Improvement of Bobrovsky-Mayor-Wolf-Zakai Bound.

This paper presents a difference-type lower bound for the Bayes risk as a difference-type extension of the Borovkov-Sakhanenko bound. The resulting bound asymptotically improves the Bobrovsky-Mayor-Wolf-Zakai bound which is difference-type extension of the Van Trees bound. Some examples are also given.

Essential role of PTPN11 mutation in enhanced haematopoietic differentiation potential of induced pluripotent stem cells of juvenile myelomonocytic leukaemia.

We established mutated and non-mutated induced pluripotent stem cell (iPSC) clones from a patient with PTPN11 (c.226G>A)-mutated juvenile myelomonocytic leukaemia (JMML). Both types of iPSCs fulfilled the quality criteria. Mutated iPSC colonies generated significantly more CD34+ and CD34+ CD45+ cells compared to non-mutated iPSC colonies in a culture coated with irradiated AGM-S3 cells to which four growth factors were added sequentially or simultaneously. The haematopoietic differentiation potential of non-mutated JMML iPSC colonies was similar to or lower than that of iPSC colonies from a healthy individual. The PTPN11 mutation coexisted with the OSBP2 c.389C>T mutation. Zinc-finger nuclease-mediated homologous recombination revealed that correction of PTPN11 mutation in iPSCs with PTPN11 and OSBP2 mutations resulted in reduced CD34+ cell generation to a level similar to that obtained with JMML iPSC colonies with the wild-type of both genes, and interestingly, to that obtained with normal iPSC colonies. Transduction of the PTPN11 mutation into JMML iPSCs with the wild-type of both genes increased CD34+ cell production to a level comparable to that obtained with JMML iPSC colonies harbouring the two genetic mutations. Thus, PTPN11 mutation may be the most essential abnormality to confer an aberrant haematopoietic differentiation potential in this disorder.

Successful hematopoietic stem cell transplantation from an HLA-mismatched parent for engraftment failure after unrelated cord blood transplantation in patients with juvenile myelomonocytic leukemia: Report of two cases.

JMML is an aggressive hematopoietic malignancy of early childhood, and allogeneic HSCT is the only curative treatment for this disease. Umbilical cord blood is one of donor sources for HSCT in JMML patients who do not have an HLA-compatible relative, but engraftment failure remains a major problem. Here, we report two cases of JMML who were successfully rescued by HSCT from an HLA-mismatched parent after development of primary engraftment failure following unrelated CBT. Both patients had severe splenomegaly and underwent unrelated CBT from an HLA-mismatched donor. Immediately after diagnosis of engraftment failure, both patients underwent HSCT from their parent. For the second HSCT, we used RIC regimens consisting of FLU, CY, and a low dose of rabbit ATG with or without TBI and additionally administered ETP considering their persistent severe splenomegaly. Both patients achieved engraftment without severe treatment-related adverse effects. After engraftment of second HSCT, their splenomegaly was rapidly regressed, and both patients showed no sign of relapse for over 4 years. These observations demonstrate that HSCT from an HLA-mismatched parent could be a feasible salvage treatment for primary engraftment failure in JMML patients.

Ovarian function after allogeneic hematopoietic stem cell transplantation in children and young adults given 8-Gy total body irradiation-based reduced-toxicity myeloablative conditioning.

