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.

Comparison of survival rates between patients treated with transcatheter arterial chemoembolization and hepatic resection for solitary hepatocellular carcinoma.

The present study aimed to retrospectively compare the survival rates between patients treated with transcatheter arterial chemoembolization and hepatic resection for solitary hepatocellular carcinoma (HCC). According to our database, derived from three affiliated hospitals, the inclusion criteria for this study were: solitary HCC [Child-Pugh class A and International Union Against Cancer (UICC) stage T1-3N0M0] treated between July 1990 and October 2001. Subsequently, hepatic resection (149 patients) as well as chemoembolization (102 patients) groups were selected. Following stratification according to tumor stage [UICC, Cancer of the Liver Italian Program (CLIP) and Milan criteria], survival rates were compared between the treatment groups. Survival rates were calculated using the Kaplan-Meier method. Age, gender and size of the HCC did not differ significantly between the groups. Moreover, no significant difference in the survival rates (average hepatic resection, 58.9 months; average chemoembolization, 45 months; P=0.1697) was observed between the groups. In the subgroup analysis, according to tumor stage, the survival rate was significantly higher for the hepatic resection group than for the chemoembolization group in the UICC T3N0M0 (P=0.017) subgroup. However, no significant differences in survival rates were observed between the hepatic resection and chemoembolization groups for UICC T1 (P=0.7329), T2N0M0 (P=0.5741), CLIP0 (P=0.3593), CLIP1-2 (P=0.3287) and within (>5 cm; P=0.4429) and beyond Milan criteria (≤5 cm; P=0.4003) subgroups. Chemoembolization is as effective as hepatic resection in treating solitary HCC in subpopulations with UICC T1-2N0M0 or CLIP 0-2 HCC or Milan criteria and adequate liver function. In the subgroup with UICC T3N0M0 HCC, hepatic resection is superior to chemoembolization.

Strong Smad4 expression correlates with poor prognosis after surgery in patients with hepatocellular carcinoma.

BACKGROUND: As a pleiotropic cytokine, transforming growth factor-beta (TGF-beta) controls the functions of proliferation, adhesion, and differentiation, and contributes to cancer promotion and suppression. Moreover, it is related to the epithelial-mesenchymal transition process and T cell differentiation associated with inflammation. The Smad4 protein is the downstream mediator of TGF-beta. In this study, we examined the relationship between Smad4 expression and clinicopathological features in patients with hepatocellular carcinoma (HCC). METHODS: Expression of Smad4 was assessed in five HCC cell lines and in paired cancerous and noncancerous tissues in three patients with HCC, using Western blotting analysis. Moreover, Smad4 expression in 121 HCC patients was evaluated by using immunohistochemistry. RESULTS: Only the Li7 and HT17 cell lines expressed the Smad4 protein. All human samples expressed the protein. Immunohistochemistry showed that Smad4 expression tended to be strong in small HCC nodules less than 45 mm in diameter (P=0.06) and in the infiltrated part of the tumor capsule. Postoperative survival analysis indicated that HCC patients with strong Smad4 expression had shorter disease-specific survival than those with weak expression (P=0.04). Multivariate analysis also showed that Smad4 expression could be one predictor of prognosis, but the correlation was not significant (P=0.07). CONCLUSIONS: Although TGF-beta/Smad4 signaling may have various biological effects on human malignancies, strong Smad4 expression in HCC is likely to suggest poor prognosis. The information has implications for predicting HCC prognosis and developing targeted therapeutics.

Surgery for hepatocellular carcinoma located in the caudate lobe.

BACKGROUND: Surgery remains difficult for hepatocellular carcinoma (HCC) originating in the caudate lobe. Our objective was to evaluate the safety and problems associated with caudate lobectomy combined with other types of hepatectomy. METHODS: We performed caudate resection for HCC in 12 patients. Clinical and operative characteristics and survival were analyzed. RESULTS: Tumors were located in the Spiegel lobe in three patients, the caudate process in six, and the paracaval portion in three. The procedure performed most was isolated partial caudate lobe resection (six patients). Three patients underwent partial caudate lobe resection combined with other hepatectomy, and the remainder underwent total caudate lobe resection combined with other hepatectomy. Tumors of the patients who underwent combined total caudate lobe resection were mainly in the paracaval portion. The median operating time for the six patients who underwent combined resection was 400 min, and their median intraoperative blood loss was 1,683 ml. There were no postoperative complications in patients who underwent combined total caudate lobe resection, except one case of total resection combined with central bisegmentectomy. In that case, the remaining right posterior sector was twisted after liver extraction, causing blockage of the outflow of the right hepatic vein. The overall and recurrence-free survival rates did not differ between the isolated and combined resection groups. CONCLUSIONS: For removal of HCC located in the caudate lobe, especially the paracaval portion, partial or total caudate lobe resection with other types of hepatectomy contributes to safe, curative surgery if the liver functional reserve and complications associated with surgery are well understood.

Relevance of apoptosis and tolerance to hypoxic stress in cells transfected with receptor for advanced glycation end products (RAGE).

