Time-varying serum gradient of hepatitis B surface antigen predicts risk of relapses after off-NA therapy.

BACKGROUND: The serum gradient of hepatitis B surface antigen (HBsAg) varies over time after cessation of nucleos(t)ide analog (NA) treatment in patients with chronic hepatitis B (CHB). The association between the time-varying HBsAg serum gradient and risk of relapse has not been elucidated. METHODS: This multicenter cohort study prospectively enrolled CHB patients who discontinued 3 year-NA treatment. Eligible patients were serologically negative for HBeAg and viral DNA at NA cessation. The participants (n = 140) were followed every 3 months through HBsAg quantification. Virological and clinical relapses were defined as viral DNA levels >2000 IU/mL and alanine aminotransferase (ALT) levels >80 U/mL, respectively. The association of time-varying HBsAg levels with relapses was assessed through a time-dependent Cox analysis. RESULTS: During a median follow-up of 19.9 (interquartile range [IQR], 10.6-25.3) months, virological and clinical relapses occurred in 94 and 49 patients, with a 2-year cumulative incidence of 79.2% (95% confidence interval [CI], 70.9%-86.4%) and 42.9% (95% CI, 34.1%-52.8%), respectively. The serum level of HBsAg was associated with virological (P < 0.001) and clinical (P = 0.01) relapses in a dose-response manner, with adjusted hazard ratios of 2.10 (95% CI, 1.45-3.04) and 2.32 (95% CI, 1.28-4.21). Among the patients (n = 19) whose HBsAg levels ever dropped below 10 IU/mL, only one and three patients subsequently developed clinical and virological relapses. CONCLUSION: The serum gradient of HBsAg measured throughout the off-therapy observation is associated with the subsequent occurrence of virological and clinical relapses in CHB patients who discontinue NA treatment.

Serum viral load at the virological relapse predicts subsequent clinical flares in chronic hepatitis B patients off entecavir therapy.

BACKGROUND AND AIM: Therapeutic duration of nucleos(t)ide analogues for chronic hepatitis B (CHB) is not indefinite in many parts of the world. Viral reactivation is common off therapy, but the risk of subsequent clinical outcome remains unclear and unpredictable. We aimed to quantify the incidence of and explore the predictors for clinical flare following virological relapse in CHB patients who discontinue entecavir therapy. METHODS: This multicenter cohort study prospectively monitored 133 CHB patients who were HBeAg-negative and viral DNA-undetectable when discontinuing entecavir after at least 3 years on therapy. Following virological relapse (viral DNA >2,000 IU/mL) that occurred in 92 patients, the incidences of subsequent clinical flare and persistent (unremittent for 3 months) or severe hepatitis (with jaundice or coagulopathy) were determined, and risk factors were explored. Patients did not resume antiviral therapy until occurrence of persistent or severe hepatitis. RESULTS: The cumulative incidence of clinical hepatitis 2 years after virological relapse was 61.0% (95% confidence interval [CI], 49.9-72.3%) and that of persistent or severe hepatitis was 53.0% (95% CI, 40.9-66.2%). Serum viral load at the virological relapse was associated with both clinical hepatitis (adjusted hazard ratio [HR], 1.31 per log IU/mL; 95% CI, 1.07-1.60) and persistent or severe hepatitis (adjusted HR, 1.63 per log IU/mL; 95% CI, 1.27-2.10), after adjustment for serum aminotransferase and alfa-fetoprotein levels in the multivariate analysis. Viral DNA >100 000 IU/mL predicted a nearly inevitable occurrence of clinical flare (P < 0.0001). CONCLUSIONS: A high viral load at the virological relapse predicts subsequent clinical hepatitis in CHB patients who discontinue entecavir.

Association Between Serum Level of Hepatitis B Surface Antigen at End of Entecavir Therapy and Risk of Relapse in E Antigen-Negative Patients.

