ALBERT

Description: In patients (pts) with mast cell (MC) proliferative disorders, the clinical course, prognosis, and outcome vary depending on age, organ-involvement, and the disease-variant. We have retrospectively analyzed the clinical course and outcome in 56 pts with MC disorders refered to the University of Vienna between 1987 and 2004. Using WHO criteria, pts were found to have cutaneous mastocytosis (CM, n=6), indolent systemic mastocytosis (ISM, n=35), aggressive SM (ASM, n=3), mast cell leukaemia (MCL, n=1), SM with associated clonal hematologic non-MC-lineage disease (SM-AHNMD, n=6), and myelomastocytic leukemia (MML, n=5). These groups differed from each other in serum tryptase levels, hemoglobin, platelet counts, and lactate dehydrogenase (p

Description: High-sensitive C-reactive protein (hs-CRP) is a marker of inflammation which has been shown in several prospective studies to predict independently myocardial infarction, stroke or peripheral artery disease. Patients with antiphospholipid antibodies (aPL) are at increased risk of recurrent thromboembolic events but the possibility to predict such risk seems rather limited. Recently, similarities were found in the pathology of thrombosis between elevated levels of hs-CRP and the presence of aPL.We studied the predictive role of hs-CRP levels in patients with the presence of aPL of a cohort of patients with neurological manifestations compared to those where aPL could be excluded. Patients A follow-up investigation was done in 55 aPL-positive and 61 aPL -negative, sex- and age matched patients of the same cohort of patients with acute manifestations of neurological diseases. Hs-CRP levels were measured in all patients at enrollment and were related to the outcome of the patients after a median time of 32 months. Methods Lupus anticoagulants were detected according to the SSC of the ISTH. Anticardiolipin tests were performed by a ß2-glycoprotein I-dependent enzyme-linked immunsorbent assay (Pharmacia ELISA). Hs-CRP was measured by latex enhanced turbidometry (dimension RXL, Dade Behring). Results Cerebral infarctions and transient ischemic attacks were the most common cerebral manifestations of the patients. In APS patients elevated levels of hs-CRP could be measured significantly more frequently than in patients where aPL could be excluded (44 % vs. 16 %, p

Description: The mammalian target of rapamycin (mTOR), a key-regulator of cell cycle progression, has recently been implicated in growth of neoplastic cells and tumor- and leukemia-associated angiogenesis. In addition, mTOR has been described as a regulator of expression of vascular endothelial growth factor (VEGF), a cytokine involved in tumor-related angiogenesis, in various neoplasms. We asked whether mTOR can be employed as a new therapeutic target in acute myeloid leukemia (AML) using the mTOR-targeting drug rapamycin and its derivatives RAD001 (everolimus) and CCI-779. As assessed by 3H-thymidine incorporation, rapamycin was found to counteract growth of AML cells in vitro in 9/11 patients examined as well as in the AML-derived cell lines U937, HL60, and KG1a. The effects of rapamycin on growth of AML cells were dose-dependent (primary AML cells: IC50: 10 pM - 1 nM; inhibition of 3H-thymidine uptake at 1 nM of rapamycin: 43±15 % of control; p

Description: -Thalassemia is very common throughout all tropical and subtropical regions of the world. In Southeast Asia and the Mediterranean regions, compound heterozygotes and homozygotes may have anemia that is mild to severe (hemoglobin [Hb] H disease) or lethal (Hb Bart's hydrops fetalis). We have developed a reliable, single-tube multiplex–polymerase chain reaction (PCR) assay for the 6 most frequently observed determinants of -thalassemia. The assay allows simple, high throughput genetic screening for these common hematological disorders. (Blood. 2000;95:360-362)

