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1.
Int J Clin Pract ; : e13235, 2018 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-30011112

RESUMO

BACKGROUND AND PURPOSE: Appropriate surveillance guidelines for patients after successful treatment of Hodgkin's lymphoma (HL) are needed to reduce mortality of iatrogenic secondary cancers (SC). This large single institutional retrospective study analyses the risk of SC in HL patients treated outside of clinical trials over past decades. MATERIAL AND METHODS: Consecutive series of HL patients were analysed with median follow-up 12 years. Standardised incidence ratio (SIR) and absolute excess risk (AER) were calculated for site-specific risk of SC. RESULTS: In total of 871 patients (491 men; median age 34 years), chemotherapy alone, radiotherapy alone, and combined treatment underwent 36%, 40%, and 24% patients. 154 SC were found with significantly increased SIR = 2.9 and AER = 80.8 for all cancers except of nonmelanoma-skin cancer. SC-related death occurred in 71 patients (15% of those who died, 8% of whole cohort). The most common SC were lung (17.5% of all malignancies, SIR = 3.2), breast carcinoma (15.6%, SIR = 4.4), and haematological malignancy (non-Hodgkin's lymphoma SIR = 13.1; leukaemia SIR = 5.8). For SC within radiation field, the highest AER was in breast (AER = 46.9), colorectal (AER = 22.8), and lung cancer (AER = 17). CONCLUSIONS: Patients with HL are generally at great risk of developing SC, which is significantly increased especially by the use of radiotherapy. We suggested special follow-up schema for patients after initial HL treatment suitable for daily real-world clinical practice. The system depends on gender, form of HL treatment and especially the form of radiation therapy in terms of location of radiation fields.

2.
Klin Onkol ; 31(5): 380-383, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30541326

RESUMO

INTRODUCTION: Exon 18-T719X EGFR mutation in non-small cell lung cancer is rare, only 1-5% of all EGFR mutations. The efficacy of EGFR tyrosin kinase inhibitors in tumours with uncommon mutations is still unclear and the prediction of response of such tumours to therapy remains unexplored. CASE: A 71-year-old woman with no previous smoking history with disseminated lung adenocarcinoma with exon 18-T719X EGFR mutation was treated with afatinib. A partial response was achieved in 2 months, progression-free survival was 19 months. The dose of afatinib was reduced to 30mg/day after 3 months due to skin toxicity and stomatitis grade 2. Next reduction to 20mg/day was performed after 10 subsequent months due to leucopenia and neutropenia grade 2. CONCLUSION: With this patient, a partial response which lasted 19 months despite 50% reduction of the afatinib dose was achieved. Key words: afatinib - non-small cell lung cancer - epidermal growth factor-mutation receptor - treatment outcome - drug toxicity This article was supported by Boehringer Ingelheim. The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study. The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers. Submitted: 27. 9. 2018 Accepted: 1. 10. 2018.


Assuntos
Adenocarcinoma de Pulmão/tratamento farmacológico , Antineoplásicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Adenocarcinoma de Pulmão/genética , Afatinib , Idoso , Carcinoma Pulmonar de Células não Pequenas/genética , Intervalo Livre de Doença , Receptores ErbB/genética , Éxons , Feminino , Humanos , Neoplasias Pulmonares/genética , Mutação , Resultado do Tratamento
3.
BMC Cancer ; 17(1): 880, 2017 12 21.
Artigo em Inglês | MEDLINE | ID: mdl-29268716

RESUMO

BACKGROUND: It is well known that patient characteristics and survival outcomes in randomized trials may not necessarily be similar to those in real-life clinical practice. The aim of the present study was to analyse second line treatment strategies in the real-world practice and to estimate the outcomes of patients treated with second-line targeted therapy for metastatic renal cell carcinoma (mRCC). METHODS: This is a retrospective, registry-based study using data from the national registry of targeted therapies for mRCC. The RENIS registry contains data on 3049 patients who started the therapy with at least one targeted agent before 31 December, 2014. Of these patients, 1029 had a record of at least two different targeted therapies and sufficient data for analysis. Survival analysis was carried out using the Kaplan-Meier method. Statistical significance of differences in survival between subgroups was assessed using the log-rank test. RESULTS: The median overall survival from the start of second-line treatment was 17.0 months (95% confidence interval [CI] 14.5-19.5 months), 17.1 months (95% CI 14.5-19.8), and 15.4 months (95% CI 11.0-19.7) for second-line everolimus, sorafenib, and sunitinib, respectively. Patients receiving second-line everolimus were older at the start of second-line treatment, more likely to have metachronous disease, and less likely to be previously treated with cytokines or to continue to third-line treatment than patients treated with second-line sunitinib or sorafenib. Progression-free survival (PFS) correlated with PFS on first-line treatment only for everolimus. CONCLUSIONS: In this retrospective study, no significant differences in survival were observed between the cohorts treated with different second-line agents including everolimus, sorafenib, and sunitinib.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Papilar/secundário , Carcinoma de Células Renais/patologia , Neoplasias Renais/secundário , Terapia de Alvo Molecular , Sistema de Registros/estatística & dados numéricos , Terapia de Salvação , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Papilar/tratamento farmacológico , Carcinoma de Células Renais/tratamento farmacológico , Feminino , Seguimentos , Humanos , Neoplasias Renais/tratamento farmacológico , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida
4.
Mol Cell Proteomics ; 14(7): 1814-30, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25903579

