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.

SinaryNon-small-cell lung cancer (NSCLC) prognosis is stnrctly related to well-established clinicopathological parameters which have unfortunately become insufficient in the prognostic evaluation of this type of cancer. As p53 and bcl-2 gene deregulations are frequently involved in several types of epithelial malignancies, we investigated the Bcl-2 and p53 protein expression in 91 and 101 cases of NSCLC respectively. The expression was then compared with established indicators of prognosis and biological behaviour of the tumours. No relationship was observed between Bcl-2 and either clinicopathological or biological parameters such as histology, grading, tumour status, nodal metastasis and proliferative activity evaluated by scoring proliferating cell nuclear antigen expression and Ki-67 immunoreactivity. However, the mean Bcl-2 expression was significantly lower in patients who developed metastasis during follow-up or died of metastatic disease (P = 0.006 and P= 0.01 respectively). Moreover, survival probability was higher in patients who expressed the Bcl-2 protein (P =0.0002). In contrast with this, p53 protein accumulation was observed in tumours with metastatic nodal involvement (P = 0.02) or in patients who developed metastasis during follow-up (P = 0.01), although no correlation was found between p53 expression and overall survival. An inverse relationship was also found between Bcl-2 and the anti-oncogene protein product p53 (P = 0.01). Thus, a high proportion of NSCLCs express p53 and Bcl-2 proteins and their expression may have prognostic importance.Keywords: oncogenes; NSCLC; prognosis; p53; Bcl-2 Lung cancer has now become the leading cause of cancer deaths in both men and women in the USA (Minna et al., 1989). In particular, non-small-cell lung cancer (NSCLC) represents a heterogeneous subgroup in terms of both behaviour and therapeutic response. Several studies have clearly demonstrated that multiple genetic events are associated with the development of lung cancer, including a range of chromosomal abnormalities, mutations activating the dominant cellular proto-oncogenes and genetic events inactivating tumour suppressor genes (Minna, 1993). p53 alterations and aberrant nuclear accumulation of this protein have been recently studied with particular interest. Many experimental data indicate that the p53-suppressor gene is the most commonly altered tumour-suppressor gene (Hollstein et al., 1991). This gene codes for a nuclear phosphoprotein, normally undetectable in human cells, which is able to regulate cell growth and division (Levine et al., 1991;Lane, 1992 Croce, 1986;Aisemberg et al., 1988). This translocation places the bcl-2 gene at chromosomal location 18q21 in juxtaposition with the immunoglobulin heavy-chain locus at 14q32, resulting in transcriptional deregulation of the bcl-2 gene (Cleary et al., 1984;Tsujimoto and Croce, 1986;Tsujimoto et al., 1987) (Silvestrini et al., 1994). In contrast with lymphomas, little or no evidence of gross alterations in the bcl-2 gene structure was obtained...

Summary 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 univaiiate 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 interrelationship, supporting the hypothesis of a wild-type p53 regulation on the angiogenetic process through a VEGF up-regulation.

The growth of newly formed vessels, or neoangiogenesis, represents an important step in both physiological and pathological situations: in particular, tumour growth and metastasis require angiogenesis. Microvessel count (MC), which represents a measure of tumour angiogenesis, has been associated with metastatic spread in cutaneous, mammary, prostatic, head and neck, and early-stage lung cancer. In this study, the role of tumour angiogenesis as a prognostic indicator was examined in 253 primary non-small lung cancer (NSCLC) patients. Microvessels were counted by highlighting endothelial cells with anti-Factor VIII monoclonal antibody (Mab) in methacarn-fixed tumour samples. In univariat analysis, MC (P< 0.000001), sex (P=0.0036), histotype (P < 0.014), tumour status (P <0.007), and vessel invasion (P < 0.019) were significantly related to hilar and/or mediastinal nodal involvement. However, in the stepwise logistic regression analysis, MC (P<0.000003) retained the most important influence on nodal metastasis. The overall survival analysis calculated by the Kaplan-Meier method revealed that tumours with high MC ( > 25 vessels/field) were significantly associated with increased death risk (log-rank test P = 0.00067; Cox's test P = 0.00046; Gehan's Wilcoxon test P = 0.00108). In 94 patients, the development of metastatic disease during follow-up was significantly related to MC. Indeed, patients who developed metastasis during follow-up showed a higher MC, either as a dichotomous (P = 0.01) or as a continuous (P = 0.003) variable, than patients who had developed no metastasis at the time of the analysis. Moreover, in the stepwise logistic regression analysis, MC retained the most important influence on distant metastases.(ABSTRACT TRUNCATED AT 250 WORDS)

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Summary Thyroid carcinomas are heterogeneous in terms of histology, clinical presentation, treatment response and prognosis. Since bcl-2 and p53 gene alterations are frequently involved in both lymphoid and epithelial malignancies, we analysed the expression of bcl-2, p53 and proliferating cell nuclear antigen (PCNA) in a group of 134 patients with thyroid neoplasms. The same markers were evaluated in fetal and adult normal thyroids as well as in 40 The protein encoded by the bcl-2 proto-oncogene is implicated in the prolongation of cell survival by blocking programmed cell death, i.e. apoptosis (Reed, 1994). The bcl-2 gene is located on band q21.3 of the human chromosome 18 and was first described as a result of the chromosomal translocation t(14;18) present in a majority of follicular B cell lines (Tsujimoto et al., 1987). It is also known that 85% of human follicular B-cell lymphomas showed a translocation of the bcl-2 gene on the immunoglobulin heavy-chain locus of chromosome 14, resulting in deregulated bcl-2 expression (Tsujimoto et al., 1985). In this type of neoplasia the protein product of the bcl-2 gene provides a growth advantage and may inhibit apoptosis. Recently, the bcl-2 protein has also been detected in a limited number of non-lymphoid tissues under different physiological conditions: (1) long-lived stem cells from complex differentiating epithelium such as skin and intestine; (2) long-lived post-mitotic cells such as neurons; and (3) glandular epithelium in which hormone and growth factors regulate hyperplasia and involution (Hockenbury et al., 1991 Materials and methodsPatients andfollow-up The study was carried out on 134 patients who had primary malignant thyroid tumours. Histotype was WDC in 70 patients (47 papillary and 23 follicular), PDC in 20, MC in 20 and UC in 24 patients. We also studied 40 benign tumours (micro-and macrofollicular adenomas) and ten fetal tissues. This series of thyroid tumours is part of a larger series of thyroid cancer patients followed at the Institute of Endocrinology, which is a referral centre for thyroid carcinomas in Italy. We studied all patients who received primary surgical treatment at the University of Pisa and whose tissues were available at the Department of Pathology. For this reason the series is to some degree selected and the histotype distribution does not reflect the biological history of thyroid carcinomas.Initial treatment was total (near-total) thyroidectomy in all patients regardless of the histotype. Lymph node dissection was performed in MCs, but not in WDCs, for which lymph node dissection was performed only in the case of evident node involvement. Post-surgical treatment included 13'1 therapy for WDCs and PDCs (if iodine uptake of wholebody scan (WBS) with "'lI was demonstrated) followed by 1-thyroxine suppressive therapy. MCs and PDCs (with no iodine uptake) were treated with chemotherapy and/or radiotherapy in case of recurrence or distant metastases. UCs were treated with total thyroidectomy whenever possible, followed by external...

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