Underlying Microstructure of the Lamina Cribrosa at the Site of Microvasculature Dropout.

Purpose: To determine the microstructure of the lamina cribrosa (LC) associated with microvasculature dropout (MvD) of the deep optic nerve head (ONH) in primary open-angle glaucoma (POAG) and to identify factors related to the presence of MvD. Methods: POAG eyes that exhibited MvD in the LC (MvD-LC) or MvD in the peripapillary choroid (MvD-PC) underwent optical coherence tomography and optical coherence tomography angiography (OCTA) to evaluate the structure and microvasculature of the deep ONH, respectively. The presence of MvD-LC or MvD-PC was determined using en face OCTA images of the deep ONH. The sectoral LC thickness (LCT) and LC curvature index (LCCI) (at MvD-LC site, when applicable), the mean LCT and LCCI of the global ONH, and other clinical characteristics were measured and compared between eyes with and without MvD-LC. Results: The study included 93 eyes with and 51 without MvD-LC. The presence of MvD-LC was associated with lower sectoral LCT (odds ratio [OR] = 0.96, P < 0.001) and mean LCT (OR = 0.97, P = 0.032), larger visual field pattern standard deviation (PSD; OR = 1.20, P = 0.038), and higher pretreatment intraocular pressure (IOP; OR = 1.22, P = 0.012). Fifteen percent of the eyes with MvD-LC (14/93) did not present MvD-PC. Those eyes had younger age (P = 0.043), thicker juxtapapillary choroid (P = 0.018), larger sectoral LCCI (P = 0.040), thicker retinal nerve fiber layer (P = 0.024), smaller PSD (P = 0.008), and higher pretreatment IOP (P = 0.006) than those with both MvD-LC and MvD-PC. Conclusions: MvD-LC was associated with a localized morphologic alteration of the LC, and eyes with MvD-LC tended to have a higher pretreatment IOP. The clinical implications of MvD-LC should differ from those of MvD-PC in eyes with POAG.

Prototype-based Domain Generalization Framework for Subject-Independent Brain-Computer Interfaces.

Brain-computer interface (BCI) is challenging to use in practice due to the inter/intra-subject variability of electroencephalography (EEG). The BCI system, in general, necessitates a calibration technique to obtain subject/session-specific data in order to tune the model each time the system is utilized. This issue is acknowledged as a key hindrance to BCI, and a new strategy based on domain generalization has recently evolved to address it. In light of this, we've concentrated on developing an EEG classification framework that can be applied directly to data from unknown domains (i.e. subjects), using only data acquired from separate subjects previously. For this purpose, in this paper, we proposed a framework that employs the open-set recognition technique as an auxiliary task to learn subject-specific style features from the source dataset while helping the shared feature extractor with mapping the features of the unseen target dataset as a new unseen domain. Our aim is to impose cross-instance style in-variance in the same domain and reduce the open space risk on the potential unseen subject in order to improve the generalization ability of the shared feature extractor. Our experiments showed that using the domain information as an auxiliary network increases the generalization performance. Clinical relevance-This study suggests a strategy to improve the performance of the subject-independent BCI systems. Our framework can help to reduce the need for further calibration and can be utilized for a range of mental state monitoring tasks (e.g. neurofeedback, identification of epileptic seizures, and sleep disorders).

Radiodensity on serial chest X-rays for the diagnosis of foreign body aspiration in children.

