Gastroenterology

A new era for understanding genetic evolution of multistep carcinogenesis Abstract Cancer development is a multistep process involving genetic and cellular alterations, and recent advances in next-generation sequencing have elucidated mutation landscapes of premalignant lesions as well as early- and late-stage tumors. In this issue of Journal of Gastroenterology, Kim and colleagues contributed to the better understanding of genetic events in putative precursors of hepatocellular carcinoma (HCC). Precancerous tissues are divided into canonical and non-canonical types, which share common driver mutations with cancerous lesions or not, and potential gatekeeper gene(s) for clonal selection play a critical role in driving precursors to cancers not only in HCC, but also in esophageal, gastric, colorectal, and pancreatic cancers.

Efficacy and safety of glecaprevir and pibrentasvir treatment for 8 or 12 weeks in patients with recurrent hepatitis C after liver transplantation: a Japanese multicenter experience Abstract Background Efficacy of 8-week regimen with direct-acting antivirals (DAA) for patients with hepatitis C after liver transplantation has not been clarified. This study aimed to clarify the efficacy and safety of glecaprevir and pibrentasvir therapy for 8 and 12 weeks in Japanese patients with recurrent hepatitis C after liver transplantation. Methods A cohort study of liver transplant recipients with recurrent hepatitis C treated with glecaprevir (300 mg/day) and pibrentasvir (120 mg/day) was performed at nine liver transplant centers in Japan. Results Twenty-five patients with hepatitis C after liver transplantation were treated with glecaprevir and pibrentasvir. Twenty-four patients completed the treatment protocol; treatment was discontinued in one patient who had nausea at 3 days after the initiation of treatment. All the 24 patients who completed the 8- or 12-week treatment protocol achieved a sustained virological response 12 weeks after completion of treatment (SVR12). The SVR12 rates in patients with HCV genotype 1 and 2 were 100% (21 of 21 patients) and 75% (3 of 4 patients), respectively. All patients with prior DAA therapy failure (n = 6), jaundice (n = 4), and liver cirrhosis (n = 4) achieved SVR12. Seven of 8 patients (88%) with severe renal impairment achieved SVR12. Adverse events occurred in 6 of 25 patients (24%), including serious adverse events in 2 patients (8%). Treatment-related adverse events were nausea, pruritus, and mild renal dysfunction. Conclusions Eight- or 12-week regimen of glecaprevir and pibrentasvir is efficacious and safe in patients with recurrent HCV infection after liver transplantation, even in difficult-to-treat populations, including patients with severe renal impairment, prior DAA experience, liver cirrhosis, or jaundice after liver transplantation.

Feasibility of a simplified narrow-band imaging classification system for Barrett's esophagus for novice endoscopists Abstract Background Narrow-band imaging (NBI) classifications for Barrett's esophagus have been proposed for the detection of early esophageal adenocarcinoma. We developed a simplified classification system with demonstrated high diagnostic accuracy and reproducibility among experienced endoscopists, but the feasibility of this system among novice endoscopists was unclear. Methods In the present study, eight novice endoscopists with no experience of magnification endoscopy were asked to review 248 images of Barrett's esophagus (72 dysplastic, 176 non-dysplastic) obtained using high-definition magnification endoscopy with NBI 6 weeks before (1st test), immediately after (2nd test), and 6 weeks after (3rd test) being taught the simplified classification system. The primary outcomes were differences in diagnostic accuracy for dysplasia among the three tests. Results The specificity and overall accuracy improved significantly in the 2nd vs. 1st test [97% vs. 80% (p < 0.001) and 94% vs. 82% (p < 0.001), respectively], but sensitivity was comparable (87% in both tests; p = 0.42). In the 3rd test, the sensitivity and overall accuracy decreased significantly compared with the 2nd test [82% vs. 87% (p < 0.001) and 93% vs. 94% (p < 0.05), respectively], but there was no significant difference in specificity (97% in both tests; p = 0.16). The kappa values for interobserver agreement for the mucosal pattern, vascular pattern, and predicted histology were substantial, and improved significantly in the 2nd vs. 1st test (0.78 vs. 0.59, 0.70 vs. 0.53, and 0.79 vs. 0.66, respectively; p < 0.001 for all). Conclusions The simplified NBI classification system may be appropriate for novice endoscopists to use in providing high accuracy and reproducibility.

