Jaw-Town Lin

The effect of metabolic risk factors on the natural course of gastro-oesophageal reflux disease

Background and aims: The effect of metabolic risk factors on the natural course of gastro-oesophageal reflux disease (GORD), which remains elusive, was quantified. Methods: The population included 3669 subjects undergoing repeated upper endoscopy. Data were analysed using a three-state Markov model to estimate transition rates (according to the Los Angeles classification) regarding the natural course of the disease. Individual risk score together with the kinetic curve was derived by identifying significant factors responsible for the net force between progression and regression. Results: During three consecutive study periods, 12.2, 14.9 and 17.9% of subjects, respectively, progressed from non-erosive to erosive disease, whereas 42.5, 37.3 and 34.6%, respectively, regressed to the non-erosive stage. The annual transition rate from non-erosive to class A–B disease was 0.151 per person year (95% CI 0.136 to 0.165) and from class A–B to C–D was 0.079 per person year (95% CI 0.063 to 0.094). The regression rate from class A–B to non-erosive disease was 0.481 per person year (95% CI 0.425 to 0.536). Class C–D, however, appeared to be an absorbing state when not properly treated. Being male (relative risk (RR) 4.31; 95% CI 3.22 to 5.75), smoking (RR 1.20; 95% CI 1.03 to 1.39) or having metabolic syndrome (RR 1.75; 95% CI 1.29 to 2.38) independently increased the likelihood of progressing from a non-erosive to an erosive stage of disease and/or lowered the likelihood of disease regression. The short-term use of acid suppressants (RR 0.54; 95% CI 0.39 to 0.75) raised the likelihood of regression from erosive to non-erosive disease. Conclusions: Intraoesophageal damage is a dynamic and migratory process in which the metabolic syndrome is associated with accelerated progression to or attenuated regression from erosive states. These findings have important implications for the design of effective prevention and screening strategies.

Randomized trial of 1-minute versus 5-minute endoscopic balloon dilation for extraction of bile duct stones

BACKGROUND Endoscopic papillary balloon dilation (EPBD) has a lower risk of hemorrhage than sphincterotomy and is easier to perform in altered/difficult anatomy. However, the sphincter of Oddi (SO) is only stretched but not cut after EPBD. Therefore, the biliary orifice is less opened, and failed stone extraction with EPBD alone occurs in up to 20% of patients. An uncut SO also may exacerbate pancreatic duct compression from edema after EPBD, and it increases the risk of pancreatitis. OBJECTIVE To determine whether a longer duration for EPBD (5-minute vs conventional 1-minute) can further weaken the SO and reduce the rates of failed stone extraction and pancreatitis. DESIGN Prospective, randomized trial. SETTING Two tertiary-care referral centers. PATIENTS This study involved 170 consecutive patients with common bile duct stones. INTERVENTION EPBD for 1 minute (n = 86) or 5 minutes (n = 84). MAIN OUTCOME MEASUREMENTS Failed stone extraction with EPBD alone and post-ERCP pancreatitis. RESULTS Failed stone extraction with EPBD alone was less frequent with 5-minute EPBD (6 of 84, 7.1%) than with 1-minute EPBD (17 of 86, 19.8%), with a relative risk (RR) of 0.36 (P = .024). The risk of pancreatitis was also lower with 5-minute EPBD (4 of 84, 4.8%) than with 1-minute EPBD (13 of 86, 15.1%), with an RR of 0.32 (P = .038). Multivariable logistic regression analyses reaffirmed that 5-minute EPBD reduced the risk of failure with EPBD alone (odds ratio [OR] 0.19, P = .010) and pancreatitis (OR 0.28, P = .035). LIMITATIONS Endoscopists could not be blinded after the dilation durations were randomly assigned. CONCLUSION Compared with conventional 1-minute EPBD, 5-minute EPBD improves efficacy of stone extraction and reduces the risk of pancreatitis. ( CLINICAL TRIAL REGISTRATION NUMBER NCT00451581).

