Factors influencing lymphocyte reconstitution after allogeneic hematopoietic stem cell transplantation in children.

BACKGROUND: Immune reconstitution (IR) after hematopoietic stem cell transplantation (HSCT) reduces transplantation-related complications such as infection and improves HSCT outcomes. METHODS: We retrospectively analyzed IR of lymphocyte subpopulations in 38 pediatric patients for hematologic malignant diseases after allogeneic HSCT from April 2006 to July 2008. T-cell-, B-cell-, and natural killer (NK) cell-associated antigens were assayed in peripheral blood by flow cytometry analysis of 5 lymphocyte subsets, CD3+, CD3+/CD4+, CD4+/CD8+, CD16+/CD56+, and CD19+, before and 3 and 12 months after transplantation. RESULTS: Reconstitutions of CD16+/CD56+ and CD3+/CD8+ lymphocytes were achieved rapidly, whereas that of CD3+/CD19+ lymphocytes occurred later. Age was not related to reconstitution of any lymphocyte subset. Total body irradiation (TBI) and anti-thymocyte globulin (ATG) administration were related to delayed reconstitution of total lymphocytes and CD3+ lymphocytes, respectively. Reconstitutions of CD3+/CD4+ lymphocytes and CD3+/CD8+ lymphocytes were significantly delayed in patients who received umbilical cord blood stem cells. In patients with chronic graft-versus-host disease (cGVHD), recovery of the total lymphocyte count and CD19+ lymphocytes at 3 months post-transplant were significantly delayed. However, acute GVHD (aGVHD) and cytomegalovirus (CMV) reactivation did not influence the IR of any lymphocyte subset. Further, delayed reconstitution of lymphocyte subsets did not correspond to inferior survival outcomes in this study. CONCLUSION: We observed that some lymphocyte reconstitutions after HSCT were influenced by the stem cell source and preparative regimens. However, delayed CD19+ lymphocyte reconstitution may be associated with cGVHD.

A novel mutation and unusual clinical features in a patient with immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome.

UNLABELLED: We report a patient with immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome with a novel splicing mutation of the FOXP3 gene. The patient is a boy, born at 39 + 2 weeks gestation with a birth weight of 3,280 g. The family history was unremarkable. He was well until 11 months of age, when he was diagnosed with type 1 diabetes mellitus. The level of urine C-peptide was 0.58 µg/day (normal range, 44-116 µg/day). Glutamic acid decarboxylase autoantibody was not detected, but a high level of anti-insulin antibody (50 IU/mL; normal range, <5 IU/mL) was noted. This patient presented with unusual clinical features, including pure red cell aplasia, membranous glomerulopathy, and posterior reversible encephalopathy syndrome after a vaccination against influenza A H1N1 virus. The diagnosis of IPEX was made when the patient was 11 years old, which is quite late compared with typical cases. CONCLUSION: Although IPEX syndrome is usually a disease of infancy, it should not be ruled out solely on the basis of age. IPEX presentation is so variable that it should be suspected in a male child with one or more autoimmune disorders and severe infections.

Favorable outcomes after allogeneic hematopoietic stem cell transplantation in children with high-risk or advanced acute myeloid leukemia.

The role of allogeneic hematopoietic stem cell transplantation (HSCT), including transplantation from an alternative donor (AD), has not been clearly defined for children with high-risk or advanced acute myeloid leukemia (AML). We retrospectively reviewed outcomes in 29 children (median age at HSCT, 6.7 y; range, 1.0-16.2 y) with high-risk or advanced AML who underwent allogeneic HSCT at the Asan Medical Center between 1998 and 2008. Donors included a matched sibling donor (MSD) for 7 patients (24%), an unrelated volunteer for 21 patients (72%), and a haploidentical mother for 1 patient (3%). The 3-year estimates of overall survival and event-free survival (EFS) were 77% [95% confidence interval (CI), 65%-99%] and 70% (95% CI, 57%-93%), respectively, whereas the cumulative incidences of relapse and transplant-related mortality were 33% (95% CI, 5%-58%) and 7% (95% CI, 0%-44%), respectively. The 3-year EFS rates did not differ between MSD and AD HSCT. Univariate analysis showed that age ≥ 10 years at diagnosis was the only factor associated with poorer EFS. Development of acute graft-versus-host disease predicted a significantly lower incidence of relapse. These findings may provide further evidence that allogeneic HSCT is a curative therapy for children with high-risk or advanced AML, and suggest the efficacy of AD transplantation.

Prognostic implications of serum alpha-fetoprotein response during treatment of hepatoblastoma.

