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).