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BACKGROUND: We compared protection of mycophenolate mofetil (MMF) and azathioprine (AZA) against acute cellular rejection (ACR) and chronic allograft nephropathy (CAN) in kidney transplant recipients on steroid-free, low-dose cyclosporine (CsA) microemulsion maintenance immunosuppression. METHODS AND FINDINGS: ATHENA, a pragmatic, prospective, multicenter trial conducted by 6 Italian transplant centers, compared the outcomes of 233 consenting recipients of a first deceased donor kidney transplant induced with low-dose thymoglobulin and basiliximab and randomized to MMF (750 mg twice/day, n = 119) or AZA (75 to 125 mg/day, n = 114) added-on maintenance low-dose CsA microemulsion and 1-week steroid. In patients without acute clinical or subclinical rejections, CsA dose was progressively halved. Primary endpoint was biopsy-proven CAN. Analysis was by intention to treat. Participants were included between June 2007 and July 2012 and followed up to August 2016. Between-group donor and recipient characteristics, donor/recipient mismatches, and follow-up CsA blood levels were similar. During a median (interquartile range (IQR)) follow-up of 47.7 (44.2 to 48.9) months, 29 of 87 biopsied patients on MMF (33.3%) versus 31 of 88 on AZA (35.2%) developed CAN (hazard ratio (HR) [95% confidence interval (CI)]: 1.147 (0.691 to 1.904, p = 0.595). Twenty and 21 patients on MMF versus 34 and 14 on AZA had clinical [HR (95% CI): 0.58 (0.34 to 1.02); p = 0.057) or biopsy-proven subclinical [HR (95% CI): 1.49 (0.76 to 2.92); p = 0.249] ACR, respectively. Combined events [HR (95% CI): 0.85 (0.56 to 1.29); p = 0.438], patient and graft survival, delayed graft function (DGF), 3-year glomerular filtration rate (GFR) [53.8 (40.6;65.7) versus 49.8 (36.8;62.5) mL/min/1.73 m2, p = 0.50], and adverse events (AEs) were not significantly different between groups. Chronicity scores other than CAN predict long-term graft outcome. Study limitations include small sample size and unblinded design. CONCLUSIONS: In this study, we found that in deceased donor kidney transplant recipients on low-dose CsA and no steroids, MMF had no significant benefits over AZA. This finding suggests that AZA, due to its lower costs, could safely replace MMF in combination with minimized immunosuppression. TRIAL REGISTRATION: ClinicalTrials.gov NCT00494741; EUDRACT 2006-005604-14.
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Azatioprina/administração & dosagem , Ciclosporina/administração & dosagem , Rejeição de Enxerto/prevenção & controle , Sobrevivência de Enxerto/efeitos dos fármacos , Imunossupressores/administração & dosagem , Transplante de Rim , Ácido Micofenólico/administração & dosagem , Adulto , Idoso , Azatioprina/efeitos adversos , Ciclosporina/efeitos adversos , Quimioterapia Combinada , Feminino , Rejeição de Enxerto/diagnóstico , Rejeição de Enxerto/imunologia , Humanos , Imunossupressores/efeitos adversos , Itália , Transplante de Rim/efeitos adversos , Masculino , Pessoa de Meia-Idade , Ácido Micofenólico/efeitos adversos , Estudos Prospectivos , Fatores de Tempo , Resultado do TratamentoRESUMO
Urothelial bladder cancer (UBC) are classified into luminal and basal subtypes showing distinct molecular features and clinical behaviour. Recent in silico data have proposed the activation on the Signal Transducer and Activator of Transcription 3 (STAT3) as relevant transcription factor in UBC. To answer this question, we have combined the retrospective analysis of clinical samples, functional assays on cell lines, interrogation of public UBC datasets and a murine model of basal-type UBC. Immunohistochemistry on a retrospective UBC cohort uncovered that STAT3 Y705 phosphorylation (pSTAT3) is significantly increased in infiltrating basal-type UBC compared to luminal UBC. In vitro, STAT3 silencing in UBC cell lines significantly reduced tumor cell viability and invasion. Gene expression profile of UBC cell lines combined with the analysis of the Cancer Genome Atlas (TCGA) and GSE32894 UBC datasets showed that increased expression of a set of STAT3 targets predicts basal-type, propensity to local progression and worse prognosis. MYC and FOSL1 represent relevant STAT3 downstream targets, as validated by their co-localization in pSTAT3+ UBC cancer cells. These findings were largely reproduced in the BBN-induced murine model of basal-type UBC. Of note, FOSL1 protein resulted strongly expressed in the non-papillary UBC pathway and FOSL1-regulated transcripts were significantly enriched in the transition from NMIBC to MIBC, as indicated by the interrogation of the GSE32894 dataset. The blockade of the STAT3 pathway might represent a novel treatment option for these neoplasms. Monitoring pSTAT3 and the downstream targets, particularly FOSL1, could provide meaningful levels of UBC stratification.
