IL-6 and IL-10 promoter gene polymorphisms do not associate with the susceptibility for multiple myeloma

Multiple myeloma (MM) is a plasma cell malignancy characterised by bone marrow infiltration and the presence of a monoclonal protein in serum and/or urine. Interleukin-6 (IL-6) has been identified as one of the most important cytokines that contributes to myeloma cell survival and proliferation. Recent investigations suggest involvement of another cytokine, IL-10, in the activation of MM cells. The present study aimed to determine whether there is an association between the polymorphic features located within the promoter regions of IL-6 and IL-10 genes and progression the disease. IL-6 (-174 G/C) and IL-10 (-1082 A/G, -819 C/T, -592 A/C) promoter single nucleotide polymorphisms (SNPs) were determined by PCR-SSP technique using commercial primers. Our single centre results were compared with the data from literature and combined in cumulative analysis employing the Mantel-Haenszel method. In univariate analysis, only IL-10 ACC genotype tended to prevail in our (Polish) group of patients. None of IL-6 genotypes or IL-10 (-1082) alleles was found to associate with MM disease either in our single centre or in cumulative study. Among patients who died within 36 months of diagnosis, a significant prevalence (P < 0.05) of IL-6 heterozygous cases as opposed to IL-6 homozygotes was observed. IL-6 and IL-10 promoter gene polymorphisms were not found to associate with the susceptibility to the development of MM. However, the IL-6 polymorphic features appeared as factors that might affect the survival of MM patients. The latter observation warrants further study.     

Serum level of beta-chemokine RANTES in patients with coronary artery disease

Chronic inflammatory process plays an important, as still not clear, role in pathophysiology of coronary artery disease (CAD), especially in acute coronary syndromes. Chemokines are present in atherosclerotic plaques and are essential factors in the recruitment of leukocytes and stabilization of atherosclerotic lesions. The aim of the study was the evaluation of RANTES serum level in patients with stabile CAD and seeking for correlations between RANTES serum level and progression of atherosclerotic lesions. The study included 83 patients from 22 to 87 years old, 41 women (mean age 61,2 +/- 12,5) and 42 men (mean age 58,8 +/- 15,4), who were admitted to the Cardiology Department for coronarography. After coronarography the patients were separated in 4 groups according to the presence of atherosclerotic lesions. Patients with atherosclerotic lesions were also divided depending on the severity of anginal pains to CCS II or CCS III classes. Blood samples for the measurement of RANTES serum level were taken at baseline conditions on the day after the admittance to the hospital. RANTES serum level was measured by enzyme-linked immunoabsorbent assay (ELISA) kit system (Endogen, MA, USA). There was not statistically significant differance in RANTES serum level between patients with CAD and subjects without atherosclerotic lesions in coronary arteries with or without arterial hypertension. Significantly higher levels of RANTES were observed in patients with atherosclerotic lesions in coronary arteries and anginal pains in CCS II class, than in patients with atherosclerotic lesions in coronary arteries and anginal pains in CCS II class, as well as in subjects without atherosclerotic lesions (respectively 58.5 vs 42.1 pg/ml and 54.5 vs 41.9 pg/ml, p<0.01). Significant positive corellations were found in patients with CAD between RANTES serum level and systolic blood pressure (r Pearson 0,291, p<0.05), and cholesterol (R Spearman 0.289, p<0.05). In all patients analysis of regression found significant correlation between RANTES serum level and systolic blood pressure (p 0.296, B 0.391, p<0.007). These results may indicate the active implication of chemokines in the pathophysiology of atherosclerotic lesions.     

Ofatumumab monotherapy in rituximab-refractory follicular lymphoma: results from a multicenter study

New treatments are required for rituximab-refractory follicular lymphoma (FL). In the present study, patients with rituximab-refractory FL received 8 weekly infusions of ofatumumab (CD20 mAb; dose 1, 300 mg and doses 2-8, 500 or 1000 mg; N = 116). The median age of these patients was 61 years, 47% had high-risk Follicular Lymphoma International Prognostic Index scores, 65% were chemotherapy-refractory, and the median number of prior therapies was 4. The overall response rate was 13% and 10% for the 500-mg and 1000-mg arms, respectively. Among 27 patients refractory to rituximab monotherapy, the overall response rate was 22%. The median progression-free survival was 5.8 months. Forty-six percent of patients demonstrated tumor reduction 3 months after therapy initiation, and the median progression-free survival for these patients was 9.1 months. The most common adverse events included infections, rash, urticaria, fatigue, and pruritus. Three patients experienced grade 3 infusion-related reactions, none of which were considered serious events. Grade 3-4 neutropenia, leukopenia, anemia, and thrombocytopenia occurred in a subset of patients. Ofatumumab was well tolerated and modestly active in this heavily pretreated, rituximab-refractory population and is therefore now being studied in less refractory FL and in combination with other agents in various B-cell neoplasms. The present study was registered at www.clinicaltrials.gov as NCT00394836.     

