Ruthenium(II)- and copper(I)-catalyzed synthesis of click-xylosides and assessment of their glycosaminoglycan priming activity.

Xylosides are small molecules that serve as primers of glycosaminoglycan biosynthesis. Xyloside mediated modulation of biological functions depends on the extent of priming activity and fine structures of primed GAG chains. In earlier studies, copper (Cu) catalyzed synthesis of click-xylosides and their priming activity were extensively documented. In the current study, ruthenium (Ru) mediated catalysis was employed to synthesize xylosides with a 1,5-linkage between the xylose and the triazole ring instead of a 1,4-linkage as found in Cu-catalyzed click-xyloside synthesis. Mono- and bis-click-xylosides were synthesized using each catalytic method and their glycosaminoglycan priming activity was assessed in vitro using a cellular system. Ru-catalyzed click-xylosides showed a higher priming activity as measured by incorporation of radioactive sulfate into primed glycosaminoglycan chains. This study demonstrates that altering the linkage of the aglycone to the triazole ring changes the priming activity. Computational modeling provides a molecular rationale for higher priming ability of Ru-mediated click-xylosides. Higher GAG priming activity is attributed to the formation of more stable interactions between the 1,5-linked xylosides and ß-1,4-galactosyltransferase 7 (ß4GalT7).

[A Case of Laparoscopic Surgery Performed for Locally Advanced Rectal Cancer Suspected of Invasion to Prostate].

A-58-year-old man was admitted to other hospital with complaints of anal pain and bloody stools, diagnosed as rectal cancer with invasion to prostate, and performed sigmoid colostomy. After taking 6 courses of mFOLFOX6 as preoperative chemotherapy, he introduced our hospital for the purpose of operation. Preoperative evaluation of chemotherapy was PR, but infiltration of the prostate remained. Therefore, laparoscopic abdomino-perineal resection of rectum, prostatectomy and urethral reconstruction by urethral-bladder anastomosis were performed. Postoperative course was good and he was discharged on 10 days after surgery. Currently 2 years after surgery, he has no dysurea and relapse free survival. This procedure was considered to be a very useful technique in that a good operative field and reliable resection can be obtained.

Pancreatic Fibroblasts Stimulate the Motility of Pancreatic Cancer Cells through IGF1/IGF1R Signaling under Hypoxia.

Pancreatic ductal adenocarcinoma (PDAC) is characterized by its hypovascularity, with an extremely poor prognosis because of its highly invasive nature. PDAC proliferates with abundant stromal cells, suggesting that its invasive activity might be controlled by intercellular interactions between cancer cells and fibroblasts. Using four PDAC cell lines and two pancreas cancer-associated fibroblasts (CAFs), the expression of insulin-like growth factor-1 (IGF1) and IGF1 receptor (IGF1R) was evaluated by RT-PCR, FACScan, western blot, or ELISA. Correlation between IGF1R and the hypoxia marker carbonic anhydrase 9 (CA9) was examined by immunohistochemical staining of 120 pancreatic specimens. The effects of CAFs, IGF1, and IGF1R inhibitors on the motility of cancer cells were examined by wound-healing assay or invasion assay under normoxia (20% O2) and hypoxia (1% O2). IGF1R expression was significantly higher in RWP-1, MiaPaCa-2, and OCUP-AT cells than in Panc-1 cells. Hypoxia increased the expression level of IGF1R in RWP-1, MiaPaCa-2, and OCUP-AT cells. CA9 expression was correlated with IGF1R expression in pancreatic specimens. CAFs produced IGF1 under hypoxia, but PDAC cells did not. A conditioned medium from CAFs, which expressed αSMA, stimulated the migration and invasion ability of MiaPaCa-2, RWP-1, and OCUP-AT cells. The motility of all PDAC cells was greater under hypoxia than under normoxia. The motility-stimulating ability of CAFs was decreased by IGF1R inhibitors. These findings might suggest that pancreas CAFs stimulate the invasion activity of PDAC cells through paracrine IGF1/IGF1R signaling, especially under hypoxia. Therefore the targeting of IGF1R signaling might represent a promising therapeutic approach in IGF1R-dependent PDAC.

