Maria Kourti

Background/Objectives: Osteosarcoma (OS) is the most common primary malignant bone tumor and remains difficult to treat when recurrent or metastatic. Its immunologically “cold” tumor microenvironment (TME) limits the activity of conventional immunotherapies. Metal-containing nanosystems have therefore been investigated as platforms that combine targeted delivery with immune modulation. Because the available literature includes both vaccine-like systems and broader multifunctional nanotherapeutics, this systematic review evaluates metal-based immunomodulatory nanoplatforms and distinguishes mechanistic immune reprogramming evidence from therapeutic outcome evidence. Methods: PubMed/MEDLINE, Scopus, and Web of Science were searched for preclinical in vivo OS studies, published from 1 May 2021 through 30 April 2026. Thirteen studies met the eligibility criteria. Data were extracted on model characteristics, nanoparticle architecture, targeting and release mechanisms, therapeutic cargo, immune/TME endpoints, tumor outcomes, metastasis-related outcomes, and reported toxicity. Results: Zinc-containing zeolitic imidazole framework-8 (ZIF-8) platforms were used in six studies and manganese-containing platforms in five, with one platform incorporating both metals. Reported mechanisms included cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) activation, immunogenic cell death, myeloid cell modulation, metabolic remodeling, and increased T-cell infiltration. All included studies reported primary tumor inhibition under their respective experimental conditions; two studies reported a distal tumor or metastasis-related endpoint. No overt systemic toxicity was reported under the short-term experimental conditions assessed, although safety evaluation was generally limited to measures such as body weight, blood tests, or organ histology. Conclusions: Metal-based immunomodulatory nanoplatforms are a promising preclinical strategy for remodeling the OS TME. However, substantial heterogeneity in models, interventions, comparators, immune assays, and toxicity assessment precludes claims of comparative material-specific efficacy or established systemic safety. More standardized orthotopic and metastatic models, durable immune-response assessment, and comprehensive pharmacokinetic and long-term biosafety studies are needed before clinical translation.

Infections caused by filamentous fungi other than Aspergillus spp. or Mucorales are uncommon but often severe, particularly in immunocompromised individuals. We conducted a prospective, nationwide, multicenter study to investigate the epidemiology, clinical spectrum, antifungal susceptibility, treatment, and outcomes of invasive and severe localized rare mold infections in Greece from 2009 to 2025. We documented 118 cases, with no significant temporal trend. The most frequent underlying conditions were hematologic malignancy (27.1%), hematopoietic cell transplantation/graft-versus-host disease (11.9%), trauma or other skin conditions (13.6%), pulmonary disease or respiratory failure (5.9%), and ocular predisposing factors for keratitis (22.9%). Bloodstream and corneal infections predominated. Fusarium spp. accounted for 66.9% of cases, followed by Scedosporium apiospermum (9.3%). Six breakthrough infections occurred during mold-active prophylaxis or empirical treatment, all caused by Fusarium spp. Amphotericin B showed the greatest in vitro activity against Fusarium spp., whereas voriconazole was most active against non-Fusarium molds. Clinical outcomes did not consistently correspond with in vitro antifungal activity. Crude mortality among non-ocular infections was 44.4% and was significantly higher in patients with hematologic malignancy or hematopoietic cell transplantation than in other patients (65% vs. 28%; p = 0.018). The number of reported rare mold infections in Greece showed no increasing trend, but they were associated with substantial morbidity and high mortality, particularly among severely immunocompromised patients.

Background: Invasive fungal disease remains a major cause of morbidity and mortality among children with malignancies and those undergoing hematopoietic stem cell transplantation (HSCT). Real-world data that describe antifungal prescribing practices in pediatric hematology–oncology units are very limited. Methods: A national prospective observational study from June 2016 through December 2019 in 5 pediatric hematology–oncology units and the single pediatric HSCT unit in Greece was conducted. The first 15 children per month admitted to these units who required initiation of new antifungal agents for prophylaxis or treatment were recorded. Demographics, presence of a central venous line, type of underlying disease, absolute neutrophil count on the first day of antifungal therapy, presence of invasive fungal disease, days of therapy, microbiologic findings and outcomes were recorded. Results: Among 1838 anti-infective courses, 737 (40.1%) involved antifungal agents. Antifungal use was predominantly prophylactic (47.6%) or empiric (50.7%), with targeted therapy accounting for only 1.5%. Prophylaxis was more common in the HSCT unit, whereas empiric therapy predominated in pediatric hematology–oncology units. Fluconazole was the most frequently used prophylactic agent, followed by micafungin and voriconazole. Proven fungemia was uncommon; Candida albicans was the most frequently isolated pathogen. Overall mortality was 1.8%, with slightly higher mortality among patients receiving antifungal therapy. Conclusions: Antifungal use in pediatric oncology and HSCT settings was extensive and heterogeneous, characterized by heavy reliance on prophylactic and empiric strategies and minimal targeted therapy. These findings support the need for structured antifungal stewardship programs to optimize antifungal exposure while preserving favorable outcomes.

