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Introduction: After the first appearance of peripheral blood neutrophils, recipients from adult donor sources have a rapid increase in neutrophil recovery, whereas cord blood transplantation (CBT) recipients have a slow increase. However, the momentum of neutrophil recovery after CBT varies widely among individuals, but optimal methods to evaluate the momentum of neutrophil recovery and their clinical impacts are yet to be clarified. Methods: We retrospectively examined the prognostic effect of the momentum of neutrophil recovery in the last 7 days until neutrophil engraftment, which was calculated by an exponential growth model, after single CBT following myeloablative conditioning for 207 adults. Results: Among patients who achieved each hematopoietic lineage recovery by day 100, the momentum of neutrophil recovery, which was represented as a growth constant, was associated with the day of neutrophil engraftment (P <.0001), red blood cell engraftment (P <.0001), and platelet engraftment (P <.0001) using the Spearman's rank correlation coefficient test. More importantly, overall survival was superior with a higher growth constant compared with a lower growth constant (P <.001). In the multivariate analysis, a higher growth constant showed a lower overall mortality compared with a lower growth constant (hazard ratio: 0.48, P =.014). Conclusion: Our data demonstrated that the momentum of neutrophil recovery during the last 7 days before neutrophil engraftment, which was measured using an exponential growth model, was associated not only with hematopoietic recovery but also with a better prognosis after single CBT. [ABSTRACT FROM AUTHOR]

The availability of alternative donor sources could allow elderly patients to receive allogeneic hematopoietic cell transplantation (HCT). We retrospectively evaluated the outcomes of single-unit cord blood transplantation (CBT) in 1577 patients aged ≥60 years with acute myeloid leukemia (AML) in Japan between 2002 and 2017. In total, 990 (63%) patients were not in complete remission (CR) at the time of CBT. A myeloablative conditioning regimen (52%) and calcineurin inhibitor (CI) + mycophenolate mofetil (MMF)–based graft-versus-host disease (GVHD) prophylaxis (45%) were more commonly used. With a median follow-up for survivors of 31 months, the probability of overall survival and the cumulative incidence of leukemia-related mortality at 3 years was 31% and 29%, respectively. The cumulative incidence of non-relapse mortality (NRM) at 100 days and 3 years were 24% and 41%, respectively. The cumulative incidences of grade II–IV and grade III–IV acute GVHD at 100 days and extensive chronic GVHD at 2 years were 44%, 16%, and 14%, respectively. The cumulative incidence of neutrophil engraftment was 80% at 42 days. Results of multivariate analysis indicated that the following factors were significantly associated with higher overall mortality: performance status ≥1, hematopoietic cell transplantation-specific comorbidity index ≥3, adverse cytogenetics, extramedullary disease at diagnosis, and non-CR status at CBT. By contrast, female sex, HLA disparities ≥2, mycophenolate mofetil–based GVHD prophylaxis, and recent CBT were significantly associated with lower overall mortality. In conclusion, single CBT offers a curative option for AML patients aged ≥60 years with careful patient selection. [ABSTRACT FROM AUTHOR]

• We retrospectively evaluated the impact of pre-engraftment syndrome (PES) and acute graft-versus-host disease (aGVHD) on relapse and survival after single cord blood transplantation (CBT) for 138 adult patients with hematologic malignancies at our institution. • The development of grade III-IV aGVHD, particularly with gut or liver involvement, contributed to higher nonrelapse mortality (P <.001), but PES and grade II-IV aGVHD did not. • In subgroup analyses of underlying disease type, the development of PES had a significant effect on decreased relapse (P =.032) and better disease-free survival (P =.046) in patients with acute myelogenous leukemia. The different effects of pre-engraftment syndrome (PES) and acute graft-versus-host disease (aGVHD) on outcomes after cord blood transplantation (CBT) are unclear. We retrospectively evaluated the impact of PES and aGVHD on relapse and survival after single-unit CBT in 138 adult patients with hematologic malignancies at our institution between 2004 and 2016. Multivariate analysis demonstrated that development of grade III-IV aGVHD, particularly with gut or liver involvement, significantly contributed to higher nonrelapse mortality (P <.001), but PES and grade II-IV aGVHD did not. In subgroup analyses of underlying disease type, the development of PES had a significant effect on decreased relapse (P =.032) and better disease-free survival (DFS) (P =.046) in patients with acute myelogenous leukemia (AML). These data suggest that PES is associated with a reduced relapse rate and better DFS in AML, indicating that the early immune reaction before neutrophil engraftment may provide a unique graft-versus-leukemia effect after single-unit CBT. [ABSTRACT FROM AUTHOR]

Although daily higher urinary sodium (Na) and potassium (K) excretion ratio is associated with the risk of cardiovascular disease in the general population, a low Na/K ratio is associated with renal dysfunction in critically ill patients. Thus, we retrospectively analyzed the impact of daily urinary Na and K excretion and their ratio on non-relapse mortality (NRM) and overall mortality in 172 adult single-unit cord blood transplantation (CBT) patients treated at our institution between 2007 and 2020. Multivariate analysis showed that a low urinary Na/K ratio at both 14 days (hazard ratio [HR], 4.82; 95% confidence interval [CI], 1.81–12.83; P = 0.001) and 28 days (HR, 4.47; 95% CI 1.32–15.12; P = 0.015) was significantly associated with higher NRM. Furthermore, a low urinary Na/K ratio at 28 days was significantly associated with higher overall mortality (HR, 2.38; 95% CI 1.15–4.91; P = 0.018). Patients with a low urinary Na/K ratio had decreased urine volume, more weight gain, experienced more grade III–IV acute graft-versus-host disease, and required corticosteroids by 28 days after CBT. These findings indicate that a low urinary Na/K ratio early after single-unit CBT is associated with poor NRM and survival in adults. [ABSTRACT FROM AUTHOR]

