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Purpose: As the number of long-term survivors of pancreatic cancer is expected to increase thanks to recent advances in multidisciplinary treatment and earlier diagnoses of pancreatic cancer, we are likely to encounter more cases of postoperative pulmonary nodules. We analyzed the clinical course and prognosis of resection of pulmonary metastases from pancreatic cancer to clarify the prognostic implication of pulmonary metastasectomy for pancreatic cancer., Method: We retrospectively analyzed 35 patients who underwent resection of lung metastases after pancreatic cancer surgery. Short- and long-term outcomes and factors associated with the prognosis were analyzed., Results: The observation period was 20 (range, 1-101) months, with 3- and 5-year survival rates of 88.3% and 64.5% from pancreatectomy and 44.1% and 28.3% from lung resection, respectively. A univariate analysis revealed that a period from pancreatic cancer resection to pulmonary nodule shadow detection of < 15 months was associated with a significantly lower overall survival from pancreatic resection than a longer period. Conversely, histological type, stage, size of lung metastases, and resection technique were not associated with the overall survival., Conclusion: A long-term prognosis may be expected in some cases with a disease-free interval of ≥ 15 months. Our findings suggest that the disease-free interval may influence the prognosis., (© 2023. The Author(s).)

Background: The systemic administration of gemcitabine (GEM) has been accepted as a standard treatment for patients with advanced pancreatic cancer. The major mediator of cellular uptake of GEM is the human equilibrative nucleoside transporter 1 (hENT1) whose expression is up-regulated by thymidylate synthase inhibitors, such as 5-fluorouracil (5-FU). S-1 is a novel oral derivative of the 5-FU prodrug tegafur combined with two modulators. Recent clinical trials have reported the promising effect of S-1 in pancreatic cancer. The purpose of this study was to evaluate the relationship between different schedules and the effects of GEM/S-1 combination therapy on pancreatic cancer xenograft models., Materials and Methods: Human pancreatic tumor xenografts were prepared by subcutaneous implantation of MiaPaCa-2 into nude mice. Expression of hENT1 was determined by quantitative RT-PCR. GEM cellular uptake was determined using [3H] GEM., Results: Significant increases in hENT1 expression and GEM cellular uptake were observed after S-1 treatment. Six different treatment schedules (no treatment, single agent of GEM or S-1, combination treatment with GEM either before, simultaneously or following administration of S-1) were compared. Significant tumor growth inhibition was observed in the mice treated with S-1 followed by GEM compared to either untreated mice or the mice treated with the other schedules., Conclusion: Based on the effects of S-1 on the uptake of GEM, S-1 should be used before GEM treatment. The GEM/S-1 combination therapy in patients with pancreatic cancer may be promising and should be tested in clinical trials.

Background: The purpose of this study was to find a novel biomarker to predict 5-fluorouracil (5-FU) or gemcitabine (2',2'-difluoro-deoxycytidine) sensitivity in pancreatic cancer., Materials and Methods: The relationship between 5-FU and gemcitabine sensitivity and the mRNA levels of human equilibrative nucleoside transporter 1 (hENT1), thymidylate synthase (TS) and dihydropyrimidine dehydrogenase (DPD) was investigated using seven types of human pancreatic carcinoma cell line (AsPC1, BxPC3, MiaPaCa-2, PSN1, Panc1, PCI6, and KMP-4). Quantitative mRNA expression was measured by LightCycler. A [3H] gemcitabine cellular uptake assay was performed to examine the inhibition of hENT1 by nitrobenzylmercaptoprine ribonucleoside (NBMPR)., Results: The expression levels of hENT1 mRNA significantly correlated with the IC50 value of 5-FU in all seven lines and also correlated with gemcitabine resistance in six lines (except AsPC1). No significant association was observed between TS or DPD mRNA levels and 5-FU sensitivity. In the PSN1 cells, [3H] gemcitabine uptake via hENT1 was significantly inhibited by NBMPR, and 5-FU sensitivity was significantly increased when the cells were pretreated with NBMPR., Conclusion: Our results suggest that hENT1 plays an important role in 5-FU resistance and that hENT1 mRNA levels might be a useful marker to predict 5-FU sensitivity in pancreatic cancer.

