Novel assay based on diluted prothrombin time reflects anticoagulant effects of direct oral factor Xa inhibitors: Results of multicenter study in Japan.

BACKGROUND: Direct oral anticoagulants targeting factor Xa (DXaIs) are administered as prophylaxis for various venothrombotic diseases without routine monitoring required. However, assessment of their anticoagulant effects is necessary to prevent severe events, including major bleeding and/or refractory thrombosis. OBJECTIVES: We examined the correlation of ratio of inhibited thrombin generation (RITG), determined using a novel assay based on dilute prothrombin time (dPT), with coagulant markers and laboratory test results to show drug effects. In addition, RITG usefulness as a confirmation test for DXaI therapy was investigated. METHODS: Citrated plasma samples were obtained from patients treated with rivaroxaban (n = 882), apixaban (n = 1214), or edoxaban (n = 820) at 4 different institutions in Japan. Laboratory tests, including prothrombin time (PT), activated partial thromboplastin time (APTT), D-dimer, and plasma concentrations of DXaIs, were conducted, with drug concentrations divided into peak and trough groups, within and after 5 h of administration. RESULTS: In each DXaI group, RITG was positively correlated with PT, APTT, and drug concentration, and negatively with D-dimer. RITG fluctuation during the peak and trough periods reflected the anticoagulant activity characteristic of each DXaI, which was different from blood concentration fluctuations. RITG showed a significant decrease in cases with thrombosis, while that was increased in those with hemorrhage. CONCLUSION: We developed RITG, a novel measurement method based on dPT. RITG represents residual coagulation ability in plasma samples, and is useful for assessment of bleeding and thrombotic tendencies in DXaI patients. RITG can be utilized to confirm the effectiveness of oral anticoagulation therapy with DXaI agents.

Rapid detection of superficial head and neck squamous cell carcinoma by topically spraying fluorescent probe targeting dipeptidyl peptidase-IV.

BACKGROUND: A fluorescent probe glutamylprolyl hydroxymethyl rhodamine green (EP-HMRG), which becomes fluorescent after cleavage by dipeptidyl peptidase-IV (DPP-IV), has been reported to be useful for the detection of esophageal cancer. Thus, we investigated whether head and neck squamous cell carcinoma (HNSCC) can be detected by spraying EP-HMRG. METHODS: Fluorescence imaging of 17 cases of HNSCCs resected using endoscopic or surgical resection was performed ex vivo after spraying EP-HMRG, and then the fluorescence intensity of the tumors and normal mucosa were measured. RESULTS: Iodine-voiding lesions became fluorescent within a few minutes after the application of EP-HMRG in 12 resected tumors without a history of radiotherapy but this was not observed in the normal mucosa. Fluorescence intensity in tumor lesions was significantly higher than normal lesions. However, 5 other tumors that developed after radiotherapy did not have sufficient contrast against normal mucosa. CONCLUSION: Fluorescence imaging with EP-HMRG would be useful for rapid detection of superficial HNSCC without a history of radiotherapy.

Multicenter observational study on functional bowel disorders diagnosed using Rome III diagnostic criteria in Japan.

BACKGROUND: The Rome III diagnostic criteria had been used to diagnose functional gastrointestinal disorders (FGIDs) world wide, and functional bowel disorders (FBDs) including irritable bowel syndrome (IBS) have recently attracted the attention of Japanese physicians. However, there have been few reports on the prevalence of FBDs diagnosed by the Rome III diagnostic criteria. AIMS: The aim of this study was to determine the prevalence of FBDs diagnosed according to the diagnostic criteria of Rome III in Japan. PATIENTS AND METHODS: All patients who were booked for colonoscopy were enrolled from eight institutions in Japan. This study was a prospective observational study in the period from April 2013 to December 2013. Patients filled out FGID questionnaires of Rome III when they were waiting for colonoscopy. RESULTS: Data for 1200 patients who underwent colonoscopy were analyzed. A total of 547 patients (45.6%) were diagnosed with FBDs. Out of those patients, 9.1% had IBS. According to the Rome III diagnostic criteria, 134 patients (11.2%) had functional bloating (FB), 73 (6.1%) had functional constipation (FC), 40 (3.3%) had functional diarrhea (FD), and 191 (15.9%) had unspecified functional bowel disorder (UFBD). Patients with FBDs had significantly higher rates of almost all symptoms (abdominal pain, hard or lumpy stools, loose or watery stools, and bloating) than those in the controls. CONCLUSIONS: In Japan, the prevalence of FBDs and IBS is high, similar to that in the US. Many patients with FBDs have multiple symptoms.

