Major molecular markers in pancreatic ductal adenocarcinoma and their roles in screening, diagnosis, prognosis, and treatment

Pancreatic cancer is notorious for its late presentation, early and aggressive local invasion, metastatic potential, and poor outcome. It presents at a clinically advanced stage that precludes the possibility of surgical resection in most cases and shows constitutive resistance to chemotherapy and radiotherapy in others. As a result, mortality from this disease parallels its incidence rates.Recent breakthroughs in the molecular biology of pancreatic cancer have assisted in translational research, giving hope for individualized therapy and better disease management. Molecular biology tools are guiding early diagnosis, the assessment of prognosis, and isolation of novel, more effective therapeutic targets.This review discusses the signature mutations of pancreatic cancer, implications of these mutations to pancreatic cancer biology, their linked pathways, and recent advances in their understanding as biomarkers as diagnostic, prognostic, and therapeutic tools in dealing with this disease.     

Synchronous gastric adenocarcinoma and pancreatic ductal adenocarcinoma

BACKGROUND:The association between gastric and pancreatic carcinoma is a relatively rare condition.In gastric carcinoma patients,the prevalence of second tumors varies 2.8% to 6.8% according to the reported statistics.Gastric cancer associated with pancreatic cancer is uncommon.METHODS:We report a case of a 73-year-old patient hospitalized for vomiting and weight loss.Esophagogastroduodenoscopy demonstrated an ulcerative lesion of the gastric antrum.Computed tomography and magnetic resonance showed a gastri...     

Microbiome and pancreatic ductal adenocarcinoma

Pancreatic ductal adenocarcinoma (PDAC) incidence and related-deaths are increasing worldwide. PDAC is characterized by poor prognosis due to late diagnosis, high metastatic capacity and resistance to therapy. This is partially due to its specific microenvironment, where the stroma is prominent over tumor cells. Besides the oral and gut microbiota, the intratumor microbiome, i.e. the bacterial and fungal microorganisms present within the tumor, was recently introduced as a new partner of the tumor microenvironment of PDAC modulating pancreatic carcinogenesis, intratumor immune infiltrates, and response to chemotherapy. In this review, we propose an overview of current knowledge about the roles of bacteria and fungi in PDAC development and biology, and discuss potential therapeutic implications.     

American gastroenterological association medical position statement: epidemiology, diagnosis, and treatment of pancreatic ductal adenocarcinoma

This document presents the official recommendations of the American Gastroenterological Association (AGA) on the Epidemiology, Diagnosis, and Treatment of Pancreatic Ductal Adenocarcinoma. It was approved by the Clinical Practice and Practice Economics Committee in March 1999 and by the AGA Governing Board in May 1999.     

Genomics of pancreatic ductal adenocarcinoma

Pancreatic cancer is one of the worst prognostic cancers because of the late diagnosis and the absence of effective treatment. Within all subtypes of this disease, ductal adenocarcinoma has the shortest survival time. In recent years, global genomics profiling allowed the identification of hundreds of genes that are perturbed in pancreatic cancer. The integration of different omics sources in the study of pancreatic cancer has revealed several molecular mechanisms, indicating the complex history of its development. However, validation of these genes as biomarkers for early diagnosis, prognosis or treatment efficacy is still incomplete but should lead to new approaches for the treatment of the disease in the future.     

Metastatic pancreatic ductal adenocarcinoma: diagnosis and treatment with a view to the future

Metastatic pancreatic ductal adenocarcinoma (mPDAC) is a lethal disease with a poor 5‐year survival. Systemic treatments can be used to control symptoms and prolong life. Cytotoxic chemotherapies are commonly administered, with combination treatments, such as fluorouracil, folinic acid, irinotecan and oxaliplatin (FOLFIRINOX) or nab‐paclitaxel and gemcitabine showing the largest clinical benefits. Newer genomic classifications of PDAC may provide a rationale for targeted therapies or immunotherapies, although at present these remain largely experimental. This review discusses the evidence behind the currently used regimens, while introducing the potential future of pancreatic cancer care.     

