Single Cord Research Articles

In vivo imaging in mouse spinal cord reveals that microglia prevent degeneration of injured axons

Microglia, the primary immune cells in the central nervous system, play a critical role in regulating neuronal function and fate through their interaction with neurons. Despite extensive research, the specific functions and mechanisms of microglia-neuron interactions remain incompletely understood. In this study, we demonstrate that microglia establish direct contact with myelinated axons at Nodes of Ranvier in the spinal cord of mice. The contact associated with neuronal activity occurs in a random scanning pattern. In response to axonal injury, microglia rapidly transform their contact into a robust wrapping form, preventing acute axonal degeneration from extending beyond the nodes. This wrapping behavior is dependent on the function of microglial P2Y12 receptors, which may be activated by ATP released through axonal volume-activated anion channels at the nodes. Additionally, voltage-gated sodium channels (NaV) and two-pore-domain potassium (K2P) channels contribute to the interaction between nodes and glial cells following injury, and inhibition of NaV delays axonal degeneration. Through in vivo imaging, our findings reveal a neuroprotective role of microglia during the acute phase of single spinal cord axon injury, achieved through neuron-glia interaction.

Prenatal phthalate exposure and pubertal development in 16-year-old daughters: reproductive hormones and number of ovarian follicles.

Is there a possible association between prenatal phthalate exposure and late effects in teenage daughters with respect to reproductive hormone levels, uterine volume, and number of ovarian follicles? Our study showed subtle associations between phthalate metabolite concentrations in maternal serum from pregnancy or cord blood and LH and insulin-like growth factor 1 (IGF-1) levels as well as uterine volume in their daughters 16 years later. Endocrine-disrupting environmental chemicals may adversely affect human reproductive health, and many societies have experienced a trend toward earlier puberty and an increasing prevalence of infertility in young couples. The scientific evidence of adverse effects of foetal exposure to a large range of chemicals, including phthalates, on male reproductive health is growing, but very few studies have explored effects on female reproduction. This follow-up study included 317 teenage daughters who were part of the Copenhagen Mother-Child Cohort, a population-based longitudinal birth cohort of 1210 females born between 1997 and 2002. A total of 317 female participants (median age 16 years) were examined for weight, height, and menstrual pattern. A serum sample was analysed for concentrations of reproductive hormones, and trans-abdominal 3D ultrasonography was performed to obtain the number of ovarian follicles, ovarian and uterine size. Prenatal maternal serum samples were available for 115 females, and cord blood samples were available for 118 females. These were analysed for concentrations of 32 phthalate metabolites. Weighted quantile sum regression was used for modelling associations of combined prenatal phthalate exposure with the reproductive outcomes in post-menarcheal females. In bivariate correlation analyses, negative significant associations were found between several prenatal phthalate metabolite concentrations and serum hormone concentrations (testosterone, 17-OH-progesterone, and IGF-1) as well as number of ovarian follicles in puberty. Positive significant correlations were found between prenatal phthalate exposure and FSH and sex hormone-binding globulin concentrations. Combined analyses of phthalate exposure (weighted quantile sums) showed significant negative associations with IGF-1 concentration and uterine volume as well as a significant positive association with LH concentration. Phthalate metabolites were measured in serum from single prenatal maternal blood samples and cord blood samples. Potential concomitant exposure to other endocrine-disrupting environmental chemicals before or after birth was not controlled for. The study population size was limited. Our results support the need for further research into possible adverse effects of environmental chemicals during foetal development of the female reproductive system. The work was supported by The Center on Endocrine Disruptors (CeHoS) under The Danish Environmental Protection Agency and The Ministry of Environment and Food (grant number: MST-621-00 065). No conflicts of interest are declared. N/A.

Haploidentical transplantation with post-transplant cyclophosphamide versus single cord blood transplantation in adults with relapsed/refractory non-Hodgkin lymphoma.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a curative treatment for relapsed or refractory non-Hodgkin lymphoma (R/R NHL). Allo-HSCT using post-transplant cyclophosphamide (PTCY-haplo) and umbilical cord blood transplantation (uCBT) are important donor options in the absence of matched related siblings. However, the data comparing these two donor sources in R/R NHL are limited. Using the Japanese nationwide transplantation registry data, we identified 857 patients with R/R NHL, including 169 patients who received PTCY-haplo and 688 who received uCBT for their first allo-HSCT between January 2013 and December 2021; 514 patients (60%) had B-cell lymphoma. More PTCY-haplo recipients received allo-HSCT using a reduced-intensity conditioning regimen in recent years. The 3-year overall survival (OS), progression-free survival (PFS), and graft-versus-host disease (GVHD)-free/relapse-free survival (GRFS) rates in the PTCY-haplo and uCBT groups were 44% versus 39% (P = 0.326), 34% versus 33% (P = 0.660), and 19% versus 23% (P = 0.910), respectively; the adjusted hazard ratios for OS, PFS, and GRFS were 0.89 (95% confidence interval: 0.69-1.15, P = 0.373), 0.98 (0.78-1.22, P = 0.852), and 0.92 (0.83-1.21, P = 0.920), respectively. The PTCY-haplo group showed faster neutrophil and platelet engraftment and a lower incidence of grade III-IV acute GVHD. Thus, PTCY-haplo and uCBT could serve as alternative donor sources in patients with R/R NHL.

