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 Society

Background: 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

The NAD+-dependent deacetylase SIRT2 attenuates oxidative stress and mitochondrial dysfunction and improves insulin sensitivity in hepatocytes

Insulin resistance is a major predictor of the development of metabolic disorders. Sirtuins (SIRTs) have emerged as potential targets that can be manipulated to counteract age-related diseases, including type 2 diabetes. SIRT2 has been recently shown to exert important metabolic effects, but whether SIRT2 regulates insulin sensitivity in hepatocytes is currently unknown. The aim of this study is to investigate this possibility and to elucidate underlying molecular mechanisms. Here, we show that SIRT2 is downregulated in insulin-resistant hepatocytes and livers, and this was accompanied by increased generation of reactive oxygen species, activation of stress-sensitive ERK1/2 kinase, and mitochondrial dysfunction. Conversely, SIRT2 overexpression in insulin-resistant hepatocytes improved insulin sensitivity, mitigated reactive oxygen species production and ameliorated mitochondrial dysfunction. Further analysis revealed a reestablishment of mitochondrial morphology, with a higher number of elongated mitochondria rather than fragmented mitochondria instigated by insulin resistance. Mechanistically, SIRT2 was able to increase fusion-related protein Mfn2 and decrease mitochondrial-associated Drp1. SIRT2 also attenuated the downregulation of TFAM, a key mtDNA-associated protein, contributing to the increase in mitochondrial mass. Importantly, we found that SIRT2 expression in PBMCs of human subjects was negatively correlated with obesity and insulin resistance. These results suggest a novel function for hepatic SIRT2 in the regulation of insulin sensitivity and raise the possibility that SIRT2 activators may offer novel opportunities for preventing or treating insulin resistance and type 2 diabetes.European Regional Development Fund (ERDF), Centro 2020 Regional Operational Programme (CENTRO-01-0145-FEDER-000012: HealthyAging2020); COMPETE 2020 - Operational Programme for Competitiveness and Internationalisation and Portuguese national funds via FCT – Fundação para a Ciência e a Tecnologia (POCI-01-0145-FEDER-007440, SFRH/BPD/109347/2015 to R.M.O., SFRH/BD/86655/2012 to L.N. and SFRH/BPD/111815/2015 to P.G.); FLAD Life Science 2020 Grant to A.C.R.; European Molecular Biology Organization (EMBO Installation Grant to T.F.O.); DFG Center for Nanoscale Microscopy and Molecular Physiology of the Brain (CNMPB) to T.F.O

The NAD+-dependent deacetylase SIRT2 attenuates oxidative stress and mitochondrial dysfunction and improves insulin sensitivity in hepatocytes

Funding Information: European Regional Development Fund (ERDF), Centro 2020 Regional Operational Programme (CENTRO-01-0145-FEDER-000012: HealthyAging2020); COMPETE 2020 - Operational Programme for Competitiveness and Internationalisation and Portuguese national funds via FCT – Fundação para a Ciência e a Tecnologia (POCI-01-0145-FEDER-007440, SFRH/BPD/109347/ 2015 to R.M.O., SFRH/BD/86655/2012 to L.N. and SFRH/BPD/ 111815/2015 to P.G.); FLAD Life Science 2020 Grant to A.C.R.; European Molecular Biology Organization (EMBO Installation Grant to T.F.O.); DFG Center for Nanoscale Microscopy and Molecular Physiology of the Brain (CNMPB) to T.F.O.Insulin resistance is a major predictor of the development of metabolic disorders. Sirtuins (SIRTs) have emerged as potential targets that can be manipulated to counteract age-related diseases, including type 2 diabetes. SIRT2 has been recently shown to exert important metabolic effects, but whether SIRT2 regulates insulin sensitivity in hepatocytes is currently unknown. The aim of this study is to investigate this possibility and to elucidate underlying molecular mechanisms. Here, we show that SIRT2 is downregulated in insulin-resistant hepatocytes and livers, and this was accompanied by increased generation of reactive oxygen species, activation of stress-sensitive ERK1/2 kinase, and mitochondrial dysfunction. Conversely, SIRT2 overexpression in insulin-resistant hepatocytes improved insulin sensitivity, mitigated reactive oxygen species production and ameliorated mitochondrial dysfunction. Further analysis revealed a reestablishment of mitochondrial morphology, with a higher number of elongated mitochondria rather than fragmented mitochondria instigated by insulin resistance. Mechanistically, SIRT2 was able to increase fusion-related protein Mfn2 and decrease mitochondrial-associated Drp1. SIRT2 also attenuated the downregulation of TFAM, a key mtDNA-associated protein, contributing to the increase in mitochondrial mass. Importantly, we found that SIRT2 expression in PBMCs of human subjects was negatively correlated with obesity and insulin resistance. These results suggest a novel function for hepatic SIRT2 in the regulation of insulin sensitivity and raise the possibility that SIRT2 activators may offer novel opportunities for preventing or treating insulin resistance and type 2 diabetes.publishersversionpublishe

