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Background Graft-versus-host disease (GvHD) and relapse remain critical challenges in allogeneic hematopoietic cell transplantation (alloHCT). Graft composition is pivotal, with naïve T cells increasing GvHD risk and NK cells improving graft-versus-leukemia (GvL) effects. Acute beta-adrenergic receptor activation mobilizes effector lymphocytes, favorably altering circulating immune cell composition. This study investigated whether infusing the non-selective beta-agonist isoproterenol (ISO) after granulocyte colony-stimulating factor (G-CSF) mobilization enhances peripheral blood hematopoietic cell (PBHC) graft composition and outcomes. Methods Ten healthy volunteers received a 20-minute ISO infusion before and after five days of G-CSF hematopoietic cell mobilization. G-CSF and G-CSF + ISO mobilized PBHCs were phenotyped and assessed for in vitro cytotoxicity. NSG leukemia-bearing mice were injected with G-CSF or G-CSF + ISO mobilized PBHCs and monitored for GvHD, tumor burden, and overall survival. Results After G-CSF mobilization, ISO increased the numbers of CD34 + cells in the blood and favorably altered graft composition, increasing NK (9.5% to 27.9%) and TCR-γδ T cells (5.0% to 7.5%) while reducing naïve CD4 (18.1% to 11.2%) and CD8 (8.9% to 5.8%) T cells. Effector lymphocytes mobilized by G-CSF + ISO, particularly effector-memory CD8 + T-cells and NK-cells, exhibited upregulated genes and enriched gene sets linked to anti-tumor activity (e.g. NKG7, GZMB, NK cells cytotoxicity). This resulted in an 8-fold increase in cytolysis against the K562 leukemia cell line compared to PBHC mobilized by G-CSF only. In xenogeneic mice, G-CSF + ISO grafts reduced GvHD, extended survival, and improved GvL effects, with 42% of mice surviving at day 40 compared to 21% for G-CSF grafts. Conclusions ISO infusion post-G-CSF mobilization favorably enhances graft composition, mitigates GvHD, prolongs survival, and augments GvL effects. Our findings suggest that acute systemic beta-adrenergic receptor activation could be a valuable strategy to enhance outcomes in alloHCT. Graphical Abstract

Selective depletion of TCRαβ+ and CD45RA+ subsets of apheresed hematopoietic progenitor cells, HPC(A), enables haploidentical hematopoietic stem cell transplant (haplo-HSCT) by circumventing risks of graft-versus-host disease. Here, we analyze our institution’s large series of ex vivo T-cell depletion processes to review procedure performance and explore factors that affect depletion efficiency and graft composition. Over 6 years, 91 haploidentical donors underwent peripheral blood CD34+ stem cell mobilization with granulocyte-colony stimulating factor, with 12 (13%) receiving additional pre-emptive plerixafor. HPC(A) was split into two fractions for TCRαβ and CD45RA depletion with the CliniMACS PLUS device. TCRαβ depletion resulted in a median 4.3 (interquartile range, 4.1–4.5) log reduction, with CD34 recovery at 98% (94%–103%) and TCRγδ+ cell recovery at 89% (74%–98%). CD45RA depletion resulted in a median 4.8 (4.3–5.2) log reduction, with CD3+/CD45RO+ cell recovery at 41% (34%–47%) and CD34 recovery at 58% (51%–68%). TCRαβ depletion efficiency was maintained even when total nucleated cell counts exceeded the maximal specified number, provided the target fraction was within capacity of the depletion kit. Platelet contamination did not affect depletion efficacy or CD34 recovery. Age increases the proportion of CD45RO+ memory cells and TCRαβ subset in HPC(A), while plerixafor increases the latter. Although statistically significant correlation exists between pre-depletion cell composition and depletion performance for some cell subsets, the post-depletion product still met pre-specified threshold without being affected to a clinically relevant extent, over a wide range of input cell numbers. Such robustness of the depletion systems is critical for successful performance of haplo-HSCT. Graphical Abstract Figure partially created in BioRender, https://BioRender.com/3n12d59 DC: dendritic cells; GCSF: granulocyte-colony stimulating factor; HPC(A): apheresed haematopoietic progenitor cells; HSC: haematopoietic stem cells; IQR: interquartile range; NK: natural killer cells; TNC: total nucleated cell.