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BACKGROUND/AIM: Clear cell renal cell carcinoma (ccRCC) shows variable chromosomal abnormalities. The aim of this study was to assess the prognostic role of ccRCC chromosomal abnormalities in a single-center cohort with an extended follow-up. MATERIALS AND METHODS: A systematic cytogenetic analysis was performed in 283 consecutive surgically-treated patients for renal masses between 1997 and 2002. Kaplan-Meier and multivariable Cox regression (MCR) models were used to calculate cancer specific survival (CSS). RESULTS: Among 174 ccRCC patients, the most common abnormality was deletion in chromosome 3 (54.6%). At a median follow-up of 119 months, 38 patients (21.8%) died from RCC. At MCR models, worse CSS was independently predicted by deletions in chromosomes 2, 19, 20 or 22 and insertions in chromosome 18. CONCLUSION: Specific ccRCC chromosomal abnormalities are independently associated with worse CSS. Cytogenetic evaluation may direct further genetic analysis for personalized prognostic stratification.
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Carcinoma de Células Renais/mortalidade , Carcinoma de Células Renais/cirurgia , Aberrações Cromossômicas , Cromossomos Humanos/genética , Neoplasias Renais/mortalidade , Neoplasias Renais/cirurgia , Idoso , Carcinoma de Células Renais/genética , Deleção Cromossômica , Citogenética , Feminino , Humanos , Estimativa de Kaplan-Meier , Neoplasias Renais/genética , Masculino , Pessoa de Meia-Idade , Mutagênese Insercional , Prognóstico , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Resultado do TratamentoRESUMO
BACKGROUND: The VALidation of IGA (VALIGA) study investigated the utility of the Oxford Classification of immunoglobulin A nephropathy (IgAN) in 1147 patients from 13 European countries. Methods. Biopsies were scored by local pathologists followed by central review in Oxford. We had two distinct objectives: to assess how closely pathology findings were associated with the decision to give corticosteroid/immunosuppressive (CS/IS) treatments, and to determine the impact of differences in MEST-C scoring between central and local pathologists on the clinical value of the Oxford Classification. We tested for each lesion the associations between the type of agreement (local and central pathologists scoring absent, local present and central absent, local absent and central present, both scoring present) with the initial clinical assessment, as well as long-term outcomes in those patients who did not receive CS/IS. RESULTS: All glomerular lesions (M, E, C and S) assessed by local pathologists were independently associated with the decision to administer CS/IS therapy, while the severity of tubulointerstitial lesions was not. Reproducibility between local and central pathologists was moderate for S (segmental sclerosis) and T (tubular atrophy/interstitial fibrosis), and poor for M (mesangial hypercellularity), E (endocapillary hypercellularity) and C (crescents). Local pathologists found statistically more of each lesion, except for the S lesion, which was more frequent with central review. Disagreements were more likely to occur when the proportion of glomeruli affected was low. The M lesion, assessed by central pathologists, correlated better with the severity of the disease at presentation and discriminated better with outcomes. In contrast, the E lesion, evaluated by local pathologists, correlated better with the clinical presentation and outcomes when compared with central review. Both C and S lesions, when discordant between local and central pathologists, had a clinical phenotype intermediate to double absent lesions (milder disease) and double present (more severe). CONCLUSION: We conclude that differences in the scoring of MEST-C criteria between local pathologists and a central reviewer have a significant impact on the prognostic value of the Oxford Classification. Since the decision to offer immunosuppressive therapy in this cohort was intimately associated with the MEST-C score, this study indicates a need for a more detailed guidance for pathologists in the scoring of IgAN biopsies.
