A Case of Langerhans Cell Histiocytosis Preceding with Central Diabetes Insipidus / 대한소아내분비학회지

A 3-year-old girl presented with polydipsia and polyuria for last 2 years. Her fluid intake was 7~8 L/day, and urinalysis showed low osmolality and specific gravity. Central diabetes insipidus (DI) was diagnosed by a water deprivation test. Intranasal 1-desamino-8-D-arginine vasopressin relieved her symptoms and normalized urinary concentrations. A T1-weighted MRI scan revealed a symmetrical thickening of the central part of the pituitary stalk. Six months after the diagnosis of central DI, she developed papular skin lesions on her forehead. The lesions were surgically removed, and histologically classified as Langerhans cell histiocytosis (LCH). We concluded that thickening of the central part of the pituitary stalk might represent the first manifestation of LCH clinically presenting with central DI. In children with central DI, special attention should be paid to the appearance of the pituitary stalk using MRI for the various manifestations of LCH in the central nervous system.

A Case of Mollaret's Meningitis Associated with Benign Pineal Cyst / 대한소아신경학회지

Mollaret's meningitis is a recurrent aseptic meningitis with characteristic clinical features and Mollaret cells in cerebrospinal fluid(CSF). We describe a case of Mollaret's meningitis in a 3-year-old boy who presented with three episodes of aseptic meningitis within a 4-month period. Each episode was characterized by sudden onset of meningeal irritation followed by spontaneous remission in several days. He was free of neurological symptoms between the episodes. In the acute phase of each episode, his CSF showed polymorphonuclear pleocytosis with normal protein and glucose concentrations. In addition, some epithelial cell clusters in the CSF were evident during the third episode. No pathogenic microorganisms were identified in the CSF or the blood cultures. Brain MRI revealed a benign pineal cyst, 0.8 cm in diameter, and epithelial cell clusters were supposed to represent ruptured cystic walls and recurrent episodes of aseptic meningitis were triggered by spontaneous rupture of the cyst. Our case appears to support "spontaneous rupture of epidermoid cysts in the central nervous system" as one of the etiologies of Mollaret's meningitis.

Percutaneous Transthoracic Biopsy for Thoracic Lesions: Comparison of the Utility of Fine Needle Aspiration (FNA), Percutaneous Cutting Needle Biopsy (PCNB) and Combination of Both Methods

PURPOSE: To assess the diagnostic role of FNA, PCNB, and a combination of both methods in patients who underwent percutaneous transthoracic biopsy for a malignant or benign intrathoracic lesion. MATERIALS AND METHODS: We retrospectively reviewed the findings of 213 patients with an intrathoracic mass or consolidation who underwent FNA (Group A, n=98), PCNB (Group B, n=31) or a combination of both methods (Group C, n=84). Under fluoroscopic guidance, diagnoses were based on the findings of surgery, biopsy at another site or clinical and radiologic follow-up. In the differential diagnosis of benign and malignant disease, and in the diagnosis of small-cell lung cancer, pulmonary tuberculosis, non-tuberculous infectious disease and benign mass, sensitivity, specificity and accuracy were statistically analysed in each group. RESULTS: Among 213 patients, lesions were malignant in 134 and benign in 79. In group A, sensitivity and specificity were 90.1% and 100% for malignant lesions, and 91.5% and 90.1% for benign, while in group B, the corresponding findings were 90.4% and 100%, and 90.0% and 90.1%. In group C, corresponding rates of 95.1% and 100% (p<0.05) and 100% and 92% (p<0.05) were recorded. In group C, accuracy and sensitivity were higher than in group A or (p<0.05). Post-procedural pneumothorax occurred in 15.3% of group A, 13.3% of group B, and 20.6% of group C, while hemoptysis was found in 7.1% of group A, 13.3% group B, and 2.9% of group C. Among the three groups, the complication rate showed no statistically significant variation (p<0.05). In the specific diagnosis of small-cell lung cancer, the sensitivity and specificity of FNA and PCNB were, respectively, 100% and 98.5%, and 90.0% and 98.0% (p<0.05) ; for tuberculosis, the corresponding figures were 35.0% and 100%, and 20.0% and 97.2 (p<0.05). FNA was better in the diagnosis of non-tuberculous infectious disease, while PCNB was better in the specific diagnosis of benign masses, without statistical significance. Conclusion: FNA is superior to PCNB in the diagnosis of tuberculosis and the differentiation of small cell lung cancer, and is thus the indicated initial approach for the majority of patients who are to undergo transthoracic bigosy. A combination of FNA and PCNB can provide more accurate differentiation between malignant and benign thoracic disease, without increasing the complication rate, than can one method used alone.

