Systematic Endoscopic Approach to Early Gastric Cancer in Clinical Practice

Gwang Ha Kim

GNL 2021; 15(6):811-817

https://doi.org/10.5009/gnl20318

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Abstract : Early gastric cancers (EGCs) are defined as gastric cancers confined to the mucosa or submucosa, regardless of regional lymph node metastasis. The proportion of EGCs has been increasing due to the increase in screening endoscopy for gastric cancers; therefore, the paradigm shift from surgical resection to endoscopic resection as a treatment modality for selected EGCs is accelerating. For successful endoscopic resection of EGCs, it is important to detect EGCs at an early stage and to accurately predict the histological type, depth of invasion, and horizontal margins of the tumor. The diagnostic process of EGCs can be divided into three steps: presence diagnosis, qualitative diagnosis, and quantitative diagnosis. The presence diagnosis of EGCs is mainly based on two endoscopic findings: a well-demarcated lesion and irregularity in the color/surface pattern. Qualitative diagnosis refers to the prediction of histological type, which is mainly possible based on the macroscopic shape and color of the lesion. Quantitative diagnosis of EGCs consists of predicting the depth of invasion by detailed examination of the macroscopic morphology and determining horizontal margins using chromoendoscopy. Although advanced diagnostic modalities, such as endosonography or magnifying endoscopy, are helpful for the qualitative and quantitative diagnosis of EGCs, these modalities are not available in most hospitals. Therefore, it is still very important to evaluate EGCs systematically during conventional endoscopy for successful endoscopic treatment.

Effects of Metformin on Hepatic Steatosis in Adults with Nonalcoholic Fatty Liver Disease and Diabetes: Insights from the Cellular to Patient Levels

Kanokwan Pinyopornpanish , Apinya Leerapun , Kanokporn Pinyopornpanish et al.

GNL 2021; 15(6):827-840

https://doi.org/10.5009/gnl20367

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Abstract : Nonalcoholic fatty liver disease (NAFLD) patients with diabetes constitute a subgroup of patients with a high rate of liver-related complications. Currently, there are no specific drug recommendations for these patients. Metformin, a conventional insulin sensitizer agent, has been widely prescribed in patients with diabetes. Metformin treatment has been shown to be effective at alleviating hepatic lipogenesis in animal models of NAFLD, with a variety of mechanisms being deemed responsible. To date, most studies have enrolled diabetic patients who are treated with metformin, with the drug being taken continuously throughout the study. Although evidence exists regarding the benefits of metformin for NAFLD in preclinical studies, reports on the efficacy of metformin in adult NAFLD patients have had some discrepancies regarding changes in liver biochemistry and hepatic fat content. Evidence has also suggested possible effects of metformin as regards the prevention of hepatocellular carcinoma tumorigenesis. This review was performed to comprehensively summarize the available in vitro, in vivo and clinical studies regarding the effects of metformin on liver steatosis for the treatment of adult NAFLD patients with diabetes. Consistent reports as well as controversial findings are included in this review, and the mechanistic insights are also provided. In addition, this review focuses on the efficacy of metformin as a monotherapy and as a combined therapy with other antidiabetic medications.

Efficacy and Safety of Rebamipide versus Its New Formulation, AD-203, in Patients with Erosive Gastritis: A Randomized, Double-Blind, Active Control, Noninferiority, Multicenter, Phase 3 Study

Gwang Ha Kim , Hang Lak Lee , Moon Kyung Joo et al.

