Ribonucleotide reductase is an effective target to overcome gemcitabine resistance in gemcitabine-resistant pancreatic cancer cells with dual resistant factors.

Gemcitabine is widely used for pancreatic, lung, and bladder cancer. However, drug resistance against gemcitabine is a large obstacle to effective chemotherapy. Nucleoside transporters, nucleoside and nucleotide metabolic enzymes, and efflux transporters have been reported to be involved in gemcitabine resistance. Although most of the resistant factors are supposed to be related to each other, it is unclear how one factor can affect the other one. In this study, we established gemcitabine-resistant pancreatic cancer cell lines. Gemcitabine resistance in these cells is caused by two major processes: a decrease in gemcitabine uptake and overexpression of ribonucleotide reductase large subunit (RRM1). Knockdown of RRM1, but not the overexpression of concentrative nucleoside transporter 1 (CNT1), could completely overcome the gemcitabine resistance. RRM1 knockdown in gemcitabine-resistant cells could increase the intracellular accumulation of gemcitabine by increasing the nucleoside transporter expression. Furthermore, a synergistic effect was observed between hydroxyurea, a ribonucleotide reductase (RR) inhibitor, and gemcitabine on the gemcitabine-resistant cells. Here we indicate that RR is one of the most promising targets to overcome gemcitabine resistance in gemcitabine-resistant cells with dual resistant factors.

Clinicopathological features, postoperative survival and prognostic variables for cancer-related survival in patients with mucinous colorectal carcinoma.

PURPOSE: To investigate the clinicopathological features and postoperative survival of patients with mucinous colorectal carcinoma (MC) and to identify the factors related to long-term survival. METHODS: Twenty-three patients who had undergone resection for MC at Miyazaki University Hospital from 1991 to 2006 were followed up for at least 5 years or until death. The effects of the clinicopathological variables on the 5-year cancer-specific survival were assessed by the univariate analyses. These patients' clinicopathological data were compared with those of 403 non-mucinous carcinoma (NMC) patients (102 well-differentiated adenocarcinomas, 301 moderately differentiated adenocarcinomas). RESULTS: The 5-year cancer-specific survival rate was significantly worse in MC (56.2 %) than in NMC (73.8 %; p = 0.008) cases. Univariate analyses showed the T factor, lymph node metastases, liver metastases, metastases to the distant peritoneum, remote metastases and curative resection to be significant factors predicting the survival. However, there were no significant differences in the postoperative survival in patients with stage II-IV disease. The rates of metastases to the distant peritoneum, M1, T4, a tumor size ≥5 cm and non-curative resection were higher in MC than in NMC patients. CONCLUSIONS: Patients with MC had advanced stage cancer, especially with metastases to the distant peritoneum, more frequently than did the patients with NMC. To improve the survival of these patients, it is therefore important to detect MC at an early stage and to perform curative resection.

Aberrant expression of monocarboxylate transporter 4 in tumour cells predicts an unfavourable outcome in patients with hepatocellular carcinoma.

BACKGROUND & AIMS: The tumour cell microenvironment, which includes local oxygen saturation, pericellular pH and stromal cells, can modulate tumour progression. This study determined the prognostic impact of infiltrating tumour-associated macrophages and the expression of monocarboxylate transporter 4 (MCT4) and glypican 3 (GPC3) in hepatocellular carcinoma (HCC) clinical specimens. METHODS: A total of 225 cases of resected HCC were subjected to immunohistochemical analyses of CD68, CD204, MCT4 and GPC3. Immunoreactivities and other common clinicopathological parameters were subjected to univariate prognostic analyses for overall survival (OS, n = 225) and disease-free survival (DFS, n = 222). All variables with prognostic impact were further analysed in multivariate analysis. RESULTS: Increased intratumoural infiltration of CD204-positive or MCT4-positive macrophages suggested shorter OS (P = 0.015 or P = 0.001 respectively), but DFS was not altered. The GPC3 score (with an emphasis on circumferential immunoreactivity) was correlated with shorter OS and DFS. Aberrant expression of MCT4 in HCC cells was observed in a subset of HCC cases (21%, 47/225). In those cases, significantly poorer OS (P < 0.0001) and DFS (P = 0.0003) were observed, and there was a positive correlation with the intratumoural infiltration of CD204- or MCT4-positive macrophages and the GPC3 score. Multivariate analysis showed that aberrant MCT4 expression in HCC cells was an independent prognostic factor for shorter OS (P = 0.018) and DFS (P = 0.006) after resection of HCC. CONCLUSION: Aberrant expression of MCT4 in carcinoma cells serves as a novel, independent prognostic factor for HCC, indicating a poorer patient outcome.

