Effectiveness of CO2-insufflated endoscopic submucosal dissection with the duodenal balloon occlusion method for early esophageal or gastric cancer: a randomized case control prospective study.

BACKGROUND: Endoscopic submucosal dissection (ESD) has typically been performed using air insufflation. Recently, however, insufflation of CO2 has been increasingly used to avoid complications. This prospective study was designed to compare the CO2 concentration, intestinal volume, and acid-base balance using the duodenal balloon procedure. METHODS: From June 2010 to February 2011, we enrolled 44 patients with esophageal or gastric cancer and randomly allocated them into two groups. We compared 22 patients undergoing CO2-insufflated ESD with a balloon placed into the duodenal bulb (duodenal balloon group) and 22 patients undergoing regular CO2-insufflated ESD (regular group). Three-dimensional computed tomography was performed before and after the procedure to measure intestinal volume. CO2 concentrations were measured every 10 minutes. The visual analogue system (VAS) scores for postoperative symptoms were recorded, and pH was measured immediately after the procedure. This was a prospective case control study randomized by the sealed envelope method. RESULTS: Intestinal CO2 gas volume before and after ESD was lower in the duodenal balloon group than in the regular group (P = 0.00027). The end-tidal CO2 level was significantly lower in the duodenal balloon group than in the regular group (P = 0.0001). No significant differences in blood ΔpH were found between the two groups. The VAS score for the occurrence of nausea due to abdominal distension after ESD indicated a significant difference (P = 0.031). CONCLUSIONS: ESD using the duodenal balloon occlusion method is effective for reduction of post-ESD intestinal CO2 gas volume, resulting in a lower total amount of CO2 insufflation during ESD and reducing harmful influences on the human body to some extent.

New technique for safer endoscopic submucosal dissection using the duodenal balloon occlusion method.

BACKGROUND AND AIM: Endoscopic submucosal dissection (ESD) enables complete, collective removal of gastrointestinal (GI) malignant tumors, but requires a long operation time. Air insufflated during ESD is distributed throughout the entire GI tract, and thus causes an enlarged feeling of the abdomen. We aimed to reduce the incidence of an enlarged feeling of the abdomen by wedging a balloon in the bulbus duodeni to reduce air flow into the lower parts of the GI tract. METHODS: Sixteen patients who were approved by the institutional ethics committee and provided consent to participate in this single-center, prospective study were divided into two groups using a sealed-envelope randomization method: ESD with a balloon wedged in the bulbus duodeni (the balloon [+] group) or conventional ESD with no balloon (the balloon [-] group). Total air volume in the entire GI tract and its change before and after ESD were measured objectively by 3-D computed tomography. RESULTS: In the balloon (+) group, the mean intestinal gas volume (± standard deviation) was 274.3 ± 142.0 mL before ESD, and 352.5 ± 183.2 mL after, with a mean change of 78.1 ± 139.7 mL. The increase in intestinal gas volume was well controlled. No postoperative complications, such as an enlarged feeling of the abdomen, was reported in the balloon (+) group. CONCLUSIONS: Our new technique has several advantages, including reduction in the frequency of postoperative abdominal symptoms, and will be useful and safe for gastric ESD.

Surgical approach for extrahepatic metastasis of HCC in the abdominal cavity.

BACKGROUND/AIMS: Despite recent development of therapeutic strategies for intrahepatic lesions, standard guidelines for treatment of extrahepatic metastases of hepatocellular carcinoma have not been established. METHODOLOGY: Surgical resection for intra-abdominal extrahepatic metastases of hepatocellular carcinoma was performed on 10 patients at our institution between 1992 and 2008. We retrospectively examined the clinicopathologic features and significance of a surgical approach in these patients. RESULTS: Nine of the 10 patients received treatment for primary hepatocellular carcinoma before surgery for intra-abdominal extrahepatic metastasis. A simultaneous intrahepatic lesion was detected in half of the patients when the extrahepatic metastasis was resected. Extrahepatic recurrent organs included adrenal glands, lymph nodes, abdominal wall, stomach and diaphragm. The mean survival period after resection was 36.1 months. Two patients are still alive without further recurrence. One patient died of retroperitoneal recurrence and 7 died of intrahepatic recurrence or liver failure after resection. CONCLUSIONS: With careful case selection, considering that not all extrahepatic metastases suggest systemic spread of hepatocellular carcinoma, surgical treatment for metastatic lesions in the abdominal cavity can provide a relatively good prognosis.

Isolated splenic metastasis of ovarian cancer 20 years after operation: a case report and literature review.

