Search

Correlation with the size of the haematoma, neurological findings and prognosis was studied in 26 cases of hypertensive pontine haemorrhage, using CT. A good prognosis was found with no or mild disturbance of consciousness, normal pupils, and transverse diameter of the haematoma 20 mm or less. Most of the patients with poor prognosis became comatose within two hours of onset. Their pupils were dilated bilaterally, pin-point or anisocoric and the transverse diameter of the haematoma was over 20 mm. [ABSTRACT FROM AUTHOR]

Objectives: To investigate the clinical characteristics and management of plexiform neurofibromas (PNs) in Japanese children with neurofibromatosis 1 (NF1) in the beginning of a new era of treatment with mitogen-activated protein kinase/extracellular signal-regulated kinase kinase (MEK) inhibitor selumetinib., Study Design: Primary and secondary surveys were conducted targeting 1612 departments of pediatrics and dermatology in hospitals with ≥300 beds and children's hospitals, which followed up pediatric patients with NF1-associated PN between April 1, 2022, and April 30, 2024, in Japan., Results: The response rates in the primary and secondary surveys were 40.4 % and 33.8 %, respectively, and 49 patients were followed up in 23 departments. Their ages at the time ranged from 3.3 to 18.8 years and the onset of PN was most frequently recognized during the first year of life. PN was most often observed superficially in the face (39 %), neck (27 %), and head (24 %), followed by the buttocks (20 %), back (18 %), and thighs (18 %). In addition, PNs could be identified radiologically in the spinal/paraspinal regions (18 %) and pelvis (16 %), where they were rarely visible on the corresponding body surfaces. Major morbidities were cosmetic disfigurement (78 %), pain (53 %), and dysfunction (61 %). Selumetinib use was frequent (69 %) and significantly associated with pain (chi-square test, p = 0.014) and dysfunction (p = 0.014)., Conclusions: This retrospective nationwide study revealed early onset, diverse tumor locations, and varying morbidities in children with NF1-PN, underscoring the need for early evaluation and optimal treatment. A prospective multicenter registry system is warranted to attain better management., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: HN received honoraria for lectures and manuscript writing from Alexion, AstraZeneca Rare Diseases. YY received honoraria for lectures and travel reimbursement from Alexion, AstraZeneca Rare Disease. AA received honoraria for lectures from Alexion, AstraZeneca Rare Disease. MM received honoraria for lectures and travel reimbursement from Alexion, AstraZeneca Rare Disease. The company was not involved in any of the study design, collection, analysis, interpretation of data, writing of the report, and decision to submit the paper for publication. The other authors declare no competing interests., (Copyright © 2024. Published by Elsevier B.V.)

