Cholecystectomy reduces the risk of cholangiocarcinoma in patients with complicated gallstones, but has negligible effect on hepatocellular carcinoma.

BACKGROUND AND AIM: Gallstones have been reported to be positively associated with hepatobiliary cancers. However, risks of these cancers by cholecystectomy or in patients with complicated gallstones are controversial. We studied the effect of cholecystectomy on the risk of cholangiocarcinoma (CCA) or hepatocellular carcinoma (HCC) in patients with gallstones and subgroup of complicated gallstones. METHODS: Patients with gallstone disease (n = 958 677) and age-matched and sex-matched controls (n = 9 586 770) were identified using the Korean National Health Insurance database. Complicated gallstones were defined as gallstones associated with acute cholecystitis or acute cholangitis. Adjusted hazard ratios (adjusted hazard ratios, 95% confidence interval) of CCA and HCC incidences were evaluated in patients with gallstones who received cholecystectomy compared to the controls. We also analyzed these effects in patients with complicated gallstones. RESULTS: Patients with gallstones showed increased risks of CCA (1.80, 1.67-1.93) and HCC (1.03, 1.00-1.07) compared with controls. Cholecystectomy had minimal effects on the risks of CCA (1.94, 1.76-2.14) and HCC (0.93, 0.87-0.99) compared with those without cholecystectomy. However, patients with complicated gallstones showed highly increased CCA risk (5.62, 4.89-6.46) and a 30% risk reduction after cholecystectomy (3.91, 3.43-4.46). Risk reduction by cholecystectomy was greater for extrahepatic CCA than for intrahepatic CCA or ampulla of Vater cancer. However, the risk of HCC was not different in patients with complicated gallstones and those who underwent cholecystectomy compared to controls. CONCLUSION: The risk of CCA was markedly increased in patients with complicated gallstones and was partially reduced by cholecystectomy. The risk change of HCC was minimal with gallstones or cholecystectomy.

Efficacy of an artificial neural network algorithm based on thick-slab magnetic resonance cholangiopancreatography images for the automated diagnosis of common bile duct stones.

BACKGROUND AND AIM: Magnetic resonance cholangiopancreatography (MRCP) can accurately diagnose common bile duct (CBD) stones but is laborious to interpret. We developed an artificial neural network (ANN) capable of automatically assisting physicians with the diagnosis of CBD stones. This study aimed to evaluate the ANN's diagnostic performance for detecting CBD stones in thick-slab MRCP images and identify clinical factors predictive of accurate diagnosis. METHODS: The presence of CBD stones was confirmed via direct visualization through endoscopic retrograde cholangiopancreatography (ERCP). The absence of CBD stones was confirmed by either a negative endoscopic ultrasound accompanied by clinical improvements or negative findings on ERCP. Our base networks were constructed using state-of-the-art EfficientNet-B5 neural network models, which are widely used for image classification. RESULTS: In total, 3156 images were collected from 789 patients. Of these, 2628 images from 657 patients were used for training. An additional 1924 images from 481 patients were prospectively collected for validation. Across the entire prospective validation cohort, the ANN achieved a sensitivity, specificity, positive predictive value, negative predictive value, and overall accuracy of 93.03%, 97.05%, 97.01%, 93.12%, and 95.01%, respectively. Similarly, a radiologist achieved a sensitivity, specificity, positive predictive value, negative predictive value, and overall accuracy 91.16%, 93.25%, 93.22%, 90.20%, and 91.68%, respectively. In multivariate analysis, only bile duct diameter > 10 mm (odds ratio = 2.45, 95% confidence interval [1.08-6.07], P = 0.040) was related to ANN diagnostic accuracy. CONCLUSION: Our ANN algorithm automatically and quickly diagnoses CBD stones in thick-slab MRCP images, therein aiding physicians with optimizing clinical practice, such as whether to perform ERCP.

Optimal procedure-related hospitalization using clinical pathway protocols following gastric endoscopic submucosal dissection.

