Hematopoietic cell transplantation corrects a hematological phenotype of Diamond-Blackfan anemia (DBA). Reduced conditioning has been recommended for patients with the cancer predisposition, but appropriate intensity is required to prevent graft failure. We conducted unrelated-donor bone marrow transplantations in six consecutive transfusion-dependent patients (median age, 5.4 years; range, 1.8–23) after targeted-busulfan (60–75 mg/L×h of cumulative AUC) and fludarabine regimen without irradiation. All obtained chronic graft-versus-host-disease-free complete donor chimerism, including one unrelated cord blood transplantation rescue. The rescued 7-year-old girl had the longest transfusion-dependency (>40 months) and highest ferritin level (>2,000 ng/mL) pretransplant. Intermediate-intensity targeted busulfan-based conditioning may cure DBA.

TitleAplastic crisis in hereditary spherocytosis associated with Kawasaki disease

Introduction: Pulmonary agenesis is a complete absence of the pulmonary parenchyma, bronchi beyond the bifurcation, and pulmonary vasculature unilaterally or bilaterally. Because of the rare occurrence, its pathophysiology and outcome remain elusive. We evaluate the clinical features and risk factors for mortality due to pulmonary agenesis. Methods: Two patients we experienced are presented as index cases. All reported cases of pulmonary agenesis were collected from online and publication databases between 1955 and 2020. We assessed the impact of comorbidity and intervention on the survival outcome. Results: We identified 230 patients—138 (60%) with right-sided, and 14 (6%) with bilateral agenesis—among 164 articles and our cases. There were 93 (40%) cardiovascular, 70 (30%) skeletal, and 48 (21%) gastrointestinal anomalies; 47 (20%) tracheal stenoses; and 33 (14%) genitourinary anomalies. Fifty-two (23%) patients had isolated pulmonary agenesis. The 2-year overall survival (OS) rate was 66% and there was no subsequent death until 13 years of age. The right agenesis was significantly associated with a lower 2-year OS rate (58% vs. 78%, p=0.019) or more frequent tracheal stenosis (28% vs. 12%, p=0.006) than left-sided disease. A multivariable analysis indicated that tracheal stenosis (hazard ratio [HR] 2.4, 95% confidence interval [CI] 1.5-4.1, p=0.004) and gastrointestinal anomaly (HR 1.9, 95% CI 1.1-3.3, p=0.018) were prognostic factors for mortality. Conclusions: The poor prognostic factors were tracheal stenosis, right agenesis and gastrointestinal anomaly. Tracheal and gastrointestinal controls are targeted at birth and in infancy for the improved survival of unilateral pulmonary agenesis.

