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Biomedical subjects

Kalman Kovacs

Publications and source records attributed to Kalman Kovacs.

At least 19 recordsLinked to original sources
PubMed2006

Temozolomide therapy in a man with an aggressive prolactin-secreting pituitary neoplasm: Morphological findings.

Administration of temozolomide to a 46-year-old man with an invasive aggressive prolactin (PRL)-secreting pituitary neoplasm resulted in improvement of the clinical condition and significant decrease of blood PRL levels. Histologic, immunohistochemical, and electron microscopic study demonstrated marked morphological differences in the tumor exposed to temozolomide compared with the unexposed tumor. Necrosis, hemorrhagic areas, accumulation of connective tissue, focal inflammatory infiltration, and neuronal transformation were seen. Immunohistochemical prognostic indicators showed a reduction in growth potential. Based on the clinical, laboratory, and morphological findings, we recommend temozolomide therapy in patients with pituitary tumors not responding adequately to other treatment options.

Antineoplastic Agents, Alkylating↗
PubMed2006

Pathology of acromegaly.

This review summarizes current knowledge on pituitary changes in patients with acromegaly. The histologic, immunohistochemical and electron microscopic study provided conclusive evidence that a marked diversity exists between the tumors which secrete growth hormone (GH) in excess, such as densely and sparsely granulated GH cell adenoma, the mixed GH prolactin cell adenoma and the mammosomatotrope adenoma. The latter two tumors produce GH and prolactin simultaneously. Densely granulated GH cell tumors may produce thyrotropin and alpha subunit as well. Somatotrope carcinomas are extremely rare. GH cell hyperplasia can also be associated with acromegaly in patients with extrapituitary GH-releasing hormone secreting tumors. The medical therapy of acromegaly is reviewed briefly, including long-acting somatostatin analogs and pegvisomant, a GH receptor blocker.

Acromegaly↗
PubMed2006

Pituitary tumor transforming gene overexpression facilitates pituitary tumor development.

Intrinsic and extrinsic stimuli result in profound pituitary growth changes ranging from hypoplasia to hyperplasia. Pituitary tumor transforming gene (PTTG) abundance correlates with pituitary trophic status. Mice with Pttg inactivation exhibit pituitary hypoplasia, whereas targeted pituitary PTTG overexpression driven by alpha-subunit glycoprotein (alphaGSU) promoter results in focal pituitary hyperplasia. To test the impact of pituitary hyperplasia on tumor development, we crossbred alphaGSU.PTTG with Rb+/- mice, which develop pituitary tumors with high penetrance. Pituitary glands of resulting bitransgenic alphaGSU.PTTGxRb+/- mice were compared with monotransgenic alphaGSU.PTTG, Rb+/-, and wild-type mice. Confocal microscopy showed that PTTG-overexpressing cells have enlarged nuclei and marked redistribution of chromatin, and electron microscopy of alphaGSU.PTTG pituitaries showed enlarged gonadotrophs with prominent Golgi complexes and numerous secretory granules. These morphological findings were even more remarkable in alphaGSU.PTTGxRb+/- pituitaries. Mice from all four genotypes were sequentially imaged by magnetic resonance imaging to evaluate pituitary volume, and glands from alphaGSU.PTTGxRb+/- mice were the largest as early as 2 months of age (P = 0.0003). Cumulative incidence of pituitary tumors visualized by magnetic resonance imaging did not differ between Rb+/- and alphaGSU.PTTGxRb+/- mice. However, anterior lobe tumors determined after necropsy were 3.5 times more frequent in alphaGSU.PTTGxRb+/- than in Rb+/- mice (P = 0.0036), whereas the frequency of intermediate lobe tumors was similar. In summary, alphaGSU.PTTGxRb+/- pituitary glands exhibit enhanced cellular activity, increased volume, and higher prevalence of anterior pituitary tumors, indicating that changes in pituitary PTTG content directly relate to both pituitary trophic status and tumorigenic potential.

