Metastatic Neuroblastoma Research Articles

Rationale for irradiation of persisting oligo-skeletal metastases to improve survival of metastatic neuroblastoma patients with a poor response to chemotherapy: A retrospective study.

Persistent metaiodobenzylguanidine (mIBG)-positive skeletal metastases post induction in high-risk neuroblastoma correlate with a poor outcome. The aim of this study was to investigate the potential rationale for a prospective randomized study evaluating the impact on event-free survival of the irradiation of residual oligo-skeletal metastases. Patients over 1year with a stage M neuroblastoma treated between 2000 and 2020 at Gustave Roussy were identified. Patients with a positive mIBG scan at diagnosis and persistent skeletal metastases after high-dose chemotherapy (HDC) were included. Data were retrospectively collected and mIBG scans reviewed by two nuclear medicine physicians. Persistent skeletal uptake after HDC was observed in 30/201 patients (15%). Four patients reached a complete response at the end of maintenance treatment and did not relapse (median follow-up [FU] 8years [1.8-11.8]), while two patients had progressive disease during maintenance. Among the 24 patients with persistent skeletal uptakes at the end of treatment, seven had a persistent response (median FU 8.2years [4-15.6]). Median SIOPEN (International Society of Paediatric Oncology European Neuroblastoma) scores post consolidation and at the end of treatment were, respectively, 2 [1-6] and 2 [0-4] for patients with persistent responses compared to 4 [1-28] and 2 [1-17] for patients with progressive diseases. Median SIOPEN score at progression was 34 [2-56]. Our study underlines that only a minority of patients had persistent skeletal mIBG-positive scans after HDC. Recurrence mainly occurred in disease sites present at diagnosis that cleared with chemotherapy. On-therapy control of the disease is the main challenge. These results highlight the complexity of conducting a randomized study exploring this strategy.

Outcome of radiotherapy for metastatic neuroblastoma

Background. Neuroblastoma (NB) is a prevalent solid extracranial tumor that primarily affects children. It is the third most common type of cancer in children, following leukemia and brain tumors. Aim. The study aimed to discuss the clinical outcomes after adjuvant radiotherapy to the primary site in case of metastatic NB after good response to chemotherapy. Methods. A retrospective clinical-dosimetric study of 25 patients metastatic NB treated with radiotherapy at Baghdad Radiotherapy and Nuclear Medicine Center, at Baghdad Medical City Complex, Baghdad, Iraq. Data collection begin from December 2023 and March 2024. Data were collected retrospectively with review of records. The following variables were studied: sex, age, date of diagnosis, site of primary tumor, site of metastasis, chemotherapy, surgery, RT, RT sites, doses of RT, fractions of RT, recurrence sites, date of relapse and survival outcome for each patient. Follow-up period include look up to metastasis, site of metastasis, recurrence, site of recurrence and survival rates. Results. In relation to sex, males (14, 56%) were more than females (11, 44%). The mean age of NB cases was 45.64±17.6 months. In NB, suprarenal masses were the most common site of primary in 21 (84%) of patients. The most common site of metastasis of NB was bone marrow in 12 (48). The multi sites of recurrence was the commonest presentation in 48%. The relapse-free survival (RFS) was 22.38 months. 5 out of 25 patients were alive whereas 20 (80%) of cases were dead. The median follow-up time was 6 years, and the OS of NB in this study after optimal treatment was 2.46 years (95%CI= 1.705-3.21) for survivors. The MS was 4.84 years. The OS was 6 yrs for those diagnosed at 2017, 2 yrs for those diagnosed at 2018, 1.5 yrs for those diagnosed at 2019, 1.75 yrs for those diagnosed at 2020, 3 yrs for those diagnosed at 2021 and 1.5 yrs for those diagnosed at 2022. There was a significant difference among doses (Log Rank (Mantel-Cox)= 11.425, p=0.044). Conclusions. This study is the first study in Iraq that examines the clinical results of radiotherapy on the primary site in cases of metastatic neuroblastoma following induction chemotherapy. The suprarenal masses of neuroblastoma are the most often occurring main site. The primary sites of metastases for neuroblastoma (NB) are the bone marrow and bones. Timely detection and proactive treatment of NB can improve overall results. Reoccurrence of skeletal issues and the infiltration of bone marrow are frequently observed. There were no significant differences observed in terms of relapse-free survival and overall survival based on factors such as sex, age, location of the main tumor, chemotherapy, radiation treatment, surgery, and radiation therapy dosages.