Prospective randomized clinical trial of a change in gastric emptying and nutritional status after a pylorus-preserving pancreaticoduodenectomy: comparison between an antecolic and a vertical retrocolic duodenojejunostomy.

BACKGROUND: Although an antecolic duodenojejunostomy was reported to reduce post-operative delayed gastric emptying (DGE) compared with a retrocolic duodenojejunostomy after a pylorus-preserving pancreaticoduodenectomy (PPPD), the long-term effects of these procedures have rarely been studied. The aim of this prospective, randomized, clinical trial was to investigate the influence of the reconstruction route on post-operative gastric emptying and nutrition. METHODS: Reconstruction was performed in 116 patients with an antecolic duodenojejunostomy (A group, n = 58) or a vertical retrocolic duodenojejunostomy (VR group, n = 58). Post-operative complications, including DGE, gastric emptying variables assessed by (13) C-acetate breath test and nutrition, were compared between the two groups for 1 year post-operatively. RESULTS: The incidence of DGE was not significantly different between the procedures (A group: 12.1%; VR group: 20.7%, P = 0.316). At post-operative month 1, gastric emptying was prolonged in the VR versus the A group but not significantly so. At post-operative month 6, gastric emptying was accelerated significantly in the A versus the VR group. Post-operative weight recovery was significantly better in the VR versus the A group at post-operative month 12 (percentage of pre-operative weight, A group: 93.8 ± 1.2%; VR group: 98.5 ± 1.3%, P = 0.015). CONCLUSIONS: A vertical retrocolic duodenojejunostomy was an acceptable procedure for the lower incidence of DGE and may contribute to better weight gain affected by moderate gastric emptying.

[A case report of gastrointestinal stromal tumor of the small intestine presenting with liver abscesses caused by Streptococcus constellatus].

A 49-year-old woman visited a local hospital in October 2007 with complaint of fever and melena. Abdominal ultrasonography and abdominal computed tomography revealed an irregular mass in the lower abdomen, together with multiple masses in the liver. She was admitted because of anemia, and the high fever was determined to be an inflammatory response. Blood tests revealed elevated biliary enzyme levels. Percutaneous biopsy of the liver mass was performed, which revealed liver abscesses caused by Streptococcus constellatus. On abdominal angiography, the mass was suspected to be a tumor of the small intestine. In late November 2007, laparoscopy-assisted partial small bowel resection was performed, and pathological examination of the surgical specimen confirmed gastrointestinal stromal tumor (GIST) of the small bowel. Because reports of small intestinal GIST with liver abscesses caused by Streptococcus constellatus are rare, this case description could provide valuable information.

Usefulness of drain amylase, serum C-reactive protein levels and body temperature to predict postoperative pancreatic fistula after pancreaticoduodenectomy.

