Clinicopathological and prognostic significance of myofibrillogenesis regulator-1 protein expression in pancreatic ductal adenocarcinoma

Myofibrillogenesis regulator-1 (MR-1) expression was detected in different malignancies and is associated with poor prognosis. However, its role in pancreatic ductal adenocarcinoma (PDAC) has not been fully elucidated. Thus, the aim of this study was to investigate the association of MR-1 expression with clinicopathologic features and prognosis in patients with PDAC. Immunohistochemistry was performed to investigate the protein expression of MR-1 and epithelial (E)-cadherin in 87 patients with PDAC. Results showed that MR-1 expression was correlated with histologic grade, tumor stage, and lymph node metastasis (all P <0.05). In addition, MR-1 expression showed a significant inverse correlation with E-cadherin expression (P?=?0.002). Furthermore, the variables associated with prognosis were analyzed by Cox’s proportional hazards model. Kaplan–Meier analysis was used to plot survival curves according to different expression levels of MR-1. Kaplan–Meier analysis revealed that MR-1 expression was significantly associated with worse disease-free survival (DFS) and overall survival (OS) rates in patients with PDAC (both P <0.001). Finally, multivariate analysis demonstrated that MR-1 expression, together with histologic grade, tumor stage, lymph node metastasis, was an independent prognostic factor for both DFS and OS rates in patients with PDAC. MR-1 overexpression was tightly associated with more aggressive tumor behavior and a poor prognosis, indicating that MR-1 is a valuable molecular biomarker for PDAC progression.     

DPC4/Smad4 expression and outcome in pancreatic ductal adenocarcinoma.

PURPOSE: Prognostic indicators in pancreatic cancer (PC) are poorly defined and difficult to quantify preoperatively, hence they may lead to inappropriate patient selection for treatment. We examined the protein expression of key cell-cycle regulatory and cell-signaling molecules that occur at high frequency in PC and assessed their relationship to clinicopathologic parameters, response to operative resection, and outcome. PATIENTS AND METHODS: We identified 348 patients with pancreatic ductal adenocarcinoma and assessed the influence of reported clinicopathologic prognostic factors and the expression of the cell-cycle regulatory genes p21(WAF1/CIP1) (CDKN1A), cyclin D1 (CCND1), p53, and p16(INK4A) (CDKN2) and the cell-signaling molecule DPC4/Smad4 (MADH4) using immunohistochemistry in a subgroup of 129 patients. RESULTS: Independent prognostic factors in resected patients were tumor size greater than 45 mm (P =.0015), involvement of surgical margins (P <.0001), and perineural invasion (P =.014). Loss of DPC4/Smad4 expression cosegregated with resectability (P <.0001) and was associated with improved survival after resection (P <.0001), whereas resection did not improve survival in patients whose tumor expressed DPC4/Smad4 (P =.5). Aberrant expression of p21(WAF1/CIP1), cyclin D1, p53, or p16(INK4A) was not associated with a difference in survival. CONCLUSION: Tumor size (> 45 mm), resection margin involvement, and perineural invasion were independent prognostic factors. Preoperative assessment of DPC4/Smad4 expression has potential as a prognostic indicator in patients with PC since resection did not benefit those patients whose cancers expressed DPC4/Smad4 and accurate assessment of DPC4/Smad4 expression, unlike tumor size, margin status, and perineural invasion, does not require resection.     

microRNAs with prognostic significance in pancreatic ductal adenocarcinoma: A meta-analysis

