Use of MACI (Autologous Cultured Chondrocytes on Porcine Collagen Membrane) in the United States: Preliminary Experience.

BACKGROUND: In December 2016, MACI (autologous cultured chondrocytes on porcine collagen membrane) received approval from the US Food and Drug Administration for the treatment of symptomatic articular cartilage defects of the knee with or without bone involvement in adults. PURPOSE: To describe the cartilage defects and patient characteristics for 1000 adult patients treated with MACI for knee cartilage repair in the United States. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: Data collected by Vericel for adult patients treated for articular cartilage defects of the knee were reconciled and summarized. Data were collected for 1000 consecutive patients starting on July 1, 2017, when Carticel (the prior generation of autologous cultured chondrocytes) was no longer available. Patient names were removed for confidentiality, and patients were identified by MACI lot number and surgery date. Safety data were derived from the pharmacovigilance database. Patient demographics, cartilage defect characteristics, concomitant surgical procedures, and adverse events were summarized with descriptive statistics. RESULTS: A total of 1000 adults and 1010 knee joints were implanted with MACI by 372 surgeons. The male (49.6%)-to-female (50.4%) ratio was evenly split, and the mean age was 34.0 years. The majority of patients (68.1%) had a single cartilage defect treated, and the mean treated defect size was 4.7 cm2. The mean total treated lesion size, including multiple defects, was 5.8 cm2. The patella was the most commonly treated joint surface (32.7%), followed by the medial femoral condyle (31.3%). Most patients (92.4%) had concomitant surgical procedures at the time of cartilage biopsy acquisition. The most common concomitant procedures at the time of biopsy procurement included cartilage debridement (83.7%) and meniscal resection (11.3%). The most common planned concomitant surgeries at the time of MACI implantation were anterior tibial tubercleplasty (7.8%) and reconstruction of dislocating patella (5.5%). Few patients (2.6%) had adverse events. CONCLUSION: Patient age and mean total MACI-treated defect size in the United States are similar to the findings of the pivotal European SUMMIT (Superiority of MACI Implant Versus Microfracture Treatment) trial and other studies from outside the United States. Treatment of multiple cartilage defects is more frequent in the United States than elsewhere.

The introduction of a safety checklist in two UK hospital emergency departments: A qualitative study of implementation and staff use.

AIMS AND OBJECTIVES: To explore the extent to which a checklist designed to support patient safety in hospital Emergency Departments was recognised and used by staff. BACKGROUND: Patient crowding in UK Emergency Departments makes it difficult for staff to monitor all patients for signs of clinical deterioration. An Emergency Department Safety Checklist was developed at a UK hospital to ensure patients are regularly monitored. It was subsequently implemented in six hospitals and recommended for use across the National Health Service in England. METHODS: This was a qualitative study in two UK hospital Emergency Departments. Data collection consisted of sixty-six hours of nonparticipant observation and interviews with twenty-six staff. Observations were sampled across different days and times. Interviews sampled a range of staff. Data were analysed thematically. The study was undertaken in accordance with COREQ guidelines. RESULTS: Staff described the Emergency Department Safety Checklist as a useful prompt and reminder for monitoring patients' vital signs and other aspects of care. It was also reported as effective in communicating patient care status to other staff. However, completing the checklist was also described as a task which could be overlooked during busy periods. During implementation, the checklist was promoted to staff in ways that obscured its core function of maintaining patient safety. CONCLUSIONS: The Emergency Department Safety Checklist can support staff in maintaining patient safety. However, it was not fully recognised by staff as a core component of everyday clinical practice. RELEVANCE TO CLINICAL PRACTICE: The Emergency Department Safety Checklist is a response to an overcrowded environment. To realise the potential of the checklist, emergency departments should take the following steps during implementation: (a) focus on the core function of clinical safety, (b) fully integrate the checklist into the existing workflow and (c) employ a departmental team-based approach to implementation and training.

Twenty-Five Years' Experience and Beyond with Cultured Epidermal Autografts for Coverage of Large Burn Wounds in Adult and Pediatric Patients, 1989-2015.

