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Malapelle U.,University of Naples Federico II | Bellevicine C.,University of Naples Federico II | Salatiello M.,University of Naples Federico II | De Luca C.,University of Naples Federico II | And 9 more authors.
Journal of Clinical Pathology | Year: 2012

Background: Sanger sequencing (SS) of PCR products is still the most frequent method to test colorectal cancer for KRAS mutations in routine practice. Methods: An audit of SS on 1720 routine cases was carried out, taking into account age, gender, specimen type (resection vs biopsies), tumour site ( primary vs metastasis), tumour stage, neoplastic cells abundance (>30% vs <30%) and fixation type (buffered formalin vs simple formalin). In a subset of 50 wild-type (WT) patients correlations between SS findings and response rate (RR), progression-free survival (PFS) and overall survival (OS) were also evaluated. Results: The tests were informative in 1691 cases (98.3%). Mutations were detected in 671 cases (39.6%). No significant differences in mutation rates were observed with respect to age (p=0.2), gender ( p=0.2), specimen type (p=0.3) and formalin fixation ( p=0.08). Conversely, KRAS mutant rate was higher in metastatic tissue (50% vs 39%, p=0.02), in samples with over 30% of neoplastic cells (43.4% vs 26.6%, p=0.02) and in tumours tested in stage IV ( p=0.05). The RR of SS KRAS WT patients was 26% (one complete and 12 partial responses). The disease control rate (objective responses plus stable disease) was 56%. Median PFS was 4.4 months and median OS was 10.4 months. Conclusions: Pathological criteria that make SS a more robust method for KRAS testing and treatment response prediction are neoplastic cell abundance, metastatic tissue sample and stage IV primary tumour.

Iacobucci I.,University of Bologna | Ferrari A.,University of Bologna | Lonetti A.,University of Bologna | Papayannidis C.,University of Bologna | And 18 more authors.
Clinical Cancer Research | Year: 2011

Purpose: The 9p21 locus, encoding three important tumor suppressors (p16/CDKN2A, p14/ARF, and p15/CDKN2B), is a major target of inactivation in the pathogenesis of many human tumors. Patients and Methods: To explore, at high resolution, the frequency and size of alterations affecting this locus in adult BCR-ABL1-positive acute lymphoblastic leukemia (ALL) and to investigate their prognostic value, 112 patients (101 de novo and 11 relapsed cases) were analyzed by genome-wide single-nucleotide polymorphism arrays and gene candidate deep exon sequencing. Paired diagnosis-relapse samples were further available and analyzed for 19 (19%) cases. Results: CDKN2A/ARF and CDKN2B genomic alterations were identified in 29% and 25% of newly diagnosed patients, respectively. Deletions were monoallelic in 72% of cases, and in 43% of them, the minimal overlapping region of the lost area spanned only the CDKN2A/B gene locus. An analysis conducted at relapse showed an increase in the detection rate of CDKN2A/ARF loss (47%) compared with the time of diagnosis (P = 0.06). Point mutations within the 9p21 locus were found at very low levels, with only a nonsynonymous substitution in the exon 2 of CDKN2A. Of note, deletions of CDKN2A/B were significantly associated with poor outcomes in terms of overall survival (P = 0.0206), disease free-survival (P = 0.0010), and cumulative incidence of relapse (P = 0.0014). Conclusions: Inactivation of the 9p21 locus by genomic deletion is a frequent event in BCR-ABL1-positive ALL. Deletions are frequently acquired during leukemia progression and are a poor prognostic marker of long-term outcomes. ©2011 AACR.

Bracco E.,University of Turin | Rosso V.,University of Turin | Serra A.,University of Turin | Carnuccio F.,University of Turin | And 6 more authors.
BMC Cancer | Year: 2013

Background: Mutation(s) of the JAK2 gene (V617F) has been described in a significant proportion of Philadelphia negative Myeloproliferative Neoplasms (MPN) patients and its detection is now a cornerstone in the diagnostic algorithm.Methods: We developed a novel assay based on peptide nucleic acid (PNA) technology coupled to immuno-fluorescence microscopy (PNA-FISH) for the specific detection at a single cell level of JAK2-mutation thus improving both the diagnostic resolution and the study of clonal prevalence.Results: Using this assay we found a percentage of mutated CD34+ cells ranging from 40% to 100% in Polycythemia Vera patients, from 15% to 80% in Essential Thrombocythemia and from 25% to 100% in Primary Myelofibrosis. This method allows to distinguish, with a high degree of specificity, at single cell level, between CD34+ progenitor stem cells harbouring the mutated or the wild type form of JAK2 in NPM patients.Conclusions: This method allows to identify multiple gene abnormalities which will be of paramount relevance to understand the pathophysiology and the evolution of any type of cancer. © 2013 Bracco et al.; licensee BioMed Central Ltd.

Barbieri V.,Centro Of Riferimento Oncologico Della Basilicata Crob | Sanpaolo P.,Centro Of Riferimento Oncologico Della Basilicata Crob | Genovesi D.,University of Chieti Pescara
Clinical Breast Cancer | Year: 2011

Background: The aim of this study was to evaluate if the interval between breast-conserving surgery and the start of radiotherapy has an effect on local relapse risk. Materials and Methods: Between January 2000 and December 2006 a total of 387 patients with T1-2N0+ breast cancer were treated with breast-conserving surgery and radiotherapy, with and without hormone therapy and chemotherapy. Adjuvant radiotherapy was administered to a total dose of 60 to 66 Gy in 30 to 33 fractions. The time intervals between breast-conserving surgery and the start of radiotherapy were < 60, 61 to 120,121 to 180 and > 180 days. The Kaplan-Meier method was used to calculate local relapse-free survival rates, and the Cox regression method was used to identify predictive factors of local relapse. Evaluated variables were age, tumor location, tumor histologic type, tumor size, surgical margin status, axillary node status, estrogen receptors, tumor grading, adjuvant therapy, adjuvant chemotherapy, radiation therapy, boost dose, and interval between breast-preserving surgery and start of radiation therapy. Results: Five-year local relapse-free survival rates were 97.3% ± 1.5% for patients who did not receive chemotherapy and 94.5% ± 1.9% for patients who received chemotherapy (P =.71). There was no significant difference in local relapse among the 4 interval groups (P =.9). Multivariate Cox regression analysis showed that intervals between breast-conserving surgery and radiotherapy were not associated with higher local relapse risk. Conclusion: In our study a delay in administering radiotherapy after breast-conserving surgery was not associated with an increased risk of local relapse. Taking into account contrasting results of many published studies, a larger evaluation of this issue is warranted. © 2011 Elsevier Inc. All rights reserved.

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