Search Results (239)

Background: Metastasis and poor chemotherapy response have stagnated therapeutic progress in osteosarcoma (OS) for the past three decades. Defining the transition from localized to metastatic OS before overt dissemination is fundamental for improving survival. However, effective early diagnostic tools remain scarce, largely due to limited exploitation of the metastasis-associated tumor microenvironment’s own record of prior environmental and stress exposures encoded in cell-intrinsic transcriptional states. Here, we employed a supervised machine learning framework with iterative resampling and multi-stage model selection to identify molecular markers associated with metastasis in osteosarcoma and to develop a computational signature, Auto-RS. Methods: Transcriptomic and clinical data from 139 OS patients with ≥5 years of follow-up were analyzed. A LASSO–Cox framework was applied to derive a gene expression-based risk score, Auto-RS, from which a nomogram integrating age and sex was generated for individualized prognosis. Model interpretability was assessed across six independent single-cell OS patient datasets, and drug sensitivity predictions were inferred by integrating Auto-RS with the Precily algorithm to uncover actionable therapeutic vulnerabilities. Results: Auto-RS, constructed from the expression of four autophagy genes (BNIP3, MYC, PEA15, and SAR1A), served as an independent prognostic factor for overall survival (HR = 1.091; 95% CI, 1.047–1.136; p < 0.001). Time-dependent ROC analysis showed that Auto-RS was the most accurate single predictor (AUC = 0.88), exceeding metastasis (0.83), sex (0.45), and age (0.39). A basic prognostic model (BpM) incorporating metastasis status yielded a C-index of 0.741 (95% CI, 0.679–0.803). The addition of Auto-RS (CpM) improved discrimination (C-index = 0.788; 95% CI, 0.731–0.845), whereas a model without metastasis information (ApM) retained predictive ability (C-index = 0.709; 95% CI, 0.640–0.778). Single-cell analysis confirmed that Auto-RS features aligned with known metastatic trajectories, reflecting the transition from proliferative to invasive tumor states and highlighting coordinated programs among cancer-associated fibroblasts and immune cells. Drug sensitivity integration through Precily identified gemcitabine and cytarabine as FDA-approved agents predicted in silico to show greater sensitivity in the high-risk subgroup. Conclusions: We identified autophagy-mediated transcriptional ‘stress fingerprints’ that are tightly associated with OS metastasis. The Auto-RS signature, composed of BNIP3, MYC, PEA15, and SAR1A, enables early therapeutic stratification of patients independent of overt metastatic status. Moreover, Auto-RS delineates key molecular underpinnings of OS metastasis at single-cell resolution. As a practical laboratory tool, Auto-RS may represent a step toward improved risk stratification, where advances in metastasis prediction and therapeutic guidance converge to improve outcomes in OS. Full article

