[Successful R0 Resection of Hilar Cholangiocarcinoma Invading the Inferior Vena Cava through Left Trisegmentectomy with Combined Resection of the Portal Vein and Inferior Vena Cava after Gemcitabine/Cisplatin Combination Chemotherapy-A Case Report].

A 65-year-old woman was admitted to our institution with sonography results indicating a caudate lobe mass. CT showed a large low-density mass in the caudate lobe, extensively involving the inferior vena cava and main portal vein. Moderately differentiated adenocarcinoma was found on transcutaneous biopsy. We therefore regarded this tumor as a severe locally advanced hilar cholangiocarcinoma and initiated gemcitabine/cisplatin combined chemotherapy. The tumor gradually reduced in size. However, after 28 courses of treatment, CT showed persistent tumor invasion in the left trunk of the portal vein and inferior vena cava invasion in succession in the middle; the tumor had not yet invaded the left hepatic vein. Owing to myelosuppression and general malaise, it was difficult to continue chemotherapy. After 32 courses of treatment, the patient underwent a left trisegmentectomy with combined resection of the portal vein and inferior vena cava. Postoperative microscopic findings revealed no apparent invasion of the tumor in the inferior vena cava, thus suggesting successful R0 resection. The patient is alive without recurrence 18 months postoperatively.

Serum IFN-λ3 Levels Correlate with Serum Hepatitis C Virus RNA Levels in Symptomatic Patients with Acute Hepatitis C.

BACKGROUND: Recent genome-wide association studies demonstrated that 2 single nucleotide polymorphisms (SNPs), upstream of the interferon-λ (IFNL) 3 gene, are associated with the spontaneous clearance of hepatitis C virus (HCV) in symptomatic patients with acute hepatitis C (AHC). Although these 2 SNPs, rs8099917 and rs12979860, have established their significant roles in the innate immunity response to spontaneously clear HCV in patients with AHC, the detailed mechanisms of their roles remain largely unknown. AIM: This study is aimed at clarifying the factors affecting IFNL3 production and assessing the roles of IFNL3 in AHC. MATERIALS AND METHODS: A total of 21 AHC patients who visited the hospital within 10 days after symptom onset were assessed. As controls, 23 healthy volunteers (HVs) were examined. Serum IFNL3 levels were quantified using an in-house, IFNL3-specific chemiluminescence enzyme immunoassay (CLEIA) kit. Serum IFNL1, IFN-α, IFN-ß, and IFN-γ induced protein-10 (IP-10) levels were assayed using commercial enzyme-linked immunosorbent assay (ELISA) kits. RESULTS: At baseline, serum IFNL3 levels were higher in AHC patients than in HVs (p < 0.0001). The higher levels in AHC patients did not differ between patients with the rs8099917 TT genotype and those with the non-TT (TG/GG) genotype (p = 0.546). Serial measurement of serum IFNL3 levels did not predict the outcome of conventional AHC. However, serum IFNL3 levels at baseline correlated positively with the HCV RNA levels (p = 0.005). Following HCV eradication, serum IFNL3 levels reduced to within the range obtained for HVs. Baseline serum IFNL1 levels did not differ significantly between AHC patients and HVs (p = 0.284). Serum levels of IFNL1 and IFNL3 at baseline also showed no correlative power (p = 0.288). Serum IFN-α and IFN-ß were detected together with remarkably high serum IFNL3 levels in only one patient who progressed to acute liver failure (ALF). CONCLUSION: These findings indicate that serum IFNL3 levels at baseline are higher in AHC patients regardless of the rs8099917 polymorphism, and primary HCV infection triggers the production of IFNL3. As a first line of defense in the innate immune system against invading HCV, increased IFNL3 levels play an important role, but serum IFNL3 levels are not the principal determinant of the clinical course of conventional AHC.

T1b primary remnant cystic duct cancer following cholecystectomy: A case report.

