Pleuroparenchymal Fibroelastosis as a Late-Onset Pulmonary Toxicity after Treatment with Anticancer Chemotherapy for High-Risk Neuroblastoma.

Pleuroparenchymal fibroelastosis (PPFE) is a rare, progressive, restrictive lung disease characterized by hypercarbic respiratory failure. In pediatrics, it has been described in patients with a history of malignancy who have received a bone marrow transplant, chemotherapy, or radiotherapy. It is characterized by pleural thickening, fibrosis, subpleural elastosis, and intraalveolar collagen deposits. Survival is poor, and the only therapy is lung transplantation. Here, we report a patient who developed PPFE as a late-onset pulmonary toxicity after treatment with anticancer chemotherapy for high-risk neuroblastoma (NB).

Case Report: A Domestic Sponge Brush Used to Clean a Milk Feeding Bottle: The Source of Neonatal Meningitis Caused by Pseudomonas aeruginosa.

Pseudomonas aeruginosa is a relatively rare cause of neonatal meningitis, and most patients have serious underlying diseases, prematurity, immunodeficiency, or anatomical abnormalities. We report the case of a 7-day-old girl with meningitis caused by P. aeruginosa. She was born full-term and had no immunodeficiency or anatomical abnormalities as far as our investigation ascertained. Through the use of anti-Pseudomonas antibiotics, she recovered without any complications other than a slight hearing disability revealed by audiology testing. P. aeruginosa was also isolated from a domestic sponge brush used to clean her milk bottle. Physicians should consider P. aeruginosa as a possible pathogen of neonatal meningitis even in full-term infants with no immunodeficiency or anatomical abnormalities. Physicians should give advice concerning appropriate hygiene practices to be applied to the neonate's environment.

Pulmonary Langerhans cell histiocytosis with thyroid involvement manifesting as recurrent bilateral pneumothorax and tension bullae in a 3-year-old child.

INTRODUCTION: Pulmonary Langerhans cell histiocytosis (PLCH) is a well known entity in adults but is exceedingly rare in children. The main complication of PLCH is the occurrence of pneumothorax (PTX) and tension bullae with subsequent recurrence and persistence despite conservative management. CASE PRESENTATION: A 3-year-old child was diagnosed with PLCH with thyroid involvement. Chemotherapy was immediately initiated and continued with chest tube drainage for repeated bilateral PTX. Tension bullae developed in the right lung 1 month after initiating treatment. Emergency resection of the bullae and ligation of pulmonary cysts were performed. On the tenth postoperative day, she developed a tension bulla in the left lung. Emergency thoracotomy was performed. On the tenth postoperative day, chest X-ray and CT suggested return of the right bulla and mediastinal shift, and reoperation was performed. Repeated lung biopsy showed no sign of active LCH. Although her condition improved after the operation, subsequent repeated PTXs occurred and were difficult to treat. She was discharged home after four months. Currently, she is receiving maintenance therapy as an outpatient. During the 12-month follow-up, the pulmonary lesions also showed a tendency for improvement. DISCUSSION: Although it is difficult to treat recurrent PTX and tension bullae in advanced PLCH, continuous treatment of the primary disease (LCH) and the complications of pulmonary lesions can improve prognosis. CONCLUSION: Treatment of PLCH accompanied by recurrent PTX and tension bullae is challenging. The condition can be resolved by treating the primary disease in parallel with combined modality treatment, including surgical operation for complications.

Acute encephalopathy with biphasic seizures and late reduced diffusion in Kawasaki disease.

Herein we describe the case of a 7-month-old girl with Kawasaki disease (KD) in whom status epilepticus with fever developed on day 3 and cluster of seizures on day 6 of illness, followed by severe disturbance of consciousness afterward. Diffusion-weighted magnetic resonance imaging on day 6 of illness showed diffuse high signals in the bilateral subcortical white matter, while electroencephalogram indicated low-voltage slow waves. This indicated acute encephalopathy with biphasic seizures and late reduced diffusion (AESD); severe neurological sequelae remained. This is the first report of AESD as a complication of KD.

