Purpose

Improved survival of patients with childhood acute lymphoblastic leukemia (ALL) has drawn attention to the potential for late consequences of previous treatments among survivors, including metabolic syndrome. In this study, we evaluated changes in 3 parameters, namely, random blood glucose, body mass index (BMI), and Z score for BMI (Z-BMI), in children with ALL during chemotherapy and after completion of treatment.

Methods

Patients newly diagnosed with ALL from January, 2005 to December, 2008 at Saint Mary's Hospital, The Catholic University of Korea, who completed treatment with chemotherapy only were included (n=107). Random glucose, BMI, and Z-BMI were recorded at 5 intervals: at diagnosis, before maintenance treatment, at completion of maintenance treatment, and 6 and 12 months after completion of maintenance treatment. Similar analyses were conducted on 2 subcohorts based on ALL risk groups.

Results

For random glucose, a paired comparison showed significantly lower levels at 12 months post-treatment compared to those at initial diagnosis (P<0.001) and before maintenance (P<0.001). The Z-BMI score was significantly higher before maintenance than at diagnosis (P<0.001), but decreased significantly at the end of treatment (P<0.001) and remained low at 6 months (P<0.001) and 12 months (P<0.001) post-treatment. Similar results were obtained upon analysis of risk group-based subcohorts.

Conclusion

For a cohort of ALL patients treated without allogeneic transplantation or cranial irradiation, decrease in random glucose and Z-BMI after completion of chemotherapy does not indicate future glucose intolerance or obesity.

Purpose

The survival rate for childhood acute lymphoblastic leukemia (ALL) has improved significantly. However, overall prognosis for the 20 to 25% of patients who relapse is poor, and allogeneic hematopoietic stem cell transplantation (HSCT) offers the best chance for cure. In this study, we identified significant prognostic variables by analyzing the outcomes of allogeneic HSCT in ALL patients in second complete remission (CR).

Methods

Fifty-three ALL patients (42 men, 79%) who received HSCT in second CR from August 1991 to February 2009 were included (26 sibling donor HSCTs, 49%; 42 bone marrow transplantations, 79%). Study endpoints included cumulative incidence of acute and chronic graft-versus-host disease (GVHD), relapse, 1-year transplant-related mortality (TRM), disease-free survival (DFS), and overall survival (OS).

Results

Cumulative incidences of acute GVHD (grade 2 or above) and chronic GVHD were 45.3% and 28.5%, respectively. The estimated 5-year DFS and OS for the cohort was 45.2±6.8% and 48.3±7%, respectively. Only donor type, i.e., sibling versus unrelated, showed significant correlation with DFS in multivariate analysis (P=0.010). The rates of relapse and 1 year TRM were 28.9±6.4% and 26.4±6.1%, respectively, and unrelated donor HSCT (P=0.002) and HLA mismatch (P=0.022) were significantly correlated with increased TRM in univariate analysis.

Conclusion

In this single institution study spanning more than 17 years, sibling donor HSCT was the only factor predicting a favorable result in multivariate analysis, possibly due to increased TRM resulting from unrelated donor HSCT.

Background

Recent clinical observation reported that there was a significant correlation between change in circulating vascular endothelial growth factor (VEGF) levels and the occurrence of severe acute graft-versus-host disease (GVHD) following allogeneic hematopoietic stem cell transplantation (allo-HSCT), but the action mechanisms of VEGF in GVHD have not been demonstrated.

Methods

This study investigated whether or not blockade of VEGF has an effect on acute GVHD in a lethally irradiated murine allo-HSCT model of B6 (H-2b)→B6D2F1 (H-2b/d). Syngeneic or allogeneic recipient mice were injected subcutaneously with anti-VEGF peptides, dRK6 (50 µg/dose) or control diluent every other day for 2 weeks (total 7 doses).

Results

Administration of the dRK6 peptide after allo-HSCT significantly reduced survival with greaterclinical GVHD scores and body weight loss. Allogeneic recipients injected with the dRK6 peptide exhibited significantly increased circulating levels of VEGF and expansion of donor CD3+ T cells on day +7 compared to control treated animals. The donor CD4+ and CD8+ T-cell subsets have differential expansion caused by the dRK6 injection. The circulating VEGF levels were reduced on day +14 regardless of blockade of VEGF.

Conclusion

Together these findings demonstrate that the allo-reactive responses after allo-HSCT are exaggerated by the blockade of VEGF. VEGF seems to be consumed during the progression of acute GVHD in this murine allo-HSCT model.

Purpose

In this study, we analyzed a cohort of children with chronic graft-versus-host disease (GvHD) according to the NIH consensus classification (NCC) in order to observe whether global assessment at diagnosis correlates with GvHD-specific endpoints. We then studied the clinical course of these patients, specifically with regards to episodes of GvHD exacerbation requiring treatment escalation.

Materials and Methods

Recipients of either allogeneic bone marrow transplantation (BMT) or peripheral blood stem cell transplantation (PBSCT) from January 2006 to August 2008 at the Department of Pediatrics, The Catholic University of Korea were evaluated for chronic GvHD, which was diagnosed according to the NCC. The course of chronic GvHD in these patients was then followed.

