Type Of Pancreatic Tumor Research Articles

Efficacy of transcatheter arterial chemoembolization for liver metastases arising from pancreatic cancer.

PurposeThe aim of the study was to evaluate the efficacy of transcatheter arterial chemoembolization (TACE) in treating patients with liver metastases from pancreatic cancer, and explore the prognostic risk factors.ResultsThree of the 27 patients were totally recovered, and 12 were partially alleviated. The total efficacy rate was 55.6% (15/27). The median survival time was 13.6 months, and the 0.5-, 1-, 2-, 3-, and 5-year survival rates were 70.4% (19/27), 48.1% (13/27), 22.2% (6/27), 14.8 (4/27), 11.1% (3/27), respectively. None of the groups showed any severe complications. Univariate analysis showed that pathological type, concomitant therapies for liver metastasis, vascular supply, CA199 levels and extrahepatic metastasis were related to prognosis (P < 0.05). Multivariate analysis indicated that pancreatic cancer pathology and extrahepatic metastasis were independent risk factors influencing patients' prognosis (χ2 = 13.182, 17.989, P < 0.05).MethodsThe clinical records of 27 patients with lliver metastases from pancreatic cancer diagnosed at the First Affiliated Hospital of Zhejiang University between May 2009 and May 2015 were retrospectively analyzed. The short-term and long-term efficacy and toxic side effects of TACE were observed. The prognostic risk factors were analyzed using Cox (proportional hazards) regression model.ConclusionTACE is an effective therapy for treating liver metastases from pancreatic malignancy. Pathological type and extrahepatic metastasis of pancreatic tumor are independent risk factors for patients' prognosis. The prognosis of patients with liver metastasis from pancreatic neuroendocrine neoplasm is superior to that of extrahepatic metastasis.

RN927C, a Site-Specific Trop-2 Antibody-Drug Conjugate (ADC) with Enhanced Stability, Is Highly Efficacious in Preclinical Solid Tumor Models.

Trop-2, also known as TACSTD2, EGP-1, GA733-1, and M1S1, is frequently expressed on a variety of human carcinomas, and its expression is often associated with poor prognosis of the diseases. However, it is also present on the epithelium of several normal tissues. A comprehensively designed Trop-2-targeting antibody-drug conjugate (ADC), balancing both efficacy and toxicity, is therefore necessary to achieve clinical utility. To this end, we developed a cleavable Trop-2 ADC (RN927C) using a site-specific transglutaminase-mediated conjugation method and a proprietary microtubule inhibitor (MTI) linker-payload, PF-06380101. Robust in vitro cytotoxicity of RN927C was observed on a panel of Trop-2-expressing tumor cell lines, with IC50 generally in the subnanomolar range. As expected for an MTI-containing ADC, RN927C readily induced mitotic arrest of treated cells in vitro and in vivo, followed by subsequent cell death. The in vivo efficacy of RN927C was tested in multiple cell line and patient-derived xenograft tumor models, including pancreatic, lung, ovarian, and triple-negative breast tumor types. Single-dose administration of RN927C at 0.75 to 3 mg/kg was generally sufficient to induce sustained regression of Trop-2-expressing tumors and showed superior efficacy over standard treatment with paclitaxel or gemcitabine. Administration of RN927C in nonhuman primate toxicity studies resulted in target-mediated effects in skin and oral mucosa, consistent with Trop-2 expression in these epithelial tissues with minimal, non-dose limiting off-target toxicities. On the basis of the combined efficacy and safety results, RN927C is postulated to have a favorable therapeutic index for treatment of solid tumors. Mol Cancer Ther; 15(11); 2698-708. ©2016 AACR.

