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The impact of letermovir (LTV)-an anti-cytomegalovirus (CMV) drug-on human herpesvirus-6 (HHV-6) encephalitis is unclear. We hypothesized that LTV prophylaxis may increase the incidence of HHV-6 encephalitis by reducing anti-CMV therapies after allogeneic hematopoietic stem cell transplantation (HSCT). To evaluate the association between HHV-6 encephalitis and antiviral prophylaxis, 7985 adult patients from a nationwide registry who underwent their first HSCT between January 2019 and December 2021 were analyzed. The incidence of HHV-6 encephalitis on day 100 after HSCT was 3.6%; 11.5% for the broad-spectrum antiviral group (foscarnet, ganciclovir, or valganciclovir); 2.8% for the LTV group, and 3.8% for the other antiviral group (p < 0.001). These differences persisted when cord blood transplantation (CBT) was analyzed separately (14.1%, 5.9%, and 7.4%, p < 0.001). In the multivariate analysis, CBT (hazard ratio [HR]: 2.90), broad-spectrum antiviral prophylaxis (HR: 1.91), and grade II-IV acute graft-versus-host disease requiring systemic corticosteroids (HR: 2.42) were independent risk factors for encephalitis (all p < 0.001). The findings of this large modern database study indicate that broad-spectrum antiviral prophylaxis, rather than LTV prophylaxis, is paradoxically associated with HHV-6 encephalitis in the LTV era. This paradoxical finding needs to be further explored in future studies., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Recently, we found significantly reduced total superoxide dismutase (SOD) activity in the cartilage of patients with end-stage knee osteoarthritis (OA). In this study, we aimed to evaluate the SOD activity in serum, joint fluid, cartilage, and synovial membrane samples collected from 52 patients with end-stage knee OA who underwent total knee arthroplasty. The relationship between the total SOD activity in each tissue was evaluated using Spearman's rank correlation coefficient. The joint fluid total SOD activity was used as the objective variable, and its association with the serum, cartilage, and synovial total SOD activities was evaluated using multiple linear regression analysis. Univariate analysis revealed that joint fluid total SOD activity was positively correlated with synovial total SOD activity. Multiple linear regression analysis using joint fluid total SOD activity as the objective variable showed a positive association with synovial total SOD activity (β = 0.493, adjusted R 2  = 0.172, P < 0.01). In patients with end-stage knee OA, the state of the synovial total SOD activity is better reflected by the total SOD activity in the joint fluid than that in the cartilage. Joint fluid total SOD activity may serve as a biomarker for the treatment and prevention of synovitis., (© 2024. The Author(s).)

Various complications can influence hematopoietic cell transplantation (HCT) outcomes. Renal complications can occur during the early to late phases of HCT along with various factors. However, studies focusing on fatal renal complications (FRCs) are scarce. Herein, we analyzed 36,596 first allogeneic HCT recipients retrospectively. Overall, 782 patients died of FRCs at a median of 108 (range, 0-3,440) days after HCT. The cumulative incidence of FRCs was 1.7% and 2.2% at one and five years, respectively. FRCs were associated with older age, male sex, non-complete remission (non-CR), lower performance status (PS), and HCT comorbidity index (HCT-CI) associated with renal comorbidity in multivariate analysis. The risk factors within 100 days included older age, multiple myeloma, PS, and HCT-CI comorbidities (psychiatric disturbance, hepatic disease, obesity, and renal disease). Older age and male sex were risk factors between 100 days and one year. After one year, HCT-CI was associated with the presence of diabetes and prior solid tumor; total body irradiation was identified as a risk factor. Non-CR was a common risk factor in all three phases. Furthermore, acute and chronic graft-versus-host disease, reactivation of cytomegalovirus, and relapse of underlying disease also affected FRCs. Systematic follow-up may be necessary based on the patients' risk factors and post-HCT events., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

