Comparison of positron emission tomography/computed tomography with classical contrast-enhanced computed tomography in the initial staging of Hodgkin lymphoma.

We compared initial computed tomography (CT) and positron emission tomography (PET)/CT in 96 patients with Hodgkin lymphoma (HL), assessing the role of baseline PET/CT in stage migration and treatment selection. The number of patients with stage I, II, III and IV disease based on CT versus PET/CT was: 5 vs. 7, 49 vs. 37, 28 vs. 22 and 14 vs. 30, respectively. In 33 (34%) patients, PET/CT changed HL stage: 27 (28%) were upstaged and six (6.3%) downstaged. Upstaging was caused by detection of new extranodal involvements (47 sites in 26 patients): bone marrow (10 patients), spleen (five patients) and lung (two patients). In nine patients≥2 further coexisting locations were detected. Downstaging resulted from the absence of fluorodeoxyglucose (18F-FDG) uptake in enlarged nodes (>15 mm) in the abdomen and pelvis. PET/CT modified HL stage in 34% of patients leading to treatment modification in the majority. Our results indicate that PET/CT should be mandatory in the initial staging of HL.

Expression of Eph A4, Eph B2 and Eph B4 receptors in AML.

Eph receptors represent the largest subfamily of receptor tyrosine kinases (RTKs). The up- regulation of Eph receptors has been documented in various solid tumors, where it often correlates with poor prognosis. Their significance in hematologic malignancies is still unclear. This study aimed to investigate the expression of Eph A4, Eph B2, and Eph B4 mRNA in non - M3 AML patients and determine their prognostic significance. Bone marrow samples from 101 newly diagnosed non - M3 AML patients and 26 healthy controls for comparison were quantified by real time reverse transcriptase polymerase chain reaction (RT-PCR), and the comparative cycle threshold (Ct) method was used to determine their relative expression levels to GUS control gene. The results showed that expression of all selected Eph receptors was significantly lower in AML patients comparing to controls. It also differed according to FAB subtypes. The decreased expression levels of Eph A4 were associated with higher leukocytes (p = 0.022) and blast cell counts (p = 0.001), and unfavorable FLT3-ITD mutation. Our study revealed significant correlation between lower EphB2 expression levels, and higher complete remission rate (p = 0.009724) and longer overall survival. Additionally, we found that patients with shorter RFS had decreased EphB4 expression (p = 0.00). In conclusion, the results suggest the prognostic impact of decreased expression levels of some Eph receptors in AML patients.

VEGF and bFGF gene polymorphisms in patients with non-Hodgkin's lymphoma.

Angiogenesis and lymphangiogenesis are important in the proliferation and survival of the malignant hematopoietic neoplasms, including non-Hodgkin's lymphomas (NHLs). Vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) play an important role in the initiation of angiogenesis. Both VEGF and bFGF have been reported to have prognostic significance in NHL. The present study aimed to determine an association between the VEGF and bFGF gene polymorphisms and disease susceptibility and progression. VEGF (rs3025039; 936 C>T) and bFGF (rs308395, -921 G>C) variants were determined in 78 NHL patients and 122 healthy individuals by PCR-RFLP technique. The presence of the VEGF 936T allele was found to significantly associate with worse prognosis of the disease (expressed by the highest International Prognostic Index (IPI)) (0.41 versus 0.20, P = 0.044 for IPI 4 among patients having and lacking the T allele). The VEGF 936T variant was also more frequent among patients with IPI 4 than in controls (OR = 3.37, P = 0.029). The bFGF -921G variant was more frequently detected among patients with aggressive as compared to those with indolent histological subtype (0.37 versus 0.18, P = 0.095) and healthy individuals (0.37 versus 0.19, OR = 2.51, P = 0.038). These results imply that VEGF and bFGF gene polymorphisms have prognostic significance in patients with NHL.

Premature cardiovascular mortality in lymphoma patients treated with (R)-CHOP regimen - a national multicenter study.

BACKGROUND: Premature cardiovascular mortality related to chemotherapy and occurred in lymphoma survivors before disease progression is one of significant clinical failure of modern hematology. The aim of this retrospective analysis was to evaluate early cardiovascular mortality and its predictors in patients treated with the (R)-CHOP regimen. METHODS: The study assessed 610 patients: 581 patients were treated with non-liposomal doxorubicin (cumulative dose of 337 ± 96 mg/m2), and 29 patients with liposomal non-pegylated doxorubicin (cumulative dose of 237 ± 126 mg/m2). Their present status, history of cardiovascular diseases and associated risk factors were recorded. RESULTS: The analysis identified 93 deaths (15.5%): 51 cases (55%) related to lymphoma disease progression and 28 (30%) to cardiovascular complications. Multivariate Cox analysis revealed history of previous heart diseases (HR=4.71; CI: 3.82-5.6; p<0.001), ECG rhythm abnormalities related to chemotherapy (HR=4,78; CI: 3.63-5.92; p=0,01), and lack of complete remission (HR=2.73; CI: 1.78-3.66; p=0.03), as the independent predictors for cardiovascular death. Neither decreased LVEF nor increasing cumulative dose of anthracyclines had a significant predictive value for cardiovascular prognosis. CONCLUSIONS: The study indicated that cardiovascular mortality in lymphoma patients treated with (R)-CHOP regimen is relatively high and ECG monitoring may be the most effective in cardiological risk assessment. The unfavorable outcome depended on lack of complete remission that seems to be a consequence of patients' individual susceptibility for cardiac events, which should become a purpose of further trials.

