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J Rüschoff

Publications and source records attributed to J Rüschoff.

At least 19 recordsLinked to original sources
PubMed2006

Expression of IGF-I, IGF-II, and IGF-IR in gallbladder carcinoma. A systematic analysis including primary and corresponding metastatic tumours.

AIMS: The insulin-like growth factor (IGF) system has been implicated in tumour development and progression. This study was designed to analyse the expression of the IGF-I receptor (IGF-IR) and its ligands (IGF-I, IGF-II) in gallbladder cancer. METHODS: IGF-I, IGF-II, and IGF-IR immunoreactivity was investigated in 57 gallbladder carcinomas and corresponding lymph node (n = 11) and hepatic (n = 7) metastases using a tissue microarray technique and correlated with tumour stage, grade, and patient outcome. RESULTS: Cancer tissue allowing a reliable evaluation of IGF-I, IGF-II, and IGF-IR was present in 55 of 57 primary tumours and 17 of 18 metastases. IGF-I and IGF-II immunoreactivity was seen in 25 and 14 of the 55 primary tumours, in addition to six and three of the 17 metastases, respectively. No associations with tumour stage, grade, or prognosis were detected. IGF-IR was expressed in 52 of 55 primary tumours and all 17 metastases. IGF-IR staining intensity decreased with tumour cell dedifferentiation. Moreover, IGF-IR expression in less than 50% of cancer cells was an independent marker of poor prognosis in multivariate analysis (risk ratio, 4.0; 95% confidence interval, 1.4 to 11.2; p = 0.01). CONCLUSIONS: The expression of IGF-IR and its ligands provides evidence for the existence of an auto/paracrine loop of tumour cell stimulation in gallbladder cancer and makes this type of cancer a candidate for therapeutic strategies aimed at interfering with the IGF pathway. The recognition of IGF-IR as a new independent prognostic biomarker may help to identify patients who might benefit from adjuvant treatment.

Adenocarcinoma↗
PubMed2005

The p53 codon 72 variation is associated with the age of onset of hereditary non-polyposis colorectal cancer (HNPCC).

The polymorphic variants at codon 72 of the p53 gene were shown to be functionally distinct in vitro, whereby the arginine (arg) variant induces apoptosis more efficiently than the proline (pro) variant. From the evidence that the DNA mismatch repair system and p53 interact to maintain genomic integrity, we hypothesized that the codon 72 variation may influence the age of onset of disease in HNPCC patients. We tested 538 patients for p53 codon 72 variants, including 167 unrelated patients with pathogenic germline mutations in MSH2 or MLH1 and colorectal carcinoma as first tumour, 126 patients with sporadic microsatellite stable colorectal cancers, and 245 healthy controls. The median age of onset was 41, 36, and 32 years for MSH2 or MLH1 mutation carriers with arg/arg, arg/pro, and pro/pro genotypes, respectively. The log rank test revealed significant differences in the age of onset between arg/arg and pro/pro individuals (p = 0.0002) and in arg/pro versus arg/arg and pro/pro individuals (p = 0.0026 and p = 0.0217, respectively). A Cox regression model indicated an additive mode of inheritance. No significant differences in age of onset were observed among different genotype carriers with microsatellite stable tumours. Our results suggest that p53 codon 72 genotypes are associated with the age of onset of colorectal carcinoma in a mismatch repair deficient background in a dose dependent manner. These findings may be relevant for preventive strategies in HNPCC.

Adaptor Proteins, Signal Transducing↗
PubMed2004

[Molecular pathology in hereditary colorectal cancer. Recommendations of the Collaborative German Study Group on hereditary colorectal cancer funded by the German Cancer Aid (Deutsche Krebshilfe)].

Although twin studies indicate that inherited genetic factors contribute to about 35% of colorectal cancers (CRC), the exact genetic background has currently been elucidated in only 5-10% of cases. These comprise several hereditary cancer predisposition syndromes that present with a high number of syn- or metachronous neoplasms within an affected person and/or family. Many of these tumors exhibit typical histopathological changes. In general, one should discriminate between cancer syndromes associated with adenomatous and non-adenomatous (i.e., hamartomatous) polyps, the latter being quite rare. The patient's age often serves as a substantial hint to hereditary cancer. The next step of diagnostic work-up includes analysis of microsatellite instability (MSI) together with immunohistochemical detection of a loss of expression in one of the most frequently affected mismatch repair genes (MSH2, MSH6; MLH1, PMS2). Finally, the molecular demonstration of a gene mutation in the blood or germline is the most expensive and tedious procedure. This requires a signed informed consent from the patient after appropriate genetic counseling.

