Lipocalin-2 is associated with a good prognosis and reversing epithelial-to-mesenchymal transition in pancreatic cancer.

BACKGROUND: Lipocalin-2 is a multifaceted modulator in cancer progression. Its clinical significance is not clear in pancreatic cancer. The purpose of this study was to investigate whether lipocalin-2 is associated with good prognosis by reversing epithelial-to-mesenchymal transition (EMT) in pancreatic cancer. METHODS: Lipocalin-2, E-cadherin, or vimentin expression was detected in 60 pancreatic adenocarcinoma specimens. Correlations between lipocalin-2 expression and EMT, the clinicopathologic characteristics, and prognosis were investigated. Whether pancreatic cancer cells' migration and invasion (some characteristics of EMT) were affected by lipocalin-2 was also explored. RESULTS: High lipocalin-2 expression was significantly associated with a good prognosis in pancreatic cancer (p < 0.05). Overexpression of lipocalin-2 correlated with a lower extent of EMT (p < 0.05), increased E-cadherin expression (p < 0.05), decreased vimentin expression (p < 0.05), and reduced cancer cell migration and invasion in pancreatic cancer. CONCLUSIONS: Lipocalin-2 may be considered an epithelial inducer, which may reverse EMT and predict a good prognosis in pancreatic cancer.

Treatment of pancreatic cancer using an oncolytic virus harboring the lipocalin-2 gene.

BACKGROUND: The 5-year survival rate for patients with pancreatic cancer is <5%, and it is always resistant to the current chemoradiotherapy. Therefore, new, effective agents for the treatment of pancreatic cancer are urgently needed. The promising strategy of cancer-targeting gene virotherapy (CTGVT) has demonstrated great anticancer potential. The objective of the current study was to determine whether 1 CTGVT approach, oncolytic virus (OV)-harboring lipocalin-2, is capable of treating pancreatic cancer. METHODS: Tissue microarrays were constructed to detect the expression of lipocalin-2 in 60 specimens of pancreatic adenocarcinoma. The clinical significance of lipocalin-2 was investigated in an analysis of correlations between lipocalin-2 expression and matched clinical characteristics. A lipocalin-2-expressing OV, ZD55-lipocalin-2, was constructed by deleting the adenoviral protein E1B55kD. The antitumor efficacy and mechanisms of the OV were investigated in pancreatic cancer cells with v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations in vitro and in vivo. RESULTS: Lipocalin-2 expression was correlated with a good prognosis in patients with pancreatic adenocarcinoma. ZD55-lipocalin-2 dramatically inhibited the growth of pancreatic cancer in vitro and in vivo by inducing cytolysis and caspase-dependent apoptosis. CONCLUSIONS: Higher lipocalin-2 expression predicted a better prognosis in patients with pancreatic cancer. The results indicated that ZD55-lipocalin-2, which specifically expressed higher levels of lipocalin-2 in tumor cells, may serve as a potent anticancer drug for pancreatic cancer therapy, especially for patients who have pancreatic adenocarcinoma with KRAS mutations.

Predictive value of serum carbohydrate antigen 19-9 in malignant intraductal papillary mucinous neoplasms.

BACKGROUND: The goal of the present study was to evaluate the predictive value of serum carbohydrate antigen 19-9 (CA 19-9) in the diagnosis of malignant intraductal papillary mucinous neoplasms of pancreas (IPMNs). METHODS: Eighty-six patients with pathological diagnosis of IPMNs in Zhongshan Hospital between March 1999 and November 2008 were retrospectively reviewed. Data reflecting clinical characteristics, tumor marker level, and prognosis were collected. The potential predictive value of CA 19-9 was analyzed by receiver operating characteristic (ROC) curve. RESULTS: Eighty-six consecutive patients with IPMNs all underwent surgical intervention. A high level of CA 19-9 or carcinoembryonic antigen (CEA) was associated with more advanced stage of malignant IPMNs. Carbohydrate antigen 19-9 was significant for judging malignant IPMNs in the binary logistic regression model (p=0.047). The hazard ratio was 1.014, whose 95.0% confidence interval was 0.91-1.028. Receiver operating characteristic analysis showed that the serum CA 19-9 level had good predictive value for malignant or invasive IPMNs, postoperative survival, and disease-specific recurrence. The area under the curve (AUC) was 0.856, 0.893, 0.815, and 0.857 (p<0.05), respectively. According to the follow-up, mean survival time for groups with CA 19-9>63.60 U/ml was dramatically shorter than that for groups with CA 19-9≤63.60 U/ml (57.38±2.85 versus 29.24±5.82 [months]; p<0.01). CONCLUSIONS: Serum CA 19-9 level has good predictive value for malignant or invasive IPMNs. Patients with CA 19-9 > 63.60 U/ml had poor postoperative prognosis in IPMNs. Preoperative abnormal serum CA 19-9 might be predictive for an aggressive surgical intervention in IPMNs.