P53 and p16Ink4a/p19Arf Loss Promotes Different Pancreatic Tumor Types from PyMT-Expressing Progenitor Cells

In human studies and mouse models, the contributions of p53 and p16Ink4a/p19Arf loss are well established in pancreatic ductal adenocarcinoma (PDAC). Although loss of functional p53 pathway and loss of Ink4a/Arf in human pancreatic acinar cell carcinoma (PACC) and pancreatic neuroendocrine tumor (PanNET) are identified, their direct roles in tumorigenesis of PACC and PanNET remain to be determined. Using transgenic mouse models expressing the viral oncogene polyoma middle T antigen (PyMT), we demonstrate that p53 loss in pancreatic Pdx1+ progenitor cells results in aggressive PACC, whereas Ink4a/Arf loss results in PanNETs. Concurrent loss of p53 and Ink4a/Arf resembles loss of p53 alone, suggesting that Ink4a/Arf loss has no additive effect to PACC progression. Our results show that specific tumor suppressor genotypes provocatively influence the tumor biological phenotypes in pancreatic progenitor cells. Additionally, in a mouse model of β-cell hyperplasia, we demonstrate that p53 and Ink4a/Arf play cooperative roles in constraining the progression of PanNETs.

Distal Pancreatectomy with Spleen Preservation in Two Rare Types of Pancreatic Tumors

Cystic neoplasms of the pancreas have an incidence of 10% of all cystic tumors, represented by serous cystadenomas, mucinous cystic neoplasm and solid pseudopapillary neoplasm. We present two cases with rare pancreatic tumors: two women of 18 years old and 67 years old respectively were admitted for non specific abdominal pain and dyspepsia. The CT-scans diagnosed with corporeal pancreatic of 30 × 40 mm in the first case and 98 × 66 mm in the second. Distal pancreatectomy with spleen preservation was performed in both cases with uneventful postoperative course. The pathological exam revealed pseudopapillary pancreatic tumor in the first case and mucinous cystic neoplasm, in the second case. A short review of the literature was also performed.

Severe Chronic Diarrhea Secondary to Primary Lymph Node Gastrinoma

Introduction: Gastrinoma is the most common type of pancreatic neuroendocrine tumors (PETs). It exists in multiple forms including sporadic and as part of Multiple endocrine neoplasia (MEN-I) syndrome, and can be malignant and metastatic. The majority of sporadic gastrinomas (90%) occur in the gastrinoma triangle with the wall of the duodenum and the pancreas being the most common sites, however ectopic sites have been reported as well. The existence of primary lymph node (LN) Gastrinomas is controversial, even-though it is described by many case reports, and supported by prospective studies. The main challenge is to determine whether it represents a primary tumor or metastasis from an occult primary site. There are some criteria used to diagnose patients with primary LN Gastrinoma, however it remains a diagnosis of exclusion and a carful follow up is always warranted. Case report: 48 year-old female presented with chronic abdominal pain, and severe watery diarrhea causing significant renal insufficiency. She had an extensive blood, stool, radiological and endoscopic workup without explanation of her chronic symptoms. Suspicion of an endocrine cause of her secretory diarrhea warranted testing serum gastrin and Chromogranin, which were elevated and suspicious for Gastrinoma. The diagnosis was confirmed radiologically by Octroetide scan, and Endoscopic Ultrasound (EUS), which showed a lesion in the posterior aspect of the head of the pancreas. Secretin stimulation test confirmed the diagnosis. Screening for MEN-I syndrome was negative. She underwent a surgical intervention for tumor enucleation near the head of pancreas. Samples were sent for histological evaluation and they showed LN with neuroendocrine tumor. No additional lesions were found in the Gastrinoma triangle after carful surgical exploration. The patient improved clinically post-operative, her serum gastrin decreased to normal range and repeated Octroetide scan was negative. Conclusion: The existence of primary LN Gastrinomas is controversial. It remains a diagnosis of exclusion and a carful follow up is warranted, and it should be in the differential diagnosis of severe chronic diarrhea.Table 1: Patient's serum gastric levelFigure 2Figure 3

Abstract NG08: Transcriptional mechanisms for autophagy regulation and metabolic reprogramming in pancreatic cancer

Abstract NG08: Transcriptional mechanisms for autophagy regulation and metabolic reprogramming in pancreatic cancer

MiR-144/451 Promote Cell Proliferation via Targeting PTEN/AKT Pathway in Insulinomas.