Colonic Neoplasms↗
PubMed2003

Histopathological diagnosis of Barrett's mucosa and associated neoplasias: results of a consensus conference of the Working Group for Gastroenterological Pathology of the German Society for Pathology on 22 September 2001 in Erlangen.

There are a number of difficulties regarding the diagnosis of Barrett's mucosa and the varying grades of neoplasia that may be associated with it. It was, therefore, the aim of a consensus conference of the Working Group for Gastroenterological Pathology within the German Society of Pathology to achieve standardisation regarding the following issues: definition and diagnostic criteria for Barrett's mucosa and its discrimination from intestinal metaplasia of the cardia, diagnostic criteria for intraepithelial neoplasia, number of biopsies necessary to establish the diagnosis, significance of additional immunohistochemical and/or molecular methods as well as importance of a second opinion in the diagnosis of intraepithelial neoplasia.

Barrett Esophagus↗
PubMed2003

[Histopathological diagnosis of Barrett's mucosa and associated neoplasias. Results of a consensus conference of the Working Group for "Gastroenterological Pathology of the German Society for Pathology" on 22 September 2001].

There are a number of difficulties regarding the diagnosis of Barrett's mucosa and the varying grades of neoplasia that may be associated with it. It was therefore the aim of a consensus conference of the "Working Group for Gastroenterological Pathology within the German Society of Pathology" to achieve standardization regarding the following issues: definition and diagnostic criteria for Barrett's mucosa and its discrimination from intestinal metaplasia of the cardia, diagnostic criteria for intraepithelial neoplasia, number of biopsies necessary to establish the diagnosis, significance of additional immunohistochemical and/or molecular biological methods as well as importance of a second opinion in the diagnosis of intraepithelial neoplasia.

Barrett Esophagus↗
PubMed2003

Gene expression pattern of laser microdissected colonic crypts of adenomas with low grade dysplasia.

BACKGROUND AND AIMS: Colorectal epithelial cells are prone to malignant transformation. Therefore, identification of differences in gene expression in the process from normal colonic crypts to adenomas with low grade dysplasia is essential for further insights into early tumorigenesis. To achieve this goal, a novel gene expression analysis strategy, screening for expressed transcripts in small histologically defined tissue samples, was performed. METHODS: First, laser mediated microdissection was used to isolate normal and adenomatous crypts from colonic cryosections. Then, nested RNA arbitrarily primed polymerase chain reaction (RAP-PCR) for differential display was performed to screen mRNA populations and to generate hybridisation probes for cDNA expression arrays. After evaluation of cDNA expression arrays, differential expression was confirmed at the protein level by immunohistochemistry. RESULTS: Evaluation of gene expression profiles of normal versus adenomatous colonic crypts of six different patients revealed, in general, dysregulation of up to 11% of all analysed genes (total number n=588): specifically, p21-rac1 was upregulated in four of six patients, mitogen activated protein kinase (MAPK) p38alpha in three of six patients, and interferon gamma receptor in three of six patients. Conversely, FAST kinase was found to be downregulated in three of six patients, p53 in three of six patients, and thrombospondin 2 in three of six patients. CONCLUSIONS: For the first time, distinct gene expression profiles of dysplastic areas within colonic adenomas, using the combination of laser mediated microdissection with RAP-PCR and cDNA expression array, were shown. In these samples, upregulation of proliferation associated genes (ras-oncogene related p21-rac1 and MAPK p38alpha) as well as downregulation of apoptosis related genes (FAST kinase and p53) most likely reflects specific alterations in adenomas with low grade dysplasia. Based on upregulation of p21-rac1 and MAPK p38alpha, activation of the MAPK pathway appears to be an early event in colonic carcinogenesis.

Adenoma↗
PubMed2003

Genomic rearrangements of hMSH6 contribute to the genetic predisposition in suspected hereditary non-polyposis colorectal cancer syndrome.

