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Purpose: Lyso-thermosensitive liposomal doxorubicin (LTLD) consists of doxorubicin contained within a heat-sensitive liposome. When heated to ≥40°C, LTLD locally releases a high concentration of doxorubicin. We aimed to determine whether adding LTLD improves the efficacy of radiofrequency ablation (RFA) for hepatocellular carcinoma (HCC) lesions with a maximum diameter (dmax) of 3 to 7 cm. Experimental Design: The HEAT Study was a randomized, double-blind, dummy-controlled trial of RFA ± LTLD. The 701 enrolled patients had to have ≤4 unresectable HCC lesions, at least one of which had a dmax of 3 to 7 cm. The primary endpoint was progression-free survival (PFS) and a key secondary endpoint was overall survival (OS). Post hoc subset analyses investigated whether RFA duration was associated with efficacy. Results: The primary endpoint was not met; in intention-to-treat analysis, the PFS HR of RFA + LTLD versus RFA alone was 0.96 [95% confidence interval (CI), 0.79-1.18; P = 0.71], and the OS HR ratio was 0.95 (95% CI, 0.76–1.20; P = 0.67). Among 285 patients with a solitary HCC lesion who received ≥45 minutes RFA dwell time, the OS HR was 0.63 (95% CI, 0.41–0.96; P < 0.05) in favor of combination therapy. RFA + LTLD had reversible myelosuppression similar to free doxorubicin. Conclusions: Adding LTLD to RFA was safe but did not increase PFS or OS in the overall study population. However, consistent with LTLD's heat-based mechanism of action, subgroup analysis suggested that RFA + LTLD efficacy is improved when RFA dwell time for a solitary lesion ≥45 minutes. Clin Cancer Res; 24(1); 73–83. ©2017 AACR.

Background Studies on temporal changes in noninvasive fibrosis indices and liver stiffness measurement (LSM) in patients with chronic hepatitis C (CHC) treated with direct-acting antiviral agents (DAAs) are limited. Methods We retrospectively enrolled consecutive patients with CHC who had received DAAs. Results In total, we recruited 395 consecutive patients, of which 388 (98.2%) achieved a sustained virologic response (SVR) at 12 weeks after therapy. In patients who received DAA therapy and achieved SVR 12 weeks after therapy (n = 388), the median aspartate aminotransferase/platelet ratio index (APRI) value decreased from 1.19 (0.62–2.44) at baseline to 0.50 (0.32–0.95), 0.51 (0.31–0.92), 0.48 (0.31–0.88), and 0.52 (0.33–0.92) at week 2, week 4, end of therapy, and PW12, respectively (all P

We developed an optimal noninvasive index comprising routine laboratory parameters for predicting cirrhosis in chronic hepatitis B (CHB) and chronic hepatitis C (CHC) patients. This study included 992 CHB patients and 1,284 CHC patients who received liver biopsy. We developed the new index, named modified Fibrosis-4 (mFIB-4) according to four independent variables of the model: age, aspartate aminotransferase (AST), alanine aminotransferase (ALT), and platelet count. The formula of the mFIB-4 index is 10 × Age(years) × AST(U/L)/Platelet count(109/L) × ALT(U/L). For predicting cirrhosis, the bootstrap areas under the receiver operating characteristic curve for platelet count, AST/ALT ratio (AAR), AAR/platelet ratio index (AARPRI), AST/platelet ratio index (APRI), FIB-4, Pohl score, age-platelet (AP) index, Lok index, fibrosis quotient (FibroQ), and mFIB-4 were 0.7680, 0.7400, 0.8070, 0.6090, 0.7690, 0.6990, 0.7850, 0.7960, 0.8110, and 0.8070 in CHB patients, and 0.8170, 0.7210, 0.8400, 0.7310, 0.8310, 0.6730, 0.8220, 0.8440, 0.8570, and 0.8480 in CHC patients, respectively. FibroQ and mFIB-4 exhibited the highest diagnostic performance levels for liver cirrhosis in CHB and CHC despite the inclusion of the international normalised ratio in the formulation of FibroQ. Thus, mFIB-4 is a simple, inexpensive, and readily available method for assessing the liver fibrosis stage of Asian patients with CHB or CHC.

Background & Aims The kinetics of serum hepatitis B surface antigen (HBsAg) levels during long-term nucleos(t)ide analogue (NA) therapy in chronic hepatitis B (CHB) patients remains unclear. We investigated the patterns of serum HBsAg kinetics and their association with therapeutic outcomes in genotype B- or C-infected CHB patients receiving long-term NA therapy. Methods We enrolled 329 treatment-naive CHB patients receiving NA therapy for >5 years to analyse the kinetic patterns by using group-based trajectory models (GBTMs). Results Most patients (82.4%) received entecavir therapy. The median treatment duration was 83.6 (68.5-89.7) months. The GBTMs revealed three groups for both the hepatitis B e antigen (HBeAg)-positive and -negative patients. The median annual decline in serum HBsAg levels during the first 5 years was significantly higher in Group 1 than in Groups 2 and 3 in HBeAg-positive (0.78 vs 0.10 vs 0.10 log10IU/mL) and HBeAg-negative (0.71 vs 0.08 vs 0.09 log10IU/mL) patients. HBsAg levels at the baseline and 12 months combined with an HBsAg decline from the baseline to 12 months of treatment predicted trajectory pattern 1 in HBeAg-positive (sensitivity, 77.8%; specificity, 99.1%; positive predictive value [PPV], 87.5%; and negative predictive value [NPV], 98.2%) and HBeAg-negative (sensitivity, 100%; specificity, 99.5%; PPV, 88.9%; and NPV, 100%) patients. The trajectory patterns were significantly associated with HBeAg loss in the HBeAg-positive patients and the achievement of HBsAg

To develop recurrence predictive models using the clinical data "before" RFA.To compare models using different feature selection methods combined with SVM.The hybrid methods combined with SVM had better performance.The predictive models can provide suggestive high-risk recurrent patients. Background and objectiveRecurrence of hepatocellular carcinoma (HCC) is an important issue despite effective treatments with tumor eradication. Identification of patients who are at high risk for recurrence may provide more efficacious screening and detection of tumor recurrence. The aim of this study was to develop recurrence predictive models for HCC patients who received radiofrequency ablation (RFA) treatment. MethodsFrom January 2007 to December 2009, 83 newly diagnosed HCC patients receiving RFA as their first treatment were enrolled. Five feature selection methods including genetic algorithm (GA), simulated annealing (SA) algorithm, random forests (RF) and hybrid methods (GA+RF and SA+RF) were utilized for selecting an important subset of features from a total of 16 clinical features. These feature selection methods were combined with support vector machine (SVM) for developing predictive models with better performance. Five-fold cross-validation was used to train and test SVM models. ResultsThe developed SVM-based predictive models with hybrid feature selection methods and 5-fold cross-validation had averages of the sensitivity, specificity, accuracy, positive predictive value, negative predictive value, and area under the ROC curve as 67%, 86%, 82%, 69%, 90%, and 0.69, respectively. ConclusionsThe SVM derived predictive model can provide suggestive high-risk recurrent patients, who should be closely followed up after complete RFA treatment.

We tried to image obstructive cholestasis by using a newly developed imaging system to measure the alterations of hepatobiliary function in living mice with their bile ducts ligated. A hepatic imaging window was installed on the upper abdomen soon after the mice underwent ligation of the common bile duct. On the next day, the mice received intravenous injection of rhodamine B isothiocyanate-dextran and carboxyfluorescein diacetate. The later would be transformed into fluorogenic carboxyfluorescein (detected at approximately 500-550 nm) by hepatocytes and then excreted into bile canaliculi. The images were acquired by multiphoton microscopy. The fluorescence intensities at approximately 500-550 nm within hepatocytes or sinusoids were measured in time series. In mice with bile duct ligation, bile canaliculi failed to appear during the whole observation period over 100 min following carboxyfluorescein diacetate injection, whereas the fluorescence was retained much longer within sinusoids. Furthermore, the fluorescence intensities in sinusoids were persistently higher than in hepatocytes during the course. Bile duct ligation impedes hepatocytes to excrete carboxyfluorescein into bile canaliculi. The kinetics of fluorescence intensities in hepatocytes and sinusoids indicated there is an active machinery operating backflow of this fluorogenic bile solute from hepatocytes into sinusoids in the liver with obstructive cholestasis.

