Search

The role of allogeneic hematopoietic stem cell transplantation (HSCT) for infants with acute lymphoblastic leukemia (ALL) and KMT2A gene rearrangement (KMT2A-r) is controversial in terms of both its efficacy and potential for acute and late toxicities. In Japanese Pediatric Leukemia/Lymphoma Study Group trial MLL-10, by introducing intensive chemotherapy, indication of HSCT was restricted to patients with high-risk (HR) features only (KMT2A-r and either age <180 days or presence of central nervous system leukemia). Of the 56 HR patients, 49 achieved complete remission. Forty-three patients received HSCT in first remission including 38 patients receiving protocol-specified HSCT with conditioning consisting of individualized targeted doses of busulfan, etoposide, and cyclophosphamide. Three-year event-free survival (EFS) of 56.8% (95% confidence interval [CI], 42.4% to 68.8%) and overall survival of 80.2% (95% CI, 67.1% to 88.5%) were accomplished. Univariable analysis showed that Interfant-HR criteria and flow cytometric minimal residual disease (MRD; ≥0.01%), both at the end of induction and at the end of consolidation (EOC), were significantly associated with poorer EFS. In the multivariable analysis, positive MRD at EOC was solely associated with poor EFS (P < .001). Rapid pretransplant MRD clearance and tailored HSCT strategy in the MLL-10 trial resulted in a favorable outcome for infants with HR KMT2A-r ALL. However, considering the high rate of potentially life-threatening toxicities and the risk of late effects, its indication should be further restricted or even eliminated in the future by introducing more effective therapeutic modalities with minimal toxicities. This trial was registered at the University Hospital Medical Information Network Clinical Trials Registry (UMIN-CTR) as #UMIN000004801.

The role of allogeneic hematopoietic stem cell transplantation (HSCT) for infants with acute lymphoblastic leukemia (ALL) and KMT2Agene rearrangement (KMT2A-r) is controversial in terms of both its efficacy and potential for acute and late toxicities. In Japanese Pediatric Leukemia/Lymphoma Study Group trial MLL-10, by introducing intensive chemotherapy, indication of HSCT was restricted to patients with high-risk (HR) features only (KMT2A-r and either age <180 days or presence of central nervous system leukemia). Of the 56 HR patients, 49 achieved complete remission. Forty-three patients received HSCT in first remission including 38 patients receiving protocol-specified HSCT with conditioning consisting of individualized targeted doses of busulfan, etoposide, and cyclophosphamide. Three-year event-free survival (EFS) of 56.8% (95% confidence interval [CI], 42.4% to 68.8%) and overall survival of 80.2% (95% CI, 67.1% to 88.5%) were accomplished. Univariable analysis showed that Interfant-HR criteria and flow cytometric minimal residual disease (MRD; ≥0.01%), both at the end of induction and at the end of consolidation (EOC), were significantly associated with poorer EFS. In the multivariable analysis, positive MRD at EOC was solely associated with poor EFS (P< .001). Rapid pretransplant MRD clearance and tailored HSCT strategy in the MLL-10 trial resulted in a favorable outcome for infants with HR KMT2A-r ALL. However, considering the high rate of potentially life-threatening toxicities and the risk of late effects, its indication should be further restricted or even eliminated in the future by introducing more effective therapeutic modalities with minimal toxicities. This trial was registered at the University Hospital Medical Information Network Clinical Trials Registry (UMIN-CTR) as #UMIN000004801.

Hematopoietic stem cell transplantation (HSCT) is a curative treatment for life-threatening malignancies and related diseases. Recently, the long-term prognosis of HSCT during childhood has greatly improved; however, the late adverse effects of HSCT have been found to cause substantial morbidity among long-term survivors. Although metabolic complications, such as diabetes mellitus (DM) and hyperlipidemia (HL), are the major late effects of pediatric HSCT, the clinical details are not clarified sufficiently. From 1983 to 2013, 75 participants underwent HSCT in our institute because of malignant or other related diseases. We retrospectively evaluated metabolic complications of eligible 22 participants (14 men and 8 women), and their clinical backgrounds. Among 22 participants, 4 and 9 participants developed DM and HL after HSCT, respectively, and all participants with DM developed HL. None of the participants with DM were obese, and all had substantial insulin resistance. Total body irradiation (TBI) was performed in 10 participants, including 4 participants with DM and 5 participants with HL, revealing that TBI is an independent risk factor for DM. The age at TBI for participants with DM was significantly lower than that for participants without DM (p= 0.01), and all participants with DM received TBI before the age of 6. Our data suggested that TBI was a risk factor for DM after HSCT, and TBI before the age of six increased the possibility of DM without obesity.