Splenic metastasis reflecting multiple metastases of cancer is often observed in the terminal stage, although solitary splenic metastasis is extremely rare. In addition, late recurrence even after 20 years of operation is very unusual. We report the case of a 52-year-old woman who was admitted to our department with a splenic tumor. She had a past history of total abdominal hysterectomy with bilateral sapingo-oophorectomy for ovarian cancer 20 years ago. Abdominal CT scan revealed a huge mass of 12 x 8 x 5.5 cm between the spleen and the left kidney. Splenectomy was performed with a diagnosis of splenic tumor. Microscopically, the tumor was a poorly differentiated adenocarcinoma including components of poorly differentiated ovarian cancer, and was diagnosed as an ovarian cancer metastasis. The patient showed no evidence of recurrence until 5 years postoperatively. Splenic metastasis is considered a terminal stage of cancer. However, when the lesion is solitary, surgical treatment is recommended.

Protective effect of lipopolysaccharide preconditioning in hepatic ischaemia reperfusion injury.

BACKGROUND: Preconditioning using lipopolysaccharide (LPS), a toll-like receptor 4 (TLR4) ligand, has been demonstrated to reduce ischaemia/reperfusion injury (IRI) in some organs, but its effect in the liver has not been elucidated. We examined the liver protective mechanism and correlated signalling pathway of LPS preconditioning in mice. METHODS: BALB/c and TLR4 mutant mice underwent 90 min of 70% hepatic ischaemia. Lipopolysaccharide (100 µg/kg) was injected intraperitoneally 20 h or 30 min before ischaemia. Liver damage after reperfusion was examined using serum samples and liver specimens. To analyse the mechanism of preconditioning in detail, phosphorylation of representative signalling mediators to nuclear factor-κB (NF-κB) activation, Akt and interleukin-1 receptor-associated kinase-1 (IRAK-1), and expression of a negative feedback inhibitor, suppressor of cytokine signalling-1 (SOCS-1), were evaluated by Western blotting. RESULTS: Pretreatment with LPS only 20 h before ischaemia elicited a preconditioning effect; however, preconditioning was absent in TLR4 mutant mice. Lipopolysaccharide significantly decreased serum alanine aminotransferase, tumour necrosis factor-α, hepatocyte necrosis and NF-κB activity after reperfusion. Phosphorylated IRAK-1 was suppressed by LPS, whereas no difference was observed in phosphorylated Akt. Pre-ischaemic LPS provided early induction of SOCS-1. DISCUSSION: Late-phase LPS preconditioning provided liver protection against IRI through the downregulation of the TLR4 cascade derived from early induction of SOCS-1 during ischaemia/reperfusion.

[A case of Stage IV AFP producing gastric cancer with long-term survival treated by adjuvant chemotherapy with S-1].

A 66-year-old woman underwent a total gastrectomy for advanced gastric cancer of cardia. The histological diagnosis was moderately-differentiated tubular adenocarcinoma and the pathological Stage was IV: T4 (diaphragm), N2, M0. Microscopically, there were findings of severe lymphatic and venous invasions with intravenous tumor thrombus around the splenic hilum. Immunohistochemical staining confirmed AFP production of the tumor. The risk of recurrence was considered very high and her prognosis very poor. The patient received adjuvant chemotherapy with S-1. There was no finding of recurrence in the series of postoperative follow-up examinations. Previous reports describe the prognosis of AFP producing gastric cancer as very poor. In several cases, however, aggressive treatments for AFP producing gastric cancer may result in a better prognosis. This is a long survival case of AFP producing gastric cancer successfully treated with S-1 after surgery.

Detection of gastric cancer using 18F-FLT PET: comparison with 18F-FDG PET.

PURPOSE: We prospectively investigated the feasibility of 3'-deoxy-3'-(18)F-fluorothymidine (FLT) positron emission tomography (PET) for the detection of gastric cancer, in comparison with 2-deoxy-2-(18)F-fluoro-D-glucose (FDG) PET, and determined the degree of correlation between the two radiotracers and proliferative activity as indicated by Ki-67 index. METHODS: A total of 21 patients with newly diagnosed advanced gastric cancer were examined with FLT PET and FDG PET. Tumour lesions were identified as areas of focally increased uptake, exceeding that of surrounding normal tissue. For semiquantitative analysis, the maximal standardized uptake value (SUV) was calculated. RESULTS: For detection of advanced gastric cancer, the sensitivities of FLT PET and FDG PET were 95.2% and 95.0%, respectively. The mean (+/-SD) SUV for FLT (7.0 +/- 3.3) was significantly lower than that for FDG (9.4 +/- 6.3 p < 0.05). The mean FLT SUV and FDG SUV in nonintestinal tumours were higher than in intestinal tumours, although the difference was not statistically significant. The mean (+/-SD) FLT SUV in poorly differentiated tumours (8.5 +/- 3.5) was significantly higher than that in well and moderately differentiated tumours (5.3 +/- 2.1; p < 0.04). The mean FDG SUV in poorly differentiated tumours was higher than in well and moderately differentiated tumours, although the difference was not statistically significant. There was no significant correlation between Ki-67 index and either FLT SUV or FDG SUV. CONCLUSION: FLT PET showed as high a sensitivity as FDG PET for the detection of gastric cancer, although uptake of FLT in gastric cancer was significantly lower than that of FDG.

