Biomedical subjects
M Barbareschi
Publications and source records attributed to M Barbareschi.
Prognostic markers in malignant mesothelioma.
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p21 expression in colorectal carcinomas: a study on 103 cases with analysis of p53 gene mutation/expression and clinic-pathological correlations.
The WAF1/CIP1 gene product, p21, an inhibitor of cyclin-dependent kinases, is a critical downstream effector in the p53 pathway. The expression of p21 in human neoplasms is heterogeneous, and may be related to p53 functional status. We evaluated p21 immunoreactivity in 103 colorectal carcinomas (CC) in relation to the p53 gene and protein alterations and clinico-pathologic parameters. High p21 expression (more than 10% reactive cells) was seen in 39% of cases. p21 staining was heterogeneous and often detected in clusters of tumour cells; in some tumours p21 staining was more pronounced in superficial areas. No relation was seen between p21 immunoreactivity and site of the tumours (right vs left), TNM stage and grade. p21 expression was related to p53 status as evaluated with IHC or with SSCP analyses, low p21 expression usually being associated with p53 protein overexpression (P=0.048) and p53 gene alteration (P=0.005). The strongest associations were seen when the combined p53/p21 immunophenotype was compared with p53 gene alterations (P=0.0002). These data support the hypothesis that p21 expression in CC is mainly related to p53 functional status, suggesting that p21 expression could be an interesting adjunct in the evaluation of the functional status of the p53 pathway in CC.
Prognostic value of estrogen receptor status can be improved by combined evaluation of p53, Bcl2 and PgR expression: an immunohistochemical study on breast carcinoma with long-term follow-up.
Steroid receptor analysis is the only widely accepted prognostic/predictive marker in breast cancer (BC) treatment. In the present study we evaluated the prognostic role of ER/PgR with p53 and Bcl2, in a series of 277 BC (153 pN1/2, 122 pNO, 2 pNx) with a long-term follow-up (67 months for DFS, 75 months for OS). Our results, besides confirming the usefulness of ER immunohistochemical expression as a prognostic marker, showed that PgR expression alone had a borderline/not significant prognostic value in the whole series (p=0.08 for DFS and p=0.09 for OS), while showed to be prognostic in N+ cases (p=0.02 for DFS and p=0.03 for OS). PgR prognostic value, however, was not independent at the multivariate analysis. By combining ER with PgR, p53 and Bcl2, we showed that ER/p53 and ER/Bcl2 phenotypes had a better discriminant role than ER/PgR phenotype. The ER+/p53+ phenotype was at higher risk of relapse/death as compared with ER+/p53- phenotype. Conversely ER-/p53+ phenotype showed the most unfavourable prognosis. Similar results could be observed concerning ER/Bcl2 phenotypes. Our study showed that the combined evaluation of ER/PgR weakly enhanced the prognostic/predictive power of ER status alone. On the contrary, the combined evaluation of ER/p53 and ER/Bcl2, improved this prognostic/predictive capability and allowed the separation of ER positive and ER negative cases into subgroups with different prognosis.
[Heterogeneous expression of cyclin D3 in breast carcinoma:absence of prognostic significance in a series of 92 cases with long follow-up].
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p27 Expression, a cyclin dependent kinase inhibitor in breast carcinoma.
p27 KIP1 is a cyclin dependent kinase inhibitor, which may act as a potential suppressor gene. Several lines of evidence support the hypothesis that reduced p27 KIP1 expression is related to uncontrolled cell proliferation and tumorigenesis. Low immunohistochemical expression of p27 KIP1 in human neoplasm seems related to tumor progression and poor prognosis. In breast cancer, low p27 is associated with high tumour grade and loss of oestrogen receptor, and it has been suggested that low p27 KIP1 is a powerful and independent prognostic marker of poor clinical outcome. There are however some discrepant results: a few studies, some of which conducted on large series of patients, do not support an independent role of p27 KIP1 as a prognostic marker. We are indeed faced with an intriguing hypothesis, but many more studies are needed to evaluate the real value of p27 KIP1 as a prognostic marker.