Perioperative transfusion for pancreaticoduodenectomy and its impact on prognosis in resected pancreatic ductal adenocarcinoma

Background and aims: Pancreaticoduodenectomy (PD) is a major operative intervention performed most commonly for malignancy in the head of pancreas. The aim of this study was to evaluate the utilization of blood transfusion for PD and to determine whether this had prognostic significance in a subset of patients with pancreatic ductal adenocarcinoma (PDAC). Material and methods: Data on blood transfusion requirement were retrospectively collected for patients undergoing PD from 1998 to 2005. Standard prognostic factors and survival data were also collected in patients with PDAC. Results: One-hundred-and-seventy patients underwent PD. Seventy-six patients (45%) received transfusion. The median (interquartile range) number of units of red cell concentrate (RCC) transfused perioperatively (intraoperatively and within 24 h of surgery) was 1.5 (0.5–2.5). The median preoperative haemoglobin (Hb) was 126 g/dl. The median number of units of RCC transfused perioperatively in patients with Hb <126 g/dl was 2 (1–3); for those with Hb ≥ 126 g/dl the median was 0 (0–1); p=0.003. Forty-nine patients who were resected for PDAC were subjected to survival analysis. Univariate and multivariate analyses showed that only posterior resection margin invasion was associated with an adverse outcome (margin positive 198 [143–470] days vs margin negative 398 [303–859] days; p=0.02). Perioperative RCC transfusion requirement was not a significant predictor of survival (transfusion 408 [214–769] days vs no transfusion 331 [217–391] days; p=0.18). Furthermore, RCC transfusion within 30 days of operation was not a significant predictor of poor survival (transfusion 331 [201–459] days vs no transfusion 317 [196–769] days; p=0.43). Conclusions: PD can be performed with a moderately low requirement for RCC transfusion; however, low preoperative haemoglobin is a predictor for the requirement of RCC transfusion. Administration of RCC transfusion does not appear to be a significant adverse prognostic factor in patients with resected PDAC.     

Ecoevolutionary biology of pancreatic ductal adenocarcinoma

Pancreatic ductal adenocarcinoma (PDAC), the most common histological subtype of pancreatic cancer, is an aggressive disease predicted to be the 2nd cause of cancer mortality in the US by 2040. While first-line therapy has improved, 5-year overall survival has only increased from 5 to ～10%, and surgical resection is only available for ～20% of patients as most present with advanced disease, which is invariably lethal. PDAC has well-established highly recurrent mutations in four driver genes including KRAS, TP53, CDKN2A, and SMAD4. Unfortunately, these genetic drivers are not currently therapeutically actionable. Despite extensive sequencing efforts, few additional significantly recurrent and druggable drivers have been identified. In the absence of targetable mutations, chemotherapy remains the mainstay of treatment for most patients. Further, the role of the above driver mutations on PDAC initiation and early development is well-established. However, these mutations alone cannot account for PDAC heterogeneity nor discern early from advanced disease. Taken together, management of PDAC is an example highlighting the shortcomings of the current precision medicine paradigm. PDAC, like other malignancies, represents an ecoevolutionary process. Better understanding the disease through this lens can facilitate the development of novel therapeutic strategies to better control and cure PDAC. This review aims to integrate the current understanding of PDAC pathobiology into an ecoevolutionary framework.     

