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M Papotti

Publications and source records attributed to M Papotti.

At least 73 records · Page 4Linked to original sources
PubMed2000

Growth hormone secretagogue binding sites in peripheral human tissues.

The family of GH secretagogues (GHS) includes peptidyl (hexarelin) and nonpeptidyl (MK 0677) molecules possessing specific receptors in the brain, pituitary, and thyroid. GHS receptor subtypes have also been identified in the heart; and a gastric-derived peptide, named ghrelin, has recently been proposed as a natural ligand. Our aim was to investigate the presence of GHS receptors in a wide range of human tissues, by radioreceptor assay with [125I]Tyr-Ala-hexarelin. GHS receptors were detected mainly in the myocardium, but they were also present (in order of decreasing binding activity) in adrenal, gonads, arteries, lung, liver, skeletal muscle, kidney, pituitary, thyroid, adipose tissue, veins, uterus, skin, and lymphnode. In contrast, negligible binding was found in parathyroid, pancreas, placenta, mammary gland, prostate, salivary gland, stomach, colon, and spleen. Hexarelin, MK 0677, and human ghrelin completely displaced the radioligand from binding sites of endocrine tissues, but MK 0677 and ghrelin were less potent than hexarelin. In nonendocrine tissues, both MK 0677 and ghrelin were inactive in displacement of [125I]Tyr-Ala-hexarelin, whereas hexarelin was as active as a displacing agent in endocrine tissues. This study provides the first detailed analysis of the tissue localization of GHS receptors and suggests that a still unknown receptor subtype, specific for peptidyl GHS, may exist in the heart and in other tissues.

Adult↗
PubMed2000

Specific binding sites for synthetic growth hormone secretagogues in non-tumoral and neoplastic human thyroid tissue.

The presence of specific receptors for synthetic growth hormone secretagogues (GHSs) has been investigated in non-tumoral and neoplastic human thyroid tissue using a radio-iodinated peptidyl GHS ((125)I-labelled Tyr-Ala-hexarelin) as ligand. Specific binding sites for Tyr-Ala-hexarelin were detected in membranes from non-tumoral and follicular-derived neoplastic thyroid tissue, but not in thyroid tumours (medullary carcinomas) of parafollicular (C cell) origin. The binding activity was greatest in well differentiated neoplasms (papillary and follicular carcinomas), followed by poorly differentiated carcinomas, non-tumoral thyroid parenchyma, follicular adenomas and anaplastic carcinomas. Both peptidyl (Tyr-Ala-hexarelin, hexarelin, growth hormone releasing peptide (GHRP6) and non-peptidyl (MK 0677) GHSs completely displaced the radioligand from binding sites of non-tumoral thyroid gland, but MK 0677 was significantly less potent. The IC(50) values were (1. 9+/-0.3)x10(-8) mol/l for Tyr-Ala-hexarelin, (2.1+/-0.2)x10(-8) mol/l for hexarelin, (2.4+/- 0.3)x10(-8) mol/l for GHRP6 and only (1. 5+/-0.4)x 10(-7) mol/l for MK 0677. Similar IC(50) values were found in neoplastic thyroid tissue. Scatchard analysis of the binding revealed a finite number of binding sites in non-tumoral (B(max): 1232+/-32 fmol/mg protein, n=3) and neoplastic (papillary carcinomas) thyroid tissue (B(max): 2483+/-380 fmol/mg protein, n=5), with dissociation constants (K(d)) of (3.8+/-0.3)x10(-9) and (4. 4+/-0.6)x 10(-9) mol/l, respectively. On the basis of this evidence, we investigated the effects of some GHS on the proliferation of three different human follicular thyroid carcinoma cell lines (NPA, WRO and ARO) in which the presence of specific GHS receptors was also demonstrated. Tyr-Ala-hexarelin, GHRP6 and MK 0677 were able to inhibit serum-stimulated [(3)H]thymidine incorporation in NPA cells at concentrations close to their binding affinity. These substances also caused a significant inhibition of cell proliferation, which was evident at the earliest time of treatment (24 h) in all the cell lines, and at the latest time (96 h) in NPA cells only. In conclusion, this paper confirms the existence of specific binding sites for GHS in normal thyroid tissue and demonstrates, for the first time, that these binding sites are present in papillary and follicular carcinomas, low in anaplastic carcinomas and absent in medullary carcinomas of the thyroid. This work also provides evidence of a growth-inhibitory effect of GHS on cell lines derived from follicular thyroid cancers.

