24 research outputs found
Effects of trans-endocardial delivery of bone marrow-derived CD133+ cells on angina and quality of life in patients with refractory angina: A sub-analysis of the REGENT-VSEL trial
Background: The REGENT-VSEL trial demonstrated a neutral effect of transendocardial injection of autologous bone marrow (BM)-derived CD133+ in regard to myocardial ischemia. The current sub-analysis of the REGENT VSEL trial aims to assess the effect stem cell therapy has on quality of life (QoL) in patients with refractory angina.Methods: Thirty-one patients (63.0 ± 6.4 years, 70% male) with recurrent CCS IIâIV angina, despite optimal medical therapy, enrolled in the REGENT-VSEL single center, randomized, double-blinded, and placebo-controlled trial. Of the 31 patients, 16 individuals were randomly assigned to the active stem cell group and 15 individuals were randomly assigned to the placebo group on a 1:1 basis. The inducibility of ischemia, (â„ one myocardial segment) was confirmed for each patient using Tc-99m SPECT. QoL was measured using the Seattle Angina Questionnaire. Each patient completed the questionnaire prior to treatment and at the time of their outpatient follow-up visits at 1, 4, 6, and 12 months after cell/placebo treatment.Results: The main finding of the REGENT-VSEL trial sub-analysis was that transendocardial injection of autologous BM-derived CD133+ stem cells in patients with chronic refractory angina did not show significant improvement in QoL in comparison to the control group. Moreover, there was no significant difference between cell therapy and placebo in a number of patients showing improvement of at least 1 Canadian Cardiovascular Society class during the follow-up period.Conclusions: Intra-myocardial delivery of autologous CD133+ stem cells is safe and feasible but does not show a significant improvement in the QoL or angina pectoris symptoms in patients with chronic myocardial ischemia
Final Evaluation of a Clinical Phase III Trial Comparing Treosulfan to Busulfan-Based Conditioning Therapy Prior to Allogeneic Hematopoietic Stem Cell Transplantation of Adult Acute Myeloid Leukemia and Myelodysplastic Syndrome Patients Ineligible to Standard Myeloablative Regimens
Background Allogeneic hematopoietic stem cell transplantation (HCT) remains a challenge in elderly and comorbid AML and MDS patients. This patient population is at increased risk for non-relapse mortality (NRM) when treated with standard myeloablative conditioning and was selected to compare a newly developed treosulfan-based with a well-established reduced intensity busulfan-based preparative regimen in a prospective randomized clinical phase III trial. Methods Adult patients with AML in remission or MDS scheduled for HCT from matched related or unrelated donors, aged â„50 years or with a comorbidity index (HCT-CI) of >2 were enrolled by a central stratified randomization procedure. Treatment arms consisted of intravenous (IV) treosulfan (10 g/mÂČ/day [d-4 to d-2]) or IV busulfan (3.2 mg/kg/day [d-4 to d-3]), both combined with IV fludarabine (30 mg/mÂČ/day [d-6 to d-2]). The primary objective was to compare event-free survival (EFS) at two years with relapse/progression of disease, graft failure, or death reported as events. Secondary endpoints were safety evaluation (according to CTCAE v4.03), engraftment, chimerism, overall survival (OS), relapse/progression incidence (RI), NRM and acute or chronic GvHD. After a previously conducted confirmatory interim analysis (based on 476 patients), which resulted in early termination of patient accrual due to significant non-inferiority of treosulfan treatment with improved EFS, NRM and OS (Beelen et al., ASH 2017), results of the final analysis of all 570 randomized patients including post surveillance data are provided here. Results Median age of the 551 patients (352 AML; 199 MDS) included in the full analysis set (268 treosulfan; 283 busulfan) was 60 years (range: 31, 70). Frequencies of early adverse events (d-6 to d+28) and incidences of acute and chronic GvHD were largely comparable between the two regimens, while extensive chronic GvHD was numerically in favor of treosulfan (19.7% vs. 26.7%; p=0.0750). Primary neutrophil recovery at day +28 was comparable, while the rate of complete donor-type chimerism (day +28) was higher after treosulfan (93.2% vs. 83.3%; p Conclusions Final evaluation of this phase III trial substantiates the previous confirmatory analysis resulting in significantly improved survival after treosulfan-based conditioning. Due to the reduction of NRM a major clinical benefit of the new treosulfan conditioning regimen was demonstrated in the selected AML/MDS patient population
Phenotype Frequencies of Autosomal Minor Histocompatibility Antigens Display Significant Differences among Populations
Minor histocompatibility (H) antigens are allogeneic target molecules having significant roles in alloimmune responses after human leukocyte antigenâmatched solid organ and stem cell transplantation (SCT). Minor H antigens are instrumental in the processes of transplant rejection, graft-versus-host disease, and in the curative graft-versus-tumor effect of SCT. The latter characteristic enabled the current application of selected minor H antigens in clinical immunotherapeutic SCT protocols. No information exists on the global phenotypic distribution of the currently identified minor H antigens. Therefore, an estimation of their overall impact in human leukocyte antigenâmatched solid organ and SCT in the major ethnic populations is still lacking. For the first time, a worldwide phenotype frequency analysis of ten autosomal minor H antigens was executed by 31 laboratories and comprised 2,685 randomly selected individuals from six major ethnic populations. Significant differences in minor H antigen frequencies were observed between the ethnic populations, some of which appeared to be geographically correlated
Genetically determined telomere length and multiple myeloma risk and outcome
This work was partially supported by intramural funds of Univerity of Pisa and
DKFZ; by Fondo de Investigaciones Sanitarias (Madrid, Spain) [PI12/02688 to J.
