Osteosarcoma (OS) is the most severe bone malignant tumor, responsible for altered osteoid deposition and with a high rate of metastasis. It is characterized by heterogeneity, chemoresistance and its interaction with bone microenvironment. The 5-year survival rate is about 67% for patients with localized OS, while it remains at 20% in case of metastases. The standard therapy for OS patients is represented by neoadjuvant chemotherapy, surgical resection, and adjuvant chemotherapy. The most used chemotherapy regimen for children is the combination of high-dose methotrexate, doxorubicin, and cisplatin. Considered that the necessary administration of high-dose chemotherapy is responsible for a lot of acute and chronic side effects, the identification of novel therapeutic strategies to ameliorate OS outcome and the patients’ life expectancy is necessary. In this review we provide an overview on new possible innovative therapeutic strategies in OS.

Anti-cancer treatments improve survival in children with cancer. A total of 80% of children treated for childhood cancer achieve 5-year survival, becoming long-term survivors. However, they undergo several chronic late effects related to treatments. In childhood cancer survivors a chronic low-grade inflammation, known as inflamm-aging, is responsible for frailty, a condition characterized by vital organ failure and by premature aging processes. Inflamm-aging is closely related to chemotherapy and radiotherapy, which induce inflammation, accumulation of senescent cells, DNA mutations, and the production of reactive oxygen species. All these conditions are responsible for the onset of secondary diseases, such as osteoporosis, cardiovascular diseases, obesity, and infertility. Considering that the pathobiology of frailty among childhood cancer survivors is still unknown, investigations are needed to better understand frailty’s biological and molecular processes and to identify inflamm-aging key biomarkers in order to facilitate the screening of comorbidities and to clarify whether treatments, normally used to modulate inflamm-aging, may be beneficial. This review offers an overview of the possible biological mechanisms involved in the development of inflamm-aging, focusing our attention on immune system alteration, oxidative stress, cellular senescence, and therapeutic strategies.

Neuroblastoma (NB) is the most common extracranial solid tumor in childhood. Patients with relapsed/refractory disease have a poor prognosis, and additional therapeutic options are needed. Mutations and amplifications in the ALK (Anaplastic Lymphoma Kinase) gene constitute a key target for treatment. Our goal, within the Italian project of PeRsonalizEdMEdicine (PREME), was to evaluate the genomic status of patients with relapsed/refractory NB and to implement targeted therapies in those with targetable mutations. From November 2018 to November 2021, we performed Whole Exome Sequencing or Targeted Gene Panel Sequencing in relapsed/refractory NB patients in order to identify druggable variants. Activating mutations of ALK were identified in 8(28.57%) of 28 relapsed/refractory NB patients. The mutation p.F1174L was found in six patients, whereas p.R1275Q was found in one and the unknown mutation p.S104R in another. Three patients died before treatment could be started, while five patients received crizotinib: two in monotherapy (one with p.F1174L and the other with p.S104R) and three (with p.F1174L variant) in combination with chemotherapy. All treated patients showed a clinical improvement, and one had complete remission after two cycles of combined treatment. The most common treatment-related toxicities were hematological. ALK inhibitors may play an important role in the treatment of ALK-mutated NB patients.

