Search

The survival of patients with high-risk, refractory, relapsed, or metastatic solid tumors remains dismal. A poly(ADP-ribose) polymerase (PARP) inhibitor could be effective for the treatment of pediatric solid tumors with defective homologous recombination.This open-label, multicenter phase 1 clinical trial evaluated the safety, tolerability, and efficacy of olaparib, a PARP inhibitor, in pediatric patients with refractory solid tumors to recommend a dose for Phase 2 trials. Olaparib (62.5, 125, and 187.5 mg/mFifteen patients were enrolled and received olaparib monotherapy, which was well tolerated. The recommended phase 2 dose for daily administration was 187.5 mg/mThis report is the first clinical trial to describe the use of a PARP inhibitor as monotherapy in children. Olaparib was well tolerated, with preliminary antitumor responses observed in DNA damage response-defective pediatric tumors.This Phase 1 trial evaluated the efficacy and safety of olaparib in patients with refractory childhood solid tumors. Olaparib was well tolerated, achieving objective response in 2/15 patients. The DNA damage response was attenuated in nearly one-half of advanced neuroblastoma patients, demonstrating the utility of the PARP inhibitor. The results support further investigation of olaparib as a new treatment for DNA damage-response or repair-defective pediatric cancers.

The risk of relapse is associated with orthodontic treatment and is a major problem. Discussions about the risk of relapse have been made for a long time. However, the detailed mechanism of relapse has not yet been elucidated, although basic research has been conducted to clarify this mechanism. This study aimed to evaluate relapse following orthodontic treatment in mice (C57BL/6) tested via the coil spring method of tooth movement for 21 days and mechanical retention for 7 days after completion of tooth movement. During the experiment, relapse was observed and evaluated over 7 days. At the end of the orthodontic tooth movement, the average distance was 259.6 (± 10.9) μm, and tooth movement was observed in all mice. No significant difference was found in the distance at the end of the experimental tooth movement nor at the end of the 7-day mechanical retention. The distance at the start of relapse observation was 258.6 (± 10.4) μm, whereas that at the end was 155.4 (± 12.4) μm, indicating that the distance decreased significantly. Relative to the total relapse distance over the 7-day period, 45.7 (± 4.3)% of the relapse was observed on Day 0-1. We established a relapse observation mouse model, which allowed us to develop an effective and reproducible method for optimal evaluation of relapse. Our findings clarified that most of the relapse occurs within 7 days at the initial observation stage.

Summary Objective To determine the feasibility of local inhibition of osteoclast activity and control of tooth movement with local intraoral reveromycin A (RMA) injection in model mice for experimental tooth movement. Materials and methods Eight-week-old wild-type mice (n = 6 per group) were divided into four groups consisting of two non-RMA groups that received normal saline for 14 (14-day non-RMA group) or 21 consecutive days (21-day non-RMA group) and 2 RMA groups that received RMA (1.0 mg/kg of weight) for 14 (14-day RMA group) or 21 consecutive days (21-day RMA group). RMA was injected locally into the buccal mucosa of the left first maxillary molar twice daily starting 3 days before placement of the 10-gf Ni-Ti closed coil spring. Tooth movement distance was analysed using micro-computed tomography. The effects on surrounding alveolar bone were evaluated by measuring the ratio of bone surface area to tissue surface area with haematoxylin-eosin-stained sections and counting the number of osteoclasts in periodontal tissue with TRAP-stained sections. Blood tests were performed and bone volume and trabecular separation at the tibial neck were measured to analyse systemic side effects. Results Local RMA injection inhibited tooth movement by 40.6 per cent, promoted alveolar bone volume maintenance by 37.4 per cent, and inhibited osteoclast activity around the tooth root at 21 days by 40.8 per cent. Systemic effects on osteoclasts or osteoblasts were not observed. Conclusion Local injection of RMA enabled control of tooth movement without systemic side effects in a mouse model.

is missing (Short communication)