Animals↗
PubMed2006

Immunohistochemical expression of nestin in the non-tumorous hypophysis and in pituitary neoplasms.

The aim of the present work was to investigate whether nestin, a member of the intermediate filament family, is immunohistochemically expressed in the non-tumoral human hypophysis and pituitary neoplasms. Twenty-three normal pituitaries and 125 pituitary neoplasms were included. The tissues were formalin-fixed and paraffin embedded. The neoplasms were identified on hematoxylin-eosin stained sections and were classified by immunohistochemistry as well as electron microscopy. For immunohistochemistry, the streptavidin-biotin-peroxidase complex method was applied using appropriate controls. Several corticotrophs in the autopsy obtained pituitaries showed cytoplasmic nestin immunopositivity. No nestin immunoreactivity was found in other cell types in non-tumorous adenohypophyses and in the cells of various pituitary adenomas. Nestin was, however, expressed in a small proportion of endothelial cells in both anterior and posterior lobes. Staining was also noted in several pituicytes, neurohypophysial nerve fibers, and Herring bodies. In contrast to CD-34 and Factor-8 immunostaining which demonstrated immunopositivity in practically all endothelial cells of every capillary, nestin expression was only focally seen suggesting that the functional status of the immunoreactive and non-staining endothelial cells was not the same. No statistically significant correlation was apparent between nestin immunoreactivity and patient age, gender, tumor size, mitotic index, Ki-67, labeling nuclear index, hormonal immunoprofile, and tumor type. In conclusion, nestin expression in adenomas cannot be viewed as a biologically relevant marker of cell proliferation and as a prognostic indicator. The patchy expression of nestin in endothelial cells remains unexplained and its significance requires further studies.

Adenoma↗
PubMed2006

Modulation of VEGF/Flk-1 receptor expression in the rat pituitary GH3 cell line by growth factors.

Both vascular endothelial growth factor (VEGF) and its receptor Flk-1 are expressed in normal pituitary cells and in the prolactin- and growth hormone-producing GH3 cell line of the rat, thus suggesting autocrine/paracrine function. Regulation of the Flk-1 receptor system in pituitary cells is poorly understood, but evidence suggests that up-regulated growth factors play a role in its expression and activation. To study the role of growth factors in this process, we examined changes in VEGF and Flk-1 expression in GH3 cells following varied exposure to betaFGF, EGF, and TGFbeta1. Immunofluorescence labelling and laser scanning cytometry were used to measure changes in VEGF and Flk-1 expression. Results showed that betaFGF, EGF and TGFbeta up-regulated the VEGF/FLK-1 receptor system. Distinct patterns of activation were detected. At 2 hours, EGF and TGFbeta caused no significant changes in VEGF and Flk-1 expression; however, betaFGF up-regulated VEGF expression in 99% of cells but only induced modest changes in Flk-1 overexpression. A similar percentage of cells overexpressed VEGF after 24-hour incubation with betaFGF, but more prominent Flk-1 overexpression was detected. At 24 hours, EGF and TGFbeta1 induced a significant increase in both VEGF and Flk-1 expression. In summary, our findings show that VEGF/Flk-1 expression in pituitary cells may be altered by different growth factors. This may affect angiogenesis and the progression of pituitary tumors.

Animals↗
PubMed2006

Vascularization of rat pituitary autografts.

Pituitary autotransplantation eliminates direct vascular contact between the hypothalamus and the adenohypophysis, and enables us to study the role of the hypothalamus in regulating adenohypophysial endocrine activity. The aim of this study was to investigate vascularization of the pituitary autografts. Three-month-old male Wistar rats were hypophysectomized, and their adenohypophyses were autotransplanted under the renal capsule. The animals were killed 3 weeks after autotransplantation. The grafts were removed and studied by using histology, immunohistochemistry and transmission electron microscopy. In the central portion of the grafts, organizing necrosis was apparent. The peripheral portion of the graft contained all adenohypophysial cell types, with a predominance of lactotrophs. Vascular endothelial growth factor and hypoxia-inducible factor were expressed in the graft mainly in the perinecrotic areas. Several capillaries inside the grafts were lined by continuous unfenestrated epithelium, while others were lined by fenestrated endothelium, suggesting that neovascularization is the result of two processes: ingrowths of capillaries from the renal capsule to the graft, and neoformation of capillaries from pre-existing adenohypophysial vessels. In conclusion, hypoxia seems to be an important factor in the vascularization of pituitary autografts. Mediated via hypoxia-inducible factor, hypoxia stimulates vascular endothelial growth factor secretion, which plays a crucial role in angiogenesis.

