Serum tenascin-C predicts resistance to steroid combination therapy in high-risk Kawasaki disease: a multicenter prospective cohort study.

BACKGROUND: Tenascin-C (TN-C) is an extracellular matrix glycoprotein related to tissue inflammation. Our previous retrospective study conducted in 2016 revealed that the serum tenascin-C level was higher in patients with Kawasaki disease (KD) who were resistant to intravenous immunoglobulin (IVIG) and developed coronary artery lesions (CALs). The present study is a prospective cohort study to assess if the serum level of tenascin-C could be used as a novel biomarker to predict the risk of resistance to initial treatment for high-risk patients. METHODS: A total of 380 KD patients were registered and provided serum samples for tenascin-C measurement before commencing their initial treatment. Patients who did not meet the inclusion criteria were excluded from analysis; of the 181 remaining subjects, there were 144 low-risk patients (Kobayashi score: ≤4 points) and 37 high-risk patients (Kobayashi score: ≥5 points). The initial treatments for low-risk patients and high-risk patients were conventional therapy (IVIG with aspirin) and prednisolone combination therapy, respectively. The patient clinical and laboratory data, including the serum tenascin-C level, were compared between initial treatment responders and non-responders. RESULTS: In the low-risk patients, there was no significant difference in the median levels of serum tenascin-C between the initial therapy responders and non-responders. However, in the high-risk patients, the median serum tenascin-C level in initial therapy non-responders was significantly higher than that in initial therapy responders (175.8 ng/ml vs 117.6 ng/ml). CONCLUSIONS: Serum tenascin-C could be a biomarker for predicting the risk of high-risk patients being non-responsive to steroid combination therapy. TRIAL REGISTRATION: This study was a prospective cohort study. It was approved by the ethics committee of each institute and performed in accordance with the Declaration of Helsinki.

A Case of Malignant Melanoma Arising in Mediastinal Malignant Teratoma.

We report about a 14-year-old boy who presented with an anterior mediastinal mass that was diagnosed as malignant teratoma. Surgical resection was performed along with pre- and postoperative chemotherapy. Although elevated alpha-fetoprotein became negative, he experienced pain in his right hip joint 3 months after resection. Systematic evaluation revealed multiple locations of metastasis, and the pathological diagnosis based on bone biopsy was malignant melanoma originating from malignant teratoma, which rapidly progressed. He died 15 months after diagnosis of the original malignant teratoma. Diagnosing and treating malignant transformation of teratoma, including malignant melanoma, is difficult because it is very rare. To our knowledge, this is the second reported case of malignant melanoma arising from a mediastinum malignant teratoma, with both cases having a poor prognosis. In addition to the follow-up of tumor markers, systematic evaluation, including imaging, should be considered even after remission to monitor malignant transformation of teratoma. We expect to establish a successful therapy and improve mortality rate after more such cases are accumulated.

Moyamoya syndrome in a pediatric patient with congenital human immunodeficiency virus type 1 infection resulting in intracranial hemorrhage.

In the era of Antiretroviral Therapy (ART) in which human immunodeficiency virus type 1 (HIV-1) infection affected children can expect a better prognosis, the importance of careful follow up of pediatric HIV-1 cases for neurological complications has been growing. We present a case of hemorrhagic Moyamoya syndrome in a child with congenital HIV-1 infection. A 10-year-old girl was referred to our hospital for the treatment of Pneumocystis Jirovecii Pneumonia (PCP: Pneumocystis pneumonia). Her HIV-1 control was poor and Moyamoya syndrome was found during the opportunistic infection screening at admission. Despite subsequent successful treatment of PCP and HIV-1 infection, we could not save her life due to the intracranial hemorrhage caused by Moyamoya syndrome. A few reported cases of Moyamoya syndrome associated with HIV-1 infection have shown negative outcomes when the control of HIV-1 infection is unsuccessful. Recently "HIV-associated vasculopathy" has been used to describe the cerebrovascular disorder related to HIV-1 infection that is caused by the endothelial dysfunction induced from chronic inflammation and cytokine imbalances due to HIV-1 infection. We assumed that "HIV-associated vasculopathy" may have contributed to the development of collateral vessels impairment related to the bleeding, although the mechanism of vascular damage with HIV-1 infection is not yet well defined. Therefore proper management of the HIV-1 infection is crucial for Moyamoya syndrome with HIV-1 cases. Furthermore it is better to take into account the risk of intracerebral hemorrhage when considering the indication and timing of the revascularization surgery, although generally hemorrhaging is rare in Moyamoya disease in children.

