Search PubMed⌕ Search

Biomedical subjects

C Doglioni

Publications and source records attributed to C Doglioni.

At least 73 records · Page 4Linked to original sources
PubMed1997

Alpha 4 beta 7 integrin expression is associated with the leukemic evolution of human and murine T-cell lymphoblastic lymphomas.

We have previously shown that the in vivo coordinated expression of individual alpha 4 and beta 7 integrin chains correlated with the leukemic potential displayed by cell lines derived from murine lymphoblastic T-cell lymphomas (T-LBLs) when transplanted subcutaneously into syngeneic AKR mice. In the present study, by using immunofluorescence and immunocytochemical analyses, we have confirmed that the in vivo up-regulation of the alpha 4 beta 7 heterodimeric complex is associated with the leukemic behavior of AKR T-LBLs. In addition, when compared with the parental, highly leukemic NQ22 cells, the variant cell line NQ22V exhibited a reduced leukemic potential that was invariably associated with a delayed alpha 4 beta 7 up-regulation in vivo Moreover, the leukemic cell line SJ-1, derived from a spontaneous T-LBL of the SJL strain, also displayed high levels of alpha 4 beta 7 expression with a pattern of tissue distribution similar to that of NQ22 cells from leukemic AKR animals. Of note, in most of the tissues involved by murine T-LBL dissemination, and particularly in liver, kidney, and lung, alpha 4 beta 7-positive leukemic cells were always located around strongly VCAM-1-positive vascular spaces. These findings are consistent with a possible role of alpha 4 beta 7/VCAM-1 interactions in the extravasation and, consequently, in the leukemic dissemination of murine T-LBL cells. Immunocytochemical analysis carried out in 11 human T-LBLs showed that pathological lymph nodes from all 7 cases with bone marrow infiltration at presentation carried alpha 4 beta 7-positive cells, whereas all 4 aleukemic T-LBLs were repeatedly alpha 4 beta 7 negative, also in metachronous lesions. These findings suggest that alpha 4 beta 7-positive human T-LBLs may represent a distinct clinicopathological entity. In addition, alpha 4 beta 7 expression was significantly more prevalent in younger patients (< 11 years; P = 0.02), further supporting such a hypothesis. Moreover, as in murine T-LBLs, the pattern of alpha 4 beta 7 positivity in involved lymph nodes was mainly focal, whereas nearly all neoplastic cells infiltrating bone marrow expressed this integrin, suggesting a possible role for alpha 4 beta 7 in the leukemic dissemination also of human T-LBLs.

Adolescent↗
PubMed1997

Molecular aberrations of the G1-S checkpoint in myxoid and round cell liposarcoma.

Myxoid and round cell liposarcoma represents a morphological spectrum in which tumor progression from low-grade myxoid to high-grade round cell areas is frequently observed. A distinctive t(12;16)(q13;p11) reciprocal translocation rearranges the CHOP gene localized to 12q13 in most cases. Data concerning the occurrence of cell cycle aberrations in this subset of mesenchymal malignancies are very limited. Therefore, we analyzed a histologically homogeneous series of 21 cases of myxoid and round cell liposarcoma. The p53 pathway was studied by investigating the TP53 gene and protein, mdm2 protein, and p21Waf1 protein. The Rb-cyclin D pathway was analyzed by studying the pRb protein, the p16MTS1 gene, cyclin D1, cyclin D3, p27Kip1, cdk4, and cdk6 proteins. In contrast with the rare involvement of the TP53 gene in well differentiated liposarcoma, aberrations of the TP53 gene were observed in approximately 30% of cases of myxoid and round cell liposarcoma. Notably, mdm2 overexpression was seen in 56% of cases and correlated with histological grade, therefore indicating a possible role in tumor progression. Abnormalities involving the Rb-cyclin D pathway were observed in more than 90% of cases. pRb loss was present in one-third of cases and, at variance with that observed in other subsets of sarcoma, overexpression of cyclin Ds represented a rare event. Interestingly, upregulation of either cdk4 or cdk6 was demonstrated in 85% of cases.

