[Clinical experience of treatment of liver metastasis of renal cell carcinoma treated with SMANCS/Lipiodol therapy].

The treatment for metastatic renal cell carcinoma (RCC) has changed dramatically after the beginning of molecular-targeted therapies. However,the treatment for liver metastasis is still difficult in patients with metastatic RCC. We treated liver metastases (8 target lesions) of RCC with stylene-maleic acid neocarzinostatin (SMANCS)/Lipiodol therapy. At the treatment procedure,a catheter was inserted at the femoral artery (Seldinger's method),a microcatheter was selectively inserted into the branch of hepatic artery which fed the liver metastasis,and then SMANCS/Lipodol was infused. We treated 1,2 and 1 patient 4,2, and 1 time,respectively. One lesion treated with SMANCS/Lipodol was further treated by radiofrequency ablation 13 days later. Of 6 metastatic lesions which could be followed up for more than 6 months after the treatment,one had partial response for 4 months and 4 had stable disease for more than 6 months. Four of the 6 lesions shrunk after SMANCS/Lipiodol treatment. Two of 4 patients survived more than 18 months after the first SMANCS/Lipiodol therapy. In all 9 SMANCS/Lipiodol treatments,grade 1 liver dysfunction (44.4%),ascites (11.1%) and fatigue (11.1%) occurred after the treatments. These adverse events were all improved by conservative treatments. SMANCS/Lipiodol therapy can be a treatment option as local treatment for liver metastasis of RCC.

[A case of long-term survival with TAE resistant multiple recurrence HCC successfully treated by hepatic resection].

A 55-year-old female was admitted to our hospital for a third recurrence of hepatoma. She was treated with transcatheter arterial embolization (TAE) in April and November 1996. Computed tomography (CT) and magnetic resonance imaging (MRI) revealed multiple tumors of S4/S8 and S7 in the liver. After the third TAE using SMANCS, Lipiodol and Spongel, abdominal CT revealed insufficient Lipiodol retention and the in efficacy of this treatment. A right lobectomy of the liver was performed for the TAE resistant multiple recurrence of HCC. After the surgery, the patient survived for over 5 years with no recurrence. It appears that this surgery may be a useful modality for TAE resistant multiple recurrence hepatoma in cases of good liver function and lesions limited to the hemi lobe.

A phase I study of hepatic arterial infusion chemotherapy with zinostatin stimalamer alone for hepatocellular carcinoma.

BACKGROUND: Hepatic arterial infusion of zinostatin stimalamer and lipiodol emulsion shows a moderate activity against hepatocellular carcinoma. However, the anti-tumor activity of zinostatin stimalamer alone is uncertain. METHODS: The primary endpoint was to evaluate the frequency of dose-limiting toxicity and determine the maximum-tolerated dose of zinostatin stimalamer when used by intra-arterial infusion. The candidates for this study were patients with hepatocellular carcinoma no longer amenable to established forms of treatment. Hepatic arterial infusion chemotherapy was performed by selectively introducing a catheter into the hepatic artery with zinostatin stimalamer alone. Treatment was repeated at 4-8-week intervals until disease progression or the appearance of unacceptable toxicity. The starting dose of zinostatin stimalamer was 3 mg/m(2), and doses were increased in 1 mg/m(2) increments in successive cohorts. At least three patients were treated at each dose level and three additional patients were treated in the presence of dose-limiting toxicity. RESULTS: Twelve patients were entered into this trial. Dose-limiting toxicity was observed in one of six patients at 3 mg/m(2), and in two of six patients at 4 mg/m(2). The maximum-tolerated dose was judged to be 3 mg/m(2) with liver dysfunction and serum creatinine increase as the dose-limiting toxicity. There was one early death suggested to be related to the protocol treatment. None of the 12 patients achieved an objective tumor response. CONCLUSION: Hepatic arterial infusion with a zinostatin stimalamer of 3 mg/m(2) may be tolerated, but not active, in patients with far advanced hepatocellular carcinoma.

Targeting DNA bulged microenvironments with synthetic agents: lessons from a natural product.