Animals↗
PubMed2006

Hypophysectomy and neurointermediate pituitary lobectomy reduce serum immunoglobulin M (IgM) and IgG and intestinal IgA responses to Salmonella enterica serovar Typhimurium infection in rats.

The influence of anterior pituitary hormones on the gastrointestinal tract of humans and animals has been reported. Hypophysectomy (HYPOX) in the rat causes atrophy of the intestinal mucosa, reduction of gastric secretion and intestinal absorption, and increased susceptibility to infections. To our knowledge, there are no studies on the humoral immune response of the gut-associated lymphoid tissue after HYPOX. We have reported that decreased secretion of vasopressin and oxytocin due to neurointermediate pituitary lobectomy (NIL) diminishes humoral and cell-mediated immune responses. However, no data have been published on whether NIL can affect intestinal immune responses. We analyzed the effects of HYPOX and NIL on bacterial colonization of the intestinal lumen, Peyer's patches, and spleen as well as the serum immunoglobulin G (IgG) and IgM and specific intestinal IgA levels in response to Salmonella enterica serovar Typhimurium oral infection. Results showed the following: (i) Salmonella serovar Typhimurium was eliminated from the intestinal lumen at the same rate in rats that underwent a sham operation, HYPOX, and NIL; (ii) Salmonella serovar Typhimurium colonization of Peyer's patches and spleen was significantly higher in both HYPOX and NIL rats than in sham-operated rats; (iii) serum IgG and IgM and intestinal IgA against surface proteins of Salmonella serovar Typhimurium were significantly lower in HYPOX and NIL rats than in sham-operated rats; and (iv) compared to NIL rats, higher Peyer's patch and spleen bacterial colonization and decreased IgG, IgM, and IgA production were observed in HYPOX rats. We conclude that hormones from each pituitary lobe affect the systemic and gastrointestinal humoral immune responses through different mechanisms.

Animals↗
PubMed2006

Patterns of gene expression in pituitary carcinomas and adenomas analyzed by high-density oligonucleotide arrays, reverse transcriptase-quantitative PCR, and protein expression.

Very few of the genes that are important in pituitary tumor initiation, progression, and metastasis have been identified to date. To identify potential genes that may be important in pituitary tumor progression and carcinoma development, we used Affymetrix GeneChip HGU-133A-oligonucleotide arrays, which contain more than 15,000 characterized genes from the human genome to study gene expression in an ACTH pituitary carcinoma metastatic to the liver and four pituitary adenomas. Reverse-transcriptase real-time quantitative- PCR (RT-qPCR) was then used to analyze 4 nonneoplastic pituitaries, 19 adenomas, and the ACTH carcinoma. A larger series of pituitary adenomas and carcinomas were also analyzed for protein expression using tissue microarrays (TMA) (n = 233) and by Western blotting (n = 18). There were 4298 genes that were differentially expressed among the adenomas compared to the carcinoma, with 2057 genes overexpressed and 2241 genes underexpressed in the adenomas. The beta-galactoside binding protein galactin-3 was underexpressed in some adenomas compared to the carcinomas. Prolactin (PRL) and ACTH tumors had the highest levels of expression of galectin-3. The human achaetescute homolog-1 ASCL1 (hASH-1) gene was also underexpressed in some adenomas compared to the carcinoma. Prolactin and ACTH tumors had the highest levels of expression of hASH-1. ID2, which has an important role in cell development and tumorigenesis, was underexpressed in some adenomas compared to the carcinomas. Transducin-like enhancer of split four/ Groucho (TLE-4) was over-expressed in adenomas compared to the ACTH carcinoma. The differential expression of these genes was validated by RT-qPCR, by immunohistochemistry using TMA and by Western blotting. These results indicate that the LGALS3, hASH1, ID2, and TLE-4 genes may have important roles in the development of pituitary carcinomas.