RESUMO

Current prognostic factors are insufficient for precise risk-discrimination in breast cancer patients with low grade breast tumors, which, in disagreement with theoretical prognosis, occasionally form early lymph node metastasis. To identify markers for this group of patients, we employed iTRAQ-2DLC-MS/MS proteomics to 24 lymph node positive and 24 lymph node negative grade 1 luminal A primary breast tumors. Another group of 48 high-grade tumors (luminal B, triple negative, Her-2 subtypes) was also analyzed to investigate marker specificity for grade 1 luminal A tumors. From the total of 4405 proteins identified (FDR < 5%), the top 65 differentially expressed together with 30 previously identified and control markers were analyzed also at transcript level. Increased levels of carboxypeptidase B1 (CPB1), PDZ and LIM domain protein 2 (PDLIM2), and ring finger protein 25 (RNF25) were associated specifically with lymph node positive grade 1 tumors, whereas stathmin 1 (STMN1) and thymosin beta 10 (TMSB10) associated with aggressive tumor phenotype also in high grade tumors at both protein and transcript level. For CPB1, these differences were also observed by immunohistochemical analysis on tissue microarrays. Up-regulation of putative biomarkers in lymph node positive (versus negative) luminal A tumors was validated by gene expression analysis of an independent published data set (n = 343) for CPB1 (p = 0.00155), PDLIM2 (p = 0.02027) and RELA (p = 0.00015). Moreover, statistically significant connections with patient survival were identified in another public data set (n = 1678). Our findings indicate unique pro-metastatic mechanisms in grade 1 tumors that can include up-regulation of CPB1, activation of NF-κB pathway and changes in cell survival and cytoskeleton. These putative biomarkers have potential to identify the specific minor subpopulation of breast cancer patients with low grade tumors who are at higher than expected risk of recurrence and who would benefit from more intensive follow-up and may require more personalized therapy.


Assuntos
Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Carboxipeptidase B/metabolismo , Perfilação da Expressão Gênica/métodos , NF-kappa B/metabolismo , Proteômica/métodos , Biomarcadores Tumorais/genética , Bases de Dados de Proteínas , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Imuno-Histoquímica , Marcação por Isótopo , Estimativa de Kaplan-Meier , Gradação de Tumores , Metástase Neoplásica , Reprodutibilidade dos Testes
5.
Carcinogenesis ; 37(10): 941-950, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27485599

RESUMO

Early detection of colorectal cancer is the main prerequisite for successful treatment and reduction of mortality. Circulating microRNAs were previously identified as promising diagnostic, prognostic and predictive biomarkers. The purpose of this study was to identify serum microRNAs enabling early diagnosis and prognosis prediction of colon cancer. In total, serum samples from 427 colon cancer patients and 276 healthy donors were included in three-phase biomarker study. Large-scale microRNA expression profiling was performed using Illumina small RNA sequencing. Diagnostic and prognostic potential of identified microRNAs was validated on independent training and validation sets of samples using RT-qPCR. Fifty-four microRNAs were found to be significantly deregulated in serum of colon cancer patients compared to healthy donors (P < 0.01). A diagnostic four-microRNA signature consisting of miR-23a-3p, miR-27a-3p, miR-142-5p and miR-376c-3p was established (AUC = 0.917), distinguishing colon cancer patients from healthy donors with sensitivity of 89% and specificity of 81% (AUC = 0.922). This panel of microRNAs exhibited high diagnostic performance also when analyzed separately in colon cancer patients in early stages of the disease (T1-4N0M0; AUC = 0.877). Further, a prognostic panel based on the expression of miR-23a-3p and miR-376c-3p independent of TNM stage was established (HR 2.30; 95% CI 1.44-3.66; P < 0.0004). In summary, highly sensitive signatures of circulating microRNAs enabling non-invasive early detection and prognosis prediction of colon cancer were identified.


