[Establishment of the method for measuring upper airway critical closing pressure].

Objective: To establish a noninvasive method for measuring upper airway critical closing pressure (Pcrit), so as to evaluate collapsibility of the upper airway during sleep. Methods: Pcrit was determined through the use of a noninvasive positive/negative pressure (CPAP/CPNP) ventilator(with independent intellectual property rights) during stageⅡ of non-rapid eye movement sleep. For the direct measurement, Pcrit was the pressure below which the upper airway occluded. For the indirect measurement, nasal pressure was plotted against maximum inspiratory flow (Vimax), and linear regression was used to interpolate the pressure (i.e., Pcrit) at which zero flow occurred. Pcrit was attained from 19 subjects without obstructive sleep apnea syndrome(OSAS), and the correlation between direct and indirect measurement methods was analyzed. Results: Directly measured and indirectly measured Pcrit showed no significant difference [(-7.02±2.74 vs (-7.26±2.96) cmH2O, 1 cmH2O=0.098 kPa; t=1.667, P>0.05] and had a highly significant correlation (r=0.986, P=0.000). Bland-Altman analysis revealed that the mean between-method difference was (0.24±0.53) cmH2O, and 95% limits of agreement ranged from -0.80 to 1.27 cmH2O, and all points except one were within limits of agreement. Conclusion: Pcrit derived from the direct and indirect measurement methods does not differ, and both methods could be used for evaluating the upper airway collapsibility.

Predictors of general discomfort, limitations in activities of daily living and intention of a second donation in unrelated hematopoietic stem cell donation.

We performed a retrospective study of 1868 consecutive unrelated donors to predict the risk factors related to general discomfort, limitations in activities of daily living (ADLs) and intention of a second donation in hematopoietic stem cell (HSC) donation. General discomfort and limitations in ADLs were assessed by numerical measurement (scores of 0-10) and donor's intention of a second donation by yes or no reply. The post-donation questionnaires were completed within 48 h after HSC collection and at 1 week, 4 weeks, and 4 months thereafter. Predictors of general discomfort included female sex (P<0.0001), bone marrow (BM) collection (P<0.0001) or PBSC collection through a central line (CL; P=0.0349), 2-day collection (P=0.0150) and negative or undetermined intention of a second donation on day 1 (P<0.0001). Predictors of limitations in ADLs included age group of 30-39 years (P=0.0046), female sex (P<0.0001), BM collection (P<0.0001) or PBSC collection through a CL (P<0.0001) and negative or undetermined intention of a second donation on day 1 (P<0.0001). The only predictor of positive intention of a second donation was male sex (P=0.0007). Age, sex and collection method and period should be considered risk factors when unrelated HSC donation is performed.

Prevalence of type 5 familial hemophagocytic lymphohistiocytosis in Korea and novel mutations in STXBP2.

Familial hemophagocytic lymphohistiocytosis (F-HLH or FHL) is a potentially fatal immune dysregulation syndrome with a heterogeneous genetic background. Most recently, STXBP2 has been identified as the causative gene of type 5 FHL (FHL5) with a worldwide distribution. In this study, we investigated the prevalence of FHL5 in Korea. About 50 Korean pediatric patients with HLH who lacked pathogenic mutations in PRF1, UNC13D, or in STX11 from the previous series of 72 patients with HLH were analyzed for STXBP2 mutations by conventional sequencing analyses. As a result, we found one patient with two novel mutations of STXBP2: c.184A>G and c.577A>C. c.184A>G (p.Asn62Asp) was located within a highly conserved region of the STXBP2 protein and predicted to be deleterious. c.577A>C in exon 7 resulted in incomplete splicing mutation with exon 7 skipping concurrent with exon 7-retained transcript with p.Lys193Gln substitution. The frequency of FHL5 was ~1% (1/72) in Korean pediatric patients with HLH. This is the first study on FHL5 in Korea, and the data from a nationwide patient cohort provide another piece of genetic profiles of FHL.

Efficacy and safety of micafungin for the prophylaxis of invasive fungal infection during neutropenia in children and adolescents undergoing allogeneic hematopoietic SCT.

