Clinical features and treatment outcomes of Langerhans cell histiocytosis: a nationwide survey from Korea histiocytosis working party.

A nationwide survey was conducted to clarify the clinical features and outcomes of Korean children with Langerhans cell histiocytosis (LCH). Korea Histiocytosis Working Party analyzed the data of 603 patients who were diagnosed with LCH between 1986 and 2010 from 28 institutions in Korea. Median age at diagnosis was 65 months (range, 0 to 276 mo). Bone was the most frequently affected organ (79.6%) followed by skin (19.2%). Initially, 419 patients (69.5%) had single-system involvement (SS), 85 (14.1%) with multisystem (MS) disease without risk organ involvement (MS-RO), and 99 (16.4%) multisystem disease with risk organ involvement (MS-RO). The 5-year overall survival (OS) rates in the SS, MS-RO, and MS-RO groups were 99.8%, 98.4%, and 77.0%, respectively (P<0.001), and the 5-year reactivation rates were 17.9%, 33.5%, and 34.3%, respectively (P<0.001). The OS rate was lower in patients with RO involvement (P=0.025) and lack of response to initial treatment (P=0.001). MS involvement (P=0.036) was an independent risk factor for reactivation. Permanent consequences were documented in 99 patients (16.4%). Reactivation of disease, MS involvement, and age at diagnosis ≤ 2 years were associated with higher incidence of permanent consequences. This study emphasized that further efforts are required to improve survival of MS-RO patients and reduce reactivation in younger patients with MS involvement.

Founder effects in two predominant intronic mutations of UNC13D, c.118-308C>T and c.754-1G>C underlie the unusual predominance of type 3 familial hemophagocytic lymphohistiocytosis (FHL3) in Korea.

Familial hemophagocytic lymphohistiocytosis (familial HLH or FHL) is a potentially fatal autosomal recessive disorder. Our previous study demonstrated that UNC13D mutations (FHL3) account for ~90 % of FHL in Korea with recurrent splicing mutation c.754-1G>C (IVS9-1G>C). Notably, half of the FHL3 patients had a monoallelic mutation of UNC13D. Deep intronic mutations in UNC13D were recently reported in patients of European descent. In this study, we performed targeted mutation analyses for deep intronic mutations and investigated on the founder effect in FHL3 in Korean patients. The study patients were 72 children with HLH including those with FHL3 previously reported to have a monoallelic UNC13D mutation. All patients were recruited from the Korean Registry of Hemophagocytic Lymphohistiocytosis. In addition to conventional sequencing of FHL2-4, targeted tests for c.118-308C>T and large intronic rearrangement mutations of UNC13D were performed. Haplotype analysis was performed for founder effects using polymorphic markers in the FHL3 locus. FHL mutations were detected in 20 patients (28 %). Seventeen patients had UNC13D mutations (FHL3, 85 %) and three had PRF1 mutations (FHL2, 15 %). UNC13D:c.118-308C>T was detected in ten patients, accounting for 38 % of all mutant alleles of UNC13D, followed by c.754-1G>C (26 %). Haplotype analyses revealed significantly shared haplotypes in both c.118-308C>T and c.754-1G>C, indicating the presence of founder effects. The deep intronic mutation UNC13D:c.118-308C>T accounts for the majority of previously missing mutations and is the most frequent mutation in FHL3 in Korea. Founder effects of two recurrent intronic mutations of UNC13D explain the unusual predominance of FHL3 in Korea.

Unrelated hematopoietic stem cell transplantation for children with acute leukemia: experience at a single institution.

We evaluate the outcomes in children with acute leukemia who received allogeneic hematopoietic stem cell transplantation (HCT) using unrelated donor. Fifty-six children in complete remission (CR) received HCT from unrelated donors between 2000 and 2007. Thirty-five had acute myeloid leukemia, and 21 had acute lymphoid leukemia. Stem cell sources included bone marrow in 38, peripheral blood in 4, and cord blood (CB) in 14. Four patients died before engraftment and 52 engrafted. Twenty patients developed grade II-IV acute graft-versus-host disease (GVHD) and 8 developed extensive chronic GVHD. With median follow-up of 39.1 months, event free survival and overall survival were 60.4% and 67.5%, respectively, at 5 yr. Events included relapse in 10 and treatment-related mortality (TRM) in 10. The causes of TRM included sepsis in 4, GVHD in 4 (1 acute GVHD and 3 chronic GVHD), veno-occlusive disease in 1 and fulminant hepatitis in 1. Patients transplanted with CB had event free survival of 57.1%, comparable to 63.2% for those transplanted with other than CB. In conclusion, HCT with unrelated donors is effective treatment modality for children with acute leukemia. In children with acute leukemia candidate for HCT but lack suitable sibling donor, unrelated HCT may be a possible treatment option at the adequate time of their disease.

