Biomedical subjects

G Bevilacqua

Publications and source records attributed to G Bevilacqua.

At least 73 records · Page 4Linked to original sources

PubMed1998

Spectrum of GCDFP-15 expression in human fetal and adult normal tissues.

GCDFP-15, a glycoprotein identified in the cyst fluid of cystic breast disease, is considered to be a marker of apocrine differentiation. Studies on GCDFP-15 localization in adult normal tissues are lacking, and no information on GCDFP-15 expression during fetal development has been reported. We investigated GCDFP-15 expression in a large series of formalin-fixed, paraffin-embedded normal human adult and fetal tissues using the monoclonal antibody BRST-2. In normal adult tissues GCDFP-15 expression was found in all apocrine, lacrimal, ceruminous and Moll's glands and in numerous serous cells of the submandibular, sublingual and minor salivary glands. The serous cells of nasal and bronchial glands were also positive; parotid and laryngeal glands showed rare immunoreactive cells. GCDFP-15-positive cells were observed in all cutaneous eccrine glands from different body sites. In fetal tissues immunoreactivity was observed in numerous acinous cells of all tracheal, bronchial and submandibular salivary glands. GCDFP-15 positivity was identified in numerous cells of all axillary sweat glands and in rare cells of some sweat glands of the thorax, abdomen, back, leg and arm. In both apocrine and nonapocrine glands GCDFP-15 was always localized in the secretory component. These data suggest that GCDFP-15 is a glandular differentiation marker associated with apocrine secretion; that it is expressed in glands that have phylogenetic origins in common with apocrine glands (submandibular salivary and submucosal bronchial glands); and that eccrine cutaneous glands express GCDFP-15 and thus might be referred to as mixed apocrine-eccrine glands. GCDFP-15 is expressed during fetal development and may represent a common marker of embryologically linked glandular structures.

Adult↗

PubMed1998

Bcl2 and p53 regulate vascular endothelial growth factor (VEGF)-mediated angiogenesis in non-small cell lung carcinoma.

The aim of this study was to investigate the expression of p53 and bcl2 proteins in a series of 107 non-small cell lung cancers (NSCLC), and to relate such protein expression to neovascularisation and the expression of vascular endothelial growth factor (VEGF). Moreover, we analysed the prognostic impact of these biological parameters on overall survival, both in univariate and multivariate analyses. An inverse association was found between bcl2 expression and microvessel count (MVC; P = 0.0004) and bcl2 and VEGF (P = 0.007). In contrast, a significant association was found between p53 expression and MVC (P = 0.03) and p53 and VEGF expression (P = 0.04). In univariate analysis, nodal status (P < 0.000001), MVC (P < 0.000001), bcl2 (P = 0.002), p53 (P = 0.03) and VEGF expression (P < 0.000001) significantly affected overall survival, but in multivariate analysis only MVC and VEGF expression retained their prognostic influence. Our results suggest that bcl2 and p53 possibly control the development of tumour angiogenesis in NSCLC, with putative mediation by VEGF. Moreover, the important influence of angiogenesis in the progression of NSCLC is further highlighted.

Aged↗

PubMed1998

Primary chemotherapy in locally advanced breast cancer (LABC): effects on tumour proliferative activity, bcl-2 expression and the relationship between tumour regression and biological markers.

