ITRAQ-based quantitative proteomics reveals apolipoprotein A-I and transferrin as potential serum markers in CA19-9 negative pancreatic ductal adenocarcinoma.

Currently the diagnosis of pancreatic ductal adenocarcinoma (PDAC) relies on CA19-9 and radiological means, whereas some patients do not have elevated levels of CA19-9 secondary to pancreatic cancer. The purpose of this study was to identify potential serum biomarkers for CA19-9 negative PDAC.A total of 114 serum samples were collected from 3 groups: CA19-9 negative PDAC patients (n = 34), CA19-9 positive PDAC patients (n = 44), and healthy volunteers (n = 36), whereas the first 12 samples from each group were used for isobaric tags for relative and absolute quantitation (iTRAQ) analysis. Thereafter, candidate biomarkers were selected for validation by enzyme-linked immunosorbent assay (ELISA) with the rest specimens.Using the iTRAQ approach, a total of 5 proteins were identified as significantly different between CA19-9 negative PDAC patients and healthy subjects according to our defined criteria. Apolipoprotein A-I (APOA-I) and transferrin (TF) were selected to validate the proteomic results by ELISA in a further 78 serum specimens. It revealed that TF significantly correlated with the degree of histological differentiation (P = 0.042), and univariate and multivariate analyses indicated that TF is an independent prognostic factor for survival (hazard ratio, 0.302; 95% confidence interval, 0.118-0.774; P = 0.013) of patients with PDAC after curative surgery.ITRAQ-based quantitative proteomics revealed that APOA-I and TF may be potential CA19-9 negative PDAC serum markers.

Increased expression of αTubulin is associated with poor prognosis in patients with pancreatic cancer after surgical resection.

BACKGROUND: αTubulin, the essential orchestrator of cytoskeletal protein polymers, critical for cell growth and division, motility, signaling development and maintenance of cell shape, plays vital roles in the oncogenesis and progression of various types of cancer, but its role in prognosis of pancreatic cancer patients remains unknown. The aim of this study was to investigate its prognostic value in patients with pancreatic cancer after surgical resection. RESULTS: αTubulin expression in pancreatic cancer was significantly associated with N classification (p = 0.013) and TNM stage (p = 0.025). Increased expression of αTubulin in tumoral tissue was associated with decreased overall survival rate (p = 0.002). Multivariate Cox regression analysis suggested that αTubulin expression was an independent prognostic indicator for pancreatic cancer except for T and N classification (p = 0.002). Using multivariate analysis, αTubulin expression, CA19-9, and N classification were selected to generate the nomogram to predict the 1-year and 3-year overall survival. The c-index of this model was 0.692. The calibration curve for probability of survival showed good agreement between prediction by nomogram and actual observation. METHODS: αTubulin expression was evaluated by tissue microarrays from 124 pancreatic cancer patients and statistically assessed for correlations with the clinical profiles and the prognosis of the patients with pancreatic cancer. The prognostic nomogram was designed to predict 1-year and 3-year overall survival probability. CONCLUSIONS: αTubulin expression might be an independent prognostic factor for pancreatic cancer after surgical resection and could potentially be a high-priority therapeutic target. Incorporating αTubulin expression into CA19-9 and N classification can provide a good prognostic model.

Value of apparent diffusion coefficient for predicting malignancy of intraductal papillary mucinous neoplasms of the pancreas.

