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1.
J Magn Reson Imaging ; 2019 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-31566845

RESUMO

BACKGROUND: Biochemical recurrence (BCR) affects a significant proportion of patients who undergo robotic-assisted laparoscopic prostatectomy (RALP). PURPOSE: To evaluate the performance of a routine clinical prostate multiparametric magnetic resonance imaging (mpMRI) and Decipher genomic classifier score for prediction of biochemical recurrence in patients who underwent RALP. STUDY TYPE: Retrospective cohort study. SUBJECTS: Ninety-one patients who underwent RALP performed by a single surgeon, had mpMRI before RALP, Decipher taken from RALP samples, and prostate specific antigen (PSA) follow-up for >3 years or BCR within 3 years, defined as PSA >0.2 mg/ml. FIELD STRENGTH/SEQUENCE: mpMRI was performed at 27 different institutions using 1.5T (n = 10) or 3T scanners and included T2 w, diffusion-weighted imaging (DWI), or dynamic contrast-enhanced (DCE) MRI. ASSESSMENT: All mpMRI studies were reported by one reader using Prostate Imaging Reporting and Data System v. 2.1 (PI-RADsv2.1) without knowledge of other findings. Eighteen (20%) randomly selected cases were re-reported by reader B to evaluate interreader variability. STATISTICAL TESTS: Univariate and multivariate analysis using greedy feature selection and tournament leave-pair-out cross-validation (TLPOCV) were used to evaluate the performance of various variables for prediction of BCR, which included clinical (three), systematic biopsy (three), surgical (six: RALP Gleason Grade Group [GGG], extracapsular extension, seminal vesicle invasion, intraoperative surgical margins [PSM], final PSM, pTNM), Decipher (two: Decipher score, Decipher risk category), and mpMRI (eight: prostate volume, PSA density, PI-RADv2.1 score, MRI largest lesion size, summed MRI lesions' volume and relative volume [MRI-lesion-percentage], mpMRI ECE, mpMRI seminal vesicle invasion [SVI]) variables. The evaluation metric was the area under the curve (AUC). RESULTS: Forty-eight (53%) patients developed BCR. The best-performing individual features with TLPOCV AUC of 0.73 (95% confidence interval [CI] 0.64-0.82) were RALP GGG, MRI-lesion-percentage followed by biopsy GGG (0.72, 0.62-0.82), and Decipher score (0.71, 0.60-0.82). The best performance was achieved by feature selection of Decipher+Surgery and MRI + Surgery variables with TLPOCV AUC of 0.82 and 0.81, respectively DATA CONCLUSION: Relative lesion volume measured on a routine clinical mpMRI failed to outperform Decipher score in BCR prediction. LEVEL OF EVIDENCE: 3 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2019.

2.
Artigo em Inglês | MEDLINE | ID: mdl-31507092

RESUMO

OBJECTIVES: To study growth and puberty in a multi-national longitudinal prospective cohort of juvenile dermatomyositis (JDM). METHODS: Children with JDM ≤18 years in active phase from 31 countries were studied, analyzing height, weight and pubertal development in children with available anthropometric data and follow-up visits over two years. RESULTS: A total of 196/275 (71%) children were included. We found a significant reduction in parent-adjusted height z score over time in females (p<0.0001) and males (p=0.001), but with catch-up growth at the final study visit. Median BMI z score peaked at 6 months (p<0.0001) and was still significantly above baseline at the final study visit at a median of 26 months (p=0.007) after baseline with no gender difference. Females with a disease duration ≥12 months after onset had significantly lower parent-adjusted height z score (p=0.002) and no 2-year catch-up growth. Growth failure was seen in 20 (21%) of the females and 11 (15%) of the males, at the final study visit. Height deflection (∆height z-score <-0.25/year) was observed in 29 (25%) of the females and 25 (31%) of the males. Delayed puberty was seen in 20/55 (36.4%) of the females and in 11/31 (35.5%) of the males. Children in early pubertal stage at baseline had the highest risk of growth failure. CONCLUSIONS: JDM and/or its treatment has a significant impact on growth and puberty in the active phase in affected children. Children with recent onset of puberty or previous growth failure, have the highest risk of delayed pubertal development and further growth retardation.

