Ryosuke Amano

HER2 overexpression correlates with survival after curative resection of pancreatic cancer.

HER2 overexpression has been linked to clinical outcomes in several solid tumors, such as breast cancer. However, the correlation between HER2 overexpression and survival in pancreatic carcinoma remains unclear. The impact of HER2 overexpression on survival in pancreatic ductal cancer was examined. Immunohistochemical staining of 129 pancreatic cancers without hematogenous metastases or peritoneal dissemination treated by macroscopically curative resection were analyzed in association with survival data. To determine HER2 overexpression in this pancreatic cancer series, the polyclonal antibody included in HercepTest, which is used worldwide for clinical examination of HER2 overexpression in breast cancer, was used. Immunoreactivity was classified according to the scale presented in the HercepTest Scoring Guidelines. Twenty‐two cases (17.1%) had a score of 0, 28 cases (21.7%) had of a score of 1+, 41 cases (31.8%) had a score of 2+, and 38 cases (29.4%) had a score of 3+. Therefore, HER2 overexpression (score 2+ or 3+) was observed in 79 cases (61.2%). Patients with HER2 overexpression tumors had significantly shorter survival times than those with HER2 normal expression (score 0 or 1+) tumors (median survival time, 14.7 vs 20.7 months, respectively; P = 0.0078 on the log‐rank test). On multivariate survival analysis, HER2 overexpression remained an independent prognostic factor (hazard ratio, 1.806; P = 0.0258). A significant percentage of pancreatic cancers were demonstrated to have HER2 overexpression, and overexpression of this tyrosine kinase receptor proved to be an independent factor for a worse prognosis. These results should encourage further investigation of treatments using new molecular targeting agents against HER2 protein to improve the survival of pancreatic cancer patients. (Cancer Sci 2009; 100: 1243–1247)

Chemokine Receptor CCR7 Expression Correlates with Lymph Node Metastasis in Pancreatic Cancer

Aims: The clinical significance of chemokine receptor CCR7 expression in pancreatic ductal cancer was investigated. Methods: Immunohistochemical staining of 89 pancreatic cancers treated macroscopically with curative resection without hematogenous metastases or peritoneal dissemination were analyzed in association with clinicopathological data. Results: The positivity of CCR7 in pancreatic cancer was 32.6% (29/89). A significant correlation was detected between CCR7-positive expression and lymph node metastasis. Patients with CCR7-positive tumors had significantly shorter survival times than those with CCR7-negative tumors (median, 12.8 vs. 21.9 months, respectively; p = 0.0039). CCR7 expression was an independent prognostic factor (hazard ratio, 1.949; p = 0.0364) by multivariate survival analysis; however, it was not an indicator for any particular site of recurrence. Conclusion: The survival impact of CCR7 expression on resectable pancreatic cancer may be associated with lymphatic spread. The results from the present study should foster further investigation of treatments using an inhibitor for the CCR7 protein to improve the survival of pancreatic cancer.

RNA interference suppression of mucin 5AC (MUC5AC) reduces the adhesive and invasive capacity of human pancreatic cancer cells

BackgroundMUC5AC is a secretory mucin normally expressed in the surface muconous cells of stomach and bronchial tract. It has been known that MUC5AC de novo expression occurred in the invasive ductal carcinoma and pancreatic intraepithelial neoplasm with no detectable expression in normal pancreas, however, its function remains uncertain. Here, we report the impact of MUC5AC on the adhesive and invasive ability of pancreatic cancer cells.MethodsWe used two MUC5AC expressing cell lines derived from human pancreatic cancer, SW1990 and BxPC3. Small-interfering (si) RNA directed against MUC5AC were used to assess the effects of MUC5AC on invasion and adhesion of pancreas cancer cells in vitro and in vivo. We compared parental cells (SW1990 and BxPC3) with MUC5AC suppressed cells by si RNA (si-SW1990 and si-BxPC3).ResultsMUC5AC was found to express in more than 80% of pancreatic ductal carcinoma specimens. Next we observed that both of si-SW1990 and si-BxPC3 showed significantly lower adhesion and invasion to extracellular matrix components compared with parental cell lines. Expression of genes associated with adhesion and invasion including several integerins, matrix metalloproteinase (MMP) -3 and vascular endothelial growth factor (VEGF) were down-regulated in both MUC5AC suppressed cells. Furthermore, production of VEGF and phosphorylation of VEGFR-1 were significantly reduced by MUC5AC down regulation. Both of si-SW1990 and si-BxPC3 attenuated activation of Erk1/2. In vivo, si-SW1990 did not establish subcutaneous tumor in nude mice.ConclusionsKnockdown of MUC5AC reduced the ability of pancreatic cancer cells to adhesion and invasion, suggesting that MUC5AC might contribute to the invasive motility of pancreatic cancer cells by enhancing the expression of integrins, MMP-3, VEGF and activating Erk pathway.

