2,4-Diamino-Quinazoline, a Wnt Signaling Inhibitor, Suppresses Gastric Cancer Progression and Metastasis.

Gastric cancer (GC) is among the most treatment-refractory epithelial malignancies. Aberrant activation of Wnt/ß-catenin-signaling has been implicated in a variety of human cancers, including gastric cancer. Here we report that the elevated expression of lymphoid enhancer binding factor 1 (Lef1) is associated with the TNM (tumor- node-metastasis) stage of gastric cancer. Subsequently, 2,4-diamino-quinazoline (2,4-DAQ), a selective inhibitor of Lef1, was identified to suppress the expression of Wnt/ß-catenin target genes such as AXIN2, MYC and LGR5 and result in the suppression of gastric cancer cell growth through the apoptotic pathway. The 2,4-DAQ also exhibited an inhibitory effect on the migration/invasion of gastric cancer cells. Importantly, the treatment of human gastric tumor xenograft with 2,4-DAQ suppressed tumor growth in a nude mouse model. Furthermore, 2,4-DAQ appears effective on patient-derived organoids (PDOs). Transcriptome sequencing analysis also revealed that 2,4-DAQ are more effective on the gastric cancers that exhibit higher expression levels of Wnt-signaling pathway-related genes than their adjacent normal gastric tissues.

Upregulation of bone morphogenetic protein 1 is associated with poor prognosis of late-stage gastric Cancer patients.

BACKGROUND: Gastric cancer is the eighth most common cancer in Taiwan, with a 40% 5-year survival rate. Approximately 40% of patients are refractory to chemotherapy. Currently, the anti-HER2 therapy is the only clinically employed targeted therapy. However, only 7% patients in Taiwan are HER2-positive. Identifying candidate target genes will facilitate the development of adjuvant targeted therapy to increase the efficacy of gastric cancer treatment. METHODS: Clinical specimens were analyzed by targeted RNA sequencing to assess the expression levels of target genes. Statistical significance of differential expression and correlation between specimens was evaluated. The correlation with patient survival was analyzed as well. In vitro cell mobility was determined using wound-healing and transwell mobility assays. RESULTS: Expression of BMP1, COL1A1, STAT3, SOX2, FOXA2, and GATA6 was progressively dysregulated through the stages of gastric oncogenesis. The expression profile of these six genes forms an ubiquitously biomarker signature that is sufficient to differentiate cancer from non-cancerous specimens. High expression status of BMP1 correlates with poor long-term survival of late-stage patients. In vitro, suppression of BMP1 inhibits the mobility of the gastric cancer cell lines, indicating a role of BMP1 in metastasis. CONCLUSIONS: BMP1 is upregulated in gastric cancer and is correlated with poor patient survival. Suppression of BMP1 reduced gastric cancer mobility in vitro. Our finding suggests that anti-BMP1 therapy will likely augment the efficacy of standard chemotherapy and improve the treatment outcome.

Dehydroepiandrosterone sulfate and dehydroepiandrosterone sulfate/cortisol ratio in cirrhotic patients with septic shock: another sign of hepatoadrenal syndrome?