Optimizing the Outcome of Pediatric Metastatic Neuroblastoma in a Nontransplant Setting in a Developing Country: Retrospective Study from a Tertiary Cancer Center in India

Abstract Objective This article estimates the survival of children over 1 year of age diagnosed with metastatic neuroblastoma (NB) and treated in a nontransplant facility and determines the factors affecting survival. Materials and Method Case records of children aged 1 to 14 years treated for metastatic NB in our center from January 2008 to December 2017 were studied. Patients received conventional chemotherapy followed by surgery, radiotherapy, and metronomic maintenance chemotherapy. Results Eighty-nine patients with metastatic NB received treatment. Mean age was 3.5 years and male:female ratio was 1.1:1. The most common primary site was suprarenal (55%) and the most common site of metastasis was bone marrow (76%). Forty percent patients had multiple metastatic sites. Mean baseline lactate dehydrogenase (LDH) was 3724 U/L (range 303–16609 U/L) and 65% patients had LDH > 750 U/L. Fifty-three patients (59.6%) had good response to chemotherapy as evidenced by clearance of metastatic disease, but out of them, 43 patients (81%) progressed subsequently. Twenty-six patients underwent surgery and 12 patients received maintenance therapy. Seventy-four patients (86%) developed recurrence and all but one died. Median time to recurrence and death were 9 months (range 0–120 months) and 10 months (range 1–123 months), respectively. At a median follow-up of 72 months (range 15–135 months), 16 patients are alive, with 5-year disease-free survival and overall survival of 17.6 and 18.4%, respectively. Age, baseline LDH, chemotherapy regimen, and response to treatment significantly affected survival. Conclusion Younger age, lower baseline LDH, and good response to chemotherapy appear to confer survival advantage in pediatric metastatic NB, and may be used for optimization of treatment in the nontransplant setting in developing countries.

Preclinical spheroid models identify BMX as a therapeutic target for metastatic MYCN nonamplified neuroblastoma.

The development of targeted therapies offers new hope for patients affected by incurable cancer. However, multiple challenges persist, notably in controlling tumor cell plasticity in patients with refractory and metastatic illness. Neuroblastoma (NB) is an aggressive pediatric malignancy originating from defective differentiation of neural crest-derived progenitors with oncogenic activity due to genetic and epigenetic alterations and remains a clinical challenge for high-risk patients. To identify critical genes driving NB aggressiveness, we performed combined chromatin and transcriptome analyses on matched patient-derived xenografts (PDXs), spheroids, and differentiated adherent cultures derived from metastatic MYCN nonamplified tumors. Bone marrow kinase on chromosome X (BMX) was identified among the most differentially regulated genes in PDXs and spheroids versus adherent models. BMX expression correlated with high tumor stage and poor patient survival and was crucial to the maintenance of the self-renewal and tumorigenic potential of NB spheroids. Moreover, BMX expression positively correlated with the mesenchymal NB cell phenotype, previously associated with increased chemoresistance. Finally, BMX inhibitors readily reversed this cellular state, increased the sensitivity of NB spheroids toward chemotherapy, and partially reduced tumor growth in a preclinical NB model. Altogether, our study identifies BMX as a promising innovative therapeutic target for patients with high-risk MYCN nonamplified NB.