Acute lymphoblastic leukemia (ALL) is the most common pediatric malignancy, characterized by the clonal proliferation of immature lymphoid precursors. The distinction between B-cell ALL (B-ALL) and T-cell ALL (T-ALL) is fundamental, as each subtype exhibits distinct cytomorphological, genetic, and clinical features influencing prognosis and therapeutic strategies. Conventional multi-phase chemotherapy has significantly improved survival rates, yet its efficacy is limited by severe short- and long-term toxicities, highlighting the need for more selective therapeutic approaches. Advances in molecular profiling have enabled the identification of key oncogenic pathways, paving the way for targeted therapies such as tyrosine kinase inhibitors (TKIs), JAK-STAT pathway inhibitors, BCL-2 antagonists, and agents modulating epigenetic and cell cycle regulators. Concurrently, immunotherapeutic strategies have transformed the therapeutic landscape of pediatric ALL. Bispecific antibodies such as blinatumomab (anti-CD19), antibody–drug conjugates like inotuzumab ozogamicin (anti-CD22), and monoclonal antibodies such as daratumumab (anti-CD38) have demonstrated efficacy in relapsed or refractory disease with improved safety profiles. Moreover, CAR-T-cell therapy, particularly CD19-directed products, has shown unprecedented remission rates in refractory B-ALL. The integration of targeted and immune-based therapies into conventional regimens represents a decisive step toward precision medicine, aiming to enhance survival outcomes while reducing treatment-related toxicity and improving quality of life in ALL children. This review aims to provide a comprehensive overview of the current understanding of ALL pathobiology and therapeutic approaches, with particular emphasis on the expanding role of immunotherapeutic strategies in pediatric disease.

Osteosarcoma (OS) is the most severe bone tumor in children. A chemotherapy regimen includes a combination of high-dose Methotrexate (MTX), doxorubicin, and cisplatin. These drugs cause acute and chronic side effects, such as infections, thrombocytopenia, neutropenia, DNA damage, and inflammation. Therefore, to identify new therapeutic strategies, effective and with a safety profile, is necessary. The Hedgehog (Hh) signaling pathway involved in tumorigenesis is active in OS. Hh components Patched receptor 1 (PTCH1), Smoothened (SMO), and glioma-associated oncogene homolog transcription factors (GLI1 and GLI2) are overexpressed in OS cell lines and patient samples. Curcumin (CUR)—with antioxidant and anti-cancer properties—downregulates Hh components in cancer, inhibiting progression. This study investigates CUR effects on the MG-63 OS cell line, alone and combined with MTX, to propose a novel therapeutic approach. Our study suggests CUR as a novel therapeutic agent in OS, particularly when combined with MTX. Targeting the Hh signaling pathway, CUR and MTX showed significant pro-apoptotic effects, increasing the BAX/Bcl-2 ratio and total apoptotic cell percentage. They reduced the expression of Hh pathway components (PTCH1, SMO, GLI1, and GLI2), inhibiting OS cell proliferation, survival, and invasion. CUR and MTX combined determined a β-Catenin decrease and a trend toward reducing NF-kB and matrix metalloproteinases (MMP-2 and MMP-9). Our findings suggest CUR as a support to OS treatment, improving outcomes and reducing the adverse effects of current therapies.

The advancement of anti-cancer therapies has markedly improved the survival rate of children with cancer, making them long-term childhood cancer survivors (CCS). Nevertheless, these treatments cause a low-grade inflammatory state, determining inflamm-aging and, thus, favoring the early onset of chronic diseases normally associated with old age. Identification of novel and safer therapeutic strategies is needed to counteract and prevent inflamm-aging. Macrophages are cells involved in immune and inflammatory responses, with a pivotal role in iron metabolism, which is related to inflammation. We obtained macrophages from CCS patients and evaluated their phenotype markers, inflammatory states, and iron metabolism by Western blotting, ELISA, and iron assays. We observed a strong increase in classically activated phenotype markers (M1) and iron metabolism alteration in CCS, with an increase in intracellular iron concentration and inflammatory markers. These results suggest that the prevalence of M1 macrophages and alteration of iron metabolism could be involved in the worsening of inflammation in CCS. Therefore, we propose macrophages and iron metabolism as novel therapeutic targets to counteract inflamm-aging. To avoid toxic regimens, we tested some nutraceuticals (resveratrol, curcumin, and oil-enriched lycopene), which are already known to exert anti-inflammatory properties. After their administration, we observed a macrophage switch towards the anti-inflammatory phenotype M2, as well as reductions in pro-inflammatory cytokines and the intracellular iron concentration. Therefore, we suggest—for the first time—that nutraceuticals reduce inflammation in CCS macrophages through a novel anti-inflammatory mechanism of action, modulating iron metabolism.