BACKGROUND: The clinical pathway (CP) protocols simplified a systematic process from hospitalization to discharge, and were conducted to achieve standardization of the treatment process as well as improve outcomes. Thus, we investigated the optimal procedure-related hospitalization period following gastric endoscopic submucosal dissection (ESD) by comparing the rate of delayed bleeding (DB) and perforation according to CP protocols. METHODS: We retrospectively enrolled 630 patients who underwent ESD for gastric dysplasia or early gastric cancer (EGC); Group A (368 patients) followed Protocol A for a hospital stay of a single night; Group B (262 patients) followed Protocol B for a hospital stay of two nights. RESULTS: The patient characteristics were comparable between the two groups, except for pathologic diagnosis (42.1% in Group A vs. 32.1% in Group B for EGC). DB occurred in 21 patients, and there was no significant difference in the overall DB rates between Group A (12/368 = 3.3%) and Group B (9/262 = 3.4%) (P = 0.904). The DB rates were 2.5% (8/315) and 7.5% (4/53) in Group A, and 2.7% (6/223) and 7.7% (3/39) in Group B, without and with the use of antiplatelets, respectively, and 33.3% (1/3) in Group A and 50.0% (1/2) in Group B with the use of dual antiplatelets. DB developed at various intervals post-discharge from 2 to 17 days, and was successfully controlled by endoscopic hemostasis in most cases. There were no deaths or surgeries required as a result of uncontrolled DB and no postoperative delayed perforation occurred. CONCLUSIONS: The CP protocols with a one-night hospitalization following gastric ESD decreased the hospital stay and did not influence postoperative complications compared to those with two-night hospitalizations.

Work-Life Conflict and Its Health Effects on Korean Gastroenterologists According to Age and Sex.

BACKGROUND: This study aimed to evaluate the work-life pattern and prevalence of occupation-related symptoms, as well as the effect of work-life balance on health status according to age and sex among Korean gastroenterologists. METHODS: A total of 222 gastroenterologists from 44 nationwide centers in South Korea participated in an anonymized self-responded electronic questionnaire survey about their daily activities and symptoms for 14 days. Musculoskeletal, gastrointestinal and mental symptoms were scored using a numerical scale. The Maslach Burnout Inventory was used to measure the burnout score. RESULTS: Korean gastroenterologists (124 men and 98 women) spent 71.5 ± 19.0 h/week for work (54.0 ± 16.2 in-hospital and 17.5 ± 9.5 out-of-hospital), without any differences regarding sex. However, women spent more time performing housework and parenting (20.7 ± 19.0) compared to men (14.3 ± 13.3, P = 0.007). Musculoskeletal pain was found in 199 respondents (89.6%), and women had a higher total pain score compared to men in all age groups (P = 0.016). Gastrointestinal and mental symptoms were found in 119 (53.6%) and 153 (68.9%), respectively. Work-life ratio was significantly correlated with musculoskeletal (P < 0.001), gastrointestinal (P = 0.048) and mental symptoms (P = 0.003). Using the Maslach Burnout Inventory, 64.4% of the respondents demonstrated burnout. Moreover, emotional exhaustion, depersonalization and personal accomplishment scores were worst in women in their 30s or 40s. CONCLUSION: Korean gastroenterologists suffered from musculoskeletal, gastrointestinal and mental symptoms and were highly prone to burnout due to long and laboring work. Work-life imbalance and burnout were most severe in young women doctors due to their domestic demands.

Diagnostic accuracy of administrative database for bile duct cancer by ICD-10 code in a tertiary institute in Korea.

BACKGROUND: Administrative database provides valuable information for large cohort studies, especially when tissue diagnosis is rather difficult such as the diagnosis for bile duct cancer (BDC). The aim of this study was to evaluate the diagnostic accuracy of administrative database for BDC by International Classification of Diseases (ICD)-10 codes in a tertiary institute. METHODS: BDC and control groups were collected from 2003 to 2016 at Seoul National University Bundang Hospital. Cases of BDC were identified in the National Health Insurance Service (NHIS) database by ICD 10-code supported by V code. The control group was selected from cases without ICD-10 codes for BDC. A definite or possible diagnosis was defined according to pathologic reports. Medical records, images, and pathology reports were analyzed to evaluate ICD-10 codes for BDC. Sensitivity, specificity, positive predictive value, and negative predictive value for BDC were analyzed according to diagnostic criteria and cancer locations. RESULTS: A total of 1707 patients with BDC and 1707 controls were collected. Among those with BDC, 1320 (77.3%) were diagnosed by definite criteria. Most (99.4%) of them had adenocarcinoma. Rate of definite diagnosis was the highest for ampulla of Vater (88.9%), followed by that for extrahepatic (84.9%) and intrahepatic (68.3%) BDCs. False positive cases commonly had hepatocellular carcinomas. For overall diagnosis of BDC, sensitivity, specificity, positive predictive value, and negative predictive value were 99.94%, 98.33%, 98.30%, and 99.94%, respectively. Diagnostic accuracies were similar regardless of diagnostic criteria or tumor locations. CONCLUSIONS: Administrative database for BDC collected according to ICD-10 code with V code shows good accuracy.

