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BACKGROUND: In Japan, a nationwide programme between 1984 and 2003 screened all infants for urinary catecholamine metabolites as a marker for neuroblastoma. Before 1989, this was done by qualitative spot tests for vanillylmandelic acid in urine, and subsequently by quantitative assay with high-performance liquid chromatography (HPLC). However, the Japanese government stopped the mass-screening programme in 2003, after reports that it did not reduce mortality due to neuroblastoma. We aimed to assess the effectiveness of the programme, by comparing the rates of incidence and mortality from neuroblastomas diagnosed before 6 years of age in three cohorts. METHODS: We did a retrospective population-based cohort study on all children born between 1980 and 1998, except for a 2-year period from 1984. We divided these 22,289,695 children into three cohorts: children born before screening in 1980-83 (n=6,130,423); those born during qualitative screening in 1986-89 (n=5,290,412); and those born during quantitative screening 1990-98 (n=10,868,860). We used databases from hospitals, screening centres, and national cancer registries. Cases of neuroblastoma were followed up for a mean of 78.7 months. FINDINGS: 21.56 cases of neuroblastoma per 100,000 births over 72 months were identified in the qualitatively screened group (relative risk [RR] 1.87, 95% CI 1.66-2.10), and 29.80 cases per 100,000 births over 72 months in the quantitatively screened group (RR 2.58, 2.33-2.86). The cumulative incidence of neuroblastoma in the prescreening cohort (11.56 cases per 100,000 births over 72 months) was lower than that in other cohorts (p<0.0001 for all comparisons), but more neuroblastomas were diagnosed after 24 months of age in this cohort (p=0.0002 for qualitative screening vs prescreening, p<0.0001 for quantitative screening vs prescreening). Cumulative mortality was lower in the qualitative screening (3.90 cases per 100,000 livebirths over 72 months) and quantitative screening cohorts (2.83 cases) than in the prescreening cohort (5.38 cases). Compared with the prescreening cohort, the relative risk of mortality was 0.73 (95% CI 0.58-0.90) for qualitative screening, and 0.53 (0.42-0.63) for quantitative screening. Mortality rates for both the qualitative and quantitative screening groups were lower than were those for the prescreening cohort (p=0.0041 for prescreening vs qualitative screening, p<0.0001 for prescreening vs quantitative screening). INTERPRETATION: More infantile neuroblastomas were recorded in children who were screened for neuroblastoma at 6 months of age than in those who were not. The mortality rate from neuroblastoma in children who were screened at 6 months was lower than that in the prescreening cohort, especially in children screened by quantitative HPLC. Any new screening programme should aim to decrease mortality, but also to minimise overdiagnosis of tumours with favourable prognoses (eg, by screening children at 18 months). [ABSTRACT FROM AUTHOR]

MYCN is the most powerful prognostic factor in cases of older children. However, how MYCN is related to the prognosis of infantile cases is not clear. A mass screening program was carried out by measuring urinary catecholamine metabolites (VMA and HVA) from 6-month-old infants. Of 2084 cases detected by the screening program, MYCN amplification (MNA) was examined by Southern blot analyses in 1533 cases from 1987 to 2000. Of the 1533 cases examined, 1500 (97.8%) showed no MNA, 20 cases (1.3%) showed MNA from three to nine copies, and 13 (0.8%) cases showed more than 10 copies. The 4-year overall survival rates of these three groups (99, 89 and 53%, respectively) were significantly different (P<0.001), indicating that MYCN copy number correlates with the prognosis. Cases with MNA more than 10 copies were more advanced than those without amplification (stage III, IV vs I, II, IVs; P<0.001). Patients with MNA more than 10 copies had significantly higher serum levels of neuron-specific-enolase (NSE) and ferritin than non-amplified patients (P=0.049, P=0.025, respectively). MYCN amplification was strongly correlated with a poor prognosis in infantile neuroblastoma cases. Therefore, for the selection of appropriate treatment, an accurate determination of MNA is indispensable. [ABSTRACT FROM AUTHOR]

Miscibility among phospholipids with different lipid chain-lengths or with different head groups has attracted a number of research efforts because of its significance in biological membrane structure and function. The general consensus about the miscibility of phosphatidylcholines with varying lipid chain-lengths appears to be that binary mixtures of phospholipids with a difference of two carbon atoms in the lipid chain mix well at the main phase transition. Miscibility between phosphatidylcholines with differences of four carbon atoms appears to be inconclusive. Previous reports on the phase transition of binary phospholipid mixtures are concerned mainly with multilamellar vesicles and are mostly limited to the main transition. In the present study, unilamellar vesicles were used and miscibility in binary systems between dimyristoyl-, dipalmitoyl- and distearoyl-phosphatidylcholines at pretransition as well as main transition temperatures was evaluated by constructing phase diagrams. Two methods were used to monitor the phase transitions: differential scanning microcalorimetry and optical absorbance methods. The optical method has the advantage that unilamellar vesicles of dilute phospholipid concentrations can be used. The liquidus and solidus phase boundaries were determined by the onset temperature of heating and cooling scans, respectively, because the completion temperature of a phase transition has no meaning in binary solutions. Dimyristoyl- and distearoyl-phosphatidylcholines, where the difference in the lipid chain-length is four carbon atoms, mixed well even at pretransition temperature. [ABSTRACT FROM AUTHOR]

