Naoki Kawai

Scheduled endoscopic surveillance controls secondary cancer after curative endoscopic resection for early gastric cancer: a multicentre retrospective cohort study by Osaka University ESD study group

Background After endoscopic submucosal dissection (ESD) of early gastric cancer (EGC), patients are at high risk for synchronous or metachronous multiple gastric cancers. Objective To elucidate the time at which multiple cancers develop and to determine whether scheduled endoscopic surveillance might control their development. Design A multicentre retrospective cohort study from 12 hospitals was conducted. Patients with EGC who underwent ESD with en bloc margin-negative curative resection were included. Synchronous cancer was classified as concomitant cancer or missed cancer. The cumulative incidence of metachronous cancers and overall survival rate were calculated using the Kaplan–Meier method. Results From April 1999 to December 2010, 1258 patients met the inclusion criteria. Synchronous or metachronous multiple cancers were detected in 175 patients (13.9%) during a mean of 26.8 months. Among the 110 synchronous cancers, 21 were missed at the time of the initial ESD. Many of the missed lesions existed in the upper third of the stomach and the miss rate was associated with the endoscopists inexperience (<500 oesophagogastroduodenoscopy cases). The cumulative incidence of metachronous cancers increased linearly and the mean annual incidence rate was 3.5%. The incidence rate did not differ between patients with or without Helicobacter pylori eradication. Four lesions (0.32%) were detected as massively invading cancers during the follow-up. Conclusions Nineteen per cent of synchronous cancers were not detected until the initial ESD. The incidence rate of metachronous cancer after ESD was constant. Scheduled endoscopic surveillance showed that almost all recurrent lesions were treatable by endoscopic resection.

Cyclooxygenases and colon cancer.

There is considerable interest in the involvement of cyclooxygenase-2 (COX-2) in colon carcinogenesis and its progression, because nonsteroidal anti-inflammatory drugs (NSAIDs) reduce mortality from colon cancer and COX-2 is one of the known targets of NSAIDs. COX-2 mRNA and protein levels are increased in colon cancer tissues from patients and in some colon cancer cell lines. The relationship between COX-2 and colon cancer is further confirmed by studies using the murine models of adenomatous polyposis coli, in which NSAIDs and gene knockouts reduce the number of spontaneously developing intestinal polyps. COX-2 expression in intestinal epithelial cells increases resistance to apoptosis, promotes tumor angiogenesis, and enhances invasion and metastasis. COX-2 expression in stromal cells appears to have a role in tumor angiogenesis because tumor growth is attenuated when colon cancer cells are implanted in COX-2 knockout mice due to a decreased vascular supply to the tumors. Although NSAIDs act via COX-2 to inhibit colon cancer growth, there also appear to be COX-2 independent actions for NSAIDs. COX-2 selective inhibitors can be the core drugs for the prevention and the treatment of colon cancer.

Submucosal tumors: comprehensive guide for the diagnosis and therapy of gastrointestinal submucosal tumors.

Small submucosal tumors (SMT) without symptoms are frequently found by endoscopic and radiological examinations. To find proper diagnostic measures and therapeutic indications for histologically undiagnosed SMT, we reviewed published articles in PubMed between 1990 and March 2013 using the key words ‘submucosal tumor’ and the name of a specific disease. SMT is observed in a wide range of gastrointestinal (GI) diseases and conditions, including compression by extra‐GI organs and lesions, congenital tumors, inflammation, and benign as well as malignant neoplastic lesions. In the diagnosis of diseases and decision‐making for therapy, endoscopic ultrasonography (EUS) and endoscopic ultrasound‐guided fine‐needle aspiration (EUS‐FNA) may play a key role. Symptomatic SMT and SMT histologically diagnosed as malignant or potentially malignant tumors such as gastrointestinal stromal tumor (GIST) should be treated by surgery. SMT >5 cm, SMT increasing in size and those with‘high‐risk features’ including irregular border, heterogeneous internal echo such as anechoic area, and heterogeneous enhancement by contrast media may also be removed by surgery. Laparoscopic approach is feasible for gastric GIST <5 cm and this is considered less invasive than the open approach. Emerging techniques using flexible endoscopes appear less invasive, but require further evidence and are still under clinical study. Correct diagnosis of SMT is challenging; however, EUS and EUS‐FNA are useful in the histological diagnosis and clinical decision‐making. In the future, minimally invasive approaches may be a mainstream of surgical treatment for small SMT.

