18q Deletion Syndrome Presenting with Late-Onset Combined Immunodeficiency.

Patients with chromosome 18q deletion syndrome generally experience hypogammaglobulinemia. Herein, we describe two patients with chromosome 18q deletion syndrome who presented with late-onset combined immune deficiency (LOCID), which has not been previously reported. Patient 1 was a 29-year-old male with 18q deletion syndrome, who was being managed for severe motor and intellectual disabilities at the Yamabiko Medical Welfare Center for 26 years. Although the patient had few infections, he developed Pneumocystis pneumonia at the age of 28. Patient 2, a 48-year-old female with intellectual disability and congenital malformations, was referred to Tokyo Medical and Dental University Hospital with abnormal bilateral lung shadows detected on her chest radiography. Computed tomography showed multiple lymphadenopathies and pneumonia. A lymph node biopsy of the inguinal region revealed granulomatous lymphadenitis, and a chromosomal examination revealed 18q deletion. Array-based genomic hybridization analysis revealed deletion at 18q21.32-q22.3 for patient 1 and at 18q21.33-qter for patient 2. Immune status work-up of the two patients revealed panhypogammaglobulinemia, decreased number of memory B cells and naïve CD4+ and/or CD8+ cells, reduced response on the carboxyfluorescein diacetate succinimidyl ester T-cell division test, and low levels of T-cell receptor recombination excision circles and Ig κ-deleting recombination excision circles. Consequently, both patients were diagnosed with LOCID. Although patients with 18q deletion syndrome generally experience humoral immunodeficiency, the disease can be further complicated by cell-mediated immunodeficiency, causing combined immunodeficiency. Therefore, patients with 18q deletion syndrome should be regularly tested for cellular/humoral immunocompetence.

[Steroid-refractory gastrointestinal acute graft-versus-host disease treated with vedolizumab and ruxolitinib in a pediatric patient with therapy-related acute myeloid leukemia].

A 12-year-old girl developed Philadelphia chromosome-positive acute myeloid leukemia due to therapy-related myelodysplastic syndrome with monosomy 7 following neuroblastoma treatment. She underwent allogenic bone marrow transplantation from a human leukocyte antigens-DR1 locus-mismatched unrelated donor. However, on day 49 post transplantation, she presented with diarrhea due to gastrointestinal acute graft-versus-host disease (aGVHD), and treatments with prednisolone, budesonide rectal foam, and human mesenchymal stem cells were ineffective. Therefore, vedolizumab was administered from day 100, which improved the symptoms from gut stage 3 to gut stage 1. Consequently, prednisolone was withdrawn without any serious adverse effects. However, the symptoms worsened to gut stage 3 again; therefore, ruxolitinib was administered to achieve complete remission. Vedolizumab exhibits gut-selective action without systemic immunosuppressive activity. Hence, vedolizumab administration before other systemic immunosuppressive agents may be recommended in patients with steroid-refractory gastrointestinal aGVHD. Thus far, only a few reports have been published regarding the administration of vedolizumab and ruxolitinib for steroid-refractory gastrointestinal aGVHD in children. Further evidence should be obtained from patients treated with vedolizumab and ruxolitinib to confirm their effectiveness for pediatric steroid-refractory gastrointestinal aGVHD.

Successful Salvage of Very Early Relapse in Pediatric Acute Lymphoblastic Leukemia With Inotuzumab Ozogamicin and HLA-haploidentical Peripheral Blood Stem Cell Transplantation With Posttransplant Cyclophosphamide.

Herein, we describe a 14-year-old female patient with B-cell precursor acute lymphoblastic leukemia who relapsed in early consolidation. Minimal residual disease-negative complete remission was obtained after 1 cycle of inotuzumab ozogamicin therapy. She underwent HLA-haploidentical peripheral blood stem cell transplantation after a myeloablative conditioning regimen. Posttransplant cyclophosphamide, tacrolimus, and mycophenolate mofetil were administered for the prophylaxis of graft-versus-host disease. At 23 months, she was in complete remission. Although the administration of inotuzumab ozogamicin followed by haploidentical peripheral blood stem cell transplantation with posttransplant cyclophosphamide has been limited in children, this strategy may be an effective treatment for pediatric refractory acute lymphoblastic leukemia.

[Improvement in platelet count and bleeding symptom during treatment with eltrombopag in a patient with X-linked thrombocytopenia].

