Treatment strategies using adefovir dipivoxil for individuals with lamivudine-resistant chronic hepatitis B

AIM:To investigate retrospectively the long-term efficacy of various treatment strategies using adefovir dipivoxil(adefovir) in patients with lamivudine-resistant chronic hepatitis B.METHODS:We included 154 consecutive patients in two treatment groups:the "add-on" group(n = 79),in which adefovir was added to ongoing lamivudine treatment due to lamivudine resistance,and the "switch/combination" group(n = 75),in which lamivudine was first switched to adefovir and then re-added later as needed.The "switch/combination" group was then divided into two subgroups depending on whether participants followed(group A,n = 30) or violated(group B,n = 45) a proposed treatment strategy that determined whether to add lamivudine based on the serum hepatitis B virus(HBV) DNA levels(< 60 IU/mL or not) after 6 mo of treatment(roadmap concept).RESULTS:The cumulative probability of virologic response(HBV DNA < 60 IU/mL) was higher in group A than in the "add-on" group and in group B(P < 0.001).In contrast,the cumulative probability of virologic breakthrough was lower in the "add-on" group than in group B(P = 0.002).Furthermore,the risk of virologic breakthrough in the multivariate analysis was significantly lower in the "add-on" group than in group A(hazard ratio = 0.096;95%CI,0.015-0.629;P = 0.015).CONCLUSION:The selective combination of adefovir with lamivudine based upon early treatment responses increased the odds of virologic breakthrough relative to the use of uniform combination therapy from the beginning of treatment.

Prognostic value of inflammation-based markers in patients with pancreatic cancer administered gemcitabine and erlotinib

AIM: To evaluate the value of systemic inflammationbased markers as prognostic factors for advanced pancreatic cancer(PC). METHODS: Data from 82 patients who underwent combination chemotherapy with gemcitabine and erlotinib for PC from 2011 to 2014 were collected retrospectively. Data that included the neutrophil-to-lymphocyte ratio(NLR), the platelet-to-lymphocyte ratio, and the C-reactive protein(CRP)-to-albumin(CRP/Alb) ratio were analyzed. Kaplan-Meier curves, and univariate and multivariate Cox proportional hazards regression analyses were used to identify the prognostic factors associated with progression-free survival(PFS) and overall survival(OS). RESULTS: The univariate analysis demonstrated the prognostic value of the NLR(P = 0.049) and the CRP/Alb ratio(P = 0.047) in relation to PFS, and a positiverelationship between an increase in inflammation-based markers and a poor prognosis in relation to OS. The multivariate analysis determined that an increased NLR(hazard ratio = 2.76, 95%CI: 1.33-5.75, P = 0.007) is an independent prognostic factor for poor OS. There was no association between the PLR and the patients' prognoses in those who had received chemotherapy that comprised gemcitabine and erlotinib in combination. The Kaplan-Meier method and the log-rank test determined significantly worse outcomes in relation to PFS and OS in patients with an NLR > 5 or a CRP/Alb ratio > 5.CONCLUSION: Systemic inflammation-based markers, including increases in the NLR and the CRP/Alb ratio, may be useful for predicting PC prognoses.

Management of entecavir-resistant chronic hepatitis B with adefovir-based combination therapies