BACKGROUND & AIMS: This study investigated whether serum level of hepatitis B surface antigen (HBsAg) at the end of entecavir treatment was associated with risk of relapse. METHODS: We performed a prospective multicenter study of 161 consecutive patients with chronic hepatitis B in whom the hepatitis B virus was no longer detected after 3 years or more of entecavir therapy. Treatment ended between July 1, 2011 and July 1, 2015. Patients were monitored for clinical relapse (hepatitis B virus DNA >2000 IU/mL and level of alanine aminotransferase more than 2-fold the upper limit of normal) and virologic relapse (hepatitis B virus DNA >2000 IU/mL). Outcomes were calculated using the Kaplan-Meier method and risk factors were identified by Cox proportional hazards modeling. RESULTS: Two years after therapy ended, 49.2% of patients in the entire cohort had a clinical relapse (95% confidence interval [CI], 40.9%-58.1%) and 81.7% had a virologic relapse (95% CI, 74.3%-88.0%). Among patients who were hepatitis B e antigen-negative at the end of therapy, 39.2% had a clinical relapse (95% CI, 30.3%-49.6%) and 77.4% had a virologic relapse (95% CI, 68.6%-85.2%). Serum level of HBsAg was associated with relapse in the hepatitis B e antigen-negative patients (Ptrend = .006 for clinical relapse; Ptrend = .0001 for virologic relapse). In multivariate Cox regression analysis, the hazard ratio (per log IU/mL increment) for clinical relapse was 2.47 (95% CI, 1.45-4.23) and for virologic relapse was 1.80 (95% CI, 1.33-2.45). The 11 (9%) patients with levels of HBsAg <10 IU/mL did not relapse. CONCLUSIONS: Serum level of HBsAg is associated with risk of relapse in patients who are hepatitis B e antigen-negative after treatment with entecavir. A low titer of HBsAg might be used to identify patients at low risk for relapse after treatment.

Hepatitis B core-related antigen dynamics and risk of subsequent clinical relapses after nucleos(t)ide analog cessation.

BACKGROUND/AIMS: Finite nucleos(t)ide analog (NA) therapy has been proposed as an alternative treatment strategy for chronic hepatitis B (CHB), but biomarkers for post-treatment monitoring are limited. We investigated whether measuring hepatitis B core-related antigen (HBcrAg) after NA cessation may stratify the risk of subsequent clinical relapse (CR). METHODS: This retrospective multicenter analysis enrolled adults with CHB who were prospectively monitored after discontinuing entecavir or tenofovir with negative HBeAg and undetectable HBV DNA at the end of treatment (EOT). Patients with cirrhosis or malignancy were excluded. CR was defined as serum alanine aminotransferase > two times the upper limit of normal with recurrent viremia. We applied time-dependent Cox proportional hazard models to clarify the association between HBcrAg levels and subsequent CR. RESULTS: The cohort included 203 patients (median age, 49.8 years; 76.8% male; 60.6% entecavir) who had been treated for a median of 36.9 months (interquartile range [IQR], 36.5-40.1). During a median post-treatment follow-up of 31.7 months (IQR, 16.7-67.1), CR occurred in 104 patients with a 5-year cumulative incidence of 54.8% (95% confidence interval [CI], 47.1-62.4%). Time-varying HBcrAg level was a significant risk factor for subsequent CR (adjusted hazard ratio [aHR], 1.53 per log U/mL; 95% CI, 1.12-2.08) with adjustment for EOT HBsAg, EOT anti-HBe, EOT HBcrAg and time-varying HBsAg. During follow-up, HBcrAg <1,000 U/mL predicted a lower risk of CR (aHR, 0.41; 95% CI, 0.21-0.81). CONCLUSION: Dynamic measurement of HBcrAg after NA cessation is predictive of subsequent CR and may be useful to guide post-treatment monitoring.