This study aimed to validate the utility of the transplant conditioning intensity (TCI) score in 1714 patients with acute myeloid leukemia (AML) undergoing allogeneic bone marrow or peripheral blood stem cell transplantation (BMT/PBSCT) and assess its applicability to 753 patients with AML undergoing umbilical cord blood transplantation (UCBT) both during first complete remission. Patients classified into a high TCI group accounted for 63% and 56% in the BMT/PBSCT and UCBT cohorts, respectively. In the BMT/PBSCT cohort, the risk of relapse was lower in patients in the high versus intermediate TCI group (P = 0.002), although non-relapse mortality (NRM) did not differ among the three TCI groups. In the UCBT cohort, both relapse and NRM did not differ among the TCI groups. Increasing cutoff points for intermediate and high TCI categories significantly improved the ability to predict relapse and NRM in the BMT/PBSCT cohort (P = 0.030 and 0.006, respectively), and relapse but not NRM in the UCBT cohort (P = 0.005 and 0.364, respectively). These findings highlight the difference in the threshold level of the TCI score for outcome discrimination between European and Japanese cohorts. The TCI scheme appears less effective for UCBT than for BMT/PBSCT., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Human leukocyte antigen (HLA)-matched sibling donors (MSDs) are the preferred choice for allogeneic hematopoietic cell transplantation (HCT). However, as myelodysplastic syndrome (MDS) is most frequently diagnosed in the elderly, MSDs are also likely to be of advanced age. It is unclear whether an MSD should be considered the primary choice for allogeneic HCT in elderly patients with MDS. We retrospectively compared survival and other outcomes in 1787 patients with MDS over 50 years of age and receiving allogeneic HCT between 2014 and 2020, using either MSD (n = 214), 8/8 allele-matched unrelated donor (MUD) (n = 562), 7/8 allele-MUD (n = 334), or unrelated cord blood (UCB) (n = 677) in Japan. In multivariate analysis, compared to MSD transplants, the risk of relapse was significantly lower following 8/8MUD transplants (hazard ratio [HR], 0.74; P = 0.047), whereas non-relapse mortality was significantly higher following UCB transplants (HR, 1.43; P = 0.041). However, donor type did not determine overall survival, disease-free survival, or graft-versus-host disease (GVHD)-free, relapse-free survival, but chronic GVHD-free, relapse-free survival was better after UCB (HR, 0.80; P = 0.025) and 8/8MUD (HR, 0.81; P = 0.032) compared to MSD transplants. Our study demonstrated that MSDs are not superior to alternative HCT methods, such as 8/8MUD, 7/8MUD, or UCB, in this population., (© 2023. The Author(s).)

Allogeneic hematopoietic cell transplantation between female donors and male recipients (female-to-male allo-HCT) is a well-established risk factor for inferior survival outcomes due to a higher incidence of graft-versus-host disease (GVHD). However, a clinical significance of anti-thymocyte globulin (ATG) in the female-to-male allo-HCT has not been elucidated. In this study, we retrospectively evaluated male patients who underwent allo-HCT between 2012 and 2019 in Japan. In the female-to-male allo-HCT cohort (n = 828), the use of ATG was not associated with a decreased risk of GVHD (HR of acute GVHD 0.691 [95% CI: 0.461-1.04], P = 0.074; HR of chronic GVHD 1.06 [95% CI: 0.738-1.52], P = 0.76), but was associated with favorable overall survival (OS) and a decreased risk of non-relapse mortality (NRM) (HR of OS 0.603 [95% CI: 0.400-0.909], P = 0.016; HR of NRM 0.506 [95% CI: 0.300-0.856], P = 0.011). The use of ATG in female-to-male allo-HCT resulted in survival outcomes that were almost equivalent to those in the male-to-male allo-HCT group. Therefore, GVHD prophylaxis with ATG might overcome the inferiority of survival outcomes in female-to-male allo-HCT., (© 2023. The Author(s).)

A conditioning regimen is an essential prerequisite of allogeneic hematopoietic stem cell transplantation for patients with myelodysplastic syndrome (MDS). However, the optimal conditioning intensity for a patient may be difficult to establish. This study aimed to identify optimal conditioning intensity (reduced-intensity conditioning regimen [RIC] or myeloablative conditioning regimen [MAC]) for patients with MDS. Overall, 2567 patients with MDS who received their first HCT between 2009 and 2019 were retrospectively analyzed. They were divided into a training cohort and a validation cohort. Using a machine learning-based model, we developed a benefit score for RIC in the training cohort. The validation cohort was divided into a high-score and a low-score group, based on the median benefit score. The endpoint was progression-free survival (PFS). The benefit score for RIC was developed from nine baseline variables in the training cohort. In the validation cohort, the hazard ratios of the PFS in the RIC group compared to the MAC group were 0.65 (95% confidence interval [CI]: 0.48-0.90, P = 0.009) in the high-score group and 1.36 (95% CI: 1.06-1.75, P = 0.017) in the low-score group (P for interaction < 0.001). Machine-learning-based scoring can be useful for the identification of optimal conditioning regimens for patients with MDS., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

