Efficacy and safety of pinaverium bromide as an add-on therapy in refractory dyspepsia: A randomized controlled trial.

Background and Aim: Functional dyspepsia (FD) remains a therapeutic challenge, and the efficacy of antispasmodic agents as adjunctive therapy is not well established. This study aimed to evaluate the efficacy and safety of pinaverium bromide added to omeprazole in treating refractory FD. Methods: We conducted a randomized, placebo-controlled trial in patients with refractory dyspepsia. Participants were randomly assigned to receive pinaverium (50 mg, 3 times/day, n = 36) or placebo (n = 36) in addition to omeprazole for 8 weeks. The primary endpoint was the responder rate for adequate relief. Secondary outcomes included the Global Overall Symptom Scale (GOSS), quality of life, and safety profile. Results: No statistically significant differences were observed in the adequate relief response rate between the pinaverium bromide and control group at week 2 (58.3% vs. 62.9%, P = 0.697), week 4 (62.9% vs. 78.1%, P = 0.173), week 6 (64.7% vs. 75.0%, P = 0.363), and week 8 (64.7% vs. 75.0%, P = 0.363). Additionally, there were no significant differences observed in the decline of symptom score between the two groups at week 4 (8.4 ± 7.6 vs. 7.7 ± 7.1, P = 0.702) and week 8 (10.9 ± 8.2 vs. 8.4 ± 7.2, P = 0.196). Similarly, there were no significant differences in terms of quality of life between the two groups. Adverse event rates were also comparable between the two groups. Conclusion: Pinaverium bromide was found to be safe in the treatment of refractory dyspepsia, but it did not demonstrate a significant benefit in improving symptoms.

The Mutographs biorepository: A unique genomic resource to study cancer around the world.

Large-scale biorepositories and databases are essential to generate equitable, effective, and sustainable advances in cancer prevention, early detection, cancer therapy, cancer care, and surveillance. The Mutographs project has created a large genomic dataset and biorepository of over 7,800 cancer cases from 30 countries across five continents with extensive demographic, lifestyle, environmental, and clinical information. Whole-genome sequencing is being finalized for over 4,000 cases, with the primary goal of understanding the causes of cancer at eight anatomic sites. Genomic, exposure, and clinical data will be publicly available through the International Cancer Genome Consortium Accelerating Research in Genomic Oncology platform. The Mutographs sample and metadata biorepository constitutes a legacy resource for new projects and collaborations aiming to increase our current research efforts in cancer genomic epidemiology globally.

Prediction of Esophageal Varices in Viral Hepatitis C Cirrhosis: Performance of Combined Ultrasonography and Clinical Predictors.

Objectives: This study is aimed at evaluating the diagnostic performance of clinical predictors and the Doppler ultrasonography in predicting esophageal varices (EV) in patients with hepatitis C-related cirrhosis and exploring the practical predictors of EV. Methods: We conducted a prospective study from July 2020 to January 2021, enrolling 65 patients with mild hepatitis C-related cirrhosis. We obtained clinical data and performed grayscale and the Doppler ultrasound to explore the predictors of EV. Esophagogastroduodenoscopy (EGD) was performed as the reference test by the gastroenterologist within a week. Results: The prevalence of EV in the study was 41.5%. Multivariable regression analysis revealed that gender (female, OR = 4.04, p = 0.02), platelet count (<150000 per ml, OR = 3.13, p = 0.09), splenic length (>11 cm, OR = 3.64, p = 0.02), and absent right hepatic vein (RHV) triphasicity (OR = 3.15, p = 0.03) were significant predictors of EV. However, the diagnostic accuracy indices for isolated predictors were not good (AUROC = 0.63-0.66). A combination of these four predictors increases the diagnostic accuracy in predicting the presence of EV (AUROC = 0.80, 95% CI 0.69-0.91). Furthermore, the Doppler assessment of the right hepatic vein waveform showed good reproducibility (κ = 0.76). Conclusion: Combining clinical and Doppler ultrasound features can be used as a screening test for predicting the presence of EV in patients with hepatitis C-related cirrhosis. The practical predictors identified in this study could serve as an alternative to invasive EGD in EV diagnosis. Further studies are needed to explore the diagnostic accuracy of additional noninvasive predictors, such as elastography, to improve EV screening.