Mosapride as an adjunct to lansoprazole for symptom relief of reflux oesophagitis.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT Reflux oesophagitis is a common clinical disorder associated with significant morbidity. Proton pump inhibitors are the current pharmacotherapy of choice, but not all treated patients achieve symptom relief. Little is known about the efficacy of mosapride, a prokinetic agent which decreases episodes of gastro-oesophageal reflux, as an adjunct to proton pump inhibitors in improving the symptoms of reflux oesophagitis. WHAT THIS STUDY ADDS Mosapride was generally not more effective than placebo as an adjunct therapy to a standard dose of lansoprazole in decreasing the symptom burden of patients with reflux oesophagitis. However, in a subgroup with more severe symptoms, combination therapy with lansoprazole and mosapride was possibly superior to monotherapy with lansoprazole. AIMS To investigate if mosapride, a prokinetic agent, was an effective adjunct to acid suppression in improving the symptoms of reflux oesophagitis. METHODS Patients (n= 96) with reflux oesophagitis were randomly assigned to either mosapride (5 mg three times daily) or placebo for 4 weeks. Symptom severity was assessed by a validated questionnaire at enrolment, 4 and 8 weeks after medication. The primary outcome for the first 4 weeks was decrease in symptom scores. After a 3 day washout period, patients initially allocated to mosapride crossed over to placebo and vice versa for the next 4 weeks. The outcome of the second phase was maintenance of symptom control. All patients received lansoprazole (30 mg once daily) throughout study. RESULTS The decreased symptom score after 4 weeks of treatment with lansoprazole and mosapride (n= 50) was 13.42 +/- 1.16 (mean +/- SEM), similar to that of lansoprazole plus placebo (10.85 +/- 1.03, n= 46), with an insignificant difference of 2.57 (95% CI -0.53, 5.67, P= 0.103). However, a sub-group analysis for patients with pre-treatment scores of >18 points (n= 48) revealed that lansoprazole plus mosapride achieved a greater reduction of symptom score than lansoprazole plus placebo (18.22 +/- 1.91 vs. 12.88 +/- 1.65; mean difference of 5.34, 95% CI 0.28, 10.40, P= 0.039). In the second phase, there was no difference between lansoprazole with mosapride or placebo in maintaining symptom control (39/44 or 86.64% vs. 41/50 or 82%, P= 0.401). Subgroup analysis for those with substantial residual symptoms revealed similar results. CONCLUSION Compared with placebo, mosapride generally does not provide additional benefit to a standard dose of lansoprazole in patients with reflux oesophagitis, except possibly in the subgroup of severely symptomatic patients.

A randomized controlled trial comparing two different dosages of infusional pantoprazole in peptic ulcer bleeding.

AIM: The optimal dosage of proton pump inhibitor in bleeding peptic ulcers remains controversial. The aim was to compare the clinical effectiveness of two doses of infusional pantoprazole in peptic ulcer bleeding. METHODS: Peptic ulcer patients (n= 120) with bleeding stigmata were enrolled after successful endoscopic therapy. After an initial bolus injection of 80 mg pantoprazole, patients were randomized to receive continuously infused pantoprazole at either 192 mg day(-1) or 40 mg every 6 h (i.e. 160 mg day(-1)) for 3 days. Clinical outcomes between the two groups within 14 days were compared, with 14-day recurrent bleeding regarded as the primary end-point. RESULTS: Both groups (n= 60 each) were well matched in demographic and clinical factors upon entry. Bleeding totally recurred in 11 (9.2%) patients, with six (10%) in the 192 mg day(-1) group and five (8.3%) in the 160 mg day(-1) group (relative risk of bleeding recurrence between two treatments 1.2; 95% CI 0.39, 3.72). All secondary outcomes between the two groups were similar, including the amount of blood transfusion (mean 1179 ml vs. 1203 ml, P > 0.1), hospital stay (mean 9.5 days vs. 9.9 days, P > 0.1), need for surgery (n= 1 vs. n= 0, P > 0.1), and mortality (n= 1 vs. n= 0, P > 0.1). CONCLUSIONS: Following endoscopic haemostasis, infusional pantoprazole at either 192 mg day(-1) or 40 mg every 6 h appear similar.

Clinical and contrast-enhanced image features in the prediction model for the detection of small hepatocellular carcinomas.

