Kousei Maemura

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.

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.

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.

Subtotal stomach-preserving pancreaticoduodenectomy (SSPPD) prevents postoperative delayed gastric emptying.

Delayed gastric emptying (DGE) is one of main complications after pylorus‐preserving pancreaticoduodenectomy (PPPD) with regional lymph node dissection (RLND). The aim of this study was to retrospectively investigate whether subtotal stomach‐preserving PD (SSPPD) decreased incidence of DGE.

Carcinoembryonic antigen messenger RNA expression using nested reverse transcription-PCR in the peripheral blood during follow-up period of patients who underwent curative surgery for biliary-pancreatic cancer: longitudinal analyses.

Purpose: Outcome for patients with biliary-pancreatic cancer is still poor, despite curative operation. We investigated the clinical significance of molecular detection of circulating cancer cells in the blood as an early indicator of relapse during follow-up of patients who underwent a curative operation for biliary-pancreatic cancer. Patients and Methods: We followed 53 patients who underwent a curative operation for biliary-pancreatic cancer between 1996 and 2001. We used reverse transcription-PCR in the peripheral blood to evaluate carcinoembryonic antigen (CEA) mRNA expression for molecular detection of circulating cancer cells. Follow-up examinations every 3 months after surgery included CEA mRNA expression in the blood, serum CEA, serum carbohydrate antigen 19-9 (CA19-9), and computed tomography or magnetic resonance imaging. Results: Sixteen of 53 patients (30.2%) were diagnosed with a recurrence by imaging studies. The CEA mRNA detection rate in the peripheral blood of these 16 patients was 75% compared with 5.4% in the 37 patients without relapse (P < 0.001). Sensitivity of CEA mRNA, CEA, and CA19-9 serum levels was 75.0%, 50.0%, and 68.8%, respectively. Similarly, specificity was 94.6%, 64.9%, and 81.1%, respectively. CEA mRNA was expressed in the blood, even though tumor markers CEA and CA19-9 were within the normal range in patients with relapse. CEA mRNA expression in the blood, as well as the serum level of CA19-9, tended to be detected a few months earlier than detection by imaging modalities. Conclusions: During the follow-up of patients who undergo a curative operation for biliary-pancreatic cancer, CEA mRNA expression in the peripheral blood might be a useful and early indicator of relapse.

Significance of lymphangiogenesis in primary tumor and draining lymph nodes during lymphatic metastasis of pancreatic head cancer

The aim of this study was to investigate the significance of lymphangiogenesis in primary pancreatic tumors and in draining lymph nodes during lymphatic metastasis of pancreatic head cancers.

Anatomical Laparoscopic Hepatectomy for Hepatocellular Carcinoma Using Indocyanine Green Fluorescence Imaging

PURPOSE It is important to minimize surgical invasiveness in the therapy of patients with hepatocellular carcinoma (HCC), and consequently laparoscopic hepatic resection is widely performed. However, most anatomical resections, except left lateral sectionectomy, remain difficult technically, and laparoscopy-assisted procedures have been introduced as an alternative approach because of the safety and curative success of the operation. We reported previously pure laparoscopic subsegmentectomy of the liver using puncture of the portal branch under percutaneous ultrasound (US) with artificial ascites. Herein, we describe pure anatomical laparoscopic segmentectomy using the puncture method with indocyanine green (ICG) injection under laparoscopic US. PATIENTS AND METHODS Pure laparoscopic segmentectomy was planned for 2 patients with HCC of the liver. Identification of the segment was performed by ICG injection for optical imaging using near-infrared fluorescence under laparoscopic US guidance. RESULTS The procedures were completed successfully, and the postoperative courses were uneventful. CONCLUSIONS Pure laparoscopic segmentectomy for HCC with a conventional puncture technique by ICG injection under laparoscopic US is considered to be a useful procedure featuring both low invasiveness and curative success.

Combined fibrinogen and neutrophil-lymphocyte ratio as a prognostic marker of advanced esophageal squamous cell carcinoma

Patients with advanced esophageal squamous cell carcinoma (ESCC) is received chemoradiotherapy or chemotherapy for clinical management. However, it is difficult to predict tumor response and prognosis using blood markers before starting treatments. The purpose of this study was to investigate the pre‐treatment plasma fibrinogen and neutrophil–lymphocyte ratio (NLR) in patients with advanced ESCC treated with chemoradiotherapy or chemotherapy, and to assess the clinical utility of a combined score using these blood markers, named as the F‐NLR (fibrinogen and NLR) score, as a predictor of tumor response and prognosis. A total of 98 advanced ESCC patients, treated with chemoradiotherapy or chemotherapy, were classified into three groups: F‐NLR score of 2, having both hyperfibrinogenemia (>400 mg/dL) and high NLR (>3.0), score of 1, one of these hematological abnormalities, and score of 0, having neither hyperfibrinogenemia nor high NLR. Fibrinogen and NLR were significantly higher in the progressive disease (PD) group than the non‐PD group (P = 0.0419, and P = 0.0001, respectively). A significantly higher F‐NLR score was found in the PD group than the non‐PD group (P = 0.0140). Overall survival was significantly lower in patients with an F‐NLR score of 2 than in those with an F‐NLR score of 0 or 1 (P < 0.0001). Multivariate analysis showed that the F‐NLR score was one of the independent prognostic factors (P = 0.0081). Our study demonstrates that the F‐NLR score is promising as a predictive marker for therapeutic effects and prognosis in patients with advanced ESCC.

CD44 and CD133 Expressions in Primary Tumor Cells Correlate to Survival of Pancreatic Cancer Patients

Background: Recent studies have suggested that CD44 and/or CD133 expressing pancreatic cancer cells have potential abilities of self-renewal, tumorigenesis and tumor metastasis. The aim of this study was to investigate whether CD44 and CD133 expressions in primary tumor cells correlate to the survival and clinicopathological findings of pancre- atic cancer patients. Methods: Pancreatic head carcinoma specimens from 80 patients who underwent surgical resection were immunohisto- chemically assessed for CD44 and CD133 expressions. Results: Of the 80 specimens, 34 (42.5 %) and 48 (60%) specimens were immunohistochemically positive for CD44 and CD133 expression, respectively. CD44 was expressed on the cell surface and CD133 expression was observed in the cy- toplasm of the positive cells, which were located at the peripheral adenocarcinoma glandular structures. There was no sig- nificant difference in the 5-year survival rate of patients based on CD44 expression, but the 5-year survival rate of CD133-positive patients was significantly lower than that of CD133-negative patients (P = 0.0002). Multivariate analysis revealed that CD44-positive and CD133-negative expression was a favorable prognostic indicator (P = 0.0424). Conclusions: CD44 and CD133 expressions are association with survival and malignant behavior in pancreatic cancer pa- tients.