AIM: To evaluate the long-term efficacy adefovir(ADV)-based combination therapies in entecavir(ETV)-resistant chronic hepatitis B(CHB) patients. METHODS: F i fty CHB pat ient s wi t h genotypic resistance to ETV at 13 medical centers in South Korea were included for the analysis. All the patients received rescue therapy with the combination of ADV plus ETV(ADV/ETV,n = 23) or ADV plus lamivudine(LMV)(ADV/LMV,n = 27) for more than 12 mo. Patients were monitored at least every 3-4 mo during ADV-based combination therapy by clinical examination as well as biochemical and virological assessments. Hepatitis B virus(HBV) DNA levels were measured by realtime PCR and logarithmically transformed for analysis. Cumulative rates of virologic response(VR; HBV DNA < 20 IU/m L) were calculated using the Kaplan-Meier method,and the difference was determined by a logrank test. Multivariate logistic regression and Cox proportional hazards models were used to identify independent risk factors significantly associated with short-term and long-term VR,respectively.RESULTS: Baseline median HBV DNA levels were 5.53(2.81-7.63) log10 IU/m L. The most commonly observed ETV genotypic mutation sites were rt184 and rt202. Patients were treated for a median of 27(12-45) mo. Overall,cumulative VR rates at 6,12,24,and 36 mo were 26%,36%,45%,and 68%,respectively. Patients treated with the ADV/ETV combination showed higher cumulative VR rates(35%,43%,65%,and 76%,respectively) than those with the ADV/LAM combination(18%,30%,30%,and 62%,respectively; P = 0.048). In the multivariate analysis,low baseline HBV DNA levels(< 5.2 log10 IU/m L) and initial virologic response at 3 mo(IVR-3; HBV DNA < 3.3 log10 IU/m L after 3 mo) were independent predictive factors for VR. Patients with favorable predictors achieved cumulative VR rates up to 90% at 36 mo. During the same period,the cumulative incidence of virologic breakthrough was as low as 6% in patients with the both favorable predictors.CONCLUSION: If tenofovir is not available,ADV/ETV combination could be considered in ETV-resistant patients with low HBV DNA titers,and may becontinued if IVR-3 is achieved.

Peroxisome proliferator-activated receptor-delta agonist ameliorated inflammasome activation in nonalcoholic fatty liver disease

AIM: To evaluate the inflammasome activation and the effect of peroxisome proliferator-activated receptors(PPAR)-δ agonist treatment in nonalcoholic fatty liver disease(NAFLD) models.METHODS: Male C57BL/6J mice were classified according to control or high fat diet(HFD) with or without PPAR-δ agonist(GW) over period of 12 wk [control, HFD, HFD + lipopolysaccharide(LPS), HFD + LPS + GW group]. Hep G2 cells were exposed to palmitic acid(PA) and/or LPS in the absence or presence of GW.RESULTS: HFD caused glucose intolerance and hepatic steatosis. In mice fed an HFD with LPS, caspase-1 and interleukin(IL)-1β in the liver were significantly increased. Treatment with GW ameliorated the steatosis and inhibited overexpression of pro-inflammatory cytokines. In Hep G2 cells, PA and LPS treatment markedly increased m RNA of several nucleotide-binding andoligomerization domain-like receptor family members(NLRP3, NLRP6, and NLRP10), caspase-1 and IL-1β. PA and LPS also exaggerated reactive oxygen species production. All of the above effects of PA and LPS were reduced by GW. GW also enhanced the phosphorylation of AMPK-α.CONCLUSION: PPAR-δ agonist reduces fatty acidinduced inflammation and steatosis by suppressing inflammasome activation. Targeting the inflammasome by the PPAR-δ agonist may have therapeutic implication for NAFLD.

Endoscopic submucosal tunnel dissection salvage technique for ulcerative early gastric cancer

Endoscopic submucosal dissection is an effective treatment modality for early gastric cancer(EGC), though the submucosal fibrosis found in ulcerative EGC is an obstacle for successful treatment. This report presents two cases of ulcerative EGC in two males, 73- and 80-year-old, with severe fibrosis. As endoscopic ultrasonography suggested that the EGCs had invaded the submucosal layer, the endoscopic submucosal tunnel dissection salvage technique was utilized for complete resection of the lesions. Although surgical gastrectomy was originally scheduled, the two patients had severe coronary heart disease, and surgeries were refused because of the risks associated with their heart conditions. The endoscopic submucosal tunnel dissection salvage technique procedures described in these cases were performed under conscious sedation, and were completed within 30 min. The complete en bloc resection of EGC using endoscopic submucosal tunnel dissection salvage technique was possible with a free resection margin, and no other complications were noted during the procedure. This is the first known report concerning the use of the endoscopic submucosal tunnel dissection salvage technique salvage technique for treatment of ulcerative EGC. We demonstrate that endoscopic submucosal tunnel dissection salvage technique it is a feasible method showing several advantages over endoscopic submucosal dissection for cases of EGC with fibrosis.