Pancreatic cancer is the most lethal of all solid tumors partially because of its chemoresistance. Although gemcitabine is widely used as a first selected agent for the treatment of this disease despite low response rate, molecular mechanisms of gemcitabine resistance in pancreatic cancer still remain obscure. The aim of this study is to elucidate the mechanisms of gemcitabine resistance. The 81-fold gemcitabine resistant variant MiaPaCa2-RG was selected from pancreatic cancer cell line MiaPaCa2. By microarray analysis between MiaPaCa2 and MiaPaCa2-RG, 43 genes (0.04%) were altered expression of more than 2-fold. The most upregulated gene in MiaPaCa2-RG was ribonucleotide reductase M1 subunit (RRM1) with 4.5-fold up-regulation. Transfection with RRM1-specific RNAi suppressed more than 90% of RRM1 mRNA and protein expression. After RRM1-specific RNAi transfection, gemcitabine chemoresistance of MiaPaCa2-RG was reduced to the same level of MiaPaCa2. The 18 recurrent pancreatic cancer patients treated by gemcitabine were divided into 2 groups by RRM1 levels. There was a significant association between gemcitabine response and RRM1 expression (p = 0.018). Patients with high RRM1 levels had poor survival after gemcitabine treatment than those with low RRM1 levels (p = 0.016). RRM1 should be a key molecule in gemcitabine resistance in human pancreatic cancer through both in vitro and clinical models. RRM1 may have the potential as predictor and modulator of gemcitabine treatment., ((c) 2006 Wiley-Liss, Inc.)

Objectives: Gemcitabine is taken up by cells mainly via human equilibrative nucleoside transporter 1 (hENT1). Pretreatment of cancer cell lines with 5-fluorouracil (5-FU) leads to an increase in the expression of hENT1 and augments the effect of single-agent gemcitabine treatment in vitro. The purpose of the present study was to evaluate the relationship between the schedules of gemcitabine/uracil-tegafur (UFT) combination therapy and their effects in pancreatic cancer in vivo., Methods: The expression level of hENT1 mRNA was examined using 6 types of human pancreatic cancer cell lines treated with 5-FU and MiaPaCa-2 xenograft tumors in BALB/c nu/nu mice treated with UFT. A [H] gemcitabine cellular uptake assay was performed using MiaPaCa-2 cells treated with 5-FU. We compared the effects of 6 different schedules of treatment using UFT and/or gemcitabine on MiaPaCa-2 xenograft tumors., Results: MiaPaCa-2 cell line was one of the lines that showed the highest rate of 5-FU-induced increase in the hENT1 mRNA level. Gemcitabine uptake was significantly increased when cells were treated with 5-FU. Treatment with UFT significantly increased the hENT1 mRNA expression in MiaPaCa-2 tumors. A significant growth inhibition of MiaPaCa-2 tumors was observed in the mice treated with UFT followed by gemcitabine as compared with either untreated mice or UFT alone-treated mice., Conclusions: Our results suggest that the schedule in which the gemcitabine is administered after UFT may be the optimal combination for gemcitabine/UFT treatment in pancreatic cancer.

Hypoxic conditions exist within pancreatic adenocarcinoma, yet pancreatic cancer cells survive and replicate within this environment. To understand the mechanisms involved in pancreatic cancer adaptation to hypoxia, we analyzed expression of a regulator of hypoxia-induced cell death, Bcl-2/adenovirus E1B 19 kDa interacting protein 3 (BNIP3). We found that BNIP3 was down-regulated in nine of nine pancreatic adenocarcinomas compared with normal pancreas despite the up-regulation of other hypoxia-inducible genes, including glucose transporter-1 and insulin-like growth factor-binding protein 3. Also, BNIP3 expression was undetectable even after hypoxia treatment in six of seven pancreatic cancer cell lines. The BNIP3 promoter, which was remarkably activated by hypoxia, is located within a CpG island. The methylation status of CpG dinucleotides within the BNIP3 promoter was analyzed after bisulfite treatment by sequencing and methylation-specific PCR. Hypermethylation of the BNIP3 promoter was observed in all BNIP3-negative pancreatic cancer cell lines and eight of 10 pancreatic adenocarcinoma samples. Treatment of BNIP3-negative pancreatic cancer cell lines with a DNA methylation inhibitor, 5-aza-2' deoxycytidine, restored hypoxia-induced BNIP3 expression. BNIP3 expression was also restored by introduction of a construct consisting of a full-length BNIP3 cDNA regulated by a cloned BNIP3 promoter. Restoration of BNIP3 expression rendered the pancreatic cancer cells notably more sensitive to hypoxia-induced cell death. In conclusion, down-regulation of BNIP3 by CpG methylation likely contributes to resistance to hypoxia-induced cell death in pancreatic cancer.

