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Background: E (epithelial)-cadherin, the cell adhesion molecule also considered a potential invasion/metastasis suppressor, is mutationally inactivated in nearly half of all undifferentiated-scattered (diffuse-type) gastric carcinomas. In addition, silencing of E-cadherin by CpG methylation within its promoter region has been reported in several gastric carcinoma cell lines. We investigated the methylation status of the E-cadherin promoter region in 53 primary human gastric carcinomas.Methods: Hypermethylation of the E-cadherin promoter was determined by utilizing methylation-specific polymerase chain reaction (PCR)-single-strand conformation polymorphism (MSP-SSCP) analysis followed by direct sequencing of PCR products. Expression of E-cadherin was studied by western blot analysis. All statistical tests were two-sided.Results: Hypermethylation of the E-cadherin promoter was evident in 27 (51%) of 53 primary gastric carcinomas examined by MSP-SSCP. It occurred more frequently in carcinomas of the undifferentiated-scattered type (in 15 [83%] of 18) than in other histologic subtypes (in 12 [34%] of 35) (P =.0011, Fisher's exact test), and it was present at similar rates in early (in six [60%] of 10) versus advanced (in 21 [49%] of 43) carcinomas (P =.73, Fisher's exact test). Methylation occurring at all cytosine-guanosine sequences (CpGs) near the transcriptional start site was confirmed in six of six tumors examined by bisulfite-DNA sequencing, including two early gastric carcinomas. In addition, loss or diminished expression of E-cadherin was confirmed by western blotting in four of the six tumor tissues demonstrating hypermethylation.Conclusions: The E-cadherin promoter frequently undergoes hypermethylation in human gastric cancers, particularly those of the undifferentiated-scattered histologic subtype. E-cadherin promoter hypermethylation is associated with decreased expression and may occur early in gastric carcinogenesis. [ABSTRACT FROM AUTHOR]

Abstract Background The use of standard chemotherapy regimens has changed the application of chemosensitivity tests from all chemotherapy-eligible patients to those who have failed standard chemotherapy, which includes patients with highly advanced, relapsed, or chemoresistant tumors. Methods We evaluated a total of 43 advanced primary and relapsed gastric cancers for chemosensitivity based on drug dose response curves to improve the objectivity and quality of quantitative measurements. The dose response curves were classified based on seven expected patterns. Instead of a binary chemosensitivity evaluation, we ranked drug sensitivity according to curve shapes and comparison with the peak plasma concentration (ppc) of each drug. Results A total of 193 dose response curves were obtained. The overall informative rate was 67.4%, and 85.3% for cases that had a sufficient number of cells. Paclitaxel (PXL)and docetaxel tended to show a higher rank, while cisplatin (CIS) and 5-fluorouracil (5-FU) tended to show resistance, particularly among the 20 cases (46.5%) that had recurrent disease after receiving chemotherapy with CIS and S-1 (5-FU). As such, we speculate that the resistant pattern of the chemosensitivity test suggests that cells with acquired drug resistance were selected by chemotherapy. Indeed, we observed a change in the chemosensitivity pattern of a sample before and after chemotherapy in terms of PXL sensitivity, which was used after primary chemotherapy. Conclusions These results suggest that: (i) the dose–response pattern provides objective information for predicting chemosensitivity; and (ii) chemotherapy may select resistant cancer cell populations as a result of the therapy.

Abstract Background The binding of EGFR and its ligands leads to autophosphorylation of receptor tyrosine kinase as well as subsequent activation of signal transduction pathways that are involved in regulating cellular proliferation, differentiation, and survival. An EGFR inhibitor, cetuximab binds to EGFR and consequently blocks a variety of cellular processes. KRAS/BRAF mutations are known to be associated with a low response rate to cetuximab. In the present study, to clarify the anti-tumor mechanisms of cetuximab, we evaluated the KRAS/BRAF status, phosphorylation level of the EGFR pathway, and the tumor suppression effect in vivo, using a human colon cancer cell line HT29, which exhibited the highest EGFR expression in response to the cetuximab therapy among the 6 colorectal cancer cell lines tested. Findings The conventional growth suppression assay did not work efficiently with cetuximab. EGF, TGF-α, and IGF activated the EGFR/MAPK cell signaling pathway by initiating the phosphorylation of EGFR. Cetuximab partially inhibited the EGFR/MAPK pathway induced by EGF, TGF-α, and IGF. However, cetuximab exposure induced the EGFR, MEK, and ERK1/2 phosphorylation by itself. Mouse xenograft tumor growth was significantly inhibited by cetuximab and both cetuximab-treated and -untreated xenograft specimens exhibited phosphorylations of the EGFR pathway proteins. Conclusions We have confirmed that cetuximab inhibited the EGFR/MAPK pathway and reduced tumor growth in the xenografts while the remaining tumor showed EGFR pathway activation. These results suggest that: ( i ) The effect of cetuximab in growth signaling is not sufficient to induce complete growth suppression in vitro; ( ii ) time-course monitoring may be necessary to evaluate the effect of cetuximab because EGFR signaling is transmitted in a minute order; and ( iii ) cetuximab treatment may have cells acquired resistant selectively survived in the heterogeneous cancer population.