The rate of tumour cell proliferation evaluated by the [3H]-thymidine labelling index ([3H]-dT-LI) is known to be an independent prognostic factor in patients with operable breast cancer and significantly predicts the response to chemotherapy in patients with advanced disease. In locally advanced breast cancer (LABG), we examined whether chemotherapy induced modifications in [3H]-dt-LI, and bcl-2 expression and their relationship with tumour regression and prognosis. 70 LABC patients received three courses of primary chemotherapy (FEC: 5-fluorouracil 600 mg/m2, epidoxorubicin 60 mg/m2, cyclophosphamide 600 mg/m2, followed by surgery and subsequent adjuvant chemotherapy consisting of three courses of FEC alternated with three courses of CMF (cyclophosphamide 600 mg/m2, methotrexate 40 mg/m2, 5-fluorouracil 600 mg/m2). Tumour biological markers were evaluated on diagnostic biopsy, before primary chemotherapy and at surgery. Tumour cell proliferation was determined by [3H]-dT-LI, whilst bcl-2 expression was examined by immunohistochemical staining. The overall response rate to primary FEC was 74.3% (95% confidence interval 57.6-83.2%). The response rate correlated with high [3H]-dT-LI: 88% (29/33) of patients with high [3H]-dT-LI achieved an objective response compared with 62% (23/37) of patients with low [3H]-dT-LI (P = 0.014). The 3 patients achieving a pathological complete response after induction treatment had high proliferative tumours. The highest 2-year relapse free survival (66.6%) was observed in patients with low [3H]-dT-LI after primary chemotherapy. The median bcl-2 expression values before and after primary chemotherapy were 0% (range 0-80) and 30% (range 0-90), respectively (P = 0.03). Our data indicate that primary chemotherapy can modulate tumour cell kinetics and apoptosis-related genes. Pretreatment proliferative activity correlated with tumour response, whilst post-treatment [3H]-dT-LI correlated with relapse free survival.

Adult↗

PubMed1998

Evaluation of FHIT gene alterations in ovarian cancer.

The FHIT gene, recently cloned and mapped on chromosome 3p14.2, has frequently been found to be abnormal in several established cancer cell lines and primary tumours. As alterations of chromosome 3p are common events in ovarian cancers with breakpoint sites at 3p14.2, we decided to investigate the role of FHIT in human ovarian tumorigenesis. Fifty-four primary ovarian carcinomas were studied by reverse transcription of FHIT mRNA followed by polymerase chain reaction (PCR) amplification and sequencing of products. The same tumours and matched normal tissues were also investigated for loss of heterozygosity using three microsatellite markers located inside the gene. We found an abnormal transcript of the FHIT gene in two cases (4%) and allelic losses in eight cases (15%). Twelve (22%) of the 54 tumours investigated belonged to young patients with a family history of breast/ovarian cancer. In none of these cases was the FHITgene found to be altered. Our results indicate that FHITplays a role in a small proportion of ovarian carcinomas.

Acid Anhydride Hydrolases↗

PubMed1998

Genetic analysis of lung tumours of non-smoking subjects: p53 gene mutations are constantly associated with loss of heterozygosity at the FHIT locus.

Lung cancer is strictly associated with tobacco smoking. Tumours developed in non-smoking subjects account for less than 10% of all lung cancers and show peculiar histopathological features, being prevalently adenocarcinomas. A number of genetic data suggest that their biological behaviour may be different from that of lung tumours caused by smoking, however the number of cases investigated to date is too low to draw definitive conclusions. We have examined the status of p53 and K-ras genes and the presence of loss of heterozygosity (LOH) at the FHIT locus in a series of 35 lung adenocarcinomas that developed in subjects who had never smoked. Results were compared with those obtained in a series of 35 lung adenocarcinomas from heavy-smoking subjects. In the group of non-smoking subjects p53 mutations and LOH at the FHIT locus were present in seven (20%) cases, and the two alterations were constantly associated (P < 0.0001), whereas they were not related in the series of carcinomas caused by smoking. In tumours developed in heavy-smoking subjects, the frequency of LOH at the FHIT locus was significantly higher (P = 0.006) than in tumours from non-smoking subjects. The frequency of p53 mutations in adenocarcinomas caused by smoking was not different from that seen in non-smoking subjects. However, in the group of smoking subjects we observed mostly G:C --> T:A transversions, whereas frameshift mutations and G:C --> A:T transitions were more frequently found in tumours from non-smoking subjects. No point mutations of the K-ras gene at codon 12 were seen in subjects who had never smoked, whereas they were present (mostly G:C --> T:A transversions) in 34% of tumours caused by smoking (P = 0.002). Our data suggest that lung adenocarcinomas developed in subjects who had never smoked represent a distinct biological entity involving a co-alteration of the p53 gene and the FHIT locus in 20% of cases.

