Search Results (480)

Background: Childhood cancer is considered one of the main causes of mortality and morbidity worldwide. There is strong evidence of the oral toxic effects of oncologic treatments, but their incidence is difficult to determine. The novel therapeutic strategies in Pediatric Oncology have led to increased survival in this population, resulting in an increased incidence of long-term effects, which diminish the patient’s quality of life. Methods: The search for articles started on 5 November 2024 and ended on 5 December 2024. Following the PRISMA Statement, a total of 1266 articles were obtained, from which 13 were selected for review. All articles were considered to be of high quality. The antineoplastic treatments used in them were chemotherapy, radiotherapy, surgery and immune therapy. Results: Most articles were cohorts and case controls. Only one case report was obtained. The results revealed that the most prevalent sequelae in the pediatric population after antineoplastic treatment were enamel alterations, microdontia, dental caries, periodontal disease, gingivitis, hyposalivation, alteration of the oral microbiome, alteration of mandibular bone density and malocclusion. The lesions are different depending on the therapy used. Conclusions: Oncologic treatments in children with cancer cause multiple oral sequelae such as microdontia, dental caries, enamel alterations, salivary gland alterations, mucositis and root resorption. It cannot be concluded which therapy has the most detrimental effect as each has a different mechanism of action in the oral cavity. Full article

Background: Acute leukemia (AL) is the most prevalent pediatric malignancy and is frequently associated with systemic iron dysregulation, often leading to iron overload. This study aimed to characterize the regulatory mechanisms of iron metabolism in children with AL, considering treatment stages and associated clinical parameters. Methods: A total of 149 children were stratified into four groups: newly diagnosed AL (n = 43), patients post-chemotherapy (n = 55), patients following hematopoietic cell transplantation (HCT; n = 32), and healthy controls (n = 19). Serum concentrations of matriptase-2 (TMPRSS6), neogenin-1 (NEO1), and soluble hemojuvelin (sHJV) were quantified using ELISA. Results: Compared to healthy children, significantly higher serum concentrations of TMPRSS6 and NEO1 were found in patients post-chemotherapy and post-HCT, while sHJV levels were markedly decreased. Higher TMPRSS6 and NEO1 levels and lower sHJV were associated with increased ferritin levels and greater numbers of transfused packed red blood cell (PRBC) units. sHJV negatively correlated with TMPRSS6, NEO1, ferritin, C-reactive protein (CRP), and PRBC transfusions. TMPRSS6 and NEO1 showed a positive correlation. Among the analyzed biomarkers, Kaplan–Meier analysis revealed no statistically significant associations with overall survival (OS) or event-free survival (EFS) within the chemotherapy and HCT subgroups. Conclusions: AL in pediatric patients is associated with profound disruptions of systemic iron homeostasis. Our investigation identified notable perturbations in TMPRSS6, NEO1, and sHJV, suggesting that these proteins could contribute mechanistically to the pathophysiological alterations underlying iron dysregulation observed in pediatric AL. Full article

Osteosarcoma (OS), the most common primary bone cancer of mesenchymal origin in children and young adolescents, remains a challenge due to metastasis and resistance to chemotherapy. It displays severe aneuploidy and a high mutation frequency which drive tumor initiation and progression; however, recent studies have highlighted the role of epigenetic modifications as a key driver of OS pathogenesis, independent of genetic mutations. DNA and RNA methylation, histone modifications and non-coding RNAs are among the major epigenetic modifications which can modulate the expression of oncogenes. Abnormal activity of these mechanisms contributes to gene dysregulation, metastasis and immune evasion. Therapeutic targeting against these epigenetic mechanisms, including inhibitors of DNA and RNA methylation as well as regulators of RNA modifications, can enhance tumor suppressor gene activity. In this review, we examine recent studies elucidating the role of epigenetic regulation in OS pathogenesis and discuss emerging drugs or interventions with potential clinical utility. Understanding of tumor- specific epigenetic alterations, coupled with innovative therapeutic strategies and AI-driven biomarker discovery, could pave the way for personalized therapies based on the molecular profile of each tumor and improve the management of patients with OS. Full article

