International Neuroblastoma Risk Group Staging Research Articles

Inter-observer variability in assessing image-defined risk factors: implications for risk stratification in locoregional abdominopelvic neuroblastoma.

Risk stratification for locoregional neuroblastoma partially relies on image-defined risk factors (IDRFs). This study aimed to evaluate how inter-observer variability in assessing IDRFs impacts risk stratification in locoregional abdominopelvic neuroblastoma. A retrospective analysis was conducted on 123 patients who underwent upfront contrast-enhanced CT scans. Two radiologists independently assessed the presence of IDRFs. Patients were staged as either L1 (IDRF-negative) or L2 (IDRF-positive) according to the International Neuroblastoma Risk Group Staging System. Based on the radiologists' evaluations, 97 cases with sufficient clinical data were classified into risk groups using the revised Children's Oncology Group neuroblastoma risk classifier. The kappa values and 95% confidence intervals (CIs) were calculated to assess inter-radiologist agreement on IDRF evaluation and risk stratification. There was low agreement between radiologists in assessing L1/L2 status with a kappa value of 0.28 (95% CI: 0.14-0.42). However, agreement for evaluating the number of IDRFs was good, with an intraclass correlation coefficient of 0.73 (95% CI: 0.64-0.80). Based on the first radiologist's evaluation, 13 patients were classified as low-risk, 52 as intermediate-risk, and 32 as high-risk. Based on the second radiologist's evaluation, 37 patients were classified as low-risk, 37 as intermediate-risk, and 23 as high-risk. The kappa value for risk stratification between the two radiologists was 0.47 (95% CI: 0.33-0.62). Inter-observer variability in assessing IDRF presence may affect risk stratification in locoregional abdominopelvic neuroblastoma.

Impact of an objective scoring system on initiation of therapy in patients with International Neuroblastoma Risk Group Staging System (INRGSS) stage MS neuroblastoma: A report from the Children’s Oncology Group.

10003 Background: A subset of children with INRGSS Stage MS neuroblastoma (NBL) may be observed without treatment, while others have rapidly evolving symptoms that can be life-threatening. ANBL1232 adapted a previously developed semi-quantitative objective scoring system (OSS) to assign a numeric value to symptoms and laboratory abnormalities. The goal was to standardize monitoring, therapy initiation, and treatment duration in this cohort. Methods: Patients with newly diagnosed Stage MS NBL were eligible for this prospective trial. An OSS score (OSSS) was assigned at enrollment; the total number was based on scoring in 5 systems: gastrointestinal (GI), respiratory, circulatory, renal, and hepatic. Within the 5 systems, individual clinical and laboratory parameters were scored as not present = 0, mild/moderate = 1 [Grade 2 CTCAEv4.0 adverse event (AE)] or severe = 2 (Grade ≥3 AE). The OSSS was the sum of highest score within each organ system (maximum score: 2 per system, 10 total). Asymptomatic MS patients with an OSSS < 2 who were either < 3 months (mo) of age without hepatomegaly or 3-18 mo of age with favorable biology tumors were eligible for observation without initial treatment. Observed patients underwent monthly physical examinations and laboratory assessments for the first 6 mo following diagnosis. Tumor imaging was performed every 3 mo for 1 year, then every 6-12 mo through 36 mo. An OSSS ≥2 or a protocol-defined increase in primary tumor size prompted initiation of therapy. Results: From July 2014 to February 2021, 89 eligible and evaluable patients with newly diagnosed stage MS NBL enrolled. Among these, 18 (20.2%; 5 male and 13 female) were eligible for observation. Observed patients were older at diagnosis (median age: 2.87 vs. 1.81 mo, p = 0.23) and more likely to have primary tumors without image-defined risk factors (62.5% vs. 30.0%, p = 0.0166) than those assigned to therapy up front. Nearly all observed patients (17/18) had abdominal/adrenal primaries. The initial OSSS was 0 in all observed patients. Median reported observation time was 36 mo (range: 1-36 mo); 13 patients completed all required monthly assessments for the first 6 mo. No patients in the observation cohort required initiation of therapy for an increase in OSSS. One patient with OSSS = 1 at mo 3 had complete GI symptom resolution by mo 5. Conclusions: An OSSS of 0 at diagnosis can aid in identifying a favorable group of patients with stage MS NBL who can be safely observed. No patients in the observation cohort developed evidence of organ dysfunction or OSSS > 1 despite frequent physical examination and comprehensive laboratory testing, suggesting that follow up may be safely liberalized in this population over time. Clinical and laboratory criteria implemented at diagnosis could be used to identify patients requiring prompt treatment. Clinical trial information: NCT02176967 .