Fluorescent imaging of superficial head and neck squamous cell carcinoma using a γ-glutamyltranspeptidase-activated targeting agent: a pilot study.

BACKGROUND: Detecting superficial head and neck squamous cell carcinoma (HNSCC) by endoscopy is challenging because of limited morphological hallmarks, and iodine cannot be applied to head and neck lesions due to severe mucosal irritation. γ-glutamyltranspeptidase (GGT), a cell surface enzyme, is overexpressed in several cancers, and it has been reported that γ-glutamyl hydroxymethyl rhodamine green (gGlu-HMRG), a fluorescent targeting agent which can be enzymatically activated and becomes fluorescent after cleavage of a GGT-specific sequence, can be activated within a few minutes after application to animal models. We investigated whether early HNSCC can be detected by applying gGlu-HMRG to clinical samples. METHODS: gGlu-HMRG was applied to four HNSCC cell lines, and fluorescence was observed by fluorescence microscopy and flow cytometry. Immunohistological examination was performed in three recent cases of endoscopic submucosal dissection (ESD) to investigate GGT expression. Fluorescence imaging with gGlu-HMRG in eight clinical samples resected by ESD or surgery was performed, and fluorescence intensity of tumor and normal mucosa regions of interest (ROI) was prospectively measured. RESULTS: All four gGlu-HMRG-applied cell lines emitted green fluorescence. Immunohistological examination demonstrated that GGT was highly expressed in HNSCC of the recent three ESD cases but barely in the normal mucosa. Fluorescence imaging showed that iodine-voiding lesions became fluorescent within a few minutes after application of gGlu-HMRG in all eight resected tumors. Tumor ROI fluorescence intensity was significantly higher than in the normal mucosa five minutes after gGlu-HMRG application. CONCLUSIONS: Fluorescence imaging with gGlu-HMRG would be useful for early detection of HNSCC.

[H. pylori-negative gastric cancer].

Broad category of H. pylori-negative gastric cancer includes true gastric cancer without history of H. pylori infection, gastric cancer after successful eradication of H. pylori, and H. pylori-negative gastric cancer with history of H. pylori infection. The frequency of gastric cancer without history of H. pylori infection was less than 1% in Japan. Although preventive effect for gastric cancer of H. pylori eradication can be expected, risk of gastric cancer incidence continues after eradication of H. pylori. The frequency of gastric cancer after successful eradication has been increasing, since eradication treatment was widely spread in Japan. The features of H. pylori-negative gastric cancer were reported to be different from conventional H. pylori-positive gastric cancer. Endoscopic screening of gastric cancer requires to understand the characteristics of gastric cancer based on status of H. pylori infection.

Technical difficulty according to location, and risk factors for perforation, in endoscopic submucosal dissection of colorectal tumors.

BACKGROUND: Colorectal endoscopic submucosal dissection (ESD) is a widely accepted treatment for colorectal tumors, but is technically more difficult and has a higher risk of complications such as perforation than gastric ESD. Few studies have investigated the factors associated with technical difficulty and perforation in colorectal ESD. This study aimed to evaluate the technical difficulty according to location, and the risk factors for perforation, in colorectal ESD. METHODS: This retrospective study included 134 consecutive colorectal tumors treated by ESD in 122 patients at the Division of Endoscopy of Hokkaido University Hospital and the Department of Gastroenterology of Kitami Red Cross Hospital from November 2011 to February 2013. To evaluate the technical difficulty of performing ESD for colorectal tumors at specific locations, the en bloc R0 resection rate, specimen diameter, procedure speed, and procedure time were compared among tumor locations using the χ (2) test or analysis of variance. Risk factors for perforation were identified by multiple logistic regression analysis. RESULTS: The en bloc R0 resection rate was 86.6 % (116/134), the mean tumor diameter was 27.1 mm, and the mean procedure time was 63.5 min. The mean speed of procedures was significantly slower in the sigmoid colon (24.7 min/cm(2)) than in other areas. Perforation occurred in nine cases (6.7 %). Submucosal fibrosis was the only factor independently associated with perforation (odds ratio 5.684, 95 % confidence interval 1.307-24.727). CONCLUSIONS: ESD was slower for sigmoid colon tumors than for tumors in other areas, suggesting that ESD was technically more difficult in the sigmoid colon than in other colorectal areas. Submucosal fibrosis was independently associated with perforation during colorectal ESD.

Endoscopic diagnosis of early neoplasia of the esophagus with narrow band imaging: correlations among background coloration and iodine staining findings.

