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1.
Br J Cancer ; 110(5): 1228-35, 2014 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-24434431

RESUMO

BACKGROUND: It is uncertain whether synchronous colorectal cancers (S-CRCs) preferentially develop through widespread DNA methylation and whether they have a prognosis worse than solitary CRC. As tumours with microsatellite instability (MSI) may confound the effect of S-CRC methylation on outcome, we addressed this issue in a series of CRC characterised by BRAF and MS status. METHODS: Demographics, clinicopathological records and disease-specific survival (DSS) were assessed in 881 consecutively resected CRC undergoing complete colonoscopy. All tumours were typed for BRAF(c.1799T>A) mutation and MS status, followed by search of germ-line mutation in patients with MSI CRC. RESULTS: Synchronous colorectal cancers (50/881, 5.7%) were associated with stage IV microsatellite-stable (MSS) CRC (19/205, 9.3%, P=0.001) and with HNPCC (9/32, 28%, P<0.001). BRAF mutation (60/881, 6.8%) was associated with sporadic MSI CRC (37/62, 60%, P<0.001) but not with S-CRC (3/50, 6.0%, P=0.96). Synchronous colorectal cancer (HR 1.82; 95% CI 1.15-2.87; P=0.01), synchronous advanced adenoma (HR 1.81; 95% CI 1.27-2.58; P=0.001), and BRAF(c.1799T>A) mutation (HR 2.16; 95% CI 1.25-3.73; P=0.01) were stage-independent predictors of death from MSS CRC. Disease-specific survival of MSI CRC patients was not affected by S-CRC (HR 0.74; 95% CI 0.09-5.75; P=0.77). CONCLUSION: Microsatellite-stable CRCs have a worse prognosis if S-CRC or synchronous advanced adenoma are diagnosed. The occurrence and the enhanced aggressiveness of synchronous MSS advanced neoplasia are not associated with BRAF mutation.


Assuntos
Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Repetições de Microssatélites , Adenoma/genética , Idoso , Neoplasias Colorretais/enzimologia , Feminino , Mutação em Linhagem Germinativa , Humanos , Masculino , Instabilidade de Microssatélites , Pessoa de Meia-Idade , Prognóstico , Proteínas Proto-Oncogênicas B-raf/genética
2.
Br J Cancer ; 109(9): 2424-33, 2013 Oct 29.
Artigo em Inglês | MEDLINE | ID: mdl-24084767

RESUMO

BACKGROUND: In pancreatic ductal adenocarcinoma (PDAC), fractalkine receptor CX3CR1 contributes to perineural invasion (PNI). We investigated whether CX3CR1 expression occurs early in PDAC and correlates with tumour features other than PNI. METHODS: We studied CX3CR1 and CX3CL1 expression by immunohistochemistry in 104 human PDAC and coexisting Pancreatic Intraepithelial Neoplasia (PanIN), and in PdxCre/LSL-Kras(G12D) mouse model of PDAC. CX3CR1 expression in vitro was studied by a spheroid model, and in vivo by syngenic mouse graft of tumour cells. RESULTS: In total, 56 (53.9%) PDAC expressed CX3CR1, 70 (67.3%) CX3CL1, and 45 (43.3%) both. CX3CR1 expression was independently associated with tumour glandular differentiation (P=0.005) and PNI (P=0.01). Pancreatic Intraepithelial Neoplasias were more frequently CX3CR1+ (80.3%, P<0.001) and CX3CL1+ (86.8%, P=0.002) than matched cancers. The survival of PDAC patients was better in those with CX3CR1+ tumour (P=0.05). Mouse PanINs were also CX3CR1(+) and -CL1(+). In vitro, cytokines significantly increased CX3CL1 but not CX3CR1 expression. Differently, CX3CR1 was upregulated in tumour spheroids, and in vivo only in well-differentiated tumours. CONCLUSION: Tumour differentiation, rather than inflammatory signalling, modulates CX3CR1 expression in PanINs and PDAC. CX3CR1 expression pattern suggests its early involvement in PDAC progression, outlining a potential target for interfering with the PanIN transition to invasive cancer.


Assuntos
Carcinogênese/metabolismo , Neoplasias Pancreáticas/metabolismo , Receptores de Quimiocinas/biossíntese , Animais , Receptor 1 de Quimiocina CX3C , Carcinogênese/genética , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/patologia , Diferenciação Celular/fisiologia , Linhagem Celular Tumoral , Quimiocina CX3CL1/biossíntese , Quimiocina CX3CL1/genética , Modelos Animais de Doenças , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , Receptores de Quimiocinas/genética , Estudos Retrospectivos , Regulação para Cima
3.
Lung Cancer ; 79(3): 236-41, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-23279873

