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Background: Cytokines play an important role in the immune response, angiogenesis, cell growth, and differentiation in hepatocellular carcinoma (HCC)., Objective: We performed a comprehensive study to identify tumor-related cytokines and pathways involved in HCC pathogenesis., Methods: Cytokine production was evaluated in human HCC tissues and adjacent non-tumor tissues using an antibody-based protein array technique. We compared cytokine expression in HCC tissues with that of hepatic hemangioma (HH), liver metastasis of colorectal cancer, and noncancerous liver tissues from transplantation donors. The protein levels and localization of the candidate cytokines were analyzed by western blotting and immunohistochemistry., Results: Increased expression of interleukin (IL)-1 receptor antagonist, macrophage migration inhibitory factor, and IL-16 was observed in HCC and paired adjacent non-tumor tissues compared with noncancerous livers. In addition, there were increased IL-16 levels in HCC tissues compared with HH. IL-16 treatment significantly increased cell proliferation in vitro. The expression of extracellular signal-regulated kinase (ERK)1/2 and cyclin D1 was markedly increased in cells from two HCC cell lines, Huh7 and HepG2, in a dose- and time-dependent manner. Phosphorylated to total ERK1/2 ratio was increased in Huh7 cells following IL-16 50 ng/ml, but not HepG2 cells. ERK phosphorylation have occurred earlier than protein accumulation at 48 h. Pretreatment with the ERK inhibitor, FR18024, or an anti-IL-16 antibody reduced the increase in IL-16 production in HCC cells., Conclusions: These results suggest that cell proliferation induced by IL-16 is mediated through the ERK pathway, thus, we identified a new factor associated with HCC tumor growth.

A 69-year-old woman with a hepatocellular carcinoma(HCC)was followed-up for type B chronic hepatitis and underwent partial hepatectomy(S6)at our hospital. Afterwards, she underwent radiofrequency ablation(RFA)therapy twice because of intrahepatic recurrence. Seven months after the first hepatectomy, a left adrenalectomy was performed for a left adrenal metastasis. Seventeen months after the first hepatectomy, a splenectomy was performed for a splenic metastasis. Forty-three months after the first hepatectomy, a second hepatectomy was performed for intrahepatic recurrence, and a right adrenalectomy was performed for an adrenal metastasis. Sixty-eight months after the first hepatectomy, an abdominal CT revealed a growing solitary lesion in the ascending colon, which was diagnosed as a peritoneal metastasis. The peritoneal dissemination was removed because there were no other extrahepatic or intrahepatic recurrences. Histologically, the resected specimen was diagnosed as a peritoneal metastasis from a HCC. The patient survived, and there were no recurrences for 6 months after the operation. We report this case of a peritoneal metastasis from a HCC after surgery with a review of the literature.

A 42-year-old man complaining of left back pain was admitted to our hospital. The hepatis B and C surface antigens were negative. The serum levels of tumor markers were within the reference ranges. Abdominal ultrasound revealed an 8 cm-sized, primarily round and hyperechoic mass in the left lateral segment. Contrast-echo showed non-uniform enhancement in the arterial phase and uniform enhancement in the portal phase. This mass did not indicate"wash-out"on contrast- enhanced CT. It showed hypointensity in the hepatobiliary phase on MRI. The definitive diagnosis could not be obtained, and the patient was suspected with malignancy, such as hepatocellular carcinoma(HCC). Therefore, left hemi-hepatectomy was performed for the diagnostic treatment. Based on the immunochemical staining results, he was diagnosed with angiomyolipoma( AML). AML is composed of fat, blood vessels, and smooth muscles. It is regarded as a tumor of perivascular epithelioid cell tumor(PEComa). Early venous return and adipose tissues in the tumor were the distinctive features of this tumor. The preoperative diagnosis of AML without any fatty component as in this case is very difficult.