Chromosome Aberrations↗
PubMed1996

p21/WAF1 cyclin-kinase inhibitor expression in non-Hodgkin's lymphomas: a potential marker of p53 tumor-suppressor gene function.

p21WAF1 (wild-type p53-activated fragment 1) is involved in the control of mammalian cell cycle through the binding and inhibition of cyclin-dependent kinases (Cdk). Because the product of WAF1 gene is a potent downstream effector of the p53 tumor-suppressor gene function, its pattern of cellular expression might correlate with nuclear accumulation of p53-encoded protein and/or p53 gene mutations occurring in malignant lymphomas. To investigate this issue, we analyzed immunohistochemically the expression of p53 and p21WAF1 proteins in tissue involved by non-Hodgkin's lymphomas (NHLs;253 cases) of various histologic types. In a proportion of them (80 cases), we also investigated the possible presence of p53 gene mutations using single-strand conformation polymorphism analysis and direct DNA sequencing. The absence of both p21WAF1 and p53 proteins was observed in 147 of 217 cases (67.7%) among CD30-NHL and in only 8 of 36 (22.2%) CD30+cases, which were mostly anaplastic large-cell lymphomas. A consistent number (> 10%) of p21WAF1-expressing cells was shown in 48 of 253 (18.9%) NHL cases, with a higher incidence in CD30+cases (25/36 [69.4%]), which mostly (21/36) coexpressed p53. These latter cases were characterized by a germline configuration of the p53 gene. In 50 of 253 NHL samples (19.7%), 47 of which (21.6%) belong to the CD30-group, neoplastic cells were p53+/p21-. In all of these cases, the p53+cells accounted for more than 50% of neoplastic cells, up to 100%. Point mutations of p53 gene were solely observed in all investigated cases with this latter phenotype. Our findings strongly suggest that the combined immunohistochemical evaluation of p53 and p21WAF1 is a valuable means of assessing the functional status of the p53 tumor-suppressor gene product in NHL with potential application in the monitorage and prognostication of individual cases.

Biomarkers↗
PubMed1996

p21 RNA and protein expression in non-small cell lung carcinomas: evidence of p53-independent expression and association with tumoral differentiation.

p21, the product of the WAF1/CIP1/SDI1/mda-6 gene, is an inhibitor of cyclin-dependent kinases. In cell cultures p21 is induced by p53-dependent and p53-independent pathways by DNA damage and induction of differentiation. We investigated p21 RNA and immunohistochemical expression in 43 non-small cell lung carcinomas and corresponding normal lung samples previously investigated for p53 and WAF1 gene status and p53 protein expression. p21 RNA and protein expression in normal and neoplastic tissues were strictly associated (p-0.0001). In normal tissue p21 RNA was expressed at low levels and p21 immunoreactivity was seen in scattered differentiated bronchial, alveolar and stromal cells. In the majority of neoplasms p21 protein and RNA were expressed at higher levels than in the corresponding normal tissues: p21 overexpression was seen in 27 (63%) and 28 (65%) cases respectively. p21 was expressed independently from p53 gene/protein alterations. p21 overexpression was more frequent in well differentiated tumors (P=0.01 and P=0.022 for RNA and protein respectively), and p21 immunoreactivity was usually seen in foci of more pronounced differentiation. We conclude that p21 expression is related to tumor differentiation, and that p53-independent p21 expression is a common feature of in vivo neoplasms.

Base Sequence↗
PubMed1996

Chromosome 13q deletion mapping in head and neck squamous cell carcinomas: identification of two distinct regions of preferential loss.

Heal and neck squamous cell carcinomas show frequent cytogenetic alterations involving the long arm of chromosome 13. To define the extent of 13q deletions and to identify the minimal areas of chromosome loss, 48 primary squamous cell carcinomas of the head and neck were analyzed for loss of heterozygosity using 11 different polymorphic loci. About 67% of the tumors displayed loss of genetic material at 13q. Most of the cases showed loss of the entire long arm of the chromosome. However, the presence of partial deletions in 10 cases provided evidence of the existence of two preferential sites of chromosome loss at 13q32-ter and 13q14.2-q14.3. The colocalization of the 13q14 minimal region of deletion with the retinoblastoma (RB) gene, which has been proposed as an oncosuppressor in diverse tumor types, prompted us to verify the involvement of this gene in the development of head and neck cancer. No significant variation in RB protein or RB mRNA expression was detected, thus excluding a role for such a gene in the genesis of this type of tumor. Taken together, our data suggest the existence of two new tumor suppressor genes (one close to and one distal to RB), which play a role in the development and/or progression of head and neck squamous cell carcinomas.

Base Sequence↗
PubMed1996

p21/WAF1/CIP1 expression in normal mucosa and in adenomas and adenocarcinomas of the colon: its relationship with differentiation.

