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IntroductionUp-to-date statistics on prostate cancer incidence and causative risk factors are essential for the primary prevention of this disease. However, the incidence of Prostate cancer (ICD-10 code C61) (PCa), or cancers in general, are poorly documented in Eritrea. This study analyses the data available to produce an estimate of the incidence of PCa in Eritrea.MethodsWe conducted a retrospective study by identifying all incident cases of PCa captured between 2011-2018 in the National Health Laboratory pathology database (Polytech 8.37.C); Urology departments of Orotta Referral Hospital and Sembel Hospital. Crude incidence rates (CIRs), age-adjusted rates per 100,000 person years and associated trends were subsequently calculated. Joinpoint Regression Program, V.4.5.0.1 was employed in these analyses.ResultsA total of 1721 cases were reported, of which 1593 (92.5%) were benign prostatic hypertrophy cases and 128 (7.5%) were PCa cases. The mean (±SD) age of the patients with PCa was 73.49 (± 8.9), confidence interval (CI) (54-98) and the minimum and maximum ages were 54 and 98, respectively. The median age interquartile ranges (IQR) was 73 (13) years. The highest and lowest PCa incidence rates were in 2017 (4.51 per 100 000) and 2014 (2.69 per 100 000), respectively. The age standardised rates (ASIR) (World) over the study period (2011-2018) was 30.26 per 100 000. The annualized ASIR values over the study period was 3.78 per 100 000. The associated average annual percentage change (APC) (CI) over the study period was 5.4 (-1.4-12.7), P-value = 0.100, showing a static trend over the study period.ConclusionThis study suggests that previous reports have under-estimated the incidence of PCa in Eritrea. The study provides ample evidence on the need for research targeted at uncovering the true burden of PCa in Eritrea. Potential solutions will require the establishment of high-quality population-based cancer registries (PBCRs) and long-term commitment to improvements in research, training, screening, diagnosis, and the overall management of PCa in the country.

We aimed to reassess renal amyloidosis in kidney biopsies with a focus on possibly misclassified or unclassified cases and changes in the prevalence of different amyloid types. Two hundred thirty-three kidney biopsies obtained from 231 patients diagnosed with amyloid during the period from 1990 to 2007 years were included in this retrospective study. Amyloid was identified by Congo red staining and polarization microscopy. Immunohistochemical classification was made with antibodies directed against AA amyloid, apolipoprotein A1, fibrinogen, lysozyme, lambda-light chain, kappa-light chain, beta2-microglobulin, transthyretin, and amyloid P-component. Amyloid was present in each biopsy as vascular, tubulo-interstitial and/or glomerular deposits. Immunoglobulin light chain-derived (AL) amyloidosis was most prevalent and diagnosed in 123 (53.2%) patients. It was categorized into AL amyloid of lambda-light chain (ALlambda) [105 (85.4%) patients] and kappa-light chain origin (ALkappa) [10 (8.1%)]. The amyloid deposits of 8 (6.5%) patients were not clearly distinguishable into ALlambda amyloid or ALkappa amyloid and categorized as AL amyloid, not otherwise specified. Reactive systemic amyloid A (AA) amyloidosis was the second most common type and was found in 93 patients (40.3%). Overall 7 patients were found to suffer from fibrinogen A alpha-chain-[amyloid of fibrinogen (AFib); 4 (1.7%) patients], transthyretin-[amyloid of transthyretin (ATTR); 2 (0.9%)], or apolipoprotein A1-derived (AApoAI) amyloidosis [1 (0.4%)]. In 8 patients (3.4%) the amyloid deposits remained unclassifiable. After additional immunostaining and further clinical information the diagnoses of 12 patients (5.1%) were modified (2 ALlambda amyloid, 4 ALkappa amyloid, 1 amyloid unclassified, 3 mixed-type amyloidosis, AA+ATTR, ALlambda+ATTR, and ALkappa+ATTR, 1 AFib, and 1 AApoAI). Although the histologic and immunohistochemical reevaluation confirmed the classifications in 221 (95.7%) patients. Renal amyloidosis is most commonly of ALlambda-origin, followed by AA amyloidosis. AFib amyloidosis was found to be the most prevalent type of hereditary renal amyloidosis, illustrating the necessity of a thorough classification of the amyloid proteins.

Rarely, zoonotic Taenia species other than Taenia solium cause human cysticercosis. The larval stages are morphologically often indistinguishable. We therefore investigated 12 samples of suspected human cysticercosis cases at the molecular level and surprisingly identified one Taenia crassiceps and one Taenia serialis (coenurosis) infection, which were caused by tapeworm larvae normally infecting rodents and sheep via eggs released from foxes and dogs.

Nasopharyngeal carcinoma (NPC) belongs to the most common malignant tumours in certain parts of the world, e.g. South-East Asia. The undifferentiated type of NPC is associated with genomic Epstein-Barr virus (EBV) DNA. In normal epithelia of the nasopharynx cytokeratins (CK) 4, 5, 6, 13, 14, 15 and 19 are expressed. The aim of this study was to analyse the expression pattern of cytokeratins in NPC in the presence of EBV infection. Twenty primary or metastatic tumours from 13 patients suffering from a NPC were evaluated (formalin-fixed, paraffin-embedded). (35)S-labelled probes were used to detect EBV DNA in the tissue sections. Fourteen specimens (70%) were EBV positive. All positive specimens were undifferentiated NPC. All NPC were identified with broad-spectrum anti-CK antibody. Using a panel of anti-CK antibodies, there was no specific CK-expression pattern in NPC. In summary, undifferentiated NPC are strongly associated with EBV. The cytoskeleton of undifferentiated NPC reveals no specific pattern of CK expression.

