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A Sapino

Publications and source records attributed to A Sapino.

At least 37 records · Page 2Linked to original sources
PubMed2001

Ex vivo host response to gastrointestinal cancer cells presented by autologous dendritic cells.

BACKGROUND: Dendritic cells (DCs) capture apoptotic tumors and cross-present their antigens in the MHC class I and class II pathways for recognition by CD4+ and CD8+ T lymphocytes. Here we have tested the ability of fresh surgically resected colon and gastric cancer tumors to specifically activate host T lymphocytes when presented by autologous DCs. METHODS: DCs derived from adherent blood mononuclear cells of five patients, after a 7-day culture with GM-CSF and IL-4, were exposed to apoptotic autologous tumor (AAT) or apoptotic autologous peritumor normal (AAN) cells and cultured 24 h with monocyte-conditioned medium to achieve full DC maturation. Tumor-specific response was evaluated as single-cell cytokine release in an enzyme-linked immunospot (ELISPOT) and as cytotoxicity in a cold target inhibition (51)Cr-release assay. RESULTS: AAT-DCs induced specific IFN-gamma by T lymphocytes of two patients (rectal and gastric cancer), whereas in another two patients (rectal and gastric cancer) this response was depressed with a similar tumor-specific pattern and in one patient (rectal cancer) there was no response. Activation of IFN-gamma release was accompanied by tumor cytotoxicity and both responses were enhanced by IL-12, indicating the functional integrity of patients' lymphocytes. CONCLUSION: These data show that T-cell memory against rectal/gastric carcinoma antigens can be triggered by tumor-loaded autologous DCs. However, escape mechanisms may exist among tumors of the same histological origin that can inhibit this host response. A DC-based antitumor immunological monitoring assay with autologous tumor biopsies may allow patients to be screened to determine those who are suitable candidates for immune-based immunotherapy.

Adenocarcinoma↗
PubMed2001

Expression of apocrine differentiation markers in neuroendocrine breast carcinomas of aged women.

Neuroendocrine (NE) breast carcinomas are a rare entity in young women; however, their frequency increases in aged patients. The present work demonstrates that NE breast carcinomas in elderly women can also express an apocrine immunophenotype and analyzes the histological and clinical aspects of such differentiation. A selected series of 50 NE tumors (positive for NE markers in >/=50% of the cells) was tested for the immunocytochemical expression of gross cystic disease fluid protein-15 (GCDFP-15). The results demonstrated that about 50% of moderately (G2) and well-differentiated (G1) NE breast carcinomas (mucinous, solid papillary, and solid cohesive histotypes) coexpressed the apocrine marker. In these cases, specific mRNA for GCDFP-15 (PIP) and for chromogranin A (ChA) was demonstrated using in situ hybridization (ISH). Carcinomas of the alveolar subtype (G2) and poorly differentiated carcinomas (G3), including one case of atypical carcinoid, were pure NE carcinomas, devoid of apocrine differentiation. The steroid receptor status of these lesions was evaluated to test a possible involvement of androgen receptors in apocrine differentiation. We demonstrated that the level of AR and the mean age of patients at diagnosis were significantly higher in apocrine than in nonapocrine differentiated tumors. The histological grade and the expression of estrogen receptor (ER) significantly influenced the prognosis of these NE carcinomas, either pure or NE-apocrine differentiated. The most original result of our study is therefore the demonstration of a possible divergent apocrine differentiation of NE breast carcinomas that might be regulated by the activation of androgen receptors in elder patients. In addition, the possibility for using Chs or GCDFP-15 serum values in the follow-up of these patients, as demonstrated in two cases of the present series, can justify the immunophenotyping of the tumors.

Adenocarcinoma, Mucinous↗
PubMed2001

Lymphoepithelioma-like carcinoma of the breast: lack of evidence of Epstein-Barr virus infection.

