The antitumor activity of o-carboxybenzoylferrocene sodium salt (1) was studied in vivo. Interaction between o-carboxybenzoylferrocene (2) and N,N -carbonyldiimidazole in boiling methylene dichloride leads to 3-(N-imidazolyl)-3-ferrocenylisobenzofuran-1(3H)-one (5). The structure of compound 5 was established by X-ray analysis. Aminolysis of compound 5 in toluene gave rise to ferrocenoylbenzamides (6a-d)-derivatives of dimethylamine, piperidine, pyrrolidine and morpholine.
Aim. To assess the relationship between isolated and combined expression of pSTAT3, pACT1 in tumor cells with the survival of patients with diffuse large B-cell lymphoma (DLBCL). Methods. The study included 100 patients with the first diagnosed diffuse large B-cell lymphoma, observed in the institute's clinic between 2010 and 2018 who received standard first-line R-CHOP (rituximab + cyclophosphamide, doxorubicin, vincristine and prednisone) chemotherapy. The relative number of expressing pSTAT3 and pAKT1 tumor cells was determined by using immunohistochemical and morphometric methods. The optimal cut-off level of expression on tumor cells estimated by using receiver operating characteristic (ROC) curve analysis for pSTAT3 was 68% and for pACT1 70%. Given these values, all patients with DLBCL were divided into groups with a high and low degree of expression of the biomarkers. As a result, 53 patients were enrolled in the pSTAT3 high expression group (68% tumor cells) and 47 patients to the pSTAT3 low expression group (68% tumor cells). Spearmans correlation coefficient was used to examine relationships. Overall survival and event-free survival were estimated by KaplanMeier curves. The log-rank test was used for groups comparison. Results. The five-year overall survival rate in the pSTAT3 high expression group was 55% versus 87% in the low expression group, p=0.015. A significant difference was found in the assessment of event-free survival: 43% for the group of pSTAT3 high expression, 66% for the group of low expression, p=0.011. A statistically significant value of a high level of pACT1 expression was revealed for 5-year overall and event-free survival (p 0.001 and p=0.003). Overall survival rate was 81% for the pACT1 low expression group and 43% for the high expression group while event-free survival rate was 64 and 41%, respectively. Also, patients with рАКТ1+/рSTAT3+ (high level) co-expression had extremely low rates of overall and event-free survival rates compared with the рАКТ1/рSTAT3 (low level) group (p=0.001; p 0.001). Conclusion. The pSTAT3 and pAKT1 biomarkers can be used as additional prognosis criteria for diffuse large B-cell lymphoma.
Aim. To study the value of PD-L1 protein expression in the combined model of diffuse large B-cell lymphoma (DLBCL) after administration of R-CHOP induction immunochemo-therapy. Materials & Methods. A retrospective analysis was based on the data of 85 DLBCL patients. The median age was 59 years (Q-Q<sub>3</sub>: 29-83). Each patient received at least 2-6 courses of R-CHOP immunochemotherapy. The median follow-up period was 17 months. The optimal cut-off threshold for assessing the proportion of tumor cells expressing PD-L1 protein was determined by the CART (Classification and Regression Tree) method. Results. Patients were divided into three groups depending on IPI (International Prognostic Index) risk and immunohis-tochemical subtype (Hans algorithm) using CART. In group 1 with immunohistochemical GCB subtype and any IPI risk, except for the high one, low PD-L1 expression measured in terms of the DLBCL expressing tumor cell count, was identified in 21 (84 %) patients, 4 (16 %) patients showed overexpression. In case of low PD-L1 expression the 2-year progression-free survival (PFS) was 76 % (median not reached). In 4 patients with protein overexpression, the life duration after DLBCL diagnosed was 4, 16, 2, and 6 months, respectively. In group 2 with immunohistochemical non-GCB subtype and any IPI risk, except for the high one, 27 (67.5 %) patients showed low, and 13 (32.5 %) patients showed high PD-L1 expression. The analysis of the 2-year PFS resulted in no significant differences in groups with different relative counts of PD-L1 expressing tumor cells, i.e., 46 % and 49 %, respectively (p = 0.803). In case of low (< 24.5 % tumor cells) PD-L1 expression, the 2-year overall survival (OS) was better than in patients with overexpression (> 24.5 % tumor cells), i.e., 87 % vs. 52 %, respectively (p = 0.049). In group 3 with IPI high risk irrespective of immunohistochemical subtype, the proportion of PD-L1 expressing cells was higher than cut-off threshold (> 24.5 %) in 9 (45 %) patients, low protein expression was identified in 11 (55 %) patients. Deaths were reported in all patients of group 3 showing PD-L1 overexpression. In case of low protein expression the proportion of patients alive was 46 % (p = 0.002). None of the patients with high PD-L1 expression lived longer than 2 years. In those with low PD-L1 expression the 2-year OS was 66 % (p = 0.008). Conclusion. Overexpression of PD-L1 by DLBCL tumor cells together with high IPI progression risk and non-GCB tumor subtype is associated with the worst OS and PFS. It can probably be accounted for by insufficient efficacy of R-CHOP induction immunochemotherapy in patients with high IPI risk. With this presumption, the PD-L1 expressing tumor cell count can be regarded as an important additional criterion for stratification of DLBCL patients into risk groups. Adding this new parameter to already established ones would probably contribute to differentiated approach to the choice of chemotherapy strategy at the onset of this aggressive lymphoma.
Background. Diffuse large B-cell lymphoma (DLBCL) amounts for 30-40 % of all adult non-Hodgkin's lymphomas. After R-CHOP immunochemotherapy 40 % of patients develop early relapsed or therapy-refractory disease. The conventional prognostic parameters in DLBCL are not always effective. Therefore, exploring further predictors of disease course remains an issue. Aim. To assess the prognostic value of pAKT1 and рSy< expression in DLBCL. Materials & Methods. The study enrolled 100 patients with newly diagnosed DLBCL treated with R-CHOP first-line immunochemotherapy. The relative count of pAKT1- and pSyk-expressing tumor cells was determined by immunohistochemical and morphometric methods. The expression cutoff of these proteins was calculated by ROC analysis. The relationship of protein expression with clinical parameters of DLBCL was analyzed by Fisher's exact two-tailed test. The 5-year overall (OS) and progression-free (PFS) survivals were estimated by Kaplan-Meier method (log-rank test). Results. High pAKT1 expression was associated with advanced DLBCL stages, International Prognostic Index > 2, serum lactate dehydrogenase concentration above normal, failures of R-CHOP therapy, as well as worse OS and PFS. No correlation between рSyk< expression and clinical lymphoma characteristics was found. The worst 5-year OS (27.6 %) was reported in cases of pAKT1 and pSyk co-overexpression (hazard ratio [HR] 5.2; 95% confidence interval [95% CI] 2.49-10.9; p < 0.001). A similar trend was observed for PFS (HR = 3.3; 95% CI 1.54-7.30; p = 0.002). Conclusion. Overexpression of pAKT1 is an informative indicator of a poor DLBCL prognosis. Co-overexpression of pAKT1 and рSyk< markers is associated with worse OS and PFS compared to their isolated expressions and other co-expression variants.
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