Bile-derived circulating extracellular miR-30d-5p and miR-92a-3p as potential biomarkers for cholangiocarcinoma.

BACKGROUND: Cholangiocarcinoma (CCA) is from cholangiocytes, and therefore bile is a potentially rich source of biomarkers for CCA. The aim of the study was to identify and validate microRNAs (miRNAs) in bile samples that are differentially expressed between benign biliary disease (BBD) and CCA. METHODS: Bile samples from 106 patients with obstructive biliary disease were allocated consecutively to a discovery set (10 patients with BBD and 11 with CCA) and then a validation set (48 patients with BBD and 37 with CCA). An miRNA microarray platform was used to screen 1209 miRNAs in the discovery set. Quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR) was used to validate the profiling results in the discovery and validation sets. In addition, the levels of carbohydrate antigen 19-9 (CA19-9) and carcinoembryonic antigen (CEA) were determined from patient serum samples. RESULTS: Microarray profiling showed that miR-30d-5p and miR-92a-3p were significantly upregulated in bile from the CCA group compared with those from the BBD group. qRT-PCR results indicated that the expression levels of miR-30d-5p and of miR-92a-3p were significantly upregulated in the CCA group compared to the BBD group, validating the miRNA microarray results. Pathway analysis suggested that putative target genes of miR-30d-5p and of miR-92a-3p were involved in CCA-associated signalling pathways, such as Hippo, Wnt, p53, MAPK, and EGFR. Receiver operating curve analysis revealed that the areas under the curve for bile miR-30d-5p, miR-92a-3p, serum CA19-9, and CEA were 0.730, 0.652, 0.675, and 0.603, respectively, and bile miR-30d-5p showed the best diagnostic performance with a sensitivity of 81.1% and a specificity of 60.5%. CONCLUSIONS: The levels of extracellular miR-30d-5p and miR-92a-3p in bile were significantly higher in patients with CCA than those in patients with BBD. Bile-derived circulating extracellular miR-30d-5p and miR-92a-3p are potential biomarkers for discriminating CCA from BBD.

Incidence and Prognosis of Subsequent Cholangiocarcinoma in Patients with Hepatic Resection for Bile Duct Stones.

BACKGROUND AND AIM: Cholangiocarcinoma (CCA) often develops after the hepatic resection for hepatolithiasis as well as indwelling it. We studied the incidence and prognosis of subsequent CCA in patients with hepatolithiasis in South Korea. METHODS: We identified individuals with diagnosed CCA at the time of or after surgery, during 2002-2016, from the Korean National Health Insurance. The incidences and survival rates of subsequent CCA were analyzed and compared with concomitant CCA. The standardized incidence ratios (SIRs) of CCA in this cohort were evaluated in the standard Korean population. All data were stratified by the presence of intrahepatic or extrahepatic CCA, age and sex. RESULTS: Of the 7852 patients with hepatectomy for BDS, 433 (5.84%) had concomitant CCA. Over the 12-year follow-up, 107 of 7419 (1.98%) patients were diagnosed with subsequent CCA. Patients with hepatic resection for BDS revealed higher SIRs for subsequent CCA (12.89, 95% CI 10.96-15.15) in cases of both intrahepatic CCA (13.40, 10.55-17.02) and extrahepatic CCA (12.42, 9.98-15.46). The median survival time for subsequent CCA was 0.87 years, while that for concomitant CCA was 2.79 years. Having subsequent CCA (HR 2.71, 95% CI 2.17-3.40) and being male (HR 1.28, 1.05-1.57) were related to a shorter survival time. The CCA site and age at CCA diagnosis were not related to prognoses. CONCLUSIONS: Subsequent CCA developed in 2% of the patients with hepatic resection for benign BDS until 10 years and was associated with poorer prognoses than concomitant CCA. Future studies focused on the long-term surveillance for CCA in such patients are needed.