AIMS: Six cases of lymphoepithelioma-like carcinomas of the breast were studied in order to better define the morphology of this type of breast tumour and to see if these neoplastic lesions are related to Epstein-Barr virus (EBV) infection by analogy with histologically similar tumours located in other organs. METHODS AND RESULTS: The cases were studied with immunohistochemistry using several antibodies and with in-situ hybridization method employing different types of nucleotides in four cases. The cases presented the distinctive morphology of the lymphoepithelioma-like carcinomas as seen in other organs. Specifically Rigaud and Schminke's patterns of growth were observed. In addition, at the edge of the neoplastic lesions, a lymphoepithelial lobulitis was seen. In-situ hybridization failed to reveal any positivity for EBV genome. CONCLUSION: Lymphoepithelioma-like carcinoma is a specific type of breast tumour, but its relation to EBV has yet to be proven. The differential diagnosis with medullary carcinoma is discussed.

Adult↗
PubMed2001

Clinical significance of neuroendocrine carcinoma of the breast.

BACKGROUND: Neuroendocrine (NE) carcinomas of the breast are defined by the diffuse expression of NE markers. This definition includes lesions with 'pure' NE phenotype as well as 'variants' which may co-express mucinous and/or apocrine phenotype. In the present work, the clinical significance of pure' NE differentiation in breast carcinoma and of its 'variants' will be analyzed. MATERIALS AND METHODS: Forty-three NE breast carcinomas immunocytochemically positive for chromogranins and/or synaptophysin in > or = 50% of cells were graded following the Elston and Ellis grading system for breast carcinomas. The production of mucin and the expressionof the apocrine marker Gross Cystic Disease Fluid Protein-15 (GCDFP-15) were correlated with the grade and the hormonal receptor status. The clinical outcome of patients was also analyzed. RESULTS: The histological grade highly influenced the clinical evolution of NE breast carcinomas. We confirmed that mucinous differentiation is an important indicator of low biological aggressiveness. Estrogen and progesterone receptor expression was also correlated with a better prognosis. Presence of androgen was correlated with the expression of GCDFP-15 in NE tumors. CONCLUSIONS: The histological grade overcomes the immunophenotype in determining the prognosis of NE differentiated carcinomas of the breast. Co-expression of exocrine products in such tumors is related to hormone dependency.

Apolipoproteins↗
PubMed2001

Biological relevance of oxytocin and oxytocin receptors in cancer cells and primary tumors.

For a long time, the hypothalamic nonapeptide oxytocin (OT) is known to play a crucial role in many reproductive and behavioral functions. In recent years, a new biological effect of OT has been identified in neoplastic pathology. In this context, OT acts as a growth regulator. through the activation of specific G-coupled transmembrane receptors (OTR). In vitro, an antiproliferative effect of OT was demonstrated in neoplastic cells of either epithelial (mammary and endometrial) or nervous or bone origin, all expressing OTR. Furthermore, the growth-inhibiting effect of OT was also tested and confirmed in mouse and rat mammary carcinomas in vivo. In neoplastic cells from another OT target tissue, trophoblast, the OT effect was to promote proliferation, the opposite of what previously observed in all the other neoplastic OT responsive cells. The signal transduction involved in the OT biological effect was different in OT growth-inhibited or growth-stimulated cells. In the former, the OT effect was mediated by the activation of the cAMP-PKA pathway, a non-conventional OT signaling, whereas in the latter by the increase of intracellular calcium and tyrosine phosphorylation, which are the 'classical' OT transducers. The unexpected role of OT (and OT analogues) in regulating cell proliferation, as well as the diffuse expression of OTR in neoplastic tissue of different origin, open new perspectives on the biological role of the OT-OTR system in cancer.

Animals↗
PubMed2001

34betaE12 cytokeratin immunodetection in the differential diagnosis of neuroendocrine carcinomas of the breast.

