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Background/Aims Covered self-expandable metallic stents (CMSs) are widely used for malignant distal biliary obstructions (MDBOs) caused by pancreatic carcinoma. This study compared the efficacy and safety of the laser-cut-type and braided-type CMSs. Methods To palliate MDBOs caused by pancreatic carcinoma, the laser-cut-type CMSs was used from April 2014 to March 2017, and the braided-type CMSs was used from April 2017 to March 2019. The tested self-expandable metallic stents were equipped with different anti-migration systems. Results In total, 47 patients received CMSs for MDBOs (24 laser-cut type, 23 braided-type). The time to recurrent biliary obstruction (TRBO) was significantly longer in the braided-type CMSs (p=0.0008), and the median time to stent dysfunction or patient death was 141 and 265 days in the laser-cut-type CMSs and braided-type CMSs, respectively (p=0.0023). Stent migration was the major cause of stent dysfunction in both groups, which occurred in 37.5% of the laser-cut-type CMSs and 13.0% of the braided-type CMSs. There were no differences in the survival duration between the groups. Conclusions The TRBO was significantly longer for the braided-type CMSs with an anti-migration system than for the laser-cut-type. Stent migration tended to be less frequent with the braided-type CMSs than with the laser-cut-type CMSs.

Abstract Background To investigate the von Willebrand factor to ADAMTS13 ratio as a potential biomarker for early detection of hepatocellular carcinoma (HCC) in cirrhosis. Methods Serum levels of alpha-fetoprotein, des-γ-carboxy prothrombin, Lens culinaris agglutinin-reactive fraction of alpha-fetoprotein (alpha-fetoprotein-L3%), vascular endothelial growth factor, and vascular endothelial growth factor receptor-2, as well as the plasma levels of von Willebrand factor antigen (von Willebrand factor: Ag) and ADAMTS13 activity (ADAMTS13:AC), were evaluated in 41 cirrhotic patients with HCC undergoing radiofrequency ablation and in 20 cirrhotic patients without HCC. The diagnostic accuracy of each biomarker was evaluated using the receiver operating characteristic curve analysis. Results The von Willebrand factor: Ag and von Willebrand factor: Ag/ADAMTS13:AC ratios were significantly higher in cirrhotic patients with HCC than in those without HCC (p

Abstract Background Gastric cancer has a wide spectrum of clinical features, imaging manifestations, and pathology. Punctate calcifications in gastric cancer are infrequent but are usually found in mucinous adenocarcinoma. However, there have only been a few autopsy case reports describing the correlation between the radiology and pathology findings of calcified mucinous adenocarcinoma of the stomach. We present an autopsy case of mucinous gastric adenocarcinoma with iris metastases as the initial symptom. Case presentation A 74-year-old Japanese woman presented with blurred vision. Her treating ophthalmologist diagnosed acute iritis with secondary glaucoma. The histopathological and immunohistochemical features of a trabeculectomy specimen favored metastatic carcinoma, most likely of gastrointestinal tract origin. Esophagogastroduodenoscopy revealed multiple irregularly shaped ulcerative lesions, multiple erosions, and thickened folds in the corpus of her stomach. Histologic examination of a gastric tissue specimen obtained by endoscopic biopsy revealed poorly differentiated carcinoma with signet ring cell features. Computed tomography revealed a tumor with multiple punctate calcifications in the thickened gastric wall with diffuse low attenuation and multiple lymph node metastases, including the para-aortic lymph nodes, and peritoneal dissemination. She was diagnosed with stage IV gastric cancer (T4N3M1) and underwent seven cycles of 5-weekly TS-1, a novel oral fluoropyrimidine derivative, plus cisplatin therapy. Serial follow-up computed tomography revealed successive increases in the gastric wall calcifications. Her disease stabilized, but she died of aspiration pneumonia 8 months after the first visit. Autopsy tissue specimens had miliary, punctate calcifications present in abundant extracellular mucin pools in the submucosa, corresponding to the thickened low-attenuating middle layer on computed tomography. The final diagnosis was mucinous gastric adenocarcinoma because mucinous adenocarcinoma is diagnosed when more than half of the tumor area contains extracellular mucin pools. Conclusions We report the pathology and computed tomography imaging characteristics of a case of calcified mucinous adenocarcinoma of the stomach metastatic to the iris, including findings at autopsy. Metastatic carcinomas in the iris originating in the stomach are exceedingly rare. Multiple punctate calcifications were present in pools of extracellular mucin, a diagnostic clue for mucinous adenocarcinoma. Possible mechanisms underlying scattered punctuate calcifications in gastric mucinous adenocarcinoma warrant further investigation.

