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F Geissler

Publications and source records attributed to F Geissler.

At least 19 recordsLinked to original sources
PubMed2005

Prenatal detection of mosaic isochromosome 20q: a fourth report with abnormal phenotype.

We described a new case of mosaic isochromosome 20q revealed by amniocentesis. The propositus presented with craniofacial dysmorphism, clubfeet, and vertebral abnormalities. A 46,XX,i(20)(q10)[14]/46,XX[1] karyotype was confirmed by FISH on cultured cells. The pregnancy was terminated. From review of literature, fetus with mosaic isochromosome 20q identified on amniocentesis are most likely to be phenotypically and cytogenetically normal after birth. So we performed CGH and array-CGH to exclude another possible imbalance. We discuss here the possible relation between this chromosomal abnormality and the abnormal phenotype.

Abnormalities, Multiple↗
PubMed2002

INK4a-ARF alterations in liver cell adenoma.

BACKGROUND: The INK4a-ARF (CDKN2A) locus on chromosome 9p21 encodes two tumour suppressor proteins, p16(INK4a) and p14(ARF), whose functions are inactivated in many human cancers. AIMS: To evaluate p14(ARF) and p16(INK4a) alterations in liver cell adenoma. METHODS: After microdissection, DNA from 25 liver cell adenomas and corresponding normal liver tissue were analysed for INK4-ARF inactivation by DNA sequence analysis, methylation specific polymerase chain reaction, restriction enzyme related-polymerase chain reaction (RE-PCR), mRNA expression, microsatellite analysis, and immunohistochemistry. In addition, microdeletion of p14(ARF) and p16(INK4a) were assessed by differential PCR. RESULTS: Methylation of p14(ARF) was found in 3/25 cases (12%) and alterations in p16(INK4a) occurred in 6/25 liver cell adenomas (24%) which correlated with loss of mRNA transcription. We failed to detect microdeletions or specific mutations of both exons. p16(INK4a) methylation appeared in the context of an unmethylated p14(ARF) promoter in six cases. In normal liver tissue, p14(ARF) or p16(INK4a) alterations were not observed. CONCLUSIONS: Our data suggest that p14(ARF) methylation occurs independently of p16(INK4a) alterations in liver cell adenomas. Furthermore, methylation of p14(ARF) and p16(INK4a) may be a result of cell cycle deregulation and does not seem to be a prerequisite of malignancy.

Adenoma, Liver Cell↗
PubMed2001

INK4a-ARF alterations and p53 mutations in hepatocellular carcinomas.

The INK4a-ARF (CDKN2A)- locus on chromosome 9p21 encodes for two tumour suppressor proteins, p16(INK4a) and p14(ARF), that act as upstream regulators of the Rb-CDK4 and p53 pathways. To study the contribution of each pathway in tumorigenesis of hepatocellular carcinoma (HCC), we analysed the alterations of p14(ARF), p16(INC4a) and p53. After microdissection, DNA of 71 hepatocellular carcinomas was analysed for INK4-ARF inactivation and p53 mutation by DNA sequence analysis, methylation-specific PCR (MSP), restriction-enzyme related polymerase chain reaction (RE-PCR), mRNA expression and immunohistochemistry. In addition, microdeletion of p14(ARF) and p16(INC4a) were assessed by differential PCR. Inactivation of p14(ARF) was found in 11/71 cases (15%), alterations of p16(INK4a) occurred in 47/71 carcinomas (66%), which correlated with loss of mRNA transcription. Five tumours (7%) had homozygous deletions of the INK4a-ARF locus. We failed to detect specific mutations of both exons. P16(INK4a) methylation with an unmethylated p14(ARF) promotor appeared in 39 cases. Mutations of p53 were found in 30 of 71 HCC (42%), and only one of them harboured p14(ARF) inactivation. We failed to establish alterations of the INK4a-ARF locus or p53 status as independent prognostic factor in these tumours. Our data indicate, that p14(ARF) methylation occurs independently of p16(INK4a) alterations in a subset of HCC together with wild type p53. The INK4a-ARF-/p53-pathway was disrupted in 86% of HCC, either by p53 mutations or by INK4a-ARF inactivation, and may have co-operative effects in hepatocarcinogenesis.

Adult↗
PubMed2001

Frequent genomic imbalances suggest commonly altered tumour genes in human hepatocarcinogenesis.