The purpose of this study was to evaluate the diagnostic efficacy of iron-oxide-enhanced MRI vs CT during arterial portography (CTAP) and intraoperative ultrasound (IOUS) in detection of liver neoplasms. Seventeen patients with malignant focal liver lesions (liver metastases, n=7), hepatocellular carcinomas (HCC, n=9), and cholangiocellular carcinoma (CCC, n=1) underwent presurgical Resovist-enhanced MRI and CTAP. Two independent observers (A and B) assessed the blinded images of unenhanced and iron-oxide-enhanced MRI vs CTAP for the presence, number, and location of the liver lesions. These results were compared lesion by lesion and segment by segment with the results of intraoperative ultrasound ( n=17) serving as the reference standard. Eighty lesions were detected by intraoperative ultrasound in 17 patients. In comparison with IOUS (lesion-by-lesion analysis) the sensitivity was 86.8% for CTAP, 65% for combined unenhanced MR imaging, and 86.8% for combined Resovist-enhanced MRI as well as 86.8% for the combination of unenhanced and Resovist-enhanced MRI. Compared with the sensitivity of combined unenhanced MRI the sensitivity of CTAP as well as the sensitivity of combined Resovist-enhanced MRI was significantly higher (p

Mutagenesis of the p53 tumor-suppressor gene represents the most common genetic alteration in human malignancies but has not yet been investigated in Klatskin tumors. Cancerous and normal liver tissues were obtained from 12 patients after surgical resection of Klatsin tumors. Genomic DNA was extracted and served as a template for PCR amplification and sequencing of a 1,574-bp fragment of the p53 gene comprising the exons 5 through 8. Immunohistochemical expression analysis was performed using five different antibodies. Missense mutations were detected in 2 of 12 patients--one transversion on codon 273 (Arg --> Leu) and a transition on codon 168 (His --> Arg). In all specimens, immunohistochemistry was negative regarding a nuclear overexpression. An apparent clinicopathologic impact of p53 mutations was not observed. This report on mutagenesis of the p53 gene in Klatskin tumors shows that the most commonly mutated tumor suppressor gene in human cancers is also mutated in a subset of patients with Klatskin tumors. Assessment of a clinical or pathological impact of p53 mutagenesis on Klatskin tumors requires evaluation in larger studies.

Background. Recurrence of hepatitis C viremia after orthotopic liver transplantation (OLT) is nearly universal, leading to variable outcome from no to severe recurrent disease. In the present study, the prognostic relevance of hepatitis C virus (HCV) genotypes and viremia for the development and severity of graft hepatitis was investigated. Methods. A total of 79 patients with chronic hepatitis C who could be followed for 1 to 78 months (mean: 30 months) after OLT were included in this study. HCV RNA concentrations were measured before OLT, 1 month after OLT, as well as in the long-term follow-up after OLT in 54 of the 79 patients. Results. Graft hepatitis could be documented in 40 of the 79 patients (51%), and 7 of them (9%) progressed to liver cirrhosis. More severe forms of graft hepatitis predominated in patients with subtype 1b infection, and all seven patients with progression to liver cirrhosis had subtype 1b (P5NS). Neither the pretransplant nor the posttransplant HCV RNA levels were significantly associated with the occurrence of graft hepatitis. However, there was a trend of more severe recurrent disease in subtype 1b-infected patients with high level viremia in the early course after OLT. Conclusions. Pretransplant HCV virological markers are not helpful to predict the outcome after OLT. However, it should be further investigated whether estimation of HCV genotype and viremia levels very early after OLT, i.e., within the first weeks, may be a better approach to recognize high-risk patients. Orthotopic liver transplantation (OLT*) has become a wellestablished treatment for end-stage liver diseases with excellent results for short-term survival, with a 30-day mortality of 3% at our center. The recurrence of the liver disease is now one of the most important problems in liver transplantation. Patients chronically infected with hepatitis C virus (HCV) before OLT will suffer graft reinfection in nearly all cases, and graft hepatitis of mild to moderate activity will occur in about 50 ‐70% (1‐5). However, in some patients, HCV reinfection induces a progressive disease leading to graft failure even within 1 year (6, 7). The mechanisms responsible for these different outcomes are still unclear. HCV genotype and hepatitis C viremia may influence the clinical course. In particular, an association between genotype 1b and manifestation of severe recurrent hepatitis C could be observed, and it was suggested that genotype 1b may play a major role in this respect (8, 9). Furthermore, the relevance of the hepatitis C viremia level for the development of graft hepatitis has also been discussed, but it seems that the evaluation of the preOLT HCV RNA concentration is of little help in this respect (10 ‐12).

RATIONALE AND OBJECTIVES. The authors correlate computed tomography (CT) findings in biphasic spiral technique with histopathology in patients with hepatocellular carcinoma (HCC) who had undergone liver resection (LR) or orthotopic liver transplantation (OLT). METHODS. Preoperative biphasic spiral CT findings in 33 consecutive patients (23 men, 10 women, aged 43-74 years; LR group: n = 17; OLT group; n = 16) with liver cirrhosis and HCC were reviewed retrospectively by consensus of two radiologists and correlated with pathology from liver specimens. RESULTS. Of the 16 patients in the OLT group with 1 to 5 confirmed HCC lesions (total lesions: 29; mean lesion diameter: 2 cm; range: 0.6-5.0 cm), CT before OLT depicted 22 lesions in 15 patients (sensitivity for lesions with a diameter of 0.5-1.0 cm, 20%; for lesions 1.1-2.0 cm, 82%; and for lesions 2.1-3.0 cm and >3.0 cm, 86% and 100%, respectively). Among the 17 patients in the LR group (total lesions: 21; mean lesion diameter: 5.4 cm; range: 1.0-11.0 cm), CT detected 18 lesions. Lesion-by-lesion sensitivity, as correlated with pathology, was calculated at 76% and 86% in the OLT and LR groups, respectively (overall sensitivity, 80%). The diameter of CT detected lesions, compared with liver specimens, corresponded in 90% of lesions (maximum deviation, 15%). Characteristic CT findings of HCC included unenhanced hypoattenuating focal liver lesions (32 lesions), with hyperattenuation (38 lesions) in the arterial phase of contrast material administration. CONCLUSIONS. Biphasic spiral CT for preoperative HCC detection correlated with pathology in 80%, thus proving this technique to represent a sensitive imaging modality for pretherapeutic evaluation of HCC.