131I-mIBG Therapy in the Management of High-Risk Neuroblastoma: A Retrospective Study from a Tertiary Level Hospital in South India

Abstract Introduction Neuroblastoma is the most common extracranial solid tumor in childhood. The data on the treatment experience with 131iodine-meta-iodo-benzyl-guanidine (131I-mIBG) and clinical outcome data are meager from India. Objectives This article studies the efficacy and treatment outcomes in patients treated with 131I-mIBG in high-risk neuroblastoma. Materials and Methods The study group consisted of 201 consecutive patients (aged between 1 and 15 years) with biopsy-proven neuroblastoma who underwent 131I-mIBG scans from 2012 to 2022. The majority of these children had a disease that was inoperable or had poor response to chemotherapy. Patients with positive scintigraphy were considered for therapy with 131I-mIBG. The findings were analyzed and correlated with the final diagnosis and outcomes obtained from survival during follow-up and reviewing patient records. Results Thirty-nine children, 22 males and 17 females, with a median age of 4 years had positive 131I-mIBG scintigraphy. Intra-abdominal primary lesions and osseous lesions were the most common sites of uptake on 131I-mIBG scan. Of these, 13 had upfront chemotherapy and 26 had surgery followed by chemotherapy. All the patients underwent therapy with 131I-mIBG. Fourteen patients had multiple therapies while the remaining 25 had only one therapy. Eight patients had no follow-up, and 13 had disease relapse. The remaining 18 had regression of disease which was confirmed by follow-up 131I-mIBG scintigraphy and with bone scintigraphy in patients with osseous metastases. Conclusion 131I-mIBG scintigraphy should be preferred in intermediate and high-risk neuroblastoma to know the extent of the disease and also for patient selection for early therapy with 131I-mIBG. It holds significant utility in the management of metastatic neuroblastoma, facilitating palliative pain relief and tumor size reduction in inoperable or metastatic disease.

Ectopic adrenocorticotropic hormone syndrome in patients with olfactory neuroblastoma.

Olfactory neuroblastomas rarely secrete adrenocorticotropic hormone, leading to ectopic adrenocorticotropic hormone syndrome. However, the prevalence, timing, and triggers of ectopic adrenocorticotropic hormone syndrome in patients with olfactory neuroblastomas remain unclear. This study aimed to investigate these factors and conduct a literature review. Fifteen patients with olfactory neuroblastomas who underwent surgery at our institution were included. The prevalence of ectopic adrenocorticotropic hormone syndrome development was assessed by evaluating adrenocorticotropic hormone expression using immunohistochemistry. Furthermore, 26 patients with olfactory neuroblastomas who developed ectopic adrenocorticotropic hormone syndrome from previous reports were reviewed. Among the 15 patients, three (20%) showed adrenocorticotropic hormone-positive tumor cells at the time of initial surgery, and two (13%) developed ectopic adrenocorticotropic hormone syndrome. The timing of developing ectopic adrenocorticotropic hormone syndrome was 2.5 and 10 years following the initial treatment of olfactory neuroblastoma. Based on the literature review, nine patients with recurrent and metastatic olfactory neuroblastoma developed ectopic adrenocorticotropic hormone syndrome after the initial surgery, of whom, three had confirmed disease after developing ectopic adrenocorticotropic hormone syndrome, three developed during disease progression, two developed after receiving chemotherapy, and one developed after undergoing a biopsy. The timing of ectopic adrenocorticotropic hormone syndrome was 2.5-15 years after initial treatment. Our study revealed that acknowledging olfactory neuroblastomas can manifest as ectopic adrenocorticotropic hormone syndrome with a certain low prevalence is crucial. Moreover, our study speculated that tumor stimulation, such as biopsy or chemotherapy, as well as disease progression, could trigger ectopic adrenocorticotropic hormone syndrome onset. Thus, olfactory neuroblastomas can develop into ectopic adrenocorticotropic hormone syndrome, even long after the initial treatment.

Response-adapted consolidation therapy strategy for patients with metastatic high-risk neuroblastoma: Results of the SMC NB-2014 study.