Neuroendocrine (NE) carcinomas of the breast share morphologic and immunohistochemical features with NE tumors of other sites, either resembling typical carcinoids or the highly aggressive small cell carcinoma. In addition, some mucinous carcinomas or solid/papillary carcinomas may show a major NE component. This is generally recognized by specific immunodetection of pan-endocrine markers, although this approach may fail to recognize NE tumors lacking immunoreactivity for some NE products, because the antigen is produced but not retained in the cytoplasm. It has recently been reported that high molecular weight (HMW) cytokeratin (CK), recognized by clone 34betaE12, immunostaining selectively labels non-NE carcinomas (squamous-cell and adenocarcinomas) of the aerodigestive tract and lung. The role of such CK immunodetection in the differential diagnosis of NE carcinoma of the breast was evaluated. Twenty-four cases of breast carcinomas having NE differentiation were selected. Twenty-four cases of non-NE invasive breast carcinomas served as controls. HMW CK immunoreactivity was found in all but one case of non-NE carcinomas, but in only two NE tumors (having scattered positive cells only). The authors conclude that in breast carcinomas the presence of HMW CK immunoreactivity favors the diagnosis of non-NE carcinoma, whereas its absence supports that of a NE tumor (either a carcinoid or a small cell carcinoma or a mucinous carcinoma). HMW CK can be added to the list of markers useful in the differential diagnosis of NE from non-NE tumors.

Biomarkers, Tumor↗
PubMed2001

Activation of functional oxytocin receptors stimulates cell proliferation in human trophoblast and choriocarcinoma cell lines.

Despite oxytocin receptors (OTR) being present in human chorio-decidual tissues, their expression and role in placental trophoblast cells in the context of tumor growth or physiological functions related to cell proliferation have never been examined. In the present study we demonstrate the presence and functionality of OTR in normal human trophoblast cell lines (ED77 and ED27) and a choriocarcinoma cell line (BeWo). RT-PCR and immunofluorescence analysis revealed the presence of OTR messenger RNA and protein in these cells. Binding studies using [(125)I]oxytocin ([(125)I]OT) antagonist confirmed the presence of specific binding sites in ED27, ED77, and BeWo cells. OTR functionality was demonstrated by measuring the OT-induced increase in the intracellular calcium concentrations. This effect was dose dependent and was blocked by the selective OT antagonist d(CH(2))(5)[Tyr(Me)(2),Thr(4), Tyr-NH(2)(9)]OVT (OT antagonist). Furthermore, two proteins with apparent molecular masses of 125 and 60 kDa became tyrosine phosphorylated in all of the cell lines after OT stimulation (and an additional protein of 45 kDa in BeWo choriocarcinoma cells), suggesting that this peptide can stimulate tyrosine kinase activity. Finally, we observed a dose-dependent OT stimulation of cell proliferation associated with OTR activation that was completely abolished by the selective OT antagonist. These findings provide the first evidence of the presence of functional OTR in normal trophoblast cell lines as well as in choriocarcinoma cells and show that a specific effect of OT on normal and neoplastic trophoblast is to promote cellular proliferation.

Calcium↗
PubMed2001

Identification, characterization, and biological activity of specific receptors for natural (ghrelin) and synthetic growth hormone secretagogues and analogs in human breast carcinomas and cell lines.

The family of GH secretagogues (GHS) includes synthetic peptidyl (hexarelin) and nonpeptidyl (MK-0677) molecules possessing specific receptors in the pituitary and central nervous system as well as in peripheral tissues, including the heart and some endocrine organs. A gastric-derived peptide, named ghrelin, has recently been proposed as the natural ligand of the GHS receptors (GHS-Rs). The presence of specific GHS-Rs has now been investigated in nontumoral and neoplastic human breast tissue using a radioiodinated peptidyl GHS ([(125)I]-Tyr-Ala-hexarelin) as ligand. Specific binding sites for GHS were detected in membranes from several types of breast carcinomas, whereas a negligible binding was found in fibroadenomas and mammary parenchyma. The highest binding activity was found in well-differentiated (G1) invasive breast carcinomas and was progressively reduced in moderately (G2) to poorly (G3) differentiated tumors. [(125)I]-Tyr-Ala-hexarelin bound to tumor membranes was displaced by different unlabeled GHS such as hexarelin, Tyr-Ala-hexarelin, human ghrelin, and MK-0677 as well as by desoctanoyl-ghrelin and hexarelin derivative EP-80317, which are devoid of GH-releasing properties in vivo. In contrast, no competition was seen between radiolabeled Tyr-Ala-hexarelin and some peptides (CRF and insulin-like growth factor I) structurally and functionally unrelated to hexarelin or when GHRH and SRIF were tested in the displacement studies. The presence of specific GHS binding sites was also demonstrated in three different human breast carcinoma cell lines (MCF7, T47D, and MDA-MB231), in which, surprisingly, no messenger RNA for GHS-R1a was demonstrated by RT-PCR. In these cell lines, ghrelin (as well as hexarelin, MK-0677, EP-80317, and even desoctanoyl ghrelin) caused a significant inhibition of cell proliferation at concentrations close to their binding affinity. In conclusion, this study provides the first demonstration of specific GHS binding sites, other than GHS-R1, in breast cancer. These receptors probably mediate growth inhibitory effects on breast carcinoma cells in vitro.