S., PI17/02276 to J.S.]; by Instituto de Salud Carlos III, co-funded by FEDER funds
âa way to build Europeâ[PI14-00613 to V.M.] and by Agency for
Management of University and Research Grants (AGAUR) of the Catalan
Government (Barcelona, Spain) [2017SGR723 to V.M.]. Open Access funding
enabled and organized by Projekt DEAL.Telomeres are involved in processes like cellular growth, chromosomal stability, and proper segregation to daughter cells. Telomere length measured in leukocytes (LTL) has been investigated in different cancer types, including multiple myeloma (MM). However, LTL measurement is prone to heterogeneity due to sample handling and study design (retrospective vs. prospective). LTL is genetically determined; genome-wide association studies identified 11 SNPs that, combined in a score, can be used as a genetic instrument to measure LTL and evaluate its association with MM risk. This approach has been already successfully attempted in various cancer types but never in MM. We tested the "teloscore" in 2407 MM patients and 1741 controls from the International Multiple Myeloma rESEarch (IMMeNSE) consortium. We observed an increased risk for longer genetically determined telomere length (gdTL) (OR = 1.69; 95% CI 1.36-2.11; P = 2.97 x 10(-6) for highest vs. lowest quintile of the score). Furthermore, in a subset of 1376 MM patients we tested the relationship between the teloscore and MM patients survival, observing a better prognosis for longer gdTL compared with shorter gdTL (HR = 0.93; 95% CI 0.86-0.99; P = 0.049). In conclusion, we report convincing evidence that longer gdTL is a risk marker for MM risk, and that it is potentially involved in increasing MM survival.Univerity of PisaHelmholtz AssociationInstituto de Salud Carlos III
PI12/02688
PI17/02276Instituto de Salud Carlos IIIEuropean CommissionFEDER funds-a way to build Europe
PI14-00613Agency for Management of University and Research Grants (AGAUR) of the Catalan Government (Barcelona, Spain)
2017SGR723Projekt DEA
Polymorphisms within autophagy-related genes as susceptibility biomarkers for multiple myeloma: a meta-analysis of three large cohorts and functional characterization
Functional data used in this project have been meticulously catalogued and archived in the BBMRI-NL data infrastructure (https://hfgp.bbmri.nl/, accessed on 12 February 2020) using the MOLGENIS open-source platform for scientific data.Multiple myeloma (MM) arises following malignant proliferation of plasma cells in the
bone marrow, that secrete high amounts of specific monoclonal immunoglobulins or light chains,
resulting in the massive production of unfolded or misfolded proteins. Autophagy can have a
dual role in tumorigenesis, by eliminating these abnormal proteins to avoid cancer development,
but also ensuring MM cell survival and promoting resistance to treatments. To date no studies
have determined the impact of genetic variation in autophagy-related genes on MM risk. We
performed meta-analysis of germline genetic data on 234 autophagy-related genes from three independent study populations including 13,387 subjects of European ancestry (6863 MM patients and
6524 controls) and examined correlations of statistically significant single nucleotide polymorphisms
(SNPs; p < 1 Ă 10â9) with immune responses in whole blood, peripheral blood mononuclear
cells (PBMCs), and monocyte-derived macrophages (MDM) from a large population of healthy
donors from the Human Functional Genomic Project (HFGP). We identified SNPs in six loci, CD46,
IKBKE, PARK2, ULK4, ATG5, and CDKN2A associated with MM risk (p = 4.47 Ă 10â4â5.79 Ă 10â14).
