Reduced-intensity allogenic transplantation for children and adolescents with Philadelphia chromosome-positive acute lymphoblastic leukemia.

Survival rates of patients with Philadelphia chromosome-positive ALL (Ph+ALL) have improved considerably with the introduction of tyrosine kinase inhibitors (TKI); however, hematopoietic stem cell transplantation (HSCT) continues to play an important role. Reduced-intensity conditioning (RIC) regimens have been widely applied particularly for older patients, but their validity for children and adolescents with Ph+ALL has not been investigated. In this study, data from patients receiving HSCT for de novo Ph+ALL in first or second remission at ages younger than 25 years and with a history of pre-HSCT TKI therapy were retrospectively collected through the nationwide registry in Japan. In 265 patients who received myeloablative conditioning (MAC) and 33 patients receiving RIC, 5-year leukemia-free survival (LFS) rates were 67.3% and 79.8%, respectively (p = 0.142). Multivariate analysis of LFS, focusing on patients with good performance status, identified RIC as a significant prognostic factor for LFS (hazard ratio 0.32, p = 0.032), as well as older age, higher leukocyte count at diagnosis, and disease with additional chromosomal abnormalities. These trends were similar when we focused on patients who received prophylactic post-HSCT TKI treatment, as 5-year LFS was 81.0% for MAC and 84.4% for RIC (p = 0.748). In summary, HSCT with RIC regimen showed at least comparable LFS to HSCT with MAC regimen, and RIC was an independent favorable prognostic factor on multivariate analysis adjusting potential prognostic factors. While patient numbers were limited, our data suggest that RIC may be safely applied in this group, particularly combined with prophylactic post-HSCT TKI maintenance therapy.

Assessing the Usefulness of Ultrasonography for the Diagnosis and Evaluation of Intra-Orbital Lesions in Pediatric Patients: A Retrospective Analysis.

OBJECTIVES: To assess the usefulness of ultrasonography in the diagnosis and evaluation of extraocular intra-orbital lesions in pediatric patients. METHODS: Twenty-three pediatric patients with intra-orbital lesions who underwent both ultrasound and computed tomography/magnetic resonance imaging (CT/MRI) were included. The following parameters were evaluated using ultrasound: 1) lesion detection rate (presence or absence of lesions), 2) lesion characteristics, 3) lesion location (extraconal or intraconal), and 4) the lesion longest linear dimensions, and these were compared using Fisher's exact test and Mann-Whitney U test. RESULTS: Two lesions could not be detected using ultrasound; in the other 21 cases, the lesion characteristics diagnosed by ultrasound were correct. Diagnostic accuracy of detection and characteristics assessment using ultrasound were 91.3% and 91.3%, respectively. The lesion location was not significantly different between the two groups (intraconal/extraconal in those detected using ultrasound versus those in the absence on ultrasound = 7/14 versus 0/2, P > .999); however, in two cases that were not detected on ultrasound, the lesions were located at extraconal. Lesions that were small in longest linear dimensions on CT/MRI were not detected using ultrasound (the longest linear dimensions in lesions detected using ultrasound versus that in the absence of ultrasound: 29.5 ± 8.2 [range, 13-46] versus 10 and 11 mm, P = .043). CONCLUSIONS: Ultrasonography proved to be useful for visualizing and evaluating intra-orbital lesions except for lesions that were relatively small in size. Therefore, although ultrasound could not detect lesions located behind bone and bone invasion, it could be used for diagnosing and selecting treatment strategies for intra-orbital lesions.

Regular prophylaxis with activated prothrombin complex concentrates in pediatric hemophilia.

BACKGROUND: Regular prophylaxis with activated prothrombin complex concentrates (aPCCs) is effective in adult patients with hemophilia with inhibitors; however, data in children are scarce. METHODS: This was a single-center retrospective study at Saitama Children's Medical Center. Patients with severe and moderate hemophilia with inhibitors aged <15 years at the start of aPCCs prophylaxis were included. Medical records were retrospectively reviewed. RESULTS: We treated nine pediatric patients with hemophilia with inhibitors (median age, 1.9 years; age range, 1.3-12.9 years; inhibitor titers before treatment with aPCCs, 5.9-69 BU/mL) using prophylactic aPCCs (doses, 50-100 U/kg; 2-3 times/week). The median prophylactic period was 13 months (range: 5-31 months). The median annualized bleeding rate (ABR) during prophylactic treatment with aPCCs was 2 (range, 0-17). In four patients, ABR was reduced by 19%-100% with prophylactic aPCCs compared to on-demand aPCCs. An adverse effect of treatment was that a patient with hemophilia B developed nephrotic syndrome 34 months after starting regular prophylaxis with aPCCs. CONCLUSIONS: Regular prophylactic aPCCs reduced the ABR even in younger children with hemophilia A and B. Serious adverse events include nephrotic syndrome, which requires caution.