BackgroundReports have described the prognostic relevance of microRNAs (miRNAs) in patients treated for pancreatic ductal adenocarcinoma (PDAC). However, many of these include small numbers of patients. To increase statistical power and improve translation, we performed a systematic review and meta-analysis to determine a pooled conclusion. We examined the impact of miRNAs on overall survival (OS) and disease-free survival (DFS) in PDAC.MethodsEligible studies were identified and quality assessed using multiple search strategies (last search December 2014). Data were collected from studies correlating clinical outcomes with dysregulated tumoural or blood miRNAs. Studies were pooled, and combined hazard ratios (HRs) with 95% confidence intervals (CIs) were used to estimate strength of the associations.ResultsTwenty studies involving 1525 patients treated for PDAC were included. After correcting for publication bias, OS was significantly shortened in patients with high tumoural miR-21 (adjusted HR = 2.48; 1.96–3.14). This result persisted when only studies adjusting for adjuvant chemotherapy were combined (adjusted HR = 2.72; 1.91–3.89). High miR-21 also predicted reduced DFS (adjusted HR = 3.08; 1.78–5.33). Similarly, we found significant adjusted HRs for poor OS for high miR-155, high miR-203, and low miR-34a; and unadjusted HRs for high miR-222 and high miR-10b. The small number of studies, limited number of miRNAs and paucity of multivariate analyses are the limitations of our study.ConclusionsThis is the first rigorous pooled analysis assessing miRNAs as prognostic biomarkers in PDAC. Tumoural miR-21 overexpression emerged as an important predictor of poor prognosis after PDAC resection independent of other clinicopathologic factors, including adjuvant chemotherapy use.     

Prognostic significance of activated Akt expression in pancreatic ductal adenocarcinoma.

PURPOSE: Akt is a serine/threonine kinase that plays a central role in tumorigenesis. Among the members of Akt family, Akt2 is associated with the development of human cancers. The present study was designed to clarify the prognostic significance of Akt2 and activated Akt expression in pancreatic ductal adenocarcinoma (PDAC). In addition, activated extracellular signal-regulated kinase 1 and 2 (ERK1/2) and the proliferation activity of tumor cells detected by Ki-67 immunohistochemistry were examined. EXPERIMENTAL DESIGN: Immunohistochemical analysis was performed on paraffin-embedded specimens from 65 patients with PDAC; 36 males and 29 females with ages ranging from 48 to 79 years (median, 66 years) of age. Expression levels of Akt2, phosphorylated Akt (p-Akt), and phosphorylated ERK 1/2 (p-ERK 1/2) were categorized as either weaker (low intensity) or equal to stronger (high intensity) compared with those in the endothelial cells of the same specimens. For Ki-67 immunohistochemistry, cases were divided into two groups: level 1, Ki-67 labeling index (LI), <20%; level 2, Ki-67 LI, > or = 20%. RESULTS: Twenty-six (42.6%), 28 (45.9%), 39 (63.9%), and 46 (75.4%) of the tumors showed high intensity of Akt2, p-Akt, and p-ERK 1/2 expression, and Ki-67 LI level 2, respectively. A significant positive correlation was observed between Akt2 and p-Akt expression (P < 0.01). Multivariate analysis revealed that p-Akt expression, Ki-67 LI, and histological differentiation are independent prognosticators for PDAC. CONCLUSIONS: p-Akt expression is a significant prognostic indicator for PDAC. Inhibition of Akt is a possible molecular approach for treatment of PDAC.     

Radiological evaluation of pancreatic ductal adenocarcinoma

Curative resection is one of the key treatments that influences the survival of pancreatic ductal adenocarcinoma patients. For curative resection, and to avoid unnecessary resection, it is important to diagnose and find the stage of pancreatic carcinoma correctly. CTis the most widely available and most validated imaging modality for this purpose. In this article, we reviewed the effective CTprotocols for detecting pancreatic carcinoma and the CTimaging findings of pancreatic carcinoma that will effect the resectability of the tumor. We also reviewed advantages and disadvantages of other imaging modalities, and imaging findings of some pancreatic carcinomas other than ductal adenocarcinoma.     

Desmogleins as prognostic biomarkers in resected pancreatic ductal adenocarcinoma

Background:

Frequent disease relapse and a lack of effective therapies result in a very poor outcome in pancreatic ductal adenocarcinoma (PDAC) patients. Thus, identification of prognostic biomarkers and possible therapeutic targets is essential. Besides their function in cell–cell adhesion, desmogleins may play a role in tumour progression and invasion that has not been investigated in PDAC to date. This study evaluated desmoglein expression as a biomarker in PDAC.

Methods:

Using immunohistochemistry, we examined desmoglein 1 (DSG1), desmoglein 2 (DSG2) and desmoglein 3 (DSG3) expression in the tumour tissue of 165 resected PDAC cases. Expression levels were correlated to the patients'' clinicopathological parameters and postoperative survival times. We confirmed these results in two independent gene expression data sets.