A novel sol particle immunoassay for fecal calprotectin in inflammatory bowel disease patients.

BACKGROUND: We introduce a new assay method to measure the concentration of fecal calprotectin that can be applied in exclusive analyzers. The assay method uses gold colloidal reagents. In addition, we report performance evaluation results for the new method and the results of comparisons with enzyme-linked immunosorbent assay (ELISA) methods. METHODS: We evaluated the new method by linearity tests and within-run tests. In addition, we collected specimens from patients with a definitive diagnosis of inflammatory bowel disease (n=566) and examined them using the new method. The results were compared with those from 2 commercially available ELISA kits. RESULTS: In the linearity tests, the correlation coefficients between the measured values and the theoretical values were 0.9980-0.9990. In the within-run tests, the CVs were 3.4-4.3%. The correlation coefficients for our method and the 2 ELISA kits showed high correlations of 0.945 and 0.942. CONCLUSIONS: Our assay is capable of measuring calprotectin concentrations in feces, and has a similar performance to commercially available ELISA methods. Our method is an automated assay system, which is an easier, cheaper, and quicker measurement method than conventional ELISA kits. Therefore, our assay is suitable for daily clinical use.

[A case of unresectable Stage IV HER2-positive advanced gastric cancer treated by using trastuzumab combined with chemotherapy].

We observed a case of unresectable Stage IV human epidermal growth factor receptor 2(HER2)-positive advanced gastric cancer treated by using trastuzumab combined with chemotherapy. A 55-year-old man was admitted to our hospital because of dysphagia for 4 months. He was diagnosed with advanced gastric cancer with pyloric stenosis, multiple lung metastases, multiple liver metastases, peritoneal dissemination, and rectal muscle invasion. First, we initiated weekly chemotherapy with paclitaxel. Because the biopsy tissue was HER2-positive, we added trastuzumab to the weekly paclitaxel regimen. After 2 courses, dietary intake became possible, and he was then discharged from our hospital. However, after 3 courses of chemotherapy, disease progression was observed. He was admitted to the hospital again. We inserted a duodenal stent and changed the chemotherapy regimen to fluorouracil plus cisplatin(CDDP)plus trastuzumab. He did not experience any major adverse events during treatment. However, after 2 courses of chemotherapy, he died owing to cancerous peritonitis and intestinal obstruction.

[A case of multifocal colon carcinoma and cholecystolithiasis in an elderly patient].

An 83-year-old woman was admitted to our hospital because of general fatigue and symptoms of anemia. For 20 years, she had experienced right hypochondrial pain several times a year. Colonoscopic examination revealed a type 2 tumor at the ascending colon. The biopsy specimen was a Group 5 and type 0-IIa polyp at the transverse colon. The endoscopic mucosal resection (EMR) specimen was a well-differentiated adenocarcinoma(Stage pSM [2mm], ly0, v0). An apple core lesion in the cecum was detected by enema. Abdominal computed tomography demonstrated cholecystolithiasis and no metastasis or distant metastases. Therefore, a diagnosis of multifocal colon carcinoma and cholecystolithiasis was made. Expanding right hemicolectomy with cholecystectomy was performed. The patient was discharged without any complications. Subsequently, she underwent adjuvant chemotherapy for 6 months. At present, 1 year after surgery, the patient is still alive and has shown no signs of recurrence.

Hypoxia stimulates the EMT of gastric cancer cells through autocrine TGFß signaling.