Abstract Background Monoclonal antibodies are used extensively throughout the biomedical sciences for detection of antigens, either in vitro or in vivo. We, for example, have used them for quantitation of proteins on "reverse-phase" protein lysate arrays. For those studies, we quality-controlled > 600 available monoclonal antibodies and also needed to develop precise information on the genes that encode their antigens. Translation among the various protein and gene identifier types proved non-trivial because of one-to-many and many-to-one relationships. To organize the antibody, protein, and gene information, we initially developed a relational database in Filemaker for our own use. When it became apparent that the information would be useful to many other researchers faced with the need to choose or characterize antibodies, we developed it further as AbMiner, a fully relational web-based database under MySQL, programmed in Java. Description AbMiner is a user-friendly, web-based relational database of information on > 600 commercially available antibodies that we validated by Western blot for protein microarray studies. It includes many types of information on the antibody, the immunogen, the vendor, the antigen, and the antigen's gene. Multiple gene and protein identifier types provide links to corresponding entries in a variety of other public databases, including resources for phosphorylation-specific antibodies. AbMiner also includes our quality-control data against a pool of 60 diverse cancer cell types (the NCI-60) and also protein expression levels for the NCI-60 cells measured using our high-density "reverse-phase" protein lysate microarrays for a selection of the listed antibodies. Some other available database resources give information on antibody specificity for one or a couple of cell types. In contrast, the data in AbMiner indicate specificity with respect to the antigens in a pool of 60 diverse cell types from nine different tissues of origin. Conclusion AbMiner is a relational database that provides extensive information from our own laboratory and other sources on more than 600 available antibodies and the genes that encode the antibodies' antigens. The data will be made freely available at http://discover.nci.nih.gov/abminer

Nonalcoholic fatty liver disease (NAFLD) develops as a result of unhealthy lifestyle but improves with laparoscopic sleeve gastrectomy (LSG). The transforming growth factor (TGF)-β signaling pathway reportedly contributes to liver fibrosis, mainly in animal experiments. The aim of the present study was to evaluate changes in serum proteins before and after LSG by proteomic analysis and to investigate their association with NAFLD. This study enrolled 36 severely obese patients who underwent LSG at our hospital from January 2020 to April 2022. As a pilot study, proteomic analysis was conducted on six patients using serum collected before and at 6 months after LSG, and significantly fluctuating proteins were extracted. Subsequently, verification by enzyme-linked immunosorbent assay (ELISA) using collected serum was performed on the remaining 30 patients. The mean weight of enrolled patients was 118.5 kg. Proteomic analysis identified 1,912 proteins, many of which were related to the TGF-β signaling pathway. Among these proteins, we focused on five TGF-β-related proteins: asporin, EMILIN-1, platelet factor-4, serglycin, and thrombospondin-1. Verification by ELISA revealed that asporin (p = 0.006) and thrombospondin-1 (p = 0.043) levels significantly fluctuated before and after LSG. Univariate analysis with a linear regression model showed that aspartate aminotransferase (p = 0.045), asporin (p = 0.011), and thrombospondin-1 (p = 0.022) levels were significantly associated with postoperative liver fibrosis. On multivariate analysis, asporin was an independent prognostic factor for postoperative liver fibrosis (95% confidence interval: 0.114-1.291, p = 0.002). TGF-β-related proteins dramatically fluctuated before and after LSG and were correlated with NAFLD pathogenesis. Asporin may be a useful prognostic marker of liver fibrosis in NAFLD after LSG.