Serum Tenascin-C as a Novel Predictor for Risk of Coronary Artery Lesion and Resistance to Intravenous Immunoglobulin in Kawasaki Disease　- A Multicenter Retrospective Study.

BACKGROUND: Tenascin-C (TN-C) is an extracellular matrix glycoprotein that is heavily upregulated at sites of inflammation. We conducted a retrospective study to assess the utility of TN-C as a novel biomarker to predict the risk of developing coronary artery lesions (CAL) and resistance to intravenous immunoglobulin (IVIG) in patients with Kawasaki disease (KD).Methods and Results:We collected blood samples of 111 KD patients (IVIG-responder: 89, IVIG-resistant: 22; CAL: 8) and 23 healthy controls, and measured the serum levels of TN-C. TN-C levels on admission were significantly higher in patients than in healthy controls and in patients during convalescence after IVIG administration (69.6 vs. 20.4 vs. 39.7 ng/ml, respectively; P<0.001), and correlated positively with C-reactive protein (P<0.001), neutrophil (percentage; P=0.005), and ALT (P<0.001), and negatively with platelet count (P=0.023) and sodium level (P=0.025). On admission, TN-C levels in patients who later developed CAL were significantly higher than in those without CAL (P=0.010), and significantly higher in IVIG-resistant subjects than in IVIG-responders (P=0.003). The accuracy of TN-C testing for the prediction of IVIG resistance was comparable to that of the Kobayashi score. CONCLUSIONS: Serum TN-C could be a biomarker for predicting the risk of developing CAL and IVIG resistance during the acute phase of KD. (Circ J 2016; 80: 2376-2381).

FDG-PET/CT for Detection of Extramedullary Disease in 2 Pediatric Patients With AML.

Positron emission tomography combined with computed tomography (PET/CT) is a promising diagnostic procedure for the detection of extramedullary disease (EMD) in acute myeloid leukemia. We studied 2 children with acute myeloid leukemia who underwent PET to assess for EMD at diagnosis as well as in remission. We detected 5 EMD lesions in 2 cases with PET, only 2 of which were detectable on clinical examination. Our cases show PET's increased sensitivity over physical examination alone in assessing and monitoring the extent of this disease.

Republication: Two Premature Neonates of Congenital Syphilis with Severe Clinical Manifestations.

Congenital syphilis (CS) is a public health burden in both developing and developed countries. We report two cases of CS in premature neonates with severe clinical manifestations; Patient 1 (gestational age 31 weeks, birth weight 1423 g) had disseminated idiopathic coagulation (DIC) while Patient 2 (gestational age 34 weeks and 6 days, birth weight 2299 g) had refractory syphilitic meningitis. Their mothers were single and had neither received antenatal care nor undergone syphilis screening. Both neonates were delivered via an emergency cesarean section and had birth asphyxia and transient tachypnea of newborn. Physical examination revealed massive hepatosplenomegaly. Laboratory testing of maternal and neonatal blood showed increased rapid plasma reagin (RPR) titer and positive Treponema pallidum hemagglutination assay. Diagnosis of CS was further supported by a positive IgM fluorescent treponemal antibody absorption test and large amounts of T. pallidum spirochetes detected in the placenta. Each neonate was initially treated with ampicillin and cefotaxime for early bacterial sepsis/meningitis that coexisted with CS. Patient 1 received fresh frozen plasma and antithrombin III to treat DIC. Patient 2 experienced a relapse of CS during initial antibiotic treatment, necessitating parenteral penicillin G. Treatment was effective in both neonates, as shown by reductions in RPR. Monitoring of growth and neurological development through to age 4 showed no evidence of apparent delay or complications. Without adequate antenatal care and maternal screening tests for infection, CS is difficult for non-specialists to diagnose at birth, because the clinical manifestations are similar to those of neonatal sepsis and meningitis. Ampicillin was insufficient for treating CS and penicillin G was necessary.

An hour-specific transcutaneous bilirubin nomogram for Mongolian neonates.