In vitro regenerative effects of a pooled pathogen-reduced lyophilized human cord blood platelet lysate for wound healing applications.

Cord blood platelets, easily obtained from blood units not suitable for haematopoietic stem cell transplantation, represent an abundant source of growth factors for use in wound healing. Although several protocols have been described for platelet lysate production, no standard manufacturing protocol is available. The use of pooled cord blood platelets could thus facilitate standardization. In this study, the effect of varying concentrations (up to 20%) of a pooled pathogen-reduced lyophilized cord blood platelet lysate (PRL-CBPL) was investigated in different cell types involved in the wound healing process. The effect of heparin addition was also evaluated. In parallel, a comparison was performed with a single donor cord blood platelet lysate (SD-CBPL). The effect of PRL-CBPL on the viability and proliferation of different cell lines (L929 mouse fibroblasts and HaCaT keratinocytes) and human primary cells (fibroblasts-NHDF, coronary artery smooth muscle cells-HCASMC and coronary artery endothelial cells-HCAEC), on HaCaT migration and the chemotactic effect on human monocytes (THP-1) was evaluated. PRL-CBPL showed a lower PDGF-AB amount compared to SD-CBPL. Differing concentrations of both CBPL were necessary to influence cell viability and proliferation. 3% was the optimal concentration for L929 and HaCaT as well as for NHDF and HCASMC, while HCAEC required 10%. The effect of added heparin was more evident on SD-CBPL and in particular on NHDF and HCASMC proliferation. Keratinocyte scratch closure was obtained with 3 and 5% PRL-CBPL and SD-CBPL respectively. Both CBPLs caused an increase in the number of migrated THP-1 monocytes in a concentration-dependent manner up to 20% with a higher monocyte migration for SD-CBPL with respect to PRL-CBPL and in cells treated with heparin. The data obtained suggest that PRL-CBPL is an effective standardized alternative to SD-CBPL.

Non-Uniform Drying Shrinkage in Robocasted Green Body Ceramic Products

The formation of defects, due to drying, in robocasted ceramic objects is an important issue arising from non-uniform shrinkage of the material during this step in the process. Common methods for shrinkage measurement are not well suited to the small size of robocasted cords or the complexity of robocasted objects. Innovative methods for shrinkage measurement were developed using non-destructive optical vision techniques with computer-controlled data acquisition, allowing measurement on millimetric cords and on specific zones of a product. The study of a single porcelain cord revealed an anisometric shrinkage related to the orientation of grains during extrusion. A differential shrinkage at the macroscopic scale was also measured on a robocasted object, indicating a moisture content gradient in the material. The methods presented in this paper are of particular relevance to real-time control of the drying process for robocasted objects.

Pencil Beam Scanning Proton Therapy as Single Vocal Cord Irradiation for Early-Stage Glottic Cancer

PurposeSingle vocal cord irradiation (SVCI) is a promising technique to maintain excellent oncologic control and potentially improve upon toxicities for treatment of early-stage glottic squamous cell carcinomas. We sought to investigate whether pencil beam scanning (PBS) proton therapy could improve upon the already favorable dose gradients demonstrated with volumetric modulated arc therapy (VMAT) SVCI. Patients and MethodsA 64-year-old gentleman was treated in our department with 6X-flattening filter-free VMAT SVCI to 58.08 Gy in 16 fractions for a T1a well-differentiated squamous cell carcinoma of the left true vocal cord and tolerated it well with good local control. Comparative PBS plans were created in Raystation for the Varian ProBeam with clinical target volume (CTVs) generated to mimic the prescription target volume extent of the VMAT planning target volumes when accounting for PBS plan robustness (±3 mm translational shifts, 3.5% density perturbation). A 3-field single-field optimization plan was selected as dosimetrically preferable. Dosimetric variables were compared. ResultsSeveral organs at risk doses improved with PBS, including the maximum and mean dose to ipsilateral carotids, maximum and mean dose to contralateral carotid, maximum dose to the spinal cord, maximum and mean dose to inferior constrictor/cricopharyngeus, maximum and mean dose to the uninvolved vocal cord, and mean dose to the thyroid gland. There are tradeoffs in skin dose depending on location relative to the target—with the highest and lowest isodoses extending more into the skin with the VMAT plan but with the moderate isodose lines covering a wider area with the PBS plan, but we deemed it tolerable regardless. ConclusionSVCI is a promising strategy for maintaining the oncologic effectiveness of whole-larynx photon radiation while potentially improving upon the historic toxicity profile. The favorable dose distribution with PBS with respect to organs at risk dosimetry for PBS may allow for further improvements upon VMAT SVCI strategies. Clinical implementation of PBS SVCI may be considered.

