Conditional survival in patients with pancreatic ductal adenocarcinoma resected with curative intent

BACKGROUND:

Prognosis after surgery for pancreatic ductal adenocarcinoma (PDAC) is typically reported from the date of surgery. Survival estimates, however, are dynamic and may change based on the time already survived. The authors sought to assess conditional survival among a large cohort of patients who underwent resection of PDAC.

METHODS:

Between 1970 and 2008, 1822 patients who underwent resection for PDAC with curative intent were identified. Kaplan‐Meier and Cox regression analyses were performed to validate established predictors of survival, and results were compared with 2‐year conditional survival.

RESULTS:

Actuarial survival was 18% at 5 years, with a median survival of 18 months. Multivariate analysis revealed that tumor size, lymph node ratio, and positive margins were associated with worse survival (all P < .001). Differences in actuarial versus conditional survival estimates were greater the more years already survived by the patient. The 2‐year conditional survival at 3 years—the probability of surviving to postoperative year 5 given that the patient had already survived 3 years—was 66% versus a 5‐year actuarial survival calculated from the time of surgery of 18%. Stratification of 2‐year conditional survival by lymph node ratio and margin status revealed that patients with high lymph node ratio or positive margins saw the greatest increase in 2‐year conditional survival as more time elapsed (both P ≤ .01).

CONCLUSIONS:

Differences in actuarial versus conditional survival estimates were more pronounced based on the additional years already survived by the patient. Conditional survival may be a helpful tool in counseling patients with PDAC, as it is a more accurate assessment of future survival for those patients who have already survived a certain amount of time. Cancer 2011. © 2011 American Cancer Society.     

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.     

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。     

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.     

Stromal galectin-1 expression is associated with long-term survival in resectable pancreatic ductal adenocarcinoma

The overall 5 year survival rate for pancreatic ductal adenocarcinoma (i.e., PDAC) is a dismal 5%, although patients that have undergone surgical resection have a somewhat better survival rate of up to 20%. Very long-term survivors of PDAC (defined as patients with ≥ 10 year survival following apparently curative resection), on the other hand, are considerably less frequent. The molecular characteristics of very long-term survivors (VLTS) are poorly understood, but might provide novel insights into prognostication for this disease. In this study, a panel of five VLTS and stage-matched short-term survivors (STS, defined as disease-specific mortality within 14 months of resection) were identified, and quantitative proteomics was applied to comparatively profile tumor tissues from both cohorts. Differentially expressed proteins were identified in cancers from VLTS vs. STS patients. Specifically, the expression of galectin-1 was 2-fold lower in VLTS compared with STS tumors. Validation studies were performed by immunohistochemistry (IHC) in two additional cohorts of resected PDAC, including: 1) an independent cohort of VLTS and 2) a panel of sporadic PDAC with a considerable range of overall survival following surgery. Immunolabeling analysis confirmed that significantly lower expression of stromal galectin-1 was associated with VLTS (p = 0.02) and also correlated with longer survival in sporadic, surgically-treated PDAC cases (hazard ratio = 4.9, p = 0.002). The results from this study provide new insights to better understand the role of galectin-1 in PDAC survival, and might be useful for rendering prognostic information, and developing more effective therapeutic strategies aimed at improving survival.     

Heparanase expression is a prognostic indicator for postoperative survival in pancreatic adenocarcinoma

Pancreatic ductal adenocarcinoma has a median survival of less than 6 months from diagnosis. This is due to the difficulty in early diagnosis, the aggressive biological behaviour of the tumour and a lack of effective therapies for advanced disease. Mammalian heparanase is a heparan-sulphate proteoglycan cleaving enzyme. It helps to degrade the extracellular matrix and basement membranes and is involved in angiogenesis. Degradation of extracellular matrix and basement membranes as well as angiogenesis are key conditions for tumour cell spreading. Therefore, we have analysed the expression of heparanase in human pancreatic cancer tissue and cell lines. Heparanase is expressed in cell lines derived from primary tumours as well as from metastatic sites. By immunohistochemical analysis, it is preferentially expressed at the invading edge of a tumour at both metastatic and primary tumour sites. There is a trend towards heparanase expression in metastasising tumours as compared to locally growing tumours. Postoperative survival correlates inversely with heparanase expression of the tumour reflected by a median survival of 34 and 17 month for heparanase negative and positive tumours, respectively. Our results suggest, that heparanase promotes cancer cell invasion in pancreatic carcinoma and could be used as a prognostic indicator for postoperative survival of patients.     