A risk of essential thrombocythemia in carriers of constitutional CHEK2 gene mutations

Germline mutations of the CHEK2 gene have been reported in some myeloid and lymphoid malignancies, but their impact on development of essential thrombocythemia has not been studied. In 16 out of 106 (15.1%) consecutive patients, newly diagnosed with essential thrombocythemia, we found one of four analyzed CHEK2 mutations: I157T, 1100delC, IVS2+1G>A or del5395. They were associated with the increased risk of disease (OR=3.8; P=0.002). The median age at ET diagnosis among CHEK2+/JAK2V617F+ patients was seven years lower than that among CHEK2-/JAK2V617F+ (52 vs. 59 years; P=0.04), whereas there was no difference in the medians of hematologic parameters between these groups. The results obtained suggest that CHEK2 mutations could potentially contribute to the susceptibility to essential thrombocythemia. The germline inactivation of CHEK2, as it seems, has no direct impact on the development of disease, but it could cause disruption of cell cycle checkpoints and initiate or support the cancerogenic process of essential thrombocythemia at a younger age.     

Expression of serum vascular endothelial growth factor correlates with clinical outcome in multiple myeloma

A total of 34 multiple myeloma (MM) patients (17 recently diagnosed and 17 in progression of the disease) treated at the Department of Haematology, Blood Neoplasms and Bone Marrow Transplantation Medical University in Wroc?aw were studied. Among the 19 females and 15 males, aged 31-72 years, there were 17 IgG, 9 IgA and 1 IgM, one with plasma cell leukaemia and 6 with light chain disease. Staging according to Durie and Salmon disclosed: 7--IIA stage, 15--IIIA and 12--IIIB. Blood hyperviscosity symptoms (HS) developed in 9 patients, and precomatic state or coma was observed in four of them. Control group was constituted of 14 healthy subjects--10 women and 4 men aged 32-51 years. Vascular endothelial growth factor (VEGF) serum concentration in MM patients varied from 0 pg/ml to 760 pg/ml, mean 148.75 pg/ml, SD = 204.4 and in controls 0 pg/ml--164 pg/ml, mean 31.5, SD = 23.3; p < 0.05. The mean VEGF level in recently diagnosed patients was higher than in progression of the disease, mean 188.6 pg/ml, SD = 230.6 and mean 110.9 pg/ml, SD = 177.9; respectively, but the difference was not statistically significant. The patients with stage III had significantly (p < 0.05) higher VEGF level than those in stage II (mean 303.1 pg/ml, SD = 302.2 and mean 89.0 pg/ml SD = 121.6) respectively. The group of MM patients with renal failure (creatinine level > 2 mg%) had higher VEGF level than those with normal renal function: mean 199.9 pg/ml, SD = 235, and mean 46.9 SD = 47 respectively, p < 0.01. Elevated VEGF level was also present in comatic and precomatic patients when compared with hyperviscosity patients without these symptoms (p < 0.05). In multiple myeloma patients no correlation was found between the serum VEGF level and percentage of bone marrow plasma cells, serum beta-2-m and monoclonal Ig levels, levels of Hb, albumine and LDH. Median survival time (M-ST) of patients with VEGF higher than 71, 0 pg/ml was 32 months, M-ST of patients with VEGF below 71 pg/ml was 52 months. In summary: serum level of VEGF in advanced state of multiple myeloma was elevated and correlated with clinical state. An elevated serum level of VEGF is associated with a poor prognosis.     