Fever is a frequent complication in children receiving chemotherapy, primarily caused by bloodstream infections and non-infectious inflammation. Yet, the pathophysiological mechanisms remain unclear, and diagnostics are insufficient, which often results in continued antibiotic treatment despite negative blood cultures. In a nationwide study, we collected whole blood in PAXgene tubes from 168 febrile episodes in children with hematological malignancies, including 37 episodes with bacteremia, and performed single-cell RNA sequencing. We compared transcriptomic profiles between febrile children with and without bacteremia. In children with bacteremia, differentially expressed genes were related to immunoregulation and cardiac and vascular function. Children without bacteremia had distinct gene expression patterns, suggesting a viral or other inflammatory cause of fever. Several differentially expressed genes overlapped with previously published transcriptomics-based diagnostic signatures developed in immunocompetent children. In conclusion, blood transcriptomics provided novel insights into the pathophysiological mechanisms of febrile children with hematological malignancies. We found differentially expressed genes suggesting viral infections or non-bacterial inflammation as causes of fever in children with negative blood cultures, supporting early antibiotic discontinuation in children with cancer. Full article

Background: Paediatric hepatocellular carcinoma (HCC), including its fibrolamellar variant (FLC), is a rare malignancy with distinct biological behaviour and limited therapeutic options. While complete surgical resection is a key determinant of survival, many patients present with unresectable tumours at diagnosis. The role of neoadjuvant chemotherapy in improving resectability, particularly in histologically distinct subtypes, remains inconclusive. Methods: We retrospectively analysed 43 patients (<18 years) with histologically confirmed conventional HCC (cHCC, n = 27) or FLC (n = 16) enrolled in the German Pediatric Liver Tumour Registry. We assessed clinical characteristics, treatment response, surgical outcomes, and survival. Special focus was placed on the impact of neoadjuvant chemotherapy in initially unresectable tumours. Results: FLC and cHCC exhibited significant differences in clinical presentation, such as age of presentation, AFP elevation, or presence of underlying liver disease. Although overall survival did not significantly differ between groups, cHCC tumours showed a markedly higher response to chemotherapy (62.5% partial remission vs. 0% in FLC). Complete resection (R0) was achieved in 77% of all patients and was the strongest predictor of survival. Importantly, a subset of cHCC patients who initially had unresectable tumours became eligible for curative surgery following neoadjuvant chemotherapy. Notably, delayed resection after chemotherapy led to outcomes comparable to those with upfront surgery, whereas progression during chemotherapy was associated with a universally poor prognosis. Conclusions: This study supports upfront resection as the preferred strategy in paediatric HCC and FLC whenever feasible. In cHCC, neoadjuvant chemotherapy demonstrated a favourable response profile and contributed to secondary resectability in a subset of initially unresectable cases, supporting a potential role within a multimodal treatment approach. In contrast, FLC showed limited responsiveness to current systemic therapies. These findings emphasise the importance of histology-specific strategies and highlight the ongoing need for more effective systemic options, particularly for unresectable FLC. Full article

(1) Background: Wilms’ tumor (WT) is the most common pediatric renal malignancy. Although survival outcomes have improved with multimodal therapy, the optimal sequence of surgery and chemotherapy remains debated, particularly in resource-limited settings. This study evaluates the effect of treatment strategy on surgical complications and survival, utilizing two decades of data from Thai tertiary centers. (2) Methods: A retrospective cohort study was conducted on 83 children who underwent radical nephrectomy for WT between 2002 and 2022 at two university hospitals in Thailand. Patients were grouped by treatment protocol: primary nephrectomy (n = 59) or neoadjuvant chemotherapy (n = 24). Clinical, pathological, operative, and follow-up data were analyzed to identify predictors of surgical complications and survival. (3) Results: Short-term postoperative complications occurred in 16.9% of cases, more frequently in males and in patients with hypoalbuminemia, anemia, or large tumors. Estimated blood loss greater than 5 mL/kg, serum albumin less than 3.5 g/dL, and hemoglobin lower than 10 g/dL were independent predictors of complications. The five-year overall survival (OS) and progression-free survival (PFS) rates were 82.4% and 68.1%, respectively. Patients with unfavorable histology or short-term complications experienced significantly poorer OS. Neoadjuvant chemotherapy was associated with increased nutritional compromise and a trend toward higher complication rates, although it was not directly linked to inferior OS. (4) Conclusions: In pediatric WT, the perioperative nutritional and hematologic statuses significantly influence surgical outcomes. While neoadjuvant chemotherapy may assist in tumor downsizing, it might also compromise surgical fitness. Customized preoperative risk assessment and nutritional support can enhance outcomes, particularly in low- and middle-income countries. 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

