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In the treatment of childhood acute lymphoblastic leukemia (ALL), excess shortening of maintenance therapy resulted in high relapse rate, as shown by our previous trial, TCCSG L92-13, in which maintenance therapy was terminated at 1 year from initiation of treatment. In this study, we aimed to confirm the long-term outcome of L92-13, and to identify who can or cannot be cured by shorter duration of maintenance therapy. To obtain sentinel cytogenetics information that had been missed before, we performed genetic analysis with genomic microarray and target intron-capture sequencing from diagnostic bone marrow smear. Disease-free survival (DFS) at 10 years from the end of therapy was 66.0±2.8%. Females (n=138) had better DFS (74.6±3.7%) than males (n=142, 57.5±4.2%, P=0.002). Patients with TCF3-PBX1(n=11) and ETV6-RUNX1(n=16) had excellent DFS (90.9±8.7% and 93.8±6.1%, respectively), whereas high hyperdiploidy (n=23) was the most unfavorable subgroup, with 56.6±10.3% of DFS. Short duration of therapy can cure more than half of pediatric ALL, especially females, TCF3-PBX1and ETV6-RUNX1. Our retrospective observations suggest a gender/karyotype inhomogeneity on the impact of brief therapy.

Overexpression of MYCN is a hallmark of neuroblastoma (NB). ALKR1275Q, an activating mutation of ALK (anaplastic lymphoma kinase), has been found in sporadic and familial NB patients. In this report, we demonstrated that ALKR1275Qknock-in, MYCN transgenic compound mice developed NB with complete penetrance. Transcriptome analysis revealed that ALKR1275Qglobally downregulated the expression of extracellular matrix (ECM)- and basement membrane (BM)-associated genes in both primary neuronal cells and NB tumors. Accordingly, ALKR1275Q/MYCN tumors exhibited reduced expression of ECM/BM-related proteins as compared with MYCN tumors. In addition, on MYCN transduction, ALKR1275Q-expressing neuronal cells exhibited increased migratory and invasive activities. Consistently, enhanced invasion and metastasis were demonstrated in ALKR1275Q/MYCN mice. These results collectively indicate that ALKR1275Qconfers a malignant potential on neuronal cells that overexpress MYCN by impairing normal ECM/BM integrity and enhancing tumor growth and dissemination. Moreover, we found that crizotinib, an ALK inhibitor, almost completely inhibited the growth of ALKR1275Q/MYCN tumors in an allograft model. Our findings provided insights into the cooperative mechanism of the mutated ALK and overexpressed MYCN in the pathogenesis of NB and demonstrated the effectiveness of crizotinib on ALKR1275Q-positive tumors.

Critically ill patients are at increased risk of thromboembolic complications. Japanese patients admitted to the intensive care unit of Gunma University Hospital were divided into critically ill (high score) and moderately ill (low score) groups according to mean Acute Physiology and Chronic Health Evaluation (APACHE) II score. White blood cell count, potassium, creatinine, immunoglobulin G and blood passage time, measured using the microchannel method, were significantly higher and the platelet aggregation score and platelet count were significantly lower in the high-score group than in the low-score group, but other haemorheological parameters did not differ significantly between the two groups. White blood cell count, potassium, creatinine, APACHE II score and levels of immunoglobulins G, A and M were positively correlated with blood passage time in all patients. Critically ill patients had impaired blood rheology, which could result from increased white blood cell count, potassium, creatinine and immunoglobulins and may be associated with the pathophysiology of the thromboembolic process.