LYVE-1 expression on high endothelial venules (HEVs) of lymph nodes

LYVE-1 (lymphatic endothelium hyaluronan receptor) has been identified as a powerful marker for lymphatic endothelium. Apart from lymphatic endothelium, LYVE-1 is expressed in normal liver blood sinusoids, spleen endothelium and activated tissue macrophages. LYVE-1 has not been detected in blood vascular endothelium with the exception of blood vessels in the lung. High endothelial venules (HEVs) belong to the vascular compartment of lymph nodes. They are the major site of entry for circulating lymphocytes into the node. HEVs are characterized by cuboidal endothelial cells, the existence of discontinuous junctions between these endothelial cells, and the presence of large numbers of lymphocytes within their walls. 40 paraffin-embedded lymph node biopsy specimens from newly diagnosed patients with non-Hodgkin lymphoma were evaluated as well as 10 lymph node biopsy specimens from adult patients with reactive lymphadenitis, and 10 normal, non-metastatic lymph nodes obtained from adult patients during cancer surgery served as controls. Samples were fixed in 10% buffered formalin, paraffin embedded, and stained with hematoxylin and eosin for histopathological evaluation. Sections were also evaluated with mouse monoclonal antibodies against LYVE-1 and CD34, and expression of both LYVE-1 and CD34 was demonstrated in HEVs. LYVE-1 expression was also found on the endothelial cells of the lymphatic sinus and in reticular cells in the lymph nodes.     

Expression of p16INK4a,p15INK4b,p21WAF1/Clip1 cell cycle inhibitors on blastic cells in patients with acute myeloblastic leukemia (AML) and acute lymphoblastic leukemia (ALL)

Cyclin-dependent kinases (cdk) play the important role in neoplastic transformation. Their activity depends on interaction with proteins called inhibitors. There are two groups of inhibitors: INK4 (p16INK4a, p15INK4b, p18INK4c, p19INK4d) and proteins p21WAF1/Clip1, p27Kip1, p57Kip2. Alteration of inhibitors expression was assessed in acute lymphoblastic leukemia (ALL) and in acute myeloblastic leukemia (AML), but the results are not clear. The aim of our study was to estimate p16INK4a, p15INK-4b, p21WAF1/Clip1 expression in blast cells in patients with AML and ALL by cytochemistry method and to compare with the result of treatment. Forty-two patients were included in the study, 23 with AML and 19 with ALL. Expression of inhibitors was considered as positive when detected in > 5% of blast cells. Complete remission (CR) rate in patients with positive expression p16INK4a and p15INK4b was statistically significantly higher than in patients with negative expression: for p16INK4a chi 2 = 7.78, p < 0.01, for p15INK4b, chi 2 with Yates' modification = 3.94, p < 0.05. There was no difference in CR rate in patients with positive and negative p21WAF1/Clip1 expression. Moreover the patients with simultaneous expression of three inhibitors reached CR more often than the others: chi 2 = 7.43, p = 0.01 for AML and chi 2 = 6.74, p < 0.01 for ALL. Our study indicates that estimation of p16INK4a, p15INK4b, p21WAF1/Clip1 expression in blast cells can be used as prognostic factor in acute leukemia.     

Aspirin resistance in ischaemic heart disease

BACKGROUND: In spite of the usage of acetylsalicylic acid (aspirin) in the secondary prevention of ischaemic heart disease (IHD), new thrombo-embolic events occur in more than half of patients. Aspirin resistance may be partially responsible for this phenomenon. AIM: To assess the prevalence of aspirin resistance in patients with IHD and to correlate this phenomenon with the progression of atherosclerosis, concomitant diseases and other medication. METHODS: The study group consisted of 205 patients (mean age 65.8 years, 95 females) with stable angina, recent coronary angiography and positive result of non-invasive stress tests, treated with 75 mg of aspirin for at least one week. Platelet aggregation was measured using the optical aggregation method. Aspirin resistance was defined as a mean collagen and ATP-induced platelet aggregation >70%. RESULTS: Aspirin resistance was found in 41 (20%) patients and was significantly associated with previous coronary artery bypass grafting (CABG) (p<0.01) and three-vessel disease (p<0.05). Previous CABG was the only independent risk factor for the presence of aspirin resistance (OR 5.6; 95% CI 2.0-15.4; p<0.01). CONCLUSIONS: Aspirin resistance is present in 20% of patients with stable angina. Previous CABG is an independent risk factor of this phenomenon.     

Extramedullary hematopoiesis in inguinal lymph nodes in the course of osteomyelofibrosis--case report

Osteomyelofibrosis (OMF) is a chronic myeloproliferative disorder characterized by bone marrow fibrosis, suppression of hematopoiesis and extramedullary hematopoiesis. Extramedullary hematopoiesis usually occurs in spleen and liver, however it may be observed in another sites. We present a patient with OMF accompanied by myeloid metaplasia in inguinal lymph nodes.