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Metastatic Prostate Cancer: An Update on Treatments and a Review of Patient Symptom Management.
No full textBACKGROUND
Available treatment options have improved overall survival and contributed to delayed progression, but metastatic prostate cancer remains incurable. Treatment strategies are based on disease progression assessed by a combination of biochemical, radiographic, and symptomatic changes.
OBJECTIVES
The aim of this article is to review metastatic prostate cancer, symptoms representing disease progression, disease treatments, and symptom management.
METHODS
A PubMed® search restricted to English-language articles published since 1990 was conducted in August 2018 with combinations of the keywords "metastatic prostate cancer," "symptom assessment," and "treatment." Review articles were excluded, but their reference lists were reviewed to identify additional articles. Information from relevant articles published after August 2018 was added as appropriate based on author consensus.
FINDINGS
Nursing professionals play vital roles in symptom recognition and reporting, identification of disease progression, patient education, and implementation of individualized treatment strategies
Reversal of Bioprosthetic Aortic Valve Thrombosis Using Rivaroxaban-A Case Report.
No full textBioprosthetic valve thrombosis (BPVT) is a rare but recognized complication causing valve dysfunction. In subacute valve thrombosis, systemic oral anticoagulation is recommended. However, there is little data comparing the efficacy of warfarin and novel oral anticoagulant (NOAC) therapy in this setting. A patient developed subacute BPVT 11 years post-implantation. The patient was initially treated with warfarin for a period of 6 months, with limited effect. Following replacement of warfarin with rivaroxaban, there was significant reversal of the BPVT, as represented by a reduction in transaortic maximal velocity (Vmax) from 4.1 to 3 m/s over 7 months. Systemic oral anticoagulation can be an effective treatment for subacute valve thrombosis. Guidelines currently recommend warfarin as first line but NOACs can be considered in such patients and may be more effective than warfarin. Randomized controlled trials are required to further establish the optimal anticoagulation for patients with subacute BPVT
Towards personalized guidelines: using machine-learning algorithms to guide antimicrobial selection.
No full textBACKGROUND
Electronic decision support systems could reduce the use of inappropriate or ineffective empirical antibiotics. We assessed the accuracy of an open-source machine-learning algorithm trained in predicting antibiotic resistance for three Gram-negative bacterial species isolated from patients' blood and urine within 48 h of hospital admission.
METHODS
This retrospective, observational study used routine clinical information collected between January 2010 and October 2016 in Birmingham, UK. Patients from whose blood or urine cultures Escherichia coli, Klebsiella pneumoniae or Pseudomonas aeruginosa was isolated were identified. Their demographic, microbiology and prescribing data were used to train an open-source machine-learning algorithm-XGBoost-in predicting resistance to co-amoxiclav and piperacillin/tazobactam. Multivariate analysis was performed to identify predictors of resistance and create a point-scoring tool. The performance of both methods was compared with that of the original prescribers.
RESULTS
There were 15 695 admissions. The AUC of the receiver operating characteristic curve for the point-scoring tools ranged from 0.61 to 0.67, and performed no better than medical staff in the selection of appropriate antibiotics. The machine-learning system performed statistically but marginally better (AUC 0.70) and could have reduced the use of unnecessary broad-spectrum antibiotics by as much as 40% among those given co-amoxiclav, piperacillin/tazobactam or carbapenems. A validation study is required.
CONCLUSIONS
Machine-learning algorithms have the potential to help clinicians predict antimicrobial resistance in patients found to have a Gram-negative infection of blood or urine. Prospective studies are required to assess performance in an unselected patient cohort, understand the acceptability of such systems to clinicians and patients, and assess the impact on patient outcome
Patient safety incidents and medication errors during a clinical trial: experience from a pre-hospital randomized controlled trial of emergency medication administration.
No full textAIM
To assess and evaluate patient safety incidents and in particular, medication errors, during a large multi-center pre-hospital trial of emergency therapy (PARAMEDIC2), in order to inform and improve future pre-hospital medicines trials.
METHODS
The PARAMEDIC2 trial was undertaken across five NHS Ambulance Services in England and Wales with randomisation between December 2014 and October 2017. Patients with an out -of-hospital cardiac arrest unresponsive to initial resuscitation were randomly assigned to 1 mg intravenous adrenaline or matching placebo. Records were reviewed to identify trial medication errors involving documentation and/or clinical protocol errors occurring in trial participants. Causes of medication errors, including root cause analysis where available, were reviewed to identify patterns and themes contributing to these errors.
