Remission of organ failure in patients with predicted severe acute pancreatitis treated by somatostation, octreotide and cyclooxygenase-2 inhibitors.

BACKGROUND: /Objectives: Persistent organ failure (OF) in severe acute pancreatitis (SAP) is caused by activation of cytokine cascades, resulting in inflammatory injury. Anti-inflammation may be helpful in OF remission in early SAP. To assess the efficacy of anti-inflammatory regimens for OF prevention and remission in patients with predicted SAP and display clinical doctors' acceptance of these strategies, we conducted this retrospective study in the real world. METHODS: Clinical data of patients with predicted SAP from 2010 to 2017 were retrospectively reviewed. Cases were divided into conventional support (C), C+ somatostatin/octreotide (C + S/O), and C + S/O + Cyclooxygenase-2-inhibitors (C + S/O + COX-2-I). The occurrence of SAP, OF, changes of proportion for three strategies, length of hospital stay, meperidine injection, and cytokine levels were compared. The constituent ratios of the three schemes over eight years were evaluated. RESULTS: A total of 580 cases (C = 124, C + S/O = 290, C + S/O + COX-2-I = 166) were included. The occurrences of SAP in the C + S/O (28.3 %) and C + S/O + COX-2-I (18.1 %) groups were significantly lower than that in C group (60.5 %, P < 0.001), mainly by reducing persistent respiratory failure (P < 0.001) and renal failure (P = 0.002). C + S/O and C + S/O + COX-2-I regimens significantly decreased new onset OF and enhanced OF amelioration within 48 h when compared with C treatment (P < 0.001) in patients with OF score <2 and ≥ 2 on admission, respectively. C + S/O and C + S/O + COX-2-I as compared with C group significantly decrease OF occurrences in a multivariate logistic regression analysis (P < 0.05). CONCLUSIONS: Somatostatin or its analogs and cyclooxygenase-2 inhibitors are promising for OF prevention and remission in patients with predicted SAP. The acceptance of combined strategies in the real world has increased, and the occurrence of SAP has decreased annually.

Incidence, prevalence, and comorbidities of chronic pancreatitis: A 7-year population-based study.

BACKGROUND: Chronic pancreatitis (CP) is a fibroinflammatory syndrome leading to reduced quality of life and shortened life expectancy. Population-based estimates of the incidence, prevalence, and comorbidities of CP in China are scarce. AIM: To characterize the incidence, prevalence, and comorbidities of CP in Sichuan Province, China, with population-based data. METHODS: Data on CP from 2015 to 2021 were obtained from the Health Information Center of Sichuan Province. During the study period, a total of 38090 individuals were diagnosed with CP in Sichuan Province. The yearly incidence rate and point prevalence rate (December 31, 2021) of CP were calculated. The prevalence of comorbid conditions in CP patients was estimated. The annual number of CP-related hospitalizations, hospital length of stay, and hospitalization costs for CP were evaluated. Yearly incidence rates were standardized for age by the direct method using the permanent population of Sichuan Province in the 2020 census as the standard population. An analysis of variance test for the linearity of scaled variables and the Cochran-Armitage trend test for categorical data were performed to investigate the yearly trends, and a two-sided test with P < 0.05 was considered statistically significant. RESULTS: The 38090 CP patients comprised 23280 males and 14810 females. The mean age of patients at CP diagnosis was 57.83 years, with male patients (55.87 years) being younger than female patients (60.11 years) (P < 0.001). The mean incidence rate of CP during the study period was 6.81 per 100000 person-years, and the incidence of CP increased each year, from 4.03 per 100000 person-years in 2015 to 8.27 per 100000 person-years in 2021 (P < 0.001). The point prevalence rate of CP in 2021 was 45.52 per 100000 individuals for the total population, with rates of 55.04 per 100000 individuals for men and 35.78 per 100000 individuals for women (P < 0.001). Individuals aged 65 years or older had the highest prevalence of CP (113.38 per 100000 individuals) (P < 0.001). Diabetes (26.32%) was the most common comorbidity in CP patients. The number of CP-related hospitalizations increased from 3739 in 2015 to 11009 in 2021. The total costs for CP-related hospitalizations for CP patients over the study period were 667.96 million yuan, with an average of 17538 yuan per patient. CONCLUSION: The yearly incidence of CP is increasing, and the overall CP hospitalization cost has increased by 1.4 times during the last 7 years, indicating that CP remains a heavy health burden.

