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    Ex vivo expansion of natural killer cells for hematological cancer immunotherapy: a systematic review and meta-analysis
    (SPRINGER-VERLAG ITALIA SRL, 2022) Çubukçu, Hikmet Can; Yurdakul Mesutoğlu, Pınar; Seval, Güldane Cengiz; Beksac, Meral
    The present systematic review aimed to investigate natural killer (NK) cell ex vivo expansion protocols within the scope of clinical trials targeting hematological cancer and to conduct a meta-analysis to assess the effect of NK cell infusion on survival. Research articles of clinical studies in which cell products produced by ex vivo expansion, consisting of a certain amount of NK cells and infused to patients with hematological cancer, were included in the systematic review. We conducted a proportion analysis with random effects for product purity and viability values. Studies having control groups were included in the survival meta-analysis. Among 11.028 identified records, 21 were included in the systematic review. We observed statistically significant heterogeneity for viability (I2 = 97.83%, p < 0.001) and purity values (I2 = 99.95%, p < 0.001), which was attributed to the diversity among isolation and expansion protocols. In addition, the survival meta-analysis findings suggested that NK cell therapy favors disease-free survival (DFS) of patients with myeloid malignancies but limited to only two clinical studies (odds ratio = 3.40 (confidence interval:1.27-9.10), p = 0.01). While included protocols yielded cell products with acceptable viability, the utility of immunomagnetic methods; feeder cells such as K562 expressing membrane-bound IL15 and 4-1BBL or expressing membrane-bound IL21 and 4-1BBL might be preferable to achieve better purity. In conclusion, NK cell therapy has a potential to improve DFS of patients with myeloid malignancies.
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    In the era of Bortezomib-based Induction, intensification of Melphalan-based conditioning with Bortezomib does not improve Survival Outcomes in newly diagnosed Multiple Myeloma: a study from the Chronic Malignancies Working Party of the EBMT
    (Springernature, 2024) Beksac, Meral; Eikema, Diderik-Jan; Koster, Linda; Hulin, Cyrille; Poire, Xavier; Hamladji, Rose-Marie; Gromek, Tomasz
    Bortezomib (Vel)- Melphalan 200 mg/m2 (Mel200) (Vel-Mel) has been utilised to intensify conditioning in autologous hematopoietic stem cell transplantation (AHCT) for multiple myeloma (MM). This EBMT registry-based study compared Vel-Mel with Mel200 during upfront AHCT. Between 2010 and 2017, MM patients who received Vel-Mel (n = 292) conditioning were compared with 4,096 Mel200 patients in the same 58 centres. Pre-AHCT, compared to Mel200 patients, Vel-Mel patients had similar International Staging System (ISS) scores and cytogenetic risk profiles; a similar proportion had received bortezomib-based induction (85% and 87.3%, respectively) though they were younger with a better performance status. Vel-Mel patients were more likely to achieve CR post-induction (40.6% vs 20.3%, p < 0.001) and by day 100 of AHCT (CR/VGPR: 70.2 % vs. 57.2%, p < 0.001). There was no difference in 3-year PFS (49% vs 46%, p = 0.06) or early post-AHCT mortality. In multivariable analysis, Vel-Mel associated with inferior PFS (HR: 1.69 (1.27-2.25, p < 0.001) and OS (HR:1.46 (1.14-1.86,p = 0.002), similar to negative effects on PFS of advanced ISS (HR:1.56 (1.33-1.83, p < 0.001), high-risk cytogenetics (HR:1.43(1.18-1.74, p < 0.001) and poor post-induction response(<=PR)(HR: 1.43(1.25-1.62, p < 0.001) Overall, despite superior pre- and post-AHCT responses, there was no improvement in PFS or OS following Vel-Mel. This data supports the findings of the smaller prospective IFM study.
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    A Novel Hypothesis: Certain KIR/Cognate Ligand Containing Genotypes Differ in Frequency Among Patients With Myeloma and Have an Effect on Age of Disease Onset
    (Cig Media Group, Lp, 2023) Beksac, Meral; Akin, Hasan Yalim; Seval, Guldane Cengiz; Mesutoglu, Pinar Yurdakul; Anliacik, Ridvan Goksel; Anliacik, Ezgi; Gurman, Gunhan
    KIR and KIR-ligand frequencies, alone or in combination, among MM (n:204) and healthy subjects (n:424) showed cAB1 as a specificity delaying onset of MM in the presence of C1C2 and AA as a predisposing one in the presence of C1C1 to be associated with earlier onset. Findings independent of R-ISS suggesting an immune modulating role of KIR plus ligand genotypes. Background: Natural killer (NK) cells are known to have cytotoxic effects mediated through killer immunoglobulin-like receptors (KIRs) and their cognate ligands. Role of KIRs in myeloma is yet unresolved. Patients and Methods: KIR genotypes and ligands of 204 newly diagnosed MM patients are compared with 424 healthy subjects. Statistical analysis included t-test, chi-square and binary logistic regression. Results: KIR ligands were significantly more (C2C2: 27.5% vs 15.1%; OR 2.128; 95% CI, 1.417-3.196; P < .001) or less (C1C2: 40.2% vs 51.9%; OR 0.623; 95% CI, 0.444-0.874; P = .006) frequent among MM. Co-occurrence of genotype AA with C2C2 was also higher in frequency among MM (OR 2.509; 95% CI, 1.171-5.378; P = .015) likewise cAB1 with C1C2 was less frequent (OR 0.553; 95% CI, 0.333-0.919; P = .021). Genotypes AA with C1C1, cAB1 with C1C2 or C1C2 alone were associated with a delay (median age: 61 [48-73]; P = .044; 62 [31-81]; P = .030 or 59 [31-85]; P = .028), but AA with C2C2 with an earlier age of onset (48 [29-77]; P = .042). In multivariate analysis including R-ISS, light chain, KIR genotype/ligands; ligand C1C2 ( P = .02) and genotype AA-C1C1 ( P = .037) were independently associated with age of onset & GE;60. Conclusion: C1C2 and C2C2 alone or in combination with KIR genotype (cAB1 and AA, respectively), is observed in less or higher frequency among MM cases and associated with delayed/earlier age of onset, respectively. Genotype AA-C1C1 although in similar frequency between patients and healthy subjects, is also associated with delay. To our knowledge, this is the first study demonstrating an association between KIR and MM onset age, independent from R-ISS or light chain type.