Introduction:The authors developed an evaluation tool to measure changes in exercise participants' awareness of disaster risk and their disaster preparedness behaviors. To create the tool, a mechanism was modeled to visualize the process of changing people's crisis awareness and behavior and questions were developed for each of the twelve factors and two outcomes within the mechanism. In this study, we conducted a disaster exercise in the pharmacy department of Hospital A, one of the disaster base hospitals, and measured the effectiveness of the exercise using the tool.Method:In the disaster exercise, participants were asked to perform dispensing tasks on five dummy prescriptions using actual medicines, based on the assumption that the dispensing support system was out of order due to a major earthquake. Participants were paired up and dispensed as much as possible within a time limit of 30 minutes. Pre- and post-education sessions were conducted before and after the exercise. Respondents were asked to score each question on a 5-point scale at three time points: before the pre-education, immediately after the disaster exercise, and after post-education.Results:59 people, including 16 participants, responded to the questionnaire using the evaluation tool. The analysis of the evaluation results revealed that the disaster exercise increased the participants' crisis awareness. Furthermore, participants improved their scores on the questions on feelings of anxiety about the current situation, assumptions about the impact, sense of ownership, and fear of not acting, but no change was observed among non-participants. However, there was no significant difference in scores between the two groups regarding whether they had taken action for disaster preparedness in the period following the exercise.Conclusion:The exercise raised the participants' crisis awareness, but did not encourage them to change their behavior. Future research should consider ways to encourage staff members to take action to prepare for disasters.

Current research on stress pathology has revealed a set of molecular and cellular mechanisms through which psychosocial stress impairs brain function. However, there are few studies that have examined how chronic stress exposure alters neuronal activity patterns at a network level. Here, we recorded ensemble neuronal activity patterns of the cortico-hippocampal network from urethane-anesthetized mice that were subjected to repeated social defeat stress. In socially defeated mice, the magnitudes of local field potential signals, including theta, slow gamma, and fast gamma oscillations, were significantly reduced in the dentate gyrus, whereas they remained unchanged in the hippocampus and somatosensory cortex. In accordance with the vast majority of histological and biochemical studies, our evidence from electrophysiological investigations highlights the dentate gyrus as a key brain area that is primarily susceptible to stress-induced dysfunction.

Background/aimsTo assess the role of specific visual subfields in collisions with oncoming cars during simulated driving in patients with advanced glaucoma.MethodsNormal subjects and patients with glaucoma with mean deviation <–12 dB in both eyes (Humphrey Field Analyzer 24-2 SITA-S program) used a driving simulator (DS; Honda Motor, Tokyo). Two scenarios in which oncoming cars turned right crossing the driver's path were chosen. We compared the binocular integrated visual field (IVF) in the patients who were involved in collisions and those who were not. We performed a multivariate logistic regression analysis; the dependent parameter was collision involvement, and the independent parameters were age, visual acuity and mean sensitivity of the IVF subfields.ResultsThe study included 43 normal subjects and 100 patients with advanced glaucoma. And, 5 of the 100 patients with advanced glaucoma experienced simulator sickness during the main test and were thus excluded. In total, 95 patients with advanced glaucoma and 43 normal subjects completed the main test of DS. Advanced glaucoma patients had significantly more collisions than normal patients in one or both DS scenarios (p<0.001). The patients with advanced glaucoma who were involved in collisions were older (p=0.050) and had worse visual acuity in the better eye (p<0.001) and had lower mean IVF sensitivity in the inferior hemifield, both 0°–12° and 13°–24° in comparison with who were not involved in collisions (p=0.012 and p=0.034). A logistic regression analysis revealed that collision involvement was significantly associated with decreased inferior IVF mean sensitivity from 13° to 24° (p=0.041), in addition to older age and lower visual acuity (p=0.018 and p<0.001).ConclusionsOur data suggest that the inferior hemifield was associated with the incidence of motor vehicle collisions with oncoming cars in patients with advanced glaucoma.

Trauma to primary teeth can cause dilaceration of permanent teeth.