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)

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.

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.

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.

Neuroblastic tumours in children: Outcome from a referral centre in India.

There is a paucity of uniform literature on the outcome of children with neuroblastic tumours from developing countries. This study aims to present the outcome in children having neuroblastic tumours. We retrospectively reviewed patients with neuroblastic tumours from January 2014 to March 2020. Data analysed were pertaining to the age, sex, presentation, site, stage, diagnostic evaluation performed, management and follow-up results, etc., The final outcomes were assessed as complete response; partial response (PR); no response (NR) and progressive disease. International Neuroblastoma Risk Group staging was used and patients were categorised on the basis of age, site and stage of tumour. Overall survival (OS) was calculated from the date of diagnosis to the date of last follow-up and event for OS was death. Forty-seven patients were included with median age of 60 months (ranges of 2-180; mean = 61.87 ± 47.56). About 72.3% (n = 34) patients were males. Out of total, 6.4% (n = 3), 53.2% (n = 25) and 38.3% (n = 18) were in stage L1, L2 and M, respectively, whereas 2.1% (n = 1) patients were in stage MS. Surgery was performed in 25 (53.19%) patients, but gross total excision was achieved in 48.90% (n = 23) patients. Onlu 10.60% (n = 5) patients were referred, whereas 14.89% (n = 7) patients reported recurrences. Mean and median follow-up time of the patients was 24.64 ± 16.04 and 18 months (range: 3-60 months). Out of total, 53.2% (n = 25) and 29.8% (n = 14) patients had complete and PRs, respectively, whereas 17% (n = 8) patients had NR. Out of the total 47 patients, 8 (17%) achieved events (deaths), whereas the rest, 39 (83%) patients, were censored. Mean event-free OS time was 50.04 months. There was a significant difference in patient deaths in recurrence and non-recurred patients (4/7, 57.1% vs. 4/40/, 10%, P = 0.011). Survival time was significantly higher in patients with stages L1-L2 as compared to Stage 4. Stage and age were found predictors of survival.

An 18F-FDG PET/CT radiomics nomogram for differentiation of high-risk and non-high-risk patients of the International Neuroblastoma Risk Group Staging System

PurposeTo develop and validate an 18F-FDG PET/CT radiomics nomogram for non-invasive differentiation of high-risk and non-high-risk patients of the International Neuroblastoma Risk Group (INRG) Staging System (INRGSS). MethodOne hundred thirty-nine neuroblastoma patients were retrospectively enrolled and classified into a training set (n = 84) and validation set (n = 55). Radiomics features were extracted from 18F-FDG PET/CT images, a radiomics signature was constructed, and a radiomics score (Rad score) was calculated. Then, univariate and multivariate logistic regression analyses were used to screen out the independent clinical factors and construct the clinical model. A radiomics nomogram was developed based on the Rad score and independent clinical factors. The performance of the clinical model, Rad score, and nomogram was assessed by receiver operating characteristic (ROC) curves, calibration curves, and decision curves analysis (DCA). ResultsSeven radiomics features were selected to build the radiomics signature. The age at diagnosis, the INRG stage, neuron-specific enolase (NSE) and Rad score showed a significant difference between the high-risk and non-high-risk patients. The radiomics nomogram incorporating the Rad score and the above clinical factors demonstrated favorable predictive value for differentiating high-risk from non-high-risk, yielded AUCs of 0.988 and 0.971 in the training and validation sets, respectively. The calibration curves showed that the radiomics nomogram had the goodness of fit, and the DCA demonstrated that the radiomics nomogram was clinically useful. ConclusionsThe radiomics nomogram, which incorporates the Rad score and clinical factors can well predict high-risk and non-high-risk patients of the INRGSS. It may help the disease follow-up and management in clinical practice and assist in personalized and precise treatment of neuroblastoma.

