Combination of clinical parameters and ¹²³I-metaiodobenzylguanidine scintigraphy in the monitoring of neuroblastoma metastases

Introduction

Neuroblastoma (NB), which arises from the sympathetic nervous system along the sympathetic chain, is the most common extracranial malignant solid tumor in children (1). Due to its heterogeneity, the course of the disease varies considerably, with some cases spontaneously regressing and others advancing rapidly with poor outcomes. The International Neuroblastoma Staging System (INSS) and the International Neuroblastoma Risk Group (INRG) staging system play crucial roles in the comprehensive assessment of NB, including both stage classification and risk stratification (2,3). The INSS uses surgical staging to assess the severity of NB; NB is classified as stage 4 when distant metastasis presents, and the survival rate after metastatic relapse is only 5% (4). The most common metastasis site is the bone/bone marrow (BM); however, the mechanism of BM metastasis has not yet been clearly elucidated. Some studies have reported that genetic variation and epigenetic changes, such as MYCN amplification, 11q deletion, and non-coding RNAs, are involved in metastasis (5-7). As metastasis is the primary cause of mortality among NB patients (8), the early identification of tumor metastasis and recurrence is important to achieve optimal outcomes (9).

Minimal residual disease (MRD), which refers to remaining tumor cells, can detect tumor relapse/regrowth in NB patients (10-12). Quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) and flow cytometry (FCM) are both sensitive methods for monitoring MRD and assessing current disease status. qRT-PCR provides an objective measure of tumor content in a clinical sample, and paired-like homeobox 2B (PHOX2B) has been identified as a sensitive and specific MRD marker (13,14). FCM detects MRD by identifying qualitative and quantitative differences in the antigenic expression of specific antigens in NB tumor cells (15). Both qRT-PCR and FCM have high specificity in detecting MRD; however, their main limitation lies in their low sensitivity due to the testing of only a small sample of BM or peripheral blood, which may lead to potential false-negative results (15). Thus, more sensitive methods for detecting MRD need to be established.

Metaiodobenzylguanidine (MIBG) is a norepinephrine analogue used to image the adrenal medulla, and it has been shown to be an effective agent for neural crest NB. Due to its superior physical properties, ¹²³I-MIBG has become a well-established method for the diagnosis and staging of NB (16-18). A prospective multicenter trial of ¹²³I-MIBG scintigraphy reported high sensitivity and specificity in patients with both newly diagnosed and previously treated NB (19). The semiquantitative Curie scoring methodology has been used and shown to be meaningful in the detection of metastasis. It improves description of disease extent and distribution, and could potentially aid in predicting prognosis (20). However, ¹²³I-MIBG scintigraphy also has several limitations, including limited spatial resolution, diminished sensitivity in detecting small lesions, and prolonged acquisition sessions (21). Currently, false positives can also arise in various clinical scenarios. Some specific cases have been reported in the accessory spleen, urinary tract tumors, benign liver tumors, and pyelonephritis (22-25). Additionally, discrepancies between ¹²³I-MIBG uptake changes during treatment and unchanged computed tomography (CT) findings can lead to false positives (26).

The accurate diagnosis of metastasis plays a pivotal role in the effective management of NB. However, a discrepancy exists between MRD and ¹²³I-MIBG scintigraphy in routine clinical practice, including instances of negative MRD results for ¹²³I-MIBG-avid lesions, and vice versa. Therefore, the development of a more precise diagnostic model for the detection of metastasis is very important. The primary objective of this study was to develop an improved diagnostic model. We present this article in accordance with the STARD reporting checklist (available at https://qims.amegroups.com/article/view/10.21037/qims-24-1201/rc).

Methods

Patients

Between April 2021 and April 2023, a total of 76 pediatric NB patients (under 14 years old) underwent ¹²³I-MIBG scintigraphy at the Nuclear Medicine Department of Beijing Friendship Hospital (Figure 1) after surgery. Throughout their treatment course, regular evaluations were conducted to assess the therapeutic response and monitor local recurrence or distant metastasis. The patients were categorized into stage 4 or non-stage 4 groups based on the INSS, and their risk levels were classified as high-risk or non-high-risk according to the INRG classification system (2,27). The patients were categorized into NB and non-NB pathological subtypes (ganglio-NB and ganglioneuroma) based on the International Neuroblastoma Pathology Classification (28). To be eligible for inclusion in the study, the patients had to meet the following inclusion criteria: (I) have undergone BM-MRD and FCM-MRD examinations; (II) have not received any treatment between ¹²³I-MIBG scintigraphy and MRD with an interval of less than 6 months. Patients were excluded from the study if they met any of the following exclusion criteria: had inadequate clinical information, were unable to cooperate to undergo ¹²³I-MIBG scintigraphy, and/or were lost to follow-up.