Single vs double umbilical cord blood transplantation in acute leukemia: Systematic review and meta-analysis

Background and aimsUmbilical cord blood transplantation (UCBT) has emerged as a promising treatment option for patients with acute leukemia needing hematopoietic stem cell transplantation. Both single (sUCBT) and double cord blood units (dUCBT) demonstrate potential benefits, but studies comparing their effectiveness have shown mixed results. This meta-analysis aimed to determine the comparative safety and efficacy of sUCBT versus dUCBT in acute leukemia patients. MethodsElectronic databases were systematically examined to identify relevant studies comparing single vs double UCBT published until November 2023. Nine studies involving 3864 acute leukemia patients undergoing UCBT were included. Outcomes analyzed were acute graft-versus-host disease (GVHD), chronic GVHD, relapse, non-relapse mortality, leukemia-free survival and overall survival. Pooled risk ratios (RR) with 95% confidence intervals (CI) were calculated using a random effects model. ResultsThe risk of Grade II-IV acute GVHD (RR 1.55, 95% CI 1.19–2.03) and Grade III-IV acute GVHD (RR 1.25, 95% CI 1.07–1.46) were significantly higher with dUCBT. Relapse risk was lower with dUCBT (RR 0.57, 95% CI 0.38–0.88) while overall survival favored sUCBT (RR 1.25, 95% CI 1.06–1.46). No significant differences were observed for chronic GVHD, non-relapse mortality or leukemia-free survival. ConclusionBoth single and double UCBT have potential as effective treatments for acute leukemia. The choice of treatment should consider various factors, including the risk of GVHD, relapse, and mortality. More research, especially randomized trials, is needed to provide definitive guidance on the optimal use of single and double unit UCBT in patients with acute leukemia.

Lymphocyte Crossmatch Testing or Donor HLA-DP and -DQ Allele Typing Effectiveness in Single Cord Blood Transplantation for Patients With Anti-HLA Antibodies Other Than Against HLA-A, -B, -C, and -DRB1

Anti-human leukocyte antigen (HLA) antibodies other than those against HLA-A, -B, -C, and DRB1 are a risk factor for engraftment delay and failure, especially in cord blood transplantation (CBT). The primary objective of this study was to assess the impact of the presence of anti-HLA antibodies on CBT and to evaluate the utility of lymphocyte crossmatch testing or additional HLA-DP and -DQ typing of CB units in improving transplant outcomes. We retrospectively assessed the engraftment rates and transplant outcomes of 772 patients who underwent their first CBT at our hospital between 2012 and 2021. Donors were routinely typed for HLA-A, -B, -C, and-DRB1 alleles, and the anti-HLA antibodies of recipients were screened before donor selection in all cases. Among patients who had antibodies against other than HLA-A, -B, -C, and DRB1 (n = 58), lymphocyte crossmatch testing (n = 32) or additional HLA-DP/-DQ alleles typing of CB (n = 15) was performed to avoid the use of units with corresponding alleles. The median patient age was 57 years (16 to 77). Overall, 75.7% had a high-risk disease status at transplantation, 83.5% received myeloablative conditioning regimens, and >80% were heavily transfused. Two hundred twenty-nine of the 772 recipients (29.6%) were positive for anti-HLA antibodies. There were no statistical differences in the number of infused CD34-positive cells between the anti-HLA antibody-positive and the anti-HLA antibody-negative patients. Of the 229 patients with anti-HLA antibodies, 168 (73.3%) had antibodies against HLA-A, -B, -C, and-DRB1 (Group A), whereas 58 (25.3%) had antibodies against HLA-DP, HLA-DQ, or -DRB3/4/5 with or without antibodies against HLA-A, -B, -C, and -DRB1 (Group B). No patients in both Groups A and B exhibited donor-specific anti-HLA antibodies against HLA-A, -B, -C, and -DRB1. The neutrophil engraftment rate was lower in patients with anti-HLA antibodies than in those without antibodies (89.9% versus 94.1%), whereas nonrelapse mortality (NRM) before engraftment was higher in antibody-positive patients (9.6% versus 4.9%). In patients who received 2 or more HLA allele-mismatched CB in the host-versus-graft (HVG) direction (n = 685), the neutrophil engraftment rate was lower in the anti-HLA antibody-positive recipients than in the antibody-negative recipients with significant differences (88.8% versus 93.8%) (P = .049). Similarly, transplant outcomes were worse in the antibody-positive patients with respect to 2-year overall survival (OS) (43.1% versus 52.3%) and NRM (44.0% versus 30.7%) than in the antibody-negative patients. In contrast, the results of Group B were comparable to those of the antibody-negative patients, while those of Group A were statistically worse than the antibody-negative patients in terms of all engraftment rate (88.6%), OS (34.2%), and NRM (49.0%). The presence of anti-HLA antibodies negatively impacts engraftment, NRM, and OS in CBT. However, HLA-DP/-DQ allele typing of CB units or lymphocyte crossmatch testing could be a useful strategy to overcome poor engraftment rates and transplant outcomes, especially in patients with anti-HLA antibodies against HLA-DP, HLA-DQ, or -DRB3/4/5.