Hepatocellular carcinoma (HCC) is one of the most frequent-occurring malignant tumours worldwide, but molecular changes of tumour DNA, with the exception of viral integrations and p53 mutations, are poorly understood. In order to search for common macro-imbalances of genomic tumour DNA, 21 HCCs and 3 HCC-cell lines were characterized by comparative genomic hybridization (CGH), subsequent database analyses and in selected cases by fluorescence in situ hybridization (FISH). Chromosomal subregions of 1q, 8q, 17q and 20q showed frequent gains of genomic material, while losses were most prevalent in subregions of 4q, 6q, 13q and 16q. Deleted regions encompass tumour suppressor genes, like RB-1 and the cadherin gene cluster, some of them previously identified as potential target genes in HCC development. Several potential growth- or transformation-promoting genes located in chromosomal subregions showed frequent gains of genomic material. The present study provides a basis for further genomic and expression analyses in HCCs and in addition suggests chromosome 4q to carry a so far unidentified tumour suppressor gene relevant for HCC development.

Carcinoma, Hepatocellular↗
PubMed2001

Human liver allograft acceptance and the "tolerance assay": in vitro anti-donor T cell assays show hyporeactivity to donor cells, but unlike DTH, fail to detect linked suppression.

Human allograft acceptance is associated with immune regulation, characterized by donor-antigen-linked suppression of delayed-type hypersensitivity (DTH). We wished to determine if "classical" in vitro assays of alloreactivity could also detect linked suppression and thus be useful in the clinical diagnosis of active immune regulation. We analyzed peripheral blood mononuclear cells from a group of eight liver transplant recipients, one of whom had stopped all immunosuppression 4.5 years ago yet continues to have good graft function (graft acceptor). The regulator phenotype was defined as the ability to suppress a DTH response to a recall antigen in the presence of donor antigen. Using the trans vivo DTH test, we identified four regulators, and four nonregulators. When we tested two of the regulators for in vitro mixed lymphocyte culture (MLC) and cytotoxic T lymphocyte (CTL) responses to B-lymphoblastoid cell lines (B-LCL), we found both patients to be specifically hyporesponsive to donor compared with third-party B-LCL stimulators. However, in contrast to the linked suppression of DTH seen when a given B-LCL expressed donor-type HLA-B antigens, there was no evidence of linked suppression in vitro, either in CTL, proliferative, or interferon-gamma cytokine release assays. The primary CTL hyporesponsiveness to donor B-LCL could not be reversed by neutralizing antibodies to transforming growth factor beta or interleukin-10, which could restore a strong DTH response to donor B-LCL. We conclude that DTH analysis can readily detect donor antigen-linked suppression in liver transplant recipients. CTL and MLC tests failed to do so. These findings may be relevant to the development of a tolerance assay suitable for use in clinical trials.

Antigens↗
PubMed2001

[Surgery for complications of chronic pancreatitis].

At least 50 % of all patients with chronic pancreatitis require surgical treatment in the course of their disease. Indications for surgery are intractable pain, intra- and extrapancreatic complications and the suspicion of a carcinoma. The basic principles of surgery are resection and drainage. The choice of the surgical procedure depends on the morphological expression and the localization of the pathological changes. Regarding resections in the head-area, previous studies demonstrated uniformly the superiority of the duodenum-preserving pancreas head resection (DPPHR) compared to the Kausch-Whipple operation with and without maintenance of the pylorus. Drainage procedures (pain recurrence in 20-40 % in the long-term course) and left pancreatic resections (de-novo diabetes mellitus in up to 45 %) should be considered critically. Between May 1994 and November 2000 117 patients underwent surgical therapy for complications of chronic pancreatitis at our institution. Resections were performed in 68 % of the patients and drainage procedures in 20 %. There was no mortality. Over the years the proportion of the DPPHR increased in comparison to the Kausch-Whipple procedure and the number of the drainage operations decreased continuously. The DPPHR was significantly superior to the Kausch-Whipple procedure with regard to the glucose metabolism and the quality-of-life. In the spectrum of surgical procedures in chronic pancreatitis, the DPPHR represents a modern, organ-preserving procedure for patients with complications in the pancreas head.

Adolescent↗
PubMed2001

Importance of microcirculatory disturbances in the pathogenesis of pancreatitis.