Objective: CA 19-9, equivalent to Sialyl Lewis antigen, is a well-known tumor marker in pancreatic cancer. At the initial step of the biosynthesis of CA 19-9, N-acetylglucosamine-beta1,3-galactosyltransferase (beta3Gal-T) transfers galactose to N-acetylglucosamine (GlcNAc). Recently, beta3Gal-T5 has been presumed to be related to the formation of the type 1 chain in an in vitro experiment in terms of kinetic enzyme characterization. The purpose of this study was to investigate which beta3Gal-T is related to the synthesis of CA 19-9 in human pancreatic cancer tissues., Methods: We examined beta;3Gal-T1, T2, T3, T4, and beta;3Gal-T5 mRNA expressions in 13 noncancerous and cancerous tissues of the human pancreas using real-time polymerase chain reaction, and compared those gene expression levels with the immunoreactivity of CA 19-9 and its precursor DUPAN-2 in cancerous tissues., Results: Beta;3Gal-T5 gene expression significantly augmented in cancerous tissues, when compared with the adjacent noncancerous tissues. Additionally, there was a good correlation between BETA;3GAL-T5 gene transcription levels and immunohistochemical grades of CA 19-9 or its precursor DUPAN-2 in cancerous tissues. However, no correlation was observed between beta;3Gal-T1, T2, T3, and beta;3Gal-T4 gene expression levels and CA 19-9 or DUPAN-2 immunoreactive grades in cancerous tissue., Conclusion: beta3Gal-T5 is presumed to be responsible for the synthesis of CA 19-9 in pancreatic cancer tissue., (Copyright 2004 S. Karger AG, Basel)

Objective: To determine the prognostic value of valosin-containing protein (VCP) expression and the Ki-67 labeling index (LI) in pancreatic endocrine neoplasms (PENs), the present analysis was employed., Methods: The Ki-67 LI and VCP expression at the mRNA and protein level were evaluated in 32 patients (12 male and 20 female) with PENs aged from 22 to 73 years (median 49 years). VCP staining intensity in tumor cells was categorized as weaker (level 1) or equal to stronger (level 2) compared to nontumorous islet cells. Ki-67 LI was divided into two categories: level 1, Ki-67 LI < 5%, and level 2, > or = 5%., Results: Five cases (15.6%) showed level 1 and 25 (84.4%) level 2 VCP expression by immunohistochemistry. A significant association was observed between VCP expression and the malignant behavior of PENs (p < 0.01). All level 1 VCP tumors were benign PENs. Quantitative reverse transcription polymerase chain reaction analysis showed higher VCP mRNA expression in malignant PENs (n = 5) than benign cases (n = 5) (p < 0.05). For Ki-67 LI, 28 cases (87.5%) showed level 1 and 4 (12.5%) level 2 expression. All patients with level 2 Ki-67 LI had metastasis., Conclusion: VCP expression analysis and Ki-67 LI are useful prognosticators for PENs., (Copyright 2004 S. Karger AG, Basel)

