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Mutations in MAPK signalling genes are driver events in melanoma, and have therapeutic relevance in the metastatic and adjuvant setting. This study evaluated the intra-patient heterogeneity of BRAF, NRAS and c-KIT mutational status between 30 primary melanomas and 39 related metastases, using molecular analysis and immunohistochemistry. BRAF mutations were identified in 46.7% of primary melanomas and 48.7% of metastases and NRAS mutations in 20% and 25.6%, respectively. Intra-patient heterogeneity was detected in 13.3% of patients for both BRAF and NRAS genes and was not associated with clinico-pathological characteristics of melanomas or metastases. High consistency was observed between immunostaining and molecular methods for BRAFV600E (k = 0.90; p < 0.001) and NRASQ61R (k = 0.87; p < 0.001). These findings demonstrate a relevant intra-patient heterogeneity between primary and metastatic lesions that is independent of clinical variables and methodological approach.

We have analysed concentrations of the p53 protein in advanced oral carcinomas immunohistochemically and genetically to detect the percentage of overexpression of this antioncogene that indicates a high probability of mutation. This would point to it being a useful prognostic factor, if we consider the importance of the relation between genetic alterations of p53 and poor overall survival. Seventy-five non-consecutive patients with oral squamous cell carcinoma and metastatic nodes were enrolled if there was homogeneity in histopathological grading (G2) of their tumours, and they were treated according to a multidisciplinary treatment plan. Monoclonal antibodies, extraction of DNA, and amplification of the polymerase chain reaction (PCR) were used for the immunohistochemical and genetic analyses. There was a significant inverse correlation between p53 overexpression and response to chemotherapy and a stronger association between high P53 overexpression (%) and a genetic mutation of p53 (p=0.0001). More than 50% overexpression indicated a strong probability of genetic mutation. There was no association between response to chemotherapy and age-groups or TNM classification (p=0.2), but there was a significant one between sex and site of tumour (p<0.001). Three prognostic factors were significantly related to prognosis: site of tumour (p=0.01), response to chemotherapy (p=0.002), and immuno p53 (p=0.0001). A tumour that is characterised by p53 overexpression of more than 50% indicates a poor prognosis., (Copyright © 2013 The British Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved.)

Emerging evidence indicates that interactions between chemokine receptors and their ligands may have a critical role in several steps of tumor development, including tumor growth, progression, and metastasis. In this report, we retrospectively evaluated CXCR4 expression in a consecutive series of 200 papillary thyroid carcinomas. We investigated the relationship between the clinicopathological features of the tumors and mutations in the BRAF gene to verify whether overexpression of CXCR4 is linked to more aggressive behavior in thyroid tumors. CXCR4 protein expression was evaluated by immunohistochemical staining. A final staining score was calculated by adding the score representing the percentage of positive cells to the intensity score. The CXCR4 expression of each papillary thyroid carcinoma sample was normalized by calculating the z score for each final staining score. Univariate analysis was used to correlate CXCR4 expression with the papillary thyroid carcinoma variant, the degree of neoplastic infiltration, the American Joint Commission on Cancer stage, the presence of lymphocytic thyroiditis and the mutation status of the BRAF gene. Multiple regression analysis confirmed a strong association between CXCR4, BRAF mutation and the degree of neoplastic infiltration. These data clearly indicate that the chemokine receptor expression induced by oncogenic activation could be the major determinant of the local aggressiveness of neoplastic cells. In conclusion, our data indicate that CXCR4 expression and BRAF mutation status could cooperatively induce and promote a more aggressive phenotype in papillary thyroid carcinoma through several pathways and specifically increase the tumors' spread outside of the thyroid gland.

In the present study, the telomerase activity and the putative alterations of genes involved in cell-cycle control (p53, Fas and pRb) were investigated in a radiation-induced meningioma with multiple recurrences and pleural-pulmonary metastases (the patient, a 34-year-old male, had a history of carcinoma of the tongue of testicular lymphocytic lymphoma). Expression of VEGF and vasculature pattern were also studied. Expression of VEGF, pRb and p53 were evaluated by immunohistochemistry on formalin-fixed, paraffin-embedded samples of the tumor. VEGFmRNA was determined by competitive PCR. Fas, FasL and hTERT were evaluated by RT-PCR. Telomerase activity was examined by the TRAP assay. An intense vascularization was observed, supported by high expression of VEGFmRNA (isoforms 121 and 165). pRb and p53 were overexpressed. Fas was undetectable with PCR, whereas FasL was positive. Furthermore, the lesion showed an elevated telomerase activity (TPG, 22), according to the high expression of hTERT. These findings emphasized that even among generally benign neoplasms, such as meningiomas, some highly malignant tumors may develop, as in our case, in which several mechanisms were activated in the cancer progression to guarantee the immortalization of cellular clones (angiogenic phenomenon, activation of telomerase and of anti-apoptotic mechanisms) and the blood spread. Thus, the data illustrate the importance of searching for genetic aberrations (which are a hallmark of malignancy) in meningiomas, as predictive and reliable factors of the possibility to recur and to metastasize.

Background: p27KiP1 is a cyclin-dependent kinase inhibitor and is a potential tumor suppressor gene. Reduced expression of p27Kip1 is a powerful negative prognostic marker in primary lung, breast, colon, bladder, and prostate carcinomas. In the current study, the prognostic value of p27Kip1 in gastric cancer was evaluated and compared with other histopathologic parameters and p53 expression., Methods: p27Kip1 and p53 protein expression were determined by immunohistochemistry in 96 gastric carcinomas. The tumors were from a low incidence population and were selected for the absence of lymph node involvement., Results: Reduced expression of p27KiP1 (< or = 50% positive cells) and nuclear p53 accumulation (> 30% positive cells) were observed in 67 (69.8%) and 9 (9%) tumors, respectively, and were not related to either the pT category or tumor histology. Kaplan-Meier analyses revealed a significant impact on survival by p27Kip1 (P = 0.0001 by log rank test), p53 (P < 0.0001) expression, and the pT category (P < 0.0001). On multivariate analysis, reduced p27Kip1 protein expression was the strongest independent predictor of reduced survival (P = 0.005; relative risk = 3.348) out weighing the pT category (P = 0.010; relative risk = 2.257) and p53 overexpression (P = 0.016; relative risk = 2.618)., Conclusions: These data indicated that immunohistochemical detection of p27Kip1 could help to identify gastric carcinoma patients who are at high risk of death, even in the absence of lymph node involvement, and who might benefit from an adjuvant treatment following surgery.

Nucleolar protein p120 is a proliferation-associated antigen expressed by cells in early G1 phase, identified by the monoclonal antibody FB-2. Its expression has been evaluated in breast and prostate cancer, and proved to be significantly correlated with other prognostic parameters. In oral pathology, p120 protein content is able to distinguish between non-neoplastic and malignant lesions. In the present study, the immunohistochemical expression of p120 protein was evaluated in fifty cases of oral squamous carcinoma and compared with histological grading, pTNM staging, DNA ploidy status and follow-up of the patients, in order to establish its prognostic value, p120 mean area was significantly correlated to all these parameters, apart from lymph node involvement, indicating the strong predictive potential of this marker. In conclusion, quantitative immunohistochemical analysis of p120 protein represents an easy and reliable method for the assessment of clinical outcome and the definition of risk groups in oral carcinoma.