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Background: In pancreatic ductal adenocarcinoma (PDAC), invasion of connective tissues surrounding major arteries is a crucial prognostic factor after radical resection. However, why the connective tissues invasion is associated with poor prognosis is not well understood., Materials and Methods: From 2018 to 2020, 25 patients receiving radical surgery for PDAC in our institute were enrolled. HyperEye Medical System (HEMS) was used to examine lymphatic flow from the connective tissues surrounding SMA and SpA and which lymph nodes ICG accumulated in was examined., Results: HEMS imaging revealed ICG was transported down to the paraaortic area of the abdominal aorta along SMA. In pancreatic head cancer, 9 paraaortic lymph nodes among 14 (64.3%) were ICG positive, higher positivity than LN#15 (25.0%) or LN#18 (50.0%), indicating lymphatic flow around the SMA was leading directly to the paraaortic lymph nodes. Similarly, in pancreatic body and tail cancer, the percentage of ICG-positive LN #16a2 was very high, as was that of #8a, although that of #7 was only 42.9%., Conclusions: Our preliminary result indicated that the lymphatic flow along the connective tissues surrounding major arteries could be helpful in understanding metastasis and improving prognosis in BR-A pancreatic cancer., (© 2024. The Author(s).)

Objective: To investigate the long-term dynamics of recurrence risk and the significance of prognostic variables using conditional recurrence-free survival (C-RFS) analysis in neoadjuvant treatment (NAT) for resectable (R) and borderline resectable (BR) pancreatic cancer (PC)., Background: C-RFS analysis assesses the probability of achieving additional RFS according to the RFS already accrued., Methods: Patients with NAT and subsequent resection for R/BRPC were enrolled. In the C-RFS analysis, the actual 5-year RFS (5yRFS) rate was calculated separately in the subgroup that had already gained a given amount of RFS. The significance levels of prognostic variables associated with 5yRFS were assessed regarding their time-dependent dynamics in a conditional fashion., Results: Among the total 397 patients, 160 survived for more than 5 years without recurrence after surgery (actual 5yRFS rate: 45%). The probability of 5yRFS incrementally increased based on the RFS already accrued. Pathological nodal and vascular involvement were significant influencers of 5yRFS. The patients with nodal involvement consistently remained at significantly higher risk of recurrence than those without, even after 5yRFS, whereas positivity of vascular involvement was significantly associated with the risk of recurrence only during the early postoperative period and lost its significance after 3yRFS accrued., Conclusions: In NAT for R/BRPC, the probability of gaining additional RFS increases as a function of RFS already accrued, and the significance of prognostic variables time-dependently evolves in their own patterns during the long-term postoperative period., Competing Interests: The authors report no conflicts of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Duke pancreatic mono-clonal antigen type 2 (DUPAN-II) is a famous tumour maker for pancreatic cancer (PC) as well as carbohydrate antigen 19-9 (CA19-9). We evaluated the clinical implications of DUPAN-II levels as a biological indicator for PC during preoperative chemoradiation therapy (CRT)., Methods: This retrospective analysis included data from 221 consecutive patients with resectable and borderline resectable PC at diagnosis who underwent preoperative CRT between 2008 and 2017. We focused on 73 patients with elevated pre-CRT DUPAN-II levels (> 230 U/mL; more than 1.5 times the cut-off value for the normal range). Pre- and post-CRT DUPAN-II levels and the changes in DUPAN-II ratio were measured., Results: Univariate analysis identified normalisation of DUPAN-II levels after CRT as a significant prognostic factor (hazard ratio [HR] = 2.06, confidence interval [CI] = 1.03-4.24, p = 0.042). Total normalisation ratio was 49% (n = 36). Overall survival (OS) in patients with normalised DUPAN-II levels was significantly longer than that in 73 patients with elevated levels (5-year survival, 55% vs. 21%, p = 0.032) and in 60 patients who underwent tumour resection (5-year survival, 59% vs. 26%, p = 0.039)., Conclusion: Normalisation of DUPAN-II levels during preoperative CRT was a significant prognostic factor and could be an indicator to monitor treatment efficacy and predict patient prognosis., (© 2023. The Author(s).)

