promoting genes was observed in the majority of the tumors examined. Some genes showed expression patterns in hepatitis B virus-positive HCCs that were different from those in hepatitis C virus-positive HCCs; most of them encoded enzymes that metabolize carcinogens and/or anticancer agents. Furthermore, we identified a number of genes associated with malignant histological type or invasive phenotype. Accumulation of such data will make it possible to define the nature of individual tumors, to provide clues for identifying new therapeutic targets, and ultimately to optimize treatment of each patient.
Various types of bioartificial livers (BALs), which are extracorporeal medical devices incorporat... more Various types of bioartificial livers (BALs), which are extracorporeal medical devices incorporating living hepatocytes in cartridges, have been developed. However, it is difficult to compare metabolic functions among BAL types or to know what proportion of the normal liver functions could be replaced by a BAL, because there is not a well-established method for the quantitative evaluation of BAL functions. In our series of studies, we have proposed methods for performing drug-loading tests and procedures to analyze drug concentration changes for the quantitative evaluation and expression of BAL metabolic functions. In this study, constant infusion tests of lidocaine were performed on a BAL device developed in our laboratory, and lidocaine concentration changes in the perfusion medium were analyzed by using pharmacokinetic equations. The lidocaine clearance value of the BAL was precisely determined by a constant infusion test, demonstrating the usefulness of the constant infusion test for quantitative evaluation of BAL functions.
Lymph node dissection is a crucial procedure for curative resection of gastric cancer [1]. To avo... more Lymph node dissection is a crucial procedure for curative resection of gastric cancer [1]. To avoid portal vein injury during laparoscopic extended lymph node dissection for gastric cancer, taping of the common hepatic artery and subsequent confirmation of the portal vein have been recommended [2, 3]. This taping method, however, makes laparoscopic nodal dissection technically complicated. This study introduces a novel procedure for safe and simple laparoscopic suprapancreatic nodal dissection without taping of the common hepatic artery. The authors' novel, simplified method consists of four steps: (1) dissection along the cranial edge of the pancreas from right to left, (2) dissection along the splenic artery with exposure of the left renal fascia, (3) dissection along the left gastric and the common hepatic arteries, and (4) retraction of the lymph nodes surrounding the common and proper hepatic arteries and their complete dissection from the portal vein. This procedure is reversely directed compared with conventional open gastrectomy (i.e., the nodal dissection is from left to right). For this study, the lymph node stations and groups were defined according to the 13th edition of the Japanese Classification for Gastric Carcinoma. The described procedures were performed for 58 consecutive patients with gastric cancer. The indication for this operation is primary T1/T2 gastric cancer without clinical nodal metastasis. In all cases, safely extended suprapancreatic lymph node dissection was successfully accomplished using the described technique. A total of 43.5 +/- 18 lymph nodes were retrieved, including 14.4 +/- 6.3 second-tier lymph nodes. The overall number of retrieved lymph nodes in this study was similar to that reported previously [4]. Postoperative morbidity occurred at a rate of 22.3%, and the mortality rate was 0%. There was no conversion to open surgery. The mean blood loss was 127 ml (range, 0-490 ml), and the mean operative time was 289 min (range, 104-416 min) in the last 20 consecutive cases. To date, no tumor recurrence has been observed. The median postoperative observation period was 1.4 years (range, 0.4-2.4 years). The described novel procedure would be sufficient and convenient for dissection of the suprapancreatic lymph nodes.
A bioartificial liver (BAL) was prepared by simple inoculation of hepatocytes into the inner spac... more A bioartificial liver (BAL) was prepared by simple inoculation of hepatocytes into the inner space of hollow fibers of a hemodialyzer and it was maintained in a closed circuit for in vitro culture. Morphology of hepatocytes in the hollow fibers was studied in detail using transmission electron microscopy (TEM). The hepatocytes formed three-dimensional, rod-shaped aggregates of 200 microm in diameter throughout the whole dimension of the hollow fibers after 1 day of culture. Approximately five hepatocyte layers existed from the surface to the center of the aggregate. The hepatocytes in the aggregate displayed mostly polygonal shapes and were surrounded by five to six cells. Abundant bile canaliculi were formed between the hepatocytes and were sealed by tight junctions. The distance between the adjacent hepatocytes except the bile canaliculus domain was approximately 20 nm, and interdigitation was observed between some hepatocytes. These observations indicate that the hepatocytes formed functionally associated aggregates, that is, organoids. Although the cells facing the inner surface of the hollow fiber lost their polygonal shape and became flattened during the following several-day culture, no drastic change was observed in the morphology of the hepatocytes located inside the aggregate. After 14 days of culture, the number of living cells decreased and most of these had a deformed nucleus, few numbers of organelles, and intermittent lipid droplets.