Acid Anhydride Hydrolases↗

PubMed1998

A region on the long arm of chromosome 16 is frequently deleted in metastatic node-negative breast cancer.

The aim of the present study was to define which region of chromosome 16q is most relevant for evaluation of the risk of metastatic recurrence in human breast cancer cases that are lymph node-negative at the time of diagnosis. For this purpose we examined 36 cases of sporadic breast carcinoma subdivided into 3 groups: the first group: no metastatic progression after an average follow-up time of 15 years; including patients with and without lymph node metastases at the time of diagnosis; the second group: N+ (node-positive) patients only, developed metastasis in five years from surgical excision. The last group was composed of patients who developed metastasis but were N0 (node-negative) at diagnosis. A statistically significant association was found between LOH (loss of heterozygosity) at 16q and metastatic progression of the neoplastic disease. 16q LOH was identified as a new independent molecular marker of progression for tumor N0 at diagnosis.

Adult↗

PubMed1998

Evaluation of epidermal growth factor-related growth factors and receptors and of neoangiogenesis in completely resected stage I-IIIA non-small-cell lung cancer: amphiregulin and microvessel count are independent prognostic indicators of survival.

We have determined the expression of transforming growth factor alpha (TGF alpha), amphiregulin (AR), CRIPTO, the epidermal growth factor receptor (EGFR), erbB-2, erbB-3, and tumor angiogenesis in a series of 195 patients with stage I-IIIA non-small cell lung cancer (NSCLC) treated with radical surgery to define their usefulness as prognostic indicators of survival. A variable degree of specific staining in cancer cells was observed for the three growth factors and for the three growth factor receptors in the majority of NSCLC patients. A statistically significant association between overexpression of TGF alpha, AR, and CRIPTO was observed. Enhanced expression of AR was significantly correlated with enhanced expression of erbB-2 and advanced T-stage. A direct association was also detected for overexpression of TGF alpha and of erbB-2 or erbB-3, respectively. Sex, tumor size, nodal status, stage, microvessel count, as a measure of neovascularization, and AR overexpression significantly correlated with overall survival at univariate analysis. In a Cox multivariate analysis, the only characteristics with an independent prognostic effect on OAS were microvessel count [relative hazard (RH), 6.61; P < 0.00001), nodal status (RH, 1.59; P = 0.0013), and AR overexpression (RH, 1.72; P = 0.02). These results suggest that evaluation of neoangiogenesis and of certain growth factors, such as AR, can be useful in addition to conventional pathological staging to select high-risk NSCLC patients who may benefit from post-surgical systemic therapies.

Adult↗

PubMed1997

Down-regulation of the nm23.h1 gene inhibits cell proliferation.

nm23 gene expression is strictly related to the state of cell growth. The level of its expression parallels the fraction of thymidine-incorporating cells (S-phase cells) in neoplastic mammary tissues and in the synchronously cycling fraction of MCF 1OA cells. nm23.h1 reaches a peak of expression in the S-phase, and is present at very low level during the GO/G1 phase. Two strategies are used to demonstrate the direct involvement of the nm23.h1 gene in the process of cell proliferation. The first consists of transient inhibition of nm23.h1 expression by using anti-sense oligonucleotide treatment; weak inhibitory effect on cell proliferation is observed. The second strategy involves the stable inhibition of nm23.h1 expression by transfection of MCF1OA cells with a plasmid vector expressing the human nm23.h1 anti-sense mRNA. The anti-sense-transfected cells show consistently slower proliferative activity than the control.

Breast↗

PubMed1997

Angiogenesis as a prognostic indicator of survival in non-small-cell lung carcinoma: a prospective study.

