Biomedical subjects

F Borchard

Publications and source records attributed to F Borchard.

At least 37 records · Page 2Linked to original sources

PubMed1999

Influence of p53 status on prognosis in preoperatively irradiated rectal carcinoma.

BACKGROUND: Even when they are analogous in microscopic and macroscopic appearance, tumors vary in their response rates to radiotherapy. Cell culture and xenograft experiments with colorectal cell lines have demonstrated that wild-type p53 increases radiosensitivity. Hence, the authors investigated, in a well-defined population of patients treated at the same institution, whether p53 status was a prognostic factor in preoperatively irradiated rectal carcinoma patients. METHODS: The p53 status of rectal adenocarcinomas was examined immunohistochemically (with monoclonal antibody DO-1) in preirradiated biopsy samples (n = 100) and corresponding postirradiated resected specimens (n = 97). The mean follow-up was 73.2 months (median, 71.3 months; range, 4.3-157 months). Statistical analysis was performed using the SPSS program (SPSS, Chicago, IL). RESULTS: p53 protein expression was detected in 55 of 100 biopsy samples (> or = 5% nuclear staining). There was essentially no difference in p53 expression between biopsy samples and corresponding resected specimens (54 of 97 vs. 55 of 97). In univariate analysis, p53 immunoreactivity of biopsy samples did not correlate with age, gender, tumor location, TNM stage, pT category, pN category, or histologic grade. Unlike clinicopathologic variables, p53 expression did not have a statistically significant association with local recurrence free, disease free, or overall survival in either univariate (P = 0.91, 0.18, and 0.17, respectively) or multivariate analysis. CONCLUSIONS: In contrast to cell line studies, this immunohistochemical study demonstrates that p53 status is not useful as a prognostic marker in preoperatively irradiated rectal carcinoma.

Adenocarcinoma↗

PubMed1999

Cyclooxygenase-2 expression in human esophageal carcinoma.

On the basis of epidemiological observations that nonsteroidal antiinflammatory drugs reduce the risk of esophageal carcinoma, we studied the expression of cyclooxygenase-2 (COX-2) in esophageal squamous cell carcinomas (SCCs; n = 172) and in esophageal adenocarcinomas (ADCs; n = 27). Using immunohistochemistry, we observed COX-2 expression in 91% of the SCCs and in 78% of the ADCs. Western blot analysis showed enhanced expression of the COX-2 protein in some tumors as compared with normal esophageal squamous epithelium, whereas similar amounts of the COX-1 protein were found in normal and cancerous tissues. COX expression was also studied in two esophageal cancer cell lines (OSC-1 and OSC-2) to evaluate the functional relevance of COX-2-derived prostaglandins (PGs). OSC-2 cells expressed COX-2 but not COX-1, whereas OSC-1 cells expressed high levels of COX-1 but showed only a very weak COX-2 expression. Accordingly, PGE2 synthesis was 600 times higher in the OSC-2 cells as compared with the OSC-1 cells. Treatment of OSC-2 cells with the selective COX-2 inhibitors flosulide and NS-398 concentration dependently suppressed PGE2 synthesis and proliferation and also induced apoptosis. In contrast, no effect of the COX-2 inhibitors was seen in OSC-1 cells. Our data demonstrate that COX-2 is expressed in the majority of esophageal SCCs and ADCs and that COX-2-derived PGs play an important role in the regulation of proliferation and apoptosis of esophageal tumor cells. It is concluded that inhibition of COX-2 may be useful in the therapy of esophageal cancer.

Carcinoma↗

PubMed1999

'Pyloric gland-type adenoma' arising in heterotopic gastric mucosa of the duodenum, with dysplastic progression of the gastric type.

'Pyloric gland-type adenoma' is a recently described and very rare entity. We report a case of a pedunculated polyp of the duodenal bulb showing the features of pyloric gland-type adenoma. Heterotopic gastric mucosa was found adjacent to the tumour. Immunohistochemically, the tumour cells at the surface of the polyp showed foveolar-type mucin (M1) while most other tumour cells showed deep gastric mucin (M2), displaying a pattern of differentiation similar to the normal gastric mucosa. The polyp also showed villous or papillary structures with disorganization of gastric differentiation and marked increase of proliferating in foci cells. This is the first case of pyloric gland-type adenoma found to arise in heterotopic gastric mucosa of the duodenum, showing dysplastic progression of the gastric type.