BACKGROUND: The spectrum of late sequelae after hematopoietic stem cell transplantation (HSCT) includes infertility, which is the most frequent complication. Some reports suggested that ovarian function may be better preserved in females undergoing HSCT with reduced-intensity conditioning (RIC) than with conventional myeloablative conditioning (MAC). However, the impact of HSCT after 8-Gy TBI-based reduced-toxicity MAC (RTMAC), whose efficacy is between those of conventional MAC and RIC, on ovarian function remains unclear. PROCEDURE: A single-center retrospective analysis of data derived from patient information for all the children who underwent transplantation at the Shinshu University Hospital was carried out. Patients who underwent 8-Gy total body irradiation (TBI)-based RTMAC before HSCT were analyzed. RESULTS: A total of 36% (five of 14) of the patients developed primary ovarian insufficiency (POI) during the observation period, but serum follicle-stimulating hormone levels reduced to normal range with spontaneous menstruation in two, implying the reversal of POI. Furthermore, only one (10%) of the 10 prepubertal patients (71%; 10/14) at the time of HSCT suffered from POI at the last observation, but all three post-pubertal patients developed POI (100%), and two (67%) continued to suffer from POI at the last observation. CONCLUSIONS: Taken together, 8-Gy TBI-based RTMAC before HSCT may decrease the possibility of POI compared with conventional MAC, especially in prepubertal patients. A longer follow-up will be required to ascertain whether a normal pregnancy and delivery can occur in such patients.

Panobinostat inhibits the proliferation of CD34+ CD38- cells under stimulation of hematopoietic growth factors on AGM-S3 cells in juvenile myelomonocytic leukemia.

BACKGROUND: Encouraging responses to histone deacetylase inhibitors have been reported for hematologic malignancies. Here, we report effects of panobinostat and 5-azacytidine on the proliferation of juvenile myelomonocytic leukemia (JMML) CD34+ cells. PROCEDURE: We previously reported that stimulation of JMML CD34+ cells with stem cell factor and thrombopoietin on irradiated murine AGM-S3 cells led to substantial expansion of JMML CD34+ cells that contained leukemic stem cells capable of transplantation into immunodeficient mice. Using this culture system, we evaluated effects of panobinostat and 5-azacytidine on the proliferation of JMML CD34+ cells. RESULTS: Panobinostat dose dependently reduced the numbers of day 7 CD34+ cells generated under stimulation of hematopoietic growth factors on AGM-S3 cells in all eight patients with JMML. These patients possessed various genetic and/or karyotypic abnormalities. CD34+ CD38- cells were substantially more sensitive to panobinostat at 10 and 20 nM than CD34+ CD38+ cells. Panobinostat, however, failed to influence the ability of AGM-S3 cells to stimulate JMML CD34+ cell production. In contrast to HL60 cells, apoptosis and cell cycle arrest in panobinostat-mediated inhibition were at low levels in JMML. The inhibitor also suppressed the factor-dependent proliferation of normal CD34+ cells on AGM-S3 cells. Meanwhile, no substantial inhibitory effects of 5-azacytidine on the growth of JMML CD34+ cells were observed. CONCLUSIONS: These results demonstrate that panobinostat directly suppresses the growth of JMML CD34+ cells, in particular CD34+ CD38- cells, regardless of the genetic abnormality type, suggesting that it is a useful antileukemic drug to target JMML stem cells at a pretransplant stage.

Clinical utility of next-generation sequencing for inherited bone marrow failure syndromes.

PURPOSE: Precise genetic diagnosis of inherited bone marrow failure syndromes (IBMFS), a heterogeneous group of genetic disorders, is challenging but essential for precise clinical decision making. METHODS: We analyzed 121 IBMFS patients using a targeted sequencing covering 184 associated genes and 250 IBMFS patients using whole-exome sequencing (WES). RESULTS: We achieved successful genetic diagnoses for 53 of 121 patients (44%) using targeted sequencing and for 68 of 250 patients (27%) using WES. In the majority of cases (targeted sequencing: 45/53, 85%; WES: 63/68, 93%), the detected variants were concordant with, and therefore supported, the clinical diagnoses. However, in the remaining 13 cases (8 patients by target sequencing and 5 patients by WES), the clinical diagnoses were incompatible with the detected variants. CONCLUSION: Our approach utilizing targeted sequencing and WES achieved satisfactory diagnostic rates and supported the efficacy of massive parallel sequencing as a diagnostic tool for IBMFS.Genet Med advance online publication 19 January 2017.

