Sanshiro Muramatsu

Induction of long-term remission in advanced hepatocellular carcinoma with percutaneous isolated liver chemoperfusion.

OBJECTIVE The aim of this study was to report the long-term results of percutaneous isolated liver chemoperfusion with hepatic venous isolation and charcoal hemoperfusion (HVI-CHP) in patients with multiple advanced hepatocellular carcinoma (HCC). SUMMARY BACKGROUND DATA The results of conventional chemotherapy including regional and systemic chemotherapy in patients with HCC remain dismal, and long-term survivors after treatment are rare among patients with multiple advanced HCC. In an effort to improve this situation, we previously developed a novel system of percutaneous isolated liver chemoperfusion with HVI-CHP. METHODS Doxorubicin (60 to 150 mg/m2) was administered via the hepatic artery, under conditions of extracorporeal drug elimination by HVI-CHP in 28 consecutive patients with advanced HCC (39 total treatments). Hepatic venous isolation and charcoal hemoperfusion was accomplished mainly by the single catheter technique using a newly developed 4-lumen-balloon catheter, which was used to isolate and capture total hepatic venous outflow and, at the same time, to direct the filtered blood to the right atrium. RESULTS Complete remission was achieved in five patients, of which four received repeated treatments (two or three times). Although 1 of 5 patients with complete remission died of pulmonary metastases at 8 months, the other 4 remain healthy and free of disease at 20, 24, 27, and 42 months after the first treatment. Partial responses were observed in 12 patients. Duration of response in responders (complete and partial) with repeated treatments was significantly longer than that with a single treatment (p = 0.01). The overall survival rate by the Kaplan-Meier method was 39.7% at 5 years. The treatments were well-tolerated, and the primary side effects were mild to moderate chemical hepatitis and reversible myelosuppression. CONCLUSIONS The results suggest that percutaneous isolated liver chemoperfusion with HVI-CHP is an effective palliative treatment in the majority of patients and yields long-term complete remission in some patients with multiple advanced HCC.

Evidence of protein synthesis during resuscitation of ischemically damaged canine pancreas by the two-layer method

The two-layer method, which supplies sufficient oxygen to the canine pancreas graft and allows adenotriphosphate synthesis within the graft, resuscitates the ischemically damaged pancreas graft during mild hypothermic (20°C) preservation, but the mechanisms are unknown. The purpose of this study was to determine whether protein synthesis was performed on ischemically damaged pancreas graft during preservation by the two-layer method in a canine autotransplantation model. The pancreas grafts subjected to 90 minutes of warm ischemia were preserved by the two-layer method (perfluorochemical/University of Wisconsin solution) at 20°C for 5 hours. Graft viability was judged from graft survival after autotransplantation. DNA, RNA, and protein synthesis was quantitated by determining incorporation of tritiated thymidine, tritiated uridine, and tritiated leucine, respectively, during preservation. Significant increases in RNA and subsequent protein syntheses were observed during preservation by the two-layer method. In contrast, DNA synthesis did not follow RNA and protein synthesis. We conclude that protein is synthesized in the process of postischemic cellular recovery of the pancreas graft during mild hypothermic preservation by the two-layer method.

Percutaneous isolated liver chemoperfusion for treatment of unresectable malignant liver tumors: technique, pharmacokinetics, clinical results.

