Yu-Wen Tien

Adiponectin as a potential differential marker to distinguish pancreatic cancer and chronic pancreatitis.

Serum adiponectin (ADP) levels are reported inversely related to the risk in breast, endometrial cancer, and gastric cancer. Serum ADP as a potential marker compared with CA-19-9 in pancreatic carcinoma (PC) and chronic pancreatitis (CP) was studied. Adiponectin and CA-19-9 levels were examined at the time of diagnosis in patients with CP and PC. Methods: Serum ADP and CA-19-9 levels were measured by immunoassays in 72 patients with PC and 39 with CP and 290 control subjects. Results: The median levels of ADP for PC were significantly higher than those for CP and control subjects (P = 0.0035). Increasing the upper reference value of ADP allowed for better discrimination between CP and PC. The introduction of 28 ng/mL as a cutoff for ADP significantly improved its specificity. At an elevated cutoff level for ADP (28 ng/mL), a better discrimination between PC and CP was obtained. Conclusions: Adiponectin might be useful in the differential diagnosis of PC and CP with elevated CA-19-9. This gives rise to the possibility that ADP has a potential role in differentiating CP and PC.

Serum vascular endothelial growth factor/soluble vascular endothelial growth factor receptor 1 ratio is an independent prognostic marker in pancreatic cancer.

Objectives: Tumor angiogenesis is the consequence of an imbalance between positive and negative angiogenic regulatory factors. We sought to determine the role of pretreated serum angiogenic factors, including vascular endothelial growth factor (VEGF), placental growth factor (PlGF), and soluble vascular endothelial growth factor receptor 1 (sVEGFR-1), in predicting clinical outcome in patients with pancreatic cancer. Methods: We assessed pretreated serum VEGF, PlGF, and sVEGFR-1 levels in 92 patients with pancreatic adenocarcinoma and 60 healthy control subjects using an enzyme-linked immunosorbent assay. The correlation between these angiogenesis-related factors and clinicopathologic factors, including staging and overall survival, was analyzed. Results: Serum levels of VEGF, PlGF, and sVEGFR-1 were significantly higher in patients with pancreatic cancer compared with those in controls (583.8 ± 559.5 vs 187.63 ± 393.32, 17.65 ± 7.34 vs 10.93 ± 1.21, and 50.94 ± 51.17 vs 15.55 ± 1.98 pg/mL, respectively; P < 0.0001). A reverse correlation was observed between sVEGFR-1 level and the advance of tumor stage. Cox regression analysis showed that the VEGF/sVEGFR-1 ratio was an independent predictor for pancreatic cancer survival. Higher VEGF/sVEGFR-1 ratio was significantly correlated with poor outcome in patents with pancreatic cancer. Conclusions: Vascular endothelial growth factor/sVEGF-1 ratio is an independent prognostic factor for survival in pancreatic cancer. Its significance should be assessed when considering antiangiogenic therapy in treating pancreatic cancer patients.

Celiac artery stenting : a new strategy for patients with pancreaticoduodenal artery aneurysm associated with stenosis of the celiac artery

We report a new strategy—celiac artery stenting—to relieve stenosis of the celiac arterial root. This was performed in two patients with pancreaticoduodenal artery (PDA) aneurysm associated with a stenotic celiac arterial root. The first patient was a 66-year-old man complaining of abrupt onset of upper abdominal pain. Abdominal computed tomography revealed a huge retroperitoneal hematoma behind the duodenum, and superior mesenteric artery (SMA) angiography demonstrated an aneurysm arising from inferior pancreaticoduodenal artery and celiac arteriography showed a stenotic celiac arterial root. Transcatheter embolization of the aneurysm was tried, but failed. Because of his unstable hemodynamics, emergent laparotomy with resection of the aneurysm was performed. Fourteen days after the operation, percutaneous transluminal angioplasty with celiac arterial stenting was done. The patient was discharged 2 days later, and has had no further bleeding episode for 3 years. The second patient was a 46-year-old woman, who also complained of acute upper abdominal pain. Abdominal computed tomography disclosed a huge retroperitoneal hematoma, and selective SMA angiography demonstrated an aneurysm arising from the inferior pancreaticoduodenal artery, and celiac arteriography showed a stenotic celiac arterial root. Because angiography showed no active bleeding from the aneurysm, percutaneous transluminal angioplastic stenting of the stenotic celiac artery was performed. She was discharged 5 days later and has had no further bleeding episode for 2 years. Celiac arterial stenting, as shown in our two patients, could be easily and safely employed in patients with PDA aneurysm associated with a stenotic celiac arterial root to release the stenosis of the celiac arterial root and to prevent further possible bleeding.

