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Background: Poorly differentiated gastric neuroendocrine neoplasms (PDGNENs) include gastric neuroendocrine carcinoma (NEC) and mixed adenoneuroendocrine carcinoma, which are highly malignant and rare tumors, and their incidence has increased over the past few decades. However, the clinicopathological features and outcomes of patients with PDGNENs have not been completely elucidated., Aim: To investigate the clinicopathological characteristics and prognostic factors of patients with PDGNENs ., Methods: The data from seven centers in China from March 2007 to November 2019 were analyzed retrospectively., Results: Among the 232 patients with PDGNENs, 191 (82.3%) were male, with an average age of 62.83 ± 9.11 years. One hundred and thirteen (49.34%) of 229 patients had a stage III disease and 86 (37.55%) had stage IV disease. Three (1.58%) of 190 patients had no clinical symptoms, while 187 (98.42%) patients presented clinical symptoms. The tumors were mainly (89.17%) solitary and located in the upper third of the stomach (cardia and fundus of stomach: 115/215, 53.49%). Most lesions were ulcers (157/232, 67.67%), with an average diameter of 4.66 ± 2.77 cm. In terms of tumor invasion, the majority of tumors invaded the serosa (116/198, 58.58%). The median survival time of the 232 patients was 13.50 mo (7, 31 mo), and the overall 1-year, 3-year, and 5-year survival rates were 49%, 19%, and 5%, respectively. According to univariate analysis, tumor number, tumor diameter, gastric invasion status, American Joint Committee on Cancer (AJCC) stage, and distant metastasis status were prognostic factors for patients with PDGNENs. Multivariate analysis showed that tumor number, tumor diameter, AJCC stage, and distant metastasis status were independent prognostic factors for patients with PDGNENs., Conclusion: The overall prognosis of patients with PDGNENs is poor. The outcomes of patients with a tumor diameter > 5 cm, multiple tumors, and stage IV tumors are worse than those of other patients., Competing Interests: Conflict-of-interest statement: The authors have no competing interests to declare., (©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.)

Background: For the rarity of type 3 gastric neuroendocrine tumours (g-NETs), their clinicopathological characteristics and prognosis are not well illustrated., Aim: To describe the clinicopathological features and outcome of type 3 g-NETs in the Chinese population., Methods: Based on the 2019 WHO pathological classification, the clinicopathological characteristics and prognosis of patients with type 3 g-NETs in China were retrospectively analysed., Results: A total of 77 patients (55.8% of females) with type 3 g-NETs were analysed, with a median age of 48 years (range: 28-79 years). The tumours were mainly located in the gastric fundus/body (83.1%) and were mostly solitary (83.1%), with a median size of 1.5 cm (0.8-3.5 cm). Of these, there were 37 G1 tumours (48.1%), 31 G2 (40.3%), and 9 G3 (11.7%). Ten (13.0%) and 24 (31.2%) patients had lymph node and distant metastasis, respectively. In addition, type 3 g-NETs were heterogeneous. Compared with G1 NETs, G2 NETs had a higher lymph node metastasis rate, and G3 NETs had a higher distant metastasis rate. G1 and G2 NETs with stage I/II disease (33/68) received endoscopic treatment, and no tumour recurrence or tumour-related death was observed within a median follow-up time of 36 mo. Grade and distant metastasis were identified to be independent risk factors for prognosis in multivariable analysis., Conclusion: Type 3 g-NETs are obviously heterogeneous, and the updated WHO 2019 pathological classification may be used to effectively evaluate their biological behaviors and prognosis. Also, endoscopic treatment should be considered for small (< 2 cm), low grade, superficial tumours., Competing Interests: Conflict-of-interest statement: The authors declare that no competing interests exist., (©The Author(s) 2020. Published by Baishideng Publishing Group Inc. All rights reserved.)

Aim: To identify suitable biomarkers of response to bevacizumab (BV) - it remains an open question. The measurement of serum vascular endothelial growth factor (VEGF) has been proposed as a predictive factor for this drug, even if literature data are contradictory., Methods: We prospectively evaluated the role of BV, total and not BV-bound VEGF and angiopoietin-2 (Ang-2) serum levels as potential predictive factors of response for BV in combination with an oxaliplatin-based chemotherapy. BV, Ang-2, total and not BV-bound VEGF levels were measured at baseline, before 2(nd) and 5(th) cycle of oxaliplatin-based chemotherapy in 20 consecutive metastatic colorectal cancer patients., Results: Results were correlated to response to treatment. Variability in BV levels have been found, with decreased level in less responding patients. In particular, the concentration of BV increased of 3.96 ± 0.69 folds in serum of responsive patients after 3 more cycles of therapy compared to those with stable or progressive disease with a 0.72 ± 0.25 and 2.10 ± 0.13 fold increase, respectively. The determination of free and total VEGF demonstrated that the ratio between the two values, evaluated immediately before the 2(nd) and the 5(th) cycle of therapy, decreased from 26.65% ± 1.33% to 15.50% ± 3.47% in responsive patients and from 53.41% ± 4.75 to 34.95% ± 2.88% in those with stable disease. Conversely, in those with progression of disease, the ratio showed the opposite behavior coming up from 25.99% ± 5.23% to 51.71% ± 5.28%. The Ang-2 levels did not show any relationship., Conclusion: Our data show that the ratio of not BV-bound VEGF to total VEGF serum and BV plasma concentrations for predicting the response to BV plus oxaliplatin-based chemotherapy could be a promising biomarker of response to BV.