Insulinoma is the main type of functional pancreatic neuroendocrine tumors. The functional microRNAs (miRNAs) regulating tumor growth and progression in insulinomas are still unknown. We conducted the miRNA expression profile analysis using miRNA quantitative RT-PCR array and identified 114 differentially expressed miRNAs in human insulinomas compared with normal pancreatic islets. Forty-one differentially expressed miRNAs belonged to 7 miRNA families, and 28 miRNAs in 3 of the families localized in the epigenetically regulated imprinted chromosome 14q32 region. We validated the most significant differentially expressed miRNA cluster miR-144/451 in another 8 human normal islet samples and 25 insulinomas. Our data showed that the overexpression of miR-144/451 in mouse pancreatic β-cells promoted cell proliferation by targeting the β-cell regulator phosphatase and tensin homolog deleted on chromosome ten/v-akt murine thymoma viral oncogene homolog pathway and cyclin-dependent kinase inhibitor 2D. Our findings highlight the importance of functional miRNAs in insulinomas.

F-18 fluorodeoxyglucose positron emission tomography for differential diagnosis of pancreatic tumors.

Positron emission tomography with 2-deoxy-2-[18F]fluoro-D-glucose (FDG-PET) has been proven useful for differentiating pancreatic ductal cancer from mass-forming chronic pancreatitis. However, there are particular pancreatic tumors having various grades of malignancy such as intraductal papillary mucinous neoplasm (IPMN) or pancreatic neuroendocrine tumor. We examined whether the cut-off value of maximum standardized uptake value (SUVmax) determined by pancreatic ductal cancers is also applicable for other pancreatic tumors.One hundred thirty six patients with pancreatic tumors underwent FDG-PET imaging. We first analyzed the cut-off value to differentiate pancreatic ductal cancers from mass-forming chronic pancreatitis. Secondly, we determined the cut-off value between malignant IPMN and benign IPMN. Thirdly, we computed a cut-off value between malignant pancreatic tumors and benign tumors irrespective of tumor type.The optimal cut-off value to differentiate ductal cancers from mass-forming chronic pancreatitis was 2.5. The optimal cut-off value for differentiating malignant IPMN from benign IPMN was also 2.5, similar to that of reported studies. In all types of pancreatic tumors, the cut-off value was also 2.5. The accuracy for detecting malignancy was 93.4% for all tumors.In the FDG-PET study for pancreatic tumors, an SUVmax of 2.5 would be justified as a cut-off value to differentiate malignant lesions.

Intraductal oncocytic papillary neoplasm of the pancreas: report of a case requiring completion pancreatectomy.

Cystic tumors of the pancreas have been diagnosed with increasing frequency. Intraductal oncocytic papillary neoplasm is a rare type of cystic pancreatic tumor. Intraductal oncocytic papillary neoplasm is considered a distinct entity with the potential of developing into invasive carcinoma and it should be differentiated from other cystic tumors of the pancreas, including mucinous cystic neoplasm and other forms of intraductal papillary mucinous neoplasm (IPMN). Histologically, the formation of oncocytic cells and the complex morphology of the papillae distinguish intraductal oncocytic papillary neoplasm from IPMN. While the number of publications addressing the diagnosis, management and follow-up of patients with IPMN has been increasing, the behavior differences between IPMN and intraductal oncocytic papillary neoplasm have not been elucidated, secondary to very limited clinical experience. Here, we are presenting a case of a patient with the diagnosis of intraductal oncocytic papillary neoplasm of the pancreas developing into invasive cancer. This case stresses the necessity for lifelong surveillance of the remnant pancreas following partial pancreatectomy for intraductal oncocytic papillary neoplasm, due to the risk of developing multifocal disease.

The limitations of endoscopic ultrasound-guided fine needle aspiration cytology in the diagnosis of pancreatic serous cystadenoma: a brief case report.