Breast↗
PubMed2001

[Rapid immunohistochemistry applied to intraoperative diagnosis: a critical analysis].

A series of 1378 intra-operative frozen diagnoses performed in our department over two years (1998-1999) was studied in order to assess the agreement with the diagnosis on formalin-fixed, paraffin-embedded sections. In selected cases, a rapid immunostaining (IS) method was applied on frozen sections to solve diagnostic problems. Rapid IS allowed us to determine the histotype of poorly differentiated neoplasms, the origin of lung nodules and the presence of nests of neoplastic cells on resection margins. The method delayed the answer by about 20 minutes, and was always previously arranged with the surgeon. Rapid IS method was performed using routine reagents and was not repeated on formalin-fixed, paraffin-embedded sections of the same cases, thus avoiding additional costs.

Biomarkers, Tumor↗
PubMed2000

Assessment of necrosis and hypoxia in ductal carcinoma in situ of the breast: basis for a new classification.

Modern classifications of ductal in situ carcinoma (DCIS) of the breast suffer from unsatisfactory reproducibility in inter-observer circulation analyses. Ducts in DCIS are markedly enlarged in the range of 360 microm in diameter. Since the diffusion of oxygen from peri-ductal vessels is limited to 100 microm, cells in the center of DCIS are poorly oxygenated and become either necrotic or remain hypoxic but viable. There is evidence that such alternative fate is dictated by the biological characteristics of the neoplastic cells. Therefore, determination of presence or absence of necrosis in ducts up to 360 microm in diameter might represent a simple, reproducible, and biologically sound criterion to classify DCIS. In the present work, following this criterion, we classified 32 cases of intra-ductal lesions as either "necrotic" or "hypoxic" and tested the reproducibility of such classification using K statistics. These cases had already been circulated among a group of European pathologists, who classified the lesions using five different classifications. The K statistics value obtained with the presently proposed system was extremely high (0.91). It remains to be established whether the classification "necrotic/hypoxic" withstands large inter-observer circulation analyses, whether it is predictive of the clinical evolution of DCIS, and whether it might constitute a reproducible basis for selecting appropriate treatments.

Breast Neoplasms↗
PubMed2000

Mammographically detected in situ lobular carcinomas of the breast.

We present ten cases of mammographically detected lobular carcinoma in situ (LCIS), involving a single area of variable size (up to a quadrant) in seven cases and the entire gland in three cases. Histologically, calcifications were associated with necrotic central areas within the in situ carcinomatous foci. Multiple foci of LCIS were observed in all five cases in which mastectomy had been performed. Cytologically, the lesions were characterized by a solid proliferation of round noncohesive cells with nuclei of intermediate size. Immunocytochemically, all cases were E-cadherin and p53 negative, and c-ErbB-2, GCDFP-15 and estrogen receptor positive. The proliferation index, evaluated with Ki67, was in the low range. Four cases were associated with foci of infiltrating lobular carcinoma (ILC). These findings contradict the commonly held opinion that LCIS is not mammographically detectable because of its lack of necrosis and calcification. This study documents the existence of a variant of LCIS exhibiting the mammographic features and central necrosis classically associated with ductal carcinoma in situ (DCIS), while retaining the spatial distribution, cytological composition and immunocytochemical features of lobular carcinoma.

Biomarkers, Tumor↗
PubMed2000

Large cell neuroendocrine carcinoma of the gallbladder: report of two cases.

