基于生物信息学筛选胰腺导管腺癌关键基因

目的:利用生物信息学方法分析胰腺导管腺癌（PDAC）基因表达谱芯片并筛选关键基因。方法:从公共数据库基因表达数据库（GEO）中下载PDAC基因表达谱芯片GSE28735、GSE15471、GSE101448,共纳入108例PDAC样本和97例癌旁组织样本。应用R语言limma包和impute包筛选差异表达基因。利用DAVID数据库和在线分析工具Kobas分别对差异基因进行GO功能富集分析和KEGG通路富集分析。利用STRING数据库和Cytoscape软件构建差异蛋白互作网络并进一步筛选关键基因。结果:3个基因表达谱芯片共有161个差异表达基因（|log2 fold-change(FC)|>2,P<0.05）,包括54个上调基因,107个下调基因。GO功能富集分析显示差异基因与extracellular exosome、extracellular space、extracellular matrix organization密切相关。KEGG通路分析显示差异基因主要富集在protein digestion and absorption、ECM-receptor interaction和focal adhesion等通路。蛋白质相互作用网络图中显示节点最多的10个枢纽基因分别是ALB、COL11A1、COL3A1、FN1、EGF、COL1A1、MMP9、COL5A2、ITGA2、COL6A3。结论:筛选所得的10个关键基因可能在PDAC发生发展中发挥重要作用,有望成为PDAC诊断及治疗的生物学靶标,为进一步研究PDAC发生发展的分子机制提供了理论依据。     

胰腺导管腺癌免疫治疗研究现状和展望

胰腺导管腺癌(Pancreatic ductal adenocarcinoma,PDAC)是胰腺癌最常见的类型,预后极差。手术切除是目前唯一的根治手段,但多数患者就诊时已失去手术机会。免疫治疗作为一种新兴的治疗手段,在多种实体瘤和血液系统恶性肿瘤治疗中显现出乐观前景。然而,PDAC肿瘤抗原性低以及免疫抑制微环境等特征导致其免疫治疗困难重重。本文通过综述PDAC的肿瘤微环境组成特点和目前开展的新型免疫治疗策略,为PDAC的免疫治疗研究提供新思路。     

糖尿病是可切除胰腺导管腺癌的预后因子

  目的   探讨合并2型糖尿病与胰腺导管腺癌（pancreatic ductal adenocarcinoma,PDAC）患者的临床病理因素及其与预后的关系。   方法   回顾性分析2009年1月至2011年2月可手术切除PDAC患者的临床病理资料,进行生存分析。   结果   136例PDAC患者中合并糖尿病的比率为27.9%,糖尿病与各临床病理特征均无关（均P>0.05）。单因素分析显示:糖尿病、肿瘤最大直径、组织学分化程度、pT分期、脉管侵润及pTNM分期,均与PDAC患者预后显著相关（均P < 0.05）。多因素分析显示:合并糖尿病（HR,1.873;P=0.007）,组织学低分化肿瘤（HR=2.647;P=0.002）及肿瘤最大直径≥4.0 cm（HR=1.699;P=0.018）,均是独立预后因子。   结论   合并糖尿病是可手术切除的PDAC患者预后差的独立预测因子。      

基于自噬相关基因识别和建立胰腺导管腺癌预后模型的研究

目的:寻找胰腺导管腺癌（pancreatic duct adenocarcinoma,PDAC）理想的预后生物标志物及预测预后的危险因素。方法:从癌症基因组图谱（TCGA）数据库下载了ARGs的表达谱和PDAC患者的临床数据。通过Wilcoxon秩和检验鉴定出具有明显差异的自噬相关基因（SD-ARGs）。借助单因素Cox回归和多因素Cox回归来建立ARGs的预后模型。利用卡普兰-米耶（K-M）曲线和观察者特性（ROC）曲线评估模型,进行了GO和KEGG富集分析,以探索潜在的信号通路和分子机制。此外,本研究进一步揭示了ARGs与临床特征之间的关系。结果:筛选出12种SD-ARGs。利用多元Cox回归确定了3个SD-ARGs作为构建模型以计算风险评分和预测患者预后的基础,而计算出的风险评分可能作为PDAC的独立预后因素。K-M曲线、ROC曲线在一定程度上证实了构建的模型预测PDAC患者的总生存期（OS）的有效性。结论:本研究借助筛选的SD-ARGs构建了预测PDAC患者的预后模型。该模型还需经过进一步验证,其可能作为预测PDAC患者OS的可靠工具。     

