Search Results (514)

Background: Atypical teratoid rhabdoid tumor (ATRT) is a highly aggressive, rare pediatric central nervous system malignancy. Prognostic factors for optimizing risk stratification and management in a large uniformly treated cohort are lacking. Methods: We conducted a single-center retrospective cohort study analyzing clinical and outcome data for 100 newly diagnosed ATRT patients aged <18 years treated at the Children’s Cancer Hospital, Egypt, from 2008 to 2022. They were treated uniformly as per the Dana-Farber Cancer Institute modified IRS-III protocol. Molecular subgroups (MYC, SHH, and TYR) were determined via a DNA methylation array for patients who had sufficient DNA material available for the methylation analysis. Treatment toxicities were graded per the Common Terminology Criteria for Adverse Events (CTCAE) v5.0. Results: The median age at diagnosis was 1.88 years (IQR 0.99, 3.01); 28% were under 1 year of age, 45% were between 1 and 3 years old, and 26% were above 3 years of age. At diagnosis, 39% of patients had metastatic disease. A total of 60% of patients had gross residual disease following surgical excision. In multivariable analysis, age < 1 year and metastatic disease had a significant impact on event-free survival (EFS) (p = 0.047 and p = 0.002, respectively); however, only metastatic disease had a significantly negative effect on overall survival (OS) and cumulative incidence of relapse (CIR) (p = 0.002 for OS and p < 0.001 for CIR). DNA methylation was performed for 69 patients who were classified as having a TYR (n = 13), SHH (n = 34), MYC (n = 17), or non-ATRT diagnosis (n = 5). In the cohort of the 64 patients with ATRT defined by methylation, no significant survival differences were observed. Treatment-related deaths were reported in 28% of our studied group. Gram-negative septicemia was the most common cause of toxic death. The 5-year EFS and OS of the whole cohort were 12% and 13%, respectively. Conclusions: In this cohort, no significant survival differences were observed among the methylation subgroups. The higher treatment-related mortality in our cohort compared to the original protocol’s toxic-related deaths suggested that intensive and lengthy chemotherapy regimens may need modification for our population. The need for a short intensified approach, including a limited induction cycle followed by an intensified high-dose consolidation therapy, may be more appropriate for our patients with low socioeconomic status to avoid a repeated and prolonged course of protracted neutropenia. Full article

Background/Objectives: Aeromonas veronii is a significant pathogen affecting aquatic animals and has the potential to infect humans. Vaccination remains the most effective strategy for preventing infections caused by this bacterial strain. Methods: This study aimed to validate the efficacy of bacterial ghosts as an oral vaccine by administering them to Cyprinus carpio and evaluating the resultant innate and acquired immune responses. Following immunization, the vaccinated Cyprinus carpio were exposed to a lethal dose of the wild-type bacterial strain to assess survival rates and relative protection efficiency. Results: Oral vaccination with bacterial ghosts led to the significant enhancement of lysozyme (LZM) and myeloperoxidase (MPO) activity in koi serum. It also resulted in the upregulation of cytokines, such as IL-2 and TNF-α, as well as an increase in both systemic (IgM) and mucosal (IgZs) antibody responses. The immunized group demonstrated reduced cumulative mortality following bacterial challenge. The relative percent survival in the vaccinated group reached as high as 87.50%. Conclusions: The oral immunization of Cyprinus carpio with A. veronii-derived bacterial ghosts confers substantial immune protection, providing a foundational basis for the development of novel vaccines against A. veronii. Full article

