Factors associated with employment status among mothers of survivors of childhood cancer: a cross-sectional study.

PURPOSE: To identify the factors associated with employment status among mothers of childhood cancer survivors (CCSs). METHODS: We conducted a questionnaire survey on mothers of survivors of childhood cancer to clarify practical factors such as care demands, psychological factors such as motivation to work, and support. After calculating descriptive statistics for all variables, binary logistic regression analysis was performed. RESULTS: Of 171 mothers, 129 (75.4%) were employed. The most common form of employment was non-regular (n = 83; 48.5%), including part-time, dispatched, and fixed-term workers. At the time of the survey, compared with nonworking mothers, working mothers tended to be more motivated to work and have lower scores for "Long-term Uncertainty" on the Parent Experience of Child Illness Scale. The results of the binary logistic regression analysis indicated that employment was related to higher motivation to work, the continuation of employment during treatment, more outpatient visits, and a higher amount of support. CONCLUSION: As employment of CCSs' mothers is associated with psychological factors such as motivation to work and long-term uncertainty, psychological support for CCSs' mothers might promote employment. In addition, because the continuation of employment during treatment affects the employment of mothers after the end of cancer treatment, a leave system that covers the treatment period for childhood cancer needs to be established.

The possible association between epidemics of hand-foot-and-mouth disease and responsiveness to immunoglobulin therapy in Kawasaki disease.

Background: Enterovirus causing hand-foot-mouth disease (HFMD) has been reported to be associated with the development of Kawasaki disease (KD), whereas the involvement of enterovirus in the clinical course of KD is uncertain. The aim of this study is to investigate the association between the clinical course of KD and HFMD epidemics. Methods: This study included 108 patients who developed KD during HFMD epidemic seasons (July and August) from 2010 to 2014 and who were initially treated with high-dose intravenous immunoglobulin (IVIG). A mean of ≥5.0 HFMD patients reported weekly from each sentinel medical facility was considered to represent a large HFMD epidemic. We compared the clinical characteristics of KD patients in summers of years with and without large HFMD epidemics. Results: Large HFMD epidemics occurred in 2011 and 2013. The number of KD patients in summer was the highest in 2011. The proportion of patients with resistance to the IVIG therapy in summers of years with the large epidemics (14%) was significantly lower than that in summers of other years (31%, P = 0.030), whereas the proportion of patients with coronary artery abnormalities did not differ to a statistically significant extent. The development of KD during large HFMD epidemics was significantly associated with a lower risk of resistance to the IVIG therapy (incidence rate ratio 0.92, P = 0.049). Conclusion: Patients developing KD during large HFMD epidemic may have good responsiveness to IVIG. It is important to identify microbes from KD patients to predict responsiveness to IVIG therapy.

Pulmonary Actinomycosis and Mucormycosis Coinfection in a Patient With Philadelphia Chromosome-positive Acute Lymphoblastic Leukemia Undergoing Chemotherapy.

Mucormycosis is an opportunistic and progressive infection, while actinomycosis usually grows gradually and rarely develops in immunocompromised patients. Here we report a patient with Philadelphia chromosome-positive acute lymphoblastic leukemia who developed a pulmonary actinomycosis and mucormycosis coinfection. Once the diagnosis of actinomycosis was confirmed by bronchoscopy, lobectomy performed before stem cell transplantation revealed mucormycosis. The patient successfully underwent transplantation using a therapeutic antifungal agent for mucormycosis. When an immunocompromised patient develops an infection of unknown etiology, physicians should consider these pathogens as the possible cause. In addition, surgical intervention should be considered as an important treatment option.

Epidemiology of child mortality and challenges in child death review in Japan: The Committee on Child Death Review: A Committee Report: The Committee on Child Death Review: A Committee Report.