BACKGROUND: Postoperative pancreatic fistula (POPF) after pancreaticoduodenectomy (PD) is a worrisome and life-threatening complication. Recently, early drain removal has been recommended as a means of preventing POPF. The present study sought to determine how to distinguish clinical POPF from non-clinical POPF in the early postoperative period after PD to aid in early drain removal. METHODS: From March 2002 through December 2010, 176 patients underwent PD and were enrolled in this study to examine factors predictive of clinical POPF after PD. POPF was defined and classified according to the International Study Group of Pancreatic Surgery guideline, and grade B/C POPF was defined as clinical POPF. RESULTS: Grade A POPF occurred in 39 (22.2 %) patients, grade B in 19 (10.8 %) patients, and grade C in 11 (6.3 %) patients. Clinical POPF (grade B/C) occurred in 17.1 % of patients. Multivariate analysis revealed male gender and body mass index (BMI) ≥22.5 kg/m(2) to be the independent preoperative risk factors predictive of POPF. Receiver operating characteristic curves showed that the combination of drain amylase ≥750 IU/L, C-reactive protein (CRP) ≥20 mg/dL, and body temperature ≥37.5 °C on postoperative day 3 could effectively distinguish clinical POPF from non-clinical POPF. Sensitivity, specificity, and accuracy were 84.6, 98.2, and 95.7 %, respectively. CONCLUSIONS: Male gender and BMI ≥22.5 were the independent preoperative predictive risk factors for POPF. We assume that when amylase is <750 IU/L, serum CRP is <20 mg/dL, and body temperature is <37.5 °C the drain can safely be removed, even if POPF is indicated.

Antiproliferative effect of 1α,25-dihydroxyvitamin D3 involves upregulation of cyclin-dependent kinase inhibitor p21 in human pancreatic cancer cells.

BACKGROUND/AIMS: The aim of this study was to investigate the effect of 1α,25-dihydroxyvitamin D3 on proliferation of human pancreatic cancer cell lines and to identify related cell cycle regulatory proteins with antiproliferative effects. METHODOLOGY: Human pancreatic cancer cell lines SUIT-2 and its four sublines, and Panc-1, AsPC-1, and MiaPaCa-2 were treated with1α,25-dihydroxyvitamin D3. The number of cells was measured by the MTT method, and the cell cycle regulatory proteins were then analyzed by Western blotting. RESULTS: Eight human pancreatic cancer cell lines expressed vitamin D receptor (VDR) mRNA. 1α,25-dihydroxyvitamin D3 inhibited proliferation of SUIT-2 and its sublines. We found p21 to be upregulated after 24 hours in S2-028, the cell line in which proliferation was most inhibited by 1α,25-dihydroxyvitamin D3. CONCLUSIONS: 1α,25-dihydroxyvitamin D3 inhibited proliferation of pancreatic cancer cells and is involved in the upregulation of cyclin-dependent kinase inhibitor p21.

Thrombin stimulates integrin ß1-dependent adhesion of human pancreatic cancer cells to vitronectin through protease-activated receptor (PAR)-1.

BACKGROUND/AIMS: The aim of this study was to investigate the effect of thrombin and the thrombin receptor protease-activated receptor (PAR)-1 on adhesion of human pancreatic cancer cell lines to extracellular matrices (ECMs) and to identify related integrins with these effects. METHODOLOGY: Human pancreatic cancer cell lines SUIT-2 and its four sublines, and Panc- 1, AsPC-1 and MiaPaCa-2 were treated with thrombin, PAR-1 agonist TRAP-6, PAR-1 antagonist SCH79797, or anti-integrin ±vß3, ±vß5 and ß1 monoclonal antibodies. Cells were incubated for 45 minutes on micro titer plates that were pre-coated with ECMs (fibronectin, laminin, vitronectin, type IV collagen). The number of adherent cells was measured by the MTT method. RESULTS: Eight human pancreatic cancer cell lines expressed PAR-1. Thrombin significantly enhanced adhesion of SUIT-2 and its sublines and MiaPaCa-2 to vitronectin, especially in the SUIT-2 subline S2-007. We obtained similar results on S2-007 cells through treatment with TRAP-6. However, SCH79797 inhibited the effect of thrombin. Furthermore, anti-integrin ß1 antibody conspicuously inhibited 1U/mL thrombin-induced enhancement of adhesion to vitronectin. CONCLUSIONS: Thrombin significantly enhanced adhesion of pancreatic cancer cells to vitronectin through PAR- 1 depending on the presence of integrin ß1. Suppression of thrombin action by anti-integrin ß1 antibody will become a useful therapy against pancreatic cancer.

Comparative study of gastric emptying and nutritional status after pylorus-preserving vs. subtotal stomach-preserving pancreaticoduodenectomy.

