Search Results (79)

Advances in molecular diagnostics have enabled precision medicine approaches in pediatric neuro-oncology, with small-molecule drugs emerging as promising therapeutic candidates targeting specific genetic and epigenetic alterations in central nervous system (CNS) tumors. This review provides a focused overview of several small-molecule agents under investigation or in early clinical use, including ONC201, tazemetostat, vorasidenib, CDK inhibitors, selinexor, and aurora kinase A inhibitors, among others. Highlighted are their mechanisms of action, pharmacokinetic properties, early efficacy data, and tolerability in pediatric populations. Despite encouraging preclinical and early-phase results, most agents face limitations due to study heterogeneity, lack of large-scale pediatric randomized trials, and challenges in drug delivery to the CNS. The review underscores the critical need for robust prospective clinical trials for the integration of these therapies into pediatric neuro-oncology care. Full article

Conventional chemotherapy continues to form the backbone of treatment for many pediatric central nervous system (CNS) tumors. Advances have been made especially in the molecular underpinning of certain pediatric CNS tumors, allowing for advancement and consideration in incorporating this molecular information in molecular targeted therapy or appropriate de-escalation or escalation of therapy. In very young children with embryonal CNS tumors, intensive high-dose chemotherapy approaches have been used with varied increased survival in medulloblastoma, atypical teratoid rhabdoid tumor (ATRT), and rare embryonal subtypes, but there are certain molecular risk groups that require new therapies, such as the ATRT MYC subtype. Some CNS tumors remain resistant or refractory to conventional chemotherapy, especially in relapsed disease. Strategies to explore combination therapies with chemotherapy, novel agents, and novel approaches are needed to improve survival in this population in the future. Full article

Atypical teratoid rhabdoid tumor (ATRT) is a rare, aggressive pediatric central nervous system (CNS) tumor that predominantly affects children under the age of 3. It is defined by the inactivation of the SMARCB1 gene, leading to the loss of INI1, a protein essential for cell lineage determination and cell differentiation. Current standard of care treatment requires aggressive multimodal therapy with maximal safe resection, high-dose chemotherapy with autologous stem cell rescue, and radiation, yet overall survival remains < 50%. These intensive regimens have improved overall survival but are associated with significant morbidity and long-term effects. Molecular profiling has significantly advanced the understanding of ATRTs, revealing four molecular subgroups, ATRT-TYR, ATRT-MYC, ATRT-SHH, and ATRT-SMARCA4, each with distinct clinical presentations, oncogenic pathways, and prognoses. Molecular characterization enables better prognostic stratification, guiding treatment decisions and allowing for more personalized therapeutic approaches. Targeted therapies based on these molecular insights remain experimental, and continued exploration of molecular mechanisms and how they differ amongst subgroups is pivotal for the development of less toxic, more effective targeted treatments. Full article

Pediatric central nervous system (CNS) tumors, including gliomas, medulloblastomas, and diffuse midline gliomas (previously diffuse intrinsic pontine gliomas), remain a major clinical challenge due to their complex biology, limited treatment effectiveness, and generally poor prognosis. Standard treatments are often aggressive and associated with substantial toxicity, particularly in advanced stages. This review highlights recent developments in radiopharmaceuticals for molecular imaging and targeted radiotherapy. A comprehensive literature analysis was conducted, focusing on radiotracers with clinical relevance in pediatric neuro-oncology, including metabolic, peptide receptor-based, and antibody-based agents. Radiopharmaceuticals such as ¹⁸F-FLT, ⁶⁴CuCl₂, and 1-L-18F-FETrp have improved the ability to monitor tumor biology, proliferation, and treatment response, aiding in diagnosis at an early stage, assessment of tumor behavior, and detection of recurrence or progression. Additionally, peptide receptor-based radiotracers, such as ⁶⁸Ga-DOTATATE and ¹⁷⁷Lu-DOTATATE, are already used for both diagnostic purposes and targeted radiotherapy, particularly in neuroblastomas and gliomas. Antibody-based radiotracers like ¹³¹I-omburtamab, targeting B7-H3, are emerging as promising tools for addressing difficult-to-treat tumors such as diffuse midline glioma. Collectively, these advances provide new hope for children afflicted by these devastating malignancies, offering promising solutions for more specific and precise diagnosis and, additionally, for more effective, personalized, and less toxic tumor therapies. Full article

