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Biomedical subjects

M Kaufmann

Publications and source records attributed to M Kaufmann.

At least 181 records · Page 10Linked to original sources
PubMed1996

Review of known prognostic variables.

The prognosis of patients with primary breast cancer depends on prognostic factors per se and on treatment. In certain subgroups of patients, the overall treatment benefits of systemic adjuvant therapy are modest. Therefore, proper selection of patients and treatment modalities is absolutely necessary. Patients with primary breast cancer and a very good prognosis can be classified by known prognostic factors such as tumor size T < or = 1 cm, grade 1, hormone receptor positive tumors, and no other factors indicating poor prognosis. [table: see text] Patients with very poor prognosis are characterized by young age (< 35 years), large tumor size (T > 3 cm), grade 3, hormone receptor-negative tumors, and high S-phase fractions. Tumor size is the best prognostic factor for the decision to treat (breast conservation surgery, primary preoperative or adjuvant systemic therapy) or not to treat. Table 4 shows possible treatment decisions (type and timing of therapy) in primary breast cancer based on known prognostic and predictive variables. The decision to treat or not to treat outside clinical trials should be based on this kind of information. The type and aggressiveness of adjuvant systemic treatment should depend on the receptor status of the tumor and on the age and menopausal status of the patient, as classical predictive factors; however, prognosticators which can describe the metastatic potential of breast cancer cells have yet to be defined.

Age Factors↗
PubMed1996

Microvessel density, expression of proto-oncogenes, resistance-related proteins and incidence of metastases in primary ovarian carcinomas.

Relationships between the incidence of metastatic spread and microvessel density, expression of proto-oncogene products, or expression of resistance-related proteins were investigated in human ovarian carcinomas by immunohistochemistry. Ovarian carcinomas with a high microvessel density showed a significantly increased formation of metastases (P = 0.005). Tumors with positive immunoreactivity of c-jun and c-myc products had a higher metastatic spread; however, these results were not statistically significant. A marginally significant correlation existed between the expression of erbB1 (EGFR) and metastatic spread (P = 0.05). No significant relationship was found between the expression of the resistance-related proteins P-glycoprotein or glutathione S-transferase-pi and the incidence of metastases. Furthermore, no correlation was detected between expression of the heat shock protein 70 and the occurrence of metastases.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1996

[Paraneoplastic cerebellar degeneration: case report of a patient with breast carcinoma].

Case Report on a Breast Cancer Patient: A description of medical history, diagnosis and therapy of a patient with breast cancer is presented. The patient showed primary symptoms of vertigo and truncal and gait ataxia. The cause of this cerebellar disorder was a paraneoplastic cerebellar degeneration (PCD) characterized by anti-Purkinje cell antibodies (anti-Yo) directed against specific epitops shared by Purkinje and tumour cells. The presence of these antibodies in some patients suggests an autoimmune mechanism, although their role in pathogenesis has not been established. Usually malignancies of the breast and the ovaries are associated with anti-Yo positive PCD. The intensive search for the underlying neoplasma led to the identification of a malignant tumour of the right breast. Tumour excision of subsequent immunosuppressive treatment resulted in a progression of PCD. Antibody titers remained nearly unchanged during the course of the disease.

Autoantibodies↗
PubMed1996

[Prognostic significance of plasminogen activator inhibitor-1 (PAI-1) in primary breast carcinoma].

The plasminogen activator system plays a key role in the proteolysis of malignant tumours. In 155 patients with primary breast cancer levels from PAI-1 and uPA were measured in cytosol with monoclonal antibodies and by an enzyme-linked immunosorbent assay. 35 tumour tissue samples form benign breast were also examined. Malignant tumours contain higher levels of PAI-1 (8.6 ng/mg) than benign tumours (1.28 ng/mg) (p < 0.01). Also the median level of uPA was significantly higher (p < 0.01) in malignant tissue (2.38 ng/mg) in comparison to benign disease (0.54 ng/mg). No correlation was found between the proteases and the classical prognostic parameters like axillary lymph node involvement, tumour size and menopausal status. However, a significant correlation (p < 0.01) was found in tumours with lymphangiosis carcinomatosa, negative hormone receptors, grade III tumour cells and high S-phase fractions (> 5%). After a median follow-up of 46 months we found that high levels of PAI-1 correlated with short DFS (p = 0.0005) and OAS (p = 0.003). However, in the Cox multivariate regression analysis only PAI-1 was significantly independent for OAS and could therefore give additional information. We conclude that levels from PAI-1 antigen measured in cytosol of primary breast cancer is an independent prognostic parameter to identify patients with high and low risk for relapse and for individualised treatment.

