Cigarette Smoking and Mortality in Patients With Pancreatic Cancer: A Systematic Review and Meta-analysis.

Current evidence on cigarette smoking associated with pancreatic cancer mortality is limited. We searched MEDLINE, Web of Science, and Embase databases to identify relevant studies published through January 31, 2018. A random-effects model was used to estimate summary hazard ratios (HRs) and 95% confidence intervals (CIs). A total of 20 studies were retrieved, involving 2,517,623 participants. Of these, more than 15,341 patients with pancreatic cancer died. Compared with never smokers, current (summary HR, 1.56; 95% CI, 1.34-1.83) and former (summary HR, 1.15; 95% CI, 1.06-1.26) smokers had elevated risk of total mortality in patients diagnosed with pancreatic cancer. This effect of cigarette smoking is observed both in the Western regions and the Asia-Pacific regions. This effect of smoking is independent of alcohol use, body mass index, and history of diabetes but is modified by tumor stage and study settings. Dose-response associations between smoking and pancreatic cancer mortality were revealed for smoking intensity, cumulative amount of cigarettes smoked, and duration of smoking. Cigarette smoking was associated with an increase in total mortality for patients with pancreatic cancer. Future studies should further clarify the role of smoking as an effect modifier in treatment trials of pancreatic cancer.

Differences and Similarities in the Clinicopathological Features of Pancreatic Neuroendocrine Tumors in China and the United States: A Multicenter Study.

The presentation, pathology, and prognosis of pancreatic neuroendocrine tumors (PNETs) in Asian patients have not been studied in large cohorts. We hypothesized that the clinicopathological features of PNETs of Chinese patients might be different from those of US patients. The objectives of this study were to address whether PNETs in Chinese patients exhibit unique clinicopathological features and natural history, and can be graded and staged using the WHO/ENETS criteria. This is a retrospective review of medical records of patients with PNETs in multiple academic medical centers in China (7) and the United States (2). Tumor grading and staging were based on WHO/ENETS criteria. The clinicopathological features of PNETs of Chinese and US patients were compared. Univariate and multivariate analyses were performed to find associations between survival and patient demographics, tumor grade and stage, and other clinicopathological characteristics. A total of 977 (527 Chinese and 450 US) patients with PNETs were studied. In general, Chinese patients were younger than US patients (median age 46 vs 56 years). In Chinese patients, insulinomas were the most common (52.2%), followed by nonfunctional tumors (39.7%), whereas the order was reversed in US patients. Tumor grade distribution was similar in the 2 countries (G1: 57.5% vs 55.0%; G2: 38.5% vs 41.3%; and G3: 4.0% vs 3.7%). However, age, primary tumor size, primary tumor location, grade, and stage of subtypes of PNETs were significantly different between the 2 countries. The Chinese nonfunctional tumors were significantly larger than US ones (median size 4 vs 3 cm) and more frequently located in the head/neck region (54.9% vs 34.8%). The Chinese and US insulinomas were similar in size (median 1.5 cm) but the Chinese insulinomas relatively more frequently located in the head/neck region (48.3% vs 26.1%). Higher grade, advanced stage, metastasis, and larger primary tumor size were significantly associated with unfavorable survival in both countries. Several clinicopathological differences are found between Chinese and US PNETs but the PNETs of both countries follow a similar natural history. The WHO tumor grading and ENETS staging criteria are applicable to both Chinese and US patients.

Role of the potassium chloride cotransporter isoform 2-mediated spinal chloride homeostasis in a rat model of visceral hypersensitivity.