Translocation of the mixed-lineage leukemia (MLL) gene with AF4, AF9, or ENL results in acute leukemia with both lymphoid and myeloid involvement. We characterized leukemia-initiating cells (LICs) in primary infant MLL-rearranged leukemia using a xenotransplantation model. In MLL-AF4 patients, CD34+CD38+CD19+ and CD34−CD19+ cells initiated leukemia, and in MLL-AF9 patients, CD34−CD19+ cells were LICs. In MLL-ENL patients, either CD34+ or CD34− cells were LICs, depending on the pattern of CD34 expression. In contrast, in patients with these MLL translocations, CD34+CD38−CD19−CD33− cells were enriched for normal hematopoietic stem cells (HSCs) with in vivo long-term multilineage hematopoietic repopulation capacity. Although LICs developed leukemic cells with clonal immunoglobulin heavy-chain (IGH) rearrangement in vivo, CD34+CD38−CD19−CD33− cells repopulated recipient bone marrow and spleen with B cells, showing broad polyclonal IGH rearrangement and recipient thymus with CD4+ single positive (SP), CD8+ SP, and CD4+CD8+ double-positive (DP) T cells. Global gene expression profiling revealed that CD9, CD32, and CD24 were over-represented in MLL-AF4, MLL-AF9, and MLL-ENL LICs compared with normal HSCs. In patient samples, these molecules were expressed in CD34+CD38+ and CD34− LICs but not in CD34+CD38−CD19−CD33− HSCs. Identification of LICs and LIC-specific molecules in primary human MLL-rearranged acute lymphoblastic leukemia may lead to improved therapeutic strategies for MLL-rearranged leukemia.

Translocation of the mixed-lineage leukemia (MLL) gene with AF4, AF9, or ENLresults in acute leukemia with both lymphoid and myeloid involvement. We characterized leukemia-initiating cells (LICs) in primary infant MLL-rearranged leukemia using a xenotransplantation model. In MLL-AF4 patients, CD34’CD38’CD19’and CD34−CD19’cells initiated leukemia, and in MLL-AF9 patients, CD34−CD19’cells were LICs. In MLL-ENL patients, either CD34’or CD34−cells were LICs, depending on the pattern of CD34 expression. In contrast, in patients with these MLL translocations, CD34’CD38−CD19−CD33−cells were enriched for normal hematopoietic stem cells (HSCs) with in vivo long-term multilineage hematopoietic repopulation capacity. Although LICs developed leukemic cells with clonal immunoglobulin heavy-chain (IGH) rearrangement in vivo, CD34’CD38−CD19−CD33−cells repopulated recipient bone marrow and spleen with B cells, showing broad polyclonal IGH rearrangement and recipient thymus with CD4’single positive (SP), CD8’SP, and CD4’CD8’double-positive (DP) T cells. Global gene expression profiling revealed that CD9, CD32, and CD24 were over-represented in MLL-AF4, MLL-AF9,and MLL-ENLLICs compared with normal HSCs. In patient samples, these molecules were expressed in CD34’CD38’and CD34−LICs but not in CD34’CD38−CD19−CD33−HSCs. Identification of LICs and LIC-specific molecules in primary human MLL-rearranged acute lymphoblastic leukemia may lead to improved therapeutic strategies for MLL-rearranged leukemia.

Hematopoietic stem cell transplantation (HSCT) for dyskeratosis congenita (DC) is challenging due to severe treatment-related adverse effects. Development of pulmonary fibrosis or veno-occlusive disease is well described in DC. However, neurological complication after HSCT has not been reported. A 9-year-old Japanese male with DC harboring the TINF2mutation received reduced-intensity HSCT. Unfortunately, patient developed posterior reversible encephalopathy syndrome–like symptoms plausibly result by combination of thrombotic microangiopathy, graft-versus-host disease, and persistent hypertension and has been persisted mental retardation. Therefore, to decrease risk in DC cases after HSCT, strict control of hypertension, graft-versus-host disease, and thrombotic microangiopathy is required.

A porcine model of severe combined immunodeficiency (SCID) promises to facilitate human cancer studies, the humanization of tissue for xenotransplantation, and the evaluation of stem cells for clinical therapy, but SCID pigs have not been described. We report here the generation and preliminary evaluation of a porcine SCID model. Fibroblasts containing a targeted disruption of the X-linked interleukin-2 receptor gamma chain gene, Il2rg, were used as donors to generate cloned pigs by serial nuclear transfer. Germline transmission of the Il2rgdeletion produced healthy Il2rg+/−females, while Il2rg−/Ymales were athymic and exhibited markedly impaired immunoglobulin and T and NK cell production, robustly recapitulating human SCID. Following allogeneic bone marrow transplantation, donor cells stably integrated in Il2rg−/Yheterozygotes and reconstituted the Il2rg−/Ylymphoid lineage. The SCID pigs described here represent a step toward the comprehensive evaluation of preclinical cellular regenerative strategies.