Background: Cytarabine (Ara-C) remains the cornerstone of remission-induction and consolidation chemotherapy for acute myeloid leukemia (AML) and related hematological malignancies. Despite more than six decades of clinical use, its multi-organ toxicity continues to be managed almost exclusively through dose attenuation and supportive care, with no approved upstream pharmacological prevention strategy available. Objectives: This scoping review aimed to systematically map the breadth and nature of pharmacological agents tested in vivo for their capacity to mitigate cytarabine-induced multi-organ toxicity, to characterize their mechanisms of action and organ targets, and to identify evidence gaps and agents with translational potential. Methods: The review was designed and reported in accordance with the PRISMA-ScR checklist. A structured electronic search was conducted across PubMed/MEDLINE, Scopus, Cochrane Library and Embase, and Web of Science from database inception to 15 July 2025. Eligible studies were restricted to full-text, peer-reviewed, English-language research involving in vivo mammalian models administered cytarabine as the principal toxin, with at least one pharmacological co-intervention and at least one quantitative or histopathological organ-injury outcome. Results: From 5701 retrieved records, 36 eligible in vivo mammalian studies (spanning 1964–2024) were identified. Included studies addressed neurotoxicity (n = 6), gastrointestinal mucositis (n = 9), ocular toxicity (n = 3), hepatotoxicity (n = 3), bone marrow suppression (n = 4), chemotherapy-induced alopecia (n = 5), and reproductive and developmental toxicity (n = 4). Five recurring mechanistic strategies were identified across the heterogeneous agents tested: redox buffering (N-acetylcysteine, α-lipoic acid, rutin, swertiamarin, α-tocopherol), mitochondrial preservation (betanin, thymoquinone, vitamin D, sodium zinc dihydrolipoylhistidinate [DHLHZn]), tissue-microenvironment reprogramming (apraglutide, BADGE, plerixafor, short-chain fatty acids, β-glucan), molecular antagonism (deoxycytidine, dCMP), and immunomodulation (lienal peptide, IL-1β, AHCC). Conclusions: This scoping review provides the first systematic cartography of pharmacological mitigation strategies for cytarabine-induced multi-organ toxicity. Five mechanistic pathways converge across eight organ systems, with apraglutide and N-acetylcysteine representing the most clinically translatable candidates. Plerixafor and PPARγ blockade by BADGE constitute high-priority candidates for bone marrow niche protection, while the deoxycytidine antagonism principle warrants formal pharmacokinetic evaluation. The complete absence of cardiotoxicity mitigation data defines the most critical gap for future research. Full article

Acute myeloid leukemia (AML) is a biologically heterogeneous malignancy in which therapeutic decision-making is increasingly guided by molecular and immunophenotypic diagnostics. Advances in genomic profiling and risk stratification have enabled the integration of targeted agents into frontline and relapsed/refractory treatment strategies. Among these, midostaurin, venetoclax, and gemtuzumab ozogamicin represent paradigm-shifting therapies whose clinical benefit depends on accurate and timely diagnosis. This review examines the diagnostic frameworks that inform the use of these agents and discusses their incorporation into contemporary AML management. Midostaurin has demonstrated improved outcomes in patients with FLT3-mutated AML when combined with intensive chemotherapy, underscoring the importance of early molecular testing. Venetoclax, a BCL-2 inhibitor, has expanded therapeutic options for older or unfit patients when used with hypomethylating agents or low-dose cytarabine, with emerging evidence linking response to cytogenetic and molecular features. Gemtuzumab ozogamicin, an anti-CD33 antibody–drug conjugate, illustrates the clinical relevance of immunophenotypic assessment and risk-adapted dosing strategies. We highlight current evidence supporting diagnosis-driven therapy selection, practical considerations for clinical implementation, and ongoing challenges, including resistance mechanisms and optimal sequencing. Integrating precise diagnostic tools with targeted therapies represents a critical step toward personalized AML care and improved patient outcomes. Full article

Background: Post-remission cytarabine consolidation is a cornerstone of therapy for acute myeloid leukemia (AML), but the optimal dosing strategy in older adults (≥60 years) remains unclear. High-dose cytarabine (HiDAC) is often avoided due to toxicity concerns, and data guiding cumulative dosing are limited. Methods: We conducted a single-center retrospective cohort study of 111 patients aged ≥60 years with AML who achieved complete remission after standard 7 + 3 induction and received at least one cycle of cytarabine consolidation between 2012 and 2024. A 90-day landmark analysis excluded early relapses or deaths. Results: The median age was 65 years; 41% proceeded to allogeneic hematopoietic stem cell transplantation (allo-SCT). Cytarabine consolidation was well tolerated, with no neurotoxicity and only one instance of reversible nephrotoxicity. Patients were stratified by median cumulative cytarabine dose into low-intensity (<18 g/m², LIC) and high-intensity (≥18 g/m², HIC) groups. HIC was associated with improved overall survival compared with LIC (median OS: 31 vs. 13 months, p = 0.02), particularly among non-transplanted patients (25 vs. 7 months, p = 0.01). On multivariable analysis, HIC (HR 0.71, 95% CI 0.51–0.82, p = 0.01) and allo-SCT (HR 0.58, 95% CI 0.44–0.79, p = 0.03) independently predicted superior survival. Conclusions: Higher cumulative cytarabine consolidation is safe, feasible, and associated with improved survival in older AML patients, especially among patients ineligible for transplant. Prospective studies are warranted to define the optimal dosing strategy in this population. Full article