Tandem high-dose chemotherapy and autologous stem cell transplantation (HDCT/auto-SCT) and incorporation of 131I-metaiodobenzylguanidine (131I-MIBG) treatment have shown positive outcomes in high-risk neuroblastoma. However, more optimized treatment strategies are still needed. The NB-2014 study was a nonrandomized, prospective trial that examined survival outcomes in metastatic high-risk neuroblastoma patients using response-adapted consolidation therapy. We used post-induction residual 123I-MIBG status at metastatic sites as a treatment response marker. Patients achieving complete resolution of MIBG uptake at metastatic sites underwent a reduced first HDCT/auto-SCT with a 20% dose reduction in HDCT. After the first HDCT/auto-SCT, patients with remaining MIBG uptake received dose-escalated (18mCi/kg) 131I-MIBG treatment. In contrast, those with complete resolution of MIBG at metastatic sites received a standard dose (12mCi/kg) of 131I-MIBG. We compared survival and toxicity outcomes with a historical control group from the NB-2009. Of 65 patients treated, 63% achieved complete resolution of MIBG uptake at metastatic sites following induction chemotherapy, while 29% of patients still had MIBG uptake at metastatic sites after the first HDCT/auto-SCT. The 3-year event-free survival (EFS) and overall survival (OS) rates were 68.2%±6.0% and 86.5%±4.5%, respectively. Compared to NB-2009, EFS was similar (p=.855); however, NB-2014 had a higher OS (p=.031), a lower cumulative incidence of treatment-related mortality (p=.036), and fewer acute and late toxicities. Our results suggest that response-adaptive consolidation therapy based on chemotherapy response at metastatic sites facilitates better treatment tailoring, and appears promising for patients with metastatic high-risk neuroblastoma.

Atypical hemolytic uremic syndrome during induction chemotherapy in neuroblastoma, a rare phenomenon or common congenital predisposition?

Atypical hemolytic uremic syndrome (aHUS) is a complement-mediated thrombotic microangiopathy sometimes associated with germline variants in genes of the complement system. Clinical findings of microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury arise due to aberrant complement protein activation in the circulation. A 13-month-old boy with metastatic neuroblastoma (NB) developed aHUS during his first cycle of induction chemotherapy with germline testing revealing a complement factor H(CFH) gene mutation, currently classified as a variant of uncertain significance (VUS). Now he is in disease remission after successful complement blockade therapy, thus highlighting a unique presentation of aHUS in a patient with newly diagnosed NB.

In vivo cisplatin-resistant neuroblastoma metastatic model reveals tumour necrosis factor receptor superfamily member 4 (TNFRSF4) as an independent prognostic factor of survival in neuroblastoma.

Neuroblastoma is the most common solid extracranial tumour in children. Despite major advances in available therapies, children with drug-resistant and/or recurrent neuroblastoma have a dismal outlook with 5-year survival rates of less than 20%. Therefore, tackling relapsed tumour biology by developing and characterising clinically relevant models is a priority in finding targetable vulnerability in neuroblastoma. Using matched cisplatin-sensitive KellyLuc and resistant KellyCis83Luc cell lines, we developed a cisplatin-resistant metastatic MYCN-amplified neuroblastoma model. The average number of metastases per mouse was significantly higher in the KellyCis83Luc group than in the KellyLuc group. The vast majority of sites were confirmed as having lymph node metastasis. Their stiffness characteristics of lymph node metastasis values were within the range reported for the patient samples. Targeted transcriptomic profiling of immuno-oncology genes identified tumour necrosis factor receptor superfamily member 4 (TNFRSF4) as a significantly dysregulated MYCN-independent gene. Importantly, differential TNFRSF4 expression was identified in tumour cells rather than lymphocytes. Low TNFRSF4 expression correlated with poor prognostic indicators in neuroblastoma, such as age at diagnosis, stage, and risk stratification and significantly associated with reduced probability of both event-free and overall survival in neuroblastoma. Therefore, TNFRSF4 Low expression is an independent prognostic factor of survival in neuroblastoma.