Adenoma↗

PubMed1999

Histogenesis of gastric foveolar metaplasia following duodenal ulcer: a definite reparative lineage of Brunner's gland.

AIMS: We aimed to clarify the histogenesis of gastric metaplasia in the duodenal mucosa, particularly in association with a reparative lineage of Brunner's glands. METHODS AND RESULTS: Using immunohistochemical methods with recently developed antimucin monoclonal antibodies (mAbs) that distinguish foveolar and deep mucins of the gastric type, as well as mAb MIB-1, the histogenesis of gastric metaplasia was investigated in the duodenal wall of 20 surgically resected specimens. In duodenal ulcers extending into Brunner's glands with destruction of the muscularis mucosae, proliferating cells positive for MIB-1 were scattered in Brunner's glands. Interestingly, a group of proliferating cells was often seen next to the ulcerated surface. These cells were also positive for M1 (gastric-foveolar type mucin) but negative for M2 (deep gastric and Brunner glands' mucin). In regenerating ducts through granulation tissue, the proliferating cell zone was elongated, above which foveolar-type cells positive for M1 but negative for M2 were detected, indicating that the G-zone is newly established in Brunner's glands at the floor of an ulcer to produce gastric-foveolar cells. Subsequently, an organoid growth of the normal stomach mucosa is completed in the duodenum. CONCLUSIONS: This study indicates a possible histogenetic pathway of gastric metaplasia in close association with a reparative lineage of Brunner's glands, suggesting that the occurrence of the gastric-foveolar type epi-thelium is not a simple expansion of Brunner's duct but a true metaplasia.

Antigens, Nuclear↗

PubMed1999

Diagnostic significance of nuclear p53 expression in the surveillance of Barrett's esophagus--a longitudinal study.

The efficacy of currently performed surveillance in patients with Barrett's esophagus (BE) is substantially compromised by shortcomings of dysplastic lesions as diagnostic markers. The aim of this study was to evaluate the possible role of p53 protein expression as complementary method in the diagnosis of neoplastic transformation in BE. A longitudinal study was performed. 41 patients were enrolled. The median time of surveillance was 46 months. 234 archival paraffin blocks containing a total of 627 biopsies were retrieved. p53 protein immunostaining by application of the monoclonal antibody DO-1 was performed. The results of immunohistochemistry were compared with the exact histopathological diagnosis and grading of dysplasia (no dysplasia, indefinite for dysplasia, low-grade dysplasia, high-grade dysplasia, carcinoma). In merely four of 206 nondysplastic mucosal sites p53 expression was found. However, p53 expression was detected with increasing frequency in sites indefinite for dysplasia (2/9), specimens with low-grade dysplasia (9/15), high-grade dysplasia (3/3) and the one with a carcinoma. This study shows a close association of nuclear p53 protein expression to the process of neoplastic transformation in Barrett's epithelium. However, it apparently does not precede the appearance of dysplasia significantly. Thus, nuclear p53 expression as detected by immunohistochemistry may serve to confirm a suspected diagnosis of dysplasia in BE.

Adenocarcinoma↗

PubMed1999

[Differential diagnosis of colitis].

The aims of the bioptical diagnosis of colitis are delineated in introductory remarks. Subsequently, the range of normality is described for mucosal structures, and the term "nonspecific chronic colitis" is critically discussed. Furthermore, some characteristic (diagnostic) forms of colitis are presented together with their differential diagnoses. Also the "less" diagnostic features of infectious colitis and chronic inflammatory bowel disease are described. An algorithmus of the differential diagnosis of colitis is proposed. Excluding 83 cases of normal findings, the practical impact of such an algorithm was critically analysed in 381 consecutive biopsies of histologically proven colitis.--Several "characteristical" types of colitis could be distinguished in about 95% of the biopsies; in a small percentage of cases only a differential diagnosis could be offered, partly because of inconclusive morphological findings, partly because clinical data were completely lacking and partly because there were no separate rectal biopsies in these cases. We wish to stress, however, that the anamnestical data relating to the length of complaints and the therapeutic interventions are very relevant to the interpretation of the morphological differential diagnosis of chronic colitis, especially in chronic colitis with low activity or inactive disease.