Aim: To evaluate the efficacy and safety of transjugular intrahepatic portosystemic shunt (TIPS) combined with stomach and esophageal variceal embolization (SEVE) in cirrhotic patients with a large gastrorenal vessel shunt (GRVS)., Methods: Eighty-one cirrhotic patients with gastric variceal bleeding (GVB) associated with a GRVS were enrolled in the study and accepted TIPS combined with SEVE (TIPS + SEVE), by which portosystemic pressure gradient (PPG), biochemical, TIPS-related complications, shunt dysfunction, rebleeding, and death were evaluated., Results: The PPGs before TIPS were greater than 12 mmHg in 81 patients. TIPS + SEVE treatment caused a significant decrease in PPG (from 37.97 ± 6.36 mmHg to 28.15 ± 6.52 mmHg, t = 19.22, P < 0.001). The percentage of reduction in PPG was greater than 20% from baseline. There were no significant differences in albumin, alanine aminotransferase, aspartate aminotransferase, bilirubin, prothrombin time, or Child-Pugh score before and after operation. In all patients, rebleeding rates were 3%, 6%, 12%, 18%, and 18% at 1, 3, 6, 12, and 18 mo, respectively. Five patients (6.2%) were diagnosed as having hepatic encephalopathy. The rates of shunt dysfunction were 0%, 4%, 9%, 26%, and 26%, at 1, 3, 6, 12, and 18 mo, respectively. The cumulative survival rates in 1, 3, 6, 12, and 18 mo were 100%, 100%, 95%, 90%, and 90%, respectively., Conclusion: Our preliminary results indicated that the efficacy and safety of TIPS + SEVE were satisfactory in cirrhotic patients with GVB associated with a GRVS (GVB + GRVS).

Perivascular epithelioid cell tumor (PEComa) of the pancreas is an unusual tumor deriving from mesenchyma. This paper described a case of pancreatic PEComa, which was initially suspected as neuroendocrine carcinoma by biopsy, and therefore surgical treatment was recommended due to undetermined diagnosis. Examination of the surgical specimen under a microscope showed that the tumor cell's morphology was epithelioid or spindle-shaped, and ranged in a nested pattern. Additionally, these cells had a large extent of acidophilic cytoplasm, no mitotic figures, and expressed HMB-45, melan-p, and smooth muscle actin immunohistochemically. Pathological examination indicated that PEComa originated from the pancreas, but symptoms related to tuberous sclerosis were absent. Since PEComa is extremely rare in the pancreas, it is likely to be ignored in differential diagnosis. In conclusion, our article highlighted the clinicopathological features of PEComa, and we conducted a literature review focusing on PEComa so as to deepen the understanding of this tumor type.

Aim: To evaluate the association of β-2 adrenergic receptor (β2-AR) gene polymorphism with response of variceal pressure to propranolol in cirrhosis., Methods: Sixty-four non-related cirrhotic patients participated in this study and accepted variceal pressure measurement before and after propranolol administration. Polymorphism of the β2-AR gene was determined by directly sequencing of the polymerase chain reaction products from the DNA samples that were prepared from the patients., Results: The prevalence of Gly16-Glu/Gln27 and Arg16-Gln27 homozygotes, and compound heterozygotes was 29.7%, 10.9%, and 59.4%, respectively. Patients with cirrhosis with Gly16-Glu/Gln27 homozygotes had a greater decrease of variceal pressure after propranolol administration than those with Arg16-Gln27 homozygotes or with compound heterozygotes (22.4% ± 2.1%, 13.1% ± 2.7% and 12.5% ± 3.1%, respectively, P < 0.01)., Conclusion: The variceal pressure response to propranolol was associated with polymorphism of β2-AR gene. Patients with the Gly(16)-Glu/Gln(27) homozygotes probably benefit from propranolol therapy.