Rare TCF3 variants associated with pediatric B cell acute lymphoblastic leukemia.

Germline genetic variants influence development of pediatric B cell acute lymphoblastic leukemia (B-ALL). Genome-wide association studies (GWAS) have identified several pediatric B-ALL susceptibility loci. IKZF1 and PAX5, transcription factors involved in B cell development, have been reported as susceptibility genes for B-ALL development. Therefore, we hypothesized that rare variants of genes involved in B cell development would be candidate susceptibility loci for pediatric B-ALL. Thus, we sequenced TCF3, a key transcription factor gene involving in B cell development. Saliva DNA from 527 pediatric patients with pediatric B-ALL in remission who were registered with the Tokyo Children's Cancer Study Group (TCCSG) were examined. As a TCF3 gene-based evaluation, the numbers of rare deleterious germline TCF3 sequence variants in patients with pediatric B-ALL were compared with those in cancer-free individuals using data in public databases. As a TCF3 single-variant evaluation, the frequencies of rare deleterious germline TCF3 sequence variants in patients with pediatric B-ALL were also compared with those in control data. TCF3 gene-based analysis revealed significant associations between rare deleterious variants and pediatric B-ALL development. In addition, TCF3 variant-based analysis showed particularly strong association between variant rs372168347 (three in 521 TCCSG and three in the 15780 gnomAD whole genome analysis cohort, p = 0.0006) and pediatric B-ALL development. TCF3 variants are known to influence B cell maturation and may increase the risk of preleukemic clone emergence.

Effectiveness of mHealth consultation services for preventing postpartum depressive symptoms: a randomized clinical trial.

BACKGROUND: Although many conventional healthcare services to prevent postpartum depression are provided face-to-face, physical and psychosocial barriers remain. These barriers may be overcome by using mobile health services (mHealth). To examine the effectiveness of mHealth professional consultation services in preventing postpartum depressive symptoms in real-world settings, we conducted this randomized controlled trial in Japan, where universal free face-to-face perinatal care is available. METHODS: This study included 734 pregnant women living in Yokohama city who could communicate in Japanese, recruited at public offices and childcare support facilities. The participants were randomized to the mHealth group (intervention, n = 365), where they could use a free app-based mHealth consultation service with gynecologists/obstetricians, pediatricians, and midwives whenever and as many times as they wanted between 6 p.m. and 10 p.m. on weekdays throughout their pregnancy and postpartum periods (funded by the City of Yokohama government) or the usual care group (control, n = 369). The primary outcome was the risk of elevated postpartum depressive symptoms, defined as Edinburgh Postnatal Depression Scale score ≥ 9. Secondary outcomes were self-efficacy, loneliness, perceived barriers to healthcare access, number of clinic visits, and ambulance usage. All outcomes were collected three months post-delivery. We also conducted subgroup analyses assessing the differences in the treatment effect by sociodemographic status. RESULTS: Most women completed all questionnaires (n = 639 of 734, response rate: 87%). The mean baseline age was 32.9 ± 4.2 years, and 62% were primipara. Three months post-delivery, women in the mHealth group had a lower risk of elevated postpartum depressive symptoms (47/310 [15.2%]) compared to the usual care group (75/329 [22.8%], risk ratio: 0.67 [95% confidence interval: 0.48-0.93]). Compared with the usual care group, women in the mHealth group had higher self-efficacy, less loneliness, and fewer perceived barriers to healthcare access. No differences were observed in the frequency of clinic visits or ambulance usage. Furthermore, in the subgroup analyses, we did not find differences in the treatment effect by sociodemographic status. CONCLUSIONS: Local government-funded mHealth consultation services have a preventive effect on postpartum depressive symptoms, removing physical and psychological barriers to healthcare access in real-world settings. TRIAL REGISTRATION: UMIN-CTR identifier: UMIN000041611. Registered 31 August 2021.

Relationship between the timing of chemotherapy and surgical complications following surgical biopsy in children with malignant solid tumors.

