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.

Clinical practice guidelines for the management of biliary tract cancers 2015: the 2nd English edition.

BACKGROUND: The Japanese Society of Hepato-Biliary-Pancreatic Surgery launched the clinical practice guidelines for the management of biliary tract and ampullary carcinomas in 2008. Novel treatment modalities and handling of clinical issues have been proposed after the publication. New approaches for editing clinical guidelines, such as the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system, also have been introduced for better and clearer grading of recommendations. METHODS: Clinical questions (CQs) were proposed in seven topics. Recommendation, grade of recommendation and statement for each CQ were discussed and finalized by evidence-based approach. Recommendation was graded to grade 1 (strong) and 2 (weak) according to the concept of GRADE system. RESULTS: The 29 CQs covered seven topics: (1) prophylactic treatment, (2) diagnosis, (3) biliary drainage, (4) surgical treatment, (5) chemotherapy, (6) radiation therapy, and (7) pathology. In 27 CQs, 19 recommendations were rated strong and 11 recommendations weak. Each CQ included the statement of how the recommendation was graded. CONCLUSIONS: This guideline provides recommendation for important clinical aspects based on evidence. Future collaboration with cancer registry will be a key for assessment of the guidelines and establishment of new evidence. Free full-text articles and a mobile application of this guideline are available via http://www.jshbps.jp/en/guideline/biliary-tract2.html.

Classification of biliary tract cancers established by the Japanese Society of Hepato-Biliary-Pancreatic Surgery: 3(rd) English edition.

The 3(rd) English edition of the Japanese classification of biliary tract cancers was released approximately 10 years after the 5(th) Japanese edition and the 2(nd) English edition. Since the first Japanese edition was published in 1981, the Japanese classification has been in extensive use, particularly among Japanese surgeons and pathologists, because the cancer status and clinical outcomes in surgically resected cases have been the main objects of interest. However, recent advances in the diagnosis, management and research of the disease prompted the revision of the classification that can be used by not only surgeons and pathologists but also by all clinicians and researchers, for the evaluation of current disease status, the determination of current appropriate treatment, and the future development of medical practice for biliary tract cancers. Furthermore, during the past 10 years, globalization has advanced rapidly, and therefore, internationalization of the classification was an important issue to revise the Japanese original staging system, which would facilitate to compare the disease information among institutions worldwide. In order to achieve these objectives, the new Japanese classification of the biliary tract cancers principally adopted the 7(th) edition of staging system developed by the International Union Against Cancer (UICC) and the American Joint Committee on Cancer (AJCC). However, because there are some points pending in these systems, several distinctive points were also included for the purpose of collection of information for the future optimization of the staging system. Free mobile application of the new Japanese classification of the biliary tract cancers is available via http://www.jshbps.jp/en/classification/cbt15.html.

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.

Randomized controlled trial for efficacy of nafamostat mesilate in preventing post-endoscopic retrograde cholangiopancreatography pancreatitis.

OBJECTIVE: The objective of this study was to investigate whether prophylactic administration of nafamostat mesilate reduces the incidence of post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis (PEP), its efficacy, and risk factors for PEP. METHODS: Potential subjects comprised 876 patients who underwent ERCP between September 2008 and February 2011. Of these, 58 patients were excluded after meeting exclusion criteria, and 818 patients were randomized. Patients in the nafamostat mesilate group were administered 20 mg of nafamostat mesilate dissolved in 500 mL of 5% glucose solution, whereas the control group received 500 mL of 5% glucose solution alone, over 2 hours from the start of ERCP. RESULTS: Post-ERCP pancreatitis occurred in 5.1% (41 patients) overall, with a significantly lower frequency in the nafamostat mesilate group (3.5%) than in the control group (6.7%; P = 0.0349). Analysis of the 322 patients who had undergone ERCP for the first time (n = 158 in the nafamostat mesilate group; n = 164 in the control group) found that PEP again significantly less frequently occurred in the nafamostat mesilate group (5.7%) than in the control group (13.4%; P = 0.0172). CONCLUSIONS: Our randomized controlled study suggested that short-term administration of nafamostat mesilate 20 mg may reduce the incidence of PEP.

