Overexpression of long noncoding RNA LINC01419 in esophageal squamous cell carcinoma and its relation to the sensitivity to 5-fluorouracil by mediating GSTP1 methylation.

BACKGROUND: Genome-wide sequencing investigations have identified numerous long noncoding RNAs (lncRNAs) among mammals, many of which exhibit aberrant expression in cancers, including esophageal squamous cell carcinoma (ESCC). Herein, this study elucidates the role and mechanism by which LINC01419 regulates the DNA methylation of glutathione S-transferase pi 1 (GSTP1) in relation to ESCC progression and the sensitivity of ESCC cells to 5-fluorouracil (5-FU). METHODS: LINC01419 and GSTP1 levels were quantified among 38 paired ESCC and adjacent tissue samples collected from patients with ESCC. To ascertain the contributory role of LINC01419 in the progression of ESCC and identify the interaction between LINC01419 and GSTP1 promoter methylation, LINC01419 was overexpressed or silenced, and the DNA methyltransferase inhibitor 5-Aza-CdR was treated. RESULTS: Data from the GEO database (GSE21362) and the Cancer Genome Atlas displayed elevated levels of LINC01419 and downregulated levels of GSTP1 in the ESCC tissues and cells. The silencing of LINC01419 led to decreased proliferation, increased apoptosis, and enhanced sensitivity to 5-FU in ESCC cells. Notably, LINC01419 could bind to the promoter region of the GSTP1 gene, resulting in elevated GSTP1 methylation and reduced GSTP1 levels via the recruitment of DNA methyltransferase among ESCC cells, whereby ESCC progression was stimulated accompanied by reduced ESCC cell sensitivity to 5-FU. GSTP1 demethylation by 5-Aza-CdR was observed to reverse the effects of LINC01419 overexpression in ESCC cells and the response to 5-FU. CONCLUSION: Highly expressed LINC01419 in ESCC promotes GSTP1 methylation, which ultimately acts to promote the event of ESCC and diminish the sensitivity of ESCC cells to 5-FU, highlighting a novel potential strategy to improve 5-FU-based chemotherapy in ESCC.

Long noncoding RNA LINC00261 induces chemosensitization to 5-fluorouracil by mediating methylation-dependent repression of DPYD in human esophageal cancer.

Approximately 85% of a single administered dose of 5-fluorouracil (5-FU) will be degraded by dihydropyrimidine dehydrogenase (DYPD). Studies have highlighted a link between the complete or partial loss of DYPD function and clinical responses to 5-FU; however, the underlying molecular basis of DPD deficiency remains poorly understood. Hence, the aim of the present study was to evaluate the prevailing hypothesis which suggests that overexpression of LINC00261 possesses the ability to modulate the methylation-dependent repression of DPYD, ultimately resulting in an elevation of the sensitivity of human esophageal cancer cells to 5-FU. LINC00261 levels were initially quantified, followed by analysis of DYPD methylation within the cancerous tissues collected from 75 patients diagnosed with esophageal cancer undergoing 5-FU-based adjuvant chemotherapy. In an attempt to determine the levels of LINC00261 related to the esophageal cancer cell resistance to 5-FU and to identify the interaction between the levels of LINC00261 and methylation of the DYPD promoter, esophageal cancer cells TE-1 and -5 were prepared, in which LINC00261 and the 5-FU-resistant TE-1 and -5 cells were overexpressed. The levels of LINC00261 were reduced among the cancerous tissues obtained from patients exhibiting resistance to 5-FU. Overexpression of LINC00261 was determined to dramatically inhibit proliferation and resistance to apoptosis among 5-FU-resistant TE-1 and -5 cells, whereas silencing of LINC00261 was determined to enhance proliferation and resistance to apoptosis among the TE-1 and -5 cells. DPYD, a confirmed target of LINC00261, displayed a greater incidence of DNA methylation among patient's sensitive to 5-FU. A key finding revealed that overexpressed LINC00261 could increase the methylation of the DPYD promoter through the recruitment of DNA methyltransferase (DNMT), which, in turn, acts to decrease DPYD activity in 5-FU-resistant TE-1 cells, whereas a reversible change was recorded once the demethylation reagent 5-aza-2'-deoxyctidine was employed to treat the 5-FU-resistant TE-1 cells. Taken together, the results of the study provided evidence emphasizing the distinct antitumor ability of LINC00261 in cases of esophageal cancer, which was manifested by overexpression of LINC00261 detected to increase the sensitivity of human esophageal cancer cells to 5-FU by mediating methylation-dependent repression of DPYD. Our study highlighted the potential of LINC00261 as a novel target capable of improving the chemotherapeutic response and survival of patients with esophageal cancer.-Lin, K., Jiang, H., Zhuang, S.-S., Qin, Y.-S., Qiu, G.-D., She, Y.-Q., Zheng, J.-T., Chen, C., Fang, L., Zhang, S.-Y. Long noncoding RNA LINC00261 induces chemosensitization to 5-fluorouracil by mediating methylation-dependent repression of DPYD in human esophageal cancer.