BACKGROUND: Biopsies for diagnosis before chemotherapy is common in children with malignant solid tumors. Wound healing is delayed by chemotherapy; however, the ideal interval between biopsy and chemotherapy remains unknown. We aimed to summarize the relationship between chemotherapy timing and postoperative surgical complications. PROCEDURE: We retrospectively reviewed patients with malignant solid tumors who underwent chemotherapy after surgical biopsy at our institution between January 2014 and August 2020. The primary outcomes were postoperative surgical complications (within 30 days) and the timing of chemotherapy. RESULTS: Forty-three patients were analyzed. The types of tumors were neuroblastoma (n = 20), hepatoblastoma (n = 10), Ewing sarcoma (n = 5), germ cell tumor (n = 3), angiosarcoma (n = 1), clear cell sarcoma (n = 1), ganglioneuroblastoma (n = 1), rhabdoid tumor (n = 1), and rhabdomyosarcoma (n = 1). The operative procedures were thoracoscopy (n = 5), laparotomy (n = 17), laparoscopy (n = 14), and superficial (n = 7). The median time [range] to chemotherapy after biopsy was 4 [0-21] days. No surgical complications occurred before chemotherapy, and two (4.7%) patients experienced complications after chemotherapy. These included postoperative hemorrhage (grade 3) and surgical site infection (grade 1). Chemotherapy was initiated 1 and 6 days after biopsy, respectively, in these cases. Complications occurred 10 and 23 days after biopsy, respectively. CONCLUSION: The rate of postoperative surgical complications related to biopsy seems acceptable, even when chemotherapy was initiated in the early postoperative period. Early initiation of chemotherapy after biopsy may be a suitable option, particularly in children with bulky or symptomatic malignant solid tumors.

Married women's decision to delay childbearing, and loneliness, severe psychological distress, and suicidal ideation under crisis: online survey data analysis from 2020 to 2021.

BACKGROUND: The COVID-19 pandemic has affected every aspect of our lives, including the decision to become pregnant. Existing literature suggests that infertility and the decision to delay childbearing at a younger age are associated with a lower level of well-being and regrets when women start to desire a baby. Thus, the decision to delay childbearing due to the pandemic could negatively affect the well-being of women. This study focuses on how pregnancy decisions affect the well-being of women during the COVID-19 pandemic. METHODS: From the Japan COVID-19 and Society Internet Survey, a nationally representative web-based survey, 768 observations of married women aged 18 to 50 years who had the intention of getting pregnant during the pre-pandemic period (conducted in 2020 and 2021) were used. Loneliness, severe psychological distress, and suicidal ideation were used as well-being indicators. For pooled data, a generalised estimated equation (GEE) model was used to estimate how pregnancy decision related to well-being indicators. For a sub-analysis, the sample was divided by the survey year and a Poisson regression model was used. RESULTS: The GEE analysis showed an association between delaying childbearing and severe psychological distress, with the prevalence ratio (PR) being 2.06 [95% CI (1.40-3.03)]. Furthermore, loneliness and suicidal ideation that occurred after the beginning of the pandemic were significantly related to the decision to delay childbearing-1.55 [95% CI (1.03,2.34)] and 2.55 [95% CI (1.45-4.51)], respectively. Moreover, these PRs were larger for 2021 compared to 2020. CONCLUSION: During the COVID-19 pandemic, approximately one-fifth of married women who had childbearing intentions before the pandemic decided to postpone pregnancy. They exhibited a deteriorated mental health state. Furthermore, the negative associations were larger in 2021 compared to 2020. Loneliness has negative consequences for both mental and physical health, as well as elevated severe psychological distress and suicidal ideation among those who decided to postpone pregnancy. Therefore, the current results should not be overlooked by society.

Remote Communication and Loneliness During the COVID-19 Pandemic: Cross-Sectional Study.