Epstein-Barr virus (EBV)-associated post-transplant lymphoproliferative disorder (PTLD) is one of the significant cause of morbidity and mortality among patients after allogeneic hematopoietic cell transplantation (HCT). In contrast, our study showed only one patient (0.4%) developed EBV-PTLD within the first year after CBT, whereas 6 patients developed EBV-PTLD over 1 year after CBT. Compared with early-onset PTLD, late-onset PTLD is less frequently characterized by EBV positivity after HCT from adult donors [[8]]. [Extracted from the article]

The article presents a case study of 62-year-old Japanese woman was diagnosed with myelodysplastic syndrome (MDS) refractory anemia. It notes that the patient was diagnosed with alloimmune hemolysis and prolonged red blood cell (RBC) transfusion was needed. The article mentions that the patient was administered with azacitidine, however, her MDS progressed to acute myeloid leukemia (AML).

This document discusses the prevalence and risk factors of polypharmacy among disease-free survivors of adults after allogeneic hematopoietic cell transplantation (HCT). The study found that 29% of adult survivors of allogeneic HCT were in a polypharmacy situation, with factors such as age over 55 years, duration from HCT exceeding 8 years, and the presence of chronic graft-versus-host disease (GVHD) being associated with polypharmacy. The study emphasizes the importance of monitoring and managing polypharmacy in allogeneic post-transplant survivors, particularly in elderly patients and those with chronic GVHD. Another article by a group of authors explores the topic of genetic mutations in cancer cells, highlighting the significance of understanding these mutations for targeted cancer therapies. The article discusses the challenges in identifying and analyzing these mutations and the potential benefits of advanced technologies in this field. It provides a comprehensive overview of current research and advancements in the study of genetic mutations in cancer. [Extracted from the article]

Keywords: busulfan; cord blood transplantation; cyclophosphamide; fludarabine; hematopoietic cell transplantation; myeloablative conditioning EN busulfan cord blood transplantation cyclophosphamide fludarabine hematopoietic cell transplantation myeloablative conditioning 374 376 3 08/05/21 20210901 NES 210901 ACKNOWLEDGEMENTS The authors thank all of the physicians and staff at the hospital and the cord blood banks in Japan for their help in this study. This retrospective study included 31 adult patients who underwent unrelated single-unit CBT (SCBT) following a radiation-free myeloablative conditioning regimen, consisting of fludarabine added to full-dose busulfan and cyclophosphamide for the treatment of hematological malignancies at our hospital between 2002 and 2020. Radiation-free myeloablative conditioning consisting of fludarabine added to full-dose busulfan and cyclophosphamide in single-unit cord blood transplantation for adults. [Extracted from the article]

This DNA damage is repaired by DNA repair genes, such as the base excision repair (BER) pathway. The conditioning regimen used for allogeneic hematopoietic cell transplantation (HCT) must eradicate residual tumor cells and provide sufficient immunosuppression to facilitate donor engraftment. Further studies are warranted to clarify the development of chronic GVHD induction by a number of variant alleles of the BER pathway in patients undergoing CBT. [Extracted from the article]

Abstract The optimal intensity of a conditioning regimen might be dependent on not only age and comorbidities but also disease activity and the type of graft source. We evaluated the outcome of unrelated single cord blood transplantation (CBT) using a conditioning regimen of fludarabine 180 mg/m2, i.v. busulfan 9.6 mg/kg, 4 Gy total body irradiation, granulocyte colony-stimulating factor–combined high-dose cytarabine (12 g/m2) in 23 elderly patients (median, 64 years) with nonremission myeloid malignancies between 2013 and 2018 in our institution. All but 1 patient achieved neutrophil engraftment at a median of 23.5 days (range, 18 to 50). With a median follow-up of 28 months, the probabilities of overall survival (OS), disease-free survival (DFS), and cumulative incidence of relapse at 2 years were 62%, 52%, and 26%, respectively. The cumulative incidences of nonrelapse mortality at 100 days and 2 years were 9% and 22%, respectively. In the univariable analysis a higher proportion of blasts in bone marrow and in peripheral blood and a monosomal or complex karyotype were significantly associated with inferior OS and DFS. Poor cytogenetics were significantly associated with inferior DFS and increased relapse incidence. These data demonstrate that this reduced-toxicity myeloablative conditioning regimen was tolerable and effective in terms of engraftment, relapse, and survival in single CBT for elderly patients with nonremission myeloid malignancies. Highlights • We designed a reduced-toxicity myeloablative conditioning regimen consisting of fludarabine 180 mg/m2, busulfan 9.6 mg/kg, 4 Gy TBI, and G-CSF–combined Ara-C for elderly patients with nonremission myeloid malignancies in single cord blood transplantation. • The cumulative incidence of neutrophil engraftment was 91% at day 42 after CBT. • The probabilities of overall survival, disease-free survival, and cumulative incidence of relapse at 2 years were 62%, 52%, and 26%, respectively. [ABSTRACT FROM AUTHOR]