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Glomerulonefrite por IGA/classificação , Glomerulonefrite por IGA/patologia , Modelos Estatísticos , Variações Dependentes do Observador , Seleção de Pacientes , Biópsia , Taxa de Filtração Glomerular , Glomerulonefrite por IGA/tratamento farmacológico , Humanos , Imunossupressores/uso terapêutico , Prognóstico , Reprodutibilidade dos Testes , Estudos RetrospectivosRESUMO
BACKGROUND: The role of positive surgical margins (PSMs) on the recurrence of renal cell carcinoma (RCC) after partial nephrectomy (PN) is debated, and available evidence lacks long-term data. The aim of this study was to evaluate the predictive role of PSMs on progression-free survival (PFS) in a large cohort followed for at least 5 years. METHODS: This study was a retrospective analysis of a prospectively compiled single-institution database collecting complete information on more than 2700 patients who had undergone surgery for renal tumor. The data of all the patients submitted to PN for RCC and with least 5 years follow-up were extracted. Surgical specimens were examined at the time of surgery only by 2 expert uro-pathologists. A PSM was defined as the presence of cancer cells at the inked surface of the specimen. The role of PSMs on survival was estimated by Cox regression models adjusted for influent covariates. RESULTS: A total of 459 patients fulfilled the inclusion criteria and were evaluated. PSMs were observed in 27 (5.9%) cases. No differences in preoperative and pathologic data were found comparing patients with and without PSMs. At a median follow-up of 96 months (interquartile range, 74-131 months), a clinically evident relapse of RCC was diagnosed in 36 (7.8%) patients at a median interval of 36 months from PN. Among these, 6 had a PSM for an incidence of relapse of 22.2% in the PSM group, whereas 30 had negative margins, for an incidence of 6.9% (P = .013). The sites of relapse were distant organs in 18 cases, and the kidney underwent PN in 21. The patients with PSMs showed a borderline significantly higher incidence of distant metastasis (11.1% vs. 3.5%; P = .071) and a significantly higher incidence of renal relapses (14.8% vs. 3.9%; P = .029). Multivariable Cox models confirmed that the presence of PSMs was an independent predictor of PFS (odds ratio, 3.127; P = .013). CONCLUSIONS: PSMs are an independent predictor of PFS in patients who underwent PN for RCC, owing to a higher incidence of distant and local relapses. Surveillance in presence of PSMs should be intensified and extended for a long time.
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Carcinoma de Células Renais/mortalidade , Neoplasias Renais/mortalidade , Margens de Excisão , Recidiva Local de Neoplasia/mortalidade , Nefrectomia/mortalidade , Néfrons/cirurgia , Tratamentos com Preservação do Órgão/mortalidade , Carcinoma de Células Renais/patologia , Carcinoma de Células Renais/cirurgia , Feminino , Seguimentos , Humanos , Neoplasias Renais/patologia , Neoplasias Renais/cirurgia , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/patologia , Recidiva Local de Neoplasia/cirurgia , Néfrons/patologia , Prognóstico , Estudos Prospectivos , Estudos Retrospectivos , Taxa de SobrevidaRESUMO
Renal cell carcinomas with t(6;11) chromosome translocation involving the TFEB gene are indolent neoplasms which often occur in young patients. In this study, we report seven cases of renal cell carcinoma with TFEB rearrangement, two of whom had histologically proven metastasis. Patients (4F, 3M) ranged in age from 19 to 55 years (mean 37). One patient developed paratracheal and pleural metastases 24 months after surgery and died of disease after 46 months; another one recurred with neoplastic nodules in the perinephric fat and pelvic soft tissue. Histologically, either cytological or architectural appearance was peculiar in each case whereas one tumor displayed the typical biphasic morphology. By immunohistochemistry, all tumors labelled for cathepsin K, Melan-A and CD68 (KP1 clone). HMB45 and PAX8 staining were detected in six of seven tumors. All tumors were negative for CD68 (PG-M1 clone), CKAE1-AE3, CK7, CAIX, and AMACR. Seven pure epithelioid PEComa/epithelioid angiomyolipomas, used as control, were positive for cathepsin K, melanocytic markers, and CD68 (PG-M1 and KP1) and negative for PAX8. Fluorescence in situ hybridization results showed the presence of TFEB gene translocation in all t(6;11) renal cell carcinomas with a high frequency of split TFEB fluorescent signals (mean 74%). In the primary and metastatic samples of the two aggressive tumors, increased gene copy number was observed (3-5 fluorescent signals per neoplastic nuclei) with a concomitant increased number of CEP6. Review of the literature revealed older age and larger tumor size as correlating with aggressive behavior in these neoplasms. In conclusion, we present the clinical, morphological and molecular features of seven t(6;11) renal cell carcinomas, two with histologically demonstrated metastasis. We report the high frequency of split signals by FISH in tumors with t(6;11) chromosomal rearrangement and the occurrence of TFEB gene copy number gains in the aggressive cases, analyzing either the primary or metastatic tumor. Finally, we demonstrate the usefulness of CD68 (PG-M1) immunohistochemical staining in distinguishing t(6;11) renal cell carcinoma from pure epithelioid PEComa/epithelioid angiomyolipoma.
