Current practices for nutritional evaluation and care during the treatment of pediatric oncology patients: a survey among AIEOP centers.

Nutritional status plays a crucial role in the mortality rates of the pediatric oncology patients. However, there is a lack of systematic approaches for nutritional assessment in this population. This study aims to assess the current practice for nutritional assessment and care of pediatric cancer patients in Italy. A 25-items web-based, nation-wide questionnaire was circulated as of January 9, 2023 among physicians within the AIEOP network, composed of 49 national centers, out of which 21 routinely perform HCT. This survey examined the practices of 21 Italian pediatric oncology centers, revealing significant heterogeneity in nutritional practices. Only half of the centers routinely assessed all patients, utilizing different clinical and biochemical parameters. The use of neutropenic diets remained prevalent after chemotherapy or stem cell transplantation. CONCLUSION: This study underscores the pressing need for unified recommendations to improve nutritional care and potentially enhance outcomes for pediatric cancer patients. WHAT IS KNOWN: • The assessment and support of nutrition are gaining interest in the overall care of children with cancer. • The assessment and management of nutritional needs in pediatric cancer patients, including those undergoing hematopoietic cell transplantation, currently lack a systematic approach. WHAT IS NEW: • There is considerable variability in the nutritional assessment and support among Italian centers treating pediatric patients with cancer. • To enhance nutritional assessment and support for pediatric cancer patients, it is essential to establish shared national and international guidelines.

Safety and Efficacy of Mek Inhibitors in the Treatment of Plexiform Neurofibromas: A Retrospective Study.

INTRODUCTION: Plexiform neurofibromas (PN) represent the main cause of morbidity in patients affected by Neurofibromatosis Type 1 (NF1). Until recently, surgery has been the main treatment option in these patients, but it is burdened with a low efficacy rate and a high incidence of side effects as well as recurrence. In recent years, MEK inhibitors (MEKi) such as selumetinib and trametinib have shown great promise. METHODS: We retrospectively describe a single center cohort of NF1 patients affected by PN1 and treated with MEKi since 2019 to 2021. Patients recruited in the study were affected by PN that were not eligible to complete surgical excision, symptomatic or with major cosmetic deformation or functional neurological deficits. RESULTS: Most patients experienced improvement in clinical symptoms and quality of life, with reduction or stabilization of lesions. However, no complete response was achieved. The most common adverse effects involved the skin, affecting every patient. Importantly, no life-threatening adverse effects occurred. CONCLUSIONS: In our experience, MEKi treatment has been shown to be both safe and effective in improving symptomatology and quality of life.

Common bone marrow signature in COVID-19-associated multisystem inflammatory syndrome in children: A first-wave small case series experience.

The hyper-inflammatory response, also known as multisystem inflammatory syndrome in children (MIS-C), represents a major concern in children with SARS-CoV-2 infection. We report bone marrow features of three patients with MIS-C who were diagnosed during the first wave of the SARS-CoV-2 pandemic. A bone marrow evaluation was performed at onset of the inflammatory condition in order to exclude secondary hemophagocytic lymphohistiocytosis (sHLH). The bone marrows of the patients presented common features: the erythroid and megakaryocytic lineages were prominently affected and hemophagocytosis was moderately increased, differently than observed in sHLH. Megakaryocytopoiesis was increased, representing a peculiar feature of MIS-C differing from sHLH. SARS-CoV-2 RT-PCR and viral panel were studied in bone marrow aspiration samples. MIS-C is a rare complication of SARS-CoV-2 infections in children. An immuno-dysregulation considering both innate and adaptive immunity together with vascular inflammation and endothelial dysfunction play a major role. Our observations, although limited due to the small sample size, suggest that there are unique features in the bone marrow of patients with MIS-C that are likely secondary to immuno-dysregulation, and there are notable differences in bone marrow features compared to those reported in sHLH.

Developing CAR T-Cell Therapies for Pediatric Solid Tumors.