Targeting IL-17B–IL-17RB signaling with an anti–IL-17RB antibody blocks pancreatic cancer metastasis by silencing multiple chemokines

Treatment with a new antibody against IL-17RB blocks pancreatic cancer metastasis and promotes survival in mice.

Spectrum of mutations and variants/haplotypes of CFTR and genotype–phenotype correlation in idiopathic chronic pancreatitis and controls in Chinese by complete analysis

Mutations in cystic fibrosis transmembrane conductance regulator (CFTR) gene have been reported in patients with chronic pancreatitis. The authors examine whether the mutations and haplotypes of CFTR will increase the risk of developing idiopathic chronic pancreatitis (ICP) in Chinese and their genotype and phenotype correlations. Seventy‐eight patients with ICP and 200 geographically and ethnically matched controls in Taiwan were analyzed. The entire 27 coding and intronic regions of the CFTR gene were identified using heteroduplex analytical techniques and confirmed by sequencing analysis. The presence of 125G/C, 1001+10C>T, IVSTn(TG)m, 1540A>G, c2694T>G, and c4521G>A were determined by directing sequencing. Abnormal CFTR allele was found to be thrice as frequent in ICP patients as in controls (22/156 vs 19/400, p < 0.0001). T5 allele was associated with early onset of ICP. In six‐loci haplotype analysis, 13 common haplotypes were assembled in the 278 individuals tested. The 125G/1001+11C/TG12/470M/2694T/4521G haplotype was associated with risk of ICP (odds ratio 11.3; 95% confidence interval 2.3–54.6, p = 0.008) in Chinese. The mutation spectrum is different from other ethnic groups. A population‐specific panel of CFTR changes should be recommended for targeted populations including ICP in Chinese. It is important to design suitable screening programs for different populations.

Simultaneous Detection of Colonic Epithelial Cells in Portal Venous and Peripheral Blood During Colorectal Cancer Surgery

PURPOSE: This study was designed to show, in certain patients, that colonic epithelial cells can be present in peripheral blood while absent in portal venous blood. METHODS: The circulating colorectal epithelial cells were detected by a reverse transcriptase-polymerase chain reaction assay, which involved amplifying guanylyl cyclase C transcripts. Portal venous and peripheral blood samples were obtained at intervals from 58 patients undergoing colorectal cancer surgery. RESULTS: Circulating colonic epithelial cells were more frequently detected in portal venous blood than in peripheral blood only before mobilization of the tumor-bearing colon segment in patients with tumors of Stage B. In five other patients, before mobilization of their tumor-bearing colon segments, and in another three patients, during the mobilization, colorectal epithelial cells were detected in peripheral blood but not in portal venous blood. These eight patients had Stage C or D tumors. CONCLUSION: In 8 of 58 patients, colorectal epithelial cells were detected in peripheral but not in portal venous blood. Metastatic deposits in lymphatic vessels or liver might be the source of these cells.

SOX4 Transcriptionally Regulates Multiple SEMA3/Plexin Family Members and Promotes Tumor Growth in Pancreatic Cancer

Semaphorin signaling through Plexin frequently participates in tumorigenesis and malignant progression in various types of cancer. In particular, the role of semaphorin signaling in pancreatic ductal adenocarcinoma (PDAC) remains unexplored, despite a high likelihood of metastasis and mortality. Unlike other epithelial malignancies that often express a small number of specific genes in the Semaphorin/Plexin family, five or more are often expressed in human PDAC. Such concomitant expression of these SEMA3/Plexin family members is not a result of gene amplification, but (at least partially) from increased gene transcription activated by SOX4 de novo expressed in PDAC. Via chromatin-immunoprecipitation, luciferase promoter activity assay and electrophoresis mobility shift assay, SOX4 is demonstrated to bind to the consensus site at the promoter of each SEMA3 and Plexin gene to enhance transcription activity. Conversely, RNAi-knockdown of SOX4 in PDAC cell lines results in decreased expression of SEMA3/Plexin family members and is associated with restricted tumor growth both in vitro and in SCID mice. We further demonstrate that SOX4 levels parallel with the summed expression of SEMA3/Plexin family members (P = 0.033, NPar Kruskal-Wallis one-way analysis), which also correlates with poor survival in human PDAC (P = 0.0409, Kaplan-Meier analysis). Intriguingly, miR-129-2 and miR-335, both of which target SOX4 for degradation, are co-repressed in human PDAC cases associated with up-regulated SOX4 in a statistically significant way. In conclusion, we disclose a miR-129-2(miR-335)/SOX4/Semaphorin-Plexin regulatory axis in the tumorigenesis of pancreatic cancer.

