Efficacy of hepatic arterial infusion chemotherapy using 5-fluorouracil and systemic pegylated interferon α-2b for advanced intrahepatic cholangiocarcinoma.

BACKGROUND: Cholangiocarcinoma is categorized into intrahepatic cholangiocarcinoma (ICC) and extrahepatic cholangiocarcinoma (ECC). The prognosis of ICC is far worse than that of ECC. In this pilot trial, the efficacy of hepatic arterial infusion chemotherapy (HAIC) using 5-fluorouracil (5-FU) combined with subcutaneous administration of pegylated interferon (PEG-IFN) α-2b in patients with advanced ICC was evaluated. METHODS: The subjects were 20 advanced ICC patients treated using subcutaneous PEG-IFNα-2b (50-100 µg on day 1 of every week, for 4 weeks) and intra-arterial infusion of 5-FU (250 mg/day for 5 h on days 1-5 of every week, for 4 weeks). One treatment cycle lasted 4 weeks. Therapy was discontinued in patients with progressive disease (PD). For responses other than PD, treatment was repeated for ≥1 cycle. RESULTS: The objective early response rate was 60.0 %. Cumulative survival rates were 71.6 % at 6 months, 53.7 % at 12 months, 28.6 % at 18 months, and 14.3 % at 24 months. Median survival time was 14.6 months. All adverse reactions were controllable by temporary suspension of treatment. Serious complications and treatment-related deaths were not observed. CONCLUSIONS: The combination therapy of PEG-IFNα-2b and 5-FU for advanced ICC seems not to be worse than the results of the previous studies. Furthermore, most adverse effects are transient and well tolerated. Based on the present findings, this combination therapy may be useful for patients with advanced ICC as one of the therapeutic option.

Therapeutic efficacy of transarterial chemo-embolization with a fine-powder formulation of cisplatin for hepatocellular carcinoma.

AIM: To evaluate the efficacy of transarterial chemoembolization (TACE) using a suspension of a fine-powder formulation of cisplatin (DDPH) in lipiodol (LPD) in the treatment of hepatocellular carcinoma (HCC). METHODS: The subjects were 262 HCC patients treated with TACE using a DDPH-LPD suspension. The DDPH-LPD suspension was prepared by mixing 50 mg of DDPH into 10 mL of LPD. TACE was repeated when treated lesions relapsed and/or new hepatic lesions were detected. These patients received additional TACE using the same agent. TACE was repeated until complete regression of the tumor was obtained. The primary efficacy endpoint of the current study was the objective early response rate. Secondary efficacy endpoints were progression-free survival (PFS) and overall survival. RESULTS: The objective early response rate was 43.6%. Cumulative PFS rates were 56.7% at 6 mo, 23.1% at 12 mo, 13.4% at 18 mo, and 10.5% at 24 mo. The median PFS was 6.6 mo. Cumulative survival rates were 90.6% at 6 mo, 81.9% at 12 mo, 70.5% at 24 mo, and 58.8% at 36 mo. Median survival time was 46.6 mo. All adverse reactions were controllable by temporary suspension of treatment. No serious complications or treatment-related deaths were observed. CONCLUSION: TACE using a suspension of DDPH in LPD may be a useful treatment for HCC.

Therapeutic efficacy of combination therapy with intra-arterial 5-fluorouracil and systemic pegylated interferon α-2b for advanced hepatocellular carcinoma with portal venous invasion.