The glioma tumor microenvironment (TME) exhibits profound heterogeneity that drives tumor progression and therapy resistance. By integrating single-cell RNA sequencing (eleven samples) and spatial transcriptomics (two samples), the cellular components of the glioma microenvironment were deconvoluted, revealing tumor-associated foam cells (TAFCs) as the most abundant and centrally connected subtype. The high expression of two prognostic candidate genes, growth differentiation factor 8 (GDF-8, also known as myostatin, MSTN) and transcription factor 12 (TCF12), in TAFCs was found to be correlated with poor overall survival. These two genes were associated with M2 macrophage infiltration, altered cholesterol homeostasis, and immunosuppressive signaling. Regulatory network and pathway analyses, based on computational motif enrichment and co-expression analysis, linked them to ribosome, Notch signaling, DNA repair, and cell-cycle pathways. Pseudotime trajectories revealed dynamic expression during differentiation. Additionally, drug sensitivity prediction analysis demonstrated that MSTN expression was significantly associated with sensitivity to paclitaxel and VE-822, while TCF12 expression showed potential associations with sensitivity to cytarabine, olaparib, Wee1 inhibitor, paclitaxel, and VE-822. Logistic regression analysis combining clinical parameters with MSTN and TCF12 expression effectively achieved risk stratification for glioma, with higher composite scores predicting worse 2- and 3-year survival outcomes. Calibration curves demonstrated high consistency between nomogram-predicted overall survival probabilities and actual observed outcomes. Immunofluorescence confirmed upregulated expression of MSTN and TCF12 in glioma tissues and their co-localization with macrophages. In conclusion, this study identified TAFCs as the central cells in the glioma microenvironment, with their signature genes MSTN and TCF12 representing candidate immunometabolic signatures associated with macrophage-mediated immunosuppression and metabolic reprogramming in glioma, suggesting their potential as biomarkers for patient stratification and as targets for immunometabolic therapies. Full article

Background/Objectives: The aberrant epigenetic landscape of cancer cells has attracted wide attention, motivating the search for new epigenetically active drugs both for anticancer therapy and for overcoming the drug resistance promoted by epigenetic changes. The use of epi-drugs in cancer therapy requires consideration of the influence of applied treatment on epigenetic regulation of gene expression. Therefore, it is reasonable to screen epigenetically active compounds among the drugs widely used in clinical oncology. Methods: We applied the HeLa TI cell-based assay to analyze the epigenetic activity of 40 drugs including 22 chemotherapeutic, 2 immunotherapeutic, 13 targeted, and 3 palliative agents. Reactivation of the epigenetically silenced GFP reporter gene integrated into the genome of HeLa TI cells was assessed using flow cytometry. Results: Statistically significant increases in the proportions of GFP-positive cells were demonstrated for the alkylating agent chlorambucil; the antimetabolites cytarabine, fluorouracil, gemcitabine, and pemetrexed; the platinum-based compounds cisplatin, and oxaliplatin; the topoisomerase inhibitor topotecan; and the antimicrotubule agents docetaxel, vincristine, and eribulin. Epigenetic activity was also detected for the targeted-therapy agents AZD8055, wortmannin, and cetuximab, as well as for the corticosteroid dexamethasone. Thus, epigenetic activity was revealed for 15 drugs widely used in cancer therapy, which possess different modes of action. Conclusions: Our findings show that many anticancer therapy agents modulate the epigenetic landscape of cancer cells, providing a rationale for expanding their therapeutic applications and enhancing the efficacy of combination strategies by overcoming epigenetically driven chemoresistance. Full article