The disease-specific impact of anti-thymocyte globulin (ATG) in allogeneic hematopoietic cell transplantation (allo-HCT) has not been determined. We retrospectively assessed the impact of ATG in allo-HCT using nationwide registry data from the Japan Society for Transplantation and Cellular Therapy. We included patients who received their first allo-HCT between 2007 and 2018 for acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), or malignant lymphoma (ML). In total, 8747 patients were included: 7635 patients did not receive ATG and 1112 patients received ATG as GVHD prophylaxis. The median follow-up period of surviving patients was 1457 days. There was no significant impact of pretransplant ATG on the OS or NRM rates in patients with ALL, AML, or ML. In patients with MDS, the probability of 3-year OS was 53.3% in the non-ATG group and 64.2% in the ATG group (P = 0.001). The cumulative incidence rates of relapse and NRM at 3 years were 14.2% and 30.3% (95% CI 27.2-33.3%), respectively, in the non-ATG group and 17.1% and 18.1% in the ATG group (P = 0.15 and P < 0.001). The same finding was observed in a propensity-score matched cohort. Our study suggests that the clinical benefit of ATG could vary among hematological diseases., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Autologous hematopoietic cell transplantation (HCT) is an effective therapy for patients with relapsed acute promyelocytic leukemia (APL). However, it remains unclear whether this procedure is equally effective for certain groups of patients. To address this question, we analyzed 296 patients with APL who had undergone autologous HCT during second or subsequent complete remission (CR2+) between 2006 and 2019. Among them, 24 patients were ≥65 years old, and 17 underwent autologous HCT during third or subsequent CR. Of the 286 patients whose measurable residual disease (MRD) data were available, 21 showed detectable MRD. The 5-year probabilities of relapse-free survival (RFS), overall survival, relapse, and nonrelapse mortality for the entire cohort were 85%, 88%, 9%, and 6%, respectively. The multivariate analysis revealed that the duration of first CR ( < or ≥2 years) was the sole factor associated with RFS (P = 0.002), but even those with CR1 duration <2 years showed a 5-year RFS of 76%. The other factors such as age, disease status, and MRD status were not predictive for the survival outcomes. Our findings demonstrate very favorable long-term results when autologous HCT is conducted during CR2 + across the various subgroups of patients with relapsed APL., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

The role of killer immunoglobulin-like receptor-ligand mismatch (KIR-ligand mismatch) between donors and recipients undergoing cord blood transplantation (CBT) is controversial. If each immunosuppressant differently affects natural killer (NK) cell function, the effect of KIR-ligand mismatch may be altered depending on the type of graft versus host disease (GVHD) prophylaxis. To verify this hypothesis, the difference in the effect of KIR-ligand mismatch was retrospectively assessed between patients who received CBT for acute leukemia, myelodysplastic syndrome, or chronic myeloid leukemia, as well as GVHD prophylaxis comprising tacrolimus plus methotrexate (MTX) or mycophenolate mofetil (MMF). In the MMF group (n = 1363), KIR-ligand mismatch augmented the incidence of non-relapse mortality (NRM; hazard ratio [HR], 1.40; P = 0.008), which worsened overall survival (OS; HR, 1.30, P = 0.0077). In the analysis of each KIR-ligand mismatch type, HLA-C2 mismatch had a favorable effect on relapse incidence (HR, 0.56; P = 0.0043) and OS (HR, 0.72; P = 0.037) only in the MTX group. In the MMF group, HLA-A3/A11 mismatch worsened NRM (HR, 1.93; P < 0.001) and OS (HR, 1.48; P = 0.014). These results imply that the effects of KIR-ligand mismatch differ with the type of GVHD prophylaxis and that assessing the KIR-ligand mismatch status is important for CBT., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

Pretransplant measurable residual disease (MRD) has been shown to be associated with relapse incidence following allogeneic hematopoietic cell transplantation (HCT) for acute myeloid leukemia (AML). However, it remains less clear whether pretransplant MRD status affects transplant outcomes in core binding factor AML (CBF-AML). We retrospectively evaluated the effect of pretransplant MRD, which was measured by a polymerase chain reaction of RUNX1-RUNX1T1 or CBFB-MYH11 fusion transcripts, on transplant outcomes for a cohort of 959 adult patients with t(8;21) or inv(16) AML treated by allogeneic HCT during complete remission (CR), between 2000 and 2018. Multivariate analysis showed the absence of pretransplant MRD was significantly associated with lower relapse (hazard ratio [HR], 0.46; P < 0.001), treatment failure (HR, 0.66; P = 0.004), and overall mortality (HR, 0.72; P = 0.037) among patients with t(8;21). However, pretransplant MRD negativity was not associated with relapse (HR, 0.73; P = 0.420), treatment failure (HR, 0.64; P = 0.063), or overall mortality (HR, 0.69; P = 0.149) among patients with inv(16). In subgroup analysis, pretransplant MRD status significantly affected relapse and LFS only in patients with t(8;21) undergoing allogeneic HCT during CR2. In conclusion, our data demonstrate the different prognostic values of pretransplant MRD for CBF-AML, highlighting the need to develop effective therapeutic strategies for such MRD-positive patients., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