Surgical management in pediatricneuroblastoma diagnosis and treatment: a 20-year, single-center experience.

The currently utilized International Neuroblastoma Risk Group (INRG) staging system developed in 2009 uses image-defined risk factors as a measure of surgical risk, separating resectable neuroblastoma from those best preceded by chemotherapy. The previous International Neuroblastoma Staging System was based primarily on surgical findings. We hypothesized there would be a change to the role of the surgeon in neuroblastoma treatment in the more recent decade. This is a single center 20-year retrospective analysis of 104 patients with International Classification of Diseases-9 and -10 codes for neuroblastoma. Patient demographics, tumor site, cancer treatment modality, survival, biopsy technique, surgical intervention, and pathology staging were collected. Data was analyzed by analysis of variance (ANOVA) and Student's t test. There was a decrease in open surgeries for extra-adrenal neuroblastomas in the later decade (77%, 31%, P = 0.01). There was a narrowing of the time interval to surgery in the later cohort, likely as a result of uniformity in surgical timing on treatment protocols relying on INRG staging. Our findings mirror changes in practice patterns globally. We found an increase in minimally invasive approaches but did not find a difference in the role of the surgeon under the INRG staging system.

The expression of PHOX2B in bone marrow and peripheral blood predicts adverse clinical outcome in non-high-risk neuroblastoma

Paired-like homeobox 2B (PHOX2B) is a highly sensitive and specific biomarker for diagnosing neuroblastoma, as well as detecting minimal residual disease in neuroblastoma. The clinical significance of PHOX2B expression in bone marrow (BM) and peripheral blood (PB) samples of newly diagnosed patients with very low-, low- and intermediate-risk neuroblastoma remains unknown, to the best of our knowledge. The expression level of PHOX2B in paired BM and PB samples of patients with newly diagnosed neuroblastoma was validated using reverse transcription-quantitative polymerase chain reaction (RTqPCR). Among the 132 patients, 26 exhibited a positive PHOX2B expression BM (19.7%) and 11 in PB (8.3%) samples. PHOX2B was highly expressed in BM and PB samples from patients aged <18 months, with International Neuroblastoma Risk Group Staging System stages M and MS, 1p loss of heterozygosity, and high levels of lactate dehydrogenase, serum ferritin and neuron-specific enolase (p < 0.05). In all eligible patients, the 2-year event-free survival (EFS) and overall survival (OS) rates were 94.7 ± 2.0% and 97.7 ± 1.3%, respectively. However, the 2-year EFS rates were significantly decreased to 76.9 ± 8.3% and 63.6 ± 14.5% in patients with a positive PHOX2B expression in BM and PB samples, respectively (p < 0.05). Similarly, the 2-year OS rates were also decreased to 88.5 ± 6.3% and 81.8 ± 11.6% in patients with a positive PHOX2B expression in BM and PB samples, respectively (p < 0.05). In conclusion, a positive PHOX2B expression in BM and PB samples at diagnosis had a strong adverse prognostic effect on patients with non-high-risk neuroblastoma.

Revised Neuroblastoma Risk Classification System: A Report From the Children's Oncology Group.