Background/Objectives: Acute myeloid leukemia (AML) is a heterogeneous hematologic malignancy with historically poor outcomes, particularly among older adults and patients harboring high-risk molecular features. Advances in genomic profiling have enabled the development of targeted therapies, reshaping treatment algorithms beyond conventional cytarabine-anthracycline induction and hypomethylating agent-based regimens. This review summarizes current evidence and emerging therapeutic strategies across four evolving areas: menin inhibition, FLT3 inhibition, IDH inhibition and treatment approaches for TP53-mutated AML. Methods: We reviewed published clinical trials, preclinical studies, and ongoing clinical trials evaluating targeted therapies in AML. Emphasis was placed on agents with regulatory approval or substantial clinical development, including menin inhibitors, FLT3 inhibitors, IDH inhibitors and novel therapies directed at TP53-mutated disease. Mechanistic data, response rates, survival outcomes, and resistance patterns were analyzed to provide an updated overview of therapeutic progress. Results: Menin inhibitors have demonstrated significant activity in NPM1-mutated and KMT2A-rearranged AML, with agents such as revumenib and ziftomenib producing meaningful remission rates and ongoing studies exploring combination strategies to mitigate resistance. FLT3 inhibitors, including midostaurin, gilteritinib, and quizartinib, have improved survival in FLT3-mutated AML, while emerging evidence supports potential benefit in selected FLT3–wild-type disease based on FLT3-like gene expression signatures. IDH inhibitors, namely ivosidenib and enasidenib, have provided increased efficacy in AML patients carrying these mutations. Questions still remain regarding their efficacy in contrast to venetoclax which has been shown to be particularly effective against this population. In contrast, TP53-mutated AML remains a therapeutic challenge: although hypomethylating-agent/venetoclax-based regimens yield improved initial responses, remissions are generally short-lived and overall survival remains poor. Early-phase therapies, including p53 reactivators and multi-kinase inhibitors, show preclinical promise but lack definitive clinical efficacy to date. Conclusions: Targeted therapies have improved outcomes in molecularly defined subsets of AML, with menin, IDH and FLT3 inhibitors representing major advances. However, TP53-mutated AML continues to carry a dismal prognosis, underscoring the need for more effective therapeutic strategies. Continued biomarker-driven research, novel drug combinations, and mechanistic insights will be essential to further refine AML treatment and improve long-term survival across disease subsets. Full article

Introduction: Chronic lymphocytic leukemia (CLL) is a common adult leukemia often treated with fludarabine, cyclophosphamide, and rituximab (FCR). While effective, FCR can lead to therapy-related myeloid neoplasms (t-MN), including aggressive therapy-related acute myeloid leukemia (t-AML). Stem cell transplantation offers the best chance for long-term remission in these cases. Here, we report a rare case of t-AML with plasmacytoid dendritic cells (pDC-AML) developing after FCR treatment for CLL that was successfully treated with haplotransplantation. Case Presentation: A 57-year-old woman with CLL-B was treated with six cycles of FCR, achieving a complete response. Six years later, at age 63, she developed t-AML with a rare morphophenotypic subtype: acute myelomonocytic leukemia with plasmacytoid dendritic cells (pDC-AML) and monosomy 8. Diagnostic challenges included distinguishing this subtype from blastic plasmacytoid dendritic cell neoplasm (BPDCN). She was treated with high-dose cytarabine followed by haploidentical stem cell transplantation from her son. Haploidentical transplantation was prioritized due to the urgent clinical need in a patient with high-risk acute leukemia (therapy-related leukemia secondary to prior chemoimmunotherapy and failure to achieve complete remission following the standard 3 + 7 induction protocol). In this critical setting, the patient’s son was immediately available as an HLA-haploidentical donor. Prior to the performance of the haploidentical stem cell transplant from her son, no HLA-matched unrelated donor (MUD) could be identified. Another viable alternative would have been the utilization of umbilical cord blood-derived stem cells harvested from the patient’s twin granddaughters. She was closely monitored post-transplant for potential complications, including graft-versus-host disease (GVHD), post-transplant lymphoproliferative disorder, and thyroid dysfunction, all of which were ruled out during follow-up. The patient remains in complete remission 15 years after her initial CLL diagnosis and 8 years after the t-AML diagnosis and haplotransplantation. Notably, no residual CLL clone was detected at the time of t-AML development, and a benign polyclonal lymphocytosis observed between 2018 and 2020 spontaneously resolved without intervention. Conclusions: This case illustrates the potential for long-term survival in high-risk patients with therapy-related AML developed after cytotoxic treatment for lymphoid malignancies. Haplotransplantation from a semi-identical Human Leukocyte Antigen (HLA) donor proved to be a viable and effective treatment option despite the patient’s age and dual hematologic malignancies. Full article