Background: Oral mucositis (OM) is a common and debilitating complication of cancer therapy, particularly in patients undergoing chemotherapy and radiotherapy. It significantly impairs quality of life and may necessitate the interruption of cancer treatment. This study aimed to evaluate the efficacy and safety of OROSOL, an oral spray device, in managing oral mucositis in pediatric patients undergoing chemotherapy or radiotherapy. Methods: This randomized, double-blind, placebo-controlled clinical trial compared OROSOL to a placebo in children with oral mucositis aged 3 to 17 years. Participants were followed for 28 days with regular medical visits. The primary endpoints were changes in the Oral Assessment Guide (OAG) scores and key symptoms (mucositis score, difficulty in oral feeding, ulceration and erythema, and pain sensation). Safety was assessed via adverse events and local tolerability. Results: Both groups were demographically balanced at baseline (p > 0.6). OROSOL demonstrated significantly greater improvements in the mucositis score beginning on Day 7 (p = 0.0122) and maintained superiority through Day 28 (p = 0.0007). Notable reductions in mucositis severity were observed, with significantly faster relief in the OROSOL group compared to the placebo (p < 0.001 for most timepoints). Oral feeding difficulty also showed a marked decline, with significant improvements starting from Day 5 (p = 0.0153). Ulceration and erythema scores significantly decreased from Day 14 onwards (p = 0.0188). Pain sensation showed a marked reduction from Day 14 (p = 0.0014). No serious adverse events were reported, and tolerability was consistent across all participants. Conclusions: OROSOL has a significant impact on reducing mucositis severity, oral feeding difficulty, ulceration, erythema, and pain. Coupled with its excellent safety profile, it is a valuable therapeutic option. This treatment is particularly beneficial for pediatric patients, ensuring improved comfort and recovery without notable adverse effects. Full article

Background/Objectives: Febrile neutropenia is a frequent and potentially life-threatening complication in pediatric oncology patients receiving chemotherapy. Due to profound immunosuppression, early diagnosis of infections remains a major clinical challenge. This review evaluates the diagnostic and prognostic utility of infection biomarkers in children with chemotherapy-induced severe neutropenia. Methods: We reviewed clinical studies that assessed the diagnostic performance of inflammatory biomarkers—including C-reactive protein (CRP), procalcitonin (PCT), interleukins (IL-6, IL-8, IL-10), and others—in pediatric febrile neutropenia. The review includes data on sensitivity, specificity, predictive value, and clinical applications. Results: CRP remains a common but nonspecific marker, often insufficient for early stratification. PCT showed consistently high negative predictive value and early responsiveness to bacterial infections. IL-6 and IL-10 demonstrated strong early diagnostic accuracy in the early phase (AUC > 0.80 in multiple studies) and were particularly useful in predicting septic shock when combined. IL-8, while less specific, may help rule out infection when levels are low. Emerging biomarkers such as presepsin, MR-proADM, and PSP showed promising diagnostic performance. Presepsin achieved near-perfect accuracy in some cohorts (AUC up to 0.996), outperforming CRP and PCT, though its ability to discriminate bacteremia at fever onset varied. MR-proADM demonstrated consistent AUCs above 0.75 and may support early sepsis identification. PSP was associated with significantly elevated levels in sepsis. Additional novel markers—including sTNFR-II, sIL-2R, IP-10, Flt-3L, MCP-1-a, and MBL—showed encouraging diagnostic profiles in individual studies, particularly due to high specificity, but require external validation. G-CSF also emerged as a promising candidate in multimarker models. In contrast, TNF-α and IL-1β displayed limited utility as standalone indicators. Conclusions: Biomarkers such as PCT, IL-6, Il-8, and IL-10 offer valuable tools for early infection detection and risk stratification in pediatric febrile neutropenia. Emerging markers—including presepsin, MR-proADM, and PSP—further enhance diagnostic precision and may support early identification of sepsis. Multimarker strategies, particularly those incorporating presepsin, IL-10, or MR-proADM, show potential to improve diagnostic performance beyond conventional markers. Further prospective validation is needed to optimize clinical implementation and guide personalized treatment decisions. Full article

