Clinical features and treatment options for pediatric adrenal incidentalomas: a retrospective single center study.

BACKGROUND: The aim of this study was to investigate the clinical features and treatment options for pediatric adrenal incidentalomas(AIs) to guide the diagnosis and treatment of these tumors. METHODS: The clinical data of AI patients admitted to our hospital between December 2016 and December 2022 were collected and retrospectively analyzed. All patients were divided into neonatal and nonneonatal groups according to their age at the time of the initial consultation. RESULTS: In the neonatal group, 13 patients were observed and followed up, and the masses completely disappeared in 8 patients and were significantly reduced in size in 5 patients compared with the previous findings. Four patients ultimately underwent surgery, and the postoperative pathological diagnosis was neuroblastoma in three patients and teratoma in one patient. In the nonneonatal group, there were 18 cases of benign tumors, including 9 cases of ganglioneuroma, 2 cases of adrenocortical adenoma, 2 cases of adrenal cyst, 2 cases of teratoma, 1 case of pheochromocytoma, 1 case of nerve sheath tumor, and 1 case of adrenal hemorrhage; and 20 cases of malignant tumors, including 10 cases of neuroblastoma, 9 cases of ganglioneuroblastoma, and 1 case of adrenocortical carcinoma. CONCLUSIONS: Neuroblastoma is the most common type of nonneonatal AI, and detailed laboratory investigations and imaging studies are recommended for aggressive evaluation and treatment in this population. The rate of spontaneous regression of AI is high in neonates, and close observation is feasible if the tumor is small, confined to the adrenal gland and has no distant metastasis.

CKLF instigates a "cold" microenvironment to promote MYCN-mediated tumor aggressiveness.

Solid tumors, especially those with aberrant MYCN activation, often harbor an immunosuppressive microenvironment to fuel malignant growth and trigger treatment resistance. Despite this knowledge, there are no effective strategies to tackle this problem. We found that chemokine-like factor (CKLF) is highly expressed by various solid tumor cells and transcriptionally up-regulated by MYCN. Using the MYCN-driven high-risk neuroblastoma as a model system, we demonstrated that as early as the premalignant stage, tumor cells secrete CKLF to attract CCR4-expressing CD4+ cells, inducing immunosuppression and tumor aggression. Genetic depletion of CD4+ T regulatory cells abolishes the immunorestrictive and protumorigenic effects of CKLF. Our work supports that disrupting CKLF-mediated cross-talk between tumor and CD4+ suppressor cells represents a promising immunotherapeutic approach to battling MYCN-driven tumors.

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

BACKGROUND: To investigate clinical characteristics, prognoses, and impacts of treatments on prognoses of neuroblastoma patients with bone or liver metastasis. METHODS: This 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. RESULTS: Totally 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). CONCLUSION: Compared 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.

Envision the future of precision medicine in pediatric cancer.

Exploring the diversity within the tumor microenvironment (TME) can offer crucial insights to steer cancer therapy toward precision medicine. In this issue of Cancer Cell, Wienke et al. undertake a comprehensive single-cell analysis of neuroblastoma, unveiling its immune landscape and identifying NECTIN2-TIGIT as a promising target for immunotherapy.

The therapeutic effect of MSCs and their extracellular vesicles on neuroblastoma.

Neuroblastoma is a common inflammatory-related cancer during infancy. Standard treatment modalities including surgical interventions, high-dose chemotherapy, radiotherapy, and immunotherapy are not able to increase survival rate and reduce tumor relapse in high-risk patients. Mesenchymal stem cells (MSCs) are known for their tumor-targeting and immunomodulating properties. MSCs could be engineered to express anticancer agents (i.e., growth factors, cytokines, pro-apoptotic agents) or deliver oncolytic viruses in the tumor microenvironment. As many functions of MSCs are mediated through their secretome, researchers have tried to use extracellular vesicles (EVs) from MSCs for targeted therapy of neuroblastoma. Here, we reviewed the studies to figure out whether the use of MSCs could be worthwhile in neuroblastoma therapy or not. Native MSCs have shown a promoting or inhibiting role in cancers including neuroblastoma. Therefore, MSCs are proposed as a vehicle to deliver anticancer agents such as oncolytic viruses to the neuroblastoma tumor microenvironment. Although modified MSCs or their EVs have been shown to suppress the tumorigenesis of neuroblastoma, further pre-clinical and clinical studies are required to come to a conclusion.