OBJECTIVE: To evaluate the utility of measuring lung radiodensity from chest X-ray for the diagnosis of foreign body aspiration. METHODS: Records of 59 children with foreign body aspiration were retrospectively reviewed. Lung radiodensity and radiodensity ratio (right/left lung radio density) before and after foreign body removal were measured. Radiodensity was calculated as the relative score compared with the tenth thoracic vertebra body (100 points) and the background (0 point). The change of radiodensity ratio (difference in radiodensity ratio of the second X-ray from that of first X-ray) was compared between 22 patients (foreign body group) and 22 normal subjects (control group). RESULTS: In the group of foreign body in the left bronchus, the mean (SD) radiodensity of the left lung [53.5 (12.8)] was lower than that of the right lung [60.8 (7.7), P<0.01] and it increased after foreign body removal [60.0 (6.9), P=0.02]. The radiodensity ratio decreased from 1.20 (0.30) to 0.96 (0.09) (P<0.01) after foreign body removal. In the group with a foreign body in the right bronchus, the radiodensity of the right lung [51.8 (12.8)] was lower than that of left lung [62.0 (11.7), P=0.03], and it also increased after foreign body removal [58.4 (9.6), P=0.03]. The change of radiodensity ratio in the foreign body group [15.7 (17.8)%] was higher than the control group [5.4 (4.3) %, P=0.01] and the cutoff value was 7.5%. CONCLUSIONS: Radiodensity from chest X-ray could be a useful tool for diagnosing foreign body aspiration in children.

Graves disease following rabbit antithymocyte globulin treatment of severe aplastic anemia in a Korean child.

Antithymocyte globulin (ATG) is used as an immunosuppressive treatment (IST) to deplete clonal suppressor T cells in patients with severe aplastic anemia (SAA). The depletion of suppressor T cells by ATG may affect the activation of B cells, which results in an increased risk for autoimmune conditions. A 12-year-old boy was diagnosed with idiopathic SAA. As he did not have an human leukocyte antigen-matched sibling, he was treated with rabbit ATG (3.5 mg/kg/day for 5 days) and cyclosporine. Five months later, he became transfusion independent. However, 23 months after IST, he complained of mild hand tremors, sweating, weight loss, palpitations, and goiter. Results of thyroid function tests revealed hyperthyroidism (free thyroxine, 3.42 ng/dL; thyroid stimulating hormone [TSH], <0.01 nIU/mL; triiodothyronine, 3.99 ng/mL). Results of tests for autoantibodies were positive for the antimicrosome antibody and TSH-binding inhibitory immunoglobulin, but negative for the antithyroglobulin antibody and antinuclear antibody. He was treated with methimazole, and his symptoms improved. The patient has been disease free for 39 months after IST and 9 months after methimazole treatment. This case report suggests that although rare, rabbit ATG may have implications in the pathogenesis of autoimmune hyperthyroidism. Our findings suggest that thyroid function tests should be incorporated in the routine follow-up of SAA patients treated with ATG.

Alveolar rhabdomyosarcoma with massive disseminated intravascular coagulopathy treated with systemic chemotherapy.

It is uncommon for pediatric patients with rhabdomyosarcoma to present with clinical and/or laboratory features of disseminated intravascular coagulation (DIC). We report a case of metastatic alveolar rhabdomyosarcoma with severe bleeding because of DIC in a 13-year-old boy. He experienced persistent oozing at the site of a previous operation, gross hematuria, and massive epistaxis. Two weeks after initiating combination chemotherapy consisting of vincristine, doxorubicin, and cyclophosphamide, the patients' laboratory indications of DIC began to resolve. During this period, the patient received massive blood transfusion of a total of 311 units (26 units of red blood cells, 26 units of fresh frozen plasma, 74 units of platelet concentrates, 17 units of single donor platelets, and 168 units of cryoprecipitate), antithrombin-III and a synthetic protease inhibitor. Despite chemotherapy and radiation therapy, he died 1 year later because of disease progression. In children with metastatic rhabdomyosarcoma and massive DIC, prompt chemotherapy and aggressive supportive care is important to decrease malignancy-triggered procoagulant activities.

Thyroid autoimmunity in children and adolescents with newly diagnosed type 1 diabetes mellitus.