Background: The JPLT3-S (Japanese Study Group for Pediatric Liver Tumors-3) study, conducted cisplatin (CDDP) monotherapy for young children (<3 years old) with standard-risk hepatoblastoma (HB) using a central review system in Japan. In the previous JPLT2 study, cases with resectable tumors without any annotation factors in the PRETEXT (PRETreatment EXTent of disease) classification (standard-risk HB) showed favorable outcomes with treatment consisting of CDDP and pirarubicin, but showed toxicities and late complications. In the JPLT3-S trial, a less intense regimen consisting of CDDP alone was evaluated., Methods: Patients who were less than 3 years of age and with PRETEXT I, II, or III HB without any annotation factors (e.g., E1, E1a, E2, E2a, H1, N1, P2, P2a, V3, and V3a) were eligible for inclusion in this study. In this trial, the central radiological and pathological features of all patients were reviewed. The primary outcome was the 3-year progression-free survival (PFS)., Results: A total of 38 patients (23 female) were included. The median patient age was 12 months (range: 2-34). Two patients discontinued treatment because of progressive disease, and five patients discontinued treatment for other reasons. The 3-year PFS rate was 93.9% (95% confidence interval [CI]: 86.4%-100%). All 38 patients survived (follow-up period 38-98 months), and the OS rate was 100% (CI: 100). Eighteen of the 38 patients (47.4%) experienced ototoxicity as a late complication., Conclusion: CDDP monotherapy regimen is feasible in young patients with localized HB, as classified by a central review., (© 2024 The Author(s). Pediatric Blood & Cancer published by Wiley Periodicals LLC.)

Background: Few previous studies evaluated the impact of time from the hospital arrival to the implementation of extracorporeal cardiopulmonary resuscitation (ECPR) (door to ECPR time) on outcomes among out-of-hospital cardiac arrest (OHCA) acute myocardial infarction (MI) patients., Methods: 50 patients with OHCA who received both ECPR and percutaneous coronary intervention (PCI) at Cardiovascular Division, NHO Osaka National Hospital were analyzed. Patients were divided into 2 groups according to the median of door to ECPR time. The primary outcome was all-cause death. Survival analyses were conducted to compare all-cause mortality at 90 days between 2 groups. Neurological outcome at 30 days was also compared between 2 groups using the Cerebral Performance Category (CPC)., Results: The multivariable Cox proportional-hazards model showed that all-cause mortality at 90 days was significantly higher among patients with door to ECPR time ≥ 25 min compared with those with door to ECPR time < 25 min (adjusted hazard ratio [HR]: 3.14; 95 % confidence interval [CI]: 1.21-8.18). The proportion of patients with CPC at 30 days ≤ 2 was significantly higher among patients with shorter door to ECPR time ( P  = 0.048)., Conclusion: Among patients with OHCA due to acute MI who received ECPR and PCI, the shorter door to ECPR time was associated with the lower mortality and favorable neurological outcomes., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Yasunori Ueda reports a relationship with 10.13039/100001316Abbott, 10.13039/501100002973Daiichi-Sankyo, Teijin, Japan Lifeline, OrbusNeich, Janssen, Otsuka, Ono, Eli Lilly, Astellas, 10.13039/100002429Amgen, 10.13039/100001003Boehringer Ingelheim, and 10.13039/100004336Novartis that includes: funding grants. Yasunori Ueda reports a relationship with Abbott, Kowa, Bayer, Daiichi-Sankyo, Nipro, Takeda, AstraZeneca, Japan Lifeline, Novartis, Ono, Boehringer Ingelheim, and Amgen that includes: speaking and lecture fees. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

Background: Conventional conditioning regimens for children with lymphoid malignancy undergoing allogeneic hematopoietic cell transplantation (HCT) are myeloablative and involve high-dose total body irradiation (TBI). Such regimens are associated with significant late complications., Observations: Here, we used a reduced-toxicity conditioning regimen comprising fludarabine, cytarabine, melphalan, and low-dose TBI (FLAMEL) to treat 5 patients with lymphoid malignancy before HCT. Four patients maintained complete remission (range, 18 to 63 mo), whereas the remaining patient who had positive minimal residual disease (MRD) before HCT relapsed., Conclusions: FLAMEL might be a suitable conditioning regimen for children with lymphoid malignancy if pre-HCT MRD is negative., Competing Interests: The authors declare no conflict of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