Binding Sites↗
PubMed2000

Growth hormone-releasing peptides and the cardiovascular system.

Growth Hormone (GH)-releasing peptides (GHRPs) and their non peptidyl analogues are synthetic molecules which exhibit strong, dosedependent and reproducible GH-releasing activity but also significant PRL- and ACTH/cortisol-releasing effects. An influence of these compounds on food intake and sleep pattern has been also shown. The neuroendocrine activities of GHRPs are mediated by specific receptors subtypes that have been identified in the pituitary gland, hypothalamus and various extra-hypothalamic brain regions with (125)I-Tyr-Ala-hexarelin, an octapeptide of the GHRP family. In addition, GHRP receptors were also present in different peripheral tissues such as heart, adrenal, ovary, testis, lung and skeletal muscle, with a density significantly higher than that found in the hypothalamo-pituitary -system. A remarkable specific (125)I-Tyr-Ala-hexarelin binding was observed in the human cardiovascular system where the highest binding levels were detected in ventricles, followed by atria, aorta, coronaries, carotid, endocardium and vena cava. The binding of the radioligand to cardiac membranes was inhibited by unlabeled Tyr Ala hexare lin and hexarelin as well as by GHRP-6, GHRP-1 and GHRP-2 but not by MK-677, a non peptidyl GHRP analog. In other experiments on H9c2 myocytes, a fetal cardiomyocytes-derived cell line, specific GHRP binding was found and hexarelin showed an anti-apoptotic activity. On the other hand, in vivo studies in animals and in humans showed that GHRPs possess direct cardiotropic actions. In fact, hexarelin protects from ischemia-induced myocardial damage in aged and GH deficient rats while hexarelin shows a positive inotropic effect in normal subjects as well as in patients with GH deficiency. In conclusion, GHRPs possess extra--neuroendocrine biological activity and, particularly, show direct GH-independent cardiotropic effects.

Animals↗
PubMed2000

Thyroid carcinomas with mixed follicular and C-cell differentiation patterns.

Divergent endocrine-neuroendocrine differentiation in thyroid carcinoma occurs in mixed medullary-follicular carcinomas (MMFC). Less than 40 cases of MMFC have been reported having highly heterogeneous patterns of growth. Classical medullary carcinoma areas may be intermingled with follicles or papillae or even oxyphilic and solid areas. Calcitonin and thyroglobulin are expressed in different cell populations. Presence of the latter suggests a potential usefulness of radioiodine treatment. The clinical behavior of MMFC does not differ from that of ordinary medullary carcinoma. The histogenesis of MMFC is controversial. The genetic analysis of the 2 neoplastic components showed that they are not derived from a common precursor, but rather display remarkable differences in the genetic profile (RET mutations and allelic losses). In addition, in some cases the follicular component was found to be oligo/polyclonal and therefore possibly hyperplastic rather than neoplastic. The follicular cells may have grown into the medullary carcinoma, after acquiring some molecular defect, being "hostage" of the true neoplastic (medullary) component.

Adenocarcinoma, Follicular↗
PubMed2000

Expression of the neuroendocrine phenotype in carcinomas of the breast.

Neuroendocrine (NE) features are detectable in carcinomas of the breast either as scattered cells immunoreactive for NE markers in carcinoma of the usual type (NOS), or as special type of tumors where the vast majority of the cells display NE characteristics. The former type of lesions, whose biological and diagnostic significance is not clear yet, might reproduce the same phenomenon known to occur in carcinomas of the gastrointestinal tract and pancreas. In the present review we focus on the latter type of lesions, a spectrum of breast tumors largely composed of NE cells. These carcinomas, that we consider the "NE differentiated carcinomas of the breast," are here distinguished from "breast carcinomas NOS with NE differentiation." The diagnostic and histogenetic features of the various types of "NE differentiated carcinomas of the breast," their histological and cytological features and the role and value of ancillary diagnostic techniques, are reviewed. Data of the literature are discussed and related to a relatively large personal series. In addition, divergent differentiation in NE carcinomas of the breast, which is a relatively frequent phenomenon of diagnostic interest but of unknown significance (mainly involving mucinous intra- and extracellular production) is discussed.