Background/Objectives: Carbon-ion radiotherapy (CIRT) offers precise dose distribution and enhanced biological effectiveness in localized prostate cancer. However, the safety of CIRT in patients with a history of surgery for benign prostatic hyperplasia (BPH), such as transurethral resection of the prostate (TURP), remains unclear. This study aimed to evaluate the long-term safety and oncological outcomes of CIRT in this population. Methods: A retrospective analysis was conducted in 74 of 3848 patients with prostate cancer and a history of surgery for BPH who underwent CIRT combined with risk-adapted androgen deprivation therapy between 2007 and 2023. Adverse events were assessed using CTCAE v5.0. Biochemical recurrence-free survival was estimated using the Kaplan–Meier method and risk factors for hematuria with multivariate logistic regression and receiver operation characteristic (ROC) analysis. Results: CIRT was generally well-tolerated. Early Grade 2 genitourinary (GU) adverse events occurred in 5.4% of patients, and late-Grade 2 or higher GU events occurred in 8.1%. The cumulative incidence of Grade 2 ≥ GU events remained 10% at 36 months. Compared to holmium laser enucleation of the prostate, a shorter interval between BPH surgery and CIRT initiation and a history of TURP were independently associated with an increased risk of hematuria. Notably, 5-year bRFS was 100% in low- and intermediate-risk groups and 88.6% in the high-risk group. Conclusions: CIRT demonstrates acceptable oncological outcomes and urinary complication rates in patients with prostate cancer and a history of BPH surgery. These findings suggest that CIRT can be a feasible treatment option in this surgically altered population, but careful patient selection, individualized treatment planning, and long-term follow-up are essential. Given the absence of a non-BPH control group, oncological efficacy should be interpreted with caution. Full article

Pesticides are used in agriculture to protect crops from disease. Among these, the herbicide glyphosate, the insecticide deltamethrin, and the fungicides propamocarb and tebuconazole are approved for use in Europe. These pesticides, along with their metabolites, have been detected in the environment including in food and water sources. Human biomonitoring studies have confirmed the presence of these compounds in biological samples, indicating persistent exposure even among the general population, unrelated to agricultural occupations. Consequently, numerous studies have investigated the health effects of these four pesticides and their metabolites. This review focuses on their impacts on gut health primarily the gut microbiota, inflammation, metabolism, cancer and gut–brain axis. Epidemiological studies were included to assess health risks among various groups including adults, children and pregnant women. Animal and in vitro models have been employed to explore in a more controlled and targeted way the physiological and biochemical effects observed in epidemiological studies. Despite some controversy, pesticides and their metabolites have been linked to gut dysbiosis, inflammatory bowel disease (IBD), metabolic disorders, cancer and neurodevelopmental disorders. Mechanistically, these pesticides influence gut microbiome composition, sugar and lipid metabolism, oxidative stress, inflammatory pathways, cell death, oncogenic signalling pathways, endocrine disruption, and epigenetics. However, further studies are needed to confirm these risks and health impacts, particularly concerning low-dose, long-term exposure as experienced by the general population. A comprehensive investigation of these effects is essential, incorporating dietary factors, age, sex, health status, and the cumulative impact of multiple pesticides, to develop a thorough risk assessment. Full article

Objectives: Oral isotretinoin remains the most effective therapy for severe acne, but its exceptional efficacy is often accompanied by relatively frequent adverse effects. In this study, we quantified the frequency- and dose-related predictors of clinical and biochemical adverse effects during isotretinoin treatment in routine Polish practice. Methods: The records of 370 patients (mean age: 28 ± 12 years) who began isotretinoin treatment between June 2020 and June 2025 were reviewed. The mean daily isotretinoin and cumulative isotretinoin doses were 23.4 ± 9.1 mg and 88.3 ± 31.5 mg/kg, respectively. The adverse events documented at two-monthly visits were correlated with age and dosing. Lipid, hepatic, thyroid and prolactin panels were compared with age- and sex-matched controls using χ² statistics and odds ratios (ORs). Results: Xerosis (70%), retinoid dermatitis (20%) and cheilitis (15.5%) predominated. Hand eczema rose with higher daily isotretinoin doses (ρ = 0.082; p = 0.037), whereas pruritus declined with greater cumulative isotretinoin exposure (ρ = −0.088; p = 0.037). Retinoid dermatitis was linked to a younger age (ρ = −0.080; p = 0.0286), whereas desquamation increased slightly with age (ρ = +0.083 p = 0.0228). Overall, dyslipidemia was twice as common as in the controls (OR: 2.06; 95% CI: 1.49–2.86; p-value: <0.0001), which was driven by an elevated total cholesterol (OR: 1.93; 95% CI: 1.34–2.77; p-value: 0.0004), LDL (OR: 3.40; 95% CI: 2.26–5.10; p-value: <0.0001) and triglycerides (OR: 1.95; 95% CI: 1.20–3.17; p-value: 0.0062) and decreased HDL (OR: 2.68; 95% CI: 1.75–4.10; p-value: <0.0001). Interestingly, hyperprolactinemia occurred eight-fold more often (OR: 8.42; 95%; 95% CI: 2.97–23.84; p-value: <0.00001). Aminotransferase and TSH elevations were infrequent and statistically non-significant. Conclusions: At moderate cumulative doses, isotretinoin was generally well tolerated; however, clinically relevant lipid and prolactin disturbances were frequent. Routine lipid and endocrine monitoring, early emollient prophylaxis and dose individualization are recommended to ensure safe isotretinoin usage in everyday practice. Full article