Purpose: To identify novel radiological features and clinical characteristics to improve diagnostic criteria for early detection of small hepatocellular carcinoma (HCC). Patients and Methods: We retrospectively recruited asymptomatic patients with no history of HCC but a high risk of HCC in whom a new, solitary, well-defined, solid nodule between 10 and 20 mm was detected through a screening ultrasound. We retrospectively collected all clinical data, and patients were examined using dynamic contrast-enhanced computed tomography or magnetic resonance imaging; subsequently, fine-needle biopsy was performed. A multivariate analysis of the predictors of small HCCs was performed by fitting a multiple logistic regression model with the stepwise variable selection method. Results: In total, 392 and 347 patients with a small liver nodule received a final pathologic confirmation of HCC and non-HCC, respectively. The estimated odds ratios and 95% confidence intervals of tumor size > 12.45 mm, age > 56.61 years, liver cirrhosis, hepatitis C virus (HCV) carrier status, ln alpha-fetoprotein (AFP) > 1.954, arterial phase enhancement, and portal or venous phase washout appearance without arterial phase enhancement were 2.0735 (1.4746-2.9155), 1.8878 (1.2949-2.7521), 1.6927 (1.1294-2.5369), 1.6186 (1.0347-2.5321), 2.0297 (1.3342-3.0876), 3.7451 (2.3845-5.8821), and 2.0327 (1.3500-3.0608), respectively. The area under the receiver operating characteristic curves for the diagnosis of small HCCs was 0.79 for arterial phase enhancement and 0.75 for portal or venous phase washout appearance without arterial phase enhancement. Conclusion: Clinical and contrast-enhanced image features are valuable in the prediction model for the detection and early diagnosis of small HCCs in patients with a high risk of HCC. In addition to negative portal or venous washout and negative arterial enhancement in images, age > 56.61 years, tumor size > 12.45 mm, HCV carrier status, and ln(AFP) > 1.954, are useful indicators for the early detection of small HCCs.

Psychopathology and personality trait in subgroups of functional dyspepsia based on Rome III criteria.

OBJECTIVES: Functional dyspepsia is a heterogeneous symptom complex that may be subdivided into postprandial distress syndrome and epigastric pain syndrome. We aimed to investigate differences among these subgroups in psychopathological factors and personality traits. METHODS: We enrolled 187 consecutive outpatients (72.2% female patients, mean age 42.6 years) with functional dyspepsia based on the Rome III criteria. Patients were interviewed and evaluated by the Brief Symptom Rating Scale and the short-form Maudsley personality inventory for severity of psychopathology and personality traits. Multiple linear regression models were built for each psychopathological dimension and personality trait to assess the independent association with each subclass diagnosis of functional dyspepsia. RESULTS: There was an overlap (n=64, 34.2%) between the patients diagnosed with epigastric pain syndrome (n=157, 84.0%) and those with postprandial distress syndrome (n=94, 50.3%). Patients with symptoms compatible with both syndromes were psychopathologically more severe than either subgroup without overlapping. Multiple linear regression analysis demonstrated that the diagnosis of postprandial distress syndrome was independently associated with higher scores in overall psychopathological stress, and specifically in somatization (P=0.034), depression (P=0.028), phobia (P=0.044), and additional symptoms (P<0.001). However, epigastric pain syndrome was not associated with psychopathology. Postprandial distress was univariately associated with neuroticism, but the association was insignificant in the multivariate analysis (P=0.136). CONCLUSIONS: The Rome III subgroups of functional dyspepsia significantly overlap. Patients fulfilling criteria for both subgroups had symptoms that were psychopathologically more severe than those of patients without overlapping. Diagnosis of postprandial distress syndrome, but not epigastric pain syndrome, is independently associated with psychopathological factors.

Combining hepatitis B core-related and surface antigens at end of nucleos(t)ide analogue treatment to predict off-therapy relapse risk.