Heavy alcohol consumption increases the incidence of hepatocellular carcinoma in hepatitis B virus-related cirrhosis

BACKGROUND & AIMS Taiwan has a high prevalence of hepatitis B viral (HBV) infection and hepatocellular carcinoma (HCC) with increasing consumption of alcohol. We investigated the impact of heavy alcohol consumption and HBV infection on HCC in cirrhotic patients. METHODS 966 cirrhotic patients (132 with HBV infection and alcoholism, 632 with HBV infection, and 202 patients with alcoholism) were enrolled between 2000 and 2009 and followed until 2011. The primary end point was newly developed HCC. RESULTS Within the three patient groups (cirrhotic patients with HBV infection and alcoholism, HBV infection alone, and alcoholism alone) 38 (28.8%), 100 (15.8%), and 21 (10.4%) showed newly developed HCC, respectively. The 10-year cumulative (52.8% vs. 39.8% vs. 25.6%, p <0.001) and annual incidences (9.9%, 4.1%, and 2.1%) of HCC were significantly higher in cirrhotic patients with HBV infection and alcoholism than those in patients with HBV infection or alcoholism alone. For patients with HBV infection and alcoholism, baseline serum HBV DNA (OR=16.8, p=0.025), antiviral nucleos(t)ides analogues (NUCs) therapy (OR=0.01, p=0.035), and serum α-fetoprotein (OR=1.18, p=0.045) were risk predictors of HCC by multivariate logistic regression models. The cumulative incidence of HCC was higher in patients with higher baseline serum HBV DNA. Antiviral NUCs therapy reduced the incidence of HCC. CONCLUSIONS Heavy alcohol consumption significantly increased the risk of HCC in HBV-related cirrhotic patients. Elevated baseline serum HBV DNA was a strong risk predictor of HCC and antiviral NUCs therapy reduced the incidence of HCC in cirrhotic patients with HBV infection and alcoholism.

Current status of Barrett's esophagus research in Asia

In Western countries, the epidemiology of esophageal cancer has changed considerably over the past decades with a rise in the ratio of adenocarcinoma to squamous cell carcinoma. Although the prevalence of gastroesophageal reflux is increasing in Asia, the prevalences of Barretts esophagus (BE) and esophageal adenocarcinoma (EAC) have remained low in most Asian countries. The Asian Barretts Consortium recently conducted a review of published studies on BE from Asia to assess the current status of BE research in Asia, and to recommend potential areas for future BE research in the region. Differences in study design, enrolled population, and endoscopic biopsy protocols used have led to substantial variability in the reported BE prevalence (0.06% to 19.9%) across Asia. In particular, some Japanese studies used diagnostic criteria that differed considerably from what was used in most Asian studies. As in Western countries, increased age, male sex, tobacco smoking, reflux symptoms, and erosive esophagitis have been found to be risk factors for BE in several case‐control studies from Asia. The Prague C and M criteria, developed to provide better interobserver reliability in diagnosis and grading of BE, are currently under extensive evaluation in the Asian population. There is a need for standardized protocols for endoscopic and histopathologic diagnosis before initiating collaborative projects to identify etiologic determinants of BE and its ensuing malignant transformation. At present, data regarding the management and long‐term outcome of BE are extremely limited in Asia. More studies of BE in this geographic area are warranted.

Time trends of endoscopic and pathological diagnoses related to gastroesophageal reflux disease in a Chinese population: eight years single institution experience.

The discrepancy between Eastern and Western countries exists regarding the time trends of Barretts esophagus (BE)/adenocarcinoma. We aimed to elucidate this issue through a retrospective review of the endoscopic and pathological diagnoses of gastroesophageal reflux disease (GERD) over time in a Chinese population. All records were analyzed from 2000 to 2007. Records included demographic data, clinical indication for endoscopy, and endoscopic findings. The total number of endoscopic procedures increased over time. The indications for referral endoscopy secondary to GERD increased from 366 cases (4.9%) in the beginning of the study to 1439 cases (14.1%) at the end. Concomitant GERD symptoms did not significantly change (range, 13-15.1%) in screening endoscopic studies. Endoscopic detection of erosive esophagitis increased in referral populations from 1546 (20.7%) to 5207 cases (51%) and by screening endoscopy from 791 (14.5%) to 1983 cases (23.5%). The prevalence of nonerosive reflux disease and BE did not change over time. BE-associated dysplasia and adenocarcinoma were rare. The detection of Los Angeles class A disease increased with time in referral endoscopy cases with a focus on erosive esophagitis composition. The endoscopic demand for GERD investigation and the GERD endoscopic diagnosis increased in our population. The results were related to a higher prevalence of low-grade erosive disease diagnosed. The incidence of BE-associated dysplasia and adenocarcinoma has been the same and the increased screening did not detect more cancers.

