Search Results (722)

Background: β-site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitors demonstrated amyloid-lowering efficacy but failed in phase II/III clinical trials due to adverse effects and limited disease-modifying outcomes. This study employed an integrated network pharmacology and molecular docking approach to quantitatively elucidate the multitarget mechanisms of 4 (phase II/III) discontinued BACE1 inhibitors (Verubecestat, Lanabecestat, Elenbecestat, and Umibecestat) and the preclinical compound AM-6494 in Alzheimer’s disease (AD). Methods: Drug-associated targets were intersected with AD-related genes to construct a protein–protein interaction (PPI) network, followed by topological analysis to identify hub proteins. Gene Ontology (GO) and KEGG pathway enrichment analyses were performed using statistically significant thresholds (p < 0.05, FDR-adjusted). Molecular docking was conducted using AutoDock Vina to quantify binding affinities and interaction modes between the selected compounds and the identified hub proteins. Results: Network analysis identified 10 hub proteins (CASP3, STAT3, BCL2, AKT1, MTOR, BCL2L1, HSP90AA1, HSP90AB1, TNF, and MDM2). GO enrichment highlighted key biological processes, including the negative regulation of autophagy, regulation of apoptotic signalling, protein folding, and inflammatory responses. KEGG pathway analysis revealed significant enrichment in the PI3K–AKT–MTOR signalling, apoptosis, and TNF signalling pathways. Molecular docking demonstrated strong multitarget binding, with binding affinities ranging from approximately −6.6 to −11.4 kcal/mol across the hub proteins. Umibecestat exhibited the strongest binding toward AKT1 (−11.4 kcal/mol), HSP90AB1 (−9.5 kcal/mol), STAT3 (−8.9 kcal/mol), HSP90AA1 (−8.5 kcal/mol), and MTOR (−8.3 kcal/mol), while Lanabecestat showed high affinity for AKT1 (−10.6 kcal/mol), HSP90AA1 (−9.9 kcal/mol), BCL2L1 (−9.2 kcal/mol), and CASP3 (−8.5 kcal/mol), respectively. These interactions were stabilized by conserved hydrogen bonding, hydrophobic contacts, and π–alkyl interactions within key regulatory domains of the target proteins, supporting their multitarget engagement beyond BACE1 inhibition. Conclusions: This study demonstrates that clinically failed BACE1 inhibitors engage multiple non-structural regulatory proteins that are central to AD pathogenesis, particularly those governing autophagy, apoptosis, proteostasis, and neuroinflammation. The identified ligand–hub protein complexes provide a mechanistic rationale for repurposing and optimization strategies targeting network-level dysregulation in Alzheimer’s disease, warranting further in silico refinement and experimental validation. Full article

Background: Non-absorbable polyvinyl alcohol sponges (Merocel) are widely used in otolaryngology for nasal and ear packing but are prone to bacterial colonization and biofilm formation, which may increase infection risk and drive frequent use of systemic antibiotics. Sustained-release drug delivery systems enable prolonged local antiseptic activity at the site of packing while minimizing systemic exposure. Methods: We developed a sustained-release varnish containing chlorhexidine (SRV-CHX) and coated sterile Merocel sponges. Antibacterial, in vitro, activity against Staphylococcus aureus and Pseudomonas aeruginosa was evaluated using kinetic diffusion assays on agar, optical density (OD₆₀₀) measurements of planktonic cultures, drop plate, ATP-based viability assays, biofilm analysis by MTT metabolic assay, crystal violet bio-mass staining, high-resolution scanning electron microscopy (HR-SEM), and spinning disk confocal microscopy. Results: SRV-CHX-coated sponges produced sustained zones of inhibition on agar plates for up to 37 days against S. aureus and 39 days against P. aeruginosa, far exceeding the usual 3–5 days of clinical sponge use. Planktonic growth was significantly reduced compared with SRV-placebo, and a bactericidal effect persisted for up to 16 days for S. aureus and 5 days for P. aeruginosa before becoming predominantly bacteriostatic. Biofilm formation was markedly inhibited, with suppression of metabolic activity and biomass for at least 33 days for S. aureus and up to 16 days for P. aeruginosa. HR-SEM and confocal imaging confirmed sparse, discontinuous biofilms and predominance of non-viable bacteria on SRV-CHX-coated sponges compared with dense, viable biofilms on the placebo controls. Conclusions: Coating Merocel sponges with SRV-CHX provides prolonged antibacterial and anti-biofilm activity against clinically relevant pathogens. This strategy may reduce dependence on systemic antibiotics and improve infection control in nasal and ear packing applications in otolaryngology. Full article

