Long-term results of elective hepatectomy for the treatment of ruptured hepatocellular carcinoma

Background/Purpose According to the General rules for the clinical and pathological study of primary liver cancer, compiled by the Liver Cancer Study Group of Japan, ruptured hepatocellular carcinoma (HCC) is classified as stage 4, even if the tumor is small and solitary. We examined the long-term results of elective hepatectomy for the treatment of ruptured HCC. Methods A first hepatectomy was performed without operative death in 193 patients with HCC. Ten patients had ruptured HCC (ruptured group) and 183 patients had nonruptured HCC (nonruptured group). The extension of HCC was macroscopically classified as stage 1 in 23 patients, stage 2 in 71, stage 3 in 53, and stage 4 in 46. Results Cumulative survival rates in the ruptured group at 1, 5, and 10 years were 90.0%, 67.5%, and 20.3%, respectively. The cumulative survival rate was lower in patients with stage 4 disease in the nonruptured group than that in patients in the ruptured group (P < 0.05). Cumulative survival rates did not differ significantly between patients in the ruptured group and those with stage 2 or stage 3 disease. Conclusions Survival rates after elective hepatectomy in patients with ruptured HCC are good, even if the disease is classified as stage 4.     

Effect of the XIAP inhibitor Embelin on TRAIL-induced apoptosis of pancreatic cancer cells

BACKGROUND: Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a potent inducer of apoptosis in a wide variety of tumor cells, while it has no toxicity for the majority of normal cells.Therefore, TRAIL may be a suitable agent for anticancer therapy. We previously reported that a number of pancreatic cancer cell lines show resistance to TRAIL-induced apoptosis via overexpression of XIAP and FLIP. The present study was conducted to further examine TRAIL-based therapeutic strategies by aiming to restore functional apoptotic pathways in resistant pancreatic cancer cells. METHODS: In various pancreatic cancer cell lines, TRAIL-induced apoptosis was evaluated in the presence or absence of an XIAP-inhibitor (Smac peptide). Second, TRAIL-induced apoptosis was evaluated in TRAIL-resistant AsPC-1 cells with or without FLIP antisense. Third, the combined effect of Smac peptide and FLIP antisense was tested, and the activation of apoptosis-related caspases and poly (ADP-ribose) polymerase was evaluated. Finally, TRAIL-induced apoptosis was evaluated in the presence or absence of FLIP antisense and an XIAP inhibitor (embelin). RESULTS: Smac peptide enhanced TRAIL-induced apoptosis in a dose-dependent manner for several pancreatic cancer cell lines, but showed no effect on TRAIL-resistant AsPC-1 cells. Smac peptide alone had no influence on cell viability. TRAIL-induced apoptosis was restored in TRAIL-resistant AsPC-1 cells by exposure to FLIP antisense, which suppressed the expression of FLIP. The effect of TRAIL was augmented by the combination of FLIP antisense and Smac peptide. Similarly, TRAIL-induced apoptosis was restored by the combination of FLIP antisense and embelin. Activation of apoptotic caspases and cleavage of poly (ADP-ribose) polymerase was observed after sensitization of TRAIL-resistant pancreatic cancer cells. CONCLUSIONS: Pancreatic cancer cells gain resistance to TRAIL-induced apoptosis via expression of the antiapoptotic proteins XIAP and FLIP. Smac peptide and FLIP antisense could restore the apoptotic effect of TRAIL. An XIAP inhibitor, embelin, enhanced the effect of TRAIL in the presence of FLIP antisense. These findings may provide useful information for the development of TRAIL-based therapeutic strategies by restoring functional apoptotic pathways in resistant pancreatic cancer cells. In addition, a low molecular weight XIAP inhibitor like embelin could be a lead compound for the development of effective XIAP inhibitors.     