Background and Aim: Peritoneal metastasis is an uncommon manifestation of hepatocellular carcinoma (HCC). The aim of the present paper was to investigate the characteristics and survival of HCC patients with peritoneal metastases. Methods: From January 1985 to December 2004, we retrospectively reviewed the records of 53 Taiwanese HCC patients with peritoneal metastases. Results: Peritoneal metastases were detected at the time of HCC diagnosis (synchronously) in 10 patients and after the initial therapy for the primary tumors (metachronously) in 43 patients. The mean time for development of the metachronous peritoneal metastases was similar whether the primary cancer was treated with surgery (24 months) or transarterial chemoembolization (22.2 months). The single patient whose primary cancer was treated with supportive care alone developed peritoneal metastasis only 7.5 months after detection of the primary cancer. Surgical resection of the peritoneal metastases was possible in two-thirds of the 43 metachronous patients. The median survival for those who received surgery for these metastases was 12.5 months vs. 2.1 months for those without surgery (P = 0.0013). However, there was no difference in survival if patients were stratified to Child-Pugh grade. Conclusions: Peritoneal metastases of HCC are rare and can occur synchronously or metachronously. Though increased long-term survival was found in patients who had surgical removal of peritoneal metastases, the main determinant of better survival is Child-Pugh grade.

According to current guidelines of hepatocellular carcinoma (HCC) treatment, multiple HCCs are usually not suitable for surgical resection. However, surgical resection is still possible for patients with multiple HCCs. The role of hepatic resection vs transarterial chemoembolization (TACE) for multiple HCCs should be further clarified. We retrospectively enrolled 1065 patients with multiple HCCs. Among them, 294 received surgical resection, 367 received transarterial chemoembolization (TACE), and 404 received chemotherapy or supportive care. Three staging systems (TNM, CLIP, and BCLC) were used for comparison of stage-specific survival between different treatment modalities. The median survival of multiple HCC patients who received surgical resection was 37.9 months, while it was 17.3 months in TACE group, and 2.8 months in supportive group (P < .001). The 1-year, 3-year, 5-year survival rates for surgical group were 77.4%, 51.9%, and 36.6%, respectively. Kaplan-Meier survival analysis demonstrated that patients who received surgical resections had the best survival, followed by TACE and supportive care. For patients of the same stage, surgical resection yields better results than TACE. Surgery could offer better survival than TACE for patients either within or beyond Milan’s criteria. Our results indicate that if patients have preserved liver functions, hepatic resection is helpful, even for patients with multiple HCCs.

To evaluate whether the tumour suppressor gene, PPP2R1B, is involved in pathogenesis of hepatocellular carcinoma (HCC), reverse transcription-polymerase chain reaction (RT-PCR) and cDNA sequencing were performed. Eleven of 38 (29%) tumours and 1 of 34 (3%) corresponding non-tumour tissues showed coexpression of wild-type and aberrant mRNA. Various deletions were found in aberrant transcripts. Southern blot analysis did not show gene deletion in tumours, suggesting abnormal RNA splicing may be involved. These data suggest the possibility that aberrant transcripts of PPP2R1B might be associated with the development of HCC.

Partial hepatectomy or carbon tetrachloride (CCl4) injury, following treatment of rats with 2-acetylaminofluorene (2-AAF) to inhibit proliferation of hepatocytes, induces proliferation of oval cells and possibly their differentiation into nodular foci of hepatocytes when higher doses of 2-AAF are used. Unfortunately, immunohistochemistry in previous studies failed to show oval cell markers in these foci, and thereby to demonstrate the precursor-product relationship between oval cells and hepatocytes. Immunohistochemistry on livers of rats treated with high dose 2-AAF/CCl4 was used. We found 7.6% of the hepatocyte foci were positive for an oval cell marker cytokeratin 19 (CK-19). These foci were positive for alpha-fetoprotein, less positive for carbamoylphosphate synthetase 1, and more positive for laminin in the basement membrane lining. Rarely present transitional foci had weaker expression of CK-19 and discontinuous laminin. Focal hepatocyte differentiation of oval cells was characterized by cell hypertrophy, membranous CK-19, and positive hepatocyte nuclear factor 4 (HNF-4). HNF-4+ small oval cells surrounding CK-19+ foci were frequently seen, suggesting that a paracrine mechanism(s) may be responsible for the enlargement of CK-19+ foci. In conclusions, oval cells appear to differentiate to CK-19+ foci and then to CK-19- foci in the high dose 2-AAF/CCl4 model.

Background/purpose Taiwan is a hyperendemic area of liver diseases. Hepatitis B virus (HBV) and hepatitis C virus (HCV) are the two major etiologies of liver diseases in Taiwan. This study investigated the seroprevalence of HBV and HCV in Taiwan. Methods Since 1996, a series of outreach community-based screening programs for liver diseases have been available to the general population aged ≥ 18 years. Blood samples were obtained from the subjects and sent for hepatitis B surface antigen (HBsAg) and antibody to HCV (anti-HCV) tests. Results The prevalence of HBsAg(+) was 17.3% (27,210/157,720), while the prevalence of anti-HCV(+) was 4.4% (6904/157,720). Geographic variation in HBV and HCV seroprevalence was found, with the highest anti-HCV positive rate in Miaoli County, Chiayi County, Chiayi City, and Yunlin County, and the highest HBsAg positive rate in Keelung City and Yilan City. The HBsAg positive rate progressively decreased after the age of 50 years, while the anti-HCV positive rate progressively increased after the age of 20 years. The estimated total number of HBsAg carriers in the general population > 20 years old is 3,067,307, while the estimated number of anti-HCV positive patients is 423,283. Conclusion This study estimated a 17.3% seroprevalence of HBV and a 4.4% seroprevalence of HCV in Taiwan. Significant geographic variations in the seroprevalence of HBV and HCV were found. These data suggest the importance of modifying programs for the prevention and treatment of chronic viral hepatitis in Taiwan to reflect its varying prevalence and epidemiology. [ J Formos Med Assoc 2007; 106(2):148-155]

In an attempt to discover cell markers for liver stem cells, a cDNA microarray analysis was carried out to compare the gene expression profiles between an adult liver stem cell line, Lig-8, and mature hepatocytes. Several genes in the categories of extracellular matrix, cell membrane, cell adhesion, transcription factor, signal molecule, transporter, and metabolic enzyme were shown to be differentially expressed in Lig-8 cells. Among them, epithelial membrane protein (EMP)-1 has been previously implicated with stem cell phenotypes. Antiserum to EMP-1 was produced to localize its expression. On monolayers of Lig-8 cells, EMP-1 was expressed along the intercellular border. In the liver harboring proliferating oval cells, the liver progenitors, EMP-1 was localized as ribbon bands, a staining pattern for epithelial junctions, all the way through bile duct epithelia, oval cell ductules, and into peri-hepatocytic regions. These peri-hepatocytic regions were proved to be bile canaliculi by co-localization of EMP-1 and dipeptidyl peptidase IV, an enzyme located on bile canaliculi. This report is the first to indicate EMP-1 to be a junctional protein in the liver.

