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Background: Transient receptor potential cation channel subfamily V member 2 (TRPV2) functions as a stretch-sensitive calcium channel, with overexpression in the sarcolemma of skeletal and cardiac myocytes leading to detrimental calcium influx and triggering muscle degeneration. In our previous pilot study, we showed that tranilast, a TRPV2 inhibitor, reduced brain natriuretic peptide levels in two patients with muscular dystrophy and advanced heart failure. Building on this, we performed a single-arm, open-label, multicenter study herein to evaluate the safety and efficacy of tranilast in the treatment of advanced heart failure in patients with muscular dystrophy. Results: This study involved 18 patients with muscular dystrophy who had brain natriuretic peptide levels > 100 pg/mL, despite receiving standard cardioprotective therapy. Tranilast was administered orally at a dose of 100 mg three times daily. Over the short-term period (28 weeks), the primary endpoint of change ratio in the logarithm of brain natriuretic peptide level from baseline to 28 weeks was not significant in the full analysis set but was lower in the per set protocol compared with data from a previous beta-blocker treatment study. All 15 patients who completed the short-term treatment consented to be enrolled in long-term therapy for an additional 116 weeks. After all participants completed the long-term treatment, we analyzed all data. TRPV2 expression on the peripheral blood mononuclear cell surfaces decreased throughout the study period, confirming that the TRPV2 inhibitory effect of tranilast was maintained over time. Despite the presence of progressive disease, cardiac indices such as brain natriuretic peptide level, human atrial natriuretic peptide level, and fractional shortening, remained stable, and only brain natriuretic peptide levels at 144 weeks showed significant changes. The survival rate was 80.7%, and no cardiac deaths were reported. Regarding safety, no serious adverse events associated with tranilast were noted, except for recurrent diarrhea during the short-term period in one case. Conclusions: The findings suggest that tranilast can inhibit TRPV2 expression for an extended period and is effective in preventing the worsening of cardiac function and subsequent death from heart failure. Clinical trial registration details: The study was registered in the UMIN Clinical Trials Registry (UMIN-CTR: UMIN000031965, URL: http://www.umin.ac.jp/ctr/) [March 30, 2018] and the Japan Registry of Clinical Trials (jRCT, registration number: jRCTs031180038, URL: https://jrct.niph.go.jp/) [November 12, 2021]. Patient registration was initiated on December 19, 2018. [ABSTRACT FROM AUTHOR]

Background: Asparaginase is essential for treating T‐cell acute lymphoblastic leukemia (T‐ALL). Despite the ongoing debate on whether T‐ALL and T‐cell lymphoblastic lymphoma (T‐LBL) are the same disease entity or two distinct diseases, patients with T‐LBL often receive the same or similar treatment protocols as those with T‐ALL. Methods: The outcomes of patients with or without L‐asparaginase discontinuation were retrospectively analyzed among four national protocols: Japan Association of Childhood Leukemia Study (JACLS) ALL‐02 and ALL‐97 for T‐ALL and Japanese Pediatric Leukemia/Lymphoma Study Group ALB‐NHL03 and JACLS NHL‐98 for T‐LBL. The hazard ratio (HR) was calculated with the Cox regression model by considering L‐asparaginase discontinuation as a time‐dependent variable. Results: In total, 199 patients with T‐ALL, and 133 patients with T‐LBL were included. L‐asparaginase discontinuation compromised event‐free survival (EFS) of T‐ALL patients (ALL‐02: HR 3.32, 95% confidence interval [CI] 1.40–7.90; ALL‐97: HR 3.39, 95%CI 1.19–9.67). Conversely, EFS compromise was not detected among T‐LBL patients (ALB‐NHL03: HR 1.39, 95%CI 0.41–4.68; NHL‐98: HR 0.92, 95%CI 0.11–7.60). Conclusion: The effects of L‐asparaginase discontinuation differed between T‐ALL and T‐LBL. We assume that the differential impact results from (1) the inherent differential response to L‐asparaginase between them and/or (2) a less stringent assessment of early treatment response in T‐LBL than in T‐ALL. Given the poor salvage rate of refractory or relapsed T‐ALL and T‐LBL, optimization of the frontline therapy is critical, and the current study provides a new suggestion for further treatment modifications. However, larger studies in contemporary intensified treatment protocols are required. [ABSTRACT FROM AUTHOR]

