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Geza Acs

Publications and source records attributed to Geza Acs.

31 records · Page 2Linked to original sources
PubMed2004

Prognostic significance of erythropoietin expression in human endometrial carcinoma.

BACKGROUND: Erythropoietin (Epo), which is induced by hypoxia, controls erythropoiesis and protects neurons from hypoxic damage. Hypoxia in malignant disease is associated with invasion, metastasis, and resistance to therapy. The authors recently demonstrated hypoxia-stimulated expression of Epo and Epo receptor (EpoR) in human breast and cervical carcinomas, suggesting a role for autocrine Epo signaling in the hypoxic adaptations of carcinomas. METHODS: The authors characterized the expression of Epo, EpoR, hypoxia-inducible factor (HIF)-1alpha, estrogen receptor (ER), and progesterone receptor (PR) by immunohistochemical methods using endometrial carcinoma samples from 107 women and benign endometrial samples from 59 women in various phases of the menstrual cycle. They then analyzed potential correlations of Epo and EpoR immunostaining and clinicopathologic tumor features with outcome. RESULTS: In benign endometrial tissue samples, Epo and EpoR expression increased over the course of the cycle, with the highest levels observed in the late secretory phase. Epo expression in benign endometrial samples showed a negative correlation with ER and PR expression. The authors found Epo and EpoR expression in 95.3 % and 100% of endometrial carcinoma samples, respectively. Increased EpoR, but not Epo, expression in tumors was associated with advanced-stage disease, lymphovascular invasion, lymph node metastasis, and loss of ER expression. Increased Epo expression was observed in perinecrotic tumor regions in a pattern similar to the HIF-1alpha expression pattern. Increased Epo expression was significantly associated with adverse clinical outcome on both univariate and multivariate analysis. CONCLUSIONS: Hypoxia-inducible autocrine Epo signaling in endometrial carcinoma may contribute to tumor progression and increased aggressiveness. Increased Epo expression in endometrial carcinomas may be an independent prognostic and/or predictive factor.

Adenocarcinoma, Clear Cell↗
PubMed2004

Conformationally constrained diacylglycerol (DAG) analogs: 4-C-hydroxyethyl-5-O-acyl-2,3-dideoxy-D-glyceropentono-1,4-lactone analogs as protein kinase C (PKC) ligands.

The (R)-DAG-lactones (5 and 7E/Z) are conformationally constrained diacylglycerol (DAG) analogs with high potency as protein kinase C (PKC) ligands. Here, we have prepared and characterized their one-carbon lengthened analogs (6 and 8E/Z). The target compounds were synthesized from 1,2-O-isopropylidene D-xylose through a key intermediate, 4-C-hydroxyethyl-2,3-dideoxy-D-glyceropentono-1,4-lactone (13); they were evaluated as competitive ligands to displace bound [(3)H]phorbol 12,13-dibutyrate (PDBU) from a recombinant single isozyme (PKC-alpha). The binding affinities of the synthesized compounds were K(i) = 2.623 microM for 6, K(i) = 1.080 microM for 8Z and K(i) = 0.92 microM for 8E, which were ca. 27, 90, and 70 times less potent than the corresponding parent compounds (5, 7Z and 7E). Molecular modeling indicated that the reduced binding affinity of the representative 3-alkylidene lactone 8Z, as compared to 7Z, may be explained by its poor fit in the sn-1 binding mode as well as by its entropic loss due to the relatively flexible hydroxyethyl group.

Binding, Competitive↗
PubMed2004

WT1 is differentially expressed in serous, endometrioid, clear cell, and mucinous carcinomas of the peritoneum, fallopian tube, ovary, and endometrium.