Treatment planning for children with neuroblastoma requires accurate assessment of prognosis. The most recent Children's Oncology Group (COG) risk classification system used tumor stage as defined by the International Neuroblastoma Staging System. Here, we validate a revised classifier using the International Neuroblastoma Risk Group Staging System (INRGSS) and incorporate segmental chromosome aberrations (SCA) as an additional genomic biomarker. Newly diagnosed patients enrolled on the COG neuroblastoma biology study ANBL00B1 between 2007 and 2017 with known age, International Neuroblastoma Staging System, and INRGSS stage were identified (N = 4,832). Tumor MYCN status, ploidy, SCA status (1p and 11q), and International Neuroblastoma Pathology Classification histology were determined centrally. Survival analyses were performed for combinations of prognostic factors used in COG risk classification according to the prior version 1, and to validate a revised algorithm (version 2). Most patients with locoregional tumors had excellent outcomes except for those with image-defined risk factors (INRGSS L2) with MYCN amplification (5-year event-free survival and overall survival: 76.3% ± 5.8% and 79.9% ± 5.5%, respectively) or patients age ≥ 18 months with L2 MYCN nonamplified tumors with unfavorable International Neuroblastoma Pathology Classification histology (72.7% ± 5.4% and 82.4% ± 4.6%), which includes the majority of L2 patients with SCA. For patients with stage M (metastatic) and MS (metastatic, special) disease, genomic biomarkers affected risk group assignment for those < 12 months (MYCN) or 12-18 months (MYCN, histology, ploidy, and SCA) of age. In a retrospective analysis of patient outcome, the 5-year event-free survival and overall survival using COG version 1 were low-risk: 89.4% ± 1.1% and 97.9% ± 0.5%; intermediate-risk: 86.1% ± 1.3% and 94.9% ± 0.8%; high-risk: 50.8% ± 1.4% and 61.9% ± 1.3%; and using COG version 2 were low-risk: 90.7% ± 1.1% and 97.9% ± 0.5%; intermediate-risk: 85.1% ± 1.4% and 95.8% ± 0.8%; high-risk: 51.2% ± 1.4% and 62.5% ± 1.3%, respectively. A revised 2021 COG neuroblastoma risk classifier (version 2) that uses the INRGSS and incorporates SCAs has been adopted to prospectively define COG clinical trial eligibility and treatment assignment.

Neuroblastoma.

The survival of patients with high-risk neuroblastoma has improved significantly with the use of intensive multimodality treatment regimens, including chemotherapy, surgery, radiation therapy, myeloablative chemotherapy followed by stem cell rescue, and immunotherapy. This report summarizes the current treatment strategies used in the COG and SIOP for children with neuroblastoma. The improved global collaboration and the adoption of a uniform International Neuroblastoma Risk Group Staging System will help facilitate comparison of homogeneous pretreatment cohorts across clinical trials. Future research strategies regarding the indications for and dosages of radiation therapy to the primary and metastatic sites, and the integration of meta-iodobenzyl guanidine therapy into the multimodal treatment program, are discussed.

Pictorial review of the clinical applications of MIBG in neuroblastoma: current practices

Neuroblastoma is the most common extra-cranial solid tumor in pediatrics. The objective of this manuscript is to present an image-rich review of the presentation, diagnosis, staging and response assessment in individuals with neuroblastoma with special attention to the role of I-123 mIBG (meta-iodobenzylguanidine). A literature search was performed in the PubMed and Scopus databases to identity articles published between 1980 and March 2020 regarding different aspects of neuroblastoma (presentation, diagnosis, pathologic classification, staging, and response monitoring). Different combinations of search terms were used including “neuroblastoma”, “presentation”, “diagnosis”, “staging”, “imaging”, “pathology”, “MIBG”, “FDG”, “norepinephrine transporter”, and “18F DOPA”. The references of the resultant articles were also used to identify additional manuscripts. A total of 101 key articles were identified that discussed the spectrum of presentation, diagnosis, staging and response assessment in individuals with neuroblastoma. These articles form the basis of this manuscript. Iodine-123-labeled meta-iodobenzylguanidine (mIBG) is the cornerstone of functional imaging for staging, therapeutic response monitoring, prognostication, and the detection of recurrence in patients with neuroblastoma. MIBG images are interpreted both qualitatively and semiquantitatively. The International Neuroblastoma Risk Group Staging System and the International Neuroblastoma Staging System are used to stage the disease extent before and after surgical resection, respectively. The Revised International Neuroblastoma Response Criteria, updated in 2017, stratify the treatment response based on findings on functional (with mIBG or if mIBG non-avid with [18F]-fluorodeoxyglucose) and anatomical (computed tomography or magnetic resonance) imaging and bone marrow aspirates.

Tailoring Therapy for Children With Neuroblastoma on the Basis of Risk Group Classification: Past, Present, and Future.