Clinical outcomes of endoscopic submucosal dissection for superficial esophageal neoplasms: a multicenter retrospective cohort study

BACKGROUND AND STUDY AIMS The safety and efficacy of endoscopic submucosal dissection (ESD) for superficial esophageal neoplasms (SENs) have not been evaluated in a multicenter survey. The aim of this study was to investigate the clinical outcomes in a multicenter study that included municipal hospitals. PATIENTS AND METHODS Of 312 consecutive patients with 373 esophageal lesions treated by ESD at 11 hospitals from May 2005 to December 2012, a total of 368 SENs in 307 patients were retrospectively analyzed. RESULTS The median tumor size was 18 mm (range 2 - 85 mm). The median procedure time was 90 minutes (range 12 - 450 minutes). The en bloc resection and complete resection rates were 96.7 % (95 % confidence interval [CI] 94.4 % - 98.1 %) and 84.5 % (95 %CI 80.5 % - 87.8 %), respectively. Perforation (including mediastinal emphysema), postoperative pneumonia, bleeding, and esophageal stricture, occurred in 5.2 % (95 %CI 3.3 % - 7.9 %), 1.6 % (95 %CI 0.7 % - 3.5 %), 0 %, and 7.1 % (95 %CI 4.9 % - 10.2 %) of patients, respectively. All of these complications were cured conservatively. No procedure-related mortality occurred. Early treatment periods (odds ratio [OR] = 4.04; P < 0.01) and low volume institutions (OR = 3.03; P  = 0.045) were significantly independent risk factors for perforation. The circumference of the lesion was significantly associated with postoperative stricture (OR = 32.3; P < 0.01). The procedure times significantly decreased in the later period of the study (P < 0.01). Follow-up data (median 35 months; range 4 - 98 months) showed significant differences in overall survival (P = 0.03) and recurrence-free survival (P < 0.01) rates between patients with curative and noncurative resections. CONCLUSIONS Esophageal ESD has become feasible with acceptable complication risks and favorable long term outcomes.

Lansoprazole Induces Mucosal Protection through Gastrin Receptor-Dependent Up-Regulation of Cyclooxygenase-2 in Rats

Proton pump inhibitors (PPIs) are antiulcer agents that have both gastric antisecretory and mucosal protective actions. The mechanisms of PPI-induced gastric mucosal protection are not known. The present study was designed to examine the mechanism for lansoprazole-induced gastric mucosal protection in rats. Rats were given 0.5, 5, and 50 mg/kg/day lansoprazole alone or both lansoprazole (50 mg/kg/day) and a specific gastrin receptor antagonist 3R-1-(2,2-diethoxyethyl)-((4-methylphenyl)amino-carbonyl methyl)-3-((4-methylphenyl)ureidoindoline-2- one) (AG-041R) (3, 10, and 30 mg/kg/day) for 14 days. Serum gastrin concentrations were measured. The expression of cyclooxygenases (COX-1 and COX-2) in the gastric mucosa was analyzed using Western blotting and immunohistochemical staining. Another series of rats was used to examine the 1) levels of prostaglandin (PG) E2 in gastric mucosa, 2) influences of the drugs on gastric damage caused by absolute ethanol, and 3) effects of a COX-2-specific inhibitor on PGE2 in the gastric mucosa and the mucosal protection afforded by lansoprazole. Lansoprazole dose dependently increased the serum gastrin concentration and enhanced the mucosal expression of COX-2 but not that of COX-1. Lansoprazole increased gastric mucosal PGE2 and reduced gastric damage caused by ethanol. Concomitant administration of AG-041R abolished the lansoprazole-induced COX-2 expression, and increased mucosal PGE2 and mucosal protection. A specific COX-2 inhibitor blocked the lansoprazole-induced increase in mucosal PGE2and mucosal protection. Activation of gastrin receptors by endogenous gastrin has a pivotal role in the effects of lansoprazole on COX-2 up-regulation and mucosal protection in the rat stomach.

Review article: inflammation-related promotion of gastrointestinal carcinogenesis – a perigenetic pathway

Chronic inflammation has been reported to accelerate neoplasmas in gastrointestinal tract. Certain bacteria including Helicobacter pylori directly interact with host cells, induce proinflammatory cytokines and stimulate production of free radicals. Free radicals cause mutations in target cells so that neoplastic clones are established. Accumulation of such genetic alterations may cause malignant transformation of some established clones. In addition, inflammatory alterations may promote growth, expansion and invasion of gastrointestinal epithelial cells. The latter changes caused by inflammation may occur even without further genetic mutations or epigenetic alterations, and therefore may be categorized as ‘perigenetic alterations’ of neoplastic cells. For an example, tumour necrosis factor α (TNF‐α) plays pivotal roles not only in the reduction but also in the growth, invasion and metastases of certain neoplasmas. Our studies show that TNF‐α increases intracellular radical production, degradates E‐cadherin / β‐catenin complex and promotes dispersion and migration in epithelial cells transformed with an activated src oncogene (v‐src). These data indicate that an inflammatory cytokine induces the malignant potential of src‐activated neoplastic cells. Interestingly, TNF‐α also induced these phenotypic changes in nonmutated cells whose c‐Src was activated by TGF‐α, suggesting that the invasive properties of the cell were not necessarily related to gene mutation. Furthermore, certain radical scavengers suppressed the invasive phenotype of the cells. These results indicate that perigenetic alterations are an important target of pharmacological intervention of carcinogenesis.

