Intraductal Papillary Mucinous Adenoma Research Articles

Pathophysiological Implications of Protein Lactylation in Pancreatic Epithelial Tumors.

Protein lactylation is a post-translational modification associated with glycolysis. Although recent evidence indicates that protein lactylation is involved in epigenetic gene regulation, its pathophysiological significance remains unclear, particularly in neoplasms. Herein, we investigated the potential involvement of protein lactylation in the molecular mechanisms underlying benign and malignant pancreatic epithelial tumors, as well as its role in the response of pancreatic cancer (PC) cells to gemcitabine. Increased lactylation was observed in the nuclei of intraductal papillary mucinous adenoma, non-invasive intraductal papillary mucinous carcinoma, and invasive carcinoma, in parallel to the upregulation of hypoxia-inducible factor-1α. This observation indicated that a hypoxia-associated increase in nuclear protein lactylation could be a biochemical hallmark in pancreatic epithelial tumors. The standard PC chemotherapy drug gemcitabine suppressed histone lactylation in vitro, suggesting that histone lactylation might be relevant to its mechanism of action. Taken together, our findings suggest that protein lactylation may be involved in the development of pancreatic epithelial tumors and could represent a potential therapeutic target for PC.

Negative correlation between the nuclear size and nuclear Lamina component Lamin A in intraductal papillary mucinous neoplasms of the pancreas.

Background: The nuclear laminar protein Lamin A and inner nuclear membrane protein Emerin plays important role in sustaining nuclear structure. However, They have not investigated the significance of these proteins for development of pancreatic intraductal papillary mucinous neoplasm (IPMN). Methods: We examined pancreatic IPMN specimens for nuclear morphology and nuclear protein expression pattern of Lamin A and Emerin. Forty-two IPMN specimens were included, with 30 classified as intraductal papillary mucinous adenoma (IPMA) and 12 as intraductal papillary mucinous carcinoma (IPMC). Results: Classification according to histological subtype revealed that 26 specimens were of the gastric subtype (1 IPMC case), 8 were pancreatobiliary (6 IPMC cases), 6 were intestinal (3 IPMC cases), and 2 were oncocytic (all cases were IPMC). The frequency of IPMN subtypes in this study seemed to agree with those in previous reports. We analyzed Feulgen staining sections for nuclear morphological analysis using computer-assisted image analysis. Nuclear area and perimeter were significantly larger in IPMC than in IPMA. Finally, we examined the positive ratios of Lamin A and Emerin in immunohistochemical staining sections by image analysis. We found a negative correlation between the nuclear size and Lamin A-positive ratio, which was significantly lower in IPMC than that in IPMA. However, no significant correlation was observed between nuclear size and Emerin expression was observed, and no differences were found in the Emerin-positive ratio between IPMA and IPMC. Conclusion: Our results suggest that a decreased Lamin A positive ratio induces nuclear enlargement in adenomas, which thereby induce promotion to carcinomas. Furthermore, Lamin A expression can be a reliable biomarker for distinguishing between IPMC and IPMA.

The molecular, immune features, and risk score construction of intraductal papillary mucinous neoplasm patients.

Intraductal papillary mucinous neoplasm (IPMN) is a common pancreatic precancerous lesion, with increasing incidence in recent years. However, the mechanisms of IPMN progression into invasive cancer remain unclear. The mRNA expression data of IPMN/PAAD patients were extracted from the TCGA and GEO databases. First, based on GSE19650, we analyzed the molecular alterations, tumor stemness, immune landscape, and transcriptional regulation of IPMN progression. The results indicated that gene expression changed dramatically, specifically at the intraductal papillary-mucinous adenoma (IPMA) stage. Gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Kyoto Encyclopedia of Genes and Genomes (GSEA) pathway analyses showed that glycoprotein-related, cell cycle, and P53 pathways displayed the most significant changes during progression. With IPMN progression, tumor stemness increased continuously, and KRAS, ERBB3, RUNX1, and ELF3 are essential driver genes affecting tumor stemness. Motif analysis suggested that KLF4 may be a specific transcription factor that regulates gene expression in the IPMA stage, while MYB and MYBL1 control gene expression in the IPMC and invasive stages, respectively. Then, GSE19650 and GSE71729 transcriptome data were combined to perform the least absolute shrinkage and selection operator (LASSO) method and Cox regression analysis to develop an 11-gene prediction model (KCNK1, FHL2, LAMC2, CDCA7, GPX3, C7, VIP, HBA1, BTG2, MT1E, and LYVE1) to predict the prognosis of pancreatic cancer patients. The reliability of the model was validated in the GSE71729 and TCGA databases. Finally, 11 additional IPMN patients treated in our hospital were included, and the immune microenvironment changes during IPMN progression were analyzed by immunohistochemistry (IHC). IHC results suggest that Myeloid-derived suppressor cells (MDSCs) and macrophages may be key in the formation of immunosuppressive microenvironment of IPMN progression. Our study deepens our understanding of IPMN progression, especially the changes in the immune microenvironment. The findings of this work may contribute to the development of new therapeutic strategies for IPMN.

