In this paper, we consider the output synchronization problem for a network of heterogeneous diffusively-coupled nonlinear agents. Specifically, we show how the (heterogeneous) agents can be ...controlled in such a way that their outputs asymptotically track the output of a prescribed nonlinear exosystem. The problem is solved in two steps. In the first step, the problem of achieving consensus among (identical) nonlinear reference generators is addressed. In this respect, it is shown how the techniques recently developed to solve the consensus problem among linear agents can be extended to agents modeled by nonlinear d-dimensional differential equations, under the assumption that the communication graph is connected. In the second step, the theory of nonlinear output regulation is applied in a decentralized control mode, to force the output of each agent of the network to robustly track the (synchronized) output of a local reference model. Simulation results are presented to show the effectiveness of the design methodology.
The 2022 guideline provides the current best evidence base for renal cell carcinoma management. Changes in medical management in recent years include the use of immune checkpoint inhibitors (ICIs), ...ICI–ICI combinations, and ICI-targeted therapy combinations. Surgery remains the mainstay for lower-grade tumours, with increasing use of minimally invasive approaches. More robust data are needed to identify optimal follow-up schedules.
The European Association of Urology (EAU) Renal Cell Carcinoma (RCC) Guideline Panel has prepared evidence-based guidelines and recommendations for the management of RCC.
To present a summary of the 2022 RCC guideline, which is based on a standardised methodology including systematic reviews (SRs) and provides transparent and reliable evidence for the management of RCC.
For the 2022 update, a new literature search was carried out with a cutoff date of May 28, 2021, covering the Medline, EMBASE, and Cochrane databases. The data search focused on randomised controlled trials (RCTs) and retrospective or controlled comparator-arm studies, SRs, and meta-analyses. Evidence synthesis was conducted using modified GRADE criteria as outlined for all the EAU guidelines.
All chapters of the RCC guideline were updated on the basis of a structured literature assessment, and clinical practice recommendations were developed. The majority of the studies included were retrospective with matched or unmatched cohorts and were based on single- or multi-institution data or national registries. The exception was systemic treatment of metastatic RCC, for which there are several large RCTs, resulting in recommendations that are based on higher levels of evidence.
The 2022 RCC guidelines have been updated by a multidisciplinary panel of experts using the highest methodological standards. These guidelines provide the most reliable contemporary evidence base for the management of RCC in 2022.
The European Association of Urology panel for guidelines on kidney cancer has thoroughly evaluated the research data available to establish up-to-date international standards for the care of patients with kidney cancer.
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Background
Several comparative randomised controlled trials (RCTs) have been performed including combinations of tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors since the ...publication of a Cochrane Review on targeted therapy for metastatic renal cell carcinoma (mRCC) in 2008. This review represents an update of that original review.
Objectives
To assess the effects of targeted therapies for clear cell mRCC in patients naïve to systemic therapy.
Search methods
We performed a comprehensive search with no restrictions on language or publication status. The date of the latest search was 18 June 2020.
Selection criteria
We included randomised controlled trials, recruiting patients with clear cell mRCC naïve to previous systemic treatment. The index intervention was any TKI‐based targeted therapy.
Data collection and analysis
Two review authors independently assessed the included studies and extracted data for the primary outcomes: progression‐free survival (PFS), overall survival (OS) and serious adverse events (SAEs); and the secondary outcomes: health‐related quality of life (QoL), response rate and minor adverse events (AEs). We performed statistical analyses using a random‐effects model and rated the certainty of evidence according to the GRADE approach.
Main results
We included 18 RCTs reporting on 11,590 participants randomised across 18 comparisons. This focuses on the primary outcomes of select comparisons.
1. Pazopanib versus sunitinib
Pazopanib may result in little to no difference in PFS as compared to sunitinib (hazard ratio (HR) 1.05, 95% confidence interval (CI) 0.90 to 1.23; 1 study, 1110 participants; low‐certainty evidence). Based on the control event risk of 420 per 1000 in this trial at 12 months, this corresponds to 18 fewer participants experiencing PFS (95% CI 76 fewer to 38 more) per 1000 participants. Pazopanib may result in little to no difference in OS compared to sunitinib (HR 0.92, 95% CI 0.80 to 1.06; 1 study, 1110 participants; low‐certainty evidence). Based on the control event risk of 550 per 1000 in this trial at 12 months, this corresponds to 27 more OSs (95% CI 19 fewer to 70 more) per 1000 participants. Pazopanib may result in little to no difference in SAEs as compared to sunitinib (risk ratio (RR) 1.01, 95% CI 0.94 to 1.09; 1 study, 1102 participants; low‐certainty evidence). Based on the control event risk of 734 per 1000 in this trial, this corresponds to 7 more participants experiencing SAEs (95% CI 44 fewer to 66 more) per 1000 participants.
