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Background Aberrant DNA methylation is induced by aging and chronic inflammation in normal tissues. The induction by inflammation is widely recognized as acceleration of age-related methylation. However, few studies addressed target genomic regions and the responsible factors in a genome-wide manner. Here, we analyzed methylation targets by aging and inflammation, taking advantage of the potent methylation induction in human gastric mucosa by Helicobacter pylori infection-triggered inflammation. Results DNA methylation microarray analysis of 482,421 CpG probes, grouped into 270,249 genomic blocks, revealed that high levels of methylation were induced in 44,461 (16.5%) genomic blocks by inflammation, even after correction of the influence of leukocyte infiltration. A total of 61.8% of the hypermethylation was acceleration of age-related methylation while 21.6% was specific to inflammation. Regions with H3K27me3 were frequently hypermethylated both by aging and inflammation. Basal methylation levels were essential for age-related hypermethylation while even regions with little basal methylation were hypermethylated by inflammation. When limited to promoter CpG islands, being a microRNA gene and high basal methylation levels strongly enhanced hypermethylation while H3K27me3 strongly enhanced inflammation-induced hypermethylation. Inflammation was capable of overriding active transcription. In young gastric mucosae, genes with high expression and frequent mutations in gastric cancers were more frequently methylated than in old ones. Conclusions Methylation by inflammation was not simple acceleration of age-related methylation. Targets of aberrant DNA methylation were different between young and old gastric mucosae, and driver genes were preferentially methylated in young gastric mucosa.

Background/Aims: Rosemont classification (RC) with endoscopic ultrasonography (EUS) is important for diagnosing chronic pancreatitis (CP) but is based only on subjective judgement. EUS shear wave measurement (EUS-SWM) is a precise modality based on objective judgment, but its usefulness has not been extensively studied yet. This study evaluated the utility of EUS-SWM for diagnosing CP and estimating CP severity by determining the presence of endocrine dysfunction along with diabetes mellitus (DM). Methods: Between June 2018 and December 2018, 52 patients who underwent EUS and EUS-SWM were classified into two groups according to RC: non-CP (indeterminate CP and normal) and CP (consistent and suggestive of CP). The EUSSWM value by shear wave velocity was evaluated with a median value. The EUS-SWM value was compared with RC and the number of EUS features. The diagnostic accuracy and cutoff value of EUS-SWM for CP and DM and its sensitivity and specificity were calculated. Results: The EUS-SWM value significantly positively correlated with the RC and the number of EUS features. The EUS-SWM values that were consistent and suggestive of CP were significantly higher than that of normal. The area under the receiver operating characteristic (AUROC) curve for the diagnostic accuracy of EUS-SWM for CP was 0.97. The cutoff value of 2.19 had 100% sensitivity and 94% specificity. For endocrine dysfunction in CP, the AUROC was 0.75. The cutoff value of 2.78 had 70% sensitivity and 56% specificity. Conclusions: EUS-SWM provides an objective assessment and can be an alternative diagnostic tool for diagnosing CP. EUS-SWM may also be useful for predicting the presence of endocrine dysfunction. (Gut Liver 2020;14:659-664)

Background/Aims This study aimed to predict sustained viral response (SVR) to low-dose pegylated interferon (PEG-IFN) plus ribavirin of elderly and/or cirrhotic patients with genotype 2 hepatitis C virus (HCV) using viral response within 2 weeks. Methods Low-dose PEG-IFN-α-2b plus ribavirin was administered to 50 elderly and/or cirrhotic patients with genotype 2 HCV for 24 weeks. The dynamics of HCV RNA and HCV core antigen levels within 2 weeks were measured. Results The patients’ median age was 66 years. There were 21 male and 29 female patients. The median baseline HCV RNA level was 5.7 log IU/mL. Rapid viral response was achieved in 17 patients (34%), SVR in 28 (56%), and two (4%) discontinued treatment. Univariate analysis of factors contributing to SVR showed significant differences for sex, baseline virus level, and response within 4 weeks. When 40 fmol/L was set as the cutoff value for the core antigen level at 1 week, the sensitivity, specificity, positive predictive value, negative predictive value, and accuracy for predicting SVR were 93%, 75%, 84%, 88%, and 85%, respectively. Conclusions Low-dose PEG-IFN plus ribavirin was a safe and cost-effective treatment for elderly and/or cirrhotic patients with genotype 2 HCV, and the viral response within 2 weeks was a useful predictor of SVR.

Background/Aims Transpapillary forceps biopsy is an effective diagnostic technique in patients with biliary stricture. This prospective study aimed to determine the usefulness of the wire-grasping method as a new technique for forceps biopsy. Methods Consecutive patients with biliary stricture or irregularities of the bile duct wall were randomly allocated to either the direct or wire-grasping method group. In the wire-grasping method, forceps in the duodenum grasps a guide-wire placed into the bile duct beforehand, and then, the forceps are pushed through the papilla without endoscopic sphincterotomy. In the direct method, forceps are directly pushed into the bile duct alongside a guide-wire. The primary endpoint was the success rate of obtaining specimens suitable for adequate pathological examination. Results In total, 32 patients were enrolled, and 28 (14 in each group) were eligible for analysis. The success rate was significantly higher using the wire-grasping method than the direct method (100% vs 50%, p=0.016). Sensitivity and accuracy for the diagnosis of cancer were comparable in patients with the successful procurement of biopsy specimens between the two methods (91% vs 83% and 93% vs 86%, respectively). Conclusions The wire-grasping method is useful for diagnosing patients with biliary stricture or irregularities of the bile duct wall.

We have previously reported that serum pepsinogen (PG) can quantify the level of gastric mucosal atrophy, and that H. pylori eradication reduces cancer development in subjects with mild atrophy identified by serum PG levels. The aim of this study was to elucidate the predictive ability of serum PG levels for the development of metachronous gastric cancer (MGC) after endoscopic resection (ER) of primary cancer in association with H. pylori eradication. A retrospective chart review was performed, and 330 patients who underwent ER for initial early gastric cancer were enrolled. Presence or absence of H. pylori, serum PG levels, and endoscopic atrophy at ER were evaluated. H. pylori eradication was performed at the patient's request after ER. The incidence of MGC in these patients was analyzed. Of 330 patients, 47 developed MGC. Endoscopic extensive atrophy was observed more frequently in patients with MGC (p = 0.001). Although PG I or PG II alone did not significantly differ according to development of MGC, the proportion of PG I/II ≤ 3.0, which is one of the criteria of PG test-positive, was significantly higher in patients with MGC (83 vs. 69%, p = 0.04). H. pylori eradication after ER did not affect MGC development (p = 0.2). On multivariate analysis, serum PG I/II ratio ≤ 3.3 was significantly associated with the development of MGC (hazard ratio: 3.66, 95% confidence interval: 1.47-12.25, p = 0.004). The risk of MGC after ER could be quantitatively predicted by the PG I/II ratio regardless of H. pylori status.

Background and Aim The preventive effect of Helicobacter pylori (HP) eradication on metachronous gastric cancer development after endoscopic resection remains controversial. The aim of the present study was to identify specific endoscopic features that correlated with the risk of metachronous gastric cancer development after endoscopic submucosal dissection (ESD) using both endoscopic findings before ESD and changes of findings after HP eradication. Methods This retrospective study investigated 122 consecutive patients who underwent ESD for early gastric cancer and successful HP eradication after ESD. Endoscopic findings linked with HP before ESD and changes after HP eradication were evaluated according to the development of metachronous cancer. Results Most patients showed severe atrophy and intestinal metaplasia (IM) before ESD (97% and 83%, respectively). Improvement of spotty redness, improvement of diffuse redness, emergence of patchy redness, and emergence of map-like redness were frequent findings after HP eradication (52%, 50%, 54%, and 32%, respectively). Kaplan–Meier curves indicated that patients without IM before ESD never developed metachronous cancer, whereas patients with emergence of map-like redness after HP eradication were significantly more likely to develop metachronous cancer (log–rank test, P = 0.031 and P