Vasoactive intestinal peptide (VIP) is a modulator of inflammatory responses. VIP receptors are expressed in several tumor types, such as colorectal carcinoma. The study described herein was conducted to confirm the presence of VIP and its receptors (VPAC1 and VPAC2) in surgically resected hepatocellular carcinoma (HCC) tissues and in the HCC cell line Huh7. The mechanism responsible for apoptosis of HCC cells was then examined because VIP treatment (10 -10  M) significantly suppressed proliferation of Huh7 cells. In examining apoptosis-related proteins, we found caspase-3 to be significantly increased and Bcl-xL and cyclic AMP (cAMP) response element-binding protein (CREB) to be significantly decreased in Huh7 cells cultured with VIP. Furthermore, the CREB level and phosphorylation were reduced. These effects were reversed by the addition of VIP receptor antagonist or cAMP antagonist Rp-cAMPS. Pretreatment with cAMP analogue blocked the increased apoptosis, suggesting that VIP induces apoptosis via a PKA-independent signaling mechanism. Our data indicate that VIP prevents the progression of HCC by apoptosis through the cAMP/Bcl-xL pathway., (© 2018 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Purpose: To clarify the development of HCC, temporal change of steatosis and Gd-EOB-DTPA enhancement of non-alcoholic steatohepatitis (NASH) model mice by magnetic resonance imaging (MRI)., Materials and Methods: All animal experiments were approved by the institution's Animal Research Committee. MRI was performed on six NASH and six simple steatosis (SS) model mice every 2weeks from the ages of 8weeks to 16weeks. The sequential changes in the number and size of the focal liver lesions detected on Gd-EOB-DTPA-enhanced MRI were evaluated. Additionally, the hepatic fat fraction (HFF), contrast-to-noise ratio (CNR) and relative enhancement (RE) were calculated at each time point. The temporal changes and correlations in these parameters were evaluated., Results: All alive NASH model mice demonstrated focal liver lesions from week 10, at the latest. Number of the lesions increased with time, and all the lesion enlarged with time. All the lesions larger than 1mm were confirmed as hepatocellular carcinoma (HCC) pathologically. While the HFF remained constant in NASH model mice, HFF in SS model mice dramatically increased with time. CNR of the NASH model mice remained constant through the study period, while CNR in SS model mice decreased with time. Although no correlation was seen in NASH model mice, the HFF showed a negative correlation against CNR and RE in SS model mice., Conclusion: Development of HCC was observed using Gd-EOB-DTPA-enhanced MRI only in NASH model mice. Degree of steatosis and hepatic enhancement by Gd-EOB-DTPA was both constant in NASH model mice, while steatosis increased and hepatic enhancement decreased with time in SS model mice., (Copyright © 2017 Elsevier Inc. All rights reserved.)

A Japanese man aged 30 years old contracted acute hepatitis B in October 2011, and was cured following conservative treatment. Mild hepatosplenomegaly was the only positive finding on computed tomography (CT) and ultrasonography at that time. In May 2012, slight impairment of the liver function was detected again in the patient; an abdominal CT at this time revealed a tumor mass in the right hepatic lobe, so subsegmentectomy of the right hepatic lobe was performed. On the basis of the findings of the resected specimen, primary hepatic circumscribed Burkitt's lymphoma (sporadic form), stage IA, was diagnosed. Multiple cycles of hyper-CVAD/MTX-Ara-C therapy with concomitant rituximab were administered, under which the patient was successfully maintained in complete remission. To date, at least 15 cases of primary hepatic Burkitt's lymphoma have been reported in the literature; all of the 11 patients without concurrent human immunodeficiency virus (HIV) infection had the sporadic form of the disease. Asians were relatively common (7 patients) among these patients, and patients in their childhood or adolescence accounted for a considerable proportion. Therefore, the present case may be regarded as rather typical. The presence of hepatitis virus infection as a background disorder other than HIV is considered to be of profound interest etiologically.

Purpose: Rho kinase is an important factor in tumor progression. We demonstrated that Rho kinase-associated coil-containing protein kinase (ROCK) is expressed in hepatic tissues in hepatocellular carcinoma (HCC) and confirmed its roles in cell survival in HCC cells using the ROCK inhibitor, fasudil., Methods: ROCK protein levels were estimated in hepatic tissues with HCC compared with healthy liver tissues or hepatic hemangioma tissues using immunohistochemistry. Furthermore, HepG2 and Huh7 cells were cultured with ROCK inhibitor, fasudil for 24 h in vitro. Cell proliferation was evaluated using the 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt assay, and apoptotic cells were detected by cell death ELISA. The expression apoptosis-related proteins were analyzed using Western blotting., Results: Fasudil significantly decreased cell proliferation and induced apoptosis mediated by increases in p53, Bax, caspase-9, and caspase-3 in HepG2 and Huh7 cells. The induction of apoptosis was inhibited in HCC cells precultured with p53 decoy oligodeoxynucleotide., Conclusion: These results suggest that ROCK inhibits the p53-mediated apoptosis pathway in HCC. Fasudil may thus be a beneficial approach to HCC therapy.

A 57 year-old woman was admitted for focal accumulation of 18F-fluorodeoxyglucose (FDG) in the liver detected by positron emission tomography (PET). A 25- mm hypovascular tumor was detected by computed tomography. Tumor biopsy revealed many atypical cells with positive staining for factor VIII-related-antigen in sinusoids. Right lobectomy was performed and the tumor was diagnosed as epithelioid hemangioendothelioma (EHE) pathologically. We demonstrated that FDG-PET was useful for the diagnosis of EHE and making deciding on therapeutic strategy.

