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- Increased expression of monocarboxylate transporters 1, 2, and 4 in colorectal carcinomasPublication . Pinheiro, C; Longatto-Filho, A; Scapulatempo, C; Mesquita-Rodrigues, A; Alves, VA; Schmitt, F; Baltazar, FTumour cells are known to be highly glycolytic, thus producing high amounts of lactic acid. Monocarboxylate transporters (MCTs), by promoting the efflux of the accumulating acids, constitute one of the most important mechanisms in the maintenance of tumour intracellular pH. Since data concerning MCT expression in colorectal carcinomas (CRC) are scarce and controversial, the present study aimed to assess the expressions of MCT1, 2, and 4 in a well characterized series of CRC and assess their role in CRC carcinogenesis. CRC samples (126 cases) were analyzed for MCT1, MCT2, and MCT4 immunoexpression and findings correlated with clinico-pathological parameters. Expression of all MCT isoforms in tumour cells was significantly increased when compared to adjacent normal epithelium. Remarkably, there was a significant gain of membrane expression for MCT1 and MCT4 and loss of plasma membrane expression for MCT2 in tumour cells. Plasma membrane expression of MCT1 was directly related to the presence of vascular invasion. This is the larger study on MCT expression in CRC and evaluates for the first time its clinico-pathological significance. The increased expression of these transporters suggests an important role in CRC, which might justify their use, especially MCT1 and MCT4, as targets in CRC drug therapy.
- TP53 codon 72 polymorphism in susceptibility, overall survival, and adjuvant therapy response of gliomas.Publication . Lima-Ramos, V; Pacheco-Figueiredo, L; Costa, S; Pardal, F; Silva, A; Amorim, J; Lopes, JM; Reis, RMTP53 is a key tumor suppressor gene that encodes a transcriptional factor involved in several cellular mechanisms, including growth arrest, DNA repair, and induction of apoptosis. In addition to TP53 gene mutations, a common polymorphism, Arg72Pro, has been involved in the carcinogenesis process. The Pro72 variant has been associated with a slower induction of apoptosis and may influence the risk of cancer development. The role of Arg72Pro polymorphism in glioma susceptibility is poorly characterized. With the objective of analyzing the role of the TP53 Arg72Pro polymorphism in glioma risk, overall survival, and patient therapy response in a Portuguese population, we conducted a retrospective case-control study, including 171 patients with gliomas and 526 cancer-free individuals. The Arg72Pro genotype was assessed by the polymerase chain reaction-restriction fragment length polymorphism technique. No statistically significant differences were observed in the genotypic and allelic frequencies between glioma and control groups, and no statistically significant differences were observed with stratification of gliomas into distinct histological subtypes: astrocytic (n = 115), glioblastoma (n = 75), and oligodendroglial (n = 54) tumors. No significant association was observed between TP53 Arg72Pro and patient overall survival, but Kaplan-Meier analysis of glioma patients harboring the Pro72 allele showed a significantly longer survival with adjuvant therapy. In this first assessment of the role of TP53 Arg72Pro polymorphism in a large series of Portuguese glioma tumors, no association was observed with glioma susceptibility or overall survival, except for patients submitted to adjuvant therapy.
- Annual costs of chronic hepatitis B disease states in PortugalPublication . Raluy, M; De Cock, E; Tato-Marinho, R; Areias, J; Calinas, F; Carvalho, A; Matos, L; Rodrigues, B; Macedo, G; Velosa, J; Perelman, J
- Expression, mutation and copy number analysis of platelet-derived growth factor receptor A (PDGFRA) and its ligand PDGFA in gliomasPublication . Martinho, O; Longatto-Filho, A; Lambros, MB; Martins, A; Pinheiro, C; Silva, AI; Pardal, F; Amorim, J; Mackay, A; Milanezi, F; Tamber, N; Fenwick, K; Ashworth, A; Reis-Filho, J; Lopes, JM; Reis, RMBACKGROUND: Malignant gliomas are the most prevalent type of primary brain tumours but the therapeutic armamentarium for these tumours is limited. Platelet-derived growth factor (PDGF) signalling has been shown to be a key regulator of glioma development. Clinical trials evaluating the efficacy of anti-PDGFRA therapies on gliomas are ongoing. In this study, we intended to analyse the expression of PDGFA and its receptor PDGFRA, as well as the underlying genetic (mutations and amplification) mechanisms driving their expression in a large series of human gliomas. METHODS: PDGFA and PDGFRA expression was evaluated by immunohistochemistry in a series of 160 gliomas of distinct World Health Organization (WHO) malignancy grade. PDGFRA-activating gene mutations (exons 12, 18 and 23) were assessed in a subset of 86 cases by PCR-single-strand conformational polymorphism (PCR-SSCP), followed by direct sequencing. PDGFRA gene amplification analysis was performed in 57 cases by quantitative real-time PCR (QPCR) and further validated in a subset of cases by chromogenic in situ hybridisation (CISH) and microarray-based comparative genomic hybridisation (aCGH). RESULTS: PDGFA and PDGFRA expression was found in 81.2% (130 out of 160) and 29.6% (48 out of 160) of gliomas, respectively. Its expression was significantly correlated with histological type of the tumours; however, no significant association between the expression of the ligand and its receptor was observed. The absence of PDGFA expression was significantly associated with the age of patients and with poor prognosis. Although PDGFRA gene-activating mutations were not found, PDGFRA gene amplification was observed in 21.1% (12 out of 57) of gliomas. No association was found between the presence of PDGFRA gene amplification and expression, excepting for grade II diffuse astrocytomas. CONCLUSION: The concurrent expression of PDGFA and PDGFRA in different subtypes of gliomas, reinforce the recognised significance of this signalling pathway in gliomas. PDGFRA gene amplification rather than gene mutation may be the underlying genetic mechanism driving PDGFRA overexpression in a portion of gliomas. Taken together, our results could provide in the future a molecular basis for PDGFRA-targeted therapies in gliomas.