Endoscopic ultrasound (EUS) fine needle aspiration (FNA) biopsy is commonly used in the diagnosis of pancreatic tumors. Although adenocarcinoma is the most commonly diagnosed primary pancreatic neoplasm, other neoplasms can also arise in this organ. For accurate diagnosis, pathologists must be familiar with the cytomorphology associated with all types of pancreatic tumors. Serous cystadenoma (SCA) is a rare, benign neoplasm that originates in the centro-acinar epithelium of the pancreas. Excluding any symptomatic or diagnostic uncertainty, patients presenting with SCA need no further management. Here, we report a case of pancreatic SCA that was suspected to be adenocarcinoma in preoperative test using EUS-guided FNA.

Symptomatic Pancreatic Insulinoma Successfully Treated With Alcohol Ablation

Introduction: Insulinomas are the most common type of functional pancreatic endocrine tumor. Representing 1-2% of all pancreatic neoplasms, these insulin secreting tumors occur in approximately 4 out of 1 million people per year. Insulinomas are characterized clinically by fasting hypoglycemia, neuroglycopenic symptoms, and occasionally, sympathoadrenal autonomic symptoms. Currently, surgical resection is the mainstay of therapy; however, in elderly patients with comorbidities, a more optimal alternative is needed. An 81-year-old woman presented with symptomatic and persistent hypoglycemia despite administration of IV glucose. Laboratory testing revealed elevated proinsulin, insulin, and c-peptide levels, consistent with insulinoma. A helical CT scan with IV contrast showed a 1.1 cm hyperdensity in the superior aspect of the body of the pancreas. Linear array EUS demonstrated a round, well demarcated, hypoechoic lesion measuring 1 cm x 1 cm in the neck of the pancreas. Cytology was obtained by EUS guided FNA which revealed numerous monomorphic appearing epithelial cells singly and in loose clusters. Findings were consistent with a pancreatic epithelial neoplasm, possibly a pancreatic neuroendocrine tumor. Patient was deemed a poor surgical candidate due to her significant cardiovascular disease. Therefore, alternative therapy with alcohol ablation was recommended. A total of 1 ml of 98% alcohol was injected under EUS guidance during a single session with adequate tissue transformation from hypoechoic to echorich. There were no complications during or after the procedure. Following alcohol ablation, serum insulin normalized and IV glucose was discontinued on post-ablation day 2. She was discharged on day 7. To date, clinical follow-up for more than 14 months with our facility as well as a local endocrinologist has shown no symptom recurrence and euglycemia. Endoscopic ultrasonography is an optimal diagnostic modality for identification of insulinoma. Surgical enucleation or resection is currently considered the therapeutic standard for treatment of insulinomas and has a high success rate. In elderly patients with comorbidities; however, this mainstay of therapy can be associated with high morbidity and mortality rates. In this particular subset of patients, alternative therapy with minimally invasive EUS guided ablative treatment may be a more optimal alternative. Currently, there have only been a few cases of EUS guided ablation of insulinomas reported. Cases varied by technique and extent of post-procedural complications. To our knowledge, this is the first case of EUS guided alcohol ablation of a solitary insulinoma performed in a single treatment session with no complications reported in the United States.

