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Background/Objectives: Relapsed B-cell acute lymphoblastic leukemia (B-ALL) remains an unresolved matter of concern regarding adverse outcomes. This case study aimed to evaluate the effectiveness of blinatumomab, with or without door lymphocyte infusion (DLI), in treating measurable residual disease (MRD)-positive B-ALL. Methods: All patients who received blinatumomab salvage therapy were included in this study. Eleven patients were included in the study. All patients were evaluated for MRD-negativity. Results: Before starting blinatumomab therapy, seven patients tested positive for MRD, three tested negative, and one had refractory disease. Hematopoietic cell transplantation (HCT) was reserved for five patients with persistent MRD. Six patients became MRD-negative and subsequent HCT was not performed. Only two patients relapsed; one patient died of relapse, and the other one received carfilzomib-based therapy and was MRD-negative thereafter. Nine patients were MRD-negative at a median follow-up of 28 months (15–52 months). Two of three MRD-positive post-transplant patients remained in complete molecular remission after preemptive DLI at the last follow-up date. In the first salvage, blinatumomab may achieve complete remission and bridging to HCT in pediatric patients with end-of-induction MRD-positive B-cell precursor ALL. Conclusions: The decision on how to treat post-transplant relapse continues to affect survival outcomes. Blinatumomab combined with DLI may extend the armamentarium of release options for high-risk pediatric patients. This approach is encouraging for high-risk ALL patients who are MRD-positive post-transplantation.

Chimeric antigen receptor-T (CAR-T) cell therapy has demonstrated impressive efficacy in the treatment of blood cancers; however, its effectiveness against solid tumors has been significantly limited. The differences arise from a range of difficulties linked to solid tumors, including an unfriendly tumor microenvironment, variability within the tumors, and barriers to CAR-T cell infiltration and longevity at the tumor location. Research shows that the reasons for the decreased effectiveness of CAR-T cells in treating solid tumors are not well understood, highlighting the ongoing need for strategies to address these challenges. Current strategies frequently incorporate combinatorial therapies designed to boost CAR-T cell functionality and enhance their capacity to effectively target solid tumors. However, these strategies remain in the testing phase and necessitate additional validation to assess their potential benefits. CAR-NK (natural killer), CAR-iNKT (invariant natural killer T), and CAR-M (macrophage) cell therapies are emerging as promising strategies for the treatment of solid tumors. Recent studies highlight the construction and optimization of CAR-NK cells, emphasizing their potential to overcome the unique challenges posed by the solid tumor microenvironment, such as hypoxia and metabolic barriers. This review focuses on CAR cell therapy in the treatment of solid tumors.

This systematic review discusses the use of prophylaxis to prevent cytomegalovirus (CMV) infection in recipients who have undergone hematopoietic cell transplantation. It highlights the need for new approaches to control and prevent CMV infection. The approval of the anti-CMV drug letermovir has made antiviral prophylaxis more popular. CMV-specific T cell-mediated immunity tests are effective in identifying patients who have undergone immune reconstitution and predicting disease progression. Maribavir (MBV) has been approved for the treatment of post-transplant CMV infection/disease in adolescents. Adoptive T-cell therapy and the PepVax CMV vaccine show promise in tackling refractory and resistant CMV. However, the effectiveness of PepVax in reducing CMV viremia/disease was not demonstrated in a phase II trial. Cell-mediated immunity assays are valuable for personalized management plans, but more interventional studies are needed. MBV and adoptive T-cell therapy are promising treatments, and trials for CMV vaccines are ongoing.

The knowledge surrounding the application of immune checkpoint inhibitors (ICIs) in the treatment of pediatric cancers is continuously expanding and evolving. These therapies work by enhancing the body’s natural immune response against tumors, which may have been suppressed by certain pathways. The effectiveness of ICIs in treating adult cancers has been widely acknowledged. However, the results of early phase I/II clinical trials that exclusively targeted the use of ICIs for treating different pediatric cancers have been underwhelming. The response rates to ICIs have generally been modest, except for cases of pediatric classic Hodgkin lymphoma. There seems to be a notable disparity in the immunogenicity of childhood cancers compared to adult cancers, potentially accounting for this phenomenon. On average, childhood cancers tend to have significantly fewer neoantigens. In recent times, there has been a renewed sense of optimism regarding the potential benefits of ICI therapies for specific groups of children with cancer. In initial research, individuals diagnosed with pediatric hypermutated and SMARCB1-deficient cancers have shown remarkable positive outcomes when treated with ICI therapies. This is likely due to the underlying biological factors that promote the expression of neoantigens and inflammation within the tumor. Ongoing trials are diligently assessing the effectiveness of ICIs for pediatric cancer patients in these specific subsets. This review aimed to analyze the safety and effectiveness of ICIs in pediatric patients with different types of highly advanced malignancies.

