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Papers by paolo palma

American Journal of Clinical Pathology, 2008

All cervical intraepithelial neoplasia (CIN) diagnoses identified during the New Technologies for... more All cervical intraepithelial neoplasia (CIN) diagnoses identified during the New Technologies for Cervical Cancer trial (ISRCTN81678807) were blindly reviewed by 2 pathologists. Original diagnoses based on colposcopy-guided biopsies were compared with those made by the reviewers who had access to all clinical histologic samples (including postsurgical). Cases downgraded from CIN 2+ by the reviewers were considered indicative of unnecessary treatments. The analyses are presented according to the molecular (high-risk human papillomavirus [HPV]) and/or cytologic diagnosis used to refer the women for colposcopy.

International Journal of Cancer, 1997

Cyclin D1 is a major positive regulator of the G 1 restriction point promoting inactivation of th... more Cyclin D1 is a major positive regulator of the G 1 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. Int.

Lancet Oncology, 2008

Background Human-papillomavirus (HPV) testing is more sensitive, but less specifi c, than convent... more Background Human-papillomavirus (HPV) testing is more sensitive, but less specifi c, than conventional cytology for detecting high-grade cervical intraepithelial neoplasia (CIN). We assessed whether HPV testing with triage by p16-INK4A overexpression can increase specifi city while maintaining sensitivity.

International Journal of Cancer, 2000

p27 Kip1 (p27) , a cyclin-dependent kinase inhibitor, has an important role in the progression of... more p27 Kip1 (p27) , a cyclin-dependent kinase inhibitor, has an important role in the progression of cells from G 1 into S phase of the cell cycle. p27 may act as a tumor suppressor, and several reports suggest that loss of its expression in breast carcinoma is related to tumor progression and poor prognosis. We evaluated p27 immunohistochemical expression in 512 consecutive cases of breast carcinoma with 9 years of median-term follow-up. p27 expression was heterogeneous and frequently less intense than in normal cells. Low p27 expression (<50% of reacting cells) was associated with grade III tumors, N0 status, estrogen receptor-negative status, and low cyclin D1 expression. In the whole series of cases, p27 expression did not predict outcome. In node-negative cases (249 patients), high p27 expression indicated poor prognosis. p27 was not prognostically relevant in the group of 223 patients with pT1 disease or in the group of 154 patients <50 years of age. We also investigated the prognostic value of the combined expression of p27 and cyclin D1, but no differences in survival were seen in this bivariate analysis. Int.

Breast Cancer Research and Treatment, 1995

In the present study we update previous results on the prognostic value of intratumoral microvess... more In the present study we update previous results on the prognostic value of intratumoral microvessel density (IMD), determined immunocytochemically using the monoclonal antibody CD-31 and a standard streptavidin-immunoperoxidase technique, published in theJ Clin Oncol 12:454–466, 1994. This study was undertaken in those 211 node-negative breast cancer (NNBC) cases of that series of which we had pathological material available to determine all the prognostic indicators. The median period of follow-up has been extended to 78 and 80 months for relapse-free survival (RFS) and overall survival (OS), respectively, and new biological indicators (i.e. Ki-67 labeling and 67 kDa laminin receptor expression) were included in the analysis. The main results obtained are:i) a confirmation that IMD is not associated with the other biological markers studied, i.e. expression of p53 protein, c-erbB-2 protein, 67 kDa laminin receptor, and cell kinetics; IMD was weakly associated only with histological grade (p=0.053);ii) IMD remains a highly significant prognostic factor for RFS and OS (p<0.0001 and p=0.018, respectively) in univariate analysis;iii) in multivariate analysis on RFS, IMD (likelihood ratio test (LRT)=30.16; p<0.0001), 67 kDa laminin receptor (LRT=9.80; p=0.0017), the IMD/67 kDa laminin receptor interaction (LRT=8.62; p=0.0033), tumor size (LRT=8.56; p=0.0034), and p53 protein (LRT=4.96; p=0.025) are significant and independent prognostic indicators. For OS, only tumor size (LRT=8.34; p=0.0038), menopausal status (LRT=5.16; p=0.023), p53 protein (LRT=4.37; p=0.036), and IMD (LRT=4.05; p=0.044) retain a significant and independent prognostic value. The results of this study confirm the prognostic importance on RFS of the variables previously tested, but not of peritumoral lymphatic vessel invasion. A novel finding is that 67 kDa laminin receptor and the IMD/67 kDa laminin receptor interaction are also significant and independent variables. For OS, the results confirm that both IMD and tumor size are significant and independent variables. With prolonged follow-up the novel finding that emerges is the prognostic importance of menopausal status and p53 protein. This new information could be useful for a more accurate selection of high-risk NNBC patients who require careful follow-up and may benefit from adjuvant therapy.