Assuntos
Biomarcadores Tumorais/sangue , Neoplasias do Colo/sangue , MicroRNAs/sangue , Idoso , Neoplasias do Colo/genética , Neoplasias do Colo/patologia , Detecção Precoce de Câncer , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico
6.
Invest New Drugs ; 33(5): 1123-32, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26205069

RESUMO

BACKGROUND: Ovarian cancer is the seventh-most common cancer amongst women and the most deadly gynecologic cancer. Cisplatin based drugs are used in first line therapy, but resistance represents a major obstacle for successful treatment. In this study, we investigated the anticancer effects and mechanism of action of three titanocene difluorides, two bearing a pendant carbohydrate moiety (α-D-ribofuranos-5-yl) on their periphery and one without any substitution. RESULTS: The efficacy of these compounds on ovarian cancer cell lines was evaluated in relation to their particular chemical structure and compared with cisplatin as the most common treatment modality for this type of cancer. The typical mechanism of cisplatin action involves DNA damage, activation of p53 protein and induction of cell death, as previously described for titanium ions. Nevertheless, our data indicate that the effect of titanocene difluoride derivatives is mediated via the endoplasmic reticulum stress pathway and autophagy. CONCLUSION: We anticipate that the presence of substituents on cyclopentadienyl ring(s) might play an important role in modulation of the activity of particular compounds. Titanocene difluorides exert comparable cytotoxic activity as cisplatin and are more efficient in cisplatin-resistant cell lines. Our results suggest potential utilization of these compounds especially in the treatment of cisplatin-resistant tumor cells.


Assuntos
Compostos Organometálicos/química , Compostos Organometálicos/farmacologia , Neoplasias Ovarianas/tratamento farmacológico , Autofagia/efeitos dos fármacos , Western Blotting , Ciclo Celular , Linhagem Celular Tumoral , Proliferação de Células , Dano ao DNA/efeitos dos fármacos , Feminino , Humanos , Estresse Oxidativo/efeitos dos fármacos , Relação Estrutura-Atividade , Proteína Supressora de Tumor p53/biossíntese
7.
BMC Gastroenterol ; 15: 37, 2015 Mar 24.
Artigo em Inglês | MEDLINE | ID: mdl-25888291

RESUMO

BACKGROUND: The aim of the present retrospective study was to analyze clinical outcome and risk factors associated with treatment outcomes according to KRAS status in patient with metastatic colorectal cancer (mCRC) treated with bevacizumab (bev) plus chemotherapy in the first-line setting. METHODS: We performed observational study on 1622 patients with mCRC treated with bev plus oxaliplatin- or irinotecan-based chemotherapy, and correlated treatment outcomes with KRAS mutation status. The primary endpoint was progression-free survival (PFS) and additionally overall survival (OS). Adverse events of bevacizumab and risk factors including location of metastases were evaluated. RESULTS: Mutation in KRAS was present in 40.6% of mCRC cases. The median PFS in patients with wild-type KRAS (wtKRAS) vs mutant KRAS was 11.5 vs 11.4 months, respectively. The median OS was 30.7 vs 28.4 months (p = 0.312). Patients with KRAS mutation had lung metastases more frequently than wtKRAS individuals (32.0% vs 23.8%; p = 0.001). We observed no difference in clinical outcome between hepatic and extrahepatic metastatic disease. CONCLUSION: KRAS mutation does not interfere with clinical benefit from first-line treatment with bevacizumab plus chemotherapy in mCRC patients.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Bevacizumab/administração & dosagem , Neoplasias Colorretais/genética , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Proteínas Proto-Oncogênicas/genética , Proteínas ras/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Bevacizumab/efeitos adversos , Camptotecina/administração & dosagem , Camptotecina/análogos & derivados , Camptotecina/uso terapêutico , Capecitabina , Neoplasias Colorretais/patologia , Desoxicitidina/análogos & derivados , Desoxicitidina/uso terapêutico , Intervalo Livre de Doença , Feminino , Fluoruracila/análogos & derivados , Fluoruracila/uso terapêutico , Humanos , Irinotecano , Leucovorina/uso terapêutico , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/secundário , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/secundário , Masculino , Pessoa de Meia-Idade , Mutação , Compostos Organoplatínicos/administração & dosagem , Compostos Organoplatínicos/uso terapêutico , Oxaliplatina , Oxaloacetatos , Proteínas Proto-Oncogênicas p21(ras) , Estudos Retrospectivos , Taxa de Sobrevida , Adulto Jovem
8.
Future Oncol ; 11(2): 225-32, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25591837

RESUMO

AIM: This retrospective analysis investigated the effectiveness of combination therapy with bevacizumab and chemotherapy in the first-line treatment of patients with KRAS wild-type metastatic colorectal cancer. PATIENTS & METHODS: Patients with KRAS wild-type metastatic colorectal cancer in the CORECT registry who initiated treatment with bevacizumab between 2008 and 2012 were enrolled. Overall survival and progression-free survival were the main effectiveness end points. RESULTS: A total of 981 patients were enrolled. Median progression-free survival was 11.3 months (95% CI: 10.7-11.8) and median overall survival was 28.4 months (95% CI: 26.2-30.6). The most common adverse events were thromboembolic disease (4%) and hypertension (3.5%). CONCLUSION: This retrospective analysis shows the effectiveness of bevacizumab with chemotherapy in patients with KRAS wild-type metastatic colorectal cancer.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/administração & dosagem , Bevacizumab , Neoplasias Colorretais/genética , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/patologia , Intervalo Livre de Doença , Fluoruracila/uso terapêutico , Humanos , Estimativa de Kaplan-Meier , Leucovorina/uso terapêutico , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/secundário , Metástase Linfática , Pessoa de Meia-Idade , Compostos Organoplatínicos/uso terapêutico , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas p21(ras) , Adulto Jovem , Proteínas ras/genética
9.
Carcinogenesis ; 35(12): 2756-62, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25322872