GNL 2021; 15(6):841-850

https://doi.org/10.5009/gnl20338

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Abstract : Background/Aims: The mucoprotective drug rebamipide is used to treat gastritis and peptic ulcers. We compared the efficacy of Mucosta^Ⓡ (rebamipide 100 mg) and its new formulation, AD-203 (rebamipide 150 mg), in treating erosive gastritis. Methods: This double-blind, active control, noninferiority, multicenter, phase 3 clinical trial randomly assigned 475 patients with endoscopically proven erosive gastritis to two groups: AD-203 twice daily or Mucosta^Ⓡ thrice daily for 2 weeks. The intention-to-treat (ITT) analysis included 454 patients (AD-203, n=229; Mucosta^Ⓡ, n=225), and the per-protocol (PP) analysis included 439 patients (AD-203, n=224; Mucosta^Ⓡ, n=215). The posttreatment assessments included the primary (erosion improvement rate) and secondary endpoints (erosion and edema cure rates; improvement rates of redness, hemorrhage, and gastrointestinal symptoms). Drug-related adverse events were evaluated. Results: According to the ITT analysis, the erosion improvement rates (posttreatment) in AD-203-treated and Mucosta^Ⓡ-treated patients were 39.7% and 43.8%, respectively. According to the PP analysis, the erosion improvement rates (posttreatment) in AD-203-treated and Mucosta^Ⓡ-treated patients were 39.3% and 43.7%, respectively. The one-sided 97.5% lower limit for the improvement rate difference between the study groups was −4.01% (95% confidence interval [CI], –13.09% to 5.06%) in the ITT analysis and −4.44% (95% CI, –13.65% to 4.78%) in the PP analysis. The groups did not significantly differ in the secondary endpoints in either analysis. Twenty-four AD-203-treated and 20 Mucosta^Ⓡ-treated patients reported adverse events but no serious adverse drug reactions; both groups presented similar adverse event rates. Conclusions: The new formulation of rebamipide 150 mg (AD-203) twice daily was not inferior to rebamipide 100 mg (Mucosta^Ⓡ) thrice daily. Both formulations showed a similar efficacy in treating erosive gastritis.

Risk Factors for Disease Behavior Evolution and Efficacy of Biologics in Reducing Progression in Pediatric Patients with Nonstricturing, Nonpenetrating Crohn’s Disease at Diagnosis: A Single-Center Experience in Korea

Hyun Jin Kim , Seak Hee Oh , Sung Hee Lee et al.

GNL 2021; 15(6):851-857

https://doi.org/10.5009/gnl20279

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Abstract : Background/Aims: Recently, the treatment of Crohn’s disease (CD) has changed to a treat-to-target strategy, in which disease progression is prevented with early intervention. We analyzed the long-term evolution of nonstricturing, nonpenetrating (B1) disease at diagnosis and factors related to disease evolution in pediatric CD. Methods: We retrospectively analyzed 402 patients between 2000 and 2013 who were younger than 18 years and had B1 disease at CD diagnosis. The median follow-up was 6.1 years (range, 1 to 13 years). The cumulative probabilities of developing stricturing (B2) or penetrating (B3) disease and associations between risk factors and disease behavior evolution were evaluated. Results: Among the 402 patients, 75 (18.7%) had B2 or B3 disease by the final follow-up. The cumulative probabilities of disease behavior evolution were 18.3%, 34.3%, and 50.9% at 5, 10, and 13 years, respectively. Patients whose disease progressed had an increased risk of intestinal resection (hazard ratio [HR], 3.61; 95% confidence interval [CI], 2.25 to 6.03; p<0.001). First-degree family history of inflammatory bowel disease (HR, 2.38; 95% CI, 1.07 to 5.28; p=0.032), isolated ileal involvement at diagnosis (HR, 7.55; 95% CI, 1.04 to 15.57; p=0.045), and positive anti-Saccharomyces cerevisiae antibody titers (HR, 2.10; 95% CI, 1.03 to 4.25; p=0.040) were associated with disease behavior evolution. Early treatment with biologics significantly reduced disease progression (HR, 0.46; 95% CI, 0.79 to 3.39; p=0.042). Conclusions: This study suggests that early aggressive therapy should be considered in B1 behavior pediatric CD patients with risk factors of disease evolution to improve long-term outcomes.

Prognostic Value of Terminal Ileal Inflammation in Patients with Ulcerative Colitis

Jongwook Yu , Jihye Park , Eun Ae Kang et al.