International Journal of Cancer, 1995

Experimental studies have shown that the 67-kDa laminin receptor (LRec) is an important molecule ... more Experimental studies have shown that the 67-kDa laminin receptor (LRec) is an important molecule for the interaction of tumour cells with the extracellular matrix, and that it plays a role in the early steps of angiogenesis and in tumour invasion and metastasis. We performed a multi-parametric study in 171 node-negative breast cancers, followed for a median time of 6 years, to verify whether determination of the LRec provides prognostic information in addition to intra-tumoral microvessel density (IMD), a measure of tumour angiogenesis, and to other biological and conventional indicators. A positive association between LRec expression and high neovascularization was found, although it did not reach significance. LRec was not associated either with other biological markers (oestrogen receptor, progesterone receptor and p53 expression) or to the conventional prognostic features [menopausal status, tumour size, histological types, grading and peri-tumoral lymphatic vessel invasion (PLVI)]. In univariate analysis, IMD, p53, PgR, PLVI, grading and tumour size were significant prognostic indicators of relapse-free survival (RFS). LRec expression approached significance when considered as a dichotomous variable, after having selected the optimum cutoff of 10% to distinguish high-risk from low-risk patients. For overall survival (OS), tumour size and IMD (continuous variable) were significant prognostic factors, and p53 approached significance. In multivariate analysis for RFS, the joint variable LRec and vascularization was the strongest independent prognostic factor, followed by PgR, PLVI and p53. For OS, tumour size was the only independent prognostic indicator in this series.

Lancet Oncology, 2006

Background: Although testing for human papillomavirus (HPV) has higher sensitivity and lower spec... more Background: Although testing for human papillomavirus (HPV) has higher sensitivity and lower specifi city than cytology alone for detecting cervical intraepithelial neoplasia (CIN), studies comparing conventional and liquid-based cytology have had confl icting results. Methods: In the fi rst phase of a two-phase multicenter randomized controlled trial, women aged 35 -60 years in the conventional arm ( n = 16 658) were screened using conventional cytology, and women in the experimental arm ( n = 16 706) had liquidbased cytology and were tested for high-risk HPV types using the Hybrid Capture 2 assay. Women in the conventional arm were referred to colposcopy with atypical cells of undetermined signifi cance (ASCUS) or higher and those in the experimental arm were referred with ASCUS or higher cytology or with a positive ( ≥ 1 pg/mL) HPV test. Sensitivity and positive predictive value (PPV) for detection of cervical intraepithelial neoplasia grade 2 or higher (CIN2+) were calculated. Results: The screening methods and referral criterion applied in the experimental arm had higher sensitivity than that in the conventional arm (relative sensitivity = 1.47; 95% confi dence interval [CI] = 1.03 to 2.09) but a lower PPV (relative PPV = 0.40; 95% CI = 0.23 to 0.66). With HPV testing alone at ≥1 pg/mL and at ≥2 pg/mL, the gain in sensitivity compared with the conventional arm remained similar (relative sensitivity = 1.43, 95% CI = 1.00 to 2.04 and relative sensitivity = 1.41, 95% CI = 0.98 to 2.01, respectively) but PPV progressively improved (relative PPV = 0.58, 95% CI = 0.33 to 0.98 and relative PPV = 0.75, 95% CI = 0.45 and 1.27, respectively). Referral based on liquid-based cytology alone did not increase sensitivity compared with conventional cytology (relative sensitivity = 1.06; 95% CI = 0.72 to 1.55) but reduced PPV (relative PPV = 0.57; 95% CI = 0.39 to 0.82). Conclusions: HPV testing alone was more sensitive than conventional cytology among women 35 -60 years old. Adding liquid-based cytology improved sensitivity only marginally but increased false-positives. HPV testing using Hybrid Capture 2 with a 2 pg/mL cutoff may be more appropriate than a 1 pg/mL cutoff for primary cervical cancer screening. [J Natl Cancer Inst 2006;98:765 -74] * Women at Trento and Imola were referred to colposcopy if repeat cytology showed low-grade squamous intraepithelial lesion or higher. ASCUS = atypical cells of undetermined signifi cance. by guest on August 22, 2015 http://jnci.oxfordjournals.org/ Downloaded from

Several studies based on double testing of all study women have shown that, compared with cytolog... more Several studies based on double testing of all study women have shown that, compared with cytology, human papillomavirus (HPV) testing has greater sensitivity but lower specifi city in detecting high-grade cervical intraepithelial neoplasia (CIN) ( 1 -14 ). A design based on double testing, although suitable for examining Padua, Italy (ADM, MZ); JNCI | Articles 493 * CI = confidence interval; CIN2+ = histology-confirmed cervical intraepithelial neoplasia grade 2 or more severe; HPV = human papillomavirus; ASCUS = atypical squamous cells of undetermined significance; CIN3+ = histology-confirmed cervical intraepithelial neoplasia grade 3 or more severe; PPV = positive predictive value. All eligible women randomly assigned in the relevant phase were considered for detection rate and relative sensitivity (relative to that of the conventional arm). Only women who actually had colposcopy were included in PPV and relative PPV calculations. † Comparing experimental arm phase 1 (taking into account only lesions detected in HPV-positive women) with conventional arm phase 1 ( 16 ). ‡ By Breslow -Day test.