The Wilms' tumor gene WT1 plays complex roles in the development of the organs of the genitourinary tract and mesothelium, as well as Wilms' tumors. Although its biologic role is still unclear, most serous carcinomas of the ovary and peritoneum, mesotheliomas, and Wilms' tumor have been shown to express WT1. A recent study, however, found no WT1 expression in serous carcinomas of the endometrium, suggesting that WT1 could be useful in identifying the primary site of serous carcinomas. We examined the expression of WT1 and p53 by immunohistochemistry in 69 cases of endometrial carcinoma (35 endometrioid, 18 clear cell, 16 serous), 68 cases of ovarian carcinoma (28 serous, 11 endometrioid, 18 clear cell, and 11 mucinous), 14 fallopian tube carcinomas (12 serous, 2 endometrioid), and 20 primary peritoneal serous carcinomas. WT1 nuclear reactivity of any extent and intensity was considered positive. Immunohistochemical stains were evaluated semiquantitatively using a four-tiered scale. Among endometrial carcinomas, WT1 immunoreactivity was seen in 10 of 16 serous, but in none of 35 endometrioid or 18 clear cell carcinomas. Among ovarian tumors, WT1 expression was seen in 24 of 28 serous and 4 of 18 clear cell carcinomas, but in none of 11 endometrioid and 11 mucinous tumors. All 12 serous carcinomas but none of 2 endometrioid carcinomas of the fallopian tube were positive for WT1. WT1 expression was seen in 19 of 20 serous primary peritoneal carcinomas. The difference in WT1 expression was highly significant between serous and other types of tumors in all sites (p<0.0001, chi-square test), although the level of WT1 expression was significantly different among serous carcinomas arising at different sites (p<0.0001, Kruskal-Wallis test). A significant positive correlation was found between the level of p53 and WT1 expression in all carcinomas combined (r = 0.3935, p<0.0001, Spearman test), but when only serous carcinomas were analyzed, the correlation between p53 and WT1 expression levels did not reach statistical significance. Our results suggest that WT1 expression in epithelial tumors of the female genital tract may be related to cell differentiation and histologic subtypes of carcinomas, rather than to primary site of origin.

Aged↗
PubMed2004

Posterior acoustic shadowing in benign breast lesions: sonographic-pathologic correlation.

OBJECTIVE: To show a variety of benign breast lesions that exhibit posterior acoustic shadowing on sonography. METHODS: The cases illustrate a variety of pathologic breast conditions that were collected at a referral breast center at a tertiary medical center. RESULTS: A variety of pathologic conditions are discussed, with pathologic-imaging correlation. CONCLUSIONS: Although posterior acoustic shadowing is a sonographic feature that is most commonly associated with mammary malignancies, this sonographic finding may also be seen with benign breast lesions.

Adult↗
PubMed2003

Hypoxia-inducible erythropoietin signaling in squamous dysplasia and squamous cell carcinoma of the uterine cervix and its potential role in cervical carcinogenesis and tumor progression.

Tissue hypoxia is a characteristic property of cervical cancers that makes tumors resistant to chemo- and radiation therapy. Erythropoietin (Epo) is a hypoxia-inducible stimulator of erythropoiesis. Acting via its receptor (EpoR), Epo up-regulates bcl-2 and inhibits apoptosis of erythroid cells and rescues neurons from hypoxic damage. In addition to human papillomavirus infection, increased bcl-2 expression and decreased apoptosis are thought to play a role in the progression of cervical neoplasia. Using reverse transcriptase-polymerase chain reaction and Western blotting we showed that HeLa and SiHa cervical carcinoma cells and human cervical carcinomas express EpoR, and that hypoxia enhances EpoR expression. Exogenous Epo stimulated tyrosine phosphorylation and inhibited the cytotoxic effect of cisplatin in HeLa cervical carcinoma cells. Using immunohistochemistry, we examined the expression of Epo, EpoR, p16, hypoxia-inducible factor (HIF)-1alpha, and bcl-2 in benign and dysplastic cervical squamous epithelia and invasive squamous cell carcinomas (ISCCs). EpoR expression in benign epithelia was confined to the basal cell layers, whereas in dysplasias it increasingly appeared in more superficial cell layers and showed a significant correlation with severity of dysplasia. Diffuse EpoR expression was found in all ISCCs. Expression of Epo and HIF-1alpha was increased in dysplasias compared to benign epithelia. Focal Epo and HIF-1alpha expression was seen near necrotic areas in ISCCs, and showed correlation in their spatial distribution. Significant correlation was found between expression of EpoR, and p16 and bcl-2 in benign and dysplastic squamous epithelia. Our results suggest that increased expression of Epo and EpoR may play a significant role in cervical carcinogenesis and tumor progression. Hypoxia-inducible Epo signaling may play a significant role in the aggressive behavior and treatment resistance of hypoxic cervical cancers.

Carcinoma, Squamous Cell↗
PubMed2003

Microglandular adenosis with transition into adenoid cystic carcinoma of the breast.