Survivin蛋白和Psmd10表达与胰腺导管腺癌的相关性分析

目的分析Survivin蛋白和Psmd10表达与胰腺导管腺癌的相关性。方法回顾性分析2010年6月至2012年6月间收治的30例胰腺导管腺癌患者的临床病理资料,采用免疫组织化学方法检测胰腺导管腺癌组织中的Survivin和Psmd10的表达。结果 30例胰腺导管腺癌患者中,Survivin表达与胰腺导管腺癌的分化程度呈正相关,与胰腺导管腺癌患者的性别、年龄以及肿瘤部位无关;Psmd 10表达与胰腺导管腺癌的分化程度呈正相关,与患者的性别、年龄以及肿瘤部位、肿瘤大小不相关;在胰腺导管腺癌组织中Survivin、Psmd 10的表达均具有相关性。结论 Survivin、Psmd10的表达与胰腺导管腺癌的发生有关。在胰腺导管腺癌的发生发展中,Survivin与Psmd10有协同作用。根据Survivin、Psmd10变化做好对胰腺导管腺癌患者的预后工作,值得临床推广。     

NDRG1与MMP-7在胰腺导管腺癌中的表达及意义

目的:检测胰腺导管腺癌中NDRG1及MMP-7的表达,探讨其与临床病理特征的关系,并分析二者在胰腺癌诊断及治疗中的意义。方法:胰腺导管腺癌标本86例,胰腺导管腺癌癌旁正常胰腺组织86例,应用免疫组化法检测NDRG1和MMP-7蛋白的表达情况,检测其表达水平与临床病理特征的关系及二者的统计学相关性。结果:NDRG1和MMP-7表达于胰腺导管腺癌导管内皮细胞膜及细胞质,平均光密度值分别为0.1934±0.0327及0.1876±0.0249,在癌旁正常胰腺组织中NDRG1、MMP-7平均光密度值分别为0.1323±0.0243及0.1156±0.0297,二者差异有统计学意义（P<0.01;P<0.05）。NDRG1高表达与肿瘤直径、肿瘤TNM分期、淋巴结转移呈正相关性（P<0.05;P<0.01;P<0.05）。MMP-7高表达与肿瘤直径、肿瘤TNM分期、淋巴结转移呈正相关性（P均<0.05）。Spearman rank相关分析结果显示,NDRG1及MMP-7呈统计学正相关性（r＝0.267,P<0.05）。结论:NDRG1和MMP-7蛋白表达增高与胰腺导管腺癌的发生、发展及侵袭转移有关。NDRG1和MMP-7在胰腺导管腺癌组织中的表达相关,二者联合检测可作为胰腺癌预后判断及治疗的靶向候选基因。     

基于肿瘤位置的改良分期系统对T1期胰腺导管腺癌预后的价值

目的:探究基于肿瘤位置的改良分期系统对T1期胰腺导管腺癌预后的价值。方法:收集南阳市第一人民医院18年间进行胰腺癌手术的患者共1 873例,其中1 291例患者的肿瘤位置在胰头,582例患者的肿瘤位置在胰体/尾部。比较不同分组患者的肿瘤特异性生存率和肿瘤术后的预后危险因素。结果:在T1期患者中,胰头肿瘤患者的预后较胰尾肿瘤的预后差。多因素分析结果显示,胰头位置、肿瘤大小、N分期是T1期胰腺导管腺癌患者更低存活率的独立危险因素（危险比为1.49,95%可信区间为1.13~1.87,P=0.022）。基于肿瘤位置的改良分期系统较第八版AJCC分期系统更能区分早期胰腺导管腺癌的不同分组。结论:肿瘤位置是可切除胰腺导管腺癌患者预后的预测因子,基于肿瘤位置的改良T1亚分期对胰腺导管腺癌的预后预测准确有效。     