Purpose: Pancreaticoduodenectomy (PD) concomitant with portal vein resection (PVR) often develops into digestive varices with an occurrence rate of 30-50%, and the variceal bleeding is sometimes untreatable and results in fatality. Against this issue, splenic artery (SpA) ligation during PD-PVR is emerging as an easy and effective prophylactic surgical option. The aim of this study was to investigate the significance of SpA ligation in the development of digestive varices in patients undergoing PD-PVR., Method: We retrospectively investigated 97 patients with PDAC who received PD-PVR in two hospitals. Vascular reconstruction of the splenic vein (SpV) was not performed in either hospital. We assessed the occurrence rate of digestive varices in these patients in association with the performance of SpA ligation., Results: The occurrence rate of digestive varices was 23%. SpA ligation was the only significant decreasing factor for the development of digestive varices (odds ratio 0.3, p = 0.035). Although SpV resection was not a significant risk factor for the development of digestive varices in all patients, SpV resection was a significant risk factor for the development of digestive varices in patients without SpA ligation, as demonstrated in previous reports. SpA ligation did not increase surgical complications or impair pancreatic function., Conclusion: PD-PVR surgery was accompanied by a 23% incidence of digestive varices, and SpA ligation significantly decreased the development of digestive varices without causing clinically significant complications., Trial Registration: No. 18196 (Osaka International Cancer Institute) and no. 19006 (National Hospital Organization Osaka National Hospital)., (© 2020. Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Biological factors are emphasized in borderline resectable pancreatic cancer (BRPC), and CA19-9 is an important factor for biological borderline resectability (b-BR). The aim of this study was to investigate the cut-off value of CA19-9 for biological borderline resectability and "biological downstaging" in chemoradiation therapy (CRT) for pancreatic cancer (PC)., Methods: A total of 407 patients with anatomically resectable PC (a-R) and BRPC (a-BR) received preoperative gemcitabine-based CRT. The b-BR was determined, according to the CA19-9 value prior to preoperative CRT (pre-CA19-9), as the subgroup of a-R cases in which the survival was comparable with that in a-BR cases. "Biological downstaging" was determined based on prognostic analyses regarding the CA19-9 value after preoperative CRT (post-CA19-9) in association with the survival of R cases (a-R cases without the b-BR factor)., Results: The 5-year survival of a-R patients with pre-CA19-9 > 120 U/mL was comparable with that of a-BR patients (44% vs 34%, p = 0.082). The survival of b-BR patients with post-CRT CA19-9 ≤ 37 U/mL (normalized) was comparably favorable with that of R patients (56% vs 65%, p = 0.369). The incidence of distant recurrence was higher in b-BR patients without post-CA19-9 normalization than in those with post-CA19-9 normalization (70% vs 50%, p = 0.003), while the incidence of local recurrence was comparable between these two groups (12% vs 13%, p = 0.986)., Conclusions: Biological BRPC was determined to be an anatomically resectable disease with pre-CA19-9 > 120 U/mL, and post-CA19-9 normalization indicated "biological downstaging" in b-BR in the preoperative CRT strategy., Competing Interests: Declaration of competing interest There is no personal conflict of interest of any of the authors., (Copyright © 2020 IAP and EPC. Published by Elsevier B.V. All rights reserved.)

Background: Intraductal papillary mucinous neoplasm (IPMN) is a premalignant cystic neoplasm of the pancreas and is frequently detected in imaging investigations. A proportion of the patients with IPMN develop malignancies including high-grade dysplasia and invasive carcinoma. To predict the presence of malignancies in IPMN, constant imaging follow-up is usually required. Pancreatic steatosis (PS) has been recently identified as a facilitating factor for pancreatic cancer, and can be predicted through computed tomography (CT). We hypothesized that the CT-number of the pancreatic parenchyma could be a new reliable imaging biomarker for IPMN patients., Methods: Eighty-six patients undergoing pancreatectomy for IPMN were investigated. Using preoperative CT, the pancreatic index (PI) was calculated by dividing the CT-number of the pancreas by that of the spleen., Results: Malignancies were pathologically detected in 63 cases (73.3%). Patients were divided into two cohorts according to the presence of malignancies and were compared for various factors including the PI scores. The comparison of the two cohorts detected significant differences in two parameters (CA19-9 and PI score), and the PI score was the most sensitive biomarker to predict the presence of malignancies in patients showing high-risk stigmata of IPMN., Conclusions: Pancreatic CT-number is an additional reliable imaging biomarker in distinguishing patients with IPMN having malignancies when investigating the patients showing high-risk stigmata., (Copyright © 2020 IAP and EPC. Published by Elsevier B.V. All rights reserved.)

Background & Aims: Neoadjuvant chemoradiotherapy (NACRT) for pancreatic cancer (PC) is potentially associated with various toxicities, which can lead to impaired nutritional status. Eicosapentaenoic acid (EPA) can reduce proinflammatory cytokines and positively influence cancer cachexia syndrome. The aim of this study is to clarify the utility of EPA enriched nutrition support during NACRT for PC., Methods: We randomly assigned 62 patients with PC that received NACRT to either a nutrition intervention (NI) or a normal diet (ND). Patients in the NI group received 2 bottles/day (550 kcal/day) of an EPA-enriched nutrition supplement during NACRT. The primary endpoints were the before-to-after NACRT ratios (post/pre ratios) of skeletal muscle mass and psoas major muscle area (PMA). The secondary endpoints were the post/pre ratios of other nutritional parameters and treatment-related toxicities., Results: Only 14 patients (45.2%) in the NI group consumed more than 50% of the EPA-enriched supplement provided. The post/pre ratio of skeletal muscle mass in the NI group (0.99 ± 0.060) was not significantly different from that of the ND group (0.96 ± 0.079, p = 0.102). However, patients that consumed ≥50% of the EPA-enriched supplement (the good intake group) had significantly higher skeletal muscle mass ratios than patients in the ND group (p = 0.042). The PMA ratio was significantly higher in the NI group (0.96 ± 0.081) than in the ND group (0.89 ± 0.072, p = 0.001). The NI and ND groups were not significantly different in other nutritional parameters or in NACRT-related toxicity., Conclusions: We found that EPA-enriched intake could potentially improve the nutritional status of patients with PC that received NACRT, but it was difficult for many patients to drink, due to its disagreeable taste. University Hospital Medical Information Network (http://www.umin.ac.jp), registration number UMIN000033589, https://upload.umin.ac.jp/cgi-bin/ctr_e/ctr_view.cgi?recptno=R000038300., (Copyright © 2019 European Society for Clinical Nutrition and Metabolism. Published by Elsevier Ltd. All rights reserved.)