RESUMO

Glioblastoma multiforme (GBM) is the most malignant primary brain tumor. The prognosis of GBM patients varies considerably and the histopathological examination is not sufficient for individual risk estimation. MicroRNAs (miRNAs) are small, non-coding RNAs that function as post-transcriptional regulators of gene expression and were repeatedly proved to play important roles in pathogenesis of GBM. In our study, we performed global miRNA expression profiling of 58 glioblastoma tissue samples obtained during surgical resections and 10 non-tumor brain tissues. The subsequent analysis revealed 28 significantly deregulated miRNAs in GBM tissue, which were able to precisely classify all examined samples. Correlation with clinical data led to identification of six-miRNA signature significantly associated with progression free survival [hazard ratio (HR) 1.98, 95% confidence interval (CI) 1.33-2.94, P < 0.001] and overa+ll survival (HR 2.86, 95% CI 1.91-4.29, P < 0.001). O(6)-methylguanine-DNA methyltransferase methylation status was evaluated as reference method and Risk Score based on six-miRNA signature indicated significant superiority in prediction of clinical outcome in GBM patients. Multivariate Cox analysis indicated that the Risk Score based on six-miRNA signature is an independent prognostic classifier of GBM patients. We suggest that the Risk Score presents promising prognostic algorithm with potential for individualized treatment decisions in clinical management of GBM patients.


Assuntos
Biomarcadores Tumorais/genética , Neoplasias Encefálicas/genética , Proliferação de Células , Perfilação da Expressão Gênica , Glioblastoma/genética , MicroRNAs/genética , Algoritmos , Encéfalo/metabolismo , Neoplasias Encefálicas/mortalidade , Neoplasias Encefálicas/patologia , Metilação de DNA , Metilases de Modificação do DNA/genética , Enzimas Reparadoras do DNA/genética , Seguimentos , Glioblastoma/mortalidade , Glioblastoma/patologia , Humanos , Estadiamento de Neoplasias , Prognóstico , Regiões Promotoras Genéticas/genética , Estudos Retrospectivos , Taxa de Sobrevida , Proteínas Supressoras de Tumor/genética
10.
BMC Cancer ; 14: 323, 2014 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-24884897

RESUMO

BACKGROUND: Data from the Czech national registry were analysed retrospectively to describe treatment outcomes for capecitabine and oxaliplatin (XELOX) regimen with bevacizumab versus 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX) regimen with bevacizumab in the first-line therapy for metastatic colorectal cancer (mCRC). METHODS: A national registry containing anonymised individual data on patients treated with targeted therapies was used as a data source. In total, 2,191 mCRC patients who received a first-line therapy with bevacizumab combined with either FOLFOX regimen (n = 1,218, 55.6%) or XELOX regimen (n = 973, 44.4%) were included in the present analysis. RESULTS: No statistically significant difference in survival was observed between the two groups, with median overall survival (OS) of 27.0 months (95% confidence interval [CI] 24.6-29.5 months) and 30.6 months (95% CI 27.8-33.4 months) for FOLFOX/bevacizumab and XELOX/bevacizumab, respectively (p = 0.281). Median progression-free survival (PFS) was 11.4 months (95% CI 10.7-12.1 months) for FOLFOX/bevacizumab and 11.5 months (95% CI 10.8-12.3 months) for XELOX/bevacizumab (p = 0.337). The number of metastatic sites was identified as the most significant predictor of PFS and, together with the presence/absence of metastatic disease at diagnosis, also for OS. CONCLUSIONS: According to this large registry-based analysis, XELOX and FOLFOX regimens have similar effectiveness for use in combination with bevacizumab in the first-line treatment of mCRC. Multiple metastatic sites and the presence of metastatic disease at diagnosis were the strongest negative predictors of OS regardless of backbone chemotherapy regimen.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Adulto , Idoso , Anticorpos Monoclonais Humanizados/administração & dosagem , Bevacizumab , Capecitabina , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/secundário , República Tcheca , Desoxicitidina/administração & dosagem , Desoxicitidina/análogos & derivados , Progressão da Doença , Intervalo Livre de Doença , Fluoruracila/administração & dosagem , Fluoruracila/análogos & derivados , Humanos , Estimativa de Kaplan-Meier , Leucovorina/administração & dosagem , Masculino , Pessoa de Meia-Idade , Compostos Organoplatínicos/administração & dosagem , Oxaliplatina , Oxaloacetatos , Modelos de Riscos Proporcionais , Sistema de Registros , Estudos Retrospectivos , Fatores de Tempo , Resultado do Tratamento
11.
BMC Gastroenterol ; 14: 53, 2014 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-24666582