Algorithms↗

PubMed1998

Hypermethylation of the p16INK4a promoter in colectomy specimens of patients with long-standing and extensive ulcerative colitis.

Functional inactivation of the p16INK4a gene has been reported to be involved in the development of a variety of human malignancies. Recent evidence shows that transcriptional silencing as a consequence of hypermethylation of CpG islands is the predominant mechanism of p16INK4a gene inactivation in sporadic colon cancer. This study sought to identify the significance of p16INK4a methylation in the colonic epithelium of patients with long-standing ulcerative colitis. A total of 89 tissue samples was retrieved from three colectomy specimens. A methylation-specific PCR assay was applied. The methylation status was compared with histological findings and the flow cytometrically determined DNA index. Hypermethylation of the p16INK4a promoter region was detected in 12.7% of samples that were negative for dysplasia. However, 70.0% of samples with dysplasia and all of the samples with carcinomatous lesions revealed hypermethylation. Hypermethylation of the p16INK4a gene promoter was detected already in 40% of specimens with lesions indefinite for dysplasia and in 13.7% of samples with exclusively diploid cell populations. These results suggest that hypermethylation of the p16INK4a promoter region is a frequent and early occurring event during the process of neoplastic progression in ulcerative colitis.

Colectomy↗

PubMed1998

Comparative analysis of histology, DNA content, p53 and Ki-ras mutations in colectomy specimens with long-standing ulcerative colitis.

Neoplastic progression in patients with chronic ulcerative colitis is characterized by the development of epithelial dysplasia, which is accompanied by genetic alterations. This study determined the time of onset of p53 and Ki-ras mutations as well as DNA aneuploidy during histological progression towards carcinoma. In all, 278 samples of 7 colectomy specimens were analyzed by flow cytometry, histology and single-strand conformation polymorphism analysis. Of the samples, 22% (61/278) were dysplastic and 43% (122/278) aneuploid, while 25% (71/278) showed p53 and 4% (11/278) Ki-ras mutations. The correlation between aneuploid status and p53 mutations varied among the patients. A strong correlation was noticed between histological progression from low-grade dysplasia to carcinoma and p53 mutations as well as DNA aneuploidy. Ki-ras mutations were found in 40% (2/5) of the carcinomatous samples. The correlation between p53 mutations and the histological status of the samples suggest the involvement of this genetic event in the development of colon cancer in patients with ulcerative colitis. In contrast to Ki-ras mutations, the appearance of p53 mutations is an early event. Therefore p53 analysis might be helpful in the classification of indefinite dysplasia and in the identification of patients at risk for cancer development. Further studies are necessary to detect the additional genetic alterations preceding the development of DNA aneuploidy.

Aneuploidy↗

PubMed1998

Mapping of chromosomal imbalances in gastric adenocarcinoma revealed amplified protooncogenes MYCN, MET, WNT2, and ERBB2.

Gastric adenocarcinoma is a malignant tumor with a high incidence and a low survival rate. In order to identify genetic alterations associated with this tumor, we screened 23 gastric adenocarcinomas for recurrent chromosomal imbalances by using comparative genomic hybridization (CGH). The most common gains of chromosomal material were found on chromosome arms 20q (10 cases), 16p (7 cases), and 1q (4 cases) and on chromosome 11 (4 cases). Losses were observed on chromosome arms 4q, 5q, 9p, and 21q (3 cases each). Four tumors exhibited high-level amplifications localized on chromosome regions 2p23-p24, 7q31-q32, 8p21-p22, 10q25-q26, 11q13, 17q11-q21, and 20q. Based on the position of these amplifications, candidate (onco)genes were selected and subsequently tested by Southern blot analysis of the respective tumors. Of the seven tested candidates, MYCN, MET, WNT2, and ERBB2 were found to participate in the amplicons of the respective tumor samples. Of these four presumably activated oncogenes, two, MYCN and WNT2, were previously not assumed to play a pathogenic role in stomach cancer. Among the other regions of imbalance, gain of 20q seems particularly interesting, because it is found in almost half of the analyzed cases and is highly amplified. Our data allowed us to narrow the relevant region down to the commonly gained bands 20q12-q13.1. This and other imbalanced regions provide a basis for searching new putative oncogenes and tumor suppressor genes involved in the development or progression of gastric adenocarcinoma.