Background: Tumor necrosis factor-α (TNFα) inhibitors have significantly improved outcomes in children with non-systemic juvenile idiopathic arthritis (JIA), achieving long-term clinical remission for many patients. However, the optimal strategy for TNF-α inhibitor withdrawal remains unknown, whether through abrupt discontinuation, gradual dose reduction, or interval extension. Objective: We aim to identify patient-, disease-, and treatment-related predictors of successful TNF-α inhibitor withdrawal in children with non-systemic JIA. Methods: In this prospective, randomized, open-label, single-center study, 76 children with non-systemic JIA in stable remission for ≥24 months on etanercept or adalimumab were enrolled. At the time of TNF-α inhibitor discontinuation, all patients underwent a comprehensive evaluation, including a clinical examination, laboratory tests (serum calprotectin [S100 proteins] and high-sensitivity C-reactive protein [hsCRP]), and advanced joint imaging (musculoskeletal ultrasound and magnetic resonance imaging [MRI]) to assess subclinical disease activity. Patients were randomized (1:1:1, sealed-envelope allocation) to one of three predefined tapering strategies: (I) abrupt discontinuation; (II) extension of dosing intervals (etanercept 0.8 mg/kg every 2 weeks; adalimumab 24 mg/m² every 4 weeks); or (III) gradual dose reduction (etanercept 0.4 mg/kg weekly; adalimumab 12 mg/m² every 2 weeks). Follow-up visits were scheduled at 3, 6, 9, 12, and 18 months to monitor for disease relapse. Results: Higher baseline Childhood Health Assessment Questionnaire (CHAQ) scores (≥2), elevated serum calprotectin [S100 proteins] and hsCRP levels at withdrawal, imaging evidence of subclinical synovitis, and a history of uveitis were all significantly associated with increased risk of flare. No significant associations were found for other clinical or demographic characteristics. Conclusions: Early significant clinical response, absence of subclinical disease activity, and concomitant low-dose methotrexate therapy were key predictors of sustained drug-free remission. These findings may inform personalized strategies for biologic tapering in pediatric JIA. Full article

Background/Objectives: There is limited data regarding the association of anti-drug antibody (ADA) levels with the efficacy of anti-tumor necrosis factor (anti-TNF) therapy in patients with inflammatory bowel disease (IBD). We aimed to investigate the association between antibody to adalimumab (ATA) and antibody to infliximab (ATI) levels and treatment failure in IBD. Methods: This single-center, retrospective cohort study included consecutive IBD patients with ADA evaluated with a drug-tolerant assay between September 2012 and February 2023. A time-to-event analysis was performed for treatment failure, defined as the need for drug discontinuation due to primary non-response, loss of response, a serious adverse event, or an IBD-related surgery. Patients were followed from first positive ADA until treatment failure or the end of the follow-up (May 2024). Results: The study population consisted of 134 patients with IBD [n = 58 (43%) on adalimumab; n = 86, (64%) with Crohn’s disease]. Multiple COX regression analysis identified higher ADA levels to be associated with treatment failure (HR: 1.034, 95%CI: 1.024–1.045, p < 0.001). A ROC analysis identified an ATA and ATI level threshold of 5.2 U/mL (AUC: 0.705; 95%CI: 0.569–0.841; p = 0.003; sensitivity: 64%; specificity: 82%) and 8.8 U/mL (AUC: 0.809; 95%CI: 0.713–0.906; p < 0.001; sensitivity: 69%; specificity: 93%), respectively, to distinguish patients with or without treatment failure. Conclusions: In this large retrospective cohort study, higher levels of ADA were associated with treatment failure to anti-TNF therapy in IBD. Moreover, we identified ATA and ATI level thresholds of 5.2 U/mL and 8.8 U/mL, respectively, to be associated with treatment failure. Full article

