Pediatric Neuroblastoma Patients Research Articles

Association between CYP2B6 genetic variability and cyclophosphamide therapy in pediatric patients with neuroblastoma

Cyclophosphamide, an oxazaphosphorine prodrug is frequently used in treatment of neuroblastoma, which is one of the most prevalent solid organ malignancies in infants and young children. Cytochrome P450 2B6 (CYP2B6) is the major catalyst and CYP2C19 is the minor enzyme in bioactivation and inactivation pathways of cyclophosphamide. CYP-mediated metabolism may contribute to the variable pharmacokinetics of cyclophosphamide and its toxic byproducts leading to insufficient response to the therapy and development of clinically significant side effects. The aim of the study was to reveal the contribution of pharmacogenetic variability in CYP2B6 and CYP2C19 to the treatment efficacy and cyclophosphamide-induced side effects in pediatric neuroblastoma patients under cyclophosphamide therapy (N = 50). Cyclophosphamide-induced hematologic toxicities were pivotal in all patients, whereas only moderate hepatorenal toxicity was developed. The patients’ CYP2B6 metabolizer phenotypes were associated with the occurrence of lymphopenia, thrombocytopenia, and monocytopenia as well as of liver injury, but not with kidney or urinary bladder (hemorrhagic cystitis) toxicities. Furthermore, the patients’ age (< 1.5 years, P = 0.03) and female gender (P ≤ 0.02), but not CYP2B6 or CYP2C19 metabolizer phenotypes appeared as significant prognostic factors in treatment outcomes. Our results may contribute to a better understanding of the impact of CYP2B6 variability on cyclophosphamide-induced side effects.

Isocitrate Dehydrogenase 1 and 2 Mutations in Pediatric Neuroblastoma Patients.

Neuroblastoma is one of the common tumors of childhood. The demonstration of new factors such as isocitrate dehydrogenase 1 (IDH1) and isocitrate dehydrogenase 2 (IDH2) mutations will be important in the diagnosis and treatment. IDH1 and IDH2 mutations have been found in many types of cancer, such as malignant gliomas, acute myeloid leukemias, chondrosarcoma, and thyroid carcinoma. This study aimed to investigate the presence of IDH1 or IDH2 mutations in patients with neuroblastoma and to determine whether these mutations were different in terms of age, clinical findings, and response to treatment. Biopsy specimens of 25 patients with pediatric neuroblastoma patients were evaluated for IDH mutations. The clinical and laboratory features of the patients with/without mutation were retrospectively analyzed from a hospital database. A total of 25 patients for whom genetic analysis could be performed were included in the study (60% male, n=15). The mean age was 32.2±25.9 months (3 days-96 months). IDH1 mutation was detected in 8 (32%) and IDH2 mutations in 5 (20%) patients. These mutations showed no statistically significant relationship with age, tumor localization, laboratory results, stage, and prognosis. However, in the case of IDH mutation, patients were diagnosed at the advanced stage. This study demonstrated the relationship between neuroblastoma and IDH mutation for the first time. Because to the fact that the mutation is very heterogeneous, it would be appropriate to conduct a larger series of patients in terms of the impact of the clinical significance of each mutation on the diagnosis and prognosis.

A phase 1b study of crizotinib in combination with temsirolimus in pediatric ALK- or MET-aberrated relapsed or refractory neuroblastoma (ITCC-053): Results of the phase 1 part.