PURPOSE: This study aim to investigate the occurrence of autoimmune thyroid disease in children and adolescents at onset of type 1 diabetes mellitus (T1DM) and to assess whether the presence of diabetes-specific autoantibodies can predict the autoimmune thyroid disorder. METHODS: Seventy-three children with T1DM were recruited. Glutamic acid decarboxylase antibodies (GADA), islet cell antibodies (ICA), insulin autoantibodies (IAA), and thyroid antibodies were determined in all patients at the time of diagnosis. RESULTS: The majority of patients (87.7%) had at least one pancreatic antibody (74.0% for GADA, 20.5% for ICA, and 24.7% for IAA). Thyroid autoantibodies were found in 19 of 73 patients (26.0%) at diagnosis. Thyroid autoimmunity (TA) incidence was not statistically significant by GADA or ICA positivity, but significantly higher by IAA positivity (P=0.03), and IAA positivity showed odds ratio, 4.931; 95% confidence interval, 1.323-18.381 for TA. CONCLUSION: The IAA positivity in children and adolescents with TIDM was strongly related to positivity of thyroid autoantibodies and thus it could serve as an index for early prediction of the development of the thyroid autoimmune disorder among children and adolescents with TIDM.

Long-term follow-up of Fanconi anemia: clinical manifestation and treatment outcome.

PURPOSE: The aim of this study was to characterize Korean patients with Fanconi anemia (FA), which is a rare but very challenging genetic disease. METHODS: The medical records of 12 FA patients diagnosed at Chonnam National University Hospital from 1991 to 2012 were retrospectively reviewed. RESULTS: The median age at diagnosis was 6.2 years. All patients showed evidence of marrow failure and one or more physical stigmata. Chromosome breakage tests were positive in 9 out of 11 available patients. The median follow-up duration was 69.5 months. The Kaplan-Meier (KM) survival of all patients was 83.3% at 10 years and 34.7% at 20 years, respectively. Seven patients underwent 9 stem cell transplantations (SCTs). Among them, 5 were alive by the end of the study. Ten-year KM survival after SCT was 71.4% with a median follow-up of 3.4 years. All 5 patients treated with supportive treatment alone died of infection or progression at the median age of 13.5 years, except for one with short follow-up duration. Acute leukemia developed in 2 patients at 15.4 and 18.1 years of age. Among 6 patients who are still alive, 3 had short stature and 1 developed insulin-dependent diabetes mellitus. CONCLUSION: We provide information on the long-term outcomes of FA patients in Korea. A nation-wide FA registry that includes information of the genotypes of Korean patients is required to further characterize ethnic differences and provide the best standard of care for FA patients.

Solitary Langerhans cell histocytosis of skull and spine in pediatric and adult patients.

PURPOSE: Langerhans cell histiocytosis (LCH) is a rare neoplasm and has heterogeneous clinical presentation and behavior. We analyzed solitary lytic lesions of the skull and spine in pediatric and adult patients. METHODS: Between 2001 and 2011, 42 patients underwent surgery for LCH. Skull and/or spine involvement were evident in 21 (63.6%) of the 33 pediatric patients and 8 (88.9%) of the 9 adults. The 21 pediatric patients showed the unifocal monosystemic lesions in 10, multifocal monosystemic in 4, and multisystemic in 7. The eight adults comprised seven unifocal lesions and one multifocal monosystemic lesion. Of these cases, we analyzed the clinical courses of solitary LCH of skull and spine in 10 pediatric patients and 7 adults. RESULTS: The median age was 10.1 years (range: 1.1-14.1) in pediatric patients and 34.6 years (range: 26.1-52.0) in adults. The median follow-up was 3.1 years (range: 0.6-9.5). Total excision was done in 15 patients and biopsy in 2. Postoperative adjuvant chemotherapy was done in four pediatric patients and one adult, and comprised mass with dural adhesion (N = 2), skull base lesion (N = 1), atlas mass (N = 1), and vertebral lesion with soft tissue extension (N = 1). During follow-up, recurrence occurred in one pediatric patient who had a skull LCH with a dural adhesion. The patient experienced central diabetes insipidus and scapular pain due to pituitary stalk and scapula involvement 1.3 and 2.4 years later, respectively. CONCLUSION: Even if the solitary lesions of skull and spine show a favorable clinical course, some patients could show aggressive behavior.