UNLABELLED: Transcutaneous bilirubin (TcB) nomograms have been developed for different populations. However, the TcB level, rate of rise and peak varies among countries and ethnicities. The aim of this study was to establish an hour-specific TcB nomogram for healthy term and late preterm Mongolian neonates during the first 144 h after birth. A total of 5084 TcB measurements from 1297 healthy neonates (gestational age ≥35 weeks, birth weight ≥2000 g) were obtained from October 2012 to October 2013. All measurements were performed using the Jaundice Meter, the JM-103 at 6 to 144 postnatal hours. Mongolian infants had the following characteristics: 27.1 % were delivered by cesarean section, 17.8 % had a birth weight >4000 g, and >90 % were being breastfed. TcB percentiles for each designated time point were calculated for the development of an hour-specific nomogram. TcB levels increased most rapidly in the first 24 h and less rapidly from 24 to 78 h, reaching a plateau after 78 h for the 50th percentile. TcB levels of Mongolian neonates for each time point were higher than those of previous studies. CONCLUSION: The higher values of the TcB nomogram for Mongolian neonates may be due to their Asian ethnicity and exclusive breastfeeding. WHAT IS KNOWN: • TcB nomograms for neonatal jaundice screening have been established for many countries and ethnicities. The pattern of the TcB nomogram varies by country and ethnicity. What is New: • A TcB nomogram for neonates of Mongolian ethnicity at 6-144 postnatal hours was created and it had higher values than those in previous studies.

Kawasaki disease refractory to standard treatments that responds to a combination of pulsed methylprednisolone and plasma exchange: Cytokine profiling and literature review.

UNLABELLED: We present a case of Kawasaki Disease (KD) that was refractory to plasma exchange (PE), but which finally responded to concurrent intravenous methylprednisolone pulse (IVMP) and PE treatment. To determine direct and indirect evidence for the efficacy of this combination therapy, we analyzed data of patients with refractory KD by review of the literature using medical databases and cytokine profiling. For literature searches, we used the Pubmed™ and Ichushi™ databases. Search terms used included "Kawasaki disease" and "plasma exchange" to extract articles that described KD cases treated with PE. For cytokine profiling, we measured interleukin (IL)-6, soluble tumor necrosis factor-α receptor (sTNF-αR) type 1 and type 2 before and after PE and PE with IVMP. Our search revealed 201 KD patients treated with PE, of which PE treatment was effective in 188 patients (93.5%), but not in 13 cases (6.5%). All 13 cases were treated successfully with additional treatment. Of the 13 cases, only six (2.5%) had recurrence during the PE treatment period. In our case, cytokine profiling showed PE treatment decreased IL6, while sTNF-αR type1 and type2 remained at high levels. PE and IVMP decreased IL-6 and sTNFα-R type 1 and type 2 levels. CONCLUSION: PE concurrent with additional anti-inflammatory treatment such as IVMP might be a very promising treatment option for PE refractory patients.

Salmonella meningitis: a report from National Hue Central Hospital, Vietnam.

Four Vietnamese infants who survived infection with Salmonella meningitis are reported. A female infant who experienced relapse recovered without complications and another had neurological sequellae. The remaining 2 infants survived without complications. The initial treatment was chloramphenicol and ceftriaxone, whereas a change of antibiotics to imipenem and fluoroquinolone was required for 2 infants. Fluoroquinolone may be a treatment option in patients with Salmonella meningitis who experience complications even though the drug is contraindicated for the pediatric age group.

Detection of trichodysplasia spinulosa-associated polyomavirus in a fatal case of myocarditis in a seven-month-old girl.

Trichodysplasia spinulosa-associated polyomavirus (TSV) was identified in a seven-month-old girl with myocarditis. The number of TSV genomes detected was higher in the heart than in the other organs. The full-length TSV genome was cloned from the heart. This suggests a possible role of TSV infection in the pathogenesis of myocarditis in infants.

Assessment of corticosteroid-induced osteonecrosis in children undergoing chemotherapy for acute lymphoblastic leukemia: a report from the Japanese Childhood Cancer and Leukemia Study Group.