Most of esophageal squamous cell carcinoma (ESCC) develop in smoking males in Japan, but the genomic etiology and immunological characteristics of rare non-smoking female ECSS remain unclear. To elucidate the genomic and immunological features of ESCC in non-smoking females, we analyzed whole-genome or transcriptome sequencing data from 94 ESCCs, including 20 rare non-smoking female cases. In addition, 31,611 immune cells were extracted from four ESCC tissues and subject to single-cell RNA-seq. We compared their immuno-genomic and microbiome profiles between non-smoking female and smoking ESCCs. Non-smoking females showed much better prognosis. Whole-genome sequencing analysis showed no significant differences in driver genes or copy number alterations depending on smoking status. The mutational signatures specifically observed in non-smoking females ESCC could be attributed to aging. Immune profiling from RNA-seq revealed that ESCC in non-smoking females had high tumor microenvironment signatures and a high abundance of eosinophils with a favorable prognosis. Single-cell RNA-sequencing of intratumor immune cells revealed gender differences of eosinophils and their activation in female cases. ESCCs in non-smoking females have age-related mutational signatures and gender-specific tumor immune environment with eosinophils, which is likely to contribute to their favorable prognosis., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

The Wnt/β-catenin signaling pathway plays a key role in development and carcinogenesis. Although some target genes of this signaling have been identified in various tissues and neoplasms, the comprehensive understanding of the target genes and their roles in the development of human cancer, including hepatoma and colorectal cancer remain to be fully elucidated. In this study, we searched for genes regulated by the Wnt signaling in liver cancer using HuH-7 hepatoma cells. A comparison of the expression profiles between cells expressing an active form of mutant β-catenin and cells expressing enhanced green fluorescent protein (EGFP) identified seven genes upregulated by the mutant β-catenin gene (CTNNB1). Among the seven genes, we focused in this study on ODAM, odontogenic, ameloblast associated, as a novel target gene. Interestingly, its expression was frequently upregulated in hepatocellular carcinoma, colorectal adenocarcinoma, and hepatoblastoma. We additionally identified a distant enhancer region that was associated with the β-catenin/TCF7L2 complex. Further analyses revealed that ODAM plays an important role in the regulation of the cell cycle, DNA synthesis, and cell proliferation. These data may be useful for clarification of the main molecular mechanism(s) underlying these cancers., (© 2022 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

There is no useful biomarker to evaluate treatment response and early relapse in head and neck squamous cell carcinoma (HNSCC). Circulating tumor DNA (ctDNA) is a promising biomarker for detecting minimal residual diseases and monitoring treatment effect. We investigated whether individualized ctDNA analysis could help monitor treatment response and relapse in HNSCC. Mutation analysis of tumor and peripheral blood mononuclear cell (PBMC) DNAs of 26 patients with HNSCC was performed using a custom squamous cell carcinoma (SCC) panel. The identified individualized mutated genes were defined as ctDNA candidates. We investigated whether frequent ctDNA monitoring via digital PCR (dPCR) is clinically valid for HNSCC patients. TP53 was the most frequently mutated gene and was detected in 14 of 24 cases (58.2%), wherein two cases were excluded owing to the absence of tumor-specific mutations in the SCC panel. Six cases were excluded because of undesignable and unusable primer-probes for dPCR. Longitudinal ctDNA was monitored in a total of 18 cases. In seven cases, ctDNA tested positive again or did not test negative, and all seven cases relapsed after initial curative treatment. In 11 cases, after initial curative treatment, ctDNA remained negative and patients were alive without recurrence. Patients who remained negative for ctDNA during follow-up after initial curative treatment (n = 11) had a significantly better prognosis than those who reverted to ctDNA positivity (n = 7; p < 0.0001; log-rank test). Individualized ctDNA monitoring using SCC panel and dPCR might be a novel and promising biomarker for HNSCC., (© 2022 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Background: We established a community-based cohort study to assess the long-term impact of the Great East Japan Earthquake on disaster victims and gene-environment interactions on the incidence of major diseases, such as cancer and cardiovascular diseases., Methods: We asked participants to join our cohort in the health check-up settings and assessment center based settings. Inclusion criteria were aged 20 years or over and living in Miyagi or Iwate Prefecture. We obtained information on lifestyle, effect of disaster, blood, and urine information (Type 1 survey), and some detailed measurements (Type 2 survey), such as carotid echography and calcaneal ultrasound bone mineral density. All participants agreed to measure genome information and to distribute their information widely., Results: As a result, 87,865 gave their informed consent to join our study. Participation rate at health check-up site was about 70%. The participants in the Type 1 survey were more likely to have psychological distress than those in the Type 2 survey, and women were more likely to have psychological distress than men. Additionally, coastal residents were more likely to have higher degrees of psychological distress than inland residents, regardless of sex., Conclusion: This cohort comprised a large sample size and it contains information on the natural disaster, genome information, and metabolome information. This cohort also had several detailed measurements. Using this cohort enabled us to clarify the long-term effect of the disaster and also to establish personalized prevention based on genome, metabolome, and other omics information.