BACKGROUND: Cirrhotic patients are susceptible to sepsis and critical illness-related corticosteroid insufficiency (CIRCI). Dehydroepiandrosterone sulfate (DHEAS) is a corticotropin-dependent adrenal androgen, which has immunostimulating and antiglucocorticoid effects. Considering the synchronized synthesis of cortisol and DHEAS and their opposing effects to each other, investigators have proposed measuring these two hormones as a ratio. Severe sepsis has been associated with low DHEAS, especially relative to high cortisol. Despite growing interest in the role of adrenal androgen replacement in critical illness, there have been no data about DHEAS and the DHEAS/cortisol ratio in patients with liver cirrhosis. We studied whether low concentrations of DHEAS and decreased DHEAS/cortisol ratio are associated with poor outcome in patients with liver cirrhosis and septic shock. METHODS: We recruited 46 cirrhotic patients with septic shock, and 46 noncirrhotic counterparts matched by age and sex. We evaluated adrenal function using the short corticotropin stimulation test and analyzed the relation between DHEAS and cortisol. RESULTS: While the nonsurvivors in the cirrhotic group had significantly lower baseline DHEAS, lower baseline DHEAS/cortisol ratio, and reduced increments of both DHEAS and cortisol upon corticotropin stimulation, the survivors had lower baseline cortisol. Cirrhotic patients with lower DHEAS/cortisol ratio (<1.50) had higher levels of interleukin-6 and tumor necrosis factor alpha, higher Sequential Organ Failure Assessment scores, and higher rates of CIRCI and hospital mortality. Using the area under the receiver operating characteristic (AUROC) curve, both DHEAS and the DHEAS/cortisol ratio demonstrated a good discriminative power for predicting hospital survival (AUROC 0.807 and 0.925 respectively). The cirrhotic group had lower DHEAS and DHEAS/cortisol ratio but higher rates of CIRCI and hospital mortality, compared to the noncirrhotic group. CONCLUSIONS: There is dissociation between cortisol (increased) and DHEAS (decreased) in those cirrhotic patients who succumb to septic shock. Low DHEAS/cortisol ratios are associated with more severe diseases, inflammation, and CIRCI and can serve as a prognostic marker. More investigations are needed to evaluate the role of adrenal androgen in this clinical setting.

Inhibition of CCAR1, a Coactivator of ß-Catenin, Suppresses the Proliferation and Migration of Gastric Cancer Cells.

The aberrant activation of Wnt signaling has been implicated in a variety of human cancers, including gastric cancer. Given the current hypothesis that cancer arises from cancer stem cells (CSCs), targeting the critical signaling pathways that support CSC self-renewal appears to be a useful approach for cancer therapy. Cell cycle and apoptosis regulator 1 (CCAR1) is a transcriptional coactivator which has been shown to be a component of Wnt/ß-catenin signaling, and which plays an important role in transcriptional regulation by ß-catenin. However, the function and clinical significance of CCAR1 in gastric cancer have not been elucidated. Here, we show that elevated CCAR1 nuclear expression correlates with the occurrence of gastric cancer. In addition, RNAi-mediated CCAR1 reduction not only suppressed the cell growth and increased apoptosis in AGS and MKN28 cells, but also reduced the migration and invasion ability of these cells. Furthermore, an in vivo xenograft assay revealed that the expression level of CCAR1 was critical for tumorigenesis. Our data demonstrates that CCAR1 contributes to carcinogenesis in gastric cancer and is required for the survival of gastric cancer cells. Moreover, CCAR1 may serve as a diagnostic marker and a potential therapeutic target.

Transpapillary biliary biopsy for malignant biliary strictures: comparison between cholangiocarcinoma and pancreatic cancer.

BACKGROUND: Tissue sampling for biliary stricture is important for differential diagnosis and further treatment. This study aims to assess the differences of transpapillary biliary biopsy for malignant biliary strictures between cholangiocarcinoma and pancreatic cancer. METHODS: From January 2010 to December 2013, we retrospectively studied 79 patients who suffered from biliary strictures and received transpapillary forceps biopsy after sphincterotomy for tissue sampling. The diagnostic sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of forceps biopsy were calculated in all cases for both cholangiocarcinoma and pancreatic cancer patients. Possible factors that distinguish malignant strictures from benign strictures and which could affect the accuracy of tissue sampling were analyzed. RESULTS: There are 65 malignant and 14 benign biliary stricture patients enrolled. The malignant group has a significantly higher serum bilirubin level than the benign group, but age, clinical presentation, level of serum carcinoembryonic antigen (CEA), carbohydrate antigen (CA) 19-9, and alkaline phosphatase are not. The sensitivity, specificity, PPV, and NPV of forceps biopsy for biliary stricture are 53.85, 100, 100, and 31.82%, respectively. The cholangiocarcinoma group has a higher sensitivity (73.53 versus 29.17%, p < 0.001), older age, lower CA 19-9 level, and more common hepatic duct strictures than the pancreatic group. The age, serum CEA, CA 19-9 and the alkaline phosphatase level, serum bilirubin level >10 mg/dL, tissue sampling ≧3 are not significant factors affecting diagnostic accuracy in forceps biopsy for pancreatobiliary strictures. There is neither major bleeding nor perforation in our study. CONCLUSIONS: Transpapillary forceps biopsy of biliary strictures after sphincterotomy for tissue sampling is safe and a significantly higher sensitive method in cholangiocarcinoma but not in pancreatic cancer.

