Intestinal Epithelial Deletion of Sphk1 Prevents Colitis-Associated Cancer Development by Inhibition of Epithelial STAT3 Activation.

BACKGROUND AND AIMS: Colitis-associated cancer (CAC) is one of the most serious complications in patients with inflammatory bowel disease. Sphingosine kinase 1 (Sphk1) is a key enzyme in the sphingolipid pathway and has oncogene potential for inducing both initiation and progression of tumors. The aim of this work is to characterize the role of epithelial Sphk1 in mouse colitis and CAC models. METHODS: We investigated the roles of Sphk1 in CAC by conditional deletion of Sphk1 in intestinal epithelial cells (IECs). RESULTS: CAC was induced in both Sphk1ΔIEC/ApcMin/+ and Sphk1IEC/ApcMin/+ mice by administration of 2% dextran sodium sulfate (DSS) for 7 days. Genetic deletion of Sphk1 significantly reduced the number and size of tumors in ApcMin/+ mice. Histologic grade was more severe in Sphk1ΔIEC/ApcMin/+ mice compared with Sphk1IEC/ApcMin/+ mice (invasive carcinoma, 71% versus 13%, p < 0.05). Deletion of Sphk1 decreased mucosal proliferation and inhibited STAT3 activation and genetic expression of cyclin D1 and cMyc in tumor cells. Conditional deletion of Sphk1 using CRISPR-Cas9 in HCT 116 cells inhibited interleukin (IL)-6-mediated STAT3 activation. CONCLUSIONS: Epithelial conditional deletion of Sphk1 inhibits CAC in ApcMin/+-DSS models in mice by inhibiting STAT3 activation and its target signaling pathways.

Survival improvement and prognostic factors in recent management of extrahepatic cholangiocarcinoma: A single-center study.

BACKGROUND: Cholangiocarcinoma was considered as a dismal disease with very poor prognosis until recently. Cholangiocarcinoma is increasingly found due to increased life expectancy. Although surgical and medical management were advanced recently, data on the prognosis, especially extrahepatic cholangiocarcinoma (ECC), were limited. This study aimed to identify clinicopathologic features and prognosis of patients with ECC. METHODS: Patients followed up and diagnosed with ECC between January 2014 and December 2016 at a tertiary hospital were included, whereas those with intrahepatic cholangiocarcinoma, gallbladder cancer, and ampullary cancer were excluded. RESULTS: A total of 83 patients were followed after the treatment (49 men and 34 women; median age 73.3 years). Cancer location was classified as distal common bile duct (25 patients), proximal common bile duct (24 patients), common hepatic duct (20 patients), and hilar (14 patients). About 14.5% of patients had history of another malignant neoplasm, and 24.1% patients had chronic illness. Surgical resection was performed in 54 patients (65%) and dysplasia was combined in 63% (34/54). Adjuvant chemotherapy was performed in 54% (29/54), but only 7 underwent palliative chemotherapy in 29 nonsurgical patients. The median overall survival in all patients was 30.9 months. In analyzing the treatment modality, median survival of adjuvant chemotherapy, surgery only, palliative chemotherapy, and supportive care groups were 42.9, 30.9, 12.0, and 8.9 months, respectively (P < 0.05). In the Cox regression analysis of survival, age, surgical resection, chemotherapy, and comorbidity were significant prognostic factors, and the comorbidity was the only significant prognostic factor in the multivariable analysis (hazard ratio [HR] = 2.80; 95% CI: 1.32-5.95; P = 0.007). In a subgroup analysis of surgical patients, the presence of dysplasia was a favorable prognostic factor in the multivariable analysis (HR = 0.29; 95% CI: 0.09-0.91; P = 0.033). CONCLUSIONS: The overall survival of patients with ECC was quite high and increased with chemotherapy. Absence of comorbidity, and presence of dysplasia were good prognostic factors.

Clinicopathologic Study of Biliary Intraepithelial Neoplasia in Cholangiocarcinoma.

