Current Trends on the Involvement of Zinc, Copper, and Selenium in the Process of Hepatocarcinogenesis.

Numerous nutritional factors increase the risk of hepatocellular carcinoma (HCC) development. The dysregulation of zinc, copper, and selenium homeostasis is associated with the occurrence of HCC. The impairment of the homeostasis of these essential trace elements results in oxidative stress, DNA damage, cell cycle progression, and angiogenesis, finally leading to hepatocarcinogenesis. These essential trace elements can affect the microenvironment in HCC. The carrier proteins for zinc and copper and selenium-containing enzymes play important roles in the prevention or progression of HCC. These trace elements enhance or alleviate the chemosensitivity of anticancer agents in patients with HCC. The zinc, copper, or selenium may affect the homeostasis of other trace elements with each other. Novel types of cell death including ferropotosis and cupropotosis are also associated with hepatocarcinogenesis. Therapeutic strategies for HCC that target these carrier proteins for zinc and copper or selenium-containing enzymes have been developed in in vitro and in vivo studies. The use of zinc-, copper- or selenium-nanoparticles has been considered as novel therapeutic agents for HCC. These results indicate that zinc, copper, and selenium may become promising therapeutic targets in patients with HCC. The clinical application of these agents is an urgent unmet requirement. This review article highlights the correlation between the dysregulation of the homeostasis of these essential trace elements and the development of HCC and summarizes the current trends on the roles of these essential trace elements in the pathogenesis of hepatocarcinogenesis.

Efficacy and outcome of molecular targeted therapies in elderly patients with hepatocellular carcinoma: Relative dose intensity associated with overall survival.

AIM: Indications of drug therapies to elderly patients with hepatocellular carcinoma (HCC) should be carefully determined. The current study assessed the safety and efficacy of molecular targeted agents (MTAs) in the elderly patients with HCC, and identified factors associated with prognosis in a real-world clinical setting. METHODS: In a retrospective observational study, clinical data of patients with unresectable HCC treated with sorafenib or lenvatinib as first-line treatment at our hospital between 2011 and 2022, were investigated. Clinical parameters, therapeutic effects, adverse events (AEs), and prognosis were evaluated separately for the non-elderly (<75 years old) and elderly patients (≥75 years old). RESULTS: Overall, 111 patients were enrolled, including 59 non-elderly and 52 elderly patients. Compared to the non-elderly patients, the elderly patients had significantly lower skeletal muscle mass and a significantly lower percentage of patients in poor general condition with performance status 2 or higher, but there were no differences in parameters related to liver function or nutritional status. There were no significant differences in the incidence of severe AEs and therapeutic effects between the groups. No significant difference in progression-free survival was observed in the elderly and non-elderly patients; however, overall survival (OS) for sorafenib treatment was shorter in the elderly patients than in the non-elderly patients. Elderly patients consumed lower doses of both the drugs, and relative dose intensity (RDI) 4 weeks after treatment (4W-RDI) was associated with OS. Further, OS in the elderly patients was significantly longer in the subgroup with high 4W-RDI as compared to that in the subgroup with low 4W-RDI. CONCLUSIONS: MTAs can be safely administered to elderly patients with HCC. Furthermore, 4W-RDI is associated with longer OS. Maintaining RDI in the early phase is crucial in predicting the success of treatment with MTAs, especially in the elderly patients.

Antitumor Effect of Zinc Acetate in Hepatocellular Carcinoma Cell Lines via the Induction of Apoptosis.

We aimed to verify antitumor effects of zinc acetate on hepatocellular carcinoma (HCC) in vitro. Five HCC cell lines (HepG2, Hep3B, Huh7, HLE and Alex) were used to evaluate the antitumor effects of zinc acetate. Cell viability was determined by the Cell Counting Kit-8 assay. The cell-cycle alteration was evaluated by a flow cytometric analysis and the detection of cell cycle-related proteins. Apoptosis was determined based on the caspase-cleaved cytokeratin 18 (cCK18) levels. The microRNAs (miRNAs) related to an antitumor effect of zinc acetate were identified using microarrays. Zinc acetate significantly inhibited the proliferation of HCC cells in a dose-dependent manner. The treatment with zinc acetate resulted in significantly increased cCK18 levels in the supernatant and enhanced the expression of heme oxygenase-1 (HO-1) in HCC cells. The flow cytometric analysis revealed an increase of HCC cells in the S and G2/M phases by the administration of zinc acetate, and the expressions of Cdk2 and cyclin E were increased. The miRNA expression profile of the HCC cells treated with zinc acetate was extremely different from that of the untreated HCC cells. These results suggest that the zinc acetate supplementation induces the apoptosis of HCC cells, but does not affect the cell cycle progression. Upregulation of HO-1 and the alteration of miRNAs' profile may be involved in antitumor effects of zinc acetate in HCC cells.

