Hiroyuki Shinchi

Significance of M2-Polarized Tumor-Associated Macrophage in Pancreatic Cancer

BACKGROUND The roles of infiltrating macrophages within the tumor microenvironment are complex because of their functional variety. The aim of this study is to examine the role and prognostic significance of tumor-associated macrophages (TAMs) that have an M2 polarized function in pancreatic cancer. MATERIALS AND METHODS Formalin-fixed, paraffin-embedded blocks were obtained from 76 patients with pancreatic head cancer. All patients underwent macroscopic curative resection. We assessed the number of infiltrating macrophages within the tumor invasive front by not only CD68 but also by CD163 and CD204, which are specific receptors on M2-polarized macrophages. Furthermore, to evaluate lymphangiogenesis, we measured the density of lymphatic vessels in the tumor invasive front by using D2-40. RESULTS High incidence of lymph node metastasis was shown in cases with a high number of CD163- or CD204-positive macrophages. Significantly increased lymphatic vessel density (LVD) was shown in cases with lymph node metastasis compared with cases without lymph node metastasis (P=0.0094). Significantly increased LVD (P=0.0175) and a poor prognosis (P=0.0171) were shown in cases with a high number of macrophages that express CD163 or CD204, however, there was no significant difference according to the number of CD68-positive macrophages. CONCLUSIONS M2-polarized TAMs in the invasive front of pancreatic cancer are associated with a poor prognosis due to accelerated lymphatic metastasis, and inhibition of the functional interaction between M2-polarized TAMs and tumor cells may improve the prognosis.

CD133 expression is correlated with lymph node metastasis and vascular endothelial growth factor-C expression in pancreatic cancer

Although CD133 has been shown to be a marker for cancer stem cells in various tumours, its expression in pancreatic cancer has not yet been clinically reported. In this study, we investigated the relationship between CD133 expression and clinicopathological factors in pancreatic cancer. Pancreatic head carcinoma specimens from 80 patients who underwent surgical resection were immunohistochemically assessed for CD133, vascular endothelial growth factor (VEGF)-C, CXCR4, CD34, Ki-67, and cytokeratin (CK) expressions. Sixty percentage (48/80) of specimens were CD133-positive, with less than 15% cells per specimen expressing the marker. CD133-positive cells were found at the peripheral site of adenocarcinoma glandular structures and were negative for CK. There was a significant correlation between CD133 expression and clinicopathological factors, including histological type, lymphatic invasion, and lymph node metastasis (P=0.0215, 0.0023, and 0.0024, respectively). Vascular endothelial growth factor-C expression was also significantly correlated with CD133 expression (P=0.0002). Consequently, the 5-year survival rate of CD133-positive patients was significantly lower than that of CD133-negative patients (P=0.0002) and multivariate analysis revealed that CD133 expression was an independent prognostic factor (P=0.0103). These results suggest that CD133 expression in pancreatic cancer was significantly associated with lymphatic metastasis, VEGF-C expression, and prognosis.

Length and quality of survival after external-beam radiotherapy with concurrent continuous 5-fluorouracil infusion for locally unresectable pancreatic cancer

PURPOSE The purpose of this study was to evaluate whether external-beam radiotherapy (EBRT) with concurrent continuous 5-fluorouracil (5-FU) infusion affects the length and quality of survival in patients with locally unresectable pancreatic cancer. METHODS Thirty-one patients with histologically proven locally advanced and unresectable pancreatic cancer without distant metastases were evaluated in this prospective randomized trial. Sixteen patients received EBRT (50.4 Gy/28 fractions) with concurrent continuous infusion of 5-FU (200 mg/m(2)/day), whereas 15 patients received no chemoradiation. The length and quality of survival was analyzed and compared for the two groups. RESULTS The median survival of 13.2 months and the 1-year survival rate of 53.3% in the chemoradiation group were significantly better than the respective 6.4 months and 0% in the group without chemoradiotherapy (p = 0.0009). The average monthly Karnofsky score, a quality of life indicator, was 77.1 in the chemoradiation group, which was significantly higher than the 65.5 in the group without chemoradiotherapy (p < 0.0001). The number of hospital days per month of survival was significantly less in the chemoradiation than in the no-therapy group (12.3 vs. 19.0 days, p < 0.05). In the chemoradiation group, 5 patients (31%) had a partial response, and 9 (56%) had radiologically stable disease at a median duration of 6.1 months. The patients who had chemoradiation had a lower rate of liver and peritoneal metastases than patients without chemoradiotherapy (31% vs. 64%). Of 10 patients who experienced pain before chemoradiation, 8 (80%) received pain relief that lasted a median of 5.2 months. CONCLUSIONS EBRT with concurrent continuous 5-FU infusion increased the length and quality of survival as compared to no chemoradiotherapy and provided a definite palliative benefit for patients with unresectable pancreatic cancer.