Childhood cancer treatments, including chemotherapy, radiation therapy, and combined modalities, pose significant risks to auditory function due to their ototoxic effects. Cisplatin, a chemotherapeutic agent commonly used in pediatric oncology, causes dose-dependent irreversible sensorineural hearing loss by damaging the inner ear structures, primarily through the generation of reactive oxygen species and the activation of apoptotic pathways. Radiation therapy exacerbates these effects, contributing to both sensorineural and conductive hearing loss via mechanisms such as vascular injury, inflammation, and fibrosis. The severity of hearing loss is influenced by the treatment timing, the cumulative dose, patient age, genetics, and concurrent therapies. The damaging effects of chemotherapy and radiation extend beyond the cochlea, involving the surrounding temporal bone as well as multiple levels of the auditory pathway. While pediatric patients may be candidates for bone-anchored hearing devices or cochlear implants, the need for serial imaging and the potential for implant-related MRI artifacts can complicate the timing of hearing rehabilitation. Moreover, the impact on the subcortical and cortical auditory structures may further influence the rehabilitation outcomes. This scoping review lays the foundation for future clinical and research efforts focused on the development of comprehensive pediatric guidelines for hearing preservation, monitoring, and rehabilitation, while also fostering multidisciplinary collaboration. Full article

Compound T1089—a novel nitrogen mustard based on an indole-3-carboxylic acid derivative (ICAD)—has been synthesized. The ICAD used as the basis for T1089 is a TLR agonist capable of activating an antitumor immune response. This study describes the synthesis method and presents the results of preliminary investigations of this compound. This research included an assessment of acute toxicity in mice, in vivo clastogenic activity evaluated via the bone marrow chromosome aberration (BMCA) test in mice, in vitro cytotoxicity determined by the MTT assay against human lung carcinoma A549 cells, and in vivo antitumor effects (ATEs) in models of conventional chemotherapy (CCT) of solid tumors in mice. The bifunctional alkylating agent cyclophosphamide (CPA) was used as a reference drug. Toxicological studies revealed that T1089 belongs to toxicity class III (moderately toxic), with acute toxicity values (LD₁₆ and LD₅₀) in mice following intraperitoneal (i.p.) administration being 191 and 202 mg/kg, respectively. The alkylating activity and clastogenic potential of T1089 were demonstrated by its effects in the BMCA test, which were comparable to those of CPA. A single i.p. administration of CPA and T1089 at a dose of 0.064 mmol/kg induced similar stimulation of structural mutagenesis associated with DNA strand breaks. The frequency of karyocytes with aberrations increased 20-fold compared to the control, primarily due to a rise in chromatid breaks and fragments, and to a lesser extent, due to an increase in exchange-type aberrations. In vitro cytotoxicity studies indicated differences in the mechanisms of alkylating activity between CPA and T1089. According to the MTT assay, the cytotoxic effects of CPA were observed only at concentrations exceeding 2 mM (IC₅₀ = 4.2 ± 0.3 mM), corresponding to lethal in vivo doses, which is expected since the formation of CPA’s alkylating metabolite requires hepatic microsomal enzymes. In contrast, significant cytotoxic effects of T1089 were observed at much lower concentrations (15–50 μM, IC₅₀ = 33.4 ± 1.3 μM), corresponding to safe in vivo doses. Differences