Aberrant DNA methylation is involved in many types of human cancers, and is induced by aging. In addition, it is known to be induced by chronic inflammation, and this inflammation-induced DNA methylation is considered as acceleration of age-related methylation. However, few studies addressed target genomic regions of age-related and inflammation-induced DNA methylation in a genome-wide manner. We previously demonstrated that Helicobacter pylori(HP) infection induces aberrant DNA methylation potently in human and gerbil gastric mucosa [Niwa, Cancer Res, 70:1430, 2010; Ushijima, Clin Cancer Res, 18:923, 2012]. Here, taking advantage of the potent methylation induction, we aimed to clarify the targets of methylation induction by aging and inflammation. We collected gastric mucosae from i) HP-never infected young individuals (under 40 years; n=4; G1), ii) HP-currently infected young individuals (n=4; G2), iii) HP-never-infected old individuals (above 60 years; n=4; G3), and vi) HP-currently-infected old individuals (n=4; G4). DNA methylation of 482,421 CpG probes was analyzed by Infinium Human Methylation 450K, and the probes were grouped into 270,249 genomic blocks. It was revealed that high levels of methylation were induced in 44,461 (16.5%) genomic blocks by current inflammation (G2/G1), even after correction of the influence of leucocyte infiltration. 61.8 % of the hypermethylation was acceleration of age-related methylation (G3/G1) while 21.6 % was specific to inflammation. Regions with H3K27me3 were frequently hypermethylated both by aging and inflammation. Basal methylation levels were essential for age-related hypermethylation while even regions with little basal methylation were hypermethylated by inflammation. When limited to promoter CpG islands, being a microRNA gene and high basal methylation levels strongly enhanced hypermethylation while H3K27me3 strongly enhanced inflammation-induced hypermethylation. Inflammation was capable of overriding active transcription. In young gastric mucosae (G2/G1), genes with high expression and frequent mutations in gastric cancers were more frequently methylated than in old ones (G4/G3).Methylation by inflammation was not simple acceleration of age-related methylation. Targets of aberrant DNA methylation were different between young and old gastric mucosae, and driver genes were preferentially methylated in young gastric mucosa [Yamashita, Clin Epigenet, in press]. Citation Format: Satoshi Yamashita, Sohachi Nanjo, Emil Rehnberg, Naoko Iida, Hideyuki Takeshima, Takayuki Ando, Takao Maekita, Toshiro Sugiyama, Toshikazu Ushijima. Distinct DNA methylation targets by aging and chronic inflammation [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1079.

We recently published in your journal a 3-year multicentre prospective cohort study demonstrating the usefulness of an epigenetic cancer risk marker for gastric metachronous cancers.1 This study achieved the first proof of concept of epigenetic cancer risk diagnosis in any type of cancer but, due to the short follow-up period, a relatively small number of events were observed, resulting in a marginally significant difference (p=0.042). It was anticipated that a longer follow-up could lead to a clearer difference and HR with a smaller 95% CI. We now report the 5-year follow-up data, which show highly significant results. Among the 826 enrolled patients, 795 patients received annual follow-ups by endoscopy for a median period of 5.46 years (IQR: 3.95–6.09). By the end, 133 patients had developed a metachronous gastric cancer. Among them, 116 patients developed a metachronous gastric cancer detected 1 year after the enrolment (authentic metachronous cancer). Statistical analyses were conducted in the same manner as previously …

Background and aim Treatment efficiency of walled-off necrosis (WON) using endoscopic ultrasound-guided drainage (EUS-D) with a double pigtail stent (DPS) is limited. Endoscopic necrosectomy is often carried out if EUS-D fails. However, endoscopic necrosectomy is associated with significant morbidity and mortality. Thus, we developed transmural nasocyst continuous irrigation (TNCCI) as an alternative therapeutic option for WON. This study aimed to evaluate the usefulness of TNCCI therapy for WON. Methods Between April 2009 and March 2018, 19 of 39 patients admitted with WON underwent EUS-D. Ten consecutive patients also received TNCCI therapy (TNCCI group) between May 2015 and March 2018. TNCCI was carried out by inserting an external tube from the gastroduodenal lumen into the WON under endoscopic ultrasonography guidance and then continuously irrigating the WON with saline at a rate of 40 ml/h. Nine consecutive patients who underwent EUS-D without TNCCI therapy between April 2009 and April 2015 were used for comparison (control group). Various parameters were compared between the TNCCI and control groups. Results Time taken to reduce WON (6 vs 32 days, P = 0.001), implementation rate of endoscopic necrosectomy (0% vs 55.6%, P = 0.01), and number of endoscopic necrosectomy sessions per patient (0 vs 0.8 ± 1.0, P = 0.008) were significantly lower in the TNCCI group than in the control group. Conclusions Walled-off necrosis can be effectively and safely treated by endoscopic drainage with a DPS and TNCCI. This technique can be an alternative therapeutic option before carrying out endoscopic necrosectomy.

Aim The present study aimed to evaluate pathological features of hepatocellular carcinomas (HCC) appearing hypointense on the apparent diffusion coefficient (ADC) map, and to elucidate the association between the signal intensity on the ADC map and metastatic recurrences after hepatectomy. Methods In total, 52 consecutive patients with initial hypervascular HCC (solitary lesion ≤5 cm in diameter) without vascular invasion on imaging were examined by diffusion-weighted magnetic resonance imaging before hepatectomy. The signal intensities of HCC on the ADC map were visually compared with the surrounding liver and categorized as hypointense or non-hypointense. Intrahepatic metastatic recurrence was defined as more than three intrahepatic recurrences. Results The 52 HCC were evaluated as 26 hypointense and 26 non-hypointense tumors. No significant differences between the hypointense and non-hypointense groups were seen for age, sex, etiology, tumor size and tumor marker levels. However, in resected specimens, significant differences between the two groups were noted for histological grade and microscopic portal invasion. The percentages of poorly differentiated HCC and microscopic portal invasion in the hypointense group were significantly higher than those in the non-hypointense group. The cumulative 3-year metastatic recurrence rates of the hypointense and non-hypointense groups on the ADC map were 56% and 13% (P = 0.001), respectively. Multivariate analyses indicated that hypointensity on the ADC map was the only independent factor related to metastatic recurrence. Conclusion Hypointense HCC on ADC mapping are characterized by poor histological differentiation and more frequent microscopic portal invasion, and are significantly associated with metastatic recurrences after hepatectomy.

Critical recurrences after radiofrequency ablation for hepatocellular carcinoma (HCC), such as intrahepatic metastases or dissemination, and extrahepatic metastases or seeding, which are difficult to treat radically, almost certainly lead to primary cancer death. The present study aimed to clarify whether the arterial tumor enhancement pattern on contrast-enhanced computed tomography (CECT) is associated with critical recurrence and cancer death after RFA for small HCC. Between April 2001 and September 2011, 226 patients with initial small hypervascular HCC (≤3 cm in diameter and ≤3 tumors) were treated by RFA. Arterial tumor enhancement patterns on CECT before RFA were categorized by whether non-enhanced areas were included inside the tumor stain. The heterogeneous enhancement group included 44 patients, and the homogeneous enhancement group included 182 patients. The cumulative 5-year critical recurrence rates of the heterogeneous and homogeneous enhancement groups were 42 and 22 % (p = 0.005), respectively. Univariate analysis for factors related to critical recurrence showed significant differences in sex, arterial enhancement pattern, and response to antiviral therapy. These factors were independent on multivariate analysis. The cumulative 5-year primary cancer death rates of the heterogeneous and homogeneous enhancement groups were 29 and 13 % (p = 0.002), respectively. Univariate analysis for factors related to primary cancer death showed significant differences in arterial enhancement pattern and response to antiviral therapy. These factors were independent on multivariate analysis. Arterial heterogeneous tumor enhancement on CECT is associated with critical recurrence and cancer death after RFA for small HCC.