Impact of Vascular Endothelial Growth Factor-C and -D Expression in Human Pancreatic Cancer: Its Relationship to Lymph Node Metastasis

Purpose: The aim of this study was to evaluate the expression of vascular endothelial growth factor (VEGF)-C and -D in pancreatic cancer and to reveal its relation to lymph node metastasis. Experimental Design: Formalin-fixed, paraffin-embedded blocks were obtained from 58 patients with pancreatic head cancer. All of the patients underwent a curative resection. The total number of resected lymph nodes was 1,058. The expressions of VEGF-C and -D were evaluated by immunohistochemical staining. To evaluate the relation to lymph node metastasis, the expressions of VEGF-C and -D between the marginal and central portions in the tumor were compared. When >25% of the tumor cells showed distinct staining, the portion was judged as high expression. Results: The two groups with high expression of VEGF-C (P = 0.015) and VEGF-D (P = 0.020) in the marginal portion had a significantly higher incidence of lymph node metastasis compared with the groups with low expression, respectively. Furthermore, the group with high expression of both VEGF-C and -D in the marginal portion had a higher incidence of lymph node metastasis compared with the group with low expression (P = 0.007). The 5-year survival rate of patients with high expression of both VEGF-C and -D in the marginal portion was significantly lower than that of patients with low expression of both VEGF-C and -D (P = 0.017). Conclusions: VEGF-C and -D expression in tumor cells in the marginal portion of the tumor significantly associated with lymphatic metastasis and prognosis in patients with pancreatic head cancer.

Modified pancreaticogastrostomy following pancreaticoduodenectomy

A modified pancreaticogastrostomy without gastrotomy was performed in 46 patients undergoing pancreaticoduodenectomy for malignant or benign disease. Postoperative complications related to the modified pancreaticogastrostomy occurred in one patient (2%). Operative mortality was 4% and was unrelated to the pancreaticogastrostomy itself. During the first postoperative year, four patients died of causes unrelated to the original disease process, and nine patients died of recurrent carcinoma. The remaining 31 patients were alive and well at a mean follow-up of 20 months. Results of postoperative gastroscopy were normal in all patients studied. A modified pancreaticogastrostomy without gastrotomy is a safe and effective procedure for pancreatic reconstruction in pancreaticoduodenectomy.

Clinical significance of midkine expression in pancreatic head carcinoma

Midkine (MK) is a heparin-binding growth factor and a product of a retinoic acid-responsive gene. Midkine is overexpressed in many carcinomas and thought to play an important role in carcinogenesis. However, no studies have been focussed on the role of MK in pancreatic carcinoma. This study sought to evaluate the clinical significance of MK expression in pancreatic head carcinoma, including the relationship between immunohistochemical expression and clinicopathologic factors such as prognosis. Immunohistochemical expression of MK and CD34 was evaluated in pancreatic head carcinoma specimens from 75 patients who underwent surgical resection. Midkine was expressed in 53.3% of patients. Midkine expression was significantly correlated with venous invasion, microvessel density, and liver metastasis (P=0.0063, 0.0025, and 0.0153, respectively). The 5-year survival rate was significantly lower for patients positive for MK vs patients negative for MK (P=0.0073). Multivariate analysis revealed that MK expression was an independent prognostic factor (P=0.0033). This is the first report of an association between MK expression and pancreatic head carcinoma. Midkine may play an important role in the progression of pancreatic head carcinoma, and evaluation of MK expression is useful for predicting malignant properties of pancreatic head carcinoma.

Length and quality of survival following external beam radiotherapy combined with expandable metallic stent for unresectable hilar cholangiocarcinoma.

Hilar cholangiocarcinoma is a morbid disease with a poor prognosis because resection cannot be performed in many cases. The purpose of this study was to evaluate whether external beam radiotherapy (RT) combined with expandable metallic biliary stent (EMS) affects the length and quality of survival of patients with unresectable hilar cholangiocarcinomas.

