Summary Background Men with high serum prostate specific antigen usually undergo transrectal ultrasound-guided prostate biopsy (TRUS-biopsy). TRUS-biopsy can cause side-effects including bleeding, ...pain, and infection. Multi-parametric magnetic resonance imaging (MP-MRI) used as a triage test might allow men to avoid unnecessary TRUS-biopsy and improve diagnostic accuracy. Methods We did this multicentre, paired-cohort, confirmatory study to test diagnostic accuracy of MP-MRI and TRUS-biopsy against a reference test (template prostate mapping biopsy TPM-biopsy). Men with prostate-specific antigen concentrations up to 15 ng/mL, with no previous biopsy, underwent 1·5 Tesla MP-MRI followed by both TRUS-biopsy and TPM-biopsy. The conduct and reporting of each test was done blind to other test results. Clinically significant cancer was defined as Gleason score ≥4 + 3 or a maximum cancer core length 6 mm or longer. This study is registered on ClinicalTrials.gov , NCT01292291. Findings Between May 17, 2012, and November 9, 2015, we enrolled 740 men, 576 of whom underwent 1·5 Tesla MP-MRI followed by both TRUS-biopsy and TPM-biopsy. On TPM-biopsy, 408 (71%) of 576 men had cancer with 230 (40%) of 576 patients clinically significant. For clinically significant cancer, MP-MRI was more sensitive (93%, 95% CI 88–96%) than TRUS-biopsy (48%, 42–55%; p<0·0001) and less specific (41%, 36–46% for MP-MRI vs 96%, 94–98% for TRUS-biopsy; p<0·0001). 44 (5·9%) of 740 patients reported serious adverse events, including 8 cases of sepsis. Interpretation Using MP-MRI to triage men might allow 27% of patients avoid a primary biopsy and diagnosis of 5% fewer clinically insignificant cancers. If subsequent TRUS-biopsies were directed by MP-MRI findings, up to 18% more cases of clinically significant cancer might be detected compared with the standard pathway of TRUS-biopsy for all. MP-MRI, used as a triage test before first prostate biopsy, could reduce unnecessary biopsies by a quarter. MP-MRI can also reduce over-diagnosis of clinically insignificant prostate cancer and improve detection of clinically significant cancer. Funding PROMIS is funded by the UK Government Department of Health, National Institute of Health Research–Health Technology Assessment Programme, (Project number 09/22/67). This project is also supported and partly funded by UCLH/UCL Biomedical Research Centre and The Royal Marsden and Institute for Cancer Research Biomedical Research Centre and is coordinated by the Medical Research Council Clinical Trials Unit (MRC CTU) at UCL. It is sponsored by University College London (UCL).
In the recent years, the vehicle-to-grid (V2G) technology has been successfully implemented to stabilize the frequency deviations in a microgrid (MG) whereby charging/discharging of battery of ...electric vehicles (EVs) is utilized depending upon their state-of-charge (SoC). Compared to the conventional battery energy storage technology, lower degradation tendency and lesser cost of an EV battery are obvious reasons for its utilization as an alternate. This paper proposes a novel adaptive intelligent model predictive control (AIMPC) scheme for frequency stabilization of an MG considering the SoC control of the battery of the EVs. The MPC scheme operates by predicting the future behavior of a plant whereby an explicit discrete-time state-space model of the plant is utilized. Since optimal performance of the MPC depends upon the tuning parameter (τw) present in its cost function, an intelligent optimization algorithm is implemented to dynamically optimize the parameter τw and simultaneously the proposed control scheme is made adaptive. Effect of the SoC control on the frequency deviation response (FDR) of the MG is demonstrated. Further, competence of the proposed control scheme is established over the adaptive fuzzy MPC and PID controller considering diverse loading conditions in the MG. Simulation results clearly establish that the FDRs of the MG are improved with the implementation of the proposed control scheme. Lastly, sensitivity of the proposed scheme is corroborated considering parametric uncertainties in the MG.