Comparison of sequential and 7-,10-,14-d triple therapy for Helicobacter pylori infection

AIM:To compare the effectiveness of sequential therapy for Helicobacter pylori(H.pylori) infection with that of triple therapy of varying durations.METHODS:The 460 patients enrolled in this study had H.pylori-associated gastritis or a gastric or duodenal ulcer.After screening,H.pylori-infected patients were randomly assigned to receive either conventional triple therapy for 7,10 or 14 d,or a new 10-d sequential therapy.Each of the 4 treatment groups included 115 patients.The outcomes of eradication therapy were assessed 4 wk after treatment by the urea breath test and histology.RESULTS:The overall eradication rate was 81.0%,and eradication rates were 75.7% for 7-d conventional triple therapy,81.9% for 10-d conventional triple therapy,84.4% for 14-d conventional triple therapy,and 82.0% for 10-d sequential therapy.Neither intention-to-treat analysis nor per protocol analysis showed significant differences in eradication rates using sequential therapy or the standard triple therapy(P = 0.416 and P = 0.405,respectively).CONCLUSION:There are no significant differences between 10-d sequential eradication therapy for H.pylori and any duration of standard triple treatment in Korean patients.

Computed tomography findings for predicting severe acute hepatitis with prolonged cholestasis

AIM: To evaluate the significance of computed tomography (CT) findings in relation to liver chemistry and the clinical course of acute hepatitis. METHODS: Four hundred and twelve patients with acute hepatitis who underwent enhanced CT scanning were enrolled retrospectively. Imaging findings were analyzed for the following variables: gallbladder wall thickness (GWT), arterial heterogeneity, periportal tracking, number and maximum size of lymph nodes, presence of ascites, and size of spleen. The serum levels of alanine aminotransferase, alkaline phosphatase, bilirubin, albumin, and prothrombin time were measured on the day of admission and CT scan, and laboratory data were evaluated every 2-4 d for all subjects during hospitalization. RESULTS: The mean age of patients was 34.4 years, and the most common cause of hepatitis was hepatitis A virus (77.4%). The mean GWT was 5.2 mm. The number of patients who had findings of arterial heterogeneity, periportal tracking, lymph node enlargement > 7 mm, and ascites was 294 (80.1%), 348 (84.7%), 346 (84.5%), and 56 (13.6%), respectively. On multivariate logistic regression, male gender [odds ratio (OR) = 2.569, 95%CI: 1.477-4.469, P = 0.001], toxic hepatitis (OR = 3.531, 95%CI: 1.444-8.635, P = 0.006), level of albumin (OR = 2.154, 95%CI: 1.279-3.629, P = 0.004), and GWT (OR = 1.061, 95%CI: 1.015-1.110, P = 0.009) were independent predictive factors for severe hepatitis. The level of bilirubin (OR = 1.628, 95%CI: 1.331-1.991, P < 0.001) and GWT (OR = 1.172, 95%CI: 1.024-1.342,P = 0.021) were independent factors for prolonged cholestasis in multivariate analysis. CONCLUSION: In patients with acute hepatitis, GWT on CT scan was an independent predictor of severe hepatitis and prolonged cholestasis.