Assessment of clinical outcomes of advanced hilar cholangiocarcinoma.

BACKGROUND: Low resectability and poor survival outcome are common for hilar cholangiocarcinoma (HCCA), especially in advanced stages. The present study was to assess the clinical outcome of advanced HCCA, focusing on therapeutic modalities, survival analysis and prognostic assessment. METHODS: Clinical data of 176 advanced HCCA patients who had been treated in our hospital between January 2013 and December 2015 were analyzed retrospectively. Prognostic effects of clinicopathological factors were explored by univariate and multivariate analysis. Survival predictors were evaluated by the receiver operating characteristic (ROC) curve. RESULTS: The 3-year overall survival rate was 13% for patients with advanced HCCA. Preoperative total bilirubin (P = 0.009), hepatic artery invasion (P = 0.014) and treatment modalities (P = 0.020) were independent prognostic factors on overall survival. A model combining these independent prognostic factors (area under ROC curve: 0.748; 95% CI: 0.678-0.811; sensitivity: 82.3%, specificity: 53.5%) was highly predictive of tumor death. After R0 resection, the 3-year overall survival was up to 38%. Preoperative total bilirubin was still an independent negative factor, but not for hepatic artery invasion. CONCLUSIONS: Surgery is still the best treatment for advanced HCCA. Preoperative biliary drainage should be performed in highly-jaundiced patients to improve survival. Prediction of survival is improved significantly by a model that incorporates preoperative total bilirubin, hepatic artery invasion and treatment modalities.

Diagnostic and therapeutic strategy and the most efficient prognostic factors of breast malignant fibrous histiocytoma.

We analyzed the clinicopathological features of 9 breast malignant fibrous histiocytoma (MFH) patients. Immunohistochemistry was used to make both diagnosis and differential diagnosis, and to identify prognostic factors. All tumors lacked epithelial markers but expressed mesenchymal markers, suggesting a mesenchymal origin. Of the five cases expressing Ki-67, two of three patients with axillary lymph node involvement died between 6-8 months, and two died at 17 and 26 months after diagnosis. The two remaining cases, with low Ki-67 expression, had no recurrent or metastatic disease at 145 months after diagnosis. Previous studies have shown that surgery is the primary treatment of choice, but no clear benefit from adjuvant chemotherapy was observed. We demonstrate that axillary lymph node involvement and high expression of Ki-67 are associated with poorer prognosis. A literature review indicates surgery remains the first choice for MFH, but benefits from adjuvant chemotherapy remain unclear.

Risk factors of choledocholithiasis formation after liver transplantation.