Hereditary hemolytic anemia in Korea from 2007 to 2011: A study by the Korean Hereditary Hemolytic Anemia Working Party of the Korean Society of Hematology.

BACKGROUND: The number of patients diagnosed with hereditary hemolytic anemia (HHA) has increased since the advent of novel diagnostic techniques that accurately identify this disorder. Here, we report data from a survey on the prevalence and characteristics of patients diagnosed with HHA in Korea from 2007 to 2011. METHODS: Information on patients diagnosed with HHA in Korea and their clinical and laboratory results were collected using a survey questionnaire. Globin gene and red blood cell (RBC) enzyme analyses were performed. In addition, we analyzed data collected by pediatricians. RESULTS: In total, 195 cases of HHA were identified. Etiologies identified for HHA were RBC membranopathies, hemoglobinopathies, and RBC enzymopathies, which accounted for 127 (64%), 39 (19.9%), and 26 (13.3%) cases, respectively. Of the 39 patients with hemoglobinopathies, 26 were confirmed by globin gene analysis, including 20 patients with ß-thalassemia minor, 5 patients with α-thalassemia minor, and 1 patient with unstable hemoglobin disease. CONCLUSION: The number of patients diagnosed with hemoglobinopathies and RBC enzymopathies has increased considerably since the previous survey on HHA in Korea, dated from 1997 to 2006. This is likely the result of improved diagnostic techniques. Nevertheless, there is still a need for more sensitive diagnostic tests utilizing flow cytometry and for better standardization of test results to improve the accuracy of diagnosis of RBC membranopathies in Korea. Additionally, more accurate assays for the identification of RBC enzymopathies are warranted.

Quantitative comparison of CDKN2B methylation in pediatric and adult myelodysplastic syndromes.

BACKGROUND/AIMS: Transcriptional repression of tumor suppressor genes is determined by the quantity of promoter hypermethylation. We analyzed the methylation quantity of CDKN2B in pediatric myelodysplastic syndromes (MDS). METHODS: Quantitative measurement of CDKN2B methylation was performed in 25 pediatric MDS patients and 12 controls using pyrosequencing, and the result was compared with those from 74 adult MDS cases and 31 adult controls. The association between CDKN2B methylation quantity and factors related to prognosis including bone marrow blast percentage and karyotype was analyzed. RESULTS: Pediatric MDS patients showed a higher methylation level (MtL) of CDKN2B than pediatric controls (2.94 vs. 1.62; p = 0.031) but a lower level than adult MDS patients (8.76; p < 0.001). MtL was higher in pediatric MDS cases with >5% blasts than in pediatric controls (3.78 vs. 1.62; p = 0.052). Pediatric MDS cases with abnormal karyotype showed a higher MtL than pediatric controls (5.95 vs. 1.62; p = 0.045). CONCLUSIONS: We confirmed that methylation of CDKN2B is associated with the pathogenesis and prognosis in pediatric MDS. The difference in MtLs between pediatric and adult MDS might be related to the physiological hypermethylation of tumor suppressor genes in aging.

Pre-engraftment syndrome after unrelated cord blood transplantation: a predictor of engraftment and acute graft-versus-host disease.