BACKGROUND: There remains an unmet need for convenient biomarkers to assess the risks of discontinuing nucleos(t)ide analogues (NAs) in chronic hepatitis B (CHB). AIM: To investigate if hepatitis B core-related antigen (HBcrAg) is an independent of surface antigen (HBsAg) for risk prediction of NA cessation. METHODS: This prospective multicentre study enrolled 135 CHB patients who stopped entecavir or tenofovir after achieving viral remission for a median of 25.2 months. All patients stopped NA with negative HBeAg and undetectable viral DNA, and were then observed for clinical relapse and HBsAg loss. Predictors including HBsAg and HBcrAg levels were explored using Cox proportional hazard model and weighted to develop a risk score. RESULTS: During a median follow-up of 25.9 months, clinical relapse and HBsAg loss occurred in 66 and eight patients, respectively, with a 5-year cumulative incidence of 56.1% (95% CI 46.7-66.0%) and 8.8% (95% CI 4.3-17.4%), respectively. HBcrAg was an independent relapse predictor, as well as HBsAg, age, ALT and tenofovir use. A score (SCALE-B) was calculated by the equation of 35*HBsAg (log IU/mL) + 20*HBcrAg (log U/mL) + 2*age (year) + ALT (U/L) + 40 for tenofovir use. The concordance rates for clinical relapse were 0.87, 0.88, 0.87, 0.85 and 0.90 at 1, 2, 3, 4 and 5 years, respectively. Moreover, HBsAg loss occurred exclusively in low-risk patients predicted by the score. CONCLUSIONS: Serum HBcrAg and HBsAg levels were independent predictors of off-NA relapse and can be factored into a risk score to guide treatment cessation in patients with CHB.

Can clinical features stratify use of endoscopy for dyspeptic patients with high background prevalence of upper gastrointestinal cancer?

BACKGROUND: Whether clinical features can stratify priority of endoscopy remains controversial for dyspeptic patients with high background prevalence of upper gastrointestinal cancer. AIM: To examine the predictive performance of clinical features for cancerous lesions in dyspeptic patients in Taiwan. METHODS: Between April 2008 and July 2009, 2530 consecutive dyspeptic outpatients underwent prospective evaluation with standardized questionnaire and then upper gastrointestinal endoscopy. Performance of using age thresholds and alarm symptoms to predict malignancy was determined. Independent risk factors associated with malignancy and those with negative endoscopic findings were identified. RESULTS: Malignant lesions were found in 31 patients (1.2%) and were independently associated with age, male gender, gastrointestinal bleeding, weight loss, and alcohol consumption. Any symptom of weight loss, bleeding and dysphagia, or simply age >45 years predicted 97% of cancer cases, with the sensitivity, specificity, positive and negative predictive values being 96.8%, 29.3%, 1.7%, and 99.9%, respectively. This strategy achieved a low negative likelihood ratio (0.11) and a high diagnostic odds ratio (12.45). Negative endoscopic finding (n=1377, 54.4%) was independently associated with younger age, female gender, no use of non-steroidal anti-inflammatory drug, and no tobacco or alcohol consumption. CONCLUSIONS: Absence of weight loss, dysphagia, and gastrointestinal bleeding predicts low likelihood of malignancy in dyspeptic Taiwanese patients aged <45 years.

Proton pump inhibitor versus prokinetic therapy in patients with functional dyspepsia: is therapeutic response predicted by Rome III subgroups?

BACKGROUND: The comparative effectiveness of proton pump inhibitor versus prokinetic therapy in relieving the symptoms of patients with functional dyspepsia remains unknown. Whether the Rome III subgroups predict therapeutic response has not been investigated. METHODS: This was an open-label, parallel randomized controlled trial. A total of 329 adult outpatients fulfilling the Rome III criteria for functional dyspepsia were randomly allocated to receive either lansoprazole 30 mg once daily (n = 166) or mosapride 5 mg thrice daily (n = 163) for 2 weeks. Enrolled patients were evaluated with the validated Hong Kong Index questionnaire for symptom severity at baseline and at the end of the trial. The primary outcome was symptom relief as defined by the Hong Kong Index, and the secondary outcome was decrease of symptom scores. Post-hoc multivariate logistic regression analysis was conducted to identify independent predictors for therapeutic response. RESULTS: After 2-week therapy, 50.6% (84/166) and 47.85% (78/163) of the patients treated with lansoprazole and mosapride, respectively, achieved significant symptom relief (odds ratio 1.12, 95% confidence interval 0.72-1.72, p = 0.62). Differences in decreases of symptom scores between lansoprazole and mosapride receivers were also insignificant (-0.08, 95% confidence interval -1.25 to 1.09, p = 0.89). Therapeutic responses to either pharmacotherapy did not differ in the subgroup of patients fulfilling the criteria for epigastric pain syndrome (n = 256) or in those fulfilling the criteria for postprandial distress syndrome (n = 161). Multivariate logistic regression confirmed that the treatment allocation and Rome III subgroup were unrelated to treatment outcome. CONCLUSIONS: The effectiveness of proton pump inhibitor therapy and that of prokinetic therapy in functional dyspepsia are not different, and cannot be predicted by Rome III subgroups (ClinicalTrials.gov number, NCT00663897).