Objectives. To investigate the usefulness of contrast-enhanced endoscopic ultrasonography (CE-EUS) for histological differentiation of pancreatic tumors.Methods. CE-EUS was performed for consecutive patients having a pancreatic solid lesion, and tumors were classified into three vascular patterns (hypervascular, isovascular, and hypovascular) at two time phases (early-phase and late-phase). Correlation between vascular patterns and histopathology of resected pancreatic cancer (PC) tissues was ascertained.Results. The final diagnoses of 147 examined tumors were PC(n=109), inflammatory mass(n=11), autoimmune pancreatitis(n=9), neuroendocrine tumor(n=8), and others(n=10). In late-phase images, 104 of 109 PCs had the hypovascular pattern, for a diagnostic sensitivity and specificity of 94% and 71%, respectively. Of 28 resected PCs, 10 had isovascular, and 18 hypovascular, patterns on the early-phase image. Early-phase isovascular PCs were more likely to be differentiated than were early-phase hypovascular PCs (6 well and 4 moderately differentiated versus 3 well, 14 moderately, and 1 poorly differentiated,P=0.028). Immunostaining revealed that hypovascular areas of early-phase images reflected heterogeneous tumor cells with fibrous tissue, necrosis, and few vessels.Conclusion. CE-EUS could be useful for distinguishing PC from other solid pancreatic lesions and for histological differentiation of PCs.

Background/Aims Although daclatasvir with asunaprevir was approved in Japan for interferon ineligible or intolerant patients, patients aged ≥75 years were excluded in the phase III trial. The present study aimed to evaluate the safety and efficacy of this therapy for elderly patients aged ≥75 years and to clarify whether an extremely high sustained virological response (SVR) rate can be achieved, even in a real-world setting when patients with resistance-associated substitutions (RASs) to nonstructural protein 5A (NS5A) inhibitors or prior simeprevir failure are excluded. Methods Daclatasvir (60 mg) and asunaprevir (100 mg) were orally administered daily for 24 weeks. Patients without pre-existing NS5A RASs and simeprevir failure were enrolled in this study. Results Overall, 110 patients were treated. The median age was 73 years old. The SVR rates of total patients, those aged ≥75 years, and those aged ＜75 years were 97% (107/110), 98% (46/47), and 97% (61/63), respectively. The treatment of two patients (2%) was discontinued because of adverse events. Conclusions Daclatasvir with asunaprevir was a safe treatment, even in patients aged ≥75 years. When patients without pre-existing NS5A RASs and prior simeprevir failure were selected, an extremely high SVR rate could be achieved irrespective of age.

Entecavir requires long-term administration. Pegylated interferon (PEG-IFN) therapy leads to significant reduction of hepatitis B surface antigen (HBs Ag) levels. This study aimed to assess the safety and efficacy of adding PEG-IFN-α-2a to entecavir toward cessation of entecavir. A total of 23 patients treated with entecavir underwent add-on PEG-IFN-α-2a therapy (90 μg per week) for 48 weeks. Viral response (VR) was defined as more than 50% reduction of baseline hepatitis B surface antigen (HBs Ag) level at 72 weeks from the start of therapy. Complete response (CR) was defined as the decline of HBs Ag levels α-2a to entecavir has limited efficacy. The percentage reduction of HBs Ag level at week 12 may be a useful predictor for VR.

Background Epigenetic alterations accumulate in normal-appearing tissues of patients with cancer, producing an epigenetic field defect. Cross-sectional studies show that the degree of the defect may be associated with risk in some types of cancer, especially cancers associated with chronic inflammation. Objective To demonstrate, by a multicentre prospective cohort study, that the risk of metachronous gastric cancer after endoscopic resection (ER) can be predicted by assessment of the epigenetic field defect using methylation levels. Design Patients with early gastric cancer, aged 40–80 years, who planned to have, or had undergone, ER, were enrolled at least 6 months after Helicobacter pylori infection discontinued. Methylation levels of three preselected genes (miR-124a-3, EMX1 and NKX6-1) were measured by quantitative methylation-specific PCR. Patients were followed up annually by endoscopy, and the primary endpoint was defined as detection of a metachronous gastric cancer. Authentic metachronous gastric cancers were defined as cancers excluding those detected within 1 year after the enrolment. Results Among 826 patients enrolled, 782 patients had at least one follow-up, with a median follow-up of 2.97 years. Authentic metachronous gastric cancers developed in 66 patients: 29, 16 and 21 patients at 1–2, 2–3 and ≥3 years after the enrolment, respectively. The highest quartile of the miR-124a-3 methylation level had a significant univariate HR (95% CI) (2.17 (1.07 to 4.41); p=0.032) and a multivariate-adjusted HR (2.30 (1.03 to 5.10); p=0.042) of developing authentic metachronous gastric cancers. Similar trends were seen for EMX1 and NKX6-1. Conclusions Assessment of the degree of an epigenetic field defect is a promising cancer risk marker that takes account of life history.

Aim It has been reported that the apparent diffusion coefficient (ADC) value of hepatocellular carcinomas (HCC) on diffusion-weighted magnetic resonance imaging (MRI) is associated with their histological grade. The present study aimed to evaluate whether the signal intensity of small hypervascular HCC on the ADC map is related to the treatment outcome of radiofrequency ablation (RFA). Methods Between February 2008 and August 2012, 136 consecutive patients with initial small hypervascular HCC (≤3 tumors and ≤3 cm in diameter) were examined by diffusion-weighted MRI before RFA. The signal intensities of HCC on the ADC map were visually compared with the surrounding liver and categorized as hypointense and non-hypointense. Critical recurrence was defined as more than three intrahepatic recurrences, recurrence with vascular invasion, seeding, dissemination and/or extrahepatic metastasis. Results The median follow up was 619 days. The cumulative 2-year recurrence rates of the hypointense and non-hypointense on the ADC map groups were 79% and 50% (P

BACKGROUND/AIMS The present study aimed to clarify whether virological response within 2 weeks after therapy initiation can predict a null response to pegylated interferon α-2b plus ribavirin therapy in patients with high viral load genotype 1b hepatitis C. METHODS The participants consisted of 72 patients with high viral load genotype 1b. The dynamics of viral load within 2 weeks were measured. RESULTS Significant differences between null responders and nonnull responders were noted for interleukin (IL)-28B genotype, amino acid 70 substitution, α-fetoprotein, low-density lipoprotein cholesterol, hyaluronic acid, and viral response. The area under the curve (AUC) for the receiver operating characteristic curve of the hepatitis C virus (HCV) RNA level decline at 2 weeks (AUC=0.993) was the highest among the factors predicting the null response. When the cutoff value for the HCV RNA level decline at 2 weeks was set at 0.80 log, the sensitivity, specificity, positive predictive value, negative predictive value, and accuracy in predicting a null response were 82%, 96%, 82%, 96%, and 94%, respectively. In comparison, values for the non-TT and mutant type of amino acid 70 substitution were similar to those for HCV RNA level decline at 2 weeks. CONCLUSIONS Virological response at 2 weeks or the combination of IL-28B and amino acid 70 substitution are accurate predictors of a null response.

Liquid-based cytology (LBC) is a thin-layer slide preparation procedure that was developed to overcome the cell crowding and contamination associated with smear cytology (SC). The present study compared diagnostic efficacy between SC alone and SC combined with LBC (SLBC) using endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) samples of pancreatic lesions. We retrospectively analyzed data derived from 311 consecutive patients. Specimens obtained via EUS-FNA from 179 patients between December 2011 and May 2016 were analyzed by SC, and those obtained from 132 patients between June 2016 and October 2017 were analyzed by SLBC. The 2 groups were compared in terms of adequate sample rate, diagnostic accuracy, sensitivity, and specificity using propensity score matching. SC and SLBC were compared using propensity score-matching in 204 patients (n = 102 per group). The adequate sample rate did not differ significantly between SLBC (100%) and SC (99.0%, P = 1). Diagnostic sensitivity, negative predictive value and accuracy were better for SLBC than for SC in terms of cytological (93.2% vs 67.4%, 68.4% vs 23.1%, and 94.1% vs 69.6%, P

Our study investigated the relationship between gastric cancer development and activity of Helicobacter pylori-associated chronic gastritis or the resulting chronic atrophic gastritis (CAG). A cohort of 4,655 healthy asymptomatic subjects, in whom serum pepsinogen (PG) and H. pylori antibody titer had been measured to assess the activity and stage of H. pylori-associated chronic gastritis, was followed for up to 16 years, and cancer development was investigated. In subjects with a serologically diagnosed healthy stomach (H. pylori-negative/CAG-negative), cancer incidence rate was low, at 16/100,000 person-years. With the establishment of H. pylori infection and progression of chronic gastritis, significant stepwise cancer risk elevations were seen from CAG-free subjects (H. pylori-positive/CAG-negative) [hazard ratio (HR) = 8.9, 95% confidence interval (CI) = 2.7-54.7] to subjects with CAG (H. pylori-positive/CAG-positive) (HR = 17.7, 95% CI = 5.4-108.6) and finally to subjects with metaplastic gastritis (H. pylori-negative/CAG-positive) (HR = 69.7, 95% CI = 13.6-502.9). In H. pylori-infected CAG-free subjects, significantly elevated cancer risk was observed in the subgroup with active inflammation-based high PG II level or potent immune response-based high H. pylori antibody titer; the former was associated with a particularly high risk of diffuse-type cancer, and both subgroups showed high cancer incidence rates of around 250/100,000 person-years, comparable to that in subjects with CAG. No such risk elevation was observed in H. pylori-infected subjects with CAG. These results clearly indicate that gastric cancer develops mainly from the gastritis-atrophy-metaplasia-cancer sequence and partly from active inflammation-based direct carcinogenesis, and that serum levels of PG and H. pylori antibody titer provide indices of cancer development in H. pylori-infected subjects.