RESULTS
Eight thousand sixteen patients were enrolled, of whom 4902 received trial medication. A total of 331 patient safety incidents was reported, involving 295 patients, representing an overall rate of 3.6% of these, 166 (50.2%) were documentation errors while 165 (49.8%) were clinical protocol/medication errors. An overall rate of 0-4.5% was reported across all five ambulance services, with a mean of 2.0%. These errors had no impact on patient care or the trial and were all resolved CONCLUSION: The overall medication error rate of 1.8% primarily consisted of administration of open-label adrenaline and confusion with trial medication packs. A similar number of patients had documentation errors. This study is the first to provide data on patient safety incidents relating to medication errors encountered during a pre-hospital trial of emergency medication administration and will provide supporting data for planning future trials in this area
Mortality benefit in the COMPASS trial: is it related to superior statistical power or better efficacy and safety?
No full textUntil recently, attempts to improve the benefit of aspirin by adding another antithrombotic agent have not resulted in a mortality reduction in patients with chronic symptomatic atherosclerosis. In this population, COMPASS is the only one among six trials to show a significant mortality reduction, thereby providing evidence of a clear net clinical benefit with the combination of low-dose rivaroxaban plus aspirin. In this systematic review, we sought to determine whether the mortality benefit of the combination arm in COMPASS is best explained by greater statistical power or by a more favorable efficacy-safety profile than the other regimens evaluated in patients with chronic symptomatic atherosclerosis
Antibody tests for identification of current and past infection with SARS-CoV-2.
No full textBACKGROUND
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus and resulting COVID-19 pandemic present important diagnostic challenges. Several diagnostic strategies are available to identify current infection, rule out infection, identify people in need of care escalation, or to test for past infection and immune response. Serology tests to detect the presence of antibodies to SARS-CoV-2 aim to identify previous SARS-CoV-2 infection, and may help to confirm the presence of current infection.
OBJECTIVES
To assess the diagnostic accuracy of antibody tests to determine if a person presenting in the community or in primary or secondary care has SARS-CoV-2 infection, or has previously had SARS-CoV-2 infection, and the accuracy of antibody tests for use in seroprevalence surveys.
SEARCH METHODS
We undertook electronic searches in the Cochrane COVID-19 Study Register and the COVID-19 Living Evidence Database from the University of Bern, which is updated daily with published articles from PubMed and Embase and with preprints from medRxiv and bioRxiv. In addition, we checked repositories of COVID-19 publications. We did not apply any language restrictions. We conducted searches for this review iteration up to 27 April 2020.
SELECTION CRITERIA
We included test accuracy studies of any design that evaluated antibody tests (including enzyme-linked immunosorbent assays, chemiluminescence immunoassays, and lateral flow assays) in people suspected of current or previous SARS-CoV-2 infection, or where tests were used to screen for infection. We also included studies of people either known to have, or not to have SARS-CoV-2 infection. We included all reference standards to define the presence or absence of SARS-CoV-2 (including reverse transcription polymerase chain reaction tests (RT-PCR) and clinical diagnostic criteria).
DATA COLLECTION AND ANALYSIS
We assessed possible bias and applicability of the studies using the QUADAS-2 tool. We extracted 2x2 contingency table data and present sensitivity and specificity for each antibody (or combination of antibodies) using paired forest plots. We pooled data using random-effects logistic regression where appropriate, stratifying by time since post-symptom onset. We tabulated available data by test manufacturer. We have presented uncertainty in estimates of sensitivity and specificity using 95% confidence intervals (CIs).