Abstract Introduction Malignant germ cell tumors (MGCTs) can develop either extracranially or intracranially. Growing teratoma syndrome (GTS) may develop in these patients following chemotherapy. Reports on the clinical characteristics and outcomes of GTS in children with MGCTs are limited. Methods We retrospectively collected the data, including the clinical characteristics and outcomes of five patients in our series and 93 pediatric patients selected through a literature review of MGCTs. This study aimed to analyze survival outcomes and risk factors for subsequent events in pediatric patients with MGCTs developing GTS. Results The sex ratio was 1.09 (male/female). In total, 52 patients (53.1%) had intracranial MGCTs. Compared with patients with extracranial GCTs, those with intracranial GCTs were younger, predominantly boys, had shorter intervals between MGCT and GTS, and had GTS mostly occurring over the initial site (all p

Abstract Cord blood transplantation (CBT) provides a treatment scheme for hematologic diseases and leukemia in both children and adults. However, adverse reactions and transplantation-related death may still occur in patients receiving CBT even when donor and recipient have fully matched HLA in high-resolution HLA typing analysis. Single nucleotide polymorphisms (SNPs) of HLA-related and unrelated genes are known to associate with disease status of patients with unrelated stem cell transplantation. In this study, the genomic regions ranging from 500 base pairs upstream to 500 base pairs downstream of the eight SNPs that were reported as transplantation determinants by Petersdorf et al. were analyzed to evaluate whether genetic variants were associated with the survival status of patients, and the risk for severe (grades 3–4) graft-versus-host disease (GVHD) or cytomegalovirus (CMV) infection/reactivation. The analyses were performed in the mode of recipient genotype, donor genotype, and recipient-donor mismatching, respectively. By analysis of sixty-five patients and their HLA-matched unrelated donors, we found that five SNPs were associated with patient survival which included the recipient genotype with SNPs of rs107822 in the RING1 gene, and rs2070120, rs17220087 and rs17213693 in the HLA-DOB gene; and the recipient-donor mismatching with SNPs of rs9282369 in HLA-DOA gene, and rs2070120, rs17220087 and rs17213693 in the HLA-DOB gene. Five SNPs were associated with the risk for severe GVHD which included the donor genotype with SNPs of rs213210 and rs2523675; the recipient genotype with SNPs of rs9281491 in the HCP5 gene; and the recipient-donor mismatching with SNPs of rs209130 in the TRIM27 gene, and rs986522 in the COL11A2 gene. Six SNPs were related to the risk for CMV infection/reactivation which included the donor genotype with SNPs of rs435766, rs380924, and rs2523957; and the recipient-donor mismatching with SNPs of rs2070120, rs17220087, and rs17213693 in the HLA-DOB gene; and rs435766 and rs380924 in the MICD gene. This study provides the basis for larger analyses and if the results are confirmed, a way of selecting better unrelated CBT candidate donors.

Abstract Improvement in outcomes of children with acute myeloid leukemia (AML) is attributed to several refinements in clinical management. We evaluated treatment outcomes of Taiwanese pediatric AML patients in the past 20 years. Overall, 860 de novo AML patients aged 0–18 years and registered in the Childhood Cancer Foundation of R.O.C during January 1996–December 2019 were included. Survival analysis was performed to identify factors that improved treatment outcomes. Regardless of treatment modalities used, patients during 2008–2019 had better 5-year event-free survival (EFS) and overall survival (OS) rates than patients during 1996–2007. For patients received the TPOG-AML-97A treatment, only 5-year OS rates were significantly different between patients diagnosed before and after 2008. Patients with RUNX1–RUNX1T1 had similar relapse-free survival rates, but 5-year OS rates were better during 2008–2019. However, the survival of patients who received hematopoietic stem-cell transplantations (HSCT) did not differ significantly before and after 2008. For patients without relapse, the 5-year OS improved during 2008–2019. Non-relapse mortality decreased annually, and cumulative relapse rates were similar. In conclusion, 5-year EFS and OS rates improved during 2008–2019, though intensities of chemotherapy treatments were similar before and after 2008. Non-relapse mortality decreased gradually. Further treatment strategies including more intensive chemotherapy, novel agents’ use, identification of high-risk patients using genotyping and minimal residual disease, early intervention of HSCT, and antibiotic prophylaxis can be considered for future clinical protocol designs in Taiwan.

Background: Mixed-phenotype acute leukemia (MPAL) poses a diagnostic and therapeutic dilemma. No consensus exists on the strategy to assign patients with MPAL to either lymphoid- or myeloid-directed treatment. Thus, a better understanding of the characteristics of MPAL is a crucial unmet need. This study aims to provide information on a population-based cohort of children who received treatment based on standard, simple immunophenotypic criteria. Methods: Single-center, retrospective clinical and laboratory reviews of patients with MPAL were provided by morphology, immunophenotyping, cytogenetics, and molecular methods. We identified 242 flow cytometry samples. Of all consecutive pediatric patients with acute leukemia, we identified 8 (3.3%) patients with MPAL fulfilling WHO 2016 criteria; these were classified as follows: B-lymphoid + myeloid (n = 4), T-lymphoid + myeloid (n = 2), and B + T-lymphoid (n = 2). Results: Of 8 MPAL cases, 4 were boys and 4 girls [median age at diagnosis: 10.8 (range 1.1–17) years]. The b3a2 (p210) and e1a2 (p190) BCR/ABL fusion transcripts were detected in 1 patient with B/myeloid MPAL. Regarding the morphology, all patients were initially diagnosed as acute lymphoblastic leukemia, but no morphological characteristics or cytogenetic aberration was particularly predictive of an MPAL. Furthermore, 4 of 8 patients (50%) with MPAL were associated with chromosome 21 monosomy or partial trisomy. Conclusion: Despite no single recurrent chromosomal abnormality that could serve as a hallmark lesion in MPAL, cytogenetic alterations are frequent and predominantly associated with complex karyotype involving chromosome 21 abnormalities.