Aberrant JAK/STAT Signaling Suppresses TFF1 and TFF2 through Epigenetic Silencing of GATA6 in Gastric Cancer.

Aberrant Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling is crucial to the development of gastric cancer. In this study, we examined the role of STAT3 in the expression and methylation of its targets in gastric cancer patients. Results from RNA sequencing identified an inverse correlation between the expression of STAT3 and GATA6 in 23 pairs of gastric cancer patient samples. We discovered that the expression of GATA6 is epigenetically silenced through promoter methylation in gastric cancer cell lines. Interestingly, the inhibition of STAT3 using a novel STAT3 inhibitor restored the expression of GATA6 and its targets, trefoil factors 1 and 2 (TFF1/2). Moreover, disruption of STAT3 binding to GATA6 promoter by small hairpin RNA restored GATA6 expression in AGS cells. A clinically significant correlation was also observed between the expression of GATA6 and TFF1/2 among tissue samples from 60 gastric cancer patients. Finally, bisulfite pyrosequencing revealed GATA6 methylation in 65% (39/60) of the patients, and those with higher GATA6 methylation tended to have shorter overall survival. In conclusion, we demonstrated that aberrant JAK/STAT signaling suppresses TFF1/2 partially through the epigenetic silencing of GATA6. Therapeutic intervention of STAT3 in reversing the epigenetic status of GATA6 could benefit the treatment of gastric cancer and is worthy of further investigation.

Alpha-Fetoprotein Measurement Benefits Hepatocellular Carcinoma Surveillance in Patients with Cirrhosis.

OBJECTIVES: Liver cirrhosis is a major risk factor for hepatocellular carcinoma (HCC), and all liver study societies recommend HCC surveillance in patients with cirrhosis. However, no ideal modality for HCC surveillance has been determined. The aim of this study is to assess the effectiveness of α-fetoprotein (AFP) measurement in HCC surveillance. METHODS: In this retrospective analysis, all patients with cirrhosis, who received HCC surveillance through ultrasound (US) and AFP measurement between January 2002 and July 2010, were followed up until June 2013. The performance effectiveness of surveillance using AFP, US, or both in HCC detection was compared. RESULTS: Overall, 1,597 patients were followed for a median duration of 4.75 (range 1.42-12) years. Over the 8563.25-person-year follow-up period, 363 patients (22.7%) developed HCCs. For HCC detection, the area under the receiver operator characteristic curve of surveillance AFP was 0.844 (95% confidence interval: 0.820-0.868, P<0.001). When the traditional cutoff value of 20 ng/ml was used, the sensitivity and specificity of AFP were 52.9% and 93.3%, respectively. US exhibited a sensitivity and specificity of 92.0% and 74.2%, respectively. A combination of US and AFP exhibited a sensitivity and specificity of 99.2% and 68.3%, respectively. By using cut-off at 20 ng/ml and AFP level increase ≥2 × from its nadir during the previous 1 year, the combination of US and AFP yielded a sensitivity of 99.2% and an improved specificity of 71.5%. CONCLUSIONS: The complementary use of AFP and US improved the effectiveness of HCC surveillance in patients with cirrhosis.

Serum levels of apolipoprotein A-I and high-density lipoprotein can predict organ failure in acute pancreatitis.