ACTH-Secreting Pituitary Adenoma↗
PubMed2006

Diversity of ACTH-immunoreactive cells in the human adenohypophysis: an immunohistochemical study with special reference to cluster formation and follicular cell association.

Horvath et al. called relatively small ACTH-immunoreactive (ACTH-IR) cells observed in basophil invasion "proopiomelanocortin (POMC) cells," and these cells were supposed to be different from larger ACTH-IR cells in human adenohypophysis. To clarify the existence of "anterior POMC cells," we examined 21 autopsy cases taking note of follicular cells (FCs). We found that smaller ACTH-IR cells were clustered forming small areas without FC association, clustered small cell island (CSCI). CSCI was found in all the specimens we examined using immunohistochemical staining for ACTH and cytokeratin (AE1/AE3) in serial sections. ACTH-IR cells outside CSCI were of various sizes, mainly consisting of larger ACTH-IR cells that were diffusely scattered among other hormone-secreting cells and closely associated with FCs. By immunohistochemistry, ACTH-IR cells within CSCI and basophil invasion showed uniformly weak reactivity and common patterns for cytokeratins (CAM5.2 and 35 beta H11), carboxypeptidase D, and LeuM1, whereas those outside CSCI showed a great variety of immunoreactivity. The similarity in the immunoreactivity of ACTH-IR cells between CSCI and basophil invasion suggests that ACTH-IR cells in these two areas have common characteristics and ACTH-IR cells in CSCI are most likely "POMC cells." The clustered "anterior POMC cells" may be distinguishable by light microscopic immunohistochemistry.

Adrenocorticotropic Hormone↗
PubMed2005

Morphologic changes of prolactin-producing pituitary adenomas after short treatment with dopamine agonists.

Treatment of patients with prolactin (PRL)-producing pituitary adenomas with dopamine agonists has proved successful for most cases. Dopamine agonists inhibit PRL secretion, suppress cell proliferation, and may induce apoptosis to adenoma cells. Dopamine agonists induce striking morphologic changes in the majority of treated PRL-producing adenomas. To date, these morphologic effects have been primarily described only after long-term treatment. To the best of our knowledge, no similar studies have investigated apoptotic alterations induced after short-term therapy. The purpose of this report is to describe the morphologic changes seen in PRL-producing adenomas after short-term dopamine agonist treatment. We present two cases of PRL-producing macroadenomas, both from male patients who received treatment with dopamine agonists, the first for 5 and the second for 8 days. In contrast to long-term treatment, no striking reduction of PRL immunoreactivity was noted. Slight stromal fibrosis was noted in case 1, which contained several cells all in late phase of apoptosis. In addition to typical apoptotic cells, numerous "dark" cells representing another common form of cell death were also noted. These novel findings represent characteristic features of short-term dopamine agonist treatment, which are not seen in long-term treatment.

Adult↗
PubMed2005

The implication of somatotroph adenoma phenotype to somatostatin analog responsiveness in acromegaly.