Radiotherapy and stereotactic radiotherapy for multifocal intracranial and intramedullary Rosai–Dorfman disease

AbstractBackgroundWe present a case of a 51‐year‐old man affected by Rosai–Dorfman disease with multiple disseminated intraparenchymal and a single spinal cord localization, presenting with dysphasia and paraparesis.Case PresentationThe patient elected to receive medical steroidal therapy and two radiotherapy cycles. Steroids allowed initial regression of some lesions, while radiotherapy constituted an optimal maintenance treatment. At 6‐year follow up, the patient did not develop any new neurological damage in respect to baseline.ConclusionsAdjuvant therapy with radiotherapy and steroidal therapy is a valid option in multicentric Rosai–Dorfman disease patients not eligible for surgery.

Comparison of long-term outcomes after first HLA-mismatched unrelated donor transplantation with single unrelated cord blood transplantation using reduced-intensity or reduced-toxicity conditioning

BackgroundNo comparative data have shown significant survival differences between HLA-mismatched unrelated donor (MMUD) transplantation and cord blood (CB) transplantation, each with reduced-intensity/reduced-toxicity conditioning (RIC/RTC). However, advances in graft-versus-host disease (GVHD) prophylaxis might help update current strategies. MethodsWe retrospectively compared the outcomes of first allogeneic hematopoietic cell transplantation from MMUDs (n = 15) or single unrelated CB (n = 35) after RIC/RTC. ResultsThe median age was 60 years. The MMUD group had a numerically lower 100-day incidence of grade III–IV acute GVHD (7% vs. 29%, P = 0.079) and non-relapse mortality (0% vs. 40%, P = 0.12). Eight MMUD recipients received anti-thymocyte globulin, bortezomib, or posttransplant cyclophosphamide for GVHD prophylaxis. They did not develop grade III–IV acute GVHD. The MMUD group had significantly better 5-year overall survival than the CB group (62% vs. 31%, P = 0.021), although relapse rates were similar. A multivariable analysis and sensitivity analysis also showed trends toward higher overall survival in the MMUD group. ConclusionMMUD with better GVHD prophylaxis might be preferred over CB in patients with older age and comorbidities.

ABO incompatibility haploidentical peripheral blood stem cell transplantation combined with a single cord blood unit for severe aplastic anemia patients.

To observe the efficacy of haploidentcial peripheral blood stem cell transplantation combined with a single unrelated cord blood unit for severe aplastic anemia patients with donor-recipient ABO incompatibility. This was a retrospective cohort study and data of 57 severe aplastic anemia patients underwent haploidentical stem cell transplantation from August 1, 2018 to February 28, 2022 in the First Affiliated Hospital of Xi'an Jiaotong University was retrospectively analyzed. All patients were divided into two groups, the donor-recipient ABO matched group (bone marrow+peripheral blood group) using haploidentical bone marrow and peripheral blood stem cells as grafts, and donor-recipient ABO mismatched group (cord blood+peripheral blood group), using unrelated cord blood and haploidentical peripheral blood stem cells as grafts. The differences of hematopoietic reconstitution, acute and chronic graft-versus-host disease, Cytomegalovirus (CMV) and Epstein-Barr virus (EBV) infection, and overall survival between the two groups were compared. There were 30 cases in cord blood+peripheral blood group and 27 cases in bone marrow+peripheral blood group. One patient in bone marrow+peripheral blood group had primary graft failure, while other patients were successfully implanted. There were no significant differences of neutrophil and platelet recovery rates between two groups. The erythrocyte recovery time of cord blood+peripheral blood group was slower than that of bone marrow+peripheral blood group (p < 0.05). There was no significant difference of the incidence of graft-versus-host disease, CMV, EB virus infection and post-transplant lymphoproliferative disorders between two groups (p > 0.05). The incidence of grade III-IV acute graft-versus-host disease in cord blood+peripheral blood group was higher than that of bone marrow+peripheral blood group (p < 0.05). The incidence of intestinal graft-versus-host disease was higher in minor ABO-mismatched transplantation than that in major ABO-mismatched transplantation (p < 0.05). There was no significant difference of overall survival between two groups (p > 0.05). These findings suggest that haploidentical peripheral blood stem cell transplantation combined with a single cord blood unit may be an alternative option for severe aplastic anemia patients with donor-recipient ABO incompatibility.

Influence of interruption of oral mycophenolate mofetil for graft-versus-host disease prophylaxis on outcomes after single cord blood transplantation

Influence of interruption of oral mycophenolate mofetil for graft-versus-host disease prophylaxis on outcomes after single cord blood transplantation

ABO Incompatibility Haploidentical Peripheral Blood Stem Cell Transplantation Combined with a Single Cord Blood Unit for Severe Aplastic Anemia Patients