Micro-RNA Analysis of Pancreatic Cyst Fluid for Diagnosing Malignant Transformation of Intraductal Papillary Mucinous Neoplasm by Comparing Intraductal Papillary Mucinous Adenoma and Carcinoma.

Although intraductal papillary mucinous neoplasm (IPMN) is thought to be a precursor lesion of pancreatic cancer, diagnosing malignant transformation of IPMN using non-invasive diagnostic methods is difficult and complicated. Micro-RNAs (miRNAs) are currently recognized as biomarkers and molecular targets of various diseases, including malignancy. In this study, we investigated a potential diagnostic approach using miRNA in pancreatic cyst fluid as a marker for evaluating malignant alternation of IPMN. Cystic fluid was sampled mainly during surgical resection. The collected samples were evaluated by performing comprehensive analysis of miRNA using a highly sensitive DNA chip. miRNA expression was compared between IPM adenoma (IPMA) and IPM carcinoma (IPMC) to evaluate the related biomarkers for malignant transformation of IPMN. miRNA analysis revealed that six miRNAs (miR-711, miR-3679-5p, miR-6126, miR-6780b-5p, miR-6798-5p, and miR-6879-5p) in IPMC were significantly enriched compared to those in IPMA. The difference was validated using quantitative real-time PCR. Cyst fluid miRNA analysis might be useful for diagnosing malignant alteration of IPMN. Further evaluations of diagnostic capability as well as functional analysis using the identified miRNAs are required with larger cohorts to confirm its efficacy.

Measurement of PODXL and SCGB1D2 for detecting intraductal papillary mucinous neoplasm

We determined whether PODXL and SCGB1D2 expressions in whole blood could be useful as diagnostic biomarkers to determine the presence of intraductal papillary mucinous neoplasm (IPMN), as compared to serum CA19-9. A discovery-stage clinical study was performed on 12 patients with IPMN, including 6 intraductal papillary mucinous adenoma (IPMA) patients and 6 intraductal papillary mucinous carcinoma (IPMC) patients who had undergone treatment at the Department of Surgery at Kochi Health Sciences Center and the Department of Gastroenterology and Hepatology at Kochi Medical School Hospital from April 2015 to January 2016;13 controls who did not have pancreatic disease were also enrolled. Serum PODXL and SCGB1D2 levels were measured using ELISA. We found that the area under the receiver-operating characteristic curve (AUC) for IPMN (IPMA+IPMC) diagnosis in IPMN patients and control individuals was 0.89 (95% CI:0.76-1) for PODXL, 0.50 (95% CI:0.25-0.74) for SCGB1D2, and 0.81 (95% CI:0.62-1) for CA19-9. Multivariable logistic regression analysis showed that PODXL was independently able to distinguish IPMN patients from controls. PODXL may be a novel, non-invasive diagnostic biomarker for the detection of IPMN. The AUC for distinguishing IPMC patients from IPMA patients was 0.78 (95% CI:0.47-1) for PODXL, 0.83 (95% CI:0.58-1) for SCGB1D2, and 0.58 (95% CI:0.22-0.95) for CA19-9. Although it was quantitatively demonstrated that the detection of PODXL and SCGB1D2 in the serum may provide a novel, non-invasive approach for distinguishing IPMC patients from IPMA patients, the present findings are preliminary until more elaborate studies are able to clarify whether PODXL and SCGB1D2 are useful as diagnostic markers for IPMC detection.