Background and Aim: Loss of heterozygosity (LOH) on chromosomes 16q and 13q, associated with tumor development, is frequently found in hepatocellular carcinoma (HCC). In light of this, an attempt was made to use the LOH pattern determined by microsatellite markers on 16q and 13q to discriminate clonality. Methods: In an effort to locate the LOH region more precisely and select the appropriate markers, LOH studies on 88 HCC using a panel of 35 microsatellite markers on 16q were carried out. Nine independent regions of frequent LOH were defined. In combination with a previous study of deletion mapping of 13q by the same authors, 12 markers on 16q and 13q were selected and polymerase chain reaction amplification, from microdissection-extracted DNA, was used to allelotype microsatellite polymorphism as an indication of clonality. Results: Two patterns of LOH were observed. In pattern A, in 8 of 16 (50%) patients, the LOH pattern of the first tumor was preserved in the second sample, with some tumors also showing additional LOH. In these patients, the original and second tumors are presumed to arise from the same original clone with or without progressive accumulation of LOH. In pattern B (8 of 16, 50%), LOH seen in the first tumor was not preserved in the second or recurrent tumors, as evidenced by retention of heterozygosity compared with the first tumor. Conclusion: The data suggest that the second tumor might have arisen from another independent clone. Moreover, this approach also provides a more sensitive and specific strategy to determine whether multiple or recurrent tumors are derived from the same or a different clone.

Although previous studies have demonstrated the ability of ultrasonography (US) screening to detect small asymptomatic hepatocellular carcinoma (HCC), the efficacy of US screening in reducing deaths from HCC still remained unresolved. A 2-stage screening program was designed to identify a high risk group in 7 townships in Taiwan by 6 markers (of risk for HCC) and repeated US screening was further applied to those with at least 1 positive result for the 6 markers, with a range of 3- to 6-month inter-screening intervals to those with liver cirrhosis or other chronic liver diseases and an annual screening regime for the remaining subjects with normal findings according to US. The 4,843 subjects in this cohort were followed up for an average of 7 years. We compared 4,385 attenders with 458 non-attenders, in conjunction with baseline assessment for self-selection bias. In addition, we assessed baseline variables with respect to their effects on risk of incidence of and mortality from HCC and on risk of incidence of liver cirrhosis. The difference in mortality between attenders and non-attenders was then re-estimated adjusting for significant predictors of cirrhosis, HCC incidence and HCC death as a further guard against baseline differences between attenders and non-attenders in risk profiles. Results of US screening for this high risk group found the mortality was lower by 24% (95% CI: −52 to 62%) in the attenders compared to the non-attenders. After adjustment for sensitivity, the mean sojourn time (MST) were 1.57 (95% CI: 0.94–4.68) for subjects with liver cirrhosis and 2.66 (95% CI: 1.68–6.37) years for non-cirrhotic patient. Significant increases in risk of HCC incidence were associated with increasing age, male gender, hepatitis B surface antigen positive (HbsAg), hepatitis C antibody positive (Anti-HCV), high levels of alanine transaminase (ALT) and alpha-fetoprotein (AFP) and a family history of HCC. Significantly increased risks of liver cirrhosis were associated with predictors of cirrhosis were increasing age, HbsAg, high levels of ALT and of AFP. Significant or borderline significant increases in risk of HCC death were associated with increasing age, male gender, HbsAg, high levels of AST and AFP. Adjusted for the significant variables, the mortality was lower by 41% (95% CI: −20 to 71%, p = 0.1446) in the attenders compared to the non-attenders. The present study provides suggestive evidence on the efficacy of US screening in a selective high risk group in an endemic area of hepatitis B. A randomized controlled trial would yield definitive evidence. Within the protocol of such a trial, a shorter interscreening interval for patients with liver cirrhosis is suggested. © 2001 Wiley-Liss, Inc.

Elucidation of the basic genetic changes of human hepatocellular carcinoma is important for the understanding and treatment of this cancer. We used microsatellite polymorphism markers to study 30 cases of hepatocellular carcinoma (34 tumours) on all human chromosomes. DNA from 34 pairs of hepatocellular carcinomas and corresponding non-tumour parts was prepared. Loss of heterozygosity (LOH) and microsatellite instability on 23 chromosomes were investigated by 231 sets of microsatellite markers. More than 20% LOH was shown for loci on 16q (47.1%), 13q (32.4%), 17p (32.4%), 5q (26.5%), 11p (23.5%) and 9p (20.6%). The commonly affected regions were mapped to 16q12.1, 16q12.2, 16q24, 13q12.1–32, 17p13, 5q32, 5q34, 5q3, 11p15, 11q23–24 and 9p21. Hepatitis B virus carriers had a significantly higher frequency of LOH on chromosomes 5q, 11p and 16q. Furthermore, larger tumour size tended to have higher frequency of LOH at D16S409 locus (16q12.1). Microsatellte instability was only found in 12 of 231 markers and the frequency is very low. These data suggest that the chromosomes 16q, 13q, 17p, 5q, 11p and 9p might participate in hepatocarcinogenesis. However, microsatellite instability might play little role in the development of this cancer in Taiwan. © 1999 Cancer Research Campaign

Aims/background Activation of human MAGE genes leads to the expression of a set of tumor rejection antigens, which are recognized by cytotoxic T lymphocytes. The antigens may become the targets of immunotherapy. The expression of MAGE genes was originally found in, but is not restricted, to melanomas. The aim of this study was to investigate the expression of MAGE genes in human hepatocellular carcinomas. Methods The expression of MAGE-1, -2, -3, -4 genes in tumorous and corresponding non-tumorous liver tissue was studied using a reverse-transcription polymerase chain reaction. Results In the 50 hepatocellular carcinomas studied, MAGE-1, -2, -3, -4 mRNA expression was detected in 23 (46%), 17 (34%), 21 (42%) and 8 (16%), respectively. Seventy-four percent of the hepatocellular carcinomas expressed at least one of the MAGE genes. MAGE mRNAs were not detected in the corresponding non-tumor liver tissues. MAGE gene expression was not significantly correlated with clinicopathological factors. Conclusions The MAGE genes are expressed in a high percentage of hepatocellular carcinomas; the MAGE gene products are potential targets for tumor-specific immunotherapy.

Telomerase activity is activated and telomere length altered in various types of cancers, including hepatocellular carcinoma (HCC). A total of 39 HCC tissues and the corresponding non-tumour livers were analysed and correlated with clinical parameters. Telomere length was determined by terminal restriction fragment assay, and telomerase activity was assayed by telomeric repeat amplification protocol. Telomerase activity was positive in 24 of the 39 tumour tissues (1.15–285.13 total product generated (TPG) units) and in six of the 39 non-tumour liver tissues (1.05–1.73 TPG units). In the 28 cases analysed for telomere length, telomere length was shortened in 11 cases, lengthened in six cases, and unaltered in 11 cases compared with non-tumour tissues. Neither telomore length nor telomerase activity was correlated to any clinical parameters.

CDKN2A (p16INK4A/MTS1) and CDKN2B (p15INK4B/MTS2) have recently been shown to be potent inhibitors of the cyclin D/cyclin-dependent kinase-4 complex. Both genes are candidates for the putative tumour suppressor genes located at chromosome 9p21 and are frequently inactivated in many human cancers through homozygous deletion. More recently, another reported pathway of inactivation involves loss of transcription associated with de novo methylation of the 5' CpG island of p16/MTS1 and p15/MTS2 in human cancers. We examined a total of 34 tumours from 30 hepatocellular carcinoma (HCC) patients for deletion, mutation and DNA methylation of these two genes by polymerase chain reaction (PCR) amplification, sequence analysis and Southern blot. Homozygous deletions of P16/MTS1 exon 1 were only identified in 1 of 30 cases (3%). Homozygous deletions of p15 exon 1 or exon 2 were found in 7 of 30 cases (13%). Automated sequencing analysis of p16 exon 1 and 2 and p15 exon 1 and 2 failed to demonstrate mutations in either p16 or p15 in any of these specimens. No aberrant 5' CpG island hypermethylation of p16 or p15 was found in any of the primary tumours by Southern blot. These data suggest that the p16/MTS1 gene has a limited role in HCC. However, deletions of the p15/MTS2 gene are found in 13% HCC and might be involved in a subset of HCC.