Distal advanced gastric cancer (AGC) occasionally causes gastric outlet obstruction (GOO). We dev... more Distal advanced gastric cancer (AGC) occasionally causes gastric outlet obstruction (GOO). We developed a laparoscopic stomach-partitioning gastrojejunostomy (LSPGJ) to restore the ability of food intake. This was a retrospective study performed at a single institution. Of consecutive 78 patients with GOO caused by AGC between 2006 and 2012, 43 patients who underwent LSPGJ were enrolled. The procedure was performed in an antiperistaltic Billroth II fashion, and the afferent loop was elevated and fixed along the staple line of the proximal partitioned stomach. Then, patients for whom R0 resection was planned received chemotherapy prior to laparoscopic gastrectomy. The primary end point was food intake at the time of discharge, which was evaluated using the GOO scoring system (GOOSS). Short- and long-term outcomes were assessed as secondary end points. Overall survival was estimated and compared between the groups who received neoadjuvant chemotherapy followed by surgery (NAC group), definitive chemotherapy followed by curative resection (Conversion group), and best supportive care (BSC group). The median operative time was 92 min, blood loss did not exceed 30 g in any patient, and postoperative complications (Clavien-Dindo grade ≥2) were only seen in four patients (9.3 %). The median time to food intake was 3 days, and GOOSS scores were significantly improved in 41 patients (95.3 %). Chemotherapy was administered to 38 patients (88.4 %), of whom 11 later underwent radical resection, and 4 of 11 patients underwent conversion surgery following definitive chemotherapy. Median survival times were significantly superior in the NAC (n = 7; 46.8 months) and Conversion (n = 4; 35.9 months) groups than in the BSC group (n = 26; 12.2 months); however, the difference was not significant between the Conversion and NAC groups. LSPGJ is a feasible and safe minimally invasive induction surgery for patients with GOO from surgical and oncological perspectives.
Background: The aim of this study was to analyze the oncological aspects of gastric cancer follow... more Background: The aim of this study was to analyze the oncological aspects of gastric cancer following laparoscopic gastrectomy with D2 lymphadenectomy (LG-D2). Methods: We retrospectively evaluated the long-term outcomes of 354 patients who underwent LG-D2 for primary gastric cancer. Recurrence patterns and predictors of peritoneal metastasis were analyzed. Results: Median follow-up time was 43.8 months. Five-year overall survival rates for yp/pStages I, II, and III gastric cancer were 93.7, 78.5, and 42.2 %, respectively. Recurrence was observed in 86 patients. Peritoneal metastasis was the most frequent recurrence pattern (n = 51), followed by hepatic metastasis (n = 17). Lymphatic recurrence at distant sites was observed in 10 patients. No locoregional lymph node metastasis or local recurrence was seen. Nine of 51 cases of peritoneal recurrence were detected by probe laparoscopy. Peritoneal recurrence rates were significantly higher in yp/pT4 and yp/pN3 diseases compared with yp/pT ≤ 3 and yp/pN ≤ 2 diseases. Multivariate analyses demonstrated that yp/pT4, yp/pN3, tumor size ≥70 mm, vascular invasion, and undifferentiated tumors were predictors of peritoneal recurrence following LG-D2. Conclusion: Long-term outcomes of gastric cancer following LG-D2, including recurrence patterns and predictors of peritoneal metastasis, were comparable to those following open D2 gastrectomy. LG-D2 showed good local control. Probe laparoscopy after LG may be effective in detecting peritoneal recurrence, which is not determined with less invasive examinations, including a CT scan. Future large-scale prospective studies are desirable to evaluate not only surgical but also oncological benefits and safety of LG-D2 for advanced gastric cancer.