3.
Minerva Urol Nefrol ; 71(5): 502-507, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31524202

RESUMO

BACKGROUND: The presence of capsular abutment or bulging can raise concern when planning surgery. In this study we aimed to test the clinical implications of capsular abutment or bulging on preoperative multiparametric magnetic resonance imaging (mpMRI). METHODS: We analyzed the data of 291 patients who underwent radical prostatectomy (RP) for a cT1-2N0 prostate cancer in a single surgeon series. All patients underwent preoperative staging with mpMRI. PIRADS v2 was used for characterizing lesions. The role of capsular abutment or bulging was tested in a multivariable logistic regression adjusting for prostate-specific antigen and highest ipsilateral biopsy Gleason grade. The presence of focal versus extensive extracapsular extension (ECE) was investigated. RESULTS: Overall, ECE on final pathology was documented in 35 (12%) cases and ECE was focal in 32 (91%) patients. Overall, mpMRI demonstrated capsule bulging or abutment in 12 (24%) cases. After adjusting for confounders, capsule bulging or abutment on mpMRI emerged as predictor for ECE (OR=6.70; 95% CI: 2.97-15.12, P<0.001). The sensitivity and specificity of capsule abutment or bulging in predicting ECE were 43% and 95%, respectively. Sensitivity and specificity were 36% and 48% respectively to predict focal ECE. CONCLUSIONS: The PIRADS v2 scoring system has a grey zone concerning ECE as defined by capsule abutment or bulging. We found an increased risk of ECE and specifically focal ECE when capsule bulging or abutment on mpMRI are documented.

4.
Eur Urol Oncol ; 2019 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-31548130

RESUMO

The 2019 European Association of Urology guidelines recommend multiparametric magnetic resonance imaging (mpMRI) for biopsy-naïve patients with clinical suspicion of prostate cancer (PC) and avoiding biopsy in patients with negative mpMRI and low clinical suspicion. However, consensus on the optimal definition of low clinical suspicion is lacking. We evaluated 266 biopsy-naïve patients who underwent mpMRI, the 4Kscore test, and prostate biopsy to define the best strategy to avoid unnecessary testing and biopsies. The European Randomized Study of Screening for Prostate Cancer risk calculator (ERSPC-RC) and prostate-specific antigen density (PSAd) were also considered. For men with Prostate Imaging-Reporting and Data System v2.0 (PI-RADS) 1â¿¿2 lesions, the highest negative predictive value was observed for those with low or intermediate 4Kscore risk (96.9% and 97.1%), PSAd <0.10ng/ml/cm3 (98.7%), and ERSPC-RC <2% (98.7%). For men with PI-RADS 3â¿¿5 lesions the lowest positive predictive value was observed for those with low 4Kscore risk (0%), PSAd <0.10ng/ml/cm3 (13.2%), and ERSPC-RC <2% (12.3%). The best biopsy strategy was an initial 4Kscore followed by mpMRI if the 4Kscore was>7.5% and a subsequent biopsy if the mpMRI was positive (PI-RADS 3â¿¿5) or the 4Kscore was â¿¥18%. This would result in missing 2.7% (2/74) of clinically significant PCs (csPCs) and avoiding 34.2% of biopsies. Initial mpMRI followed by biopsy for negative mpMRI (PI-RADS 1â¿¿2) if the 4Kscore was â¿¥18% or PSAd was â¿¥0.10ng/ml/cm3 resulted in a similar percentage of csPC missed (2.7% [2/74] and 1.3% [1/74]) but slightly fewer biopsies avoided (25.2% and 28.1%). Physicians should consider clinical risk screening tools when ordering and interpreting mpMRI results to avoid unnecessary testing and diagnostic errors. PATIENT SUMMARY: Performing the 4Kscore test in conjunction with multiparametric magnetic resonance imaging for men with a clinical suspicion of prostate cancer may help to reduce unnecessary biopsies.