2. Sunitinib versus avelumab and axitinib
Sunitinib probably reduces PFS as compared to avelumab plus axitinib (HR 1.45, 95% CI 1.17 to 1.80; 1 study, 886 participants; moderate‐certainty evidence). Based on the control event risk of 550 per 1000 in this trial at 12 months, this corresponds to 130 fewer participants experiencing PFS (95% CI 209 fewer to 53 fewer) per 1000 participants. Sunitinib may result in little to no difference in OS (HR 1.28, 95% CI 0.92 to 1.79; 1 study, 886 participants; low‐certainty evidence). Based on the control event risk of 890 per 1000 in this trial at 12 months, this would result in 29 fewer OSs (95% CI 78 fewer to 8 more) per 1000 participants. Sunitinib may result in little to no difference in SAEs (RR 1.01, 95% CI 0.93 to 1.10; 1 study, 873 participants; low‐certainty evidence). Based on the control event risk of 705 per 1000 in this trial, this corresponds to 7 more SAEs (95% CI 49 fewer to 71 more) per 1000 participants.
3. Sunitinib versus pembrolizumab and axitinib
Sunitinib probably reduces PFS as compared to pembrolizumab plus axitinib (HR 1.45, 95% CI 1.19 to 1.76; 1 study, 861 participants; moderate‐certainty evidence). Based on the control event risk of 590 per 1000 in this trial at 12 months, this corresponds to 125 fewer participants experiencing PFS (95% CI 195 fewer to 56 fewer) per 1000 participants. Sunitinib probably reduces OS (HR 1.90, 95% CI 1.36 to 2.65; 1 study, 861 participants; moderate‐certainty evidence). Based on the control event risk of 880 per 1000 in this trial at 12 months, this would result in 96 fewer OSs (95% CI 167 fewer to 40 fewer) per 1000 participants. Sunitinib may reduce SAEs as compared to pembrolizumab plus axitinib (RR 0.90, 95% CI 0.81 to 1.02; 1 study, 854 participants; low‐certainty evidence) although the CI includes the possibility of no effect. Based on the control event risk of 604 per 1000 in this trial, this corresponds to 60 fewer SAEs (95% CI 115 fewer to 12 more) per 1000 participants.
4. Sunitinib versus nivolumab and ipilimumab
Sunitinib may reduce PFS as compared to nivolumab plus ipilimumab (HR 1.30, 95% CI 1.11 to 1.52; 1 study, 847 participants; low‐certainty evidence). Based on the control event risk of 280 per 1000 in this trial at 30 months' follow‐up, this corresponds to 89 fewer PFSs (95% CI 136 fewer to 37 fewer) per 1000 participants. Sunitinib reduces OS (HR 1.52, 95% CI 1.23 to 1.89; 1 study, 847 participants; high‐certainty evidence). Based on the control event risk 600 per 1000 in this trial at 30 months, this would result in 140 fewer OSs (95% CI 219 fewer to 67 fewer) per 1000 participants. Sunitinib probably increases SAEs (RR 1.37, 95% CI 1.22 to 1.53; 1 study, 1082 participants; moderate‐certainty evidence). Based on the control event risk of 457 per 1000 in this trial, this corresponds to 169 more SAEs (95% CI 101 more to 242 more) per 1000 participants.
Authors' conclusions
Based on the low to high certainty of evidence, several combinations of immune checkpoint inhibitors appear to be superior to single‐agent targeted therapy in terms of PFS and OS, and with a favourable AE profile. Some single‐agent targeted therapies demonstrated a similar or improved oncological outcome compared to others; minor differences were observed for AE within this group. The certainty of evidence was variable ranging from high to very low and all comparisons were based on single trials.
The European Association of Urology Renal Cell Carcinoma (RCC) Guideline Panel has prepared evidence-based guidelines and recommendations for the management of RCC.
To provide an updated RCC ...guideline based on standardised methodology including systematic reviews, which is robust, transparent, reproducible, and reliable.