Background: Approximately 1% of clinically treatable tyrosine kinase fusions, including anaplastic lymphoma kinase, neurotrophic tyrosine receptor kinase, RET proto-oncogene, and ROS proto-oncogene 1, have been identified in soft tissue sarcomas via comprehensive genome profiling based on DNA sequencing. Histologic tumor-specific fusion genes have been reported in approximately 20% of soft tissue sarcomas; however, unlike tyrosine kinase fusion genes, these fusions cannot be directly targeted in therapy. Approximately 80% of tumor-specific fusion-negative sarcomas, including myxofibrosarcoma and leiomyosarcoma, that are defined in complex karyotype sarcomas remain genetically uncharacterized; this mutually exclusive pattern of mutations suggests that other mutually exclusive driver oncogenes are yet to be discovered. Tumor-specific, fusion-negative sarcomas may be associated with unique translocations, and oncogenic fusion genes, including tyrosine kinase fusions, may have been overlooked in these sarcomas., Questions/purposes: (1) Can DNA- or RNA-based analysis reveal any characteristic gene alterations in bone and soft tissue sarcomas? (2) Can useful and potential tyrosine kinase fusions in tumors from tumor-specific, fusion-negative sarcomas be detected using an RNA-based screening system? (3) Do the identified potential fusion tumors, especially in neurotrophic tyrosine receptor kinase gene fusions in bone sarcoma, transform cells and respond to targeted drug treatment in in vitro assays? (4) Can the identified tyrosine kinase fusion genes in sarcomas be useful therapeutic targets?, Methods: Between 2017 and 2020, we treated 100 patients for bone and soft tissue sarcomas at five institutions. Any biopsy or surgery from which a specimen could be obtained was included as potentially eligible. Ninety percent (90 patients) of patients were eligible; a further 8% (8 patients) were excluded because they were either lost to follow-up or their diagnosis was changed, leaving 82% (82 patients) for analysis here. To answer our first and second questions regarding gene alterations and potential tyrosine kinase fusions in eight bone and 74 soft tissue sarcomas, we used the TruSight Tumor 170 assay to detect mutations, copy number variations, and gene fusions in the samples. To answer our third question, we performed functional analyses involving in vitro assays to determine whether the identified tyrosine kinase fusions were associated with oncogenic abilities and drug responses. Finally, to determine usefulness as therapeutic targets, two pediatric patients harboring an NTRK fusion and an ALK fusion were treated with tyrosine kinase inhibitors in clinical trials., Results: DNA/RNA-based analysis demonstrated characteristic alterations in bone and soft tissue sarcomas; DNA-based analyses detected TP53 and copy number alterations of MDM2 and CDK4 . These single-nucleotide variants and copy number variations were enriched in specific fusion-negative sarcomas. RNA-based screening detected fusion genes in 24% (20 of 82) of patients. Useful potential fusions were detected in 19% (11 of 58) of tumor-specific fusion-negative sarcomas, with nine of these patients harboring tyrosine kinase fusion genes; five of these patients had in-frame tyrosine kinase fusion genes ( STRN3-NTRK3, VWC2-EGFR, ICK-KDR, FOXP2-MET , and CEP290-MET ) with unknown pathologic significance. The functional analysis revealed that STRN3-NTRK3 rearrangement that was identified in bone had a strong transforming potential in 3T3 cells, and that STRN3-NTRK3 -positive cells were sensitive to larotrectinib in vitro. To confirm the usefulness of identified tyrosine kinase fusion genes as therapeutic targets, patients with well-characterized LMNA-NTRK1 and CLTC-ALK fusions were treated with tyrosine kinase inhibitors in clinical trials, and a complete response was achieved., Conclusion: We identified useful potential therapeutic targets for tyrosine kinase fusions in bone and soft tissue sarcomas using RNA-based analysis. We successfully identified STRN3-NTRK3 fusion in a patient with leiomyosarcoma of bone and determined the malignant potential of this fusion gene via functional analyses and drug effects. In light of these discoveries, comprehensive genome profiling should be considered even if the sarcoma is a bone sarcoma. There seem to be some limitations regarding current DNA-based comprehensive genome profiling tests, and it is important to use RNA testing for proper diagnosis and accurate identification of fusion genes. Studies on more patients, validation of results, and further functional analysis of unknown tyrosine kinase fusion genes are required to establish future treatments., Clinical Relevance: DNA- and RNA-based screening systems may be useful for detecting tyrosine kinase fusion genes in specific fusion-negative sarcomas and identifying key therapeutic targets, leading to possible breakthroughs in the treatment of bone and soft tissue sarcomas. Given that current DNA sequencing misses fusion genes, RNA-based screening systems should be widely considered as a worldwide test for sarcoma. If standard treatments such as chemotherapy are not effective, or even if the sarcoma is of bone, RNA sequencing should be considered to identify as many therapeutic targets as possible., Competing Interests: All ICMJE Conflict of Interest Forms for authors and Clinical Orthopaedics and Related Research® editors and board members are on file with the publication and can be viewed on request., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the Association of Bone and Joint Surgeons.)

Cancer treatment is increasingly evolving toward personalized medicine, which sequences numerous cancer-related genes and identifies therapeutic targets. On the other hand, patients with germline pathogenic variants (GPV) have been identified as secondary findings (SF) and oncologists have been urged to handle them. All SF disclosure considerations for patients are addressed and decided at the molecular tumor boards (MTB) in the facility. In this study, we retrospectively summarized the results of all cases in which comprehensive genomic profiling (CGP) test was conducted at our hospital, and discussed the possibility of presumed germline pathogenic variants (PGPV) at MTB. MTB recommended confirmatory testing for 64 patients. Informed consent was obtained from attending physicians for 53 of them, 30 patients requested testing, and 17 patients tested positive for a confirmatory test. Together with already known variants, 4.5 % of the total confirmed in this cohort. Variants verified in this study were BRCA1 (n = 12), BRCA2 (n = 6), MSH2 (n = 2), MSH6 (n = 2), WT1 (n = 2), TP53, MEN1, CHEK2, MLH1, TSC2, PTEN, RB1, and SMARCB1. There was no difference in the tumor's VAF between confirmed positive and negative cases for variants determined as PGPV by MTB. Current results demonstrate the actual number of cases until confirmatory germline test for patients with PGPV from tumor-only CGP test through the discussion at the MTB. The practical results at this single facility will serve as a guide for the management of the selection and distribution of SF in the genome analysis., (© 2023. The Author(s), under exclusive licence to The Japan Society of Human Genetics.)

