[This corrects the article DOI: 10.3389/fonc.2022.879167.].

The connection and causality between cancer and neurodevelopmental disorders have been puzzling. How can the same cellular pathways, proteins, and mutations lead to pathologies with vastly different clinical presentations? And why do individuals with neurodevelopmental disorders, such as autism and schizophrenia, face higher chances of cancer emerging throughout their lifetime? Our broad review emphasizes the multi-scale aspect of this type of reasoning. As these examples demonstrate, rather than focusing on a specific organ system or disease, we aim at the new understanding that can be gained. Within this framework, our review calls attention to computational strategies which can be powerful in discovering connections, causalities, predicting clinical outcomes, and are vital for drug discovery. Thus, rather than centering on the clinical features, we draw on the rapidly increasing data on the molecular level, including mutations, isoforms, three-dimensional structures, and expression levels of the respective disease-associated genes. Their integrated analysis, together with chromatin states, can delineate how, despite being connected, neurodevelopmental disorders and cancer differ, and how the same mutations can lead to different clinical symptoms. Here, we seek to uncover the emerging connection between cancer, including pediatric tumors, and neurodevelopmental disorders, and the tantalizing questions that this connection raises.

Pediatric low grade brain tumors and neurodevelopmental disorders share proteins, signaling pathways, and networks. They also share germline mutations and an impaired prenatal differentiation origin. They may differ in the timing of the events and proliferation. We suggest that their pivotal distinct, albeit partially overlapping, outcomes relate to the cell states, which depend on their spatial location, and timing of gene expression during brain development. These attributes are crucial as the brain develops sequentially, and single-cell spatial organization influences cell state, thus function. Our underlying premise is that the root cause in neurodevelopmental disorders and pediatric tumors is impaired prenatal differentiation. Data related to pediatric brain tumors, neurodevelopmental disorders, brain cell (sub)types, locations, and timing of expression in the developing brain are scant. However, emerging single cell technologies, including transcriptomic, spatial biology, spatial high-resolution imaging performed over the brain developmental time, could be transformational in deciphering brain pathologies thereby pharmacology.

BACKGROUND: Pineal region tumors have historically been challenging to treat. Advances in surgical techniques have led to significant changes in care and outcomes for these patients, and this is well demonstrated by our single institution\'s experience over a 17-year-period in which the evolution of diagnosis, treatment, and outcomes of pineal tumors in pediatric patients will be outlined.
METHODS: We retrospectively collected data on all pediatric patients with pineal region lesions treated with surgery at Children\'s National Hospital (CNH) from 2005 to 2021. Variables analyzed included presenting symptoms, presence of hydrocephalus, diagnostic and surgical approach, pathology, and adverse events, among others. IRB approval was obtained (IRB: STUDY00000009), and consent was waived due to minimal risk to patients included.
RESULTS: A total of 43 pediatric patients with pineal region tumors were treated during a 17-year period. Most tumors in our series were germinomas (n = 13, 29.5%) followed by pineoblastomas (n = 10, 22.7%). Twenty seven of the 43 patients (62.8%) in our series received a biopsy to establish diagnosis, and 44.4% went on to have surgery for resection. The most common open approach was posterior interhemispheric (PIH, transcallosal) - used for 59.3% of the patients. Gross total resection was achieved in 50%; recurrence occurred in 20.9% and mortality in 11% over a median follow-up of 47 months. Endoscopic third ventriculostomy (ETV) was employed to treat hydrocephalus in 26 of the 38 patients (68.4%) and was significantly more likely to be performed from 2011 to 2021. Most (73%) of the patients who received an ETV also underwent a concurrent endoscopic biopsy. No difference was found in recurrence rate or mortality in patients who underwent resection compared to those who did not, but complications were more frequent with resection. There was disagreement between frozen and final pathology in 18.4% of biopsies.
CONCLUSIONS: This series describes the evolution of surgical approaches and outcomes over a 17-year-period at a single institution. Complication rates were higher with open resection, reinforcing the safety of pursuing endoscopic biopsy as an initial approach. The most significant changes occurred in the preferential use of ETVs over ventriculoperitoneal shunts. Though there has been a significant evolution in our understanding of and treatment for these tumors, in our series, the outcomes for these patients have not significantly changed over that time.

The family of the neurotrophic tyrosine kinase receptor (NTRK) gene encodes for members of the tropomyosin receptor kinase (TRK) family. Rearrangements involving NTRK1/2/3 are rare oncogenic factors reported with variable frequencies in an extensive range of cancers in pediatrics and adult populations, although they are more common in the former than in the latter. The alterations in these genes are causative of the constitutive activation of TRKs that drive carcinogenesis. In 2017, first-generation TRK inhibitor (TRKi) larotrectinib was granted accelerated approval from the FDA, having demonstrated histologic-agnostic activity against NTRKs fusions tumors. Since this new era has begun, resistance to first-generation TRKi has been described and has opened the development of second-generation molecules, such as selitrectinib and repotrectinib. In this review, we provide a brief overview of the studies on NTRK alterations found in pediatric central nervous system tumors and first and second-generation TRKi useful in clinical practice.