were also observed in the in vivo ATEs of CPA and T1089 in the Ehrlich solid carcinoma (ESC) CCT model. Following seven i.p. administrations at 48 h intervals (33 mg/kg), both compounds exhibited increasing toxicity, manifested as cumulative body weight loss in treated mice. However, despite the aggressive CCT regimen, ESC showed low sensitivity to CPA. The ATE of CPA developed slowly, reaching a significant level only after four injections, and even after seven administrations, tumor inhibition (TI) did not exceed 30%. In contrast, ESC was significantly more sensitive to T1089 under the same CCT conditions. The ATE of T1089 exhibited a cumulative pattern but developed more rapidly and to a greater extent. A significant antitumor effect was observed after just two injections, with maximal efficacy (TI = 53%) achieved after four injections and sustained until the end of the observation period. A high ATE of T1089 was also observed in the B-16 melanoma CCT model. Following six i.p. administrations at 48 h intervals (28 mg/kg), T1089 treatment was associated with minimal toxicity. Despite this mild CCT regimen, melanoma exhibited high sensitivity to T1089. Maximal ATE (TI = 56%) was achieved after two injections, and subsequent administrations maintained a consistently high efficacy (TI = 52–55%) until the end of the study. In summary, preliminary findings demonstrate that T1089 possesses alkylating activity characteristic of bifunctional agents, accompanied by high in vitro cytotoxicity and in vivo ATEs in CCT models (at high doses). Given that the ICAD used as the basis for T1089 is a TLR agonist capable of stimulating antitumor immunity, T1089 can be considered a dual-action alkylating agent with combined antitumor effects. These results justify further investigation of T1089 in conventional and metronomic chemotherapy regimens, particularly in combination with immune checkpoint inhibitors and antitumor vaccines. Full article

Background/Objectives: Chronic retinal diseases usually require repetitive local dosing. Depending on factors such as dosing frequency, mode of administration, and associated costs, this can result in poor patient compliance. A better alternative involves using controlled-release drug delivery systems to reduce the frequency of intravitreal dosing and extend drug release. However, reaching the market stage is a time-consuming process. Methods: In this study, we employed two computational approaches to model and estimate the parameters governing the diffusion-controlled drug release from bi-layered microspheres. The case study involved microspheres composed of a chitosan core and a polycaprolactone (PCL) shell. The model drugs were bovine serum albumin and bevacizumab (an agent that slows neovascularization due to retinal disorders). Drug release from the microspheres is described by a mathematical model that was solved numerically using the finite difference and the finite element approaches. The parameter estimation was performed by nonlinear least-squares regression. Results: We used the estimated parameters to simulate the cumulative release under various conditions and optimize the device design to guide future experimental efforts and improve the duration of release beyond a target daily therapeutic release rate from the microspheres. Conclusions: We investigated the effects of polymeric layer sizes on drug release and provided recommendations for optimal sizes. We provide straightforward computational tools for others to reuse in designing bi-layered microspheres for intravitreal drug delivery needs in the treatment of chronic ocular neovascularization. Full article