Steroid-induced osteonecrosis (ON) is a challenging complication encountered during modern chemotherapy for childhood acute lymphoblastic leukemia (ALL). We retrospectively assessed the incidence of ON and its risk factors in a total of 1095 patients enrolled in 3 consecutive Japanese Children's Cancer and Leukemia Study Group ALL studies (ALL941 [1994 to 2000], n=464; ALL2000 [2000 to 2004], n=305; and ALL2004 [2004 to 2010], n=326). ON was diagnosed in 16 patients, of whom 15 were symptomatic. The cumulative incidence of ON was 0.76% in ALL941, 0.35% in ALL2000, and 3.6% in ALL2004. The incidence of ON in ALL941/2000, in which only prednisolone was administered as a steroid, was significantly lower than that in ALL2004, in which dexamethasone was used as a partial substitute for prednisolone (P<0.01). In ALL2004, sex and age were significantly correlated with the incidence of ON (1.3% in boys vs. 6.7% in girls, P=0.0132; 0.42% for age <10 y vs. 15.6% for age ≥10 y, P<0.0001), suggesting that girls aged 10 years and above are at a greater risk of ON onset. These results indicate that the risk of ON should be considered when administering dexamethasone as part of ALL protocol treatment in girls aged 10 years and above.

Validation of a transcutaneous bilirubin meter in Mongolian neonates: comparison with total serum bilirubin.

BACKGROUND: Neonatal hyperbilirubinemia, especially kernicterus, can be prevented by screening for neonatal jaundice. The transcutaneous bilirubin (TcB) meter is a non-invasive medical device for screening neonates. The study aimed to investigate the validity of a TcB meter in a resource-limited setting such as Mongolia. METHODS: Term and late preterm neonates from the National Center for Maternal and Child Health of Ulaanbaatar in Mongolia who met the inclusion criteria (gestational age ≥35 weeks, birth weight ≥2000 g, postnatal age ≤ 1 month) were enrolled in the study. We used a TcB meter, JM-103 to screen for neonatal jaundice. TcB measurements at the infant's forehead and midsternum were performed within 3 h of obtaining samples for total serum bilirubin (TSB) measurement. We analyzed the correlation between TcB measurements and TSB measurements to validate the meter. RESULTS: A total of 47 term and six late preterm neonates were included in the study. TcB measured by the meter at both the forehead and the midsternum showed a strong correlation with TSB measured in the laboratory. The correlation equations were TSB = 1.409+0.8655 × TcB (R2=0.78871) at the forehead, and TSB = 0.7555+0.8974 × TcB (R2=0.78488) at the midsternum. Bland-Altman plots and the Bradley-Blackwood test showed no significant differences between the two methods at all measured ranges of bilirubin. The mean areas under the curves of TcB at the forehead and midsternum at three TSB levels (>10 mg/dL, >13 mg/dL, >15 mg/dL) of TcB were greater than 0.9, and all had high sensitivity and specificity. CONCLUSIONS: This study established the validity of the JM-103 meter as a screening tool for neonatal jaundice in term and late preterm infants in Mongolia. Future studies are needed, including the establishment of a TcB hour-specific nomogram, for more effective clinical practice to prevent severe hyperbilirubinemia.

Associations of maternal and neonatal serum trace element concentrations with neonatal birth weight.

BACKGROUND: Trace elements play important nutritional roles in neonates. Our objective was to examine whether there are differences in maternal/neonatal serum trace element concentrations between mature infants and premature infants. METHODS: During 2012, 44 infants born at National Center for Global Health and Medicine, Tokyo, Japan, were enrolled. Serum samples were collected to measure serum iron, zinc, copper, and selenium concentrations 5 days after birth. Maternal serum samples were obtained before delivery and cord blood was taken at delivery to measure the same trace elements. We compared the results between term group whose birth weight were ≥2500 g and gestational age were ≥37 weeks and premature group whose birth weight were <2500 g or gestational age were <37 weeks. Variables significantly different between two groups were included in linear regression models to identify significant predictors of birth weight. Values of P<0.05 were considered statistically significant. RESULTS: Serum selenium concentrations were lower in premature group than in term group (43.3±7.0 µg/L vs. 52.0±8.9 µg/L, P = 0.001). Maternal serum selenium concentrations were also significantly lower in the mothers of premature group than in the mothers of term group (79.3±19.3 µg/L vs. 94.1±18.1 µg/L, P = 0.032). There were no significant differences in neonatal or maternal iron, zinc, or copper concentrations between two groups. Multivariate linear regression analysis showed that, except for gestational age, only maternal serum selenium was significantly associated with birth weight (P = 0.015). CONCLUSIONS: Serum selenium concentrations were lower in premature group and their mothers compared with the term group. The maternal serum selenium concentration was positively correlated with birth weight. These results suggest that maternal serum selenium concentration may influence neonatal birth weight.