Outcome of children with acute lymphoblastic leukemia (ALL) has improved over the years, but not for those with multiple recurrences because of high therapy resistance and heavily pretreated history that potentially cause physical damages. We describe the case of an 11-year-old boy with a third relapse of ALL and a history of 2 allogeneic bone marrow transplantations. He was successfully treated with clofarabine combination chemotherapy and achieved a fourth remission at 16 months following haploidentical bone marrow transplantation with conditioning regimen of clofarabine and busulfan. Clofarabine/busulfan conditioning might be a preferable option for children with multiple recurrent ALL, and warrants further investigation.

Background KMT2A-rearranged acute lymphoblastic leukemia (KMT2A-r ALL) is a rare and dismal disease in infants. Despite restriction of the indication of allogeneic hematopoietic stem cell transplantation to the high-risk group (patients aged <180 days with KMT2A-r ALL or central nervous system involvement), adoption of an Interfant-06-based induction therapy with stricter age-related dosing followed by COG AALL0631-based post-remission chemotherapy with additional administration of high-dose cytarabine in the early intensification phase led to rapid clearance of minimal residual disease (MRD) in the Japanese Pediatric Leukemia/Lymphoma Study Group (JPLSG) MLL-10 trial. The MLL-10 trial demonstrated an improved outcome of 66.2% in 3-year event-free survival (EFS) among infants with KMT2A-r ALL (Tomizawa D. Blood 2021). As the Interfant-06 study showed an association between the expression levels of myeloid markers (MM) and poor MRD clearance at end of induction (EOI) and a high relapse rate (Stutterheim J, J Clin Oncol.2021), we analyzed the significance of MM expression in the MLL-10 cohort and its association with prognosis.

No relevant conflicts of interest to declare.

Abstract PZT films were fabricated using various targets of Pb(ZrxTi1 - x)O3 with Zr/Ti ratios of 70/30, 58/42, 52/48, 45/55 and 30/70, and with excess PbO of 20 wt% on Pt/Ti/SiO2/Si(100) substrates. The rosette structure was observed in the films derived from the target with a Zr/Ti ratio of 70/30 and disappeared with increasing titanium composition. The observations on surface and cross-sectional microstructure were consistent with a higher perovskite nucleation for the higher Ti content films. The PZT films derived from the target with a Zr/Ti ratio of 45/55 had a polycrystalline columnar microstructure extending throughout the thickness of the film and no pyrochlore phase on the surface was observed. The PZT films derived from the target with a Zr/Ti ratio of 45/55 exhibited better electric properties than those derived from the target with a Zr/Ti ratio of 52/48.

Epoxy resins used for reinforcement of bridges and buildings are explored in the light of both curing rates and mechanical properties when resins are contaminated with water in outdoor construction. The developed resin is composed of a conventional resin of bisphenol A diglycidyl ether and a hardener with a polyoxipropyldiamine base. Curing rates were obtained by time variation of the near infrared absorbance of amine groups in the hardener at various water contents. They obeyed the second-order reaction law with respect to the hardener, of which the activation energy was 70 kJ mol⁻¹. Water increased the reaction rate. Mechanical properties such as ultimate tensile strength, adhesive shear stress, and flexural strength were measured at various water contents for the developed epoxy resin and the commercially available low-temperature epoxy resin. The developed cured resin shows not only higher mechanical strengths but also much less deterioration by water than the conventional cured resin. © 2000 John Wiley & Sons, Inc. J Appl Polym Sci 79: 214–220, 2001

The superfluid 3He B phase, one of the oldest unconventional fermionic condensates experimentally realized, is recently predicted to support Majorana fermion surface states. Majorana fermion, which is characterized by the equivalence of particle and antiparticle, has a linear dispersion relation referred to as the Majorana cone. We measured the transverse acoustic impedance $Z$ of the superfluid 3He B phase changing its boundary condition and found a growth of peak in $Z$ on a higher specularity wall. Our theoretical analysis indicates that the variation of $Z$ is induced by the formation of the cone-like dispersion relation and thus confirms the important feature of the Majorana fermion in the specular limit.