The assessment of auscultation using a stethoscope is unsuitable for continuous monitoring. Therefore, we developed a novel acoustic monitoring system that continuously, objectively, and visually evaluates respiratory sounds. In this report, we assess the usefulness of our revised system in a ventilated extremely low birth weight infant (ELBWI) for the diagnosis of pulmonary atelectasis and evaluation of treatment by lung lavage. A female infant was born at 24 weeks of age with a birth weight of 636 g after emergency cesarean section. The patient received invasive mechanical ventilation immediately after birth in our neonatal (NICU). After obtaining informed consent, we monitored her respiratory status using the respiratory-sound monitoring system by attaching a sound collection sensor to the right anterior chest wall. On day 26, lung-sound spectrograms showed that the breath sounds were attenuated simultaneously as hypoxemia progressed. Finally, chest radiography confirmed the diagnosis as pulmonary atelectasis. To relieve atelectasis, surfactant lavage was performed, after which the lung-sound spectrograms returned to normal. Hypoxemia and chest radiographic findings improved significantly. On day 138, the patient was discharged from the NICU without complications. The continuous respiratory-sound monitoring system enabled the visual, quantitative, and noninvasive detection of acute regional lung abnormalities at the bedside. We, therefore, believe that this system can resolve several problems associated with neonatal respiratory management and save lives., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Clinical Ethics Committee, Hiroshima University issued approval E-784-4. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Zuiki et al.)

Syntaxin-binding protein 1 (STXBP1) is a presynaptic protein that plays important roles in synaptic vesicle docking and fusion. STXBP1 haploinsufficiency causes STXBP1 encephalopathy (STXBP1-E), which encompasses neurological disturbances including epilepsy, neurodevelopmental disorders, and movement disorders. Most patients with STXBP1-E present with regression and movement disorders in adulthood, highlighting the importance of a deeper understanding of the neurodegenerative aspects of STXBP1-E. An in vitro study proposed an interesting new role of STXBP1 as a molecular chaperone for α-Synuclein (αSyn), a key molecule in the pathogenesis of neurodegenerative disorders. However, no studies have shown αSyn pathology in model organisms or patients with STXBP1-E. In this study, we used Drosophila models to examine the effects of STXBP1 haploinsufficiency on αSyn-induced neurotoxicity in vivo. We demonstrated that haploinsufficiency of Ras opposite (Rop), the Drosophila ortholog of STXBP1, exacerbates compound eye degeneration, locomotor dysfunction, and dopaminergic neurodegeneration in αSyn-expressing flies. This phenotypic aggravation was associated with a significant increase in detergent-insoluble αSyn levels in the head. Furthermore, we tested whether trehalose, which has neuroprotective effects in various models of neurodegenerative disorders, mitigates αSyn-induced neurotoxicity exacerbated by Rop haploinsufficiency. In flies expressing αSyn and carrying a heterozygous Rop null variant, trehalose supplementation effectively alleviates neuronal phenotypes, accompanied by a decrease in detergent-insoluble αSyn in the head. In conclusion, this study revealed that Rop haploinsufficiency exacerbates αSyn-induced neurotoxicity by altering the αSyn aggregation propensity. This study not only contributes to understanding the mechanisms of neurodegeneration in STXBP1-E patients, but also provides new insights into the pathogenesis of α-synucleinopathies., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Objectives: Erythropoietin (EPO) exerts tissue-protective effects on various organs including the kidney. However, the effects of EPO on established renal fibrosis remain unclear. In this study, we aimed to examine the therapeutic potential of EPO against established renal fibrosis., Methods: Renal fibrosis was induced in mice by unilateral ureteral obstruction (UUO) and the mice were treated with recombinant human EPO (rhEPO) daily during 7 and 13 days after UUO. The degrees of renal fibrosis, myofibroblast accumulation, and macrophage infiltration; the mRNA expression levels of transforming growth factor (TGF)-β1 and α1(I) collagen; and the protein levels of Kelch-like ECH-associated protein 1 (Keap1) and nuclear NF-E2-related factor 2 (Nrf2) in the kidneys were assessed on day 14 after UUO., Results: Treatment with rhEPO significantly decreased fibrosis, myofibroblast accumulation, and α1(I) collagen mRNA expression, but it did not significantly affect TGF-β1 mRNA expression. Although treatment with rhEPO did not significantly affect the total number of interstitial macrophages, it significantly decreased the number of CD86-positive cells (M1 macrophages), while significantly increased the number of CD206-positive cells (M2 macrophages) in the interstitium. Treatment with rhEPO did not affect the Keap1/Nrf2 protein level or the peripheral blood hematocrit value., Conclusions: These results indicate for the first time that EPO exerts antifibrotic effects against the evolution of established renal fibrosis, possibly by influencing the polarization of infiltrating macrophages., (© 2024 The Japanese Urological Association.)