Among many mutational "hot spots" on hepatitis B virus (HBV) genome, A-to-T1762 and G-to-A1764 within the core promoter have been underscored in view of disease association as well as viral expression/replication. Although to a lesser extent, C-to-T1653 and T-to-V(C/A/G)1753 were also noteworthy in our previous study. To assess the clinical significance of these mutations, we determined the nucleotide sequence of an HBV DNA fragment covering these sites in HBsAg-positive blood donors (n = 160) and patients with chronic hepatitis (n = 66), liver cirrhosis (n = 45), and hepatocellular carcinoma (n = 58), most of whom were infected with genotype C HBV (subtype adr). In cases where HBe antigen was positive, the frequency of T1653 and/or V1753 showed a striking increment from chronic hepatitis patients (18%) to liver cirrhosis and/or hepatoma patients (82%), whereas that of T1762/A1764 was already high in chronic hepatitis patients (76%). In HBe antigen-negative cases, by contrast, significant difference in the frequency of T1653/V1753 mutants was found between blood donors (22%) and chronic hepatitis patients (67%). Our results suggest that T1653/V(particularly C)1753 mutants are more closely associated than T1762/A1764 with the progression of liver disease from chronic hepatitis to cirrhosis in HBe antigen-positive patients. A system of site-directed mutagenesis PCR RFLP was constructed to diagnose T1653 and C/A1753 more conveniently. Detecting T1653 and C/A1753 by this method would contribute to the differential diagnosis of HBV-associated liver disease.

We determined full-length nucleotide sequence of hepatitis B virus (HBV) genome in sera from 40 Japanese patients with HBsAg-positive hepatocellular carcinoma (HCC), in order to obtain information on HCC-specific characteristics, if any, of the HBV genome. Direct sequencing of the long distance PCR products starting from 50 microliters of serum samples revealed that 95% of our isolates were of genotype C, and that mutations and deletions/insertions were very common. With respect to envelope protein genes, deletions and missense mutations were frequent in preS2, and the determinant a domain of HBsAg was rich in "antibody-escape" mutations. Within the precore/core region, the most remarkable mutation was the replacement of proline of wild type by other amino acids at codon 130 of the core gene, which was found in 58% of our isolates, while precore-stop mutation was found in 45%. Most interestingly, however, about 90% of our isolates had mutations at nt positions 1762 (A-to-T) and 1764 (G-to-A) within the core promoter, which had been implicated in "e-suppressive" phenotype of HBV genome. G-to-A at nt 1613 and C-to-T at nt 1653 within enhancer II and T-to-C/A at nt 1753 within core promoter were also evident: 38%, 53%, and 40%, respectively. It was interesting that some of the characteristics observed in our isolates form HCC patients had been previously implicated in fulminant hepatitis and/or acute exacerbation of chronic hepatitis.

A patient with hepatocellular carcinoma exhibiting a concentric structure of different histologic grades was examined with chondroitin sulfate iron colloid (CSIC)-enhanced MR imaging. After CSIC injection, the advanced component was enhanced in comparison with the surrounding liver, and the well-differentiated component was not enhanced. CSIC-enhanced MR imaging was helpful in evaluating histologic grade on the basis of reticuloendothelial function.

Twenty patients with hepatocellular carcinoma were studied by dynamic sequential inversion recovery snap shot fast low angle shot (FLASH) imaging after the bolus injection of various amounts of Gd-DTPA. We determined the optimal dose of Gd-DTPA for depicting tumors as early marked enhancement and compared the method with dynamic CT by matching data acquisition time. The optimal dose was estimated to be 0.1 mmol/kg. Compared with dynamic CT, dynamic MRI showed rapid short-term enhancement in the early phase, while the contrast enhancement in the late phase lasted longer and was stronger than that of CT.

The association between contrast enhancement by chondroitin sulfate iron colloid (CSIC) and the histological grade of hepatocellular carcinoma (HCC) was evaluated in 24 patients diagnosed by histological examination of surgical specimens (26 nodules: 11 well-differentiated and 15 poorly-moderately-differentiated nodules). In the well-differentiated HCC nodules, the tumor-liver contrast to noise ratio (CNR) was not significantly increased after i.v. CSIC injection on both T1-weighted and T2-weighted images. In the moderately-poorly-differentiated HCC, CNR was significantly increased after CSIC administration on both T1-weighted and T2-weighted images (p < 0.01). MR imaging using CSIC may be useful for diagnosing the degree of HCC differentiation.