RESUMO

BACKGROUND: Patients aged 65 years and older represent the majority of patients with metastatic colorectal cancer (mCRC). However, this patient population is often underrepresented in clinical trials and probably undertreated in the clinical practice. METHODS: We have analysed the outcomes of 3,187 mCRC patients treated with first-line bevacizumab based on data from the Czech national registry of mCRC patients aiming to compare the treatment efficacy and safety according to the age categories. RESULTS: In total, 2,126 (66.7%), 932 (29.2%), and 129 (4.0%) patients were aged <65 years, 65 to 75 years, and 75+ years, respectively. Median progression-free survival (PFS) was 11.4, 11.3, and 11.8 months for patients aged <65 years, 65 to 75 years, and 75+ years, respectively (p = 0.94). Median overall survival (OS) was 26.9, 27.5, and 25.1 months for patients aged <65 years, 65 to 75 years, and 75+ years, respectively (p = 0.73). Using multivariable Cox model for both PFS and OS, the patient age was not significantly associated with either PFS or OS. No increase in bevacizumab-related toxicity was observed among the elderly mCRC patients with the exception of hypertension, which was observed in 71 (3.3%), 34 (3.6%), and 10 (7.8%) patients aged <65 years, 65 to 75 years, and 75+ years, respectively. CONCLUSIONS: The results of the present study suggest similar outcome in terms of OS and PFS with bevacizumab-containing therapy in elderly mCRC patients fit for chemotherapy combined with targeted therapy compared to younger patients. Thus, chronological age should not be considered to represent a limitation in prescribing bevacizumab-containing therapy in mCRC patients.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/patologia , Fatores Etários , Idoso , Anticorpos Monoclonais Humanizados/efeitos adversos , Antineoplásicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Bevacizumab , Capecitabina , República Tcheca , Desoxicitidina/análogos & derivados , Desoxicitidina/uso terapêutico , Intervalo Livre de Doença , Feminino , Fluoruracila/análogos & derivados , Fluoruracila/uso terapêutico , Humanos , Hipertensão/induzido quimicamente , Estimativa de Kaplan-Meier , Leucovorina/uso terapêutico , Masculino , Pessoa de Meia-Idade , Compostos Organoplatínicos/uso terapêutico , Oxaloacetatos , Modelos de Riscos Proporcionais , Sistema de Registros , Estudos Retrospectivos , Tromboembolia/induzido quimicamente
12.
Tumour Biol ; 34(1): 481-91, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23150176

RESUMO

Renal cell carcinoma (RCC) is the most common neoplasm of adult kidney accounting for about 3 % of adult malignancies. MicroRNAs (miRNAs) are a class of naturally occurring, short non-coding RNAs that regulate gene expression at the post-transcriptional level. We determined global miRNA expression profiles of RCC and parallel renal parenchyma tissues by using quantitative reverse transcriptase-polymerase chain reaction-based TaqMan low-density arrays. Afterward, we validated the difference in miR-210 expression levels on the larger group of RCC patients (35 RCC versus 10 non-tumorous parenchyma samples). Functional in vitro experiments were performed on ACHN and CAKI-2 RCC cell lines transfected with miRNA-210 inhibitor. Cell viability, apoptosis, cell cycle, scratch wound migration assay, and invasion assay (xCELLigence) were performed. We have identified original ccRCC-specific miRNA signature in clinical samples (73 miRNAs were significantly downregulated and five miRNAs upregulated (P < 0.003)). Increased expression levels of miR-210 in RCC tumor tissue were independently validated. We observed decreased viability of ACHN and CAKI-2 cells and accumulation of CAKI-2 in G2 phase of cell cycle after silencing of miR-210 expression. Downregulation of miR-210 also reduced the migratory and invasive potential of ACHN metastatic RCC cells. Moreover, we showed downregulation of HIF1a protein in both cell lines after miR-210 silencing indicating participation of miR-210 in hypoxic processes of RCC not only through regulation of its target mRNAs but also by indirect regulation of HIF1a. To our knowledge, this is the first report to show miR-210 regulatory effects on cell migration, invasive potential, and HIF1a protein in RCC cells.


