2 PATIENTS AND METHODS
The present, retrospective, cohort study was performed using data from the medical records of patients who received the diagnosis of neuroblastoma between January 2003 and December 2018 at Tokyo Metropolitan Children’s Medical Center (TMCMC) or Nagoya University Hospital (NUH). The study was conducted in accordance with the Helsinki Declaration of the World Medical Association and Ethics Review Procedures concerning Research with Human Subjects. The protocol was approved by the Ethics Committee of TMCMC. The requirement for informed consent was waived because the data were anonymized and the study was retrospective. All the data were subject to a strict privacy protection policy with an opt-out clause.
Patients were enrolled if they had newly diagnosed, histologically-proven, International Neuroblastoma Staging System (INSS) stage 3 or 4 neuroblastoma4 and no history of previous anti-tumor treatment. Intermediate risk and high risk were defined in accordance with the International Neuroblastoma Risk Group Classification System.5 MYCN amplification was determined by fluorescence in situ hybridization.6Fever preceding induction therapy was defined as a single temperature reading equal to or higher than 38.0 degrees Celsius during the first week preceding induction therapy. The outcome was ARE concomitant with severe hypoxia between the first and 14th days of the initial induction chemotherapy. Severe hypoxia was defined as grade 3 or higher according to CTCAE v4.0 or decreased oxygen saturation at rest (e.g., pulse oximeter < 88% or PaO2 ≤ 55 mmHg). The definition of the Pediatric Acute Lung Injury Consensus Conference7 was applied to confirm the diagnosis of pediatric ARDS. Patients with hypoxia caused by the comorbidities of pneumonia and bacteremia, which were respectively diagnosed by chest computed tomography scanning and blood culture, were excluded. Clinical data, including laboratory data, such as the lactate dehydrogenase (LDH) value, were extracted from the electronic medical records. The Japanese Ministry of Health, Labour and Welfare’s old DIC diagnostic criteria, which includes underlying diseases, clinical symptoms, platelet count, fibrin-related markers, fibrinogen, and prothrombin time (PT) ratio, were used to derive the disseminated intravascular coagulation (DIC) score.8 All data used were derived from hospitalized patients. Continuous variables were expressed as the median and interquartile range (IQR). Discrete variables were expressed as a frequency and percentage. Logistic regression analysis was used to screen for predictive factors of ARE. For each significant variable, an odds ratio (OR) with a corresponding 95% confidence interval (95% CI) and P value were computed. P < 0.05 was considered to indicate statistical significance. The discriminatory power of the model was assessed using the receiver-operating characteristic (ROC) curve and the area under the curve (AUC). An AUC of 0.5 indicated no discrimination, 0.7 to 0.8 was considered acceptable, 0.8 to 0.9 was considered excellent, and more than 0.9 was considered outstanding. All the data were analyzed using Stata, version 16.0 (StataCorp LLC).