Background: Diagnosing food allergy (FA) typically involves a detailed clinical history and confirmation of allergen-specific IgE. Oral food challenges (OFCs) remain the gold standard in FA diagnosis. This study aimed to present our experience in performing OFCs in pediatric patients with particular focus on challenges performed with cow’s milk and hen’s egg. Methods: We conducted a retrospective analysis of 205 OFCs. Clinical data were evaluated and multiple logistic regression was used to identify associations between challenge outcomes, reaction severity, and comorbidities. Results: The mean age of patients was 5.7 ± 3.1 years, with 135 (65.9%) being male. The tested foods included cow’s milk protein (CMP, 103 challenges; 50.2%), hen’s egg white protein (HEWP, 84; 41.0%), peanuts (3; 1.5%), tree nuts (4; 2.0%), gluten (3; 1.5%), hen’s egg yolk (4; 2.0%), and other foods (4; 2.0%). The overall OFC failure rate was 32.2%, and five challenges (2.4%) yielded inconclusive results. The median cumulative reactive dose was 0.27 g for baked CMP and 0.58 g for baked HEWP. Most failed OFCs involved mucocutaneous symptoms (44 cases; 66.7%). Severe multisystemic reactions occurred in four patients (2.0%), all of whom required epinephrine (6.1% of positive challenges). An increased risk of OFC failure was associated with asthma (p = 0.028; 95% CI: 0.07–1.27) and multi-food allergy (p = 0.021; 95% CI: 0.14–1.67). Additionally, the coexistence of asthma and a prior history of anaphylaxis to any food was related to OFC failure (p = 0.049; 95% CI: 0.01–2.19), as was the combination of multi-food allergy and previous anaphylaxis (p = 0.043; 95% CI: 0.03–1.70). Receiver operating characteristic (ROC) curve analysis was utilized to predict outcomes of OFCs to baked milk and baked egg and determined a specific IgE (sIgE) cutoff level of 58.1 kU/L for baked milk challenges (AUC: 0.77; sensitivity: 0.588; specificity: 0.882), and 11.3 kU/L for baked egg challenges (AUC: 0.66; sensitivity: 0.692; specificity: 0.607). Conclusions: Our findings confirm that OFCs are a safe and effective tool for diagnosing FA in children. With appropriate patient selection, the risk of severe reactions remains low. Nonetheless, comorbidities such as asthma and multi-food allergy are associated with an increased likelihood of OFC failure. Full article

Primary cutaneous lymphomas (PCLs), including cutaneous T-cell lymphomas (CTCL) and primary cutaneous B-cell lymphomas (PCBCL), are a diverse group of non-Hodgkin lymphomas that primarily affect the skin. Radiotherapy (RT) plays a pivotal role in the treatment of these lymphomas, particularly for localized disease, due to its ability to deliver precise, skin-directed treatment. Mycosis fungoides (MF) and Sézary syndrome (SS), the most common subtypes of CTCL, often require skin-directed therapies such as electron beam therapy and superficial brachytherapy to manage localized lesions. Electron beam therapy, including total skin electron beam therapy (TSEBT), has been utilized for decades, offering high response rates but with the risk of cumulative skin toxicity. Recently, low-dose radiotherapy (LDRT) has gained attention as an effective alternative that reduces toxicity while maintaining durable responses. Superficial brachytherapy is another modality that delivers radiation through custom molds, allowing for homogeneous dosing over complex anatomical areas like the face. Both teleradiotherapy and brachytherapy have demonstrated high complete response rates, with low recurrence rates observed when higher doses are used. In the context of primary cutaneous B-cell lymphomas, such as primary cutaneous marginal zone lymphoma (PCMZL) and primary cutaneous follicle center lymphoma (PCFCL), radiotherapy also offers excellent local control, particularly for indolent subtypes. However, more aggressive subtypes, such as diffuse large B-cell lymphoma, leg type (PCDLBCL-LT), may require systemic therapies in addition to radiation. Overall, teleradiotherapy and brachytherapy are essential components of the therapeutic arsenal for primary cutaneous lymphomas, offering effective disease control with manageable toxicity, while ongoing research focuses on optimizing treatment strategies and exploring novel combinations with systemic therapies. Full article