Through a genome-wide cDNA microarray, we identified that the paternally expressed gene 10 (PEG10... more Through a genome-wide cDNA microarray, we identified that the paternally expressed gene 10 (PEG10) was highly expressed in a great majority of hepatocellular carcinomas, although its expression was absent in normal liver cells. Exogenous expression of PEG10 conferred oncogenic activity and transfection of hepatoma cells with antisense S-oligonucleotides suppressing PEG10 resulted in their growth inhibition. Additional experiments revealed that PEG10 protein associated with SIAH1, a mediator of apoptosis, and that overexpression of PEG10 decreased the cell death mediated by SIAH1. These findings suggested that development of drug(s) inhibiting PEG10 activity could be a novel approach for the treatment of hepatocellular carcinomas.
To shed light on mechanisms that underlie development and/or progression of intestinal-type gastr... more To shed light on mechanisms that underlie development and/or progression of intestinal-type gastric cancer, we compared expression profiles of cancer cells obtained by laser-capture microdissection of 20 intestinaltype gastric tumors with expression of genes in corresponding noncancerous mucosae, by a cDNA microarray consisting of 23,040 genes. We identified 61 genes that were commonly up-regulated and 63 that were commonly down-regulated in the cancer tissues. Altered expression of 12 of those genes was associated with lymph node metastasis. A "predictive score," based on expression profiles of five of the genes that were able to distinguish tumors with metastasis from node-negative tumors in our panel, correctly diagnosed the lymph node status of nine additional gastric cancers. This genome-wide information contributes to an improved understanding of molecular changes during the development of intestinaltype gastric cancers. It may help clinicians predict metastasis to lymph nodes and assist researchers in identifying novel therapeutic targets for this type of cancer.
Background. The influence of xenogeneic humoral immunoreaction on hepatic nonparenchymal cells (N... more Background. The influence of xenogeneic humoral immunoreaction on hepatic nonparenchymal cells (NPCs) was evaluated ex situ in xenoperfused rat livers. Methods. Isolated rat livers were perfused via the portal vein (PV) for 240 min. The perfusates consisted of fresh rat blood (group 1), fresh human blood (group 2), and fresh human blood containing 5 g/mL soluble complement receptor type 1 (Group 3). Results. Deposition of human IgM and C 5b-9 complement was observed in group 2, although only human IgM deposition was detected in group 3. Portal vein pressure in group 2 rose drastically during the first 10 min. Creatine kinase BB component gradually increased in all groups, followed by an elevation in alanine aminotransferase and both parameters were significantly higher in group 2 than in groups 1 and 3. In group 2, platelet thrombi in the peripheral PVs and periportal hemorrhage were observed after 10 min, and massive necrosis around the central veins after 240 min; these changes were not observed in group 1 or 3. Production of tumor necrosis factor ␣ and ␣ interferon and expression of intercellular adhesion molecule 1 (ICAM-1) were lower in group 2 than in groups 1 and 3. In group 2, there were negative areas for ICAM-1 and tumor necrosis factor ␣ staining around the central veins after 240 min, which were consistent with necrotic areas. Conclusions. In xenoperfused rat livers, humoral mediators initially caused the disturbance of microcirculation, which would induce long ischemia in the pericentral areas, resulting in massive necrosis. NPC necrosis may be responsible for less production of cytokines and adhesion molecules in the xenoperfused livers.
