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Use of cell-based medicinal products (CBMPs) represents a state-of-the-art approach for reducing general immunosuppression in organ transplantation. We tested multiple regulatory CBMPs in kidney transplant trials to establish the safety of regulatory CBMPs when combined with reduced immunosuppressive treatment. The ONE Study consisted of seven investigator-led, single-arm trials done internationally at eight hospitals in France, Germany, Italy, the UK, and the USA (60 week follow-up). Included patients were living-donor kidney transplant recipients aged 18 years and older. The reference group trial (RGT) was a standard-of-care group given basiliximab, tapered steroids, mycophenolate mofetil, and tacrolimus. Six non-randomised phase 1/2A cell therapy group (CTG) trials were pooled and analysed, in which patients received one of six CBMPs containing regulatory T cells, dendritic cells, or macrophages; patient selection and immunosuppression mirrored the RGT, except basiliximab induction was substituted with CBMPs and mycophenolate mofetil tapering was allowed. None of the trials were randomised and none of the individuals involved were masked. The primary endpoint was biopsy-confirmed acute rejection (BCAR) within 60 weeks after transplantation; adverse event coding was centralised. The RTG and CTG trials are registered with ClinicalTrials.gov, NCT01656135, NCT02252055, NCT02085629, NCT02244801, NCT02371434, NCT02129881, and NCT02091232. The seven trials took place between Dec 11, 2012, and Nov 14, 2018. Of 782 patients assessed for eligibility, 130 (17%) patients were enrolled and 104 were treated and included in the analysis. The 66 patients who were treated in the RGT were 73% male and had a median age of 47 years. The 38 patients who were treated across six CTG trials were 71% male and had a median age of 45 years. Standard-of-care immunosuppression in the recipients in the RGT resulted in a 12% BCAR rate (expected range 3·2–18·0). The overall BCAR rate for the six parallel CTG trials was 16%. 15 (40%) patients given CBMPs were successfully weaned from mycophenolate mofetil and maintained on tacrolimus monotherapy. Combined adverse event data and BCAR episodes from all six CTG trials revealed no safety concerns when compared with the RGT. Fewer episodes of infections were registered in CTG trials versus the RGT. Regulatory cell therapy is achievable and safe in living-donor kidney transplant recipients, and is associated with fewer infectious complications, but similar rejection rates in the first year. Therefore, immune cell therapy is a potentially useful therapeutic approach in recipients of kidney transplant to minimise the burden of general immunosuppression. The 7th EU Framework Programme.

Outcomes for children and adults with advanced soft tissue sarcoma are poor with traditional therapy. We investigated whether the addition of pazopanib to preoperative chemoradiotherapy would improve pathological near complete response rate compared with chemoradiotherapy alone. In this joint Children's Oncology Group and NRG Oncology multicentre, randomised, open-label, phase 2 trial, we enrolled eligible adults (aged ≥18 years) and children (aged between 2 and <18 years) from 57 hospitals in the USA and Canada with unresected, newly diagnosed trunk or extremity chemotherapy-sensitive soft tissue sarcoma, which were larger than 5 cm in diameter and of intermediate or high grade. Eligible patients had Lansky (if aged ≤16 years) or Karnofsky (if aged >16 years) performance status score of at least 70. Patients received ifosfamide (2·5 g/m2 per dose intravenously on days 1–3 with mesna) and doxorubicin (37·5 mg/m2 per dose intravenously on days 1–2) with 45 Gy preoperative radiotherapy, followed by surgical resection at week 13. Patients were randomly assigned (1:1) using a web-based system, in an unmasked manner, to receive oral pazopanib (if patients <18 years 350 mg/m2 once daily; if patients ≥18 years 600 mg once daily) or not (control group), with pazopanib not given immediately before or after surgery at week 13. The study projected 100 randomly assigned patients were needed to show an improvement in the number of participants with a 90% or higher pathological response at week 13 from 40% to 60%. Analysis was done per protocol. This study has completed accrual and is registered with ClinicalTrials.gov, NCT02180867. Between July 7, 2014, and Oct 1, 2018, 81 eligible patients were enrolled and randomly assigned to the pazopanib group (n=42) or the control group (n=39). At the planned second interim analysis with 42 evaluable patients and a median follow-up of 0·8 years (IQR 0·3–1·6) in the pazopanib group and 1 year (0·3–1·6) in the control group, the number of patients with a 90% pathological response or higher was 14 (58%) of 24 patients in the pazopanib group and four (22%) of 18 patients in the control group, with a between-group difference in the number of 90% or higher pathological response of 36·1% (83·8% CI 16·5–55·8). On the basis of an interim analysis significance level of 0·081 (overall one-sided significance level of 0·20, power of 0·80, and O'Brien-Fleming-type cumulative error spending function), the 83·8% CI for response difference was between 16·5% and 55·8% and thus excluded 0. The improvement in pathological response rate with the addition of pazopanib crossed the predetermined boundary and enrolment was stopped. The most common grade 3–4 adverse events were leukopenia (16 [43%] of 37 patients), neutropenia (15 [41%]), and febrile neutropenia (15 [41%]) in the pazopanib group, and neutropenia (three [9%] of 35 patients) and febrile neutropenia (three [9%]) in the control group. 22 (59%) of 37 patients in the pazopanib group had a pazopanib-related serious adverse event. Paediatric and adult patients had a similar number of grade 3 and 4 toxicity. There were seven deaths (three in the pazopanib group and four in the control group), none of which were treatment related. In this presumed first prospective trial of soft tissue sarcoma spanning nearly the entire age spectrum, adding pazopanib to neoadjuvant chemoradiotherapy improved the rate of pathological near complete response, suggesting that this is a highly active and feasible combination in children and adults with advanced soft tissue sarcoma. The comparison of survival outcomes requires longer follow-up. National Institutes of Health, St Baldrick's Foundation, Seattle Children's Foundation.