•A novel adaptive intelligent MPC scheme is proposed for LFC analysis of an MG.•State-of-charge (SoC) control of EV battery is simultaneously considered.•Effect of SoC control is demonstrated on the LFC performance of the microgrid.•Competence of the proposed scheme is established over some reputed control schemes.•Diverse loading patterns are considered in the MG for the performance comparison.
A Phase 3 Trial of Bevacizumab in Ovarian Cancer Perren, Timothy J; Swart, Ann Marie; Pfisterer, Jacobus ...
New England journal of medicine/The New England journal of medicine,
12/2011, Letnik:
365, Številka:
26
Journal Article
Recenzirano
Odprti dostop
The addition of bevacizumab to chemotherapy (15 mg/kg for six cycles) followed by extended therapy with bevacizumab every 3 weeks for a total of 15 months of treatment improved progression-free ...survival by 4 months in incompletely resected stage III or IV ovarian cancer.
Ovarian cancer is the fourth most common cause of cancer-related deaths in women, with an estimated 200,000 cases and 125,000 deaths occurring annually worldwide. For the past decade, the standard treatment for women with advanced ovarian cancer has been surgery and platinum-based chemotherapy. Attempts to improve this standard two-drug chemotherapy by adding a third cytotoxic drug failed to affect either progression-free survival or overall survival and resulted in an increase in toxic effects.
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Although intraperitoneal chemotherapy has extended overall survival by 12 to 17 months, it is an option only for women with advanced ovarian cancer who have a . . .
Designs and analyses of clinical trials with a time-to-event outcome almost invariably rely on the hazard ratio to estimate the treatment effect and implicitly, therefore, on the proportional hazards ...assumption. However, the results of some recent trials indicate that there is no guarantee that the assumption will hold. Here, we describe the use of the restricted mean survival time as a possible alternative tool in the design and analysis of these trials.
The restricted mean is a measure of average survival from time 0 to a specified time point, and may be estimated as the area under the survival curve up to that point. We consider the design of such trials according to a wide range of possible survival distributions in the control and research arm(s). The distributions are conveniently defined as piecewise exponential distributions and can be specified through piecewise constant hazards and time-fixed or time-dependent hazard ratios. Such designs can embody proportional or non-proportional hazards of the treatment effect.
We demonstrate the use of restricted mean survival time and a test of the difference in restricted means as an alternative measure of treatment effect. We support the approach through the results of simulation studies and in real examples from several cancer trials. We illustrate the required sample size under proportional and non-proportional hazards, also the significance level and power of the proposed test. Values are compared with those from the standard approach which utilizes the logrank test.
We conclude that the hazard ratio cannot be recommended as a general measure of the treatment effect in a randomized controlled trial, nor is it always appropriate when designing a trial. Restricted mean survival time may provide a practical way forward and deserves greater attention.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The logrank test is routinely applied to design and analyse randomized controlled trials (RCTs) with time-to-event outcomes. Sample size and power calculations assume the treatment effect follows ...proportional hazards (PH). If the PH assumption is false, power is reduced and interpretation of the hazard ratio (HR) as the estimated treatment effect is compromised. Using statistical simulation, we investigated the type 1 error and power of the logrank (LR)test and eight alternatives. We aimed to identify test(s) that improve power with three types of non-proportional hazards (non-PH): early, late or near-PH treatment effects.
We investigated weighted logrank tests (early, LRE; late, LRL), the supremum logrank test (SupLR) and composite tests (joint, J; combined, C; weighted combined, WC; versatile and modified versatile weighted logrank, VWLR, VWLR2) with two or more components. Weighted logrank tests are intended to be sensitive to particular non-PH patterns. Composite tests attempt to improve power across a wider range of non-PH patterns. Using extensive simulations based on real trials, we studied test size and power under PH and under simple departures from PH comprising pointwise constant HRs with a single change point at various follow-up times. We systematically investigated the influence of high or low control-arm event rates on power.