Programmed death-ligand 1 expression and overall survival in Thai patients with gastric cancer.

Programmed death-ligand 1 (PD-L1) expression has now been implicated in gastric cancer (GC). This study was conducted to determine the impact of clinicopathological characteristics on PD-L1 expression and its association with survival in GC patients receiving standard-of-care. In total, 268 GC patients receiving upfront surgery were enrolled at Chiang Mai University Hospital. PD-L1 expression was assayed by immunohistochemistry staining using the Dako 22C3 pharmDx. The rates of PD-L1 positivity by combined positive score (CPS) at a cutoff value of 1 and 5 were 22% and 7%. PD-L1 positivity was significantly higher in patients younger than 55 than those older than 55 (32.6% vs. 16.5%, p = 0.003; 11.6% vs. 4.4%, p = 0.027). PD-L1 positivity was observed more frequently in GC with metastases than without (25.2% vs. 17.1%, p = 0.112; 7.2% vs. 6.7%, p = 0.673). Patients with PD-L1 positive had a significantly shorter median overall survival than those with PD-L1 negative (32.7 vs. 41.6 months, p = 0.042, 27.6 vs. 40.8 months, p = 0.038). In conclusion, PD-L1 expression has been associated with young age, short survival, and metastases, although unrelated to the tumor stage. For GC patients, PD-L1 testing is recommended, especially among young patients with metastases.

Prevalence and factors associated with atrophic gastritis and intestinal metaplasia: A multivariate, hospital-based, statistical analysis.

BACKGROUND: Atrophic gastritis (AG) and intestinal metaplasia (IM) play an essential role in gastric carcinogenesis. This study aimed to determine the prevalence of AG and IM and their associated factors. METHODS: Subjects who underwent upper endoscopy at Chiang Mai University Hospital from January 2018 to Dec 2021 were included. All participants were interviewed using a structured questionnaire to collect their personal histories. In addition, clinical and histological data and associated factors of AG and IM were analyzed. RESULTS: A total of 947 subjects (mean age, 53.61 ± 9.73 years; 60% male) were included. The prevalence of AG and IM, diagnosed by histopathology, was 39% and 19%. Prevalence of AG and IM increased from 28% and 9% in those under 50 years to 43% and 30% in those above 60 (p < 0.05). In a multivariate analysis, Helicobacter pylori (H. pylori) infection, age 50-59 and over 60 years were significantly associated with higher odds of AG (odds ratio (OR), 2.07, 2.06, and 1.98) and IM (OR, 2.07, 2.18, and 4.46), respectively. Conversely, ingestion of spicy food was significantly associated with lower odds of AG and IM (OR, 0.75, and 0.62). CONCLUSIONS: This study confirms that age and H. pylori infection are risk factors, whereas spicy food intake is a protective factor against AG and IM, which are common in patients over 50. Therefore, upper endoscopy and gastric mapping sampling are recommended for patients with chronic dyspepsia older than 50 to reduce gastric cancer risk.

Randomised clinical trial: the effects of pregabalin vs placebo on functional dyspepsia.

BACKGROUND: Currently, central neuromodulators are among the therapeutic options for the treatment of functional dyspepsia (FD). Pregabalin, a gabapentinoid, is a neuromodulator that could potentially improve visceral hypersensitivity in FD patients. AIM: To assess the efficacy and safety of pregabalin for the treatment of FD METHODS: We performed a randomised placebo-controlled study including FD patients who did not respond to proton pump inhibitors. Patients were randomly assigned to receive pregabalin (75 mg daily) or placebo for 8 weeks. The primary outcome was an adequate relief response rate. The secondary outcomes were improvement in quality of life, pain scores in divided categories, and safety profile. RESULTS: Of 72 patients enrolled, 34 received pregabalin and 38 received placebo. The self-reported adequate relief rates in the pregabalin and placebo groups were 70.6% and 42.1% at week 4 (P = 0.02), and 70.6% and 44.7% at week 8 (P = 0.03), respectively. The reduction in global symptoms in the pregabalin and placebo groups were 11.7 ± 10.6 and 3.7 ± 8.9 points at week 4 (P < 0.01) and 15.1 ± 12.2 and 8.0 ± 10.2 points at week 8 (P = 0.01), respectively. Pregabalin improved the overall quality of life (P = 0.03). The most common adverse event with pregabalin was dizziness, occurring in 51.6% of patients. CONCLUSIONS: Pregabalin led to significant alleviation of dyspeptic symptoms, especially in patients with predominant epigastric pain . Thaiclinicaltrials.org #TCTR20200404002.