Hepatocellular carcinoma induces body mass loss in parallel with osmolyte and water retention in rats.

AIMS: The number of cancer survivors with cardiovascular disease is increasing. However, the effect of cancer on body fluid regulation remains to be clarified. In this study, we evaluated body osmolyte and water imbalance in rats with hepatocellular carcinoma. MAIN METHODS: Wistar rats were administered diethylnitrosamine, a carcinogenic drug, to establish liver cancer. We analyzed tissue osmolyte and water content, and their associations with aldosterone secretion. KEY FINDINGS: Hepatocellular carcinoma rats had significantly reduced body mass and the amount of total body sodium, potassium, and water. However, these rats had significantly increased relative tissue sodium, potassium, and water content per tissue dry weight. Furthermore, these changes in sodium and water balance in hepatocellular carcinoma rats were significantly associated with increased 24-h urinary aldosterone excretion. Supplementation with 0.25% salt in drinking water improved body weight reduction associated with sodium and water retention in hepatocellular carcinoma rats, which was suppressed by treatment with spironolactone, a mineralocorticoid receptor antagonist. Additionally, the urea-driven water conservation system was activated in hepatocellular carcinoma rats. SIGNIFICANCE: These findings suggest that hepatocellular carcinoma induces body mass loss in parallel with activation of the water conservation system including aldosterone secretion and urea accumulation to retain osmolyte and water. The osmolyte and water retention at the tissue level may be a causative factor for ascites and edema formation in liver failure rats.

L-carnitine reduces hospital admissions in patients with hepatic encephalopathy.

AIM: The aim of this study was to determine whether oral L-carnitine administration reduces the blood ammonia concentration and number of hospital admissions for hepatic encephalopathy in patients with advanced cirrhosis. METHODS: Of 68 patients with hepatic encephalopathy treated with oral L-carnitine supplementation from April 2013 to March 2016, we enrolled 19 patients who had received full standard treatment. We analyzed blood ammonia concentration, number of hospital admissions, and prognosis to determine how effective L-carnitine was in achieving mid-term to long-term suppression of recurrent hepatic encephalopathy. RESULTS: Median blood ammonia concentrations at the start, 1 week, 12 weeks, 24 weeks, and 48 weeks were 159, 79, 75, and 82 µg/dL, respectively. Blood ammonia concentrations 12 week, 24 weeks, and 48 weeks after L-carnitine administration were significantly lower than those at the start (P < 0.0001, respectively). During the 3 years prior to oral L-carnitine administration, the enrolled patients were hospitalized a total of 29 times for hepatic encephalopathy. However, during the 3 years following oral L-carnitine administration, they were admitted a total of six times for hepatic encephalopathy (P < 0.001). Median survival time was 40.9 months. Child-Pugh scores before and after oral L-carnitine administration differed significantly, whereas liver reserve function, nutritional status, and muscle index did not change significantly. CONCLUSIONS: Oral L-carnitine administration is effective and free of adverse effects in patients with hyperammonemia and reduces the number of hospital admissions for hepatic encephalopathy.

Current Trends of Essential Trace Elements in Patients with Chronic Liver Diseases.

Essential trace elements play crucial roles in the maintenance of health, since they are involved in many metabolic pathways. A deficiency or an excess of some trace elements, including zinc, selenium, iron, and copper, frequently causes these metabolic disorders such as impaired glucose tolerance and dyslipidemia. The liver largely regulates most of the metabolism of trace elements, and accordingly, an impairment of liver functions can result in numerous metabolic disorders. The administration or depletion of these trace elements can improve such metabolic disorders and liver dysfunction. Recent advances in molecular biological techniques have helped to elucidate the putative mechanisms by which liver disorders evoke metabolic abnormalities that are due to deficiencies or excesses of these trace elements. A genome-wide association study revealed that a genetic polymorphism affected the metabolism of a specific trace element. Gut dysbiosis was also responsible for impairment of the metabolism of a trace element. This review focuses on the current trends of four trace elements in chronic liver diseases, including chronic hepatitis, liver cirrhosis, nonalcoholic fatty liver disease, and autoimmune liver diseases. The novel mechanisms by which the trace elements participated in the pathogenesis of the chronic liver diseases are also mentioned.

