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Background Secondary cancer is the most life-threatening late effect of childhood cancer. We investigated the clinical features of secondary bone/soft tissue sarcoma among childhood cancer survivors (CCSs). Methods We conducted a retrospective case-series study of 10 069 CCSs newly diagnosed with cancer between 1980 and 2009 across 15 Japanese hospitals. Twenty-one cases of pathologically diagnosed secondary bone/soft tissue sarcoma were selected, and the respective clinical courses were determined using additional questionnaires. Results The primary cancers included retinoblastoma (n = 7), acute lymphoblastic leukemia (n = 5), lymphoma (n = 5), osteosarcoma (n = 1), rhabdomyosarcoma (n = 1), brain tumor (n = 1) and Langerhans cell histiocytosis (n = 1). The median age at the primary cancer diagnosis was 2.9 years, and the male-to-female ratio was 16:5. The histological classifications of the secondary sarcoma included osteosarcoma (n = 10), malignant peripheral nerve sheath tumor (n = 4), rhabdomyosarcoma (n = 3), Ewing's sarcoma (n = 3) and primitive neuroectodermal tumor (n = 1). The median latency period to the secondary sarcoma was 10.2 years. Significant risk factors for secondary sarcoma in the multivariate Cox regression model included a history of retinoblastoma as the primary cancer (hazard ratio [HR], 20.9; 95% confidence interval [CI], 5.70-76.5) and autologous stem cell transplantation (SCT) (HR, 2.56; 95% CI, 1.08-6.03). Seventeen CCSs with secondary sarcoma underwent radiation, and nine, hematopoietic SCT. Twelve CCSs with secondary sarcoma achieved disease-free survival, while CCSs with hematological cancer or relapsed primary cancer who developed secondary sarcoma had the worst prognoses. Conclusion The prognoses of CCSs with secondary sarcoma may depend on the primary cancer or prior relapse of primary cancer.

Background The pain associated with bone marrow aspiration and biopsy (BMAB) has an enormous impact on pediatric cancer patients and their families, but no specific reference standards for sedation and analgesia have been developed in Japan. To determine the problems associated with pain management during BMAB, a cross-sectional investigation was conducted. Methods A survey was sent in October 2011 to data managers in institutions belonging to the Tokyo Children's Cancer Study Group, addressing the non-pharmacological and pharmacological pain management for BMAB performed on pediatric cancer inpatients between January 2010 and December 2010. Results The eligible response rate was 41 of 57 institutions (71.9%). Non-pharmacological pain intervention was provided in 68% of surveyed institutions. All institutions provided pharmacological pain management. In most institutions, sedation/analgesia was performed by pediatric oncologists in a treatment room in the ward. Standards for pain management were developed and utilized in only four institutions. Other means of pain management were provided in various settings. Twelve institutions reported insufficient sedation/analgesia. In total, 80% of institutions reported some adverse events. Two serious adverse events were reported in cases of underlying or complicated conditions. No serious long-term consequences were reported. Conclusions Significant issues were identified regarding the efficacy and safety of pain management. Adverse events can occur in any institution. Children with underlying or complicated conditions are at high risk for serious adverse events. Therefore, adequate and systematic assessment, patient monitoring, preparation and treatment for adverse events, and cooperation with skilled specialists of pediatric oncology, anesthesiology, and intensive care are essential.

Summary With improvement in survival, it is important to evaluate the impact of treatment on secondary cancers in acute lymphoblastic leukaemia (ALL) survivors. A retrospective cohort study comprising 2918 children diagnosed with ALL and enrolled on Tokyo Children's Cancer Study Group (TCCSG) protocols between 1984 and 2005 was conducted to evaluate the incidence of secondary cancers and associated factors including treatment protocol, cranial irradiation and other characteristics of the primary ALL. Thirty-seven patients developed secondary cancers, including acute myeloid leukaemia (n = 11), myelodysplastic syndrome (n = 5), non-Hodgkin lymphoma (n = 2), brain tumours (n = 13) and other solid carcinomas (n = 6) within a median follow-up duration of 9·5 years. The cumulative incidence of any secondary cancers was 1·0% (95% confidence interval (CI), 0·7–1·4%) at 10 years and 2·4% (95% CI, 1·5–3·7%) at 20 years, respectively. Standardized incidence rate ratio of secondary cancers was 9·3 (95% CI, 6·5–12·8). Multivariate analyses showed an increased risk of secondary cancers associated with the recent treatment protocol and cranial irradiation. There was no evidence of a reduction in secondary cancer incidence despite marked decreases in cranial irradiation use in the recent protocols.

比較的稀な小腸リンパ管腫を伴う腸間膜リンパ管腫の小児例を経験したので報告する.症例は8歳,男児.平成16年1月17日より嘔吐・下痢が出現,その後38°C台の発熱があり,腹部腫瘤の指摘を受け緊急入院となった.腹部全体に圧痛のある硬い可動性のない腫瘤を触知し,白血球・CRPの上昇と貧血,腫瘍マーカーのCA125, S-IL2Rの上昇を認めた.腹部画像検査で上腹部より骨盤腔に拡がる充実性部分の多い腫瘤を認めた.悪性を否定できず,生検にてリンパ管腫の結果をえた.消化管造影, multi-slice CT検査を追加施行し,開腹手術を施行した.回腸腸間膜に約35cm×30cm×10cm大の腫瘤を認め,回腸を合併切除し3,830gの腫瘤を全摘出した.病理組織診断は腸間膜および小腸の海綿状リンパ管腫であった.