RESUMO

BACKGROUND: The WHO-classification was shown to be an independent prognostic marker in some but not all retrospective studies possibly due to lack of reproducibility. We investigated the reproducibility of the WHO-classification and its prognostic implication using a large series of resected thymomas. METHODS: Four independent pathologists histologically classified a surgical series of 129 thymic tumors in a blinded fashion. Fleiss' kappa-coefficient was used to assess the pathologists' overall agreement, and Cohen-Kappa to assess the agreement between two observers. Disease-related-survival (DRS) and progression-free-survival (PFS) curves were generated by Kaplan-Meier method and compared by log-rank test. RESULTS: In 63/129 (48.8%) cases there was a complete agreement; in 43/129 (33.3%) cases 3/4 pathological diagnoses were identical; in 15/129 (11.6%) cases the diagnoses were identical by pair; in 8/129 (6.2%) cases three different pathological diagnoses were on record. The Kappa-correlation coefficient was only moderate (0.53). A following web review carried out on the 23 cases with at least two different diagnoses reached a complete consensus. The histotype showed a statistically significant impact on PFS and DRS in the classification provided by only two pathologists. CONCLUSIONS: In this study, the agreement on WHO classification of thymomas was only moderate and this impacted on patients management. Web consensus conference on the diagnosis, more stringent diagnostic criteria or the adoption of referral diagnostic centres may substantially reduce discrepancies.


Assuntos
Timoma/classificação , Timoma/patologia , Organização Mundial da Saúde , Adulto , Idoso , Idoso de 80 Anos ou mais , Consenso , Conferências de Consenso como Assunto , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Guias de Prática Clínica como Assunto , Prognóstico , Reprodutibilidade dos Testes , Timoma/mortalidade , Adulto Jovem
4.
Cell Death Dis ; 3: e351, 2012 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-22825469

RESUMO

The molecular pathology of thymic epithelial tumors (TETs) is largely unknown. Using array comparative genomic hybridization (CGH), we evaluated 59 TETs and identified recurrent patterns of copy number (CN) aberrations in different histotypes. GISTIC algorithm revealed the presence of 126 significant peaks of CN aberration, which included 13 cancer-related genes. Among these peaks, CN gain of BCL2 and CN loss of CDKN2A/B were the only genes in the respective regions of CN aberration and were associated with poor outcome. TET cell lines were sensitive to siRNA knockdown of the anti-apoptotic molecules BCL2 and MCL1. Gx15-070, a pan-BCL2 inhibitor, induced autophagy-dependent necroptosis in TET cells via a mechanism involving mTOR pathways, and inhibited TET xenograft growth. ABT263, an inhibitor of BCL2/BCL-XL/BCL-W, reduced proliferation in TET cells when administered in combination with sorafenib, a tyrosine kinase inhibitor able to downregulate MCL1. Immunohistochemistry on 132 TETs demonstrated that CN loss of CDKN2A correlated with lack of expression of its related protein p16(INK4) and identified tumors with poor prognosis. The molecular markers BCL2 and CDKN2A may be of potential value in diagnosis and prognosis of TETs. Our study provides the first preclinical evidence that deregulated anti-apoptotic BCL2 family proteins may represent suitable targets for TET treatment.


Assuntos
Inibidor de Quinase Dependente de Ciclina p15/genética , Inibidor p16 de Quinase Dependente de Ciclina/genética , Neoplasias Epiteliais e Glandulares/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/genética , Neoplasias do Timo/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Algoritmos , Compostos de Anilina/farmacologia , Animais , Proteínas Reguladoras de Apoptose/antagonistas & inibidores , Proteínas Reguladoras de Apoptose/metabolismo , Autofagia/efeitos dos fármacos , Benzenossulfonatos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Hibridização Genômica Comparativa , Inibidor de Quinase Dependente de Ciclina p15/metabolismo , Inibidor p16 de Quinase Dependente de Ciclina/metabolismo , Variações do Número de Cópias de DNA , Feminino , Humanos , Indóis , Masculino , Camundongos , Camundongos Nus , Pessoa de Meia-Idade , Proteína de Sequência 1 de Leucemia de Células Mieloides , Neoplasias Epiteliais e Glandulares/diagnóstico , Neoplasias Epiteliais e Glandulares/patologia , Niacinamida/análogos & derivados , Compostos de Fenilureia , Prognóstico , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-bcl-2/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Piridinas/farmacologia , Pirróis/farmacologia , Interferência de RNA , RNA Interferente Pequeno , Sorafenibe , Sulfonamidas/farmacologia , Serina-Treonina Quinases TOR/metabolismo , Neoplasias do Timo/diagnóstico , Neoplasias do Timo/patologia , Transplante Heterólogo , Proteína bcl-X/antagonistas & inibidores , Proteína bcl-X/metabolismo
5.
Br J Cancer ; 105(10): 1542-53, 2011 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-21970874