Figure 1 Patient inclusion and exclusion flow diagram. BM, bone marrow; FCM, flow cytometry; MIBG, metaiodobenzylguanidine; MRD, minimal residual disease; NB, neuroblastoma.

The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Institutional Review Board of Beijing Friendship Hospital, Capital Medical University (No. 2022-P2-314-01), and the requirement of individual consent for this retrospective analysis was waived.

Functional imaging of ¹²³I-MIBG scintigraphy

Preparation

Thyroid blockage was necessary in the administration of the ¹²³I-MIBG agent to prevent unnecessary exposure. Therefore, Lugol’s iodine solution was administered before and after imaging. The recommended dose is 5.2 MBq/kg, with a minimum of 37 MBq (1 mCi) and a maximum of 370 MBq (10 mCi) (29). The agent was provided by Beijing Atomic High Technology Co. (China).

Image acquisition

The whole body anterior and posterior planar image was acquired 24 hours post-injection using a gamma camera equipped with a low-energy high-resolution collimator. Subsequently, single-photon emission computed tomography (SPECT)/CT imaging was performed immediately (30); the field of tomography was optimized to focus on suspicious lesions exhibiting increased uptake on the planar images. In cases in which no abnormalities were observed on planar images, SPECT/CT targeted the primary sites or previously identified areas of abnormal uptake from prior pre-treatment studies or records. SPECT acquisition (Simens Symbia T16, Simens Healthcare, Germany) was performed using the following parameters: step mode; 3°/step; total projections collected: 120; projection: 25 s; and matrix: 128×128 (reconstructed using the iterative method); CT was performed using the following parameters: tube voltage: 80–100 kV; technology: automatic tube current adjustment; and total image time: 15–30 min.

Image analysis

The images, including the planer and SPECT/CT images, were individually reviewed by two nuclear medicine physicians, each with more than 10 years of experience, in a double-blind manner. In case of any discrepancies in the interpretations, an additional experienced physician provided a consistent assessment. An abnormality was defined as any uptake intensity exceeding background activity and not corresponding to physiological distribution. The semiquantitative Curie score was used for ¹²³I-MIBG scintigraphy, with a Curie score of 0 indicating negative ¹²³I-MIBG findings. The Curie score was used to document the metastatic sites, which comprised nine osteo-medullary regions and an additional sector for any extraosseous metastases.

Diagnostic criteria

To be classified as a lesion, one or more of the following criteria had to be met: (I) a histopathologic diagnosis of the lesion. When a histopathologic diagnosis could not be obtained. (II) Metastasis confirmed by additional imaging examinations, such as ultrasound, contrast-enhanced CT, magnetic resonance imaging, ¹⁸F-fluorodeoxyglucose positron emission tomography/CT, ¹²³I/¹³¹I-MIBG SPECT/CT; ultimately. (III) A minimum clinical follow-up period of 18 months (30).

Clinical information

The study incorporated various clinical indicators, including age at diagnosis, primary tumor site, pathological type, and therapeutic regimen. Genetic markers such as chromosome 11q23 aberration and amplification of MYCN were assessed using fluorescence in situ hybridization. Following the collection of BM samples through aspiration, qRT-PCR was conducted to qualitatively and quantitatively evaluate the expression level of the PHOX2B gene. Additionally, FCM analyses were performed. The outcomes for the PHOX2B gene were defined as the number of PHOX2B gene copies per 10,000 of the β-glucosidase endogenous gene, with a copy number >0 considered positive (13). A proportion of CD45/CD56/CD81/GD2 positive nucleated cells exceeding ≥0.01% among all the nucleated cells indicated the presence of NB cells and BM involvement.

Statistical analysis

The qualitative data were presented as the number of cases and percentage. Comparisons of the factors between groups were evaluated using the Chi-squared (χ²) test or Fisher’s exact test. The predictive value of ¹²³I-MIBG scintigraphy was assessed by quantifying the area under the curve (AUC) of the receiver operating characteristic (ROC) curve. The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were sequentially computed. A multivariate logistic regression analysis was employed to develop diagnostic models for discriminating between metastatic and non-metastatic patients. All the statistical tests were two-tailed, and a P value <0.05 indicated a statistically significant difference. The Delong test was performed using the pROC package. The statistical analysis was performed using SPSS 22.0 (IBM Corp, Armonk, NY, USA) and R software program version 4.0.2 (Bell Laboratories, USA).