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Antígenos CD/análise , Antígenos de Diferenciação Mielomonocítica/análise , Biomarcadores Tumorais/análise , Carcinoma de Células Renais/química , Carcinoma de Células Renais/secundário , Neoplasias Renais/química , Neoplasias Renais/patologia , Adulto , Angiomiolipoma/química , Angiomiolipoma/patologia , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/genética , Carcinoma de Células Renais/genética , Cromossomos Humanos Par 11/genética , Cromossomos Humanos Par 6/genética , Diagnóstico Diferencial , Feminino , Humanos , Imuno-Histoquímica , Hibridização in Situ Fluorescente , Neoplasias Renais/genética , Masculino , Pessoa de Meia-Idade , Neoplasias de Células Epitelioides Perivasculares/química , Neoplasias de Células Epitelioides Perivasculares/patologia , Translocação GenéticaRESUMO
BACKGROUND: Poor data are reported on the pathogenesis of ipsilateral relapse (IR) after partial nephrectomy (PN). The objective of this study was to investigate features of IR after PN with the intention to propose a pathogenetic classification. MATERIALS AND METHODS: Retrospective consultation of an institutional database that stores the data of 683 patients submitted to PN since 1993. The clinical, radiological, and follow-up data of the cases submitted to salvage nephrectomy due to an IR were analyzed. The slides of the sections from the tumor-parenchyma interface of PN and the bed of resection from the specimen of nephrectomy were reviewed. RESULTS: Eighteen patients were submitted to salvage nephrectomy for an IR. In 12 cases the IR harbored into the site of PN and a mixture of cancer cells and granulomatous reaction was found at the resection bed (IR type A). In the remaining 6, in microscopy of the resection bed was found only fibrosis: 3 of these cases had a clear-cell renal cell carcinoma (RCC) with diffuse microvascular embolization and the relapse in the same portion of the kidney of the primary tumor (IR type B); the other 3 had a non-clear-cell RCC and the primary and relapsing tumors were located in distinct portions of the kidney (IR type C). Six patients (4 IR type A, 2 type B) had a further progression and 5 of them died due to RCC. CONCLUSION: More frequently an IR is due to the incomplete resection of the primary tumor (IR type A), in a minority of the cases to the local spread of the tumor by microvascular embolization (IR type B), or true multifocality (IR type C). The prognosis of IR not due to multifocality (type A and B) is poor, despite salvage nephrectomy.
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Carcinoma de Células Renais/patologia , Neoplasias Renais/patologia , Recidiva Local de Neoplasia/patologia , Idoso , Carcinoma de Células Renais/cirurgia , Feminino , Humanos , Neoplasias Renais/cirurgia , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/cirurgia , Nefrectomia , Tratamentos com Preservação do Órgão , Prognóstico , Estudos Retrospectivos , Terapia de Salvação , Resultado do TratamentoRESUMO
PURPOSE: The surface, intermediate, and basis (SIB) is a system based on surgeon׳s visual assessment of the thickness of healthy parenchyma remaining on the intrarenal portion of the tumor. This system has been proposed to standardize the nomenclature of the resection technique (RT) during partial nephrectomy (PN). Our study aims at evaluating whether the SIB score visually assigned is related to the thickness of parenchyma measured by microscopy. MATERIALS AND METHODS: Data of 52 patients submitted to PN from April to October 2015 were perspectively collected. All the excisions were performed following a "nonanatomical" strategy according to our institutional intention to resect the tumor with a visible margin of parenchyma. After the removal of the specimen, 2 trained examiners applied the SIB system: the intrarenal portion of the nodule was ideally divided into 3 circumferential sectors (surface, intermediate, and basis); on each of these was identified the area covered by the lowest amount of parenchyma (score specific area [SSA]); and a score descriptive of the thickness of parenchyma was assigned to each area. The RT performed (enucleation, enucleoresection, or wedge resection) was defined by the sum of the scores. The same examiners inked every SSAs with a different color and then dedicated pathologists, blinded of the scores assigned, and microscopically measured the parenchyma covering each SSA. The relationship between these values and the SIB scores was assessed. RESULTS: According to the SIB nomenclature, the technique performed was enucleation for 31 patients (60%), enucleoresection for 16 (31%), and wedge resection for 5 (9%). For the surface SSA, the median/mean values of the thickness for S = 0 vs. S = 1 was 0.35/0.84 vs. 2.00/2.26mm and for the intermediate or base SSA, the median/mean value of the thickness for S = 0 vs. 1 vs. 2 was 0.35/0.47 vs. 1.00/1.50 vs. 2.00.5/2.33mm. All the comparison reached statistical significance. CONCLUSIONS: The visual description of the surgical plane followed during PN according to the SIB system is related to the microscopic thickness of healthy parenchyma covering the tumor. The SIB system can correctly discriminate among different R techniques, and therefore could be a crucial tool to standardize the nomenclature of PN.