p53 tumor suppressor gene, have been focusing on this gene’s immunohistochemical detection. From November 1991 to October 1993, seven patients suffering from gallbladder carcinoma underwent surgical resection. Cancerous and normal liver tissues were obtained immediately after surgery, snap-frozen in liquid nitrogen, and stored at −80°C for immunohistochemistry and DNA isolation. Exons 5, 6, 7, and 8 of the p53 gene were completely sequenced following polymerase chain reaction (PCR) amplification of a 1574-bp fragment. Missense mutations were detected in the cancerous tissues of two patients: one transition each on codons 134 (Phe→Leu) and 146 (Trp→Arg). Immunohistochemical p53 staining was positive in the latter patient only. This is the first report on sequence analysis and mutagenesis of the p53 gene in Caucasian patients with gallbladder cancer. Both mutations were transitions and seem to represent a rather rare event. The possible impact of p53 mutagenesis on gallbladder tumorigenesis requires evaluation in larger studies.

Background. Quadruple immunosuppressive induction therapy has been shown to markedly reduce the incidence of acute rejection episodes without increasing the incidence of infectious complications after liver transplantation. However, the use of polyclonal antibody preparations (e.g. antithymocyte globulin [ATG]) is associated with side effects such as fever and tachycardia. To evaluate the efficacy and the safety of a monoclonal antibody directed against the interleukin-2 receptor (BT563) in comparison with ATG as part of a quadruple induction regimen, a prospective, randomized study was conducted. Methods. Eighty consecutive adult recipients of primary orthotopic liver transplants were randomized to receive either BT563 (10 mg/day; days 0-12; n=39) or ATG (5 mg/kg/day; days 0-6; n=41) in addition to the standard immunosuppressive protocol consisting of cyclosporine, and prednisolone, and azathioprine. Results. Patients treated with BT563 had a significantly lower incidence of steroid-sensitive rejection episodes (3 vs. 11; P

Background. There is a limited amount of data regarding the estrogen receptor (ER) and progesterone receptor (PgR) status of hepatocellular carcinomas (HCCs), and the relationship between receptor status and clinicopathologic features of tumors has not been reported. Methods. Between April 1992 and December 1993, cancerous tissues for cytosolic preparation and receptor quantification in a monoclonal solid-phase enzyme immunoassay were obtained from 28 patients undergoing resection, three patients with total hepatectomy and subsequent liver transplantation, and two patients suffering from nonresectable HCC. Results. ER and PgR were detected in the HCCs of 13 (39%) and 6 patients (18%), respectively. A lower age was observed among the female patients whose receptor status was negative for ER or PgR or both, as compared with the respective receptor-positive groups. No significant differences with respect to tumor stage and grading could be observed. There was one perioperative death (3%). In patients undergoing curative resection, 1-year survival in the ER(+) group was significantly lower than in the ER(−) group (40% versus 79%, p < 0.05). The 2-year survival rates in the ER(+) and ER(−) groups were 40% and 71%, respectively. A comparable trend did not become evident for PgR(+) and PgR(−) patients. Conclusions. Our data suggest a negative effect of an ER(+) tumor on patient survival after curative resection of advanced HCC.

Prior to the FK506 era, OKT3 was primarily used for treatment of steroid-resistant rejection. Initially FK506 has been used as a last treatment of refractory acute or chronic rejection. We provide strong evidence that the use of FK506 is more successful if rescue therapy is performed early instead of using it as the last resort. Between September 1988 and March 1995 a total of 600 liver transplantations were performed in 550 patients. Of these 550 patients, 426 received primarily cyclosporine A (CsA)-based immunosuppression. Of the 426 CsA patients, 70 (16.4%) required either FK506 (51.4%), or OKT3 rescue therapy (27.1%), or a combination of the two drugs (21.5%). The latter group of patients received first OKT3 and then FK506 rescue when OKT3 therapy failed. Treatment was initiated simultaneously (within 1 week) in 11 patients, and 4 patients received FK506 rescue later during the course of rejection. The highest success rates (88.9%) were observed in patients given FK506 rescue therapy. Retransplantation was necessary more often in patients receiving OKT3 than in those with FK506 rescue therapy (15.8% versus 5.5%, respectively). Retransplantation and death due to chronic rejection increased with the need for additional FK506 rescue therapy after OKT3 failure. This increase was most pronounced in patients receiving FK506 during the late course of rejection, reaching a failure rate of 75.0% (50. 0% of deaths were due to chronic rejection). The lowest incidence of cytomegalovirus infection and of infectious, neurologic, and renal complications was observed in the FK506 rescue group. We conclude that early FK506 rescue therapy may be the treatment of choice for acute steroid-resistant rejection.