GNL 2021; 15(6):858-866

https://doi.org/10.5009/gnl20294

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Abstract : Background/Aims: Few studies have investigated terminal ileal lesions and their prognostic value in patients with ulcerative colitis (UC). We evaluated the clinical significance of these lesions as a prognostic factor in patients with UC who were in clinical remission. Methods: We retrospectively selected 567 of 4,066 colonoscopy reports that included positive findings from orificial observations of the terminal ileum (TI) and appendix in patients with UC. We finally recruited patients who were in clinical remission (n=204). We compared the clinical courses, including relapse and other prognostic parameters associated with UC, between the groups. Results: The baseline patient characteristics were not significantly different between patients with (n=69, TI+ group) and without TI lesions (n=135, TI– group), although there were more never-smokers in the TI+ group (n=57 [82.6%] in the TI+ group; n=86 [63.7%] in the TI– group; p=0.005). Of note, appendiceal orifice inflammation (AOI) was less frequently found in the TI+ group (14.5%) than in the TI– group (71.9%, p<0.001). The cumulative relapse rate was numerically higher in the TI– group, but it was not significantly different according to the Kaplan-Meier analysis (p=0.116). Multivariate Cox regression analysis also revealed advanced age at diagnosis as the most significant factor (adjusted hazard ratio, 0.964; 95% confidence interval, 0.932 to 0.998; p=0.037), but neither TI inflammation nor AOI were significantly associated with the cumulative relapse rate in patients with UC in clinical remission. Conclusions: For patients with UC in clinical remission, neither terminal ileal lesions nor AOI had significant clinical or predictive value for future relapse.

Real-World Incidence of Suboptimal Response to Anti-Tumor Necrosis Factor Therapy for Ulcerative Colitis: A Nationwide Population-Based Study

Ju-Young Shin , Hye-Min Park , Min-Young Lee et al.

GNL 2021; 15(6):867-877

https://doi.org/10.5009/gnl20353

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Abstract : Background/Aims: Although anti-tumor necrosis factor (TNF) agents have been widely used to treat ulcerative colitis (UC), the real-world incidence of suboptimal response to anti-TNF agents has not been thoroughly investigated, especially among Asians. Methods: Using the Korean National Health Insurance database, we collected data on UC patients who initiated anti-TNF agents between July 1, 2014, and June 30, 2017. We assessed suboptimal responses, including anti-TNF discontinuation or dose escalation, switching to other biologics, augmentation with a non-biologic therapy, and the requirement for colectomy. Results: A total of 1,268 patients were included as new anti-TNF users (infliximab 713, adalimumab 433, golimumab 122). The proportion of patients who experienced at least one suboptimal response within 1 year among all patients was 63.5%, including 59.1%, 69.5%, and 68.0% of patients treated with infliximab, adalimumab, and golimumab, respectively. The cumulative incidences of at least one suboptimal response over time were 41.5%, 63.7%, 80.5%, and 87.1% at 6, 12, 24, and 36 months, respectively. Cox proportional hazards modeling revealed that adalimumab was associated with a higher risk of at least one suboptimal response (hazard ratio [HR], 1.29; 95% confidence interval [CI], 1.13 to 1.48), dose escalation (HR, 4.35; 95% CI, 2.97 to 6.38) and discontinuation (HR, 1.25; 95% CI, 1.03 to 1.52) than infliximab. Golimumab was associated with a higher risk of switching to other biologics than infliximab (HR, 1.78; 95% CI, 1.21 to 2.60). Conclusions: More than half of Korean UC patients had suboptimal responses to anti-TNF agents within 1 year. UC patients treated with infliximab might be less prone to suboptimal responses than those treated with adalimumab or golimumab.

Adherence to Surveillance Guidelines after the Removal of Colorectal Polyps: A Multinational, Multicenter, Prospective Survey

Chang Kyo Oh , Satimai Aniwan , Panida Piyachaturawat et al.