Intraductal neoplasms of the pancreas

There are three types of pancreatic neoplasms that predominantly have an intraductal growth pattern: the common, usually cystic, intraductal papillary mucinous neoplasms (IPMNs); the rare, usually solid intraductal tubulopapillary neoplasms (ITPNs); and the rare intraductal tubular pyloric gland-type adenoma. In addition to these three tumor types, pancreatic neoplasms with a usually solid growth pattern such as acinar cell carcinomas, neuroendocrine tumors, and undifferentiated carcinomas may present, though very rarely, as predominantly intraductally growing neoplasms. IPMNs can be subclassified into main duct and branch duct tumors; into low- and high-grade dysplasia groups; and into tumors with intestinal, pancreatobiliary, oncocytic, or gastric cellular differentiation. The intestinal-, pancreatobiliary-, and oncocytic-type IPMNs occur predominantly in the main duct of the head of the pancreas and more commonly progress to invasive adenocarcinomas. The gastric-type IPMNs are frequently multifocal, occur predominantly in the branch ducts of the uncinate process, and have a low risk of progressing to invasive carcinoma. The prognosis for patients with an IPMN depends largely on the subtype and the presence and the stage of an invasive carcinoma. ITPNs are nodular tumors, often in the pancreatic head, and composed of densely packed tubular glands. Molecular genetics reveal KRAS, GNAS, and RNF43 as the most frequently mutated genes in IPMNs, while ITPNs show wild-type KRAS. Recent progress in genetic sequencing of pancreatic neoplasms and the identification of specific genetic mutations also holds promise for the future development of novel gene-based diagnostic tests in intraductal neoplasms of the pancreas that might even be used in preoperative conditions.

An invitation to the 2nd Cancer Cachexia Conference, Montréal, Canada.

The National Cancer Institute in the USA has recently placed greater emphasis on cancer cachexia research by identifying this syndrome as a provocative question needing to be addressed in order to drive progress against cancer. Such funding mechanisms are expected to stimulate cutting edge approaches at both the basic and clinical science levels to advance our understanding of the underlying causes of cachexia. The goal is to identify and test lead compounds that preserve the loss of adipose and skeletal muscle tissues in pancreatic and other tumor types prone to developing cachexia. Complementing the Provocative Questions mechanism, a cancer cachexia conference was organized in 2012 in Boston, Massachusetts, USA, with the goal of creating a forum whereby basic and clinical scientists from academia and industry could freely interact to share ideas from published and unpublished work so as to advance our understanding on the factors and mechanisms driving weight loss, weakness, and fatigue in cancer patients. This first cancer cachexia conference was viewed as a success as evidenced by the high number of registrations from Ph.D. and M.D. scientists, the balanced representation from academia and industry, the quality of unpublished data presented, the breath of the science, and the positive feedback received from a solicited questionnaire. Based on these achievements and significant scientific advancements made within the last few years, the decision was made to organize a second international cancer cachexia conference. The expectation of conducting a second conference is that it brings awareness to the many fields and accelerates research leading to better diagnosis and therapies for the cancer syndrome. Therefore, on behalf of the organizing and scientific committees, and in collaboration with the Society on Sarcopenia, Cachexia and Wasting Disorders (SCWD), it is a pleasure to announce the 2nd Cancer Cachexia Conference: Evolving Mechanisms and Therapies, which will take place at the exciting city of Montreal, Canada on September 26–28, 2014. We hope you take the opportunity to join us in what we anticipate will be another exciting conference leading to new insights that will bring researchers and physicians one step closer to effectively treating the cancer cachexia syndrome. For more information on the conference, the venue, and how to register, please visit: http://cancercachexia2014.com/ Thank you and look forward to seeing you in Montreal!

Mo1480 EUS-FNA Is Useful to Diagnose Pancreatic Neuroendocrine Tumors Based on the World Health Organization Classification

A new grading classification for pancreatic neuroendocrine tumors (pNET) was proposed by the World Health Organization (WHO) in 2010 (2010 WHO classification). pNET are classified as neuroendocrine tumors (NET) G1, NET G2, and neuroendocrine carcinoma (NEC) based on the proliferative indices. It has been shown that EUS-FNA is useful to diagnose several types of pancreatic tumors histologically, but it is still controversial whether EUS-FNA using a 22-gauge (G) needle is useful to diagnose pNET.