The objective of this study was to evaluate the efficacy and safety of micafungin for the prevention of invasive fungal infection (IFI) during the neutropenic phase of allogeneic hematopoietic SCT (allo-HSCT) in children and adolescents. This was a prospective, multicenter, open-label, single-arm study. Micafungin was administered i.v. at a dose of 1 mg/kg/day (max 50 mg) from the beginning of conditioning until neutrophil engraftment. Treatment success was defined as the absence of proven, probable, possible or suspected IFI through to 4 weeks after therapy. From April 2010 to December 2011, 155 patients were enrolled from 11 institutions in Korea, and 147 patients were analyzed. Of the 147 patients, 121 (82.3%) completed the protocol without premature interruption. Of the 132 patients in whom micafungin efficacy could be evaluated, treatment success was achieved in 119 patients (90.2%). There was no proven fungal infection in any patient. The number of patients with probable, possible and suspected IFI was two, two and nine, respectively. Thirty-five patients (23.8%) experienced 109 adverse events (AEs) possibly related to micafungin. No patients experienced grade IV AEs. Two patients (1.4%) discontinued micafungin administration due to adverse effects. None of the deaths were related to the study drug.

Population-specific spectrum of the F11 mutations in Koreans: evidence for a founder effect.

The aim of this study was to investigate a mutation spectrum of F11 among Korean patients with factor XI (FXI) deficiency and to determine the haplotypes of mutations frequently found in Koreans. Thirteen unrelated patients from non-consanguineous families with FXI deficiency were included in the study. In the mutation analysis, the most frequently found mutations were Q263X (four cases; 31%) and Q226X (three cases; 23%). The frequency of Q263X-bearing haplotype was significantly different between normal and patient groups (p = 0.001), which is consistent with a founder effect of Q263X mutation. Testing for the presence of these two mutations should be the first genetic screening in Korean patients with FXI deficiency.

Comprehensive clinical follow-up of late effects in childhood cancer survivors shows the need for early and well-timed intervention.

BACKGROUND: Due to recent advances in treatment, nearly 80% of childhood cancer patients become long-term survivors. Studies on the late effects of survivors are under way worldwide. However, data on Asian survivors remain limited. METHODS: Data on 241 survivors at the Long-term Follow-up Clinic in Severance Hospital, South Korea, were collected and late effects were confirmed by oncologists. RESULTS: The median follow-up from diagnosis was 7.8 years. Late effects were identified in 59.8% of survivors and 23.2% had two or more late effects. Grade 3 or higher late effects were present in 10.8%. The most common late effects involved endocrine system (29.0%). Late effects were present in 95.7% of brain tumor survivors and 36.0% of Wilms' tumor survivors. Chemotherapy, hematopoietic stem-cell transplantation and radiotherapy were significant factors associated with the number and severity of late effects (P < 0.05). Brain tumor survivors had more severe late effects (P < 0.001), whereas Wilms' tumor survivors had fewer and milder late effects (P < 0.05). CONCLUSION: The observation that over 50% of cancer survivors suffered from late effects during the short follow-up period and that a high frequency of endocrine late effects was present indicates the need for early and well-timed intervention of the survivors.

Retroviral-mediated IL-2 gene transfer into murine neuroblastoma.