Pediatric central nervous system (CNS) tumor survivors are highly susceptible to long-term toxicity due to tumor location and also the treatment received. Advancements in treatment techniques, risk-adapted approaches to therapy with adjustments to treatment regimens—including de-escalation when feasible—along with the addition of supportive therapy and surveillance in these survivors, serve to minimize and manage late effects of therapy. Full article

Central nervous system (CNS) tumors are the most common solid malignancy in the pediatric population. These lesions are the result of the aberrant cell signaling step proteins, which normally regulate cell proliferation. Mitogen-activated protein kinase (MAPK) pathways and tyrosine kinase receptors are involved in tumorigenesis of low-grade gliomas. High-grade gliomas may carry similar mutations, but loss of epigenetic control is the dominant molecular event; it can occur either due to histone mutations or inappropriate binding or unbinding of DNA on histones. Therefore, despite the absence of genetic alteration in the classic oncogenes or tumor suppressor genes, uncontrolled transcription results in tumorigenesis. Isocitric dehydrogenase (IDH) mutations do not predominate compared to their adult counterpart. Embryonic tumors include medulloblastomas, which bear mutations of transcription-regulating pathways, such as wingless-related integration sites or sonic hedgehog pathways. They may also relate to high expression of Myc family genes. Atypical teratoid rhabdoid tumors harbor alterations of molecules that contribute to ATP hydrolysis of chromatin. Embryonic tumors with multilayered rosettes are associated with microRNA mutations and impaired translation. Ependymomas exhibit great variability. As far as supratentorial lesions are concerned, the major events are mutations either of NFkB or Hippo pathways. Posterior fossa tumors are further divided into two types with different prognoses. Type A group is associated with mutations of DNA damage repair molecules. Lastly, germ cell tumors are a heterogeneous group. Among them, germinomas manifest KIT receptor mutations, a subgroup of the tyrosine kinase receptor family. Full article

Background: Oncological care of adolescent patients is often inconsistent, as they frequently fall between pediatric and adult services. The Childhood Cancer Registry of Campania (CCRC) is the Italian largest population-based registry specializing in children 0–19 years old, with a target population of approximately 1.1 million inhabitants. Material and Methods: This report presents epidemiological indicators and clinical pathways on primary brain tumors in adolescents (15–19 years) from the Campania region. Results: Over the study period (2008–2020), the cohort included 219 adolescents with newly diagnosed central nervous system (CNS) tumors with an annual average incidence rate (IR) of 48.9 cases per million/year. The 5-year observed survival rate after diagnosis of CNS tumor was 84.8%. Overall, the most common tumor site was the pituitary gland and craniopharyngeal duct, representing 22.4% of all tumors. The most frequently occurring malignant primary CNS tumor was germinoma, while the most common non-malignant tumor was pituitary adenoma. Most patients were referred to adult services and nearly half migrated outside the region to receive cancer care. Conclusions: Challenges in the care of adolescent oncology patients include limited access to specialized care, difficulties in transitioning from pediatric to adult institutions, distinct tumor biology, and the underrepresentation of adolescents in clinical trials. The care of adolescents with CNS tumors is fragmented across institutions and significant variations in practice exist between adult and pediatric practitioners. Full article

Background/Objectives: Prostate-specific membrane antigen (PSMA) is a well-established target in prostate cancer therapy that has shown potential as a theranostic target across non-central nervous system (CNS) and CNS tumor types. We aimed to investigate the pan-tissue expression pattern of the PSMA-encoding gene FOLH1 to assess whether transcriptome profiling can inform tumor diagnostic and theranostic probes. Methods: We assessed FOLH1 expression from the Open Pediatric Cancer Project (OpenPedCan, n = 2132 specimens), the Cancer Genome Atlas (TCGA, n = 10,411 specimens), and the Genotype Tissue Expression Project (GTEx, n = 17,382 specimens) in relation to published reports of PSMA radionuclide uptake in various tumors. Results: When comparing FOLH1 expression across tumor versus normal tissues, we found that non-CNS tumors exhibiting elevated expression of at least two-fold (FDR < 0.05) were reported to have significant PSMA radionuclide uptake in contrast to tumors with less than a two-fold elevation or with lower expression of FOLH1 relative to normal tissues. Notably, CNS tumors universally exhibited lower expression of FOLH1 relative to normal brain tissue, but we observed considerable variation in the expression of blood–tumor barrier (BTB) components associated with reports of BTB integrity and uptake of PSMA radiotracers. Conclusions: Large-scale transcriptomics data may help guide the application of PSMA-based radionuclide therapies in non-CNS tumors, but care should be taken to account for BTB effects in CNS tumors when assessing the potential for radionuclide success. This study demonstrates that FOLH1 showed a lack of tumor-specific expression for both adult and pediatric CNS tumors when compared to normal brain tissue, suggesting that PSMA is not a desirable target in brain tumors. Full article