Bulged regions of nucleic acids are important structural motifs whose function has been linked to a number of key nuclear processes. Additionally, bulged intermediates have been implicated in the etiology of several genetic diseases and as targets for viral regulation. Despite these obvious ramifications, few molecules are capable of selective binding to bulged sequences. Prompted by the remarkable affinity of a natural product metabolite, we have designed and prepared a series of readily accessible synthetic agents with selective bulge binding activity. Furthermore, by screening a library of bulge-containing oligodeoxynucelotides, correlations between structure and affinity of the agents can be drawn. In addition to potential applications in molecular biology, the availability of these spirocyclic agents now opens the door for rational drug design.

[Styrene maleic acid neocarzinostatin-transcatheter embolization for hepatocellular carcinoma--third report].

To evaluate the effect of styrene maleic neocarzinostatin-transcatheter arterial embolization (SMANCS-TAE), 40 patients with unresectable hepatocellular carcinoma (HCC) of hypervascular radiological feature, associated with liver cirrhosis (LC), 18 in clinical stage 2 and 20 in stage 3, were treated by SMANCS-TAE. SMANCS with Lipiodol and then gelatin sponge particles were injected into the artery branch supplying HCC using selective catheterization, and its effect was evaluated by computed tomography (CT) Grade. In patients with Grade III or less (Lipiodol accumulation < 99% in the entire tumor) after the first course of therapy, SMANCS-TAE or arterial injection of SMANCS-Lipiodol was performed once or twice more. Consequently, 32 of 40 patients (80%) obtained Grade IV (100% Lipiodol accumulation in the entire tumor) after from once to thrice (median, 1.6 courses). Grade IV was maintained in 26 of 32 patients, and non-recurrence was found 16 of 40 (40%) at the primary tumor to the time at last of follow up. Severe side effects were not noted except in 10 cases with narrowness of hepatic artery and cases of 2 biloma in patients undergoing therapy two or more times. The 1-, 2-, 3-, and 5-year survival rate was 85, 64, 35, and 26%, respectively. No significant difference was noted in the survival rate between clinical stage 2 and 3 liver cirrhosis (LC). But the survival rate of patients who continued to exhibit Grade IV at the primary tumor was significantly better than in those exhibiting Grade III or less (96, 68, 56, and 43% vs 64, 29, 0, and 0%, respectively; p < 0.01). In conclusion, the HCC patients, even those with decompensated LC, who obtained and maintained Grade IV after SMANCS-TAE could reduce the courses of treatment without severe side effects and survived longer. SMANCS-TAE might be useful for the good quality of life of HCC patients.

Changes in the microvascular architecture of colorectal liver metastases following the administration of SMANCS/lipiodol.

BACKGROUND: Liver metastases are the major cause of death for patients with colorectal cancer. Surgical resection is at present the only curative option. Styrene maleic acid neocarzinostatin [SMANCS/Lipiodol (S/L)] targets the unique vascular architecture of tumor blood vessels, which are hyperpermeable and lack a well-developed lymphatic system. Here we report changes in the microvascular architecture of liver metastases by scanning electron microscopy (SEM) following the administration of S/L. MATERIALS AND METHODS: Liver metastases were induced by the intrasplenic injection of dimethylhydrazine induced colon cancer cells in mice. In this model tumor angiogenesis occurs at day 10, while exponential tumor growth occurs at day 16. Changes in the tumor microvasculature were observed at 3 weeks following treatment with S/L at these time points by SEM of corrosion casts. RESULTS: Tumors treated with S/L at day 10 appear similar to day 10 controls. Tumor vessels, 50 +/- 18 microm in diameter, are easily identified from hepatic vessels. Within the hepatic sinusoids are avascular spaces, 144 +/- 60 microm in diameter, which correspond to tumor cell aggregates at the initial stages of growth. Similarly, day 16 treated tumors appear comparable to day 16 controls. These vessels are narrower (84 +/- 32 microm vs. 150 +/- 70 microm) than their control counterparts. This is in contrast to vessels (216 +/- 36 microm in diameter) of a complex nature at 3 weeks. CONCLUSIONS: S/L exerts a marked and immediate effect on the tumor microvessels at both the angiogenic and the exponential phases of tumor growth. This agent is effective at the microvascular level during inhibition of metastatic growth.

Multiple hepatic infarction after transcatheter arterial infusion with SMANCS.