Protruded duodenal tumor arising from Santorini\u2019s duct of the pancreas: a rare case of intraductal papillary mucinous neoplasm mimicking a duodenal polypoid tumor

BackgroundWe experienced a rare case of intraductal papillary mucinous neoplasm arising from Santorini’s duct (SD) forming a tumor protruding into the duodenum .Case presentationA 71-year-old woman was incidentally diagnosed with a 3 cm type Isp polypoid tumor in the second portion of the duodenum at another hospital. Enhanced CT and endoscopic ultrasound revealed that the origin of this protruding tumor was arising from SD and that the tumor mimicked a pedunculated duodenal tumor. Our preoperative diagnosis was a malignant pancreatic tumor arising from SD with invasion into the duodenum. She underwent a subtotal stomach-preserving pancreaticoduodenectomy, and the resected specimen showed a 25 mm tumor protruding into the duodenum with a villous surface. The pathological findings revealed that the tumor was intraductal papillary mucinous adenoma (IPMA) arising from SD.ConclusionsTo the best of our knowledge, this is the first case of IPMA protruding into the duodenal lumen from SD, although most of the tumors arising from SD have been reported to be malignant.

Gastric volvulus with perforation 1 year after total pancreatectomy: a case report

BackgroundBecause of its rare indication and relatively simple reconstruction procedure (only choledochojejunostomy and gastrojejunostomy) compared to those for pancreatoduodenectomy, the technical tips and pitfalls of total pancreatectomy are rarely discussed. Herein, we discuss a rare case of gastric volvulus 1 year after total pancreatectomy and provide advice to prevent such cases.Case presentationA 66-year-old woman underwent total pancreatectomy with splenectomy for mixed-type intraductal papillary mucinous neoplasm of the pancreas. Choledochojejunostomy (retro-colic route) and gastrojejunostomy (ante-colic route, Billroth II method) were performed for reconstruction. The final diagnosis was mixed-type intraductal papillary mucinous adenoma of the pancreas without malignant neoplasm. She had no clinical symptoms, such as abdominal pain and fever, during postoperative follow-up. However, at 1 year postoperatively, she complained of abdominal pain. Contrast-enhanced abdominal computed tomography showed volvulus and perforation of the stomach. Emergent surgery was performed. The stomach fornix was located on the right side and was partly perforated. We resected the perforation site with a linear cutter® (New Type Linear Cutter, Ethicon, USA) and released the gastric volvulus. Moreover, we fixed the stomach to the left abdominal wall using non-absorbable thread. The cause of the perforation was clinically and pathologically unclear. Her serum albumin and cholinesterase levels temporarily decreased postoperatively, but gradually increased. A recurrence of volvulus-related symptoms has not been observed.ConclusionsAfter total pancreatectomy with splenectomy, although the stomach is connected with the jejunum, it is typically fixed only by the pedicle of the left gastric artery and vein. In the present case, this anatomical change may have been a cause of the gastric volvulus. Thus, it might be better to fix the remnant stomach in total pancreatectomy with splenectomy.

Novel targets identified by integrated cancer-stromal interactome analysis of pancreatic adenocarcinoma.

The pancreatic cancer microenvironment is crucial in cancer development, progression and drug resistance. Cancer-stromal interactions have been recognized as important targets for cancer therapy. However, identifying relevant and druggable cancer-stromal interactions is challenging due to the lack of quantitative methods to analyze the whole cancer-stromal interactome. Here we studied 14 resected pancreatic cancer specimens (8 pancreatic adenocarcinoma (PDAC) patients as a cancer group and 6 intraductal papillary-mucinous adenoma (IPMA) patients as a control). Shotgun proteomics of the stromal lesion dissected with laser captured microdissection (LCM) was performed, and identified 102 differentially expressed proteins in pancreatic cancer stroma. Next, we obtained gene expression data in human pancreatic cancer and normal pancreatic tissue from The Cancer Genome Atlas database (n = 169) and The Genotype-Tissue Expression database (n = 197), and identified 1435 genes, which were differentially expressed in pancreatic cancer cells. To identify relevant and druggable cancer-stromal-interaction targets, we applied these datasets to our in-house ligand-receptor database. Finally, we identified 9 key genes and 8 key cancer-stromal-interaction targets for PDAC patients. Furthermore, we examined FN1 and ITGA3 protein expression in pancreatic cancer tissues using tissue microarrays (TMAs) of 271 PDAC cases, and demonstrated that FN1-ITGA3 had unfavorable prognostic impact for PDAC patients.