Tylosis is an inherited disorder characterized by abnormal palmoplantar skin thickening and a highly elevated risk of esophageal squamous cell carcinoma (ESCC). Analyses of tylosis in families have localized the responsible gene locus to a region of chromosome 17q25.1. Frequent loss of heterozygosity (LOH) in 17q25.1 was also observed in the sporadic form of ESCC. A putative tumor suppressor gene for ESCC may exist at this locus. We investigated the expression patterns of genes on 17q25.1 in tumor and corresponding normal tissues from patients with sporadic ESCC using RNA sequence analysis. For candidate genes, quantitative real-time reverse transcription-PCR (qRT-PCR), direct sequence, LOH and methylation analyses were performed using 93 clinical ESCC samples and 10 cell lines. A significant downregulation of ST6GALNAC1 was demonstrated in ESCC tissues compared to its expression in normal tissues by qRT-PCR (n=93, p<0.0001). Frequent LOH (17/27, 62.9%) and hyper‑methylation in ST6GALNAC1 were also observed in all cell lines. Our results indicated that ST6GALNAC1 was downregulated in sporadic ESCC via hyper-methylation and LOH, and it may be a candidate responsible gene for ESCC. Furthermore, recent studies suggest that multiple genes on chromosome 17q25 are involved in ESCC development.

Purpose: Laparoscopy-assisted pylorus-preserving gastrectomy has been increasingly reported as a treatment for early gastric cancer located in the middle third of the stomach because of its low invasiveness and preservation of pyloric function. Advantages of a totally laparoscopic approach to distal gastrectomy, including small wound size, minimal invasiveness, and safe anastomosis, have been recently reported. Here, we introduce a new procedure for intracorporeal gastro-gastrostomy combined with totally laparoscopic pylorus-preserving gastrectomy (TLPPG)., Methods: The stomach is transected after sufficient lymphadenectomy with preservation of infrapyloric vessels and vagal nerves. The proximal stomach is first transected near the Demel line, and the distal side is transected 4 to 5 cm from the pyloric ring. To create end-to-end gastro-gastrostomy, the posterior wall of the anastomosis is stapled with a linear stapler and the anterior wall is made by manual suturing intracorporeally. We retrospectively assessed the postoperative surgical outcomes via medical records. The primary endpoint in the present study is safety., Results: Sixteen patients underwent TLPPG with intracorporeal reconstruction. All procedures were successfully performed without any intraoperative complications. The mean operative time was 275 min, with mean blood loss of 21 g. With the exception of one patient who had gastric stasis, 15 patients were discharged uneventfully between postoperative days 8 and 11., Conclusions: Our novel hybrid technique for totally intracorporeal end-to-end anastomosis was performed safely without mini-laparotomy. This technique requires prospective validation.

Background: Systemic chemotherapy in advanced cancer cases often provokes serious adverse events., Purpose: We aimed to examine the fundamental properties and efficacy of a novel chitin sol, an anti-cancer agent with minor side effects designed to avoid the adverse effects of chemotherapy and enhance the QOL and ADL of patients., Methods: DAC-70 was used to create the novel agent termed DAC-70 sol. The anti-proliferative activity was assayed by the WST method using different types of cell lines. The anti-cancer efficacy of the novel agent was examined using cancer-bearing mice., Results: DAC-70 sol was easily injectable through a 21-G needle. The sol suppressed proliferation of the cells in vitro. Intra-tumor injection of DAC-70 sol inhibited the rapid growth of solid tumors in the mice. CDDP-loaded DAC-70 sol, CDDP/DAC-70 sol, successfully controlled malignant ascites in the mice (p<0.05). Neither recurrence nor severe complications were encountered in these animals., Discussion: These basic data strongly suggest that locoregional administration of our newly designed DAC-70 sol and CDDP/DAC-70 sol is clinically useful as novel cancer chemotherapy for advanced cases. This warrants further clinical studies in cancer chemotherapy.