Clinically, stem cells with matched human leukocyte antigens (HLAs) must be selected for allogeneic transplantation to avoid graft rejection. However, adverse reactions still occur after cord blood transplantation (CBT). It was inferred that the HLA system is not the only regulatory factor that may influence CBT outcomes. Therefore, we plan to investigate whether the single-nucleotide polymorphisms (SNPs) located in non-HLA genes are associated with the effectiveness of CBT. In this study, the samples of 65 donors from CBT cases were collected for testing. DNA sequencing was focused on the SNPs of non-HLA genes, cytotoxic T-lymphocyte-associated protein 4 (CTLA4), CD28, tumor necrosis factor ligand superfamily 4 (TNFSF4), and programmed cell death protein 1 (PDCD1), which were selected in regard to the literatures published in 2017 and 2018, which indicated that they were related to stem cell transplantation. Then, in combination with the detailed follow-up transplantation tracking database, these SNPs were analyzed with the risk of mortality, relapse, cytomegalovirus (CMV) infection, and graft-versus-host disease (GVHD). We found that there were 2 SNPs of CTLA4, 1 SNP of TNFSF4, and 2 SNPs of PDCD1 associated with the effectiveness of unrelated CBT. These statistically significant SNPs and haplotypes would be used in clinical to choose the best donor for the patient receiving CBT. Moreover, the polygenic risk scores (PRSs) with these SNPs could be used to predict the risk of CBT adverse reactions with an area under the receiver operating characteristic curve (AUC) of 0.7692. Furthermore, these SNPs were associated with several immune-related diseases or cancer susceptibility, which implied that SNPs play an important role in immune regulation.

Background: Children with cancer undergo many invasive medical procedures that are often painful and highly distressing, including bone marrow aspiration (BMA) and lumbar puncture (LP). Psychosocial interventions have been demonstrated to reduce children's distress resulting from invasive medical procedures. The aim of the study is to assess the efficacy of psychosocial interventions to reduce distress in children with cancer undergoing BMA and LP in a pediatric cancer center in Taiwan. Methods: Children with cancer who received treatment between March 2015 and December 2016 at Chang Gung Memorial Hospital, Linkou, Taiwan were eligible for the study. The psychosocial intervention comprised preparation and cognitive behavioral intervention and was provided by a certified child life specialist. The assessment instrument was the revised version of the Observational Scale of Behavioral Distress (OSBD-R). The behavioral distress of patients who underwent psychosocial interventions for BMA and LP was compared with patients without interventions. We also analyzed the difference of behavioral distress in patients’ pre- and post-psychosocial intervention for BMA and LP. Results: Eighteen patients were enrolled into this study. The mean age of diagnosis of leukemia was 6.6 years old (range: 3–11 years). Fifteen patients were diagnosed with acute lymphoblastic leukemia, and 3 were diagnosed with acute myeloid leukemia. The mean of OSBD-R total scores in 7 patients with psychosocial intervention was significantly lower than the mean score in 6 patients without intervention (0.65 vs. 4.81, p = 0.002). Pre- and post-psychosocial intervention for BMA and LP behavioral distress were evaluated for the remaining 5 patients. Consistently, there was a significant reduction of the OSBD-R score following interventions (3.04 vs. 7.81, p = 0.025). Conclusion: Psychosocial interventions provided by a certified child life specialist have a significant potential to reduce children's distress during BMA and LP in pediatric healthcare settings in Taiwan. Key Words: child life services, children with leukemia, distress, invasive procedures, psychosocial interventions

Capillary leak syndrome (CLS) is a severe complication of allogeneic hematopoietic stem cell transplantation (HSCT) characterized by weight gain, generalized edema, hypotension, and hypoalbuminemia. The primary pathogenesis is injury of the capillary endothelium resulting in a loss of intravascular fluid into the interstitial space. Treatment is limited to vascular endothelial growth factor withdrawal and systemic corticosteroids. We report two cases with CLS where weight gain, ascites, and hypotension developed after neutrophil engraftment following allogeneic HSCT. We obtained serial electrolytes, blood urea nitrogen, creatinine, and albumin from these patients. Ultrasound with Doppler tracing performed on both patients showed no reversal of portal venous flow. Issues addressed were the restoration of regular hydration by hydroxyethyl starch (HES) solutions, together with systemic corticosteroids and forced diuresis. Tetrastarch was administered 10 and 20 days, respectively. Both patients recovered without sequelae. CLS is a frequent complication after allogeneic HSCT. The effects of HES on CLS merit further consideration and prospective study.