Osteoporosis is a prevalent skeletal disorder characterized by reduced bone mass and microarchitectural deterioration, leading to increased fracture risk, particularly in aging populations. Postmenopausal osteoporosis (PMOP) remains the most common primary form and results from abrupt estrogen deficiency after menopause, which disrupts bone remodeling by accelerating the receptor activator of nuclear factor-κB ligand (RANKL)-mediated osteoclastogenesis, suppressing Wnt/β-catenin signaling, and promoting inflammatory cytokine production. In contrast, drug-induced osteoporosis (DIOP) encompasses a heterogeneous group of secondary bone disorders arising from pharmacologic exposures. Glucocorticoids suppress osteoblastogenesis, enhance osteoclast activity, and increase reactive oxygen species; long-term bisphosphonate therapy may oversuppress bone turnover, resulting in microdamage accumulation; denosumab withdrawal triggers a unique rebound surge in RANKL activity, often leading to rapid bone loss and multiple vertebral fractures. Medications including aromatase inhibitors, SSRIs, proton pump inhibitors, heparin, and antiepileptic drugs impair bone quality through diverse mechanisms. Standard antiresorptive agents remain first-line therapies, while anabolic agents such as teriparatide, abaloparatide, and romosozumab provide enhanced benefits in high-risk or drug-suppressed bone states. Transitional bisphosphonate therapy is essential when discontinuing denosumab, and individualized treatment plans—including drug holidays, lifestyle interventions, and monitoring vulnerable patients—are critical for optimizing outcomes. Emerging approaches such as small interfering RNA (siRNA)-based therapeutics, anti-sclerostin agents, digital monitoring technologies, and regenerative strategies show promise for future precision medicine management. Understanding the distinct and overlapping molecular mechanisms of osteoporosis is essential for improving fracture prevention and long-term skeletal health. Full article

Background/Objectives: Patients with moderate-to-severe psoriasis who experience inadequate response or loss of efficacy to multiple biologic agents (“multi-failure patients”) represent a particularly challenging subgroup in clinical practice. Evidence regarding the efficacy of bimekizumab in this setting is still limited. This multicentre, real-life study aimed to evaluate the effectiveness, safety, and treatment persistence of bimekizumab in patients with moderate-to-severe psoriasis who had failed at least two previous biologic therapies. Methods: This multicentre, retrospective, real-life study across Italian referral centers retrospectively collected clinical data from 33 adult patients with plaque psoriasis treated with bimekizumab across Italian referral centers. Efficacy was assessed through changes in Psoriasis Area and Severity Index (PASI) and Dermatology Life Quality Index (DLQI) scores at weeks 4 and 16. Logistic regression was performed to identify predictors of treatment response, and Kaplan–Meier analysis evaluated drug survival up to 12 months. Results: The mean baseline PASI was 14.5 ± 7.1, decreasing to 1.5 ± 4.0 at week 16 (p < 0.001). PASI90 and PASI100 responses were achieved by 57.6% and 42.4% of patients at this timepoint, respectively, while mean DLQI improved by 84.2%. In this small cohort, no significant differences in efficacy were observed according to the number or class of prior biologic failures. Genital psoriasis was associated with a lower likelihood of achieving PASI100. Adverse events were generally mild to moderate in severity and manageable in routine clinical practice. No discontinuations occurred due to lack of efficacy; all withdrawals were related to mild adverse events or personal reasons. Twelve-month drug survival reached 85.4% (95% CI 63.8–100). Conclusions: Bimekizumab demonstrated rapid, marked, and sustained clinical improvements with a favorable safety profile in multi-failure psoriasis patients. These findings support its role as an effective and well-tolerated therapeutic option for individuals with highly refractory disease in real-life practice. Full article

Pembrolizumab, an anti-PD-1 monoclonal antibody, showed promising results in the treatment of different types of solid tumors and generally an improvement in overall survival and patients’ outcome. However, as a drug that targets the immune system to enhance the anti-tumor response, it simultaneously increases the risk of autoimmune reactions, producing immune-related adverse events (irAEs). These irAEs might involve any body organ, and in some cases may lead to treatment discontinuation. In this article, we discuss two cases of triple-negative breast cancer (TNBC) patients, who developed irAEs during the course of neoadjuvant pembrolizumab, highlighting the mechanism of the reactions, possible clinical manifestations, and potential management. Full article

Inflammatory bowel disease is a result of inappropriate continuous non-specific inflammation in the intestinal tract, which in turn is aggravated by defects in the activation of the mucosal immune system and in the barrier function of the intestinal epithelium. The most prominent manifestations of IBD are ulcerative colitis (UC) and Crohn’s disease (CD). UC is characterized by a continuous pattern that commonly starts with lesions in rectum mucosa and is contained in the colon. On the other hand, CD affects the ileum and colon in a discontinuous pattern, and the lesions are often transmural. Conventional therapies often face limitations such as systemic side effects, poor drug stability, and low site-specificity. In recent years, nanoparticle (NP) systems have emerged as a promising strategy to overcome these challenges, offering improved targeting, controlled release, and enhanced therapeutic efficacy. Several studies have shown that the preferential accumulation of NPs in the inflamed colon is influenced by the pathophysiological changes associated with IBD, including alterations in transit time, pH value, enzymatic activity, microbial composition, and mucus integrity. These disease-specific characteristics provide unique opportunities to design smart and responsive NPs that enhance drug delivery and therapeutic efficacy while minimizing systemic exposure. This work presents an overview of novel technologies based on nanosystems, with the ability to specifically target the affected areas of the GI tract in inflammatory bowel disease. Full article