Bile duct hamartomas (von Meyenburg's complexes) of the liver are usually detected at laparotomy or autopsy as an incidental finding, and usually they are multiple. We report two cases of proved bile duct hamartomas of the liver. The first was in a 65-year-old man whose initial sepsis and many hepatic lesions were interpreted as microabscess of the liver. The second patient was a 39-year-old man, a hepatitis B surface antigen carrier, in whom an incidental hepatic tumor was found. We suggest that liver biopsy be done in hepatic lesions with uncertain clinical features, because the histologic findings may change the treatment plan.

To provide an efficient way for tracking patients' condition over long periods of time and to facilitate the collection of clinical data from different types of narrative reports, it is critical to develop an efficient method for smoothly analyzing the clinical data accumulated in narrative reports.To facilitate liver cancer clinical research, a method was developed for extracting clinical factors from various types of narrative clinical reports, including ultrasound reports, radiology reports, pathology reports, operation notes, admission notes, and discharge summaries. An information extraction (IE) module was developed for tracking disease progression in liver cancer patients over time, and a rule-based classifier was developed for answering whether patients met the clinical research eligibility criteria. The classifier provided the answers and direct/indirect evidence (evidence sentences) for the clinical questions. To evaluate the implemented IE module and the classifier, the gold-standard annotations and answers were developed manually, and the results of the implemented system were compared with the gold standard.The IE model achieved an F-score from 92.40% to 99.59%, and the classifier achieved accuracy from 96.15% to 100%.The application was successfully applied to the various types of narrative clinical reports. It might be applied to the key extraction for other types of cancer patients.

Hepatocellular carcinoma (HCC) is the leading cause of cancer-related deaths in Taiwan. HCC with duodenal involvement are rare and are associated with a poor prognosis. The purpose of this retrospective study was to collect clinical information and data regarding survival following various treatments.Between 1996 and 2009, 21 cases (17 men) were diagnosed with HCC and duodenal invasion and metastases by diagnostic imaging, endoscopy with biopsy, or surgically collected specimens sent to pathology. The clinical course was analyzed from the patients' medical records.Gastrointestinal bleeding was reported in 18/21 patients. Diagnostic imaging showed that the majority of cases involved direct tumor invasion (predominantly from the right liver lobe) and six cases from metastasis. Tumor mass and ulcerations were the most common features noted on endoscopy. In addition to the component therapy and medication treatment, panendoscopic hemostasis, surgery, transcatheter arterial embolization, and radiotherapy were performed for the management of duodenal involvement and gastrointestinal bleeding. Survival duration after duodenal involvement ranged from 0.2 to 57.8 months (mean 10.5 months).Gastrointestinal bleeding in advanced HCC should raise suspicions of duodenal involvement. HCC can involve the duodenum by direct invasion (from either the left or right liver lobes) or metastasis. The prognosis for HCC patients with duodenal involvement is poor, but is improved by supportive care and application of various treatment modalities.

Background: The clonality of hepatocellular carcinoma is still controversial. To evaluate the clonality of this cancer, mostly small multiple hepatocellular carcinomas of 18 patients were analyzed by DNA finger-printing. Methods: DNA from the liver tissues was digested with Hinfl. After gel electrophoresis, in gel-hybridization with a synthetic oligonucleotide probe GTGGTGGTGGTGGTG was performed. The band patterns were compared among the tumors and the nontumor part. In patients positive for hepatitis B surface antigen (HBsAg), the Integration pattern of hepatitis B viral DNA in liver tissues was also analyzed. Results: Seven of the 9 HBsAg-positive patients had tumors with different clonalitles by both methods. In the remaining 9 HBsAg-negative patients, 4 had different band patterns in their tumors by DNA fingerprinting. Conclusions: Multiple hepatocellular carcinomas frequently have different clonalitles; this finding reiterates the importance of eliminating the underlying cause and the contributing factors of hepatocarcinogenesis.

Background and Aim: Antemortem diagnosis of hepatocellular carcinoma (HCC) with cardiac metastasis is uncommon. To clarify the clinical manifestation and survival of HCC patients with cardiac metastases, we initiated the present study. Methods: We retrospectively analyzed 48 HCC patients with metastases into cardiac cavity diagnosed antemortem. The baseline clinical characteristics, echocardiogram, treatment modality and the outcome data were collected. Results: The most common symptoms of cardiac metastasis included asymptomatic in 19 cases (39.5%), bilateral lower leg edema in 18 cases (37.5%) and exertional dyspnea in 15 cases (31.3%). The median and mean survival times from the time of diagnosis of cardiac metastasis were 102 days and 161 days, respectively. Compared with another cohort of 48 patients with age-, gender-, and stage-matched HCC patients without cardiac metastasis, the median survival in the cardiac metastasis group was similar to the control group (68 days) (P = 0.67). The cause of death was HCC in 29, hepatic failure in seven, multiple organ failure in four, gastrointestinal bleeding in three, sepsis in two, pulmonary embolism in one, respiratory failure in one, and acute myocardial infarction in one. Conclusions: Hepatocellular carcinoma patients with cardiac metastases were in the advanced stages. These patients had limited survival from the diagnosis of cardiac metastases. The most common cause of death was related to HCC per se or the underlying liver disease. Only a few patients expired because of cardiac metastases.

Liver progenitors, so-called oval cells, proliferate remarkably from periportal areas after severe liver injury when hepatocyte regeneration is compromised. These cells invade far into the liver parenchyma. Molecular mechanisms underlying these behaviors of oval cells remain poorly understood. In this study, we treated rats with 2-acetylaminofluorene/carbon tetrachloride to induce hepatic oval cells. By expression microarray analysis, we investigated global gene expression profiles in liver tissue, with an emphasis on adhesion molecules, extracellular matrix proteins, matrix metalloproteinases (MMPs), growth factors/cytokines, and receptors that might contribute to the distinct behaviors of oval cells. Genes upregulated at least twofold were selected. We then performed immunostaining to verify the microarray results and identified expression of MMP-7 and CD44 in oval cells. Staining of cytokeratin (CK)-19, an oval-cell marker, was similar between oval cells located next to periportal areas and those located far within the parenchyma. In contrast, CD44 staining was more intense in the parenchyma than in periportal areas, suggesting a role of CD44 in oval-cell invasion. Moreover, newly differentiated CK-19+ hepatocytes within foci did not show CD44 staining, suggesting that CD44 is related to the undifferentiated oval-cell phenotype. We then investigated oval-cell reactivity in CD44-deficient mice fed an oval cell-inducing diet of 3,5-diethoxycarbonyl-1,4-dihydrocollidine. Results showed significantly reduced oval-cell reactivity in CD44-deficient mice. Thus, oval cells express MMP-7 and CD44, and CD44 appears to play critical roles in the proliferation, invasion, and differentiation of hepatic oval cells in rodents.

The aim of this study was to compare six prognostic staging systems (Okuda stage, TNM stage, CLIP score, BCLC stage, JIS score and Tokyo score) in predicting survival in patients with hepatocellular carcinoma (HCC). A total of 2010 Taiwanese HCC patients were included. Demographic, laboratory and tumour characteristics were determined at diagnosis. Predictors of survival included serum levels of albumin, total bilirubin, alkaline phosphatase, alpha-fetoprotein, ascites, tumour size and portal vein invasion. The Tokyo score was the most informative one for predicting the survival of HCC patients as a whole, receiving surgical resection, or receiving transarterial chemoembolisation. CLIP score was the best fit system for HCC patients receiving chemotherapy or supportive care. Each staging system showed a significant difference in predicting the probability of survival across different stages. The applicability of staging systems for patients with HCC was dependent on treatment methods.