BACKGROUND: Germline mutations in mismatch repair genes, mainly in hMLH1, hMSH2, and hMSH6, predispose to the hereditary non-polyposis colorectal cancer (HNPCC) syndrome. A substantial fraction of these mutations exists in genomic rearrangements of hMSH2 and hMLH1. In contrast, genomic rearrangements have not been reported in hMSH6. METHODS: Out of 15 HNPCC or HNPCC-like patients who developed tumours with loss of hMSH6 protein expression, we selected three patients who still had no germline mutations after gene sequencing. Genomic DNA of these patients was analysed using PCR based relative quantification of hMSH6 fragments. Indicated exon deletions and amplifications were characterised by long range PCR and sequencing. RESULTS: Genomic rearrangements were identified in two of the three patients. Breakpoint analyses showed an Alu repeat mediated deletion of 13.0 kb affecting the promoter region, exon 1, and exon 2 in one patient, and a duplication of 4.9 kb containing 1.6 kb of the 3' end of exon 4 and exon 5, integrated into intron 5, in the other patient. CONCLUSIONS: Although genomic rearrangements of hMSH6 only play a small role in the spectrum of all mutations predisposing to HNPCC, our results suggest that up to 10-20% of patients with hMSH6 negative tumours harbour germline rearrangements in this gene.

Chromosome Breakage↗
PubMed2002

Glucose transporter 1 gene expression is related to thyroid neoplasms with an unfavorable prognosis: an immunohistochemical study.

PURPOSE: An accelerated rate of glucose metabolism mediated by overexpression of key regulatory glycolytic enzymes and glucose transporters is among the most characteristic biochemical marker of malignant transformed cells. In thyroid neoplasms, however, an increased uptake of glucose [measured by 2-[18F]-fluoro-2-deoxy-D-glucose (FDG) and positron emission tomography (PET)] seems to be restricted to more aggressive and high-grade tumors, whereas tumors with favorable prognosis demonstrate no significant tracer uptake. We therefore studied the expression of glucose transporters in thyroid carcinomas with different grades of malignancy. METHODS: Sections of formalin-fixed and paraffin-embedded tissue obtained from 45 patients with thyroid cancer (5 anaplastic, 20 papillary and 20 follicular tumors) were investigated. Polyclonal rabbit antiglucose transporter antibodies, reactive with glucose transporters 1-5 (GLUT1-5), were used after heat pretreatment of the sections. Staining was performed by the avidin-biotin conjugate immunoperoxidase reaction and evaluated semiquantitatively. RESULTS: Expression of GLUT1 transporter on the cell membrane was closely related to the grade of malignancy in thyroid neoplasms (Fisher exact test p < 0.05). All anaplastic tumors showed a high level of GLUT1 expression in the cytoplasm and on the cell membrane. Positive membranous staining in differentiated tumors was detected predominantly in neoplasms with unfavorable prognosis, e.g., in widely invasive follicular or metastatic tumors, whereas low or no immunoreactivity could be seen in well-differentiated tumors or in normal thyroid epithelium. CONCLUSIONS: These data indicate that overexpression of GLUT1 on the cell membrane of thyroid neoplasms is closely related to tumors demonstrating a more aggressive biological behavior. Therefore, determination of GLUT1 expression in thyroid cancer tissue may be a prognostic marker, and FDG-PET may be a helpful technique in identifying patients at a higher risk.

Biomarkers, Tumor↗
PubMed2001

[Clinical and histopathological characteristics of early Leser-Trélat syndrome].

Leser-Trélat-syndrome is characterized as the eruptive appearance of multiple seborrheic keratoses in association with underlying malignant disease. A 73 year old female patient with a metastatic adenocarcinoma of the colon presented with this paraneoplastic change. The rapid appearance of solitary seborrheic keratoses with associated inflammation, seen clinically and histologically, may be an early sign of Leser-Trélat-syndrome. The recognition of this inflammatory component as an early sign may contribute to the prompt diagnosis of this paraneoplasia, even before the eruption of numerous seborrheic keratoses.

Adenocarcinoma, Mucinous↗
PubMed2001

[Pigmented pheochromocytoma. Case report with immunohistochemical and electron microscopic characterization].

We present a case of pigmented adrenal paraganglioma in a 39-year-old female patient with associated neurofibromatosis type 1 (NF1). Histology showed features typical for phaeochromocytomas except for varying amounts of brown pigment within the cytoplasm of tumour cells, which proved to be melanin by histochemical and ultrastructural analysis. The occurrence of melanin is believed to reflect the origin of this neoplasm from multipotent cells of the neural crest. Pigmented phaeochromocytoma has to be taken in consideration in the differential diagnosis of pigmented neoplasms, especially in the adrenal gland, where it has to be discriminated from pigmented cortical adenoma (so-called black adenoma) and primary malignant melanoma.

Adrenal Gland Neoplasms↗
PubMed2001

[Acute segmental hemorrhagic antibiotic-associated colitis].

