Long-term results of laparoscopic Hassab's procedure for esophagogastric varices with portal hypertension.

INTRODUCTION: Recent reports have shown laparoscopic gastric devascularization and splenectomy (Hassab's procedure) to be a safe and effective treatment for esophagogastric varices with portal hypertension. However, the long-term postoperative results remain unclear. METHODS: Between 2009 and 2015, 17 patients with portal hypertension and esophagogastric varices underwent laparoscopic Hassab's procedure at our institution. Two patients were lost to long-term follow-up (at least 2 years) and excluded. The remaining 15 patients' data and endoscopic findings were retrospectively reviewed. RESULTS: The median postoperative follow-up period was 56 months. The median spleen volume, operation time, blood loss, and length of postoperative hospital stay were 651 (320-1,265) mL, 305 (275-547) minutes, 347 (24-1,131) mL, and 20 (8-41) days, respectively. According to the endoscopic findings 1 year after surgery, the esophagogastric varices disappeared in three patients and improved in 12 patients. The median platelet count was significantly higher 1 year after surgery (19.7 × 104 /dL) than before surgery (5.5 × 104 /dL) (P < .001) and remained stable 2 years after surgery. Two patients died of liver disease. The remaining 13 patients, with a median postoperative follow-up of 57 months, were alive without bleeding from esophagogastric varices. CONCLUSION: Laparoscopic Hassab's procedure is a feasible treatment for esophagogastric varices with portal hypertension in terms of both short- and long-term results.

Evaluation of the Micellization Mechanism of an Amphipathic Graft Copolymer with Enhanced Solubility of Ipriflavone.

The main purpose of this study was to investigate the solubilization enhancement properties of an amphipathic graft copolymer, Soluplus(®), on test compounds. Micellization of Soluplus(®) in solution was characterized by evaluating the changes in the surface activity, turbidity, and thermodynamic behavior. To assess the feasibility of Soluplus(®) as a polymeric carrier of solid dispersions, freeze-dried samples of ipriflavone were prepared, and the physicochemical properties of the carrier plus ipriflavone were evaluated in terms of solubility, dissolution, and crystallinity. The surface tension of the solution decreased depending on the polymer concentration, and gradual turbidity increase was observed. Isothermal titration calorimetry was used to measure the thermal reaction accompanying the micellization of Soluplus(®) and indicated that a colloidal micelle formation improved solubility. The prepared formulations, particularly at a ratio of ipriflavone : Soluplus(®)=1 : 10 (w/w) exhibited a dramatically improved solubility of ipriflavone that was ca. 70-fold higher than that of untreated ipriflavone. The solubilization mechanism of Soluplus(®) was partially elucidated and suggested that its strategic application could improve the solubility of hydrophobic compounds.

Case of cholangiocellular carcinoma in a patient with glycogen storage disease type Ia.

Glycogen storage disease (GSD) type Ia is caused by a deficiency in glucose-6-phosphatase. Long-term complications, including renal disease, gout, osteoporosis and pulmonary hypertension, develop in patients with GSD type Ia. In the second or third decade, 22-75% of GSD type Ia patients develop hepatocellular adenoma (HCA). In some of these patients, the HCA evolves into hepatocellular carcinoma. However, little is known about GSD type Ia patients with HCA who develop cholangiocellular carcinoma (CCC). Here, we report for the first time, a patient with GSD type Ia with HCA, in whom intrahepatic CCC was developed.

Pifithrin-α, a pharmacological inhibitor of p53, downregulates lipopolysaccharide-induced nitric oxide production via impairment of the MyD88-independent pathway.

The effect of pifithrin (PFT)-α, a pharmacological inhibitor of p53, on lipopolysaccharide (LPS)-induced nitric oxide (NO) production in RAW 264.7 macrophage-like cells was examined. PFT-α inhibited the production of NO but not tumor necrosis factor (TNF)-α in response to LPS. PFT-α inhibited LPS-induced NO production via reduced expression of an inducible NO synthase (iNOS). Moreover, PFT-α inhibited LPS-induced iNOS expression in p53-silenced cells. PFT-α inhibited the production of interferon (IFN)-ß, characteristic of the MyD88-independent pathway of LPS signaling, whereas it did not affect the activation of nuclear factor (NF)-κB and mitogen-activated protein kinases in the MyD88-dependent pathway. PFT-α inhibited poly I:C-induced NO production whereas it did not inhibit IFN-ß-induced NO production. Further, PFT-α reduced the expression of IFN regulatory factor 3 that leads to the IFN-ß production in the MyD88-independent pathway. The most upstream event impaired by PFT-α was the reduced expression of TNF receptor-associated factor (TRAF) 3 in the MyD88-independent pathway. PFT-α also reduced the in vivo expression of iNOS in the livers of mice injected with LPS. Taken together, PFT-α was suggested to inhibit LPS-induced NO production via impairment of the MyD88-independent pathway and attenuated LPS-mediated inflammatory response.