[Clinical and prognostic analysis of opsoclonus-myoclonus-ataxia syndrome in children].

Objective: To summarize the clinical and prognostic features of children with opsoclonus-myoclonus-ataxia syndrome (OMAS). Methods: A total of 46 patients who met the diagnostic criteria of OMAS in the Department of Neurology, Beijing Children's Hospital from June 2015 to June 2023 were retrospectively analyzed. Centralized online consultations or telephone visits were conducted between June and August 2023. The data of the children during hospitalization and follow-up were collected, including clinical manifestations, assistant examination, treatment and prognosis. According to the presence or absence of tumor, the patients were divided into two groups. The chi-square test or Mann-Whitney U test was used to compare the differences between the two groups. Univariate Logistic regression was used to analyze the factors related to OMAS recurrence and prognosis. Results: There were 46 patients, with 25 males and the onset age of 1.5 (1.2, 2.4) years. Twenty-six (57%) patients were diagnosed with neuroblastoma during the course of the disease, and no patients were categorized into the high-risk group. A total of 36 patients (78%) were followed up for≥6 months, and all of them were treated with first-line therapy with glucocorticoids, gammaglobulin and (or) adrenocorticotrophic hormone. Among the 36 patients, 9 patients (25%) were treated with second-line therapy for ≥3 months, including rituximab or cyclophosphamide, and 17 patients (47%) received chemotherapy related to neuroblastoma. At the follow-up time of 4.2 (2.2, 5.5) years, 10 patients (28%) had relapsed of OMAS. The Mitchell and Pike OMS rating scale score at the final follow-up was 0.5 (0, 2.0). Seven patients (19%) were mildly cognitively behind their peers and 6 patients (17%) were severely behind. Only 1 patient had tumor recurrence during follow-up. The history of vaccination or infection before onset was more common in the non-tumor group than in the tumor group (55%(11/20) vs. 23%(6/26), χ²=4.95, P=0.026). Myoclonus occurred more frequently in the non-tumor group (40%(8/20) vs. 4%(1/26), χ²=7.23, P=0.007) as the onset symptom. Univariate Logistic regression analysis showed that the tumor group had less recurrence (OR=0.19 (0.04-0.93), P=0.041). The use of second-line therapy or chemotherapy within 6 months of the disease course had a better prognosis (OR=11.64 (1.27-106.72), P=0.030). Conclusions: OMAS in children mostly starts in early childhood, and about half are combined with neuroblastoma. Neuroblastoma in combination with OMAS usually has a low risk classification and good prognosis. When comparing patients with OMAS with and without tumors, the latter have a more common infection or vaccination triggers, and myoclonus, as the onset symptom, is more common. Early addition of second-line therapy is associated with better prognosis in OMAS.

Survival Benefit of Myeloablative Therapy with Autologous Stem Cell Transplantation in High-Risk Neuroblastoma: A Systematic Literature Review.