PURPOSE: We aimed to explore the potential value of the whole tumor apparent diffusion coefficient (ADC) for discriminating between benign and malignant intraductal papillary mucinous neoplasms (IPMNs) of the pancreas. METHODS: Forty-two patients underwent 1.5 T magnetic resonance imaging that included diffusion-weighted imaging (DWI, b=0.500 s/mm2). The mean, minimum, and maximum ADC values were measured for the whole tumor. The differences between benign and malignant IPMNs were calculated for the mean ADC, ADC-min, and ADC-max values. Receiver operating characteristics (ROC) analysis was conducted to evaluate their potential diagnostic performance. RESULTS: Fifteen of 25 benign IPMNs demonstrated low or iso-signal intensity on DWI with a b value of 500 s/mm2 compared with normal pancreatic parenchyma, whereas all malignant IPMNs demonstrated high signal intensity. The mean value of ADC was significantly higher in benign IPMNs compared with malignant IPMNs (3.39×10-3 mm2/s vs. 2.39×10-3 mm2/s, P < 0.001), with an area under the ROC curve (AUC) of 0.92 (95% confidence interval [CI], 0.79-0.98). The ADC-min value of malignant IPMNs was also significantly lower than that of benign IPMNs (1.24×10-3 mm2/s vs. 2.58×10-3 mm2/s, P < 0.001), with an AUC of 0.94 (95% CI, 0.82-0.99). No marked difference was found between benign and malignant IPMNs for the ADC-max value (3.89×10-3 mm2/s vs. 3.78×10-3 mm2/s, P = 0.299). CONCLUSION: Lower mean and minimum ADC values of the whole tumor might be potential predictors of malignant IPMNs of the pancreas.

MicroRNA-454 regulates stromal cell derived factor-1 in the control of the growth of pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is a highly malignant carcinoma with an extremely high lethality. We recently reported that hypoxia-inducible factor 1 (HIF-1) targets quiescin sulfhydryl oxidase 1 to facilitate PDAC cell growth and invasion. Here, we analyzed the control of another HIF-1 target, stromal cell derived factor-1 (SDF-1), in PDAC cells. We detected significantly more CD68+ macrophages in the PDAC, compared to normal human pancreas (NT). Since macrophages are recruited to the tissue through their expression of CXCR4 in response to SDF-1, we thus examined the SDF-1 levels in the PDAC specimens. Surprisingly, the SDF-1 protein but not mRNA significantly increased in PDAC, compared to NT. Moreover, a SDF-1-targeting microRNA, miR-454, was found to decrease in PDAC. Promoter luciferase assay confirmed that bindings of miR-454 to 3'-UTR of SDF-1 mRNAs inhibited SDF-1 protein translation. Co-culture of bone marrow derived macrophages and miR-454-modified PDAC cells in a transwell migration experiment showed that macrophages migrated less towards miR-454-overexpressing PDAC cells, and migrated more towards miR-454-depleted cells. Implanted miR-454-depleted PDAC cells grew significantly faster than control, while implanted miR-454-overexpressing PDAC cells grew significantly slower than control. Together, our data suggest that miR-454 may regulate SDF-1 in the control of the growth of PDAC.

Laparoscopic versus open distal pancreatectomy for benign or premalignant pancreatic neoplasms: a two-center comparative study.

OBJECTIVE: To compare the peri-operative outcomes for laparoscopic distal pancreatectomy (LDP) and open distal pancreatectomy (ODP) for benign or premalignant pancreatic neoplasms in two institutions. METHODS: This prospective comparative study included 91 consecutive patients who underwent LDP (n=45) or ODP (n=46) from Jan. 2010 to Dec. 2012. Demographics, intra-operative characteristics, and post-operative outcomes were compared. RESULTS: The median operating time in the LDP group was (158.7±38.3) min compared with (92.2±24.1) min in the ODP group (P<0.001). Patients had lower blood loss in LDP than in the ODP ((122.6±61.1) ml vs. (203.1±84.8) ml, P<0.001). The rates of splenic conservation between the LDP and ODP groups were similar (53.3% vs. 47.8%, P=0.35). All spleen-preserving distal pancreatectomies were conducted with vessel preservation. LDP also demonstrated better post-operative outcomes. The time to oral intake and normal daily activities was faster in the LDP group than in the ODP group ((1.6±0.5) d vs. (3.2±0.7) d, P<0.01; (1.8±0.4) d vs. (2.1±0.6) d, P=0.02, respectively), and the post-operative length of hospital stay in LDP was shorter than that in ODP ((7.9±3.8) d vs. (11.9±5.8) d, P=0.006). No difference in tumor size ((4.7±3.2) cm vs. (4.5±1.8) cm, P=0.77) or overall pancreatic fistula rate (15.6% vs. 19.6%, P=0.62) was found between the groups, while the overall post-operative complication rate was lower in the LDP group (26.7% vs. 47.8%, P=0.04). CONCLUSIONS: LDP is safe and effective for benign or premalignant pancreatic neoplasms, featuring lower blood loss and substantially faster recovery.

