Portuguese Institute of Oncology IPO

Lisbon, Portugal

Portuguese Institute of Oncology IPO

Lisbon, Portugal
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Faustino-Rocha A.I.,Royal University | Silva A.,University of Porto | Gabriel J.,University of Porto | Teixeira-Guedes C.I.,Royal University | And 7 more authors.
Biomedicine and Pharmacotherapy | Year: 2013

Background: As the worldwide breast cancer burden increases, non-invasive tools, such as ultrasonography and thermography are being increasingly sought after. N-methyl- N-nitrosourea-induced rat mammary tumors are important tools to investigate the usefulness of such imaging techniques. Objective: This study aimed to integrate both ultrasonographic and thermographic approaches to the vascularization and the superficial temperature of chemically-induced rat mammary tumors. Materials and methods: Twenty-five female Sprague-Dawley rats were divided into two groups: group I (intraperitoneally administered with N-methyl- N-nitrosourea) and group II (control group). Thirty-five weeks after the administration of the carcinogen, mammary tumors were evaluated using Power Doppler, B Flow and Contrast-enhanced ultrasound, thermography and histology analyses. Results: Group I animals showed an average of 2.5 mammary tumors per animal, mostly papillary and cribriform non-invasive carcinomas. B Flow detected higher counts of colour pixels than Power Doppler. Contrast-enhanced ultrasound analysis showed a centripetal enhancement order of contrast agent and clear margins. Maximum tumor temperature and thermal amplitude determined by thermography were significantly correlated with tumor volume and with color pixel density, determined by Power Doppler. Conclusion: B Flow was more sensitive than Power Doppler in detecting tumor vessels, but Power Doppler correlates with thermographic data concerning superficial temperature and may reflect tumor angiogenesis. © 2013 Elsevier Masson SAS.


Amorim M.H.R.,University of Porto | Gil Da Costa R.M.,University of Porto | Gil Da Costa R.M.,Portuguese Institute of Oncology IPO | Lopes C.,Portuguese Institute of Oncology IPO | Bastos M.M.S.M.,University of Porto
Critical Reviews in Toxicology | Year: 2013

Sesquiterpene lactones (STLs) present a wide range of biological activities, mostly based on their alkylating capabilities, which underlie their therapeutic potential. These compounds are the active constituents of a variety of plants, frequently used as herbal remedies. STLs such as artemisinin and its derivatives are in use as first-line antimalarials while others, such as parthenolide, have recently reached cancer clinical trials. However, the toxicological profile of these compounds must be thoroughly characterized, since the same properties that make STL useful medicines can also cause severe toxicity. STL-containing plants have long been known to induce a contact dermatitis in exposed farm workers, and also to cause several toxic syndromes in farm animals. More recently, concerns are been raised regarding the genotoxic potential of these compounds and the embryotoxicity of artemisinins. A growing number of STLs are being reported to be mutagenic in different in vitro and in vivo assays. As yet no systematic studies have been published, but the genotoxicity of STLs seems to depend not so much on direct DNA alkylation as on oxidative DNA damage and other partially elucidated mechanisms. As the medicinal use of these compounds increases, further studies of their toxic potential are needed, especially those focusing on the structural determinants of genotoxicity and embryotoxicity. © 2013 Informa Healthcare USA, Inc. All rights reserved: reproduction in whole or part not permitted.


Botelho M.C.,National Institute of Health | Botelho M.C.,University of Porto | Ribeiro R.,Portuguese Institute of Oncology IPO | Vale N.,University of Porto | And 6 more authors.
Oncology Reports | Year: 2012

We recently reported the expression of an estradiol-like molecule by a trematode parasite Schistosoma haematobium. We further established that this estradiol-like molecule is an antagonist of estradiol, repressing the transcriptional activity of the estrogen receptor (ER) in estrogen-responsive MCF7 cells and also that S. haematobium total antigen (Sh) contains estrogenic molecules detected by mass spectrometry. In the present study, we used HCV29 cells, a cell line derived from normal urothelial cells, as well as an in vivo model to evaluate the expression of ER in the bladders of Sh-instilled animals. We show that, similarly to MCF7 cells, Sh down-regulates the transcriptional activity of ER in HCV29 cells and also in the bladders of Sh-treated mice. The antiestrogenic activity of the S. haematobium extract and its repressive role in ER could have implications in the carcinogenic process in bladders with S. haematobium infection.