It is important to monitor cerebral perfusion in infants because hypo- and hyperperfusion can contribute to neurological injury. This study aimed to clarify the relationship between trans-systolic time (TST) and critical closing pressure (CrCP) or estimated cerebral perfusion pressure (CPPe) in neonates. Moreover, we aimed to determine the TST values in preterm and term infants with stable cerebral perfusion to clarify normative reference data. This multicentre prospective study included infants with arterial lines admitted to the neonatal intensive care units between December 2021 and August 2023. TST, CrCP, and CPPe were calculated using middle cerebral artery waveforms recorded using transcranial Doppler ultrasonography when clinicians collected arterial blood samples. Three hundred and sixty samples were obtained from 112 infants with a gestational age of 32 (interquartile range, 27-37) weeks and a birth weight of 1481 (956-2355) g. TST was positively correlated with CPPe (r = 0.60, p < 0.001), but not with CrCP (r = 0.08, p = 0.10). The normative reference values of TST in preterm and term infants without samples of hyper- or hypocapnia and/or hyper- or hypotension, which may affect cerebral perfusion, were as follows: ≤ 29 weeks, 0.12 (0.11-0.14) s; 30-36 weeks, 0.14 (0.12-0.15) s; and ≥ 37 weeks, 0.16 (0.14-0.17) s, respectively.  Conclusion: TST in neonates significantly correlated with CPPe, but not with CrCP. TST may be a good predictor of cerebral perfusion and potentially have wider clinical applications. What is Known: • Trans-systolic time (TST) is used in evaluating the effects of increased intracranial pressure on cerebral haemodynamics. However, little is known about the efficacy of TST in predicting neonatal cerebral perfusion pressure. What is New: • This study added evidence that TST correlated with estimated cerebral perfusion pressure, but not with critical closing pressure. Additionally, we showed the normative reference values of the TST in preterm and term infants., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Advances in fluorescence microscopy and tissue-clearing have revolutionised 3D imaging of fluorescently labelled tissues, organs and embryos. However, the complexity and high cost of existing software and computing solutions limit their widespread adoption, especially by researchers with limited resources. Here, we present Acto3D, an open-source software, designed to streamline the generation and analysis of high-resolution 3D images of targets labelled with multiple fluorescent probes. Acto3D provides an intuitive interface for easy 3D data import and visualisation. Although Acto3D offers straightforward 3D viewing, it performs all computations explicitly, giving users detailed control over the displayed images. Leveraging an integrated graphics processing unit, Acto3D deploys all pixel data to system memory, reducing visualisation latency. This approach facilitates accurate image reconstruction and efficient data processing in 3D, eliminating the need for expensive high-performance computers and dedicated graphics processing units. We have also introduced a method for efficiently extracting lumen structures in 3D. We have validated Acto3D by imaging mouse embryonic structures and by performing 3D reconstruction of pharyngeal arch arteries while preserving fluorescence information. Acto3D is a cost-effective and efficient platform for biological research., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2024. Published by The Company of Biologists Ltd.)

Background: Recent studies have identified that low levels of some tumour suppressor microRNAs (miRNAs) in the blood contribute to tumour progression and poor outcomes in various cancers. However, no study has proved these miRNAs are associated with cancer immune mechanisms., Methods: From a systematic review of the NCBI and miRNA databases, four tumour suppressor miRNA candidates were selected (miR-5193, miR-4443, miR-520h, miR-496) that putatively target programmed cell death ligand 1 (PD-L1)., Results: Test-scale and large-scale analyses revealed that plasma levels of miR-5193 were significantly lower in gastric cancer (GC) patients than in healthy volunteers (HVs). Low plasma levels of miR-5193 were associated with advanced pathological stages and were an independent prognostic factor. Overexpression of miR-5193 in GC cells suppressed PD-L1 on the surface of GC cells, even with IFN-γ stimulation. In the coculture model of GC cells and T cells stimulated by anti-CD3/anti-CD28 beads, overexpression of miR-5193 increased anti-tumour activity of T cells by suppressing PD-L1 expression. Subcutaneous injection of miR-5193 also significantly enhanced the tumour-killing activity and trafficking of T cells in mice., Conclusions: Low blood levels of miR-5193 are associated with GC progression and poor outcomes and could be a target of nucleic acid immunotherapy in GC patients., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Previous reports have shown that a gain of the chromosome 9 short arm (9p) is associated with choroid plexus hyperplasia (CPH). Furthermore, CPH can lead to communicating hydrocephalus; however, no cases of CPH with 9p gain requiring choroid plexus resection have been reported. Here, we describe the first case in which a 9p hexasomy/tetrasomy mosaic patient required choroid plexus resection for hydrocephalus. This finding suggested that the 9p copy number is correlated with CPH severity., (© 2024. The Author(s).)

Retinoids are vitamin A derivatives and include trans-retinoic acid, isotretinoin, tamibarotene, and bexarotene, all of which are currently available for clinical use. The clinical development of retinoid therapy for neuroblastoma has a history spanning more than four decades. The most promising agent is isotretinoin, which can contribute to improving event-free survival in patients with high-risk neuroblastoma by approximately 10% when administered over six months as maintenance therapy. Although isotretinoin is regarded as an essential component in the standard clinical management of high-risk neuroblastoma, its use for this purpose in the US and EU is off-label. To promote isotretinoin use in Japan as a treatment for neuroblastoma, our clinical research team is planning to launch an investigator-initiated, registration-directed clinical trial. The present review article discusses the basic science behind retinoid therapy, pre-clinical/clinical evidence on neuroblastoma, the concept of the proposed clinical trial, and prospects for this therapy.