Aberrant methylation of protocadherin 17 and its prognostic value in pediatric acute lymphoblastic leukemia.

BACKGROUND: The outcome of approximately 20% of patients with acute lymphoblastic leukemia (ALL) remains poor because of disease recurrence. We examined whether DNA methylation of cadherin superfamily genes is a useful biomarker for ALL relapse. PROCEDURE: We used Infinium Methylation 450K Arrays to assess genome-wide DNA methylation status. The methylation status of each individual gene was then determined by a combination of bisulfite restriction analysis and genome bisulfite sequencing. mRNA expression was evaluated by reverse-transcriptase PCR (RT-PCR) and quantitative real-time PCR. RESULTS: Cadherin superfamily genes including cadherin (CDH) 1, protocadherin (PCDH) 8, and PCDH17 were selected for analysis of methylation status. In 40 patient samples with B-cell precursor (BCP) ALL at diagnosis, the methylation frequencies of CDH1, PCDH8, and PCDH17 were 62.5, 55, and 30%, respectively. CDH1 and PCDH8 methylation was also detected in 80 and 20% of control bone marrow (BM) samples, respectively. On the contrary, PCDH17 was unmethylated in all control BM samples. There was a significant correlation between the methylation status of PCDH17 (but not CDH1 and PCDH8) and event-free survival or overall survival. Univariate and multivariate analyses showed that only PCDH17 methylation was associated with an increased risk for relapse and mortality in patients with BCP ALL. CONCLUSION: PCDH17 methylation at diagnosis was closely related to poor prognosis and thus could be used as a new biomarker to predict relapse in patients with BCP ALL.

IFR4/MUM1-positive lymphoma in Waldeyer ring with co-expression of CD5 and CD10.

IRF4/MUM1-positive lymphoma is a new subgroup of germinal center-derived B-cell lymphoma, predominantly involving the Waldeyer ring (WR) in children. CD5 expression is rare in these lymphomas. We report a 7-year-old Chinese male with B-cell lymphoma. Evaluation of his specimen by morphology, immunohistochemistry, and FISH analysis demonstrated IRF4/MUM1-positive lymphoma with strong and extensive CD5 and CD10 positivity. Despite the lack of t(14;18)(q32;q21) rearrangement, BCL2 protein was expressed. Our report highlights the clinicopathologic features of IFR4/MUM1-positive lymphoma in WR with co-expression of CD5 and CD10, and thereby provides insight into this newly recognized disease entity.

Prognostic Significance of QT Interval Dispersion in the Response to Intravenous Immunoglobulin Therapy in Kawasaki Disease.

BACKGROUND: Kawasaki disease (KD) is classified as a systemic vasculitis syndrome and QT interval dispersion (QTD) has been associated with cardiac involvement and disease activity in patients with cardiovasculitis. We examined whether baseline QTD could predict a response to intravenous immunoglobulin (IVIG) in KD.Methods and Results:QTD was recorded in 86 patients with KD before IVIG, who were separated into IVIG responders (R group; n=62) and nonresponders (N group; n=24). The association between baseline QTD and response to IVIG was investigated, and the predictive response value was compared with conventional risk scores from Gunma and Kurume universities. Baseline-corrected QTDs with Bazett's (QTbcD) and Fridericia's (QTfcD) formulae were significantly increased in the N group (R group vs. N group: 31.6 [28.3, 44.0] ms vs. 66.6 [50.5, 76.3] ms and 27.4 [25.2, 39.1] ms vs. 55.2 [42.4, 66.3] ms, respectively, both P<0.001). Multiple logistic regression analysis revealed QTfcD as an independent predictor of a response to IVIG after adjustment for conventional scores (odds ratio: 1.133, 95% confidence interval: 1.061-1.210, P<0.001). Moreover, QTfcD provided incremental predictive value for IVIG nonresponders over Gunma score (increment in global χ2=25.46, P<0.001). CONCLUSIONS: QTD was significantly associated with a response to IVIG in KD patients and may represent a useful identifier of IVIG nonresponders with high risk of coronary aneurysm.