Biomarkers, Tumor↗
PubMed2000

Gonadotroph cell pituitary adenomas in males.

BACKGROUND: Considered exceptional in the past, gonadotroph cell pituitary adenomas account for 3.5-6.4% of total surgically excised pituitary adenomas when examined with immunospecific staining. The aim of this study was to describe the clinical, hormonal, radiological and immunohistochemical features, the management and the follow-up of our patients with gonadotroph adenoma. METHODS: In this retrospective study we describe 14 male subjects aged 19-70 yrs affected by gonadotroph cell pituitary adenomas; the patients were studied by hormonal, radiological and immunohistochemical investigations and followed up for 3-13 yrs by ambulatory and/or hospitalized care. RESULTS: Visual impairment and/or decreased libido and erectile dysfunction were the symptoms at presentation. Increased serum gonadotropin concentrations were shown in 3 patients. Reduced levels of testosterone were present in 9 patients, and normal in the remainder. At diagnosis all patients had pituitary macroadenomas, with wide extrasellar extension in 12. All patients underwent trans-sphenoidal surgery and immunohistochemical staining of surgically excised specimens showed the presence of gonadotroph and alpha-subunit cells in all pituitary adenomas. After surgery 3 patients had clear radiological evidence of normal pituitary; in the others a doubtful MRI picture or a residual adenomatous tissue were present. In the patients who did not undergo radiotherapy immediately after surgery, a regrowth of tumoral tissue was shown in 1-10 yrs. CONCLUSIONS: We stress the importance of a close follow-up of patients with gonadotroph adenomas after surgery, and we raise the question of whether radiotherapy may be useful for avoiding any further adenomatous regrowth.

Adenoma↗
PubMed1999

Mixed medullary-follicular thyroid carcinoma. Molecular evidence for a dual origin of tumor components.

Mixed medullary-follicular carcinomas (MMFCs) are tumors of the thyroid that display morphological and immunohistochemical features of both medullary and follicular neoplasms. The histogenetic origin and possible molecular mechanisms leading to MMFCs are still unclear. To address these questions, we have isolated the two histological components of 12 MMFCs by (laser-based) microdissection, analyzed them for mutations in the RET proto-oncogene and allelic losses of nine loci on six chromosomes, and studied the clonal composition of MMFCs in female patients. Our results provide strong evidence that the follicular and medullary components in MMFCs are not derived from a single progenitor cell, because the seven tumors amenable for analysis consistently exhibited a different pattern of mutations, allelic losses, and clonal composition. We also demonstrate that follicular structures in MMFCs are often oligo/polyclonal and more frequently exhibit hyperplastic than neoplastic histological features, indicating that at least a subset of MMFCs are composed of a medullary thyroid carcinoma containing hyperplastic follicles.

Adult↗
PubMed1999

Endocrine and non-endocrine activities of growth hormone secretagogues in humans.

Growth hormone (GH) secretagogues (GHS) are synthetic peptidyl and non-peptidyl molecules which possess strong, dose-dependent and reproducible GH releasing effects as well as significant prolactin (PRL) and adrenocorticotropic hormone (ACTH) releasing effects. The neuroendocrine activities of GHS are mediated by specific receptors mainly present at the pituitary and hypothalamic level but also elsewhere in the central nervous system. GHS release GH via actions at the pituitary and (mainly) the hypothalamic level, probably acting on GH releasing hormone (GHRH) secreting neurons and/or as functional somatostatin antagonists. GHS release more GH than GHRH and the coadministration of these peptides has a synergistic effect but these effects need the integrity of the hypothalamo-pituitary unit. The GH releasing effect of GHS is generally gender-independent and undergoes marked age-related variations reflecting age-related changes in the neural control of anterior pituitary function. The PRL releasing activity of GHS probably comes from direct pituitary action, which indeed is slight and independent of both age and gender. The acute stimulatory effect of GHS on ACTH/cortisol secretion is similar to that of corticotropin releasing hormone (CRH) and arginine vasopressin (AVP). In physiological conditions, the ACTH releasing activity of GHS is mediated by central mechanisms, at least partially, independent of both CRH and AVP but probably involving GABAergic mechanisms. The ACTH releasing activity of GHS is gender-independent and undergoes peculiar age-related variations showing a trend towards increase in ageing. GHS possess specific receptors also at the peripheral levels in endocrine and non-endocrine human tissues. Cardiac receptors are specific for peptidyl GHS and probably mediate GH-independent cardiotropic activities both in animals and in humans.