Despite the discovery of multiple TAAs, only a limited number is available for clinical applicati... more Despite the discovery of multiple TAAs, only a limited number is available for clinical application, particularly against epithelial malignancies. In this study we searched for novel TAAs using expression profiles of gastric cancer examined with cDNA microarray, and identified the SCRN1 gene as a candidate. SCRN1 was confirmed to be expressed in five out of seven gastric cancers with semiquantitative RT-PCR. With Northern blot analysis, it was detected abundantly in the testis and ovary, but it was barely detectable in 14 other normal human adult organs. Colony formation assay revealed that its augmented expression is associated with promoted cell growth. As these expression profiles and functional features of SCRN1 appeared to be compatible with the characteristics of the hypothesized ideal TAAs, we examined whether SCRN1 protein contains antigenic epitope peptides restricted to HLA-A*0201. We synthesized the candidate peptides derived from SCRN1, and tried to induce CTLs with each peptide. The CTL clones were successfully induced with a peptide SCRN1-196 (KMDAEHPEL), and they lyzed not only the peptide-pulsed targets but also the tumor cells expressing both SCRN1 and HLA-A*0201 endogenously. These results strongly suggest that SCRN1-196 is an epitope peptide restricted to HLA-A*0201. Furthermore, we synthesized an anchor-modified peptide SCRN1-9 V (KMDAEHPEV), in which leucine at position 9 was substituted for valine to increase the binding affinity to the HLA-A*0201 molecules. The CTL clones induced by SCRN1-9 V also recognized tumor cells expressing its natural SCRN1 protein endogenously. These results strongly suggest that SCRN1 is a novel TAA and these peptides, both native and modified, may be applicable for cancer vaccines to treat gastric cancer.
To shed light on mechanisms that underlie development and/or progression of intestinal-type gastr... more To shed light on mechanisms that underlie development and/or progression of intestinal-type gastric cancer, we compared expression profiles of cancer cells obtained by laser-capture microdissection of 20 intestinaltype gastric tumors with expression of genes in corresponding noncancerous mucosae, by a cDNA microarray consisting of 23,040 genes. We identified 61 genes that were commonly up-regulated and 63 that were commonly down-regulated in the cancer tissues. Altered expression of 12 of those genes was associated with lymph node metastasis. A "predictive score," based on expression profiles of five of the genes that were able to distinguish tumors with metastasis from node-negative tumors in our panel, correctly diagnosed the lymph node status of nine additional gastric cancers. This genome-wide information contributes to an improved understanding of molecular changes during the development of intestinaltype gastric cancers. It may help clinicians predict metastasis to lymph nodes and assist researchers in identifying novel therapeutic targets for this type of cancer.
To elucidate the molecular mechanism of colorectal carcinogenesis, we have been attempting to iso... more To elucidate the molecular mechanism of colorectal carcinogenesis, we have been attempting to isolate genes involved in the -catenin/T-cell factor pathway. In the experiments reported here, analysis by cDNA microarray indicated that AF17, a fusion partner of the MLL gene in acute leukemias with t(11;17)(q23;q21), was transactivated according to accumulation of -catenin. Expression of AF17 was significantly enhanced in 8 of the 12 colorectal cancer tissues examined. Introduction of a plasmid designed to express AF17 stimulated growth of NIH3T3 cells, and fluorescence-activated cell sorter analysis indicated that the AF17 regulation of cell-cycle progression was occurring mainly at the G 2-M transition. Our results suggest that the AF17 gene product is likely to be involved in the -catenin-T-cell factor/lymphoid enhancer factor signaling pathway and to function as a growth-promoting, oncogenic protein. These findings should aid development of new strategies for diagnosis, treatment, and prevention of colon cancers and acute leukemias by clarifying the pathogenesis of these conditions.
-Catenin plays significant roles in cell-to-cell adhesion and the Wnt/Wg signal transduction pat... more -Catenin plays significant roles in cell-to-cell adhesion and the Wnt/Wg signal transduction pathway. Accumulation of this protein in the cytoplasm and nucleus as a result of mutations of the adenomatous polyposis coli tumor suppressor gene or of the -catenin gene itself is often seen in a wide variety of tumors including carcinomas of the colon, liver, uterus, and brain. Interaction of accumulated -catenin with Tcf/Lef transcription factors is known to deregulate expression of some downstream genes, but the precise mechanisms whereby -catenin contributes to carcinogenesis remain to be disclosed. Here we report isolation of a novel murine gene, Drctnnb1a (downregulated by Ctnnb1, a), the expression of which was experimentally down-regulated in response to the activated form of -catenin. To investigate a possible role of DRCTNNB1A in cancers, we also isolated the human homologue, DRCTNNB1A, the deduced product of which was 91% identical to the murine protein. The transcript was expressed in all human tissues examined, and we assigned the genomic location of DRCTNNB1A to chromosomal band 7p15.3 by in situ hybridization. Expression of DRCTNNB1A in SW480 colon cancer cells was significantly increased in response to reduction of intracellular -catenin by adenovirus-mediated transfer of the -cateninbinding domain of the adenomatous polyposis coli gene into the cells. Furthermore, we documented reduced expression of DRCTNNB1A in 12 of 15 primary colorectal cancers examined, compared with corresponding adjacent noncancerous mucosae. Our results implied that DRCTNNB1A is one of the genes involved in the -catenin-Tcf/Lef signaling pathway, and that reduced expression of DRCTNNB1A may have some role in colorectal carcinogenesis.