We report a patient with hepatocellular carcinoma who developed multiple hepatic infarction after transcatheter arterial infusion (TAI) with a suspension of styrene maleic acid neocarzinostatin (SMANCS) and Lipiodol (SMANCS/Lipiodol). The parameters of hepatic functional reserve were apparently decreased after the second TAI with SMANCS/Lipiodol, and the patient died of hepatic failure 103 days after the second TAI. The autopsy liver specimen revealed multiple hepatic infarctions associated with peripheral arterial stenosis or occlusion, and portal thrombosis. It is speculated that both the arterial occlusion and the portal thrombosis caused the hepatic infarction, based on a long-term insufficiency of blood supply to the hepatocytes arising from toxic arteritis caused by SMANCS/Lipiodol.

Tumor-targeted chemotherapy with SMANCS in lipiodol for renal cell carcinoma: longer survival with larger size tumors.

OBJECTIVES: To evaluate the anticancer effects of a lipophilic macromolecular anticancer agent, poly(styrene-co-maleic acid)-conjugated neocarzinostatin (SMANCS), dissolved in a lipid contrast medium (Lipiodol) given via the renal artery to patients with renal cell carcinoma. METHODS: Among 467 patients with renal cell carcinoma treated between April 1984 and March 1993, 191 were treated with SMANCS dissolved in a lipid contrast medium (a 3:2 mixture of Lipiodol F and Lipiodol Ultrafluid; Lpd). Selective arterial infusion of SMANCS/Lpd was performed at a dose of 1.0 or 1. 5 mg/mL. The infusion was repeated at intervals of about 2 weeks or longer, but the doses and the total number of infusions varied among patients, according to results of computed tomography analysis. RESULTS: Statistical analysis was performed for 415 patients who met the criteria of this study. Twenty-six surgical patients with metastases who underwent infusion therapy of SMANCS/Lpd for primary lesions showed 3 and 5-year survival rates of 23.0% and 12.8%, respectively; the rates were 19.3% and 9.7% in 31 patients who did not receive SMANCS infusion therapy. In 125 surgical patients without metastases who underwent SMANCS/Lpd infusion, the 5 and 10-year survival rates were 83.0% and 75.2%, respectively, whereas rates of 84.6% and 78.9% were observed in 199 surgical patients whose median tumor size was significantly smaller, however, than the SMANCS/Lpd infusion group. The maximal tumor diameter at the beginning of treatment was significantly larger (mean diameter 70.8 mm) in the SMANCS/Lpd infusion group than in the noninfusion group (59.1 mm). The survival rate was statistically better for patients with tumors of 100 mm diameter or larger in the SMANCS/Lpd infusion group (P <0.05): 5 and 10-year survival rates were 70.4% and 61.6%, respectively, for the infusion group and 64.6% and 50.9% for the group receiving no drug. In patients with larger tumor (greater than 110 mm), the survival rate at 13 years was 75% in the SMANCS/Lpd infusion group and 0% in the surgery group. CONCLUSIONS: Arterial infusion therapy with SMANCS/Lpd appears to be effective for large renal cell carcinoma without metastases in conjunction with surgery.

Focal therapeutic efficacy of transcatheter arterial infusion of styrene maleic acid neocarzinostatin for hepatocellular carcinoma.

We evaluated the focal therapeutic effect of oily carcinostatic agents administered by transcatheter arterial infusion (TAI) as the initial therapy in patients with hepatocellular carcinoma in a randomized controlled clinical trial. Group A (19 patients) received 4 mg of styrene maleic acid neocarzinostatin in 4 ml of Lipiodol, and group B (18 patients) received 100 mg of epirubicin in 4 ml of Lipiodol via the tumor feeding arteries as peripherally as possible. The grade of Lipiodol accumulation and the tumor regression rate were determined 2 weeks after TAI by computerized tomography. Adverse effects within 2 weeks after TAI were evaluated by subjective signs and symptoms such as fever (maximum body temperature) and the frequency of shaking chills and abdominal pain, and by biochemical parameters such as albumin, prothrombin time, and aspartate and alanine aminotransferases. Lipiodol accumulation in the tumor was significantly greater in group A (12/19; 63.2% showing grade IV Lipiodol accumulation) than in group B (3/18; 16.7% showing grade IV) (P<0.05). The tumor regression rate was also significantly greater in group A (8/17; 47.1% showing more than 25% tumor regression) than in group B (1/13; 7.7% showing more than 25% tumor regression) (P<0.05). Although clinically significant elevations of aminotransferases and reductions of cholinesterase, and shaking chills were observed more often in group A than in group B (P<0.0001), these factors had little influence on the clinical outcome. Our results suggest that styrene maleic acid neocarzinostatin in Lipiodol exerts a more favorable focal therapeutic effect than does epirubicin in Lipiodol in the initial treatment of hepatocellular carcinoma.