Application of artificial intelligence in gastrointestinal disease: a narrative review.

OBJECTIVE: We collected evidence on the application of artificial intelligence (AI) in gastroenterology field. The review was carried out from two aspects of endoscopic types and gastrointestinal diseases, and briefly summarized the challenges and future directions in this field. BACKGROUND: Due to the advancement of computational power and a surge of available data, a solid foundation has been laid for the growth of AI. Specifically, varied machine learning (ML) techniques have been emerging in endoscopic image analysis. To improve the accuracy and efficiency of clinicians, AI has been widely applied to gastrointestinal endoscopy. METHODS: PubMed electronic database was searched using the keywords containing "AI", "ML", "deep learning (DL)", "convolution neural network", "endoscopy (such as white light endoscopy (WLE), narrow band imaging (NBI) endoscopy, magnifying endoscopy with narrow band imaging (ME-NBI), chromoendoscopy, endocytoscopy (EC), and capsule endoscopy (CE))". Search results were assessed for relevance and then used for detailed discussion. CONCLUSIONS: This review described the basic knowledge of AI, ML, and DL, and summarizes the application of AI in various endoscopes and gastrointestinal diseases. Finally, the challenges and directions of AI in clinical application were discussed. At present, the application of AI has solved some clinical problems, but more still needs to be done.

Artificial intelligence technique in detection of early esophageal cancer.

Due to the rapid progression and poor prognosis of esophageal cancer (EC), the early detection and diagnosis of early EC are of great value for the prognosis improvement of patients. However, the endoscopic detection of early EC, especially Barrett's dysplasia or squamous epithelial dysplasia, is difficult. Therefore, the requirement for more efficient methods of detection and characterization of early EC has led to intensive research in the field of artificial intelligence (AI). Deep learning (DL) has brought about breakthroughs in processing images, videos, and other aspects, whereas convolutional neural networks (CNNs) have shone lights on detection of endoscopic images and videos. Many studies on CNNs in endoscopic analysis of early EC demonstrate excellent performance including sensitivity and specificity and progress gradually from in vitro image analysis for classification to real-time detection of early esophageal neoplasia. When AI technique comes to the pathological diagnosis, borderline lesions that are difficult to determine may become easier than before. In gene diagnosis, due to the lack of tissue specificity of gene diagnostic markers, they can only be used as supplementary measures at present. In predicting the risk of cancer, there is still a lack of prospective clinical research to confirm the accuracy of the risk stratification model.

Suppressing growth and invasion of human hepatocellular carcinoma cells by celecoxib through inhibition of cyclooxygenase-2.

Purpose: Biomarkers are lacking in hepatocellular carcinoma (HCC). Cyclooxygenase-2 (COX-2) and its metabolites play crucial roles in the process of inflammation-tumor transformation. This study was aimed to detect COX-2 expression in HCC tissues and evaluate the effects of a COX-2 inhibitor, celecoxib, on biological behaviors of HCC cell lines in vitro. Methods: COX-2 expression was detected by immunohistochemistry on a human HCC tissue microarray. The correlations of COX-2 expression with tumor clinicopathological variables and overall survival were analyzed. The proliferation, apoptosis, cell cycle distribution, invasion capacity, and related signaling molecules of HCC cells after incubated with COX-2 inhibitor celecoxib were evaluated in vitro. Results: Expression levels of COX-2 in HCC tissues were significantly higher than those in paracancerous tissues. The TNM stage III-IV, tumor size >5 cm, lymphovascular invasion and distant metastasis was higher in high COX-2 expression group compared with that in low COX-2 expression group. Patients with low COX-2 expression achieved better 5-year overall survival than those with high COX-2 expression. Treatment with celecoxib was sufficient to inhibit cell proliferation, promote apoptosis, and induce G0/G1 cell cycle arrest in HCC cells with concentration- and time-dependent manners. Celecoxib up-regulated E-cadherin protein through inhibiting COX-2-prostaglandin E2 (PGE2)-PGE2 receptor 2 (EP2)-p-Akt/p-ERK signaling pathway to suppress HCC cells migration and invasion. Conclusion: High COX-2 expression was associated with advanced TNM stage, larger tumor size, increased lymphovascular invasion and short survival. Targeting inhibition of COX-2 by celecoxib exhibited anti-tumor activities by suppressing proliferation, promoting apoptosis, and inhibiting the aggressive properties of HCC cells.