Aim: To explore the effect of intravariceal-mucosal sclerotherapy using small dose of sclerosant on the recurrence of esophageal varices., Methods: We randomly assigned 38 cirrhotic patients with previous variceal bleeding and high variceal pressure (> 15.2 mmHg) to receive endoscopic variceal ligation (EVL) and combined intravariceal and esophageal mucosal sclerotherapy (combined group) using small-volume sclerosant. The end-points of the study were rebleeding and recurrence of esophageal varices., Results: During a median follow-up period of 16 mo, varices recurred in 1 patient in the combined group as compared with 7 patients in the EVL group (P = 0.045). Rebleeding occurred in 3 patients in the EVL group as compared with 1 patient in the combined group (P = 0.687). No patient died in the two groups. No significant differences were observed between the two groups with respect to serious adverse events., Conclusion: Intravariceal-mucosal sclerotherapy using small dose of sclerosant is more effective than EVL in decreasing the incidence of variceal recurrence for cirrhotic patients.

Aim: To explore the association of MYO9B gene polymorphisms with clinical phenotypes and intestinal permeability of individuals with inflammatory bowel disease (IBD) in China., Methods: A total of 442 IBD patients and 402 healthy volunteers were genotyped for two single nucleotides (rs962917 and rs1545620) using the ligase detection reaction and polymerase chain reaction. Allelic and genotype frequency analyses were performed for the two groups. Intestinal permeability was evaluated using lactulose (L) and mannitol (M) excretion. The association of MYO9B gene polymorphisms with intestinal permeability between the normal and high intestinal permeability groups was analyzed., Results: Overall, there was no significant difference in the genotypic and allelic frequencies of MYO9B between IBD patients and controls. Although no association was found with ulcerative colitis in the comparison between the subgroups, the frequencies of rs962917 and rs1545620 were different in the Crohn's disease (CD) subgroup with ileocolitis (CC vs CT and TT, P = 0.014; and AA vs AC and CC, P = 0.022, respectively). rs1545620 variants appear to be the genetic susceptibility factor for perianal disease in CD patients (AA vs AC CC, P = 0.029). In addition, the L/M ratio was significantly higher in IBD patients than in controls (0.065 ± 0.013 vs 0.020 ± 0.002, P = 0.02), but no association was found between the MYO9B gene and the L/M ratio in IBD patients., Conclusion: MYO9B gene polymorphisms may influence the sub-phenotypic expression of CD in China. No association between these MYO9B polymorphisms and intestinal permeability in IBD patients was found.

Mesalamine suppositories have been used widely for the treatment of distal ulcerative colitis and considered to be safer than systemic administration for its limited systemic absorption. However, previous studies have shown that mesalamine suppository occasionally causes severe hypersensitivity reactions including fever, rashes, colitis exacerbation and acute eosinophilic pneumonia. Here we present a 25-year-old woman with ulcerative colitis with bloody diarrhea accompanied by abdominal pain and fever which were aggravated after introduction of mesalamine suppositories. In light of symptom exacerbation of ulcerative colitis, increased inflammatory injury of colon mucosa shown by colonoscopy and elevated peripheral eosinophil count after mesalamine suppositories administration, and the Naranjo algorithm score of 10, the possibility of hypersensitivity reaction to mesalamine suppositories should be considered, warning us to be aware of this potential reaction after administration of mesalamine formulations even if it is the suppositories.

Aim: To construct normal values for the tests of the psychometric hepatic encephalopathy score (PHES) and to evaluate its usefulness in the diagnosis of minimal hepatic encephalopathy (MHE) among Chinese individuals with cirrhosis., Methods: The five tests of PHES, number connection test-A (NCT-A), number connection test-B, serial dotting test, line tracing test and digit symbol test (DST), were administered to all enrolled subjects in a quiet room with sufficient light. Cirrhotic subjects with overt HE were excluded by the West-Haven criteria and a detailed neurological examination. Based on the nomograms of healthy volunteers, the patients were classified as having MHE when their PHES was less than -4., Results: In total, 146 healthy volunteers completed all the PHES tests. Age and education years were confirmed to be predictors of all five tests. In total, 53 patients with liver cirrhosis completed the PHES. Of the patients with liver cirrhosis, 24 (45.3%), 22(41.5%) and 7(13.2%) had Child-Pugh grades A, B and C, respectively. MHE was diagnosed in 26 patients (49.1%). Compared with compensated cirrhotic patients (Child A), decompensated cirrhotic patients (Child B and C) had a higher proportion of MHE (65.5% vs 29.2%). No differences in age and education years were found between the MHE and non-MHE groups. NCT-A and DST were able to diagnose MHE with a sensitivity of 76.9% and a specificity of 96.3% (AUC = 0.866, K = 0.735)., Conclusion: The proportion of MHE is associated with liver function. NCT-A and DST are simple tools that can be used for the diagnosis of MHE in China.