Hepatitis B virus (HBV) DNA was assayed using the polymerase chain reaction in serum samples of 116 hepatitis B surface antigen (HBsAg) carriers, including 30 positive for hepatitis B e antigen (HBeAg) and 86 negative for HBeAg. In the HBeAg-positive group, all were positive for HBV DNA. In the HBeAg-negative group, 80.2% were positive for HBV DNA (80.0% in the healthy carrier group, 90.0% in the chronic active liver disease group, and 69.2% in patients with cirrhosis). This study indicated that every HBeAg-positive carrier as well as the majority of HBeAg-negative carriers were infectious and, in the latter group, that viral replication is most active in patients with chronic active liver disease.

Tumor may induce local immunosuppression and make the tumor-infiltrating lymphocytes (TILs) functionally inhibited and lose the antitumor effects. Therefore, we did the phenotypic analysis of TILs in hepatocellular carcinoma (HCC) tissues.Lymphocytes were isolated from paired HCC tissues (TILs) and the corresponding non-tumor liver tissues (non-tumor-liver infiltrating lymphocytes, NILs) of 28 patients and were subjected to flow cytometric analysis.Compared with the non-tumor portion, HCC tissues had less intensity of lymphocyte infiltration. TILs had higher CD3+/CD56+ ratio than NILs. Around 70%-90% NILs or TILs expressed the antigen-experienced or memory phenotypes. Around 60%-70% CD4+ or CD8+ NILs and TILs expressed the activation markers CD69 and HLA-DR. However, we found that CD25 is under-expressed in both the CD8+ NILs and TILs. In addition, more percentage of CD4+ CD25+ T cells was detected in the TILs than in the NILs.HCC tissues had less lymphocytes infiltration. Most of infiltrating lymphocytes from the HCC tissues and the corresponding non-tumor liver tissues were activated and expressed antigen-experienced phenotypes. However, the CD25 was underexpressed in the CD8+ TILs and the CD4+ CD25+ T cells were increased in the TILs. These factors might impair the antitumor immunity in HCCs.

Gene inactivation through DNA hypermethylation plays a pivotal role in carcinogenesis. This study aimed to profile aberrant DNA methylation in different stages of liver disease, namely noncirrhosis, cirrhosis and hepatocellular carcinoma (HCC), and also to clarify the influence of hepatitis B virus (HBV) infection on the aberrant DNA methylation in HCCs. Promoter methylation in p14(ARF), p16(INK4a), O(6)-methylguanine-DNA methyltransferase (MGMT), glutathione S-transferase pi (GSTP1) and E-cadherin (E-Cad) genes of 58 HCCs paired with adjacent nontumorous tissues was assayed by methylation-specific PCR. HBV infection was determined using a hepatitis B virus surface antigen (HBsAg) serological assay. The frequency of p16(INK4a) promoter methylation increased from noncirrhotic, cirrhotic, to HCC tissues (noncirrhotic vs. HCC, p < 0.001), while that of GSTP1 promoter methylation increased in cirrhotic tissues compared to noncirrhotic ones (p = 0.029). The frequency of GSTP1 promoter hypermethylation is significantly higher in HCC than in nontumorous tissues (p = 0.022) from HBsAg-positive patients, but not the HBsAg-negative controls (p = 0.289). While the frequency of E-Cad promoter hypermethylation remained high in both nontumorous tissues and HCCs from HBsAg-positive patients (p = 0.438), it was lower in HCCs than in nontumorous tissues from HBsAg-negative patients (p = 0.002). In contrast, the frequency of p16(INK4a), MGMT and p14(ARF) promoter hypermethylation in HCCs was unrelated to HBsAg status. In conclusion, aberrant DNA methylation may begin at different stages of liver disease in a gene-dependent manner. Moreover, HBV infection may enhance or maintain GSTP1 and E-Cad promoter methylation and thereby affect hepatocarcinogenesis.

It is not rare to find hepatic hemangiomas in people in Taiwan where hepatitis B is endemic during ultrasonographic examinations for the screening of hepatocellular carcinoma, and we can therefore monitor these hemangiomas longitudinally since detected.Totally 180 hepatic hemangiomas in 130 adult patients were followed up for more than 5 years with at least twice ultrasound examinations in our hospital. The diagnosis of hemangiomas was made by typical ultrasonographic findings as well as compatible findings in other imaging modalities. The largest diameter of the same tumor at various examinations was compared in each patient. The doubling time of tumor volume was calculated for the enlarging hepatic hemangiomas.The diameters of the 180 hemangiomas ranged from8 cm -4 cm in 11 (6.1%),or =4 cm -2 cm in 55 (30.6%), andor =2 cm in 114 (63.3%). Among them, the diameter of 14 (7.7%) hemangiomas in 13 patients increased. The tumor volume doubling time of these hemangiomas ranged from 17.3 to 178.1 months.Although hepatic hemangiomas are benign, some of them indeed grow slowly. The growth rates of these hemangiomas varied and were definitely slower as compared with those of malignant hepatic tumors.

The purpose of this study was to compare the clinical features and survival in patients with hepatitis B virus-related hepatocellular carcinoma (HBV-HCC) and hepatitis C virus-related hepatocellular carcinoma (HCV-HCC). A total of 2820 HCC patients were included. The mean age of HBV-HCC patients was 52.5+/-13.4 years, while it was 64.8+/-8.7 years in HCV-HCC patients. The male/female ratio was 7.8 in HBV-HCC, while it was 1.7 in HCV-HCC. The mean alpha-fetoprotein level in HBV-HCC was 11,661+/-22,805 ng/mL, while it was 5079+/-15,005 ng/mL in HCV-HCC. The mean tumour size was 6.4+/-4.1 cm in HBV-HCC, while it was 4.6+/-3.1 cm in HCV-HCC. The median survival was 11.1 months in HBV-HCC, while it was 23.9 months in HCV-HCC. Compared with HBV-HCC patients, HCV-HCC patients were older, had a lower male/female ratio, lower white blood cell count, lower serum albumin level, higher serum ALT level, lower serum alpha-fetoprotein level, smaller tumour size and survived longer.

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death throughout the world. Although hepatitis B or C viral infections are main risk factors for HCC, the molecular mechanisms leading to HCC formation have not been clarified. To reduce the mortality and improve the effectiveness of therapy, it is important to search for changes in tumor-specific biomarkers whose function may involve in disease progression and which may be useful as potential therapeutic targets. In this study, we employed two-dimensional difference gel electrophoresis (2D-DIGE) combined with nano flow liquid chromatography tandem mass spectrometry (nanoLC-MS/MS) to investigate differentially expressed proteins in HCC. For each of eight HCC patients, Cy3-labeled proteins isolated from tumor tissue were combined with Cy5-labeled proteins isolated from the surrounding nontumor tissue and separated by 2D gel electrophoresis along with a Cy2-labeled mixture of all tumor and nontumor samples as an internal standard. Thirty-four protein spots corresponding to 30 different proteins were identified by nanoLC-MS/MS as showing significant change (paired t-test, p0.05) in the level of expression between tumor and nontumor tissues. Sixteen proteins were up-regulated and 14 were down-regulated in HCC; they seem to play important roles in a variety of pathways including glycolysis, fatty acid transport and trafficking, amino acid metabolism, iron and xenobiotic metabolism, ethanol metabolism, cell cycle regulation, cytoskeleton, and stress. A remarkable finding is the up-regulation of 14-3-3gamma protein in HCC. 14-3-3 isoforms had been linked to carcinogenesis because they are involved in various cellular processes such as cell cycle regulation, apoptosis, proliferation, and differentiation. In conclusion, 2D-DIGE is an efficient strategy that enables us to identify differentially expressed proteins in HCC. Identification of potential biomarkers, such as the pinpointing of 14-3-3gamma in our findings, may provide further useful insights into the pathogenesis of HCC.

