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Tommasi S.,National Cancer Center Giovanni Paolo | Pinto R.,National Cancer Center Giovanni Paolo | Petriella D.,National Cancer Center Giovanni Paolo | Pilato B.,National Cancer Center Giovanni Paolo | And 6 more authors.
Journal of Cellular Physiology | Year: 2011

K-RAS and BRAF gene mutations are mandatory to set anti-EGFR therapy in metastatic colorectal cancer (mCRC) patients. Due to the relationship of these mutations with tumor epigenotype, we hypothesized the potential role of oncosuppressor methylation of genes involved in K-RAS/BRAF pathway (CDKN2A, RASSF1A, and RARbeta suppressor genes) in inhibiting EGFR signaling cascade. Primary tumor and synchronous liver metastatic tissues of 75 mCRC patients were characterized for promoter methylation by QMSP and for K-RAS and BRAF mutations. RARbeta, RASSF1A, and CDKN2A genes were methylated in 82%, 35%, and 26% of primary tumors, respectively. RASSF1A resulted significantly more frequently methylated in liver metastasis than in primary site (P=0.015), while RARbeta was significantly lower methylated in distant metastasis (P=1.2×10-6). As regards methylation content, RASSF1A methylation status was significantly higher in liver metastasis with respect to primary tumor (P=0.000) underlying the role of this gene in liver metastatic progression. In our series K-RAS and BRAF were mutated in 39% and 4% of cases, respectively. Methylation frequencies seemed to be unrelated to gene mutations; on the other hand, RASSF1A mean content methylation resulted significantly higher in liver than in primary tumor (288.78 vs. 56.23, respectively, P=0.05) only in K-RAS wild-type cases sustaining a specific role of this gene in metastatic site thus supporting its function in strengthening the apoptotic role of K-RAS. These evidences held the role of oncosuppressor methylation in both colon tumorigenesis and progression and suggested that epigenetic events should be taken into account when biological therapies in mCRC patients have to be set. © 2010 Wiley-Liss, Inc.

De Ceglie A.,National Cancer Center Giovanni Paolo | Filiberti R.,Epidemiology | Baron T.H.,Mayo Medical School | Ceppi M.,Epidemiology | Conio M.,General Hospital
Critical Reviews in Oncology/Hematology | Year: 2013

The best approach to resolve colonic obstruction in patients with left-sided colon cancer is not established.In this meta-analysis the efficacy of stenting as bridge-to-surgery was compared to emergency surgery for the management of left-sided colonic obstruction. Fourteen studies (randomized and non controlled studies) were identified, including 405 patients in the stent group and 471 in the emergency group. The difference between proportions was evaluated as effect size (ESi). There was large heterogeneity among the studies.Stenting offered advantages over emergency surgery in terms of increase in primary anastomosis (ES. = 25.1%, p<. 0.001), successful primary anastomosis (ES = 23.7%, p<. 0.001), reduction of stoma creation (ES = -27.1%, p= 0.03), infections (ES = -7.9%, p= 0.006) and other morbidities (ES = -13.4%, p<. 0.001). The interventions were similar in regards to length of hospitalization, preoperative mortality and long-term survival. © 2013 Elsevier Ireland Ltd.

Conio M.,General Hospital | De Ceglie A.,National Cancer Center Giovanni Paolo | Filiberti R.,IRCCS AOU San Martino IST Instituto Nazionale per la Ricerca sul Cancro | Fisher D.A.,Durham Veterans Affairs Medical Center | Siersema P.D.,University Utrecht
Gastrointestinal Endoscopy | Year: 2012

Background: EMR is an effective alternative to surgery for the removal of nonampullary duodenal polyps (NADPs). Cap-assisted EMR (EMR-C) has been rarely performed in the duodenum because of the risk of perforation. Objective: To evaluate the safety and effectiveness of EMR-C for the removal of large (<15 mm) NADPs. Design: Retrospective study. Setting: Tertiary-care referral center. Patients: Between 2000 and 2010, 26 consecutive patients with sporadic NADPs underwent EMR-C. Intervention: EMR with the cap technique. Main Outcome Measurements: Complete eradication of polyps, complications, and recurrence. Results: A total of 14 sessile polyps (53.8%), 7 lateral spreading type nongranular tumors (26.9%), and 5 lateral spreading type granular tumors (19.2%) were treated. The median size of lesions was 15 mm. Five lesions involved one-half of the luminal circumference. Post-EMR histologic assessment showed low-grade dysplasia in 5 patients (19.2%) and high-grade dysplasia in 18 patients (69.2%). Three patients (11.5%) had well-differentiated endocrine tumors. Complete eradication was obtained in 25 of 26 (96%) patients. No perforations occurred. Three cases of intraprocedural bleeding were managed endoscopically. Median follow-up was 6 years (range 1-10 years). Residual adenomatous tissue was observed in 3 patients in lesions of 50 mm. In one of these cases, an adenocarcinoma occurred after 8 months, which was managed surgically. Limitations: Retrospective design, single center. Conclusion: This study supports the efficacy and safety of EMR-C for removing NADPs. Regular follow-up is mandatory because of the high risk of residual or recurrent adenomatous tissue and even cancer. © 2012 American Society for Gastrointestinal Endoscopy.

