Neuroblastoma Risk Research Articles

Genetic variants of m7G modification genes influence neuroblastoma susceptibility

ObjectiveNeuroblastoma is a life-threatening pediatric solid tumor whose etiology remains unclear. N7-methylguanosine (m7G) is one of the most important epigenetic modifications of RNA, which plays a crucial role in tumorigenesis. The m7G-mediated genes METTL1 and WDR4 also have been reported to be dysregulated in various cancers. However, the implications of METTL1 and WDR4 in neuroblastoma have not been clarified. MethodsGiven the oncogenic potential of m7G modification, we performed a case-control study to assess the association of METTL1 and WDR4 genes polymorphisms with neuroblastoma risk in a Chinese population consisting of 402 cases and 473 controls. Odds ratios (ORs) and 95 % confidence intervals (CIs) were applied to evaluate the associations between studied polymorphisms and neuroblastoma risk. The adjusted odds ratio (AOR) was adjusted for age and gender. ResultsOverall, four polymorphisms were significantly associated with neuroblastoma risk, including METTL1 rs2291617 (recessive model: adjusted OR = 1.59, 95 % CI = 1.08–2.34, P = 0.019), WDR4 rs2156316 (dominant model: adjusted OR = 0.74, 95 % CI = 0.57–0.97, P = 0.028), WDR4 rs6586250 (dominant model: adjusted OR = 0.59, 95 % CI = 0.42–0.84, P = 0.004) and WDR4 rs15736 (dominant model: adjusted OR = 0.60, 95 % CI = 0.42–0.85, P = 0.004). Stratified analysis showed stronger correlations between significant polymorphisms and neuroblastoma risk among subgroups divided by age, gender, tumor origin, and clinical stage. Furthermore, expression quantitative trait loci (eQTL) analysis revealed that significant polymorphisms were associated with the expression of the adjacent genes. ConclusionsOur study indicated that four polymorphisms in m7G-mediated genes contribute to neuroblastoma susceptibility in the eastern Chinese population. However, our findings should be verified further by large-scale and well-designed studies.

Perioperative complication incidence and risk factors for retroperitoneal neuroblastoma in children: analysis of 571 patients

BackgroundSurgery plays an important role in the treatment of neuroblastoma. Perioperative complications may impact the course of neuroblastoma treatment. To date, comprehensive analyses of complications and risk factors have been lacking.MethodsPatients with retroperitoneal neuroblastoma undergoing tumor resection were retrospectively analyzed between 2014 and 2021. The data collected included clinical characteristics, operative details, operative complications and postoperative outcomes. Risk factors for perioperative complications of retroperitoneal neuroblastoma were analyzed.ResultsA total of 571 patients were enrolled in this study. Perioperative complications were observed in 255 (44.7%) patients. Lymphatic leakage (28.4%), diarrhea (13.5%), and injury (vascular, nerve and organ; 7.5%) were the most frequent complications. There were three operation-related deaths (0.53%): massive hemorrhage (n = 1), biliary tract perforation (n = 1) and intestinal necrosis (n = 1). The presence of image-defined risk factors (IDRFs) [odds ratio (OR) = 2.09, P < 0.01], high stage of the International Neuroblastoma Risk Group staging system (INRGSS) (OR = 0.454, P = 0.04), retroperitoneal lymph node metastasis (OR = 2.433, P = 0.026), superior mesenteric artery encasement (OR = 3.346, P = 0.003), and inferior mesenteric artery encasement (OR = 2.218, P = 0.019) were identified as independent risk factors for perioperative complications.ConclusionsDespite the high incidence of perioperative complications, the associated mortality rate was quite low. Perioperative complications of retroperitoneal neuroblastoma were associated with IDRFs, INRGSS, retroperitoneal lymph node metastasis and vascular encasement. Patients with high-risk factors should receive more serious attention during surgery but should not discourage the determination to pursue total resection of neuroblastoma.8e95DYrdivwNpNwDkEtfUxVideo (MP4 94289 KB)

Functional TET2 gene polymorphisms increase the risk of neuroblastoma in Chinese children.

