川平 洋

Background/Aims: It is important to retract the lateral liver segment during laparoscopic gastrectomy to achieve an optimal surgical field. Few retractors cause transient liver dysfunction after surgery therefore, for an easier and safer procedure, we devised a new liver retractor and implemented a trial clinical application. Methodology: The novel liver retractor comprises a metallic, flexible arm retractor attached to the operating table and an air compressor which pneumatically moves and fixes the retractor. It was inserted directly into the abdominal cavity just below the xiphisternum to retract the left lobe of the liver anterosuperiorly, thereby exposing the hiatus. Blood samples were collected from the patients on days 1, 3, and 7 after surgery to assess the levels of the liver enzymes AST and ALT. Results: During laparoscopic gastrectomy, no liver damage was observed macroscopically. The surgical fields obtained were optimal and efficient for laparoscopic surgery. Notably, it was possible to retract the liver as often as needed. Further, none of the patients developed postoperative liver dysfunction. Conclusions: The novel flexible-arm retractor provided an optimal surgical field without inducing liver dysfunction. © H.G.E. Update Medical Publishing S.A.

Background/Aims: It is important to retract the lateral liver segment during laparoscopic gastrectomy to achieve an optimal surgical field. Few retractors cause transient liver dysfunction after surgery therefore, for an easier and safer procedure, we devised a new liver retractor and implemented a trial clinical application. Methodology: The novel liver retractor comprises a metallic, flexible arm retractor attached to the operating table and an air compressor which pneumatically moves and fixes the retractor. It was inserted directly into the abdominal cavity just below the xiphisternum to retract the left lobe of the liver anterosuperiorly, thereby exposing the hiatus. Blood samples were collected from the patients on days 1, 3, and 7 after surgery to assess the levels of the liver enzymes AST and ALT. Results: During laparoscopic gastrectomy, no liver damage was observed macroscopically. The surgical fields obtained were optimal and efficient for laparoscopic surgery. Notably, it was possible to retract the liver as often as needed. Further, none of the patients developed postoperative liver dysfunction. Conclusions: The novel flexible-arm retractor provided an optimal surgical field without inducing liver dysfunction. © H.G.E. Update Medical Publishing S.A.

Many aspects of medical imaging require innovative measures to improve the quality of diagnosis and treatment. The FERMI Project is promoting these innovations through new developments and improvements of high-dimension, high-definition, quantification of physical or physiological parameters of biological objects and integration of multimodal medical images. The FERMI Project consists of three sub projects: (1) development of essential imaging technologies in medicine; (2) development of dynamic imaging technologies; and (3) integration of spatial information in medical treatment. In this paper, some ongoing research studies are reviewed. These include: ultrasound-based tissue characterization; magnetic resonance elastography; 4D-MRI reconstruction; knee motion analysis from X-ray fluoroscopy and CT images; projector-based assistance for laparoscopic surgery; and a surgical navigation system with three-dimensional ultrasound imaging.

We have rationally designed and synthesized a novel near-infrared (NIR) photoactivating probe, designated by iDOPE, in which an indocyanine green (ICG) fluorophore is covalently conjugated with a phospholipid moiety, 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE), to incorporate into liposome bilayers. NIR irradiation showed that iDOPE retained the optical and fluorescence properties of ICG and demonstrated photoactivator characteristics: fluorescence emission at around 820 nm in a solvent, singlet oxygen production, and concentration-dependent heat generation. Additionally, iDOPE was incorporated into liposome bilayers and maintained stable liposomally formulated iDOPE (LP-iDOPE) over 1 week under physiological conditions. We also observed the tumor-specific biodistribution of LP-iDOPE of in vivo xenografts. These findings suggest that LP-iDOPE might be a promising tool for NIR optical imaging, photodynamic therapy, and photothermal therapy. (C) 2012 Elsevier Ltd. All rights reserved.