Respiratory viral infections (RVIs) have been described traditionally as clinically important infectious complications in pediatric patients with immunosuppression, particularly in those with malignancies (hematological or solid) and recipients of hematopoietic cell or solid organ transplantation. Specifically, advances in the field of cancer therapy and novel immune-based pharmaceuticals have significantly expanded the population of children with prolonged and complex immunosuppression, whereas the widespread use and availability of molecular diagnostics have increased the detection of respiratory viruses. Additionally, these developments have improved the etiologic identification of RVIs, while introducing important challenges in clinical interpretation, mainly in differentiating incidental viral identification from clinically significant diseases. Furthermore, RVIs in immunocompromised children are characterized by heterogeneous and diverse clinical manifestations, with a range from mild upper respiratory tract involvement to severe lower respiratory tract disease, which can lead to substantial morbidity and mortality. Diagnostic strategies in this field are primarily based on nucleic acid amplification tests, requiring careful interpretation because of the possible prolonged viral shedding, co-detection, and overlapping infectious syndromes. Beyond direct clinical consequences, viral detection has an impact on infection control measures, antimicrobial stewardship decisions, and the timing of therapies. In this literature review, we offer an overview of current evidence on the epidemiology, clinical manifestations, diagnostic approaches, and management of RVIs in immunocompromised pediatric populations, underscoring the unmet need for structured, risk-adapted integration of virologic data into pediatric oncology care.

Candidozyma auris (previously named Candida auris) has been recognized as a significant public health threat due to its extensive transmission in hospital settings, high mortality rates, and multidrug resistance. Evidence regarding optimal antifungal treatment in children remains limited. The present systematic review aims to synthesize available evidence on pediatric C. auris infections, focusing on antifungal treatment, resistance profiles, and clinical outcomes. A systematic search was conducted across PubMed, Scopus, and Web of Science, identifying case reports and case series of pediatric patients with confirmed C. auris infection. Data were extracted on demographics, comorbidities, infection site, antifungal therapy, and outcomes. Risk of bias was assessed using JBI Critical Appraisal checklists. Fourteen studies comprising 62 patients were included, with most cases being bloodstream infections. C. auris showed widespread fluconazole resistance and variable susceptibility to amphotericin B. Echinocandins were the most commonly used agents, generally associated with survival. Overall mortality was 35%, similar to that reported for adults. Combination therapy showed numerically higher survival, although given the small sample size and heterogeneity of treatment regimens, no comparative inferences can be made. Pediatric C. auris infections mirror adult patterns of antifungal resistance and mortality. Echinocandins remain first line therapy; however, the emergence of echinocandin resistance underscores the urgent need for antifungal stewardship, standardized pediatric guidelines, and novel antifungal development.

(Background) Retinoblastoma is the most common intraocular malignancy in childhood, primarily caused by mutations in the RB1 gene. However, increasing evidence highlights the significant role of epigenetic mechanisms, particularly DNA methylation and histone acetylation, in tumor initiation and progression. This review aims to summarize and critically assess recent findings on how DNA methylation and histone acetylation contribute to the pathogenesis of retinoblastoma, and to explore their potential role as diagnostic biomarkers and therapeutic targets. (Methods) We searched the databases PubMed, Scopus, and ScienceDirect following PRISMA guidelines. Eligible studies were English-language, open-access articles published within the last ten years, including cohort studies, research articles, and case reports. After rigorous screening, 18 studies were included in the final analysis. (Results) Aberrant DNA methylation was found to inactivate tumor suppressor genes (RB1, RASSF1A, p16INK4A, MGMT) and promote oncogenesis through hypermethylation of regulatory elements. Similarly, histone acetylation’s dysregulation contributed to chromatin remodeling and overexpression of oncogenic factors such as SYK, GALNT8, and lincRNA-ROR. Elevated histone deacetylase (HDAC) activity was also linked to tumor cell proliferation, metastasis, and treatment resistance. Epigenetic inhibitors targeting these pathways demonstrated promising therapeutic potential. (Conclusions) DNA methylation and histone acetylation play a crucial role in the epigenetic regulation of genes implicated in retinoblastoma. Their dysregulation promotes tumorigenesis, and targeting these mechanisms represents a promising avenue for novel diagnostic and therapeutic strategies in pediatric oncology.