Pancreatic microvascular control is a complex physiological process which is incompletely understood. Blood flow in the pancreas is altered by a large number of endogenous and exogenous factors in the context of acute and chronic pancreatitis. The frequency of progression from acute pancreatitis to a chronic form is a controversial question. In acute pancreatitis reductions in blood flow and alterations of microvascular integrity resulting in impaired tissue oxygenation play an important part in the progression and possibly the initiation of the disease. Endothelin and nitric oxide are believed to be two of the most effective vasoactive mediators. The beneficial effect of therapeutic strategies affecting vasoactive mediators is confirmed in experimental studies. Chronic disease is associated with decreased pancreatic blood flow and histological changes in the vasculature in both patients and animal models. Further studies are needed to clarify whether ischemia in chronic pancreatitis is more important in perpetuating the disease or as primary cause of the inflammatory processes.

Acute Disease↗
PubMed2000

[Treatment concept of adenomas of Vater's ampulla].

INTRODUCTION: The most common benign ampullary tumors are adenomas (80%). They are considered as premalignant lesions with a transformation rate to carcinoma of up to 30%. METHODS: From 1 January 1997 to 28 February 1999 we treated 11 patients with adenoma of the ampulla of Vater. An ampullectomy was performed in 10 cases. One poor-risk patient could not be operated on. RESULTS: No operative mortality occurred. In two patients a pT1 adenocarcinoma was diagnosed postoperatively. One of the two patients with a high-risk carcinoma underwent a second operation, a Whipple pancreatoduodenectomy. Nine of 10 patients had no recurrence with a median follow-up of 12 months. CONCLUSION: One patient died of glioblastoma. We would therefore recommend ampullectomy as the first-line treatment for benign tumors of the ampulla of Vater. In low-risk pT1 carcinoma (G1/G2, L0) and R0 resection, local excision is acceptable. In high-risk pT1 carcinoma (G3 and/or L1) Whipple pancreatoduodenectomy is mandatory.

Adenocarcinoma↗
PubMed2000

Diagnosis and monitoring of acute cytomegalovirus infection in peripheral blood of transplant recipients by nested reverse transcriptase polymerase chain reaction (RT-PCR).

The aim of this novel diagnostic approach is to monitor cytomegalovirus (CMV) infection in immunocompromised transplant recipients using early, sensitive, and specific predictors before and during antiviral therapy. The peripheral blood cells of 20 patients after transplantation (9 liver, 7 kidney, 4 simultaneous kidney-pancreas) were studied for an early diagnosis of acute infection. The mRNA and DNA of human CMV immediate-early antigen (IEA) were detected by nested-polymerase chain reaction (PCR) assay. Results of nested PCR were compared with the immunological detection of antigen pp65 and serological diagnosis of CMV infection. All data were correlated with clinical symptoms like leukopenia, thrombopenia, pneumonia, and allograft-rejection reaction. Of 20 transplant recipients, 12 were infected by CMV, and 9 suffered from a CMV-related disease. CMV mRNA were detected simultaneously with antigen pp65 and CMV DNA in all patients with symptomatic infection. Additionally, CMV mRNA was found over a longer period after ganciclovir treatment of infected recipients. Nested reverse transcriptase (RT)-PCR for CMV-IEA mRNA allows a sensitive and specific diagnosis of an acute CMV infection. CMV mRNA was found to be a good marker of acute viremia and could be a useful tool for CMV monitoring over the whole period of disease management, even during antiviral therapy.

Cytomegalovirus↗
PubMed2000

Mutations of p53 tumor suppressor gene, apoptosis, and proliferation in intrahepatic cholangiocellular carcinoma of the liver.