[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.

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.

Phase II clinical study of alternate-day oral therapy with S-1 as first-line chemotherapy for locally advanced and metastatic pancreatic cancer.

PURPOSE: Based on the results of first-line chemotherapy for advanced pancreatic cancer, S-1 was confirmed to be non-inferior to gemcitabine. However, the recommended regimen of 4 weeks of administration followed by 2 weeks of drug withdrawal frequently causes adverse effects. On the other hand, we experienced in clinical practice that alternate-day administration of S-1 reduced adverse effects and were tolerable for advanced pancreatic cancer patients unwilling to continue the standard daily administration. We therefore conducted a multicenter cooperative prospective study to compare daily with alternate-day administration of S-1 for advanced pancreatic cancer. METHODS: Patients with advanced pancreatic cancer were eligible for enrollment in this trial. S-1 was administered at a dose of 40-60 mg twice daily, calculated according to body surface area, on Monday, Wednesday, Friday, and Sunday. Each treatment cycle was 42 days. The primary end point was overall survival (OS). Secondary end points were safety, response rate (RR), progression-free survival (PFS), and time to treatment failure (TTF). RESULTS: Forty-eight patients were evaluable for response. OS as the primary end point was 8.4 months (95 % CI 5.4-10.8), and the 1-year survival rate was 29.2 %. PFS was 5.5 months, and TTF was 3.9 months. RR was 10.4 %, and the disease control rate was 79.2 %. Grade 3/4 hematological and non-hematological toxicities were minor. All of these adverse reactions were tolerable and reversible. CONCLUSIONS: The current data demonstrate the mitigation of adverse effects with alternate-day administration of S-1, and this appears to be a more sustainable option for advanced pancreatic cancer.

Pancreatobiliary reflux in individuals with a normal pancreaticobiliary junction: a prospective multicenter study.

BACKGROUND: Pancreatobiliary reflux (PBR) can occur in individuals without pancreaticobiliary maljunction. The aim of this study was to elucidate the incidence of PBR in individuals with a normal pancreaticobiliary junction and its impact on the biliary tree. METHODS: Data were prospectively collected from 15 centers on 420 patients with a morphologically normal pancreaticobiliary junction who had undergone bile sampling and measurement of the biliary amylase level. We investigated the incidence and predictive factors for high biliary amylase levels (HBAL), as well as the relationship of HBAL with biliary malignancy. RESULTS: Twenty-three patients (5.5%) showed HBAL (≥10,000 IU/L). Univariate analysis showed that risk factors for the elevation of biliary amylase levels were the existence of a relatively long common channel (≥5 mm), acute pancreatitis, and papillitis. Multivariate analysis revealed that only the existence of a relatively long common channel was a significant factor for PBR. Biliary amylase levels in patients with a relatively long common channel were significantly higher than in patients without a long common channel (12,333 vs. 2,070 IU/L, P = 0.001). The incidence of HBAL (P < 0.001), as well as the overall biliary amylase levels (P = 0.007) were significantly higher in patients with gallbladder cancer than in those without gallbladder cancer. CONCLUSIONS: The PBR was frequently observed in individuals with a relatively long common channel. Patients showing HBAL with normal pancreaticobiliary junction are at high risk for gallbladder cancer.

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.

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.

The usefulness of (18)F-FDG PET/MRI fusion image in diagnosing pancreatic tumor: comparison with (18)F-FDG PET/CT.