Background: The benefit of adding rituximab to standard lymphomes malins B (LMB) chemotherapy for children with high‐risk mature B‐cell non‐Hodgkin lymphoma (B‐NHL) has previously been demonstrated in an international randomized phase III trial, to which the Japanese Pediatric Leukemia/Lymphoma Study Group could not participate. Methods: To evaluate the efficacy and safety of rituximab in combination with LMB chemotherapy in Japanese patients, we conducted a single‐arm multicenter trial. Results: In this study, 45 patients were enrolled between April 2016 and September 2018. A total of 33 (73.3%), 5 (11.1%), and 6 (13.3%) patients had Burkitt lymphoma/leukemia, diffuse large B‐cell lymphoma, and aggressive mature B‐NHL, not otherwise specified, respectively. Ten (22.2%) and 21 (46.7%) patients had central nervous system disease and leukemic disease, respectively. The median follow‐up period was 47.5 months. Three‐year event‐free survival and overall survival were 97.7% (95% confidence interval, 84.9–99.7) and 100%, respectively. The only event was relapse, which occurred in a patient with diffuse large B‐cell lymphoma. Seven patients (15.6%) developed Grade 4 or higher non‐hematologic adverse events. Febrile neutropenia was the most frequent Grade 3 or higher adverse event after the pre‐phase treatment, with a frequency of 54.5%. Conclusion: The efficacy and safety of rituximab in combination with LMB chemotherapy in children with high‐risk mature B‐NHL was observed in Japan. [ABSTRACT FROM AUTHOR]

Summary: 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. [ABSTRACT FROM AUTHOR]

Summary: In this study, we performed a retrospective analysis of a cohort of Japanese paediatric patients with B‐cell precursor (BCP)‐acute lymphoblastic leukaemia (ALL) treated with a Berlin‐Frankfurt‐Münster (BFM)95‐based protocol, to clarify the incidence, clinical characteristics, and risk factors of osteonecrosis (ON) in comparison to the ALL‐02 protocol. We identified a high frequency of ON with the BFM95‐based protocol compared to the ALL‐02 protocol. The incidence of symptomatic ON with the BFM95‐based protocol is comparable to previous studies in Western countries. We believe that the type of treatment regimen has more impact on the incidence of symptomatic ON in paediatric ALL than ethnicity. [ABSTRACT FROM AUTHOR]

Summary: Peripheral T‐cell lymphoma (PTCL) is a group of heterogeneous non‐Hodgkin lymphomas showing a mature T‐cell or natural killer cell phenotype, but its molecular abnormalities in paediatric patients remain unclear. By employing next‐generation sequencing and multiplex ligation‐dependent probe amplification of tumour samples from 26 patients, we identified somatic alterations in paediatric PTCL including Epstein–Barr virus (EBV)‐negative (EBV–) and EBV‐positive (EBV+) patients. As recurrent mutational targets for PTCL, we identified several previously unreported genes, including TNS1, ZFHX3, LRP2,NCOA2 and HOXA1, as well as genes previously reported in adult patients, e.g. TET2, CDKN2A, STAT3 and TP53. However, for other reported mutations, VAV1‐related abnormalities were absent and mutations of NRAS, GATA3 and JAK3 showed a low frequency in our cohort. Concerning the association of EBV infection, two novel fusion genes: STAG2‐AFF2 and ITPR2‐FSTL4, and deletion and alteration of CDKN2A/2B, LMO1 and HOXA1 were identified in EBV– PTCL, but not in EBV+ PTCL. Conversely, alterations of PCDHGA4, ADAR, CUL9 and TP53 were identified only in EBV+ PTCL. Our observations suggest a clear difference in the molecular mechanism of onset between paediatric and adult PTCL and a difference in the characteristics of genetic alterations between EBV– and EBV+ paediatric PTCL. [ABSTRACT FROM AUTHOR]

The objective of this study was to assess the impact of the primary prophylaxis of granulocyte colony-stimulating factor (G-CSF) in the management of childhood B-cell non-Hodgkin lymphoma (B-NHL). Patients with advanced-stage mature B-NHL were randomized to receive prophylactic G-CSF (G-CSF+) or not receive G-CSF (G-CSF−) based on protocols of the B-NHL03 study. The G-CSF group received 5 μg/kg/d Lenograstim from day 2 after each course of six chemotherapy courses. Fifty-eight patients were assessable, 29 G-CSF + and 29 G-CSF−. G-CSF + patients showed a positive impact on the meantime to neutrophil recovery and hospital stay. On the other hand, they had no impact in the incidences of febrile neutropenia, serious infections, stomatitis and total cost. Our study showed that administration of prophylactic G-CSF through all six chemotherapy courses for childhood B-NHL showed no clinical and economic benefits for the management of childhood B-NHL treatment. [ABSTRACT FROM AUTHOR]

The article presents a case study of a nine-year-old boy who presented to the emergency room because of abdominal pain and an elevated white blood cell (WBC) count. Immunophenotyping of his lymphoblasts and a chromosomal analysis of his bone marrow cells revealed an abnormal karyotype. The article discusses Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph + ALL), resistance to the drugs imatinib and dasatinib, and remission from monotherapy with the drug nilotinib.