- Sweet syndrome as the presenting symptom of hairy cell leukemiaPublication . Ventura, F; Rocha, J; Pereira, T; Marques, H; Pardal, F; Brito, C
- Echocardiographic assessment of a cardiac lymphoma: beyond two-dimensional imagingPublication . Gaspar, A; Salomé, N; Nabais, S; Brandão, A; Simões, A; Portela, C; Salgado, A; Pereira, A; Correia, ALymphoma is usually recognized as the third most frequent metastatic malignancy involving the heart. In recent years, the incidence of cardiac lymphoma has increased, mainly because of HIV-infected patients. We present a case of secondary cardiac lymphoma in an HIV patient presenting with heart failure. Transthoracic echocardiography showed increased left ventricular (LV) wall thickness and an extensive mass in the right cavities with involvement of the tricuspid annulus (Figure 1). Doppler tissue imaging (DTI) showed reduced systolic and diastolic velocities at mitral and tricuspid annulus, compatible with systolic and diastolic myocardial dysfunction, likely owing to infiltration. After 2 weeks of chemotherapy, repeated exam showed significant reduction of the tumour mass and of the LV wall thickness, as well as normalized systolic and diastolic velocities at mitral and tricuspid annulus, as assessed by DTI. Use of transthoracic echocardiography, mostly two-dimensional imaging, has been described for several years for the diagnosis of cardiac involvement as well as for the assessment of tumour regression in response to chemotherapy. The present case report highlights the potential utility of other echocardiographic modalities, particularly DTI, for the assessment of cardiac lymphoma but also for monitoring the tumour response to adequate therapy.
- Recomendações para o diagnóstico, tratamento e monitorização da leucemia mielóide crónicaPublication . Almeida, A; Castro, I; Coutinho, J; Guerra, L; Marques, H; Pereira, AMChronic Myeloid Leukemia (CML) is a clonal stem cell disease characterized by the expression of the fusion protein bcr-abl1, which has deregulated tirosine-kinase activity. Tyrosine kinase inhibitors (TKIs), and in particular imatinib, introduced fundamental changes in the treatment of CML, becoming, in most cases, the first-line treatment of choice in the chronic phase of this disease. Compared to other available therapies imatinib results in a marked increase in overall survival, tolerability and quality of life. The introduction of second generation TKI, with increased potency against bcr-abl1, expanded the number of therapeutic options for this disease and offers an alternative for patients resistant or intolerant to imatinib or who have progressed to the accelerated phase under this therapy. In order to achieve optimal outcomes, TKI therapy must be managed rigorously, requiring a careful monitoring of treatment response in pre-established time periods, thus permitting disease evaluation and safe decision of the most adequate option. Despite the definition of the criteria for imatinib treatment response, the therapeutic strategies to adopt according to the responses obtained are less clear. The objective of this paper is to review the criteria for CML diagnosis, treatment and monitoring, with recommendations as to the most adequate therapeutic choice according to the response to TKI therapy. The paper also focuses the current lines of investigation and debate areas that in the short term can significantly change the therapeutic scenario in this disease. These recommendations, supported by published scientific evidence and by the clinical practice of the expert panel involved in their elaboration, may constitute an important instrument for a better understanding and standardisation of the treatment and monitoring of CML in Portugal.