Background/aim: The significance of the anatomical variations of proximal jejunal vein [the so-called 1st jejunal vein (J1v)] has been reported from a technical standpoint. The aim of this study was to retrospectively investigate the prognostic impact of the anatomical variations of J1v in the surgical treatment of resectable pancreatic cancer (PC)., Patients and Methods: A total of 49 patients with resectable PC located in the uncinate process were included in this study. The J1v converging pattern was divided into 2 groups in terms of its relation to the SMA (i.e., the J1v status): i) group D: the J1v travels posterior to the SMA; ii) group V: the J1v travels anterior to the SMA. The associations between the J1v status and surgical outcome were assessed., Results: The 5-year survival rate after resection in group V (35%) was significantly lower than that in group D (70%) (p=0.029), and the J1v status of group V was the only independent negative prognostic factor (HR=5.49; 95% CI=1.69-19.3; p=0.005)., Conclusion: The J1v converging pattern is a significant prognostic variable in patients with PC located in the uncinate process: the J1v status of group V was significantly associated with impaired survival., (Copyright© 2019, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: Preoperative chemoradiation therapy is a promising strategy for pancreatic cancer. Peritoneal recurrence is a major recurrence pattern after surgery for pancreatic cancer following preoperative chemoradiation therapy, even in patients with negative peritoneal lavage fluid cytology. Previous reports have indicated that the detection of carcinoembryonic antigen mRNA by reverse transcription polymerase chain reaction is useful for evaluating subclinical tumor cell dissemination in peritoneal lavage fluid., Methods: Patients with resectable and borderline resectable pancreatic cancer treated with preoperative gemcitabine-based chemoradiation therapy and subsequent surgery were enrolled in this study. In all patients, a conventional cytologic examination of peritoneal lavage fluid from laparotomy confirmed the negative peritoneal cytology status. Carcinoembryonic antigen mRNA was detected in the peritoneal lavage fluid at laparotomy using reverse transcription polymerase chain reaction. Recurrence patterns and survival were evaluated in association with the carcinoembryonic antigen mRNA status in the peritoneal lavage fluid., Results: The peritoneal lavage fluid from 57 of the 237 patients (24%) was carcinoembryonic antigen mRNA(+). The carcinoembryonic antigen mRNA(+) patients had a significantly higher incidence of peritoneal recurrence than the carcinoembryonic antigen mRNA(-) patients (36% vs. 15%, P < .001). The 5-year survival rates of the carcinoembryonic antigen mRNA(+) and carcinoembryonic antigen mRNA(-) patients were 31% and 51%, respectively (P = .037). A multivariable analysis for survival revealed that borderline resectability, positive nodal status, and positive carcinoembryonic antigen mRNA status were independent variables for impaired survival., Conclusion: Carcinoembryonic antigen mRNA(+) status was associated with a significantly increased incidence of peritoneal recurrence in patients with pancreatic cancer treated with preoperative chemoradiation therapy, resulting in impaired survival., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: The efficacy of neoadjuvant chemoradiotherapy (NACRT) for resectable and borderline resectable pancreatic cancer is important for predicting outcomes after radical surgery, but few clinical indicators predict outcome before resection. This study examined the utility of FDG-PET in predicting the efficacy of NACRT and outcome after radical surgery., Methods: Eighty-three pancreatic cancer patients who underwent FDG-PET before and after NACRT and had positive standard uptake values (SUVs) before NACRT were enrolled in this study. Peri-operative clinical factors, including FDG-PET findings, were examined to predict the efficacy of NACRT and outcome after surgery., Results: Evans grade I, IIA, IIB, III, and IV was determined in 11, 31, 27, 11, and 3 patients, respectively. The maximum SUVs after NACRT (post SUV-max) and tumor size were significantly decreased compared to pretreatment values (p < 0.001 and p = 0.007, respectively). The post SUV-max and regression index were significantly related to grade III/IV (p = 0.04 and p < 0.001, respectively), but only the regression index predicted NACRT efficacy (p = 0.002). The AUC of the regression index for the detection of grade III/IV was 0.822, and 13 of 14 grade III/IV patients were picked up using 50% as the threshold (p < 0.001). Patients with a regression index >50% had a significantly better prognosis after radical resection than patients with <50% (p = 0.032). Regression index as well as pathological lymph node status and resectability status were independent prognostic factors in multivariate analysis (exp 2.086, p = 0.043)., Conclusion: The regression index is potentially a good indicator of the efficacy of NACRT and outcome after radical resection for pancreatic cancer., (Copyright © 2017 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.)

Objective: To evaluate the outcome of preoperative gemcitabine-based chemoradiation therapy (CRT) for borderline resectable pancreatic cancer (BRPC), focusing on the associations among the tumor-vascular relationship, surgical outcomes, and pattern of recurrence., Summary Background Data: Among the various multimodal treatment strategies for pancreatic cancer, preoperative CRT and subsequent surgery is 1 promising strategy for BRPC., Methods: A total of 184 patients with BRPC received preoperative CRT. BRPC was classified as follows, based on radiographic findings before the initiation of preoperative CRT: BR-V, a tumor involving the portal-superior mesenteric vein without arterial involvement; and BR-A, a tumor with the involvement of a relevant major artery. We assessed the association of these 2 subgroups with the following parameters: (1) resection rate, (2) survival, and (3) pattern of recurrence., Results: The resection rate of BR-V cases (84%) was significantly higher than that of BR-A cases (57%) (P < 0.001). The 5-year survival rates of the resected BR-V and BR-A cases were 51% and 25%, respectively (P = 0.003). The 5-year cumulative incidence of distant recurrence was significantly higher in the BR-A cases compared with the BR-V cases (67% vs 54%, P = 0.006); however, the 5-year cumulative incidence of local recurrence was not significantly different between the groups., Conclusions: In BRPC, arterial involvement was associated with impaired outcome regarding resection rate and survival, possibly due to the difference in the underlying pathophysiology between BR-V and the advanced nature of BR-A as a systemic disease.

