Search Results (46)

Background/Objectives: Severe oral mucositis is widely viewed as a transient toxicity of antineoplastic therapy. Whether its long-term consequences differ between cancers that directly damage the upper aerodigestive tract (cancers of the lip, oral cavity, pharynx [CLOP]) and systemic hematologic malignancies is unknown. The aim of this study was to compare lifetime risks of mortality, dysphagia, malnutrition, respiratory disease, and cardiovascular disease in propensity-score-matched survivors of CLOP cancer versus leukemia with and without a history of ulcerative oral mucositis. Methods: Population-based retrospective cohort study using the TriNetX US Collaborative Network (90 healthcare organizations, >110 million patients). We identified 80,526 adults with a personal history of CLOP cancer (ICD-10-CM Z85.81) and 43,684 with leukemia (Z85.6) from 2005 to 2024. Cohorts were stratified by presence/absence of severe oral mucositis (K12.31 or K12.33 at any time). Separate 1:1 propensity-score matching was performed within each cancer type on age, sex, race/ethnicity, hypertension, diabetes, BMI, ECOG status, and external causes of morbidity. Exposures included documented severe (ulcerative) oral mucositis. Main outcomes and measures were all-cause mortality and incident dysphagia, malnutrition, respiratory disease (J00–J99), influenza/pneumonia (J09–J18), and circulatory disease (I00–I99) after the index date. Results: After 1:1 matching, 4181 CLOP patients with mucositis were compared with 4181 without, and 2508 leukemia patients with mucositis were compared with 2508 without. In CLOP survivors, mucositis was associated with markedly higher lifetime mortality (adjusted HR 1.94, 95% CI 1.87–2.01), dysphagia (HR 3.42, 95% CI 3.28–3.57), malnutrition (HR 2.81, 95% CI 2.66–2.97), any respiratory disease (HR 1.68, 95% CI 1.63–1.73), and influenza/pneumonia (HR 1.79, 95% CI 1.72–1.86). In leukemia survivors, mucositis conferred only modest or null excess risk (mortality HR 1.12, 95% CI 1.05–1.19; dysphagia HR 1.18, 95% CI 1.07–1.30; malnutrition HR 1.24, 95% CI 1.12–1.37; any respiratory disease HR 1.09, 95% CI 1.03–1.15). Conclusions and Relevance: Severe oral mucositis is a powerful, durable prognostic determinant in cancers of the upper aerodigestive tract, where it identifies patients associated with elevated lifelong risk of swallowing dysfunction, aspiration-related lung disease, malnutrition, and premature death. The markedly attenuated effect in leukemia survivors suggests that direct high-dose radiation-induced structural damage to the pharynx and oral cavity—rather than systemic immunosuppression or chemotherapy intensity alone—is the dominant mechanism. Full article