SK-Hep1: not hepatocellular carcinoma cells but a cell model for liver sinusoidal endothelial cells.

SK-Hep1 cells serve as a cell model of hepatocellular carcinoma and hepatocyte biology. However, SK-Hep1 cells are markedly different from normal hepatocytes and other hepatocellular carcinoma cells in their gene expression and protein levels. Furthermore, endothelial-specific makers and morphological characteristics are found in SK-Hep1 cells, indicating an endothelial origin. To confirm their cell phenotype, we investigated and compared the surface ultrastructure, endothelial function, and molecular markers of SK-Hep1 cells in vitro and in vivo. The results revealed that SK-Hep1 cells expressed endothelial-specific makers and exhibited the endothelial function of endocytosis and tubular formation. Capillary-like structures with CD31 expression were also observed in SK-Hep1 allografts in nude mice. Moreover, SK-Hep1 cells possessed fenestrae without diaphragms, consistent with liver sinusoidal endothelial cells, as seen by electron microscopy. In conclusion, SK-Hep1 cells would be better considered a cell model for liver sinusoidal endothelial cells instead of hepatocellular carcinoma cells.

High HIF-1α expression predicts poor prognosis of patients with colon adenocarcinoma.

Hypoxia inducible factor 1 alpha subunit (HIF-1α) is induced in hypoxic conditions and plays a crucial role in the neoangiogenesis and metastasis of cancer. In this study, we aimed to evaluate the expression of HIF-1α in colon adenocarcinoma and to explore its clinicopathological characteristics and prognosis. A tissue microarray involving colon adenocarcinoma tissues and their corresponding paracancerous tissues from 92 patients was utilized to detect HIF-1α. The expression of HIF-1α in colon adenocarcinoma tissues was significantly higher than it was in the corresponding paracancerous tissues (P < 0.001). Furthermore, similar results were observed in HCT116 and RKO human colon adenocarcinoma xenografts in node mice (P < 0.05). Additionally, augmented HIF-1α expression was positively associated with TNM stage III-IV (P = 0.025), the presence of distant metastasis and vascular invasion (P = 0.048), and the presence of positive lymph nodes (P = 0.041). A Kaplan-Meier survival analysis showed that up-regulation of HIF-1α was associated with poor 5-year or 10-year survival (P < 0.05). A multivariable Cox regression analysis also found HIF-1α was an independent risk factor for poor prognosis in colon adenocarcinoma. Thus, targeting HIF-1α might be a viable strategy to treat patients with colon adenocarcinoma.

[Effect of Proton Pump Inhibitors on Severe Acute Pancreatitis--a Prospective Randomized Trial].

OBJECTIVE: To evaluate the effect of proton pump inhibitors (PPIs) therapy on severe acute pancreatitis (SAP) patients. METHODS: Forty five patients with SAP recruited in our center from October 2015 to October 2016,were randomly assigned into two groups: convention group (C group,n=21) and convention+esomeprazole group (C+E group,n=24). C+E group received esomeprazole 40 mg/d intravenously for 1 week,whereas C group only received baseline treatment. Serum C-reactive protein (CRP),interleukin-6 (IL-6) and interleukin-8 (IL-8),tumor necrosis factor-α (TNF-α) and procalcitonin (PCT) were detected by ELISA on the first day (baseline) and the seventh day. Acute physiology and chronic health evaluation Ⅱ scores (APACHE Ⅱ),systemic inflammatory response syndrome scores (SIRS) and modified Marshall scoring system (Marshall) were obtained at 1 d (baseline),3 d and 7 d. Upper gastrointestinal manifestation (peptic ulcer) and gastric pH were detected by endoscopic examination at 7 d. Fecal occult blood test was performed at 7 d. RESULTS: No significant difference was found in CRP,IL-6,IL-8,TNF-α and PCT between the two groups ( P>0.05),also no difference in APACHE Ⅱ,SIRS and Marshall scores ( P>0.05). The gastric pH was remarkably higher in C+E group when compared to C group (5.02±1.61 vs.2.83±1.08, P<0.001). There was no significant difference in the incidence of peptic ulcer and the rate of positive fecal occult blood between the two groups. CONCLUSION: PPIs therapy did not show benefit on alleviating systemic inflammatory response and clinical scores in SAP patients,and didn't improve the prevention of peptic ulcer and gastrointestinal hemorrhage.