BACKGROUND/AIMS: Delayed gastric emptying (DGE) is a specific, worrisome complication after pancreaticoduodenectomy (PPPD), whereas subtotal stomach-preserving pancreaticoduodenectomy (SSPPD) that excises the pylorus ring seems to be effective in reducing DGE. This study compared gastric emptying and nutritional status between PPPD and SSPPD over 1 year. METHODOLOGY: From June 2003 to December 2007, 41 patients (PPPD: 33, SSPPD: 8) were enrolled in this study to evaluate differences in gastric emptying and nutritional status at 1, 3, 6, 9 and 12 months after pancreaticoduodenectomy. Gastric emptying was evaluated by 13C-acetate breath test. Nutritional status (body weight, serum levels of total protein, albumin and total cholesterol) was similarly assessed. RESULTS: At 1 month, gastric emptying evaluated at T1/2 (half-emptying time) was significantly prolonged in the PPPD but not in the SSPPD compared to the preoperative level. Thereafter, T1/2 was decreased and showed function significantly better preserved at 3, 6 and 12 months after PPPD than after SSPPD. Body weight recovery was significantly better at 6 and 12 months after PPPD than after SSPPD. Other nutritional parameters were better preserved in the PPPD during 1-year follow-up. CONCLUSIONS: PPPD seems to be a more suitable surgical procedure than SSPPD in regard to gastric emptying and nutritional status.

Characteristics and surgical outcome of HCC patients with low platelet count.

BACKGROUND/AIMS: Hepatocellular carcinoma (HCC) patients often have low platelet count (LPC). The aim of this study was to determine unique features of HCC patients with LPC. METHODOLOGY: HCC patients who underwent surgery were divided into two groups: LPC group (platelet count ≤100,000/mm³, n=84) and control group (platelet count >100,000/mm³, n=240). Surgical outcomes, risk factors for postoperative complications and prognostic factors were retrospectively compared. RESULTS: HCC patients with LPC had poorer liver function, smaller tumors, less anatomical resection and more frequent postoperative liver failure than control group patients. Postoperative survival was not different between the two groups. Tumor invasion to the main branch or trunk of portal vein (Vp3, 4) was the only risk factor for postoperative substantial complications in the LPC group. Postoperative survival was worse in patients with tumor diameter ≥4 cm or multiple tumors and in those who underwent preoperative transcatheter arterial chemoembolization (TACE) in the LPC group by multivariate analysis. Among them, preoperative TACE were not prognostic factors in the control group. CONCLUSIONS: In HCC patients with LPC, Vp3, 4 patients should be carefully monitored after surgery and preoperative TACE is not recommended for long-term postoperative survival.

Role of hilar resection in the treatment of hilar cholangiocarcinoma.

BACKGROUND/AIMS: The aim of this study was to clarify the role of bile duct resection without hepatectomy (hilar resection) in hilar cholangiocarcinoma. METHODOLOGY: We retrospectively compared surgical results for hilar cholangiocarcinoma between 8 patients treated with hilar resection and 21 patients treated with hepatectomy. RESULTS: All hilar resections were performed for Bismuth type I or II tumors with T2 or less lesions, whereas hepatectomy was done for type III or IV tumors excluding one type II tumor. R0 resection was equally achieved in both groups (62.5% in hilar resection group and 76.2% in hepatectomy group, p=0.469) and overall 5-year survival rates were comparable (21.9% vs. 23.6%, p=0.874). With respect to gross tumor appearance, R0 resection was achieved in all patients with papillary tumor in both groups with the excellent 5-year survivals (100% vs. 100%). In patients with nodular and flat tumors, R0 resection was achieved less frequently in the hilar resection vs. hepatectomy group (50% vs. 77.8%) mainly due to failure to clear the proximal ductal margin, resulting in poorer 5-year survival (0% vs. 18.7%). CONCLUSIONS: Hilar resection may be indicated for papillary T1 or 2 tumors in Bismuth type I or II cholangiocarcinoma.