Given that all six patients developed thyrotoxicosis with no apparent antecedent infection, immune-mediated reactions might be associated with thyrotoxicosis after CBT. A retrospective study by EUROCORD showed that autoimmune diseases occurred after CBT in approximately 5% of patients, and the most common autoimmune disease was cytopenia followed by autoimmune diseases of the thyroid [[10]]. Dear Editor, Thyroid dysfunction is a common endocrine complication after allogeneic hematopoietic cell transplantation (HCT). [Extracted from the article]

Interleukin-2 (IL-2) is one of the most important cytokines that regulate the activation and proliferation of T cells and natural killer cells. The production of IL-2 may be affected by polymorphisms in the promoter region of the IL-2 gene (rs2069762). In allogeneic hematopoietic cell transplantation (HCT) from adult donors, rs2069762 has been associated with the incidence of acute and chronic graft-versus-host disease (GVHD). However, the impacts of IL-2 polymorphism on cord blood transplantation (CBT) outcomes remain unclear. The objective of this study was to assess the impact of IL-2 polymorphism rs2069762 on transplant outcomes, such as hematopoietic recovery, GVHD, overall survival, relapse, and non-relapse mortality (NRM) after CBT. We conducted a retrospective analysis of data from adult patients who underwent single-unit CBT at our institution from November 2005 to March 2023 for whom DNA samples from recipients and donors were available. IL-2 genotyping was performed using real-time polymerase chain reaction with the TaqMan® SNP genotyping assay for rs2069762. A total of 143 recipient and donor pairs were included in this study. The proportion of recipient IL-2 polymorphism rs2069762 was 48 % (n = 69) for AA, 42 % (n = 60) for CA, and 10 % (n = 14) for CC. The proportion of donor IL-2 polymorphism rs2069762 was 43 % (n = 61) for AA, 48 % (n = 69) for CA, and 9 % (n = 13) for CC. In the multivariate analysis, the use of an rs2069762 CA + CC donor was associated with lower neutrophil recovery compared to an rs2069762 AA donor (hazard ratio [HR], 0.66; 95 % confidence interval [CI], 0.50–0.88; P = 0.004). Furthermore, recipients of rs2069762 CA + CC were associated with higher NRM compared to recipients of rs2069762 AA (HR, 2.32; 95 % CI, 1.01–5.34; P = 0.047). Serum IL-2 levels at 8 weeks were significantly higher in rs2069762 CA + CC recipients compared to those with rs2069762 AA recipients (P = 0.014). Our data showed that donor IL-2 polymorphism affects neutrophil recovery and recipient IL-2 polymorphism affects NRM in adults undergoing single-unit CBT. The polymorphism of IL-2 rs2069762 in recipients and donors might be associated with the clinical outcomes of single-unit CBT. [ABSTRACT FROM AUTHOR]

Comparative studies between total body irradiation (TBI)-based and busulfan-based myeloablative conditioning (MAC) regimens for cord blood transplantation (CBT) have been limited. We retrospectively analyzed the results of single-unit CBT in 333 adult patients who received either TBI-based (n = 258) or busulfan-based (n = 75) MAC regimens at our institute. After adjusting for significant variables in the univariate analysis, there were no significant differences in neutrophil recovery (hazard ratio (HR), 0.88; p =.460), grade III–IV acute graft-versus-host disease (GVHD) (HR: 1.40, p =.410), extensive chronic GVHD (HR: 0.73, p =.380), relapse (HR: 0.61, p =.270), non-relapse mortality (HR: 1.38, p =.420), overall survival (HR: 1.18, p =.637), or event-free survival (HR: 1.08, p =.773), although platelet recovery was lower with marginal significance for the busulfan-based regimen (HR: 0.67, p =.068). In subgroup analysis, TBI-based regimens were superior to busulfan-based regimens in terms of survival for acute lymphoblastic leukemia, but not for myeloid malignancies. Further investigation is warranted even for CBT. [ABSTRACT FROM AUTHOR]

An intensified myeloablative conditioning regimen, involving the addition of granulocyte colony-stimulating factor (G-CSF)-combined high-dose cytarabine (12 g/m2) to standard total body irradiation and cyclophosphamide, has been performed for adult patients with myeloid malignancies in single-unit cord blood transplantation (CBT) since 1998 in our institute. We update the results of CBT, as the first allogeneic hematopoietic cell transplantation after this conditioning regimen, in 169 patients with a median long-term follow-up of 10.4 years. The median age was 43 years (range, 16 to 59 years). Ninety-four patients (56%) were in non-remission at the time of CBT, and 124 patients (73%) were acute myeloid leukemia. The median cryopreserved cord blood total nucleated cell dose and CD34+ cell dose was 2.40 × 107/kg and 0.93 × 105/kg, respectively. The cumulative incidence of neutrophil recovery at 42 days was 94.4% (95% confidence interval [CI]: 88.6–97.3%). Among the whole cohort, 105 patients were still alive at the end of the study period. The cumulative incidences of relapse and non-relapse mortality at 10 years were 26.0% (95% CI: 19.5–33.0%) and 16.9% (95% CI: 11.4–23.4%), respectively. There was an overall survival probability of 62.5% (95% CI: 54.3–69.7%) at 10 years. Higher disease risk index alone significantly affected higher overall mortality (hazard ratio 2.21, P = 0.003) in multivariate analysis. These outcomes demonstrate that G-CSF-combined myeloablative conditioning could have favorable long-term remission rates for adult patients with myeloid malignancies undergoing single-unit CBT. [ABSTRACT FROM AUTHOR]