Background: For young severe aplastic anemia (SAA) patients without HLA matched donors, haploidentical hematopoietic stem cell transplantation can be used as an alternative selection. The grafts of classic Beijing protocol in China is a combination of bone marrow and peripheral blood stem cell. For patients with major or minor blood type incompatibility, bone marrow stem cells need to undergo red blood cell or plasma removal treatment. There was rare reports about haploidentical peripheral blood stem cell combined with a single unrelated cord blood unit for ABO incompatibility haploidentical stem cell transplantation in SAA patients. Objective: To observe the efficacy of ABO incompatibility haploidentcial peripheral blood hematopoietic stem cell transplantation combined with a single unrelated cord blood unit for SAA patients. Method s : Fifty-five SAA patients underwent stem cell transplantation from August 2018 to February 2022 in the First Affiliated Hospital of Xi'an Jiaotong Univeristy were divided into two groups based on donor-recipient ABO compatibility, the donor-recipient ABO matched group（BM+PB group）using haploidentical bone marrow and peripheral blood stem cell as grafts, and donor-recipient ABO mismatched group（CB+PB group）, using unrelated cord blood and haploidentical peripheral blood stem cell as grafts. The differences of hematopoietic reconstitution, acute and chronic GVHD, CMV and EB virus infection, PFS, and OS between the two groups were compared. Result s : There were 30 cases in CB+PB group and 27 cases in the BM+PB group. Except for differences in donor-recipient ABO compatibility, the other characteristics of the two groups of patients were comparable((P&amp;gt;0.05). One patient in the BM+PB group had primary graft failure, while the rest of the patients were successfully implanted. There were no significant statistical differences in neutrophil,platelet and red blood cells recovery rates, the incidence of acute and chronic GVHD, CMV, EB virus infection, and PTLD between the two groups of patients(P&amp;gt;0.05). There was no significant statistical difference in OS between the two groups of patients(P&amp;gt;0.05)(Figure 1). Conclusion: For SAA patients with donor-recipient ABO incompatibility could use haploidentical peripheral blood cell combined with unrelated cord blood for transplantation which had compared outcome with haploidentcal bone marrow and peripheral blood cell transplantation.

Infusion of UM171-Expanded Cord Blood Led to Excellent Survival in Patients with High-Risk Leukemias: Results from Two Independent Phase II Studies

Background: Cord blood transplant (CBT) recipients experience delayed hematopoietic recovery and an increased risk of non-relapse mortality (NRM). UM171 is a small molecule that expands hematopoietic stem and progenitor cells (HSPC). An initial phase I-II clinical trial of a single UM171-expanded CBT was associated with low NRM and excellent long-term outcomes. (S Cohen et al. Lancet Haematology 2020). With the primary goal of generating increased numbers of HSPC to supplement a conventional single cord blood (CB) graft, we tested the same approach exclusively in high and very high-risk patients with acute leukemias/myelodysplastic syndromes (MDS). Methods: Between 2019 and 2022, two single independent prospective phase II studies were conducted in Montreal, at the Maisonneuve Rosemont Hospital and in Seattle, at the Fred Hutchinson Cancer Center. Primary objectives were safety/NRM and progression free survival at 2-years post-transplant. Only patients with high and very-high risk acute myeloid leukemia (AML), acute lymphoid leukemia (ALL) and MDS were eligible. Patients were required to have adequate organ function and comorbidity index as defined by the transplant center. Patients received a single UM171 7-day expanded and cryopreserved CB after either a myeloablative or mid-intensity conditioning regimen. All patients received tacrolimus and mycophenolate mofetil for GVHD prophylaxis. Results: A total of 52 patients were enrolled (31 in Montreal and 21 in Seattle) with 2 patients not receiving the UM171 expanded product and therefore removed from the final analysis. Patient's characteristics are shown in Table 1. The median age was 44 years (range 19-66) and weight 78 kg (range, 44-145). Twenty-eight patients (54%) were either in a no complete response (CR) status or in ≥CR2, ten (19%) were p53+ and 17 (33%) were second or third transplants. Forty patients (77%) received a 5/8 HLA-matched CB unit and the median of CD34+ cells infused was 4.7 10 6/Kg (0.9-7.5). All patients engrafted (ANC &amp;gt;500 10^ 9/L for 2 consecutive days) at a median of 17 days (range, 9-39 days). The median time to platelet recovery (&amp;gt;20 x 10^ 9/L) was 37 days (range 24-116). With a median follow-up of 24 months (range 0.7 - 39), the probability of 2-year overall survival (OS) and progression-free survival (PFS) was 67% (95% CI, 54-82) and 63% (95% CI, 50-79). OS for second/third transplants and p53+ patients was 64% (95% CI, 43-96) and 40 (95% CI, 19-86), PFS was 51 % (95% CI, 29-87) and 40 (95% CI, 19-86), respectively. At 2 years, the cumulative incidence of NRM was 19% (95% CI, 8-31) while the incidence of relapse was 18% (95% CI, 6-29). The incidence of grade II-IV and III-IV acute GVHD was 69% (95% CI, 56−82%) and 16% (95% CI, 6−27%). The rate of moderate/severe chronic GVHD was 7% (95% CI,1−15%) and translated in an incidence of a chronic-relapse-free-survival of 55% (95% CI, 42−72%). Of note, Kaplan-Meier analysis of all clinical outcomes showed no difference for patients treated in Montreal and Seattle, and results were similar for both centers (Figure 1). Conclusions: The results of 2 independent Phase II clinical studies demonstrated that infusion of a UM171 single CBT led to excellent clinical outcomes in patients with high and very-high risk malignancies including patients with p53+ mutation. We also observed encouraging results for patients undergoing second/third transplants (33% of the entire cohort). Clinical outcomes were similar between the two Transplant Centers. Based on these positive results, a multicenter randomized clinical trial is currently in the planning stage.