Two-stage hepatectomy for multiple bilobular liver metastases from colorectal cancer

BACKGROUND/AIMS: To determine an appropriate surgical treatment for patients with multiple liver metastases, we evaluated the efficacy of two-stage hepatectomy in patients with multiple bilobular liver metastases from colorectal carcinoma. METHODOLOGY: Some patients with multiple liver metastases are not candidates for a complete resection by a single hepatectomy, even when downstaged by chemotherapy, after portal embolization. In two-stage hepatectomy, the highest possible number of tumors is resected in a first, noncurative intervention, and the remaining tumors are resected after a period of liver regeneration. Two-stage hepatectomy was performed in 11 patients. RESULTS: Two-stage hepatectomy was feasible in all of the 11 patients. In 3 of them, the first stage was a major resection (more extensive than a lobectomy). This first hepatectomy was uneventful in all patients. The second hepatectomy was also uneventful in nine patients, but in one of the other two, a perihepatic fluid infection occurred, and in the other, postoperative liver failure developed due to a right subphrenic abscess. However, all patients were discharged. The percentage of the expected resection volume at one time, calculated from CT volumetry, was 75.5+/-1.2% and the prognostic score as surgical risk was 56.6+/-4.5. In two-stage hepatectomy cases, the percentage of the resected volume and the prognostic score in the first hepatectomy were 25.4+/-6.4% and 6.7+/-7.3, and in the second, 45.7+/-4.5% and 28.5+/-5.8. During the follow-up procedures, a residual hepatic recurrence was observed in 6 patients, and pulmonary recurrence in 9. The 1- and 3-year survival rates after the first hepatectomy were 90% and 45%, with median survivals of 18 months from the first hepatectomy. CONCLUSIONS: Two-stage hepatectomy is a surgical modality intended for patients with initial unresectable metastases. However, following such surgery, protective treatment against residual liver recurrence and lung metastasis will be a most important issue.     

Nucleoside-nucleotide free diet protects rat colonic mucosa from damage induced by trinitrobenzene sulphonic acid.

BACKGROUND: Growing evidence suggests that intestinal recovery from injury induced by radiation, endotoxin, and protein deficiency is improved by the ingestion of nucleosides and nucleotides. AIM: This study examined the effect of dietary nucleosides and nucleotides supplementation on trinitrobenzene sulphonic acid induced colonic damage in experimental colitis. METHODS: Sprague-Dawley rats were randomised into two groups and fed nucleic acid free 20% casein diet (control) or this diet supplemented with 0.5% nucleoside-nucleotide mixture for four weeks. On the second week, colonic inflammation was induced in rats by intracolonic administration of 0.25 ml of 50% ethanol containing 25 mg of trinitrobenzene sulphonic acid. Additionally, other sets of rats were treated with 0.25 ml of 50% ethanol, 25 mg of trinitrobenzene sulphonic acid in 0.25 ml saline, or 0.25 ml of 0.9% saline. RESULTS: After two weeks, colon weight, macroscopic and microscopic damage scores, were significantly greater (p < 0.05) in the nucleoside-nucleotide supplemented group compared with the non-supplemented control groups. The same variables seen in the trinitrobenzene sulphonic acid-ethanol group fed nucleoside-nucleotide free diet were greater (p < 0.05) than in the rest of the groups fed nucleoside-nucleotide free diet and treated with ethanol, trinitrobenzene sulphonic acid in saline, or saline. Histologically, segmental ulceration and inflammation associated with significantly increased infiltration of polymorphonuclear leucocytes, macrophages, lymphocytes, fibroblasts were observed in the supplemented group compared with the controls. In the nucleoside-nucleotide supplemented group the epithelial damage, mucosal erosion, oedema, and coagulative necrosis of the muscularis propria was more extensive in comparison to the non-supplemented control groups. CONCLUSIONS: This study suggests that dietary nucleosides and nucleotides may aggravate colonic damage and inflammation in chemically induced experimental colitis in rats; and that nucleoside-nucleotide free diet combined with other pharmacological agents may offer a better response.