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The rationale for implantation of autologous human Schwann cells (SCs) in persons with subacute spinal cord injury (SCI) is based on evidence that transplanted SCs are neuroprotective, support local axonal plasticity, and are capable of myelinating axons. A Phase I clinical trial was conducted to evaluate the safety of autologous human SC transplantation into the injury epicenter of six subjects with subacute SCI. The trial was an open-label, unblinded, non-randomized, non-placebo controlled study with a dose escalation design and standard medical rehabilitation. Participants were paraplegics with neurologically complete, trauma-induced spinal lesions. Autologous SCs were cultured in vitro from a sural nerve harvested from each participant and injected into the epicenter of the spinal lesion. Outcome measures for safety were protocol compliance, feasibility, adverse events, stability of neurological level, absence of detectable mass lesion, and the emergence of clinically significant neuropathic pain or muscle spasticity no greater than expected for a natural course cohort. One year post-transplantation, there were no surgical, medical, or neurological complications to indicate that the timing or procedure for the cell transplantation was unsafe. There were no adverse events or serious adverse events related to the cell therapy. There was no evidence of additional spinal cord damage, mass lesion, or syrinx formation. We conclude that it is feasible to identify eligible candidates, appropriately obtain informed consent, perform a peripheral nerve harvest to obtain SCs within 5–30 days of injury, and perform an intra-spinal transplantation of highly purified autologous SCs within 4–7 weeks of injury.

ObjectivesTo assess the safety of intra-articular (IA) autologous tolerogenic dendritic cells (tolDC) in patients with inflammatory arthritis and an inflamed knee; to assess the feasibility and acceptability of the approach and to assess potential effects on local and systemic disease activities.MethodsAn unblinded, randomised, controlled, dose escalation Phase I trial. TolDC were differentiated from CD14+ monocytes and loaded with autologous synovial fluid as a source of autoantigens. Cohorts of three participants received 1×106, 3×106 or 10×106 tolDC arthroscopically following saline irrigation of an inflamed (target) knee. Control participants received saline irrigation only. Primary outcome was flare of disease in the target knee within 5 days of treatment. Feasibility was assessed by successful tolDC manufacture and acceptability via patient questionnaire. Potential effects on disease activity were assessed by arthroscopic synovitis score, disease activity score (DAS)28 and Health Assessment Questionnaire (HAQ). Immunomodulatory effects were sought in peripheral blood.ResultsThere were no target knee flares within 5 days of treatment. At day 14, arthroscopic synovitis was present in all participants except for one who received 10×106 tolDC; a further participant in this cohort declined day 14 arthroscopy because symptoms had remitted; both remained stable throughout 91 days of observation. There were no trends in DAS28 or HAQ score or consistent immunomodulatory effects in peripheral blood. 9 of 10 manufactured products met quality control release criteria; acceptability of the protocol by participants was high.ConclusionIA tolDC therapy appears safe, feasible and acceptable. Knee symptoms stabilised in two patients who received 10×106 tolDC but no systemic clinical or immunomodulatory effects were detectable.Trial registration numberNCT01352858.

Study design: Randomized controlled trial with single-blinded primary outcome assessment. Objectives: To determine the efficacy and safety of autologous incubated macrophage treatment for improving neurological outcome in patients with acute, complete spinal cord injury (SCI). Setting: Six SCI treatment centers in the United States and Israel. Methods: Participants with traumatic complete SCI between C5 motor and T11 neurological levels who could receive macrophage therapy within 14 days of injury were randomly assigned in a 2:1 ratio to the treatment (autologous incubated macrophages) or control (standard of care) groups. Treatment group participants underwent macrophage injection into the caudal boundary of the SCI. The primary outcome measure was American Spinal Injury Association (ASIA) Impairment Scale (AIS) A–B or better at ⩾6 months. Safety was assessed by analysis of adverse events (AEs). Results: Of 43 participants (26 treatment, 17 control) having sufficient data for efficacy analysis, AIS A to B or better conversion was experienced by 7 treatment and 10 control participants; AIS A to C conversion was experienced by 2 treatment and 2 control participants. The primary outcome analysis for subjects with at least 6 months follow-up showed a trend favoring the control group that did not achieve statistical significance ( P =0.053). The mean number of AEs reported per participant was not significantly different between the groups ( P =0.942). Conclusion: The analysis failed to show a significant difference in primary outcome between the two groups. The study results do not support treatment of acute complete SCI with autologous incubated macrophage therapy as specified in this protocol.