Background/Objectives: Sarcopenia, defined as the progressive loss of muscle mass and function, is increasingly recognized in pediatric cancer patients as a significant clinical and prognostic factor. Sarcopenia in children arises from malignancy-related inflammation, malnutrition, and treatment toxicity, negatively affecting treatment response, recovery, and quality of life. Methods: We searched MEDLINE and Scopus for English-written articles published over the last five years using synonyms for the terms “sarcopenia” and “pediatric cancer”. Screening and data extraction were performed in a duplicate-blinded method. We qualitatively synthesized eligible articles. Results: Recent studies identify pre-treatment sarcopenia as a marker of poor prognosis, especially in hepatoblastoma and neuroblastoma. Total psoas muscle area (tax) and skeletal muscle index (SMI) are emerging diagnostic tools, though standardized methods remain lacking. Sarcopenia’s etiology is multifactorial, involving impaired mitochondrial metabolism, chemotherapy-induced appetite loss, and systemic inflammation. Sarcopenic obesity is common, particularly among leukemia survivors, often masked by normal BMI. Survivors also face reduced bone density, impaired immunity, and persistent muscle loss, linked to prior therapies such as radiotherapy and hematopoietic stem cell transplantation. Increase in muscle mass post-treatment correlates with better survival outcomes. Conclusions: Early detection of sarcopenia can support timely interventions such as nutritional support and physical activity. Yet, significant diagnostic heterogeneity across existing studies hampers definitive conclusions regarding its true prevalence and the optimal assessment method. Standardized diagnostic criteria are urgently needed to enable more reliable prevalence estimates and evidence-based clinical strategies.

Chimeric antigen receptor (CAR)-T immunotherapy has revolutionized the management of patients with relapsed/refractory B-cell hematological malignancies. There is emerging evidence that CAR-engineered cells—not only T cells, but also natural killers and macrophages—might have a crucial role in the treatment of autoimmune disorders and solid tumors. Moreover, given the burden of chronic infectious diseases, the mortality and morbidity of infections in immunocompromised individuals, and the development of multidrug-resistant pathogens, including bacteria, fungi, and mycobacteria, a need for novel and personalized therapeutics in this field is emerging. To this end, the development of CAR cells for the management of chronic infections has been reported. In this literature review, we summarize the ongoing clinical and pre-clinical data about CAR cell products in the field of infectious diseases. Currently, clinical studies on CAR immunotherapy for infections mainly concern human immunodeficiency virus infection treatment, and data regarding other infections largely originate from preclinical in vitro and in vivo models. In the era of personalized medicine, effective and safe therapies for the management of chronic infections and infectious complications in immunocompromised patients are crucial.

Introduction: Fungal endophthalmitis (FE) is a rare but serious intraocular inflammatory disorder, resulting from an infection of the vitreous cavity from either endogenous or exogenous components that ultimately results in blindness. This current research study aims to elucidate the histological effects of the intravitreal injection of the maximum safe dosage of voriconazole and micafungin on the retina and investigate potential histological alterations after the double and combined administration of voriconazole and micafungin. Methodology: Nine New Zealand Albino Rabbits were randomly assigned into three groups (V2, M2, and VM), and in each, voriconazole, micafungin, and a combination of the two medications were administered respectively. After the administration of the antifungal agents, the animals were sacrificed and their retinas were retrieved and studied under optical and electron microscopes. The immunohistochemical markers TNF-a and IL6 were also studied. Results: TNF-a was positive in the VM group, as it was found to be mildly positive in the presence of apoptotic cells in the ganglion cell layer. Conclusions: This study revealed voriconazole has a greater toxicity in a multi-dosage administration. However, micafungin revealed a greater toxicity than voriconazole from the extent of the lesions observed.

We prospectively analyzed antifungal use in immunocompromised children through a multicenter 12-week weekly point-prevalence survey in 31 hematology-oncology (HO) and hematopoietic stem cell/solid organ transplant (HSCT/SOT) units of 18 hospitals in 11 European countries. All patients hospitalized and receiving systemic antifungals were included. Ward policies, and weekly ward/patient data were collected. All 21 HO and 10 HSCT/SOT units had prophylaxis policies for high-risk patients (27/31 used azoles, 14/31 echinocandins and 15/31 liposomal amphotericin B [LAMB]). Among 572 courses recorded, prophylaxis was indicated in 439/572 (77%) and treatment in 133/572 (62/133 empirical, 43/133 pre-emptive, 28/133 targeted). Among patients receiving prophylaxis, 56% belonged to the non-high-risk group. Most common reasons for empirical, pre-emptive and targeted treatment were antibiotic-resistant febrile neutropenia (52%), abnormalities on chest-CT with/without positive galactomannan (77%) and candidiasis (82%), respectively. Fluconazole and LAMB were the most frequently prescribed agents both for prophylaxis (31%, 21%) and treatment (32%, 23%). Underdosing of micafungin for treatment in 50% of prescriptions and of fluconazole for treatment and prophylaxis in 70% of cases was noticed. In conclusion, most antifungal prescribing was for prophylaxis, with fluconazole being the main antifungal prescribed. Inadequate doses of antifungal prescribing and prophylaxis of non-high-risk patients could be targets for improvement.