Background: Laparoscopic liver resection for liver metastases from colorectal cancer (CRLM) is performed in a relatively small number of institutions. Its operative results have been reported to be comparable with that of open laparotomy; however, information on its oncologic outcomes is scarce. This study aimed to compare the long-term outcomes of laparoscopic hepatectomy (LH) and open hepatectomy (OH) to treat CRLM at a single institution., Methods: We retrospectively reviewed data from 168 consecutive patients who underwent LH (n = 100) or OH (n = 68) for CRLM. The tumor characteristics, operative results, overall survival (OS) rate, recurrence-free survival (RFS) rate, and recurrence patterns were analyzed and compared. A previously published survival-predicting nomogram was applied to compare OS and RFS between the 2 patient groups., Results: The largest tumor diameter and the number of tumors were significantly larger in the OH group than in the LH group; however, no differences in other tumor factors were observed between the 2 groups. When matched by the nomogram, OS and RFS remained comparable between the 2 groups in every examined stratum, not only for low-risk patients but also for those with high risk. The recurrence patterns also were similar (liver: 30.2% vs 26.8%, P = .72; lung: 22.6% vs 34.1%, P = .22; peritoneum: 7.6% vs 4.9%, P = .45)., Conclusion: The long-term outcomes of laparoscopic liver resection for CRLM were comparable with those of the open procedure in not only low-risk but also high-risk patients., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Purpose: Postoperative hyperglycemia is associated with infectious complications after various types of surgery. Our objective was to determine whether postoperative blood glucose levels up to 1 week after highly invasive esophageal cancer surgery are associated with the incidence of postoperative infections (POIs)., Methods: We conducted a retrospective chart review of 109 consecutive thoracic esophageal squamous cell cancer patients who underwent invasive esophagectomy with thoracotomy and laparotomy. The incidence of postoperative POIs and risk factors for POIs, including postoperative blood glucose levels, were evaluated., Results: Of the 109 patients, 37 (34.0 %) developed POIs. Clinically, 73.0 % of the POIs became evident on or after postoperative day 4 (median, 5.25 days; interquartile range, 3.00-9.25 days). On and after postoperative day 3, chronological changes in blood glucose levels were significantly different between two groups of patients with or without POIs, as indicated by repeated measures ANOVA (P = 0.006). Multivariate logistic regression analysis results showed that an increased blood glucose concentration on postoperative day 3 was a significant risk factor for POIs., Conclusions: Our findings suggested that postoperative hyperglycemia on postoperative day 3 was a predictive factor of POIs after highly invasive esophageal cancer surgery.

Background: The important point in safely performing laparoscopic hepatectomy (LH) is to control bleeding. The aims of this study were: (i) to assess the bleeding reduction effect by occlusion of the hepatic artery in LH; and (ii) to evaluate the risk of carbon dioxide (CO2 ) gas embolism (GE) in the case of high pneumoperitoneum (PP)., Methods: Nine piglets underwent laparoscopic left medial lobe and left lateral lobe resection, receiving either occlusion of the hepatic artery (hepatic artery clamping group: HACG, n = 9) or no occlusion (hepatic artery declamping group: HADCG, n = 9) using a PP of 15 mmHg. In addition, we observed changes in hemodynamics induced by PP. The state of GE was observed using transesophageal echocardiography (TEE) during LH (n = 8). GE was graded as grade 0 (none), grade 1 (minor), and grade 2 (major)., Results: The HACG had significantly less bleeding compared to the HADCG (P < 0.01). During LH, four animals showed grade 1 (37.5%) and one animal showed grade 2 (12.5%) GE at 15 mmHg. At 20 mmHg, all animals showed grade 2 (100%) GE., Conclusion: The occlusion of the hepatic artery in LH reduces blood loss. The control of bleeding from the hepatic vein is feasible with a high PP, but there is a possibility of GE., (© 2014 Japanese Society of Hepato-Biliary-Pancreatic Surgery.)