Results:

A total of 36% of the tumours showed high DSG3 expression that correlated significantly with shorter patient survival (P=0.011) and poor tumour differentiation (P<0.001), whereas no such association was detected for DSG1 or DSG2. In RNA-Seq data and in microarray expression data, high DSG3 expression correlated significantly with poor survival (P=0.000356 and P=0.00499).

Conclusions:

We identify DSG3 as a negative prognostic biomarker in resected PDAC, as high DSG3 expression is associated with poor overall survival and poor tumour-specific survival. These findings suggest DSG3 and its downstream signalling pathways as possible therapeutic targets in DSG3-expressing PDAC.     

胰腺导管腺癌中酪氨酸蛋白激酶-7的表达及临床意义

  目的  探讨酪氨酸蛋白激酶-7(protein tyrosine kinase-7, PTK7)在胰腺导管腺癌组织中的表达及其临床意义。  方法   回顾性分析天津医科大学肿瘤医院2011年5月至2016年1月接受胰腺癌根治手术治疗的85例胰腺癌患者的临床与随访资料。采用免疫组织化学法检测85例胰腺癌组织和对应的癌旁组织中PTK7的表达, 分析其与临床病理学特征及预后的关系。  结果  PTK7的阳性表达主要在细胞质内, 呈棕黄色颗粒。PTK7在胰腺癌和癌旁组织中的阳性表达率分别为70.6%(60/85)和52.9%(45/85), 前者表达率显著高于后者, 差异具有统计学意义(P < 0.05)。PTK7的异常表达与肿瘤分期、淋巴结转移和脉管内瘤栓相关(P < 0.05)。生存分析提示在胰腺导管腺癌中PTK7高表达的患者生存时间和肿瘤无进展时间明显短于低表达的患者(均P < 0.05)。shRNA成功干扰PTK7建立细胞稳系后, MTT和克隆形成结果显示, shRNA实验组较对照组细胞存活数显著减少(P < 0.05), 克隆形成数显著减少(P < 0.05), 增殖相关蛋白Ki67和PCNA的表达水平显著降低(均P < 0.05)。  结论   胰腺导管腺癌组织中PTK7表达水平上调, 且与胰腺癌肿瘤分期、淋巴结转移、脉管内瘤栓有关, 其表达可能提示预后不良。在胰腺癌细胞系中, PTK7能通过调节增殖相关因子Ki-67和PCNA的水平而促进胰腺癌细胞的增殖。      

胰腺导管腺癌术后患者Nomogram预后模型的构建

目的:分析胰腺导管腺癌（pancreatic dust adenocarcinoma，PDAC）术后患者的预后影响因素，建立Nomogram预后模型。方法:收集SEER数据库2004年至2015年PDAC术后患者的临床病理及随访数据。应用倾向得分匹配（propensity score matching，PSM）均衡放疗、化疗基线数据的差异。采用Kaplan-Meier法进行单因素生存分析，Log-rank检验比较生存率的差异；多因素Cox比例风险模型分析PDAC术后患者的独立预后影响因素并建立Nomogram预后模型，其性能通过一致性指数值及决策曲线分析法（decision curve analysis，DCA）进行验证。结果:本研究共纳入10 442例PDAC术后患者。经PSM后生存分析显示化疗（P<0.001）与放疗（P=0.003 7）可改善患者的预后。单因素及多因素分析显示年龄、婚姻状态、分化程度、TNM分期、肿瘤大小、化疗及放疗为PDAC术后患者的独立预后影响因素（P<0.05）。进一步建立的Nomogram预后模型在预测1年、3年及5年总生存方面表现出良好的准确性，内部验证的一致性指数为0.722，较TNM系统一致性指数高（C-index=0.656）。DCA显示Nomogram预后模型较TNM模型具有更高的临床获益。结论:年龄、婚姻状态、分化程度、TNM分期、肿瘤大小、化疗及放疗均为PDAC术后患者的独立预后影响因素（P<0.05），依此建立的Nomogram较传统的AJCC TNM系统具有更高的准确性及临床获益。     

The SMAD4 protein and prognosis of pancreatic ductal adenocarcinoma.