Successful management of venous thromboembolism with apixaban in a multiple myeloma patient on lenalidomide therapy.

A 69-year-old man was diagnosed with multiple myeloma (IgG-κ) in January 2012. He received autologous hematopoietic stem cell transplantation in August 2012 and subsequently maintained a stringent complete remission. In March 2016, he relapsed and was treated with lenalidomide and low-dose dexamethasone (Ld). On day22, he developed an asymptomatic venous thromboembolism (VTE) despite receiving prophylactic aspirin treatment. Thus, heparin and warfarin were administered. However, his prothrombin time-international normalized ratio did not remain within the target range of 2-3. Therefore, 10 mg/day of apixaban, a factor Xa inhibitor, was administered. The apixaban treatment resulted in favorable and effective control of the patient's VTE on day33. He has continued to receive Ld treatment and has suffered no further VTE or bleeding. Further large studies are needed to assess the efficacy and safety of factor Xa inhibitors for the treatment of MM-associated VTE.

High-dose Cepharanthin for pediatric chronic immune thrombocytopenia in Japan.

BACKGROUND: A nationwide, multicenter and observational study was retrospectively conducted to evaluate the clinical utility of Cepharanthin (CEP) for pediatric patients with chronic immune thrombocytopenia (ITP). METHODS: Clinical and laboratory data for 46 Japanese patients aged <16 years who were diagnosed as having chronic ITP in 14 hospitals during 2001-2011, and were treated with CEP for >12 months, were analyzed. RESULTS: Median daily CEP dose was 1 mg/kg (range, 0.12-2 mg/kg). Median platelet count prior to CEP was 20.5 × 109 /L (IQR, 8.3-53.0 × 109 /L), and then significantly increased to 58.5 × 109 /L (IQR, 22.8-115.0 × 109 /L) and 69.0 × 109 /L (IQR, 23.0-134.0 × 109 /L) at 12 and 24 months of treatment, respectively. No life-threatening bleeds or moderate-severe adverse events were reported. Of 38 patients who received both corticosteroids (CS) and CEP, 17 patients (45%) were weaned from CS, and 15 patients (39%) attained the reduced dose of CS. The duration from the start of CEP to the stopping of CS was a median of 413 days (range, 49-1734 days) in patients who were weaned from CS. CONCLUSIONS: CEP alone or combined with CS was useful for the management of pediatric chronic ITPs.

Chronic GVHD complicated with polymyositis and cardiomyopathy after myeloablative hematopoietic stem cell transplantation.

A 50-year-old woman presented with leukocytosis, anemia, and thrombocytopenia in June 2013. She was diagnosed with de novo acute myeloid leukemia with the t(16;21)(q24;q22) translocation. She received an allogeneic hematopoietic stem cell transplant from an HLA-DRB1 locus-mismatched unrelated donor in June 2014. The myeloablative preparative regimen consisted of cyclophosphamide at 60 mg/kg for 2 days and total body irradiation at 12 Gy. On Day 55, she was treated with prednisolone at 20 mg/day for acute GVHD (Grade III; Skin Stage 2, Gut Stage 2, Liver Stage 0) and gradually improved. She had fever, myalgia in the upper limbs, and asymptomatic sinus tachycardia on Day 145. Laboratory tests showed elevated CK, CKMB, aldolase, and troponin I. Electromyographic examination revealed myopathic abnormalities compatible with the diagnosis of myositis. Electrocardiography showed tachycardia and anteroseptal ST elevation, and echocardiography showed hypokinesia of the left interventricular septal wall without evidence of infection or leukemia relapse. She was immediately treated with 40 mg/day prednisolone after the diagnosis of polymyositis and cardiomyopathy, associated with chronic GVHD. The polymyositis and cardiomyopathy improved promptly after the administration of prednisolone and the patient remains in remission with a current maintenance program of prednisolone at 5 mg/day.