Background/Aims L-carnitine not only alleviates hyperammonemia and reduces muscle cramps in patients with liver cirrhosis, but also improves anemia in patients with chronic hepatitis and renal dysfunction. This study prospectively evaluated the preventative efficacy of L-carnitine supplementation against hemolytic anemia during antiviral treatment using ribavirin in patients with hepatitis C virus (HCV)-related chronic liver disease. Methods A total of 41 patients with chronic hepatitis were consecutively enrolled in this study. Group A (n=22) received sofosbuvir plus ribavirin for 3 months, whereas group B (n=19) was treated with sofosbuvir, ribavirin, and L-carnitine. Hemoglobin concentration changes, the effects of antiviral treatment, and the health status of patients were analyzed using short form-8 questionnaires. Results A significantly smaller decrease in hemoglobin concentration was observed in group B compared to group A at every time point. Moreover, the prescribed dose intensity of ribavirin in group B was higher than that of group A, resulting in a higher ratio of sustained virological response (SVR) 24 in group B compared with group A. The physical function of patients in group B was also significantly improved compared to group A at the end of antiviral treatment. Conclusions L-carnitine supplementation alleviates ribavirin-induced hemolytic anemia in patients with HCV and helps relieve the physical burden of treatment with ribavirin-containing regimens. These advantages significantly increase the likelihood of achieving SVR.

Abstract Background Insulin resistance (IR) is closely associated with the progression of hepatocellular carcinoma (HCC). Acyclic retinoid (ACR) targets retinoid X receptor α and reportedly prevents HCC recurrence in clinical practice. Angiotensin-II receptor blocker (ARB) can also inhibit experimental hepatocarcinogenesis and HCC development. These are reported to suppress IR-based hepatocarcinogenesis; however, limited data are available regarding the combined effects of both these agents. This study aimed to investigate the combined chemopreventive effect of ACR and ARB on liver tumorigenesis on rats with congenital diabetes. Methods Male diabetic Otsuka Long-Evans Tokushima Fatty (OLETF) and non-diabetic Long-Evans Tokushima Otsuka (LETO) rats underwent 70% partial hepatectomy following a single intraperitoneal injection of diethylnitrosamine to induce hepatocarcinogenesis and the administration of ACR (peretinoin, 40 mg/kg/day), ARB (losartan, 30 mg/kg/day), and a combination of ACR and ARB. Six weeks thereafter, we assessed the size and number of the pre-neoplastic lesions (PNL) as well as the altered angiogenesis, oxidative stress, and chronic inflammation in the liver. Moreover, we assessed the effects exerted by ACR and ARB on in vitro cell growth in human HCC cell lines and human umbilical vascular endothelial cells (HUVECs). Results OLETF rats showed increase in the size and number of PNLs compared to LETO rats. ACR suppressed the augmentation in size and number of PNLs in the OLETF rats with suppression of cell growth, intrahepatic angiogenesis, lipid peroxidation, oxidative DNA damage, and proinflammatory cytokine production. Combining ACR with ARB enhanced the tumor-suppressive effect and ameliorated intrahepatic angiogenesis, lipid peroxidation, and proinflammatory status; however, cell growth and oxidative DNA damage remained unchanged. IR-mimetic condition accelerated in vitro proliferative activity in human HCC cells, while ACR inhibited this proliferation with G0/G1 arrest and apoptosis. Furthermore, ACR and ARB significantly attenuated the HUVECs proliferation and tubular formation under the IR-mimetic condition, and a combination of both agents demonstrated greater inhibitory effects on HUVEC growth than each single treatment. Conclusions ACR and ARB exert a combined inhibitory effect against IR-based hepatocarcinogenesis by the inhibition of cell growth, intrahepatic angiogenesis, and oxidative stress. Thus, this combination therapy appears to hold potential as a chemopreventive treatment therapy against HCC.