A prospective multicenter study of submucosal injection to improve endoscopic snare papillectomy for ampullary adenoma.

BACKGROUND AND AIMS: Whether or not submucosal injection of a diluted epinephrine solution should be used to lift ampullary tumors during endoscopic snare papillectomy is unclear. This study aimed to investigate the clinical efficacy of a simple snaring method versus submucosal injection for papillectomy. METHODS: A prospective multicenter study was performed at 4 tertiary referral centers. Patients with papillary lesions were randomized to undergo either simple snare papillectomy (SSP) or submucosal injection papillectomy (SIP) using 1:10,000 diluted epinephrine. The main outcome measures were complete resection rate and post-papillectomy adverse events. RESULTS: A total of 50 patients with biopsy-proven papillary adenomas were enrolled. Complete resection rates in the SSP and SIP groups were 80.8% (21/26) and 50.0% (12/24), respectively (P = .02). However, tumor persistence at 1 month (15.4% vs 8.3%, P = .62) and recurrence at 12 months (12.0% vs 9.5%, P = .58) did not differ despite initial differences in the prevalence of a positive resection margin. The mean tumor size was 12 mm in the SSP group and 9.29 mm in the SIP group. Post-papillectomy bleeding developed in 42.3% (11/26) and 45.8% (11/24) of patients, respectively (P = .80). Delayed bleeding (>12 h) occurred in 27.3% (3/11) and 36.4% (4/11) of patients, respectively (P = .50). Post-procedure pancreatitis occurred in 15.4% (4/26) and 25% (6/24) of patients, respectively (P = .49). Pancreatitis severity did not differ between the groups, and there were no procedure-related mortalities. CONCLUSIONS: Although the recurrence rate was similar between the SSP and SIP groups, SIP showed no advantage over SSP in terms of achieving complete resection or decreasing the frequency of post-papillectomy adverse events, such as bleeding. SSP may thus be a simpler and primarily recommendable technique. (Clinical trial registration number: NCT02165852.).

Comparison of sequential therapy and amoxicillin/tetracycline containing bismuth quadruple therapy for the first-line eradication of Helicobacter pylori: a prospective, multi-center, randomized clinical trial.

BACKGROUND: The <80 % Helicobacter pylori eradication rate with sequential therapy is unsatisfactory. Modified bismuth quadruple therapy, replacing metronidazole with amoxicillin, could be promising because H. pylori resistance to tetracycline or to amoxicillin is relatively low. A 14-day modified bismuth quadruple protocol as first-line H. pylori treatment was compared with 10-day sequential therapy. METHODS: In total, 390 H. pylori-infected subjects participated in the randomized clinical trial: 10-day sequential therapy (40 mg pantoprazole plus 1 g amoxicillin twice a day for 5 days, then 40 mg pantoprazole and 500 mg clarithromycin twice a day and 500 mg metronidazole three times a day for 5 days) or 14-day modified bismuth quadruple therapy (40 mg pantoprazole, 600 mg bismuth subcitrate, 1 g tetracycline, and 1 g amoxicillin, twice a day). (13)C-urea breath test, rapid urease testing, or histology was performed to check for eradication. RESULTS: Intention-to-treat (ITT) eradication rates of 10-day sequential and 14-day quadruple therapy were 74.6 % and 68.7 %, respectively, and the per-protocol (PP) rates were 84.2 and 76.5 %, respectively. The eradication rate was higher in the sequential therapy group, but neither the ITT nor the PP analyses had a significant difference (P = 0.240 and P = 0.099, respectively). However, the adverse events were significantly lower in the modified bismuth quadruple therapy group than the sequential therapy group (36.9 vs. 47.7 %, P = 0.040). CONCLUSIONS: Ten-day sequential therapy appears to be more effective despite frequent adverse events. However, both 10-day SQT and 14-day PBAT did not reach the excellent eradication rates that exceed 90 %. Additional trials are needed to identify a more satisfactory first-line eradication therapy. TRIAL REGISTRATION: ClinicalTrials.gov ( NCT02159976 ); Registration date: 2014-06-03, CRIS ( KCT0001176 ); Registration date: 2014-07-23.