Results

Clinical parameters

A total of 76 pediatric patients with NB were ultimately enrolled in this study, and the clinical characteristics between the metastatic and non-metastatic patients are summarized in Table 1. As Table 1 shows, significant differences were observed between the non-metastatic and metastatic NB patients in terms of MYCN gene amplification [22 (28.9%) vs. 13 (17.1%), P=0.008], chromosome 11q23 aberration [16 (21.1%) vs. 31 (40.8%), P=0.012], radiotherapy [30 (39.5%) vs. 24 (31.6%), P=0.025], and BM-MRD positivity based on PHOX2B gene detected by qRT-PCR [3 (3.9%) vs. 17 (22.4%), P=0.001]. However, no statistically significant differences were observed between the non-metastatic and metastatic pediatric patients in terms of a diagnostic age less than 18 months [27 (35.5%) vs. 35 (46.1%)], the primary tumor in adrenal [12 (15.8%) vs. 17 (22.4%)], the pathological histological type [9 (11.8%) vs. 16 (21.1%)], INSS stage 4 [31 (40.8%) vs. 36 (47.4%)], high-risk INRG staging [33 (43.4%) vs. 36 (47.4%)] and FCM positivity [1 (1.3%) vs. 5 (6.6%)].

Value of ¹²³I-MIBG scintigraphy in the evaluation of NB metastasis

¹²³I-MIBG scintigraphy showed 25 (32.9%) positive findings and 51 (67.1%) negative findings for metastasis diagnosis, of which, 57 [negative: 34 (44.7%); positive: 23 (30.2%)] were consistent with the gold standard. Additionally, there was a statistically significant difference between the NB patients with and without metastasis using ¹²³I-MIBG scintigraphy, which had an AUC of 0.760 (95% CI: 0.649–0.870), a sensitivity of 57.5%, a specificity of 94.4%, a PPV of 92.0%, and a NPV of 66.7% (Table 2).

Value of multi-parameter diagnostic model in the evaluation of NB metastasis

We subsequently developed a diagnostic model by logistic regression analysis that incorporated parameters such as ¹²³I-MIBG scintigraphy, MYCN gene amplification status, chromosome 11q23 aberration, radiotherapy, and BM-MRD based on the PHOX2B gene. The multi-parameter diagnostic model had an AUC of 0.907 (95% CI: 0.834–0.979), and a sensitivity, specificity, PPV, and NPV of 82.1%, 87.9%, 88.9%, and 80.6%, respectively (Table 2 and Figure 2). Notably, the DeLong test revealed that our model had a significantly better ROC curve than that of ¹²³I-MIBG scintigraphy alone (Z=3.964, P<0.001).

Figure 2 ROC curves of ¹²³I-MIBG and the multi-parameter diagnostic model. AUC, area under the curve; MIBG, metaiodobenzylguanidine; ROC, receiver operating characteristic curve.

Discussion

NB is a malignant tumor, and 70% of NB patients exhibit metastasis at diagnosis (31). The early and accurate assessment of metastasis is helpful in selecting the optimal treatment and improving prognosis (32). However, only a few studies have been conducted on the development of diagnostic models for finding metastases in patients. Our findings suggest that ¹²³I-MIBG scintigraphy can effectively monitor metastasis in pediatric NB patients, but its sensitivity needs to be improved. Combining clinical parameters (i.e., BM-MRD, MYCN gene, chromosome 11q23, and radiotherapy) with ¹²³I-MIBG scintigraphy can significantly enhance the diagnostic efficacy of metastatic disease models for in NB patients.

The most common site of metastasis is the bone/BM, which always means a worse prognosis (33). BM aspiration biopsy has been the gold standard for assessing NB metastasis in BM for many years; however, its sensitivity is limited when the NB cell contamination is <10%, and it can seriously underestimate the prevalence of BM infiltration (34). Therefore, more sensitive and accurate methods for the detection of MRD are needed. Currently, methods targeting single tumor cells such as FCM and qRT-PCR are widely used; however, despite enhanced sensitivity, the issue of false-negative results from sampling site variability remains unresolved (34). In comparison to qRT-PCR, FCM has a number of advantages, such as rapidity, wide coverage, simplicity of execution, and cost effectiveness (35). However, its further application is limited due to its lack of sensitivity and the potential for immune phenotypic changes in NB cells during treatment (36).