Adenocarcinoma↗

PubMed1998

Intramucosal carcinomas of the stomach: phenotypic expression and loss of heterozygosity at microsatellites linked to the APC gene.

Evaluation of the role of somatic genetic alterations in cancer development is best performed by examining small tumors in the earlier stages of carcinogenesis. We examined the relationship between allelic deletions of 4 microsatellites linked to the adenomatous polyposis coli (APC) gene and differential histogenetical phenotypes in 34 intramucosal carcinomas of the stomach, of which, structurally, 24 cases were the gland-forming type (so-called "intestinal type") and 10 were the diffuse type. Using mucin and immunohistochemical staining techniques specific for gastric- and intestinal-type mucins, the phenotype of each tumor was histogenetically classified as exclusively gastric, predominantly gastric, predominantly intestinal or exclusively intestinal. There was generally a free combination between structural types and phenotypic mucin expression. Allelic deletions were detected in 6 carcinomas of the exclusively intestinal phenotype. The incidence of allelic deletions was significantly higher in the predominantly and exclusively intestinal phenotypes (6/16, 37.5%) than in the predominantly and exclusively gastric phenotypes (0/18) (p = 0.0060, Fisher's test). Taking the high frequency of allelic deletions in 5q in invasive stomach carcinomas, the present study suggests that genetic alteration in this region is a very early event in stomach carcinomas with intestinal differentiation but a relatively late event in those with gastric differentiation.

Adenocarcinoma, Mucinous↗

PubMed1998

Value of liver biopsy prior to interferon therapy for chronic viral hepatitis.

The present study prospectively evaluated the value of liver biopsy in patients with chronic hepatitis B (N=75) and C (N=135) prior to interferon therapy. Biopsy specimens revealed cirrhosis in 26% of patients with hepatitis B and 30% with hepatitis C. Although cirrhosis was not predictable by laboratory values in individual patients mean gamma-GT, alkaline phosphatase, and bilirubin levels were significantly higher in patients with cirrhosis compared to those without. Since cirrhosis significantly impairs the response rate to interferon therapy in hepatitis C but not in hepatitis B, liver biopsy is important for the management of chronic hepatitis C infection. In 88% of patients with serum HBV-DNA, irrespective of the serum HBeAg status, chronic active hepatitis was seen. Similarly, chronic active hepatitis was found in 84% of patients with elevated aminotransferases and hepatitis C antibodies. Thus, chronic active hepatitis was diagnosed in the majority of cases with chronic viral hepatitis, showing that this histopathological diagnosis is of little additional value for the recommendation on interferon treatment in these patients. However, none of the other grading systems of liver biopsy specimens described so far have been evaluated for their ability to predict overall prognosis or response rates to interferon therapy. Therefore, the physician is presently left with the questionable value of a procedure with well-known risks and costs in patients suitable for interferon treatment. Hence, prospective randomized controlled studies to evaluate histopathological grading systems are urgently needed to redefine the necessity of liver biopsy in this routine clinical setting.

Antiviral Agents↗

PubMed1998

Primitive neuroectodermal tumors of the cerebral hemispheres in two siblings with TP53 germline mutation.

AWe report on two siblings (brother and sister) who developed cerebral PNETs at the age of 5 years and 6 months, respectively. Both children were treated by operation followed by polychemotherapy. The brother also received cranio-spinal irradiation. Nevertheless, the children died about 12 months and 24 months post-operatively due to extensive cerebral tumor recurrences. Shortly after having lost both of her children, the mother developed an intra-abdominal tumor, which was resected and histologically diagnosed as ovarian carcinoma. Because of this unusual familial clustering of tumors and a positive history of brain tumors and other cancers in several maternal relatives, we analyzed DNA isolated from both PNETs and the ovarian carcinoma as well as constitutional (leukocyte) DNA from the whole family for mutation of the TP53 tumor suppressor gene. This analysis revealed that all tumors were homozygous for a missense mutation at codon 213 (CGA => TGG) resulting in an amino acid exchange from arginine to tryptophane. The same mutation was present in one TP53 allele in the constitutional DNA of the mother and the children, indicating that the mother had transmitted a TP53 germline mutation to both of her children. Analysis of loss of heterozygosity at microsatellite markers from 17p confirmed deletion of the paternal (wild-type) allele in both PNETs. Further investigation of the PNETs by comparative genomic hybridization revealed multiple chromosomal abnormalities. Interestingly, some genomic changes were common to both PNETs, while many others were not, a finding suggesting substantial genomic instability, probably as a consequence of p53 inactivation.