Long-term survival following total pancreatectomy and superior mesenteric-portal vein resection for pancreatic ductal adenocarcinoma: A case report.

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with few therapeutic options. At present, surgical resection remains the only potential curative treatment for PDAC. However, only 15-20% of patients with PDAC are eligible for lesion resection. Total pancreatectomy (TP) and superior mesenteric-portal vein resection (SMPVR) may increase the rate of resection of PDCA, but the effect of this approach on improving long-term patient outcomes remains controversial. The present study investigated a case of PDAC in the pancreatic neck of a male patient. The patient underwent a TP, combined with SMPVR, for a margin-negative resection. Following an uneventful post-operative recovery, the patient received adjuvant chemoradiotherapy. The patient is currently alive at six years post-surgery, with a high quality of life. Given the clinical outcome of this patient, TP combined with SMPVR may provide PDAC patients with an opportunity for long-term survival. Therefore, patients with PDAC that is believed to be unresectable based on pre-operative assessment, may benefit from TP and SMPVR.

Post-splenectomy intrapancreatic accessory spleen mimicking endocrine tumor of the pancreas.

INTRODUCTION: Intrapancreatic accessory spleen is an uncommon congenital abnormality of the spleen with no indication for surgical intervention. Among the few cases reported, IPAS coexisted with a normal spleen. We here report the first case of IPAS arising a couple years after splenectomy with the appearance of an endocrine tumor of the pancreas. PRESENTATION OF CASE: A 62-year-old female presented with a one-week history of left upper quadrant discomfort. She had splenectomy for the treatment of hypersplenism caused by cirrhotic portal hypertension two years before this admission. Her physical examination was unremarkable and laboratory data was within the normal range. Both the ultrasonography and magnetic resonance image revealed a small oval-shaped mass in the tail of her pancreas with the diameter 2cm or less. A distal pancreatectomy was performed for the suspection of malignant neuroendocrine tumor of the pancreas. An intrapancreatic accessory spleen was confirmed by the pathologic examination. DISCUSSION: Intrapancreatic accessory spleen is one kind of congenital ectopic spleen without indication for operative intervention. We present the case to support that intrapancreatic accessory spleen may enlarge through a compensatory mechanism, and raise the awareness of this intrapacreatic entity to avoid unnecessary surgical operation. CONCLUSION: IPAS should be highly considered as a differential diagnosis while the lesion is no more than 2.5cm in diameter and/or other accessory spleens show around the splenic hilum.

Clinical strategies for differentiating autoimmune pancreatitis from pancreatic malignancy to avoid unnecessary surgical resection.

OBJECTIVE: The study aimed to determine a practical strategy for differentiating between autoimmune pancreatitis (AIP) and pancreatic malignancy in order to avoid unnecessary surgical resection. METHODS: Altogether, 19 patients with AIP or other pancreatic diseases underwent routine examinations including liver function test and carbohydrate antigen 19-9, computed tomography and/or magnetic resonance imaging. Serum immunoglobulin G (IgG) and/or IgG4 was determined in patients with clinically suspected or pathologically proven AIP. Patients with suspected AIP either received diagnostic steroid therapy or laparotomy (if malignant tumors could not be excluded). Surgery was not performed in patients with a definite diagnosis of AIP by fast intraoperative frozen biopsy. Those with confirmed AIP received steroid treatment. RESULTS: In total, 15 cases were finally confirmed as AIP with eight diagnosed preoperatively, five confirmed by surgical pathology (preoperatively misdiagnosed) and two by intraoperative biopsy. Of these 15 patients with AIP and one without AIP, 14 had elevated serum γ-globulin levels. It was proven by subsequent antibody tests that serum IgG or IgG4 were simultaneously increased. CONCLUSIONS: Elevated serum γ-globulin level can be used as a preoperative sentinel indicator for differentiating between IgG4-related AIP and pancreatic malignancy. Serum IgG or IgG4 tests should be further performed in those with elevated serum γ-globulin level, which helps to identify AIP in order to avoid unnecessary operation.