Adrenocorticotropic Hormone↗
PubMed1999

Oncocytic and oncocytoid tumors of the exocrine pancreas, liver, and gastrointestinal tract.

Tumors having typical oncocytic features very rarely affect the gastrointestinal (GI) tract, liver, and pancreas, although several tumors with prominent "pink" (eosinophilic) cytoplasm are recognizable in the digestive tract. From a practical point of view, interest in the former lesions is limited to the differential diagnosis of a primary neoplasm versus metastatic deposits of malignant oncocytic tumors from other sites. This article briefly reviews the diagnostic features and clinical significance of the currently known tumors of the alimentary tract displaying a prominent oxyphilic character.

Adenoma, Oxyphilic↗
PubMed1999

Muscular cushions of the vessel wall at the periphery of thyroid nodules.

Insufficient vascular compliance might be the cause of regressive changes commonly observed within long-standing thyroid nodules. This hypothesis induced us to study the morphology of vessels at the periphery of nodular thyroid lesions. A series of 104 consecutive nodular goiters and 10 follicular adenomas were collected and stained for elastic fibers and alpha smooth muscle actin to study the morphology of vessel walls. Ninety carcinomas of different histologic type were reviewed as well. Cases of diffuse thyroid enlargement, such as Grave's disease and Hashimoto's thyroiditis, served as controls. In the peripheral zone of eight follicular adenomas and of about 50% of nodular goiters, muscular cushions, connected with the vessel walls, were merged within the fibrous tissue. Such structures were found only in five out of 90 cases (6%) of carcinomas and only when the tumors developed in a gland affected by long-standing nodular goiter. Muscular cushions were never observed in cases of diffuse thyroid enlargement. Such cushions were stained with anti-smooth muscle actin antibody and showed variable amount of elastic fibers, suggesting an origin either from arterial or vein walls. We suggest that the muscular cushions of the vessel walls are the result of nodular thyroid disease and that they should be considered real anatomical entities with a specific function as sphincteric structures.

Actins↗
PubMed1998

Chromogranin A gene expression in non-small cell lung carcinomas.

Evidence for the existence of neuroendocrine (NE) differentiation in non-small cell lung carcinomas (NSCLCs) is at present based on histochemical, ultrastructural, and immunohistochemical data. The aim of this study was to investigate the extent of NE differentiation in NSCLCs as revealed by mRNA analysis. Different techniques including immunohistochemistry (IHC), northern blot analysis (NBA), and reverse transcriptase-polymerase chain reaction (RT-PCR) were employed in parallel to reveal the panendocrine marker chromogranin A (CgA). The data were related to pathological, immunocytochemical (PGP 9.5, synaptophysin, Leu-7 and neuron-specific enolase), and prognostic indicators. Forty surgically resected cases of NSCLC (24 squamous cell carcinomas, 12 ordinary type adenocarcinomas, 3 bronchiolo-alveolar carcinomas, and 1 anaplastic large cell carcinoma), in which fresh frozen material was available for mRNA analysis, were collected. CgA immunoreactivity was present in five cases (12.5 per cent), generally confined to a minority of the neoplastic cell population. By RT-PCR, CgA mRNA was found in 20 cases (50 per cent), including the five tumours positive by IHC. A statistically significant correlation was found between the two techniques. By NBA, no CgA mRNA expression was detected. Leu-7 immunoreactivity was present in 15 per cent of cases, NSE in 52.5 per cent, synaptophysin in 10 per cent, and PGP 9.5 in 82.5 per cent. In NSCLC, no correlations were found between CgA production, as detected by IHC or RT-PCR methods, and the histological type, stage, grade and proliferative activity of tumours, or the disease-free interval. It is concluded that CgA gene expression can be revealed in NSCLC at both mRNA and protein levels and that RT-PCR is a valuable tool for identifying NE differentiated NSCLCs. Our data suggest that NE differentiation does not represent an independent prognostic factor in surgically resected NSCLCs.

