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Biomedical subjects

H Höfler

Publications and source records attributed to H Höfler.

At least 55 records · Page 3Linked to original sources
PubMed2001

Molecular diagnosis of a Mycobacterium chelonae infection.

A 23-year-old female presented with enlarged cervical lymph nodes, and a diagnosis of nonspecific lymphadenitis with formation of pyogranulomas was rendered. Despite an initial oral antibiosis and subsequent long-term intravenous and oral antibiosis under hospitalized conditions, the symptoms progressed. The lymph nodes became larger and then affected the cervical region bilaterally. Her general condition worsened, and an exanthema of the extremities accompanied by a reactive arthritis occurred. Serological assays of various viral and bacterial markers and blood cultures were negative. Application of a polymerase chain reaction (PCR) protocol allowing specific amplification of mycobacterial DNA revealed DNA of Mycobacterium chelonea in formalin-fixed, paraffin-embedded lymph node tissue. Sequencing of the PCR product showed a 97% homology with the known Mycobacterium chelonae sequence. Modification of the antibiotic therapy with clarithromycin, imipenem and amikacin resulted in a rapid regression of the symptoms. The clinical course, in combination with the difficulties in detecting the infectious agent, supports the usefulness of molecular pathological analyses specific for nontuberculous mycobacteria (NTM).

Adult↗
PubMed2001

Giant malignant mesenchymoma of the spermatic cord with bidirectional differentiation.

BACKGROUND: Spermatic cord neoplasms are a rare tumor entity and, moreover, of benign behavior. Malignant tumors of the spermatic cord are mostly of mesenchymal origin. We present the unusual case of a giant malignant mesenchymoma of the spermatic cord with bidirectional differentiation into a liposarcoma and a leiomyosarcoma. CASE REPORT: A 84-year-old male patient presented with a scrotal mass on the left side which was observed growing since 1 year and misdiagnosed as scrotal hernia or testicular hydrocele. Ultrasound and computed tomography demonstrated a solid tumor suggesting a spermatic cord tumor. The patient underwent hemiscrotectomy, and the histological examination of the 2,500-gram specimen revealed a malignant mesenchymoma originating from the spermatic cord with two distinct histopathological compartments of liposarcoma and leiomyosarcoma. Because an adjuvant therapy protocol is of questionable effect and because of the patient's age no further therapy was applied. The patient was closely followed and is now, 5 years after surgery, still free of disease. CONCLUSION: Even in older patients, scrotal masses should be considered malignant tumors as long as no benign diagnosis has been proven. Although malignant mesenchymomas are rare tumors with poor prognosis, in selected cases even large tumor masses, as presented, can be cured by surgery.

Aged↗
PubMed2001

Mutant cell surface receptors as targets for individualized cancer diagnosis and therapy.

The catalogue of gene alterations in human cancer is growing rapidly. Alterations in specific genes that play important roles in diverse cellular functions such as cell adhesion, signal transduction, differentiation, development or DNA-repair have been identified. Cancer-associated mutant cell surface molecules are very attractive candidates to target tumor cells because they offer the possibility of minimizing toxic effects to non-tumor cells. The cell adhesion molecule E-cadherin has been shown to play a major role in determining which of the two subtypes of gastric cancer, diffuse or intestinal type, develops. E-cadherin gene mutations typically affect the extracellular portion of the homophilic receptor and are frequently found in patients with diffuse-type tumors. Cancer-specific monoclonal antibodies against the E-cadherin mutational hot spot region are now available. In cell culture and in animal studies we have shown that mutation-specific antibodies exclusively target cells expressing abnormal E-cadherin. Those cells expressing the normal protein were not affected, demonstrating the specificity of our approach. After linking to toxins, drugs or radiolabeled mutation-specific antibodies could serve as very specific agents to treat small tumor deposits. Patients for this novel individualized cancer therapy can be identified within a day using routine immunohistochemistry of biopsies.

Cadherins↗
PubMed2001

The intracellular domain of cadherin-11 is not required for the induction of cell aggregation, adhesion or gap-junction formation.