RESUMO

BACKGROUND: Although pemetrexed, a potent thymidylate synthase (TS) inhibitor, enhances the cytoytoxic effect of platinum compounds against malignant pleural mesothelioma (MPM), novel combinations with effective targeted therapies are warranted. To this end, the current study evaluates new targeted agents and their pharmacological interaction with carboplatin-pemetrexed in human MPM cell lines. METHODS: We treated H2052, H2452, H28 and MSTO-211H cells with carboplatin, pemetrexed and targeted compounds (gefitinib, erlotinib, sorafenib, vandetanib, enzastaurin and ZM447439) and evaluated the modulation of pivotal pathways in drug activity and cancer cell proliferation. RESULTS: Vandetanib emerged as the compound with the most potent cytotoxic activity, which interacted synergistically with carboplatin and pemetrexed. Drug combinations blocked Akt phosphorylation and increased apoptosis. Vandetanib significantly downregulated epidermal growth factor receptor (EGFR)/Erk/Akt phosphorylation as well as E2F-1 mRNA and TS mRNA/protein levels. Moreover, pemetrexed decreased Akt phosphorylation and expression of DNA repair genes. Finally, most MPM samples displayed detectable levels of EGFR and TS, the variability of which could be used for patients' stratification in future trials with vandetanib-pemetrexed-carboplatin combination. CONCLUSION: Vandetanib markedly enhances pemetrexed-carboplatin activity against human MPM cells. Induction of apoptosis, modulation of EGFR/Akt/Erk phosphorylation and expression of key determinants for pemetrexed and carboplatin activity contribute to this synergistic interaction, and, together with the expression of these determinants in MPM samples, warrant further clinical investigation.


Assuntos
Carboplatina/uso terapêutico , Glutamatos/uso terapêutico , Guanina/análogos & derivados , Mesotelioma/tratamento farmacológico , Piperidinas/uso terapêutico , Neoplasias Pleurais/tratamento farmacológico , Quinazolinas/uso terapêutico , Apoptose/efeitos dos fármacos , Western Blotting , Carboplatina/farmacologia , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Sinergismo Farmacológico , Ensaio de Imunoadsorção Enzimática , Glutamatos/farmacologia , Guanina/farmacologia , Guanina/uso terapêutico , Humanos , Imuno-Histoquímica , Mesotelioma/patologia , Pemetrexede , Fosforilação , Piperidinas/farmacologia , Neoplasias Pleurais/patologia , Reação em Cadeia da Polimerase , Polimorfismo Genético , Proteínas Proto-Oncogênicas c-akt/metabolismo , Quinazolinas/farmacologia
6.
Cell Death Differ ; 18(10): 1608-16, 2011 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-21455220

RESUMO

The simplicity of BCR-ABL 'oncogene addiction' characterizing leukemia contrasts with the complexity of solid tumors where multiple 'core pathways', including receptor tyrosine kinases (RTKs) and p53, are often altered. This discrepancy illustrates the limited success of RTK antagonists in solid tumor treatment compared with the impact of Imatinib in BCR-ABL-dependent leukemia. Here, we identified c-Abl as a signaling node interconnecting Met-RTK and p53 core pathways, and showed that its inhibition impairs Met-dependent tumorigenesis. Met ensures cell survival through a new path in which c-Abl and p38-MAPK are employed to elicit p53 phosphorylation on Ser(392) and Mdm2 upregulation. We found a clinical correlation between activated Met, phospho-p53, and Mdm2 levels in human tumors, supporting the role of this path in tumorigenesis. Our findings introduce the concept that RTK-driven tumors may be therapeutically treated by hitting signaling nodes interconnecting core pathways. Moreover, they underline the importance of evaluating the relevance of c-Abl antagonists for combined therapies, based on the tumor signaling signature.


Assuntos
Proteínas Proto-Oncogênicas c-abl/metabolismo , Proteínas Proto-Oncogênicas c-met/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Animais , Antineoplásicos/uso terapêutico , Benzamidas , Linhagem Celular Tumoral , Imunoprecipitação da Cromatina , Células Hep G2 , Humanos , Mesilato de Imatinib , Camundongos , Mutação , Fosforilação , Piperazinas/uso terapêutico , Ligação Proteica , Proteínas Proto-Oncogênicas c-abl/genética , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , Proteínas Proto-Oncogênicas c-met/genética , Pirimidinas/uso terapêutico , Reação em Cadeia da Polimerase em Tempo Real , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismo , Proteína Supressora de Tumor p53/genética , Ensaios Antitumorais Modelo de Xenoenxerto , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
7.
Pathologica ; 102(3): 93-5, 2010 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-21171511

