Recent progress in radiofrequency ablation therapy for hepatocellular carcinoma.

In order to attain better ablation and more effective management of hepatocellular carcinoma (HCC), new approaches and devices in radiofrequency ablation (RFA) therapy were presented and discussed in a workshop at the 50th Annual Meeting of the Liver Cancer Study Group of Japan. A novel bipolar RFA apparatus was introduced in Japan in January 2013. Hundreds of subjects with HCC were treated with multipolar RFA with varied devices and plans. Among these, no-touch ablation was one of the most useful procedures in the treatment of HCC with the apparatus. In RFA therapy, a few assisting devices and techniques were applied for convenience and improvement of the thermal ablation procedure. Contrast-enhanced ultrasonography and three-dimensional fusion imaging technique using volume data of CT or MRI could improve exact targeting and shorten the treatment time for RFA procedures under ultrasonographic guidance. A more complicated method using a workstation was also reported as being helpful in planning the ablated shape and volume in multineedle RFA. The effective use of sedatives and antianalgesics as well as a novel microwave apparatus with a cooled-tip electrode was also discussed.

Successful treatment of a patient with Budd-Chiari syndrome with main hepatic vein obstruction with percutaneous transluminal angioplasty and stent placement.

A woman in her 40s presented at our department with abdominal fullness. Abdominal computed tomography showed hepatomegaly and ascites, and gastrointestinal endoscopy showed esophageal varices. A diagnosis of Budd-Chiari syndrome (BCS) was confirmed by percutaneous hepatic venography, which detected obstruction of the main hepatic vein. It was treated using percutaneous transluminal angioplasty and metallic stent placement. Rupture of the esophageal varices occurred 5 months later because of the occlusion of the stent lumen; however, she was successfully retreated with further stent placement.

Phosphorylated Smad2 and Smad3 signaling: Shifting between tumor suppression and fibro-carcinogenesis in chronic hepatitis C.

AIM: Insight into hepatic fibrogenesis and carcinogenesis (fibro-carcinogenesis) caused by hepatitis C virus (HCV) infection has come from recent analyses of transforming growth factor (TGF)-ß signaling. TGF-ß type I receptor and pro-inflammatory cytokine-activated kinases differentially phosphorylate Smad2 and Smad3 to create C-terminally (C), linker (L) or dually (L/C) phosphorylated (p) isoforms. This study aimed to elucidate how HCV infection affected hepatic fibro-carcinogenesis, particularly via phospho-Smad signaling. METHODS: We first studied phospho-Smad2/3 positivity of 100 patients in different stages of HCV-related chronic liver disease. To examine changes in phospho-Smad2/3 after HCV clearance, we analyzed 32 paired liver biopsy samples obtained before and after sustained virological response (SVR), dividing patients into two groups: 20 patients not developing hepatocellular carcinoma (HCC) after attaining SVR (non-HCC group), and 12 patients who developed HCC despite SVR (HCC group). RESULTS: Hepatocytic tumor-suppressive pSmad3C signaling shifted to carcinogenic pSmad3L and fibrogenic pSmad2L/C signaling as liver diseases progressed. In the non-HCC group, 13 patients (65%) displayed fibrotic regression and inflammation reduction after SVR. Interestingly, SVR restored cytostatic pSmad3C signaling in hepatocytes, while eliminating prior carcinogenic pSmad3L and fibrogenic pSmad2L/C signaling. In the HCC group, seven patients (58%) displayed unchanged or even progressed fibrosis despite smoothened inflammatory activity, reflecting persistently high numbers of hepatocytes with pSmad3L- and pSmad2L/C-signaling and low pSmad3C-signaling. CONCLUSION: HCV clearance limits fibrosis and reduces HCC incidence by switching inflammation-dependent phospho-Smad signaling from fibro-carcinogenesis to tumor suppression. However, progression to HCC would occur in severely fibrotic livers if an inflammation-independent fibro-carcinogenic process has already begun before HCV clearance.

Acute necrotizing pancreatitis as a fatal complication following DC Bead transcatheter arterial chemoembolization for hepatocellular carcinoma: A case report and review of the literature.