Statin pretreatment inhibits the lipopolysaccharide-induced epithelial-mesenchymal transition via the downregulation of toll-like receptor 4 and nuclear factor-κB in human biliary epithelial cells.

BACKGROUND AND AIM: Epithelial-mesenchymal transition (EMT) of biliary epithelial cells (BECs) plays an important role in biliary fibrosis. This study investigated the effects of simvastatin on the lipopolysaccharide (LPS)-induced EMT and related signal pathways in BECs. METHODS: Biliary epithelial cells were exposed to LPS (2 µg/mL) or transforming growth factor ß1 (TGF-ß1) (5 ng/mL) for 5 days. The EMT was assessed by a gain of mesenchymal cell markers (vimentin, N-cadherin, slug, and Twist-1) and a loss of epithelial cell markers (E-cadherin). The effects of simvastatin on the EMT induced by LPS or TGF-ß1 were determined by the changes in the levels of EMT markers and TLR4 and in the c-Jun N-terminal kinase (JNK), p38, and nuclear factor-κB (NF-κB) signaling pathways. RESULTS: Compared with the BECs treated with LPS alone, co-treatment with simvastatin and LPS induced an increase in the expression of E-cadherin and decreases in the expression levels of mesenchymal cell markers. The LPS-induced TLR4 expression level was slightly decreased by co-treatment with simvastatin. LPS-induced BEC growth was markedly inhibited by co-treatment with simvastatin. Furthermore, pretreatment with simvastatin inhibited the LPS-induced EMT in BECs by downregulating NF-κB and JNK phosphorylation. The suppressive effects of simvastatin pretreatment on the induction of the EMT by TGF-ß1 were also demonstrated in H69 cells. CONCLUSIONS: Our results demonstrate that LPS or TGF-ß1 promote the EMT in BECs that that pretreatment with simvastatin inhibited the induced EMT by downregulating toll-like receptor 4 and NF-κB phosphorylation. This finding suggests that simvastatin can be considered a new agent for preventing biliary fibrosis associated with the EMT of BECs.

Attitudes towards second opinion services in cancer care: a nationwide survey of oncologists in Korea.

OBJECTIVE: Second opinion is a common phenomenon in many health systems, especially in the care of patients with cancer. However, it is not clear whether second opinion seeking should be promoted or discouraged and how second opinion services and policies can be better formalized to maximize the benefits and minimize the disadvantages. METHODS: A nationwide survey was conducted with a representative sample of 678 physicians involved in cancer care (75.5% participation rate) recruited in 13 cancer centres. RESULTS: Most physicians involved with cancer care perceived patients' second opinion seeking as a legitimate right (96.0%) and they acknowledged the need for second opinion services under certain conditions (98.2%). Many believed that second opinions can enhance patient satisfaction (77.3%) and quality of care (74.3%), but they also had concerns about increase in healthcare and societal costs (91.3%) and concentration in a high-volume centre (90.7%). While the majority agreed with the involvement of the first opinion physicians in the second opinion services (69.5%), there were mixed opinions regarding the desirability of remote (teleconsultation) second opinion services (49.0%) and coverage by national health insurance (51.9%). CONCLUSION: Physicians were generally positive to second opinion services and expected positive consequences in terms of patient satisfaction and quality of care. However, they had concerns about the consequences regarding cost and equity, and disagreements were observed regarding the way to improve second opinion services. The physicians' opinions revealed in our study will be helpful in developing clearer guidelines used to maximize the benefits of second opinion services.

Urgent ERCP for acute cholangitis reduces mortality and hospital stay in elderly and very elderly patients.

