Unique cell tropism of HHV-6B in an infantile autopsy case of primary HHV-6B encephalitis.

Human herpes virus 6 (HHV-6) is known to cause primary encephalitis in the frontal lobes/cerebral hemisphere or reactivated encephalitis in the hippocampus, but the pathogenesis remains unclear. HHV-6B has also been detected in hippocampal samples in patients with mesial temporal lobe epilepsy. A 1 year and 3 months old female, who had been clinically diagnosed with exanthema subitum and febrile convulsion, was found dead on the third day after onset. Macroscopic findings showed massive brain edema. Microscopic examination revealed gemistocytic astrocytes and ballooned oligodendrocytes in the frontal white matter, along with neuronal cell death with microglial infiltration in the frontal cortex. Polymerase chain reaction detected HHV-6B in the cerebrospinal fluid and necropsy brain samples. The hippocampus showed a 4-5-fold increase in virus copy number of HHV-6B compared to samples from other brain sites. Immunostaining indicated that HHV-6B had infected vascular endothelial cells, neurons and oligodendrocytes but not astrocytes or microglia. Hippocampal neurons were infected with highly concentrated HHV-6B, but the hippocampus had neither neuronal loss nor reactive glial response. Silent and abundant HHV-6B infection in the hippocampus might be associated with latent infection, reactivation and some hippocampus-oriented disorders, including mesial temporal lobe epilepsy.

Toxic epidermal necrolysis in a child 6 months post-hematopoietic stem cell transplantation.

TEN is a rare and critical disease mostly caused by drugs. It is mediated by activated CD8+ T cells that cause keratinocyte apoptosis with the assistance of cytokines/chemokines. We herein report a pediatric case of TEN after allogeneic HSCT with precursor B-cell acute lymphoblastic leukemia (pre-B-ALL) in second complete remission. Although we did not evaluate the T-cell subpopulation in blood or skin lesion of the patient, an imbalanced immune reconstitution after HSCT might additively contribute to the development of TEN.

Cord blood transplantation in a young child with pyruvate kinase deficiency.

Unrelated cord blood transplantation (CBT) was performed for the treatment of pyruvate kinase (PK) deficiency in a female pediatric patient at the age of 1 year 7 months, who had been in severe and frequent transfusion-dependent hemolytic anemia, despite red blood cell (RBC) PK activity 5.52 IU/gHb. pyruvate kinase-liver and RBC (PK-LR) had a compound heterozygous mutation located on exon 8: c.1044G > T/c.1076G > A (K348N/R359H). Hemoglobin and RBC PK corrected to 13.5 g/dL and 9.00 IU/gHb, respectively, with gene correction at 6 months after CBT. CBT should be considered as an option for useful treatment in children with severe PK deficiency in the absence of HLA identical sibling with normal RBC PK activity.

Long-Term Morbidity and Mortality in Children with Chronic Graft-versus-Host Disease Classified by National Institutes of Health Consensus Criteria after Allogeneic Hematopoietic Stem Cell Transplantation.

We report the long-term morbidity and mortality of 105 pediatric patients who developed chronic graft-versus-host disease (cGVHD) after allogeneic hematopoietic stem cell transplantation (HSCT). According to the consensus criteria of the National Institutes of Health, the global severity of cGVHD was mild in 26 patients (25%), moderate in 30 patients (29%), and severe in 49 patients (47%). Patients with severe cGVHD had a significantly lower cumulative incidence of cGVHD remission and higher probability of continuing cGVHD at 8 years from cGVHD diagnosis compared with those with mild or moderate cGVHD. The 10-year cumulative incidence of nonrelapse mortality in severe cGVHD patients was significantly higher and the probability of disease-free survival was significantly lower than those among patients with mild and moderate cGVHD. Of the 59 patients who survived for more than 5 years, 20 (34%) (4 with moderate and 16 with severe cGVHD) had persistent functional impairment caused by cGVHD with a Karnofsky/Lansky performance score of 90% in 3 patients, 80% in 4 patients, and below 70% in 13 patients at the time of relapse, death, or last follow-up. Better therapeutic strategies are needed to lower the incidence of severe cGVHD, considering the longer life expectancy of pediatric HSCT survivors.

An overall characterization of pediatric acute lymphoblastic leukemia with CRLF2 overexpression.