With no preconceived type of treatment effect, the preferred test is VWLR2. Expecting an early effect, tests with acceptable power are SupLR, C, VWLR2, J, LRE and WC. Expecting a late effect, acceptable tests are LRL, VWLR, VWLR2, WC and J. Under near-PH, acceptable tests are LR, LRE, VWLR, C, VWLR2 and SupLR. Type 1 error was well controlled for all tests, showing only minor deviations from the nominal 5%. The location of the HR change point relative to the cumulative proportion of control-arm events considerably affected power.
Assuming ignorance of the likely treatment effect, the best choice is VWLR2. Several non-standard tests performed well when the correct type of treatment effect was assumed. A low control-arm event rate reduced the power of weighted logrank tests targeting early effects. Test size was generally well controlled. Further investigation of test characteristics with different types of non-proportional hazards of the treatment effect is warranted.
•Interconnected power system with multi-source power generation.•LFC in deregulated environment for all possible contracts.•Optimal output feedback controller is proposed (simple, lesser cost, ...robust).•More feasible combination of hydro, thermal and gas in each control area.•Simulation results matching with desired values.
In this paper, an interconnected power system with multi-source power generation is proposed for load frequency control (LFC) in deregulated power environment. Keeping in view the new power environment, modified LFC scheme is proposed in deregulated environment for multi-source combination of hydro, reheat thermal and gas generating units in each control area. Optimal output feedback controller with pragmatic viewpoint is presented which uses less number of state variables for feedback as measurement of all of the state variables of a large system is impossible in the real world. The proposed controller incorporates all possible power transactions taking place in a deregulated power market. An extensive analysis is done for LFC and it is found that dynamic responses obtained satisfy the LFC requirements in deregulated power environment.
► Realistic power system with multi-source power generation is proposed. ► Optimal output feedback controller is proposed (simple, lesser cost, robust). ► Dynamical response of the LFC problem is ...improved with a practical point of view. ► Power system with and without GRC and the effect of GRC on the system response. ► The sensitivity analysis, selection of best value of R for the proposed system.
In this paper, load frequency control (LFC) of a realistic power system with multi-source power generation is presented. The single area power system includes dynamics of thermal with reheat turbine, hydro and gas power plants. Appropriate generation rate constraints (GRCs) are considered for the thermal and hydro plants. In practice, access to all the state variables of a system is not possible and also their measurement is costly and difficult. Usually only a reduced number of state variables or linear combinations thereof, are available. To resolve this difficulty, optimal output feedback controller which uses only the output state variables is proposed. The performances of the proposed controller are compared with the full state feedback controller. The action of this proposed controller provides satisfactory balance between frequency overshoot and transient oscillations with zero steady state error in the multi-source power system environment. The effect of regulation parameter (R) on the frequency deviation response is examined. The sensitivity analysis reveals that the proposed controller is quite robust and optimum controller gains once set for nominal condition need not to be changed for ±25% variations in the system parameters and operating load condition from their nominal values. To show the effectiveness of the proposed controller on the actual power system, the LFC of hydro power plants operational in KHOZESTAN (a province in southwest of Iran) has also been presented.