Title

Cytotoxic agents are the major part of current therapeutic arsenal in pediatric oncology. Recently, small molecules have been combined in the standard regimen for targeted cancer therapy. Both drugs provoke adverse effects on the living cells via the specific and non-specific actions to neoplastic cells. Considering genetic and epigenetic events, the late effect rather than acute toxicity is a matter of concern for healthy subjects at risk of exposure to anticancer drugs. To reduce the risk, a list of hazardous drugs (HDs) has been updated by the National Institute for Occupational Safety and Health (NIOSH) including commonly used cytotoxic agents. HDs are defined by their association with genotoxicity, carcinogenicity, teratogenicity, impaired fertility, reproductive toxicity, and/or serious organ toxicity even at a lower dose.1 The American Society of Clinical Oncology (ASCO) standard promotes the safety of professional staff of pharmacists, physicians, nurses, and other collaborators in oncology care.2 It recommends the preventive measures to avoid the toxic products, incorporating the latest evidence of the deleterious late effects after exposure, and the benefits of control measures, along with expert consensus. United States Pharmacopeia Chapter <800> requires an appropriate list of HDs in healthcare settings, providing concrete information regarding the articles of personal protective equipment, as well as where and how they should be donned, used, and removed is prescribed.3Several guidelines for the occupational exposure to HDs have been established for the health of hospital workers,1-5 but not the family members of childhood cancer. We thus investigated the exposure of caregiver and medical staff to anticancer drugs and the environmental contamination. Fifteen inpatients with pediatric cancer were recruited who received high-dose cyclophosphamide (CPM) from 2017 to 2018. Seven infants and 8 adolescents had 4 leukemias and 11 solid tumors. The median age at the time of this study was 78 months ranging from 13 to 200 months. The infants and adolescents received CPM of 1g /m2 or more; median 640 (range 620~1300) mg, and 1230 (range 780~1230) mg, respectively. Six hours after the first administration, the concentration of CPM was measured in the urine and saliva from attending mothers, nurses, doctors, nursery teachers, child-life specialists, and housekeeping staff members in the ward, using the liquid chromatography/mass spectrometry method (Shionogi Analysis Centre Co., Ltd., Osaka, Japan)6. Safe handling and closed-system-drug-transfer devices (JMS Co. Ltd., Hiroshima, Japan) are the standard of our center to minimize the technical exposure.7 This study was approved by the institutional review board of Kyushu University. Five of 7 (71%) infant’s and 2 of 8 (25%) adolescent’s mothers showed increased urine levels of CPM. The median value of infant’s mothers (192 ng/10 mL, range 0~1,510) was significantly higher than that of adolescent’s mothers (0 ng/10 mL, 0~58.4) (p =0.005). CPM was detected in the saliva samples of two mothers caring infants, but not in the urine or saliva of any medical staff (Figure ). The environmental contamination in a room of the infant whose mother showed the highest concentrations was assessed by the modified method.6 High levels of CPM were determined in the monitoring samples from a 17-year-old boy; toilet floor (1020 times of the detection limit), toilet seat (167 times), wash basin (45.6 times), a 13-year-boy; underwear (735 times) bed sheets (224 times), bed fence (34.8 times), bedside floor (20.9 times), exhaust vent (13.1 times), bedside table (7.4 times), door knob (4.9 times), curtain (4.7 times), and a 2-year-boy; bathing hot water (205 times) at 24 hours after the first administration, respectively. No staff having detectable CPM levels represented the control of HDs exposure in our hospital. In contrast, the exposure was frequently found in attending mothers caring infants. The higher levels of CPM in infants’ mothers than in adolescents’ mothers are explained by the closer contact for care. The environmental contamination has occurred from the body fluid of patients but not the drug delivery.The latest systems and guidelines have effectively controlled the accidental exposures of drugs to medical staff, as shown in the present results, throughout the process from the formulation in the pharmacy department, transportation, and administration to bed-side patients. The mother’s exposure is categorized as an intermediate risk. It may occur in case of high-dose therapy with limited duration. However, the metabolites of CPM including 4-hydroxycyclophosphamide show cytotoxicity.9 The mixture of selected cytostatic drugs has an augmented cytotoxicity leading to the late effects on genome even at low concentrations.10 During the long-term intense chemotherapy for pediatric cancer, the preliminary results may raise the need for preventive measures for caregivers according to the equivalent levels to medical staffs.

Background: Severe asthma exacerbation is an important comorbidity of the 2009 HIN1 pandemic [A(H1N1)pdm09] in asthmatic patients. However, the mechanisms underlying severe asthma exacerbation remain unknown. In this study, airway hyperresponsiveness (AHR) was measured in paediatric asthma patients infected with A(H1N1)pdm09. We also evaluated AHR in asthmatic mice with A(H1N1)pdm09 infection and those with seasonal influenza for comparison. Methods: AHRs in asthmatic children were defined as the provocative acetylcholine concentration causing a 20% reduction in FEV1.0 (PC20). To investigate the pathophysiology using animal models, BALB/c mice aged 6-8 weeks were sensitized and challenged with ovalbumin. Either mouse-adapted A(H1N1)pdm09, seasonal H1N1 virus (1×105 pfu/20 μL), or mock treatment as a control was administered intranasally. At 3, 7, and 10 days after infection, each group of mice was evaluated for AHR by methacholine challenge using an animal ventilator, flexiVent®. Lung samples were resected and observed using light microscopy to assess the degree of airway inflammation. Results: AHRs in the children with bronchial asthma were temporarily increased, and alleviated by 3 months after discharge. AHR was significantly enhanced in A(H1N1)pdm09-infected asthmatic mice compared to that in seasonal H1N1-infected mice (p<0.001), peaking at 7 days post-infection and then becoming similar to control levels by 10 days post-infection. Histopathological examination of lung tissues showed more intense infiltration of inflammatory cells and severe tissue destruction in A(H1N1)pdm09-infected mice at 7 days post-infection than at 10 days post-infection. Conclusions: Our results suggest that enhanced AHR could contribute to severe exacerbation in human asthmatic patients with A(H1N1)pdm09 infection.