Introduction: The appearance of erythroblasts (EBLs) in peripheral blood occurs in a variety of serious conditions and has been associated with mortality in critically ill patients. However, the incidence, risk factor, and outcomes of EBLs after cord blood transplantation (CBT) remain unclear. Methods: We have investigated the impact of EBLs on transplant outcomes on 225 adult patients who underwent single‐unit CBT at our single institute. Results: The cumulative incidences of EBL ≥200 × 106/L and EBL ≥1000 × 106/L at 60 days after CBT were 17% and 4%, respectively, detected after a median of 35 days and 36.5 days. Multivariate analysis using erythroblastosis as time‐dependent covariates demonstrated the significant association of EBL ≥1000 × 106/L, but not EBL ≥200 × 106/L, with the development of grade III‐IV acute graft‐versus‐host disease (GVHD, hazard ratio [HR]: 18.56; P <.001), higher nonrelapse mortality (HR: 13.38; P <.001), and overall mortality (HR: 4.97; P =.001). Conclusion: These data suggested that higher levels of EBLs were recognized as a significant risk factor for severe acute GVHD and mortality after single‐unit CBT. Higher levels of EBLs may serve as a surrogate marker for poor single CBT outcomes. [ABSTRACT FROM AUTHOR]

By December 2021, about 80% of people over the age of 12 had been vaccinated in Japan, and almost all people were vaccinated with the mRNA vaccine. We investigated here the anti-spike protein antibody titer at the time of breakthrough infection of SARS-CoV-2 omicron. A total of 32 SARS-CoV2 omicron breakthrough infection was included in the study. The median antibody titer at breakthrough infection was 776 AU/mL overall, of which the median antibody titer of BNT162b2 vaccinated was 633 AU/mL and that of mRNA-1273 vaccinated was 9416 AU/mL. This result suggests that low levels of antibody titers 6 months after vaccination do not provide sufficient antibodies to prevent the omicron variant breakthrough infection, which may occur with a higher anti-spike antibody titer after vaccination with mRNA-1273. However, antibody titers in some patients were comparable to those immediately after the second vaccination with either mRNA vaccine. [ABSTRACT FROM AUTHOR]

Vancomycin (VCM) is frequently used for neutropenic patients undergoing cord blood transplantation (CBT). We retrospectively examined the relationship between VCM trough levels and the efficacy and toxicity in 122 adult patients undergoing CBT in our institute. The median initial dose of VCM based on body weight was 9.1 mg/kg/dose (range, 6.0–22.6 mg/kg/dose). The median initial trough level of VCM for all patients was 4.50 µg/mL (range, 1.20–24.05 µg/mL), at a median of 3 days (range, 2–6 days) after VCM administration. The cumulative incidence of acute kidney injury (AKI) was 19% at 30 days after VCM administration. A higher median trough level of VCM during the first 7 days was significantly associated with the development of AKI in the multivariate analysis (Hazard ratio: 1.28, p =.026). These data suggest that a lower VCM trough level may be safe in adult patients undergoing CBT under therapy with nephrotoxic drugs. [ABSTRACT FROM AUTHOR]

• A greater diversity of intestinal microbiota at 1 month was significantly associated with higher counts of plasmacytoid dendritic cells at 7 months after single-unit cord blood transplantation (CBT). • The families Neisseriaceae, Burkholderiaceae, Propionibacteriaceae , and Coriobacteriaceae were increased in higher classical monocyte reconstitution at 7 months post-CBT, whereas the family Bacteroidaceae was increased in lower classical monocyte reconstitution at 7 months post-CBT. • Intestinal microbiota composition affected immune reconstitution of classical monocyte and plasmacytoid dendritic cells following single-unit CBT. The intestinal microbiota plays a fundamental role in the development of host innate immune cells, such as monocytes, dendritic cells (DCs), and natural killer (NK) cells. We examined the association between intestinal microbiota and subsequent immune reconstitution of circulating monocyte, DC, and NK cell subsets in 38 adult patients undergoing single-unit cord blood transplantation (CBT). A higher diversity of intestinal microbiota at 1 month was significantly associated with higher counts of plasmacytoid DCs at 7 months after CBT, as measured by the Chao1 index. Principal coordinate analysis of unweighted UniFrac distances showed significant differences between higher and lower classical monocyte reconstitution at 7 months post-CBT. The families Neisseriaceae, Burkholderiaceae, Propionibacteriaceae , and Coriobacteriaceae were increased in higher classical monocyte reconstitution at 7 months post-CBT, whereas the family Bacteroidaceae was increased in lower classical monocyte reconstitution at 7 months post-CBT. These data show that intestinal microbiota composition affects immune reconstitution of classical monocyte and plasmacytoid DCs following single-unit CBT. [ABSTRACT FROM AUTHOR]