Visceral hypersensitivity represents an important hallmark in the pathophysiology of irritable bowel syndrome (IBS), of which the mechanisms remain elusive. The present study was designed to examine whether cation-chloride cotransporter (CCC)-mediated chloride (Cl(-)) homeostasis of the spinal cord is involved in chronic stress-induced visceral hypersensitivity. Chronic visceral hypersensitivity was induced by exposing male Wistar rats to water avoidance stress (WAS). RT-PCR, Western blotting, and immunohistochemistry were used to assess the expression of CCCs in the spinal cord. Patch-clamp recordings were performed on adult spinal cord slices to evaluate Cl(-) homeostasis and Cl(-) extrusion capacity of lamina I neurons. Visceral sensitivity was estimated by measuring the abdominal withdrawal reflex in response to colorectal distension (CRD). After 10 days of WAS exposure, levels of both total protein and the oligomeric form of the K(+)-Cl(-) cotransporter isoform 2 (KCC2), but not Na(+)-K(+)-2Cl(-) transporter isoform 1 (NKCC1), were significantly decreased in the dorsal horn of the lumbosacral spinal cord. The downregulation of KCC2 resulted in a depolarizing shifted equilibrium potential of GABAergic inhibitory postsynaptic current and impaired Cl(-) extrusion capacity in lamina I neurons of the lumbosacral spinal cord from WAS rats. Acute noxious CRD disrupted spinal KCC2 expression and function 2 h after the final distention in sham rats, but not in WAS rats. Pharmacological blockade of KCC2 activity by intrathecal injection of a KCC2 inhibitor [(dihydroindenyl)oxy] alkanoic acid enhanced visceral nociceptive sensitivity in sham rats, but not in WAS rats. These results suggest that KCC2 downregulation-mediated impairment of spinal cord Cl(-) homeostasis may play an important role in chronic stress-induced visceral hypersensitivity.

BMP2 induces PANC-1 cell invasion by MMP-2 overexpression through ROS and ERK.

The emerging roles of bone morphogenetic proteins (BMPs) in the initiation and progression of multiple cancers have drawn great attention in cancer research. We hypothesized that BMP2 promotes cancer metastasis by modulating MMP-2 secretion and activity through intracellular ROS regulation and ERK activation in human pancreatic cancer. Our data show that stimulation of PANC-1 cells with BMP2 induced MMP-2 secretion and activation, associated with decreased E-cadherin expression, resulting in epithelial-to-mesenchymal transformation (EMT) and cell invasion. Blockade of ROS by the ROS scavenger, 2-MPG, abolished cell invasion, inhibited the EMT process and decreased MMP-2 expression, suggesting ROS accumulation caused an increase in MMP-2 expression in BMP2-stimulated PANC-1 cell invasion. Furthermore, treatment of PANC-1 cells with 2-MPG or ERK inhibitor PD98059 reduced the phosphorylation of ERK, resulting in attenuation of BMP2-induced cell invasion and MMP-2 activation. Taken together, these results suggest that BMP2 induces the cell invasion of PANC-1 cells by enhancing MMP-2 secretion and acting through ROS accumulation and ERK activation.

The origins of vacularization in tumors.

Vascularization is crucial for tumor growth and metastasis. Angiogenesis and vasculogenesis are widely accepted processes of tumor vascularization, particularly for endothelium-dependent vessels. In both these processes, the tumor vascular endothelial cells are derived from the host cells, including cells in normal tissues around the tumor or endothelial progenitor cells. In addition, the mosaic vessels occur as a transitional pattern between endothelium-dependent vessels and vasculogenic mimicry (VM), wherein both host endothelium and tumor cells participate in tumor vascularization. VM provides a special passage not involving endothelial cells and is conspicuously different from angiogenesis and vasculogenesis. The biological features of the tumor cells that form VM remain unknown. Tumor stem cells may participate in VM. In this review, we discuss the patterns involved in the origin of vascularization in tumors.

Low expression of IGFBP7 is associated with poor outcome of pancreatic ductal adenocarcinoma.

