Streptococcal Toxic Shock Syndrome in a Child With Venous Malformation.

We report the case of a child with a venous malformation (VM), in whom streptococcal toxic shock syndrome (STSS) developed from cellulitis. A six-year-old boy with VM of the left lower limb had a fever and left lower limb pain since the afternoon of the day before admission. He presented with swelling, redness, heat, and tenderness on an area extending from the sole of the foot to the lower leg on the left side. Disturbance of consciousness gradually appeared, and he was admitted to the intensive care unit. We administered intravenous antibiotics and an immunoglobulin. On day two of hospitalization, group A hemolytic streptococci were detected in the blood culture. We managed the patient in coordination with a plastic surgeon for consideration of surgical interventions. The local findings subsequently improved to change the antibiotics promptly without debridement, and he was discharged after 14 days of antibiotic therapy. In this case, the VM may have contributed to the worsening of the infection. In children with VM, soft tissue inflammation with local pain and fever must be treated promptly, with the expectation of prompt surgical intervention, because the condition can progress to sepsis and necrotizing fasciitis.

Case report: Cerebellar swelling and hydrocephalus in familial hemophagocytic lymphohistiocytosis.

Familial hemophagocytic lymphohistiocytosis (FHL) is a severe inborn error of immunity caused by a genetic defect that impairs the function of cytotoxic T and NK cells. There are only a few reported cases of FHL with diffuse swelling of the cerebellum and obstructive hydrocephalus. We report a case of FHL3 with neurological symptoms associated with cerebellar swelling and obstructive hydrocephalus. A male patient was hospitalized several times due to fever and decreased feeding, hepatosplenomegaly, and cytopenia since the first month of life. At 7 months of age, disturbance of consciousness was seen. Brain magnetic resonance imaging revealed signal intensity in the bilateral cerebellar hemispheres, diffusely increased periventricular white matter, and ventriculomegaly. Although he was treated with methylprednisolone pulse therapy, he was unresponsive to the treatment. He was then transferred to a local hospital after tracheotomy but died. Targeted clinical sequencing revealed a homozygous splice-site mutation in UNC13D. Pediatric hemophagocytic lymphohistiocytosis (HLH) includes some cases of central nervous symptom (CNS)-isolated HLH or CNS HLH preceding systemic lesions, which often do not initially meet the diagnostic criteria for FHL. Patients with FHL initiated by cerebellar symptoms may present with an atypical clinical course for HLH, leading to delayed diagnosis and poor outcomes. Despite the usefulness of a combination of a high percentage of lymphocytes in the peripheral leukocytes, a low lactate dehydrogenase level, and a high sIL-2R/ferritin ratio for identifying FHL, the diagnosis may be missed due to the absence of these results. Presymptomatic diagnosis of FHL by screening of newborns and subsequent early treatment of patients with a predicted poor prognosis may contribute to better outcomes.

Genetic features of B-cell lymphoblastic lymphoma with TCF3-PBX1.

BACKGROUND: Lymphoblastic lymphoma (LBL) and acute lymphoblastic leukemia (ALL) are categorized as the same entity under precursor lymphoid neoplasms in the World Health Organization classification. However, compared to B-cell ALL, the molecular genetic makeup of B-cell LBL remains to be understood, mainly due to its rarity. We performed whole exome sequencing (WES) on seven patients with TCF3-PBX1-positive B-cell LBL. METHODS: WES was performed using DNA extracted from tumor specimens and paired blood samples at remission for six patients, and tumor-only analysis was performed for one patient whose remission sample was not available. For one patient, a relapsed sample was also analyzed. RESULTS: KMT2D variants and 6q LOH were found as recurrent alterations. Somatic variants of KMT2D were identified in three of the seven patients. Of note, the two patients with heterozygous nonsense variant of KMT2D were at stage III, without bone marrow infiltration. 6q LOH was also identified in two others, out of the seven patients. The common 6q deleted region of the two patients ranged from 6q12 to 6q16.3. Both patients had bone marrow infiltration. Analysis of recurrent case also revealed that the relapsed clone might be derived from a minor clone of the bone marrow at diagnosis. CONCLUSION: In this study, through WES for seven patients with TCF3-PBX1-positive B-LBL, we identified KMT2D mutations and 6q LOH as recurrent alterations. In order to elucidate the relationship between these recurrent alterations and disease specificity or outcomes, further studies comparing with TCF3-PBX1-positive B-ALL are required.