Background/Aims: Recently, postendoscopic submucosal dissection electrocoagulation syndrome (PEECS) has attracted attention. However, the criteria for computed tomography (CT) scanning following esophageal endoscopic submucosal dissection (ESD) are unclear. In this study, we aimed to identify the predictive factors of PEECS and the usefulness of CT scanning after esophageal ESD. Methods: A total of 245 lesions in 223 patients who underwent esophageal ESD between February 2008 and October 2018 were retrospectively analyzed. Patients with double cancers, those who experienced procedural accidents, such as aspiration pneumonitis or perforation, and those who were unable to undergo CT were excluded from the study. PEECS evaluation items included body temperature (≤37.7°C = 1 point, ≥37.8°C = 2 points), white blood cell count (Results: The PEECS-positive group comprised 18 out of the 163 patients (11.0%), and mediastinal emphysema was stratified into grades 0 (94), 1 (51), 2 (12), 3 (5), and 4 (1 patient). Three independent risk factors for the onset of PEECS were identified, as follows: resected area ≥750 mm2 (OR 7.28, 95% CI 1.42–37.33, p = 0.017), treatment duration ≥75 min (OR 10.26, 95% CI 1.20–87.77, p = 0.034), and muscle layer exposure (OR 10.92, 95% CI 2.22–53.74, p = 0.003). Two independent predictive factors of high-grade mediastinal emphysema were identified, which were PEECS positivity (OR 4.31, 95% CI 1.29–14.41, p = 0.018), and muscle layer exposure (OR 4.08, 95% CI 1.18–14.06, p = 0.026). Conclusions: A large resected area, prolonged treatment duration, and muscle layer exposure are risk factors for the onset of PEECS. Mediastinal emphysema was observed in 43% of patients following ESD. When marked clinical symptoms of PEECS appear, high-grade mediastinal emphysema may be observed, and therefore CT should be performed in these cases.

Transition metal dichalcogenides (TMDCs) have received attention as atomically thin post‐silicon semiconducting materials. Tuning the carrier concentrations of the TMDCs is important, but their thin structure requires a non‐destructive modulation method. Recently, a surface‐charge transfer doping method was developed based on contacting molecules on TMDCs, and the method succeeded in achieving a large modulation of the electronic structures. The successful dopant is a neutral benzyl viologen (BV0); however, the problem remains of how to effectively prepare the BV0 molecules. A reduction process with NaBH4 in water has been proposed as a preparation method, but the NaBH4 simultaneously reacts vigorously with the water. Here, a simple method is developed, in which the reaction vial is placed on a hotplate and a fragment of air‐stable metal is used instead of NaBH4 to prepare the BV0 dopant molecules. The prepared BV0 molecules show a strong doping ability in terms of achieving a degenerate situation of a TMDC, MoS2. A key finding in this preparation method is that a convection flow in the vial effectively transports the produced BV0 to a collection solvent. This method is simple and safe and facilitates the tuning of the optoelectronic properties of nanomaterials by the easily‐handled dopant molecules.

Individual busulfan (BU) dosing based on pharmacokinetic (PK) data is preferable for hematopoietic stem cell transplantation (HSCT) conditioning, but information on BU PK in infants is scarce. We report BU PK data on HSCT conditioning for infants with KMT2A-gene-rearrangement-positive acute lymphoblastic leukemia (MLL-r ALL). Infants showed wide variation in BU PK indices, such as clearance (CL) and volume of distribution (Vd) value, which are distributed more widely among those who received oral, rather than intravenous (IV), BU. Because the steady state concentration (Css) fluctuates readily in infants, dose re-adjustment based on PK at the initial administration was important even if the initial dose was determined by a PK test. HSCT can be performed safely within the Css range of 600–900 ng/mL per dose, although it was difficult to fit within the therapeutic index of BU. The clinical outcome of engraftment, graft-versus-host disease, adverse events, including sinusoidal obstruction syndrome, and survival did not correlate with the BU PK data, which paradoxically suggests that remaining within this Css range helped minimize transplant-related toxicities, while securing engraftment in infants with MLL-r ALL.

Mutation in the gene encoding tRNA nucleotidyl transferase, CCA-adding 1 (TRNT1), an enzyme essential for the synthesis of the 3′-terminal CCA sequence in tRNA molecules, results in a disorder that features sideroblastic anemia, B-cell immunodeficiency, periodic fever, and developmental delay. Mutations in TRNT1 are also linked to phenotypes including retinitis pigmentosa, cataracts, and cardiomyopathy. To date, it has remained unclear how defective TRNT1 is linked to B-cell deficiency. Here we report the case of a 12-year-old boy without sideroblastic anemia who harbors novel compound heterozygous mutations in TRNT1. Immunophenotypic analysis revealed severely decreased levels of B cells and follicular helper T cells. In the bone marrow, B-cell maturation stopped at the CD19+CD10+CD20+/− pre-B-cell stage. Severe combined immunodeficiency mice transplanted with bone marrow hematopoietic stem cells from the patient showed largely normal B-cell engraftment and differentiation in the bone marrow and periphery at 24 weeks post-transplantation, comparable to those in mouse transplanted with healthy hematopoietic stem cells. Biochemical analysis revealed augmented endoplasmic reticulum (ER) stress response in activated T cells. Peripheral B-cell deficiency of TRNT1 deficiency may be associated with augmented ER stress in immature B cells in the bone marrow.