Description: The antiphospholipid syndrome (APS) is one of the most common acquired causes of thrombosis on the venous or arterial site. The initial type of the thrombosis appears to be the most likely type of event to recur. In general, APS patients present more common venous thrombosis, especially deep vein thrombosis of the legs. Arterial thromboses are less common and mostly manifest with ischemia or infarction. It is not clear whether a combination of phospholipid antibodies or the additional presence of lupus anticoagulants in patients with anticardiolipin antibodies increase the risk of manifestation of APS. Methods: We investigated retrospectively 300 patients with elevated aCL antibodies. IgG and IgM aCL antibodies were tested by enzyme-linked immunosorbent assay (ELISA). LA were tested by more than 2 different methods according to the proposed criteria of the SSC of the ISTH. Results: Of these patients, 61 % suffered from manifestations of APS, 35 % from venous and 28 % from arterial thrombosis, 7 % of the patients had abortions. In 39 % no thromboembolic disease was found. The coincidence of venous and arterial thrombosis was found in 25/300 (8 %) of the patients. An increased titer of IgG aCL was found in 135 of 300 patients (45 %, median 49 GPL-U/ml, normal range: - 11,3 GPL-U/ml), and an increased titer of IgM aCL in 260 patients (87 %, median 13 MPL-U/ml, normal range: 5,6 MPL-U/ml). Lupus anticoagulants were additionally detected in 130/300 patients (43 %). The rate of clinical manifestations did not differ between LA-positive patients (78 of 130 patients, 60 %) and LA-negative patients (105 of 170, 62 %) patients with elevated aCL antibodies. Regarding the patients with the coincidence of venous and arterial thrombosis, we found a significantly higher rate of positive lupus anticoagulants than in the patients with APS manifestation of one site only (17/25 vs. 113/275, p 〈 0.05, OR 3.04; 95 % CI 1.31 – 7.06). An elevation of IgG-aCL titres were more frequently found, too. Table 1: Characteristics of the patients with a coincidence of venous and arterial thrombosis compared to patients with thrombosis of one site only Conclusion: The additional presence of lupus anticoagulants in patients with anticardiolipin antibodies identifies a group of patients with high risk of recurrent manifestations of the antiphospholipid syndrome. Particularly the risk of manifestation of both, arterial and venous thrombosis in these patients should be early recognized to initiate a careful follow-up and antithrombotic therapy in these patients. Venous and Arterial Thrombosis Thrombosis of One Site No APS Manifestation n 25/300 (8 %) 157/300 (59 %) 118/300 (39 %) Age (yrs) median 48.5 50 46 Sex (F/M) 17/8 (2.1) 62/157 (2.1) 51/118 (2.3) LA 17/25 (68 %) 62/157 (39 %) 51/118 (43 %) IgG-aCL 15/25 (60 %) 73/157 (46 %) 47/118 (40 %) median titre 108 GPL 87 GPL 37 GPL IgM-aCL 24/25 (96 %) 129/157 (82 %) 104/118 (88 %) median titre 13 MPL 14 MPL 14 MPL

Description: The presence of antiphospholipid antibodies has been reported in a large variety of malignancies. It is not clear, however, if the antiphospholipid antibodies are related to thrombotic associations of the antiphospholipid syndrome (APS) in these patients. We investigated the frequency of thrombotic manifestations in 58 patients with the presence of antiphospholipid antibodies and a history of neoplasia, including haematologic and lymphoproliferative malignancies. Methods Antiphospholipid antibodies were detected by clotting assay (lupus anticoagulant, LA) or by enzyme-linked immunosorbent assay (anticardiolipin antibodies). LA were tested by more than 2 different methods according to the proposed criteria of the SSC of the ISTH. Results 39/58 patients suffered from solid tumours mostly from carcinoma of the breast, prostate, and colon and 19/58 patients from malignant haematologic or lymphoproliferative diseases mostly from Non-Hodgkin lymphoma. One patient was suffering simultaneously from two carcinomas of the prostate and the testicle and a Non-Hodgkin’s lymphoma. Among the patients with solid tumours 18/39 (46 %) patients had thromboembolic complications of the antiphospholipid syndrome. Among the patients with haematologic and lymphoproliferative malignancies only 6/19 (32 %) suffered from thromboembolic complications. Thrombotic manifestations were more common on the arterial than the venous site. There was no relation between the titres of aCL antibodies and the rate of clinical manifestations. In two patients aPL disappeared after the effective treatment of the tumor. Especially patients with very high titres did not present any thromboembolic manifestation. Conclusion The presence of antiphospholipid antibodies may identify a subset of cancer patients with high risk of developing thrombotic complications but the frequency of thrombosis is lower in aPL positive patients with lymphoproliferative and haematological malignancies. Especially in these patients very high titres of aCL antibodies do not seem to be associated with clinical manifestations of the APS.