Purpose: Pancreatic fistula (PF) remains an obstacle to safe distal pancreatectomy (DP). A thick pancreatic parenchyma is a major risk factor for PF. In this paper, we elucidate the feasibility of the new closure method using soft coagulation and polyglycolic acid felt with fibrin glue., Methods: In 2009-2013, 96 patients underwent DP with a novel closure method for pancreatic stump that utilized soft coagulation and polyglycolic acid felt with fibrin glue. We evaluated amylase levels in drainage fluid on postoperative days (POD) 1 and 3 and the incidence of postoperative PF according to International Study Group of Pancreatic Fistula (ISGPF) definitions., Results: Drain amylase levels on POD1 and POD3 were 275 and 241 U/L, respectively, and ISGPF-defined Grade B/C PF rates were 16.7%. No clinical factors were significantly associated with PF. Average pancreatic parenchymal thicknesses were similar in PF-positive and PF-negative patients (10.4 ± 2.6 mm vs. 10.1 ± 2.2 mm, P = 0.639). There was no significant difference in the postoperative PF rate between patients with thick (≥12 mm) and thin (<12 mm) pancreas (11.1 vs. 18.8%, P = 0.544)., Conclusion: Our novel pancreatic stump closure method appears to be simple and effective, particularly in patients with thick pancreas.

Background: Among the various multimodal treatment strategies for pancreatic ductal adenocarcinoma (PDA), preoperative chemoradiation therapy (CRT) and subsequent operation is a promising strategy. The aim of this study is to evaluate the outcome of preoperative gemcitabine-based CRT for PDA of the body and tail, focusing on the associations among splenic vessel involvement, surgical outcomes, and pattern of recurrence., Methods: A total of 99 patients with PDA of the body and tail received preoperative CRT. The status of tumor involvement of the splenic artery (SA) and vein (SV) were evaluated based on radiographical findings obtained before the initiation of preoperative CRT. We assessed the following in association with the status of SA and SV involvement: (1) resection rate, (2) survival, and (3) pattern of recurrence., Results: The resection rate of SA-positive cases (71%) was significantly lesser than that of SA-negative cases (94%; P = .004), whereas SV involvement was not associated with the resection rate. The 5-year survival rates of the resected SA-negative and SA-positive cases were 76% and 20%, respectively (P < .001). The 5-year cumulative incidence of distant recurrence was significantly higher in the SA-positive patients than in the SA-negative patients (74% vs. 17%; P < .001)., Conclusion: In preoperative CRT for PDA of the body and tail, positive SA involvement was associated with a lesser resection rate, and the survival rate for the patients with SA-positive tumors was lesser than that for patients with SA-negative tumors because of the greater incidence of distant recurrence in SA-positive patients., (Copyright © 2015 Elsevier Inc. All rights reserved.)

A 73-year-old woman underwent a craniotomy for an atypical meningioma in 1993, and underwent re-excision for local recurrence 4 years later. In 2008, a chest X-ray film revealed 2 nodules in the right lung. A wedge resection of S2 and a middle lobectomy of the right lung were performed. Pathological findings indicated that the 2 tumors originated from the intracranial meningioma resected in 1993. In 2013, a computed tomography (CT) scan demonstrated hypervascular masses in the liver (S4), pancreatic body, and lower portion of the right kidney. She underwent partial hepatectomy, distal pancreatectomy, and partial nephrectomy, and the final diagnosis was hepatic, pancreatic, and renal metastases from meningioma. After 10 months, a transcatheter arterial embolization (TAE) was performed for hepatic recurrence (S5). She is presently doing well, 5 months after TAE, without any signs of recurrence.

Background and Aims: The purpose of this prospective study was to demonstrate the ability to measure pancreatic tumor tissue blood flow (TBF) with a noninvasive method using xenon inhalation computed tomography (xenon-CT) and to correlate TBF with histological features, particularly microvascular density (MVD)., Methods: TBFs of pancreatic tumors in 14 consecutive patients were measured by means of xenon-CT at diagnosis and following therapy. Serial abdominal CT scans were obtained before and after inhalation of nonradioactive xenon gas. TBF was calculated using the Fick principle. Furthermore, intratumoral microvessels were stained with anti-CD34 monoclonal antibodies before being quantified by light microscopy (×200). We evaluated MVD based on CD34 expression and correlated it with TBF., Results: The quantitative TBF of pancreatic tumors measured by xenon CT ranged from 22.3 to 111.4 ml/min/100 g (mean ± SD, 59.6 ± 43.9 ml/min/100 g). High correlation (r = 0.885, P < 0.001) was observed between TBF and intratumoral MVD., Conclusion: Xenon-CT is feasible in patients with pancreatic tumors and is able to accurately estimate MVD noninvasively.

The prognosis of pancreatic cancer is most dismal in all gastrointestinal cancers, because the patients with pancreatic cancer are vulnerable for recurrence such as local relapse and liver metastasis even after a complete surgical resection. We herein report a case of pancreatic cancer, which underwent resection of local relapse and multiresections of liver metastases, resulting in a relatively longer survival. A 71-year-old woman was referred to our hospital for a local recurrence in the tail of the pancreas in October 2006, 17 months after the first distal pancreatectomy. A second distal pancreatectomy was curatively performed on this patient. After the second surgery, sequent solitary liver metastases appeared, and we then performed partial hepatectomies repeatedly in August 2007, December 2007 and December 2008. The histopathological findings of each specimen from the resected liver showed tubular adenocarcinoma, same as the original pancreatic tumor obtained from the first surgery. Although chemotherapy was not permitted due to gemcitabine-induced interstitial pneumonitis, the patient is still alive over 4 years after the first operation under palliative care. This study discusses a controversial issue about the resection of the liver metastases from pancreatic cancer, along with the necessity for careful selection of the patients before attempting the operation.

