The importance of biomarcers for estimation of joint damage in patients with hemophilia

Hemofilna artropatija,, sa karakterističnim oštećenjima zglobova, vodeći je uzrok morbiditeta kod bolesnika sa teškom hemofilijom. Kontinuirana profilaksa intravenskom primenom primenom faktora (F) VIII i IX je glavna klinička strategija u lečenju ovih bolesnika. Nedavno je pokazano da se biomarkeri razgradnje zglobne hrskavice mogu detektovati u serumu iili urinu i odražavaju stepen ukupnog oštećenja zglobova kod bolesnika sa hemofilijom. Ciljevi ove studije bili su: a) uporediti validnost dva laboratorijska testa – rotaciona tromboelastometrija (ROTEM) i potencijal endogenog trombina (ETP) u praćenju efikasnosti dva različita profilaktička režima lečenja bolesnika sa teškom hemofilijom; b) odrediti korelaciju između koncentracije biomarkera degradacije zglobne hrskavice u serumu i urinu i radiološkog skora za hemofilnu artropatiju; c) proceniti da li određivannje koncentracije ovih biomarkera može biti korisna u praćenju efikasnosti različitih režima profilakse teške hemofilije. Ova studija obuhvatila je 20 odraslih bolesnika sa teškom hemofilijom. Pet bolesnika sa hemofilijom A primalo je profilaksu koncentratom FVIII u standardnoj dozi od 20 i.j./kg tri puta nedeljno, pet bolesnika sa hemofilijom A primalo je kao profilaksu intermedijarne doze koncentrata FVIII, 10-15 i.j./kg tri puta nedeljno. Sedam bolesnika sa hemofilijom A i tri bolesnika sa hemofilijom B primalo je koncentrat FVIII/IX samo po potrebi (“on demand). Kod bolesnika na profilaktičkoj terapiji, ROTEM i ETP određivani su inicijalno pre početka profilakse, zatim, 20 minuta nakon primene prve doze profilakse i posle tri meseca, pre primene sledeće profilaktičke doze. Kod bolesnika na “on demand” terapiji, ROTEM i ETP rađeni su dva puta u intervalu od tri meseca. U ROTEM testu određivano je vreme koagulacije (CT) unutrašnjeg puta (INTEM), dok je kod ETP određivana kalkulisana vrednost površine ispod krive generacije trombina (ETP.AUC.cal) i kalkulisane vrednosti maksimalne koagulacije (ETP.Cmax.cal)...Haemophilic arthropathy, with characteristic joint damage, is the main cause of morbidity in individuals with severe haemophilia. The most important clinical strategy for management of these patients is treatment by continous prophylaxis with intravenously applied factor (F) VIII/IX. Recently, it was shown that serum and/or urine biomarkers of cartilage turnover in joints reflected the degree of total joint degradation in haemophilia patients. The aims of this study were: a) to compare validity of two laboratory assays – rotating thromboelastometry (ROTEM) and endogenous thrombin potential (ETP) in monitoring and evaluating different prophylactic treatment regimens in patients with severe haemophilia; b) to detect correlations between serum and urine concentrations of biomarkers of joint cartilage degradation and the radiological score for haemophilic arthropathy and c) to estimate whether measurement of these biomarkers could be useful in monitoring the efficacy of different prophylaxis regimens for severe haemophilia. This study included 20 adults patients with severe haemophilia, without inhibitor. Five patients with haemophilia A were received prophylaxis with factor VIII (FVIII) concentrate in standard dose 20 IU/kg three times per week, five patients with haemophilia A were received intermediate dose of FVIII concentrate as prophylaxis, 10- 15 IU/kg three times per week. Seven patients with haemophilia A and 3 with haemophilia B, were received FVIII/IX concentrate only on-demand. In patients on prophylactic therapy, ROTEM and ETP were done initially before start of prophylaxis, in addition, 20 minutes after application of first prophylactic dose and afterwards 3 months, before receiving next prophylactic dose. In patients treated only on-demand, ROTEM and ETP were done twice per three-months period. In ROTEM, clotting time (CT) in intrinsic system (INTEM) was measured, whereas in ETP,calculated values of area under the thrombin generation curve (ETP.AUC2.cal) and calculated values of maximal clotting (ETP.Cmax.cal) were estimated..

