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The effect of genetic variation on second malignant neoplasms (SMNs) remains unclear. First, we identified the pathogenic germline variants in cancer-predisposing genes among 15 children with SMNs after childhood leukemia/lymphoma using whole-exome sequencing. Because the prevalence was low, we focused on the association between SMNs and NUDT15 in primary acute lymphoblastic leukemia (ALL) cases. NUDT15 is one of the 6-mercaptopurine (6-MP) metabolic genes, and its variants are common in East Asian individuals. The prevalence of NUDT15 hypomorphic variants was higher in patients with SMNs (n = 14; 42.9%) than in the general population in the gnomAD database (19.7%; P = .042). In the validation study with a cohort of 438 unselected patients with ALL, the cumulative incidence of SMNs was significantly higher among those with (3.0%; 95% confidence interval [CI], 0.6% to 9.4%) than among those without NUDT15 variants (0.3%; 95% CI, 0.0% to 1.5%; P = .045). The 6-MP dose administered to patients with ALL with a NUDT15 variant was higher than that given to those without SMNs (P = .045). The 6-MP–related mutational signature was observed in SMN specimens after 6-MP exposure. In cells exposed to 6-MP, a higher level of 6-MP induced DNA damage in NUDT15-knockdown induced pluripotent stem cells. Our study indicates that NUDT15 variants may confer a risk of SMNs after treatment with 6-MP in patients with ALL.

確定診断前に凝固第VIII因子(F VIII)製剤の緊急投与を要した重症型血友病A の2 乳児例を報告する.症例1 は10 か月男児.反復する嘔吐を主訴に入院した.左上肢に腫張を伴う筋肉内出血と硬膜外血腫を認めた.症例2 は10 か月男児.止血困難な口唇裂傷後の出血を主訴に来院し,重度の貧血を認めた.2 例ともプロトロンビン時間(PT)正常,活性化プロトロンビン時間(APTT)の著明な延長より,血友病を強く疑った.いずれも重篤な出血を認めたため,凝固因子活性値による確定診断を待たず,緊急でF VIII製剤の投与を試みた.投与後2 例ともAPTT は改善し,出血症状も改善した.後日2 例ともにF VIII活性が1%未満と判明し,重症型血友病A と確定診断された., The cause of hemophilia A and B involves loss of factor VIII( FVIII) and factor IX( FIX), respectively. The hereditary form of this hemorrhagic disease is X-linked recessive. It is well established that the critical region for hemophilia A is localized on Xq28 and for hemophilia B on Xq27.1- 27.2. The initial symptom is bleeding in the mucous membranes often accompanied by intramuscular and intraarticular hemorrhage. The hemorrhages in the joints cause joint contracture as a sequela. The diagnosis of hemophilia is based on a normal bleeding and prothrombin time(PT)and prolonged activated partial thromboplastin time (APTT). We report here two infants of the severe typical from of hemophilia A who were treated with sufficient needed dosage of recombinant factor VIII before a final diagnosis was made. Case 1 was a 10-month-old boy. He was hospitalized for recurrent vomiting. He had intramuscular bleeding with swelling of the left shoulder and upper extremity. A head CT showed multiple epidural hematomas. Case 2 was a 10-month-old boy. He was sent to our hospital because of a lip laceration that did not stop bleeding, and he had severe anemia. We made the diagnosis of hemophilia A based on both their normal laboratory finding of PT and on the finding of extended APTT. Before confirming the decision diagnosis of hemophilia, we intravenously injected recombinant FVIII immediately, because of the severe hemorrhagic symptoms. After the therapy, both the APTT and hemorrhagic symptoms improved. These two cases were later confirmed as a severe infantile form of hemophilia A with less than 1 % factor VIII activity.

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-PBX1 and ETV6-RUNX1. Our retrospective observations suggest a gender/karyotype inhomogeneity on the impact of brief therapy.