The cadherin family of cell adhesion molecules demonstrates calcium-dependent homophilic binding, leading to cellular recognition and adhesion. The adhesion mediated by the classical type I cadherins is strengthened through catenin-mediated coupling of the cytoplasmic domain to the cytoskeleton. This cytoskeletal interaction may not be essential for the adhesion promoted by all cadherins, several of which lack cytosolic catenin-binding sequences. Cadherin-11, a classical cadherin, possesses a cytoplasmic domain that interacts with catenins, but may also occur as a variant form expressing a truncated cytoplasmic domain. To study the role of the cytoplasmic sequence in cadherin-11 mediated adhesion we have constructed and expressed a truncated cadherin-11 protein lacking the cytoplasmic domain and unable to bind beta-catenin. Expression of the truncated cadherin-11 in MDA-MB-435S human mammary carcinoma cells reduced their motility and promoted calcium-dependent cell aggregation, frequent cell contacts, and functional gap-junctions. We conclude that the intracellular catenin-binding domain of cadherin-11, and by inference cytoskeletal interaction, is not required for the initiation and formation of cell adhesion.

Blotting, Western↗
PubMed2001

Prognostic impact of proteolytic factors (urokinase-type plasminogen activator, plasminogen activator inhibitor 1, and cathepsins B, D, and L) in primary breast cancer reflects effects of adjuvant systemic therapy.

PURPOSE: Prognostic and predictive impact of five proteolytic factors associated with tumor invasion and metastasis in primary breast cancer were evaluated after long-term follow-up. EXPERIMENTAL DESIGN: Antigen levels of urokinase-type plasminogen activator, plasminogen activator inhibitor-1 (PAI-1), Cathepsins B, D, and L were determined using immunochemical assays in primary tumor tissue of 276 patients. RESULTS: During follow-up (median 109 months), 119 (43%) patients relapsed, and 117 (42%) died. In the whole collective, lymph node status (P < 0.001; RR 3.8), Cathepsin L (P < 0.001; RR 2.6), and PAI-1 (P = 0.027; RR 1.7) were the only independent significant factors in multivariate analysis for disease-free survival (DFS). For overall survival (OS), lymph node status (P < 0.001; RR 2.9), Cathepsin L (P = 0.017; RR 1.9), PAI-1 (P = 0.01; RR 1.9), and grading (P = 0.026; RR 1.7) were significant. In the node-negative subgroup, PAI-1 was the only significant factor for DFS (P = 0.004; RR 3.7) and the strongest factor (P = 0.004; RR 3.7) for OS next to grading (P = 0.017; RR 3.1). In node-positive patients, Cathepsin L was the only significant factor for both DFS (P < 0.001; RR 3.2) and OS (P = 0.003; RR 2.5). For all proteolytic factors but Cathepsin L, the univariate prognostic impact on DFS was substantial in patients without adjuvant systemic therapy but was diminished if adjuvant therapy had been administered. Cathepsin L maintained its strong prognostic impact on DFS even in patients with adjuvant endocrine therapy (P = 0.01; RR 2.8). CONCLUSIONS: The observed effect of adjuvant systemic therapy on their prognostic strength suggests that the assessed proteolytic factors supply predictive information on therapy response.

Adult↗
PubMed2001

[How can the effectiveness of multimodality therapy concepts be evaluated? From the viewpoint of the pathologist].

Prognostically relevant histopathological grading of tumor regression (grades I-III) is possible, although laborious. Morphological changes after chemotherapy indicate a specific response to treatment with central fibrosis and residual tumor islands in the periphery. Prognostic factors, such as TNM categories, UICC-R status, tumor size, and lymphangiosis, which are not intrinsic part of regression grading still correlate with patient survival.

Combined Modality Therapy↗
PubMed2001

[Oncogene amplification and genetic heterogeneity in the metaplasia-dysplasia-adenocarcinoma sequence of Barrett esophagus].

AIMS: Information about numerical genomic alterations in the tumorigenesis of Barrett's adenocarcinoma (BCA) is still limited. In order to search for gene amplification and ploidy status, a series of locus-specific DNA probes and associated centromere probes was analysed in the metaplasia-dysplasia-adenocarcinoma-sequence. METHODS: Fluorescence in situ hybridisation (FISH) was performed on paraffin sections with locus-specific DNA probes for D7S486, c-myc, cyclin D1, Her-2/neu, 20q13.2 and associated chromosomes 7, 8, 11, 17 and 20. Corresponding areas of intestinal metaplasia (IM, n = 5), low grade dysplasia (LGD, n = 9), high grade dysplasia (HGD, n = 15) and BCA (n = 16) were analysed. RESULTS: Gene amplification of c-myc, Cyclin D1, Her-2/neu and 20q13.2 was observed in 15-35% of BCA. Coincident amplification of genes was also present. Polysomies for all investigated centromere probes were highly prevalent (up to 85%). Gene amplification was also demonstrated in HGD lesions. Polysomies were observed in HGD in high frequency (up to 80%). Extensive genetic heterogeneity was observed in both, BCA and HGD displaying different levels of amplification. None of the samples with LGD showed a locus-specific amplification, but polysomies for all investigated chromosomes were present in 18-48% of LGD. No changes were detected in BCA associated IM and squamous epithelium. CONCLUSIONS: Our data indicate that oncogene amplification of c-myc, cyclin D1, Her-2/neu, and 20q13.2 occurring in BCA and less frequently in HGD is a late event in the tumorigenesis. Polysomies of chromosomes 7, 8, 11, 17 and 20, which were highly prevalent in BCA and HGD occur already at the stage of LGD. This may be a result of an early polyploidization, preceding the later genetic events, such as gene amplification in HGD and BCA. The detection of shared numerical genomic changes and the detected extensive genetic heterogeneity in the metaplasia-dysplasia-carcinoma-sequence in Barrett's esophagus supports the hypothesis of a process of multiclonal expansion underlying this progression.

