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Normanno N.,Cell Biology and Biotherapy Unit | Normanno N.,Centro Of Ricerche Oncologiche Of Mercogliano Crom | Rachiglio A.M.,Centro Of Ricerche Oncologiche Of Mercogliano Crom | Lambiase M.,Centro Of Ricerche Oncologiche Of Mercogliano Crom | And 41 more authors.
Annals of Oncology | Year: 2015

Background: Evidence suggests that metastatic colorectal carcinoma (mCRC) has a high level of intratumor heterogeneity. We carried out a quantitative assessment of tumor heterogeneity for KRAS, NRAS, BRAF and PIK3CA mutations, in order to assess potential clinical implications. Patients and methods: Tumor samples (n = 182) from the CAPRI-GOIM trial of first-line cetuximab + FOLFIRI in KRAS exon-2 wild-type mCRC patients were assessed by next-generation sequencing that allows quantitative assessment of mutant genes. Mutant allelic frequency was normalized for the neoplastic cell content and, assuming that somatic mutations usually affect one allele, the Heterogeneity Score (HS) was calculated by multiplying by 2 the frequency of mutant alleles in neoplastic cells. Therefore, HS virtually corresponds to the fraction of neoplastic cells carrying a specific mutation. Results: The KRAS HS ranged between 12 and 260 with mean value of 87.1 and median value of 84.4, suggesting that in most CRC, the majority of neoplastic cells carry mutant KRAS. Similar findings were observed for NRAS (HS range 35.5-146.7; mean 102.8; median 117.1). In contrast, in BRAF (HS range 17.1-120; mean 54.8; median 54.3) and PIK3CA (HS range 14.3-120; mean 59.5; median 47.3) mutant cases, only a fraction of neoplastic cells seem to carry the mutant allele. The response rate was 70% in KRAS mutant patients with an HS <33 (low KRAS; n = 10) and 45.7% in KRAS HS >33 patients (high KRAS; n = 35); median progression-free survival were 7.97 and 8.37 months, respectively. Low-KRAS tumors had a higher frequency of additional mutations in PIK3CA when compared with high-KRAS (6/10 versus 8/35). Conclusions: KRAS and NRAS mutations are usually present in the majority of neoplastic cells, whereas BRAF and PIK3CA mutations often affect a limited fraction of transformed cells. Resistance to cetuximab in low-KRAS patients might be driven by the complex mutational profile rather than KRAS mutation load. © The Author 2015. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved.

Fusco R.,Radiant Imaging | Sansone M.,University of Naples Federico II | Petrillo M.,Radiant Imaging | Setola S.V.,Radiant Imaging | And 6 more authors.
Magnetic Resonance Imaging | Year: 2016

Introduction: Early promising data suggest that combined use of both morphological and functional MRI (multi-parametric MR, mpMRI) including MRSI, DWI and DCE may be of additional value for prostate cancer localization and its local staging. The objective of this paper is to evaluate the diagnostic performance of mpMRI in the detection of prostate cancer. Methods: Thirty-one consecutive male patients were screened to be enrolled in a single center prospective observational study. All eligible patients underwent multi-parametric MRI and TRUS (Trans Rectal Ultra Sound) guided prostate biopsies. A register, approved by the Institutional Ethics Committee, included patients enrolled in this study. All patients who decided to undergo the MRI examination signed an explicit informed consensus. MRI data were aligned on a common spatial grid and several functional parameters (perfusion, diffusion and metabolic parameters) were computed. Statistical analysis was conducted in order to compare mpMRI with biopsy-based analysis. Results: Statistically significant differences between median values in high Gleason score (≥5) and low Gleason score (<5) to Wilcox on rank sum test were obtained for MRSI parameters and for plasma fraction (Tofts model) of DCE-MRI. The area under curve obtained with ROC analysis showed that the best-performing single-parameter was vp (plasma fraction of Tofts model), while the best parameters combination to discriminate the area with high Gleason score were (Cho + Cr)/Cit and Cho + Cr. Linear Discrimination Analysis showed that the best results were obtained considering the linear combination of all MRSI parameters and the linear combination of all features (perfusion, diffusion and metabolic parameters). Conclusions: In conclusion, our findings showed that by combining morphological MRI, DWI, DCE-MRI and MRSI, an increase in sensitivity and specificity correlated to biopsy Gleason grade could be obtained. Furthermore, morphological and functional MRI could have a diagnostic role in patients with prostate cancer, identifying those patients who will have a negative work-up and those patients at high risk for a high Gleason score cancer of the prostate. © 2016 Elsevier Inc..