Relationship between serum insulin-like growth factor-1, IGF binding protein-3 levels and body height before and after gonadotropin-releasing hormone agonist therapy.

PURPOSE: The gonadotropin-releasing hormone agonist (GnRHa) is widely used to treat patients with precocious puberty. However, its effect on growth is often difficult to predict because of the diverse nature of its causes and presentation. This study aims to show the impact of GnRHa treatment on insulin-like growth factor-1 (IGF-I) and IGF binding protein-3 (IGFBP-3) secretion, growth, and on other parameters that may help estimate the height velocity. METHODS: Data from 60 girls (mean age, 8.8±0.7 years) treated with GnRHa were analyzed. Their height, bone age (BA), serum IGF-I, and IGFBP-3 concentrations were measured at the start and after a year of GnRHa treatment. To eliminate the confounding effect of chronological age (CA), the standard deviation scores (SDSs) of their height, IGF-I, and IGFBP-3 concentrations according to their CA at the start and after a year of GnRHa treatment were calculated. We looked for possible correlations between these variables and compared the subgroups based on their height velocities and midparental heights. RESULTS: During their one-year GnRHa therapy, height SDS for CA significantly decreased to 0.81±0.83 (P<0.001), but height SDS for BA increased to -0.28±0.68 (P<0.001). There was no significant change in serum IGF-I SDS, IGFBP-3 SDS, and IGF-I/IGFBP-3 ratio. The advanced BA was the factor most strongly correlated to the height velocity (R=0.265, P=0.041). CONCLUSION: These findings suggest that GnRHa treatment may affect the height velocity due to mechanisms other than suppression of the IGF-I and IGFBP-3 secretory axis.

Clinical outcomes of cerebral infarctions in neonates.

Cerebral infarctions are uncommon in neonates. However, they should be considered among causes of neonatal seizures. We describe seven neonates with cerebral infarctions. Clinical presentations, perinatal history, perinatal risk factors, cranial magnetic resonance imaging and electroencephalography findings, thrombophilic factors, and clinical outcomes were reviewed. Six patients manifested seizures, whereas one exhibited cyanosis. Six neonates manifested left middle cerebral artery infarctions, and one exhibited a borderzone infarction between the anterior cerebral and middle cerebral arteries. Electroencephalograms indicated epileptiform discharges on the left hemisphere in three neonates with left middle cerebral artery territory infarctions, and epileptiform discharges on both hemispheres in one patient. At most recent follow-up visit, five patients had achieved normal development, whereas one exhibited right hemiparesis and aphasia, and another manifested toe-in gait. These findings may help predict neurodevelopmental outcomes in neonates with cerebral infarctions.

Prophylactic low-dose heparin or prostaglandin E1 may prevent severe veno-occlusive disease of the liver after allogeneic hematopoietic stem cell transplantation in Korean children.

Studies investigating the effect of prophylactic drugs on hepatic veno-occlusive disease (VOD) development are rare in children that have undergone allogeneic hematopoietic stem cell transplantation (HSCT). This study examined risk factors for VOD, the effect of prophylactic low-dose heparin or lipo-prostaglandin E1 (lipo-PGE1) and the survival rate at day +100 in children undergoing allogeneic HSCT. Eighty five children underwent HSCT between June 1997 and September 2004. Patients were diagnosed and classified as having mild, moderate or severe VOD according to Seattle clinical criteria. Among 85 patients, 25 (29%) developed VOD. VOD occurred more frequently in patients receiving busulfan-based conditioning (24/65, 37%) than in those receiving TBI-based (1/10, 10%) or other (0/10, 0%) regimens (p<0.05). The incidence of VOD was lower in patients with non-malignant disease compared to those with malignant disease (p<0.05). Survival at day +100 for non-VOD patients was better than that for VOD patients (92% vs. 76%, p<0.05). No patients receiving prophylactic heparin or lipo-PGE1 were found to develop severe VOD, whereas 5 of 35 patients not receiving such prophylaxis developed severe VOD. Given severe VOD is associated with a high mortality rate, this study indicates that prophylactic heparin or lipo-PGE1 may decrease mortality in children undergoing HSCT.

