301 research outputs found
Use of prior manufacturer specifications with Bayesian logic eludes preliminary phase issues in quality control: An example in a hemostasis laboratory
No full textThe present study seeks to demonstrate the feasibility of avoiding the preliminary phase, which is mandatory in all conventional approaches for internal quality control (IQC) management. Apart from savings on the resources consumed by the preliminary phase, the alternative approach described here is able to detect any analytic problems during the startup and provide a foundation for subsequent conventional assessment. A new dynamically updated predictive control chart (PCC) is used. Being Bayesian in concept, it utilizes available prior information. The manufacturer's prior quality control target value, the manufacturer's maximum acceptable interassay coefficient of variation value and the interassay standard deviation value defined during method validation in each laboratory, allow online IQC management. An Excel template, downloadable from journal website, allows easy implementation of this alternative approach in any laboratory. In the practical case of prothrombin percentage measurement, PCC gave no false alarms with respect to the 1(ks) rule (with same 5% false-alarm probability on a single control sample) during an overlap phase between two IQC batches. Moreover, PCCs were as effective as the 1(ks) rule in detecting increases in both random and systematic error after the minimal preliminary phase required by medical biology guidelines. PCCs can improve efficiency in medical biology laboratories
A comparison of the 12s rule and Bayesian approach for quality control: Application to one-stage clotting factor VIII assay
No full textAn ideal medical biology internal quality control (IQC) plan should both monitor the laboratory methods efficiently and implement the relevant clinical-biological specifications. However, many laboratories continue to use the 1(2s) quality control rule without considering the high risk of false rejection and without considering the relationship of analytical performance to quality requirements. Alternatively, one can move to the Bayesian arena, enabling probabilistic quantification of the information coming in, on a daily basis from the laboratory's IQC tests, and taking into account the laboratory's medical and economic contexts. Using the example of one-stage clotting factor VIII assay, the present study compares frequentist (1(2s) quality control rule) and Bayesian IQC management with respect to prescriber requirements, process start-up phase issues, and abnormal scenarios in IQC results. To achieve comparable confidence, the traditional 1(2s) quality control rule requires more data than the Bayesian approach in order to detect an increase in the random or systematic error of the method. Moreover, the Bayesian IQC management approach explicitly implements respect of prescriber requirements in terms of calculating the probability that the variable in question lies in a given predefined interval: for example, the factor VIII concentration required after knee surgery in a hemophilia patient. (C) 2014 Wolters Kluwer Health I Lippincott Williams & Wilkins
Bayesian logic in statistical test control: Application to coagulation factor VIII assay
No full textCoagulation factor VIII was assayed around the critical concentration of 80 U/dl, which is optimal for postoperative haemostasis in haemophiliac patients, in order to assess the use of Bayesian logic in interpreting internal quality control results during a change of reagent or control batch. A mathematical model based on Bayesian inference, requiring no preliminary control-plan phase, was compared with a classical approach, which necessarily involves performing a preliminary phase. Tsiamyrtzis and Hawkins' Bayesian model proved applicable to rapid statistical control of factor VIII assay, detecting shift at least as efficiently as classical approaches, which depend on running the kind of costly and controversial preliminary control phase recommended by Shewhart. Blood Coagul Fibrinolysis 21:289-295 (C) 2010 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins
VWF/FVIII concentrates in high-risk immunotolerance : the resist studies
No full textBackground: Inhibitor eradication with immune tolerance induction (ITI) is the best long-term therapeutic strategy in Haemophilia A (HA) patients with inhibitors. Several parameters are known to be related to the ITI success. One that has more recently been proposed is the type of FVIII concentrate. Recent clinical findings indicate that plasma-derived FVIII products containing von Willebrand factor (VWF/FVIII) could have an impact on ITI success rate, even in poor prognosis patients.
Study design: Two key prospective clinical studies have been designed to confirm the previous results supporting the use of VWF/FVIII in ITI: RESIST experienced (RESISTexp) and RESIST naïve (RESIST-naïve).
RESIST: Exp is a prospective, nonrandomized study designed to assess rescue treatment with VWF/FVIII at high dosage (200 IU/kg daily) in patients who failed a previous ITI attempt with any dose of a VWF-free FVIII concentrate (plasma-derived or recombinant). RESISTnaïve is a prospective, controlled, randomized, open-label study comparing two types of FVIII concentrates (VWF-free FVIII and VWF/FVIII) in their ability to induce tolerance in high responding HA patients, with no previous ITI attempt and with poor prognosis for success. Both types of concentrates will be administered at high dosage (200 IU/kg daily). Enrolment criteria are: severe haemophilia A (FVIII 5 BU), any inhibitor level at study enrolment, and at least one of the following risk factors for ITI failure: (a) peak inhibitor titer > 200 BU, (b) titer at ITI start > 10 BU, (c) age > 7 years, (d) time between inhibitor occurrence and ITI > 2 years. Patient undergoing concomitant immunosuppressive treatment are not eligible for either study. Primary end point is success in achieving ITI defined as: complete or partial. Secondary endpoints are: ITI maintenance, time to success, safety/compliance to treatment and cost of care.