INTRODUCTION: Although primary cystic duct cancer is a rare entity, remnant cystic duct cancer is even more rare. We report a case of early cystic duct cancer following cholecystectomy. PRESENTATION OF THE CASE: A 81 year-old man complained temporary loss of appetite. He had underwent cholecystectomy for acute cholecystitis 5 years prior. Contrast enhanced computed tomography, magnetic resonance image and endoscopic ultrasonography showed remnant cystic duct tumor with protrusion to common bile duct. Endoscopic retrograde cholangiography revealed defect of contrast medium around confluence of the remnant cystic duct and common bile duct. We performed step biopsy by using forceps which revealed adenocarcinoma. Based on these findings, extrahepatic bile duct and remnant cystic duct resection were performed. The histopathology showed adenocarcinoma, pap > tub2, filling in remnant cystic duct, 30 mm in size but showed no lymphovascular or perineural invasion, no lymph node metastasis and negative surgical margin, and was classified as pT1bN0M0. CONCLUSION: This is a rare case of primary carcinoma of remnant cystic duct cancer which is detected during computed tomography follow up for hepatic cell carcinoma recurrence. We confirmed remnant cystic duct cancer and its superficial extension to common bile duct with endoscopic ultrasonography and intraductal ultrasonography. Proper curative surgery was performed.

Metastatic primary pulmonary leiomyosarcoma to the pancreas diagnosed by endoscopic ultrasound-guided fine-needle aspiration.

A 77-year-old female patient consulted our hospital for an abnormal shadow observed on chest X-ray. Computed tomography revealed the shadow of a mass in the right lower lung lobe and two shadows of masses in the pancreatic head and body. 18F-fluorodeoxyglucose-positron emission tomography showed an intense uptake only in the fields corresponding to these three masses. Each mass was diagnosed as leiomyosarcoma by transcutaneous needle biopsy of the pulmonary mass and endoscopic ultrasound-guided fine-needle aspiration of the pancreatic masses. The primary site was the lung because the pulmonary lesion was solitary, and no tumor was found in other organs. In English language literature, a case of primary pulmonary leiomyosarcoma with metastasis solely to the pancreas has not yet been reported to the best of our knowledge.

Comparison of three current staging systems for hepatocellular carcinoma: Japan integrated staging score, new Barcelona Clinic Liver Cancer staging classification, and Tokyo score.

BACKGROUND AND AIM: Although various staging systems for hepatocellular carcinoma (HCC) have been developed in recent years, there is no worldwide consensus which staging system is best. The aim of the present study was to compare the performance of the currently developed three staging systems: the Japan integrated staging (JIS) score, new Barcelona Clinic Liver Cancer (BCLC) staging classification, and the Tokyo score. METHODS: A total of 290 consecutive patients with HCC before initial treatment at Kinki University between January 1999 and December 2001 were included. The patients were stratified according to the three staging systems, and the performance of the staging systems was compared using survival time as the only outcome measure. RESULTS: There were significant differences between all stages in the JIS score, while no significant difference was found between stages C and D in the BCLC staging classification and between all the scores, except between scores 0 and 1 and 2 and 3 in the Tokyo score. For all patients (n = 290), the radical treatment group (n = 208) and the non-radical treatment group (n = 82), the likelihood ratio chi(2)-test showed the highest value, and the Akaike information criterion value was lowest in the JIS score. CONCLUSION: The JIS score provided the best prognostic stratification in a Japanese cohort of HCC patients who were mainly diagnosed at early stages and treated with radical therapies.

Natural course of small nodular lesions with intranodular preserved portal supply in cirrhotic liver.

BACKGROUND AND AIM: Due to recent advances in imaging technology, small nodules or lesions in cirrhotic liver are now seen easily. Intranodular blood supply is useful in characterizing these nodules. However, nodules with preserved portal blood supply may be malignant or benign, and it is unknown how often these nodules develop into overt hepatocellular carcinoma (HCC). This study was performed to clarify the rate of malignant transformation in such lesions with preserved portal perfusion in cirrhotic liver. METHODS: From 1995 to 1997, in 98 patients, we performed CT during arterial portography and ultrasound angiography with intra-arterial CO2 injection for 113 nodules <3 cm in diameter to determine the intranodular blood supply. Of these, 48 nodules in 36 patients were diagnosed as 'benign nature nodules' on the basis of the blood supply of the nodules, which included arterial hypovascularity with preserved portal supply. Percutaneous biopsy of the nodule was undertaken for all nodules for histopathologic diagnosis. Thirty-two nodules in 22 patients that were not diagnosed as early HCC were followed-up clinically without any treatment to clarify the natural course of the nodules. RESULTS: Twelve nodules in 14 patients did not increase in size and no new nodules appeared in any part of the liver. Ten nodules in 7 patients did not increase in size or arterial vascularity but typical overt HCC appeared in other areas of the liver. Only two nodules in 2 patients increased in size and developed into hypervascular overt HCC during the 15- and 34-month observation periods, respectively. CONCLUSION: Nodules with preserved portal perfusion in cirrhotic liver have a low risk of malignant transformation compared with the surrounding liver parenchyma.