Autologous haematopoietic stem cell transplantation (HSCT) is a viable option for treatment of aggressive multiple sclerosis (MS). No randomised controlled trial has been performed, and thus, experiences from systematic and sustained follow-up of treated patients constitute important information about safety and efficacy. In this observational study, we describe the characteristics and outcome of the Swedish patients treated with HSCT for MS. Neurologists from the major hospitals in Sweden filled out a follow-up form with prospectively collected data. Fifty-two patients were identified in total; 48 were included in the study and evaluated for safety and side effects; 41 patients had at least 1 year of follow-up and were further analysed for clinical and radiological outcome. In this cohort, 34 patients (83%) had relapsing-remitting MS, and mean follow-up time was 47 months. At 5 years, relapse-free survival was 87%; MRI event-free survival 85%; expanded disability status scale (EDSS) score progression-free survival 77%; and disease-free survival (no relapses, no new MRI lesions and no EDSS progression) 68%. Presence of gadolinium-enhancing lesions prior to HSCT was associated with a favourable outcome (disease-free survival 79% vs 46%, p=0.028). There was no mortality. The most common long-term side effects were herpes zoster reactivation (15%) and thyroid disease (8.4%). HSCT is a very effective treatment of inflammatory active MS and can be performed with a high degree of safety at experienced centres.

Background Poland syndrome is a rare congenital condition characterized by unilateral breast deformity. Autologous fat transplantation has emerged as the preferred treatment due to its minimal invasiveness, rapid recovery, absence of rejection reactions, and potential for multiple surgeries to enhance postoperative outcomes. Previous animal studies have shown that botulinum toxin significantly improves fat retention rates following fat transplantation. Therefore, we aim to initiate a clinical study to investigate the effects of botulinum toxin on human fat transplantation. Objective This prospective comparative clinical study aims to evaluate the impact of combining botulinum toxin with autologous fat grafting on fat retention rates in patients with Poland syndrome. Method From October 2017 to December 2023, we enrolled 20 Poland syndrome patients, assigning them to an experimental group receiving fat and botulinum toxin for breast augmentation and a control group undergoing standard autologous fat grafting. Postoperative fat retention rates were compared, and outcomes were assessed using the Breast‐Q score, alongside baseline patient data. Results There were no significant differences in baseline data between the two groups. At 3 and 6 months postoperatively, the fat retention rate in the experimental group was significantly higher than that in the control group. Regarding Breast‐Q scores, the control group exhibited significantly lower scores in the Satisfaction with breast domain than the experimental group, with no notable differences in other domains. Conclusion The injection of a mixture of fat and botulinum toxin significantly enhances fat retention rates in patients with isolated breast deformities associated with Poland syndrome. Trial Registration This study has been registered with the China Clinical Trial Center (ChiCTR2100054878)