The 5-methylcytosine (m5C) is the key chemical modification in RNAs. As one of the demethylases in m5C, TET2 has been shown as a tumor suppressor. However, the impact of TET2 gene polymorphisms on neuroblastoma has not been elucidated. 402 neuroblastoma patients and 473 controls were genotyped for TET2 gene polymorphisms using the TaqMan method. The impact of TET2 gene polymorphisms on neuroblastoma susceptibility was determined using multivariate logistic regression analysis. We also adopted genotype-tissue expression database to explore the impact of TET2 gene polymorphisms on the expression of host and nearby genes. We used the R2 platform and Sangerbox tool to analyze the relationship between gene expression and neuroblastoma risk and prognosis through non-parametric testing and Kaplan-Meier analysis, respectively. We found the TET2 gene polymorphisms (rs10007915 G > C and rs7670522 A > C) and the combined 2-5 risk genotypes can significantly increase neuroblastoma risk. Stratification analysis showed that these significant associations were more prominent in certain subgroups. TET2 rs10007915 G > C and rs7670522 A > C are significantly associated with reduced expression of TET2 mRNA. Moreover, lower expression of TET2 gene is associated with high risk, MYCN amplification, and poor prognosis of neuroblastoma. The rs10007915 G > C and rs7670522 A > C are significantly related to the increased expression of inorganic pyrophosphatase 2 mRNA, and higher expression of PPA2 gene is associated with high risk, MYCN amplification, and poor prognosis of neuroblastomas. In summary, TET2 rs10007915 G > C and rs7670522 A > C significantly confer neuroblastoma susceptibility, and further research is needed to investigate the underlying mechanisms.

RTEL1 gene polymorphisms and neuroblastoma risk in Chinese children

BackgroundNeuroblastoma, a neuroendocrine tumor originating from the sympathetic ganglia, is one of the most common malignancies in childhood. RTEL1 is critical in many fundamental cellular processes, such as DNA replication, DNA damage repair, genomic integrity, and telomere stability. Single nucleotide polymorphisms (SNPs) in the RTEL1 gene have been reported to confer susceptibility to multiple cancers, but their contributing roles in neuroblastoma remain unclear.MethodsWe conducted a study on 402 neuroblastoma cases and 473 controls to assess the association between four RTEL1 SNPs (rs3761124 T>C, rs3848672 T>C, rs3208008 A>C and rs2297441 G>A) and neuroblastoma susceptibility.ResultsOur results show that rs3848672 T>C is significantly associated with an increased risk of neuroblastoma [CC vs. TT/TC: adjusted odds ratio (OR)=1.39, 95% confidence interval (CI)=1.02-1.90, P=0.038]. The stratified analysis further indicated that boy carriers of the rs3848672 CC genotype had a higher risk of neuroblastoma, and all carriers had an increased risk of developing neuroblastoma of mediastinum origin. Moreover, the rs2297441 AA genotype increased neuroblastoma risk in girls and predisposed children to neuroblastoma arising from retroperitoneal.ConclusionOur study indicated that the rs3848672 CC and rs2297441 AA genotypes of the RTEL1 gene are significantly associated with an increased risk of neuroblastoma in Chinese children in a gender- and site-specific manner.

MIR938 rs2505901 T>C polymorphism is associated with increased neuroblastoma risk in Chinese children.

Neuroblastoma (NB) is a kind of childhood cancer that is a prevailing and deadly solid neoplasm among pediatric malignancies. The transcriptional output of MIR938 is capable of participating in the posttranscriptional modulation of gene expression, whereby it exerts its regulatory effect by modulating both the stability and translation of target mRNAs. Previous studies showed that MIR938 was associated with many cancers. Hence, functional genetic variants in the MIR938 can be attributed to NB risk. We recruited 402 neuroblastoma patients and 473 controls from the Children's Hospital of Nanjing Medical University and genotyped one MIR938 single-nucleotide polymorphism (SNP) (rs2505901 T>C). There were significant associations between the rs2505901 T>C and NB risk [CC vs. TT: adjusted odds ratio (OR) = 1.90, 95% confidence interval (CI) = 1.02-3.55, P=0.045; CC vs. TT/TC: adjusted OR = 2.02, 95% CI = 1.09-3.75, P=0.026]. This analysis of genotypes revealed that T>C increased the risk of NB. Some borderline significant different relationships were observed in the stratified analyses: age ≤ 18 months (adjusted OR = 2.95, 95% CI = 0.92-9.51, P=0.070), male sex (adjusted OR = 2.19, 95% CI = 0.95-5.08, P=0.067), and clinical stage III+IV (adjusted OR = 2.12, 95% CI = 0.98-4.56, P=0.055). The present study revealed that the MIR938 rs2505901 T>C polymorphism may be a potential risk factor for neuroblastoma in Chinese children. In the long term, conducting large and diverse sample studies from different ethnicities will indeed be crucial in determining the role of MIR938 polymorphisms in NB risk. By including individuals from various ethnic backgrounds, researchers can account for potential genetic variations that may exist between populations.