Small solid tumors (< or = 2 cm) of the pancreas: relative accuracy and differentiation of CT and MR imaging.

BACKGROUND/AIMS: To determine the relative accuracy of CT and MRI in characterization of solid pancreatic masses (< or = 2cm) and useful imaging appearance for differentiating small pancreatic duct adenocarcinoma (PDAC) from other small solid pancreatic neoplasms. METHODOLOGY: CT and MRI scans of 46 patients with evidence of small pancreatic solid tumor were retrospectively evaluated, who underwent CT (n=30), MRI (n=4), or both (n=12). Two gastrointestinal radiologists independently recorded specific morphological features of tumors and the most likely diagnosis. RESULTS: With respect to specific histopathological characterization, CT and MRI were equally accurate. The mean number of correct diagnoses made by the two reviewers was 37.5 (88.4%) of 42 cases for CT compared to 12 (75%) of 16 cases for MRI (p=0.388). Location in the pancreatic head (p=0.000), presence of dilatation of MPD (p=0.000), presence of dilatation of CBD (p=0.001) and enhancement pattern (p=0.000) were statistically significant for differentiating PDAC from the other small solid pancreatic tumors, while pancreatic atrophy (p=0.069) was statistically inadequate for differentiation, although it gave a 96.4% specificity for the diagnosis of PDAC. CONCLUSIONS: CT and MRI are similarly accurate in the characterization of small solid pancreatic tumors. Small PDAC has characteristic CT and MRI findings that differentiate it from other small solid tumors.

[Application of serum protein profiling in diagnosis, prognosis and evaluation of curative effect of pancreatic adenocarcinoma].

OBJECTIVE: To establish decision tree and logistic regression classification models for diagnosing pancreatic adenocarcinoma (PaCa) and for screening serum biomarkers related to evaluation of different stages and curative effects. METHODS: Serum samples obtained from subjects with pancreatic adenocarcinoma (n = 58) and normal pancreas (n = 51) were applied to strong anion exchange chromatography (SAX2) chips for protein profiling by SELDI-TOF-MS to screen multiple serum biomarkers. Biomarker Wizard software and several statistical methods including algorithm of decision tree, logistic regression and ROC curves were used to construct the decision tree or logistic regression classification models. RESULTS: Average of 61 mass peaks were detected at the molecular range of 2000-30,000, ten decision trees with the highest cross validation rate were chosen to construct the classification models, which can differentiate PaCa from normal pancreas with a sensitivity of 83.3% and a specificity of 100%. Logistic regression was used to achieve the AUC (0.976 +/- 0.011, P < 0.001) with a sensitivity of 77.6% - 91.4% and a specificity of 92.2% - 100%. Six mass peaks were combined by logistic regression to achieve the AUC 0.897 +/- 0.054, 0.978 +/- 0.021 and 0.792 +/- 0.107 (P < 0.05) in the three groups (patients at stage I and II, stage II and III, stage III and IV). One mass peak (M/Z 4,016) was screened (P < 0.05) significantly between the preoperative and postoperative PaCa samples and the intensity decreased weeks after operation. CONCLUSION: Decision tree and logistic regression classification models of the mass peaks screened by SELDI-TOF-MS serum profiling can be used to differentiate pancreatic adenocarcinoma from normal pancreas, and is superior to CA 199. The detected mass peaks are helpful for the evaluation of curative effect and prognosis of pancreatic adenocarcinoma.

[Clinical implication of BRSK2 expression in pancreatic ductal adenocarcinoma].