Werdnig-Hoffmann病(WH)は乳児期早期に発症する進行性の筋萎縮を主体とする常染色体劣性疾患で,知的な障害を認めない.生命予後は不良であり2歳までに呼吸筋力の低下に伴う呼吸不全のため死亡する.我々はWHと遺伝子診断された男児の終末期ケアを経験した.児の疾患および終末期ケアについて,両親との医療面接により十分な説明および話し合いを行なった.その結果,両親より「体に侵襲のある気管切開手術や人工呼吸管理を含めた延命処置は希望しない」との方針が示され,我々も同意した.その後,児は6か月で重度の誤嚥性肺炎を発症し入院管理を要した.排痰の目的で気管内挿管を施行し,急性呼吸不全に対し酸素投与を施行した.気管内挿管後は適時サクションチューブから喀痰の喀出につとめた.栄養は経鼻胃管を用いた.児は入院から6病日目に家族や知人に見守られる中,母親に抱かれながら永眠した.WHの終末期ケアについてガイドラインはない.医療者は個々の症例に応じて家族と児の最大の利益を考慮した終末期ケアを励行することが肝要である.その際,両親へのインフォームド・コンセントに際し,挿管管理と人工呼吸管理を同様に説明するのではなく,本例のように気管内挿管を施行しかつ人工呼吸管理はしないという選択肢もあり,一考を要する., Werdnig-Hoffmann disease (WH) develops progressiveamyotrophy in the early infantile stage and does not progressto mental retardation. The heredity of WH is autosomalrecessive. The life prognosis is poor, and breathing muscularstrength deteriorates by 2 years of age and the infantdies of respiratory failure. This report describes the hospicecare of the boy of WH. A medical interview was providedto the parents concerning hospice care of the child beforehand.The parents did not want the patient to undergo atracheal surgical operation, or receive artificial respirationmanagement, or life-prolonging treatment, and, after informedconsent, the medical staff agreed to the parents requests.Afterwards, the child developed severe aspirationrelatedpneumonia at six months of age and thus requiredhospitalization. The patient was treated with tracheal intubationfor acute respiratory failure and administered oxygen.The condition of a patient was temporarily stable aftertracheal incubation. He thereafter received nasogastric tubefeeding. Unfortunately, the child died in six days after indergoingtracheal intubation.There are no guidelines for the hospice care of patientswith WH. It is important that the medical staff provideshospice care that provides the maximum benefit to the familyand the child depending on each individual case. Informedconsent should be obtained for the parents, with regardto intubation and artificial respiration. The decisionsconcerning intubation and artificial respiratory managementare important issues of medical ethics.

A 9-year-old male presented with a renal tumor that showed a cystic structure with calcification on computed tomography. A pathological analysis of the resected tumor suggested clear cell sarcoma of the kidney (CCSK). Thus, this patient suffered atypical CCSK with significant calcification and gross necrosis. A novel chromosomal abnormality was also identified in the tumor.

3年間に当院周産期センター新生児部門に入院し,経皮的中心静脈(PCV)カテーテルを使用した新生児は69例であった。これらの症例を対象とし,カテーテルの挿入理由,抜去理由,維持日数,合併症などについて後方視的に検討した。カテーテルの挿入理由は,超低出生体重児の輸液管理目的が最も多く,抜去理由は輸液が不要となった症例が最も多かった。カテーテルの平均維持日数は17.7日であった。カテーテルの留置中の合併症としては敗血症が4例(5.8%)であったが,カテーテル敗血症と診断したのは1例(1.4%)のみであった。その他に胸水貯留と横隔膜挙上の症例を計2例経験した。経皮的中心静脈カテーテルは,長期間にわたって留置が可能であり,合併症が少ないことから,新生児の輸液管理に非常に有用であると考えられた。, We used percutaneous central venous catheters (PCV catheters) for 69 neonates, who entered our neonatal intensive care unit for recent 3 years. We retrospectively researched the reasons of insertion and removal of PCV catheters, and complications of the catheters. The catheters were inserted mainly for the maintenance of fluid administration of extremely low birth weight infants, and were removed mainly for the end of fluid administration. The catheters were maintained for 17.7 days on the average. The sepsis occurred in 4 infants (5.8%) during indwelling of PCV catheters, however, only one infant (1.4%) was diagnosed as the catheter-related sepsis. Expect for the sepsis, two infants complicated retention of pleural fluid or elevation of diaphragm. Our results disclosed that PCV catheter caused be use for the long-term indwelling of catheter for fluid administration, and had rare frequency of complications. We conclude that PCV catheter is very useful for the fluid administration of neonates.