Purpose: Recent studies revealed that both disseminated tumor cells and noncancerous cells contributed to cancer progression cooperatively in the bone marrow. Here, RNA-seq analysis of bone marrow from gastric cancer patients was performed to identify prognostic markers for gastric cancer., Experimental Design: Bone marrow samples from eight gastric cancer patients (stages I and IV: n = 4 each) were used for RNA-seq analysis. Results were validated through quantitative real-time PCR (qRT-PCR) analysis of HIST1H3D expression in 175 bone marrow, 92 peripheral blood, and 115 primary tumor samples from gastric cancer patients. miR-760 expression was assayed using qRT-PCR in 105 bone marrow and 96 primary tumor samples. Luciferase reporter assays were performed to confirm whether histone mRNAs were direct targets of miR-760. miR-760 expression was also evaluated in noncancerous cells from gastric cancer patients., Results: RNA-seq analysis of bone marrow samples from gastric cancer patients revealed higher expression of multiple histone mRNAs in stage IV patients. HIST1H3D expression in the bone marrow, peripheral blood, and primary tumor of stage IV patients was higher than that in stage I patients (P = 0.0284, 0.0243, and 0.0006, respectively). In contrast, miR-760 was downregulated in the bone marrow and primary tumor of stage IV patients compared with stage I patients (P = 0.0094 and 0.0018, respectively). Histone mRNA and miR-760 interacted directly. Furthermore, miR-760 was downregulated in noncancerous mucosa in stage IV gastric cancer patients., Conclusion: Histone mRNA was upregulated, whereas miR-760 was downregulated in the bone marrow and primary tumor of advanced gastric cancer patients, suggesting that the histone mRNA/miR-760 axis had a crucial role in the development of gastric cancer., (©2013 AACR.)

Background: Cancer cells synthesize substantial amounts of protoporphyrin IX( PPIX) from aminolevulinic acid( ALA). PPIX emits red fluorescence when illuminated under blue light. Photodynamic diagnosis (PDD), based on this phenomenon, is currently used; however, various microorganisms also show the same fluorescence with ALA when illuminated under blue light, resulting in false-positive PDD results., Purpose and Methods: To avoid misdiagnosis, we incorporated novel systems into the PDD system. ALA, blue light (wavelength, 380-450 nm), different kinds of cell lines, and bacteria were used in this in vitro study. We used a 70% deacetylated chitosan solution (DAC-70 Sol), developed in-house, as an antibacterial agent and prepared ALA/DAC-70 Sol, used as a novel photoimaging agent. The antibacterial function of ALA/DAC-70 Sol was examined in vitro, and the photodiagnostic effects on using the novel systems were clinically evaluated using bile from patients with biliary tract cancer., Results: DAC-70 Sol demonstrated an effective bactericidal function in vitro. Red fluorescence could clearly be identified, enabling the detection of cancer cells in the bile using ALA/DAC-70 Sol., Conclusions: Our novel systems have a great potential for use in clinical photodynamic cytodiagnosis( PDCD), which plays an important role in preoperative cancer chemotherapy.

Background: Laparoscopic liver resection remains limited to a relatively small number of institutions because of insufficient hepatic and laparoscopic surgical experience and few training opportunities. The aim of this study was to assess the feasibility and safety of an improved laparoscopic left lateral sectionectomy technique as a training procedure for new surgeons., Methods: Twenty-four laparoscopic left lateral sectionectomies (LLLSs) were retrospectively reviewed. Patients were divided into 3 groups with 8 patients in each: those undergoing surgery by expert surgeons prior to 2008 (Group A); those undergoing surgery by expert surgeons after 2008, when a standardized LLLS technique was adopted (Group B); and those undergoing LLLS by junior surgeons being trained (Group C)., Results: The median operative time was significantly shorter for Group B (103 min; range, 99-109 min) and C (107 min; range, 85-135 min) patients than for Group A (153 min; range, 95-210 min) patients. There were no significant differences in blood loss or hospital stay. In Groups B and C, no conversions to open laparotomy or complications occurred., Conclusion: The standardized LLLS procedure was both safe and feasible as a technique for training surgeons in laparoscopic hepatectomy.