Abstract Background We present the first description of en bloc endoscopic submucosal dissection (ESD) for total circumferential Barrett’s adenocarcinoma, predominantly of the long-segment Barrett’s esophagus (LSBE), with a 2-year follow-up and management strategies for esophageal stricture prevention. Case presentation A 59-year-old man was diagnosed with LSBE and Barrett’s adenocarcinoma by esophagogastroduodenoscopy (EGD). A 55-mm-long circumferential tumor was completely resected by ESD. Histopathology revealed a well-differentiated adenocarcinoma within the LSBE superficial muscularis mucosa. For post-ESD stricture prevention, the patient underwent an endoscopic triamcinolone injection administration, oral prednisolone administration, and preemptive endoscopic balloon dilatation. Two years later, there is no evidence of esophageal stricture or recurrence. Conclusions ESD appears to be a safe, effective option for total circumferential Barrett’s adenocarcinoma in LSBE.

Background: Hepatic stellate cell (HSC) activation is essential for the development of liver fibrosis. Epigenetic machinery, such as DNA methylation, is largely involved in the regulation of gene expression during HSC activation. Although the pharmacological DNA demethylation of HSC using 5-aza-2′-deoxycytidine (5-aza-dC) yielded an antifibrotic effect, this drug has been reported to induce excessive cytotoxicity at a high dose. Hydralazine (HDZ), an antihypertensive agent, also exhibits non-nucleoside demethylating activity. However, the effect of HDZ on HSC activation remains unclear. In this study, we performed a combined treatment with 5-aza-dC and HDZ to obtain an enhanced antifibrotic effect with lower cytotoxicity. Methods: HSC-T6 cells were used as a rat HSC cell line in this study. The cells were cultivated together with 1 µM 5-Aza-dC and/or 10 µg/mL of HDZ, which were refreshed every 24 h until the 96 h treatment ended. Cell proliferation was measured using the WST-1 assay. The mRNA expression levels of peptidylprolyl isomerase A (Ppia), an internal control gene, collagen type I alpha 1 (Cola1), RAS protein activator like 1 (Rasal1), and phosphatase and tensin homolog deleted from chromosome 10 (Pten) were analyzed using quantitative reverse transcription polymerase chain reaction. Results: The percentage cell viability with 5-aza-dC, HDZ, and combined treatment vs. the vehicle-only control was 101.4 ± 2.5, 95.2 ± 5.7, and 79.2 ± 0.7 (p < 0.01 for 5-aza-dC and p < 0.01 for HDZ), respectively, in the 48 h treatment, and 52.4 ± 5.6, 65.9 ± 3.4, and 29.9 ± 1.3 (p < 0.01 for 5-aza-dC and p < 0.01 for HDZ), respectively, in the 96 h treatment. 5-Aza-dC and the combined treatment markedly decreased Cola1 mRNA levels. Accordingly, the expression levels of Rasal1 and Pten, which are antifibrotic genes, were increased by treatment after the 5-aza-dC and combined treatments. Moreover, single treatment with HDZ did not affect the expression levels of Cola1, Rasal1, or Pten. These results suggest that HDZ sensitizes to the antifibrotic effect of 5-aza-dC in HSC-T6 cells. The molecular mechanism underlying the sensitization to the antifibrotic effect of 5-aza-dC by HDZ remains to be elucidated. The expression levels of rat equilibrative nucleoside transporter genes (rEnt1, rEnt2, and rEnt3) were not affected by HDZ in this study. Conclusions: Further confirmation using primary HSCs and in vivo animal models is desirable, but combined treatment with 5-aza-dC and HDZ may be an effective therapy for liver fibrosis without severe adverse effects.

Abstract A new subtype of serrated lesions, superficially serrated adenoma (SuSA), has been proposed as a lesion that histopathologically exhibits the morphological features of both conventional adenomas and serrated lesions and is difficult to classify as either one. SuSA has been elucidated to be a precursor lesion of KRAS‐type traditional serrated adenoma. It has also been reported that SuSA may have malignant potential. We report a case treated with endoscopic submucosal dissection and detailed observation. Endoscopy revealed a raised lesion with a two‐tier raised appearance in the sigmoid colon: a tall pinecone‐like reddish structure and flattened whitish elevation on white light imaging. Magnifying narrow‐band imaging revealed conspicuous blood vessels in the pinecone‐like structure and slightly dilated reticular vessels in the flattened area. Crystal violet staining showed that the pinecone‐like structure had a type IVH pit pattern and the flattened area had a stellate to slightly elongated type IIIH pit pattern diagnosed based on Kudo's classification and other pit pattern classification systems. Ki67‐positive cells were distributed in the basal and middle layers of the gland in the flattened elevated area. Genetic analysis results were positive for KRAS mutation and negative for BRAF mutation. Histopathological examination revealed a traditional serrated adenoma in the pinecone‐like structure and SuSA in the adjacent flattened elevated area.