10036 Background: Preclinical data in neuroblastoma (NBL) models provided evidence that the addition of an mTOR inhibitor with crizotinib may overcome the relative resistance to ALK inhibitors (Berry et al., 2012, Cancer Cell). The primary objective of this phase 1b trial was to establish the recommended phase 2 dose (RP2D) of crizotinib in combination with the mTOR inhibitor temsirolimus in pediatric NBL patients. Methods: Patients aged 1-21 years with relapsed/refractory ALK/MET aberrated NBL were eligible to enroll onto stratum 2 of the CRISP trial (EudraCT: 2015-005437-53, ITCC-053), sponsored by Erasmus MC. This was an open-label, non-randomized, two-stage phase 1b dose finding study. Crizotinib was dose escalated using the EWOC method in four dose levels (DL) ranging from 100 mg/m2 to 280 mg/m2 twice daily (BID) in 28 day cycles. Temsirolimus was administered intravenously in a fixed dose of 60 mg/m2/week. Both starting doses were reduced compared to the single agent RP2D because of an expected CYP3A4 interaction. Primary endpoint was dose limiting toxicity (DLT) during cycle 1. Radiological disease assessments and blood sampling for pharmacokinetics were scheduled per protocol. Results: Nine NBL patients were enrolled onto stratum 2 between 06-2018 and 12-2022. Eight patients with a median age of 7 years (range: 1-12) received trial treatment. The temsirolimus dose was reduced to 40 mg/m2 after the first 3 patients based on unexpected toxicity. DLTs occurred in 2/3 patients treated with crizotinib at DL2 (200 mg/m2 BID); grade 3 elevated ALT (alanine aminotransferase) and grade 3 gastritis (temsirolimus dose; see table). No DLT occurred in 5 patients treated with crizotinib DL1 (150 mg/m2 BID). Dose re-escalation of crizotinib to DL2 was considered not feasible. The RP2D was established at 150 mg/m2 BID crizotinib with 40 mg/m2 temsirolimus. Frequent grade 3 treatment-related adverse events were anorexia, gastritis, oral mucositis (n = 2) and anemia (n = 3). Treatment, toxicity and response are summarized in table. Conclusions: We established a RP2D of 150 mg/m2 BID crizotinib in combination with 40 mg/m2 temsirolimus. The expansion cohort is currently open for enrollment. Clinical trial information: EUCTR2015-005437-53 . [Table: see text]

Psoas Muscle Area and Surgical Implications in Pediatric Neuroblastoma Patients

Dougherty, Danielle MD; Gamsarian, Vahram BE; Ehrlich, Peter F MD, FACS; Singleterry, Marquise D BS; VanHulle, Rachel MD; Koblick, Sarah MD; Simon, Caroline MD; Sedig, Laura MD; Geiger, James D MD, FACS; Newman, Erika A MD, FACS Author Information

Predictors of mortality in children with neuroblastoma

Background Neuroblastoma is an extracranial solid tumor originating from neural crest cells which failed to properly migrate. Neuroblastoma is commonly found in children under 12 months of age. The survival rate of these patients is still relatively low, both in developed countries and Indonesia.&#x0D; Objective To determine whether age, sex, primary tumor location, degree of cell differentiation, and patient compliance are associated with the survival of children with neuroblastoma at Dr.Sardjito Hospital.&#x0D; Methods This retrospective cohort study included pediatric neuroblastoma patients at Dr. Sardjito Hospital, Yogyakarta, Central Java, between January 2012 to September 2020, however there has been no evaluation about survival of neuroblastoma. We collected secondary data from medical records and registration data of pediatric cancer patients in the Pediatric Hematology Oncology Department of Dr. Sardjito Hospital, we matched te data based on medicals records and manual data in the ward and olyclinic, which included age at diagnosis, sex, primary tumor location, degree of cell differentiation, and patient adherence to therapy. To confirm weather the information about survived or death, apart from medical record we do tracking by telephone to the parent.&#x0D; Results we do the observation and calculating based on our retrospective data , Of 54 pediatric neuroblastoma patients, 54% were female. The median length of observation was 13.25 months, with an incidence rate of 62/100 person-years and a median survival of 13 months from the time of diagnosis. The 5-year survival rate in our study was 21.3%. Multivariate analysis revealed that stage IV patients had higher risk of death (HR 10.9; 95%CI 1.47 to 81.01; P=0.02) compared to other stages. Sub-group follow-up analysis revealed no significant difference in stage IV male patients compared to female patients (HR 1.62; 95%CI 0.81 to 3.22; P=0.172). The survivial in group with primary tumor location outside the adrenal medulla and stage IV was not significantly different from patients whose tumor location was unknown (HR 2.45; 95%CI 0.71 to 8.43; P=0.155). The group whose primary tumor location was in the adrenal medulla did not have a significant difference in survival compared to patients whose primary tumor location was unknown (HR 2.09; 95%CI 0.84 to 5.22; P=0.114).&#x0D; Conclusion The predictor factors studied are not significantly associated with mortality in children with neuroblastoma.

