Unit of Pathological Anatomy

Pisa, Italy

Unit of Pathological Anatomy

Pisa, Italy
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Di Villa Bianca R.D.,University of Naples Federico II | Coletta C.,University of Naples Federico II | Mitidieri E.,University of Naples Federico II | De Dominicis G.,Unit of Pathological Anatomy | And 5 more authors.
British Journal of Pharmacology | Year: 2010

BACKGROUND AND PURPOSE Hydrogen sulphide (H 2S), considered as a novel gas transmitter, is produced endogenously in mammalian tissue from L-cysteine by two enzymes, cystathionine β-synthase and cystathionine γ-lyase. Recently, it has been reported that H 2S contributes to the local and systemic inflammation in several experimental animal models. We conducted this study to investigate on the signalling involved in H 2S-induced inflammation.EXPERIMENTAL APPROACH L-cysteine or sodium hydrogen sulphide (NaHS) was injected into the mouse hind paw and oedema formation was evaluated for 60 min. In order to investigate H 2S-induced oedema formation, we used 5-HT and histamine receptor antagonists, and inhibitors of K ATP channels or arachidonic acid cascade. Prostaglandin levels were determined in hind paw exudates by radioimmunoassay. Paws injected with L-cysteine or NaHS were examined by histological methods.KEY RESULTS Both NaHS and L-cysteine caused oedema characterized by a fast onset which peaked at 30 min. This oedematogenic action was not associated with histamine or 5-HT release or K ATP channel activation. However, oedema formation was significantly inhibited by the inhibition of cyclooxygenases and selective inhibition of phospholipase A 2. Prostaglandin levels were significantly increased in exudates of hind paw injected with NaHS or L-cysteine. The histological examination clearly showed an inflammatory state with a loss of tissue organization following NaHS or L-cysteine injection.CONCLUSIONS AND IMPLICATIONS Phospholipase A 2 and prostaglandin production are involved in pro-inflammatory effects of H 2S in mouse hind paws. The present study contributes to the understanding of the role of L-cysteine/H 2S pathway in inflammatory disease. © 2010 The Authors. British Journal of Pharmacology © 2010 The British Pharmacological Society.


Ali G.,Unit of Pathological Anatomy | Proietti A.,Unit of Pathological Anatomy | Pelliccioni S.,Unit of Pathological Anatomy | Niccoli C.,University of Pisa | And 12 more authors.
Archives of Pathology and Laboratory Medicine | Year: 2014

Context. - Echinoderm microtubule associated protein-like 4-anaplastic lymphoma receptor tyrosine kinase (EML4-ALK) translocation has been described in a subset of patients with non-small cell lung cancer (NSCLC) and has been shown to have oncogenic activity. Fluorescence in situ hybridization (FISH) is used to detect ALK-positive NSCLC, but it is expensive, time-consuming, and difficult for routine application. Objective. - To evaluate the potential role of immunohistochemistry (IHC) as a screening tool to identify candidate cases for FISH analysis and for ALK inhibitor therapy in NSCLC. Design. - We performed FISH and IHC for ALK and mutational analysis for epidermal growth factor receptor (EGFR) and KRAS in 523 NSCLC specimens. We conducted IHC analysis with the monoclonal antibody D5F3 (Ventana Medical Systems, Tucson, Arizona) and a highly sensitive detection system. We also performed a MassARRAY-based analysis (Sequenom, San Diego, California) in a small subset of 11 samples to detect EML4-ALK rearrangement. Results. - Of the 523 NSCLC specimens, 20 (3.8%) were positive for ALK rearrangement by FISH analysis. EGFR and KRAS mutations were identified in 70 (13.4%) and 124 (23.7%) of the 523 tumor samples, respectively. ALK rearrangement and EGFR and KRAS mutations were mutually exclusive. Of 523 tumor samples analyzed, 18 (3.4%) were ALK+ by IHC, 18 samples (3.4%) had concordant IHC and FISH results, and 2 ALK+ cases (0.3%) by FISH failed to show ALK protein expression. In the 2 discrepant cases, we did not detect any mass peaks for the EML4-ALK variants by MassARRAY. Conclusions. - Our results show that IHC may be a useful technique for selecting NSCLC cases to undergo ALK FISH analysis. © 2014, College of American Pathologists. All rights reserved.


Borrelli N.,University of Pisa | Giannini R.,University of Pisa | Proietti A.,Unit of Pathological Anatomy | Ali G.,Unit of Pathological Anatomy | And 7 more authors.
Lung Cancer | Year: 2013

A new RET fusion gene has been recently described in a subset of non-small cell lung cancer (NSCLC) identified by specific clinico-pathologic characteristics. This transforming gene arise from the fusion of KIF5B and the RET proto-oncogene, and it is mutually exclusive with EGFR, KRAS and EML4/ALK alterations. For this reason it could represent a putative target for specific inhibitory drugs and its evaluation could be necessary in the future daily molecular characterization of NSCLCs. One of the major challenge in diagnostic molecular pathology is to optimize genotyping tests with the minimally invasive techniques used to acquire diagnostic tumor tissue or cells. This is a significant relevant issue for approximately 60% of NSCLC patients presenting with unresectable disease, where the only pathologic materials available for diagnostic use are small biopsy or cytological specimens. Thus, the aim of this study was to verify the possibility to use RNA purified from cytological specimens to perform KIF5B/RET gene fusion expression analysis. Accordingly, we looked for the presence of the rearrangement in formalin fixed paraffin embedded tissues (FFPETs) and cytological specimens (CSs) of a selected series of "triple-marker" negative adenocarcinomas. The tests conducted revealed the presence of 1 positive patient for variant 1 of KIF5B/RET among the 49 analyzed. The presence of this fusion transcript was found in both FFPET and CS of the same patient demonstrating that the RNA obtained from minimally invasive techniques is perfectly suitable for this kind of tests. The presence of the rearrangement was also confirmed by FISH analysis.In conclusion, our findings confirm that the performance of cytology-based molecular testing for KIF5B/RET rearrangements is at least as effective as histology-based analysis, both with regard to the success rate for nucleic acid isolation and the ability to detect gene alterations. © 2013 Elsevier Ireland Ltd.


