An effective training system for endoscopic submucosal dissection of gastric neoplasm.

BACKGROUND AND STUDY AIMS: A standard training system for endoscopic submucosal dissection (ESD) remains to be established. In this study, we evaluated the validity of our training program for gastric ESD. PATIENTS AND METHODS: Four trainees performed gastric ESD for a total of 117 lesions in 107 patients (27 to 30 consecutive lesions per trainee) at a tertiary referral center during 2 years in the training program. Trainees, who already had the fundamental skills and knowledge needed for ESD, each assisted at 40 gastric ESD procedures, then in 20 cases applied post-ESD coagulation (PEC) to gastric mucosal defects; they then began to perform ESD, starting with gastric antral lesions. Treatment outcomes, including mean procedure time, and rates of en bloc resection, en bloc plus R0 resections, complications, and self-completion, were evaluated, for the initial 15 and subsequent 12 to 15 cases. RESULTS: Overall rates of en bloc resection and en bloc plus R0 resection were as high as 100 % and 96.6 %, respectively. Regarding complications, seven cases of delayed hemorrhage (6.0 %) and three cases of perforation (2.6 %) occurred; all complications were solved endoscopically. The most frequent reason for operator change was lack of submucosal dissection skill. The self-completion rate was more than 80 % even in the early period, and did not increase for later cases. CONCLUSIONS: Our training system enabled novice operators to perform gastric ESD without a decline in clinical outcomes. Key features of this training are prior intensive learning and actual ESD during the learning period under expert supervision.

Long-term outcomes of endoscopic submucosal dissection for colorectal epithelial neoplasms.

BACKGROUND AND AIMS: Endoscopic submucosal dissection (ESD) provides a high en bloc resection rate with less invasiveness than surgical resection for large or scarring gastrointestinal neoplasms. However, detailed outcomes in colorectal ESD are still lacking. The aim of our study was to elucidate short- and long-term outcomes of colorectal ESD. PATIENTS AND METHODS: 310 consecutive colorectal epithelial neoplasms (146 adenomas, 164 carcinomas), in 290 patients, which fulfilled our indication criteria and were treated with ESD between July 2000 and December 2008 were studied. ESD was done by three skilled endoscopists. As short-term outcomes, rates of en bloc resection, en bloc plus R0 resection, and major complications were analyzed. As long-term outcomes, disease-free and overall survival were assessed in 224 patients. RESULTS: Rates of en bloc resection and en bloc plus R0 resection were 90.3 % and 74.5 %, respectively. Eight patients underwent additional colectomy due to histopathologically proven possible node-positive cancer. Intraoperative perforations occurred with 14 lesions (4.5 %), which were treated successfully only by endoscopic clipping. Emergent surgery was needed for one case of postoperative perforation. Blood transfusion due to intraoperative massive bleeding was required in 1 case (0.3 %). Postoperative bleeding occurred with four lesions (1.3 %), and was endoscopically managed without blood transfusion. Local recurrence was detected in 4 lesions (4/202 patients, 2.0 %); resection had been piecemeal in all 4. During a median follow-up of 38.7 months (range 12.8 - 104.2), the 3- and 5-year overall/disease-specific survivals were 97.1/100 % and 95.3/100 %, respectively. CONCLUSIONS: Colorectal ESD showed favorable long-term outcomes. It may largely replace colectomy for node-negative colorectal epithelial neoplasia.

Inhibitory effects of Japanese apricot (Prunus mume Siebold et Zucc.; Ume) on Helicobacter pylori-related chronic gastritis.