We performed a retrospective survey and verification of the medical records of death cases of children (and adolescents; aged <18 years) between 2014 and 2016 in pediatric specialty training facilities in Japan. Of the 2,827 registered cases at 163 facilities, 2,348 cases were included. The rate of identified deaths compared with the demographic survey, was 18.2%-21.0% by age group. The breakdown of deaths was determined as follows: 638 cases (27.2%) were due to external factors or unknown causes, 118 (5.0%) were suspected to involve child maltreatment, 932 (39.7%) were of moderate or high preventability or were indeterminable. Further detailed verification was required for 1,333 cases (56.8%). Comparison of the three prefectures with high rates of identified deaths in Japan revealed no significant differences, such as in the distribution of diseases, suggesting that there was little selection bias. The autopsy rate of deaths of unknown cause was 43.4%, indicating a high ratio of forensic autopsies. However, sufficient clinical information was not collected; therefore, thorough evaluations were difficult to perform. Cases with a moderate or high possibility of involvement of child maltreatment accounted for 5%, similar to previous studies. However, more objective evaluation is necessary. Preventable death cases including potentially preventable deaths accounted for 25%, indicating that proposals need to be made for specific preventive measures. Individual primary verification followed by secondary verification by multiple organizations is effective. It is anticipated that a child death review (CDR) system with such a multi-layered structure will be established; however, the following challenges were revealed: The subjects of CDR are all child deaths. Even if natural death cases are entrusted to medical organizations, and complicated cases to other special panels, the numbers are very high. Procedures need to be established to sufficiently verify these cases. Although demographic statistics are useful for identifying all deaths, care must be taken when interpreting such data. Detailed verification of the cause of death will affect the determination of subsequent preventability. Verification based only on clinical information is difficult, so a procedure that collates non-medical information sources should be established. It is necessary to organize the procedures to evaluate the involvement of child maltreatment objectively and raise awareness among practitioners. To propose specific preventive measures, a mechanism to ensure multiprofessional diverse perspectives is crucial, in addition to fostering the foundation of individual practitioners. To implement the proposed measures, it is also necessary to discuss the responsibilities and authority of each organization. Once the CDR system is implemented, verification of the system should be repeated. Efforts to learn from child deaths and prevent deaths that are preventable as much as possible are essential duties of pediatricians. Pediatricians are expected to undertake the identified challenges and promote and lead the implementation of the CDR system. This is a word-for-word translation of the report in J. Jpn. Pediatr. Soc. 2019; 123 (11): 1736-1750, which is available only in the Japanese language.

Overlapping Features in Kawasaki Disease-Related Arthritis and Systemic-Onset Juvenile Idiopathic Arthritis: A Nationwide Study in Japan.

Background: Arthritis may occur after the diagnosis of Kawasaki disease (KD). Most cases are self-limiting; however, some patients require prolonged treatment. Method: To characterize KD-related arthritis, 14 patients who required arthritis treatment within 30 days after the diagnosis of KD were recruited from the 23rd KD survey in Japan. Twenty-six additional patients were included from our tertiary center and literature review cohorts. Results: The estimated prevalence of KD-related arthritis in Japan was 48 per 100,000 KD patients. Patients with KD-related arthritis had an older age at onset (52 vs. 28 months, P = 0.002) and higher rate of intravenous immunoglobulin (IVIG) resistance in comparison to those without arthritis (86 vs. 17%, P < 0.001). Among 40 patients, 18 had arthritis in the acute phase KD (continued fever-onset type) and 22 did in the convalescent phase (interval fever-onset type). Both showed a similar rate of complete KD or IVIG response. Interval-type patients required biologics for arthritis control less frequently (5 vs. 39%, P = 0.02) and had a higher 2-year off-treatment rate (100 vs. 43%, P = 0.009) than continued-type ones. Interval-types showed lower serum ferritin and interleukin-18 levels than continued-types. When continued-types were grouped according to whether or not they required biologics (n = 7 and n = 11, respectively), the former subgroup had higher ferritin and interleukin-18 levels (P = 0.01 and 0.02, respectively). A canonical discriminant analysis differentiated interval-type from continued-type with the combination of age, time to arthritis, and the ferritin and matrix metalloproteinase-3 levels. Conclusion: Arthritis requiring treatment is a rare complication of KD. KD-associated arthritis includes interval-type (KD-reactive) and continued-type (true systemic-onset juvenile idiopathic arthritis [JIA] requiring biologics), and overlapping arthritis, suggesting the pathophysiological continuity of autoinflammation between KD and JIA.