Smoking Status and the Incidence of Pancreatic Cancer Concomitant With Intraductal Papillary Mucinous Neoplasm.

The effect of smoking status on the incidence of pancreatic ductal adenocarcinoma (PDAC) concomitant with intraductal papillary mucinous neoplasm (IPMN) has not been clarified. This study investigated the association of smoking status with PDAC concomitant with IPMN. The subjects were 124 consecutive patients undergoing resection of IPMNs (intraductal papillary mucinous adenoma (IPMA): N = 77, invasive IPMN: N = 31, and PDAC with IPMN: N = 16) between April 2008 and October 2015. The associations between smoking status (never/former/current smoker) or cumulative pack-years (0-19/20-39/≥40) and the incidence of PDAC concomitant with IPMN or invasive IPMN were evaluated. Current smoking, not former smoking, was associated with the incidence of PDAC concomitant with IPMN (PDAC with IPMN vs IPMN alone; P = 0.004, PDAC with IPMN vs IPMA; P = 0.004, PDAC with IPMN vs invasive IPMN; P = 0.04, respectively), but not that of invasive IPMN (invasive IPMN vs IPMA; P = 0.85). Cumulative pack-years were higher in patients who had PDAC concomitant with IPMN than in patients with invasive IPMN (P = 0.04). Cumulative pack-years were not associated with smoking status (current vs former). Current smoking, not former smoking, was associated with the incidence of PDAC concomitant with IPMN. Cessation of smoking may be recommended for patients with IPMN.

Surgical treatment of pancreatic cystic tumors.

We retrospectively reviewed medical records of 46 patients (31 women and 15 men) who had undergone surgery for pancreatic cystic tumors in our department. Pancreatic cystic tumors were located within the pancreatic head (21), body (11), tail (13), and whole pancreas (1). The following surgical procedures were performed: pancreatoduodenectomy (20), central pancreatectomy (9), distal pancreatectomy (3), distal pancreatectomy with splenectomy (3), distal extended pancreatectomy with splenectomy (2), total pancreatectomy (1), duodenum preserving pancreatic head resection (1), local tumor resection (4), and other procedures (2). Histopathological tumor types were as follows: serous cystadenoma (14), intraductal papillary mucinous adenoma (5), intraductal papillary mucinous carcinoma (5), solid pseudopapillary tumor (5), mucinous cystadenoma (5), mucinous cystadenoma with border malignancy (1), mucinous cystadenocarcinoma (2), adenocarcinoma (4), and other tumors (5). Early postoperative complications were observed in 14 (30.43%) patients. Reoperations were performed in 9 (19.56%) patients. The perioperative mortality rate was 6.52%. Serous cystadenoma was the most common pancreatic cystic tumor in the analyzed group. PCTs were most frequently located within the pancreatic head. Pancreatic resection was possible in most patients, and pancreatoduodenectomy was the most common pancreatic resection type.

Middle segment-preserving pancreatectomy for metachronous intraductal papillary mucinous neoplasm after pancreatoduodenectomy: a case report

Total pancreatectomy has occasionally been performed to treat patients with multiple lesions (such as intraductal papillary mucinous neoplasm (IPMN)) or patients who have undergone repeated pancreatic resection. However, deficiencies of the exocrine and endocrine functions worsen patients’ quality of life. Recently, there have been several case reports citing middle segment-preserving pancreatectomy (MSPP) as a safe procedure and beneficial with respect to preservation of the exocrine and endocrine functions. We herein report the case of a patient who underwent MSPP for repeat pancreatectomy for IPMN and in whom a favorable outcome was achieved. The patient, a 70-year-old man, was diagnosed with branch duct-type IPMN (BD-IPMN) with worrisome features in the pancreatic head and a single cyst in the pancreatic tail, during a preoperative examination of early gastric cancer. Pancreatoduodenectomy was performed for BD-IPMN in the pancreatic head and gastric cancer. A histopathological examination showed an intraductal papillary mucinous adenoma (IPMA) with mild-moderate atypia. During the follow-up, the size of the cystic lesion in the pancreatic tail and the diameter of the main pancreatic duct were gradually increasing. Therefore, at 2 years and 6 months after surgery, distal pancreatectomy with preservation of the spleen (namely MSPP) was performed. The pancreatic resection margin was histologically negative. The length and volume of the remnant pancreas were approximately 6 cm and 10 ml, respectively. A histopathological examination showed an IPMA. The patient had no diarrhea or weight loss without digestive enzymes and maintained favorable glucose tolerance without oral hypoglycemic agents or insulin. He has showed no evidence of new lesions in the remnant pancreas at 3 years of follow-up after the last surgery.