Polymer-based drug delivery systems offer robust opportunities to improve chemotherapy performance while mitigating systemic toxicity, a critical challenge in leukemia treatment. In this study, poly(ε-caprolactone) (PCL) microparticles were developed as carriers for the co-delivery of cytarabine (ARA-C), a frontline antileukemic agent, and a pecan-derived polyphenolic extract (PRE) as a complementary bioactive component. Microparticles were prepared by a double emulsion solvent evaporation method and formulated with varying drug and extract loadings. The systems were characterized in terms of morphology, particle size, colloidal properties, encapsulation efficiency, and chemical composition using optical microscopy, scanning electron microscopy, dynamic light scattering, zeta potential analysis, UV–Vis spectroscopy, Folin–Ciocalteu assay, and FTIR spectroscopy. In vitro release studies revealed sustained and formulation-dependent release profiles for both ARA-C and PRE, which were successfully fitted to kinetic models, indicating diffusion- and matrix-controlled release mechanisms. Additionally, preliminary cell viability assays using fibroblasts supported the cytocompatibility of the formulations. The results support the use of PCL-based microparticles as reproducible polymeric systems for the co-encapsulation and controlled release of cytarabine and polyphenol-rich extracts, contributing to the development of combination delivery approaches relevant to leukemia treatment. Full article

Myeloid malignancies exhibit profound metabolic dependence on mitochondrial oxidative phosphorylation (OXPHOS) for survival and proliferation. Antileukemic therapies such as Venetoclax combined with Azacitidine or cytarabine induce rapid mitochondrial collapse, disrupting electron transport, NADH oxidation, and ATP synthesis, followed by a selective rebound of fatty-acid oxidation (FAO) and redox-buffering programs that sustain minimal residual disease. This review integrates current mechanistic and clinical insights into therapy-induced mitochondrial suppression, delineates the regulatory circuitry that enables metabolic recovery, and frames these events as a reversible model of clinical energy deficiency. By linking mitochondrial stress signaling, lipid oxidation, and adaptive redox metabolism, we outline how bioenergetic reprogramming drives therapeutic resistance and propose interventions that target this adaptive axis in acute myeloid leukemia (AML), myelodysplastic syndromes (MDS), and related myeloid neoplasms. Full article