Adult↗
PubMed1998

Postmenopausal virilization in a woman with gonadotropin dependent ovarian hyperthecosis.

We report a case of a 66-yr-old woman with progressive hair balding, hirsutism and virilization. Gonadotropins and estradiol levels were in the postmenopausal range; total testosterone (TT), free testosterone (FT) and 17-hydroxyprogesterone (17-OHP) were elevated with dehydroepiandrosterone sulphate, androstendione and cortisol serum levels in the normal range, as 24-hr free urinary cortisol. TT, FT and 17-OHP were normalized, and FSH and LH fell to premenopausal levels on 18th day after a single i.m. injection of the GnRH analogue (GnRHa), triptorelin. Then, a diagnosis of hyperandrogenism of ovarian origin was made and bilateral ovariectomy was performed. Histological study of gonadal tissue revealed diffuse stromal hyperplasia of both ovaries with occasional nests of luteinized cells. With immunoperoxidase techniques these cells stained positively for testosterone and progesterone. One month after surgery, androgen levels were normalized together with regression of most of the clinical signs of virilization. In conclusion, our patient showed a severe virilization developed after menopause; hormonal investigations suggested a gonadotropin dependent ovarian hyperandrogenism, confirmed by histological examination; the presence of luteinized cells in the ovarian stroma was responsible for hyperandrogenism, as confirmed by the immunoperoxidase technique.

17-alpha-Hydroxyprogesterone↗
PubMed1998

Diagnostic cytological features of neuroendocrine differentiated carcinoma of the breast.

Neuroendocrine (NE) features characterize a minority of carcinomas of the breast corresponding to definite subtypes, which cover a wide spectrum of differentiation. Breast metastases from NE tumours of gastrointestinal origin are not rare, and to determine whether NE carcinomas in the breast could be differentiated from other tumours on fine needle aspiration (FNA) we analysed the cytological features of 13 primary NE breast carcinomas of different types (7 carcinoid-like, 5 mucinous and 1 solid spindle cell). Smears of carcinoid-like carcinomas showed specific features that made it possible to differentiate them from other primary tumours, but not from breast metastases of NE carcinomas. These features were: cell clusters with rigid borders, single cells with a plasmacytoid appearance and peripheral cytoplasmic granules evident on Giemsa staining and immunoreactive for chromogranin A. In mucinous NE carcinomas such granules were less apparent, and the cytological features could have been mistaken for those of fibroadenomas, as in the case of non-NE mucinous carcinomas. The solid spindle cell type showed noncohesive fusiform cells and moderate nuclear pleomorphism, a pattern similar to that of atypical carcinoids of the lung.

Adenocarcinoma, Mucinous↗
PubMed1998

Pulmonary giant cell carcinoma: pathological entity or morphological phenotype?

AIMS: To evaluate the morphological spectrum and clinical significance of giant cell carcinoma and to assess the frequency of tumour giant cell production in a consecutive series of primary (non-giant cell) lung tumours. METHODS AND RESULTS: Forty-six cases of giant cell carcinoma of the lung were collated from two centres over a 12-year period. Giant cell carcinoma was found to be associated with areas of clear cell carcinoma, spindle cell carcinoma and showed trophoblastic differentiation (syncytiotrophoblastic giant cells and beta-human chorionic gonadotrophin immunopositivity) in 57%, 34% and 26% cases, respectively. 'Pure' giant cell carcinoma was identified in five (11%) cases. Eleven of the tumours contained diastase-resistant periodic acid-Schiff positive material and were separately designated as giant cell adenocarcinomas. Areas of squamous cell and neuroendocrine differentiation (as determined by chromogranin A and Leu-7 immunopositivity) were not found. The median survival for giant cell carcinoma (excluding the giant cell adenocarcinomas) was 18 months. Median survival was not adversely affected by the extent of tumour giant cell formation or by the presence of trophoblastic differentiation. Of 200 consecutive non-small cell lung carcinomas, tumour giant cells constituting < 10% of the tumour were identified in 32% of adenocarcinomas and 26% of squamous cell carcinomas. CONCLUSIONS: The presence of tumour giant cells in lung carcinoma does not, in itself, indicate a more aggressive tumour type, Giant cell carcinoma of the lung does not appear to be a distinct entity but a morphological phenotype expressed by a heterogenous group of tumours. We support and advocate the use of an encompassing term such as 'pleomorphic' or 'anaplastic' carcinoma for those tumours showing no specific differentiation pattern but which express diverse morphological features such as giant cell formation, clear or spindle cell change.

