Eduardo Bullorsky

Efficacy of extended thrombo-prophylaxis in major abdominal surgery: What does the evidence show? - A meta-analysis

Venous thromboembolism (VTE) is a frequent complication following major abdominal surgery. The use of low-molecular-weight heparins (LMWH) to prevent thrombotic events in these patients is a common and well documented practice. However, there is some controversy surrounding the duration of the prophylaxis, as it has been suggested that the risk persists for several weeks after surgery. The objective of this meta-analysis is to systematically review the clinical studies that compared safety and efficacy of extended use of LMWH (for three to four weeks after surgery) versus conventional in-hospital prophylaxis. An electronic data base search was performed. Only randomized, controlled studies were eligible. Data on the incidence of deep vein thrombosis (DVT), VTE and bleeding were extracted. Only three studies fulfilled the inclusion criteria. The indication for surgery was neoplastic disease in 70.6% (780/1104) of patients. The administration of extended LMWH prophylaxis significantly reduced the incidence of VTE, 5.93% (23/388) versus 13.6% (55/405), RR 0.44 (CI 95% 0.28 - 0.7); DVT 5.93% (23/388) versus 12.9% (52/402), RR 0.46 (CI 95% 0.29 - 0.74); proximal DVT 1% (4/388) versus 4.72% (19/402), RR 0.24 (CI 95% 0.09 - 0.67). We found no significant difference in major or minor bleeding between the two groups: 3.85% (21/545) in the extended thrombo-prophylaxis (ETP) group versus 3.48% (19/559) in the conventional prophylaxis group; RR 1.12 (CI 95% 0.61 - 2.06). There was no heterogeneity between the studies. We conclude that ETP with LMWH should be considered as a safe and useful strategy to prevent VTE in high-risk major abdominal surgery.

Cross-sectional study of adherence to venous thromboembolism prophylaxis guidelines in hospitalized patients. The Trombo-Brit study

BackgroundDVT is the main cause of death in hospitalized patients and thromboprophylaxis is the only way to prevent these deaths. International recommendations suggested that active monitoring of DVT/PE prophylaxis can improve the efficacy in Hospitals.MethodsWe performed a cohort study in three consecutives periods to evaluate DVT prophylaxis in 388 adults hospitalized in a General Hospital.Results85% of the population had high risk factors for DVT. Thromboprophylaxis was in accordance with local and International guidelines (ACCP 2008) in 72.7% and 86% of the patients respectively. No significant difference could be founded between clinical and surgical patients. One every 10 patients received higher prophylaxis than suggested by guidelines and two out of ten received deficient or no prophylaxis. The worst 2 groups of patients were those with moderate/low risk of DVT and the group with a contraindication to pharmacologic prophylaxis. We observed a progressive improvement of the DVT prophylaxis in the 3 periods of evaluation.ConclusionsAlthough the rate of recommended thromboprophylaxis is higher than many other reports in the region we still have some areas where we need to improve. Regular audits like these are very helpful to find out what specific areas of the hospital needs some careful attention in order to have a better quality of assistance.

Clinical outcome of chronic myeloid leukemia imatinib-resistant patients: do BCR–ABL kinase domain mutations affect patient survival? First multicenter Argentinean study

In imatinib-treated patients with chronic myeloid leukemia (CML), BCR–ABL mutations are the most common mechanism of resistance. Here we report the first multicenter Argentinean study investigating mutations in those patients with CML who fail or lose response to imatinib, with or without previous interferon treatment. Point mutations were detected in 36 of 154 patients by direct sequencing. In our series, the single most common mutations were G250E, E255K/V, and M351T. The presence of mutations correlated significantly with accelerated phase, lack of molecular response, and lower cytogenetic and hematological responses. While overall survival did not differ between patients with or without mutations, the probability of progression was higher in patients with mutations. Cases with non-P-loop mutations showed a significantly better overall survival from diagnosis. Multivariate analysis showed that the most significant variables related to the development of mutations were accelerated phase, duration of imatinib treatment, and time delay to starting imatinib. Our results demonstrated that mutation frequency increased with the progression of disease, and suggest that imatinib treatment should be started early.

Síndrome hematofagocítico: Reporte de cuatro casos y revisión de la literatura

Hemophagocytic syndrome in four patients and Literature Review . Hemophagocytic syndromes (HS) represent a severe hyperinflammatory condition with the cardinal symptoms comprises a prolonged fever, cytopenias, hepatosplenomegaly, and the hemophagocytosis by activated, morphologically benign macrophages. The clinical course resembles sepsis, sharing similar physiopathological features. Biochemical markers include elevated ferritin and triglycerides, and low fibrinogen. Whereas in children several inherited immune deficiencies may lead to this syndrome, most adult with HS have no known underlying immune defect. Nevertheless, impaired function of natural killer cells and cytotoxic T-cells is characteristic for both genetic and acquired forms of HS. Frequent triggers are infectious agents, mostly viruses of the herpes group and the malignant lymphomas. A special form of HS in rheumatic diseases is called macrophage-activation syndrome. Patients with HS cannot control the hyperinflammatory response which, if untreated, is fatal in genetic cases and the in a high percentage of acquired cases. Awareness of the clinical symptoms and of the diagnostic criteria of HS is important to start life-saving therapy in time. We present four patients and discuss current therapeutic approaches.

