AIMS:This study aimed to identify and characterize drugs disproportionately associated with central nervous system vasculitis (CNSV) and reversible cerebral vasoconstriction syndrome (RCVS) in VigiBase, the World Health Organization (WHO) global pharmacovigilance database, and to describe their pharmacological and temporal profiles. METHODS:We conducted a case-non-case study in VigiBase, the WHO global pharmacovigilance database (extract June 2025). Both unadjusted and adjusted reporting odds ratios (aROR) were estimated, the latter using multivariate logistic regression accounting for age, sex, geographic region and reporting characteristics. Time-to-onset, dechallenge outcomes and fatality rates were also analysed. RESULTS:We identified 735 CNSV cases and 1553 RCVS cases. CNSV was predominantly associated with immune checkpoint inhibitors (pembrolizumab and nivolumab) and antithyroid drugs (propylthiouracil), with a median time-to-onset of 35.50 days (interquartile range [IQR] 7.75-123.25). RCVS was primarily associated with serotonergic and vasoactive agents (triptans, ergot derivatives, selective serotonin reuptake inhibitors [SSRIs] and cannabis), with a markedly shorter onset of 8.75 days (IQR 3.25-52.88). The strongest RCVS signal was a novel association with teprotumumab, an insulin-like growth factor-1 receptor (IGF-1R) inhibitor approved for thyroid eye disease (6 cases; aROR 60.17, 95% confidence interval [CI] 18.66-194.05). Female sex was independently associated with RCVS (aROR 2.57, 95% CI 2.23-2.97). CONCLUSIONS:Drug-associated CNSV and RCVS exhibit distinct pharmacological and temporal profiles, which may help inform drug withdrawal decisions and optimal management of these neurovascular emergencies.
BACKGROUND:Radiation-induced dermatitis (RID) is an important side effect that occurs in 95% of patients receiving radiation therapy. The purpose of this study was to evaluate the efficacy and safety of alpha lipoic acid (ALA) in preventing RID in breast cancer patients. METHODS:In this randomized-controlled, single-blinded trial, 40 patients with breast cancer who were scheduled for radiotherapy were randomly allocated to ALA group (n = 20) who received 300 mg ALA three times daily starting at the first day of radiotherapy for 3 weeks or control group (n = 20) who did not receive any prophylaxis for RID. Primary outcomes were the incidence and severity of RID using Radiation Therapy Oncology Group (RTOG) grading criteria. Secondary outcomes were maximum grade of RID and changes in serum concentrations of interleukin-6 (IL-6). RESULTS:In ALA group, 90% and 60% of patients remained asymptomatic at the end of the second and third weeks of radiotherapy compared to 50% and 20%, respectively, in the control group. Moreover, only 10% of patients in ALA group developed ≥ grade 2 RID compared to 45% in control. A significant reduction in the serum levels of IL-6 was observed in the ALA group at the end of the study compared to control (p = 0.044). ALA was safe and well-tolerated. CONCLUSION:Prophylactic administration of ALA significantly delayed the onset and reduced the severity of RID besides its anti-inflammatory effect in breast cancer patients.
AIMS:Conventional pharmacovigilance identifies drug-event reporting signals but not heterogeneity among anti-HER2 cardiac dysfunction reports. We benchmarked this association using disproportionality analysis and assessed whether report-level clustering added information beyond cardiovascular co-reporting. METHODS:We analysed OpenVigil/FAERS data. A separate openFDA analysis estimated overall, individual-drug and drug-group reporting odds ratios (RORs) and proportional reporting ratios (PRRs). The clustering cohort comprised 589 unique reports, grouped by cardiovascular co-reporting and clustered using Gower distance-based partitioning around medoids. Severe outcome comprised death, hospitalization, life-threatening events or disability. Multivariable logistic regression and a nested likelihood-ratio test compared conventional and cluster-based models. RESULTS:Echocardiography-related cardiac dysfunction was disproportionately reported with anti-HER2 therapies overall (ROR 26.64, 95% CI 25.61-27.71; PRR 25.95, 95% CI 24.97-26.96) and across evaluated drugs and groupings. Among 589 reports, 383 (65.0%) had dysfunction only and 206 (35.0%) had cardiovascular co-reporting; severe outcomes occurred in 17.5% and 41.7%, respectively (adjusted OR 3.24, 95% CI 2.14-4.95). Five clusters were retained. The LV dysfunction with cardiovascular co-reporting cluster had the highest severe outcome proportion (52.0%) and higher adjusted odds than the ADC-associated EF-decline cluster (adjusted OR 4.18, 95% CI 1.55-11.68). Adding the cluster term improved model fit (χ2 = 11.34; p = 0.023). CONCLUSIONS:Conventional analyses confirmed a strong anti-HER2 reporting signal and an association between cardiovascular co-reporting and severe outcomes. The retained clusters added complementary report-level resolution without constituting a validated clinical classification or prediction tool.
