Giacomo Bellomo

Differential levels of soluble endoglin (CD105) in myeloid malignancies.

Angiogenesis contributes to disease progression in solid and hematopoietic malignancies, and endoglin (CD105), a component of the transforming growth factor (TGF)‐β receptor complex, is a powerful marker of neovascularization. Elevated amounts of soluble CD105 (sCD105) have been recently identified in selected solid tumors but no data are available on sCD105 in hematopoietic malignancies. Therefore, levels of sCD105 were investigated in sera of patients with acute myeloid leukemia (AML) (n = 10) or chronic myeloproliferative disorders (CMD) (n = 28), and correlated with those of soluble TGF‐β1 (sTGF‐β1). Dot blot assay detected higher amounts of sCD105 (P < 0.05) both in AML (4.34 ± 2.62 OD/mm2) and in CMD (3.71 ± 2.09 OD/mm2) patients than in healthy subjects (n = 14, 2.38 ± 1.18 OD/mm2). Instead, enzyme‐linked immunosorbent assay (ELISA) identified (P < 0.05) lower and higher levels of sTGF‐β1 in AML (32,017 ± 1,900 pg/ml) and CMD (60,700 ± 19,200 pg/ml) patients, respectively, compared to healthy individuals (n = 11, 47,173 ± 5,443 pg/ml). In essential thrombocythemia (ET) patients with thrombotic episodes, levels of sCD105 were lower (P < 0.05) compared to patients without thrombotic complications, and inversely correlated with those of sTGF‐β1 (r = 0.94). Conversely, amounts of sCD105 directly correlated with levels of sTGF‐β1 (r = 0.74) in ET patients without thrombotic events. Our results show that high levels of sCD105 are present in myeloid malignancies that are characterized by a high cellular proliferation rate, and suggest that an altered balance between sCD105 and sTGF‐β1 might favor disease progression and clinical complications.

Differential levels of soluble angiopoietin-2 and Tie-2 in patients with haematological malignancies

The system involving angiopoietin‐2 (Ang‐2) and its receptor, Tie‐2, appears to play an important role not only in tumor angiogenesis, but also in the biology of haematological and non‐haematological malignancies. In the present study we evaluated the serum levels of soluble Ang‐2 (sAng‐2) and soluble Tie‐2 (sTie‐2) in patients with haematological malignancies. Measurements were carried out in 15 patients with chronic myeloid leukaemia (CML), 25 with essential thrombocythemia (ET), 24 with multiple myeloma (MM) and six with monoclonal gammopathy of undetermined significance (MGUS). In addition, we correlated the levels of angiopoietins with known prognostic factors. sAng‐2 and sTie‐2 were quantified with enzyme‐linked immunosorbent assay (ELISA). In patients with CML and MM the levels of sAng‐2 were significantly higher (1686.53 ± 936.41 pg/mL and 1917.82 ± 1427 pg/mL, respectively) than in controls (n = 15; 996.096 ± 414.65 pg/mL) (P < 0.01). In patients with MM sAng‐2 levels were significantly increased with increasing stage of disease, from stage I to stage III (P < 0.03) and presented a trend of correlation with Beta2‐microglobulin levels (r = 0.317) and grade of bone involvement. Furthermore, the levels of sAng‐2 determined after 6 months of chemotherapy in CML patients were significantly lower than at diagnosis in the patients who achieved haematological remission. Circulating sTie‐2 levels were increased in patients with ET (17.5 ± 9.2 vs 9 ± 3.5 ng/mL; P < 0.01) and in those with CML (16.29 ± 8.7 ng/mL; P < 0.04). In conclusion, abnormal levels of sAng‐2 and sTie‐2 are present in some haematological malignancies. These markers may play a role in the pathophysiology of these conditions and their progression.

Evaluation of circulating endothelial cells, VEGF and VEGFR2 serum levels in patients with chronic myeloproliferative diseases

Authors evaluated some markers of angiogenetic activity in patients with chronic myeloproliferative diseases (CMDs). In this study by using a cytofluorimetric analysis we evaluated circulating endothelial progenitor cells (EPCs) in patients with chronic myeloproliferative disease. Moreover, in the same group of subjects, we evaluated serum levels of vascular endothelial growth factor (VEGF) and vascular endothelial growth factor receptor‐2 (VEGFR2). In our patients, we have found an increase in the number of endothelial progenitor cells in primary myelofibrosis (PMF) and polycythaemia vera (PV) patients, while an increase of circulating endothelial cells (CECs) was found in all patients with CMD. Moreover, we found higher serum levels of VEGF with respect to control subjects in every group of patients with CMD, and a not significant reduction of VEGFR2 levels in essential thrombocythaemia (ET) patients. A correlation was also found in PV patients between VEGF levels and erythrocyte number and in PMF subjects with the count of white cells. Our data suggest that some markers of angiogenesis are activated in CMD patients and angiogenesis may have a role in the pathophysiology of chronic myeloproliferative disorders. Copyright

Markers of Endothelial and Platelet Status in Patients with Essential Thrombocythemia and Polycythemia Vera.

