Wenhui Lou

IRF-2 is over-expressed in pancreatic cancer and promotes the growth of pancreatic cancer cells

Pancreatic cancer is one of the most malignant diseases in the world. Interferon regulator factor 2 (IRF-2), an interferon regulatory factor, has been known to act as an oncogene in distinct types of cancer. In this study, we found that the expression of IRF-2 was up-regulated in primary pancreatic cancer samples and associated with tumor size, differentiation, tumor–node–metastasis stage, and survival of the patients. In pancreatic cancer cells, knockdown on the expression of IRF-2 inhibited cell growth in the liquid culture and on the soft agar. Mechanistically, IRF-2 modulated the growth of pancreatic cancer cells through regulating proliferation and apoptosis effectors, such as cyclin D1 and BAX. Collectively, these results suggest that IRF-2 plays an important role in the tumorigenesis of pancreatic cancer and down-regulation of IRF-2 would be a new treatment target for pancreatic cancer.

The value of serum chromogranin A as a predictor of tumor burden, therapeutic response, and nomogram-based survival in well-moderate nonfunctional pancreatic neuroendocrine tumors with liver metastases.

ObjectiveTo investigate the usefulness of serum chromogranin A (CgA) for the prediction of tumor burden, therapeutic response, and nomogram-based survival in well-moderate nonfunctional pancreatic neuroendocrine tumors (NF-PNETs) with liver metastases (LMs). Materials and methodsThis prospective study included 51 NF-PNETs of LMs patients, 134 other neuroendocrine tumors, and 125 controls. Serum CgA levels were determined by enzyme-linked immunosorbent assay at baseline and after treatment. LMs tumor burden was computed simultaneously from computed tomography/MRI scan with thin slices using a semiquantitative three-dimensional reconstruction approach. Predictive CgA for therapeutic response was assessed using the response evaluation criteria in solid tumors criteria. A nomogram to predict the prognostic value of CgA with variables selected in the multivariate Cox proportional hazards model was constructed; the accuracy of the nomogram was quantified by the (concordance index) C-index and a calibration plot. ResultsConsidering NF-PNETs, CgA correlated with the tumor grade and differentiation (P<0.05). There was a nonlinear exponential regression between LMs tumor burden and CgA levels (P<0.001). The alteration in CgA correlated with therapeutic response (P<0.001). Increased CgA presented significantly lower progression-free survival than the stable/decreased CgA subgroup (P<0.001). For overall survival, a baseline CgA increase greater than 2.5 upper limit of normal level was predictive of a poor prognosis (P<0.001). Baseline CgA level, LMs tumor burden, and Ki-67 were selected as independent factors for the nomogram to predict overall survival; the nomogram showed fitting calibration with a C-index of 0.87 (95% confidence interval, 0.82–0.92). ConclusionSerum CgA could be used to reflect tumor burden, evaluate the therapeutic response, and predict the survival outcomes for NF-PNETs with LMs. An effective nomogram including CgA was proposed for prediction.

Clinicopathological characteristics and prognosis-related factors of resectable pancreatic neuroendocrine tumors: a retrospective study of 104 cases in a single Chinese center.

Objective The purpose was to describe the clinicopathological characteristics of pancreatic neuroendocrine tumors (pNETs) and evaluate prognosis-related factors in potentially resectable pNETs. Methods The clinical data of 104 patients with pNETs who underwent surgery were retrospectively analyzed. Results The mean (SD) age was 49.8 (14.6) years. The percentages of TNM stages I, II, III, and IV tumors were 25.0%, 44.2%, 22.1%, and 8.7%, respectively. Twenty-seven cases were functional. Nonfunctional pNETs were more common in patients with large tumors, advanced age, higher mitotic count, neural invasion, extrapancreatic organ invasion, liver metastases, and advanced staging (P < 0.05). The 5-year overall survival rate was 93%. The relapse rate was 28.6% (28/98), and the mean (SD) relapse time was 38.7 (31.7) months. Reduced survival rate was associated with older patients (>60 years) (P = 0.026), patients with a higher Ki-67 index (>2%) (P = 0.024), regional lymph node metastases (P = 0.033), liver metastases (P = 0.015), neural invasion (P = 0.017), necrosis (P = 0.042), and major vascular invasion (P = 0.023). Age of more than 60 years (P = 0.047; hazard ratio [HR], 5.2), major vascular invasion (P = 0.030; HR, 5.8), and a Ki-67 index greater than 2% (P = 0.008; HR, 10.3) were independent predictors. Conclusions Nonfunctional pNETs were more common with aggressive clinical presentation. Age of more than 60 years, major vascular invasion, and a Ki-67 index greater than 2% were independent predictive factors. Patients who underwent a potentially curative resection seemed to achieve long-term survival.