What is the best time to evaluate treatment response after radiofrequency ablation of hepatocellular carcinoma using contrast-enhanced sonography?

PURPOSE: To observe the visibility and changes in the echogenicity of ablated tumor and ablated nontumor areas after radiofrequency ablation (RFA) over time using gray-scale sonography, and, consequently, to decide on the best timing for contrast-enhanced sonography to evaluate the response of hepatocellular carcinoma to RFA. MATERIALS AND METHODS: Thirty-eight patients with 48 hepatocellular carcinoma nodules underwent RFA. Consecutive gray-scale sonographic observations were made 10 min before RFA and at five points within 4 days after RFA. Two hepatologists blindly reviewed the sonographic images to assess the identifiability of the boundary of the ablated nodules and to semiquantitatively score the echogenicity of the ablated tumor and ablated nontumor regions in 15 hypoechoic nodules with detectable boundaries within 4 days after RFA. RESULTS: The detection rates of the boundaries of ablated tumors were 56.5, 65.2, 54.3, 43.5, and 39.1% at 3-6 h and 15-22 h and on the 3rd, 4th, and 5th days after RFA. There was a significant difference between the detection rate for ablated tumors at 15-22 h and that on the 3rd and 4th days. The difference in echogenicity between ablated tumor and ablated nontumor tissue reached a maximum at 15-22 h after RFA. CONCLUSION: Ablated tumor can be clearly identified within the ablated area in 65.2% of cases using gray-scale sonography at 15-22 h after RFA. The day following RFA is most appropriate and practical for the performance of contrast-enhanced sonography to evaluate the therapeutic response, including a safety margin.

Percutaneous radiofrequency ablation of sonographically unidentifiable liver tumors. Feasibility and usefulness of a novel guiding technique with an integrated system of computed tomography and sonographic images.

OBJECTIVE: The purpose of this study was to evaluate the safety and feasibility of a real-time integrated system with computed tomography (CT) and sonographic images for radiofrequency (RF) ablation of hepatic malignancies poorly defined on B-mode sonography, and to clarify the suitable phase of CT images for using this virtual sonography. METHODS: Between September 2004 and December 2004, 12 patients with 16 hepatocellular carcinomas and two metastatic lesions arising from colorectal adenocarcinoma (n = 1) and rectal carcinoid (n = 1) were treated. The maximum diameter of nodules ranged from 1.0 to 2.5 cm (mean +/- SD; 1.5 +/- 0.6 cm) on CT images. RESULTS: Complete tumor necrosis was achieved in a single session in 19 lesions (90%), while a second session was required for the remaining two lesions (10%). Portal phase multi-planar reconstruction images were displayed under a suitable position corresponding to the ultrasound images in 9 patients (HCC = 7, metastasis = 2), and arterial phase multi-planar reconstruction images were displayed in the 3 remaining patients with hepatocellular carcinoma. CONCLUSION: Percutaneous RF ablation guidance using virtual sonography is an effective treatment for patients with hepatic malignancies. The portal phase of CT images may be the most suitable to indicate the 3-dimensional relationship between the liver vasculature and tumors on virtual sonography.

Outcomes of nontransplant potentially curative therapy for early-stage hepatocellular carcinoma in Child-Pugh stage A cirrhosis is comparable with liver transplantation.