Purpose: Castration-resistant prostate cancer (CRPC) responds poorly to conventional chemotherapy. We evaluated a cell-based enzyme–prodrug therapy using adipose-derived stem cells (ADSCs) engineered to express cytosine deaminase (CD) or carboxylesterase 2 (CE2), paired with their respective prodrugs 5-fluorocytosine (5-FC) or irinotecan (CPT-11), to compare their antitumor efficacy. Materials and Methods: Human telomerase reverse transcriptase (hTERT)-immortalized ADSCs were transduced with CD or CE2, and transgene expression and stem cell phenotype were confirmed. CD expression was verified at the transcript level and by functional 5-FC-to-5-fluorouracil (5-FU) conversion, whereas CE2 expression was verified by transcript analysis and immunoblotting. Tumor tropism toward PC3 prostate cancer cells was tested using migration assays and analysis of chemoattractant ligand/receptor expression. Prodrug-induced self-killing and bystander tumor cell killing were assessed through viability assays and co-culture with PC3 cells. For the CE2/CPT-11 system, SN-38 was not directly quantified; functional activity was inferred from prodrug-dependent cytotoxicity and in vivo efficacy. In vivo efficacy was evaluated in nude mice with PC3 tumors treated systemically with engineered ADSCs plus prodrug. Results: CD- and CE2-expressing ADSCs were successfully established and retained mesenchymal stem cell (MSC) characteristics. Both cell types exhibited significant migration toward PC3 cells. The CE2/CPT-11 system produced stronger prodrug-mediated cytotoxicity than CD/5-FC, with CE2-modified ADSCs showing higher sensitivity to CPT-11 and inducing greater apoptosis in co-cultured PC3 cells. In vivo, both treatments suppressed tumor growth, but CE2/CPT-11 achieved greater inhibition (tumor volume ~26% of control vs. ~32% for CD/5-FC at day 14). No overt clinical toxicity was observed based on body weight and daily clinical monitoring; however, hematology/serum chemistry were not assessed. Conclusions: Engineered ADSCs home to CRPC tumors and enable local prodrug activation, producing significant antitumor effects. Within the constraints of our in vitro assays and subcutaneous xenograft model, CE2/CPT-11 demonstrated stronger efficacy outcomes than CD/5-FC. Mechanistic attribution to intratumoral SN-38 exposure should be confirmed by direct metabolite measurements in future studies. Full article

Doxorubicin (DOX) is a highly effective chemotherapeutic agent whose clinical use is limited by dose-dependent cardiotoxicity associated with oxidative stress, inflammation, and cellular stress responses. Here, we investigated whether preventive aerobic training could protect against DOX-induced cardiac injury in Wistar rats. Animals were assigned to sedentary control (C), sedentary DOX (D), trained control (CT), and trained DOX (DT) groups. The moderate-intensity (~50–80% maximal exercise test) treadmill protocol (40 min/day, 4 days/week for 4 weeks) was performed before intraperitoneal administration of DOX (4 mg/kg, weekly for 4 weeks) or saline. Preventive training markedly improved exercise capacity (p < 0.001) and attenuated oxidative damage, maintaining antioxidant enzyme activity (GR, SOD) at control levels (p > 0.05). DOX significantly upregulated cardiac IL-6 and IL-1β expression (p < 0.01), while trained animals preserved IL-1β expression similar to controls (p > 0.99). In parallel, DOX increased cardiac HIF-1 expression (p < 0.05), indicating activation of hypoxia- and stress-related signaling pathways, an effect that was attenuated by preventive training (p > 0.99). DOX-induced cardiac atrophy was evidenced by reduced left ventricular mass (p < 0.001), which was partially prevented by training (p < 0.05). Although hematological toxicity persisted, preventive aerobic exercise effectively counteracted DOX cardiotoxicity by restoring redox homeostasis, dampening inflammation, and limiting apoptotic signaling. Collectively, these findings highlight exercise preconditioning as a promising non-pharmacological strategy in cardio-oncology to mitigate chemotherapy-associated cardiac injury. Full article

(1) Background: Chemotherapy-induced hematological toxicity remains a major limitation to treatment continuity. Docetaxel is widely used in solid tumors due to its clinical efficacy, despite cumulative bone marrow suppression and splenic alterations. Curcuma longa is a phytochemical with antioxidant and anti-inflammatory properties that may confer cytoprotective effects on hematopoietic tissues. (2) Methods: One hundred and five male Wistar rats were randomly allocated into five treatment groups and evaluated at 7, 14, and 21 days. Animals received placebo, docetaxel alone, or docetaxel combined with Curcuma longa at doses of 25, 50, or 500 mg/kg/day. Post-treatment hematological parameters and relative spleen weight were analyzed using one-way ANOVA and Tukey’s post hoc test. (3) Results: Docetaxel induced progressive reductions in red blood cell count, hemoglobin, hematocrit, leukocytes, and platelets, with greater severity at day 21. Curcuma longa co-treatment partially mitigated these alterations in a dose- and time-dependent manner. Intermediate doses (25–50 mg/kg) showed the most consistent hematoprotective effects. High-dose treatment (500 mg/kg) was associated with no statistically significant change in relative spleen weight. (4) Conclusions: Curcuma longa partially mitigated docetaxel-induced hematological toxicity and modulated splenic responses in this experimental model. These findings support further translational studies on chemotherapy-induced hematological toxicity to clarify the role of Curcuma longa as a low-toxicity strategy. Full article