Periostin is a 90‑kDa extracellular matrix protein, which is secreted primarily from fibroblasts and is expressed in the lungs, kidneys and heart valves. Angiotensin II (AT‑II) serves pivotal roles in the pathogenesis of several diseases with accompanying fibrosis, including chronic liver diseases. AT‑II induces periostin expression by regulating transforming growth factor‑β1 (TGF‑β1)/Smad signaling during cardiac fibrosis. The aim of the present study was to investigate the interaction between AT‑II and periostin during liver fibrosis development. Fischer 344 rats were fed a choline‑deficient L‑amino‑acid (CDAA)‑defined diet for 12 weeks to simulate the development of steatohepatitis with liver fibrosis. Losartan, an AT‑II type I receptor blocker, was administered to inhibit the effect of AT‑II. The therapeutic effect of losartan on hepatic fibrosis development and on periostin expression was then evaluated. Several in vitro experiments were performed to examine the mechanisms underlying the interaction between AT‑II and periostin in activated hepatic stellate cells (Ac‑HSCs). Treatment with losartan suppressed the development of liver fibrosis induced by the CDAA diet, and reduced hepatic periostin expression. In addition, losartan treatment suppressed hepatic Ac‑HSC expansion and hepatic TGF‑β1 expression. In vitro analysis using LX2 HSC cells indicated that AT‑II can augment TGF‑β1 and collagen type I α1 mRNA expression via periostin expression, suggesting that the interaction between AT‑II and periostin may serve a role in liver fibrosis development. In conclusion, blockade of AT‑II‑induced periostin may suppress the progression of liver fibrosis development. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC) is prone to recurrence following curative treatment. The purpose of the present study was to identify the predisposing factors of HCC recurrence following complete remission achieved by transarterial chemoembolization (TACE). A retrospective cohort study of 70 consecutive patients with HCC who underwent TACE as the initial treatment was conducted. The patients were divided into two groups according to their 1-year disease-free survival (DFS) status; the early recurrence group (ER group; n=32), with HCC recurring within 1 year of initial TACE; and the non-early recurrence group (NER group; n=38), who did not experience recurrence within 1 year. The parameters identified as significantly associated with DFS time on univariate analysis were aspartate aminotransferase (AST), alanine aminotransferase and a-fetoprotein levels, as well as the tumor number (P=0.003, P=0.027, P=0.002 and P=0.005, respectively). Multivariate analysis revealed that AST levels and tumor number were significantly associated with a shorter DFS period (P=0.009 and P=0.038, respectively). The Mantel-Haenszel test revealed a significant trend of decreasing DFS with increasing tumor number. Among the patients with HCC in the ER group, locoregional recurrence occurred more frequently in those who received TACE alone compared with those treated with TACE combined with radiofrequency ablation treatment. In summary, multinodularity of HCC is the most potent predictive factor for the recurrence of HCC within 1 year of initial TACE. [ABSTRACT FROM AUTHOR]

Abstract Rectal tonsils are localized hyperplastic lymphoid tissues in the rectum, and the initial endoscopic findings are consistent with those for neoplastic lesions. However, rectal tonsils are benign entities, and the diagnosis should be made cautiously. A 70‐year‐old man presented with pain on defecation with rectal bleeding. Colonoscopy revealed a 3‐cm protruding mass in the rectum with mucosal erosion, but no malignant features were observed on forceps biopsy. Endoscopic ultrasonography (EUS) showed that the lesion was a hypoechoic mass without blood flow. Fine needle aspiration under EUS revealed no malignant components, although the size of the lesion had shrunk, and symptoms, such as blood‐stained stool, tenesmus, and discomfort during defecation, had resolved. A second forceps biopsy showed intermediate‐sized lymphocytes without lymphoepithelial lesions. Based on immunostaining, the lesion was diagnosed as a rectal tonsil. Rectal tonsils occur due to localized proliferation of reactive lymphoid follicles in the submucosa or muscularis mucosa. However, endoscopic diagnosis is difficult since less invasive treatment is performed for neoplastic lesions of the rectum to preserve the function of the anal sphincter. Diagnosis and treatment of small lesions might be possible by endoscopic resection; however, for relatively large lesions, formulating a diagnosis based only on biopsy specimens becomes even more difficult. Therefore, repeated biopsies might be helpful for the diagnosis of rectal tonsils and for excluding other neoplasms.