BACKGROUND: This study was undertaken to assess the outcome of potentially curative therapy for early-stage hepatocellular carcinoma (HCC) in patients with Child-Pugh stage A cirrhosis as well as to investigate the impact of low-dose interferon (IFN) therapy after curative therapy on survival. METHODS: This study retrospectively evaluated clinical outcomes in a cohort of 224 Child-Pugh stage A cirrhotic patients who received either resection (53 cases) or radiofrequency ablation (RFA: 171 cases) for HCC within Milan criteria. Thirty patients were treated with low-dose maintenance IFN therapy after initial curative therapy. The median follow-up period was 36.7 months. RESULTS: The 5-year survival rate of all patients was 74.9%, with similar rates for the resection and RFA groups (70.4 vs. 76.8%; p = 0.561). The 5-year HCC recurrence rate was higher in the RFA group than the resection group (85.3 vs. 73.2%; p = 0.012). The maintenance IFN-treated group maintained their liver function within Child-Pugh stage A for a significantly longer time (median time 36.9 vs. 32.2 months; p = 0.0025). CONCLUSION: The 5-year outcomes of resection and RFA in patients with Child-Pugh stage A cirrhosis and early stage HCC were comparable with liver transplantation. Low-dose, long-term maintenance IFN therapy after curative therapy was significantly beneficial on survival.

Review of current staging systems for hepatocellular carcinoma.

Several staging systems have been developed to classify patients with hepatocellular carcinoma (HCC), however, there is no consensus on which of these is the most useful and reliable. In this review article, currently available integrated staging systems taking into account both liver function and tumor progression are presented, and their characteristics and applicability for current HCC patients, many of whom are diagnosed in the early stage of the disease and treated by curative therapy, are discussed. Based on the original andsubsequent validation studies of these staging systems, we recommend that further validation studies of staging systems for HCC should focus on the revised Barcelona Clinic Liver Cancer (BCLC) staging classification, Japan Integrated Staging (JIS) score and Tokyo score.

Prognostic factors for portal venous invasion in patients with hepatocellular carcinoma.

BACKGROUND: Factors involved in portal venous invasion (PVI) must be clarified to enable better determination of therapeutic strategies and outcomes in patients with hepatocellular carcinoma (HCC). METHODS: Of 365 patients with HCC who consulted our department between January 1999 and January 2003, 53 with PVI at the initial consultation were excluded, and the other 312 without PVI were included in this study. Of these patients, we compared liver function, tumor markers, and initial treatment between 287 patients without PVI during follow-up (until December 2004) and 25 patients who developed PVI, and investigated prognostic factors. RESULTS: Multivariate analysis using a COX regression model showed that a Lens culinaris A-reactive fraction of alpha-fetoprotein (AFP-L3) rate of 15% or more, a des-gamma-carboxy prothrombin (DCP) level of 100 mAU/ml or more, multiple tumors, and a platelet count of 130 000/mm(3) or more were correlated with PVI. CONCLUSIONS: HCC frequently infiltrated the portal vein in patients with a high rate of AFP-L3, a high level of DCP, or multiple tumors. Furthermore, the incidence of PVI was significantly higher in patients with a platelet count of 130 000/mm(3) or more.

Differential diagnosis of nodular lesions in cirrhotic liver by post-vascular phase contrast-enhanced US with Levovist: comparison with superparamagnetic iron oxide magnetic resonance images.

BACKGROUND: We investigated the diagnostic utility of post-vascular phase contrast-enhanced ultrasonography (US) and superparamagnetic iron oxide (SPIO)-enhanced magnetic resonance imaging (MRI) as compared to the histological diagnosis of differential grades of hepatocellular carcinomas (HCCs). METHODS: Forty-nine patients with histologically characterized liver nodules (well-differentiated HCC, n = 20; moderately differentiated HCC, n = 19; poorly differentiated HCC, n = 1; dysplastic nodule, n = 9) received contrast-enhanced US and SPIO-MRI. Subsequently, we quantitatively evaluated the relationships between the images of the nodules and their histological diagnosis and differential grades. RESULTS: The ratio of the echogenicity of the tumorous area to that of the nontumorous area with post-vascular phase contrast-enhanced US (post-vascular phase ratio) decreased as nodules became less differentiated (P < 0.05; Kruskal-Wallis test). The ratio of the intensity of the nontumorous area to that of the tumorous area on SPIO-enhanced MR images (SPIO intensity index) also decreased as nodules became less differentiated (P < 0.01). The post-vascular phase ratio correlated with the SPIO intensity index for HCCs and dysplastic nodules (r = 0.76). The conformity of the result from the post-vascular phase contrast-enhanced US and SPIO-MRI was 96%. CONCLUSIONS: Contrast-enhanced US is a valuable method for predicting the histological grade of HCCs in cirrhotic patients, and may be a good alternative to SPIO-enhanced MRI.