Experience with intraarterial infusion of styrene maleic acid neocarzinostatin (SMANCS)-lipiodol in pancreatic cancer.

A 54 year-old man was admitted to our hospital and diagnosed with inoperable cancer in the body and tail of the pancreas. The spleen was embolized at its hilum with a coil to infuse an anti-tumor agent selectively into the pancreatic parenchyma and transcatheter intraarterial infusion (TAI) of styrene maleic acid neocarzinostatin (SMANCS)-Lipiodol, 3 mg, was performed. The computed tomography (CT) scan taken immediately after TAI revealed the incorporation of SMANCS-Lipiodol into the site of the pancreatic tail. At 2 weeks, a small amount of SMANCS-Lipiodol remained and clearness of the tumor margin was lacking in the pancreatic tail, but no remarkable change was noted in the body. As for the laboratory data, pancreatic enzyme level was not elevated immediately after TAI. At 2 weeks, tumor markers showed improvement in CEA (3.9-->2.6 ng/ml) and Elastase 1 (370-->230 ng/ml), but little change was seen in CA 19-9 (1600 U/ml: no change) and DUPAN-2 (730-->740 U/ml). In pancreatic cancer, SMANCS-Lipiodol could be infused from the splenic artery into the pancreatic parenchyma by the splenic arterial embolization.

Nausea and vomiting induced by arterial chemo-embolization in patients with hepatocellular carcinoma and the antiemetic effect of ondansetron hydrochloride.

To determine the incidence of nausea and vomiting and the antiemetic effect of ondansetron hydrochloride (OND) in patients with hepatocellular carcinoma treated with arterial chemo-embolization, we studied 59 patients with hepatocellular carcinoma who were treated with transcatheter arterial embolization (TAE) or lipiodolized transcatheter arterial infusion (L-TAI). We investigated the incidence of nausea and vomiting and the amount of food intake when TAE or L-TAI was performed. All patients who experienced nausea and vomiting received OND administered prophylactically at the time of the next TAE or L-TAI to evaluate the antiemetic effect of the drug. Cumulative rates of nausea and vomiting during the week following arterial chemo-embolization were 44.8% and 27.6%, respectively. There was a tendency for the incidence to be higher in patients treated with the anticancer agent zinostatin stimalamer (SMANCS) than in those treated with epirubicin hydrochloride (EPI). Regarding food intake, 53.1% of the patients stated that they ate "half or more than half" of the food provided on the day of arterial chemo-embolization. The rate improved as time went on. In 5 patients who experienced nausea and vomiting at the time of arterial chemo-embolization, nausea and vomiting were inhibited satisfactorily by OND. When arterial chemo-embolization was performed, antiemetic treatment for approximately 3 days was necessary to improve patients' quality of life (QOL) to an acceptable level, and OND was found to be effective for the purpose in our 5 patients who had experienced nausea and/or vomiting at the previous treatment.

[A case of hepatocellular carcinoma with tumor thrombus in the right atrium successfully treated by arterial administration of lipiodol-SMANCS].

In February, 1996, a 73-year-old male with liver dysfunction was admitted to our hospital for further examination and treatment of liver tumor. The liver tumor was revealed by imaging examination, which was mainly in the S4-S8 of liver with a thrombus growing from the right anterior branch to the right branch of the portal vein, and from the right hepatic vein to the inferior vena cava and right atrium. The serum AFP and PIVKA-II levels were elevated to 3.610 ng/ml and 54 AU/ml, respectively. The patient was diagnosed as having hepatocellular carcinoma, and was treated by arterial administration of anticancer drugs (epirubicin hydrochloride, mitomycin C and carboplatin) and TAE. Though the main tumor (S4-S8 of liver) was reduced by TAE, the portal and atrial tumor thrombus did not respond. One month after TAE (20 May, 1996), the first arterial administration of Lipiodol-SMANCS was given, followed by 4 successive procedures with an interval of about 1.5 months (total dose 15 mg), resulting in remarkable tumor thrombus shrinkage and reduction of AFP levels to 80 ng/ml. This case shows that arterial administration of SMANCS may be one of the effective treatments for hepatocellular carcinoma, even with tumor thrombus of hepatic vein, IVC and right atrium.