BACKGROUND: Multimodal treatment of newly diagnosed high-risk neuroblastoma (HRNB) includes induction chemotherapy, consolidation with myeloablative therapy (MAT) and autologous stem cell transplantation (ASCT), followed by anti-disialoganglioside 2 (GD2) immunotherapy, as recommended by the Children's Oncology Group (COG) and the Society of Paediatric Oncology European Neuroblastoma (SIOPEN). Some centres proposed an alternative approach with induction chemotherapy followed by anti-GD2 immunotherapy, without MAT+ASCT. OBJECTIVE: The aim of this systematic literature review was to compare survival outcomes in patients with HRNB treated with or without MAT+ASCT and with or without subsequent anti-GD2 immunotherapy. PATIENTS AND METHODS: The review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. MEDLINE via PubMed and EMBASE databases were systematically searched for randomised controlled trials (RCT) and observational comparative studies in patients with HRNB using search terms for 'neuroblastoma' and ('myeloablative therapy' OR 'stem cell transplantation'). Reporting of at least one survival outcome [event-free survival (EFS), progression-free survival, relapse-free survival and/or overall survival (OS)] was required for inclusion. Outcomes from RCTs were synthesized in meta-analysis, while meta-analysis of non-RCTs was not planned owing to expected heterogeneity. RESULTS: Literature searches produced 2587 results with 41 publications reporting 34 comparative studies included in the review. Of these, 7 publications reported 4 RCTs, and 34 publications reported 30 non-RCT studies. Studies differed with respect to included populations, induction regimen, response to induction, additional treatments and transplantation procedures. Subsequent treatments of relapse were rarely reported and could not be compared. In the meta-analysis, EFS was in favour of MAT+ASCT over conventional chemotherapy or no further treatment [hazard ratio (HR) = 0.78, 95% confidence interval (CI) 0.67-0.91, p = 0.001] with a trend favouring MAT+ASCT for OS (HR = 0.86, 95% CI 0.73-1.00, p = 0.05). Tandem MAT+ASCT was found to improve EFS compared with the single procedure, with improvement in both EFS and OS in patients treated with anti-GD2 therapy. Non-RCT comparative studies were broadly consistent with evidence from the RCTs; however, not all reported survival benefits of MAT+ASCT (single or tandem). Limited comparative evidence on treatment without MAT+ASCT in patients treated with anti-GD2 immunotherapy suggests an increased risk of relapse. In relapsed patients, MAT+ASCT appears to improve OS, but evidence remains scarce. CONCLUSIONS: Survival benefits in patients treated with MAT+ASCT confirm that the procedure should remain an integral part of multimodal therapy. In patients treated with anti-GD2 immunotherapy, limited evidence suggests that omitting MAT+ASCT is associated with an increased risk of relapse, and therefore, a change in clinical practice can currently not be recommended. Evidence suggests the use of tandem MAT+ASCT compared with the single procedure, with greater benefits observed in patients treated with anti-GD2 immunotherapy. Limited evidence also suggests improved survival following MAT+ASCT in relapsed patients, which needs to be viewed in light of emerging chemoimmunotherapy in this setting.

The Oncolytic Activity of Zika Viral Therapy in Human Neuroblastoma In Vivo Models Confers a Major Survival Advantage in a CD24-dependent Manner.

Neuroblastoma is the most common extracranial tumor, accounting for 15% of all childhood cancer-related deaths. The long-term survival of patients with high-risk tumors is less than 40%, and MYCN amplification is one of the most common indicators of poor outcomes. Zika virus (ZIKV) is a mosquito-borne flavivirus associated with mild constitutional symptoms outside the fetal period. Our published data showed that high-risk and recurrent neuroblastoma cells are permissive to ZIKV infection, resulting in cell type-specific lysis. In this study, we assessed the efficacy of ZIKV as an oncolytic treatment for high-risk neuroblastoma using in vivo tumor models. Utilizing both MYCN-amplified and non-amplified models, we demonstrated that the application of ZIKV had a rapid tumoricidal effect. This led to a nearly total loss of the tumor mass without evidence of recurrence, offering a robust survival advantage to the host. Detection of the viral NS1 protein within the tumors confirmed that a permissive infection preceded tissue necrosis. Despite robust titers within the tumor, viral shedding to the host was poor and diminished rapidly, correlating with no detectable side effects to the murine host. Assessments from both primary pretreatment and recurrent posttreatment isolates confirmed that permissive sensitivity to ZIKV killing was dependent on the expression of CD24, which was highly expressed in neuroblastomas and conferred a proliferative advantage to tumor growth. Exploiting this viral sensitivity to CD24 offers the possibility of its use as a prognostic target for a broad population of expressing cancers, many of which have shown resistance to current clinical therapies. SIGNIFICANCE: Sensitivity to the tumoricidal effect of ZIKV on high-risk neuroblastoma tumors is dependent on CD24 expression, offering a prognostic marker for this oncolytic therapy in an extensive array of CD24-expressing cancers.