The efferent blood flow of early hepatocellular carcinoma and borderline lesions: Demonstration by color Doppler imaging.

We performed waveform analysis of the efferent signal detected within early hepatocellular carcinomas and borderline lesions, in which portal flow was demonstrated. Continuity of this flow with the surrounding vessels was also analyzed. Nine nodules in 7 patients with early hepatocellular carcinomas and borderline lesions were included in this study. Tumor diameter ranged from 1.2 to 3.5 cm; average, 2.1 cm. Waveform of the efferent flow signal from within these nodules was continuous in 5 nodules and biphasic venous in 4 nodules. Outside the nodules, the waveform of the efferent flow signal was that of a biphasic venous wave. All efferent signals were confirmed to continue in the hepatic vein. These findings thus suggest that the draining vessel in early hepatocellular carcinomas and their borderline lesions is the hepatic vein.

Proximal bifurcation of hepatic artery: Novel findings on hepatic arteries demonstrated by ultrasound Doppler imaging, B-flow, and US angiography.

PURPOSE: It has generally been held that each portal branch is always accompanied by a single arterial branch in the liver. During Doppler ultrasound examination, however, we sometimes encounter a portal branch that appears to be associated with two arterial branches, a phenomenon referred to below asthis finding orthis phenomenon. Here we attempt to confirm that this finding is based on a correct interpretation of the image and to disclose its basic mechanism. MATERIAL AND METHODS: Five cases of chronic liver disease in which this phenomenon appeared were analyzed with B-flow imaging. Videotapes obtained from 30 patients who had chronic liver disease and had undergone ultrasound angiography (USAG) with arterial infusion of CO2 micro bubbles were reviewed in order to look for similar findings. Sixty-nine healthy controls were also examined with Doppler sonography for this purpose. Histopathologic specimens from 7 patients who had undergone hepatectomy (3 with hepatocellular carcinoma, 3 with metastatic tumor, and 1 with focal nodular hyperplasia) were examined to study the basic structure of the hepatic vessels. RESULTS AND DISCUSSION: Three parallel color signals (two pulsatile and one of a constant waveform) observed on Doppler examination were confirmed by the B-flow method to be three independent vessels in all five cases in which both Doppler sonography and B-flow imaging were used. In 13 (43%) of the 30 cases of USAG, two vessels along a portal branch were visualized by the inflow of micro bubbles, indicating that the two vessels were arteries. The trio of one portal and two arterial branches was also detected with Doppler sonography in 12 (17%) of the 69 healthy controls. In 10 (59%) of the 17 cases (5 of liver disease and 12 normal) that showed this finding on Doppler examination, bifurcations of the hepatic artery and portal vein were both visualized. Hepatic arterial branches were found to bifurcate slightly more proximal to the hepatic hilus than the accompanying portal branch. Histopathologic study revealed Glisson's areas that contained one portal branch and two arterial vessels in nontumorous parts of specimens from all 7 patients with hepatectomy. CONCLUSION: Two arterial branches can be demonstrated along a portal branch as a result of a more-proximal bifurcation of the hepatic artery than of the portal vein.

Clinical characteristics of NonBNonC- HCC: Comparison with HBV and HCV related HCC.