We used retroviral-mediated gene transfer of the human interleukin (IL)-2 gene into murine neuroblastoma cells to investigate whether locally-secreted IL-2 is able to influence the generation of anti-tumor immune responses. Supernatant obtained from cultures of approximately 1 x 10(6) IL-2 gene-transduced, G-418 selected neuro-2a cells was assayed for human IL-2 production by ELISA kit. First, to estimate whether the local secretion of IL-2 from the genetically-modified tumor cells would affect their tumorigenicity in vivo, IL-2-secreting neuro-2a cells were s.c. injected into A/J mice and tumor growth was measured weekly. And to estimate whether IL-2 transfected neuroblastoma cells protect mice from tumor development after wild-type tumor cell challenge, IL-2-secreting neuro-2a cells were s.c. injected into A/J mice. Seven days after IL-2 gene-transfected neuroblastoma cell injection, unmodified neuro-2a cells were s.c. injected into the contralateral site of A/J mice and tumor growth was measured weekly. Finally, to estimate IL-2 effect on pre-established large tumor burdens, IL-2-secreting neuro-2a cells were s.c. injected into A/J mice with established tumor and its growth was measured weekly. The IL-2 gene-transduced neuro-2a clones secreted 120.25-177.3 IU of IL-2 per ml per 10(6) cells during 24 hr. None of the mice injected with IL-2-secreting neuro-2a cells developed tumors within 6 weeks, while all of the mice injected with wild-type neuro-2a cells developed tumors. Immunization of mice with IL-2 gene-transfected, irradiated neuro-2a cells protected these animals against a subsequent challenge with wild-type tumor cells. Finally, the size of large neuroblastomas decreased after IL-2-secreting neuro-2a cell injection into mice. Local secretion of IL-2 gene-transduced tumor cells abrogates their tumorigenicity and induces protective immunity and may inhibit the growth of neuroblastoma.

Effects of retroviral-mediated herpes simplex virus thymidine kinase gene transfer to murine neuroblastoma cell lines in vitro and in vivo.

Selective introduction of genes conferring chemosensitivity on proliferating tumor cells can be used to treat cancer. We investigated the efficacy of retrovirus-mediated gene transfer of the herpes simplex virus thymidine kinase (HSV-TK) gene to murine neuroblastoma cell lines (neuro-2a) in vitro and in vivo. Retrovirus-mediated HSV-TK gene transfer to the neuro-2a cells resulted in sensitivity to ganciclovir (GCV) in vitro. In A/J mice, tumors produced from HSV-TK transduced neuro-2a cells regressed after GCV treatment. Intratumoral injection of recombinant retrovirus expressing HSV-TK gene also inhibited growth of the tumor established in A/J mice. These results demonstrate that HSV-TK gene therapy might be a feasible approach for inhibiting the growth of neuroblastoma.

Expression of a knocked-in AML1-ETO leukemia gene inhibits the establishment of normal definitive hematopoiesis and directly generates dysplastic hematopoietic progenitors.

The t(8;21)-encoded AML1-ETO chimeric product is believed to be causally involved in up to 15% of acute myelogenous leukemias through an as yet unknown mechanism. To directly investigate the role of AML1-ETO in leukemogenesis, we used gene targeting to create an AML1-ETO "knock-in" allele that mimics the t(8;21). Unexpectedly, embryos heterozygous for AML1-ETO (AML1-ETO/+) died around E13.5 from a complete absence of normal fetal liver-derived definitive hematopoiesis and lethal hemorrhages. This phenotype was similar to that seen following homozygous disruption of either AML1 or CBFbeta. However, in contrast to AML1- or CBFbeta-deficient embryos, fetal livers from AML1-ETO/+ embryos contained dysplastic multilineage hematopoietic progenitors that had an abnormally high self-renewal capacity in vitro. To further document the role of AML1-ETO in these growth abnormalities, we used retroviral transduction to express AML1-ETO in murine adult bone marrow-derived hematopoietic progenitors. AML1-ETO-expressing cells were again found to have an increased self-renewal capacity and could be readily established into immortalized cell lines in vitro. Taken together, these studies suggest that AML1-ETO not only neutralizes the normal biologic activity of AML1 but also directly induces aberrant hematopoietic cell proliferation.

EBV-elicited familial hemophagocytic lymphohistiocytosis.

Familial hemophagocytic lymphohistiocytosis (FHL) is a rapidly fatal illness, usually encountered in infancy, characterized by fever, hepatosplenomegaly, pancytopenia, and central nervous system involvement. Microscopic examination of tissue shows a non-malignant lymphohistiocytic infiltrate, with prominent erythrophagocytosis. FHL is an autosomal recessive hereditary disorder but may develop secondarily to other conditions such as immunosuppression, malignancies, fat overload and certain infections. We recently experienced a case of siblings developing FHL, which may be associated with EBV infection.