CONTEXT: Persistently elevated GH and IGF-I levels are associated with increased mortality. Their response to somatostatin analogs (SSA) is variable. OBJECTIVE: The objective of this study was to examine the significance of somatotroph adenoma type on response to SSA. DESIGN: This study was a retrospective examination of postoperatively treated acromegalic patients with the SSA octreotide. SETTING: The study was performed at a university-affiliated tertiary care center. PATIENTS: Forty patients with acromegaly were studied. MAIN OUTCOME MEASURES: Normalization of IGF-I levels and GH responses were the main outcome measures. RESULTS: Univariate analysis revealed that responders were more likely to have densely granulated somatotroph adenomas (80% vs. 43.8%; P = 0.024), to be older (51.3 vs. 38.2 yr; P < 0.003), to have smaller tumors (stage < or =3; 78.6% vs. 35.7%; P = 0.022), to have lower baseline IGF-I (453 vs. 716 microg/liter; P < 0.001) and GH levels (2.7 vs. 7.8 microg/liter; P < 0.05), and to require a lower maximum dose of SSA (24 vs. 31 mg every 4 wk; P = 0.013). Multivariate analysis confirmed that a densely granulated adenoma was the strongest predictor of complete response [adjusted odds ratio (OR), 58.41; 95% confidence interval (CI), 1.24-1000.00; P = 0.04] compared with other covariates, including older age at time of diagnosis (OR, 1.15/yr; 95% CI, 1.01-1.31; P = 0.03), and tumor stage of 3 or less (OR, 29.77; 95% CI, 1.01-885.45; P < 0.05). CONCLUSIONS: Somatotroph tumor type represents a strong clinical predictor of response to SSA treatment and will help to identify patients who warrant more vigilant management of their disease.

Acromegaly↗
PubMed2005

Pituitary hypoplasia in Pttg-/- mice is protective for Rb+/- pituitary tumorigenesis.

Pituitary tumor transforming gene (Pttg) is induced in pituitary tumors and associated with increased tumor invasiveness. Pttg-null mice do not develop tumors, but exhibit pituitary hypoplasia, whereas mice heterozygous for the retinoblastoma (Rb) deletion develop pituitary tumors with high penetrance. Pttg-null mice were therefore cross-bred with Rb+/- mice to test the impact of pituitary hypoplasia on tumor development. Before tumor development, Rb+/-Pttg-/- mice have smaller pituitary glands with fewer cycling pituitary cells and exhibit induction of pituitary p21 levels. Pttg silencing in vitro with specific short hairpin interfering RNA in AtT20 mouse corticotrophs led to a marked induction of p21 mRNA and protein levels, decreased RB phosphorylation, and subsequent 24% decrease in S-phase cells. Eighty-six percent of Rb+/-Pttg+/+ mice develop pituitary adenomas by 13 months, in contrast to 30% of double-crossed Rb+/-Pttg-/- animals (P < 0.01). Pituitary hypoplasia, associated with suppressed cell proliferation, prevents the high penetrance of pituitary tumors in Rb+/- animals, and is therefore a protective determinant for pituitary tumorigenesis.

Animals↗
PubMed2005

Effects of DNA methylation on galectin-3 expression in pituitary tumors.

Galectin-3 (Gal-3), a beta-galactoside-binding protein is expressed in a specific cell-type manner in pituitary tumors. Here we questioned the mechanism of Gal-3 expression in pituitary tumors, by using methylation-specific PCR and DNA sequence analyses to analyze the methylation status of the promoter region of the LGALS3 gene. DNA analysis of a human pituitary tumor, breast carcinoma cell lines, and thyroid carcinoma cell lines showed that in cells expressing Gal-3 protein, the LGALS3 gene was unmethylated, whereas in Gal-3 null cells, the promoter of the LGALS3 gene was methylated. Treatment of cells with 30 mumol/L 5-aza-2'-deoxycytidine induced Gal-3 mRNA and protein expression. Among pituitary tumors, 30% (7/23), mainly in follicle-stimulating hormone/luteinizing hormone-producing (38%) and null cell (57%) adenomas, the promoter of the LGALS3 was found to be methylated and silenced, although prolactin- and adrenocorticotropic hormone-producing tumors, which were unmethylated, expressed the Gal-3 protein. These results show for the first time that Gal-3 expression is regulated in part by promoter methylation in pituitary as well as in other tumors. Because it is functionally involved in cancer progression and metastasis, Gal-3 may serve as a possible therapeutic target in the treatment of pituitary tumors.