¹²³I-MIBG scintigraphy is an optimal tumor-specific imaging technique and is the preferred functional imaging method for the diagnosis, staging, prognosis prediction, and assessment of the therapeutic response of NB. ¹²³I-MIBG uptake is observed in 90% of NB cases, enabling the identification of sites with metastatic disease (37). A single-institution retrospective analyses confirmed that ¹²³I-MIBG imaging is more likely to detect metastatic disease than anatomic imaging (19). Many previous studies have shown that ¹²³I-MIBG scintigraphy has a high level of sensitivity and specificity (38,39). One study reported that its sensitivity varies from 67% to 100% (40). The efficacy and reproducibility of ¹²³I-MIBG scintigraphy make it an important component in the diagnostic evaluation of patients with NB.

Our study showed the clinical significance of ¹²³I-MIBG scintigraphy in distinguishing between patients with and without metastasis, and its superior diagnostic efficacy (AUC: 0.760). Consistent with previous reports, our study reported a specificity rate of 94.4%, but a sensitivity of only 57.5%, which was slightly lower than that reported in previous studies. However, Liu et al. reported a sensitivity of 61%, which is consistent with our findings. The difference in sensitivity could be attributed to: (I) the limited resolution; (II) the presence of small lesions near the site of physiological MIBG uptake; and (III) myelosuppression after chemotherapy (30). For example, among the ¹²³I-MIBG negative patients, there was one case in which ¹²³I-MIBG scintigraphy produced a false-negative result; however, this might have been due to the close proximity between the time of the child’s chemotherapy and the scan, which were only 14 days apart (Figure 3).

Figure 3 A 7-year-old boy was found to have a left adrenal mass, which was resected and confirmed to be stage 4 and high-risk NB. (A,B) The purpose of the ¹²³I-MIBG scan, which was performed 14 days post-treatment, was to assess the efficacy of chemotherapy and evaluate metastasis. No metastatic lesions were detected. (C-E) The axial images showed no ¹²³I-MIBG uptake in the primary tumor site. BM-MRD and flow cytometry were performed four days later. The BM-MRD was 40.21×10^–4, and FCM was also able to detect NB cells, but the number was below 0.001%. BM, bone marrow; FCM, flow cytometry; MIBG, metaiodobenzylguanidine; MRD, minimal residual disease; NB, neuroblastoma.

The limitations of ¹²³I-MIBG scintigraphy, which include its unsuitability for dynamic testing due to radioactivity and its cumbersome procedure that requires at least two days scheduling, as well as the occurrence of false-negative scans, primarily in MRD (+) subjects following chemotherapy and/or surgery (38), necessitates the development of new methods to diagnose recurrence and metastatic in NB patients. Figures 3,4 show the high sensitivity of ¹²³I-MIBG and MRD, respectively. It is important to note that while the model enhanced the sensitivity of MIBG, this improvement came at the cost of reduced specificity. Other factors in the model might have contributed to this decrease in specificity.

Figure 4 A 5-year-old girl with treated high-risk neuroblastoma underwent ¹²³I-MIBG imaging nine months post-therapy to assess for MIBG-avid recurrent disease. (A,B) The presence of bone/bone marrow metastasis was indicated by the increased uptake of ¹²³I-MIBG in the right distal femur and proximal tibia (red arrows). (C-H) Intense activities were observed on the axial images. However, both the BM-MRD results based on the PHOX2B gene by qRT-PCR and FCM-MRD were negative, indicating no detection of NB tumor cells. BM, bone marrow; FCM, flow cytometry; MIBG, metaiodobenzylguanidine; MRD, minimal residual disease; NB, neuroblastoma; PHOX2B, paired-like homeobox 2B; qRT-PCR, quantitative reverse transcriptase polymerase chain reaction.

Current research on diagnostic metastasis models, especially those that include imaging, is very limited. Lin et al. established a nomogram (which included the primary site, histology, chemotherapy, radiotherapy and second malignant neoplasms) that could appropriately predict distant metastases, which had AUC values of 0.872 and 0.824 in the training and validation groups, respectively (41). In our study, by combining 123-MIBG positivity, MYCN gene amplification, chromosome 11q23 aberration, the receipt of radiotherapy by the patient, and BM-MRD positivity based on the PHOX2B gene, higher diagnostic efficacy was achieved (AUC: 0.907). When it is impossible to determine whether a child has metastasis, the above parameters can be combined to comprehensively evaluate and finally obtain a reliable result.

