Indicators of stress hematopoiesis in the blood predict COVID-19 progression in patients over 65 years old.

OBJECTIVES: Advanced age is a well-established risk factor for severe coronavirus disease 2019 (COVID-19). Exacerbated inflammation affects multiple organs, among which hematopoiesis responds by increased output of various cells. We aimed to determine the association between COVID-19 progression and large immature cell (LIC) counts, changes in erythrocyte and platelet distribution widths (RDW, PDW) with reference to patients' age. METHODS: A total of 755 patients with complete blood cell (CBC) analysis in the first 24 h of hospitalization were enrolled. Patients were divided into two groups: under and above 65 years of age. RESULTS: The LIC counts were different in both groups (p < 0.003). However, only the senior patients had markedly different values of RDW and PDW (p < 0.001). The receiver operating characteristic (ROC) curve analysis provided increased LIC (AUC = 0.600), RDW (AUC = 0.609), PDW (AUC = 0.556), and platelet to LIC ratio (AUC = 0.634) as significant in discriminating outcome in the older group. Importantly, these results were not repeated in the younger patients. In the elderly, the progression was predicted with LIC cut-off at ≥ 0.305 × 109/L (OR = 3.166) and RDW over 12.15% (OR = 2.081). DISCUSSION: Aging is characterized by a decline in immunological competence with a compromised control of inflammation leading to a proinflammatory state. This background together with the actions of pathogens may lead to emergency myelopoiesis. CONCLUSION: Our results point to the important differences between age groups regarding CBC-related parameters of stress hematopoiesis during severe infection. Higher LIC, RDW and PDW levels were reliable in the early identification of COVID-19 progression only in the elderly.

Impact of quality of response on survival outcomes among multiple myeloma patients treated with novel agents - a retrospective analysis.

BACKGROUND: In this era of target therapies, novel data on the correlation between response endpoints and survival outcomes in multiple myeloma have arisen. OBJECTIVE: To determine the impact of quality of response on clinical outcomes, using first-line treatment, and identify risk factors influencing progression-free survival (PFS) and overall survival (OS) among myeloma patients. DESIGN AND SETTING: Retrospective analysis on myeloma patients who were treated at the Clinic of Hematology and Clinical Immunology, University Clinical Centre, Nis, Serbia, over a four-year period. METHODS: A total of 108 newly diagnosed patients who received first-line therapy consisting of conventional chemotherapy or novel agent-based regimens were included in this analysis. RESULTS: The quality of response to first-line therapy for the whole cohort was classified as follows: complete response (CR) in 19%; very good partial response (VGPR) in 23%; partial response (PR) in 38%; and less than PR for the remaining patients. After a median follow-up of 25.4 months, the three-year PFS and OS for the entire study population were 47% and 70%, respectively. Achievement of CR was the main factor associated with significantly prolonged PFS and OS, in comparison with patients who reached VGPR and PR. Likewise, addition of the new drugs bortezomib and thalidomide to standard chemotherapy led to considerably extended PFS and OS, compared with conventional therapy alone. CONCLUSIONS: This analysis demonstrated that the quality of response after application of first-line treatment using novel agent-based regimens among multiple myeloma patients was a prognostic factor for PFS and OS, which are the most clinically relevant outcomes.

Impact of quality of response on survival outcomes among multiple myeloma patients treated with novel agents - a retrospective analysis

Abstract BACKGROUND: In this era of target therapies, novel data on the correlation between response endpoints and survival outcomes in multiple myeloma have arisen. OBJECTIVE: To determine the impact of quality of response on clinical outcomes, using first-line treatment, and identify risk factors influencing progression-free survival (PFS) and overall survival (OS) among myeloma patients. DESIGN AND SETTING: Retrospective analysis on myeloma patients who were treated at the Clinic of Hematology and Clinical Immunology, University Clinical Centre, Niš, Serbia, over a four-year period. METHODS: A total of 108 newly diagnosed patients who received first-line therapy consisting of conventional chemotherapy or novel agent-based regimens were included in this analysis. RESULTS: The quality of response to first-line therapy for the whole cohort was classified as follows: complete response (CR) in 19%; very good partial response (VGPR) in 23%; partial response (PR) in 38%; and less than PR for the remaining patients. After a median follow-up of 25.4 months, the three-year PFS and OS for the entire study population were 47% and 70%, respectively. Achievement of CR was the main factor associated with significantly prolonged PFS and OS, in comparison with patients who reached VGPR and PR. Likewise, addition of the new drugs bortezomib and thalidomide to standard chemotherapy led to considerably extended PFS and OS, compared with conventional therapy alone. CONCLUSIONS: This analysis demonstrated that the quality of response after application of first-line treatment using novel agent-based regimens among multiple myeloma patients was a prognostic factor for PFS and OS, which are the most clinically relevant outcomes.