Results

Of 59 evaluable patients, 23 developed chronic GvHD for a cumulative incidence of 39.3%. Upon multivariate analysis, previous acute GvHD (≥grade II) had a significant impact on chronic GvHD incidence. With a median duration of systemic treatment for chronic GvHD of 501 days, no significant relationship was found between initial global severity of chronic GvHD and either duration of immunosuppressive treatment or final clinical response to treatment. Fifteen patients (65%) experienced at least one episode of chronic GvHD exacerbation during the period of follow-up, with a median of four exacerbations in the subgroup of patients who experienced such events. Lung GvHD resulted in the highest number of exacerbations per diagnosed patient, followed by oral GvHD.

Conclusion

Analysis of this small cohort indicates that global assessment as proposed by the NCC may have limited correlations with GvHD-specific endpoints, possibly due to the favorable response of children to treatment.

Purpose

Enterovirus 71, one of the enteroviruses that are responsible for both hand-foot-and-mouth disease and herpangina, can cause neural injury. During periods of endemic spread of hand-foot-andmouth disease caused by enterovirus 71, CNS infections are also frequently diagnosed and may lead to increased complications from neural injury, as well as death. We present the results of our epidemiologic research on the clinical manifestations of children with CNS infections caused by enterovirus 71.

Methods

The study group consisted of 42 patients admitted for CNS infection by enterovirus 71 between April 2009 and October 2009 at the Department of Pediatrics of 5 major hospitals affiliated with the Catholic University of Korea. We retrospectively reviewed initial symptoms and laboratory findings on admission, the specimen from which enterovirus 71 was isolated, fever duration, admission period, treatment and progress, and complications. We compared aseptic meningitis patients with encephalitis patients.

Results

Of the 42 patients (23 men, 19 women), hand-foot-and-mouth disease was most prevalent (n=39), followed by herpangina (n=3), upon initial clinical diagnosis. Among the 42 patients, 15 (35.7%) were classified as severe, while 27 (64.3%) were classified as mild. Factors such as age, fever duration, presence of seizure, and use of intravenous immunoglobulin (IVIG) were statistically different between the 2 groups.

Conclusion

Our results indicate that patients with severe infection caused by enterovirus 71 tended to be less than 3 years old, presented with at least 3 days of fever as well as seizure activity, and received IVIG treatment.

Background

Combination treatment with all-trans-retinoic acid (ATRA) and anthracycline-based chemotherapy has led to major advances in the treatment of acute promyelocytic leukemia (APL).

Methods

In this study, we reviewed the outcome of pediatric APL patients treated using a modified AIDA protocol at our institution.

Results

Between May 1999 and December 2007, 23 patients were diagnosed with APL at the Department of Pediatrics, Saint Mary's Hospital, The Catholic University of Korea. Eleven patients were male (48%) (median age at diagnosis, 11 (range, 2-14) years). The treatment protocol consisted of remission induction (achieved by coadministration of ATRA and idarubicin), 3 courses of consolidation treatment, and 2 years of maintenance treatment during which ATRA was also administered. Three patients died early during remission induction due to CNS hemorrhage. The remaining 20 patients achieved complete remission (CR), with an overall CR rate of 87%. Two patients relapsed and died, and another patient died of pneumonia unrelated to APL. Four patients (17%) were diagnosed with ATRA syndrome, and all patients showed resolution of symptoms. The event-free survival (EFS) and overall survival (OS) of the cohort were 78.3±8.6% and 76.3±9.5%, respectively. Initial WBC count at diagnosis was the only significant prognostic factor for the rate of CR (P=0.039) and OS (P=0.039).

Conclusion

A modified AIDA protocol for the treatment of childhood APL leads to improved EFS and OS, with limited ATRA syndrome-associated toxicity. Active monitoring and treatment of patients with high initial WBC counts may help in reducing mortality.

Purpose

It has been suggested that p16 has a role in glucocorticoid (GC)-related apoptosis in leukemic cells, but the exact mechanisms have yet to be clarified. We evaluated the relationship between the GC response and p16 expression in a lymphoma cell line.

Methods

We used p16 siRNA transfection to construct p16-inactivated cells by using the B-cell lymphoblast cell line NC-37. We compared glucocorticoid receptor (GR) expression, apoptosis, and cell viability between control (p16+ NC-37) and p16 siRNA-transfected (p16- NC-37) cells after a single dose of dexamethasone (DX).

Results

In both groups, there was a significant increase in cytoplasmic GR expression, which tended to be higher for p16+ NC-37 cells than for p16- NC37 cells at all times, and the difference at 18 h was significant (P<0.05). Similar patterns of early apoptosis were observed in both groups, and late apoptosis occurred at higher levels at 18 h when the GR had already been downregulated (P<0.05). Cell viability decreased in both groups but the degree of reduction was more severe in p16+ NC-37 cells after 18 h (P<0.05).