Although graft failure (GF) is a fatal complication after allogeneic stem cell transplantation (SCT), no mortality risk assessments after salvage SCT have been reported. We developed a comprehensive prognostic scoring system consisting of patient and comorbidity factors with 470 patients as a training cohort out of 940; these patients underwent salvage SCT for GF. The multivariate analysis demonstrated that older age, poorer performance status, a continuation of antimicrobial treatment, and severe organ dysfunction were independently associated with worse overall survival (OS) and non-relapse mortality (NRM). Based on each factor's hazard ratio, weighted scores of 1-3 were assigned to these factors. Using the summed scores (0-8), a prognostic scoring system successfully stratified outcomes after salvage SCT in the cohort. For patients in the low (0-2, n = 122), intermediate (3-4, n = 209), and high score (5-8, n = 110) groups, the 1-year OS was 62.8%, 40.8%, and 14.2%, respectively (P < 0.001), whereas the 1-year NRM was 24.1%, 43.9%, and 72.7%, respectively (P < 0.001). The prognostic value of the scoring system was confirmed in the validation cohort (n = 470). Our scoring system is useful for predicting survival after salvage SCT., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

Antithymocyte globulin (ATG) has been shown to reduce chronic graft-versus-host disease (GVHD) particularly in allogeneic peripheral blood stem cell transplantation (PBSCT) from unrelated donors; however, anti-GVHD effects of lower doses of ATG remains to be elucidated. We conducted a nationwide retrospective study to compare the outcomes of unrelated PBSCT with or without rabbit ATG (thymoglobulin) in 287 patients. A median ATG dose was 2.0 mg/kg. The primary endpoint, the cumulative incidence of moderate-severe chronic GVHD at 2 years was 22.1% in the ATG group, which was significantly less than that in the non-ATG group (36.3%, P = 0.025). The ATG group had a higher incidence of immunosuppressant discontinuation, GVHD-free, relapse-free survival, and moderate-severe chronic GVHD-free, relapse-free survival at 2 years compared to the non-ATG group. The incidences of grade III-IV aGVHD and moderate-severe chronic GVHD were significantly higher in patients with high absolute lymphocyte count (ALC) before the administration of ATG, whereas relapse rate was significantly higher in patients with low ALC before ATG. In conclusion, low-dose ATG effectively suppresses chronic GVHD in unrelated PBSCT, and ALC before ATG may be a potential predictor for GVHD and relapse., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

Stimulator of interferon genes (STING) is essential for the type I interferon response induced by microbial DNA from virus or self-DNA from mitochondria/nuclei. In response to emergence of such DNAs in the cytosol, STING translocates from the endoplasmic reticulum to the Golgi, and activates TANK-binding kinase 1 (TBK1) at the trans-Golgi network (TGN). Activated TBK1 then phosphorylates STING at Ser365, generating an interferon regulatory factor 3-docking site on STING. How this reaction proceeds specifically at the TGN remains poorly understood. Here we report a cell-free reaction in which endogenous STING is phosphorylated by TBK1. The reaction utilizes microsomal membrane fraction prepared from TBK1-knockout cells and recombinant TBK1. We observed agonist-, TBK1-, "ER-to-Golgi" traffic-, and palmitoylation-dependent phosphorylation of STING at Ser365, mirroring the nature of STING phosphorylation in vivo. Treating the microsomal membrane fraction with sphingomyelinase or methyl-β-cyclodextrin, an agent to extract cholesterol from membranes, suppressed the phosphorylation of STING by TBK1. Given the enrichment of sphingomyelin and cholesterol in the TGN, these results may provide the molecular basis underlying the specific phosphorylation reaction of STING at the TGN.

Posttransplant relapse represents the greatest obstacle to the success of allogeneic hematopoietic cell transplantation (HCT) for patients with acute myeloid leukemia (AML). This study investigated clinical features and outcomes of posttransplant relapse of AML based on data for 1265 patients with AML suffering relapse after allogeneic HCT conducted during complete remission (CR). Relapse occurred at a median of 6.1 months. The incidence rate of relapse peaked at 29.0 per 100 patient-years during the first 3-6 months period post transplant, after which the rate declined over time, and after 3 years remained consistently at less than 1 per 100 patient-years. The probability of overall survival (OS) after posttransplant relapse was 19% at 2 years, with 68% of deaths being attributed to leukemia. The interval from transplantation to relapse was identified as the strongest indicator for OS. Donor lymphocyte infusion (DLI) and second allogeneic HCT (HCT2) were administered to 152 (12%) and 481 (38%) patients, respectively. Landmark analyses showed some signs of survival benefit when these procedures were performed during CR, but no benefit was gained when performed during non-CR. Our findings clarify clinical features of posttransplant relapse of AML, and indicate the urgent need for developing effective bridging to cellular therapies.