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Carcinoma de Células Renais/cirurgia , Neoplasias Renais/cirurgia , Margens de Excisão , Nefrectomia/métodos , Tecido Parenquimatoso/diagnóstico por imagem , Tecido Parenquimatoso/patologia , Idoso , Feminino , Humanos , Masculino , Microscopia , Pessoa de Meia-Idade , Terminologia como AssuntoRESUMO
Prostate cancer is a leading cause of cancer-related death in males worldwide. Indeed, advanced and metastatic disease characterized by androgen resistance and often associated with neuroendocrine (NE) differentiation remains incurable. Using the spontaneous prostate cancer TRAMP model, we have shown that mast cells (MCs) support in vivo the growth of prostate adenocarcinoma, whereas their genetic or pharmacologic targeting favors prostate NE cancer arousal. Aiming at simultaneously targeting prostate NE tumor cells and MCs, both expressing the cKit tyrosine kinase receptor, we have tested the therapeutic effect of imatinib in TRAMP mice. Imatinib-treated TRAMP mice experience a partial benefit against prostate adenocarcinoma, because of inhibition of supportive MCs. However, they show an unexpected outgrowth of prostate NE tumors, likely because of defective signaling pathway downstream of cKit receptor. Also unexpected but very effective was the inhibition of epithelial-stromal tumors of the seminal vesicles achieved by imatinib treatment. These tumors normally arise in the seminal vesicles of TRAMP mice, independently of the degree of prostatic glandular lesions, and resemble phyllodes tumors found in human prostate and seminal vesicles, and in breast. In both mice and in patients, these tumors are negative for cKit but express PDGFR-ß, another tyrosine kinase receptor specifically inhibited by imatinib. Our results imply a possible detrimental effect of imatinib in prostate cancer patients but suggest a promising therapeutic application of imatinib in the treatment of recurrent or metastatic phyllodes tumors. Mol Cancer Ther; 16(2); 365-75. ©2016 AACR.
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Antineoplásicos/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Mesilato de Imatinib/farmacologia , Tumores Neuroendócrinos/genética , Tumores Neuroendócrinos/metabolismo , Neoplasias da Próstata/genética , Neoplasias da Próstata/metabolismo , Proteínas Proto-Oncogênicas c-kit/genética , Receptor beta de Fator de Crescimento Derivado de Plaquetas/antagonistas & inibidores , Animais , Biomarcadores , Modelos Animais de Doenças , Feminino , Humanos , Imuno-Histoquímica , Masculino , Camundongos , Camundongos Transgênicos , Tumores Neuroendócrinos/tratamento farmacológico , Tumores Neuroendócrinos/patologia , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/patologia , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-kit/metabolismo , Receptor beta de Fator de Crescimento Derivado de Plaquetas/genética , Receptor beta de Fator de Crescimento Derivado de Plaquetas/metabolismo , Glândulas Seminais/metabolismo , Glândulas Seminais/patologia , Transdução de Sinais/efeitos dos fármacos , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
BACKGROUND: There is a need for early identification of children with immunoglobulin A nephropathy (IgAN) at risk of progression of kidney disease. METHODS: Data on 261 young patients [age <23 years; mean follow-up of 4.9 (range 2.5-8.1) years] enrolled in VALIGA, a study designed to validate the Oxford Classification of IgAN, were assessed. Renal biopsies were scored for the presence of mesangial hypercellularity (M1), endocapillary hypercellularity (E1), segmental glomerulosclerosis (S1), tubular atrophy/interstitial fibrosis (T1-2) (MEST score) and crescents (C1). Progression was assessed as end stage renal disease and/or a 50 % loss of estimated glomerular filtration rate (eGFR) (combined endpoint) as well as the rate of renal function decline (slope of eGFR). Cox regression and tree classification binary models were used and compared. RESULTS: In this cohort of 261 subjects aged <23 years, Cox analysis validated the MEST M, S and T scores for predicting survival to the combined endpoint but failed to prove that these scores had predictive value in the sub-group of 174 children aged <18 years. The regression tree classification indicated that patients with M1 were at risk of developing higher time-averaged proteinuria (p < 0.0001) and the combined endpoint (p < 0.001). An initial proteinuria of ≥0.4 g/day/1.73 m2 and an eGFR of <90 ml/min/1.73 m2 were determined to be risk factors in subjects with M0. Children aged <16 years with M0 and well-preserved eGFR (>90 ml/min/1.73 m2) at presentation had a significantly high probability of proteinuria remission during follow-up and a higher remission rate following treatment with corticosteroid and/or immunosuppressive therapy. CONCLUSION: This new statistical approach has identified clinical and histological risk factors associated with outcome in children and young adults with IgAN.