Seawater reverse osmosis (SWRO) is the most energy-efficient process for desalination to produce drinking water from seawater. However, its sustainability is still challenged by membrane fouling. Appropriate feed water quality is one of the crucial prerequisites for SWRO operation. In the current study, a ceramic adsorption filter (CAF), which was predominantly coated with an aluminum-based adsorbent (i.e., Alumina, Al2O3), was employed to enhance the pretreatment performance of SWRO. The fouling performance of SWRO pre-treated with a CAF was evaluated by feeding with real ultrafiltration (UF)-filtrated seawater collected from a seawater desalination R&D facility in Singapore. The flux decline profile showed that the presence of CAF after UF could mitigate around 10–30% of SWRO fouling. Based on the autopsy of the fouled SWRO membranes, it was observed that SWRO with CAF pre-treatment and daily regeneration could alleviate around 77.5% of Ca-induced inorganic fouling as well as 76% of lower biofouling. The present work highlights the potential of applying adsorption technology to enhance pre-treatment performance to extend the lifespan of SWRO membranes. Coupling the adsorbents on a ceramic filter should be a useful way to ease their implementation, i.e., inline adsorption and re-generation.

Heyde syndrome describes the triad of aortic stenosis, acquired coagulopathy, and anemia due to bleeding from intestinal angiodysplasia. An 87-year-old man with iron deficiency anemia due to melena was admitted to our hospital. On examination, a systolic murmur was heard and echocardiography confirmed the presence of aortic stenosis. Esophagogastroduodenoscopy and colonoscopy were unremarkable. Capsule endoscopy and double balloon endoscopy revealed angiodysplasia throughout the small intestine. Laboratory investigations were significant for reduced plasma levels of high molecular weight von Willebrand factor multimers. On the basis of these findings, the patient was diagnosed with Heyde syndrome. The patient required frequent blood transfusions because of the intestinal bleeding, and underwent bioprosthetic aortic valve replacement. Twenty months after the operation, the gastrointestinal bleeding resolved and the patient no longer required blood transfusions. This is the first case report to describe an improvement in bleeding from angiodysplasia, one year after aortic valve replacement. It demonstrates the effective treatment of Heyde syndrome with aortic valve replacement, and highlights the importance of considering this differential diagnosis when evaluating patients presenting with repeated episodes of gastrointestinal bleeding and a concurrent systolic murmur. [ABSTRACT FROM AUTHOR]

Aim: To clarify whether Agtr1a methylation is involved in the development of nonalcoholic steatohepatitis (NASH)-related liver fibrosis in adult rats., Methods: A choline-deficient amino acid (CDAA) diet model was employed for methylation analysis of NASH-related liver fibrosis. Agtr1a methylation levels were measured in the livers of CDAA- and control choline-sufficient amino acid (CSAA)-fed rats for 8 and 12 wk using quantitative methylation-specific PCR. Hepatic stellate cells (HSCs) were isolated by collagenase digestion of the liver, followed by centrifugation of the crude cell suspension through a density gradient. Agtr1a methylation and its gene expression were also analyzed during the activation of HSCs., Results: The mean levels of Agtr1a methylation in the livers of CDAA-fed rats (11.5% and 18.6% at 8 and 12 wk, respectively) tended to be higher ( P = 0.06 and 0.09, respectively) than those in the livers of CSAA-fed rats (2.1% and 5.3% at 8 and 12 wk, respectively). Agtr1a was not methylated at all in quiescent HSCs, but was clearly methylated in activated HSCs (13.8%, P < 0.01). Interestingly, although Agtr1a was hypermethylated, the Agtr1a mRNA level increased up to 2.2-fold ( P < 0.05) in activated HSCs compared with that in quiescent HSCs, suggesting that Agtr1a methylation did not silence its expression but instead had the potential to upregulate its expression. These findings indicate that Agtr1a methylation and its upregulation of gene expression are associated with the development of NASH-related liver fibrosis., Conclusion: This is the first study to show that DNA methylation is potentially involved in the regulation of a renin-angiotensin system-related gene expression during liver fibrosis., Competing Interests: Conflict-of-interest statement: The authors declare that they have no conflicts of interest.