Efficacy of anti-PD-1 monotherapy for recurrent or metastatic olfactory neuroblastoma

BackgroundOlfactory neuroblastoma (ONB) is a rare malignant tumor of the head and neck. Due to its rarity, standard systemic therapy for this condition has yet to be established. In particular, the use of immune checkpoint inhibitors (ICIs) for the recurrent or metastatic (R/M) ONB population remains unclear.MethodsWe retrospectively evaluated 11 patients with R/M ONB who received any systemic chemotherapy at two Japanese institutions (National Cancer Center Hospital East and Kyushu Medical Center) between January 2002 and March 2022 and analyzed outcomes by use of anti-PD-1 antibody (nivolumab or pembrolizumab) monotherapy.ResultsOf the 11 patients, 6 received ICI (ICI-containing treatment group) and the remaining 5 were treated with systemic therapy but not including ICI (ICI-non-containing treatment group). Overall survival (OS) was significantly longer in the ICI-containing group (median OS: not reached vs. 6.4 months, log-rank p-value: 0.035). The fraction of ICI systemic therapy in the entire treatment period of this group reached 85.9%. Four patients (66.7%) in the ICI-containing treatment group experienced immune-related adverse events (irAE), with grades of 1/2. No irAE of grade 3 or more was seen, and no patient required interruption or discontinuation of treatment due to toxicity.ConclusionICI monotherapy appears to be effective and to contribute to prolonged survival in R/M ONB.

Optimising Palliative Care for Children with Metastatic Neuroblastoma and the Paediatrician’s Role in a Shared Care Model – Proposal from a Regional Cancer Centre in India

Optimising Palliative Care for Children with Metastatic Neuroblastoma and the Paediatrician’s Role in a Shared Care Model – Proposal from a Regional Cancer Centre in India

Revisiting the role of radiotherapy in the treatment of neuroblastoma 4S: 30 years of institutional experience and systematic review

Background and purposeNeuroblastoma 4S is a rare subtype of metastatic neuroblastoma found in children younger than 12 months, characterized by liver, skin, or bone marrow metastases. While the prognosis for patients is generally favorable, rapid progression of liver metastases can lead to life-threatening organ insufficiency. In such cases, immediate treatment with chemotherapy or radiotherapy is necessary. Given the recent decline in radiotherapy utilization, this study aims to reassess its role, evaluating its effectiveness and toxicity. Materials and methodsWe conducted a systematic review and an institutional retrospective analysis to assess the use of radiotherapy for hepatomegaly in patients with neuroblastoma 4S. The study included data from 164 patients from the literature and 16 patients from our institutional cohort. We extracted and analyzed data on short- and long-term outcomes, as well as reports of radiotherapy-induced toxicity. ResultsOur institutional data showed that 81 % of patients responded to low-dose radiotherapy administered at a median dose of 450 cGy in three fractions, resulting in liver shrinkage and symptom resolution. Based on the systematic review, 1-year survival rate was 80 %, while 5-year survival rate was 75 %. No serious toxicity was observed with the current low-dose radiotherapy; however, one case of induced secondary malignancy was reported. ConclusionRadiation therapy is an effective treatment modality for hepatomegaly in patients with neuroblastoma 4S, with a success rate of about 80 %. Despite being administered to infants, a low dose of 450–600 cGy does not result in toxicity related to the kidneys, liver, or posture defects.

Physical examination a boon-racoon eyes in a child with neuroblastoma

Metastatic neuroblastoma often presents with prolonged fever, cytopenias and significant constitutional symptoms, before the abdominal mass is evident clinically. Clues like subcutaneous nodules and racoon eyes can help a clinician to suspect and evaluate appropriately to arrive at a timely diagnosis. We report a 3-year-old girl who had prolonged fever and constitutional symptoms for more than 2 weeks. On evaluation in outpatient visits, child was found to have cytopenia, hence was referred to our center for further management. Clinical examination revealed raccoon eyes with scalp nodules, hepatomegaly and abdominal mass predominantly over left lumbar area crossing over midline. On further investigations including radiological imaging and bone marrow biopsy child was diagnosed with metastatic neuroblastoma. Metastatic neuroblastoma often presents with prolonged fever, cytopenias and significant constitutional symptoms, before the abdominal mass is evident clinically. Clues like subcutaneous nodules and racoon eyes can help a clinician to suspect and evaluate appropriately to arrive at a timely diagnosis.

