Risa Inoue

Intraoperative blood loss is not a predictor of prognosis for pancreatic cancer

PurposeThe relationship between intraoperative blood loss (IBL) and prognosis has been reported for some types of cancer, but not for pancreatic cancer, which has one of the highest mortality rates of any cancer. We conducted this study to analyze the relationship between IBL and clinical outcome for patients undergoing radical surgery for pancreatic cancer.MethodsThe subjects of this study were 144 patients who underwent curative pancreatectomy for invasive pancreatic cancer between 2002 and 2014. Clinicopathological characteristics were recorded and prognostic factors were identified by univariate and multivariate analyses.ResultsLarge IBL was significantly associated with advanced tumor stage, a long operation time, a large tumor, portal vein resection, and blood transfusion. According to univariate analysis, IBL was also significantly associated with overall survival (OS) and relapse-free survival (RFS); however, it was not an independent prognostic factor for OS and RFS in multivariate analysis. According to multivariate analysis, lymph node metastasis and R-status were independent prognostic factors for OS and RFS. A subgroup analysis of patients who received no blood transfusion showed similar results.ConclusionMinimizing IBL is very important; however, the present study found that positive lymph node metastasis and R-status were stronger independent prognostic factors for pancreatic cancer.

Heterogeneity of KRAS Mutations in Pancreatic Ductal Adenocarcinoma

Objectives Activating Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations are the most common and frequent changes observed in pancreatic cancer. This study aimed to determine the frequency and extent of intratumoral and metastatic lymph node KRAS mutation heterogeneity of resected pancreatic ductal adenocarcinoma. Methods Tumor tissues macrodissected from tumor centers, invasion fronts (n = 97), and lymph nodes (n = 11) were subjected to DNA extraction and mutation analysis of KRAS codons 12 and 13 by pyrosequencing. Results Activating mutations in codon 12 of KRAS were detected in 90 (92.8%) tumor centers. No mutations were detected in KRAS codon 13 in any patient. After a comparison of tumor centers and invasion fronts, intratumoral heterogeneity of KRAS was observed only in 4 (4.1%) cases. Additional invasion front tumor analysis revealed the same mutation status consistent with each tumor center. No heterogeneity was observed between primary tumors and metastatic lymph nodes. Conclusions Intratumoral heterogeneity of the KRAS mutational status is rare in pancreatic ductal adenocarcinoma. In addition, no KRAS heterogeneity between primary tumors and metastatic lymph nodes was detected in this study. This finding is consistent with the hypothesis that oncogenic activation of KRAS is the first driver mutation in pancreatic cancer.

Abstract 3350: Verification of mechanism that CSC markers are implicated in poor prognosis for pancreatic ductal adenocarcinoma

Background: Cancer stem cells (CSCs) refer to a subset of tumor cells that have self-renewal ability and generate plenty of non-CSC cells that comprise a tumor. In addition, CSCs play crucial roles in various processes during tumor progression and metastasis as well. A number of CSC markers candidates have been explored to date, and Aldehyde dehydrogenase 1 (ALDH1), c-Met, and CD44 have been identified as CSC markers in pancreatic ductal adenocarcinoma (PDAC). On the other hand, prostaglandin E2 (PGE2) is one of metabolites in arachidonate cascade and is implicated in the expansion of hematopoietic and tissue stem cell fraction. The aim of this study is to single out the most important CSC marker and elucidate the functional role of PGE2 for CSC expansion in PDAC. Methods: Three CSC markers (ALDH1, CD44, and c-Met) expression was examined by immunohistochemistry in 121 primary surgical specimens of PDAC and analyzed a relationship with clinicopathological factors and clinical outcomes. The clonogenic growth potential of CSC marker-positive PDAC cells was assessed in vitro by growth assays and sphere formation assays. We next investigated the expression of CSC markers and self-renewal related genes in PDAC cell lines with PGE2 or 15-PGDH inhibitor treatment. We further conducted functional experiments using siRNA to identify the critical molecule in PDAC progression. Results: A high level of ALDH1 expression was detected in 63 of the 121 cases, and was significantly associated with large tumor size and poor prognosis in PDAC patiants. On the other hand, CD44 and c-Met expression were not associated with the prognosis. Among CSC markers, the expression of ALDH1 was significantly increased by PGE2 treatment in PDAC cells. By suppressing ALDH1 expression by siRNA, growth and sphere formation potential were inhibited in ALDH1 high-expressing PDAC cells. In contrast, the expression of ALDH1 was remarkably increased by PGE2 or 15-PGDH inhibitor treatment in ALDH1 low-expressing PDAC cells. Finally, we found that Nanog and Oct-4 were down-stream molecules of PGE2-ALDH1 signaling and played crucial roles for PDAC cell expansion. Conclusion: Our results demonstrated that PGE2 positively regulated ALDH1 expression, and the growth and sphere formation potential were promoted by increasing ALDH1 expression, resulting in poor prognosis of PDAC patients. Inhibiting PGE2-ALDH1 signaling could lead to the suppression of tumor growth in PDAC patients. Citation Format: Kota Arima, Takatsugu Ishimoto, Hirohisa Okabe, Yuki Kitano, Risa Inoue, Kensuke Yamamura, Takayoshi Kaida, Takaaki Higashi, Katsunobu Taki, Katsunori Imai, Daisuke Hashimoto, Akira Chikamoto, Toru Beppu, Hideo Baba. Verification of mechanism that CSC markers are implicated in poor prognosis for pancreatic ductal adenocarcinoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3350.