Background/Aims: The treatment of gastric submucosal tumors (SMTs) is strictly surgical and enucleation of the tumor or wedge resection of the stomach is efficient to achieve R0 resection. Laparoscopic and endoscopic cooperative surgery (LECS) can be safely performed with adequate cutting lines. This study describes the initial 16 cases treated by LECS and evaluates the advantages by LECS for gastric SMTs retrospectively. Methodology: Sixteen patients with gastric SMT underwent LECS from June 2007 to December 2010, their surgical data, clinical characteristics and surgical specimens of SMTs were compared. The surgical specimens of 9 gastric SMTs treated by laparoscopic wedge resection (LWR) were compared as a control. Results: The median (range) length of operation time, blood loss, hospital stay after surgery were minutes 172 (115-220), <5mL (<5-115) and 10 days (6-17), respectively. The median (range) ratio of the longest diameter of the tumor divided by the longest diameter of the surgical specimen in LECS and LWR were 0.86 (0.625-1.0) and 0.69 (0.44-1.0), respectively (p=0.0189, Wilcoxon rank sum test). Conclusions: LECS minimizes the surgical specimen while still providing sufficient surgical margins to successfully cure gastric SMTs.

Purpose: Recent surgical techniques have been advancing under endoscopic view and insufflation of carbon dioxide gas to expand the abdominal cavity. Isotonic fluid could be one candidate for expanding cavities to facilitate surgical maneuvering. We tested the feasibility and drawbacks of replacement of irrigating materials using a porcine model (water-filled laparoendoscopic surgery [WAFLES]). Materials and Methods: Laparoscopic cholecystectomy was performed in two porcine models using instillation of sorbitol solution as irrigant. Solution irrigation was performed through one of four ports, with drainage via another port. Conventional forceps equipped with a monopolar electrode for electrocautery, laparoscope, video processor, ultrasound, and transducer for measuring intraabdominal pressure were used. Results: Laparoscopic cholecystectomy was successfully undertaken with the following benefits: (1) clear observation of the dissecting plane throughout maneuvering; (2) control of oozing and spilled bile by irrigation and suction; and (3) ultrasonographic and laparoscopic images can be obtained simultaneously without any restriction to probe location. However, two disadvantages should be noted: (1) difficulties in managing floating organs and (2) interruption of vision by blood. Conclusions: WAFLES provides some benefits for endoscopic surgery with proper devices, including apparatuses for irrigation and suction. Efficient irrigation and selection of proper irrigant and apparatuses are required to establish an acceptable procedure.

症例は100歳の女性で,主訴は吐血.誤嚥性肺炎の重症化に伴い当院救急部集中治療部へ入院,入院時胸腹部CTにてupside down stomachを呈した食道裂孔ヘルニアの診断となった.誤嚥性肺炎重症化による急性呼吸窮迫症候群の治療を行い,全身状態の改善を得た後に手術施行した.腹腔鏡下に腹腔内を検索すると,ヘルニア内容は胃と大網であった.脱出した胃および大網を腹腔内へ牽引・還納した後,食道裂孔を縫縮,Toupet法による噴門形成術を施行し胃を固定した.経過良好にて術後13日で退院した.本症例は100歳という超高齢者かつ急性呼吸窮迫症候群を併発していたが,全身状態の改善が得られ,upside down stomachを呈した食道裂孔ヘルニアに対し腹腔鏡下手術を施行し,良好な結果を得られた非常にまれな症例であったため,若干の文献的考察を含めて報告する.(著者抄録)

Methods to detect metastases in biopsy specimens with certain rapidity and accuracy are essential to performing tailor-made surgeries for solid malignancies. Reverse transcription loop-mediated isothermal amplification (RT-LAMP) reaction is a novel technique for detecting mRNA expression of target sequences with high sensitivity and rapidity, even from crude samples without RNA purification. Applicability to detect lymph node (LN) micrometastasis of gastric cancer was tested. Total of 26 LNs were retrieved from 10 patients with primary gastric cancer. Each LN was serially sectioned, and every set of three serial sections were tested for routine histopathological (H&E) and immunohistochemical examination with anti-cytokeratin antibodies (IHC), and RT-LAMP analysis targeted cytokeratin 19 mRNA. Results from H&E/IHC and RT-LAMP analysis were compared in each set of sections. All the sections of those containing metastatic lesions equivalent to a volume of overt metastasis (maximum diameter >2 mm), 90% of those containing micrometastasis (between 2 and 0.2 mm) and 83% of those containing isolated tumor cells (<0.2 mm) were detectable using this procedure. Total analysis from lysates of clinical specimens required <75 min. This new technique is suggested to be an alternative to rapid diagnosis of micrometastasis based on conventional histopathological analysis.