Vascular complications are the main cause of morbidity in polycythemia vera (PV) and essential thrombocythemia (ET). To investigate plasma concentrations of soluble P-selectin (sP-Sel.), soluble E-selectin (sE-Sel.) and soluble thrombomodulin (sTM) in relation to the presence of thromboembolic events 38 patients with Chronic Myeloproliferative Disorders (CMD) (14 PV pts and 24 ET pts), 15 age-matched controls and 15 patients with secondary thrombocytosis were studied. Plasma levels of P-Sel., E-Sel. and TM were significantly increased in the group of patients as compared with control subjects (respectively p < 0.001, p < 0.04 and p < 0.01). sP-Sel. levels showed no significant difference between the patients and those with secondary thrombocytosis. No difference in sP-sel levels were also observed between subgroups of CMD patients with and without vascular complications. However, among patients with ET, those with thrombosis had higher sP-Sel levels than those without thrombosis (1.177 ± 110.48 ng/ml vs 816.25 ± 99.27 ng/ml). High levels of sE-Sel and sTM were found in CMD patients (71.93 ± 39.08 ng/ml and 35.81 ± 20.79 ng/ml, respectively). Plasma sE-Sel. concentration was significantly higher in CMD patients with thrombosis than that in CMD patients without thrombosis (p < 0.001). There was no difference in sTM concentration between two groups. These findings indicate that sustained endothelium and platelet activation is present in patients with ET and PV and it might contribute to the pathogenesis of thromboembolic events in these patients.

Patients with bisphosphonate-associated osteonecrosis of the jaw have unmodified levels of soluble vascular endothelial growth factor receptor 1.

In an article recently published in Leukemia and Lymphoma, Pozzi et al. reported 35 cases of bisphosphonate-associated osteonecrosis of the jaw (ONJ) in multiple myeloma patients [1]. In fact, sinc...

Increased serum levels of neutrophil gelatinase-associated lipocalin in patients with essential thrombocythemia and polycythemia vera

Neutrophil gelatinaase-associated lipocalin (NGAL) is a glycoprotein bound with matrix metalloproteinase-9 (MMP-9) in human neutrophils, and elevated tissue NGAL expression has been documented in different infectious and inflammatory conditions. Recent evidence suggests that NGAL expression is induced in many types of human cancer. Moreover, NGAL is required for BCR–ABL-induced tumorigenesis. The aim of the present study was to measure serum levels of NGAL in patients with essential thrombocythemia (ET) and polycythemia vera (PV). We also evaluated NGAL levels in patients with ET and PV with and without thrombotic events, to explore a possible correlation of NGAL with platelet and leukocyte activation, and in patients with sepsis. Serum NGAL levels in the study population were significantly higher than in healthy adults and in subjects with sepsis. A correlation between NGAL and the number of white cells and neutrophils was found in patients with PV and ET. NGAL serum levels were not different depending on the presence or not of the JAK2 mutation, and a mutant allele dosage effect was not observed for NGAL levels. Patients with PV and ET with thrombosis did not have significantly higher levels of NGAL. We were unable to demonstrate a significant association between serum NGAL levels and CD11b or CD62 expression. In conclusion, our study reports evidence demonstrating that increased levels of NGAL appear to be a characteristic of patients with PV and ET.

Increase of novel biomarkers for oxidative stress in patients with plasma cell disorders and in multiple myeloma patients with bone lesions

ObjectivesProtein oxidation plays a key role in the pathogenesis of oncological diseases. In this study, we analyzed the oxidative stress in untreated multiple myeloma (MM) patients and in patients affected by monoclonal gammopathy of uncertain significance (MGUS).MethodsWe evaluated serum levels of advanced oxidation protein products (AOPPs), advanced glycation end products (AGEs), and protein nitrosylation in patients with monoclonal gammopathy and in control subjects.ResultsSerum levels of AOPPs and S-nitrosylated proteins were significantly increased in MM patients in comparison to controls and to MGUS subjects. Moreover, in MM patients the levels of AOPPs, AGEs and S-nitrosylated proteins were significantly higher in patients with bone lesions compared with those without lytic bone lesions.ConclusionsMM is closely associated with oxidative stress and further investigation might provide an insight to understand a putative causal link between oxidative stress and MM disease onset and progression or MM complications.