BACKGROUND:Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) have substantially improved outcomes in non-small cell lung cancer (NSCLC); however, the development of treatment resistance remains a major clinical challenge. This study examines the association between concomitant prescriptions of H1-antihistamines (H1AHs) and clinical outcomes in NSCLC patients undergoing EGFR-TKIs therapy. METHODS:We conducted a retrospective cohort study using the Taipei Medical University Clinical Research Database (TMUCRD) linked to the Taiwan Cancer Registry. Patients with advanced NSCLC receiving EGFR-TKI therapy between 1 January 2008 and 31 December 2022 were classified according to concomitant prescription of H1AHs. The primary and secondary endpoints were time to treatment failure (TTF) and all-cause mortality, respectively. Adjusted hazard ratios (aHR) and 95% confidence intervals (CI) were estimated using Cox proportional hazards models. Sensitivity analyses and landmark analyses were performed to evaluate the robustness of the findings. RESULTS:Among 828 eligible patients, 475 (57.37%) received concomitant H1AHs during EGFR-TKIs therapy, whereas 353 (42.63%) did not. Concomitant prescriptions of H1AHs exhibited a significantly reduced risk of treatment failure (aHR; 0.61, 95% CI; 0.53-0.71, p < .001), corresponding to longer mean TTF (2.09 vs. 1.25 years), as well as a lower risk of all-cause mortality (aHR; 0.36, 95% CI; 0.30-0.44, p < .001). A stronger association was observed in patients with extended durations of H1AHs exposure (≥60 or ≥90 days). CONCLUSIONS:Concomitant prescriptions of H1AHs with EGFR-TKIs therapy were associated with a significantly reduced risk of treatment failure and mortality in patients with advanced NSCLC.
AIMS:Considering the inconvenience brought by long-term administration of intravenous (IV) immune checkpoint inhibitors for cancer treatment, subcutaneous (SC) formulation needs to be explored. METHODS:This dose-finding Phase 1 study (NCT05751486) investigated SC toripalimab in patients with recurrent or metastatic nasopharyngeal carcinoma (RM-NPC). In the initial dose-exploration cohorts, patients received SC toripalimab 240 mg Q3W or 480 mg Q6W, followed by a subsequent exploratory cohort receiving 360 mg Q3W, in combination with gemcitabine and cisplatin. The primary endpoint was pharmacokinetic profile of SC toripalimab. RESULTS:Between 24 November 2022 and 31 July 2023, 38 patients were enrolled (12, 13 and 13 patients received 240 mg Q3W, 360 mg Q3W and 480 mg Q6W SC toripalimab, respectively). As of the data cut-off date, the median follow-up was 17.2 months. SC toripalimab 360 mg Q3W provided similar serum trough concentration (Ctrough) and area under the curve (AUC) in Cycle 1 to the corresponding IV toripalimab 240 mg Q3W. SC toripalimab was well tolerated and exhibited a safety profile consistent with the established IV formulation. The objective response rates were 100% (95% CI 73.5, 100), 92.3% (95% CI 64.0, 99.8) and 92.3% (95% CI 64.0, 99.8) in the 240 mg Q3W, 360 mg Q3W and 480 mg Q6W cohorts, respectively. CONCLUSIONS:SC toripalimab showed consistent safety and antitumour activity with IV toripalimab for the first-line treatment of RM-NPC. Similar Ctrough and AUC values in cycle 1 of SC toripalimab 360 mg Q3W with IV toripalimab reference support further study.