BACKGROUND AND AIM: It was previously reported that high-grade intraepithelial neoplasia of the esophagus turns pink within a few minutes after iodine staining (pink-color sign; PCS); however, iodine staining is uncomfortable. By using narrow band imaging (NBI), color change in the area between the intraepithelial papillary capillary loop (background coloration; BGC) is often observed within the brownish area. The diagnostic usefulness of BGC findings for differentiating high-grade intraepithelial neoplasia from low-grade intraepithelial neoplasia was evaluated. METHODS: In a prospective observational study from September 2010 to August 2012, 285 patients who were in a high-risk group for esophageal squamous cell carcinoma underwent endoscopic examination. Lesions with both endoscopic findings of dilated intraepithelial papillary capillary loop on NBI and iodine-unstained areas were studied, in which endoscopic biopsy or endoscopic resection was subsequently performed. The esophageal background mucosa was also evaluated on the basis of the iodine staining pattern (uniform type: Group U, scattered type: Group S). RESULTS: One hundred three esophageal lesions in 87 patients were studied. When BGC was used as the differentiation index, sensitivity was 93.8%, specificity was 88.2%, and accuracy was 91.3%. When PCS was used, sensitivity was 97.9%, specificity was 88.2%, and accuracy was 93.2% (P = 0.79). In Group U (n = 54), BGC had an accuracy of 93.8%, and PCS had an accuracy of 92.3% (P = 1.0). On the other hand, in Group S (n = 33), BGC had an accuracy of 86.8%, while PCS had an accuracy of 94.7% (P = 0.27). CONCLUSIONS: Diagnosis using BGC on NBI may substitute for diagnosis based on PCS in many patients.

Endoscopic in vivo cellular imaging of superficial squamous cell carcinoma of the head and neck by using an integrated endocytoscopy system (with video).

BACKGROUND: Recently, some patients have been found to have superficial squamous cell carcinoma (SCC) of the head and neck region during GI endoscopy; however, endoscopic biopsy from a lesion in the head and neck region is troublesome. An endocytoscopy system has been reported to enable optical biopsy of an esophageal lesion. OBJECTIVE: To evaluate the feasibility of in vivo cellular imaging with an integrated endocytoscopy system for patients with superficial SCC of the head and neck. DESIGN: Experimental pilot study. SETTING: University hospital. PATIENTS: This study involved 12 patients who were found to have superficial SCC of the head and neck during GI endoscopy. INTERVENTION: Endocytoscopic images were taken of each lesion and of the surrounding mucosa. The images were later reviewed by 1 pathologist and 2 endoscopists who were unaware of any other findings. MAIN OUTCOME MEASUREMENTS: Correlation between endocytoscopy diagnosis and histologic diagnosis. RESULTS: Adequate endocytoscopic images could be obtained in 11 of the 12 patients (15 of 16 lesions). For endocytoscopic images of 15 lesions and 12 areas of surrounding mucosa, the overall accuracy of endocytoscopic diagnosis in differentiating between nonmalignant and malignant histopathology by the pathologist, endoscopist 1, and endoscopist 2 were 96%, 96%, and 96%, respectively. The kappa value for interobserver agreement was 0.77. LIMITATIONS: Single-center experience, small number of patients. CONCLUSION: An endocytoscopy system has the potential to be used as an optical biopsy for superficial head and neck lesions.

Outcomes and predictive factors of "not self-completion" in gastric endoscopic submucosal dissection for novice operators.

BACKGROUND: Endoscopic submucosal dissection (ESD) has become the standard endoscopic treatment for gastric neoplasms because of its safety and high rate of curability; however, it is not easy for novice operators to learn the technique of ESD. In this study, predictive factors of gastric neoplasms in which novices could not finish ESD by self-completion were evaluated. METHODS: Eighty consecutive ESD procedures performed by four novice operators were retrospectively analyzed. Standard ESD procedures were performed using an insulation-tipped (IT) knife under supervision. Self-completion rates, procedure time, and complete resection rates were evaluated, and predictive factors for "not self-completion" were assessed. RESULTS: The overall self-completion rate and en bloc plus R0 resection rate were 87.5% (70/80) and 95.7 % (67/70), respectively. In "not self-completion" cases (n = 10), the procedure time was longer and resected specimens were larger than those in self-completion cases (83.7 ± 47.3 min vs. 189.5 ± 106.8 min, p < 0.05; 641.2 ± 487.8 vs. 1,116 ± 480.4 mm(2), p < 0.01). Predictive factors of "not self-completion" were tumor location in the middle or upper third of the stomach or in the greater curvature and size of resected specimens larger than 900 mm(2). The self-completion rate of ESD was decreased in cases with more than two predictive factors. CONCLUSIONS: For novice operators, tumor location and resected areas are predictive factors for failure to finish gastric ESD by self-completion. Selection of cancer lesions could be a key factor for effectiveness of ESD training.