5.
Eur Urol Oncol ; 2019 Apr 04.
Artigo em Inglês | MEDLINE | ID: mdl-31411971

RESUMO

BACKGROUND: The impact of positive surgical margins (PSMs) on the risk of metastases in prostate cancer (PCa) patients treated with radical prostatectomy (RP) is still debated. OBJECTIVE: To identify PSM features associated with recurrence in a stage-by-stage analysis. DESIGN, SETTING, AND PARTICIPANTS: A total of 1757 PCa patients treated with RP without neoadjuvant or adjuvant treatments between 2011 and 2017 were identified. Patients were stratified according to the presence of PSM and to margins characteristics in three groups: no versus favourable (single margin <3mm) versus unfavourable (≥3mm or multifocal margin) PSMs. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Predictors of biochemical recurrence (BCR) and clinical recurrence (CR) were assessed using semiparametric Cox proportional hazard models. RESULTS AND LIMITATIONS: Overall, 285 (16%) patients had PSMs; 146 (51%) had a unifocal PSM, while 139 (49%) had a multifocal PSM. The median length of a PSM was 1mm. Overall, 120 (42%) versus 165 (58%) patients had favourable versus unfavourable PSMs. In patients with ≤pT3a and pathologic grade group ≤3 disease (n=1351), favourable (hazard ratio [HR]: 2.24; 95% confidence interval [CI]: 1.19-4.22) and unfavourable (HR: 2.68; 95% CI: 1.49-4.84) PSMs significantly increased the risk of BCR (p<0.01). However, they were not associated with CR (all p>0.05). Conversely, in patients with pT3b/4 and/or pathologic grade group 4-5 and/or pN1 (n=406), only an unfavourable PSM was associated with both BCR (HR: 2.96; 95% CI: 1.19-4.22) and CR (HR: 2.60; 95% CI: 1.07-6.30; all p≤0.04). CONCLUSIONS: Although the presence of PSMs was associated with an increased risk of BCR in all stages, only men with adverse pathologic characteristics and an unfavourable PSM were at an increased risk of experiencing metastases as compared with their counterparts with no or a single margin shorter than 3mm. PATIENT SUMMARY: In this study, we defined a new category of unfavourable positive surgical margins (namely, ≥3mm and/or multifocal), which confers a higher risk of developing metastasis in men with more aggressive pathologic features.

6.
Artigo em Inglês | MEDLINE | ID: mdl-31421019

RESUMO

OBJECTIVE: To evaluate safety and effectiveness of adalimumab (ADA) in polyarticular-course juvenile idiopathic arthritis (pcJIA) in the STRIVE registry (NCT00783510). METHODS: STRIVE enrolled patients with pcJIA into 2 arms based on treatment with methotrexate (MTX) alone or ADA with/without MTX (ADA±MTX). Adverse events (AEs) per 100 patient-years (PY) of observation time were analyzed by registry arm. Patients who entered the registry within 4 weeks of starting MTX or ADA±MTX, defined as new users, were evaluated for change in disease activity assessed by the C-reactive protein-based 27-joint Juvenile Arthritis Disease Activity Score (JADAS27CRP ). RESULTS: At the 7-year cut-off date (June 1, 2016), data from 838 patients were available (MTX-arm, N=301; ADA±MTX-arm, N=537). The most common AEs were nausea (10.3%), sinusitis (4.7%), and vomiting (4.3%) in the MTX-arm and arthritis (3.9%), upper respiratory tract infection (3.5%), sinusitis, tonsillitis, and injection site pain (3.0% each) in the ADA±MTX-arm. Rates of serious infection were 1.5 events/100 PY in the MTX-arm and 2.0 events/100 PY in the ADA±MTX-arm. AE and serious AE rates were similar in patients receiving ADA with versus without MTX. No deaths or malignancies were reported. New users in the ADA±MTX-arm showed a trend toward lower mean JADAS27CRP compared with new users in the MTX-arm in the first year of STRIVE. CONCLUSIONS: The STRIVE registry 7-year interim results support that ADA±MTX is well tolerated by most children. Registry median (interquartile range) ADA exposure was 2.47 (1.0-3.6) years, with 42% of patients continuing ADA at the 7-year cut-off date.

7.
World J Urol ; 2019 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-31435731

RESUMO

PURPOSE: To develop a model based on preoperative variables to predict apical prostate cancer. METHODS: We performed a retrospective analysis of 459 patients who underwent a robotic assisted radical prostatectomy (RALP) between January 2016 and September 2017. All patients had a preoperative biopsy and mpMRI of the prostate. Significant apical pathology (SAP) was defined as those patients who had a dominant nodule at the apex with a Gleason score > 6 and/or ECE at the apex. Binary logistic regression analyses were adopted to predict SAP. Variables included in the model were PSA, apical lesions prostate imaging reporting and data system (PI-RADS) score and apical biopsy Gleason score. The area under the curve (AUC) of the model was computed. RESULTS: A total of 121 (43.2%) patients had SAP. On univariable analysis, all apex-specific variables investigated emerged as predictors of SAP (all p < 0.05). On multivariable analysis PSA and apical PI-RADS score > 3 (all p < 0.05) emerged as significant predictors of SAP. The AUC of the model was 0.722. CONCLUSION: Patients with PI-RADS 3, 4 or 5 lesions at the apex were three times as more likely to have true SAP compared to those who have PI-RADS < 3 or negative mpMRI prior to undergoing RALP.

