Background: Passive immunotherapy with convalescent plasma (CP) is a potential treatment for COVID-19 for which evidence from controlled clinical trials is lacking. Methods: We conducted a multi-center, randomized clinical trial in patients hospitalized for COVID-19. All patients received standard of care treatment, including off-label use of marketed medicines, and were randomized 1:1 to receive one dose (250-300 mL) of CP from donors with IgG anti-SARS-CoV-2. The primary endpoint was the proportion of patients in categories 5, 6 or 7 of the COVID-19 ordinal scale at day 15. Results: The trial was stopped after first interim analysis due to the fall in recruitment related to pandemic control. With 81 patients randomized, there were no patients progressing to mechanical ventilation or death among the 38 patients assigned to receive plasma (0%) versus 6 out of 43 patients (14%) progressing in control arm. Mortality rates were 0% vs 9.3% at days 15 and 29 for the active and control groups, respectively. No significant differences were found in secondary endpoints. At inclusion, patients had a median time of 8 days (IQR, 6-9) of symptoms and 49,4% of them were positive for anti-SARS-CoV-2 IgG antibodies. Conclusions: Convalescent plasma could be superior to standard of care in avoiding progression to mechanical ventilation or death in hospitalized patients with COVID-19. The strong dependence of results on a limited number of events in the control group prevents drawing firm conclusions about CP efficacy from this trial. (Funded by Instituto de Salud Carlos III; NCT04345523).
The presence of cytogenetic aberrations on mesenchymal stem cells (MSC) from myelodysplastic syndrome (MDS) patients is controversial. The aim of the study is to characterize bone marrow (BM) derived MSC from patients with MDS using: kinetic studies, immunophenotyping, fluorescent in situ hybridization (FISH) and genetic changes by array-based comparative genomic hybridization (array-CGH). In all 36 cases of untreated MDS were studied. MDS-MSC achieved confluence at a significantly slower rate than donor-MSC, and the antigenic expression of CD105 and CD104 was lower. Array-CGH studies showed DNA genomic changes that were proved not to be somatic. These results were confirmed by FISH. To confirm that genomic changes were also present in freshly obtained MSCs they were enriched by sorting BM cells with the following phenotype:They also showed genomic changes that were confirmed by FISH. To analyze the relationship of these aberrations with clinicalbiological data an unsupervized hierarchical cluster analysis was performed, two clusters were identified: the first one included the 5qÀ syndrome patients, whereas the other incorporated other MDS. Our results show, for the first time that MSC from MDS display genomic aberrations, assessed by array-CGH and FISH, some of them specially linked to a particular MDS subtype, the 5qÀ syndrome.
MSC expansion procedure, cell characterization and obtaining platelet lysate were performed according to standard procedures and are shown in the Online Supplementary Appendix. Patients' characteristics and MSC infusionOverall, 18 patients diagnosed with either acute (n=10) or chronic (n=8) GVHD refractory to prior treatment were included in the study once written informed consent had been obtained. Refractory GVHD was defined as progression or absence of response to last treatment. Patients' characteristics are summarized in Table 2. Eleven patients had received reduced intensity conditioning and 6 received myeloablative conditioning. Fourteen patients had received hematopoietic stem cells from an unrelated donor and 7 received them from an HLA-mismatched donor. Eight patients had received GVHD prophylaxis based on a calcineurin inhibitor plus methotrexate.Inclusion criteria were: patients who had undergone an allogeneic stem cell transplant and developed GVHD refractory to conventional treatment; adequate cardiac and pulmonary functions; aged between 18 and 65 years; signed informed consent from patient and donor. Exclusion criteria were: patients who did not fulfill all of the inclusion criteria; progression of the hematologic disease; active infection; women who were either pregnant or at risk of pregnancy. The study was conducted between February 2007 and December 2009.Patients received 1-2x10 6 MSCs/kg intravenously in a single dose. Eventually, when a partial response was obtained or in the case of relapse after achieving complete remission, patients could receive a second dose of MSCs at least two weeks after the first infusion. Patients who were receiving 6-methylprednisolone were kept on the same doses for at least seven days after MSC infusion and a taper of 10% every five days was planned later when there was a response. Other immunosuppressive drugs were managed according to the criteria of the attending physician. Response to therapy was measured according to previously reported criteria. [9][10][11] Patients were taken off the study if fewer than 1x10 6 MSCs/kg were obtained after eight weeks of expansion. All patients receiving at least one dose of MSCs were included in the safety and efficacy analysis.The treatment protocol was reviewed and approved by the local authorities and ethical committee of all participanting centers.Mesenchymal cells for graft vs. host disease treatment haematologica | 2011; 96 (7) 1073 Statistical analysisVariables of the expansion procedure were analyzed from the day of inclusion in the trial, i.e. the day when informed consent was signed. Mean and median values and their corresponding 95% confidence intervals (CIs) and ranges were calculated for each continuous variable. Student's two-sample t test and Pearson's X 2 test were used to compare continuous and qualitative variables. In those comparisons where the number of cases precluded the use of parametric tests, the Mann-Whitney test and Fisher's exact test were used. To analyze patient outcome after infusi...