219 HIV-negative adults ≤70 years with primary CNS lymphoma (PCNSL) were enrolled in the randomized IELSG32 trial. Enrolled patients were randomly assigned to receive methotrexate-cytarabine (arm A), or methotrexate-cytarabine-rituximab (B), or methotrexate-cytarabine-thiotepa-rituximab (MATRix; arm C). A second randomization allocated patients with responsive/stable disease to whole-brain irradiation (WBRT) or carmustine-thiotepa-conditioned autologous transplantation (ASCT). First results, after a median follow-up of 30 months, showed that MATRix significantly improves outcome, with both WBRT and ASCT being similarly effective. However, sound assessment of overall survival (OS), efficacy of salvage therapy, late complications, secondary tumors, and cognitive impairment requires longer follow-up. Herein, we report the results of this trial at a median follow-up of 88 months. As main findings, MATRix was associated with excellent long-lasting outcome, with a 7-year OS of 21%, 37%, and 56% respectively for arms A, B, and C. Notably, patients treated with MATRix and consolidation had a 7-year OS of 70%. The superiority of arm B on arm A suggests a benefit from the addition of rituximab. Comparable efficacy of WBRT and ASCT was confirmed. Salvage therapy was ineffective; benefit was recorded only in patients with late relapse re-treated with methotrexate. Eight (4%) patients developed a second cancer. Importantly, MATRix and ASCT did not result in higher non-relapse mortality or second tumors incidence. Patients who received WBRT experienced impairment in attentiveness and executive functions, whereas patients undergoing ASCT experienced improvement in these functions as well as in memory and quality of life.

Disc herniation treated by discectomy results in a significant loss of nucleus material and disc height. Biological restoration through the use of autologous disc chondrocyte transplantation (ADCT) offers a potential to achieve functional integration of disc metabolism and mechanics. Nucleus regeneration using autologous cultured disc-derived chondrocytes has been demonstrated in a canine model and in clinical pilot studies. In 2002 a prospective, controlled, randomized, multicentre study comparing safety and efficacy of ADCT plus discectomy, with discectomy alone was initiated. The clinical goals were to provide long-term pain relief, maintain disc height, and prevent adjacent segment disease. Interim analysis was performed after 2 years; Oswestry (Low Back Pain/disability), Quebec Back Pain Disability Scale, as well as Prolo and VAS Score were used for the evaluation. Disc height was assessed by MRI. A clinically significant reduction of low back pain in the ADCT-treated group was shown by all three pain score systems. The median total Oswestry Score was 2 in the ADCT group compared with 6 in the control group. Decreases in the Disability index in ADCT-treated patients correlated with the reduction of low back pain. Decreases in disc height over time were only found in the control group, and of potential significance, intervertebral discs in adjacent segments appeared to retain hydration when compared to those adjacent to levels that had undergone discectomy without cell intervention.

We sought to conduct a quality improvement initiative to compare the wash quality and speed of autologous red blood cell (RBC) processing of four autotransfusion devices during cardiac surgery. Using a prospective observational cohort study approach, we prospectively evaluated four commercially available autologous cell savage devices (autoLog IQ™, Medtronic plc, Minneapolis, MN, USA [135 mL]; Xtra™, LivaNova, plc, Houston, TX, USA [125 mL, 225 mL]; Cell Saver® Elite®+, Haemonetics Corp., Boston, MA, USA [125 mL, 225 mL]; and CATSmart®, Fresenius Kabi AG, Bad Homburg vor der Höhe, Germany) in adult patients undergoing cardiac surgery. Device settings were determined by manufacturer recommendations for optimal wash quality. We collected pre- and postprocessing samples, volumes, and processing times from each device to calculate removal ratios of heparin, potassium, plasma free hemoglobin (PfHb), white blood cells (WBCs), platelets, reinfusion concentrations of heparin and potassium, and red blood cell (RBC) recovery rates. A total of 130 consecutive patients underwent autologous cell salvage, but 15 cases were excluded because of incomplete data. All devices removed > 99% heparin, > 95% potassium, > 94% platelets, and > 85% PfHb from collected shed blood. Comparison of processing sets showed significant differences in median [interquartile range] WBC removal ratios, ranging from 26 [19-33]% to 59 [42-68]%, and median heparin reinfusion concentrations, which ranged from 0.09 [0.08-0.11] to 0.63 [0.55-0.70] U·mL processed red cells. Median RBC recovery rates also showed significant differences between processing sets, ranging from 8 [8-10] mL RBC·min to 24 [22-25] mL RBC·min . Wash quality and processing speed differed between autotransfusion devices and processing sets. These findings may have clinical implications when large volumes of shed blood are processed and reinfused.

