Background/Aim. Polymorphisms of genes which encode transporter P-glycoprotein and most important enzymes for tacrolimus pharmacokinetics can have significant influence reflecting on blood concentrations of this drug. The aim of this study was to examine the distribution of polymorphisms of CYP3A5, CYP3A4 and ABCB1 genes in patients subjected to renal transplantation, for the first time in our transplantation center. Methods. The research was designed as a prospective cross-sectional study which included 211 patients subjected to renal transplantation in the Centre for Solid Organ Transplantation of the university tertiary health care hospital, Military Medical Academy, Belgrade, Serbia. Patients of both genders, 22?69-year-old, Caucasians, subjected to immunosuppressive regimen, including tacrolimus, were recruited for the study. CYP3A5 6986A>G (the *3 or *1, rs776746), CYP3A4 - 392A>G (the *1 or *1B, rs2740574) and ABCB1 3435C>T (rs1045642) genotypes were determined by TaqMan? SNP genotyping assays. Results. Most of our patients (94.8%) had functional CYP3A4 enzyme, while 87.7% of all the patients had diminished CYP3A5 enzymatic activity. On the other hand, about one third of them, 31.3%, had functional ABCB1 transporter. Conclusion. A total of 84.8% of our patients were found to express both the CYP3?5*3*3 genotype (associated with diminished CYP3?5 enzymatic activity) and CYP3?4*1*1/*1*1B (associated with functional CYP3?4 enzymatic activity), while out of all the patients with diminished CYP3A5 enzymatic activity, 68.7% had diminished activity of ABCB1 transporter. However, further studies are necessary in order to show the influence of these genetic polymorphisms on tacrolimus blood concentrations in patients after renal transplantation.

Background/Aim. Tacrolimus concentration-dose ratio as a potential therapeutic drug monitoring strategy was suggested to be used for the patients subjected to renal transplantation. The aim of this study was examining the relationship between tacrolimus concentration-dose ratio, suggested to be used as a therapeutic drug monitoring strategy and the polymorphisms of genes encoding the most important enzymes, such as CYP3A5 and CYP3A4, as well as the transporter P-glycoprotein, for its metabolism and elimination. Methods. The study was designed as a prospective case series study, in which the unit of monitoring was the outpatient examination of 54 patients subjected to renal transplantation. Genotyping was performed by 7500 Real-Time PCR System by assessing allelic discrimination based on TaqMan (R) methodology. Results. Patients (n = 13) who were treated with less than 2 mg of tacrolimus/day (0.024 +/- 0.006 mg/kg/day) had the tacrolimus concentration-dose ratio larger than 150 ng/mL/mg/kg. In this group, 84.62% patients had CYP3.5 *3*3 allele. All of these patients had CYP3.4 *1*1/*1*1B allele. Regarding ABCB1 C3435T gene, 30.77% of patients had the TT gene variant, while 69.23% of our patients had CC and CT gene variants. Conclusion. Tacrolimus concentration-dose ratio greater than 150 ng/mL/mg/kg is cut-off value in patients subjected to renal transplantation which might point to patients who are poor CYP3A5 metabolizers and/or with dysfunctional P-glycoprotein.

Background/Objectives: This study evaluates the prognostic value of baseline inflammatory biomarkers, neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), monocyte-to-lymphocyte ratio (MLR), lymphocyte-to-monocyte ratio (LMR), systemic immune-inflammation index (SII), and pan-immune-inflammation value (PIV) in advanced cutaneous melanoma treated with first-line immunotherapy. Methods: This multicenter retrospective study included 162 patients with unresectable stage III/IV cutaneous melanoma treated with first-line pembrolizumab, nivolumab, or nivolumab plus ipilimumab. Biomarkers were calculated from complete blood counts obtained within 30 days before treatment start. Cut-offs were defined by ROC analysis. Progression-free survival (PFS) and overall survival (OS) were analyzed using Kaplan–Meier and Cox regression. Response was assessed by RECIST v1.1. Results: Higher baseline NLR, PLR, MLR, SII, and PIV were more common in patients with adverse baseline features, including liver metastases, elevated LDH, and poorer ECOG performance status. Patients with biomarker values below the cut-offs had significantly longer PFS and OS. In biomarker-specific multivariable models adjusted for selected clinical covariates, PIV retained the most consistent association with PFS and OS, while MLR was associated with PFS, and PLR with OS. Conclusions: Baseline inflammatory biomarkers from routine blood counts provide useful prognostic information in advanced melanoma treated with first-line ICIs. PIV showed the most consistent association with survival outcomes and may support initial risk stratification alongside LDH, ECOG, and metastasis pattern. However, prospective validation in independent cohorts is needed before routine clinical implementation.