Afonso J.,University of Minho | Afonso J.,ICVS 3Bs PT Government Associate Laboratory | Longatto-Filho A.,University of Minho | Longatto-Filho A.,ICVS 3Bs PT Government Associate Laboratory | And 9 more authors.
Virchows Archiv | Year: 2013

Urothelial bladder cancer (UBC) is a heterogeneous type of disease. It is urgent to screen biomarkers of tumour aggressiveness in order to clarify the clinical behaviour and to personalize therapy in UBC patients. Raf kinase inhibitory protein (RKIP) is a metastasis suppressor, and its downregulation is associated with metastatic events in an increasing number of solid tumours. We evaluated the clinical and prognostic significance of RKIP expression in patients with high risk of progression UBC. Using immunohistochemistry, we determined RKIP expression levels in a series of 81 patients with high-grade pT1/pTis or muscle-invasive UBC. Staining of CD31 and D2-40 was used to assess blood and lymphatic vessels, in order to distinguish between blood and lymphatic vessel invasion (LVI). We found that 90 % of pT1/pTis tumours, 94 % of non-muscle invasive papillary tumours and 76 % of the cases without LVI occurrence expressed RKIP in >10 % of cells. In this group, we observed a subgroup of tumours (42 %) in which the tumour centre was significantly more intensely stained than the invasion front. This heterogeneous pattern was observed in 63 % of the cases with LVI. Low RKIP expression was associated with poorer 5-year disease-free and overall survival rates, and remained as an independent prognostic factor for disease-free survival. Loss of RKIP expression may be an important prognostic factor for patients with high risk of progression bladder cancer. © 2013 Springer-Verlag Berlin Heidelberg.


Afonso J.,University of Minho | Afonso J.,ICVS 3Bs PT Government Associate Laboratory | Santos L.L.,Portuguese Institute of Oncology IPO | Santos L.L.,Fernando Pessoa University | And 10 more authors.
Molecular Carcinogenesis | Year: 2015

The relapsing and progressive nature of bladder tumors, and the heterogeneity in the response to cisplatin-containing regimens, are the major concerns in the care of urothelial bladder carcinoma (UBC) patients. The metabolic adaptations that alter the tumor microenvironment and thus contribute to chemoresistance have been poorly explored in UBC setting. We found significant associations between the immunoexpressions of the microenvironment-related molecules CD147, monocarboxylate transporters (MCTs) 1 and 4, CD44 and CAIX in tumor tissue sections from 114 UBC patients. The presence of MCT1 and/or MCT4 expressions was significantly associated with unfavorable clinicopathological parameters. The incidence of CD147 positive staining significantly increased with advancing stage, grade and type of lesion, and occurrence of lymphovascular invasion. Similar associations were observed when considering the concurrent expression of CD147 and MCT1. This expression profile lowered significantly the 5-year disease-free and overall survival rates. Moreover, when selecting patients who received platinum-based chemotherapy, the prognosis was significantly worse for those with MCT1 and CD147 positive tumors. CD147 specific silencing by small interfering RNAs (siRNAs) in UBC cells was accompanied by a decrease in MCT1 and MCT4 expressions and, importantly, an increase in chemosensitivity to cisplatin. Our results provide novel insights for the involvement of CD147 and MCTs in bladder cancer progression and resistance to cisplatin-based chemotherapy. We consider that the possible cooperative role of CD147 and MCT1 in determining cisplatin resistance should be further explored as a potential theranostics biomarker. © 2014 Wiley Periodicals, Inc.


Afonso J.,University of Minho | Afonso J.,ICVS 3Bs PT Government Laboratory | Afonso J.,Health Institute of Alto Ave | Longatto-Filho A.,University of Minho | And 13 more authors.
European Journal of Surgical Oncology | Year: 2011

Background: Urothelial bladder carcinoma (UBC) is a chemo-sensitive tumour, but the response to treatment is heterogeneous. CD147 has been associated with chemotherapy resistance. We aimed to define tumours with an aggressive phenotype by the combined analysis of clinicopathological and biological parameters. Methods: 77 patients with T1G3 or muscle-invasive UBC treated by radical cystectomy were studied. Immunohistochemistry was performed to detect CD147, heparanase, CD31 (blood vessels identification) and D2-40 (lymphatic vessels identification) expressions. The immunohistochemical reactions were correlated with the clinicopathological and the outcome parameters. 5-year disease-free survival (DFS) and overall survival (OS) rates were estimated using the Kaplan-Meier method. Multivariate analysis was performed by Cox proportional hazards analysis. Results: The 5-year DFS and OS rates were significantly influenced by the classical clinicopathological parameters, and by the occurrence of lymphovascular invasion. CD147 and heparanase immunoexpression did not affect patients' outcome. However, patients with pT3/pT4 tumours had a median OS time of 14.7 months (95% CI 7.1-22.3, p = 0.003), which was reduced to 9.2 months (95% CI 1.5-17.0, p = 0.008) if the tumours were CD147 positive. We developed a model of tumour aggressiveness using parameters as stage, grade, lymphovascular invasion and CD147 immunoexpression, which separated a low aggressiveness from a high aggressiveness group, remaining as an independent prognostic factor of DFS (HR 3.746; 95% CI 1.244-11.285; p = 0.019) and OS (HR 3.247; 95% CI 1.015-10.388, p = 0.047). Conclusion: CD147 overexpression, included in a model of UBC aggressiveness, may help surgeons to identify patients who could benefit from a personalized therapeutic regimen. Additional validation is needed. © 2011 Elsevier Ltd. All rights reserved.