For an overall characterization of pediatric B-cell precursor acute lymphoblastic leukemia (BCPALL) with CRLF2 overexpression (OE), we conducted genetic analysis of CRLF2 in 167 pediatric BCPALL patients. CRLF2 OE was detected in 30 (18%) of 167 patients, the P2RY8-CRLF2 fusion was identified in only 3 (1.8%) of 167 patients, all of which demonstrated CRLF2 OE. Moreover, CRLF2 gain was identified in 18 (11%) of 167 patients. Messenger RNA sequencing revealed a novel fusion transcript, CSF2RA-CRLF2, in a case with CRLF2 OE, suggesting that this fusion is associated with CRLF2 OE. In survival analysis, no significant differences in 5-year event-free survival (EFS) and overall survival were observed between patients with and without CRLF2 OE (70.7 vs. 75.4%, log rank P = 0.68 and 96.4 vs. 82.1%, log rank P = 0.11, respectively). However, a significant difference in 5-year EFS between CRLF2 OE patients with and without IKZF1 deletion was observed (44.4 vs. 83.1%, log rank P = 0.02). In multivariate analysis, only IKZF1 deletion was a significant predictor of inferior OS (hazard ratio: 2.427, P = 0.04).These findings suggest that CRLF2 OE is not an independent prognostic factor in pediatric BCPALL.

Characteristic phenotypes of ADH5/ALDH2 deficiency during childhood.

ADH5/ALDH2 deficiency is a rare inherited syndrome characterized by short stature, microcephaly, delayed mental development, and hematopoietic dysfunction and has recently been proposed as a disease paradigm. Acute and severe presentations include aplastic anemia, myelodysplastic syndrome, or leukemia, requiring bone marrow transplantation during childhood. Conversely, non-hematological manifestations may exhibit a prolonged and nonspecific clinical trajectory, with growth failure and developmental delay, most of which are often overlooked, particularly in patients with milder symptoms. Here, we describe the clinical course of a girl with a wide spectrum of clinical presentations, including nonspecific hematopoietic disorders, growth retardation, mild developmental delay, amblyopia, hemophagocytic lymphohistiocytosis, and verruca vulgaris, culminating in a genetic diagnosis of AMeD syndrome at 12 years of age. We also summarized the clinical manifestations of previously reported cases of AMeD syndrome. Cumulatively, 13 females and 5 males have been documented, with a cardinal triad of symptoms, aplastic anemia, short stature, and intellectual disability. Additional characteristic observations included pigmentary deposition in approximately half of the cases and skeletal difficulties in one-quarter. We propose that early diagnosis of patients who exhibit relatively mild phenotypes of skin or skeletal lesions is important for managing and improving the quality of life of patients with AMeD syndrome.

A transient myelodysplastic/myeloproliferative neoplasm in a patient with cardio-facio-cutaneous syndrome and a germline BRAF mutation.

A male infant, born at 32 weeks gestation by cesarean because of hydrops fetalis, presented with multiple anomalies, such as sparse and curly scalp hair, absent eyebrows, frontal bossing, an atrial septal defect, pulmonary artery stenosis, and whole myocardial thickening. He was clinically diagnosed with cardio-facio-cutaneous (CFC) syndrome, and was confirmed to have a germline V-raf murine sarcoma viral oncogene homologue B1 (BRAF) c.721 A>C mutation. At 1 month of age, he presented with a transient myelodysplastic/myeloproliferative neoplasm (MDS/MPN), which improved within a month without the administration of antineoplastic agents. This is the first report of CFC syndrome with MDS/MPN. The coexistence of MDS/MPN may be related to this BRAF c.721 A>C mutation.

[Treatment outcome of non-Hodgkin lymphoma in childhood: KYCCSG NHL-89, 96].

Two consecutive treatment protocols, NHL-89 and NHL-96, for pediatric diffuse large cell lymphoma (DLC) and lymphoblastic lymphoma (LBL) were conducted between March 1989 and December 2004 by Kyushu-Yamaguchi Children's Cancer Study Group. Forty-two patients (DLC: 15, LBL: 27) and 34 patients (DLC: 8, LBL: 26) were enrolled in NHL-89 and NHL-96, respectively. DLC patients received induction therapy of high-dose methotrexate (MTX) followed by repeated administration of intermediate MTX. LBL patients received a 4-drug induction followed by intensification, consolidation with cranial radiotherapy (15 to 24Gy), and maintenance. The maintenance phase consisted of multiple drug treatment; including prednisolone, vincristine, cyclophosphamide, and 6-mercaptopurine. With a median follow-up of 150 months for NHL-89 and 90.5 months for NHL-96, the estimated event-free survival at 5 years are 76.2±6.6% and 67.7±8.0%, respectively. Both studies improved the prognosis of DLC and LBL over our previous study of NHL-858.