Epidemiological analysis of achalasia in Japan using a large-scale claims database Abstract Background Achalasia is a well-known esophageal motility disorder, but epidemiological studies in Japan are lacking. We investigated the incidence and period prevalence of achalasia in Japan, including the rate of coexistence of esophageal carcinoma, and evaluated treatment trends. Methods To estimate the nationwide number of patients with achalasia, a large-scale insurance claims database from 2005 to 2017 were used for our analyses. Patients with achalasia and coexistence of esophageal carcinoma were identified based on the diagnosis code registered. Interventional treatment was also evaluated. Results Of the total 5,493,650 populations, 385 were diagnosed with primary achalasia. The incidence was calculated as 0.81–1.37 per 100,000 person-years (male-to-female ratio was almost 1; mean age at diagnosis was 43.3 ± 14.4 years). The period prevalence was 7.0 per 100,000 persons. There were statistically significant trends of increase in the incidence and period prevalence over age groups (all p values < 0.0001). Four men with achalasia developed esophageal carcinoma, and the incidence of esophageal carcinoma with achalasia was estimated as 0.25 per 100 person-years. With regard to intervention, esophageal dilation was performed as a first treatment in 64.7% of patients, with repeat intervention required in 56.9% of these. The proportion of patients treated using peroral endoscopic myotomy (POEM) increased annually to 41.1% in 2017. Conclusions In Japan, the incidence and period prevalence of achalasia is comparable to that in other countries. The absolute risk of esophageal carcinoma is rather low. Esophageal dilation has been the mainstay of achalasia treatment, and the role of POEM has increased annually.

Management of elderly ulcerative colitis in Japan Abstract Japan has the largest aging society, where many elderly people have intractable diseases including ulcerative colitis (UC). Along with the increasing total number of UC patients, the number of elderly UC patients has also been increasing and will continue to do so in the future. Although the clinical features and natural history of UC in the elderly have many similarities with UC in the non-elderly population, age-specific concerns including comorbidities, immunological dysfunction, and polypharmacy make the diagnosis and management of elderly UC challenging compared to UC in non-elderly patients. Based on increasing data related to elderly UC patients from Japan, as well as other countries, we reviewed the epidemiology, clinical course, differential diagnosis, management of comorbidities, surveillance, medical therapy, and surgery of UC in the elderly.

Establishment of a system to evaluate the therapeutic effect and the dynamics of an investigational drug on ulcerative colitis using human colonic organoids Abstract Background Ulcerative colitis (UC) is a chronic inflammatory disease of the colon with an intractable, recurrent course. The goal of UC therapy is to target mucosal healing because immune-suppressive therapy for UC frequently results in relapse. However, few drugs directly target mucosal healing. We, therefore, aim to evaluate the therapeutic effect of an investigational drug on intestinal epithelial cells in an in vitro UC model using human colonic organoids. Methods Colonic organoids were isolated from human colon and cultured. A mixture of cytokines and bacterial components were used to mimic UC in humans. The effect of the investigational drug on colonic organoid was evaluated by microarray analysis and 3D immunofluorescence. The enrichment of stem cells was assessed with a colony formation assay. Results Inflammatory stimulation resulted in a significant induction of inflammatory-related genes in colonic organoids whereas cell differentiation was suppressed. Treatment with the investigational drug KAG-308 showed reciprocal dynamics of gene expression to inflammatory stimulation, which resulted in not only the suppression of immune response but also the promotion of cellular differentiation towards secretory lineages. Moreover, SPDEF and Reg4 were identified as novel targets for the enrichment of intestinal epithelial stem cells and mucosal healing. Conclusions The establishment of in vitro UC model using human colonic organoid could reveal the effects and targets of investigational drugs in intestinal epithelial cells under inflammation conditions. Further maturation of this system might be more efficient to predict the effect on UC, as compared with the use of animal model, for the development of new drugs.

Comprehensive analysis of genetic aberrations linked to tumorigenesis in regenerative nodules of liver cirrhosis Abstract Background Hepatocellular carcinoma (HCC) recurrently develops in cirrhotic liver containing a number of regenerative nodules (RNs). However, the biological tumorigenic potential of RNs is still unclear. To uncover the molecular bases of tumorigenesis in liver cirrhosis, we investigated the genetic aberrations in RNs of cirrhotic tissues using next-generation sequencing. Methods We isolated 205 RNs and 7 HCC tissues from the whole explanted livers of 10 randomly selected patients who had undergone living-donor liver transplantation. Whole-exome sequencing and additional targeted deep sequencing on 30 selected HCC-related genes were conducted to reveal the mutational landscape of RNs and HCCs. Results Whole-exome sequencing demonstrated that RNs frequently harbored relatively high-abundance genetic alterations, suggesting a clonal structure of each RN in cirrhotic liver. The mutation signature observed in RNs was similar to those determined in HCC, characterized by a predominance of C>T transitions, followed by T>C and C>A mutations. Targeted deep sequencing analyses of RNs identified nonsynonymous low-abundance mutations in various tumor-related genes, including TP53 and ARID1A. In contrast, TERT promoter mutations were not detected in any of the RNs examined. Consistently, TERT expression levels in RNs were comparable to those in normal livers, whereas every HCC tissue demonstrated an elevated level of TERT expression. Conclusion Analyses of RNs constructing cirrhotic liver indicated that a variety of genetic aberrations accumulate in the cirrhotic liver before the development of clinically and histologically overt HCC. These aberrations in RNs could provide the basis of tumorigenesis in patients with liver cirrhosis.

