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- Remaining kidney volume indexed to weight as a strong predictor of estimated glomerular filtration rate at 1 year and mid‐term renal function after living‐donor nephrectomy ‐ a retrospective observational studyPublication . Nunes-Carneiro, Diogo; Madanelo, Mariana; Silva, Filipa; Pestana, Nicole; Ribeiro, Catarina; Gil‐Sousa, Diogo; Martins, La Salete; Almeida, Manuela; Dias, Leonidio; J, Malheiro; Cavadas, Vítor; Castro‐Henriques, Antonio; Fraga, Avelino; Silva-Ramos, MiguelThe donors' estimated glomerular filtration rate (eGFR) after living nephrectomy has been a concern, particularly in donors with smaller kindeys. Therefore, we developed this retrospective observational study in 195 donors to determine the ability remaining kidney volume indexed to weight (RKV/W) to predict eGFR at 1 year through multivariate linear regression and to explore this relationship between annual eGFR change from 1 to 4 years postdonation evaluated by a linear mixed model. Comparing RKV/W tertiles (T1, T2, T3), RKV/W was a good predictor of 1-year eGFR which was significantly better in T3 donors. Gender, predonation eGFR, and RKV/W were independent predictors of eGFR at 1-year. In a subgroup with predonation eGFR < 90mL/min/1.73 m2 , a significant prediction of eGFR < 60mL/min/1.73 m2 was detected in males with RKV/W ≤ 2.51cm3 /kg. Annual eGFR (ml/min/year) change from 1 to 4 years was + 0.77. RKV/W divided by tertiles (T1-T3) was the only significant predictor: T2 and T3 donors had an annual eGFR improvement opposing to T1. RKV/W was a good predictor of eGFR at 1 year, independently from predonation eGFR. A higher RKV/W was associated with improved eGFR at 1 year. A decline in eGFR on the four years after surgery was only noticeable in donors with RKV/W ≤ 2.13cm3 /kg.
- Evaluation of Patterns of Presentation, Practice, and Outcomes of Upper Tract Urothelial Cancer: Protocol for an Observational, International, Multicenter, Cohort Study by the Clinical Research Office of the Endourology SocietyPublication . Baard, Joyce; Celebi, Merve; de la Rosette, Jean; Alcaraz, Antonio; Shariat, Shahrokh; Cormio, Luigi; Cavadas, Vítor; Laguna, M PilarBackground: Available guidelines on the management of upper tract urothelial carcinoma (UTUC) are restricted due to the lack of strong evidence-based recommendations. Adequate, well-powered randomized trials are missing due to the rarity of the disease. To overcome this problem, we need alternative study designs to provide generalizable data. Objective: The primary aim of this registry is to provide a real-world overview on patterns of presentation and management of UTUC. Secondary objectives include comparison of outcomes of different treatments and tumor stages and evaluation of compliance with the current European Association of Urology recommendations for UTUC. Methods: For this observational, international, multicenter, cohort study, clinical data of consecutive patients suspected of having UTUC, irrespective of type of management, will be prospectively collected up to 5 years after inclusion. Data on the patterns of presentation, diagnostics, and treatment as well as short-, mid-, and long-term oncological and functional outcomes will be analyzed. Possible associations between variables, basal characteristics, and outcomes will be tested by multivariable analyses. The methodology will address potential sources of bias and confounders. Results: The registry was initiated in November 2014 after obtaining institutional review board approval. Data collection started in December 2014. At the time of submission of this manuscript, 2451 patients from 125 centers from 37 countries were included. Inclusion of patients will be closed 5 years after initiation of the registry. Quality checks will be performed centrally with continuous communication and feedback with the centers to ensure accuracy. The first results are expected in the first trimester of 2020. Conclusions: This large observational prospective cohort will generate landmark "real-world" data and hypotheses for further studies. We expect these data to optimize the management of UTUC, provide insights on harms and benefits of treatment, and serve as quality control.