Attenuation of the systemic inflammatory response and infectious complications after gastrectomy with preoperative oral arginine and omega-3 fatty acids supplemented immunonutrition.

BACKGROUND: Past trials have shown perioperative immunonutrition to improve the outcome for patients with gastric cancer. The present study was designed to evaluate the effect of preoperative oral immunonutrition on cellular immunity, the duration of the systemic inflammatory response syndrome (SIRS), and detailed postoperative complications in patients with gastric cancer. METHODS: Sixty patients with gastric cancer were randomly assigned to two groups: one group received immune-enhanced formulas supplemented with arginine and omega-3 fatty acids (immune-enhancing diet (ID) group, n = 30); the other received standard formulas (conventional diet (CD) group, n = 30) for 7 days before the operation. These groups were well matched in terms of age, sex, operations, cancer stages, and intraoperative variables. The postoperative outcome was evaluated based on clinical variables, including postoperative infectious complications, noninfectious complications, and SIRS duration. In addition, the perioperative state of cellular immunity was evaluated and compared between the two groups. RESULTS: The incidence of postoperative infectious complications in the ID group (6%) was significantly (p < 0.05) lower than that of the CD group (28%). The duration of SIRS in the ID group (0.77 +/- 0.9 days) was significantly (p < 0.05) shorter than that in the CD group (1.34 +/- 1.45 days). The postoperative lymphocyte and CD4(+)T-cell counts significantly decreased (p < 0.05) in both groups. However, the number of CD4(+)T-cells on preoperative day 1 and postoperative day 7 was significantly (p < 0.05) higher in the ID group than in the CD group. CONCLUSIONS: Preoperative oral immune-enhanced formulas supplemented with arginine and omega-3 fatty acids enhanced the immune status of the patients, reduced the duration of SIRS, and decreased the incidence of postoperative infectious complications. CD4(+)T-cell immunity likely played an important role in the modulation of the postoperative immune and inflammatory response after gastrectomy.

Annexin A2 expression and phosphorylation are up-regulated in hepatocellular carcinoma.

Annexins (ANXs) constitute a family of Ca2+-dependent membrane-binding proteins; at least 20 of them have been described to date. Among these, Annexin A2 (ANXA2) has been revealed as a multi-functional protein in vitro. Its actual role in vivo, however, requires further investigation. We already reported that ANX-I (ANXA1) was up-regulated in hepatocellular carcinoma (HCC). The role of ANXA2 in various liver diseases including HCC remains obscure. In the present study, the protein and mRNA levels of ANXA2, as well as its localization, were determined for the normal human liver, chronic hepatitis liver, and non-tumorous and tumorous portions of HCC tissues. ANXA2 was rarely detected in either normal or chronic hepatitis liver tissues, whereas it was overexpressed at both the transcriptional and translational levels in tumorous and non-tumorous regions of HCC. In addition, in many cases, more ANXA2 was expressed in the tumorous portion than in the non-tumorous portion of HCC. The expression of ANXA2 was mainly localized in cancer cells, especially in poorly differentiated HCC. Furthermore, ANXA2 was tyrosine-phosphorylated in HCC. These data suggest that overexpression and tyrosine phosphorylation of ANXA2 play important roles in the malignant transformation process leading to HCC and are related to the histological grade of HCC.

Role of 18F-fluorodeoxyglucose positron emission tomography imaging in surgery for pancreatic cancer.