Epithelial mesenchymal transition (EMT) is considered to be correlated with malignancy of cancer cells and responsible for cancer invasion and metastasis. We previously reported that distant metastasis was associated with hypoxia in gastric cancer. We therefore investigated the effect of hypoxic condition on EMT of gastric cancer cells. Gastric cancer cells were cultured in normoxia (21% O2) or hypoxia (1% O2) for 24 h. EMT was evaluated as the percentage of spindle-shaped cells in total cells. Effect of transforming growth factor ß1 (TGFß1) or tyrosine kinase inhibitors on the EMT was evaluated. The expression level of TGFß1 and TGFßR was evaluated by real time RT-PCR. The TGFß1 production from cancer cells was measured by ELISA. Hypoxia stimulated EMT of OCUM-2MD3 and OCUM-12 cells, but not that of OCUM-2M cells. The expression level of TGFß1 mRNA under hypoxia was significantly higher than that under normoxia in all of three cell lines. The expression level of TGFßR mRNA was significantly increased by hypoxia in OCUM-2MD3 cells, but not in OCUM-2M cells. TGFßR inhibitor, SB431542 or Ki26894, significantly suppressed EMT of OCUM-2MD3 and OCUM-12. TGFß1 production from OCUM-2MD3 and OCUM-12 cells was significantly increased under hypoxia in comparison with that under normoxia. These findings might suggest that hypoxia stimulates the EMT of gastric cancer cells via autocrine TGFß/TGFßR signaling.

MUC1 and HER2 might be associated with invasive phenotype of intraductal papillary mucinous neoplasm.

BACKGROUND/AIMS: The purpose of this study was to clarify the biomarkers which distinguish invasive Intraductal papillary mucinous neoplasms (IPMNs) from noninvasive IPMNs. METHODOLOGY: In tumor specimens from sixty patients with IPMNs (42 noninvasive IPMNs and 18 invasive IPMNs) who underwent surgical resection at our institute, we analyzed the correlation between the immunohistochemical expression level of MUC1, MUC2, MUC4, MUC5AC, p53, VEGFR2, HER2, and HER3. RESULTS: The 5-year survival rate was 100% in noninvasive IPMNs, while that of invasive IPMNs was only 36.5%. MUC1, MUC4, HER2 and HER3 were significantly associated with invasive IPMNs in univariate analysis. Multivariate analysis revealed that MUC1 and HER2 were significantly associated with invasive IPMNs. The 5-year survival of IPMN patients with either MUC1-positive and/or HER2-positive (54.5%) is significantly poorer than that of IPMN patients with MUC1 negative and HER2 negative (100%). CONCLUSIONS: MUC1 and HER2 might be closely associated with invasive phenotype of IPMNs.

VEGF-A/VEGFR-2 signaling plays an important role for the motility of pancreas cancer cells.

BACKGROUND: Pancreatic cancer is one of the most lethal solid tumors. Vascular endothelial growth factor receptors (VEGFRs) are expressed not only by endothelial cells but also by pancreatic cancer cells. VEGFRs might play an important role for the development of pancreatic cancer cells. The purpose of this study was to evaluate the efficacy of VEGF/VEGFR-2-targeted therapy in pancreatic carcinoma. METHODS: Five pancreatic carcinoma cell lines were used. The expression level of VEGFR-2 of cancer cells was examined by RT-PCR and Western blot. The effects of VEGFs, bevacizumab as an anti-VEGF antibody, sunitinib as a tyrosine kinase inhibitor against VEGFRs, and VEGF-R2 siRNA on the motility activity of pancreatic cancer cells were examined by invasion assay and wound healing assay. The effect of VEGF, bevacizumab, and sunitinib on the phosphorylation of VEGFR-2 and downstream effecter molecules, MAPK and PI3K, was examined by western blot. RESULTS: Pancreatic cancer cell lines expressed VEGFR-2. VEGF-A significantly increased the motility of pancreas cancer cells, which was inhibited by VEGFR-2 siRNA. Conditioned medium from pancreas cancer cells significantly stimulated the motility of pancreas cancer cells. VEGF/VEGFR inhibitors, bevacizumab and sunitinib, significantly decreased the motility of pancreas cancer cells. VEGFR-2 phosphorylation level of pancreas cancer cells was increased by VEGF-A. Bevacizumab and sunitinib decreased the level of VEGFR-2 phosphorylation, p-ERK, and p-Akt expression. VEGF-A decreased zonula occludens (ZO-1) or ZO-2 expression in pancreas cancer cells. CONCLUSIONS: VEGF-A/VEGFR-2 signaling plays an important role in inducing invasion and migration of pancreatic cancer cells.