Effect of L-arginine supplement on liver regeneration after partial hepatectomy in rats.

BACKGROUND: Nitric oxide (NO) has been reported to be a key mediator in hepatocyte proliferation during liver regeneration. NO is the oxidative metabolite of L-arginine, and is produced by a family of enzymes, collective termed nitric oxide synthase (NOS). Thus, administration of L-arginine might enhance liver regeneration after a hepatectomy. Another amino acid, L-glutamine, which plays an important role in catabolic states and is a crucial factor in various cellular and organ functions, is widely known to enhance liver regeneration experimentally. Thus, the present study was undertaken to evaluate the effects of an L-arginine supplement on liver regeneration, and to compared this with supplementation with L-glutamine and L-alanine (the latter as a negative control), using a rat partial hepatectomy model. METHODS: Before and after a 70% hepatectomy, rats received one of three amino acid solutions (L-arginine, L-glutamine, or L-alanine). The effects on liver regeneration of the administered solutions were examined by assessment of restituted liver mass, staining for proliferating cell nuclear antigen (PCNA), and total RNA and DNA content 24 and 72 hours after the operation. RESULTS: At 72 hours after the hepatectomy, the restituted liver mass, the PCNA labeling index and the DNA quantity were all significantly higher in the L-arginine and L-glutamine groups than in the control. There were no significant differences in those parameters between the L-arginine and L-glutamine groups, nor were any significant differences found between the L-alanine group and the control. CONCLUSION: Oral supplements of L-arginine and L-glutamine enhanced liver regeneration after hepatectomy in rats, suggesting that an oral arginine supplement can clinically improve recovery after a major liver resection.

Laparoscopic surgery in the management of hypersplenism and esophagogastric varices: our initial experiences.

BACKGROUND: Owing to recent advances in laparoscopic surgery, devascularization of the upper stomach with splenectomy (Spx) or Hassab's procedure (Has) as well as Spx for patients with portal hypertension have been attempted laparoscopically in some facilities, the results of which have been reported. This article describes the authors' surgical techniques and their results. METHODS: Between August 1999 and August 2010, the authors treated 110 cases of portal hypertension with Spx or Has. Among these patients, 56 who simultaneously underwent additional major operations were eliminated from the study, leaving 54 patients eligible. They included 38 with open surgeries and 16 with laparoscopic surgeries, which consisted of 10 splenectomies and 6 Has operations. The perioperative data for the 2 groups were compared. RESULTS: Purely laparoscopic Spx (L-Spx) was completed for 9 patients. Conversion from laparoscopic to hand-assisted laparoscopic surgery (HALS) was necessary for 1 patient because of poor visualization. Operative time was significantly longer in L-Spx than in the open method. Postoperative hospital stays were shorter for L-Spx. HALS was used for all 6 laparoscopic Has patients. There was no conversion from the laparoscopic to the open method. Operative time was significantly longer for laparoscopic Has than for open Has. Postoperative complication rates were significantly reduced, and postoperative hospital stays were significantly shorter for laparoscopic Has. CONCLUSIONS: Although the data are still preliminary, laparoscopic surgery for patients with portal hypertension may prove to be a successful strategy.

Peroxisome proliferator-activated receptor α (PPARα) mRNA expression in human hepatocellular carcinoma tissue and non-cancerous liver tissue.

