Andreas Donner

Treatment of chronic hepatitis delta with pegylated interferon‐α2b

Abstract: Background/Aims: Chronic hepatitis D is difficult to treat. The present pilot study investigated the efficacy and tolerability of pegylated (PEG)‐interferon (IFN)‐α2b in chronic hepatitis D.

HFE mutations and chronic hepatitis C: H63D and C282Y heterozygosity are independent risk factors for liver fibrosis and cirrhosis

BACKGROUND/AIMS The impact of heterozygous HFE mutations on the course of chronic hepatitis C and iron indices was studied. METHODS Ferritin, transferrin saturation (TS), serum iron, C282Y and H63D mutations were determined in 401 patients with chronic hepatitis C virus (HCV) infection and 295 healthy controls. Liver histologies were available in 217 and HCV genotypes in 339 patients. RESULTS Allele frequencies of the C282Y and H63D mutation did not differ between HCV patients and healthy controls (6.95 vs. 6.2%; 14.75 vs. 16.4%; n.s.). HFE heterozygous HCV patients had higher ferritin (349+/-37 vs. 193+/-15 microg/l; P<0.0005), TS (38+/-2 vs. 32+/-1%; P<0.0005), serum iron (144+/-6 vs. 121+/-3 microg/dl; P<0.0005), semiquantitative liver iron staining (0.26+/-0.07 vs. 0.09+/-0.03; P<0.006) and fibrosis scores (1.9+/-0.2 vs. 1.4+/-0.1; P<0.003) compared to HFE wildtypes. By multivariate regression analysis odds ratios for liver cirrhosis were 5.9 (confidence interval (CI) 1.6-22.6; P<0.009) for C282Y heterozygotes and 2.9 (CI 1.0-8.4; P<0.05) for H63D heterozygotes compared to HFE wildtypes. Considering all HFE heterozygous HCV patients, odds ratios of 3.6 (CI 1.4-9.3; P<0.009) for cirrhosis and 3.1 (CI 1.3-7.3; P<0.009) for fibrosis were calculated. CONCLUSIONS C282Y or H63D heterozygosity is an independent risk factor for liver fibrosis and cirrhosis in HCV infected individuals. Screening for HFE mutations should be considered in HCV infection.

Histopathology of the gastroesophageal junction: a study on 36 operation specimens.

The entire gastroesophageal junction of 36 patients who had been operated for squamous cell carcinoma of the upper or middle esophagus was examined. Hematoxylin and eosin-stained slides were evaluated by two pathologists for the following histologic details: minimal and maximal length of cardiac mucosa (CM) and oxyntocardiac mucosa (OCM, mixture of cardiac and fundic glands), degree of inflammation in CM and OCM, and presence of intestinal metaplasia or pancreatic metaplasia. Sections of gastric corpus mucosa were evaluated for the presence of gastritis and Helicobacter pylori infection; sections of esophageal squamous epithelium were evaluated for the presence of reflux esophagitis. CM was present in the entire circumference of the gastroesophageal junction in 20 cases, in parts of the circumference in 15 cases, and entirely absent in one case. The maximal length per case ranged between 1 and 15 mm (median 5 mm). OCM was circumferentially present in 22 cases and partially present in 14 cases. The maximal length ranged between 2 and 24 mm (median 7 mm). Locations of CM/OCM over submucosal esophageal glands or squamous epithelium-lined ducts, both indicating a location in the esophagus, were found in eight cases (22%) and in four cases (11%), respectively. In 18 cases (50%) intestinal metaplasia was present in CM/OCM; pancreatic metaplasia was found in 22 cases (61%). A statistically not significant trend for increase of minimal length of CM, OCM, and the sum of both was found in the presence of gastroesophageal reflux disease. Neither the presence of intestinal metaplasia nor of pancreatic metaplasia in CM/OCM was correlated with gastroesophageal reflux disease. In conclusion, the high variability in length, the frequent occurrence of intestinal metaplasia and pancreatic metaplasia, and the frequent extension into the esophagus suggest that CM/OCM is a dynamic structure that probably mirrors the influence of underlying gastroesophageal diseases. Because of the short length and incomplete circumferential extension of CM/OCM, future endoscopic–bioptic investigations will probably have to be based on more extensive sampling of the gastroesophageal junction.