Abstract 3544: ALK signaling activity stabilizes SLC3A2 protein levels in neuroblastoma tumorigenesis

Abstract Background: Neuroblastoma is the most common childhood tumor that grows in the adrenal glands or sympathetic ganglia. Approximately 10% of pediatric neuroblastoma patients harbor mutations in anaplastic lymphoma kinase (ALK). In a previous study, we identified SLC3A2 as a potential interacting partner with ALK using BioID-based in vivo proximity labeling. SLC3A2 is a multifunctional protein that mediates integrin-dependent signaling, acts as a trafficking chaperone for amino acid transporters, and regulates polyamine transport. No previous link to ALK signaling has been reported and the underlying mechanisms and functional consequences of a SLC3A2-ALK interaction in ALK-driven neuroblastoma are unclear. Materials &amp; Methods: The interaction of SLC3A2 and ALK initially detected with BioID-based in vivo proximity labeling was validated by immunoprecipitation. The effect of ALK signaling on SLC3A2 expression and protein stability was evaluated by quantitative PCR and immunoblotting. The functional effect of SLC3A2 on cell viability were investigated by siRNA and inhibitor treatments in both human and mouse ALK-driven neuroblastoma cells. Results: SLC3A2 was confirmed to interact with ALK in both anti-ALK and anti-SLC3A2 antibody co-immunoprecipitations from NB1 cells (ALK-wild-type) and CLB-GE (ALK-F1174V). Moreover, this interaction was decreased by ALK inhibitor (lorlatinib) treatment. Upon ALKAL2 ligand treatment, ALK signaling increased the protein levels of SLC3A2 and this was abrogated by lorlatinib treatment in NB1 cells. Furthermore, lorlatinib treatment suppressed SLC3A2 expression and significantly affected protein stability in neuroblastoma cells with different ALK mutations including CLB-BAR (ALK exon4-11 deletion), CLB-GAR (ALK-R1275Q), and CLB-GE (ALK-F1174V) during cycloheximide chase analysis. Knockdown of SLC3A2 significantly inhibited cell growth and down-regulated the amino acid transporter SLC7A5 (LAT1) expression in CLB-GE cells (ALK-F1174V). While mono treatment of either lorlatinib (ALK TKI) or AMXT-1501 (polyamine transport inhibitor) only showed moderate effects, combinatorial treatment exhibited a synergistic effect on cell growth in ALK-driven primary-cultured mouse neuroblastoma #9883 (Th-MYCN; Alk-F1178S) and #111 (Th-MYCN; Rosa26_Alkal2) cells. Conclusions: SLC3A2 protein stability and its interaction with ALK is dependent on ALK signaling in an ALK-driven neuroblastoma context. The synergistic effect of combined ALK and polyamine transport inhibitors suggests a potential therapeutic option for ALK-driven neuroblastoma. Citation Format: Wei-Yun Lai, Tzu-Po Chuang, Marcus Borenäs, Ruth Palmer, Bengt Hallberg. ALK signaling activity stabilizes SLC3A2 protein levels in neuroblastoma tumorigenesis. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3544.

Establishment and validation of a nomogram to predict cancer-specific survival in pediatric neuroblastoma patients.