AIM: To evaluate the role of positron emission tomography using 18F-fluorodeoxyglucose (FDG-PET) in the surgical management of patients with pancreatic cancer, including the diagnosis, staging, and selection of patients for the subsequent surgical treatment. METHODS: This study involved 53 patients with proven primary pancreatic cancer. The sensitivity of diagnosing the primary cancer was examined for FDG-PET, CT, cytological examination of the bile or pancreatic juice, and the serum levels of carcinoembrionic antigens (CEA) and carbohydrate antigen 19-9 (CA19-9). Next, the accuracy of staging was compared between FDG-PET and CT. Finally, FDG-PET was analyzed semiquantitatively using the standard uptake value (SUV). The impact of the SUV on patient management was evaluated by examining the correlations between the SUV and the histological findings of cancer. RESULTS: The sensitivity of FDG-PET, CT, cytological examination of the bile or pancreatic juice, and the serum levels of CEA and CA19-9 were 92.5%, 88.7%, 46.4%, 37.7% and 69.8%, respectively. In staging, FDG-PET was superior to CT only in diagnosing distant disease (bone metastasis). For local staging, the sensitivity of CT was better than that of FDG-PET. The SUV did not correlate with the pTNM stage, grades, invasions to the vessels and nerve, or with the size of the tumor. However, there was a statistically significant difference (4.6 +/- 2.9 vs 7.8 +/- 4.5, P = 0.024) in the SUV between patients with respectable and unresectable disease. CONCLUSION: FDG-PET is thus considered to be useful in the diagnosis of pancreatic cancer. However, regarding the staging of the disease, FDG-PET is not considered to be a sufficiently accurate diagnostic modality. Although the SUV does not correlate with the patho-histological prognostic factors, it may be useful in selecting patients who should undergo subsequent surgical treatment.

A patient with unresectable advanced pancreatic cancer achieving long-term survival with gemcitabine chemotherapy.

A 68-year-old female visited a local clinic with epigastralgia. A routine laboratory test revealed jaundice and liver dysfunction. She was referred to this hospital. Abdominal computed tomography (CT) and endoscopic retrograde cholangio-pancreatography (ERCP) revealed that the density of the entire pancreas had decreased, and showed dilatation of the common bile duct (CBD) and the main pancreatic duct (MPD). Pancreatic cancer was diagnosed by cytological examination analyzing the pancreatic juice obtained by ERCP. When jaundice had decreased the tumor was observed via laparotomy. No ascites, liver metastasis, or peritoneal dissemination was observed. The entire pancreas was a hard mass, and a needle biopsy was obtained from the head, body and tail of the pancreas. These biopsies diagnosed a poorly differentiated adenocarcinoma. Hepaticojejunostomy was thus performed, and postoperative progress was good. Chemotherapy with 1000 mg/body per week of gemcitabine was administered beginning 15 d postoperatively. However, the patient suffered relatively severe side effects, and it was necessary to change the dosing schedule of gemcitabine. Abdominal CT revealed a complete response (CR) after 3 treatments. Therefore, weekly chemotherapy was stopped and was changed to monthly administration. To date, for 4 years after chemotherapy, the tumor has not reappeared.

Increasing numbers of hepatic dendritic cells promote HMGB1-mediated ischemia-reperfusion injury.

Endogenous ligands released from damaged cells, so-called damage-associated molecular pattern molecules (DAMPs), activate innate signaling pathways including the TLRs. We have shown that hepatic, warm ischemia and reperfusion (I/R) injury, generating local, noninfectious DAMPs, promotes inflammation, which is largely TLR4-dependent. Here, we demonstrate that increasing dendritic cell (DC) numbers enhance inflammation and organ injury after hepatic I/R. High-mobility group box 1 (HMGB1), a NF released by necrotic cells or secreted by stimulated cells, is one of a number of ligands promoting TLR4 reactivity. Augmentation of DC numbers in the liver with GM-CSF hydrodynamic transfection significantly increased liver damage after I/R when compared with controls. TLR4 engagement on hepatic DC was required for the I/R-induced injury, as augmentation of DC numbers in TLR4 mutant (C3H/HeJ) mice did not worsen hepatic damage. It is interesting that TLR4 expression was increased in hepatic DC following HMGB1 stimulation in vitro, suggesting a mechanism for the increased liver injury following I/R. It thus appears that functional TLR4 on DC is required for I/R-induced injury. Furthermore, HMGB1 may direct the inflammatory responses mediated by DC, at least in part, by enhancing TLR4 expression and reactivity to it and other DAMPs.

The discrepancy in thymidylate synthase and dihydropyrimidine dehydrogenase expression depending on measurement methodologies in stage 4 gastric cancer.