The immunoreactivity of p21 was evaluated in normal mucosa and in adenomas and adenocarcinomas of the human large bowel. In normal mucosa, p21 immunoreactivity was seen in the superficial third of the crypts (maturation compartment) and in surface (terminally differentiated) epithelium, and was mutually exclusive with Ki67/MIB1 reactivity. These data show that p21 expression is inversely related to proliferation and directly related to terminal differentiation. In adenomas, p21-reactive cells were frequently clustered in the superficial areas and were non-reactive for MIB1. In adenocarcinomas, p21 staining was heterogeneous: high p21 expression (19 cases) was associated with lower stage and lack of p53 overexpression. p21-reactive cells were devoid of MIB1 immunoreactivity, but no relationship could be found between p21 and MIB1 labelling indices. p21 heterogeneity may be related to alterations in the p53-dependent induction pathway: high p21 expression was associated with low to absent p53 reactivity, with presumed normal p53 function; low p21 expression was associated with p53 overexpression, with presumed p53 alteration resulting in loss of function.

Adenocarcinoma↗
PubMed1996

Bcl-2 and p53 expression in node-negative breast carcinoma: a study with long-term follow-up.

Bcl-2 and p53 gene products (Bcl-2, p53) are important regulators of apoptosis and cell proliferation, and their immunohistochemical expression may help to identify high-risk breast cancer patients. The authors evaluated p53 and Bcl-2 immunoreactivity in 178 node-negative breast cancers (NNBC) with long-term follow-up (median, 60 months). Bcl-2 was seen in 111 (62%) cases, and was significantly associated with small tumor size, nonductal morphology, low tumor grade, estrogen-receptor (ER) positivity, and p53 negativity. p53 overexpression (ie, > 15% reactive nuclei) was observed in 31 (17%) cases, and was associated with lower age, large tumor size, ductal morphology, high tumor grade, negative ER status, and lack of Bcl-2 immunoreactivity. In univariate analysis, the variables associated with short relapse-free survival (RFS) were large tumor size (P = .002), high histological grade (P = .01), high mitotic count (P = .03), and high Nottingham prognostic index (NPI) (P = .0002). In multivariate analysis (final model), only the NPI was of independent prognostic value concerning RFS.

Analysis of Variance↗
PubMed1996

p21WAF1 immunohistochemical expression in breast carcinoma: correlations with clinicopathological data, oestrogen receptor status, MIB1 expression, p53 gene and protein alterations and relapse-free survival.

p21 protein (p21) inhibitor of cyclin-dependent kinases is a critical downstream effector in the p53-specific pathway of growth control. p21 can also be induced by p53-independent pathways in relation to terminal differentiation. We investigated p21 immunoreactivity in normal breast and in 91 breast carcinomas [three in situ ductal carcinomas (DCIS) with microinfiltration and 88 infiltrating carcinomas, 17 of which with an associated DCIS; 57 node negative and 34 node positive] with long-term follow-up (median = 58 months). Seven additional breast carcinomas with known p53 gene mutations were investigated. In normal breast p21 expression was seen in the nuclei of rare luminal cells of acinar structures, and in occasional myoepithelial cells. Poorly differentiated DCIS showed high p21 expression, whereas well-differentiated DCIS tumours showed few p21-reactive cells. p21 was seen in 82 (90%) infiltrating tumours; staining was heterogeneous; the percentage of reactive nuclei ranged from 1% to 35%. High p21 expression (more than 10% of reactive cells) was seen in 24 (26%) cases, and was associated with high tumour grade (P = 0.032); no associations were seen with tumour size, metastases, oestrogen receptor status, MIB1 expression and p53 expression. p21 expression in cases with p53 gene mutations was low in six cases and high in one. High p21 expression was associated with short relapse-free survival (P = 0.003).

Breast Neoplasms↗
PubMed1996

Involvement of BCL-2 oncoprotein in the development of enterochromaffin-like cell gastric carcinoids.

To evaluate the involvement of the apoptosis-suppressing protein BCL-2 in the gastrin-dependent mechanism of induction of gastric enterochromaffin-like (ECL) cell carcinoids, the endocrine cell of the oxyntic mucosa were immunohistochemically investigated in (a) 10 normogastrinemic subjects with histologically normal gastric mucosa; (b) 22 patients with endocrine cell hyperplasia and affected by hypergastrinemic conditions with different risk of gastric carcinoid development, such as sporadic Zollinger-Ellison syndrome (sZES; n = 9), ZES associated with multiple endocrine neoplasia-1 (MEN-1; n = 4), and atrophic fundal gastritis (AFG; n = 9); (c) 14 patients with ECL gastric carcinoids accounting for a total of 31 tumors investigated. In the normal oxyntic mucosa, BCL-2 was consistently expressed by a subset of endocrine cells accounting for 50.0% (median; range, 24.6-74.0%) of the total number of endocrine cells immunostained for chromogranin A (CgA) in consecutive sections. BCL-2 immunoreactive cells were located mostly in the middle mucosal layer, suggesting a role for the protein during downward migration of maturing endocrine cells. No BCL-2 immunoreactivity was found in other specialized gastric epithelial cells. Expression of BCL-2 by hyperplastic oxyntic endocrine cells (mostly ECL cells) varied in parallel with the risk of carcinoid development. In fact, the ratio of BCL-2- to CgA-immunoreactive cells was reduced (median, 4.6%; p less than 0.0001; range, 0.9-42.0%) in sZES, a condition showing virtually no risk, unchanged (median, 55.6%; range 29.4-83.8 %) in cases of MEN-1/ZES with intermediate risk, and increased (median 87.6%; p less than 0.014; range, 48.8-199.4%) in cases of AFG, a condition at the highest risk of carcinoid. In ECL cell carcinoids, BCL-2 expression varied markedly from one tumor to another even in the same patient and was low or absent in most cases. In both hyperplastic and neoplastic ECL cells, an inverse relation between BCL-2 expression and CgA immunoreactivity, that is, the cell granule content, was found. These results suggest that BCL-2 expression by hyperplastic ECL cells is independent of the influence of serum gastrin and may contribute to the development of ECL cell carcinoid tumors by extending cell exposure to oncogenic factors. Once a carcinoid tumor is established, BCL-2 expression becomes inconsistent.