GNL 2021; 15(6):878-886

https://doi.org/10.5009/gnl20166

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Abstract : Background/Aims: As the number of colonoscopies and polypectomies performed continues to increase in many Asian countries, there is a great demand for surveillance colonoscopy. The aim of this study was to investigate the adherence to postpolypectomy surveillance guidelines among physicians in Asia. Methods: A survey study was performed in seven Asian countries. An email invitation with a link to the survey was sent to participants who were asked to complete the questionnaire consisting of eight clinical scenarios. Results: Of the 137 doctors invited, 123 (89.8%) provided valid responses. Approximately 50% of the participants adhered to the guidelines regardless of the risk of adenoma, except in the case of tubulovillous adenoma ≥10 mm combined with high-grade dysplasia, in which 35% of the participants adhered to the guidelines. The participants were stratified according to the number of colonoscopies performed: ≥20 colonoscopies per month (high volume group) and <20 colonoscopies per month (low volume group). Higher adherence to the postpolypectomy surveillance guidelines was evident in the high volume group (60%) than in the low volume group (25%). The reasons for nonadherence included concern of missed polyps (59%), the low cost of colonoscopy (26%), concern of incomplete resection (25%), and concern of medical liability (15%). Conclusions: A discrepancy between clinical practice and surveillance guidelines among physicians in Asia was found. Physicians in the low volume group frequently did not adhere to the guidelines, suggesting a need for continuing education and appropriate control. Concerns regarding the quality of colonoscopy and complete polypectomy were the main reasons for nonadherence.

Clinical and Immunological Factors Associated with Postpartum Hepatic Flares in Immune-Tolerant Pregnant Women with Hepatitis B Virus Infection Treated with Telbivudine

Junfeng Lu , Xiaoxiao Wang , Yunxia Zhu et al.

GNL 2021; 15(6):887-894

https://doi.org/10.5009/gnl21001

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Abstract : Background/Aims: To investigate postpartum hepatic flares and associated factors in highly viremic pregnant patients in the immune tolerance phase who adopted telbivudine (LdT) treatment in the last trimester to reduce vertical transmission of hepatitis B virus. Methods: Hepatitis B e antigen (HBeAg)-positive, highly viremic pregnant women were recruited for this prospective study. Treatment with LdT was started from 28 weeks of gestation. Virological and biochemical markers were examined before LdT treatment, antepartum and postpartum. Serial blood samples at the same time were collected to detect cytokines and cortisol (COR). Results: Fifty-six of 153 patients (36.6%) had postpartum hepatic flares, defined as a 2-fold increase in alanine aminotransferase 6 weeks after delivery. Age and the antepartum alanine aminotransferase and postpartum HBeAg levels were independent influencing factors of postpartum hepatic flares. Cytokines showed no regularity during or after pregnancy. Compared with the patients with no postpartum flares, the patients with flares had lower baseline interferon γ and COR levels (p=0.022 and p=0.028) and higher postpartum interferon γ levels (p=0.026). Conclusions: A high proportion of highly viremic and immune-tolerant pregnant patients treated with LdT in the last trimester had postpartum hepatic flares, which implied that these patients entered the immune clearance phase after delivery. Thus, this may create an appropriate opportunity for re-antiviral therapy.

Efficacy and Safety of Glecaprevir/Pibrentasvir in Korean Patients with Chronic Hepatitis C: A Pooled Analysis of Five Phase II/III Trials

Jeong Heo , Yoon Jun Kim , Jin-Woo Lee et al.

GNL 2021; 15(6):895-903

https://doi.org/10.5009/gnl20321

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Abstract : Background/Aims: Glecaprevir/pibrentasvir (G/P) is the first pan-genotypic direct-acting antiviral combination therapy approved in Korea. An integrated analysis of five phase II and III trials was conducted to evaluate the efficacy and safety of G/P in Korean patients with chronic hepatitis C virus (HCV) infection. Methods: The study analyzed pooled data on Korean patients with HCV infection enrolled in the ENDURANCE 1 and 2, SURVEYOR II part 4 and VOYAGE I and II trials, which evaluated the efficacy and safety of 8 or 12 weeks of G/P treatment. The patients were either treatment-naïve or had received sofosbuvir or interferon-based treatment. Efficacy was evaluated by assessing the rate of sustained virologic response at 12 weeks posttreatment (SVR12). Safety was evaluated by monitoring adverse events (AEs) and laboratory assessments. Results: The analysis included 265 patients; 179 (67.5%) were HCV treatment-naïve, and most patients were either subgenotype 1B (48.7%) or 2A (44.5%). In the intention-to-treat population, 262 patients (98.9%) achieved SVR12. Three patients did not achieve SVR12: one had virologic failure and two had non-virologic failures. Most AEs were grade 1/2; eight patients (3.0%) experienced at least one grade ≥3 AE. No serious AEs related to G/P treatment were reported, and grade ≥3 hepatic laboratory abnormalities were rare (0.8%). Conclusions: G/P therapy was highly efficacious and well tolerated in Korean patients with HCV infection, with most patients achieving SVR12. The safety profile was comparable to that observed in a pooled analysis of a global pan-genotypic population of patients with HCV infection who received G/P.