PURPOSE: This study aimed at demonstrating the feasibility of retrospectively fused (18)F FDG-PET and MRI (PET/MRI fusion image) in diagnosing pancreatic tumor, in particular differentiating malignant tumor from benign lesions. In addition, we evaluated additional findings characterizing pancreatic lesions by FDG-PET/MRI fusion image. METHODS: We analyzed retrospectively 119 patients: 96 cancers and 23 benign lesions. FDG-PET/MRI fusion images (PET/T1 WI or PET/T2WI) were made by dedicated software using 1.5 Tesla (T) MRI image and FDG-PET images. These images were interpreted by two well-trained radiologists without knowledge of clinical information and compared with FDG-PET/CT images. We compared the differential diagnostic capability between PET/CT and FDG-PET/MRI fusion image. In addition, we evaluated additional findings such as tumor structure and tumor invasion. RESULTS: FDG-PET/MRI fusion image significantly improved accuracy compared with that of PET/CT (96.6 vs. 86.6 %). As additional finding, dilatation of main pancreatic duct was noted in 65.9 % of solid types and in 22.6 % of cystic types, on PET/MRI-T2 fusion image. Similarly, encasement of adjacent vessels was noted in 43.1 % of solid types and in 6.5 % of cystic types. Particularly in cystic types, intra-tumor structures such as mural nodule (35.4 %) or intra-cystic septum (74.2 %) were detected additionally. Besides, PET/MRI-T2 fusion image could detect extra benign cystic lesions (9.1 % in solid type and 9.7 % in cystic type) that were not noted by PET/CT. CONCLUSIONS: In diagnosing pancreatic lesions, FDG-PET/MRI fusion image was useful in differentiating pancreatic cancer from benign lesions. Furthermore, it was helpful in evaluating relationship between lesions and surrounding tissues as well as in detecting extra benign cysts.

Selection of prophylactic antibiotics according to the microorganisms isolated from surgical site infections (SSIs) in a previous series of surgeries reduces SSI incidence after pancreaticoduodenectomy.

BACKGROUND: The incidence of surgical site infections (SSIs) is high after pancreaticoduodenectomy (PD). METHODS: We divided 116 consecutive patients who underwent PD into an early group (n = 58) and a later group (n = 58) according to time of surgery. In both groups, endoscopic retrograde biliary drainage was mainly employed for the patients with obstructive jaundice. In the later group, prophylactic antibiotics were selected according to the susceptibility of microorganisms isolated from SSIs in the early group. The incidence of SSIs was compared between the groups. RESULTS: The background characteristics (including methods of preoperative biliary drainage and microorganisms in the bile obtained before or during operation) of the patients were not significantly different between the groups, except for the serum albumin level, which was lower in the later group than in the early group (P = 0.0026). The incidence of SSIs was significantly lower in the later group (24.1 %) than in the early group (46.6 %) (P = 0.0116). Belonging to the later group was one independent negative risk factor for SSI. CONCLUSIONS: Selection of prophylactic antibiotics on the basis of microorganisms isolated from SSIs in the early group contributed to the reduced incidence of SSIs in the later group after PD.

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.

Difference in recurrence patterns between anastomosis and strictureplasty after surgical treatment for crohn disease.

This study aimed to investigate whether the initial indication for surgery or type of surgery (strictureplasty or resection) performed determines recurrence patterns in patients with Crohn disease. Recurrence patterns of 41 patients (31 patients: only resection and anastomosis of the intestine, and 10 patients: strictureplasty with/without resection and anastomosis) who underwent operation for recurrent Crohn disease (June 2002-December 2010) were evaluated. Strictureplasty for nonperforating disease was performed at 17 sites, and reoperation was required at 11 sites (10 sites for nonperforating disease and 1 site for perforating disease). There was a significant difference in the recurrence pattern in patients who underwent resection and anastomosis (P < 0.01) and in patients who underwent strictureplasty with resection and anastomosis (P < 0.05) between sites at which resection and anastomosis was performed for nonperforating and for perforating disease. Initial indication for surgery, but not the type of surgery, appeared to determine recurrence patterns.

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.

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.

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.

[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.