Monitoring serum levels ELR+ CXC chemokines and the relationship between microvessel density and angiogenic growth factors in multiple myeloma.

BACKGROUND: The ELR+ CXC chemokines are important mediators of tumorigenesis, related to their angiogenic properties. Angiogenesis appears to be a prominent feature in the progression of multiple myeloma (MM). CXC chemokines have four highly conserved cysteine amino acid residues, with the first two cysteine molecules separated by a single amino acid. The angiogenic potential of this group is determined by the presence of three amino acid residues (Glu-Leu-Arg: the ELR motif) preceding the first cysteine amino acid, in the NH2 terminus. AIMS: The purpose of this study was to determine serum concentrations of angiogenesis-related chemokines ELR+ motif, such as interleukin-8 (IL-8), epithelial neutrophil activating protein-78 (ENA-78) and growth-related gene alpha (GRO-α), as well the bone marrow microvascular density (MVD) in patients with MM at diagnosis and after treatment, in plateau phase. We also evaluated the relationship among them with other known growth factors involved in angiogenesis. METHODS: Serum levels of the ELR+ CXC chemokines: IL-8, ENA-78 and GRO-α as well as of the angiogenic factors: hepatocyte growth factor (HGF), vascular endothelial growth factor (VEGF) and tumor necrosis factor-α (TNF-α) were determined in 63 newly diagnosed MM patients, in 30 in plateau phase and in 20 healthy controls. Serum measurements of them were performed with commercially available kits for ELISA. Bone marrow biopsies were performed before and after treatment, in plateau phase, in order to determine MVD by staining vessels with anti-CD31. RESULTS: Serum concentrations of IL-8, ENA-78, GRO-α and TNF-α were significantly higher in the group of MM patients (44.5±25.3, 765±572.1, 186.5±129.1 and 4.2±2.8 pg/ml, respectively) in comparison to control group (27.3±6.4, 335.1±268.6, 112.5±76.1 and 1.3±0.8 pg/ml) (p<0.02 for GRO-α, p<0.001 for other cases). We also found that untreated patients had higher levels of IL-8, ENA-78, GRO-α than post treatment patients, but statistical significant difference was found only for IL-8 (48.36±30.93 pg/ml vs. 35.05±19.77 pg/ml, p<0.001). Furthermore IL-8, GRO-α, TNF-α, HGF and VEGF were significantly higher with increasing disease stage (p<0.001 in all cases). ENA-78 serum levels were higher in stage III than in stage I and II, but without statistical significance. Additionally we correlated each proinflammatory cytokine with well known angiogenic factors such as HGF, VEGF and TNF-α. A positive correlation was found between serum HGF and IL-8 and GRO-α (r=0.316 p<0.01, r=0.297 p<0.02, respectively). Similarly serum VEGF correlated with ENA-78 and GRO-α (r=0.323 p<0.01, r=0.469 p<0.001, respectively). In the pretreatment group of patients a positive correlation between bone marrow MVD and serum levels of GRO-α was found (r=0.304 p<0.01). There was a difference in survival times between patients with higher than median versus low IL-8, ENA-78 and GRO-α levels, but the differences could not reach statistical significance in either case. CONCLUSIONS: These findings support the hypothesis that ELR+ motif CXC chemokines, such as IL-8, ENA-78 and GRO-α correlate with angiogenic growth factors and may play a role in the progression of MM. Further studies are needed to determine their prognostic and predictive significance.

Angiogenesis-related cytokines, RANKL, and osteoprotegerin in multiple myeloma patients in relation to clinical features and response to treatment.

