Fumitake Kubo

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.

Surgical resection versus radiofrequency ablation for small hepatocellular carcinomas within the Milan criteria

BACKGROUND/PURPOSE It has been reported that hepatic resection may be preferable to other modalities for the treatment of small hepatocellular carcinomas (HCCs), by contributing to improved overall and disease-free survival. Ablation techniques such as radiofrequency ablation (RFA) have also been used as therapy for small HCCs; however, few studies have compared the two treatments based on long-term outcomes. The effectiveness of hepatic resection and RFA for small nodular HCCs within the Milan criteria were compared. METHODS A retrospective cohort study was performed with 278 consecutive patients who underwent curative hepatic resection (n = 123) or initial RFA percutaneously (n = 110) or surgically (thoracoscopic-, laparoscopic-, and open-approaches; n = 45) for HCC. The selection criteria for treatment were based on uniform criteria. Mortality related to therapy and 3- and 5-year overall and disease-free survivals were analyzed. RESULTS The model for endstage liver disease (MELD) scores for all patients in the series were less than 13. There were no therapy-related mortalities in either the hepatic resection or RFA groups. The incidence of death within 1 year after therapy (1.6 and 1.9%, respectively) was similar in the hepatic resection and RFA groups. The group that underwent hepatic resection showed a trend towards better survival (P = 0.06) and showed significantly better disease-free survival (P = 0.02) compared with the RFA group, although differences in liver functional reserve existed. The advantage of hepatic resection was more evident for patients with single tumors and patients with grade A liver damage. In contrast, patients with multinodular tumors survived longer when treated with RFA, regardless of the grade of liver damage. Further analysis showed that surgical RFA could potentially have survival benefits similar to those of hepatic resection for single tumors, and that surgical RFA had the highest efficacy for treating multinodular tumors. CONCLUSIONS In patients with small HCCs within the Milan criteria, hepatic resection should still be employed for those patients with a single tumor and well-preserved liver function. RFA should be chosen for patients with an unresectable single tumor or those with multinodular tumors, regardless of the grade of liver damage. In order to increase long-term oncological control, surgical RFA seems preferable to percutaneous RFA, if the patients condition allows them to tolerate surgery.

Acceleration of primary liver tumor growth rate in embolized hepatic lobe after portal vein embolization.

Background: Portal vein embolization (PVE) is now widely accepted as a useful preoperative procedure in selected patients undergoing extended hepatectomy. However, the effect of PVE on the growth of liver tumors has not been fully elucidated. Purpose: To retrospectively evaluate the effects of PVE on the growth of liver tumors in the embolized lobes. Material and Methods: Eight patients with a primary liver tumor, six hepatocellular carcinomas (HCC) and two cholangiocellular carcinomas (CCC), were studied. The growth rates of the tumors in the embolized lobes and non-embolized liver parenchyma were calculated using the computed tomography (CT) volume values at the time of tumor identification, and before and after PVE. Result: The median tumor growth rate was 0.59 cm3/day (range 0.22–6.01 cm3/day) before PVE and 2.37 cm3/day (range 0.29–13.97 cm3/day) after PVE (P = 0.018). The tumor growth acceleration ratios ranged from 1.50 to 7.46 (median 2.65) in the six HCCs, and were 1.00 and 1.32 in the two CCCs. There was no apparent correlation between the tumor growth rate after PVE and the growth rate of non-embolized liver parenchyma (median 6.00 cm3/day, range 1.24–11.0 cm3/day). Conclusion: Liver tumor growth in an embolized lobe accelerates after PVE, in patients with HCC.

Interleukin 8 in Human Hepatocellular Carcinoma Correlates With Cancer Cell Invasion of Vessels But Not With Tumor Angiogenesis

BackgroundAngiogenic factor seems necessary for the development of hepatocellular carcinoma (HCC), which is a hypervascular malignancy. This study examined the expression of interleukin (IL)-8, a potent angiogenic factor, in HCC samples.MethodsWe measured IL−8 expression by using reverse transcriptase-polymerase chain reaction in clinical HCC tissues from 45 patients who underwent surgical resection. We then assessed correlations between IL−8 expression and microvessel growth or clinicopathologic factors. We also elucidated the in vitro effect of IL−8 on HepG2 development by using fluorometric assays of proliferation, chemotaxis, and invasion.ResultsThe expression of IL−8 did not significantly correlate with the microvessel count in HCC tissues, but the incidence of microscopic vessel invasion was significantly higher in IL−8–positive than in IL−8–negative tissues. Thus, more IL−8 was expressed in HCCs at pathologic stage III/IV than in those at stage I/II. Assays in vitro showed that IL−8 stimulates HepG2 chemotactic and invasive activities rather than cell proliferation.ConclusionsThe expression of IL−8 in human HCC has more relevance to metastatic potential, such as vessel invasion, than to angiogenesis or cell proliferation.