RESUMO

OBJECTIVE: The diagnosis of follicular tumors of the thyroid mainly rests on the examination of peri-lesional capsule. Lesions with an intact shell are labeled as adenoma, those with capsular invasion are considered carcinoma and those with doubtful aspects are regarded as tumors of uncertain malignant potential. AIM: To better understand the biology of capsular invasion and its practical implication by applying a peculiar three dimension (3-D) reconstruction. METHOD: Two follicular carcinoma (FC) and one follicular tumour of uncertain malignant potential (FT-UMP) were considered. Areas of true/doubtful capsular invasion were labeled using Tissue Micro Array technology and the corresponding paraffin blocks underwent serial sectioning. H&E slides (range 30-100, mean 70) were captured as pictures, aligned using automated method based on the maximization of mutual information and imported into a 3-D image processing software (AMIRA). RESULTS: The 3-D reconstruction revealed that capsular openings were oval shaped and sized approximately equal to 100-200 microm. In one FC the hole was entirely engaged by a tumor mass. In the remaining cases (1 FC and 1 FT-UMP) the 3-D reconstruction showed a small feeding vessel (approximately equal to 50 micro) passing through the capsule together with the bulge of the lesion [see 3-D reconstruction at http://www.ibfm. cnr.it/ricerca/inv_cap.php]. CONCLUSIONS: Our approach allows a better spatial reconstruction of the exact point of capsular interruption; the results obtained suggest that capsular invasion can be due either by abruptly interruption of the shell or by a protrusion along the path of a small feeding vessel.


Assuntos
Adenocarcinoma Folicular/patologia , Imageamento Tridimensional/métodos , Neoplasias da Glândula Tireoide/patologia , Análise Serial de Tecidos/métodos , Humanos , Processamento de Imagem Assistida por Computador
8.
Ann Oncol ; 21(3): 562-567, 2010 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-19767315

RESUMO

BACKGROUND: The purpose of this study is to investigate the prognostic role of insulin-like growth factor receptor 1 (IGF1R) expression in surgically resected non-small-cell lung cancer (NSCLC). Patient characteristics and methods: This retrospective study was conducted in 369 stage I-II-IIIA, surgically resected, NSCLC patients. Patients exposed to anti-epidermal growth factor receptor (EGFR) agents were excluded. IGF1R expression was evaluated by immunohistochemistry in tissue microarray sections. RESULTS: A positive IGF1R expression (score > or = 100) was observed in 282 cases (76.4%) and was significantly associated with squamous cell histology (P = 0.04) and with grade III differentiation (P = 0.02). No difference in survival was observed between the positive and negative group when score 100 was used as cut-off for discriminating a positive versus a negative IGF1R result (52 versus 48 months, P = 0.99) or when median value of IGF1R expression was used (45 versus 55 months, P = 0.36). No difference in survival was observed between IGF1R-positive and -negative patients in a subgroup of stage I-II adenocarcinoma (n = 137) with known EGFR mutation and copy number status. CONCLUSIONS: IGF1R expression does not represent a prognostic factor in resected NSCLC patients. Patients with squamous cell carcinoma overexpress IGF1R more frequently than patients with nonsquamous histology, justifying the different sensitivity to anti-IGF1R agents observed in clinical trials.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/mortalidade , Receptor IGF Tipo 1/metabolismo , Adenocarcinoma/metabolismo , Adenocarcinoma/mortalidade , Adenocarcinoma/cirurgia , Adenocarcinoma Bronquioloalveolar/metabolismo , Adenocarcinoma Bronquioloalveolar/mortalidade , Adenocarcinoma Bronquioloalveolar/cirurgia , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Pulmonar de Células não Pequenas/cirurgia , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/mortalidade , Carcinoma de Células Escamosas/cirurgia , Estudos de Coortes , Feminino , Humanos , Técnicas Imunoenzimáticas , Neoplasias Pulmonares/cirurgia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Estudos Retrospectivos , Taxa de Sobrevida , Análise Serial de Tecidos , Resultado do Tratamento
9.
Ann Oncol ; 21(6): 1228-1232, 2010 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-19875751

RESUMO

BACKGROUND: Breast cancer micrometastases are frequently found during pathological examination of sentinel lymph nodes and complete axillary lymph node dissection. Despite this, their clinical relevance is still debated. The aim of this study is to investigate features that affect disease-free survival (DFS) and overall survival (OS) in patients with nodal micrometastases from breast cancer. MATERIAL AND METHODS: We retrospectively investigated the outcome of 122 patients with nodal micrometastases from breast cancer followed up for 60 months. RESULTS: At univariate analysis, worse DFS was related to features of primary tumor (multifocality P = 0.002; size >2 cm, P = 0.022; grade P = 0.022; absence of estrogen P < 0.001 and progesterone P < 0.001 receptors; HER-2 overexpression P = 0.006; vascular invasion P = 0.039; proliferative fraction > or =20% P = 0.034) and micrometastases (sinusal localization P = 0.010). Among the above-mentioned features, two were strongly associated with worse DFS in the multivariate model, i.e. negative receptorial status [hazard ratio (HR) = 11.24, 95% confidence interval (CI) 4.06-31.09; P < 0.001] and sinusal localization of micrometastasis (HR = 3.66, 1.18-11.36; P = 0.025). The OS was influenced by multifocality (P < 0.001) and receptor status (P = 0.005). CONCLUSION: Our results indicate that in patients affected by breast cancer, in addition to the well-known pathological features of primary tumor, sinusal localization of micrometastasis strongly impacts on the prognosis.