RATIONALE Central nervous system (CNS) leukemia is a frequent diagnosis in pediatric acute myeloblastic leukemia (AML) and includes neural symptoms. However, CNS leukemia is rarely associated with central hypsothyroidism. PATIENT CONCERNS AND DIAGNOSES A 2-year-old female with AML with MLL rearrangement presented with CNS infiltration. Laboratory tests suggested the presence of central hypothyroidism (thyroid-stimulating hormone [TSH]: 0.48 mIU/ml, normal range 0.7-6.4 mIU/ml; serum free thyroxine [FT4]: 0.62 ng/dl, normal range 0.8-2.2 ng/dl; free triiodothyronine: 1.57 pg/ml, normal range 2.7-5.6 pg/ml). Magnetic resonance imaging detected no lesions in the hypothalamus, pituitary, or thyroid. INTERVENTIONS AND OUTCOMES Levothyroxine (2.5 mg/kg/day) was administered together with chemotherapy and intrathecal injection of methotrexate, cytarabine, and hydrocortisone into the cerebrospinal fluid. The FT4 concentration increased after levothyroxine treatment, but later decreased after relapse of CNS leukemia. The TSH concentrations remained low. After remission of CNS leukemia, the TSH and FT4 concentrations quickly recovered to their normal ranges. LESSONS We believe that the CNS leukemia directly affected TSH and thyroid hormone secretion in our patient.

Hematopoietic stem cell transplantation for X-linked thrombocytopenia from a mild symptomatic carrier

Burkitt-type acute lymphoblastic leukemia (B-ALL) is thought as a variant of Burkitt lymphoma/leukemia and derived from mature B-cell lymphoblast.B-ALL was developed in a 10-year-old girl. Two characteristics were apparent in this case. First, the lymphoblastic cells were positive for CD10, CD19, CD20, and CD22, but negative for terminal deoxynucleotidyl transferase and surface immunoglobulins, indicating a B-cell immunophenotype. The detection of t(8;14)(q24;q32) with a chromosomal analysis is required for a diagnosis of B-ALL. Second, der(1)(pter → q32.1::q32.1 → q21.1::q11 → qter) was detected, in which 1q21.1 to 1q32.1 was inverted and inserted. Finally, partial tetrasomy of 1q was also present. Because B-ALL with abnormal chromosome 1 has been reported poor outcome, the usual chemotherapy for stage 4 Burkitt lymphoma with added rituximab was administered for our patient.We report B-ALL with precursor B-cell immunophenotype and interesting partial tetrasomy of 1q.

In pro-B cell acute lymphoblastic leukemia (ALL), expression of the E2A-HLF fusion gene as a result of t(17;19)(q22;p13) is associated with poor prognosis, hypercalcemia, and hemorrhagic complications. We previously reported that the E2A-HLF fusion protein protects interleukin-3 (IL-3)–dependent lymphoid cells from apoptosis caused by cytokine starvation. Here, we report that annexin II, a surface phospholipid-binding protein and one of the proposed causes of the hemorrhagic complications of acute promyelocytic leukemia (APL), is also implicated in t(17;19)+ ALL. Annexin II was expressed at high levels in APL cells and in each of 4 t(17;19)+ leukemia cell lines, and annexin II expression was induced by enforced expression of E2A-HLF in leukemia cells. In IL-3–dependent cells, we found that annexin II expression was regulated by IL-3 mainly by Ras pathways, including Ras/phosphatidylinositol 3-kinase pathways. Moreover, E2A-HLF increased annexin II expression in IL-3–dependent cells in the absence of the cytokine. These findings indicate that E2A-HLF induces annexin II by substituting for cytokines that activate downstream pathways of Ras. (Blood. 2004;103:3185-3191)