BACKGROUNDS AND AIMS: Biliary intraepithelial neoplasia (BilIN) is a precursor of cholangiocarcinoma (CC) and it has been associated with several chronic inflammatory conditions. This study aimed to elucidate the prevalence of BilIN in CC and its clinicopathological significance. METHODS: Medical records of 193 patients with histologically confirmed CC were analyzed. We reviewed the pathology findings of 48 patients who underwent curative surgery for CC. RESULTS: Of the 48 patients analyzed, 34 and 14 patients had extrahepatic and intrahepatic CC respectively. BilIN was detected in 28 patients (58%) and showed a significantly higher prevalence in extrahepatic CC (75%) than in intrahepatic CC (21%; p < 0.001). In the subgroup of 34 patients with extrahepatic CC, 25 and 9 patients were BilIN positive and negative respectively. Poor differentiation and T3 stage were significantly more common in the BilIN-negative group than in the BilIN-positive group (p < 0.05). The expression of MUC5AC, p53, and loss of Smad4 showed no difference between BilIN-positive CC and in BilIN-negative CC, but the Ki-67 expression was significantly higher (p < 0.05). CONCLUSION: BilIN-positive CC showed less invasiveness than negative cases. The Ki-67 expression was significantly higher in BilIN-positive CC.

Usefulness of CA 19-9 for pancreatic cancer screening in patients with new-onset diabetes.

BACKGROUND: Generally, carbohydrate antigen 19-9 (CA 19-9) is not useful for screening pancreatic cancer in the asymptomatic general population. This study aimed to evaluate the utility of CA 19-9 level as a screening indicator of pancreatic cancer in asymptomatic patients with new-onset diabetes. METHODS: We retrospectively reviewed the medical records of patients who visited our health promotion center for health check-ups without cancer related symptoms from January 2005 to January 2014, and were newly diagnosed with diabetes mellitus (DM) within 2 years before their visit. RESULTS: Of the 5111 asymptomatic patients with new-onset DM (<2 years) selected for analyses, 87 (1.7%) eventually developed pancreatic cancer after the health check-up. In the subgroup of 322 patients with high total bilirubin levels (>1.7 mg/dL) at the screening time, 42 (73.7%) of 57 patients with high CA 19-9 levels (>37 IU/mL) had been diagnosed as pancreatic cancer during follow-up period and 12 (4.5%) of 265 patients with normal CA 19-9 levels had finally developed pancreatic cancer (OR = 16.3). In the subgroup of 4789 patients with normal bilirubin levels, pancreatic cancer had been detected in 20 (3.8%) of 522 patients with high CA 19-9 level, while only 13 (0.3%) in 4267 patients with normal CA 19-9 levels (OR = 12.6), respectively. CONCLUSION: CA 19-9 levels after a diagnosis of new-onset DM could be a useful biomarker of pancreatic cancer, especially in patients with high serum bilirubin.

Treatment of Severe Alcoholic Hepatitis With Corticosteroid, Pentoxifylline, or Dual Therapy: A Systematic Review and Meta-Analysis.

BACKGROUND AND AIMS: Although both corticosteroids and pentoxifylline are currently recommended drugs for the treatment of patients with severe alcoholic hepatitis, their effectiveness in reducing mortality remains unclear. In this systematic review, we aimed to evaluate the therapeutic and adverse effects of corticosteroids, pentoxifylline, and combination by using Cochrane methodology and therefore determine optimal treatment for severe alcoholic hepatitis. METHODS: We searched MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials from their inauguration until October 2015. Combinations of the following keywords and controlled vocabularies were searched: alcoholic hepatitis, corticosteroid, and pentoxifylline. RESULTS: A total of 2639 patients from 25 studies were included. The treatment groups did not differ significantly in terms of overall mortality. Analysis of 1-month mortality revealed corticosteroid monotherapy reduced mortality compared with placebo (OR=0.58; 95% CI, 0.34-0.98; P=0.04), but pentoxifylline monotherapy did not. The mortality with dual therapy was similar to corticosteroid monotherapy (OR=0.91; 95% CI, 0.62-1.34; P=0.63). However, dual therapy decreased the incidences of hepatorenal syndrome or acute kidney injury (OR=0.47; 95% CI, 0.26-0.86; P=0.01) and the infection risk (OR=0.63; 95% CI, 0.41-0.97; P=0.04) significantly more than corticosteroid monotherapy did. None of the treatments conferred any medium-term or long-term survival benefits in the present study. CONCLUSIONS: Dual therapy was not inferior to corticosteroid monotherapy and could reduce the incidence of hepatorenal syndrome or acute kidney injury and risk of infection. Therefore, dual therapy might be considered in treatment of patients with severe alcoholic hepatitis.