Hyperemesis gravidarum and the risk of childhood cancer – A case-control study in Denmark

ObjectiveOnly a few studies have reported on the association between hyperemesis gravidarum and the risk of childhood cancer. We examined possible associations in this population-based study in Denmark. MethodsPediatric cancer cases (n = 6420) were ascertained from the Denmark Cancer Registry among children born between 1977 and 2013. Twenty-five controls were matched to each case by sex and birth date from the Central Person Registry (n = 160500). Mothers with hyperemesis gravidarum were ascertained from the National Patient Register. The risk of childhood cancer was estimated using conditional logistic regression. In a separate analysis, we examined pregnancy prescription of antinauseant medications, ascertained from the National Pharmaceutical Register, to determine associations with childhood cancers. ResultsIn Denmark, hyperemesis gravidarum was associated with an increased risk of childhood cancer [all types combined; Odds Ratio (OR) = 1.43, 95% confidence interval (CI) 1.12, 1.81; n = 73 exposed cases). Hyperemesis gravidarum was also associated with an increased risk of neuroblastoma (OR = 2.52, 95% CI 1.00, 6.36; n = 5 exposed cases), acute lymphoblastic leukemia (OR = 1.63, 95% CI 0.98, 2.72; n = 16 exposed cases), and non-Hodgkin’s lymphoma (OR = 2.41, 95% CI 0.95, 6.08; n = 5 exposed cases). We observed no childhood cancer risk increase from antinauseant prescriptions (OR = 1.05, 95% CI 0.84, 1.30; n = 91 exposed cases). ConclusionOur results are suggestive of an association between hyperemesis gravidarum and the overall cancer risk in offspring, particularly for neuroblastoma. Mothers with hyperemesis gravidarum should be closely monitored and receive appropriate treatment during pregnancy.

Residential proximity to vines and risk of childhood embryonal tumours in France - GEOCAP case-control study, 2006–2013

BackgroundExposure to pesticides has been suggested as a potential risk factor for childhood embryonal tumour. The existing literature has mainly focused on parental occupational exposure and domestic use of pesticides, and is very limited for residential exposures to agricultural pesticides. The study aimed to test the hypothesis of an increased risk of embryonal tumour in children living close to viticultural plots, likely to be subject to frequent pesticide applications. MethodsThe study is part of the French national registry-based GEOCAP program. We included 2761 cases of neuroblastoma, retinoblastoma, Wilms tumour and rhabdomyosarcoma diagnosed before the age of 15 years in the 2006–2013 period, and 40,196 controls representative of the same age population during this period. Indicators of proximity to vines, the presence of vines and viticulture density within 1000 m of the geocoded addresses of residence, were evaluated combining three sources of data on agricultural land use in a geographic information system. We estimated odds ratios (ORs) and 95% confidence intervals (CIs) using unconditional logistic regressions and carried out several sensitivity analyses to test the stability of the results. ResultsApproximately 10% of the controls lived within 1000 m of vines, with regional variations ranging from <1% to 38%. We observed a 5% increase in the risk of neuroblastoma for a 10% increase in viticulture density (OR = 1.05, 95% CI: 0.98–1.13), with a regional heterogeneity. The indicators of proximity to vines were not associated with the other non-CNS embryonal tumours. ConclusionThe study showed a slight increase in the risk of neuroblastoma in children living close to vines, suggesting that residential exposure to agricultural pesticides may be involved in the occurrence of these tumours.

Functionalized GD2 Electrochemical Immunosensor to Diagnose Minimum Residual Disease of Bone Marrow in Neuroblastoma Effectively.

Neuroblastoma (NB) is known as the "king of childhood tumors" due to its highly metastatic, recurrence-prone, and difficult-to-treat characteristics. International Neuroblastoma Risk Grading Group (INRG) has recommended GD2, a disialoganglioside expressed on neuroectodermal tumor cells, as the target for detecting minimal residual disease in bone marrow metastases of high-risk neuroblastoma in children. Therefore, accurately identifying GD2-positive cells is crucial for diagnosing children with high-risk NB. Here, we designed a graphene/AuNP/GD2 Ab-functionalized electrochemical biosensor for GD2 detection. A three-electrode system was processed using a screen-printed technique with a working electrode of indium tin oxide, a counter electrode of carbon, and a reference electrode of silver/silver chloride. Graphene/AuNPs were modified on the indium tin oxide electrode using chronoamperometric scans, and then, the GD2 antibody was modified on the biosensor by electrostatic adsorption to achieve sensitive and specific detection of GD2-positive cells in bone marrow fluid. The results showed that a graphene/AuNP/GD2 Ab-functionalized electrochemical biosensor achieved GD2-positive cell detection in the range of 102 cells/mL~105 cells/mL by differential pulse voltammetry. Bone marrow fluid samples from 12 children with high-risk NB were retained for testing on our biosensor and showed 100% compliance with the clinical application of the gold-standard immunocytochemical staining technique for detecting GD2-positive cells qualitatively. The GD2-based electrochemical assay can accurately detect children with high-risk NB, providing a rapidly quantitative basis for clinical diagnosis and treatment.