Endoscopic transorbital approach in children: surgical technique and early results.

In this study, the authors aimed to describe the endoscopic transorbital approach (ETOA) in children. Six pediatric patients (2 girls and 4 boys) underwent the ETOA for paramedian skull base lesions at a single institution between September 2016 and February 2023. The median age at the time of surgery was 7.5 (range 4-18) years. The median follow-up period was 33 (range 9-60) months. In this series, the ETOA level of difficulty included stage 1 (n = 2, 33.3%), stage 3 (n = 3, 50%), and stage 5 (n = 1, 16.7%). The ETOA was performed for tumor resection in 4 cases; the final pathology consisted of fibrous dysplasia, pilocytic astrocytoma, metastatic neuroblastoma, and choroid plexus papilloma. The procedure was also performed for repair of a petrous apex meningocele and for lateral orbital wall decompression of traumatic lateral rectus muscle entrapment. One patient experienced a transient cranial nerve III palsy after the procedure. There were no operative deaths in this series. In select cases, the ETOA can be considered a minimally invasive alternative for conventional skull base approaches in the armamentarium of pediatric skull base surgery. Further investigation and the accumulation of experience are warranted in the future to enhance the efficacy and applicability of the ETOA in pediatric patients.

Differential Competitive Growth of Transgenic Subclones of Neuroblastoma Cells Expressing Different Levels of Cathepsin D Co-Cultured in 2D and 3D in Response to EGF: Implications in Tumor Heterogeneity and Metastasis.

Neuroblastoma (NB) is an embryonal tumor arising from the sympathetic central nervous system. The epidermal growth factor (EGF) plays a role in NB growth and metastatic behavior. Recently, we have demonstrated that cathepsin D (CD) contrasts EGF-induced NB cell growth in 2D by downregulating EGFR/MAPK signaling. Aggressive NB is highly metastatic to the bone and the brain. In the metastatic process, adherent cells detach to form clusters of suspended cells that adhere once they reach the metastatic site and form secondary colonies. Whether CD is involved in the survival of metastatic NB clones is not known. Therefore, in this study, we addressed how CD differentially affects cell growth in suspension versus the adherent condition. To mimic tumor heterogeneity, we co-cultured transgenic clones silenced for or overexpressing CD. We compared the growth kinetics of such mixed clones in 2D and 3D models in response to EGF, and we found that the Over CD clone had an advantage for growth in suspension, while the CD knocked-down clone was favored for the adherent growth in 2D. Interestingly, on switching from 3D to 2D culture conditions, the expression of E-cadherin and of N-cadherin increased in the KD-CD and Over CD clones, respectively. The fact that CD plays a dual role in cancer cell growth in 2D and 3D conditions indicates that during clonal evolution, subclones expressing different level of CD may arise, which confers survival and growth advantages depending on the metastatic step. By searching the TCGA database, we found up to 38 miRNAs capable of downregulating CD. Interestingly, these miRNAs are associated with biological processes controlling cell adhesion and cell migration. The present findings support the view that during NB growth on a substrate or when spreading as floating neurospheres, CD expression is epigenetically modulated to confer survival advantage. Thus, epigenetic targeting of CD could represent an additional strategy to prevent NB metastases.

Abstract 5466: In vivo characterization of neuroblastoma intratumoral heterogeneity