Gan to Kagaku Ryoho Cancer Chemotherapy, Jul 1, 2012
In Japan, the usefulness of robot-assisted surgery using da Vinci surgical system(DVSS)has rapidl... more In Japan, the usefulness of robot-assisted surgery using da Vinci surgical system(DVSS)has rapidly become widely acknowledged. At Fujita Health University, DVSS was introduced in 2009. Thus far, 347 patients were treated by DVSS at our institute, including 204 gastroenterological operations. In our department, robot-assisted gastrectomy(RAG, n=111)and robot-assisted esophagectomy(REG, n=26)have been technically standardized. Recently, we reported that both RAG and REG are minimally invasive. Moreover, we showed that the incidence of recurrent nerve palsy by lymphadenectomy was significantly reduced by REG, compared with conventional thoracoscopic esophagectomy. Although robot-assisted surgery is a highly expensive treatment, these results prompt the need for further evaluation of the effectiveness of robot-assisted surgery in the gastroenterological field. Development of a more accurate and less invasive robotic surgery system would contribute to a better quality of life patients with gastroenterological malignancies.
We investigated the influence of humoral injury during xenoperfusion of porcine livers by human b... more We investigated the influence of humoral injury during xenoperfusion of porcine livers by human blood. The porcine livers were perfused under physiological conditions for 9 hr. The perfusates consisted of porcine whole blood in group 1, human whole blood in group 2, and human whole blood with soluble complement receptor type 1 (300 microg/ml) in group 3. Liver enzyme release and serum hemoglobin in group 2 increased significantly after 3 hr of xenoperfusion, compared with those in group 1 and group 3 (P<0.05). Severe histological damage with minimal cellular infiltration was observed in group 2 after 6 hr of xenoperfusion, but was present only at trace levels in group 1 and group 3. In group 2, von Willebrand factor, a possible target of natural antibodies, was induced on sinusoidal endothelial cells after 3 hr of xenoperfusion, correlating with diffuse deposition of human IgM and membrane attack complex. In group 3, von Willebrand factor, human IgM, and membrane attack complex staining in the intralobular region were present at trace levels. In group 3, the indocyanine green removal capacity, representing hepatocyte function, was significantly higher than in group 2 (P<0.05). Based on these results, we suggest that humoral injury is a major cause of liver damage during liver xenoperfusion. The pattern of humoral injury in xenoperfused livers may be attributed to anatomical features of the liver and unique responses of sinusoidal endothelial cells to xenoperfusion.
To disclose detailed genetic mechanisms in hepatocellular carcinoma (HCC) with a view toward deve... more To disclose detailed genetic mechanisms in hepatocellular carcinoma (HCC) with a view toward development of novel therapeutic targets, we analyzed expression profiles of 20 primary HCCs and their corresponding noncancerous tissues by means of cDNA microarrays consisting of 23,040 genes. Up-regulation of mitosis-promoting genes was observed in the majority of the tumors examined. Some genes showed expression patterns in hepatitis B virus-positive HCCs that were different from those in hepatitis C virus-positive HCCs; most of them encoded enzymes that metabolize carcinogens and/or anticancer agents. Furthermore, we identified a number of genes associated with malignant histological type or invasive phenotype. Accumulation of such data will make it possible to define the nature of individual tumors, to provide clues for identifying new therapeutic targets, and ultimately to optimize treatment of each patient.
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Papers by Seiji Satoh