The MYCN gene has been extensively studied in NB, and the overexpression of MYCN is associated with a poor prognosis, an advanced disease stage, rapid tumor growth, and metastasis (42). Zhang et al. concluded that the MYCN oncogene plays a vital role in promoting metastasis, which is consistent with our findings (43). Further, 11q status is an important factor in the INRG classification system (2,44). Spitz et al. and Attiyeh et al. both found that aberrations in chromosome 11q were associated with a poorer prognosis and enabled the identification of patients at an increased risk of worse overall survival and metastatic relapse (6,45). As metastasis has worse clinicopathological features, aggressive treatment is recommended for children with high-risk NB and distant metastasis (46). Previous research has shown that in comparison to those who did not receive radiotherapy, metastatic NB patients who underwent radiotherapy had improved overall survival (47-49). The feasibility of administering radiotherapy to metastatic sites has been observed in stage 4 or high-risk NB, which might explain the role of radiotherapy in our findings.

The present study had some limitations. First, it was a retrospective study with a limited sample size. Second, the study was exclusively conducted at a single center. Third, this study involved patients for whom various INRG classification systems had been used. Consequently, diverse treatment regimens were applied, and the timing of imaging relative to treatment varied, which might have influenced the study outcomes. Finally, a selection bias might have been introduced because of missing data in the sample, and a validation group was lacking. Thus, prospective, multicenter, and large-scale studies need to be conducted to further validate our findings.

Conclusions

The use of ¹²³I-MIBG scintigraphy shows significant value in the assessment of NB metastasis. By incorporating a multi-parameter diagnostic model that integrates MYCN gene amplification status, chromosome 11q23 aberration, radiotherapy, and BM-MRD based on PHOX2B gene, the diagnostic efficacy for NB patients with or without metastasis can be further enhanced.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the STARD reporting checklist. Available at https://qims.amegroups.com/article/view/10.21037/qims-24-1201/rc