Clinical experience with conservative surgery for vaginal endodermal sinus tumor.

Two cases of vaginal endodermal sinus tumor (EST), a rare pediatric malignancy, were managed with conservative surgery followed by adjuvant chemotherapy. The first case involved a 9-month-old girl with EST of the vagina, who was treated with a partial vaginectomy and VAC regimen (vincristine, actinomycin D, cyclophosphamide) during a 2-year period. The serum alpha-fetoprotein (AFP) level returned to normal after excision of the tumor, and it remained normal throughout the treatment period. There was no evidence of disease 30 months after diagnosis. The second case involved an 8-month-old girl with EST of the vagina, who was treated with local excision of the mass through a vaginotomy. The VAC regimen was administered, but the serum AFP level remained elevated. A follow-up abdominopelvic computed tomography scan, taken 4 months after the operation, showed local recurrence of the tumor. The VAC regimen was then changed to a BEP regimen (bleomycin, etoposide, cisplatin). The serum AFP level returned to normal after 2 courses of the new regimen, and no tumor was visible on the follow-up magnetic resonance imaging study. For vaginal EST, primary conservative surgery and adjuvant chemotherapy are attractive measures to preserve both reproductive and sexual function. The extent of conservative surgery requires at least a partial vaginectomy. Simple tumor excision may not be adequate to achieve cure or to prevent local recurrence, even with adjuvant chemotherapy. The serum AFP level is useful for diagnosing and monitoring vaginal EST in the infant.

[Interleukin-2 production and alteration of T cell subsets in mice infected with Naegleria fowleri].

Naegleria fowleri is the cause of primary amoebic meningoencephalitis in man. IL-2 levels after stimulation of T lymphocytes by PHA or N. fowleri lysates, the amounts of T lymphocyte subsets and the blastogenic responses of T lymphocytes in mice after infected with pathogenic N. fowleri were studied comparing between two study groups, one 1 x 10(4) trophozoites inoculated mice and the other 1 x 10(5) trophozoites inoculated mice. All experimental samples were obtained on the day 7, 14 and 24 after inoculation. The mice inoculated with 1 x 10(4) trophozoites showed a 14.3% mortality rate, and 72.2% in the mice inoculated with 1 x 10(5) trophozoites. The IL-2 levels on day 14 of two experimental groups were significantly decreased as compared with the control group. Thy 1.2+ T cells in the total spleen lymphocytes of 1 x 10(5) trophozoites inoculated group on day 7 were significantly increased compared with the control group. There was no significant difference between 1 x 10(4) trophozoites inoculated group and the control group. L3T4+ T cells and Ly2+ T cells in the total spleen lymphocytes of 1 x 105 trophozoites inoculated group on day 7 were significantly increased compared with the control group. The DNA S fraction of T cells in the spleen of 1 x 10(5) trophozoites inoculated group was significantly increased on day 7. The amount of S fractions of DNA were sequentially decreased on day 14 and 24, but they were also significantly increased compared with the control group.(ABSTRACT TRUNCATED AT 250 WORDS)

Glucose-6-phosphate dehydrogenase deficiency--report of 4 cases.

Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the most common hereditary enzyme disorder and more than 200 million people have a deficiency in this enzyme. It is a globally important cause of neonatal jaundice and causes life-threatening hemolytic crisis in childhood. At later ages, certain drugs such as antimalarials, and fava beans cause hemolysis among G6PD deficiency patients. The frequency and severity is influenced by genetic and cultural factors. It is common in Mediterranean, African, and some East Asian populations but rare in Korea. Four cases of G6PD deficiency which were first noticed in Korea are investigated with their clinical features.

Hodgkin's disease in a child with acute lymphoblastic leukemia.

Hodgkin's disease, manifested as a second malignant neoplasm in acute lymphoblastic leukemia, rarely occurs, with seventeen cases reported including this cases. We presented the clinical and pathological features of a nine-year-old male child with acute lymphoblastic leukemia in remission. He had cervical lymph node involvement 22 months after the diagnosis of leukemia as an initial presentation of Hodgkin's disease of mixed cellularity. A brief review of related literatures was also done.