Adult↗
PubMed1996

Calretinin: a novel immunocytochemical marker for mesothelioma.

Immunohistochemistry is a powerful diagnostic adjunct in the differential diagnosis between malignant mesothelioma (especially of the epithelial type) and adenocarcinoma metastatic to the serous membranes. Most of the immunological probes commonly used, however, recognize antigens expressed by the epithelial malignancies and absent from mesothelial cells and mesotheliomas. Probes suitable for the positive identification of mesotheliomas are comparatively scarce and much less commonly used because of their reduced sensitivity and specificity, their unsuitability for staining routinely fixed and embedded tissues, or their lack of commercial availability. We now document that two different polyclonal antisera to calretinin consistently immunostain mesothelial cells and malignant mesotheliomas both in routinely fixed and embedded tissue sections and in cytological preparations of serous effusions. The diagnostic sensitivity of this novel immunocytochemical approach reached 100%, allowing immunostaining of all 44 mesotheliomas investigated, which included five biphasic and three sarcomatoid types. The specificity of calretinin immunoreactivity was checked against 294 adenocarcinomas of different origin (19 serosal metastases and 275 primary tumors potentially able to metastatize to serosal membranes) relevant for the discussion of the differential diagnosis with malignant mesothelioma: only 28 cases showed focal immunoreactivity for calretinin. We conclude that calretinin is a most useful marker for the positive identification of malignant mesotheliomas.

Adenocarcinoma↗
PubMed1996

Basaloid squamous cell carcinoma of the head and neck: clinicopathological features and differential diagnosis.

Basaloid squamous cell carcinoma is a recently recognized variant of squamous cell carcinoma. The lesion is histologically distinctive and manifests a predilection for the supraglottis, pyriform sinus, and tongue base. The immunohistochemical profile is discussed. The differential diagnoses include adenoid cystic carcinoma, small cell neuroendocrine carcinoma, basal cell adenocarcinoma, adenosquamous carcinoma, squamous cell carcinoma, spindle cell squamous carcinoma, mucoepidermoid carcinoma, and adenoid squamous cell carcinoma. Basaloid squamous cell carcinoma is a biologically high-grade tumor with a propensity for nodal as well as systemic metastases. It is a morphologic and phenotypic entity with a separate prognostic significance.

Adult↗
PubMed1996

Tumor suppressor genes and related molecules in leiomyosarcoma.

Soft tissue sarcomas represent a heterogeneous group of mesenchymal malignancies, and the majority of the previous scientific studies that have analyzed the occurrence of cell cycle regulators aberrations within soft tissue sarcomas have dealt with broad categories of different tumors. As a consequence, data concerning single classes of sarcomas are very limited. The authors analyze herein a histologically homogeneous series of 23 cases of leiomyosarcoma of the deep soft tissue. The p53 pathway was studied by investigating the p53 gene and protein, MDM2 protein, and p21waf1 protein. The Rb-cyclin D pathway was analyzed by studying the Rb gene and protein, p16MTS1/INK4A gene and protein, cyclin D1Prad1/bcl1 and cyclin D3 proteins. Aberrations of the p53 pathway were observed in about 16 percent of cases and were limited to the p53 gene. Such a finding contrasts with the higher rates of p53/MDM2 abnormalities reported in other types of sarcomas such as liposarcoma. Interestingly, abnormalities involving the Rb-cyclin D pathway were detected in about 90 percent of cases. The Rb-cyclin D pathway therefore emerges as the preferred target for molecular abnormalities in this subset of soft tissue sarcomas.

Base Sequence↗