Liver transplantation for congenital protein C deficiency with initial poor graft function: a case report with literature review.

Congenital deficiency of protein C (PC) is a rare disease that causes thrombophilia during the neonatal and infantile periods. Despite anticoagulative treatments, purpura fulminans and major vessel thrombosis often occur. We report a 7-year-old girl with congenital PC deficiency who underwent deceased donor liver transplantation (LT) and experienced complications accompanied by initial poor graft function (IPGF). Before LT, she had cerebral and ophthalmic hemorrhage, and seven episodes of purpura fulminans. The operation was successfully performed; however, the liver graft developed IPGF. Hyperammonemia and coagulopathy required continuous hemodiafiltration and infusion of fresh frozen plasma. It took 22 days for PC activity to reach reference levels. The changes in clotting and anticlotting activities in the patient's plasma were revealed using clot waveform analysis and the HemosIL ThromboPath® assay. PC activity remained normal for 5 years after LT. Even when IPGF occurs, liver function including PC activity can remain normal for a long time after recovery from IPGF. LT can be a curative treatment for congenital PC deficiency.

The indication and effectiveness of low-dose erythromycin therapy in pediatric patients with bronchial asthma.

To elucidate the mechanisms of intractable pediatric bronchial asthma and the indication of low-dose erythromycin (EM) therapy, the serum chemokine levels of and the angiogenic factor were evaluated in 55 pediatric patients with bronchial asthma; 7.4 +/- 3.5 yr old, who had been treated with inhaled steroid, leukotriene receptor antagonist, theophylline and others for more than a year. Both the levels of interleukin (IL) 8 (p = 0.036) and vascular endothelial growth factor (VEGF) (p = 0.005) were higher in patients with severe type than those of patients with the milder type, while other chemokine levels such as serum eotaxin and MCP1 did not show the correlation with the severity of bronchial asthma. Induction of therapy with low-dose EM induced improvement of the clinical symptoms in patients with severe type and decrease of their serum chemokine levels: IL8; from 736 +/- 88 to 75 +/- 85 pg/ml (p < 0.0005), and VEGF; from 352.0 +/- 160.5 to 132.2 +/- 59.9 pg/ml (p = 0.021) within the next 6 months. Moreover, low-dose EM resulted in a decreased daily peak-trough fluctuation rate of the serum theophylline concentration; (C(max )- C(min))/C(min), from 1.3 +/- 0.5 to 0.5 +/- 0.3, which led to the maintenance of effective serum levels. These results indicated that IL8 and VEGF affect the severity of standard therapies resistance intractable bronchial asthma. Through the suppression of these chemokines and maintenance of effective theophylline levels, low-dose EM therapy improves the symptoms of bronchial asthma.

Risk-adjusted therapy for pediatric non-T cell ALL improves outcomes for standard risk patients: results of JACLS ALL-02.

This study was a second multicenter trial on childhood ALL by the Japan Childhood Leukemia Study Group (JACLS) to improve outcomes in non-T ALL. Between April 2002 and March 2008, 1138 children with non-T ALL were enrolled in the JACLS ALL-02 trial. Patients were stratified into three groups using age, white blood cell count, unfavorable genetic abnormalities, and treatment response: standard risk (SR), high risk (HR), and extremely high risk (ER). Prophylactic cranial radiation therapy (PCRT) was abolished except for CNS leukemia. Four-year event-free survival (4yr-EFS) and 4-year overall survival (4yr-OS) rates for all patients were 85.4% ± 1.1% and 91.2% ± 0.9%, respectively. Risk-adjusted therapy resulted in 4yr-EFS rates of 90.4% ± 1.4% for SR, 84.9% ± 1.6% for HR, and 66.5% ± 4.0% for ER. Based on NCI risk classification, 4yr-EFS rates were 88.2% in NCI-SR and 76.4% in NCI-HR patients, respectively. Compared to previous trial ALL-97, 4yr-EFS of NCI-SR patients was significantly improved (88.2% vs 81.2%, log rank p = 0.0004). The 4-year cumulative incidence of isolated (0.9%) and total (1.5%) CNS relapse were significantly lower than those reported previously. In conclusion, improved EFS in NCI-SR patients and abolish of PCRT was achieved in ALL-02.

Discontinuation of L-asparaginase and poor response to prednisolone are associated with poor outcome of ETV6-RUNX1-positive pediatric B-cell precursor acute lymphoblastic leukemia.