Inhibition of Ceramide Decreased the Expression of ATP-Binding Cassette Transporter G5/8 mRNA in an Animal Model of Cholesterol Gallstone.

BACKGROUND: The increased risk of gallstone has been reported in patients with ATP-binding cassette (ABC) transporter polymorphism. The half-transporters ABCG5 and ABCG8 mediate the efflux of cholesterol in hepatocytes and the intestine. We investigated whether ceramide plays a role in cholesterol efflux through the ABC transporters. METHODS: Six-week-old C57BL/6J mice were assigned to 3 groups. The normal group (n = 5) was fed a normal chow diet, the cholesterol group (n = 10) was fed a lithogenic diet, and the myriocin group (n = 15) was fed the lithogenic diet and myriocin, a specific inhibitor of serine-palmitoyl transferase. After 6 weeks, the ABCG5 and ABCG8 transporters were analyzed. RESULTS: The rate of cholesterol gallstone formation in cholesterol group was also higher than that in normal and myriocin groups (0, 70, and 40%, respectively). ABCG5 and ABCG8 mRNA levels were significantly increased in cholesterol group and less increased in myriocin group, relative to that in normal group (p < 0.05). CONCLUSIONS: The inhibition of ceramide biosynthesis by myriocin suppressed gallstone formation and ABCG5/8 mRNA expression. We expect that ceramide's role as a regulator of the ABCG5/8 transporter might be linked to cholesterol gallstone formation.

Radiation recall gastritis secondary to combination of gemcitabine and erlotinib in pancreatic cancer and response to PPI - a case report.

BACKGROUND: Radiation recall gastritis is rare but can be induced after concurrent chemoradiation for pancreatic cancer. We report a patient with pancreatic cancer who developed radiation-recall gastritis related to a combination of gemcitabine and erlotinib. CASE PRESENTATION: A 54-year-old female with unresectable pancreatic cancer received gemcitabine in combination with radiation therapy followed by chemotherapy with gemcitabine and erlotinib. After completing 2 cycles of chemotherapy, the patient had epigastric pain, nausea, and vomiting. Abdominal computed tomography (CT) scan revealed diffuse wall thickening of the stomach, and esophagogastroduodenoscopy (EGD) showed multiple gastric ulcers. The patient was treated with proton pump inhibitors (PPI) and was continued on maintenance chemotherapy. Two months later, the patient presented with the similar symptoms and persistent gastric ulcers were observed during subsequent EGD. Nevertheless, the patient's symptom had resolved with PPI therapy. Thus, the patient underwent maintenance chemotherapy with gemcitabine and erlotinib for additional 4 cycles. Eventually, follow-up abdominal CT Scan and EGD at 6 months demonstrated resolution of the gastric ulcers. CONCLUSIONS: Physicians should be aware of the possibility of radiation recall gastritis associated with a combination of gemcitabine and erlotinib. Administration of PPIs may mitigate the adverse effects of gemcitabine and erlotinib in the presence of radiation recall gastritis; however further studies are warranted.

Cholangiocarcinoma Risk as Long-term Outcome After Hepatic Resection in the Hepatolithiasis Patients.