Long-term Follow-up of an Evans Syndrome with Chronic, Refractory Course: Response to 5 Different Regimens / 대한소아혈액종양학회지

Evans syndrome is the combination of direct Coombs' positive hemolytic anemia and immune thrombocytopenic purpura, in the absence of a known underlying etiology. Being reported rarely in pediatric patients, the syndrome is characterized by periods of remission and exacerbation with viable responses to therapy. Management of the disease remains a challenge despite a variety of therapeutic trials. We experienced a 11-years old male patient of Evans syndrome who was initially presented as having an autoimmune hemolytic anemia 17 months before. Over the 5 years of follow-up, he had a chronic, relapsing courses, showing partial responses to a variety of therapeutic trials, including IVIG, oral prednisolone, methylprednisolone pulse therapy, cyclosporine A and vincristine. A brief review of the literature ensues with the case report.

Evaluation of Cytokine Combination to Improve the Transduction of Retroviral-mediated NeoR Gene into CD34+ Cells Purified from Umbilical Cord Blood / 대한소아혈액종양학회지

PURPOSE: Retrovirs-mediated transduction of target genes into bone marrow progenitor cells or peripheral lymphocytes has been less optimal due to low efficiency and minimal expression on long-term analysis. This study aims to establish an efficient 4-day culture condition for the increased transduction efficacy into CD34+ cells selected on umbilical cord blood by comparing combination of various cytokines. METHODS: CD34+ cells from umbilical cord blood selected by Isolex-50R were incubated with supernatant containing XM5/PA317 vector for 96 hours. Cytokine combinations were used including IL-6+SCF, IL-6+IL-3+SCF, and IL-6+IL-3+SCF+TPO. Methylcellulose colony assay was done after culture. The data were expressed as mean+/-SD with 3 experiments. The efficiency of gene transfer was assessed by the ability of transduced CFU-GM to grow in the presence of G418 and PCR analysis of individual CFU-GM. RESULTS: The mean recovery rate of CD34+ cells after purification was 22%, and the purity of the final CD34+-enriched fraction was 82+/-13% (mean+/-SD). After a 4-day culture, the cell number increased 5~10 fold in each culture condition. The transduction efficiency evaluated by both G418-screened CFU-GM and PCR-positive CFU-GM with the above cytokine combinations was 46% and 64%, 41% and 57%, and 28% and 45%. However, there were no significant differences of colony counts between the cytokine combinations. CONCLUSION: We were unable to establish the best recipe of cytokine combination as the number of experiments was small and we tried only a fixed concentration of cytokines. For the future, the study of developing a novel vector, a better condition of transduction, and better combination of cytokines is warranted to attain the goal of highly effective, long-lasting method of gene transfer.

Expression of Multidrug Resistance Genes, mdr1, mrp, Topo IIalpha and Topo IIbeta in Childhood Acute Lymphoblastic Leukemia / 대한소아혈액종양학회지

PURPOSE: Multidrug resistance in the treatment of cancer mediated by several drug resistant genes impedes the successful management of cancer. The authors investigated the expression of drug resistant genes, including multidrug resistance (mdr1), multidrug resistance-associated protein (mrp), topoisomerase IIalpha (Topo IIalpha), and topoisomerase IIbeta (Topo IIbeta) in patients with childhood acute lymphoblastic leukemia (ALL; n=24) and in normal controls (n=6). METHODS: The levels of their transcripts in the bone marrow mononuclear cells were compared by semiquantitative RT-PCR, comparing the optical density ratio of PCR products of target genes to that of beta2-microglobulin. RESULTS: The expression of all 4 genes were detected in ALL patients as well as in normal controls except for Topo IIalpha, which were not detected in controls. The expression levels of mdr1, mrp and Topo IIbeta in ALL patients were significantly higher than those of normal controls [(2.1+/-2.2 vs 0.9+/-0.3, P> 0.024), (0.5+/-0.2 vs 0.2+/-0.1, P=0.016), and (0.7+/-0.2 vs 0.3+/-0.1, P=0.016)], respectively. The expression level of mdr1 gene transcript was relatively higher than those of mrp and Topo IIbeta. However, there was no correlation between the expression of multidrug resistant genes and survival and/or relapse of ALL. CONCLUSION: Though multidrug resistance genes did not serve as an independent prognostic factor, they might be used for markers for disease progression or relapse in childhood ALL. A longitudinal study of those genes is necessary to elucidate the prognostic significance in childhood ALL.