Clinical Courses of IKAROS and CTLA4 Deficiencies: A Systematic Literature Review and Retrospective Longitudinal Study.

IKAROS and CTLA4 deficiencies are inborn errors of immunity and show similar clinical phenotypes, including hypogammaglobulinemia and autoimmune diseases (ADs). However, the differences in clinical features and pathogenesis of these are not fully understood. Therefore, we performed systematic literature reviews for IKAROS and CTLA4 deficiencies. The reviews suggested that patients with IKAROS deficiency develop AD earlier than hypogammaglobulinemia. However, no study assessed the detailed changes in clinical manifestations over time; this was likely due to the cross-sectional nature of the studies. Therefore, we conducted a retrospective longitudinal study on IKAROS and CTLA4 deficiencies in our cohort to evaluate the clinical course over time. In patients with IKAROS deficiency, AD and hypogammaglobulinemia often develop in that order, and AD often resolves before the onset of hypogammaglobulinemia; these observations were not found in patients with CTLA4 deficiency. Understanding this difference in the clinical course helps in the clinical management of both. Furthermore, our results suggest B- and T-cell-mediated ADs in patients with IKAROS and CTLA4 deficiencies, respectively.

Fibrodysplasia ossificans progressiva: Review and research activities in Japan.

Fibrodysplasia ossificans progressiva (FOP) is a rare genetic skeletal disorder manifesting progressive heterotopic ossification (HO) and congenital malformation of the great toes. Since 2007, we have conducted research on FOP. Here, we review the findings on FOP published to date, including the results of our research. Epidemiological studies in Japan have indicated that FOP has nearly the same prevalence in Japan as in the rest of the world. Basic research on its pathoetiology has progressed rapidly since the identification of the causal gene in 2006. Clinical and radiological findings have been thoroughly researched, including early radiological signs, and diagnostic criteria were established, designating FOP as an intractable disease in Japan. In patients with FOP, the progression of HO is associated with numerous disabilities, often manifesting in vicious cycles that can lead to early mortality. Through cross-sectional and short-term longitudinal studies, we have explored patient education, quality of life, and activities of daily living among Japanese patients. The management of FOP requires education of patients and caregivers, the use of medications to settle inflammation and flare-ups, instructions to ensure proper oral care, and other compensatory approaches that aid in rehabilitation. An avoidance of medical intervention, which may cause HO to progress, is also important. The advent of new drugs to prevent HO could have clinical benefit.

Seasonality in clinical courses of Kawasaki disease.

OBJECTIVE: Epidemics of Kawasaki disease (KD) are well known; however, the seasonal variation in the clinical course of KD is uncertain. The aim of this study was to investigate the seasonality in the clinical course of KD. METHODS: This study included 744 patients who were admitted to six hospitals in Kitakyushu City for KD from 2010 to 2014. We divided the patients into two groups according to the average monthly temperature (warm and cold periods) and compared the clinical courses of KD. RESULTS: The clinical courses of 715 patients who were initially treated with intravenous immunoglobulin (IVIG) were investigated. The proportion of patients with resistance to the initial IVIG therapy was significantly higher during the warm period than during the cold period (p=0.016). There was no seasonality in the proportion of patients with coronary artery abnormalities. CONCLUSION: Seasonality was observed in the response to IVIG therapy of patients with KD.