BACKGROUND: Insulin-like growth factor binding protein 7(IGFBP7) has been implicated as a potential tumor suppressor in various human cancers, although the role of IGFBP7 in pancreatic ductal adenocarcinoma (PDAC) is still unknown. We investigated the expression pattern and clinical significance of IGFBP7 in human PDAC. METHODS: IGFBP7 expression was evaluated by immunohistochemistry in 190 patients with PDAC who underwent surgical tumor resection. Expression of IGFBP7 was correlated with that of p53 and Ki-67, clinicopathologic features. We also evaluated overall survival (OS) according to expression of IGFBP7 by Kaplan-Meier and Cox regression analyses. RESULTS: IGFBP7 expression was significantly downregulated in pancreatic cancer tissues compared with adjacent normal pancreas (P < 0.001) and was inversely associated with Ki-67 expression (r = -0.284, P < 0.001). No significant relationships were found for clinicopathologic features, such as diameter of tumor, node status, grade, and stage. Importantly, low expression of IGFBP7 was associated with poor OS, and this was also significant in multivariate Cox regression analysis (hazard ratio [HR], 1.38; 95 % confidence interval [95 % CI], 1.00-1.91; P = 0.05). CONCLUSIONS: We demonstrate for the first time that IGFBP7 is downregulated in pancreatic cancer, and low expression of IGFBP7 is correlated with increased proliferation and poor postoperative survival. IGFBP7 may be a tumor suppressor in PDAC.

Incidence of hyperamylasemia after endoscopic ultrasound-guided fine needle aspiration of pancreatic lesions: a multicenter study from China.

OBJECTIVES: There have been few reports regarding the incidence of hyperamylasemia after endoscopic ultrasound-guided fine needle aspiration (EUS-FNA). In particular, the potential risk factors involved in the development of hyperamylasemia have not been analyzed owing to the small number of cases reported. The aim of this study was to evaluate hyperamylasemia and associated risk factors after EUS-FNA of a large sample of pancreatic lesions. METHODS: Patients who underwent EUS-FNA for treatment of a pancreatic lesion were recruited from 6 medical centers in China. RESULTS: A total of 1023 patients presenting with pancreatic lesions between January 2004 and June 2008 were enrolled in this study, with 48 (4.7%) of the 1023 patients presenting with hyperamylasemia 3 hours after the procedure. These patients had a mean ± SD serum amylase level of 331.64 ± 138.60 UI/L. With the use of unconditional logistic regression analysis, the incidence of hyperamylasemia was found to be affected by the type of cystic lesion present and the gauge of the needle used. In 4 (0.4%) of the 1023 patients, acute pancreatitis developed. CONCLUSIONS: The overall incidence of hyperamylasemia after EUS-FNA is relatively low. However, the type of cystic lesion present and the gauge of the needle (19G) used for EUS-FNA may represent risk factors for the incidence of hyperamylasemia.

Adiponectin levels in patients with colorectal cancer and adenoma: a meta-analysis.

Inconsistent results with regard to adiponectin levels in patients with colorectal cancer (CRC) and adenoma have been reported. To evaluate adiponectin levels in patients with CRC and adenoma, a meta-analysis on studies which compared adiponectin levels in patients with CRC or adenoma with healthy controls was carried out. A literature search was performed through Pubmed, EMBASE, and Science Citation Index Expanded database. Pooled-weighted mean differences and 95% confidence intervals (95%CI) were calculated by using random-effects models. Heterogeneity between studies was assessed using the Cochran's Q and I statistics. A total of 13 studies were identified, which included 2632 cases of CRC or adenoma and 2753 healthy controls. Adiponectin levels were significantly lower in patients with CRC or adenoma compared with healthy controls, with significant heterogeneity [weighted mean differences of -1.51 (95% CI: -2.42 to -0.59; Pheterogeneity<0.001) for CRC and -1.29 (95% CI: -2.01to -0.58; Pheterogeneity<0.001) for colorectal adenoma, respectively]. On stratified analysis of CRC, significant difference in adiponectin levels between patients with CRC and healthy controls was reported only in case-control studies or small sample size studies (n<100), but not in nested case-control studies or large sample size studies (n≥100). In addition, metaregression analysis indicated that study design and sample size partly contributed to the significant heterogeneity (P=0.022 for study design and P=0.018 for sample size, respectively). For colorectal adenoma studies, stratified analysis indicated that sample size was one of the heterogeneous factors. Sensitivity analysis showed that there were no changes in the direction of effect when any one study was excluded. No publication bias was detected. Adiponectin levels are lower in patients with CRC or colorectal adenoma compared with those in healthy controls. Future studies are warranted to clarify the association of adiponectin levels and carcinogenesis of the colorectum.