N-isopropyl-p-[123I] Iodoamphetamine (IMP) scintigraphy was performed in 10 lesions of metastatic hepatocellular carcinoma. Five of 10 lesions (50%) were detected with planar images, which was superior to the 2 of 8 lesions (25%) detected with 67Ga-citrate (Ga) scintigraphy. The positive ratio was increased to 83% (5/6) with SPECT. Thus our findings suggested that IMP could compensate for Ga scintigraphy in detecting distant metastases of hepatocellular carcinoma.

Pedunculated hepatocellular carcinoma (HC) is an uncommon tumor of the liver. We present the case of a 56-year-old man with pedunculated HC arising from the lower surface of the liver. We recommend sagittal magnetic resonance imaging, which offers a superior choice of scanning planes, in the diagnosis of pedunculated HC.

Conventional bone scintigraphy is often inconclusive in detecting bone metastases of hepatocellular carcinoma, suggesting the necessity of alternative scintigraphic agents. In this study, the diagnostic value of I-123 IMP scintigraphy was evaluated in 8 patients with 12 pelvic bone metastases from hepatocellular carcinoma, then compared with Ga-67 scintigraphy. Eleven of 12 lesions (91.7%) were detected by I-123 IMP scintigraphy; Ga-67 scintigraphy visualized 8 lesions (66.7%) in the same patient population. I-123 IMP scintigraphy is useful for detecting pelvic bone metastases of hepatocellular carcinoma with less physiologic accumulation in the intestine as compared with Ga-67 scintigraphy.

Although bone scintigraphy with 99mTc-MDP is a sensitive diagnostic method to detect bone metastasis, it is not specific for malignancy. A radioactive substance which accumulates specifically into metastatic lesions should be of value. 123I-IMP and bone scintigraphy with 99mTc-MDP were consecutively performed in patients with vertebral bone metastases from hepatocellular carcinoma and lumbar spondylosis deformans in a 7-day interval or shorter. The intensity of uptake was compared. Eighteen of the 20 metastatic lesions (90%) were classified as increased uptake areas in 123I-IMP scintigraphy. MDP-scintigraphy disclosed 16 metastatic lesions (80%), 9 as "hot" lesions (56%) and 7 as "cold" lesions (44%). 123I-IMP scintigraphy was negative in all 12 lesions of lumbar spondylosis deformans. Compared to MDP-scintigraphy, 123I-IMP scintigraphy was more sensitive in detecting vertebral bone metastases of hepatocellular carcinoma with smaller rates of false-positive and false-negative findings.

Arterial infusion chemotherapy has become one of the major treatments for malignant tumors. Since 1988, we have attempted repeated arterial infusion of anticancer drugs using an implantable drug delivery system in 68 patients who had inoperable hepatocellular carcinoma (HCC). Most of our patients could not undergo transcatheter arterial embolization (TAE) because of extreme tumor extension and/or accompanying advanced liver cirrhosis. In most patients we implanted a 5-F catheter via the femoral artery nonsurgically and connected it to a subcutaneously implanted drug delivery system without any difficulty. The treatment consisted of weekly or biweekly intrahepatic one-shot administration of anticancer drugs. As one therapeutic regimen, epirubicin was given alone. Other regimens consisted of combined chemotherapy using two or more of the following drugs: mitomycin C. Adriamycin, 5-fluorouracil, cisplatin, and epirubicin. In some cases, these drugs mixed with Lipiodol were given for targeting and slow release in the liver. The response rate (CR+PR) of the cases was 25.0%. The median survival period was 389.9 days. The 6-month, 1-year, and 2-year survival rates were 75%, 45%, and 17%, respectively. There was no severe side effect or complication except arterial occlusion that precluded further infusion chemotherapy. We think that the implantable drug delivery system will contribute not only to improved therapeutic efficacy for inoperable HCC but also to an improved quality of life for the patients.

The Cooperative Study Group conducted a study to assess the therapeutic effects of chemoembolization in patients with advanced hepatocellular carcinoma (HCC) using either epirubicin hydrochloride (FARM) or doxorubicin hydrochloride (ADR). A total of 77 patients were enrolled in this study and randomized into 2 groups: 39 patients were treated with a FARM solution as the material for Lipiodol-transcatheter arterial embolization (TAE; FARM group), and 38 patients were treated with an ADR solution as the material for L-TAE (ADR group). For the FARM group, the 1-year survival rate was 69.9% and the 2-year survival rate was 44.5%. For the ADR group, the corresponding survival rates were 74.7% and 44.0%. The differences among the above figures were not statistically significant. As side effects, fever, nausea, and generalized fatigue occurred at almost the same frequencies in the two groups. Changes detected in the liver function and the peripheral blood cell count in both groups were not severe. There was no significant difference between the toxic effects observed in the two groups. In conclusion, there was no significant difference in therapeutic efficacy between the FARM and ADR groups.