Self-expandable metal stents in patients with postoperative delayed gastric emptying after distal gastrectomy

AIM To investigate the efficacy and safety of endoscopic stent insertion in patients with delayed gastric emptying after gastrectomy.METHODS In this study, we prospectively collected data from patients who underwent stent placement for delayed gastric emptying(DGE) after distal gastrectomy between June 2010 and April 2017, at a tertiary referral academic center. Clinical improvement, complications, and consequences after stent insertion were analyzed.RESULTS Technical success was achieved in all patients(100%). Early symptom improvement was observed in 15 of 20 patients(75%) and clinical success was achieved in all patients. Mean follow-up period was 1178.3 ± 844.1 d and median stent maintenance period was 51 d(range 6-2114 d). During the follow-up period, inserted stents were passed spontaneously per rectum without any complications in 14 of 20 patients(70%). Symptom improvement was maintained after stent placement without the requirement of any additional intervention in 19 of 20 patients(95%).CONCLUSION Endoscopic stent placement provides prompt relief of obstructive symptoms. Thus, it can be considered an effective and safe salvage technique for post-operative DGE.

Radiotherapy for 65 patients with advanced unresectable hepatocellular carcinoma

AIM: To evaluate the efficacy of radiotherapy (RT) in patients with advanced unresectable hepatocellular carcinoma (HCC). METHODS: A total of 65 patients were treated with RT in the Korea University Medical Center. The median age of the patients was 60 years, and 86.2% were men. 18.5% and 81.5% of the patients were diagnosed as TNM stage Ⅲ and Ⅳ-A, respectively. Treatment response was assessed 4 mo after initiation of RT. Tumor regression rate 1 mo after initiation of RT (TRR1m) was also assessed. Duration of survival was calculated from the initiation of RT. RESULTS: The objective treatment response was 56.9%. The 12 mo survival rate was 34.7%. Predictive factors for survival were Child-Pugh grade, α-fetoprotein level and treatment response. An objective response was achieved more frequently in patients with TRR1m ≥ 20% than in those with TRR1m < 20% (P < 0.001). CONCLUSION: RT is effective in treating advanced HCC with a tumor response rate of 56.9%.

Antiviral efficacy of adefovir dipivoxil versus lamivudine in patients with chronic hepatitis B sequentially treated with lamivudine and adefovir due to lamivudine resistance

AIM： To compare the antiviral efficacy of adefovir （ADV） in lamivudine （LMV）-resistant patients with LMV treatment in nucleoside-naive patients, using serum samples collected sequentially during the course of treatment progressing from LMV to ADV.METHODS： Forty-four patients with chronic hepatitis B （CHB） were included. The patients were initially treated with LMV and then switched to ADV when LMV resistance developed. Antiviral efficacy was assessed by measuring the following： reduction in serum HBV DNA from baseline, HBV DNA negative conversion （defined as HBV DNA being undectable by the hybridization assay）, and HBV DNA response （either HBV DNA level ≤ 10^s copies/mL or a ≥ 2 log10 reduction from baseline HBV DNA level）.RESULTS： After two and six months of treatment, HBV DNA reduction was greater with LMV compared to ADV treatment （P = 0.021）. HBV DNA negative conversion rates were 64% and 27% after one month of LMV and ADV treatment respectively （P = 0.001）. Similarly, HBV DNA response rates were 74% and 51% after two months of LMV and ADV treatment respectively （P = 0.026）. The time taken to HBV DNA negative conversion and to HBV DNA response were both delayed in ADV treatment compared with LMV.CONCLUSION： The antiviral efficacy of ADV in LMV-resistant patients is slower and less potent than that with LMV in nucleoside-naive patients during the early course of treatment.