Mutations in the MECOM encoding EVI1 are observed in infants who have radioulnar synostosis with amegakaryocytic thrombocytopenia. MECOM-associated syndrome was proposed based on clinical heterogeneity. Allogeneic hematopoietic stem cell transplantation (HSCT) is a curative treatment for progressive bone marrow failure. However, data regarding allogeneic HSCT for this rare disease are limited. We retrospectively assessed overall survival, conditioning regimen, regimen-related toxicities and long-term sequelae in six patients treated with allogeneic HSCT. All patients received a reduced-intensity conditioning (RIC) regimen consisting of fludarabine, cyclophosphamide or melphalan, and rabbit anti-thymocyte globulin and/or low-dose total body/thoracic-abdominal/total lymphoid irradiation, followed by allogeneic bone marrow or cord blood transplantation from unrelated donors between 4 and 18 months of age. All patients survived and achieved stable engraftment and complete chimerization with the donor type. Moreover, no patient experienced severe regimen-related toxicities, and only lower grades of acute graft-versus-host disease were observed. Three patients treated with low-dose irradiation had relatively short stature compared to three patients not treated with irradiation. Therefore, allogeneic HSCT with RIC is an effective and feasible treatment for infants with MECOM-associated syndrome. Future studies are needed to evaluate the use of low-dose irradiation to avoid risks of other long-term sequelae., (© 2022. The Author(s).)

Background: A paradigm shift has occurred in cancer chemotherapy from tumor-specific treatment with cytotoxic agents to personalized medicine with molecular-targeted drugs. Thus, it is essential to identify genomic alterations and molecular features to recommend effective targeted molecular medicines regardless of the tumor site. Nevertheless, it takes considerable expertise to identify treatment targets from primary-sequencing data in order to provide drug recommendations. The Molecular Tumor Board (MTB) denotes a platform that integrates clinical and molecular features for clinical decisions., Methods: This study retrospectively analyses all the cases of discussion and decision at the MTB in Tohoku University Hospital and summarizes genetic alterations and treatment recommendations., Results: The MTB discussed 1003 comprehensive genomic profiling (CGP) tests conducted in patients with solid cancer, and the resulting rate of assessing treatment recommendations was approximately 19%. Among hundreds of genes in the CGP test, only 30 genetic alterations or biomarkers were used to make treatment recommendations. The leading biomarkers that led to treatment recommendations were tumor mutational burden-high (TMB-H) (n = 32), ERBB2 amplification (n = 24), BRAF V600E (n = 16), and BRCA1/2 alterations (n = 32). Thyroid cancer accounted for most cancer cases for which treatment recommendation was provided (81.3%), followed by non-small cell lung cancer (42.4%) and urologic cancer (31.3%). The number of tests performed for gastrointestinal cancers was high (n = 359); however, the treatment recommendations for the same were below average (13%)., Conclusion: The results of this study may be used to simplify treatment recommendations from the CGP reports and help select patients for testing, thereby increasing the accuracy of personalized medicine., (© 2022 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Recessive gene mutations in ABCA3 cause lethal neonatal respiratory distress, and pediatric and adult interstitial lung disease. The effectiveness of medical treatments is limited and a subset of such patients will eventually require lung transplantation. A 20 months old boy developed interstitial lung disease and was treated with hydroxychloroquine, which had a significant effect. Sequence analysis of ABCA3 gene revealed newly discovered compound heterozygous mutations. His respiratory dysfunction gradually progressed over years and he underwent living-donor lobar lung transplantation (LDLLT) at 8 years of age with his parents serving as bilateral lobar donors. The parents had been genetically examined beforehand and found to be carriers who had one allele with an ABCA3 gene mutation and the other with no mutation. The recipient has been well without chronic lung allograft dysfunction and his parents have been enjoying healthy social lives for 7 years since the operations. LDLLT appears to be a valid option for selected children with ABCA3 gene mutations who are too ill to wait for cadaveric lung transplantation. When relatives of the recipient with ABCA3 gene mutation are deemed potential donors for LDLLT, sequence analyses of the donors are indispensable to exclude the possibility that they are late-onset patients of this recessive hereditary disease., Competing Interests: Disclosures The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this article., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objective: We recently reported cases of adipsic hypernatremia caused by autoantibodies against the subfornical organ in patients with hypothalamic-pituitary lesions. This study aimed to clarify the clinical features of newly identified patients with adipsic hypernatremia whose sera displayed immunoreactivity to the mouse subfornical organ., Design: Observational cohort study of patients diagnosed with adipsic hypernatremia in Japan, United States, and Europe., Methods: The study included 22 patients with adipsic hypernatremia but without overt structural changes in the hypothalamic-pituitary region and congenital disease. Antibody response to the mouse subfornical organ was determined using immunohistochemistry. The clinical characteristics were compared between the patients with positive and negative antibody responses., Results: Antibody response to the mouse subfornical organ was detected in the sera of 16 patients (72.7%, female/male ratio, 1:1, 12 pediatric and 4 adult patients). The prolactin levels at the time of diagnosis were significantly higher in patients with positive subfornical organ (SFO) immunoreactivity than in those with negative SFO immunoreactivity (58.9 ± 33.5 vs. 22.9 ± 13.9 ng/ml, p < .05). Hypothalamic disorders were found in 37.5% of the patients with positive SFO immunoreactivity. Moreover, six patients were diagnosed with rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation/neural tumor syndrome after the diagnosis of adipsic hypernatremia. Plasma renin activity levels were significantly higher in patients with serum immunoreactivity to the Na x channel., Conclusions: The patients with serum immunoreactivity to the SFO had higher prolactin levels and hypothalamic disorders compared to those without the immunoreactivity. The clinical characteristics of patients with serum immunoreactivity to the subfornical organ included higher prolactin levels and hypothalamic disorders, which were frequently associated with central hypothyroidism and the presence of retroperitoneal tumors., (© 2022 John Wiley & Sons Ltd.)