To determine the influence of graft composition in haplo-HSCT, we summarized the long-term consequences of 251 consecutive transplantations from haploidentical donors. For donor-recipient HLA3/6-matched setting, 125 cases used G-CSF-mobilized BM and PBSCs mixtures, while 126 cases only used G-CSF-mobilized PBSCs in HLA4/6-matched transplantation. On the one hand, we wanted to explore the effect of harvests (CD34+ cells and TNCs dosages) on transplantation outcome in the context of haplo-HSCT no matter HLA4/6 or HLA3/6-matched setting. On the other hand, for patients using G-CSF-mobilized BM and PBSCs combination in HLA3/6-matched setting, we attempted to analyze whether TNCs or CD34+ cells from G-CSF-mobilized BM or G-CSF-mobilized PBSCs play the most paramount role on transplantation prognosis. Collectively, patients with hematologic malignancies receiving G-CSF-primed BM and PBSCs harvests had comparable consequences with patients only receiving G-CSF-mobilized PBSCs. Moreover, when divided all patients averagely according to the total amount of transfused nucleated cells, 3-year TRM of the intermediate group (13.06-18.05×10 8 /kg) was only 4.9%, which was remarkably reduced when compared to lower and higher groups with corresponding values 18.3%, 19.6% ( P =0.026). The 3-year probabilities of OS and DFS of this intermediate group were 72.6% and 66.5%, which were slightly improved than the lower and higher groups. Most importantly, these data suggest that the transfused nucleated cells from G-CSF-primed BM above than 5.20×10 8 /kg could achieve remarkably lower TRM in haplo-HSCT receiving G-CSF-mobilized BM and PBSCs harvests. These encouraging results suggested that we could improve the efficacy of haplo-HSCT by adjusting the component and relative ratio of transfused graft cells. Nevertheless, the above findings should be confirmed in a randomized prospective comparative research with adequate follow-up.

Because of the perception that depleting hematopoietic grafts of T cells will result in poorer immune recovery and in increased risk of graft rejection, pure hematopoietic stem cells (HSC), which avoid the potentially lethal complication of graft-versus-host disease (GVHD), have not been used for allogeneic hematopoietic cell transplantation (HCT) in humans. Ideal grafts should contain HSC plus mature cells that confer only the benefits of protection from pathogens and suppression of malignancies. This goal requires better understanding of the effects of each blood cell type and its interactions during engraftment and immune regeneration. Here, we studied hematopoietic reconstitution post-HCT, comparing grafts of purified HSC with grafts supplemented with T cells in a minor histocompatibility antigen (mHA)-mismatched mouse model. Cell counts, composition, and chimerism of blood and lymphoid organs were evaluated and followed intensively through the first month, and then subsequently for up to 1 yr. Throughout this period, recipients of pure HSC demonstrated superior total cell recovery and lymphoid reconstitution compared with recipients of T cell-containing grafts. In the latter, rapid expansion of T cells occurred, and suppression of hematopoiesis derived from donor HSC was observed. Our findings demonstrate that even early post-HCT, T cells retard donor HSC engraftment and immune recovery. These observations contradict the postulation that mature donor T cells provide important transient immunity and facilitate HSC engraftment.

Although blood stem cells have been widely used to support high-dose therapy in the autologous setting, limited data are available on the effects of graft characteristics in patient outcomes other than haematopoietic engraftment. Retrospective studies suggest that patients who mobilize more CD34 + cells have better outcomes than do patients who mobilize less well. Furthermore, immunological reconstitution may be important in terms of post-transplant outcome and is apparently affected by graft composition. There is accumulating evidence that the mobilization regimen used may be an important determinant of graft content. Plerixafor has been recently introduced combined with G-CSF in patients who mobilize poorly. In addition to enhancing mobilization of CD34 + cells, there are indications that plerixafor may also affect other graft components. A combination of chemotherapy plus G-CSF with plerixafor has been shown to be very effective in stem-cell mobilization, but more data are needed in regard to other graft characteristics in this setting. Prospective studies are needed to evaluate whether higher CD34 + doses or other modifications to graft composition translate into better long-term outcomes in the autologous setting. These studies are not only important in regard to defining the optimal stem-cell graft in the autologous setting, but also in identifying the optimal mobilization regimen.

The optimal dose of posttransplant cyclophosphamide (PTCy) for use in patients undergoing HLA-haploidentical hematopoietic cell transplantation with posttransplant cyclophosphamide (PTCy-haplo) has not been sufficiently examined. This study evaluates the safety and efficacy of HLA-haploidentical hematopoietic cell transplantation with a reduced dose of PTCy for patients with a poor prognosis or those with refractory hematological malignancies. We conducted a prospective clinical study of PTCy-haplo with peripheral blood stem cells (PBSCs) using a modified PTCy dosage regimen consisting of 50 mg/kg on day 3 posttransplantation and a reduced dose of 25 mg/kg on day 4. The cumulative incidences of grades II to III and IV acute graft-versus-host disease (GVHD) at day 100 posttransplantation were 30% and 0%, respectively. The cumulative incidence of moderate-to-severe chronic GVHD after transplantation was 7.0%. The cumulative incidence of nonrelapse mortality at 1 year posttransplantation was 6.1%. Overall survival (OS) at 1 year was 66%. In addition, the restricted cubic-spline Cox regression analysis showed nonlinear relationship between the number of infused CD34+ cells and CD3+ cells, and OS. A graft composition of >4.54 × 106/kg CD34+ cells and >1.85 × 108/kg but ≤3.70 × 108/kg CD3+ cells was significantly associated with better survival, irrespective of the disease status (hazard ratio, 0.13; 95% confidence interval, 0.04–0.41; P < 0.001). These results suggest that PTCy-haplo with PBSCs using a de-escalated dose of 50 mg/kg on day 3 and 25 mg/kg on day 4 posttransplantation is a feasible option.