Molecular detection of circulating cancer cells during surgery in patients with biliary-pancreatic cancer

BACKGROUND It remains unclear whether surgical treatment for biliary-pancreatic cancers provokes the hematogenous dissemination of cancer cells. The aim of this study was to detect circulating cancer cells in the blood stream before and during tumor resection for biliary-pancreatic cancer. METHODS We analyzed blood samples obtained perioperatively from the portal vein, peripheral artery, and superior vena cava, using a carcinoembryonic antigen (CEA)-specific nested reverse transcriptase-polymerase chain reaction. RESULTS CEA-mRNA expression was detected in the blood of 21 (52.5%) of 40 patients with biliary-pancreatic cancer. The patients with detectable CEA-mRNA expression included 8 (42.1%) of 19 with bile duct cancers and 13 (61.9%) of 21 with pancreatic cancers. CEA-mRNA expression was not detected in blood obtained from 15 healthy volunteers and 15 patients with benign disease. The positive rate of CEA-mRNA of advanced clinical stage (TNM pStage III and IV) showed higher than that of early stage (pStage I and II; P <0.05). Tumor resection increased significantly the positive rates of CEA-mRNA in the blood stream of three kinds of vessel. CONCLUSIONS Surgical procedures provoke the hematogenous dissemination of cancer cells perioperatively. Therefore, new strategies during operations to prevent liver metastases are needed to improve the survival of patients with biliary-pancreatic cancer.

M2-polarized tumor-associated macrophage infiltration of regional lymph nodes is associated with nodal lymphangiogenesis and occult nodal involvement in pN0 pancreatic cancer.

Objective Tumor-associated macrophages (TAMs) are reportedly involved in lymphangiogenesis in primary tumors, playing a crucial role in lymphatic metastasis. Furthermore, nodal lymphangiogenesis precedes and promotes regional lymph node (RLN) metastasis. We investigated the relationship of M2-polarized TAM infiltration of the RLNs, nodal lymphangiogenesis, and occult nodal involvement in pN0 pancreatic cancer. Methods Hematoxylin-eosin–stained primary tumor and regional LN specimens from 40 patients diagnosed with pN0 pancreatic cancer according to the pathological TNM classification were assessed. To evaluate lymphangiogenesis, lymphatic vessel density was measured by using D2-40 antibody. CD163 and cytokeratin AE1/AE3 antibodies were used to detect M2-polarized TAMs and isolated tumor cells in the RLNs, respectively. Results The nodal lymphatic vessel density had a strong association with the M2-polarized TAM density in the RLNs (P < 0.0001). Most of these TAMs expressed vascular endothelial growth factor C. Furthermore, in the RLNs, the M2-polarized TAM density was significantly associated with the incidence of isolated tumor cells (P = 0.0477). Conclusions M2-polarized TAM infiltration of RLNs is significantly associated with nodal lymphangiogenesis and occult nodal involvement in pN0 pancreatic cancer. Node-infiltrating M2-polarized TAMs may facilitate nodal lymphangiogenesis via the production of vascular endothelial growth factor C and thus promote RLN metastasis.

Intraoperative molecular detection of circulating tumor cells by reverse transcription-polymerase chain reaction in patients with biliary-pancreatic cancer is associated with hematogenous metastasis

BackgroundCirculating tumor cells in the blood were frequently detected by reverse transcription-polymerase chain reaction during operation in patients with biliary-pancreatic cancer. We investigated the relationship between circulating tumor cells during operation and hematogenous metastases.MethodsBlood samples from 67 patients with biliary-pancreatic cancer were obtained from the portal vein, peripheral artery, and superior vena cava during operation. Afer total RNA was extracted from each blood sample, carcinoembryonic antigen (CEA)-specific reverse transcription-polymerase chain reaction was performed.ResultsIntraoperative CEA-messenger RNA (mRNA) expression was detected in the blood of 32 (47.8%) of 67 patients with biliary-pancreatic cancer, although it was not detected in the blood obtained from 20 healthy volunteers or 15 patients with benign disease of the biliary pancreas. The incidence (37.5%) of hematogenous metastases after surgery in the CEA-mRNA-positive group (n =32) was significantly higher than that (11.4%) in the negative group (n=35;P=.01). In stage I, II, and III patients, survival of the CEA-mRNA-positive group was significantly worse compared with that of negative group (P=.03)ConclusionsIntraoperative molecular detection of circulating tumor cells in patients with biliary-pancreatic cancer relates to a high risk of hematogeneous metastasis and is associated with unfavorable prognosis even after curative resection.