Imatinib mesylate therapy induces reduction in neutrophil gelatinase-associated lipocalin serum levels and increase in leptin concentrations in chronic myeloid leukemia patients in molecular remission.

The aim of the present study was to determine serum levels of neutrophil gelatinase-associated lipocalin (NGAL) and leptin in patients with chronic myeloid leukemia (CML) at diagnosis and after imatinib therapy when patients achieved a complete molecular remission. The study was conducted on 22 patients with CML in the chronic phase and 10 healthy subjects. The median serum NGAL levels in CML patients at diagnosis were significantly higher compared to age-matched controls. After imatinib therapy, all patients achieved complete molecular remission and NGAL levels decreased and were found significantly lower with respect to the baseline. No significant correlations were found between NGAL levels and other disease parameters. Before imatinib therapy, the median blood leptin levels were not significantly different from those of controls. After therapy with imatinib, all patients in molecular remission presented an increase in leptin levels. Future research is eagerly awaited as it may demonstrate the real role of NGAL and leptin in the onset and progression of CML.

Serum levels of interleukin-16 in lymphoid malignancies

Interleukin-16 (IL-16), also named lymphocytic chemoattractant factor, is produced mainly by CD8þ peripheral blood lymphocytes but also by CD4þ T cells, eosinophils, mast cells, and bronchial epithelial cells after stimulation. IL-16 induces chemotaxis of CD4þ T cells, monocytes, and eosinophils [1]. The cytokine contributes in fact to the regulatory process of CD4þ cell recruitment and activation at sites of inflammation [2]. In addition, it stimulates the production of cytokines such as IL-6, TNF-alpha, IL-1, and IL-15 by monocytes, playing an essential role in initiating the inflammatory response [3]. It was recently reported that B-lymphocytes too express IL-16 mRNA and synthetize protein [4], and that the levels of IL-16 can be modified in lymphoid neoplastic diseases. Previous studies reported that serum IL-16 levels were higher in untreated multiple myeloma (MM) patients as compared with normal controls and that there was a strong correlation between the serum IL-16 level and disease activity [5]. Moreover, it has recently been reported that IL16 mRNA was detected in all of 18 mycosis fungoides (MF) lesions investigated by an in situ hybridization technique, suggesting that IL-16 might be involved in skin homing in MF [6]. In our study, we investigated the levels of IL-16 in sera of patients affected by haematologic malignancies and correlated them with known prognostic factors to provide preliminary insights on the biological relevance of this cytokine in selected haematologic malignancies. Sixty-four previously untreated chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/ SLL) patients were included in this study. Their median age was 65 years (range 43 – 87) and the male/female ratio was 35:29. Routine laboratory studies consisted of complete blood count with differential, platelet count, and blood chemistry including beta-2microglobulin (b2m) and lactate dehydrogenase (LDH), as well as immunonophenotyping. Physical examination, chest X-ray, and abdominal ultrasound were performed in all instances. In this group of patients a bone marrow biopsy allowed us to select 52 patients with B-chronic lymphocytic leukemia (B-CLL) that were clinically staged according to the Rai system and distributed as follows: Stage 0, 14; Stages I – II, 28; and Stages III – IV, 10. Four previously untreated patients with mantle cell lymphoma and five with follicular lymphoma were also studied. Their median age was 64 years (range 47 – 79). Diagnosis was made by routine histological and immunohistochemical examination. The study population included 19 newly diagnosed patients with MM with a median age of 62 years (range 37 – 78 years). According to the DurieSalmon staging system, three patients had MM disease stage I, nine patients had stage II, and seven patients had disease stage III. The paraprotein class was immunoglobulin IgG in 12 patients and IgA in 7 patients. Serum samples were collected from patients and from 20 ageand sex-matched normal controls and were aliquoted into separate vials and stored at 7708C until use. Informed consent was obtained from all individuals participating in the study. The

Cardiac Involvement in Patients With Hematologic Malignancies

Authors have reviewed literature about the management of patients with cardiologic disease occurring secondary to hematologic pathology itself or its therapy, with a focus on infiltration of myocardium in acute and chronic leukemia, lymphoma, multiple myeloma, and hypereosinophilic syndrome. Moreover, they evaluated chemotherapy-associated toxicity, particularly for new drugs such as monoclonal antibody therapy, tyrosine kinase inhibitors, arsenic trioxide, bortezomib, and epigenetic therapy. In fact, cardiac toxicity may range from asymptomatic subclinical abnormalities, such as electrocardiographic changes and left ventricular ejection decline, to life-threatening events and lead to chemotherapy dose reduction and delay and, in some cases, for patients with severe side effects, discontinuation of treatment. Finally, they discussed on the identification of early markers of cardiac injury and on cardiac stem cell therapy as a promising approach to facilitate myocardial regeneration.