Objectives Emergency services utilisation is a critical policy concern. The paediatric population is the main user of emergency department (ED) services, and the main contributor to low acuity (LA) ED visits. We aimed to describe the trends of ED and LA ED visits under a comprehensive, universal health insurance programme in Taiwan, and to explore factors associating with potentially unnecessary ED utilisation.Design and setting We used a population-based, repeated cross-sectional design to analyse the full year of 2000, 2005, 2010 and 2015 National Health Insurance claims data individually for individuals aged 18 years and under.Participants We identified 5 538 197, 4 818 213, 4 401 677 and 3 841 174 children in 2000, 2005, 2010 and 2015, respectively.Primary and secondary outcome measures We adopted a diagnosis grouping system and severity classification system to define LA paediatric ED (PED) visits. Generalised estimating equation was applied to identify factors associated with LA PED visits.Results The annual LA PED visits per 100 paediatric population decreased from 10.32 in 2000 to 9.04 in 2015 (12.40%). Infectious ears, nose and throat, dental and mouth diseases persistently ranked as the top reasons for LA visits (55.31% in 2000 vs 33.94% in 2015). Physical trauma-related LA PED visits increased most rapidly between 2000 and 2015 (0.91–2.56 visits per 100 population). The dose–response patterns were observed between the likelihood of incurring LA PED visit and either child’s age (OR 1.06–1.35 as age groups increase, p

Deficiencies in T regulatory (Treg) and Th17 cells attenuate peripheral tolerance and the IL-17 family of cytokines, contributing to autoimmune disorders and opportunistic (fungal) infections, respectively. Because of limited blood samples from patients with primary immunodeficiency diseases (PIDs), a positive correlation/linear relationship between Treg and Th17 cells and their respective expressions of transcription factors forkhead box P3 (FOXP3) and retinoic acid-related orphan receptor γ (RORγt) by real-time PCR (RT-PCR) amplification, was used to predict the percentages of Treg and Th17 cells in peripheral blood. Compared to glyceraldehyde 3-phosphate dehydrogenase (GAPDH) expression, the percentages of Treg and Th17 cells were calculated as the linear relationship to the 2−ΔCT value (cycle threshold). Among 91 PIDs patients, 68 and 78 had predicted Treg and Th17 percentages below 5% of the normal ranges (0.859 and 0.734%, respectively), which expanded different categories beyond obvious T cell deficiency. Notably, FOXP3 was undetectable in one patient (CVID), RORγt was undetectable in six patients (one CVID, one CID, two neutropenia, one WAS, and one CMC), and both were undetectable in four patients (two SCID, one STAT1, and one periodic fever). In contrast, two patients with auto-IFNγ antibodies had increased susceptibility to intracellular mycobacterial infections, interrupted Th1 development and subsequent elevation in the Th17 cells. Both predicted Treg and Th17 percentages in the PIDs patients were more independent of age (months) than in the controls. The predicted Th17/Treg ratio in the PIDs patients, overall, was lower than that in the healthy controls (0.79 ± 0.075 vs. 1.16 ± 0.208; p = 0.038). In conclusion, lower predicted Treg and Th17 cell populations calculated by RT-PCR-amplified FOXP3 and RORγt in PIDs patients at diagnosis can explain the higher potential phenotypes of autoimmune disorders and opportunistic infections, although effective interventions in the early stage might have prevented such phenotypic development and caused a statistical bias in the comparisons.

Real-time quantitative polymerase chain reaction (RQ-PCR) for fusion transcripts and flow cytometry for leukemia-specific markers are widely used for minimal residual disease (MRD) detection in acute lymphoblastic leukemia, but the relation between the results of either method is unclear. Methods: Mononucleated cells from 108 bone marrow samples collected from 55 B-precursor acute lymphoblastic leukemia patients (30 with t(12;21)/ETV6-RUNX1, 16 with t(9;22)/BCR-ABL1 and nine with t(1;19)/TCF3-PBX1) were examined in tandem by RQ-PCR and six-color flow cytometry. Results: MRD results were concordant in 91 of the 108 paired samples (84.2%; K=0.690); 49 samples were MRD-negative while 42 were MRD-positive by both methods, with < 1 log difference in positive MRD estimates in 39 samples (92.9%). Of the 17 discordant samples, 16 were MRD-positive by RQ-PCR but MRD-negative by flow cytometry; the opposite was true in one sample. Kappa value/concordance was 0.690/85.0% (n = 60) for ETV6-RUNX1, 0.842/93.3% (n = 15) for TCF3-PBX1, and 0.535/78.8% (n = 33) for BCR-ABL1. Specific immunophenotypic abnormalities were more prevalent in each genetic subgroup, such as CD38 underexpression, CD58 overexpression, and CD34 overexpression in ETV6-RUNX1, TCF3-PBX1, and BCR-ABL1, respectively. Conclusion: In most follow-up samples, MRD estimates by two methods are in agreement, especially in patients with TCF3-PBX1.