Increasing Risk of Disturbed Root Development in Permanent Teeth in Childhood Cancer Survivors Undergoing Cancer Treatment at Older Age.

BACKGROUND: Structural anomalies of teeth are observed at high rates in childhood cancer survivors (CCS). Several therapeutic exposures have been shown to be associated with dental developmental disturbances. This study was conducted to analyze the risk factors for dental developmental abnormality (DDA) and investigate the association between age at the time of cancer treatment and DDA in CCS. PATIENTS AND METHODS: Fifty-six CCS were enrolled. Orthopantomography and dental examination were performed in all the patients. We evaluated the prevalence of DDA and analyzed the risk factors for each type of DDA. RESULTS: DDAs were observed in 46.4% of CCS, including hypodontia in 9 (16.1%), abnormal roots in nine (16.1%), enamel defects/hypoplasia in 6 (10.7%), and microdontia in 12 (21.4%) patients. The number of patients with abnormal roots was significantly higher in the group treated with stem cell transplantation or at an age older than 4 years. We observed that the formation period of abnormal teeth coincided with the treatment period in the majority of CCS with DDA. CONCLUSIONS: Particularly regarding the root abnormality, treatment at elder age may be a risk factor for root developmental disturbances. Risk evaluation, appropriate follow-up, and early detection of dental issues are required for all CCS.

Differential roles of MMP-9 in early and late stages of dystrophic muscles in a mouse model of Duchenne muscular dystrophy.

Matrix metalloprotease (MMP)-9 is an endopeptidase associated with the pathogenesis of Duchenne muscular dystrophy (DMD). The precise function of MMP-9 in DMD has not been elucidated to date. We investigated the effect of genetic ablation of MMP-9 in the mdx mouse model (mdx/Mmp9(-/-)). At the early disease stage, the muscles of mdx/Mmp9(-/-) mice showed reduced necrosis and neutrophil invasion, accompanied by down-regulation of chemokine MIP-2. In addition, muscle regeneration was enhanced, which coincided with increased macrophage infiltration and upregulation of MCP-1, and resulted in increased muscle strength. The mdx/Mmp9(-/-) mice also displayed accelerated upregulation of osteopontin expression in skeletal muscle at the acute onset phase of dystrophy. However, at a later disease stage, the mice exhibited muscle growth impairment through altered expression of myogenic factors, and increased fibroadipose tissue. These results showed that MMP-9 might have multiple functions during disease progression. Therapy targeting MMP-9 may improve muscle pathology and function at the early disease stage, but continuous inhibition of this protein may result in the accumulation of fibroadipose tissues and reduced muscle strength at the late disease stage.

Superoxide-Generating Nox5α Is Functionally Required for the Human T-Cell Leukemia Virus Type 1-Induced Cell Transformation Phenotype.