BACKGROUND: Hepatolithiasis is a well-known risk factor of cholangiocarcinoma. Despite advances in diagnostic modalities, diagnosing cholangiocarcinoma in patients with hepatolithiasis still challenging and there are not enough reports on the incidence of cholangiocarcinoma in patient with hepatolithiasis after treatment. We aimed to evaluate the incidence and clinical characteristics of cholangiocarcinoma in patients with hepatolithiasis who underwent liver resection or non-resection. METHODS: Among a total of 257 patients who received treatment for hepatolithiasis, 236 patients were eligible for analysis. Exclusion criteria were follow-up period less than 9 months, preoperative diagnosis of cholangiocarcinoma, occurrence of cholangiocarcinoma within 1 year after treatment. Completeness of stone clearance was defined when there was no intrahepatic duct stone during whole follow-up period. A retrospective study was done to analyze the patients' characteristics, the results and complications of the procedure, and the long-term outcomes for these patients. Kaplan-Meier method and cox proportional regression were used for statistical analysis. RESULTS: 95 patients underwent hepatic resection (resection group) and 144 patients did not (non-resection group). Complete stone clearance was 71% (67/95) in resection group and 41% (58/141) in non-resection group (p < 0.001). The incidence of cholangiocarcinoma was 6.8% (16/236) during follow-up period (mean 41 ± 41 months). Cholangiocarcinoma occurred 6.3% (6/95) and 7.1% (10/141) in resection and non-resection group, respectively. There was no significant difference in survival between two groups (p = 0.254). In analysis of according to completeness of stone clearance regardless of treatment modality, cholangiocarcinoma incidence was higher in patients with residual stone (10.4%) than complete stone removal (3.3%) (p = 0.263). On multivariate analysis, none of the factors (age, gender, CA19-9, stone location, bile duct stenosis, liver atrophy, stone recurrence, residual stone, and hepatic resection) showed relationship with the incidence of cholangiocarcinoma. CONCLUSION: Hepatic resection for hepatolithiasis is considered to have a limited value in preventing cholangiocarcinoma and the patients should be carefully followed even after hepatic resection. A combination of different treatment modalities is necessary to decrease the residual stone and improve the outcome of the patients with hepatolithiasis.

Digital design of a surgical guide for placement of definitive implants before orthodontic treatment.

Interdisciplinary treatment planning is an essential part of orthodontic therapy for patients with partial edentulism, especially when dental implants are to serve initially as anchorage and ultimately as prosthetic abutments for the definitive fixed restoration. A technique is presented for designing and fabricating a computed tomography-based surgical guide to place definitive implants before orthodontic therapy. First, the diagnostic cast and the orthodontic tooth arrangement and diagnostic waxing cast are scanned with a 3-dimensional optical scanner. Three-dimensional renderings of these scans are then merged and superimposed onto the cone beam computed tomography (CBCT) image with implant planning software to develop definitive implant positions. A custom surgical guide is fabricated from these data.

Comparison of the methods for tumor response assessment in patients with hepatocellular carcinoma undergoing transarterial chemoembolization.

BACKGROUND & AIMS: Recently, new methods, including the concept of viable enhancing tumor such as EASL and mRECIST, have been proposed for substitution of the conventional WHO and RECIST criteria in hepatocellular carcinoma (HCC) undergoing transarterial chemoembolization (TACE). Herein, we evaluated the differences of four methods and compared the association of these methods with the prognosis of HCC patients undergoing TACE. METHODS: We retrospectively reviewed 114 consecutive newly diagnosed HCC patients who underwent TACE as initial treatment. We evaluated the intermethod agreement (κ values) between the methods and compared their association with the prognosis of HCC patients. RESULTS: The κ values for EASL vs. WHO, EASL vs. RECIST, mRECIST vs. WHO, and mRECIST vs. RECIST were low, of 0.102, 0.088, 0.112, and 0.122, respectively. However, good correlations were observed for WHO vs. RECIST and EASL vs. mRECIST (κ=0.883, κ=0.759, respectively p<0.001). The median OS was 32.3 months. Hazard ratios (HR) for survival in responders compared with non-responders were 0.21 (95% CI; 0.12-0.37, p<0.001) for EASL and 0.27 (95% CI; 0.15-0.48, p<0.001) for mRECIST. The mean survival of responders was significantly longer than that of non-responders in both EASL (40.8 vs. 16.9 months, p<0.001) and mRECIST (41.1 vs. 20.7 months, p<0.001). In multivariate analysis, EASL response (HR 0.21, 95% CI 0.11-0.40, p<0.001) and mRECIST response (HR; 0.31, 95% CI, 0.17-0.59, p<0.001) were independently associated with survival. CONCLUSIONS: The response assessment by EASL and mRECIST could reliably predict the survival of HCC patients undergoing TACE and could be applicable in practice in preference to the conventional WHO and RECIST criteria.

In vitro assessment of three types of zirconia implant abutments under static load.