Laparoscopy-assisted distal gastrectomy (LADG) is a less invasive alternative compared with an open procedure. However, it is difficult to obtain a full-view image and to estimate the three-dimensional (3D) relationships between organs during laparoscopic procedures. Determining the vascular anatomy by 3D CT imaging has been shown to play a critical role in reducing the risks associated with laparoscopic gastric cancer surgery. The purpose of this study was to evaluate the clinical anatomic variations and to estimate its positive contribution in obtaining less intraoperative bleeding. Scanning was performed using a 64-row MDCT scanner. Three-dimensional CT images in the arterial and portal phase were reconstructed and fused together using the volume-rendering technique. The intraoperative bleeding findings were compared between two periods. The anatomic variations of the celiac trunk were divided into six types. There were 159 patients with Adachi's type I, type II = 8, type III = 1, type IV = 1, type V = 2, type VI = 3, and other = 1. The inflows of the left gastric coronary vein (LCV) were divided into three types. The LCV flowed into the portal vein (PV) in 79 patients, into the splenic vein (SpV) in 65, and into the junction of these two veins in 27. The splenic artery was divided into flat type and curved type, and 65 cases (37%) showed the flat type. Intraoperative bleeding was significantly less between 2007 and 2008, in which the operations were performed without first making a 3D anatomy study, than in 2009, in which 3D anatomy studies were made and analyzed before surgery in all patients. Dual-phase 3D CT is a useful and essential modality to visualize the precise anatomy around the stomach. As a result, by comparing 3D CT images with our classifications, it is believed that any surgeons may reduce the degree of intraoperative blood loss.

This single-institution experience retrospectively reviewed the outcomes in 21 patients with primary duodenal adenocarcinoma. Twelve patients underwent curative surgery, and 9 patients underwent palliative surgery at the Chiba University Hospital. The maximum follow-up period was 8650 days. All pathologic specimens from endoscopic biopsy and surgical specimens were reviewed and categorized. Twelve (57.1%) patients underwent curative surgery (R0): 4 pancreaticoduodenectomies (PD), 4 pylorus-preserving PDs (PpPD), 2 local resections of the duodenum and 2 endoscopic mucosal resections (EMR). Palliative surgery was performed for 9 patients (42.9%) following gastro-intestinal bypass. The median cause-specific survival times were 1784 days (range 160-8650 days) in the curative surgery group and 261 days (range 27-857 days) in the palliative surgery group (P = 0.0003, log-rank test). The resectability of primary duodenal adenocarcinoma was associated with a smaller tumor size, a lower degree of tumor depth invasiveness, and less spread to the lymph nodes and distant organs.

Background/Aims: Peritoneal immune response as well as systemic response was objectively evaluated in laparoscopy-assisted distal gastrectomy (LADG) compared to open distal gastrectomy (ODG). Methodology: A total of 42 patients with gastric cancer were enrolled, with 23 undergoing LADG and 19 ODG. We evaluated the levels of IL-6 in peritoneal drain fluid, serum C-reactive protein (CRP), white blood cells (WBC), and the postoperative presence of systemic inflammatory response syndrome (SIRS). Results: The serum CRP level was significantly higher in the ODG group than in the LADG group (p=0.007) on postoperative day (POD) 1. WBC counts showed no statistically significant difference between the two groups (p=0.105). The rate of cases exhibiting SIRS was significantly higher in the ODG group than in the LADG group (p<0.001). The IL-6 level of drain fluid was significantly higher in the ODG group than the LADG group (p<0.01) on POD1. Although weak correlation between IL-6 on POD1 and blood loss (R=0.38, p=0.0154) was observed, no significant correlation between IL-6 and operation time was noted. Conclusions: LADG seems to be a lesser traumatic approach for the treatment of gastric cancer.