胰腺导管腺癌microRNA表达谱的研究

目的 应用microRNA( miRNA)高通量生物芯片筛选胰腺导管腺癌及癌旁组织差异表达的miRNA,分析其相关的靶基因.方法 收集9例新鲜的胰腺导管腺癌和3例癌旁组织,运用标记713个miRNA的Agilent miRNA生物芯片筛选胰腺导管腺癌差异表达的miRNA,应用荧光实时定量PCR方法验证表达上调的miRNA.采用TargetScan 5.1和miRandaV5分析软件分析差异表达miRNAs的靶基因.结果 miRNA芯片筛选出11个胰腺导管腺癌相关的差异表达的miRNA,其中miR-194*、miR-192*、miR-602、miR-194表达上调,miR-139-3p、miR-513a-5p、miR-630、miR-30c-1*、miR-887、miR-508-5p、miR-516a-5p表达下调.miR-192、miR-194及其同源体的表达在31例胰腺癌组织中得到验证.经软件分析,miR.192靶基因有ZEB2、CXCL-2、EEF1A1、ERCC3,miR-192*靶基因有DCC、SMAD4、FAS,miR-194靶基因有DACH1、IGSF11、PTPN2、RBBP4,miR-194*靶基因有CD40LG、CIDEB、FHL1.结论胰腺导管腺癌存在11个表达差异的miRNA,这些miRNA可能与胰腺导管腺癌的发生、发展有关.     

Pathology of pancreatic ductal adenocarcinoma: Facts,challenges and future developments

Despite major improvements concerning its diagnosis and treatment, pancreatic ductal adenocarcinoma (PDAC) remains an aggressive disease with an extremely poor prognosis. Pathology, as interface discipline between basic and clinical medicine, has substantially contributed to the recent developments and has laid the basis for further progress. The definition and classification of precursor lesions of PDAC and their molecular characterization is a fundamental step for the potential identification of biomarkers and the development of imaging methods for early detection. In addition, by integrating findings in humans with the knowledge acquired through the investigation of transgenic mouse models for PDAC, a new model for pancreatic carcinogenesis has been proposed and partially validated in individuals with genetic predisposition for PDAC. The introduction and validation of a standardized system for pathology reporting based on the axial slicing technique has shown that most pancreatic cancer resections are R1 resections and that this is due to inherent anatomical and biological properties of PDAC. This standardized assessment of prognostic relevant parameters represents the basis for the successful conduction of multicentric studies and for the interpretation of their results. Finally, recent studies have shown that distinct molecular subtypes of PDAC exist and are associated with different prognosis and therapy response. The prospective validation of these results and the integration of molecular analyses in a comprehensive pathology report in the context of individualised cancer therapy represent a major challenge for the future.     

Clinical significance of cathepsin E in pancreatic juice in the diagnosis of pancreatic ductal adenocarcinoma

BACKGROUND: It has been reported that cathepsin E (CTSE) is a non-secretory and intracellular aspartic proteinase found in the superficial epithelial cells of the stomach and that it is also expressed in pancreatic ductal adenocarcinoma. We evaluated the diagnostic value of CTSE in the pancreatic juice in the diagnosis of pancreatic ductal adenocarcinoma compared with that of CA19-9, carcinoembryonic antigen (CEA) and K-ras mutations. METHODS: One hundred and one patients (25 with pancreatic ductal adenocarcinoma and 76 with chronic pancreatitis) were examined for the diagnostic significance of CTSE in the pancreatic juice in the diagnosis of pancreatic ductal adenocarcinoma. Forty of 101 patients (15 with pancreatic ductal adenocarcinoma and 25 with chronic pancreatitis) were examined to compare the diagnostic value of various tumor markers in the pancreatic juice, namely CA19-9, CEA, K-ras mutations and CTSE. RESULTS: The detection frequency of CTSE was significantly higher in patients with pancreatic ductal adenocarcinoma (64.0%) than in patients with chronic pancreatitis (7.9%; chi2 = 34.76; P < 0.0001). The sensitivity, specificity and diagnostic accuracy of CTSE in the pancreatic juice for pancreatic ductal adenocarcinoma was 66.7, 92.0 and 82.5%, respectively. These values were more efficient in comparison with those of CA19-9, CEA and K-ras mutations. The main cause of the detection failure of CTSE in pancreatic ductal adenocarcinoma was obstruction of the main pancreatic duct. Sensitivity was 85.7% in patients without obstruction of the main pancreatic duct. CONCLUSIONS: Cathepsin E in the pancreatic juice is a novel marker for a definitive diagnosis of pancreatic ductal adenocarcinoma.