Conclusion

These results suggest a relationship between GR expression and cell cycle inhibition, in which the absence of p16 leads to reduced cell sensitivity to DX.

The efficacy of tandem high-dose chemotherapy and autologous stem cell rescue (HDCT/ASCR) was investigated in patients with high-risk neuroblastoma. Patients over 1 yr of age who were newly diagnosed with stage 4 neuroblastoma from January 2000 to December 2005 were enrolled in The Korean Society of Pediatric Hematology-Oncology registry. All patients who were assigned to receive HDCT/ASCR at diagnosis were retrospectively analyzed to investigate the efficacy of single or tandem HDCT/ASCR. Seventy and 71 patients were assigned to receive single or tandem HDCT/ASCR at diagnosis. Fifty-seven and 59 patients in the single or tandem HDCT group underwent single or tandem HDCT/ASCR as scheduled. Twenty-four and 38 patients in the single or tandem HDCT group remained event free with a median follow-up of 56 (24-88) months. When the survival rate was analyzed according to intent-to-treat at diagnosis, the probability of the 5-yr event-free survival±95% confidence intervals was higher in the tandem HDCT group than in the single HDCT group (51.2±12.4% vs. 31.3±11.5%, P=0.030). The results of the present study demonstrate that the tandem HDCT/ASCR strategy is significantly better than the single HDCT/ASCR strategy for improved survival in the treatment of high-risk neuroblastoma patients.

Background

Acute colonic pseudo-obstruction (ACPO) refers to dilatation of the colon and decreased bowel motility without evidence of mechanical obstruction. Neostigmine, an acetylcholinesterase inhibitor, has been used in patients in whom supportive therapy failed to resolve ACPO. Here, we report the results of administering neostigmine to treat ACPO in children with hematologic malignancies.

Methods

Between September 2005 and December 2009, 10 patients (8 male and 2 female) were diagnosed with ACPO at the Department of Pediatrics, Catholic University of Korea. Diagnosis of ACPO was based on typical clinical features as well as colonic dilatation found on abdominal CT imaging. Neostigmine was administered subcutaneously at a dosage of 0.01 mg/kg/dose (maximum 0.5 mg) twice daily for a maximum of 5 total doses. ACPO was determined to be responsive to neostigmine if the patient showed both stool passage and improvement of clinical symptoms.

Results

The study group included 8 acute lymphoblastic leukemia patients, 1 patient with malignant lymphoma, and 1 patient with juvenile myelomonocytic leukemia. The median age at ACPO diagnosis was 8.5 years (range, 3-14). Overall, 8 patients (80%) showed therapeutic response to neostigmine at a median of 29 hours after the initial administration (range, 1-70). Two patients (20%) showed side effects of grade 2 or above, but none complained of cardiovascular symptoms that required treatment.

Conclusion

In this study, ACPO was diagnosed most often in late-childhood ALL patients. Subcutaneous neostigmine can be used to effectively treat ACPO diagnosed in children with hematologic malignancies without major cardiovascular complications.

Mesenchymal stem cells (MSCs) have recently been identified and characterized in humans. Moreover, MSC secrete cytokines that can support hematopoietic progenitor growth. In the present study, we evaluated whether the efficacy of hematopoietic stem cell transplantation is improved by their co-transplantation with MSC, and whether this is positively correlated with the dose of infused MSCs. Accordingly, irradiated NOD/SCID mice were transplanted with 1×105 human CD34+ cells in the presence or absence of culture expanded MSCs (1×106 or 5×106). We evaluated human hematopoietic cell engraftment by flow cytometry and assessed MSC tissue distributions by fluorescence in situ hybridization. We found that CD45+ and CD34+ cell levels were significantly elevated in a dose-dependent manner in cotransplanted mice 4 weeks after transplantation. The engraftments of CD33+ and CD19+ cells also increased dose-dependently. However, the engraftment of CD3+ cells did not increase after co-transplantation with MSCs. Human Y chromosome+ cells were observed in multiple tissues and were more frequently observed in mice co-transplanted with 5×106 rather than 1×106 MSCs. These results suggest that MSCs are capable of enhancing hematopoietic cell engraftment and distribution in multiple organs in a dose-dependent fashion.

The delivery of transgenes to the central nervous system (CNS) can be a valuable tool to treat CNS diseases. Various systems for the delivery to the CNS have been developed; vascular delivery of viral vectors being most recent. Here, we investigated gene transfer to the CNS by intravenous injection of recombinant adenoviral vectors, containing green fluorescence protein (GFP) as a reporter gene. Expression of GFP was first observed 6 days after the gene transfer, peaked at 14 days, and almost diminished after 28 days. The observed expression of GFP in the CNS was highly localized to hippocampal CA regions of cerebral neocortex, inferior colliculus of midbrain, and granular cell and Purkinje cell layers of cerebellum. It is concluded that intravenous delivery of adenoviral vectors can be used for gene delivery to the CNS, and hence the technique could be beneficial to gene therapy.