BACKGROUND: Peroxisome proliferator-activated receptor α (PPARα) regulates lipid metabolism in the liver. It is unclear, however, how this receptor changes in liver cancer tissue. On the other hand, mouse carcinogenicity studies showed that PPARα is necessary for the development of liver cancer induced by peroxisome proliferators, and the relationship between PPARα and the development of liver cancer have been the focus of considerable attention. There have been no reports, however, demonstrating that PPARα is involved in the development of human liver cancer. METHODS: The subjects were 10 patients who underwent hepatectomy for hepatocellular carcinoma. We assessed the expression of PPARα mRNA in human hepatocellular carcinoma tissue and non-cancerous tissue, as well as the expression of target genes of PPARα, carnitine palmitoyltransferase 1A and cyclin D1 mRNAs. We also evaluated glyceraldehyde 3-phosphate dehydrogenase, a key enzyme in the glycolytic system. RESULTS: The amounts of PPARα, carnitine palmitoyltransferase 1A and glyceraldehyde 3-phosphate dehydrogenase mRNA in cancerous sections were significantly increased compared to those in non-cancerous sections. The level of cyclin D1 mRNA tends to be higher in cancerous than non-cancerous sections. Although there was a significant correlation between the levels of PPARα mRNA and cyclin D1 mRNA in both sections, however the correlation was higher in cancerous sections. CONCLUSION: The present investigation indicated increased expression of PPARα mRNA and mRNAs for PPARα target genes in human hepatocellular carcinoma. These results might be associated with its carcinogenesis and characteristic features of energy production.

Risk factors for surgical site infection after hepatectomy for hepatocellular carcinoma.

BACKGROUND/AIMS: Clarification of risk factors for surgical site infection (SSI) after hepatectomy for hepatocellular carcinoma (HCC) is important for improvement of surgical outcome. METHODOLOGY: The incidences of SSI under various states were evaluated in 171 patients who underwent hepatectomy for HCC. Univariate and logistic regression analysis were performed to identify risk factors for SSI. The relation between postoperative hepatic failure and SSI was also evaluated. Data were analyzed using Stat View 5.0. RESULTS: SSI occurred in 36 patients (21%). Of the 36 patients with SSI, organ/space SSI occurred in 27. Bile leakage occurred in 22 patients, of which 18 patients had accompanying organ/space SSI. Postoperative hepatic failure occurred in 6 patients, and 5 of these 6 patients also had organ/ space SSI. The postoperative mortality rate was significantly higher in the patients with organ/space SSI (3 of 27 patients, 11%) than in those without organ/space SSI (1 of 144 patients, 0.7%). Logistic regression analysis revealed bile leakage and blood loss to be independent right factors for occurrence of organ/space SSI. CONCLUSIONS: Bile leakage frequently causes organ/space SSI after hepatectomy. Organ/space SSI is closely related to postoperative hepatic failure and death. Prevention of bile leakage is important to improve the surgical outcome of hepatectomy for HCC.

Acute NADPH oxidase activation potentiates cerebrovascular permeability response to bradykinin in ischemia-reperfusion.

Free radical generation is a key event in cerebral reperfusion injury. Bradykinin (Bk) and interleukin-1ß (IL-1ß) have both been implicated in edema formation after stroke, although acute Bk application itself results in only a modest permeability increase. We have investigated the molecular mechanism by assessing the permeability of single pial venules in a stroke model. Increased permeability on reperfusion was dependent on the duration of ischemia and was prevented by applying the B(2) receptor antagonist HOE 140. Postreperfusion permeability increases were mimicked by applying Bk (5µM) for 10 min and blocked by coapplying the IL-1 receptor antagonist with Bk. Furthermore, 10 min pretreatment with IL-1ß resulted in a 3 orders of magnitude leftward shift of the acutely applied Bk concentration-response curve. The left shift was abolished by scavenging free radicals with superoxide dismutase and catalase. Apocynin coapplied with IL-1ß completely blocked the potentiation, implying that NADPH oxidase assembly is the immediate target of IL-1ß. In conclusion, this is first demonstration that bradykinin, released during cerebral ischemia, leads to IL-1ß release, which in turn activates NADPH oxidase leading to blood-brain barrier breakdown.

Effects of 1-O-hexyl-2,3,5-trimethylhydroquinone on carbon tetrachloride-induced hepatic cirrhosis in rats.