A serious case of primary Raynaud's phenomenon in an infant.

We present a case of severe Raynaud phenomenon (RP) in an infant. The current strategy of RP treatment is incomplete; excluding secondary Raynaud phenomenon is vital as well. This case aims to help those with similar symptoms in the future by gathering data on cases.

Can a pulse oxygen saturation of 95% to 96% help predict further vital sign destabilization in school-aged children?: A retrospective observational study.

To determine whether a peripheral capillary oxygen saturation (SpO2) of 95% to 96% should be considered "nonurgent" in school-aged children, as suggested by the Canadian Emergency Department Triage and Acuity Scale.School-aged children (6-12 years old) with a normal body temperature (36.5-37.4°C) who visited our department between September, 2014 and August, 2015 (n = 4556) were divided into 4 groups based on SpO2: group A: 99% to 100%; group B: 97% to 98%; group C: 95% to 96%; and group D: ≤94%. The heart rate (HR), respiratory rate (RR), and hospitalization rate were compared among the groups, and also between children with SpO2 95% to 96% and matched controls with SpO2 ≥97% (n = 280 each).Among 4556 eligible patients, groups A, B, C, and D comprised 2700 patients (59.3%), 1534 patients (33.6%), 280 patients (6.2%), and 42 patients (0.9%), respectively. The median (interquartile range [IQR]) RR significantly increased with decreasing SpO2 (23 [20-25], 24 [20-26], 24 [23-30], and 30 [24-40] breaths/min in groups A-D, respectively; P < .001). Similarly, the median (IQR) HR significantly increased with decreasing SpO2 (93 [83-104], 98 [87-110], 107 [93-119], and 121 [109-137] bpm, groups A-D, respectively; P < .001). Group D had the highest annual hospital admission rate (18 cases/42 patients, 42.9%). Further, the HR and RR differed significantly between the cases (107 [93-119] bpm; 24 [23-30] breaths/min) and controls (96 [86-106] bpm; 24 [20-28] breaths/min, respectively) (P < .001 and P = .02, respectively).An SpO2 of 95% to 96% among school-aged children should not be considered "nonurgent," but rather a significant clinical situation that requires early review of HR and RR. Prompt interventions among this group of children will help prevent further destabilization of vital signs, which will, in turn, contribute to decreased healthcare costs.

Abnormal hematopoiesis and autoimmunity in human subjects with germline IKZF1 mutations.

BACKGROUND: Ikaros, which is encoded by IKZF1, is a transcriptional factor that play a critical role in hematopoiesis. Somatic IKZF1 alterations are known to be involved in the pathogenesis of leukemia in human subjects. Recently, immunodeficiency caused by germline IKZF1 mutation has been described. OBJECTIVE: We sought to describe the clinical and immunologic phenotypes of Japanese patients with heterozygous IKZF1 mutations. METHODS: We performed whole-exome sequencing in patients from a dysgammaglobulinemia or autoimmune disease cohort and used a candidate gene approach in 4 patients. Functional and laboratory studies, including detailed lymphopoiesis/hematopoiesis analysis in the bone marrow, were performed. RESULTS: Nine patients from 6 unrelated families were identified to have heterozygous germline mutations in IKZF1. Age of onset was 0 to 20 years (mean, 7.4 years). Eight of 9 patients presented with dysgammaglobulinemia accompanied by B-cell deficiency. Four of 9 patients had autoimmune disease, including immune thrombocytopenic purpura, IgA vasculitis, and systemic lupus erythematosus. Nonautoimmune pancytopenia was observed in 1 patient. All of the mutant Ikaros protein demonstrated impaired DNA binding to the target sequence and abnormal diffuse nuclear localization. Flow cytometric analysis of bone marrow revealed reduced levels of common lymphoid progenitors and normal development of pro-B to pre-B cells. CONCLUSIONS: Germline heterozygous IKZF1 mutations cause dysgammaglobulinemia; hematologic abnormalities, including B-cell defect; and autoimmune diseases.