Two Cases of Pichia Ohmeri Fungemia / 대한소아혈액종양학회지

Pichia ohmeri is an yeast-like fungus used in the food industry for fermentation. This organism has been implicated in human disease only in a few case reports. We describe herewith two cases of Pichia ohmeri fungemia in immunocompromised pediatric patients with central venous catheters. A 7-year-old patient with Burkitt's lymphoma undergoing chemotherapy and a newborn with low birth weight developed fungemia during hospitalizations. Both patients were receiving parenteral nutrition through central venous catheters. Both patients succumbed despite empiric treatment with amphotericin B in Case 1. A brief review of the literature ensues with the case reports.

Recovery of Lymphocyte Subpopulations in Children with Hematologic Malignancies after Completion of Chemotherapy / 대한소아혈액종양학회지

PURPOSE: Children with cancer are immunosuppressed as a result of the underlying malignancies and their treatment. The aim of this study was to investigate immunophenotypic recovery of lymphocyte populations following completion of treatment in children with hematologic malignancies. METHODS: Thirty eight patients were followed up to the Department of Pediatrics, Chonnam National University Hospital from Jan. 1995 to Nov. 1999. Using flow cytometry with fluorescein-conjugated monoclonal antibodies of lymphocytes, T-, B-, and Natural killer (NK) cells and CD4/CD8 ratio were enumerated in 38 patients {acute lymphoblastic leukemia (ALL), 19; acute myeloid leukemia (AML), 14; non-Hodgkin's lymphoma (NHL), 5} from 3 months after completion of therapy and every 3 months thereafter over 2 years. The recovery rates of each parameters were compared according to diseases, age and gender. RESULTS: Absolute lymphocyte count was achieved in 50.0% (19/38) and 73.7% (28/38) of patients at 3 and 12 months after completion of therapy, respectively. Absolute B cell counts as well as the proportion of patients with normal B cell counts were low in NHL than in AML (298+/-250/microliter vs 594+/-356/microliter; P=0.037) at 12 months. T cell recovery tended to be faster in ALL, followed by AML and NHL. NK cell recovery was comparable among 3 disease subgroups. CD4/CD8 ratio was significantly lower in NHL (0.14+/-0.16) than ALL (0.79+/-0.33; P=0.018) at 3 months. CD4/CD8 ratio of NHL (0.41+/-0.14) was lower than ALL (0.79+/-0.29; P=0.033) at 6 months. Differences of CD4/CD8 ratio among the three disease groups were not statistically significant after 9 months. CD4/CD8 ratio was inverted in 22 of 38 (57.9%) patients even after 24 months of therapy. At 12 months higher proportion of male (47.4%, 9/19) achieved a normal CD4/CD8 ratio than that of female (15.8%, 3/19; P=0.036). Age did not make any differences in the recovery. CONCLUSION: Children with hematologic malignancies have persistent abnormalities of lymphocyte subpopulations often after 2 years following completion of chemotherapy. These results suggest that immunologic assessment are required and that preventive measures for infections might be required for more than 2 years after chemotherapy in some patients. Duration of follow-up observation should be differed according to underlying malignancies and their treatment intensity.

Successful allogeneic bone marrow transplantation for childhood-onset refractory anemia with ringed sideroblasts

Refractory anemia with ringed sideroblasts (RARS) is an extremely rare type of myelodysplastic syndrome in children. We describe a 10-year-old boy with RARS presented with pancytopenia. He remained relatively stable with only a few transfusions until age of 20 years, when he underwent an allogeneic bone marrow transplantation (BMT) because of increased transfusion requirements. He remains in complete chimeric state at 20 months posttransplant with normal hematologic parameters. To our knowledge, this is the first description of successful BMT in a patient with childhood-onset RARS. The indication of BMT for this rare disorder in children is discussed.