PubMed | Portuguese Institute of Oncology IPO and University of Minho
Type: Journal Article | Journal: Molecular carcinogenesis | Year: 2015

The relapsing and progressive nature of bladder tumors, and the heterogeneity in the response to cisplatin-containing regimens, are the major concerns in the care of urothelial bladder carcinoma (UBC) patients. The metabolic adaptations that alter the tumor microenvironment and thus contribute to chemoresistance have been poorly explored in UBC setting. We found significant associations between the immunoexpressions of the microenvironment-related molecules CD147, monocarboxylate transporters (MCTs) 1 and 4, CD44 and CAIX in tumor tissue sections from 114 UBC patients. The presence of MCT1 and/or MCT4 expressions was significantly associated with unfavorable clinicopathological parameters. The incidence of CD147 positive staining significantly increased with advancing stage, grade and type of lesion, and occurrence of lymphovascular invasion. Similar associations were observed when considering the concurrent expression of CD147 and MCT1. This expression profile lowered significantly the 5-year disease-free and overall survival rates. Moreover, when selecting patients who received platinum-based chemotherapy, the prognosis was significantly worse for those with MCT1 and CD147 positive tumors. CD147 specific silencing by small interfering RNAs (siRNAs) in UBC cells was accompanied by a decrease in MCT1 and MCT4 expressions and, importantly, an increase in chemosensitivity to cisplatin. Our results provide novel insights for the involvement of CD147 and MCTs in bladder cancer progression and resistance to cisplatin-based chemotherapy. We consider that the possible cooperative role of CD147 and MCT1 in determining cisplatin resistance should be further explored as a potential theranostics biomarker.


PubMed | Portuguese Institute of Oncology IPO and University of Minho
Type: Journal Article | Journal: Cell cycle (Georgetown, Tex.) | Year: 2016

Monocarboxylate transporters (MCTs) are vital for intracellular pH homeostasis by extruding lactate from highly glycolytic cells. These molecules are key players of the metabolic reprogramming of cancer cells, and evidence indicates a potential contribution in urothelial bladder cancer (UBC) aggressiveness and chemoresistance. However, the specific role of MCTs in the metabolic compartmentalization within bladder tumors, namely their preponderance on the tumor stroma, remains to be elucidated. Thus, we evaluated the immunoexpression of MCTs in the different compartments of UBC tissue samples (n = 111), assessing the correlations among them and with the clinical and prognostic parameters. A significant decrease in positivity for MCT1 and MCT4 occurred from normoxic toward hypoxic regions. Significant associations were found between the expression of MCT4 in hypoxic tumor cells and in the tumor stroma. MCT1 staining in normoxic tumor areas, and MCT4 staining in hypoxic regions, in the tumor stroma and in the blood vessels were significantly associated with UBC aggressiveness. MCT4 concomitant positivity in hypoxic tumor cells and in the tumor stroma, as well as positivity in each of these regions concomitant with MCT1 positivity in normoxic tumor cells, was significantly associated with an unfavourable clinicopathological profile, and predicted lower overall survival rates among patients receiving platinum-based chemotherapy. Our results point to the existence of a multi-compartment metabolic model in UBC, providing evidence of a metabolic coupling between catabolic stromal and cancer cells compartments, and the anabolic cancer cells. It is urgent to further explore the involvement of this metabolic coupling in UBC progression and chemoresistance.


Martinalbo J.,European Medicines Agency EMA | Bowen D.,European Medicines Agency EMA | Camarero J.,Spanish Agency for Medicines and Healthcare Products AEMPS | Chapelin M.,European Medicines Agency EMA | And 9 more authors.
Annals of Oncology | Year: 2016

Patient access to new cancer drugs in the EU involves centralised licensing decisions by regulators as well as reimbursement recommendations in the context of national healthcare systems. Differences in assessment criteria and evidence requirements may result in divergent decisions at central and national levels, ultimately compromising effective access to patients. Early access decisions are particularly challenging due to the limited clinical evidence available to conclude on the benefit-risk and relative (cost-) effectiveness of new high-priced cancer drugs. We describe mechanisms to accelerate approval of promising anticancer drugs that fulfil an unmet medical need, review the experience from the European Medicines Agency, compare timelines and outcomes of reimbursement decisions in major EU markets, and discuss shortcomings of the current system, ongoing initiatives, and future steps to facilitate effective early access. © The Author 2015.


PubMed | Spanish Agency for Medicines and Healthcare Products AEMPS, French National Agency for Medicines and Health Products Safety ANSM, Swedish Medical Products Agency MPA, Medicines and Healthcare products Regulatory Agency MHRA and 3 more.
Type: Journal Article | Journal: Annals of oncology : official journal of the European Society for Medical Oncology | Year: 2015

Patient access to new cancer drugs in the EU involves centralised licensing decisions by regulators as well as reimbursement recommendations in the context of national healthcare systems. Differences in assessment criteria and evidence requirements may result in divergent decisions at central and national levels, ultimately compromising effective access to patients. Early access decisions are particularly challenging due to the limited clinical evidence available to conclude on the benefit-risk and relative (cost-) effectiveness of new high-priced cancer drugs. We describe mechanisms to accelerate approval of promising anticancer drugs that fulfil an unmet medical need, review the experience from the European Medicines Agency, compare timelines and outcomes of reimbursement decisions in major EU markets, and discuss shortcomings of the current system, ongoing initiatives, and future steps to facilitate effective early access.

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