Petrillo M.,Radiant Imaging | Fusco R.,Radiant Imaging | Catalano O.,Radiant Imaging | Sansone M.,University of Naples Federico II | And 4 more authors.
BioMed Research International | Year: 2015

To evaluate MRI for neoadjuvant therapy response assessment in locally advanced rectal cancer (LARC) using dynamic contrast enhanced-MRI (DCE-MRI) and diffusion weighted imaging (DWI), we have compared magnetic resonance volumetry based on DCE-MRI (V(DCE)) and on DWI (V(DWI)) scans with conventional T2-weighted volumetry (V(C)) in LARC patients after neoadjuvant therapy. Twenty-nine patients with LARC underwent MR examination before and after neoadjuvant therapy. A manual segmentation was performed on DCE-MR postcontrast images, on DWI (b-value 800 s/mm2), and on conventional T2-weighted images by two radiologists. DCE-MRI, DWI, and T2-weigthed volumetric changes before and after treatment were evaluated. Nonparametric sample tests, interobserver agreement, and receiver operating characteristic curve (ROC) were performed. Diagnostic performance linked to DCE-MRI volumetric change was superior to T2-w and DW-MRI volumetric changes performance (specificity 86%, sensitivity 93%, and accuracy 93%). Area Under ROC (AUC) of V(DCE) was greater than AUCs of V(C) and V(DWI) resulting in an increase of 15.6% and 11.1%, respectively. Interobserver agreement between two radiologists was 0.977, 0.864, and 0.756 for V(C), V(DCE), and V(DWI), respectively. V(DCE) seems to be a promising tool for therapy response assessment in LARC. Further studies on large series of patients are needed to refine technique and evaluate its potential value. © 2015 Mario Petrillo et al.

Ciardiello F.,The Second University of Naples | Normanno N.,Italian National Cancer Institute | Martinelli E.,The Second University of Naples | Troiani T.,The Second University of Naples | And 51 more authors.
Annals of Oncology | Year: 2016

Background: Cetuximab plus chemotherapy is a first-line treatment option in metastatic KRAS and NRAS wild-type colorectal cancer (CRC) patients. No data are currently available on continuing anti-epidermal growth factor receptor (EGFR) therapy beyond progression. Patients and methods: We did this open-label, 1:1 randomized phase II trial at 25 hospitals in Italy to evaluate the efficacy of cetuximab plus 5-fluorouracil, folinic acid and oxaliplatin (FOLFOX) as second-line treatment of KRAS exon 2 wild-type metastatic CRC patients treated in first line with 5-fluorouracil, folinic acid and irinotecan (FOLFIRI) plus cetuximab. Patients received FOLFOX plus cetuximab (arm A) or FOLFOX (arm B). Primary end point was progressionfree survival (PFS). Tumour tissues were assessed by next-generation sequencing (NGS). This report is the final analysis. Results: Between 1 February 2010 and 28 September 2014, 153 patients were randomized (74 in arm A and 79 in arm B). Median PFS was 6.4 [95% confidence interval (CI) 4.7-8.0] versus 4.5 months (95% CI 3.3-5.7); [hazard ratio (HR), 0.81; 95% CI 0.58-1.12; P = 0.19], respectively. NGS was performed in 117/153 (76.5%) cases; 66/117 patients (34 in arm A and 32 in arm B) had KRAS, NRAS, BRAF and PIK3CA wild-type tumours. For these patients, PFS was longer in the FOLFOX plus cetuximab arm [median 6.9 (95% CI 5.5-8.2) versus 5.3 months (95% CI 3.7-6.9); HR, 0.56 (95% CI 0.33-0.94); P = 0.025]. There was a trend in better overall survival: median 23.7 [(95% CI 19.4-28.0) versus 19.8 months (95% CI 14.9-24.7); HR, 0.57 (95% CI 0.32-1.02); P = 0.056]. Conclusions: Continuing cetuximab treatment in combination with chemotherapy is of potential therapeutic efficacy in molecularly selected patients and should be validated in randomized phase III trials. © The Author 2016.

Fusco R.,Radiant Imaging | Sansone M.,University of Naples Federico II | Filice S.,Radiant Imaging | Granata V.,Radiant Imaging | And 6 more authors.
BioMed Research International | Year: 2015

Objective. The purpose of our study was to evaluate the diagnostic value of an imaging protocol combining dynamic contrast-enhanced MRI (DCE-MRI) and diffusion-weighted MRI (DW-MRI) in patients with suspicious breast lesions. Materials and Methods. A total of 31 breast lesions (15 malignant and 16 benign proved by histological examination) in 26 female patients were included in this study. For both DCE-MRI and DW-MRI model free and model based parameters were computed pixel by pixel on manually segmented ROIs. Statistical procedures included conventional linear analysis and more advanced techniques for classification of lesions in benign and malignant. Results. Our findings indicated no strong correlation between DCE-MRI and DW-MRI parameters. Results of classification analysis show that combining of DCE parameters or DW-MRI parameter, in comparison of single feature, does not yield a dramatic improvement of sensitivity and specificity of the two techniques alone. The best performance was obtained considering a full combination of all features. Moreover, the classification results combining all features are dominated by DCE-MRI features alone. Conclusion. The combination of DWI and DCE-MRI does not show a potential to dramatically increase the sensitivity and specificity of breast MRI. DCE-MRI alone gave the same performance as in combination with DW-MRI. © 2015 Roberta Fusco et al.

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