Monosomy 12 and deletion of 13q34 in a case of chronic lymphocytic leukemia with concomitant lung cancer

Background. We described a patient with chronic lymphocytic leukemia (CLL) and lung cancer and unusual chromosomal aberrations. Case report. At the same time with the diagnosis of B-cell CLL, squamocellular lung carcinoma diagnosis was established. Using interphase fluoresecence in situ hybridization technique (FISH) we detected monosomy 12 and deletion of 13q34 occured in the same clone. One month after the beginning of examination the patient died unexpectedly during sleep immediately before we applied a specific treatment for CLL or lung carcinoma. Conclusion. Simultaneous occurrence of monosomy 12 and deletion of 13q34 in a patient with B-cell CLL has been described only once before, but as a part of a complex karyotype. The prognostic significance of these abnormalities remains uncertain

Influence of applied CD34+ cell dose on the survival of Hodgkin's lymphoma and multiple myeloma patients following autologous stem cell transplants

Background/Aim. Autologous stem cell transplants (ASCTs) improve the rate of overall survival (OS) in patients with hematological malignancies such as multiple myeloma (MM) after induction chemotherapy, aggressive non-Hodgkin's lymphomas (NHL), and relapsed, chemotherapy-sensitive Hodgkin's lymphoma (HL). The study aim was to evaluate influence of applied CD34+ cell quantity on clinical outcome, as well as early post-transplant and overall survival (OS) of HL and MM patients following ASCT. Methods. This study included a total of 210 patients (90 HL/120 MM) who underwent ASCT. Stem cell (SC) mobilization was accomplished by granulocyte-colony stimulating factor (G-CSF) 10–16 μg/kg body mass (bm) following chemotherapy. For proven poor mobilizers, mobilization with G-CSF (16 μg/kgbm) and Plerixafor (24 or 48 mg) was performed. To our best knowledge, it was the first usage of the Plerixafor in our country in the ASCT-setting. Harvesting was initiated merely at "cut-off-value" of CD34+ cells ≥ 20 × 106/L in peripheral blood with "target-dose" of CD34+ cells ≥ 5 × 106/kgbm in harvest. The CD34+ cell count and viability was determined using flow cytometry. Results. The majority of HL patients (76.7%) were infused with > 5.0 × 106/kgbm CD34+ cells, while 68.3% of MM patients were treated by approximately 4.0–5.4 × 106/kgbm CD34+ dose, respectively. Beneficial response (complete/partial remission) was achieved in 83.3% (HL) and 94.2% (MM) patients. Among parameters that influenced survival of HL patients with positive response to the therapy, multivariate analysis (pre-ASCT performance status, CD34+ cell quantity applied, rapid hematopoietic, i.e. lymphocyte and platelet recovery) indicated that higher CD34+ cell dose used, along with pre-ASCT performance status correlated with superior event-free survival (EFS) and OS following ASCT. In MM patients, multivariate analysis (renal impairment, infused CD34+ cell quantity, early platelet recovery) indicated that the number of CD34+ cells infused was the most important parameter that influenced both EFS and OS after ASCT. Conclusion. Data obtained in this study undoubtedly confirmed that CD34+ cell dose applied is an independent factor that may contribute to superior clinical outcome and OS of HL and MM patients following ASCT

Cytomegalovirus infection may be oncoprotective against neoplasms of B-lymphocyte lineage: single-institution experience and survey of global evidence

Although cytomegalovirus (CMV) is not considered tumorigenic, there is evidence for its oncomodulatory effects and association with hematological neoplasms. Conversely, a number of experimental and clinical studies suggest its putative anti-tumour effect. We investigated the potential connection between chronic CMV infection in patients with B-lymphocyte (B-cell) malignancies in a retrospective single-center study and extracted relevant data on CMV prevalences and the incidences of B-cell cancers the world over

Acquired von Willebrand syndrome in multiple myeloma

Acquired von Willebrand syndrome (AvWS) is an uncommon complication of multiple myeloma (MM), and it is believed to be connected with paraprotein. The aim of this study was to determine the incidence of AvWS in patients with MM, and estimate the role of paraprotein in its occurrence. The study included 40 patients with MM. The plasma level of paraprotein, platelet adhesion on glass pearls, plasma von Willebrand factor antigen concentration, and ristocetin-induced platelet aggregation (RIPA) were measured initially. Absence of RIPA was found in six patients with MM (15%); however, all six of them had normal levels of von Willebrand factor antigen. Paraprotein was isolated from the serum of these patients. Platelet aggregation was measured in six healthy donors before and after addition of the isolated paraprotein. RIPA was significantly decreased in healthy donors in the presence of paraprotein (P lt 0.001). The same test was repeated with added human immunoglobulins for intravenous use without any change in RIPA. A significant negative correlation between plasma paraprotein level and RIPA was found (P lt 0.001). These investigations have shown that paraprotein is associated with AvWS in patients with MM