A sodium-glucose cotransporter 2 inhibitor attenuates renal capillary injury and fibrosis by a vascular endothelial growth factor-dependent pathway after renal injury in mice.

Multiple large clinical trials have shown that sodium-glucose cotransporter (SGLT) 2 inhibitors reduce the risk of renal events. However, the mechanism responsible for this outcome remains unknown. Here we investigated the effects of the SGLT2 inhibitor luseogliflozin on the development of renal fibrosis after renal ischemia/reperfusion injury in non-diabetic mice. Luseogliflozin significantly suppressed development of renal fibrosis, prevented peritubular capillary congestion/hemorrhage, attenuated CD31-positive cell loss, suppressed hypoxia, and increased vascular endothelial growth factor (VEGF)-A expression in the kidney after ischemia/reperfusion injury. Luseogliflozin failed to induce the above-mentioned protection in animals co-treated with sunitinib, a VEGF receptor inhibitor. Additionally, luseogliflozin reduced glucose uptake and increased VEGF-A expression in the kidneys of glucose transporter 2 (GLUT2)-downregulated mice following ischemia/reperfusion and in GLUT2-knock-down cells compared with those in normal controls. Withdrawal of glucose from cultured medium, to halt glucose uptake, remarkably increased VEGF-A expression and reversed the luseogliflozin-induced increase in VEGF-A expression in the proximal tubular cells. Thus, luseogliflozin prevented endothelial rarefaction and subsequent renal fibrosis after renal ischemia/reperfusion injury through a VEGF-dependent pathway induced by the dysfunction of proximal tubular glucose uptake in tubules with injury-induced GLUT2 downregulation.

Associations between Zinc Deficiency and Metabolic Abnormalities in Patients with Chronic Liver Disease.

Zinc (Zn) is an essential trace element which has favorable antioxidant, anti-inflammatory, and apoptotic effects. The liver mainly plays a crucial role in maintaining systemic Zn homeostasis. Therefore, the occurrence of chronic liver diseases, such as chronic hepatitis, liver cirrhosis, or fatty liver, results in the impairment of Zn metabolism, and subsequently Zn deficiency. Zn deficiency causes plenty of metabolic abnormalities, including insulin resistance, hepatic steatosis and hepatic encephalopathy. Inversely, metabolic abnormalities like hypoalbuminemia in patients with liver cirrhosis often result in Zn deficiency. Recent studies have revealed the putative mechanisms by which Zn deficiency evokes a variety of metabolic abnormalities in chronic liver disease. Zn supplementation has shown beneficial effects on such metabolic abnormalities in experimental models and actual patients with chronic liver disease. This review summarizes the pathogenesis of metabolic abnormalities deriving from Zn deficiency and the favorable effects of Zn administration in patients with chronic liver disease. In addition, we also highlight the interactions between Zn and other trace elements, vitamins, amino acids, or hormones in such patients.

Hand-Foot Syndrome and Post-Progression Treatment Are the Good Predictors of Better Survival in Advanced Hepatocellular Carcinoma Treated with Sorafenib: A Multicenter Study.

OBJECTIVE: To determine the relationship between treatment outcomes and hand-foot syndrome (HFS), and the relationship between survival rate and post-progression treatment after sorafenib therapy. METHODS: The study assessed 314 patients with advanced hepatocellular carcinoma (HCC) treated with sorafenib at 5 general hospitals in Kagawa Prefecture, Japan. RESULTS: At the start of sorafenib therapy, 23.6% of the patients had HCC of a Child-Pugh class other than A. The initial sorafenib dose was 800 mg in 9.2% of the patients and 400 mg in 64.3%. Time to progression was 129 days (95% CI: 87.3-170.7) and the median overall survival (OS) was 392 days (95% CI: 316.0-468.0). The OS of the patients with Child-Pugh class A HCC was significantly better than that of the patients with Child-Pugh class B HCC (p < 0.0001). The survival curves for Child-Pugh class A-5 points and class A-6 points were significantly different, with that for class A-5 points being better (p < 0.0001). A significant difference was observed between the patients who exhibited HFS and those who did not, with the former exhibiting a better survival rate (p < 0.001). In addition, the survival rate of the patients who received post-progression treatment after sorafenib therapy was significantly better than that of the patients who did not (p < 0.001). CONCLUSION: In sorafenib therapy, patients with HFS and those who received post-progression treatment exhibited good OS.