A case of phlebosclerotic colitis with involvement of the entire colon.

Phlebosclerotic colitis is a rare type of ischemic colitis caused by obstruction of the veins in the intestinal wall and adjacent mesentery, and is most commonly seen in the ascending colon. We report a 56-year-old woman presenting with intermittent abdominal pain and diarrhea for three years. She had a liver abscess and two episodes of pancreatitis during this time and experienced progressive body weight loss. Initial radiologic findings showed multiple tortuous threadlike calcifications in the region of the right side of the colon and transverse colon on plain abdominal radiographs and computed tomography images. A colonoscopy demonstrated brownish-black pigmentation on the right side of the colon with scattered hyperemic patches. The more distal along the colon, the more normal the color of the bowel appeared. Follow-up studies revealed calcifications not only alongside the colonic and mesenteric veins, but also extending into the superior and inferior mesenteric veins. These findings have not been reported previously. As noted in our patient, this disease entity may not be confined to the tributaries of the superior mesenteric vein. The entire colon may be involved in advanced disease.

Synchronous triple cancers at middle and lower esophagus and stomach with different histological features and genetic alterations.

Synchronous multiple primary malignancies are relatively unusual. We describe a case of synchronous triple cancers located at the middle and lower esophagus and the stomach in a 59-year-old Taiwanese man who presented with progressive dysphagia, epigastralgia, and bodyweight loss in 1 month. Endoscopic and histological features, microsatellite instability status of genomic DNA, and immunohistochemical staining of p53, MUC2, Fhit, c-erbB-2 and E-cadherin of all three cancers were demonstrated. We noted that these three cancers arose from different clones and that p53 mutation, instead of microsatellite instability, may play a major role in the development of multiple primary malignancies in this patient.

Endoscopic hemostasis of a bleeding marginal ulcer: hemoclipping or dual therapy with epinephrine injection and heater probe thermocoagulation.

BACKGROUND AND AIMS: Endoscopic hemoclipping and dual therapy with epinephrine injection and heater probe thermocoagulation have been proven effective in the hemostasis of bleeding peptic ulcers. However, the hemostatic efficacy has not been investigated in bleeding marginal ulcers. The aim of this study is to investigate the hemostatic efficacy of endoscopic hemoclipping and dual therapy with epinephrine injection and heater probe thermocoagulation in bleeding marginal ulcers. METHODS: From November 1997 to July 2000, 50 patients with active marginal ulcer bleeding underwent either hemoclipping (20 patients) or dual therapy (30 patients) for hemostasis. The demographic data, clinicopathological characteristics, endoscopic findings, initial hemostatic rates, rebleeding rates, amount of blood transfusion, the need of surgery, and mortality rates were collected and analyzed. RESULTS: Marginal ulcers were located at the anastomotic site (64%), saddle portion (22%), efferent loop (10%), or at the afferent loop (4%). The bleeding stigmata were classified into spurting artery (32%), oozing vessel (38%), visible vessel (20%), and blood clot adhesion (10%). The overall therapeutic results in 50 patients were initial hemostasis (100%), rebleeding rate (22%), need for surgery (4%), and hospital mortality rate (4%). There was no significant difference in demographic data and clinicopathological characteristics between the two modes of treatments, whereas recurrent bleeding developed in 5% in the hemoclipping group and 33% in the dual therapy group. No complication related to the procedure occurred in either mode of therapy. The hospital mortality rates were 0 and 6.7%, respectively. CONCLUSION: Endoscopy is effective in achieving initial hemostasis from bleeding marginal ulcers. However, the rebleeding rate remains high and repeated endoscopy may be needed to arrest the hemorrhage.