For children with neuroblastoma, the likelihood of cure varies widely according to age at diagnosis, disease stage, and tumor biology. Treatments are tailored for children with this clinically heterogeneous malignancy on the basis of a combination of markers that are predictive of risk of relapse and death. Sequential risk-based, cooperative-group clinical trials conducted during the past 4 decades have led to improved outcome for children with neuroblastoma. Increasingly accurate risk classification and refinements in treatment stratification strategies have been achieved with the more recent discovery of robust genomic and molecular biomarkers. In this review, we discuss the history of neuroblastoma risk classification in North America and Europe and highlight efforts by the International Neuroblastoma Risk Group (INRG) Task Force to develop a consensus approach for pretreatment stratification using seven risk criteria including an image-based staging system-the INRG Staging System. We also update readers on the current Children's Oncology Group risk classifier and outline plans for the development of a revised 2021 Children's Oncology Group classifier that will incorporate INRG Staging System criteria to facilitate harmonization of risk-based frontline treatment strategies conducted around the globe. In addition, we discuss new approaches to establish increasingly robust, future risk classification algorithms that will further refine treatment stratification using machine learning tools and expanded data from electronic health records and the INRG Data Commons.

Thoraco-abdominal neuroblastoma resection: the thoracophrenolaparotomic (TPL) approach.

The aim of the present study is to describe, for the first time in paediatric age, the technique and the outcomes of the thoracophrenolaparotomic (TPL) approach for surgical resection of thoraco-abdominal neuroblastomas (NBs) in children. A retrospective study was performed analysing clinical features and surgical outcomes of all children undergoing surgical resection of thoraco-abdominal NBs via the TPL approach in our third referral children's hospital, from January 2010 to November 2018. The details of the surgical technique were also reported. 5 children suffering from thoraco-abdominal NBs (n = 4 stage L2, n = 1 stage M-according to the International Neuroblastoma Risk Group Staging System, INRGSS-and n = 4 stage 3, n = 1 stage 4-according to International Neuroblastoma Staging System, INSS) underwent the TPL approach at a mean age of 72 months (range 27-180months). The surgical procedure was performed in a mean operative time of 5h 57min (range 2h 56min-9h) without any major intraoperative or postoperative complications. Following 24h in intensive care unit, all patients were safely discharged in a mean time of 12days (range 4-21 days). All patients were alive, without any tumour relapse, at the last follow-up visit (mean 3.2years, range 1-7years). This is the first study reporting the excellent surgical results we gained applying the TPL approach for surgical excision of multi-compartment tumours in children, allowing a gross total resection without intra- or post-operative complications.

Iron deficiency in children at the time of initial neuroblastoma diagnosis.

ABSTRACTImportanceThere is a high incidence of iron deficiency in children worldwide. Notably, however, while iron deficiency is the most common cause of anemia, little is known about the prevalence and different types of iron deficiency in neuroblastoma patients.ObjectiveThe aim of the present study was to investigate the prevalence of iron deficiency in patients newly diagnosed with neuroblastoma.MethodsA total of 195 newly diagnosed neuroblastoma patients from November 2015 to January 2018 were analyzed retrospectively. The survival analysis was estimated by the Kaplan‐Meier method.ResultsOf the 195 neuroblastoma patients included in the study, 121 (62.1%) had iron deficiency, 55 (28.2%) had absolute iron deficiency, and 66 (33.9%) had functional iron deficiency. Being aged ≥ 18 months, tumor originating in the abdomen, International Neuroblastoma Risk Group Staging System M, high‐risk neuroblastoma, lactate dehydrogenase ≥ 1500 U/L, neuron‐specific enolase ≥ 100 U/L, unfavorable histologic category, MYCN amplification, chromosome 1p loss, and bone marrow metastasis were associated with significantly higher rates of functional iron deficiency (P < 0.05).InterpretationFunctional iron deficiency at the time of initial neuroblastoma diagnosis predicted lower event‐free survival. Long‐term effects of iron supplementation in neuroblastoma patients with different types of iron deficiency need to be further studied.

Neuroblastoma image-defined risk factors in adrenal neuroblastoma: role of radiologist.