BACKGROUND: It has previously been reported that RAGE plays a role in resisting hypoxia in cancer cells. Here the mechanism of resistance of RAGE-transfected Cos7 cells to hypoxia is investigated from the standpoint of apoptosis. MATERIALS AND METHODS: RAGE-transfected and mock-transfected Cos7 cells were subjected to hypoxia for 12, 24 and 36 h in an MTT assay. The expression of the apoptosis-regulatory proteins, hypoxia inducible factor-1(HIF-1a) and p53 in them was assessed by Western blotting. RESULTS: RAGE-transfected Cos7 cells showed better survival than mock-transfected Cos7 cells during hypoxia. The expression of many apoptosis-regulatory proteins was not affected. However, the expression of HIF-1a and p53 was weaker in RAGE-transfected Cos7 cells than in mock-transfected Cos7 cells. CONCLUSION: The presence of RAGE might suppress HIF-1a protein expression, which in turn might induce an anti-apoptosis effect in RAGE-transfected Cos7 cells. Moreover, the p53 suppression induced by HIF-1a may lead to malignant potential in RAGE-transfected Cos7 cells.

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 patient's condition allows them to tolerate surgery.

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.

Efficacy of anatomic resection vs nonanatomic resection for small nodular hepatocellular carcinoma based on gross classification.

BACKGROUND/PURPOSE: It has been reported that anatomic resection may be preferable to nonanatomic resection for small hepatocellular carcinomas (HCCs), by reducing so-called "micrometastases" (portal venous tumor extension and intrahepatic metastases). Nonanatomic resection or ablation has also been used as therapy for small HCCs. We studied the effectiveness of anatomic resection for small nodular HCCs, especially from the viewpoints of tumor size and gross classification. METHODS: A retrospective cohort study was performed in 116 consecutive patients who underwent curative hepatic resection for HCCs 3 cm or smaller and with three or fewer nodules. The outcome of anatomic resection (including segmentectomy, sectoriectomy, and hemihepatectomy) was compared to that of nonanatomic partial hepatectomy. RESULTS: The group that underwent anatomic resection (n = 52) had relatively better overall survival and significantly better recurrence-free survival than those with nonanatomic resection (n = 64). On Cox multivariate analysis, however, liver function was more closely associated with survival. The effect of anatomic resection was more prominent in the subgroup with the nonboundary type nodules (single nodular type with extranodular growth, confluent multinodular type, and invasive type) than in the subgroup with the boundary type (vaguely nodular and single nodular type). Micrometastases in the nonboundary type were found further from the main tumor (9.5 +/- 6.2 mm) than those in the boundary type (within 3.1 +-1.4 mm). CONCLUSIONS: In patients with HCC nodules equal to or less than 3 cm and with the nonboundary type, anatomic resection should be employed to the extent that liver function allows, because this procedure would be more favorable than nonanatomic resection in eradicating micrometastases that have extended away from the tumor's margin.

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

BACKGROUND: The 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. METHODS: The 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. RESULTS: The 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. CONCLUSIONS: Our 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.

[A case of gemcitabine-based chemo-radiation therapy for locally advanced unresectable pancreatic cancer].

A 49-year-old man was admitted to our hospital with vomiting. Abdominal CT revealed an avascular tumor at the uncinate process of the pancreas measuring 36x30 mm. Preoperative serum CA 19-9 was 361 U/ml. During laparotomy,the tumor was deemed unresectable (T4NXM0, Stage IVa),and duodenojejunostomy was performed. External-beam radiotherapy (EBRT) (50.4 Gy/28Fr) with concurrent twice-weekly gemcitabine (GEM) (40 mg/m(2)/day) was delivered. In the outpatient setting, and 1,000 mg/m(2) of GEM was administered intravenously on days 1, 8, and 15. Cycles were repeated every 28 days. The patient received 13 cycles of GEM chemotherapy until the appearance of a grade 2 facial rash. A decrease in tumor size was observed, and the serum CA 19-9 level dropped to 16 U/ml. He remained well without any symptoms and pursued normal activity for 33 months. He died of peritoneal dissemination 43 months after diagnosis. Gemcitabine-based chemo-radiation seems to be a safe and effective regimen for unresectable pancreatic cancer.

Interleukin 8 in human hepatocellular carcinoma correlates with cancer cell invasion of vessels but not with tumor angiogenesis.

BACKGROUND: Angiogenic 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. METHODS: We 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. RESULTS: The 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. CONCLUSIONS: The expression of IL-8 in human HCC has more relevance to metastatic potential, such as vessel invasion, than to angiogenesis or cell proliferation.

Roxithromycin inhibits constitutive activation of nuclear factor {kappa}B 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 kappaB, 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 kappaB activation induced by experimental hepatocarcinogenesis. The data provide additional evidence for the potential use of roxithromycin in treatment of hepatocellular carcinoma prevention.

Roxithromycin inhibits angiogenesis of human hepatoma cells in vivo by suppressing VEGF production.