Allelic Loss Involving the Tumor Suppressor Genes APC and MCC and Expression of the APC Protein in the Development of Dysplasia and Carcinoma in Barrett Esophagus

Samples of Barrett metaplastic specialized epithelium (SE), low-grade dysplasia (LGD), high-grade dysplasia (HGD), and invasive adenocarcinoma (CA) derived from 36 esophagectomy specimens were studied for loss of heterozygosity (LOH) in APC and MCC and for expression of APC protein. Of 18 cases that were heterozygous (informative) for APC, LOH was found in none of 14 SE samples, 2 of 8 LGD samples, 3 of 11 HGD samples, and 5 of 17 CA samples. Immunohistochemically, markedly reduced expression of APC protein (< 50% positive cells) was found in 3 of 19 HGD samples and 4 of 35 CA samples but not in SE or LGD samples. Of 17 cases informative for the MCC gene, LOH was detectable in 1 of 14 SE samples, none of 7 LGD samples, none of 9 HGD samples, and 4 of 16 CA samples. Allelic loss of APC and/or loss of APC protein expression occurs earlier in the metaplasia-dysplasia-carcinoma sequence in Barrett esophagus than LOH in the MCC gene. The determination of alterations at APC or MCC would be of limited importance for the surveillance of patients with Barrett esophagus.

In vitro invasiveness of human epithelioid‐sarcoma cell lines: Association with cell motility and inverse correlation with the expression of tissue inhibitor of metalloproteinases

Epithelioid sarcoma (ES) is a very aggressive soft‐tissue tumor in vivo, but no experimental data on its invasive and metastatic behavior have been reported. In the present study, 3 different clonal sub‐populations (GRU‐1A, GRU‐1B and GRU‐1C), derived from the same human ES cell line, GRU‐1, were investigated for in vitro invasiveness in relation to migration, adhesion and the expression of different invasion‐ and metastasis‐related genes. Tumor spheroids of GRU‐1A were markedly more invasive in the chick‐heart invasion assay (CHIA) than spheroids of GRU‐1B and GRU‐1C. These results were paralleled by a significantly higher cell motility of GRU‐1A than GRU‐1B and GRU‐1C (p < 0.05) on distinct substrates, suggesting that the observed differences in invasion result at least in part from differences in motility. When invasion was assayed with suspended tumor cells in the Matrigel assay, differences between the 3 cell lines were much more pronounced than in the CHIA, where cell‐cell contacts are established. These results indicate that interclonal differences in ES invasion result mainly from differences in motility, but also partly depend on differences in cell‐cell adhesion. On the molecular level, low invasive potential was associated with over‐expression of distinct tissue inhibitor of metalloproteinases (TIMPs) relative to matrix metalloproteinase‐2 and ‐9. However, no association was found between invasion and the expression of CD44 splicing variants or nm23 isoforms. Our results suggest that differences in invasion between GRU‐1A, GRU‐1B and GRU‐1C are caused mainly by interclonal differences in migration, and might result from differences in the expression of distinct TIMPs. Int. J. Cancer 80:406–412, 1999.