Abstract Background: Neuroblastoma is a pediatric solid tumor that arises from neural crest-derived progenitor cells of the peripheral sympathetic nervous system (PSNS). Neuroblastoma patients display a significant level of genetic and phenotypic heterogeneity, with amplification of the MYCN oncogene associated with poor clinical outcomes. To better understand underlying genetic mechanisms associated with aggressive neuroblastoma, our group incorporated patient-relevant loss-of-function mutations into the established MYCN-driven zebrafish model of neuroblastoma (Tg(dbh:EGFP-MYCN)), which resulted in increased tumor penetrance and a highly metastatic phenotype. Aims & Methods: We aimed to investigate metastases-associated intratumoral heterogeneity in vivo using our patient-relevant metastatic zebrafish models, with functional validations performed using human neuroblastoma cell lines. Results: Single-cell RNA sequencing of metastatic zebrafish neuroblastoma tumors revealed intra-tumor cell heterogeneity, with a subset of cells highly expressing markers of more differentiated adrenergic-like cell fates (th, dbh, phox2a) while others enriched for markers of less differentiated mesenchymal-like progenitor cells (prrx1a, vim, fn1a). Differential cell labeling in zebrafish neuroblastoma suggests distinct tumor cell populations for follow-up validation and characterization throughout metastatic progression. Conclusion: Single-cell RNA sequencing of zebrafish metastatic neuroblastoma showed evidence of intratumoral heterogeneity that warrants further investigation. We are characterizing neuroblastoma intratumoral heterogeneity in our in vivo metastatic zebrafish models to examine the association between neuroblastoma tumor composition and metastatic potential. Altogether, this work aims to improve our understanding of the evolution of tumor cell heterogeneity associated with neuroblastoma metastasis and uncover novel therapeutic opportunities to improve patient outcomes. Citation Format: Willow R. Squires, Alex Weiss, Sarah Cohen-Gogo, Adam Shlien, David Kaplan, Meredith S. Irwin, Madeline N. Hayes. In vivo characterization of neuroblastoma intratumoral heterogeneity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5466.

Clinical characteristics and prognoses in pediatric neuroblastoma with bone or liver metastasis: data from the SEER 2010–2019

BackgroundTo investigate clinical characteristics, prognoses, and impacts of treatments on prognoses of neuroblastoma patients with bone or liver metastasis.MethodsThis retrospective cohort study extracted data from the Surveillance, Epidemiology, and End Results (SEER) database 2010–2019. The outcomes were 3-year cancer-specific survival (CSS) and 5-year CSS. Multivariable COX risk proportional models were established to assess the association between metastasis types and CSS. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated.ResultsTotally 425 patients with metastatic neuroblastoma were eligible for 3-year CSS analysis and 320 for 5-year CSS analysis. For 3-year follow-up, 62 (14.59%) patients had liver metastasis alone, 289 (0.68%) had bone metastasis alone, and 74 (17.41%) had both liver and bone metastasis. For 5-year follow-up, 44 (13.75%) patients had liver metastasis alone, 223 (69.69%) had bone metastasis alone, and 53 (16.56%) had both liver and bone metastasis. Significant differences were observed in age, tumor size, surgery for the primary site, chemotherapy, radiation, brain metastasis, lung metastasis, and vital status between patients with liver metastasis alone, bone metastasis alone, and both liver and bone metastasis (all P < 0.05). Compared with patients with liver metastasis alone, patients with bone metastasis alone (HR = 2.30, 95%CI: 1.10–4.82, P = 0.028) or both (HR = 2.35, 95%CI: 1.06–5.20, P = 0.035) had significantly poorer 3-year CSS; patients with bone metastasis alone (HR = 2.32, 95%CI: 1.14–4.70, P = 0.020) or both liver and bone metastasis (HR = 2.33, 95%CI: 1.07–5.07, P = 0.032) exhibited significantly worse 5-year CSS than those with liver metastasis alone. In patients with bone metastasis, those with chemotherapy had significantly better 3-year CSS than those without (HR = 0.24, 95%CI: 0.07–0.75, P = 0.014). Among patients with liver metastasis, receiving radiation was associated with significantly worse 3-year CSS (HR = 2.00, 95%CI: 1.05–3.81, P = 0.035).ConclusionCompared with patients with liver metastasis alone, those with bone metastasis alone or both had poorer 3- and 5-year CSS. For patients with bone metastasis, undergoing chemotherapy was associated with better 3-year CSS. For patients with liver metastasis, receiving radiation was associated with worse 3-year CSS.