Background/Objectives: Despite therapeutic advances, managing relapsed/refractory multiple myeloma (RRMM) remains challenging. For patients with frailty, comorbidities, mobility limitations, or when treatment preference and drug accessibility are key considerations, the all-oral ixazomib–lenalidomide–dexamethasone (IRd) regimen offers a practical alternative. Methods: We performed a multicenter retrospective study of RRMM patients treated with IRd in Hungary between 1 January 2020 and 30 June 2025. Results: The median age at treatment initiation was 73.7 years. Treatment was initiated for clinical progression in 38.2%, biochemical progression in 53.3%, and for intolerance or toxicity of prior therapy in 8.6%. Median progression-free survival (PFS) was 18.7 months, and median overall survival (OS) was 34.7 months. Patients treated at biochemical progression had significantly longer PFS than those treated at clinical progression (24.3 vs. 15.6 months; p = 0.004), with additional benefit when IRd was initiated owing to intolerance or toxicity of previous therapy (p = 0.04). In the second-line setting, median PFS was 24.5 months, and median OS was not reached. Adverse events occurred in 68.3% of patients; dose reductions were required in 18.4%, and 21.6% discontinued treatment because of intolerance or toxicity. Most common toxicities were neutropenia (32.9%), thrombocytopenia (27.6%), diarrhoea (25%), peripheral neuropathy (25.3%), and infections (22.4%). Conclusions: IRd initiation at biochemical progression was associated with superior PFS compared with treatment at clinical progression. When compared with a recent Hungarian multicenter cohort treated with second-line daratumumab, lenalidomide, and dexamethasone, outcomes with IRd are not significantly inferior (36-month OS calculated from 2nd line treatment initiation: 65.5% for DRd vs. 60% in our cohort; p = 0.56). These real-world data support IRd as an effective, convenient, all-oral option for appropriately selected RRMM patients. Full article

Background: Type 2 diabetes mellitus (T2DM) is often associated with hyperuricemia, both conditions worsening kidney function. Sodium–glucose cotransporter 2 (SGLT2) inhibitors improve glycemic control and kidney function; however, data on their long-term antihyperuricemic effects in real-world clinical settings remain limited. Therefore, we aimed to compare the effects of SGLT2 inhibitors versus allopurinol on serum uric acid (sUA), kidney function, and clinical outcomes. Methods: This retrospective cohort study evaluated patients with T2DM and hyperuricemia initiated on 10 mg empagliflozin (n = 70), 10 mg dapagliflozin (n = 78), or 100 mg allopurinol (n = 66) between 1 January 2017, and 1 January 2020. Drug dosages were kept constant throughout the study. Baseline and follow-up data (3, 6, 12, 24, and 36 months) were collected. Results: Over 36 months, empagliflozin and dapagliflozin significantly reduced sUA (from 452 (95) to 399 (69) µmol/L and from 450 (81) to 364 (71) µmol/L, respectively) and stabilized eGFR without a significant decline. Allopurinol also reduced sUA (from 430 (89) to 345 (69) µmol/L) but was associated with a progressive eGFR decline (from 70 (35) to 57 (32) mL/min/1.73 m²). Mortality was the highest in the allopurinol group; however, therapy discontinuation was the lowest with this treatment. Conclusions: SGLT2 inhibitors achieved comparable sUA reduction to allopurinol by 36 months while preserving eGFR. Allopurinol was associated with higher mortality and hospitalization rates; SGLT2 inhibitor therapy was associated with favorable multidomain outcomes, but strategies to address adverse effects are needed to enhance adherence. Full article