PURPOSE: SMAD4 (also called Dpc4) is a tumor suppressor in the TGF-beta signaling pathway that is genetically inactivated in approximately 55% of all pancreatic adenocarcinomas. We investigated whether prognosis after surgical resection for invasive pancreatic adenocarcinoma is influenced by SMAD4 status. EXPERIMENTAL DESIGN: Using immunohistochemistry, we characterized the SMAD4 protein status of 249 pancreatic adenocarcinomas resected from patients who underwent pancreaticoduodenectomy (Whipple resection) at The Johns Hopkins Hospital, Baltimore, MD, between 1990 and 1997. The SMAD4 gene status of 56 of 249 (22%) pancreatic carcinomas was also determined. A multivariate Cox proportional hazards model assessed the relative risk of mortality associated with SMAD4 status, adjusting for known prognostic variables. RESULTS: Patients with pancreatic adenocarcinomas with SMAD4 protein expression had significantly longer survival (unadjusted median survival was 19.2 months as compared with 14.7 months in patients with pancreatic cancers lacking SMAD4 protein expression; P = 0.03). This SMAD4 survival benefit persisted after adjustment for prognostic factors including tumor size, margins, lymph node status, pathological stage, blood loss, and use of adjuvant chemoradiotherapy. The relative hazard of mortality for cancers lacking SMAD4 after adjusting for other prognostic factors was 1.36 (95% confidence interval, 1.01-1.83; P = 0.04). CONCLUSION: Patients undergoing Whipple resection for pancreatic adenocarcinoma survive longer if their cancers express SMAD4.     

Mathematical evaluation of prognostic significance of clinico-morphological and immunohistochemical features of endometrioid adenocarcinoma

Complex examination was given to 76 patients with endometrioid adenocarcinoma and immunohistochemical parameters of estrogen and progesterone receptors, proliferative index (Ki-67), HER2 oncoprotein and clinico-morphological characteristics were entered into Excel database. Five-year relapse-free survival, development of regional metastases and relapse were used to work out three functional mathematical models. Those were employed to investigate endometrial tumorigenesis. A minimal set of the most advanced criteria of prognosis and assessment of tumor course served as tools for practical evaluation on the basis of clinico-morphological parameters, relapse, menopause duration, Ki-67 index and expression of PR and HER2.     

Weighted gene co-expression network analysis reveals key genes involved in pancreatic ductal adenocarcinoma development

Purpose

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy. Up till now, the patient’s prognosis remains poor which, among others, is due to the paucity of reliable early diagnostic biomarkers. In the past, candidate diagnostic biomarkers and therapeutic targets have been delineated from genes that were found to be differentially expressed in normal versus tumour samples. Recently, new systems biology approaches have been developed to analyse gene expression data, which may yield new biomarkers. As of yet, the weighted gene co-expression network analysis (WGCNA) tool has not been applied to PDAC microarray-based gene expression data.

Methods

PDAC microarray-based gene expression datasets, listed in the Gene Expression Omnibus (GEO) database, were analysed. After pre-processing of the data, we built two final datasets, Normal and PDAC, encompassing 104 and 129 patient samples, respectively. Next, we constructed a weighted gene co-expression network and identified modules of co-expressed genes distinguishing normal from disease conditions. Functional annotations of the genes in these modules were carried out to highlight PDAC-associated molecular pathways and common regulatory mechanisms. Finally, overall survival analyses were carried out to assess the suitability of the genes identified as prognostic biomarkers.

Results

Using WGCNA, we identified several key genes that may play important roles in PDAC. These genes are mainly related to either endoplasmic reticulum, mitochondrion or membrane functions, exhibit transferase or hydrolase activities and are involved in biological processes such as lipid metabolism or transmembrane transport. As a validation of the applied method, we found that some of the identified key genes (CEACAM1, MCU, VDAC1, CYCS, C15ORF52, TMEM51, LARP1 and ERLIN2) have previously been reported by others as potential PDAC biomarkers. Using overall survival analyses, we found that several of the newly identified genes may serve as biomarkers to stratify PDAC patients into low- and high-risk groups.

Conclusions

Using this new systems biology approach, we identified several genes that appear to be critical to PDAC development. As such, they may represent potential diagnostic biomarkers as well as therapeutic targets with clinical utility.