ENO1在胰腺上皮内瘤变和胰腺导管腺癌中的表达

摘 要：［目的］ 检测烯醇化酶-1（ENO1）在人和大鼠胰腺上皮内瘤变(PanIN)和胰腺导管腺癌组织中的表达情况。［方法］ 收集病理科存档人组织标本,胰腺导管腺癌18例,PanIN 4例,正常胰腺组织7例,免疫组化检测ENO1蛋白表达。SD大鼠20只采用胰腺包埋种植7,12-二甲基苯并蒽（DMBA）诱导法,建立大鼠PanIN和胰腺导管腺癌模型,Real-time PCR检测ENO1 mRNA表达,免疫组化和免疫印迹检测ENO1 蛋白表达。［结果］ ENO1蛋白在人PanIN（9.63±1.80）和胰腺导管腺癌组织（12.14±2.71）中的表达均显著高于人正常胰腺组织（P<0.01）。与造模后大鼠正常胰腺比较,ENO1 mRNA在大鼠PanIN-3（P<0.01）和胰腺导管腺癌组织（P<0.001）中表达显著增加,在大鼠PanIN-2（P<0.001）、PanIN-3（P<0.01）和PDAC（P<0.001）组织中,ENO1 蛋白表达呈进行性升高。［结论］ ENO1在PanIN和胰腺导管腺癌的表达显著增高,在胰腺上皮的癌变过程中可能发挥重要作用。     

胰腺囊腺瘤及囊腺癌

１９５８－１９９０年该院收治１６例胰腺囊性肿瘤，其中包括７例胰腺囊腺瘤和９例胰腺囊腺癌。体征主要为上腹疼痛和肿块，本组大部在诊断前已有５－１０年病史。肿瘤直径平均８厘米。病变２例位于胰头，１４例位于胰尾和体部。７例在治疗前误诊为胰腺假性囊肿。远侧胰腺切除７例，４例肿瘤局部切除，５／９囊腺癌术中已发现有腹内转移。胰腺囊腺瘤手术后得到长期生存７～２５年。胰腺囊腺癌术后生存８月至６．５年。作者认为对胰腺囊性肿瘤，如条件许可，应争取外科治疗并可取得长期生存的结果。     

An overview of polyamine metabolism in pancreatic ductal adenocarcinoma

Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest major cancers, with a five year survival rate of less than 8%. With current therapies only giving rise to modest life extension, new approaches are desperately needed. Even though targeting polyamine metabolism is a proven anticancer strategy, there are no reports, which thoroughly survey the literature describing the role of polyamine biosynthesis and transport in PDAC. This review seeks to fill this void by describing what is currently known about polyamine metabolism in PDAC and identifies new targets and opportunities to treat this disease. Due to the pleiotropic effects that polyamines play in cells, this review covers diverse areas ranging from polyamine metabolism (biosynthesis, catabolism and transport), as well as the potential role of polyamines in desmoplasia, autophagy and immune privilege. Understanding these diverse roles provides the opportunity to design new therapies to treat this deadly cancer via polyamine depletion.     

Outcomes of robotic surgery for pancreatic ductal adenocarcinoma

Background

To explore the effectiveness, safety, and efficacy of the robot-assisted surgery in the radical resection of pancreatic ductal adenocarcinoma (PDAC).

Methods

The clinical data of 72 patients with PDAC who underwent radical resection using the da Vinci Surgical System from April 2010 to December 2014 were retrospectively analyzed.

Results

Among these 72 patients, three were converted to conventional laparotomy due to the vascular invasion or due to the difficulties in tissue isolation from the surrounding organs. Among 39 patients who underwent the pancreatoduodenectomy, the average operative time was 395.3±118.8 min, and the mean intra-operative blood loss was 447.3±269.9 mL. Among 31 patients who underwent the distal pancreatectomy (DP), the average operative time was 185.5±74.1 min, and the mean intra-operative blood loss was 267.1±305.3 mL. In two patients who received the middle pancreatectomy (MP), the average operative time was 225 min and mean intra-operative blood loss was 100 mL. Among all the 72 patients, an average of 4.2±2.6 lymph nodes were dissected, with an average hospital stay of 22.6±10.7 days. Complications were observed in 18 patients, which included pancreatic fistula (n=11), bile leak (n=5), anastomotic bleeding (n=2), pancreatic fistula complicated with portal vein thrombosis (n=1), and anastomotic bleeding complicated with acute renal failure (n=1). Except that one patient died due to post-operative bleeding and acute renal failure, all the other patients were cured after conservative treatment. These 72 patients were followed for 1-45 (15.6±5.8) months, during which 10 patients died. Eleven patients suffered from recurrence or metastasis, among which 6 had local recurrence, 4 had liver metastasis, and 1 had ascites accompnaied with incision site tumor metastasis.