OBJECTIVE: To investigate the expression of BRSK2 (brain selective kinase 2) in pancreatic ductal adenocarcinoma and to understand its clinical implication. METHODS: Resected tumor specimens of 79 pancreatic ductal adenocarcinoma were collected and paraffin-embedded for prepare. 0.5 microm sections. Immunohistochemical staining was employed to examine the expression pattern of BRSK2 translated protein. Semi-quantitative analysis was used to evaluate the intensity and content of protein expression in tumor tissues. The expression outcome was compared in peri-tumorous tissues and normal pancreatic tissues. Meanwhile, tumor samples were grouped according to their differentiation, TNM stage, with or without vascular or neural invasion. Then the possible relationship was explored between clinical, pathological and survival data and the expression profile of BRSK2 in tumor tissues. RESULTS: BRSK2's expression was weak in normal pancreatic tissues, including islets and minor ducts such as intercalated ducts, intralobular ducts and interlobular ducts. BRSK2's expression was also weak in peri-tumorous tissues. BRSK2's expression was strong in pancreatic ductal adenocarcinomas. It had a close relationship with lymphatic metastasis, distant metastasis, TNM staging as well as peri-pancreatic neural invasion. Tumors with lymphatic metastasis, distant metastasis and peri-pancreatic neural invasion or at later stages showed a higher expression of BRSK2 than those without or those at early stages. However the expression had no correlation with tumor size, differentiation and vascular invasion. The expression of BRSK2 in pancreatic ductal adenocarcinomas was correlated with the prognosis of patients. Those with a higher expression pattern showed a shorter survival period. CONCLUSION: BRSK2 is up-regulated in pancreatic ductal adenocarcinoma. And its expression is correlated with tumor biological behaviors and patient prognosis.

Biodegradable Nanoprodrugs: "Delivering" ROS to Cancer Cells for Molecular Dynamic Therapy.

Biodegradable nanoprodrugs, inheriting the antitumor effects of chemotherapy drugs and overcoming the inevitable drawback of side effects on normal tissues, hold promise as next-generation cancer therapy candidates. Biodegradable nanoprodrugs of transferrin-modified MgO2 nanosheets are developed to selectively deliver reactive oxygen species to cancer cells for molecular dynamic therapy strategy. The nanosheets favor the acidic and low catalase activity tumor microenvironment to react with proton and release nontoxic Mg2+ . This reaction simultaneously produces abundant H2 O2 to induce cell death and damage the structure of transferrin to release Fe3+ , which will react with H2 O2 to produce highly toxic ·OH to kill tumor cells.

[Postoperative adjuvant radiotherapy for pancreatic carcinoma patients after radical resection].

OBJECTIVE: To retrospectively investigate the difference in survival of pancreatic adenocarcinoma patients treated by radical surgery with or without adjuvant radiation therapy. METHODS: Forty-four patients with pancreatic cancer underwent surgical resection with a curative intent, and were divided into two groups: surgery alone (n = 24) or surgery combined with postoperative external beam radiotherapy (EBRT) (n = 20). Survival as an endpoint was analyzed between the two groups. RESULTS: All 44 patients completed their scheduled treatment. The median survival time of the patients treated with radical resection alone was 379 days versus 665 days for those treated with combined therapy. The 1-, 3-, 5-year survival rates of the patients treated with radical resection alone were 46.3%, 8.3%, 4.2% versus 65.2%, 20.2%, 14.1% for the patients treated with combined therapy, respectively, with a significant difference between the two groups (P = 0.017). The failures in local-regional relapse were significantly lower in the postoperative EBRT group than that in the surgery alone group (P < 0.05), while the additional postoperative radiation therapy did not increase the complication rate (P > 0.05). CONCLUSION: Postoperative external beam radiation therapy can improve the survival in patients with pancreatic adenocarcinoma.

[Comparison of MRI manifestations and histopathologic findings in pancreatic head carcinoma in vivo ex vivo].