Prognostic Value of Metabolic Parameters and Textural Features in Pretreatment 18F-FDG PET/CT of Primary Lesions for Pediatric Patients with Neuroblastoma

Our study evaluated the prognostic value of the metabolic parameters and textural features in pretreatment 18F-Fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) of primary lesions for pediatric patients with neuroblastoma. In total, 107 pediatric patients with neuroblastoma who underwent pretreatment 18F-FDG PET/CT were retrospectively included and analyzed. All patients were diagnosed by pathology, and baseline characteristics and clinical data were collected. The four metabolic parameters and 43 textural features of 18F-FDG PET/CT of the primary lesions were measured. The prognostic significance of metabolic parameters and other clinical variables was assessed using Cox proportional hazards regression models. Differences in progression-free survival (PFS) and overall survival (OS) in relation to parameters were examined using the Kaplan-Meier method. During a median follow-up period of 34.3 months, 45 patients (42.1%) experienced tumor recurrence or progression, and 21 patients (19.6%) died of cancer. In univariate Cox regression analysis, age, location of disease, International Neuroblastoma Risk Group Staging System (INRGSS) stage M, neuron-specific enolase (NSE), lactate dehydrogenase (LDH), four positron emission tomography (PET) metabolic parameters, and 33 textural features were significant predictors of PFS. In multivariate analysis, INRGSS stage M (hazard ratio [HR]=19.940, 95% confidence interval [CI]=2.733-145.491, P=0.003), skewness (＞0.173; PET first-order features; HR=2.938, 95% CI=1.389-6.215, P=0.005), coarseness (＞0.003; neighborhood gray-tone difference matrix; HR=0.253, 95% CI=0.132-0.484, P＜0.001), and variance (＞103.837; CT first-order gray histogram parameters; HR=2.810, 95% CI=1.160-6.807, P=0.022) were independent predictors of PFS. In univariate Cox regression analysis, gender, INRGSS stage M, MYCN amplification, NSE, LDH, two PET metabolic parameters, and five textural features were significant predictors of OS. In multivariate analysis, INRGSS stage M (HR=7.704, 95% CI=1.031-57.576, P=0.047), MYCN amplification (HR=3.011, 95% CI=1.164-7.786, P=0.023), and metabolic tumor volume (＞138.788; HR=3.930, 95% CI=1.317-11.727, P=0.014) were independent predictors of OS. The metabolic parameters and textural features in pretreatment 18F-FDG PET/CT of primary lesions are predictive of survival in pediatric patients with neuroblastoma.

Unraveling the Mystery: Next Generation Sequencing Sheds Light on Neuroblastoma Pathogenesis and Targeted Therapies.

There is considerable interest in the molecular evaluation of solid tumors in pediatric cases. Although clinical trials are in progress for targeted therapies against neuroblastoma (NB), novel therapeutic strategies are needed for high-risk cases that are resistant to therapy. The aim of the present study was to document the specific gene mutations related to targeted therapy in relapsed or refractory NB patients by using next generation sequencing (NGS). The study included 57 NB patients from amongst 1965 neuroblastic cases in Turkey who experienced a recurrence after multi-model therapy. The cases were diagnosed, risk-stratified, and treated according to the classification system from the International Neuroblastoma Risk Group. Single nucleotide variations in 60 genes were investigated using the Pillar Onco/Reveal Multicancer v4 panel and Pillar RNA fusion panel on the Illumina Miniseq platform. ERBB2 I655V was the most frequent mutation and was found in 39.65% of cases. Anaplastic Lymphoma Kinase (ALK) mutations (F1174L, R1275Q, and rare mutations in the tyrosine kinase domain) were detected in 29.3% of cases. Fusion mutations in NTRK1, NTRK3, ROS1, RET, FGFR3, ALK and BRAF were observed in 19.6% of cases. This study presents valuable mutation data for relapsed and refractory NB patients. The high frequency of the ERBB2 I655V mutation may allow further exploration of this mutation as a potential therapeutic target. Rare BRAF mutations may also provide opportunities for targeted therapy. The role of ABL1 mutations in NB should also be explored further.