Herein, we describe a 13-year-old male adolescent who had chronic thrombocytopenia since infancy. In this case, X-linked thrombocytopenia (XLT) was suspected owing to a family history of chronic thrombocytopenia and small-sized platelets. Moreover, the patient was refractory to immunoglobulin therapy. The Wiskott-Aldrich syndrome protein (WASP) expression analysis revealed a decreased expression. Results showed a missense mutation [c.296A>G (p.Gln99Arg)] in exon 3 of the WASP-interacting protein region. Therefore, a diagnosis of XLT was made. To lift exercise restrictions, we initiated treatment with eltrombopag at a dose of 12.5 µg/day. The platelet count of the patient increased to approximately 50×103/µl after the treatment dose was escalated to 25 µg/day, and bleeding symptoms decreased after the patient resumed exercise. Ultrastructural platelet abnormalities and abnormal platelet aggregation were observed on transmission electron microscopy after the administration of eltrombopag. Therefore, eltrombopag treatment can increase platelet count and reduce bleeding symptoms in patients with XLT.

Brentuximab Vedotin and High-dose Methotrexate Administrated Alternately for Refractory Anaplastic Large-cell Lymphoma With Central Nervous System Disease.

Pediatric anaplastic large-cell lymphoma (ALCL), which is characterized by strong expression of CD30, is usually responsive to multidrug chemotherapy. Brentuximab vedotin (BV) which is an anti-CD30 antibody-drug conjugate is a promising drug with effects on relapsing or refractory ALCL. However, its effects may not be sufficient for the central nervous system disease. The authors herein reported an 11-year-old boy with ALCL that progressed as central nervous system disease receiving intensive induction chemotherapy has achieved and maintained remission by BV and high-dose methotrexate administrated alternately. Alternate therapy with high-dose methotrexate may complement these shortcomings of BV to provide safe treatment without worsening adverse events.

Importance of Acute Lymphoblastic Leukemia-type Therapy for Bilineal Acute Leukemia.

We examined 3 pediatric patients with bilineal acute leukemia. Patient 1 with B-cell acute lymphoblastic leukemia (ALL) and acute myelogenous leukemia (AML) with B-ALL dominance responded well to prednisolone and ALL-type induction therapy. Patients 2 and 3 with T-ALL and AML with AML dominance responded poorly to prednisolone. Patient 2 was resistant to AML-type therapy; patient 3 was resistant to ALL-type induction therapy until day 15. However, all 3 patients eventually achieved complete remission after ALL-type induction therapy. Thus, ALL-type induction therapy should be initiated for bilineal acute leukemia even with AML-dominant, poor prednisolone response, or poor early response features.

Epstein-Barr Virus (EBV)-induced B-cell Lymphoproliferative Disorder Mimicking the Recurrence of EBV-associated Hemophagocytic Lymphohistiocytosis.

We describe the case of a 23-month-old male infant with Epstein-Barr virus (EBV)-associated lymphoproliferative disorder, which mimicked the recurrence of EBV-associated hemophagocytic lymphohistiocytosis. Chemotherapy with dexamethasone, etoposide, and cyclosporine resolved fever, hepatosplenomegaly, and pancytopenia. However, on day 81 of illness, the patient developed similar symptoms. Plasma EBV-DNA levels markedly increased again, but no T-cell clonality was observed. B cells were identified to be infected with EBV. He was successfully treated with rituximab, dexamethasone and etoposide. When recurrence of EBV-associated hemophagocytic lymphohistiocytosis is suspected, performing tests to identify the infected cells will enable accurate understanding of the clinical condition, resulting in proper treatments.

Liver abscess due to Sterigmatomyces halophilus in a boy with acute lymphoblastic leukemia.

We report the first case of liver abscess due to Sterigmatomyces halophilus. Because this pathogen grows poorly in culture medium without added salts, it was identified by sequencing analysis targeting the rRNA gene internal transcribed spacer (ITS) region. This method could be useful for pathogens that cannot be cultured using standard methods.

Influence of GST polymorphisms on busulfan pharmacokinetics in Japanese children.