A 52-year-old man was admitted for detailed examination of a mass with extensive calcification in the tail of the pancreas by fluoro-deoxy glucose-positron emission tomography/computed tomography (FDG-PET/CT). Abdominal CT and magnetic resonance imaging (MRI) findings showed a calcified tumor 5 cm in diameter with a smooth surface. The tumor mainly showed calcification at it center and a partially solid element around it margin which was enhanced in the early phase. With no definiture preoperative diagnossi, we performed distal pancreatectomy and splenectomy. Pathological and immunohistochemical studies revealed a nonfunctioning islet cell tumor with calcification. A nonfunctioning islet cell tumor with central calcification formation as it grew to a maximum diameter of 7 cm is rare. When diagnosing pancreatic tumors it must be kept in mind that some nonfunctioning islet cell tumors of the pancreas can show nontypical features such as calcification formation.

We report a case of advanced unresectable pancreatic cancer (cT4N1M0/stage IVa). The patient was a 68-year-old man. Chemo-radiation therapy (CRT) with GEM (1,000 mg/body) was administered once a week on days 1, 8 and 15 for 3 weeks. The radiotherapy dose was 45 Gy (1.5 Gy x 2/day, 15 days). After CRT, the patient was treated with a GEM+ UFT-E combination chemotherapy. When that was done, CT scan revealed metastases of umbilicus (Sister Mary Joseph's nodule) and the liver. Microwave Coagulation Therapy for the liver metastasis and tumorectomy for metastasis of umbilicus were performed. But he died after 4 months from the therapies.

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.

We report a case of advanced unresectable pancreatic cancer with multiple liver metastases (cT4N x M1, stage IVb). The patient is a 68-year-old man. Serum DUPAN-2 was 15,800 U/mL. Abdominal CT scan revealed the body and tail of pancreatic cancer and multiple liver metastases. Chemo-radiation therapy (CRT) with GEM 1000 mg/body was given once a week on days 1, 8 and 15 for 3 weeks. The radiotherapy dose was 45 Gy (1.5 Gy x 2/day, 15 days). Hematological side effect such as anemia (grade 3) and thrombopenia (grade 2) appeared, but could be well controlled. Abdominal CT scan revealed no change in size, but serum DUPAN-2 decreased up to 4590 U/mL. After CRT, the patient was treated thereafter by the combination chemotherapy with GEM and S-1. After 7 months, CT scan revealed no change in tumor size.

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.)

Purpose: Hepatoma-derived growth factor (HDGF) is a nucleus-targeted growth factor playing an important role in the development and progression of cancers. This study investigated the correlation of HDGF expression and prognosis in patients with pancreatic ductal carcinoma., Patients and Methods: HDGF expression in pancreatic cancer cell lines was analyzed by Western blotting. HDGF expression was analyzed by immunohistochemistry for 50 patients with primary ductal carcinoma of the pancreas (33 male and 17 female) ranging in age from 48 to 80 years (median, 65 years) receiving surgical treatment. Cancer cells showing stronger staining than the noncancerous ducts were regarded as positive. Cases showing positive staining in < 90% and > 90% of tumor cells were regarded as HDGF labeling index (LI) levels 1 and 2, respectively. HDGF LI was determined separately for the nucleus and the cytoplasm., Results: Western blotting showed HDGF expression in pancreatic cancer cells similar to that of hepatic cell lines. Twenty-three (46%) and 27 (54%) cases and 22 (44%) and 28 (56%) cases showed HDGF LI levels 1 and 2 for the nucleus and the cytoplasm, respectively. Patients with nuclear HDGF LI level 1 showed a significantly better 5-year survival rate (37.0%) than those with level 2 (6.8%; P = 0.023). No significant difference was observed in the cytoplasmic HDGF LI classification. Multivariate analysis revealed nuclear HDGF LI to be an independent prognosticator., Conclusions: These findings suggest that HDGF could be a novel prognostic factor for pancreatic ductal carcinoma.

Background: We conducted a Phase I/II study to evaluate the local efficacy and toxicity of hyperfractionated accelerated radiotherapy (HART) combined with 5-fluorouracil (5-FU) and cisplatin (CDDP) in patients with unresectable advanced pancreatic cancer., Methods: Thirty-five patients (15 with Stage 4A and 20 with Stage 4B disease according to TNM classification) were enrolled between August 1997 and August 2001 into this Phase I/II trial. All patients received concurrent HART (1.5 Gy twice daily separated by 6 h for 5 days per week), 5-FU (375 mg/m(2) given as continuous intravenous infusion), and CDDP (2 mg/m(2) given as 30-min infusion just before each fraction of irradiation). In the Phase I trial, the total dose of radiation was escalated from 27 to 45 Gy., Results: Twenty-one patients were enrolled in the Phase I study and six patients were given the final planned dose (45 Gy) which did not exceed the maximum tolerated dose. Eleven patients (52.4%) suffered from Grade 3 or worse neutropenia. Vomiting and mucositis were observed in 21 (100%) and 12 (57.1%) patients, respectively. An additional 14 patients were entered in the Phase II trial and received a total dose of 45 Gy, which is recommended in Phase I trial. Concerning the local tumor control of 20 patients with the recommended regimen, 7 patients (35%) achieved partial response, 10 (50%) remained stable and local progressive disease occurred in 3 (15%). The median survival time and the overall 1-year survival rate were 11.2 months and 40.0%, respectively, in 20 patients who received the recommended regimen. In Stage 4A patients, they were 13.0 months and 70.0%, respectively. The trend of toxicities in patients with the recommended regimen was almost the same as that observed in the Phase I study., Conclusion: The chosen combined modality treatment was well tolerated, and showed an expected local efficacy for the treatment of unresectable advanced pancreatic cancer.