Using a 6‐week porcine full‐thickness excisional wound grafting model, we evaluated the Autologous Regeneration of Tissue (ART®) System, a novel skin harvesting device designed to collect autologous full‐thickness autologous microcolumns (FTAM) at 0.5 mm in diameter. The donor skin sites were harvested using the ART® System and compared to split‐thickness skin grafts (STSGs). Recipient sites were divided into three treatment groups: FTAM, STSG and Untreated control. Comparing the FTAM donor sites to the STSG donor sites, we observed significantly faster re‐epithelization by Day 4 (p < 0.05), earlier adnexal structures and rete ridge formation by Week 3, and increased collagen and elastin content by Week 6. We also observed an increased rate of healing at the FTAM donor site whilst limiting donor site morbidity compared to traditional STSG donor sites. Time to recipient site closure was 2.4 weeks for STSG treated, 3.3 weeks for FTAM treated and 4.1 weeks for the Untreated control (p < 0.05). The STSG and FTAM recipient sites reached complete re‐epithelialization by Weeks 4 and 5, respectively which was significantly faster compared to the Untreated control. However, the FTAM recipient site received only 10% of the donor site tissue relative to the recipient site area and the amount of donor site tissue grafted on the STSG recipient sites was 5× more than the FTAM recipient sites. Additionally, the FTAMs harvested by the ART® System augmented recipient wound site healing as a result of ‘epithelial island’ expansion in contrast to Untreated control sites that closed primarily by contracture.