Chimeric antigen receptor (CAR) T cells have revolutionized the treatment of hematological malignancies, inducing notable and durable clinical responses. However, for solid tumors, including but not limited to pediatric tumors, several peculiar biological features posed substantial challenges for achieving comparable results. Despite sound pre-clinical evidence of the ability of CAR T cells to eradicate solid malignancies, their activity remains suboptimal when facing the in vivo complexity of solid tumors, characterized by antigen heterogeneity, scarce T-cell infiltration, and an immunosuppressive microenvironment. Neuroblastoma was amongst the first tumors to be evaluated as a potential candidate for GD2-targeting CAR T cells, which recently documented promising results in high-risk, heavily pre-treated patients. Moreover, innovative engineering strategies for generating more potent and persistent CAR T cells suggest the possibility to reproduce, and potentially improve, these promising results on a larger scale. In the next years, harnessing the full therapeutic potential of CAR T cells and other immunotherapeutic strategies may open new possibilities for effectively treating the most aggressive forms of pediatric tumors.

Genetic Predisposition to Hematologic Malignancies in Childhood and Adolescence.

Advances in molecular biology and genetic testing have greatly improved our understanding of the genetic basis of hematologic malignancies and have enabled the identification of new cancer predisposition syndromes. Recognizing a germline mutation in a patient affected by a hematologic malignancy allows for a tailored treatment approach to minimize toxicities. It informs the donor selection, the timing, and the conditioning strategy for hematopoietic stem cell transplantation, as well as the comorbidities evaluation and surveillance strategies. This review provides an overview of germline mutations that predispose to hematologic malignancies, focusing on those most common during childhood and adolescence, based on the new International Consensus Classification of Myeloid and Lymphoid Neoplasms.

Unlocking the power of precision medicine for pediatric low-grade gliomas: molecular characterization for targeted therapies with enhanced safety and efficacy.

In the past decade significant advancements have been made in the discovery of targetable lesions in pediatric low-grade gliomas (pLGGs). These tumors account for 30-50% of all pediatric brain tumors with generally a favorable prognosis. The latest 2021 WHO classification of pLGGs places a strong emphasis on molecular characterization for significant implications on prognosis, diagnosis, management, and the potential target treatment. With the technological advances and new applications in molecular diagnostics, the molecular characterization of pLGGs has revealed that tumors that appear similar under a microscope can have different genetic and molecular characteristics. Therefore, the new classification system divides pLGGs into several distinct subtypes based on these characteristics, enabling a more accurate strategy for diagnosis and personalized therapy based on the specific genetic and molecular abnormalities present in each tumor. This approach holds great promise for improving outcomes for patients with pLGGs, highlighting the importance of the recent breakthroughs in the discovery of targetable lesions.

Targeted therapy for pediatric central nervous system tumors harboring mutagenic tropomyosin receptor kinases.

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.

A systematic review of data sources for artificial intelligence applications in pediatric brain tumors in Europe: implications for bias and generalizability.

Introduction: Europe works to improve cancer management through the use of artificialintelligence (AI), and there is a need to accelerate the development of AI applications for childhood cancer. However, the current strategies used for algorithm development in childhood cancer may have bias and limited generalizability. This study reviewed existing publications on AI tools for pediatric brain tumors, Europe's most common type of childhood solid tumor, to examine the data sources for developing AI tools. Methods: We performed a bibliometric analysis of the publications on AI tools for pediatric brain tumors, and we examined the type of data used, data sources, and geographic location of cohorts to evaluate the generalizability of the algorithms. Results: We screened 10503 publications, and we selected 45. A total of 34/45 publications developing AI tools focused on glial tumors, while 35/45 used MRI as a source of information to predict the classification and prognosis. The median number of patients for algorithm development was 89 for single-center studies and 120 for multicenter studies. A total of 17/45 publications used pediatric datasets from the UK. Discussion: Since the development of AI tools for pediatric brain tumors is still in its infancy, there is a need to support data exchange and collaboration between centers to increase the number of patients used for algorithm training and improve their generalizability. To this end, there is a need for increased data exchange and collaboration between centers and to explore the applicability of decentralized privacy-preserving technologies consistent with the General Data Protection Regulation (GDPR). This is particularly important in light of using the European Health Data Space and international collaborations.