BACKGROUND: Although remote communication technologies have been widely used to maintain connections with others against interpersonal contact restrictions and exacerbated loneliness during the COVID-19 pandemic, it is unclear whether and what types of remote communication technologies are effective in mitigating loneliness. OBJECTIVE: This study aimed to investigate the association between remote communication and loneliness when face-to-face meetings with others were strongly prohibited and whether this association varied across types of communication tools, age, and gender. METHODS: We used cross-sectional data from the Japan COVID-19 and Society Internet Survey conducted from August to September 2020. From registered panelists of the research agency, 28,000 randomly sampled participants completed the survey on the website. We created 2 study cohorts who stopped meeting with family members living apart and friends during the pandemic. We categorized whether participants had technology-based remote communication (voice calling, text messaging, and video calling) with family and friends. Loneliness was assessed using the 3-item University of California, Los Angeles Loneliness Scale. We used a modified Poisson regression model to investigate the association between loneliness and remote communication with family members living apart or friends. We also conducted subgroup analyses based on age and gender. RESULTS: A total of 4483 participants stopped meeting with family members living apart, and 6783 participants stopped meeting with friends during the COVID-19 pandemic. Remote communication with family members living apart did not show an association with loneliness, whereas remote communication with friends was associated with a low prevalence of loneliness (family: adjusted prevalence ratio [aPR]=0.89, 95% CI 0.74-1.08; P=.24 and friends: aPR=0.82, 95% CI 0.73-0.91; P<.001). From analyses by tools, voice calling was associated with low loneliness (family: aPR=0.88, 95% CI 0.78-0.98; P=.03 and friends: aPR=0.87, 95% CI 0.80-0.95; P=.003). Similarly, text messaging was associated with low loneliness (family: aPR=0.82, 95% CI 0.69-0.97; P=.02 and friends: aPR=0.81, 95% CI 0.73-0.89; P<.001). However, we did not find an association between video calling and loneliness (family: aPR=0.88, 95% CI 0.75-1.02; P=.09 and friends: aPR=0.94, 95% CI 0.85-1.04; P=.25). Text messaging with friends was associated with low loneliness regardless of age, whereas voice calling with family or friends was associated with low loneliness only among participants aged ≥65 years. An association between remote communication with friends and low loneliness was found regardless of the type of remote communication tool among men, whereas it was found only for text messaging with friends among women. CONCLUSIONS: In this cross-sectional study of adults in Japan, remote communication, especially via voice calling and text messaging, was associated with low loneliness. Promoting remote communication may reduce loneliness when face-to-face contact is restricted, which should be the subject of future research.

Impact of the COVID-19 pandemic on pregnancy postponement - evidence from Japan.

Japan has faced a decline in fertility since the coronavirus disease 2019 (COVID-19) pandemic. This study aimed to investigate the rate of pregnancy postponement and its contributing factors, with a particular focus on economic- and COVID-19 infection-related indicators. This study used data from 768 observations of married women aged 18 to 50 years with pregnancy intentions. The data were obtained from two rounds of a large web-based survey conducted by the Japan COVID-19 and Society Internet Survey (JACSIS) in 2020 and 2021. A generalised estimating equation (GEE) model was employed, as well as Poisson regression models for sub-sample analysis divided by year to estimate the year differential magnitude of the contributing factors' impacts. Approximately 20% of married women with childbearing intentions postponed their childbearing. The analyses revealed that declining income and anxiety about future household finances were significantly related to delayed childbearing, while fear of COVID-19 and infection rate were not. Additionally, the adverse effects of unfavourable economic conditions were stronger in 2021. Notably, age did not influence the decision of pregnancy postponement. Older women postponed pregnancy just as much as younger women. In conclusion, this study confirmed that the COVID-19 pandemic, particularly its related adverse economic conditions, contributed to Japan's current baby bust. Considering that advanced maternal age is already common in Japan, this decreased fertility may result in the long-term negative consequence of further population decline.

Useful sonographic findings for diagnosing dermal metastases of rhabdomyosarcoma.

Rhabdomyosarcoma developing in deep locations, such as the genitourinary tract, and perianal and perineal regions, symptoms may be obscure. Dermal rhabdomyosarcoma metastases may be first symptom of that and those arise in the subcutaneous fat tissue, presenting as a high echoic area surrounded by a low echoic area, accompanied by a high echoic peripheral area. These sonographic findings might indicate an aggressive malignant disease, and that would be useful to differentiate from other dermal lesions.

Exploring the Impact of Intermolecular Interactions on the Glassy Phase Formation of Twist-Bend Liquid Crystal Dimers: Insights from Dielectric Studies.