Background: DNA replisome is a molecular complex that plays indispensable roles in normal DNA replication. IMAGE-I syndrome is a DNA replisome-associated genetic disease caused by biallelic mutations in the gene encoding DNA polymerase epsilon catalytic subunit 1 ( POLE ). However, the underlying molecular mechanisms remain largely unresolved., Methods: The clinical manifestations in two patients with IMAGE-I syndrome were characterised. Whole-exome sequencing was performed and altered mRNA splicing and protein levels of POLE were determined. Subcellular localisation, cell cycle analysis and DNA replication stress were assessed using fibroblasts and peripheral blood from the patients and transfected cell lines to determine the functional significance of POLE mutations., Results: Both patients presented with growth retardation, adrenal insufficiency, immunodeficiency and complicated diffuse large B-cell lymphoma. We identified three novel POLE mutations: namely, a deep intronic mutation, c.1226+234G>A, common in both patients, and missense (c.2593T>G) and in-frame deletion (c.711&#95;713del) mutations in each patient. The unique deep intronic mutation produced aberrantly spliced mRNAs. All mutants showed significantly reduced, but not null, protein levels. Notably, the mutants showed severely diminished nuclear localisation, which was rescued by proteasome inhibitor treatment. Functional analysis revealed impairment of cell cycle progression and increase in the expression of phospho-H2A histone family member X in both patients., Conclusion: These findings provide new insights regarding the mechanism via which POLE mutants are highly susceptible to proteasome-dependent degradation in the nucleus, resulting in impaired DNA replication and cell cycle progression, a characteristic of DNA replisome-associated diseases., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Ataxia-telangiectasia (A-T) is an autosomal recessive chromosomal breakage syndrome caused by mutation of the ATM (A-T mutated) gene, which encodes a protein kinase that has a major role in the cellular response to DNA damage. Approximately, 10% of A-T patients develop lymphoid malignancies. Deaths caused by extreme sensitivity to chemotherapy for malignancy have been reported, and cancer treatment in A-T is extraordinarily difficult, needing careful monitoring and individualized protocols. We report the case of a 12-year-old girl with A-T diagnosed at the age of 3 in association with IgA deficiency and recurrent pulmonary infections. Sanger sequencing revealed compound heterozygosity of the ATM gene, which bore two novel mutations. At the age of 12, she developed stage IV T-cell/histiocyte-rich large B-cell lymphoma. The tumor was resistant to chemotherapy, and she unfortunately died of cardiac insufficiency and multiple organ failure induced by rapid progression of the disease. The treatment approach for children with A-T and advanced-stage B-non-Hodgkin lymphoma must be refined., (© 2021. Japanese Society of Hematology.)