Frequency and characterization of cognitive impairments in patients diagnosed with paediatric central nervous system tumours: a systematic review.

Background: This systematic review has been conducted with the aim of characterizing cognitive deficits and analyzing their frequency in survivors of paediatric Central Nervous System tumours. Materials and methods: All literature published up to January 2023 was retrieved searching the databases "PubMed", "Cochrane", "APA PsycInfo" and "CINAHL". The following set of pre-defined inclusion criteria were then individually applied to the selected articles in their full-text version: i) Retrospective/prospective longitudinal observational studies including only patients diagnosed with primary cerebral tumours at ≤ 21 years (range 0-21); ii) Studies including patients evaluated for neuro-cognitive and neuro-psychological deficits from their diagnosis and/or from anti-tumoral therapies; iii) Studies reporting standardized tests evaluating patients' neuro-cognitive and neuro-psychological performances; iv) Patients with follow-ups ≥ 2 years from the end of their anti-tumoral therapies; v) Studies reporting frequencies of cognitive deficits. Results: 39 studies were included in the analysis. Of these, 35 assessed intellectual functioning, 30 examined memory domains, 24 assessed executive functions, 22 assessed attention, 16 examined visuo-spatial skills, and 15 explored language. A total of 34 studies assessed more than one cognitive function, only 5 studies limited their analysis on a single cognitive domain. Attention impairments were the most recurrent in this population, with a mean frequency of 52.3% after a median period post-treatment of 11.5 years. The other cognitive functions investigated in the studies showed a similar frequency of impairments, with executive functions, language, visuospatial skills and memory deficits occurring in about 40% of survivors after a similar post-treatment period. Longitudinal studies included in the systematic review showed a frequent decline over time of intellectual functioning. Conclusions: Survivors of paediatric Central Nervous System tumours experience cognitive sequelae characterized by significant impairments in the attention domain (52.3%), but also in the other cognitive functions. Future studies in this research field need to implement more cognitive interventions and effective, but less neurotoxic, tumour therapies to preserve or improve neurocognitive functioning and quality of life of this population.

Venetoclax plus cyclophosphamide and topotecan in heavily pre-treated relapsed metastatic neuroblastoma: a single center case series.

The prognosis of relapsed/refractory (R/R) neuroblastoma (NB) is dismal, calling for new therapeutic strategies. Venetoclax (VEN) is a highly selective, potent, orally bioavailable, BCL-2 inhibitor small-molecule that showed a synergistic effect with cyclophosphamide and topotecan (Cy-Topo) in murine NB models. Our aim was to evaluate the feasibility of VEN plus Cy-Topo in children with R/R NB. Four patients, who had previously failed > 3 lines of treatment, were treated with VEN plus Cy-Topo based on a 28-day schedule in an outpatient setting. BCL-2 expression in immunochemistry on tumor samples at relapse and the BCL2 gene status was evaluated in all patients. The main toxicity was hematological, with grade 4 neutropenia and thrombocytopenia occurring in all courses and leading to transient VEN discontinuation. Grade 3 oral mucositis was observed in 1/8 courses. No other grade 2-4 toxicities were observed. BCL-2 was expressed in all tumors, while no molecular abnormalities in the BCL-2 genes were detected. A stable disease was observed in all patients, without any progression during the study period. VEN plus Cy-Topo is well tolerated, with encouraging results that may be improved by testing the schedule in less advanced patients.

Case report: A safeguard in the sea of variants of uncertain significance: a case study on child with high risk neuroblastoma and acute myeloid leukemia.

The increased availability of genetic technologies has significantly improved the detection of novel germline variants conferring a predisposition to tumor development in patients with malignant disease. The identification of variants of uncertain significance (VUS) represents a challenge for the clinician, leading to difficulties in decision-making regarding medical management, the surveillance program, and genetic counseling. Moreover, it can generate confusion and anxiety for patients and their family members. Herein, we report a 5-year-old girl carrying a VUS in the Succinate Dehydrogenase Complex Subunit C (SHDC) gene who had been previously treated for high-risk neuroblastoma and subsequently followed by the development of secondary acute myeloid leukemia. In this context, we describe how functional studies can provide additional insight on gene function determining whether the variant interferes with normal protein function or stability.