Neuromyelitis optica spectrum disorder presenting with repeated hypersomnia due to involvement of the hypothalamus and hypothalamus-amygdala linkage.

We report the case of a 46-year-old Japanese woman with neuromyelitis optica spectrum disorder presenting with repeated hypersomnia accompanied by decreased CSF orexin level. First episode associated with hypothalamic-pituitary dysfunction showed bilateral hypothalamic lesions that can cause secondary damage to the orexin neurons. The second episode associated with impaired memory showed a left temporal lesion involving the amygdala. The mechanism remains unknown, but the reduced blood flow in the hypothalamus ipsilateral to the amygdala lesion suggested trans-synaptic hypothalamic dysfunction secondary to the impaired amygdala. A temporal lesion involving the amygdala and hypothalamus could be responsible for hypersomnia due to neuromyelitis optica spectrum disorder.

Regression of glomerular and tubulointerstitial injuries by dietary salt reduction with combination therapy of angiotensin II receptor blocker and calcium channel blocker in Dahl salt-sensitive rats.

A growing body of evidence indicates that renal tissue injuries are reversible. We investigated whether dietary salt reduction with the combination therapy of angiotensin II type 1 receptor blocker (ARB) plus calcium channel blocker (CCB) reverses renal tissue injury in Dahl salt-sensitive (DSS) hypertensive rats. DSS rats were fed a high-salt diet (HS; 4% NaCl) for 4 weeks. Then, DSS rats were given one of the following for 10 weeks: HS diet; normal-salt diet (NS; 0.5% NaCl), NS + an ARB (olmesartan, 10 mg/kg/day), NS + a CCB (azelnidipine, 3 mg/kg/day), NS + olmesartan + azelnidipine or NS + hydralazine (50 mg/kg/day). Four weeks of treatment with HS diet induced hypertension, proteinuria, glomerular sclerosis and hypertrophy, glomerular podocyte injury, and tubulointerstitial fibrosis in DSS rats. A continued HS diet progressed hypertension, proteinuria and renal tissue injury, which was associated with inflammatory cell infiltration and increased proinflammatory cytokine mRNA levels, NADPH oxidase activity and NADPH oxidase-dependent superoxide production in the kidney. In contrast, switching to NS halted the progression of hypertension, renal glomerular and tubular injuries. Dietary salt reduction with ARB or with CCB treatment further reduced blood pressure and partially reversed renal tissues injury. Furthermore, dietary salt reduction with the combination of ARB plus CCB elicited a strong recovery from HS-induced renal tissue injury including the attenuation of inflammation and oxidative stress. These data support the hypothesis that dietary salt reduction with combination therapy of an ARB plus CCB restores glomerular and tubulointerstitial injury in DSS rats.

Efficacy and safety of over-the-scope clip: including complications after endoscopic submucosal dissection.