Microglandular adenosis (MGA) is a well-recognized, if rare and incompletely characterized, entity in which carcinoma is rarely thought to develop. We report 17 cases in which patterns of adenoid cystic carcinoma (ACC) coexisted with MGA. Immunocharacterization with beta-catenin, E-cadherin, cytokeratins (AE1/AE3), epithelial membrane antigen, S-100 protein, smooth muscle actin, and vimentin was also performed. Most cases had areas of invasive ACC characterized by its defining dual-lumen types. Some cases of ACC appeared to have expanded glands intermingled within the MGA, whereas in other cases ACC formed a transition with the characteristic small, gland-like spaces of MGA. MGA and "atypical MGA" stained irregularly and similarly to that seen in myoepithelium with the three markers of myoepithelial cells in breast: S-100 protein, smooth muscle actin, and vimentin. These markers were also positive in the more solid elements of the ACC. Our study suggests that ACC may develop in a background of and in continuity with MGA. Altered myoepithelial cells appear to be the major neoplastic element in both ACC and "atypical MGA." "Atypical MGA" with transition to ACC may show histologic patterns and an immunohistochemical profile similar to that of ACC. These lesions might be best interpreted as ACC in situ. Both MGA and ACC of the breast grow in an expansile and diffusely infiltrative pattern without having significant metastatic capacity. Their unusual interaction with the surrounding stroma may play a role in this benign biologic behavior.

Adult↗
PubMed2003

C-kit immunoreactivity in endometrial adenocarcinomas and its clinicopathologic significance.

The proto-oncogene c-kit is a transmembrane-tyrosine-kinase receptor that is structurally related to the platelet-derived growth-factor receptor (PDGFR) and is involved in cell differentiation. C-kit has been found to be expressed in certain solid tumors and may play a role in their tumorigenesis. Recently, a tyrosine-kinase inhibitor specific for the PDGFR family, bcr-abl, and c-kit (STI571) has been reported to have therapeutic effects in tumors expressing the aberrant forms or high quantities of target proteins. Expression of c-kit has not been well evaluated in endometrial adenocarcinomas. In this study, c-kit immunoreactivity was evaluated on paraffin sections of 72 endometrial adenocarcinomas (57 endometrioid, 10 serous, and 5 clear cell) with a polyclonal antibody. Immunoreactivity of c-kit was analyzed semiquantitatively and correlated with various clinicopathologic factors. Cytoplasmic c-kit immunoreactivity was detected in 42 (58%) tumors. Thirty-four (60%) endometrioid, 8 (80%) serous, and 0 of the 5 clear-cell adenocarcinomas were c-kit positive. There was a significant correlation between c-kit positivity and the depth of myometrial invasion. Patients with c-kit-positive endometrial adenocarcinomas more frequently had metastases and shorter disease-free survival. Expression of c-kit may be a potentially adverse prognostic feature in endometrial adenocarcinoma. Patients with c-kit-positive advanced endometrial adenocarcinoma might benefit from tyrosine-kinase-inhibitor therapy.

Adenocarcinoma↗
PubMed2003

Role of different immunostaining patterns in HercepTest interpretation and criteria for gene amplification as determined by fluorescence in situ hybridization.

Immunohistochemical (IHC) detection of HER-Z overexpression by HercepTest on paraffin sections has been proposed for selecting patients with metastatic breast carcinoma for Herceptin therapy. Interpretation of intermediate (2+) reactivity could be subjective and has been shown to have low concordance with fluorescence in situ hybridization (FISH). FISH assay for gene amplification (GA) has been used as a confirmatory test in equivocal cases with different criteria judging gene amplification. A wide range of discordance between IHC and FISH has been reported in the literature, with ongoing debate about which assay is more accurate for HER-Z test. Little attention has been paid to the role of different criteria in judging protein overexpression on IHC and GA on FISH. We evaluated HER-Z overexpression and GA by IHC (HercepTest) and FISH (PathVysion), respectively, on paraffin sections of 142 primary breast carcinomas. For the HercepTest, in addition to scoring guidelines proposed by the manufacturer, scoring systems taking into consideration the pattern of membranous staining and staining in benign epithelium were also evaluated. For the FISH assay, the ratios of HER-Z:CEP17, HER-Z:cell, and CEP17:cell were used to evaluate the impact of the different criteria for determining GA. HER-Z overexpression was detected in 53 (37.3%), 48 (33.8%), and 36 (25.4%) cases according to the HercepTest, normal epithelium-modified, and pattern-modified scoring systems, respectively. The HER-Z gene was considered amplified in 41 (28.9%), 37 (26.1%), and 34 (23.9%) cases according to the HER-Z:cell criteria, HER-Z:CEP17 criteria, and the combined criteria, respectively. Our results suggest that a high concordance (95.8%) between HER-Z overexpression and GA can be achieved by using more stringent pattern-modified criteria for judging protein overexpression and combined criteria for GA.