Hepatocellular carcinoma (HCC) frequently develops in cirrhotic liver and is one of the most common malignancies worldwide. The tumor volume doubling time (TVDT) reflects the natural tumor growth rate and is an indicator of the biological malignant potential of a tumor. The present study aimed to elucidate the association between the serological and histological indices of HCC and TVDT. TVDT was analyzed for 53 HCCs by measuring the enlargement of the tumor diameter on dynamic computed tomography. Differences in TVDT were compared among histological grades of HCC differentiation. The α-fetoprotein (AFP) doubling time (T2AFP) for 44 HCCs with AFP levels >200 ng/ml was calculated and the differences in T2AFP were compared according to the histological grade of HCC differentiation and positivity for Lens culinaris agglutinin-reactive fraction of α-fetoprotein (AFP-L3). Among these 44 HCCs, the correlation between T2AFP and TVDT was analyzed for the 27 tumors for which TVDT could be calculated. The mean ± standard deviation (SD) TVDT in Edmondson grade 1 (Ed1), Ed2 and Ed3 HCC was 138.3±110.3, 94.9±91.5 and 32.2±20.8 days, respectively (P

AIM Rapid virological response (RVR), defined as serum hepatitis C virus (HCV) RNA negativity at 4 weeks, is the most useful predictor of sustained virological response (SVR) to standard pegylated interferon (PEG IFN) plus ribavirin therapy for patients infected with genotype 2 HCV. The aim of the present study was to predict SVR using viral response within 2 weeks of therapy initiation. METHODS Of 64 HCV genotype 2 patients with a high viral load treated with standard PEG IFN-α-2b plus weight-based ribavirin for 24 weeks, 58 patients whose adherence was more than 67% were analyzed. RNA and core antigen levels were measured at four time points: the day of therapy initiation, the following day, and at 1 and 2 weeks. RESULTS SVR was achieved in 73% (47/64) of patients. Univariate analysis of SVR contributing factors showed significant differences with age, bodyweight, white blood cell count, platelet count, fibrosis marker levels, baseline core antigen level and viral response. The area under the receiver-operator curve (AUC) of the core antigen level at 1 week (AUC, 0.940) was the highest among the significant SVR predicting factors. Setting 100 fmol/L as the cut-off value for core antigen level at 1 week, the sensitivity, specificity, positive predictive value, negative predictive value and accuracy for predicting SVR were 100%, 86%, 96%, 100% and 97%, respectively, and for predicting RVR were 66%, 93%, 97%, 46% and 72%, respectively. CONCLUSION The HCV core antigen level at 1 week after therapy initiation is the most useful predictor for SVR.

Background No mouthpiece has been designed to control salivary flow during endoscopic procedures. A new continuous suction mouthpiece (CSM) was developed, and its usefulness for percutaneous endoscopic gastrostomy (PEG) was evaluated. Patients and Methods Seventy-two patients who were scheduled to undergo PEG or the exchange of a gastrostomy button or tube were assigned to one of two groups: the group using the CSM and the group using the conventional mouthpiece. Aspiration pneumonia, procedure duration, extent of salivary flow, frequency of saliva suction, and number of choking episodes during the procedures were evaluated and compared between the two groups. Results The same number of patients was randomly allocated to each group. There were no significant differences between the two groups in sex, age, procedure type, duration of procedure,depth of sedation, and indication for the procedure. The grade of salivary flow was significantly lower in patients with the CSM than in patients with the conventional mouthpiece (P

Aim Elderly and/or cirrhotic patients with hepatitis C virus (HCV) are at high risk of adverse effects during interferon therapy. The aim of the present study was to evaluate the efficacy, safety and predictive factors for sustained virological response (SVR) of low-dose pegylated interferon-α-2a (PEG IFN-α-2a) monotherapy in elderly and/or cirrhotic patients with HCV genotype-2 or genotype-1 low level infection. Methods Sixty-four elderly (≥65 years) and/or cirrhotic patients with HCV genotype-2 or genotype-1 low level (

Background/Aims: The present study aimed to evaluate the safety and efficacy of simeprevir-based triple therapy with reduced doses of pegylated interferon (PEG-IFN) and ribavirin for interferon (IFN) ineligible patients, such as elderly and/or cirrhotic patients, and to elucidate the factors contributing to a sustained virologic response (SVR). Methods: One hundred IFN ineligible patients infected with genotype 1b hepatitis C virus (HCV) were treated. Simeprevir (100 mg) was given orally together with reduced doses of PEG-IFN-α 2a (90 μg), and ribavirin (200 mg less than the recommended dose). Results: The patients` median age was 70 years, and 70 patients were cirrhotic. Three patients (3%) discontinued treatment due to adverse events. The SVR rate was 64%. Factors that significantly contributed to the SVR included the γ-glutamyl transferase and α-fetoprotein levels, interleukin- 28B (IL28B) polymorphism status, and the level and reduction of HCV RNA at weeks 2 and 4. The multivariate analysis showed that the IL28B polymorphism status was the only independent factor that predicted the SVR, with a positive predictive value of 77%. Conclusions: Simeprevir-based triple therapy with reduced doses of PEG-IFN and ribavirin was safe and effective for IFN ineligible patients infected with genotype 1b HCV. IL28B polymorphism status was a useful predictor of the SVR. (Gut Liver 2017;11:551-558)

Helicobacter pylori (H. pylori) infection induces methylation silencing of tumor suppressor genes causing gastric carcinogenesis. Impairment of autophagy induces DNA damage leading to genetic instability and carcinogenesis. We aimed to identify whether H. pylori infection induced methylation silencing of host autophagy-related (Atg) genes, impairing autophagy and enhancing gastric carcinogenesis. Gastric mucosae were obtained from 41 gastric cancer patients and 11 healthy volunteers (8 H. pylori-uninfected and 3 H. pylori-infected). Methylation status of Atg genes was analyzed by a methylation microarray and quantitative methylation-specific PCR (qMSP); mRNA expression was assessed by quantitative reverse transcription PCR (qRT-PCR). Cell proliferation, migration and invasion were assessed in normal rat gastric epithelial cells. Gene knock-down was performed by siRNA. Autophagy was assessed by western blotting. Of 34 Atg genes, MAP1LC3A variant 1 (MAP1LC3Av1) and ULK2 were identified by methylation microarray analysis as exhibiting specific methylation in H. pylori-infected mucosae and gastric cancer tissues. Methylation silencing of MAP1LC3Av1 was confirmed by qMSP, qRT-PCR and de-methylation treatment in two gastric cancer cell lines. Knock-down of map1lc3a, the rat homolog of the human MAP1LC3Av1, inhibited autophagy response and increased cell proliferation, migration and invasion in normal rat gastric epithelial cells, despite the presence of map1lc3b, the rat homolog of the human MAP1LC3B gene important for autophagy. Furthermore, MAP1LC3Av1 was methylation-silenced in 23.3% of gastric cancerous mucosae and 40% of non-cancerous mucosae with H. pylori infection. MAP1LC3Av1 is essential for autophagy and H. pylori-induced methylation silencing of MAP1LC3Av1 may impair autophagy, facilitating gastric carcinogenesis.