Aim: To investigate the prevalence of minimal hepatic encephalopathy (MHE) and to assess corresponding health-related quality of life (HRQoL) in hospitalized cirrhotic patients in China., Methods: This multi-center cross-sectional study included 16 teaching hospitals, which were members of "Hepatobiliary Cooperation Group, Society of Gastroenterology, Chinese Medical Association", from different areas of China carried out between June and October in 2011. All the eligible hospitalized cirrhotic patients (n = 538) were required to complete triplicate number connection tests combined with one digit symbol test for diagnosing MHE. Patients' clinical examination data were complemented by a modified questionnaire assessing HRQoL. Written informed consent was obtained from each patient., Results: Male was predominant (68.6%) in 519 patients who met the criteria of the study, with a mean age of 49.17 ± 11.02 years. The most common cause of liver cirrhosis was chronic hepatitis B (55.9%). The prevalence of MHE was 39.9% and varied by Child-Pugh-Classification score (CPC-A: 24.8%, CPC-B: 39.4% and CPC-C: 56.1%, P < 0.01). MHE (P < 0.01) and higher CPC scores (P < 0.01) were associated with a high HRQoL scores (reflecting poorer quality of life). The prevalence of MHE was proportionate to CPC (P = 0.01) and high quality of life scores (P = 0.01)., Conclusion: Hospitalized cirrhotic patients have a high prevalence of MHE that is proportionate to the degree of liver function and HRQoL impairment.

Aim: To compare the effects of propranolol (PR) to that of PR plus isosorbide-5-mononitrate (ISMN) on variceal pressure in patients with schistosomiasis., Methods: Forty-eight patients with schistosomiasis who had no previous variceal bleeding were treated with PR alone or PR plus ISMN. Seven patients refused variceal pressure manometry (3 receiving PR and 4 receiving PR plus ISMN). One patient withdrew from the trial due to headache after taking ISMN. At the time of termination, twenty patients were randomly assigned to treatment with PR plus ISMN or PR alone. The dose of PR was adjusted until the resting heart rate had been reduced by 25% or was less than 55 bpm. In the PR plus ISMN group, after PR was titrated to the same target, the dose of ISMN was increased up to 20 mg orally twice a day. Variceal pressure was measured using a noninvasive endoscopic balloon technique at the end of the 6-mo treatment period., Results: In 40 patients (20 in the PR group and 20 in the PR plus ISMN group), variceal pressure was measured before treatment and at the end of the 6-mo treatment period. PR or PR plus ISMN treatment caused a significant reduction in variceal pressure (PR group: from 24.15 ± 6.05 mmHg to 22.68 ± 5.70 mmHg, P = 0.001; PR plus ISMN group: from 25.69 ± 5.26 mmHg to 20.48 ± 5.43 mmHg; P < 0.001). The percentage decrease in variceal pressure was significant after PR plus ISMN compared with that after PR alone (15.93% ± 8.37% vs 6.05% ± 3.67%, P = 0.01). One patient in the PR plus ISMN group and two patients in the PR group had variceal bleeding during follow-up. There were no significant differences between the two groups regarding the incidence of variceal bleeding. In the PR plus ISMN group, three patients had headache and hypotension. The headache was mild and transient and promptly disappeared after continuation of the relevant drug in two patients. Only one patient withdrew from the trial due to severe and lasting headache after taking ISMN. No side effects occurred in the PR group., Conclusion: PR plus ISMN therapy may be an alternative treatment for patients with schistosomiasis who have a high risk of bleeding.

Many studies have demonstrated the impact of UGT1A1 on toxicity of irinotecan. In particular, patients bearing UGT1A1 28 (TA 7/7) have a higher risk of severe neutropenia and diarrhea. Based on this, prescribers of irinotecan are advised that patients with UGT1A1 28 (TA 7/7) should start with a reduced dose of irinotecan, although a particular dose is not specified. Research in Asian countries has shown a lower incidence of UGT1A1 28 (TA 7/7), while UGT1A1 6 (A/A) is more often found and is associated with severe irinotecan-related neutropenia. We report here a case of a metastatic colorectal cancer patient who is heterozygous for the UGT1A1 28 polymorphism (TA 6/7) as well as the UGT1A1 6 polymorphism (G/A). The patient was treated with FOLFIRI for 9 cycles and underwent two irinotecan dose reductions according to pharmacokinetic data regarding exposure to the active metabolite, SN-38. Simultaneous heterozygous UGT1A1 28 and UGT1A1 6 polymorphisms may produce higher exposure to SN-38 and a higher risk of adverse effects related to irinotecan. Additional studies will be necessary to determine the optimal starting dose of irinotecan for patients with both UGT1A1 28 and UGT1A1 6 polymorphisms.