- Calyceal migration of vascular embolization coils used to treat massive hemorrhage following percutaneous nephrolithotomy: an endoscopic finding during repeat percutaneous nephrolithotomyPublication . Nunes-Carneiro, Diogo; Xambre, Luís; Cavadas, Vítor
- Opposing Effects of Adenosine and Inosine in Human Subcutaneous Fibroblasts May Be Regulated by Third Party ADA Cell ProvidersPublication . Herman-de-Sousa, Carina; Pinheiro, Ana Rita; Paramos-de-Carvalho, Diogo; Costa, Maria Adelina; Ferreirinha, Fátima; Magalhães-Cardoso, Teresa; Ribeiro, Severino; Pelletier, Julie; Sévigny, Jean; Correia-de-Sá, PauloHuman subcutaneous fibroblasts (HSCF) challenged with inflammatory mediators release huge amounts of ATP, which rapidly generates adenosine. Given the nucleoside's putative relevance in wound healing, dermal fibrosis, and myofascial pain, we investigated the role of its precursor, AMP, and of its metabolite, inosine, in HSCF cells growth and collagen production. AMP (30 µM) was rapidly (t½ 3 ± 1 min) dephosphorylated into adenosine by CD73/ecto-5'-nucleotidase. Adenosine accumulation (t½ 158 ± 17 min) in the extracellular fluid reflected very low cellular adenosine deaminase (ADA) activity. HSCF stained positively against A2A and A3 receptors but were A1 and A2B negative. AMP and the A2A receptor agonist, CGS21680C, increased collagen production without affecting cells growth. The A2A receptor antagonist, SCH442416, prevented the effects of AMP and CGS21680C. Inosine and the A3 receptor agonist, 2Cl-IB-MECA, decreased HSCF growth and collagen production in a MRS1191-sensitive manner, implicating the A3 receptor in the anti-proliferative action of inosine. Incubation with ADA reproduced the inosine effect. In conclusion, adenosine originated from extracellular ATP hydrolysis favors normal collagen production by HSCF via A2A receptors. Inhibition of unpredicted inosine formation by third party ADA cell providers (e.g., inflammatory cells) may be a novel therapeutic target to prevent inappropriate dermal remodeling via A3 receptors activation.
- Urinary Biomarkers in Bladder Cancer: Where Do We Stand and Potential Role of Extracellular VesiclesPublication . Castanheira De Oliveira, Manuel; Caires, Hugo R.; Oliveira, Maria J; Fraga, Avelino; Vasconcelos, M. Helena; Ribeiro, RicardoExtracellular vesicles (EVs) are small membrane vesicles released by all cells and involved in intercellular communication. Importantly, EVs cargo includes nucleic acids, lipids, and proteins constantly transferred between different cell types, contributing to autocrine and paracrine signaling. In recent years, they have been shown to play vital roles, not only in normal biological functions, but also in pathological conditions, such as cancer. In the multistep process of cancer progression, EVs act at different levels, from stimulation of neoplastic transformation, proliferation, promotion of angiogenesis, migration, invasion, and formation of metastatic niches in distant organs, to immune escape and therapy resistance. Moreover, as products of their parental cells, reflecting their genetic signatures and phenotypes, EVs hold great promise as diagnostic and prognostic biomarkers. Importantly, their potential to overcome the current limitations or the present diagnostic procedures has created interest in bladder cancer (BCa). Indeed, cystoscopy is an invasive and costly technique, whereas cytology has poor sensitivity for early staged and low-grade disease. Several urine-based biomarkers for BCa were found to overcome these limitations. Here, we review their potential advantages and downfalls. In addition, recent literature on the potential of EVs to improve BCa management was reviewed and discussed.