For the 2019 update, evidence synthesis was undertaken based on a comprehensive and structured literature assessment for new and relevant data. Where necessary, formal systematic reviews adhering to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines were undertaken. Relevant databases (Medline, Cochrane Libraries, trial registries, conference proceedings) were searched until June 2018, including randomised controlled trials (RCTs) and retrospective or controlled studies with a comparator arm, systematic reviews, and meta-analyses. Where relevant, risk of bias (RoB) assessment, and qualitative and quantitative syntheses of the evidence were performed. The remaining sections of the document were updated following a structured literature assessment. Clinical practice recommendations were developed and issued based on the modified GRADE framework.
All chapters of the RCC guidelines were updated based on a structured literature assessment, for prioritised topics based on the availability of robust data. For RCTs, RoB was low across studies. For most non-RCTs, clinical and methodological heterogeneity prevented pooling of data. The majority of included studies were retrospective with matched or unmatched cohorts, based on single- or multi-institutional data or national registries. The exception was for the treatment of metastatic RCC, for which there were several large RCTs, resulting in recommendations based on higher levels of evidence.
The 2019 RCC guidelines have been updated by the multidisciplinary panel using the highest methodological standards. These guidelines provide the most reliable contemporary evidence base for the management of RCC in 2019.
The European Association of Urology Renal Cell Carcinoma Guideline Panel has thoroughly evaluated the available research data on kidney cancer to establish international standards for the care of kidney cancer patients.
The 2019 European Association of Urology renal cell cancer guidelines have been updated by a multidisciplinary panel of experts, based on the highest methodological standards. These guidelines provide the most reliable contemporaneous evidence base for the management of patients with renal cell cancer in 2019.
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We consider the problem of controlling the vertical, lateral, longitudinal and yaw attitude motion of a helicopter along desired arbitrary trajectories with only restrictions on the time derivatives ...imposed by the functional controllability of the system. To this purpose we design a nonlinear controller, obtained by suitably combining feedforward control actions and high-gain and nested saturation feedback laws, which succeeds in enforcing the desired trajectories robustly with respect to uncertainties characterizing the physical and aerodynamical parameters of the helicopter. Experimental results are also given to show the effectiveness of the method to accomplish aggressive maneuvers.
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Recent randomised trials have demonstrated a survival benefit for a front-line ipilimumab and nivolumab combination therapy, and pembrolizumab and axitinib combination therapy in metastatic ...clear-cell renal cell carcinoma. The European Association of Urology Guidelines Panel has updated its recommendations based on these studies.
Pembrolizumab plus axitinib is a new standard of care for patients diagnosed with kidney cancer spread outside the kidney and who did not receive any prior treatment for their cancer (treatment naïve). This applies to all risk groups as determined by the International Metastatic Renal Cell Carcinoma Database Consortium criteria.
Pembrolizumab plus axitinib are recommended as a new standard of care in all International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk groups. For treatment-naïve IMDC intermediate- and poor-risk patients, ipilimumab plus nivolumab remains the standard treatment. Sunitinib, pazopanib, and cabozantinib (in IMDC intermediate- and poor-risk disease) are alternative treatment options in patients who cannot receive or tolerate immune checkpoint inhibition in a first-line setting.
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Longer follow-up and new trial data from phase 3 randomised controlled trials investigating immune checkpoint blockade (PD-1 or its ligand PD-L1) in advanced clear-cell renal cell carcinoma (RCC) ...have recently become available. The CheckMate 9ER trial demonstrated an improved progression-free survival (PFS) and overall survival (OS) benefit for the combination of cabozantinib plus nivolumab. A Keynote-426 update demonstrated an ongoing OS benefit for pembrolizumab plus axitinib in the intention-to-treat population, with a PFS benefit seen across all International Metastatic Database Consortium (IMDC) subgroups, while an update of CheckMate 214 confirmed the long-term benefit of ipilimumab plus nivolumab in IMDC intermediate and poor risk patients. The RCC Guidelines Panel continues to recommend these tyrosine kinase inhibitors + immunotherapy (IO) combination across IMDC risk groups in advanced first-line RCC and dual immunotherapy of ipilimumab and nivolumab in IMDC intermediate and poor risk.
New data from trials of immune checkpoint inhibitors for advanced kidney cancer confirm a survival benefit with the combination of cabozantinib plus nivolumab and pembrolizumab plus axitinib and ipilimumab plus nivolumab. These combination therapies are recommended as first-line treatment for advanced kidney cancer.
