Germline pathogenic
ETV6
variants have been discovered in families with inherited thrombocytopenia and predisposition to hematological and solid malignancies. We present a patient with short stature ...who was initially diagnosed with chronic immune thrombocytopenia. Subsequently, the patient developed acute lymphoblastic leukemia, followed by mammary analog secretory carcinoma. Sequencing analysis identified an
ETV6
c.641C > T (p.Pro214Leu) germline variant. The variant protein exhibited attenuated nuclear localization, increased protein degradation, and reduced transcription repression function. Our findings suggest that the
ETV6
gene should be sequenced in patients with inherited thrombocytopenia and malignancy, and emphasize the importance of careful follow-up to identify secondary cancer in patients with pathogenic
ETV6
variants.
The JLSG-96 study reported very low mortality rates for children newly diagnosed with multifocal Langerhans cell histiocytosis (LCH). The JLSG-02 study was performed to further improve the prognosis ...from 2002 to 2009. The present study compared the therapeutic results of these two studies in terms of multisystem disease. All patients were treated with 6 weeks of the Induction A regimen, comprising cytarabine, vincristine and prednisolone, followed by maintenance therapy. Poor responders to Induction A were switched to Induction B. JLSG-02 has been revised from JLSG-96 in the following respects: prednisolone dosage during Induction A increased; duration of maintenance therapy extended from 24 to 48 weeks; cyclosporine introduced to Induction B for progressive disease. One hundred forty-seven children with multisystem LCH were evaluated. Of these, 84 were positive for risk of organ involvement (RO) and 63 were RO-negative. At the 6-week point, 76.2 % of RO+ and 93.7 % of RO− patients responded to Induction A. Five-year event-free survival (EFS) was 46.2 % 95 % confidence (CI), 35.5–56.9 for RO+ and 69.7 % (58.4–81.1) for RO−, which was significantly superior to that in JLSG-96 26.8 % (13.3–40.4) and 38.9 % (16.4–61.4), respectively. The intensified induction and prolonged maintenance regimens in JLSG-02 improved EFS in patients with multisystem LCH.
Tyrosine kinase 2 (Tyk2) is a nonreceptor tyrosine kinase that belongs to the Janus kinase (Jak) family. Here we identified a homozygous Tyk2 mutation in a patient who had been clinically diagnosed ...with hyper-IgE syndrome. This patient showed unusual susceptibility to various microorganisms including virus, fungi, and mycobacteria and suffered from atopic dermatitis with elevated serum IgE. The patient's cells displayed defects in multiple cytokine signaling pathways including those for type I interferon (IFN), interleukin (IL)-6, IL-10, IL-12, and IL-23. The cytokine signals were successfully restored by transducing the intact Tyk2 gene. Thus, the Tyk2 deficiency is likely to account for the patient's complex clinical manifestations, including the phenotype of impaired T helper 1 (Th1) differentiation and accelerated Th2 differentiation. This study identifies human Tyk2 deficiency and demonstrates that Tyk2 plays obligatory roles in multiple cytokine signals involved in innate and acquired immunity of humans, which differs substantially from Tyk2 function in mice.
Proteins are modified and folded within the endoplasmic reticulum (ER). When the influx of proteins exceeds the capacity of the ER to handle the load, the ER is "stressed" and protein biogenesis is ...affected. We have previously shown that the induction of ER stress by ATP depletion in podocytes leads to mislocalization of nephrin and subsequent injury of podocytes. The aim of the present study was to determine whether ER stress is associated with proteinuria in vivo and whether the immunosuppressant mizoribine may exert its antiproteinuric effect by restoring normal nephrin biogenesis. Induction of nephrotic-range proteinuria with puromycin aminonucleoside in mice increased expression of the ER stress marker GRP78 in podocytes, and led to the mislocalization of nephrin to the cytoplasm. In vitro, mizoribine, through a mechanism likely dependent on the inhibition of inosine 5'-monophosphate dehydrogenase (IMPDH) activity in podocytes, restored the intracellular energy balance by increasing levels of ATP and corrected the posttranslational processing of nephrin. Therefore, we speculate that mizoribine may induce remission of proteinuria, at least in part, by restoring the biogenesis of slit diaphragm proteins in injured podocytes. Further understanding of the ER microenvironment may lead to novel approaches to treat diseases in which abnormal handling of proteins plays a role in pathogenesis.
Lymphoblasts of acute lymphoblastic leukemia origin reappeared in a male patient 34 years after the initial diagnosis. Comparison of DNA profiles of the initial and reappeared lymphoblasts revealed a ...partially identical sequence, indicating the possibility that these lymphoblasts may have been present as preleukemic stem cells at the time of diagnosis and remained dormant for a long period until additional events conferred proliferative activity to these dormant preleukemic stem cells. Thus, in some cases of very late relapse, the reappearance of lymphoblasts may not be due to the relapse of the original leukemic clone, but to a clonal progression of a pre-existing subclone derived from preleukemic stem cells.