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

ObjectiveTo compare the peri-operative outcomes for laparoscopic distal pancreatectomy (LDP) and open distal pancreatectomy (ODP) for benign or premalignant pancreatic neoplasms in two institutions.MethodsThis 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.ResultsThe 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 postoperative 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).ConclusionsLDP is safe and effective for benign or premalignant pancreatic neoplasms, featuring lower blood loss and substantially faster recovery.總結目 的评估腹腔镜胰体尾切除术安全有效性,对比腹腔镜胰体尾切除术与开腹胰体尾切除术治疗胰腺体尾部良性或低度恶性病变临床疗效。创新点本研究为回顾性对照研究,相较于过往腹腔镜胰体尾切除术与开腹胰体尾切除术的对照研究,其创新点一为本组91 例病例均为良性或低度恶性病例,剔除了恶性病变病例;二为本研究中腹腔镜胰体尾切除术组及开腹胰体尾切除术组分别由两家大型综合医院胰腺疾病诊治中心的两组医生分别施行手术,这样避免了病人及手术方式选择等造成的影响,结果更为客观。方法回顾分析自2010 年1 月至2012 年12 月浙江大学医学院附属邵逸夫医院45 例施行腹腔镜胰体尾切除术治疗胰腺体尾部良性或低度恶性病变病例(LDP 组),以及同期上海复旦大学附属中山医院46 例施行开腹胰体尾切除术胰腺体尾部良性或低度恶性病变病例(ODP 组)的相关临床资料,进行对照研究。结论本研究包括胰腺体尾部良性或低度恶性病例91 例,其中LDP 组45 例(无中转开腹)和ODP 组 46 例。手术时间分别为(158.7±38.3) min(LDP 组)和(92.2±24.1) min(ODP 组);术中出血LDP 组明显少于ODP 组( (122.6±61.1) ml vs. (203.1±84.8) ml,P<0.001)。两组保脾率相似(53.3% vs. 47.8%,P=0.35),其中LDP 组中保脾病例均保留脾血管。在术后恢复指标方面,LDP 组优于ODP 组,恢复进食流质时间((1.6±0.5) d vs. (3.2±0.7) d,P<0.01)及恢复活动时间((1.8±0.4) d vs. (2.1±0.6) d,P=0.02)较短,且LDP 组术后住院时间也少于ODP 组((7.9±3.8) d vs. (11.9±5.8) d, P=0.006)。术后胰瘘率两组无明显差异(15.6% vs. 19.6%,P=0.62),但术中总并发症率LDP 组低于ODP 组(26.7% vs. 47.8%,P=0.04)。研究结果显示腹腔镜胰体尾切除术治疗胰腺体尾部良性或低度恶性肿瘤安全可行,与开腹胰体尾切除术术相比术中出血更少、术后恢复更快,具有明显微创优势。

TRAF6 is over-expressed in pancreatic cancer and promotes the tumorigenicity of pancreatic cancer cells.

Pancreatic cancer is one of the most lethal malignancies, with a poor response to chemotherapy and therefore it is important to identify novel therapeutic targets. TNF receptor-associated factor 6 (TRAF6) , a regulator of NF-κB signaling, has been found recently to be involved in tumorigenesis. However, its function in pancreatic cancer remains poorly understood. Here, we found that the expression of TRAF6 was up-regulated in pancreatic cancer tissues. Moreover, over-expression of TRAF6 in pancreatic cancer cells promoted cell proliferation and migration, whereas down-regulation of TRAF6 impaired the tumorigenicity of pancreatic cancer cells in vitro and in vivo. Mechanistically, TRAF6 regulated the expression of multiple genes involved in cell growth, apoptosis and migration. Our results suggested several important roles of TRAF6 in the pathogenesis of pancreatic cancer. TRAF6 might therefore represent a potential therapeutic target.

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

Highlights • The first case of IPAS arising after splenectomy.• The IPAS has similar features of pancreatic neuroendocrine tumor on images.• Typical pathologic data and characteristics of IPAS were presented and described.• A brief review of IPAS was included.

IL-8-Positive Tumor-Infiltrating Inflammatory Cells Are a Novel Prognostic Marker in Pancreatic Ductal Adenocarcinoma Patients.