Comparison of intracellular responses between HBV genotype A and C infection in human hepatocyte chimeric mice Abstract Background and aims The clinical course and responsiveness to antiviral treatments differs among hepatitis B virus (HBV) genotypes. However, the cause of these differences is unclear. In the present study, we compared mRNA expression profiles in human hepatocyte chimeric mice infected with HBV genotypes A and C. Methods Fifteen chimeric mice were prepared and divided into the following three groups: uninfected control mice, HBV genotype A-infected mice, and HBV genotype C-infected mice. Human hepatocytes were collected from these mouse livers and gene expression analyses were performed using next-generation RNA sequencing. Results Although similar pathways were influenced by HBV infection, including inflammation mediated by chemokine and cytokine signaling, p53, and integrin signaling pathways, expression levels of up-regulated genes by HBV genotype A or C infection were quite different. In HBV genotype A-infected hepatocytes, 172 genes, including KRT23 and C10orf54, were significantly more highly expressed than in HBV genotype C-infected cells, whereas 10 genes, including SPX and IER3, were expressed at significantly lower levels. Genes associated with the p53 pathway and the inflammation mediated by chemokine and cytokine signaling pathway were more highly expressed in cells with HBV genotype A infection, whereas genes associated with CCKR signaling map and oxidative stress response were more highly expressed in cells with HBV genotype C infection. Conclusion Several differences in gene expression with respect to HBV genotype A and C infection were detected in human hepatocytes. These differences might be associated with genotypic difference in the clinical course or responsiveness to treatment.

Marked impact of tumor location on the appropriate cutoff values and the prognostic significance of the lymph node ratio in stage III colon cancer: a multi-institutional retrospective analysis Abstract Background The prognostic significance of lymph node ratio (LNR) is not constant among studies. Exploration of appropriate location-specific cutoffs might be necessary because the number of lymph nodes harvested is generally higher in right than in left colon cancer. We aimed to determine appropriate cutoff values of LNR in right and left colon cancer and to clarify its clinical significance. Methods The clinicopathologic data of 5463 patients with stage III colon cancer were collected. The best cutoff for LNR as a prognostic indicator for patients with right and left colon cancer was studied separately. We compared the prognostic impact between LNR and the number of lymph node metastasis using the Akaike information criterion (AIC), and evaluated the prognostic significance of LNR in each stage III subcategory. Results The best performance was noted when LNR was categorized by cutoffs of 0.16 and 0.22 for right and left colon cancer, respectively. AIC scores were better with these categorizations than with subgrouping by number of positive nodes. LNR-low right colon cancer patients showed better cancer-specific survival than LNR-high in stage IIIA (95.7% vs. 89.3%), IIIB (86.7% vs. 77.2%), and IIIC (71.2% vs. 58.7%). The same results were obtained in left colon cancer patients with stage IIIB (88.3% vs. 80.7%) and IIIC (79.8% vs. 68.4%). Conclusions We demonstrated the difference in the appropriate cutoffs of LNR between right and left colon cancer. Categorization by location-specific cutoff of LNR may be useful for risk stratification of patients with stage III cancer.

Safety and efficacy of glecaprevir and pibrentasvir in Japanese hemodialysis patients with genotype 2 hepatitis C virus infection Abstract Background Until recently, interferon-free anti-hepatitis C virus (HCV) therapy for genotype 2 (GT2) HCV-infected hemodialysis patients was an unfulfilled medical need. Recent clinical trials of glecaprevir and pibrentasvir (G/P) for hemodialysis patients showed high efficacy and safety; however, the number of GT2 HCV-infected patients, especially Asian patients, was limited and most of them were treated with a 12-week regimen. In this prospective multicenter study, we aimed to investigate the efficacy and safety of G/P in Japanese hemodialysis patients with GT2 HCV infection. Methods Twenty-seven Japanese hemodialysis patients with GT2 HCV infection who were started on with 8- or 12-week G/P regimen between November 2017 and June 2018 were included and followed up for around 12 weeks after treatment completion. Results Among the 27 included patients, 13 non-liver cirrhosis (LC) and direct-acting antivirals (DAAs)-naïve patients were treated with 8 weeks of G/P and 14 patients with LC (n = 13) or history of failure of DAAs (n = 1) were treated with a 12-week regimen. The overall sustained virological response at 12 weeks after treatment completion (SVR 12) was 96.3% (26/27). All patients with 8 weeks of treatment achieved SVR12. Two patients discontinued the therapy at 2 and 11 weeks after treatment initiation. The patient who discontinued at 2 weeks due to pruritus alone failed to respond to G/P. No patients experienced lethal adverse events during the therapy, and the most common adverse event was pruritus. Conclusions An 8- or 12-week G/P regimen is highly effective and safe in GT2 HCV-infected hemodialysis patients.

Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182

6948891480

alsfakia@gmail.com