[Liposomal cytarabine in prophylaxis of the central nervous system involvement in rare aggresive lymphomas]. / Liposomalna cytarabina w profilaktyce zajEcia centralnego systemu nerwowego w rzadkich chloniakach agresywnych.

UNLABELLED: The involvement of central nervous system in the course of lymphoma is an adverse prognostic factor, therefore primary prevention is a standard of care of aggressive lymphoma subtypes. The aim of the paper is the safety and efficiency, retrospective analysis of liposomal cytarabine used profilactically in patients with rare aggressive lymphomas. MATERIALS AND METHODS: In the analysis we included 19 patients with aggressive lymphomas: LBL (lymphoblastic lymphoma), BL (Burkitt lymphoma) and PTCL (peripheral T- cell lymphoma) from three PLRG (Polish Lymphoma Research Group) centers, who received liposomal cytarabine as primary prevention of central nervous system involvement. All the included patients had a high risk of CNS due to histological subtype (10 patients with LBL, 4 patients with BL), the specific location of the disease (N=3) or the presence of at least 2 risk factors for CNS involvement (elevated LDH, IPI 3-5 or involvement of at least 2 extranodal sites, N = 16). In this group, 18 patients were subjected to prophylaxis during the 1-st line therapy and one after relapse. None of the patients had symptoms of central nervous system involvement at the time of diagnosis. The median age was 43 years (the range of 20-60 years). In this group there were 14 males (73.68%) and 5 females (26.32%). The patients were treated with liposomal cytarabine every 2 to 4 weeks during the systemic chemotherapy. The median number of cytarabine doses was 2 (the range of 1-5). RESULTS: Liposomal cytarabine was well-tolerated. 63.1% of patients had transient side effects (nausea, vomiting, fever, dizziness) in grade 1-2, 5.2% of patients experienced a more severe headache (grade 3). During the average follow-up of 18 months, 50% of patients died and 27.7% of systemic recurrences were noted. Only one patient had a relapse in the CSN con comitant with a systemic recurrence. CONCLUSIONS: Lipo somal cytarabine is well-tolerated and effective medicine used in the prevention of CNS relapse in patients with ag gressive lymphoma subtypes.

Central nervous system prophylaxis with intrathecal liposomal cytarabine in diffuse large B-cell lymphomas.

INTRODUCTION:  Central nervous system (CNS) involvement is a serious and potentially fatal complication in patients with lymphoma because it is associated with a particularly poor prognosis (median progression­free survival [PFS] of 4-6 months). Although CNS prophylaxis is considered necessary, there are no clear guidelines on identifying high­risk patients or selecting treatment regimen.  OBJECTIVES:  The aim of the study was to assess the safety and efficacy of CNS prophylaxis with intrathecal liposomal cytarabine. PATIENTS AND METHODS:  We analyzed the data of 79 patients (46 men and 33 women; median age, 48.5 years [20-79]) with diffuse large B­cell lymphoma (83.5% of the patients) and primary mediastinal large B­cell lymphoma (16.5%). Patients were treated in the departments of hematology in Kraków and Wroclaw, Poland, between the years 2009-2012. They were considered to be at a high risk of developing CNS involvement associated with a lymphoma. RESULTS:  Adverse reactions after intrathecal liposomal cytarabine were reported in 59 patients (74.7%); in 7 cases, the reactions were severe. The most common side effect was headache (67.1%). During antilymphoma therapy and prophylaxis, the functional status assessed by the Karnofsky score improved in 56 patients (70.9%) and remained unchanged in the remaining cases. A median follow­up time did not exceed 28 months (range, 1.4-52.1); during follow­up, neither median overall survival (OS) nor PFS were reached (projected OS and PFS at 48 months are 86.1% and 90.1%, respectively).  CONCLUSIONS:  Our results encourage the use of intrathecal liposomal cytarabine in CNS prophylaxis in patients with lymphoma.

High CD74 expression correlates with ZAP70 expression in B cell chronic lymphocytic leukemia patients.