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.
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.
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.
Tissue carcinoembryonic antigen and oestrogen receptor status in breast carcinoma: an immunohistochemical study of clinical outcome in a series of 252 patients with long-term follow-up.
Carcinoembryonic antigen (CEA) is a well-known tumour marker whose immunohistochemical expression could be prognostically relevant in breast carcinomas. We evaluated CEA immunohistochemical expression, using the specific T84.66 monoclonal antibody, in a series of 252 consecutive cases of infiltrating breast carcinomas (104 N0, 148 N1/2) with median follow-up of 84 months. Oestrogen receptor (ER) status has been evaluated with the immunohistochemical method (ER1D5 antibody, 10% cut-off value): 121 cases were ER negative, 128 cases were ER positive and in three cases ER status was unknown. CEA staining was cytoplasmic; staining intensity and percentage of reacting cells were combined to obtain a final score (CEA score). The difference between the distribution of CEA score within the modalities of the other variables was not statistically significant. Univariate survival analysis has been performed on the series of node-negative and node-positive patients. In the latter subgroup, this has been performed separately for patients treated with systemic adjuvant hormonal therapy or chemotherapy. A multivariate analysis was only performed for node-positive patients treated with adjuvant therapy. CEA immunoreactivity was not prognostically relevant in any subset of analysed patients. The most important prognostic markers were nodal status and tumour size.
Skin manifestations caused by pigeon ticks (Argas reflexus).
Three adult patients (one woman and two men) presented with polymorphous skin manifestations caused by pigeon ticks (Argas reflexus). These manifestations were characterized by wheals with a central hemorrhagic point in the first patient, crusted-ulcerative lesions in the second, and pustular lesions in the third patient. We observed specific IgE against a somatic extract (antigen A) and the saliva (antigen B) of A. reflexus in two patients.
[Pulmonary neuroendocrine neoplasia: from molecular biology to the clinic, by way of immunohistochemistry].
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[MALT gastric lymphoma: update].
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Family with "pure" hair-nail ectodermal dysplasia.
"Pure" ectodermal dysplasias are developmental disorders affecting only tissues of ectodermal origin. Two different pure ectodermal dysplasias involving only hair and nails have been described to date. Here we describe congenital nail dystrophy and hypotrichosis associated with folliculitis decalvans in a family suggesting autosomal-dominant transmission. This report documents peculiar clinical and ultrastructural hair findings that fit poorly into previously described conditions. Thus the reported patients could represent a new type of pure ectodermal dysplasia.
Cyclin-D1-gene amplification and expression in breast carcinoma: relation with clinicopathologic characteristics and with retinoblastoma gene product, p53 and p21WAF1 immunohistochemical expression.
Cyclin D1 is a major positive regulator of the G1 restriction point promoting inactivation of the retinoblastoma protein (RB). The cyclin D1 gene is rearranged, amplified and/or over-expressed in several human neoplasms. In the present series of 64 human breast carcinomas, cyclin D1 amplification (4- to 8-fold) was seen in 24% of cases, and cyclin-D1 immunohistochemical over-expression was seen in 50% of cases. Amplification and over-expression were statistically associated; however, divergent result were seen in 30% of cases. Some of these discrepancies may reflect the fact that cyclin-D1 expression may be due to mechanisms other than gene amplification. Cyclin-D1 over-expression, but not cyclin-D1 amplification, was associated with positive oestrogen-receptor immunoreactivity. Cyclin-D1 amplification was associated with high RB expression, and 4 cases (7%) with absent RB immunoreactivity showed no cyclin-D1 amplification nor expression. Our data support the hypothesis that cyclin-D1 amplification may be associated with enhanced gene transcription and with high RB expression, that high ER expression may cooperate in maintaining high levels of cyclin-D1 protein, and that loss of RB function, as assessed by the lack of RB immunoreactivity, may be related to normal cyclin-D1 gene copy number and low cyclin-D1 expression.
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).
Cutaneous manifestations in systemic vasculitis.
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Low grade fibromyxoid sarcoma.
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