BACKGROUND:Guidelines recommend oral anticoagulation for stroke prevention in atrial fibrillation and secondary prevention of venous thromboembolism. Outside the United States, apixaban is unlicensed for use in patients with end-stage renal disease (ESRD) receiving renal replacement therapy (RRT). AIM:To compare thrombotic and safety outcomes in patients receiving either vitamin K antagonists (VKAs) or apixaban 2.5 mg twice daily in the context of ESRD and RRT. METHOD:Retrospective service evaluation comparing bleeding and thrombotic outcomes in patients treated with apixaban 2.5 mg BD or VKA in a tertiary anticoagulation clinic. Trough anti-Xa levels of apixaban patients were reviewed. Clinical features and outcomes were reviewed using electronic patient records. RESULTS:Fifty-five VKA and 33 apixaban patients were included in the analysis. There were no major bleeds in the apixaban cohort compared with 4 (7.3%) in the VKA cohort (χ2 = 2.667, p = 0.102). No difference in time to major or clinically relevant non-major bleeding (CRNMB) was found (χ2 = 1.252, p = 0.263). Rates of thrombotic events (all stroke) were 1 vs. 3 (1.1 and 7.1 events/100 patient-years) for VKA and apixaban, respectively (χ2 = 3.291, p = 0.070). Only one stroke was related to AF. Eighty-four of 85 trough anti-Xa levels analysed were below the upper limit of normal of the reference range for the general population. DISCUSSION:Our results suggest similar outcomes with VKA and apixaban in those receiving RRT, indicating apixaban may be a viable second-line treatment option in those for whom VKA may not be appropriate. Further investigation into the safety of the apixaban 5-mg regimen is warranted.
AIMS:Imatinib improves hemodynamics in pulmonary arterial hypertension (PAH), but dose-dependent toxicity has limited its clinical development. We aimed to quantify the dose-efficacy-toxicity relationship and evaluate alternative dosing strategies using data from the PIPAH trial. METHODS:We analysed data from the Phase II PIPAH trial (17 enrolled; 15 contributed pharmacokinetic and safety data, 11 daily hemodynamic data). Total pulmonary resistance (TPR) was described using a turnover model and recurrent adverse events (AEs) using a repeated time-to-event model. RESULTS:Simulations showed that TPR reduction was dose-dependent ( E max 50%; E D 50 247 mg), whereas AE risk increased nonlinearly with dose ( E D 50 307 mg). Although a cumulative dose of 2400 mg produced similar TPR reductions, 300 mg once daily achieved a 20% reduction earlier than 200 mg (8 vs. 12 weeks) with only a modest increase in AE burden. CONCLUSIONS:Simulations support initiating treatment at 200 mg once daily with escalation to 300 mg after 8-12 weeks in patients who tolerate treatment.
Health information is now widely accessed through smartphones, online searches and increasingly through generative artificial intelligence (AI). These systems create new opportunities for communication, and in some routine contexts, well-governed AI assistants could reduce exposure to lower quality sources by providing cautious, evidence-aligned answers. During health emergencies, however, evidence is incomplete, and demand for rapid guidance is high. Under these conditions, generative AI could produce or amplify inaccurate therapeutic claims at a speed and scale that compound the challenges regulators already face in countering misinformation. Current regulatory responses remain largely reactive, but the speed and scale of AI-generated health claims require proactive preparedness. We propose a two-layer framework that separates assessment of a claim's evidentiary status from action on its distribution across digital platforms. Regulatory Infodemic Triggers would identify claims that warrant rapid assessment and, where necessary, proportionate and time-limited intervention.
BACKGROUND:Levothyroxine is widely prescribed, yet its real-world safety profile remain unclear. Although disproportionality analysis (DA) can detect potential safety signals, reporting raw findings without systematic prioritization may overemphasize statistical artifacts rather than clinically meaningful hypotheses. RESEARCH DESIGN AND METHODS:We analyzed FAERS Individual Case Safety Reports (2004-2023), identifying levothyroxine as the primary suspect drug. Signal detection used four DA measures: Reporting Odds Ratio (ROR), Proportional Reporting Ratio (PRR), Information Component (IC), and Empirical Bayes Geometric Mean (EBGM) with standard thresholds, including a dose-stratified comparison (≥100 µg vs <100 µg). Detected drug-event pairs were evaluated using a structured Signal Prioritization Framework integrating statistical strength, clinical seriousness, biological plausibility, and novelty to assign high, moderate, or low priority. Inter-rater reliability was assessed using weighted Cohen's κ. RESULTS:We identified 291 signals (22 labeled; 269 unexpected) and 21 dose-dependent signals. Fifteen signals were classified as high priority , while high-dose therapy identified additional moderate-priority signals, including acute kidney injury.Inter-rater agreement was substantial (κ = 0.63; SE = 0.092; 95% CI 0.45-0.81). CONCLUSION:A structured approach combining FAERS-based signal detection with systematic prioritization distinguished clinically plausible levothyroxine safety signals from statistical noise, supporting targeted pharmacoepidemiologic evaluation and improved clinical interpretation.