Background: The therapeutic response in Graves’ Disease (GD) remains largely unpredictable. Patients often experience persistent symptoms that are poorly correlated with thyroid hormone levels, an undefined treatment duration, and the need for long-term or definitive therapies. Based on the nuclear antagonistic properties of L-carnitine (LCT) on thyroid hormone action and the immunomodulatory role of selenium (Se), we aimed to assess the impact of adding a combined LCT and Se supplement to standard methimazole (MMI) therapy on the biochemical profile and quality of life (QoL) of patients with overt GD. Methods: This multicenter prospective randomized trial enrolled 60 consecutive patients with newly diagnosed overt GD. Participants were randomized to receive either standard treatment with MMI alone (Control Group) or MMI plus the combined LCT/Se supplement (Intervention Group). TSH, fT3, fT4, and TSH–receptor antibodies (TRAb) levels were evaluated every two months for up to 24 months or until spontaneous remission or definitive therapy. At each visit, patients completed a symptom questionnaire addressing the frequency of typical thyrotoxic symptoms. Results: No significant differences were observed between groups in the trend or time-to-normalization of TSH, fT3, and fT4 levels. However, the Intervention Group reached TRAb negativity significantly earlier (HR = 2.35 (1.14–4.81), p = 0.016), with a synergistic interaction with MMI therapy. MMI requirements were consistently lower in the Intervention Group, both in average dosage (p = 0.013) and cumulative dose (p = 0.020). The rate of spontaneous remission was significantly higher (OR = 11.22 (3.35–46.11), p < 0.001). Overall symptom burden did not differ significantly between groups; however, the supplement exerted an independent effect in reducing the severity of tremor, irritability, mood lability, heat intolerance, and exertional dyspnea. Conclusions: Our findings suggest the clinical benefits of adding combined LCT and Se supplementation to MMI in the treatment of overt GD, including shorter disease duration, lower cumulative MMI exposure and earlier TRAb normality, that could positively influence TRAb-related prognostic outcomes. Full article

Objectives: This study aimed to assess the precision of dose delivery to the target in adaptive carbon ion radiotherapy (CIRT) for locally advanced non-small cell lung cancer (LA-NSCLC) in cumulative dosimetry. Methods: Forty-six patients who received CIRT were included (64 Gy[relative biological effectiveness, RBE] in 16 fractions) with treatment plan computed tomography (CT) and weekly CT scans. Offline adaptive radiotherapy (ART) was administered if the dose distribution significantly worsened. Daily doses were calculated from weekly CTs and integrated into plan CT scans using deformable image registration. The dosimetry parameters were compared between the as-scheduled plan and adaptive replan in patients receiving ART. Survival outcomes and toxicity were compared between the ART and non-ART groups. Results: ART was implemented for 27 patients in whom adaptive replans significantly increased the median V_98% of the clinical tumor volume from 96.5% to 98.1% and D_98% from 60.5 to 62.7 Gy(RBE) compared with the as-scheduled plans (p < 0.001). The conformity and uniformity of the dose distribution improved (p < 0.001), with no significant differences in the doses to normal tissues (lungs, heart, esophagus, and spinal cord) from the as-scheduled plans (p > 0.05). The ART and non-ART groups demonstrated comparable local control, progression-free survival, and overall survival (p > 0.05). No grade 3 or higher radiation-related toxicities were observed. Conclusions: ART enhanced target dose coverage while maintaining acceptable normal tissue exposure, supporting weekly CT monitoring integration during CIRT for the timely intervention for anatomical variations, ensuring precise dose delivery in LA-NSCLC. Full article

Background/Objectives: Propofol and Thiopental are widely used anesthetic agents, yet their cumulative and high-dose effects on hepatic metabolism remain insufficiently characterized. This study aimed to evaluate the impact of supra-therapeutic concentrations of these agents on carnitine and amino acid metabolism in AML12 hepatocytes, with a focus on their toxicometabolic profiles. Methods: AML12 mouse hepatocytes were exposed to escalating concentrations (2.5–500 µg/mL) of Propofol and Thiopental to assess cytotoxicity. IC₅₀ values (~255 µg/mL for both) were determined, and two high-dose concentrations (100 µg/mL and 200 µg/mL) were selected for metabolic profiling. Cell viability was assessed via the MTT assay. Intracellular carnitine and amino acid levels were quantified using LC-MS/MS. Statistical analyses included one-way ANOVA with post hoc tests, unpaired t-tests, and effect size estimations (Cohen’s d). Results: Propofol significantly suppressed carnitine metabolism in a dose-dependent manner, with a 79% reduction in free carnitine (C0), indicative of impaired mitochondrial β-oxidation. Thiopental, however, preserved or partially restored several acylcarnitines, including C16:1. While both agents reduced intracellular amino acid levels, 200 µg/mL Thiopental partially restored key metabolites such as glutamine, alanine, and histidine. Propofol exhibited broader metabolic suppression. Effect size analysis further confirmed the stronger inhibitory impact of Propofol. Conclusion: Although the concentrations used exceed typical clinical plasma levels, they may reflect prolonged or high-dose exposure scenarios observed in ICU settings. The findings highlight distinct toxicometabolic signatures for each agent and underscore the utility of metabolite profiling in modeling anesthetic-induced hepatic stress and guiding anesthetic selection in vulnerable populations. Full article