Assuntos
Carcinoma de Células Renais/genética , Carcinoma de Células Renais/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , MicroRNAs/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Apoptose , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Carcinoma de Células Renais/patologia , Ciclo Celular , Pontos de Checagem do Ciclo Celular , Linhagem Celular Tumoral , Movimento Celular , Regulação para Baixo , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Inativação Gênica , Humanos , Neoplasias Renais/genética , Neoplasias Renais/metabolismo , Neoplasias Renais/patologia , Masculino , MicroRNAs/biossíntese , Pessoa de Meia-Idade , Invasividade Neoplásica , RNA Mensageiro/genética , RNA Mensageiro/metabolismo
13.
Nutr Cancer ; 65(2): 247-54, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23441612

RESUMO

Sporadic colorectal cancer (CRC) is a typical multifactorial disease. Isothiocyanates (ITC) have been recently shown to inhibit development of CRC in many experimental models. MicroRNAs (miRNAs) are short noncoding RNAs that posttranscriptionally regulate gene expression through binding to 3' untranslated regions (3'UTR) of target mRNAs. MiRNAs are regulated by natural agents, ITCs included. In our study, using global expression profiling based on TaqMan Low-Density Arrays, we identified 3 common miRNAs (miR-155, miR-23b, miR-27b) regulated by ITCs (sulforaphane, iberin) in colonic epithelial cell lines NCM460 and NCM356. In silico predictions allowed us to find 9 relevant single nucleotide polymorphisms (SNPs) localized within the 3'UTRs of genes (AGTR1, TNFAIP2, PRKCB, HSPA9, RABGAP1, DICER1, ADAM19, VWA5A, and SIRT5) targeted by these ITC-related miRNAs. Finally, we observed that homozygous CC genotype of DICER1, rs1057035, was significantly associated with decreased risk of CRC (odds ratio = 0.49; 95% confidence interval: 0.25-0.95, P = 0.036) when compared to TT homozygote genotype; also, the C allele tended to have a protective effect (P = 0.072). This study showed that miRNAs could be involved in chemoprotective effects of natural agents; their function alteration through SNPs in their binding sites and flanking regions presents a new class of CRC risk factors.


Assuntos
Neoplasias Colorretais/genética , RNA Helicases DEAD-box/genética , Isotiocianatos/farmacologia , MicroRNAs/genética , Polimorfismo de Nucleotídeo Único , Ribonuclease III/genética , Regiões 3' não Traduzidas , Idoso , Sítios de Ligação/genética , Estudos de Casos e Controles , Linhagem Celular/efeitos dos fármacos , Simulação por Computador , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/patologia , Feminino , Perfilação da Expressão Gênica , Regulação da Expressão Gênica/efeitos dos fármacos , Predisposição Genética para Doença , Homozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Substâncias Protetoras/farmacologia , Sulfóxidos
14.
Genes Chromosomes Cancer ; 51(7): 707-16, 2012 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-22492545

RESUMO

Renal cell carcinoma (RCC) is the most common neoplasm of adult kidney. One of the important unmet medical needs in RCC is prognostic biomarker enabling identification of patients at high risk of relapse after nephrectomy. MicroRNAs (miRNAs) constitute a robust regulatory network with posttranscriptional regulatory efficiency for almost one-half of human coding genes, including oncogenes and tumor suppressors. To identify potential prognostic miRNAs, we analyzed expression profiles in tumors of different prognostic groups of RCC patients. Seventy-seven patients with clear cell RCC and detailed clinicopathological data were enrolled in a single-center study. Global miRNA expression profiles were obtained by use of TaqMan Low Density Arrays (754 parallel quantitative reverse-transcriptase polymerase chain reactions (qRT-PCR) reactions). For validation of identified miRNAs individual miRNA TaqMan assays were performed in an independent group of patients. We identified tumor relapse-signature based on the expression of 64 miRNAs differentially expressed between relapse-free RCC patients and RCC patients who developed relapse (20 miRNAs were increased, 44 miRNAs were decreased). In the validation phase of the study, we successfully confirmed that expression levels of miR-143, miR-26a, miR-145, miR-10b, miR-195, and miR-126 are lower in the tumors of RCC patients who developed tumor relapse, moreover, the lowest levels of these miRNAs we observed in primary metastatic tumors. By using Kaplan-Meier analysis, we identified that miR-127-3p, miR-145, and miR-126 are significantly correlated with relapse-free survival of nonmetastatic RCC patients. If further validated, we suggest that identified miRNAs might be used for identification of RCC patients at high risk of early relapse after nephrectomy in clinical practice.


Assuntos
Carcinoma de Células Renais/genética , Carcinoma de Células Renais/cirurgia , Neoplasias Renais/genética , Neoplasias Renais/cirurgia , MicroRNAs/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/genética , Análise por Conglomerados , Estudos de Coortes , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Nefrectomia , Prognóstico , Recidiva , Reprodutibilidade dos Testes , Estatísticas não Paramétricas
15.
Stud Health Technol Inform ; 186: 165-9, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23542990

RESUMO

Chemotherapeutic regimens (CHR) and their administration are routine practice in contemporary oncology. The development of a structured, electronic database of standard CHR can help the faster propagation of information about new CHR and at the same time enable assessment of their adherence in clinical practice. The goal was to develop a standardized way to describe a regimen using XML, fill the database with currently available regimens and develop tools to assess the adherence of the treatment to chosen regimen, compare the dose-intensity and recognize the regimen from existing data on drug administration. The data are being inserted in cooperation with expert oncologists and the database currently contains about 260 CHRs. Such system can be used to enhance decision support systems and interoperability of HIS. The database and tools are available online on the internet.