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Glomerulonefrite por IGA/epidemiologia , Corticosteroides/uso terapêutico , Fatores Etários , Biópsia , Criança , Pré-Escolar , Estudos de Coortes , Progressão da Doença , Determinação de Ponto Final , Europa (Continente)/epidemiologia , Feminino , Taxa de Filtração Glomerular , Glomerulonefrite por IGA/tratamento farmacológico , Glomerulonefrite por IGA/patologia , Humanos , Imunossupressores , Lactente , Rim/patologia , Falência Renal Crônica/epidemiologia , Falência Renal Crônica/patologia , Masculino , Proteinúria/epidemiologia , Proteinúria/patologia , Estudos Retrospectivos , Fatores de Risco , Fatores Sexuais , Análise de SobrevidaRESUMO
BACKGROUND: The aim of this study was to analyze the rates of positive surgical margins (PSM) after radical prostatectomy in patients undergoing robotic surgery (robot assisted laparoscopic prostatectomy [RALP]) compared with those undergoing open surgery (radical retropubic prostatectomy [RRP]), at an institution with medium case load. METHODS: Retrospective consultation of a perspectively-maintained database that stores the data of all the patients submitted to radical prostatectomy at our institution since 1/2008. The indication to RRP vs. RALP was based almost exclusively on the period of the study: RRP was the sole available option between 1/2008 and 3/2010 and afterwards RALP become the standard of treatment, once a learning curve of 50 cases was concluded. A PSM was defined as the presence of cancer at the inked surface of prostate. A univariate and multivariate binary logistic regression estimated which factors were related to PSMs. RESULTS: The data of 576 patients (285 RRP, 291 RALP) were evaluated. The overall PSM rate was 28.1% (162/414 patients; 20.6% for pT2 stage, 51.8% for pT>2); overall PSM rate for RRP vs. RALP was 31.9% vs. 24.4 % (P=0.044). At multivariable analysis the factors related to the risk of PSM were stage pT>2 (RR 2.979, P=0.001), Gleason Score >6 (RR 1.662, P=0.026), the volume of tumor (RR 1.019, P=0.008) and the surgical technique (RALP vs. RRP, RR 0.647, P=0.039). CONCLUSIONS: In a series from a medium case-load institution, once data are adjusted for local staging, tumor volume and Gleason score, the risk of PSM is lower for RALP than RRP. This evidence could be of support for health-care practitioners to introduce robotic systems.
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Margens de Excisão , Prostatectomia/métodos , Neoplasias da Próstata/patologia , Neoplasias da Próstata/cirurgia , Procedimentos Cirúrgicos Robóticos , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Tempo , Resultado do TratamentoRESUMO
OBJECTIVE: To evaluate the features and the predictors of "very late" recurrences after surgery for localized renal cell carcinoma. METHODS: Since 1983, an institutional database with data of more than 2300 consecutive patients treated for renal cancer has been prospectively maintained. Patients N0 /Nx M0 followed for a minimum of 10 years without recurrences were retrieved. The site, time and treatment of recurrences observed afterwards were recorded, and the predictors were investigated by Cox regression analysis. RESULTS: A total of 554 patients (231 women, 323 men; age 59.3 ± 11.6 years) followed for a mean/median time of 15.1/13.6 years (range 10.0-34.1 years) were analyzed. A recurrence was observed in 26 patients (4.6%) after a mean/median interval of 13.3/12.3 years (range 10.5-30.2 years). The pathological stage 2/3 was the only independent predictor of recurrence (P = 0.003), and it was related also to the latency of recurrence (mean/median latency 15.4/14.0, 11.4/10.8 and 12.5/12.0 years, respectively, for stage 1, 2 and 3; P < 0.005 for stage 1 vs stage 2 or 3). The contralateral kidney was the most frequent site of relapse in patients with stage pT1, whereas multiple sites were more frequent for stage pT2 and pT3. CONCLUSIONS: The risk of a "very late" recurrence of renal cancer is approximately 5%, and it depends on the pathological stage. For stage pT1, the kidney/s should be surveilled for indefinite time, preferably by ultrasound to reduce the X-ray exposition; for stage pT2 and pT3, the abdomen and the lungs should be monitored, by computed tomography scan during the first years, and then by abdominal ultrasound and chest X-ray.