We have previously reported that serum pepsinogen (PG) can quantify the level of gastric mucosal atrophy, and that H. pylori eradication reduces cancer development in subjects with mild atrophy identified by serum PG levels. The aim of this study was to elucidate the predictive ability of serum PG levels for the development of metachronous gastric cancer (MGC) after endoscopic resection (ER) of primary cancer in association with H. pylori eradication. A retrospective chart review was performed, and 330 patients who underwent ER for initial early gastric cancer were enrolled. Presence or absence of H. pylori, serum PG levels, and endoscopic atrophy at ER were evaluated. H. pylori eradication was performed at the patient's request after ER. The incidence of MGC in these patients was analyzed. Of 330 patients, 47 developed MGC. Endoscopic extensive atrophy was observed more frequently in patients with MGC (p = 0.001). Although PG I or PG II alone did not significantly differ according to development of MGC, the proportion of PG I/II ≤ 3.0, which is one of the criteria of PG test-positive, was significantly higher in patients with MGC (83 vs. 69%, p = 0.04). H. pylori eradication after ER did not affect MGC development (p = 0.2). On multivariate analysis, serum PG I/II ratio ≤ 3.3 was significantly associated with the development of MGC (hazard ratio: 3.66, 95% confidence interval: 1.47-12.25, p = 0.004). The risk of MGC after ER could be quantitatively predicted by the PG I/II ratio regardless of H. pylori status.

In a previous population-based case-control study, we demonstrated an elevated risk of colorectal neoplasia with Helicobacter pylori (H. pylori) infection. The present study investigated the effects of H. pylori-associated chronic gastritis on the development of colorectal neoplasia by analyzing the recurrence of colorectal neoplasia subsequent to endoscopic resection. Ninety-nine patients who had undergone endoscopic resection of colorectal neoplasia were monitored under colonoscopy, and the recurrence of colorectal neoplasia was prospectively investigated. The stage of H. pylori-associated chronic gastritis in each subject was evaluated using a combination of two serum tests: H. pylori antibody and pepsinogen. In the present cohort, colorectal neoplasia recurred at a rate of 15,296/100,000 person-years during the study period. After adjusting for the confounding factors, chronic atrophic gastritis (CAG) was identified as an independent risk factor [adjusted hazard ratio (HR), 2.72; 95% confidence interval, 1.33-5.57], while H. pylori-infected non-atrophic gastritis was not identified as an independent risk factor for recurrent colorectal neoplasia. Colorectal neoplasia recurred earlier and was significantly more frequent in patients with CAG (22,573/100,000 person-years) compared to patients without CAG (11,089/100,000 person-years; P=0.029, log-rank test). Patients with more extensive CAG showed a higher risk of recurrence. These results demonstrated a significant elevation of the risk of recurrent colorectal neoplasia with the establishment and progression of CAG, indicating the involvement of H. pylori infection in the development of colorectal neoplasia. The two serum tests were useful clinical markers for noninvasively evaluating the risk of each individual for recurrent colorectal neoplasia subsequent to endoscopic resection.

Aim: Although frequent vomiting reflexes during esophagogastroduodenoscopy (EGD) causes suffering in patients, very few studies have investigated the characteristics of subjects who frequently develop vomiting reflexes. This study examined the incidence of the vomiting reflex and related factors, especially upper gastrointestinal symptoms, among individuals undergoing transoral EGD. Methods: Subjects included 488 consecutive adults (mean age, 56.1 ± 8.9 years) who underwent transoral EGD for gastric cancer screening between February 2010 and March 2011. All procedures were performed by an endoscopist with 15 years of experience. Based on a questionnaire survey using the frequency scale for the symptoms of gastroesophageal reflux disease (FSSG), symptoms (dyspepsia and acid reflux symptoms) and the number of vomiting reflexes during EGD were recorded. Results: Of the 488 subjects, 271 (56%) developed vomiting reflexes (mean, 4.2 times). This reflex-positive group was younger (54.3 ± 9.5 years) than the reflex-negative group (58.3 ± 7.7 years, P

Epigenomic damage induced by Helicobacter pylori infection is accumulated in gastric mucosae before the development of malignancy. In individuals without current H. pylori infection, DNA methylation levels of specific CpG islands (CGIs) are associated with gastric cancer risk. Because risk estimation in individuals with past infection is clinically important, we here aimed to identify the risk markers that reflect epigenomic damage induced by H. pylori infection, and that are informative in these individuals. Gastric mucosae were obtained from 55 gastric cancer patients (GC-Pt) (21 with current infection and 34 with past infection) and 55 healthy volunteers (HV) (7 never-infected, 21 with current infection, and 27 with past infection). Hypermethylated CGIs were searched for by methylated DNA immunoprecipitation-CGI microarray, and methylation levels were analyzed by quantitative methylation-specific polymerase chain reaction (PCR). By microarray analysis of a pool of three samples from GC-Pt with past infection and another pool of samples from HV with past infection, 15 hypermethylated CGIs in the former pool were isolated. Seven of them had significantly higher methylation levels in GC-Pt with past infection (n = 10) than in HV with past infection (n = 10) (P

A 67-year-old woman with compensated cirrhosis type B associated with hepatocellular carcinoma was started on sorafenib for multiple pulmonary metastases. The patient developed right upper quadrant pain and high fever 4 weeks later. Imaging revealed marked enlargement of the gallbladder without calculi. Following percutaneous transhepatic gallbladder aspiration, her symptoms resolved, but the gallbladder remained enlarged. Laparoscopic cholecystectomy was performed. Arteriolar occlusion with intimal thickening in the muscular layer of the gallbladder was seen sporadically. The fact that this patient had no risk factors for acalculous cholecystitis suggested that the cholecystitis resulted from ischemia, implying a strong causal relationship with sorafenib.

Aim: Continuation of pegylated interferon (PEG-IFN) plus ribavirin at the recommended dose is difficult in elderly patients and/or patients with cytopenia or complications. Whether the therapeutic efficacy of low-dose PEG-IFN plus ribavirin therapy could be predicted based on virological response within 2 weeks of therapy initiation was evaluated. Methods: A total of 106 patients with a high viral load of genotype-1b hepatitis C virus (HCV) underwent low-dose PEG-IFN plus ribavirin therapy. PEG-IFN alpha 2b (0.75 µg/kg per week) and ribavirin (600–800 mg/day) were administered for 48 weeks. Results: Sustained virological response (SVR) was achieved in 37%, and treatment was discontinued in 9%. On univariate analysis of SVR-contributing factors, significant differences were noted in the white blood cell count, platelet count, fibrosis markers, and viral reduction within 2 weeks from therapy initiation. On multivariate analysis, the platelet count and the reduction in the HCV core antigen level at week 2 were independent factors. The positive predictive value (PPV) and the negative predictive value (NPV) for SVR based on a 1-log or greater HCV-RNA level reduction at week 2 were 65% and 90%, respectively, and those based on HCV core antigen level at week 2 were 64% and 97%, respectively. PPV and NPV based on a 2-log or greater reduction of the RNA level were 86% and 67%, respectively, and those based on the core antigen level were 93% and 69%, respectively. Conclusion: Evaluation of viral reduction at week 2 after therapy initiation is useful for predicting SVR to low-dose PEG-IFN plus ribavirin therapy.

Aim: To clarify the clinical features of and risk factors for extrahepatic seeding, a major complication following radiofrequency ablation (RFA) for hepatocellular carcinoma (HCC). Methods: Our prospective database of 351 nodules in 257 patients with HCC who had undergone RFA between April 2001 and April 2008 was reviewed. The following variables were assessed to identify the risk factors for extrahepatic seeding: age, sex, viral markers, Child–Pugh class, tumor size, number of tumors, RFA indication (tumor size ≤3 cm, number of tumors ≤3), tumor biopsy prior to RFA, degree of histological differentiation, tumor markers, tumor location, number of sessions, and combined transcatheter arterial chemoembolization. Results: The median follow-up period was 36.5 months, during which the rate of seeding after was 5.1% and the 5-year cumulative seeding rate was 8.4%. The survival rate after neoplastic seeding was 21% at 5 years. Univariate analysis of the risk factors for neoplastic seeding showed significant differences in tumor size, RFA indication, subcapsular lesion, number of sessions, tumor biopsy prior to RFA, and des-gamma-carboxy prothrombin value. However, multivariate analysis showed that the only independent risk factor was RFA indication. Conclusions: The prognosis of patients with neoplastic seeding was poor. In particular, RFA performed for HCC not satisfying the RFA indication showed a high risk of seeding, and careful consideration should be given to the optimal treatment method and avoiding direct puncture of subcapsular tumors.