Adult↗

PubMed1998

Frequent inactivation of CDKN2A and rare mutation of TP53 in PCNSL.

Twenty primary central nervous system lymphomas (PCNSL) from immunocompetent patients (nineteen B-cell lymphomas and one T-cell lymphoma) were investigated for genetic alterations and/or expression of the genes BCL2, CCND1, CDK4, CDKN1A, CDKN2A, MDM2, MYC, RB1, REL, and TP53. The gene found to be altered most frequently was CDKN2A. Eight tumors (40%) showed homozygous and two tumors (10%) hemizygous CDKN2A deletions. Furthermore, methylation analysis of six PCNSL without homozygous CDKN2A loss revealed methylation of the CpG island within exon 1 of CDKN2A in three instances. Reverse transcription PCR analysis of CDKN2A mRNA expression was performed for 11 tumors and showed either no or weak signals. Similarly, immunocytochemistry for the CDKN2A gene product (p16) remained either completely negative or showed expression restricted to single tumor cells. None of the PCNSL showed amplification of CDK4. Similarly, investigation of CCND1 revealed no amplification, rearrangement or overexpression. The retinoblastoma protein was strongly expressed in all tumors. Only one PCNSL showed a mutation of the TP53 gene, i.e., a missense mutation at codon 248 (CGG to TGG:Arg to Trp). No evidence of BCL2 gene rearrangement was found in 11 tumors investigated. The bcl-2 protein, however, was strongly expressed in most tumors. None of the 20 PCNSL demonstrated gene amplification of MDM2, MYC or REL. In summary, inactivation of CDKN2A by either homozygous deletion or DNA methylation represents an important molecular mechanism in PCNSL. Mutation of the TP53 gene and alterations of the other genes investigated appear to be of minor significance in these tumors.

Aged↗

PubMed1998

Fibroid polyps of intestinal tract are inflammatory-reactive proliferations of CD34-positive perivascular cells.

AIMS: Our aim was to determine the histogenesis of fibroid polyps (FP). These polyps are rare inflammatory-reactive, tumour-like lesions of unknown aetiology, arising in the submucosa or mucosa of the gastrointestinal tract. They are mainly due to a proliferation of characteristic spindle cells. METHODS AND RESULTS: Nine FP were investigated by light microscopy and immunohistochemistry with endothelial markers (Factor VIII, CD34, CD31), a neuronal marker (S100), muscular markers (desmin, alpha-smooth muscle actin) and histiocytic markers (PGMI, KP1, MAC387) using the highly sensitive avidin-biotin-peroxidase technique. We demonstrate, for the first time, a consistent positivity of the characteristic spindle cells of FP for CD34. The proposed endothelial, histiocytic or neuronal origin of FP could be completely ruled out. CONCLUSIONS: Because of the consistent positivity of the spindle cells of FP for CD34 we suggest an origin of these lesions from primitive perivascular or vascular cells. This origin and a probable relationship to gastrointestinal stromal tumours (GIST) is discussed.

Actins↗

PubMed1997

Overexpression or ectopic expression of MUC2 is the common property of mucinous carcinomas of the colon, pancreas, breast, and ovary.

Mucinous carcinomas of the colorectum have been reported to overexpress the intestinal mucin MUC2. The purpose of this study was to determine whether this alteration is shared by mucinous tumours of the ovary, breast, and pancreas. A total of 40 breast carcinomas (22 of mucinous and 18 of ductal invasive type), 39 ovarian adenocarcinomas (16 mucinous, 23 serous), 47 colorectal carcinomas (25 mucinous and 22 non-mucinous), and 41 pancreatic adenocarcinomas (14 mucinous, 27 non-mucinous) were investigated by immunohistochemistry with the anti-MUC2 monoclonal antibody 4F1 and the expression pattern was ranked. MUC2 mucin is expressed in the normal colonic epithelium; in the normal epithelium of the breast, ovary, and pancreas, it was not detectable by immunohistochemistry or by reverse transcriptase-polymerase chain reaction (RT-PCR). In agreement with previous reports, the colonic mucinous carcinomas differed significantly from the non-mucinous carcinomas by strong MUC2 expression. In all mucinous carcinomas of the ovary, breast, and pancreas, de novo expression of the MUC2 gene was observed, which differentiated mucinous and non-mucinous carcinomas of these tissues (P < 0.001). The overexpression or ectopic expression of the MUC2 gene exhibited by mucinous carcinomas of four organs indicates a common genetic lesion associated with the mucinous tumour phenotype.