AIMS:S100A4 is a damage-associated molecular pattern protein that amplifies pro-inflammatory and pro-fibrotic signalling. CAL101 is a first-in-class humanized monoclonal antibody that neutralizes S100A4. This first-in-human study evaluated safety, pharmacokinetics (PK), immunogenicity and exploratory pharmacodynamics (PD) of CAL101. METHODS:This Phase 1, randomized, double-blind, placebo-controlled study, included two parts. Part A assessed single ascending intravenous doses of CAL101 (0.5-20 mg/kg) or placebo in 40 healthy volunteers. Part B evaluated multiple ascending doses, 4 infusions of CAL101 (10 and 20 mg/kg) or placebo every 3 weeks, in 17 patients with mild-to-moderate psoriasis. The primary endpoint was safety and tolerability. RESULTS:CAL101 was well tolerated, with no dose-limiting toxicities or serious adverse events. Treatment-emergent adverse events were balanced between treatment groups. The PK profile showed target-mediated, nonlinear kinetics at lower doses. Mean terminal half-life increased from 86 h at 0.5 mg/kg to 437 h at 20 mg/kg after a single dose and 16-22 days after multiple dosing. Antidrug antibodies were detected in some participants at low titers and had no effect on PK or safety. In psoriasis patients included in Part B, baseline disease severity was low (mean Psoriasis Area and Severity Index of 5.5-6.0). No meaningful differences in psoriasis measures were observed between CAL101 and placebo. In psoriasis lesions, CAL101 reduced tenascin C deposition and decreased pSTAT3, consistent with modulation of S100A4-dependent pathways. CONCLUSIONS:CAL101 demonstrated an acceptable safety profile, predictable PK and PD effects consistent with extracellular S100A4 neutralization. These findings support further clinical development of CAL101 in fibro-inflammatory diseases.
Haemodialysis has been used clinically for more than 70 years, but data regarding the clearance of medicines during dialysis are often based on studies with outdated, less efficient dialysers. Moreover, dialysis clearance is still frequently estimated using empirical approaches which lack mechanistic interpretability, are not readily generalizable across medicines or dialysis modalities and may underestimate medicine clearance with contemporary dialysers. Furthermore, the increasing use of haemodiafiltration, which combines diffusion and convection, limits the applicability of haemodialysis models that account only for diffusion clearance. We therefore developed a mechanistic, theory-based framework to quantify both diffusion and convection clearance during haemodialysis or haemodiafiltration. Dialysance, described by Michaels in 1966, was extended to demonstrate its applicability to both obsolete recirculating and contemporary single-pass dialysis systems. Diffusion clearance was described using blood and dialysate flow rate and the mass transfer-area coefficient. Convection clearance was described using convection volume, plasma water flow and sieving coefficients. We introduce a dimensionless metric for dialysis efficiency, which we show is equivalent to the well-known hepatic extraction ratio. This metric provides a bounded, physiologically interpretable measure of dialyser performance that avoids ambiguity associated with traditional solute clearance-based efficiency metrics. The proposed framework supports a mechanistic approach to estimation of dialysis clearance applicable to population pharmacokinetic models. This approach offers a theoretically generalizable method for quantifying dialysis clearance and a target concentration approach to individualized dosing of medicines during haemodialysis or haemodiafiltration.
AIMS:Safe prescribing and effective medication review during acute hospitalization depends on accurate information about liver and kidney function because these organs are responsible for the elimination of most medications. While estimates for kidney function are widely used, comparable markers of hepatic drug-metabolizing capacity are not routinely available. We evaluated the clinical relevance of pharmacogenomic (PGx) information for key pharmacogenes implicated in medication elimination in older adults presenting to the emergency department. METHODS:Fourteen pharmacogenes were analysed using the Personal Medicine Profile™ test. GeneYouIn PillCheck™ software performed genotype-to-phenotype translations, identified drug-gene interactions (DGIs) and generated a clinical decision report based on each patient's actual medication use. RESULTS:Among 125 acutely admitted older medical patients (median age 78.3 years; 10 medications; 7 chronic diseases), PGx testing identified 88 DGIs across 63 patients (50.4%). Of these, 46.5% were considered by clinical experts to be clinically relevant for the individual patient, affecting 33 patients (26.4%) in the total study population. Frequently implicated pharmacogenes included CYP2C19 (25.0%), SLCO1B1 (25.0%), CYP2D6 (20.5%), CYP2C9 (14.8%) and OPRM1 (6.8%), and frequently implicated medications included losartan (13.6%), pantoprazole (12.5%), simvastatin (12.5%), atorvastatin (11.4%) and metoprolol (11.4%). CONCLUSION:With more than one-quarter of acutely admitted older medical patients having one or more clinically relevant DGIs, these findings suggest that PGx information may have meaningful clinical utility for improving prescribing practices in acute care. However, interpretation in this population requires careful consideration of other factors such as nutritional status and inflammation that may modify pharmacogene activity.