Peroxisome prolixferator-activated receptor gamma (PPARgamma), a ligand-activated transcription factor, forms a heterodimer with retinoid X receptor alpha (RXRalpha), and its transcriptional activity is thought to be maximal in the presence of both PPARgamma and RXRalpha ligands. Although previous studies suggested that thiazolidinediones (TZDs), known as PPARgamma ligands, inhibit the growth of several types of tumor cells, the precise mechanism still remains obscure. The present study was designed to examine the effects of PPARgamma/RXRalpha transcriptional activation on cell growth in cancer cells. We compared the effects of six types of TZDs (troglitazone, RS-1303, RS-1330, RS-1387, RS-1455, and RS-1456) and 9-cis RA, an RXRalpha ligand, on the activation of PPARgamma/RXRalpha and the growth inhibition of six types of adenocarcinoma cell lines (MKN45, HT-29, HCT116, HuCCT1, KMP-2, and BxPC3) established from abdominal malignancies. PPARgamma was expressed in all six tumor cell lines and transcriptionally functional in five of the six lines. The stronger PPARgamma activator showed the stronger growth inhibitor in these five cell lines. However, no significant growth inhibitory effect of six types of PPARgamma activators was observed in BxPC3 cells, which showed no significant PPARgamma transactivation by these activators. Simultaneous addition of troglitazone and 9-cis RA enhanced both activation of PPARgamma/RXRalpha and growth inhibition in several types of cancer cells. The degree of PPARgamma/RXRalpha activation correlated with the extent of growth inhibition (r > 0.70, P < 0.05). This growth inhibition was associated with G1 cell cycle arrest and cell differentiation. These findings suggest that activation of the PPARgamma/RXRalpha pathway plays an important role in the growth inhibition of tumor cells and that this nuclear hormone receptor may be a possible novel molecular target for treatment of tumors in humans.

Peroxisome proliferator-activated receptor gamma (PPARgamma), a ligand activated transcription factor, forms a heterodimer with retinoid X receptor alpha (RXRalpha), and its transcriptional activity is thought to be maximal in the presence of both PPARgamma and RXRalpha ligands. Though previous studies suggested that thiazolidinediones (TZDs), known as PPARgamma ligands, inhibit the growth of certain types of cancer cells, little is known about the growth inhibitory effects mediated though activation of PPARgamma/RXRalpha. We examined the effects of troglitazone (one type of TZDs) and 9-cis retinoic acid, a RXRalpha ligand, on activation of PPARgamma/RXRalpha and growth inhibition of human pancreatic cancer cell lines (AsPC1, BxPC3, PSN1, PCI6, Panc1, KMP-4, and KMP-7). Combined treatment of troglitazone and 9-cis retinoic acid showed enhanced transcriptional activity and enhanced antiproliferative effects. In PSN1 cells, G1 cell cycle arrest and apoptosis were induced by troglitazone and these effects were enhanced with additional 9-cis RA. Our findings suggest that activation of PPARgamma/RXRalpha pathway might play an important role in growth inhibition of pancreatic cancer cells via G1 cell cycle arrest and apoptosis. This nuclear receptor might be a suitable molecular target for treatment of pancreatic cancers.

We report a patient in whom systemic chemotherapy using gemcitabine was effective against liver metastases of pancreatic cancer. A 72-year-old woman underwent pancreatoduodenectomy with lymphadenectomy and partial resection of the portal vein following a diagnosis of pancreatic cancer, and her postoperative course was uneventful. The diagnosis was stage III anaplastic ductal carcinoma (t2n1P0H0M0). One year and 3 months after the operation, however, her serum level of carbohydrate antigen 19-9 (CA19-9) was found to be elevated, and CT examination revealed a mass in the liver that was diagnosed as liver that was metastases. Systemic chemotherapy was performed with a regimen of gemcitabine 600 mg/m2/week for 3 weeks, followed by a week rest, for the first three courses. On and after fourth course, gemcitabine 1,000 mg/m2/week was administered. The serum CA19-9 level was down from 882 U/ml to normal after 5 courses of chemotherapy and CT examination revealed that liver metastases had completely vanished. Although no evidence of deterioration was observed, the patient died of infectious pneumonia 10 months after recurrence. The prognosis of liver metastases of pancreatic cancer is quite unfavorable. However, if remission is achieved with gemcitabine, the patient has the possibility to obtain a better outcome.