A Proactive Policy to Eliminate Viral Hepatitis Infection: Five-Year Results for the Subdistrict Model in Thailand.

The objective of this study was to ascertain hepatitis B (HBV) and hepatitis C (HCV) infection rates in individuals toward the early initiation of treatment and prevention of developing hepatocellular carcinoma (HCC). This cross-sectional study was performed on 2084 participants from two subdistricts in Chiang Mai and Lampang provinces, northern Thailand. Screening for viral hepatitis in the general population was conducted at subdistrict health-promoting hospitals in Nong Pa Krang, in the suburb of Chiang Mai city, and Thoenburi, a subdistrict in the rural area of Lampang province, northern Thailand. Ninety-one (4.4%) participants tested positive for either HBV or HCV, with 3.3% of all participants infected with HBV and 1.1% infected with HCV. Treatment follow-up was 29.0% of HBV and 54.5% of HCV. A proactive approach to eliminate viral hepatitis can be carried out at the subdistrict level in Thailand. Success could increase participation in other subdistricts in a cascade-like manner by 2030. The identified factors of success are leadership by the local government supported by the Local Health Fund and Village Health Volunteers.

Chronic gastritis according to age and Helicobacter pylori in Thailand: histopathological patterns.

OBJECTIVES: We aimed to evaluate the histopathological characteristics of chronic gastritis in dyspeptic patients without visible mucosal lesions in different age groups and different biopsy sites. METHODS: Patients who underwent upper endoscopy for the investigation of dyspepsia as the sole indication were recruited. We selected data from patients without visible mucosal lesions for the study. Gastric biopsy specimens were evaluated by Update Sydney classification according to age, Helicobacter pylori (Hp), and biopsy sites. RESULTS: A total of 626 patients were retrospectively studied. 58.2% had histopathological features of chronic gastritis, while 41.8% had normal gastric mucosa. The prevalence of glandular atrophy, intestinal metaplasia, and Hp infection was 36.7, 19.3 and 36.6%. Complete and incomplete metaplasia was found to be 17.0 and 2.2%. The mean score of chronic inflammation, neutrophil activity, glandular atrophy, and intestinal metaplasia was significantly higher in the antrum than in the corpus. The positivity of gastritis increases with age; however, Hp positivity decreased considerably with advanced age. Concerning gastritis's topography, antral-predominant gastritis and corpus-predominant gastritis increased with age. The prevalence of glandular atrophy and intestinal metaplasia markedly increased with age, especially after age 50. Gastric atrophy and intestinal metaplasia were significantly higher in patients positive for Hp than in negative patients. CONCLUSION: Overall chronic gastritis is common in dyspeptic patients without visible lesions. Prevalence, grading, and severity of chronic gastritis increase with age and Hp infection. Temporal changes of the gastric mucosa are caused by aging rather than by Hp alone.

Efficacy and Safety of Fingerroot (Boesenbergia rotunda) Extract in Patients with Functional Dyspepsia: A Randomized, Placebo-Controlled Trial.