OBJECTIVE: To prospectively analyze the correlation of MRI image characteristics with histopathological findings in pancreatic head carcinoma in vivo and ex vivo. METHODS: Sixteen patients with pancreatic head carcinoma were examined by 1.5T MRI. MR sequences included pre-and post-contrast dynamic 2D FLASH T1WI, TSE T2WI + fat suppressed (FS). All fresh specimens were scanned again within an hour after resection during the Whipple procedure, and were then cut into slices along the direction of MRI scan. The MRI image characteristics were compared with gross and histopathologic findings of the specimens. RESULTS: The tumor size ranged from 1.5 cm x 2.0 cm to 4.8 cm x 4.2 cm with a mean value of 3.6 cm x 3.1 cm. The MRI findings in vivo showed hypointensity in 14 lesions and isointensity in 2, and on 2D FLASH T1WI and TSE T2WI, all lesions displayed mixed intensity except 3 lesions with iso-intensity. During post-contrast dynamic pancreatic parenchymal phase, 15 lesions showed mild enhancement and 11 lesions had ring enhancement sign. Nine lesions displayed progressive irregular moderate enhancement during post-contrast dynamic hepatic phase. Four lesions showed enhancement with iso- and hyperintensity in post-contrast dynamic delayed phase. The MRI findings demonstrated that all lesions ex vivo had hypointensity on 2D FLASH T1 WI and mixed intensity on TSE T2WI + FS. Tumor tissues mainly displayed hypointensity, and the area containing tumor and inflammatory tissue showed iso-intensity on 2D FLASH T1WI. On T2WI + FS, the fibrosis proportion displayed hypo or isointensity, while the tumor and chronic inflammatory tissue demonstrated slight hyperintensity, and the zones of mucous degeneration or pancreatic ductal dilatation displayed hyper-intensity. The ring enhancement of tumor was caused by multiple factors and no obvious enhancement within tumor and fibrosis area were observed during post-contrast dynamic pancreatic parenchymal phase. Progressive irregular enhancement originated from desmoplastic reaction within the tumor during post-contrast dynamic hepatic phase and delayed phase, respectively. CONCLUSION: Pancreatic head carcinomas contain various kinds of tissues. MRI can reveal these pathologic characteristics. No obvious hemorrhage and necrosis within the tumor were observed in this series.

[Evaluation of CT diagnostic criteria for peri-pancreatic artery and vein invasion in pancreatic carcinoma].

UNLABELLED: OBJECTIVE; To evaluate the clinical value of different CT diagnostic criteria for peripancreatic artery and vein invasion in pancreatic carcinoma through comparison with the findings on surgical exploration. METHODS: Of 72 patients of having suspected pancreatic carcinoma were examined by multiplane spiral CT. Among 43 confirmed by surgical pathology; 15 underwent pancreaticoduodenectomy; 28 were found to have unresectable tumors. The peri-pancreatic major vessels including the superior mesenteric artery, celiac artery, hepatic artery, superior mesenteric vein and portal vein were explored carefully during surgical exploration. RESULTS: The criteria for peri-pancreatic artery invasion was the presence of one of the following signs: artery embeded in tumor, or more than half of the artery circumference involved by tumor with wall irregularity or stenosis. The sensitivity of the above described criteria was 75.0% (12/16). If the criteria of tumor involvement exceeding half of the vessel circumference were adhered to, the sensitivity was 87.5% (14/16), which was high than the former, but the specificity was lower than that of the former one (90.2% versus 95.1%). The criteria for peri-pancreatic vein invasion was presence of any of the following signs: vein obliteration, more than half of the vein circumference involved by tumor, vein wall irregularity, vein stenosis, tear-drop sign of superior mesenteric artery. The sensitivity of the above described criteria was 92.9% (39/42), higher than that of the criteria that more than half of the vessel circumference was involved by the tumor (69.0%, 29/42), but the specificity of both criteria was the same (97.4%, 37/38). CONCLUSION: For assessing peri-pancreatic artery and vein invasion, using the combination of different CT diagnostic criteria has higher accuracy than when using only criteria of more than half of vessel circumference involved by tumor.

[MRI in the evaluation of peripancreatic vessel invasion and resectability of pancreatic carcinoma].