The formation of the nematic to twist-bend nematic (NTB) phase has emerged as a fascinating phenomenon in the field of supramolecular chemistry, based on complex intermolecular interactions. Through a careful analysis of molecular structures and dynamics, we elucidate how these intermolecular interactions drive the complex twist-bend modulation observed in the NTB. The study employs broadband dielectric spectroscopy spanning frequencies from 10 to 2 × 109 Hz to investigate the molecular orientational dynamics within the glass-forming thioether-linked cyanobiphenyl liquid crystal dimers, namely, CBSC7SCB and CBSC7OCB. The experimental findings align with theoretical expectations, revealing the presence of two distinct relaxation processes contributing to the dielectric permittivity of these dimers. The low-frequency relaxation mode is attributed to an "end-over-end rotation" of the dipolar groups parallel to the director. The high-frequency relaxation mode is associated with precessional motions of the dipolar groups about the director. Various models are employed to describe the temperature-dependent behavior of the relaxation times for both modes. Particularly, the critical-like description via the dynamic scaling model seems to give not only quite good numerical fittings, but also provides a consistent physical picture of the orientational dynamics in accordance with findings from infrared (IR) spectroscopy. Here, as the longitudinal correlations of dipoles intensify, the m1 mode experiences a sudden upsurge in enthalpy, while the m2 mode undergoes continuous changes, displaying critical mode coupling behavior. Interestingly, both types of molecular motion exhibit a strong cooperative interplay within the lower temperature range of the NTB phase, evolving in tandem as the material's temperature approaches the glass transition point. Consequently, both molecular motions converge to determine the glassy dynamics, characterized by a shared glass transition temperature, Tg.

Social isolation, loneliness, and their correlates in older Japanese adults.

BACKGROUND: Loneliness and social isolation are elevated in older adults and associated with a range of detrimental outcomes. Despite this, there has been little research on these phenomena or on similarities and differences in their occurrence or combination in older Japanese adults. The current study aims to (i) determine what factors are associated with social isolation and loneliness among older adults in Japan; and (ii) describe the characteristics of individuals who are socially isolated but not lonely, as well as those who feel lonely but are not socially isolated. METHODS: Data were analysed from 13 766 adults aged ≥65 years who participated in the 2019 wave of the Japan Gerontological Evaluation Study. Poisson regression analysis was used to examine associations. RESULTS: Among older Japanese adults, the attributes of higher age, male gender, lower socioeconomic status, being a welfare recipient, and having depressive symptoms were associated with social isolation, while lower socioeconomic status, unemployment, welfare receipt, and poor physical and mental health were associated with loneliness. In addition, better educated, and mentally and physically healthy people were less likely to feel lonely even when socially isolated, while people who were not working and who had mental or physical health problems were more likely to feel lonely even if they were not socially isolated. DISCUSSION: Our results indicate that in order to reduce unwanted social isolation and loneliness among older Japanese adults, in the first instance the focus should be on those individuals who are socioeconomically disadvantaged and unhealthy.

Alteration of the immune environment in bone marrow from children with recurrent B cell precursor acute lymphoblastic leukemia.

Due to the considerable success of cancer immunotherapy for leukemia, the tumor immune environment has become a focus of intense research; however, there are few reports on the dynamics of the tumor immune environment in leukemia. Here, we analyzed the tumor immune environment in pediatric B cell precursor acute lymphoblastic leukemia by analyzing serial bone marrow samples from nine patients with primary and recurrent disease by mass cytometry using 39 immunophenotype markers, and transcriptome analysis. High-dimensional single-cell mass cytometry analysis elucidated a dynamic shift of T cells from naïve to effector subsets, and clarified that, during relapse, the tumor immune environment comprised a T helper 1-polarized immune profile, together with an increased number of effector regulatory T cells. These results were confirmed in a validation cohort using conventional flow cytometry. Furthermore, RNA transcriptome analysis identified the upregulation of immune-related pathways in B cell precursor acute lymphoblastic leukemia cells during relapse, suggesting interaction with the surrounding environment. In conclusion, a tumor immune environment characterized by a T helper 1-polarized immune profile, with an increased number of effector regulatory T cells, could contribute to the pathophysiology of recurrent B cell precursor acute lymphoblastic leukemia. This information could contribute to the development of effective immunotherapeutic approaches against B cell precursor acute lymphoblastic leukemia relapse.

Prominence of NUDT15 genetic variation associated with 6-mercaptopurine tolerance in a genome-wide association study of Japanese children with acute lymphoblastic leukaemia.