BACKGROUND: Fatal adverse effects or relapse can occur with excessive or insufficient busulfan exposure in hematopoietic stem cell transplantation. Given that busulfan is mainly metabolized by glutathione S-transferase (GST), we investigated the influence of GST polymorphisms on busulfan pharmacokinetics in Japanese pediatric patients. METHODS: Blood samples were taken from patients receiving high-dose i.v. busulfan as the first dose. Plasma busulfan concentration was measured using high-performance liquid chromatography. The area under the plasma busulfan concentration-time curve (AUC) was calculated. The genotype of GSTA1 was determined on polymerase chain reaction (PCR)-restriction fragment length polymorphism. Multiplex PCR was used to detect the presence or absence of GSTM1 and GSTT1 in the genomic DNA samples. RESULTS: Twenty patients were consecutively enrolled. Phenotype prediction was defined as follows: poor metabolizer (n = 4), one or more GSTA1*B haplotype or GSTM1/GSTT1 double-null genotypes; and extensive metabolizer (n = 16), other genotypes. GSTA1, M1, and T1 independently had no significant differences in AUC0-∞ , clearance or elimination rate constant. For the infant with unexpectedly high AUC0-∞ (2,591 µmol/L min), the GSTA1, M1, and T1 polymorphisms were wild type. On further analysis, the poor metabolizer group had lower clearance and higher AUC0-∞, except for the aforementioned patient, compared with the extensive metabolizer group (1,531 vs 1,010 µmol/L min; P < 0.01). CONCLUSIONS: GST polymorphisms may have affected busulfan pharmacokinetics, but these effects were obscured by other factors, such as underlying disease, systemic conditions, treatment history, and race.

Thiamylal Plus Pentazocine Shows Similar Efficacy as Ketamine Plus Midazolam for Painful Procedures in Children With Leukemia.

This retrospective study compared the use of thiamylal plus pentazocine (TP) to ketamine plus midazolam (KM) in children with leukemia who were undergoing bone marrow aspiration and/or intrathecal chemotherapy. A total of 268 procedures in 35 children with leukemia were retrospectively analyzed for efficacy and adverse events. All procedures were successfully completed without severe adverse events. TP induced significantly faster sedation. The incidents of desaturation were significantly greater in the TP group, but were transient and recovered by oxygen supplementation alone. Therefore, TP can be a useful combination with a similar efficacy as KM for painful procedures in children.

Risk Factors and the Prevention of Weight Gain During Induction Chemotherapy in Children With Acute Lymphoblastic Leukemia.

Weight gain is often observed in children with acute lymphoblastic leukemia (ALL) who undergo chemotherapy including steroids. An increase in body mass index (BMI)-standard deviation score (SDS) during induction therapy is reported as a risk factor for obesity after treatment. However, risk factors of an increase in BMI-SDS during induction therapy are not known. Ninety-six patients with ALL who were treated at our hospital between 1996 January and September 2013 were analyzed retrospectively. Daily body weight measurement was initiated in July 2005 in an attempt to control weight. Fifty-four patients were boys and 42 were girls. The median age at onset was 5.1 years (0.5-16.6 y), and 7.3% of patients were overweight/obese at onset. BMI-SDS increased +0.1% (-3.3% to +3.2%) during induction therapy. BMI-SDS increased by 1 and 2 or more SDs in 20% and 3% of patients, respectively. In multivariate analysis, non-high-risk treatment and earlier treatment start date (before daily body weight measurement) were independent risk factors. Ten percent of patients were overweight/obese at 3 years after completion therapy, and high BMI-SDS after induction therapy was a risk factor. Daily body weight measurement might prevent excess weight gain during induction therapy, resulting in patients maintaining a healthy weight after ALL treatment.

Maternal T and B cell engraftment in two cases of X-linked severe combined immunodeficiency with IgG1 gammopathy.

X-linked severe combined immunodeficiency (X-SCID), caused by defects in the common gamma chain, is typically characterized by T and NK cell defects with the presence of B cells. T cell dysfunction and impaired class-switch recombination of B cells mean that patients typically have defects in class-switched immunoglobulins (IgG, IgA, and IgE) with detectable IgM. Here, we describe two patients with X-SCID with IgG1 gammopathy, in whom we identified maternal T and B cell engraftment. Exclusively, maternal B cells were found among the IgD-CD27+ class-switched memory B cells, whereas the patients' B cells remained naïve. In vitro stimulation with CD40L+IL-21 revealed that peripheral blood cells from both patients produced only IgG1. Class-switched maternal B cells had restricted receptor repertoires with various constant regions and few somatic hypermutations. In conclusion, engrafted maternal B cells underwent class-switch recombination and produced immunoglobulin, causing hypergammaglobulinemia in patients with X-SCID.