Stathmin 1 promotes the proliferation and malignant transformation of pancreatic intraductal papillary mucinous neoplasms.

Pancreatic intraductal papillary mucinous neoplasms (IPMNs) are a type of pancreatic tumor, which have been identified following improvements in diagnostic imaging. However, the malignant transformation of IPMN has been difficult to diagnose clinically. To date, the mechanisms driving the progression of IPMN to cancer remain to be fully elucidated. The present study focused on Stathmin 1 (STMN1), a protein that is associated with the development of various types of cancer. The expression of STMN1 was examined immunohistochemically in tissues from cases of IPMN. The correlation between the STMN1 staining and clinical pathological factors was evaluated, and the expression of STMN1, p27 and S-phase kinase-associated protein 2 (SKP2) were compared. High expression levels of STMN1 were significantly correlated with regions of malignancy, and was associated with high expression of SKP2, low expression of nuclear p27 and a high Ki-67 index. High expression levels of STMN1 and SKP2 were significantly correlated with the transformation of IPMN to carcinoma. In addition, within the regions of carcinoma, the expression of STMN1 was weak in regions of adenoma and high in the cancerous regions. It was concluded that the high expression of STMN1 contributed to tumor proliferation and malignant transformation in the patients with IPMN. These results suggested that characterization of the expression of STMN1 may be a promising approach for predicting malignant transformation of pancreatic intraductal papillary mucinous adenoma.

The Neutrophil-to-Lymphocyte Ratio Predicts Malignant Potential in Intraductal Papillary Mucinous Neoplasms

BackgroundAccurately identifying malignant components in patients with pancreatic intraductal papillary mucinous neoplasms (IPMN) remains challenging. Preoperative neutrophil-to-lymphocyte ratio (NLR) is a marker of poor prognosis in patients with several types of malignancy. This study assessed whether NLR was predictive of intraductal papillary mucinous carcinoma (IPMC) in patients with IPMN. MethodThis study retrospectively assessed 76 patients who underwent curative resection for IPMN from 1995 to 2015. The correlation between the presence of malignant components and preoperative NLR was analyzed. ResultsPreoperative NLR in IPMC was significantly higher in patients with in IPMC (2.51 ± 0.84) than in patients with intraductal papillary mucinous adenoma (2.01 ± 0.71, P = 0.0079) and healthy volunteers (1.37 ± 0.33, P < 0.0001). NLR was significantly reduced after curative tumor resection. The main duct type (P = 0.0231) and NLR >2.074 (P = 0.0329) were independent predictors of IPMC in all patients. Combined criteria including international consensus guidelines, CA19-9 >37 IU/ml, and NLR >2.074 shows a high positive predictive value of 78 % and high specificity of 96 %. ConclusionsPreoperative NLR is a useful supportive marker to predict IPMC in patients with IPMN.

A large mural nodule in branch duct intraductal papillary mucinous adenoma of the pancreas: a case report.

Indications for resection of branch duct intraductal papillary mucinous neoplasms (IPMNs) remain controversial because of their low tendency to be malignant. Surgical resection should be recommended if any factors indicating malignancy are present. However, preoperative differentiation between benign and malignant tumors is very difficult, especially in cases of branch duct IPMNs. We herein report a case of branch duct intraductal papillary mucinous adenoma (IPMA) of the pancreas with a large mural nodule of 25 mm. A 74-year-old woman was admitted for examination and treatment for a cystic tumor in the head of the pancreas. Magnetic resonance cholangiopancreatography and computed tomography showed a cystic lesion, 50 mm in diameter, with an irregular mural nodule in the pancreatic head. Endoscopic ultrasonography demonstrated a multicystic tumor connected with the main pancreatic duct (MPD). The mural nodule had a diameter of 18 mm, and the MPD had a slight dilation of 6 mm. These findings suggested a high potential for malignancy. The patient underwent pancreaticoduodenectomy with lymph node dissection. The excised pancreas showed multiple cysts located in the branch pancreatic duct with a maximum diameter of 75 mm. The mural nodule had a maximum diameter of 25 mm. The tumor was diagnosed as an IPMA by pathological examination. After operation, the patient was discharged without any complications. Two years after resection, the patient remains in remission with no evidence of tumor recurrence.