Funding: This work was supported by the National Natural Science Foundation of China (No. 82102088 to W.W.) and the National Natural Science Foundation of China (No. 82272034 to J.Y.).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://qims.amegroups.com/article/view/10.21037/qims-24-1201/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Institutional Review Board of Beijing Friendship Hospital, Capital Medical University (No. 2022-P2-314-01), and the requirement of individual consent for this retrospective analysis was waived.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Matthay KK, Maris JM, Schleiermacher G, Nakagawara A, Mackall CL, Diller L, Weiss WA. Neuroblastoma. Nat Rev Dis Primers 2016;2:16078. [Crossref] [PubMed]
2. Cohn SL, Pearson AD, London WB, Monclair T, Ambros PF, Brodeur GM, Faldum A, Hero B, Iehara T, Machin D, Mosseri V, Simon T, Garaventa A, Castel V, Matthay KK. INRG Task Force. The International Neuroblastoma Risk Group (INRG) classification system: an INRG Task Force report. J Clin Oncol 2009;27:289-97. [Crossref] [PubMed]
3. Park JR, Bagatell R, Cohn SL, Pearson AD, Villablanca JG, Berthold F, Burchill S, Boubaker A, McHugh K, Nuchtern JG, London WB, Seibel NL, Lindwasser OW, Maris JM, Brock P, Schleiermacher G, Ladenstein R, Matthay KK, Valteau-Couanet D. Revisions to the International Neuroblastoma Response Criteria: A Consensus Statement From the National Cancer Institute Clinical Trials Planning Meeting. J Clin Oncol 2017;35:2580-7. [Crossref] [PubMed]
4. Maris JM. Recent advances in neuroblastoma. N Engl J Med 2010;362:2202-11. [Crossref] [PubMed]
5. Bhavsar SP. Metastasis in neuroblastoma: the MYCN question. Front Oncol 2023;13:1196861. [Crossref] [PubMed]
6. Spitz R, Hero B, Simon T, Berthold F. Loss in chromosome 11q identifies tumors with increased risk for metastatic relapses in localized and 4S neuroblastoma. Clin Cancer Res 2006;12:3368-73. [Crossref] [PubMed]
7. Liu PY, Tee AE, Milazzo G, Hannan KM, Maag J, Mondal S, et al. The long noncoding RNA lncNB1 promotes tumorigenesis by interacting with ribosomal protein RPL35. Nat Commun 2019;10:5026. [Crossref] [PubMed]
8. Lynch J, Fay J, Meehan M, Bryan K, Watters KM, Murphy DM, Stallings RL. MiRNA-335 suppresses neuroblastoma cell invasiveness by direct targeting of multiple genes from the non-canonical TGF-β signalling pathway. Carcinogenesis 2012;33:976-85. [Crossref] [PubMed]
9. Burchill SA, Selby PJ. Molecular detection of low-level disease in patients with cancer. J Pathol 2000;190:6-14. [Crossref] [PubMed]
10. Hirase S, Saitoh A, Hartomo TB, Kozaki A, Yanai T, Hasegawa D, Kawasaki K, Kosaka Y, Matsuo M, Yamamoto N, Mori T, Hayakawa A, Iijima K, Nishio H, Nishimura N. Early detection of tumor relapse/regrowth by consecutive minimal residual disease monitoring in high-risk neuroblastoma patients. Oncol Lett 2016;12:1119-23. [Crossref] [PubMed]
11. Nishimura N, Ishida T, Yokota I, Matsumoto K, Shichino H, Fujisaki H, Sarashina T, Kamijo T, Takimoto T, Iehara T, Tajiri T, On Behalf Of The Jccg Neuroblastoma Committee. Minimal Residual Disease Detected by the 7NB-mRNAs ddPCR Assay Is Associated with Disease Progression in High-Risk Neuroblastoma Patients: A Prospective Multicenter Observational Study in Japan. Biology (Basel) 2023.
12. Luskin MR, Murakami MA, Manalis SR, Weinstock DM. Targeting minimal residual disease: a path to cure? Nat Rev Cancer 2018;18:255-63. [Crossref] [PubMed]
13. Stutterheim J, Gerritsen A, Zappeij-Kannegieter L, Kleijn I, Dee R, Hooft L, van Noesel MM, Bierings M, Berthold F, Versteeg R, Caron HN, van der Schoot CE, Tytgat GA. PHOX2B is a novel and specific marker for minimal residual disease testing in neuroblastoma. J Clin Oncol 2008;26:5443-9. [Crossref] [PubMed]
14. Stutterheim J, Gerritsen A, Zappeij-Kannegieter L, Yalcin B, Dee R, van Noesel MM, Berthold F, Versteeg R, Caron HN, van der Schoot CE, Tytgat GA. Detecting minimal residual disease in neuroblastoma: the superiority of a panel of real-time quantitative PCR markers. Clin Chem 2009;55:1316-26. [Crossref] [PubMed]