AIM: The present study was undertaken to evaluate the effects of 1-O-hexyl-2,3,5-trimethylhydroquinone (HTHQ), a synthesized vitamin E derivative, on carbon tetrachloride (CCl(4))-induced cirrhosis. METHODS: Rats were treated with hypodermic injections of CCl(4) twice a week to induce the hepatic cirrhosis, and given drinking water containing HTHQ or solvent. Primary cultures of rat hepatocytes were performed to evaluate the effects of HTHQ on the expression of inducible nitric oxide synthase (iNOS). RESULTS: Masson's staining of rat livers showed fibrosis around pseudo-lobules in the CCl(4) group, the lesions being reduced in the CCl(4) HTHQ group. Increases in liver tissue hydroxyproline and alpha(1)(I) collagen, alpha-smooth muscle actin and iNOS induced by CCl(4), were also markedly diminished by HTHQ. Furthermore, both HTHQ and vitamin E attenuated interleukin-1beta-induced iNOS protein expression in cultured hepatocytes, the potency of HTHQ being 10-times higher than that of vitamin E. CONCLUSION: HTHQ may inhibit development of hepatic cirrhosis in rats, more potently than vitamin E, by inhibiting the iNOS expression in hepatocytes. Because vitamin E has a radical scavenging action, roles of NO and peroxynitrite will be discussed in the effects of HTHQ on the fibrosis.

Results of laparoscopic liver resection: retrospective study of 68 patients.

BACKGROUND: Although an increasing number of reports and publications have dealt with the laparoscopic approach to liver resection, this procedure remains uncommon, and its feasibility, safety and effectiveness are still not established. There are few reports of the advantages of this approach on postoperative recovery. METHODS: From December 1997 to March 2007, laparoscopic hepatic resection were performed in 68 patients. RESULTS: There were 52 malignant tumors (36 hepatocellular carcinomas, three intrahepatic cholangiocarcinomas, one cystadenocarcinoma, liver metastases from ten colorectal carcinomas and two other organs) and 16 benign lesions among our 68 patients. Fifteen patients with hepatocellular carcinoma had cirrhosis. The mean tumor size was 3.1 +/- 1.8 cm (range 1.0-14.0 cm), and the tumors were located in every liver segment except segment I. Liver resection was anatomical in 17 patients and consisted of a lobectomy in four patients and a lateral segmentectomy in 13 patients. Non-anatomical resections were performed in 51 patients. The operative time was 214 +/- 93 min. Mean blood loss was 393 +/- 564 g. A hand-assisted laparoscopic method or mini-laparotomy method was required in 35 patients (51.4%). Operative complications occurred mainly in our early cases and included three patients (4.4%) with operative bleeding, 2 of whom (2.9%) requiring a conversion to open surgery. Postoperative complications occurred in seven patients (10.0%), and two of then eventually required a re-operation. The mean hospital stay was 17 days. There were no complications in the more recent cases. CONCLUSIONS: The laparoscopic approach for liver tumors is feasible, if the indication is carefully selected. The safety of this procedure depends on the surgical experience of the surgeon and team and the availability of the necessary technology.

Hand-assisted laparoscopic hepatectomy for tumors located in posterior segment.

BACKGROUND/AIMS: In spite of recent advances in laparoscopic surgery, laparoscopic approach is still not a standard option for the tumors located in the posterior segment of the right hepatic lobe mainly due to its technical difficulties and the risk for injuring major adjacent vessels. METHODOLOGY: In order to evaluate the feasibility of laparoscopic posterior segment hepatectomy (LPSH) compared to open posterior segment hepatectomy (OPSH), we retrospectively reviewed a total of 46 laparoscopic hepatectomies and 169 open hepatectomies. Among them, three patients underwent LPSH and seven patients underwent OPSH for tumors located in the posterior segment of the right hepatic lobe. RESULTS: Although duration of operation showed a trend toward being longer in LPSH, LPSH was not accompanied by significant increase of blood loss. Furthermore, LPSH had a trend to result in earlier recovery of the patients, including shorter hospital stay and earlier start of walking or meal. CONCLUSIONS: In conclusion, our data suggested that LPSH could be as safe and feasible as OPSH for tumors located in the posterior segment.

Hydrogen peroxide induces the production of tumor necrosis factor-alpha in RAW 264.7 macrophage cells via activation of p38 and stress-activated protein kinase.