STATEMENT OF PROBLEM: Although various zirconia abutments have been introduced, insufficient data exist regarding the maximum load capacity of internal tri-channel connection zirconia implant abutments with various implant-abutment interfaces. PURPOSE: The purpose of this in vitro study was to compare the maximum load capacity of 3 different types of internal tri-channel connection zirconia abutments and to assess their mode of failure. MATERIAL AND METHODS: The study investigated 3 groups (n=20) of zirconia implant abutments with different implant-abutment interfaces. Group AllZr consisted entirely of zirconia (Aadva CAD/CAM Zirconia Abutment), group FrZr of a titanium insert friction-fitted to the zirconia abutment component (NobelProcera Abutment Zirconia), and group BondZr of a titanium insert bonded to the zirconia abutment component (Lava Zirconia abutment). All the abutments were thermal cycled for 20 000 cycles between 5°C and 55°C. Sixty test implants made of titanium (Dummy NobelReplace) were embedded in autopolymerizing acrylic resin, and 60 zirconia copings (Lava Zirconia) with a uniform thickness of 2.0 mm were fabricated and bonded to the abutments. A universal testing machine was used to statically load all the specimens at a crosshead speed of 1 mm/min. The maximum load was recorded and used as the failure load. The fractured specimens were collected and representative specimens were studied with a stereomicroscope and scanning electron microscope (SEM). One-way ANOVA and post hoc comparisons with the Tukey HSD tests were used for statistical analysis (α=.05). RESULTS: The mean (SD) maximum load capacity was 484.6 (56.6) N for NobelProcera, 503.9 (46.3) N for Aadva, and 729.2 (35.9) N for Lava abutments. The maximum load capacity of Lava abutments was significantly higher than that of Aadva or NobelProcera (P< 05). No significant difference between Aadva and NobelProcera abutments was noted. The mode of failure among the Aadva, NobelProcera, and Lava abutments was different. CONCLUSIONS: With standard diameter internal tri-channel connection implants, the maximum load capacity of the Lava abutment was significantly higher than that of the Aadva or NobelProcera abutment. No significant difference in maximum load capacity was noted between Aadva and NobelProcera abutments. However, the fracture behavior of all 3 abutments was different.

Clinical Significance of Sphingosine 1-phosphate Receptor 2 and Takeda G Protein-coupled Receptor 5 in Extrahepatic Cholangiocarcinoma Patients.

BACKGROUND AND AIMS: In biliary epithelial cells, two bile acid receptors, sphingosine 1-phosphate receptor 2 (S1PR2) and Takeda G protein-coupled receptor 5 (TGR5) have been reported to trigger cell proliferation, as well as neoplastic cell invasiveness. In this study, we aimed to investigate the clinical significance of S1PR2/ TGR5 expression in extrahepatic cholangiocarcinoma (CCA) patients. METHODS: Patients who underwent surgical resection of extrahepatic CCA at Korea University Guro Hospital between 2002 and 2018 were included. Data on immunohistochemical staining and H-score of S1PR2 and TGR5 were evaluated using digital image analysis. RESULTS: A total of 115 cases of invasive CCA were analyzed. The H-score of S1PR2 showed a decrease in invasive CCA (p=0.052) but that of TGR5 showed a significant increase (p=0.02). Overall survival and disease-free survival were significantly lower in the low S1PR2 expression group (p<0.05) than in the control group; however, TGR5 expression was not significant (p=0.096). In multivariate analysis, low S1PR2 was only significant for poor prognosis. CONCLUSION: Low S1PR2 level was the only independent poor prognostic factor in patients with resected extrahepatic CCA.

Significance of dysplasia in bile duct resection margin in patients with extrahepatic cholangiocarcinoma: A retrospective analysis.