Assuntos
Neoplasias da Mama/diagnóstico , Neoplasias da Mama/patologia , Carcinoma/diagnóstico , Carcinoma/patologia , Linfonodos/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/mortalidade , Carcinoma/mortalidade , Feminino , Humanos , Metástase Linfática , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Análise de Sobrevida , Distribuição Tecidual , Carga Tumoral
10.
Breast ; 18(4): 263-6, 2009 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-19682903

RESUMO

T1N0M0 (stage I) breast cancer (BC) has been increasing in recent decades but the optimal adjuvant approach remains controversial. To assess the outcome of BC patients stratified and treated with multimodal therapies according to St. Gallen consensus meeting recommendations, we retrospectively evaluated an unselected cohort of T1N0M0 BC patients, with respect to the St. Gallen criteria. At a median follow-up of 5 years, the recurrence rate, recurrence-free survival and overall survival were 7%, 94% and 96% respectively, and 60% of relapses were locoregional. No statistically significant difference was observed between T1a,b/T1c groups, or among risk categories (high/intermediate/low). The very low rate of distant recurrences even in patients with unfavorable prognostic factors seems to support the use of adjuvant systemic therapies but better prognostic and predictive factors are strongly needed for this subset of patients.


Assuntos
Neoplasias da Mama/terapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Neoplasias da Mama/cirurgia , Terapia Combinada , Feminino , Humanos , Estimativa de Kaplan-Meier , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/epidemiologia , Estadiamento de Neoplasias , Prognóstico , Estudos Retrospectivos , Medição de Risco , Análise de Sobrevida
11.
Ann Oncol ; 20(2): 298-304, 2009 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-18836087

RESUMO

BACKGROUND: MET amplification has been detected in approximately 20% of non-small-cell lung cancer patients (NSCLC) with epidermal growth factor receptor (EGFR) mutations progressing after an initial response to tyrosine kinase inhibitor (TKI) therapy. PATIENTS AND METHODS: We analyzed MET gene copy number using FISH in two related NSCLC cell lines, one sensitive (HCC827) and one resistant (HCC827 GR6) to gefitinib therapy and in two different NSCLC patient populations: 24 never smokers or EGFR FISH-positive patients treated with gefitinib (ONCOBELL cohort) and 182 surgically resected NSCLC not exposed to anti-EGFR agents. RESULTS: HCC827 GR6-resistant cell line displayed MET amplification, with a mean MET copy number >12, while sensitive HCC827 cell line had a mean MET copy number of 4. In the ONCOBELL cohort, no patient had gene amplification and MET gene copy number was not associated with outcome to gefitinib therapy. Among the surgically resected patients, MET was amplified in 12 cases (7.3%) and only four (2.4%) had a higher MET copy number than the resistant HCC827 GR6 cell line. CONCLUSIONS: MET gene amplification is a rare event in patients with advanced NSCLC. The development of anti-MET therapeutic strategies should be focused on patients with acquired EGFR-TKI resistance.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/genética , Dosagem de Genes , Neoplasias Pulmonares/genética , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas/genética , Quinazolinas/uso terapêutico , Receptores de Fatores de Crescimento/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/cirurgia , Linhagem Celular Tumoral , Ensaios Clínicos Fase II como Assunto , Estudos de Coortes , Progressão da Doença , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Gefitinibe , Regulação Neoplásica da Expressão Gênica , Genes erbB-1/efeitos dos fármacos , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/cirurgia , Masculino , Pessoa de Meia-Idade , Proteínas Proto-Oncogênicas c-met , Análise de Sobrevida
12.
Br J Cancer ; 99(1): 83-9, 2008 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-18577988

RESUMO

The impact of KRAS mutations on cetuximab sensitivity in epidermal growth factor receptor fluorescence in situ hybridisation-positive (EGFR FISH+) metastatic colorectal cancer patients (mCRC) has not been previously investigated. In the present study, we analysed KRAS, BRAF, PI3KCA, MET, and IGF1R in 85 mCRC treated with cetuximab-based therapy in whom EGFR status was known. KRAS mutations (52.5%) negatively affected response only in EGFR FISH+ patients. EGFR FISH+/KRAS mutated had a significantly lower response rate (P=0.04) than EGFR FISH+/KRAS wild type patients. Four EGFR FISH+ patients with KRAS mutations responded to cetuximab therapy. BRAF was mutated in 5.0% of patients and none responded to the therapy. PI3KCA mutations (17.7%) were not associated to cetuximab sensitivity. Patients overexpressing IGF1R (74.3%) had significantly longer survival than patients with low IGF1R expression (P=0.006), with no difference in response rate. IGF1R gene amplification was not detected, and only two (2.6%) patients, both responders, had MET gene amplification. In conclusion, KRAS mutations are associated with cetuximab failure in EGFR FISH+ mCRC, even if it does not preclude response. The rarity of MET and IGF1R gene amplification suggests a marginal role in primary resistance. The potential prognostic implication of IGF1R expression merits further evaluation.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Resistencia a Medicamentos Antineoplásicos/genética , Receptores ErbB/genética , Proteínas Proto-Oncogênicas/genética , Proteínas ras/genética , Anticorpos Monoclonais Humanizados , Antineoplásicos/uso terapêutico , Cetuximab , Feminino , Humanos , Hibridização in Situ Fluorescente , Masculino , Pessoa de Meia-Idade , Proteínas Nucleares/genética , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas c-met , Proteínas Proto-Oncogênicas p21(ras) , Receptores de Fatores de Crescimento/genética , Receptores de Somatomedina/genética , Fatores de Transcrição/genética
13.
Ann Oncol ; 19(9): 1605-12, 2008 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-18467317