Mechanistically, we found that the ULK4rs6599175 SNP correlated with circulating concentrations
of vitamin D3 (p = 4.0 Ă 10â4), whereas the IKBKErs17433804 SNP correlated with the number of
transitional CD24+CD38+ B cells (p = 4.8 Ă 10â4) and circulating serum concentrations of Monocyte
hemoattractant Protein (MCP)-2 (p = 3.6 Ă 10â4). We also found that the CD46rs1142469 SNP corre lated with numbers of CD19+ B cells, CD19+CD3â B cells, CD5+ IgDâ cells, IgMâ cells, IgDâIgMâ
cells, and CD4âCD8â PBMCs (p = 4.9 Ă 10â4â8.6 Ă 10â4
) and circulating concentrations of interleukin (IL)-20 (p = 0.00082). Finally, we observed that the CDKN2Ars2811710 SNP correlated with levels
of CD4+EMCD45RO+CD27â cells (p = 9.3 Ă 10â4
). These results suggest that genetic variants within
these six loci influence MM risk through the modulation of specific subsets of immune cells, as well
as vitamin D3â, MCP-2â, and IL20-dependent pathways.This work was supported by the European Unionâs Horizon 2020 research and innovation program, N° 856620 and by grants from the Instituto de Salud Carlos III and FEDER (Madrid, Spain; PI17/02256 and PI20/01845), ConsejerĂa de TransformaciĂłn EconĂłmica, Industria, Conocimiento y Universidades and FEDER (PY20/01282), from the CRIS foundation against cancer, from the Cancer Network of Excellence (RD12/10 Red de CĂĄncer), from the Dietmar Hopp Foundation and the German Ministry of Education and Science (BMBF: CLIOMMICS [01ZX1309]), and from National Cancer Institute of the National Institutes of Health under award numbers: R01CA186646, U01CA249955 (EEB).This work was also funded d by Portuguese National funds, through the Foundation for Science and Technology (FCT)âproject UIDB/50026/2020 and UIDP/50026/2020 and by the project NORTE-01-0145-FEDER-000055, supported by Norte Portugal Regional Operational Programme (NORTE 2020), under the PORTUGAL 2020 Partnership Agreement, through the European Regional Development Fund (ERDF)
Stem cell transplantation for congenital dyserythropoietic anemia : an analysis from the European Society for Blood and Marrow Transplantation
Non peer reviewe
Treating oral mucositis with a supersaturated calcium phosphate rinse: comparison with control in patients undergoing allogeneic hematopoietic stem cell transplantation
Polymorphisms within Autophagy-Related Genes as Susceptibility Biomarkers for Multiple Myeloma: A Meta-Analysis of Three Large Cohorts and Functional Characterization
Multiple myeloma (MM) arises following malignant proliferation of plasma cells in the bone marrow, that secrete high amounts of specific monoclonal immunoglobulins or light chains, resulting in the massive production of unfolded or misfolded proteins. Autophagy can have a dual role in tumorigenesis, by eliminating these abnormal proteins to avoid cancer development, but also ensuring MM cell survival and promoting resistance to treatments. To date no studies have determined the impact of genetic variation in autophagy-related genes on MM risk. We performed meta-analysis of germline genetic data on 234 autophagy-related genes from three independent study populations including 13,387 subjects of European ancestry (6863 MM patients and 6524 controls) and examined correlations of statistically significant single nucleotide polymorphisms (SNPs; p < 1 Ă 10â9) with immune responses in whole blood, peripheral blood mononuclear cells (PBMCs), and monocyte-derived macrophages (MDM) from a large population of healthy donors from the Human Functional Genomic Project (HFGP). We identified SNPs in six loci, CD46, IKBKE, PARK2, ULK4, ATG5, and CDKN2A associated with MM risk (p = 4.47 Ă 10â4â5.79 Ă 10â14). Mechanistically, we found that the ULK4rs6599175 SNP correlated with circulating concentrations of vitamin D3 (p = 4.0 Ă 10â4), whereas the IKBKErs17433804 SNP correlated with the number of transitional CD24+CD38+ B cells (p = 4.8 Ă 10â4) and circulating serum concentrations of Monocyte Chemoattractant Protein (MCP)-2 (p = 3.6 Ă 10â4). We also found that the CD46rs1142469 SNP correlated with numbers of CD19+ B cells, CD19+CD3â B cells, CD5+IgDâ cells, IgMâ cells, IgDâIgMâ cells, and CD4âCD8â PBMCs (p = 4.9 Ă 10â4â8.6 Ă 10â4) and circulating concentrations of interleukin (IL)-20 (p = 0.00082). Finally, we observed that the CDKN2Ars2811710 SNP correlated with levels of CD4+EMCD45RO+CD27â cells (p = 9.3 Ă 10â4). These results suggest that genetic variants within these six loci influence MM risk through the modulation of specific subsets of immune cells, as well as vitamin D3â, MCP-2â, and IL20-dependent pathways.This work was supported by the European Unionâs Horizon 2020 research and innovation program, N° 856620 and by grants from the Instituto de Salud Carlos III and FEDER (Madrid, Spain; PI17/02256 and PI20/01845), ConsejerĂa de TransformaciĂłn EconĂłmica, Industria, Conocimiento y Universidades and FEDER (PY20/01282), from the CRIS foundation against cancer, from the Cancer Network of Excellence (RD12/10 Red de CĂĄncer), from the Dietmar Hopp Foundation and the German Ministry of Education and Science (BMBF: CLIOMMICS [01ZX1309]), and from National Cancer Institute of the National Institutes of Health under award numbers: R01CA186646, U01CA249955 (EEB). This work was also funded d by Portuguese National funds, through the Foundation for Science and Technology (FCT)âproject UIDB/50026/2020 and UIDP/50026/2020 and by the project NORTE-01-0145-FEDER-000055, supported by Norte Portugal Regional Operational Programme (NORTE 2020), under the PORTUGAL 2020 Partnership Agreement, through the European Regional Development Fund (ERDF).Peer reviewe