Determination of N¹,N¹²-diacetylspermine in urine: a novel tumor marker.

N¹,N¹²-diacetylspermine (DiAcSpm) is a minor component of human urine that constitutes less than 0.5% of total polyamine species in human urine. Structurally related polyamines and acetylpolyamines were separated and analyzed by HPLC and gas chromatography, and refinement of these procedures led to the identification of this minor component. Subsequent analyses of urines from cancer patients as well as healthy persons revealed that DiAcSpm is a promising candidate for a novel tumor marker. It is much more sensitive than established tumor markers in detecting colorectal and other cancers, and most importantly, is able to detect 60% of early colorectal cancers confined to mucous membranes. Serum CEA is able to detect only about 10% of colorectal cancers at this stage. Collection of urine is easy and does not give any pain to patients, which adds another merit to urinary DiAcSpm as a tumor marker. DiAcSpm-specific antibodies were then developed for simpler determination of DiAcSpm in urine, and the antibodies were used to construct an ELISA system. More recently, a reagent kit for DiAcSpm determination based on colloidal gold aggregation that can be used with automatic biochemical analyzers was also developed.

Clinical significance of vimentin-positive gastric cancer cells.

BACKGROUND/AIM: Vimentin expression in epithelial cells is reported to be associated with the malignant phenotype of cancer cells in vitro. However, the clinical significance of vimentin expression in carcinomas is not well understood. The aim of this study was to clarify the significance of vimentin-positive gastric cancer (GC). PATIENTS AND METHODS: A total of 265 GCs were examined by immunofluorescent staining with antibodies against vimentin and carcinoembryonic antigen. GCs were determined to be vimentin-positive when cells were positive for both vimentin and carcinoembryonic antigen staining. RESULTS: A total of 86 (32%) of 265 GCs were vimentin positive. There was a statistically significant correlation between vimentin-positive GCs and advanced clinical stage (p<0.001), macroscopic scirrhous-type (p < 0.001), histological diffuse-type (p < 0.001), lymph node metastasis (p = 0.008) and lymphatic invasion (p = 0.013). The prognosis of patients with vimentin-positive GCs was significantly (p < 0.001) worse than that with vimentin-negative GCs. CONCLUSION: Vimentin expression might contribute to the high invasive phenotype of GC, and may be a useful biomarker to determine the biological aggressiveness of GC.

Significance of keratinocyte growth factor receptor in the proliferation of biliary tract cancer.

BACKGROUND/AIM: Biliary tract carcinoma (BTC) has extremely poor prognosis because of rapid cancer cell proliferation. The aim of this study was to clarify the significance of keratinocyte growth factor receptor (KGFR) in the proliferation of BTC. MATERIALS AND METHODS: The expression of KGFR in 34 surgical specimens of BTC was investigated by immunohistochemical staining. The effect of Ki23057, a small synthetic molecule that interrupts the autophosphorylation of KGFR, on the proliferation of human BTC cell lines was examined in vitro and in vivo. RESULTS: The prognosis for BTC patients with KGFR-positive tumour was significantly poorer than that for those with KGFR-negative tumour. KGF significantly stimulated the proliferation of BTC cell lines. Ki23057 significantly decreased the growth of BTC cells in vitro and in vivo. CONCLUSION: KGFR may play an important role in the proliferation of BTC. KGFR phosphorylation inhibitor, Ki23057, therefore appears to be therapeutically promising in BTC.

Phosphorylated smad2 in advanced stage gastric carcinoma.