8.
Eur Urol Oncol ; 2019 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-31375428

RESUMO

Following partial nephrectomy (PN), it is important to prevent any deterioration in estimated glomerular filtration rate (eGFR). At present there are no evidence-based recommendations on when a nephrology consultation should be requested and how to adjust postoperative management when the risk of renal function decline is high. In an effort to address this void, we used our previously published nomogram to define risk groups for a significant decline in eGFR between 3-15 mo after PN. We used the nomogram-derived probability as the independent variable for the classification and regression tree and identified four risk groups: low (0-10%), intermediate (10-21%), high (21-65%), and very high (65-100%). Overall, 336 (34%), 386 (39%), 243 (24%), and 34 (4%) patients fell in the low, intermediate, high, and very high risk groups, respectively. The rates of significant eGFR decline across the low, intermediate, high, and very high risk groups were 4%, 14%, 29%, and 79%. With the low risk category as a reference, the hazard ratio for eGFR decline was 3.21 (95% confidence interval [CI] 1.83-5.64) for the intermediate, 7.80 (95% CI 4.52-13.48) for the high, and 27.24 (95% CI 13.8-53.8) for the very high risk group (all p < 0.001). These prognostic risk categories can be used to design postoperative follow-up schedules. A multidisciplinary approach can be considered for patients at high and very high risk of eGFR decline. PATIENT SUMMARY: We propose a new stratification system to identify individuals at high risk of a decline in renal function after robotic partial nephrectomy.

9.
Ann Rheum Dis ; 78(10): 1357-1362, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31296501

RESUMO

OBJECTIVE: To develop and validate a diagnostic score that aids in identifying macrophage activation syndrome (MAS) in patients with systemic juvenile idiopathic arthritis (sJIA). METHODS: The clinical and laboratory features of 362 patients with sJIA-associated MAS and 404 patients with active sJIA without evidence of MAS were collected in a multinational collaborative project. Eighty percent of the study population was used to develop the score and the remaining 20% constituted the validation sample. A Bayesian Model Averaging approach was used to assess the role of each clinical and laboratory variables in the diagnosis of MAS and to obtain the coefficients of selected variables. The final score, named MAS/sJIA (MS) score, resulted from the linear combination of these coefficients multiplied by the values of each variable. The cut-off that best discriminated MAS from active sJIA was calculated by means of receiver operating characteristic (ROC) curve analysis. Score performance was evaluated in both developmental and validation samples. RESULTS: The MS score ranges from -8.4 to 41.8 and comprises seven variables: central nervous system dysfunction, haemorrhagic manifestations, active arthritis, platelet count, fibrinogen, lactate dehydrogenase and ferritin. A cut-off value ≥-2.1 revealed the best performance in discriminating MAS from active sJIA, with a sensitivity of 0.85, a specificity of 0.95 and a kappa value of 0.80. The good performance of the MS score was confirmed in the validation sample. CONCLUSION: The MS score is a powerful and feasible tool that may assist practitioners in making a timely diagnosis of MAS in patients with sJIA.

10.
BJU Int ; 2019 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-31310696

RESUMO

OBJECTIVE: To describe the natural history of untreated muscle-invasive bladder cancer (MIBC) and compare the oncological outcomes of treated and untreated patients. PATIENTS AND METHODS: We utilised a database encompassing all patients with newly diagnosed bladder cancer in Stockholm, Sweden between 1995 and 1996. The median follow-up for survivors was 14.4 years. Overall, 538 patients were diagnosed with bladder cancer of whom 126 had clinically localised MIBC. Patients were divided into two groups: those who received radical cystectomy or radiation therapy, and those who did not receive any form of treatment. Multivariable Cox or competing-risks regressions were adopted to predict metastasis, overall survival (OS), and cancer-specific mortality (CSM), when appropriate. Analyses were adjusted for age at diagnosis, sex, tumour stage, clinical N stage, and treatment. RESULTS: In all, 64 (51%) patients did not receive any definitive local treatment. In the untreated group, the median (interquartile range) age at diagnosis was 79 (63-83) vs 69 (63-74) years in the treated group (P < 0.001). Overall, 109 patients died during follow-up. At 6 months after diagnosis, 38% of the untreated patients had developed metastatic disease and 41% had CSM. The 5-year OS rate for untreated and treated patients was 5% (95% confidence interval [CI] 1, 12%) vs 48% (95% CI 36, 60%), respectively. Patients not receiving any treatment had a 5-year cumulative incidence of CSM of 86% (95% CI 75, 94%) vs 48% (95% CI 36, 60%) for treated patients. Untreated patients had a higher risk of progression to metastatic disease (hazard ratio [HR] 2.40, 95% CI 1.28, 4.51; P = 0.006), death from any cause (HR 2.63, 95% CI 1.65, 4.19; P < 0.001) and CSM (subdistribution HR 2.02, 95% CI 1.24, 3.30; P = 0.004). CONCLUSIONS: Untreated patients with MIBC are at very high risk of near-term CSM. These findings may help balance the risks vs benefits of integrating curative intent therapy particularly in older patients with MIBC.