The term "neuroblastoma (NB)" refers to a type of solid pediatric tumor that develops from undivided neuronal cells. According to the American Cancer Society report, between 700 and 800 children under the age of 14 are diagnosed with NB every year in the United States (U.S.). About 6% of all cases of pediatric cancer in the U.S. are caused by NB. NB is the most frequent malignancy in children younger than 1 year; however, it is rarely found in those over the age of 10 and above. To accurately predict cancer-specific survival (CSS) in children with NB, this research developed and validated an all-encompassing prediction model. The present retrospective study used the Surveillance, Epidemiology, and End Results (SEER) database to collect information on 1,448 individuals diagnosed with NB between 1998 and 2019. The pool of potentially eligible patients was randomly split into two groups, a training cohort (N = 1,013) and a validation cohort (N = 435). Using multivariate Cox stepwise regression, we were able to identify the components that independently predicted outcomes. The accuracy of this nomogram was measured employing the consistency index (C-index), area under the time-dependent receiver operating characteristic curve (AUC), calibration curve, and decision-curve analysis (DCA). In this study, we found that age, primary location, tumor size, summary stage, chemotherapy, and surgery were all significant predictors of CSS outcomes and integrated them into our model accordingly. The C-index for the validation cohort was 0.812 (95% CI: 0.773-0.851), while for the training cohort it was 0.795 (95% CI: 0.767-0.823). The C-indexes and AUC values show that the nomogram is able to discriminate well enough. The calibration curves suggest that the nomogram is quite accurate. Also, the DCA curves demonstrated the prediction model's value. A novel nomogram was developed and validated in this work to assess personalized CSS in NB patients, and it has been indicated that this model could be a useful tool for calculating NB patients' survival on an individual basis and enhancing therapeutic decision-making.

Axial Skeleton Radiomics of 18F-FDG PET/CT: Impact on Event-Free Survival Prediction in High-Risk Pediatric Neuroblastoma

To construct and validate a combined model based on axial skeleton radiomics of 18F-FDG PET/CT for predicting event-free survival in high-risk pediatric neuroblastoma patients. Eighty-seven high-risk neuroblastoma patients were retrospectively enrolled in this study and randomized in a 7:3 ratio to the training and validation cohorts. The radiomics model was constructed using radiomics features that were extracted from the axial skeleton. A univariate Cox regression analysis was then performed to screen clinical risk factors associated with event-free survival for building clinical model. Radiomics features and clinical risk factors were incorporated to construct the combined model for predicting the event-free survival in high-risk neuroblastoma patients. The performance of the models was evaluated by the C-index. Eighteen radiomics features were selected to build the radiomics model. The radiomics model achieved better event-free survival prediction than the clinical model in the training cohort (C-index: 0.846 vs. 0.612) and validation cohort (C-index: 0.754 vs. 0.579). The combined model achieved the best prognostic prediction performance with a C-index of 0.863 and 0.799 in the training and validation cohorts, respectively. The combined model integrating radiomics features and clinical risk factors showed more accurate predictive performance for event-free survival in high-risk pediatric neuroblastoma patients, which helps to design individualized treatment strategies and regular follow-ups.

Investigation of Imidazolium-Based Ionic Liquids as Additives for the Separation of Urinary Biogenic Amines via Capillary Electrophoresis

Ionic liquids (ILs), such as imidazoles, can be used to prevent the sorption of analytes onto the walls of the capillary. Prior works have confirmed that coating the capillary wall with a cationic layer can increase its surface stability, thereby improving the repeatability of the separation process. In this study, micellar electrokinetic chromatography (MEKC) is employed to evaluate how two ILs with different anions—namely, 1-hexyl-3-methylimidazolium chloride [HMIM+Cl−] and 1-hexyl-3-methylimidazolium tetrafluoroborate [HMIM+BF4−]—affect the separation efficiency for biogenic amines (BAs) such as metanephrine (M), normetanephrine (NM), vanilmandelic acid (VMA), and homovanillic acid (HVA) in urine samples. To this end, solid-phase extraction (SPE) is employed using different sample pH values, with the results demonstrating that HVA and VMA is easily extracted at a sample pH of 5.5, while a sample pH of 9.0 facilitated the extraction of M and NM. In the applied SPE protocol, selected analytes were isolated from urine samples using hydrophilic–lipophilic-balanced (HLB) columns and eluted with methanol (MeOH). The validation data confirmed the method’s linearity (R2 &gt; 0.996) for all analytes within the range of 0.25–10 µg/mL. The applicability of the optimized SPE-MEKC-UV method was confirmed by employing it to quantify clinically relevant BAs in real urine samples from pediatric neuroblastoma (NBL) patients.