Patients with leukemia are at heightened risk for invasive fungal infections (IFIs) due to profound immunosuppression caused by both the malignancy and its treatment. Chemotherapy-induced neutropenia, mucosal barrier disruption, and impaired innate and adaptive immune responses create a highly permissive environment for opportunistic fungal pathogens. Antifungal prophylaxis, particularly in acute myeloid leukemia (AML), has become a cornerstone in reducing IFI-related morbidity and mortality. This review outlines the immunopathogenic mechanisms underlying susceptibility to IFI and discusses current evidence on the optimal timing and therapeutic strategies for antifungal intervention. The clinical utility of key antifungal agents, namely, posaconazole, isavuconazole, and voriconazole, is critically evaluated. We also examine the potential role of emerging agents such as opelconazole, which enables targeted pulmonary delivery and prolonged epithelial retention, representing a promising approach to IFI prevention. Drug-specific considerations, including pharmacokinetics, drug–drug interactions, toxicity profiles, and cost-effectiveness, are analyzed in the context of clinical decision-making. Finally, we emphasize the importance of tailoring antifungal strategies based on leukemia subtype, immunosuppressive status, and individual patient factors to optimize outcomes and support antifungal stewardship in hematologic malignancies. Full article

Background/Objectives: Breast cancer remains a major cause of cancer-related mortality among women worldwide, highlighting the need for new therapeutic strategies. Pyrimidine derivatives have shown promise in oncology due to their ability to modulate immune responses and influence tumor growth pathways. Methods: Cytotoxicity of Xymedon was evaluated using MTT and colony formation assays on cancer MCF-7, NCI-H322M, HCT-15 cells, and primary human foreskin fibroblasts. In vivo efficacy was assessed in an orthotopic MCF-7 xenograft model in female Balb/c nude mice. Xymedon was administered orally at 410 mg/kg daily alone or in combination with intraperitoneal doxorubicin (1 mg/kg weekly). Hematological, histological, and immunohistochemical analyses were performed. Results: In vitro, Xymedon (up to 3 mM) showed no cytotoxicity against cancer cell lines or human skin fibroblasts. In vivo, Xymedon significantly increased tumor necrosis (44.1% vs. 28.5%, p < 0.01) and enhanced intratumoral infiltration of CD3+, CD8+, and CD20+ lymphocytes, with peritumoral counts increasing 2.2–5.3-fold. It mitigated Doxorubicin-induced myelosuppression by improving red blood cell counts, hemoglobin, and hematocrit levels, while platelet recovery remained limited. Combination therapy with Xymedon did not affect tumor volume or weight, but resulted in a non-significant trend toward improved survival (80% vs. 30%, p ≈ 0.11; Hazard Ratio [HR] = 0.268, 95% CI: 0.07082 to 1.012) without affecting fibrous capsule formation. Conclusions: These results suggest that Xymedon is a non-cytotoxic immunomodulator with potential as an adjuvant to enhance antitumor immunity and reduce hematologic toxicity associated with chemotherapy. Further studies are needed to elucidate the molecular pathways and confirm clinical efficacy. Full article