INTRODUCTION: Predicting severity of pancreatitis is an important goal. Clinicians are still searching for novel and simple biomarkers that can better predict persistent organ failure (OF). Lipoproteins, especially high-density lipoprotein (HDL), and apolipoprotein A-I (APO A-I), have been shown to have anti-inflammation effects in various clinical settings. Severe acute pancreatitis (SAP) is associated with hypo-lipoproteinemia. We studied whether the concentrations of HDL and APO A-I can predict persistent OF in patients with predicted SAP admitted to the ICU. METHODS: In 66 patients with predicted SAP, we prospectively evaluated the relationship between lipid levels, inflammatory cytokines and clinical outcomes, including persistent OF and hospital mortality. Blood samples were obtained within 24 hours of admission to the ICU. RESULTS: HDL and APO A-I levels were inversely correlated with various disease severity scores. Patients with persistent OF had lower levels of HDL and APO A-I, while those with transient OF had lower levels of interleukin-6, tumor necrosis factor-α and lower rates of hospital mortality. Meanwhile, hospital non-survivors had lower concentrations of HDL, and APO A-I compared to the survivors. By using the area under the receiver operating characteristic (AUROC) curve, both HDL and APO A-I demonstrated an excellent discriminative power for predicting persistent OF among all patients (AUROC 0.912 and 0.898 respectively) and among those with OF (AUROC 0.904 and 0.895 respectively). Pair-wise comparison of AUROC showed that both HDL and APO A-I had better discriminative power than C-reactive protein to predict persistent OF. CONCLUSIONS: Serum levels of HDL and APO A-I at admission to the ICU are inversely correlated with disease severity in patients with predicted SAP and can predict persistent OF in this clinical setting.

Gastrointestinal metastasis from primary sarcomatoid carcinoma of the lung: a case report and review of the literature.

Gastrointestinal metastases in lung cancer are extremely rare. The report presents a rare case of primary lung sarcomatoid carcinoma with both gastric and colonic metastases, and reviews the literature about endoscopic presentation of colonic metastases.

Critical illness-related corticosteroid insufficiency in cirrhotic patients with acute gastroesophageal variceal bleeding: risk factors and association with outcome*.

OBJECTIVES: Critical illness-related corticosteroid insufficiency can adversely influence the prognosis of critically ill patients. However, its impact on the outcomes of patients with cirrhosis and acute gastroesophageal variceal bleeding remains unknown. We evaluated adrenal function using short corticotropin stimulation test in patients with cirrhosis and gastroesophageal variceal bleeding. The main outcomes analyzed were 5-day treatment failure and 6-week mortality. DESIGN: Prospective observational study. SETTING: Ten-bed gastroenterology-specific medical ICU at a 3,613-bed university teaching hospital in Taiwan. PATIENTS: Patients with liver cirrhosis and acute gastroesophageal variceal bleeding. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We evaluated adrenal function using short corticotropin stimulation test in 157 episodes of gastroesophageal variceal bleeding in 143 patients with cirrhosis. Critical illness-related corticosteroid insufficiency occurred in 29.9% of patients. The patients with critical illness-related corticosteroid insufficiency had higher rates of treatment failure and 6-week mortality (63.8% vs 10.9%, 42.6% vs 6.4%, respectively; p < 0.001). The cumulative rates of survival at 6 weeks were 57.4% and 93.6% for the critical illness-related corticosteroid insufficiency group and normal adrenal function group, respectively (p < 0.001). The cortisol response to corticotropin was inversely correlated with Model for End-Stage Liver Disease and Child-Pugh scores and positively correlated with the levels of high-density lipoprotein and total cholesterol. Hypovolemic shock, high-density lipoprotein, platelet count, and bacterial infection at inclusion are independent factors predicting critical illness-related corticosteroid insufficiency, whereas critical illness-related corticosteroid insufficiency, Model for End-Stage Liver Disease score, hypovolemic shock, hepatocellular carcinoma, and active bleeding at endoscopy are independent factors to predict treatment failure. Multivariate analysis also identified Model for End-Stage Liver Disease score, hypovolemic shock, and bacterial infection at inclusion as independent factors associated with 6-week mortality. CONCLUSIONS: Critical illness-related corticosteroid insufficiency is common in cirrhotic patients with acute gastroesophageal variceal bleeding and is an independent factor to predict 5-day treatment failure.

Acute renal failure in cirrhotic patients with severe sepsis: value of urinary interleukin-18.