Ziel: Die Zielsetzung der Studie umfast die Analyse der hochauflosenden endorektalen MRT zur pratherapeutischen Diagnostik und Verlaufskontrolle in Korrelation mit der Histopathologie. Material und Methode: Die Wertigkeit dieser neuen Methode wurde bei insgesamt 10 Probanden und 29 Patienten mit Verdacht auf Neoplasien des Rektums bestimmt. An einem 1,5-T-Magnetom wurden alle Untersuchungen mittels einer Endorektalspule unter Anwendung von T2-gewichteten Turbo-Spin-Echo-Sequenzen nativ und T1 -gewichteten- und Turbo-FLASH-Sequenzen vor und nach Applikation von Gd-DTPA (0,1 mmol/kgKG) durchgefuhrt. Bei 17 Patienten mit Rektumkarzinomen sowie bei 12 Patienten mit Rektumadenomen konnte das praoperativ erhobene Tumorstadium mit dem histologischen Ergebnis vorglichen werden. Bei 4 Patienten mit Adenomen wurde die MRT-Endorektalspule vor und nach endoskopischer Elektro-Laserresektion zur Verlaufs- und Therapiekontrolle eingesetzt. Ergebnisse: Die Detauerkennbarkeit der anatomischen Strukturen im Bereich des Rektums war mit Hilfe der Endorektalspule verbessert. Das praoperative Staging mittels endorektaler MRT im Vergleich zur Histologie stimmte bei 15 von 17 Karzinomen und 10 von 12 Adenomen uberein (diagnostische Treffsicherheit: 85 %). Perirektale Lymphknoten konnten bis zu einer Grose ≥3 mm sicher erkannt werden. Die vollstandige Abtragung von Adenomen (n = 4) durch eine endoskopische Elektro-Laserresektion konnte durch die endorektale MRT in allen Fallen verifiziert werden. Schlusfolgerung: Die hochauflosende, endorektale MRT ist eine vielversprechende Methode zur praoperativen Diagnostik rektaler Lasionen und eignet sich zur Verlaufs- und Therapiekontrolle bei Rektumadenomen. Purpose: To assess the value of high-resolution MRI of the rectum using an endorectal coil. Methods: 10 volunteers and in 31 patients with suspected rectal tumors were examined. In 17 patients (n = 17) with rectal carcinoma, of which 15 subsequently underwent radical surgery, the preoperatively obtained tumor stage was compared with histology. In 12 patients (n = 12) with rectal adenoma (severe and medium graded epithelial dysplasias according to the WHO) who underwent endoscopy the results of the endorectal surface coil examination were compared with endoscopy and histology. In 4 patients (n = 4) with large rectal adenomas the surface coil was used before and as follow-up after endoscopic electro laser resection and the absence of adenoma after therapy also in the deeper layers of the rectal wall could be confirmed. Results: Visualization of anatomical structures of rectum and adjacent structures is improved by the use of the endorectal surface coil. The diagnosis of carcinoma and adenoma of the rectum and the documentation of the exact extension can be reached with high accuracy (85 %). Conclusion: MRI with an endorectal surface coil may play an important role in the preoperative diagnosis of rectal carcinoma. This method is useful for primary diagnosis and follow-up of large rectal adenoma after endoscopic electro laser resection.

We have reviewed our experience with conversion to tacrolimus after 435 liver transplantations. Tacrolimus was administered as a rescue agent in 33 patients until October 1993. Indications for rescue therapy were: cholestatic forms of severe, steroid-resistant cellular rejection (n = 8), OKT3-resistant cellular rejections (n = 6), cellular rejections in patients suffering from cyclosporin malabsorption (n = 4), late onset cellular rejections (n = 4), early chronic rejections (n = 3), and chronic vascular or ductopenic rejections (n = 8). Response was evident in 29 of the 33 patients (88%), whereas 4 patients (12%) were nonresponsive. Patient and graft survival were 76% and 70%, respectively. Graft loss with or without patient death occurred in three of eight patients suffering from severe, steroid-resistant cellular rejection, in two of six patients with OKT3-resistant cellular rejections, and in five of eight patients undergoing chronic rejection. In severe steroid-resistant cellular rejection, successful tacrolimus rescue therapy corresponded to a significantly lower total serum bilirubin than unsuccessful therapy (12.0 +/- 5.6 mg% vs 29.7 +/- 5.9 mg%, P0.05). We conclude that tacrolimus rescue therapy is a safe and efficient alternative for high-risk cases that do not respond to conservative treatment. In severe, steroid-resistant cellular rejection and in chronic ductopenic rejection, conversion to tacrolimus is beneficial only in a limited number of cases. A predictive parameter, which total serum bilirubin may prove to be in severe, steroid-resistant cellular rejection, is needed to select those cases that might benefit more from retransplantation than from conversion to tacrolimus.

The outcome after OLT was studied in 53 patients with chronic hepatitis B virus (HBV)* infection, 15 of whom had, in addition, evidence of hepatitis delta virus (HDV) superinfection. Nine of 53 patients received short-term immunoprophylaxis with anti-hepatitis B surface (HBs) hyperimmunoglobulin up to 1 week after OLT and 44 of 53 patients received long-term unlimited immunoprophylaxis. Eight of 9 (89%) patients with short-term immunoprophylaxis showed reactivation of replication with HBV DNA in serum10 pg/ml independently of the preoperative HBV DNA level and HBsAg reappeared in all cases. Four (44%) patients in this group lost their graft because of fulminant hepatitis or cirrhosis and required retransplantation, and 2 patients (22%) died after reinfection in the second graft. Nineteen of 44 (43%) patients with long-term immunoprophylaxis developed HBV values10 pg/ml after transplant and 12 of 44 (27%) became HBsAg+ again. Most of them had quantifiable HBV DNA levels before OLT. Retransplantation was required in 5 of 44 (11%) patients and 4 of them died after HBV recurrence. The frequency of HBV reactivation and the development of viral hepatitis after OLT were associated with the preoperative presence of HBV, as determined by the molecular hybridization assay. With nested polymerase chain reaction, all 53 patients were HBV-DNA+ in the serum before and after OLT. with just one exception, none of the patients with HDV superinfection died, in spite of increased HDV replication after OLT. The data indicate that long-term immunoprophylaxis with anti-HBs hyperimmunoglobulin after OLT improves the prognosis in HBV-infected patients. The preoperative detection of HBV DNA in serum by molecular hybridization assay is correlated with graft infection and represents a prognostic parameter. The presence of HDV may have a protective effect after OLT.

Pathogenetic pathways of gastrointestinal stromal tumors (GIST) lacking mutations in KIT and PDGFRA (similar to 15%) are still poorly studied. Nearly nothing is known about PI3K alterations in GISTs and only a few GISTs with BRAF mutations have been reported. BRAF mutations (V600E) were found in 3/87 tumors (3.5%) concomitantly were wild type for KIT and PDGFRA. No mutations were detected in KRA.S, NRAS, and FGFR3. For the first-time we demonstrated a PIK3CA mutation (H1047L) simultaneously occurring with a 15-bp deletion in KIT exon 11 in one tumor. We suggest that BRAF mutations are of pathogenetic significance in wild type GISTs. The PI3K pathway should be assessed in future studies. (C) 2011 Elsevier Ireland Ltd. All rights reserved.