Single-cell analyses of metastatic bone marrow in human neuroblastoma reveals microenvironmental remodeling and metastatic signature.

Neuroblastoma is an aggressive pediatric cancer with a high rate of metastasis to the BM. Despite intensive treatments including high-dose chemotherapy, the overall survival rate for children with metastatic neuroblastoma remains dismal. Understanding the cellular and molecular mechanisms of the metastatic tumor microenvironment is crucial for developing new therapies and improving clinical outcomes. Here, we used single-cell RNA-Seq to characterize immune and tumor cell alterations in neuroblastoma BM metastases by comparative analysis with patients without metastases. Our results reveal remodeling of the immune cell populations and reprogramming of gene expression profiles in the metastatic niche. In particular, within the BM metastatic niche, we observed the enrichment of immune cells, including tumor-associated neutrophils, macrophages, and exhausted T cells, as well as an increased number of Tregs and a decreased number of B cells. Furthermore, we highlighted cell communication between tumor cells and immune cell populations, and we identified prognostic markers in malignant cells that are associated with worse clinical outcomes in 3 independent neuroblastoma cohorts. Our results provide insight into the cellular, compositional, and transcriptional shifts underlying neuroblastoma BM metastases that contribute to the development of new therapeutic strategies.

Incidence of subclinical and overt hypothyroidism in children treated with [131I]mIBG: a systematic review and meta-analysis.

Treatment with [131I]mIBG is commonly used in pediatric metastatic neuroblastoma (NB); however, unbound [131I]I might be taken up by the thyroid, causing hypothyroidism. To prevent this occurrence, thyroid blockade with iodine salts is commonly used; despite this precaution, thyroid dysfunction still occurs. This review and meta-analysis aim to clarify the mean frequency of hypothyroidism in children with NB treated with [131I]mIBG and to investigate the possible causes. The literature was searched for English-language scientific manuscripts describing the incidence of TSH elevation and overt hypothyroidism in children with NB treated with [131I]mIBG. Preclinical studies, small-case series, and reviews were excluded. A proportion meta-analysis was conducted to test the influence of potentially relevant factors (type and duration of thyroid blockade, year of the study, sample size) on the incidence of TSH elevation/overt hypothyroidism. Eleven studies were included. The pooled percentage of TSH elevation was 0.41 (95% CI: 0.27-0.55); the duration of the thyroid blockade (P=0.004) was inversely correlated with the incidence of TSH elevation. Moreover, a TSH increase was more common in patients treated with potassium iodide (KI) alone than in those managed with a multi-drug thyroid blockade (P<0.001). The pooled percentage of children requiring hormone replacement therapy was 0.33 (95% CI: 0.16-0.49). As in the case of TSH elevation, a longer duration of the thyroid blockade (P=0.006) and a multi-pronged approach (P<0.001) were associated with a lower incidence of overt hypothyroidism. Hypothyroidism appears to occur frequently in children treated with [131I]mIBG, which should be monitored closely after the radionuclide treatment to start hormone replacement therapy as soon as needed. The duration, as well as the type of thyroid blockade, seem to influence the incidence of hypothyroidism; however, more data from prospective evaluations are needed.

MR Imaging Features of Pediatric Bone Marrow

MRI plays a crucial role in bone marrow (BM) assessment, and has very high sensitivity in diagnosing marrow disorders. However, for radiologists who may not frequently encounter pediatric imaging, distinguishing pathologic BM lesion from normal BM can be challenging. Conditions involving the BM in pediatric patients, such as leukemia and metastatic neuroblastoma, often manifest with diverse musculoskeletal symptoms and may be diagnosed using musculoskeletal MRI examinations. Accurate interpretation of pediatric MRI requires not only an understanding of the normal composition of BM but also an awareness of agerelated developmental changes in the marrow and familiarity with conditions that commonly involve pediatric BM. We aim to describe the composition of normal BM and outline the normal and abnormal MRI findings in pediatric BM. Additionally, we aim to present clinical cases of malignant BM disorders including leukemia, neuroblastoma metastasis, and other malignant BM disorders.