Needle liver biopsy is essential for the diagnosis of liver fibrosis and cirrhosis. However, sampling variability has been reported by semiquantitative methods. The aim of the present study was to investigate quantitatively the sampling variability of needle liver biopsy on the assessment of liver fibrosis/cirrhosis.Liver samples of 12 patients undergoing autopsy, liver transplantation, or liver tumor resection were investigated. Nine to 10 liver biopsies at least 5 mm apart were taken from each of 12 removed human livers using Trucut needles. Hydroxyproline level of each liver core was determined. Sections1 cm(2) and stained by Sirius red were used for the reference staging of liver fibrosis in each patient according to the METAVIR scoring system.Hydroxyproline levels for the three groups, F0-1, F2-3, and F4, were significantly elevated as the fibrosis score increased. There was a wide range of hydroxyproline contents for the 9-10 biopsy samples from each liver, the coefficient of variation being between 13% and 36% (mean, 23%). Several differences were noted between the amount of collagen present according to hydroxyproline measurement and the stages of fibrosis according to histology.Although increases in collagen content (by hydroxyproline) approximately paralleled increases in fibrosis stage (by histology), there was considerable overlap and some discrepancies. Much work remains to be done to clarify the significance of the apparent huge variations in fibrosis within diseased livers. It is advisable for clinicians to interpret staging diagnoses by histological staging with some caution.

Background: An accurate staging system is required to assess hepatocellular carcinoma (HCC) patients in order to benefit from hepatic resection before surgery. Cancer of the Liver Italian Program (CLIP) score was considered to be better than the Okuda staging system to predict survival. Japan Integrated Staging Score (JIS score) includes tumor, nodes, metastases (TNM) stage and Child–Pugh grade as a new staging system for HCC. The purpose of the present paper was to compare the CLIP, Okuda, TNM and JIS staging systems for HCC patients undergoing surgery. Methods: From 1991 to 1995, 599 patients undergoing hepatic resection for HCC from four medical centers in Taiwan were evaluated. All patients were classified by Okuda, CLIP, TNM and JIS systems. Factors associated survivals were analyzed. Results: There was no statistical difference in survival between CLIP 0 and 1 patients, or among CLIP 2–4 patients. The prognostic validation of the Okuda and CLIP scoring systems in discriminating survival in HCC patients undergoing surgery was not satisfied. The TNM system was successful in predicting survival for HCC patients undergoing surgery. The JIS score could also differentiate survivals for those patients except for JIS 3. By multivariate analysis, age ≥60 years old, serum albumin 5 cm and TNM stage were associated with survival. Conclusion: Both the Okuda and CLIP systems are not superior to TNM staging for HCC patients who undergo surgical resection. Whether JIS score is feasible for those patients with advanced HCC needs further evaluation.

Summary Background: Transcatheter arterial embolization is a major palliative treatment for unresectable hepatocellular carcinoma, but the survival benefit of transcatheter arterial embolization is controversial. Aim: To evaluate the role of transcatheter arterial embolization in different stage of unresectable hepatocellular carcinoma and to select patients who can get the best benefit from the treatment. Methods: From 1991 to 1995, 476 patients who had unresectable hepatocellular carcinoma from four medical centres in Taiwan were enrolled. Among them, 425 underwent transcatheter arterial embolization, and 51 received supportive treatment alone. The survivals between the two groups were compared. Results: Among the 476 patients, transcatheter arterial embolization can significantly prolong survival. The 1-, 2-, and 5-year survival rates for patients who underwent transcatheter arterial embolization were 60.2%, 39.3%, and 11.5%; and the rates for patients who underwent supportive treatment were 37.3%, 17.6%, and 2%, respectively (P = 0.0002). The survival benefit of transcatheter arterial embolization was observed in patients between Cancer and the Liver Italian Program 0 and Cancer and the Liver Italian Program 4. In multivariate analysis, transcatheter arterial embolization, tumour size

Percutaneous microwave coagulation therapy (PMCT) can effectively treat hepatocellular carcinomas (HCCs) smaller than 2 cm. However, for tumors 2 to 3 cm in size, combination of transarterial chemoembolization (TACE) or multiple insertions of electrodes may be more effective. This study investigated the treatment efficacy of PMCT for tumors 2 to 3 cm in size.Nineteen HCCs smaller than 3 cm in diameter (2 cm in 11, and 2-3 cm in 8) in 18 patients (including 14 previously treated patients) were treated by PMCT under ultrasound guidance. One or 2 PMCT electrodes were consecutively inserted either into the left and right portion, or into the distal and proximal portion of the tumor, according to the size, shape, and margin of tumors and puncture direction. Liver function tests and contrast-enhanced computed tomography were used to examine preoperative status and response to PMCT.After an average of 1.6 emissions of PMCT, 18 tumors (95%) were completely ablated. The only case of treatment failure was due to a tumor location which made the approach of the electrode difficult. Bacteremia developed after the procedure in 1 patient (5%) and local inflammatory reaction of the puncture wound in another (5%). During follow-up ranging from 5 to 19 months, no recurrence was noted at the site of the original tumors. Tumor recurrence was detected at another site 2-9 months after PMCT in 9 of the 14 previously treated patients.PMCT can effectively and safely treat HCCs smaller than 3 cm in size without combination of TACE or multiple insertions of electrodes.

Purpose: The role of transcatheter arterial embolization (TAE) for patients with resectable hepatocellular carcinoma (HCC) is controversial. Analyzing a cohort of nation-wide data can delineate the beneficial effect of TAE for those patients. Methods: From 1991 to 1995, 818 patients who had potentially resectable HCC from four medical centers in Taiwan were enrolled. Among them, 599 underwent curative resection, 157 received TAE and 62 received supportive treatment alone. The survivals among the three groups were compared. Results: The 5-year survival rates for patients who underwent surgery, TAE and supportive treatment were 43.6%, 25.6% and 3.7%, respectively. Surgery offered the best survival for those patients. TAE could also prolong survival as compared with supportive treatment (P=0.0001). However, among patients who were in advanced tumor stage (Cancer and the Liver Italian Program (CLIP) score ≥2), no statistical difference in survival was noted between patients who underwent TAE or supportive treatment. In multivariate analysis, single tumor, serum albumin ≥3.5 g/dl, tumor size less than 5 cm, early-stage tumor (CLIP score=0–1) and aggressive treatment including surgery and TAE were independent factors associated with a better survival. Conclusions: Surgery is superior to TAE for patients with resectable HCC. In patients who refuse surgery, TAE can be considered for selected patients whose tumors are in early stage.

Although 2-dimensional (2D) ultrasonography (US) with conventional color and power Doppler US has been applied widely in the differential diagnosis of hepatic tumors and in the follow-up of treatment of hepatocellular carcinomas (HCCs), it has limited capabilities for demonstrating associated arteries of HCCs. Three-dimensional (3D) US can provide more accurate depiction of stereotypic vascular patterns than 2D US. This study investigated the efficacy of 3D power Doppler US versus angiography for demonstrating associated arteries of HCCs.A total of 24 HCCs with surrounding or intratumoral arteries detected by 2D power Doppler US were studied using a US machine equipped with power Doppler software and a built-in stereo image processing workstation. Serial 2D images were reconstructed into 3D images to analyze the distribution and routes of arteries associated with HCCs. These results were compared with angiographic findings.Three-dimensional US imaging of vasculature associated with HCCs in the 24 patients was categorized into 3 patterns: peripheral arteries around the tumor (pattern I, n = 9); no more than 4 intratumoral arteries with or without originating peripheral arteries (pattern II, n = 9); and prominent (more than 4) intratumoral arteries (pattern III, n = 6). Most feeding arteries shown in angiograms that could be demonstrated by 3D power Doppler US were in HCCs with pattern I and II vasculature. In HCCs with pattern III, the basket vascular pattern shown on angiograms could also be demonstrated on 3D power Doppler US. The vascular proficiency, including major feeding arteries and branches of feeding arteries,could be shown to significantly increase from pattern I to III on 3D power Doppler, but this method had a lower detection rate of smaller branches and neovascularization than angiographic study.Three-dimensional power Doppler US can effectively depict the associated arteries of HCCs, especially the major feeding arteries. Three vascularization patterns of HCCs were categorized in 3D images. There is a good correlation of the findings of 3D power Doppler US with angiographic study. These findings demonstrate the usefulness of 3D power Doppler as a non-invasive alternative to angiographic examination.

