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.