This report presents the case of a seven-year-old West Highland White Terrier diagnosed with relapsed and refractory multiple myeloma (MM), managed using multiple treatment approaches, including conventional chemotherapy (melphalan, vincristine, doxorubicin, and dexamethasone), radiation therapy (RT), and novel agents such as the selective inhibitor of nuclear export (verdinexor), proteasome inhibitors (bortezomib, carfilzomib, and ixazomib), and tyrosine kinase inhibitors (TKIs; toceranib and sorafenib). Treatment response was monitored using serum globulin concentration and imaging studies. Verdinexor achieved the longest period of stable remission with minimal toxicity post-RT. Bortezomib + dexamethasone was effective in controlling hyperglobulinemia at doses ≥ 1.45 mg/m², although cumulative hematologic and gastrointestinal toxicity limited its prolonged use. Second-line proteasome inhibitors and TKIs demonstrated limited efficacy. Despite initial therapeutic response, the patient’s condition deteriorated due to persistent hyperglobulinemia and hyperviscosity syndrome. The absence of advanced supportive options, including plasmapheresis, contributed to a fatal outcome. This case highlights the potential utility of novel therapies such as verdinexor and bortezomib in managing refractory canine MM. Timely intervention, individualized dosing, and supportive care are essential for optimizing treatment outcomes. Further research is required to define effective combinations and integrate advanced care options, including stem cell transplantation and targeted antibody therapies, in veterinary MM. Full article

Doxorubicin (Dox) is a potent anthracycline antitumor drug whose clinical utility is significantly restricted by its dose-dependent, cumulative cardiotoxicity, driven by increased oxidative stress, impaired antioxidant defenses, and apoptosis-mediated cardiomyocyte loss. Methylene blue (MB), a phenothiazine derivative with well-documented redox-modulating properties, is being explored as a viable cardioprotective agent due to its antioxidant and anti-apoptotic effects. This study evaluated the protective role of MB against Dox-induced cardiotoxicity in rats by examining its impact on oxidative stress markers (Kelch-like ECH-associated protein 1; KEAP1, nuclear factor erythroid 2-related factor 2; NRF2, Glutathione peroxidase 4; GPX-4, 8-hydroxy-2′-deoxyguanosine; 8-OHdG), neurohormonal indicators (noradrenaline), cardiac injury biomarkers (troponin I), and apoptotic mediators (p53, Caspase-3). Forty male albino rats were divided equally into four groups: control, Dox (15 mg/kg, i.p.), MB alone (4 mg/kg/day, p.o. for 7 days), and Dox plus MB. Dox administration significantly increased serum troponin I and noradrenaline levels, elevated cardiac KEAP1 and 8-OHdG, and reduced NFE2L2, NRF2, and GPX-4 expression. It also upregulated p53 and Caspase-3 and caused marked myocardial degeneration, necrosis, and inflammatory infiltration. MB co-treatment significantly reduced troponin I and noradrenaline levels, restored KEAP1/NFE2L2 (NRF2)/GPX-4 pathway balance, decreased oxidative DNA damage, and attenuated p53 and Caspase-3 activation, preserving myocardial architecture with minimal inflammatory changes. These findings demonstrate that MB confers potent cardioprotection against Dox-induced cardiac injury by enhancing antioxidant defenses, limiting oxidative DNA damage, suppressing apoptosis, and normalizing neurohormonal imbalance, suggesting its promise as an adjunctive strategy to mitigate anthracycline-associated cardiotoxicity. Full article