The prognostic and predictive value of plasma D-dimer in children with neuroblastoma: a 7-year retrospective analysis at a single institution.

Elevated plasma D-dimer level is a poor prognostic factor for many solid tumors. However, limited research has been conducted on D-dimer in children with neuroblastoma (NB), and its clinical significance remains unclear. The present study investigated the clinical and prognostic significance of D-dimer in pediatric NB patients. A retrospective analysis of all newly admitted NB patients was conducted from January 2014 to December 2020. Baseline clinicopathological features, preoperative laboratory parameters, and follow-up information were collected. Univariate and multivariate analyses were performed to determine the relationship between D-dimer level, clinical features, and the prognostic value. Among 266 patients, the median value of D-dimer was 2.98 ng/mL, of which 132 patients showed elevated D-dimer levels before surgery (>2.98 ng/mL). Univariate analysis revealed that elevated D-dimer was significantly associated with age, hemoglobin, neutrophil-to-lymphocyte ratio, neuron-specific enolase, 24-hour vanillylmandelic acid, overall survival, and so on (P < 0.05). Patients with elevated D-dimer levels had shorter median overall survival time when compared with normal D-dimer levels (P = 0.01). The prognosis was better in patients with normal D-dimer levels when combined with lower age, ganglioneuroblastoma tumor type, lower stage on International Neuroblastoma Staging System, low-risk group, and without bone metastasis or bone marrow metastasis. The continuous increase of D-dimer level after treatment indicated tumor recurrence or progression. A high D-dimer level is associated with low overall survival, and an elevated D-dimer level after treatment indicates tumor recurrence and progression. D-dimer can be used as one of the evaluation factors for NB treatment or prognosis.

A novel cuproptosis-related gene signature predicting overall survival in pediatric neuroblastoma patients.

Cuproptosis is a novel cell death pathway, and the regulatory mechanism in pediatric neuroblastoma (NB) remains to be explored. We amid to investigate cuproptosis-related genes (CRGs) and construct a novel prognostic model for NB. To evaluate the role of CRGs on the clinical outcome of pediatric NB, the dataset of pediatric patients with NB of GSE49710 dataset was used to identify CRGs in association with patient overall survival (OS), and TARGET database was used to validate the predictive value of cuproptosis-related signature (CRG-score). The correlation between the CRG-score and the tumor microenvironment (TME), clinicopathological parameters, chemotherapy, and the response to immunotherapy was explored. Overall, 31 CRGs were associated with OS in the univariate Cox regression analysis. Then, a prognostic model incorporating 9 CRGs was established with the LASSO regression analysis, which could classify all NB patients into two CRG-score groups. The performance of the signature was verified in both internal and external validation cohorts. Multivariate analysis indicated that the CRG-score was an independent prognostic indicator, and stratification analysis still showed a high predictive ability for survival prediction. The CRG-score was associated with age, MYCN status, INSS stage, and COG risk. Additionally, the higher CRG-score group exhibited lower immune scores, immune cell infiltration, and decreased expression of immune checkpoints. Meanwhile, the CRG-score could predict the drug sensitivity of administering chemotherapeutic agents for NB patients. Our comprehensive analysis of cuproptosis-associated genes in NB provides a new approach for the prediction of clinical outcomes and more effective treatment strategies.

Imaging of pediatric neuroblastoma: A COG Diagnostic Imaging Committee/SPR Oncology Committee White Paper.

Neuroblastoma is the most common extracranial solid neoplasm in children. This manuscript provides consensus-based imaging recommendations for pediatric neuroblastoma patients at diagnosis and during follow-up.

RRS1 knockdown inhibits the proliferation of neuroblastoma cell via PI3K/Akt/NF-κB pathway.