Favorable outcome of hepatosplenic candidiasis in a patient with acute leukemia

Introduction. Acute leukemias treatment requires strong chemotherapy. Patients that develop bone marrow aplasia become immunocompromised, thus becoming liable to bacterial and fungal infections. Fungal infections caused by Candida are frequent. Hepatosplenic candidiasis (HSC) is a frequent consequence of invasive candidiasis which is clinically presented with prolonged febrility unresponsive to antibiotics. Case Outline. A 53-year-old patient with acute myeloid leukemia was submitted to standard chemotherapy “3+7” regimen (daunoblastine 80 mg i.v. on days 1 to 3, cytarabine 2Ч170 mg i.v. during 7 days) and achieved complete remission. However, during remission he developed febrility unresponsive to antibiotics. Computerised tomography (CT) of the abdomen showed multiple hypodense lesions within the liver and spleen. Haemocultures on fungi were negative. However, seroconversion of biomarkers for invasive fungal infection (IFI) (Candida and Aspergillus antigen/Ag and antibody/Ab) indicated possible HSC. Only high positivity of anti-Candida IgG antibodies, positivity of mannan and CT finding we regarded sufficient for the diagnosis and antimycotic therapy. Three months of treatment with different antimycotics were necessary for complete disappearance of both clinical symptoms and CT findings. Conclusion. In patients with prolonged febrile neutropenia IFI has to be strongly suspected. If imaging techniques show multiple hypodense lesions within liver and spleen, HSC has to be taken seriously into consideration. We believe that, along with CT finding, positive laboratory Candida biomarkers (mannan and IgG antibodies) should be considered sufficient for “probable HSC” and commencement of antifungal therapy, which must be long enough, i.e. until complete disappearance of clinical symptoms and CT findings are achieved. [Projekat Ministarstva nauke Republike Srbije, br. OI 175034

Hypercalcemia with multiple osteolytic lesions and increased circulating tumor necrosis factor in an adult patient with B-cell acute lymphoblastic leukemia

Introduction. Acute lymphoblastic leukemia (ALL) is very rarely presented with diffuse osteolytic lesions and hypercalcemia. Case Outline. We report a 28-year-old male with the B-cell ALL who presented with extensive osteolytic lesions, bone pain, hepatosplenomegaly, and pancytopenia without circulating blasts in peripheral blood. An increased serum level of tumor necrosis factor (TNF-α) was registered while the levels of IL-1α and IL-1β were normal. The patient failed to achieve remission on two induction regimens but achieved one after the successful allogeneic stem cell transplantation, which lasted for six months, after which he developed a relapse and died. Conclusion. The presented case may serve as a clinical demonstration of possible involvement of TNF-α as a pathogenic factor in the evolution of osteolytic lesions that are occasionally observed in patients with ALL. This might have relevance in the management of such patients as chemotherapy alone may not represent the beneficial option in this clinical context

Prognostic significance of cellular vascular endothelial growth factor (VEGF) expression in the course of chronic myeloid leukaemia

Introduction. Increased angiogenesis in bone marrow is one of the characteristics of chronic myeloid leukaemia (CML), a clonal myeloproliferative disorder that expresses a chimeric bcr/abl protein. Vascular endothelial growth factor (VEGF) is one of the most potent and a specific regulator of angiogenesis which principally targets endothelial cells and regulates several of their functions, including mitogenesis, permeability and migration. The impact of elevated VEGF expression on the course of chronic myeloid leukaemia is unknown. Objective. The aim of this study was the follow-up of VEGF expression during the course of CML. Methods. We studied VEGF expression of 85 CML patients (median age 50 years, range 16-75 years). At the commencement of the study, 29 patients were in chronic phase (CP), 25 in an accelerated phase (AP), and 31 in the blast crisis (BC). The temporal expression (percentage positivity per 1000 analysed cells) VEGF proteins over the course of CML were studied using the immunohistochemical technique utilizing relevant monoclonal antibodies. It was correlated with the laboratory (Hb, WBC and platelet counts, and the percentage of blasts) and clinical parameters (organomegaly, duration of CP, AP, and BC) of disease progression. Results. The expression of VEGF protein was most pronounced in AP (ANOVA, p=0.033). The level of VEGF expression correlated inversely with the degree of splenomegaly (Pearson, r=-0.400, p=0.011). High expression of VEGF correlated with a shorter overall survival (log rank, p=0.042). Conclusion. Immunohistochemically confirmed significance of the expression of VEGF in dependence of the CML stage could be of clinical importance in deciding on the timing therapy. These data suggest that VEGF plays a role in the biology of CML and that VEGF inhibitors should be investigated in CML