OBJECTIVE: To investigate the role of MRI in evaluating the peripancreatic vessel invasion and resectability of pancreatic carcinoma based on the comparison of MRI image with surgical exploration, and try to establish the criteria for assessment of the sensitivity, specificity and accuracy of resectability. METHODS: Forty-one pancreatic carcinoma patients confirmed by pathology received preoperative plain and contrast enhanced MRI scan, and 37 of them had additional coronal MRA scan. Peripancreatic vessel invasion was preoperatively assessed based on MRI features, and the vessel invasion degree from the uninvolved to the severely involved was divided into 6 grades represented by 1, 2a, 2b, 3a, 3b and 4, respectively. Compared with the findings during the surgery, the sensitivity and specificity of each vessel invasion grade were studied and the receiver operator characteristic curve (ROC) was drawn. The sensitivity, specificity, positive predictive value, negative predictive value and accuracy of resectability evaluation based on 2 and 2a degree were calculated respectively. The resectability of involved arteries and veins of grade 2 were also analyzed. RESULTS: Of the 41 patients, 22 had resectable tumor, with 20 curative resection and 2 palliative. Compared with the findings during surgery, seven vessels including three arteries and four veins were not correctly interpreted by MRI. If grade 1,2a,2b,3a and 3b was used as the resectable standard,respectively, the sensitivity to predict the unresectbility was 78.3%, 84.8%, 67.4%, 56.5% and 47.8%, respectively. Receiver operator characteristic curve demonstrated that grade 2a was the optimal critical point. The sensitivity, specificity, positive predictive value, negative predictive value and accuracy of grade 2a in predicting the unresectbility were 84.8%, 98.5%, 92.9%, 96.6% and 95.9%. CONCLUSION: Our data showed that grade 2a (tumor involvement < 2 cm long and < 1/2 circumference of the vessel) may be more sensitive and accurate in predicting the resectability, which may be considered as the line of demarcation between the respectable and unresectable cases in clinical practice.

[Evaluation of 2D and 3D MRI imaging in the diagnosis of pancreatic carcinoma].

OBJECTIVE: To evaluate various kinds of sequences and modified dynamic contrast-enhanced MRI methods in the diagnosis of pancreatic carcinoma. METHODS: Forty-nine pancreatic carcinoma patients proved by histopathology or clinical examination and follow-up underwent MR examination. Plain MR sequences included: T1-weighted 2D FLASH, T1 WI 3D VIBE, TSE T2 WI and HASTE with FS. Modified dynamic contrast-enhanced scanning procedures were coronal scaning with 3D FLASH and axial scaning using T1 WI 3D VIBE sequences in turn for the upper abdominal area and pancreatic area. The coronal imaging were used to obtain 3D peripancreatic vessels during arterial phase and portal vein phase scanning, respectively. The axial imaging were used to detect the tumor in pancreatic parenchymal phase and delayed phase scanning, respectively. Final scanning for the whole upper abdomen was performed using T1 WI 2D FLASH axial sequence. RESULTS: (1) Of 49 lesions in these patients, 45 showed hypo-intensity and 4 iso-intensity on 3D VIBE. Forty-six lesions showed hypo-intensity and 3 isointensity on 2D FLASH. On TSE T2 + FS, lesion contour was not clear enough; 3 of them displayed isointensity, the other showed iso- or hyper-intensity. (2) During pancreatic parenchymal phase, 48 lesions showed hypo-intensity and 39 ring enhancement. Twenty-four lesions displayed marginal tubercle and inner compartment enhancement during portal vein and delayed phase. Six lesions showed iso- or hyper-intensity in delayed phase. (3) Thirty-seven patients underwent surgical exploration. MRI and MRA had a good correlation with surgical findings for peripancreatic vessels which were diagnosed as being invasive or noninvasive by tumors except three superior mesenteric arteries and four superior mesenteric veins being misdiagnosed. CONCLUSION: As"one-stop-shop" MRI examination, modified MRI sequences consisting of dynamic coronal and axial contrast-enhanced scanning is feasible and helpful in diagnosing, staging and assessing the resectability for pancreatic carcinoma.

[Clinicopathologic analysis of 92 cases of pancreatic cystic neoplasm].