Adenoma↗
PubMed2005

MAP-2 expression in the human adenohypophysis and in pituitary adenomas. An immunohistochemical study.

MAP-2, a well characterized member of the microtubule associated protein (MAP) family, binds to and stabilizes microtubules and is involved in cell proliferation as well as neuronal differentiation. The aim of the present work was to study MAP-2 expression in human adenohypophyses and pituitary adenomas. To our knowledge, data regarding MAP-2 expression in human pituitaries has not been reported to date. For immunohistochemistry, the streptavidin-biotin-peroxidase complex method was used. Nine non-tumorous adenohypophyses and 77 adenomas (GH-, PRL-, ACTH-, TSH-, FSH/LH- and/or alpha subunit- producing or immunonegative tumors) were investigated. The results show that MAP-2 is expressed in the cytoplasm of non-tumorous adenohypophysial cells as well as of various pituitary adenoma types. No significant correlation was found between MAP-2 expression and gender, patient age, mitotic activity, MIB-1 labelling indices, hormone immunoprofile, and endocrine status, ie. hormonal activity or lack thereof. Thus MAP-2 expression cannot be used to estimate cell proliferation rate, growth potential, endocrine activity or biologic behaviour of an adenoma. Immunopositivity appeared to be stronger in the cytoplasm of adenoma cells than in that of non-tumorous adenohypophysial cells, implying that the adenoma cells contain larger quantities of MAP-2. It can be concluded that the functional activity of MAP-2 is not associated with the manufacture of any specific adenohypophysial hormone(s) and is not limited to one specific cell type.

Adenoma↗
PubMed2005

Sellar neuroblastoma mimicking pituitary adenoma.

OBJECTIVE AND IMPORTANCE: Primary intracranial neuroblastomas are rare. They generally arise in the supratentorial parenchyma or paraventricular region. Even more rare are primary sellar neuroblastomas. We present a neuroblastoma that arose in the sellar region and mimicked a non-functioning pituitary adenoma. CLINICAL PRESENTATION: This 33-year-old man presented with bitemporal hemianopsia. MRI showed a sellar mass with suprasellar extension mimicking a pituitary adenoma. INTERVENTION: Because of tumor recurrence and dissemination to the cervical region, he underwent 6 operations and radiosurgery. Detailed histologic examination confirmed the diagnosis of neuroblastoma. Postoperative conventional radiotherapy was effective in reducing the size of the tumor. CONCLUSION: Neuroblastoma should be considered in the differential diagnosis of patients with sellar lesions.

Adenoma↗
PubMed2005

Immunohistochemical study on so-called follicular cells and folliculostellate cells in the human adenohypophysis.

Non-hormone-secreting cells in human adenohypophysis have been designated as either follicular cells (FC) or folliculostellate cells (FSC). They have similarly long cytoplasmic processes, and the difference between FC and FSC remains unclear. An immunohistochemical study for S-100 protein, cytokeratin (CK, detected by AE1/AE3) and glial fibrillary acidic protein (GFAP) was performed in autopsy pituitaries. Double immunohistochemistry for S-100 protein and CK revealed that there were numerous coexpressed cells. The most frequent type ('CK-type cell') was cells weakly positive for S-100 protein in the nucleus and for CK-immunoreactivity in the cytoplasm. The next numerous type ('S-100 protein cell') was cells strongly positive for S-100 protein and weakly positive or negative for CK. The CK-type cells were frequently observed in the vicinity of follicular structures and in neighborhood of adrenocorticotropic hormone -immunoreactive cells, and were most likely the cells termed FC. They were often observed around necrotic areas. The S-100 protein cells were individually found in the circumference of endocrine cell nest, and seemed to be the so-called stellate cells. GFAP-positive cells were rare. It is implied that S-100 protein-positive FSC could be divided into at least two main subtypes: FC (CK-type cells) and stellate cells (S-100 protein cells).

Adrenocorticotropic Hormone↗