Acute lymphoblastic leukemia (ALL) is the most common malignancy in children. Good overall survival rates of about 90% are the result of improvements in risk stratification and risk-adapted therapy, intensive chemotherapy regimens, hematopoietic stem cell transplantation, and better supportive care. Background and Objectives: The aim of this study is to review the epidemiology, prognostic factors, and causes of death in pediatric ALL patients treated at a tertiary care center, and to identify risk factors influencing clinical outcomes. Materials and Methods: A retrospective study was conducted at the Department of Pediatric Hematology and Oncology, University Hospital Centre Zagreb, including 302 children (0–18 years) diagnosed with ALL between January 2001 and December 2015. Results: Two hundred fifty-one children survived (5-year overall survival 83%). Relapse occurred in 13.6% of patients. Relapse rates were higher for B-cell precursor (Bcp)-ALL than for T-cell ALL (14.3% vs. 10.4%), and no patient with relapsed T-cell ALL survived. The main causes of death were refractory/relapsed disease (43% of patients), followed by infections (35%) and GVHD (8%). The most frequent causes of infectious death were Pseudomonas aeruginosa and Aspergillus fumigatus. The most critical treatment periods were the induction and reinduction phases, especially the de-escalation of corticosteroids. The time of relapse and risk group were independent factors in predicting the outcome. Conclusions: Relapse and infections were the leading causes of death in children with ALL, with the highest mortality observed during induction and reinduction phases. Survival was significantly influenced by relapse timing and risk group, with no survivors among relapsed T-ALL patients. Full article

Background/Objectives: Acute lymphoblastic leukemia (ALL) is the most common malignant disease in children. Contemporary antitumor treatment protocols provide long-term survival rates in over 90% of patients with ALL. High effectiveness of the treatment has been achieved as a result of chemotherapy optimization, use of targeted drugs, up-to-date genetic information, and detection of minimal residual disease (MRD). Current highly sensitive methods for MRD detection have advantages and disadvantages, and the challenge is to distinguish between false-positive and false-negative tests. Methods: A comprehensive search through MEDLINE, PubMed, Scopus, and ScienceDirect using the MRD-related keywords was performed, and included a final set of 72 academic articles. Results: At present, flow cytometry for MRD detection provides the necessary sensitivity of 10⁻⁴ and allows for reliable prediction of ALL dynamics and effective therapeutic strategies. However, even multicolor flow cytometry (MFC) cannot avoid cases of false-positive or false-negative results. Highly sensitive and productive genomic methods in addition to MFC may enhance the accuracy of MRD evaluation. On the other hand, overwhelming efforts to reach the highest sensitivity of the detection methods may lead to the detection of clinically insignificant manifestations of minimal residual disease and, subsequently, to unjustified escalation of antitumor therapy. Conclusions: The necessary ground for an adequate sensitivity of the MRD detection methods could ensure the fine line between false-positive and false-negative MRD results in patients with childhood ALL to develop an appropriate therapeutic strategy. Full article

High-grade osteosarcoma (HGOS) is the most common primary malignant bone tumor in children and adolescents. Poor response to chemotherapy is linked to worse prognosis and increased risk of recurrence and metastasis. However, current assessment methods, such as tumor necrosis evaluation, are time-consuming and delay treatment decisions. Thus, identifying molecular pathways and predictive biomarkers is essential for guiding early therapeutic strategies. In this study, RNA-seq analysis of HGOS tissues revealed enrichment of cholesterol biosynthesis and mitotic pathways in poor responders. Additionally, high HMGCR expression, as analyzed from TCGA data, was associated with poor prognosis in sarcoma. Functional validation using SaOS-2 cells, which exhibited poor drug sensitivity and elevated HMGCR levels, demonstrated that simvastatin enhanced the efficacy of cisplatin and doxorubicin by inducing mitochondrial-mediated apoptosis and downregulating anti-apoptotic proteins. Simvastatin also reduced cell migration and invasion by suppressing epithelial–mesenchymal transition and extracellular matrix degradation. Mechanistically, simvastatin disrupted Ras prenylation and inhibited downstream oncogenic signaling pathways, including Akt/mTOR and Akt/GSK3, which regulate survival and metastasis-associated gene expression. These findings suggest that the cholesterol biosynthesis pathway particularly plays a critical role in chemoresistance and metastasis in HGOS and may serve as a promising predictive molecular target for guiding early therapeutic strategies. 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