This report summarizes the characteristics of 954 burned patients treated with cultured epidermal autografts (CEA), the largest number of patients to date. Data collected include patient demographics, survival, and final graft take. Source data were provided by the treating physician or attending burn team. Safety data were provided by the treating physician, attending burn team, and the pharmacovigilance database. In this dataset collected between 1989 and 2015, 954 patients were treated with cultured epidermal autographs for burns. Three hundred twenty-five (34%) were pediatric patients and 628 (66%) were adult (≥22 years of age); age unknown for one patient. The mean percentage total BSA (TBSA) burned was 67% (±17), median graft take at discharge was 75%, and overall survival at discharge was 84% (804/954). Survival rates were similar for pediatric and adult patients (89% vs 82%, respectively) and higher than the similar patient population reported in the National Burn Repository. Median graft take at discharge was also similar for pediatric and adult patients (80% vs 73%, respectively). The most frequently reported adverse reactions were infections in both pediatric and adult patients. There were no signals of increased risk of adverse reactions in pediatric compared with adult patients. When used as an adjunct to conventional split-thickness skin grafting for treatment of large burns in pediatric and adult patients, the analysis in this report shows an increased survival rate for patients treated with CEA compared with that reported for patients in the National Burn Repository with comparable burns.

Ixmyelocel-T for patients with ischaemic heart failure: a prospective randomised double-blind trial.

BACKGROUND: Ixmyelocel-T is an expanded, multicellular therapy produced from a patient's own bone marrow by selectively expanding two key types of bone marrow mononuclear cells: CD90+ mesenchymal stem cells and CD45+ CD14+ auto-fluorescent+ activated macrophages. Early phase clinical trials suggest that intramyocardial delivery of ixmyelocel-T might improve clinical, functional, symptomatic, and quality-of-life outcomes in patients with heart failure due to ischaemic dilated cardiomyopathy. We aimed to assess the safety and efficacy of catheter-based transendocardial injection of ixmyelocel-T cell therapy in patients with heart failure and reduced ejection fractions. METHODS: In this randomised, double-blind, placebo-controlled phase 2B trial (ixCELL-DCM), patients from 31 sites in North America with New York Heart Association class III or IV symptomatic heart failure due to ischaemic dilated cardiomyopathy, who had left ventricular ejection fraction 35% or less, an automatic implantable cardioverter defibrillator, and who were ineligible for revascularisation procedures were randomly assigned (1:1) to receive ixmyelocel-T or placebo at the time of bone marrow aspiration and followed for 12 months. Randomisation was done through an interactive (voice/web) response system. The pharmacist, treating physician, and coordinator at each site were unblinded, but the the follow-up team was completely blinded. The primary endpoint was a composite of all-cause death, cardiovascular admission to hospital, and unplanned clinic visits to treat acute decompensated heart failure based on the blinded adjudication of an independent clinical endpoint committee. Primary efficacy endpoint analyses and safety analyses were done by modified intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01670981. FINDINGS: Between April 2, 2013, and Jan 28, 2015, 126 participants were randomly assigned to receive either ixmyelocel-T (n=66) or placebo (n=60). 114 (90%) patients comprised the modified intention-to-treat population and 109 (87%) patients were included in the per-protocol primary efficacy analysis (58 in the ixmyelocel-T group and 51 in the placebo group). The primary efficacy endpoint was observed in 47 patients: 50 events in 25 (49%) of 51 patients in the placebo group and 38 events in 22 (38%) of 58 patients in the ixmyelocel-T group, which represents a 37% reduction in cardiac events compared with placebo (risk ratio 0·63 [95% CI 0·42-0·97]; p=0·0344). 41 (75%) of 51 participants in the placebo group had serious adverse events versus 31 (53%) of 58 in the ixmyelocel-T group (p=0·0197). INTERPRETATION: To the best of our knowledge, ixCELL-DCM is the largest cell therapy study done in patients with heart failure so far. The transendocardial delivery of ixmyelocel-T in patients with heart failure and reduced ejection fraction due to ischaemic dilated cardiomyopathy resulted in a significant reduction in adjudicated clinical cardiac events compared with placebo leading to improved patient outcomes. FUNDING: Vericel Corporation.

The ixCELL-DCM Trial: Rationale and Design.