Conclusions: The results of RESIST studies will be crucial in understanding the role of VWF/FVIII in ITI outcome and will contribute to providing effective treatment for the devastating complication of FVIII antibody development in HA patient
SAFETY AND EFFECTIVENESS OF ACTIVATED PROTHROMBIN COMPLEX CONCENTRATE (APCC) MONOTHERAPY IN PATIENTS WITH HEMOPHILIA AND INHIBITORS (PWHI) UNDERGOING SURGERY: A SYSTEMATIC REVIEW AND META-ANALYSIS
No full textIntroduction: Control of hemostasis during and after surgical procedures in PwHI is challenging. aPCC (Feiba®, Baxalta Inc, a Takeda company, Lexington, MA, USA), a bypassing agent, is indicated for patients with congenital hemophilia A or B with inhibitors for on-demand, prophylaxis and perioperative management, and for acquired hemophilia patients. We present a systematic literature review of studies reporting aPCC safety and a meta-analysis of the hemostatic effectiveness of aPCC monotherapy during major and minor surgical procedures in PwHI.
Methods: This systematic review and meta-analysis was carried out in MedLine through Pubmed from January 1, 1980 (aPCC inception) to June 30, 2018. Prospective, retrospective, randomized and non-randomized studies that reported the safety and hemostatic effectiveness of aPCC monotherapy in PwHI during surgery were eligible. Studies investigating concomitant/sequential infusion of aPCC with rFVIIa, tranexamic acid or emicizumab were excluded. Safety outcomes included serious adverse events (SAEs), including thromboembolic event (TEE), thrombotic microangiopathy (TMA), and other AEs associated with aPCC monotherapy. The hemostatic effectiveness was assessed intraoperatively by the surgeon and late postoperatively by the hematologist and rated as “excellent, good, fair or poor”.
Results: Of 645 publications describing aPCC as monotherapy in PwHI, 14 publications (including 158 patients) reported aPCC monotherapy in a surgical setting (100 major and 162 minor surgeries). TEE occurrence was reported in 4 major surgeries in 4 patients. One SAE of a clot in an arteriovenous fistula (possibly-related to aPCC) was reported. No reports of TMAs were identified in publications of studies that used aPCC as monotherapy. The proportion (95% confidence interval, CI) of major procedures in which hemostatic effectiveness was rated as excellent/good was 0.91 [(0.83-0.99); p=0.04 for heterogeneity] and for minor procedures this was 0.98 [(0.95-1.00); p=0.86 for heterogeneity].
Discussion/Conclusion: In this analysis of published studies involving patients treated with aPCC monotherapy in a surgical setting, a low rate of TEE occurrence and no TMAs were reported, while the hemostatic effectiveness of aPCC monotherapy was rated as excellent/good in >90% of both minor and major surgical procedures
Open-label phase 2 trial of first-line everolimus monotherapy in patients with papillary metastatic renal cell carcinoma: RAPTOR final analysis
No full textBackground: Papillary histology accounts for 10-15% of renal cell carcinoma (RCC), and treatment options for patients with this subtype are limited. The RAPTOR (RAD001 in Advanced Papillary Tumor Program in Europe; ClinicalTrials.gov, NCT00688753) study evaluated first-line everolimus in patients with papillary metastatic RCC (mRCC). Methods: This phase 2 trial enrolled previously untreated patients with type 1 or type 2 papillary mRCC. Papillary histology was confirmed by central review and was performed for every patient. Patients received oral everolimus 10 mg once daily until disease progression or unacceptable toxicity. The primary end-point was progression-free survival (PFS) rate at 6 months among the first 44 patients of the per protocol (PP) population. Secondary end-points included PFS, tumour response, overall survival (OS), and safety. Findings: Analysis sets included safety (NZ 92; 100%), intent-to-treat (ITT) (n=88), and PP populations (n = 46). In the safety population, most patients were men (78%) and the mean age was 60 years (range 23-84). Papillary histology was confirmed in 78% of patients (type 1, 32%; type 2, 64%; missing information, 4%). PFS rate at 6 months was 34% (80% confidence interval [CI] 25-45). In the ITT population, median PFS was 4.1 months (95% CI 3.6-5.5), 65% of patients achieved stable disease, and median OS was 21.4 months (95% CI 15.4-28.4). Among patients with type 1 or type 2 histology, median PFS was 7.9 months (95% CI 2.1 -11.0) and 5.1 months (95% CI 3.3-5.5), respectively, and median OS was 28.0 months (95% CI 7.6-not estimable) and 24.2 months (95% CI 15.8-32.8), respectively. Common grade > 2 adverse events were asthenia (13%), anaemia (7%), and fatigue (5%). Interpretation: Results of this large prospective study in papillary mRCC demonstrated that everolimus provides some clinical benefit to this patient population and highlight the need for central pathological review of this rare tumour. (C) 2016 Elsevier Ltd. All rights reserved
How clinical practice is changing the rules: the sunitinib 2/1 schedule in metastatic renal cell carcinoma
No full textIntroduction: Currently, sunitinib is a standard of care in first-line treatment for metastatic renal cell carcinoma (mRCC). However, with the standard 4/2 schedule (sunitinib 50 mg/day; 4 consecutive weeks on treatment; 2 weeks' rest), 50% of patients require dose reductions to mitigate toxicity, highlighting the need to investigate alternative dosing schedules that improve tolerability without compromising efficacy. Areas covered: We present a concise critical review of published studies comparing the efficacy and safety of the 4/2 and 2/1 schedule (2 weeks on treatment; 1 week rest) for sunitinib. While all studies evaluating the 2/1 schedule have a low level of evidence, the results indicate that the 2/1 schedule improves tolerability compared with the 4/2 schedule, including significant reductions in the incidence of specific adverse events. It was not possible to make any definitive conclusions regarding efficacy due to methodologic limitations of these studies. Expert commentary: In the absence of strong evidence supporting the safety and efficacy of the 2/1 schedule, we recommend that patients should be initiated on sunitinib therapy with the standard 4/2 schedule and only be switched to the 2/1 schedule after the development of dose-limiting toxicities from weeks 3-4 (cycle 1) of the 4/2 schedule cycle
Switching patients in the age of long-acting recombinant products?