BACKGROUND AND AIM: Acute renal failure (ARF) is a common complication of liver cirrhosis and severe sepsis. Differentiating functional renal failure from acute tubular necrosis (ATN) has been difficult in this clinical setting. It has been shown that urinary interleukin 18 (IL-18) can serve as a sensitive marker for ARF and ATN. This study was aimed to investigate the diagnostic and prognostic values of urinary IL-18 in ARF associated with liver cirrhosis and severe sepsis. METHODS: We prospectively evaluated the relationship between urinary IL-18 and clinical outcomes in 168 consecutive cirrhotic patients with severe sepsis. RESULTS: One hundred and eight patients (64.3%) developed ARF at admission to the intensive care unit. ARF was associated with higher urinary IL-18 and impaired effective arterial volume. Renal failure was functional in 64 (59.2%), due to acute tubular necrosis (ATN) in 30 (27.7%), and mixed type in 14 (12.9%). Patients with ATN had significantly higher levels of urinary IL-18, rates of vasopressor dependency, and hospital mortality than those with functional renal failure. By using the areas under receiver operating characteristic (AUROC) curve, urinary IL-18 demonstrated an excellent discriminative power (AUROC 0.882) for diagnosing tubular injury in those with ARF. Meanwhile, hospital survivors had significantly lower urinary and serum IL-18 levels, compared to non-survivors. In multivariate analysis, urinary IL-18, international normalized ratio, and mean arterial pressure were independent factors to predict hospital mortality. CONCLUSIONS: Urinary IL-18 can serve as a diagnostic and prognostic marker in cirrhotic patients with severe sepsis.

Cardiovascular outcomes in hepatitis C virus infected patients treated with direct acting antiviral therapy: a retrospective multi-institutional study.

BACKGROUND: Chronic hepatitis C virus (HCV) infection is associated with increased cardiovascular risks. We aimed to investigate the impact of direct acting antiviral (DAA) on HCV-associated cardiovascular events. METHODS: In this retrospective cohort study, patients with the diagnosis of chronic HCV were retrieved from multi-institutional electronic medical records, where diagnosis of HCV was based on serum HCV antibody and HCV-RNA test. The patients eligible for analysis were then separated into patients with DAA treatment and patient without DAA treatment. Primary outcomes included acute coronary syndrome, heart failure (HF), venous thromboembolism (VTE), stroke, cardiovascular death, major adverse cardiovascular event (MACE), and all-cause mortality. Outcomes developed during follow-up were compared between DAA treatment and non-DAA treatment groups. RESULTS: There were 41 565 patients with chronic HCV infection identified. After exclusion criteria applied, 1984 patients in the DAA treatment group and 413 patients in the non-DAA treatment group were compared for outcomes using inverse probability of treatment weighting. Compared to patients in non-DAA treatment group, patients in DAA treatment group were associated with significantly decreased HF (hazard ratio [HR]: 0.65, 95% confidence interval [CI]: 0.44-0.97, P = 0.035), VTE (HR: 0.19, 95% CI: 0.07-0.49, P = 0.001), MACE (HR: 0.73, 95% CI 0.59-0.92, P = 0.007), and all-cause mortality (HR: 0.50, 95% CI: 0.38-0.67, P < 0.001) at 3-year follow-up. CONCLUSIONS: Chronic HCV patients treated with DAA experienced lower rates of cardiovascular events and all-cause mortality than those without treatment. The reduction of VTE was the most significant impact of DAA treatment among the cardiovascular outcomes.

Direct-Acting Antivirals Reduce the De Novo Development of Esophageal Varices in Patients with Hepatitis C Virus Related Liver Cirrhosis.