Aim: To evaluate effects of UDP-glucuronosyltransferase1A1 (UGT1A1) and thymidylate synthetase (TS) gene polymorphisms on irinotecan in metastatic colorectal cancer (mCRC)., Methods: Two irinotecan- and fluorouracil-based regimens, FOLFIRI and IFL, were selected as second-line therapy for 138 Chinese mCRC patients. Genomic DNA was extracted from peripheral blood samples before treatment. UGT1A1 and TS gene polymorphisms were determined by direct sequencing and restriction fragment length polymorphism, respectively. Gene polymorphisms of UGT1A1*28, UGT1A1*6 and promoter enhancer region of TS were analyzed. The relationship between genetic polymorphisms and clinical outcome, that is, response, toxicity and survival were assessed. Pharmacokinetic analyses were performed in a subgroup patients based on different UGT1A1 genotypes. Plasma concentration of irinotecan and its active metabolite SN-38 and inactive metabolite SN-38G were determined by high performance liquid chromatography. Differences in irinotecan and its metabolites between UGT1A1 gene variants were compared., Results: One hundred and eight patients received the FOLFIRI regimen, 29 the IFL regimen, and one irinotecan monotherapy. One hundred and thirty patients were eligible for toxicity and 111 for efficacy evaluation. One hundred and thirty-six patients were tested for UGT1A1*28 and *6 genotypes and 125 for promoter enhancer region of TS. Patients showed a higher frequency of wild-type UGT1A1*28 (TA6/6) compared with a Caucasian population (69.9% vs 45.2%). No significant difference was found between response rates and UGT1A1 genotype, although wild-type showed lower response rates compared with other variants (17.9% vs 24.2% for UGT1A1*28, 15.7% vs 26.8% for UGT1A1*6). When TS was considered, the subgroup with homozygous UGT1A1*28 (TA7/7) and non-3RG genotypes showed the highest response rate (33.3%), while wild-type UGT1A1*28 (TA6/6) with non-3RG only had a 13.6% response rate, but no significant difference was found. Logistic regression showed treatment duration was closely linked to clinical response. In toxicity comparison, UGT1A1*28 TA6/6 was associated with lower incidence of grade 2-4 diarrhea (27.8% vs 100%), and significantly reduced the risk of grade 4 neutropenia compared with TA7/7 (7.8% vs 37.5%). Wild-type UGT1A1*6 (G/G) tended to have a lower incidence of grade 3/4 diarrhea vs homozygous mutant (A/A) genotype (13.0% vs 40.0%). Taking UGT1A1 and TS genotypes together, lower incidence of grade 2-4 diarrhea was found in patients with non-3RG TS genotypes, when TA6/6 was compared with TA7/7 (35.3% vs 100.0%). No significant association with time to progression (TTP) and overall survival (OS) was observed with either UGT1A1 or TS gene polymorphisms, although slightly longer TTP and OS were found with UGT1A1*28 (TA6/6). Irinotecan PK was investigated in 34 patients, which showed high area under concentration curve (AUC) of irinotecan and SN-38, but low AUC ratio (SN-38G / SN-38) in those patients with UGT1A1*28 TA7/7., Conclusion: A distinct distribution pattern of UGT1A1 genotypes in Chinese patients might contribute to relatively low toxicity associated with irinotecan and 5-fluorouracil in mCRC patients.

Aim: To investigate the protective effect and mechanism of rebamipide on small intestinal permeability induced by diclofenac in mice., Methods: Diclofenac (2.5 mg/kg) was administered once daily for 3 d orally. A control group received the vehicle by gavage. Rebamipide (100 mg/kg, 200 mg/kg, 400 mg/kg) was administered intragastrically once a day for 3 d 4 h after diclofenac administration. Intestinal permeability was evaluated by Evans blue and the FITC-dextran method. The ultrastructure of the mucosal barrier was evaluated by transmission electron microscopy (TEM). Mitochondrial function including mitochondrial swelling, mitochondrial membrane potential, mitochondrial nicotinamide adenine dinucleotide-reduced (NADH) levels, succinate dehydrogenase (SDH) and ATPase activities were measured. Small intestinal mucosa was collected for assessment of malondialdehyde (MDA) content and myeloperoxidase (MPO) activity., Results: Compared with the control group, intestinal permeability was significantly increased in the diclofenac group, which was accompanied by broken tight junctions, and significant increases in MDA content and MPO activity. Rebamipide significantly reduced intestinal permeability, improved inter-cellular tight junctions, and was associated with decreases in intestinal MDA content and MPO activity. At the mitochondrial level, rebamipide increased SDH and ATPase activities, NADH level and decreased mitochondrial swelling., Conclusion: Increased intestinal permeability induced by diclofenac can be attenuated by rebamipide, which partially contributed to the protection of mitochondrial function.