Radice P.,Unit of Molecular Bases of Genetic Risk and Genetic Testing | Radice P.,Fondazione Instituto Firc Of Oncologia Molecolare | de Summa S.,National Cancer Center Giovanni Paolo | Caleca L.,Unit of Molecular Bases of Genetic Risk and Genetic Testing | Tommasi S.,National Cancer Center Giovanni Paolo
Annals of Oncology | Year: 2011

In the last few years, several studies have focused on the interpretation of unclassified variants (UVs) of BRCA1 and BRCA2 genes. Analysis of UVs through a unique approach is not sufficient to understand their role in the development of tumors. Thus, it is clear that assembling results from different sources (genetic and epidemiological data, histopathological features, and in vitro and in silico analyses) represents a powerful way to classify such variants. Building reliable integrated models for UV classification requires the joining of many working groups to collaborative consortia, allowing data exchange and improvements of methods. This will lead to improvement in the predictivity of gene testing in BRCA1 and BRCA2 and, consequently, to an increase in the number of families that can be correctly classified as linked or unlinked to these genes, allowing more accurate genetic counseling and clinical management. © The Author 2011. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved.

Ranieri G.,Interventional Radiology Unit with Integrated Section of Translational Medical Oncology | Gadaleta-Caldarola G.,Interventional Radiology Unit with Integrated Section of Translational Medical Oncology | Goffredo V.,Interventional Radiology Unit with Integrated Section of Translational Medical Oncology | Patruno R.,University of Bari | And 4 more authors.
Current Medicinal Chemistry | Year: 2012

Angiogenesis and signaling through the RAS/RAF/mitogen-activated protein/extracellular signal-regulated kinase (ERK) kinase (MEK)/ERK cascade have been reported to play important roles in the development of hepatocellular carcinoma (HCC). Sorafenib (Nexavar), a novel bi-aryl urea BAY 43-9006, is an orally administered multikinase inhibitor with activity against RAS/RAF kinases multikinase inhibitor with activity against RAFkinases and several receptor tyrosine kinases, including vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR), FLT3, Ret, and c-Kit. It is involved in angiogenic pathway and cell proliferation. Sorafenib has demonstrated potent anti-tumor activity in in vitro studies, preclinical xenograft models of different tumor types and human clinical trials. This review summarizes the history of sorafenib from its discovery by the medicinal chemistry approach through to clinical development and ongoing trials on the combination between sorafenib and trans-arterial chemoembolization (TACE) in HCC patients. © 2012 Bentham Science Publishers.

Mangia A.,National Cancer Center Giovanni Paolo | Malfettone A.,National Cancer Center Giovanni Paolo | Rossi R.,University of Bari | Paradiso A.,National Cancer Center Giovanni Paolo | And 3 more authors.
Histopathology | Year: 2011

Aims: Cancerogenesis is characterized by increase of differentiated myofibroblasts. Mast cells (MCs) exert powerful effects on fibroblasts through a variety of mediators. We investigated α-smooth-muscle actin (α-SMA+) and CD34+ fibroblasts, density of toluidine blue-stained (MCs-TB) and tryptase-immunolabelled MCs (MCs-Try) in 30 primary breast tumours. Methods and results: Tumour (T), peri-tumoral (PT) and non-tumoral (NT) tissue was studied by immunohistochemistry and electron microscopy. MCs-TB and MCs-Try increased gradually from NT to PT and T and the comparison between the three compartments varied significantly. Degranulated MCs were present more significantly in NT and adjacent PT than T. Transition between NT, PT and T was marked by increasing α-SMA+ fibroblasts and slow disappearance of CD34+ stromal cells. In NT, CD34+ fibroblasts correlated with low density both of MCs-TB and intact MCs-Try (P=0.0346 and P=0.0409, respectively). In T, the few preserved CD34+ fibroblasts were associated with low-density degranulated MCs-Try (P=0.0173). The α-SMA+ fibroblasts correlated with high density of intact MCs-Try in PT, and with high density of degranulated MCs-Try in T (P=0.0289), also confirmed by ultrastructural analysis. Conclusions: This preliminary investigation suggests that during breast cancer progression the MCs may contribute to stromal remodelling and differentiation of myofibroblasts, through tryptase released in stromal microenvironment. © 2011 Blackwell Publishing Limited.