BACKGROUND: Functional dyspepsia (FD) is a common upper gastrointestinal disorder, but the current treatments are still unsatisfactory. Fingerroot (Boesenbergia rotunda [L.] Mansf.; BR) is used as a traditional medicine for dyspepsia despite a lack of proven evidence. OBJECTIVE: This study aimed to evaluate the efficacy and safety of BR extract in the treatment of patients with FD. METHODS: In a randomized, double-blinded, placebo-controlled trial, 160 patients with FD based on Rome IV criteria were to be recruited and randomly assigned (1:1 ratio) to receive BR (350 mg extract powder) or placebo 3 times daily for 4 weeks. Primary end point was change in the summed total score of Short-Form Leeds Dyspepsia Questionnaire. Secondary end points were the rate of symptom relief, the reduction of blood inflammatory markers and the improvement in gastric histology according to the Updated Sydney System. RESULTS: One hundred sixty patients (62 [38.8%] men, aged 56.9 ± 14.8 years) were randomized to the BR group (n = 80) and placebo group (n = 80), and 138 patients completed this study. Overall symptom improvement was significantly greater in the BR group than in the placebo group (-7.1 ± 2.0 vs. -3.7 ± 0.8, repeated measures ANOVA, p < 0.05). Total symptom scores significantly improved with decrease in blood inflammatory markers in the BR group compared with the placebo group (p < 0.05). Proportion of responders was higher in the BR group (58%) than in the placebo group (34.6%) according to the intention-to-treat analysis (p < 0.05) with the number needed to treat calculated as 4.3. No difference in gastric histology was observed in both groups. BR extract was well tolerated with few adverse events. These effects were associated with acute phase reactants reduction. CONCLUSIONS: BR extract represents an effective and safe alternative to manage dyspepsia symptoms in FD patients.

Efficacy and Safety of Clidinium/Chlordiazepoxide as an Add-on Therapy in Functional Dyspepsia: A Randomized, Controlled, Trial.

BACKGROUND/AIMS: The treatment of refractory functional dyspepsia (FD) is a challenge. Clidinium/chlordiazepoxide is a combination of antispasmodic and anxiolytic drugs that has been used as an adjunct treatment for FD in clinical practice with limited supporting evidence of efficacy. The aim of the study is to assess the efficacy and safety of clidinium/chlordiazepoxide as an adjunct treatment to a proton pump inhibitor (PPI) in refractory dyspepsia. METHODS: We performed a study of patients who met the Rome IV criteria for FD who failed to respond to PPIs. Patients were randomly assigned to groups that received clidinium/chlordiazepoxide or placebo as an add-on treatment to PPI for 4 weeks. The primary outcome was the rate of responders, which was defined as a > 50% reduction in dyspepsia symptom score after 4 weeks of treatment. The secondary outcomes were an improvement in the quality of life and the safety profile. RESULTS: Between March 2017 and February 2018, 78 patients were enrolled. The rates of responders in the clidinium/chlordiazepoxide group and placebo groups were 41.03 % and 5.13% at week 4 (P < 0.001). The clidinium/chlordiazepoxide group also showed significant improvement in overall quality of life over placebo. However, the clidinium/chlordiazepoxide group had more frequent drowsiness than the placebo group (30.27% vs 6.52%, P = 0.034). There were no major adverse events in either group. CONCLUSIONS: Clidinium/chlordiazepoxide significantly improved dyspeptic symptoms and quality of life. This combination may be used as an add-on therapy in FD patients without major adverse events.

Arginine, glutamine, and fish oil supplementation in cancer patients treated with concurrent chemoradiotherapy: A randomized control study.

We evaluated the effectiveness of arginine, glutamine, and fish oil supplementation in patients' ability to adhere to the planned regimen and associated toxicities in patients who received concurrent chemoradiotherapy (CCRT). Eighty-eight cancer patients were randomized into 2 groups, A; regular diet and B; regular diet plus nutritional supplementation during their CCRT course. Logistic regression was used to assess the association between toxicity and the study groups. Survival analysis was performed using the Kaplan-Meier method, and log-rank tests were used to compare between the 2 groups. Among 88 patients, 45%, 32%, and 23% were head and neck cancer, esophageal cancer, and cervical cancer patients, respectively. Significantly higher grade 3-4 hematologic toxicities were found in group A than in group B (23% vs 5%, P= 0.03). The CCRT completion rate was lower in group A than in group B (75% vs 91%), but the difference was not statistically significant (P= 0.09). Adjusted for type of cancer and age, group B patients were associated with lower hematologic toxicities of CCRT, P= 0.03. Two-year overall survival was 47% for group A, and 61% for group B, P= 0.22. In conclusion, incidence of severe hematologic toxicities were significantly lower in patients with arginine, glutamine, and fish oil supplementation during CCRT. These findings, therefore, need further studies on the isocaloric design.