GATA 2 Deficiency: Focus on Immune System Impairment.

GATA2 deficiency is a disease with a broad spectrum of clinical presentation, ranging from lymphedema, deafness, pulmonary dysfunction to miscarriage and urogenital anomalies, but it is mainly recognized as an immune system and bone marrow disorder. It is caused by various heterozygous mutations in the GATA2 gene, encoding for a zinc finger transcription factor with a key role for the development and maintenance of a pool of hematopoietic stem cells; notably, most of these mutations arise de novo. Patients carrying a mutated allele usually develop a loss of some cell populations, such as B-cell, dendritic cell, natural killer cell, and monocytes, and are predisposed to disseminated human papilloma virus and mycobacterial infections. Also, these patients have a predisposition to myeloid neoplasms, including myelodysplastic syndromes, myeloproliferative neoplasms, chronic myelomonocytic leukaemia. The age of symptoms onset can vary greatly even also within the same family, ranging from early childhood to late adulthood; incidence increases by age and most frequently clinical presentation is between the second and third decade of life. Currently, haematopoietic stem cell transplantation represents the only curative treatment, restoring both the hematopoietic and immune system function.

Multidisciplinary Management of Craniopharyngiomas in Children: A Single Center Experience.

BACKGROUND: Craniopharyngioma (CP) is a rare brain tumor involving the sellar region. The best management is still debated. Gross total resection (GTR) is considered the best option to improve recurrence-free survival, but considerable long-term sequelae with a significant impact on quality of life have been reported. Subtotal resection followed by radiotherapy achieves similar disease control compared to GTR with less complications. METHODS: We retrospectively reviewed 10 pediatric patients affected by CP treated with partial resection and subsequent proton therapy (PBT). We reviewed visual, endocrinological, and neuropsychological data at baseline, after surgery, and after radiation for all patients. RESULTS: At the time of diagnosis, visual impairment was detected in 70% of patients and endocrinological abnormalities in 50%. All patients were subject to one or more surgical procedures. Surgery had no impact on visual status; however, it caused a worsening of endocrine function in half of patients. After surgery, all patients underwent PBT, achieving a partial response in 7 out of 10 patients (70%), while stable disease was observed in the other three patients (30%) at a median follow-up of 78 months from the end of PBT. Both visual and endocrine deficits were stable after PBT, with neurocognitive performance scores unchanged from baseline. CONCLUSIONS: A conservative surgical approach followed by PBT represents a safe and effective strategy to manage CP and limit long-term sequelae.

Pediatric Diffuse Midline Gliomas: An Unfinished Puzzle.

Diffuse midline glioma (DMG) is a heterogeneous group of aggressive pediatric brain tumors with a fatal prognosis. The biological hallmark in the major part of the cases is H3K27 alteration. Prognosis remains poor, with median survival ranging from 9 to 12 months from diagnosis. Clinical and radiological prognostic factors only partially change the progression-free survival but they do not improve the overall survival. Despite efforts, there is currently no curative therapy for DMG. Radiotherapy remains the standard treatment with only transitory benefits. No chemotherapeutic regimens were found to significantly improve the prognosis. In the new era of a deeper integration between histological and molecular findings, potential new approaches are currently under investigation. The entire international scientific community is trying to target DMG on different aspects. The therapeutic strategies involve targeting epigenetic alterations, such as methylation and acetylation status, as well as identifying new molecular pathways that regulate oncogenic proliferation; immunotherapy approaches too are an interesting point of research in the oncology field, and the possibility of driving the immune system against tumor cells has currently been evaluated in several clinical trials, with promising preliminary results. Moreover, thanks to nanotechnology amelioration, the development of innovative delivery approaches to overcross a hostile tumor microenvironment and an almost intact blood-brain barrier could potentially change tumor responses to different treatments. In this review, we provide a comprehensive overview of available and potential new treatments that are worldwide under investigation, with the intent that patient- and tumor-specific treatment could change the biological inauspicious history of this disease.