Adult↗
PubMed1996

Repeated dural punctures increase the incidence of postdural puncture headache.

Previous studies have failed to find a significant correlation between the number of dural punctures and the incidence of postdural puncture headache (PDPH), questioning the hypothesis that leakage of cerebrospinal fluid (CSF) through the dural tear is the cause of PDPH. We hypothesized that insufficient statistical power of these studies was the cause for this unexpected finding, and re-examined whether repeated dural punctures increase the incidence of PDPH by analyzing prospectively collected data on 8034 spinal anesthetics. Uneventful spinal anesthetics, including a single subarachnoid injection of local anesthetics, occurred in 7865 (97.9%) cases, whereas failed spinal anesthetics requiring repeated dural puncture for a second subarachnoid injection of local anesthetics occurred in 165 (2.1%) cases. The two groups were similar with regard to age, sex, and ASA physical status. We found that repeated dural punctures significantly increased the incidence of PDPH. We conclude that increased risk of PDPH is a disadvantage of performing a second subarachnoid injection of local anesthetics after a failed spinal anesthetic. Moreover, this result suggests that leakage of CSF through the dural tear is the most plausible cause of PDPH.

Adolescent↗
PubMed1996

How reliable are conventional and color-coded sonography of the breast in the differential diagnosis of breast cancer?

Sonographic examinations of the female mammary gland within the frameworks of the diagnosis of breast cancer playa fundamental role in the early detection of benign and, in particular, of malignant growths. Sonographic blood flow determinations can be used as an auxiliary noninvasive examination method. This is based on the fact that malignomas differ from benign tumors in that they display a pathological increase in vascular-ization. These changes of the circulatory conditions can be utilized in the diagnosis of the dignity of breast cancer.

Journal Article↗
PubMed1996

Activity of the DNA repair protein O6-methylguanine-DNA methyltransferase in human tumor and corresponding normal tissue.

The DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT) is a main determinant of resistance of cells towards the cytostatic effect of N-nitrosoureas. Here we report the activity of MGMT in different types of human tumors. Colorectal tumors showed the highest mean of MGMT activity (481 +/- 258 fmol/mg protein) followed by ovarian tumors (437 +/- 291 fmol/mg), breast (306 +/- 204 fmol/mg), testicular (299 +/- 179 fmol/mg), and brain tumors (55 +/- 44 fmol/mg). Only in breast and brain tumors were MGMT-deficient samples found, with a frequency of 3 and 5%, respectively. No significant difference in mean MGMT activity was observed between breast tumors of grading I, II, and III. For brain tumors there was a tendency of MGMT to decline with increasing grading. Breast and colorectal carcinomas were compared with the corresponding normal tissue obtained from the same patient. The data showed for 11 out of 12 pairs of breast tissue and for 13 out of 15 pairs of colorectal tissue that MGMT activity in the tumor was equal to or, more frequently, higher than the activity found in the corresponding normal tissue. Thus, it appears that in these groups of tumors, increase of MGMT activity during tumor formation and progression is the rule rather than the exception.

Brain Neoplasms↗
PubMed1996

Characterization of 17 beta-hydroxysteroid dehydrogenase IV.

17 beta-Hydroxysteroid dehydrogenase (17 beta-HSD) IV is coded by 2.9 kb mRNA translated to an 80 kDa protein which is N-terminally cleaved to a 32 kDa enzyme. The 17 beta-HSD IV is dedicated to steroid inactivation and reveals only 25% amino acid similarity with 17 beta-HSD I-III enzymes. Despite five Asn-Xaa-Ser/Thr (Xaa = unspecified amino acid) sites in the 80 kDa protein the enzyme is not glycosylated. The porcine 32 kDa 17 beta-HSD IV forms dimers of 75 kDa. The highest 17 beta-HSD IV mRNA expression and specific activities are found in liver and kidney followed by ovary and testes. In porcine gonads the immunofluorescence assigned the 17 beta-HSD IV to granulosa cells and to Leydig and Sertoli cells. As shown by the treatment with phorbol-myristate-acetate in vitamin D-differentiated monocytic leukemia THP1 cells, steroid synthesis and inactivation are regulated differentially by the protein kinase C pathway: an increase in aromatase is accompanied by a decrease in 17 beta-HSD IV mRNA levels.