Predicting Neuroblastoma Patient Risk Groups, Outcomes, and Treatment Response Using Machine Learning Methods: A Review.

Neuroblastoma, a paediatric malignancy with high rates of cancer-related morbidity and mortality, is of significant interest to the field of paediatric cancers. High-risk NB tumours are usually metastatic and result in survival rates of less than 50%. Machine learning approaches have been applied to various neuroblastoma patient data to retrieve relevant clinical and biological information and develop predictive models. Given this background, this study will catalogue and summarise the literature that has used machine learning and statistical methods to analyse data such as multi-omics, histological sections, and medical images to make clinical predictions. Furthermore, the question will be turned on its head, and the use of machine learning to accurately stratify NB patients by risk groups and to predict outcomes, including survival and treatment response, will be summarised. Overall, this study aims to catalogue and summarise the important work conducted to date on the subject of expression-based predictor models and machine learning in neuroblastoma for risk stratification and patient outcomes including survival, and treatment response which may assist and direct future diagnostic and therapeutic efforts.

Blasting off: persistent hypertension in a child with neuroblastoma.

Hypertension in children with neuroblastoma is uncommon and can be difficult to control due to the potential for multiple underlying causes. We present the case of a pediatric patient with high-grade neuroblastoma which was complicated by hypertensive emergency. The patient had imaging suggestive of renal artery compression, as well as significantly elevated normetaphrine levels. Multiple anti-hypertensive agents, including an angiotensin converting enzyme inhibitor, α- and ß-adrenergic receptor blockers, and a tyrosine hydroxylase inhibitor, were initiated prior to tumor excision. While her blood pressure improved during the post-operative period, she continued to require multiple antihypertensive medications due to residual tumor burden. In this report, we highlight the importance of careful, multidisciplinary management to avoid peri-operative complications in patients with catecholamine-producing tumors.

Factors influencing parents' choice of palliative treatment goals for children with relapsed or refractory neuroblastoma: A multi-site longitudinal survey study.

BACKGROUND: Many parents of children with advanced cancer report curative goals and continue intensive therapies that can compound symptoms and suffering. Factors that influence parents to choose palliation as the primary treatment goal are not well understood. The objective of this study was to examine experiences impacting parents' report of palliative goals adjusted for time. The authors hypothesized that awareness of poor prognosis, recall of oncologists' prognostic disclosure, intensive treatments, and burdensome symptoms and suffering would influence palliative goal-setting. METHODS: The authors collected prospective, longitudinal surveys from parents of children with relapsed/refractory neuroblastoma at nine pediatric cancer centers across the United States, beginning at relapse and continuing every 3 months for 18 months or until death. Hypothesized covariates were examined for possible associations with parental report of palliative goals. Generalized linear mixed models were used to evaluate factors associated with parents' report of palliative goals at different time points. RESULTS: A total of 96 parents completed surveys. Parents were more likely to report a primary goal of palliation when they recalled communication about prognosis by their child's oncologist (odds ratio [OR], 52.48; p = .010). Treatment intensity and previous ineffective therapeutic regimens were not associated with parents' report of palliative goals adjusted for time. A parent who reported new suffering for their child was less likely to report palliative goals (OR, 0.13; p = .008). CONCLUSIONS: Parents of children with poor prognosis cancer may not report palliative goals spontaneously in the setting of treatment-related suffering. Prognostic communication, however, does influence palliative goal-setting. Evidence-based interventions are needed to encourage timely, person-centered prognostic disclosure in the setting of advanced pediatric cancer. PLAIN LANGUAGE SUMMARY: Many parents of children with poor-prognosis cancer continue to pursue curative treatments that may worsen symptoms and suffering. Little is known about which factors influence parents to choose palliative care as their child's main treatment goal. To explore this question, we asked parents of children with advanced neuroblastoma across the United States to complete multiple surveys over time. We found that the intensity of treatment, number of treatments, and suffering from treatment did not influence parents to choose palliative goals. However, when parents remembered their child's oncologist talking about prognosis, they were more likely to choose palliative goals of care.