Embryonic stem cell factors and pancreatic cancer

Pancreatic ductal adenocarcinoma (PDAC), the most common type of pancreatic tumor, is a highly aggressive human cancer with the lowest five-year survival rate of any human maligancy primarily due to its early- metastasis and lack of response to chemotherapy and radiation. Recent research suggests that PDAC cells comprise a hierarchy of tumor cells that develop around a population of cancer stem cells (CSCs), a small and distinct population of cancer cells that mediates tumoregenesis, metastasis and resistance to standard treatments. Thus, CSCs could be a target for more effective treatment options. Interestingly, pancreatic CSCs are subject to regulation by some of key embryonic stem cell (ESC) transctiption factors abberently expressed in PDAC, such as SOX2, OCT4 and NANOG. ESC transcription factors are important DNA-binding proteins present in both embryonic and adult somatic cells. The critical role of these factors in reprogramming processes makes them essential not only for embryonic development but also tumorigenesis. Here we provide an overview of stem cell transcription factors, particularly SOX2, OCT4, and NANOG, on their expression and function in pancreatic cancer. In contrast to embryonic stem cells, in which OCT4 and SOX2 are tightly regulated and physically interact to regulate a wide spectrum of target genes, de novo SOX2 expression alone in pancreatic cancer cells is sufficient to promote self-renewal, de-differentiation and imparting stemness characteristics via impacting specific cell cycle regulatory genes and epithelial-mesnechymal transtion driver genes. Thus, targeting ESC factors, particularly SOX2, could be a worthy strategy for pancreatic cancer therapy.

Differentiation of solid pancreatic tumors by using dynamic contrast-enhanced MRI

Distinguishing among different solid pancreatic tumor types, pancreatic ductal adenocarcinomas, neuroendocrine tumors (NETs), and solid pseudopapillary tumors (SPTs) is important, as the treatment options are vastly different. This study compared characteristics of solid pancreatic tumors by using dynamic contrast enhanced magnetic resonance imaging (MRI). Fifty patients underwent MR imaging of pancreatic masses with a histopathology that was later confirmed as an adenocarcinoma (n = 27), a NET (n = 16), and a SPT (n = 7). For qualitative analysis, two reviewers evaluated the morphologic features of the tumors: locations, margins, shapes, contained products, pancreatic ductal dilatation, and grade of signal intensity (SI). For the quantitative analysis, all phases of the MR images were co-registered using proprietary image registration software; thus, a region of interest (ROI) defined on one phase could be re-applied in other phases. The following four ratios were considered: tumor-to-uninvolved pancreas SI ratio, percent SI change, tumor-touninvolved pancreas enhancement index, and arterial-to-delayed washout rate. The areas under the receiver operating characteristic (ROC) curves were assessed for the four ratios. Adenocarcinomas had ill-defined margins, irregular shapes, and ductal dilatation compared with NETs and SPTs (P < 0.001). The tumor-to-uninvolved pancreas ratio on all dynamic phases was significantly higher for NETs than for both adenocarcinomas and SPTs (P < 0.05). Percentage SI changes of pancreatic tumors on the pancreatic and the portal venous phases were significantly higher for NETs than for both adenocarcinomas and SPTs (P < 0.05). A significant difference between NETs and adenocarcinomas was also found with respect to the tumor-to-uninvolved pancreas enhancement index and arterial-to-delayed washout rate. The percentage SI changes in the pancreatic phase and the arterial-to-delayed washout rate best distinguished between adenocarcinomas and NETs with the area under the ROC curve being 0.87. The percentage SI changes in the pancreatic and the portal venous phases best distinguished between NETs and SPTs with area under the ROC curve 0.87. In summary, contrast-enhanced MRI can be useful in differentiating solid pancreatic tumors in qualitative and quantitative analyses.

Resection or cryosurgery relates with pancreatic tumor type: Primary pancreatic cancer with previous non-pancreatic cancer or secondary metastatic cancer within the pancreas