AIM Evaluation of malignant potential is important to determine the treatment strategy for small hepatocellular carcinoma (HCC). The aim of the present study was to establish a method of assessing the malignant potential of small hypervascular HCC using B-mode ultrasonography. METHODS One hundred and thirteen arterial hypervascular HCC nodules under 3 cm diagnosed by biopsy or surgical resection (20.5 ± 6.3 mm) were classified into two groups ultrasonographically: type 1 with (n = 27) and type 2 without (n = 86) a halo. Type 2 was categorized into three subgroups: type 2a, homogenous hyperechoic (n = 9); type 2b, hypoechoic with a smooth margin (n = 35); and type 2c, hypoechoic with an irregular or unclear margin (n = 42). RESULTS The mean diameter of type 2a nodules was significantly smaller than that of other HCC types (P

To establish a method of assessing the malignant potential of hepatocellular carcinoma (HCC) using magnetic resonance imaging (MRI).For 69 nodules [12 Edmondson (Ed)-I, 48 Ed-II, 9 Ed-III] in 54 HCC patients, signal intensity patterns and enhancement patterns of gadopentate dimeglumine (Gd-DTPA) dynamic studies were correlated with histological differentiation and serum lens culinaris agglutinin-reactive alpha-fetoprotein (AFP-L3) level, which is an indicator of poor prognosis.Hypointensity on T1-weighted imaging was seen in 17, 72, and 89% of Ed-I, Ed-II, and Ed-III HCCs, respectively (P 0.001). Meanwhile, hyperintensity on T2-weighted imaging was seen in 42, 88, and 89% (P 0.005). Tumor stain during the arterial phase of Gd dynamic MRI was seen in 75, 86, and 89%. Tumor stain washout during the portal phase was seen in 43% of Ed-II and 100% of Ed-III HCCs (P 0.005). In the Ed-II and Ed-III HCCs, hypointensity on T1-weighted imaging was seen in 65% of AFP-L3-negative HCCs and 90% of AFP-L3-positive HCCs (P = 0.071). Washout of tumor stain during the portal phase was seen in 39% of AFP-L3-negative HCCs and 75% of AFP-L3-positive HCCs (P 0.05).Although hyperintensity of tumor on T2-weighted imaging and arterial hypervascularity of tumor are considered to be useful for differential diagnosis between well differentiated HCCs and moderately/poorly differentiated HCCs, hypointensity of tumor on T1-weighted imaging and tumor stain washout during the portal phase of Gd-DTPA dynamic MRI reflected poorer histological differentiation of HCCs and correlated with AFP-L3 levels.

A 53-year-old woman was admitted because of a giant pancreatic tumor. Hypercalcemia and a high serum parathyroid hormone-related peptide (PTHrP) level were observed. A hypoglycemic attack occurred during pancreatectomy, and the surgical specimen revealed a PTHrP-secreting glucagonoma. Liver metastases developed 1 and 5.5 years later, and bone metastases appeared 6 years after surgery. Her serum PTHrP concentrations remained normal after surgery, despite re-elevation of the serum glucagon concentration after recurrence. The clinical course of this case illustrates the process of development of neuroendocrine tumors secreting two or more hormones.

Altered patterns of DNA methylation associated with Helicobacter pylori (HP) infection of gastric epithelial cells are thought to contribute to gastric cancer risk. However, it is unclear whether this increased risk reflects an infection-associated inflammatory response or the infection itself. In this study, we sought to clarify mechanisms in a gerbil model of gastric cancer where we showed that HP infection is causally involved in induction of aberrant DNA methylation. By genome-wide screening, CpG islands that were aberrantly methylated in gerbil gastric cancer cell lines were isolated, and 10 islands were shown to be specifically methylated only in gastric mucosae infected with HP. By temporal analysis, methylation levels in gastric epithelial cells started to increase at 5 to 10 weeks after infection and reached high levels by 50 weeks. When HP was eradicated, methylation levels markedly decreased 10 and 20 weeks later, but they remained higher than those in gerbils that were not infected by HP. Expression levels of several inflammation-related genes (CXCL2, IL-1β, NOS2, and TNF-α) paralleled the temporal changes of methylation levels. Significantly suppressing inflammation with the immunosuppressive drug cyclosporin A did not affect colonization by HP but blocked the induction of altered DNA methylation. Our findings argue that DNA methylation alterations that occur in gastric mucosae after HP infection are composed of transient components and permanent components, and that it is the infection-associated inflammatory response, rather than HP itself, which is responsible for inducing the altered DNA methylation. Cancer Res; 70(4); 1430–40

Two patients developed segmental, diffuse intrahepatic recurrence after percutaneous radiofrequency ablation (RFA) to treat a primary, solitary, and small (2.5 cm) hepatocellular carcinoma (HCC). Despite the size of the HCC, levels of the tumor markers (α-fetoprotein, α-fetoprotein-L3%, and des-γ-carboxyprothrombin) were all elevated before RFA, and tumors in both patients were contiguous with a major branch of the portal vein. Tumor biopsies of both patients revealed moderately differentiated HCC but diagnostic imaging showed an area of reduced tumor blood flow, suggesting a poorly differentiated component. Since early detection of post-RFA malignancies by standard ultrasonography and contrast-enhanced computed tomography was difficult, the most sensitive indicator of recurrence in these two patients was the elevated tumor markers. The diffuse intrahepatic recurrence was thought to be caused by increased intratumoral pressure during RFA, resulting in the dissemination of cancer cells through the contiguous portal vein. The clinical course of these tumors indicate that the choice of RFA should be carefully considered when treating specific subtype of HCC that is adjacent to main portal vein branch and involves a possible poorly differentiated component and that surgical resection or combinations of RFA with other treatment modalities such as transcatheter arterial chemoembolization should be considered as alternative treatment strategies.

To clarify the alterations in lower intestinal microflora induced by gastric acid reduction, the dynamics of 12 major genera or groups of bacteria comprising the microflora in feces and colonic contents were examined by quantitative real-time PCR in proton pump inhibitor-treated rats and in asymptomatic human subjects with hypochlorhydria. In both rat and human experiments, most genera or groups of intestinal microflora (facultative and obligate anaerobes) proliferated by gastric acid reduction, and marked and significant increases in the Lactobacilli group and Veillonella, oropharyngeal bacteria, were observed. In rats, potent gastric acid inhibition led to a marked and significant increase of intestinal bacteria, including the Bacteroidesfragilis group, while Bifidobacterium, a beneficial bacterial species, remained at a constant level. These results strongly indicate that the gastric acid barrier not only controls the colonization and growth of oropharyngeal bacteria, but also regulates the population and composition of lower intestinal microflora.

Background Both double-balloon enteroscopy (DBE) and video capsule endoscopy (VCE) have similar diagnostic yields for patients with overt obscure gastrointestinal bleeding (OGIB). However, the choice of initial modality is still controversial. The aim of this study was to show the clinical outcome of the strategy of initial VCE, followed by DBE. Methods Eighty-nine consecutive overt OGIB patients who had undergone VCE as the initial examination were analyzed. The interpreters of VCE evaluated the necessity of performing DBE, and the antegrade or retrograde route was chosen, depending on the transit time of the capsule. Results Thirty-seven patients (42 %) underwent DBE depending on the findings of VCE. Of these, bleeding sites in the small bowel were identified in 29 patients with the initially selected route (21 antegrade and 8 retrograde). The remaining 8 later underwent DBE by the other route, but 7 had no bleeding lesion, which was confirmed by second-look VCE. One remaining patient had a jejunal varix found by VCE, but DBE from either side could not reach the lesion. The sensitivity and negative predictive value of VCE were 100 %, both for the presence of small bowel lesions and the requirement of hemostasis in the small bowel; this indicated that VCE never misses relevant findings in the small bowel, and that negative VCE findings correspond to the lack of necessity for further examination. Conclusions VCE as the initial examination can efficiently identify overt OGIB patients who require DBE. The strategy of initial VCE for overt OGIB appears to be reasonable.