BACKGROUND: Transforming growth factor ß (TGFß) receptor signaling is closely associated with the invasion ability of gastric cancer cells. Although Smad signal is a critical integrator of TGFß receptor signaling transduction systems, not much is known about the role of Smad2 expression in gastric carcinoma. The aim of the current study is to clarify the role of phosphorylated Smad2 (p-Smad2) in gastric adenocarcinomas at advanced stages. METHODS: Immunohistochemical staining with anti-p-Smad2 was performed on paraffin-embedded specimens from 135 patients with advanced gastric adenocarcinomas. We also evaluated the relationship between the expression levels of p-Smad2 and clinicopathologic characteristics of patients with gastric adenocarcinomas. RESULTS: The p-Smad2 expression level was high in 63 (47%) of 135 gastric carcinomas. The p-Smad2 expression level was significantly higher in diffuse type carcinoma (p = 0.007), tumours with peritoneal metastasis (p = 0.017), and tumours with lymph node metastasis (p = 0.047). The prognosis for p-Smad2-high patients was significantly (p = 0.035, log-rank) poorer than that of p-Smad2-low patients, while a multivariate analysis revealed that p-Smad2 expression was not an independence prognostic factor. CONCLUSION: The expression of p-Smad2 is associated with malignant phenotype and poor prognosis in patients with advanced gastric carcinoma.

Expression of a hypoxia-associated protein, carbonic anhydrase-9, correlates with malignant phenotypes of gastric carcinoma.

BACKGROUND/AIMS: Gastric cancers are characterized by a heterogeneously hypoxic environment. Hypoxia might stimulate the malignant potential of cancer cells. The purpose of our study was to clarify the significance of hypoxia in gastric carcinoma by evaluating the expression of a hypoxic marker, namely carbonic anhydrase-9 (CA-9). METHODS: A total of 265 patients who had undergone a resection of the primary tumor and were confirmed histologically to have sporadic gastric cancer were enrolled in this study. We evaluated the immunohistochemical expression of CA-9 in the paraffin-embedded specimens of 265 gastric adenocarcinomas. RESULTS: The CA-9 expression was positive in 88 (33%) of 265 gastric carcinomas. The CA-9 expression level was significantly high in cases of type 4 carcinoma (60%, p < 0.001) and diffuse type carcinoma (41%, p < 0.001), and significantly correlated with the invasion depth (p < 0.001), lymph node metastasis (p < 0.001) and lymphatic invasion p = 0.002). The prognosis for CA-9-positive patients was significantly poorer than that of CA-9-negative patients (p = 0.003, log-rank). CONCLUSION: Hypoxia might be associated with aggressive tumor phenotypes of gastric carcinomas. The hypoxic marker CA-9 may be a useful prognostic indicator.

Significance of phospho-vascular endothelial growth factor receptor-2 expression in pancreatic cancer.

Vascular endothelial growth factor receptors (VEGFRs) are mainly expressed by endothelial cells, but they are also expressed by some cancer cells, including pancreatic cancer. The objective of this study was to evaluate the significance of VEGFRs expression in pancreatic cancer cells. A total of 107 primary pancreatic tumors were stained with antibodies against VEGFR-1, VEGFR-2, phospho-VEGFR-2 (pVEGFR-2), VEGFR-3, VEGF-A, VEGF-C, and VEGF-D. VEGFR-2 and pVEGFR-2 expression were positive in 74 (69%) and 54 (50%) of 107 pancreatic cancers. There was a significant correlation (P < 0.001) between VEGFR-2 expression and pVEGFR-2 expression. pVEGFR-2 was significantly associated with invasion to the anterior capsule of pancreas (P = 0.032) and arterial invasion (P = 0.012). In contrast, VEGFR-1 and VEGFR-3 expression was only observed in 13 (12%) and 15 (14%) of 107 pancreatic cancers, and was not associated with any clinicopathological features. The prognosis of pVEGFR-2 positive patients with stage IIA tumors was significantly (P = 0.0441) poorer than that of pVEGFR-2-negative patients. VEGF-A, VEGF-C, and VEGF-D expression was positive in 42 (39%), 82 (77%), and 39 (36%) of 107 pancreatic cancers, respectively. The prognosis for VEGF-A-positive patients was significantly (P = 0.0425) poor, but not for VEGF-C-positive and VEGF-D-positive patients. A multivariate analysis indicated pVEGFR-2 expression to be an independent prognostic factor, but not VEGF-A. These findings suggested that VEGFR-2 signaling might therefore be associated with the prognosis of patients with pancreatic cancer. The expression of pVEGFR-2 might be a novel predictive prognostic marker for patients with pancreatic cancers, especially at clinical stage IIA.