No full textIntroduction: Prophylaxis with factor replacement therapy is the gold standard for the treatment of hemophilia, but this often requires frequent infusions. A number of long-acting factor products have been developed to reduce the burden on patients. Areas covered: This is an overview of information presented at two symposia held at the World Federation of Hemophilia and International Society on Thrombosis and Haemostasis–Scientific and Standardization Committee annual meetings. The pharmacokinetic, safety and efficacy data for long-acting recombinant products are reviewed, with a focus on recombinant factor IX albumin fusion protein (rIX-FP) and rVIII-SingleChain. This overview also provides a guide for managing a patient’s switch to long-acting products. Expert opinion: Long-acting products may allow patients to maintain or decrease bleeding rates whilst increasing their dosing interval, which may in turn reduce the burden on patients and caregivers. When switching patients to long-acting products health-care professionals should provide balanced and thorough education to the patient, whilst supporting their emotional well-being. Regimens should address patients’ needs and goals but should also be guided by clinical phenotype and pharmacokinetic assessment. Follow-up should assess safety concerns, bleeding rates, joint health and the impact of the regimen on patients’ lifestyle
The application of bypassing-agent prophylaxis in haemophilia A patients with inhibitors: a meeting report
No full textMetastatic Renal Cell Carcinoma Rapidly Progressive to Sunitinib: What to Do Next?
No full textBackground: From 10% to 26% of patients with metastatic renal cell carcinoma (mRCC) experience rapidly progressive disease (PD) on treatment with sunitinib. Objective: To investigate the benefit of subsequent treatment with another tyrosine kinase inhibitor (TKI) or a mammalian target of rapamycin (mTOR) inhibitor in such primary refractory patients. Design, setting, and participants: A total of 150 mRCC patients with rapidly PD on first-line sunitinib (within two cycles, n = 93, or four cycles, n = 57) were identified: median age 59 yr; nephrectomy 86%; histological subtypes: clear cell (77.8%), papillary (14%), and sarcomatoid features (18%); according to the Memorial Sloan-Kettering Cancer Center and French classifications: good risk (11% and 7%, respectively), intermediate (68% and 63%, respectively), and poor (21% and 29%, respectively). Outcome measurements and statistical analysis: Data were retrospectively collected by a questionnaire from 19 European oncology centers between March 2005 and March 2011. Progression-free survival (PFS) and overall survival (OS) were calculated (Kaplan-Meier method). Results and limitations: Median OS from the start of first-line treatment was 7.4 mo. Second-line treatment was administered to 86 (57%) patients (44 mTOR inhibitors: 23 everolimus and 21 temsirolimus; 39 TKIs alone or in combination; three chemotherapy). Second-line PFS was not significantly different between TKIs and mTOR inhibitors (2.0 vs 0.9 mo; p = 0.536). Median OS from the start of second-line treatment was 5.0 mo for mTOR inhibitors and 6.6 mo for TKIs (p = 0.15). Conclusions: Treatment with further TKIs or mTOR inhibitors for mRCC patients primarily refractory to first-line sunitinib in the observed time period achieved very minimal benefit, suggesting avoiding TKI rechallenge and possibly preferring alternative strategies, such as immune checkpoint inhibitors, after PD to a treatment line including a TKI in this setting. Patient summary: The present work collected data about 150 patients affected by metastatic renal cell carcinoma, who received one of the current standard of care as first-line treatment, namely, the antiangiogenic drug sunitinib, and experienced rapid worsening of the disease. We investigated and described the subsequent outcome of such patients treated with two different types of drug, administered as second-line therapy, to better understand the best strategy to adopt for patients who got no benefit from sunitinib and to describe the current therapeutic approach in such cases
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