Assessment of morbidity and mortality associated with EUS-guided FNA: a systematic review.

BACKGROUND: EUS-guided FNA (EUS-FNA) permits both morphologic and cytologic analysis of lesions within or adjacent to the GI tract. Although previous studies have evaluated the accuracy of EUS-FNA, little is known about the complications of EUS-FNA. Moreover, the frequency and severity of complications may vary from center to center and may be related to differences in individual experience. OBJECTIVE: To systematically review the morbidity and mortality associated with EUS-FNA. DESIGN: MEDLINE and EMBASE were searched to identify relevant English-language articles. MAIN OUTCOME MEASUREMENTS: EUS-FNA-specific morbidity and mortality rates. RESULTS: We identified 51 articles with a total of 10,941 patients who met our inclusion and exclusion criteria; the overall rate of EUS-FNA-specific morbidity was 0.98% (107/10,941). In the small proportion of patients with complications of any kind, the rates of pancreatitis (36/8246; 0.44%) and postprocedure pain (37/10,941; 0.34%) were 33.64% (36/107) and 34.58% (37/107), respectively. The mortality rate attributable to EUS-FNA-specific morbidity was 0.02% (2/10,941). Subgroup analysis showed that the morbidity rate was 2.44% in prospective studies compared with 0.35% in retrospective studies for pancreatic mass lesions (P=.000), whereas it was 2.33% versus 5.07% for pancreatic cysts (P=.036). LIMITATIONS: Few articles reported well-designed, prospective studies and few focused on overall complications after EUS-FNA. CONCLUSIONS: EUS-FNA-related morbidity and mortality rates are relatively low, and most associated events are mild to moderate in severity.

Periostin, a matrix specific protein, is associated with proliferation and invasion of pancreatic cancer.

Overexpression of periostin is present in various malignant tumors and correlates with disease progression. However, its clinicopathological significance in pancreatic cancer is currently not known. Expression of periostin was analyzed by RT-PCR and western blotting in pancreatic cancers and cell lines. Using immunohistochemistry, expression of periostin in pancreatic cancers was evaluated according to factors influencing overall survival with Kaplan-Meier analysis. Ectopic expression of periostin was used to examine the effects of periostin on proliferation and invasiveness of pancreatic cancer cells in vitro. There was no detectable periostin mRNA and protein expression in the 4 pancreatic cell lines. Expression of periostin was found to be up-regulated in pancreatic cancer compared to the adjacent tumor free (TF) tissues by western blotting. The positive ratio of periostin expression in the neoplastic stroma was significantly correlated with the depth of invasion (p=0.007) and lymph node metastasis (p=0.027). Survival analysis showed that stromal or epithelium expression of periostin was associated with poor survival (p=0.035, p=0.022, log-rank test, respectively). In vitro studies showed that periostin was able to promote proliferation and invasiveness of pancreatic cancer cells. These results suggest that periostin may be involved in the progression and invasion of pancreatic cancer.

Positive expression of L1-CAM is associated with perineural invasion and poor outcome in pancreatic ductal adenocarcinoma.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) frequently invades and migrates along neural tissue, which results in local tumor recurrences, distant metastases, and poor prognosis. We evaluated whether L1 cell adhesion molecule (L1-CAM) and glial cell line-derived neurotrophic factor (GDNF) expression in PDAC correlated with neural invasion and overall survival on a large cohort of previously untreated patients. METHODS: L1-CAM and GDNF were examined by immunohistochemistry in pancreatic cancer tissue samples of 94 cases with PDAC on a tissue microarray. The molecular findings were correlated with pain, clinicopathologic characteristics, and overall survival in these patients. RESULTS: L1-CAM and GDNF were overexpressed in pancreatic cancer tissues compared with the adjacent normal tissues of pancreas. Positive L1-CAM expression was associated with node involvement (P = 0.007), vascular invasion (P = 0.012), perineural invasion (P = 0.001), and higher degree of pain (P = 0.005). In univariate analysis, tissue expression of L1-CAM was associated with poor survival (hazard ratio, 2.508; 95% confidence interval, 1.551-4.053; P < 0.001), and this was also significant in multivariate analysis (hazard ratio, 2.046; 95% confidence interval, 1.200-3.488; P = 0.009). Positive staining of GDNF, neural invasion, and vascular invasion were all statistically significantly related to unfavorable prognosis. CONCLUSIONS: Enhanced expression of L1-CAM may contribute to the pain syndrome and perineural invasion and may correlate with poor overall survival in human pancreatic cancer.