Advances in the Management of Neuroblastoma.

Neuroblastoma is a malignant tumor of neuroblasts, immature nerve cells found in several areas of the body. It usually affects children under age of 5. As usual, the tumor has ability to grow rapidly and to expand vastly which ultimately leads to death. Mostly, management decisions can be drawn by the prediction of the stage of the disease as well as age at the time of its diagnosis. There are four main stages of neuroblastoma, and treatment is according to the low and high risk of the disease. Several cytotoxic agents along with other therapies (antibody therapy, gene therapy, and even immunological therapies, antiangiogenic therapy, etc.) are used. Immunotherapy also has an important treatment option used nowadays for neuroblastoma. The discovery of major neuroblastoma-predisposition gene anaplastic lymphoma kinase cause somatic transformation or gene strengthening in diagnosed neuroblastoma. Promising new antiangiogenic strategies have also been introduced for the treatment of neuroblastoma with multiple mylomas. To manage numerous myelomas and cancers, including neuroblastoma, bone marrow transplantation and peripheral blood stem cell transplantation may be used.

PD-L1-expressing natural killer cells predict favorable prognosis and response to PD-1/PD-L1 blockade in neuroblastoma.

T/NK cell-based immunotherapy has achieved remarkable success in adult cancers but has limited efficacy in pediatric malignancies including high-risk neuroblastoma (NB). Immune defects of NB tumor microenvironment are poorly understood compared with adults. Here, we described the unique characteristics of NB immune contexture and determined the phenotype signatures of PD-L1-expressing CD8+ T and NK cells in NB tumors by systemically analyzing the spatial distribution of T and NK cells and the distinct expression of programmed death 1 (PD-1) and its ligand (PD-L1) in patients with NB. We found that PD-L1-expressing CD8+ T and NK cells in NB tumors were highly activated and functionally competent and associated with better clinical outcomes. Intratumoral NK cells were a favorable prognostic biomarker independent of CD8+ T cells, PD-1/PD-L1 expression, tumor stage, MYCN amplification, and risk classification. NK cells combined with anti-PD-1/PD-L1 antibodies showed potent antitumor activity against both MYCN-amplified and non-amplified NBs in vitro and in vivo, and PD-L1-expressing NK cells associated with improved antitumor efficacy. Collectively, we raise novel insights into the role of PD-L1 expression on CD8+ T-cell and NK-cell activation. We highlight the great potential of intratumoral NK cells in better defining risk stratification, and predicting survival and response to anti-PD-1/PD-L1 therapy in NB. These findings explain why single anti-PD-1/PD-L1 therapy may not be successful in NB, suggesting its combination with NK cell-adoptive cellular therapy as a promising strategy for relapsing/refractory NB. This study provides a potential prospect that patients with PD-L1-expressing NK cells may respond to anti-PD-1/PD-L1 therapy.

GD2-CAR CAR T cells in patients with osteosarcoma and neuroblastoma-it's not only the T cells that matter.