Background

No relevant conflicts of interest to declare.

Acute lymphoblastic leukemia (ALL) with rearrangement of the mixed-lineage leukemia (MLL) gene frequently affects infants and is associated with a poor prognosis. Standard treatment protocol for infant MLL-rearranged ALL (MLL-ALL) includes glucocorticoids (GCs). However, resistance to GCs remains a major problem. Therefore, it is important to find new treatment strategies that overcome GC resistance in MLL-ALL.

Kada: Bayer Yakuhin: Other: personal fees for a member of independent data monitoring committee of clinical trials, outside of the submitted work..

Monolayer molybdenum disulfide's (MoS2) direct band gap nature makes it a good platform for realizing atomically thin optoelectronic devices. However, an issue is its low luminescence brightness. In this research, we demonstrate a strategy to achieve strong photoluminescence (PL) of monolayer MoS2, by treatment with a redox-active molecule, fluoranil. An important finding is that the factor of PL enhancement depends strongly on the solvent used and the PL changes by more than one order of magnitude. This work is useful for harnessing the strong optical properties of MoS2by the combination of oxidizing molecules and engineering the solvent used.

Spatial firing of hippocampal place cells varies depending on the animal’s behavior relative to its goals. Here, rats were trained to approach visually guided reward ports in a two-dimensional open field. Hippocampal place cells encoded two independent pieces of information, spatial representation and goal-directed representation, by amplifying firing rates within their place fields specifically while the animal was moving toward a specific goal location. Irrespective of running speed and direction, substantial place-selective firing was observed that sustained a basal spatial map independent of goal-directed signals. When animals were allowed to freely forage in the field, in-field firing rates similarly increased when the animals transiently ran toward remembered goal locations. Disruption of medial septal activity significantly decreased goal-directed firing while maintaining spatial representation patterns. The findings indicate that the integrated encoding of spatial and goal-directed signals by hippocampal circuits is crucial for flexible spatial navigation to a goal location.

[Background] Infant acute lymphoblastic leukemia (ALL) accounts for less than 5% of childhood leukemia, and is characterized by Mixed lineage leukemia (MLLalso called KMT2A) rearrangements found in approximately 80% of patients. Also found in 5-10% of ALL in older children and adults, MLL-rearrangement positivity is highly associated with poor outcome in ALL; there is an urgent need for molecular findings of potential therapeutic targets and/or risk stratification markers, which can be translated into the clinical practice. Recently, the mechanisms that MLL fusion proteins recruit epigenetic regulators, including histone H3 lysine 79 methyltransferase DOT1L and BET family histone readers, to activate the transcription of target genes have been reported, suggesting epigenetic dysregulation should play a central role in the leukemogenesis. However, DNA-level methylation profiles of MLL-rearranged leukemia and their associations with gene expression profiles are not fully characterized.

Ogawa: Kan research institute: Consultancy, Research Funding; Takeda Pharmaceuticals: Consultancy, Research Funding; Sumitomo Dainippon Pharma: Research Funding.

[Background] Mixed lineage leukemia (MLLalso called KMT2A) rearrangement-positive leukemia is one of the most aggressive types of leukemia. It is diagnosed predominantly in infants and typically shows a multi-lineage phenotype. Since current chemotherapy fails in more than 50% of infantile acute lymphoblastic leukemia (ALL) with MLL-rearrangement, a better understanding of biological features of the disease is important in order to develop more specific and successful treatment strategies. Despite the evident biological and clinical significance of MLL-rearrangement, it has also been shown in vitro and in vivo that MLL-rearrangement is not sufficient to induce full leukemic transformation, indicating additional hits are required for complete leukemogenesis.

Off Label Use: Off-label use of CliniMACS purified CD34+ cells.

Dose adjustment of busulfan (BU) based on individual pharmacokinetics (PK) has been established as an important clinical tool in conditioning of hematopoietic stem cell transplantation (HSCT). Wide interindividual variety of achievable BU concentration in infants by recommended formula is a problematic issue. Nevertheless, there is no sizable BU PK data in infants. We report here the characteristics of BU PK data in infants with MLL gene-rearranged acute lymphoblastic leukemia (MLL-r ALL) and its relevance to the outcome of HSCT.

A pyrrolo-pyrimidine kinase inhibitor, RK-20449, eliminates chemotherapy-resistant human primary AML stem cells in vivo.

No relevant conflicts of interest to declare.

Abstract 1422