Impact of the COVID-19 pandemic on the demographic and disease burden of pediatric malignant solid tumors in China: a single-center, cross-sectional study.

Background: With the development of the novel coronavirus disease 2019 (COVID-19), China implemented measures in an attempt to control the infection rate. We conducted a single-center, cross-sectional study to ascertain the impact of the COVID-19 pandemic on the equitable availability of medical resources for children diagnosed with malignant solid tumors in China. Methods: Data on the demographics, clinical characteristics, and medical expenses of 876 patients diagnosed with neuroblastoma, rhabdomyosarcoma (RMS), Wilms tumor, hepatoblastoma (HB), Ewing sarcoma (ES), and central nervous system (CNS) tumors from 2019 to 2021, during the COVID-19 pandemic, were retrospectively collected from the National Center for Children's Health. The Pearson χ2 test and Mann-Whitney test were performed to analyze the differences among variables. Results: Except for the regional origin of children with tumors during the epidemic, no significant differences were found in the demographic or clinical characteristics of patients at initial diagnosis. The number of patients from northern China and northeastern China who attended Beijing Children's Hospital (BCH) increased after the outbreak of COVID-19 (P=0.001). There was no significant alteration observed in the frequency of hospitalizations per individual per annum (P=0.641) or the mean expense incurred per individual per hospitalization (P=0.361). In addition, the medical insurance coverage rate of real-time settlement increased year by year. Conclusions: After the COVID-19 outbreak, the origin of patients with solid tumor who visited BCH was concentrated in the northern region of China. COVID-19 had no impact on the other demographic factors, clinical characteristics, or economic burden of patients with pediatric malignant solid tumors.

Hepatoblastoma with neonatal necrotizing enterocolitis: Two case reports.

We report two children with hepatoblastoma (HB) with a history of neonatal necrotizing enterocolitis (NEC). Case 1 was diagnosed with HB at 5 months of age. Liver enlargement was found during the NEC operation at 3 months of age and then was clinically diagnosed by imaging. After six chemotherapy courses, a partial hepatectomy was performed. Three months after ceasing the chemotherapy, a chest computed tomography scan suggested that distant metastasis of the tumor should be considered, and the lesion was removed. However, 9 months after the operation, alpha-fetoprotein concentrations were increased, and abdominal imaging showed a recurrence of the tumor in situ, resulting in a hepatectomy. Case 2 was diagnosed with NEC shortly after birth and underwent an intestinal resection and anastomosis 1 month later. He was diagnosed with HB at 3 years of age. Hepatectomy was performed after five courses of chemotherapy. Chemotherapy was stopped after 10 courses, and alpha-fetoprotein concentrations were normal. At present, both children have survived and are in a healthy condition. Physicians should be aware of the possibility of HB and a history of NEC in children. Premature birth and low birth weight are common factors leading to the pathogenesis of HB and NEC. The association between these two diseases requires further study.

BPTF in bone marrow provides a potential progression biomarker regulated by TFAP4 through the PI3K/AKT pathway in neuroblastoma.

BACKGROUND: Neuroblastoma (NB) is the most common extracranial malignant solid tumor in children, which is highly prone to bone marrow (BM) metastasis. BM can monitor early signs of mild disease and metastasis. Existing biomarkers are insufficient for the diagnosis and treatment of NB. Bromodomain PHD finger transcription factor (BPTF) is an important subunit of the chromatin-remodeling complex that is closely associated with tumors. Here, we evaluated whether BPTF in BM plays an important role in predicting NB progression, and explore the molecular mechanism of BPTF in NB. METHODS: The clinical relevance of the BPTF was predicted in the GEO (GSE62564) and TARGET database. The biological function of BPTF in NB was investigated by constructing cell lines and employing BPTF inhibitor AU1. Western blot was used to determine the changes of BPTF, TFAP4, PI3K/AKT signaling and Epithelial-mesenchymal transition (EMT) related markers. A total of 109 children with newly diagnosed NB in Beijing Children's Hospital from January 2018 to March 2021 were included in this study. RT-PCR was used to measure the BPTF and TFAP4 expression in BM. The cut-off level was set at the median value of BPTF expression levels. RESULTS: Databases suggested that BPTF expression was higher in NB and was significantly associated with stage and grade. Proliferation and migration of NB cells were slowed down when BPTF was silenced. Mechanistically, TFAP4 could positively regulate BPTF and promotes EMT process through activating the PI3K/AKT signaling pathway. Moreover, detection of the newly diagnosed BM specimens showed that BPTF expression was significantly higher in high-risk group, stage IV group and BM metastasis group. Children with high BPTF at initial diagnosis were considered to have high risk for disease progression and recurrence. BPTF is an independent risk factor for predicting NB progression. CONCLUSIONS: A novel and convenient BPTF-targeted humoral detection that can prompt minimal residual and predict NB progression in the early stages of the disease were identified. BPTF inhibitor AU1 is expected to become a new targeted drug for NB therapy. It's also reveal previously unknown mechanisms of BPTF in NB cell proliferation and metastasis through TFAP4 and PI3K/AKT pathways.

