Prognostic Implications of Routine, Immunohistochemical, and Molecular Staging in Resectable Pancreatic Adenocarcinoma
ABSTRACT Cure for ductal adenocarcinoma of the pancreas is restricted to resectable tumors, but survival after surgery is still poor. Despite apparently curative resection, these cancers rapidly recur. Thus, the present pathologic examination should be enriched by sensitive methods to detect minimal residual disease. In a prospective setting we studied the frequency of minimal residual disease after curative resection by routine histopathology, immunohistology, and polymerase chain reaction (PCR) for mutated K-ras. Furthermore, the prognostic implication of detecting of MRD was determined. Prospectively, tumor tissue and corresponding paraaortic lymph nodes were obtained from 78 patients, who underwent surgery for pancreatic head tumors between 1999 and 2001. Sixty-nine of 78 cases were diagnosed for ductal adenocarcinoma (study group), whereas nine cases were diagnosed for benign pancreatic tumors (control group). Paraaortic lymph nodes were examined in step sections by routine histopathology (hematoxylin and eosin) and immunohistology using a pan-cytokeratin antibody. DNA of the primary tumor and corresponding paraaortic lymph nodes were analyzed by PCR-based assays with respect to mutated K-ras in codon 12. The recurrence-free survival and overall survival were correlated with the results of the latter methods. In 3 of 69 patients tumor cells were detected in paraaortic lymph nodes by routine histopathology and in 5 of 69 patients by immunohistology. K-ras mutations were detected in 42 of 69 ductal adenocarcinomas (61%), whereas 12 (17%) were positive in paraaortic lymph nodes. All of the latter patients had recurrence after surgery and a significant poorer survival than those without mutated K-ras. Furthermore, paraaortic lymph nodes diagnosed for K-ras mutation were independent prognostic markers in multivariate analysis. In the control group K-ras mutations were detected in one adenoma of Vater's papilla but not in paraaortic lymph nodes. Tumor cell DNA can be detected more sensitively by the described PCR method than with hematoxylin and eosin or immunohistologic staining, leading to a higher sensitivity for detection of micrometastases. The described PCR method clearly determines subgroups of patients after curative resection with early recurrence and poor survival and could therefore enrich the pathologic examination.
- SourceAvailable from: Chuan-Yong Guo
[Show abstract] [Hide abstract]
- "Previous research has demonstrated a relationship between K-ras mutation and the presence of lymph node metastases. Niedergethmann et al. have reported that para-aortic lymph nodes diagnosed for K-ras mutation were independent pancreatic cancer prognostic markers in multivariate analysis . All of the patients with the K-ras mutation in lymph nodes had recurrence after surgery and a significantly poorer survival than those without mutated K-ras. "
ABSTRACT: Background. More clinically meaningful diagnostic tests are needed in pancreatic cancer (PC). K-ras mutations are the most frequently acquired genetic alteration. Methods. Original research articles involving the diagnostic accuracy of K-ras mutation detection in PC were selected. Data were presented as forest plots and summary receiver operating characteristic (SROC) curve analysis was used to summarize the overall test performance. Results. We assessed 19 studies from 16 published articles. The reports were divided into three groups according to the process used to obtain the test material. The summary estimates for detecting K-ras status using an invasive method (fine needle aspiration (FNA), endoscopic retrograde cholangiopancreatography (ERCP), or surgery) were better than cytology: the pooled sensitivity was 77% (95% confidence interval (CI): 74-80%) versus 54% (95% CI: 47-61%); specificity was 88% (95% CI: 85-91%) versus 91% (95% CI: 83-96%); and diagnostic odds ratio (DOR) was 20.26 (11.40-36.03) versus 7.52 (95% CI: 2.80-20.18), respectively. When two procedures were combined, the diagnostic accuracy was markedly improved. Conclusions. The analysis of K-ras mutations in pancreatic tissue has a promising diagnostic significance in PC. Further valuable studies are needed.Disease markers 07/2014; 2014:573783. DOI:10.1155/2014/573783 · 2.17 Impact Factor