Conclusions

Radical resection of PDAC by robotic surgical system is safe and feasible. It has less surgical trauma and enables faster post-operative recovery, and therefore can achieve the lymph node dissection scope and tumor resection margin required by the standards of radical resection for pancreatic cancer. Nevertheless, its long-term efficacy requires further validation.     

Overexpression of rhophilin 2 promotes pancreatic ductal adenocarcinoma

Pancreatic ductal adenocarcinoma (PDAC) is the most common type of pancreatic cancer and is the seventh leading cause of global cancer deaths. In recent years, targeted therapy has been used for pancreatic cancer; however, the drugs available for use in targeted therapy for pancreatic cancer are still very limited. Hence, identification of novel targeted molecules for PDAC is required. Rhophilin 2 (RHPN2) was proven to be a driver gene in glioblastoma. However, the function of RHPN2 in PDAC remains unknown. In the present study, the function of RHPN2 was investigated. The RHPN2 levels were overexpressed by pcDNA3.1-RHPN2 and downregulated by si-RHPN2. Cell proliferation was assessed using the MTT assay and apoptosis was assessed using flow cytometry. The results revealed that high RHPN2 levels in PDAC tissue were correlated with a low overall survival rate of patients with PDAC. Inhibition of RHPN2 reduced SW1990 and PANC1 proliferation and increased the rate of apoptosis. Network analysis demonstrated that centrosomal protein 78 expression was negatively correlated with RHPN2 expression. In conclusion, the present study demonstrated that RHPN2 may promote PDAC making it a potential candidate for targeted therapy.     

Persistent activation of pancreatic stellate cells creates a microenvironment favorable for the malignant behavior of pancreatic ductal adenocarcinoma

Pancreatic ductal adenocarcinoma (PDAC) is one of the most common malignant tumors with poor prognosis due to extremely high malignancy, low rate of eligibility for surgical resection and chemoradiation resistance. Increasing evidence indicate that the interaction between activated pancreatic stellate cells (PSCs) and PDAC cells plays an important role in the development of PDAC. By producing high levels of cytokines, chemotactic factors, growth factors and excessive extracellular matrix (ECM), PSCs create desmoplasia and a hypoxic microenvironment that promote the initiation, development, evasion of immune surveillance, invasion, metastasis and resistance to chemoradiation of PDAC. Therefore, targeting the interaction between PSCs and PDAC cells may represent a novel therapeutic approach to advanced PDAC, especially therapies that target PSCs of the pancreatic tumor microenvironment.     

Predicting early recurrence for resected pancreatic ductal adenocarcinoma: a multicenter retrospective study in China

A precise classification of early recurrence (ER) after radical surgery of pancreatic ductal adenocarcinoma (PDAC) has not been standardized. We aim to develop an optimal cut-off based on scientific evidence to distinguish early and late recurrence (LR) for PDAC after radical surgery and develop a predictive model for ER of PDAC. The best threshold for recurrence-free survival (RFS) was assessed with a minimum P-value method, and patients were categorized into ER and LR groups. We used a logistic regression model to assess potential risk factors for ER and develop a predictive model for ER risk. The best threshold between high-risk and intermediate-high-risk groups was identified by using the receiver operating characteristic curve. Among 3,279 patients included, 1,234 (37.6%) experienced ER. The RFS of 9 months is the optimal threshold to distinguish ER and LR. Univariable and multivariable analysis identified four preoperative risk factors for ER, including larger tumor maximal diameter on computed tomography (CT), enlarged lymph nodes on CT, carbohydrate antigen (CA) 125 > 35 U/ml, and CA19-9 > 235 U/ml. The concordance index (C-index) for the predictive model in the training cohort and the validation cohort was 0.651 (95% confidence interval (CI): 0.624-0.678), and 0.636 (95% CI: 0.593-0.679), respectively, showing promising predictive ability. The high-risk group had a score above 203, and the corresponding risk of ER for this group was 56.7%. An RFS of 9 months is the best threshold to distinguish ER and LR. The model can accurately predict the risk of ER in PDAC after radical resection, and risk grouping can predict the patients who could benefit from upfront surgery.