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Biomedical subjects

C Doglioni

Publications and source records attributed to C Doglioni.

At least 55 records · Page 3Linked to original sources
PubMed1998

Bax immunohistochemical expression in breast carcinoma: a study with long term follow-up.

Bax and Bcl2 are functionally antagonistic proteins which control apoptosis, whose expression in human tumours could be of prognostic value. We evaluated Bax and Bcl2 expression in 239 breast carcinomas (99 N0, 140 N1/2) with long term follow-up (median 79 months, range 11-140) in relation to clinico-pathologic parameters, clinical outcome, adjuvant therapy and expression of oestrogen receptor protein and p53. The prognostic value of Bax was investigated in the whole series of patients and in subgroups of homogeneously staged and treated patients (i.e., node-negative, N1/2 CMF-treated, N1/2 tamoxifen-treated). Bax immunostaining was cytoplasmic and heterogeneous. Cases were scored as Bax-positive if there were more than 20% reacting cells. High Bax expression was associated with positive nodal status (p = 0.03) and high Bcl2 expression (p = 0.01) and was more frequent in high-grade tumours. In the node-negative subgroup, Bax expression was associated with small tumour size. No association was seen with other parameters or with clinical outcome in any subgroup of patients. Since the apoptotic rate of a tumour is influenced by the ratio Bcl2/Bax, we investigated the combined effects of Bax and Bcl2 expression in relation to clinical outcome. However, no differences in survival were seen in the Bcl2-negative and Bcl2-positive groups when they were subdivided on the basis of the level of Bax expression and vice versa. In experimental systems, p53 is a direct transcriptional activator of the human bax gene. However, we could not observe any relation between Bax and p53 expression. We investigated whether the combined p53/Bax expression could have any prognostic value since it is predicted that tumours with normal p53 expression and concurrent high levels of Bax should be less aggressive and more susceptible to therapy. However, while p53 itself was of prognostic value, Bax expression was not related to prognosis in p53-negative or in p53-positive groups.

Breast Neoplasms↗
PubMed1998

Cyclin D1 and retinoblastoma susceptibility gene alterations in non-small cell lung cancer.

Among the major regulators of the G1 restriction point are cyclin D1 and the retinoblastoma gene product (RB). In non-small cell lung cancer (NSCLC), the cyclin D1 gene is amplified/over-expressed in almost 50% of cases, and RB is inactivated in 6-32% of cases. It is of interest to evaluate concurrently the alterations of both genes on the same series of NSCLCs, to investigate whether cyclin D1 and RB alterations are alternative pathways leading to inactivation of the G1 restriction point or if they can occur in the same tumor, possibly exerting an additive effect on cancer progression. We investigated a series of 57 NSCLCs, analyzing cyclin D1 and RB at the gene and protein levels by Southern blot, Northern blot and immunohistochemistry. The cyclin D1 gene was amplified in 18 cases, cyclin D1 immunoreactivity was seen in 25 tumors. Amplification and expression were significantly associated. RB immunohistochemical expression was absent in 9 of 42 informative cases. RB mRNA expression was low to absent in 9 of 45 informative cases, cyclin D1 amplification was associated with normal RB mRNA, and cyclin D1 over-expression was associated with normal RB immunoreactivity, supporting the hypothesis that alterations of cyclin D1 and RB are alternative mechanisms by which tumor cells may escape the G1 restriction point. A concurrent alteration of RB and cyclin D1 was seen in a small subset of NSCLCs. Abnormalities of cyclin D1 and/or RB at the gene and/or expression level were present in more than 90% of cases, stressing that cyclin D1 and/or RB alterations represent an important step in lung tumorigenesis.

Carcinoma, Non-Small-Cell Lung↗
PubMed1998

Cyclin D3 expression in normal, reactive and neoplastic tissues.