BACKGROUND: Tumors acquire nutrients that are essential for continued growth and an avenue for dissemination to the rest of the body by inducing angiogenesis (i.e., the formation of new blood vessels). Preliminary studies involving a number of different kinds of cancer have indicated that an assessment of tumor angiogenesis may be useful in predicting disease outcome. PURPOSE: In a prospective study, we evaluated the relationship between tumor angiogenesis and survival for 407 patients with non-small-cell lung carcinoma who were treated with potentially curative surgery. METHODS: The study population consisted of 360 male and 47 female patients who underwent surgery consecutively at the Department of Surgery, University of Pisa, Italy, from March 1991 through December 1994. Follow-up lasted through February 1996, with a median follow-up for living patients of 29 months (range, 15-60 months). An anti-CD34 monoclonal antibody, which is specific for endothelial cells, and standard immunohistochemical techniques were used to measure angiogenesis in tumor samples. Angiogenesis was quantified in terms of microvessel counts; the counts for single, high-power microscopic fields (magnification x250) in the three most intense areas of blood vessel growth for each sample were averaged. The median microvessel count in this series was 20, and the counts were categorized as follows: 1) low versus high (< or =20 versus >20 microvessels) or 2) in five categories (1-10, 11-20, 21-30, 31-40, and > or =41 microvessels). Disease-free and overall survival during follow-up were assessed. Kaplan-Meier survival curves were modeled in a univariate analysis of patient and tumor characteristics; the Cox proportional hazards model was used in multivariate analysis. Reported P values are two-sided. RESULTS AND CONCLUSIONS: In the univariate analysis, patients with larger tumors (P for trend <.00001), a more advanced tumor stage (P for trend <.00001), a greater degree of regional lymph node involvement (P for trend <.00001), or more vascularized tumors (high versus low microvessel count, P<.00001) experienced significantly reduced overall survival. When microvessel counts were analyzed in five categories, a highly significant trend (P<.00001) toward worse prognosis was observed with increasing tumor vascularity. In multivariate analysis, tumor microvessel count (P<.00001), tumor size (P = .0006), and regional lymph node status (P<.00001) retained independent prognostic value with respect to overall survival; among these variables, tumor microvessel count, considered as a continuous variable, was the most important, with a relative hazard of death of 8.38 (95% confidence interval = 4.19-16.78) associated with the highest microvessel counts. IMPLICATIONS: An evaluation of tumor angiogenesis may be useful in the postsurgical staging of patients with non-small-cell lung carcinoma and in identifying subsets of patients who may benefit from different postsurgical treatments.

Adult↗

PubMed1997

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.

Blotting, Southern↗

PubMed1997

NM23 gene expression in human breast carcinomas: loss of correlation with cell proliferation in the advanced phase of tumor progression.

NM23 is a protein associated with tumor progression, expressed in all tissues and in human tumors. Reduced expression of NM23.H1 is related to high incidence of lymph node and distant metastasis or to poor prognosis of the patient in several human malignant tumors. In this study we analyze NM23 expression in non-neoplastic mammary tissues surrounding the tumoral lesions, in human mammary carcinomas and in lymph node metastasis. Our analysis shows that NM23.H1 expression is lower in the mammary cells surrounding the tumor than in the tumor itself. In the primary tumors we observed a negative trend between degree of local invasion and level of NM23.H1 expression. A further decrease of NM23.H1 was detected in the invasive tumors that metastasized to axillary lymph nodes and in the metastasis. NM23.H2 was always more highly expressed than NM23.H1, and reduced expression of NM23.H1 but not NM23.H2 was concordant with the presence of lymph node metastasis or local invasiveness of the primary tumor. A positive correlation between NM23.H1 mRNA content and cell growth rate of breast tumor cells has been confirmed. However, this trend was not maintained in cancer cells from tumors that metastasized to axillary lymph nodes and in metastatic cells; in these 2 situations the NM23.H1 mRNA content varied without any relationship to the proliferative rate of the cells. In addition, in comparison with the initial tumor, the metastatic cell population showed a strong decrease of NM23.H1 expression and increased proliferative activity.