Taspase1, a highly conserved threonine protease encoded by TASP1, cleaves nuclear histone-modifying factors and basal transcription regulators to orchestrate diverse transcription programs. Hereditary loss-of-function mutation of TASP1 has recently been reported in humans as resulting in an anomaly complex syndrome, which manifests with hematological, facial, and skeletal abnormalities. Here, we demonstrate that Taspase1-mediated cleavage of TFIIAα-β, rather than of MLL1 or MLL2, in mouse embryos was required for proper fetal liver hematopoiesis and correct segmental identities of the axial skeleton. Homozygous genetic deletion of Taspase1 disrupted embryonic hematopoietic stem cell self-renewal and quiescence states and axial skeleton fates. Strikingly, mice carrying knockin noncleavable mutations of TFIIAα-β, a well-characterized basal transcription factor, displayed more pronounced fetal liver and axial skeleton defects than those with noncleavable MLL1 and MLL2, 2 trithorax group histone H3 trimethyl transferases. Our study offers molecular insights into a syndrome in humans that results from loss of TASP1 and describes an unexpected role of TFIIAα-β cleavage in embryonic cell fate decisions.

Signal transducer and activator of transcription 1 gain-of-function (STAT1 GOF) mutations are the most common cause of chronic mucocutaneous candidiasis (CMC). We report the effect of oral ruxolitinib, an inhibitor of Janus kinase (JAK) family tyrosine kinases, on the clinical and immune status of a 3-year-old male with steroid-dependent severe autoimmunity due to a STAT1 GOF T385M mutation. The patient's susceptibility to infection improved with antimicrobial prophylaxis and immunoglobulin replacement therapy, but he continued to exhibit severely disabling symptoms of autoimmunity. More than one-third of patients with STAT1 GOF mutations present with autoimmune manifestations, and this patient's mutation was reported to cause CMC with autoimmunity. We analyzed the interleukin (IL)-17A and IFN-γ levels and immunophenotype by flow cytometry before and during treatment with ruxolitinib. The peripheral IL-17A level did not increase, but the IFN-γ level decreased after 4 months of therapy. The STAT1 phosphorylation level decreased significantly upon stimulation of patient cells with IFN-γ. Clinically, cytomegalovirus reactivation occurred, but was controlled. No other adverse effect was noted. We report the potential of JAK1/2 inhibition with ruxolitinib for both CMC and steroid-dependent autoimmunity. However, long-term administration is necessary, as the effect is not sustained after treatment is discontinued.

Parapharyngeal neuroglial heterotopia is a rare entity, and the specific radiographical findings are unclear. We present a case of parapharyngeal neuroglial heterotopia examined with proton magnetic resonance spectroscopy ( 1 H-MRS) and 18 F-fluorodesoxyglucose positron emission tomography ( 18 F-FDG PET). Our neonate patient presented with neck mass and polyhydramnios during gestation. Computed tomography and magnetic resonance imaging demonstrated the morphological characteristics, but failed to establish the diagnosis. 1 H-MRS showed a non-malignant pattern, but 18 F-FDG PET demonstrated high glucose metabolism. Complete resection was achieved and the histopathological diagnosis was neuroglial heterotopia. Assessment of biological activity may be useful for both preoperative diagnosis and postoperative evaluation of residual lesions.

Background: X-linked inhibitor of apoptosis protein (XIAP) deficiency is a rare immunodeficiency that is characterized by recurrent hemophagocytic lymphohistiocytosis (HLH) and splenomegaly and sometimes associated with refractory inflammatory bowel disease (IBD). Although hematopoietic stem cell transplantation (HSCT) is the only curative therapy, the outcomes of HSCT for XIAP deficiency remain unsatisfactory compared with those for SLAM-associated protein deficiency and familial HLH., Aim: To investigate the outcomes and adverse events of HSCT for patients with XIAP deficiency, a national survey was conducted., Methods: A spreadsheet questionnaire was sent to physicians who had provided HSCT treatment for patients with XIAP deficiency in Japan., Results: Up to the end of September 2016, 10 patients with XIAP deficiency had undergone HSCT in Japan, 9 of whom (90%) had survived. All surviving patients had received a fludarabine-based reduced intensity conditioning (RIC) regimen. Although 5 patients developed post-HSCT HLH, 4 of them survived after etoposide administration. In addition, the IBD associated with XIAP deficiency improved remarkably after HSCT in all affected cases., Conclusion: The RIC regimen and HLH control might be important factors for successful HSCT outcomes, with improved IBD, in patients with XIAP deficiency.