BACKGROUND: The prognosis of advanced hepatocellular carcinoma (HCC) remains poor, particularly among patients with portal vein tumor thrombosis (PVTT). This study evaluated the efficacy of combined 5-fluorouracil and pegylated interferon (PEG-IFN) α-2b in patients with advanced HCC. METHODS: Subjects comprised 59 HCC patients with PVTT treated using subcutaneous administration of PEG-IFNα-2b (50-100 µg on day 1 of each week for 4 weeks) and intra-arterial infusion of 5-fluorouracil (250 mg/d for 5 hours on days 1-5 of each week for 4 weeks). One treatment cycle lasted 4 weeks. The current therapy was discontinued in patients with progressive disease (PD). For responses other than PD, treatment was repeated for ≥1 cycle. The primary efficacy endpoint was the objective early response rate. Secondary efficacy endpoints were progression-free survival (PFS) and overall survival. RESULTS: Objective early response rate was 73.0%. Cumulative PFS rates were 67.4% at 6 months, 30.2% at 12 months, 25.9% at 18 months, and 20.7% at 24 months. Median PFS was 9.7 months. Cumulative survival rates were 82.4% at 6 months, 73.6% at 12 months, 52.8% at 24 months, and 44.0% at 36 months. Median survival time was 29.9 months. All adverse reactions were controllable by temporary suspension of treatment. Serious complications and treatment-related deaths were not observed. CONCLUSIONS: Although a prospective randomized controlled trial using a larger population of patients with advanced HCC is needed to evaluate combination therapy with 5-fluorouracil and PEG-IFNα-2b, this new combination therapy may be useful for patients with advanced HCC.

[A case of advanced adenocarcinoma of esophagogastric junction with severe esophageal invasion effectively treated by chemoradiotherapy using paclitaxel and cisplatin, and S-1 after chemoradiotherapy].

The patient was a 66-year-old male with adenocarcinoma of the esophagogastric junction and severe esophageal invasion, which was diagnosed as cType 3, cT4a (SE) cN3cM1 (LYM), cStage IV(histopathology: por 1). We tried concurrent chemoradiotherapy consisting of PTX 60 mg/m(2) and CDDP 25 mg/m(2), respectively (once a week), and a total of 45 Gy of radiotherapy treatment. Then, for effective continuation, chemotherapy using S-1 was performed as second-line therapy. A complete response was achieved and continued for more than 2 years after initial chemoradiotherapy; his complaints abated and his quality of life improved. Although gastro-intestinal symptoms and bone marrow suppression were observed as adverse effects, they were within a tolerable range and did not interfere with the concurrent chemoradiotherapy. This regimen appears to be feasible and effective for advanced gastric carcinoma refractory to other regimens.

Conservative treatment of an aortoesophagial fistula after endovascular stent grafting for a thoracic aortic aneurysm.

BACKGROUND: Aortoesophageal fistula (AEF) is an uncommon condition that presents a problem in therapy because of the high rate of morbidity and mortality associated with its surgical management and the uniformly fatal outcome of medical treatment. In this article we describe a case of secondary AEF after endoluminal stent grafting of the thoracic aorta, which was observed by only conservative management and followed up for 14 months with no signs of recurrent hemorrhage or chronic mediastinitis. CASE REPORT: A 54-year old man with hepatocellular carcinoma (HCC) was admitted to our hospital because of tarry stool. He had a history of traumatic aneurysm, and undergone segmental replacement with a stent graft three years ago. After admission, Esophagogastroduodenoscopy and computed tomography identified AEF. He was treated conservatively, because his stage of HCC was advanced. Oral intake was prohibited, and the patient received proton pump inhibitors, intravenous hyperalimentation and antibiotics. Afterwards, no signs of hemorrhage were observed. Although oral intake was resumed after that, another bleeding event or development of mediastinitis was not observed. Subsequently, He was received chemotherapy for advanced HCC, and we observed downstaging of his advanced HCC. CONCLUSIONS: Although we observed 14 months survival in our case under conservative management of secondary AEF, it seems that the treatment of secondary AEF should do the operative management.

Combination therapy of intra-arterial 5-fluorouracil and systemic pegylated interferon α-2b for advanced hepatocellular carcinoma.