Stem cell-based therapies for degenerative disorders and injuries are promising in the new era. Multipotential mesenchymal stem cells (MSCs) from bone marrow (BM) are on the leading edge because they are easy to expand in culture while maintaining their multilineage potential. In vitro assessment of the chondrogenic and osteogenic potentials of cultured MSCs has been established, and the BM used in those experiments was exclusively from healthy donors via iliac crest aspiration. It is unknown whether human marrow obtained from femurs also contains these multipotential MSCs. We collected marrow from proximal femurs of two patients undergoing total hip replacement surgery for femoral head osteonecrosis and isolated and culture expanded MSCs to about 20 population doublings. These cells were homogeneously positive for beta1-integrin. When pelleted into aggregates and cultured in a medium containing transforming growth factor-beta3 for 14 days, the cells began to express mRNA for aggrecan and collagen type II and to deposit immunoreactive collagen type II and sulfated proteoglycans in the matrix, hallmarks of chondrogenic differentiation. These MSCs could also be differentiated into osteocytic lineage in vitro, as shown by increased expression of alkaline phosphatase activity and deposition of mineral content onto culture plates. These results indicate that femoral BM obtained during hip surgeries also contained multipotential MSCs. These data imply that direct replacement therapy using MSCs from in situ marrow may be possible in the future and that an MSC bank may be established by using marrow from this approach, bypassing the necessity for iliac marrow aspiration from healthy donors.

Though regular sonographic examination can early detect small hepatocellular carcinoma, the therapeutic results remains unsatisfactory. Antigen-specific immunotherapy is an alternative approach for controlling tumors. The prerequisite for antigen-specific cancer immunotherapy is the identification of appropriate tumor antigens. Recently, a new category of tumor-specific shared antigens, called cancer-testis antigens, has been identified. The cancer-testis antigens have been found in a variety of cancers. However, the expression of cancer-testis antigens in human hepatocellular carcinomas is unknown. The aim of this current study is to investigate the expression of cancer-testis antigens in human hepatocellular carcinomas. Reverse-transcription polymerase chain reaction (RT-PCR) was used to investigate the expression of the SSX-1,-2,-4,-5, SCP-1, NY-ESO-1 genes in tumorous and corresponding non-tumorous liver tissues. In the 30 hepatocellular carcinomas studied, SSX-1,-2,-4,-5, SCP-1, and NY-ESO-1 mRNA expressions were detected in 24 (80%), 14 (46.7%), 22 (73.3%), 10 (33.3%), 2 (6.7%), and 11 (36.7%), respectively. Expressions of these genes were detected in few non-tumor liver tissues. The cancer-testis antigens are expressed in a high percentage of hepatocellular carcinomas. These cancer-testis antigen gene products are potential targets for antigen-specific immunotherapy of hepatocellular carcinoma.

Loss of heterozygosity (LOH) on chromosome 13q is one of the most common genetic alterations in hepatocellular carcinoma (HCC) and might be involved in liver cancer development through inactivation of tumour suppressor genes. In order to narrow down the region of 13q loss, we examined the pattern of loss of heterozygosity (LOH) in tumours from 88 HCC patients, using 18 microsatellite markers on 13q. Thirty-eight of the 88 tumours (43%) showed LOH for at least one marker. Of these, two tumours (5%) showed 13q whole arm allelic loss, while the remaining 36 tumours (95%) had partial allelic loss. The LOH pattern defined by the 36 tumours suggested the existence of at least three different smallest common deleted regions which might be involved in the carcinogenesis of HCC. The first, the most centromeric in the 13q12.3 is, close to the BRCA2 gene, defined by D13S171; the second, the most telomeric region in the 13q31-32 band, is defined by D13S154 and D13S157; the third, the intermediate region at 13q14.3, which is near the RB gene, is defined by loci D13S268. The rate of LOH at 13q31-32 was significantly higher in Hepatitis B-surface antigen (HBsAg)-positive patients than HBsAg-negative HCC patients, pointing to a candidate gene related to the development of HBsAg-positive HCCs.

The elucidation of the genetic changes of hepatocellular carcinoma (HCC) is very important for understanding the molecular mechanism of liver carcinogenesis. In order to identify the gains or losses in DNA sequence copy number in HCC, we used comparative genomic hybridisation to study 40 cases (44 tumours) of HCC. Tumour DNA and DNA from non-neoplastic liver tissue were labelled with different fluorochromes and then simultaneously hybridised to normal metaphase spread chromosomes. An image acquisition system was used to quantitate signal intensities contributed by tumour and reference DNA along the entire length of each chromosome. Regions of amplification and deletion were demonstrated as quantitative alterations. Losses were prevalent on chromosome regions 16q (43%), 17p (20%), 13q (20%), 4q (15%) and 8p (15%). Gains frequently occurred on 8q (30%), 1q (20%), 6p (20%) and 17q (18%). Hepatitis B virus carriers had a significantly higher frequency of losses on chromosome 16q. Furthermore, the minimal region of losses was narrowed down to 16q11-q22. This study confirms the presence of previously known chromosomal aberrations in HCC and highlights a new significant correlation between losses on chromosome 16q and hepatitis B virus carriers.

Sepsis and liver abscess are serious complications following transarterial embolization (TAE) for hepatocellular carcinoma (HCC). However, the exact incidence and the necessity of antibiotic prophylaxis remain undetermined. Between November 1996 and November 1997, we prospectively studied bacterial infections in 231 HCC patients who underwent 287 angiographic procedures without antibiotic prophylaxis, including 176 TAEs and 111 hepatic arteriographies (HAs). Four of the 111 HAs were complicated by transient asymptomatic bacteremia. Of the 176 TAEs, 2 were associated with asymptomatic bacteremia, and 7 (4%) were associated with symptomatic bacterial infection, including 3 cases of sepsis, 2 of liver abscess, and 2 of infected biloma. For patients with HCC, TAE was associated with a higher risk of developing symptomatic bacterial infections than was HA (4% vs. 0, respectively; P = .03). Previous gastrectomy was the only possible risk factor for liver abscess. Finally, early diagnosis and treatment of these infectious complications usually result in successful outcome.

Family history is a risk factor for hepatocellular carcinoma (HCC). However, the risk of first-degree relatives is not known. To investigate the risk of HCC among the first-degree relatives of probands and whether screening can lead to early diagnosis of HCCs in these relatives, we conducted a screening program. The probands' first-degree relatives who were >20 years old were included. Serum aminotransferase, hepatitis viral marker, alpha-fetoprotein, and abdominal sonography were done. HCCs were found in 20 (1.9%) of the 1,046 first-degree relatives, especially in the male siblings. Eighty-five percent of these 20 HCC patients were hepatitis B virus carriers. Forty percent of these 20 HCC patients had tumors

Icteric type hepatocellular carcinoma is rare, and a poor prognosis has been demonstrated in the past. We performed this study to re-evaluate prognosis since the availability of modern diagnostic modalities. Of 3921 patients with hepatocellular carcinoma in our hospital, 9 patients who presented with tumor fragments in common bile duct and had a patent portal vein were submitted for analysis. Cholangiocarcinoma was suspected in 7 patients before the study was completed, and icteric type hepatocellular carcinoma was diagnosed in all 9 patients after serial studies that included serum alpha-fetoprotein levels, computed tomography, angiography, and histology. The prognosis was better in the 4 resectable patients (survival time 16, 31, 33, and 63 months, respectively), and was extremely poor for the 5 patients who received palliative treatment only (mean survival time, 4.5 months). Because of the apparently discrepant outcomes, this specific type of hepatocellular carcinoma should be kept in mind in areas where hepatocellular carcinomas are prevalent, and the suspected cases should be thoroughly investigated, because prognosis may be improved when resection is done at an earlier stage.