Inherited genetic variation is associated with 6-mercaptopurine (6-MP) dose reduction and frequent toxicities induced by 6-MP. However, the tolerable dose for 6-MP is not fully predicted by the known variation in NUDT15 and TPMT among Asian children with acute lymphoblastic leukaemia (ALL). We performed a genome-wide association study (GWAS) related to 6-MP dose among Japanese children with ALL. This GWAS comprised 224 patients previously enrolled in Tokyo Children's Cancer Study Group clinical studies with replication attempted in 55 patients. Genome-wide single nucleotide polymorphism (SNP) genotypes were evaluated for association with average 6-MP dose during the initial 168 days of maintenance therapy. Possible associations were observed across five gene-coding regions, among which only variants at 13q14.2 were significant and replicated genome-wide (rs116855232, NUDT15, ß = -10.99, p = 3.7 × 10-13 ). Notable findings were observed for variants in AFF3 (rs75364948, p = 2.05 × 10-6 ) and CHST11 (rs1148407, p = 2.09 × 10-6 ), but were not replicated possibly due to small numbers. A previously reported candidate SNP in MTHFR was associated with higher average 6-MP dose (rs1801133, p = 0.045), and FOLH1 (rs12574928) was associated in an evaluation of candidate regions (padjust  = 0.013). This study provides strong evidence that rs116855232 in NUDT15 is the genetic factor predominantly associated with 6-MP tolerable dose in children in Japan.

Low NUDT15 expression levels due to biallelic NUDT15 variants and 6-mercaptopurine intolerance.

6-Mercaptopurine (6-MP) is widely used for the treatment of paediatric leukaemia and lymphoma. Recently, germline variants in the NUDT15 gene have been identified as one of the major genetic causes for 6-MP-associated adverse effects such as myelosuppression. Patients with hypomorphic NUDT15 variants accumulate excessive levels of DNA-incorporated thioguanine in white blood cells, resulting in severe myelosuppression. Although preclinical studies suggest that these variants may influence the protein stability of NUDT15, this has not been directly characterised in patients. In this study, we report the development of a series of novel monoclonal antibodies against NUDT15, using which we quantitatively assessed NUDT15 protein levels in 37 patients with acute lymphoblastic leukaemia treated with 6-MP, using sandwich enzyme-linked immunosorbent assay (ELISA). The NUDT15 genotype was highly correlated with its protein levels (p < 0.0001), with homozygous and compound heterozygous patients showing exceedingly low NUDT15 expression. There was a positive correlation between NUDT15 protein level and 6-MP tolerance (r = 0.631, p < 0.0001). In conclusion, our results point to low NUDT15 protein abundance as the biochemical basis for NUDT15-mediated 6-MP intolerance, thus providing a phenotypic readout of inherited NUDT15 deficiency.

A risk-stratified therapy for infants with acute lymphoblastic leukemia: a report from the JPLSG MLL-10 trial.

The prognosis for infants with acute lymphoblastic leukemia (ALL), particularly those with KMT2A gene rearrangement (KMT2A-r), is dismal. Continuous efforts have been made in Japan to investigate the role of hematopoietic stem cell transplantation (HSCT) for infants with KMT2A-r ALL, but improvement in outcome was modest. In the Japanese Pediatric Leukemia/Lymphoma Study Group MLL-10 trial, infants with ALL were stratified into 3 risk groups (low risk [LR], intermediate risk [IR], and high risk [HR]) according to KMT2A status, age, and presence of central nervous system leukemia. Children's Oncology Group AALL0631 modified chemotherapy with the addition of high-dose cytarabine in early intensification was introduced to KMT2A-r patients, and the option of HSCT was restricted to HR patients only. The role of minimal residual disease (MRD) was also evaluated. Ninety eligible infants were stratified into LR (n = 15), IR (n = 19), or HR (n = 56) risk groups. The 3-year event-free survival (EFS) rate for patients with KMT2A-r ALL (IR + HR) was 66.2% (standard error [SE], 5.6%), and for those with germline KMT2A (KMT2A-g) ALL (LR), the 3-year EFS rate was 93.3% (SE, 6.4%). The 3-year EFS rate was 94.4% (SE, 5.4%) for IR patients and 56.6% (SE, 6.8%) for HR patients. In multivariable analysis, female sex and MRD ≥0.01% at the end of early consolidation were significant factors for poor prognosis. Risk stratification and introduction of intensive chemotherapy in this study were effective and were able to eliminate HSCT for a subset of infants with KMT2A-r ALL. Early clearance of MRD seems to have translated into favorable outcomes and should be incorporated into risk stratifications in future trials. This trial was registered at the University Hospital Medical Information Network Clinical Trials Registry (UMIN-CTR) as #UMIN000004801.

