Jin-Chuan Sheu

Growth rate of asymptomatic hepatocellular carcinoma and its clinical implications.

The growth rate of 31 asymptomatic hepatocellular carcinomas (diameter less than or equal to 5 cm) discovered in 28 patients by a prospective screening program was determined by real-time ultrasonography over 36-860 days. Except for one tumor that shrank on follow-up, the doubling time ranged from 29 to 398 days, with a median of 117 days, an arithmetic mean of 136 days, and a geometric mean of 110 days. In 17 tumors with more than two measurements, the growth rate remained exponential in nine, declined in growth in seven, and showed an initial lag period in one. Doubling time correlated with initial tumor diameter but was independent of the patients age, sex, hepatitis B surface antigen status, tumor location, liver function tests, stage of liver cirrhosis, histologic type, or grade of malignancy. Although initial alpha-fetoprotein levels did not correlate well with growth rate, in 14 patients with an exponential increase of serum alpha-fetoprotein, the alpha-fetoprotein doubling time was closely related to the tumor doubling time. Based on the above data, the median detectable subclinical period of hepatocellular carcinoma was deduced to be 3.2 yr, and the suitable screening interval for its early detection in our area was 4-5 mo.

High α‐fetoprotein level correlates with high stage, early recurrence and poor prognosis of hepatocellular carcinoma: Significance of hepatitis virus infection, age, p53 and β‐catenin mutations

α‐Fetoprotein (AFP) is often elevated in hepatocellular carcinoma (HCC). This study was to elucidate the significance and related factors of AFP elevation in HCC in 781 unifocal HCCs receiving curative hepatectomy. We showed that high AFP (> 200 ng/ml), which was associated with AFP mRNA expression in HCC (p = 0.00001), correlated with major clinicopathologic factors. Younger age (≤ 55 years; p = 0.00001), hepatitis B surface antigen (HBsAg) in serum (p = 0.00001), p53 mutation (p = 0.008), large tumor (p = 0.00001), vascular invasion (p = 0.00001) and early tumor recurrence (p = 0.00001) were significant associates of high AFP, while anti‐HCV in serum and β‐catenin mutation in HCC had less frequent high AFP (p = 0.013 and < 0.0001, respectively). We also showed that HCC with high AFP had a lower 10‐year survival (p < 0.0001), particularly in large HCC (p < 0.0001). At univariate analysis, high AFP (p < 0.0001), HBsAg positivity (p = 0.05), p53 mutation (p = 0.0004), liver cirrhosis (p = 0.0094), large tumor (p = 0.0003), vascular invasion (p < 0.0001) and early recurrence (p < 0.0001) were significant unfavorable prognostic factors. In Cox proportional hazards regression analysis, high AFP remained a borderline significance (OR = 1.2; CI = 1.0–1.4) after adjustment for the effect of tumor size and tumor stage (p = 0.0821). Furthermore, the detection of AFP mRNA in the liver of AFP mRNA‐positive HCC was associated with more frequent early recurrence (p = 0.0026) and might be a useful marker of intrahepatic spread. We therefore conclude that AFP elevation, more than a coincidental epiphenomenon, appears to contribute to vascular invasion and HCC progression and help to identify subsets of HCC patients with increased risk for early recurrence and poor prognosis after hepatectomy.

Overexpression of osteopontin is associated with intrahepatic metastasis, early recurrence, and poorer prognosis of surgically resected hepatocellular carcinoma

Intrahepatic metastasis via portal vein spread is an important feature and a crucial unfavorable prognostic factor of hepatocellular carcinoma (HCC). To identify the molecular factors for tumor progression, the authors used differential display (DD) to analyze aberrant gene expression in HCC. The goal of the current study was to elucidate the clinicopathologic and prognostic significance of osteopontin (OPN) in HCC progression.

Early detection of hepatocellular carcinoma by real-time ultrasonography. A prospective study

For early detection of hepatocellular carcinoma (HCC), real‐time ultrasonography (US) was performed prospectively in 528 patients, including 236 with cirrhosis, 81 with chronic hepatitis, 168 asymptomatic hepatitis B surface antigen carriers, and 43 with a family history of HCC. Simultaneous measurement of serum alpha‐fetoprotein (AFP) level was also done. In addition, 233 patients had regular controls at 3‐ to 6‐month intervals, with an average follow‐up period of 1.4 years. On initial screening, a total of 17 patients were found to have HCC: 13 in the cirrhotic group, 3 in the HCC family group, and 1 in the asymptomatic carriers. Of these HCCs, 7 were smaller than 3 cm, 6 were between 3 to 5 cm, and 4 were larger than 5 cm. In patients with tumors smaller than 5 cm, the AFP levels were normal in 46.2%, between 20 to 400 ng/ml in another 46.2%, and only 7.6% were over 400 ng/ml. On follow‐up, another seven patients, all in the cirrhotic group, were found to have HCCs varying from 1.6 to 4.7 cm; three of them had normal serum AFP level. The authors conclude that real‐time US is more sensitive than AFP assay in early detection of HCC, and the high‐risk subjects should receive this procedure at regular intervals.

