Browsing by Author "Colovic, Natasa (6701607753)"

B-Chronic lymphocytic leukaemia (B-CLL) is a monoclonal malignancy characterized by an accumulation of terminally differentiated small and anergic B lymphocytes in the blood, bone marrow and other tissues. CD23 antigen, a trans-membrane glycoprotein, promotes the activation and proliferation of normal B lymphocytes and has an important role in the process of malignant transformation in B-CLL. This retrospective cohort study of 77 consecutive newly diagnosed B-CLL patients, 43 males, 34 females, median age of 62 years, examined CD23 expression and correlations with clinical parameters. CD23+ was negatively correlated with pro-lymphocyte infiltration of the bone marrow (P < 0.01) and peripheral blood lymphocyte counts (P < 0.001). Lower CD23 expression was correlated with lower serum immunoglobulin levels (P < 0.05), especially IgG; while greater CD23 expression was positively correlated with higher CD5 levels. B-CLL patients with a percentage of CD23+ lymphocytes >40% had longer survival (92.8 months) than those expressing <40% (35.3 months) (P = 0.001). CD23 is not uniformly expressed by lymphocytes in B-CLL patients, and the differences in expression are dependent on a number of clinical parameters, including the peripheral blood lymphocyte count and the degree of pro-lymphocyte infiltration of the bone marrow. CD23 expression is significantly decreased in patients with extremely high lymphocyte counts (PBL counts of >100 × 109/l) and in the advanced stages of disease. © 2008 Humana Press Inc.

B-Chronic lymphocytic leukaemia (B-CLL) is a monoclonal malignancy characterized by an accumulation of terminally differentiated small and anergic B lymphocytes in the blood, bone marrow and other tissues. CD23 antigen, a trans-membrane glycoprotein, promotes the activation and proliferation of normal B lymphocytes and has an important role in the process of malignant transformation in B-CLL. This retrospective cohort study of 77 consecutive newly diagnosed B-CLL patients, 43 males, 34 females, median age of 62 years, examined CD23 expression and correlations with clinical parameters. CD23+ was negatively correlated with pro-lymphocyte infiltration of the bone marrow (P < 0.01) and peripheral blood lymphocyte counts (P < 0.001). Lower CD23 expression was correlated with lower serum immunoglobulin levels (P < 0.05), especially IgG; while greater CD23 expression was positively correlated with higher CD5 levels. B-CLL patients with a percentage of CD23+ lymphocytes >40% had longer survival (92.8 months) than those expressing <40% (35.3 months) (P = 0.001). CD23 is not uniformly expressed by lymphocytes in B-CLL patients, and the differences in expression are dependent on a number of clinical parameters, including the peripheral blood lymphocyte count and the degree of pro-lymphocyte infiltration of the bone marrow. CD23 expression is significantly decreased in patients with extremely high lymphocyte counts (PBL counts of >100 × 109/l) and in the advanced stages of disease. © 2008 Humana Press Inc.

Background: In chronic lymphocytic leukemia (CLL), in vivo apoptotic resistance of malignant B lymphocytes results, in part, from the intrinsic defects of their apoptotic machinery. These include genetic alterations and aberrant expression of many apoptosis regulators, among which the Bcl2 family members play a central role. Aim: The aim of this study was to investigate the association of pro-apoptotic Bax gene expression and Bcl2/Bax ratio with the clinical features of CLL patients as well as with molecular prognostic markers, namely the mutational status of rearranged immunoglobulin heavy variable (IGHV) genes and lipoprotein lipase (LPL) gene expression. Methods: We analyzed the expression of Bax mRNA and Bcl2/Bax mRNA ratio in the peripheral blood mononuclear cells of 58 unselected CLL patients and 10 healthy controls by the quantitative reverse-transcriptase polymerase chain reaction. Results: We detected significant Bax gene overexpression in CLL samples compared to non-leukemic samples (p=0.003), as well as an elevated Bcl2/Bax ratio (p=<0.001). Regarding the association with prognostic markers, the Bcl2/Bax ratio showed a negative correlation to lymphocyte doubling time (r=-0.307; p=0.0451), while high-level Bax expression was associated with LPL-positive status (p=0.035). Both the expression of Bax and Bcl2/Bax ratio were higher in patients with unmutated vs. mutated IGHV rearrangements, but this difference did not reach statistical significance. Conclusions: Our results suggest that dysregulated expression of Bcl2 and Bax, which leads to a high Bcl2/Bax ratio in leukemic cells, contributes to the pathogenesis and clinical course of CLL.