RESUMO

BACKGROUND: Approximately 10% of unselected non-small-cell lung cancer (NSCLC) patients responded to the epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) treatment. However, resistance mechanisms are not well understood. We evaluated several potential biological markers of intrinsic EGFR-TKIs-resistance in NSCLC. MATERIALS AND METHODS: pAKT, pERK, cSRC, E-cadherin, cMET[pY1003], cMET[pY1230/1234/1235], and cMET[pY1349] immunohistochemistry, cMET FISH analysis, and EGFR-, KRAS-, and cMET mutation analysis were carried out on tumor samples from 51 gefitinib-treated NSCLC patients. Biological parameters and survival end points were compared by univariate and multivariate analyses. cMET expression was also investigated in two additional series of patients. The in vitro antiproliferative activity of gefitinib alone or in combination with hepatocyte growth factor and the cMET antibody DN-30 was assessed in NSCLC cells. RESULTS: EGFR19 deletion and pAKT expression were significantly associated with response (P < 0.0001) and longer time to progression (TTP) (P = 0.007), respectively. Strong cMET[pY1003] membrane immunoreactivity was expressed in 6% of 149 tumors analyzed and was significantly associated with progressive disease (P = 0.019) and shorter TTP (P = 0.041). In vitro, the DN-30 combination synergistically (CI < 1) enhanced gefitinib-induced growth inhibition in all cMET[pY1003]-expressing cell lines studied. CONCLUSIONS: Activated cMET[pY1003] appears to be a marker of primary gefitinib resistance in NSCLC patients. cMET may be a target in treatment of NSCLC.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Proteínas Tirosina Quinases/genética , Quinazolinas/administração & dosagem , Idoso , Biópsia por Agulha , Western Blotting , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Estudos de Coortes , Resistencia a Medicamentos Antineoplásicos , Ensaios de Seleção de Medicamentos Antitumorais , Receptores ErbB/antagonistas & inibidores , Feminino , Gefitinibe , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Imuno-Histoquímica , Hibridização in Situ Fluorescente , Estimativa de Kaplan-Meier , Neoplasias Pulmonares/mortalidade , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Mutação/efeitos dos fármacos , Estadiamento de Neoplasias , Probabilidade , Modelos de Riscos Proporcionais , Inibidores de Proteínas Quinases/administração & dosagem , Proteínas Tirosina Quinases/efeitos dos fármacos , Análise de Sobrevida , Resultado do Tratamento
14.
Ann Oncol ; 19(4): 717-23, 2008 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-17974556

RESUMO

BACKGROUND: Standardized conditions to distinguish subpopulations of colorectal cancer (CRC) patients more and less sensitive to cetuximab therapy remain undefined. MATERIALS AND METHODS: We retrospectively analyzed epidermal growth factor receptor (EGFR) copy number by fluorescence in situ hybridization (FISH) in paraffin-embedded tumor blocks from 85 chemorefractory CRC patients treated with cetuximab. Results were analyzed according to different score systems previously reported in colorectal and lung cancers. The primary end point of the study was identification of the EGFR FISH score that best associates with response rate (RR). RESULTS: Using receiver operating characteristic (ROC) analysis, the cut-off that best discriminated responders versus nonresponders to cetuximab was a mean of 2.92 EGFR gene copies per cell. This model showed sensitivity of 58.6% [95% confidence interval (CI) = 47.1-70.1) and specificity of 93.3% (95% CI = 80.6-100). EGFR FISH-positive patients (N = 43, 50.6%) had significantly higher RR (P = 0.0001) and significantly longer time to disease progression (P = 0.02) than EGFR FISH negative (N = 42, 49.4%). Other scoring systems resulted less accurate in discriminating patients with the highest likelihood of response to cetuximab therapy. CONCLUSIONS: CRC patients with high EGFR gene copy number have an increased likelihood to respond to cetuximab therapy. Prospective clinical trials with a careful standardization of assay conditions and pattern interpretation are urgently needed.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Antineoplásicos/uso terapêutico , Biomarcadores Tumorais/análise , Neoplasias Colorretais/química , Neoplasias Colorretais/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos , Receptores ErbB/análise , Hibridização in Situ Fluorescente , Adulto , Idoso , Anticorpos Monoclonais Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais/genética , Cetuximab , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Intervalos de Confiança , Intervalo Livre de Doença , Receptores ErbB/genética , Feminino , Humanos , Imuno-Histoquímica , Itália , Masculino , Pessoa de Meia-Idade , Seleção de Pacientes , Valor Preditivo dos Testes , Curva ROC , Estudos Retrospectivos , Sensibilidade e Especificidade , Análise de Sobrevida , Resultado do Tratamento
15.
Horm Metab Res ; 39(11): 781-9, 2007 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-17992631