12.
Eur Urol Oncol ; 2(4): 456-463, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31277783

RESUMO

BACKGROUND: Given the prolonged natural history of clinically localized, high-risk prostate cancer, there is a need for the identification of intermediate clinical endpoints (ICEs) to predict long-term overall survival (OS). OBJECTIVE: To explore the role of novel potential ICEs based on clinical follow-up to predict long-term survival in patients with high-risk prostate cancer. DESIGN, SETTING, AND PARTICIPANTS: Overall, 3507 patients treated at 12 tertiary referral centers between 1988 and 2016 were evaluated. INTERVENTION: Radical prostatectomy (RP) with extended pelvic lymph node dissection. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The impact of biochemical recurrence (BCR) and clinical recurrence (CR) within 1, 3, 5, and 7yr after surgery on the risk of OS was evaluated in multivariable Cox regression analyses. In patients with BCR, the impact of progression to CR within 6mo and 1, 3, and 5yr on long-term OS was investigated. Discrimination was assessed using Harrell's c index. RESULTS AND LIMITATIONS: Median follow-up for survivors was 76mo. The 5- and 10-yr OS and cancer-specific survival rates were 94% and 81% versus 98% and 95%, respectively. On a time-varying multivariable analysis, BCR (hazard ratio [HR]: 1.02; 95% confidence interval [CI]: 1.00, 1.04) and CR (HR: 1.05; 95% CI: 1.03-1.07) emerged as predictors of OS (p<0.001). The development of CR within 5yr after surgery was the most informative ICE for predicting OS (c index: 0.74). In patients with BCR, progression to CR within 12mo represented the most informative predictor for the subsequent risk of dying from all causes. Patients who developed BCR within 5yr after RP and progressed to CR within 12mo had a 10-yr OS rate of 47%. These results require prospective validation. CONCLUSIONS: When predicting long-term survival in surgically treated high-risk patients, progression to CR within 5yr of RP confers the highest discrimination with respect to other landmark points. In men experiencing BCR, progression to CR within the subsequent 12mo achieved the highest discrimination. Further studies are needed to validate our findings. PATIENT SUMMARY: We investigated the most informative intermediate clinical endpoints for predicting overall survival (OS). Occurrence of clinical recurrence within 5yr after radical prostatectomy confers the highest discrimination to a model predicting OS.

13.
Eur Urol ; 76(5): 599-603, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31272788

RESUMO

Prior studies have demonstrated that fibroblast receptor 3 (FGFR3)-mutant urothelial cancers (UCs) are associated with decreased T-cell infiltration. As FGFR3 mutations are enriched in luminal-like UC and luminal-like UC has been shown to be relatively less responsive to PD-1/PD-L1 inhibition (checkpoint inhibition [CPI]), these data have led to the speculation that FGFR3 mutations may be causally related to poor T-cell infiltration and that UC patients harboring FGFR3 mutations may be suboptimal candidates for CPI. Using data derived from two clinical trials exploring CPI in metastatic UC, we demonstrate no statistically significant difference in response rates in patients with FGFR3-mutant versus wild-type UC. We present hypothesis-generating data, suggesting that similar response rates may be explained by a "balancing out" of previously identified independent positive and negative predictors of CPI sensitivity; that is, compared with FGFR3 wild-type UC, FGFR3-mutant UC is associated with a similar tumor mutational burden, lower T-cell infiltration, but also lower stromal/transforming growth factor beta (TGF-ß) signals. Based on our findings, FGFR3 mutation status is not a biomarker of resistance to CPI. Indeed, the single-agent activity of both FGFR3 inhibitors and CPI in FGFR3-mutant UC, and potential non-cross resistance provide a strong pragmatic rationale for combination approaches. PATIENT SUMMARY: In this report, we examined the impact of a mutated gene found in a subset of urothelial cancers on response to treatment with immunotherapy. We found that patients with tumors harboring mutations in the gene FGFR3 respond to immunotherapy similarly to patients without such mutations.

