Joerg S. Bleck

Hepatocellular telomere shortening correlates with chromosomal instability and the development of human hepatoma

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 patients 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.)

COACH syndrome associated with multifocal liver tumors

Here, we describe a 20-yr-old woman with COACH syndome (hypoplasia of Cerebellar vermis, Oligophrenia, congenital Ataxia, Coloboma, and Hepatic fibrosis) developing multiple liver lesions. Epigastric and right upper abdominal pain and lack of appetite led to clinical evaluation. Liver function tests showed an increase in transaminases and cholestatic parameters; α-fetoprotein was in the normal range. Ultrasound and magnetic resonance imaging examinations revealed multiple liver lesions. Histological examinations of ultrasonographically guided biopsies were consistent with regenerative hepatic nodules without features of malignant or dysplastic cells. The sizes of these tumors did not change over a period of 12 months. Our report presents the 10th case of COACH syndrome with a hitherto undescribed association with hepatic tumors.

Popliteal Artery Embolism in Abdominal Aortal Thrombus with Liver Abscesses Caused by Heterozygous Prothrombin Mutation with Protein S Deficiency and Factor VIII Elevation

We report on a 64-year-old woman who was admitted to a peripheral hospital with known cholecystolithiasis complicated by acute abdominal pain. Her past medical history included pulmonary embolism and deep vein thrombosis (DVT) 3 years ago, arterial hypertension and obesity. The following day, laparoscopic cholecystectomy was performed because of gallbladder hydrops. Postoperatively, she complained of progressive right-sided abdominal pain. A CT scan was performed 2 weeks postoperatively showing multiple hepatic and splenic abscesses as well as rightsided thoracic effusion. Furthermore, an extensive aortal thrombus of about 10 cm above the coeliac trunc was visible without radiological signs of dissection or infection. Intravenous therapeutical heparinization was started aiming at an anti Xa level of around 0.6 U/ml. During the following days, further CT scans revealed progressive liver necrosis, and severe impairment of liver function developed necessitating transfer to ICU. The patient was transferred to our hospital and directly admitted to the intensive care unit on day 42. She presented in poor general condition with confusion, severe dyspnea and sepsis without signs of shock. Biochemistry showed signs of systemic infection (leucocytosis of 62000/μl, C-reactive protein of 230 mg/l), a disturbed liver function with signs of hepatocellular necrosis (prothrombin time 50%, cholinesterase 2.4 kU/l, AST 750 U/l) and impaired respiratory parameters (blood gas analysis under oxygen administration of 8 l/min: pO2 63, pH 7.46, lactate 3.4 mmol/l). Imaging procedures (ultrasound, CT scan) confirmed the aortal thrombus, extensive hepatic and splenic abscesses and a right-sided thoracic empyema as well as basal pneumonia. Immediate therapy with a total of three percutaneous thoracic and hepatic abscess drainages was initiated under ultrasound-guidance. In addition to other germs (Enterococcus faecalis, Candida spp.), a multiresistant strain (Enterobacter cloacae) was detected in cultures taken from the drainages. Therefore, quadruple antibiotic therapy was administered. The hepatic drainages rested in place (with several changes) for several months. Internal drainage by a stent placed by ERCP was ineffective, the stent had to be removed by a second ERCP. During these months, several problems complicated the clinical course (relapse of thoracic empyema necessitating repeated thoracic drainage, severe episodes of arterial hypertension, recurrent AV-reentry tachycardia, repeated vomiting, symptomatic transitory psychotic syndrome).

Induction of aneuploidy by increasing chromosomal instability during dedifferentiation of hepatocellular carcinoma

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 < or = 0.0002). Four HCC G1 had constant chromosome patterns for chromosomes 1 and/or 8 with a mean of signals per nucleus < or =5.08 and < or =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 > or =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.

Artifact Resistant Gray Scale Windows in Clinical Ultrasound of the Liver

Perception of complex structures independent from viewing angle and distance demonstrates the superiority of the human eye compared to every computed system. Thus qualitative image improvement can only try to improve information presentation of images offered to the retinal receptor-cortex system. In ultrasound images obtained from the subcostal view of the liver the parenchyma consists of a range of 80–100 gray levels. The human eye being capable of differentiating up to 35 gray levels in moving images1 looses offered information content to a great extend.