Combination Treatment of IFNα2b and Ribavirin in Patients with Chronic Hepatitis C and Persistently Normal ALTs

Combination therapy of interferon-α2b and ribavirin was prospectively evaluated in 20 patients with chronic replicative hepatitis and persistently normal ALTs. Patients with normal ALTs on three or more occasions within 6 months received interferon-α2b 3 MU three times a week with ribavirin 1000–1200 mg everyday for 12 months and had a follow-up of 6 months. HCV genotype 1 was found in 16, and HCV genotype 2 or 3 in 4 patients. No patient experienced an ALT elevation during therapy. Ten of 20 patients (50%) cleared virus at the end of treatment. In an intent-to-treat analysis, a sustained virological response (SR) was achieved in 8 of 20 patients (40%). Nonresponse occurred in 5 patients. Relapse and breakthrough were seen in 2 patients each. Treatment was discontinued in 3 patients due to side effects. Interferon (IFN) ribavirin combination therapy is effective in patients with normal ALTs and appears superior to IFN monotherapy.

Kasabach-Merritt-Syndrom bei Riesenhämangiom der LeberEin Fallbericht

ZusammenfassungDas Kasabach-Merritt-Syndrom (KMS) ist eine seltene Störung der Blutgerinnung, die durch eine Verbrauchskoagulopathie bei Gefäßfehlbildungen hervorgerufen wird. Wir berichten hier den Fall einer 44-jährigen Patientin, die bei mehreren kleinen und mittleren operativen Eingriffen trotz normaler Messwerte in den Suchtests der plasmatischen Gerinnung jeweils schwere Blutungskomplikationen erlitten hatte. Erst nachdem ein Riesenhämangiom der Leber durch andere klinische Erscheinungen symptomatisch geworden war, konnte die Diagnose gestellt werden. Nachdem durch präoperative i.v.-Heparinisierung die Aktivierung der Gerinnung gestoppt war, konnte die Patientin ohne Probleme durch Hemihepatektomie rechts kurativ behandelt werden.AbstractKasabach-Merritt-syndrome is rare coagulation disorder with consumption coagulopathy caused by vascular malformations. We report the case of a 44-year-old woman with repeated severe bleeding complications after small and medium sized operations with normal results in the tests of plasmatic coagulation. After discovery of a giant hemangioma of the liver the diagnosis was established. Activation of coagulation was stopped preoperatively by i.v.-heparinization and curative treatment by right-sided hemihepatectomy followed.

Kontrastmittelsonographie der Leber als wegweisende Untersuchung für die Therapieplanung des hepatozellulären Karzinoms

Zusammenfassung.Vorgestellt wird der Fall einer 65-jährigen Patientin mit chronischer Hepatitis C, bei der in der B-Bild-Sonographie eine solitäre Raumforderung < 3 cm im rechten Leberlappen diagnostiziert wurde, welche sich in der histopathologischen Untersuchung des Biopsats als gering differenziertes hepatozelluläres Karzinom (HCC; G3) darstellte. Bei der im Rahmen des Tumorstagings durchgeführten Computertomographie (CT) und der Resovist-Magnetresonanztomographie (MRT) ergab sich in Übereinstimmung mit der B-Bild-Sonographie ein solitärer HCC-Knoten ohne Anhalt für weitere fokale Leberläsionen. Ergänzend erfolgte eine Untersuchung mit dem Ultraschallkontrastmittel Levovist® unter Einsatz der Phaseninversionssonographie in der Spätphase. Aufgrund dieser Kontrastmittelsonographie ließen sich zusätzlich multiple Tumorareale im rechten Leberlappen nachweisen, welche weder im CT noch im Resovist-MRT darstellbar waren. Dieser Kontrastmittelbefund des multifokalen HCC war von therapieentscheidender Bedeutung, da dadurch rechtzeitig erkannt werden konnte, dass aufgrund des multifokalen Befunds eine Lebertransplantation kontraindiziert war. Im Gegensatz dazu wäre die Lebertransplantation bei einem solitären HCC < 3 cm die Therapie der Wahl gewesen. Stattdessen erfolgte eine Hemihepatektomie rechts. Bei der histopathologischen Untersuchung des Leberresektats bestätigte sich der Kontrastmittelbefund des multifokalen HCC.Abstract.In a 65-year-old female patient, B-mode sonography detected a single focal lesion in the right liver lobe with a diameter < 3 cm. Histopathologic examination revealed a low differentiated hepatocellular carcinoma (HCC; G3). Tumor staging was performed by CT (computed tomography) scan and Resovist MRI (magnetic resonance imaging). Both examinations found a single liver lesion without signs of additional focal hepatic lesions. In addition, phase-inversion sonography in the late phase was performed using the ultrasound contrast agent Levovist. This examination of late-phase Levovist uptake detected more than five additional focal hepatic lesions in the right liver lobe, which were invisible by CT scan and Resovist MRI. This finding of multiloculated HCC was very important to decide on the patient’s correct therapy. While liver transplantation is the treatment of choice in single HCC < 3 cm, it is contraindicated in multicentric HCC. In the patient described here, hemihepatectomy of the right liver lobe was performed. The histopathologic examination of the resected liver confirmed the diagnosis of multicentric HCC, which was noninvasively diagnosed only by contrast-enhanced sonography, but not by CT scan or MRI.