[Recent advances in research on SMANCS].

During the past five years we observed many advances in the study of the polymer drug, "SMANCS". This first polymeric drug was approved by the Japanese Ministry of Health and Welfare in 1994 as a drug for primary liver cancer, in which the arterial injection of oily formulation in Lipiodol (a lipid contrast medium) is the standard procedure. The advantage of this tactic is the most extraordinary cancer targeting efficiency with the least systemic side effect and very prolonged slow release of SMANCS. The mechanism of tumor selective accumulation of SMANCS and polymeric drugs in general is discussed in view of the so called-EPR (enhanced permeability and retention) effect of solid tumor. The mode of action of SMANCS at the cellular level seems to accompany the generation of superoxide radical which damages DNA; strand break and modification of guaninine by 8-hydroxylguanine. Immunological potentiation involves either the cellular (M phi, T-cell, NK-cell) or molecular level (induction of cytokines, including interferon gamma). The in vivo effect of SMANCS is most pronounced in the tumor vessels where more concentrated SMANCS is accessible due to the EPR effect, and perhaps the generation of O2.-. Nitric oxide generated by both inducible form of NO synthase (iNOS) by the infiltrated macrophages and NOS of endothelial cells, and superoxide from SMANCS will readily react to form peroxynitrite (O2- + NO-->ONOO-), which is a very potent cytotoxic molecule and will damage (nitrate and oxidize) DNA and proteins. Thus, tissue damage and vascular injury or collapse will be the principle tumor toxic mechanism of SMANCS at tissue level. The dose of SMANCS (or grade I-IV tumor filling) and tumor regression parallel each other, and a profile of AFP-value and technical issues of SMANCS/Lipiodol administration intraarterially are also discussed.

[Targeted chemotherapy of hepatocellular carcinoma with SMANCS/Lipiodol--how to use SMANCS/Lipiodol].

The first drug only for arterial injection, SMANCS/Lipiodol, which offers targeted chemotherapy for hepatocellular carcinoma (HCC), now commercially available. Based on our experience using SMANCS/Lipiodol for 424 patients with HCC, the golden standard of how to use SMANCS/Lipiodol for complete necrosis of tumor was described. The initial dose of SMANCS/Lipiodol was varied 2 to 6 mg per body, mainly depending on the size of the tumor. All feeding arteries of HCC have to be verified on angiogram, and the drug must be injected via an adequate artery. Sometimes, a tumor changes its feeding arteries. Additional administrations with an interval of one month were done till the entire tumor was filled with SMANCS/Lipiodol (grade 4). One or two months after achievement of grade 4, we must examine how much drug was removed from tumor on CT. If the entire tumor is not filled with the drug, further injections are recommended to maintain grade 4. Almost all tumors shrank in 3 to 4 months while maintaining grade 4. Frequent administration of low doses (1-3 mg per body) is recommended. Discontinvation of administration was done on the following findings; tumor size reduction of over 90% or complete disappearance of tumor stain. With arterial injection therapy of SMANCS/Lipiodol, survival of patients with unresectable HCC was prolonged, especially in 272 patients who were good candidates for therapy. (Those with Child C liver cirrhosis, with a tumor occupying all four segments of the liver, and/or with extrahepatic spread at initial arterial injection of the drug were excluded.) The 1, 2, 5, and 10 year survival rates were 83%, 58%, 34%, and 25%, respectively.

[Effect of arterial administration of a high molecular weight anti-tumor agent styrene maleic acid neocarzinostatin for multiple small liver cancer].