Image-defined risk factors in localized thoracic neuroblastoma and ganglioneuroma.

The pretreatment International Neuroblastoma Risk Group Staging System (INRGSS) discriminates localized tumors L1/L2 depending on the absence/presence of image-defined risk factors (IDRFs) at diagnosis. Referring to this new staging system, we assessed initial imaging of localized thoracic neuroblastoma (NB) and ganglioneuroma (GN) and the extent of initial tumor resection. Patients with localized thoracic NB/GN from the German clinical trials NB97 and NB2004 were included. Imaging at diagnosis and operative reports were reviewed retrospectively. IDRFs were assessed centrally and correlated to International Neuroblastoma Staging System (INSS) stage and extent of tumor resection. Additionally, we analyzed data on surgery-related complications. Imaging series of 88 patients were available for central review. In 18 children, no IDRF was present, 28 exhibited one IDRF, 42 two or more IDRFs, resulting in 70 patients with L2 disease. The most frequently observed IDRF was encasement of any vessel (n=38). Initial surgical resection was aimed for in 45 patients (L1: n=11; L2: n=34). Complete and gross total resection rates were higher children with L2 NB (n=8/25 L1, n=17/25 L2 vs. n=2/15 L1, n=13/15 L2, respectively). The proportion of surgical complications was very similar between INRGSS L1 and L2 (n=4/11 vs. n=17/34). All complications were manageable, and no surgery-related deaths were observed. In this retrospective cohort, the extent of resection and the rate of surgical complications did not differ substantially between patients classified as L1/L2, indicating that INRGSS L2 does not equate unresectability. It appeared that individual IDRFs differ in value. Larger studies are needed to assess the significance and therapeutic/prognostic impact of such findings.

MiR-100 rs1834306 a > G polymorphism decreases neuroblastoma risk in Chinese children.

Neuroblastoma is a common malignant tumor stemming from the sympathetic nervous system in children, which is often life-threatening. The genetics of neuroblastoma remains unclear. Studies have shown that miRNAs participate in the regulation of a broad spectrum of biological pathways. The abnormity in the miRNA is associated with the risk of various cancers, including neuroblastoma. However, research on the relationship of miRNA polymorphisms with neuroblastoma susceptibility is still in the initial stage. In this research, a retrospective case-control study was conducted to explore whether miR-100 rs1834306 A > G polymorphism is associated with neuroblastoma susceptibility. We enrolled 402 cases and 473 controls for the study. The logistic regression analysis was adopted to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for the association between miR-100 rs1834306 A > G and neuroblastoma risk. Our results elucidated that the miR-100 rs1834306 A > G polymorphism was associated with the decreased risk of neuroblastoma (AG versus AA: adjusted OR = 0.72, 95% CI = 0.53-0.98, and P = 0.038). The subsequent stratified analysis further found that rs1834306 AG/GG genotype reduced the risk of neuroblastoma in the subgroup with tumors of the mediastinum origin (adjusted OR = 0.63, 95% CI = 0.41-0.95, and P = 0.029). In summary, miR-100 rs1834306 A > G polymorphism was shown to associate with decreased neuroblastoma risk in Chinese children, especially for neuroblastoma of mediastinum origin. This conclusion needs to be verified in additional large-size case-control studies.

Persistence of racial and ethnic disparities in risk and survival for patients with neuroblastoma over two decades