Ixmyelocel-T is an investigational patient-specific, expanded, multicellular therapy produced from a patient's own bone marrow. It is produced by selectively expanding two key types of bone marrow mononuclear cells (BM-MNCs), CD90+ mesenchymal stem cells (MSCs), and CD45+CD14+ autofluorescent, alternatively activated macrophages. Earlier clinical trials suggested that intramyocardial ixmyelocel-T might improve clinical, functional, symptomatic, and quality of life outcomes in patients with ischemic dilated cardiomyopathy (IDCM). This ongoing randomized, double-blinded, placebo-controlled phase 2b trial (ixCELL-DCM) was designed to assess the efficacy, safety, and tolerability of catheter-based transendocardial injection of ixmyelocel-T in patients with heart failure due to IDCM. Patients (N = 114) with New York Heart Association class III or IV symptomatic heart failure due to IDCM, who have left ventricular ejection fraction ≤35% and an automatic implantable cardioverter defibrillator, but are ineligible for revascularization procedures, were randomly assigned (1:1 ratio) to ixmyelocel-T or placebo (vehicle control). The primary efficacy endpoint is a composite of the total number of deaths, cardiovascular hospitalizations, or unplanned clinic visits to treat acutely decompensated heart failure during the 12 months following treatment administration. Secondary endpoints include the win ratio analysis for hierarchical occurrences of clinical events in the primary endpoint, total numbers of clinical events, left ventricular structure and function, and quality-of-life assessments. ixCELL-DCM is one of the largest cell therapy trials in heart failure patients to date and the first double-blinded, placebo-controlled study of ixmyelocel-T administered via transendocardial catheter-based injections in patients with heart failure secondary to IDCM.

Safety and efficacy of ixmyelocel-T: an expanded, autologous multi-cellular therapy, in dilated cardiomyopathy.

RATIONALE: Ixmyelocel-T is associated with a wide range of biological activities relevant to tissue repair and regeneration. OBJECTIVE: To evaluate the safety and efficacy of ixmyelocel-T in 2 prospective randomized phase 2A Trials administered via minithoracotomy or intramyocardial catheter injections in patients with dilated cardiomyopathy (DCM) stratified by ischemic or nonischemic status. METHODS AND RESULTS: In IMPACT-DCM, patients were randomized to either ixmyelocel-T or standard-of-care control in a 3:1 ratio (n=39); ixmyelocel-T was administered intramyocardially via minithoracotomy. In Catheter-DCM, patients were randomized to either ixmyelocel-T or standard of care control in a 2:1 ratio (n=22); ixmyelocel-T was administered intramyocardially using the NOGA Myostar catheter. Only patients randomized to ixmyelocel-T underwent bone marrow aspiration and injections. In the 2 studies, a total of 61 patients were randomized, and 59 were treated or received standard of care. Fewer ischemic patients treated with ixmyelocel-T experienced a major adverse cardiovascular event during follow-up when compared with control patients. A similar benefit was not seen in the nonischemic patients. Heart failure exacerbation was the most common major adverse cardiovascular event. Ixmyelocel-T treatment was associated with improved New York Heart Association class, 6-minute walk distance, and Minnesota Living with Heart Failure Questionnaire scores in the ischemic population relative to control; a similar trend was not observed in the nonischemic population. CONCLUSIONS: Intramyocardial injection with ixmyelocel-T reduces major adverse cardiovascular event and improves symptoms in patients with ischemic DCM but not in patients with nonischemic DCM.

Quantitative imaging of cartilage morphology at 3.0 Tesla in the presence of gadopentate dimeglumine (Gd-DTPA).

MRI-based cartilage morphometry was previously validated in the absence of gadopentate dimeglumine (Gd-DTPA). However, Gd-DTPA is required for compositional (proteoglycan) imaging using delayed gadolinium-enhanced MRI of cartilage (dGEMRIC). Therefore, the effect of Gd-DTPA on cartilage morphometry was studied. A total of 165 female participants (67 with and 98 without osteoarthritis [OA]) were imaged at 3.0 Tesla before and 2 hr after intravenous Gd-DTPA injection. Flip angles in post-Gd-DTPA scans varied between 12 degrees and 35 degrees . Cartilage volume and thickness of post- vs. pre-Gd-DTPA scans showed intraclass correlation coefficients (ICCs) of 0.85 > or = r > or = 0.95, mean differences between -2.1% and +1.1%, and standard deviations (SDs) of differences between 4.7% and 9.2%. Mixed-effect models found no consistent impact of flip angle and OA status on post- vs. pre-Gd-DTPA differences. Accurate morphological measurements of cartilage can be obtained after Gd-DTPA injection, allowing compositional and morphological imaging to be combined into one session.

Effects of lasofoxifene on the pharmacokinetics and pharmacodynamics of single-dose warfarin.