Nectin2 influences cell apoptosis by regulating ANXA2 expression in neuroblastoma.

Neuroblastoma (NB) is a pediatric cancer of the peripheral sympathetic nervous system and represents the most frequent solid malignancy in infants. Nectin2 belongs to the immunoglobulin superfamily and has been shown to play a role in tumorigenesis. In the current study, we demonstrate that serum Nectin2 level is increased in NB patients compared with that in healthy controls and Nectin2 level is correlated with neuroblastoma international neuroblastoma staging system (INSS) classification. There is a positive correlation between Nectin2 level and shorter overall survival in NB patients. Knockdown of Nectin2 reduces the migration of SH-SY5Y and SK-N-BE2 cells and induces their apoptosis and cell cycle arrest. RNA-seq analysis demonstrates that Nectin2 knockdown affects the expressions of 258 genes, including 240 that are upregulated and 18 that are downregulated compared with negative controls. qRT-PCR and western blot analysis confirm that ANXA2 expression is decreased in Nectin2-knockdown SH-SY5Y cells, consistent with the RNA-seq results. ANXA2 overexpression rescues the percentage of apoptotic NB cells induced by Nectin2 knockdown and compensates for the impact of Nectin2 knockdown on cleaved caspase3 and bax expressions. In addition, western blot analysis results show that ANXA2 overexpression rescues the effect of Nectin2 knockdown on MMP2 and MMP9 expressions. The current data highlight the importance of Nectin2 in NB progression and the potential of Nectin2 as a novel candidate target for gene therapy.

Quantitative proteomics identifies and validates urinary biomarkers of rhabdomyosarcoma in children.

BACKGROUND: Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma with poor prognosis in children. The 5-year survival rate for early RMS has improved, whereas it remains unsatisfactory for advanced patients. Urine can rapidly reflect changes in the body and identify low-abundance proteins. Early screening of tumor markers through urine in RMS allows for earlier treatment, which is associated with better outcomes. METHODS: RMS patients under 18 years old, including those newly diagnosed and after surgery, were enrolled. Urine samples were collected at the time points of admission and after four cycles of chemotherapy during follow-up. Then, a two-stage workflow was established. (1) In the discovery stage, differential proteins (DPs) were initially identified in 43 RMS patients and 12 healthy controls (HCs) using a data-independent acquisition method. (2) In the verification stage, DPs were further verified as biomarkers in 54 RMS patients and 25 HCs using parallel reaction monitoring analysis. Furthermore, a receiver operating characteristic (ROC) curve was used to construct the protein panels for the diagnosis of RMS. Gene Ontology (GO) and Ingenuity Pathway Analysis (IPA) software were used to perform bioinformatics analysis. RESULTS: A total of 251 proteins were significantly altered in the discovery stage, most of which were enriched in the head, neck and urogenital tract, consistent with the most common sites of RMS. The most overrepresented biological processes from GO analysis included immunity, inflammation, tumor invasion and neuronal damage. Pathways engaging the identified proteins revealed 33 common pathways, including WNT/ß-catenin signaling and PI3K/AKT signaling. Finally, 39 proteins were confirmed as urinary biomarkers for RMS, and a diagnostic panel composed of 5 candidate proteins (EPS8L2, SPARC, HLA-DRB1, ACAN, and CILP) was constructed for the early screening of RMS (AUC: 0.79, 95%CI = 0.66 ~ 0.92). CONCLUSIONS: These findings provide novel biomarkers in urine that are easy to translate into clinical diagnosis of RMS and illustrate the value of global and targeted urine proteomics to identify and qualify candidate biomarkers for noninvasive molecular diagnosis.

Chromosome 10 abnormality predicts prognosis of neuroblastoma patients with bone marrow metastasis.

BACKGROUND: Neuroblastoma (NB) is the most common extracranial solid tumor in children. It is known for high heterogeneity and concealed onset. In recent years, the mechanism of its occurrence and development has been gradually revealed. The purpose of this study is to summarize the clinical characteristics of children with NB and abnormal chromosome 10, and to investigate the relationship between the number and structure of chromosome 10 abnormalities and NB prognosis. METHODS: Chromosome G-banding was used at the time of diagnosis to evaluate the genetics of chromosomes in patients with NB and track their clinical characteristics and prognosis. All participants were diagnosed with NB in the Medical Oncology Department of the Beijing Children's Hospital from May 2015 to December 2018 and were followed up with for at least 1 year. RESULTS: Of all 150 patients with bone marrow metastases, 42 were clearly diagnosed with chromosomal abnormalities. Thirteen patients showed abnormalities in chromosome 10, and chromosome 10 was the most commonly missing chromosome. These 13 patients had higher LDH and lower OS and EFS than children with chromosomal abnormalities who did not have an abnormality in chromosome 10. Eight patients had both MYCN amplification and 1p36 deletion. Two patients had optic nerve damage and no vision, and one patient had left supraorbital metastases 5 months after treatment. CONCLUSIONS: The results indicated that chromosome 10 might be a new prognostic marker for NB. MYCN amplification and 1p36 deletion may be related to chromosome 10 abnormalities in NB. Additionally, NB patients with abnormal chromosome 10 were prone to orbital metastases.