RESUMO

AOX1, a member of the cytosolic molybdenum hydroxylase family, has been identified by us earlier as an ABCA1-interacting protein. AOX1 is well-described as xenobiotic metabolizing enzyme, which upon oxidation of acetaldehyde and retinaldehyde to acetic acid and retinoic acid generates reactive oxygen species. Here we show that knock-down of AOX1 in HepG2 by small interfering RNA significantly reduced ABCA1-dependent lipid efflux and enhanced phagocytic uptake of microspheres similar to ABCA1 deficiency, without affecting ABCA1 mRNA and protein levels. ABCA1 and AOX1 are coexpressed in human hepatocytes, kidney proximal tubular epithelial cells, Leydig, and adrenocortical cells. Expression of ABCA1 and AOX1 was investigated by immunohistochemistry in liver tissue arrays. A strong AOX1 expression was found in normal liver, and in cirrhosis. In contrast, hepatocellular carcinomas showed either a complete loss or reduced expression of AOX1. Significant correlations were found between reduced AOX1 expression and tumor stage, or metastatic or regional lymph node states. Deregulation was also observed for ABCA1 expression but to a lesser extent. Our findings show that the interaction of ABCA1 with AOX1 modulates ABCA1-linked cellular functions such as lipid efflux and phagocytosis in hepatocytes, and the reduced expression of AOX1 in malignant transformed hepatocytes supports the differentiation dependent upregulation of AOX1.


Assuntos
Transportadores de Cassetes de Ligação de ATP/metabolismo , Aldeído Oxidase/metabolismo , Carcinoma Hepatocelular/enzimologia , Hepatócitos/metabolismo , Transportador 1 de Cassete de Ligação de ATP , Transportadores de Cassetes de Ligação de ATP/genética , Aldeído Oxidase/genética , Linhagem Celular , Linhagem Celular Tumoral , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Ácidos Graxos/metabolismo , Biblioteca Gênica , Inativação Gênica/fisiologia , Hepatócitos/enzimologia , Hepatócitos/patologia , Humanos , RNA Mensageiro/análise , RNA Interferente Pequeno/fisiologia , Transdução de Sinais/fisiologia , Estatísticas não Paramétricas , Distribuição Tecidual
16.
Pathologica ; 99(3): 76-80, 2007 Jun.
Artigo em Italiano | MEDLINE | ID: mdl-17987727

RESUMO

We report an unusual case of primary angiosarcoma of the nasal cavity (AS-nc). Clinical--monolateral epistaxis in a young person--, radiological--polypoid hemorrhagic tumor arising within the nasal cavity and expanding into paranasal sinuses--, pathological--a network of anastomosing channels and solid areas immunoreactive for CD31 and CD34--and prognostic features--patient alive and well 36 months after the original diagnosis--are superimposable to those of previously reported AS-nc, suggesting that this lesion should be considered as a peculiar variant of classical AS.


Assuntos
Hemangiossarcoma/patologia , Cavidade Nasal , Neoplasias Nasais/patologia , Feminino , Hemangiossarcoma/cirurgia , Humanos , Imageamento por Ressonância Magnética , Pessoa de Meia-Idade , Cavidade Nasal/patologia , Cavidade Nasal/cirurgia , Neoplasias Nasais/cirurgia
17.
Br J Cancer ; 95(8): 1101-7, 2006 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-16969349

RESUMO

Colorectal cancer (CRC) develops as multistep process, which involves genetic and epigenetic alterations. K-Ras, p53 and B-Raf mutations and RASSF1A, E-Cadherin and p16INK4A promoter methylation were investigated in 202 CRCs with and without lymph node and/or liver metastasis, to assess whether gene abnormalities are related to a metastogenic phenotype. K-Ras, B-Raf and p53 mutations were detected in 27, 3 and 32% of the cases, with K-Ras mutations significantly associated with metastatic tumour (P=0.019). RASSF1A, E-Cadherin and p16INK4A methylation was documented in 20, 44 and 33% of the cases with p16INK4A significantly associated with metastatic tumours (P=0.001). Overall, out of 202 tumours, 34 (17%) did not show any molecular change, 125 (62%) had one or two and 43 (21%) three or more. Primary but yet metastatic CRCs were prevalent in the latter group (P=0.023) where the most frequent combination was one genetic (K-Ras in particular) and two epigenetic alterations. In conclusion, this analysis provided to detect some molecular differences between primary metastatic and nonmetastatic CRCs, with K-Ras and p16INK4A statistically altered in metastatic tumours; particular gene combinations, such as coincidental K-Ras mutation with two methylated genes are associated to a metastogenic phenotype.