Adenocarcinoma↗
PubMed2001

[Organization and contents of future research in pathology].

The organisation of research in Pathology in the future will be driven by the pressure for profitableness. This situation is already now leading to a continuous shifting of capacity from "non profitable" research (and teaching) to diagnostics. Since research continues to be a central future goal of the university institutes of Pathology, we have to claim that all our institutes shall have a financially incontestable research unit (at least 1 x BAT1 and 1 x BAT2, 1-2 BATV and consumables for approx. TDM75/year) and appropriate space. Additionally, academically orientated full pathologists and fellows, research assistants on grant money and M.D. students will perform research. One of the central future goals must be increase in motivation of researchers through output-orientated individual support and the enhancement of their career expectations. Research planned by politicians ("planned research") can--as "planned economy"--not be successful. Main goal of our future research efforts in the postgenomic era will be further clarification of the molecular basis of diseases. Applied research will be driven by the need for molecular classifications including individual prediction of prognosis, progression and choice and response to therapy. The future face of Pathology entirely depends on the fact, how actively this type of research is done in our labs and, consequently, how well we will be trained to do non-morphologic diagnostics on tissue in the future.

Humans↗
PubMed2000

Extensive ductal carcinoma In situ with small foci of invasive ductal carcinoma: evidence of genetic resemblance by CGH.

Although ductal carcinoma in situ (DCIS) of the breast is accepted as a potential precursor lesion for invasive ductal cancer (IDC), the critical genetic events associated with the tumor progression remain unknown. Since some extensive DCIS may show a small focus of IDC, these cases seem to be particularly suitable to investigate the primary abnormalities that determine the progression from in situ to early invasive cancer. We combined laser-microdissection with degenerative oligonucleotide-primed PCR (DOP-PCR) and comparative genomic hybridization (CGH) to detect copy number changes in 7 cases of extensive (>4 cm) DCIS with 1 small adjacent invasive focus. In 3 of the cases, single lymph node metastases (LN) were already present and were also investigated. Analysis of DCIS, IDC and LN components in the same patients revealed several consistent chromosomal changes present at all 3 sites: 1q, 7q, 8q, 16, 17, 19, 20q, 21q and 22q, the most frequent losses on 4q, 11q and 13q. DNA gain on 3p and 12q were more frequently found in IDC than in DCIS, suggesting the presence of proto-oncogenes activated during the progression to invasive cancer on these regions. Using paired analysis, resemblence of alterations found in DCIS and IDC could be quantified (odds ratio 7.0, p< or = 0.01). Gains on 6p, 10q, 14q and 15q and losses on 9p were identified in DCIS and IDC but not in LN, which may, therefore, represent early events in the carcinogenic process. Additional losses were found in the LNs on 2q, 3q, 5q, 6q, 12q and 16q. CGH results on chromosome 1 and 20 were confirmed by FISH and on chromosomal region 9p by microsatellite analyses. Our findings strongly underline the precursor status of high-grade DCIS, in which most of the chromosomal changes identified in IDC are already present. However, although the early stages of breast cancer, i.e., DCIS and the small foci of IDC were mainly characterized by DNA gains, the progression to metastatic tumor (LN) must have involved additional DNA losses on several regions.

Breast Neoplasms↗
PubMed2000

Molecular analysis of E-cadherin and cadherin-11 in Wilms' tumours.