Micafungin (MCFG) is an echinocandin antifungal drug used for prophylaxis and treatment of fungal infections after allogeneic hematopoietic cell transplantation (HCT). However, its efficacy and safety in patients undergoing cord blood transplantation (CBT) has not been clarified. We retrospectively analyzed the efficacy and safety of MCFG in 92 adult patients undergoing CBT in our institute. Of the entire cohort, 83 patients (90%) received MCFG for empirical or preemptive therapy. Documented breakthrough fungal infection occurred in 2 patients during MCFG treatment. Among the 49 patients who received MCFG as empirical therapy for febrile neutropenia, 41 (84%) patients had resolution of fever during neutropenia. Elevation of serum levels of hepatobiliary parameters during MCFG treatment was commonly observed, but grade 3 or higher elevation was rare. We also compared the efficacy and safety of 2 different initial daily doses of MCFG (150 mg vs. 300 mg). There were no significant differences of efficacy and safety between the two groups. These data suggest that MCFG was effective and safe for adult patients undergoing CBT. The optimal daily dose of MCFG treatment is a matter of future investigation for adult patients undergoing CBT. [ABSTRACT FROM AUTHOR]

Summary: T memory stem cells (TSCMs) are a subset of primitive T cells capable of both self‐renewal and differentiation into all subsets of memory and effector T cells. Therefore, TSCMs may play a role in immune reconstitution and graft‐versus‐host disease (GVHD) in patients receiving allogeneic haematopoietic cell transplantation (HCT). We conducted a cross‐sectional study to evaluate the proportions, absolute counts, phenotypes and functions of TSCMs in 152 adult patients without disease recurrence at least 12 months after undergoing HCT. CD4+TSCMs were negatively correlated with number of months after transplantation in HCT patients that received cord blood transplantation, but not in patients that received bone marrow transplantation or peripheral blood stem cell transplantation. The proportions and absolute counts of CD4+TSCMs and expression levels of inducible co‐stimulator (ICOS) in CD8+TSCMs were significantly higher in patients with mild and moderate/severe cGVHD compared to patients without cGVHD. These data suggested that, more than 12 months after allogeneic HCT, the kinetics of CD4+TSCMs were dependent on the type of donor source, and further that CD4+TSCMs and ICOS levels in CD8+TSCMs were associated with cGVHD. [ABSTRACT FROM AUTHOR]

In the present study, we retrospectively analyzed the results of myeloablative single-unit CBT in adult patients with FLT3-ITD SP + sp and FLT3-ITD SP - sp AML and clarified whether FLT3-ITD remains a prognostic factor in CBT. There were no significant differences between patients with or without FLT3-ITD, except that the proportion of poor cytogenetics was significantly higher in patients without FLT3-ITD than with FLT3-ITD ( I p i = .011). The cumulative incidence of relapse at 3 years was 37% (95% CI: 7-69%) for FLT3-ITD+ patients and 35% (95% CI: 15-56%) for FLT3-ITD- patients (g). [Extracted from the article]

The introduction of the prophylactic use of antifungal drugs caused the increased occurrence of invasive fungal infections due to previously rare molds, such as fusariosis, after allogeneic hematopoietic stem cell transplantation. We herein report the case of a patient with diffuse large B-cell lymphoma who developed fungemia due to Fusarium solani during liposormal amphotericin B on day 25 after cord blood transplantation (CBT). Because Fusarium species might differ in virulence and drug susceptibility, the sequencing of the internal transcribed spacer region of the ribosomal RNA gene accurately identified Fusarium solani to be the cause of fungemia at the species level. This case highlights Fusarium solani as the cause of fungemia in a patient under liposormal amphotericin B treatment after CBT. [ABSTRACT FROM AUTHOR]

• We retrospectively evaluated the impact of pretransplantation inflammatory and nutritional status, using such measures as the controlling nutritional status (CONUT) score, Prognostic Nutritional Index (PNI), Glasgow Prognostic Score (GPS), and C-reactive protein-albumin ratio (CAR), on survival, as well as nonrelapse mortality, relapse, engraftment, and graft-versus-host disease (GVHD)in 165 adult recipients of myeloablative single cord blood transplantation. • A higher CONUT score, which is indicative of poor inflammatory and nutritional status, was significantly associated with poor outcomes, including low neutrophil engraftment and development of extensive chronic GVHD. • A higher CAR, which is also suggestive of poor inflammatory and nutritional status, was significantly associated with poor neutrophil engraftment and higher overall mortality. • Body mass index was not associated with transplantation outcomes. Markers of inflammatory and nutritional status, such as the Controlling Nutritional Status (CONUT) score, Prognostic Nutritional Index, Glasgow Prognostic Score, and C-reactive protein-albumin ratio (CAR) has been demonstrated to be associated with poor prognosis in patients with various cancers. Although the relatively low cell dose of a single cord blood unit restricts the indication for cord blood transplantation (CBT) to pediatric and relatively smaller and lighter adult patients, the impact of malnutrition on outcomes after CBT is unclear. We retrospectively analyzed 165 adult patients who underwent myeloablative single-unit CBT in our institute. In multivariate analysis, a higher CONUT score, which is indicative of poor inflammatory and nutritional status, was significantly associated with poor outcomes, including low neutrophil engraftment and development of extensive chronic graft-versus-host disease. A higher CAR, which is also suggestive of poor inflammatory and nutritional status, was significantly associated with poor neutrophil engraftment and higher overall mortality. Body mass index (BMI) was not associated with transplantation outcomes. These data suggest that poor pretransplantation inflammatory and nutritional status might be a more practical parameter than lower BMI, for predicting transplantation outcomes after single CBT for adults. [ABSTRACT FROM AUTHOR]