A novel inclusion complex of a fluorinated pyrazolopiperidine derivative (5-benzyl-7-(2-fluorobenzylidene)-2,3-bis(2-fluorophenyl)-3,3a,4,5,6,7-hexahydro-2H-pyrazolo [4,3-c]pyridine hydrochloride, PP·HCl) with β-cyclodextrin (PPβCD) was designed, synthesized, and characterized as a potential therapeutic agent for chemotherapy-induced myelosuppression and lymphopenia. Encapsulation of PP within β-cyclodextrin increased aqueous solubility by approximately 3.4-fold and improved dissolution rate by 2.8-fold compared with the free compound. Structural analysis using IR, ^1H/^13C NMR, and TLC confirmed the formation of a stable 1:1 host–guest complex, and the disappearance of free PP signals further supported complete encapsulation. In vivo evaluation in a cyclophosphamide-induced myelosuppression model demonstrated that PPβCD accelerated hematopoietic recovery, restoring leukocyte and erythrocyte counts 35–40% faster than methyluracil, without any signs of systemic toxicity. These findings indicate that β-cyclodextrin complexation significantly enhances solubility, dissolution, and biological efficacy of the pyrazolopiperidine scaffold, supporting further preclinical development of PPβCD as a supportive therapy for chemotherapy-related hematological complications. Full article

Background/Objectives: Hematological toxicities (i.e., neutropenia, thrombocytopenia, and anemia), are common chemotherapy complications and may be exacerbated by renal or hepatic impairment due to altered drug exposure. This study assessed the association between renal and hepatic impairment and hematologic toxicities during chemotherapy in routine clinical practice. Methods: A single-center retrospective cohort study using the Utrecht Patient Oriented Database (UPOD) identified all chemotherapy administrations at the University Medical Centre Utrecht between 2011 and 2024. Regimens administered in ≥10 patients and ≥5 renally (GFR < 60 mL/min) or hepatically (bilirubin or AST > 1× ULN) impaired patients were included in descriptive analyses. Cox proportional hazards models estimated associations between organ impairment and grade ≥ 3 hematologic toxicities for regimens with ≥10 events per toxicity endpoint. Results: Overall, 4489 patients were included in renal analyses and 6218 in hepatic analyses, with smaller endpoint-specific subgroups for survival analyses. Renal impairment was associated with grade ≥ 3 neutropenia (HR: 1.43 [95% CI: 1.18–1.73]), thrombocytopenia (HR: 1.46 [95% CI: 1.15–1.86], and anemia (HR: 1.66 [1.27–2.16]). Hepatic impairment was similarly associated with neutropenia (HR: 1.25 [95% CI: 1.11–1.40]), thrombocytopenia (HR: 1.33 [95% CI: 1.13–1.57]), and anemia (HR: 1.62 [95% CI: 1.34–1.95]). Cyclophosphamide (pro-drug) regimens showed higher toxicity risk in renally impaired patients and reduced risk in hepatically impaired patients. Etoposide, melphalan and methotrexate were associated with increased toxicity in hepatically impaired patients. Conclusions: Renal and hepatic impairment significantly increase chemotherapy-induced hematologic toxicity. Several high-risk chemotherapy regimens were identified; however, larger multi-center datasets are needed to refine dosing guidance based on renal and hepatic function. Full article

Doxorubicin (DOX) is a highly effective chemotherapy drug used in the treatment of many cancers, including solid tumors, hematological malignancies, and soft tissue sarcomas. Despite its potent antitumor effects, DOX is known to have toxic effects in non-tumorous tissues, such as skeletal muscle. Potential mediators of DOX-induced skeletal muscle toxicity are reactive oxygen species (ROS). An overproduction of ROS can disrupt the balance between oxidants and antioxidants in a cell, leading to oxidative stress. Chronic oxidative stress has been shown to upregulate proteolysis, ultimately leading to muscle wasting. Exercise stands as a potent nonpharmacological therapy capable of attenuating muscle wasting by enhancing metabolic function and antioxidant defenses while suppressing harmful ROS production. This review focuses on the current understanding of the role of oxidative stress in DOX-induced skeletal muscle toxicity. In addition, we highlight the effects of various exercise types on oxidative stress and muscle remodeling during DOX chemotherapy. Full article