The presence of hepatitis C virus (HCV) RNA in serum and liver tissue was examined in seven patients with hepatocellular carcinoma (HCC), using the reverse transcriptase-polymerase chain reaction method with primers for the 5'-noncoding region. Plus-strand HCV-RNA was detected in the serum and liver tissue (both cancerous and noncancerous tissue) of all five patients who were positive for anti-HCV antibodies (C100-3 and P22) and was not detected in both of two patients who were negative for anti-HCV antibodies. Minus-strand HCV-RNA was only detected in the liver tissue (cancerous and noncancerous portion) of the five anti-HCV antibody-positive patients. The relative liver tissue content of minus-strand HCV-RNA ranged from 1 to 100 time less than that of plus strand HCV-RNA in cancerous and noncancerous tissue in each patient, respectively. There was no similar tendency in the HCV-RNA content between the cancerous and noncancerous portions of the liver in each patient. These results suggest that HCV exists and replicates in HCC tissue and may have some role in the development of HCC.

The diagnostic value of N-isopropyl-p-[123I]-iodoamphetamine (123I-IMP) scintigraphy was evaluated in 12 patients with 20 bone metastases from hepatocellular carcinoma, in comparison with 99mTc-methylene diphosphonate (99mTc-MDP) bone scintigraphy. Sixteen lesions (80%) were detected by 123I-IMP scintigraphy, whereas four lesions (two lesions in the rib and two lesions after a radiation of 40 Gy) were missed. Of 16 lesions demonstrated as areas of increased uptake in 123I-IMP scan, only eight (50%) showed an increased pattern of uptake in 99mTc-MDP bone scintigraphy. In conclusion, 123I-IMP is a promising radiopharmaceutical for the detection of bone metastases from hepatocellular carcinoma.

Using a 1.5 T MR imaging unit, T1- and T2-weighted images were obtained before and after i.v. administration of chondroitin sulfate iron colloid (CSIC) in order to differentiate hepatocellular carcinoma (n = 20) from adenomatous hyperplasia without atypia (n = 16). Differentiation was made from the tumor-liver contrast to noise ratio (CNR) and visual evaluation of the nodule, with reference to signal intensity relative to that of the surrounding liver. The CNR of adenomatous hyperplasia was on T1-weighted images significantly decreased after CSIC administration (p < 0.01). On T2-weighted images, there was no significant difference in CNR after CSIC administration. On the other hand, the CNR of hepatocellular carcinoma was significantly increased after CSIC administration on both T1- and T2-weighted images (p < 0.01). CSIC reflects intratumor reticuloendothelial cellular functions, and is therefore useful in differentiating hepatocellular carcinoma from adenomatous hyperplasia without atypia.

We performed a clinical evaluation of repeated arterial infusion chemotherapy using an implantable drug delivery system for 41 patients with inoperable hepatocellular carcinoma (HCC). About half of our patients could not undergo transcatheter arterial embolization (TAE) because of extreme tumor extension and/or accompanying advanced cirrhosis. In most patients we implanted a 5 Fr. catheter non-surgically and connected it to an implanted injection port through a subcutaneous tunnel. The treatment schedule was weekly or biweekly intrahepatic one-shot administration of mitomycin C, adriamycin, 5-fluorouracil and epirubicin. The response rate (CR + PR) was 24.4%. The median survival period was 401.1 days. The 6 month, 1-year and 2-year survival rates were 73%, 48% and 24%, respectively. There were no severe side effects nor complications. The implantable drug delivery system will contribute not only to improved therapeutic efficacy for inoperable HCC but also improve the quality of life for patients.

To investigate the decrease in natural killer (NK) activity in chronic liver disease, interleukin-2 receptor beta chain (IL-2R beta) expression was assessed by peripheral blood lymphocytes (PBL) using flow cytometry and an IL-2R beta chain-specific mouse monoclonal antibody. The percentage of IL-2R beta chain-positive PBL was significantly decreased in patients with chronic viral hepatitis, liver cirrhosis and hepatocellular carcinoma in comparison with normal controls (P less than 0.01). Among chronic viral hepatitis patients, it was significantly less in those with chronic active hepatitis than in those with chronic persistent hepatitis (P less than 0.05). Two-colour flow cytometry revealed that the IL-2R beta chain was mainly expressed by CD8+ or CD16+ cells in both the controls and the liver disease patients. CD8dull+ cells (NK cells) constituted more than 60% of the CD8+ cells expressing the IL-2R beta chain. Expression of the IL-2R beta chain with CD8 or CD16 was also significantly decreased in chronic liver disease patients compared with controls. In chronic viral hepatitis, there was a significant correlation between NK activity and the percentage of IL-2R beta+ PBL (P less than 0.001, r = 0.916), as well as between NK activity and the percentage of PBL co-expressing both the IL-2R beta chain and CD16 (P less than 0.001, r = 0.850). These findings suggest that decreased expression of the IL-2R beta chain by PBL may result in diminished NK activity in chronic liver disease.