Despite improvements in the prognosis of acute myelogenous leukemia in patients with Down syndrome, the prognosis of acute lymphocytic leukemia (DS-ALL) in these patients is still poorer than that of ...ALL in the general population. We compared treatment results between 4 patients with DS-ALL and 16 non-Down syndrome patients with ALL (NDS-ALL). Four patients with DS-ALL treated with TCCSG protocols achieved complete remission by the end of the induction phase. During the high-dose methotrexate (HD-MTX) phase, the dosage of MTX was reduced from 3 to 2 g/m
2
after the syndrome of inappropriate ADH secretion developed in the first patient. All DS-ALL patients had severe mucositis and a longer period of anorexia than NDS-ALL patients, even after dose reductions, resulting in a longer HD-MTX phase in DS-ALL patients than in NDS-ALL patients. The mean dosages of 6-MP and MTX during the maintenance phase were significantly lower in DS-ALL patients than in NDS-ALL patients (6-MP 22.1 ± 9.9 mg/m
2
and MTX 16.1 ± 4.5 mg/m
2
vs. 6-MP 43.5 ± 23.1 mg/m
2
and MTX 25.2 ± 8.8 mg/m
2
, respectively). All DS-ALL patients have been in complete remission for a median of 10 years 0 month (range: 8 years 10 months-14 years 1 month) as of January 1, 2017. DS-ALL patients may receive the same treatment protocol as that for NDS-ALL patients with adequate care and few modifications, and this strategy may result in the expansion of treatment protocols suitable for DS-ALL patients in the future.
Although the therapeutic outcome of acquired aplastic anemia has improved markedly with the introduction of immunosuppressive therapy using antithymocyte globulin and cyclosporine, a significant ...proportion of patients subsequently relapse and require second-line therapy. However, detailed analyses of relapses in aplastic anemia children are limited.
We previously conducted two prospective multicenter trials of immunosuppressive therapy for children with aplastic anemia: AA-92 and AA-97, which began in 1992 and 1997, respectively. In this study, we assessed the relapse rate, risk factors for relapse, and the response to second-line treatment in children with aplastic anemia treated with antithymocyte globulin and cyclosporine.
From 1992 to 2007, we treated 441 children with aplastic anemia with standard immunosuppressive therapy. Among the 264 patients who responded to immunosuppressive therapy, 42 (15.9%) relapsed. The cumulative incidence of relapse was 11.9% at 10 years. Multivariate analysis revealed that relapse risk was significantly associated with an immunosuppressive therapy regimen using danazol (relative risk, 3.15; P=0.001) and non-severe aplastic anemia (relative risk, 2.51; P=0.02). Seventeen relapsed patients received additional immunosuppressive therapy with antithymocyte globulin and cyclosporine. Eight patients responded within 6 months. Seven of nine non-responders to second immunosuppressive therapy received hematopoietic stem cell transplantation and five are alive. Eleven patients underwent hematopoietic stem cell transplantation directly and seven are alive.
In the present study, the cumulative incidence of relapse at 10 years was relatively low compared to that in other studies mainly involving adult patients. A multicenter prospective study is warranted to establish optimal therapy for children with aplastic anemia.
Data on long-term outcomes of children with refractory immune thrombocytopenia (ITP) treated with rituximab are limited. We retrospectively analyzed the long-term effect of rituximab on 22 pediatric ...ITP patients (11 boys and 11 girls). Compete response (CR) (platelet count ≥100 × 10
9
/L) and partial response (PR) (platelet count 30–99 × 10
9
/L) were achieved in nine (41 %) and two (9 %) patients, respectively. Of the 11 responders, eight subsequently relapsed 2–26 months after initial rituximab treatment. The 5-year relapse-free rate was 14 % (3/22, 95 % confidence interval: 0–27 %) with a median follow-up period of 6.4 years. Five initial responders with subsequent relapse and one non-responder received multiple rituximab treatments of nine courses; all patients responded to the second rituximab therapy without any significant toxicity. All eight patients who relapsed after an initial response and six of 11 non-responders achieved CR or PR with subsequent treatment, including repeated courses of rituximab, splenectomy, steroids, and other immunomodulating agents. Our findings indicated that the sustained effect of rituximab on children with refractory ITP is low, but that the long-term outcome of ITP itself is not poor. Furthermore, repeated rituximab administration may be a promising therapy for those who relapse after an initial response.
The present study aimed to identify optimal treatment intensity in children with mosaic Down syndrome (DS) and acute megakaryoblastic leukemia (AMKL). A retrospective review of AMKL patients was ...undertaken to identify mosaic DS children. Between November 1992 and November 2007, seven children were diagnosed as mosaic DS and AMKL. The median age at diagnosis was 29 months (range 4–34 months). Three patients had a past history of transient abnormal myelopoiesis. UPN1–4 were treated with intermediate-dose cytarabine and UPN4 received additional one course of high-dose cytarabine. All of these patients were remained in first CR. UPN5–7 were treated with high-dose cytarabine according to the AML99 protocol. UPN5 with
GATA1
mutation suffered from acute pneumonia and pancreatitis and discontinued chemotherapy. UPN7 relapsed after cessation of chemotherapy and was rescued with allo-PBSCT. The cumulative doses of cytarabine were 3.5–10.65 g/m
2
in the UPN1–4 and 40.4–78.4 g/m
2
in the UPN5–7. The 8-year overall survival was 100% and the 8-year event-free survival 85.7%, respectively. Our retrospective study reveals that patients with mosaic DS and AMKL have a good prognosis. Reduction in intensity may work in patients with mosaic DS as well as with AML-DS.
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