- β3 Adrenoceptor-induced cholinergic inhibition in human and rat urinary bladders involves the exchange protein directly activated by cyclic AMP 1 favoring adenosine releasePublication . Silva, Isabel; Magalhães‐Cardoso, M. Teresa; Ferreirinha, Fátima; Moreira, Sílvia; Costa, Ana Filipa; Silva, Diogo; Vieira, Cátia; Silva-Ramos, Miguel; Correia‐de‐Sá, PauloBackground and purpose: The mechanism by which β3 receptor agonists (e.g. mirabegron) control bladder overactivity may involve adenosine release from human and rat detrusor smooth muscle. Retrograde activation of adenosine A1 receptors reduces ACh release from cholinergic bladder nerves. β3 -Adrenoceptors usually couple to adenylyl cyclase. Here we investigated, which of the cAMP targets, protein kinase A or the exchange protein directly activated by cAMP (EPAC) could be involved in this cholinergic inhibition of the bladder. Experimental approach: [3 H]ACh and adenosine release from urothelium-denuded detrusor strips of cadaveric human organ donors and rats were measured by liquid scintillation spectrometry and HPLC, respectively. In vivo cystometry was also performed in urethane-anaesthetized rats. Key results: The exchange protein directly activated by cAMP (EPAC) inhibitor, ESI-09, prevented mirabegron- and isoprenaline-induced adenosine release from human and rat detrusor strips respectively. ESI-09, but not the PKA inhibitor, H-89, attenuated inhibition of [3 H]ACh release from stimulated (10 Hz) detrusor strips caused by activating β3 -adrenoceptors, AC (forskolin) and EPAC1 (8-CTP-2Me-cAMP). Isoprenaline-induced inhibition of [3 H]ACh release was also prevented by inhibitors of PKC (chelerythrine and Go6976) and of the equilibrative nucleoside transporter 1 (ENT1; dipyridamole and NBTI), but not by PLC inhibition with U73122. Pretreatment with ESI-09, but not with H-89, prevented the reduction of the voiding frequency caused by isoprenaline and forskolin in vivo. Conclusion and implications: Data suggest that β3 -adrenoceptor-induced inhibition of cholinergic neurotransmission in human and rat urinary bladders involves activation of an EPAC1/PKC pathway downstream cAMP production resulting in adenosine outflow via ENT1.
- The impact of the coronavirus disease 2019 pandemic on the utilisation of emergency urological servicesPublication . Madanelo, Mariana; Ferreira, Carlos; Nunes-Carneiro, Diogo; Pinto, André; Rocha, Maria Alexandra; Correia, Jorge; Teixeira, Bernardo; Mendes, Gonçalo; Tavares, Catarina; Mesquita, Sofia; Fraga, AvelinoObjectives: To compare the number of patients attending the Urology Emergency Department (ED) of the Centro Hospitalar Universitário do Porto (CHUP), as well as their demographic characteristics, the reasons for admission, the clinical severity under the Manchester triage system (MTS), and the need for emergency surgery or hospitalisation, during the coronavirus disease 2019 (COVID-19) pandemic and the equivalent period in 2019. Patients and methods: Data were collected from patients attending the Urology ED of the CHUP over 3 weeks, from 11 March to 1 April 2020, and from the same period in the previous year (from 11 March to 1 April 2019). Results: During the pandemic, 46.4% fewer patients visited our urological ED (122 vs 263). There was no significant difference in the mean age or the number of old patients (aged ≥65 years) between the two periods. However, significantly fewer female patients sought emergency urological services during the COVID-19 pandemic period (32.7% vs 14.8%, P < 0.05). No significant differences were noted between different clinical severity groups under the MTS. In 2019, significantly less patients required hospitalisation. The most common reasons for admission, during both periods, were haematuria, renal colic and urinary tract infections. The authors recognise that the study has several limitations, namely, those inherent to its retrospective nature. Conclusion: COVID-19 significantly influenced people's urological care-seeking behaviour. Understanding the present situation is helpful for predicting future urological needs. Based on the results of this study, we have reason to speculate that people's requirements for urological services might grow explosively in the post-COVID-19 period. There should be further studies about the real state of long-term urological services and the consequences that this pandemic may have in terms of morbimortality not directly related to the severe acute respiratory syndrome coronavirus 2.
- eHealth and mHealth in prostate cancer detection and active surveillancePublication . Pereira-Azevedo, Nuno; Venderbos, L.eHealth and mobile health (mHealth) offer patients, healthcare providers, researchers, and policy makers new potential to improve wellness, practice prevention and reduce suffering from diseases. While the eHealth market is growing to an expected US $26 billion, its potential in the field of Urology is still underused. Research has shown that currently only 176 apps (of the 300,000 medical apps available) were found in the Apple App Store and Google Play Store, of which 20 were prostate cancer related. Three good examples of eHealth/mHealth applications are the Rotterdam Prostate Cancer Risk Calculator (RPCRC) website and app, the Prostate cancer Research International Active Surveillance (PRIAS) website and the Follow MyPSA app for men on active surveillance for prostate cancer: they are tools with a clear vision that offer true added value in daily clinical practice and which positively influence healthcare beyond borders. To increase the uptake of eHealth applications in the coming years, it is important to involve professionals in their design and development, and to guarantee the safety and privacy of its users and their data.