Genetic mosaicism for somatic mutations of oncogenes is common in genodermatoses, which can be complicated with extra-cutaneous abnormalities. Here we describe an infant with a congenital anaplastic astrocytoma, a linear syringocystadenoma papilliferum, and ocular abnormalities. The BRAF c.1799T>A p.V600E mutation was detected in both the brain and skin tumor cells but not in the blood or normal skin cells, suggesting somatic mosaicsism for the mutation. Clinically, the brain tumor gradually became life threatening without any response to conventional chemotherapies including carboplatin, etoposide, and temozolomide. Vemurafenib, a BRAF p.V600E inhibitor, was administered daily after the detection of the BRAF mutation. This single-agent therapy was dramatically effective against the anaplastic astrocytoma; the tumor regressed, the cerebrospinal fluid cell count and protein levels decreased to normal levels, and hydrocephalus resolved. Moreover, other lesions including a corneal cyst also responded to vemurafenib. The brain tumor continued shrinking after 6 months of treatment. We present a genodermatosis syndrome associated with BRAF c.1799T>A p.V600E mosaicism. This syndrome may represent a new entity in the mosaic RASopathies, partly overlapping with Schimmelpenning-Feuerstein-Mims syndrome, which is driven by mosaicism of HRAS and/or KRAS activating mutations. Screening for BRAF c.1799T>A p.V600E is especially useful for those with malignant tumors, because it is one of the most-druggable targets., (© 2015 Wiley Periodicals, Inc.)

Taspase 1 (TASP1) cleaves the mixed-lineage leukemia (MLL) and transcription factor (TF) IIA families of nuclear proteins to orchestrate various biological processes. TASP1 is not a classical oncogene, but assists in cell proliferation and permits oncogenic initiation through cleavage of MLL and TFIIA. TASP1 is thus better classified as a "non-oncogene addiction" protease, and targeting TASP1 offers a novel and attractive anticancer therapeutic strategy.

IPEX syndrome is a rare and fatal disorder caused by absence of regulatory T cells (Tregs) due to congenital mutations in the Forkhead box protein 3 gene. Here, we report a patient with IPEX syndrome treated with RIC followed by allogeneic BMT from an HLA-matched sibling donor. We could achieve engraftment and regimen-related toxicity was well tolerated. Although the patient was in mixed chimera and the ratio of donor cells in whole peripheral blood remained relatively low, selective and sustained expansion of Tregs determined as CD4+CD25+Foxp3+ cells was observed. Improvement in clinical symptoms was correlated with expansion of donor-derived Tregs and disappearance of anti-villin autoantibody, which was involved in the pathogenesis of gastrointestinal symptoms in IPEX syndrome. This clinical observation suggests that donor-derived Tregs have selective growth advantage in patients with IPEX syndrome even in mixed chimera after allogeneic BMT and contribute to the control of clinical symptoms caused by the defect of Tregs., (© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Epstein-Barr virus (EBV)-infected T or NK cells cause chronic active EBV infection (CAEBV). Allogeneic hematopoietic stem cell transplantation (HSCT) is curative treatment for CAEBV patients. However, chemotherapy prior to HSCT and optimal conditioning regimen for allogeneic HSCT are still controversial., Patients and Methods: We retrospectively analyzed five patients with CAEBV treated with reduced-intensity conditioning (RIC) consisted of fludarabine, cyclophosphamide, and low-dose total-body irradiation followed by allogeneic bone marrow transplantation in a single institute. Only one of five patients received chemotherapy prior to transplantation. We analyzed EBV-infected cells in a patient whose EBV load increased after HSCT by T-cell repertoire assay, separation of T-cell subpopulations, in situ hybridization and microsatellite analysis., Results: All five patients achieved engraftment, complete chimera, and eradication of EBV load. All patients have been alive without any serious regimen-related toxicity for more than 16 months following HSCT. However, one patient transplanted from HLA-matched sibling donor developed clonal proliferation of CD4+ Vβ3+ T cells caused by monoclonal EBV infection on day 99 after transplantation. Further analysis revealed that the CD4+ Vβ3+ T cells selectively harbored EBV genome, and these infected cells were derived from donor T cells., Conclusions: Allogeneic HSCT with RIC is a safe and effective treatment for better overall survival and less regimen-related toxicity in patients with CAEBV. Our first pediatric case reported in the literature suggests that we should consider the possibility of persistent EBV infection in donor T cells as well as the relapse in recipient cells if EBV load increases after allogeneic HSCT., (© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Autoimmune hemolytic anemia (AIHA) is a rare disease in infants, for which steroids are recognized as a first-line therapy for patients. Rituximab, a humanized monoclonal antibody raised against CD20, has been used in the treatment of autoimmune diseases, including AIHA, in adults and children. Due to limited follow-up study of the use of rituximab in the treatment for AIHA, its long-term efficacy, adverse effects, and immunological reconstitution of B cells have not been fully evaluated in infants. Here, we report a 3-month-old female patient with refractory AIHA, who was successfully treated with rituximab. Hemolytic anemia improved rapidly, and there were no severe adverse effects caused by rituximab. After 4.5 months following rituximab treatment, peripheral B cells were gradually reconstituted and required no intravenous immunoglobulin replacement thereafter. The patient has remained disease-free for more than 30 months without any additional treatment. This case suggests that rituximab may be a valuable therapeutic option, given its efficacy and minimal adverse effects in infants with therapy-resistant AIHA.