BACKGROUND: Recently, 14-member macrolide antibiotics such as Clarithromycin and Roxithromycin (RXM) have been shown to have anti-cancer and anti-angiogeneic effects. However, it is not fully understood whether and how RXM suppresses angiogenesis in human hepatoma, which is a well-known hypervascular tumor. MATERIALS AND METHODS: In the present study, we examined the effects of RXM on tumor angiogenesis in the human hepatoma cell line, HepG2. In vivo, angiogenesis was examined using a mouse dorsal air sac model. RESULTS: The inhibitory effect of RXM was dose-dependent and the angiogenesis index of 100mg/kg/day of RXM administered intraperitoneally twice a day was significantly lower than the control. Next, we examined the effect of RXM on vascular endothelial growth factor (VEGF) mRNA expression and its protein level in HepG2 cells. When 100 microM of RXM were added, VEGF mRNA expression in HepG cells was inhibited and its protein level reduced. CONCLUSION: These results suggest that RXM inhibits tumor angiogenesis in human hepatoma, and that VEGF alteration may be involved in the mechanism of this inhibitory effect. Because RXM is widely used in clinical practice, it may represent an effective new strategy for human hepatoma therapy.

Preoperative assessment of multicentric occurrence in synchronous small and multiple hepatocellular carcinoma based on image-patterns and histological grading of non-cancerous region.

Recent studies have shown that the prognosis of patients with multicentric occurrence (MO) of hepatocellullar carcinoma (HCC) after curative resection, whether synchronous or metachronous, is significantly better than that of patients with intrahepatic metastasis (IM). We attempted to elucidate a group with high probability of MO of HCC by comparing the preoperative ultrasonography (US), computed tomography during arterial portography (CTAP) and CT arteriography (CTA) images with the histological grading of the non-cancerous region of the liver. The imaging and pathological characteristics of 97 nodules in 45 patients diagnosed as having small (<5cm) and oligonodular HCCs preoperatively were investigated. Histological diagnoses were as follows: 18 MO, 23 IM, and 4 unclassified (HCC with benign nodule). Histological grade of the liver tissue was assessed using the hepatitis activity index (HAI) score. No significant differences in tumor location and the mean size of co- or daughter nodules were noticed between the MO and IM patients. Of the 38 nodules in the MO patients, 20 were diagnosed as hyperechoic lesions on US, 20 as negative enhanced lesions on CTA and 12 as having positive portal flow on CTAP. A comparison of image-patterns between the synchronous nodules revealed that the MO group showed different images in at least one imaging technique, whereas in most IM patients similar images were produced by two or three imaging techniques. Moreover, all MO patients had an [Formula: see text], although more than half the IM patients had an [Formula: see text]. In patients with small and oligonodular HCCs, the nodules are highly likely to display MO, when showing both 1 or more different image patterns among US, CTA and CTAP and severe hepatitis such as HAI score >/=8.

Quality of life after hepatectomy in patients with hepatocellular carcinoma: implication of change in hepatic protein synthesis.

BACKGROUND/AIMS: Surgical removal has been accepted as a therapeutic option for hepatocellular carcinoma. However, little is known about the quality of life after hepatectomy for hepatocellular carcinoma. In this report, we describe the risk factors most affecting impaired quality of life after partial hepatectomy in patients with hepatocellular carcinoma. METHODOLOGY: Ninety-six patients who received curative resections 12-60 months previously, answered our original questionnaire, mailed to them. The questions consisted of 14 items concerning physical function, social function, psychological function, physical sensation, and recognition of the disease, with a scoring system of 1, 2, and 3. Based on the pre- and postoperative serum alanine aminotransferase or cholinesterase levels at 3-month intervals during the follow-up period, the changes were classified into three types: those staying in the favorable or unfavorable range at one year (no change, Type 1 or Type 3), and those entering the unfavorable range postoperatively (Type 2). RESULTS: Total quality of life score: the sum of scores to questions 1-12, displayed two peaks of normal distribution. Based on a point of intersection of the two curves: i.e., score of 22, the patients were classified into 2 groups: those with preserved quality of life (n = 75) i.e., total quality of life scores of 12-21, and impaired quality of life, scores of 22 or more (n = 21). Older age (> or = 65 y) at hepatectomy, in the course of treatment for recurrence, and Type 2 change of serum cholinesterase level were associated with the impaired quality of life. Multivariate analysis revealed that Type 2 change of serum cholinesterase levels was an independent risk factor for an impaired quality of life. Furthermore, the patients exhibiting Type 2 change of serum cholinesterase levels were clearly impaired in their physical and social functions compared to the other patients. Hepatitis-related or cancer-related factors showed no correlation with the deterioration of the quality of life. CONCLUSIONS: The quality of life after hepatectomy in patients with hepatocellular carcinoma was impaired in cases of aged patients, treatment for recurrence, and Type 2 change of the serum cholinesterase level. Postoperative maintenance of protein synthesis including cholinesterase is one measure to preserve a satisfactory quality of life after hepatectomy.