The aim of this study was to develop a comprehensive system for predicting non-relapse mortality after allogeneic hematopoietic cell transplantation (HCT) during first complete remission (CR) of acute myeloid leukemia (AML). After dividing 2344 eligible patients randomly into a training set and a validation set, we first identified and scored five parameters, that is, age, sex, performance status, HCT-comorbidity index (HCT-CI), and donor type, on the basis of their impact on non-relapse mortality for patients in the training set. The non-relapse mortality-J (NRM-J) index using the sum of these scores was then applied to patients in the validation set, resulting in a clear differentiation of non-relapse mortality, with expected 2-year rates of 11%, 16%, 27%, and 33%, respectively (P < 0.001). The estimated c-statistic was 0.67, which was significantly higher than that of the European Society for Blood and Marrow Transplantation score (0.60, P = 0.002) and the HCT-CI (0.57, P < 0.001). The NRM-J index showed a significant association with overall survival, but not with relapse. Our findings demonstrate that the NRM-J index is useful for predicting post-transplant non-relapse mortality for patients with AML in first CR, for whom the decision of whether to perform allogeneic HCT is critical.

To elucidate the impact of infused CD34 + cell doses on transplant outcome, we retrospectively analyzed 851 adult patients who received peripheral blood stem cell transplantation (PBSCT) from human leukocyte antigen (HLA)-matched related donors. The patients were divided into high- and low-CD34 groups at the cutoff value of 4.5 × 10 6 /kg. Overall, the high CD34 group showed early neutrophil and platelet recovery. Stratification of disease risks demonstrated that among the patients with low-risk diseases, the high-CD34 group showed better disease-free survival (DFS) (64.9% vs. 55.5%, P = 0.0415) than did the low-CD34 group, without any increase in graft-versus-host disease (GVHD). Meanwhile, a higher CD34 + cell dose had no impacts on the outcomes of patients with high-risk diseases. Multivariate analyses for the patients with low-risk diseases revealed that a high CD34 + cell dose (hazard ratio [HR] 0.72, P = 0.048) and development of grade III-to-IV acute GVHD (HR 1.64, P = 0.018) were significantly associated with DFS. An excessive dose of CD34 + cells (>8.0 × 10 6 /kg) led to an increase in acute GVHD. By stratification of disease risk, a CD34 + cell dose between 4.5 and 8.0 × 10 6 /kg can be suggested for patients with low-risk diseases who undergo PBSCT from HLA-matched related donors.

There are few reports on allogeneic hematopoietic stem cell transplantation (allo-HSCT) for adult B-cell acute lymphoblastic leukemia (B-ALL) harboring t(1;19)(q23;p13.3). We used nationwide registry data of Japan for 2003-2016 to evaluate transplant outcomes and clarified prognostic factors among adult allo-HSCT recipients with B-ALL harboring t(1;19)(q23;p13.3) (n = 125). Compared with cytogenetically normal (CN) B-ALL patients (n = 1057), their 3-year overall survival (OS) rates were comparable (55.4% for t(1;19) and 54.4% for CN; P = 0.76). Considering only patients in first complete hematological remission (CR1), the 3-year OS rates remained comparable (70.5% for t(1;19) and 67.8% for CN; P = 0.86). For t(1;19) patients in CR1, minimal residual disease (MRD) at transplantation was associated with relatively worse outcomes. The 3-year OS rates were 43.6% for patients with MRD and 77.4% for those without it (P = 0.016). The 3-year relapse rates were 54.5% for patients with MRD and 12.8% for those without it (P < 0.001). Multivariate analyses revealed that MRD at transplantation was a significant risk factor for OS and relapse. In the high-intensity chemotherapy era, t(1;19)(q23;p13.3) did not have a poorer posttransplant prognosis than the normal karyotype. However, even for patients in CR1, MRD at transplantation was associated with comparatively worse OS and higher relapse rates.

A prospectively registered observational study was conducted to assess the significance of allogeneic hematopoietic stem cell transplantation from highly HLA-matched unrelated donors (UD) and cord blood (CB) on outcomes in adult acute leukemia (AL) and myelodysplastic syndrome (MDS). Between 2007 and 2015, 231 transplant-eligible patients were registered for a phase 2 study of alternative donor transplantation. After registration, a sufficient time period was given to find appropriate UD. Patients received CB transplantation (CBT) if an appropriate UD was unavailable. In total, 119 patients received CBT (106 AL and 13 MDS) and 91 patients received UD transplantation (UDT) (86 AL and 5 MDS). The median age was 39 years in both groups. The primary objective was overall survival (OS); secondary objectives included cumulative incidences of non-relapse mortality (NRM) and relapse, and disease-free survival. Diagnosis, disease status at transplantation, refined disease risk index, and hematopoietic cell transplant-specific comorbidity index did not differ between UDT and CBT. In multivariate analyses, graft source was not a significant risk factor for all objectives. In adjusted analyses, UDT and CBT showed similar OS, NRM, and relapse in this prospective study. CB can be a comparable alternative stem cell source to UD by achieving a timely transplant.