OBJECTIVES The role of contrast-enhanced sonography in the diagnosis of recurrent hepatocellular carcinoma is still unclear. This study aimed to clarify the usefulness and limitations of contrast-enhanced sonography with a perfluorobutane microbubble contrast agent (Sonazoid; Daiichi-Sankyo, Tokyo, Japan) after contrast-enhanced computed tomography (CT) for diagnosis of recurrent hepatocellular carcinoma and to establish its optimal use. METHODS A total of 514 patients, who were suspected to have recurrent hepatocellular carcinoma on contrast-enhanced CT, underwent contrast-enhanced sonography. Of 514 suspicious lesions, 484 were diagnosed as recurrent hepatocellular carcinomas, including 142 recurrent hepatocellular carcinomas measuring 1 cm or smaller in diameter. The largest lesion was evaluated in each patient. A final diagnosis of recurrent hepatocellular carcinoma after contrast-enhanced CT was reached on the basis of the typical hallmarks of hepatocellular carcinoma on any of the other contrast imaging modalities or by resected tissue or tumor enlargement during follow-up. RESULTS The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of contrast-enhanced CT were 68%, 93%, 99%, 15%, and 70%, respectively, and the values of contrast-enhanced sonography were 91%, 100%, 100%, 31%, and 91%, excluding 60 unassessable lesions on contrast-enhanced sonography. The diagnostic rate for recurrent hepatocellular carcinoma on contrast-enhanced sonography for lesions with an atypical enhancement pattern on contrast-enhanced CT was 71%. On multivariate analysis of factors contributing to the unassessability of contrast-enhanced sonography, lesion size, location, and abdominal wall thickness were independent factors. CONCLUSIONS Although the assessability of contrast-enhanced sonography depends on lesion size, location, and abdominal wall thickness, contrast-enhanced sonography after contrast-enhanced CT is useful for confirmative diagnosis of small recurrent hepatocellular carcinoma with an atypical enhancement pattern on contrast-enhanced CT, even for lesions measuring 1 cm or smaller in diameter.

To investigate the effects of Japanese apricot (JA) consumption on gastroesophageal reflux disease (GERD)-related symptoms.Participants included individuals living in Minabe-cho, a well-known JA-growing region, who received specific medical check-ups by the local community health service in 2010. GERD-related symptoms were examined in 1303 Japanese individuals using a validated questionnaire, the Frequency Scale for Symptoms of GERD (FSSG), which consists of 7 questions associated with acid reflux symptoms and 5 questions asking about gastrointestinal dysmotility symptoms. Each question was answered using a 4-point scale, with higher scores indicating more severe GERD-related symptoms. Subjects were divided into two groups according to their intake of dried and pickled JA: daily intake (≥ 1 JA daily) (392 subjects) and none or occasional intake (1 JA daily) (911 subjects). FSSG scores were compared between subjects who consumed JA daily and those who did not. Next, subjects were stratified by age, gender and Helicobacter pylori (H. pylori) status for subanalyses.Those who ate JA daily were significantly older than those who did not (60.6 ± 10.5 years vs 56.0 ± 11.0 years, P0.001). Total FSSG scores were significantly lower in subjects with daily JA intake than in those with none or only occasional intake (2.13 ± 3.14 vs 2.70 ± 3.82, P = 0.005). In particular, subjects who consumed JA daily showed significantly improved FSSG dysmotility scores compared with subjects who did not (1.05 ± 1.58 vs 1.46 ± 2.11, P0.001). In contrast, the FSSG reflux score did not differ between subjects with and without daily intake of JA (1.08 ± 1.90 vs 1.24 ± 2.11, P = 0.177). Subanalysis indicated that improvement in dysmotility by JA intake was specifically observed in non-elderly (1.24 ± 1.68 vs 1.62 ± 2.22, P = 0.005) and H. pylori-negative subjects (0.99 ± 1.58 vs 1.57 ± 2.06, P0.001). GERD patients (total FSSG score ≥ 8) were less frequently observed among subjects with daily intake of JA as compared to those without daily intake of JA (6.1% vs 9.7%, P = 0.040).Daily JA intake may improve digestive dysmotility symptoms, resulting in relief of GERD symptoms. The effect is more obvious in non-elderly and H. pylori-negative subjects.

Background and Aim Esophageal varices are usually treated with endoscopic injection sclerotherapy (EIS) or endoscopic band ligation (EBL). However, frequent recurrences of varices after those procedures have been problematic. Argon plasma coagulation (APC) after EIS may be effective for preventing varix recurrence and, in recent years, we have routinely carried out APC after EIS. The aim of the present study was to verify the effectiveness of APC for preventing recurrence of varices after EIS. Methods A case–control study was carried out using a historical control cohort in a single center. The varix recurrence rate in 62 patients (34 men and 28 women, median age; 69 years) who underwent APC after EIS for hemorrhagic or risky esophageal varices (APC group) was compared with that of control patients who did not undergo APC after EIS (control group). Age-, sex-, and liver function-matched two control subjects were selected for one case subject (control group). Recurrence of varices was defined as rupture of varices or reappearance of risky varices. Results The 1-year and 2-year recurrence rates of the APC group were 9.7% and 11.3%, respectively. In contrast, the rates of the control group were 29.0% and 34.7%, respectively. Kaplan–Meier curves showed a significantly lower recurrence rate in the APC group (P = 0.013, log–rank test). No APC-related severe adverse events were observed. Conclusion APC after EIS was safe and could significantly prevent recurrence of esophageal varices. Therefore, the addition of APC should be routinely carried out after EIS.

A previous multicenter prospective randomized study from Japan showed that Helicobacter pylori eradication reduced the development of metachronous gastric cancer (MGC) after endoscopic resection for early gastric cancer. MGC risk, however, is not eliminated; yet few studies have evaluated its long-term incidence and risk factors. In this study, we investigated the incidence of and risk factors for MGC in patients who underwent endoscopic resection for early gastric cancer with successful H. pylori eradication.A total of 594 patients who underwent endoscopic resection for early gastric cancer and successful H. pylori eradication at three institutions (National Cancer Center Hospital, University of Tokyo Hospital, and Wakayama Medical University Hospital) were analyzed retrospectively. Annual endoscopic surveillance was performed after initial endoscopic resection. MGC was defined as a gastric cancer newly detected at least 1 year after successful H. pylori eradication.Ninety-four MGCs were detected in 79 patients during the 4.5-year median follow-up period. Kaplan-Meier analysis showed the cumulative incidence of MGC 5 years after successful H. pylori eradication was 15.0 %; the incidence of MGC calculated by use of the person-year method was 29.9 cases per 1000 person-years. Multivariate analysis using the Cox proportional hazards model revealed that male sex, severe gastric mucosal atrophy, and multiple gastric cancers before successful H. pylori eradication were independent risk factors for MGC. Eleven percent of MGCs (10 of 94) were detected more than 5 years after successful H. pylori eradication.Surveillance endoscopy for MGC in patients who have undergone endoscopic resection for early gastric cancer should be performed even after successful H. pylori eradication.

Objectives An ultrasound contrast agent consisting of perfluorobutane microbubbles (Sonazoid; Daiichi Sankyo, Tokyo, Japan) accumulates in Kupffer cells, which thus enables Kupffer imaging. This study aimed to elucidate the association of defect patterns of hepatocellular carcinoma during the Kupffer phase of Sonazoid contrast-enhanced sonography with outcomes after radiofrequency ablation (RFA). Methods For this study, 226 patients with initial hypervascular hepatocellular carcinoma, who could be evaluated by contrast-enhanced sonography with Sonazoid before RFA, were analyzed. Patients were divided into 2 groups according to the tumor defect pattern during the Kupffer phase. The irregular-defect group was defined as patients with hepatocellular carcinoma that had a defect with an irregular margin, and the no-irregular-defect group was defined as patients with hepatocellular carcinoma that had either a defect with a smooth margin or no defect. Critical recurrence was defined as more than 3 intrahepatic recurrences, vascular invasion, dissemination, or metastasis. Results The irregular-defect and no-irregular-defect groups included 86 and 140 patients, respectively, and had cumulative 5-year critical recurrence rates of 49% and 17% (P < .01). Multivariate analysis indicated that the tumor diameter, lens culinaris agglutinin– reactive α-fetoprotein level, and defect pattern were independent factors related to critical recurrence. The cumulative 5-year overall survival rates for the irregular-defect and no-irregular-defect groups were 46% and 61% (P< .01). Multivariate analysis indicated that the Child-Pugh class, tumor diameter, lens culinaris agglutinin–reactive α-fetoprotein level, and defect pattern were independent factors related to survival. Conclusions The defect pattern of hepatocellular carcinoma during the Kupffer phase of Sonazoid contrast-enhanced sonography is associated with critical recurrence and survival after RFA.