Journal of Cutaneous Medicine and Surgery, 2003

Background: A Skin Cancer Registry was established in the province of Trento in northeast Italy i... more Background: A Skin Cancer Registry was established in the province of Trento in northeast Italy in 1992 with the aim of collecting data on all cutaneous tumors affecting residents. These neoplasms are responsible for considerable morbidity and utilization of the Health Service because of their high frequency and, therefore, knowledge of the exact incidence is very important in planning health policies. Registry data are also very helpful in performing studies of analytical and descriptive epidemiology. Methods: For each patient, we collected personal data, phenotypical characteristics, professional history, concurrent diseases, previous therapy or trauma, and all data regarding the tumors. Patients were interviewed in person or, less frequently, by phone. All data were verified and put in a computerized file, in a protected room. The Statistics Institute of Trento University analyzed the data. Comparison among means was performed using the analysis of variance and differences among proportions were tested by chi-squared analysis. Poisson regression and the likelihood ratio test were used to compare incidence rates. We analyze here the data regarding epiteliomas and melanoma. Results: During the study period we registered 3435 primary skin tumors in 2868 individuals. Crude incidence rates, calculated using the number of subjects (not the number of tumors), were 87.9 for basal cell carcinoma (BCC), 28.9 for squamous cell carcinoma (SCC), and 14.2 for cutaneous melanoma (CM), per 100,000 per annum. We also calculated the same figures in females and males and specific incidence rates in both sexes and evaluated the distribution of skin cancer according to sex and anatomical site. Conclusion: We report the analysis of the data collected by the Skin Cancer registry in a 6 year period and compare the data with published data in literature and with data of a previously registered melanoma file. Our results confirm the high incidence of nonmelanoma skin cancers and the variation in the histological patterns of CM. Antécédents: En 1992, un registre de cancer de la peau a été établi dans la province de Trento, nord-est de l’Italie, dans l’objectif de collecter toutes les tumeurs malignes affectant les résidents. Vu leur fréquence élevée, ces néoplasmes sont la cause d’une forte morbidité et d’une grande utilisation du système de santé. Donc, connaÑtre leur incidence exacte contribue à une meilleure planification des politiques en matière de santé. Les données du registre sont également très utiles dans les études d’pidémiologie analytique et descriptive. Méthodes: Nous avons recueilli, pour chaque patient, des données personnelles, les caractéristiques phénotypiques, les antécédents professionels, les maladies actuelles, les thérapies ou les traumatismes précédents ainsi que toutes les données relatives aux tumeurs. Une entrevue a été effectuée auprès de chaque patient en personne, plus rarement par téléphone. Toutes les données ont été vérifiées, consignées dans un fichier informatique et gardées dans une chambre protégée. L’institut des statistiques de l’université de Trento a analysé les données. Une comparaison des moyens a été effectuée par analyse de la variance et les différences entre les proportions ont été évaluées par Khi carré. La régression Poisson et le taux de probabilité ont servi à comparer les taux d’incidence. Nous analysons dans le présent article les données relatives aux tumeurs épithéliales et aux mélanomes. Résultats: Durant l’étude, nous avons enregistré 3 435 tumeurs cutanées primaires chez 2 868 personnes. Les taux d’incidence bruts, calculés en utilisant le nombre de sujets (et non le nombre de tumeurs), étaient de 87,9 dans les cas de carcinomes basocellulaires, de 28,9 dans les cas de carcinomes spinocellulaires et de 14,2 dans les cas de mélanomes, par 100 000 sujets par an. Nous avons également effectué les mémes calculs pour les femmes et pour les hommes séparément, avec les taux d’incidence selon le sexe et une évaluation de la distribution du cancer de la peau selon le sexe. Conclusion: Nous présentons les données recueillies par le registre de cancer de la peau durant une période de six ans et les comparons aux données publiées dans les revues spécialisées et aux données tirées d’un registre précédent. Nos résultats confirment une incidence élevée de cancers non mélaniques et une variation des tendances histologiques des mélanomes.

International Journal of Cancer, 1998

Among the major regulators of the G 1 restriction point are cyclin D1 and the retinoblastoma gene... more Among the major regulators of the G 1 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 G 1 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 G 1 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. Int.

Lancet Oncology, 2010

Human papillomavirus (HPV) testing is known to be more sensitive, but less specific than cytology... more Human papillomavirus (HPV) testing is known to be more sensitive, but less specific than cytology for detecting cervical intraepithelial neoplasia (CIN). We assessed the efficacy of cervical-cancer screening policies that are based on HPV testing.

Diagnostic Cytopathology, 1997

Radial scar/complex sclerosing lesion (RS/CSL) of the breast has become more frequently detected ... more Radial scar/complex sclerosing lesion (RS/CSL) of the breast has become more frequently detected with the increasing performance of mammography as a screening test. The clinical, mammographic, and cytologic features of 22 cases of histologically proved breast RS/CSL, 3 of which associated with carcinoma arising at the periphery of the lesion, were reviewed. Clinical examination and mammography did not show specific features in differentiating RS/CSL from carcinoma of the breast. Cytology of RS/CSL without associated malignant changes was dominated by bland epithelial clusters and bipolar naked nuclei. Apocrine cells, papillary clusters, foam cells, and fibrillary elastoid material were also frequently seen. At the cytologic review, only one case of RS with apocrine adenosis, showing atypical cells, was diagnosed as suspicious. Two of the three cases of CSL with associated carcinoma in situ were cytologically characterized by the presence of single atypical cells. In the third case, characterized by a small tubular carcinoma near to CSL, fine-needle aspiration cytology revealed few tubular clusters without myoepithelial cells. Although cytology of RS/CSL without associated carcinoma does not seem characteristic, in most cases a diagnosis of benignancy can be performed correctly. The application of fine-needle aspiration cytology to mammographic lesions with features suggesting RS/CSL may permit a better planning of these lesions.