Although endoscopic submucosal dissection (ESD) for patients with gastric tumors under the conditions of unconsciousness is considered to be minimally invasive, no objective assessment of the perioperative stress of ESD has yet been conducted. Today, stress levels can be easily and objectively assessed by monitoring salivary amylase activity (sAMY). We evaluated the perioperative changes in the sAMY in patients undergoing ESD and identified the causes of such changes. A total of 40 patients with gastric cancers/adenomas removed by ESD under general anesthesia (GA; n = 20) and under deep sedation (DS; n = 20) were enrolled. sAMY was measured using the enzyme analysis equipment, sAMY Monitor (NIPRO, Osaka, Japan) during the perioperative period of the ESD. Also, all patients were interviewed to determine their subjective stress level, using a questionnaire asking "How did you feel during ESD?", with the choice of responses ranging from "did not wake up at all" to "I was awake and ESD was extremely stressful". The sAMY of the DS group increased soon after the start of ESD. Meanwhile, that of the GA group decreased just after the ESD started and was maintained at a stable level throughout the ESD. In response to the stress level questionnaire, all of the patients in the GA group and a majority of the patients in the DS group responded, "did not wake up at all". Sympathetic agitation, expressed as an increase of sAMY, was absent in the GA group. Meanwhile, in the DS group, some patients showed high levels of sAMY which went down following the administration of an analgesic agent, thus suggesting that pain caused an elevation in the level of the stress and thereby induced an increase in sAMY. The measurement of sAMY is therefore considered to be useful for the assessment of analgesic status under DS.

We detected adenoviral DNA fragments in excretions of 10 esophageal cancer patients by DNA-PCR after tumor injection of Ad-CMV-vector. A total of 220 samples consisting of feces, gargling saliva, urine, and blood plasma were assessed. A total of 29.7% of feces samples and 13.2% of gargling saliva samples were positive for adenoviral DNA fragments, but 89.7% of the positive feces samples and all of the positive gargling saliva samples turned negative on day 12 after tumor injection. Although adenoviral DNA fragments may be pathogen-free, patients' feces and gargling saliva contain adenoviral DNA fragments for 12 days after injection. (Cancer Sci 2010; 101: 289-291).

Background: Apoptosis is a hallmark of beta-cell death in both type 1 and type 2 diabetes mellitus. Understanding how apoptosis contributes to beta-cell turnover may lead to strategies to prevent progression of diabetes. A key mediator of apoptosis, mitochondrial function, and cell survival is apoptosis inducing factor (AIF). In the present study, we investigated the role of AIF on beta-cell mass and survival using the Harlequin (Hq) mutant mice, which are hypomorphic for AIF. Methodology/Principal Findings: Immunohistochemical evaluation of pancreata from Hq mutant mice displayed much smaller islets compared to wild-type mice (WT). Analysis of beta-cell mass in these mice revealed a greater than 4-fold reduction in beta-cell mass together with an 8-fold increase in beta-cell apoptosis. Analysis of cell cycle dynamics, using BrdU pulse as a marker for cells in S-phase, did not detect significant differences in the frequency of beta-cells in S-phase. In contrast, double staining for phosphorylated Histone H3 and insulin showed a 3-fold increase in beta-cells in the G2 phase in Hq mutant mice, but no differences in M-phase compared to WT mice. This suggests that the beta-cells from Hq mutant mice are arrested in the G2 phase and are unlikely to complete the cell cycle. beta-cells from Hq mutant mice display increased sensitivity to hydrogen peroxide-induced apoptosis, which was confirmed in human islets in which AIF was depleted by siRNA. AIF deficiency had no effect on glucose stimulated insulin secretion, but the impaired effect of hydrogen peroxide on beta-cell function was potentiated. Conclusions/Significance: Our results indicate that AIF is essential for maintaining beta-cell mass and for oxidative stress response. A decrease in the oxidative phosphorylation capacity may counteract the development of diabetes, despite its deleterious effects on beta-cell survival.