Cyclin D3 immunohistochemical expression was investigated in normal, reactive, and neoplastic human embryonal and adult tissues. In the fetus, cyclin D3 was expressed in selected developmental phases of a limited number of cell systems. In normal adult tissues, cyclin D3 showed two patterns of distribution: in lymphoid tissues it was expressed in proliferative compartments, while in most other tissues it was expressed by terminally differentiated/quiescent cells. This dual role in proliferation and differentiation was partially conserved in neoplasms. In non-Hodgkin lymphomas, cyclin D3 immunolabelling was correlated with proliferative activity and progression; a significant exception was seen in cyclin D1-positive mantle cell lymphomas, which were cyclin D-negative. Benign endocrine tumours were frequently strongly cyclin D3-positive, while high-grade (small cell) neuroendocrine carcinomas were always negative. In most other epithelial neoplasms, cyclin D3 immunostaining was heterogeneous. In breast carcinomas, no relationship was seen between ER status and MIB1 labelling; cyclins D3 and D1 were frequently expressed in the same tumour, while occasional tumours showed an inverse quantitative relationship between cyclins D1 and D3, and rare tumours were negative for both. In soft tissue neoplasms, cyclin D3 was consistently expressed in some tumours, such as stromal tumours of the gastrointestinal tract and embryonal rhabdomyosarcomas. Our data suggest that cyclin D3 has a dual role in proliferation and differentiation in normal tissues and in some neoplastic conditions; that the cyclin D3 expression pattern is different from cyclin D1, suggesting non-redundant functions; that cyclin D3 expression is strong in endocrine cells secreting steroid hormones, and in their neoplastic counterparts; and that cyclin D3 deregulation may be of pathogenetic relevance in lymphomagenesis and could be diagnostically useful.

Adult↗
PubMed1998

The relevance of genetics and molecular pathology in mesenchymal tumours.

Genetic and molecular analyses of soft tissue tumours have provided a great amount of valuable information over the past ten years. One of the most useful diagnostic application is tumour types. Technical advances in techniques such as FISH as well as RT-PCR permit, now, the analysis of archival material, expanding further the practical usefulness of genetic analysis. Genetics has also proved useful as a tool for validating current classification schemes, which still represent a source of endless debate. On the basis of cytogenetic data, relevant subsets of mesenchymal neoplasms are now categorised more rationally. Molecular pathology has greatly contributed to a better understanding of the mechanisms involved in both the pathogenesis and the progression of soft tissue sarcomas. Furthermore, the analysis of distinct subsets of tumours has shown that abberations involving the control of the cell cycle machinery exhibit a certain degree of tumour specificity. This wealth of information provides the necessary scientific background for both innovative therapeutic approaches and epidemiologic strategies for tumour prevention.

Journal Article↗
PubMed1998

Differential expression of cyclin-dependent kinase 6 in cortical thymocytes and T-cell lymphoblastic lymphoma/leukemia.

Cyclin-dependent kinase-6 (CDK6) is the earliest inducible member of the CDK family in human T lymphocytes, involved in growth factor stimulation and cell cycle progression. CDK6 is one of the targets of p16 and p15, CDK inhibitors encoded by MTS1 and MTS2, two tumor suppressor genes that are frequently deleted in T-cell leukemia. In this study we have investigated CDK6 expression in normal and neoplastic lymphoid tissues using immunohistochemistry and flow cytometry. In normal (six samples) and hyperplastic (four samples) thymuses, strong CDK6 expression was observed in a discrete proportion of cortical thymocytes (10 to 15%), mainly located in the peripheral (subcapsular) zone of the cortex. All tested cases of T-cell lymphoblastic lymphoma/leukemia (T-LBL/ALL) showed strong CDK6 expression in the majority (up to 100%) of neoplastic lymphoid cells. Western blot analysis confirmed the expected CDK6 protein size (40 kd). According to Southern blot analysis, CDK6 overexpression in neoplastic T lymphoblasts was not due to gene amplification. In all other lymphomas investigated (28 peripheral T-cell non-Hodgkin's lympohomas (T-NHLs), 7 CD30+ anaplastic NHLs, 22 high-grade B-NHLs, 15 low-grade B-NHLs, 25 B-cell precursor ALLs), CDK6 was not expressed or expressed at low levels, with the only exception of three nasal angiocentric T-NHLs, all exhibiting CDK6 immunoreactivity comparable to that observed in T-LBL/ALL. These data provide evidence that CDK6 is abnormally expressed in T-LBL/ALL and may be involved in the pathogenesis of this malignancy. In addition, the quantitative difference of CDK6 expression between neoplastic and non-neoplastic cortical thymocytes can be potentially useful in the differential diagnosis of thymic neoplasms on histological and cytological specimens.

Blotting, Southern↗
PubMed1998

Differential expression of p57kip2, a maternally imprinted cdk inhibitor, in normal human placenta and gestational trophoblastic disease.