OBJECTIVES: We investigated the correlation between Japanese apricot (JA) intake and Helicobacter pylori-related chronic atrophic gastritis (CAG). METHODS: A questionnaire was administered and serum anti-H. pylori IgG antibodies measured in 1358 asymptomatic adults. The subjects were divided into high-intake and low-intake groups. Histological and serological evaluation of H. pylori-related CAG was performed in 68 non-elderly volunteers. RESULTS: The H. pylori-negative rate did not differ significantly between the high-intake and low-intake groups. Mean antibody titers were lower in the high-intake group, but the difference was not significant. There was no significant difference in the rate of H. pylori infection on the basis of JA intake when subjects were stratified by age. Among H. pylori-positive non-elderly subjects, antibody titers were significantly lower in the high-intake group (P=0.041). Endoscopic tissue biopsy from the 68 volunteers showed less H. pylori bacterial load and mononuclear infiltration irrespective of gastric site in the high-intake group. In the high-intake group, antral neutrophil infiltration was significantly less pronounced and corporal atrophy was less extensive. Serological evaluation using serum PG levels also confirmed these histopathological data. CONCLUSIONS: Our findings strongly indicate a preventive effect of JA intake on CAG by inhibiting H. pylori infection and reducing active mucosal inflammation.

Predictors of postoperative stricture after esophageal endoscopic submucosal dissection for superficial squamous cell neoplasms.

BACKGROUND AND STUDY AIMS: Although endoscopic submucosal dissection (ESD) is becoming accepted as an established treatment for superficial esophageal squamous cell neoplasms, the risks for developing postoperative stricture have not been elucidated. PATIENTS AND METHODS: This was a retrospective study at a single institution. From January 2002 to October 2008, 65 patients with high-grade intraepithelial neoplasms (HGINs) or m2 carcinomas treated by ESD were enrolled. Predictors of postoperative stricture were investigated by comparing results from 11 patients who developed strictures with those from 54 patients who did not. RESULTS: Significant differences between the two groups were observed in longitudinal diameter (45.0 +/- 15.9 mm vs. 31.5 +/- 13.6 mm) and circumferential diameter (37.2 +/- 8.6 mm vs. 26.8 +/- 9.7 mm) of the resected specimens, and the proportion of extension to the whole circumference of the lumen (< 1 / 2/ > 1 / 2/ > 3 / 4 : 2 / 4 / 5 vs. 40 / 13 / 1), histologic depth (HGIN/m2 : 2 / 9 vs. 41 / 13), and procedure time (85.6 +/- 42.8 minutes vs. 53.3 +/- 30.1 minutes). Multivariate analysis revealed that circumferential extension of > 3 / 4 (odds ration [OR]: 44.2; 95 % confidence interval [CI]: 4.4 - 443.6) and histologic depth to m2 (OR: 14.2; 95 %CI: 2.7 - 74.2) are reliable risk factors. Subanalysis for each category by combinations of these risk factors revealed that patients with lesions in > 3 / 4 of the circumferential area were associated with a high rate of postoperative stricture. By contrast, patients with HGIN lesions in < 3 / 4 extension have no probability of postoperative strictures. Additionally, subanalysis of patients with m2 lesions in < 3 / 4 circumferential extension revealed that circumferential diameter can be a reliable predictor for postoperative stricture. CONCLUSIONS: Circumferential extension and histologic depth are the reliable risk factors for postoperative strictures. In combination with circumferential diameter, we can perform effective and appropriate preventive balloon dilatations after esophageal ESD.

Comparison of standard endoscopic submucosal dissection (ESD) versus an optimized ESD technique for the colon: an animal study.

BACKGROUND AND STUDY AIMS: Endoscopic submucosal dissection (ESD) is a promising therapeutic technique for en bloc resection of large gastrointestinal tumors. However, this technique has disadvantages such as a long intervention time, complexity of the procedure, and a higher rate of complications. The primary aims of the study were to show the feasibility of ESD in the pig colon and to evaluate a new ESD technique comprising the use of a newly developed hybrid knife for colon procedures combining RF (radiofrequency) application and a distance-dependent water-jet application. MATERIALS AND METHODS: ESD was conducted at three different locations in the colon according to the computer-generated randomization list, using either the standard technique (injection needle, flex knife, and hook knife as therapeutic instruments and DRY CUT and SWIFT COAG as RF currents), or the new ESD technique (hybrid knife as the therapeutic instrument combined with the new cutting mode ENDO CUT D) in 12 healthy pigs. The perforation and bleeding rates were documented and statistically analyzed. Intervention time, resected specimen size, thermal and mechanical damage of the resection bed, and number of instrument changes required were also recorded. RESULTS: A total of 16 and 18 ESD procedures were performed by the standard and new techniques, respectively. Complete en bloc resection was achieved in all cases. The standard ESD technique showed a perforation rate of 25 % (4/16) whereas the new ESD technique resulted in a 5.5 % perforation rate (1/18) ( P = 0.035); bleeding rates were similar. The new ESD technique was significantly safer compared with the standard ESD technique. CONCLUSIONS: A new ESD technique for the successful en bloc resection in thin-walled regions such as pig colon has been described. This procedure is as effective as the standard procedure but is easier to handle and significantly safer.