Reactivation of human herpesvirus (HHV)-6B is relatively common after allogeneic hematopoietic stem cell transplantation (HSCT) and HHV-6B diseases may consequently develop. Among them, HHV-6B encephalitis is a serious and often fatal complication. The aim of these clinical practice recommendations is to provide diagnostic and therapeutic guidance for HHV-6B encephalitis after allogeneic HSCT. In this evidence-based review, we critically evaluated data from the published literature. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology was used to assist in generating recommendations. We have summarized the findings that contribute to decision-making and we have provided our recommendations. In cases where rigorous clinical data are unavailable, recommendations have been developed in discussions with physicians who have relevant expertize.

This prospective randomized double-masked study investigated the effects of 20 mg lutein supplementation with two different capsules (beeswax or glycerol fatty acid esters) for 6 months on the fellow eyes of 39 Japanese patients with unilateral age-related macular degeneration, and assessed the factors associated with baseline plasma lutein concentration via lifestyle interviews. Macular pigment optical density (MPOD), determined with the two-wavelength autofluorescence method, increased over time in the beeswax group (ANOVA, p = 0.0451), although the increase from 3 months to 6 months was only marginally significant. No significant increase was observed in the glycerol fatty acid esters group (ANOVA, p = 0.7396). Plasma lutein concentrations significantly increased at 3 and 6 months from baseline in both groups (both p < 0.01). In a multiple regression model, age was negatively associated with higher plasma lutein concentration (p = 0.0305), while consumption of green vegetables was positively associated with baseline plasma lutein concentration (p = 0.0322). In conclusion, a significant increase in MPOD was not fully confirmed with 6 months intake duration despite a significant increase in plasma lutein concentrations. Consumption of green vegetable was confirmed to be associated with plasma lutein concentration after adjusting for other potential factors including age.

Graft failure (GF) remains a major complication of cord blood transplantation (CBT). Although the presence of pretransplant, donor-specific anti-HLA antibodies (DSA) was reported to be associated with an increased risk of GF after CBT, data are still limited. Thus, we conducted a retrospective analysis of recipients of single-unit CBT with pretransplant anti-HLA antibodies using the database of Japan Society for Hematopoietic Cell Transplantation (JSHCT). Data for recipients of single-unit CBT with pretransplant anti-HLA antibodies from 2010 to 2014 were obtained. In total, 343 patients who received CBT and who had detailed information about anti-HLA antibodies were included. The median age was 51 years (range, 0-71). Regarding DSA, 25 patients had a mean fluorescence intensity (MFI) ≥ 1000 (DSA-positive group) and 318 patients had a MFI <1000 (DSA-negative group). The cumulative incidence of neutrophil engraftment at 60 days after CBT was 75.7% (95% CI, 70.6-80.1) in the DSA-negative group and 56.0% (95% CI, 34.1-73.1) in the DSA-positive group (P = 0.03). In conclusion, pretransplant DSA with a MFI ≥ 1000 was associated with an increased risk of GF in single-unit CBT.

The conserved serine-threonine kinase, Cdc7, plays a crucial role in initiation of DNA replication by facilitating the assembly of an initiation complex. Cdc7 is expressed at a high level and exhibits significant kinase activity not only during S-phase but also during G2/M-phases. A conserved mitotic kinase, Aurora B, is activated during M-phase by association with INCENP, forming the chromosome passenger complex with Borealin and Survivin. We show that Cdc7 phosphorylates and stimulates Aurora B kinase activity in vitro. We identified threonine-236 as a critical phosphorylation site on Aurora B that could be a target of Cdc7 or could be an autophosphorylation site stimulated by Cdc7-mediated phosphorylation elsewhere. We found that threonines at both 232 (that has been identified as an autophosphorylation site) and 236 are essential for the kinase activity of Aurora B. Cdc7 down regulation or inhibition reduced Aurora B activity in vivo and led to retarded M-phase progression. SAC imposed by paclitaxel was dramatically reversed by Cdc7 inhibition, similar to the effect of Aurora B inhibition under the similar situation. Our data show that Cdc7 contributes to M-phase progression and to spindle assembly checkpoint most likely through Aurora B activation.