Switching from Intravenous to Oral Tacrolimus Reduces its Blood Concentration in Paediatric Cancer Patients.

BACKGROUND/AIM: Tacrolimus is an essential immunosuppressant for successful allogeneic haematopoietic stem cell transplantation (Allo-HSCT). This study aimed to examine the change in the blood concentration of tacrolimus during switching from intravenous to oral administration in allo-HSCT for paediatric cancer to predict the optimal dosage. PATIENTS AND METHODS: We retrospectively examined the medical records of 63 patients who received allo-HSCT and were administered tacrolimus. To compare bioavailability among different dose ranges, the blood concentration was divided by the dose (C/D). RESULTS: Thirty-nine patients (age range=children 1-15 years, adults 17-67 years) were switched to oral administration of tacrolimus. The C/D after switching was significantly lower in children than in adults (p=0.039). There was a strong positive correlation between age and C/D in children, whereas no correlation was observed in adults. CONCLUSION: In paediatric cancer patients, switching tacrolimus administration route may result in reduced blood concentrations. This tendency is more prominent in younger children.

Regulatory T cells in Crohn's disease following anti-TNF-α therapy.

BACKGROUND AND AIM: Anti-tumor necrosis factor alpha (TNF-α) therapy is an effective therapy for Crohn's disease (CD). We investigated FoxP3+ and CD127- regulatory T cells (Tregs) before and after administration of anti-TNF-α therapy in CD. METHODS: Eight patients with active CD who had received anti-TNF-α antibodies were enrolled. Treatment responses were followed by physical examination and Crohn's disease activity index (CDAI) scoring before and 2 weeks after the initial administration of anti-TNF-α antibodies. Peripheral blood samples were collected before and 2 weeks after treatment. White blood cell count and serum levels of C-reactive protein (CRP) and albumin were measured. FoxP3+ expression and CD127- Tregs were measured by fluorescence activated cell sorting (FACS) analysis of whole blood samples. RESULTS: Median values of CDAI decreased significantly after treatment. The proportion of FoxP3+ Tregs increased significantly after treatment. There was a significant negative correlation between ΔCD127- Tregs and Δlymphocyte. CONCLUSIONS: Anti-TNF-α therapy would enhance Tregs, which may account for the mechanism underlying the positive effect of the anti-TNF-α treatment in CD patients.

Successful Liposteroid Therapy for a Recurrent Idiopathic Pulmonary Hemosiderosis with Down Syndrome.

Idiopathic pulmonary hemosiderosis (IPH) is a rare and life-threatening disorder. Early diagnosis and appropriate management are essential for their better prognosis and patients' quality of life (QOL). It is considered that Down syndrome patients with IPH have a worse prognosis compared to other IPH cases. A 2-year-old girl with Down syndrome received the diagnosis of IPH after two episodes of massive pulmonary hemorrhage requiring assist ventilation, who suffered from recurrent IPH during tapering period of oral corticosteroid, started liposteroid therapy. We report here a case of successful control of recurrent IPH and improved QOL enormously with tapering dose of corticosteroid after starting liposteroid therapy.

Clinical, cytogenetic, and molecular analyses of 17 neonates with transient abnormal myelopoiesis and nonconstitutional trisomy 21.

BACKGROUND: Transient abnormal myelopoiesis (TAM) is a unique myeloproliferative disorder that occurs in neonates with constitutional trisomy 21/Down syndrome (DS). Although TAM also develops in neonates without constitutional trisomy 21, the clinical, cytogenetic, and molecular characteristics of those patients are not fully understood. PROCEDURE: We retrospectively evaluated the clinical and cytogenetic findings and GATA1 mutation status of 17 neonates with TAM and nonconstitutional trisomy 21 tested for GATA1 mutations at our institute, and compared the findings with those of 64 neonates with TAM and constitutional trisomy 21/DS. RESULTS: DS clinical features were observed in five of the 17 (29%) patients. In all patients, both trisomy 21 and GATA1 mutations were detected in diagnostic samples. Over a median follow-up of 33 (range, 0-139) months, early death (< 6 months of age) occurred in four patients (24%). Overall and event-free survivals were not significantly different between the patients with TAM and nonconstitutional trisomy 21 and those with TAM and constitutional trisomy 21/DS (five-year overall survival: 76% ± 10% vs 53% ± 13%, P = 0.40; five-year event-free survival: 55% ± 13% vs 48% ± 12%, P = 0.90). The five-year cumulative incidence of progression to myeloid leukemia of DS was also similar between the groups (21% vs 24%, P = 0.80). CONCLUSIONS: Patients with TAM and nonconstitutional trisomy 21 exhibited similar biology and outcomes to those with TAM and constitutional trisomy 21/DS. The possibility of TAM should be considered even in phenotypically normal neonates with TAM symptoms, for appropriate management.