Evidence has recently been provided to support a role for genomic imprinting in the regulation of embryonic implantation and development and placental growth, as well as in the pathogenesis of proliferative trophoblastic diseases. The cyclin-dependent kinase inhibitor p57KIP2 has recently been recognized as a maternally imprinted gene. We investigated p57KIP2 expression in first-trimester normal placentas from interrupted pregnancy, spontaneous abortions, and different types of proliferative trophoblastic diseases using single- and double-marker immunohistochemical techniques. In normal placenta, nuclear p57KIP2 expression was observed at high frequency (up to 100%) in extravillous trophoblast, cytotrophoblast, and implantation-site interstitial trophoblast, but was absent in syncytiotrophoblast. p57KIP2 was also expressed in the stromal cells of maternal decidua, which was one of the few adult tissues retaining p57KIP2 expression (most other adult tissues investigated were negative). p57KIP2 expression was either absent or low in all cases of diploid/tetraploid complete moles (20 cases) and in three cases of gestational choriocarcinoma. On the other hand, all spontaneous abortions (12 cases) and triploid partial moles (19 cases) showed p57KIP2 levels comparable to those observed in normal placenta. These findings are in line with the hypothesis that deregulation of genomic imprinting, particularly the loss of cell-cycle inhibitors such as p57KIP2, is involved in the abnormal development of androgenetic trophoblastic proliferations. In addition, this simple immunohistochemical analysis could provide a useful diagnostic marker in difficult cases.

Choriocarcinoma↗
PubMed1997

Human non-Hodgkin's lymphomas overexpress a wild-type form of p53 which is a functional transcriptional activator of the cyclin-dependent kinase inhibitor p21.

A large fraction of non-Hodgkin's lymphomas (NHLs) accumulate a wild-type form of the p53 tumor suppressor protein at the nuclear level. In normal cells, p53 induction is associated with a temporary cell growth arrest at the G1-S boundary of the cell cycle. This activity of p53 as a G1 checkpoint molecule is strictly dependent on its ability to induce the transcription of the inhibitor of the cyclin dependent kinase, p21. To verify the functionality of the wild-type p53 protein accumulated in NHL cells, 70 cases were comparatively analyzed for p53 and p21 expression and status of the respective genes. Overexpression of the wt p53 protein was associated with the accumulation of p21, indicating that p53 is functional with respect to p21 induction in these tumors. The coaccumulation of p53 with Ki-67 antigen indicates that wt p53-positive cells and p21-positive cells, as well, are actively proliferative elements, supporting the notion that p53-induced, p21-mediated growth arrest is somehow overridden in NHL cells. No p21 mutation or particular allele variant was shown to correlate with p21 protein accumulation, thus excluding a role for p21 structural abnormalities. Taken together, our data suggest the existence in NHL of a peculiar mechanism of functional inactivation of the p53 G1 checkpoint pathway occurring downstream of the CDK inhibitor p21.

Cell Division↗
PubMed1997

p16/CDKN2 and CDK4 gene mutations in sporadic melanoma development and progression.

The p16/CDKN2(MTS1) gene encoding for the p16 inhibitor of cyclin D/CDK4 complexes is frequently mutated and deleted in a large fraction of melanoma cell lines, and p16 germline mutations have also been observed in familial melanomas. Moreover, a CDK4 gene mutation, responsible for a functional resistance of CDK4 kinase to p16 inhibitory activity, has been described to occur in some cases of familial melanoma. These data strongly support the idea that deregulation of the CDK4/cyclin D pathway, via CDKN2 or CDK4 mutations, is of biological significance in the development of melanoma. To shed light on the role of these alterations in the development and progression of sporadic melanoma, 12 primary melanomas and 9 corresponding metastases were analyzed for CDKN2 and CDK4 gene mutations. Of the 12 primary melanomas analyzed, 4 showed the presence of mutational inactivation of the p 16 protein and 2 carried silent mutations. No metastases showed the presence of CDKN2 mutations, indicating that mutations of this cyclin-dependent kinase inhibitor is not common in the progression of sporadic melanoma. On the other hand, the absence, in the metastases, of the CDKN2 mutation detected in the corresponding primary tumors suggests that 9p21 homozygous deletion may play a major role in the metastatic spreading of this type of tumor. None of the cases analyzed showed the presence of an Arg24Cys mutation, which functionally protects CDK4 from p16 inhibition. This indicates that CDK4 mutation plays a minor role in the development and progression of sporadic melanoma.

Biomarkers, Tumor↗
PubMed1997

Molecular abnormalities of the p53 pathway in dedifferentiated liposarcoma.

Dedifferentiated liposarcoma represents a distinct subtype of liposarcoma and is characterized by the presence of abrupt transition from well-differentiated liposarcoma to high-grade pleomorphic sarcoma (mostly MFH-like). A key role for p53 in tumour progression of this subset of liposarcomas has been suggested on the basis of p53 immunopositivity. A series of 14 dedifferentiated liposarcomas has been investigated by analysing the p53 gene and protein together with the p53-related molecules p21Waf1 and mdm2, to verify whether the p53 pathway is involved in the development and progression of this tumour type. The results indicate that the p53 gene is rarely involved in dedifferentiated liposarcoma (7 per cent of cases analysed) and that low percentages of p53 immunopositivity are still compatible with integrity of the p53 gene. This concept is also supported by the observed preservation of p21Waf1 immunoreactivity in all but the p53-mutated cases. By contrast, mdm2 overexpression emerges as the most frequent abnormality in dedifferentiated liposarcoma (57 and 78 per cent of cases in well-differentiated and high-grade areas, respectively).