Different studies of Wilms' tumours have demonstrated a loss of heterozygosity (LOH) of chromosome 16q ranging from 17 to 25%. In order to search for a potential tumour suppressor gene on 16q, we chose the calcium-dependent cell adhesion molecules E-cadherin and cadherin-11 as candidate genes, which are both located on the long arm of chromosome 16. E-cadherin is known to be expressed in epithelial structures, whereas cadherin-11 is supposed to be expressed in mesenchymal structures and developing epithelium, including renal tubules. For the present study, fresh frozen tissue from 30 Wilms' tumours and corresponding non-tumour tissues were analysed. Single nucleotide polymorphisms of the E-cadherin and cadherin-11 genes were chosen and analysed for allelic inactivation by polymerase chain reaction (PCR) amplification and sequence analysis. Loss of expression of one E-cadherin allele was seen in 10% (2/20) of the informative cases. Two out of 11 informative cases (18%) showed loss of expression of one cadherin-11 allele. No length alterations of either the E-cadherin or the cadherin-11 messenger RNAs were identified using reverse transcription PCR and agarose gel electrophoresis in tumour tissue. Sequencing of the entire E-cadherin coding region in seven cases showed the wild-type sequence. These data imply that E-cadherin and cadherin-11 are not likely to play typical tumour suppressor roles in Wilms' tumour. Interestingly, the E-cadherin immunohistochemistry showed a deviation from the normal reaction pattern in 50% of the cases, with 27% (8/30) showing an apical or cytoplasmic reaction and 23% (7/30) being completely negative. Northern blot analysis revealed that the overall expression of cadherin-11 is much stronger than that of E-cadherin. In several cases, the expression levels of the two genes were inversely correlated, suggesting the existence of a regulatory mechanism. Analysis of differential expression of the various cadherins and their subsequent signal transduction pathways might contribute to a better understanding of the complexity of Wilms' tumour formation.

Adolescent↗
PubMed2000

[Current classification of gastrointestinal stromal tumors].

Gastrointestinal mesenchymal tumors traditionally have been designated as smooth muscle tumors. However, with increasingly accurate analytic tools most investigators were unable to demonstrate true myogenic differentiation. Diagnostic criteria and grading vary among different studies and the biological behavior of these gastrointestinal stromal tumors (GIST) is difficult to predict. In this manuscript the recent concept of GIST is reviewed, including a suggestion for tumor classification. Furthermore, MIB-1 and p53 immunohistochemistry and myogenic differentiation were evaluated as potential prognostic factors. Diagnosis requires the use of immunohistochemistry. Classification as GIST seems appropriate, since only few tumors show complete myogenic differentiation. Besides a tumor size over 5 cm, mitotic rate still seems to be the best predictor of treatment failure in tumors that are resected with a rim of uninvolved tissue. MIB-1 proliferation index above 4% and p53 positivity indicate a more aggressive course.

Antigens, Nuclear↗
PubMed2000

Quality assessment in diagnostic molecular pathology: experience from a German-Austrian-Swiss multicenter trial.

In order to assess the current technical standard of diagnostic molecular pathology, we have conducted a multicenter trial with 34 participating pathology laboratories in Germany, Austria and Switzerland. Formalin-fixed, paraffin-embedded tissue blocks were selected from 15 cases, comprising 4 B-cell non-Hodgkin's lymphomas, 4 T-cell non-Hodgkin lymphomas, 4 cases with lymphadenitis, 2 cases with confirmed tuberculosis and 1 case of sarcoidosis. All participating laboratories received one 10-microm section from each of the 15 cases to detect clonality using immunoglobulin heavy chain (IgH) gene or T-cell receptor (TCR)-gamma gene rearrangement analysis in 12 and mycobacterial DNA in 3 cases. In addition, participants had to answer technical questions about the application of internal quality controls and performance of fragment length or sequence analysis. Correct results were reported in 80% and 90% for IgH and TCR-gammagene rearrangement analysis, respectively, and in 83% for mycobacterial DNA analysis. No significant differences in the quality of results were obvious when the individual techniques used for molecular analysis were compared. However, when two independent techniques were used by the same laboratory, a higher rate of correct results was obtained for IgH and TCR rearrangement analysis. In conclusion, this study demonstrates a high technical standard of molecular diagnostic adjuncts among the participating laboratories. Regular multicenter trials with a greater number of participating laboratories working in this field will be indispensable to ensure a continuing or increasing standard in diagnostic molecular pathology.

Austria↗
PubMed2000

Stromelysin-3 expression in invasive ovarian carcinomas and tumours of low malignant potential.