ETV6-RUNX1-positive B precursor acute lymphoblastic leukemia (B-ALL) is a common subtype of pediatric B-ALL that has shown excellent outcomes in contemporary clinical trials for pediatric B-ALL. Examinations of the possibility of reducing therapeutic intensity may thus be explored. This prospective study examined outcomes in 205 pediatric patients with ETV6-RUNX1-positive B-ALL uniformly treated following the Japan Association of Childhood Leukemia Study Group (JACLS) ALL-02 protocol. The JACLS ALL-02 protocol does not employ minimal residual disease detected by polymerase chain reaction (PCR-MRD)-based risk stratification; however, 4-year event-free survival (EFS) and overall survival (OS) were 94.4 ± 1.6 and 97.5 ± 1.1%, respectively. In particular, 92 of 205 (44.9%) patients were successfully treated with a less intensive regimen involving only two cycles of high dose methotrexate and one course of re-induction therapy comprising vincristine, L-asparaginase (L-asp), pirarubicin, and prednisolone. Multivariate analysis revealed that discontinuation of L-asp and poor response to prednisolone was, respectively, associated with poor EFS (HR 6.3; 95% CI 1.3-27.0) and OS (HR 17.5; 95% CI 2.3-130), suggesting that the majority of ETV6-RUNX1-positive B-ALL cases may be cured by a less-intensive chemotherapy regimen if the risk stratification system including PCR-MRD monitoring and insufficient use of L-asp is avoided.

Impact of sirolimus treatment for refractory kaposiform hemangioendothelioma with exacerbation of the disease 10 years after initial diagnosis.

We describe our experience with a 12 year-old girl with kaposiform hemangioendothelioma accompanied by Kasabach-Merritt phenomenon with exacerbation of the disease 10 years after the initial diagnosis. Kaposiform hemangioendothelioma infiltrated into the subcutaneous tissue of the facial skin with deterioration of coagulopathy despite conventional therapies including corticosteroid, vincristine, and propranolol. Sirolimus, a mammalian target of rapamycin inhibitor, produced rapid and dramatic improvement of the Kasabach-Merritt phenomenon and kaposiform hemangioendothelioma shrinkage. Eventually, multifocal lesions of kaposiform hemangioendothelioma disappeared on the images of magnetic resonance imaging and have remained in remission for 27 months after sirolimus cessation. We demonstrated that the AKT/mammalian target of rapamycin signaling pathway played a pivotal role in the kaposiform hemangioendothelioma growth. Sirolimus must be a strong candidate for molecular therapy targeting kaposiform hemangioendothelioma.

Low Incidence of Osteonecrosis in Childhood Acute Lymphoblastic Leukemia Treated With ALL-97 and ALL-02 Study of Japan Association of Childhood Leukemia Study Group.

Purpose Osteonecrosis (ON) is a serious complication of the treatment of childhood acute lymphoblastic leukemia (ALL); however, data relating to ON in Asian pediatric patients with ALL are scarce. Therefore, we performed a retrospective analysis of cohorts of Japanese patients with ALL to clarify the incidence, clinical characteristics, and risk factors of ON. Patients and Methods The incidence and characteristics of ON were determined in patients with ALL (n = 1,662) enrolled in two studies from the Japan Association of Childhood Leukemia Study (JACLS) group (n = 635 and n = 1,027 patients treated with the ALL-97 and ALL-02 protocols, respectively). Results In total, 24 of 1,662 patients suffered from ON, of which 12 of 635 and 12 of 1,027 patients were treated with the ALL-97 and the ALL-02 protocol, respectively. Of the 24 patients, 23 were older than 10 years. In multivariate analysis, age (≥ 10 years) was the sole significant risk factor for ON ( P < .001). Separate evaluation of patients ≥ 10 years of age indicated a 5-year cumulative incidence of ON of 7.2% (95% CI, 4.0% to 12.6%) and 5.9% (95% CI, 3.3% to 10.4%) in the ALL-97 and the ALL-02 protocol, respectively, which was lower than reported previously, despite an administration of dexamethasone (DEX) similar to that in comparable studies; however, concomitant administration of DEX and l-asparaginase was reduced in the JACLS protocols. Conclusion We identified a low frequency of ON in the JACLS ALL-97 and ALL-02 studies. Although the sole risk factor for ON was age (≥ 10 years), even among high-risk patients, ON incidence was significantly lower than that reported in previous studies. These results suggest that, not only the total amount of DEX, but also how DEX and l-asparaginase are administered, which affects the clearance of DEX, may be associated with ON incidence in patients with ALL.

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.