A Japanese neonatal case of glucose-6-phosphate dehydrogenase deficiency presenting as severe jaundice and hemolytic anemia without apparent trigger.

BACKGROUND: Glucose-6-phosphate dehydrogenase (G6PD) deficiency is rare among Japanese ethnicity although it is known as one of the most common hereditary disorders of erythrocytes, causing intravascular hemolysis. It is well-known that G6PD deficiency may cause hemolysis even in the neonatal period. However, most cases are asymptomatic, and the frequency of severe anemia is low. FINDINGS: We describe a Japanese male neonatal case of G6PD deficiency presenting as severe, persistent indirect hyperbilirubinemia on day 2 and hemolytic anemia. He was born to non-consanguineous Japanese parents without any family history. We could not find any triggers that could have induced hemolysis during pregnancy. CONCLUSIONS: This case encouraged us to investigate G6PD deficiency as a differential diagnosis of severe neonatal jaundice and hemolytic anemia despite the low prevalence in Japan.

Predisposing individual characteristics and perinatal outcomes of women in the Tokyo metropolitan area who initiate prenatal care late in their pregnancy: a case-control study.

Purpose. The purpose of this study was to investigate the individual characteristics and perinatal outcomes of women who initiate prenatal care late in their pregnancy in the Tokyo metropolitan area. Methods. Retrospective study. The study enrolled all women at our hospital who initiated prenatal care after 22 weeks of gestation (late attenders) and control women who initiated prenatal care prior to 11 weeks of gestation participated in the study at the National Center for Global Health and Medicine between January 1, 2007 and June 30, 2011. We compared the maternal characteristics and perinatal outcomes of late attenders with those of the control group. Results. A total of 121 late attenders and 1,787 controls were enrolled. Late attenders had a higher incidence of unmarried compared with the control group (P < 0.01). There were no differences in the incidence of preterm delivery and low birth weight; however, babies of the late attenders had a higher incidence of admission to the neonatal intensive care unit compared with the control group (P < 0.01). Conclusions. Our results indicate that there is a pressing need for further steps to promote the importance of receiving prenatal care during pregnancy.

Development and evaluation of a line probe assay for rapid typing of influenza viruses and detection of the H274Y mutation.

Adequate treatment of influenza requires identification of viral type as well as detection of mutation(s) conferring drug resistance. Reverse hybridization-based line probe assays (LiPA) can be performed using several probes immobilized on nitrocellulose, strips enabling LiPA to determine simultaneously viral subtypes and detect the presence or absence of the H274Y mutation, which confers oseltamivir resistance of H1N1 influenza viruses. LiPA was developed for identification of H1N1 influenza virus subtypes (pandemic 2009 and seasonal types), as well as H3N2 and B subtypes, and to detect the H274Y mutation. The diagnostic capability of this assay was evaluated using cultured virus isolates as well as nasal swabs obtained from patients suspected of infection with influenza. In examining 354 cultured virus isolates, the LiPA showed 100% specificity for virus typing and 99% specificity for detecting the H274Y mutation. In 49 nasal swabs from a clinical study, the assay showed 100% specificity for virus typing and 88% specificity for detecting the absence of the H274Y mutation, although none of these swabs was PCR-positive for this mutation. These findings indicate that LiPA for influenza viruses may be used to monitor viral trends during the influenza season.

Systemic corticosteroids and early administration of antiviral agents for pneumonia with acute wheezing due to influenza A(H1N1)pdm09 in Japan.