Simulation of the needle puncture and volume estimation for the tumors in the liver were carried out with the three-dimensional image reconstruction system, which consists of a medical image acquisition system, a data processing system, and a graphic display. A set of sliced-image data from a computerized tomography and/or a magnetic resonance imaging was used to reconstruct the liver, the vessels, and the tumors of the patients with liver cancer. A good agreement of anatomic locations of both the intrahepatic vessels and the tumors between the reconstructed liver model and the echography done intraoperatively was observed. Surgical simulations with these graphic models clearly indicated safety areas for needle puncture in the laser coagulation therapy. In addition liver volumes were calculated within 3% of error in comparison to the measured values. These results indicate that the computer-aided surgery system is a highly promising method that avoids cumbersome stereoscopic recognition of the anatomical location of the diseased area and the vessels, before and after surgery.

Because hepatocellular carcinoma treated by transcatheter arterial embolization often regains its size, routine follow-up is necessary. The usefulness of pulsed Doppler ultrasound for detection of this type of recurrence was compared with ultrasonography and computed tomography in 21 such hepatocellular carcinomas. Of 15 hepatocellular carcinomas diagnosed by angiography as showing recurrence, four were detected with ultrasonography and five were detected with computed tomography. Doppler signals were obtained in the peripheral portions corresponding to tumor vessels or stains on angiograms in 14 of these 15 hepatocellular carcinomas, but they were undetectable in six hepatocellular carcinomas with no recurrence. All signals disappeared after transcatheter arterial embolization. One false-negative hepatocellular carcinoma with pulsed Doppler ultrasound showed faint tumor stains on angiograms; these were also negative on ultrasonography and computed tomography. Pulsed Doppler ultrasound may be superior to ultrasonography and computed tomography as a routine procedure to detect the recurrence of hepatocellular carcinoma treated by transcatheter arterial embolization.

Total hepatic blood flow and portal blood flow were measured separately using a modified xenon 133 clearance method during angiography in 71 patients with chronic liver diseases, including 40 with proven hepatocellular carcinoma, and in 12 patients without detectable chronic liver injury who served as controls. Total hepatic and portal blood flow rates in controls were 805 +/- 149 ml/min and 667 +/- 206 ml/min, respectively. Total hepatic blood flow was significantly decreased in patients with compensated and decompensated liver cirrhosis (519 +/- 156 ml/min and 317 +/- 153 ml/min, respectively; P less than 0.01), as was portal blood flow (399 +/- 134 ml/min and 271 +/- 134 ml/min, respectively; P less than 0.01). Following transcatheter arterial embolization or hepatic resection (in 35 and 13 patients, respectively), hepatic failure occurred in 3 cases each. Embolization appeared contraindicated when hepatic portal blood flow was under 125 ml/min, and safe hepatic resection required an anticipated residual hepatic portal blood flow of at least 250 ml/min.

A possible causative role for the recently discovered hepatitis C virus (HCV) in the development of hepatocellular carcinoma (HCC) was investigated by assay of sera from HCC patients in Japan for antibodies to a recombinant HCV antigen and to hepatitis B virus (HBV) antigens. Among the 253 HCC patients examined, 156 (61.7%) had no serum markers of either a previous or a current HBV infection (group I), 46 (18.2%) were negative for HBV surface antigen but positive for anti-HBV surface and/or anti-HBV core antibody, indicating the occurrence of a previous, transient HBV infection (group II), and 51 (20.2%) were chronically infected HBV carriers as evidenced by positivity for HBV surface antigen (group III). The prevalence of HCV antibody in group I (68.6%) and II (58.7%) patients was significantly higher than for group III (3.9%) or in 148 additional patients with other (non-HCC) cancers (10.1%) (P less than 0.01). Thus, there appears to be a strong association between HCV infection and the development of HCC, particularly in patients for which HBV infection cannot be implicated as a causative factor. The data also suggest an additional mode of transmission for HCV other than blood transfusion, since a history of blood transfusion was shown in only about 30% of the HCV antibody-positive HCC patients in groups I and II. A high prevalence of HCV antibody was also shown among patients with HCC whose disease was originally thought to be due to very high ethanol consumption.