RRS1 plays an important role in regulating ribosome biogenesis. Recently, RRS1 has emerged as an oncoprotein involved in tumorigenicity of some cancers. However its role in neuroblastoma remains unknown. RRS1 expression was detected in pediatric neuroblastoma patients' tissues and cell lines. The effects of RRS1 knockdown on proliferation, apoptosis, and cell cycle were evaluated in neuroblastoma cell lines. RRS1-related survival pathway was analyzed by co-immunoprecipitation (Co-IP), mass spectrometry, reverse transcription-quantitative real-time PCR (RT-qPCR), and western blot. Protein-protein interaction (PPI) network was constructed using Cytoscape software and the STRING databases. Increased RRS1 level was found in neuroblastoma cases (35.6%) and cell lines. High RRS1 expression levels were associated with poor prognosis. RRS1 knockdown inhibited cell proliferation, induced apoptosis, and caused cell cycle arrest in SK-N-AS and SH-SY5Y cells. Co-IP and mass spectrometry analysis showed that RRS1 affects PI3K/Akt and nuclear factor κB (NF-κB) pathways. RT-qPCR and western blot results revealed that RRS1 knockdown inhibited the PI3K/Akt/NF-κB pathway through dephosphorylation of key proteins. In PPI network, AKT, PI3K, and P65 connected RRS1 with differentially expressed proteins more closely. This study suggests RRS1 knockdown may inhibit neuroblastoma cell proliferation by the PI3K/Akt/NF-κB pathway. Therefore, RRS1 may be a potential target for neuroblastoma treatment. RRS1 is involved in the progression of neuroblastoma. Knockdown of RRS1 contributes to inhibit the survival of neuroblastoma cells. RRS1 is associated with the PI3K/Akt/NF-κB signaling pathway in neuroblastoma cells. RRS1 may be a promising target for neuroblastoma therapy.

High Expression of the Lysosomal Protease Cathepsin D Confers Better Prognosis in Neuroblastoma Patients by Contrasting EGF-Induced Neuroblastoma Cell Growth.

Neuroblastoma is a malignant extracranial solid tumor arising from the sympathoadrenal lineage of the neural crest and is often associated with N-MYC amplification. Cathepsin D has been associated with chemoresistance in N-MYC-overexpressing neuroblastomas. Increased EGFR expression also has been associated with the aggressive behavior of neuroblastomas. This work aimed to understand the mechanisms linking EGFR stimulation and cathepsin D expression with neuroblastoma progression and prognosis. Gene correlation analysis in pediatric neuroblastoma patients revealed that individuals bearing a high EGFR transcript level have a good prognosis only when CTSD (the gene coding for the lysosomal protease Cathepsin D, CD) is highly expressed. Low CTSD expression was associated with poor clinical outcome. CTSD expression was negatively correlated with CCNB2, CCNA2, CDK1 and CDK6 genes involved in cell cycle division. We investigated the biochemical pathways downstream to EGFR stimulation in human SH-SY5Y neuroblastoma cells engineered for overexpressing or silencing of CD expression. Cathepsin D overexpression decreased the proliferative potential of neuroblastoma cells through downregulation of the pro-oncogenic MAPK signaling pathway. EGFR stimulation downregulated cathepsin D expression, thus favoring cell cycle division. Our data suggest that chemotherapeutics that inhibit the EGFR pathway, along with stimulators of cathepsin D synthesis and activity, could benefit neuroblastoma prognosis.