Gene expression ratio as a predictive determinant of nelarabine chemosensitivity in T-lymphoblastic leukemia/lymphoma.

BACKGROUND: Nelarabine has been used for the treatment of T-cell malignancies including T-acute lymphoblastic leukemia (T-ALL)/T-lymphoblastic lymphoma. However, the mechanisms that underlie the susceptibility or resistance to nelarabine have not been fully elucidated. The aim of this study was to determine the significance of nelarabine transport and metabolism in the context of nelarabine cytotoxicity. PROCEDURE: The expression profiles of six genes in the nelarabine pathway were analyzed in blast cells from six patients with T-ALL as well as in three T-ALL cell lines. In vitro cytotoxicity (LC50 of 9-ß-d-arabinofuranosylguanine [ara-G]) was evaluated. RESULTS: The mRNA expression of ENT1, DCK, CDA, NT5C2, RRM1, and RRM2 in patients showed inter-individual variability and was not correlated with the LC50 of ara-G. However, the ratio of (ENT1 × DCK)/(CDA × RRM1) expression was significantly correlated with LC50 (r = -0.831, P = 0.0405). CONCLUSIONS: Chemosensitivity to nelarabine is influenced by the balance of the expression of these four genes, and the ratio of their expression predicts the response of T-cell malignancies to nelarabine.

Decrease of Cardiac Base Rotation in 2D Speckle Tracking Indicates Drug-induced Cardiomyopathy After Chemotherapy in Children With Cancer.

Drug-induced cardiomyopathy can be life-threatening in patients with cancer. Our objective was to explore early detection of drug-induced cardiomyopathy in children with cancer. We enrolled pediatric outpatients diagnosed with cancer between 2012 and 2013. In addition, we recruited pediatric outpatients in good general condition without cardiac disease or cancer, as controls. We measured the serum levels of biomarkers and performed chest radiography, electrocardiography, and ultrasound cardiography (UCG). We analyzed left ventricular (LV) torsion and torsion-related parameters using 2-dimensional (2D) speckle tracking on UCG. In total, 35 pediatric patients were enrolled. All patients showed negative findings for plasma troponin T, radiography, and electrocardiography. During 2D speckle tracking, 9 patients were excluded due to inappropriate dynamic echo images. We compared UCG findings between 26 patients and 16 controls. Although there was no difference in ejection fraction between patients and controls, peak LV torsion tended to be lower in patients than in controls, and the absolute basal rotation value at the timing of peak LV torsion was significantly lower in patients than in controls. In conclusion, a decrease of basal rotation in 2D speckle tracking might indicate the initial changes leading to myocardial disorder after chemotherapy.

Persistent positive metaiodobenzylguanidine scans after autologous peripheral blood stem cell transplantation may indicate maturation of stage 4 neuroblastoma.

Metaiodobenzylguanidine (MIBG) scans are sensitive testing tools for neuroblastoma. Persistent positive MIBG scans in patients with stage 3 neuroblastoma have previously been found to indicate maturation rather than regression. We assessed the significance of this finding in stage 4 neuroblastoma in the present study. Fifteen consecutive pediatric patients with stage 4 neuroblastoma treated between 2004 and 2014 at the Kagoshima University Hospital were retrospectively examined. Treatment involved a combination of multiagent chemotherapy, resection, autologous peripheral blood stem cell transplantation (PBSCT), radiotherapy, and maintenance therapy with retinoic acid. The MIBG uptake in each patient during treatment was assessed using a Curie score. The 5-year event-free and overall survival rates in 15 patients were 38.9% and 58.7%, respectively. Four patients with persistent positive MIBG scans who underwent autologous PBSCT but experienced decreased 123I-MIBG uptake during the clinical course survived without progression, and their event-free survival (EFS) was significantly superior to that of patients who showed negative MIBG scans after PBSCT (5-year EFS rate: 18.2%, p = 0.0176). Therefore, persistent positive MIBG scans with gradually decreased uptake after PBSCT do not always indicate neuroblastoma progression, and may instead indicate tumor maturation in some selected cases, if not all cases, of stage 4 neuroblastoma.