BACKGROUND:Long-acting intramuscular cabotegravir plus rilpivirine (LA-CAB + RPV) is an effective maintenance antiretroviral regimen for virologically suppressed people with HIV. However, its use in individuals receiving chronic anticoagulation is limited by concerns regarding intramuscular bleeding risk, and real-world data are scarce. METHODS:We conducted an observational, prospective, single-centre cohort study including all people with HIV (PVIH) who initiated LA-CAB + RPV at Hospital Clínic of Barcelona since February 2023 until April 2026. Patients receiving chronic anticoagulation during the follow-up were identified and assessed for safety and virological outcomes. RESULTS:Among 964 PVIH who started LA-CAB + RPV in our cohort, three were identified who received concomitantly chronic anticoagulation (direct oral anticoagulants or low-molecular-weight heparin). They received injections using standard deep intramuscular technique with post-injection compression. No clinically relevant injection-site hematomas or haemorrhagic complications were observed. Viral suppression was maintained in all cases. CONCLUSIONS:This real-world case series suggest that chronic anticoagulant therapy alone should not automatically preclude the use of LA-CAB + RPV. With careful patient selection and appropriate injection techniques, LA-CAB + RPV may represent a safe and effective treatment option for selected people with HIV receiving anticoagulation.
BACKGROUND:Cardiovascular diseases (CVDs) represent a leading cause of global mortality. Myocardial fibrosis (MF), a common pathological hallmark in CVDs, signifies disease progression to severe stages. Its pathogenesis is highly complex, with autophagy playing a pivotal regulatory role. METHODS:This narrative review synthesizes and critically evaluates the current literature to elucidate the interplay between MF and autophagy. The focus lies on systematically examining the molecular mechanisms and key signaling pathways involved in autophagy-mediated regulation of MF. Review Content: We systematically examine key molecular pathways and components through which autophagy regulates MF, including mitophagy, the NLRP3 inflammasome, FOXO signaling, the ULK1 complex, the mTOR pathway, and TGF-β signaling. These pathways collectively influence fibroblast activation, collagen metabolism, and overall cardiac extracellular matrix remodeling. CONCLUSIONS:Autophagy serves as a crucial modulator of myocardial fibrosis through multiple interconnected molecular pathways. Targeting specific nodes within the autophagic process holds significant therapeutic promise for mitigating MF and slowing CVD progression. This review consolidates current understanding and highlights novel insights, underscoring the need for further research to translate these mechanisms into effective clinical interventions.
This study integrated network pharmacology and metabolomics to investigate the mechanism of allopurinol in treating hyperuricemia. Therapeutic targets were identified by screening drug and disease databases. A drug-target-disease network was constructed and validated by molecular docking using Cytoscape. A mouse model of hyperuricemia was established with yeast extract and potassium oxonate. Allopurinol efficacy was evaluated via body weight, renal histopathology, and serum biochemical indices. Enrichment analyses of Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathways were performed using DAVID platform. Serum metabolite profiles were analyzed by UPLC-Q-TOF/MS-based metabolomics, and metabolic pathways were explored using MetaboAnalyst 6.0. Network pharmacology and molecular docking identified 23 key targets and 43 signaling pathways related to allopurinol treatment. Animal experiments confirmed allopurinol significantly reduced serum levels of uric acid, creatinine, blood urea nitrogen, and xanthine oxidase activity. Metabolomic analysis revealed 5 differentially regulated metabolites and 13 key metabolic pathways associated with allopurinol intervention. The integrated results indicated that allopurinol treats hyperuricemia not only by modulating purine metabolism but also potentially through influencing oxidative stress and apoptosis-related pathways. This study provided preliminary experimental insights into the potential mechanistic basis of allopurinol in the treatment of hyperuricemia.