Carbohydrate antigen 125 and carcinoembryonic antigen in the differentiation of tuberculous peritonitis and peritonitis carcinomatosa.

Tumor markers could increase in both tuberculous peritonitis and peritonitis carcinomatosa, confusing the differentiation of these diseases. This study aimed to better understand the extent of elevation and diagnostic efficacies of carbohydrate antigen 125 (CA 125), carcinoembryonic antigen (CEA) and combinative use of them in tuberculous peritonitis and peritonitis carcinomatosa. Of 2998 patients reviewed, 101, 120 and 71 patients were assigned to TBP group (tuberculous peritonitis), non-OCA group (non-ovarian carcinoma-related peritonitis carcinomatosa) and OCA group (ovarian carcinoma-related peritonitis carcinomatosa), respectively. The composite index was calculated by CA 125 multiplying CEA. Receiver operator characteristic curves for CA 125, CEA and composite index were acquired. As a result, CA 125 value in OCA group was higher than other two groups (serum CA 125: P < 0.001; ascites CA 125: P < 0.001). On the other hand, non-OCA group had the highest CEA value among three groups (serum CEA: P < 0.001; ascites CEA: P < 0.001). Area under curves of serum/ascites composite index and serum/ascites CEA were larger than those of serum/ascites CA 125. Furthermore, ascites and serum composite index displayed the best sensitivity (0.907) and specificity (0.989), respectively. In conclusion, CA 125 increases in tuberculous peritonitis and non-ovarian carcinoma-related peritonitis carcinomatosa, but it elevates more in ovarian carcinoma-related peritonitis carcinomatosa. CEA is found to increase more significantly in non-ovarian carcinoma-related peritonitis carcinomatosa. CEA and composite index are helpful in distinguishing peritonitis carcinomatosa from tuberculous peritonitis, but composite index is slightly superior to CEA in the differential diagnosis.

Adjuvant celecoxib and lanreotide following transarterial chemoembolisation for unresectable hepatocellular carcinoma: a randomized pilot study.

Recurrence of hepatocellular carcinoma (HCC) after transarterial chemoembolisation (TACE) is common due to neoangiogenesis. Cyclooxygenase-2 inhibitors and somatostatin analogues were reported to inhibit tumour angiogenesis. The pilot randomized controlled trial was aimed to prospectively evaluate the protocol of TACE combined with celecoxib and lanreotide (TACE+C+L) in patients with unresectable and advanced HCC. A total of 71 patients with HCC were enrolled and randomly assigned to either TACE (n=35) or TACE+C+L (n=36) group. Overall survival, disease control rate (DCR), and adverse events were assessed during a 3-year follow-up period. The median overall survival of the TACE+C+L group (15.0 months) was doubled compared to that of TACE group (7.5 months), p = 0.012. DCR of the TACE+C+L group was significantly higher than that of the TACE group either at 6 months (72.2% vs 42.9%, p = 0.012) or at 12 months (61.1% vs 28.6%, p = 0.006). The median overall survivals (13 months vs 4.5 months, p = 0.013) and DCR at 12 months (50% vs 13.6%, p = 0.008) of patients with advanced HCC in TACE+C+L groups were significantly higher than those in TACE group. No significant difference of adverse events was observed between the two groups. The occurrence of post-embolisation syndrome in TACE+C+L group was significantly lower than that in TACE group (16.7% vs 60.0%, p = 0.001). In conclusion, the regimen of TACE+C+L prolonged overall survival, enhanced tumour response, reduced post-embolisation syndrome and was well-tolerable in the patients with unresectable HCC. It may be more beneficial for advanced HCC.

Correlations between VEGF-A expression and prognosis in patients with gastric adenocarcinoma.