Assuntos
Sistemas de Gerenciamento de Base de Dados , Bases de Dados de Produtos Farmacêuticos , Sistemas de Apoio a Decisões Clínicas , Tratamento Farmacológico , Armazenamento e Recuperação da Informação/métodos , Internet , Interface Usuário-Computador
16.
Cancers (Basel) ; 15(6)2023 Mar 22.
Artigo em Inglês | MEDLINE | ID: mdl-36980787

RESUMO

Immune checkpoint inhibitors (ICI) are the main therapy currently used in advanced malignant melanoma (MM) and non-small cell lung cancer (NSCLC). Despite the wide variety of uses, the possibility of predicting ICI efficacy in these tumor types is scarce. The aim of our study was to find new predictive biomarkers for ICI treatment. We analyzed, by immunohistochemistry, various cell subsets, including CD3+, CD8+, CD68+, CD20+, and FoxP3+ cells, and molecules such as LAG-3, IDO1, and TGFß. Comprehensive genomic profiles were analyzed. We evaluated 46 patients with advanced MM (31) and NSCLC (15) treated with ICI monotherapy. When analyzing the malignant melanoma group, shorter median progression-free survival (PFS) was found in tumors positive for nuclear FoxP3 in tumor-infiltrating lymphocytes (TILs) (p = 0.048, HR 3.04) and for CD68 expression (p = 0.034, HR 3.2). Longer PFS was achieved in patients with tumors with PD-L1 TPS ≥ 1 (p = 0.005, HR 0.26). In the NSCLC group, only FoxP3 positivity was associated with shorter PFS and OS. We found that FoxP3 negativity was linked with a better response to ICI in both histological groups.

17.
J Cell Mol Med ; 16(1): 8-21, 2012 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-21692980

RESUMO

MicroRNAs (miRNAs) are small non-coding RNAs, which regulate gene expression. Single nucleotide polymorphisms (SNPs) may occur in miRNA biogenesis pathway genes, primary miRNA, pre-miRNA or a mature miRNA sequence. Such polymorphisms may be functional with respect to biogenesis and actions of mature miRNA. Specific SNPs were identified in predicted miRNA target sites within 3' untranslated regions of mRNAs. These SNPs have a potential to affect the efficiency of miRNA binding to the target sites or can create or disrupt binding sites. Resulting gene dysregulation may involve changes in phenotype and may eventually prove critical for the susceptibility to cancer and its onset as well as for estimates of prognosis and therapy response. In this review, we provide a comprehensive list of potentially functional miRNA-related SNPs and summarize their importance as candidate cancer biomarkers.


Assuntos
MicroRNAs/genética , MicroRNAs/metabolismo , Epidemiologia Molecular/métodos , Neoplasias/genética , Polimorfismo de Nucleotídeo Único , Regiões 3' não Traduzidas , Animais , Predisposição Genética para Doença , Genótipo , Humanos , Neoplasias/patologia
18.
J Cell Mol Med ; 16(11): 2655-66, 2012 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-22469014

RESUMO

MicroRNAs (miRNAs) constitute a robust regulatory network with post-transcriptional regulatory efficiency for almost one half of human coding genes, including oncogenes and tumour suppressors. We determined the expression profile of 667 miRNAs in colorectal cancer (CRC) tissues and paired non-tumoural tissues and identified 42 differentially expressed miRNAs. We chose miR-215, miR-375, miR-378, miR-422a and miR-135b for further validation on an independent cohort of 125 clinically characterized CRC patients and for in vitro analyses. MiR-215, miR-375, miR-378 and miR-422a were significantly decreased, whereas miR-135b was increased in CRC tumour tissues. Levels of miR-215 and miR-422a correlated with clinical stage. MiR-135b was associated with higher pre-operative serum levels of CEA and CA19-9. In vitro analyses showed that ectopic expression of miR-215 decreases viability and migration, increases apoptosis and promotes cell cycle arrest in DLD-1 and HCT-116 colon cancer cell lines. Similarly, overexpression of miR-375 and inhibition of miR-135b led to decreased viability. Finally, restoration of miR-378, miR-422a and miR-375 inhibited G1/S transition. These findings indicate that miR-378, miR-375, miR-422a and miR-215 play an important role in CRC as tumour suppressors, whereas miR-135b functions as an oncogene; both groups of miRNA contribute to CRC pathogenesis.