ObjectivesWe investigated the incidence of primary pancreatic cancer with previous non-pancreatic cancer (PPC) and secondary metastatic cancer within the pancreas (SMC) to elucidate the differential diagnosis and treatment of these lesions. MethodsThe clinical data of 2539 patients with pancreatic mass in Tianjin Cancer Hospital from January 2000 to December 2012 were retrospectively analyzed. All of the 66 patients who showed double or multiple primary cancers or metastatic pancreatic malignancies were included into the PPC group or SMC group, respectively. In addition, PPC patients were compared with 570 patients suffering from pancreatic cancer (PC) alone. ResultsFor the PPC group (n = 34), the most common previous non-pancreatic cancers were gastric cancer, breast cancer, and thyroid cancer. For the SMC group (n = 32), the most common metastatic tumors were lung cancer, renal cell carcinoma (RCC), and gastric cancer. Multivariate analysis identified age (OR = 1.099; 95% CI, 1.007–1.199), previous tumor type (OR = 1.164; 95% CI, 1.046–1.296), and time interval between two tumors (OR = 1.021; 95% CI, 1.003–1.039) as significant indicators. Significantly better survival times were observed after resection than after cryosurgery in the PPC group (p < 0.001) but not in the SMC group (p = 0.670). ConclusionsOverall, primary pancreatic cancers are as common as metastasis to the pancreas in patients with a previous cancer. A longer time interval between two tumors indicates a higher possibility that a new pancreatic cancer will occur. Some cancers (particularly RCC) are more likely to metastasize to the pancreas than other cancers. For metastatic cancers, cryosurgery is as effective as resection as a treatment option.

APKCλ/ι is a beneficial prognostic marker for pancreatic neoplasms

Pancreatic cancer is a lethal disease. Overall survival is typically 6 months from diagnosis. Determination of prognostic factors in pancreatic cancer that would allow identification of patients who could potentially benefit from aggressive treatment is important. However, until date, there are no established reliable prognostic factors for pancreatic cancer patients. Herein, we propose a beneficial biomarker which is significantly correlated with the prognosis in pancreatic cancer patients. Atypical protein kinase C λ/ι (aPKCλ/ι) is overexpressed and has been implicated in the progression of several cancers. We tested the expression levels of aPKCλ/ι in two types of pancreatic neoplasm, pancreatic ductal adenocarcinoma (PDAC) and intraductal papillary mucinous neoplasms (IPMNs), by immunohistochemistry. Examination of the aPKCλ/ι expression levels in surgically resected specimens of PDCA (n = 115) demonstrated that the expression levels of aPKCλ/ιin PDAC had prognostic implications, independent of the Tumor-Node-Metastasis classification and World Health Organization tumor grade. In the case of IPMNs (n = 46) also, the expression levels of aPKCλ/ιin IPMN were found to be of prognostic importance, independent of the World Health Organization histological grade or morphological type. Interestingly, high expression levels of aPKCλ/ι were significantly correlated with a worse histological grade (p = 0.010) and advanced stage of the tumor (p = 0.0050) in IPMN patients. These findings suggest that high expression levels of aPKCλ/ι could be involved in the malignant transformation of IPMNs. Based on these observations, we propose the expression level of aPKCλ/ι as a prognostic marker common to different types of pancreatic neoplasms.

Abstract 5110: Activation of Wnt/β-catenin, hedgehog and androgen receptor signaling pathways in solid pseudopapillary neoplasm of pancreas.

Abstract Solid pseudopapillary neoplasm (SPN), is an uncommon pancreatic tumor with distinct clinicopathologic features. Mutations in the exon 3 of β-catenin are characteristically identified in SPNs, however little is known about gene and microRNA expression characteristics. To investigate the molecular characteristics of SPNs, we analyzed mRNA and microRNA expression profiles of 14 SPNs and compared their expressions to that of 6 pancreatic ductal adenocarcinomas, 6 endocrine tumors of pancreas, and 5 non-neoplastic pancreas tissues. We demonstrated both mRNA and microRNA expression profiles completely distinguish SPNs to the other pancreatic tumors and non-neoplastic pancreas tissues. We found that Wnt/β-catenin, Hedgehog and androgen receptor signaling pathways are activated in SPNs by analyzing 1,686 genes that showed specific expression changes in SPN. We also found that 7 microRNAs were specifically down-regulated in SPNs, and miR-30a was most closely associated with the up-regulation of the genes belong to the three distinct activated pathways of SPN. We also demonstrated that genes involved in epithelial to mesenchymal transition (EMT) are up-regulated in SPNs than the other type of pancreatic tumors. SPN is characterized by increased expression of mesenchymal markers (N-cadherin, MMP9, Vercican, TIMP1) and decreased expression of epithelial markers (E-cadherin, Desmoplakin, Mucin1, Caveolin). Considering that activated Wnt/β-catenin and Hedgehog pathways are related to the activation of the genes involved in EMT, these activated signaling pathways of SPNs can explain lack of epithelial cell differentiation, and the molecular mechanism of SPN tumorigenesis. Citation Format: Minhee Park, Minhyung Kim, Daehee Hwang, SangKyum Kim, Eunsung Park, Youngki Paik, Jeonhan Park, Hogeun Kim. Activation of Wnt/β-catenin, hedgehog and androgen receptor signaling pathways in solid pseudopapillary neoplasm of pancreas. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5110. doi:10.1158/1538-7445.AM2013-5110