Abstract Background The quality of pediatric emergency care has been a major concern in health care. Following a series of health system reforms in China, it is important to do this assessment of pediatric emergency care, and to explore potential influences of health care system. This study aimed to compare practice differences in treating children with respiratory illnesses in two emergency department (ED) settings within different health care systems: China and Taiwan. Methods A pooled cross-sectional hospital-based study was conducted in two tertiary teaching hospitals in Xiamen, China and Keelung, Taiwan belong to the same hospital chain group. A team of 21 pediatricians rotated between the EDs of the two hospitals from 2009 to 2012. There were 109,705 ED encounters treated by the same team of pediatricians and 6596 visits were analyzed for common respiratory illnesses. Twelve quality measures in process and outcomes of asthma, bronchiolitis and croup were reported. Descriptive statistics and multiple logistic regression models were applied to assess. In order to demonstrate the robustness of our findings, we analyzed the data using an alternative modeling technique, multilevel modeling. Results After adjustment, children with asthma presented to the ED in China had a significantly 76% lower likelihood to be prescribed a chest radiograph, and a 98% lower likelihood to be prescribed steroids and discharged home than those in Taiwan. Also, children with asthma presented to the ED in China had significantly 7.76 times higher risk to incur 24-72 h return visits. Furthermore, children with bronchiolitis in China (Odds ratio (OR): 0.21; 95% Confidence interval (CI): 0.17-0.28) were significantly less likely to be prescribed chest radiograph, but were significantly more likely to be prescribed antibiotics (OR: 2.19; 95% CI: 1.46-3.28). Conclusions This study illustrated that although high quality care depends on better assessment of physician performance, the delivery of pediatric emergency care differed significantly between these two healthcare systems after holding the care providers the same and adjusting for important patient characteristics. The findings suggest that the features of the health care system may play a significant role.

Abstract Diarrhoea lasting longer than 14 days and failing to respond to conventional management is defined as severe and protracted diarrhoea (SD). In this study, we investigated the prevalence, pathogens and prognosis of SD in primary immunodeficiency diseases (PIDs). Among 246 patients with predominantly paediatric-onset PIDs from 2003–2015, 21 [Btk (six), IL2RG (four), WASP, CD40L, gp91 (three each), gp47, RAG2 (one each)] and five [CVID (four), SCID (one)] without identified mutations had SD before prophylactic treatment. Detectable pathogens included pseudomonas, salmonella (six each), E. coli, cytomegalovirus, coxsackie virus and cryptosporidium (one each), all of whom improved after a mean 17 days of antibiotics and/or IVIG treatment. Seven (7/26; 27.0%) patients died [respiratory failure (four), lymphoma, sepsis and intracranial haemorrhage (one each)]. The patients with WAS, CGD and CD40L and SD had a higher mortality rate than those without. Another five males with mutant XIAP, STAT1, FOXP3 (one each) and STAT3 (two) had undetectable-pathogenic refractory diarrhoea (RD) that persisted >21 days despite aggressive antibiotic/steroid treatment and directly resulted in mortality. For the patients with RD without anti-inflammatory optimization, those with mutant XIAP and FOXP3 died of Crohn’s-like colitis and electrolyte exhaustion in awaiting transplantation, while transplantation cured the STAT1 patient.

The T-cell receptor (TCR)/CD3 complex is crucial for T-cell development and regulation. In humans, CD3D, CD3E, and CD3Z gene defects cause severe combined T- and B-cell immunodeficiency. However, CD3G mutations alone lead to a less severe condition, which is mainly characterized by autoimmunity. In the present study, we report the case of a 36-year-old male who presented with recurrent sinopulmonary infections without opportunistic infections; this was compatible with hypogammaglobulinemia, but normal PHA-lymphocyte proliferation. This patient had the common variable immunodeficiency (CVID) phenotype and received regular immunoglobulin infusions over 20-years; he gradually developed nodular regenerative hyperplasia over a 5-year period. Distinct from the previously reported CD3G mutations, which mainly present as autoimmunity, the novel CD3G deletion (c.del213A) in our patient caused an obvious decrease in switched memory B cells and diminished CD40L expression. However, sufficient Treg suppression function was maintained so that he remained free of autoimmune thyroiditis (AIT), inflammatory bowel disease (IBD), and autoimmune pancytopenia. A PubMed search for this rare disease entity revealed seven Turkish and two Spanish patients (five unrelated families). Among a total of 20 alleles, there were 14 splicing mutations (80(-1)G>C), two missense mutations (c.1G>A), two nonsense mutations (c.250A>T), and two deletions (c.del213A). Three patients presented with isolated AIT without significant infections. Three patients died, one from a severe infection at 31 months, one from post-transplant respiratory failure due to viral pneumonia at 17 months, and one from graft-vs.-host disease at 47 months. Those experiencing opportunistic infections, severe life-threatening infections in need of hematopoietic stem cell transplantation, and IBD-like diarrhea had a significantly higher mortality rate compared with those without these features (p = 0.0124, p = 0.01, and p = 0.0124, respectively). The patients with AIT had a significantly better prognosis (p = 0.0124) to those without AIT. Our patient with the novel CD3G mutation presented with predominant B-cell deficiency overlapping with the CVID phenotype but without recognizable autoimmunity, which was consistent with his normal Treg suppression function.

Invasive fungal infections in children with acute lymphoblastic leukemia have been a major cause of mortality. Recent reports have described increasing incidence of invasive non-Aspergillus mold infections in patients with hematological malignancies. It is always challenging to treat invasive fungal infection and underlying hematological malignancies successfully. Here we report a girl with high-risk acute lymphoblastic leukemia who developed disseminated Cunninghamella bertholletiae infection during induction chemotherapy. This case illustrates the difficulties of diagnosis and treatment of invasive C. bertholletiae infection. It also highlights the necessity for physicians to keep high suspicion and awareness for this infrequent fungal infection.