Kontrastmittelsonographie der Leber als wegweisende Untersuchung für die Therapieplanung des hepatozellulären Karzinoms*@@@Contrast-Enhanced Sonography Using Levovist is Decisive for Staging and Therapeutic Schedule in Hepatocellular Carcinoma

Zusammenfassung.Vorgestellt wird der Fall einer 65-jährigen Patientin mit chronischer Hepatitis C, bei der in der B-Bild-Sonographie eine solitäre Raumforderung < 3 cm im rechten Leberlappen diagnostiziert wurde, welche sich in der histopathologischen Untersuchung des Biopsats als gering differenziertes hepatozelluläres Karzinom (HCC; G3) darstellte. Bei der im Rahmen des Tumorstagings durchgeführten Computertomographie (CT) und der Resovist-Magnetresonanztomographie (MRT) ergab sich in Übereinstimmung mit der B-Bild-Sonographie ein solitärer HCC-Knoten ohne Anhalt für weitere fokale Leberläsionen. Ergänzend erfolgte eine Untersuchung mit dem Ultraschallkontrastmittel Levovist® unter Einsatz der Phaseninversionssonographie in der Spätphase. Aufgrund dieser Kontrastmittelsonographie ließen sich zusätzlich multiple Tumorareale im rechten Leberlappen nachweisen, welche weder im CT noch im Resovist-MRT darstellbar waren. Dieser Kontrastmittelbefund des multifokalen HCC war von therapieentscheidender Bedeutung, da dadurch rechtzeitig erkannt werden konnte, dass aufgrund des multifokalen Befunds eine Lebertransplantation kontraindiziert war. Im Gegensatz dazu wäre die Lebertransplantation bei einem solitären HCC < 3 cm die Therapie der Wahl gewesen. Stattdessen erfolgte eine Hemihepatektomie rechts. Bei der histopathologischen Untersuchung des Leberresektats bestätigte sich der Kontrastmittelbefund des multifokalen HCC.Abstract.In a 65-year-old female patient, B-mode sonography detected a single focal lesion in the right liver lobe with a diameter < 3 cm. Histopathologic examination revealed a low differentiated hepatocellular carcinoma (HCC; G3). Tumor staging was performed by CT (computed tomography) scan and Resovist MRI (magnetic resonance imaging). Both examinations found a single liver lesion without signs of additional focal hepatic lesions. In addition, phase-inversion sonography in the late phase was performed using the ultrasound contrast agent Levovist. This examination of late-phase Levovist uptake detected more than five additional focal hepatic lesions in the right liver lobe, which were invisible by CT scan and Resovist MRI. This finding of multiloculated HCC was very important to decide on the patient’s correct therapy. While liver transplantation is the treatment of choice in single HCC < 3 cm, it is contraindicated in multicentric HCC. In the patient described here, hemihepatectomy of the right liver lobe was performed. The histopathologic examination of the resected liver confirmed the diagnosis of multicentric HCC, which was noninvasively diagnosed only by contrast-enhanced sonography, but not by CT scan or MRI.