BACKGROUND: We evaluated the outcomes and prognostic factors, especially serum levels of alpha-fetoprotein (AFP) and their changes during the treatment of hepatoblastoma (HB). PROCEDURE: We retrospectively analyzed the medical records of 43 consecutive children with HB treated at a single institution between 1991 and 2010. RESULTS: Of 43 patients, 5 (12%) underwent primary tumor resection at diagnosis and 38 (88%) received preoperative chemotherapy. Of those 38 patients, 7 (16%) died of progressive disease during preoperative chemotherapy, and 31 (72%) underwent curative operations, including 5 who underwent liver transplantation, after a median 4 cycles of chemotherapy (range, 3-14 cycles). The 5-year overall survival and disease-free survival rates were 62.1 ± 8.3% and 65.6 ± 7.6%, respectively. AFP >263,000 ng/mL at diagnosis, a decline of <1 log in AFP levels after the first cycle of chemotherapy, preoperative AFP levels in the highest tertile, and postoperative AFP levels in the highest tertiles were significantly associated with treatment failure. Age younger than 1 year at diagnosis, thrombocytosis at diagnosis, and early PRETEXT (pretreatment extent of disease) stage were significantly associated with better survival outcomes, whereas gender and metastasis were not. Multivariate analysis showed that high level of preoperative AFP was an independent predictor of treatment failure. CONCLUSIONS: Serial monitoring of changes in AFP levels during the treatment, especially perioperative changes, may help identify favorable and poor responders to chemotherapy. Alternative treatment, such as liver transplantation, should be considered for poor responders.

Improved outcome in childhood ALL with intensive consolidation and hematopoietic stem cell transplant.

BACKGROUND: Despite advances in chemotherapy, the prognosis of relapsed acute lymphoblastic leukemia (ALL) remains poor. Few studies on relapsed ALL have reported the importance of intensive consolidation followed with or without allogeneic hematopoietic stem cell transplantation (HSCT). METHODS: We evaluated the post-relapse outcomes in 47 Korean children with a first marrow relapse, and analyzed the prognostic factors. RESULTS: A second complete remission (CR) was achieved in 40 patients (85.1%), and at the time of this study, second CR was maintained in 12 of these patients. The estimated 3-yr event-free survival (EFS) rate after the first marrow relapse was 29.8±6.7%, and the overall survival (OS) rate was 45.3±7.5%. We found that second remission, consolidation of pediatric oncology group chemotherapy regimen (POG 9411), and HSCT significantly affected the outcome of the disease after relapse (P<0.001; P=0.004; P=0.05). CONCLUSION: The results of our study revealed that an intensified POG 9411 consolidation chemotherapy regimen followed by HSCT can improve the outcome of patients with relapsed ALL.

A case of anemia caused by combined vitamin B12 and iron deficiency manifesting as short stature and delayed puberty.

Anemia caused by vitamin B12 deficiency resulting from inadequate dietary intake is rare in children in the modern era because of improvements in nutritional status. However, such anemia can be caused by decreased ingestion or impaired absorption and/or utilization of vitamin B12. We report the case of an 18-year-old man with short stature, prepubertal sexual maturation, exertional dyspnea, and severe anemia with a hemoglobin level of 3.3 g/dL. He had a history of small bowel resection from 50 cm below the Treitz ligament to 5 cm above the ileocecal valve necessitated by midgut volvulus in the neonatal period. Laboratory tests showed deficiencies of both vitamin B12 and iron. A bone marrow examination revealed dyserythropoiesis and low levels of hemosiderin particles, and a cytogenetic study disclosed a normal karyotype. After treatment with parenteral vitamin B12 and elemental iron, both anemia and growth showed gradual improvement. This is a rare case that presented with short stature and delayed puberty caused by nutritional deficiency anemia in Korea.

Early changes in SOFA score as a prognostic factor in pediatric oncology patients requiring mechanical ventilatory support.