A retrospective study of immunochemical fecal occult blood testing for colorectal cancer detection.

BACKGROUND: Colonoscopic examination is the common pathway for positive screening tests detecting colorectal lesions. We evaluated a specific, quantitative high-throughput automatic immunochemical fecal occult blood test (Auto iFOBT) method for colorectal cancer (CRC) screening and to determine its concordance with physician assessments informed by complete colonoscopy, the gold-standard technique for evaluation of the colonic mucosa. METHODS: 1200 CRC symptomatic patients were recruited for a retrospective investigation. Colorectal neoplasia were localized by colonoscopy and cancer outcomes were enumerated according to severity. In addition, stool samples were collected and analyzed by Auto iFOBT to derive sensitivity, specificity, and positive predictive value. Qualitative colonoscopy and Auto iFOBT results were correlated, as were cancer severities and quantitative hemoglobin concentrations. RESULTS: Ninety-one patients were found positive for CRC; 50 mucosal, 20 submucosal, and 21 advanced. At standard cutoff, sensitivity was 60%, 90%, and 95%, respectively. Specificity and positive predictive value for all neoplasia and cancers were 89.6% and 86.4%, and 60.9% and 33.7%, respectively. Cancer severities could be approximated roughly according to hemoglobin concentrations. CONCLUSIONS: Specific qualitative 2-day Auto iFOBT is an accurate tool for the detection of colorectal cancer and therefore provides the basis for a large-scale screening program.

Myofibroblasts are associated with the progression of scirrhous gastric carcinoma.

Fibroblasts, particularly myofibroblasts, affect the malignant progression of cancer cells in vitro. However, to date few reports have addressed the clinical significance of myofibroblasts in the gastric cancer microenvironment. This study examined the correlation between myofibroblast expression and clinicopathological features in gastric carcinoma. A total of 265 primary gastric tumors resected by gastrectomy were stained with antibodies against α-smooth muscle actin and vimentin. Stromal cells positive for vimentin were considered to be fibroblasts. Myofibroblasts were defined as fibroblasts positive for α-smooth muscle staining. Myofibroblast-positive gastric carcinoma was established when myofibroblasts accounted for more than 25% of fibroblasts in the cancer stroma. Myofibroblast expression was positive in 92 (35%) of the 265 gastric carcinomas. Myofibroblast expression showed a significantly (p<0.001) high frequency in advanced gastric cancers (76 of 146), in comparison to the early stage cancers (16 of 119). Taken together, there was a statistically significant correlation between myofibroblast expression and scirrhous type gastric cancer (p<0.001), lymph node metastasis (p<0.001), lymphatic invasion (p<0.001) and peritoneal dissemination (p=0.005). The prognosis of patients with tumors positive for myofibroblast expression was significantly (p<0.001) worse, while a multivariate analysis revealed that myofibroblast expression was not an independent prognostic factor. These findings suggest that myofibroblasts are associated with scirrhous gastric cancer. Overexpression of myofibroblasts may therefore be a useful prognostic indicator of gastric carcinoma.

[A case of liver metastasis of pancreatic cancer that was resistant to S-1 and gemcitabine successfully treated by 5-FU and cisplatin hepatic arterial infusion].

