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Mesenchymal Stromal Cell-Based Therapy-An Alternative to Arthroplasty for the Treatment of Osteoarthritis? A State of the Art Review of Clinical Trials.

ABSTRACT: Osteoarthritis (OA) is the most common degenerative joint disorder worldwide and to date no regenerative treatment has been established in clinical practice. This review evaluates the current literature on the clinical translation of mesenchymal stromal cell (MSC)-based therapy in OA management with a focus on safety, outcomes and procedural specifics. PubMed, Cochrane Library and clinicaltrials.gov were searched for clinical studies using MSCs for OA treatment. 290 articles were initially identified and 42 articles of interest, including a total of 1325 patients, remained for further examination. Most of the included studies used adipose tissue-derived MSCs or bone-marrow-derived MSCs to treat patients suffering from knee OA. MSC-based therapy for knee OA appears to be safe and presumably effective in selected parameters. Yet, a direct comparison between studies was difficult due to a pronounced variance regarding methodology, assessed outcomes and evidence levels. Intensive scientific engagement is needed to identify the most effective source and dosage of MSCs for OA treatment in the future. Consent on outcome measures has to be reached and eventually patient sub-populations need to be identified that will profit most from MSC-based treatment for OA.

SUBMITTER: Maleitzke T

PROVIDER: S-EPMC7409016 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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Mesenchymal Stromal Cell-Based Therapy-An Alternative to Arthroplasty for the Treatment of Osteoarthritis? A State of the Art Review of Clinical Trials.

Maleitzke Tazio T Elazaly Hisham H Festbaum Christian C Eder Christian C Karczewski Daniel D Perka Carsten C Duda Georg N GN Winkler Tobias T

Journal of clinical medicine 20200630 7

Osteoarthritis (OA) is the most common degenerative joint disorder worldwide and to date no regenerative treatment has been established in clinical practice. This review evaluates the current literature on the clinical translation of mesenchymal stromal cell (MSC)-based therapy in OA management with a focus on safety, outcomes and procedural specifics. PubMed, Cochrane Library and clinicaltrials.gov were searched for clinical studies using MSCs for OA treatment. 290 articles were initially ident ...[more]

PMID: 32630066

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Project description:BACKGROUND:Gastrointestinal stromal tumors (GISTs) are the most frequently diagnosed mesenchymal neoplasms of the gastrointestinal tract. Despite their biological and clinical heterogeneity, the majority of these tumors are positive for the receptor tyrosine kinase KIT and are driven by KIT- or platelet-derived growth factor receptor alpha (PDGFRA)-activating mutations. There are still uncertainties regarding their clinical and molecular characterization and the optimal treatment regimens, making it difficult to establish a universal treatment algorithm for these tumors. SUMMARY:From a clinical perspective, the main difference between GISTs and other gastrointestinal neoplasms is that the benign or malignant behavior of GISTs cannot be predicted from histopathology, but instead relies on empirically established scoring systems. Clinical data suggest that malignant potential may be an inherent quality of some GISTs rather than a feature acquired by the tumor during disease progression. Thus, some patients may require prolonged anti-tumor treatment even after complete surgical removal of the tumor. KEY MESSAGE:Although GISTs are the most frequently occurring mesenchymal neoplasms in the gastrointestinal tract, no universal treatment algorithms exist. This paper reviews the current evidence that guides the management of GISTs. PRACTICAL IMPLICATIONS:The management of localized GISTs involves the use of surgical resection, with the inclusion of preoperative tyrosine kinase inhibitor treatment for locally advanced, primarily unresectable tumors and for resectable cases requiring extensive surgery. Imatinib is also indicated as adjuvant therapy after complete surgical removal of GISTs with a high estimated risk of recurrence unless specific mutations conferring imatinib resistance are present. The optimal duration of adjuvant treatment is still controversial. For patients with metastatic imatinib-sensitive GISTs, imatinib constitutes the first-line standard treatment. Molecular characterization of the tumor (with respect to the PDGFRA and KIT genes) is mandatory prior to imatinib therapy. Sunitinib and regorafenib are established as alternative treatments for patients demonstrating generalized disease progression on imatinib. New tyrosine kinase inhibitors such as ponatinib and crenolanib as well as drugs targeting alternative pathways are currently under investigation. Surgery and locally ablative treatments may be indicated in some metastatic patients.