BACKGROUND: Pneumonia patients with wheezing due to influenza A(H1N1)pdm09 were frequently treated with systemic corticosteroids in Japan although systemic corticosteroid for critically ill patients with pneumonia caused by influenza A(H1N1)pdm09 has been controversial. Applicability of systemic corticosteroid treatment needs to be evaluated. METHODS/PRINCIPAL FINDINGS: We retrospectively reviewed 89 subjects who were diagnosed with influenza A(H1N1)pdm09 and admitted to a national hospital, Tokyo during the pandemic period. The median age of subjects (45 males) was 8 years (range, 0-71). All subjects were treated with antiviral agents and the median time from symptom onset to initiation of antiviral agents was 2 days (range, 0-7). Subjects were classified into four groups: upper respiratory tract infection, wheezing illness, pneumonia with wheezing, and pneumonia without wheezing. The characteristics of each group was evaluated. A history of asthma was found more frequently in the wheezing illness (55.6%) and pneumonia with wheezing (43.3%) groups than in the other two groups (p = 0.017). Corticosteroid treatment was assessed among subjects with pneumonia. Oxygen saturation was lower in subjects receiving corticosteroids (steroid group) than in subjects not receiving corticosteroids (no-steroid group) (p<0.001). The steroid group required greater oxygen supply than the no-steroid group (p<0.001). No significant difference was found by the Kaplan-Meier method between the steroid and the no-steroid groups in hours to fever alleviation from the initiation of antiviral agents and hospitalization days. In logistic regression analysis, wheezing, pneumonia and oxygen saturation were independent factors associated with using systemic corticosteroids. CONCLUSION: Patients with wheezing and a history of asthma were frequently found in the study subjects. Systemic corticosteroids together with early administration of antiviral agents to pneumonia with wheezing and possibly without wheezing did not result in negative clinical outcomes and may prevent progression to severe pneumonia in this study population.

Multicenter prospective evaluation of a novel rapid immunochromatographic diagnostic kit specifically detecting influenza A H1N1 2009 virus.

BACKGROUND: Definitive diagnosis is crucial in reducing morbidity and mortality from pandemic influenza A H1N1 2009 (A/H1N1/2009), especially in high-risk populations. We recently developed a rapid diagnosis kit (RDK) capable of specifically detecting A/H1N1/2009. OBJECTIVES: To evaluate the diagnostic capability of the RDK in a multicenter, prospective trial. STUDY DESIGN: Samples were obtained by nasal swab from patients with suspected influenza. The diagnostic capability of the RDK was compared with that of the standard, real-time reverse transcription-polymerase chain reaction (RT-PCR) method. RESULTS: Of 266 patients who met the criteria, 122 and 92 were positive for A/H1N1/2009 influenza by PCR and by the newly developed RDK, respectively. The sensitivity, specificity and positive and negative predictive values of the RDK were 73.0%, 97.9%, 96.7% and 81.0%, respectively. A/H1N1/2009 detection rates by the RDK were significantly lower in samples obtained from patients more than 3 days after onset than in samples obtained between 1 and 2 days. CONCLUSIONS: The A/H1N1/2009-specific RDK is a reliable test that can be used easily at a patient's bedside for rapid diagnosis of A/H1N1/2009. This test will be of key importance in the control of A/H1N1/2009.

Favourable outcomes in children with diffuse large B-cell lymphoma treated by a short-term ALL-like regimen: a report on the NHL960 study from the Japanese Childhood Cancer and Leukemia Study Group.

In the NHL960 non-LB study, we treated diffuse large B-cell lymphoma (DLBCL) using a short-term ALL-like protocol. Thirty children up to 16 years of age with DLBCL were stratified into group 1 with stage I/II disease, or group 2 with stage III/IV disease. Their ages ranged from 9 months to 16 years of age, with a median of 9 years of age. The Murphy's stages were stage I in 7, stage II in 10, stage III in 6, and stage IV in 7 subjects. They received an ALL-like treatment without prophylactic cranial irradiation for 6 or 9 months. All children achieved a complete remission. Two patients with stage 3 disease experienced recurrences at 18 and 37 months after the start of chemotherapy. They responded to a short intensive regimen with Rituximab, followed by stem cell transplantation, and are alive without disease. The follow-up time ranged from 41 to 124 months with a median of 80 months. For all patients analyzed in this study, their overall survival and event-free survival (EFS) at 7-years was 100% and 93% +/- 4%, respectively. The 7-year EFS according to the treatment group was 100% for group 1, and 83% +/- 11% for group 2, respectively.