Technical feasibility of endoscopic submucosal dissection for early gastric cancer in patients taking anti-coagulants or anti-platelet agents.

BACKGROUND: Endoscopic submucosal dissection is a novel technique that is expected to be a curative treatment for early gastric cancers. Anti-coagulants and anti-platelet agents are widely used, especially in elderly patients, to prevent thromboembolic disease. However, the feasibility of endoscopic submucosal dissection for such patients has not been investigated. AIMS: To determine the feasibility of endoscopic submucosal dissection for patients using anti-coagulant and anti-platelet agents via retrospective investigation of clinical outcomes. METHODS: Of 408 patients with 444 early gastric cancers consecutively treated by endoscopic submucosal dissection from January 2000 to December 2007 in our hospital, 47 patients with 56 early gastric cancers were receiving anti-coagulants or anti-platelet agents. All patients were classified into groups for high and low risk of thromboembolism. In 44 low-risk patients, these agents were stopped for 1 week before and after treatment. Only three high-risk patients underwent intravenous heparin replacement during the cessation period. RESULTS: Comparison with other patients showed no significant differences in complete en-bloc resection (96.4%) or perforation (1.8%). Postoperative bleeding requiring endoscopic treatment occurred for six early gastric cancers (10.7%) in the anti-coagulant and anti-platelet group; this frequency was slightly higher than that observed for other patients (5.2%). The healing of endoscopic submucosal dissection ulcers was not delayed by anti-coagulant and anti-platelet treatment (91% in the scarring stage) when checked at the 8th week after endoscopic submucosal dissection. CONCLUSION: The clinical outcomes of endoscopic submucosal dissection for early gastric cancers in patients receiving anti-coagulants or anti-platelet agents indicated that endoscopic submucosal dissection for low-risk patients could be a reliable technique with equivalent efficacy and risk in comparison with that for other early gastric cancer patients.

Outcomes of endoscopic submucosal dissection for early gastric cancer with special reference to validation for curability criteria.

BACKGROUND AND STUDY AIMS: Endoscopic submucosal dissection (ESD) is a novel, promising endoscopic technique for gastrointestinal neoplasms. We aimed to elucidate the feasibility of ESD as curative treatment for intestinal-type early gastric cancer (EGC) potentially without lymph-node metastases. PATIENTS AND METHODS: For the short-term analysis, 276 consecutive, intestinal-type EGCs, which fulfilled the criteria for node-negative EGC in 231 patients who had undergone ESD from January 2000 to March 2007, were retrospectively investigated. For the long-term analysis, 212 lesions checked by endoscopy later than 1 year or recurrence within 1 year after ESD were assessed for local recurrence, and 208 patients followed for over 1 year or to death within 1 year after ESD were assessed for metastases and survival. All lesions/patients were divided into three groups: intramucosal cancer without ulcerative findings (M-Ul[-]); intramucosal cancer with ulcerative findings, < or = 3 cm (M-Ul[+]); and slight invasive cancer into submucosa (< 500 microm), < or = 3 cm (SM1). RESULTS: En bloc and complete resection rates were 96.7 % and 91.7 %, respectively. During a median follow-up of 36 months (range 2 - 93 months), two local recurrences occurred (0.9 %), which were detected at 2 and 6 months after ESD, respectively. During a median follow-up of 38 months (range 6 - 97 months), the 5-year overall and disease-specific survival rates were 96.2 % and 100 %, respectively, with neither lymph node nor other-organ metastasis; one patient died due to other disease 6 months after ESD. No disease-related death occurred. No significant differences were found between the groups in short- and long-term analyses. CONCLUSIONS: The prognostic analyses demonstrated the validity of the criteria of node-negative intestinal-type EGC as curability criteria for ESD. ESD can be proposed as an alternative method to gastrectomy for the treatment of these EGCs.