The predictive value and role of stromal tumor-infiltrating lymphocytes in pancreatic ductal adenocarcinoma (PDAC)

Recently, increasing evidence has indicated that the presence of tumor infiltrating immune cells has shown predictive significance for many solid tumors. Present study was performed to evaluate the predictive value of stromal tumor-infiltrating lymphocytes (TILs) for the presence of liver metastasis and overall survival in PDAC (pancreatic ductal adenocarcinoma) patients after complete resection and to explore the potential role of lymphocytes in PDAC. A total of 155 resectable patients with PDAC were enrolled in our study. Stromal TIL density was investigated in hematoxylin and eosin-stained sections of surgical specimens and scored. The effect and possible mechanism of lymphocytes on cancer cells was evaluated using co-culture techniques and ELISA test. Stromal TIL negative status (HR = 2.80, 95% CI 1.75-4.48, P < 0.01) was not only an independent predictor of worse OS (HR = 2.7, 95% CI 1.80-4.06, P = <0.01) but also a significant independent predictor of liver metastasis. Higher CEA (P = 0.01) or CA19-9 (P = 0.01) levels were associated with low stromal TIL density. Stromal TIL negative patients appeared to develop tumors with a higher CEA (P = 0.01), larger diameter (P = 0.05) and advanced stage (P = 0.02). The co-culture experiment suggests that lymphocytes can inhibit pancreatic cancer cell proliferation. Further ELISA and cell culture test indicate that lymphocytes may cause pancreatic cancer cells apoptosis through TNF-alpha secretion. Our data suggest a potential favorable role of stromal TILs in predicting liver metastasis and overall survival of patients with PDAC after complete resection. Lymphocytes may inhibit the growth of PDAC through TNF-alpha secretion, which suggest a potential therapeutic approach against PDAC.     

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.     

RET,a targetable driver of pancreatic adenocarcinoma

Pancreatic ductal adenocarcinoma (PDA) remains a deadly disease, affecting about 40,000 individuals in the United States annually. We aimed to characterize the role of RET as a co-driver of pancreas tumorigenesis. To assess the role of RET as a co-driver of PDA, we generated a novel triple mutant transgenic mouse based on the cre-activated p53^R172H gene and a constitutively active RET ^M919T mutant (PRC). Survival analysis was performed using Kaplan–Meier analysis. Study of human PDA specimens and Pdx-1-Cre/Kras^G12D /p53^R172H (KPC) mice revealed that RET is upregulated during pancreas tumorigenesis, from inception through precursor lesions, to invasive cancer. We demonstrated that activation of RET is capable of inducing invasive pancreatic carcinomas in the background of the P53 inactivation mutation. Compared to KPC mice, PRC animals had distinct phenotypes, including longer latency to tumor progression, longer survival, and the presence of multiple macrometastases. Enhanced activation of the MAPK pathway was observed as early as the PanIN 2 stage. Sequencing of the exonic regions of KRAS in PRC-derived PDA cells revealed no evidence of KRAS mutations. RET can be an essential co-driver of pancreatic tumorigenesis in conjugation with KRAS activity. These data suggest that RET may be a potential target in the treatment of PDA.     

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.     

胰腺导管腺癌CT、MR相关研究进展

胰腺导管腺癌（pancreatic ductal adenocarcinoma,PDAC）是最常见的胰腺恶性肿瘤,其恶性程度高,患者生存率低。CT、MR是PDAC诊断最常用的影像检查,其不仅可以帮助PDAC进行诊断、鉴别,还能通过特殊序列来提供相应功能参数。此外,影像组学可以挖掘更多的影像信息供临床医生分析、预测患者术后生存率。CT、MR对于PDAC临床治疗具有重要的指导意义,故本文对PDAC相关CT、MR进展进行综述。     

肺腺癌患者驱动基因表达及生存分析

目的 检测晚期肺腺癌患者肿瘤组织中驱动基因表皮生长因子受体(epidermal growth factor receptor,EGFR)突变和棘皮动物微管样蛋白4-间变淋巴瘤激酶(echinoderm microtubule associated protein like 4-anaplasiticlymphoma kinase,EML4-ALK)融合状态,并分析其与生存的相关性.方法 通过过扩增受阻突变系统(amplificationrefractory mutation system,ARMS) PCR方法检测74例晚期肺腺癌患者中EGFR基因突变状态,荧光原位杂交(fluo-rescence in situ hybridization,FISH)方法检测ALK基因融合状态,分析EGFR基因突变率与性别、吸烟史的相关性,EGFR基因突变和ALK基因融合对生存的影响.结果 肺腺癌患者中EGFR基因突变率分别为40.5％ (30/74),ALK基因融合6.8％ (5/74).EGFR基因外显子18、19、20、21的突变率分别为1.4％ (1/74)、20.3％ (15/74)、1.4％ (1/74)、17.6％ (13/74),肺腺癌患者中女性EGFR基因突变高于男性(P=0.007),但未见与吸烟史有明显相关(P =0.099).EGFR基因突变和ALK基因融合的患者接受靶向治疗后有明显的生存优势(P=0.007).结论 肺腺癌患者中EGFR基因19和21外显子存在较高的突变率,女性患者中尤为明显,针对驱动基因靶向治疗的患者有明显的生存优势.