Acute leukemia and SARS-CoV-2 infection: clinical characteristics and risk factors for mortality.

Patients with acute leukemia (AL) have a high mortality rate from coronavirus disease 2019 (COVID-19). However, studies including patients with AL and COVID-19 are few. Fifty-one patients with AL and COVID-19 were included in our study. The mortality rate was 17/51 (29.4%). In all cases, death was associated with COVID-19 pneumonia. The major driver of outcome was the disease status (worse outcome was observed in newly diagnosed (OR, 6.00; 95% CI, 1.133 - 15.188) and patients with bone marrow aplasia (OR 4.148 [95% CI 1.133 - 15.188])). Higher mortality rate was associated with lower platelet count, prolonged PT, higher ISTH DIC score, CRP and LDH. Moreover, careful risk-benefit assessment regarding the continuation of anticancer therapy is required in patients receiving nonintensive and supportive therapy. Considering the high frequency of intrahospital viral transmission (50.98%), isolation of AL patients in single rooms, and permanent symptom monitoring and testing should be prioritized.

Potential role of IFN-γ and IL-5 in sepsis prediction of preterm neonates.

Not fully maturated immune system in preterm neonates may contribute to the increased susceptibility to infection. The levels of some cytokines can be useful in the prediction and diagnosis of sepsis in premature neonates. In the present study, we evaluated the potential predictive role of IFN-γ and IL-5 in cord and venous blood, together with the determination of C-reactive protein and procalcitonin (PCT) for sepsis development in premature neonates. A total of 80 participants were included. The laboratory results and clinical histories showed that 21 participants had sepsis. Early onset sepsis was detected in 3 patients while late onset sepsis was observed in 18 participants. The venous plasma levels of IFN-γ and PCT was markedly increased in sepsis groups when compared to the participants without sepsis. On the other hand, levels of IL-5 did not significantly change in the evaluated groups of sepsis and in the control group of participants. Simultaneously, plasma venous levels were not altered in any of the evaluated groups. Obtained findings suggest that venous plasma levels of IFN-γ, rather than levels of IFN-γ in cord blood plasma, and PCT may have predictive potential for sepsis development in preterm neonates. Further studies are necessary to get more comprehension of the complex function of cytokines for sepsis development in preterm neonates.

Generic Imatinib in Chronic Myeloid Leukemia Treatment: Long-Term Follow-up.

BACKGROUND: Similar to the application of other generic drugs, the use of generic imatinib in the treatment of chronic myeloid leukemia (CML) leads to significant cost savings, but it also raises issues related to efficacy, safety, and quality. This study assessed the long-term outcome of CML patients after administration of generic imatinib. PATIENTS AND METHODS: The cohort of 83 patients was divided into 2 groups depending on whether generic imatinib was applied in the front-line setting or after switching from original imatinib. The groups were compared regarding rates of optimal treatment response, adverse events, and survival. RESULTS: In the first group, at the time of switching, rates of complete cytogenetic response experienced, and major molecular response were 95% and 87.5% of patients in the front-line generic imatinib group and the group that switched from original to generic imatinib, respectively. After 24 months of treatment with generic imatinib, the rates of sustained, lost, and experienced major molecular response were 72.5%, 15%, and 12.5%, respectively. In the group treated with front-line generic imatinib at 6 months, 67.4% experienced complete cytogenetic response, while for major molecular response at 12 and 24 months, it was 58.1% and 69.8%, respectively. Estimated 5-year overall survival in the group treated with front-line generic imatinib was 86.1%, while 10-year overall survival in the group treated with second-line generic imatinib was 93.8%. CONCLUSION: Results of this study with long-term follow-up are further evidence that generic imatinib is at least noninferior to original imatinib regarding efficacy and survival, both when provided initially and as a subsequent replacement for original imatinib.

The effect of curcumin and PI3K/Akt inhibitor on monosodium glutamate-induced rat thymocytes toxicity.