Aim: To investigate the protective effects of melatonin on carbon tetrachloride (CCl4)-induced hepatic fibrosis in experimental rats., Methods: All rats were randomly divided into normal control group, model control group treated with CCl4 for 12 wk, CCl4 + NAC group treated with CCl4 + NAC (100 mg/kg, i.p.) for 12 wk, CCl4 + MEL-1 group treated with CCl4 + melatonin (2.5 mg/kg) for 12 wk, CCl4 + MEL-2 group treated with CCl4 + melatonin (5.0 mg/kg) for 12 wk, and CCl4 + MEL-3 group treated with CCl4 + melatonin (10 mg/kg). Rats in the treatment groups were injected subcutaneously with sterile CCl4 (3 mL/kg, body weight) in a ratio of 2:3 with olive oil twice a week. Rats in normal control group received hypodermic injection of olive oil at the same dose and frequency as those in treatment groups. At the end of experiment, rats in each group were anesthetized and sacrificed. Hematoxylin and eosin (HE) staining and Van Gieson staining were used to examine changes in liver pathology. Serum activities of alanine aminotransferase (ALT), aspartate aminotransferase (AST) and protein concentration were measured with routine laboratory methods using an autoanalyzer. Hydroxyproline (HYP) content in liver and malondialdehyde (MDA) and glutathione peroxidase (GPx) levels in liver homogenates were assayed by spectrophotometry. Serum hyaluronic acid (HA), laminin (LN), and procollagen III N-terminal peptide (PIIINP) were determined by radioimmunoassay., Results: Pathologic grading showed that the fibrogenesis was much less severe in CCl4 + MEL3 group than in model control group (u = 2.172, P < 0.05), indicating that melatonin (10 mg/kg) can significantly ameliorate CCl4-induced hepatic fibrotic changes. The serum levels of ALT and AST were markedly lower in CCl4 + MEL treatment groups (5, 10 mg/kg) than in model control group (ALT: 286.23 +/- 121.91 U/L vs 201.15 +/- 101.16 U/L and 178.67 +/- 103.14 U/L, P = 0.028, P = 0.007; AST: 431.00 +/- 166.35 U/L vs 321.23 +/- 162.48 U/L and 292.42 +/- 126.23 U/L, P = 0.043, P = 0.013). Similarly, the serum laminin (LN) and hyaluronic acid (HA) levels and hydroxyproline (HYP) contents in liver were significantly lower in CCl4 + MEL-3 group (10 mg/kg) than in model control group (LN: 45.89 +/- 11.71 microg/L vs 55.26 +/- 12.30 microg/L, P = 0.012; HA: 135.71 +/- 76.03 microg/L vs 201.10 +/- 68.46 microg/L, P = 0.020; HYP: 0.42 +/- 0.08 mg/g tissue vs 0.51 +/- 0.07 mg/g tissue, P = 0.012). Moreover, treatment with melatonin (5, 10 mg/kg) significantly reduced the MDA content and increased the GPx activity in liver homogenates compared with model control group (MDA: 7.89 +/- 1.49 noml/mg prot vs 6.29 +/- 1.42 noml/mg prot and 6.25 +/- 2.27 noml/mg prot, respectively, P = 0.015, P = 0.015; GPx: 49.13 +/- 8.72 U/mg prot vs 57.38 +/- 7.65 U/mg prot and 61.39 +/- 13.15 U/mg prot, respectively, P = 0.035, P = 0.003)., Conclusion: Melatonin can ameliorate CCl4-induced hepatic fibrosis in rats. The protective effect of melatonin on hepatic fibrosis may be related to its antioxidant activities.

Aim: To determine the accuracy of high-resolution magnetic resonance imaging (MRI) using phased-array coil for preoperative assessment of T staging and mesorectal fascia infiltration in rectal cancer with rectal distention., Methods: In a prospective study of 67 patients with primary rectal cancer, high-resolution magnetic resonance imaging (in-plane resolution, 0.66 multiply 0.56) with phased-array coil were performed for T-staging and measurement of distance between the tumor and the mesorectal fascia. The assessment of MRI was compared with postoperative histopathologic findings. Sensitivity, specificity, accuracy, positive predictive value, and negative predictive value were evaluated., Results: The overall magnetic resonance accuracy was 85.1% for T staging and 88% for predicting mesorectal fascia involvement. Magnetic resonance sensitivity, specificity, accuracy, positive predictive value, and negative predictive value was 70%, 97.9%, 89.6%, 93.3% and 88.5% for