Assuntos
Neoplasias Colorretais/genética , Metilação de DNA , Mutação/genética , Idoso , Idoso de 80 Anos ou mais , Caderinas/genética , Neoplasias Colorretais/patologia , Inibidor p16 de Quinase Dependente de Ciclina/genética , Análise Mutacional de DNA , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Metástase Neoplásica , Polimorfismo Conformacional de Fita Simples , Regiões Promotoras Genéticas/genética , Proteínas Proto-Oncogênicas B-raf/genética , Proteína Supressora de Tumor p53/genética , Proteínas Supressoras de Tumor/genética , Proteínas ras/genética
18.
Aliment Pharmacol Ther ; 24(5): 797-804, 2006 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-16918883

RESUMO

BACKGROUND: Biopsy is the gold standard for assessing cirrhosis in patients with chronic hepatitis C virus infection, but it is expensive and at risk of complications. Alternative non-invasive methods have been developed but their usefulness remains uncertain. AIM: To compare the accuracy of five non-invasive scores in detecting cirrhosis. METHODS: We reviewed the charts and liver biopsies of 228 consecutive, treatment-naïve, hepatitis C virus-positive patients, 13.2% of whom with histological diagnosis of cirrhosis. The five alternative scores were age-platelet index, cirrhosis discriminant score, aspartate transaminases to platelet ratio index, Pohl's index, and aspartate transaminases/alanine transaminases ratio. RESULTS: The specificities of the scores were good (87-100%), but not so their sensitivities (17-67%). Accordingly positive likelihood ratios were generally good but negative likelihood ratios were suboptimal. Combinations of the scores independently related to cirrhosis only slightly change this diagnostic accuracy. Using double cut-offs to exclude/diagnoses cirrhosis, cirrhosis discriminant score classified 21% of patients without misdiagnoses and aspartate transaminases to platelet ratio index classified 85% of case with 9% of misdiagnoses. CONCLUSIONS: The five scores showed variable sensitivities and specificities in detecting liver cirrhosis, both individually and in combination. The use of double cut-off points may make the cirrhosis discriminant score and aspartate transaminases to platelet ratio index useful to reduce the number of patients submitted to liver biopsy.


Assuntos
Testes Diagnósticos de Rotina/métodos , Hepatite C Crônica/complicações , Cirrose Hepática/diagnóstico , Adolescente , Adulto , Idoso , Alanina Transaminase/sangue , Aspartato Aminotransferases/sangue , Bilirrubina/sangue , Feminino , Hepatite C Crônica/sangue , Humanos , Cirrose Hepática/sangue , Cirrose Hepática/virologia , Testes de Função Hepática , Masculino , Pessoa de Meia-Idade , Contagem de Plaquetas , Valor Preditivo dos Testes , Tempo de Protrombina , Estudos Retrospectivos , Sensibilidade e Especificidade , gama-Glutamiltransferase/sangue
19.
Lung Cancer ; 51(2): 207-15, 2006 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-16384623

RESUMO

The epidermal growth factor receptor (EGFR) is overexpressed in many epithelial malignancies, against which some antitumoral drugs have been developed. There is a lack of information as to EGFR expression in malignant pleural mesothelioma (MPM), an aggressive and fatal cancer poorly responsive to current oncological treatments. Our aim was to: (a) compare EGFR immunohistochemical expression with mRNA levels measured by real time PCR; (b) assess the relationships between EGFR expression and clinico-pathological data including survival; (c) analyze the EGFR mutations. We developed an immunohistochemical method of EGFR evaluation based on the number of immunoreactive cells and staining intensity in 61 MPMs. EGFR immunoreactivity was documented in 34/61 (55.7%) cases. A significant correlation between EGFR protein and mRNA levels (p = 0.0077) was found, demonstrating the reliability of our quantification method of EGFR membrane expression. Radically resected patients (p = 0.005) and those with epithelial histotype (p = 0.048) showed an increased survival. No statistical correlation between EGFR immunoreactivity and patients survival was observed. No EGFR mutation was documented. This study documents EGFR overexpression in MPM at the protein and the transcriptional levels; it proposes a reliable method for EGFR expression evaluation in MPM. EGFR levels are not associated with clinico-pathological features of patients, including survival.


Assuntos
Receptores ErbB/análise , Mesotelioma/química , Neoplasias Pleurais/química , Adulto , Idoso , Cromatografia Líquida de Alta Pressão , Receptores ErbB/genética , Feminino , Humanos , Imuno-Histoquímica , Masculino , Mesotelioma/patologia , Pessoa de Meia-Idade , Mutação , Neoplasias Pleurais/patologia , RNA Mensageiro/análise
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