We report a case of postoperative liver metastasis of pancreatic cancer that was resistant to S-1 and gemcitabine (GEM) successfully treated by hepatic arterial infusion of 5-fluorouracil (5-FU) and cisplatin (CDDP). A 70s woman was referred to our hospital for treatment of a pancreatic head cancer in November 2007. Pancreaticoduodenectomy with a regional lymphadectomy was performed in December 2007 and the pathological stage was Stage IVa. Adjuvant chemotherapy of UFT was administered one month after operation. However, a second chemotherapy of S-1 was administered because DUPAN-2 levels showed a high range 8 months after operation. Ten months after operation, abdominal computed tomography demonstrated a 2 cm tumor in the liver. Although, we performed a systemic GEM infusion and a combination of GEM and S-1, the liver metastasis had progressed. Then, hepatic arterial infusion (HAI) chemotherapy of 5-FU/CDDP was instituted weekly. This efficacy maintained a Partial Response from the start of HAI to the fifth month. She is alive to date, maintaining a stable tumor growth of 30 months after surgery. We suggest that HAI chemotherapy of 5-FU+CDDP might be an effective treatment to liver metastasis of pancreatic cancer and prolong prognosis of those patients.

Synergistic antiproliferative effect of mTOR inhibitors in combination with 5-fluorouracil in scirrhous gastric cancer.

The aim of this study is to clarify the benefit of combination chemotherapy in gastric cancer based on a cell-signal inhibitor and an anticancer drug. Two scirrhous gastric cancer cell lines and two non-scirrhous gastric cancer cell lines were used. Five anticancer drugs (5-fluorouracil [5FU], paclitaxel, oxaliplatin, irinotecan, and gemcitabine) and four cell-signal inhibitors, mammalian target of rapamycin (mTOR) inhibitor, glycogen synthase kinase 3beta, p38alphabetaMAPK, and cyclin-dependent kinase, were used. The proliferation of cancer cells was examined by MTT assay and in vivo study. The apoptosis of cancer cells and the expression of apoptosis-related molecules were examined by flow cytometry, real-time PCR, and immunostaining. mTOR inhibitors with 5FU showed a synergistic antiproliferative effect in scirrhous gastric cancer, whereas the other signal inhibitors showed no synergistic effect with any anticancer drugs. mTOR inhibitor decreased the IC(50) of 5FU and increased the apoptosis rate in scirrhous gastric cancer cells, but not in non-scirrhous gastric cancer cells. The pan-caspase inhibitor, zVAD-fmk, inhibits apoptosis induced in combination with 5FU and mTOR inhibitor. mTOR inhibitor decreased dihydropyrimidine dehydrogenase, thymidylatesynthase, and bcl-2 expression, and increased caspase-3 and p21 expression of scirrhous gastric cancer cells, but did not affect those of non-scirrhous gastric cancer cells. In an in vivo study, mTOR inhibitor significantly enhanced the therapeutic efficacy of S1, an analog of 5FU. These findings suggest that mTOR inhibitor interacts with 5FU in a synergistic manner in scirrhous gastric cancer cells by the activation of the apoptosis signal. Therefore, mTOR inhibitor is a promising therapeutic agent in combination with 5FU in scirrhous gastric cancer.

[A case of liver metastasis of mixed acinar-endocrine carcinoma treated with various loco-regional cancer therapies].

Mixed acinar-endocrine carcinoma of pancreas is a very rare tumor. We report a 60s female patient with pancreatic mixed acinar-endocrine carcinoma and liver metastasis. The patient admitted for further examination of pancreatic head mass. Computed tomography scan of abdomen showed a large tumor in pancreatic head and liver tumor. Angiography revealed a presence of embolism in portal vein. We conducted a pylorus-preserved pancreatoduodenectomy with resection of the portal vein on the diagnosis of acinar cell carcinoma by fine needle aspiration biopsy. Pathological examination showed a mixed acinar-endocrine carcinoma. Following the operation, the liver metastasis was controlled with various loco-regional cancer therapies.