In addition to malignant diseases, hematopoietic stem cell transplantation (HSCT) is also a vital option as a curative therapy for non-malignant diseases, such as immunodeficiency, and other hematological disorders. Not only for malignant diseases, but for non-malignant diseases, cytotoxic therapy of conditioning regimens are associated with high risks of adverse effects; however, clinical details regarding the long term outcomes of cytotoxic therapy for non-malignant diseases are not documented yet. To clarify the endocrinological consequences of pediatric HSCT for non-malignant disease patients, we conducted a retrospective analysis. From 1983 to 2014, 75 patients that underwent HSCT for non-malignant diseases were selected for this study. Of these, 23 patients (19 men, 4 women) were continuously followed up in our institute, with regular health check-ups for late effects. Based on a multiple linear regression analysis, the glucocorticoid treatment duration for chronic graft-versus-host disease (cGVHD) and the conditioning regimen were found to be independent predictors of growth retardation. All four female patients developed hypogonadism, and required hormone replacement therapy. The conditioning regimen for the four female patients with hypogonadism was based on the use of alkylating agents, and two female patients were treated with a reduced-intensity conditioning (RIC) regimen. Our study revealed that even the RIC regimen was toxic for the gonads in female patients, and that the survivors of both non-malignant and malignant diseases should be followed up carefully after pediatric HSCT.

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

Bone scintigraphy has often been used to evaluate bone metastases. Its functionality is evident in detecting bone metastasis in patients with malignant tumor including prostate cancer, as appropriate treatment and prognosis are dependent on the presence and degree of bone metastasis. The development of a deep learning-based algorithm in the field of information processing has been remarkable in recent years. We hypothesized that a deep learning-based algorithm is useful in diagnosing osseous metastases in patients with prostate cancer using bone scintigraphy. Thus, this study aims to examine the utility of deep learning-based algorithm in detecting bone metastases in patients with prostate cancer, as compared with nuclear medicine specialists. In total, 139 serial patients with prostate cancer, who underwent whole-body bone scintigraphy, were enrolled in this study. Each scintigraphy examination was evaluated visually and independently by nuclear medicine specialists; this was also analyzed using a deep learning-based algorithm. The number of abnormal uptakes was assessed by the nuclear medicine specialists and with a software which used the deep learning-based algorithm, and the per-patient detection rate and the per-region detection rate were then calculated. The software automatically analyzed bone scintigraphy for the presence or absence of osseous metastasis in individual patients, for the 12 body regions. The detection rates analyzed separately by the nuclear medicine specialists and using the software were then compared. The sensitivity, specificity, and accuracy by the specialist and with the software were calculated. The sensitivity, specificity, and accuracy by the nuclear medicine specialists were 100%, 94.9% and 97.1%. On the other hand, they with the software were 91.7%, 87.3% and 89.2%. No statistically significant difference was determined between the per-patient detection rates assessed by the specialists versus the software. In regional assessment, there was also no statistically significant difference between most of the per-region detection rates (10 of 12 regions) by the specialists versus the results obtained by the software. The software with the deep learning-based algorithm might be used as diagnostic aid in the evaluation of bone metastases for prostate cancer patients.

The purpose of our study was to compare the safety and efficacy of hematopoietic cell transplantation (HCT) using fludarabine (Flu)-based reduced intensity conditioning (RIC) with busulfan (BU) or melphalan (Mel) for primary immunodeficiency diseases (PID). We retrospectively analyzed transplant outcome, including engraftment, chimerism, immune reconstitution, and complications in 15 patients with severe combined immunodeficiency (SCID) and 27 patients with non-SCID PID. The patients underwent Flu-based RIC-HCT with BU (FluBU: 7 SCID, 16 non-SCID) or Mel (FluMel: 8 SCID, 11 non-SCID). The targeted low-dose BU with therapeutic drug monitoring was set to 30 mg hour/L for SCID. The 2-year overall survival of all patients was 79.6% and that of patients with SCID in the FluBU and FluMel groups was 100% and 62.5%, respectively. In the FluBU group, all seven patients achieved engraftment, good immune reconstitution, and long-term survival. All five patients receiving umbilical cord blood transplantation achieved complete or high-level mixed chimerism and sufficient specific IgG production. In the FluMel group, six of eight patients achieved complete or high-level mixed chimerism. Viral reactivation or new viral infection occurred in one FluBU group patient and four FluMel group patients. In the non-SCID group, 10 of 11 patients (91%) who received FluMel achieved complete or high-level mixed chimerism but had variable outcomes. Patients with WAS (2/2 patients), NEMO deficiency (2/2 patients), and X-linked hyper IgM syndrome (2/3 patients) who received FluBU achieved complete or high-level mixed chimerism and long-term survival. RIC-HCT with FluBU is a safe and effective strategy for obtaining high-level donor chimerism, immune reconstitution including B cell function, and long-term survival in patients with SCID. In patients with non-SCID PID, the results varied according to the subtype of the disease. Further prospective studies are required to optimize the conditioning regimen for non-SCID PID.