Background/Objectives: This study evaluates the prognostic value of baseline inflam-matory biomarkers neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), monocyte-to-lymphocyte ratio (MLR), lymphocyte-to-monocyte ratio (LMR), systemic immune-inflammation index (SII) and pan-immune-inflammation value (PIV) in advanced cutaneous melanoma treated with first-line immunotherapy. Methods: This multicenter retrospective study included 162 patients with unresectable stage III/IV cutaneous melanoma treated with first-line pembrolizumab, nivolumab, or nivolumab plus ipilimumab. Biomarkers were calculated from complete blood counts obtained within 30 days before treatment start. Cut-offs were defined by ROC analysis. Progression free survival (PFS) and overall survival (OS) were analyzed using Kaplan–Meier and Cox regression. Response was assessed by RECIST v1.1. Results: Higher baseline NLR, PLR, MLR, SII and PIV were more common in patients with adverse baseline features, including liver metastases, elevated LDH and poorer ECOG performance status. Patients with biomarker values below the cut-offs had sig-nificantly longer PFS and OS. In multivariable models adjusted for clinical covariates, PIV remained independently associated with the duration of PFS and OS; MLR inde-pendently predicted PFS, while PLR independently predicted OS. Conclusions: Baseline inflammatory biomarkers from routine blood counts provide useful prognostic information in advanced melanoma treated with first-line ICIs. PIV showed the most consistent independent association with survival outcomes and may support initial risk stratification alongside LDH, ECOG and metastasis pattern. However, prospective validation in independent cohorts is needed before routine clinical implementation.

Carbamazepine (CBZ) is a widely used medication in treating epilepsy, bipolar disorder, and neuropathic pain. Its pharmacokinetic profile is highly variable due to slow absorption, extensive metabolism, and auto-induction. Genetic polymorphisms affect transporters and metabolic enzymes, additionally modifying therapeutic response, and lead to nonlinear and unpredictable toxicokinetics in overdose. CBZ is primarily metabolized by cytochrome P450 (CYP) enzymes CYP3A4, CYP3A5, and CYP2C8 to the active metabolite CBZ-10, 11-epoxide (CBZ-E), with subsequent hydrolysis by epoxide hydrolase 1 (EPHX1) and glucuronidation by uridine diphosphate glucuronosyltransferase 2B7 (UGT2B7), with other CYPs additionally contributing to the formation of reactive intermediates and inactive CBZ metabolites. Polymorphisms in genes encoding enzymes (EPHX1, CYP3A4/5, and UGT2B7) and transporters (ABCB1, ABCC2, RALBP1) can affect CBZ and CBZ-E exposure, maintenance dose, and the risk of adverse drug reactions. In overdose cases, CBZ exhibits saturable epoxidation, which leads to the accumulation of the drug and its active metabolite, prolonged elimination, and neurotoxicity, while serum concentrations correlate poorly with clinical findings. Therapeutic monitoring of the drug and its active metabolite in patients’ blood, together with pharmacogenetic testing, could improve both the individualization of therapy and the management of overdose.

Background/Objectives: Immunotherapy and targeted therapy improve melanoma survival but raise costs. Real-world cost and outcome data are scarce, especially in Central and Eastern Europe. We estimated per-patient costs and outcomes in Serbia’s public healthcare system. Methods: This retrospective, single-centre study assessed costs in 183 patients with cutaneous melanoma who received systemic therapy at a Serbian tertiary centre (2019–2026). Direct medical costs were reconstructed from invoices and discharge letters from the healthcare-sector perspective. Censoring-adjusted mean 24-month costs were estimated from diagnosis (n = 165) and treatment start (n = 179). Outcomes included overall survival (OS), real-world progression-free survival (rwPFS), and time to next treatment or death (TNT-D). Results: Mean 24-month costs per patient were EUR 66,466 (95% CI 58,465–75,334) from diagnosis (EUR 75,388 with the partitioned estimator), 94.7% for systemic therapy, and EUR 107,229 (95% CI 97,405–118,201) from treatment start. At diagnosis, costs were about twice as high in stages III–IV as in stages I–II. By stage at treatment start, costs were similar in stages III and IV (EUR 102,122 vs. 104,535) despite shorter stage IV survival (p < 0.001). Two-year OS was 91.5% for adjuvant and 51.9% for metastatic first-line intent. Conclusions: Systemic therapy drove costs, which were similar in stages III and IV despite poorer stage IV survival. The cost measurement starting point substantially affected estimates and should be reported.