Project description:Study Design: Meta-analysis. Objectives: We aimed to analyze the impact of cultured expansion of autologous mesenchymal stromal cells (MSCs) in the management of osteoarthritis of the knee from randomized controlled trials (RCTs) available in the literature. Materials and Methods: We conducted independent and duplicate electronic database searches including PubMed, Embase, Web of Science, and Cochrane Library until August 2021 for RCTs analyzing the efficacy and safety of culture-expanded compared to non-cultured autologous MSCs in the management of knee osteoarthritis. The Visual Analog Score (VAS) for pain, Western Ontario McMaster University's Osteoarthritis Index (WOMAC), Lysholm score, Knee Osteoarthritis Outcome Score (KOOS), and adverse events were the analyzed outcomes. Analysis was performed in R-platform using OpenMeta [Analyst] software. Results: Overall, 17 studies involving 767 patients were included for analysis. None of the studies made a direct comparison of the culture expanded and non-cultured MSCs, hence we pooled the results of all the included studies of non-cultured and cultured types of MSC sources and made a comparative analysis of the outcomes. At six months, culture expanded MSCs showed significantly better improvement (p < 0.001) in VAS outcome. Uncultured MSCs, on the other hand, demonstrated significant VAS improvement in the long term (12 months) in VAS (p < 0.001), WOMAC (p = 0.025), KOOS score (p = 0.016) where cultured-expanded MSCs failed to demonstrate a significant change. Culturing of MSCs did not significantly increase the complications noted (p = 0.485). On sub-group analysis, adipose-derived uncultured MSCs outperformed culture-expanded MSCs at both short term (six months) and long term (12 months) in functional outcome parameters such as WOMAC (p < 0.001, p = 0.025), Lysholm (p < 0.006), and KOOS (p < 0.003) scores, respectively, compared to their controls. Conclusions: We identified a void in literature evaluating the impact of culture expansion of MSCs for use in knee osteoarthritis. Our indirect analysis of literature showed that culture expansion of autologous MSCs is not a necessary factor to obtain superior results in the management of knee osteoarthritis. Moreover, while using uncultured autologous MSCs, we recommend MSCs of adipose origin to obtain superior functional outcomes. However, we urge future trials of sufficient quality to validate our findings to arrive at a consensus on the need for culture expansion of MSCs for use in cellular therapy of knee osteoarthritis.

Project description:: Osteoarthritis (OA) is the most widespread musculoskeletal disorder in adults. It leads to cartilage damage associated with subchondral bone changes and synovial inflammation, causing pain and disability. The present study aimed at evaluating the safety of a dose-escalation protocol of intra-articular injected adipose-derived stromal cells (ASCs) in patients with knee OA, as well as clinical efficacy as secondary endpoint. A bicentric, uncontrolled, open phase I clinical trial was conducted in France and Germany with regulatory agency approval for ASC expansion procedure in both countries. From April 2012 to December 2013, 18 consecutive patients with symptomatic and severe knee OA were treated with a single intra-articular injection of autologous ASCs. The study design consisted of three consecutive cohorts (six patients each) with dose escalation: low dose (2 × 10(6) cells), medium dose (10 × 10(6)), and high dose (50 × 10(6)). The primary outcome parameter was safety evaluated by recording adverse events throughout the trial, and secondary parameters were pain and function subscales of the Western Ontario and McMaster Universities Arthritis Index. After 6 months of follow-up, the procedure was found to be safe, and no serious adverse events were reported. Four patients experienced transient knee joint pain and swelling after local injection. Interestingly, patients treated with low-dose ASCs experienced significant improvements in pain levels and function compared with baseline. Our data suggest that the intra-articular injection of ASCs is a safe therapeutic alternative to treat severe knee OA patients. A placebo-controlled double-blind phase IIb study is being initiated to assess clinical and structural efficacy.Although this phase I study included a limited number of patients without a placebo arm, it showed that local injection of autologous adipose-derived stem cells was safe and well tolerated in patients with knee osteoarthritis. This study also provides encouraging preliminary evidence of efficacy. Larger and controlled long-term studies are now mandatory to confirm whether this new strategy of cell therapy can improve pain and induce structural benefit in osteoarthritis.

Dataset Information

Mesenchymal Stromal Cell-Based Therapy-An Alternative to Arthroplasty for the Treatment of Osteoarthritis? A State of the Art Review of Clinical Trials.

Publications

Mesenchymal Stromal Cell-Based Therapy-An Alternative to Arthroplasty for the Treatment of Osteoarthritis? A State of the Art Review of Clinical Trials.

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