Adenocarcinoma, Mucinous↗

PubMed1997

Distribution of cell populations with DNA aneuploidy and p53 protein expression in ulcerative colitis.

OBJECTIVE: Patients with ulcerative colitis are at an increased risk for developing colorectal neoplasms. p53 mutations and the occurrence of DNA aneuploidies are common events in the development of sporadic colorectal neoplasias. This study tried to determine the frequency of these events during the development of colitis-associated colorectal neoplasms. DESIGN/METHODS: Four colectomy specimens with a total of 124 biopsies were investigated. DNA content was measured by flow cytometry and p53 protein expression was detected by immunohistochemistry. These results were correlated with histological findings. RESULTS: DNA aneuploidies were found in 58 (46.8%), and p53 protein expression in 30 samples (24.2%). The presence of DNA aneuploidy as well as of p53 protein expression correlated with the histological characteristics of neoplastic transformation. In areas without dysplasias or with indefinite dysplasias, 31.5% of the samples showed DNA aneuploidies and in about 9% of the samples p53 protein expression could be detected; 33.7% of samples without or with indefinite dysplasias showed p53 protein expression and/or DNA aneuploidies. CONCLUSION: These results show that the occurrence of DNA aneuploidies and nuclear p53 protein expression is a common event in the development of colitis-associated colorectal neoplasias. p53 protein expression seems to be an early event in this process. DNA aneuploidies occur even earlier and more frequently in the absence of p53 protein expression. Therefore, other genetic alterations besides p53 gene mutations might be involved in colitis-associated tumour development.

Adult↗

PubMed1997

A new aspect of gastric metaplasia in Crohn's disease: bidirectional (foveolar and pyloric) differentiation in so-called 'pyloric metaplasia' in the ileum.

Mucus-secreting cells found at the site of ileac ulceration in Crohn's disease have been described as 'pyloric metaplasia'. Using mucin-histochemical methods and immunohistochemical stainings for Ki-67 antigen and foveolar-type mucin (M1) of the stomach, the characteristics of this type of metaplasia were studied in surgically resected ileac specimens from two Japanese patients with Crohn's disease. Not only pyloric-type cells but also foveolar-type cells were demonstrated; often displaying an organoid growth of the normal stomach mucosa. Stem cells of the ileac crypt may differentiate potentially to intestinal-, pyloric- and also to foveolar-type cells. The term 'pyloric metaplasia' is not appropriate and 'gastric metaplasia' should be used when describing this type of metaplasia.

Adult↗

PubMed1997

Non-alcoholic duct destructive chronic pancreatitis.

BACKGROUND: The pathology of non-alcoholic chronic pancreatitis has not yet been sufficiently studied. AIMS: To identify the major changes of pancreatic tissue in patients surgically treated for non-alcoholic chronic pancreatitis. PATIENTS: Pancreatectomy specimens from 12 patients with non-alcoholic chronic pancreatitis, including four patients with autoimmune or related diseases (Sjögren's syndrome, primary sclerosing cholangitis, ulcerative colitis, and Crohn's disease), were reviewed. METHODS: Morphological changes were studied histologically and immunohistochemically (to type inflammatory cells) and compared with the pancreatic alterations found in 12 patients with alcoholic chronic pancreatitis. RESULTS: In patients with non-alcoholic chronic pancreatitis, with or without associated autoimmune or related diseases, pancreatic inflammation particularly involved the ducts, commonly resulting in duct obstruction and occasionally duct destruction. None of these features was seen in alcoholic chronic pancreatitis which, however, showed pseudocysts and calcifications. CONCLUSION: The pancreatic changes in patients with non-alcoholic chronic pancreatitis clearly differ from those with alcoholic chronic pancreatitis. The term chronic duct destructive pancreatitis is suggested for this type of pancreatic disease.

Adolescent↗