Exploring the Functional Disorder and Corresponding Key Transcription Factors in Intraductal Papillary Mucinous Neoplasms Progression.

This study has analyzed the gene expression patterns of an IPMN microarray dataset including normal pancreatic ductal tissue (NT), intraductal papillary mucinous adenoma (IPMA), intraductal papillary mucinous carcinoma (IPMC), and invasive ductal carcinoma (IDC) samples. And eight clusters of differentially expressed genes (DEGs) with similar expression pattern were detected by k-means clustering. Then a survey map of functional disorder in IPMN progression was established by functional enrichment analysis of these clusters. In addition, transcription factors (TFs) enrichment analysis was used to detect the key TFs in each cluster of DEGs, and three TFs (FLI1, ERG, and ESR1) were found to significantly regulate DEGs in cluster 1, and expression of these three TFs was validated by qRT-PCR. All these results indicated that these three TFs might play key roles in the early stages of IPMN progression.

FDG-PET/CTにて高集積を示し，膵癌との鑑別に難渋した膵管内乳頭粘液性腺腫の1例

FDG-PET/CTにて高集積を示し，膵癌との鑑別に難渋した膵管内乳頭粘液性腺腫の1例

Clinical role of Notch signaling pathway in intraductal papillary mucinous neoplasm of the pancreas.

This study was performed to elucidate the expression of the Notch signaling pathway and its correlations to clinicopathological factors of intraductal papillary mucinous neoplasms (IPMNs). It is incontrovertible that regulatory T cells (Tregs) play an important role in tumor immunity. However, the whole mechanism of control of peripheral Tregs remains unclear. It is also known that the Notch signaling pathway is involved in Treg suppressor function. Moreover, IPMNs have a high malignant potential. Peripheral blood samples and resected specimens from 18 patients with IPMN were evaluated. All patients were pathologically diagnosed with IPMN. Resected specimens were immunohistochemically evaluated (anti-Notch1, anti-Notch2, and anti-Notch2-intracellular domain antibody staining) and compared in terms of clinicopathological factors. Peripheral Treg populations were analyzed with an automated flow cytometer. Disease-free survival was significantly worse in the Notch1 high-expression group (P = 0.023). Notch2 family expressions were higher in intraductal papillary mucinous carcinoma (IPMC) than in intraductal papillary mucinous adenoma (IPMA) (Notch2, P = 0.012; Notch2-intracellular domain, P = 0.036). Jagged1 expression was significantly higher in IPMC than in IPMA (P < 0.05) and was significantly related to recurrence. The Treg population in peripheral blood was higher in patients with IPMC than in those with IPMA (P < 0.01). Notch signaling, especially Jagged1 expression, reflects IPMN aggressiveness. Our data may suggest that the Notch signaling pathway is a key pathway that determines IPMN pathological aggressiveness and reflects the peripheral Treg population.

Subcellular localization of KL-6 mucin in intraductal papillary mucinous neoplasm of the pancreas.

This study aimed to clarify the expression profile of KL-6 mucin in intraductal papillary mucinous neoplasm (IPMN) and its relation to tumor malignancy. Expression of KL-6 mucin in 38 IPMNs (intraductal papillary mucinous adenoma (IPMA), 24 cases; minimally invasive intraductal papillary mucinous carcinoma (MI-IPMC), 8 cases; invasive carcinoma originating from IPMC (IC-IPMC), 6 cases) and 66 pancreatic ductal adenocarcinomas (PDACs) was evaluated immunohistochemically. IC-IPMCs and MI-IPMCs had positive staining of KL-6 mucin whereas 58% of IPMAs tested negative. Subcellular localization of KL-6 mucin varied among IPMNs whereas all of the PDAC had positive expression in the circumferential membrane and cytoplasm of cancer cells. IC-IPMCs and MI-IPMCs had a higher frequency of circumferential membrane and cytoplasmic localization of KL-6 mucin than did IPMAs. These results suggest that localization of KL-6 mucin could be used to predict the malignancy of IPMN.