Background/Aims: To evaluate ultrasound-guided cutting biopsy for hepatocellular carcinoma, we report findings from 10 years of experience. Methods: We performed 455 ultrasound-guided cutting biopsies of hepatic tumors in 420 patients with hepatocellular carcinoma from 1981 to 1990. Results: Liver tissues were adequately sampled for a histological diagnosis of hepatocellular carcinoma in the initial biopsy in 391 sessions. The remaining 64 were proved to have hepatocellular carcinoma after subsequent studies. Ultrasound-guided biopsy changed the initial diagnosis in 9 of the 420 patients: three had been diagnosed with liver abscess, and six with metastatic liver tumors. Complications of the biopsy were rare: the tumor had spread to the chest wall in nine, and internal bleeding was noted in five patients. There was no mortality and no other sequelae. Conclusions: Ultrasound-guided biopsy of hepatic tumors is important in the diagnosis of liver cancer, but this technique should be applied only when the image diagnosis and results of fine needle biopsy are equivocal to minimize possible complications. For patients with small HCCs, who are candidates for surgical resection of hepatocellular carcinoma or liver transplantation, it should not be considered as a first-step invasive procedure.

Background The mechanisms of blood flow during closed-chest cardiopulmonary resuscitation (CPR) in humans have been debated since the technique was first described in 1960. Two competing models, the cardiac pump theory and the thoracic pump theory, have been proposed, and some investigators have used mitral valve position during the downstroke of chest compression to distinguish between them. Previous studies using either transthoracic or transesophageal echocardiography have yielded conflicting results, and there have been few, if any, hemodynamic or echocardiographic studies on pulmonary venous flow (PVF) during CPR. Methods and Results In this study, transesophageal two-dimensional and pulsed Doppler echocardiography were used to study mitral valve position and flow, together with PVF, in 20 adult patients undergoing manual CPR. In the 17 patients who could be analyzed, the mitral valve closed in 5 patients (group 1) during chest compression but stayed open or opened further in the remaining 12 patients (group 2). Peak forward mitral flow occurred during the release phase in group 1 but during the compression phase in group 2. During chest compression, PVF occurred in the forward direction (from the pulmonary vein to the left atrium) in 8 of the group 2 patients (group 2a) and in the backward direction (from the left atrium to the pulmonary vein) in all group 1 patients and the remaining 4 patients in group 2 (group 2b). The downtime (time from collapse to CPR) was significantly shorter ( P Conclusions Transesophageal echocardiography performed during manual CPR in humans disclosed three different patterns of mitral valve position and PVF during chest compression. The presence of an opened mitral valve with forward mitral flow and backward pulmonary venous flow during chest compression in a small number of subjects underscores this heterogeneity in blood flow and suggests the possible existence of a “left atrium pump” in addition to the currently known “left ventricle pump” and “chest pump” mechanisms.

The relative role of hepatitis C virus and hepatitis B virus in hepatitis B surface antigen-negative hepatocellular carcinoma was evaluated by polymerase chain reaction in 31 patients from Taiwan. Twenty-one were positive for antibody to hepatitis C virus (group 1) and 10 were negative (group 2). Of the group 1 patients, hepatitis C viral RNA was detected in the serum by polymerase chain reaction in 16 and in the liver tissue in 17, whereas hepatitis B viral DNA was found in the liver tissue in only 4, and none were found in the serum. In group 2 patients, hepatitis C viral RNA was detected in the serum of 1 and in the liver tissue of another. In contrast, hepatitis B viral DNA was found in the serum of 4 patients and in the liver tissues of 5. It was concluded that hepatitis C virus plays an important role in hepatocarcinogenesis in hepatitis B surface antigen-negative patients in Taiwan, especially in those who had antibody to hepatitis C virus; in those without antibody to hepatitis C virus, hepatitis B virus might still be associated with the development of hepatocellular carcinoma in a significant proportion of such patients.

Laserthermia by a novel interstitial probe adapted to low power Nd-YAG laser machine was used to treat small hepatocellular carcinoma (HCC). The set condition was 43–45°C in thermocouple with power of 2–3 W and the duration 20–30 min. In the 5 cases studied, 1 had a good result with total necrosis of the tumour without recurrence in 16 months. 1 died of liver failure 2.5 months later although death was not related to the procedure. 1 patient died of progressive disease 18 months later. The remaining 2 had recurrent tumours 5 and 12 months later, although the treated small tumours showed good response. Histological examination showed cell degeneration and necrosis. It is concluded that laserthermia is potentially useful in the treatment of the patients with small HCC.

Serum hepatitis B virus (HBV) DNA was assayed using polymerase chain reaction, in 107 HBsAg-negative normal Chinese subjects. The results showed that eight subjects (7.5%) had HBV DNA. In the subgroup with antibody to hepatitis B surface antigen (anti-HBs) and to hepatitis B core antigen (anti-HBc), 7.3% (5/68) were positive for HBV DNA; HBV DNA was not detected in six individuals with anti-HBs only and in nine with anti-HBc only. In four persons with anti-HBc and anti-HBe, one had HBV DNA. In 20 subjects negative for all hepatitis B serological markers, two (10%) were found to have HBV DNA. This study indicates that serological markers are not adequate to rule out HBV infection, and it further implies that present blood donor screening methods may need improving.

To evaluate the role of plasma des-gamma-carboxyprothrombin in the early diagnosis of hepatocellular carcinoma, we simultaneously studied both des-gamma-carboxyprothrombin activities by staphylocoagulase method and des-gamma-carboxyprothrombin antigen levels by enzyme immunoassay in 39 patients with early stage hepatocellular carcinoma (tumor size less than 3 cm in 21 patients, 3 to 5 cm in 18 patients); 68 patients had large hepatocellular carcinoma and 54 patients had chronic hepatitis or cirrhosis. Des-gamma-carboxyprothrombin levels by staphylocoagulase method (X) and enzyme immunoassay method (Y) on the same plasma specimens of hepatocellular carcinoma patients showed a linear correlation (Y = 0.15X - 10.5, r = 0.533, n = 67, p less than 0.001). Elevated des-gamma-carboxyprothrombin activities were present in 10 of 21 patients (47.6%) with hepatocellular carcinoma less than 3 cm, 66.7% of 18 with hepatocellular carcinoma 3 to 5 cm, 67.6% of 68 with hepatocellular carcinomas greater than 5 cm and 27.8% of 54 with chronic hepatitis or cirrhosis. The plasma des-gamma-carboxyprothrombin levels did not correlate with the tumor size or serum alpha-fetoprotein levels. Plasma des-gamma-carboxyprothrombin and serum alpha-fetoprotein measurements were comparable in the diagnosis of hepatocellular carcinoma because 22 (56.4%) and 21 (53.8%) of 39 patients with hepatocellular carcinoma less than 5 cm had increased des-gamma-carboxyprothrombin and alpha-fetoprotein levels, respectively. Up to 77% had an abnormal elevation in either marker.(ABSTRACT TRUNCATED AT 250 WORDS)