Background: The blood–brain barrier (BBB) plays an important role in regulating homeostasis of the central nervous system (CNS), and it is an obstacle for molecules with a molecular weight higher than 500 Da seeking to reach it, making many drugs ineffective simply because they cannot be delivered to where they are needed. As a result, crossing the BBB remains the rate-limiting factor in brain drug delivery during the treatment of brain diseases, specifically tumors such as diffuse intrinsic pontine glioma (DIPG), a highly aggressive pediatric tumor with onset in the pons Varolii, the middle portion of the three contiguous parts of the brainstem, located above the medulla and below the midbrain. Methods: Currently, radiotherapy (RT) relieves DIPG symptoms but chemotherapy drugs do not lead to significant results as they do not easily cross the BBB. Focused ultrasound (FUS) and microbubbles (MBs) can temporarily open the BBB, facilitating radiotherapy and the entry of drugs into the CNS. A patient-derived xenograft DIPG model exposed to high-intensity focalized ultrasound (HIFU) or low-intensity focalized ultrasound (LIFU) combined with MBs was treated with doxorubicin, panobinostat, olaparib, ONC201 (Dordaviprone^®) and anti-PD1. Panobinostat has also been used in children with diffuse midline glioma, a broad class of brain tumors to which DIPG belongs. Results: Preliminary studies were performed using FUS to temporarily open the BBB and allow a milder use of radiotherapy and facilitate the passage of drugs through the BBB. The data collected show that after opening the BBB with FUS and MBs, drug delivery to the CNS significantly improved. Conclusions: FUS associated with MBs appears safe and feasible and represents a new strategy to increase the uptake of drugs in the CNS and therefore enhance their effectiveness. This review reports pre-clinical and clinical studies performed to demonstrate the usefulness of FUS in patients with DIPG treated with some chemotherapy. The papers reviewed were published in PubMed until the end of 2024 and were found using a combination of the following keywords: diffuse intrinsic pontine glioma (DIPG), DIPG H3K27-altered, blood–brain barrier and BBB, focused ultrasound (FUS) and radiotherapy (RT). Full article

Radiation therapy (RT) is a cornerstone in the management of pediatric central nervous system (CNS) tumors. Recent advancements in RT delivery and techniques aim to enhance therapeutic effectiveness while minimizing both acute and long-term complications associated with pediatric brain RT. This paper highlights innovative developments in the field, including the clinical indications, benefits, and challenges of proton therapy and stereotactic radiotherapy. The ongoing refinement of risk-adapted RT volumes is highlighted, with examples of newly proposed germinoma RT volumes and hippocampal-sparing RT. Additionally, emerging experimental approaches, including FLASH therapy and theranostics, are also discussed as promising future directions. Further prospective, multi-institutional collaborative studies are essential to validate and expand upon the benefits outlined in this review. Full article