We have developed a single-catheter technique for percutaneous isolated liver chemoperfusion (PILP) with hepatic venous isolation and charcoal hemoperfusion (HVI-CHP) for the treatment of malignant liver tumors. We report here the surgical technique, pharmacokinetics, and effectiveness of PILP in multiple advanced liver tumors. Twenty-eight patients with hepatocellular carcinoma (HCC) and 18 with metastatic liver tumors underwent a total of 61 PILPs with HVI-CHP. HVI-CHP was accomplished mainly by the single-catheter technique using a novel four-lumen, two-balloon catheter; it was used to isolate and capture total hepatic venous outflow and, at the same time, to direct the filtered blood to the right atrium. Under HVI-CHP, either doxorubicin 960-150 mg/m2) or cisplatin (150-200 mg/m2) was infused via the hepatic artery. The PILP was completed successfully in all 61 trials. Two of forty-six patients died early; one of necrotizing pancreatitis and the other of hepatic arterial thrombosis. Both deaths were related directly to the hepatic arterial catheter. Excluding these two deaths, the treatments were well tolerated. The major side effects were mild to moderate chemical hepatitis and reversible myelosuppression. Of the 27 evaluable HCC patients, 17 (63%) had an objective tumor response (5 complete and 12 partial responses). In 15 patients with colorectal hepatic metastases (CHM), 7 had a sharp decrease in serum carcinoembryonic antigen (CEA) levels (to < 50% of their pretreatment levels) after treatment. However, a single PILP had limited efficacy in terms of the durability of remission (< or = 6 months in most CHM patients, as assessed by CEA levels). These results indicate that PILP with HVI-CHP has high efficacy in most patients with multiple advanced liver tumors. In addition, the results suggest a role of multiple treatment courses of PILP in the induction of long-term remission, especially for patients responsive to the first treatment.

Successful rescue of severe recurrent hepatitis C with interferon and ribavirin in a liver transplant patient

BACKGROUND Rapid graft dysfunction caused by hepatitis C virus (HCV) reinfection, although uncommon, is a disastrous complication in liver transplant patients. Finding an effective therapy for this subgroup of patients with severe recurrent HCV is a priority. METHOD We describe a successful rescue of a 46-year-old man with recurrent hepatitis C (HCV genotype 1b) using long-term interferon (IFN) and ribavirin. The patient had a very aggressive type of posttransplantation HCV infection, as judged by biochemical and histologic findings. RESULTS Despite high pretreatment values of serum alanine aminotransferase (ALT; peak value of 901 IU/L) and HCV-RNA (2.3 x 10(6) copies/ml), the combination therapy with IFN and ribavirin produced a rapid normalization of the serum ALT values, accompanied by the clearance of serum HCV-RNA. Although HCV-RNA reappeared in the serum at 3 months, the patient had continued ALT normalization and histological improvement with follow-up of over 26 months to date after the initiation of the combination therapy. CONCLUSION This observation suggests that IFN in combination with ribavirin may offer an effective therapeutic option for liver transplant patients with severe recurrent hepatitis C.

Effect of Sodium Thiosulfate on Cisplatin Removal With Complete Hepatic Venous Isolation and Extracorporeal Charcoal Hemoperfusion: A Pharmacokinetic Evaluation

AbstractBackground: Complete hepatic venous isolation and extracorporeal charcoal hemoperfusion (HVI·CHP) can limit systemic exposure to high-dose chemotherapeutic agents when given by hepatic arterial infusion (HAI). The purpose of this study was to determine if the concomitant use of sodium thiosulfate (STS) could further expand the advantages of pharmacologic delivery of HVI·CHP for cisplatin (CDDP) during HAI chemotherapy. Methods: CDDP (4mg/kg) was administered over 20 minutes via HAI under conditions of HVI·CHP in 14 mongrel dogs. HVI·CHP was performed for 30 minutes after initiation of HAI. During CDDP infusion, 7 dogs each received 400 mg/kg STS (a 100-fold molar ratio to CDDP) over 20 minutes via the prefilter (STS group) circuit line, while the remaining 7 dogs (controls) received no STS. Blood samples were taken serially from the prefilter circuit line (hepatic venous blood), postfilter line, and the left carotid artery (systemic blood). The free and total CDDP concentrations in these samples were determined by flameless atomic absorption spectrophotometry. Results:During 20 minutes HAI of CDDP, the mean CDDP extraction ratios (ER) by CHP filter were always higher in the STS group than in the control group, regardless of the form (free or total) of CDDP. The differences between the STS and control groups in the extraction ratios of free and total CDDP were significant at all time points measured (P < .05). Consequently, systemic exposure to CDDP, as assessed by area under the time-concentration curve of total CDDP, was significantly lower in the STS group than in the control group (P < .05). Conclusions: These results indicated that concomitant STS infusion could further increase the effect of HVI·CHP on CDDP removal after HAI.