Background: Recent reports have suggested that laparoendoscopic single site (LESS) surgery is technically feasible. The aim of this study was to describe our initial experience with LESS adrenalectomy for benign adrenal tumors, focusing the attention about cosmetic satisfaction and reduction of postoperative pain., Methods: Medical records of consecutive patients undergoing LESS adrenalectomy were analyzed. All procedures were performed through a single multichannel port. Demographic and operative data were assessed. A visual analog scale (VAS) was used with a 10-point scale for an objective assessment of incisional pain and incisional cosmesis., Results: Between January 2010 and July 2012, 14 consecutive patients with benign adrenal tumors underwent LESS adrenalectomies. Of the planned LESS adrenalectomies, 12 (86%) were completed with a single-port, whereas two required an additional port placement. Mean operating time was 128.1 ± 31.5 min and mean blood loss 10.5 ± 12.1 ml. Mean pain scores using the VAS on postoperative days 1, 3, and 14 were 2.3, 1.0, and 0.3 points, respectively. The rate of analgesic use was also lower within 12 hours after surgery (14%). The patient was highly satisfied with the single small wound procedure, and mean cosmesis scores of postoperative days 3 and 14 were 9.4 and 9.8 points, respectively. The postoperative course was uneventful with no morbidity within one month of follow-up., Conclusions: LESS adrenalectomy is a safe and technically feasible procedure for patients with benign adrenal tumors, and offers cosmetic benefit and the potential for postoperative pain reduction. However, surgeons with lack of experience as LESS surgery should be comprehended that the assistance of the needlescopic instrument does not compromise the cosmetic outcomes for difficult cases and the obese patients may not always be suitable candidates for pure LESS technique.

We evaluated the outcome of esophageal stenting for esophagorespiratory fistula in patients with advanced esophageal cancer. Six patients with such fistula underwent esophageal stenting at our department from January 2000 to May 2012. Intraoral ingestion improved in all patients. Cough decreased immediately after stenting in 3 patients, and pneumonia detected by chest radiography improved within 1 week in 2 patients. Ventilation was weaned 2 days after stenting in 1 patient. The median survival duration after stenting was 31 days, and the cause of death was cancer in all patients. The following background factors were identified at the time of death: bleeding(n=3), mediastinitis(n=1), and pneumonia(n=1). Esophageal stenting, which should always be performed with the informed consent of the patient, improves respiratory symptoms, intraoral ingestion, and quality of life. Therefore, it is one of the best palliative therapies for patients with esophagorespiratory fistula associated with advanced esophageal cancer.

Purpose: To evaluate the outcomes of totally laparoscopic distal pancreatectomy (LDP)., Methods: A prospective database of patients treated within a single institution was studied retrospectively. Between March 2003 and January 2010, 15 patients underwent pancreatic transection with the use of a stapler, followed by sealing of the pancreatic stump with fibrin-coated collagen fleece (TachoComb) in LDP., Results: LDP was completed successfully in all 15 patients. The median operating time and blood loss were 168 min (range 105-213 min) and 36 ml (range 12-89 ml), respectively. The median drain amylase level peaked at 969 IU/l (93-3077 IU/l) on postoperative day (POD) 1, and then dropped to 165 IU/l (30-846 IU/l) on POD 3. The median hospital stay was 7 days (range 4-15 days). Biochemical pancreatic leaks developed in three patients (20 %), but there was no clinical pancreatic fistula or postoperative hemorrhage., Conclusions: Our study shows that the combined use of a stapler and TachoComb decreased the incidence of pancreatic fistulas after LDP. This procedure offers more efficient and consistent results than those achieved by closing the pancreatic stump by stapling alone.

The authors used 70% deacetylated chitin and cisplatin (CDDP) to devise a novel anticancer drug delivery system (DDS). We examined in vitro release of the CDDP from the system. The novel system was intraperitoneally( ip) given to malignant ascites-bearing mice, and the survival time of each animal was recorded. The related oncolytic mechanism was immunologically investigated. More than 70-90% of the CDDP was gradually delivered from the system in 24 hours. Nineteen animals among 30 treated with our system survived for longer than 4 weeks, and a recurrence of ascites was nil. A 4- week survival rate of the animals with ip injected conventional CDDP was 5/14. All non-treated animals had massive ascites and died within 4 weeks. Immunologic studies suggested that cytotoxic immunoresponse was induced in the mice treated with the novel system. Our newly devised system warrants for clinical applications in the treatment of malignant ascites.