Nationwide retrospective review of hematopoietic stem cell transplantation in children with refractory Langerhans cell histiocytosis.

The efficacy of and indications for hematopoietic stem cell transplantation (HSCT) in pediatric Langerhans cell histiocytosis (LCH) remain undetermined. This retrospective study analyzed 30 children with refractory LCH who underwent HSCT in Japan between 1996 and 2014. Eleven patients received a myeloablative conditioning (MAC) regimen, while 19 patients received a reduced-intensity conditioning (RIC) regimen. Among the 26 patients with complete data, 23 patients had risk organ (RO) involvement during clinical course. Disease status at HSCT was no active disease (NAD) (4), active disease-regression (AD-r) (2), active disease-stable (AD-s) (4), and active disease-progressive (AD-p) (16). Seventeen of the 30 patients (57%) were alive with a median follow-up of 433 days (range 9-5307) after HSCT. Death occurred within 3 months after HSCT in eight of 13 patients. RIC and MAC patients were similar in both overall survival (OS) (56.8% vs. 63.6%, respectively, p = 0.789) and failure-free survival (56.8% vs. 54.6%, respectively, p = 0.938). Regarding disease status at HSCT, the six patients with NAD/AD-r experienced better outcomes than the 20 with AD-s/AD-p (5-year OS, 100% vs. 54.5%, respectively, p = 0.040). Disease state at the time of HSCT was the most important prognostic factor.

Resistance of t(17;19)-acute lymphoblastic leukemia cell lines to multiagents in induction therapy.

t(17;19)(q21-q22;p13), responsible for TCF3-HLF fusion, is a rare translocation in childhood B-cell precursor acute lymphoblastic leukemia(BCP-ALL). t(1;19)(q23;p13), producing TCF3-PBX1 fusion, is a common translocation in childhood BCP-ALL. Prognosis of t(17;19)-ALL is extremely poor, while that of t(1;19)-ALL has recently improved dramatically in intensified chemotherapy. In this study, TCF3-HLF mRNA was detectable at a high level during induction therapy in a newly diagnosed t(17;19)-ALL case, while TCF3-PBX1 mRNA was undetectable at the end of induction therapy in most newly diagnosed t(1;19)-ALL cases. Using 4 t(17;19)-ALL and 16 t(1;19)-ALL cell lines, drug response profiling was analyzed. t(17;19)-ALL cell lines were found to be significantly more resistant to vincristine (VCR), daunorubicin (DNR), and prednisolone (Pred) than t(1;19)-ALL cell lines. Sensitivities to three (Pred, VCR, and l-asparaginase [l-Asp]), four (Pred, VCR, l-Asp, and DNR) and five (Pred, VCR, l-Asp, DNR, and cyclophosphamide) agents, widely used in induction therapy, were significantly poorer for t(17;19)-ALL cell lines than for t(1;19)-ALL cell lines. Consistent with poor responses to VCR and DNR, gene and protein expression levels of P-glycoprotein (P-gp) were higher in t(17;19)-ALL cell lines than in t(1;19)-ALL cell lines. Inhibitors for P-gp sensitized P-gp-positive t(17;19)-ALL cell lines to VCR and DNR. Knockout of P-gp by CRISPRCas9 overcame resistance to VCR and DNR in the P-gp-positive t(17;19)-ALL cell line. A combination of cyclosporine A with DNR prolonged survival of NSG mice inoculated with P-gp-positive t(17;19)-ALL cell line. These findings indicate involvement of P-gp in resistance to VCR and DNR in Pgp positive t(17;19)-ALL cell lines. In all four t(17;19)-ALL cell lines, RAS pathway mutation was detected. Furthermore, among 16 t(1;19)-ALL cell lines, multiagent resistance was usually observed in the cell lines with RAS pathway mutation in comparison to those without it, suggesting at least a partial involvement of RAS pathway mutation in multiagent resistance of t(17;19)-ALL.

[Prognostic significance of chimeric fusion gene analysis in pediatric acute megakaryoblastic leukemia].