Background and Objectives: Patellofemoral pain (PFP) is the most prevalent running-related injury due to underlying biomechanical factors, particularly among female runners. Although instrument-assisted soft tissue mobilization (IASTM) is a popular therapeutic technique, the optimal application site for the short-and long-term outcomes of PFP has not been well established. This aim of this study was to compare the immediate and short-term (1-week) effects of a single IASTM treatment applied to the hip and knee versus the knee alone on running-related pain. Range of motion (ROM), muscle strength, and functional performance were also assessed to compare change between the two treatment conditions. Materials and Methods: Twenty-eight female runners with PFP were randomly assigned to either the Hip and Knee (HK) group (n = 14) or the knee-only (K) group (n = 14). The HK group received a 7-min IASTM treatment targeting the quadriceps, patella, iliotibial band (ITB), and gluteus medius, whereas the K group received a 3-min treatment targeting the quadriceps and patella. Visual analog scale (VAS), hip adduction ROM, hip abduction/external rotation strength, and step-down test scores were measured at baseline, immediately post-intervention, and 1 week later. Results: Running-related pain significantly decreased in both groups (main effect of time, p < 0.001) from baseline (HK: 5.49 ± 2.14 [95% CI: 4.78–6.68]; K: 5.30 ± 1.45 [95% CI: 4.69–5.91]) to week 1 (HK: 1.30 ± 1.08 [95%CI: 0.69–1.90]; K: 1.57 ± 1.20 [95%CI: 0.93–2.21]). However, no significant difference was found between the groups. Significant improvement was also observed in hip adduction ROM (p < 0.001), hip abduction strength (p = 0.02), step-down pain (p < 0.001), and patellofemoral function (p < 0.001) immediately after the intervention, which was sustained at the 1-week follow-up. However, no significant difference was found between the groups. Also, hip external rotation strength showed no significant change over time or between groups (p = 0.737). Conclusions: A single IASTM session effectively reduced pain and improved function in female runners with PFP. However, the hip treatment did not show a significant additional benefit compared with knee treatment alone. IASTM can provide immediate and short-term relief of pain and functional limitations.

Cell therapies offer the promise of treating and altering the course of diseases which cannot be addressed adequately by existing pharmaceuticals. Cell therapies are a diverse group across cell types and therapeutic indications and have been an active area of research for many years but are now strongly emerging through translation and towards successful commercial development and patient access. In this article, we present a description of a classification of cell therapies on the basis of their underlying technologies rather than the more commonly used classification by cell type because the regulatory path and manufacturing solutions are often similar within a technology area due to the nature of the methods used. We analyse the progress of new cell therapies towards clinical translation, examine how they are addressing the clinical, regulatory, manufacturing and reimbursement requirements, describe some of the remaining challenges and provide perspectives on how the field may progress for the future.