Acute erythroid leukemia (AEL) is a rare and aggressive hematological malignancy managed with chemotherapy, targeted therapies, and stem cell transplantation. However, these treatments often suffer from limitations such as refractoriness, high toxicity, recurrence, and drug resistance, underscoring the urgent need for novel therapeutic approaches. Dibromo-edaravone (D-EDA) is a synthetic derivative of edaravone (EDA) with unreported anti-leukemic properties. In this study, D-EDA demonstrated potent cytotoxicity against HEL cells with an IC₅₀ value of 8.17 ± 0.43 μM using an MTT assay. Morphological analysis via inverted microscopy revealed reductions in cell number and signs of cellular crumpling and fragmentation. Flow cytometry analysis, Hoechst 33258 staining, Giemsa staining, a JC-1 assay, and a reactive oxygen species (ROS) assay showed that D-EDA induced apoptosis in HEL cells. Furthermore, D-EDA induced S-phase cell cycle arrest. Western blot analysis showed significant upregulation of key apoptosis-related proteins, including cleaved caspase-9, cleaved caspase-3, and cleaved poly ADP-ribose polymerase (PARP), alongside a reduction in Bcl-2 expression. Additionally, oncogenic markers such as c-Myc, CyclinA2, and CDK2 were downregulated, while the cell cycle inhibitor p21 was upregulated. Mechanistic studies involving molecular docking, a cellular thermal shift assay (CETSA), the caspase inhibitor Z-VAD-FMK, JAK2 inhibitor Ruxolitinib, and STAT3 inhibitor Stattic revealed that D-EDA activates the caspase cascade and inhibits the JAK2-STAT3 signaling pathway in HEL cells. In vivo, D-EDA improved spleen structure, increased the hemolysis ratio, and extended survival in a mouse model of acute erythroleukemia. In conclusion, D-EDA induces apoptosis via the caspase cascade and JAK2-STAT3 signaling pathway, demonstrating significant anti-leukemia effects in vitro and in vivo. Thus, D-EDA may be developed as a potential therapeutic agent for acute erythroleukemia. Full article

Chemotherapy-induced neutropenia (CIN) and chemotherapy-induced alopecia (CIA) are significant toxicities affecting cancer patients. CIN is a potentially fatal complication of chemotherapy caused by myelosuppression and increased infection susceptibility, while CIA, although not fatal, severely affects treatment adherence and mental health. This study provides a comprehensive comparative analysis of CIN and CIA, focusing on patient, disease, treatment, and genetic risk factors. Key risk factors for CIN and CIA include age, poor performance status, body mass index (BMI), laboratory abnormalities, and pre-existing comorbidities. Both toxicities were significantly associated with breast cancer patients, although CIN patients were more likely to have hematological cancer, and CIA patients were more likely to have solid tumors. Notably, anthracyclines, alkylators, and taxanes frequently induce both toxicities, although their timelines and clinical implications differed. There was no clear overlap between genetic predispositions and toxicities beyond single-nucleotide polymorphisms (SNPs) in the ABCB1 gene. This is the first study to directly compare CIN and CIA, offering insights into personalized oncology care. Understanding the risk factors implicated in the development of CIN and CIA will enable physicians to manage patient outcomes. Full article

This study aims to evaluate the clinical effectiveness of trilaciclib in preventing myelosuppression in patients with esophageal cancer undergoing chemotherapy. Based on the use of trilaciclib, 81 patients were divided into a primary prevention group (PP group, n = 49) and a secondary prevention group (SP group, n = 32). The incidence of myelosuppression, antibiotic usage rate, survival outcomes, and other treatment-related toxicities were analyzed using chi-square tests and Kaplan–Meier survival curves. The incidence of chemotherapy-induced myelosuppression in the SP group was significantly higher than that in the PP group (96.9% vs. 79.6%), with a significantly higher proportion of grade III and above events (37.6% vs. 8.2%, p < 0.05). For chemotherapy-induced neutropenia, the incidence of grade III/IV events in the SP group was significantly higher than in the PP group (28.1% vs. 8.2%, p = 0.017). Additionally, the SP group experienced higher rates and severity of chemotherapy-induced anemia and thrombocytopenia. The PP group provided better protection against grade III/IV leukopenia and neutropenia (p < 0.05). Non-hematological toxicities and efficacy outcomes were similar between groups (p > 0.05). The study is the first to demonstrate that trilaciclib is a safe and effective option for the prevention of myelosuppression in esophageal cancer patients. Full article