OBJECTIVE: To study the clinicopathologic and immunohistochemical features of cystic neoplasms of the pancreas. METHODS: Ninety-two cases of cystic neoplasm of pancreas were retrieved from the Department archival file during the period from 1999 to 2005. Histologic features were studied and the tumors were typed according to WHO classification. Immunohistochemistry was also carried out using paraffin-embedded tissues. RESULTS: The age of patients ranged from 16 to 80 years. The patients included 33 males and 59 females. The tumors varied from 2 cm to 21 cm in diameter. They consisted of intraductal papillary mucinous neoplasm (36/92), serous cystic neoplasm (18/92), solid pseudopapillary tumor (18/92), mucinous cystic neoplasm (14/92), cystic pancreatic ductal adenocarcinoma (4/92) and cystic pancreatic endocrine neoplasm (2/92). Immunohistochemical study revealed variable staining patterns, with frequent overlaps between different tumor types. In general, serous cystic neoplasm expressed MUC1, while mucinous cystic neoplasm was positive for MUC-5AC, intraductal papillary mucinous neoplasm for MUC-2 and cystic pancreatic ductal adenocarcinoma for MUC-1. On the other hand, solid pseudopapillary tumor expressed alpha-antitrypsin, alpha-antichymotrypsin, vimentin and progesterone receptor. CONCLUSIONS: Accurate diagnosis of pancreatic cystic neoplasms requires correlation of clinical findings, radiologic examination, histologic features and immunostaining results. Pathologic distinction is important because of different prognostic significance. Two-thirds of pancreatic cystic neoplasms are premalignant or malignant and warrant surgical resection, whereas the remaining one-third (including pseudocyst and serous cystadenoma) are benign and can be treated conservatively.

[Clinical evaluation of 21 cases of total pancreatectomy].

OBJECTIVE: To evaluate the clinical outcome of 21 cases of total pancreatectomy. METHODS: The clinical data of 21 cases of total pancreatectomy performed from April 2003 to June 2006 was retrospectively analyzed. RESULTS: Among the 21 patients, 1 case combined with transverse colon resection, 1 case with total gastrectomy, 9 cases with portal-superior mesentery vein resection with end-to-end anastomosis, 9 cases with portal-superior mesentery vein resection and grafts implantation, 8 cases with concomitant celiac axis resection, 4 cases with concomitant celiac axis and common hepatic artery resection, 1 case with concomitant celiac axis, portal vein and superior mesentery artery resection and reconstruction. Complications occurred in 12 cases (57.1%) post the operation and 5 cases (23.8%) died in 30 days after the operation. Insulin was given at the dose of 18 - 28 U daily post operation and blood glucose was maintained normal effectively. Sixteen cases were followed-up and median survival was 9.2 months (1.2 - 13.0 months). The median survival of tubular adenocarcinoma and intraductal papillary mucinous neoplasms of the pancreas (IPMNs) were 7 months (1.2 - 9.0 months) and 11.3 months (10.0 - 13.0 months), respectively. CONCLUSIONS: Total pancreatectomy could not improve survival and it increases the complications and death, but it could improve the quality of life. It's an operation of choice for IPMNs, but with pancreatic carcinoma, the warranty of operation should be considered. The blood glucose level could be maintained normal effectively after the operation.

Moscatilin induces apoptosis of pancreatic cancer cells via reactive oxygen species and the JNK/SAPK pathway.

Moscatilin is a bibenzyl derivative extracted from the Dendrobium aurantiacum var. denneanum, which has traditionally been used as an immunomodulatory treatment in China. The present study was designed to determine whether moscatilin is a pro­apoptotic agent in pancreatic cancer, and to elucidate the underlying mechanisms. The apoptotic and anti­proliferative effects of moscatilin on pancreatic cancer cells were determined in vitro using biochemical assays, such as the MTT assay, colony formation assay, Hoechst staining and DNA fragmentation assay, and in vivo using Panc­1 pancreatic cancer xenografts. Western blotting was also conducted to evaluate the expression levels of B­cell lymphoma 2 (Bcl2), Bcl2­associated X protein (Bax), Bcl2 homologous antagonist killer (Bak), caspase 3, cleaved­caspase 3, poly (ADP­ribose) polymerase, p­c­Jun N­terminal kinase (JNK)/stress­activated protein kinases (SAPK) and JNK/SAPK in response to moscatilin. We used DCFH­DA to detect the production of reactive oxygen species (ROS) induced by moscatilin. The present study demonstrated that moscatilin markedly inhibited pancreatic cancer cell viability and induced cell apoptosis in a concentration­dependent manner. Conversely, moscatilin did not affect the cell viability of human umbilical vein endothelial cells at the comparable dosage. Treatment with moscatilin suppressed clonogenicity of Panc­1 cells in a concentration­dependent manner. Furthermore, a decrease in Bcl2 expression, and an increase in the expression levels of Bak and Bax, was detected following treatment with moscatilin, resulting in an increase in the proapoptotic/anti­apoptotic expression ratio (Bax/Bcl2) in Panc­1 cells. Moscatilin also induced activation of the caspase­dependent mitochondrial apoptotic pathway. In addition, moscatilin enhanced cellular ROS production and induced activation of JNKSAPK signaling pathway. Conversely, pretreatment with the ROS scavenger N­acetylcysteine or the JNK/SAPK­specific inhibitor SP600125 prevented moscatilin­mediated reductions in cell viability. Furthermore, moscatilin inhibited tumor growth in nude mice bearing Panc­1 cells, without apparent toxicity. In conclusion, these results demonstrated that moscatilin may induce pancreatic cell apoptosis, and therefore may be considered a potential therapeutic agent for the treatment of pancreatic cancer.