- Análise económica do rituximab, em associação com ciclofosfamida, vincristina e prednisolona no tratamento de doentes com linfoma folicular avançado em PortugalPublication . Braga, P; Carvalho, S; Gomes, M; Guerra, L; Lúcio, P; Marques, H; Negreiro, F; Pereira, C; Silva, C; Teixeira, AOBJECTIVE: Evaluate costs and benefits of rituximab in combination with cyclophosphamide/vincristine/prednisolone chemotherapy regimen (R-CVP), in previously untreated patients with indolent non-Hodgkin lymphoma (NHL), compared to CVP alone from a Portuguese National Health System (NHS) perspective. METHODS: Cost-effectiveness (Life Years Gained--LYG) and cost-utility analysis (Quality Adjusted Life Years--QALYs) were performed for a time horizon of 10 years, according to a Markov economic model with three health states (progression free survival, progression and death) and monthly cycles for a population of previously untreated patients with indolent NHL. Data from a phase III clinical trial was used and expanded to include unpublished 53-month median follow-up data. Survival after first-line therapy was estimated from the Scotland and Newcastle Lymphoma Group registry data and utilities were derived from a study in the UK performed in patients with follicular lymphoma. Resource consumption was estimated by a Portuguese expert panel (Delbecq Panel). Costs were calculated from the Portuguese NHS perspective through official data with prices updated to 2008. Only direct medical costs were considered. Costs and clinical outcomes were discounted at 5% per annum. Deterministic and probabilistic sensitivity analysis were performed around assumptions on the time horizon, costs, utilities and excess mortality rate due to progression applied in the base-case analysis. RESULTS: The 10-year base-case analysis showed a lower total cost per patient with CVP alone (€ 85,838) in comparison with R-CVP (€ 87,774). Life expectancy and Quality adjusted life expectancy per patient were higher with R-CVP (6.361 and 4.166, respectively) than with CVP alone (5.557 and 3.438, respectively), representing increases of 0.804 in LYG and 0.728 (8.7 months) in QALYs gained. The incremental cost per LYG was € 2,407 and the incremental cost per QALY gained was € 2,661. The probabilistic sensitivity analysis confirmed the robustness of the base-case analysis results. CONCLUSIONS: This study demonstrates that the combination R-CVP in previously untreated indolent NHL patients improves life expectancy and is a cost-effective alternative to CVP in Portugal.
- Association of adult mastocytosis with M541L in the transmembrane domain of KITPublication . Rocha, J; Duarte, ML; Marques, H; Torres, F; Tavares, P; Silva, A; Brito, C
- Prognostic value of MGMT promoter methylation in glioblastoma patients treated with temozolomide-based chemoradiation: a Portuguese multicentre studyPublication . Costa, BM; Caeiro, C; Guimarães, I; Martinho, O; Jaraquemada, T; Augusto, I; Castro, l; Osório, L; Linhares, P; Honavar, M; Resende, M; Nabiço, R; Almeida, R; Alegria, C; Pires, M; Pinheiro, C; Carvalho, E; Lopes, JM; Costa, P; Damasceno, M; Reis, RMGlioblastoma (GBM) is the most common and aggressive primary brain tumor. The identification of novel molecular prognostic markers of GBM has recently been an area of great interest in neuro-oncology. The methylation status of the MGMT gene promoter is currently a promising molecular prognostic marker, but some controversial data have precluded its clinical use. We analyzed MGMT methylation by methylation-specific PCR in 90 GBM patients from four Portuguese hospitals, uniformly treated with radiotherapy combined with concomitant and adjuvant temozolomide (Stupp protocol). The Kaplan-Meier method was used to construct survival curves, and the log-rank test and a Cox-regression model were used to analyze patient survival. The methylation status of MGMT was successfully determined in 89% (80/90) of the tumors. The frequency of tumoral MGMT promoter methylation was 47.5%. The median overall survivals (OSs) were 16 months (95% CI 12.2-19.8) and 13 months (95% CI 13.3-18.7) for patients whose tumors had a methylated or unmethylated MGMT, respectively. Univariate and multivariate analyses did not show any statistically significant association between MGMT methylation status and patient OS (P=0.583 by the log-rank test; P=0.617 by the Cox-regression test) or progression-free survival (P=0.775 by the log-rank test; P=0.691 by the Cox-regression test). None of the patient clinical features were significantly correlated with survival. This is the first study to report the frequency of MGMT methylation among Portuguese GBM patients. Our data did not show statistically significant associations between MGMT promoter methylation and the outcome of GBM patients treated with temozolomide. Additional robust prospective studies are warranted to clarify whether the MGMT status should be used in clinical decisions.