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.

Background: Noninvasive and minimally invasive intraductal papillary-mucinous neoplasms (IPMNs) have a favorable surgical outcome. However, cases of recurrent noninvasive or minimally invasive IPMN are sometimes encountered, and the patterns of the recurrence of those tumors have not yet been fully clarified. In this study, we evaluated the surgical outcome of noninvasive and minimally invasive IPMNs, concentrating particularly on the pattern of recurrences., Methods: Twenty patients with noninvasive and minimally invasive IPMNs were assessed. Resected specimens were evaluated histopathologically with regard to the malignant nature of the tumors, the status of the surgical margin, and peripancreatic lymph node involvement. Cumulative overall survival rates and recurrence after surgery were assessed., Results: Of the 20 patients, 13 had benign IPMNs, including adenomas (n = 10) and borderlines (n = 3), and 7 had malignant IPMNs, including carcinomas in situ (n = 4) and minimally invasive IPMNs (n = 3). Histopathologic examination confirmed the absence of tumor involvement in the resected lymph nodes and at the surgical margins. During the follow-up period, one patient with minimally invasive IPMN and one patient with noninvasive IPMN died of tumor recurrence in the peritoneum that was presumably caused by intraoperative manipulation. All of the patients with benign IPMNs survived, whereas the 10-year survival rate of the patients with malignant IPMNs was 67%., Conclusions: Surgical resection can offer a favorable outcome for noninvasive and minimally invasive IPMNs. Tumor recurrence was observed only in the peritoneal cavity. More careful perioperative management concerned with peritoneal recurrence should be emphasized for noninvasive and minimally invasive IPMNs.

A 56-year-old man is presented with diarrhea, which he had experienced since February 2004. He was diagnosed as having advanced pancreatic cancer by enhanced abdominal CT scan in May 2004. He was diagnosed with unresectable pancreatic cancer, and treated with a combination of radiation (3 Gy/day) and injections of gemcitabine (GEM) 1,200 mg/week (800 mg/m2, BSA 1.6). Abdominal CT scan revealed a minor response (tumor diameter 5.7 x 4.8 --> 5.2 x 4.4). Accordingly, the improvement of performance status and reduction in serum levels of arcinoembryonic/carbohydrate antigen 19-9 (CA19-9) were observed. In July 2004, chemotherapy and radiotherapy were switched to GEM+UFT (UFT 360 mg/day, a total of 4,320 mg, GEM 1,200 mg according to the body mass, a total of 2,400 mg). The patient's performance state was stable for 6 months but serum levels of CA19-9 increased from March 2005, and he complained of diarrhea and back-pain. Therefore, the combination chemotherapy with GEM and cisplatin (CDDP) was started in April 2005, but there was no clinical effect. GEM and TS-1 are currently being administered. Pancreatic cancer is one of the worst prognoses of any malignant disease. Although the prognosis of unresectable pancreatic cancer is very poor, we presented a case where performance status and survival benefits were obtained by undergoing chemoradiation with GEM and combination chemotherapy with UFT and GEM.

The expression of the Wilms' tumor gene WT1 was examined by immunohistochemistry in 40 cases of pancreatic ductal adenocarcinoma. WT1 protein was expressed in 30 (75%) of the 40 pancreatic ductal adenocarcinomas, but not in the remaining 10 (25%). In normal pancreatic ductal cells, WT1 protein was undetectable. No correlations between WT1 expression and clinicopathological parameters such as age, sex, T or N stage, tumor location, and tumor differentiation were observed. Treatment with WT1 antisense oligomers significantly inhibited the growth of five human pancreatic cancer cell lines, PSN1, MiaPaCa2, ASPC1, BxPC3, and PCI6, expressing the WT1 gene. These results indicate an important role of the WT1 gene in the tumorigenesis of pancreatic ductal adenocarcinoma expressing WT1 and provide a rationale for new treatment strategies to treat pancreatic ductal adenocarcinoma by targeting the WT1 gene and its product.

Purpose: Akt is a serine/threonine kinase that plays a central role in tumorigenesis. Among the members of Akt family, Akt2 is associated with the development of human cancers. The present study was designed to clarify the prognostic significance of Akt2 and activated Akt expression in pancreatic ductal adenocarcinoma (PDAC). In addition, activated extracellular signal-regulated kinase 1 and 2 (ERK1/2) and the proliferation activity of tumor cells detected by Ki-67 immunohistochemistry were examined., Experimental Design: Immunohistochemical analysis was performed on paraffin-embedded specimens from 65 patients with PDAC; 36 males and 29 females with ages ranging from 48 to 79 years (median, 66 years) of age. Expression levels of Akt2, phosphorylated Akt (p-Akt), and phosphorylated ERK 1/2 (p-ERK 1/2) were categorized as either weaker (low intensity) or equal to stronger (high intensity) compared with those in the endothelial cells of the same specimens. For Ki-67 immunohistochemistry, cases were divided into two groups: level 1, Ki-67 labeling index (LI), <20%; level 2, Ki-67 LI, > or = 20%., Results: Twenty-six (42.6%), 28 (45.9%), 39 (63.9%), and 46 (75.4%) of the tumors showed high intensity of Akt2, p-Akt, and p-ERK 1/2 expression, and Ki-67 LI level 2, respectively. A significant positive correlation was observed between Akt2 and p-Akt expression (P < 0.01). Multivariate analysis revealed that p-Akt expression, Ki-67 LI, and histological differentiation are independent prognosticators for PDAC., Conclusions: p-Akt expression is a significant prognostic indicator for PDAC. Inhibition of Akt is a possible molecular approach for treatment of PDAC.