Feasibility of electrocautery snaring as the final step of endoscopic submucosal dissection for stomach epithelial neoplasms.

BACKGROUND: Endoscopic submucosal dissection (ESD) is a novel endoluminal technique that permits the resection of gastric neoplasms. AIM: To analyse the feasibility of snaring as the final step of ESD. PATIENTS AND METHODS: One hundred and ninety-nine consecutive gastric neoplasms resected by four ESD experts from January 2004 to May 2007 were investigated. Forty-five (22.6%) were finally resected finally using a snare. Rates of en bloc resection, complete (R0 plus en bloc) resection, mean operation time, and complications were assessed between the snaring and the non-snaring groups. RESULTS: En bloc resection rate was significantly lower and delayed bleeding rate was significantly higher in the snaring group than in the non-snaring group (91.1% [41/45] vs. 100% [154/154], 11.1% [5/45] vs. 1.9% [3/154], respectively), although complete resection rate (86.7% [39/45] vs. 92.9% [143/154]) and mean operation time (70.2 min vs. 75.8 min) were not significantly different between the two groups. Six perforation cases (3 [6.7%] in the snaring group, 3 [1.9%] in the non-snaring group) were observed, but snaring did not lead to perforation in any case. When the subjects were divided into small (< or = 2 cm) and large (> 2 cm) tumours, en bloc resection rate in large tumours was still significantly different between the groups (76.9% [10/13] vs. 100% [67/67]), whereas in small tumours it was no longer significantly different (96.9% [31/32] vs. 100% [87/87]). CONCLUSIONS: Snaring may facilitate successful ESD for smaller tumours, but multiple-piece resection should be taken into account especially for larger tumours.

Long-term forskolin stimulation induces AMPK activation and thereby enhances tight junction formation in human placental trophoblast BeWo cells.

BeWo cells, derived from human choriocarcinoma, have been known to respond to forskolin or cAMP analogues by differentiating into multinucleated cells- like syncytiotrophoblasts on the surfaces of chorionic villi of the human placenta. In this study, we demonstrated that long-term treatment with forskolin enhances the tight junction (TJ) formation in human placental BeWo cells. Interestingly, AMPK activation and phosphorylation of acetyl-CoA carboxylase (ACC), a molecule downstream from AMPK, were induced by long-term incubation (>12h) with forskolin, despite not being induced by acute stimulation with forskolin. In addition, co-incubation with an AMPK inhibitor, compound C, as well as overexpression of an AMPK dominant negative mutant inhibited forskolin-induced TJ formation. Thus, although the molecular mechanism underlying AMPK activation via the forskolin stimulation is unclear, the TJ formation induced by forskolin is likely to be mediated by the AMPK pathway. Taking into consideration that TJs are present in the normal human placenta, this mechanism may be important for forming the placental barrier system between the fetal and maternal circulations.

Efficacy and safety of endoscopic submucosal dissection for gastric cancer in patients with liver cirrhosis.

Endoscopic submucosal dissection (ESD) has become a widely accepted method for treating gastrointestinal cancer. The aim of this study was to evaluate the efficacy and safety of ESD for gastric cancer in patients with liver cirrhosis. A total of 18 gastric cancers were treated by ESD in 15 patients with cirrhosis. The rate of en bloc resection was 88.9% (16/18). En bloc resection with tumor-free lateral/basal margins (R0 resection) was 77.8% (14/18). Three patients had postoperative bleeding and underwent emergency gastroscopy for hemostasis. No recurrence was observed during the median follow-up of 21.4 months, excluding three patients in whom additional endoscopic resection or surgery was carried out. ESD can be safely performed for gastric cancer in patients with cirrhosis, resulting in a high en bloc resection rate.

Detailed comparison between endocytoscopy and horizontal histology of an esophageal intraepithelial squamous cell carcinoma.