Systematic study of risk factors for biliary stone post-liver transplantation is rarely performed. To investigate the risk factor of choledocholithiasis formation after liver transplantation, we conducted a case-control study. Fourteen patients were selected into a study group. The stones of the bile duct of the patients were confirmed and treated successfully by endoscopic retrograde cholangiopancreatography. For univariate analysis, we selected carefully some potential risk factors such as cold ischemia time, warm ischemia time, and biliary stricture. The results revealed that cold ischemia time and biliary stenosis were significant predictors. But multivariate analysis revealed that only biliary stenosis was a significant risk factor. In conclusion, biliary stenosis is a risk factor of bile duct stones formation after liver transplantation. Endoscopic retrograde cholangiopancreatography is effective and safe in the diagnosis or treatment of bile duct stones after liver transplantation.

Risk factors and incidence of acute pyogenic cholangitis.

BACKGROUND: Acute cholangitis varies from mild to severe form. Acute suppurative cholangitis (ASC), the severe form of acute cholangitis, is a fatal disease and requires urgent biliary decompression. Which patients are at a high risk of ASC and need emergency drainage is still unclear. The present study aimed to identify the factors for determining early-stage ASC and distinguishing ASC from acute cholangitis. METHODS: We analyzed 359 consecutive patients with acute cholangitis who had been admitted to the First Affiliated Hospital, Zhejiang University School of Medicine from January 2004 to May 2011. Emergency endoscopic retrograde cholangiopancreatography (ERCP) was carried out in all patients to decompress or clear the stones by experienced endoscopists. Clinical and therapeutic data were collected, and univariate and multivariate analyses were performed to identify the potential risk factors of ASC. RESULTS: Of the 359 patients, 1 was excluded because of failure of ERCP drainage. Of the remaining 358 patients with an average age of 62.7 years (range 17-90), 162 were diagnosed with ASC, and 196 with non-ASC. ENBD catheters were placed in 343 patients (95.8%), of whom 182 patients had stones removed at the same time, and plastic stent was placed in 25 patients (7.0%). Clinical conditions were improved quickly after emergency biliary drainage in all patients. Complications were identified in 11 patients (3.1%): mild pancreatitis occurred in 8 patients and hemorrhage in 3 patients. There was no mortality. Univariate analysis showed that several variables were associated with ASC: age, fever, decreased urine output, hypotension, tachycardia, abnormal white blood cell count (WBC), low platelet, high C reactive protein (CRP), and duration of the disease. Multivariate analysis revealed that advanced age, hypotension, abnormal WBC, high CRP, and duration of the disease were independent risk factors for ASC. CONCLUSIONS: This study demonstrates that advanced age, hypotension, abnormal WBC, high CRP, and long duration of antibiotic therapy are significantly associated with ASC. We recommend decompression by ERCP should be carried out in patients as early as possible.

[Surgical treatment of Siewert II adenocarcinoma of the esophagogastric junction].

OBJECTIVE: To explore the outcomes after surgical treatment of esophagogastric junction carcinoma (EGJC). METHODS: One hundred and eighty-five patients with EGJC undergoing surgery from October 2000 to September 2006 at the Cancer Hospital of Shantou University were reviewed retrospectively. The clinical outcomes were compared between transthoracic and transabdominal approach. RESULTS: Of the 185 patients, 133 underwent operation via transthoracic approach and 52 via transabdominal approach. The postoperative complication rates were 10.5%(14/133) and 11.5%(6/52) and the 1-, 3-, 5-year overall survival rates were 83.9%, 44.5%, 32.9% and 86.0%, 38.0%, 30.0% in transthoracic and transabdominal groups respectively, and the difference were not statistically significant (both P>0.05). CONCLUSION: Surgical approach should be individualized for EGCJ.

No therapeutic ERCP in anastomotic stricture without intrahepatic biliary dilation after liver transplantation.