14.
Cancer ; 125(18): 3155-3163, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31150110

RESUMO

BACKGROUND: Achieving a pathologic complete response (pCR) with neoadjuvant chemotherapy (NAC) in patients with muscle-invasive bladder cancer (MIBC) has been associated with improved overall survival (OS). This study was aimed at evaluating the impact of pathologic downstaging (pDS; ie, a pT stage at least 1 stage lower than the pre-NAC cT stage) on the OS of patients with MIBC treated with NAC. METHODS: The Retrospective International Study of Cancers of the Urothelial Tract (RISC) and the National Cancer Database (NCDB) were queried for cT2-4N0M0 patients treated with NAC. A multivariable Cox model including either pDS or pCR was generated. A nested model was built to evaluate the added value of pDS (excluding patients achieving a pCR) to a model including pCR alone. C indices were computed to assess discrimination. NCDB was used for validation. The treatment effect of NAC versus cystectomy alone in achieving pDS was estimated through an inverse probability-weighted regression adjustment. RESULTS: Overall, 189 and 2010 patients from the RISC and NCDB cohorts, respectively, were included; pDS and pCR were achieved by 33% and 35% and by 20% and 15% in RISC and NCDB, respectively. In both data sets, pDS and pCR were associated with better OS and C indices. Adding pDS excluding pCR to the model with pCR fit the data better (likelihood ratio, P = .019 for RISC and P < .001 for NCDB), and it yielded better discrimination (incremental C index, 4.2 for RISC and 1.6 for NCDB). The treatment effect of NAC in achieving pDS was 2.07-fold (P < .001) in comparison with cystectomy alone. CONCLUSIONS: A decrease of at least 1 stage from the cT stage to the pT stage is associated with improved OS in patients with MIBC treated with NAC.

15.
Artigo em Inglês | MEDLINE | ID: mdl-31194989

RESUMO

BACKGROUND: Cryopyrin-associated periodic syndromes (CAPS) are a group of autoinflammatory diseases linked to gain-of-function mutations in the NOD-like receptor family, pyrin domain containing 3 (NLRP3) gene, which cause uncontrolled IL-1ß secretion. Proton pump inhibitors (PPIs), which are commonly used as inhibitors of gastric acid production, also have anti-inflammatory properties, protect mice from sepsis, and prevent IL-1ß secretion by monocytes from patients with CAPS. OBJECTIVE: We sought to develop a novel Nlrp3 knock-in (KI) mouse model of CAPS to study amyloidosis, a severe CAPS complication, and test novel therapeutic approaches. METHODS: We generated KI mice by engineering the N475K mutation, which is associated with the CAPS phenotype, into the mouse Nlrp3 gene. KI and wild-type mice received PPIs or PBS intraperitoneally and were analyzed for survival, inflammation, cytokine secretion, and amyloidosis development. RESULTS: Mutant Nlrp3 KI mice displayed features that recapitulate the immunologic and clinical phenotype of CAPS. They showed systemic inflammation with high levels of serum proinflammatory cytokines, inflammatory infiltrates in various organs, and amyloid deposits in the spleen, liver, and kidneys. Toll-like receptor stimulated macrophages from KI mice secreted high levels of IL-1ß, IL-18, and IL-1α but low amounts of IL-1 receptor antagonist. Treatment of KI mice with PPIs had a clear clinical effect, showing a reduction in inflammatory manifestations, regression of amyloid deposits, and normalization of proinflammatory and anti-inflammatory cytokine production by macrophages. CONCLUSION: Nlrp3 KI mice displayed a CAPS phenotype with many characteristics of autoinflammation, including amyloidosis. The therapeutic effectiveness of PPIs associated with a lack of toxicity indicates that these drugs could represent relevant adjuvants to the anti-IL-1 drugs in patients with CAPS and other IL-1-driven diseases.