Background: In chronic lymphocytic leukemia (CLL), in vivo apoptotic resistance of malignant B lymphocytes results, in part, from the intrinsic defects of their apoptotic machinery. These include genetic alterations and aberrant expression of many apoptosis regulators, among which the Bcl2 family members play a central role. Aim: The aim of this study was to investigate the association of pro-apoptotic Bax gene expression and Bcl2/Bax ratio with the clinical features of CLL patients as well as with molecular prognostic markers, namely the mutational status of rearranged immunoglobulin heavy variable (IGHV) genes and lipoprotein lipase (LPL) gene expression. Methods: We analyzed the expression of Bax mRNA and Bcl2/Bax mRNA ratio in the peripheral blood mononuclear cells of 58 unselected CLL patients and 10 healthy controls by the quantitative reverse-transcriptase polymerase chain reaction. Results: We detected significant Bax gene overexpression in CLL samples compared to non-leukemic samples (p=0.003), as well as an elevated Bcl2/Bax ratio (p=<0.001). Regarding the association with prognostic markers, the Bcl2/Bax ratio showed a negative correlation to lymphocyte doubling time (r=-0.307; p=0.0451), while high-level Bax expression was associated with LPL-positive status (p=0.035). Both the expression of Bax and Bcl2/Bax ratio were higher in patients with unmutated vs. mutated IGHV rearrangements, but this difference did not reach statistical significance. Conclusions: Our results suggest that dysregulated expression of Bcl2 and Bax, which leads to a high Bcl2/Bax ratio in leukemic cells, contributes to the pathogenesis and clinical course of CLL.

Treatment of hairy cell leukemia (HCL) with alfa-interferon and purine analogs significantly prolongs survival in these patients. However, with life prolongation, an increased risk of secondary malignancies has been reported. Acute myeloid leukemia (AML), as a second malignancy after HCL treatment is extremely rare and has been reported in only 12 cases so far. We here report additional 2 cases of CD56+ AML developed after sustained clinical remission of HCL achieved with cladribine (2 and 6 years after, respectively). The first patient refused chemotherapy and shortly thereafter died. The second patient responded to chemotherapy and was successfully allo-transplanted. Three years later, the patient is in stable clinical remission, which is a unique case in the literature. In conclusion, it is not clear whether development of AML in HCL patients is caused by mutagenic potential of the applied chemotherapy or by immune suppression/ perturbations as a characteristic of the underlying disease. © 2019 The Author(s).

Myelofibrosis is a clonal myeloproliferative disorder characterized by splenomegaly, abnormal deposition of collagen in the bone marrow, extramedullary hematopoiesis, dacriocytosis, and leukoerythroblastic blood smear. Development and maintenance of fibrosis are mediated by a complex network of several cytokines, including tumor necrosis factor-α (TNF-α). Osteosclerosis is the most frequently observed bone change in myelofibrosis. Based on this, we present an atypical case of leukemic transformation in myelofibrosis associated with diffuse osteolytic lesions and extremely elevated TNF-α and lactate dehydrogenase (LDH). Parathormone was not disturbed. © 2007 Elsevier GmbH. All rights reserved.

Myelofibrosis is a clonal myeloproliferative disorder characterized by splenomegaly, abnormal deposition of collagen in the bone marrow, extramedullary hematopoiesis, dacriocytosis, and leukoerythroblastic blood smear. Development and maintenance of fibrosis are mediated by a complex network of several cytokines, including tumor necrosis factor-α (TNF-α). Osteosclerosis is the most frequently observed bone change in myelofibrosis. Based on this, we present an atypical case of leukemic transformation in myelofibrosis associated with diffuse osteolytic lesions and extremely elevated TNF-α and lactate dehydrogenase (LDH). Parathormone was not disturbed. © 2007 Elsevier GmbH. All rights reserved.