Teprenone for the prevention of low-dose aspirin-induced gastric mucosal injury in Helicobacter pylori-negative patients.

Objectives: Low-dose aspirin is the standard treatment for the prevention of cardiovascular events in at-risk patients. We performed a randomized, placebo-controlled study to determine the efficacy of teprenone for primary prevention of gastrointestinal injury in patients taking LDA for vascular protection.Methods: Patients were eligible for enrollment if they required aspirin 100 mg/day. Aspirin- naïve patients without gastroduodenal ulcer and Helicobacter pylori infection were randomized to receive teprenone 150 mg/day or placebo for 12 weeks. Primary outcome was assessed by the incidence rate of gastroduodenal ulcer. Secondary outcomes were assessed by the incidence rate of gastric mucosal injury, the improvement in modified Lanza score (MLS), gastrointestinal symptom rating scale (GSRS) and the change of gastric immunohistochemical expression for COX-1.Results: Total of 130 patients were randomized, 64 in teprenone group and 66 in placebo group. There was no incidence of ulcer after 12 weeks in both groups. Incidence of gastric mucosal injury was higher in placebo group than in teprenone group (40.0 vs. 13.38%, p = .039). Mean change of MLS was higher in placebo group than in teprenone group (0.767 ± 0.467 vs. 0.271 ± 0.158, p = .003). Scores of mucosal edema, hyperemia and hemorrhage and the change of GSRS were not different between the two groups. Change of COX-1 immunoreactive score was higher in placebo group than in teprenone group (2.433 ± 1.476 vs. 1.233 ± 0.955, p = .001). There were no treatment-related adverse events.Conclusions: Teprenone is effective in preventing gastric mucosal injury in patients taking LDA. Preventive effects of teprenone on LDA-related gastroduodenal ulcers require further investigation.

Thailand Dyspepsia Guidelines: 2018.

The management of dyspepsia in limited-resource areas has not been established. In 2017, key opinion leaders throughout Thailand gathered to review and evaluate the current clinical evidence regarding dyspepsia and to develop consensus statements, rationales, levels of evidence, and grades of recommendation for dyspepsia management in daily clinical practice based on the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) approach. This guideline is mainly focused on the following 4 topics: (1) evaluation of patients with dyspepsia, (2) management, (3) special issues (overlapping gastroesophageal reflux disease/irritable bowel syndrome and non-steroidal anti-inflammatory drug/aspirin use), and (4) long-term follow-up and management to provide guidance for physicians in Thailand and other limited-resource areas managing such patients.

Thailand Consensus on Helicobacter pylori Treatment 2015.

Management of Helicobacter pylori infection is an important aspect of many upper gastrointestinal tract diseases, such as chronic gastritis, peptic ulcer disease, gastric cancer and mucosa-associated lymphoid tissue (MALT) lymphoma. The Thailand Consensus on H. pylori treatment 2015 consisted of 22 national experts who took active roles, discussed all important clinical information and investigated clinical aspects in four workshops, focuising on: (1) Diagnosis (2) Treatment (3) Follow-up after eradication and (4) H. pylori infection and special conditions. Experts were invited to participate on the basis of their expertise and contribution to H. pylori works and/or consensus methodology. The results of each workshop were taken to a final consensus vote by all experts. Recommendations were developed from the best evidence and availability to guide clinicians in management of this specific infection associated with variety of clinical outcomes.

Risk Factors for the Development of Hepatocellular Carcinoma in Thailand.