BACKGROUND/AIMS: Differentiating surgical jaundice from non-surgical jaundice is of vital importance after liver transplantation (LT) and endoscopic retrograde cholangiopancreatography (ERCP) is not effective for all anastomotic stricture (AS) cases. In the present study, we aim to determine the optimal indication of ERCP treatment for AS after LT. METHODOLOGY: Twenty-eight jaundice patients who underwent successful ERCP treatments for post-transplant AS were classified into two groups: AS with intrahepatic biliary dilation (group 1, n=22) and AS without intrahepatic biliary dilation (group 2, n=6). The outcomes of the two groups were evaluated. RESULTS: The median time intervals from LT to the occurrence of AS were 38 days and 434 days for group 1 and group 2, respectively. The median total bilirubin significantly decreased from 142umol/L to 49umol/L (p<0.05) two weeks after ERCP treatment in group 1. Fourteen patients (63.6%) were cured and for the other 8 the treatment proved effective in group 1. But total bilirubin was not improved after the ERCP treatment in group 2 (p>0.05). CONCLUSIONS: Therapeutic ERCP is not effective in AS without intrahepatic biliary dilation after LT.

Prevention and treatment of lymphorrhoea following surgery for gastric cancer.

BACKGROUND: Lymphorrhoea is a rare complication of abdominal surgery. However, there have been a few reports of lymphorrhoea following radical gastrectomy. Here, we retrospectively review the clinical analysis and treatment of lymphorrhoea based on our experiences. METHODS: We retrospectively reviewed a total of 1596 patients who underwent surgery for gastric cancer between January 1995 and January 2007. D1 and D2 lymphadenectomies were performed in 1104 patients, and D3 and D4 lymphadenectomies were performed in the other 492 patients. Disrupted lymph vessels were ligated in 545 patients, and electrically cauterized in 559 patients. Before December 31 2000, total parenteral nutrition (TPN) was administered to all the patients, and after 1 January 2001, TPN was supplemented with octreotide in all the post-operative patients. RESULTS: The incidence of lymphorrhoea in patients with D3 and D4 lymphadenectomy was much higher than that in D1 and D2 lymphadenectomy patients (P < 0.05). In addition, the incidence of lymphorrhoea in patients in whom the electrotome cautery was significantly higher than that in patients who received ligation. The addition of octreotide to TPN can reduce the quantity and duration of lymphorrhoea (P < 0.05). CONCLUSION: Ligating rather than cauterizing the disrupted lymph vessels can be done to minimize the incidence of lymphorrhoea. The combination of Octreotide and TPN appears to be an effective therapeutic modality for lymphorrhoea.

Evaluation of surgical approach for extrahepatic cholangiocarcinoma.

BACKGROUND: The incidence of extrahepatic cholangiocarcinoma increases in recent years. But the diagnosis and treatment are still troublesome to surgeons. This study was designed to explore the value of surgical approach in the treatment of extrahepatic cholangiocarcinoma. METHODS: We retrospectively analyzed the clinical data of 135 patients with extrahepatic cholangiocarcinoma who had been treated in our hospital from January 1992 to December 2006. RESULTS: The ratio of extrahepatic cholangiocarcinoma to biliary duct diseases was 1.81%. The rates of total resection and radical resection were 70.75% (75/106) and 56.60% (60/106), respectively. The overall 1-, 3-, 5-year survival rates were 46.93%, 37.33% and 18.75%, respectively. The 1-, 3-, 5-year survival rates were better in the radical resection group (74.94%, 55.74% and 41.27%, respectively) than in the palliative resection group (42.86%, 26.79% and 26.79%, respectively) (P<0.05). The survival rates of patients who had undergone palliative resection were higher than those of patients who had been subjected to palliative drainage or non-operation: 1-, 3-, 5-year survival rates were 42.86%, 26.79%, 26.79% vs. 23.33%, 6.67%, 0 or 17.86%, 0, 0 (P<0.05). While the survival rates were not significantly different between palliative drainage and non-operation (P<0.05). Multivariate analysis revealed that the histopathological grades, TNM stages and modalities were key factors influencing the outcome. CONCLUSIONS: The outcome of the patients with extrahepatic cholangiocarcinoma is still not optimistic. Radical resection is the first choice for the treatment of tumors.