UNLABELLED: Human T-cell leukemia virus type 1 (HTLV-1) is associated with adult T-cell leukemia (ATL) and transforms T cells in vitro. To our knowledge, the functional role of reactive oxygen species (ROS)-generating NADPH oxidase 5 (Nox5) in HTLV-1 transformation remains undefined. Here, we found that Nox5α expression was upregulated in 88% of 17 ATL patient samples but not in normal peripheral blood T cells. Upregulation of the Nox5α variant was transcriptionally sustained by the constitutive Janus family tyrosine kinase (Jak)-STAT5 signaling pathway in interleukin-2 (IL-2)-independent HTLV-1-transformed cell lines, including MT1 and MT2, whereas it was transiently induced by the IL-2-triggered Jak-STAT5 axis in uninfected T cells. A Nox inhibitor, diphenylene iodonium, and antioxidants such as N-acetyl cysteine blocked proliferation of MT1 and MT2 cells. Ablation of Nox5α by small interfering RNAs abrogated ROS production, inhibited cellular activities, including proliferation, migration, and survival, and suppressed tumorigenicity in immunodeficient NOG mice. The findings suggest that Nox5α is a key molecule for redox-signal-mediated maintenance of the HTLV-1 transformation phenotype and could be a potential molecular target for therapeutic intervention in cancer development. IMPORTANCE: HTLV-1 is the first human oncogenic retrovirus shown to be associated with ATL. Despite the extensive study over the years, the mechanism underlying HTLV-1-induced cell transformation is not fully understood. In this study, we addressed the expression and function of ROS-generating Nox family genes in HTLV-1-transformed cells. Our report provides the first evidence that the upregulated expression of Nox5α is associated with the pathological state of ATL peripheral blood mononuclear cells and that Nox5α is an integral component of the Jak-STAT5 signaling pathway in HTLV-1-transformed T cells. Nox5α-derived ROS are critically involved in the regulation of cellular activities, including proliferation, migration, survival, and tumorigenicity, in HTLV-1-transformed cells. These results indicate that Nox5α-derived ROS are functionally required for maintenance of the HTLV-1 transformation phenotype. The finding provides new insight into the redox-dependent mechanism of HTLV-1 transformation and raises an intriguing possibility that Nox5α serves as a potential molecular target to treat HTLV-1-related leukemia.

Clinical and laboratory outcomes after umbilical cord blood transplantation in a patient with mucolipidosis II alpha/beta.

Mucolipidosis (ML) II alpha/beta is an autosomal recessive disease caused by reduced enzyme activity of N-acetylglucosamine-1-phosphotransferase. Clinical symptoms of ML II are severe psychomotor delay and dysostosis multiplex; death usually occurs by 5-8 years of age from cardiopulmonary complications. Allogeneic hematopoietic stem cell transplantation (HSCT) has been attempted for ML; however, few reports have documented the detailed outcomes of HSCT for ML. A 26-month-old girl received a human leukocyte antigen 3/6-allele-matched transplant from cord blood. The preparative regimen consisted of fludarabine, cyclophosphamide, 6-Gy total body irradiation, and rabbit antithymocyte globulin. Although comparing before and after cord blood transplantation results, we observed that lysosomal enzyme activities in the plasma decreased by approximately 20-40%. Low serum levels of immunoglobulin A, G2, and G4 were also observed before HSCT; however, these values normalized after transplantation. Despite undergoing HSCT, she was treated twice for bacterial pneumonia with acute respiratory distress syndrome at ages 37 and 38 months. Although HSCT effects on the clinical manifestations were limited, laboratory data including plasma lysosomal enzyme activities and serum levels of immunoglobulin showed improvement.

Loss of Mismatched HLA on the Leukemic Blasts of Patients With Relapsed Lymphoid Malignancies Following Bone Marrow Transplantation From Related Donors With HLA Class II Mismatches in the Graft Versus Host Direction.

Mechanisms of relapse of acute lymphoblastic leukemia (ALL) after human leukocyte antigen (HLA) class II mismatched hematopoietic stem cell transplantation (HSCT) remain unclear. We report two children with relapsed ALL after HSCT from related donors with HLA-DRB1 and -DQB1 mismatches in the graft versus host direction. One lost HLA-DRB1, DQB1, and DPB1 alleles, and the other lost one HLA haplotype of the leukemic blasts at relapse. HLA class II loss may be a triggering event for ALL relapse after partially HLA-mismatched-related HSCT. In addition, HLA typing of relapsed leukemic blasts could be vital in the selection of retransplant donors.

Cardiovascular Remodeling and Dysfunction Across a Range of Growth Restriction Severity in Small for Gestational Age Infants　- Implications for Fetal Programming.