Background and study aims: Early gastric cancers show gastric and/or intestinal phenotypes with specific mucin production profiles, and the phenotypes can vary with tumor progression. The aim of this study was to evaluate the correlation between tumor invasion patterns and phenotypes in the mucosa and submucosa of early gastric cancers. Methods: Phenotypic expressions of 44 endoscopically resected gastric cancers with submucosal invasion were evaluated immunohistochemically using MUC5AC and MUC6 as gastric and MUC2 and CD10 as intestinal phenotypic markers. Results: Cancers were classified into two patterns by invasion pattern: 19 collapsing pattern (C-pattern) tumors had cancer cells that invaded to the submucosa with expansive destruction of the muscularis mucosae, while 25 passing-through pattern (P-pattern) tumors formed focal cancer cell aggregations in the submucosa without massive destruction of the muscularis mucosae. Cancers with C-pattern invasion were likely to show similar phenotypes between the mucosa and submucosa, while phenotypes of cancers with P-pattern invasion were likely to differ between the two layers (rate of the same phenotypes: C-pattern 68% vs. P-pattern 28%, p = 0.008). Of 22 cancers with P-pattern invasion that included the intestinal phenotype component in the mucosa, 13 (59%) expressed the gastric phenotype alone in the submucosa. Conclusions: Phenotype presentation in the mucosa and submucosa differ by the invasion pattern in early gastric cancer. Tumors with P-pattern invasion are likely to express the gastric phenotype in the submucosa, regardless of phenotype in the mucosa, suggesting that such cancers might achieve submucosal invasion prior to intestinalization occurring in the mucosa.

Aberrant DNA methylation can be accumulated in normal-appearing tissues, and its degree can be correlated with cancer risk [Hattori, Genome Med, 8:10, 2016]. Such accumulation is especially prominent in inflammation-associated cancers, including gastric cancer. To bring the findings into cancer risk diagnosis, we conducted a multicenter prospective cohort study with 826 patients [Asada, Gut, 64:388, 2015]. Between 2008 and 2010, 826 patients after endoscopic treatment of gastric cancer and without current H. pylori infection were enrolled, and a gastric biopsy was collected. Methylation levels of pre-defined three marker genes (miR-124a-3, EMX1 and NKX6-1) were measured by quantitative methylation-specific PCR. Patients were classified into quartiles according to methylation levels of individual genes (Q1, the lowest; Q4, the highest). Among the 826 enrolled patients, 795 patients received annual follow-ups by endoscopy with a median period of 5.46 years (interquartile range: 3.95 - 6.09). By the end, 133 patients developed a metachronous gastric cancer, and 116 of them developed a cancer after 1 year of the enrollment (authentic metachronous cancer). Kaplan-Meier analysis showed that Q4 had a higher cumulative incidence of metachronous gastric cancer than Q1 with p-values of The results clearly showed that accumulation levels of aberrant DNA methylation can be used for cancer risk diagnosis. Even among the patients who carried a high risk of metachronous gastric cancer, cancer risk stratification was achieved. The strong influence of methylation accumulation on gastric cancer risk indicated a large contribution of aberrant DNA methylation to H. pylori infection-induced gastric carcinogenesis. Epigenetic cancer risk diagnosis is now becoming real. Citation Format: Masahiro Maeda, Takeshi Nakajima, Ichiro Oda, Taichi Shimazu, Nobutake Yamamichi, Takao Maekita, Kiyoshi Asada, Chizu Yokoi, Takayuki Ando, Takeichi Yoshida, Sohachi Nanjo, Mitsuhiro Fujishiro, Takuji Gotoda, Masao Ichinose, Toshikazu Ushijima. High impact of methylation accumulation on cancer risk: 5-year follow-up of a multicenter prospective cohort study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-092. doi:10.1158/1538-7445.AM2017-LB-092

We report a case of a 16-year-old male who suffered from Crohn's disease (CD) with esophageal involvement, showing remarkable improvement with granulocyte/monocyte adsorption (GMA). The patient had been diagnosed as ileocolic CD and was treated with 5-aminosalicylate. He was admitted to our hospital with symptoms of fever, diarrhea, and odynophagia. Endoscopic examinations revealed that the exacerbation of ileocolic ulcers, and advent of ulcers in esophagus. Because of the patient's refusal to receive corticosteroids, immunomodulators, or biologics, he underwent GMA twice a week. After 10 sessions of GMA, he entered remission with significant decrease in clinical activity. In addition, endoscopic examinations showed remarkable improvement of ileocolic ulcers and disappearance of esophageal lesions. No adverse events were observed. GMA could be effective for manifestations of CD in gastrointestinal tract other than ileum or colon. J. Clin. Apheresis, 2011. © 2011 Wiley-Liss, Inc.

The aim of the present study was to predict sustained virological response (SVR) to telaprevir with pegylated interferon (PEG-IFN) and ribavirin using viral response within 2 weeks after therapy initiation. Thirty-six patients with genotype 1 hepatitis C virus (HCV) and high viral load were treated by telaprevir-based triple therapy. SVR was achieved in 72% (26/36) of patients. Significant differences between the SVR group and non-SVR group were noted regarding response to prior PEG-IFN plus ribavirin, interleukin (IL)28B polymorphism, amino acid substitution at core 70, cirrhosis, hyaluronic acid level, and HCV-RNA reduction within 2 weeks. Setting 4.56 logIU/mL as the cut-off value for HCV-RNA reduction at 2 weeks, the sensitivity, specificity, positive predictive value, negative predictive value, and accuracy for predicting SVR were 77%, 86%, 95%, 50%, and 79%, respectively, and for neither the IL28B minor allele nor core 70 mutant were 80%, 71%, 91%, 50%, and 78%, respectively. In conclusion, evaluation of viral reduction at 2 weeks or the combination of IL28B polymorphism and amino acid substitution at core 70 are useful for predicting SVR to telaprevir with PEG-IFN and ribavirin therapy.

It has been reported that the apparent diffusion coefficient (ADC) value of hepatocellular carcinomas (HCC) on diffusion-weighted magnetic resonance imaging (MRI) is associated with their histological grade. The present study aimed to evaluate whether the signal intensity of small hypervascular HCC on the ADC map is related to the treatment outcome of radiofrequency ablation (RFA).Between February 2008 and August 2012, 136 consecutive patients with initial small hypervascular HCC (≤3 tumors and ≤3 cm in diameter) were examined by diffusion-weighted MRI before RFA. The signal intensities of HCC on the ADC map were visually compared with the surrounding liver and categorized as hypointense and non-hypointense. Critical recurrence was defined as more than three intrahepatic recurrences, recurrence with vascular invasion, seeding, dissemination and/or extrahepatic metastasis.The median follow up was 619 days. The cumulative 2-year recurrence rates of the hypointense and non-hypointense on the ADC map groups were 79% and 50% (P 0.001), respectively, with cumulative 2-year local recurrence rates of 18% and 7% (P = 0.014) and cumulative 2-year critical recurrence rates of 38% and 13% (P = 0.005), respectively. The cumulative 3-year survival rates were 60% and 82% (P = 0.007), respectively. On multivariate analysis, hypointensity on the ADC map was the strongest independent factor related to recurrence and survival after RFA.The signal intensity of HCC on the ADC map was strongly associated with outcome after RFA. These results suggest that treatment strategy should be determined carefully even for small HCC when they appear hypointense on the ADC map.