Breast Neoplasms↗
PubMed2002

Immunohistochemical expression of erythropoietin and erythropoietin receptor in breast carcinoma.

BACKGROUND: Erythropoietin (Epo), induced by hypoxia, controls the survival, proliferation, and differentiation of Epo receptor (EpoR)-bearing erythroid progenitors and plays a role in the protection of neurons from hypoxic damage. Hypoxia in malignant disease is associated with invasion, metastasis, resistance to therapy, and selection for cells with diminished apoptotic potential. The authors recently demonstrated the basal and hypoxia-stimulated expression of Epo and EpoR in human breast carcinoma cell lines and in breast carcinomas, suggesting a role for autocrine Epo signaling in the hypoxic adaptations of mammary neoplasms. METHODS: The authors characterized the expression of Epo and EpoR by immunohistochemistry in 184 invasive mammary carcinomas and 158 in situ mammary carcinomas and benign mammary epithelium. They analyzed the correlation of Epo and EpoR immunostaining with clinicopathologic tumor features and the patients' smoking history. RESULTS: Benign mammary epithelial cells showed weak-to-moderate expression of Epo and EpoR. EpoR immunostaining was increased in carcinomas compared with benign epithelium both in nonsmokers and smokers, and Epo immunostaining was increased in carcinomas compared with benign epithelium in nonsmokers but not in smokers. Prominent Epo staining was seen in tumor cells adjacent to necrotic areas and at the infiltrating edge of tumors. EpoR staining, but not Epo staining, was significantly greater in tumors that showed high histologic grade, tumor necrosis, lymphovascular invasion, lymph node metastases, and loss of hormone receptor expression. CONCLUSIONS: The current findings suggest that increased EpoR expression may play an important role in breast carcinogenesis. The induction of autocrine or paracrine Epo signaling may represent a novel mechanism by which hypoxia can promote breast carcinoma.

Breast Neoplasms↗
PubMed2002

Intraoperative consultation in gynecologic pathology.

Intraoperative consultation is widely used in gynecologic surgical practice to make intraoperative diagnosis, primarily to aid the surgeon to plan the extent of surgery. This article reviews the indications, performance and interpretation, accuracy and diagnostic pitfalls in the three major areas of gynecologic malignancies where intraoperative consultations are most frequently requested: ovarian masses, endometrial carcinoma and carcinoma of the cervix. For ovarian masses intraoperative consultation is usually requested either for histologic confirmation of malignant or borderline primary ovarian tumors before proceeding with radical surgery, or to rule out malignancy at the time of surgery for presumed benign disease. The diagnosis of endometrial carcinoma is usually made preoperatively before definitive surgical treatment. Thus, intraoperative consultation is most often used to identify the subgroup of patients with features of high risk disease who have an increased risk of metastases and who will benefit from formal surgical staging. In cases of carcinoma of the cervix frozen section is most commonly used to estimate the extent of spread of known invasive carcinoma at the time of radical surgery. Despite its restrictions, frozen section diagnosis is an important and reliable tool in the clinical management of patients with ovarian, endometrial and cervical tumors. The specificity of the method in experienced hands is high, the sensitivity is sufficient. The diagnosis of borderline ovarian tumors may be troublesome however, mainly due to their heterogeneity in appearance, especially in the case of large tumors of mucinous histologic type. It is important for pathologists to have a clear idea of the role and limitations of frozen section diagnosis in gynecological surgery in order to play a meaningful and optimal role in the management of the gynecologic oncology patient.

Female↗
PubMedDate not supplied

HIF transcription factor expression and induction of hypoxic response genes in a retroperitoneal angiosarcoma.

Angiosarcoma is a rare and highly aggressive tumor of endothelial origin. The molecular mechanisms driving angiosarcoma growth have not been fully elucidated, although autocrine stimulation by vascular endothelial growth factor (VEGF) secretion may play a role in the pathogenesis of this tumor. We identified a patient with a very rare form of angiosarcoma arising from the retroperitoneum. Immunohistochemical analysis demonstrated widespread up-regulation of the hypoxic response pathway as a mechanism of enhanced VEGF expression. Disordered regulation of the hypoxic response pathway can result in the expression of factors such as VEGF and erythropoietin, which may promote autocrine tumor growth in angiosarcoma.

Basic Helix-Loop-Helix Proteins↗