Angiogenesis induced by vascular endothelial growth factor A (VEGF-A) plays a critical role in tumor growth and metastasis. The study aimed to evaluate the expression of VEGF-A in gastric adenocarcinoma and investigate its correlations with tumor clinicopathological features and prognostic significance. VEGF-A expression was detected by immunohistochemistry on a tissue microarray containing 90 pairs of human gastric adenocarcinoma and paracancerous tissues. Levels of VEGF-A in gastric adenocarcinoma were significantly higher than those in paracancerous tissues (P=0.018). Furthermore, the result was coincident with that of human gastric adenocarcinoma xenografts in nude-mice (P<0.01). In addition, the VEGF-A expression was positive correlation with TNM stage (P=0.047), tumor size (P=0.028), positive lymph nodes (P=0.002) and lymphovascular invasion (P=0.001). Finally, Kaplan-Meier survival analysis showed that VEGF-A up-regulation indicated a poor prognosis for overall survival (P=0.039). In conclusions, VEGF-A may be used as a biomarker for evaluating both the biological behavior of tumor and the prognosis in patients with gastric adenocarcinoma.

Celecoxib and octreotide synergistically ameliorate portal hypertension via inhibition of angiogenesis in cirrhotic rats.

Abnormal angiogenesis is critical for portal hypertension in cirrhosis. Except for etiological treatment, no efficient medication or regime has been explored to treat the early stage of cirrhosis when angiogenesis is initiated or overwhelming. In this study, we explored an anti-angiogenesis effort through non-cytotoxic drugs octreotide and celecoxib to treat early stage of cirrhotic portal hypertension in an animal model. Peritoneal injection of thioacetamide (TAA) was employed to induce liver cirrhosis in rats. A combination treatment of celecoxib and octreotide was found to relieve liver fibrosis, portal venous pressure, micro-hepatic arterioportal fistulas, intrahepatic and splanchnic angiogenesis. Celecoxib and octreotide exerted their anti-angiogenesis effect via an axis of cyclooxygenase-2/prostaglandin E2/EP-2/somatostatin receptor-2, which consequently down-regulated phosphorylation of extracellular signal-regulated kinase (p-ERK)-hypoxia-inducible factor-1α (HIF-1α)-vascular endothelial growth factor (VEGF) integrated signaling pathways. In conclusions, combination of celecoxib and octreotide synergistically ameliorated liver fibrosis and portal hypertension of the cirrhotic rats induced by TAA via the inhibition of intrahepatic and extrahepatic angiogenesis. The potential mechanisms behind the regimen may due to the inactivation of p-ERK-HIF-1α-VEGF signaling pathway.

Inhibition of cyclooxygenase-2 alleviates liver cirrhosis via improvement of the dysfunctional gut-liver axis in rats.

Inflammatory transport through the gut-liver axis may facilitate liver cirrhosis. Cyclooxygenase-2 (COX-2) has been considered as one of the important molecules that regulates intestinal epithelial barrier function. This study was aimed to test the hypothesis that inhibition of COX-2 by celecoxib might alleviate liver cirrhosis via reduction of intestinal inflammatory transport in thiacetamide (TAA) rat model. COX-2/prostaglandin E2 (PGE2)/EP-2/p-ERK integrated signal pathways regulated the expressions of intestinal zonula occludens-1 (ZO-1) and E-cadherin, which maintain the function of intestinal epithelial barrier. Celecoxib not only decreased the intestinal permeability to a 4-kDa FITC-dextran but also significantly increased expressions of ZO-1 and E-cadherin. When celecoxib greatly decreased intestinal levels of LPS, TNF-α, and IL-6, it significantly enhanced T cell subsets reduced by TAA. As a result, liver fibrosis induced by TAA was significantly alleviated in the celecoxib group. These data indicated that celecoxib improved the integrity of intestinal epithelial barrier, blocked inflammatory transport through the dysfunctional gut-liver axis, and ameliorated the progress of liver cirrhosis.

Targeting inhibition of extracellular signal-regulated kinase kinase pathway with AZD6244 (ARRY-142886) suppresses growth and angiogenesis of gastric cancer.