AIM: To retrospectively review the results of over-the-scope clip (OTSC) use in our hospital and to examine the feasibility of using the OTSC to treat perforations after endoscopic submucosal dissection (ESD). METHODS: We enrolled 23 patients who presented with gastrointestinal (GI) bleeding, fistulae and perforations and were treated with OTSCs (Ovesco Endoscopy GmbH, Tuebingen, Germany) between November 2011 and September 2012. Maximum lesion size was defined as lesion diameter. The number of OTSCs to be used per patient was not decided until the lesion was completely closed. We used a twin grasper (Ovesco Endoscopy GmbH, Tuebingen, Germany) as a grasping device for all the patients. A 9 mm OTSC was chosen for use in the esophagus and colon, and a 10 mm device was used for the stomach, duodenum and rectum. The overall success rate and complications were evaluated, with a particular emphasis on patients who had undergone ESD due to adenocarcinoma. In technical successful cases we included not only complete closing by using OTSCs, but also partial closing where complete closure with OTSCs is almost difficult. In overall clinical successful cases we included only complete closing by using only OTSCs perfectly. All the OTSCs were placed by 2 experienced endoscopists. The sites closed after ESD included not only the perforation site but also all defective ulcers sites. RESULTS: A total of 23 patients [mean age 77 years (range 64-98 years)] underwent OTSC placement during the study period. The indications for OTSC placement were GI bleeding (n = 9), perforation (n = 10), fistula (n = 4) and the prevention of post-ESD duodenal artificial ulcer perforation (n = 1). One patient had a perforation caused by a glycerin enema, after which a fistula formed. Lesion closure using the OTSC alone was successful in 19 out of 23 patients, and overall success rate was 82.6%. A large lesion size (greater than 20 mm) and a delayed diagnosis (more than 1 wk) were the major contributing factors for the overall unsuccessful clinical cases. The location of the unsuccessful lesion was in the stomach. The median operation time in the successful cases was 18 min, and the average observation time was 67 d. During the observation period, none of the patients experienced any complications associated with OTSC placement. In addition, we successfully used the OTSC to close the perforation site after ESD in 6 patients. This was a single-center, retrospective study with a small sample size. CONCLUSION: The OTSC is effective for treating GI bleeding, fistulae as well as perforations, and the OTSC technique proofed effective treatment for perforation after ESD.

Difficulty in differentiating two cases of sigmoid stenosis by diverticulitis from cancer.

The incidence of colonic diverticulosis with or without diverticulitis has increased in the Japanese population due to the modernization of food and aging. The rate of diverticulitis in colon diverticulosis ranges from 8.1% to 9.6%. However, few cases of stenosis due to diverticulitis have been reported. These reports suggest that the differentiation between sigmoid diverticulitis and colon cancer is difficult. This report describes two cases of colon stenosis due to diverticulitis that were difficult to differentiate from colon cancer. Case 1 was a 70-year-old woman with narrowed stools for 1 month who underwent colonofiberscopy (CFS). CFS revealed a diverticulum and circumferential stenosis in the sigmoid colon. Barium enema revealed a marked, hourglass-shaped, 2-cm circumferential stenosis in the sigmoid colon. Fluorodeoxyglucose (FDG)-positron emission tomography computed tomography (CT) revealed an increased FDG uptake at the affected portion of the sigmoid colon. Sigmoid colon cancer was suspected, and laparoscopic sigmoidectomy was performed. Pathological examination demonstrated active inflammation with no evidence of malignancy. Case 2 was a 50-year-old man who presented to a nearby clinic with reduced stool output despite the urge to defecate. CFS detected severe stenosis in the sigmoid colon approximately 25 cm from the dentate line. Contrast-enhanced abdominal CT revealed multiple diverticula, wall thickening, and swelling of the lymph nodes around the peritoneal aorta and the inferior mesenteric artery. A partial sigmoidectomy was performed. Pathological examination of the resected specimen revealed no changes in the mucosal epithelial surface, but a marked infiltration of inflammatory cells was observed.

Rectal perforations and fistulae secondary to a glycerin enema: closure by over-the-scope-clip.

Rectal perforations due to glycerin enemas (GE) typically occur when the patient is in a seated or lordotic standing position. Once the perforation occurs and peritonitis results, death is usually inevitable. We describe two cases of rectal perforation and fistula caused by a GE. An 88-year-old woman presented with a large rectal perforation and a fistula just after receiving a GE. Her case was further complicated by an abscess in the right rectal wall. The second patient was a 78-year-old woman who suffered from a rectovesical fistula after a GE. In both cases, we performed direct endoscopic abscess lavage with a saline solution and closed the fistula using an over-the-scope-clip (OTSC) procedure. These procedures resulted in dramatic improvement in both patients. Direct endoscopic lavage and OTSC closure are very useful for pararectal abscess lavage and fistula closure, respectively, in elderly patients who are in poor general condition. Our two cases are the first reports of the successful endoscopic closure of fistulae using double OTSCs after endoscopic lavage of the debris and an abscess of the rectum secondary to a GE.

Selenium deficiency is associated with insulin resistance in patients with hepatitis C virus-related chronic liver disease.