Abstract 2511: Comprehensive metabolic profiling of hepatocellular carcinoma and pancreatic tumors by capillary electrophoresis-mass spectrometry.

Abstract (Background) Most cancer types have been widely known to generate energy primarily by glycolysis rather than oxidative phosphorylation even under normoxia (Warburg effect). However, inadequate blood supply resulting from defective angiogenesis is often observed in different kinds of cancer tissues, and their microenvironment is considered nutritionally unfavorable. How these cancer cells generate ATP is therefore still unclear. We previously reported enhanced glycolysis and significant accumulation of all amino acids except glutamine in both colon and stomach cancer tissues (Hirayama A, et al Cancer Res 2009). (Methods) Here, we investigated the metabolic microenvironment of hepatocelluar carcinoma (HCC)(n=28, HBV-positive (B) 7, HCV-positive (C) 6, NonBnonC (NBNC) 15), and pancreatic tumors (n=40, Invasive ductal adenocarcinoma (PDAC) 21, Intraductal papillary mucinous adenoma (IPMA) 5, Intraductal papillary mucinous carcinoma (IPMC) 14), using capillary electrophoresis-mass spectrometry (CE-MS). (Results) The amount of glucose were more than ten times higher in liver tissues, which indicates that liver tissue exist in nutritionally favorable microenvironment even in tumor tissue compared with pancreas tissue. Significant lactate accumulation was found in all cancer tissues (HCC, IPMC, and PDAC), which imply enhanced glycolysis. However, significant organ-specific differences were found in the levels of amino acids. Organ and etiology-specific difference were found in intermediates of TCA cycle. For example, citrate was increased in B-HCC, malate was decreased in NBNC-HCC, fumarate was decreased in B-HCC, NBNC-HCC, and PDAC, citrate was decreased in IPMC, iso-citrate was decreased in PDAC, compared to normal tissue, significantly. The concentration of most amino acids were not changed between normal and tumor tissues in HCC and pancreatic tumors, which suggests that these type of cancers do not depend on autophagy for their amino acid source. (Conclusions)Overall, these results provide metabolic phenotypes of different cancer tissues that reflect the tumor microenvironment. Citation Format: Motohisa Tada, Akiyoshi Hirayama, Fumihiko Kanai, Hideyuki Yoshitomi, Masayuki Ohtsuka, Masaru Miyazaki, Tomoyoshi Soga, Osamu Yokosuka. Comprehensive metabolic profiling of hepatocellular carcinoma and pancreatic tumors by capillary electrophoresis-mass spectrometry. [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 2511. doi:10.1158/1538-7445.AM2013-2511

Evaluation of SOX9 Expression in Pancreatic Ductal Adenocarcinoma and Intraductal Papillary Mucinous Neoplasm

Sex-determining region Y (SRY) box 9 (SOX9) is an important transcription factor required for development and has been implicated in several types of cancer. Sex-determining region Y box 9 has never been linked to pancreatic ductal adenocarcinoma (PDAC) and intraductal papillary mucinous neoplasm (IPMN) of the pancreas. The aim of this study was to investigate the relationship between SOX9 and PDAC and that between SOX9 and IPMN. Surgical specimens were obtained from 55 patients with PDAC and 68 patients with IPMN and were investigated using SOX9 immunohistochemical analysis. The rate of SOX9 positive cells to total pancreatic duct epithelial cells in a normal pancreas was 82.7%. On the other hand, the SOX9 positive rate in PDAC was 0.8%. There was a significant difference between the normal pancreas and PDAC (P = 0.0002). In IPMN, the SOX9 positive rate gradually decreased according to tumor progression, with the following rates observed: intraductal papillary mucinous adenoma (66.3%); noninvasive intraductal papillary mucinous carcinoma (46.3%); minimally invasive intraductal papillary mucinous carcinoma (30.5%); and invasive carcinoma originating in intraductal papillary mucinous carcinoma (2.3%). There were significant differences between each group (P < 0.05). Our data suggested that SOX9 might contribute to carcinogenesis in PDAC and IPMN.