Aim: To investigate the effects of 5-aminosalicylic acid (5-ASA) in combination with nimesulide on the proliferation of HT-29 colon carcinoma cells and its potential mechanisms., Methods: Inhibitory effects of drugs (5-ASA, nimesulide and their combination) on HT-29 colon carcinoma cells were investigated by thiazolyl blue tetrazolium bromide (MTT) assay. Cellular apoptosis and proliferation were detected by TUNEL assay and immunocytochemical staining, respectively., Results: Pretreatment with 5-ASA or nimesulide at the concentration of 10-1000 micromol/L inhibited proliferation of HT-29 colon carcinoma cells in a dose-dependent manner in vitro (t=5.122, P<0.05; t=3.086, P<0.05, respectively). The inhibition rate of HT-29 colon carcinoma cell proliferation was also increased when pretreated with 5-ASA (100 micromol/L) or nimesulide (100 micromol/L) for 12-96 h, which showed an obvious time-effect relationship (t=6.149, P<0.05; t=4.159, P<0.05, respectively). At the concentration of 10-500 micromol/L, the apoptotic rate of HT-29 colon carcinoma cells significantly increased (t=18.156, P<0.001; t=19.983, P<0.001, respectively), while expression of proliferating cell nuclear antigen (PCNA) was remarkably decreased (t=6.828, P<0.05; t=14.024, P<0.05, respectively). 5-ASA in combination with nimesulide suppressed the proliferation of HT-29 colon carcinoma cells more than either of these agents in a dose-dependent and time-dependent manner (t=5.448, P<0.05; t=4.428, P<0.05, respectively)., Conclusion: 5-ASA and nimesulide may inhibit the proliferation of HT-29 colon carcinoma cells and coadministration of these agents may have additional chemopreventive potential.

Aim: To investigate H pylori expression in gastric cancer patients in relation to primary tumor angiogenic markers, such as microvessel density (MVD), thymidine phosphorylase (TP), vascular endothelial growth factor receptor-1 (VEGF-R1), p53 and circulating VEGF levels., Methods: Angiogenic markers were analyzed immunohistochemically in 56 primary gastric cancers. H pylori cytotoxin (vacA) and the cytotoxin-associated gene (cagA) amplification were evaluated using PCR assay. Serum H pylori IgG antibodies and serum/plasma circulating VEGF levels were detected in 39 and 38 patients by ELISA, respectively., Results: A total of 69% of patients were positive for circulating IgG antibodies against H pylori. cagA-positive H pylori strains were found in 41% of gastric patients. vacA was found in 50% of patients; s1 strains were more highly expressed among vacA-positive patients. The presence of the s1 strain was significantly associated with cagA (P = 0.0001). MVD was significantly correlated with both tumor VEGF expression (r = 0.361, P = 0.009) and serum VEGF levels (r = -0.347, P = 0.041). Conversely, neither VEGF-R1 expression nor MVD was related to p53 expression. However, H pylori was not related to any angiogenic markers except for the plasma VEGF level (P = 0.026)., Conclusion: H pylori antigen is related to higher plasma VEGF levels, but not to angiogenic characteristics. It can be hypothesized that the toxic effects of H pylori on angiogenesis occurs in early preclinical disease phase or in long-lasting aggressive infections, but only when high H pylori IgG levels are persistent.

Aim: To analyze the biological effects of prolonged in vitro exposure of HT-29 and LoVo colon cancer cell lines to gefitinib (Iressa), an inhibitor of epidermal growth factor receptor (EGFR) activity, and ZD6474, an inhibitor of both KDR and EGFR activities., Methods: Cells were treated with each drug for up to 2 wk using either a continuous or an intermittent (4 d of drug exposure followed by 3 d of washout each week) schedule., Results: In both cell types, prolonged exposure (up to 14 d) to gefitinib or ZD6474 produced a similar inhibition of cell growth that was persistent and independent of the treatment schedule. The effects on cell growth were associated with a pronounced inhibition of p-EGFR and/or p-KDR expression. Treatment with gefitinib or ZD6474 also inhibited the expression of EGFR downstream signal molecules, p-Erk1/2 and p-Akt, although the magnitude of these effects varied between treatments and cell lines. Furthermore, expression of the drug resistance-related protein ABCG2 was shown to significantly increase after 14 d of continuous exposure to the two drugs., Conclusion: We conclude that long-term exposure of colon cancer cells to gefitinib and ZD6474 does not modify their cytotoxic effects but it might have an effect on sensitivity to classical cytotoxic drugs.