Development of donor cell leukemia mimicking hematogones after unrelated cord blood transplantation for relapsed acute lymphoblastic leukemia.

A 26-year-old woman, who developed ALL when she was eighteen years old, achieved remission after chemotherapy. Her ALL relapsed when she was twenty-two years old. After re-induction therapy, she underwent cord blood transplantation. Her bone marrow examination on the 42nd day revealed a lymphoblast count of 16%. She was observed without any therapy, but her bone marrow blast count continued to be around 6% for three years without any symptoms. The bone marrow blast fraction originated from the cord blood. Surface marker analysis of the blast fraction initially revealed a pattern of hematogones that was CD10 and CD19 positive, but then showed a myeloblast pattern that was CD13 and CD33 positive. AML developed as donor cell leukemia. When blasts appear in the early phase after transplantation and persist, an observation period is necessary with molecular chimerism, morphology, and surface marker analysis of the blast fraction to consider relapse, hematogones, or donor cell leukemia.

Fatigue in survivors of childhood acute lymphoblastic and myeloid leukemia in Japan.

BACKGROUND: Fatigue in cancer survivors is a serious problem in pediatric oncology, but reports on this issue are limited, especially in Asian countries. METHODS: Sixty-three patients with acute lymphoblastic leukemia and 18 patients with acute myeloid leukemia who attended a follow-up outpatient clinic were enrolled. Participants were required to be >8 years of age, in remission, and without any cancer treatment for at least the previous 1 year. A control group consisted of 243 subjects whose age and gender were matched with the patient group. A questionnaire consisting of 12 items was devised for fatigue measurement. RESULTS: Principal factor analysis identified three dimensions, defined as physical fatigue, decreased function, and altered mood. The mean total and the three fatigue dimension scores tended to be higher in the control group, but significant differences between the scores were seen only in the total and physical fatigue scores. Multiple regression analysis indicated an association of present older age or shorter duration after completion of treatment with total and physical fatigue, and an association of presence of total body irradiation with decreased function. CONCLUSION: Pediatric leukemia survivors in Japan experience equal or less fatigue compared with that of controls in different fatigue dimensions. Elucidation of underlying mechanisms of cancer-related fatigue including the differences of cultural background among different countries is necessary for future study of this issue.

Characterization of chronic idiopathic thrombocytopenic purpura in Japanese children: a retrospective multi-center study.

The objectives of this study are to clarify (1) the difference in demographic and clinical variables at initial presentation between acute and chronic idiopathic thrombocytopenic purpura (ITP), and (2) the prognostic factors of patients with chronic ITP. We conducted a retrospective analysis of 247 children with newly diagnosed ITP between April 1991 and March 2006 who visited one of the 12 hospitals belonging to the Kyoto University Pediatric Hematologic Study Group. 180 and 67 cases were classified as the acute type and as the chronic type, respectively. Older age, higher initial platelet count, positive medical history or concomitant medical diagnosis, the absence of preceding infection or vaccination, and the absence of an increase in immunoglobulin were risk factors for the chronicity. The prognostic factors in chronic ITP were evaluated in 53 patients after excluding patients receiving splenectomy or having insufficient follow-up data. The overall time required for 50% resolution in patients with chronic ITP was approximately 5.6 years. Age at presentation of less than 3 years and higher platelet counts at the time of chronic ITP diagnosis were good prognostic factors. On the other hand, gender, initial platelet counts, and preceding infection or vaccination were not associated with the prognosis.

A case of drug-induced hypersensitivity syndrome-like symptoms following HHV-6 encephalopathy.