Transcatheter arterial chemoembolization (TACE) is one of the most effective palliative measures for patients with inoperable hepatocellular carcinoma (HCC). Acute pancreatitis is a rare but well-known complication following TACE. We herein present the case of a patient with HCC who developed fatal complications (acute necrotizing pancreatitis and upper gastrointestinal ulcers) after TACE with DC Beads. The patient was diagnosed with HCC in segments 4 and 8, measuring ~70 mm in greatest diameter, and he was treated by TACE. Hepatic arteriography revealed replacement of the origin of the right hepatic artery to the superior mesenteric artery, while the left hepatic artery originated from the celiac artery. After selection of the segmental arterial branches feeding the tumor, 2 ml of 100-300-µm-sized DC Beads loaded with 150 mg epirubicin were injected through the microcatheter. The patient complained of abdominal pain after the TACE procedure. Upper gastrointestinal endoscopy revealed longitudinal ulcers from the esophagus to the duodenum, and contrast-enhanced computed tomography revealed swelling of the pancreas and focal areas of low density in the pancreatic body, suggesting necrosis. The patient developed respiratory insufficiency, renal failure and sepsis, and finally succumbed to the complications 54 days after the procedure, despite general management of the acute pancreatitis. An autopsy revealed that the main cause of the patient's death was extensive pancreatic necrosis due to a gastroduodenal artery embolism after TACE with DC Beads. Therefore, it is crucial for treating physicians to be aware of this complication following TACE with DC Beads, particularly in patients with anatomical variations.

Clinicopathologic study of small hepatocellular carcinoma with microscopic satellite nodules to determine the extent of tumor ablation by local therapy.

To determine the optimal treatment margin of local ablation therapy for small hepatocellular carcinoma (HCC), we investigated characteristics of microscopic satellite HCC nodules (msn) using resected livers, and the incidence of local recurrences in patients who underwent percutaneous microwave coagulation therapy (PMCT) according to whether or not an adequate treatment margin was achieved. We reviewed 117 single small HCCs (tumor size < or =3 cm ) resected with a > or =1-cm surgical margin. Among the surgically resected tumors, none of the msn were detected by preoperative imaging. When an msn was observed in the resected specimen, the maximum distance from the edge of the tumor to the msn was measured. Among the tumors sized < or =2 cm (n=66), the number having msn and the distance (mm) from the main tumor according to the degree of tumor differentiation were as follows: well (n=16), 1 (6.2%) and 1.4 mm; moderate (n=46), 5 (19.2%) and 5.8+/-1.2 mm; and poor (n=4), 1 (25.0%) and 4.8 mm. Among the tumors sized 2 to 3 cm (n=51), the corresponding results were: well (n=11), 3 (27.2%) and 3.5+/-2.2 mm; moderate (n=36), 6 (16.7%) and 5.4+/-1.4 mm; and poor (n=4), 1 (25.0%) and 4.9 mm. Of the 112 vascular tumors, 17 (15%) had msn. The 5 avascular tumors had no msn. Among the patients who underwent PMCT with a treatment margin measuring <5 mm, local recurrence occurred in 2 of 25 patients whose original tumor was < or =2 cm, and 3 of 25 (12%) patients of those with tumors of 2 to 3 cm. No patient with a tumor < or =3 cm and a > or =5-mm treatment margin suffered a local recurrence. The results of this study suggest that the incidence of local recurrence may be reduced by achieving a treatment margin of any width for avascular tumors and a margin of 1 cm for vascular tumors during local ablation therapy for small HCCs of < or =3 cm.

S-1 monotherapy in a patient with cholangiolocellular carcinoma: A case report.

A 71-year-old man with alcoholic cirrhosis was found to have multiple hypervascular lesions in the liver on enhanced computed tomography. An ultrasound-guided biopsy of the lesion was performed. Immunohistochemical analysis for hepatocyte paraffin 1 expression was negative; cytokeratin (CK) 7, CK19, epithelial cell adhesion molecule and epithelial membrane antigens were positive; mucicarmine staining was negative. The tumor was thus histologically diagnosed as cholangiolocellular carcinoma (CoCC). The tumor was inoperable due to the associated advanced liver disease. In addition, the patient preferred systemic chemotherapy using only orally administered agents. Thus, S-1 monotherapy was recommended. S-1 was initially administered orally at a dose of 80 mg/day. Although the levels of tumor marker (prothrombin induced by vitamin K absence/antagonist-II and carbohydrate antigen 19-9) levels were marginally elevated, their values did not change over the entire course. The patient achieved a partial response according to the Response Evaluation Criteria In Solid Tumors (RECIST) and modified RECIST 1 year after chemotherapy initiation. In conclusion, S-1 monotherapy exhibited promising efficacy against unresectable CoCC.

Interstitial pneumonia induced by sorafenib in a patient with hepatocellular carcinoma: An autopsy case report.

Sorafenib is a multikinase inhibitor currently approved in Japan for the treatment of unresectable hepatocellular carcinoma. Interstitial pneumonia induced by sorafenib may have a fatal outcome, and therefore, has recently been the focus of many studies. The current report presents an autopsy case of diffuse alveolar damage (DAD) that occurred in a 59-year-old male, who had been treated with sorafenib. The patient had been given sorafenib for six months and had exhibited no respiratory symptoms during this time. However, 19 days after sorafenib treatment was resumed, acute interstitial pneumonia developed. In previously reported cases, the first symptoms of pulmonary toxicity appeared following a limited treatment duration with sorafenib; this was in contrast to the patient in the current study, who developed the first symptoms after eight months. We therefore conclude that physicians must be aware of interstitial pneumonia as a potential pulmonary toxicity associated with sorafenib treatment when treatment with sorafenib is resumed, even after prolonged use. In addition, to best of our knowledge, this is the first case of a postmortem examination reported in patient with interstitial pneumonia induced by sorafenib treatment.