The real-world benefits of direct-acting antiviral (DAA)-induced sustained virologic response (SVR) on the de novo occurrence and progression of esophageal varices (EV) remain unclear in patients with hepatitis C virus (HCV)-related liver cirrhosis (LC). This is a retrospective cohort study evaluating all patients with Child-Pugh class A HCV-related LC during 2013 to 2020 in the Chang Gung Medical System. A total of 215 patients fit the inclusion criteria and were enrolled. Of them, 132 (61.4%) patients achieved DAA induced-SVR and 83 (38.6%) did not receive anti-viral treatment. During a median follow-up of 18.4 (interquartile range, 10.1−30.9) months, the 2-year incidence of de novo EV occurrence was 8 (7.0%) in the SVR group and 7 (12.7%) in the treatment-naïve group. Compared to the treatment-naïve group, the SVR group was associated with a significantly lower incidence of EV occurrence (adjusted hazard ratio [aHR]: 0.47, p = 0.030) and a significantly lower incidence of EV progression (aHR: 0.55, p = 0.033). The risk of EV progression was strongly correlated with the presence of baseline EV (p < 0.001). To the best of our knowledge, this is the first study to demonstrate that DAA-induced SVR is associated with decreased risk of de novo EV occurrence and progression in the real world.

Fusobacterium nucleatum colonization is associated with decreased survival of helicobacter pylori-positive gastric cancer patients.

BACKGROUND: An increased amount of Fusobacterium nucleatum (F. nucleatum) is frequently detected in the gastric cancer-associated microbiota of the Taiwanese population. F. nucleatum is known to exert cytotoxic effects and play a role in the progression of colorectal cancer, though the impact of F. nucleatum colonization on gastric cancer cells and patient prognosis has not yet been examined. AIM: To identify F. nucleatum-dependent molecular pathways in gastric cancer cells and to determine the impact of F. nucleatum on survival in gastric cancer. METHODS: Coculture of F. nucleatum with a gastric cancer cell line was performed, and changes in gene expression were investigated. Genes with significant changes in expression were identified by RNA sequencing. Pathway analysis was carried out to determine deregulated cellular functions. A cohort of gastric cancer patients undergoing gastrectomy was recruited, and nested polymerase chain reaction was performed to detect the presence of F. nucleatum in resected cancer tissues. Statistical analysis was performed to determine whether F. nucleatum colonization affects patient survival. RESULTS: RNA sequencing and subsequent pathway analysis revealed a drastic interferon response induced by a high colonization load. This response peaked within 24 h and subsided after 72 h of incubation. In contrast, deregulation of actin and its regulators was observed during prolonged incubation under a low colonization load, likely altering the mobility of gastric cancer cells. According to the clinical specimen analysis, approximately one-third of the gastric cancer patients were positive for F. nucleatum, and statistical analysis indicated that the risk for colonization increases in late-stage cancer patients. Survival analysis demonstrated that F. nucleatum colonization was associated with poorer outcomes among patients also positive for Helicobacter pylori (H. pylori). CONCLUSION: F. nucleatum colonization leads to deregulation of actin dynamics and likely changes cancer cell mobility. Cohort analysis demonstrated that F. nucleatum colonization leads to poorer prognosis in H. pylori-positive patients with late-stage gastric cancer. Hence, combined colonization of F. nucleatum and H. pylori is a predictive biomarker for poorer survival in late-stage gastric cancer patients treated with gastrectomy.

Epigenetic Silencing of STAT3-Targeted miR-193a, by Constitutive Activation of JAK/STAT Signaling, Leads to Tumor Progression Through Overexpression of YWHAZ in Gastric Cancer.