Background: It remains controversial whether a cancer history increases the risk of cardiovascular (CV) events among patients with myocardial infarction (MI) who undergo revascularization., Methods and results: Patients who were confirmed as type 1 acute MI (AMI) by coronary angiography were retrospectively analyzed. Patients who died in hospital or those not undergoing revascularization were excluded. Patients with a cancer history were compared with those without it. A cancer history was examined in the in-hospital cancer registry. The primary outcome was a composite of cardiac death, recurrent type 1 MI, post-discharge coronary revascularization, heart failure hospitalization, and stroke. Among 551 AMI patients, 55 had a cancer history (cancer group) and 496 did not (non-cancer group). Cox proportional hazards model revealed that the risk of composite endpoint was significantly higher in the cancer group than in the non-cancer group (adjusted hazard ratio [HR]: 1.78; 95% confidence interval [CI]: 1.13-2.82). Among the cancer group, patients who were diagnosed as AMI within 6 months after the cancer diagnosis had a higher risk of the composite endpoint than those who were diagnosed as AMI 6 months or later after the cancer diagnosis (adjusted HR: 5.43; 95% CI: 1.55-19.07)., Conclusions: A cancer history increased the risk of CV events after discharge among AMI patients after revascularization.

Background: Very low birthweight infants (VLBWIs) often undergo chest radiographic examinations without standardization or objectivity. This study aimed to assess the association of two radiographic scores, the Brixia and radiographic assessment of lung edema (RALE), with oxygenation index (OI) in ventilated VLBWIs and to determine the optimal cutoff values to predict hypoxic respiratory severity., Methods: VLBWIs who received invasive respiratory support with arterial lines between January 2010 and October 2023 were enrolled in this study (n = 144). The correlation between the Brixia or RALE scores and OI was investigated. Receiver operating characteristic curve analysis was performed to determine the optimal cutoff points of the two radiographic scores for predicting OI values (OI ≥5, ≥10, and ≥15)., Results: The enrolled infants had a median gestational age of 27 weeks (interquartile range [IQR], 25-28 weeks) and a median birthweight of 855 g (IQR, 684-1003 g). Radiographic scoring methods correlated with the OI (Brixia score: r = 0.79, p < 0.001; RALE score: r = 0.72, p < 0.001). The optimal cutoff points for predicting OI values were as follows: Brixia score: OI ≥5, 10; OI ≥10, 13; OI ≥15, 15; RALE score: OI ≥5, 22; OI ≥10, 31; and OI ≥15, 40., Conclusions: Brixia and RALE scores are useful predictive markers of the oxygenation status in intubated VLBWIs with stable hemodynamics. These scores are easy to use and promising tools for clinicians to identify patients with a higher risk of hypoxic respiratory failure., (© 2024 Japan Pediatric Society.)

Purpose: To confirm the hypothesis that brain white matter damage is involved in the pathogenesis and disease progression of Langerhans cell histiocytosis (LCH)-associated neurodegenerative disease (ND), we aimed to analyze pediatric patients with LCH using diffusion tensor imaging (DTI)., Methods: We enrolled 33 patients with LCH and obtained 33 DTI datasets. Using DTI-based tractography, fractional anisotropy (FA), apparent diffusion coefficient (ADC), axial diffusivity (AD), and radial diffusivity (RD) were measured in the cerebral and cerebellar white matter tracts. The participants were divided into three groups-non-ND, ND without clinical symptoms (r-ND), and ND with clinical symptoms (c-ND)-according to their clinical status during the examination with DTI. We compared the DTI parameters in white matter tracts were compared among the three groups., Results: In the order of non-ND, r-ND, and c-ND groups, the FA in superior cerebellar peduncle (SCP) and middle cerebellar peduncle (MCP) significantly decreased, the ADC, AD, and RD of MCP, and the RD of SCP were significantly elevated (FA-SCP; p < 0.001, FA-MCP; p = 0.026, ADC-MCP; p < 0.001, AD-MCP; p = 0.002, RD-MCP; p = 0.003, and RD-SCP; p = 0.018). Furthermore, in the simple linear regression analysis, the FA, ADC, AD, and RD values in the MCP and the FA value in the SCP were significantly influenced by the presence of neurological symptoms and ND findings on MRI (all p < 0.001)., Conclusion: In LCH-ND, we identified microstructural damage in the SCP and MCP. DTI parameters in these tracts may help monitor LCH-ND; therefore, future studies are required to validate these results in a large cohort., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Congenital heart disease (CHD) is common among patients with trisomy 18 (T18), but cardiac surgery has been rarely indicated for T18 patients due to their short life span. Although the therapeutic effects of aggressive interventions were recently demonstrated for T18 patients, the subjects and factors examined varied, resulting in inconsistent findings. Therefore, the effects of cardiac surgery for T18 remain unclear. We herein investigated the outcomes of cardiac palliative surgery for CHD with increased pulmonary blood flow in T18 patients. 27 patients were examined: 13 (48.1%) underwent cardiac palliative surgery and 14 (51.9%) did not. Median survival times in the no-surgery and surgery groups were 223.0 days (95% confidence interval [CI]: 46-361 days) and 723.0 days (95% CI: 360-1447 days), respectively. The number of patients with pulmonary hypertension significantly differed between the two groups (5 of 14 in the no-surgery group and 0 in the surgery group). Five of 14 patients in the no-surgery group and 10 of 13 in the surgery group were discharged to home care (odds ratio: 10.8 [95% CI: 1.07-110.0]). Therefore, cardiac palliative surgery may be used to treat CHD with increased pulmonary blood flow in T18 patients., (© 2023 Wiley Periodicals LLC.)

