No abstract

Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide. However, treatment options are limited and often inefficient. The aim of this study was to determine current survival rates for patients diagnosed with HCC and to identify prognostic factors, which will help in choosing optimal therapies for individual patients. A retrospective analysis of medical records was performed on 389 patients who were identified through the central tumour registry at our institution from 1998 to 2003. Clinical parameters, treatments received and survival curves from time of diagnosis were analysed. Overall median survival was 11 months. Liver cirrhosis was diagnosed in 80.5% of all patients. A total of 170 patients received transarterial chemoembolisation (TACE) and/or percutaneous ethanol injections (PEI) with a median survival rate of 16 months for patients receiving TACE, 11 months for patients receiving PEI and 24 months for patients receiving TACE followed by PEI. Independent negative prognostic parameters for survival were the presence of portal vein thrombosis, advanced liver cirrhosis (Child -Pugh score B or C) and a score of 42. This study will help to estimate survival rates for patients with HCC according to their clinical status at diagnosis and the treatments received.

The telomere hypothesis of cancer initiation indicates that telomere shortening initiates cancer by induction of chromosomal instability. To test whether this hypothesis applies to human hepatocellular carcinoma (HCC), we analyzed the telomere length of hepatocytes in cytological smears of fine-needle biopsies of liver tumors from patients with cirrhosis (n ‫؍‬ 39). The tumors consisted of 24 HCC and 15 regenerative nodules as diagnosed by combined histological and cytological diagnostics. In addition, we analyzed the telomere length of hepatocytes in HCC and surrounding noncancerous liver tissue within individual patients in another cohort of 10 patients with cirrhosis. Telomere length analysis of hepatocytes was correlated with tumor pathology and ploidy grade of the tumors, which was analyzed by cytophotometry. Telomeres were significantly shortened in hepatocytes of HCC compared to hepatocytes in regenerative nodules or surrounding noncancerous liver tissue. Hepatocyte telomere shortening in HCC was independent of the patient's age. There was no overlap in mean telomere lengths of individual samples when comparing HCC with regenerative nodules or noncancerous surrounding liver. Within the HCC group, telomeres were significantly shorter in hepatocytes of aneuploid tumors compared to diploid tumors. In conclusion, our data suggest that the telomere hypothesis of cancer initiation applies to human HCC and that cell type-specific telomere length analysis might indicate the risk of HCC development. (HEPATOLOGY 2004;40:80 -86.) L iver cirrhosis is the major risk factor for the development of hepatocellular carcinoma (HCC), and the incidence of HCC in cirrhotic patients is 3% to 6% annually. 1-3 One of the common features of human epithelial cancer is the prevalence of chromosomal instability (CIS). 4 As in other epithelial cancers, HCCs show a high incidence of CIS. 5 A current hypothesis is that telomere shortening and loss of telomere function play a role in the induction of CIS. 6,7 The main function of telomeres is the capping of chromosomal ends. 8 Due to the "end-replication problem" of DNA polymerase, telomeres shorten during each round of cell division. 9 Telomere shortening limits the proliferative capacity of primary human cells to a finite number of cell divisions 10 and appears to restrain the regenerative capacity of tissues and organs in aging and chronic diseases. 7 In the liver, hepatocyte telomere shortening has been linked to cirrhosis formation. 11 When telomeres reach a critically short length, they lose capping function, resulting in chromosomal fusions. 12 When cells with fused chromosomes enter the cell cycle, these fusions will be disrupted during mitosis, resulting in the breakage of chromosomes and chromosomal gains and losses. 13 This phenomenon has been termed the fusion-bridge-breakage cycle and might contribute to the induction of CIS and cancer in the aged. 13 In line with this hypothesis, the initiation of cancer is increased by telomere shortening in telomerase-deficient mice. 1...

To gain more insight into the role of chromosomal instability (CIN), the cytogenetic hallmark of most solid tumors, we performed fluorescence in situ hybridization (FISH) on interphase nuclei of cytological specimens enabling the correct detection of chromosome copies in intact tumor cells of 18 well (G1), moderately (G2), or poorly (G3) differentiated hepatocellular carcinomas (HCCs). A close correlation between the morphological dedifferentiation and increasing copy numbers and variation of FISH signals was seen for chromosomes 1 and 8, respectively (P < 0.0002). Four HCC G1 had constant chromosome patterns for chromosomes 1 and͞or 8 with a mean of signals per nucleus <5.08 and <3 different signal combinations, indicating a low level of CIN, as confirmed by FISH using probes for centromeres of chromosomes 3, 7, and 17. In contrast to this, five HCC G2-3 revealed >8.46 signals per nucleus and 23-41 different signal combinations, indicating high levels of CIN. In the remaining cases, signal counts from 5.96 -8.46 and 7-15 combinations were seen. Here, nuclei with constant aberration patterns and low copy numbers occurred alongside nuclei with inconstant patterns and high copy numbers. It is evident that in these cases a transition from well to moderately differentiated HCC developed in parallel to an increase in CIN, possibly induced by a major dysregulation of mitotic control mechanisms. In conclusion, CIN may induce a stepwise increase of aneuploidy in HCC that is mirrored by the morphological dedifferentiation of tumor cells.

Sinusoidal uptake capacity for hepatocyte or MAA particles varies at a wide range in normal rabbits. Scintigraphic monitoring of transplanted cells allows efficient monitoring of cell translocation into the lungs. No significant impairments of portal hemodynamics and liver function were detected.