Single CBT As 2nd Allo-SCT Is Promising for Selected Patients with Relapsed Hematopoietic Malignancies

Background: Hematopoietic malignancies that relapse after allogeneic stem cell transplantation (allo-SCT) generally have a poor prognosis, and there is no standard treatment. Second allo-SCT is a potentially curative treatment, but many patients do not receive 2nd allo-SCT at the best time because of the long preparation time for transplantation, and even if they do, treatment-related complications and relapse of the underlying disease often lead them to fatal outcomes. Umbilical cord blood is considered to be a promising source of 2nd allo-SCT because of its short preparation time, rapid and high graft-versus Leukemia (GVL) effect after transplantation, and better response to GVHD treatment compared to other donor sources. Therefore, we investigated the usefulness of cord blood transplantation for relapsed hematopoietic malignancies after allo-SCT. Methods: We retrospectively analyzed the outcomes of patients with hematopoietic malignancies who received single cord blood transplantation (CBT) as 2nd allo-SCT for relapse after allo-SCT in Toranomon Hospital between Apr. 1999 and Mar. 2022. We exclude the patients with Eastern Cooperative Oncology Group (ECOG) performance status(PS) of 4. Results: 263 patients were included in this study. There were 179 patients with myeloid neoplasms and 84 with lymphoid neoplasms. Median age was 45 years (range: 18-71). 239 patients were in non-remission and 24 in remission before SCT. Median interval between 1st SCT and 2nd SCT was 293 days (26-4703). Donor sources of 1st allo-SCT were related donor in 80, unrelated donor in 62, and sCBT in 121 patients. 135 patients received myeloablative conditioning for 2nd allo-SCT, and 128 patients underwent reduced intensity-conditioning. About cord blood as the donor source of 2nd allo-SCT, the median total nucleated cell count at cryopreservation was 2.71(×10 7)/kg (1.67-5.85), and median CD34 + cell count at cryopreservation was 0.97(×10 5)/kg (0.25-3.18). Median observation period of survivors was 1726 (122-6286) days after 2nd allo-SCT. Overall survival (OS), non-relapse mortality and relapse at 2-year were 16.7%, 46.9% and 40.6%, respectively. Younger patients (&amp;lt; 50 years) had significantly better OS than older patients (50 years and more), with 2-year OS of 21.5% and 9.9%, respectively (P &amp;lt; 0.001). Patients with good PS (0 and 1) had significantly better survival than those with poor PS(2 and 3), with 2-year OS of 23.4% and 2.4%, respectively (P&amp;lt;0.001). Patients with myeloid malignancies tended to have better survival than those with lymphoid malignancies, with 2-year survival rates of 19.2% and 11.9%, respectively (P=0.341). Patients with longer interval between SCTs (&amp;gt;1 year) had significantly better survival than those with shorter interval (&amp;lt;1 year), with 2-year OS of 23.6% and 11.6%, respectively (P=0.00443). In multivariate analysis, younger age (&amp;lt;50), good PS (0-1), long interval between SCTs(≧1 year) showed a superior OS. In the younger age population, patients with myeloid neoplasms showed a superior OS compared to those with lymphoid neoplasms (2yrOS: 30.3% vs 10.6%, P=0.00318). Furthermore, patients with myeloid neoplasms having good PS and long interval between SCTs showed an extremely high survival rate of 50.5% at 2 years (n=31)(Figure 1). In the elderly population, patients with long interval and good PS showed a relatively good OS of 31.4% at 2 years (n=28)(Figure 2). The type of disease (myeloid vs lymphoid) didn't have a significant influence on OS in this subpopulation (28.1% vs 50.0%, P=0.129). Conclusion: Although the outcomes of CBT as 2nd allo-SCT haven't been satisfactory, there are certain populations, including elderly patients, with favorable OS.

Comparison of Non-Relapse Mortality after Haploidentical Hematopoietic Stem Cell Transplantation with Post-Transplant Cyclophosphamide Versus Single Umbilical Cord Blood Transplantation for Hematologic Disease