The relationship between selenium (Se) deficiency and insulin resistance has not much been established in persistent hepatitis C virus (HCV) infection, although Se deficiency is often observed in patients with liver cirrhosis. We hypothesized that the decreased serum Se levels were associated with the severity of hepatic fibrosis or insulin resistance in patients with HCV-related chronic liver disease (CLD). To test the hypothesis, 52 patients with HCV-related CLD including chronic hepatitis and liver cirrhosis were enrolled in this study. The severity of hepatic fibrosis was divided into 4 categories (F(1) through F(4)) according to the new Inuyama classification. Insulin resistance was defined by the homeostasis model for assessment of insulin resistance value. Serum Se levels significantly declined in proportion to the severity of hepatic fibrosis and were positively correlated with serum albumin (r = 0.372, P = .0065) and zinc (r = 0.403, P = .0081) concentrations. Serum Se levels were also linked to glutathione peroxidase activities in the sera of the enrolled patients (r = 0.374, P = .0148). By contrast, serum Se levels were inversely correlated with the homeostasis model for assessment of insulin resistance values (r = -0.304, P = .0338). However, serum Se levels were independent of HCV genotype and loads of HCV-RNA. These findings suggest that Se deficiency was associated with the severity of hepatic fibrosis in patients with HCV-related CLD and that Se deficiency was likely to be one of the factors contributing to insulin resistance in those patients.

Efficacy of zinc administration in patients with hepatitis C virus-related chronic liver disease.

OBJECTIVE: Zinc supplementation has been shown to contribute to inhibition of liver fibrosis and improvement in hepatic encephalopathy. However, little is known about the anti-inflammatory effect of zinc on hepatitis C virus (HCV)-related chronic liver disease (CLD). We therefore examined the effects of zinc administration on inflammatory activity and fibrosis in the liver of patients with HCV-related CLD. MATERIAL AND METHODS: Polaprezinc, a complex of zinc and l-carnosine, was administrated at 225 mg/day for 6 months to 14 patients with HCV-related CLD, in addition to their ongoing prescriptions. Peripheral blood cell counts, liver-related biochemical parameters, serological markers for liver fibrosis, HCV-RNA loads, and serum levels of zinc and ferritin were evaluated before and after zinc administration. RESULTS: Serum zinc concentrations were positively correlated with hepatic reserve before zinc supplementation. A significant increase in serum zinc level was observed after zinc supplementation (64+/-15 versus 78+/-26 mg/dl, p=0.0156). Treatment with polaprezinc significantly decreased serum aminotransferase levels (aspartate aminotransferase (AST): 92+/-33 versus 63+/-23 IU/l, p=0.0004; alanine aminotransferase (ALT): 106+/-43 versus 65+/-32 IU/l, p=0.0002), whereas alkaline phosphatase levels were significantly increased (305+/-117 versus 337+/-118 U/l, p=0.0020). Serum ferritin levels were significantly decreased by treatment with polaprezinc (158+/-141 versus 101+/-80 ng/ml, p=0.0117). The reduction rate of ALT levels by polaprezinc was positively correlated with that of ferritin (r(2)=0.536, p=0.0389). There was a tendency toward a decrease in serum type IV collagen 7S levels after treatment with polaprezinc. However, administration of polaprezinc did not affect peripheral blood cell counts, other liver function tests, or HCV-RNA loads. CONCLUSIONS: These findings suggest that polaprezinc exerts an anti-inflammatory effect on the liver in patients with HCV-related CLD by reducing iron overload.

Successful treatment of hypovascular advanced hepatocellular carcinoma with lipiodol-targetting intervention radiology.

We report a case of hypovascular advanced hepa-tocellular carcinoma (HCC) successfully treated with a novel combination therapy of percutaneous ethanol-lipiodol injection (PELI) and intervention radiology (IVR), lipiodol-targetting IVR (Lipi-IVR). The present case had a hypovascular HCC (3 cm in diameter) located in the S6 region of the liver. Although the tumor was not detectable at all by both of early and late phase of helical dynamic computed tomography (CT), it could be detected by ultrasonography (US) as a low echoic space occupying lesion (SOL) beside the gallbladder and right kidney. Serum levels of alpha fetoprotein (AFP) and AFP-L3 were extremely high. Combination therapy of PELI, firstly reported in our department, and IVR (PELI and IVR, lipiodol-targetting IVR) was performed twice for the treatment. PELI could effectively visualize the location of the tumor for IVR treatment and show the presence of a thin blood vessel branching from the right hepatic artery flowing into the lipiodol deposit. After treatment, the serum levels of AFP and AFP-L3 were rapidly decreased to normal and maintained for more than eight months. Thus, this case expressing the tremendous effect might give us insight into the effectiveness of the novel combination therapy of PELI and IVR for the treatment of hypovascular HCC.