Endocytoscopy allows the real-time microscopic observation of living cells. Unlike the cross-sectional images obtained by conventional histology, endocytoscopy provides cellular images in a plane parallel to the surface of the mucosa. However, there is little knowledge about the endocytoscopic diagnosis of carcinomas. Using a specimen obtained by the endoscopic submucosal dissection of an intraepithelial esophageal squamous cell carcinoma, a detailed comparison between endocytoscopic and horizontal histological images was made, revealing the similarity between the images. Sharp lateral borders between atypical and normal epithelium and differences in cellularity and the sizes and shapes of the nuclei were clearly identified by endocytoscopy. Further horizontal histological investigations of this case also showed the variety of endocytoscopic images in non-cancerous and cancerous epithelia.

Endoscopic submucosal dissection as a staging measure may not lead to worse prognosis in early gastric cancer patients with additional gastrectomy.

BACKGROUND: Endoscopic submucosal dissection is a novel endoluminal technique that enables resection of early stage gastrointestinal malignancies in an en bloc fashion. AIM: To assess whether preceding endoscopic submucosal dissection affected the prognoses of patients who underwent additional gastrectomy with lymph node dissection due to suspicion of nodal metastasis from endoscopic submucosal dissection specimens. PATIENTS AND METHODS: Thirty-one patients with early gastric cancer who underwent gastrectomy after endoscopic submucosal dissection were retrospectively investigated in terms of their survival and tumour recurrence. Additional gastrectomy was performed when histology of the endoscopic submucosal dissection specimens revealed that the tumours did not meet the criteria for node-negative cancers. RESULTS: Twenty-three (74%) and eight (26%) patients had undergone endoscopic submucosal dissection previously due to clinical diagnoses of node-negative cancers and possible node-positive cancers, respectively. Histology of the resected stomachs and lymph nodes revealed residual carcinoma of the stomach in two (6.5%) patients and nodal metastases in four (13%) patients. All patients remain alive without recurrence (median follow-up, 3.4 years; range, 0.6-5.2 years). CONCLUSIONS: Based on the histology of endoscopic submucosal dissection specimens, preceding endoscopic submucosal dissection itself had no negative influence on a patient's prognosis when additional gastrectomy was performed. It may be permissible to resect some early gastric cancers by endoscopic submucosal dissection as a first step to prevent unnecessary gastrectomy, if technically resectable.

Ex vivo pilot study using computed analysis of endo-cytoscopic images to differentiate normal and malignant squamous cell epithelia in the oesophagus.

BACKGROUND AND STUDY AIMS: An endo-cytoscopy system allows acquisition of optical biopsies that are quite similar to conventional histology. To simplify discrimination between normal and malignant tissue in the oesophagus using endo-cytoscopy system, we analysed the nuclear (dark staining) area in the obtained images with the goal of an accurate, automatic diagnosis. PATIENTS AND METHODS: Ex vivo endo-cytoscopic observation was performed using endoscopically or surgically resected oesophagus from 10 enrolled patients. Oesophageal tissues were stained using 1% methylene blue, and endo-cytoscopic images were obtained at normal and malignant areas (two areas of each) in each oesophagus. The centre of each image (4x10(-2) mm(2)) was processed by computer, and the area occupied by the total nuclei in each selected field and its ratio to the entire field were calculated. RESULTS: The mean area of the total nuclei was 0.10x10(-2)+/-0.03x10(-2) mm(2) (range 0.05x10(-2) to 0.18x10(-2) mm(2)) in the normal group and 0.40x10(-2)+/-0.06x10(-2) mm(2) (range 0.33x10(-2) to 0.55x10(-2) mm(2)) in the malignant group (P<0.001). The mean ratio of total nuclei to the entire selected field was 6.4+/-1.9% (range 3.1-11.3%) in the normal tissues and 25.3+/-3.8% (range 20.5-34.5%) in the malignant samples (P<0.001). CONCLUSIONS: Endo-cytoscopy system allowed automatic differentiation of normal and malignant tissues in the oesophagus, which could simplify endo-cytoscopic diagnosis. Further study will elucidate whether such analysis is applicable to inflammatory or pre-malignant epithelia in the oesophagus or other gastrointestinal organs.