Introduction: Unrelated cord blood transplantation (UCBT) and haploidentical stem cell transplantation with post-transplant cyclophosphamide as graft-versus-host disease (GVHD) prophylaxis (PTCy-haplo) are alternative options for patients with hematologic disease lacking a human leukocyte antigen (HLA)-matched donor. Non-relapse mortality (NRM) after UCBT may vary depending on the cord blood CD34+ cell count, but no study has accounted for CD34+ cell count when comparing the outcomes after UCBT and PTCy-haplo. Therefore, we analyzed transplant outcomes after UCBT and PTCy-haplo in patients with hematologic disease from data of a nationwide registry that included cord blood CD34+ cell count. Methods: Patients with hematologic disease receiving first UCBT or PTCy-haplo between 2014 and 2020 were identified from the nationwide registration data of the Japanese Data for Hematopoietic Cell Transplantation. Acute GVHD-related mortality was defined as death caused primarily by GVHD or occurred secondary to GVHD, and infection-related mortality as death due to graft failure or infection but not acute GVHD. Patients treated by UCBT were stratified by the median CD34+ cell count for comparison (0.84 × 10 5/kg). Results: A total of 7,499 patients were enrolled and classified into 3 groups: PTCy-haplo (n = 1,142), UCBT with high CD34+ cell count (UCB-H; ≥ 0.84 × 10 5/kg, n = 3,185), and UCBT with low CD34+ cell count (UCB-L; &amp;lt; 0.84 × 10 5/kg, n = 3,172). Patients in the PTCy-haplo group were slightly younger than UCB-H and UCB-L patients (median age: 54 vs. 56 and 55 years). The PTCy-haplo group also included a greater proportion of males than the UCB-H group (62.4% vs. 50.0%) but not the UCB-L group (64.2%). A greater proportion of PTCy-haplo patients had a PS score of 0 (53.2% vs. 46.2% and 45.6%), a hematopoietic cell transplantation-specific comorbidity index of 0 (57.6% vs. 52.7% and 54.4%) and donor-specific anti-HLA antibody (2.7% vs. 1.0% and 1.6%), received reduced-intensity conditioning (58.0% vs. 40.5% and 41.6%), calcineurin inhibitor with mycophenolate mofetil (88.5% vs. 38.6% and 38.4%), and underwent transplantation in the later period (82.0% vs. 54.6% and 50.7%). There were no significant differences in disease-risk index between groups. At 2 years post-transplantation, NRM and overall survival (OS) were significantly better in the PTCy-haplo group than the UCB-H and UCB-L groups (NRM: 18.8% vs. 21.6% and 25.3%, P &amp;lt; 0.001; OS: 56.2% vs. 53.3% vs. 49.6%, P &amp;lt; 0.001). Neutrophil engraftment rate at 42 days was also significantly higher in the PTCy-haplo group than the UCB-H and UCB-L groups (93.7% vs. 87.5% and 82.9%, P &amp;lt; 0.001). The PTCy-haplo group less frequently developed grade II-IV (26.4% vs. 37.3% and 34.4%, P &amp;lt; 0.001) and III-IV acute GVHD (7.0% vs. 12.2% and 10.5%, P &amp;lt; 0.001). While neither the differences in NRM nor that in OS remained significant between PTCy-haplo and UCB-H groups in multivariable analysis (NRM: hazard ratio [HR], 1.18, 95% confidence interval [CI], 0.99-1.41, P = 0.073; OS: HR, 1.05, 95% CI, 0.94-1.17, P = 0.42), significant differences were maintained between PTCy-haplo and UCB-L groups (NRM: HR, 1.35, 95% CI, 1.13-1.61, P = 0.001; OS: HR, 1.12, 95% CI, 1.00-1.26, P = 0.042). Regarding the cause-specific mortality, infection-related mortality was also significantly lower in the PTCy-haplo group compared to UCB-H and UCB-L groups (8.1% vs. 11.1% and 13.6%, P &amp;lt; 0.001) while GVHD-related mortality did not differ among groups (5.0% vs. 5.2% and 4.9%, P = 0.69). Conclusion: UCBT-H resulted in similar NRM and OS as patients receiving PTCy-haplo, whereas outcomes were worse in UCBT-L. These findings indicate that high CD34+ cell count in cord blood is a critical criterion for alternative donor selection.

Outcomes of Haplo-Cord and Dual-Cord Transplants: A Single-Center Retrospective Analysis