BACKGROUND: This study evaluated the efficacy of combined 5-fluorouracil (5-FU) and pegylated interferon (PEG-IFN) α-2b in patients with advanced hepatocellular carcinoma (HCC). METHODS: Fifty patients with portal vein tumor thrombosis were enrolled. Of these, 21 patients were treated using subcutaneous administration of PEG-IFNα-2b and intra-arterial infusion of 5-FU (5-FU/PEG-IFN group), 12 patients were treated using intramuscular administration of IFNα-2b and intra-arterial infusion of 5-FU (5-FU/IFN group), and 17 patients received intra-arterial infusion chemotherapy with lipiodol-cisplatin (CDDP) suspension (CDDP group). RESULTS: The objective early response rate was significantly higher in the 5-FU/PEG-IFN group than in the 5-FU/IFN or CDDP groups (71.4 vs. 8.3% and 17.6%, respectively; P < 0.0001). Cumulative survival rates at 6 and 12 months were 83.8 and 77.8% in the 5-FU/PEG-IFN group, 60.8 and 16.2% in the 5-FU/IFN group, and 58.4 and 12.5% in the CDDP group, respectively. The cumulative survival rate was significantly higher in the 5-FU/PEG-IFN group than in the other 2 groups (P = 0.0272). Serious complications and treatment-related deaths were not observed in any of the 3 groups. CONCLUSION: Although a prospective randomized controlled trial using a larger population of patients with advanced HCC is needed to evaluate combination therapy with 5-FU and PEG-IFNα-2b, this new combination therapy may be useful for patients with advanced HCC.

Effects of branched-chain amino acid-enriched nutrient for patients with hepatocellular carcinoma following radiofrequency ablation: a one-year prospective trial.

BACKGROUND AND AIM: This prospective control study examined whether supplementation with branched-chain amino acid (BCAA)-enriched nutrients can help maintain and improve residual liver function and nutritional status in cirrhotic patients with hepatocellular carcinoma (HCC) after radiofrequency ablation (RFA). METHODS: Subjects were 49 patients with hepatitis C-related HCC who underwent RFA. Two groups were formed: BCAA group (BCAA-enriched nutrient, aminoleban EN) and controls (standard diet only). Event-free survival rate, liver function tests, and Short Form (SF)-8 scores were evaluated in both groups before and one year after RFA. Energy metabolism using indirect calorimetry was measured before and after 3 months. RESULTS: Complete data were obtained from 35 patients (BCAA group, n = 20; controls, n = 15). Six events (death, recurrence of HCC, rupture of esophageal varices and liver failure) occurred during the observation period, but frequencies of these events did not differ between groups. Event-free survival rate tended to be higher in the BCA group than in controls. Among the parameters of liver function, serum albumin level was only significantly increased over 6 months, and remained at similar values for one year (P < 0.05). SF-8 scores for general health, physical functioning, and social functioning were significantly elevated in the BCAA group (P < 0.05). Non-protein respiratory quotient was significantly improved in the BCAA group (P < 0.01). CONCLUSION: Supplementation with BCAA-enriched nutrients for one year in cirrhotic patients with HCC after RFA therapy can perform safety and improve both nutritional state and quality of life.

Transcatheter arterial chemoembolization with a fine-powder formulation of cisplatin for hepatocellular carcinoma.

AIM: To evaluate the efficacy of transcatheter arterial chemoembolization (TACE) using a suspension of a fine-powder formulation of cisplatin (DDPH) for hepatocellular carcinoma (HCC). METHODS: The study population was comprised of 164 patients who were treated by TACE alone. Of these patients, 76 underwent TACE using a suspension of DDPH in lipiodol (LPD) (DDPH group), and the remaining 88 underwent TACE with an emulsion of doxorubicin (ADM) with LPD (ADM group). We compared the DDPH group with the ADM group in terms of the objective early response rate, progression free survival (PFS) and overall survival (OS). RESULTS: The objective early response rate in the DDPH group was significantly higher than that in the ADM group (54% vs 24%, P < 0.001). The PFS rate in the DDPH group was also significantly higher than that in the ADM group (P < 0.001). Moreover, the OS in the DDPH group was significantly longer than that in the ADM group (P = 0.002). Although the incidence rate of nausea or vomiting in the DDPH group was higher than that in the ADM group, the ADM group showed a higher incidence rate of the adverse events of hepatic arterial damage and leucopenia. No other serious complications were observed in either group. CONCLUSION: We conclude that TACE using a suspension of DDPH in LPD could be a useful treatment for HCC.