High-risk neuroblastoma (HR-NB) patients remain far from obtaining optimal outcomes, with more than 50% relapse/regrowth rate despite current intensive multimodal therapy. This originated from the activation/proliferation of chemoresistant minimal residual disease (MRD). MRD with a significant prognostic was reported by several quantitative PCR (qPCR) or droplet digital PCR (ddPCR) assays quantitating different sets of NB-associated mRNAs (NB-mRNAs). The 7NB-mRNAs ddPCR assay quantitating CRMP1, DBH, DDC, GAP43, ISL1, PHOX2B, and TH mRNAs was reported to outperform other qPCR assays by a retrospective in-house observational study. In the present study, the Japan Children's Cancer Group (JCCG) Neuroblastoma Committee conducted a prospective multicenter observational study aimed at evaluating a prognostic value of MRD in bone marrow (BM-MRD) and peripheral blood (PB-MRD) detected by 7NB-mRNAs ddPCR assay. Between August 2018 and August 2022, 7 HR-NB patients who registered for JCCG clinical trials (JN-H-11 and JN-H-15) were enrolled. A total of 19 BM and 19 PB samples were collected, and 4/15 BM and 4/15 PB samples were classified as progressive disease (PD)/non-PD samples. BM-MRD and PB-MRD estimated area under curve (AUC) of 0.767 and 0.800 with a significant accuracy (AUC > 0.7). The present study validated a prognostic value of BM-MRD obtained by a previous study (AUC 0.723) and revealed the significant accuracy of PB-MRD as well as BM-MRD.

Pathogenic variants in the HIBCH gene cause HIBCH deficiency, leading to mitochondrial disorders associated with valine metabolism. Patients typically present with symptoms such as developmental regression/delay, encephalopathy, hypotonia and dystonia. Brain magnetic resonance imaging (MRI) shows bilateral lesions in the basal ganglia with/without brainstem involvement. Here, we report a case of a Japanese patient with Leigh-like syndrome caused by novel HIBCH variants. Long-term follow-up MRI revealed progressive cerebellar atrophy, which expands the phenotypic spectrum of HIBCH deficiency., (© 2023. Japan Society of Human Genetics.)

The NUP98::NSD1 fusion gene is associated with extremely poor prognosis in patients with acute myeloid leukemia (AML). NUP98::NSD1 induces self-renewal and blocks differentiation of hematopoietic stem cells, leading to development of leukemia. Despite its association with poor prognosis, targeted therapy for NUP98::NSD1-positive AML is lacking, as the details of NUP98::NSD1 function are unknown. Here, we generated 32D cells (a murine interleukin-3 (IL-3)-dependent myeloid progenitor cell line) expressing mouse Nup98::Nsd1 to explore the function of NUP98::NSD1 in AML, including comprehensive gene expression analysis. We identified two properties of Nup98::Nsd1 + 32D cells in vitro. First, Nup98::Nsd1 promoted blocking of AML cell differentiation, consistent with a previous report. Second, Nup98::Nsd1 increased dependence on IL-3 for cell proliferation, due to overexpression of the alpha subunit of the IL-3 receptor (IL3-RA, also known as CD123). Consistent with our in vitro data, IL3-RA was also upregulated in samples from patients with NUP98::NSD1-positive AML. These results highlight CD123 as a potential new therapeutic target in NUP98::NSD1-positive AML., (© 2023. Japanese Society of Hematology.)