Three cases of acute segmental hemorrhagic antibiotic-associated colitis are described occurring in three male adults between 30 and 33 years of age after treatment with oral ampicillin or amoxicillin because of upper respiratory tract infection, tonsillitis, or HLO eradication therapy, respectively. All presented with cramping abdominal pain and bloody diarrhoea of acute onset, however, microbial analysis of fecal samples was negative. Endoscopy showed right-sided segmental hemorrhagic colitis. Histopathological examination demonstrated edema, patchy superficial hemorrhage and a scattered predominantly mononuclear infiltrate of the lamina propria. The surface epithelium was partly desquamated and displayed foci of grouped intraepithelial red blood cells. All patients spontaneously recovered after discontinuation of antimicrobial therapy. The value and limitations of diagnostic features are discussed with respect of the literature.

Abdominal Pain↗
PubMed2001

[Concomitant occurrence of angiomyolipoma, focal nodular hyperplasia, bile duct adenoma, and cavernous hemangioma in the liver].

The simultaneous occurrence of different hepatic tumors is rare. We present for the first time a concomitant manifestation of an angiomyolipoma, a focal nodular hyperplasia, a bile duct adenoma, and a cavernous hemangioma in a 63-year-old female patient. The largest of the tumors, preoperatively suspected to be hepatocellular carcinoma, was an angiomyolipoma with monotypic epithelioid histology and positive immunoreactivity for HMB-45, actin, desmin, and pancytokeratin. The significance of immunohistochemistry for the differential diagnosis of hepatic neoplasms is emphasized. Finally, a review of the literature with special regard to etiology and pathogenesis of neoplastic liver disease is given, leading to the assumption that the association of four different benign intrahepatic tumors is rather more fortuitous than pathogenetically related, despite the putative similar pathogenesis of focal nodular hyperplasia and hemangioma.

Adenoma, Bile Duct↗
PubMed2001

Clinical and histopathological features of dextran sulfate sodium induced acute and chronic colitis associated with dysplasia in rats.

We examined the clinical and histopathological features of the dextran sulfate sodium (DSS) induced acute and chronic colitis in rats as a model for studying basic biology of the inflamed colonic mucosa. Acute colitis was induced in male Wistar rats by 4 days (AI) or 7 days (AII) of oral 5% (wt/vol) DSS (mol. wt. 54,000) in their drinking water. Chronic colitis was induced in 8 experimental groups: CI=7 days DSS followed by 10 days water (=one cycle); CII=two cycles; CIII to CVIII (three to eight cycles) received only 4 days 5% DSS followed by 10 days drinking water. The entire colons were examined histologically; dysplasia was graded as: indefinite/probably negative for dysplasia, indefinite/probably positive for dysplasia, low-grade dysplasia, or high-grade dysplasia. The earliest clinical findings in the acute colitis group over 4 days occurred on day 2 (hemoccult positive stools, loose stools or diarrhea and weight loss). The maximal disease activity was noted on day 7 accompanied by a 53% mortality rate. The histological inflammation scores were significantly higher on day 7 than on day 4. All rats had extensive ulcerations predominantly in the rectum and cecum. The number of rats having ulcerations was markedly lower in the chronic colitis groups. The majority (75%) of the crypt lesions suspicious for dysplasia were classified as mucosa indefinite/probably negative for dysplasia. We classified 18 crypt lesions as low-grade dysplasia and one lesion as high-grade dysplasia (after eight cycles). No invasive carcinoma was observed. Most low-grade dysplasias (83%) occurred after five cycles of DSS/water, located mostly in the rectum (44%) and colon transversum (33%). Our findings suggest that the DSS colitis model in rats may be an interesting model for studying the sequence chronic inflammation-dysplasia in human ulcerative colitis. Further long-term studies with the present DSS colitis model in rats might also prove it as a reliable model to study the sequence high-grade dysplasia and colitis associated-cancer.

Acute Disease↗
PubMed2001

Piffalls in diagnostic molecular pathology--significance of sampling error.