Treatment of Helicobacter pylori Infection- Where are we now?

Gastric cancer and Helicobacter pylori infection remain a burden in many Asian countries. In the face of rising antibiotic resistance, the eradication rate of standard triple therapy is declining in many Asian countries. We reviewed the updated epidemiology of gastric cancer, prevalence of H. pylori infection, and antibiotic resistance in Asia. We also reviewed the strategies to improve the efficacy of H. pylori eradication therapies, including the use of high dose proton pump inhibitor, four drug therapies (including bismuth quadruple, concomitant, and sequential therapy), susceptibility guided therapy, extending the treatment duration to 14 days, and development of effective rescue therapy. Four drug therapies are usually more effective than triple therapy when given in the same duration, except in areas with concomitantly high metronidazole resistance and low clarithromycin resistance. The efficacies of different four drug regimens appeared to be similar. However, trials from different geographic areas showed contradictory results, indicating that the optimal therapy should be decided according to the local prevalence of antibiotic resistance. We proposed a prediction model to calculate the efficacy of different regimens according to the prevalence of antibiotic resistance. More large randomized trials which provide information on the antibiotic resistance are urgently needed to build a more accurate and reliable model. It is hoped that we will be able to decide the optimal regimens by routine surveillance of antibiotic resistance.

Quantification of tumor infiltrating Foxp3+ regulatory T cells enables the identification of high-risk patients for developing synchronous cancers over upper aerodigestive tract

OBJECTIVES Patients with squamous cell carcinomas (SCC) of upper aerodigestive tract, either over head and neck (HNSCC) or esophagus (ESCC), frequently developed synchronous multiple cancers, leading to worse prognosis. This study validated whether suppression of host cancer immunosurveillance mediated by regulatory T cells (Treg) may predispose to the development of synchronous cancers. METHODS Tumor tissues of 200 patients (100 ESCC only, 50 HNSCC only, and 50 synchronous SCCs) were quantitatively accessed for the tumor infiltrating Treg by immunohistochemistry. The density of Treg was also correlated to the level of Treg-associated inhibitory cytokines (IL-10, IL-35 and TGF-β1), and chemokine (CCL22). RESULTS The density of tumor infiltrating Treg in the index tumor (i.e. the first malignancy diagnosed) of synchronous SCC group was higher than those of HNSCC or ESCC only (p<0.05). Selecting the optimal cut-off value of Treg density as 34.6 cells/mm(2) by ROC curve, an increased Treg density of the index tumor can be an independent factor for developing synchronous SCCs (OR: 6.13; 95% CI: 2.84-13.26). The Treg density was positively correlated with serum IL-10 level and the degree of CCL22-positive cells infiltration in tumor. Furthermore, the serum inhibitory cytokine IL-10 level was higher in synchronous SCC than in non-synchronous ones (p<0.001), that indicated the cellular immunosuppression in patients with synchronous cancers. CONCLUSIONS A more severe defect in cellular immunity may predispose to multifocal tumor. The Treg cell number in SCC may serve as a novel predictive biomarker for the risk of synchronous cancer development to initiate a proper surveillance program.

Concomitantly elevated serum matrix metalloproteinases 3 and 9 can predict survival of synchronous squamous cell carcinoma of the upper aero-digestive tract.