One of the elements that make up VR is “self-projection”. This is to create a state where a person can enter the virtual space and experience it as a first person. If not only HMD but also haptic devices can be used to touch and move objects in the virtual space with the haptic sensation, it is thought that self-projection performance will improve. Therefore, we developed a haptic device with two rings (two-point control type SPIDAR-GCC) so that the user can perform knob operation in the same way as in reality. And we constructed workspaces in virtual and real space with highly similarity to investigate the difference between the work performed in virtual space and in real space. Using this device and HMD, the experimental participants were asked to accomplish a pick-and-place task which is pinching the peg with two fingers and insert it into the hole in the pegboard. In this experiment, the difference in the manner to move objects between in real space and in virtual space was observed. It was mainly due to the errors of measuring the displacements of fingers in the haptic device.

Histiocytic sarcoma in advanced clinical stages is typically an aggressive neoplasm, with poor response to conventional chemotherapy. An 18-year-old male with refractory histiocytic sarcoma that had transformed from Rosai-Dorfman disease was admitted to our hospital. A pathogenic variant of MAP2K1 was detected by next-generation sequencing of tumor specimens. Affected regions showed excellent responses to the MEK inhibitor trametinib. It has been reported that RAS/MEK/ERK pathway is activated in many cases of histiocytic sarcoma. MEK inhibition may represent a useful treatment option in histiocytic sarcoma.

Background Acute lymphoblastic leukaemia with mixed lineage leukaemia gene rearrangement (MLL-ALL) frequently affects infants and is associated with a poor prognosis. Primary refractory and relapsed disease due to resistance to glucocorticoids (GCs) remains a substantial hurdle to improving clinical outcomes. In this study, we aimed to overcome GC resistance of MLL-ALL. Methods Using leukaemia patient specimens, we performed bioinformatic analyses to identify target genes/pathways. To test inhibition of target pathways in vivo, we created pre-clinical therapeutic mouse patient-derived xenograft (PDX)-models by transplanting human MLL-ALL leukaemia initiating cells (LIC) into immune-deficient NSG mice. Finally, we conducted B-cell lymphoma-2 (BCL-2) homology domain 3 (BH3) profiling to identify BH3 peptides responsible for treatment resistance in MLL-leukaemia. Findings Src family kinases (SFKs) and Fms-like tyrosine kinase 3 (FLT3) signaling pathway were over-represented in MLL-ALL cells. PDX-models of infant MLL- ALL recapitulated GC-resistance in vivo but RK-20449, an inhibitor of SFKs and FLT3 eliminated human MLL-ALL cells in vivo, overcoming GC-resistance. Further, we identified BCL-2 dependence as a mechanism of treatment resistance in MLL-ALL through BH3 profiling. Furthermore, MLL-ALL cells resistant to RK-20449 treatment were dependent on the anti-apoptotic BCL-2 protein for their survival. Combined inhibition of SFKs/FLT3 by RK-20449 and of BCL-2 by ABT-199 led to substantial elimination of MLL-ALL cells in vitro and in vivo. Triple treatment combining GCs, RK-20449 and ABT-199 resulted in complete elimination of MLL-ALL cells in vivo. Interpretation SFKs/FLT3 signaling pathways are promising targets for treatment of treatment-resistant MLL-ALL. Combined inhibition of these kinase pathways and anti-apoptotic BCL-2 successfully eliminated highly resistant MLL-ALL and demonstrated a new treatment strategy for treatment-resistant poor-outcome MLL-ALL. Funding This study was supported by RIKEN (RIKEN President's Discretionary Grant) for FI, Japan Agency for Medical Research and Development (the Basic Science and Platform Technology Program for Innovative Biological Medicine for FI and by NIH CA034196 for LDS. The funders had no role in the study design, data collection, data analysis, interpretation nor writing of the report.

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.

Key Clinical Message Myeloid/natural killer cell precursor acute leukemia (MNKPL) is a rare leukemia subtype characterized by a high incidence of extramedullary infiltration. No appropriate treatment strategy has so far been developed. Acute myelogenous leukemia‐type chemotherapy combined with L‐Asparaginase is an effective treatment for MNKPL. Hematopoietic cell transplantation is a second option in refractory cases.