BACKGROUND: Radical resection is the only indicator associated with survival in extrahepatic cholangiocarcinoma (EHCC). However, limited data are available regarding the implications of dysplasia at the resection margin following surgery. AIM: To evaluate the prognostic significance of dysplasia-positive margins in patients diagnosed with EHCC. METHODS: We reviewed the records of patients who had undergone surgery for EHCC with curative intent between January 2013 and July 2017. We retrospectively analyzed the clinicopathological data of 116 patients followed for longer than 3 years. The status of resection margin was used to classify patients into negative low-grade dysplasia (LGD) and high-grade dysplasia (HGD)/carcinoma in situ (CIS) categories. RESULTS: Based on postoperative status, 72 patients underwent resection with negative margins, 19 had LGD-positive margins, and 25 showed HGD/CIS-positive margins. The mean survival rates of the patients with negative margins, LGD margins, and HGD/CIS margins were 49.1 ± 4.5, 47.3 ± 6.0, and 20.8 ± 4.4 mo, respectively (P < 0.001). No difference in survival was found between groups with LGD margins and negative margins (P = 0.56). In the multivariate analysis, age > 70 years and HGD/CIS-positive margins were significant independent factors for survival (hazard ratio = 1.90 and 2.47, respectively). CONCLUSION: HGD/CIS margin in resected EHCC is associated with a poor survival. However, the LGD-positive resection margin is not a significant indicator of survival in patients with EHCC.

Clinical outcomes of endoscopic papillectomy of ampullary adenoma: A multi-center study.

BACKGROUND: Ampullary adenoma is a rare premalignant lesion, but its incidence is increasing. Endoscopic papillectomy has become the first treatment of choice for ampullary adenomas due to its safety and effectiveness, thereby replacing surgical resection. However, recurrence rates and adverse events after endoscopic papillectomy were reported in up to 30% of cases. AIM: To review the long-term outcomes of endoscopic papillectomy and investigate the factors that affect these outcomes. METHODS: We retrospectively analyzed the data of patients who underwent endoscopic papillectomy for ampullary adenoma at five tertiary hospitals between 2013 and 2020. We evaluated clinical outcomes and their risk factors. The definitions of outcomes were as follow: (1) curative resection: complete endoscopic resection without recurrence; (2) endoscopic success: treatment of ampullary adenoma with endoscopy without surgical intervention; (3) early recurrence: reconfirmed adenoma at the first endoscopic surveillance; and (4) late recurrence: reconfirmed adenoma after the first endoscopic surveillance. RESULTS: A total of 106 patients were included for analysis. Of the included patients, 81 (76.4%) underwent curative resection, 99 (93.4%) had endoscopic success, showing that most patients with non-curative resection were successfully managed with endoscopy. Sixteen patients (15.1%) had piecemeal resection, 22 patients (20.8%) had shown positive/uncertain resection margin, 11 patients (16.1%) had an early recurrence, 13 patients (10.4%) had a late recurrence, and 6 patients (5.7%) had a re-recurrence. In multivariate analysis, a positive/uncertain margin [Odds ratio (OR) = 4.023, P = 0.048] and piecemeal resection (OR = 6.610, P = 0.005) were significant risk factors for early and late recurrence, respectively. Piecemeal resection was also a significant risk factor for non-curative resection (OR = 5.424, P = 0.007). Twenty-six patients experienced adverse events (24.5%). CONCLUSION: Endoscopic papillectomy is a safe and effective treatment for ampullary adenomas. Careful selection and follow-up of patients is mandatory, particularly in cases with positive/uncertain margin and piecemeal resection.

HBsAg seroclearance in chronic hepatitis B: implications for hepatocellular carcinoma.

GOALS AND BACKGROUND: The long-term clinical course, including the development of hepatocellular carcinoma (HCC) after hepatic B surface antigen (HBsAg) seroclearance is not established. We discovered that the incidence of HCC and the risk factors for HCC in chronic hepatitis B (CHB) patients after HBsAg seroclearance. STUDY: During 28 years, 96 CHB patients with HBsAg seroclearance were retrospectively reviewed. These patients continued to undergo HCC surveillance. The median follow-up time from initial visit was 166.5 months (range, 7 to 321 mo). RESULTS: The mean age at the initial visit and at the time of seroclearance was 39.2 ± 10.6 years and 46.4 ± 9.9 years, respectively. The mean age at the time of HBsAg seroclearance was significantly lower (P=0.03) in patients with spontaneous HBsAg seroclearance than patients with treatment-associated HBsAg seroclearance. During a median of 56 months (range, 7 to 238 mo) of follow-up after HBsAg seroclearance, 6 (6.5%) patients developed HCC. The mean age at the time of developing HCC was 55.8 ± 10.3 years. On univariate analysis, the evidence of liver cirrhosis from the time of HBsAg seroclearance and age more than 45 years at the time of HBsAg seroclearance were significant risk factors for HCC development. In multivariate analysis, the evidence of liver cirrhosis at HBsAg seroclearance was the only significant risk factor for HCC development. CONCLUSIONS: HCC can develop after HBsAg seroclearance in patients with known cirrhosis. Patients who achieved HBsAg seroclearance at older age (>45) may have undiagnosed cirrhosis and hence remain at risk for HCC. HCC surveillance should be carried out for both of those patient populations.