A novel cleansing score system for capsule endoscopy

AIM:To suggest a new cleansing score system for small bowel preparation and to evaluate its clinical efficacy.METHODS:Twenty capsule endoscopy cases were reviewed and small bowel preparation was assessed with the new scoring system.For the assessment,two visual parameters were used:proportion of visualized mucosa and degree of obscuration.Representative frames from small bowel images were serially selected and scored at 5-min intervals.Intraclass correlation coefficient(ICC)was obtained to assess the reliability of the new scoring system.For efficacy evaluation and validation,scores of our new scoring system were compared with another previously reported cleansing grading system.RESULTS:Concordance with the previous system,inter-observer agreement,and intra-patient agreement were excellent with ICC values of 0.82,0.80,and 0.76,respectively.The intra-observer agreements at four-week intervals were also excellent.The cutoff value of adequate image quality was found to be 2.25.CONCLUSION:Our new scoring system is simple,efficient,and can be considered to be applicable in clinical practice and research.

Lens culinaris agglutinin-reactive fraction of alpha-fetoprotein improves diagnostic accuracy for hepatocellular carcinoma

BACKGROUND Diagnostic accuracy of various tumor markers and their combinations for hepatocellular carcinoma(HCC)was not fully investigated.AIM To evaluate the diagnostic accuracy of alpha-fetoprotein(AFP),the Lens culinaris agglutinin-reactive fraction of AFP(AFP-L3),and protein induced by vitamin K absence or antagonist-II(PIVKA-II)and their combination for HCC diagnosis.METHODS Patients with newly detected liver mass or elevated serum AFP levels were considered eligible.Serum AFP level,AFP-L3 fraction,and PIVKA-II level were measured at the first visit.RESULTS In total,622 patients were included;355 patients(57.1%)had chronic liver disease,and 208(33.4%)had liver cirrhosis.HCC was diagnosed in 160 patients(25.7%).The area under the receiver operating characteristics curves(AUROCs)of the serum AFP,AFP-L3 fraction,AFP-L3,and PIVKA-II levels for the diagnosis of HCC were 0.775,0.792,0.814,and 0.834,respectively.A novel diagnostic model was developed by classifying patients in a 1:1 ratio into training and validation sets.Using the binary regression analysis of the training cohort,the AFP,AFP-L3 fraction,and PIVKA-II(ALPs)score was calculated as follows:ALPs score=3.8×[serum AFP level(ng/mL)×AFP-L3 fraction(%)×0.01]+0.2×PIVKA-II level(mAU/mL).The AUROC of the ALPs score for diagnosis of HCC was 0.878,significantly higher than that of serum AFP level(P<0.001),AFP-L3 fraction(P<0.001),PIVKA-II level(P=0.036),and AFP-L3 level(P=0.006).The optimal ALPs score cut-off was 5.3(sensitivity,85.0%,specificity 80.1%).The validation cohort showed similar results.CONCLUSION The ALPs score calculated using serum AFP level,AFP-L3 fraction,and PIVKA-II level showed improved accuracy in HCC diagnosis.

Removal of press-through-packs impacted in the upper esophagus using an overtube

Foreign bodies in the upper esophagus should be re-moved as soon as possible to avoid serious complica-tions. However, removals of foreign bodies in the upper esophagus are very difficult, especially if they have sharp edges, such as press-through-packs (PTPs). We expe-rienced four cases of the impacted PTPs in the upper esophagus which was successfully extracted endoscopi-cally with the overtube. Because two edges of PTPs were so firmly impacted in the esophageal wall in all cases, the PTPs were not movable in the upper esophagus. However, after insertion of the overtube, PTPs became movable and were successfully extracted and no serious complications occurred after extraction of PTPs. In one case, insertion of the overtube rapidly expanded the up-per esophagus and PTP progressed to the gastric cavity and it could be extracted with the endoscopic protector hood. The endoscopic removal with the overtube was a simple, safe and effective technique for the removal of the impacted PTPs in upper esophagus.

