Hirohide Kawasaki

Herpes zoster infection after bone marrow transplantation in children

OBJECTIVE To determine the frequency of, risk factors for, and clinical course of herpes zoster (HZ) after bone marrow transplantation (BMT) in children. STUDY DESIGN A total of 107 children with hematologic malignancy or solid tumor who underwent allogeneic or autologous BMT were studied retrospectively. RESULTS Of the 107 patients, HZ developed in 35 (33%) after BMT; 31 (89%) of these 35 patients had localized HZ. The median onset of infection was day 96 after BMT, and 89% of cases of HZ occurred before day 365 after BMT. HZ developed in 26 (58%) of 45 patients (13/21 (62%) allogeneic and 13/24 (54%) autologous patients) with hematologic malignancy; most of these patients had undergone total body irradiation. Of 33 patients with solid tumor, HZ developed in 9 (27%). All patients with HZ were treated with acyclovir, and no patients died of complications directly resulting from HZ. CONCLUSION Herpes zoster occurred earlier after BMT than in adults, and it occurred frequently in children who had hematologic malignancy and/or had undergone total body irradiation. Prompt antiviral therapy reduced the mortality rate and significant morbidity associated with HZ.

Novel Method for Efficient Production of Multipotential Hematopoietic Progenitors from Human Embryonic Stem Cells

We propose a novel method for the efficient production of hematopoietic progenitors from human embryonic stem cells (hESC) via coculture with murine fetal liver-derived stromal cells, in which embryonic hematopoiesis dramatically expands at midgestation. We generated various hematopoietic progenitors in coculture, and this hematopoietic activity was concentrated in cobblestone-like cells derived from differentiated hESC. The cobblestone-like cells mostly expressed CD34 and retained an endothelial cell potential. They also contained hematopoietic colony-forming cells, especially erythroid and multilineage colony-forming cells at high frequency. The multipotential hematopoietic progenitors abundant among the cobblestone-like cells produced almost all types of mature blood cells, including adult-type β-globin-expressing erythrocytes and tryptase/chymase double-positive mast cells. These progenitors showed neither the immature properties of ESC nor the potential to differentiate into endoderm and ectoderm at a clonal level. The coculture system developed for hESC can provide a novel source of hematopoietic and blood cells for applications in cellular therapy and drug screening.

IKZF1 deletion is associated with a poor outcome in pediatric B-cell precursor acute lymphoblastic leukemia in Japan

Genetic alterations of Ikaros family zinc finger protein 1 (IKZF1), point mutations in Janus kinase 2 (JAK2), and overexpression of cytokine receptor‐like factor 2 (CRLF2) were recently reported to be associated with poor outcomes in pediatric B‐cell precursor (BCP)‐ALL. Herein, we conducted genetic analyses of IKZF1 deletion, point mutation of JAK2 exon 16, 17, and 21, CRLF2 expression, the presence of P2RY8‐CRLF2 fusion and F232C mutation in CRLF2 in 202 pediatric BCP‐ALL patients newly diagnosed and registered in Japan Childhood Leukemia Study ALL02 protocol to find out if alterations in these genes are determinants of poor outcome. All patients showed good response to initial prednisolone (PSL) treatment. Ph+, infantile, and Down syndrome–associated ALL were excluded. Deletion of IKZF1 occurred in 19/202 patients (9.4%) and CRLF2 overexpression occurred in 16/107 (15.0%), which are similar to previous reports. Patients with IKZF1 deletion had reduced event‐free survival (EFS) and overall survival (OS) compared to those in patients without IKZF1 deletion (5‐year EFS, 62.7% vs. 88.8%, 5‐year OS, 71.8% vs. 90.2%). Our data also showed significantly inferior 5‐year EFS (48.6% vs. 84.7%, log rank P = 0.0003) and 5‐year OS (62.3% vs. 85.4%, log rank P = 0.009) in NCI‐HR patients (n = 97). JAK2 mutations and P2RY8‐CRLF2 fusion were rarely detected. IKZF1 deletion was identified as adverse prognostic factor even in pediatric BCP‐ALL in NCI‐HR showing good response to PSL.

Methylation status of the p15 and p16 genes in paediatric myelodysplastic syndrome and juvenile myelomonocytic leukaemia

Aberrant DNA methylation is frequently observed in adults with myelodysplastic syndrome (MDS), and is recognized as a critical event in the diseases pathogenesis and progression. This is the first report to investigate the methylation status of p15 and p16, cell cycle regulatory genes, in children with MDS (n = 9) and juvenile myelomonocytic leukaemia (JMML; n = 18) by using a methylation‐specific polymerase chain reaction. The frequency of p15 hypermethylation in paediatric MDS was 78% (7/9), which was comparable to that in adult MDS. In contrast, p15 hypermethylation in JMML was a rare event (17%; 3/18). In JMML, clinical and laboratory characteristics including PTPN11 mutations and aberrant colony formation were not different between the three patients with hypermethylated p15 and the others. Aberrant methylation of p16 was not detected in children with either MDS or JMML. Since p15 and p16 genes were unmethylated in two children with JMML, in whom the disease had progressed with an increased number of blasts, a condition referred to as blastic crisis, we infer that the aberrant methylation of these genes is not responsible for the progression of JMML. The results suggest that demethylating agents may be effective in most children with MDS and a few patients with JMML.