Treatment with monoclonal IL-2 receptor antibodies has been successfully used for immunosuppressive induction therapy following organ transplantation in the recent past. The present study was conducted to compare for the first time a cyclosporine-based quadruple immunosuppressive regimen including a monoclonal IL-2 receptor antibody or ATG as induction therapy after orthotopic liver transplantation. In two groups of 33 patients each, postoperative survival, graft biopsies, liver function enzymes, and the clinical courses after OLT were evaluated. Our results indicate that monoclonal IL-2 receptor antibody therapy as part of a quadruple immunosuppressive regimen is better tolerated and is at least as effective as ATG in prevention of allograft rejection following OLT. Furthermore, our data indicate that a slightly better liver function in general and a lower incidence of rejection reactions necessitating treatment could be observed in the group of patients treated with the monoclonal IL-2 receptor antibody. This study provides evidence that monoclonal IL-2 receptor antibody therapy may be a useful tool for the immunosuppressive induction therapy following clinical orthotopic liver transplantation.

From September 1988 to May 1991, 160 orthotopic liver transplantations were performed in our hospital. Twenty-four patients had end-stage cirrhosis caused by chronic non-A, non-B hepatitis. Antibodies against hepatitis C virus were documented before and after orthotopic liver transplantation in 13 patients. Studies using the polymerase chain reaction demonstrated hepatitis C virus RNA in the serum and liver tissue of 17 patients (10 of whom tested positive for hepatitis C virus antibodies) before orthotopic liver transplantation. Tissue samples taken from liver grafts during the operation were hepatitis C virus RNA negative in every case. Ten of these 17 patients had positive hepatitis C virus RNA findings in serum and liver biopsy specimens within the first month after surgery. One patient died of Mucor sepsis 2 mo after orthotopic liver transplantation. Another patient died of multiorgan failure 3 mo after a retransplantation. Two patients underwent retransplantation for graft rejection at 2 and 3 mo, respectively. One year after orthotopic liver transplantation, hepatitis C virus RNA was demonstrated in allograft biopsy specimens in 13 of 15 patients. Two patients remained hepatitis C virus RNA negative in repeated biopsies up to 12 mo. Mild portal and lobular hepatitis developed within 6 months of orthotopic liver transplantation in four patients and within 1 yr in five additional patients. The data suggest that persistent hepatitis C virus reinfects the allograft in most cases, but the risk of acute organ damage caused by hepatitis C virus reinfection is low. (HEPATOLOGY 1992;16:1137–1143.)

Mutations in codon 12, 13 or 61 of one of the three ras genes, Ha-ras, Ki-ras, and N-ras, convert these genes into active oncogenes. To determine the role mutated ras genes play in the carcinogenesis of renal cell carcinoma, we analysed tumour DNA and unaffected renal tissue derived from 55 patients. The polymerase chain reaction technique was used to amplify DNA fragments containing Ki-, Ha-, and N-ras codons 12, 13, and 61. The amplified fragments were then probed on slot-blots with labeled mutation-specific oligomers. A single Ki-ras mutation (codon 12, gly- greater than val) was detected in a patient with a pT2N2M1 tumour. We concluded that ras oncogene mutations do not play an important role in the initiation of renal cell carcinoma.

Eradication of Helicobacter pylori usually consists of a 7-day course of triple therapy including metronidazole or amoxicillin plus clarithromycin plus a proton pump inhibitor. We report about a rare adverse event of Hp eradication in a patient with moderate chronic and moderate active pangastritis. Shortly after the end of treatment cholestatic hepatitis occurred which was most likely related to clarithromycin, perhaps enhanced by amoxicillin. Since liver dysfunction was self-limited, no further treatment was required. In summary, clinicians should be aware about the presented rare adverse event of Helicobacter pylori eradication treatment for a close monitoring of those patients and rapid management of acute liver failure.

Liver transplantation for advanced hepatocellular carcinoma is often followed by early tumour recurrence and death. At the beginning of the liver transplantation programme at Berlin Virchow we decided to offer liver transplantation only to patients with solitary tumours not exceeding a maximum diameter of 5 cm or to patients with two or three tumour nodes with a maximum diameter of 4 cm. From September 1988 to October 1993 435 liver transplants were performed in 403 patients. Of these, 32 patients (8%) had a histologically confirmed hepatocellular carcinoma (29 males, 3 females, median age 56 years). The overall actuarial survival according to Kaplan-Meier for the whole series of 32 patients with hepatocellular carcinoma was 82%, 78%, and 78% at 1, 2 and 3 years, respectively. Tumour size alone did not seem to be a relevant factor when comparing patients with tumours up to or larger than 3 cm in diameter. Patients with solitary tumours had a better prognosis than patients with multiple tumours. The largest difference was found between patients with stage I-III (UICC) tumours and those with stage IVA tumours: 1-, 2- and 3-year survival rates were 89% throughout in the former group, while the corresponding figures for patients with stage IVA tumours were 63%, 47% and 47%. Efforts should be made to identify stage IVA tumours preoperatively in order to use the precious resource of scarce donor livers in an optimal way.

BACKGROUND Sound information is lacking about the clinical presentation of cryptogenic cirrhosis and its outcome after orthotopic liver transplantation (OLT). METHODS Among 856 patients who have been transplanted at our center, 40 patients had no evidence of any known etiologies and were therefore defined as suffering from cryptogenic cirrhosis. Their median follow-up period before OLT was 78 months (range, 1-264), and after OLT 97 months (range, 1-132). Laboratory and histological data were evaluated according to features being compatible either with a toxic, hepatitic, or cholestatic condition. RESULTS The clinical and histological findings differed specifically between these three groups. The toxic-like group (GGT 4-18 x upper limit of normal [ULN]) expressed significantly higher IgA levels, had histologically more often fatty liver changes, and risk factors for non-alcoholic steatohepatitis predominated (56% compared with 3% in the other groups, P=0.01). The hepatitic-like group (ALT 2-18 x ULN) showed histologically features of chronic hepatitis or hepatitic cirrhosis, and only among these patients a median International Autoimmune Hepatitis (IAH) score of 13 was found suggesting autoimmune hepatitis (AiH). In the cholestatic group (AP 2-8 x ULN) histology was compatible with a non-toxic inflammatory process but IAH score excluded AiH in all. After OLT, actuarial graft and patients survival was 90% at 5 years. Mild or moderate graft hepatitis occurred in 9 patients (23%) and was significantly associated with a pre-OLT IAH score >or= 10 (P =0.008). CONCLUSIONS This study provides arguments that cryptogenic cirrhosis is a heterogeneous disease in which autoimmune mechanisms might be predominately involved and being responsible for recurrence of chronic liver disease observed in some instances after OLT.