We performed hepatic arterial infusion (HAI) chemotherapy for 11 patients with liver metastasis from gastric cancer, who had no other metastasis. The main antineoplastic drug was 5-fluorouracil (5-FU). The catheter was inserted into the hepatic artery using the GDA coiling method by interventional radiologic technique in 9 patients, and by operative treatment in 2 patients. The response rate for 10 patients was 91 % (CR 3, PR 7, PD1). The survival time from the beginning of the HAI chemotherapy was 8-34 months. The causes of withdrawal from the chemotherapy were PD in 7 patients and catheter troubles in 4 patients. There was no patient suffering from severe adverse effect. The HAI chemotherapy was effective and useful for patients with liver metastasis of gastric cancer. We thought a gastric cancer patient with liver metastasis who didn't have an uncontrollable other organ metastasis was a good target for this regimen.

Embryonic Hedgehog signaling is essential for proper tissue morphogenesis and organ formation along the developing gastrointestinal tract. Hedgehog ligands are expressed throughout the endodermal epithelium at early embryonic stages but excluded from the region that will form the pancreas. Ectopic activation of Hedgehog signaling at the onset of pancreas development has been shown to inhibit organ morphogenesis. In contrast, Hedgehog signaling components are found within pancreatic tissue during subsequent stages of development as well as in the mature organ, indicating that a certain level of pathway activation is required for normal organ development and function. Here, we ectopically activate the Hedgehog pathway midway through pancreas development via expression of either Sonic (Shh) or Indian Hedgehog (Ihh) under control of the human Pax4-promoter. Similar pancreatic defects are observed in both Pax4-Shh and Pax4-Ihh transgenic lines, suggesting that regulation of the overall level of Hedgehog activity is critical for proper pancreas development. We also show that Hedgehog signaling controls mesenchymal vs. epithelia] tissue differentiation and that pathway activation impairs formation of epithelial progenitors. Thus, tight control of Hedgehog pathway activity throughout embryonic development ensures proper pancreas organogenesis. (c) 2005 Elsevier Inc. All rights reserved.

Purpose: Among invasive ductal carcinomas of the pancreas (IDCP), there is a morphologically characteristic subgroup accompanied by abundant intraductal carcinoma components (ICCs). With the aim of determining whether ICC-rich IDCP are biologically different from ICC-poor IDCP, the expression status of Dpc4 protein was analyzed. Experimental Design: A total of 43 IDCP was subdivided into two groups: (a) ICC-rich IDCP (ICCs area occupies greater than or equal to10% of the entire tumorous area); and (b) ICC-poor IDCP (with <10% of ICCs area). A total of 10 invasive carcinomas derived from intraductal papillary-mucinous neoplasms (ICs from IPMNs) were also analyzed. Each invasive and intraductal carcinoma area was then evaluated for Dpc4 protein status by immunohistochemistry. Results: In a total of 43 IDCP, there were 23 ICC-rich IDCP and 20 ICC-poor IDCP. Dpc4-positive immuno-staining was observed in the invasive carcinoma component of ICC-rich IDCP, ICC-poor IDCP, and ICs from IPMN in 18 of 23 (78%), 4 of 20 (20%), and 7 of 10 (70%) cases, respectively. In the intraductal component, positive staining for Dpc4 was found in 20 of 23 (87%), 3 of 7 (41%), and 8, of 10 (80%) cases, respectively. Dpc4 expression was found in both the invasive and ICC components of ICC-rich IDCP, similar to that found in IC derived from IPMN, whereas the expression of Dpc4 was largely diminished in ICC-poor IDCP. Conclusions: Morphologically distinct subgroups of invasive ductal carcinomas of the pancreas, namely ICC-rich IDCP and ICC-poor IDCP, are also biologically distinguishable as revealed by the differential expression of Dpc4.