Endoscopic resection (endoscopic mucosal resection/ endoscopic submucosal dissection) for superficial esophageal squamous cell carcinoma: current status of various techniques.

Endoscopic resection (ER) has been widely accepted as an effective and minimally invasive treatment for patients with superficial esophageal squamous cell carcinoma (SCC). Techniques of conventional endoscopic mucosal resection (EMR) were first developed for ER. There are three representative methods of conventional EMR: endoscopic esophageal mucosal resection (EEMR)-tube method, EMR using a cap-fitted endoscope (EMRC) method and two-channel EMR method. In the past decade, techniques of endoscopic submucosal dissection (ESD) have become established as standard methods of ER. ESD allows en bloc resection of a lesion, irrespective of the size and shape of the lesion. Recently, results of retrospective cohort studies confirming that ESD is superior to EMR as a curative treatment for superficial esophageal SCC have been reported. Representative knives that are now frequently used in esophageal ESD include Hook knife, Triangle tip knife, IT knife nano, Flush knife-BT, Dual knife, SB knife, and so on. Although there are various knives developed for ESD, the basic techniques for safe and effective ESD are the same.

Comparison of gastric relaxation and sensory functions between functional dyspepsia and healthy subjects using novel drinking-ultrasonography test.

BACKGROUND: Functional dyspepsia (FD) is a heterogeneous disease characterized by various upper abdominal symptoms. The major mechanism of FD includes impaired fundic accommodation, delayed gastric emptying and visceral hypersensitivity. We developed a novel drinking-ultrasonography test to combine a drink test with ultrasonography to assess gastric motility and sensory function of FD patients. METHOD: Subjects were 20 healthy volunteers and 26 successive FD patients according to the Rome III criteria. The subjects ingested 200 ml of water at 2-min intervals 4 times (total 800 ml) through a straw. The maximum cross section of the proximal stomach was visualized before water intake, after each water intake, and 5 and 10 min after the completion of drinking using extracorporeal ultrasonography. Abdominal symptoms were evaluated using the visual analog scale (VAS) a total of 5 times. RESULTS: The mean cross-sectional area of the fornix after 800 ml of water intake was significantly lower in the FD group compared with the control group. In the FD group, marked abdominal symptoms developed immediately after initiation of water intake, and VAS score differed significantly (p < 0.01) between the control and FD groups at each time point. CONCLUSION: We developed the novel drinking-ultrasonography test which revealed abnormalities in gastric accommodation and sensation in patients with FD compared with healthy controls. This approach can be readily performed and allows the simultaneous evaluation of gastric accommodation, emptying and sensation.

Identification of a high risk gastric cancer group using serum pepsinogen after successful eradication of Helicobacter pylori.

BACKGROUND AND AIM: Pepsinogen (PG) method is widely used to identify high risk groups of gastric cancer. It is very useful before Helicobacter pylori eradication, but after eradication the method becomes useless because the PGI, PGII, PGI/II ratios change. Therefore, we aimed to identify a high risk group for gastric cancer using serum pepsinogen after successful eradication of H. pylori. METHODS: A total of 261 participants were enrolled after successful eradication of H. pylori in Hokkaido University Hospital from 1995 to 2010. Participants with renal failure, taking proton pump inhibitors, and those with advanced gastric cancer were excluded. Serum levels of PGI and II were measured using chemiluminescent immunoassay method. RESULTS: Receiver operating characteristic curves using cancerous and non-cancerous data in post-eradication determined the optimal cut-off value of PGI/II as 4.5. The sensitivity and the specificity were 65.9% and 79.3%, respectively. The usual PG method includes 48.9% of cancer cases, and the PGI/II ≤ 4.5 in post-eradication includes 65.9% of them, and it includes approximately half of the high risk group of diffuse type cancer. PGI/II ≤ 4.5 in post-eradication included many gastric cancer cases detected after eradication (12/16 = 75%). CONCLUSION: In the identification of a high risk group for gastric cancer, we suggest that the optimal cut-off value of PGI/II after successful eradication of H. pylori is 4.5. PGI/II ≤ 4.5 in post-eradication includes more gastric cancer cases compared with the traditional PG method, and 75% of gastric cancer cases detected after eradication.