Cyclo-oxygenase-2 inhibitors suppress epithelial cell kinetics and delay gastric wound healing in rats

Background and Aims : The present study examined the effects of NS‐398, a specific cyclo‐oxygenase‐2 inhibitor, on gastric mucosal cell kinetics and gastric wound healing following acid‐induced injury.

Gastric ESD under Heparin Replacement at High-Risk Patients of Thromboembolism Is Technically Feasible but Has a High Risk of Delayed Bleeding: Osaka University ESD Study Group

Objectives. Heparin replacement (HR) is often performed in patients with a high risk of thrombosis undergoing endoscopic procedures. However, information about the influence of HR is scarce. The aim of this study is to assess the clinical impact of HR for gastric endoscopic submucosal dissection (ESD). Methods. This is a retrospective study comprising approximately 1310 consecutive gastric neoplasms in 1250 patients, who underwent ESD in 5 institutes. We assessed the clinical findings and outcomes of ESD under HR, compared to ESD without HR as control. Results. A total of 24 EGC lesions in 24 patients were treated by ESD under HR. In the HR group, the complete en-bloc resection rate was 100%. The delayed bleeding rate was, however, higher in the HR group than in the controls (38% versus 4.6%). The timing of bleeding in the HR group was significantly later than in controls. In the control group, 209 patients discontinued antithrombotic therapy during perioperative period, and their delayed bleeding rate was not different from those without antithrombotic therapy (5.7% versus. 4.4%). A thromboembolic event was encountered in 1 patient under HR after delayed bleeding. Conclusion. ESD under HR is technically feasible but has a high risk of delayed bleeding.

Evaluation of the PyloriTek test for detection of Helicobacter pylori infection in cases with and without eradication therapy

Objective:The accuracy of the PyloriTek test (a 1-h rapid urease test) used after eradication therapy of Helicobacter pylori (H. pylori) has not been well clarified. This study was done to evaluate the accuracy of the PyloriTek test results for cases with and without eradication therapy, using culture and histology as gold standard methods, and to establish the suitable timing of the PyloriTek test after eradication treatment.Methods:One hundred sixty-three patients undergoing upper endoscopy were randomly selected; 100 patients had not received eradication therapy and 63 had. Three biopsy specimens each were obtained from the gastric antrum and the body for examination by PyloriTek, culture, and histology. The absence of H. pylori was established with negative results from both culture and histology.Results:In cases without eradication therapy, PyloriTek, correctly identified 66 of 67 H. pylori-positive cases and 30 of 33 H. pylori-negative cases, yielding 98.5% sensitivity and 90.9% specificity. In cases with eradication therapy, PyloriTek gave correct diagnoses in 10 of 17 H. pylori-positive cases and in 45 of 46 H. pylori-negative cases, for 58.8% sensitivity and 97.8% specificity. However, when PyloriTek was used more than 4 months after the end of eradication therapy, both the sensitivity and the specificity increased to 100%.Conclusion:Considering time and cost, the use of PyloriTek alone may be satisfactory for detecting H. pylori infection in cases without eradication therapy. When patients are examined more than 4 months after intervention, the use of PyloriTek alone may be sufficient for correctly diagnosing H. pylori infections.

A novel endoscopic submucosal dissection technique with robust and adjustable tissue traction.

BACKGROUND AND STUDY AIMS A novel esophageal endoscopic submucosal dissection (ESD) technique was devised using a newly developed overtube to achieve adequate tissue traction. The aim of this study was to evaluate the feasibility and safety of this new full-traction ESD (tESD) technique. METHODS The key feature of tESD is tissue traction by grasping forceps, which is passed through the built-in side channel of the overtube. The strength and direction of traction is controlled by rotating the overtube and by adjusting its depth. The en bloc resection rate, procedure time, adverse events, and dissected area per minute were evaluated in a porcine model (n = 10) and compared with those of conventional ESD (n = 10). RESULTS tESD provided robust and adjustable tissue traction during the procedure. En bloc resection was accomplished in all lesions with no complications. Median procedure time was similar to that of the conventional technique (25 vs. 27 minutes; P = 0.4723) but the submucosal injection catheter was used less often (1.5 vs. 6; P < 0.01). CONCLUSIONS tESD might contribute to more efficient esophageal ESD by providing adequate tissue traction. This inexpensive technique may become an attractive option in esophageal ESD.