IGF-1 receptor and IGF binding protein-3 might predict prognosis of patients with resectable pancreatic cancer

BackgroundThe present study aimed to elucidate the clinicopathologic role of insulin-like growth factor-1 receptor (IGF1R) and IGF binding protein-3 (IGFBP3) in patients with pancreatic cancer. The function of IGFBP3 is controversial, because both inhibition and facilitation of the action of IGF as well as IGF-independent effects have been reported. In this study, IGF1R and IGFBP3 expression was examined, and their potential roles as prognostic markers in patients with pancreatic cancer were evaluated.MethodsClinicopathological features of 122 patients with curatively resected pancreatic cancer were retrospectively reviewed, and expression of IGF1R and IGFBP3 was immunohistochemically analyzed.ResultsExpression of IGF1R and IGFBP3 was observed in 50 (41.0%) and 37 (30.3%) patients, respectively. IGF1R expression was significantly associated with histological grade (p = 0.037). IGFBP3 expression had a significant association with tumor location (p = 0.023), and a significant inverse association with venous invasion (p = 0.037). Tumors with IGF1R-positive and IGFBP3-negative expression (n = 32) were significantly frequently Stage II and III (p = 0.011). The prognosis for IGF1R positive patients was significantly poorer than that for IGF1R negative patients (p = 0.0181). IGFBP3 protein expression did not correlate significantly with patient survival. The subset of patients with both positive IGF1R and negative IGFBP3 had worse overall survival (8.8 months versus 12.6 months, respectively, p < 0.001).ConclusionIGF1R signaling might be associated with tumor aggressiveness, and IGFBP3 might show antiproliferative effects in pancreatic cancer. Both high IGF1R expression and low IGFBP3 expression represent useful prognostic markers for patients with curatively resected pancreatic cancer.

VEGF-A/VEGFR-2 Signaling Plays an Important Role for the Motility of Pancreas Cancer Cells

BackgroundPancreatic 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.MethodsFive 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.ResultsPancreatic 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.ConclusionsVEGF-A/VEGFR-2 signaling plays an important role in inducing invasion and migration of pancreatic cancer cells.

Prognostic significance of the lymphocyte-to-monocyte ratio in patients with metastatic colorectal cancer

AIM To evaluate the prognostic significance of the lymphocyte to monocyte ratio (LMR) in patients with unresectable metastatic colorectal cancer who received palliative chemotherapy. METHODS A total of 104 patients with unresectable metastatic colorectal cancer who underwent palliative chemotherapy were enrolled. The LMR was calculated from blood samples by dividing the absolute lymphocyte count by the absolute monocyte count. Pre-treatment LMR values were measured within one week before the initiation of chemotherapy, while post-treatment LMR values were measured eight weeks after the initiation of chemotherapy. RESULTS The median pre-treatment LMR was 4.16 (range: 0.58-14.06). We set 3.38 as the cut-off level based on the receiver operating characteristic curve. Based on the cut-off level of 3.38, 66 patients were classified into the high pre-treatment LMR group and 38 patients were classified into the low pre-treatment LMR group. The low pre-treatment LMR group had a significantly worse overall survival rate (P = 0.0011). Moreover, patients who demonstrated low pre-treatment LMR and normalization after treatment exhibited a better overall survival rate than the patients with low pre-treatment and post-treatment LMR values. CONCLUSION The lymphocyte to monocyte ratio is a useful prognostic marker in patients with unresectable metastatic colorectal cancer who receive palliative chemotherapy.

The outcome of surgical treatment for elderly patients with gastric carcinoma

The aim of this study was to clarify the operative mortality and long‐term survival of gastrectomy for elderly patients with gastric cancer.