A National Survey on the Environment and Basic Techniques of Endoscopic Retrograde Cholangiopancreatography in Korea

Jae Min Lee , Sung Hoon Moon , Sang Wook Park et al.

GNL 2021; 15(6):904-911

https://doi.org/10.5009/gnl20329

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Abstract : Background/Aims: The work environment in which endoscopic retrograde cholangiopancreatography (ERCP) is conducted has influence on its efficacy and safety. We aimed to assess the current status of ERCP work environments and to investigate the trends associated with the basic techniques of ERCP in Korea. Methods: The work environment and information on the basic techniques of ERCP were acquired by the Korean Pancreatobiliary Association (KPBA) through a national survey in 2019. The survey was performed at the KPBA conference in 2019. The contents of survey comprised of the current environment of ERCP, preparation before ERCP, and the preferred basic techniques used in ERCP. Results: Completed questionnaires were returned from 84 KPBA members. The mean ERCP volume per year was approximately 500. About 60% (50/84) reported that they worked with a dedicated ERCP team with experienced nurses. Two-thirds (57/84, 68%) answered that they had a fluoroscopy room used solely for ERCP procedures. All respondents intravenously hydrated the patient to prevent post-ERCP pancreatitis (84/84, 100%). The preferred procedural sedations were balanced propofol sedation (50%) and midazolam-only sedation (47%). Wire-guided cannulation was most commonly used for selective cannulation (81%). Endoscopic retrograde biliary drainage was preferred over endoscopic nasobiliary drainage (60% vs 22%). The initial method of ampullary intervention was endoscopic sphincterotomy in 60%. Conclusions: Data from the survey involving a large number of Korean ERCP doctors revealed considerable variabilities with regard to the work environment and basic techniques of ERCP in Korea. The study provides information regarding the current trends of ERCP that can be used to establish ERCP standards in Korea.

Development and External Validation of Survival Prediction Model for Pancreatic Cancer Using Two Nationwide Databases: Surveillance, Epidemiology and End Results (SEER) and Korea Tumor Registry System-Biliary Pancreas (KOTUS-BP)

Jae Seung Kang , Lydia Mok , Jin Seok Heo et al.

GNL 2021; 15(6):912-921

https://doi.org/10.5009/gnl20306

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Abstract : Background/Aims: Several prediction models for evaluating the prognosis of nonmetastatic resected pancreatic ductal adenocarcinoma (PDAC) have been developed, and their performances were reported to be superior to that of the 8th edition of the American Joint Committee on Cancer (AJCC) staging system. We developed a prediction model to evaluate the prognosis of resected PDAC and externally validated it with data from a nationwide Korean database. Methods: Data from the Surveillance, Epidemiology and End Results (SEER) database were utilized for model development, and data from the Korea Tumor Registry System-Biliary Pancreas (KOTUS-BP) database were used for external validation. Potential candidate variables for model development were age, sex, histologic differentiation, tumor location, adjuvant chemotherapy, and the AJCC 8th staging system T and N stages. For external validation, the concordance index (C-index) and time-dependent area under the receiver operating characteristic curve (AUC) were evaluated.Results: Between 2004 and 2016, data from 9,624 patients were utilized for model development, and data from 3,282 patients were used for external validation. In the multivariate Cox proportional hazard model, age, sex, tumor location, T and N stages, histologic differentiation, and adjuvant chemotherapy were independent prognostic factors for resected PDAC. After an exhaustive search and 10-fold cross validation, the best model was finally developed, which included all prognostic variables. The C-index, 1-year, 2-year, 3-year, and 5-year time-dependent AUCs were 0.628, 0.650, 0.665, 0.675, and 0.686, respectively. Conclusions: The survival prediction model for resected PDAC could provide quantitative survival probabilities with reliable performance. External validation studies with other nationwide databases are needed to evaluate the performance of this model.