Highlights • We retrospectively evaluated incidence of and risk factors for PTR, and the impact of PTR on hematopoietic engraftment and survival after single-unit CBT for 185 adult patients in our institute. • The mean 16-hour CCI for the 5840 platelet transfusions was 3.68 × 109/L. Among them, 3196 transfusions (54.7%) were associated with a PTR with 16-hour CCI <4.5 × 109/L. • Non-immune factors were the main determinants of PTR after CBT. • PTR was the significant indicator for poor neutrophil and platelet engraftment, and overall mortality after single-unit CBT for adults. Abstract Platelet transfusion refractoriness (PTR) is frequently observed after allogeneic hematopoietic cell transplantation (HCT). However, the incidence of and risk factors for PTR, and impact of PTR on transplant outcomes after cord blood transplantation (CBT) have not been fully investigated. We retrospectively analyzed 185 adult patients who received single-unit CBT in our institute. The mean 16-hour corrected count increment (CCI) for the 5840 platelet transfusions was 3.68 × 109/L. Among them, 3196 transfusions (54.7%) were associated with a PTR with 16-hour-CCI <4.5 × 109/L. Results of multivariate analysis indicated that the following factors were significantly associated with decreased platelet transfusion responses: female sex with pregnancy history, male sex, the presence of HLA class I antibody, lower cord blood total nucleated cell dose, lower cord blood CD34+ cell dose, 3 locus HLA disparities, body temperature ≥38°C, C-reactive protein ≥10 mg/dL, cytomegalovirus reactivation, use of foscarnet, and use of liposomal amphotericin B. By contrast, graft-versus-host disease prophylaxis including methotrexate, ABO minor mismatch, use of ganciclovir, and use of linezolid were significantly associated with better platelet transfusion responses. PTR had a significant effect on poor neutrophil and platelet recovery, and overall mortality after CBT. These data suggest that early phase PTR may be predictive of engraftment and mortality after single-unit CBT for adults. [ABSTRACT FROM AUTHOR]

Therefore, some patients require the discontinuation of CSP due to various toxicities including neurotoxicity, nephrotoxicity, and fluid retention early after CBT. Among the 175 patients, CSP was discontinued and switched to corticosteroids in 27 patients with a median of 15 days (range, 0-30) within the first 30 days of CBT. [Extracted from the article]

Telomere length in CD4+ and CD8+ T cells among long-term survivors of adults after single cord blood transplantation Relative telomere length in CD4+ T cells and CD8+ T cells according to the NIH grade of cGVHD (F). Correlation between time since CBT to TL assessment and relative telomere length in CD4+ T cells (H) or CD8+ T cells (I). [Extracted from the article]

Candida colonization is associated with severe acute GVHD in adult patients undergoing single-unit cord blood transplantation Our study showed that candidemia occurred in two previous I Candida i -colonized patients, indicating that I Candida i colonization is not useful predictor for the development of candidemia after CBT. This is consistent with previous studies.[[2]] However, this result should be interpreted with caution because antifungal therapy was changed based on the results of an antifungal susceptibility test of the isolated I Candida i during neutropenic episode. [Extracted from the article]

Clinical manifestation of high-grade fever and skin rash before neutrophil engraftment, termed pre-engraftment syndrome (PES) or pre-engraftment immune reaction, has been frequently observed after cord blood transplantation (CBT). The pathophysiology of PES is poorly understood, but cytokine storm during the early phase of CBT is thought to be 1 of the main cause of PES. However, the cytokine profiles of PES after CBT are unclear. Therefore, we examined the relationship between serum cytokine profiles and PES in 44 adult patients who received CBT in our institution between February 2013 and June 2016. Serum levels of 21 cytokines, IL-1β, IL-2, IL-4, IL-5, IL-6, IL-8, IL-9, IL-10, IL-12p70, IL-13, IL-17A, IL-17F, IL-18, IL-21, IL-22, IL-23, IL-33, monocyte chemoattractant protein-1, IFN-α, IFN-γ, and TNF-α, were measured by multiplex bead assays using a flow cytometer. The median time until the absolute neutrophil count was >.5 × 10 9 /L was 21 days (range, 15 to 41 days). The cumulative incidence of PES was 79.6% (95% confidence interval, 63.3% to 88.5%) at 60 days after CBT. Serum levels of IL-5 ( P  = .009) and IL-6 ( P  = .01) at 2 weeks were significantly higher in patients who developed PES compared with those who did not develop PES. The conversion from naïve to effector or central memory phenotype of T cells was observed in PES. These data indicate that elevations of IL-5 and IL-6 around the time of clinical manifestation may be possible biomarkers for PES after CBT. [ABSTRACT FROM AUTHOR]

Low cryopreserved total nucleated cell (TNC) dose in a cord blood (CB) unit has been shown to be associated with engraftment failure and mortality after single-unit cord blood transplantation (CBT) in adults. Although CB banks offer specific characteristics of cryopreserved cell dose, such as TNC, CD34 + cells, and colony-forming unit for granulocyte/macrophage (CFU-GM), the impact of each cell dose on engraftment and outcomes after single-unit CBT in adults remains unclear. We retrospectively analyzed the results of 306 CBTs for 261 adult patients in our institution between 1998 and 2016. The median age was 43 years (range, 16 to 68), the median actual body weight (ABW) was 56.2 kg (range, 36.2 to 104.0), the median ideal body weight (IBW) was 62.3 kg (range, 39.7 to 81.3), the median TNC dose was 2.46 × 10 7 /ABW kg (range, 1.07 to 5.69), the median CD34 + cell dose was .91 × 10 5 /ABW kg (range, .15 to 7.75), and the median CFU-GM dose was 24.46 × 10 3 /ABW kg (range, .04 to 121.81). Among patients who achieved engraftment, the speed of neutrophil, platelet, and red blood cell engraftment significantly correlated with CD34 + cell dose, but not with TNC and CFU-GM dose, based on both ABW and IBW. In multivariate analysis, the incidence of extensive chronic graft-versus-host disease (GVHD) was significantly higher in patients receiving the highest CD34 + cell dose, based on both ABW and IBW. Nevertheless, no cell dose was associated with survival, transplantation-related mortality, and relapse. In conclusion, cryopreserved CD34 + cell dose was the best predictor for hematopoietic recovery and extensive chronic GVHD after CBT. The cryopreserved CD34 + cell dose should be used for unit selection criteria in single-unit CBT for adults. [ABSTRACT FROM AUTHOR]