Serum alpha-fetoprotein from 146 patients with hepatocellular carcinoma, other malignancies, and benign liver diseases, was fractionated by lectin-affinity electrophoresis coupled with our sensitive detection method of antibody-affinity blotting. Compared with chronic hepatitis and liver cirrhosis, hepatocellular carcinoma was characterized by the increase in proportions of lentil lectin A-reactive alpha-fetoprotein-L3 and erythroagglutinating phytohemagglutinin-reactive alpha-fetoprotein-P4; the yolk sac tumor was characterized by the increase of concanavalin A-nonreactive alpha-fetoprotein-C1, lentil lectin-A-weakly reactive alpha-fetoprotein-L2, erythroagglutinating phytohemagglutinin-strongly reactive alpha-fetoprotein-P5, and Allomyrina dichotoma lectin-nonreactive, slow-migrating alpha-fetoprotein-Als; and gastrointestinal tumors were characterized by alpha-fetoprotein-C1, alpha-fetoprotein-L2, alpha-fetoprotein-L3, alpha-fetoprotein-P5 and Allomyrina dichotoma-nonreactive alpha-fetoprotein-A1. By combined evaluation of alpha-fetoprotein-L3 and alpha-fetoprotein-P4, hepatocellular carcinoma was discriminated from chronic hepatitis and liver cirrhosis with a sensitivity of 97% at a specificity of 99.7%. Because the alpha-fetoprotein level of the studied cases ranged from 60-1,500,000 ng/mL (60-1,500,000 micrograms/L), mostly greater than 200 ng/mL (200 micrograms/L), additional patients with lower levels of alpha-fetoprotein [16-177 ng/mL (16-177 micrograms/L) for 16 cases of hepatocellular carcinoma with liver cirrhosis and 28-185 ng/mL (28-185 micrograms/L) for 17 cases of liver cirrhosis alone] were analyzed for alpha-fetoprotein-L3 and alpha-fetoprotein-P4. The resulting sensitivity for combined evaluation was still as high as 88% at the same high specificity of 99.7%, indicating that the simultaneous analysis of alpha-fetoprotein-L3 and alpha-fetoprotein-P4 is effective in monitoring the evolution of hepatocellular carcinoma in cirrhotic patients.

A 78-year-old Japanese man with chronic liver disease developed hypervascular liver tumors accompanied by marked elevation of alphafetoprotein value (the highest level; 26200 ng/ml) and pathologic fracture of the femur. After an operation for the fracture followed by gastrointestinal bleeding and repeated transfusions of blood, the tumors disappeared with normalization of the alpha-fetoprotein level, and the radiolucent area around the fracture site of the femur became consolidated. The necrotic tissue responsible for the fracture histologically showed an appearance of hepatocellular carcinoma. The patient survives 62 months after the initial increase in alpha-fetoprotein level. This is a case of spontaneous regression of both hypervascular liver tumors which are highly suggestive of hepatocellular carcinoma and their metastasis.

Transcatheter arterial embolization (TAE) with the concurrent use of caerulein was assessed for the purpose of preventing gallbladder complications often seen after TAE of hepatic carcinoma. Ninety-six cases with primary hepatic carcinoma, who had undergone TAE in the right hepatic arterial region over the past 4 years, were divided into three groups: 22 cases for which embolization was possible on a selective basis by passing the catheter to the peripheral side beyond the bifurcated region of the cystic artery; 40 cases who had undergone TAE in which caerulein was not administered, from the central side of the bifurcated region of the cystic artery; and 34 cases given 20 micrograms caerulein 15-30 min before TAE. A comparison was made using the abdominal pain, pyrexia, rate of leukocytosis and the US findings of the gallbladder as the indices of the gallbladder complications. As a result, it became evident that it was possible to prevent or alleviate gallbladder complications if caerulein were administered before TAE in cases where the embolizing substances were infused in the right hepatic artery from the central side of the bifurcated region of the cystic artery. It was conclusively shown that the gallbladder blood flow decreases if the organ is contracted by caerulein, which in turn causes a decrease in the inflow of the embolizing substances whereby complications are alleviated.