An essential cytokine system for the osteoclast biology in multiple myeloma (MM) consists of the receptor of activator of NF-κB ligand (RANKL), its receptor (RANK), and the soluble decoy receptor, osteoprotegerin (OPG). Myeloma cells cause imbalance in OPG/RANKL interactions. We measured serum levels of OPG, soluble (s) RANKL, sRANKL/OPG ratio, markers of disease activity [LDH, CRP, interleukin-6 (IL-6), ß2-microglobulin (B2M)], and angiogenic factors [hepatocyte growth factor (HGF), vascular endothelial growth factor (VEGF)], in 54 newly diagnosed MM patients and in 25 of them in plateau phase. All the above values were higher in MM patients compared to controls and decreased in plateau phase. sRANKL and RANKL/OPG were higher with advancing disease stage and skeletal grade. Significant correlations were found among RANKL and RANKL/OPG with HGF, LDH, VEGF, IL-6, and B2M. In conclusion, RANKL and OPG play significant roles in MM pathophysiology, as regulators of bone turnover and mediators of angiogenesis.

Impact of the COVID-19 pandemic on hospitalizations for acute coronary syndromes: a multinational study.

BACKGROUND: COVID-19 has challenged the health system organization requiring a fast reorganization of diagnostic/therapeutic pathways for patients affected by time-dependent diseases such as acute coronary syndromes (ACS). AIM: To describe ACS hospitalizations, management, and complication rate before and after the COVID-19 pandemic was declared. DESIGN: Ecological retrospective study. Methods: We analyzed aggregated epidemiological data of all patients > 18 years old admitted for ACS in twenty-nine hub cardiac centers from 17 Countries across 4 continents, from December 1st, 2019 to April 15th, 2020. Data from December 2018 to April 2019 were used as historical period. RESULTS: A significant overall trend for reduction in the weekly number of ACS hospitalizations was observed (20.2%; 95% confidence interval CI [1.6, 35.4] P = 0.04). The incidence rate reached a 54% reduction during the second week of April (incidence rate ratio: 0.46, 95% CI [0.36, 0.58]) and was also significant when compared to the same months in 2019 (March and April, respectively IRR: 0.56, 95%CI [0.48, 0.67]; IRR: 0.43, 95%CI [0.32, 0.58] p < 0.001). A significant increase in door-to-balloon, door-to-needle, and total ischemic time (p <0.04 for all) in STEMI patents were reported during pandemic period. Finally, the proportion of patients with mechanical complications was higher (1.98% vs. 0.98%; P = 0.006) whereas GRACE risk score was not different. CONCLUSIONS: Our results confirm that COVID-19 pandemic was associated with a significant decrease in ACS hospitalizations rate, an increase in total ischemic time and a higher rate of mechanical complications on a international scale.

Clinical significance of sCD105 in angiogenesis and disease activity in multiple myeloma.

BACKGROUND: Τhe importance of angiogenesis in malignancies' growth is well recognized. CD105 (Endoglin), a proliferation-associated glycoprotein, is a powerful marker of neovascularization. Elevated amounts of soluble CD105 (sCD105) have been identified in selected solid tumors. The aim of the study was to estimate circulating levels of sCD105 and soluble transforming growth factor-ß(1) (sTGF-ß(1)), in multiple myeloma (MM) patients, to determine their significance in tumor progression and to investigate the correlation between sCD105 and markers of disease activity. METHODS: We studied 50 newly diagnosed MM patients. Twenty-five of them were also investigated in plateauphase. Twenty patients with monoclonal gammopathy of undetermined significance (MGUS) were enrolled in this study. As control group 28 healthy persons were studied. We determined sCD105, sTGF-ß(1) and interleukin-6 (IL-6) in the serum, Ki-67 proliferation index (Ki-67 PI) expression and microvascular density(MVD) in bone marrow with immunohistochemistry. RESULTS: The mean concentrations of sCD105 and IL-6 were higher in MM and MGUS patients compared to controls, whereas serum levels of sTGF-ß(1) were lower in MM patients compared to MGUS patients and controls. sCD105 levels, were significantly different among disease stages, with higher values in advanced stages. It was found that sCD105 correlated with Ki-67 PI, MVD and IL-6. CONCLUSIONS: CD105 seems to play an important role in angiogenesis and tumor progression. Circulating levels of sCD105 could detect patients with more advanced disease and might help in evaluating the response to treatment.