Mutations in genes critical for surfactant metabolism, including surfactant protein C (SP-C) and ABCA3, are well-recognized causes of interstitial lung disease. Recessive mutations in ABCA3 were first attributed to fatal respiratory failure in full-term neonates, but they are also increasingly being recognized as a cause of respiratory disorders with less severe phenotypes in older children and also adults. Here, we report a 20-month-old boy with interstitial lung disease caused by two distinct ABCA3 mutations. Initial treatment with methylprednisolone was unsuccessful, but the additional administration of hydroxychloroquine was effective. The family history revealed that the patient's older brother had died of idiopathic interstitial lung disease at 6 months of age, suggesting a genetic etiology of the disease. Sequence analyses of SP-C and ABCA3 genes were performed using DNA samples from the patient himself, his parents, and his brother. These analyses revealed novel compound heterozygous mutations in the coding exons of ABCA3 in both the patient and his brother: c.2741A > G, of paternal origin, and c.3715&#95;3716insGGGGGG, of maternal origin. Conclusion Since ABCA3 mutations seem to be a heterogeneous entity with various phenotypes, we recommend genetic testing for mutations in SP-C and ABCA3 genes to be considered in children with unexplained interstitial lung disease.

Background: Post-transplantation lymphoproliferative disorder (PTLD) is a group of life-threatening complications of organ transplantation, which occurs most frequently in pediatric patients. This retrospective study evaluates a single-institution experience of five cases of PTLD after living-donor liver transplantation (LDLT)., Patients and Method: We reviewed the records of 78 pediatric patients (<18 years old) and 54 adult patients, who underwent LDLT between July 1991 and December 2009., Result: PTLD was diagnosed in five pediatric patients, yielding an overall incidence of 3.8%. There were no significant differences between the pediatric patients with and those without PTLD in terms of their age, sex, reason for transplantation, calcineurin inhibitor, Epstein-Barr virus (EBV) serostatus, ABO compatibility, lymphocyte cross-matching, or episodes of biopsy proven rejection. Two patients with abdominal lymphadenopathy and one with gastrointestinal PTLD responded to a reduction in immunosuppression. Treatment with rituximab was necessary for another gastrointestinal PTLD patient. Diffuse large-B-cell lymphoma was diagnosed in one patient with mediastinal and lung masses. This patient was treated with chemotherapy and rituximab, followed by surgical resection. All patients survived and no evidence of recurrence has been found since., Conclusion: Although PTLD is potentially life-threatening, it can be managed by appropriate and prompt treatment, with a good outcome.