Patients with newly diagnosed multiple myeloma and high-risk cytogenetic abnormalities (HRCA) represent an unmet medical need. In the FORTE trial, lenalidomide and dexamethasone plus carfilzomib (KRd) induction resulted in a higher proportion of patients with at least a very good partial response as compared with carfilzomib, cyclophosphamide, and dexamethasone (KCd), and carfilzomib plus lenalidomide maintenance prolonged progression-free survival compared with lenalidomide maintenance. In this prespecified analysis of the FORTE trial, we described the outcomes of enrolled patients according to their cytogenetic risk. The UNITO-MM-01/FORTE was a randomised, open-label, phase 2 trial done at 42 Italian academic and community practice centres, which enrolled transplant-eligible patients with newly diagnosed multiple myeloma aged 18–65 years. Eligible patients had newly diagnosed multiple myeloma based on standard International Myeloma Working Group criteria, a Karnofsky performance status of at least 60%, and had not received any previous treatment with anti-myeloma therapy. At enrolment, patients were stratified according to International Staging System stage (I vs II/III) and age (<60 years vs 60–65 years) and randomly assigned (1:1:1) to KRd plus autologous stem-cell transplantation (ASCT; four 28-day induction cycles with KRd, melphalan at 200 mg/m2 and ASCT [MEL200-ASCT], followed by four 28-day KRd consolidation cycles), 12 28-day KRd cycles, or KCd plus ASCT (four 28-day induction cycles with KCd, MEL200-ASCT, and four 28-day KCd consolidation cycles), using a web-based system (block randomisation, block size of 12). Carfilzomib was administered at 20 mg/m2 on days 1 and 2 of cycle 1, followed by 36 mg/m2 intravenously administered on days 8, 9, 15, and 16 of cycle 1, and then 36 mg/m2 intravenously administered for all subsequent doses on days 1, 2, 8, 9, 15, 16; lenalidomide 25 mg was administered orally on days 1–21; cyclophosphamide 300 mg/m2 was administered orally on days 1, 8, and 15; and dexamethasone 20 mg was administered orally or intravenously on days 1, 2, 8, 9, 15, 16, 22, and 23. After the consolidation phase, patients were stratified according to induction–consolidation treatment and randomly assigned (1:1; block size of 8) to maintenance treatment with carfilzomib plus lenalidomide or lenalidomide alone. Carfilzomib 36 mg/m2 was administered intravenously on days 1–2 and days 15–16, every 28 days for up to 2 years, and lenalidomide 10 mg was administered orally on days 1–21 every 28 days until progression or intolerance in both groups. The primary endpoints were the proportion of patients with at least a very good partial response after induction with KRd versus KCd and progression-free survival with carfilzomib plus lenalidomide versus lenalidomide alone as maintenance treatment. In this preplanned analysis, we included patients enrolled in the FORTE trial with complete cytogenetic data on del(17p), t(4;14), t(14;16), del(1p), gain(1q) (3 copies), and amp(1q) (≥4 copies) assessed by fluorescence in-situ hybridisation analysis on CD138-positive sorted cells. We assessed progression-free survival, overall survival, minimal residual disease negativity, and 1-year sustained minimal residual disease negativity according to the presence of zero, one, and two or more HRCA across treatment groups. The FORTE trial is ongoing, and registered with ClinicalTrials.gov, NCT02203643. Between Feb 23, 2015, and April 5, 2017, 477 patients were enrolled, of whom 396 (83%) had complete cytogenetic data and were analysed (176 [44%] of whom were women and 220 [56%] were men). The median follow-up from first randomisation was 51 months (IQR 46–56). 4-year progression-free survival was 71% (95% CI 64–78) in patients with zero HRCA, 60% (95% CI 52–69) in patients with one HRCA, and 39% (95% CI 30–50) in patients with two or more HRCA. Compared with patients with zero HRCA, the risk of progression or death was similar in patients with one HRCA (hazard ratio [HR] 1·33 [95% CI 0·90–1·97]; p=0·15) and higher in patients with two or more HRCA (HR 2·56 [95% CI 1·74–3·75]); p<0·0001) across the induction–intensification–consolidation groups. Moreover, the risk of progression or death was also higher in patients with two or more HRCA versus those with one HRCA (HR 1·92 [95% CI 1·34–2·76]; p=0·0004). 4-year overall survival from the first randomisation was 94% (95% CI 91–98) in patients with zero HRCA, 83% (95% CI 76–90) in patients with one HRCA, and 63% (95% CI 54–74) in patients with two or more HRCA. Compared with patients with zero HRCA, the risk of death was significantly higher in patients with one HRCA (HR 2·55 [95% CI 1·22–5·36]; p=0·013) and two or more HRCA (HR 6·53 [95% CI 3·24–13·18]; p<0·0001). Patients with two or more HRCA also had a significantly higher risk of death than those with one HRCA (HR 2·56 [95% CI 1·53–4·28]; p=0·0004). The rates of 1-year sustained minimal residual disease negativity were similar in patients with zero HRCA (53 [35%] of 153] and with one HRCA (57 [41%] of 138) and were lower in patients with two or more HRCA (25 [24%] of 105). The median duration of follow-up from second randomisation was 37 months (IQR 33–42). 3-year progression-free survival from the second randomisation was 80% (95% CI 74–88) in patients with zero HRCA, 68% (95% CI 59–78) in patients with one HRCA, and 53% (95% CI 42–67) in patients with two or more HRCA. The risk of progression or death was higher in patients with one HRCA (HR 1·68 [95% CI 1·01–2·80]; p=0·048) and two or more HRCA (2·74 [95% CI 1·60–4·69], p=0·0003) than in patients with zero HRCA. This preplanned analysis of the FORTE trial showed that carfilzomib-based induction–intensification–consolidation regimens are effective strategies in patients with standard risk (zero HRCA) and high-risk (one HRCA) myeloma, resulting in similar rates of progression-free survival and 1-year sustained minimal residual disease negativity. Despite promising progression-free survival, patients with ultra-high-risk disease (those with 2 or more HRCA) still have an increased risk of progression and death and therefore represent an unmet medical need. Amgen and Celgene/Bristol Myers Squibb.