The Comparison of Endoscopic Biliary Drainage in Malignant Hilar Obstruction by Cholangiocarcinoma: Bilateral Metal Stents versus Multiple Plastic Stents

Jun Young Kim , Sang-geul Lee , Danbee Kang et al.

GNL 2021; 15(6):922-929

https://doi.org/10.5009/gnl20257

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Abstract : Background/Aims: For the management of hilar malignant biliary obstruction (HMBO), endoscopic biliary drainage (EBD) is preferred over percutaneous transhepatic biliary drainage (PTBD) because of its convenience. However, there is no established guideline for malignant hilar obstruction that requires multiple stenting. In this study, we compared the efficacy of bilateral metal stents (BMS) versus multiple plastic stents (MPS). Methods: In this retrospective study, we analyzed 102 patients who underwent EBD with either BMS or MPS due to HMBO caused by hilar cholangiocarcinoma between 1996 and 2018 at Samsung Medical Center. We compared the successful drainage rates, cholangitis events, overall complications, mortality, and conversion rates to PTBD between the two groups. Results: The successful drainage rates in the BMS group and the MPS group were 71.4% (25/35) and 65.6% (44/67), respectively, with no significant difference. The MPS group had a higher cholangitis risk (hazard ratio [HR], 2.08; 95% confidence interval [CI], 1.21 to 3.58) and higher 6-month mortality (HR, 2.91; 95% CI, 1.26 to 6.71) than the BMS group. There were no significant differences in overall complications or the conversion rate to PTBD between the groups. Conclusions: In patients with malignant HMBO, the BMS group showed better outcomes in terms of the cholangitis rate and 6-month mortality than the MPS group. Therefore, if possible, bilateral metal stenting is recommended for HMBO caused by hilar cholangiocarcinoma.

Long-term Outcomes of Direct Endoscopic Necrosectomy for Complicated or Symptomatic Walled-Off Necrosis: A Korean Multicenter Study

Yeon Suk Kim , Jae Hee Cho , Dong Hui Cho et al.

GNL 2021; 15(6):930-939

https://doi.org/10.5009/gnl20304

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Abstract : Background/Aims: The endoscopic step-up approach is accepted as the preferred treatment for complicated or symptomatic walled-off necrosis (WON). Direct endoscopic necrosectomy (DEN) is an effective therapeutic option, but few reports describe long-term follow-up in this patient population. Thus, we aim to assess the long-term outcomes of DEN following severe necrotizing pancreatitis. Methods: The data of all acute pancreatitis patients who underwent DEN following endoscopic transmural drainage from six referral centers between 2007 and 2017 were retrospectively collected. Results: Sixty patients (76.7% male, mean age 48.3 years) underwent a median of 4 sessions of DEN starting at a median of 45.5 days after the onset of acute pancreatitis. Clinical success was achieved in 51 patients (85%), with a 35% complication rate and a 5% mortality rate. Using multivariate analysis, the risk factor associated with DEN failure or major DEN complications requiring intervention or surgery was an identified bacterial/fungal WON infection (odds ratio, 19.3; 95% confidence interval, 1.5 to 261.7). During the median follow-up period of 27 months, complicated WON recurrence was observed in 5.3% of patients, and long-term complications occurred in 24.6% of patients (four exocrine insufficiency, nine newly developed diabetes mellitus, one recurrent small bowel obstruction, one chylous ascites). Conclusions: Considering that long-term complications are similar to those observed after pancreatectomy, DEN should be performed meticulously while minimizing damage to the viable pancreatic parenchyma with adequate antibiotic escalation.