Peripheral Blood Stem Cell Collection and Engraftment Kinetics in Pediatric Patients / 대한소아혈액종양학회지

PURPOSE: Peripheral blood stem cell transplantation (PBSCT) has recently been used to rescue from myelosuppression following high-dose chemo-radiotherapy in patients with leukemia and solid tumor. Nevertheless, few data are still available on PBSC collection in pediatric patients, owing to technical problems. The time of stem cell harvest and the mobilization regimen may play important roles in terms of achieving adequate numbers of stem cells by leukapheresis. In this study, we analyse; 1) the technical aspects of leukapheresis as to feasibility and safety, 2) the optimal timing for PBSC collection after cytokine-based mobilizing regimens, 3) the engraftment kinetics. Method: A total of 93 leukapheresis was performed 22 children by Fenwall CS 3000 continuous cell separator, of whom 15 children weighed less than 25 kg. To mobilize hematopoietic stem cells into circulation, hematopoietic growth factor plus chemotherapy were used. Nineteen patients underwent autologous peripheral blood stem cell transplantation. RESULTS: The mean body weight was 25.3 kg (range: 10 to 56 kg). A total of 3 to 12 L of blood was processed (mean 265.4 65.9 mL/kg) for 2.5 to 5 hours (mean 3.15 hours). Extracorporeal line was primed with packed red blood cells below 25 kg. Serious morbidity was not noted. Each apheresis products contained a mean of 2.41 1.63x108 mononuclear cells/kg, 2.83 3.40x106 CD34 cells/kg, 9.30 10.3x104 colony forming unit (CFU-GM)/kg, respectively. Absolute neutrophil count (r=0.38, P<0.01) and CD34 cell count (r=0.65, P<0.001) on the day of leukapheresis seemed to predict the CFU-GM count collected in leukapheresis. A significant statistical correlation between the number of infused CFU-GM and the time to achieve an absolute neutrophil count of greater than 500/mm3 (P<0.01) was found. CONCLUSION: Leukapheresis for PBSCT seemed to be feasible and reliable in pediatric patients, conferring no major additional risks than adult patients, only if red cells are primed in extracorporeal line for small children. Absolute neutrophil count and CD34 cell number seemed to predict the timing of leukapheresis. In the PBSCT patient, engraftment was influenced by the infused CFU-GM count and bone marrow environment.

Therapeutic Results of Two Regimens for Childhood Acute Myelogenous Leukemia / 대한소아혈액종양학회지

PURPOSE: The purpose of this study was to compare the therapeutic results between the two groups of children with acute myelogenous leukemia (AML) who were treated either by 3-year Okayama regimen or by 2-year KSBRM regimen. METHODS: The subjects were 38 newly diagnosed AML patients at Chonnam University Hospital from Apr. 1991 to Dec. 1998. Until April, 1994, 10 patients were treated by the Okayama regimen for 3 years while 28 patients received KSBRM regimen for 2 years thereafter. The remission induction rate, relapse rate, and survival rate were compared retrospectively between the two groups. RESULTS: 1) The remission induction rate was 78.9% (30/38): Okayama group, 80.0% (8/10); KSBRM group, 78.6% (22/28). 2) The relapse rate after remission in the Okayama group was 37.5% (3/8) while that in the KSBRM group was 27.3% (6/22). 3) Deaths were encountered in 16 patients (42.1%): 60.0% (6/10) of Okayama group vs 35.7% (10/28) of KSBRM group (P=0.27). 4) Kaplan-Meier 3-year disease free survival (DFS) for all of the patients was 45.2%. The 3-year DFS was 40.0% for Okayama group and 48.2% for KSBRM group, respectively. The remission induction rate, relapse rate and DFS rate were not different between the two groups. CONCLUSION: The current study showed that KSBRM regimen was as equivalent as Okayama regimen for remission induction rate, relapse rate and 3-year Kaplan-Meier DFS despite the advantage of shortening of treatment duration by 1 year.

Different Phase of Telomere Shortening with Age in Peripheral Blood Mononuclear Cells / 대한소아혈액종양학회지

PURPOSE: Telomeres, special protein and tandem repeat DNA structure that cap the ends of linear eukaryotic chromosomes, are essential for chromosome structure and stability. Human telomeric DNA is known to shorten by 30~200 bp with each somatic cell division. However, the phase of telomere changes has not been studied extensively. METHODS: Telomere length was analyzed in the peripheral blood mononuclear cells (PBMCs) of 39 normal controls aged from newborn to 72 years by Southern blot hybridization using PharMingen's TeloQunatTM Telomere Length Assay Kit (Becton Dickinson Co.). RESULTS: The mean telomere length of the population was 9.68 kb (range, 5.65~14.40 kb). The length (kb) decreased with age (A) by the following regression: T=10.86 0.04 A (T=telomere length in kb; A=age in years) (r= 0.38; P=0.016). The mean telomere lengths according to age groups were: 10.26 kb for less than 15 years; 9.92 kb for 16 to 40 years; 8.03 kb for over 40 years. The telomere length of over 40 years was significantly shorter than that of less than 15 years (P=0.013), and than that of 16 to 40 years (P=0.011). The phase of telomere changes was evaluated by age subgroups. The shortening was fastest in individuals of age <5, while the length showed a plateau or slight increment in age group between 5 to 35. The length decreased steadily with age by the regression of 12.43+/-0.07 A (r= 0.500; P=0.034) in age group over 35. CONCLUSION: Telomere length of PBMCs decreases with age, and the different phase of telomere length shortening may suggest that the shortening of telomere is not a constant process over lifespan, but a dynamic process that is differently regulated in age groups.

