Doki Y

Immunohistochemical evaluation of E-cadherin adhesion molecule expression in human gastric cancer.

E-cadherin (ECD) is one of subclasses of the cadherin family which plays a major role in the maintenance of intercellular adhesion in epithelial tissues. An immunohistochemical study of ECD expression was performed on gastric adenocarcinoma from 103 patients using our monoclonal antibody for human ECD (HECD-1). ECD was strongly expressed in normal gastric epithelium without exception; however, various staining patterns were observed in cancer tissues. The frequency of tumours with preserved ECD expression (Pre-type) and reduced ECD expression (Rd-type) was 42% and 58% respectively. Tumours with a high frequency of Rd-type expression particularly included: undifferentiated tumours (85%, 46/54), Borrmanns type 4 (90%, 9/10), tumours larger than 2.6 cm in diameter (65%, 53/81), tumours invading beyond the subserosa layer (78%, 46/59), and tumours with infiltrative growth (87%, 41/47). Furthermore, the frequency of Rd-type expression in cases with peritoneal dissemination (82%, 9/11) or lymph node metastasis (73%, 43/59) was significantly higher than that in cases without dissemination or metastasis. These results suggest that ECD might play a key role in the genesis of histological differentiation, and that the reduction of ECD expression may affect the mode of invasion and metastasis of human gastric cancer cells.

Activation of Wnt/ β -catenin signalling pathway induces chemoresistance to interferon- α /5-fluorouracil combination therapy for hepatocellular carcinoma

Type I IFN receptor type 2 (IFNAR2) expression correlates significantly with clinical response to interferon (IFN)-α/5-fluorouracil (5-FU) combination therapy for hepatocellular carcinoma (HCC). However, some IFNAR2-positive patients show no response to the therapy. This result suggests the possibility of other factors, which would be responsible for resistance to IFN-α/5-FU therapy. The aim of this study was to examine the mechanism of anti-proliferative effects of IFN-α/5-FU therapy and search for a biological marker of chemoresistance to such therapy. Gene expression profiling and molecular network analysis were used in the analysis of non-responders and responders with IFNAR2-positive HCC. The Wnt/β-catenin signalling pathway contributed to resistance to IFN-α/5-FU therapy. Immunohistochemical analysis showed positive epithelial cell adhesion molecule (Ep-CAM) expression, the target molecule of Wnt/β-catenin signalling, only in non-responders. In vitro studies showed that activation of Wnt/β-catenin signalling by glycogen synthesis kinase-3 inhibitor (6-bromoindirubin-3′-oxime (BIO)) induced chemoresistance to IFN-α/5-FU. BrdU-based cell proliferation ELISA and cell cycle analysis showed that concurrent addition of BIO and IFN-α/5-FU significantly to hepatoma cell cultures reduced the inhibitory effects of the latter two on DNA synthesis and accumulation of cells in the S-phase. The results indicate that activation of Wnt/β-catenin signalling pathway induces chemoresistance to IFN-α/5-FU therapy and suggest that Ep-CAM is a potentially useful marker for resistance to such therapy, especially in IFNAR2-positive cases.

Characterization of soluble E-cadherin as a disease marker in gastric cancer patients.

The soluble fragment of E-cadherin protein (S-ECD) is reported to be increased in the peripheral blood of cancer patients. In this study, we investigated the clinical significance of serum S-ECD in 81 patients with gastric cancer. The amount of serum S-ECD was significantly higher in the gastric cancer patients (4735 +/- 2310 ng ml(-1)) than in healthy volunteers (2515 +/- 744 ng ml(-1)). With the normal range cut-off at average +2 s.d., 67% patients showed abnormally high serum S-ECD levels. This frequency was significantly higher than that of other tumour markers, such as CEA (4.4%) or CA19-9 (13.3%). However, there was no significant correlation between the amount of S-ECD and clinicopathological factors. Serum S-ECD might be derived from cancer tissue, as removal of cancers by surgical treatment results in quick decline of the serum S-ECD and S-ECD can be detected by immunoblot in cancer tissues but not in normal epithelium. The serum S-ECD amount was compared with the E-cadherin expression in cancer tissues, which were classified into those showing preserved (+), partially reduced (+/-) or lost (-) expression. Interestingly, E-cadherin (+/-) tumours showed higher serum S-ECD levels than the other types, and a higher amount of S-ECD in the immunoblot analysis. Thus, the serum level of S-ECD may serve as an excellent tumour marker with high sensitivity. Furthermore, analysis of S-ECD in serum and cancer tissue can offer clues for elucidating the mechanism of reduction of E-cadherin expression in cancer cells.

Role of multidrug resistance protein 2 (MRP2) in chemoresistance and clinical outcome in oesophageal squamous cell carcinoma.