Filgrastim is usually combined with chemotherapy to mobilize hematopoietic progenitor cells in non-Hodgkin lymphoma (NHL) patients. Limited information is available on the efficacy of a preemptive plerixafor (PLER) injection in poor mobilizers after chemotherapy and pegfilgrastim. In this prospective study, 72 patients with NHL received chemotherapy plus pegfilgrastim, and 25 hard-to-mobilize patients received also PLER. The usefulness and efficacy of our previously developed algorithm for PLER use in pegfilgrastim-containing mobilization regimen were evaluated as well as the graft cellular composition, hematological recovery, and outcome after autologous stem cell transplantation (auto-SCT) according to the PLER use. A median 3.4-fold increase in blood CD34 + cell counts was achieved after the first PLER dose. The minimum collection target was achieved in the first mobilization attempt in 66/72 patients (92%) and 68 patients (94%) proceeded to auto-SCT. An algorithm for PLER use was fulfilled in 76% of the poor mobilizers. Absolute numbers of T-lymphocytes and NK cells were significantly higher in the PLER group, whereas the number of CD34 + cells collected was significantly lower. Early neutrophil engraftment was slower in the PLER group, otherwise hematological recovery was comparable within 12 months from auto-SCT. No difference was observed in survival according to the PLER use. Chemotherapy plus pegfilgrastim combined with preemptive PLER injection is an effective and convenient approach to minimize collection failures in NHL patients intended for auto-SCT. A significant effect of PLER on the graft cellular composition was observed, but no difference in outcome after auto-SCT was detected.

Early lymphocyte recovery as manifested by an absolute lymphocyte count at d+15 (ALC-15) ≥ 0.5 × 109/L after autologous hematopoietic stem cell transplantation (AHCT) has been associated with a better outcome. This prospective multicenter study aimed to clarify factors associated with ALC-15 ≥ 0.5 × 109/L after AHCT among 178 patients with non-Hodgkin lymphoma. The mobilization capacity, as manifested by peak blood CD34+ cell numbers > 45 × 106/L correlated with higher ALC-15 levels (p = 0.020). In addition, the amount of CD3+CD4+ T cells > 31.8 × 106/kg in the infused graft predicted ALC-15 ≥ 0.5 × 109/L (p < 0.001). Also, the number of infused graft CD3+CD8+ T cells > 28.8 × 106/kg (p = 0.017) and NK cells > 4.4 × 106/kg was linked with higher ALC-15 (p < 0.001). The two-year progression-free survival after AHCT was significantly better in patients with ALC-15 ≥ 0.5 × 109/L (74 vs. 57%, p = 0.027). The five-year OS in patients with higher ALC-15 was 78% vs. 60% in those with lower ALC-15 (p = 0.136). To conclude, the mobilization capacity of CD34+ cells and detailed measures of graft cellular content mark prognostic tools that predict ALC-15 ≥ 0.5 × 109/L, which is associated with a better outcome in NHL patients after AHCT.

The CD34 + compartment of grafts for clinical allogeneic hematopoietic cell transplantation (HCT) is very heterogeneous. It contains hematopoietic stem cells and several different progenitor cell populations. This study assesses (1) the content of these populations in clinical grafts from G-CSF-mobilized PBMCs, BM and cord blood, (2) the functional correlation of the graft composition with time to engraftment of neutrophils, platelets and reticulocytes and (3) donor age-related changes. Quantitative flow cytometry showed that the distribution of the progenitor subsets differed significantly between the graft sources and that donor age-related changes occur. In patients after myeloablative allogeneic HCT, accelerated platelet and reticulocyte engraftment correlated with the content of common myeloid and/or megakaryocyte erythroid progenitors in the graft. These findings show that a better understanding of the progenitor compartment in human hematopoietic grafts could lead to improved strategies for the development of cellular therapies, for example in situations where platelet engraftment is delayed.

Urinary stress incontinence is a significant health concern affecting millions of women and is due to poor anatomical support of the urethra. Sub-urethral tapes aim to correct this lack of support to achieve continence. The simplicity and success rates of the tension-free vaginal tape (TVT) technique compare favourably with Burch colposuspension. The last 13 years have seen the introduction of new materials and approaches used for sub-urethral tapes to optimise the efficacy and reduce the complications of the procedure. We present a case series using a tape made of siliconised polyester (LIFT, Cousin®). Approximately half of the cases have presented with an array of symptoms suggestive of an intense inflammatory response, which resolved only on removal of the tape. A low yield on microbiological samples was evident. We suggest that the material is as important as the weave in deciding which mesh to use.