AIM: To investigate the effect of steady-state lasofoxifene on the pharmacokinetics and pharmacodynamics of warfarin. METHODS: Twelve healthy postmenopausal women received warfarin (single 20-mg dose) alone and during lasofoxifene. R- and S-warfarin concentrations, prothrombin time (PT) and international normalized ratio (INR) were determined with each treatment. RESULTS: Lasofoxifene had no clinically meaningful effect on R- or S-warfarin pharmacokinetics. The S-warfarin area under the plasma concentration-time curve (AUC) was 23% and 67% larger in subjects with *1/*2 and *1/*3 heterozygous mutations, relative to *1/*1, respectively. The mean PT AUC and Cmax ratio (90% confidence interval) was 91.9 (89.6, 94.2) and 84.2 (80.6, 87.8), respectively. INR results were similar. CONCLUSIONS: Lasofoxifene has no clinically meaningful effect on the pharmacokinetics of warfarin. Although the decrease in PT/INR may not be clinically meaningful, more frequent INR monitoring may be considered during lasofoxifene introduction and discontinuation, consistent with warfarin's label.

Accuracy and precision of quantitative assessment of cartilage morphology by magnetic resonance imaging at 3.0T.

OBJECTIVE: Quantitative magnetic resonance imaging (MRI) of articular cartilage represents a powerful tool in osteoarthritis (OA) research, but has so far been confined to a field strength of 1.5T. The aim of this study was to evaluate the precision of quantitative MRI assessments of human cartilage morphology at 3.0T and to correlate the measurements at 3.0T with validated measurements at 1.5T. METHODS: MR images of the knee of 15 participants with OA and 15 healthy control subjects were acquired using Siemens 1.5T and 3.0T scanners. Double oblique coronal scans were obtained at 1.5T with a 1.5-mm partition thickness, at 3.0T with a 1.5-mm partition thickness, and at 3.0T with a 1.0-mm partition thickness. Cartilage volume, thickness, and surface area of the femorotibial cartilage plates were quantified using proprietary software. RESULTS: For 1.5-mm partition thickness at 1.5T, the precision error was 3.0% and 2.6% for cartilage volume and cartilage thickness, respectively. The error was smaller for a 1.5-mm partition thickness at 3.0T (2.6% and 2.5%) and still smaller for a 1.0-mm partition thickness at 3.0T (2.1% and 2.0%). Correlation coefficients between values obtained at 3.0T and 1.5T were high (r > or = 0.96), with no significant deviation between the two field strengths. CONCLUSION: Quantitative MRI measurement of cartilage morphology at 3.0T (partition thickness 1 mm) was found to be accurate and tended to be more reproducible than at 1.5T (partition thickness 1.5 mm). Imaging at 3.0T may therefore provide superior ability to detect changes in cartilage status over time and to determine responses to treatment with structure-modifying drugs.

Relationship between rate and extent of G protein activation: comparison between full and partial opioid agonists.

Opioid agonists acting at their receptors alter intracellular events by initiating activation of various types of Gi/Go proteins. This can be measured by the binding of the stable GTP analog [(35)S]guanosine-5'-O-(3-thio)triphosphate ([(35)S]GTPgammaS). In this study agonist efficacy is defined by the degree to which an opioid stimulates the binding of [(35)S]GTPgammaS. This allows for a definition of full and partial agonists; a full agonist causing a greater stimulation of [(35)S]GTPgammaS binding than a partial agonist. The hypothesis that the rate of agonist-stimulated [(35)S]GTPgammaS binding is dependent upon agonist efficacy was tested using membranes from C6 glioma cells expressing mu- or delta-opioid receptors. At maximal concentrations the rate of agonist-stimulated [(35)S]GTPgammaS binding followed the efficacy of mu-agonists in stimulating [(35)S]GTPgammaS binding, i.e., [D-Ala(2),N-Me-Phe(4),Gly(5)-ol]-enkephalin > morphine > meperidine > butorphanol > nalbuphine. At submaximal concentrations of mu- or delta-full agonists the [(35)S]GTPgammaS association rate was also reduced, such that the rate of [(35)S]GTPgammaS binding correlated with the extent of [(35)S]GTPgammaS bound, whether this binding was stimulated by a full agonist or a partial agonist. Agonists also stimulated [(35)S]GTPgammaS dissociation, showing that binding of this stable nucleotide was reversible. Comparison of the delta-agonists [D-Ser(2),Leu(5)]-enkephalin-Thr and (+/-)-4-((alpha-R*)-alpha-((2S*,5R*)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxylbenzyl)-N,N-diethylbenzamide, a compound with slow dissociation kinetics, showed the measured rate of G protein activation was not influenced by the agonist switching between receptors. The results are consistent with the idea that the active state(s) of the receptor induced by full or partial agonists is the same, but the number of activated receptors determines the rate of G protein activation.