Genetic information encoded by DNA is packaged in the nucleus using the chromatin structure. The accessibility of transcriptional elements in DNA is controlled by the dynamic structural changes of chromatin for the appropriate regulation of gene transcription. Chromatin structure is regulated by two general mechanisms, one is histone modification and the other is chromatin remodeling in an ATP-dependent manner. Switch/sucrose nonfermentable (SWI/SNF) complexes utilize the energy from ATP hydrolysis to mobilize nucleosomes and remodel the chromatin structure, contributing to conformational changes in chromatin. Recently, the inactivation of encoding genes for subunits of the SWI/SNF complexes has been documented in a series of human cancers, accounting for up to almost 20% of all human cancers. For example, human SNF5 (hSNF5), the gene that encodes a subunit of the SWI/SNF complexes, is the sole mutation target that drives malignant rhabdoid tumors (MRT). Despite remarkably simple genomes, the MRT has highly malignant characteristics. As a key to understanding MRT tumorigenesis, it is necessary to fully examine the mechanism of chromatin remodeling by the SWI/SNF complexes. Herein, we review the current understanding of chromatin remodeling by focusing on SWI/SNF complexes. In addition, we describe the molecular mechanisms and influences of hSNF5 deficiency in rhabdoid tumors and the prospects for developing new therapeutic targets to overcome the epigenetic drive of cancer that is caused by abnormal chromatin remodeling., (© 2023 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Syntaxin-binding protein 1 (STXBP1, also known as Munc18-1) regulates exocytosis as a chaperone protein of Syntaxin1A. The haploinsufficiency of STXBP1 causes early infantile-onset developmental and epileptic encephalopathy, known as STXBP1 encephalopathy. Previously, we reported impaired cellular localization of Syntaxin1A in induced pluripotent stem cell-derived neurons from an STXBP1 encephalopathy patient harboring a nonsense mutation. However, the molecular mechanism of abnormal Syntaxin1A localization in the haploinsufficiency of STXBP1 remains unknown. This study aimed to identify the novel interacting partner of STXBP1 involved in transporting Syntaxin1A to the plasma membrane. Affinity purification coupled with mass spectrometry analysis identified a motor protein Myosin Va as a potential binding partner of STXBP1. Co-immunoprecipitation analysis of the synaptosomal fraction from the mouse and tag-fused recombinant proteins revealed that the STXBP1 short splice variant (STXBP1S) interacted with Myosin Va in addition to Syntaxin1A. These proteins colocalized at the tip of the growth cone and axons in primary cultured hippocampal neurons. Furthermore, RNAi-mediated gene silencing in Neuro2a cells showed that STXBP1 and Myosin Va were required for membrane trafficking of Syntaxin1A. In conclusion, this study proposes a potential role of STXBP1 in the trafficking of the presynaptic protein Syntaxin1A to the plasma membrane in conjunction with Myosin Va., (Copyright © 2023 IBRO. Published by Elsevier Ltd. All rights reserved.)

Background/aim: Using the tyrosine hydroxylase (TH)-MYCN mouse neuroblastoma (NB) model, we have previously reported the accumulation of mouse mesenchymal stem cells (mMSCs) on tumors in vivo and the antitumor effect of mMSCs transfected with a small molecule (IFN-β) expression gene. In this study, we have developed novel MSCs secreting anti-disialoganglioside GD2 antibody (anti-GD2-MSCs) and evaluated their antitumor effects in vitro., Materials and Methods: We generated an anti-GD2 antibody construct (14.G2a-Fcx2-GFP) incorporating FLAG-tagged single-chain fragment variable against GD2 fused to a linker sequence, a fragment of the constant portion of human IgG1, and GFP protein. The construct was lentivirally transduced into mMSCs and the transduction efficiency was assessed by GFP expression. The secretion of FLAG-tagged anti-GD2 antibody was detected by Western blotting using anti-FLAG antibody. Antibody binding capacity was confirmed by flow cytometry. Antibody-dependent cellular cytotoxicity (ADCC) was evaluated using human NB cells and human natural killer (NK) cells to assess whether the antitumor activity was enhanced in the presence of the produced antibodies., Results: The transduction efficiency of anti-GD2-MSCs was more than 90%. anti-GD2-MSCs secreted antibodies extracellularly and these antibodies had high affinity to GD2-expressing human NB cells. ADCC assays showed that the addition of antibodies secreted from anti-GD2-MSCs significantly increased the cytotoxic activity of NK cells against NB cells., Conclusion: Newly developed anti-GD2-MSCs produced functional antibodies that have affinity to the GD2 antigen on NB cells and can induce ADCC-mediated cytotoxicity. Anti-GD2-MSCs based cellular immunotherapy has the potential to be a novel therapeutic option for intractable NB., (Copyright © 2023 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

ETV6::Fyn-related kinase (FRK), which is a Src family tyrosine-kinase-related fusion gene and firstly identified in our patient with paediatric high risk B cell precursor acute lymphoblastic leukaemia (B-ALL), has no evidence of efficacy of tyrosine kinase inhibitor in vivo. We performed functional analysis of ETV6::FRK to establish molecular targeting therapy and determined that dasatinib could abrogate proliferation activity of ETV6::FRK through the repression of FRK-STAT3/STAT5 pathway in vitro and significantly extended the survival time of the xenografted mice in vivo ( p  < 0.01). Our data support the potential of dasatinib as a therapeutic option for patients with B-ALL harboring FRK rearrangements., Competing Interests: The authors declare no competing financial interests., (© 2023 The Authors. eJHaem published by British Society for Haematology and John Wiley & Sons Ltd.)

Maternal obesity and malnutrition during gestation and lactation have been recognized to increase the risk of obesity and metabolic disorders in the offspring across their lifespan. However, the gestational period during which malnutrition exerts a decisive effect is unclear. Brown adipose tissue (BAT) plays a critical role in energy metabolism owing to its high efficiency in oxidizing glucose and fatty acids. This study aimed to determine the impact of maternal high-fat diet (HFD) consumption only during pregnancy on BAT and energy metabolism in offspring mice. Dams were fed an HFD or a normal chow diet from embryonic day 2.5. HFD consumption during pregnancy induced glucose intolerance and hypertension in dams. In the offspring of HFD-fed dams, maternal HFD lowered fetal weight without affecting placental weight, whereas HFD consumption after birth exacerbated oxygen consumption and cold-induced thermogenesis at 12 months of age, accompanied by increased lipid droplet size in BAT. These data demonstrate that HFD consumption only during pregnancy exerts a long-lasting effect on BAT. Collectively, these findings indicate the importance of nutrition during pregnancy with respect to the energy metabolism of the offspring, and pregnant women should thus ensure proper nutrition during pregnancy to ensure normal energy metabolism in the offspring.