BACKGROUND: The purpose of this study was to clarify cardiovascular structure and function in small for gestational age (SGA) infants across a range of intrauterine growth restriction (IUGR) severity. METHODS AND RESULTS: This prospective study included 38 SGA infants and 30 appropriate for gestational age (AGA) infants. SGA infants were subclassified into severe and mild SGA according to the degree of IUGR. Cardiovascular structure and function were evaluated using echocardiography at 1 week of age. Compared with the AGA infants, both the severe and mild SGA infants showed increased left ventricular diastolic dimensions (severe SGA 10.2±2.4, mild SGA 8.2±1.3, and AGA 7.3±0.7 mm/kg, P<0.05 for all) and decreased global longitudinal strain (severe -21.1±1.6, mild -22.5±1.8, and AGA -23.8±1.8%, P<0.05 for all). Severe SGA infants showed a decreased mitral annular early diastolic velocity (severe 5.6±1.4 vs. AGA 7.0±1.3 cm/s, P<0.01) and increased isovolumic relaxation time (severe 51.3±9.2 vs. AGA 42.7±8.2 ms, P<0.01). Weight-adjusted aortic intima-media thickness and arterial wall stiffness were significantly greater in both SGA infant groups. These cardiovascular parameters tended to deteriorate with increasing IUGR severity. CONCLUSIONS: SGA infants, including those with mild SGA, showed cardiovascular remodeling and dysfunction, which increased with IUGR severity. (Circ J 2016; 80: 2212-2220).

Successful treatment of arrhythmia-induced cardiomyopathy in an infant with tuberous sclerosis complex.

BACKGROUND: Tuberous sclerosis complex (TSC) is an autosomal-dominant tumor suppressor gene syndrome that is characterized by the development of distinctive benign tumors and malformations in multiple organ systems (N Eng J Med 355:1345-1356, 2006). Cardiac rhabdomyomas are intracavitary or intramural tumors observed in 50-70 % of infants with TSC but only cause serious clinical problems in a very small fraction of these patients (N Eng J Med 355:1345-1356, 2006; Pediatrics 118:1146-1151, 2006; Eur J Pediatr 153:155-7, 1994); most individuals have no clinical symptoms and their tumors spontaneously regress. However, despite being clinically silent, these lesions can provoke arrhythmias and heart failure (Pediatrics 118:1146-1151, 2006; Eur J Pediatr 153:155-7, 1994). CASE PRESENTATION: We here report the clinical findings of an infant suffering from TSC complicated with dilated cardiomyopathy (DCM) after the regression of cardiac rhabdomyomas. Although his tumors improved spontaneously, tachycardia and irregular heart rate due to frequent premature ventricular and supraventricular contractions persisted from the newborn period and were refractory to several medications. His cardiomyopathy was suspected to have been induced by the tachycardia or arrhythmia. We found carvedilol therapy to be safe and highly effective in treating the cardiomyopathy. To our knowledge, this is the first case report of TSC with DCM after regression of cardiac tumors and its successful treatment. CONCLUSION: The patient's clinical course suggests that careful life-long disease management is important, even in TSC patients without apparent symptoms.

Rapidly progressive Kaposi's Sarcoma in an Iraqi boy received Valproic acid: a case report and review of literature.