Background: Valosin-containing protein (VCP, also known as p97) exhibits antiapoptotic function and metastasis by activation of nuclear factor kappa-B signaling pathway. Our previous study showed that VCP expression level correlated with prognosis of hepatocellular and gastric carcinoma. In the present study, association of VCP expression with lymph node metastasis and prognosis of pancreatic ductal adenocarcinoma (PDAC) was examined., Methods: VCP expression in 83 patients (46 males and 37 females) of ages ranging from 43 to 80 (median, 66) years who had undergone curative surgery for primary PDAC was analyzed by immunohistochemistry, in which staining intensity in tumor cells was categorized as weaker or equal to (low expression) or stronger (high expression) than that in noncancerous ductal tissue., Results: Thirty-two tumors (38.6%) and 51 tumors (61.4%) were classified as low-VCP-expressing and high-VCP-expressing tumors, respectively. VCP expression correlated significantly with lymph node metastasis (P <.01) but not with various clinicopathologic factors, including age, gender, and histologic differentiation. Multivariate analysis revealed VCP expression as an independent prognosticator for both disease-free and overall survival, along with histologic differentiation, T stage of pathologic tumor-node-metastasis (pTNM) classification, and lymph node metastasis. Furthermore, VCP expression was a prognosticator for disease-free and overall survival in each relatively early stage (I or II) and advanced stage (III) group of pTNM classification., Conclusions: Our results indicate the potential usefulness of VCP expression as a marker of metastasis and overall prognosis of PDAC.

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)

A phase I study of gemcitabine (GEM) and UFT combination chemotherapy was performed for unresectable pancreatic cancer. The regimen included UFT orally from day 1 through day 6 and from day 8 through 13, GEM intravenously on day 7 and 14, and 1 week rest as 1 course. Administration of more than 2 courses was attempted for each patient, with the same dosage levels at all 3 scheduled steps. Nine patients were enrolled in the study. Leukopenia and neutropenia of grade 3 occurred in 2 of 6 patients at level 2, and maximum tolerated dose (MTD) was considered to be 800 mg/m2 for GEM and 250 mg/m2 for UFT. Clinical effects of the patients included: 2 PR, 4 NC, and 3 PD, for a response rate of 22% (2/9 patients). Reduced CA19-9 level of less than half of that at starting time was observed in 4 of 9 (44%) patients. The recommended dose for the phase II study is GEM 800 mg/m2 and UFT 250 mg/m2 with consideration of application to outpatients and continuing courses.

Uridine diphosphate (UDP) N-acetyl-alpha-D-galactosamine:polypeptide N-acetylgalactosaminyl transferase 3 (GalNAc-T3), one of the enzymes that catalyze the initial glycosylation of mucin type O-linked proteins, was shown to associate with the differentiation of cancer cell lines and the prognosis of some kinds of cancers. In the present study, the association of GalNAc-T3 expression with clinicopathologic features of pancreatic adenocarcinoma and patients' survival was examined. The level of expression of GalNAc-T3 was analyzed immunohistochemically in paraffin-embedded tumor samples from surgically resected specimens of 59 patients with pancreatic ductal adenocarcinoma. The correlations of GalNAc-T3 expression with clinicopathologic features and prognosis were studied. Thirty-five tumors showed high- intensity GalNAc-T3 staining, whereas 24 showed low-intensity staining. A close association was observed between GalNAc-T3 staining intensity and histologic differentiation and the stage of the tumors. The low-intensity group showed a high rate of the poorly differentiated subtype (p < 0.001) and T4 of the pTNM staging system (p < 0.05). These findings indicate that the expression of GalNAc-T3 is associated with the differentiation and aggressiveness of ductal adenocarcinoma of the pancreas., (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.

Ets-2, a transcriptional factor, has been linked to carcinoma progression but in-depth studies on its expression in human carcinoma have not been done. The present study investigated ets-2 expression in pancreatic adenocarcinoma. The ets-2 labeling index (LI) in normal pancreatic duct and pancreatic adenocarcinoma averaged 33.1+/-8.4 and 43.1+/-18.6, respectively. No statistical significance was found between the LI of normal duct and that of carcinoma with low biological aggressiveness. However, in cases with highly aggressive phenotypes such as stage IV, moderate or poor differentiation, lymph node metastasis, larger size, vascular invasion, lymphatic invasion, perineural invasion, retropancreatic invasion and capsular invasion, the ets-2 LI was significantly higher than in normal ducts and in cases with lower biological aggressiveness. Also, ets-2 transfected pancreatic carcinoma cells, when injected into athymic mice caused the formation of large tumors. These results suggest that ets-2 plays a role in the progression of pancreatic adenocarcinoma predominantly in the late phase.

The significance of p53, a prominent tumor suppressor gene, and its product in various neoplasms including pancreatic adenocarcinoma has been established. We investigated the expression of two types of homologue of p53, p73 and p63, in pancreatic adenocarcinoma by means of immunohistochemistry. Overexpression of p73 was observed in 45.6% of the cases and this phenomenon was more frequently seen in cystic adenocarcinomas than in ductal carcinomas. Furthermore, p73 overexpression was inversely linked to lymph node metastasis, tumor size, and Ki-67 labeling index. On the other hand, p63 overexpression was observed in 68.2% of the cases, but was not related to any clinicopathological features. No correlation was established between the expression of these proteins and aberrant p53 expression. These results suggest that decreased expression of p73 protein and over-expression of p63 protein may play a role in the development of pancreatic adenocarcinoma.