BACKGROUND: Acute cholangitis in old people is a cause of mortality and prolonged hospital stay. We evaluated the effects of methods and timing of biliary drainage on the outcomes of acute cholangitis in elderly and very elderly patients. METHODS: We analyzed 331 patients who were older than 75 years and were diagnosed with acute calculous cholangitis. They were admitted to our hospital from 2009 to 2014. Patients' demographics, severity grading, methods and timing of biliary drainage, mortality, and hospital stay were retrospectively obtained from medical records. Clinical parameters and outcomes were compared between elderly (75-80 years, n=156) and very elderly (≥81 years, n=175) patients. We analyzed the effects of methods [none, endoscopic retrograde cholangiopancreatography (ERCP), percutaneous transhepatic biliary drainage, or failure] and timing (urgent or early) of biliary drainage on mortality and hospital stay in these patients. RESULTS: Acute cholangitis in older patients manifested as atypical symptoms characterized as infrequent Charcot's triad (4.2%) and comorbidity in one-third of the patients. Patients were graded as mild, moderate, and severe cholangitis in 104 (31.4%), 175 (52.9%), and 52 (15.7%), respectively. Urgent biliary drainage (≤24 hours) was performed for 80.5% (247/307) of patients. Very elderly patients tended to have more severe grades and were treated with sequential procedures of transient biliary drainage and stone removal at different sessions. Hospital stay was related to methods and timing of biliary drainage. Mortality was very low (1.5%) and not related to patient age but rather to the success or failure of biliary drainage and severity grading of the acute cholangitis. CONCLUSIONS: The methods and timing used for biliary drainage and severity of cholangitis are the major determinants of mortality and hospital stay in elderly and very elderly patients with acute cholangitis. Urgent successful ERCP is mandatory for favorable prognosis in these patients.

Helicobacter pylori-induced epithelial-mesenchymal transition, a potential role of gastric cancer initiation and an emergence of stem cells.

We know little concerning the expression of transforming growth factor-ß1 (TGF-ß1) and TGF-ß1-induced epithelial-mesenchymal transition (EMT) markers in gastric mucosa and their changes after eradication of Helicobacter pylori infection have not yet been clarified. In the present study, we compared the time course of messenger RNA (mRNA) expression of TGF-ß1 and five EMT markers (Twist, Snail, Slug, vimentin and E-cadherin) in 111 controls, 55 patients with gastric dysplasia and 71 patients with early gastric cancer, following eradication of H.pylori. mRNA levels in non-cancerous gastric mucosa were measured using quantitative real time-polymerase chain reaction and the histologic findings of gastric mucosa were compared before and after eradication. The average duration of follow-up was 46.7 months (6.0-112.4). The levels of TGF-ß1, Twist, Snail, Slug and vimentin mRNA, in addition to levels of CD44 detected by immunohistochemistry, showed all up-regulation in patients with dysplasia or early gastric cancer compared with controls (P < 0.05); moreover, the mRNA levels of E-cadherin, an epithelial marker, were decreased in these patients compared with the control group (P < 0.001). Eradication of H.pylori reduced the expression of TGF-ß1, Twist, Snail, Slug and vimentin mRNA (P-value for slope <0.001), as well as the immunohistochemical expression of CD44 (P = 0.014), whereas it enhanced the expression of E-cadherin (P-value for slope < 0.05). Thus, H.pylori infection may trigger the TGF-ß1-induced EMT pathway and the emergence of gastric cancer stem cells (CSCs). Its eradication may prevent the carcinogenesis of gastric cancer by inhibiting these two pathways.

Helicobacter pylori Might Induce TGF-ß1-Mediated EMT by Means of cagE.

BACKGROUND: Epithelial-mesenchymal transition (EMT), in which polarized epithelial cells have mesenchymal cell phenotypes, is thought to be a key process of invasion and metastasis of cancer. Transforming growth factor beta-1 (TGF-ß1) is known to be carcinogenic and Helicobacter pylori is a predominant carcinogen of gastric cancer. Our study aimed to determine whether TGF-ß1 or H. pylori infection enhances EMT process and cytotoxin-associated gene E (CagE) is associated with EMT. MATERIALS AND METHODS: Human gastric cancer cell AGS and MKN45 were treated with recombinant TGF-ß1 or H. pylori including cagE-negative (ΔcagE) mutant. Besides the assessment of EMT-related markers expression levels by means of RT-qPCR, Western blot, and immunofluorescence assay, the induction of in vitro EMT on gastric cancer cells (AGS and MKN cell lines) was confirmed by wound-healing assay and invasion assay. RESULTS: When gastric cancer cells were treated with TGF-ß1 or various strains of cagE-positive H. pylori, EMT-related marker altered significantly. However, the ΔcagE mutant did not. Wound-healing assay and invasion assay showed enhanced migration ability of the cells treated with cagE-positive H. pylori but not in ΔcagE mutant. CONCLUSIONS: EMT induction in gastric cancer cells by TGF-ß1 was confirmed. Only infection with cagE-positive H. pylori upregulated the TGF-ß1-mediated EMT pathway and consequently promotes EMT. Therefore, H. pylori might induce TGF-ß1-mediated EMT associated with the cagE.