We report two cases of primary large cell neuroendocrine carcinoma (LCNEC) of the gallbladder, which, to the best of our knowledge, represent the first description of this entity. One of the tumors consisted entirely of LCNEC, whereas the second tumor was composed of LCNEC and the more common intestinal-type adenocarcinoma. Both tumors were morphologically similar to their pulmonary counterpart and were characterized by large cells with prominent nucleoli, coarse chromatin, and a high mitotic rate. The cells showed an organoid growth pattern with rosette formation and frequent areas of necrosis. Panendocrine markers were expressed in a variable proportion of tumor cells in both cases, and one of the cases also showed focal positivity for type 2 somatostatin receptors. One of the tumors followed a rapidly fatal course despite aggressive surgical treatment and chemotherapy administration, and the second patient is still alive and disease-free 12 months after surgery. The description of these two cases of LCNEC of the gallbladder is significant for two reasons. From an academic standpoint, we now know that all the neuroendocrine tumors described in other organs can arise de novo in the gallbladder. More importantly, however, the recognition of this rare tumor type carries important clinical implications in regard to the use of chemotherapeutic agents and supplemental treatments (for example, somatostatin analogs).

Aged↗
PubMed2000

What modifies the relation between tumour size and lymph node metastases in T1 breast carcinomas?

AIMS: To evaluate which pathological and clinical parameters modify the relation between tumour size and lymph node metastases in invasive breast carcinomas < 20 mm. METHODS: In a retrospective study, 1075 patients with pT1 invasive breast carcinoma and with known nodal status were analysed. The size of the infiltrating tumour was microscopically evaluated, and the in situ component was not considered. The additional pathological parameters considered were: tumour grade, peritumoral vascular invasion, multicentricity, and angiogenesis. The immunophenotype of the tumour was determined as: the expression of oestrogen (ER) and progesterone (PR) receptors, p53, and c-erbB2. The patients were grouped by age as follows: < 50, 51-70, and > 70 years old. RESULTS: Three hundred and seventy four patients (34.8%) were node positive. Univariate analysis showed that nodal positivity was significantly correlated with large tumour size (> 10 mm), vascular invasion, grade 2-3, multicentricity, and high angiogenesis (> 100 microvessels/x20 high power frame). No significant correlation was found between nodal positivity and ER, PR, p53, or c-erbB2 status. Interestingly, the association with in situ carcinoma was correlated with lower nodal positivity in tumours presenting equally sized infiltrating components. Age was an independent variable and significantly modified the risk of nodal positivity in tumours < 1 cm. In fact, in patients under 51 years of age, the proportion of nodal positivity in pT1a tumours was sevenfold higher than in older patients. In patients from 51 to 70 years old, nodal positivity correlated with tumour size, and multicentricity was an additional risk factor. CONCLUSIONS: These data suggest that, together with tumour size, the presence of in situ carcinoma, and vascular invasion, age is one of the most important predictors of metastatic diffusion in breast carcinomas.

Adult↗
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↗
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

Presence and significance of oxytocin receptors in human neuroblastomas and glial tumors.

To determine whether oxytocin (OT) could be added to the list of growth factors acting on neoplastic cells of nervous origin, we investigated the presence of oxytocin receptors (OTR) in human primary neuroblastomas and glioblastomas and related cell lines. OTR were demonstrated both at mRNA level (using a RT-PCR procedure) and at protein level (using immunocytochemical and immunofluorescence procedures). In order to clarify whether OT exerts any biological effect on these tumors through OTR, we also studied cell proliferation in 3 human neuroblastoma cell lines (SK-N-SH, SH-SY5Y, IMR-32) and one human anaplastic astrocytoma cell line (MOG-G-UVW) treated with OT 1 nM to 100 nM for 48 and 96 hr. At these doses, a dose-dependent inhibitory effect on cell proliferation was demonstrated. This inhibition was accompanied by a significant increase in the intracellular concentration of cAMP, which we have reported to be the intracellular mediator of the OT anti-proliferative effect in breast-carcinoma cell lines. Our data indicate that specific OTR are present in human neuroblastomas and glioblastomas. Through these receptors, OT could inhibit cell proliferation and modulate tumor growth.

Brain Neoplasms↗