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Glioblastoma is the most frequent and aggressive primary tumor of the central nervous system. Prognosis is poor, with a median survival of 15 months after diagnosis. Various tumor biomarkers show prognostic value for glioblastomas, including VEGFR2, which is a receptor of VEGF related to the growth of the blood vessel network. VEGFR2 expression associates with poor prognosis in some tumors. Here we studied the prognostic value of the VEGFR2 immunohistochemical expression in glioblastoma. We used tissue microarrays to analyze 45 surgically excised samples from glioblastomas. Clinical data (age, sex, and Karnofsky Performance Status [KPS]) and morphological data (tumor necrosis, palisading, and vascular thrombosis) were collected. We performed a molecular study of MGMT and IDH1 expression (which are potential prognostic factors for glioblastomas) and an immunohistochemical study of VEGFR2 expression. Our results indicate that age, KPS, tumor necrosis, vascular thrombosis, treatment (STUPP versus other), and VEGFR2 immunoreactivity were related to prognosis (p < .005). In a multivariate analysis, only age > 65 years (Hazard Ratio (HR) (95% CI): 4.9 (2.1¿11.4), p < .01), and VEGFR2 immunoexpression (HR (95% CI): 2.8 (1.3¿6.1), p = .008), were found to have a statistically significant relation to prognosis. We conclude that immunohistochemical evaluation of VEGFR2 provides added prognostic value to the study of glioblastoma., This work was supported by grants from the Fundació La Marató (num.20130332) to FA, and the Spanish Ministerio de Economía y Competitividad/ ISCIIIFEDER (PI14/00125; PI17/00199) and the "Generalitat de Catalunya" (2017/SGR/225) to PN.

Purpose: Met receptor phosphorylation is associated with poor prognosis in human small cell lung cancer (SCLC). The aim of our work was to investigate the effects of hepatocyte growth factor (HGF)/Met–mediated epithelial-to-mesenchymal transition (EMT) in SCLC and to evaluate the role of Met inhibition in mesenchymal/chemorefractory SCLC models. Experimental Design: SCLC models of HGF-induced EMT were evaluated in vitro and in vivo (subcutaneous xenografts in BALB/c nude mice) for chemosensitivity and response to Met inhibition with PF-2341066 (crizotinib). Human SCLC samples at diagnosis (N = 87) and relapse (N = 5) were evaluated by immunohistochemistry and immunofluorescence for EMT markers and Met status and these were correlated with patient outcome. Results: We identified that the activation of the Met receptor through HGF induced expression of mesenchymal markers, an aggressive phenotype, and chemoresistance. Blockade of this process with the Met inhibitor resensitized cells to chemotherapy in vitro and in vivo. Moreover, mesenchymal markers in human SCLC specimens were associated with Met activation, predicted worse survival, and were upregulated in chemorefractory disease. Conclusion: These results provide novel evidence on an important role of Met-dependent EMT in the adverse clinical behavior of SCLC and support clinical trials of Met inhibitors and chemotherapy in this fatal disease. Clin Cancer Res; 20(4); 938–50. ©2013 AACR.

MET is a tyrosine kinase receptor that, upon binding of its natural ligand, the hepatocyte growth factor (HGF), is phosphorylated and subsequently activates different signalling pathways involved in proliferation, motility, migration and invasion. MET has been found to be aberrantly activated in human cancer via mutation, amplification or protein overexpression. MET expression and activation have been associated with prognosis in a number of tumour types and predict response to MET inhibitors in preclinical models. Here we review the HGF/MET signalling pathway, its role in human cancer and the different inhibitory strategies that have been developed for therapeutic use.

Dysplastic nevi were generally recognized, thanks to the contributions of Clark et al. in 1978. These lesions were described in a familial context, which was called the 'B-K mole syndrome'. However, it is worth noting that this was not the first time that these nevi had been described in the literature. If we look back in history, we can find that in 1820, Norris had already described some very similarly pigmented lesions, also in a familial context, just as Cawley subsequently did in 1952. Clark coined the term of dysplastic nevi for lesions presenting in patients with personal and family histories of malignant melanoma, having from 10 to 100 nevus lesions of a certain size, irregular shape and variable pigmentation of more than 5 mm. In addition, he pointed out that histologically, such lesions were principally characterized by the presence of atypical melanocytic hyperplasia.

Nevi with architectural disorder and cytologic atypia of melanocytes (NAD), aka "dysplastic nevi," have varying degrees of histologic abnormalities, which can be considered on a spectrum of grades of atypia. Somewhat controversial and subjective criteria have been developed for grading of NAD into three categories "mild," "moderate," and "severe." Grading involves architectural and cytological features, which often correlate with each other. Architectural criteria were intraepidermal junctional extension beyond any dermal component, complex distortion of rete ridges, and dermal fibrosis. Cytological criteria were based on nuclear size, dispersion of chromatin, prominence of nucleoli, hyperchromasia and variation in nuclear staining. Few tests have been made of the relationship between specific grades of atypia and patient risk for melanoma. Retrospective review of pathology reports was performed on 20,275 nevi examined between 1989 and 1996. From the total, 6,275 were diagnosed as NAD, which were in 4,481 patients. These patients were divided into those whose worst NAD was mild (2,504), moderate (1,657), or severe (320). Review of accession data revealed that a personal history of melanoma was present in 5.7% of patients with mild, 8.1% with moderate, and 19.7% with severe atypia. The male/female ratios were similar in each group. In the three groups, the mean ages of men were similar and of women were similar, but the mean age of men tended to be 6-11 yrs. older than women in each group. Family histories of melanoma were not considered. The odds ratio as a measure of association between NAD and personal history of melanoma, shows an odds ratio of 4.08 (2.91-5.7) for NAD-severe versus NAD mild, odds ratio 2.81 (2-3.95) for NAD-severe versus NAD-moderate and odds ratio 1.45 (1.13-1.87) for NAD moderate versus NAD-mild. These data show that the probability of having personal history of melanoma, for any given NAD patient, correlates with the NAD grade. Likewise, the risk of melanoma is greater for persons who tend to make nevi with high grade histological atypia.

Nevi with architectural disorder and cytologic atypia of melanocytes (NAD) (also called dysplastic nevi) have been controversial with regard to their relationship with melanoma risk and to their gradation in 3 degrees of atypia. Versican and the melanoma-associated proteoglycan (mel-CSPG) are 2 major proteoglycans expressed by malignant melanoma, and they have a role in the regulation of cell adhesion, migration, and differentiation. We evaluated the differences in versican and mel-CSPG expression in nevi, NAD with several degrees of atypia, and primary malignant melanoma. Immunoreactivity for versican was negative in benign melanocytic nevi, positive in NAD (ranging from weakly to intensely positive), and intensely positive in malignant melanoma. Immunostaining for mel-CSPG was negative in benign melanocytic nevi and mild to moderately positive in NAD and melanoma. Our results suggest that versican expression may be of value for distinguishing NAD from benign melanocytic nevi and for distinguishing severe NAD from mild and moderate NAD.