Allogeneic hematopoietic stem cell transplantation (HCT) offers the most effective prevention of relapse and has significant overall survival (OS) benefits for patients with acute myeloid leukemia (AML) in first complete remission (CR1). We conducted a retrospective analysis of a cohort of patients with intermediate- or poor-risk AML. The purpose of the present study was to investigate the role of alternative donors for AML in CR1. We analyzed 1561 patients who underwent HCT from an HLA-matched related donor (MRD), HLA 8/8-matched unrelated donor (MUD), or umbilical cord blood (UCB). The results of a multivariate analysis showed that HCT from UCB (HR = 1.28, 95% CI: 1.07-1.52), age ≥50 years (HR = 1.36, 95% CI: 1.14-1.62), male (HR = 1.42, 95% CI: 1.21-1.66), PS > 1 (HR = 1.68, 95% CI: 1.17-2.42), and poor-risk cytogenetics (HR = 1.53, 95% CI: 1.29-1.81) had an inferior prognostic impact on OS. We conclude that an MUD is the best alternative to an HLA identical MRD for patients with AML in CR1. UCB is an alternative option if neither MRD nor MUD are available, or when patients need to receive urgent HCT for poor-risk AML in CR1.

To investigate optimal unit selection for umbilical cord blood transplantation (UCBT), we conducted a registry-based study of 1355 adults with acute myeloid leukemia in first or second complete remission who underwent single-unit UCBT. To be eligible for analysis, UCB units had to contain a total nucleated cell (TNC) dose of 2.0 × 10 7 /kg or higher and present at least a 4/6-match for HLA-A, -B, and -DR antigens in line with clinical practice in Japan, both of which are less stringent criteria than those used in Western countries. Neither TNC dose nor the degree of HLA matching affected survival (P = 0.138 and P = 0.696, respectively). As for HLA-A, -B antigens and -DRB1 allele, better HLA matching was associated with lower non-relapse mortality (P = 0.011) but higher relapse (P = 0.046), resulting in no improvement in survival (P = 0.680). Taking the allele level for each HLA-A, -B, and -DRB1 into consideration was less useful for predicting non-relapse mortality (P = 0.198). These findings suggest that the less stringent criteria for UCB unit selection are acceptable for Japanese patient population and perhaps even more beneficial in terms of providing a better chance to find a suitable UCB unit.

Clinical trials evaluating the role of autologous hematopoietic stem cell transplantation (auto-HCT) in multiple myeloma have mostly included patients aged <65 years. Therefore, this study was aimed to evaluate the efficacy and safety of auto-HCT in elderly patients with multiple myeloma in the era of novel agents. We retrospectively analyzed 2056 patients with multiple myeloma, who underwent auto-HCT in 2007-2014 (287 were aged ≥65 years). We evaluated the 100-day treatment-related mortality (TRM) and overall survival (OS) in two groups; elderly patients ( ≥65 years) who underwent auto-HCT compared with younger patients ( <65 years). In the propensity score-matched-pair analysis used to adjust for possible selection bias, the incidence of 100-day TRM between patients aged <65 (0.4%; 95% confidence interval [CI]: 0.0-2.0%) and ≥65 years (1.2%; 95% CI: 0.3-3.1%) showed no statistically significant difference (p = 0.31). The probability of the 5-year OS after transplantation in those aged <65 (62.5%; 95% CI: 58.6-66.1%) and ≥65 (63.5%; 95% CI: 52.2-72.7%) years was also not significantly different (p = 0.56). This study showed that the safety and efficacy of auto-HCT in elderly patients with multiple myeloma in the era of novel agents compared with younger patients were similar.

The BRAF inhibitors dabrafenib and vemurafenib induce remarkable clinical responses in patients with BRAF-mutated melanomas. However, adverse events, including the emergence of secondary tumors and drug resistance, have been reported. Studies have revealed that undesirable RAF dimerization induced by inhibitors promotes these adverse effects. Here, we developed highly sensitive biosensors of RAF dimerization in cells utilizing the split enhanced click beetle luciferase (Emerald Luc, ELuc) complementation technique. We demonstrated that our biosensor system works effectively for high-throughput screens in the microplate format. A comprehensive analysis of commercially available RAF inhibitors performed using this assay system revealed that the inhibitors exhibit various potencies in inducing the dimerization of RAF isoforms, and their dimerization potencies do not always correlate with the RAF enzyme inhibition. This sensitive assay system will become a powerful tool to discover next-generation BRAF inhibitors with safer profiles.

