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Marina di Pisa, Italy

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. Source


Rosati P.,Bambino Gesu Childrens Hospital | Jenkner A.,Unit of Haematology Oncology | De Vito R.,Unit of Pathological Anatomy | Boldrini R.,Unit of Pathological Anatomy | And 3 more authors.
BMJ Case Reports | Year: 2011

A 7-year-old girl was brought to our outpatient clinic to investigate recurrent abdominal pain. She was unwilling to attend the school. Her mother reported bullying at school and nosebleeds. The girl rated her pain 9 on a visual analogue score card ranging from 1 to 10. Physical examination disclosed painful bruising and haematomas. Emergency laboratory blood tests indicated by the history, physical examination and the pain intensity showed reduced numbers of white blood cells and platelets. A bone marrow smear on admission disclosed 100% blasts and suggested an initial diagnosis of leukaemia but also disclosed the pseudo-rosettes typically seen in neuro-ectodermic tumours. The diagnosis of stage IV primary neuroblastoma was confi rmed by trephine biopsies and high urinary catecholamines . The girl died 10 months later. This unusual case underlines the need for outpatient paediatricians to involve children in their initial diagnostic work-up by asking them about their pain thus expediting the diagnosis. Copyright 2011 BMJ Publishing Group. All rights reserved. Source


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. Source


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. Source


Proietti A.,University of Pisa | Ali G.,Unit of Pathological Anatomy | Pelliccioni S.,Unit of Pathological Anatomy | Lupi C.,Unit of Pathological Anatomy | And 8 more authors.
Cancer Cytopathology | Year: 2014

BACKGROUND: Anaplastic lymphoma kinase (ALK) gene rearrangements are detected in approximately 5% of cases of non-Small cell lung cancer (NSCLC). Patients who are positive for ALK rearrangements may be successfully treated with the ALK inhibitor crizotinib. Because advanced-Stage lung cancers are not suitable for surgical resection, approximately 70% of patients are diagnosed via preoperative specimens. In the current study, the authors evaluated the suitability of stained cytologic direct smears and cell blocks for fluorescence in situ hybridization (FISH) to determine ALK status compared with small biopsies. METHODS: A total of 493 consecutive patients with NSCLC were analyzed by FISH for ALK gene rearrangements. The analyzed sample comprised 180 cytological samples, 94 direct smears, 86 cell blocks, and 313 preoperative small biopsies. Moreover, in the same series, 426 patients and 369 patients, respectively, were evaluated for epidermal growth factor receptor and KRAS mutations, respectively. RESULTS: Of the total of 493 patients, 18 patients who were positive for a gene rearrangement (4.4%) demonstrated ALK FISH rearrangements, whereas 387 patients (95.6%) were negative. All other cases were classified as inadequate (7.7%) and insufficient (10.1%). A strong statistical association was found between the cytology and the small biopsy with respect to ALK rearrangements (P5.0048). Fiftythree patients (12.4%) demonstrated an epidermal growth factor receptor mutation, whereas 90 patients (24.4%) were found to have KRAS mutations. None of these patients presented with ALK gene rearrangements. CONCLUSIONS: ALK gene rearrangements may be easily detected in cytological samples and particularly in direct smears, thereby yielding important improvements in the diagnostic approach to patients with advanced NSCLC. Cytological samples may be useful for ALK analysis when insufficient material is available in cell blocks or small biopsies. © 2014 American Cancer Society. Source

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