Targeted Delivery of C/EBPα -saRNA by Pancreatic Ductal Adenocarcinoma-specific RNA Aptamers Inhibits Tumor Growth In Vivo

The 5-year survival rate for pancreatic ductal adenocarcinoma (PDAC) remains dismal despite current chemotherapeutic agents and inhibitors of molecular targets. As the incidence of PDAC constantly increases, more effective multidrug approaches must be made. Here, we report a novel method of delivering antitumorigenic therapy in PDAC by upregulating the transcriptional factor CCAAT/enhancer-binding protein-α (C/EBPα), recognized for its antiproliferative effects. Small activating RNA (saRNA) duplexes designed to increase C/EBPα expression were linked onto PDAC-specific 2′-Fluropyrimidine RNA aptamers (2′F-RNA) - P19 and P1 for construction of a cell type–specific delivery vehicle. Both P19- and P1-C/EBPα-saRNA conjugates increased expression of C/EBPα and significantly suppressed cell proliferation. Tail vein injection of the saRNA/aptamer conjugates in PANC-1 and in gemcitabine-resistant AsPC-1 mouse-xenografts led to reduced tumor size with no observed toxicity. To exploit the specificity of the P19/P1 aptamers for PDAC cells, we also assessed if conjugation with Cy3 would allow it to be used as a diagnostic tool on archival human pancreatic duodenectomy tissue sections. Scoring pattern from 72 patients suggested a positive correlation between high fluorescent signal in the high mortality patient groups. We propose a novel aptamer-based strategy for delivery of targeted molecular therapy in advanced PDAC where current modalities fail.

Is Surgery Indicated for Patients with Symptomatic Nonfunctioning Pancreatic Neuroendocrine Tumor and Unresectable Hepatic Metastases

BackgroundPatients with advanced pancreatic neuroendocrine tumor, even in the presence of unresectable hepatic metastases, have survival usually measured in years than in months. Theoretically, we would have reason to resect symptomatic primary pancreatic neuroendocrine tumors from these patients palliatively. However, the effect and feasibility of removing symptomatic primary pancreatic neuroendocrine tumor in patients with unresectable hepatic metastases has never been addressed.MethodsIn 2000, we instituted a prospective study to resect symptomatic primary tumors and treat unresectable hepatic metastases by lanreotide and hepatic artery embolization in patients with definite tissue proof of pancreatic neuroendocrine tumor.ResultsThirteen patients were included in this study; seven patients underwent pancreaticoduodenectomy, and six underwent distal pancreatectomy and splenectomy. There were no operative deaths. Eight of thirteen patients had no radiologic evidence of disease progression. The other five patients had disease progression by their 6-month follow-up; they underwent hepatic artery chemoembolization or chemotherapy. One patient died of multiple lung and bone metastases 80 months after operation, and one patient died of continuous progression of liver metastases 18 months after operation. Telephone interviews of 11 patients who survived revealed that 10 reported improved quality of life after resection of symptomatic primary pancreatic neuroendocrine tumor and one patient reported no change.ConclusionsWe suggest that symptomatic primary pancreatic neuroendocrine tumors should be resected even when unresectable hepatic metastases are found at diagnosis because of the relatively low risk of pancreatic surgery, effective elimination of symptoms caused by primary tumors, and slow progression of hepatic metastases under lanreotide and hepatic artery embolization.

Serum heat shock protein 27 is increased in chronic pancreatitis and pancreatic carcinoma.

Objectives: A prior study suggested serum heat shock protein 27 (HSP27) as a potential marker for pancreatic carcinoma, but its accuracy in differentiating cancer from chronic pancreatitis was not evaluated. We aimed to analyze HSP27 levels in pancreatic carcinoma, chronic pancreatitis, and healthy subjects and assess its diagnostic efficacy. Methods: Pretreatment serums from 58 pancreatic carcinoma, 44 chronic pancreatitis, and 102 control subjects were collected. Serum HSP27 and carbohydrate antigen 19-9 (CA19-9) levels were analyzed using an enzyme-linked immunosorbent assay and radioimmunoassay, respectively. Results: Heat shock protein 27 levels were significantly higher in cancer and pancreatitis compared with control (P < 0.001 for both), but no significant difference was noted between cancer and pancreatitis (P = 0.978). By logistic regression, HSP27 was a significant predictor of differentiation between cancer and control (P < 0.0001) but not between cancer and pancreatitis (P = 0.885). At a cutoff of 1650 ng/L, the sensitivity and specificity for differentiating cancer from healthy control were 62.1% and 95.1%, respectively. Receiver operating characteristic analyses showed a greater area under curve for CA19-9 compared with HSP27 in differentiating between cancer and control (0.92 and 0.84, respectively, P = 0.014). Conclusions: Serum HSP27 is increased in both chronic pancreatitis and pancreatic carcinoma. It should not be recommended as a diagnostic marker for pancreatic carcinoma.