Guilt, censure, and concealment of active smoking status among cancer patients and family members after diagnosis: a nationwide study.

OBJECTIVES: We aimed to identify the prevalence of feelings of guilt, censure, and concealment of smoking status among cancer patients and their family members who continued to smoke after the patient's diagnosis. METHODS: Among 990 patient-family member dyads, 45 patients and 173 family members who continued to smoke for at least 1 month after the patients' diagnoses were administered questions examining feelings of guilt, censure, and smoking concealment. RESULTS: Most patients who continued to smoke reported experiencing feelings of guilt toward their families (75.6%) and censure from their family members (77.8%), and many concealed their smoking from their family members (44.4%) or healthcare professionals (46.7%). Family members who continued to smoke also reported feelings of guilt with respect to the patient (63.6%) and that the patient was critical of them (68.9%), and many concealed their smoking from the patient (28.5%) or healthcare professionals (9.3%). Patients' feeling of guilt was associated with concealment of smoking from family members (55.9% vs. 10.0%) or health care professionals (55.9% vs. 20.0%). Family members who reported feeling guilty (36.5% vs. 16.3%) or censured (34.5% vs. 16.7%) were more likely to conceal smoking from patients. CONCLUSION: Many patients and family members continue to smoke following cancer diagnosis, and the majority of them experience feelings of guilt and censure, which can lead to the concealment of smoking status from families or health care professionals. Feelings of guilt, censure, and concealment of smoking should be considered in the development and implementation of smoking cessation programs for cancer patients and family members.

Epithelial-mesenchymal transition-related protein expression in biliary epithelial cells associated with hepatolithiasis.

BACKGROUND AND AIM: Epithelial-mesenchymal transition (EMT) of biliary epithelial cells (BECs) plays major roles in many cholangiopathies. This study evaluated whether EMT of BECs has a role in hepatolithiasis-induced biliary fibrosis and types of BECs that are involved. METHODS: The expression of EMT-related proteins and epidermal growth factor receptor was evaluated by immunohistochemistry of liver tissues from 102 patients with hepatolithiasis, 32 patients with post-hepatitis cirrhosis, and 48 normal livers. Antibodies against E-cadherin, ß-catenin, and cytokeratin were used to identify epithelial cells and antibodies against vimentin, S100A4, podoplanin, and α-smooth muscle actin (α-SMA) were used to identify mesenchymal cells. The relationship between clinical and histological parameters and immunohistochemistry findings in BECs, and the surrounding stroma were evaluated. RESULTS: Loss of E-cadherin and acquisition of S100A4 and vimentin were observed in BECs. In all BECs, cytokeratin and ß-catenin expression were unchanged, while podoplanin and α-SMA were not expressed. Although hepatic fibrosis was more severe in post-hepatitis cirrhosis, EMT of BECs was more widespread in hepatolithiasis. In hepatolithiasis, EMT-related proteins were more highly expressed in small bile ducts than in medium or large bile ducts. Their expression was associated with the severity of biliary fibrosis and the expressions of epidermal growth factor receptor. Expression of α-SMA in fibroblasts from the portal space was closely linked to pathological changes in small bile ducts and EMT-related protein expressions in BECs. CONCLUSIONS: Proliferating cholangiocytes that form small bile ducts may contribute to cholangiopathies in hepatolithiasis through an EMT-like phenomenon or through interactions with stromal myofibroblasts.

H2 Receptor-Mediated Relaxation of Circular Smooth Muscle in Human Gastric Corpus: the Role of Nitric Oxide (NO).