SN38 increases IL-8 expression through the MAPK pathways in HCT8 cells.

The overexpression of interleukin-8 (IL-8) is closely associated with poor tumor differentiation, metastasis and tumor progression. This study aimed to examine the effects and mechanisms of action of SN38 (a metabolite of the camptothecin derivative, CPT-11) on IL-8 expression in HCT8 cells, using ELISA, CCK-8 and western blot analysis. Among jatrorrhizine, evodiamine, 5-fluorouracil and SN38, SN38 was found to inhibit the proliferation of HCT8 cells in a dose-dependent manner, but to increase IL-8 secretion from HCT8 cells. Of the other agents, evodiamine was found to inhibit both IL-8 secretion and cell proliferation, and jatrorrhizine was found to increase IL-8 secretion without any obvious inhibitory effect on cell proliferation. Further experiments revealed that the increased activation of p38 mitogen-activated protein kinase (MAPK), extracellular signal-regulated kinase (ERK)1/2 and c-Jun N-terminal kinase (JNK) by SN38 contributed to the decreased cell proliferation and to the overexpression of IL-8 induced by SN38. Our results suggested that the MAPK pathways are activated by SN38, resulting in the upregulation of IL-8 expression and in the inhibition of cell proliferation in an IL-8-independent manner. Thus, the potential benefit of the use of a combination of camptothecin-11 with other chemical drugs with inhibitory effects on IL-8 expression, should be paid more attention in treating colon cancer.

Serous cystic neoplasms of the pancreas: a clinicopathologic and immunohistochemical analysis.

OBJECTIVE: To clarify whether the various subtypes of serous cystic neoplasms (SCNs) of the pancreas can be distinguished from each other by marker profiles. METHODS: The immunoprofiles of 13 SCNs were defined by using antibodies against cytoskeletal, neuroendocrine, hormone receptor, and mucin markers. In addition, we examined the expression of calrentinin and alpha-inhibin. RESULTS: SCN included 7 cases of serous microcystic adenomas (SMA), 3 cases of serous oligocystic ill-defined adenomas (SOIA), 1 case of solid serous adenoma (SSA), 1 case of von Hippel-Lindau-associated cystic neoplasm (VHL-CN), and 1 case of serous cystadenocarcinoma (SCC). These neoplasms are histologically similar, but differ in their localization, gross appearance, gender distribution, and biological behavior. The various types of SCNs showed a very similar immunoprofile, characterized by positivity for cytokeratins (100%) and negativity for vimentin and synaptophysin. Other markers that were commonly expressed in the SCNs were alpha-inhibin (85%), MUC1 (69%) and MUC6 (77%). CONCLUSION: The results suggest that, despite their biologic differences, the various types of SCNs have the same (or a very similar) cell type and may therefore have a common direction of differentiation. A centroacinar origin is supported by the finding that a number of SCNs share MUC1 and MUC6 expression with pancreatic centroacinar cells. Alpha-inhibin, and MUC6 may be regarded as new markers for this type of pancreatic tumor.

Influence of glutamine on pancreatic blood flow and apoptosis of pancreatic acinar in rats with severe acute pancreatitis.