Changes in liver function parameters after percutaneous radiofrequency ablation therapy in patients with hepatocellular carcinoma.

AIM: To evaluate changes in liver function parameters and risk factors 1 year after percutaneous radiofrequency ablation (RFA) therapy in patients with hepatocellular carcinoma (HCC). METHODS: Subjects in this retrospective study comprised 45 patients with HCC who underwent RFA therapy (RFA alone, n = 25; transcatheter arterial embolization therapy before RFA, n = 20) and showed no recurrence of HCC 1 year after RFA. Serial changes in serum total bilirubin, albumin, prothrombin time and Child-Pugh score (CPs) were evaluated before and after RFA. In addition, Cox proportional hazards regression analysis was used to clarify risk factors for aggravation of liver function after RFA therapy. RESULTS: Serum albumin levels showed a significant decrease from before (3.6 +/- 0.4 g/dL) to 12 months after RFA therapy (3.2 +/- 0.4 g/dL; P

[Three (3) cases of advanced hepatocellular carcinoma (HCC) treated successfully by transcatheter arterial chemoembolization (TACE) using lipiodol and a fine- powder formulated cisplatin (DH)].

Although great advances have been made in therapies for patients with hepatocellular carcinoma(HCC), the prognosis for advanced HCC remains poor because liver transplantation is not applicable. We report three(3)cases of HCC treated successfully by transcatheter arterial chemoembolization(TACE)using a suspension of Lipiodol and a fine powder formulation of cisplatin(DDPH). Case No. 1 was a 64-year-old man with multiple HCCs who had undergone several sessions of TACE using doxorubicin(ADM). During the course of the treatment, the HCC became intractable and residual tumors were observed repeatedly within a short period. He was then treated by TACE using DDPH instead of ADM. The tumor marker levels decreased in response to this treatment and no recurrence of HCC has been observed. Case No. 2 was a 71-year-old man who had been diagnosed with multiple HCCs in 2004. He was treated by TACE with ADM, but the procedure had to be repeated more than three(3)times due to residual tumors. Despite the treatment, the tumor grew gradually and a formation of tumor thrombus was observed in the inferior vena cava. Both the tumor and tumor thrombus reduced in size after TACE with DDPH. Case No. 3 was a 52-year-old man who had been monitored diabetes mellitus and chronic hepatitis at our hospital. Multiple HCCs were diagnosed in 2006. TACE with DDPH was performed as an initial therapy. The tumors shrank or disappeared in response to this treatment. These results propose that TACE with DDHP against advanced HCC is effective.

Evaluation of newly developed combination therapy of intra-arterial 5-fluorouracil and systemic pegylated interferon alpha-2b for advanced hepatocellular carcinoma with portal venous invasion: preliminary results.

AIM: Prognosis is extremely poor for advanced hepatocellular carcinoma (HCC) in patients with portal invasion. The present study evaluated the efficacy of combined intra-arterial 5-fluorouracil (5-FU) and systemic pegylated interferon (PEG-IFN)alpha-2b in patients with advanced HCC. METHODS: The subjects comprised nine HCC patients with portal vein thrombosis treated using subcutaneous administration of PEG-IFNalpha-2b (50-100 microg on day 1 of every week, for 4 weeks) and intra-arterial infusion of 5-FU (250 mg/day for 5 h on days 1-5 of every week, for 4 weeks). For four patients with hepatitis C virus (HCV) infection, oral administration of ribavirin (400-800 mg/day) was added. At the end of every cycle, response to therapy was assessed using Response Evaluation Criteria in Solid Tumors (RECIST) guidelines. RESULTS: Partial response (PR) was observed in seven of nine patients, with stable or progressive disease in the remaining two patients. Tumors were resectable in three patients displaying PR after treatment. Tumor markers decreased significantly after therapy. Serum HCV-RNA titers were markedly decreased and became undetectable in all patients with HCV infection. National Cancer Institute-Common Toxicity Criteria: version 3.0 (NCI-CTC) grade 3 thrombocytopenia was seen in one case at the end of treatment, but was resolved with cessation of treatment. Other adverse effects were manageable. CONCLUSION: Combination therapy with intra-arterial 5-FU and systemic PEG-IFNalpha-2b may be useful as a palliative treatment for patients with advanced HCC. A prospective controlled trial using a larger population of patients with advanced HCC is needed to evaluate this new combination therapy.