The development and initial evaluation of referral flowchart for suspected neuroblastoma for pediatricians in nononcology clinics in China.

BACKGROUND: The delayed diagnosis of neuroblastoma (NB) is common in China, which results in the prognosis of NB in China lagging behind that in developed countries. METHODS: A referral flowchart for suspected NB was implemented in nononcology clinics at Beijing Children's Hospital (BCH). Patients with symptoms of suspected NB were referred from nononcology clinics in BCH to oncology clinics and confirmed NB cases were regarded as referral group. The control group comprised patients initially diagnosed with NB who came directly to oncology clinics in BCH from other regions nationwide. The age at NB diagnosis was compared as primary outcome, and the 5-year overall survival (OS) and event-free survival (EFS) were compared via the Kaplan-Meier method and log-rank tests. RESULTS: In total, 3337 children with suspected NB were screened consecutively from 687 070 pediatric patients. Through examination of urine vanillylmandelic acid and homovanillic acid, or B-ultrasound, 102 of 3337 patients were referred to oncologists for comprehensive evaluations. Eventually, 29 referred patients were diagnosed as NB and the hospital-based diagnosis rate of NB was 4.2 per 100 000 visits. The median age at diagnosis in the referral group was 21.0 months, which was 9 months earlier than that of the control group (30.0 months, P = .026). The 5-year OS rate was 72.4% in the referral group, which was higher than that of the control group (66.7%) but without statistical significance (P = .664). CONCLUSION: Delayed NB detection could be avoided by training pediatricians in nononcology clinics to detect suspected NB and refer these patients to oncologists.

Economic burden for retinoblastoma patients in China.

BACKGROUND: Although retinoblastoma (Rb) is considered to have a good prognosis, economical stress is still a huge problem for patients' families. Besides, doctors, the government, and social foundation staff do not precisely know how much is truly required for complete Rb therapy, especially the non-medical costs and indirect costs. This study was conducted to estimate the economic burden of Rb patients. METHODS: This was a retrospective study. Fifty Rb patients were finally enrolled in the study. The questionnaire survey was conducted with surviving Rb patient' main family caregivers to collect the information on costs during illness through the phone. Costs included direct and indirect cost; direct costs included medical and non-medical costs. Medical costs include drug costs, surgery costs, treatment fees, lab tests, non-lab tests costs, and medical consumptive stuff costs (including hospital expenses and outpatient fees). RESULTS: The total direct cost was $27,814.62 ± 15,137.73, and the average medical cost was $15,034.48 ± 8,224.19 ($3,963.99-36,826.53). The total non-medical expenses averaged $12,252.93 ± 9,872.64 ($728.86-48,104.95). The average reduced working time was 11.50 ± 8.06 months, and the average lost income was $13,512.23 ± 11,545.83. Among the non-medical expenses, the average non-medical expenses for children in Beijing and surrounding areas was $6,557.68 ± 6,385.42, and the average non-medical expenses for children in other provinces and was $14,502.29 ± 10,484.86, t-test p-value = 0.011. The average transportation cost for children in Beijing and surrounding areas (Hebei, Tianjin) was $1,871.09 ± 1,428.91, other provinces was $4,909.62 ± 3,697.02. Of children in Beijing and surrounding areas the average accommodation fee was $2,788.42 ± 3,065.00, in other provinces it was $6,599.27 ± 3,065.00. CONCLUSION: Children with Rb have a heavy economic burden. Direct non-medical expenses are higher. Getting medical treatment nearby can help reduce the economic burden of the disease. Besides, work-related issues are also a major financial problem for families with Rb, and the government should properly provide economic subsidies. Simplifying the national health insurance process and purchasing commercial supplementary medical insurance will increase the family's ability to afford the cost of cancer treatment.

Analysis of treatment cost for neuroblastoma to the family: a single-center cross-sectional study in China.