Background:Although multidrug resistance protein 2 (MRP2) confers chemoresistance in some cancer types, its implication on oesophageal squamous cell carcinoma (ESCC) remains unclear.Methods:We evaluated MRP2 expression by immunohistochemistry and RT–PCR using 81 resected specimens from ESCC patients who did or did not receive neo-adjuvant chemotherapy (NACT), including 5-fluorouracil, doxorubicin, and cisplatin (CDDP). Correlation between MRP2 expression and response to chemotherapy was also examined in 42 pre-therapeutic biopsy samples and eight ESCC cell lines.Results:MRP2-positive immunostaining was more frequently observed in ESCCs with NACT than in those without NACT (27.3 vs 5.4%). The MRP2-positive patients showed poorer prognosis than MRP2-negative patients (5-year survival rate, 25.6 vs 55.7%). Concordantly, ESCC with NACT showed 2.1-fold higher mRNA expression of MRP2 than those without NACT (P=0.0350). In pre-therapeutic biopsy samples of patients with NACT, non-responders showed 2.9-fold higher mRNA expression of MRP2 than responders (P=0.0035). Among the panel of ESCC cell lines, TE14 showed the highest MRP2 mRNA expression along with the strongest resistance to CDDP. Inhibition of MRP2 expression by small-interfering RNA reduced chemoresistance to CDDP.Conclusion:Our data suggested that MRP2 is one of molecules, which regulate the sensitivity to chemotherapy including CDDP in advanced ESCC patients.

Overexpression of hypoxia-inducible factor-1 alpha in gastric adenocarcinoma.

BackgroundThe transcriptional factor hypoxia-inducible factor 1α (HIF-1α) controls angiogenesis and metabolism by upregulating hypoxia-induced genes, such as the vascular endothelial growth factor (VEGF) gene and the glucose transporter (GLUT-1) gene. In addition to its regulation by oncogenes or tumor suppressor genes such as HER2, p53, VHL, and PTEN, overexpression of HIF-1α is induced by hypoxia. Increased HIF-1α expression is associated with malignant potential, and with patient prognosis and response to chemoradiotherapy in some cancer types.MethodsWe investigated the association between HIF-1α expression and clinicopathological characteristics, including the expression of VEGF and p53 proteins, in gastric cancer. Furthermore, we analyzed the impact of HIF-1α, VEGF, and p53 protein expression on resistance to chemotherapy in advanced gastric cancer.ResultsAmong 146 specimens from patients with gastric adenocarcinoma, 89 (61.0%), 52 (35.6%), and 102 (69.9%) were positive for HIF-1α, p53, and VEGF expression, respectively. The increased expression of HIF-1α protein correlated significantly with the increased expression of p53 (P < 0.0001) and VEGF (P = 0.0007). However, overexpression of these proteins was not associated with prognosis or clinicopathological status, with the exception of infrequent distant metastases. Furthermore, overexpression of these proteins was not associated with chemosensitivity in these patients with gastric cancer.ConclusionOur results indicate that overexpression of HIF-1α correlates significantly with p53 and VEGF protein expression in patients with gastric cancer; however, this overexpression shows no association with clinicopathological status, patient prognosis, or chemosensitivity.

Lack of fludeoxyglucose F 18 uptake in posttreatment positron emission tomography as a significant predictor of survival after subsequent surgery in multimodality treatment for patients with locally advanced esophageal squamous cell carcinoma

OBJECTIVE Patients with advanced esophageal squamous cell carcinoma receive neoadjuvant chemotherapy or chemoradiotherapy to improve survival, but benefits are observed only in those with histologic response. Positron emission tomography with fludeoxyglucose F 18 (INN fludeoxyglucose [(18)F]) detects accumulation of glucose analog in viable cancer cells. This study investigated the usefulness of positron emission tomography with fludeoxyglucose F 18 in assessment of response of advanced esophageal squamous cell carcinoma to neoadjuvant treatment to establish new criteria to predict postoperative long-term survival. METHODS Fifty patients with locally advanced esophageal squamous cell carcinoma who received neoadjuvant therapy (chemotherapy 35, chemoradiotherapy 15) underwent positron emission tomography with fludeoxyglucose F 18 before surgical resection in evaluation of posttreatment maximum standardized uptake value, residual tumor size (maximum square area of longitudinal axis), histologic response, and postoperative survival. RESULTS After treatment, uptake was not noted in 21 patients (posttreatment maximum standardized uptake value < 2.5, negative) but was detected in 29 (> or = 2.5, positive). Residual tumor size ranged from 0 to 54.0 mm(2) for negative results and 55.0 to 676.0 mm(2) for positive, clearly distinguishing histologic major response from nonresponse. The negative group demonstrated significantly higher 5-year cause-specific survival (67.7%) and lower hematogenous recurrence (4.8%) than the 36.5% and 37.0% values in the positive group, (P < .0042 and P = .0083, respectively). Univariate Cox regression analyses identified posttreatment maximum standardized uptake value (cutoff 2.5) as the only preoperative prognostic factor (P = .0071). CONCLUSION Posttreatment positron emission tomography with fludeoxyglucose F 18 reliably predicted histologic response and postoperative survival in advanced esophageal squamous cell carcinoma. This tool could potentially be used to tailor optimal treatment according to individual responses.