This study was designed to examine the effects of histamine on gastric motility and its specific receptor in the circular smooth muscle of the human gastric corpus. Histamine mainly produced tonic relaxation in a concentration-dependent and reversible manner, although histamine enhanced contractility in a minor portion of tissues tested. Histamine-induced tonic relaxation was nerve-insensitive because pretreatment with nerve blockers cocktail (NBC) did not inhibit relaxation. Additionally, K(+) channel blockers, such as tetraethylammonium (TEA), apamin (APA), and glibenclamide (Glib), had no effect. However, N(G)-nitro-L-arginine methyl ester (L-NAME) and 1H-(1,2,4)oxadiazolo (4,3-A) quinoxalin-1-one (ODQ), an inhibitor of soluble guanylate cyclase (sGC), did inhibit histamine-induced tonic relaxation. In particular, histamine-induced tonic relaxation was converted to tonic contraction by pretreatment with L-NAME. Ranitidine, the H2 receptor blocker, inhibited histamine-induced tonic relaxation. These findings suggest that histamine produced relaxation in circular smooth muscle of human gastric smooth muscle through H2 receptor and NO/sGC pathways.

Podoplanin, α-smooth muscle actin or S100A4 expressing cancer-associated fibroblasts are associated with different prognosis in colorectal cancers.

The interactions between the tumor microenvironment and tumor cells determine the behavior of the primary tumors. Whether cancer-associated fibroblasts (CAF) have a tumor progressive or a protective role likely depends on the type of tumor cells and the CAF subpopulation. In the present study, we analyzed the prognostic significance of CAF subpopulations in colorectal cancer (CRC). CAF phenotypes were analyzed in 302 CRC patients by using antibodies against podoplanin (PDPN), α-smooth muscle actin (α-SMA), and S100A4. The relationship between the CAF phenotypes and 11 clinicopathological parameters were evaluated and their prognostic significance was analyzed from the disease-free and overall survival times. We observed that at the tumor invasive front, PDPN CAFs were present in 40% of the cases, and S100A4 or α-SMA CAFs were detected in all the cases. PDPN/S100A4 and α-SMA/S100A4 dual-stained CAFs were observed in 10% and 40% of the cases, respectively. The PDPN(+) CAFs were associated with 6 favorable clinicopathological parameters and prolonged disease-free survival time. The PDPN(-)/α-SMA(high) CAFs were associated with 6 aggressive clinicopathological parameters and tended to exhibit shorter disease-free survival time. On the other hand, the PDPN(-)/S100A4(high) CAFs were associated with 2 tumor progression parameters, but not with disease prognosis. The PDPN(+) CAF phenotype is distinct from the α-SMA or S100A4 CAFs in that it is associated with less aggressive tumors and a favorable prognosis, whereas the PDPN(-)/α-SMA(high) or PDPN(-)/S100A4(high) CAFs are associated with tumor progression in CRC. These findings suggest that CAFs can be a useful prognostic biomarker or potential targets of anti-cancer therapy in CRC.

Direct-acting antivirals for the treatment of chronic hepatitis C: open issues and future perspectives.

Currently, two direct-acting antivirals (DAAs) show well-established efficacy against hepatitis C virus (HCV), namely, first-wave protease inhibitors telaprevir and boceprevir. Most clinical trials have examined DAAs in combination with standard of care (SOC) regimens. Future therapeutic drugs were divided into three categories. They are second-wave protease inhibitors, second-generation protease inhibitors, and polymerase inhibitors. Second-wave protease inhibitors are more improved form and can be administered once a day. Oral drug combinations can be favored because interferon (IFN) not only has to be given as intradermal injection, but also can cause several serious side effects. Combination of drugs with different mechanisms shows a good sustained virological response (SVR). But several mutations are associated with viral resistance to DAAs. Therefore, genotypic resistance data may provide insights into strategies aimed at maximizing SVR rates and minimizing resistance. Combined drug regimens are necessary to prevent the emergence of drug-resistant HCV. Many promising DAA candidates have been identified. Of these, a triple regimen containing sofosbuvir shows promise, and treatment with daclatasvir plus asunaprevir yields a high SVR rate (95%). Oral drug combinations will be standard of care in the near future.