[Show abstract] [Hide abstract]
- "If this is true in humans, it may be the route through which activated carcinogens reach the head of pancreas (carcinogen containing bile refluxing into the pancreatic duct). This theory is attractive given that the pancreatic head is the most frequent site for adenocarcinoma   . A study in rhesus monkeys (n = 4), however, found that biliary excretion of the NNK metabolites was significantly less than predicted from rat experiments. "
ABSTRACT: The extremely poor outcome from pancreas cancer is well known. However, its aetiology less well appreciated, and the molecular mechanisms underlying this are poorly understood. Tobacco usage is one of the strongest risk factors for this disease, and this is a completely avoidable hazard. In addition, there are well described hereditary diseases which predispose, and familial pancreas cancer. We have sought here to summarise the role of tobacco-derived carcinogens and the mode of their tumorigenic action on the pancreas. There is compelling evidence from animal and human studies (laboratory including cell line studies and epidemiologic) that tobacco derived carcinogens cause pancreas cancer. However, the manner in which they do so is not entirely apparent. There is also compelling evidence that synergism with genetic and other life-style factors-like diet obesity-results in a multifactorial causation of the disease. Ascertaining the role of tobacco carcinogens in the development of this cancer and their interaction with other risk factors will enable novel therapeutic and preventative strategies to improve outcome from this appalling malignancy.07/2011; 2011:249235. DOI:10.5402/2011/249235
- [Show abstract] [Hide abstract]
ABSTRACT: Die Bestimmung der Proteinexpression in 8 humanen genotypisch gut charakterisierten Pankreastumorzelllinien ergab vergleichbare Expressionslevel von CK1delta. Die Bestimmung der subzellulären Verteilung von CK1 delta in pankreatischen Tumorzellen ergab eine konstitutive Assoziation von CK1delta mit den Zentrosomen. In mitotischen Zellen war zudem eine Assoziation von CK1delta an den Mikrotubuli in der Nähe der Zentrosomen zu beobachten. Da CK1delta über einen autoregulatorischen Loop eng mit p53 verbunden ist, wurden die p53-Proteinexpressionslevel untersucht. Dabei wurde in Colo357 und in AsPC1 Zellen kein p53 detektiert. Hingegen wurde in allen anderen Zelllinien stabilisiertes Mutanten p53 nachgewiesen. Die Wachstumskurven nach IC261 Behandlung zeigten, dass IC261 zu einer Hemmung des Wachstums aller untersuchten Zelllinien führte. Diese Hemmung ist darauf zurückzuführen, dass IC261 zur Störung der mitotischen Spindel führt und, wie die durchgeführten Immunfluoreszenzanalysen belegen, insbesondere numerische Veränderungen der Zentrosomen hervorruft. Die Effekte von IC261 auf den Zellzyklus der Zellen wurden im Durchflusszytometer analysiert und ergaben, dass im Verlauf der IC261 Behandlung in allen untersuchten Zelllinien eine Anhäufung der Zellen mit einem DNA-Gehalt von 2Nx auftrat. Änderungen in der Expressionsrate von p53 nach IC261 Behandlung war auf Proteinebene weder bei den Zelllinien mit Mutanten p53 noch bei wt-Colo357 zu erkennen. Dies spricht für die Vermutung, dass es sich bei Colo357 nicht um funktionelles wt-p53 handelt. Die Wirkungen des CK1delta spezifischen Inhibitors IC261 auf den Zellzyklus etablierter Pankreastumorzelllinien wurden mit denen klassischer Spindelgifte verglichen. Während die Wirkungen von Nocodazol denjenigen von IC261 ähnelten, führte die Behandlung der Zellen mit Taxol vermehrt zum Absterben der Zellen. Durch IC261/Nocodazol Kombination konnte Polyploidie unterdrückt werden.