Decision making for pancreatic resection in patients with intraductal papillary mucinous neoplasms.

AIM: To identify a practical approach for preoperative decision-making in patients with intraductal papillary mucinous neoplasms (IPMNs) of the pancreas. METHODS: Between March 1999 and November 2006, the clinical characteristics, pathological data and computed tomography/magnetic resonance imaging (CT/MRI) of 54 IPMNs cases were retrieved and analyzed. The relationships between the above data and decision-making for pancreatic resection were analyzed using SPSS 13.0 software. Univariate analysis of risk factors for malignant or invasive IPMNs was performed with regard to the following variables: carcinoembryonic antigen, carbohydrate antigen 19-9 (CA19-9) and the characteristics from CT/MRI images. Receiver operating characteristic (ROC) curve analysis for pancreatic resection was performed using significant factors from the univariate analysis. RESULTS: CT/MRI images, including main and mixed duct IPMNs, tumor size > 30 mm or a solid component appearance in the lesion, and preoperative serum CA19-9 > 37 U/mL had good predictive value for determining pancreatic resection (P < 0.05), but with limitations. Combining the above factors (CT/MRI images and CA19-9) improved the accuracy and sensitivity for determining pancreatic resection in IPMNs. Using ROC analysis, the area under the curve reached 0.893 (P < 0.01, 95%CI: 0.763-1.023), with a sensitivity, specificity, positive predictive value and negative predictive value of 95.2%, 83.3%, 95.2% and 83.3%, respectively. CONCLUSION: Combining preoperative CT/MRI images and CA19-9 level may provide useful information for surgical decision-making in IPMNs.

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.

Survival analysis of pancreatic and periampullary collision cancers.

OBJECTIVE: Collision cancers are malignancies in the same organ or anatomical site that comprises at least two different tumor components, with no mixed or transitional area between two components. Collision cancers are very rare in the pancreas and periampullary region. The aim of this study was to analyze the clinical and pathological features and prognosis of collision cancer in the pancreas and periampullary region. METHODS: Patients with collision cancers of the pancreas and periampullary region (n= 10) who had undergone radical surgery were retrospectively studied. Their clinical and pathological features were summarized and the prognostic data were compared with patients with pancreatic adenocarcinomas who underwent radical surgery (n= 87) and with patients with pancreatic or periampullary malignancies who underwent palliative surgery (n= 89). RESULTS: Compared with other cancers at these sites, collision cancer presents no specific clinical features. However, the median survival period of patients with such malignancies was only 10.0 months, which was much less than those with pancreatic adenocarcinomas who underwent radical surgery (27.0 months) and those who received a palliative operation (20.9 months) only. CONCLUSION: Collision cancers of the pancreas and periampullary region are difficult to diagnose preoperatively. Their prognosis is poor even after radical resection and adjuvant chemotherapy were given.

Induction of antigen-specific CTL and antibody responses in mice by a novel recombinant tandem repeat DNA vaccine targeting at mucin 1 of pancreatic cancer.