Clinical efficacy of allogeneic hematopoietic cell transplantation (HCT) using reduced-intensity conditioning (RIC) for younger patients remains unclear. We therefore performed a retrospective registry-based study to evaluate outcomes for patients with AML aged between 16 and 49 years who underwent RIC allogeneic HCT. Patients receiving RIC (N=125) showed significantly worse survival than those receiving myeloablative conditioning (MAC; N=1,554) (47.7% for RIC and 54.2% for MAC at 4 years, P=0.047). However, the difference became marginal after adjustment for patient characteristics (P=0.080), and inclusion in the multivariate analysis of the HCT comorbidity index or the propensity score for estimating the likelihood of choosing RIC or MAC further reduced statistical significance (P=0.371 and 0.206, respectively), indicating the existence of a selection bias against RIC. Nevertheless, outcomes for our patients receiving RIC were still acceptable, so that RIC constitutes a potential therapeutic option for younger AML patients who are deemed unsuitable for MAC. Subgroup analyses showed that patients aged between 40 and 49 years as well as those in first or second CR at the time of transplantation exhibited similar outcomes regardless of whether they were treated with RIC or MAC.

Intestinal transplant-associated microangiopathy (i-TAM) is an important complication after allogeneic hematopoietic SCT. From 1997 to 2006, 87 of 886 patients with diarrhea after transplantation received colonoscopic biopsy. i-TAM, GVHD and CMV colitis were diagnosed histopathologically. The median duration from transplantation to the onset of diarrhea was 32 days (range: 9-130 days) and that from the onset of diarrhea to biopsy was 12 days (range: 0-74 days). The median maximal amount of diarrhea was 2 l/day (range: 130-5600 ml/day). Histopathological diagnosis included i-TAM (n=80), GVHD (n=26), CMV colitis (n=17) and nonspecific findings (n=2) with overlapping. Among 80 patients with i-TAM, abdominal pain was a major symptom, and only 11 patients fulfilled the proposed criteria for systemic TAM. Non-relapse mortality (NRM) among patients without resolution of diarrhea was 72% and i-TAM comprised 57% of NRM. NRM was 25% among patients without intensified immunosuppression, but was 52, 79 and 100% among those with intensified immunosuppression before diarrhea, after diarrhea, and before and after diarrhea, respectively. In conclusion, i-TAM is a major complication presenting massive refractory diarrhea and abdominal pain, which causes NRM. Avoiding intensified immunosuppression that damages vascular endothelium until the resolution of i-TAM may improve transplant outcome.

Chronic GVHD is a significant complication following allogeneic hematopoietic stem cell transplantation; however, the clinical characteristics of chronic GVHD following cord blood transplantation (CBT) in adults have not been well described. Between March 2001 and November 2005, a total of 77 patients underwent CBT at eight transplantation centers of the Nagoya Blood and Marrow Transplantation Group. Of 77 patients, 29 survived without graft failure or progression of underlying diseases for at least 100 days after transplantation. The median age of the 29 patients was 42 years (range, 18-67 years). Seven patients developed chronic GVHD (extensive, n=4; limited, n=3) disease. The cumulative incidence of chronic GVHD 1 year after day 100 was 24% (95% confidence interval (CI), 11-41%), and the organs involved were the skin (n=6), oral cavity (n=4), liver (n=1) and gastrointestinal tract (n=1). In three patients, chronic GVHD was resolved with supportive care. The remaining four were successfully treated with additional immunosuppressive therapy. Event-free survival rates of the 29 patients with and without chronic GVHD 3 years after day 100 were 83 (95% CI, 27-97%) and 36% (95% CI, 17-56%), respectively (P=0.047). These results suggest that chronic GVHD following CBT is mild and has a graft-versus-malignancy effect.

Post transplant immune disorders are problematic in cord blood transplantation (CBT) for adult patients, and optimal prophylaxis has not been established. We investigated whether intensive graft-versus-host disease (GVHD) prophylaxis using short-term methotrexate (MTX) has a prognostic impact on CBT. Post-CBT immune reactions were classified according to time course as pre-engraftment immune reaction (PIR), engraftment syndrome (ES) or acute GVHD. Between March 2001 and November 2005, a total of 77 patients underwent CBT at eight transplantation centers. Median age was 48 years (range, 18-69 years). Preparative regimens comprised myeloablative (n=31) or reduced-intensity (n=46). Acute GVHD prophylaxis included cyclosporine alone (n=23), tacrolimus alone (n=12), cyclosporine plus MTX (n=17), tacrolimus plus short-term MTX (n=23) or cyclosporine plus methylprednisolone (n=2). Cumulative incidences of PIR, ES and grade II-IV GVHD were 36, 12 and 23%, respectively. Short-term MTX exerted significant favorable effects on post-CBT immune reactions (hazard ratio, 0.55; 95% confidence interval (95% CI), 0.31-0.98; P=0.04) in multivariate analysis. Overall survival rates for patients with and without short-term MTX at day 180 were 59% (95% CI, 42-73%) and 16% (95% CI, 6.6-30%) (P=0.0001), respectively. Short-term MTX could offer one optimal regimen to reduce immune reactions and improve outcomes in CBT.