Stromelysin (ST)-3 is considered to be a marker of invasion and preinvasive lesions to indicate the likelihood of subsequent invasion. The expression of ST-3 has not been systematically studied in ovarian neoplasms. We studied 47 ovarian carcinomas and 49 ovarian tumours of low malignant potential (LMP) to see whether the expression of ST-3 correlated with any histopathologic features and, in the LMP tumours, whether its expression might be a prognostic indicator. All of the primary tumours and available metastases or implants were studied using immunohistochemistry (IHC) for ST-3 and, in 52 selected lesions, in situ hybridisation (ISH) using a cDNA probe. Expression of ST-3 was seen in 42 of 47 (89%) of the carcinomas and in 16 of 49 (33%) of the LMP cases. A significantly higher percentage of carcinomas than LMP tumours (P<0.00001) expressed ST-3 in the stroma adjacent to the tumour, with a correlation to increasing FIGO (International Federation of Gynecology and Obstetrics) tumour stage. ST-3 was expressed in the surrounding stroma of 1 of 8 LMP implants and 46 of 55 (84%) of the carcinoma metastases. The single LMP patient who died of tumour recurrence had ST-3 expression, but a significant prognostic impact was not found. The infrequent expression of ST-3 in LMP compared with carcinoma metastases appears to be more consistent with a peritoneal "field effect" than spread from the ovarian LMP tumour.

Adenocarcinoma, Mucinous↗
PubMed2000

Comparison of loss of heterozygosity and microsatellite instability in adenocarcinomas of the distal esophagus and proximal stomach.

Adenocarcinoma of the gastroesophageal junction is rapidly rising in incidence. It has been proposed that these tumors be classified as three different types: distal esophageal (AEG I), cardia (AEG II), and subcardia (AEG III). Using comparative genomic hybridization (CGH) analysis, one recent study reported that the 14q chromosomal arm showed a significantly higher rate of deletion in esophageal than in cardia adenocarcinoma. Using a microsatellite analysis technique, we analyzed this area and regions in the vicinity of the APC, DCC, and p53 genes. Tumor and normal tissues were microdissected from 54 cases (27 AEG I and 27 AEG III). DNA was extracted and then amplified using seven fluorescent-labeled microsatellite markers, one pair each on 5q, 18q, and 17p and four on 14q. The results were analyzed for loss of heterozygosity (LOH) and microsatellite instability (MSI). LOH varied from 20% to 30% at each locus except for the 17p locus, where it was slightly above 50% in both groups. No significant differences in LOH or MSI were found between the esophageal and gastric tumors, including the 14q chromosomal arm. These results fail to confirm the finding that abnormalities on the 14q chromosomal arm distinguish between distal esophageal and proximal gastric tumors.

Adenocarcinoma↗
PubMed2000

Kinetic profiles of intraepithelial and invasive prostatic neoplasias: the key role of down-regulated apoptosis in tumor progression.

The cell kinetic of prostatic intraepithelial neoplasia (PIN) is poorly understood. Herein we report the kinetic pattern of PIN, both not associated (primary) and associated (secondary) with coexistent invasive carcinoma (PCa). Surgical specimens collected in 20 cases of primary PIN, 20 of secondary PIN and 20 of PCa were studied by MIB-1 immunostaining, in situ end-labeling (ISEL) and DNA histogram analysis, and the cell density in each case was estimated using the formula N = (n pi/4)2. Fifty high-power fields (HPF), or the complete lesion if smaller, were screened in each lesion, and both mean and standard deviation were recorded. Statistical differences were studied by means of Fisher's exact test. ISEL indices were significantly (P < 0.0001) lower in PCa (0.1 +/- 0.3) than in primary PIN (0.5 +/- 0.3), while the MIB-I indices were similar in both conditions (P = 0.56). Statistically significant differences were also detected for both MIB-1 and ISEL indices when secondary PIN (MIB-1 1.9 +/- 0.7, ISEL 3.7 +/- 3.3) was compared with primary PIN (MIB-1 2.5 +/- 2.1, ISEL 0.5 +/- 0.3) and PCa (P < 0.0001). In terms of cellularity, primary PIN (26.3 +/- 7.1) revealed scores significantly lower (P < 0.0001) than those recorded in PCa (39.0 +/- 8.8) and secondary PIN (32.9 +/- 14.3). In conclusion, early prostatic tumor is mainly defined by down-regulated apoptosis rather than by increased proliferation. Secondary PIN displays unique kinetic features suggesting an evolved stage of primary PIN.

Aged↗