MAIN RESULTS
We included 57 publications reporting on a total of 54 study cohorts with 15,976 samples, of which 8526 were from cases of SARS-CoV-2 infection. Studies were conducted in Asia (n = 38), Europe (n = 15), and the USA and China (n = 1). We identified data from 25 commercial tests and numerous in-house assays, a small fraction of the 279 antibody assays listed by the Foundation for Innovative Diagnostics. More than half (n = 28) of the studies included were only available as preprints. We had concerns about risk of bias and applicability. Common issues were use of multi-group designs (n = 29), inclusion of only COVID-19 cases (n = 19), lack of blinding of the index test (n = 49) and reference standard (n = 29), differential verification (n = 22), and the lack of clarity about participant numbers, characteristics and study exclusions (n = 47). Most studies (n = 44) only included people hospitalised due to suspected or confirmed COVID-19 infection. There were no studies exclusively in asymptomatic participants. Two-thirds of the studies (n = 33) defined COVID-19 cases based on RT-PCR results alone, ignoring the potential for false-negative RT-PCR results. We observed evidence of selective publication of study findings through omission of the identity of tests (n = 5). We observed substantial heterogeneity in sensitivities of IgA, IgM and IgG antibodies, or combinations thereof, for results aggregated across different time periods post-symptom onset (range 0% to 100% for all target antibodies). We thus based the main results of the review on the 38 studies that stratified results by time since symptom onset. The numbers of individuals contributing data within each study each week are small and are usually not based on tracking the same groups of patients over time. Pooled results for IgG, IgM, IgA, total antibodies and IgG/IgM all showed low sensitivity during the first week since onset of symptoms (all less than 30.1%), rising in the second week and reaching their highest values in the third week. The combination of IgG/IgM had a sensitivity of 30.1% (95% CI 21.4 to 40.7) for 1 to 7 days, 72.2% (95% CI 63.5 to 79.5) for 8 to 14 days, 91.4% (95% CI 87.0 to 94.4) for 15 to 21 days. Estimates of accuracy beyond three weeks are based on smaller sample sizes and fewer studies. For 21 to 35 days, pooled sensitivities for IgG/IgM were 96.0% (95% CI 90.6 to 98.3). There are insufficient studies to estimate sensitivity of tests beyond 35 days post-symptom onset. Summary specificities (provided in 35 studies) exceeded 98% for all target antibodies with confidence intervals no more than 2 percentage points wide. False-positive results were more common where COVID-19 had been suspected and ruled out, but numbers were small and the difference was within the range expected by chance. Assuming a prevalence of 50%, a value considered possible in healthcare workers who have suffered respiratory symptoms, we would anticipate that 43 (28 to 65) would be missed and 7 (3 to 14) would be falsely positive in 1000 people undergoing IgG/IgM testing at days 15 to 21 post-symptom onset. At a prevalence of 20%, a likely value in surveys in high-risk settings, 17 (11 to 26) would be missed per 1000 people tested and 10 (5 to 22) would be falsely positive. At a lower prevalence of 5%, a likely value in national surveys, 4 (3 to 7) would be missed per 1000 tested, and 12 (6 to 27) would be falsely positive. Analyses showed small differences in sensitivity between assay type, but methodological concerns and sparse data prevent comparisons between test brands.
AUTHORS' CONCLUSIONS
The sensitivity of antibody tests is too low in the first week since symptom onset to have a primary role for the diagnosis of COVID-19, but they may still have a role complementing other testing in individuals presenting later, when RT-PCR tests are negative, or are not done. Antibody tests are likely to have a useful role for detecting previous SARS-CoV-2 infection if used 15 or more days after the onset of symptoms. However, the duration of antibody rises is currently unknown, and we found very little data beyond 35 days post-symptom onset. We are therefore uncertain about the utility of these tests for seroprevalence surveys for public health management purposes. Concerns about high risk of bias and applicability make it likely that the accuracy of tests when used in clinical care will be lower than reported in the included studies. Sensitivity has mainly been evaluated in hospitalised patients, so it is unclear whether the tests are able to detect lower antibody levels likely seen with milder and asymptomatic COVID-19 disease. The design, execution and reporting of studies of the accuracy of COVID-19 tests requires considerable improvement. Studies must report data on sensitivity disaggregated by time since onset of symptoms. COVID-19-positive cases who are RT-PCR-negative should be included as well as those confirmed RT-PCR, in accordance with the World Health Organization (WHO) and China National Health Commission of the People's Republic of China (CDC) case definitions. We were only able to obtain data from a small proportion of available tests, and action is needed to ensure that all results of test evaluations are available in the public domain to prevent selective reporting. This is a fast-moving field and we plan ongoing updates of this living systematic review
Reply to Flück et al.: Alternative androgen pathway biosynthesis drives fetal female virilization in P450 oxidoreductase deficiency.