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Carcinoma de Células Renais/secundário , Carcinoma de Células Renais/cirurgia , Neoplasias Renais/patologia , Neoplasias Renais/cirurgia , Recidiva Local de Neoplasia/patologia , Idoso , Intervalo Livre de Doença , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Estudos Retrospectivos , Fatores de Risco , Taxa de Sobrevida , Fatores de TempoRESUMO
OBJECTIVES: To evaluate the prognostic role of venous tumor thrombus consistency in patients with renal cell carcinoma. METHODS: A retrospective evaluation of the data of patients with renal cell carcinoma and a tumor thrombosis submitted to surgery from 2000 to 2013 was carried out. Histological slides were revised by two uropathologists, blinded of the clinical outcome, to assess venous tumor thrombus consistency classified as solid venous tumor thrombus consistency or friable venous tumor thrombus consistency. The statistical correlation between venous tumor thrombus consistency and other adverse features was assessed. Then the predictive ability of an integrated prognostic model, generated by Cox regression and random survival forest, was evaluated, with and without the inclusion of venous tumor thrombus consistency, by integrated Brier score, dynamic receiver operating characteristic curves, integrated discrimination improvement index and category-less net reclassification index. RESULTS: The data of 147 patients were analyzed, 79 with a solid venous tumor thrombus consistency and 68 with a friable venous tumor thrombus consistency, followed for a median period of 40.5 months. Venous tumor thrombus consistency was assessed with a high interobserver agreement (145/147 cases). The presence of a friable venous tumor thrombus consistency was associated with some adverse prognostic factors (symptoms, lymphnodal and distant metastasis, larger tumor diameter, higher cephalad thrombosis level, necrosis, microvascular invasion) and to a worse cancer-specific and overall survival at univariate analysis. However, venous tumor thrombus consistency was not predictive of survival, and did not improve the performance of a multivariable model that included a set of informative predictors. CONCLUSION: Venous tumor thrombus consistency does not seem to have an independent prognostic role in patients with renal cell carcinoma.
Assuntos
Carcinoma de Células Renais/patologia , Neoplasias Renais/patologia , Veias Renais/patologia , Trombose/patologia , Veia Cava Inferior/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica , Valor Preditivo dos Testes , Prognóstico , Estudos Retrospectivos , Taxa de SobrevidaRESUMO
Apolipoprotein A-I is the main protein of high-density lipoprotein particles, and is encoded by the APOA1 gene. Several APOA1 mutations have been found, either affecting the lecithin:cholesterol acyltransferase activity, determining familial HDL deficiency, or resulting in amyloid formation with prevalent deposits in the kidney and liver. Evaluation of familial tubulointerstitial nephritis in patients with the Leu75Pro APOA-I amyloidosis mutation resulted in the identification of 253 carriers belonging to 50 families from Brescia, Italy. A total of 219 mutation carriers underwent clinical, laboratory, and instrumental tests. Of these, 62% had renal, hepatic, and testicular disease; 38% were asymptomatic. The disease showed an age-dependent penetrance. Tubulointerstitial nephritis was diagnosed in 49% of the carriers, 13% of whom progressed to kidney failure requiring dialysis. Hepatic involvement with elevation of cholestasis indices was diagnosed in 30% of the carriers, 38% of whom developed portal hypertension. Impaired spermatogenesis and hypogonadism was found in 68% of male carriers. The cholesterol levels were lower than normal in 80% of the mutation carriers. Thus, tubulointerstitial nephritis was highly prevalent in this large series of patients with Leu75Pro apoA-I amyloidosis. Persistent elevation of alkaline phosphatase, reduced HDL cholesterol plasma levels, and hypogonadism in men are key diagnostic features of this form of amyloidosis.
Assuntos
Amiloidose Familiar/genética , Apolipoproteína A-I/genética , Nefrite Intersticial/etiologia , Adulto , Idade de Início , Idoso , Fosfatase Alcalina/sangue , Amiloidose Familiar/complicações , Amiloidose Familiar/diagnóstico , HDL-Colesterol/sangue , Creatinina/sangue , Feminino , Taxa de Filtração Glomerular , Heterozigoto , Humanos , Hipogonadismo/etiologia , Hepatopatias/etiologia , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Nefrite Intersticial/epidemiologia , Nefrite Intersticial/patologia , Nefrite Intersticial/fisiopatologia , Penetrância , Estudos Retrospectivos , Doenças Testiculares/etiologia , Doenças Testiculares/patologiaRESUMO
Glomerular planted antigens (histones, DNA, and C1q) are potential targets of autoimmunity in lupus nephritis (LN). However, the characterization of these antigens in human glomeruli in vivo remains inconsistent. We eluted glomerular autoantibodies recognizing planted antigens from laser-microdissected renal biopsy samples of 20 patients with LN. Prevalent antibody isotypes were defined, levels were determined, and glomerular colocalization was investigated. Renal and circulating antibodies were matched, and serum levels were compared in 104 patients with LN, 84 patients with SLE without LN, and 50 patients with rheumatoid arthritis (RA). Autoantibodies against podocyte antigens (anti-α-enolase/antiannexin AI) were also investigated. IgG2 autoantibodies against DNA, histones (H2A, H3, and H4), and C1q were detected in 50%, 55%, and 70% of biopsy samples, respectively. Anti-DNA IgG3 was the unique non-IgG2 anti-DNA deposit, and anti-C1q IgG4 was mainly detected in subepithelial membranous deposits. Anti-H3, anti-DNA, and anti-C1q IgG2 autoantibodies were also prevalent in LN serum, which also contained IgG3 against the antigen panel and anti-C1q IgG4. Serum and glomerular levels of autoantibodies were not strictly associated. High serum levels of all autoantibodies detected, including anti-α-enolase and antiannexin AI, identified LN versus SLE and RA. Anti-H3 and anti-α-enolase IgG2 levels had the most remarkable increase in LN serum and represented a discriminating feature of LN in principal component analysis. The highest levels of these two autoantibodies were also associated with proteinuria>3.5 g/24 hours and creatinine>1.2 mg/dl. Our findings suggest that timely autoantibody characterization might allow outcome prediction and targeted therapies for patients with nephritis.