Dysregulation of apoptosis is a distinctive feature of chronic lymphocytic leukemia (CLL), although a unique mechanism underlying apoptosis resistance of CLL B lymphocytes has not been identified yet. Aberrant expression as well as genetic and epigenetic alterations of numerous genes involved in different pathways of apoptosis regulation has been described in CLL. Here, we report the expression analysis of Bcl2L12 (Bcl2-like 12), a novel apoptotic gene belonging to Bcl2 family, in 58 Serbian CLL patients. Quantitative reverse-transcriptase polymerase chain reaction (qRT-PCR) analysis revealed a significant overexpression of Bcl2L12 mRNA in CLL samples compared to non-leukemic samples, implying its role in the pathogenesis of the disease. Receiver operating characteristic (ROC) analysis showed that Bcl2L12 expression efficiently discriminates CLL cases from healthy controls. However, relatively homogenous Bcl2L12 mRNA expression among patients did not reflect their clinical characteristics (with the exception of lactate dehydrogenase status and time from diagnosis to treatment) and failed to show association with the most informative prognostic markers, namely the mutational status of rearranged immunoglobulin heavy chain variable region genes, CD38 and lipoprotein lipase gene (LPL) expression. © 2013 Springer Science+Business Media New York.

Dysregulation of apoptosis is a distinctive feature of chronic lymphocytic leukemia (CLL), although a unique mechanism underlying apoptosis resistance of CLL B lymphocytes has not been identified yet. Aberrant expression as well as genetic and epigenetic alterations of numerous genes involved in different pathways of apoptosis regulation has been described in CLL. Here, we report the expression analysis of Bcl2L12 (Bcl2-like 12), a novel apoptotic gene belonging to Bcl2 family, in 58 Serbian CLL patients. Quantitative reverse-transcriptase polymerase chain reaction (qRT-PCR) analysis revealed a significant overexpression of Bcl2L12 mRNA in CLL samples compared to non-leukemic samples, implying its role in the pathogenesis of the disease. Receiver operating characteristic (ROC) analysis showed that Bcl2L12 expression efficiently discriminates CLL cases from healthy controls. However, relatively homogenous Bcl2L12 mRNA expression among patients did not reflect their clinical characteristics (with the exception of lactate dehydrogenase status and time from diagnosis to treatment) and failed to show association with the most informative prognostic markers, namely the mutational status of rearranged immunoglobulin heavy chain variable region genes, CD38 and lipoprotein lipase gene (LPL) expression. © 2013 Springer Science+Business Media New York.

Mutations in the fms-like tyrosine kinase 3 (FLT3) gene, such as internal tandem duplication (FLT3/ITD) in the juxtamembrane domain and point mutations in the tyrosine kinase domain, are the most common abnormalities in acute myeloid leukemia (AML). FLT3/ITD and FLT3/D835 mutations were analyzed in 113 Serbian adult AML patients using polymerase chain reaction. Twenty patients were found to be FLT3/ITD positive (17.7%). The mutations occurred most frequently in M5 and M0 subtypes of AML. They were mainly associated with the normal karyotype. All patients harboring FLT3/ITD had a higher number of white blood cells than patients without it (p=0.027). FLT3/ITD mutations were associated with lower complete remission (CR) rate (χ2=5.706; p=0.017) and shorter overall survival (OS; Log rank=8.76; p=0.0031). As for disease-free survival, the difference between FLT3/ITD-positive and FLT3/ITD-negative patients was not statistically significant (Log rank=0.78; p=0.3764). In multivariate analysis, the presence of FLT3/ITD mutations was the most significant prognostic factor for both OS and CR rate (p=0.0287; relative risk=1.73; 95% CI=1.06-2.82). However, in the group of patients with the intermediate-risk karyotype, the mere presence of FLT3/ITD was not associated with inferior clinical outcome. FLT3/D835 point mutation was found in four patients (3.5%) only. Follow-up of the FLT3/ITD-positive patients revealed stability of this mutation during the course of the disease. However, changes in the pattern of FLT3/D835 mutations in initial and relapsed AML were observed. Our results indicate an association of FLT3/ITD with the adverse outcome in AML patients treated with standard induction chemotherapy. Because FLT3/ITD mutation is a target for specific therapeutic inhibition, its early detection could be helpful in clinical practice. © Springer-Verlag 2007.