Radiographic characteristics of the hand and cervical spine in fibrodysplasia ossificans progressiva.

Fibrodysplasia ossificans progressiva (FOP) is a disabling heritable disorder of connective tissue characterized by progressive heterotopic ossification in various extraskeletal sites. Early correct diagnosis of FOP is important to prevent additional iatrogenic harm or trauma. Congenital malformation of the great toes is a well-known diagnostic clue, but some patients show normal-appearing great toes. The thumb shortening and cervical spine abnormalities are other skeletal features often observed in FOP. This study aimed to address the quantitative assessment of these features in a cohort of patients with FOP, which potentially helps early diagnosis of FOP. Radiographs of the hand and cervical spine were retrospectively analyzed from a total of 18 FOP patients (9 males and 9 females) with an average age of 13.9 years (range 0.7-39.3 years). The elevated ratio of the second metacarpal bone to the distal phalanx of the thumb (> +1SD) was a consistent finding irrespective of the patient's age and gender. Infant FOP patients, in addition, exhibited an extremely high ratio of the second metacarpal bone to the first metacarpal bone (> +3SD). The height/depth ratio of the C5 vertebra increased in patients over 4 years of age (> +2SD). Additionally, the ratio of (height+depth) of the C5 spinous process to the C5 vertebral depth was markedly elevated in young patients (> +2SD). We quantitatively demonstrated the hand and cervical spine characteristics of FOP. These findings, which can be seen from early infancy, could be useful for early diagnosis of FOP even in patients without great toe abnormalities.

Copy number variations due to large genomic deletion in X-linked chronic granulomatous disease.

Mutations in genes for any of the six subunits of NADPH oxidase cause chronic granulomatous disease (CGD), but almost 2/3 of CGD cases are caused by mutations in the X-linked CYBB gene, also known as NAD (P) H oxidase 2. Approximately 260 patients with CGD have been reported in Japan, of whom 92 were shown to have mutations of the CYBB gene and 16 to have chromosomal deletions. However, there has been very little detailed analysis of the range of the deletion or close understanding of the disease based on this. We therefore analyzed genomic rearrangements in X-linked CGD using array comparative genomic hybridization analysis, revealing the extent and the types of the deletion genes. The subjects were five Japanese X-linked CGD patients estimated to have large base deletions of 1 kb or more in the CYBB gene (four male patients, one female patient) and the mothers of four of those patients. The five Japanese patients were found to range from a patient exhibiting deletions only of the CYBB gene to a female patient exhibiting an extensive DNA deletion and the DMD and CGD phenotype manifested. Of the other three patients, two exhibited CYBB, XK, and DYNLT3 gene deletions. The remaining patient exhibited both a deletion encompassing DNA subsequent to the CYBB region following intron 2 and the DYNLT3 gene and a complex copy number variation involving the insertion of an inverted duplication of a region from the centromere side of DYNLT3 into the deleted region.

Nationwide survey of bisphosphonate therapy for children with reactivated Langerhans cell histiocytosis in Japan.

BACKGROUND: Several studies have suggested that Langerhans cell histiocytosis (LCH) is responsive to treatment with bisphosphonates (BPs). However the efficacy and safety of BPs therapy for childhood LCH is unknown. PROCEDURE: Data on children with LCH who had received BPs therapy were collected retrospectively from hospitals participating in the Japanese Pediatric Leukemia/Lymphoma Study Group. RESULTS: Twenty-one children with histologically proven LCH were identified. Of these, the case histories of 16 children who had been treated with pamidronate (PAM) for disease reactivation were analyzed in detail. The median post-PAM therapy follow-up period was 2.8 years (range: 0.9-9.3 years). The median age at commencement of PAM therapy was 9.4 years (range: 2.3-15.0 years). All children had one or more bone lesions but none had risk organ (RO) involvement. In the majority of the children, six courses of PAM were administered at a dose of 1.0 mg/kg/course at 4-week intervals. In 12 of the 16 children, all active lesions including lesions of the skin (n = 3) and soft tissues (n = 3) resolved. Of these children, eight children had no active disease for a median of 3.3 years post-PAM therapy (range: 1.8-9.3 years). Progression-free survival (PFS) was 56.3 ± 12.4% at 3 years. PFS was significantly higher in children with a first reactivation compared with children experiencing a second or subsequent reactivation. CONCLUSIONS: PAM may be an effective treatment for reactivated LCH with bone lesions. A prospective trial of the efficacy of PAM in recurrent pediatric LCH is warranted.