BACKGROUND: Neuroblastoma (NB) is notorious in childhood cancer because of its high incidence and poor prognosis. The Children's Oncology Group reported that the 3-year OS in the high-risk (HR) group is 50%, and the HR-NB with bone marrow metastasis in our center is 43.1%. Thousands of families in China suffer from the cost of NB, but the true costs of therapy are unknown; to date, no study has ever performed a detailed therapy costs analysis for NB. The objective of this study was to assess the economic burden of NB treatment in children to the family, to ultimately reduce related expenses for patients and promote the establishment of NB management policy. MATERIALS AND METHODS: Data in this cross-sectional study were collected via questionnaires completed by parents at the outpatient clinic and was verified via a computer system. Therapy costs of children with NB of differing risks were analyzed through descriptive statistics (1 CNY ≈ 0.1412 USD). RESULTS: Median direct medical costs of low risk (LR), middle risk (MR), and HR NB during treatment were 180.0 (120.0, 300.0), 200.0 (166.0, 300.0), and 650.0 (415.5, 850.0) thousand Chinese yuan (CNY), respectively. Direct non-medical costs including transportation, food, and accommodation were 60.0 (37.0, 100.0), 80.0 (60.0, 120.0), and 100.0 (80.0, 157.5) thousand CNY in the LR, MR, and HR groups, respectively. Additionally, parents accrued work absences to attend treatment, and lost a total of 100.0 (50.0, 150.0) thousand CNY in indirect costs. LIMITATIONS: Families whose children had relapsed or died were excluded from this analysis and therefore limited the conclusions drawn. Parents were asked to recall costs since initial diagnosis (1-6 years in the past), but this extended time period may have introduced recall bias. CONCLUSIONS: Direct non-medical and indirect costs play an important role in the total treatment costs of NB. Children with NB treated in local hospitals and followed up in hospital specialized in childhood oncology may save many unnecessary expenses. China's healthcare system should establish mechanisms and provide financial support for children with NB.

Increased plasma concentration of cell-free DNA precedes disease recurrence in children with high-risk neuroblastoma.

BACKGROUND: Neuroblastoma is the most common extracranial solid tumor of childhood. The high rate of recurrence is associated with a low survival rate for patients with high-risk neuroblastoma. There is thus an urgent need to identify effective predictive biomarkers of disease recurrence. METHODS: A total of 116 patients with high-risk neuroblastoma were recruited at Beijing Children's Hospital between February 2015 and December 2017. All patients received multidisciplinary treatment, were evaluated for the therapeutic response, and then initiated on maintenance treatment. Blood samples were collected at the beginning of maintenance treatment, every 3 months thereafter, and at the time of disease recurrence. Plasma levels of cell-free DNA (cfDNA) were quantified by qPCR. Receiver operating characteristic (ROC) curve analysis was performed to evaluate the ability of plasma cfDNA concentration to predict recurrence. RESULTS: Of the 116 patients, 36 (31.0%) developed recurrence during maintenance treatment. The median time to recurrence was 19.00, 9.00, and 8.00 months for patients who had achieved complete response (n = 6), partial response (n = 25), and stable disease (n = 5), respectively, after multidisciplinary treatment. The median plasma cfDNA concentration at the time of recurrence was significantly higher than the concentration in recurrence-free patients throughout maintenance treatment (29.34 ng/mL vs 10.32 ng/mL). Patients recorded a plasma cfDNA level ≥ 29 ng/mL an average of 0.55 months before diagnosis of disease recurrence. ROC analysis of the power of plasma cfDNA to distinguish between patients with or without recurrence yielded an area under the curve of 0.825, with optimal sensitivity and specificity of 80.6 and 71.3%, respectively, at a cfDNA level of 12.93 ng/mL. CONCLUSIONS: High plasma cfDNA concentration is a potential molecular marker to signal disease recurrence in patients with high-risk neuroblastoma.

CD56-chimeric antigen receptor T-cell therapy for refractory/recurrent rhabdomyosarcoma: A 3.5-year follow-up case report.

RATIONALE: Rhabdomyosarcoma (RMS) is a common soft tissue sarcoma in children with high malignancy. The prognosis of refractory recurrent RMS is extremely poor, and the 5-year survival rate is less than 20%. PATIENT CONCERNS: We reported a 2-year-old male patient with RMS who underwent 3 operations and 2 recurrences while being treated with regular multidisciplinary therapy. DIAGNOSES: A diagnosis of embryonal rhabdomyosarcoma with primary bladder (IIIa, TNM stage 2, and medium risk group) was made. INTERVENTIONS: After repeated recurrence, the patient was treated with chimeric antigen receptor T (CAR-T) cells, which had a safety mechanism and specifically bound the CD56 antigen in the fourth generation. OUTCOMES: The process of CAR-T cell transfusion was smooth, and there were no significant cytokine release syndrome manifestations after reinfusion. The patient was in complete remission at last follow-up visit after 3.5 years. CONCLUSION: CD56-CAR-T cell therapy is a safe and effective approach and may be an option for children with solid tumors who are nonresponsive to conventional radiotherapy and chemotherapy, or are unsuitable for hematopoietic stem cell transplantation.