Glioblastoma multiforme (GBM) is the most aggressive primary brain cancer (with a median survival time of 14.5 months), characterized by heterogeneity. Identifying prognostic molecular subtypes could provide a deeper exposition of GBM biology with potential therapeutic implications. In this study, we classified GBM into two prognostic subtypes, C1-GBM (n = 57; OS: 313 days) and C2-GBM (n = 109; OS: 452 days), using pathway-based signatures derived from RNA-seq data. Unsupervised consensus clustering revealed that only binary classification (cluster number, CN = 2; mean cluster consensus score = 0.84) demonstrated statistically prognostic differences. We characterized C1 and C2 based on oncogenic pathway and immune signatures. Specifically, C1-GBM was categorized as an immune-infiltrated “hot” tumor, with high infiltration of immune cells, particularly macrophages and CD4⁺ T cells, while C2-GBM as an “inherent driving” subtype, showing elevated activity in G2/M checkpoint genes. To predict the C1 or C2 classification and explore therapeutic interventions, we developed a neural network model. By using Weighted Correlation Network Analysis (WGCNA), we obtained the gene co-expression module based on both gene expression pattern and distribution among patients in TCGA dataset (n = 166) and identified nine hub genes as potentially prognostic biomarkers for the neural network. The model showed strong accuracy in predicting C1/C2 classification and prognosis, validated by the external CGGA-GBM dataset (n = 85). Based on the classification of the BP neural network model, we constructed a Cox nomogram prognostic prediction model for the TCGA-GBM dataset. We predicted potential therapeutic small molecular drugs by targeting subtype-specific oncogenic pathways and validated drug sensitivity (C1-GBM: Methotrexate and Cisplatin; C2-GBM: Cytarabine) by assessing IC₅₀ values against GBM cell lines (divided into C1/C2 subtypes based on the nine hub genes) from the Genomics of Drug Sensitivity in Cancer database. This study introduces a pathway-based prognostic molecular classification of GBM with “hot” (C1-GBM) and “inherent driving” (C2-GBM) tumor subtypes, providing a prediction model based on hub biomarkers and potential therapeutic targets for treatments. Full article

Bioactive natural products (NPs) may play a critical role in cancer progression by targeting nucleic acids and a wide array of proteins, including enzymes. Furthermore, a large number of derivatives (NPDs), including semi-synthetic products and pharmacophores from NPs, have been developed to enhance the solubility and stability of NPs. Acute myeloid leukemia (AML) is a poor-prognosis hematologic malignancy characterized by the clonal accumulation in the blood and bone marrow of myeloid progenitors with high proliferative capacity, survival and propagation abilities. A number of potential pathways and targets have been identified for development in AML, and include, but are not limited to, Fms-like tyrosine kinase 3 (FLT3) and isocitrate dehydrogenases resulting from genetic mutations, BCL2 family members, various signaling kinases and histone deacetylases, as well as tumor-associated antigens (such as CD13, CD33, P-gp). By targeting nucleic acids, FLT3 or CD33, several FDA-approved NPs and NPDs (i.e., cytarabine, anthracyclines, midostaurin, melphalan and calicheamicin linked to anti-CD33) are the major agents of upfront treatment of AML. However, the effective treatment of the disease remains challenging, in part due to the heterogeneity of the disease but also to the involvement of the bone marrow microenvironment and the immune system in favoring leukemic stem cell persistence. This review summarizes the current state of the art, and provides a summary of selected NPs/NPDs which are either entering or have been investigated in preclinical and clinical trials, alone or in combination with current chemotherapy. With multifaceted actions, these biomolecules may target all hallmarks of AML, including multidrug resistance and deregulated metabolism. Full article

Background: Dendritic cells (DCs) are heterogeneous antigen-presenting cells that bridge innate and adaptive immunity. Recent classifications of hematolymphoid neoplasms highlight the complex origins of DC-related neoplasms. DCs have also been associated with the progression of multiple myeloma (MM). This report presents the case of a patient with MM in whom bone marrow analysis revealed an unusual additional clonal population of immature cells, in addition to plasmacytoid DCs, that later evolved into plasmacytoid dendritic cell proliferation associated with acute myeloid leukemia (pDC-AML). Methods: The bone marrow of a 69-year-old man with neutropenia and thrombocytopenia was examined by morphology, immunohistochemistry, flow cytometry, cytogenetics, fluorescence in situ hybridization (FISH), and next-generation sequencing (NGS). Serial assessments were performed before and during treatment with bortezomib and dexamethasone for MM, and later with daunorubicin/cytarabine for AML. Results: Initial bone marrow analysis revealed coexisting clonal plasma cells with t(11;14) and a population of CD34+/CD123+/CD45RA+ cells lacking lineage markers, in addition to pDCs, suggestive of precursor DCs rather than acute undifferentiated leukemia. Cytogenetic analysis identified a small clone with isolated del(20q), which corresponded in size to the clone of undifferentiated cells and to the clone with pathogenic variants detected by NGS in the BCOR, RUNX1, and SRSF2 genes. Myeloma therapy decreased both MM and undifferentiated cells; however, within four months, pDC-AML evolved with del(20q) and higher variant allele frequencies of the previously detected gene variants. Remission was achieved with standard AML chemotherapy. Conclusions: This case supports evidence that MM-associated immune dysfunction and bone marrow niche alterations may promote secondary myeloid malignancies independently of cytotoxic therapy. It demonstrates the earliest events in pDC-AML evolution. Furthermore, the immature immunophenotype raises the question of appropriate treatment, since a diagnosis of acute undifferentiated leukemia can be established. Full article