Chronic lymphocytic leukemia (CLL) is the most common leukemia in adults in Western countries. It is characterized by heterogeneous clinical course of the disease and new prognostic factors are still needed. CD74 plays an important role in signal transduction in B cell proliferation and survival pathway. CD74 expression has been shown in solid tumors and has been connected with poor prognosis and tumor progression. The aim of the study was to evaluate the expression of CD74 in chronic lymphocytic leukemia patients with combination with other known prognostic factors. Expression of CD74 was determined in 90 patients and 28 healthy controls. CD74 expression was significantly higher in CLL group than in controls. There was positive correlation between CD74 and ZAP70 expression (p = 0.008). High expression of CD74 was positively correlated with more advanced stage of the disease (p = 0.02). No correlation was shown between CD74 and sex, mutational status IgVH and time to first treatment.

VEGF and bFGF gene polymorphisms in Polish patients with B-CLL.

Among a variety of angiogenic factors involved in the B cell chronic lymphocytic leukemia (B-CLL), vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) were identified. Their levels have been regarded as prognostic markers of the progression of disease. The objective of the present study was to assess whether polymorphisms located within the genes coding for these key angiogenic activators contribute to disease susceptibility and/or progression in patients with B-CLL. For this purpose, 180 individuals were investigated, including 68 B-CLL patients and 112 healthy controls. All individuals were typed for the VEGF (936 C > T) and bFGF (-921 C > G) alleles using PCR-RFLP technique. Only a slight prevalence of the VEGF T variant was observed among patients as compared to healthy individuals (p = 0.095) with a significant difference when high risk (stage III/IV) patients were considered (OR = 3.81, p = 0.045). No other significant association was observed between the VEGF polymorphism and progression of the disease. The VEGF alleles and genotypes segregated similarly in patients with different stage of the disease according to Rai classification. No significant relationships were also observed for the bFGF polymorphism with either susceptibility to B-CLL (when compared to control group) or progression of the disease. These results suggest the possible association of the VEGF polymorphism with high risk B-CLL.

Bendamustine as monotherapy and in combination regimens for the treatment of chronic lymphocytic leukemia and non-hodgkin lymphoma: a retrospective analysis.

BACKGROUND/AIM: In this study, we carried out a retrospective analysis of the efficacy and toxicity of bendamustine in patients with B-cell lymphoproliferative diseases. METHODS: Bendamustine was administered both as monotherapy and in combined protocols to 92 patients, including 76 patients with chronic lymphocytic leukemia (CLL) and 16 patients with indolent lymphomas. Bendamustine plus rituximab was used to treat 65.2% of the patients, and 34.8% of the patients received bendamustine as monotherapy. RESULTS: The overall response rate was 64.2%, including the complete response rate (18.5%) and the partial response rate (45.7%). The median overall survival (OS) was 11.5 months. Among the pretreatment parameters, ß2-microglobulin (RR = 1.413; p = 0.001) and hemoglobin levels (RR = 0.85; p = 0.03) significantly influenced survival. The OS was significantly longer in patients who received ≤2 lines of previous therapy compared to >3 lines (p = 0.043; log-rank test) and those who received ≥4 courses of therapy with bendamustine (p = 0.0007; log-rank test). Toxicity was predominantly hematological, including grade III/IV neutropenia in 33.7%, thrombocytopenia in 13%, and anemia in 13% of patients. CONCLUSION: Bendamustine, both in monotherapy and in combination regimens, is an effective therapy with a favorable toxicity profile in patients with indolent B-cell malignancies.

High expression of hematopoietic cell specific Lyn substrate-1 (HS1) predicts poor survival of B-cell chronic lymphocytic leukemia patients.

UNLABELLED: B-cell chronic lymphocytic leukemia (B-CLL) is the most common leukemia in adults in western countries. HS1 protein regulates leukemic cell migration and homing, and can indirectly promote disease progression and influence patient survival. The aim of this study was to evaluate HS1 expression in CLL patients in connection with other known prognostic factors and patients' survival. METHODS: 90 untreated CLL patients were included into the study. The control group consisted of 28 healthy matched people. HS1 detection was performed by western-blotting. Mutational status of IgVH, as well as CD38 and ZAP70 expression was also analyzed. RESULTS: HS1 expression was significantly higher in CLL patients comparing to controls. Positive correlation was shown between HS1 and: age (p=0.0454), Rai stage (p=0.0412), leukocytosis (p=0.0129) and beta-2-microglobulin (p=0.0342). Patients with lymphocyte doubling time shorter or equal to 6 months had higher expression of HS1. Patients with higher HS1 expression had shorter survival than those with lower HS1 expression (p=0.0329). CONCLUSIONS: We showed, that high HS1 expression predicts poor survival of chronic lymphocytic leukemia patients.

Expression of cyclin A and bone morphogenetic protein receptors and response to induction therapy in patients with acute leukemias.