Biomarkers, Tumor↗

PubMed1997

Alterations of P16 (MTS1) in node-positive non-small cell lung carcinomas.

The status of the P16 gene was investigated by Southern blot, polymerase chain reaction-single strand conformational polymorphism (PCR-SSCP), and DNA sequencing analyses in 30 primary resected non-small cell lung carcinomas (NSCLCs) with metastatic involvement of thoracic lymph nodes and 33 NSCLCs without node metastases. Direct sequencing of tumour DNA samples scored positive by PCR-SSCP showed five somatic mutations of the P16 gene: four nonsense and one frameshift. The Southern blot analysis revealed the presence of a homozygous deletion of the P16 locus in one tumour. All of the six NSCLCs with somatic aberrations of the P16 gene belonged to the series of tumours with metastatic diffusion to thoracic lymph nodes. In each of these six cases, the genetic aberration was seen in both the primary tumour and the node metastasis. No P16 alteration was found in tumours without metastatic lymph nodes. This difference was statistically significant (P = 0.02). No correlation was present between P16 alterations and other clinicopathological parameters including age of patients, tumour size, histological type, and grade. In three tumours with genetic aberration of P16, there was a concomitant alteration of the p53 gene. Our results indicate that the P16 gene is infrequently mutated (10 per cent of the cases examined) in primary resected NSCLC. However, since P16 mutations were found only in metastatic tumours, they may be important events in late phases of tumour progression and could represent useful markers of tumour aggressiveness in NSCLC.

Adult↗

PubMed1997

The spectrum of 67-kD laminin receptor expression in breast carcinoma progression.

Laminin is a glycoprotein of the basement membrane (BM), involved in a variety of normal and pathological cellular events including tumour invasion and metastasis. Cells bind laminin through different types of receptor. The 67-kD laminin receptor (67LR) is a cell-surface protein which binds laminin with high affinity. 67LR expression has been shown to increase in neoplastic cells, compared with normal tissues, and 67LR seems to play an important role during the first steps of neoplastic progression. In this study, 67LR expression was analysed during the morphological phases of breast cancer progression from normal tissue to invasive carcinoma. A total of 506 formalin-fixed, paraffin-embedded normal breast structures and lesions were stained by immunohistochemistry usign the MLuC5 monoclonal antibody, which is specific for 67LR. The results show that in normal breast and in any kind of breast lesion, myoepithelial and endothelial cells express 67LR. While 67LR is not seen in the epithelium of normal breast, cysts, adenosis, and benign tumours, it is expressed in the epithelial cells of several hyperplasias and carcinomas in situ, both ductal and lobular, as well as in all invasive carcinomas. The 67LR-positive cell subpopulation expands from hyperplastic lesions to invasive carcinoma, suggesting that 67LR could be related to the induction and progression of breast cancer.

Breast↗

PubMed1997

Apocrine epithelium of the breast: does it result from metaplasia?

Benign and malignant breast lesions may show an apocrine epithelium considered to be the result of metaplasia. In an attempt to clarify the histogenesis of the breast apocrine epithelium we searched for the presence of apocrine cells or cells with apocrine differentiation during human breast development. We analysed 10 autopsy specimens of female breasts from fetuses between 28 and 40 weeks of gestational age and tissue from 6 normal breasts, obtained after breast reduction in nulliparous young women between 22 and 28 years of age. Formalin-fixed, paraffin-embedded sections were stained with haematoxylin-eosin, PAS-diastase and a monoclonal antibody (BRST-2) anti-GCDFP-15, which is a specific apocrine marker. A 40-week fetal breast was analysed by electron microscopy. No cells with histological and ultrastructural apocrine features were found in the ducts of fetal breasts. All fetal breasts showed some ducts with sparse GCDFP-15-immunoreactive cells; the number of these cells increased with gestational age. PAS-diastase was negative. No cells with apocrine morphology were found in ducts and lobules of normal adult breasts. Scattered GCDFP-15-positive luminal epithelial cells and rare PAS-diastase-positive cells were observed in some lobules of all adult breasts. Cells with biochemical characteristics (GCDFP-15 expression) of apocrine differentiation are evident during human fetal breast development and persist in adult mammary glands. Unknown stimuli may induce these cells to take on an apocrine morphology. Apocrine epithelium of the breast may be a normal process of differentiation rather than metaplasia. We suggest the term "apocrine differentiation precursor cells" for GCDFP-15-positive breast epithelial cells with no apocrine morphology.