Development of a naftopidil-chitosan-based fumaric acid solid dispersion to improve the dissolution rate and stability of naftopidil.

Naftopidil (NAF), an α1-adrenoceptor antagonist, is administered as a treatment for benign prostatic hyperplasia; however, according to the Biopharmaceutical Classification System (BCS IV), it is a poorly-soluble drug that exhibits poor permeability. We aimed to increase the dissolution (%) of NAF by adding chitosan to a polymer-free formulation. Compared to the formulation prepared using Flivas®, at 60 min, the solid dispersion (SD) formulation containing NAF, fumaric acid, chitosan, and US2® in a 1:1:2:1 weight ratio improved the dissolution (%) of NAF in distilled water, pH 1.2 media, pH 4.0 and pH 6.8 buffers by 27.2-, 1.2-, 1.1- and 6.5-fold, respectively. The physicochemical properties of the SD1 formulation were also found to be altered, including its thermal properties, crystal intensity, and chemical interaction. As a result, the hydrogen bonding that occurs between NAF and fumaric acid was identified as a major factor in the increase in NAF dissolution (%). Further, chitosan was observed to contribute to the stability of NAF and SD1, which was assessed over a 3-month period. To our knowledge, this is the first study to employ a polymer-free system to improve the solubilization of NAF.

Change in serum hepatitis B surface antigen level and its clinical significance in treatment-naïve, hepatitis B e antigen-positive patients receiving entecavir.

BACKGROUND/AIM: We investigated changes in hepatitis B surface antigen (HBsAg) level and its correlation with clinical outcomes in treatment-naive chronic hepatitis B (CHB) patients undergoing entecavir therapy. PATIENTS AND METHODS: Among 51 hepatitis B e antigen (HBeAg)-positive treatment-naive CHB patients receiving entecavir for more than 1 year, 28 were enrolled. HBsAg levels were measured at baseline, 6 months, and 12 months after treatment using the Architect HBsAg QT assay (Abbott, dynamic; range: 0.05 to 125,000 IU/mL). Serum alanine aminotransferase, HBeAg, anti-HBe, and hepatitis B virus (HBV) DNA (Cobas Taqman: low detection limit 1.84 log10 copies/mL) were measured at baseline and every 3 months. The HBsAg response was defined as an HBsAg level that decreased more than 1 log10 IU/mL from baseline level at 12 months after entecavir treatment. RESULTS: Twenty-eight patients were treated for a median period of 21 months (range: 18 to 24 mo). Serum HBsAg level showed a mean of 4.0, 3.7, and 3.6 log10 IU/mL at pretreatment, 6, and 12 months, respectively, and declined significantly (P<0.001). Serum HBV DNA level showed a mean of 8.1, 3.1, and 2.4 log10 copies/mL at pretreatment, 6, and 12 months, respectively, and declined significantly (P<0.001). The decline in HBsAg level was significantly correlated with that of the HBV DNA level at 12 months from baseline (γ=0.391, P=0.044). Five patients showed an HBsAg response, and cumulative incidence of HBeAg loss at 1 year after entecavir treatment was 80% versus 30% in patients with an HBsAg response and those without, respectively (P=0.034). CONCLUSIONS: Monitoring changes in quantitative HBsAg level could be a useful parameter for assessing the response to entecavir therapy in HBeAg-positive treatment-naive CHB patients.

Effects of sphingolipid synthesis inhibition on cholesterol gallstone formation in C57BL/6J mice.