We showed that the LAF4 gene on 2q11.2–12 was fused to the MLL gene on 11q23 in a pediatric patient with CD10 positive acute lymphoblastic leukemia (ALL) having t(2;11)(q11;q23). The LAF4 gene, which encodes a lymphoid nuclear protein of 1227 amino acids with transactivation potential, is thought to have a role in early lymphoid development. The LAF4 protein was homologous to AF4 and AF5q31 proteins that are fused to MLL in infant early pre-B ALL and the breakpoint of LAF4 was located within the region homologous to the transactivation domain of AF4 and AF5q31. Expression of the 8.5-kb LAF4 transcript was detected in the adult heart, brain, and placenta and in the fetal brain. LAF4 expression was found to be higher in ALL cell lines than in AML and Epstein–Barr virus-transformed B-lymphocyte cell lines. These findings suggest that LAF4, AF4 and AF5q31 might define a new family particularly involved in the pathogenesis of 11q23-associated ALL.

Maintenance therapy is a key component of ALL treatment. Although maintenance with 6-mercaptopurine (6-MP) and methotrexate (MTX) is generally less hemato-toxic, it occasionally causes severe complications such as infections, and too long maintenance is possibly associated with lower adherence. Thus, the duration of maintenance should be as short as possible, but excess shortening of maintenance therapy leads to high relapse incidence, as shown in our previous clinical trial, the Tokyo Children's Cancer Study Group (TCCSG) L92-13 (1992 - 1995, n = 347). In this study, the shortened maintenance therapy to 6 months resulted in EFS of 59.5% at 5.5 years although OS was as good as 81.5%. Especially, higher relapse rate in standard-risk (SR) resulted in EFS of as low as 60.2% (Toyoda Y, et al. J Clin Oncol 2000). However, it should be noted that about 60% of ALL achieved continuous complete remission (CCR) with short maintenance therapy. Thus, to confirm long-term outcome of ALL with this short maintenance therapy, we conducted an extended follow up study of patients enrolled on the TCCSG L92-13. In the L92-13 trial, previously untreated children (15 years or younger) with ALL were enrolled, and were assigned to three risk groups, standard-risk (SR), high-risk (HR) and extremely high-risk (HEX), according to age at diagnosis, immunephenotype, sentinel cytogenetics and initial leukocyte count. All patients received four-drug induction, followed by consolidation therapy including re-induction. Maintenance therapy with daily 6-MP and weekly MTX was shortened to 6 months, and all treatment was discontinued at 12 months after diagnosis. The data was analyzed as of 2014 July. A median of follow up period of this extended study was 14.8 years, and the survival curve is shown in Figure 1A. Relapse was reported in 128 patients, with a median time of relapse was 1.8 years from diagnosis. EFS at 12 years for all patients was 58.7 +- 2.7% (59.2% for SR [n = 127], 57.8% for intermediate-risk [IR, n = 122], and 59.2% for high-risk [HR, n = 101]) and OS was 78.7 +- 2.2% (85.4% for SR, 80.0% for IR, and 69.0% for HR). Incidences of relapse and non-relapse mortality were 37.2 +- 2.6% and 3.2 +- 0.9%, respectively. Five patients (0 in SR group, 3 in HR group, and 2 in HEX group) developed secondary malignant neoplasms before relapse, which resulted in cumulative incidence of secondary malignancy of 0.9 +- 0.5% at 12 years. Patient gender was associated with the outcome, and female had better EFS (65.3 +- 3.7%) compared to male (52.2 +- 3.8%) (p = 0.04, Figure 1B). High-hyperdiploid (HHD) patients had relatively worse prognosis, with EFS of 50.0 +- 11.8%, although it is generally considered as good prognostic factor, and most of the relapsed HHD patients were salvaged and OS was 94.4 +- 5.4%. It is confirmed that 6 months maintenance therapy is insufficient for male, HHD, and standard risk patients. In contrast, most of patients who had been in first CR at previous analysis maintained CCR status. Our results demonstrate that short maintenance therapy can cure a substantial portion of ALL with extremely low non-relapse mortality, and that it may be possible to shorten the duration of maintenance therapy for female and non-HHD patients. This study provides precise information of leukemia biology and highlights the role of maintenance therapy. Ongoing molecular characterization of the cured patients will clarify the subset of patients who can be cured with short maintenance therapy. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Iodine-131-metaiodiobenzylguanidine (131I-MIBG) therapy combined with allogeneic cord blood stem cell transplantation (SCT) was used to treat a 4-year-old girl with recurrent neuroblastoma. The patient experienced relapse 2 years after receiving first-line therapies, which included chemotherapy, surgical resection, irradiation, and autologous peripheral SCT. Although 131I-MIBG treatment did not achieve complete remission, the size of the tumor was reduced after treatment. Based on our findings, we suggest that 131I-MIBG treatment with myeloablative allogeneic SCT should be considered as first-line therapy for high-risk neuroblastoma patients when possible.