This study was performed to examine the correlation between mutations of the p53 tumor suppressor gene, the occurrence of apoptosis, and proliferation in cholangiocellular carcinoma of the liver. The results obtained were compared with pathohistological stage (according to UICC) and grade and with disease related survival rate. In 41 curatively (R0-) resected intrahepatic cholangiocellular carcinomas, the status of the p53 gene was determined by direct sequencing of exons 4-9 and immunohistochemically. Apoptosis was assessed using the in situ end labeling (ISEL) technique in combination with morphological criteria. Proliferation was analyzed by immunohistochemistry of MIB-1 (Ki-67), Proliferating cell nuclear antigen (PCNA), and silver-stained nucleolar organizer regions (AgNOR). The results obtained were compared with pathohistological stage (according to UICC), grade, several other histopathological factors, and survival rate. Mutations of p53 were detected in 15/41 carcinomas examined (37%). The most common change was a G-->C and C-->T transition, changing the hot spot amino acid determined by exons 4-8. Of these 15 tumors, 14 were also p53-positive by immunohistochemistry. In each carcinoma examined, we could demonstrate MIB-1, PCNA, and AgNOR dots and also apoptotic cells in variable proportions. The proliferation markers showed a significant correlation among themselves. In univariate survival analysis, the extent of the primary tumor, lymph node status, grade, and p53 were significant factors influencing patient survival. Performing multivariate Cox regression survival analysis, however, only the extent of primary tumor and lymph node status had an independent prognostic impact. Apoptosis was not related to patient prognosis or to other parameters examined. In conclusion, these results indicated that p53 could serve as an additional prognostic parameter that could provide auxiliary information for patient outcome. However, tumor stage and lymph node involvement were the strongest prognostic factors. We failed to establish apoptosis or other pathological parameters as factors predicting the prognosis of patients with cholangiocellular carcinoma.

Apoptosis↗
PubMed2000

Human allograft acceptance is associated with immune regulation.

The ultimate goal of transplantation is drug-free allograft acceptance, which is rarely encountered in transplant recipients. Using a novel human-to-mouse "trans vivo" delayed-type hypersensitivity assay, we assessed donor-reactive cell-mediated immune responses in kidney and liver transplant patients, four of whom discontinued all immunosuppression. One of these subjects (J.B.) rejected his graft after 7 years of stable function, while the others (D.S., R.D., M.L.) continue to have excellent graft function 5, 28, and 4 years after the cessation of immunosuppression. PBMCs from J.B. exhibited strong responses to both donor and recall antigens whereas PBMCs from patients D.S., R.D., and M.L. responded strongly to recall, but not donor, antigens. Furthermore, when donor and recall antigens were colocalized, the recall response in these three patients was inhibited. This donor antigen-linked nonresponsiveness was observed in four other patients who are still maintained on immunosuppression. The weakness of donor-reactive DTH responses in these patients is due to donor alloantigen-triggered regulation that relies on either TGF-beta or IL-10. In D.S., regulation is triggered by a single donor HLA Class I antigen, either in membrane-bound or soluble form. This demonstrates that allograft acceptance in humans is associated with an immune regulation pattern, which may be useful in the diagnosis and/or monitoring of transplant patients for allograft acceptance.

Animals↗
PubMed2000

[Isolated tumor cells in primary malignant liver tumors].

The failure to reduce the mortality of patients with malignant liver tumors (hepatocellular carcinoma, cholangiocarcinoma) is probably a result of the early dissemination of cancer cells to secondary sites, which is usually missed by conventional diagnostic procedures used for tumor staging. Recent developments in the field of molecular biology enable us to detect tumor cells at a submicroscopic level. Therefore, over the past 10 years, sensitive assays have been developed to detect individual carcinoma cells disseminated to regional lymph nodes or distant organs. In contrast to colorectal and also breast cancer where disseminated tumor cells may be of additional prognostic value, few data exist for hepatocellular carcinomas. Until now, no relevant studies have been reported for cholangiocarcinoma. Alpha-fetoprotein and also albumin mRNA have been used for the detection of circulating micrometastatic tumor foci of hepatocellular carcinoma (HCC); however, the interpretation of the results has been equivocal. If hepatocyte-specific mRNAs are detected in the circulation, it is possible to infer the presence of circulating, presumably malignant, liver cells. The literature about the incidence of "micrometastases" and specificity of different assays for hepatocellular carcinomas varies tremendously. This clearly indicates the need for uniformity in protocols. For hepatocellular carcinoma, mRNA for alpha-fetoprotein and albumin is not a specific marker of circulating micrometastases, but may serve for treatment monitoring. Nevertheless, PCR-based techniques are a powerful tool in the therapeutical monitoring of hepatocellular carcinoma and will find their way into the daily practice of diagnostic histopathologists in the near future.

Bile Duct Neoplasms↗
PubMed2000

[Hepatocellular carcinoma: resection versus transplantation].