     

miR-24-3p在胰腺癌中的表达及意义

目的:分析57例胰腺癌患者的癌组织与癌旁组织中的miR-24-3p的表达情况及临床意义。方法:收集57例胰腺癌初诊患者术后的癌组织及癌旁组织，用实时荧光定量PCR技术检测miR-24-3p在胰腺癌组织和相应癌旁组织中的表达情况，用χ2检验分析miR-24-3p的表达与胰腺癌患者临床病理指标之间的相关性；用Kaplan－Meier单因素分析计算累积生存率和Log-rank检验分析胰腺癌组织中miR-24-3p的表达量与胰腺癌患者术后预后的关系。结果:miR-24-3p在胰腺癌组织中相对高表达；miR-24-3p的表达与患者的年龄、性别、肿瘤分化程度、肿瘤位置和血管浸润无关（P＞0.05）,而与肿瘤的大小、TNM分期和淋巴结转移相关（P＜0.05）；miR-24-3p高表达组患者的3年累计生存率明显低于miR-24-3p低表达组患者（P＜0.05）。结论:miR-24-3p在胰腺癌组织中的表达明显高于其癌旁组织，提示其参与了胰腺癌的发生发展过程。     

GOT1/AST1 expression status as a prognostic biomarker in pancreatic ductal adenocarcinoma

Prognostication in pancreatic ductal adenocarcinoma (PDAC) remains a challenge. Recently, a link between mutated KRAS and glutamic-oxaloacetic transaminase (GOT1/AST1) has been described as part of the metabolic reprogramming in PDAC. The clinical relevance of this novel metabolic KRAS-GOT1 link has not been determined in primary human patient samples. Here we studied the GOT1 expression status as a prognostic biomarker in PDAC. We employed three independent PDAC cohorts with clinicopathological- and follow-up data: a) ICGC, comprising 57 patients with whole-exome sequencing and genome-wide expression profiling; b) ULM, composed of 122 surgically-treated patients with tissue-samples and KRAS status; c) a validation cohort of 140 primary diagnostic biopsy samples. GOT1 expression was assessed by RNA level (ICGC) or immunolabeling (ULM/validation cohort). GOT1 expression varied (ICGC) and correlation with the KRAS mutation- and expression status was imperfect (P = 0.2, ICGC; P = 0.8, ULM). Clinicopathological characteristics did not differ when patients were separated based on GOT1 high vs. low (P = 0.08–1.0); however, overall survival was longer in patients with GOT1-expressing tumors (P = 0.093, ICGC; P = 0.049, ULM). Multivariate analysis confirmed GOT1 as an independent prognostic marker (P = 0.009). Assessment in univariate (P = 0.002) and multivariate models in the validation cohort (P = 0.019), containing 66% stage IV patients, confirmed the independency of GOT1.We propose the GOT1 expression status as a simple and reliable prognostic biomarker in pancreatic ductal adenocarcinoma.     

Clinical significance of RECK promoter methylation in pancreatic ductal adenocarcinoma

The aim of this study was to analyze the clinical significance of reversion-inducing-cysteine-rich protein with Kazal motifs (RECK) promoter methylation in pancreatic ductal adenocarcinoma (PDA). Methylation-specific polymerase chain reaction was used to examine the promoter methylation status of RECK in 60 pairs of PDA tissue samples and adjacent non-cancerous tissue samples. Statistical analyses were applied to test the associations between RECK promoter methylation status, clinicopathologic factors, and prognosis. The rate of RECK promoter methylation was significantly higher in PDA tissues than in adjacent non-cancerous tissues (P?<?0.001). RECK methylation status was significantly associated with clinical stage (P?=?0.017), histological differentiation (P?=?0.046), and lymph node metastasis (P?=?0.003), but was not associated with gender, age, and tumor location (all P?>?0.05). Additionally, RECK promoter methylation is associated with malignant behavior and poor prognosis. In conclusion, determination of RECK promoter methylation status in tumor tissues may assist in the identification of patients who require aggressive postoperative intervention in order to improve prognosis.     

Prognostic significance of tissue factor in pancreatic ductal adenocarcinoma.