Neuroblastoma, one of the most common extracranial solid malignancies in children, is often localized in the adrenal glands (49%). The staging system for prognostic purpose was one of the first points of disagreement, which led to the International Neuroblastoma Staging System (INSS) of 1986, revised in 1989, which relies on surgical staging. The limit of this classification was the different surgical resection, also done at interval times from diagnosis. To overcome this difficulty, a new staging system was made based on preoperative imaging by the International Neuroblastoma Risk Group (INRG) in 2009. This new staging system uses 20 Image-Defined Risk Factors (IDRFs) across multiple organ systems. The scope of this IDRFs is to predict surgical outcomes and, in addition with clinical data, to provide risk stratification. The INRG Staging System (INRGSS) relies on Imaging-Defined Risk Factors (IDRFs) that are determined before surgery or other therapy. With the application of the INRGSS the radiologist's role in staging children with neuroblastoma increased. The review provides an overview of the INRGSS and the IDRFs in adrenal neuroblastoma.

MiR‑181c expression in neuroblastoma children and proliferation of neuroblastoma M17 cells

Expression level of miR-181c in neuroblastoma children and its effect on proliferation of neuroblastoma M17 cells were investigated. Fifty-seven neuroblastoma patients admitted to Weifang People's Hospital from January 2013 to December 2017 were selected and their cancer tissues and normal adjacent tissues were obtained. The expression level of miR-181c in the tissues of neuroblastoma patients was measured. The association of miR-181c expression level with the clinical and pathological features was analyzed. Neuroblastoma M17 cells were cultured in vitro, and cells were transfected and divided into miR-181c and blank groups. MTT assay was used to observe the proliferation of cells at 24, 48 and 72 h. The results of RT-qPCR detection showed that the expression level of miR-181c was significantly lower in neuroblastoma cancer tissues than that in adjacent tissues, with a statistically significant difference (t=18.570, P<0.001). The expression of miR-181c was not associated with sex (P=0.632), but associated with age, differentiation degree, lymph node metastasis, distant metastasis and the International Neuroblastoma Risk Group Staging System (INRGSS), with statistically significant differences (P<0.05). Following transfection of miR-181c into M17 cells, the results of MTT assay showed that there was no significant difference between the two groups in the proliferation of M17 cells at 24 h (P>0.05). After 48 h, differences between the two groups were recorded. Proliferation of M17 cells was significantly lower in the miR-181c group than that in the blank group, with a statistically significant difference (P<0.05). Age, differentiation degree, lymph node metastasis, distant metastasis, and INRGSS staging were independent risk factors for neuroblastoma (P<0.05). miR-181c has certain clinical significance in evaluating pathogenesis, early diagnosis and treatment of patients with neuroblastoma.

Radiological staging in neuroblastoma: computed tomography or magnetic resonance imaging?

PurposeTo compare the effectiveness of computed tomography (CT) and magnetic resonance imaging (MRI) in the staging of neuroblastomas according to the International Neuroblastoma Risk Group Staging System (INRGSS).Material and methodsIn this single-centre retrospective study we identified a total of 20 patients under the age of 18 years, who were admitted to our hospital with neuroblastoma between January 2005 and May 2018, and who had both CT and MRI examination. The INRGSS stages of tumours were evaluated by CT scan and MRI. Then, stages of tumours were described according to the INRGSS for CT and MRI, separately. The Spearman rank correlation test was used for statistical analysis. The p-value < 0.05 was considered as statistically significant.ResultsThe median age was 11 months, and the age range was one month to nine years. In our results; both MRI and CT were significant in the determination of radiological staging of NBL, p < 0.001 and p = 0.002, respectively. MRI was superior to CT in radiological staging. MRI was also superior for the detection of intraspinal extension, involvement of multiple body compartments, metastatic disease, and bone marrow infiltration. CT was more useful to consider the relationship between tumours and vascular structures.ConclusionsMRI and CT have high diagnostic accuracy rates in the staging of pre-treatment neuroblastomas. MRI is important in pre-treatment evaluation of neuroblastomas because of the higher detection of metastases as well as the lack of ionising radiation.