Background: Food protein-induced enterocolitis syndrome (FPIES) is a non-IgE cell-mediated food allergy characterized by repetitive vomiting and other gastrointestinal symptoms. Although little is known about FPIES pathophysiology, some cytokines have been reported to be involved. Since one of the main symptoms is vomiting, which is common to other diseases, it is difficult to distinguish acute FPIES from other conditions such as infectious enterocolitis. Thus, specific biomarkers are required for differential diagnosis. We aimed to identify potential biomarkers distinguishing acute FPIES from infectious enterocolitis and IgE-mediated anaphylaxis, which also cause vomiting. Methods: Seven patients with acute FPIES, nine with IgE-mediated anaphylaxis, and six with infectious enterocolitis were enrolled. The serum concentrations of interleukins (IL)-2, -4, -6, -8, -10, interferon-γ, and tumor necrosis factor-α were measured and compared among the three groups of patients. The serum concentrations of IL-2 and IL-10 were also compared between the symptomatic and asymptomatic stages. Alterations in serum cytokine levels were evaluated in acute FPIES during an oral food challenge test. Results: Serum IL-2 and IL-10 levels were significantly higher in acute FPIES patients than in patients with infectious enterocolitis and IgE-mediated anaphylaxis, whereas no significant differences were detectable in the serum levels of the other cytokines. The IL-2 and IL-10 elevation was only observed in the symptomatic stage of acute FPIES. Conclusion: The elevation in serum levels of IL-2 and IL-10 was specifically observed in symptomatic acute FPIES cases, suggesting that the measurement of IL-2 and IL-10 could be employed for differential diagnosis.

Background: Severe asthma exacerbation is an important comorbidity of the 2009 HIN1 pandemic [A(H1N1)pdm09] in asthmatic patients. However, the mechanisms underlying severe asthma exacerbation remain unknown. Using a mouse model of asthma, we evaluated airway hyperresponsiveness (AHR) in mice with A(H1N1)pdm09 infection and those with seasonal influenza for comparison. We also measured AHR in paediatric participants infected with A(H1N1)pdm09. Methods: BALB/c mice aged 6-8 weeks were sensitized and challenged with ovalbumin. Either mouse-adapted A(H1N1)pdm09, seasonal H1N1 virus (1×105 pfu/20 μL), or mock treatment as a control was administered intranasally. At 3, 7, and 10 days after infection, each group of mice was evaluated for AHR by methacholine challenge using an animal ventilator, flexiVent®. Lung samples were resected and observed using light microscopy to assess the degree of airway inflammation. AHRs in paediatric participants were defined as the provocative acetylcholine concentration causing a 20% reduction in FEV1.0 (PC20). Results: Airway resistance was significantly enhanced in A(H1N1)pdm09-infected asthmatic mice compared to that in seasonal H1N1-infected mice (p<0.001), peaking at 7 days post-infection and then becoming similar to control levels by 10 days post-infection. Histopathological examination of lung tissues showed more intense infiltration of inflammatory cells and severe tissue destruction in A(H1N1)pdm09-infected mice at 7 days post-infection than at 10 days post-infection. AHRs in the paediatric participants were temporarily increased, and alleviated by 3 months after discharge. Conclusions: Our results suggest that enhanced AHR could contribute to severe exacerbation in human asthmatic patients with A(H1N1)pdm09 infection.