Pre-engraftment syndrome (PES) is poorly characterized, and its clinical significance and the prognostic impact after unrelated cord blood transplantation (CBT) are unclear. To address these issues, we retrospectively analyzed the incidence, risk factors, and clinical outcomes of PES in unrelated CBT recipients. Data of 381 patients who received unrelated CBT from 18 medical centers in Korea were reviewed. PES was defined as unexplained fever >38.3°C not associated with infection, and/or unexplained skin rash with or without evidence of fluid retention before neutrophil recovery. PES developed in 102 patients (26.8%) at a median of 7 days after CBT. Of these patients, 74 patients (72.5%) received intravenous corticosteroid at a median dose of 1 mg/kg/day, and of these, 95% showed clinical improvement. Risk factors for developing PES included low risk disease, myeloablative conditioning, graft-versus-host disease (GVHD) prophylaxis without methotrexate or corticosteroid, and >5.43 x 10(7)/kg infused nucleated cells. Absence of PES was one of the risk factors for graft failure in multivariate analysis. The cumulative incidence of grade II to grade IV acute GVHD by 100 days after CBT was higher in patients with PES than in those without PES (56.0% versus 34.4%, P < .01). PES was not associated with chronic GVHD, treatment-related mortality, relapse, or overall survival. PES seems to be common after CBT and may be associated with enhanced engraftment without significant morbidity.

Implication of early lymphocyte recovery after allogeneic hematopoietic stem cell transplantation in children with leukemia.

PURPOSE: The repopulating lymphocytes after allogeneic hematopoietic stem cell transplantation have an important role not only on the prevention of serious infections in the early transplantation period, but also on the killing of residual leukemic cells by graft-versus-leukemia effect. The aim of this study was to analyze the impact of lymphocyte recovery after allogeneic stem cell transplantation in children with hematologic malignancies. MATERIALS AND METHODS: We evaluated 69 children transplanted for acute lymphoblastic leukemia (ALL) (n=34), acute myeloid leukemia (AML) (n=26), chronic leukemia (n=7) and juvenile myelomonocytic leukemia (n=2) between 1996 and 2008 at the Chonnam National University Hospital, Korea. The patients were grouped based on absolute lymphocyte counts (ALC) <500/µL or ≥ 500/µL at D+21 and D+30 after transplant. RESULTS: Patients with a High ALC at D+21 and D+30 had a faster neutrophil and platelet engraftment. The High at D+30 group had a better 5 year overall survival (71% vs. 53%, p=0.043) and event-free survival (72% vs. 53%, p=0.065) than the Low at D+30 group. The incidence of grade II-IV acute and chronic graft-versus-host disease (GVHD), and relapse rate did not differ by the ALC counts. However, the Low at D+30 group had a significantly increased risk for transplant-related mortality (p=0.019). The univariate analysis showed that the factors associated with decreased survival were a Low ALC at D+30, patients with high risk ALL, and grade II-IV aGVHD in patients with ALL and AML. CONCLUSION: Early posttransplant serial lymphocyte measurement would be a simple but useful method for predicting transplant outcomes.

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.

Recurrent plastic bronchitis in a child with 2009 influenza A (H1N1) and influenza B virus infection.

Plastic bronchitis is an uncommon disorder characterized by the formation of bronchial casts. It is associated with congenital heart disease or pulmonary disease. In children with underlying conditions such as allergy or asthma, influenza can cause severe plastic bronchitis resulting in respiratory failure. A review of the literature showed nine cases of plastic bronchitis with H1N1 including this case. We report a case of a child with recurrent plastic bronchitis with eosinophilic cast associated with influenza B infection, who had recovered from plastic bronchitis associated with an influenza A (H1N1) virus infection 5 months previously. To the best of our knowledge, this is the first case of recurrent plastic bronchitis related to influenza viral infection. If patients with influenza virus infection manifest acute respiratory distress with total lung atelectasis, clinicians should consider plastic bronchitis and early bronchoscopy should be intervened. In addition, management for underlying disease may prevent from recurrence of plastic bronchitis.

Mosaic ring chromosome 6 in an infant with significant patent ductus arteriosus and multiple congenital anomalies.

The clinical features of ring chromosome 6 include central nervous system anomalies, growth retardation, facial dysmorphism and other congenital anomalies. Ring chromosome 6 occurs rarely and manifests as various phenotypes. We report the case of mosaic ring chromosome 6 by conventional karyotyping in a 7-day-old male infant diagnosed with a large patent ductus arteriosus (PDA) with hypoplasia of aortic valve and aortic arch. These have not been previously reported with ring chromosome 6. He recovered from heart failure symptoms after ligation of the PDA. He showed infantile failure to thrive and delayed milestone in a follow-up evaluation. To the best of our knowledge, this is the first report of a Korean individual with ring chromosome 6 and hemodynamically significant PDA.