MicroRNA155 is induced in activated CD4(+) T cells of TNBS-induced colitis in mice.

AIM: To investigate the expression of microRNA155 (miRNA155) in trinitrobenzene sulphonic acid (TNBS)-induced colitis and the relationship between miRNA155 and tumor necrosis factor (TNF) expressions. METHODS: In TNBS colitis mice, miRNA155 and TNF mRNA expressions were measured in colons and CD4(+) T cells of draining lymph nodes (LNs). CD4(+) T cells were cultured in vitro with or without anti-CD3/CD28 antibody, and the expressions of miRNA155 and TNF mRNA in cells and TNF concentration in culture media were examined. RESULTS: miRNA155 and TNF mRNA expressions in colons and in cells of LNs were significantly increased in TNBS colitis compared with controls. In TNBS colitis, miRNA155 and TNF mRNA expressions in CD4(+) T cells of LNs and TNF concentration in CD4(+) T cells culture media increased compared with controls. When cultured with anti-CD3/CD28 antibody, miRNA155 and TNF mRNA expressions in CD4(+) T cells and TNF concentration in the CD4(+) T cells culture media were significantly higher than those cultured without anti-CD3/CD28 antibody. Following analysis using the Pearson's correlation coefficient, miRNA155 expression had a significant positive correlation with either TNF mRNA expression in CD4(+) T cells (r = 0.860, P < 0.05) or TNF concentration in CD4(+) T cells culture media (r = 0.892, P < 0.05). CONCLUSION: miRNA155 is induced in colons and activated CD4(+) T cells in TNBS colitis, and the levels of miRNA155 and TNF expressions have a significant positive correlation.

Circulating levels of periostin may help identify patients with more aggressive colorectal cancer.

Elevated levels of periostin have been implicated as playing important roles in tumor invasion and metastasis in various tissues. Thus, we determined whether serum periostin levels were associated with progression and poor prognosis in colorectal cancer (CRC) patients. We measured serum periostin levels by ELISA in 67 CRC patients and 120 controls. We also evaluated periostin expression in human CRC specimens (n=15) using immunohistochemistry, and measured expression of periostin mRNA in 7 CRC tissue samples, matched normal tissues and in 4 colon cancer cell lines by RT-PCR. We analyzed the relationship between serum levels of periostin and other clinicopathologic characteristics in patients with CRC. The serum levels of periostin in CRC patients (40.9+/-15.4 ng/ml) were significantly elevated compared to that in healthy volunteers (21.0+/-7.3 ng/ml, P<0.0001) and benign colorectal polyps or adenomas (22.4+/-8.5 ng/ml, P<0.0001). Higher preoperative serum levels of periostin in CRC were found to correlate with distant metastasis (P=0.003), advanced-stage disease (stage III/IV, P<0.0001) and poor prognosis. Preoperative serum periostin levels of 15 cases were significantly higher than matched postoperative levels (47.2+/-13.5 ng/ml vs. 31.3+/-11.0 ng/ml, P=0.008). Twelve of 15 patients (80%) had positive immunohistochemical periostin staining in CRC samples. Interestingly, periostin mRNA was highly upregulated in CRCs in comparison with matched normal tissues, and no expression of periostin mRNA was detected in 4 colon cancer cell lines. Serum levels of periostin detected by ELISA may be of clinical value in identifying patients who may be at high risk for aggression and metastasis of CRC. Periostin may be produced by the stromal cells surrounding the tumor, but not by the CRC cells themselves.