The online version of this article has a Supplementary Appendix. BackgroundRecent findings suggest that a specific deletion of Dicer1 in mesenchymal stromal cell-derived osteoprogenitors triggers several features of myelodysplastic syndrome in a murine model. Our aim was to analyze DICER1 and DROSHA gene and protein expression in mesenchymal stromal cells (the osteoblastic progenitors) obtained from bone marrow of myelodysplastic syndrome patients, in addition to microRNA expression profile and other target genes such as SBDS, a DICER1-related gene that promotes bone marrow dysfunction and myelodysplasia when repressed in a murine model. Design and MethodsMesenchymal stromal cells from 33 bone marrow samples were evaluated. DICER, DROSHA and SBDS gene expression levels were assessed by real-time PCR and protein expression by Western blot. MicroRNA expresion profile was analyzed by commercial low-density arrays and some of these results were confirmed by individual real-time PCR. ResultsMesenchymal stromal cells from myelodysplastic syndrome patients showed lower DICER1 (0.65±0.08 vs. 1.91±0.57; P=0.011) and DROSHA (0.62±0.06 vs. 1.38±0.29; P=0.009) gene expression levels, two relevant endonucleases associated to microRNA biogenesis, in comparison to normal myelodysplastic syndrome. These findings were confirmed at protein levels by Western blot. Strikingly, no differences were observed between paired mononuclear cells from myelodysplastic syndrome and controls. In addition, mesenchymal stromal cells from myelodysplastic syndrome patients showed significant lower SBDS (0.63±0.06 vs. 1.15±0.28; P=0.021) gene expression levels than mesenchymal stromal cells from healthy controls. Furthermore, mesenchymal stromal cells from myelodysplastic syndrome patients showed an underlying microRNA repression compared to healthy controls. Real-time PCR approach confirmed that mir-155, miR-181a and miR-222 were down-expressed in mesenchymal stromal cells from myelodysplastic syndrome patients. ConclusionsThis is the first description of an impaired microRNA biogenesis in human mesenchymal stromal cells from myelodysplastic syndrome patients, where DICER1 and DROSHA gene and protein downregulation correlated to a gene and microRNA abnormal expression profile, validating the animal model results previously described.Key words: mesenchymal stem cells, DICER, DROSHA, myelodysplastic syndrome.Citation: Santamaría C, Muntión S, Rosón B, Blanco B, López-Villar O, Carrancio S, Sánchez-Guijo FM, Díez-Campelo M, Alvarez-Fernández S, Sarasquete ME, de las Rivas J, González M, San Miguel JF, and del Cañizo MC. Impaired expression of DICER, DROSHA, SBDS and some microRNAs in mesenchymal stromal cells from myelodysplastic syndrome patients. Haematologica 2012;97(8):1218-1224. doi:10.3324/haematol.2011 This is an open-access paper. ABSTRACT© F e r r a t a S t o r t i F o u n d a t i o n
We evaluated the feasibility, safety, and efficacy of the administration of 4 sequential doses (intravenously administered on days 1, 4, 11, and 18) of cryopreserved bone marrow-derived mesenchymal stromal cells (MSC) expanded with platelet lysate and obtained from third-party donors as a second-line treatment for steroid-refractory acute graft-versus-host (aGVHD) disease in a series of 25 patients. All patients received at least 2 doses of MSC, whereas 21 received 3 doses and 18 received the initially planned 4 doses. Because of the achievement of partial response, 4 patients received additional doses of MSC. Median single cell dose administered was 1.1 × 10(6) MSC/kg of recipient body weight. There were no adverse events related to the MSC infusion in the 99 procedures performed, with the exception of a cardiac ischemic event that occurred twice in a patient with prior history of cardiac ischemia. Response to MSC at 60 days after the first dose was evaluable in 24 patients. Seventeen patients (71%) responded (11 complete and 6 partial responses), with a median time to response of 28 days after the first MSC dose, whereas 7 patients did not respond. In summary, we can conclude that sequential cryopreserved third-party MSC therapy administered on days 1, 4, 11, and 18 is a safe procedure for patients with steroid-refractory aGVHD. This strategy may provide a high rate of overall responses of aGVHD with a low toxicity profile.
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