Human Pathology, 1996

Bcl-2 and p53 gene products (Bcl-2, p53) are important regulators of apoptosis and cell prolifera... more 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, &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt; 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.

European Journal of Cancer, 2007

In the experimental arm of a randomised trial, women were tested both for liquid-based cytology a... more In the experimental arm of a randomised trial, women were tested both for liquid-based cytology and human papillomavirus (HPV) DNA and referred for colposcopy if cytology was ASCUS (atypical cells of undetermined significance) or more severe. We considered those with ASCUS (757) or LSIL (low-grade squamous intraepithelial lesions) (485) and a valid HPV test who received colposcopy. We computed sensitivity, specificity and ROC 0959-8049/$ -see front matter Ó ( 2 0 0 7 ) 4 7 6 -4 8 0 a v a i l a b l e a t w w w . s c i e n c e d i r e c t . c o m j o u r n a l h o m e p a g e : w w w . e j c o n l i n e . c o m Keywords: Cervical cancer Human papillomavirus Screening Triage curves with different values of relative light units (RLU, that are related to viral load) as cut off, using cervical intraepithelial neoplasia grade 2 or more severe (CIN2+) at blind histology review as the endpoint.

International Journal of Surgical Pathology, 2000

... As recently recalled by Welland Sowter [1], many developments in science, including medicine,... more ... As recently recalled by Welland Sowter [1], many developments in science, including medicine, are prefigured in science fiction. What is fiction now will be reality in the near future, and the futureis running every day faster into present life. ...

British Medical Journal, 2007

Objective To compare the accuracy of conventional cytology with liquid based cytology for primary... more Objective To compare the accuracy of conventional cytology with liquid based cytology for primary screening of cervical cancer. Design Randomised controlled trial. Setting Nine screening programmes in Italy. Participants Women aged 25-60 attending for a new screening round: 22 466 were assigned to the conventional arm and 22 708 were assigned to the experimental arm.

Journal of Pathology, 1998

Cyclin D3 immunohistochemical expression was investigated in normal, reactive, and neoplastic hum... more 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.

International Journal of Cancer, 1998

Bax and Bc12 are functionally antagonistic proteins which control apoptosis, whose expression in ... more Bax and Bc12 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 CMFtreated, N1/2 tamoxifen-treated). Bax immunostaining was cytoplasmic and heterogeneous. Cases were scored as Baxpositive 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. Int. J. Cancer (Pred. FIGURE 3 -Bc12 immunoreactivity in infiltrating duct carcinoma of the breast. Scale bar, 70 µm.

Journal of Pathology, 1995

This study investigates the mdm2 gene status and expression in 66 surgically resected human breas... more This study investigates the mdm2 gene status and expression in 66 surgically resected human breast carcinomas, with correlations with clinico-pathological and biological data (histological type, grading, steroid receptor status, p53 expression, proliferative activity). Four (7.7 per cent) out of 52 informative cases bear mdm2 gene amplification (four- to ten-fold) and 8 (15.4 per cent) of 52 cases showed borderline amplification (three-fold). Nine (13.6 per cent) out of 66 cases showed strong mdm2 nuclear immunoreactivity. Twenty-seven (40.9 per cent) cases showed isolated mdm2 reactive nuclei. All cases with clear amplification showed a high percentage of mdm2 immunoreactive nuclei. The relationship between gene amplification and mdm2 protein expression is highly significant (P<0.0001). No association was observed between mdm2 gene amplification and any of the considered clinico-pathological and biological parameters, while mdm2 immunoreactivity showed a significant association only with oestrogen receptor immunoreactivity (P=0.009). p53 expression was associated neither with mdm2 gene amplification nor with mdm2 immunoreactivity. It could be tempting to hypothesize that the evaluation of the combined mdm2/p53 immunohistochemical phenotype in human breast carcinoma could give us better prognostic information than the evaluation of the expression of the p53 protein alone.

International Journal of Cancer, 2002

Thymidine phosphorylase (TP), also known as platelet-derived endothelial cell growth factor (PD-E... more Thymidine phosphorylase (TP), also known as platelet-derived endothelial cell growth factor (PD-ECGF), is an enzyme that catalyzes the reversible dephosphorylation of thymidine, deoxyuridine and their analogs. TP has also angiogenic properties, although the precise mechanism by which it promotes angiogenesis is not known. We examined TP expression using immunohistochemistry (654-1 Mab) in 182 invasive breast carcinomas (67 N0 and 115 N1/2; median follow-up 78 months [range, 3–177]; 51 patients treated with adjuvant systemic cyclophosphamide, methotrexate and 5-fluorouracil [CMF] chemotherapy and 82 with tamoxifen). High TP expression was found in 142 cases (78%) and correlated with lower histologic grade and low p53 expression. No correlation was found between TP expression and vascular density. TP-positive tumors had a significant increase in both disease-free survival (DFS; p = 0.0025) and overall survival (OS; p = 0.0070) in the total cohort of patients and in the subgroups of node-positive patients and patients treated with CMF adjuvant therapy; no significant difference in either DFS or OS was observed in patients without CMF treatment. Our findings suggest that TP has little effect on tumor angiogenesis of breast carcinoma, whereas it could represent an interesting marker that could predict response to CMF chemotherapy. © 2001 Wiley-Liss, Inc.