OBJECTIVE: To better define the overall performance of the current radiomics-based models for the discrimination of pediatric posterior fossa tumors.
METHODS: A comprehensive literature search of the databases PubMed, Ovid MEDLINE, Ovid EMBASE, Web of Science, and Scopus was designed and conducted by an experienced librarian. We estimated overall sensitivity (SEN) and specificity (SPE). Event rates were pooled across studies using a random-effects meta-analysis, and the χ2 test was performed to assess the heterogeneity.
RESULTS: Overall SEN and SPE for differentiation between MB, PA, and EP were found to be promising, with SEN values of 93% (95% CI = 0.88-0.96), 83% (95% CI = 0.66-0.93), and 85% (95% CI = 0.71-0.93), and corresponding SPE values of 87% (95% CI = 0.82-0.90), 95% (95% CI = 0.90-0.98) and 90% (95% CI = 0.84-0.94), respectively. For MB, there is a better trend for LR classifiers, while textural features are the most used and the best performing (ACC 96%). As for PA and EP, a synergistic employment of LR and NN classifiers, accompanied by geometrical or morphological features, demonstrated superior performance (ACC 94% and 96%, respectively).
CONCLUSIONS: The diagnostic performance is high, making radiomics a helpful method to discriminate these tumor types. In the forthcoming years, we expect even more precise models.

BACKGROUND: Fine needle aspiration cytology (FNAC) is gaining popularity in diagnosing pediatric tumors because of ease of performance, easy reproducibility, and low morbidity. However, literature on its efficacy in resource-limited settings is lacking. Hence, the present study evaluated the diagnostic accuracy of FNAC in pediatric tumors in a North Indian center where ancillary diagnostic techniques are unavailable.
METHODS: This was a four-year retrospective and 1-year prospective study. Both direct and radiology-guided FNAs were performed in children under 14 years. Cytomorphologic diagnoses were compared with the corresponding histopathologic diagnoses, wherever available, and the concordance rates determined. The diagnostic accuracy of FNAC for pediatric tumors was assessed using sensitivity, specificity, and positive and negative predictive values.
RESULTS: The present study included 125 cases of pediatric tumors, of which 65 were benign and 60 were malignant. The most common site of involvement was the head and neck. The most common benign pediatric tumor was pleomorphic adenoma, while the most common malignant tumor was non-Hodgkin lymphoma. The overall cytologic-histopathologic concordance was high (96.3%), with an overall sensitivity and specificity of 95.65% and 96.88%, respectively.
CONCLUSIONS: FNAC is a highly sensitive and specific technique for diagnosing pediatric tumors, with a high histopathologic concordance, even in resource-limited setups where advanced ancillary techniques are unavailable. Nevertheless, additional ancillary techniques can complement FNAC to improve this diagnostic accuracy further.

[This corrects the article DOI: 10.3389/fonc.2022.879167.].

Many pediatric patients with malignant tumors continue to suffer poor outcomes. The current standard of care includes maximum safe surgical resection followed by chemotherapy and radiation which may be associated with considerable long-term morbidity. The emergence of oncolytic virotherapy (OVT) may provide an alternative or adjuvant treatment for pediatric oncology patients.
We reviewed seven virus types that have been investigated in past or ongoing pediatric tumor clinical trials: adenovirus (AdV-tk, Celyvir, DNX-2401, VCN-01, Ad-TD-nsIL-12), herpes simplex virus (G207, HSV-1716), vaccinia (JX-594), reovirus (pelareorep), poliovirus (PVSRIPO), measles virus (MV-NIS), and Senecavirus A (SVV-001). For each virus, we discuss the mechanism of tumor-specific replication and cytotoxicity as well as key findings of preclinical and clinical studies.
Substantial progress has been made in the past 10 years regarding the clinical use of OVT. From our review, OVT has favorable safety profiles compared to chemotherapy and radiation treatment. However, the antitumor effects of OVT remain variable depending on tumor type and viral agent used. Although the widespread adoption of OVT faces many challenges, we are optimistic that OVT will play an important role alongside standard chemotherapy and radiotherapy for the treatment of malignant pediatric solid tumors in the future.

Phosphatase of regenerating liver 3 (PRL3) is a specific tumor antigen overexpressed in a broad range of adult cancer types. However, its physiological expression in pediatric embryonal and mesenchymal tumors and its association with clinical outcomes in children is unknown. We sought to profile the expression of PRL3 in pediatric tumors in relation to survival outcomes, expression of angiogenesis markers, and G-protein-coupled receptor (GPCR)-mitogen-activated protein kinase (MAPK) signaling targets. PRL3-zumab, a first-in-class humanized antibody, was administered in a dose escalation schedule in a first-in-child clinical trial to study toxicity, pharmacokinetics, and clinical outcomes. Among 64 pediatric tumors, PRL3 was most frequently expressed in neuroblastoma (100%), rhabdomyosarcoma and non-rhabdomyosarcoma soft tissue sarcomas (71%), and renal sarcomas (60%) but absent in paired normal tissues. PRL3 was expressed in 75% of relapsed tumors and associated with shorter median event-free survival. Microarray profiling of PRL3-positive tumors showed elevation of angiogenin, TIMP1 and TIMP2, and GPCR-MAPK signaling proteins that commonly interacted with PRL3. The first use of PRL3-zumab in a pediatric patient saw no adverse events. A 28.6% reduction in maximum target lesion diameter was achieved when PRL3-zumab was administered concurrently with hypofractionated radiation. These findings support wider exploration of PRL3 expression in embryonal and mesenchymal tumors and further clinical application of PRL3-zumab in pediatric patients.