Cell Differentiation↗
PubMed1997

bcl-2 expression in pleural and extrapleural solitary fibrous tumours.

This study evaluated the immunoreactivity for bcl-2, a molecule involved in the control of programmed cell death, in cases of pleural (14) and extrapleural (2) solitary fibrous tumour (SFT), malignant mesotheliomas of different histological types, and a variety of extrapleural CD34-positive and CD34-negative spindle-cell tumours. In all SFTs, strong and diffuse immunostaining was demonstrated with anti-bel-2 antibody, sharply contrasting with the complete lack of staining observed in all mesotheliomas. The specificity of immunodetection of bcl-2 in SFT was confirmed by immunoblot analysis, showing a band consistent with the bcl-2 protein. At extrapleural locations, strong bcl-2 immunoreactivity was observed in Schwannoma (2/3 cases), synovial sarcoma (4/4 cases), and all cases of CD34-positive gastrointestinal stromal tumour (GIST; 10/10 cases). Most sarcomas were bcl-2-negative. Lack of bcl-2 expression was demonstrated in tumours which can pose problems in the differential diagnosis of SFT and can exhibit haemangiopericytoma-like features, including haemangiopericytoma (3 cases), dermatofibrosarcoma protuberans (16 cases), and deep-seated fibrous histiocytoma (3 cases). The constitutive expression of bcl-2 in SFT widens the spectrum of available markers for these tumours, providing a useful adjunct to their differential diagnosis in difficult cases at pleural and extrapleural sites, and contributing to the understanding of their histogenesis and molecular pathogenesis.

Adult↗
PubMed1997

HpSS: a new silver staining method for Helicobacter pylori.

AIMS: To verify whether the proposed new silver staining method compares favourably with other well established methods in the detection of Helicobacter pylori in gastric biopsies. METHODS: One hundred and forty pairs of antral and fundic biopsies, routinely formalin fixed and paraffin wax embedded, from 70 consecutive unselected patients were stained with haematoxylin and eosin, modified Giemsa, and the proposed H pylori silver stain (HpSS). H pylori immunodetection was performed in the same material with a polyclonal antiserum against H pylori. RESULTS: H pylori was detected in 89 biopsies from 48 patients with haematoxylin and eosin; in a further five biopsies (one antral and four fundic) with Giemsa stain, thereby identifying one more H pylori infected patient. The new silver staining method was positive in all the cases detected by these two methods and detected three extra infected patients (five more positive biopsies). Immunohistochemistry detected one more positive case (two positive biopsies) not identified by any of the other methods. CONCLUSIONS: The HpSS method proposed is highly sensitive in detecting H pylori; it is simple and it compares well with other methods used routinely for evaluating gastric biopsies for H pylori.

Biopsy↗
PubMed1997

Basaloid squamous cell carcinoma of the larynx and hypopharynx.

Basaloid squamous cell carcinoma (BSCC) is a recently described bimorphic variant of squamous cell carcinoma with distinct morphological and biological features. We describe the clinicopathological findings, along with immunohistochemical and ultrastructural investigations, in 15 new cases of BSCC of the larynx or hypopharynx observed and treated at the otolaryngology department of the University of Padua between 1989 and 1995. The world literature is also reviewed in order to develop a more accurate clinicopathological profile of the tumor. Patient records and histologic slides were reviewed in all of our 15 cases. The patient group consisted of 13 men (86.67%) and 2 women with a mean age of 63.33 years (median 69 years; range 44 to 84 years). Nine patients presented with cervical lymph node metastases. Surgical treatment was the therapy of choice; radiotherapy and chemotherapy have been applied in different combinations. Follow-up was available on all 15 cases. Local recurrence was described in 3 cases. Five of the 9 patients with cervical lymph node metastases developed distant metastases. Distant spread of the tumor without lymph node involvement was observed during follow-up in 4 cases. Nine patients died of disease, 2 are alive with widespread metastases, 2 are alive with no evidence of disease, and 2 have died of other causes. The determined 5-year survival was estimated to be 17.5% by the Kaplan-Meier method. In conclusion, BSCC is a distinctive carcinoma that is important to recognize, because it has a more aggressive biological behavior than conventional squamous cell carcinoma.

Adult↗