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.

Background: The precise intraoperative localization of insulinoma is essential for successful surgical treatment. In addition to various imaging modalities developed recently, arterial stimulation and venous sampling (ASVS) has also been used for tumor localization., Methods: Preoperative and intraoperative ASVS procedures were performed in 6 patients with insulinoma. Intraoperative ASVS was performed before and after tumor resection. Immunoreactive insulin (IRI) concentrations and the IRI ratio (IRI concentration at each time interval after calcium injection/baseline IRI concentration) were determined by the conventional or a quick IRI method., Results: The site of the tumor was identified preoperatively in all patients. The peak of the IRI ratio varied widely, but setting the cutoff value at 3.0 clearly differentiated peak IRA ratios in feeding arteries from those of nonfeeding arteries. Intraoperative ASVS showed a similar elevation of IRI levels, but the elevation disappeared after tumor resection in all but 1 patient. In 2 patients, resection of the tumor was confirmed during surgery by measuring IRI levels by the quick IRI method., Conclusions: A combination of ASVS and conventional imaging modalities is useful for precise localization of insulinoma. Resection of the tumor can be confirmed intraoperatively by comparing IRI levels associated with preoperative and postresective ASVS.

We present two cases of ductal adenocarcinoma of the pancreas with intratumoral calcification. The two cases indicate two different etiologies for intratumoral calcification in ductal adenocarcinoma. Thus, the possibility of adenocarcinoma should be considered when a tumor with intratumoral calcification is found, although the incidence of intratumoral calcification in the ductal adenocarcinoma of the pancreas remains rare.

Increased expression of sialyl Lewis antigens, sLe(a) and sLe(x), is frequent during malignant transformation and tumor progression of gastrointestinal cancers and it is assumed to be correlated with the increased metastatic potential of tumor cells and, consequently, with poor patient survival. To determine the influence of the increased expression of these antigens in disease progression of ductal carcinoma of the pancreas, immunohistochemical expressions of sLe(x) and sLe(a) in 51 ductal carcinomas of the pancreas were examined. We also examined the expression of glycosyltransferase genes, which are involved in the synthetic pathways of these antigens to understand the molecular mechanism involved in the increased expression of these antigens. Of the 51 primary ductal carcinomas of the pancreas, 40 (78.4%) were sLe(a)-positive and 11 (21.6%) were sLe(a)-negative; 16 (31.4%) were sLe(x)-positive and 35 (68.6%) were sLe(x)-negative. Although there were no significant differences in any examined clinicopathological factors such as age, sex, histological type, tumor size, presence of lymph node metastasis, or presence of vessel invasion between the positive and negative groups with both the sLe(a) and sLe(x) antigens, patient survival tended to be worse in the antigens-positive group than in the antigens-negative group. Increased expression, however, was not dependent on the increased expression of a single glycosyltransferase gene examined among five such genes, which are postulated to be responsible for the synthesis of the sLe(a) and sLe(x) epitopes in the glycosylation pathway. Furthermore, the increased expression of these antigens was not closely associated with mutations status of the K-ras or p53 genes. These findings suggested that increased expression of sialyl Lewis antigens are involved in pancreatic tumorigenesis and that the accumulation of genetic alterations or epigenetic changes is responsible for the molecular mechanisms of increased expression of the sLe(a) and sLe(x) antigens in ductal carcinomas of pancreas.

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.

We investigated the presence of K-ras gene mutation in plasma DNA and assessed its clinical value in patients with pancreatic adenocarcinoma. Mutations in codon 12 of the K-ras gene were examined by mutant allele-specific amplification method using DNA extracted from surgical specimens and plasma samples of 21 patients with pancreatic adenocarcinoma. K-ras gene mutation was detected in 15 of 21 (71%) primary tumors. In 9 of 15 (60%) patients with K-ras gene mutation-positive tumors, an identical mutation was detected in the plasma DNA. None of four patients with chronic pancreatitis or five healthy subjects had such mutations in plasma DNA. Tumors positive for K-ras gene mutation in plasma DNA were significantly larger (P = 0.04) and less likely to result in a curative cure after surgical resection (P = 0.09) than those negative for the mutation. Other clinicopathological features, including age, sex, histological type, mode of invasion, and metastasis, did not correlate with K-ras gene mutations in plasma DNA. Treatment resulted in disappearance of K-ras gene mutations in plasma DNA in six of nine (67%) patients. Three patients with a persistently positive K-ras gene mutation in pre- and post-treatment plasma samples were likely to show early recurrence or have a progressive disease. Our findings suggest that K-ras gene mutation can be detected in plasma DNA of patients with pancreatic adenocarcinoma. Detection of K-ras mutations in plasma may be clinically useful for evaluating tumor burden and efficacy of treatment.

Chemotherapy for pancreatic acinar cell carcinoma has not been well studied. We report herein one patient, in whom arterial chemotherapy with 5-FU, CDDP and MMC was extremely effective. He underwent distal pancreatectomy associated with partial resection of transverse colon. Hepatic recurrence was detected by MRI 8 months after the surgery. 5-FU (250 mg/day), CDDP (20 mg/day), and MMC (10 mg) was injected through a catheter introduced into the proper hepatic artery. His tumor became hardly detectable by MRI, and he was discharged about 1 month after admission. 5-FU (250 mg) and CDDP (20 mg) were injected every two weeks, and recurrence was not observed for 5 months.