American Journal of Clinical Pathology, 2008

All cervical intraepithelial neoplasia (CIN) diagnoses identified during the New Technologies for... more All cervical intraepithelial neoplasia (CIN) diagnoses identified during the New Technologies for Cervical Cancer trial (ISRCTN81678807) were blindly reviewed by 2 pathologists. Original diagnoses based on colposcopy-guided biopsies were compared with those made by the reviewers who had access to all clinical histologic samples (including postsurgical). Cases downgraded from CIN 2+ by the reviewers were considered indicative of unnecessary treatments. The analyses are presented according to the molecular (high-risk human papillomavirus [HPV]) and/or cytologic diagnosis used to refer the women for colposcopy.

International Journal of Cancer, 1997

Cyclin D1 is a major positive regulator of the G 1 restriction point promoting inactivation of th... more Cyclin D1 is a major positive regulator of the G 1 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. Int.

Lancet Oncology, 2008

Background Human-papillomavirus (HPV) testing is more sensitive, but less specifi c, than convent... more Background Human-papillomavirus (HPV) testing is more sensitive, but less specifi c, than conventional cytology for detecting high-grade cervical intraepithelial neoplasia (CIN). We assessed whether HPV testing with triage by p16-INK4A overexpression can increase specifi city while maintaining sensitivity.

International Journal of Cancer, 2000

p27 Kip1 (p27) , a cyclin-dependent kinase inhibitor, has an important role in the progression of... more p27 Kip1 (p27) , a cyclin-dependent kinase inhibitor, has an important role in the progression of cells from G 1 into S phase of the cell cycle. p27 may act as a tumor suppressor, and several reports suggest that loss of its expression in breast carcinoma is related to tumor progression and poor prognosis. We evaluated p27 immunohistochemical expression in 512 consecutive cases of breast carcinoma with 9 years of median-term follow-up. p27 expression was heterogeneous and frequently less intense than in normal cells. Low p27 expression (<50% of reacting cells) was associated with grade III tumors, N0 status, estrogen receptor-negative status, and low cyclin D1 expression. In the whole series of cases, p27 expression did not predict outcome. In node-negative cases (249 patients), high p27 expression indicated poor prognosis. p27 was not prognostically relevant in the group of 223 patients with pT1 disease or in the group of 154 patients <50 years of age. We also investigated the prognostic value of the combined expression of p27 and cyclin D1, but no differences in survival were seen in this bivariate analysis. Int.

Breast Cancer Research and Treatment, 1995

In the present study we update previous results on the prognostic value of intratumoral microvess... more In the present study we update previous results on the prognostic value of intratumoral microvessel density (IMD), determined immunocytochemically using the monoclonal antibody CD-31 and a standard streptavidin-immunoperoxidase technique, published in theJ Clin Oncol 12:454–466, 1994. This study was undertaken in those 211 node-negative breast cancer (NNBC) cases of that series of which we had pathological material available to determine all the prognostic indicators. The median period of follow-up has been extended to 78 and 80 months for relapse-free survival (RFS) and overall survival (OS), respectively, and new biological indicators (i.e. Ki-67 labeling and 67 kDa laminin receptor expression) were included in the analysis. The main results obtained are:i) a confirmation that IMD is not associated with the other biological markers studied, i.e. expression of p53 protein, c-erbB-2 protein, 67 kDa laminin receptor, and cell kinetics; IMD was weakly associated only with histological grade (p=0.053);ii) IMD remains a highly significant prognostic factor for RFS and OS (p<0.0001 and p=0.018, respectively) in univariate analysis;iii) in multivariate analysis on RFS, IMD (likelihood ratio test (LRT)=30.16; p<0.0001), 67 kDa laminin receptor (LRT=9.80; p=0.0017), the IMD/67 kDa laminin receptor interaction (LRT=8.62; p=0.0033), tumor size (LRT=8.56; p=0.0034), and p53 protein (LRT=4.96; p=0.025) are significant and independent prognostic indicators. For OS, only tumor size (LRT=8.34; p=0.0038), menopausal status (LRT=5.16; p=0.023), p53 protein (LRT=4.37; p=0.036), and IMD (LRT=4.05; p=0.044) retain a significant and independent prognostic value. The results of this study confirm the prognostic importance on RFS of the variables previously tested, but not of peritumoral lymphatic vessel invasion. A novel finding is that 67 kDa laminin receptor and the IMD/67 kDa laminin receptor interaction are also significant and independent variables. For OS, the results confirm that both IMD and tumor size are significant and independent variables. With prolonged follow-up the novel finding that emerges is the prognostic importance of menopausal status and p53 protein. This new information could be useful for a more accurate selection of high-risk NNBC patients who require careful follow-up and may benefit from adjuvant therapy.