BackgroundRacial/ethnic survival disparities in neuroblastoma were first reported more than a decade ago. We sought to investigate if these disparities have persisted with current era therapy. MethodsTwo patient cohorts were identified in the International Neuroblastoma Risk Group Data Commons (INRGdc) (Cohort 1: diagnosed 2001–2009, n = 4359; Cohort 2: diagnosed 2010–2019, n = 4891). Chi-squared tests were used to assess the relationship between race/ethnicity and clinical and biologic features. Survival was estimated by the Kaplan-Meier method. Cox proportional hazards regression analyses were performed to investigate the association between racial/ethnic groups and prognostic markers. ResultsSignificantly higher 5-year event-free survival (EFS) and overall survival (OS) were observed for Cohort 2 compared to Cohort 1 (P < 0.001 and P < 0.001, respectively). Compared to White patients, Black patients in both cohorts had a higher proportion of high-risk disease (Cohort 1: P < 0.001; Cohort 2: P < 0.001) and worse EFS (Cohort 1: P < 0.001; Cohort 2 P < 0.001) and OS (Cohort 1: P < 0.001; Cohort 2: P < 0.001). In Cohort 1, Native Americans also had a higher proportion of high-risk disease (P = 0.03) and inferior EFS/OS. No significant survival disparities were observed for low- or intermediate-risk patients in either cohort or high-risk patients in Cohort 1. Hispanic patients with high-risk disease in Cohort 2 had significantly inferior OS (P = 0.047). Significantly worse OS, but not EFS, (P = 0.006 and P = 0.02, respectively) was also observed among Black and Hispanic patients assigned to receive post-Consolidation dinutuximab on clinical trials (n = 885). ConclusionRacial/ethnic survival disparities have persisted over time and were observed among high-risk patients assigned to receive post-Consolidation dinutuximab.

Correlations between contrast-enhanced CT-measured extracellular volume fraction, histopathological features, and MYCN amplification status in abdominal neuroblastoma: a retrospective study.

To retrospectively investigate the correlations between contrast-enhanced CT (CECT)-measured extracellular volume fraction (fECV) and histopathological features, as well as MYCN amplification status, in abdominal neuroblastoma. One hundred and forty-one patients with abdominal neuroblastoma who underwent CECT scanning were retrospectively enrolled. Calculation of fECV involved the measurement of CT values within regions of interest located within the neuroblastoma and aorta on both non-contrast-enhanced CT and equilibrium CECT. The correlations between fECV and various factors, including pathological subtype, mitosis karyorrhexis index (MKI), Shimada classification, MYCN amplification status, International Neuroblastoma Risk Group (INRG) stage, and risk group were analyzed using either the Mann-Whitney U test or Kruskal-Wallis test. Neuroblastoma and ganglioneuroblastoma exhibited fECV values of 0.349 (0.252, 0.424) and 0.438 (0.327, 0.508), respectively, indicating a statistically significant difference (Z = 2.200, P = 0.028). Additionally, the fECV decreased significantly in neuroblastoma with high MKI (H = 8.314, P = 0.016) or unfavorable histology (Z = 3.880, P < 0.001), as well as in those with MYCN amplification (Z = 5.486, P < 0.001). Notably, a significant variation in fECV was observed among different INRG stages (H = 16.881, P <0.001) and risk groups (H = 29.014, P < 0.001). CECT-derived fECV is associated with histopathological features, MYCN amplification status, INRG stage, and risk stratification of abdominal neuroblastoma, reflecting a potential correlation between the extracellular matrix and the biological behavior of neuroblastoma.

An Optimal Radiomics Nomogram Based on 18F-FDG PET/CT for Identifying Event-Free Survival in Pediatric Neuroblastoma

To investigate whether the 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) radiomics features that combine tumor and bone marrow can more accurately identify event-free survival (EFS) in pediatric neuroblastoma. A total of 126patients with neuroblastoma were retrospectively included and randomly divided into the training and validation cohorts (7:3 ratio). Radiomics features were extracted to develop a tumor- and bone marrow-based radiomics risk score (RRS). The Kaplan-Meier method was used to evaluate the effectiveness of RRS in EFS risk stratification. Univariate and multivariate Cox regression analyses were used to determine independent clinical risk factors and construct the clinical models. The conventional PET model was constructed based on conventional PET parameters, and the noninvasive combined model integrated the RRS and the noninvasive independent clinical risk factors. The performance of the models was evaluated using C-index, calibration curves, and decision curve analysis (DCA). A total of 15 radiomics features were selected to build the RRS. According to Kaplan-Meier analysis, there was a significant difference in EFS between the low-risk and high-risk groups as defined by the value of RRS (P<.05). The noninvasive combined model combining RRS and the International Neuroblastoma Risk Group stage achieved the best prognostic prediction of EFS, with a C-index of 0.810 and 0.783 in the training and validation cohorts, respectively. The calibration curves and DCA indicated that the noninvasive combined model had good consistency and clinical utility. The 18F-FDG PET/CT-based radiomics of neuroblastoma allows a reliable evaluation of EFS. The performance of the noninvasive combined model was superior to the clinical and conventional PET models.

Functional polymorphisms of the TET1 gene increase the risk of neuroblastoma in Chinese children.