BACKGROUND: Sphingolipids play a very important role in cell membrane formation, signal transduction and plasma lipoprotein metabolism. The first rate-limiting step in the sphingolipid biosynthetic pathway is catalyzed by serine palmitoyltransferase (SPT), and myriocin is a potent and specific inhibitor of SPT. We investigated the impact of SPT inhibition on cholesterol gallstone formation in C57BL/6J mice. METHODS: Three groups of eight-week-old C57BL/6J mice were utilized. Each group consisted of 20 mice; group A, B, and C were fed normal chow, lithogenic diet with phosphate buffered saline, and lithogenic diet with myriocin (0.3 mg/kg), respectively, for 6 weeks. The ceramide levels in both serum and bile were assessed by high performance liquid chromatography analysis. Protein expression of ERK, JNK and p38 in the extracted gallbladder were determined by Western-blot analysis. RESULTS: Myriocin treatment caused a significant decrease in the rate of cholesterol gallstone formation. The lithogenic diet mice (group B) showed the highest ceramide activities in both the serum and bile among all the tested groups and there was significant suppression of the ceramide levels in both the serum and bile of the myriocin-treated mice (group C, p < 0.05). Phosphorylation of p38 in the gallbladder was increased in the lithogenic-diet mice and the expression of phosphorylated p38 was significantly suppressed in the myriocin treated mice. CONCLUSIONS: SPT inhibition by myriocin suppressed gallstone formation and the levels of ceramide in both the serum and bile. p38 in the cellular signaling pathways might be associated with cholesterol gallstone formation.

Long-term outcomes of prophylactic endoscopic histoacryl injection for gastric varices with a high risk of bleeding.

PURPOSE: Endoscopic histoacryl injection (EHI) is reported to be an effective treatment modality for bleeding gastric varices (GVs) but controversial as a prophylactic treatment for non-bleeding GVs because efficacy and safety have yet to be determined. The aim of this study was to evaluate safety and long-term outcomes of prophylactic EHI for non-bleeding GVs with a high risk of bleeding. METHODS: Thirty-three patients (23 males/10 females, mean age 56.6 years old) with a high risk of gastric variceal bleeding (large tumorous (27), red color sign (14) or rapidly growing in size (1)) underwent EHI. According to the grade of GVs, 25 patients belonged to F3, seven to F2, and one to F1. In terms of the locations of GVs, four patients belonged to type IGV1, 21 to type GOV2, and eight to type GOV1. RESULTS: Obliteration of GVs was achieved in all of the treated patients. Twenty-three patients required one session and ten needed more than two sessions to obliterate their GVs. A mean volume of histoacryl used per session was 2.0 ml. Complications related to the procedure included immediate bleeding in two patients and bacteremia in one patient. The mean duration of follow-up was 12.2 months and eradication of GVs was achieved in 21 (95%) of 22 patients who were followed-up more than 3 months. Index GVs recurred in three of 21 patients (14%) and re-bleeding in index GVs after EHI occurred in two of 26 patients (8%). CONCLUSIONS: Prophylactic EHI can be a promising procedure for eradication of non-bleeding GVs in case with a high risk of bleeding.

Hepatitis B viral surface mutations in patients with adefovir resistant chronic hepatitis B with A181T/V polymerase mutations.

The hepatitis B virus (HBV) polymerase gene has overlapping reading frames with surface genes, which allows to alter the amino acid codon of the surface genes. In adefovir (ADV) treated chronic hepatitis B patients carrying rtA181T/rtA181V mutations, overlap with surface gene mutations such as sW172stop/sL173F has been reported. However, the clinical consequences of such surface mutations have not been determined. The aim of this study was to determine the surface gene sequence in ADV-resistant patients carrying the A181T/V mutation and to describe the clinical significance. Of the 22 patients included in this study, 13 were ADV-resistant with rtA181T/V mutations (polymerase mutation group, Group P) and nine were antiviral treatment-naïve (control group, Group C). The Pre-S1 gene mutation, V60A, was detected in 11 patients (Group P=8, Group C=3). A start codon mutation in the Pre-S2 gene was found in five patients (Group P=3, Group C=2). An S gene mutation, sA184V, was found in nine patients, all of whom were in group P. Although sW172stop and sL173F mutations were detected, reduced HBsAg titer was not observed. Further study of these mutations and their clinical implications are needed.