Assuntos
Neoplasias Colorretais/genética , Regulação Neoplásica da Expressão Gênica , MicroRNAs/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Apoptose/genética , Pontos de Checagem do Ciclo Celular/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Neoplasias Colorretais/patologia , Feminino , Genes Supressores de Tumor , Humanos , Masculino , Pessoa de Meia-Idade , Reprodutibilidade dos Testes
19.
J Transl Med ; 10: 55, 2012 Mar 22.
Artigo em Inglês | MEDLINE | ID: mdl-22440013

RESUMO

BACKGROUND: There is no standard serum biomarker used for diagnosis or early detection of recurrence for renal cell carcinoma (RCC) patients. MicroRNAs (miRNAs) are abundant and highly stable in blood serum, and have been recently described as powerful circulating biomarkers in a wide range of solid cancers. Our aim was to identify miRNA signature that can distinguish the blood serum of RCC patients and matched healthy controls and validate identified miRNAs as potential biomarkers for RCC. METHODS: In the screening phase of the study, blood serum of 15 RCC patients and 12 matched healthy controls were analyzed by use of the TaqMan Low-Density Arrays enabling parallel identification of expression levels of 667 miRNAs through qRT-PCR-based approach. In the validation phase, identified miRNAs were further evaluated on the independent group of 90 RCC patients and 35 matched healthy controls by use of individual qRT-PCR assays and statistically evaluated. RESULTS: We identified 30 miRNAs differentially expressed between serum of RCC patients and healthy controls: 19 miRNAs were up-regulated and 11 miRNAs were down-regulated in RCC patients. MiR-378, miR-451 and miR-150 were further evaluated in the independent group of patients, and two of them were successfully validated: levels of miR-378 were increased (p = 0.0003, AUC = 0.71), miR-451 levels were decreased (p < 0.0001, AUC = 0.77) in serum of RCC patients. Combination of miR-378 and miR-451 enable identification of RCC serum with the sensitivity of 81%, specificity 83% and AUC = 0.86. CONCLUSIONS: Circulating miRNAs in serum are promising biomarkers in RCC.


Assuntos
Biomarcadores Tumorais/sangue , Carcinoma de Células Renais/sangue , Carcinoma de Células Renais/genética , Neoplasias Renais/sangue , Neoplasias Renais/genética , MicroRNAs/sangue , Adulto , Idoso , Biomarcadores Tumorais/genética , Carcinoma de Células Renais/diagnóstico , Estudos de Casos e Controles , Análise por Conglomerados , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Renais/diagnóstico , Masculino , Programas de Rastreamento , MicroRNAs/genética , Pessoa de Meia-Idade , Curva ROC , Reprodutibilidade dos Testes
20.
Int J Colorectal Dis ; 27(11): 1401-8, 2012 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-22476768

RESUMO

PURPOSE: MicroRNA-21 (miR-21) is one of the miRNAs that are frequently and highly overexpressed in tumor tissue of colorectal cancer (CRC) patients; however, only a little is known about its functional role in CRC. METHODS: We examined the expression level of miR-21 in 44 paired samples of tumoral and non-tumoral colon tissues diagnosed for CRC using TaqMan real-time PCR method. Furthermore, we used miR-21 inhibitor (anti-miR-21) to transient knockdown of miR-21 in DLD-1 colon cancer cells and examined the effects of miR-21 silencing on viability, apoptosis, chemosensitivity, cell cycle, and migration of DLD1 cells. RESULTS: The expression levels of miR-21 were significantly increased in CRC tumor tissue (P < 0.0001). Significant differences in miR-21 levels were observed also between CRC tissues of patients with CRC in different clinical stages: I vs. II (P = 0.033) and I vs. IV (P = 0.021). Kaplan-Meier analysis proved that the miR-21 expression levels are correlated to shorter overall survival of CRC patients (P = 0.0341). MiR-21 silencing in DLD1 cell line had no effect on the cell viability; however, when combined with chemotherapeutics (5-FU, L-OHP, and SN38), it contributed to the decrease of cell viability. Suppression of miR-21 decreased cell migration ability of DLD-1 cells by nearly 30 % (P = 0.016). CONCLUSION: We have confirmed the overexpression of miR-21 in CRC samples and its correlation with advanced disease and shorter overall survival. These findings could be described in part by the fact that CRC cells with increased expression of miR-21 have higher migration ability.


Assuntos
Neoplasias Colorretais/genética , MicroRNAs/antagonistas & inibidores , MicroRNAs/genética , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Apoptose/genética , Ciclo Celular/efeitos dos fármacos , Ciclo Celular/genética , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Movimento Celular/genética , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Neoplasias do Colo/genética , Neoplasias do Colo/patologia , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/patologia , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Estimativa de Kaplan-Meier , Masculino , MicroRNAs/metabolismo , Pessoa de Meia-Idade
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