Assuntos
Autoanticorpos/análise , Nefrite Lúpica/imunologia , Podócitos/imunologia , Adolescente , Adulto , Idoso , Linhagem Celular , Complemento C1q/imunologia , DNA/imunologia , Feminino , Histonas/imunologia , Humanos , Nefrite Lúpica/sangue , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
One of the main concerns associated with renal transplantation in HIV-infected patients is the high risk of acute rejection, which makes physicians reluctant to use steroid-free immunosuppressive therapy in this subset of patients. However, steroid therapy increases cardiovascular morbidity and mortality. The aim of this study was to define the efficacy of a steroid-sparing regimen in HIV-infected renal transplant recipients. Thirteen HIV-infected patients were consecutively transplanted. The induction therapy consisted of basiliximab and methylprednisolone for 5 days followed by a calcineurin inhibitor plus mycophenolate acid. The mean follow-up was 50 ± 22 months. Eight patients (61.5%) experienced acute rejection, and 75% of the first episodes occurred within 2 months after transplantation. The probability of first acute rejection was 58% after 1 year and 69% after 4 years. Seven of eight patients recovered or maintained their kidney function after antirejection therapy and steroid resumption. At the last follow-up, seven of 13 patients (54%) had resumed steroid therapy. The 4-year patient and graft survivals were 100% and 88.9%, respectively. The benefits of this steroid-free regimen in HIV-infected renal recipients must be reconsidered because of the high rate of acute rejection. New immunosuppressive steroid-free strategies should be identi-fied in this set of patients.
Assuntos
Inibidores de Calcineurina/administração & dosagem , Infecções por HIV/cirurgia , Imunossupressores/administração & dosagem , Falência Renal Crônica/cirurgia , Transplante de Rim/métodos , Ácido Micofenólico/administração & dosagem , Adulto , Quimioterapia Combinada , Feminino , Seguimentos , Rejeição de Enxerto , Sobrevivência de Enxerto , Infecções por HIV/complicações , Infecções por HIV/diagnóstico , Infecções por HIV/mortalidade , Humanos , Terapia de Imunossupressão/métodos , Falência Renal Crônica/complicações , Falência Renal Crônica/diagnóstico , Falência Renal Crônica/mortalidade , Transplante de Rim/efeitos adversos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Medição de Risco , Esteroides , Análise de Sobrevida , Imunologia de Transplantes/fisiologia , Resultado do Tratamento , Adulto JovemRESUMO
Renal targets of autoimmunity in human lupus nephritis (LN) are unknown. We sought to identify autoantibodies and glomerular target antigens in renal biopsy samples from patients with LN and determine whether the same autoantibodies can be detected in circulation. Glomeruli were microdissected from biopsy samples of 20 patients with LN and characterized by proteomic techniques. Serum samples from large cohorts of patients with systemic lupus erythematosus (SLE) with and without LN and other glomerulonephritides were tested. Glomerular IgGs recognized 11 podocyte antigens, with reactivity varying by LN pathology. Notably, IgG2 autoantibodies against α-enolase and annexin AI were detected in 11 and 10 of the biopsy samples, respectively, and predominated over other autoantibodies. Immunohistochemistry revealed colocalization of α-enolase or annexin AI with IgG2 in glomeruli. High levels of serum anti-α-enolase (>15 mg/L) IgG2 and/or anti-annexin AI (>2.7 mg/L) IgG2 were detected in most patients with LN but not patients with other glomerulonephritides, and they identified two cohorts: patients with high anti-α-enolase/low anti-annexin AI IgG2 and patients with low anti-α-enolase/high anti-annexin AI IgG2. Serum levels of both autoantibodies decreased significantly after 12 months of therapy for LN. Anti-α-enolase IgG2 recognized specific epitopes of α-enolase and did not cross-react with dsDNA. Furthermore, nephritogenic monoclonal IgG2 (clone H147) derived from lupus-prone MRL-lpr/lpr mice recognized human α-enolase, suggesting homology between animal models and human LN. These data show a multiantibody composition in LN, where IgG2 autoantibodies against α-enolase and annexin AI predominate in the glomerulus and can be detected in serum.