17-Hydroxysteroid Dehydrogenases↗
PubMed1996

[Prognostic significance of p53 autoantibodies in serum of patients with breast carcinoma].

Mutations in the p53 tumor suppressor gene are the most common genetic alterations associated with malignant tumors including breast and gynecologic carcinomas. Overexpression of p53 protein is a result of increased protein stability caused through conformationally alteration. Accumulation of mutant p53 in tumor cells may lead to a humoral immune response with development of p53 autoantibodies. In the present study we investigated the sera of 72 patients undergoing surgery for primary breast cancer and the relation between p53 antibody production, prognostic parameters and clinical outcome. Circulating p53 antibodies were detected in 15 of the 72 examined patients (21%). A correlation to conventional prognostic factors was not observed. Yet the overall survival was worse in patients with p53 antibodies (p < 0.04), suggesting a more aggressive tumor type.

Adult↗
PubMed1995

Monoclonal immunoglobulin A antibody directed against serotype-specific epitope of Shigella flexneri lipopolysaccharide protects against murine experimental shigellosis.

To determine the role of humoral mucosal immune response in protection against shigellosis, we have obtained a monoclonal dimeric immunoglobulin A (IgA) antibody specific for Shigella flexneri serotype 5a lipopolysaccharide (mIgA) and used a murine pulmonary infection model that mimics the lesions occurring in natural intestinal infection. Adult BALB/c mice challenged with 10(7) S. flexneri organisms developed a rapid inflammatory response characterized by polymorphonuclear cell infiltration around and within the bronchi and strong systemic interleukin 6 response. Implantation of hybridoma cells in the back of mice, resulting in the development of a myeloma tumor producing mIgA in the serum and subsequently secretory mIgA in local secretions, or direct intranasal administration of these antibodies, protected the animals against subsequent intranasal challenge with S. flexneri serotype 5a. Absence of histopathological lesion and significant decrease in bacterial load of the lungs and of systemic interleukin 6 response were the three major criteria of protection. This protection was shown to be serotype-specific and dependent on local concentration of mIgA. These data demonstrate that mucosal antibodies directed against a single polysaccharidic surface epitope of Shigella can protect against the disease.

Administration, Intranasal↗
PubMed1995

O6-methylguanine-DNA methyltransferase activity in breast and brain tumors.

The DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT) is a main determinant of resistance of tumor cells to the cytostatic activity of chemotherapeutic alkylating agents (methylating and chloroethylating nitrosoureas) and is effective in protecting normal cells against genotoxic and carcinogenic effects resulting from DNA alkylation. Therefore, the level of expression of MGMT is significance for the response of both the tumor and the non-target tissue following application of nitrosoureas in tumor therapy. To determine the expression of MGMT in tumor tissue, we have assayed MGMT activity in 68 breast carcinomas and 38 brain tumors. There was a wide variation of MGMT expression in breast carcinomas ranging from below the level of detection up to 863 fmol/mg protein. About 4% of breast tumors did not display detectable MGMT, 15% had activity lower than 100 fmol/mg protein, and 26% expressed more than 500 fmol/mg. The mean level of expression was 321 fmol/mg. In brain tumors (astrocytoma WHO grade I, II, and III, and glioblastoma WHO grade IV) the MGMT activity was generally lower than in breast tumors, ranging from below the level of detection up to 238 fmol/mg. The mean level of expression was 55 fmol/mg. Five percent of the brain tumors had no detectable MGMT activity. The MGMT repair activity correlated well with the amount of MGMT protein present in tumor samples, as shown by Western-blot analysis, indicating that loss of MGMT repair activity is due to inability of these tumor cells to synthesize the protein.

Adult↗
PubMed1995

CD44 variant exon epitopes in primary breast cancer and length of survival.