The article presents a case study of 34-year-old Japanese man diagnosed with myelodysplastic syndrome. Topics discussed include effect of myeloablative single-unit cord blood transplantation in adult acute myeloid leukemia, donor–recipient mixed chimerism status observed in patients after allogeneic hematopoietic cell transplantation following myeloablative conditioning, and conditioning regimen consisted of irradiation, cyclophosphamide and colony-stimulating factor combined with cytarabine.

Recurrent mutations in the gene encoding additional sex combs-like 1 (ASXL1) are found in various hematologic malignancies and associated with poor prognosis. In particular, ASXL1 mutations are common in patients with hematologic malignancies associated with myelodysplasia, including myelodysplastic syndromes (MDSs), and chronic myelomonocytic leukemia. Although loss-of-function ASXL1 mutations promote myeloid transformation, a large subset of ASXL1 mutations is thought to result in stable truncation of ASXL1. Here we demonstrate that C-terminal–truncating Asxl1 mutations (ASXL1-MTs) inhibited myeloid differentiation and induced MDS-like disease in mice. ASXL1-MT mice displayed features of human-associated MDS, including multi-lineage myelodysplasia, pancytopenia, and occasional progression to overt leukemia. ASXL1-MT resulted in derepression of homeobox A9 (Hoxa9) and microRNA-125a (miR-125a) expression through inhibition of polycomb repressive complex 2–mediated (PRC2-mediated) methylation of histone H3K27. miR-125a reduced expression of C-type lectin domain family 5, member a (Clec5a), which is involved in myeloid differentiation. In addition, HOXA9 expression was high in MDS patients with ASXL1-MT, while CLEC5A expression was generally low. Thus, ASXL1-MT–induced MDS-like disease in mice is associated with derepression of Hoxa9 and miR-125a and with Clec5a dysregulation. Our data provide evidence for an axis of MDS pathogenesis that implicates both ASXL1 mutations and miR-125a as therapeutic targets in MDS. [ABSTRACT FROM AUTHOR]

Recurrent mutations in the gene encoding additional sex combs-like 1 (ASXL1) are found in various hematologic malignancies and associated with poor prognosis. In particular, ASXL1 mutations are common in patients with hematologic malignancies associated with myelodysplasia, including myelodysplastic syndromes (MDSs), and chronic myelomonocytic leukemia. Although loss-of-function ASXL1 mutations promote myeloid transformation, a large subset of ASXL1 mutations is thought to result in stable truncation of ASXL1. Here we demonstrate that C-terminal-truncating Asxl1 mutations (ASXL1-MTs) inhibited myeloid differentiation and induced MDS-like disease in mice. ASXL1-MT mice displayed features of human-associated MDS, including multilineage myelodysplasia, pancytopenia, and occasional progression to overt leukemia. ASXL1-MT resulted in derepression of homeobox A9 (Hoxa9) and microRNA-125a (miR-125a) expression through inhibition of polycomb repressive complex 2-mediated (PRC2-mediated) methylation of histone H3K27. miR-125a reduced expression of C-type lectin domain family 5, member a (Clec5a), which is involved in myeloid differentiation. In addition, HOXA9 expression was high in MDS patients with ASXL1-MT, while CLEC5A expression was generally low. Thus, ASXL1-MT-induced MDS-like disease in mice is associated with derepression of Hoxa9 and miR-125a and with Clec5a dysregulation. Our data provide evidence for an axis of MDS pathogenesis that implicates both ASXL1 mutations and miR-125a as therapeutic targets in MDS. [ABSTRACT FROM AUTHOR]

D300C is highly homologous with an inhibitory receptor CD300A in an immunoglobulin-like domain among the human CD300 family of paired immune receptors. To clarify the precise expression and function of CD300C, we generated antibodies discriminating between CD300A and CD300C, which recognized a unique epitope involving amino acid residues CD300A(F56-L57) and CD300C(L63-R64). Notably, CD300C was highly expressed in human monocytes and mast cells. Cross-linking of CD300C by its specific antibody caused cytokine/ chemokine production of human monocytes and mast cells. Fc receptor γ was indispensable for both efficient surface expression and activating functions of CD300C. To identify a ligand for CD300A or CD300C, we used reporter cell lines expressing a chimera receptor harboring extracellular CD300A or CD300C and intracellular CD3ζ, in which its unknown ligand induced GFP expression. Our results indicated that phosphatidylethanolamine (PE) among the lipids tested and apoptotic cells were possible ligands for both CD300C and CD300A. PE and apoptotic cells more strongly inducedGFPexpression in the reporter cells through binding to extracellular CD300A as compared with CD300C. Differential recognition of PE by extracellular CD300A and CD300C depended on different amino acid residues CD300A(F56-L57) and CD300C(L63-R64). Interestingly, GFP expression induced by extracellular CD300C-PE binding in the reporter cells was dampened by co-expression of full-length CD300A, indicating the predominance of CD300A over CD300C in PE recognition/signaling. PE consistently failed to stimulate cytokine production in monocytes expressing CD300C with CD300A. In conclusion, specific engagement of CD300C led to Fc receptor γ-dependent activation of mast cells and monocytes. [ABSTRACT FROM AUTHOR]