PURPOSE: To evaluate whether changes in outcome prediction scores during the first 72 hours after admission to a pediatric intensive care unit (PICU) are more predictive of outcome than single assessments at admission in pediatric oncology patients requiring mechanical ventilatory support for more than 3 days. PATIENTS AND METHODS: The medical records of 54 consecutive pediatric oncology patients requiring mechanical ventilation over 72 hours in the PICU of the Asan Medical Center, Seoul, Korea, between January 2006 and December 2008, were retrospectively reviewed. RESULTS: Although both initial Sequential Organ Failure Assessment (SOFA) score and change in SOFA score (Δ-SOFA) correlated well with mortality, Δ-SOFA score showed a significantly stronger correlation (P<0.001) and a larger area under the receiver operating characteristic curve than did initial SOFA score. Patients with positive and negative Δ-SOFA scores showed statistically significant differences in mortality (18.5% vs. 88.2%, P<0.001). In addition, early changes in respiratory parameters, such as PaO2/FiO2 (P/F) ratio, oxygenation index (OI), and ventilation index (VI), evaluated serially during the first 3 days, also correlated with mortality. Patients showing improvement in these respiratory parameters displayed significantly lower mortality than did patients with worsening of these parameters (P<0.01). CONCLUSIONS: Serial evaluation of SOFA score during the first few days after PICU admission was a good predictor of prognosis in pediatric oncology patients mechanically ventilated over 3 days. Independent of initial SOFA score, Δ-SOFA score during the first 72 hours closely correlated with outcome. Early changes in respiratory parameters, such as P/F ratio, OI, and VI, may also provide valuable prognostic information in such patients.

UNC13D is the predominant causative gene with recurrent splicing mutations in Korean patients with familial hemophagocytic lymphohistiocytosis.

BACKGROUND: Familial hemophagocytic lymphohistiocytosis is a fatal disease characterized by immune dysregulation from defective function of cytotoxic lymphocytes. Three causative genes have been identified for this autosomal recessive disorder (PRF1, UNC13D, and STX11). We investigated the molecular genetics of familial hemophagocytic lymphohistiocytosis in Korea. DESIGN AND METHODS: Pediatric patients who fulfilled the HLH-2004 criteria were recruited from the Korean Registry for Histiocytosis. Molecular genetic studies were performed on the patients' DNA samples by direct sequencing of all coding exons and flanking sequences of PRF1, UNC13D, and STX11. RESULTS: Forty patients were studied and familial hemophagocytic lymphohistiocytosis mutations were identified in nine; eight patients had UNC13D mutations (89%) and one had a mutation in PRF1. No patient had a STX11 mutation. Notably, four patients had only one UNC13D mutant allele, suggesting that the other mutation was missed by conventional direct sequencing. All UNC13D mutations were deleterious in nature. One known splicing mutation, c.754-1G>C, was recurrent, accounting for 58% of all the mutant alleles (7/12). Five UNC13D mutations were novel (p.Gln98X, p.Glu565SerfsX7, c.1993-2A>G, c.2367+1G>A, and c.2954+5G>A). The one patient with PRF1 mutation was homozygous for a frameshift mutation (p.Leu364GlufsX93), which was previously reported to be the most frequent PRF1 mutation in Japan. CONCLUSIONS: This is the first investigation on the molecular genetics of familial hemophagocytic lymphohistiocytosis in Korea. The data showed that UNC13D is the predominant causative gene in the Korean population. The identification of mutations missed by conventional sequencing would better delineate the mutation spectrum and help to establish the optimal molecular diagnostic strategy for familial hemophagocytic lymphohistiocytosis in Korea, which might need an RNA-based screening strategy.

Stem cell transplant in the treatment of childhood biphenotypic acute leukemia.

BACKGROUND: Many studies have found that biphenotypic acute leukemia (BAL) is associated with a poor outcome. METHODS: We retrospectively reviewed the medical records and analyzed clinicopathological data on 25 children with BAL, and correlated outcomes with prognostic factors. RESULTS: BAL constituted 4.4% of all acute childhood leukemia cases. In terms of immunophenotype, 14 patients had leukemia with myeloid plus B-lymphoid (M + B) marker, 7 with myeloid plus T-lymphoid (M + T) marker, and 4 with myeloid plus B-lymphoid and T-lymphoid (M + B + T) markers. Overall survival was superior in patients with the M + B immunophenotype (P = 0.004). Hematopoietic stem cell transplantation (HSCT) did not improve either overall survival or event-free survival compared to chemotherapy alone (hazard ratio 0.98, 95% CI 0.35-2.76, P = 0.966; hazard ratio 1.07, 95% CI 0.41-2.78, P = 0.88). Each of four patients with high-hyperdiploidy (>50 chromosomes) displayed a good treatment response and long-term overall survival even though these patients were treated with chemotherapy alone. CONCLUSIONS: Treatment outcomes in childhood BAL patients differed by immunophenotype and cytogenetics. HSCT did not offer a significantly greater survival advantage compared to chemotherapy. While these data suggest that treatment should be individualized and stratified according to biologic characteristics and prognostic factors in BAL, prospective trial data are still needed.