A Case of Moyamoya Syndrome Associated with Hereditary Spherocytosis / 대한소아신경학회지

Moyamoya is a chronic cerebrovascular disease characterized by progressive stenosis or occlusion of the terminal parts of both intermal carotid arteries with telangiectatic vascular network of collateral circulation at the base of the brain and leptomeningeal arteries. The etiology and pathophysiology of this disease are still unknown. Although the idiopathic presentattion is the commonest, moyamoya disease has also been reported in several hereditary or acquired clinical conditions including neurofibromatosis, sickle cell anemia, tuberculous meningitis, atherosclerosis, and following radiation therapy to the head. The term moyamoya disease should be reserved for those cases in which the characteristic angiogrphic pattern is idiopathic; moyamoya syndrome is used when the underlying condition is known. We have experienced a case of coexistence of moyamoya syndrome and hereditary spherocytosis in a 6-year-8-month-old girl who presented with right-sided hemiparesis and pallor. A cerebral angiogram revealed occlusion of proximal portion of left middle cerebral artery and abnormal collateral network. The peripheral blood smear and osmotic fragility test disclosed hereditary spherocytosis. To our knowledge, the coexistence of moyamoya syndrome and hereditary spherocytosis has not been documented. We report here the case and the brief review of related literatures. Further studies are needed to clarify the intimate relationship between the two diseases.

A Clinical Study of Fanconi's Anemia / 대한소아혈액종양학회지

BACKGROUND: Fanconi's anemia(FA) is an autosomal recessive disease characterized by aplastic anemia and congenital malformations. As up to 30% of patients have no physical stigmata, the modern diagnosis of FA rests on chromosomal breakage of patient's cells induced by chemical clastogens such as diepoxybutane(DEB) or mitomycin-C(MMC). METHODS: We reviewed the clinical manifestations, laboratory findings, diagnostic methods, treatment and outcome of 6 patients diagnosed to have a FA at the Chonnam University Hospital for the last 6 years. RESULTS: Six cases(16.2 %) were found to have FA among 37 aplastic children who were diagnosed during the same period. The mean age at diagnosis was 6.3 years which was the usual onset of hematologic findings. All patients had features of aplastic anemia, and had one or more anomalies, such as low birth weight, hyperpigmentation, cafeau-lait spots, mental retardation, developmental delay, peculiar face(broad nasal bases, epicanthal folds, micrognathia), polydactyly, microcephaly, short stature, and dislocation of hip. We found increased breaks in cultured cells with DEB and MMC in 5 cases tested. The median duration of follow-up was 30 months. Oxymetholone and prednisolone treatment was partially beneficial in three cases. Immunosuppressive treatment with ALG/ATG was not successful in two cases tried. Four cases are living now, without transfusion in three. Two patients were died of disseminated fungal infection and transplant-related problems, respectively. CONCLUSIONS: Fanconi's anemia should be sought carefully in any patients with aplastic anemia because the prognosis, treatment modality, and the approach to bone marrow transplantation are quite different when the hematologic disorder is inherited rather than acquired.

A Familial Case of Leigh Disease / 대한소아신경학회지

In two female siblings, growth and developmental retardation, poor sucking, anorexia, floppiness and respiratory difficulty developed around 2 and 4 monthes of age in each, and the respiratory symptoms rapidly aggravated to comatose states and finally into death one month later. On admission at emergency room, severe acidosis and high lactate and pyruvate levels in serum and cerebrospinal fluid were revealed in one. Brain computed tomography and magnetic resonance imaging revealed identical bilateral involvement of putamen in both of the sibs, which made the diagnosis of Leigh disease(subacute necrotizing encephalomyelopathy) possible. There is also a family history of early death in infancy period; an elder sister and a brother of mother died with unknown cause at their 5 and 10 months of age. Mitochondrial enzyme functions could not be assayed.