AIM:The first aim of this study was to develop physiologically based pharmacokinetic (PBPK) models for irbesartan (IRB) and repaglinide (REP) and then apply the REP/IRB PBPK model to describe the drug-drug interaction (DDI) of REP and IRB in the population with SLCO1B1 c.521 T > C gene polymorphism. Second, the REP/IRB model was used to predict REP exposure under different administration protocols and provide dose adjustment recommendations for the population with SLCO1B1 c.521 T > C gene polymorphism. METHOD:The PBPK model was developed from literature and laboratory data, some parameters in the PBPK model were optimized and data from published clinical studies were used to evaluate the PBPK model. RESULT:The REP/IRB PBPK model showed good performance for accurately describing the plasma concentration-time profiles, area under the plasma concentration-time curve (AUC), maximum plasma concentrations (Cmax) and peak times (Tmax). The REP/IRB PBPK model predicted that, compared to the population with SLCO1B1 c.521TC genotype, in the population with SLCO1B1 c.521TT genotype, co-medicating with IRB significantly increased the exposure of REP. When co-administered with 300-mg IRB in patients with the SLCO1B1 c.521TT genotype, REP should be given either 2 h earlier or 4 h later (AUC0-∞ ratio: 0.90-0.97), or at 60-70% of the initial dose (AUC0-∞ ratio: 0.99-1.10), depending on available dosage strengths. CONCLUSION:A PBPK model was built for REP and IRB and used to predict DDI for the population with SLCO1B1 c.521 T > C gene polymorphism. Moreover, the model was applied to provide individualized drug recommendations for the SLCO1B1 c.521TT genotype population.
AIM:Anticholinergic medications are frequently prescribed to older adults and are associated with adverse outcomes including cognitive impairment, delirium and mortality. In patients with hip fracture-a population characterized by frailty and polypharmacy-the impact of anticholinergic burden on survival remains uncertain. This study aimed to examine the association between anticholinergic burden and all-cause mortality after hip fracture in adults aged ≥65 years. METHODS:A systematic review and meta-analysis was conducted according to PRISMA 2020 guidelines (PROSPERO CRD420251181616). PubMed, Embase, Scopus and Cochrane Library were searched through September 2025. Observational studies assessing mortality by validated anticholinergic burden scales-Anticholinergic Cognitive Burden (ACB), Anticholinergic Risk Scale (ARS) or Drug Burden Index (DBI)-were included. Pooled hazard ratios (HR) with 95% confidence intervals were calculated using a random-effects model. RESULTS:Five cohort studies including 65 435 patients met inclusion criteria. High anticholinergic burden was associated with increased 12-month (HR = 1.47; 95% CI 1.11-1.94; p = 0.006) and 36-month mortality (HR = 1.45; 95% CI 1.05-2.00; p = 0.02). No significant association was observed at 1-6 months. Overall, pooled analysis showed a 40% higher mortality risk in patients with high anticholinergic burden (HR = 1.40; 95% CI 1.22-1.61; p < 0.001). Heterogeneity was high, and the certainty of evidence ranged from low to very low. CONCLUSION:Higher anticholinergic burden was associated with an increased risk of medium- and long-term mortality after hip fracture in older adults. Routine assessment and reduction of anticholinergic exposure should be incorporated into perioperative geriatric management to improve survival outcomes.
BACKGROUND:Fluoropyrimidines are widely used for the treatment of solid tumours, but they carry a significant risk of severe toxicity in patients with dihydropyrimidine dehydrogenase (DPD) deficiency. CASE PRESENTATION:We describe a 50-year-old male with colorectal cancer who received adjuvant XELOX (oxaliplatin and capecitabine) and developed life-threatening grade 3-4 toxicities. Routine DPYD genotyping showed no pathogenic variants. Subsequent DPYD exon sequencing identified three heterozygous variants: c.1627A>G, c.2194G>A, and c.2766+3A>T. The latter, a rare intronic variant, was demonstrated to cause exon 21 skipping by mRNA analysis of peripheral blood mononuclear cells (PBMCs). The patient presented a profound DPD deficiency. CONCLUSION:The c.2766+3A>T variant leads to a non-functional DPD enzyme and is a likely cause of severe fluoropyrimidine-related toxicity. This variant should be considered deleterious.