Tissue factor (TF) is a transmembrane glycoprotein that plays roles in the blood coagulation and intracellular signaling pathways, and has also been suggested to modulate the biological behavior of cancer cells. In order to examine the clinicopathologic significance of TF expression in pancreatic ductal adenocarcinoma, TF expression was determined by immunohistochemistry using a newly raised anti-TF monoclonal antibody in 113 patients who had undergone surgical resection of pancreatic ductal adenocarcinoma. According to the incidence of tumor cell immunopositivity, patients were divided into "negative TF" (0%), "weak TF" (<25%), or "high TF" (25% or more) groups, which accounted for 11.6% (n = 13), 44.2% (n = 50), and 44.2% (n = 50) of the total, respectively. Increased TF expression was correlated with the extent of the primary tumor (P = 0.0043), lymph node metastasis (P = 0.0043), lymphatic distant metastasis (P = 0.0039), advanced tumor-node-metastasis stage (P = 0.0002), and high tumor grade (P = 0.0164). Multivariate analysis using the Cox proportional hazards model showed that high TF expression was an independent negative predictor for survival (hazard ratio, 2.014; P = 0.0076). Moreover, patients with TF-negative tumors had a significantly better prognosis even if lymph node metastasis was present (P < 0.0001). We also showed that TF knockdown by RNA interference suppressed the invasiveness of a pancreatic adenocarcinoma cell line in vitro. These results indicate that TF expression may contribute to the aggressiveness of pancreatic ductal adenocarcinoma by stimulating tumor invasiveness, and that evaluation of the primary tumor for TF expression may identify patients with a poor prognosis.     

High expression of tumor-associated antigen RCAS1 in pancreatic ductal adenocarcinoma is an unfavorable prognostic marker

RCAS1 (receptor-binding cancer antigen expressed on SiSo cells) is a recently identified human tumor-associated antigen expressed on various cancer cells. It is thought that tumor cells evade immune surveillance by expression of RCAS1, which induces apoptotic cell death in receptor-positive immune cells. The purpose of our study was to investigate the relation between RCAS1 expression and the clinicopathological variables and clinical outcome in patients with pancreatic adenocarcinoma. Immunohistochemical analysis for RCAS1 was performed on paraffin-embedded specimens of 80 patients (mean age, 62 years) who underwent surgical resection for pancreatic adenocarcinoma. Of the 80 specimens, 77 (96%) were positive for RCAS1. No significant correlation was found between RCAS1 expression and age, gender, depth of invasion, tumor diameter, surgical margin, lymphatic invasion, venous invasion or histopathological grading. Borderline correlations between RCAS1 expression were noted for lymph node metastasis and stage (p = 0.0608 and 0.0934, respectively). RCAS1 expression was very frequently observed and the survival of patients with high RCAS1 expression was significantly shorter than that of those with low expression (p = 0.0012). Multivariate analysis using the Cox regression model indicated that high RCAS1 expression was an independent prognostic factor (risk ratio, 3.090; p = 0.0090). These results suggested that RCAS1 might be a significant tumor marker for pancreatic adenocarcinoma and an unfavorable predictor for prognosis of patients who have undergone surgical resection.     

A systematic review of economic evaluation in pancreatic ductal adenocarcinoma

ObjectivesThe economic evaluation (EE) of healthcare interventions has become a necessity. However, high quality needs to be ensured in order to achieve validated results and help making informed decisions. Thus, the objective of the present study was to systematically identify and review published pancreatic ductal adenocarcinoma-related EEs and to assess their quality.MethodsSystematic literature research was conducted in PubMed and Cochrane to identify published EEs between 2000 and 2015. The quality of each selected EE was assessed by two independent reviewers, using the Drummond's checklist.ResultsOur systematic review was based on 32 EEs and showed a wide variety of methodological approaches, including different perspectives, time horizon, and cost effectiveness analyses. Nearly two-thirds of EEs are full EEs (n = 21), and about one-third of EEs had a Drummond score ≥7, synonymous with ‘high quality’. Close to 50% of full EEs had a Drummond score ≥7, whereas all of partial EEs had a Drummond score <7 (n = 11).ConclusionsOver the past 15 years, a lot of interest has been evinced over the EE of pancreatic ductal adenocarcinoma (PDAC) and its direct impact on therapeutic advances in PDAC. To provide a framework for health care decision-making, to facilitate transferability and to lend credibility to health EEs, their quality must be improved. For the last 4 years, a tendency towards a quality improvement of these studies has been observed, probably coupled with a context of rational decision-making in health care, a better and wider spread of recommendations and thus, medical practitioners' full endorsement.