Rhabdomyosarcoma (RMS) is the most common highly malignant pediatric soft tissue sarcoma. While recent multidisciplinary treatments have improved the 5‑year survival rate of low/intermediate‑risk patients to 70‑90%, there are various complications that arise due to treatment‑related toxicities. Immunodeficient mice‑derived xenograft models have been widely used in cancer drug research; however, these models have some limitations, including i) they are time‑consuming and expensive, ii) their use needs to be approved by animal experimental ethics committees, and iii) the inability to visualize where tumor cells or tissues were engrafted. The present study performed a chorioallantoic membrane (CAM) assay in fertilized chicken eggs, which is time‑saving, simple, and easy to standardize and handle because of the high vascularization and the immature immune system of the fertilized eggs. The present study aimed to examine the usability of the CAM assay as a novel therapeutic model for the development of precision medicine for pediatric cancer. A protocol was developed for constructing cell line‑derived xenograft (CDX) models using a CAM assay by transplanting RMS cells on the CAM. It was then examined as to whether these CDX models could be used as therapeutic drug evaluation models using vincristine (VCR) and human RMS cell lines. After grafting and culturing the RMS cell suspension on the CAM, three‑dimensional proliferation over time was observed visually and by comparing volumes. VCR reduced the size of the RMS tumor on the CAM in a dose‑dependent manner. Currently, treatment strategies based on patient‑specific oncogenic backgrounds have not been adequately developed in the field of pediatric cancer. The establishment of a CDX model with the CAM assay may lead to the advancement of precision medicine and help formulate novel therapeutic strategies for intractable pediatric cancer.

CD19-specific chimeric antigen receptor T (CAR T) immunotherapy is used to treat B-cell malignancies. However, antigen-escape mediated relapse following CAR T therapy has emerged as a major concern. In some relapsed cases, especially KMT2A rearrangement-positive B-acute lymphoblastic leukemia (KMT2A-r B-ALL), most of the B-cell antigens are lost via lineage conversion to the myeloid phenotype, rendering multi-B-cell-antigen-targeted CAR T cell therapy ineffective. Fms-related tyrosine kinase-3 (FLT3) is highly expressed in KMT2A-r B-ALL; therefore, in this study, we aimed to evaluate the antitumor efficacy of CAR T cells targeting both CD19 and FLT3 in KMT2A-r B-ALL cells. We developed piggyBac transposon-mediated CAR T cells targeting CD19, FLT3, or both (dual) and generated CD19-negative KMT2A-r B-ALL models through CRISPR-induced CD19 gene-knockout (KO). FLT3 CAR T cells showed antitumor efficacy against CD19-KO KMT2A-r B-ALL cells both in vitro and in vivo; dual-targeted CAR T cells showed cytotoxicity against wild-type (WT) and CD19-KO KMT2A-r B-ALL cells, whereas CD19 CAR T cells demonstrated cytotoxicity only against WT KMT2A-r B-ALL cells in vitro. Therefore, targeting FLT3-specific CAR T cells would be a promising strategy for KMT2A-r B-ALL cells even with CD19-negative relapsed cases., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Malignant rhabdoid tumor (MRT) is a highly aggressive pediatric malignancy with no effective therapy. Therefore, it is necessary to identify a target for the development of novel molecule-targeting therapeutic agents. In this study, we report the importance of the runt-related transcription factor 1 ( RUNX1 ) and RUNX1-Baculoviral IAP (inhibitor of apoptosis) Repeat-Containing 5 (BIRC5/survivin) axis in the proliferation of MRT cells, as it can be used as an ideal target for anti-tumor strategies. The mechanism of this reaction can be explained by the interaction of RUNX1 with the RUNX1-binding DNA sequence located in the survivin promoter and its positive regulation. Specific knockdown of RUNX1 led to decreased expression of survivin, which subsequently suppressed the proliferation of MRT cells in vitro and in vivo . We also found that our novel RUNX inhibitor, Chb-M, which switches off RUNX1 using alkylating agent-conjugated pyrrole-imidazole polyamides designed to specifically bind to consensus RUNX-binding sequences (5'-TGTGGT-3'), inhibited survivin expression in vivo . Taken together, we identified a novel interaction between RUNX1 and survivin in MRT. Therefore the negative regulation of RUNX1 activity may be a novel strategy for MRT treatment.

Erythroid sarcoma is a very rare subtype of myeloid sarcoma with undetermined biological features. Here, we present an infant with a multifocal erythroid sarcoma, diagnosed because the tumor cells were positive for glycophorin A. After acute myeloid leukemia-oriented chemotherapy and surgical resection followed by cord blood transplantation, he has successfully maintained complete remission without any late effects. Total transcriptome analysis of the tumor identified a novel fusion gene, RCC1-LCK, and high LCK expression levels, suggesting that LCK overexpression was involved in leukemogenesis in this case., (© 2022 Wiley Periodicals LLC.)