The E2A-HLF fusion transcription factor generated by the t(17;19)(q22;p13) translocation is found in a small population of pro-B cell ALL. Patients associated with this chimera share distinct clinical features such as hypercalcemia, coagulopathy and very poor prognosis due to resistance to intensive chemotherapy including aggressive conditioning for BMT, all of which are unusual for this type of ALL. We have previously demonstrated that inhibition of the trans-activation potential of the E2A-HLF chimera by the dominant negative mutant results in apoptosis in t(17;19)+ ALL cells but does not affect cell cycle. Moreover, E2A-HLF blocks apoptosis induced by cytokine deprivation in IL-3-dependent cells, suggesting that this fusion protein contributes to leukemogenesis by substituting for the anti-apoptotic function of cytokines. The present study shows that survivin is a downstream target molecule of E2A-HLF. Four t(17;19)+ ALL cell lines expressed survivin at high levels and down-regulation of E2A-HLF function by the dominant negative mutant suppressed survivin expression. In addition, forced expression of E2A-HLF in Nalm-6, a t(17;19)− ALL cell line, up-regulated survivin expression. Survivin is known to be expressed predominantly in the G2/M phase. Indeed, separation of the fractions enriched for in each phase of the cell cycle using a counterflow centrifugal elutriator revealed G2/M phase-dominant survivin expression in t(17;19) − ALL cells including Nalm-6. In t(17;19)+ ALL cells, however, survivin was expressed throughout the cell cycle. Moreover, Nalm-6 cells forced to express E2A-HLF showed cell cycle-independent survivin expression. Reporter assay revealed that E2A-HLF induced luciferase activity by transfecting with each reporter construct containing the survivin promoter at a different length from the initial ATG, suggesting that E2A-HLF induces survivin expression at the transcriptional level, but not by direct binding of E2A-HLF to the survivin promoter. To test whether survivin plays anti-apoptotic roles in t(17:19)+ cells, we used a survivin mutant lacking a phosphorylation site (T34A-survivin) and considered to inhibit survivin function in a dominant negative manner. T34A-survivin induced massive apoptosis throughout the cell cycle in t(17;19)+ cells. In contrast, T34A-survivin in t(17;19) − cells induced cell death in only a small population in G2/M phase. In addition to caspase-dependent pathways, T34A-survivin induced apoptosis in t(17;19)+ ALL cells through caspase-independent pathways, in which apoptosis-inducing factor (AIF) translocated from cytoplasm to the nucleus. These results indicate that cell cycle-independent up-regulation of survivin by the E2A-HLF chimera is indispensable for the survival of t(17;19)+ ALL cells, and that inhibition of survivin may offer an effective therapeutic strategy against this refractory ALL.