Hereditary hemorrhagic teleangiectasia, or M. Osler (Osler-Weber-Rendu disease), is an autosomal dominant, systemic fibrovascular dysplasia. This may lead to increased liver blood flow from arteriovenous fistulas. A 45-year-old woman with a known M. Osler was admitted for liver transplantation. On admission, exertional dyspnea was the predominant symptom. Radiological investigations revealed multiple intrahepatic arteriovenous fistulas and consecutive high-output heart failure. Laboratory findings revealed remarkably elevated bilirubin and alkaline phosphatase. To alleviate the high-output cardiac failure, the hepatic artery was ligated. Fourteen months later, the patient presented again with increased levels of bilirubin and recurrent bleeding episodes from esophageal varices grade IV. The patient underwent liver transplantation and post-transplant recovery was excellent. A hyperdynamic circulatory state due to a hepatic M. Osler has been treated in several cases by ligation or embolization of the hepatic artery. This procedure, however, is recommended only for patients with normal liver function and carries a considerable risk of bile duct necrosis.

Recurrence-free survival (RFS) in patients with small hepatocellular carcinoma (HCC) after orthotopic liver transplantation (OLT) was analyzed. From 1988 until 1996, 725 OLTs were performed in 669 patients. In 52 adults, HCC was confirmed histologically. OLT was limited to patients with small (< 5 cm) HCC with a maximum number of three nodules. Actuarial survival for these 52 patients at 1 and 5 years is 88 % and 71 %. RFS was defined as time until death without recurrence, time until follow up with a diagnosis of recurrence, or, in patients without recurrence, time of last follow up. Overall, the 5-year RFS was 60 %. Five-year RFS was less for bilobar compared to unilobar tumors (36 % vs 70 %), less for stage IVa tumors (UICC) compared to stage I–III tumors (17 % vs 71 %), and less for multiple compared to solitary tumors (54 % vs 67 %). In conclusion, potential cure may be achieved in more than 50 % of all transplanted patients.

Derzeit sind weltweit ca. 300 Dunndarmtransplantationen durchgefuhrt worden mit 1-Jahres Patienten-Uberlebensraten von uber 90% in einigen Zentren. Problematisch ist jedoch nach wie vor die hohe Immunogenitat des Dunndarmes. In diesem Zusammenhang konzentrieren sich verschiedene Untersuchungen auf die Reduktion des Reperfusionsschadens, um die damit verbundene Aktivierung der spezifischen Immunantwort sowie das Risiko fruh-postoperativer Abstosungen zu vermindern [1].

F K 506 is a potent immunosuppressive agent for prevention and reversal of acute steroid-resistant and early chronic rejection following liver transplantation.‘,’ We and others1-4 have reported a decreased incidence of chronic rejection in FK 506-treated patients. However, there is still a small group of FK 506-treated patients who will develop acute steroid-resistant or early chronic rejection. In fact, chronic rejection has been reported to be responsible for at least 20% of graft failures following liver transplantation.5 FK 506 has been shown very effective for suppression of T-cell-mediated immune response, but less effective in suppressing the humoral B-cell-mediated response. Therefore, the combination of FK 506 with a B-cell suppressive immunosuppressant like mycofenolate mofetil (MMF) may be of advantage. In the present study, we analyzed the outcome of patients developing acute steroid-resistant and chronic rejection with respect to the kind of rescue treatment.

Hepatitis B virus (HBV) infection of the liver graft is a major complication after orthotopic liver transplantation (OLT) for HBV-related cirrhosis. A high viral load before OLT is a known risk factor, whereas the relevance of precore mutants of HBV is a subject of controversy. The aim of this study was to correlate the pretransplantation viral load and a pretransplantation infection with precore mutant HBV (pmHBV) or wildtype HBV (wtHBV) with allograft damage, graft failure, and survival after OLT. Sixty-nine patients with HBV cirrhosis underwent OLT under high dose immunoprophylaxis with anti-hepatitis B surface (HBs) hyperimmunoglobulins (HBIg). A pretransplantation infection with pmHBV and wtHBV was detected by polymerase chain reaction (PCR) and direct sequencing in 30 patients each (pmHBV and wtHBV group). Nine of 69 patients were PCR-negative (noHBV group). Median pretransplantation levels of HBV DNA assessed by hybridization assay were 42 pg/mL for pmHBV and 54 pg/mL for wtHBV patients. HBV recurred in 17 of 30 (57%) of pmHBV and in 14 of 30 (47%) of wtHBV patients and graft failure occurred in 6 of 30 (20%) of pmHBV and 7 of 30 (23%) of wtHBV patients. Neither HBV recurrence nor graft failure occurred in patients in whom no HBV DNA could be detected by PCR using primers flanking the HBV precore region (noHBV) patients. Allograft damage assessed by histology activity index (HAI) scoring was median 6 for pmHBV and 7 for wtHBV patients. Cumulative survival after 5 years was 72% for pmHBV, 74% for wtHBV, and 100% for noHBV patients. In this study, we provide evidence that pretransplantation viral load, but not infection with pmHBV, determines the outcome after OLT in patients on high dose HBIg prophylaxis.