Hematopoietic stem cell transplantation in the era of tyrosine kinase inhibitors

Until the 1990s, the treatment of chronic myeloid leukemia (CML) recognized hematopoietic stem cell transplantation as the best treatment for those patients with an available donor. With the advent of imatinib in 2001, this paradigm changed dramatically as this drug provided outstanding and durable rates of hematologic, cytogenetic, and molecular responses. As a consequence it became the gold standard first-line treatment for most patients. However, after almost a decade of its use, it is clear that although very effective, imatinib cannot cure CML as transplantation has already proven so. Furthermore, the new non-myeloablative regimens and the improvements in survival after allogeneic transplant, especially in the field of unrelated transplants, offer this option to a broader population of patients with CML. This adds to the old question of whom to transplant, when and how to proceed with the allograft. This article reviews the current role of transplantation in the era of tyrosine kinase inhibitors and will try to elucidate its role in the frontline setting as well as after first- and second-line kinase inhibitors failure.

New mutation L324M in the ABL1 kinase domain: does it confer high resistance to second-generation inhibitors?

Chronic myeloid leukemia (CML) is a clonal myeloproliferative disorder of pluripotent hematopoietic stem cells characterized by the presence of the Philadelphia chromosome (Ph). Th is chromosome marker results from a reciprocal translocation t(9;22)(q34;q11.2), allowing fusion of the BCR at 22q11.2 with ABL1 at 9q34, resulting in production of a BCR – ABL1 fusion protein with constitutive up-regulated tyrosine kinase (TK) activity [1]. CML is normally a triphasic disease. It starts with a relatively indolent chronic phase (CP) that can progress to an accelerated phase (AP) characterized by the appearance of 10 – 20% blasts in the blood and bone marrow, and subsequent evolution to blast crisis (BC) [2]. Discovery of the fusion gene BCR – ABL1 , its TK activity and demonstration that it is the pathogenic event of CML led to the development of specifi c TK inhibitors (TKIs). Th e initial effi cacy of these inhibitors has been overshadowed mainly due to the appearance of mutations in the TK domain in the ABL1 gene. Imatinib mesylate (IM) is a selective BCR – ABL1 kinase inhibitor highly eff ective in the treatment of CML, particularly in CP. It acts by binding to the receptor of adenosine triphosphate (ATP) in BCR – ABL1 , competitively inhibiting the phosphorylation of tyrosine residues of the substrate. It has become the fi rst-line agent for the treatment of newly diagnosed patients with CML [3]. Secondgeneration TKIs, which have increased potency relative to IM and activity against many BCR – ABL1 kinase domain mutations, have been developed as alternative therapeutic agents [4]. To date, dasatinib, nilotinib and bosutinib have been approved for the treatment of CML in adults with secondary resistance (mainly by acquisition of mutations in the TK domain) [5] or intolerance to previous IM therapy. Recent studies have demonstrated the effi cacy of these drugs in the treatment of patients with newly diagnosed CML [6,7]. We report a case of a patient who was diagnosed with CML 16 years ago, who acquired the L324M mutation during dasatinib treatment, with a good response to nilotinib. Chromosomal analysis was performed in unstimulated cultures of bone marrow (BM). Chromosomal aberrations were identifi ed by G banding and reported according to the International System for Cytogenetic Nomenclature (ISCN). Total RNA was isolated by conventional extraction technique with TRIzol – chloroform. Quantifi cation of transcript levels of BCR – ABL1 and ABL1 (reference gene) was performed by quantitative real-time polymerase chain reaction (QRT-PCR) method using a Rotor-Gene Q cycler (Qiagen) and a One-Step quantitative RT-PCR commercial kit (Molecular MD). Th e obtained results were expressed as % BCR – ABL1 / ABL1 on the International Scale (the conversion factor was obtained from the Institute of Medical and Veterinary Science, Adelaide, South Australia [8]). High resolution melting (HRM) analysis was performed for mutation screening in the BCR – ABL1 kinase domain. For this analysis, we used primers previously described by Pol à kov à et al . [9]. Th e HRM was analyzed using Rotor-Gene software. For direct sequencing analysis, BCR – ABL1 chimeric transcripts were amplifi ed by nested PCR using primers described by Gorre et al . [10]. Th e amplifi ed products were separated through agarose gel, purifi ed and bidirectionally sequenced. Results were analyzed using the Mutation Surveyor Ò program quantifi cation tool and the ChromasLite Ò program. A 44-year-old man was diagnosed with CML in CP (CML-CP) in February 1996. Conventional karyotype and G banding analysis in BM showed the classical t(9;22) (q34;q11.2) in 100% of cells. Th e BM biopsy showed 5% blasts. Hematological parameters were: white blood cells: 58 10 9 /L (neutrophils: 38, promyelocytes: 6, myelocytes: 34, neutrophil bands: 13), 3 cm splenomegaly, 4.5 cm hepatomegaly. He was treated with 500 mg/day of hydroxyurea 5 mIU/day interferon α for 5 days/week, achieving complete hematologic remission as the best response. L eu k L ym ph om a D ow nl oa de d fr om in fo rm ah ea lth ca re .c om b y Se lc uk U ni ve rs ite si o n 12 /3 0/ 14