The effect of hydrogen peroxide (H(2)O(2)) on production of tumor necrosis factor (TNF)-alpha was examined in RAW 264.7 murine macrophage cells. H(2)O( 2) led to production of TNF-alpha up to 24 h after the treatment, but not nitric oxide in RAW 264.7 cells. H(2)O(2) induced TNF-alpha production in mouse peritoneal macrophages as well as RAW 264.7 cells. The H(2)O(2)induced TNF-alpha production was prevented by inhibitors of p38 and stress-activated protein kinase (SAPK/JNK), and H(2)O( 2) induced the phosphorylation of p38 and SAPK. Further, H(2)O( 2) significantly augmented the AP-1 activity, but not nuclear factor (NF)-kappaB activity in RAW 264.7 cells. A high level of intracellular reactive oxygen radicals (ROS) was detected in H(2)O(2)-exposed RAW 264.7 cells. Ebselen, a cell permeable antioxidant, prevented the H( 2)O(2)-induced TNFalpha production. H(2)O(2) significantly enhanced lipopolysaccharide (LPS)-induced TNF-alpha production. Therefore, H( 2) O(2) was suggested to induce TNF-alpha production in macrophages via activating p38 and SAPK/JNK as oxidative stress-related signal pathways.

Roles of naofen, a novel WD-repeat-2 protein, in the CCl4-treated livers--a possible relationship to cell proliferation.

Naofen (GenBank accession no. EF613262), a newly found intracellular protein in the WD-repeat-2 protein family, has been cloned as an anti-verotoxin II antibody immunoreactive substance, and the nucleotide- and amino acid-sequences have been clarified. The present study was undertaken to evaluate the roles of naofen especially in carbon tetrachloride (CCl4-induced cirrhosis model of rats, also in partial hepatectomy. Naofen mRNA expressions were observed from the early phases of cirrhosis development and during regenerative phases after partial hepatectomy, more remarkable in the former. Naofen immunoreactive fragments located in the vascular endothelial cells and peri-vascular spaces in normal livers especially in Glisson's areas, being strongly stained in the connective tissues 8 weeks after starting CCl4-injections, besides in the cytoplasm of hepatocytes in pseudo-lobules. In contrast, partial hepatectomy caused a small increase of naofen expressions in the whole hepatocytes, and significantly in the endothelial cells of portal veins and hepatic arterioles. Furthermore, in parallel to the degree of naofen mRNA and protein expressions, the rates of double-nuclei cells to total hepatocytes in the Glisson's areas increased in both cirrhosis and partial hepatectomy, suggesting a relationship between naofen expression and mitosis. In in-vitro studies with cell lines, vascular endothelial growth factor, a cell proliferation stimulant, increased the naofen mRNA expressions in HepG(2) cell lines, whereas paclitaxel, a cytotoxic anti-cancer drug, diminished them in NRK52E, both concentration-dependently. These results indicated that naofen immunoreactive fragments play an important role in the cell proliferation, relevant for analyzing the regenerative phases during cirrhosis developments and after partial hepatectomy.

[A case of lumbar metastases from rectal cancer successfully treated by UFT plus oral leucovorin (LV) therapy].

A 63-year-old man had undergone a low anterior resection for rectal cancer with multiple liver metastases. Oral UFT (450 mg/day) administration alone was started after the operation. After 6 months post operatively, the patient was diagnosed as anastomosis recurrence because of ileus by abdominal X-ray. Transverse loop colostomy was performed by emergency surgery. After surgery, he suffered from paraplegia for lumbar vertebrae metastases. UFT+LV therapy was started. After chemotherapy a significant reduction of the lymph node and liver metastases and an apparent decrease in CEA and CA19-9 were observed. The patient left the hospital and showed no signs of tumor exacerbation for three months. The patient died of aggravation of primary disease afterwards. The therapy was safe and effective, and has successfully maintained the quality of life (QOL) of this patient.

Relationship between serum concentrations of saturated fatty acids and unsaturated fatty acids and the homeostasis model insulin resistance index in Japanese patients with type 2 diabetes mellitus.