Objective To determine the extent of growth impairment resulting from imatinib treatment in children with chronic myeloid leukemia (CML). Study design Clinical records of 48 chronic-phase CML children administered imatinib as the first-line therapy between 2001 and 2006 were analyzed retrospectively. Cumulative change in height was assessed using the height height-SDS and converted height data from age- and sex-adjusted Japanese norms. Results A decrease in height-SDS was observed in 72.9% of children, with a median maximum reduction in height-SDS of 0.61 during imatinib treatment. Median follow-up time was 34 months (range, 10-88 months). Growth impairment was seen predominantly in children who started imatinib at a prepubertal age compared with those who started at pubertal age. Growth velocity tended to recuperate in prepubertal children with growth impairment, as they reached pubertal age, suggesting that imatinib had little impact on growth during puberty. Conclusions Growth impairment was a major adverse effect of long-term imatinib treatment in children with CML. We report the distinct inhibitory effect of imatinib on growth in prepubertal and pubertal children with CML. We should be aware of growth deceleration in children, especially in young children given imatinib before puberty and subjected to prolonged exposure.

A 6-year-old boy developed bronchiolitis obliterans organizing pneumonia and nephrotic syndrome 5 months after allogeneic bone marrow transplantation from an unrelated donor for acute lymphoblastic leukemia. His renal biopsy showed membranous nephropathy. He was treated with prednisolone and cyclosporine A. Proteinuria disappeared 3 months after the onset of nephrotic syndrome. To our knowledge, this patient is the youngest case with nephrotic syndrome due to membranous nephropathy after hematopoietic stem cell transplantation.

A pilot study was undertaken using a myeloablative conditioning with fludarabine, busulfan, and melphalan to improve the outcome of HSCT in 10 children, aged six months to six yr, with JMML. All patients were conditioned with oral busulfan (560 mg/m(2)), fludarabine (120 mg/m(2)), and melphalan (180-210 mg/m(2)) prior to HSCT, and received stem cells from bone marrow in seven cases, and from cord blood in three cases. Engraftment was documented in eight patients, whereas graft failure occurred in two, one of whom had received HLA-mismatched cord blood and other had received bone marrow from HLA-mismatched mother. Three patients, including two in who graft failure had occurred, relapsed. Five patients developed acute GVHD and two developed chronic GVHD. Seven patients are alive and in remission 27-69 months after transplantation. Thus, our study showed that HSCT following conditioning with fludarabine, busulfan, and melphalan was well tolerated and appeared to be effective for JMML.

Noonan syndrome is characterized by short stature, facial dysmorphia and a wide spectrum of congenital heart defects1,2. Mutations of PTPN11, KRAS and SOS1 in the RAS-MAPK pathway cause ∼60% of cases of Noonan syndrome3,4,5,6,7,8,9. However, the gene(s) responsible for the remainder are unknown. We have identified five different mutations in RAF1 in ten individuals with Noonan syndrome; those with any of four mutations causing changes in the CR2 domain of RAF1 had hypertrophic cardiomyopathy (HCM), whereas affected individuals with mutations leading to changes in the CR3 domain did not. Cells transfected with constructs containing Noonan syndrome–associated RAF1 mutations showed increased in vitro kinase and ERK activation, and zebrafish embryos with morpholino knockdown of raf1 demonstrated the need for raf1 for the development of normal myocardial structure and function. Thus, our findings implicate RAF1 gain-of-function mutations as a causative agent of a human developmental disorder, representing a new genetic mechanism for the activation of the MAPK pathway.

Although tyrosine kinase inhibitor (TKI) is popular in controlling chronic myeloid leukemia in the chronic phase (CML-CP), its long-term adverse effects in children are an issue of concern. One such concern is the negative impact on growth in these children. We previously demonstrated that growth impairment was a major adverse effect in imatinib-treated CML children. However, severity of impairment was not completely elucidated because of the short follow-up period. The Japanese Pediatric Leukemia/Lymphoma Study Group CML committee reviewed the clinical records of 107 Japanese children diagnosed with CML-CP ( In total, 77 children (47 boys and 30 girls) met these criteria. Median age at diagnosis was 10 years (2 to 15 years) and median observation period was 38 months (12 to 119 months). Median height-SDS at diagnosis and during the study was −0.14 SD (−2.3 to 2.3 SD) and −0.75 SD (−3.2 to 1.9 SD), respectively. Decrease in height-SDS (change in height-SDS from initiation of TKI till last follow-up point) was observed in 84.4% of children, which was >1 SD in 21 children (27.2%). Decrease in height-SDS was more severe in prepubertal children than in pubertal children (0.85 vs. 0.36, p< 0.01). However, in prepubertal children median annual change in height-SDS significantly decreased 2 years after TKI initiation, and was Because of the possibility of TKI discontinuation, growth impairment is assumed to be a huge issue particularly in children who are inevitable of prolonged exposure to TKI. We previously discussed the possibility that growth velocity may recuperate in prepubertal children as they reach pubertal age, suggesting that imatinib had less impact on growth during puberty. However, this updated study data demonstrated that period of TKI treatment may influence alleviation of growth impairment by TKI to a greater extent than puberty. We suggest that severity of growth impairment could be mitigated 2 years after TKI initiation. Thus, therapeutic intervention, such as reduced-intensity hematopoietic stem cell transplantation and discontinuation of TKI, may not be necessary for improvement of growth in TKI-treated CML children. Disclosures: No relevant conflicts of interest to declare.