Drug repurposing is a strategy to discover new therapeutic uses for existing drugs, which have well-established toxicity profiles and are often more affordable. This approach has gained significant attention in recent years due to the high costs and low success rates associated with traditional drug development. Drug repositioning offers a more time- and cost-effective path for identifying new treatments. Several FDA-approved non-chemotherapy drugs have been investigated for their anticancer potential. Among these, anthelmintic benzimidazoles (such as albendazole, mebendazole, and flubendazole) have garnered interest due to their effects on microtubules and oncogenic signaling pathways. Blood cancers, which frequently develop resistance and have high mortality rates, present a critical need for effective therapies. This review highlights the recent advances in repurposing benzimidazoles for blood malignancies. These compounds induce cell cycle arrest, differentiation, tubulin depolymerization, loss of heterozygosity, proteasomal degradation, and inhibit oncogenic signaling to exert their anticancer effects. We also discuss current limitations and strategies to overcome them, emphasizing the potential of combining benzimidazoles with standard therapies for improved treatment of hematological cancers. Full article

KMT2A (alias: mixed-lineage leukemia [MLL]) gene mapping on chromosome 11q23 encodes the lysine-specific histone N-methyltransferase 2A and promotes transcription by inducing an open chromatin conformation. Numerous genomic breakpoints within the KMT2A gene have been reported in young children and adults with hematologic disorders and are present in up to 10% of acute leukemias. These rearrangements describe distinct features and worse prognosis depending on the fusion partner, characterized by chemotherapy resistance and high rates of relapse, with a progression-free survival of 30–40% and overall survival below 25%. Less intensive regimens are used in pediatric patients, while new combination therapies and targeted immunotherapeutic agents are being explored in adults. Beneficial therapeutic effects, and even cure, can be reached with hematopoietic stem cell transplantation, mainly in young children with dismal molecular lesions; however, delayed related toxicities represent a concern. Herein, we summarize the translocation partner genes and partial tandem duplications of the KMT2A gene, their molecular impact, clinical aspects, and novel targeted therapies. Full article

T-cell malignancies, including T-cell acute lymphoblastic leukemia (T-ALL) and T-cell lymphoblastic lymphoma (T-LBL), present significant challenges to treatment due to their aggressive nature and chemoresistance. Chemotherapies remain a mainstay for their management, but the aggressiveness of these cancers and their associated toxicities pose limitations. Immunepotent CRP (ICRP), a bovine dialyzable leukocyte extract, has shown promise in inducing cytotoxicity against various cancer types, including hematological cancers. In this study, we investigated the combined effect of ICRP with a panel of chemotherapies on cell line models of T-ALL and T-LBL (CEM and L5178Y-R cells, respectively) and its impact on immune system cells (peripheral blood mononuclear cells, splenic and bone marrow cells). Our findings demonstrate that combining ICRP with chemotherapies enhances cytotoxicity against tumoral T-cell lymphoblasts. ICRP + Cyclophosphamide (CTX) cytotoxicity is induced through a caspase-, reactive oxygen species (ROS)-, and calcium-dependent mechanism involving the loss of mitochondrial membrane potential, an increase in ROS production, and caspase activation. Low doses of ICRP in combination with CTX spare non-tumoral immune cells, overcome the bone marrow-induced resistance to CTX cell death, and improves the CTX antitumor effect in vivo in syngeneic Balb/c mice challenged with L5178Y-R. This led to a reduction in tumor volume and a decrease in Ki-67 proliferation marker expression and the granulocyte/lymphocyte ratio. These results set the basis for further research into the clinical application of ICRP in combination with chemotherapeutic regimens for improving outcomes in T-cell malignancies. Full article