Ali G.,Unit of Pathological Anatomy | Proietti A.,University of Pisa | Niccoli C.,University of Pisa | Pelliccioni S.,Unit of Pathological Anatomy | And 8 more authors.
Lung Cancer | Year: 2013

The EML4-ALK gene translocation was described in a non small cell lung cancer (NSCLC) subset, with a potent oncogenic activity. It represents one of the newest molecular targets in NSCLC. We report on the case of a metachronous second primary lung sarcomatoid carcinoma after resection of lung adenocarcinoma both with ALK translocation, in a non-smoking patient. EML4-ALK rearrangement was detected with immunohistochemistry and confirmed with fluorescent in situ hybridization (FISH). To assess the clonal relationship between the two tumors, both adenocarcinoma and sarcomatoid carcinoma were analyzed by array comparative genomic hybridization (aCGH). We observed different genomic profiles suggesting that the tumors arose independently and were thus multiple primaries. To the best of our knowledge, this is the first report concerning the presence of the EML4-ALK fusion gene in a sarcomatoid carcinoma of the lung. Crizotinib, the ALK tyrosine kinase inhibitor, is highly effective in ALK-rearranged NSCLC; therefore, it may be imperative to identify all NSCLC that harbor ALK translocations in the near future. Starting from our evidence, tumors with sarcomatoid histology may need to be screened for the presence of EML4-ALK rearrangement. © 2013 Elsevier Ireland Ltd.


Ali G.,Unit of Pathological Anatomy | Borrelli N.,University of Pisa | Riccardo G.,University of Pisa | Proietti A.,University of Pisa | And 6 more authors.
Journal of Thoracic Oncology | Year: 2013

INTRODUCTION:: Malignant pleural mesothelioma (MPM) is a highly aggressive neoplasm associated with asbestos exposure. Currently, the molecular mechanisms that induce MPM development are still unknown. The purpose of this study was to identify new molecular biomarkers for mesothelial carcinogenesis. METHODS:: We analyzed a panel of 84 genes involved in extracellular matrix remodeling and cell adhesion by polymerase chain reaction (PCR) array in 15 samples of epithelioid mesothelioma and 10 samples of reactive mesothelial hyperplasia (MH; 3 of 25 samples were inadequate for mRNA analysis). To validate the differentially expressed genes identified by PCR array, we analyzed 27 more samples by immunohistochemistry, in addition to the 25 samples already studied. RESULTS:: Twenty-five genes were differentially expressed in MPM and MH by PCR array. Of these we studied matrix metalloproteinase 7 (MMP7), MMP14, CD44, and integrin, alpha3 expression by immunohistochemistry in 26 epithelioid MPM and 26 MH samples from the entire series of 52 cases. We observed higher MMP14 and integrin, alpha3 expression in MPM samples compared with MH samples (p = 0.000002 and p = 0.000002, respectively). Conversely, CD44 expression was low in most (57.7%) mesothelioma samples but only in 11.5% of the MH samples (p = 0.0013). As regards MMP7, we did not observe differential expression between MH and MPM samples. CONCLUSIONS:: We have extensively studied genes involved in cell adhesion and extracellular matrix remodeling in MPM and MH samples, gaining new insight into the pathophysiology of mesothelioma. Moreover, our data suggest that these factors could be potential biomarkers for MPM. Copyright © 2013 by the International Association for the Study of Lung.


Macerola E.,University of Pisa | Loggini B.,Unit of Pathological Anatomy | Giannini R.,University of Pisa | Garavello G.,Unit of Pathological Anatomy | And 5 more authors.
Virchows Archiv | Year: 2015

The recently described telomerase reverse transcriptase (TERT) promoter mutations are recurrent in cutaneous melanoma. Several authors have described an association between these molecular alterations, some histological parameters, and patient survival. BRAF mutations are very frequent in melanoma, but their actual role in the evolution of the disease is still unclear. Here, we investigated the relationship of TERT promoter mutations and BRAF mutations with the most relevant clinicopathological parameters, individually and coexisting, in order to evaluate their role as independent prognostic markers and to determine the effect of their coexistence. A TERT promoter alteration was found in 20 of 53 cases (38 %), significantly associated with histological type, increasing tumor thickness and mitotic rate, more advanced pathologic tumor (pT) stage, and absence of regression. A BRAF mutation was found in 21 of 53 cases (40 %), significantly associated with tumor thickness and presence of metastases in the sentinel lymph node. Coexistence of a TERT promoter and BRAF mutation was detected in 11 of 53 cases (21 %). This was associated with increasing thickness, high mitotic rate, lymph node metastasis, presence of ulceration, and absence of regression. Coexistence of a mutation in the TERT promoter and in the BRAF gene correlated with more prognostically relevant factors than either mutation alone. Our data lead us to hypothesize that TERT promoter and BRAF mutations cooperate in cutaneous melanoma. Further studies in larger cohorts of patients are needed to investigate how this synergistic effect is involved in the evolution of the disease. © 2015, Springer-Verlag Berlin Heidelberg.

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