Effectiveness of novel combination chemotherapy, consisting of 5-fluorouracil, vincristine, cyclophosphamide and etoposide, in the treatment of low-grade gliomas in children.

Low-grade gliomas (LGG), which account for about 30% of brain tumors in children, are usually treated with surgical excision and/or radiotherapy. For patients who have significant residual tumor after resection or relapse after radiation, the proper chemotherapy regimen has not yet been identified. Thirteen children diagnosed with LGG outside the cerebellum between January 1999 and December 2004, all of whom had significant residual tumor after surgical resection, relapsed after radiation or showed visual deterioration, were treated for 18 months with a multi-drug regimen of vincristine, etoposide, cyclophosphamide and 5-fluorouracil. Of the 7 patients who completed chemotherapy, 1 showed complete response (CR), 5 showed partial response (PR), and 1 had stable disease (SD). In 5 patients, chemotherapy was prematurely discontinued; 4 of these patients showed tumor progression and 1 had SD. One patient is still undergoing treatment. The side effects of chemotherapy were manageable. The median time to tumor response was 34 months (range, 2-82 months). The progression free survival was 67.3%. Pediatric LGG patients with residual tumor after surgery or who undergo relapse(s) may be successfully treated using our combination chemotherapy regimen.

Whole-body MRI of Langerhans cell histiocytosis: comparison with radiography and bone scintigraphy.

BACKGROUND: In Langerhans cell histiocytosis (LCH) evaluation of the extent of disease is one of the major predictors of patient outcome. Historically this is undertaken using plain radiography and bone scintigraphy. Recently, whole-body (WB) MRI has been reported to be useful in detecting skeletal and extraskeletal metastases in both adults and children. OBJECTIVE: To evaluate the usefulness of WB MRI in patients with LCH in comparison with plain radiography and bone scintigraphy. MATERIALS AND METHODS: In nine children (1-7 years of age; mean 3.3 years) who had a pathological diagnosis of LCH and had either plain radiography or bone scintigraphy for comparison, 43 WB MR examinations were performed. Skeletal and extraskeletal lesions of the disease on WB MRI were compared with those on plain radiography and bone scintigraphy. RESULTS: LCH showed unifocal single-system involvement in one patient, multifocal single-system involvement in three, and multifocal multisystem disease in five. WB MRI identified additional skeletal lesions in three (38%) of eight patients, compared with plain radiography, and in two (25%) of eight, compared with bone scintigraphy. WB MRI detected extraskeletal lesions of the disease in five (56%) of the nine patients exclusively, except for one patient whose lung lesions were also detected on plain radiography. In two patients, treatment was changed according to WB MRI findings. CONCLUSION: WB MRI is a useful initial and follow-up diagnostic method to assess the extent of LCH because WB MRI not only identifies more skeletal lesions of the disease than do plain radiography and bone scintigraphy, but also detects extraskeletal lesions of the disease.

Ambroxol inhibits peroxynitrite-induced damage of alpha1-antiproteinase and free radical production in activated phagocytic cells.

The present study examined the effect of ambroxol on toxic action of peroxynitrite and the respiratory burst in activated phagocytic cells. Ambroxol decreased the inactivation or destruction of alpha1-antiproteinase induced by peroxynitrite (ONOO-) or hypochlorous acid (HOCl), which was similar to penicillamine and glutathione and was greater than diclofenac sodium and naproxen sodium. Ambroxol significantly decreased ONOO--mediated tyrosine nitration and iron plus EDTA-mediated degradation of 2-deoxy-D-ribose. Ambroxol significantly attenuated the production of superoxide, hydrogen peroxide, HOCl, and nitric oxide in fMLP- or IL-1-activated phagocytic cells, while the inhibitory effects of antiinflammatory and thiol compounds were only observed in HOCl production. Ambroxol and antiinflammatory drugs did not show a cytotoxic effect on macrophages. The results suggest that ambroxol protects tissue components against oxidative damage by an action different from antiinflammatory drugs. Ambroxol may interfere with oxidative damage of alpha1-antiproteinase through a scavenging action on ONOO- and HOCl and inhibition of the respiratory burst of phagocytic cells.