- Head-to-head comparison of prostate cancer risk calculators predicting biopsy outcomePublication . Pereira-Azevedo, Nuno; Verbeek, J.; Nieboer, D.; Bangma, C.; Roobol, M.Background: Multivariable risk calculators (RCs) predicting prostate cancer (PCa) aim to reduce unnecessary workup (e.g., MRI and biopsy) by selectively identifying those men at risk for PCa or clinically significant PCa (csPCa) (Gleason ≥7). The lack of an adequate comparison makes choosing between RCs difficult for patients, clinicians and guideline developers. We aim to perform a head-to-head comparison of seven well known RCs predicting biopsy outcome. Methods: Our study comprised 7,119 men from ten independent contemporary cohorts in Europe and Australia, who underwent prostate biopsy between 2007 and 2015. We evaluated the performance of the ERSPC RPCRC, Finne, Chun, ProstataClass, Karakiewicz, Sunnybrook, and PCPT 2.0 (HG) RCs in predicting the presence of any PCa and csPCa. Performance was assessed by discrimination, calibration and net benefit analyses. Results: A total of 3,458 (48%) PCa were detected; 1,784 (25%) men had csPCa. No particular RC stood out predicting any PCa: pooled area under the ROC-curve (AUC) ranged between 0.64 and 0.72. The ERSPC RPCRC had the highest pooled AUC 0.77 (95% CI: 0.73-0.80) when predicting csPCa. Decision curve analysis (DCA) showed limited net benefit in the detection of csPCa, but that can be improved by a simple calibration step. The main limitation is the retrospective design of the study. Conclusions: No particular RC stands out when predicting biopsy outcome on the presence of any PCa. The ERSPC RPCRC is superior in identifying those men at risk for csPCa. Net benefit analyses show that a multivariate approach before further workup is advisable.
- Epigenome-wide DNA methylation profiling of periprostatic adipose tissue in prostate cancer patients with excess adiposity-a pilot studyPublication . Cheng, Y.; Monteiro, C.; Matos, A.; You, J.; Fraga, A.; Pereira, C.; Catalán, V.; Rodríguez, A.; Gómez-Ambrosi, J.; Frühbeck, G.; Ribeiro, R.; Hu, P.Background: Periprostatic adipose tissue (PPAT) has been recognized to associate with prostate cancer (PCa) aggressiveness and progression. Here, we sought to investigate whether excess adiposity modulates the methylome of PPAT in PCa patients. DNA methylation profiling was performed in PPAT from obese/overweight (OB/OW, BMI > 25 kg m-2) and normal weight (NW, BMI < 25 kg m-2) PCa patients. Significant differences in methylated CpGs between OB/OW and NW groups were inferred by statistical modeling. Results: Five thousand five hundred twenty-six differentially methylated CpGs were identified between OB/OW and NW PCa patients with 90.2% hypermethylated. Four hundred eighty-three of these CpGs were found to be located at both promoters and CpG islands, whereas the representing 412 genes were found to be involved in pluripotency of stem cells, fatty acid metabolism, and many other biological processes; 14 of these genes, particularly FADS1, MOGAT1, and PCYT2, with promoter hypermethylation presented with significantly decreased gene expression in matched samples. Additionally, 38 genes were correlated with antigen processing and presentation of endogenous antigen via MHC class I, which might result in fatty acid accumulation in PPAT and tumor immune evasion. Conclusions: Results showed that the whole epigenome methylation profiles of PPAT were significantly different in OB/OW compared to normal weight PCa patients. The epigenetic variation associated with excess adiposity likely resulted in altered lipid metabolism and immune dysregulation, contributing towards unfavorable PCa microenvironment, thus warranting further validation studies in larger samples.