Adenocarcinoma↗
PubMed1998

Specific receptors for synthetic GH secretagogues in the human brain and pituitary gland.

In vitro studies have been performed to demonstrate and characterize specific binding sites for synthetic GH secretagogues (sGHS) on membranes from pituitary gland and different human brain regions. A binding assay for sGHS was established using a peptidyl sGHS (Tyr-Ala-hexarelin) which had been radioiodinated to high specific activity at the Tyr residue. Specific binding sites for 125I-labelled Tyr-Ala-hexarelin were detected mainly in membranes isolated from pituitary gland and hypothalamus, but they were also present in other brain areas such as choroid plexus, cerebral cortex, hippocampus and medulla oblongata with no sex-related differences. In contrast, negligible binding was found in the thalamus, striatum, substantia nigra, cerebellum and corpus callosum. The binding of 125I-labelled Tyr-Ala-hexarelin to membrane-binding sites is a saturable and reversible process, depending on incubation time and pH of the buffer. Scatchard analysis of the binding revealed a finite number of binding sites in the hypothalamus and pituitary gland with a dissociation constant (Kd) of (1.5 +/- 0.3) x 10(-9) and (2.1 +/- 0.4) x 10(-9) mol/l respectively. Receptor activity is sensitive to trypsin and phospholipase C digestion, suggesting that protein and phospholipids are essential for the binding of 125I-labelled Tyr-Ala-hexarelin. The binding of 125I-labelled Tyr-Ala-hexarelin to pituitary and hypothalamic membranes was displaced in a dose-dependent manner by different unlabelled synthetic peptidyl (Tyr-Ala-hexarelin, GHRP2, hexarelin, GHRP6) and non-peptidyl (MK 0677) sGHS. An inhibition of the specific binding was also observed when binding was performed in the presence of [D-Arg1-D-Phe5-D-Trp7,9-Leu11]-substance P, a substance P antagonist that has been found to inhibit GH release in response to sGHS. In contrast, no competition was observed in the presence of other neuropeptides (GHRH, somatostatin, galanin or Met-enkephalin) which have a known influence on GH release. In conclusion, the present data demonstrate that sGHS have specific receptors in human brain and pituitary gland and reinforce the hypothesis that these compounds could be the synthetic counterpart of an endogenous GH secretagogue involved in the neuroendocrine control of GH secretion and possibly in other central activities.

Adult↗
PubMed1997

Mixed medullary-follicular carcinoma of the thyroid. A morphological, immunohistochemical and in situ hybridization analysis of 11 cases.

Mixed medullary-follicular carcinomas (MMFC) of the thyroid are rare tumours showing the morphological and immunochemical properties of both parafollicular and follicular cell lineages. Their recognition is based on a classical WHO definition, although several other patterns have been described in recent years. We investigated 11 cases of MMFC by immunohistochemistry and in situ hybridization (ISH) to analyse the structural features, the immunophenotypic profile and the calcitonin (CT) and thyroglobulin (TG) gene expression of the neoplasm. Histologically, 10 cases had mixed parafollicular and follicular cell populations in the primary tumour and 1 only in the lymph node metastasis. All cases were immunoreactive for CT (in medullary areas) and TG (in follicular areas and also in the solid component of 8/11 cases). These findings were confirmed by ISH analysis. Combined ISH and immunostaining showed that most cases had separate CT and TG gene expression, although rare cells with concurrent CT and TG gene expression were identified in 2 tumours. We conclude that (a) MMFC display heterogeneous morphological patterns and are a special type of thyroid tumour undergoing divergent differentiation; (b) in MMFC, CT and TG genes are generally not simultaneously expressed by the same cell, although dual expression of CT and TG was present in rare neoplastic elements; and (c) the origin of MMFC, whether they are derived from the ultimo-branchial body or result from neoplastic transformation of different cell populations following common oncogenic stimuli, is unclear.

Adenocarcinoma, Follicular↗