Novas Técnicas Endoscópicas de Diagnóstico do Carcinoma Urotelial do Trato Urinário Superior

Upper tract urothelial carcinoma (UTUC) is uncommon, but most cases are invasive at diagnosis. Standard of care in patients with UTUC is radical nephroureterectomy (RNU), but low risk UTUC can be treated with kidney sparing surgery (KSS) without compromising oncological outcomes. Current diagnostic techniques have many limitations on UTUC diagnosis, mainly in the detection of carcinoma in situ (CIS), a flat, high grade lesion with high progression risk. Therefore, investigating new diagnostic techniques which allow earlier detection of UTUC lesions has become a relevant matter. This review provides an overview of the new imaging diagnostic techniques currently available for UTUC diagnosis. A PubMed literature search was performed and articles on narrow band imaging (NBI), Image1 S, photodynamic diagnosis (PDD), confocal laser endomicroscopy (CLE) and optical coherence tomography (OCT) were reviewed. Six articles were selected for review, all of them referring to in vivo human studies. There were no articles on Image1 S. All techniques are compatible with existing flexible ureterorenoscopes. NBI, Image1 S and PDD aim at improving UTUC detection. CLE and OCT aim at providing minimally invasive and real-time histopathological diagnostic. Either NBI or PDD show a better lesion detection rate in comparison with conventional flexible ureterorenoscopy (FURS), but only PDD has shown a better CIS detection. CLE can differentiate healthy from malignant urothelium and high grade lesions from low grade ones. However, it does not allow staging. OCT shows higher UTUC staging and grading sensitivity than biopsy, but lesions greater than 2 mm can cause false-positives. Combining FURS with new diagnostic techniques could improve its diagnostic precision and capability to properly select KSS candidates. Further research needs to be conducted to validate these new diagnostic techniques on the UTUC diagnosis.O carcinoma urotelial do trato superior (CUTS) é raro, mas a maioria dos casos apresenta-se invasiva ao diagnóstico. O tratamento padrão do CUTS consiste na nefroureterectomia radical. No entanto, os CUTS de baixo risco podem ser abordados com cirurgia poupadora de nefrónios (CPN), sem compromisso do prognóstico oncológico. As técnicas de diagnóstico atuais apresentam várias falhas no diagnóstico de CUTS, principalmente na deteção de carcinoma in situ (CIS), uma lesão plana, de alto grau e com elevado risco de progressão. Assim, torna-se pertinente a investigação de novas técnicas de diagnóstico capazes de detetar as lesões de CUTS numa fase mais precoce. Esta revisão procura analisar o desempenho das novas técnicas de imagem disponíveis para o diagnóstico do CUTS. Foi conduzida uma pesquisa da literatura atual na base de dados PubMed e foram revistos artigos sobre a narrow band imaging (NBI), Image1 S, diagnóstico fotodinâmico (DFD), confocal laser endomicroscopy (CLE) e optical coherence tomography (OCT). Foram selecionados seis artigos para revisão, todos referentes a estudos in vivo em humanos. Não foi encontrado nenhum artigo sobre o Image1 S. Todas as técnicas descritas são compatíveis com os ureterorrenoscópios flexíveis atuais. A NBI, o Image1 S e o DFD visam uma melhor deteção do CUTS. A CLE e a OCT visam a caracterização histopatológica e minimamente invasiva das lesões, em tempo real. Quer a NBI, quer o DFD apresentam melhor taxa de deteção das lesões em comparação com a ureterorrenoscopia flexível (URSF) convencional, mas apenas o DFD mostrou melhor deteção de CIS. A CLE permite distinguir o urotélio saudável do maligno e as lesões de baixo grau das de alto grau. No entanto, não avalia o estadiamento. A OCT apresenta maior sensibilidade do que a biópsia para o estadiamento e gradação do CUTS, mas as lesões com mais de 2 mm de espessura podem gerar diagnósticos falsos-positivos. A combinação da URSF com uma ou várias das novas técnicas de diagnóstico poderia aumentar a sua precisão diagnóstica e capacidade de selecionar adequadamente os candidatos para CPN. São necessários mais estudos que validem a utilização das novas técnicas no diagnóstico de CUTS

Calyceal migration of vascular embolization coils used to treat massive hemorrhage following percutaneous nephrolithotomy: an endoscopic finding during repeat percutaneous nephrolithotomy

info:eu-repo/semantics/publishedVersio

Litíase em Rim em Ferradura em Doente com Ureter Reimplantado: A Propósito de um Caso Clínico