Hepatocellular carcinoma (HCC) is the most common type of liver cancer worldwide. The incidence of HCC is on the rise in Thailand, where it has become the most common malignancy in males and the third most common in females. Here, we review some of the risk factors that have contributed to this increase in HCC incidence in the Thai population. Hepatitis B virus (HBV) is the main etiologic risk factor for HCC, followed by hepatitis C virus (HCV). Patients with HBV genotype C have a higher positive rate of hepatitis B early antigen (HBeAg) and progress to cirrhosis and HCC earlier than genotype B. For HCV patients, 16% developed HCC associated cirrhosis by year 5 after diagnosis, and the cumulative risk for death from HCC at year 10 was 60%. Dietary exposure to the fungal hepatocarcinogen aflatoxin B1 has been shown to interact synergistically with HBV infection to increase the risk of early onset HCC. Chronic alcohol abuse remains an important risk factor for malignant transformation of hepatocytes, frequently in association with alcohol-induced cirrhosis. In recent years, obesity and metabolic syndrome have markedly increased the incidence of HCC and are important causes of HCC in some resource-rich regions.

Three-day versus five-day somatostatin infusion combination with endoscopic variceal ligation in the prevention of early rebleeding following acute variceal hemorrhage: A randomized controlled trial.

AIM: Combined pharmacological and endoscopic therapy is recommended for initial treatment of acute variceal bleeding (AVB). The optimal duration of therapy with a vasoactive agent is not well established. The aim of this study was to compare the efficacy and safety of 3-day and 5-day somatostatin treatment in the prevention of early rebleeding after endoscopic variceal ligation (EVL). METHODS: In a double-blind, prospective trial, cirrhotic patients with AVB who underwent EVL were randomly assigned to receive a continuous infusion of somatostatin for either 3 days or 5 days. RESULTS: A total of 95 patients were enrolled; 50 patients in the 3-day group and 45 patients in the 5-day group after initial hemostasis by combination therapy with somatostatin and EVL. Both groups were comparable in terms of baseline data. Very early and early rebleeding within 5 days and 42 days occurred in one and three patient (2%, 6%) in the 3-day group and three and two patients (6.67%, 4.45%) in the 5-day group (P = 0.342, 0.735), respectively. Overall, eight patients died (three from variceal rebleeding and five from causes other than variceal bleed); four (8%) in the 3-day group and four (8.89%) in the 5-day group (P = 0.876). Multivariate analysis revealed that none of the factors was a predictor of rebleeding. No serious side-effects and complications were observed. CONCLUSION: A 3-day course of somatostatin is as effective as a 5-day course for the control of variceal bleeding and prevention of early rebleeding when used as combination therapy with EVL.

The association of rectal equivalent dose in 2 Gy fractions (EQD2) to late rectal toxicity in locally advanced cervical cancer patients who were evaluated by rectosigmoidoscopy in Faculty of Medicine, Chiang Mai University.

PURPOSE: To evaluate association between equivalent dose in 2 Gy (EQD2) to rectal point dose and gastrointestinal toxicity from whole pelvic radiotherapy (WPRT) and intracavitary brachytherapy (ICBT) in cervical cancer patients who were evaluated by rectosigmoidoscopy in Faculty of Medicine, Chiang Mai University. MATERIALS AND METHODS: Retrospective study was designed for the patients with locally advanced cervical cancer, treated by radical radiotherapy from 2004 to 2009 and were evaluated by rectosigmoidoscopy. The cumulative doses of WPRT and ICBT to the maximally rectal point were calculated to the EQD2 and evaluated the association of toxicities. RESULTS: Thirty-nine patients were evaluated for late rectal toxicity. The mean cumulative dose in term of EQD2 to rectum was 64.2 Gy. Grade 1 toxicities were the most common findings. According to endoscopic exam, the most common toxicities were congested mucosa (36 patients) and telangiectasia (32 patients). In evaluation between rectal dose in EQD2 and toxicities, no association of cumulative rectal dose to rectal toxicity, except the association of cumulative rectal dose in EQD2 >65 Gy to late effects of normal tissue (LENT-SOMA) scale ≥ grade 2 (p = 0.022; odds ratio, 5.312; 95% confidence interval, 1.269-22.244). CONCLUSION: The cumulative rectal dose in EQD2 >65 Gy have association with ≥ grade 2 LENT-SOMA scale.

Clinical features and prognostic factors for liver cancer from a referral center in northern Thailand.