Summary Background Serum CA125 concentration often rises several months before clinical or symptomatic relapse in women with ovarian cancer. In the MRC OV05/EORTC 55955 collaborative trial, we aimed ...to establish the benefits of early treatment on the basis of increased CA125 concentrations compared with delayed treatment on the basis of clinical recurrence. Methods Women with ovarian cancer in complete remission after first-line platinum-based chemotherapy and a normal CA125 concentration were registered for this randomised controlled trial. Clinical examination and CA125 measurement were done every 3 months. Patients and investigators were masked to CA125 results, which were monitored by coordinating centres. If CA125 concentration exceeded twice the upper limit of normal, patients were randomly assigned (1:1) by minimisation to early or delayed chemotherapy. Patients and clinical sites were informed of allocation to early treatment, and treatment was started as soon as possible within 28 days of the increased CA125 measurement. Patients assigned to delayed treatment continued masked CA125 measurements, with treatment commencing at clinical or symptomatic relapse. All patients were treated according to standard local practice. The primary outcome was overall survival. Analysis was by intention to treat. This study is registered, ISRCTN87786644. Findings 1442 patients were registered for the trial, of whom 529 were randomly assigned to treatment groups and were included in our analysis (265 early, 264 delayed). With a median follow-up of 56·9 months (IQR 37·4–81·8) from randomisation and 370 deaths (186 early, 184 delayed), there was no evidence of a difference in overall survival between early and delayed treatment (HR 0·98, 95% CI 0·80–1·20, p=0·85). Median survival from randomisation was 25·7 months (95% CI 23·0–27·9) for patients on early treatment and 27·1 months (22·8–30·9) for those on delayed treatment. Interpretation Our findings showed no evidence of a survival benefit with early treatment of relapse on the basis of a raised CA125 concentration alone, and therefore the value of routine measurement of CA125 in the follow-up of patients with ovarian cancer who attain a complete response after first-line treatment is not proven. Funding UK Medical Research Council and the European Organisation for Research and Treatment of Cancer.
It is unclear whether adjuvant or early salvage radiotherapy following radical prostatectomy is more appropriate for men who present with localised or locally advanced prostate cancer. We aimed to ...prospectively plan a systematic review of randomised controlled trials (RCTs) comparing these radiotherapy approaches.
We used a prospective framework for adaptive meta-analysis (FAME), starting the review process while eligible trials were ongoing. RCTs were eligible if they aimed to compare immediate adjuvant radiotherapy versus early salvage radiotherapy, following radical prostatectomy in men (age ≥18 years) with intermediate-risk or high-risk, localised or locally advanced prostate cancer. We searched trial registers and conference proceedings until July 8, 2020, to identify eligible RCTs. By establishing the ARTISTIC collaboration with relevant trialists, we were able to anticipate when eligible trial results would emerge, and we developed and registered a protocol with PROSPERO before knowledge of the trial results (CRD42019132669). We used a harmonised definition of event-free survival, as the time from randomisation until the first evidence of either biochemical progression (prostate-specific antigen PSA ≥0·4 ng/mL and rising after completion of any postoperative radiotherapy), clinical or radiological progression, initiation of a non-trial treatment, death from prostate cancer, or a PSA level of at least 2·0 ng/mL at any time after randomisation. We predicted when we would have sufficient power to assess whether adjuvant radiotherapy was superior to early salvage radiotherapy. Investigators supplied results for event-free survival, both overall and within predefined patient subgroups. Hazard ratios (HRs) for the effects of radiotherapy timing on event-free survival and subgroup interactions were combined using fixed-effect meta-analysis.
We identified three eligible trials and were able to obtain updated results for event-free survival for 2153 patients recruited between November, 2007, and December, 2016. Median follow-up ranged from 60 months to 78 months, with a maximum follow-up of 132 months. 1075 patients were randomly assigned to receive adjuvant radiotherapy and 1078 to a policy of early salvage radiotherapy, of whom 421 (39·1%) had commenced treatment at the time of analysis. Patient characteristics were balanced within trials and overall. Median age was similar between trials at 64 or 65 years (with IQRs ranging from 59 to 68 years) across the three trials and most patients (1671 77·6%) had a Gleason score of 7. All trials were assessed as having low risk of bias. Based on 270 events, the meta-analysis showed no evidence that event-free survival was improved with adjuvant radiotherapy compared with early salvage radiotherapy (HR 0·95, 95% CI 0·75–1·21; p=0·70), with only a 1 percentage point (95% CI −2 to 3) change in 5-year event-free survival (89% vs 88%). Results were consistent across trials (heterogeneity p=0·18; I2=42%).
This collaborative and prospectively designed systematic review and meta-analysis suggests that adjuvant radiotherapy does not improve event-free survival in men with localised or locally advanced prostate cancer. Until data on long-term outcomes are available, early salvage treatment would seem the preferable treatment policy as it offers the opportunity to spare many men radiotherapy and its associated side-effects.
UK Medical Research Council.
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