Background/Objectives: Lanadelumab is approved in the EU for long-term HAE prevention in patients aged ≥2 years. While trials show high efficacy, real-world data on reimbursement and outcomes are limited. This study presents real-world clinical results in Poland and compares reimbursement criteria across European countries, assessing how effectiveness influences access restrictions. Methods: This retrospective analysis examined patients in the Polish drug program for lanadelumab. It collected demographics, disease features, attack frequency, and rescue medication use before and after at least six months of treatment. Additionally, a review of European reimbursement policies was conducted using health technology assessments, policy documents, and literature. Results: The data of 72 patients with HAE with C1 inhibitor deficiency were analyzed. The median follow-up was 20.0 months (IQR 15.0–25.0). The median baseline attack frequency was 15 over 6 months. After 6 months of lanadelumab, attacks dropped to 0 (IQR 0.0–0.0; p < 0.001), with 77.8% achieving >90% reduction. Most remained attack-free beyond 6 months; on-demand medication use decreased from 16 to 0 doses (p < 0.001). Outcomes persisted beyond 6 months. No demographic or baseline variables predicted response. No discontinuations due to adverse events. Reimbursement criteria across Europe vary, from broad access to restrictions based on attack frequency or treatment response, with differences in care settings. Conclusions: Data from Poland confirm lanadelumab nearly eliminates severe HAE attacks in practice, regardless of attack frequency. Some European reimbursement models may exclude patients who could benefit. Using real-world effectiveness evidence in policies could improve access and outcomes for HAE patients. Full article

Background: Ticagrelor is a reversible, direct inhibitor of the platelet adenosine diphosphate (P2Y12) receptor, widely used in combination with acetylsalicylic acid (ASA) as dual antiplatelet therapy (DAPT) in patients with acute coronary syndrome (ACS) to prevent cardiovascular events. Despite its well-established efficacy, ticagrelor may cause adverse effects ranging from common ones (e.g., bleeding, dyspnea) to rare but potentially serious reactions such as bradyarrhythmias. These rare events are likely related to elevated adenosine levels secondary to inhibition of the human equilibrative nucleoside transporter 1 (hENT1). Methods: We describe two clinical cases of ticagrelor-associated bradyarrhythmia observed in patients following ACS. Both cases were analyzed in terms of clinical presentation, ECG findings, management strategy, and outcomes after discontinuation of the drug. Results: The first case concerns a 67-year-old woman with non-ST-segment elevation myocardial infarction (NSTEMI) who developed complete atrioventricular block (third degree) with a 45 s asystolic pause and syncope. The second case involves a 67-year-old man with anterior ST-segment elevation myocardial infarction (STEMI) who experienced recurrent sinus pauses lasting up to 5 s. In both cases, symptoms resolved following ticagrelor discontinuation and theophylline administration. No recurrence of arrhythmia was observed after switching to prasugrel. Conclusions: Ticagrelor-induced bradyarrhythmias, although rare, represent an important and reversible adverse effect that clinicians should be aware of, particularly during the early post-ACS phase. Prompt recognition and drug withdrawal may prevent severe outcomes and avoid unnecessary interventions such as pacemaker implantation. Further studies are warranted to identify patient-specific risk factors predisposing to ticagrelor-related conduction disturbances. Full article

Advection–diffusion–reaction-type interface models have wide-ranging applications in environmental science, chemical engineering, and biological systems, particularly in modeling pollutant transport in groundwater, reactive flows, and drug diffusion across biological membranes. This paper presents a novel numerical method for the solution of these models. The proposed method integrates the meshless collocation technique with the finite difference method. The temporal derivative is approximated using a finite difference scheme, while spatial derivatives are approximated using radial basis functions. The interface across the fixed boundary is treated with discontinuous diffusion, advection, and reaction coefficients. The proposed numerical scheme is applied to both linear and non-linear models. The Gauss elimination method is used for the linear models, while the quasi-Newton linearization method is employed to address the non-linearity in non-linear cases. The $L_{\infty }$ error is computed for varying numbers of collocation points to assess the method’s accuracy. Furthermore, the performance of the method is compared with the Haar wavelet collocation method and the immersed interface method. Numerical results demonstrate that the proposed approach is more efficient, accurate, and easier to implement than existing methods. The technique is implemented in MATLAB R2024b software. Full article