Factors influencing quality of life after abdominal surgery for Crohn's disease.

BACKGROUND/AIMS: Although fecal diversion is reported to improve the quality of life (QOL) of the patients with active perianal disease, the effect of the concomitant abdominal surgery was not well studied. The aim of this study was to investigate factors that impair postoperative QOL of patients with Crohn's disease. METHODOLOGY: A SF-36v2 questionnaire was mailed to patients who underwent abdominal operation between January 2001 and February 2007. Patients were also asked about the medical therapy they were receiving. RESULTS: Data from 50 patients were analyzed. Univariate analyses revealed that patients with active perianal disease had lower scores for role physical, bodily pain and social functioning than did patients without it. Social functioning and role emotional scores were lower in patients older than 40 years than in those younger. The physical component summary score was significantly affected in patients with active perianal disease. Fecal diversion had no effect on QOL after abdominal surgery for Crohn's disease. Multivariate analysis showed that the physical component summary score was significantly lower in patients with active perianal disease than in patients without it. CONCLUSIONS: Active perianal disease is an important factor that impairs QOL in patients who have undergone surgery for intestinal Crohn's disease.

Side-to-side isoperistaltic strictureplasty for chronic ischemic enteritis: report of a case.

Chronic ischemic enteritis can cause intestinal strictures, but extensive resection of the small intestine may leave patients with short bowel syndrome. Thus, the importance of preserving diseased small bowel is now recognized. We report a case of successful side-to-side isoperistaltic strictureplasty (SSIS), performed to prevent short bowel syndrome, in a patient with ischemic enteritis caused by strangulated intestinal obstruction. SSIS is useful for preserving the intestinal absorptive function in patients with a long narrowed bowel loop caused by ischemic change. To our knowledge, this is the first report of the successful treatment of a long stricture resulting from ischemic enteritis, achieved by performing SSIS.

Role of the standardized uptake value of 18-fluorodeoxyglucose positron emission tomography-computed tomography in detecting the primary tumor and lymph node metastasis in colorectal cancers.

PURPOSE: To assess the role of positron emission tomography-computed tomography (PET-CT) and multidetector-row CT (MD-CT) in detecting the primary lesion and lymph node metastasis in patients with colorectal cancers. METHODS: A collective total of 80 lesions resected from 77 patients were examined pathologically. We analyzed the significance of the standardized uptake value (SUV) and its relationship with the clinicopathologic findings of primary lesions and lymph node metastasis. The detectability of primary lesions and lymph node metastases on PET-CT images was compared with that on MD-CT images. RESULTS: The detectability of primary lesions was better on PET-CT images than on MD-CT images (p = 0.0023). We observed no significant differences in the SUV with respect to staging, tumor grade, lymphatic or vessel invasion, and macroscopic type; however, primary tumor size analysis revealed that tumors larger than 3 cm had a higher SUV than those smaller than 3 cm. The sensitivity of PET-CT for detecting lymph node metastasis was lower than that of MD-CT, but the specificity of PET-CT was higher than that of MD-CT. CONCLUSIONS: The SUV of primary cancers tends to increase in proportion to tumor size. Although the value of PET-CT in detecting lymph node metastasis is limited, PET -positive lymph nodes can be considered metastatic.

Nuclear expression of thioredoxin-1 in the invasion front is associated with outcome in patients with gallbladder carcinoma.