BACKGROUND: Primary liver cancer included hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA), is the leading cancer with high mortality in Thailand. We aim to evaluate the overall survival and predictor of mortality in patients with HCC and CCA. MATERIAL AND METHOD: We reviewed medical records of 786 patients with liver mass between July 2007 and June 2010, 287 patients were HCC and 449 patients were CCA. The overall survival and prognostic variables for survival were analyzed. RESULTS: The mean age of HCC patients and CCA patient were 53.8 years and 59.2 years. Male was predominant, 85% and 74% in HCC and CCA. By BCLC staging for HCC, patients at early stage (A), intermediate stage (B), advanced stage (C), and terminal stage (D) were 40 (13.9%), 105 (36.6%), 95 (33.1%), and 43 (15.0%). Among 449 CCA patients, 143 (31.8%) were intrahepatic type and 306 (68.2%) were ductal type. The mean follow-up time for HCC and CCA patients were 20.1 and 16.7 months. The 1-year, 2-year, and 3-year survival of HCC and CCA were 55%, 34%, 31.3% and 54%, 21.2%, 19.1%, respectively. Predictor of death in HCC patients included portal vein thrombosis and did not receive any treatment (p < 0.05). Meanwhile, the predictor of death in CCA patient included intrahepatic type, total bilirubin > 2 mg/dl, CA 19-9 > 100, and unresectable tumor (p< 0.05). CONCLUSION: The survival of patients who received any type of treatment was much better than in the past. Still, in patients with advanced disease whom only supportive treatments were provided, the prognosis is grave.

Inducible NOS mediates CNP-induced relaxation of intestinal myofibroblasts.

Contraction of intestinal myofibroblasts (IMF) contributes to the development of strictures and fistulas seen in inflammatory bowel disease, but the mechanisms that regulate tension within these cells are poorly understood. In this study we investigated the role of nitric oxide (NO) signaling in C-type natriuretic peptide (CNP)-induced relaxation of IMF. We found that treatment with ODQ, a soluble guanylyl cyclase (sGC) inhibitor, or N(G)-nitro-L-arginine (L-NNA) or N(G)-monomethyl-L-arginine (L-NMMA), inhibitors of NO production, all impaired the relaxation of human and mouse IMF in response to CNP. ODQ, L-NNA, and L-NMMA also prevented CNP-induced elevations in cGMP concentrations, and L-NNA or L-NMMA blocked CNP-induced decreases in myosin light phosphorylation. IMF isolated from transgenic mice deficient in inducible nitric oxide synthase (iNOS) had reduced relaxation responses to CNP compared with IMF from control mice and were insensitive to the effects of ODQ, L-NNA, and L-NMMA on CNP treatment. Together these data indicate that stimulation of sGC though NO produced by iNOS activation is required for maximal CNP-induced relaxation in IMF.

Intestinal myofibroblasts produce nitric oxide in response to combinatorial cytokine stimulation.

Inflammatory bowel disease (IBD) patients display elevated levels of intraluminal nitric oxide (NO). NO can react with other molecules to form toxic compounds, which has led to the idea that NO may be an important mediator of IBD. However, the cellular source of NO and how its production is regulated in the intestine are unclear. In this study we aimed to determine if intestinal myofibroblasts produce NO in response to the IBD-associated cytokines IL-1ß, TNFα, and IFNγ. Intestinal myofibroblasts were isolated from mice and found to express inducible nitric oxide synthase (iNOS) mRNA, but not endothelial NOS or neuronal NOS. Individual treatment of myofibroblasts with IL-1ß, TNFα, or IFNγ had no effect on NO production, but stimulation with combinations of these cytokines synergistically increased iNOS mRNA and protein expression. Treatment with TNFα or IFNγ increased cell surface expression of IFNγRI or TNFRII, respectively, suggesting that these cytokines act in concert to prime NO production by myofibroblasts. Impairment of NF-κB activity with a small molecule inhibitor was sufficient to prevent increased expression of IFNγRI or TNFRII, and inhibition of Akt, JAK/STAT, or NF-κB blocked nearly all NO production induced by combinatorial cytokine treatment. These data indicate that intestinal myofibroblasts require stimulation by multiple cytokines to produce NO and that these cytokines act through a novel pathway involving reciprocal cytokine receptor regulation and signaling by Akt, JAK/STAT, and NF-κB.