Background/Objectives: AXL, a receptor tyrosine kinase of the TAM family, has emerged as a key target in cancer therapy due to its role in tumour growth, metastasis, immune evasion, and therapy resistance. SLC-391, a novel, orally bioavailable and selective AXL inhibitor, has demonstrated potent anti-tumour effects in preclinical studies. This first-in-human, open-label, multi-centre Phase I clinical trial (NCT03990454) was conducted to evaluate the safety, tolerability, pharmacokinetics (PK), and preliminary efficacy of SLC-391 in patients with advanced solid tumours. Methods: Using a 3 + 3 design, SLC-391 was administered orally, either once daily (from 25 mg up to 175 mg QD) or twice daily (from 75 mg to 200 mg BID) in 21-day cycles. Results: Following single and repeated dosing, SLC-391 was generally well tolerated by subjects. The maximum tolerated dose (MTD) was not reached in this study. A total of 34/35 subjects experienced at least one TEAE. Three (8.6%) subjects experienced Grade 3 TRAEs that were considered related to SLC-391. Eight SAEs were reported in five (14.3%) subjects (seven Grade 3 SAEs and one Grade 2 SAE), in 150 mg QD (3/6, 50%), 175 mg QD (1/2, 50%), and 110 mg BID (1/3, 33.3%) cohorts. Four SAEs in three (8.6%) subjects led to dose interruption, drug withdrawal, or study discontinuation. Three DLTs were reported in two subjects: one subject experienced Grade 3 hematochezia (SUSAR/DLT) at 175 mg QD, and another subject experienced Grade 3 thrombocytopenia associated with Grade 1 hematuria at 200 mg BID. The median T_max was 2.0 h. Plasma concentrations following multiple doses generally increased with higher doses and appeared to reach steady state by Day 21 and were generally dose-proportional. Twelve (12) out of 35 subjects with solid tumours achieved stable disease according to RECIST or mRECIST (mesothelioma), with durations of stable disease lasting up to 318 days on SLC-391 monotherapy. The clinical benefit rate was 34.3%. Conclusions: This first study of SLC-391 in adult subjects with advanced solid tumours demonstrated that a total daily dose of 300 mg (150 mg BID) of SLC-391 monotherapy was generally well tolerated, with no DLTs or SAEs observed at this dose. The drug’s promising safety profile, along with stable disease reported for several subjects with advanced solid tumours, provides a strong rationale for the phase 1b/2a clinical investigation of SLC-391 in combination with pembrolizumab in subjects with advanced or metastatic non-small cell lung cancer (NSCLC) (NCT05860296). Full article

Background and Clinical Significance: Tyrosine kinase inhibitors (TKIs) have transformed Philadelphia chromosome-positive chronic myeloid leukemia (Ph+ CML) into a largely manageable chronic disease. However, off-target toxicities are increasingly recognized; rarer complications such as bone marrow edema (BME) remain underreported. BME is a radiological syndrome characterized by excess intramedullary fluid on fat-suppressed T2/STIR magnetic resonance imaging sequences and may progress to irreversible osteochondral damage if unrecognized. We report a case series of TKI-associated BME and propose a practical diagnostic-therapeutic framework. Case Presentation: We describe three patients with Ph+ CML who developed acute, MRI-confirmed BME of the lower limb during TKI therapy. Case 1 developed unilateral then bilateral knee BME, temporally associated first with dasatinib and subsequently with imatinib; symptoms improved after TKI interruption, bisphosphonate therapy, and supportive measures, and did not recur after switching to bosutinib. Case 2 presented with proximal femoral BME during long-term imatinib; imatinib was stopped, intravenous neridronate administered, and bosutinib initiated with clinical recovery and later near-complete radiological resolution. Case 3 experienced multifocal foot and ankle BME during imatinib; symptoms resolved after drug discontinuation and bisphosphonate therapy, and disease control was re-established with bosutinib without recurrence of BME. All patients underwent molecular monitoring and mutational analysis to guide safe therapeutic switching. Discussion: Temporal association across cases and the differential kinase profiles of implicated drugs suggest PDGFR (and to a lesser extent, c-KIT) inhibition as a plausible mechanistic driver of TKI-associated BME. PDGFR-β blockade may impair pericyte-mediated microvascular integrity, increase interstitial fluid extravasation, and alter osteoblast/osteoclast coupling, promoting intramedullary edema. Management combining MRI confirmation, temporary TKI suspension, bone-directed therapy (bisphosphonates, vitamin D/calcium), symptomatic care, and, when required, therapeutic switching to a PDGFR-sparing agent (bosutinib) led to clinical recovery and preservation of leukemia control in our series. Conclusions: BME is an underrecognized, potentially disabling, TKI-related adverse event in CML. Prompt recognition with targeted MRI and a multidisciplinary, stepwise approach that includes temporary TKI adjustment, bone-directed therapy, and consideration of PDGFR-sparing alternatives can mitigate morbidity while maintaining disease control. Prospective studies are needed to define incidence, risk factors, optimal prevention, and management strategies. Full article