Monosodium glutamate (MSG), the sodium salt of glutamic acid, is widely used in modern nutrition as flavor enhancer. However, it has been shown that curcumin has ability to induce apoptosis in the cells of the immune system. In the present study, we evaluate the potential protective effects of curcumin in MSG-induced apoptosis and signaling pathway which may be involved. Rat thymocytes were treated with increased (1, 10, 50 mM) MSG concentrations and/or curcumin (3 µM). Cell apoptosis rate, reactive oxygen species (ROS) production, mitochondrial membrane potential (MMP), Bcl-2, Bax protein expression and caspase-3 activity were determined after 24 hours of incubation. Treatment with MSG resulted with increased apoptosis, ROS production and caspase-3 activity, followed with decreased MMP and Bcl-2/Bax protein ratio. Inhibition of caspase-3 and caspase-9 activity reduced cell apoptosis, indicating the involvement of mitochondrial apoptotic pathway. Co-treatment with curcumin markedly reduced apoptosis and ROS production, together with increased MMP and Bcl2/Bax protein ratio. Inhibition of PI3K/Akt signaling pathway abolished protective effect of curcumin in MSG-induced toxicity in rat thymocytes. Obtained findings suggest that curcumin may attenuate the MSG-induced apoptosis through PI3K/Akt signaling pathway which could be useful in preventing the potential deficiencies in T cell-mediated immunity.

Evaluation of platelet activation in leukocyte-depleted platelet concentrates during storage.

Structural and functional changes in platelets during storage can lead to the loss of platelet reactivity and response. Our aim was to evaluate leukocyte-depleted platelet concentrates on storage days 0, 3 and 5, obtained by in-line filtration. In non-filtered platelet concentrates (NF-PC) group, 180 whole blood units were collected with quadruple blood bags and then compared to another group of 180 whole blood units (leukocyte-depleted platelet concentrates [LD-PC]), collected in Imuflex Whole Blood Filter Saving Platelets (WB-SP) bags with an integrated leukoreduction filter, with regard to the platelet quality and characteristics. The efficacy of the two techniques for platelet concentrate preparation was evaluated by white blood cell (WBC) and platelet count on day 0. The partial pressure of oxygen (pO2), pH, platelets positive for P-selectin (CD62P), CD63, cluster of differentiation 42b (CD42b), phosphatidylserine (PS), and mitochondrial membrane potential (MMP) were analyzed during the storage in both groups. A significantly lower WBC count and higher platelet count was observed in LD-PC compared to NF-PC group, indicating the overall efficacy of the first technique. During the 5-day storage, pH and pO2 decreased in both groups. In LD-PC group, higher pH, increased pO2 and decreased platelet surface expression of CD62P, CD63 and PS were observed compared to NF-PC group. In both groups, the percentage of CD42b positive platelets and MMP did not change significantly during the 5-day period. The assessment of different markers of platelet activation may be an effective tool in evaluating the quality of platelets during storage. A better understanding of platelet activation may provide new insights for developing a novel therapeutic approach in the manipulation of platelet aggregation.

Analyses of Treatment Outcome According to Age in Patients With Chronic Myeloid Leukemia Receiving Front-line Imatinib Therapy.

BACKGROUND: Previous studies have indicated that the effect of age at the diagnosis of chronic myeloid leukemia (CML) is minimized in patients treated with imatinib. The treatment response and survival rates were similar for younger and elderly patients. The aim of the present study was to evaluate the effect of age on the treatment outcomes in patients with CML receiving front-line imatinib therapy. PATIENTS AND METHODS: Using age, 101 patients were divided into 3 groups: young (age, 18-44 years; YP), middle-age (age, 45-64 years; MP), and elderly (age, ≥ 65 years; EP). The patients' clinical features, treatment responses, survival, and adverse events were evaluated. RESULTS: The complete cytogenetic response rates were similar in all 3 groups (81.8% in YP, 86.8% in MP, and 76.7% in EP; P = .328). However, the major molecular response rate was greatest in the MP group (84.2% vs. 63.6% in the YP and 60.0% in the EP group; P < .001). Most of the nonhematologic adverse events (all grades) were in the EP group (40.0% vs. 27.3% in the YP and 21.1% in the MP group; P = .005). The estimated 6-year event-free survival in the MP group (75.5%) was significantly greater than that in the YP group (58.6%) or EP group (43.4%). Also, the estimated 6-year overall survival rate in the EP group (73.5%) was significantly lower than that in the YP group (90.8%) and MP group (86.4%) (P < .001 for all). CONCLUSION: Our results have shown that middle-age patients have the best clinical outcomes, with the greatest rates of an optimal therapeutic response, longer event-free survival, and longer overall survival.