Indocyanine green (ICG) is specifically excreted through the biliary tracts. The authors applied ICG as a carrier of gemcitabine (GEM) to devising a novel drug delivery system. Our newly devised chitin flakes, ICG and GEM were mixed together. Then physiological saline solution was added to the mixture to form the system. The release profiles of GEM and ICG from the system were examined at various times in vitro. Anticancer activities of the GEM and ICG delivered from the system were detected by MTT assay method using human pancreatic cancer cell lines. The novel system was visco-elastic green sol at room temperature and changed to gel at body temperature. Seventy to 80% of GEM was gradually delivered from the system in 24 hours, and 30 to 50% of ICG was slowly released over 24 hours. The released GEM favorably demonstrated anticancer activities against the cancer cells, while the ICG released from the system showed no oncolytic activities. These suggested that our devised system would be clinically useful as a novel tool in cancer chemotherapy.

Background: The authors performed Asia's first robotic surgery in March 2000 and a clinical trial was launched in the following year in order to obtain governmental approval for the da Vinci(®) Surgical System., Methods: Fifty-two robotic surgeries were performed at Keio University Hospital, of which the authors performed 28 hepato-biliary-pancreatic surgeries., Results: In robotic laparoscopic cholecystectomy, articulated monopolar electrocautery scalpels are flexible, enabling precise dissection around the gall bladder and clipless ligation of the cystic artery and cystic ducts. For laparoscopic hepatectomy, hepatic parenchyma was safely resected without hemorrhage by Glisson's pedicles ligation and bipolar hemostatic forceps., Conclusions: We review robotic laparoscopic cholecystectomy and hepatectomy and discuss the potential and future outlook for robotic hepato-biliary-pancreatic surgery.

Laparoscopy-assisted distal gastrectomy for gastric cancer was first reported by Kitano et al. in 1991. Laparoscopic wedge resection (LWR) and intragastric mucosal resection (IGMR) were quickly adapted for gastric cancer limited to the mucosal layer and having no risk of lymph node metastasis. Following improvements in endoscopic mucosal resection (EMR) and endoscopic submucosal dissection (ESD), the use of LWR and IGMR for these indications decreased, and patients with gastric cancer, including those with a risk of lymph node metastases, were more likely to be managed with laparoscopic gastrectomy (LG) with lymph node dissection. Many retrospective comparative trials and randomized-controlled trials (RCT) have confirmed that LG is safe and feasible, and that short-term outcomes are better than those of open gastrectomy (OG) in patients with early gastric cancer (EGC). However, these trials did not include a satisfactory number of patients to establish clinical evidence. Thus, additional multicenter randomized-controlled trials are needed to delineate significantly quantifiable differences between LG and OG. As laparoscopic experience has accumulated, the indications for LG have been broadened to include older and overweight patients and those with advanced gastric cancer. Moreover, advanced techniques, such as laparoscopy-assisted total gastrectomy, laparoscopy-assisted proximal gastrectomy, laparoscopy-assisted pylorus-preserving gastrectomy (PPG), and extended lymph node dissection (D2) have been widely performed.In the near future, sentinel node navigation and robotic surgery will become additional options in minimally invasive surgery (MIS) involving LG. Such developments will improve the quality of life of patients following gastric cancer surgery.

The authors devised two different types of cisplatin (CDDP) delivery systems; namely, System A and System B. The anticancer efficacy with each system was examined using cancer-bearing animals. Seventy-percent deacetylated chitin (DAC-70) was used as the drug carrier in the system. Cancer-bearing animals were prepared by intra-peritoneally (ip) inoculating the MM-46 cancer cells to C3H mice. Each novel system was also ip injected to the cancer-bearing mouse, and then survival time of each animal was recorded to evaluate the anti-cancer efficacy of the system. Both Systems A and B were viscoelastic sol at 25°C and slowly changed to gel at 37°C. Four-week survival rate of each animal treated with the System was as follows: System A 6/10 (60%), System B 10/11 (90.9%), conventional CDDP alone 3/9 (33.3%) and non-treated 0/7 (0%). No signs of recurrence of ascites were encountered in the long-term survived animals treated with System A and B. Our newly devised systems provided a favorable antitumor efficacy in vivo. Now, we will carry out further studies by making a clinically applicable novel conjugated system, DAC-70 and CDDP.