Successful treatment of large-size advanced hepatocellular carcinoma by transarterial chemoembolization followed by the combination therapy of percutaneous ethanol-lipiodol injection and radiofrequency ablation.

We report a case of large-size hepatocellular carcinoma (HCC) successfully treated with transarterial chemoembolization (TACE) followed by the combination therapy of percutaneous ethanol-lipiodol injection and radiofrequency ablation (PELI-RFA) and percutaneous ethanol-lipiodol injection (PELI) therapy. In the present case, the patient had a large-size advanced HCC, 7 cm in diameter, located in the S8 region of the liver. In addition, the hepatic reserve of the patient was severely poor. In order not to impair the poor hepatic reserve, we chose PELI-RFA and PELI, originally developed in our department and reported as milder treatment modalities than others. After TACE , PELI-RFA and PELI were performed several times, the HCC was totally destroyed and early enhancement shown by helical dynamic computed tomography disappeared completely after treatment. The hepatic reserve of the patient was not impaired by the series of treatments. Serum levels of tumor markers, alpha-fetoprotein and Des-gamma-carboxy prothrombin, were rapidly decreased to almost normal levels. PELI-RFA and PELI may be effective for the treatment of large-size HCC of patients with poor hepatic reserve.

Efficacy of combination therapies of percutaneous or laparoscopic ethanol-lipiodol injection and radiofrequency ablation.

Percutaneous radiofrequency ablation (RFA) is able to destroy hepatocellular carcinoma (HCC) in a few sessions without major complications. We have previously shown that not only the combined use of percutaneous ethanol injection and RFA (PEI-RFA) but also injection of mixture of ethanol and lipiodol (PELIT) was useful for the treatment of HCC. In the present study, we further developed the combined use of PELIT and RFA through percutaneous or laparoscopic approach (PELI-RFA or LELI-RFA) and evaluated its usefulness. Nineteen nodules in 18 cases were treated with PELI-RFA or LELI-RFA. In the cases treated with LELI-RFA, no bleeding and no spilling milky fluid containing tumor cells were observed from the surface of ablated tumors. In the cases sufficiently treated with PELI-RFA or LELI-RFA, the mixture of ethanol and lipiodol was accumulated in the entire region of the tumor and low-density area was observed around the lipiodol deposit by computed tomography (CT). These delineations of coagulated area were helpful to evaluate the precise area of safety margin around the tumor treated with PELI-RFA or LELI-RFA. Furthermore, the total volume of coagulated necrosis significantly and positively correlated with the product of energy requirement for ablation and the volume of ethanol injected by PELI-RFA or LELI-RFA. Among the cases treated with PELI-RFA or LELI-RFA, local recurrence emerged only in one case in whom enough safety margin could not be achieved by PELI-RFA. Therefore, it is critical to evaluate whether enough safety margin could be obtained with RFA therapy, and PELI-RFA and LELI-RFA are helpful in visualizing the safety margin area.

Percutaneous ethanol and lipiodol injection therapy for hepatocellular carcinoma.

Radiofrequency ablation (RFA) therapy is of great significance in the treatment of hepatocellular carcinoma (HCC) or metastatic liver tumors. RFA is able to achieve widely coagulated necrosis in a few sessions without major complications. However, HCC cases exist that are resistant to RFA therapy for several reasons. In the present study, we performed injection of the mixture of ethanol and lipiodol (percutaneous ethanol-lipiodol injection therapy: PELIT) for HCCs that lacked clear visuality of the entire shape of the tumor by ultrasonography (US) or computed tomography (CT), or that were difficult to treat with RFA alone due to their locations in the liver or due to severe liver dysfunction of the patients. Local recurrence rates of HCC treated with PELIT were shown to be low in patients followed up for at least 4 months. In all patients treated with PELIT, lipiodol was accumulated in the entire region of the tumor after several trials of PELIT and the accumulation was kept for many months. The biopsy examination from the tumor treated with PELIT showed that HCC cells were totally destroyed by the PELIT. Although RFA therapy serves as a central role for the treatment of HCCs, PELIT, considered to be milder therapy, is likely to be important as a supportive treatment for HCCs and useful for the treatment of HCCs that are difficult to treat with RFA.