BACKGROUND: Consumption of polyunsaturated fatty acids (PUFA) improves the lipid metabolism of diabetics, leading to prevents of arteriosclerosis. Exact relationship between saturated fatty acids (SFA) or PUFA and the insulin resistance of diabetics are unknown. SUBJECTS AND METHODS: We investigated the relationship between the serum concentrations of saturated and unsaturated fatty acids and the homeostasis model insulin resistance index (HOMA-R) in Japanese patients with type 2 diabetes mellitus. RESULTS: The SFA, i.e., lauric acid, myristic acid, palmitic acid, and stearic acid; the monounsaturated fatty acids (MUFA), i.e., palmitoleic acid, oleic acid, and erucic acid; and the PUFA, i.e., eicosadienoic acid, dihomo-gamma-linolenic acid, docosatetraenoic acid, and docosapentaenoic acid were positively correlated with HOMA-R. However, no correlations were found between HOMA-R and SFA, i.e., arachidic acid, behenic acid, and lignoceric acid; the MUFA, i.e., eicosenoic acid and nervonic acid; and the PUFA, i.e., linoleic acid, gamma-linolenic acid, linolenic acid, 5-8-11 eicosatrienoic acid, arachidonic acid, eicosapentaenoic acid, and docosahexaenoic acid. CONCLUSIONS: Some PUFA as well as SFA were positively correlated with HOMA-R. These results indicate that the intake of diet fatty acid must be well balanced in diabetic patients and it is not always true to refrain from taking SFA and increase the unsaturated fatty acids in their diets.

Alterations of DNA methylation and histone modifications contribute to gene silencing in hepatocellular carcinomas.

AIM: The aim of the present study was to examine DNA methylation and histone modification changes in hepatocellular carcinomas (HCC). METHODS: DNA methylation in the P16, RASSF1a, progesterone receptor (PGR) and estrogen receptor alpha (ERalpha) promoters was determined by quantitative bisulfite-pyrosequencing technique in HCC patients. Histone H3-lysine (K) 4, H3-K9 and H3-K27 modifications in all these four genes were examined by chromatin immunoprecipitation (ChIP) assay in HCC cell lines. Expression of two DNA methyltransferases (DNMT1 and DNMT3b) and three histone methyltransferases (SUV39H1, G9a and EZH2) in HCC patients was measured by real-time polymerase chain reaction. RESULTS: Aberrant DNA methylation was detected in all the HCC. Patients with DNA methylation in the RASSF1a, PGR andERalpha promoters in cancers also had substantial DNA methylation in their non-cancerous liver tissues, whereas DNA methylation in the P16 promoter was cancer specific. Epigenetic states in HCC cell lines showed that silencing of P16 and RASSF1a depended on DNA methylation and histone H3-K9 methylation. However, silencing of the PGR and ERalpha genes was more closely related to H3-K27 methylation rather than DNA methylation. Consistent with the alteration of histone status, higher expression of G9a and EZH2 was found in HCC than in non-cancerous liver tissues (P < 0.01). CONCLUSION: These data suggest that multiple epigenetic silencing mechanisms are inappropriately active in HCC cells.

Regulation of branched-chain amino acid metabolism and pharmacological effects of branched-chain amino acids.

Significant evidence of the pharmacological and physiological effects of branched-chain amino acids (BCAA) has accumulated, attracting the interest of not only clinicians but also basic medical researchers. We summarize here the characteristic features of BCAA catabolism, focusing on the initial two enzymes in the pathway, branched-chain aminotransferase and branched-chain alpha-keto acid dehydrogenase complex. In addition, we describe a unique characteristic of the valine catabolic pathway. Finally, we present evidence obtained in animal studies that indicates that BCAA treatment may be appropriate for liver cirrhosis, but not acute liver failure.

[A case of giant hepatocellular carcinoma treatable with radio frequent ablation therapy after effective UFT administration].

A 71-year-old man was diagnosed with giant hepatocellular carcinoma (HCC) and hepatitis C cirrhosis at a nearby hospital. Image diagnosis showed no other metastasis, but the tumor was very huge with daughter nodules in the bilateral lobe of the liver. He was thus treated by oral administration of UFT (300 mg/day). Two months later, the giant liver tumor had shrunk remarkably, and the daughter tumors had disappeared. Eight months later, the levels of serum AFP and PIVKA-II had also reduced remarkably. Twelve months following the first treatment, the levels of both serum AFP and PIVKA-II began increasing again, and he was referred to our hospital. CT showed 2 liver tumors, 1 of which showed viability with moderately differentiated hepatocellular carcinoma and the other evidencing necrosis histologically. Radio frequency ablation therapy was performed for 2 tumors by open laparotomy. It was considered that administration of UFT is a useful and safe therapy for far advanced HCC.