Today, molecular diagnostic tests are widely used in clinical medicine with polymerase chain reaction (PCR)-based techniques being of particular interest. In tissue specimens, however, false-positive and false-negative results can be obtained if pathomorphological and processing aspects are not considered. We therefore studied the impact of tissue sampling in three widely used diagnostic tests: (1) assessment of clonality in B-cell non-Hodgkin's lymphoma, (2) analysis of microsatellite instability (MSI) in colorectal neoplasia, and (3) demonstration of mycobacterium tuberculosis. Tissue sections of routinely formalin-fixed and paraffin-embedded diagnostic specimens were taken, and the significance of sampling was systematically investigated using laser microdissection or processing of the entire section. PCR analyses were done according to standard protocols. False-positive pseudo-monoclonality was obtained in small gastrointestinal biopsies and in laser microdissected lymph follicles of non-neoplastic tonsils. False negativity (pseudo-stability) could be demonstrated in a case with hereditary rectal adenoma if whole tissue sections were taken without microdissection of the most dysplastic subareas. Demonstration of mycobacteria failed in tissue sections of a formalin-fixed lymph node that was positive after complete digestion or in fresh frozen material of the same patient. In diagnostic molecular pathology, sampling error is an important source of false-positive and false-negative results, particularly if disease- and tissue-specific morphological features, such as sample size, type of fixation, and intralesional heterogeneity, are ignored.

Clone Cells↗
PubMed2001

The reliability of immunohistochemistry as a prescreening method for the diagnosis of hereditary nonpolyposis colorectal cancer (HNPCC)--results of an international collaborative study.

Hereditary nonpolyposis colorectal cancer syndrome (HNPCC) is an autosomal dominant condition accounting for 2-5% of all colorectal carcinomas as well as a small subset of endometrial, upper urinary tract and other gastrointestinal cancers. An assay to detect the underlying defect in HNPCC, inactivation of a DNA mismatch repair enzyme, would be useful in identifying HNPCC probands. Monoclonal antibodies against hMLH1 and hMSH2, two DNA mismatch repair proteins which account for most HNPCC cancers, are commercially available. This study sought to investigate the potential utility of these antibodies in determining the expression status of these proteins in paraffin-embedded formalin-fixed tissue and to identify key technical protocol components associated with successful staining. A set of 20 colorectal carcinoma cases of known hMLH1 and hMSH2 mutation and expression status underwent immunoperoxidase staining at multiple institutions, each of which used their own technical protocol. Staining for hMSH2 was successful in most laboratories while staining for hMLH1 proved problematic in multiple labs. However, a significant minority of laboratories demonstrated excellent results including high discriminatory power with both monoclonal antibodies. These laboratories appropriately identified hMLH1 or hMSH2 inactivation with high sensitivity and specificity. The key protocol point associated with successful staining was an antigen retrieval step involving heat treatment and either EDTA or citrate buffer. This study demonstrates the potential utility of immunohistochemistry in detecting HNPCC probands and identifies key technical components for successful staining.

Adaptor Proteins, Signal Transducing↗
PubMed2001

Use of simplified transcriptors for the analysis of gene expression profiles in laser-microdissected cell populations.

Because colorectal epithelia are prone to malignant transformation, it is important to understand their normal regulation and then to identify differences between the normal cells and the transformed cells. We investigated the gene expression pattern along colonic crypts using a novel gene expression analysis strategy. We combined laser-mediated microdissection of distinct areas within colonic crypts and used modified RNA arbitrarily primed PCR to generate probes for cDNA array hybridization. In the basal part of the crypt, proliferation-related and cell cycle-related genes such as the multifunctional transcription factor e2f-1 or the mismatch-related gene p58/HHR23B were predominantly expressed. In the lumenal part of the crypt, up-regulations of the cysteine protease mch4 and the proto-oncogene c-jun were found. Our findings indicate that e2f1, p58/HHR23B, and mch4 may be involved in key mechanisms leading to malignant transformation in the colonic crypt. Our results also suggest that the technique elucidated here allows identification of gene expression patterns in distinct areas of intestinal tissue samples.

Biopsy↗
PubMed2001

Tracheobronchial stenosis in Keutel syndrome.

In 1971 Keutel et al. described a new syndrome in two siblings presenting with peripheral pulmonary stenoses, brachytelephalangism, neural hearing loss and abnormal cartilage calcification. Recent investigations provided evidence that mutations in the gene encoding the human matrix GLA protein cause Keutel syndrome. With these new insights in the disease the symptomatology of Keutel syndrome was reassessed. The follow-up of the two siblings was studied by clinical and post mortem examination. As a new feature of Keutel syndrome tracheobronchial stenosis and concentric calcification of pulmonary, coronary, hepatic, renal, meningeal and cerebral arteries were described. Complementary to the results in molecular genetics the symptomatology of Keutel syndrome could be revised by clinical and post mortem examination.

Abnormalities, Multiple↗