Pancreatic cancer is characterized by invasive and metastatic potential. In this study, effects of the COX-2 inhibitor JTE-522 on cell viability, invasion, and invasion-related cellular properties were determined. JTE-522 (10 microM) induced a 75-90% reduction in invasion, compared to cells treated with a vehicle only, in the COX-2-expressing cells. In contrast, this inhibitor caused no significant reduction in cells lacking COX-2. Determinants of cell invasion, such as cell motility, adhesion to the extracellular matrix, and gelatinolytic activity of metalloproteinase, were also modulated in COX-2-positive pancreatic cancer cells. Thus, COX-2-specific inhibitors may be a useful anti-invasive therapeutic option in pancreatic cancer.

Cyclooxygenase (COX) is a key rate-limiting enzyme in prostaglandin biosynthesis. There are two isoforms of COX, referred to as COX-1 and COX-2. COX-2, an inducible form of COX, is found to be overexpressed in various neoplasms and is believed to play an important role in tumorigenesis and tumor development. In this study, we investigated expression of the COX-2 protein in human endocrine tumors of the pancreas (N=23; 6 insulinomas, one glucagnoma, 2 gastrinomas, and 14 non-functioning tumors) using immunohistochemistry. Strong COX-2 expression was confirmed in normal islet tissue as previously reported. COX-2 immunoreactivity was detected in 65% (15 out of 23) of these tumors with a moderate to strong intensity. In all nine functioning tumors, COX-2 expressions were preserved with the weak or strong intensity. In contrast, COX-2 was present in 6 out of 14 nonfunctioning tumors. The correlation between COX-2 expression and their function was significant (p<0.05). We found that expression of this enzyme was detected in 11 out of 15 benign tumors and in 4 out of 8 malignant tumors, respectively. Our results suggest that COX-2 may play an important role in the endocrine function of islet tumors. Additionally, malignancy was not related to COX-2 expression.

We prospectively assessed the clinical value of genetic staging of lymph node metastasis in patients with pancreatic adenocarcinoma who underwent curative surgery. K-ras gene mutations were detected in the primary tumors in 18 of 25 patients with pancreatic adenocarcinoma. Among these 18 patients, mutated K-ras gene was also found in at least one lymph node in 13 patients. Of these 13 patients, seven had no evidence of histological nodal involvement and six had histological lymph node metastasis. Although there was no significant difference in overall survival rates between the pathological node-negative and -positive patients, overall survival of the five patients with nodes-negative for the mutated K-ras gene were significantly better than that of the 13 patients with genetically metastasis-positive nodes (p<0.001). Furthermore, overall survival of the six patients with genetically metastasis-positive nodes limited to peripancreatic area was significantly better than that of seven patients with genetical metastasis in lymph nodes beyond the peripancreatic areas (p=0.018). These findings suggest that detection of K-ras gene mutations in lymph nodes may be clinically useful to assess the accurate tumor staging and to stratify the patient with pancreatic adenocarcinoma who are at high or low risk for recurrence after curative surgery.

The level of cyclooxygenase (COX)-2 has been investigated recently in various human carcinomas. In the present study, we examined the distribution and extent of COX-2 protein in human pancreatic tumors using immunohistochemistry. A strong expression of COX-2 protein was present in 23 of 52 (44%) pancreatic carcinomas, a moderate expression was present in 24 of 52 (46%) pancreatic carcinomas, and a weak expression was present in 5 of 52 (10%) pancreatic carcinomas. In contrast, benign tumors showed weak expression or no expression of COX-2, and only islet cells displayed COX-2 expression in normal pancreatic tissues. Overexpression of COX-2 in carcinoma tissues was also confirmed by Western blot analysis. Furthermore, consistent with the results at protein levels, reverse transcription-PCR analyses indicated that COX-2 mRNA was overexpressed in 7 of 13 (54%) carcinomas, but in none of 3 benign tumors. Our findings suggest that COX-2 inhibitors might be potentially effective against pancreatic carcinomas and that COX-2 may be involved in certain biological processes in pancreatic islets.