Purpose: In a recent study to purify adult T-cell leukemia-lymphoma (ATL) cells from acute-type patients by flow cytometry, three subpopulations were observed in a CD3 versus CD7 plot (H: CD3highCD7high; D: CD3dimCD7dim; L: CD3dimCD7low). The majority of leukemia cells were enriched in the L subpopulation and the same clone was included in the D and L subpopulations, suggesting clonal evolution. In this study, we analyzed patients with indolent-type ATL and human T-cell leukemia virus type I (HTLV-I) asymptomatic carriers (ACs) to see whether the CD3 versus CD7 profile reflected progression in the properties of HTLV-I-infected cells. Experimental Design: Using peripheral blood mononuclear cells from patient samples, we performed multi-color flow cytometry. Cells that underwent fluorescence-activated cell sorting were subjected to molecular analyses, including inverse long PCR. Results: In the D(%) versus L(%) plot, patient data could largely be categorized into three groups (Group 1: AC; Group 2: smoldering- and chronic-type ATL; and Group 3: acute-type ATL). Some exceptions, however, were noted (e.g., ACs in Group 2). In the follow-up of some patients, clinical disease progression correlated well with the CD3 versus CD7 profile. In clonality analysis, we clearly detected a major clone in the D and L subpopulations in ATL cases and, intriguingly, in some ACs in Group 2. Conclusion: We propose that the CD3 versus CD7 plot reflects progression of disease stage in patients infected with HTLV-I. The CD3 versus CD7 profile will be a new indicator, along with high proviral load, for HTLV-I ACs in forecasting disease progression. [ABSTRACT FROM AUTHOR]

Summary: Mast cells (MCs) are key effector cells in allergic reactions. However, the inhibitory mechanism that prevents excessive activation of MCs remains elusive. Here we show that leukocyte mono-immunoglobulin-like receptor 3 (LMIR3; also called CD300f) is a negative regulator of MC activation in vivo. LMIR3 deficiency exacerbated MC-dependent allergic responses in mice, including anaphylaxis, airway inflammation, and dermatitis. Both physical binding and functional reporter assays via an extracellular domain of LMIR3 showed that several extracellular lipids (including ceramide) and lipoproteins were possible ligands for LMIR3. Importantly, MCs were frequently surrounded by extracellular ceramide in vivo. Upon engagement of high-affinity immunoglobulin E receptor, extracellular ceramide-LMIR3 binding inhibited MC activation via immunoreceptor tyrosine-based inhibitory and switch motifs of LMIR3. Moreover, pretreatment with LMIR3-Fc fusion protein or antibody against either ceramide or LMIR3 interfered with this binding in vivo, thereby exacerbating passive cutaneous anaphylaxis. Thus, the interaction between extracellular ceramide and LMIR3 suppressed MC-dependent allergic responses. [ABSTRACT FROM AUTHOR]

Leukocyte mono-Ig-like receptor 5 (LMIR5, also called CD300bJ is an activating receptor expressed in myeloid cells. We have previously demonstrated that T cell Ig mucin 1 works as a ligand for LMIR5 in mouse ischemia/reperfusion injury of the kidneys. In this article, we show that LMIR5 is implicated in LPS-induced sepsis in mice. Notably, neutrophils constitutively released a soluble form of LMIR5 (sLMIR5) through proteolytic cleavage of surface LMIR5. Stimulation with TLR agonists augmented the release of sLMIR5. LPS administration or peritonitis induction increased serum levels of sLMIR5 in mice, which was substantially inhibited by neutrophil depletion. Thus, neutrophils were the main source of LPS-induced sLMIR5 in vivo. On the other hand, i.p. administration of LMIR5-Fc, a surrogate of sLMIR5, bound to resident macrophages (M&phgr;) and stimulated transient inflammation in mice. Consistently, LMIR5-Fc induced in vitro cytokine production of peritoneal M&phgr; via its unknown ligand. Interestingly, LMIR5 deficiency profoundly reduced systemic cytokine production and septic mortality in LPS-administered mice, although it did not affect in vitro cytokine production of LPS-stimulated peritoneal M&phgr;. Importantly, the resistance of LMIR5-deficient mice to LPS- or peritonitis-induced septic death was decreased by LMIR5-Fc administration, implicating sLMIR5 in LPS responses in vivo. Collectively, neutrophil-derived sLMIR5 amplifies LPS-induced lethal inflammation. [ABSTRACT FROM AUTHOR]

The front cover image is based on the Letter to Editor* I Telomere length in CD4 SP + sp and CD8 SP + sp T cells among long-term survivors of adults after single cord blood transplantation i by Takaaki Konuma** et al., https://doi.org/10.1111/ejh.13385.*** GLO:8DW/01may20:ejh13415-toc-0001.jpg PHOTO (COLOR): . gl. [Extracted from the article]