PURPOSE: Tandem repeat (TR) is the key epitope of mucin 1 (MUC1) for inducing cytotoxic T lymphocytes (CTL) to kill the tumor cells specifically. This study aimed to construct a new recombinant DNA vaccine based on single TR and to investigate the induced immune responses in mice. MATERIALS AND METHODS: After the synthesis of a recombinant human TR(rhTR)and the construction of the recombinant plasmid pcDNA3.1-TR/Myc-his (+) A (pTR plasmid), C57BL/6 (H-2(b)) mice were immunized with it (TR group, n = 15). Mice inoculated with the empty vector (EV group, n = 15) and normal saline (NS group, n = 15) were used as vector and blank control, respectively. Cytotoxic assay was carried out to measure the CTL activity. And indirect enzyme-linked immunosorbent assay (ELISA) was used to detect anti-TR-specific antibodies. RESULTS: TR group resulted in more efficient induction of CTL-specific cytolysis against TR polypeptide than both EV and NS groups (both P < 0.01). Vaccine-immunized mice had a higher equivalent concentration of anti-TR-specific antibodies (2,324 ± 238 µg/ml) than either of EV group (1,896 ± 533 µg/ml, P < 0.01) or NS group (1,736 ± 142 µg/ml, P < 0.01). CONCLUSION: The novel recombinant TR DNA vaccine targeting at MUC1 of pancreatic cancer was constructed successfully, effectively expressing TR polypeptide in the transfected mammalian cells and inducing TR-specific CTL and antibody response.

Clinical epidemiological analysis of the relationship between pancreatic cancer and diabetes mellitus: data from a single institution in China.

OBJECTIVE: To investigate the relationship between pancreatic cancer (PC) and diabetes mellitus. METHODS: All PC patients diagnosed and treated at Zhongshan hospital from January 1991 to December 2007 were retrospectively analyzed. During this period, 770 non-digestive tract, non-neoplastic and non-hormone-related patients matched for sex and age were collected as controls. The incidence of diabetes mellitus between the two groups was compared. RESULTS: Between the PC group and the control group, sex and age of the patients were well matched. The incidence of diabetes mellitus was 34.63% in the PC group and 8.83% in the control group (P < 0.001, RR = 5.19). In the PC group there was no correlation between age, sex, site of the cancer, tumor differentiation, lymph node metastasis, TNM staging and the incidence of diabetes mellitus. In this group with diabetes, 74.56% experienced onset within two years of cancer diagnosis. Of the control patients, 57.35% had had diabetes for under 2 years (P = 0.009, RR = 2.18). In the PC group with diabetes, 5.9% had had diabetes for more than 10 years while compared with 8.8% of the controls (P = 0.42). CONCLUSION: Whether diabetes mellitus is a result of or a risk factor for PC is still unclear. The incidence of diabetes mellitus is much higher in the PC patients. The onset of diabetes mellitus in adults might be an alerting factor that could lead to an early diagnosis of pancreatic cancer.

[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.

[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.

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.

Human interleukin 10 gene therapy decreases the severity and mortality of lethal pancreatitis in rats.

BACKGROUND: Studies have proven the validity of interleukin-10 (IL-10) in the treatment of experimental pancreatitis. Prophylactic human IL-10 (hIL-10) gene treatment attenuated the severity in cerulein models. Our research aims to study whether the therapeutic hIL-10 gene could decrease both severity and mortality in a lethal pancreatic model. METHODS: Severe acute pancreatitis (SAP) was induced by sodium taurocholate. A plasmid-hIL-10 construct (pcDNA3-hIL-10) complexed with cationic liposomes was administered to SAP rats by a single intraperitoneal injection. Levels of hIL-10 in the pancreas, liver, and lungs were determined by ELISA kits. The severity of pancreatitis was assessed in terms of serum amylase, histology, and tissue tumor necrosis factor alpha (TNF-alpha). Mortality, observed for 7 days, was evaluated for gene therapy or control groups. RESULTS: After hIL-10 gene therapy, hIL-10 levels in the pancreas, liver, and lungs increased significantly and the serum amylase, tissue TNF-alpha, and histological changes in pancreas, liver, and lungs decreased markedly. Therefore, mortality was significantly reduced in the hIL-10 gene therapy group, in which 70% of rats survived in the 7-day observation, while only 10% survived in untreated groups (P < 0.05). CONCLUSION: We found that liposome/hIL-10 gene therapy decreased severity and mortality in SAP, even carried out after SAP establishment, predicting a more convenient shift to clinical applications.