Ratio of circulating follistatin and activin A reflects the severity of acute liver injury and prognosis in patients with acute liver failure.

BACKGROUND AND AIM: The activin A-follistatin system is known to play a critical role in hepatocyte regeneration during the repair of liver tissue. However, the relationship between blood levels of these compounds and the severity and prognosis of acute liver injury remains unclear. The aim of this study was to evaluate the clinical significance of circulating activin A and follistatin in patients with acute liver disease. METHODS: Serum activin A and plasma follistatin levels were determined on admission by enzyme-linked immunosorbent assay in 32 patients with acute hepatitis (AH), 23 patients with acute severe hepatitis (ASH) and 16 patients with acute liver failure (ALF). RESULTS: Both serum activin A and plasma follistatin levels were significantly elevated in patients with ASH and ALF when compared with those in patients with AH and normal controls (NC). Although plasma follistatin levels were significantly and positively correlated with serum activin A levels (r = 0.413, P < 0.001), the follistatin and activin A (F/A) ratio showed distinct deviation from NC between AH and ALF patients. The F/A ratio in AH patients was significantly elevated when compared with NC, but was significantly reduced in ALF patients. Furthermore, the F/A ratio in non-surviving ALF patients was significantly lower than that in survivors. Levels of serum activin A and plasma follistatin were significantly and negatively correlated with prothrombin time (PT) and normotest (NT) levels, while the F/A ratio showed significant and positive correlations with PT and NT. CONCLUSIONS: Decreased blood F/A ratio in ALF patients may be a reliable indicator of the severity of acute liver injury and prognosis in ALF.

Induction of Bcl-xL is a possible mechanism of anti-apoptotic effect by prostaglandin E2 EP4-receptor agonist in human hepatocellular carcinoma HepG2 cells.

Because fulminant hepatic failure has a poor prognosis without liver transplantation, it is required to develop new therapies directed toward hepatocyte protection and regeneration. Previously, we showed the anti-apoptotic effects of a prostaglandin E2 EP4-receptor agonist (PGE2R-A) in a rat model of acute liver failure. The aim of this study is to determine the anti-apoptotic mechanism underlying the hepatocyte protective effect of PGE2R-A in vitro. Method: (1) Apoptosis was induced in HepG2 cells using CH11, an agonistic anti-Fas antibody. The apoptosis index (percentage of apoptotic cells with respect to the total number of cells) was sequentially estimated after the administration of CH11 alone or CH11 together with indomethacin or PGE2R-A (ONO-AE1-437). (2) The expression levels of Bcl-xL and Mcl-1, members of the anti-apoptotic Bcl-2 family, were sequentially determined by western blot analysis after treatment with PGE2R-A. Results: (1) Apoptosis indexes 6h after treatment with CH11 alone, CH11 plus indomethacin, and CH11 plus PGE2R-A were 24, 42, and 16%, respectively. (2) The expression level of the Bcl-xL protein and mRNA significantly increased 30-180min after treatment with PGE2R-A, while indomethacin decreased the expression levels of Mcl-1 proteins. Conclusion: Direct induction of Bcl-xL plays an important role in the hepatocyte protective effects induced by PGE2R-A.