Background: The natural history of pediatric patients with metastasis of primary brain tumors within and outside the central nervous system is poorly understood, as too are possible clinical correlates with outcome. Correspondingly, the aim of this study was to interrogate a national database to characterize this diagnosis and its clinical course in pediatric patients. Methods: The U.S. National Cancer Database (NCDB) was interrogated between the years 2005–2016 for all patients aged 18 years and younger with a primary brain tumor diagnosis, as well as evidence of disease metastasis at initial diagnosis. Data were summarized and overall survival (OS) was modeled using Kaplan–Meier and Cox regression analyses. Results: Out of a total of 8615 pediatric brain tumor patients, 356 (4%) had evidence of metastasis at initial diagnosis. Compared to patients without metastasis, patients with metastasis were statistically younger, more often male, and less likely to have private health insurance (all p < 0.050). With respect to clinical characteristics, the primary tumors of patients with metastasis were statistically more likely to be located in the cerebellum; be of higher histologic grading, with a higher proportion of medulloblastoma diagnoses and lower proportion of malignant glioma and pilocytic astrocytoma diagnoses; and were more likely to be treated by subtotal surgical resection, chemotherapy and radiation therapy (all p < 0.050) when compared to patients without metastasis. Five-year OS for those with metastasis was significantly lower than those without (48% vs. 75%, p < 0.001), with the median overall survival for patients with metastasis being 53 months (95% CI 29–86). Multivariate analysis indicated that a shorter OS was independently associated with the primary diagnoses of malignant glioma (HR 27.7, p = 0.020) and Atypical Teratoid/Rhabdoid Tumor (ATRT, HR 41.1, p = 0.041) and with WHO grades 3 (HR 20.1, p = 0.012) and 4 (HR 11.5, p < 0.001). Longer OS was significantly and independently associated with surgery (HR 0.49, p < 0.001), chemotherapy (HR 0.53, p = 0.041), and radiation therapy (HR 0.57, p = 0.026). Conclusions: Although uncommon, pediatric brain tumors with evidence of metastasis at initial diagnosis will present with a distinct socioeconomic and clinical profile compared to patients without metastasis. Multiple predictors are independently associated with overall prognosis, and understanding these features should be validated in prospective efforts to identify vulnerable patients earlier in order to maximize the impact of treatment. Full article

Background and Objectives: Primary central nervous system (CNS) tumors are often associated with relatively poor outcomes. Data on the epidemiology and outcome of CNS tumors in Jordan are scarce. We aim to report the epidemiology and outcome of primary CNS tumors of patients managed at a comprehensive cancer care center in Jordan. Methods: We performed a retrospective chart review of all Jordanian patients with a primary CNS tumor diagnosis who were managed at the center between July 2003 and June 2019. We included all entities described in the 2021 CNS WHO classification system, in addition to pituitary neuroendocrine tumors (PitNETs). We used the Kaplan–Meier method to estimate the 1-year, 2-year, and 5-year overall survival (OS) rates for each entity. Results and Findings: We included 2094 cases. The numbers of pediatrics and adults were 652 (31.1%) and 1442 (68.9%), respectively. The three most common groups of tumors were “gliomas, glioneuronal tumors, and neuronal tumors” (n = 1200 [57.30%]), followed by meningiomas (n = 261 [12.5%]), embryonal tumors (n = 234 [11.2%]). The three most common tumor families were adult-type diffuse gliomas (n = 709 [33.8%]), medulloblastoma (n = 199 [9.5%]), and circumscribed astrocytic gliomas (n = 183 [8.7%]). The median survival for the entire cohort was 97 months (95CI; 81–112). Survival was significantly worse for males and adults compared to their respective counterparts. Among the most common tumor group, “gliomas, glioneuronal tumors, and neuronal tumors”, OS rates for adult-type diffuse gliomas were significantly lower than all other types. Overall, adult gliomas with IDH-mutations had a survival advantage over wildtype cases (IDH-mutant 1-year OS, 89% [82–97%] vs. IDH-wildtype 1-year OS, 60% [52–70%]; p < 0.001). Conclusions: We present a detailed analysis of the primary CNS tumors diagnosed in the largest cancer center in Jordan between 2003 and 2019. We compared the epidemiology and overall survival of these patients to worldwide estimates and found the epidemiology and outcome of these tumors comparable to worldwide trends. Full article