Malfettone A.,National Cancer Center Giovanni Paolo | Silvestris N.,Medical Oncology Unit | Paradiso A.,National Cancer Center Giovanni Paolo | Mattioli E.,National Cancer Center Giovanni Paolo | And 2 more authors.
Experimental and Molecular Pathology | Year: 2012

Over 57% of colorectal cancer (CRC) patients have regional or distant spread of their disease at the time of diagnosis. Despite recent advances, there is a compelling need to better characterize prognostic markers for advanced CRC. The present study investigates protein expression of NHERF1, HIF-1α and TWIST1 and their relationship in distant normal mucosa (DNM), tumor (T) and adjacent normal mucosa (ANM), lymph node metastasis (LNM) and liver metastasis (LM), determining their role as potential markers in advanced stages of human CRC. Overexpression of nuclear NHERF1 was shown in 47% of tumors, which exhibited a significant association with poor histological grade (P= 0.0346). Nuclear NHERF1 showed a higher expression in T, LNM and LM than both DNM (P< 0.0001) and ANM (P< 0.05). Nuclear HIF-1α was significantly higher in T, LNM and LM than DNM and ANM (P< 0.05, P< 0.001, P< 0.0001, respectively). A positive correlation between nuclear NHERF1 and nuclear HIF-1α was found in LNM (r= 0.331, P= 0.020), where an extended co-localization of the two proteins was demonstrated. TWIST1 was more expressed in T than DNM and ANM (P< 0.0001) and was higher in T than LNM and LM (P< 0.0001). Moreover, nuclear NHERF1 was directly correlated to TWIST1 (r= 0.339, P= 0.015) in T samples, where a high co-expression of the two proteins was demonstrated both in no longer polarized epithelial cells and in invasive mesenchymal elements adjacent to hypoxic and perinecrotic colonic areas. Overall, nuclear NHERF1 expression was associated with poorer differentiation grade and with higher expression both of HIF-1α in lymphatic metastasis and TWIST1 in invasive front of tumor. Our results support the oncogenic role of NHERF1 and promote nuclear NHERF1 as a potential new biomarker of advanced CRC. © 2012 Elsevier Inc.

Calvert H.,Northumbria University | Azzariti A.,National Cancer Center Giovanni Paolo
Annals of Oncology | Year: 2011

A number of inhibitors of DNA repair have been evaluated or are undergoing development as potential cancer treatments. Inhibitors of poly(ADP-ribose) polymerase (PARP) are of particular interest in treating hereditary breast cancers occurring in patients who are carriers of BRCA1 or BRCA2 mutations. In vitro PARP inhibitors are highly cytotoxic to cell lines carrying BRCA mutations while only minimally toxic to cell lines without these mutations. This is thought to be due to a phenomenon known as synthetic lethality where the accumulation of single-strand breaks consequent on PARP inhibition are converted to double-strand breaks on cell division. Cancer cells in BRCA carriers are uniquely unable to repair the consequent double-strand breaks that result during cell division. PARP inhibitors were initially developed as possible chemo-potentiating agents but have now been evaluated clinically in BRCA-related tumors, showing remarkable single-agent activity. The potential future development and use is reviewed. © The Author 2011. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved.

Muggia F.,New York University | Smaldone V.,New York University | Paradiso A.,National Cancer Center Giovanni Paolo
Annals of Oncology | Year: 2011

Genes implicated in the devastating occurrences of cancers mostly arising in the breast and ovaries within certain 'high-risk' families were mapped and then cloned not even two decades ago. Some clairvoyant students of the subject anticipated that this 'assignation of risk' would herald a new era in the prevention, treatment and insights into pathogenesis of neoplasia. However, few would have predicted the accelerated pace of knowledge that ensued. The successive symposia that we held on this subject have given us a unique perspective on the extent of this progress. This supplement and the selected papers that have been assembled document accomplishments in genetics, epidemiology, early detection, treatment, preventive measures, as well as in the ethical and psychosocial consequences enveloping families at risk. It also reveals how the convergence of the laboratory, the clinic and the public across two continents is able to ignite discovery and its applications. © The Author 2011. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved.

Tommas S.,National Cancer Center Giovanni Paolo | Danza K.,National Cancer Center Giovanni Paolo | Pilato B.,National Cancer Center Giovanni Paolo | de Summa S.,National Cancer Center Giovanni Paolo
Annals of Oncology | Year: 2011

After completion of the Human Genome Project, analysis of genetic and genomic variations in different pathological states became possible. The capillary system based on Sanger methods is still very expensive in terms of time, cost and professionalism required. For this reason, the National Human Genome Institute proposed an 'advanced sequencing technology development' project with the aim of sequencing a genome in 1 day for $1000. Three validated platforms are commercially available and single molecule sequencing methods have been recently introduced, which are not only competitive in time and costs, but display greater accuracy than 'past generation' sequencing. Next generation technology allows, in a single experiment, the identification of copy number variation and large rearrangements, or detection of fusion transcripts analysis thus permitting the evaluation of cancer risk at multiple levels (genomic, transcriptomic, proteomic, epigenetic). © The Author 2011. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved.

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