Postchemotherapy immune status in infants with acute lymphoblastic leukemia: A report from the JPLSG MLL-10 trial.

The MLL-10 trial (UMIN000004801) modified a Children's Oncology Group (COG) AALL0631 therapy for infants with KMT2A-rearranged acute lymphoblastic leukemia (ALL). In 2016, one registered case developed secondary immunodeficiency during maintenance therapy and eventually died due to cytomegalovirus infection. Around the same time, fatal secondary immunodeficiencies were reported in five infants with ALL in North America who had received COG-based chemotherapy between 1996 and 2015. Given these cases, we decided to conduct a retrospective study on the postchemotherapy immune status of infants with ALL. A questionnaire collected data on posttreatment immune function, frequency of infections, and supportive care for the 34 infants in the MLL-10 trial. Patients receiving allogeneic hematopoietic stem cell transplantation in first remission were excluded. Responses to the survey were obtained in 28 cases (85%). Most patients were immunocompetent after the completion of chemotherapy (median follow-up duration from the day of chemotherapy completion was 431 days), except for the aforementioned case. There were seven patients with nonsevere viral infection, all of whom recovered. In conclusion, severe chemotherapy-induced immunodeficiency in infants with ALL appears to be rare, but prospective data collection of immune function is necessary to clarify this finding.

Successful perioperative management using prothrombin complex concentrates in patients with severe congenital protein C deficiency.

Perioperative management of severe congenital protein C deficiency remains unestablished. This deficiency is often treated with anticoagulants, such as warfarin. Although anticoagulants need to be perioperatively discontinued, there are few methods for the management of such patients. We adopted a method for administering prothrombin complex concentrates (PCC), which includes intermittent administration of inactive protein C (PPSB-HT), and examined its outcome as a perioperative management approach for severe congenital protein C deficiency. Three patients underwent our perioperative management six times. We monitored activity levels of protein C, factor IX, and so forth. These patients could be perioperatively managed with PCC treatment.

Nontrivial ultraslow dynamics under electric-field in nematics of bent-shaped molecules.

For over decades, nematic liquid crystals have been recognized as highly fluidic materials that respond to electric field on the millisecond scale. In contrast to traditional nematics with fast responsivity, we herein report nontrivial ultraslow electric-driven dynamics in bent-shaped nematic materials. Varying the alkyl chain spacers of bent-shaped cyanobiphenyl dimers (COOm and OCOm) shows a 'transition' in the dynamics behavior between the bent-dimeric and bent-core materials. Interestingly, with short alkyl chain spacers, COO2 exhibits unexpected ultra-slow dynamic pathways, i.e., "quasi-static" electrohydrodynamic convection. A significant observation is that the on/off-electro-switching time of COO2 is 10 000 times higher than that of typical nematic materials, which is the largest value reported ever in the kilo-second range. In addition, the threshold voltage for inducing the reorientation of the nematic director for COO2 is higher than 5 V, which is uncommon in traditional N materials. These properties are distinct from those of traditional nematic materials and discussed in terms of dielectric constants and electrohydrodynamic convection.

Prognostic Implication of DNA Methylation Signature in Atypical Choroid Plexus Papilloma With Intracranial Dissemination.

An underestimation of pathologic diagnosis could be expected if disseminated choroid plexus tumors (CPTs) are diagnosed as lower grade tumors. Thus, molecular diagnosis using genome-wide DNA methylation profiling may be useful for clarifying the malignant potential of the tumor entity. Herein, we report a 2.7-year-old girl of pathologically atypical choroid plexus papilloma with intracranial dissemination. She was treated without radiotherapy and has been well, without recurrence for 32 months following the diagnosis. Subsequently, after a year from the diagnosis, T-stochastic neighbor embedding analysis was performed on methylation data of the case and compared with those of reference data of CPTs, revealing that the case was separated from the cluster of "Plexus tumor subclass pediatric B," which includes a majority of choroid plexus carcinomas with the worst prognosis of these entities, and was categorized into the cluster of "Plexus tumor subclass pediatric A" consisting of choroid plexus papilloma and atypical choroid plexus papillomas diagnosed pathologically. Our case indicates the clinical significance of molecular confirmation for diagnosis among CPTs, particularly lower grade tumors with dissemination.