Endoscopic management of biliary complications after orthotopic liver transplantation.

BACKGROUND: Biliary complications are a serious problem in patients after liver transplantation and often require reoperation. This study was conducted to summarize the endoscopic diagnosis and management of biliary complications after orthotopic liver transplantation (OLT). METHODS: From December 2000 to November 2003, twelve endoscopic retrograde cholangiopancreatographies (ERCPs) were performed in 7 patients after OLT at Digestive Endoscopic Center of Changhai Hospital in Shanghai, China. The therapeutic maneuvers included endoscopic sphincterotomy (EST), biliary stent placement, balloon and basket extraction, irrigation, and nasobiliary tube placement. A retrospective study was made to determine the types of biliary tract complications after OLT. The success of ERCP and therapeutic maneuvers was also evaluated. RESULTS: Biliary tract complications including biliary stricture, biliary leak, biliary sludge, and stump leak of the cyst duct were treated respectively by endoscopic sphincterotomy with sludge extraction, stricture dilation or endoscopic retrograde biliary drainage. Two of the 3 patients with proximal common bile duct stricture were successfully treated with ERCP and stent placement. Four patients with anastomotic stricture and/without bile leak were treated successfully by dilation and stent placement or endoscopic nosobiliary drainage. No severe ERCP-related complications occurred. CONCLUSIONS: ERCP is an effective and accurate approach for the diagnosis of biliary tract complications after OLT, and placement of a stent is a safe initial treatment for biliary complications after liver transplantation.

[Long-term results of 84 surgically treated patients with extrahepatic bile duct carcinoma].

OBJECTIVE: Extrahepatic bile duct carcinoma is a rare but dismal malignacy. This study is conducted to show retrospective review and analysis of the correlation between the prognosis and different treatment modalities. METHODS: The data of 84 such patients treated by different modalities from January, 1992 to July, 2000 were retrospectively reviewed and analyzed using SPSS 10.0 statistical package. The survivals were estimated by the Kaplan-Meier method and the difference among groups was tested by the log-rank test. The prognostic factors were determined by Cox multivariate analysis. RESULTS: Of the 84 patients, 33 had complete resection, 19 palliative resection, 12 exploration alone, and the remaining 20 were treated by chemotherapy and/or radiotherapy. The mean follow-up time was 592 days. The overall 5-year survival rate was 13.1%. The 1-, 3- and 5-year survival rate following complete resection was 76.8%, 52.6% and 30.5% respectively, which was significantly higher than those of palliative surgery or chemotherapy/radiotherapy (P < 0.01). Multivariate analysis revealed that lymph node status (P = 0), histopathological grade (P = 0.001) and distant metastasis (P = 0.002) were significant high risk factors. CONCLUSION: The prognosis of extrahepatic bile duct carcinoma remains poor even after complete resection as shown to have a 5-year survival of 30.5%. More effective adjuvant therapy is needed. Extended resection may be helpful in improving the prognosis for carefully selected patients. Early diagnosis and early treatment is still the key to improve the long-term survival of extrahepatic bile duct carcinoma.

[The long-term results of managements in 98 cases of gallbladder carcinomas].