Acute megakaryoblastic leukemia in children without Down syndrome (non-DS AMKL) is considered to be a poor prognostic subtype in acute myeloid leukemia. Recently, some chimeric fusion genes were found in pediatric non-DS AMKL; therefore, we attempted to detect chimeric fusion genes RBM15-MKL1, CBFA2T3-GLIS2, and NUP98-KDM5A from 10 pediatric non-DS AMKL diagnostic samples using polymerase chain reaction and Sanger sequencing methods. Two samples were positive for RBM15-MKL1, four had CBFA2T3-GLIS2, and only one case had NUP98-KDM5A. Both RBM15-MKL1-positive patients showed long-term remission after chemotherapy. The eight RBM15-MKL1-negative patients received hematopoietic stem cell transplantation (HSCT). In four CBFA2T3-GLIS2-positive patients, three had HSCT without complete remission and two of themdied. Additional treatment stratification depending on chimeric fusion genes and development of new therapeutic drugs are required for non-DS AMKL.

Fetal intracranial hemorrhage due to maternal subclinical vitamin K deficiency associated with long-term eating disorder.

Vitamin K deficiency in pregnant women causes intracranial hemorrhage (ICH) in fetuses. Fetal ICH frequently causes life-threatening and persistent neurological damage. However, indicators for preventing fetal ICH are not established. Two pregnant women developed long-term eating disorders caused by psychosis. They were administered intravenous fluid and vitamin supplementation, excluding vitamin K. The intracranial low-hypoechoic area on fetal ultrasound was suggestive of fetal ICH due to vitamin K deficiency. Their neonates showed severe developmental delay. Laboratory analysis revealed a normal prothrombin time, but elevated protein induced by vitamin K absence II. Pregnant women who have eating disorders more than 3 weeks could develop fetal ICH due to maternal subclinical vitamin K deficiency. Illness duration and protein induced by vitamin K absence II of pregnant woman may be indicators for vitamin K administration to prevent fetal intracranial hemorrhage.

Allogeneic hematopoietic stem cell transplantation for Chediak-Higashi syndrome.

The clinical outcome of allogeneic HSCT was retrospectively analyzed in eight patients with CHS. In total, six of these eight patients are alive. Four of five patients transplanted with MAC achieved prompt engraftment, and three of the four patients, including two patients with AP before transplant, are alive without disease. In contrast, three patients transplanted with RIC without active AP disease achieved prompt engraftment and survive long term. RIC-HSCT might be an alternative treatment for CHS similar to other types of HLH, at least for patients without active AP disease.

Protracted Administration of L-Asparaginase in Maintenance Phase Is the Risk Factor for Hyperglycemia in Older Patients with Pediatric Acute Lymphoblastic Leukemia.

Although L-asparaginase related hyperglycemia is well known adverse event, it is not studied whether the profile of this adverse event is affected by intensification of L-asparaginase administration. Here, we analyzed the profile of L-asparaginase related hyperglycemia in a 1,176 patients with pediatric acute lymphoblastic leukemia treated according to the Japan Association of Childhood Leukemia Study ALL-02 protocol using protracted L-asparaginase administration in maintenance phase. We determined that a total of 75 L-asparaginase related hyperglycemia events occurred in 69 patients. Although 17 events (17/1176, 1.4%) developed in induction phase, which was lower incidence than those (10-15%) in previous reports, 45 events developed during the maintenance phase with protracted L-asparaginase administration. Multivariate analysis showed that older age at onset (≥ 10 years) was a sole independent risk factor for L-asparaginase-related hyperglycemia (P<0.01), especially in maintenance phase. Contrary to the previous reports, obesity was not associated with L-asparaginase-related hyperglycemia. These findings suggest that protracted administration of L-asparaginase is the risk factor for hyperglycemia when treating adolescent and young adult acute lymphoblastic leukemia patients.

Outcome of TCF3-PBX1 positive pediatric acute lymphoblastic leukemia patients in Japan: a collaborative study of Japan Association of Childhood Leukemia Study (JACLS) and Children's Cancer and Leukemia Study Group (CCLSG).