Pediatric cancers, while rare, pose unique challenges due to the heightened sensitivity of developing tissues and the increased risk of long-term radiation-induced effects. Radiotherapy (RT) is a cornerstone in pediatric oncology, but its application is limited by concerns about toxicity, particularly secondary malignancies, growth abnormalities, and cognitive deficits. CyberKnife (CK), an advanced robotic radiosurgery system, has emerged as a promising alternative due to its precision, non-invasiveness, and ability to deliver hypofractionated, high-dose RT while sparing healthy tissues. This narrative review explores the existing evidence on CK application in pediatric patients, synthesizing data from case reports, small series, and larger cohort studies. All the studies analyzed reported cases of tumors located in the skull or in the head and neck region. Findings suggest CK’s potential for effective tumor control with favorable toxicity profiles, especially for complex or inoperable tumors. However, the evidence remains limited, with the majority of studies involving small sample sizes and short follow-up periods. Moreover, concerns about the “dose-bath” effect and limited long-term data on stochastic risks warrant cautious adoption. Compared to Linac-based RT and proton therapy, CK offers unique advantages in reducing session numbers and enhancing patient comfort, while its real-time tracking provides superior accuracy. Despite these advantages, CK is associated with significant limitations, including a higher potential for low-dose scatter (often referred to as the “dose-bath” effect), extended treatment times in some protocols, and high costs requiring specialized expertise for operation. Emerging modalities like π radiotherapy further underscore the need for comparative studies to identify the optimal technique for specific pediatric cases. Notably, proton therapy remains the benchmark for minimizing long-term toxicity, but its cost and availability limit its accessibility. This review emphasizes the need for balanced evaluations of CK and highlights the importance of planning prospective studies and long-term follow-ups to refine its role in pediatric oncology. A recent German initiative to establish a CK registry for pediatric CNS lesions holds significant promise for advancing evidence-based applications and optimizing treatment strategies in this vulnerable population. Full article

Central nervous system (CNS) tumors are the leading cause of cancer-related mortality in children, with prognosis remaining dismal for some of these malignancies. Though the past two decades have seen advancements in surgery, radiation, and targeted therapy, major unresolved hurdles continue to undermine the therapeutic efficacy. These include challenges in suboptimal drug delivery through the blood–brain barrier (BBB), marked intra-tumoral molecular heterogeneity, and the elusive tumor microenvironment. Drug repurposing or re-tasking FDA-approved drugs with evidence of penetration into the CNS, using newer methods of intracranial drug delivery facilitating optimal drug exposure, has been an area of intense research. This could be a valuable tool, as most of these agents have already gone through the lengthy process of drug development and the evaluation of safety risks and the optimal pharmacokinetic profile. They can now be used and tested in clinics with an accelerated and different approach. Conclusions: The next-generation therapeutic strategy should prioritize repurposing oncologic and non-oncologic drugs that have been used for other indication, and have demonstrated robust preclinical activity against pediatric brain tumors. In combination with novel drug delivery techniques, these drugs could hold significant therapeutic promise in pediatric neurooncology. Full article

Background/Objectives: Vaccine hesitancy among immunocompromised patients is complex and not well understood. This study aimed to determine the rate of COVID-19 vaccine hesitancy among pediatric oncology and bone marrow transplant (BMT) patients and to understand associated factors. Methods: Parents of patients (≤18 years) with cancer or post-BMT completed the Parent Attitudes about Childhood Vaccines Survey. A COVID-19 vaccine hesitancy score (VHS-COVID) was calculated from 0 to 100 (higher scores indicating increasing hesitancy). A small group of patients (patients older than 15 years) were also surveyed directly. Results: Among 113 parent respondents, the majority were female (58%) and at least college/university educated (78%). The majority (73%) of patients had cancer (61% leukemia/lymphoma, 37% solid/CNS tumors), while 27% had received BMT for malignant and non-malignant conditions. Only 48% of patients had been vaccinated against COVID-19, compared to 88% of parents. Ineligibility due to phase of cancer/BMT treatment (27%), vaccine hesitancy (24%), and age (24%) were the top three reasons for not vaccinating against COVID-19. Only 13% of parents said they would “definitely vaccinate” if their child became eligible. VHS-COVID scores were higher for parents of patients in surveillance versus active therapy (mean 61 vs. 48; p = 0.03). Parents who had received fewer COVID-19 vaccine doses (0–1 vs. ≥2) were more hesitant toward all vaccines (p = 0.0002), COVID-19 vaccines (p = 0.0003), and influenza vaccines (p = 0.005). Conclusions: Vaccine hesitancy is common among this population and was demonstrated through beliefs (hesitancy scores) as well as vaccine uptake. Future work should focus on education targeting vaccine eligibility and engaging with vaccine hesitant families in the immunocompromised community. Full article