Background/Objectives: Cytarabine (Ara-C) remains central to acute myeloid leukemia therapy but is limited by unpredictable systemic toxicities. Preclinical studies have long documented multi-organ injury, yet findings remain fragmented. This systematic review synthesizes animal evidence to clarify the spectrum, dose–response patterns, and mechanisms of cytarabine-induced toxicity. Methods: Following PRISMA 2020 guidelines and PROSPERO registration (CRD420251081384), a comprehensive search of PubMed, MEDLINE, Scopus, Cochrane Library and Embase identified eligible in vivo animal studies. Data extraction covered animal models, dosing regimens, routes of administration, histopathological and biochemical endpoints and mechanistic findings. Risk of bias and study quality were assessed using SYRCLE’s tool, CAMARADES checklist and an adapted Newcastle–Ottawa Scale, with reporting benchmarked against ARRIVE 2.0. Results: Eighty-one studies (1964–2024) were included. Cytarabine produced dose- and regimen-dependent toxicities across multiple organs. Neurotoxicity was most frequently reported, followed by intestinal mucositis, ocular injury, alopecia, hepatotoxicity, nephrotoxicity, and developmental anomalies. Mechanistic analyses consistently implicated oxidative stress, inflammatory cascades, apoptosis, and epigenetic dysregulation. Study quality was moderate, with frequent deficiencies in randomization, blinding, and sample-size justification, raising concerns about reproducibility. Cardiotoxicity, despite clinical relevance, was virtually absent from preclinical evaluation. Conclusions: Preclinical evidence suggests cytarabine’s systemic toxicity as a multifactorial process extending beyond rapidly proliferating tissues. While animal studies provide mechanistic insights, methodological weaknesses and translational gaps limit predictive value. Future research must adopt rigorous design, systematically assess underexplored toxicities, and integrate molecular profiling to identify biomarkers and protective strategies. Full article

Background/Objectives: Several studies reported that olive leaf extract (OLE) may exert potent anti-cancer activities against human solid and hematological tumors. Such effects are mostly related to the polyphenol oleuropein and its derivatives, which are highly concentrated in OLE. Here, we investigated the anti-tumor effects of OLE in vitro against human acute leukemia and lymphoma cells. Methods: Cell proliferation and apoptosis have been evaluated by flow cytometry (using CFSE and Annexin-V/7AAD, respectively) in the presence or absence of OLE at different concentrations and in combination with or without chemotherapeutic drugs. Cellular pathways have been analyzed using antibody arrays. Results: OLE inhibited cell proliferation and induced apoptosis in B-acute lymphoblastic leukemia (B-ALL) and, to a lesser extent, in lymphomas and acute myeloid leukemia (AML) cell lines. Notably, OLE-induced apoptosis also occurs in primary leukemic blasts from B-ALL patients, both at diagnosis and at relapse, but only marginally in primary AML blasts. The expression and phosphorylation of proteins involved in the induction of apoptosis were modulated by OLE in B-ALL, whereas modest effects were observed in AML. Interestingly, some proteins were modulated in opposite ways in B-ALL and AML, potentially explaining their different responses to OLE. Finally, a synergistic and additive effect was observed for OLE in combination with cytarabine, but not with cyclophosphamide. Conclusions: We may envisage that OLE may be used as a food supplement in B-ALL patients treated with cytarabine, taking advantage of the potentiated effect of chemotherapy, without additional side effects. Full article