Aim: To observe the pharmacokinetics and pharmaco-dynamics of rabeprazole and compare serum gastrin concentrations in different CYP2C19 genotype groups., Methods: The CYP2C19 genotype status of Chinese Han healthy volunteers was determined by polymerase chain reaction-restriction fragment length polymorphism method. Twenty H pylori-negative healthy subjects voluntary participated in the study. They were divided into the following three groups: homozygous extensive metabolizers (homEM), heterozygous extensive metabolizers (hetEM) and poor metabolizers (PM). After they orally received rabeprazole 20 mg once daily in the morning of d 1 and d 8, blood samples were collected at various time-points until 24 h after administration and intragastric pH values were monitored for 24 h by Digitrapper pH. Serum gastrin concentrations were measured by radioimmunoassay. Serum concentrations of rabeprazole were measured by high performance liquid chromatography., Results: The mean AUC values for rabeprazole after a single and repeated doses were significantly different between the homEM and PM groups, but not between the homEM and hetEM, or the hetEM and PM groups. No significant differences in intragastric pH medians were observed among the three different genotype groups after a single dose or repeated doses. The ratio of pH medians between d 1 and d 8 ranged from 84% to 108%. The mean gastrin AUC values were also different among the three genotype groups, with a relative ratio of 1.0, 1.2 and 1.5 after a single dose and 1.0, 1.5 and 1.6 after repeated doses in the homEM, hetEM and PM groups, respectively. The gastrin AUC values among the three different genotype groups showed no significant difference either after a single dose or repeated doses. The subject who had lower intragastric acidity showed higher serum gastrin levels and concentrations of rabeprazole., Conclusion: In Chinese Han healthy people, the pharmacokinetics of rabeprazole are dependent on the CYP2C19 genotype status, but acid-inhibitory efficacy of rabeprazole and the gastrin level are not influenced significantly.

Aim: To investigate the role of cyclooxygenase-2(COX-2) and vascular endothelial growth factor (VEGF) in the development of gastric carcinoma and correlation between expression of COX-2 and VEGF and clinicopathologic features in tissues from patients with gastric carcinoma., Methods: 281 patients with gastric carcinoma who underwent surgical resection between 1990 and 1999 at the First Affiliated Hospital, Anhui Medical University, PRC, were followed up. Expression of COX-2 and VEGF was investigated retrospectively in 232 gastric carcinoma tissues and 60 noncancerous specimens by using immunohistochemistry., Results: The 5-year survival rates of early gastric carcinoma (EGC) and advanced gastric carcinoma (AGC) were 93.4 % and 59.0 %, respectively. Survival time was highly correlated with lymph node metastasis, vascular invasion, depth of invasion and treatment with chemotherapy. Compared with paired noncancerous tissues, expression of COX-2 and VEGF and microvessel density (MVD) value in carcinoma tissue were significantly higher. The MVD value was much higher in COX-2-positive group and VEGF-positive group than that in COX-2-negative group and VEGF-negative group. Expression of COX-2 and VEGF, as well as MVD value were highly correlated with lymph node metastasis and vascular invasion. The 5-year survival rate of patients with expression of COX-2 or VEGF was significantly lower than that of patients without COX-2 or VEGF expression. Multivariate analysis revealed that VEGF overexpression, lymph node metastasis, COX-2 overexpression, depth of invasion and vascular invasion were all independent prognostic factors of gastric carcinoma., Conclusion: Overexpression of COX-2 and VEGF in patients with gastric carcinoma can enhance the possibility of invasion and metastasis, implicating a poor prognosis. They may serve as the fairly good prognostic factors to indicate biologic behaviors of gastric carcinoma.

Aim: To investigate the effects of melatonin (MT) on the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) in rat models of colitis., Methods: Healthy adult Sprague-Dawlay (SD) rats of both sexes, weighing 280+/-30 g, were employed in the present study. The rat models of colitis were induced by either acetic acid or 2,4,6-trinitrobenzene sulfonic acid (TNBS) enemas. The experimental animals were randomly divided into melatonin treatment and model control group that were intracolicly treated daily with melatonin at doses of 2.5, 5.0, 10.0 mg/kg(-1) and equal amount of saline respectively from 24 h following induction of colitis in rats inflicted with acetic acid enema and the seventh day in rats with TNBS to the end of study. A normal control group of rats treated with neither acetic acid nor TNBS but saline enema was also included in the study. On the 28(th) day of the experiment, the rat colon mucosal damage index (CDMI) was calculated, and the colonic prostaglandin E(2) (PGE(2)), nitric oxide (NO), as well as the iNOS and COX-2 expression were also determined biochemically or immunohistochemically., Results: CDMI increased to 2.87+/-0.64 and 3.12+/-1.12 respectively in rats treated with acetic acid and TNBS enema, which was in accordance with the significantly elevated colonic NO and PGE(2) contents, as well as the up-regulated colonic iNOS and COX-2 expression in both of the two rat models of colitis. With treatment by melatonin at the doses of 5.0 and 10.0 mg/kg(-1), CDMI in both models of rat colitis was significantly decreased (P<0.05-0.01), which accorded synchronously and unanimously with the reduced colonic NO and PGE(2) content, as well as the down-regulated expression of colonic iNOS and COX-2., Conclusion: Melatonin has a protective effect on colonic injury induced by both acetic acid and TNBS enemas, which is probably via a mechanism of local inhibition of iNOS and COX-2 expression in colonic mucosa.