AZD6244 (ARRY-142886), a highly selective MAPK-ERK kinase inhibitor, has shown excellent clinical efficacy in many tumors. However, the anti-tumor and anti-angiogenesis efficacy of AZD6244 on gastric cancer has not been well characterized. In this study, high p-ERK expression was associated with advanced TNM stage, increased lymphovascular invasion and poor survival. For absence of NRAS, KRAS and BRAF mutation, SGC7901 and BGC823 gastric cancer cells were relative resistance to AZD6244 in vitro. And such resistance was not attributed to the insufficient inhibition of ERK phosphorylation. However, tumor growth was significantly suppressed in SGC7901 xenografts by blockage of angiogenesis. This result was further supported by suppression of tube formation and migration in HUVEC cells after treatment with AZD6244. Moreover, the anti-angiogenesis effect of AZD6244 may predominantly attribute to its modulation on VEGF through p-ERK - c-Fos - HIF-1α integrated signal pathways. In conclusions, High p-ERK expression was associated with advanced TNM stage, increased lymphovascular invasion and poor survival. Targeting inhibition of p-ERK by AZD6244 suppress gastric cancer xenografts by blockage of angiogenesis without systemic toxicity. The anti-angiogenesis effect afford by AZD6244 may attribute to its modulation on p-ERK - c-Fos - HIF-1α - VEGF integrated signal pathways.

Celecoxib attenuates hepatic cirrhosis through inhibition of epithelial-to-mesenchymal transition of hepatocytes.

BACKGROUND AND AIM: The epithelial-mesenchymal transition (EMT) of hepatocytes is a key step for hepatic fibrosis and cirrhosis. Long-term administration of celecoxib, a selective cyclooxygenase-2 (COX-2) inhibitor, can ameliorate hepatic fibrosis. This research aimed to examine the effect of celecoxib on the EMT of hepatocytes during the development of liver cirrhosis. METHODS: Cirrhotic liver model of rat was established by peritoneal injection of thiacetamide (TAA). Thirty-six rats were randomly assigned to control, TAA, and TAA + celecoxib groups. Hepatic expressions of tumor necrosis factor-α (TNF-α), interleukin 6 (IL-6), COX-2, prostaglandin E2 (PGE2 ), matrix metalloproteinase (MMP)-2 and -9, transforming growth factor-ß1 (TGF-ß1), Phospho-Smad2/3, Snail1, α-smooth muscle actin (α-SMA), vimentin, collagen I, fibroblast-specific protein (FSP-1), E-cadherin and N-cadherin were quantitated. Hepatic fibrosis was assessed by the visible hepatic fibrotic areas and Ishak's scoring system. RESULTS: Exposed to TAA treatment, hepatocytes underwent the process of EMT during hepatic fibrosis. Compared with those in TAA group, celecoxib significantly downregulated the hepatic expressions of TNF-α, IL-6, COX-2, PGE2 , MMP-2, MMP-9, TGF-ß1, Phospho-Smad2/3, Snail1, α-SMA, FSP-1, and vimentin while greatly restoring the levels of E-cadherin. The fibrotic areas and collagen I levels of TAA + celecoxib group were much lower than those in TAA group. CONCLUSIONS: Celecoxib could ameliorate hepatic fibrosis and cirrhosis in TAA-rat model through suppression of the mesenchymal biomarkers in the hepatocytes while restoring the levels of their epithelial biomarkers. The inhibitory effect of celecoxib on the EMT of hepatocytes is associated with reduction of intrahepatic inflammation, preservation of normal basement matrix, and inhibition of TGF-ß1/Smad pathway.

The crosstalk between gut inflammation and gastrointestinal disorders during acute pancreatitis.

The intestinal inflammation caused by intestinal ischemia reperfusion during acute pancreatitis (AP) often leads to multiple organ dysfunction and aggravation of acute pancreatitis. This review concerns up-date progress of the pathophysiology and molecular mechanism of the excessive production of gut-derived cytokines. The regulation effects of immuno-neuro-endocrine network for pancreatic necrosis are the basis for pharmacological therapeutic in AP. The translation from basic research to clinical trials for the prevention or treatment of severe acute pancreatitis (SAP) is of great value. Early enteral nutrition is necessary for the restitution, proliferation, and differentiation of the intestinal epithelial cells adjacent to the wounded area. Clearance of the excess intestinal bacteria and supplement of probiotics may be helpful to prevent bacterial translocation and infection of pancreas.