Bone morphogenetic proteins (BMPs) are multifunctional cytokines that belong to the transforming growth factor ß (TGFß) family. They participate in the regulation of growth, differentiation and apoptosis in a variety of cell types including hematopoietic lineages. To date, the role of BMPs in carcinogenesis has not been well known. Cyclin A is a cell cycle regulatory protein which plays the role of a parameter of cell proliferation in various types of carcinomas including hematological malignancies. The role of BMPRIA, BMPRIB, BMPRI and cyclin A in the pathogenesis of acute leukemias remains unclear. The aim of this study was to evaluate the expression of BMP receptors and cyclin A on blast cells and their possible relationship with clinical outcome. Seventy patients with acute leukemias (28 female and 42 male) and 10 aged-matched healthy controls were studied. All patients were examined before cytostatic treatment. The expression of BMP receptors and cyclin A was detected by flow cytometry. The results show that higher expression of BMPRIA, BMPRIB, BMPRII and cyclin A is related with a higher complete response (CR) rate, higher overall survival (OS) and lower relapse risk. The expressions of BMPRIA, BMPRIB, BMPRII and cyclin A could be useful as prognostic parameters of the proliferation status of acute leukemia cells, but further studies are needed to assess this phenomenon.

Expression of bone morphogenetic proteins (BMPs) receptors in patients with B-cell chronic lymphocytic leukemia (B-CLL).

Bone morphogenetic proteins (BMPs) are multifunctional cytokines which belong to transforming growth factor ß (TGF ß) superfamily. They regulate proliferation, differentiation, and apoptosis in a variety of cells including hematopoietic cells. BMPs act because of binding to two types of serine/threonine kinase receptors: BMP type I receptors (IA and IB) and BMP type II receptor. Deregulation of BMPs signaling pathways has been reported in some of human cancers, but the role of BMPs in hematopoietic malignancies remains unknown. The aim of our study was to examine the percentage of expression of BMPs receptors on lymphocytes of patients with B-cell chronic lymphocytic leukemia (B-CLL). A total of 46 patients with B-CLL (27 men and 19 women) and 10 healthy persons were evaluated. Freshly isolated mononuclear cells were incubated with antibodies against BMPs receptors: BMPRIA, BMPRIB, and BMPRII and examined in 2-color flow cytometry. On cells of patients with B-CLL, the percentage of expression of BMP RIA, BMP RIB, and BMP RII was significantly higher than in normal cells of the control group. The percentage of the expression of BMP RIA and BMP RIB was higher in patients with advanced stage of disease.

Expression of complement regulatory proteins: CD46, CD55, and CD59 and response to rituximab in patients with CD20+ non-Hodgkin's lymphoma.

Rituximab is an anti-CD20 humanized monoclonal antibody widely used in the treatment of B-cell non-Hodgkin's lymphomas (NHLs). Its mechanism of action is related with complement function-complement mediated cytotoxicity. CD46, CD55, and CD59 are complement regulatory proteins. The aim of this study was to analyze expression of complement inhibitors CD46, CD55, and CD59 in patients with CD20(+) NHLs treated with rituximab combined with chemotherapy. A total of 27 patients with CD20(+) NHLs were evaluated (13 females and 14 males). The median age of patients was 56 years. All patients were examined before treatment with rituximab. Expression of CD46, CD55, and CD59 was determined by two-color flow cytometry. A total of 15 patients achieved complete response (CR), 5 patients achieved partial response, and 7 patients had no or minimal response (NR) after rituximab therapy. We observed that expression of CD46 and CD59 were higher in patients with CR than in group with NR. Expression of CD55 and CD59 were higher in patients with bulky disease. In conclusion level of expression of CD46, CD55, and CD59 could be clinically helpful to predict the response to rituximab therapy.

Asymmetric dimethylarginine in hematological malignancies: a preliminary study.

Asymmetric dimethylarginine (ADMA) is a product of protein hydrolysis and an endogenous competitive inhibitor of nitric oxide synthase. It is considered a new independent risk factor for endothelial dysfunction and cardiovascular diseases. Increased protein turnover, oxidative stress and impaired dimethylarginine dimethylaminohydrolase activity occurring in hematological malignancies may lead to increased dimethylarginines production. We have measured ADMA, symmetric dimethylarginine (SDMA) and L-arginine plasma levels in 43 patients with different types of hematological malignancies and in control group of 43 healthy volunteers. Mean ADMA and L-arginine plasma levels were higher in hematological group than in control group (1.59 vs 0.64; p<0.001 and 34.84 vs 28.35; p=0.044 respectively). Mean plasma levels of SDMA were not significantly different between the groups. Elevated ADMA plasma levels in patients with hematological malignancies interfere with nitric oxide metabolism and may influence their prognosis. Further prognostic studies are postulated to assess this phenomenon.