GD2-CAR T cells were safe and anti-tumor responses were limited. In this issue of Cancer Cell, Kaczanowska et al. find that apheresis products and peripheral blood at baseline contained significantly higher proportions of CXCR3+ monocytes in good expanders. CXCR3+ monocytes may influence CAR T cell function.

Prognostic factors for intermediate- or high-risk neuroblastomas in children in China.

BACKGROUND: Evidence regarding the characteristics and prognosis of neuroblastoma (NBL) in China is limited. We aimed to investigate the characteristics and prognosis of intermediate- or high-risk NBL in children in China. METHODS: We included 147 patients with intermediate- or high-risk NBL evaluated from January 2006 to March 2015. The patients were aged 1 month to 15.5 years, 66% of them were boys, and 117 (79.6%) were diagnosed with high-risk NBL. RESULTS: After a median follow-up of 32.5 months, 80 (45.6%) patients survived, with a median survival time of 48 months (95% confidence interval [CI]: 36.41-59.59). High-risk patients (hazard ratio [HR]: 12.467; 95% CI: 11.029-12.951), partial response (PR) (HR: 1.200; 95% CI: 1.475-2.509) or progression disease (PD) (HR: 1.924; 95% CI: 1.623-3.012) after induction chemotherapy, and intracranial metastasis (HR: 3.057; 95% CI: 0.941-4.892) were independent risk factors for survival (p < 0.05) and postrelapse survival (p < 0.05). NBL relapse, male sex, and PR or PD after induction chemotherapy were risk factors for event-free survival (p < 0.05). CONCLUSIONS: In addition to previously established independent risk factors, such as age, risk group, and relapse, efficacy of induction chemotherapy and intracranial metastasis play significant roles in the prognosis of NBL.

In Vitro Imaging and Molecular Characterization of Ca2+ Flux Modulation by Nanosecond Pulsed Electric Fields.

In recent years, the application of pulsed electric fields with very short durations (nanoseconds) and extremely high amplitudes (MV/m) has been investigated for novel medical purposes. Various electric protocols have been explored for different objectives, including the utilization of fractionated pulse doses to enhance cell electrosensitization to the uptake of different markers or an increase in apoptosis. This study focused on the use of fluorescence imaging to examine molecular calcium fluxes induced by different fractionated protocols of short electric pulses in neuroblastoma (SH-SY5Y) and mesenchymal stem cells (HaMSCs) that were electroporated using nanosecond pulsed electric fields. In our experimental setup, we did not observe cell electrosensitization in terms of an increase in calcium flux following the administration of fractionated doses of nanosecond pulsed electric fields with respect to the non-fractionated dose. However, we observed the targeted activation of calcium-dependent genes (c-FOS, c-JUN, EGR1, NURR-1, ß3-TUBULIN) based on the duration of calcium flux, independent of the instantaneous levels achieved but solely dependent on the final plateau reached. This level of control may have potential applications in various medical and biological treatments that rely on calcium and the delivery of nanosecond pulsed electric fields.

Targeting of intracellular oncoproteins with peptide-centric CARs.

The majority of oncogenic drivers are intracellular proteins, constraining their immunotherapeutic targeting to mutated peptides (neoantigens) presented by individual human leukocyte antigen (HLA) allotypes1. However, most cancers have a modest mutational burden that is insufficient for generating responses using neoantigen-based therapies2,3. Neuroblastoma is a paediatric cancer that harbours few mutations and is instead driven by epigenetically deregulated transcriptional networks4. Here we show that the neuroblastoma immunopeptidome is enriched with peptides derived from proteins essential for tumorigenesis. We focused on targeting the unmutated peptide QYNPIRTTF discovered on HLA-A*24:02, which is derived from the neuroblastoma-dependency gene and master transcriptional regulator PHOX2B. To target QYNPIRTTF, we developed peptide-centric chimeric antigen receptors (PC-CARs) through a counter panning strategy using predicted potentially cross-reactive peptides. We further proposed that PC-CARs can recognize peptides on additional HLA allotypes when presenting a similar overall molecular surface. Informed by our computational modelling results, we show that PHOX2B PC-CARs also recognize QYNPIRTTF presented by HLA-A*23:01, the most common non-A2 allele in people with African ancestry. Finally, we demonstrate potent and specific killing of neuroblastoma cells expressing these HLAs in vitro and complete tumour regression in mice. These data suggest that PC-CARs have the potential to expand the pool of immunotherapeutic targets to include non-immunogenic intracellular oncoproteins and allow targeting through additional HLA allotypes in a clinical setting.