Background Cervical disc herniation (CDH) is a common musculoskeletal disorder characterized by chronic neck pain, impaired proprioception, kinesiophobia, and functional limitations, often requiring multimodal conservative care. Myofascial techniques, including Instrument-Assisted Soft Tissue Mobilization (IASTM) and percussion massage therapy (PMT), have emerged as supportive physiotherapy interventions. This randomized controlled trial compared the effects of IASTM and PMT on pain, disability, kinesiophobia, and proprioceptive function in individuals with CDH. Methods In this double-blinded RCT, 57 participants with CDH were randomly allocated to Conventional Therapy (CT), CT + PMT, or CT + IASTM ( n  = 19 each). Interventions were delivered three times per week for 3 weeks. PMT was applied with a percussion massage device (33–40 Hz) for 3 min to each target muscle group (trapezius, levator scapulae, cervical paravertebral) using longitudinal strokes. IASTM used stainless-steel tools on trapezius, splenius, and suboccipital muscles, with sweep and fan techniques at 30°–60°, for 9 min per session. Primary outcomes were pain (VAS) and disability (NDI); secondary outcomes included kinesiophobia (TSK) and joint position sense (JPS). Between-group differences were analyzed using ANCOVA with baseline values as covariates. Results All groups showed significant within-group improvements across all outcomes ( p  < 0.001). Compared to CT, both PMT and IASTM produced greater improvements in pain, kinesiophobia, and JPS ( p  < 0.001). VAS-rest reductions were − 4.00 ± 0.89 (d = 4.49) for IASTM, − 3.38 ± 1.95 (d = 1.74) for PMT, and − 2.13 ± 1.49 (d = 1.43) for CT. VAS-activity decreased by − 4.89 ± 1.44 (d = 3.41) for IASTM and − 3.89 ± 1.84 (d = 2.11) for PMT. NDI improved by − 11.47 ± 4.23 (d = 2.71) in IASTM, − 12.11 ± 6.86 (d = 1.76) in PMT, and − 6.63 ± 5.47 (d = 1.21) in CT, all exceeding the MCID threshold of 7.5 points. JPS-flexion improved by − 3.80 ± 1.61 (d = 2.36) in IASTM, − 3.67 ± 1.34 (d = 2.73) in PMT, and − 1.09 ± 0.84 (d = 1.29) in CT. Similar patterns occurred for extension, right rotation, and left rotation. Overall, IASTM and PMT yielded comparable improvements, suggesting similar clinical efficacy. Conclusions IASTM and PMT provide added benefits over conventional therapy alone in managing CDH, especially in reducing pain and kinesiophobia and enhancing proprioception. Both can be effectively integrated into conservative rehabilitation programs targeting sensorimotor deficits in CDH. Trial registration Prospectively registered in the ClinicalTrials.gov registry (NCT06903000) on 24/03/2025.

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. 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. 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). 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. Vericel Corporation.

Background. Community-associated Staphylococcus aureus infections often affect multiple members of a household. We compared 2 approaches to S. aureus eradication: decolonizing the entire household versus decolonizing the index case alone. Methods. An open-label, randomized trial enrolled 183 pediatric patients (cases) with community-onset S. aureus skin abscesses and colonization of anterior nares, axillae, or inguinal folds from 2008 to 2009 at primary and tertiary centers. Participants were randomized to decolonization of the case alone (index group) or of all household members (household group). The 5-day regimen included hygiene education, twice-daily intranasal mupirocin, and daily chlorhexidine body washes. Colonization of cases and subsequent skin and soft tissue infection (SSTI) in cases and household contacts were ascertained at 1, 3, 6, and 12 months. Results. Among 147 cases with 1-month colonization data, modified intention-to-treat analysis revealed S. aureus eradication in 50% of cases in the index group and 51% in the household group (P = 1.00). Among 126 cases completing 12-month follow-up, S. aureus was eradicated from 54% of the index group versus 66% of the household group (P = .28). Over 12 months, recurrent SSTI was reported in 72% of cases in the index group and 52% in the household group (P = .02). SSTI incidence in household contacts was significantly lower in the household versus index group during the first 6 months; this trend continued at 12 months. Conclusions. Household decolonization was not more effective than individual decolonization in eradicating community-associated S. aureus carriage from cases. However, household decolonization reduced the incidence of subsequent SSTI in cases and their household contacts. Clinical Trials Registration. NCT00731783.

The stromal vascular fraction (SVF) is a heterogeneous population of stem/stromal cells isolated from perivascular and extracellular matrix (ECM) of adipose tissue complex (ATC). Administration of SVF holds a strong therapeutic potential for regenerative and wound healing medicine applications aimed at functional restoration of tissues damaged by injuries or chronic diseases. SVF is commonly divided into cellular stromal vascular fraction (cSVF) and tissue stromal vascular fraction (tSVF). Cellular SVF is obtained from ATC by collagenase digestion, incubation/isolation, and pelletized by centrifugation. Enzymatic disaggregation may alter the relevant biological characteristics of adipose tissue, while providing release of complex, multiattachment of cell‐to‐cell and cell‐to‐matrix, effectively eliminating the bioactive ECM and periadventitial attachments. In many countries, the isolation of cellular elements is considered as a “more than minimal” manipulation, and is most often limited to controlled clinical trials and subject to regulatory review. Several alternative, nonenzymatic methods of adipose tissue processing have been developed to obtain via minimal mechanical manipulation an autologous tSVF product intended for delivery, reducing the procedure duration, lowering production costs, decreasing regulatory burden, and shortening the translation into the clinical setting. Ideally, these procedures might allow for the integration of harvesting and processing of adipose tissue for ease of injection, in a single procedure utilizing a nonexpanded cellular product at the point of care, while permitting intraoperative autologous cellular and tissue‐based therapies. Here, we review and discuss the options, advantages, and limitations of the major strategies alternative to enzymatic processing currently developed for minimal manipulation of adipose tissue. Stem Cells Translational Medicine 2019;8:1265&1271 Main strategies for adipose tissue processing.