Description: Background: The role of von Willebrand factor cleaving protease (ADAMTS-13) in the pathogenesis of ischemic stroke is still undefined. ADAMTS-13 cleaves ultra-large multimers of von Willebrand factor (ULVWF), and is believed to regulate the size thus the activity of VWF, especially on sites of high shear stress. By assuming the hypothesis, that a deficiency of ADAMTS-13 influences the thrombotic tendency such as intravascular aggregation and platelet thrombus formation, we analysed adult patients with onset of cerebral ischemia. Methods and Patients: 158 unrelated patients (female:89 /male:69) with an objectively confirmed ischemic stroke (n=126) or TIA (n=32), median age at first onset:42 years (range:17–71 years), and 82 healthy subjects, median age:28 years (range:16–52 years), were studied. In our study group we analysed on the one hand 95 patients (pts) with early onset of stroke/TIA 45 years (median age:54 years). None of the pts enrolled had overt evidence of autoimmune or malignancy disease. ADAMTS13 was measured with an assay based on the positive correlation between multimeric size and Ristocetin Cofactor activity of the VWF. Results: In our population the ADAMTS-13 activity was in median 95% (range= 40–185%) significantly higher than 91% (range=52–150%) among controls (p=0.002; OR 0.54). In the subgroup analysis we found no statistical differences in the mean ADAMTS-13 activities among pts with early onser (99% vs 91%; p=0.76, OR 0.93), and among pts with onset at age 45 years as compared to healthy controls (88% vs 91%; p=0.30, OR 1.25). Furthermore, we found statistical differences in the mean VWF:Ag levels among all pts as compared to healthy controls (135% vs 110%; p=0.01, OR 0.63), and in the elderly pts (140% vs 110%; p=0.01, OR 1.63). The young pts showed no statistical differences in the mean VWF:Ag levels compared with the control group (127% vs 110%; p=0.98, OR 0.99). Conclusion: The results from this study show that higher levels of ADAMTS-13 activity and VWF:Ag as compared to healthy controls are associated with ischemic stroke/TIA. Only in the elderly pts we observed a tendency to a negative association between ADAMTS-13 and VWF (lower ADAMTS-13 levels and higher levels of VWF:Ag). It may be, that higher ADAMTS-13 levels have a relevance to prevent thrombotic events. Further studies are needed to confirm whether the relationship between VWF and ADAMTS-13 plays an additional role in the pathogenesis on the onset of ischemic stroke.

Description: Circulating bone marrow–derived endothelial progenitor cells (EPCs) promote vascular reparative processes and neoangiogenesis, and their number in peripheral blood correlates with endothelial function and cardiovascular risk. We tested the hypothesis that the cytokine erythropoietin (EPO) stimulates EPCs in humans. We studied 11 patients with renal anemia and 4 healthy subjects who received standard doses of recombinant human EPO (rhEPO). Treatment with rhEPO caused a significant mobilization of CD34+/CD45+ circulating progenitor cells in peripheral blood (measured by flow cytometry), and increased the number of functionally active EPCs (measured by in vitro assay) in patients (week 2, 312% ± 31%; week 8, 308% ± 40%; both P 〈 .01 versus baseline) as well as in healthy subjects (week 8, 194% ± 15%; P 〈 .05 versus baseline). The effect on EPCs was already observed with an rhEPO dose of about 30 IU/kg per week. Administration of rhEPO increased the number of functionally active EPCs by differentiation in vitro in a dose-dependent manner, assessed in cell culture and by tube formation assay. Furthermore, rhEPO activates the Akt protein kinase pathway in EPCs. Erythropoietin increases the number of functionally active EPCs in humans. Administration of rhEPO or EPO analogs may open new therapeutic strategies in regenerative cardiovascular medicine.

Description: -Thalassemia is very common throughout all tropical and subtropical regions of the world. In Southeast Asia and the Mediterranean regions, compound heterozygotes and homozygotes may have anemia that is mild to severe (hemoglobin [Hb] H disease) or lethal (Hb Bart's hydrops fetalis). We have developed a reliable, single-tube multiplex–polymerase chain reaction (PCR) assay for the 6 most frequently observed determinants of -thalassemia. The assay allows simple, high throughput genetic screening for these common hematological disorders. (Blood. 2000;95:360-362)

Description: A novel intravenous liposomal formulation of all-transretinoic acid (ATRA) was evaluated in 69 patients with acute promyelocytic leukemia (APL): 32 new diagnoses, 35 relapses, and 2 oral ATRA failures. Liposomal ATRA (90 mg/m2) was administered every other day until complete remission (CR) or a maximum of 56 days. Treatment following CR was liposomal ATRA with or without chemotherapy. In an intent-to-treat (ITT) analysis of all patients, CR rates were 62%, 70%, and 20% in newly diagnosed, group 1 first relapses (ATRA naive or off oral ATRA more than or equal to 1 year), or group 2 relapses (second or subsequent relapse or first relapses off oral ATRA less than 1 year), respectively. In 56 evaluable patients (receiving 4 or more doses), CR rates for the same groups were 87% (20 of 23), 78% (14 of 18), and 23% (3 of 13). Remission failure in newly diagnosed patients was not from resistant disease. Several patients in CR became polymerase chain reaction (PCR) negative for promyelocytic leukemia/retinoic acid receptor-alpha (PML/RARα) after liposomal ATRA alone. Toxicity was generally mild, most commonly headaches (67.5%). Eighteen patients (26%) had ATRA syndrome develop during induction. One-year survival of ITT patients was 62%, 56%, and 20% for newly diagnosed, group 1, and group 2, respectively. The medium duration of CR has not yet been reached and was 18 and 5.5 months in the same groups. These results demonstrate that liposomal ATRA is effective in inducing CR in newly diagnosed or group 1 APL patients. It provides a reliable dosage of ATRA for patients with APL unable to swallow or absorb medications and can induce molecular remissions without chemotherapy.