International Journal of Cancer, 1995

Experimental studies have shown that the 67-kDa laminin receptor (LRec) is an important molecule ... more Experimental studies have shown that the 67-kDa laminin receptor (LRec) is an important molecule for the interaction of tumour cells with the extracellular matrix, and that it plays a role in the early steps of angiogenesis and in tumour invasion and metastasis. We performed a multi-parametric study in 171 node-negative breast cancers, followed for a median time of 6 years, to verify whether determination of the LRec provides prognostic information in addition to intra-tumoral microvessel density (IMD), a measure of tumour angiogenesis, and to other biological and conventional indicators. A positive association between LRec expression and high neovascularization was found, although it did not reach significance. LRec was not associated either with other biological markers (oestrogen receptor, progesterone receptor and p53 expression) or to the conventional prognostic features [menopausal status, tumour size, histological types, grading and peri-tumoral lymphatic vessel invasion (PLVI)]. In univariate analysis, IMD, p53, PgR, PLVI, grading and tumour size were significant prognostic indicators of relapse-free survival (RFS). LRec expression approached significance when considered as a dichotomous variable, after having selected the optimum cutoff of 10% to distinguish high-risk from low-risk patients. For overall survival (OS), tumour size and IMD (continuous variable) were significant prognostic factors, and p53 approached significance. In multivariate analysis for RFS, the joint variable LRec and vascularization was the strongest independent prognostic factor, followed by PgR, PLVI and p53. For OS, tumour size was the only independent prognostic indicator in this series.

Lancet Oncology, 2006

Background: Although testing for human papillomavirus (HPV) has higher sensitivity and lower spec... more Background: Although testing for human papillomavirus (HPV) has higher sensitivity and lower specifi city than cytology alone for detecting cervical intraepithelial neoplasia (CIN), studies comparing conventional and liquid-based cytology have had confl icting results. Methods: In the fi rst phase of a two-phase multicenter randomized controlled trial, women aged 35 -60 years in the conventional arm ( n = 16 658) were screened using conventional cytology, and women in the experimental arm ( n = 16 706) had liquidbased cytology and were tested for high-risk HPV types using the Hybrid Capture 2 assay. Women in the conventional arm were referred to colposcopy with atypical cells of undetermined signifi cance (ASCUS) or higher and those in the experimental arm were referred with ASCUS or higher cytology or with a positive ( ≥ 1 pg/mL) HPV test. Sensitivity and positive predictive value (PPV) for detection of cervical intraepithelial neoplasia grade 2 or higher (CIN2+) were calculated. Results: The screening methods and referral criterion applied in the experimental arm had higher sensitivity than that in the conventional arm (relative sensitivity = 1.47; 95% confi dence interval [CI] = 1.03 to 2.09) but a lower PPV (relative PPV = 0.40; 95% CI = 0.23 to 0.66). With HPV testing alone at ≥1 pg/mL and at ≥2 pg/mL, the gain in sensitivity compared with the conventional arm remained similar (relative sensitivity = 1.43, 95% CI = 1.00 to 2.04 and relative sensitivity = 1.41, 95% CI = 0.98 to 2.01, respectively) but PPV progressively improved (relative PPV = 0.58, 95% CI = 0.33 to 0.98 and relative PPV = 0.75, 95% CI = 0.45 and 1.27, respectively). Referral based on liquid-based cytology alone did not increase sensitivity compared with conventional cytology (relative sensitivity = 1.06; 95% CI = 0.72 to 1.55) but reduced PPV (relative PPV = 0.57; 95% CI = 0.39 to 0.82). Conclusions: HPV testing alone was more sensitive than conventional cytology among women 35 -60 years old. Adding liquid-based cytology improved sensitivity only marginally but increased false-positives. HPV testing using Hybrid Capture 2 with a 2 pg/mL cutoff may be more appropriate than a 1 pg/mL cutoff for primary cervical cancer screening. [J Natl Cancer Inst 2006;98:765 -74] * Women at Trento and Imola were referred to colposcopy if repeat cytology showed low-grade squamous intraepithelial lesion or higher. ASCUS = atypical cells of undetermined signifi cance. by guest on August 22, 2015 http://jnci.oxfordjournals.org/ Downloaded from

Several studies based on double testing of all study women have shown that, compared with cytolog... more Several studies based on double testing of all study women have shown that, compared with cytology, human papillomavirus (HPV) testing has greater sensitivity but lower specifi city in detecting high-grade cervical intraepithelial neoplasia (CIN) ( 1 -14 ). A design based on double testing, although suitable for examining Padua, Italy (ADM, MZ); JNCI | Articles 493 * CI = confidence interval; CIN2+ = histology-confirmed cervical intraepithelial neoplasia grade 2 or more severe; HPV = human papillomavirus; ASCUS = atypical squamous cells of undetermined significance; CIN3+ = histology-confirmed cervical intraepithelial neoplasia grade 3 or more severe; PPV = positive predictive value. All eligible women randomly assigned in the relevant phase were considered for detection rate and relative sensitivity (relative to that of the conventional arm). Only women who actually had colposcopy were included in PPV and relative PPV calculations. † Comparing experimental arm phase 1 (taking into account only lesions detected in HPV-positive women) with conventional arm phase 1 ( 16 ). ‡ By Breslow -Day test.