Pediatric emergency medicine is a young field that has established itself in recent decades. Many unanswered questions remain regarding how to deliver better pediatric emergency care. The implementation of full-time pediatric emergency physicians is a quality improvement strategy for child care in Taiwan. The aim of this study is to evaluate the quality of care under different physician coverage models in the pediatric emergency department (ED). Methods: The medical records of 132,398 patients visiting the pediatric ED of a tertiary care university hospital during January 2004 to December 2006 were retrospectively reviewed. Full-time pediatric emergency physicians are the group specializing in the pediatric emergency medicine, and they only work in the pediatric ED. Part-time pediatricians specializing in other subspecialties also can work an extra shift in the pediatric ED, with the majority working in their inpatient and outpatient services. We compared quality performance indicators, including: mortality rate, the 72-hour return visit rate, length of stay, admission rate, and the rate of being kept for observation between full-time and part-time pediatric emergency physicians. Results: An average of 3678 ± 125 [mean ± standard error (SE)] visits per month (with a range of 2487–6646) were observed. The trends in quality of care, observed monthly, indicated that the 72-hour return rate was 2–6% and length of stay in the ED decreased from 11.5 hours to 3.2 hours over the study period. The annual mortality rate within 48 hours of admission to the ED increased from 0.04% to 0.05% and then decreased to 0.02%, and the overall mortality rate dropped from 0.13% to 0.07%. Multivariate analyses indicated that there was no change in the 72-hour return visit rate for full-time pediatric emergency physicians; they were more likely to admit and keep patients for observation [odds ratio = 1.43 and odds ratio = 1.71, respectively], and these results were similar to those of senior physicians. Conclusion: Full-time pediatric emergency physicians in the pediatric ED decreased the mortality rate and length of stay in the ED, but had no change in the 72-hour return visit rate. This pilot study shows that the quality of care in pediatric ED after the implementation of full-time pediatric emergency physicians needs further evaluation.

Disease relapse occurs in unrelated cord blood transplantation (CBT) even when the alleles of human leukocyte antigen (HLA) are fully matched between donor and recipient. This is similar to that observed in other types of hematopoietic stem cell transplantation. Fourteen single nucleotide polymorphisms (SNPs) within the HLA region have been reported previously by Petersdorf et al. and Piras et al. as transplantation determinants in unrelated hematopoietic cell transplantation. In this study, the genomic sequences within 500 base pairs upstream and downstream of the fourteen transplantation-related SNPs from 53 patients and their HLA-matched unrelated donors were analyzed for determining whether or not genetic variants, conferred by either recipient or donor SNP genotype or by recipient-donor SNP mismatching, were associated with the risk of relapse. Seven SNPs were associated with the risk of relapse in unrelated CBT. These included the donor genotype with the SNPs of rs2523675 and rs2518028 at the telomeric end of HCP5 gene, rs2071479 in the intron of the HLA-DOB gene, and rs2523958 in the MICD gene; and the recipient genotype with SNPs of rs9276982 in the HLA-DOA gene, and rs435766 and rs380924 in the MICD gene. As measured by pair-wise linkage disequilibrium (LD) with D′ as the parameter for normalized standard measurement of LD which compares the observed and expected frequencies of one haplotype comprised by alleles at different loci, rs2523675 had high LD with rs4713466 (D′ = 0.86) and rs2523676 (D′ = 0.91) in the HCP5 gene. The rs2518028 had no LD with all other SNPs except rs2523675 (D′ = 0.76). This study provides the basis for developing a method or algorithm for selecting better unrelated CBT candidate donors.

Cryopreservation is widely used in umbilical cord blood (UCB) banking, yet its impact on progenitor cell function remains largely unaddressed. It is unknown whether long-term cryopreservation affects UCB transplantation outcomes. Herein, we evaluated the impact of UCB age on clinical outcomes and investigated the effect of cryopreservation duration of UCB on hematopoietic potency in 91 patients receiving single cord blood transplantations. UCB cryopreservation duration was 0.7 to 13.4 y. The most common indication of transplant was thalassemia (48%). There was no significant association between cryopreservation duration and neutrophil engraftment probability ( P = 0.475). Cryopreservation duration did not affect the post-thaw viability and subsequent neutrophil engraftment rate. Therefore, UCB units can undergo cryopreservation for at least 8 y with no impact on clinical outcomes.

Malignant triton tumor (MTT) is a highly aggressive malignant neoplasm, classified as a variant of malignant peripheral nerve sheath tumor with rhabdomyoblastic differentiation. MTT is rarely reported in children, and its true prevalence may be underestimated. We herein report such a case in an 8-year-old boy who presented with a mass over the trapezius muscle. He was previously diagnosed with neurofibromatosis in the same area. Four years later, a follow-up magnetic resonance imaging revealed an intradural tumor recurrence at the level of C1–C7. An immunohistochemical test result was positive for S-100 protein and desmin, which confirmed the diagnosis. The patient outcome was fatal despite multimodal therapy. The possibility of this rare but devastating tumor must always be considered when patients present with new compressive spinal symptoms.