Hedgehog signaling is known to regulate tissue morphogenesis and cell differentiation in a dose-dependent manner. Loss of Indian hedgehog (Ihh) results in reduction in pancreas size, indicating a requirement for hedgehog signaling during pancreas development. By contrast, ectopic expression of sonic hedgehog (Shh) inhibits pancreatic marker expression and results in transformation of pancreatic mesenchyme into duodenal mesoderm. These observations suggest that hedgehog signaling activity has to be regulated tightly to ensure proper pancreas development. We have analyzed the function of two hedgehog inhibitors, Hhip and patched 1 (Ptch), during pancreas formation. Our results indicated that loss of Hhip results in increased hedgehog signaling within the pancreas anlage. Pancreas morphogenesis, islet formation and endocrine cell proliferation is impaired in Hhip mutant embryos. Additional loss of one Ptch allele in Hhip(-/-)Ptch(+/-) embryos further impairs pancreatic growth and endodermal cell differentiation. These results demonstrate combined requirements for Hhip and Ptch during pancreas development and point to a dose-dependent response to hedgehog signaling within pancreatic tissue. Reduction of Fgf10 expression in Hhip homozygous mutants suggests that at least some of the observed phenotypes result from hedgehog-mediated inhibition of Fgf signaling at early stages.

Background/Aims: Virtual endoscopy is a new method of diagnosis using computer processing of three-dimensional images data sets. However, there are few reports about the clinical application of virtual endoscopy for the pancreas. In this study, we evaluated the feasibility of surface-rendered magnetic resonance virtual endoscopy for pancreatic cancer. Methodology: Twenty-six cases of pancreatic cancer were studied. Fifteen patients had pancreatic head cancer, 7 had pancreatic body cancer, and 4 had pancreatic tail cancer. Twelve patients underwent surgical resection of the pancreas. Magnetic resonance imaging data were acquired with a 1.5-T clinical imager (Signal.5; GE Medical Systems, USA). We used a multislab single-shot fast spin-echo sequence. Section thickness was between 2 and 3mm in the coronal plane. Three-dimensional reconstructed images and virtual endoscopic images were generated with Advantage Windows by GE. Results: Virtual endoscopic images could be generated in 20 patients with pancreatic cancer (76.9%). In these cases, we were able to observe the-inner surface of the pancreatic duct and the stricture from not only the pancreatic head but also the pancreatic tail. Clear virtual images could not be generated in 6 cases. We were able to divide the 20 cases in which images could be generated, into groups according to the appearance of the stricture. The edge of the stricture appeared to be protruding in 4 cases (15.4%), and appeared to be polygonal in 13 cases (50.0%). In 3 cases, we recognized the existence of a stricture, but the detail of the stricture was unclear. Conclusions: Virtual endoscopy caused minimal discomfort compared to real endoscopic examination, and it can access cystic lesions and the pancreatic duct behind the stricture. It is concluded that virtual endoscopy for pancreatic cancer has potential clinical utility.

We have sometimes encountered invasive ductal carcinomas (IDCs) of the pancreas containing intraductal carcinoma components in the intra- and/or extra-tumor area. The purpose of this study was to investigate whether intraductal carcinoma components would be useful for predicting the outcome of IDC patients. Forty-seven surgically treated IDCs were examined, and all histological tumor sections were stained with Elastica to accurately confirm intraductal carcinoma components. Well-known clinicopathological parameters that exhibited a significant correlation in the univariate analyses for predicting disease-free survival (DFS) and overall survival (OS) were entered into the Cox proportional hazard multivariate analysis. Since the lowest P-value predicting DFS or OS periods was observed in IDCs with more than 10% intraductal carcinoma components and those with 10% or less intraductal carcinoma components (P = 0.028 and P = 0.019), we established the cutoff value of intraductal carcinoma components at 10%. In the multivariate analyses for DFS and OS, the presence of more than 10% intraductal carcinoma components showed a marginally significant increase in the hazard rate (HR) of tumor recurrence (P = 0.067) and significantly increased the HR of mortality (P = 0.040). The present study demonstrated that IDCs with more than 10% intraductal carcinoma components were associated with a significantly better patient outcome than those with 10% or less intraductal carcinoma components.