Hypercalcemia in children with rhabdomyosarcoma

Purpose: Hypercalcemia complicating malignancy is a serious and frequent occurrence in adults but rare in children. The aim of this study was to determine the incidence, symptoms, outcome, and cause of hypercalcemia in children with rhabdomyosarcoma. Patients and Methods: Among 93 children with rhabdomyosarcoma, six with hypercalcemia were identified and their clinical course, pathologic findings, treatment, and outcome were evaluated. In addition, serum and intratumor parathyroid hormone-related protein (PTHrP) concentrations were measured to ascertain the potential of hypercalcemia. Results: All six patients with hypercalcemia had bone metastasis, and four with severe hypercalcemia had multiple bone metastases. Serum PTHrP levels were moderately elevated. There were no significant trends detected based on age, gender, primary site, and pathologic type. All patients achieved transient resolution of hypercalcemia after treatment. However, none survived for a long period of time because their original tumor eventually recurred. Conclusions: Hypercalcemia is not an uncommon complication in patients with rhabdomyosarcoma. Bone absorption seems to be the predominant factor that induces the hypercalcemia in rhabdomyosarcoma. However, PTHrP may be a powerful stimulator of bone absorption, which contributes to the growth of bone metastasis.

Imatinib use immediately before stem cell transplantation in children with Philadelphia chromosome-positive acute lymphoblastic leukemia: Results from Japanese Pediatric Leukemia/Lymphoma Study Group (JPLSG) Study Ph+ALL04

Incorporation of imatinib into chemotherapeutic regimens has improved the prognosis of children with Philadelphia chromosome‐positive acute lymphoblastic leukemia (Ph+ALL). We investigated a role of imatinib immediately before hematopoietic stem cell transplantation (HSCT). Children with Ph+ALL were enrolled on JPLSG Ph+ALL 04 Study within 1 week of initiation of treatment for ALL. Treatment regimen consisted of Induction phase, Consolidation phase, Reinduction phase, 2 weeks of imatinib monotherapy phase, and HSCT phase (Etoposide+CY+TBI conditioning). Minimal residual disease (MRD), the amount of BCR–ABL transcripts, was measured with the real‐time PCR method. The study was registered in UMIN‐CTR: UMIN ID C000000290. Forty‐two patients were registered and 36 patients (86%) achieved complete remission (CR). Eight of 17 patients (47%) who had detectable MRD at the beginning of imatinib monotherapy phase showed disappearance or decrease in MRD after imatinib treatment. Consequently, 26 patients received HSCT in the first CR and all the patients had engraftment and no patients died because of complications of HSCT. The 4‐year event‐free survival rates and overall survival rates among all the 42 patients were 54.1 ± 7.8% and 78.1 ± 6.5%, respectively. Four of six patients who did achieve CR and three of six who relapsed before HSCT were salvaged with imatinib‐containing chemotherapy and subsequently treated with HSCT. The survival rate was excellent in this study although all patients received HSCT. A longer use of imatinib concurrently with chemotherapy should eliminate HSCT in a subset of patients with a rapid clearance of the disease.

A case of primary Ewing's sarcoma of the occipital bone presenting with obstructive hydrocephalus.

BackgroundEwing’s sarcomas account for approximately 10% of primary malignant bone tumors. While most of the primary Ewing’s sarcomas occur in the long bones, pelvis, or ribs, approximately 1–6% of these sarcomas arise in the skull. We found approximately 50 cases of Ewing’s sarcoma of the calvarium reported in our search of the literature. Of these, 36 cases were reported in detail.Case report and discussionIn this article we describe a rare case of primary Ewing’s sarcoma of the occipital bone presenting with acute obstructive hydrocephalus and review the literature.

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.

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 Childrens 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.

Postmortem Computed Tomography Imaging in the Investigation of Nontraumatic Death in Infants and Children

Objective. To determine the accuracy of postmortem computed tomography (PMCT) for the assessment of causes in nontraumatic deaths in children. Study Design. We enrolled cases of nontraumatic deaths of infants and children who underwent PMCT at a single center. The presumed cause of death determined by PMCT was prospectively compared with the clinical and pathological diagnoses of deaths. Results. Thirty-eight cases were enrolled for analysis. Among them, seven cases also underwent conventional medical autopsy. PMCT revealed an identifiable cause of death in accordance with the clinical diagnosis of death in 16 cases of the 38 cases (the concordance rate was 42%) and in accordance with the autopsy cause of death in four of the seven autopsy cases (the concordance rate was 57%). Among eight cases with unknown cause of death by clinical diagnosis, four cases (50%) were identified with cardiac tamponade as a cause of death (one case) and intracranial hemorrhage suggesting abuse (3 cases). Conclusions. PMCT seems to be a promising technique that might serve as a substitute for conventional medical autopsy and give us the complementary information to clinical diagnoses particularly in cases of child abuse. Larger multicenter trials are worthwhile to validate the general feasibility of PMCT.