PURPOSE: The purpose of this study was to identify genes that were epigenetically silenced by STAT3 in gastric cancer. METHODS: MBDcap-Seq and expression microarray were performed to identify genes that were epigenetically silenced in AGS gastric cancer cell lines depleted of STAT3. Cell lines and animal experiments were performed to investigate proliferation and metastasis of miR-193a and YWHAZ in gastric cancer cell lines. Bisulfite pyrosequencing and tissue microarray were performed to investigate the promoter methylation of miR-193a and expression of STAT3, YWHAZ in patients with gastritis (n = 8) and gastric cancer (n = 71). Quantitative methylation-specific PCR was performed to examine miR-193a promoter methylation in cell-free DNA of serum samples in gastric cancer patients (n = 19). RESULTS: As compared with parental cells, depletion of STAT3 resulted in demethylation of a putative STAT3 target, miR-193a, in AGS gastric cancer cells. Although bisulfite pyrosequencing and epigenetic treatment confirmed that miR-193a was epigenetically silenced in gastric cancer cell lines, ChIP-PCR found that it may be indirectly affected by STAT3. Ectopic expression of miR-193a in AGS cells inhibited proliferation and migration of gastric cancer cells. Further expression microarray and bioinformatics analysis identified YWHAZ as one of the target of miR-193a in AGS gastric cancer cells, such that depletion of YWHAZ reduced migration in AGS cells, while its overexpression increased invasion in MKN45 cells in vitro and in vivo. Clinically, bisulfite pyrosequencing revealed that promoter methylation of miR-193a was significantly higher in human gastric cancer tissues (n = 11) as compared to gastritis (n = 8, p < 0.05). Patients infected with H. pylori showed a significantly higher miR-193a methylation than those without H. pylori infection (p < 0.05). Tissue microarray also showed a positive trend between STAT3 and YWHAZ expression in gastric cancer patients (n = 60). Patients with serum miR-193a methylation was associated with shorter overall survival than those without methylation (p < 0.05). CONCLUSIONS: Constitutive activation of JAK/STAT signaling may confer epigenetic silencing of the STAT3 indirect target and tumor suppressor microRNA, miR-193a in gastric cancer. Transcriptional suppression of miR-193a may led to overexpression of YWHAZ resulting in tumor progression. Targeted inhibition of STAT3 may be a novel therapeutic strategy against gastric cancer.

Helios Expression in Tumor-Infiltrating Lymphocytes Correlates with Overall Survival of Advanced Gastric Cancer Patients.

Immunotherapy is a highly promising approach for the treatment of gastric cancer, the third-leading cause of overall cancer death worldwide. In particular, tumor-infiltrating lymphocytes and peripheral blood mononuclear cells are believed to mediate host immune responses, although this activity may vary depending on the activation status and/ or their microenvironments. Here, we examined the expression of a specific zinc finger transcription factor, Helios (IKZF2), in gastric tumor-infiltrating lymphocytes by immunohistochemistry and the correlation with survival. Segregation of gastric cancer patients into high- vs. low-Helios-expressing tumor-infiltrating lymphocytes showed those with high expression to exhibit longer survival in gastric cancer patients, Helicobacter pylori-infected gastric cancer patients and advanced stage (III-IV) gastric cancer patients. In particular, Helios expression was an independent factor for survival in advanced gastric cancer patients. We performed immunofluorescence staining to detect Helios expression in tumor-infiltrating lymphocytes and peripheral blood mononuclear cells. We found that Helios is expressed more in CD4+ T cells and little in CD8+ T cells in infiltrated lymphocytes in gastric cancer. In summary, we believe that the study of specific characteristics of tumor-infiltrating lymphocytes can delineate the interactions of immune and tumor cells to improve upon immunotherapy strategies.

Nationwide cohort study of outcomes of acute myocardial infarction in patients with liver cirrhosis: A nationwide cohort study.

Liver cirrhotic predisposes patients to coagulopathy and bleeding. Little is known about outcomes of acute myocardial infarction (AMI) in cirrhotic patients.Data from Taiwan National Health Insurance Research Database during 2001 to 2013 were retrieved for patients admitted with cirrhosis and AMI. We excluded patients with missing information, <20 years old, previous AMI, previous coronary intervention, and liver transplant. Patients were separated into cirrhotic and non-cirrhotic. Primary outcomes included all-cause mortality, recurrent myocardial infarction (MI), major cardiac and cerebrovascular events (MACCE: recurrent MI, revascularization, ischemic stroke, and heart failure), and liver outcomes (hepatic encephalopathy, ascites tapping, spontaneous peritonitis, and esophageal varices bleeding).A total of 3217 cirrhotic patients and 6434 non-cirrhotic patients were analyzed, with a mean follow up of 2.8 ±â€Š3.3 years. In cirrhotic patients with AMI, subsequent coronary and cerebrovascular events were lower in comparison to non-cirrhotic patients, with higher all-cause mortality observed from adverse liver related outcomes and bleeding. There were significantly lower cumulative incidence of both recurrent MI and MACCE in cirrhotic patients with AMI compared with non-cirrhotic patients with AMI (hazard ratio [HR] 0.82, confidence interval [CI] 0.71-0.94, P = .006 and HR 0.86, 95% CI 0.79-0.92, P < .001, respectively). There was significantly higher cumulative incidence of liver related outcome in cirrhotic patients with AMI compared with non-cirrhotic patients with AMI (HR 2.27, 95% CI 2.06-2.51, P < .001). And there was significantly higher all-cause mortality in cirrhotic patients with AMI compared with non-cirrhotic patients with AMI (HR 1.30, 95% CI 1.23-1.38, P < .001).In cirrhotic cohort with AMI, a decreased in coronary and cerebrovascular events were observed. However, these patients also had higher all-cause mortality due to adverse liver outcomes and bleeding.