The objective of this study was to determine the incidence, risk factors, outcome, and clinical significance of pericardial effusion (PE). We retrospectively analyzed outcomes of 272 pediatric patients undergoing their first hematopoietic stem cell transplantation (HSCT) from 1998 to 2016. In total, 15% (3/20) and 5.9% (15/252) of autologous and allogeneic HSCT recipients, respectively, were identified with PE. However, there was no statistically significant difference in the incidence of PE between the 2 groups. The mean age at transplantation was 11.12 ± 5.41 y. Eighteen patients developed PE at 4.13 ± 4.44 mo after HSCT. PE was confirmed by echocardiogram in all patients. Three patients presented with severe PE with cardiac tamponade and required urgent pericardiocentesis. Overall survival (OS) rates for patients who developed PE were 83.3% and 38.9% at 100 d and 3 y, respectively, after HSCT. Death was not directly attributable to PE in patients who died in the first year after HSCT. Multivariable analysis identified the following variables to be associated with OS: PE (relative risk[RR]: 3.70; 95% confidence interval [95% CI]: 1.89-7.23; P < 0.001), active disease at HSCT (RR: 1.59; 95% CI: 1.02-2.49; P < 0.001), and thalassemia (RR: 0.62; 95% CI: 0.45-0.84; P < 0.001). PE is, thus, a debilitating and significant complication of pediatric HSCT. Therefore, prospective studies are required for better determination of the etiology and optimal method of PE treatment after HSCT.

The gastrointestinal tract contains the largest lymphoid organ to react with pathogenic microorganisms and suppress excess inflammation. Patients with primary immunodeficiency diseases (PIDs) can suffer from refractory diarrhea. In this study, we present two siblings who began to suffer from refractory diarrhea with a poor response to aggressive antibiotic and immunosuppressive treatment after surgical release of neonatal intestinal obstruction. Their lymphocyte proliferation was low, but superoxide production and IL-10 signaling were normal. Candidate genetic approach targeted to genes involved in PIDs with inflammatory bowel disease (IBD)-like manifestation was unrevealing. Whole-genome sequencing revealed novel heterozygous mutations Glu75Lys and nucleotide 520–521 CT deletion in the tetratricopeptide repeat domain 7A (TTC7A) gene. A Medline search identified 49 patients with TTC7A mutations, of whom 20 survived. Their phenotypes included both multiple intestinal atresia (MIA) and combined T and/or B immunodeficiency (CID) in 16, both IBD and CID in 14, isolated MIA in 8, MIA, IBD, and CID complex in 8, and isolated IBD in 3. Of these 98 mutant alleles over-through the coding region clustering on exon 2 (40 alleles), exon 7 (12 alleles), and exon 20 (10 alleles), 2 common hotspot mutations were c.211 G>A (p.E71K in exon 2) in 26 alleles and AAGT deletion in exon 7 (+3) in 10 alleles. Kaplan–Meier analysis showed that those with biallelic missense mutations (p = 0.0168), unaffected tetratricopeptide repeat domains (p = 0.0311), and developing autoimmune disorders (p = 0.001) had a relatively better prognosis. Hematopoietic stem cell transplantation (HSCT) restored immunity and seemed to decrease the frequency of infections; however, refractory diarrhea persisted. Clinical improvement was reported upon intestinal and liver transplantation in a child with CID and MIA of unknown genetic etiology. In conclusion, patients with TTC7A mutations presenting with the very early onset of refractory diarrhea had limit improvement by HSCT or/and tailored immunosuppressive therapy in the absence of suitable intestine donors. We suggest that MIA–CID–IBD disorder caused by TTC7A mutations should also be included in the PID classification of “immunodeficiencies affecting cellular and humoral immunity” to allow for prompt recognition and optimal treatment.

Wilms tumor is the most common primary renal malignancy occurring in childhood. Significant improvement has been made in the treatment of children with Wilms tumor. However, the treatment of patients with non-Wilms renal tumors remains challenging. Methods: Between 1991 and 2010, 70 children with renal tumors were diagnosed at a single institution. Fifty-four patients were histologically confirmed and divided into three groups, including 42 Wilms tumors, seven clear cell sarcomas of kidney, and five malignant rhabdoid tumors. Most patients underwent unilateral nephrectomy and lymph node sampling followed by adjuvant chemotherapy. Twenty-one of these patients subsequently received radiotherapy. Results: During follow-up, 12 patients died of progressive disease and one died of operative mortality. One patient with unilateral pleural metastases subsequently underwent hematopoietic stem cell transplantation. The median survival time of all patients was 88 months. Children under 2 years of age at diagnosis with Wilms tumor or clear cell sarcoma of kidney had an excellent survival rate of 100% compared to the 0% survival rate of MRT. Conclusion: Younger age at diagnosis bore a better prognosis than did older age, whereas a diagnosis of malignant rhabdoid tumor portended a worse prognosis. Younger patients and appropriate treatment may have contributed to the improved prognosis of clear cell sarcoma of kidney.