Common genetic mutations are absent in neuroblastoma, one of the most common childhood tumours. As a demethylase of 5-methylcytosine (m5C) modification, TET1 plays an important role in tumourigenesis and differentiation. However, the association between TET1 gene polymorphisms and susceptibility to neuroblastoma has not been reported. Three TET1 gene polymorphisms (rs16925541 A > G, rs3998860 G > A and rs12781492 A > C) in 402 Chinese patients with neuroblastoma and 473 cancer-free controls were assessed using TaqMan. Multivariate logistic regression analysis was used to evaluate the association between TET1 gene polymorphisms and susceptibility to neuroblastoma. The GTEx database was used to analyse the impact of these polymorphisms on peripheral gene expression. The relationship between gene expression and prognosis was analysed using Kaplan-Meier analysis with the R2 platform. We found that both rs3998860 G > A and rs12781492 A > C were significantly associated with increased neuroblastoma risk. Stratified analysis further showed that rs3998860 G > A and rs12781492 A > C significantly increased neuroblastoma risk in certain subgroups. In the combined risk genotype model, 1-3 risk genotypes significantly increased risk of neuroblastoma compared with the 0 risk genotype. rs3998860 G > A and rs12781492 A > C were significantly associated with increased STOX1 mRNA expression in adrenal and whole blood, and high expression of STOX1 mRNA in adrenal and whole blood was significantly associated with worse prognosis. In summary, TET1 gene polymorphisms are significantly associated with increased neuroblastoma risk; further research is required for the potential mechanism and therapeutic prospects in neuroblastoma.

Stage 4N neuroblastoma before and during the era of anti-GD2 immunotherapy.

10037 Background: Patients with stage 4N neuroblastoma (distant metastases limited to lymph nodes) stand out as virtually the only survivors of high-risk neuroblastoma (HR-NB) before myeloablative therapy (MAT) and immunotherapy with anti-GD2 monoclonal antibodies (mAb) became standard. No report presents results with contemporary treatment programs for 4N. The only large study to date (from the International Neuroblastoma Risk Group) analyzed patients diagnosed 1990-2002, found 4N to have significantly better event-free (EFS) and overall survival (OS) compared to other stage 4 patients, and recommended considering less intensive therapy for 4N. Methods: We conducted a retrospective analysis of patients treated at our center from 1985-2021 to analyze our large experience to fill the gap in the literature on treatment of 4N, namely, results with contemporary multi-modality therapy including MAT and anti-GD2 mAbs. Results: We found and reviewed 48 pediatric 4N patients ( &lt; 18 years old) treated 1985-2021 at our center. Biological features included segmental chromosomal aberrations in 21/21 MYCN-non-amplified patients, mutations of ALK in 4/22 (18%), ATRX in 4/16 (25%), and TERT in 4/12 (33%) patients. Among 33 MYCN-non-amplified high-risk patients ( &gt; 18 months old), 19 are relapse-free 1.6+-to-36.9+ (median 12.2+) years post-diagnosis, including 13 without prior MAT and 3 with no mAb, while 14 patients (7 without prior immunotherapy) relapsed (all in soft tissue initially). Eleven of the 14 died, including 3 who developed late osteomedullary metastases after 3-5 relapses in soft tissue alone. Of 13 MYCN-amplified 4N patients, 6 are relapse-free 4.5+-to-25.8+ (median 11.7+) post-diagnosis (all received mAbs; 3 underwent MAT) and 3 are in 2nd remission 4.4+-to-21.1+ years post-relapse (all soft tissue). For all high-risk 4N patients, 5/10-year EFS was 55%/52%, and OS was 76%/64%. MAT was not prognostic. The 2 patients with intermediate-risk 4N (14 months old) are relapse-free 7+ years post-resection of primary tumors; distant disease spontaneously regressed. Conclusions: The natural history of 4N is marked by NB confined to soft tissue without early relapse in bones or bone marrow, sites where mAbs have proven efficacy. These findings plus the possibility of survival without MAT and/or mAb immunotherapy, as seen elsewhere and at our center, support consideration of treatment reduction for selected MYCN-non-amplified 4N patients.

Ganglioneuroblastoma intermixed: Clinicopathological implications of diagnosis at presentation and genomic correlations.