HER3 Overexpression as an Independent Indicator of Poor Prognosis for Patients with Curatively Resected Pancreatic Cancer

Objective: The association between human epidermal growth factor receptor 3 (HER3) overexpression and survival in patients with curatively resected pancreatic cancer was investigated. Methods: Tissue samples from 126 pancreatic cancers without hematogenous or peritoneal metastases recovered from macroscopically curative resection were fixed with formalin, embedded in paraffin and subjected to immunohistochemical staining. Semiquantitative scores of zero (no staining or staining in less than 10% of cancer cells), 1+, 2+, or 3+ were assigned to each sample based on the intensity of staining. Scores of 2+ or 3+ were defined as HER3-positive staining, i.e., HER3 overexpression. Results: HER3 overexpression was observed in 52 of the 126 tissue samples (41.3%). There were no associations between HER3 overexpression and clinicopathological factors, including tumor location, tumor size, tumor differentiation, T/N categories according to the International Union against Cancer, and serum carbohydrate antibody 19-9 level (CA19-9). Univariate analysis demonstrated the median survival time of patients with HER3 overexpression was 37.2 months, while that of patients with HER3-negative samples was 58.6 months (p = 0.008). HER3 overexpression, lymph node metastasis, and elevated serum CA19-9 level were independent predictors of poor prognosis based on multivariate survival analysis. Conclusion: A new prognostic predictor, HER3 overexpression, was identified for resected pancreatic cancer.

In vitro and in vivo evidence that a combination of lapatinib plus S-1 is a promising treatment for pancreatic cancer

Lapatinib is a small molecule inhibitor of both HER2 and the epidermal growth factor receptor (EGFR). We investigated the effect of treatment with lapatinib alone or in combination with a fluoropyrimidine derivative S‐1 against pancreatic cancer. The HER2/EGFR expression in each of the four pancreatic cancer cell lines MiaPaca‐2, PANC‐1, Capan‐1 and Capan‐2 was measured by flow cytometry. The anti‐tumor effects of lapatinib (30 mg/kg) and/or S‐1 (10 mg/kg) were evaluated using female BALB/c nude mice xenografts generated using these four cell lines. Synergy between lapatinib and S‐1 was examined by median effect analysis in vitro. Resected pancreatic cancer tissues from 137 patients were immunohistochemically stained with anti‐human HER2 and EGFR antibodies. The administration of lapatinib as a single agent substantially suppressed tumor growth in vivo of all pancreatic cancer cell lines examined. A strong correlation was observed between HER2 expression and the anti‐tumor effect of lapatinib in vivo. Lapatinib synergized with S‐1 to inhibit the tumor growth of MiaPaca‐2 and PANC‐1 xenografts. When used as a single agent in vitro, lapatinib barely inhibit the cell growth of any cell line. However, lapatinib synergized with the anti‐tumor activity of the S‐1 components 5‐fluorouracil and 5‐chloro‐2,4‐dihydrogenase against all cell lines. Immunohistochemical staining demonstrated that 70% of the pancreatic cancers overexpressed HER2 and/or EGFR. Both lapatinib monotherapy and combined treatment with S‐1 may be promising treatments for patients with pancreatic cancers; the majority these cancers express lapatinib target molecules. (Cancer Sci 2009; 00: 000–000)

Predictive value of expression of ERCC 1 and GST-p for 5-fluorouracil/oxaliplatin chemotherapy in advanced colorectal cancer.

BACKGROUND/AIMS The aim of this study was to determine whether expression of the excision repair cross complementing protein (ERCC1), glutathione S-transferase pi (GST-p) and thymidylate synthase (TS) predict response in patients with advanced colorectal cancer treated with 5-fluorouracil/oxaliplatin chemotherapy. METHODOLOGY The study population consisted of 39 patients with advanced colorectal cancer (median age, 65 years). Patients were treated with the modified FOLFOX 6 regimen. The expression of ERCC-1, GST-p and TS of primary tumors were examined by immunohistochemistry. RESULTS The response rate of modified FOLFOX 6 chemotherapy was 51.3%. The positive rates of ERCC-1, GST-p and TS were 43.6%, 33.3% and 66.7%, respectively. The patients without ERCC-1 (p=0.0248) or GST-p? (p=0.0019) expression were more likely to respond to chemotherapy. TS expression did not correlate with chemotherapeutic response. CONCLUSIONS Immunohistochemical studies for ERCC-1 and GST-p may be useful in prediction of the response to 5-fluorouracil/oxaliplatin chemotherapy in advanced colorectal cancer patients.