A retrospective survey of 210 consecutive patients aged ≥65 years (median age 69 years, range 65- 88 years) with acute myeloid leukemia (AML) diagnosed at a single center over a 6-year period (January 2001 to December 2006) is presented. De novo AML was diagnosed in 179 (85.2 %) patients and 31 (14.7 %) patients had a secondary AML. Twenty-three patients had M0 (11 %), 36 M1 (17.15 %), 57 M2 (27.1 %), eight M3 (3.8 %), 45 M4 (21.4 %), 31 M5 (14.8 %), one M6 (0.5 %), one M7 (0.5 %), and eight patients had unclassified myeloid leukemia (3.8 %) according to French-American-British (FAB) Study Group Classification. Eight patients with M3 (acute promyelocytic leukemia) were excluded from the study. Cytogenetic analysis was performed in 172/202 (85 %) patients. The normal karyotype was found in 81/ 172 (47 %), high risk aberrations in 32/172 (18.6 %), and favorable karyotype in 13/172 (7.5 %) patients. Supportive and palliative therapies were applied in 115 (56.9 %) patients, a no induction chemotherapy (NIC) group, and 87 (43.1 %) patients received induction chemotherapy (IC group). Complete remission (CR) was achieved in 45/87 (51.7 %) in the IC group and in 5/115 (4.3 %) in the NIC group of patients. After a median follow up of 4 years, 194 (96 %) patients died. The variables significantly associated with a longer overall survival (OS) by univariate analysis were an age of <75 years, a better ECOG performance status (PS) (p00.000, CI 95.0 %, 1.358-2.049), a serum LDH activity <600 U/l (p00.000, CI 95.0 %, 1.465-2.946), lower white blood cell (WBC) count at diagnosis (p00.011, CI 95.0 %, 1.102-2.100), lower comorbidity HCT-CI index (p00.000, CI 95 % 2.209-3.458), absence of splenomegaly (p00.015, CI 95.0 %, 1.082-2.102) and hepatomegaly (p0 0.008, CI 95.0 %, 1.125-2.171), and no preceding nonhematological malignancy. Multivariate analysis showed that significant factors affecting OS in the IC group were achievement of CR (p00.000), the ECOG PS (p00.045) and the ECOG PS (p00.000), and HCT-CI (p00.000) in the NIC group of elderly patients. The present study suggests that a subgroup of elderly patients with both ECOG PS and HCT-CI≤2 at presentation may be eligible for intensive induction chemotherapy. © 2012 Springer-Verlag.

Background: Non-albicans Candida spp. are an emerging cause of hospital-acquired bloodstream infections, associated with high mortality due to the challenges in diagnosis and delayed treatment. Objectives: We aimed to investigate a cluster of healthcare-associated invasive candidiasis caused by C tropicalis and review the literature of healthcare-associated outbreaks or clusters caused by C tropicalis. Methods: An investigation was performed to determine clinical presentation, treatment outcomes and the factors contributing to C tropicalis candidemia occurrence. We searched the Medline database via PubMed and Ovid using the keywords of “Candida tropicalis” combined with “outbreak” or “clustering” or “clusters,” and we limited the search to studies conducted from January 1989 to January 2019. Results: We report two related cases of C tropicalis candidemia among patients with AML following a period of neutropenia, who had erythematous skin rash as a first manifesting sign of candidiasis. C tropicalis was isolated from blood and skin cultures of both patients, which were identical by pulsed-field gel electrophoresis typing. Our systematic review of outbreaks caused by C tropicalis suggests that (a) most reported outbreaks have occurred in neonatal and adult ICUs; (b) patients who receive total parenteral therapy, antibiotics and those who have indwelling catheters and recent surgery are at high risk of infection; and (c) environmental and healthcare personnel surveillance suggest that cross-contamination is a major risk factor. Conclusion: Control of nosocomial outbreaks caused by C tropicalis should include better infection control measures, education of healthcare professionals especially working in adult and neonatal intensive care and haematology units. © 2020 Blackwell Verlag GmbH