To assess the characteristics of a zinostatin derivative, 29 patients with multiple hepatocellular carcinoma of 3 cm or less in diameter were treated with intra-arterial injection of the high molecular weight anti-tumor agent, styrene-maleic acid neocarzinostatin, mixed with Lipiodol. Computerized tomography 3 months after the first therapy showed complete accumulation of Lipiodol in 8 patients (27.6%), 50% to 99% accumulation in 4 (13.8%), 10 to 49% in 10 (34.5%), and less than 10% in 7 (24.1%). After repeated injections, Lipiodol accumulation of the entire area of the original tumor was found in 11 patients (37.9%). The degree of Lipiodol accumulation depended on the angiographic vascularity of the tumor and on the images of computerized tomogram during arterial portography. Although complete accumulation of Lipiodol was found in all tumors in 10 (58.8%) of the 17 patients with well-demarcated round-shaped hypervascularity, only one (8.3%) of 12 patients with ill-demarcated tumors could achieve complete accumulation of the Lipiodol in the tumors. Taking into account the fact that hypervascularity on angiograms is closely correlated with the degree of Lipiodol accumulation on computerized tomograms obtained later, well-demarcated round-shaped liver cancer is the best candidate for styrene-maleic acid neocarzinostatin therapy among various stages of liver cancer.

[Repeated arterial infusion of zinostatin stimalamer using port for advanced hepatocellular carcinoma].

Four patients with advanced hepatocellular carcinoma were treated by repeated arterial infusion of zinostatin stimalamer (SMANCS). Every 4 weeks, 4 mg of SMANCS and 4 ml of Lipiodol were administered via the proper hepatic artery using an implantable arterial port. Three patients with advanced liver cirrhosis (Child B or C) could no longer be treated after 2 or 3 courses of SMANCS infusion because of hepatic failure. In the remaining patient also with compensated liver cirrhosis (Child A), a partial response was observed after 5 courses of chemo-infusion, but we discontinued infusion of SMANCS because of hepatic failure. To assess the usefulness of SMANCS for repeated arterial chemo-infusion by the port, we evaluated 103 patients with advanced HCC treated by Lipiodol emulsion mixed with 70 mg of epirubicin (EPI) using a port. An average course was 11 arterial infusions, and the overall response rate was 40%. One-year survival rates were 62% in Child A, 59% in Child B, and 53% in Child C. Compared with Child A and B patients, both elevation of serum total bilirubin levels and decrease of serum albumin levels were observed after 9 months in Child C patients. In conclusion, SMANCS may have more severe hepatic toxicity in comparison with Lipiodol emulsion mixed with EPI.

[Arterial infusion chemotherapy with SMANCS-Lipiodol for multiple hepatocellular carcinoma].

Fifty-five patients with hepatocellular carcinoma were treated with oily anticancer agent SMANCS dissolved in Lipiodol (SMANCS-LPD). The local response rate after the first arterial infusion in all patients was 39%, against 63% in 27 patients with Lipiodol accumulation occupying more than two thirds of tumor areas. The infusion therapy with SMANCS-LPD is adapted for a vascular-rich hepatocellular carcinoma. An infusion of 4 mg of SMANCS was ineffective for patients with tumors distributing in bilateral lobes of liver. Thus, an increase of infusion dosage or repeated infusions were recommended for such cases.

[Arterial infusion of SMANCS for multiple recurrent tumors after hepatic resection].

We investigated the possible side effects and efficacy of arterial infusion of SMANCS as compared to Lipiodol + epirubicin TAE for multiple recurrent tumors after hepatic resection. As a result, no significant difference in GOT, GPT, and total bilirubin was observed between the two groups. No significant difference was found in white blood cell count and platelet count, and there was no significant difference in clinical side effects between the two groups. Grade III response rates after arterial infusion of SMANCS were found in 4 patients (66.6%), and these results showed no significant difference as compared to Lipiodol + epirubicin TAE. Proper hepatic arterial infusion of SMANCS appeared to be useful in multiple recurrent tumors from the standpoints of safety and the rate of Lipiodol deposition.

[Arterial infusion of SMANCS-Lipiodol for advanced hepatocellular carcinoma].

Twenty-four patients were treated with arterial infusion of SMANCS dissolved in Lipiodol. Twenty of these patients had HCC with the main trunks of portal vein occluded by tumor, and four patients had severe cirrhosis and multiple HCC. The actual dose of SMANCS administered each patient ranged from 4 to 6 mg. Side effects occurred in 50%. Severe side effects such as shock and shivering-chilliness were observed in 18%. The differences between the values of hepatic functional serum indexes obtained before and after treatment with SMANCS were small and transient. With regard to the therapeutic response of the arterial infusion of SMANCS, the mean survival time was approximately 2.8 months. It was suggested that the more effective administration of SMANCS was combination of the arterial infusion of SMANCS-Lipiodol with TAE at the level of the right hepatic artery of left hepatic artery for multiple HCC.