Background/Aims: The hepatitis C virus genotypes have been shown to be differently distributed between distinct geographical areas and to be associated with different clinical presentations. In the present study we investigated the distribution of HCV genotypes in 379 Germany patients with chronic hepatitis C in relation to age, sex, route of infection, liver histology and viremia. Methods: Typing of HCV was done using restriction fragment length polymorphism analysis as well as a DNA enzyme immunoassay. HCV RNA concentrations were determined by quantitative polymerase chain reaction. Liver biopsies were performed in 187 patients and the histological activity was graded by the Knodell score. Results: Seventy percent were infected with genotype 1 (20% subtype 1a, 80% subtype 1b), 4% with genotype 2 and 26% with genotype 3 (all subtype 3a). Genotype 3a and 1a infection was significantly associated with intravenous drug abuse. In contrast, genotype 1 predominated in patients with post-transfusion hepatitis and infection of unknown origin. A changing relative prevalence of HCV genotypes in relation to age was also observed. Patients with genotype 3 infection showed significantly lower HCV RNA levels and a lower mean histological activity score as compared to patients with genotype 1 and genotype 2. However, using multivariate analysis, only age and mode of transmission but not histological activity score were shown to be independent variables. Conclusions: Our study confirms previous reports from other countries that HCV variants can be classified into a relatively small number of discrete genotypes, and that the subtype 1b clearly predominates. However, we found evidence that there is a changing relative prevalence of HCV genotypes in relation to age, and that the mode of transmission is reflected in the predominance of certain genotypes.

Obwohl durch die zunehmende Erfahrung der letzten Jahrzehnte die orthotope Lebertransplantation heute eine anerkannte Standardmethode zur Behandlung terminaler Lebererkrankungen darstellt und in erfahrenen Zentren 1-Jahres-Uberlebensraten von 90% erreicht werden, wird die Wahl der immunsuppressiven Induktionstherapie noch kontrovers diskutiert [1]. Durch die Addition einer poliklonalen anti-Thymozytenpraparation (ATG) konnten Kalayoglu und Mitarbeiter die Inzidenz von Abstosungsreaktionen mindern ohne die Anzahl von Infektionen zu erhohen [2]. Unsere eigenen Erfahrungen mit dieser Vierfach-Induktionstherapie bestatigten die guten Ergebnisse, allerdings werden beim Einsatz von ATG Nebenwirkungen, wie Tachykardie, Hypertension, Fieber, Ubelkeit und Erbrechen beobachtet [3, 4].

Zur Expression von Rezeptoren weiblicher Geschlechtshormone in hepatozellularen Karzinomen sowie ihrer klinischen Bedeutung sind kaum Daten bekannt [1]. Hinweise auf mogliche endokrine Mechanismen der Wachstumskontrolle hepatozellularer Karzinome wurden durch einen signifikanten Uberlebensvorteil nicht-resektabler hepatozellularer Karzinome unter antihormoneller Therapie mit Tamoxifen gegeben [2].

The pathogenesis of hepatitis C virus (HCV) infection is likely to be associated with viral replication in vivo, but little is known concerning the dynamics of HCV turnover. We performed serial measurements of serum HCV-RNA levels following orthotopic liver transplantation (OLT) in nine patients with HCV-positive cirrhosis. Serum HCV-RNA levels were determined by quantitative polymerase chain reaction before, immediately after, and for up to 1 month after OLT. There was a rapid decline in HCV-RNA levels from 3.1 +/- 1.3 x 105 copies/ mL (mean +/- SEM) preoperatively to 0.15 +/- 0.6 x 105 copies/mL on the first and 0.16 +/- 0.6 x 105 copies/mL on the second postoperative day (mean viral half-life, 4.0 +/- 0.5 h). Thereafter, HCV-RNA levels increased in all but one patient, and by postoperative day 8 reached 3.6 +/- 1.3 x 105 copies/mL, exceeding the preoperative levels irrespective of the use or not of rescue immunosuppressive therapy including steroid bolus administration. In most patients, serum virions continued to increase averaging 11.6 +/- 2.8 x 105 copies/mL on the 30th postoperative day. These findings indicate that the half- life of HCV is quite short, and that extrahepatic viral replication contributes little to the total virus pool in serum. Furthermore, the marked HCV replication beginning as early as the third postoperative day strongly suggests that the liver graft is rapidly reinfected by HCV after OLT. (Hepatology 1996 Dec;24(6):1351-4)

Despite improvements in immunosuppression, rejection occurs in 50% of liver transplant patients and may cause significant morbidity. The most frequent cause of death after liver transplantation is severe infection. Determination of the cytokine network may lead to earlier detection of patients at risk for severe rejection and infection. For this purpose, 81 patients with 85 liver transplants were monitored for cytokines and neopterin on a daily basis. During the first postoperative month, 28 patients (34.6%) developed acute rejection; 14 patients were successfully treated with methylprednisolone (steroid-sensitive rejection), while 14 patients required additional treatment with FK506 and OKT3 (steroid-resistant rejection). Ten patients developed severe infections, and 11 patients experienced asymptomatic cholangitis. Patients with an uneventful postoperative course (n=37) were the control group. One-year patient survival was 88.9%: 1 patient died because of chronic rejection and Pseudomonas urosepsis; a further 4 patients died of aspergillus pneumonia and bacterial sepsis. Soluble TNF-RII, sIL-2R-, and IL-10 levels were significantly elevated 3 days prior to or at the onset of acute steroid-resistant rejection (P < or = 0.01 versus steroid-sensitive rejection and on uneventful postoperative course). An increase in IL-8, neopterin, and sTNF-RII was indicative of severe infection 3 days prior to onset of infection. In this group of patients, a simultaneous increase in IL-10 indicated a lethal outcome of severe infection. During the second week of acute steroid-resistant rejection and lethal infection, a significant rise in IL-1beta, IFN-gamma, and IL-6 was observed (P < or = 0.01 versus control groups). The different patterns in neopterin- and cytokine-increase could differentiate between severe rejection and severe infection. Furthermore, the increase in these parameters indicated severe rejection--i.e., steroid resistance at the onset of acute rejection--which could prompt us to initiate rescue therapy immediately. The ability to detect patients at risk for severe or lethal infection may result in intensified infectious screening and more aggressive antiinfectious treatment. Therefore, routine monitoring of these parameters may lead to changes in therapeutic management of severe acute rejection and infection after liver transplantation.