Background: Chronic lymphocytic leukemia (CLL) results from the clonal expansion of mature B lymphocytes and is characterized by extreme clinical heterogeneity. One of the most reliable prognostic markers in chronic lymphocytic leukemia (CLL) is the mutational status of immunoglobulin heavy variable (IGHV) genes, which defines 2 subsets, mutated CLL (M-CLL) and unmutated CLL (U-CLL), with different clinical courses. Biased IGHV gene use between M-CLL and U-CLL clones, as well as population differences in the IGHV gene repertoire have been reported. Patients and Methods: In this study, mutational status and configuration of IGHV-IGHD-IGHJ rearrangements in 85 Serbian patients were analyzed using reverse transcriptase-polymerase chain reaction (RT-PCR) and sequencing methodology. Results: We found that 55.3% of cases belonged to M-CLL and 44.7% belonged to U-CLL, with progressive disease predominating in the unmutated subset. Most frequently expressed was the IGHV3 subgroup (55.7%), followed by IGHV1 (27.3%), IGHV4 (12.5%), IGHV5 (2.3%), IGHV2 (1.1%), and IGHV6 (1.1%). The distribution of IGHD subgroups was as follows: IGHD3, 39.1%; IGHD2, 21.8%; IGHD6, 12.6%; IGHD1, 10.3%; IGHD4, 8%; IGHD5, 6.9%; and IGHD7, 1.1%. The most frequent IGHJ gene was IGHJ4 (48.9%), followed by IGHJ6 (28.4%), IGHJ3 (11.4%), and IGHJ5 (11.4%). In 15.3% of cases, heavy complementarity-determining region 3 (VH CDR3) amino acid sequences could be assigned to previously defined stereotyped clusters. Conclusions: Our study showed a strong correlation between IGHV gene mutational status and clinical course of CLL. IGHV gene use was comparable to that obtained for Mediterranean countries, with the exception of the IGHV4 subgroup, which was underrepresented in our cohort. © 2012 Elsevier Inc. All rights reserved.

Background: Chronic lymphocytic leukemia (CLL) results from the clonal expansion of mature B lymphocytes and is characterized by extreme clinical heterogeneity. One of the most reliable prognostic markers in chronic lymphocytic leukemia (CLL) is the mutational status of immunoglobulin heavy variable (IGHV) genes, which defines 2 subsets, mutated CLL (M-CLL) and unmutated CLL (U-CLL), with different clinical courses. Biased IGHV gene use between M-CLL and U-CLL clones, as well as population differences in the IGHV gene repertoire have been reported. Patients and Methods: In this study, mutational status and configuration of IGHV-IGHD-IGHJ rearrangements in 85 Serbian patients were analyzed using reverse transcriptase-polymerase chain reaction (RT-PCR) and sequencing methodology. Results: We found that 55.3% of cases belonged to M-CLL and 44.7% belonged to U-CLL, with progressive disease predominating in the unmutated subset. Most frequently expressed was the IGHV3 subgroup (55.7%), followed by IGHV1 (27.3%), IGHV4 (12.5%), IGHV5 (2.3%), IGHV2 (1.1%), and IGHV6 (1.1%). The distribution of IGHD subgroups was as follows: IGHD3, 39.1%; IGHD2, 21.8%; IGHD6, 12.6%; IGHD1, 10.3%; IGHD4, 8%; IGHD5, 6.9%; and IGHD7, 1.1%. The most frequent IGHJ gene was IGHJ4 (48.9%), followed by IGHJ6 (28.4%), IGHJ3 (11.4%), and IGHJ5 (11.4%). In 15.3% of cases, heavy complementarity-determining region 3 (VH CDR3) amino acid sequences could be assigned to previously defined stereotyped clusters. Conclusions: Our study showed a strong correlation between IGHV gene mutational status and clinical course of CLL. IGHV gene use was comparable to that obtained for Mediterranean countries, with the exception of the IGHV4 subgroup, which was underrepresented in our cohort. © 2012 Elsevier Inc. All rights reserved.

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Objective: Until recently, imatinib was the standard first-line treatment in chronic myeloid leukemia (CML). The inclusion of nilotinib and dasatinib as first-line options in CML raised a debate on treatment selection. The aim of our study was to analyze predictive parameters for imatinib response as the first-line treatment of CML patients. Methods: The study included 168 consecutive patients with chronic phase Philadelphia-positive CML who were diagnosed and treated with Imatinib 400 mg once daily at a single university hospital. Numerous parameters were analyzed in terms of imatinib response including comorbidities as well as occurrence of second malignancies. Results: After the median follow-up of 87 months in 61 patients (36.3%), the imatinib failure was verified. Cox regression analysis identified hepatomegaly (p = 0.001), leukocytosis ≥ 100 × 109/l (p = 0.001), blood blasts ≥ 1% (p = 0.002), and the presence of additional cytogenetic aberrations (p = 0.002) as predictors of Imatinib failure. Based on these findings, a new prognostic model was developed according to which imatinib failure had 17% (8/47) of patients in low risk, 34.9% (30/86) of patients in intermediate risk, and 76.7% (23/30) of patients in high-risk group (HR = 3.973, 95% CI for HR 2.237–7.053, p < 0.001). Conclusion: The new score allows better selection of patients who are suitable for treatment with imatinib and may guideline the clinical decision for front-line treatment of CML. © 2017 Informa UK Limited, trading as Taylor & Francis Group.