Journal of Cutaneous Medicine and Surgery, 2003

Background: A Skin Cancer Registry was established in the province of Trento in northeast Italy i... more Background: A Skin Cancer Registry was established in the province of Trento in northeast Italy in 1992 with the aim of collecting data on all cutaneous tumors affecting residents. These neoplasms are responsible for considerable morbidity and utilization of the Health Service because of their high frequency and, therefore, knowledge of the exact incidence is very important in planning health policies. Registry data are also very helpful in performing studies of analytical and descriptive epidemiology. Methods: For each patient, we collected personal data, phenotypical characteristics, professional history, concurrent diseases, previous therapy or trauma, and all data regarding the tumors. Patients were interviewed in person or, less frequently, by phone. All data were verified and put in a computerized file, in a protected room. The Statistics Institute of Trento University analyzed the data. Comparison among means was performed using the analysis of variance and differences among proportions were tested by chi-squared analysis. Poisson regression and the likelihood ratio test were used to compare incidence rates. We analyze here the data regarding epiteliomas and melanoma. Results: During the study period we registered 3435 primary skin tumors in 2868 individuals. Crude incidence rates, calculated using the number of subjects (not the number of tumors), were 87.9 for basal cell carcinoma (BCC), 28.9 for squamous cell carcinoma (SCC), and 14.2 for cutaneous melanoma (CM), per 100,000 per annum. We also calculated the same figures in females and males and specific incidence rates in both sexes and evaluated the distribution of skin cancer according to sex and anatomical site. Conclusion: We report the analysis of the data collected by the Skin Cancer registry in a 6 year period and compare the data with published data in literature and with data of a previously registered melanoma file. Our results confirm the high incidence of nonmelanoma skin cancers and the variation in the histological patterns of CM. Antécédents: En 1992, un registre de cancer de la peau a été établi dans la province de Trento, nord-est de l’Italie, dans l’objectif de collecter toutes les tumeurs malignes affectant les résidents. Vu leur fréquence élevée, ces néoplasmes sont la cause d’une forte morbidité et d’une grande utilisation du système de santé. Donc, connaÑtre leur incidence exacte contribue à une meilleure planification des politiques en matière de santé. Les données du registre sont également très utiles dans les études d’pidémiologie analytique et descriptive. Méthodes: Nous avons recueilli, pour chaque patient, des données personnelles, les caractéristiques phénotypiques, les antécédents professionels, les maladies actuelles, les thérapies ou les traumatismes précédents ainsi que toutes les données relatives aux tumeurs. Une entrevue a été effectuée auprès de chaque patient en personne, plus rarement par téléphone. Toutes les données ont été vérifiées, consignées dans un fichier informatique et gardées dans une chambre protégée. L’institut des statistiques de l’université de Trento a analysé les données. Une comparaison des moyens a été effectuée par analyse de la variance et les différences entre les proportions ont été évaluées par Khi carré. La régression Poisson et le taux de probabilité ont servi à comparer les taux d’incidence. Nous analysons dans le présent article les données relatives aux tumeurs épithéliales et aux mélanomes. Résultats: Durant l’étude, nous avons enregistré 3 435 tumeurs cutanées primaires chez 2 868 personnes. Les taux d’incidence bruts, calculés en utilisant le nombre de sujets (et non le nombre de tumeurs), étaient de 87,9 dans les cas de carcinomes basocellulaires, de 28,9 dans les cas de carcinomes spinocellulaires et de 14,2 dans les cas de mélanomes, par 100 000 sujets par an. Nous avons également effectué les mémes calculs pour les femmes et pour les hommes séparément, avec les taux d’incidence selon le sexe et une évaluation de la distribution du cancer de la peau selon le sexe. Conclusion: Nous présentons les données recueillies par le registre de cancer de la peau durant une période de six ans et les comparons aux données publiées dans les revues spécialisées et aux données tirées d’un registre précédent. Nos résultats confirment une incidence élevée de cancers non mélaniques et une variation des tendances histologiques des mélanomes.

International Journal of Cancer, 1998

Among the major regulators of the G 1 restriction point are cyclin D1 and the retinoblastoma gene... more Among the major regulators of the G 1 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 G 1 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 G 1 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. Int.

Lancet Oncology, 2010

Human papillomavirus (HPV) testing is known to be more sensitive, but less specific than cytology... more Human papillomavirus (HPV) testing is known to be more sensitive, but less specific than cytology for detecting cervical intraepithelial neoplasia (CIN). We assessed the efficacy of cervical-cancer screening policies that are based on HPV testing.

Diagnostic Cytopathology, 1997

Radial scar/complex sclerosing lesion (RS/CSL) of the breast has become more frequently detected ... more Radial scar/complex sclerosing lesion (RS/CSL) of the breast has become more frequently detected with the increasing performance of mammography as a screening test. The clinical, mammographic, and cytologic features of 22 cases of histologically proved breast RS/CSL, 3 of which associated with carcinoma arising at the periphery of the lesion, were reviewed. Clinical examination and mammography did not show specific features in differentiating RS/CSL from carcinoma of the breast. Cytology of RS/CSL without associated malignant changes was dominated by bland epithelial clusters and bipolar naked nuclei. Apocrine cells, papillary clusters, foam cells, and fibrillary elastoid material were also frequently seen. At the cytologic review, only one case of RS with apocrine adenosis, showing atypical cells, was diagnosed as suspicious. Two of the three cases of CSL with associated carcinoma in situ were cytologically characterized by the presence of single atypical cells. In the third case, characterized by a small tubular carcinoma near to CSL, fine-needle aspiration cytology revealed few tubular clusters without myoepithelial cells. Although cytology of RS/CSL without associated carcinoma does not seem characteristic, in most cases a diagnosis of benignancy can be performed correctly. The application of fine-needle aspiration cytology to mammographic lesions with features suggesting RS/CSL may permit a better planning of these lesions.