Background/Aims: Patients with chronic hepatitis C are often coinfected with the new identified Flaviviridae-like agent, termed hepatitis G virus (HGV). The aim of the study was to investigate the responsiveness of hepatitis G virus to interferon alpha and to evaluate whether a hepatitis G virus coinfection negatively influences the outcome of treatment in chronic hepatitis C. Methods: One hundred and fifteen patients with histologically proven chronic hepatitis C were treated with interferon alpha and investigated for the presence of hepatitis G virus coinfection by nested polymerase chain reaction with primers from the helicase region of hepatitis G virus. All patients received at least 3 MU (range 3–6) interferon alpha thrice weekly for at least 6 months (mean 8, range 6–12). Polymerase chain reaction products of seven pre- and post-treatment hepatitis G virus positive patients were directly sequenced for identification of sequence variability during the follow-up. Results: Eighteen (16%) patients were coinfected with hepatitis G virus. Although nine (50%) of these patients became HGV RNA negative during interferon alpha therapy, only three patients (17%) remained HGV RNA negative at the end of follow-up (mean 24 months). The rate of sustained response of chronic hepatitis C was not significantly different between patients with hepatitis C virus infection and HCV/HGV coinfection (19% vs 28%). Severity of liver disease as determined by alanine aminotransferase levels, histology and hepatitis C virus viremia was not significantly different in patients with hepatitis C virus or HCV/HGV coinfection. Sequence analysis of the helicase region revealed that our isolates all belonged to the hepatitis G virus and not to the GBV-C like genotype. No amino acid exchanges during the observation period of up to 48 months were observed, indicating that this region is highly conserved. Conclusions: The responsiveness of hepatitis G virus to interferon alpha in chronic HCV/HGV coinfected patients is similar to that observed in chronic hepatitis C. Hepatitis G virus coinfection seems not to interfere with the efficacy of interferon alpha treatment in patients with chronic hepatitis C.

Primary biliary cirrhosis (PBC) represents a classic indication for orthotopic liver transplantation (OLT); as an autoimmune disease, however, the existence and incidence of recurrent PBC is a matter of significant controversy. Between September 1988 and September 1994 a total of 544 OLTs was performed at our institution. Forty-nine patients (40 female) with a median age of 50.5 years and previous surgery in 36.4%, received a liver graft for PBC. The mean serum bilirubin level was 8.9 mg/dl (range 0.7–29.7). Immunosuppression was commenced as a cyclosporine Abased quadruple therapy or with FK 506 and prednisolone. Protocol liver biopsies were taken at defined intervals posttransplant. Two patients died due to Legionella pneumonia and hypoxic brain damage 2 and 8 weeks after OLT, resulting in an actuarial 5-year survival rate of 95% with 47/49 patients being alive compared to 83.5% of all other liver recipients. Evidence of recurrence of PBC, as defined by elevated cholestatic parameters and histological features of PBC, was found in four patients, another five patients showed only histological signs. Recurrence of PBC, which might compromise the long-term outcome after OLT, was suspected in 4/47 patients (8.5%). This evidence of recurrent PBC is in conflict with findings of other groups that did not report recurrent PBC. OLT is still the optimal therapy for advanced PBC, with an excellent prognosis.

We report a symptomatic multicystic seminal vesicle with ipsilateral renal agenesis in a 37-year-old man. Preoperatively the diagnosis could be suggested by different imaging modalities, including endorectal surface coil magnetic resonance imaging. To our knowledge, we present the 1 st case of seminal vesicle cyst to be evaluated by magnetic resonance imaging using a rectal coil. The value of different imaging modalities is discussed.

Die effektive Verhutung akuter, zellularer Abstosungsreaktionen ist eine wesentliche Voraussetzung des Erfolgs der Organtransplantation. Interleukin-2 (IL-2) kommt eine zentrale Rolle bei der Abstosungsreaktion zu, indem es nach Antigenprasentation in aktivierten T-Zellen zur IL-2 Produktion, vermehrter Expression des IL-2 Rezeptors auf der Zelloberflache und im Sinne eines positiven ”feedback” Mechanismus zu weiterer Zellproliferation, IL-2 Produktion und Expression des IL-2 Rezeptors kommt. Eine Reihe verschiedener monoklonaler Antikorper gegen den IL-2 Rezeptor (IL2r-mAK) zur Verhutung dieses Mechanismus wurden in den letzten Jahren entwickelt und klinisch eingesetzt [1, 3]. BT563, ein muriner IL2 vom Isotyp IgG1-k wurde erstmals von Otto u. Mitarb. nach Lebertransplantation eingesetzt [4] und hatte sich in der eigenen Erfahrung im historischen Vergleich mit ATG-Therapie als mindestens gleich effektiv bei deutlich verbesserter Vertraglichkeit erwiesen [5]. Im Rahmen einer prospektiv randomisierten Studie wurde die Effizienz und Vertraglichkeit eines IL2r-mAK mit einem polyklonalen Antithymozytenglobulin (ATG) in der Induktionstherapie nach Lebertransplantation verglichen.

A 54-year-old male patient with end-stage liver failure from Budd-Chiari syndrome due to paroxysmal nocturnal hemoglobinuria (PNH) underwent liver transplantation (OLT) in 1989. Retransplantation became necessary 1 year later when thrombotic occlusion of the portal vein and common hepatic artery led to graft loss after withdrawal of anticoagulation therapy because of several gastrointestinal bleeding episodes. The patient is now alive 3 years after the first OLT. To the best of our knowledge and according to the literature, this is, to date, the longest that any PNH patient has survived after liver transplantation. Although the course of this patient was complicated in a way similar to that reported for other cases in the literature, patients with PNH should not, in principle, be excluded from liver transplantation. Lifelong anticoagulation with coumarin and the use of steroids together with cyclosporin reduce the risk of recurrent thrombosis and PNH crises.