Estimation of Seroprevalence of Hepatitis B Virus and Hepatitis C Virus in Taiwan from a Large-scale Survey of Free Hepatitis Screening Participants

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 > or = 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.

Percutaneous Ethanol Injection Versus Surgical Resection for the Treatment of Small Hepatocellular Carcinoma: A Prospective Study

Objective:To compare disease recurrence and survival among patients with small hepatocellular carcinoma after surgical resection or percutaneous ethanol injection therapy, 2 treatments that have not been evaluated with a prospective study. Methods:A total of 76 patients were randomly assigned to 2 groups based on treatment; all had one or 2 tumors with diameter ≤3 cm, with hepatitis without cirrhosis or Child class A or B cirrhosis without evident ascites or bleeding tendency. Results:Follow-up ranged from 12 to 59 months. Among percutaneous injection patients, 18 had recurrence 1 to 37 months after treatment (true recurrence, 11; original safety margin inadequate, 3; limitation of imaging technology to detect tiny tumors, 4). Three injection therapy patients died of cancer 25, 37, and 57 months after treatment. For the surgical resection group, 15 had recurrence 2 to 54 months after treatment (true recurrence, 12; limitation of imaging, 2; neck metastasis, 1). Five resection patients died of cancer at 11, 20, 23, 26, and 52 months, respectively. By Cox regression model and Kaplan-Meier survival analysis, there is no statistical significance for recurrence and survival between treatment groups. However, tumor size larger than 2 cm and alpha-fetoprotein over 200 ng/mL correlated with higher recurrence rate, and Child class B liver cirrhosis correlated with shorter survival. Conclusions:Percutaneous ethanol injection therapy appears to be as safe and effective as resection, and both treatments can be considered first-line options for small hepatocellular carcinoma.

Serum α-Fetoprotein in the Early Stage of Human Hepatocellular Carcinoma

The serum alpha-fetoprotein levels of 17 patients with cancers less than or equal to 3 cm in size were studied using radioimmunoassay to determine alpha-fetoprotein response in the early stage of human hepatocellular carcinoma. The levels were normal in 6 patients (35%), and elevated to 645 +/- 1140 micrograms/L (mean +/- SD) in the remaining patients. The levels were not correlated with tumor size. In 10 surgically resected patients, 5 had elevated levels of alpha-fetoprotein that returned to normal after surgery. The levels and tumor sizes were serially observed for 3-26 mo in the remaining 7 patients not surgically treated. In 1 patient alpha-fetoprotein levels were persistently normal and in the other 6 patients, the levels tended to increase with a median doubling time of 60-75 days (range 30-223 days). Despite continued tumor growth, a spontaneous fall in serum alpha-fetoprotein levels was encountered in 4 patients; in 2 patients the levels even fell within the normal range. After this fall, the levels increased drastically in 4 patients. We concluded that in the early stage of hepatocellular carcinoma, serum alpha-fetoprotein level is frequently normal, and thus determination of serum alpha-fetoprotein levels only is not a reliable indicator in the early detection of human hepatocellular carcinoma. A spontaneous fall in the level of alpha-fetoprotein is not an uncommon finding in the early stages of this cancer and cannot be used to rule out the diagnosis of hepatocellular carcinoma.

Genetic alterations in gastric cancer: relation to histological subtypes, tumor stage, and Helicobacter pylori infection

BACKGROUND & AIMS A different spectrum of genetic changes including p53, c-erbB-2, c-met, adenomatous polyposis coli (APC), and deleted in colorectal cancer (DCC) is involved in gastric cancer (GC). The aim of this study was to correlate these alterations with histological subtypes, tumor stages, and Helicobacter pylori infection. METHODS Specimens of 163 patients with GC were immunostained for p53, c-erbB-2, and c-met, and polymerase chain reaction was performed in them to determine loss of heterozygosity (LOH) of APC and DCC. RESULTS Overexpression of p53 was more frequent in early intestinal than early diffuse GC and was noted in the stage progression of diffuse but not intestinal GC. Overexpression of c-erbB-2 occurred more commonly in intestinal GC and advanced GC of both types. Overexpression of c-met was greater in diffuse GC, particularly at advanced stage. LOH of APC was more common in intestinal GC irrespective of the stage but rarely in diffuse GC. LOH of DCC occurred primarily in advanced intestinal GC and infrequently in early GC or advanced diffuse GC. Alterations of these five genes were not correlated with H. pylori infection. CONCLUSIONS A distinct genetic pathway exists in gastric carcinogenesis of different histological subtypes and their tumor progression, in which H. pylori infection may play an equal role or no role.

Hepatitis C and B viruses in hepatitis B Surface antigen-negative hepatocellular carcinoma

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.

Ultrasound-guided cutting biopsy for the diagnosis of hepatocellular carcinoma — a study based on 420 patients

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.