CD44 designates a group of closely related cell-surface proteins generated by alternative splicing. We have previously shown that splice variants carrying sequences encoded by exon v6 are preferentially expressed in metastatic animal cancer cell lines and that they confer metastatic behaviour on non-metastatic animal tumour cell lines. In this study we set out to assess the expression of CD44 epitopes specific for variant exon sequences in human breast cancer and their potential for determining prognosis. We used affinity-purified polyclonal sera and four monoclonal antibodies raised against the human homologues of CD44 variant exon sequences to investigate the presence of CD44 on 100 primary invasive breast tumours, 12 local recurrences, 18 lymph node metastases, and normal tissue controls. Whereas normal mammary ductal epithelial cells and cells derived from hyperplastic lesions do not express CD44 variant exons, expression of v3, v5, and v6 epitopes was found in most tumour samples. The DIII (exon v6) epitope was present in 84% of the primary tumours and in 100% of axillary lymph node metastases and local recurrences. The presence of these CD44 epitopes is correlated with poor overall survival. 15 patients with exon-v6-negative tumours had good survival compared with 76 patients with exon-v6-positive tumours (p = 0.005; log rank test). Multivariate analysis showed that the CD44 epitope encoded by exon v6 was a good marker for prognosis independent of progesterone receptor, lymph node status, tumour size, and grade.

Adult↗
PubMed1995

Comparison of immunohistochemistry and RT-PCR for detection of CD44v-expression, a new prognostic factor in human breast cancer.

In different human tumors, splice variants of the surface glycoprotein CD44 (CD44v) are correlated with advanced stages of tumor growth and metastatic potential. In breast cancer and colon cancer, expression of epitopes encoded by exon v6 on primary tumors is an independent prognostic factor for poor patient survival. Two different screening methods for the detection of CD44 variants in tumors have been applied: immunohistochemistry (IHC) and semi-quantitative reverse transcription PCR (RT-PCR). In this study, we have compared the predictive capacity and the applicability of both approaches, using 31 human breast-tissue specimens (normal and neoplastic). IHC reveals lack of expression of CD44v on normal ductal epithelial cells but strong expression on myoepithelial cells. The majority of tumors express CD44 epitopes encoded by several variant exons. RT-PCR detects splice variants in normal epithelium, probably derived from RNA expressed in the myoepithelium. In tumors, RT-PCR reveals expression of a wide range of splice variants, including new ones that are not detected in normal breast tissue, e.g. ones that contain all variant exons. The conclusion of this comparison is that IHC is the better method for breast-tumor sample screening but that the increased sensitivity of RT-PCR can help to distinguish CD44v-positive from CD44v-negative tumors in cases where only a few tumor cells express variants or where epitopes are masked.

Antigens, Neoplasm↗
PubMed1995

Human mammary carcinomas express homologues of rat metastasis-associated variants of CD44.

Splice variants of CD44 expressed in a metastasizing cell line derived from a rat pancreatic adenocarcinoma have been shown recently to confer metastatic potential onto non-metastasizing rat pancreatic carcinoma and sarcoma cell lines. Homologues of these variants have also been detected in a variety of human malignancies. Using antibodies raised against a bacterially expressed fusion protein containing variant CD44 sequences, we have explored the expression of variant CD44 glycoproteins on tumors of the female breast. The material examined included normal tissue, hyperplastic lesions, 103 primary invasive mammary carcinomas, 10 in situ carcinomas, 12 local recurrences and 18 lymph node metastases. Using a polyclonal serum directed against several variant CD44 epitopes, normal mammary epithelia as well as ductal hyperplasias were negative for these splice variants, while the variant CD44 epitopes were detectable in all but six of the primary invasive carcinomas. From the reaction with various monoclonal antibodies and polyclonal sera specific for individual epitopes it is obvious that the tumors predominantly express CD44 variants encoded by exons v5 to v7. Interestingly, all investigated lymph node metastases reacted positively with the variant-specific antibodies, in contrast to primary tumors which reacted in 54% to 86% of the cases, depending on the antibody used. Statistical analysis revealed a significant correlation between expression of variant exons v3/v4 and v6 and increased tumor grade (p = 0.001 and p < 0.05, respectively; Fisher's exact test). Exon v6 is carried by the variants which confer metastatic capability in the rat. These results indicate that the expression of the CD44 variants is upregulated in mammary carcinomas and is closely linked to tumor anaplasia.

Animals↗