Rapamycin induces autophagy in islets: relevance in islet transplantation.

Islet transplantation can provide insulin independence in patients with type 1 diabetes mellitus. However, islet allograft recipients exhibit a gradual decline in insulin independence, and only 10% do not require insulin at 5 years. This decline may reflect drug toxicity to islet beta cells. Rapamycin, a central immunosuppressant in islet transplantation, is a mammalian target of rampamycin inhibitor that induces autophagy. The relative contributions of autophagy in transplanted islets are poorly understood. Therefore, in the present study we sought to evaluate the effects of rapamycin on islet beta cells. Rapamycin treatment of islets resulted in accumulation of membrane-bound light chain 3 (LC3-II) protein, an early marker of autophagy. In addition, rapamycin treatment of isolated islets elicited not only reduction of viability but also downregulation of in vitro potency. To further examine the occurrence of autophagy in rapamycin-treated islets, we used GFP (green fluorescent protein)-LC3 transgenic mice that express a fluorescent autophagosome marker. The GFP-LC3 signals were markedly increased in rapamycin treated islets compared with control islets. In addition, to show improvement by blockade of autophagic signaling, islets were treated with rapamycin in the presence of 3-methyladenine, which inhibits autophagy. Thereafter, both islet viability and islet potency were dramatically improved. The number of GFP-LC3 dots clearly increased after 3-MA treatment. Thus, rapamycin treatment of islets induces autophagy in vitro. This phenomenon may contribute to the progressive graft dysfunction of transplanted islets. Therapeutically targeting this novel signaling may yield significant benefits for long-term islet survival.

Surgical strategy for the gastric gastrointestinal stromal tumors (GISTs) larger than 5 cm: laparoscopic surgery is feasible, safe, and oncologically acceptable.

Background: The efficacy and feasibility of laparoscopic surgery (LAP) for gastric GISTs >5 cm has not been adequately assessed. Here we investigated the clinical outcomes of these patients. Patients and Methods: Twenty-seven consecutive patients who underwent resection for gastric GISTs >5 cm were enrolled in this retrospective study. We assessed the tumor characteristics, surgical outcomes, tumor recurrence, and patient survival in the open surgery (OPEN) group and in the LAP group. Results: The tumor size in the OPEN group was larger than that in the LAP group, but there were no differences in the mitotic count. There were no differences in operative complications. Finally, there were no differences in the disease-free and no patients in the LAP group died. Conclusions: In patients with gastric GISTs >5 cm, LAP can be performed with outcomes equivalent to those of OPEN if patient selection and intraoperative judgment are appropriate.

Portal Vein Calcification: A Clinical Review of the Last 50 Years and Report of a Case Associated with Dysplasminogenemia

We report herein a case of a 68-year-old Japanese woman in whom calcification of the portal vein was recognized by plain abdominal X-ray radiograph and computed tomography (CT) scan when she presented with repeated thrombosis of the portal system. Following emergency small bowel resection for intestinal necrosis caused by superior mesenteric vein thrombosis, hematological studies revealed the association of dysplasminogenemia. A review of 21 cases of portal vein calcification reported between 1940 and 1990 revealed the average age to be 53.7±10.2 years and the male/female ratio 17:4. Although the majority of cases suffered from portal hypertension (81%), only 38% had any evidence of liver cirrhosis, while 52% had normal liver function, being comparable to idiopathic portal hypertension. The calcified lesions were located in the portal vein in 100% of cases, the splenic vein in 62%, the superior mesenteric vein in 33%, and the inferior mesenteric vein in 0%. The precise etiology of the calcification was not elucidated in any of the reviewed cases. The patient reported herein is the first reported case of portal vein calcification due to repeated thrombosis of the portal system caused by dysplasminogenemia, which could be accounted as a cause of idiopathic portal hypertension.

Laparoscopic intraoperative navigation surgery for gastric cancer using real-time rendered 3D CT images.

AbstractPurposeRecent advances in laparoscopic surgical technology have made it possible to perform advanced high-level surgery, such as lymph node dissection for malignancy. Grasping the anatomy during such procedures is important for a safe operation. We have developed a new image information system that provides three-dimensional (3D) reconstructed CT images synchronized with the motion of the laparoscope. This study assesses this new navigation system.MethodsEnhanced CT using a custom-made software program can provide 3D angiography images reconstructed as a laparoscopic view. A motion sensor mounted on the laparoscope can detect the direction angle of the laparoscope. The real-time rendered 3D CT images are synchronized with the laparoscopic video images according to the motion of the scope. These 3D CT images are projected on another monitor close to the laparoscopic video monitor. Lymph node dissection can be performed with the help of the real-time navigation system that provides a detailed 3D view of the vasculature.ResultsTen laparoscopic gastrectomies were performed using this navigation system. Real-time intraoperative navigation of the vasculature was available, allowing for an excellent surgical outcome. No complications occurred in this series.ConclusionOur intraoperative navigation system allows for safe laparoscopic gastric lymph node dissection.