Scrub typhus-associated severe hemophagocytic lymphohistiocytosis with encephalomyelitis leading to permanent sequelae: a case report and review of the literature.

Hemophagocytic lymphohistiocytosis (HLH) is a rare but potentially fatal disorder. There have been a few reports on HLH secondary to scrub typhus in adults. Here, we describe the case of a 9-year-old Korean girl who presented with the typical findings of HLH. Despite adequate antirickettsial and HLH treatment, the neurological impairment worsened and remained. This is the first case report of severe neurological impairment resulting from the very rare association of HLH with scrub typhus. Therefore, in endemic areas, a high index of suspicion for scrub typhus is warranted in patients presenting with HLH.

Unicentric Castleman disease relapsed after rituximab-CHOP chemotherapy or radiation therapy in an adolescent.

Castleman disease (CD), an atypical lymphoproliferative disorder of unknown etiology, is rare. Unicentric CD can be cured after resection of the involved lymph nodes. However, rarely, patients with the unicentric-plasma cell variant may require additional therapy after resection for persistent systemic symptoms. The clinical course of such patients has not been well characterized. We report the case with relapsed unicentric-plasma cell variant CD who was eventually treated with complete surgical resection. This patient had no response to combination chemotherapy with rituximab after incomplete resection and no response to radiation after relapse.

Long-term graft-versus-tumor effect following reduced intensity hematopoietic stem cell transplantation in a child with metastatic renal cell carcinoma.

Pediatric renal cell carcinoma (RCC) is rare and different from adult RCC. Although target agents have recently been introduced, allogeneic hematopoietic stem cell transplantation exploiting graft-versus-tumor effect still remains an important treatment option for metastatic RCC. A 2-year-old male with RCC developed hepatic metastases 6 months following radical nephrectomy and subsequent cytokine therapy. Allogeneic reduced-intensity stem cell transplantation (RIST) with early withdrawal of immunosuppression and delayed donor lymphocyte infusions was performed. A second transplantation was undertaken following marrow aplasia. Now he remains progression-free with regression of hepatic metastases 5.7 years after RIST, along with complete donor chimerism.

Hematopoietic stem cell transplantation in children with leukemia: a single institution experience with respect to donors.

Aim of this study was to compare the outcomes of transplantation by donor source and to help select the best alternative donor in children with leukemia. Donor sources included matched related donor (MRD, n = 35), allele-matched unrelated donor (M-UD, n = 10) or -mismatched (MM)-UD (n = 13) or unrelated umbilical cord blood (UCB, n = 11). UCB group had a significantly higher incidence of grade II-IV acute graft versus host disease (MRD, 11.8%; M-UD, 30.0%; MM-UD, 15.4%, UCB, 54.4%, P = 0.004) but there was no difference in incidence of chronic graft versus host disease between 4 groups. The 5-yr leukemia-free survival (LFS) was 76.7%, 60.0%, 69.2%, and 45.5%, respectively (P = 0.128). MRD group showed higher LFS rate than UCB group (P = 0.022). However, LFS of M-UD and MM-UD together (65.2%) was not different from that of MRD group (76.7%, P = 0.325), or from that of UCB (45.5%, P = 0.190). The relapse incidence at 5 yr was 17.1%, 20.0%, 15.4%, and 0%, respectively (P = 0.460). The 100-day treatment-related mortality was 2.9%, 20.0%, 7.7%, and 36.4%, respectively (P = 0.011). Despite the limitations of small number of patients, unrelated donor transplants including even allele-mismatched ones, seem to be as effective in children with leukemia lacking suitable relative donors. Also, UCB transplant may serve as another possible option in urgent transplants.