Human Pathology, 1996

Bcl-2 and p53 gene products (Bcl-2, p53) are important regulators of apoptosis and cell prolifera... more 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, &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt; 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.

European Journal of Cancer, 2007

In the experimental arm of a randomised trial, women were tested both for liquid-based cytology a... more In the experimental arm of a randomised trial, women were tested both for liquid-based cytology and human papillomavirus (HPV) DNA and referred for colposcopy if cytology was ASCUS (atypical cells of undetermined significance) or more severe. We considered those with ASCUS (757) or LSIL (low-grade squamous intraepithelial lesions) (485) and a valid HPV test who received colposcopy. We computed sensitivity, specificity and ROC 0959-8049/$ -see front matter Ó ( 2 0 0 7 ) 4 7 6 -4 8 0 a v a i l a b l e a t w w w . s c i e n c e d i r e c t . c o m j o u r n a l h o m e p a g e : w w w . e j c o n l i n e . c o m Keywords: Cervical cancer Human papillomavirus Screening Triage curves with different values of relative light units (RLU, that are related to viral load) as cut off, using cervical intraepithelial neoplasia grade 2 or more severe (CIN2+) at blind histology review as the endpoint.

International Journal of Surgical Pathology, 2000

... As recently recalled by Welland Sowter [1], many developments in science, including medicine,... more ... As recently recalled by Welland Sowter [1], many developments in science, including medicine, are prefigured in science fiction. What is fiction now will be reality in the near future, and the futureis running every day faster into present life. ...

British Medical Journal, 2007

Objective To compare the accuracy of conventional cytology with liquid based cytology for primary... more Objective To compare the accuracy of conventional cytology with liquid based cytology for primary screening of cervical cancer. Design Randomised controlled trial. Setting Nine screening programmes in Italy. Participants Women aged 25-60 attending for a new screening round: 22 466 were assigned to the conventional arm and 22 708 were assigned to the experimental arm.

Journal of Pathology, 1998

Cyclin D3 immunohistochemical expression was investigated in normal, reactive, and neoplastic hum... more 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.

International Journal of Cancer, 1998

Bax and Bc12 are functionally antagonistic proteins which control apoptosis, whose expression in ... more Bax and Bc12 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 CMFtreated, N1/2 tamoxifen-treated). Bax immunostaining was cytoplasmic and heterogeneous. Cases were scored as Baxpositive 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. Int. J. Cancer (Pred. FIGURE 3 -Bc12 immunoreactivity in infiltrating duct carcinoma of the breast. Scale bar, 70 µm.

Journal of Pathology, 1995

This study investigates the mdm2 gene status and expression in 66 surgically resected human breas... more This study investigates the mdm2 gene status and expression in 66 surgically resected human breast carcinomas, with correlations with clinico-pathological and biological data (histological type, grading, steroid receptor status, p53 expression, proliferative activity). Four (7.7 per cent) out of 52 informative cases bear mdm2 gene amplification (four- to ten-fold) and 8 (15.4 per cent) of 52 cases showed borderline amplification (three-fold). Nine (13.6 per cent) out of 66 cases showed strong mdm2 nuclear immunoreactivity. Twenty-seven (40.9 per cent) cases showed isolated mdm2 reactive nuclei. All cases with clear amplification showed a high percentage of mdm2 immunoreactive nuclei. The relationship between gene amplification and mdm2 protein expression is highly significant (P<0.0001). No association was observed between mdm2 gene amplification and any of the considered clinico-pathological and biological parameters, while mdm2 immunoreactivity showed a significant association only with oestrogen receptor immunoreactivity (P=0.009). p53 expression was associated neither with mdm2 gene amplification nor with mdm2 immunoreactivity. It could be tempting to hypothesize that the evaluation of the combined mdm2/p53 immunohistochemical phenotype in human breast carcinoma could give us better prognostic information than the evaluation of the expression of the p53 protein alone.

International Journal of Cancer, 2002

Thymidine phosphorylase (TP), also known as platelet-derived endothelial cell growth factor (PD-E... more Thymidine phosphorylase (TP), also known as platelet-derived endothelial cell growth factor (PD-ECGF), is an enzyme that catalyzes the reversible dephosphorylation of thymidine, deoxyuridine and their analogs. TP has also angiogenic properties, although the precise mechanism by which it promotes angiogenesis is not known. We examined TP expression using immunohistochemistry (654-1 Mab) in 182 invasive breast carcinomas (67 N0 and 115 N1/2; median follow-up 78 months [range, 3–177]; 51 patients treated with adjuvant systemic cyclophosphamide, methotrexate and 5-fluorouracil [CMF] chemotherapy and 82 with tamoxifen). High TP expression was found in 142 cases (78%) and correlated with lower histologic grade and low p53 expression. No correlation was found between TP expression and vascular density. TP-positive tumors had a significant increase in both disease-free survival (DFS; p = 0.0025) and overall survival (OS; p = 0.0070) in the total cohort of patients and in the subgroups of node-positive patients and patients treated with CMF adjuvant therapy; no significant difference in either DFS or OS was observed in patients without CMF treatment. Our findings suggest that TP has little effect on tumor angiogenesis of breast carcinoma, whereas it could represent an interesting marker that could predict response to CMF chemotherapy. © 2001 Wiley-Liss, Inc.