Abstract 5460: Effects of nuclear receptor HNF4α repression in human pancreatic ductal adenocarcinoma cells.

Abstract HNF4α transcription factor is an orphan nuclear receptor that belongs to the hepatocyte nuclear factors (HNFs) group. HNFs are essential for differentiation and functionality of liver, pancreas, intestine and kidney during ontogenesis. A number of studies revealed that HNF4α is a key regulator of HNFs transcription control network in hepatocytes. Derangement of HNF4α expression is crucial for the development and progression of hepatocellular carcinoma (HCC); restoration of HNF4α expression in dedifferentiated HCC cells results in partial reversion of their malignant properties. Also HNF4α acts as a tumor suppressor in kidney and intestinal epithelium cells, but it's functions in pancreatic cells are very poorly investigated. HNF4α expression is regulated by two independent promoters, P1 and P2. Resulting HNF4αP1 and HNF4αP2 groups of isoforms differ by distinct expression pattern in various epithelial tissues and trans-activation ability. In normal pancreatic tissue HNF4αP2 isoforms are predominant. We have shown that development of pancreatic ductal adenocarcinoma (PDAC), the most aggressive type of pancreatic tumors, is accompanied by derangement of HNF4α expression. Similar patterns of HNF4α isoforms expression were described in PDAC cell lines and clinical samples of pancreatic tumor tissue. Highly differentiated PDAC cells are characterized by retaining of HNF4αP2 isoforms expression, whereas extrinsic HNF4αP1 isoforms are activated in moderately differentiated cells and poorly differentiated cells lack the expression of both groups of HNF4α isoforms. To find out the role of HNF4α deregulation in PDAC progression we have studied the biological impact of HNF4α knock-down in human moderately differentiated PDAC cell line AsPC1. Using lentiviral infection we have obtained AsPC1 cell cultures constitutively expressing shRNAs to HNF4α (AsPC1-sh cells). HNF4α downregulation in AsPC1-sh cells resulted in diminished expression of HNF1α, direct target gene of HNF4α and important regulator of pancreatic cells differentiation. Cells with repressed HNF4α expression demonstrated drastic increase in their ability for directional migration and induction of N-cadherin expression. On the other hand, AsPC1-sh cells exhibit lower colony formation ability and significant decrease in proliferation and DNA synthesis. These results indicate that deregulation of HNF4α expression is frequent event in pancreatic carcinogenesis. The repression of HNF4α in PDAC cells exerts complex alterations of biological properties of PDAC cells, which include both promotion and attenuation of certain cell characteristics that determine the degree of malignant cell phenotype manifestation. The work was partly supported by grants from RFBR (13-04-02080) and grant from Russian ministry of education and science (№ 8066, code 2012-1.1-12-000-1002-064). Citation Format: Mikhail S. Chesnokov, Artem D. Gorev, Natalia L. Lazarevich. Effects of nuclear receptor HNF4α repression in human pancreatic ductal adenocarcinoma cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5460. doi:10.1158/1538-7445.AM2013-5460