16.
Eur Urol ; 2019 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-31200951

RESUMO

CONTEXT: Several anti-programmed death-1 (anti-PD-1) and anti-programmed death ligand-1 (anti-PD-L1) antibodies have been approved by regulatory authorities for treatment of platinum-resistant metastatic urothelial cancer (mUC). The impact of these therapies on survival, and comparability of PD-1 versus PD-L1 blockade are unknown. OBJECTIVE: To determine the restricted mean survival time (RMST) of patients with platinum-resistant mUC treated with PD-1/PD-L1 inhibitors and to compare RMSTs in patients treated with PD-1 versus PD-L1 inhibitors. EVIDENCE ACQUISITION: We searched for phase 1, 2, and 3 clinical trials that assessed PD-1 or PD-L1 inhibition for patients with platinum-resistant mUC. Literature review and study selection, data abstraction, and risk of bias assessment were performed by two reviewers. Survival data were reconstructed using an algorithm that derives individual time-to-event data from published Kaplan-Meier curves. The RMST with 95% confidence interval (CIs) was calculated. EVIDENCE SYNTHESIS: From 836 references, six clinical trials were included. Survival data were reconstructed for 1315 and 736 patients treated with PD-1/PD-L1 inhibitors and chemotherapy, respectively. The RMSTs with PD-1/PD-L1 blockade up to 12 and 18mo of follow-up were 7.8mo (95% CI 7.6, 8.1) and 10mo (95% CI 9.7, 10.5), respectively. A network meta-analysis of two randomized trials revealed no significant difference in the RMST up to 18mo with PD-1 versus PD-L1 blockade (1.0mo; 95% CI -0.5, 2.3mo). Using reconstructed survival data from all six trials, the RMSTs with PD-1 versus PD-L1 blockade up to 12 and 18mo follow-up were 7.8mo (95% CI 7.7, 8.2) versus 7.8mo (95% CI 7.5, 8.2) and 10.1mo (95% CI 9.6, 10.7) versus 10mo (95% CI 9.5, 10.6), respectively. CONCLUSIONS: Our RMST estimates may be used as benchmarks to contextualize survival outcomes and inform future trial design with PD-1/PD-L1 inhibitors. PD-1 versus PD-L1 blockade in patients with mUC yields comparable survival outcomes. PATIENT SUMMARY: In this study, we found that outcomes for patients with metastatic bladder cancer treated with programmed death-1 and programmed death ligand-1 inhibitors, who received prior platinum-based chemotherapy, were similar.

18.
Arthritis Res Ther ; 21(1): 125, 2019 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-31122296

RESUMO

BACKGROUND: To describe the 6-year safety and efficacy of etanercept (ETN) in children with extended oligoarticular juvenile idiopathic arthritis (eoJIA), enthesitis-related arthritis (ERA), and psoriatic arthritis (PsA) METHODS: Patients who completed the 2-year, open-label, phase III CLinical Study In Pediatric Patients of Etanercept for Treatment of ERA, PsA, and Extended Oligoarthritis (CLIPPER) were allowed to enroll in its 8-year long-term extension (CLIPPER2). Children received ETN at a once-weekly dose of 0.8 mg/kg, up to a maximum dose of 50 mg/week. Efficacy assessments included the JIA core set of outcomes, the JIA American College of Rheumatology response criteria (JIA-ACR), and the Juvenile Arthritis Disease Activity Score (JADAS). Efficacy data are reported as responder analyses using a hybrid method for missing data imputation and as observed cases. Safety assessments included treatment-emergent adverse events (TEAEs). RESULTS: Out of 127 patients originally enrolled in CLIPPER, 109 (86%) entered CLIPPER2. After 6 years of trial participation (2 years in CLIPPER and 4 years in CLIPPER2), 41 (32%) patients were still taking ETN, 13 (11%) entered the treatment withdrawal phase after achieving low/inactive disease (of whom 7 had to restart ETN), 36 (28%) discontinued treatment for other reasons but are still being observed, and 37 (29%) discontinued treatment permanently. According to the hybrid imputation analysis, proportions of patients achieving JIA ACR90, JIA ACR100, and JADAS inactive disease after the initial 2 years of treatment were 58%, 48%, and 32%, respectively. After the additional 4 years, those proportions in patients who remained in the trial were 46%, 35%, and 24%. Most frequently reported TEAEs [n (%), events per 100 patient-years] were headache [28 (22%), 5.3], arthralgia [24 (19%), 4.6], and pyrexia [20 (16%), 3.8]. Number and frequency of TEAEs, excluding infections and injection site reactions, decreased over the 6-year period from 193 and 173.8, respectively, during year 1 to 37 and 61.3 during year 6. A single case of malignancy (Hodgkin's lymphoma) and no cases of active tuberculosis, demyelinating disorders, or deaths were reported. CONCLUSIONS: Open-label etanercept treatment for up to 6 years was safe, well tolerated, and effective in patients with eoJIA, ERA, and PsA. TRIAL REGISTRATION: ClinicalTrials.gov: CLIPPER, NCT00962741 , registered 20 August, 2009, CLIPPER2, NCT01421069 , registered 22 August, 2011.