Deformity of the great toe in fibrodysplasia ossificans progressiva.

BACKGROUND: As invasive medical procedures can induce permanent heterotopic ossification in fibrodysplasia ossificans progressiva (FOP), caution should be exercised in clinical practice. The present study was conducted to examine the characteristics of the great toe deformity in patients with FOP, which may lead to an early diagnosis of this condition. METHODS: The subjects consisted of 31 feet from 16 FOP patients (8 males, 8 females) with an average age of 17.3 years (range 1-47 years) at the time of this study. Gross and radiographic findings, including the hallux valgus angles (HVA), intermetatarsal angles (IMA), and the deformity of the proximal phalanx and metatarsal bone, were examined. RESULTS: Of the 31 feet, 29 (93.5%) showed several degrees of great toe deformity. A shortened great toe was the typical gross finding and was observed in 20 feet (64.5%). The mean HVA and IMA were 19.7° and 8.5°, respectively; and 22 (71.0%) feet satisfied the radiographic definition of hallux valgus (HVA ≥ 20° or IMA ≥ 10°). The proximal phalanx was consistently shortened but morphologically dissimilar from case to case. The metatarsal bone was also shortened and sharpened to the medial side, deviating the proximal phalanx laterally from the metatarsal axis. Fusion between the distal and proximal phalanx occurred with advancing age. Only two feet in one patient showed no obvious deformity of the great toe. CONCLUSIONS: A shortened great toe and hallux valgus were frequently found in patients with FOP. Shortening and sharpening of the proximal phalanx and metatarsal bone consistently existed and contributed to the great toe deformity. These findings were thought to exist from birth and may be a key to an early diagnosis.

Outcome of pediatric patients with Langerhans cell histiocytosis treated with 2 chlorodeoxyadenosine: a nationwide survey in Japan.

The aim of this study was to assess the outcome of treatment with 2-chlorodeoxyadenosine (2-CdA) in pediatric patients with Langerhans cell histiocytosis (LCH) in Japan. We retrospectively identified 17 pediatric LCH patients treated with 2-CdA. All patients were refractory or reactivated cases who had been initially treated according to the JLSG-02 protocol of the Japan LCH study group. At initiation of 2-CdA therapy, 4 patients had primary refractory multisystem (MS) disease with risk organ (RO) involvement (MS+), 9 patients had reactivated MS disease [5 MS+ and 4 without RO involvement (MS-)], and the remaining 4 patients had refractory/reactivated multifocal bone disease (MFB). Treatment with 2-CdA (4-9 mg/m(2)/day) was administered on 2-5 consecutive days and repeated every 3-4 weeks for a period that ranged from 2 to 12 months. Four primary refractory patients were treated with 2-CdA combined with high dose of cytarabine. In MS+ patients, response to treatment was observed in 5 of the 9 patients. In MS-/MFB patients, 5 of the 8 patients showed response to treatment. In the patients who were primary refractory or had reactivation during initial chemotherapy, 4 of 10 patients showed good response. On the other hand, in the patients having reactivation while off therapy, 6 of 7 patients showed good response. These findings suggest that 2-CdA is effective for reactivated LCH while off therapy.