Cerebellar mutism syndrome: From pathophysiology to rehabilitation.

Cerebellar mutism syndrome (CMS) is a common complication following surgical resection of childhood tumors arising in the posterior fossa. Alteration of linguistic production, up to muteness and emotional lability, generally reported at least 24 h after the intervention, is the hallmark of post-operative CMS. Other associated traits include hypotonia and other cerebellar motor signs, cerebellar cognitive-affective syndrome, motor deficits from the involvement of the long pathways, and cranial neuropathies. Recovery usually takes 6 months, but most children are burdened with long-term residual deficits. The pathogenic mechanism is likely due to the damage occurring to the proximal efferent cerebellar pathway, including the dentate nucleus, the superior cerebellar peduncle, and its decussation in the mesencephalic tegmentum. Proven risk factors include brain stem invasion, diagnosis of medulloblastoma, midline localization, tumor size, invasion of the fourth ventricle, invasion of the superior cerebellar peduncle, left-handedness, and incision of the vermis. Currently, rehabilitation is the cornerstone of the treatment of patients with cerebellar mutism syndrome, and it must consider the three main impaired domains, namely speech, cognition/behavior, and movement.

Case report: A new pathogenic variant of LRBA deficiency with a complex phenotype and Rosai-Dorfman disease.

We reported a new pathogenic variant of LRBA deficiency with a complex phenotype-neonatal diabetes, very early-onset inflammatory bowel disease, and polyarthritis-who presented with lymph node enlargement. A case of Rosai-Dorfman's disease (RDD) was confirmed. The occurrence of an RDD lesion in LRBA-deficiency has never been reported so far.

Liquid Biopsy with Detection of NRASQ61K Mutation in Cerebrospinal Fluid: An Alternative Tool for the Diagnosis of Primary Pediatric Leptomeningeal Melanoma.

Primary leptomeningeal melanoma (PLMM) is a very rare disease in childhood with a poor prognosis. NRASQ16K mutation frequently drives malignant transformation in this population, so its evaluation should be considered in childhood PLMM diagnosis. In the presented case, the mutation was detected by Sanger sequencing performed on DNA extracted from cerebrospinal fluid neoplastic cells. Liquid biopsy has been shown to be a safe and reliable technique for the diagnosis of PLMM. Its use can potentially be extended to other neoplasms of the central nervous system bearing well-defined molecular mutations, sparing the patient invasive surgery and finally allowing a more rapid diagnosis and early initiation of targeted therapies.

Gaps and Opportunities of Artificial Intelligence Applications for Pediatric Oncology in European Research: A Systematic Review of Reviews and a Bibliometric Analysis.

The application of artificial intelligence (AI) systems is emerging in many fields in recent years, due to the increased computing power available at lower cost. Although its applications in various branches of medicine, such as pediatric oncology, are many and promising, its use is still in an embryonic stage. The aim of this paper is to provide an overview of the state of the art regarding the AI application in pediatric oncology, through a systematic review of systematic reviews, and to analyze current trends in Europe, through a bibliometric analysis of publications written by European authors. Among 330 records found, 25 were included in the systematic review. All papers have been published since 2017, demonstrating only recent attention to this field. The total number of studies included in the selected reviews was 674, with a third including an author with a European affiliation. In bibliometric analysis, 304 out of the 978 records found were included. Similarly, the number of publications began to dramatically increase from 2017. Most explored AI applications regard the use of diagnostic images, particularly radiomics, as well as the group of neoplasms most involved are the central nervous system tumors. No evidence was found regarding the use of AI for process mining, clinical pathway modeling, or computer interpreted guidelines to improve the healthcare process. No robust evidence is yet available in any of the domains investigated by systematic reviews. However, the scientific production in Europe is significant and consistent with the topics covered in systematic reviews at the global level. The use of AI in pediatric oncology is developing rapidly with promising results, but numerous gaps and challenges persist to validate its utilization in clinical practice. An important limitation is the need for large datasets for training algorithms, calling for international collaborative studies.