BACKGROUND/AIMS: Thymidylate synthase (TS) and dihydropyrimidine dehydrogenase (DPD) are reported to be a major determinant of variations in the sensitivity for fluoropyrimidines in gastric cancer. The aim of this study was to investigate whether there is a discrepancy in the TS and DPD expression depending on measuring method. METHODOLOGY: The protein levels and mRNA level of TS and DPD were estimated in primary gastric cancer tissue specimens after a non-curative resection. The protein levels were determined by ELISA from frozen tissue specimens. The gene expressions were measured using real-time reverse transcriptional polymerase chain reaction (RT-PCR). For the extraction of RNA, laser-captured microdissection (LCM) was performed in formalin-fixed paraffin-embedded (FFPE) specimens. RESULTS: There was no correlation between the protein levels and mRNA levels of TS and DPD. The protein levels and mRNA expression levels were not correlated with survival. High levels of TS mRNA showed a trend toward reduced survival (p=0.074). CONCLUSIONS: The discrepancy in TS and DPD expressions depending on the measurement methodologies utilized should thus be emphasized in these far advanced gastric cancer patients.

Identification of c-Yes expression in the nuclei of hepatocellular carcinoma cells: involvement in the early stages of hepatocarcinogenesis.

It is thought that the subcellular distribution of Src-family tyrosine kinases, including c-Yes binding to the cellular membrane, is membranous and/or cytoplasmic. c-Yes protein tyrosine kinase is known to be related to malignant transformation. However, the expression patterns of c-Yes in hepatocellular carcinoma (HCC) remains unknown. In the present study, we report that c-Yes is expressed not only in the membrane and cytoplasm, but also in the nuclei of cancer cells in some human HCC tissues and in a human HCC cell line. We examined the expression and localization of c-Yes in human HCC cell lines (HLE, HLF, PLC/PRF/5 and Hep 3B) by Western blotting and immunohistochemical analyses; we also examined the expression of c-Yes by immunohistochemistry and Western blotting in the tissues of various liver diseases, including 39 samples from HCC patients. We used an antibody array to detect proteins that bind to nuclear c-Yes in PLC/PRF/5 cell line. c-Yes was found to be expressed in the membranes and cytoplasm of HLE, HLF and Hep 3B HCC cells; it was also detected in the nuclei in addition to the membranes and cytoplasm of PLC/PRF/5 HCC cells. HCC with nuclear c-Yes was detected in 5 of 39 cases (13.0%), and nuclear c-Yes expression was not detected in normal, chronic hepatitis or cirrhotic livers. All HCCs with nuclear c-Yes expression were well-differentiated, small tumors at the early stages. In the PLC/PRF/5 cell line, the nuclear localization of c-Yes with cyclin-dependent kinase 1 was confirmed by a protein antibody array. In conclusion, nuclear c-Yes expression was found in cancer cells at the early stages of hepatocarcinogenesis, suggesting that nucleus-located c-Yes may be a useful marker to detect early-stage HCC.

Improved microcirculatory effect of D-allose on hepatic ischemia reperfusion following partial hepatectomy in cirrhotic rat liver.

D-allose, one of the rare sugars produced from D-psicose, has been shown to be effective against reperfusion injury after ischemia and partial hepatectomy in cirrhotic rat liver by improving remnant liver blood flow and survival rates, and decreasing liver enzyme levels and liver tissue injury levels. These findings demand further study of the clinical implications of this sugar in view to the advancing fields of liver surgery and transplantation.

Recent Strategies for Treating Stage IV Gastric Cancer: Roles of Palliative Gastrectomy, Chemotherapy, and Radiotherapy.

Recently, many strategies have been reported for the effective treatment of gastric cancer. However, the strategy for treating stage IV gastric cancer remains controversial. Conducting a prospective phase III study in stage IV cancer patients is difficult because of heterogeneous performance status, age, and degree of cancer metastasis or extension. Due to poor prognosis, the variance in physical status, and severe symptoms, it is important to determine the optimal strategy for treating each individual stage IV patient. In the past decade, many reports have addressed topics related to stage IV gastric cancer: the 7th Union for International Cancer Control (UICC) TNM staging system has altered its stage IV classification; new chemotherapy regimens have been developed through the randomized ECF for advanced and locally advanced esophagogastric cancer (REAL)-II, S-1 plus cisplatin versus S-1 in RCT in the treatment for stomach cancer (SPIRITS), trastuzumab for gastric cancer (ToGA), ramucirumab monotherapy for previously-treated advanced gastric or gastro-oesophageal junction adenocarcinoma (REGARD), and ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients with previously-treated advanced gastric or gastro-oesophageal junction adenocarcinoma (RAINBOW) trials; and the survival efficacy of palliative gastrectomy has been denied by the reductive gastrectomy for advanced tumor in three Asian countries (REGATTA) trial. Current strategies for treating stage IV patients can be roughly divided into the following five categories: palliative gastrectomy, chemotherapy, radiotherapy, gastric stent, or bypass. In this article, we review recent publications and guidelines along with above categories in the light of individual symptoms and prognosis.