ObjectivesTumor-infiltrating inflammatory cells (TIICs) in pancreatic ductal adenocarcinoma (PDAC) are reported to initiate and exacerbate invasion and metastasis. Interleukin-8 (IL-8), a proinflammatory cytokine, is expressed in both neoplastic cells and TIICs in PDAC tissues and increased in patient serum. The aim of this study is to evaluate the values of IL-8 expression profiles in tumor tissues and predict the source of serum IL-8 in PDAC patients. MethodsWe used 2 independent groups of PDAC patient samples that included 240 cases. Tissue expression profiles of cytokines were evaluated with immunohistochemistry and serum levels with human IL-8 assay. The prognostic values of the variables were assessed by Kaplan-Meier or Cox regression analysis. ResultsHigher levels of IL-8–positive TIICs but not tumor cells in PDAC patients correlated with worse prognosis (P = 0.009) and higher blood serum IL-8 levels (P = 0.002). Controlling other independent factors, the relative hazard ratio for PDAC with higher IL-8–positive TIIC levels compared with those with lower TIIC levels was 1.588 (95% confidence interval, 1.04–2.42). ConclusionsHigher IL-8–positive TIIC levels in PDAC tumors indicate poorer prognosis and positively correlate with serum IL-8 concentrations and vice versa. These data suggested that IL-8 might have a potential target for PDAC therapies.

DNA-PKcs deficiency sensitizes the human hepatoma HepG2 cells to cisplatin and 5-fluorouracil through suppression of the PI3K/Akt/NF-κB pathway

The aim of the present study was to investigate the effects of DNA-PKcs deficiency on the chemosensitivity of human hepatoma HepG2 cells to cisplatin (CDDP) and 5-fluorouracil (5-Fu), and to explore the underlying molecular mechanism. After transfection with DNA-PKcs siRNA or control siRNA, HepG2 cells were exposed to combination treatment of CDDP and 5-Fu. The cell viability, DNA damage, cell apoptosis, intracellular reactive oxygen species and glutathione (GSH) level, expression of apoptosis related proteins, activity of phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) pathway, and nuclear factor-κB (NF-κB) pathways were assessed. The combination of CDDP and 5-Fu had a synergistic cytotoxic effect in HepG2 cells in terms of the cell viability, DNA damage, apoptosis, and oxidative stress level. DNA-PKcs siRNA could sensitize the HepG2 cells to the combined treatment. DNA-PKcs suppression further reduced the Akt phosphorylation level and Bcl-2 expression in HepG2 cells exposed to CDDP and 5-Fu, but enhanced the expression of pro-apoptotic proteins p53 and caspase-3. Moreover, CDDP could inhibit the transcriptional activity of NF-κB through degradation of IkB-α, while 5-Fu alone seemed in some extent increases the NF-κB activity. The combined treatment with CDDP and 5-Fu resulted in significantly decrease of the transcriptional activity of NF-κB, which was further aggravated by DNA-PKcs siRNA treatment. In conclusion, DNA-PKcs suppression had complementary effects in combination with CDDP and 5-Fu treatment in HepG2 cells, which was associated with suppression of NF-κB signaling pathway cascade, activation of caspase-3 and p53, as well as down-regulation of Bcl-2 and GSH.

Nab-Paclitaxel Plus S-1 Shows Increased Antitumor Activity in Patient-Derived Pancreatic Cancer Xenograft Mouse Models.

Objectives To investigate the antitumor activity of nanoparticle albumin-bound paclitaxel (nab-paclitaxel) plus S-1 in patient-derived pancreatic cancer xenograft mouse models and to explore biomarkers that could predict drug efficacy. Methods Ten patient-derived xenograft models were established. The third-generation tumor-bearing mice were randomized into 4 treatment groups: (1) control; (2) S-1; (3) nab-paclitaxel; (4) S-1 plus nab-paclitaxel. Resected tumors were tested by immunohistochemistry for the expression of thymidylate synthase, orotate phosphoribosyltransferase (OPRT), dihydropyrimidine dehydrogenase (DPD), secreted protein that is acidic and rich in cysteine, human epidermal growth factor receptor 2 (HER2), collagen-1, and CD31. Results Tumor growth inhibition of the S-1 group, nab-paclitaxel group, and combination group was 69.52%, 86.63%, 103.56%, respectively (P < 0.05). The efficacy of S-1 is better in thymidylate synthase–negative, OPRT-positive, and DPD-negative tumors. The efficacy of nab-paclitaxel is better in HER2-positive tumors. Collagen-1 was decreased and CD31 was increased in tumors treated with nab-paclitaxel and S-1 plus nab-paclitaxel compared with control or S-1. Conclusions This preclinical study showed that S-1 plus nab-paclitaxel exerted significantly better antitumor activity than S-1 or nab-paclitaxel alone. Thymidylate synthase, OPRT, and DPD were possibly biomarkers of S-1 and HER2 of nab-paclitaxel.

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.