Ganglioneuroblastoma intermixed (GNBI) is classified as "favorable" histology by International Neuroblastoma Pathology Classification system. However, the International Neuroblastoma Risk Group (INRG) stratifies patients using wider clinicopathological and cytogenetic/molecular parameters. While the diagnosis of GNBI is typically made on resected tumor, it may sometimes be rendered on initial biopsy. We studied GNBI noted at diagnosis to evaluate its correlation with INRG staging and other clinicopathological and molecular features. In this retrospective study, clinical, radiological, pathological, cytogenetic, and molecular information from patients with GNBI at diagnosis seen between 1995 and 2021 was analyzed. INRG staging was performed. Of the 15,827 neuroblastoma specimens, GNBI was noted in 237 patients. Of these, 53 had the initial pathological diagnosis of GNBI; median follow-up 3.5 (range: 0.2-14) years. Disease was locoregional in 41 (77%, 16 stage L1 and 25 L2); none relapsed. Twelve (23%) had metastatic disease at presentation; six (50%) relapsed, and two died of disease. MYCN was amplified in two metastatic tumors. Six of 31 (19%) tumors tested had recurrent cytogenetic abnormalities and nonrecurrent somatic gene mutations in 10/23 (43%). The presence of any adverse molecular/cytogenetic findings was associated with metastatic disease (p<.05). For patients with localized GNBI undergoing both biopsy and resection, GNBI was diagnosed in both in 17/19 (90%). Localized GNBI at diagnosis has excellent long-term clinical outcome even without cytotoxic therapy. For localized GNBI, a biopsy sample is adequate to make the diagnosis. When associated with metastasis at diagnosis, prognosis is poorer, possibly due to associated adverse biological features.

Prognostic value of xenograft engraftment in patients with metastatic high-risk neuroblastoma.

Successful engraftment of human cancer biopsies in immunodeficient mice correlates with the poor prognosis of patients. This was reported 30 years ago for children with neuroblastoma, but the standard of care treatment evolved significantly during the last 15 years, leading to improved survival of these patients. Here, we evaluated the association of patient-derived xenograft (PDX) engraftment and prognosis in patients receiving up-to-date treatments for cancers classified as metastatic (stage M) high-risk neuroblastoma (HR-NB) by the International Neuroblastoma Risk Group Staging System (INRGSS). We obtained biopsies from patients with stage M HR-NB. We inoculated biopsy fragments subcutaneously in mice. We studied the association of PDX engraftment with event-free survival (EFS) and overall survival (OS) of patients. Since 2009, we established 17 PDX from 97 samples of 66 patients with stage M HR-NB, with a follow-up of at least two years. Factors associated with higher probability of engraftment were the death as outcome (p=.0006) and the amplification of the gene MYCN in tumors (p=.0271). Patients whose biopsies established a PDX had significantly shorter EFS and OS (p=.0039 and .0002, respectively) than patients whose samples did not engraft. The association of PDX engraftment and OS was significant in patients without MYCN amplification (p=.0041), but not in patients with MYCN amplification (p=.2707). Positive PDX engraftment is a factor related to poor prognosis and fatal outcome in patients with stage M HR-NB treated with up-to-date therapies.

Association between GPC2 polymorphisms and neuroblastoma risk in Chinese children.

The cell surface glycoprotein glypican 2 (GPC2) has been shown to increase susceptibility to neuroblastoma, which is the most common malignancy in children. However, associations between single nucleotide polymorphism(s) of GPC2 and neuroblastoma risk remain unclarified. We conducted a case-control study to investigate two GPC2 polymorphisms (rs1918353 G>A and rs7799441 C>T) in 473 healthy controls and 402 pediatric patients with neuroblastoma. Single nucleotide polymorphism (SNP) genotyping was conducted on the samples by the TaqMan technique, and the data were subsequently analyzed by the t test, chi-squared test, and logistic regression model. In addition, we further performed stratification analysis by age, sex, tumor site of origin, or clinical stage to control confounding factors. According to the data of dominant models (GA/AA vs. GG: adjusted OR=0.99, 95% CI=0.76-1.29, p=0.943; CT/TT vs. CC: adjusted OR=0.91, 95% CI=0.70-1.19, p=0.498) or other comparisons, as well as the conjoint analysis (adjusted OR=1.22, 95% CI=0.93-1.59, p=0.152), we unfortunately proved that the analysis of single or multiple loci did not support any significant association of GPC2 polymorphisms with susceptibility to neuroblastoma. GPC2 polymorphisms (rs1918353 G>A and rs7799441 C>T) are unable to statistically affect neuroblastoma risk in Chinese children. Therefore, more samples, especially from patients of various ethnic backgrounds, are required to increase the sample size and verify the effect of GPC2 polymorphisms on neuroblastoma risk in the presence of ethnic factor.