Matrix metalloproteinases (MMPs) are elevated in patients with squamous cell carcinoma (SCC) over either the head and neck (HNSCC) or the esophagus (ESCC). Synchronous SCC with both HNSCC and ESCC predispose to worse survival. This study tested if serum MMP levels correlate with clinical features and predict survival for HNSCC, ESCC, and synchronous SCC. One hundred and thirty patients with SCCs in upper aero‐digestive tract (70 ESCC, 20 HNSCC, and 40 synchronous SCC) and 74 healthy controls were assessed for serum MMP‐3, ‐7, and ‐9 titers by enzyme‐linked immunosorbent assay. The titers were validated to their correlations to clinical features and survival rates of the different SCC groups. Patients with SCCs had significantly higher serum MMP‐3, ‐7, and ‐9 titers than the controls (P < 0.001) but there was no difference among the three SCC groups. Based on the optimal MMP cut‐off values by ROC curve, elevated MMP‐3 and MMP‐9, but not MMP‐7, correlated with distant metastasis and poor survival (P < 0.05). Concomitantly elevated MMP‐3 (>14 ng/mL) and MMP‐9 (>329.3 ng/mL) independently correlated with poor two‐year survival (P = 0.002, by log rank test). Cox regression confirmed that such concomitant elevation was superior to the tumor stage of either ESCC or HNSCC in predicting survival for synchronous SCC. Serum MMPs are elevated in SCC of the upper aero‐digestive tract. Especially for synchronous SCC, concomitantly elevated MMP‐3 and MMP‐9 levels serve as better biomarkers to predict prognosis than TNM staging of ESCC or HNSCC.

Emergency endoscopy for upper gastrointestinal bleeding in patients with coronary artery disease

BACKGROUND Endoscopy is useful for diagnosis and treatment of upper gastrointestinal bleeding (UGIB). However, both endoscopy and UGIB may compromise the cardiovascular function. The present study is to investigate the cardiovascular responses of emergency endoscopy for patients with UGIB and stable coronary artery disease (CAD). METHODS Consecutive 50 patients with known CAD and 50 patients without CAD history (non-CAD group) in whom emergency endoscopy was requested for UGIB were prospectively enrolled. All patients received ambulatory electrocardiographic monitoring before, during, and after endoscopies. Cardiac indices including supraventricular and ventricular arrhythmia, ST ischemic change, and autonomic nervous function evaluated by heart rate variability were compared. RESULTS All patients in both groups had successful primary hemostasis, and peptic ulcer bleeding was the main etiology (82%). Compared with the non-CAD group, patients with CAD had a significantly higher incidence (42% vs 16%, P = .004) and frequency (1.19 vs 0.12 events per minute, P = .003) of ventricular arrhythmias during endoscopy. Nine patients with CAD and 1 patient without CAD had ischemic ST changes (P = .016). Comorbidity with congestive heart failure was not only associated with a higher frequency (P = .02) but also a more severe fluctuation (P = .002) of ventricular arrhythmia. None in both groups had angina or MI before, during, or after endoscopy. Heart rate variability did not show a difference. CONCLUSIONS Ventricular arrhythmias and myocardial ischemia, although mostly subclinical, were common in patients with stable CAD undergoing emergent endoscopy for UGIB, especially in those with concomitant congestive heart failure.

CURRENT STATUS AND FUTURE PERSPECTIVE OF ENDOSCOPIC DIAGNOSIS AND TREATMENT FOR COLORECTAL NEOPLASIA – SITUATION IN TAIWAN

The incidence of colorectal cancer (CRC) is rising substantially in Taiwan. Hence, both effective screening and management of colorectal neoplasms, including precursor lesions and early cancers, have become critically important. Colorectal cancer is not only curable, but also can be managed endoscopically if detected at the stage of precursor lesions or early cancer. Optimal management of colorectal neoplasia relies largely on accurate evaluation of the characteristics of lesions, including malignant transformation, and the depth of invasion of the malignant lesions. In this context, observation using image enhancing endoscopy (IEE) to magnify the image during colonoscopy is of utmost importance. Polypectomy or endoscopic mucosal resection is now the standard procedure for the treatment of colorectal adenoma or early cancerous lesions in Taiwan. Endoscopic submucosal dissection (ESD) is performed at only a few institutions; its long‐term efficacy and cost‐effectiveness require further elucidation. More attention from the government, academic societies, and individual clinicians is necessary.