The objective of this single-center study was to determine the pretreatment risk factors and influence of comorbidity on outcome in patients with acute myeloid leukemia (AML). The research involved 145 patients with AML during a 58-month follow-up period. The results suggest that the most significant predictor of poor overall survival (OS) is an adverse karyotype (P = 0.007), while for poor rate of complete remission (CR) it is age ≥55 years, and for early death the most significant predictor is comorbidity, as scored by the Hematopoetic Cell Transplantation Comorbidity Index (HCT-CI), P = 0.001. When we divided the patients into two groups: aged ≥55 years and aged <55 years, these predictors differed. In the group aged ≥55 years the most significant predictor of OS (P = 0.013) and for early death (P = 0.003) was HCT-CI (P = 0.013), while in the younger group it was karyotype (P < 0.001). The most significant predictor of CR in the elderly was increased serum lactate dehydrogenase (LDH) level (P = 0.045). In the younger patients, the most significant predictor of CR was leukocytosis (P = 0.001) and for early death it was infection as the comorbidity (P = 0.007). We point out the importance of comorbidity for OS and early death, as well as the impact of infection in patients with AML. © W.S. Maney & Son Ltd 2012.

Based on current findings, the presence of NPM1 mutations in acute myeloid leukemia (AML) patients is associated with an increased probability of complete remission (CR) and better overall survival (OS). We determined the incidence and prognostic relevance of NPM1 mutations, their association with FLT3 and IDH mutations, and other clinical characteristics in Serbian adult AML patients. Samples from 111 adult de novo AML patients, including 73 AML cases with a normal karyotype (NK-AML), were studied. NPM1, FLT3, and IDH mutations were detected by PCR and direct sequencing. NPM1 mutations were detected in 22.5% of patients. The presence of NPM1 mutations predicted a low CR rate and shorter OS. NPM1 mutations showed an association with both FLT3 and IDH mutations. Survival analysis based on NPM1/FLT3 mutational status revealed a lower OS for NPM1 +/FLT3- compared to the NPM1-/FLT3- group in NK-AML patients. The lack of impact or unfavorable prognostic effect of NPM1 mutations found in this study can be assigned to a small cohort of analyzed AML patients, as can the presence of FLT3 and IDH mutations or other genetic lesions that cooperate with NPM1 mutations influencing prognosis. Copyright © 2012 S. Karger AG, Basel.

Using various risk factor scores, we aimed to identify a subset of elderly patients with acute myeloid leukaemia (AML) for whom it was possible to assess the prognosis. We also aimed to develop a novel prognostic score system. This single centre study involved 102 patients of ≥60 years of age with non-promyelocytic AML. The adverse cytogenetic risk group appeared as the most significant independent prognostic factor for overall survival (OS). Our prognostic scoring system was developed after analysing prognostic risk factors and was applied for patients with favourable and intermediate (I and II) cytogenetic risk groups: age <65 years of age, normal lactate dehydrogenase (LDH) and a comorbidity score obtained applying the haematopoietic cell transplantation-specific comorbidity index (HCT-CI) < 3 = 0 points, in which age ≥65 years = 1 point and an elevated LDH score and HCT-CI ≥3 = 2 points. According to this prognostic model, patients without adverse cytogenetics were classified into three risk groups: favourable = 0-2 points, intermediate = 3-4 points and poor = > 4 points. The OS between these groups was highly significant (p < 0.001). The prognostic model developed in this study may refine the prognosis procedure of elderly AML patients without an adverse karyotype regarding OS, thereby guiding the treatment approach. © 2012 Springer Science+Business Media New York.