No full textEvent-Free Survival, a Prostate-Specific Antigen-Based Composite End Point, Is Not a Surrogate for Overall Survival in Men With Localized Prostate Cancer Treated With Radiation.
No full textPURPOSE
Recently, we have shown that metastasis-free survival is a strong surrogate for overall survival (OS) in men with intermediate- and high-risk localized prostate cancer and can accelerate the evaluation of new (neo)adjuvant therapies. Event-free survival (EFS), an earlier prostate-specific antigen (PSA)-based composite end point, may further expedite trial completion.
METHODS
EFS was defined as the time from random assignment to the date of first evidence of disease recurrence, including biochemical failure, local or regional recurrence, distant metastasis, or death from any cause, or was censored at the date of last PSA assessment. Individual patient data from trials within the Intermediate Clinical Endpoints in Cancer of the Prostate-ICECaP-database with evaluable PSA and disease follow-up data were analyzed. We evaluated the surrogacy of EFS for OS using a 2-stage meta-analytic validation model by determining the correlation of EFS with OS (patient level) and the correlation of treatment effects (hazard ratios [HRs]) on both EFS and OS (trial level). A clinically relevant surrogacy was defined a priori as an ≥ 0.7.
RESULTS
Data for 10,350 patients were analyzed from 15 radiation therapy-based trials enrolled from 1987 to 2011 with a median follow-up of 10 years. At the patient level, the correlation of EFS with OS was 0.43 (95% CI, 0.42 to 0.44) as measured by Kendall's tau from a copula model. At the trial level, the was 0.35 (95% CI, 0.01 to 0.60) from the weighted linear regression of log(HR)-OS on log(HR)-EFS.
CONCLUSION
EFS is a weak surrogate for OS and is not suitable for use as an intermediate clinical end point to substitute for OS to accelerate phase III (neo)adjuvant trials of prostate cancer therapies for primary radiation therapy-based trials
Targeting the rheumatoid arthritis synovial fibroblast via cyclin dependent kinase inhibition: An early phase trial.
No full textINTRODUCTION
Targeted biologic therapies demonstrate similar efficacies in rheumatoid arthritis despite distinct mechanisms of action. They also exhibit a ceiling effect, with 10% to 20% of patients achieving remission in clinical trials. None of these therapies target synovial fibroblasts, which drive and maintain synovitis. Seliciclib (R-roscovitine) is an orally available cyclin-dependent kinase inhibitor that suppresses fibroblast proliferation, and is efficacious in preclinical arthritis models. We aim to determine the toxicity and preliminary efficacy of seliciclib in combination with biologic therapies, to inform its potential as an adjunctive therapy in rheumatoid arthritis.
METHODS AND ANALYSIS
TRAFIC is a non-commercial, multi-center, rolling phase Ib/IIa trial investigating the safety, tolerability, and efficacy of seliciclib in patients with moderate to severe rheumatoid arthritis receiving biologic therapies. All participants receive seliciclib with no control arm. The primary objective of part 1 (phase Ib) is to determine the maximum tolerated dose and safety of seliciclib over 4 weeks of dosing. Part 1 uses a restricted 1-stage Bayesian continual reassessment method based on a target dose-limiting toxicity probability of 35%. Part 2 (phase IIa) assesses the potential efficacy of seliciclib, and is designed as a single arm, single stage early phase trial based on a Fleming-A'Hern design using the maximum tolerated dose recommended from part 1. The primary response outcome after 12 weeks of therapy is a composite of clinical, histological and magnetic resonance imaging scores. Secondary outcomes include adverse events, pharmacodynamic and pharmacokinetic parameters, autoantibodies, and fatigue.
ETHICS AND DISSEMINATION
The study has been reviewed and approved by the North East - Tyne & Wear South Research Ethics Committee (reference 14/NE/1075) and the Medicines and Healthcare Products Regulatory Agency (MHRA), United Kingdom. Results will be disseminated through publication in relevant peer-reviewed journals and presentation at national and international conferences.
TRIALS REGISTRATION
ISRCTN, ISRCTN36667085. Registered on September 26, 2014; http://www.isrctn.com/ISRCTN36667085Current protocol version: Protocol version 11.0 (March 21, 2019)