Impact of cyclic changes in pharmacokinetics and absorbed dose in pediatric neuroblastoma patients receiving [177Lu]Lu-DOTATATE

PurposeRecent reports personalizing the administered activity (AA) of each cycle of peptide receptor radionuclide therapy based on the predicted absorbed dose (AD) to the kidneys (dose-limiting organ) have been promising. Assuming identical renal pharmacokinetics for each cycle is pragmatic, however it may lead to over- or under-estimation of the optimal AA. Here, we investigate the influence that earlier cycles of [177Lu]Lu-DOTATATE had on the biokinetics and AD of subsequent cycles in a recent clinical trial that evaluated the safety and activity of [177Lu]Lu-DOTATATE in pediatric neuroblastoma (NBL). We investigated whether predictions based on an assumption of unchanging AD per unit AA (Gy/GBq) prove robust to cyclical changes in biokinetics.MethodsA simulation study, based on dosimetry data from six children with NBL who received four-cycles of [177Lu]Lu-DOTATATE in the LuDO trial (ISRCTN98918118), was performed to explore the effect of variable biokinetics on AD. In the LuDO trial, AA was adapted to the patient’s weight and SPECT/CT-based dosimetry was performed for the kidneys and tumour after each cycle. The largest tumour mass was selected for dosimetric analysis in each case.ResultsThe median tumour AD per cycle was found to decrease from 15.6 Gy (range 8.12–26.4) in cycle 1 to 11.4 Gy (range 9.67–28.8), 11.3 Gy (range 2.73–32.9) and 4.3 Gy (range 0.72–20.1) in cycles 2, 3 and 4, respectively. By the fourth cycle, the median of the ratios of the delivered AD (ADD) and the predicted (or “expected”) AD (ADE) (which was based on an assumption of stable biokinetics from the first cycle onwards) were 0.16 (range 0.02–0.92, p = 0.013) for the tumour and 1.08 (range 0.84–1.76, p > 0.05) for kidney. None of the patients had an objective response at 1 month follow up.ConclusionThis study demonstrates variability in Gy/GBq and tumour AD per cycle in children receiving four administrations of [177Lu]Lu-DOTATATE treatment for NBL. NBL is deemed a radiation sensitive tumour; therefore, dose-adaptive treatment planning schemes may be appropriate for some patients to compensate for decreasing tumour uptake as treatment progresses.Trial registration ISRCTN ISRCTN98918118. Registered 20 December 2013 (retrospectively registered).

Reply to Schramm, L. Comment on "Li et al. BDP1 Variants I1264M and V1347M Significantly Associated with Clinical Outcomes of Pediatric Neuroblastoma Patients Imply a New Prognostic Biomarker: A 121-Patient Cancer Genome Study. Diagnostics 2021, 11, 2364".

We thank Professor Laura Schramm for her comment on the history and clarification of BDP1 nomenclature, her contribution to gene cloning [...].

Comment on Li et al. BDP1 Variants I1264M and V1347M Significantly Associated with Clinical Outcomes of Pediatric Neuroblastoma Patients Imply a New Prognostic Biomarker: A 121-Patient Cancer Genome Study. Diagnostics 2021, 11, 2364.

In 2021, Li et al. published an article on BDP1 variants and implications in pediatric neuroblastoma patients [...].

Prediction for Mitosis-Karyorrhexis Index Status of Pediatric Neuroblastoma via Machine Learning Based 18F-FDG PET/CT Radiomics.

Accurate differentiation of intermediate/high mitosis-karyorrhexis index (MKI) from low MKI is vital for the further management of neuroblastoma. The purpose of this research was to investigate the efficacy of 18F-FDG PET/CT–based radiomics features for the prediction of MKI status of pediatric neuroblastoma via machine learning. A total of 102 pediatric neuroblastoma patients were retrospectively enrolled and divided into training (68 patients) and validation sets (34 patients) in a 2:1 ratio. Clinical characteristics and radiomics features were extracted by XGBoost algorithm and were used to establish radiomics and clinical models for MKI status prediction. A combined model was developed, encompassing clinical characteristics and radiomics features and presented as a radiomics nomogram. The predictive performance of the models was evaluated by AUC and decision curve analysis. The radiomics model yielded AUC of 0.982 (95% CI: 0.916, 0.999) and 0.955 (95% CI: 0.823, 0.997) in the training and validation sets, respectively. The clinical model yielded AUC of 0.746 and 0.670 in the training and validation sets, respectively. The combined model demonstrated AUC of 0.988 (95% CI: 0.924, 1.000) and 0.951 (95% CI: 0.818, 0.996) in the training and validation sets, respectively. The radiomics features could non-invasively predict MKI status of pediatric neuroblastoma with high accuracy.