Horseshoe kidney is a common congenital renal anomaly and is often associated with urinary tract infections and renal calculi as a consequence of anatomical changes that impair the efficient drainage of the urine. The treatment of urinary stones in these cases becomes a challenge due to the underlying anatomical abnormalities requiring an adaptation of the techniques normally used for the treatment of renal lithiasis. We report the case of a 44-year-old woman with a past history of Cohen left ureteral reimplantation due to vesico-ureteral reflux in childhood and renal lithiasis. The patient had two 12 and 10 mm stones in the upper calix of the left hemi-kidney, with a narrow infundibulum. A flexible ureteroscopy with laser Holmium lithotripsy was performed by placement of a ureteral sheath over the narrowed infundibulum and the patient was left stone-free at the end of the procedure. It is important, in cases of horseshoe kidney stones, to think and adapt the various techniques available for the treatment of renal lithiasis, and to choose the one that will provide a higher success rate with fewer complications.O rim em ferradura é uma anomalia renal congénita muito comum, estando muitas vezes associada a infeções do trato urinário e a litíase renal como consequência das alterações anatómicas que dificultam uma drenagem eficaz de urina. O tratamento dos cálculos nestes casos torna-se um desafio devido às anomalias anatómicas subjacentes exigindo uma adaptação das técnicas normalmente utilizadas para o tratamento da litíase renal. O artigo reporta o caso de uma mulher de 44 anos, com uma história de reimplantação ureteral à esquerda do tipo Cohen por refluxo vesico-ureteral na infância e com litíase renal. A doente apresentava dois cálculos com 12 e 10 mm de maior diâmetro no pielão superior do hemi-rim esquerdo, cujo infundíbulo tinha um calibre estreito. Procedeu-se a uma ureterorrenoscopia flexível com litotrícia laser Holmium através da colocação de uma baínha ureteral acima do infundíbulo estreitado tendo a doente ficado sem cálculos no final do procedimento. Torna-se importante, nos casos de litíase em rim em ferradura, pensar e adaptar as várias técnicas disponíveis para o tratamento da litíase renal e eleger aquela que, à partida, proporcionará uma maior taxa de sucesso com menos complicações

Contemporary patterns of presentation, diagnostics and management of upper tract urothelial cancer in 101 centres: The Clinical Research Office of the Endourological Society Global upper tract urothelial carcinoma registry

PURPOSE OF REVIEW: To assess patterns of presentation, diagnostics and treatment in patients with upper tract urothelial carcinoma (UTUC), a multicentre registry was launched. Clinical data of UTUC patients were prospectively collected over a 5-year period. RECENT FINDINGS: Data from 2380 patients were included from 2014 to 2019 (101 centres in 29 countries). Patients were predominantly male (70.5%) and 53.3% were past or present smokers. The majority of patients (58.1%) were evaluated because of symptoms, mainly macroscopic hematuria. Computed tomography (CT) was the most common performed imaging modality (90.5%). A ureteroscopy (URS) was part of the diagnostic process in 1184 (49.7%) patients and 488 (20.5%) patients were treated endoscopically. In total, 1430 patients (60.1%) were treated by a radical nephroureterectomy, 59% without a prior diagnostic URS. Eighty-two patients (3.4%) underwent a segmental resection, 19 patients (0.8%) were treated by a percutaneous tumour resection. SUMMARY: Our data is in line with the known epidemiologic characteristics of UTUC. CT imaging is the preferred imaging modality as also recommended by guidelines. Diagnostic URS gained a stronger position, however, in almost half of patients a definitive treatment decision was made without complete endoscopic information. Only one-third of patients with UTUC are currently treated with kidney sparing surgery

SIRT2 Deficiency Exacerbates Hepatic Steatosis via a Putative Role of the ER Stress Pathway

Nonalcoholic fatty liver disease (NAFLD), a condition strongly associated with obesity and insulin resistance, is characterized by hepatic lipid accumulation and activation of the endoplasmic reticulum (ER) stress response. The sirtuin 2 (SIRT2) protein deacetylase is emerging as a new player in metabolic homeostasis, but its role in the development of hepatic steatosis and its link with ER stress activation remains unknown. SIRT2-knockout (SIRT2-KO) and wild-type mice were fed either a control or a high-fat diet (HFD) for 4 weeks. Genetic manipulation of SIRT2 levels was performed in human hepatic cells. Although apparently normal under a control diet, SIRT2-KO mice showed accelerated body weight gain and adiposity on a HFD, accompanied by severe insulin resistance. Importantly, SIRT2-KO mice exhibited worsened hepatic steatosis independently from diet, consistent with upregulated gene expression of lipogenic enzymes and increased expression of ER stress markers. Exposure of hepatic cells to palmitate induced lipid accumulation, increased ER stress, and decreased SIRT2 expression. Moreover, SIRT2-silenced cells showed enhanced lipid accumulation and ER stress activation under basal conditions, whereas SIRT2 overexpression abrogated palmitate-induced lipid deposition and ER stress activation. Our findings reveal a role for SIRT2 in the regulation of hepatic lipid homeostasis, potentially through the ER stress response, suggesting that SIRT2 activation might constitute a therapeutic strategy against obesity and its metabolic complications

Prospective evaluation on the effect of interobserver variability of digital rectal examination on the performance of the Rotterdam Prostate Cancer Risk Calculator

To assess the level of agreement between digital rectal examination findings of two urologists and its effect on risk prediction using the digital rectal examination-based Rotterdam Prostate Cancer Risk Calculator

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 study

The 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.info:eu-repo/semantics/publishedVersio