A novel function of the receptor for advanced glycation end-products (RAGE) in association with tumorigenesis and tumor differentiation of HCC.

BackgroundThe expression of the receptor for advanced glycation end products (RAGE) has an impact on the mechanisms giving rise to characteristic features of various cancer cells. The purpose of this study was to elucidate the clinicopathological relevance of the level of RAGE expression in patients with hepatocellular carcinoma (HCC) and to explore the effect of RAGE expression on the characteristic features of HCC.MethodsThe expression of RAGE was assessed in paired cancer and noncancerous tissues with HCC, using reverse-transcription polymerase chain reaction (RT-PCR), and immunohistochemistry. The quantitative RT-PCR data were analyzed in association with the clinicopathological factors of the patients with HCC. In in vitro experiments, the survival of RAGE-transfected Cos7 and mock-transfected Cos7 cells was compared under hypoxic conditions. In addition, after reducing RAGE levels in RAGE-transfected Cos7 cells by siRNA, similar experiments were performed.ResultsThe expression of RAGE mRNA was lower in normal liver than in hepatitis and highest in HCC. Furthermore, in HCC, it was high in well- and moderately differentiated tumors but declined as tumors dedifferentiated to poorly differentiated HCC. Furthermore, HCC lines resistant to hypoxia were found to have higher levels of RAGE expression, and RAGE transfectant also showed significantly prolonged survival under hypoxia.ConclusionsOur results suggest that HCC during the early stage of tumorigenesis with less blood supply may acquire resistance to stringent hypoxic milieu by hypoxia-induced RAGE expression.

Expression of receptor for advanced glycation end products (RAGE) is related to prognosis in patients with esophageal squamous cell carcinoma.

The receptor for advanced glycation end products (RAGE), known as a multiligand receptor for certain stress-associated factors, has been considered to affect the characteristic differences of various cancer cells. We analyzed the expression and clinicopathological significance of RAGE in esophageal squamous cell carcinoma. We investigated immunohistochemically the relationship between RAGE expression and clinicopathological factors, including prognosis, in surgical specimens of primary tumors in 216 patients with esophageal squamous cell carcinoma. Prognostic factors were examined by univariate and multivariate analyses (Cox proportional hazard regression model). The positive expression rate of RAGE was 50%. RAGE expression was negatively correlated with depth of invasion and venous invasion. Moreover, tumors with positive RAGE expression exhibited better prognosis than those with negative RAGE expression (5-year survival, 52% vs. 32%, respectively). Multivariate analysis indicated that the positive expression of RAGE was an independent prognostic factor, along with tumor depth and nodal metastasis. Our findings suggest that loss of RAGE expression may play an important role in the progression of esophageal squamous cell carcinoma. Evaluation of the expression of RAGE could be useful for determining the tumor properties, including those associated with prognosis, in patients with esophageal squamous cell carcinoma.

Roxithromycin Inhibits Constitutive Activation of Nuclear Factor κB by Diminishing Oxidative Stress in a Rat Model of Hepatocellular Carcinoma

Purpose: Recently, 14-member macrolide antibiotics such as clarithromycin and roxithromycin have been shown to have anticancer and antiangiogenic effects. We investigated the suppressive effect of roxithromycin on accelerated hepatocellular carcinoma growth in a rat hepatocarcinogenetic model and compared results with effects from TNP-470. Experimental Design: Tumor was induced by oral diethylnitrosamine administration for 17 weeks. Normal saline, TNP-470 (50 mg/kg), or roxithromycin (40 or 100 mg/kg) was administered i.p. thrice per week from week 10 to 17. Results: Carcinomatous tissue growing outside dysplastic nodules and a marked expression of placental glutathione S-transferase were detected in rats with induced carcinogenesis. Tumor growth was accompanied by augmented expression of inducible nitric oxide synthase, activation of nuclear factor κB, and increased lipid peroxidation level. All these effects were absent in animals that received roxithromycin or TNP-470. The inhibitory effect of roxithromycin was dose dependent and no clear differences were noted between groups given roxithromycin 100 mg/kg and TNP-470 50 mg/kg. Conclusions: Our results indicate that roxithromycin inhibits oxidative stress, nitric oxide production, and nuclear factor κB activation induced by experimental hepatocarcinogenesis. The data provide additional evidence for the potential use of roxithromycin in treatment of hepatocellular carcinoma prevention.