19.
Urol Oncol ; 37(7): 445-451, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31076354

RESUMO

BACKGROUND: Acute Kidney Injury (AKI) is a common occurrence after partial nephrectomy and is a significant risk factor for chronic kidney disease. We aimed to create a model that predicts postoperative AKI in patients undergoing robot-assisted partial nephrectomy (RAPN). METHODS: We identified 1,190 patients who underwent RAPN between 2008 and 2017 from a multicenter database. AKI was defined as a >25% reduction in eGFR from pre-RAPN to discharge. A nomogram was built based on a binary logistic regression that ultimately included age, sex, BMI, diabetes, baseline eGFR, and RENAL Nephrometry score. Internal validation was performed using the leave-one-out cross validation. Calibration was graphically investigated. The decision curve analysis was used to evaluate the net clinical benefit; a classification tree was used to identify risk categories. The same model was fit adding ischemia time during RAPN. RESULTS: Median (IQR) age at surgery was 61 (50, 68) years; 505 (42%) patients were female, while 685 (58%) were male. Median (IQR) ischemia time during RAPN was 14 (10, 18) min. postoperative AKI occurred in 274 (23%) patients. All variables fitted in the model emerged as predictors of AKI (all P ≤ 0.005) and all were considered to build a nomogram. After internal validation, the area under the curve was 73%. The model demonstrated excellent calibration and improved clinical risk prediction at the decision curve analysis. In the low, intermediate, and high-risk groups the postoperative AKI rates were: 10%, 30%, and 48%, respectively. Adding ischemia time to the preoperative model fit the data better (likelihood ratio test: P < 0.001) and yielded an incremental area under the curve of 3% (95% confidence interval: 1, 5%) CONCLUSION: We developed a nomogram that accurately predicts AKI in patients undergoing RAPN. This model might serve (1) in the preoperative setting: for counsel patients according to their preoperative AKI risk (2) in the immediate postoperative: for identifying patients who would benefit from an early multidisciplinary evaluation, when considering also ischemia time.

20.
Pediatr Rheumatol Online J ; 17(1): 24, 2019 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-31118099

RESUMO

BACKGROUND: Prednisone (PDN) in juvenile dermatomyositis (JDM), alone or in association with other immunosuppressive drugs, namely methotrexate (MTX) and cyclosporine (CSA), represents the first-line treatment option for new onset JDM patients. No clear evidence based guidelines are actually available to standardize the tapering and discontinuation of glucocorticoids (GC) in JDM. Aim of our study was to provide an evidence-based proposal for GC tapering/discontinuation in new onset juvenile dermatomyositis (JDM), and to identify predictors of clinical remission and GC discontinuation. METHODS: New onset JDM children were randomized to receive either PDN alone or in combination with methotrexate (MTX) or cyclosporine (CSA). In order to derive steroid tapering indications, PRINTO/ACR/EULAR JDM core set measures (CSM) and their median absolute and relative percent changes over time were compared in 3 groups. Group 1 included those in clinical remission who discontinued PDN, with no major therapeutic changes (MTC) (reference group) and was compared with those who did not achieve clinical remission, without or with MTC (Group 2 and 3, respectively). A logistic regression model identified predictors of clinical remission with PDN discontinuation. RESULTS: Based on the median change in the CSM of 30/139 children in Group 1, after 3 pulses of methyl-prednisolone, GC could be tapered from 2 to 1 mg/kg/day in the first two months from onset if any of the CSM decreased by 50-94%, and from 1 to 0.2 mg/kg/day in the following 4 months if any CSM further decreased by 8-68%, followed by discontinuation in the ensuing 18 months. The achievement of PRINTO JDM 50-70-90 response after 2 months of treatment (ORs range 4.5-6.9), an age at onset > 9 years (OR 4.6) and the combination therapy PDN + MTX (OR 3.6) increase the probability of achieving clinical remission (p < 0.05). CONCLUSIONS: This is the first evidence-based proposal for glucocorticoid tapering/discontinuation based on the change in JDM CSM of disease activity. TRIAL REGISTRATION: Trial full title: Five-Year Single-Blind, Phase III Effectiveness Randomized Actively Controlled Clinical Trial in New Onset Juvenile Dermatomyositis: Prednisone versus Prednisone plus Cyclosporine A versus Prednisone plus Methotrexate. EUDRACT registration number: 2005-003956-37 . CLINICAL TRIAL: gov is NCT00323960 . Registered on 17 August 2005.

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