This study reviewed the clinical characteristics of 112 pediatric B-cell precursor acute lymphoblastic leukemia (BCP-ALL) patients with TCF3-PBX1 fusion treated according to the Japan Association of Childhood Leukemia Study (JACLS) ALL02 protocol (n = 82) and Children's Cancer and Leukemia Study Group (CCLSG) ALL 2004 protocol (n = 30). The 3-year event-free survival (EFS) and overall survival (OS) rates were 85.4 ± 3.9% and 89.0 ± 3.5% in JACLS cohort, and the 5-year EFS and OS were 82.8 ± 7.0% and 86.3 ± 6.4% in CCLSG cohort, respectively, which are comparable to those reported in western countries. Conventional prognostic factors such as age at onset, initial white blood cell count, and National Cancer Institute risk have also no impact on OS in both cohorts. Surprisingly, the pattern of relapse in JACLS cohort, 9 of 82 patients, was unique: eight of nine patients relapsed during the maintenance phase and one patient had primary induction failure. However, bone marrow status and assessment of minimal residual disease on days 15 and 33 did not identify those patients. Interestingly, the two patients with IKZF1 deletion eventually relapsed in JACLS cohort, as did one patient in CCLSG cohort. International collaborative study of larger cohort is warranted to clarify the impact of the IKZF1 deletion on the poor outcome of TCF3-PBX1 positive BCP-ALL.

Subcutaneous panniculitis-like T-cell lymphoma (SPTCL) with hemophagocytosis (HPS): successful treatment using high-dose chemotherapy (BFM-NHL & ALL-90) and autologous peripheral blood stem cell transplantation.

Subcutaneous panniculitis-like T-cell lymphoma (SPTCL) is a rare form of non-Hodgkin lymphoma, in which lymphoma cells infiltrate preferentially into subcutaneous adipose tissue. Although various treatment trials for SPTCL have been attempted, no standardized therapy has been established. Here, we report a case of α/ß(+) T-cell-phenotype SPTCL (SPTCL-AB) with hemophagocytosis (HPS) in a 14-year-old girl, who presented with low-grade fever, general fatigue and chest swelling. Laboratory examinations revealed leukocytopenia, and bone marrow aspiration cytology showed HPS. The diagnosis of SPTCL-AB was made by biopsy on the basis of thickened subcutaneous tissue in the chest wall. Following high-dose chemotherapy (HDT) of BFM-NHL & ALL-90, autologous peripheral blood stem cell transplantation (auto-PBSCT) was performed. The patient responded to the treatment and has remained asymptomatic for 2 years. Our results suggest that a combination of HDT of BFM-NHL & ALL-90 and auto-SCT treatment is effective for SPTCL associated with HPS.

Naturally occurring oncogenic GATA1 mutants with internal deletions in transient abnormal myelopoiesis in Down syndrome.

Children with Down syndrome have an increased incidence of transient abnormal myelopoiesis (TAM) and acute megakaryoblastic leukemia. The majority of these cases harbor somatic mutations in the GATA1 gene, which results in the loss of full-length GATA1. Only a truncated isoform of GATA1 that lacks the N-terminal 83 amino acids (GATA1-S) remains. We found through genetic studies of 106 patients with TAM that internally deleted GATA1 proteins (GATA1-IDs) lacking amino acid residues 77-119 or 74-88 (created by splicing mutations) contributed to the genesis of TAM in 6 patients. Analyses of GATA1-deficient embryonic megakaryocytic progenitors revealed that the GATA1 function in growth restriction was disrupted in GATA1-IDs. In contrast, GATA1-S promoted megakaryocyte proliferation more profoundly than that induced by GATA1 deficiency. These results indicate that the internally deleted regions play important roles in megakaryocyte proliferation and that perturbation of this mechanism is involved in the pathogenesis of TAM.

Peripheral Blood CD64 Levels Decrease in Crohn's Disease following Granulocyte and Monocyte Adsorptive Apheresis.

Granulocyte and monocyte adsorptive apheresis (GMA) is reportedly useful as induction therapy for Crohn's disease (CD). However, the effects of GMA on CD64 have not been well characterized. We report here our assessment of CD64 expression on neutrophils before and after treatment with GMA in two patients with CD. The severity of CD was assessed with the CD activity index (CDAI). The duration of each GMA session was 60 min at a flow rate of 30 ml/min as per protocol. CD64 expression on neutrophils was measured by analyzing whole blood with a FACScan flow cytometer. In case 1, CD64 levels after each session of GMA tended to decrease compared to pretreatment levels, whereas in case 2, CD64 levels dropped significantly after treatment. The CDAI decreased after GMA in both cases 1 and 2. A significant correlation was noted between CDAI scores and CD64 levels in both cases. In conclusion, GMA reduced blood CD64 levels, which would be an important factor for the decrease of CDAI scores.