BACKGROUND: Kaposi's sarcoma (KS), an endothelial neoplasm, is associated with human herpes virus (HHV) -8 infection. KS has four clinical sub-types: Mediterranean/classic, African/endemic, human immunodeficiency virus (HIV) -associated/epidemic, and transplantation-related/iatrogenic. Immunosuppression is an important cofactor in KS process. Classic KS (CKS) is exceedingly rare in children and when occurs, it is much more disseminated than adults. The epidemic, HIV-associated and the iatrogenic forms of childhood KS are a result of a profound and acquired T-cell deficiency. To our knowledge, this is the first paediatric KS case report from Iraq. Our patient was showing an unusual aggressive course of the disease while receiving Valproic acid (VPA) of the potential immune-suppressive effect. CASE PRESENTATION: A six-year-old Iraqi boy, who had cerebral palsy (CP) and epilepsy since the age of 9-months, had received VPA to control his seizures. He developed skin discoloration followed by nodules that disseminated proximally from the lower extremities to the groin, face, ears and oral cavity, and then he died from severe respiratory distress after 110 days from the disease evolution. KS diagnosis was proved by a skin biopsy. As the patient was of Arab-Asian ethnicity and was HIV-seronegative status, accordingly, his condition best fitted the classic form of KS. However, recent studies showed the link of VPA with the reactivation of HHV-8. Moreover, accumulated experimental and clinical data elucidated that VPA induces T-cell suppression. Given that there was a lack of facilities to perform the laboratory immunological diagnostic tests in Iraq, the VPA-induced effect on immunity in our case (iatrogenic KS) could not be evaluated. CONCLUSIONS: Our report demonstrates a rare, rapidly progressing paediatric KS case and highlights the possible role of the 5-years' administration of VPA and its challenging effect on cellular immunity based on recent studies. Thus, VPA could have promoted the development of the KS in our patient. This report also recalls the need of paediatricians to consider KS especially when the skin lesion appears at the child's foot even in countries outside the geographical map of the disease.

Diagnosis and treatment of juvenile myelomonocytic leukemia.

Juvenile myelomonocytic leukemia (JMML) is a rare myelodysplastic/myeloproliferative disorder that occurs during infancy and early childhood; this disorder is characterized by hypersensitivity of the myeloid progenitor cells to granulocyte-macrophage colony-stimulating factor in vitro. JMML usually involves somatic and/or germline mutations in the genes of the RAS pathway, including PTPN11, NRAS, KRAS, NF1, and CBL, in the leukemic cells. Almost all patients with JMML experience an aggressive clinical course, and hematopoietic stem cell transplantation (HSCT) is the only curative treatment. A certain proportion of patients with somatic NRAS and germline mutations in CBL, however, have spontaneous resolution. A suitable treatment after diagnosis and conditioning regimen prior to HSCT are yet to be determined, but several clinical trials have been initiated throughout the world to develop suitable pre- or post-allogeneic HSCT treatments and new targeted therapies that are less toxic, to improve patient outcome.

Early-onset colorectal cancer in young adult survivors of childhood cancer.

We describe the cases of two childhood cancer survivors (CCS) who developed colorectal cancer at 21 and 30 years of age. They had been treated with 30 Gy abdominal irradiation and chemotherapy including platinum and high-dose alkylating agents at age 1 year, and 12 Gy total body irradiation and high-dose cyclophosphamide at age 15 years, respectively. Both had not been screened for colorectal cancer. One patient with advanced cancer died, whereas the other with early cancer was still alive at the time of writing. Two guidelines for long-term follow-up of CCS recommend that CCS who had >30 Gy irradiation receive periodic check-ups at age ≥ 35 years. The present cases suggest that CCS, even with irradiation <30 Gy, should receive earlier check-ups for colorectal cancer. © 2016 Japan Pediatric Society.

Left ventricular non-compaction revealed by aortic regurgitation due to Kawasaki disease in a boy with LDB3 mutation.

Kawasaki disease (KD) is an acute febrile illness of childhood characterized by systemic vasculitis, especially coronary arteritis. Aortic valve regurgitation (AVR) is a relatively common complication. There have been no reports to date of heart failure and left ventricular non-compaction (LVNC) after acute KD, although the precise etiology of this condition remains unclear. A 6-month-old boy with KD was admitted to hospital. Despite high-dose i.v. gammaglobulin for dilation of the coronary artery, moderate AVR appeared, and thereafter he developed heart failure. A rough, dense LV myocardium indicated LVNC. On genetic testing a heterogenous 163G > A substitution changing a valine to isoleucine in LIM domain binding protein 3 (LDB3) was identified. Additional cardiac stress, such as that caused by AVR and/or KD might have triggered cardiac failure in the form of LVNC due to LDB3 mutation.