Adult↗

PubMed1997

Further characterisation of [3H]8-hydroxy-2-(di-N-propylamino)tetralin binding sites in human brain postmortem.

The saturation parameters and the pharmacological characteristics of the binding of the serotonin 1A (5-HT1A) receptor agonist [3H]8-hydroxy-2-(di-N-propylamino)tetralin ([3H]8-OH-DPAT), as well as the effects of nucleotides and divalent cations (Mg2+, Mn2+) on it, were compared in some human postmortem brain regions: the main cortical areas, hippocampus and striatum. [3H]8-OH-DPAT labelled a single population of recognition sites with the highest maximal capacity (Bmax) in the hippocampus and the lowest affinity in the striatum. Among the various cortical areas, the frontal cortex exhibited the highest Bmax. The pharmacological profile of the [3H]8-OH-DPAT binding sites was consistent with the labelling of the 5-HT1A receptor in the hippocampus and cortex, whereas the striatal site shared strong similarity to the presynaptic serotonin transporter. Modulation of [3H]8-OH-DPAT binding by divalent cations and nucleotides was detectable and stable in autopsy brains. In particular, nucleotide effects were area-dependent: guanosine thiotriphosphate (GTP gamma S) reduced [3H]8-OH-DPAT binding to the same extent in the hippocampus and frontal cortex, while having no effect in the striatum. Divalent cation effects depended also upon the brain area: in the striatum, they inhibited [3H]8-OH-DPAT binding, while stimulating it in the hippocampus and, with less extent, in the frontal cortex. In summary, these findings suggest that the [3H]8-OH-DPAT binding and its modulatory parameters in human brain tissues seem to show similarities but also some differences with respect to those determined in the rat brain. Furthermore, postmortem stability of GTP and divalent cation sensitive 5-HT1A receptors underlines the need for further studies on the regulatory and functional properties of this receptor in the human brain.

8-Hydroxy-2-(di-n-propylamino)tetralin↗

PubMed1997

Tumor angiogenesis and biologic markers in resected stage I NSCLC.

OBJECTIVE: Microvessel count (MC), as a measure of tumor angiogenesis, has been shown to be significantly correlated with metastatic disease in cutaneous, mammary, prostatic, head and neck cancer. We have previously assessed the role of intensity of angiogenesis as predictor of metastasis in surgically resected T1N0M0 NSCLC. We needed to confirm its value, in a prospective larger study on Stage I NSCLC, before its utilization as a prognostic tool for further clinical investigations. METHODS: In the present report we prospectively investigated 227 patients (206 males, 21 females; median age 65 years) with Stage I NSCLC treated only by radical surgery between March 1991 and December 1994 with utmost care for some biological characteristics (proliferative activity, the blood vessel invasion, angiogenesis and the p53 protein expression). RESULTS: The operative procedures consisted of 62 pneumonectomies, 148 lobectomies and 17 segmentectomies or wedge resections. With a median follow-up of 36 months (range 15-60), eighty patients have already experienced a local (n = 22) or systemic (n = 58) relapse. Univariate analysis revealed that T factor (T1 versus T2)(P = 0.008) and angiogenesis count (< or = versus > median, 17) (P = 0.0006) were significant predictors of survival. The same variables were also significant predictors of long Disease Free Survival (P = 0.006 and P = 0.004, respectively). On multivariate analysis, however, only the microvessel count retained its level of prognostic significance as regards both overall (P < 0.01) and disease-free survival (P < 0.01). CONCLUSIONS: The present study corroborates the role of angiogenesis in the metastatic spread of NSCLC and emphasizes its value in the identification of patients in whom surgery should be supplemented by systemic treatment.