OBJECTIVE: To clarify the frequency and trends of both HBsAg and HCVAb negative hepatocellular carcinoma (NonBNonC-HCC) in all HCC, to clarify the etiology of NonBNonC-HCC, and to elucidate the clinical characteristics of NonBNonC-HCC compared with those of HBsAg-positive HCC (B-HCC) and HCVAb-positive HCC (C-HCC). METHODS: A total of 2,542 patients with HCC examined at three institutions between 1991 and 2004 were categorized based on their serum viral antigen/antibody positivities, and compared between groups for the etiology, annual trend of the incidence, and clinical characteristics. RESULTS: For the etiology, C-HCC was most prevalent, followed by B-HCC, NonBNonC-HCC, and both HBsAg and HCVAb-positive HCC (BC-HCC) in order. For survival, C-HCC had the most favorable prognosis, followed by NonBNonC-HCC, and B-HCC patients had the poorest prognosis in the three groups (C-HCC, B-HCC, and NonBNonC-HCC). In tumor-node metastasis (TNM) stages I+II, however, NonBNonC-HCC patients took the most favorable clinical course. The incidence of NonBNonC-HCC in all HCC was 5-8% from 1991 to 1998, and has increased to 10-12% since 1999. Additionally, the incidence of HBcAb-positive HCC in NonBNonC-HCC declined each year. Among NonBNonC-HCC patients, the morbidity of diabetic complications was significantly higher in HBcAb-negative patients than in HBcAb-positive patients. CONCLUSION: Although the incidence of NonBNonC-HCC among all HCC has an increasing trend recently, the incidence of HBcAb-positive HCC in NonBNonC-HCC has a tendency of decreasing. This fact suggest its etiology might be changing from occult HBV related HCC to unknown etiology such as nonalcoholic fatty liver disease (NAFLD)/nonalcoholic steatohepatitis (NASH) related HCC. The prognosis of NonBNonC-HCC was fairly good if the HCC was found in its early stage.

Clinical significance of the genotype and core promoter/pre-core mutations in hepatitis B virus carriers.

It has been shown that clinical and virological characteristics vary among hepatitis B virus (HBV) genotypes. In this study, we measured the virus level, disease severity, and presence or absence of core promoter (CP)/pre-core (PC) mutations in 241 HBV carriers, and investigated the clinical significance of measuring the HBV genotype. In genotype C HBV carriers, the proportion of hepatitis B e antigen (HBeAg)-positive patients was significantly higher than that in genotype B HBV carriers (0 vs. 34.4%, p < 0.05), and the virus level was higher (4.9 vs. 4.05 LGE/ml). In the genotype B HBV carriers, the incidence of PC mutation was significantly higher (69 vs. 34%, p < 0.05). In the genotype C HBV carriers, the incidence of CP mutation was significantly higher (13 vs. 78%, p < 0.05). We compared patients with the wild (W)/mutant (M) pattern in the CP/PC regions to those with the M/W pattern in the CP/PC regions among the genotype C HBV carriers. Both the proportion of HBeAg-positive patients (65.8 vs. 15.4%, p < 0.05) and the alanine aminotransferase (ALT) level (48 vs. 21.5 IU, p < 0.05) were higher in the patients with the M/W pattern in the CP/PC regions, and the disease severity was deteriorated. In conclusion, genotype B HBV may more frequently induce HBe seroconversion via PC mutation compared to genotype C HBV. Among the genotype C HBV carriers, hepatitis activity and the deterioration of the disease severity were significantly inhibited in the group in which PC mutation initially occurred, in comparison to the group in which CP mutation initially occurred.

Low-dose, long-term, intermittent interferon-alpha-2b therapy after radical treatment by radiofrequency ablation delays clinical recurrence in patients with hepatitis C virus-related hepatocellular carcinoma.

OBJECTIVE: To assess whether or not interferon (IFN) therapy prevents recurrence, and eventually improves the prognosis of patients with hepatocellular carcinoma (HCC) after completion of radical radiofrequency ablation (RFA) therapy. METHODS: Included as the IFN group in this study were 24 patients in total, who received radical RFA therapy first, followed by medication with IFN-alpha2b at such a low dose of 3 MIU x 2/week for as long as possible. On the other hand, the control group comprised 33 patients in total, who received radical RFA therapy without subsequent treatment with IFN. The control group was matched to the IFN group in age, platelet counts and size of nodules. RESULTS: Of the 24 patients treated with IFN, only one patient showed sustained virologic response. The median tumor-free period until the first recurrence after radical RFA therapy was 3.4 years in the IFN group and 1.4 years in the control group (p = 0.02). During the first 3 years after commencement of IFN administration, the cumulative recurrence rate in the IFN group was found to be lower than in the control group (p = 0.01); however, with the lapse of time over 3 years, the recurrence rate in the IFN group increased. There was no difference in the cumulative survival rates between the IFN group and the control group (p = 0.25). CONCLUSION: Subsequently after radical RFA therapy, long-term, low-dose, intermittent IFN therapy successfully delayed clinical recurrence of HCC.