Delayed platelet engraftment is a well-known complication of umbilical cord blood transplantation (CBT). Megakaryocytes derived from cord blood (CB) in vitro are smaller than megakaryocytes derived from bone marrow (BM) in adults. A small megakaryocyte size might contribute to delayed megakaryocytic maturation. This study included 37 patients undergoing hematopoietic stem cell transplantation (HSCT) at Chang Gung Children's Hospital between July 2011 and June 2013. Blood samples were obtained at different times: preconditioning and post-HSCT days 56 and 97. To test whether platelet activation persists posttransplantation, two commonly used platelet activation marker antibodies, CD62P (P-selectin) and CD42b, were evaluated using whole blood flow cytometry, combining thiazole orange and anti-CD41a staining, to assess reticulated platelets. Serial peripheral blood (PB) samples were obtained posttransplantation from patients undergoing CBT (CBT group; n = 15) and mobilized peripheral blood transplantation (PBT group; n = 22). Platelet activation in the postengraftment samples was considerably higher in the PBT group than the CBT group. Moreover, immature platelet fractions (IPF) were higher in the CBT group. Our results emphasize the role of IPF for dynamic prediction of platelet engraftment in CBT.

Natural human immunity to the mycobacteria group, including Mycobacterium tuberculosis, Bacille Calmette-Guérin (BCG) or nontuberculous mycobacteria (NTM), and/or Salmonella species, relies on the functional IL-12/23-IFN-γ integrity of macrophages (monocyte/dendritic cell) connecting to T lymphocyte/NK cells. Patients with severe forms of primary immunodeficiency diseases (PIDs) have more profound immune defects involving this impaired circuit in patients with severe combined immunodeficiencies (SCID) including complete DiGeorge syndrome, X-linked hyper IgM syndrome (HIGM) (CD40L mutation), CD40 deficiency, immunodeficiency with or without anhidrotic ectodermal dysplasia (NEMO and IKBA mutations), chronic granulomatous disease (CGD) and hyper IgE recurrent infection syndromes (HIES). The patients with severe PIDs have broader diverse infections rather than mycobacterial infections. In contrast, patients with an isolated inborn error of the IL-12/23-IFN-γ pathway are exclusively prone to low-virulence mycobacterial infections and nontyphoid salmonella infections, known as Mendelian susceptibility to the mycobacterial disease (MSMD) phenotype. Restricted defective molecules in the circuit, including IFN-γR1, IFN-γR2, IL-12p40, IL-12R-β1, STAT-1, NEMO, IKBA and the recently discovered CYBB responsible for autophagocytic vacuole and proteolysis, and interferon regulatory factor 8 (IRF8) for dendritic cell immunodeficiency, have been identified in around 60% of patients with the MSMD phenotype. Among all of the patients with PIDs referred for investigation since 1985, we have identified four cases with the specific defect (IFNRG1 for three and IL12RB for one), presenting as both BCG-induced diseases and NTM infections, in addition to some patients with SCID, HIGM, CGD and HIES. Furthermore, manifestations in patients with autoantibodies to IFN-γ (autoAbs-IFN-γ), which is categorized as an anticytokine autoantibody syndrome, can resemble the relatively persistent MSMD phenotype lacking BCG-induced diseases.

Cardiac troponin I (cTnI) is a very specific and sensitive marker of myocardial injury. The degree of myocardial injury associated with transcatheter atrial septal defect (ASD) closure in children is unknown. Methods: In a longitudinal study on children with ASD, cTnI serum concentrations were measured after transcatheter ASD closure. Implantation success, complications, and latest patient follow-up were described. Results: We inserted 73 Amplatzer septal occluders in 73 patients. Of these, we excluded two patients in whom the device embolized to the right ventricle the day after deployment. The median age was 4.5 years (range, 1.1–18.0) with 20 boys and 51 girls (male:female ratio, 1:2.6). The mean ASD size was 17±7 mm, and device size ranged from 7 mm to 38 mm. The Amplatzer size/body surface area ratio was validated by demonstrating positive correlation with cTnI elevation. In children who had a successful attempt, 30 samples had a cTnI value higher than 1.0 μg/L l at 6 hours after procedure. Six patients had a significant release of cTnI greater than normal limits (mean level of 1.51±0.26 μg/L). Conclusion: In our study, transcatheter ASD closure induced minor myocardial lesion, the extent of which depended on the ratio of the occluder size to body surface area (p

Hepatoblastoma is the most common malignant liver tumor in children. Comparative studies have elucidated the optimal pre- or postoperative chemotherapeutic regimens. The aim of this study was to investigate the prognostic significance of baseline tumor characteristics for overall survival and disease-free survival in children with hepatoblastoma. Methods: There were 19 male and 16 female children with a median age of 19 months at diagnosis (range: 1–169 months) in our institution between February 1990 and June 2009. We reviewed the clinical presentation, serum α-fetoprotein level at diagnosis, histological subtype, treatment, and outcomes. Results: Twenty-seven patients (78%) underwent neoadjuvant chemotherapy. The majority of patients subsequently underwent either hemihepatectomy (56%) or bisegmentectomy (16%). Only six patients underwent extended hepatic resection, and one of them required rescue liver transplantation. During follow-up, six patients died of progressive disease and two of perioperative mortality. Four of the six who died had pulmonary metastases at the time of diagnosis or follow-up. The median survival time was 28 months (range: 1–181 months). Five-year overall survival was 67.7% (95% confidence interval: 52.0–87.8%) and disease-free survival was 60.2% (95% confidence interval: 41.9–86.5%). Conclusion: The potential down-staging effect of neoadjuvant chemotherapy on hepatoblastoma might facilitate remission and convert unresectable tumors into operable ones.