Low serum concentration of apolipoprotein A-I is an indicator of poor prognosis in cirrhotic patients with severe sepsis.

BACKGROUND/AIMS: Severe sepsis is frequently associated with hypocholesterolemia which is also a common finding in cirrhotic patients. Lipoprotein is capable of binding endotoxin to which cirrhotic patients exhibit an excessive pro-inflammatory response. METHODS: We evaluated the relationship between lipid levels, inflammatory cytokines and clinical outcomes in 103 cirrhotic patients with severe sepsis. RESULTS: The non-survivors had significantly lower concentrations of total cholesterol, high-density lipoprotein (HDL), and apolipoprotein A-I (APO A-I). HDL and APO A-I levels were inversely correlated with interleukin-6, tumor necrosis factor-alpha, and various disease severity scores. Serum creatinine, mean arterial pressure and low level of APO A-I (<47.5mg/dl) were independent factors to predict 90-day mortality. The cumulative survival rates at 90 days were 63.8% and 8.9% for the high APO A-I and low APO A-I groups (p<0.0001). Low APO A-I was also associated with lower mean arterial pressure, higher rate of vasopressor dependency, and greater plasma renin activity. CONCLUSIONS: Serum levels of HDL and APO A-I are inversely correlated with liver reserve and disease severity in cirrhotic patients with severe sepsis. Low level of APO A-I is associated with a marked impairment of effective arterial volume, multiple organ dysfunction and a poor prognosis.

Critical illness-related corticosteroid insufficiency in patients with severe acute biliary pancreatitis: a prospective cohort study.

INTRODUCTION: Gallstones are the most common cause of acute pancreatitis worldwide. Patients with severe acute biliary pancreatitis (SABP) constitute a subgroup of severe acute pancreatitis (SAP) patients in whom systemic inflammation may be triggered and perpetuated by different mechanisms. The aim of this prospective investigation was to examine the adrenal response to corticotropin and the relationship between adrenal function and outcome in patients with SABP. METHODS: Thirty-two patients with SABP were enrolled in this study. A short corticotropin (250 microg) stimulation test (SST) was performed within the first 24 hours of admission to the ICU. Critical illness related corticosteroid insufficiency (CIRCI) was defined as follows: baseline value less than 10 microg/dL, or cortisol response less than 9 microg/dL. RESULTS: CIRCI occurred in 34.4% of patients. The patients with CIRCI were more severely ill as evidenced by higher APACHE II and SOFA scores and numbers of organ system dysfunction on the day of SST. The in-hospital mortality for the entire group was 21.9%. The CIRCI group had a higher hospital mortality rate compared to those with normal adrenal function (45.5% vs. 9.5%, P = 0.032). The hospital survivors had a higher cortisol response to corticotropin (17.4 (8.3-27.1) vs. 7.2 (1.7-12) microg/dL, P = 0.019). The cortisol response to corticotropin inversely correlated with SOFA score and the number of organ dysfunction on the day of SST. The rates of pancreatic necrosis and bacteremia were significantly higher in the CIRCI group (100% vs 42.9%, P = 0.002; 81.8% vs 23.8%, P = 0.003, respectively). CONCLUSIONS: CIRCI is common in patients with SABP. It is associated with bacteremia, multiple organ dysfunction and increased mortality.