BACKGROUND: Multifunctional redox protein human thioredoxin (TRX-1) is reduced by thioredoxin reductase (TRX-R). The aim of the present study was to examine the distribution of TRX-1 and TRX-R expressions in gallbladder carcinoma (GBC) to clarify their usefulness as prognostic factors after surgical resection. METHODS: Immunohistochemical staining for TRX-1 and TRX-R was performed in GBC tissue from 38 patients who underwent surgical resection, and TRX-1/TRX-R localization in relation to outcome was examined. RESULTS: TRX-1 protein levels were significantly higher in GBC samples than in cholecystolithiasis samples (P = 0.0174). TRX-1 expression was observed in 100% (38/38) of tumour samples and in the nucleus in 76% (29/38), with nuclear expression in the invasion front observed in 45% (13/29). TRX-R expression was only detected in the cytoplasm of cancer cells and in the invasion front in 28 samples. In all of the samples, the depth of tumour invasion, lymph node metastasis, surgical margin, curability and nuclear expression of TRX-1 in the invasion front were significant prognostic factors by univariate analysis. In 27 selected patients who underwent curative resection, both TRX-1 nuclear expression and TRX-R cytoplasmic expression in the invasion front was a significantly prognostic factor. CONCLUSION: TRX-1 nuclear expression in the GBC invasion front is a significant prognostic marker. Patients with both TRX-1 nuclear expression and TRX-R cytoplasmic expression in the tumour invasion front should be observed carefully even if after curative resection.

[Docetaxel in combination with epirubicin as the first-line chemotherapy for advanced and recurrent breast cancer: a multicenter phase II study].

This study examined the efficacy and tolerability of docetaxel(DOC)in combination with epirubicin(EPI)as the first-line treatment for patients with advanced and recurrent breast cancer. A total of 56 female patients with metastatic breast cancer not previously treated for metastatic disease received DOC(60mg/m²)and EPI(60mg/m2)on day 1 every 3 weeks. The patient characteristics included a median age of 53 years. Advanced disease was present in 86% of patients, and recurrent disease was found in 14%; 3 or more metastatic sites had been diagnosed in 38% of patients, and 59% patients were ER+. The median number of courses administered was 6. The median dose intensity was 18. 7mg/m²week for DOC and EPI, and the relative dose intensities were 93. 5%and 93. 3%, respectively. The clinical responses included a complete response in 5%, a partial response in 54%, and stable disease in 33% of patients, with a disease control rate of 92%. The progression-free survival was 78. 3%, and the overall survival was 91. 9% at 1 year. Grade 3/4 toxicities included neutropenia in 82%, leukopenia in 71%, febrile neutropenia in 16%, anorexia in 9%, and anemia in 7%of the patients. Neither congestive heart failure nor toxic death occurred. The D and E combination with doses of 60mg/m2 is an active and generally well-tolerated regimen that can be used as first-line chemotherapy for patients with metastatic breast cancer.

Prognostic significance of circumferential cell surface immunoreactivity of glypican-3 in hepatocellular carcinoma.

BACKGROUND: GC33 is a recently developed monoclonal antibody against human glypican-3 (GPC3), which is significantly upregulated in hepatocellular carcinoma (HCC). GC33 recognizes a GPC3 ectodomain and shows significant antitumour activity in vivo. Thus, humanized GC33 antibody may be a promising tool for treating HCC having cell surface GPC3 expression. AIMS: This study aims to determine the specificity, subcellular localization and prognostic impact of GPC3 immunoreactivity detected by GC33 in HCC clinical specimens. METHODS: Immunohistochemical analysis was performed for 194 cases of resected HCC and prognostic analysis was performed for 185 eligible cases. Two antigen retrieval methods (autoclave and protease pretreatments) were used for immunohistochemistry and compared. The immunoscore system reflecting circumferential membranous GPC3 immunoreactivity was developed using either the autoclave or protease methods. The GPC3 mRNA level was analysed by quantitative real-time reverse transcription-polymerase chain reaction. RESULTS: GC33 immunostaining after autoclave is a sensitive method and revealed the GPC3 expression (≥20% of tumour cells) in the majority (77%) of HCC samples tested. Alternatively, protease pretreatment showed lower sensitivity, but was superior for evaluating the intensity and subcellular localization of GPC3. Correlation between immunoscores and the GPC3 mRNA level was also confirmed. Subsequent clinicopathological analysis revealed worse prognoses in HCC patients with circumferential membranous GPC3 immunoreactivity. For HCC patients with hepatitis C virus (HCV) infection in particular, the high membranous GPC3 immunoreactivity was an independent prognostic factor for disease-free survival. CONCLUSIONS: Circumferential membranous GPC3 immunoreactivity in HCC indicates poorer prognosis particularly in patients with HCV infection.