While transcatheter hepatic arterial embolization (TAE) has been extensively performed as a form of treatment for nonresectable malignant hepatic tumors, complications, such as abdominal pain, fever or leukocytosis due to gallbladder infarction by embolic materials frequently occur and have not yet been overcome. We devised a new procedure for reducing the incidence of gallbladder infarction by administering caerulein prior to TAE. Between 1984 and 1986, 63 patients with hepatocellular carcinoma were treated by TAE with the use of Gelfoam. These patients were divided into 3 groups. Fourteen patients underwent TAE in which the tip of the catheter was placed in the right hepatic artery distal to the origin of the cystic artery (group A). In the other patients the tip of the catheter was placed proximal to the origin of the cystic artery; 40 patients were not treated by caerulein (group B); 9 patients were administered caerulein 20 micrograms intramuscularly 15 to 30 minutes prior to TAE. The incidence of complications after TAE, such as abdominal pain, fever over 38 degrees C, leukocytosis and ultrasonographical abnormalities of the gallbladder was compared in these 3 groups. The results showed that in group C (TAE after administration of caerulein), the incidence of complications was significantly decreased compared with group B(TAE without caerulein). The authors suggest that post-TAE infarction of the gallbladder is effectively diminished by contracting it with caerulein.

Tegafur fine granule preparation orally administered to the patients with primary hepatoma and liver cirrhosis, and the concentration of tegafur and 5-fluorouracil in the blood were determined. The concentration of tegafur in blood was maintained well in the injured liver, and remained same 3 weeks after administration of tegafur fine granules. The concentration of 5-fluorouracil in the blood decreased distinctly when the dysfunction of the liver was severe (KICG less than 0.070). In the case of malignant disease with the injured liver, oral administration or tegafur might be less effective. However, the concentration of 5-fluorouracil in the blood did not decrease 3 weeks after administration of tegafur fine granules. No cases showed noticeable clinical effects by only oral administration.

We have measured the plasma PIVKA-II levels in 188 cases of various liver disease with HCC and malignant diseases in other organs by an EIA, using a monoclonal antibody (E-1023 kit, Eisai), and also have measured the plasma vitamin K levels in cases of HCC and cholestasis by an HPLC. Plasma PIVKA-II was detected in many cases of HCC (67%, 35 of 52 cases) and cholestasis (60%, 6 of 10 cases). In contrast, the positivities of PIVKA-II in the other diseases including benign liver diseases were very low. Combination assays of PIVKA-II and vitamin K revealed that PIVKA-II correlates with vitamin K in cholestasis but not in HCC, suggesting that PIVKA-II in HCC does not depend on a systemic deficiency of vitamin K. From these results, it was concluded that PIVKA-II is a reliable marker which can reflect the clinical course of HCC.

Transcatheter arterial embolization (TAE) for unresectable hepatocellular carcinoma (HCC) was performed in cirrhotic patients with nonoccluded main portal trunk and total bilirubin levels less than 5 mg/dl. In 48 patients with tumor response to TAE, its benefit was evaluated by comparing their survival with that in 28 patients after conservative treatments, matched by clinical data. In TAE-treated patients, tumor findings on computerized tomography and angiogram were significantly different between those dying within 3 months and those surviving over 18 months. In cases of tumors occluding the first- or second-order portal branches or occupying more than 20% of the liver, or relatively hypovascular tumors with unclear boundaries, survival was not different between TAE- and non-TAE-treated patients, whereas it was significantly improved by TAE in cases without these findings. These results suggest that TAE is beneficial in cases of unresectable HCC complicating liver cirrhosis, but its benefit is limited under certain conditions.

To clarify the role of the hepatitis B virus (HBV) in hepatocellular carcinoma (HCC) associated with alcohol consumption, HBV-DNA in the liver of 19 patients with HCC were investigated. HBV-DNA was examined by Southern blot hybridization. HBV-DNA was integrated into tumor cells from five out of six (83%) patients with HCC associated with HBs antigen (HBsAg)-positive post-hepatitic liver cirrhosis (LC), but this was not related to the history of alcohol intake. In 13 HCC patients of HBsAg-negative alcoholic LC, HBV-DNA integration was not detected in any patient. These findings suggest that HBV does not play a major role in the pathogenesis of HCC in HBsAg-negative alcoholics in Japan.

In 6 patients with spontaneous rupture of hepatocellular carcinoma complicating liver cirrhosis, but with no occlusion of the main portal trunk, transcatheter arterial embolization was performed within 7 days of the rupture. All 6 patients were thought to be inoperable because of shock state or severe hepatic dysfunction. In all 6 patients, the progressive decrease in the hematocrit ceased soon after the embolization. Five patients survived for 31-168 days after the embolization; 1 patient who developed septicemia died 10 days later. We conclude that transcatheter arterial embolization is beneficial as a procedure of first choice for ruptured hepatocellular carcinoma when the portal blood flow is maintained.