Aged↗

PubMed1997

Neoangiogenesis and p53 protein in lung cancer: their prognostic role and their relation with vascular endothelial growth factor (VEGF) expression.

Following up-regulation of an angiogenesis inhibitor by the wild-type p53 protein proven recently, we have analysed on the one hand the prognostic impact of microvessel count (MC) and p53 protein overexpression in non-small-cell lung carcinoma (NSCLC) progression and, on the other hand, the inter-relation between the microvascular pattern and the p53 protein expression. Moreover, we assessed the expression of vascular endothelial growth factor (VEGF), one of the pivotal mediators of tumour angiogenesis, in order to investigate its relation to p53 protein expression and MC. Tumours from 73 patients resected for NSCLC between March 1991 and April 1992 (median follow-up 47 months, range 32-51 months) were analysed using an immunohistochemical method. In univariate analysis, MC and p53 accumulation were shown to affect metastatic nodal involvement, recurrence and death significantly. Multiple logistic regression analysis showed an important prognostic influence of MC and nodal status on overall (P = 0.0009; P = 0.01) and disease-free survival (P = 0.0001; P = 0.03). Interestingly, a strong statistical association was observed between p53 nuclear accumulation and MC (P = 0.0003). The same inter-relationship was found in non-squamous histotype (P = 0.002). When we analysed the concomitant influence of MC and p53 expression on overall survival, we were able to confirm a real predominant role of MC in comparison with p53. With regard to VEGF expression, p53-negative and lowly vascularized tumours showed a mean VEGF expression significantly lower than p53-positive and highly vascularized cancers (P = 0.02). These results underline the prognostic impact of MC and p53 protein accumulation in NSCLC and their reciprocal inter-relationship, supporting the hypothesis of a wild-type p53 regulation on the angiogenetic process through a VEGF up-regulation.

Aged↗

PubMed1997

p53 alterations are predictive of chemoresistance and aggressiveness in ovarian carcinomas: a molecular and immunohistochemical study.

Chemotherapeutic management of ovarian cancers is a difficult task as these neoplasms show significant differences in chemosensitivity, even if they share identical clinicopathological features. The present study was undertaken to investigate the prognostic and predictive role of p53 alterations in ovarian cancer. To this end, using different technical approaches, i.e. genetic and immunohistochemical analyses, we analysed a series of 68 ovarian neoplasms including 15 low malignant potential (LMP) tumours and 53 invasive carcinomas. We never observed p53 abnormalities in LMP tumours. p53 alterations were present only in invasive ovarian carcinomas, and they were detected much more frequently in tumours characterized by high histological grade (P = 0.01) and advanced-stage disease (P = 0.006 and P = 0.05 for gene mutations and protein expression respectively). For 33 patients with invasive ovarian cancer, information was available concerning response to cisplatin-based chemotherapy. A strong correlation (P = 0.001) has emerged between p53 alterations and response to chemotherapy; only one (14%) of seven patients who had a pathological complete response to antiblastic drugs showed p53 aberrations, whereas 18 (82%) of 22 cases with partial response and all of the four non-responsive patients scored positive for p53 abnormalities. We also observed that patients with p53 mutations had a significantly shorter progression-free survival than patients with p53-negative tumours (P = 0.05). Taken together, our results strongly suggest that in epithelial ovarian malignancies tumours showing p53 aberrations are significantly less sensitive to chemotherapy and more aggressive than those with functional p53. Thus, a routine analysis of this gene could have profound implications for the treatment of ovarian cancer.

Antineoplastic Agents↗