Results of seton drainage and infliximab infusion for complex anal Crohn's disease.

BACKGROUND/AIMS: To investigate the efficacy of infliximab for complicated perianal Crohn's disease with special reference to maintenance therapy. METHODOLOGY: Between June 2002 and April 2009, 20 patients (15 men and 5 women, aged 31.4±2.9 years old (mean ± standard error)) with complicated fistulizing anal Crohn's disease underwent seton placement. For the induction therapy, intravenous infusion of infliximab was given 3 times after surgical treatment. Thereafter, infliximab was given every 8 weeks as maintenance therapy. Patients were followed-up for 31.8±4.2 months after the first infliximab infusion. The number of the infliximab treatments given was 13.6±2.5. RESULTS: After induction therapy, complete response (CR) was observed in 8 patients (40%), partial response (PR) in 9 and progress disease (PD) in 3. With (n=17) or without (n=3) maintenance therapy following the induction therapy, CR was observed in 15 of 20 patients (75%). Of the 17 patients who received maintenance therapy, CR was of observed in 13 patients, of whom 7 patients showed PR or PD before maintenance therapy. CONCLUSIONS: Seton drainage and infliximab therapy is effective in the patients with fistulizing perianal Crohn's disease. Maintenance infliximab therapy might be effective in patients with perianal Crohn's disease.

Synchronous solid pseudopapillary neoplasm and intraductal papillary mucinous neoplasm of the pancreas: report of a case.

Solid pseudopapillary neoplasm (SPN) of the pancreas, most commonly found in young female subjects, is a rare neoplasm with low potential for malignancy. We report an unusual case of a 66-year-old male patient who had a simultaneous malignant SPN and an intraductal papillary mucinous adenoma (IPMA) of the pancreas. The patient was admitted to our department for the evaluation of the main solid tumor with calcification and small multilocular cystic lesions apart from the main tumor in the pancreatic head. We performed pylorus-preserving pancreaticoduodenectomy to treat the calcified tumor and multilocular cystic lesions. The diagnosis of malignant SPN was confirmed on the basis of histological invasion to the adjacent structures. The separate cystic lesions were diagnosed as a branch-type IPMA. The synchronous occurrence of IPMA and SPN in the present case did not demonstrate that there were tumors maintained through the common abnormal Wnt signaling pathway by immunohistochemical study. To our knowledge, this is the first known case of synchronous SPN and IPMA of the pancreas.

Dickkopf-1 is overexpressed in human pancreatic ductal adenocarcinoma cells and is involved in invasive growth.

The protein products of the Dickkopf (DKK) genes are antagonists of Wnt glycoproteins, which participate in tumor development and progression by binding to frizzled receptors. In this study, the expression of DKK-1 was analyzed in a panel of 43 human cultured carcinoma cell lines. DKK-1 expression was consistently and significantly upregulated in pancreatic carcinoma cell lines. Low level of DKK-3 expression was also seen. In contrast, the expression of DKK-2 and -4 was not detectable in most pancreatic carcinoma cell lines. The overexpression of DKK-1 was confirmed in surgically resected human pancreatic cancer tissues, in which the mRNA level was evaluated in paired samples from cancerous and noncancerous pancreatic tissues. In ductal adenocarcinomas (23 cases), DKK-1 mRNA levels were significantly upregulated compared to corresponding noncancerous tissues in a statistically significant level. To test the biological role of DKK-1 in pancreatic carcinoma cells, we performed a knockdown of DKK-1 in SUIT-2 human pancreatic adenocarcinoma cell line and S2-CP8, its metastatic subline, using a retroviral short hairpin RNA expression vector. DKK-1 knockdown resulted in reduced migratory activity of SUIT-2 in vitro. The in vitro growth rate and Matrigel invasion were also suppressed by DKK-1 knockdown in S2-CP8 cells. Collectively, the evidence suggests that, despite of its presumed antagonistic role in Wnt signaling, DKK-1 may have a role in the aggressiveness of pancreatic carcinoma cells and could, therefore, serve as a novel biomarker of pancreatic cancer.