Sensitivity of the suspected blood indicator:An experimental study

AIM： To investigate whether suspected blood indicator （SBI） in capsule endoscopy （CE） is affected by back- ground color and capsule passage velocity. METHODS： Experimental models of the small intestine constructed from paper in a variety of colors were used to simulate the background colors observed in CE im- ages. The background colors studied included very pale yellow, yellow, very pale magenta, light grayish pink, burnt sienna, and deep and dark brown, and red spots were attached inside them. An endoscopic capsule was manually passed through the models. The rate of detection of the red spots by the SBI was evaluated based on the colors of the models and the capsule pas- sage velocities （0.5 cm/s, 1 cm/s, and 2 cm/s）.RESULTS： The rate of detection of the red spots byground color of the model （P 〈 0.001）. Detection rates were highest for backgrounds of very pale magenta, burnt sienna, and yellow, in that order. They were lowest for backgrounds of dark brown and very pale yellow. The rate of detection of red spots by the SBI tended to decrease at rapid capsule passage velocities （1-2 cm/s） compared to slow velocities （0.5 cm/s） for backgrounds of very pale yellow （P = 0.042）, yellow （P = 0.001）, very pale magenta （P = 0.002）, and burnt sien- na （P = 0.001）. No significant differences in the rate of detection were observed according to velocity for light grayish pink （P = 0.643） or dark brown （P = 0.396）. CONCLUSION： SBI sensitivity was affected by back- ground color and capsule passage velocity in the models. These findings may facilitate the rapid detection of bleeding lesions by CE.

Upper gastrointestinal bleeding from duodenal vascular ectasia in a patient with cirrhosis

We report a cirrhotic patient with duodenal vascular ectasia and spontaneous bleeding. The bleeding was successfully controlled with argon plasma coagulation. Duodenal vascular ectasia may be a cause of upper gastrointestinal bleeding in patients with cirrhosis, and argon plasma coagulation may be effective and safe to achieve hemostasis of this lesion.

Predictors of the patency of self-expandable metallic stents in malignant gastroduodenal obstruction

AIM:To investigate the predictive factors of selfexpandable metallic stent patency after stent placement in patients with inoperable malignant gastroduodenal obstruction. METHODS:A total of 116 patients underwent stent placements for inoperable malignant gastroduodenal obstruction at a tertiary academic center. Clinical success was defined as acceptable decompression of the obstructive lesion within the malignant gastroduodenal neoplasm. We evaluated patient comorbidities and clinical statuses using the World Health Organization's scoring system and categorized patient responses to chemotherapy using the Response Evaluation Criteria in Solid Tumors criteria. We analyzed the relationships between possible predictive factors and stent patency. RESULTS:Self-expandable metallic stent placement was technically successful in all patients(100%),and the clinical success rate was 84.2%. In a multivariate Cox proportional hazards model,carcinoembryonic antigen(CEA) levels were correlated with a reduction in stent patency [P = 0.006; adjusted hazard ratio(a HR)= 2.92,95%CI:1.36-6.25]. Palliative chemotherapy was statistically associated with an increase in stent patency(P = 0.009; a HR = 0.27,95%CI:0.10-0.72).CONCLUSION:CEA levels can easily be measured at the time of stent placement and may help clinicians to predict stent patency and determine the appropriate stent procedure.

Inverted cystic tubulovillous adenoma involving Brunner’s glands of duodenum

Benign neoplasia of the duodenum are very rare. Moreover, duodenal tubulovillous adenomas are more uncommon lesions. The microscopic structure of tubulovillous adenoma has frond-like projection of mucosa with branching papillary structure and generally upward growth into the lumen. We describe a 72-year-old man who showed aduodenal tubulovillous adenoma with unusual inverted cystic growth pattern. Interestingly, this tubulovillous adenomatous lesion was interrupted by gastric metaplasia in the deep portion of the cyst and was closely surrounded by Brunner’s glands. Although histogenesis of gastric metaplasia of duodenum is not fully understood, Brunner’s glands has been suggested as a precursor for gastric metaplasia. Therefore, these findings argued that this adenoma arises from Brunner’s glands through gastric metaplasia. This is the first case of inverted cystic tubulovillous adenoma involving Brunner’s glands of duodenum with gastric metaplasia.