OBJECTIVE: To investigate the role of glutamine on splanchnic blood flow, apoptosis of pancreatic acinar and the underlying mechanism in rats with severe acute pancreatitis. METHODS: Forty-eight rats were randomized into two groups: the glutamine group (n = 24) and the severe acute pancreatitis group (n = 24). Jejunotomy was performed in all rats: the glutamine group also received glutamine, and the severe acute pancreatitis group received normal saline. Each group was then subdivided into three subgroups of eight rats each, with the rats be killed at 12, 24 and 36 h after the operation, respectively. A control group underwent sham operation (n = 8). The regional pancreatic microvascular blood flow was measured by Doppler ultrasound. The blood flow of the portal vein, splenic artery and superior mesenteric artery were also recorded. Apoptosis of pancreatic acinar cells was evaluated by TUNEL method. RESULTS: The regional pancreatic microvascular blood flow (KHz) decreased significantly in the severe acute pancreatitis group (P < 0.01), and continued to decrease after 24 h (vs. 12 h, P < 0.01). The blood flow of the portal vein, splenic artery and superior mesenteric artery also decreased in the severe acute pancreatitis group. The glutamine group showed increased regional pancreatic microvascular blood flows, as well as increased blood flow of the portal vein, splenic artery and superior mesenteric artery (vs. the severe acute pancreatitis group, P < 0.01). The apoptotic index of pancreatic acinar in the glutamine group was higher than in the severe acute pancreatitis group (P < 0.01), and both were much higher than that in the control group (P < 0.01). CONCLUSIONS: Enteral administration of glutamine increased the splanchnic blood flow in severe acute pancreatitis rats. The apoptotic index of pancreatic acinar was negatively correlated with the severity of the disease. The interrelation between glutamine and apoptosis in severe acute pancreatitis is worthy of further investigation.

[CT diagnosis of intraductal papillary mucinous tumor of the pancreas].

OBJECTIVE: To investigate the CT and MRI manifestatitions of intraductal papillary mucinous neoplasm (IPMN) of the pancreas. METHODS: Both clinical and imaging data of 12 pathologically confirmed intraductal papillary mucinous neoplasm, of the pancreas were retrospectively analyzed. RESULTS: The pancreatic IPMN can be classified into two types based on CT image: the branch duct IPMN (n=7) originated from the head and uncinate process of the pancreas. The tumor consisted of lobulated or clustered small cyst lesions with septa among them, the wall and septa can be enhanced; the combined IPMN (n=5) involved branch ducts of the uncinate process as well as the main pancreatic ducts with dilatation (diameter: 4-7 mm), one of these involved the branch ducts along the pancreatic body. The pancreatic IPMN was mainly found in elderly patient with a chief clinical symptoms of abdominal pain and/or pancreatitis. CONCLUSION: The intraductal papillary mucinous neoplasm of the pancreas enjoys specific features in CT and MRI image, which are helpful to the diagnosis.

[Clinical features and prognosis of intraductal papillary mucinous neoplasms of pancreas: analysis of 38 cases].

OBJECTIVE: To explore the diagnosis, clinical manifestation, treatment, and prognosis of intraductal papillary mucinous neoplasms (IPMNs) of pancreas. METHODS: The clinical data of 38 patients with IPMNs, 23 males and 15 females, aged 64.1 +/- 10.7 (41 - 81), were analyzed respectively. RESULTS: The main symptoms included abdominal pain and jaundice. Pancreaticoduodenectomy was performed on 32 patients, total pancreatectomy on 1 patient, distal pancreatectomy on 3 patients; and pancreatic biopsy on 2 patients. One patient died during the peri-operational period. Pathology showed 15 cases of main-duct type, 14 cases of branch-duct type, 1 case of mixed type, and 8 cases being un-differentiated, all with dilatation of pancreatic duct at different degrees 4.6 mm in diameter on average. There were 30 cases of invasive IPMNs, with significantly higher level of carbohydrate antigen 19-9 (CA19-9), and 8 non-invasive. The median survival time was 18.5 months in general. In the invasive IPMN group the general median survival time was 16.1 months, and the 1, 2, and 5-year survival times were 54%, 31%, and 21% respectively; and in the non-invasive IPMN group the median survival time was 24.3 months, and the 1, 2, and 5-year survival times were 58% and 38% respectively; without significant differences in the survival times between these 2 groups. TMN staging showed 6 cases of stage 0, 15 cases of stage I, 9 cases of stage II, and 4 cases of stage III among the 34 patients of malignant IPMNs. The median survival times of the patients of the stages 0, I, II, and III were 31.3, 27, 9.1, and 8.9 months respectively with significant differences among them (P = 0.0124). CONCLUSION: IPMN of pancreas has no specific clinical manifestation. Dilatation of pancreatic duct is a manifestation in imaging examination characteristic of IPMN. The serum CA19-9 level is significantly higher in the patients with invasive IPMN. There are significant differences in survival rate among different groups according to TMN staging.