Background: Despite the concurrent use of tandem haploidentical-umbilical cord (haplo-cord) and dual-umbilical cord (dual-cord) allogeneic hematopoietic stem cell transplant (HSCT) approaches for over a decade, there have been few comparisons of their outcomes (van Besien et al. Hematologica, 2016). No previous studies have evaluated differences following identical conditioning regimens. We report a retrospective analysis comparing patients treated with haplo-cord or dual-cord HSCTs at our institution following the same conditioning regimen. Methods: Between 10/2012-10/2022, 70 haplo-cord and 133 dual-cord transplants were performed following 50 mg/kg of IV cyclophosphamide, 150 mg/m 2 of IV fludarabine, 10 mg/kg of IV thiotepa, and 4 Gy total body irradiation conditioning. Cyclosporine and mycophenolate mofetil were used for graft versus host disease (GVHD) prophylaxis. Patient selection, infectious disease prophylaxis, and donor selection were per institutional standards. Patient characteristics between groups were compared using Fisher's exact test. Kaplan-Meier estimates were used to evaluate OS and RFS. Cumulative incidence estimates were used to compare relapse, aGVHD, cGVHD, and neutrophil and platelet engraftment. Two-tailed t-test was used to compare average in-hospital stays for transplant admissions. Results: There were no significant differences between median age at transplant (51.6 vs 50.3), female representation (41.4% vs 45.1%), or disease types (47.1% vs 51.1% acute myeloid leukemia (AML), 25.75% vs 17.3% acute lymphoblastic leukemia (ALL), 17.2% vs 15.1% myelodysplastic syndrome/myeloproliferative neoplasm (MDS/MPN), 10% vs 16.5% other; p=0.373). With a median follow-up of over 2 years, there was no difference in or OS (p=0.96) or RFS (Figure 1, p=1) for all patients, or for the MDS/MPN and AML subset (OS p=0.47, RFS p=0.43). There was a significant increase in grade 3-4 acute GVHD (aGVHD) in haplo-cord recipients (Figure 2, p=0.007), but no difference in grade 2-4 aGVHD (p=0.11), all chronic GVHD (p=0.8), and moderate-severe cGVHD (p=0.3). Time to neutrophil recovery was faster in haplo-cord recipients (p=0.021), but there was no difference in platelet recovery to 20,000/uL (p=0.12). Average days admitted for haplo-cord HSCTs was 20.61 days compared to 27.56 days for dual-cord HSCTs (p&amp;lt;0.0001). Conclusion: In our experience, there were no differences in survival, relapse, or cGVHD between haplo-cord and dual cord HSCT. Haplo-cord HSCTs were associated with faster neutrophil engraftment and shorter hospital stays compared to dual-cord HSCTs; however, haplo-cord SCTs had significantly higher grade 3-4 aGVHD. When both are options, the choice of haplo-cord versus dual-cord HSCTs should consider these opposing factors. Reference: 1. Koen van Besien, Parameswaran Hari, Mei-Jie Zhang, Hong-Tao Liu, Wendy Stock, Lucy Godley, Olatoyosi Odenike, Richard Larson, Michael Bishop, Amittha Wickrema, Usama Gergis, Sebastian Mayer, Tsiporah Shore, Stephanie Tsai, Joanna Rhodes, Melissa M. Cushing, Sandra Korman, Andrew Artz. Reduced intensity haplo plus single cord transplant compared to double cord transplant: improved engraftment and graft-versus-host disease-free, relapse-free survival. Haematologica 2016;101(5):634-643; https://doi.org/10.3324/haematol.2015.138594.

Clinical implications of augmented renal clearance after unrelated single cord blood transplantation in adults

Augmented renal clearance (ARC) is a phenomenon characterized by increased renal functionality, which can impact the pharmacokinetics and pharmacodynamics of antimicrobial drugs eliminated by the kidneys. It is a potential concern for infection treatment. Cord blood transplantation (CBT) is primarily impeded by delayed neutrophil recovery and immune reconstitution, thereby increasing susceptibility to infection. However, the clinical implications of ARC following CBT remain unexplored. We retrospectively assessed the influence of ARC on post-transplant outcomes at various time points in 194 adult recipients of single-unit unrelated CBT between 2007 and 2022 at our institution. ARC was observed in 52.9% of patients at 1 day, 39.8% at 15 days, and 26.5% at 29 days post-CBT. ARC was not significantly associated with bloodstream infection, acute graft-versus-host disease, or veno-occlusive disease/sinusoidal obstruction syndrome at any time point. ARC at 1 day, 15 days, and 29 days post-CBT was not significantly associated with overall survival, non-relapse mortality, or relapse rates. These findings suggest that ARC is common in adults during the early stages of CBT, but does not discernibly influence clinical outcomes or post-CBT complications.

Expansion strategies for umbilical cord blood haematopoietic stem cells in vitro.

Haematopoietic stem cell transplantation (HSCT) is considered an effective treatment for some haematopoietic malignancies, haematopoietic failure and immunodeficiency. Compared with bone marrow and mobilized peripheral blood, cord blood has the advantages of easy access, being harmless to donors and low requirement for HLA matching. In addition, umbilical cord blood transplantation (UCBT) has achieved remarkable clinical success in the past 30 years due to the low recurrence rate of malignancies treated by UCBT, mild degree of chronic graft-versus-host disease (GVHD) and good quality of life for patients after transplantation. However, the number of cells in a single cord blood is too small for rapid bone marrow implantation. We summarize the various factors involved that need to be considered in the expansion of haematopoietic stem cells (HSCs) in vitro, which all avoid complex operations, such as vector construction and virus transfection. We also found it necessary to identify a new molecule as the carrier of HSCs cultured in vitro, which not only would provide a three-dimensional structure conducive to the self-renewal of HSCs but also prevent their differentiation.

An optimized procedure for preparation of conditioned medium from Wharton's jelly mesenchymal stromal cells isolated from umbilical cord.

Cell-free therapy based on conditioned medium derived from mesenchymal stromal cells (MSCs) has gained attention in the field of protective and regenerative medicine. However, the exact composition and properties of MSC-derived conditioned media can vary greatly depending on multiple parameters, which hamper standardization. In this study, we have optimized a procedure for preparation of conditioned medium starting from efficient isolation, propagation and characterization of MSCs from human umbilical cord, using a culture medium supplemented with human platelet lysate as an alternative source to fetal bovine serum. Our procedure successfully maximizes the yield of viable MSCs that maintain canonical key features. Importantly, under these conditions, the compositional profile and biological effects elicited by the conditioned medium preparations derived from these MSC populations do not depend on donor individuality. Moreover, approximately 120L of conditioned medium could be obtained from a single umbilical cord, which provides a suitable framework to produce industrial amounts of toxic-free conditioned medium with predictable composition.