15. Beiske K, Burchill SA, Cheung IY, Hiyama E, Seeger RC, Cohn SL, Pearson AD, Matthay KK. International neuroblastoma Risk Group Task Force. Consensus criteria for sensitive detection of minimal neuroblastoma cells in bone marrow, blood and stem cell preparations by immunocytology and QRT-PCR: recommendations by the International Neuroblastoma Risk Group Task Force. Br J Cancer 2009;100:1627-37. [Crossref] [PubMed]
16. Sharp SE, Trout AT, Weiss BD, Gelfand MJ. MIBG in Neuroblastoma Diagnostic Imaging and Therapy. Radiographics 2016;36:258-78. [Crossref] [PubMed]
17. Pfluger T, Piccardo A. Neuroblastoma: MIBG Imaging and New Tracers. Semin Nucl Med 2017;47:143-57. [Crossref] [PubMed]
18. Chang MC, Peng CL, Chen CT, Shih YH, Chen JH, Tai YJ, Chiang YC. Iodine-123 Metaiodobenzylguanidine (I-123 MIBG) in Clinical Applications: A Comprehensive Review. Pharmaceuticals (Basel) 2024.
19. Kushner BH, Kramer K, Modak S, Cheung NK. Sensitivity of surveillance studies for detecting asymptomatic and unsuspected relapse of high-risk neuroblastoma. J Clin Oncol 2009;27:1041-6. [Crossref] [PubMed]
20. Voss SD. Functional and anatomical imaging in pediatric oncology: which is best for which tumors. Pediatr Radiol 2019;49:1534-44. [Crossref] [PubMed]
21. Bar-Sever Z, Biassoni L, Shulkin B, Kong G, Hofman MS, Lopci E, Manea I, Koziorowski J, Castellani R, Boubaker A, Lambert B, Pfluger T, Nadel H, Sharp S, Giammarile F. Guidelines on nuclear medicine imaging in neuroblastoma. Eur J Nucl Med Mol Imaging 2018;45:2009-24. [Crossref] [PubMed]
22. Granata C, Carlini C, Conte M, Claudiani F, Campus R, Rizzo A. False positive MIBG scan due to accessory spleen. Med Pediatr Oncol 2001;37:138-9. [Crossref] [PubMed]
23. Moralidis E, Arsos G, Papakonstantinou E, Badouraki M, Koliouskas D, Karakatsanis C. 123I-Metaiodobenzylguanidine accumulation in a urinoma and cortex of an obstructed kidney after surgical resection of an abdominal neuroblastoma. Pediatr Radiol 2008;38:118-21. [Crossref] [PubMed]
24. Pfluger T, Schmied C, Porn U, Leinsinger G, Vollmar C, Dresel S, Schmid I, Hahn K. Integrated imaging using MRI and 123I metaiodobenzylguanidine scintigraphy to improve sensitivity and specificity in the diagnosis of pediatric neuroblastoma. AJR Am J Roentgenol 2003;181:1115-24. [Crossref] [PubMed]
25. Jacobs A, Lenoir P, Delree M, Ramet J, Piepsz A. Unusual Tc-99m MDP and I-123 MIBG images in focal pyelonephritis. Clin Nucl Med 1990;15:821-4. [Crossref] [PubMed]
26. Satharasinghe K, Trahair TN, Barbaric D, O'Brien TA, Russell SJ, Cohn RJ, Marshall GM, Ziegler DS. False-positive MIBG scans with normal computed tomography imaging in patients with high-risk neuroblastoma. J Clin Oncol 2009;27:e233-4; author reply e235. [Crossref] [PubMed]
27. Irwin MS, Naranjo A, Zhang FF, Cohn SL, London WB, Gastier-Foster JM, Ramirez NC, Pfau R, Reshmi S, Wagner E, Nuchtern J, Asgharzadeh S, Shimada H, Maris JM, Bagatell R, Park JR, Hogarty MD. Revised Neuroblastoma Risk Classification System: A Report From the Children's Oncology Group. J Clin Oncol 2021;39:3229-41. [Crossref] [PubMed]
28. Shimada H, Umehara S, Monobe Y, Hachitanda Y, Nakagawa A, Goto S, Gerbing RB, Stram DO, Lukens JN, Matthay KK. International neuroblastoma pathology classification for prognostic evaluation of patients with peripheral neuroblastic tumors: a report from the Children's Cancer Group. Cancer 2001;92:2451-61. [Crossref] [PubMed]
29. Olivier P, Colarinha P, Fettich J, Fischer S, Frökier J, Giammarile F, Gordon I, Hahn K, Kabasakal L, Mann M, Mitjavila M, Piepsz A, Porn U, Sixt R, van Velzen J. Guidelines for radioiodinated MIBG scintigraphy in children. Eur J Nucl Med Mol Imaging 2003;30:B45-50. [Crossref] [PubMed]
30. Liu B, Servaes S, Zhuang H. SPECT/CT MIBG Imaging Is Crucial in the Follow-up of the Patients With High-Risk Neuroblastoma. Clin Nucl Med 2018;43:232-8. [Crossref] [PubMed]
31. Ara T, DeClerck YA. Mechanisms of invasion and metastasis in human neuroblastoma. Cancer Metastasis Rev 2006;25:645-57. [Crossref] [PubMed]
32. Morgenstern DA, Bagatell R, Cohn SL, Hogarty MD, Maris JM, Moreno L, Park JR, Pearson AD, Schleiermacher G, Valteau-Couanet D, London WB, Irwin MS. The challenge of defining "ultra-high-risk" neuroblastoma. Pediatr Blood Cancer 2019;66:e27556. [Crossref] [PubMed]