OBJECTIVE: Carcinoma of the gallbladder is an uncommon, but patients with the disease are associated with a dismal prognosis. The purpose of this study was to analyze the characters, prognostic factors of gallbladder carcinoma and investigate the measures of diagnosis and treatment. METHODS: 98 patients admitted into our hospital from January 1992 to July 2000 were followed up, with a mean follow-up time of 478 days (1 - 2,280 days). All statistical analyses were performed with SPSS10.0 statistical package. Survival curves were estimated by the Kaplan-Meier method and differences among groups were tested by the log-rank test. The Cox multivariate analysis was performed to determine prognostic factors on survival. RESULTS: Among 98 patients, 31 with radical resection, 29 with palliative resection, 18 with exploration and 20 with chemo- and/or radiotherapy, The overall 5-year survival rate of the gallbladder carcinoma was 6.67%, The 1-, 3-, and 5-year survival rate following radical resection for gallbladder cancer was 77.29%, 34.37%, 21.48% respectively, The survival rate in radical resection group was remarkably higher than that of the others (P < 0.01). Multivariate analysis revealed that tumor, node, metastases (TNM) stage and therapeutic interventions had significantly higher risk ratios for gallbladder cancer. CONCLUSIONS: With careful patient selection, aggressive resection may help to improve the prognosis, although the disease with ominous reputation. Resection alone is inadequate for a significant improvement in survival, so there is a need to evaluate more effective adjuvant therapy in the form of radiotherapy or newer chemotherapeutic agents. Emphasis to improve the long-term survival should be pay on early diagnosis and early management.

[Early expression of pro-inflammatory cytokines in the lung of rat with small-for-size liver transplantation and the significance].

OBJECTIVE: To investigate the expression of tumor necrosis factor-alpha(TNF-alpha), interleukin-1 beta (IL-1beta), and intercellular adhesion molecule-1 (ICAM-1) in the lung of rat with small-for-size liver transplantation and the significance of the expression of these cytokine in lung injury after liver transplantation. METHODS: 150 SD rats were randomly divided into 4 groups: sham operation group (n = 6), whole graft liver transplantation group (n = 48), 50% size graft liver transplantation group (n = 48), and 30% size liver transplantation group (n = 48). Six rats from each group were killed 0.5, 2, 6, and 24 hours after operation. Blood samples from subhepatic inferior vena cava were obtained to examine the plasma TNF-alpha by ELISA. Specimens of lung were obtained to be examined pathologically. RT-PCR was used to examine the expression of TNF-alpha mRNA, IL-1beta mRNA, and ICAM-1 mRNA in lung, and chromatometry was performed to detect the activity of myeloperoxidase (MPO). RESULTS: (1) The plasma TNF-alpha at any time point was higher in the 3 transplantation groups than in the sham operation group. The plasma TNF-alpha 2 hours after operation in the whole graft group was significantly higher than that in the 30% size group (P < 0.05). (2) The expression levels of TNF-alpha mRNA 2 and 6 hours after operation in the whole graft group and in the 50% graft group were significantly higher than those in the 30% graft group (all P < 0.01). The expression levels of TNF-alpha mRNA remained significantly higher than those in the sham operation group since the second hour after operation (all P < 0.01). (3) IL-1beta mRNA was expressed in the 3 liver transplantation groups without significant differences between any levels at all the time points and was not expressed in the sham operation group. The expression of ICAM-1 mRNA was higher at all the time points in the liver transplantation groups than in the sham operation group (P < 0.01 or P < 0.05) without significant difference between the values of any transplantation group at any time point (all P > 0.05). The MPO activity was stronger in the 3 liver transplantation groups at any time point than in the sham operation group (all P < 0.01). The peak occurred 2 hours after operation in the whole graft group and 50% size group and occurred 6 hours after operation in the 30% graft group. The plasma TNF-alpha level was positively correlated to the MPO activity in lung tissue with a correlation coefficient of 0.422 (P < 0.05). (4) The morphology of lung was normal in the sham operation group. Obvious interstitial hyperemia and hemorrhage, neutrophil infiltration, and pulmonary septal thickening were found in the 3 transplantation groups, in particular being severe at the 2-hour time point. CONCLUSION: Increase of plasma TNF-alpha is one of the causes of lung injury after small-for-size liver transplantation. Upregulation of TNF-alpha mRNA, IL-1beta mRNA, and ICAM-1 mRNA expression may be also responsible for the lung injury and their expression may be correlated to the size of graft.