Childhood cerebral ALD is a rapidly progressive and neurodegenerative disorder for which HSCT is the curative therapy if carried out at early stages. We successfully treated two patients of childhood cerebral ALD by CBT with RIC. The proband was a seven-yr-old boy whose brain MRI severity score (Loes score) was 14.5. Unrelated CBT was performed in five wk. To minimize conditioning regimen-related neurotoxicity, the combination of fludarabine (125 mg/m(2)), melphalan (140 mg/m(2)), and 4 Gy of brain-sparing TBI was used. The second patient was a six-yr-old brother of the proband. Four wk after the detection of a single small lesion (Loes score 1), he received unrelated CBT with the same RIC as the proband. In both patients, the engraftment was fast and stable, and severe complications were not observed. Furthermore, gadolinium-enhanced inflammation on brain MRI rapidly disappeared after CBT. Now, 20 and 13 months have passed after CBT, respectively, and both patients are neurologically stable. The RIC we used was sufficient for stable engraftment of cord blood and also tolerable even to the patient with advanced ALD. RIC-CBT should be considered for the patients with cerebral ALD at advanced stages, as well as those at early stages., (© 2011 John Wiley & Sons A/S.)

Three pediatric patients with infratentorial metastatic non-epithelial malignant brain tumors were successfully treated by radical surgical resection followed by aggressive radiochemotherapy. One patient with neuroblastoma and two with rhabdomyosarcoma were successfully treated by first line multimodal treatments, but developed infratentorial metastasis after several months of remission. All patients revealed intracranial metastases manifesting as rapidly progressing neurological symptoms caused by mass effect in the posterior fossa. Radical surgical resection was performed without morbidity. The patients were then treated by adjuvant radiochemotherapy with or without autologous peripheral blood stem cell transplantation, resulting in complete remission. Two patients developed extracranial recurrences 4 months after the treatments for intracranial metastases. One patient was treated by second high-dose chemotherapy with allogeneic cord blood transplantation, again resulting in complete remission. Another patient was treated by second chemotherapy and maintaining stable disease. The other patient maintained complete remission. All three patients were alive without neurological deficit for 8, 11, and 12 months after diagnosis of brain metastasis. Patients with infratentorial brain metastases of highly malignant pediatric non-epithelial tumors are in a severe clinical state, but still can have longer and useful lives with aggressive multimodal treatments combined with radical surgical resection.

Immune thrombocytopenic purpura (ITP) has been associated with several hematologic malignancies such as Hodgkin and non-Hodgkin lymphomas and chronic lymphocytic leukemia, but it is rare in children with acute lymphoblastic leukemia (ALL). Here, we report a 7-year-old girl with chronic ITP during early intensive phase of chemotherapy for ALL. She underwent splenectomy because thrombocytopenia had persisted even after treatment with intravenous immunoglobulin (IVIG), steroids, vincristine, rituximab, and anti-D antibody. After splenectomy, her platelet count had recovered, and maintenance therapy could be resumed with a support of IVIG. To our knowledge, this is the first child case of chronic ITP during chemotherapy for ALL and splenectomy was effective in this patient.

Neuroblastoma shows complex patterns of genetic aberrations including MYCN amplification, deletion of chromosome 1p or 11q, and gain of chromosome 17q. The 17q gain is frequently observed in high-risk neuroblastomas, however, the candidate genes still remain elusive. In the present study, we integrated the data of comparative genomic hybridization of 236 tumors by BAC array and expression profiling of 136 tumors by using the in-house cDNA microarray carrying 5,340 genes derived from primary neuroblastomas. A novel candidate gene mapped to chromosome 17q25.1 with two splicing variants, Nbla10727 and Nbla12061, was identified. The transcript size appeared to be 2.3 kb by Northern blot, however, the cDNA sequences had no obvious open reading frame. The protein product was undetectable by both in vivo and in vitro translation assays, suggesting that the transcript might not encode any protein product. Therefore, we named it as ncRAN (non-coding RNA expressed in aggressive neuroblastoma). In analysis of 70 patients with sporadic neuroblastoma, the high levels of ncRAN mRNA expression were significantly associated with poor outcome of the patients (p<0.001). The multivariate analysis showed that expression of ncRAN mRNA was an independent prognostic factor among age, stage, origin and MYCN expression. Ectopic expression of ncRAN induced transformation of NIH3T3 cells in soft agar, while knockdown of endogenous ncRAN with RNA interference significantly inhibited cell growth in SH-SY5Y cells. Collectively, our results suggest that ncRAN may be a novel non-coding RNA mapped to the region of 17q gain and act like an oncogene in aggressive neuroblastomas.