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

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

Neuroblastoma Interaction with the Tumour Microenvironment and Its Implications for Treatment and Disease Progression.

Neuroblastoma, a paediatric malignancy of the peripheral nervous system, displays a wide range of clinical outcomes, including regression to fatality despite extensive treatment. Neuroblastoma tumours display a complex interplay with their surrounding environment, known as the tumour microenvironment, which may affect disease progression and patient prognosis. This study aimed to dissect the ways in which neuroblastoma biology, treatment, prognosis, progression, and relapse are linked with the extracellular matrix, the dichotomous identities of neuroblastoma, various regulatory proteins and RNA, and extracellular vesicles within the backdrop of the tumour microenvironment. In addition, other aspects, such as immune cell infiltration, therapeutic options including monoclonal antibodies and small molecule inhibitors; and the ways in which these may affect disease progression and immunosuppression within the context of the neuroblastoma tumour microenvironment, are addressed. Such studies may shed light on useful therapeutic targets within the tumour microenvironment that may benefit groups of NB patients. Ultimately, a detailed understanding of these aspects will enable the neuroblastoma scientific community to improve treatment options, patient outcomes, and quality of life.

The etiologies and management of spinal cord compression in childhood cancers: Are we aware of the emergency of cord compression?

BACKGROUND: The spinal cord compression causes irreversible long-term permanent neurological sequelae. This study aims to increase awareness of childhood cancers that cause cord compression by comparing histopathological diagnosis, treatments, and survival rates to the literature. METHODS: Seventy-three patients (38 male, 35 female) with spinal cord compression, among 1085 patients diagnosed with solid tumors at Gazi University Department of Pediatric Oncology between 1991 and 2021 were retrospectively evaluated. RESULTS: The mean time between the onset of complaints and diagnosis was 27.5± 24.9 (2-150) days. The first three most common tumors that caused cord compression; were central nervous system tumors in 22 (30%), neuroblastoma in 17 (23%), and malignant germ cell tumors in 8 (10%) cases. Of the patients, 46 (63%) had compression due to extradural masses, and 27 (37%) patients had an intradural compression. The most common symptoms were pain in 60 (82%), weakness in 57 (78%), and pins and needles in 28 (38%) patients, respectively. The clinical physical neurological examination findings were motor deficit in 62 (84%), and deep tendon reflex changes in 54 patients (73.9%). Compression findings were detected in 58 (79.5%) patients at diagnosis, and in 15 (20.5%) of them during follow-up. The most common level of compression was seen in the thoracolumbar region in 19 (26%) cases. In 65 (89%) patients with cord compression, corticosteroids were given as anti-edema treatment. Surgical excision was performed in 39 (53%) patients. Spinal radiotherapy was given to 35 patients (48%) with radiosensitive tumors. Chemotherapy protocols were started in 52 (71.2%) cases according to their diagnoses. Complete neurological recovery was achieved in 33 (45%) patients. The 5-year overall survival rates for solid tumors with extradural compression and intradural compression were 62% and 22%, respectively (p=0.002). CONCLUSIONS: Neurological sequela-free recovery is possible with early diagnosis and urgent treatment. Spinal compression must be detected by detailed systemic and neurological examination and imaging methods. Patients should be rapidly transferred to pediatric oncology units after starting anti-edema treatment.