BACKGROUND: Drug-induced hypersensitivity syndrome (DIHS) is a rare but severe disorder due to a systemic hypersensitivity reaction. We report on a case with DIHS-like symptoms following human herpes virus 6 (HHV-6) infection complicated with encephalopathy. CASE SUMMARY: An 11-month-old girl suffered from a human herpes virus 6 (HHV-6) infection (exanthema subitum) complicated with encephalopathy. We treated the patient with continuous infusion of thiopental, assisted mechanical ventilation, methylprednisolone pulse therapy, and gamma-globulin infusion therapy starting on the fifth day of the illness and started phenobarbital administration on the eleventh day. The patient developed a fever, systemic erythematous exanthema, lymphadenopathy, and eosinophilia two weeks after the start of phenobarbital administration. Steroid therapy, methylprednisolone (4 mg/kg/day) followed by oral prednisolone (1 mg/kg/day), was started on the 28th day and was tapered off on the 72nd day after admission. Serum anti-HHV-6 IgG antibody elevation and the presence of HHV-6 DNA in the peripheral blood detected by polymerase chain reaction (PCR) analysis suggested reactivation of HHV-6 after the primary infection of HHV-6. Lymphocyte transformation test for phenobarbital was positive three weeks after the DIHS crisis. DISCUSSION: HHV-6 reactivation is a unique feature in DIHS. In general one develops DIHS accompanied by reactivation of HHV-6 which has been residing in the body since the initial infection (exanthema subitum) in early childhood. This is the first report of a patient with DIHS-like symptoms which developed immediately following the primary infection of HHV-6.

Mitochondrial dysfunction is related to necrosis-like programmed cell death induced by A23187 in CEM cells.

We have previously reported that calcium ionophore A23187 differentially induces necrosis in CEM cells, a T-lymphoblastic leukemia cell line, and apoptosis in HL60 cells, a promyelocytic leukemia cell line. Stimulation with VP16, however, induces typical apoptosis in both cell lines. Necrosis in CEM cells, characterized by cell shrinkage and clustering, began within 5 min of treatment. Swelling of the mitochondria, lumpy chromatin condensation and intact plasma membranes were evident by electron microscopy. These A23187-mediated changes in CEM cells were suppressed by clonazepam or CGP37157, inhibitors of the mitochondrial Na(+)/Ca(2+) exchanger. The changes, however, were not affected by cyclosporin A, an inhibitor of the mitochondrial permeability transition pore. In both CEM and HL60 cells, intra-cellular calcium increased with similar amplitude within 1 min of treatment with 2 microM A23187. Intra-mitochondrial calcium increased with clonazepam pre-treatment alone in both CEM and HL60 cells. However, intra-mitochondrial calcium did not change drastically in response to A23187 in CEM or HL60 cells, either untreated or pre-treated with clonazepam. A23187 induces necrosis in CEM cells concurrent with mitochondrial dysfunction, which is independent of the mitochondrial permeability transition, but affected by intra-mitochondrial calcium, while HL60 cells lack these early changes. Differences in the responses to A23187 between these two cell lines might derive from differences in the susceptibility of the mitochondrial membrane to rapid increases in intra-cellular calcium.

Somatic cell mutation in pediatric patients undergoing allogeneic bone marrow transplantation.

In order to examine whether bone marrow transplantation (BMT) has genotoxic effects in vivo, mutant frequencies (Mfs) at the hypoxanthine-guanine phosphoribosyl transferase (Hprt) locus were evaluated. Thirty-seven pediatric patients who had received allogeneic BMT for various hematologic or immunologic disorders were enrolled. Nine out of the 37 patients (24.3%) were found to have Hprt-Mfs exceeding the 99% confidence limits calculated from observation of healthy controls. Among factors including gender, primary disease of the patient, donor-recipient histocompatibility relationship, age of donor, and total body irradiation as conditioning regimen, none was associated with an increased Hprt-Mf. In three patients who had chimerism in their peripheral blood after BMT, Hprt mutant clones turned out to be of donor- or recipient-origin. Mfs at the T-cell receptor (TCR) locus were examined in 28 patients. Four patients (14.3%) were found to have increased TCR-Mfs. However, there were not any patients who showed elevation of both Hprt-and TCR-Mfs. These data, taken together, suggest that BMT may cause genotoxicity in vivo in some patients.