33. London WB, Bagatell R, Weigel BJ, Fox E, Guo D, Van Ryn C, Naranjo A, Park JR. Historical time to disease progression and progression-free survival in patients with recurrent/refractory neuroblastoma treated in the modern era on Children's Oncology Group early-phase trials. Cancer 2017;123:4914-23. [Crossref] [PubMed]
34. Cheung NK, Heller G, Kushner BH, Liu C, Cheung IY. Detection of metastatic neuroblastoma in bone marrow: when is routine marrow histology insensitive? J Clin Oncol 1997;15:2807-17. [Crossref] [PubMed]
35. Uemura S, Ishida T, Thwin KKM, Yamamoto N, Tamura A, Kishimoto K, Hasegawa D, Kosaka Y, Nino N, Lin KS, Takafuji S, Mori T, Iijima K, Nishimura N. Dynamics of Minimal Residual Disease in Neuroblastoma Patients. Front Oncol 2019;9:455. [Crossref] [PubMed]
36. Hillengass J, Merz M, Delorme S. Minimal residual disease in multiple myeloma: use of magnetic resonance imaging. Semin Hematol 2018;55:19-21. [Crossref] [PubMed]
37. Bagatell R, Park JR, Acharya S, Aldrink J, Allison J, Alva E, et al. Neuroblastoma, Version 2.2024, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw 2024;22:413-33. [Crossref] [PubMed]
38. Vik TA, Pfluger T, Kadota R, Castel V, Tulchinsky M, Farto JC, Heiba S, Serafini A, Tumeh S, Khutoryansky N, Jacobson AF. (123)I-mIBG scintigraphy in patients with known or suspected neuroblastoma: Results from a prospective multicenter trial. Pediatr Blood Cancer 2009;52:784-90. [Crossref] [PubMed]
39. Matthay KK, Shulkin B, Ladenstein R, Michon J, Giammarile F, Lewington V, Pearson AD, Cohn SL. Criteria for evaluation of disease extent by (123)I-metaiodobenzylguanidine scans in neuroblastoma: a report for the International Neuroblastoma Risk Group (INRG) Task Force. Br J Cancer 2010;102:1319-26. [Crossref] [PubMed]
40. Bleeker G, Tytgat GA, Adam JA, Caron HN, Kremer LC, Hooft L, van Dalen EC. 123I-MIBG scintigraphy and 18F-FDG-PET imaging for diagnosing neuroblastoma. Cochrane Database Syst Rev 2015;2015:CD009263. [Crossref] [PubMed]
41. Lin Y, Wang Z, Liu S. Risk factors and novel predictive models for metastatic neuroblastoma in children. Eur J Surg Oncol 2023;49:107110. [Crossref] [PubMed]
42. Seeger RC, Brodeur GM, Sather H, Dalton A, Siegel SE, Wong KY, Hammond D. Association of multiple copies of the N-myc oncogene with rapid progression of neuroblastomas. N Engl J Med 1985;313:1111-6. [Crossref] [PubMed]
43. Zhang HF, Delaidelli A, Javed S, Turgu B, Morrison T, Hughes CS, et al. A MYCN-independent mechanism mediating secretome reprogramming and metastasis in MYCN-amplified neuroblastoma. Sci Adv 2023;9:eadg6693. [Crossref] [PubMed]
44. Monclair T, Brodeur GM, Ambros PF, Brisse HJ, Cecchetto G, Holmes K, Kaneko M, London WB, Matthay KK, Nuchtern JG, von Schweinitz D, Simon T, Cohn SL, Pearson AD. INRG Task Force. The International Neuroblastoma Risk Group (INRG) staging system: an INRG Task Force report. J Clin Oncol 2009;27:298-303. [Crossref] [PubMed]
45. Attiyeh EF, London WB, Mossé YP, Wang Q, Winter C, Khazi D, McGrady PW, Seeger RC, Look AT, Shimada H, Brodeur GM, Cohn SL, Matthay KK, Maris JMChildren's Oncology Group. Chromosome 1p and 11q deletions and outcome in neuroblastoma. N Engl J Med 2005;353:2243-53. [Crossref] [PubMed]
46. Liu S, Yin W, Lin Y, Huang S, Xue S, Sun G, Wang C. Metastasis pattern and prognosis in children with neuroblastoma. World J Surg Oncol 2023;21:130. [Crossref] [PubMed]
47. Robbins JR, Krasin MJ, Pai Panandiker AS, Watkins A, Wu J, Santana VM, Furman WL, Davidoff AM, McGregor LM. Radiation therapy as part of local control of metastatic neuroblastoma: the St Jude Children's Research Hospital experience. J Pediatr Surg 2010;45:678-86. [Crossref] [PubMed]
48. Casey DL, Pitter KL, Kushner BH, Cheung NV, Modak S, LaQuaglia MP, Wolden SL. Radiation Therapy to Sites of Metastatic Disease as Part of Consolidation in High-Risk Neuroblastoma: Can Long-term Control Be Achieved? Int J Radiat Oncol Biol Phys 2018;100:1204-9. [Crossref] [PubMed]
49. Zhao Q, Liu Y, Zhang Y, Meng L, Wei J, Wang B, Wang H, Xin Y, Dong L, Jiang X. Role and toxicity of radiation therapy in neuroblastoma patients: A literature review. Crit Rev Oncol Hematol 2020;149:102924. [Crossref] [PubMed]