Longer follow-up data and new trial data from phase 3 randomised controlled trials investigating immune checkpoint blockade (PD-1 or its ligand PD-L1) in advanced clear-cell renal cell carcinoma (RCC) have recently become available. A recent update of Keynote-426 demonstrated an ongoing overall survival benefit for pembrolizumab plus axitinib in the intention-to-treat population, with a progression-free survival benefit seen across all International Metastatic RCC Database Consortium (IMDC) subgroups. The RCC Guidelines Panel continues to recommend this combination across IMDC risk groups in advanced first-line RCC.
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Summary Local treatment of metastases such as metastasectomy or radiotherapy remains controversial in the treatment of metastatic renal cell carcinoma. To investigate the benefits and harms of ...various local treatments, we did a systematic review of all types of comparative studies on local treatment of metastases from renal cell carcinoma in any organ. Interventions included metastasectomy, radiotherapy modalities, and no local treatment. The results suggest that patients treated with complete metastasectomy have better survival and symptom control (including pain relief in bone metastases) than those treated with either incomplete or no metastasectomy. Nevertheless, the available evidence was marred by high risks of bias and confounding across all studies. Although the findings presented here should be interpreted with caution, they and the identified gaps in knowledge should provide guidance for clinicians and researchers, and directions for further research.
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This paper addresses the design and experimental evaluation of a robust controller for a quadrotor landing maneuver comprising the approach to a landing slope and sliding on that slope, before coming ...to a complete halt. During the critical landing flight phase, the dynamics of the vehicle change with the type of contact with the ground, and a hybrid automaton, whose states reflect the several dynamic behaviors of the quadrotor, is employed to model the vehicle throughout the complete maneuver. The quadrotor landing problem is broken down as separate maneuver generation and robust trajectory tracking problems, which are combined to achieve a successful maneuver that is robust to possible uncertainties. The experimental results are provided to attest to the feasibility of the proposed landing procedure.
Abstract Context It remains unclear whether patients with a suspicion of prostate cancer (PCa) and negative multiparametric magnetic resonance imaging (mpMRI) can safely obviate prostate biopsy. ...Objective To systematically review the literature assessing the negative predictive value (NPV) of mpMRI in patients with a suspicion of PCa. Evidence acquisition The Embase, Medline, and Cochrane databases were searched up to February 2016. Studies reporting prebiopsy mpMRI results using transrectal or transperineal biopsy as a reference standard were included. We further selected for meta-analysis studies with at least 10-core biopsies as the reference standard, mpMRI comprising at least T2-weighted and diffusion-weighted imaging, positive mpMRI defined as a Prostate Imaging Reporting Data System/Likert score of ≥3/5 or ≥4/5, and results reported at patient level for the detection of overall PCa or clinically significant PCa (csPCa) defined as Gleason ≥7 cancer. Evidence synthesis A total of 48 studies (9613 patients) were eligible for inclusion. At patient level, the median prevalence was 50.4% (interquartile range IQR, 36.4–57.7%) for overall cancer and 32.9% (IQR, 28.1–37.2%) for csPCa. The median mpMRI NPV was 82.4% (IQR, 69.0–92.4%) for overall cancer and 88.1% (IQR, 85.7–92.3) for csPCa. NPV significantly decreased when cancer prevalence increased, for overall cancer ( r = –0.64, p < 0.0001) and csPCa ( r = –0.75, p = 0.032). Eight studies fulfilled the inclusion criteria for meta-analysis. Seven reported results for overall PCa. When the overall PCa prevalence increased from 30% to 60%, the combined NPV estimates decreased from 88% (95% confidence interval 95% CI, 77–99%) to 67% (95% CI, 56–79%) for a cut-off score of 3/5. Only one study selected for meta-analysis reported results for Gleason ≥7 cancers, with a positive biopsy rate of 29.3%. The corresponding NPV for a cut-off score of ≥3/5 was 87.9%. Conclusions The NPV of mpMRI varied greatly depending on study design, cancer prevalence, and definitions of positive mpMRI and csPCa. As cancer prevalence was highly variable among series, risk stratification of patients should be the initial step before considering prebiopsy mpMRI and defining those in whom biopsy may be omitted when the mpMRI is negative. Patient summary This systematic review examined if multiparametric magnetic resonance imaging (MRI) scan can be used to reliably predict the absence of prostate cancer in patients suspected of having prostate cancer, thereby avoiding a prostate biopsy. The results suggest that whilst it is a promising tool, it is not accurate enough to replace prostate biopsy in such patients, mainly because its accuracy is variable and influenced by the prostate cancer risk. However, its performance can be enhanced if there were more accurate ways of determining the risk of having prostate cancer. When such tools are available, it should be possible to use an MRI scan to avoid biopsy in patients at a low risk of prostate cancer.
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