The significance of angiogenesis for predicting optimal therapeutic response in chronic myeloid leukaemia patients.

In this study the correlation and the prognostic value of the morphometric parameters of angiogenesis for optimal therapeutic response to tyrosine kinase inhibitor (TKI) therapy in patients with chronic myeloid leukaemia (CML), i.e. complete cytogenetic response (CCgR) and major molecular response (MMoR), were investigated. Microvascular density (MVD) and a number of different size- and shape-related morphometric parameters of microvessels of bone marrow biopsy from 40 CML patients and 20 controls were examined. Microvessels of bone marrow were examined by using immunohistochemical staining for CD34 and quantified in the region of the most intense vascularisation by using image analysis. CML patients had significantly higher angiogenesis parameters when compared with controls. A statistically significant correlation was found between some parameters of angiogenesis and evaluated CCgR and MMoR. For achievement of CCgR, lower values of MVD, minor axis, area, circularity, and roundness and higher value of aspect ratio, while for achievement of MMoR only lower values of MVD have been identified as positive prognostic factors. Besides confirming increased angiogenesis in CML patients, this study also demonstrated prognostic significance of the degree of angiogenesis for the clinical outcome and identified angiogenic predictive factors for achieving optimal response on TKIs therapy.

Improved prediction of clinical outcome in chronic myeloid leukemia.

We sought to develop and compare prognostic models, based on clinical and/or morphometric diagnostic data, to enable better prediction of complete cytogenetic response (CCgR). This prospective longitudinal study included a consecutive series of patients with chronic myeloid leukemia (CML) who were started on imatinib therapy. Logistic regression analysis using backward selection was performed with CCgR at 6, 12, and 18 months as the outcome variables. We evaluated both calibration and discrimination of the model. Internal validation of the model was performed with bootstrapping techniques. A total of 40 patients on imatinib therapy were included in the final analysis. Of these, 25 (62.5 %), 29 (72.5 %), and 32 (80 %), respectively, achieved CCgR at 6, 12, and 18 months after initiation of imatinib. Models included EUTOS score on diagnosis and one of the following morphometric parameters: microvascular density, length of the minor axis, area or circularity of the blood vessel. Models including morphometric parameters and EUTOS score were superior for prediction of CCgR at 6, 12, and 18 months. In particular, the superior models showed better specificity than EUTOS score alone. Using morphometric parameters in conjunction with EUTOS score improves prediction of CCgR. If validated, these models could aid in individual patient risk stratification.

[Maternal smoking during pregnancy and socioeconomic factors as predictors of low birth weight in term pregnancies in Nis].

BACKGROUND/AIM: Low birth weight (LBW) is a result of preterm birth or intrauterine growth retardation, and in both cases is the strongest single factor associated with perinatal and neonatal mortality. It is considered that socioeconomic factors, as well as mothers bad habits, play the most significant role in the development of LBW, which explains notable number of researches focused on this particular problem. The aim of this study was to characterize socioeconomic factors, as well as smoking habits of the mothers, and their connection with LBW. METHODS: The questionnaire was carried out among mothers of 2 years old children (n = 956), born after 37 gestational weeks. The characteristics of mothers who had children with LBW, defined as < 2,500 g, (n = 50), were matched with the characteristices of mothers who had children > or = 2,500 g, (n = 906). For defining risk factors, and protective factors as well, we used univariant and multivariant logistic modeles. RESULTS: As significant risk factors for LBW in an univariant model we had education level of the mothers, smoking during pregnancy, smoking before pregnancy, the number of daily cigarettes, the number of cigarettes used during pregnancy, paternal earnings and socioeconomic factors. In a multivariant model the most significant factors were socioeconomic factors, education level of the mothers, paternal earnings and mothers smoking during pregnancy. CONCLUSION: Smoking during pregnancy and socioeconomic factors have great influence on LBW. Future studies should be carried out in different social groups, with the intention to define their influence on LBW and reproduction, as well. This should be the proper way of adequate health breeding planning for giving up smoking, the prevention of bad habits and melioration of mothers and children health, as the most vulnerable population.