The Diagnostic Value of 18F-FDG PET/CT Bone Marrow Uptake Pattern in Detecting Bone Marrow Involvement in Pediatric Neuroblastoma Patients.

Objectives To explore the diagnostic value of 18F-FDG PET/CT bone marrow uptake pattern (BMUP) in detecting bone marrow involvement (BMI) in pediatric neuroblastoma (NB) patients. Methods Ninety-eight NB patients were enrolled in BMI analysis. Four patterns of bone marrow uptake were categorized based on pretreatment cF-FDG PET/CT images. Some crucial inspection indexes and 18F-FDG PET/CT metabolic parameters were analyzed. The BMUP was divided into BMUP1, BMUP2, BMUP3, and BMUP4. Paired-like homeobox 2b (PHOX2B) of bone marrow and blood, bone marrow biopsy (BMB) result, and 18F-FDG PET/CT were compared to detect BMI. All patients were followed up for at least six months. Results BMUP had excellent consistency among different physicians. Kappa coefficients of two residents and two attending physicians and between the resident and attending physician, were 0.857, 0.891, and 0.845, respectively. The optimal cut-off value of SUVmax-Bone/Liver was 2.08 to diagnose BMI for BMUP3 patients, and the area under curve (AUC) was 0.873. AUC of PHOX2B of bone marrow (PHOX2B of BM), PHOX2B of blood, BMB, and 18F-FDG PET/CT were 0.916, 0.811, 0.806, and 0.904, respectively. There was no significant difference between PHOX2B of BM and PET/CT. Positive predictive value, negative predictive value, sensitivity, and specificity in diagnosis of BMI were 92.9%, 92.9%, 97.0%, and 83.9% for PET/CT and 96.7%, 80.6%, 89.6%, and 93.5% for PHOX2B of BM, respectively. Conclusions BMUP of pretreatment 18F-FDG PET/CT is a simple and practical method, which has a relatively high diagnostic efficiency in detecting BMI and might decrease unnecessary invasive inspections in some pediatric NB patients.

Prognostic Value of Interim 18F-DOPA and 18F-FDG PET/CT Findings in Stage 3-4 Pediatric Neuroblastoma.

This retrospective study aimed to determine the prognostic value of imaging parameters derived from midtherapy 18F-fluorodihydroxyphenylalanine (18F-DOPA) and 18F-FDG PET in pediatric patients with stage 3-4 neuroblastoma. We enrolled 32 stage 3-4 pediatric neuroblastoma patients who underwent 18F-DOPA and 18F-FDG PET/CT scans before and after 3 chemotherapy cycles. We measured metabolic and volumetric parameters and applied a metabolic burden scoring system to evaluate the primary tumor extent and soft tissue metastases and that of bone/bone marrow involvement. The associations between these parameters and clinical outcomes were investigated. Over a median follow-up period of 47 months (range, 3-137 months), 16 patients experienced disease progression, and 13 died. After adjustment for clinical factors, multivariate Cox proportional hazard models showed that interim tumor FDG/FDOPA SUVmax (hazard ratio [HR], 5.94; 95% confidence interval [CI], 1.10-34.98) and interim FDOPA whole-body metabolic burden scores (WBMB) (HR, 7.30; 95% CI, 1.50-35.50) were significant prognostic factors for overall survival (OS). Only interim FDOPA WBMB scores (HR, 7.05; 95% CI, 1.02-48.7) were predictive of progression-free survival. Based on median cutoff values, prognosis (OS and progression-free survival) was significantly associated with an interim FDOPA WBMB score ≥21.92 (all P < 0.05) and interim tumor FDG/FDOPA (SUVmax) score ≥0.57 with poor OS (P < 0.05). Our results indicate that midtreatment FDG and FDOPA PET/CT could serve as prognostic markers in stage 3-4 neuroblastoma patients.