For decision of adequate surgical therapy and comparison of results differentiation of hepatocellular carcinomas (HCC) in cirrhotic and noncirrhotic livers is important. Liver resection is the treatment of choice for HCC in noncirrhotic liver. Between 4/94 and 8/99 we treated 54 patients with hepatocellular carcinoma (HCC) by subtotal hepatic resection (n = 40) and orthotopic liver transplantation (n = 14). Overall 1- and 3-year survival rates of the resection group were 45 and 25% (median follow up: 3.5 years). One-year survival in the transplantation group was 72% (median follow up: 2.2 years). In patients with HCC in cirrhosis in UICC stage I to III the optimal therapy is a controversial issue. In these patients the results after liver resection are poor due to high operative mortality and recurrence (3-year recurrence-free survival: 30%). Regarding the literature, liver transplantation is the treatment of choice in small (< 3-5 cm, < or = 2 tumors) HCCs arising in cirrhosis with better outcome compared to resection. The data in the literature report 3-year-survival rates after liver transplantation of 60-80%. However, consequent patient selection is necessary for this treatment modality. Due to the limited donor resources liver transplantation is rarely justified in advanced tumors.

Carcinoma, Hepatocellular↗
PubMed1999

Expression of p73 and its relation to histopathology and prognosis in hepatocellular carcinoma.

BACKGROUND: The protein p73, the first identified homologue of the tumor suppressor gene p53 (also known as TP53), has been shown to induce apoptosis (programmed cell death), but its function in tumor development has not been established. This study was undertaken to investigate the expression of p73 in liver tissue of patients with hepatocellular carcinoma (HCC) and to determine whether this expression has any impact on prognosis. METHODS: In situ hybridization and immunohistochemistry for the detection of p73 RNA transcripts and protein, respectively, were performed in tissues from 193 patients with curatively (R0-) resected HCC. Patients receiving liver transplantation were excluded. The results obtained were analyzed with respect to their association with pathohistologic stage, Edmondson grade, p53 expression status and several histopathologic factors of possible prognostic value, and, finally, with patient survival. RESULTS: RNA transcripts encoding p73 were detected by in situ hybridization in tumor cells but not in stromal, endothelial, or inflammatory cells or in cholangiocytes. Transcripts were also found occasionally in non-neoplastic hepatocytes. By immunohistochemistry, we detected p73 protein in 61 (32%) of the 193 carcinomas examined. Positive immunohistochemical staining was confined to the cell nucleus. Univariate survival analysis showed that p73 expression status was statistically significantly related to prognosis (two-sided P<.0001). Patients with p73-positive tumors had a poorer prognosis than those with p73-negative carcinomas. Multivariate Cox survival analysis identified the age of the patient, p73 expression status, co-existing cirrhosis, and Edmondson grade as independent prognostic factors. CONCLUSION: The protein p73 is overexpressed by a subset of HCCs and could serve as a useful indicator of prognosis in patients with this disease.

Apoptosis↗
PubMed1999

Apoptosis and proliferation in relation to histopathological variables and prognosis in hepatocellular carcinoma.

The prognosis of patients with resectable hepatocellular carcinoma depends mainly on the anatomical extent of the tumour and on the general condition of the patient. Given the growing evidence that proliferation indices may be of prognostic significance in hepatocellular carcinomas and that parameters of cell loss (usually, but not exclusively, due to programmed cell death) are biologically relevant, the identification and quantitation of proliferative capacity and apoptosis may be of prognostic importance. In this study four different methods have been used to assess proliferation in a series of 193 curatively (R0) resected hepatocellular carcinomas: mitotic count, immunohistochemical assessment of MIB-1 (Ki-67), proliferating cell nuclear antigen (PCNA), and silver-stained nucleolar organizer regions (AgNORs). Apoptosis was assessed using the in situ-end labelling (ISEL) technique in combination with morphological criteria. Patients who received liver transplantation were excluded. The results obtained were compared with histopathological stage (according to UICC), Edmondson grade, several other histopathological factors, and survival rate. Significant statistical correlations were seen between the mitotic index, the rate of nuclear positivity for MIB-1 and PCNA, and the number of AgNOR dots. In univariate survival analysis, tumour stage and Edmondson grade, mitotic index, MIB-1 and PCNA index, and mean AgNOR number were significant factors influencing patients' survival. On multivariate Cox survival analysis, mitotix index, concomitant cirrhosis, Edmondson grade, and patient age were the only significant independent prognostic factors. Apoptosis was not related to prognosis or to other parameters examined. These results indicated that mitotic index is an additional prognostic parameter which could provide auxiliary information for patients' outcome. MIB-1 and PCNA immunostaining and AgNORs showed a good correlation among themselves. Apoptosis did not predict prognosis in hepatocellular carcinoma.

Apoptosis↗