Background: Intra-arterial chemotherapy (IAC) is increasingly useful for treating intraocular retinoblastoma (Rb). It offers targeted delivery of chemotherapy with reduced systemic exposure. In this study, we evaluate management outcomes and identify predictive factors for globe salvage following IAC in children with Rb. Methods: This retrospective study included 20 eyes of 20 melphalan-based IAC-treated patients (67 sessions) between 2015 and 2023 in a tertiary cancer center (King Hussein Cancer Center) in Jordan. Data collection included patients’ demographics, tumor staging, eye salvage, complications, and survival, followed by statistical comparisons between eye salvage rates and clinical factors. Results: The median age of IAC initiation was 38 months (range: 6–78 months). IAC was used as a primary treatment in 35% (7/20) of eyes and as a secondary treatment following systemic chemotherapy in 65% (13/20) of eyes. Nineteen (95%) eyes showed initial tumor regression, 15 (75%) eyes showed short term tumor control, and long-term eye salvage was achieved in 11 (55%) eyes. Poor prognostic factors for eye salvage included advanced tumor stage (Group D/E: 43% salvage rate vs. Group C: 83%; p = 0.047), vitreous seeding at the time of IAC (38% with seeding vs. 75% without; p = 0.046), use of IAC as a secondary rather than a primary treatment (46% vs. 71%; p = 0.047), and the need for >3 IAC cycles (20% success with >3 cycles vs. 67% with ≤3 cycles; p = 0.034). Complications were notable: systemic adverse effects were seen in five (25%) patients, including neutropenia (20%) and bronchospasm (6%). Procedure-related complications were seen with 22% of injections, including failure of the procedure (7%), ophthalmic artery spasm (6%), and intra-procedural stroke (3%). Five (25%) eyes developed ocular complications, including vitreous hemorrhage (15%), retinal detachment (10%), optic atrophy (10%), and retinal or choroidal ischemia (10%). Notably, all infants under 12 months of age (4/4) developed complications, including the two events of stroke. At a median follow-up of 60 months, eye salvage was achieved in 11 (55%) eyes, and none of the 9 (45%) enucleated eyes showed high-risk pathological features. There was no orbital recurrence, and one (5%) child developed CNS metastasis and passed away. Conclusion: IAC achieves long-term globe salvage in 55% of Rb cases; however, outcomes are poorer with Group D/E tumors, vitreous seeds, prior IVC failure, or requiring >3 IAC cycles. While reducing systemic chemotherapy toxicity, IAC carries significant risks of vision- and life-threatening complications. Infants and single-eyed patients require particularly cautious consideration. Though IAC remains crucial for globe preservation, optimal implementation demands improved patient selection criteria, multicenter collaboration, and long-term outcome studies to maximize safety and efficacy. Full article

Background: The optimal treatment for proximal tibial osteosarcoma (OS) in skeletally immature patients remains controversial. A custom hinged endoprosthesis has been used to preserve the growth potential of the distal femur. This study aims to report (1) the 2-year follow-up outcomes after surgery for pediatric proximal tibial OS; (2) the complications associated with this endoprosthesis; and (3) the extent to which the growth potential of the adjacent open physis can be preserved. Methods: Seven skeletally immature patients (mean age, 11.1 years; range, 9–13 years) with proximal tibial OS were included between November 2020 and December 2022. All underwent tumor resection and reconstruction by this custom endoprosthesis. Postoperative limb function was evaluated by the Musculoskeletal Tumor Society (MSTS) score system and complications were recorded. Overall leg length and femoral length were measured radiographically to determine the growth rate. Results: The mean follow-up time was 34.7 months (standard deviation (SD), 8.9 months). One patient presented with local recurrence 12 months after surgery, and another patient had pulmonary metastasis 3 months postoperatively. The range of flexion of the knee after rehabilitation was between 90° and 125°, with an average of 103.6° (SD, 12.5°). The average MSTS score of the patients after surgery was 27.4 (SD, 1.5). Wound dehiscence took place in three patients after chemotherapy. At the last follow-up, the overall limb length discrepancy was 2.1 cm (SD, 2.4 cm). Growth at the distal femoral physis after surgery was observed in all patients during follow-up, with an average of 81.4% (range, 57.78–100%) of growth of the contralateral distal femoral physis. Conclusions: This custom hinged endoprosthesis can preserve the growth potential of the adjacent distal femur and provide satisfying functional outcomes with lower postoperative complication rate. It could serve as an alternative for proximal tibial OS in skeletally immature children. Full article