Microwave coagulation using a perfusion microwave electrode: Preliminary experimental study using ex vivo and in vivo liver.

To assess the coagulation capability of a perfusion microwave electrode (PME) as a key component of microwave coagulation therapy, a preliminary experimental study was performed using ex vivo and in vivo livers. For a microwave electrode, a PME was employed. Using a PME, saline was passed through the electrode and injected continuously into the target tissue. Using an ex vivo bovine liver, the range of tissue coagulation was measured for various volumes of infused saline and microwave outputs. Using an in vivo porcine liver, the efficiency of coagulation by a PME was compared with that of radiofrequency ablation (RFA) using a cool-tip needle. In an ex vivo bovine liver, the range of tissue coagulation increased as the flow rate of saline increased. In the in vivo porcine liver, the range of coagulation was similar to that found in the ex vivo bovine liver. With a PME under conditions of a microwave output of 80 W, a flow rate of 3 ml/min and irradiation time of 5 min, the range of coagulation was 44.8±2.8 mm [maximum vertical diameter: (a)] x 31.2±2.4 mm [maximum transverse diameter: (b)]. The range of RFA (cool-tip needle) at 12 min was 46.0±2.0 mm (a) x 30.2±2.0 mm (b). With only 5 min of microwave irradiation, the use of a PME enabled induction of the same range of coagulation that was obtainable by RFA for 12 min. In comparison with microwave coagulation without saline infusion, the use of a PME made it possible to extend the range of tissue coagulation to a range equal to that of RFA in a short time. Microwave coagulation using a PME may be one of the suitable tissue coagulation systems for local ablation treatment.

Combined treatment of large hepatocellular carcinoma with transcatheter arterial chemoembolization and percutaneous ethanol injection with a multipronged needle: experimental and clinical investigation.

PURPOSE: This study was designed to evaluate the usefulness of percutaneous ethanol injection (PEI) with a multipronged needle for the treatment of large hepatocellular carcinoma (HCC). An experimental animal study and a clinical investigation were performed. METHODS: In the experimental study, 20 ml of 99.5% ethanol was injected into porcine liver in vivo with a multipronged needle (n = 5) or a straight needle (n = 5), and the volumes of coagulation necrosis were compared. In the clinical investigation, PEI was performed in 17 patients (10 men, 7 women; mean age 73.4 ± 6.7 years) with single, large HCC (mean tumor diameter, 47.2 ± 11.5 mm; range, 32-70 mm) by using a multipronged needle. Fifteen of 17 patients received transarterial chemoembolization (TACE) before PEI. RESULTS: The volume of coagulation in porcine liver in vivo was significantly increased with the multipronged needle compared with the straight needle (longest perpendicular diameters, 34.2 ± 3.6 mm × 30.2 ± 3.6 mm vs. 22.6 ± 2.5 mm × 19 ± 2.2 mm, respectively; P < 0.05). In the clinical trial, initial complete response (CR) of the tumor was achieved in 17 of 17 patients, 7 of whom required two PEI sessions. During the follow-up, local recurrence was detected in 4 of 17 patients at 3-19 months after the procedure, for a rate of sustained local CR of 76%. No major complication occurred. CONCLUSIONS: Use of a multipronged needle substantially increases the volume of coagulation in vivo with respect to the conventional PEI technique. Combined TACE and PEI with multipronged needles is a safe and effective option for percutaneous treatment of single, large HCC.

Percutaneous microwave coagulation therapy for hepatocellular carcinoma: increased coagulation diameter using a new electrode and microwave generator.

We performed percutaneous microwave co-agulation therapy (PMCT) using a new microwave electrode and microwave generator to lessen the number of microwave electrode insertions for hepatocellular carcinoma (HCC) measuring 2 to 2.5 to or=5 mm on dynamic computed tomography. Necrosis of HCC and the non-cancerous area surrounding the tumor was obtained by a single needle insertion in 23 patients (tumor size: 2 to 2.5 to 2 to 2.5 to or=5 mm, we have not detected local recurrences. On the other hand, 4 of the 10 patients who could not obtain the treated margin of >or=5 mm, experienced a local recurrence. No fatal complications were observed. However, bile duct stricture was observed in 2 patients. The new microwave coagulation system can induce extensive necrosis with a small number of microwave electrode insertions. This system may enhance the efficacy of PMCT for HCC measuring <3.0 cm in diameter.