Luciana Correa de Oliveira

Determination of P‐glycoprotein, MDR‐related protein 1, breast cancer resistance protein, and lung‐resistance protein expression in leukemic stem cells of acute myeloid leukemia

The most primitive leukemic precursor in acute myeloid leukemia (AML) is thought to be the leukemic stem cell (LSC), which retains the properties of self‐renewal and high proliferative capacity and quiescence of the hematopoietic stem cell. LSC seems to be immunophenotypically distinct and more resistant to chemotherapy than the more committed blasts. Considering that the multidrug resistance (MDR) constitutive expression may be a barrier to therapy in AML, we have investigated whether various MDR transporters were differentially expressed at the protein level by different leukemic subsets.

Thalidomide plus dexamethasone as a maintenance therapy after autologous hematopoietic stem cell transplantation improves progression-free survival in multiple myeloma

Despite the good response of stem cell transplant (SCT) in the treatment of multiple myeloma (MM), most patients relapse or do not achieve complete remission, suggesting that additional treatment is needed. We assessed the impact of thalidomide in maintenance after SCT in untreated patients with MM. A hundred and eight patients (<70 years old) were randomized to receive maintenance with dexamethasone (arm A; n = 52) or dexamethasone with thalidomide (arm B; n = 56; 200 mg daily) for 12 months or until disease progression. After a median follow‐up of 27 months, an intention to treat analysis showed a 2‐year progression‐free survival (PFS) of 30% in arm A (95% CI 22–38) and 64% in arm B (95% CI 57–71; P = 0.002), with median PFS of 19 months and 36 months, respectively. In patients who did not achieve at least a very good partial response, the PFS at 2 years was significantly higher when in use of thalidomide (19 vs. 59%; P = 0.002). Overall survival at 2 years was not significantly improved (70 vs. 85% in arm A and arm B, respectively; P = 0.27). The addition of thalidomide to dexamethasone as maintenance improved the PFS mainly in patients who did not respond to treatment after SCT. Am. J. Hematol.

Increased expression of miR-221 is associated with shorter overall survival in T-cell acute lymphoid leukemia.

BackgroundCD56 expression has been associated with a poor prognosis in lymphoid neoplasms, including T-cell acute lymphoblastic leukemia (T-ALL). MicroRNAs (miRNAs) play an important role in lymphoid differentiation, and aberrant miRNA expression has been associated with treatment outcome in lymphoid malignancies. Here, we evaluated miRNA expression profiles in normal thymocytes, mature T-cells, and T-ALL samples with and without CD56 expression and correlated microRNA expression with treatment outcome.MethodsThe gene expression profile of 164 miRNAs were compared for T-ALL/CD56+ (n=12) and T-ALL/CD56- (n=36) patients by Real-Time Quantitative PCR. Based on this analysis, we decided to evaluate miR-221 and miR-374 expression in individual leukemic and normal samples.ResultsmiR-221 and miR-374 were expressed at significantly higher levels in T-ALL/CD56+ than in T-ALL/CD56- cells and in leukemic blasts compared with normal thymocytes and peripheral blood (PB) T-cells. Age at diagnosis (15 or less vs grater than 15 years; HR: 2.19, 95% CI: 0.98-4.85; P=0.05), miR-221 expression level (median value as cut off in leukemic samples; HR: 3.17, 95% CI: 1.45-6.92; P=0.004), and the expression of CD56 (CD56-vs CD56+; HR: 2.99, 95% CI: 1.37-6.51; P=0.006) were predictive factors for shorter overall survival; whereas, only CD56 expression (HR: 2.73, 95% CI: 1.03-7.18; P=0.041) was associated with a shorter disease-free survival rate.ConclusionsmiR-221 is highly expressed in T-ALL and its expression level may be associated with a poorer prognosis.

Ovarian recovery after stem cell transplantation.

Autologous or allogeneic SCT with conventional conditioning (chemotherapy with or without irradiation) has emerged as an effective and potentially curative therapy in patients with hematologic malignancies and in other selected solid tumors; however, several patients experience significant early and delayed side effects, including long-term endocrine imbalance and infertility. In spite of several reproductive recovery and pregnancy reports published in the oncology literature, review of medical literature reveals a paucity of comparable information in the SCT field. We report here four cases of ovarian recovery in patients who received hormonal replacement therapy after diagnosis of primary ovarian failure due to high-dose chemotherapy and SCT.

Therapeutic Leukapheresis in Patients with Leukostasis Secondary to Acute Myelogenous Leukemia

Leukostasis is a relatively uncommon but potentially catastrophic complication of acute myelogenous leukemia (AML). Prompt leukoreduction is considered imperative to reduce the high mortality rate in this condition. Leukapheresis, usually associated with chemotherapy, is an established approach to diminish blast cell counts. We report a single center experience in managing leukostasis with leukapheresis. Fifteen patients with leukostasis of 187 patients with AML (8.02%) followed at our institution were treated with leukapheresis associated with chemotherapy. The procedures were scheduled to be performed on a daily basis until clinical improvement was achieved and WBC counts were significantly reduced. Overall and early mortalities, defined as that occurred in the first 7 days from diagnosis, were reported. A high proportion of our patients with leukostasis (46.66%) had a monocytic subtype AML (M4/M5, according to French‐American‐British classification). The median overall survival was 10 days, despite a significant WBC reduction after the first apheresis procedure (from 200.7 × 109/L to 150.3 × 109/L). Almost half of patients (7/15) had an early death. Therapeutic leukapheresis, associated or not to chemotherapy, is an effective approach to reduce WBC counts in patients with AML and leukostasis; however, this therapeutic procedure does not appear to change significantly the sombre prognosis observed in the majority of patients with this complication. Other forms of treatment must be found to reduce the high mortality rate related to leukostasis. J. Clin. Apheresis, 2011.

Confirmation of the utility of the International Staging System and identification of a unique pattern of disease in Brazilian patients with multiple myeloma

Multiple myeloma (MM) is one of the most frequent hematologic malignancies, and its incidence varies worldwide. Except for occasional case series or correlative biological studies, little is known about the incidence and clinical features of MM in Latin America. In Brazil, national estimates for the

Cardiac stunning as a manifestation of ATRA differentiation syndrome in acute promyelocytic leukemia

Acute promyelocytic leukemia (APL) is a specific type of acute myelogenous leukemia characterized by the reciprocal translocations between the long arms of chromosomes 15 and 17 [t(15;17)] leading to the fusion of the retinoic acid receptor and the promyelocytic leukemia (PML) genes, called PML/RARalpha. The PML/RARalpha gene product acts as a transcription repressor, resulting in the blocking of the differentiation of APL blasts at the stage of promyelocytes. Pharmacological doses of all-trans retinoic acid (ATRA) reverse this blockage and induce disease remission. However, although ATRA is well tolerated in the majority of the APL patients treated with ATRA and idarubicin regimen (AIDA), approximately one quarter of them develop a complication denominated ATRA differentiation syndrome (DS), formerly known as retinoic acid syndrome [1–3]. The onset of DS ranges from 2 to 21 days (median of 10 days) after initiating ATRA therapy. The full development of DS is characterized by unexplained fever, weight gain, edema, interstitial pulmonary infiltrates with dyspnea, pleural and pericardial effusions, episodic hypotension, and acute renal failure. The most frequent manifestations are respiratory distress and fever, affecting more than 80% of DS patients. Acute myocardial ischemia is not commonly observed in DS. As far as we know, there is only one case report describing this complication [4]. Through early diagnosis, DS responds well to the administration of dexamethasone, with decrease in mortality from 30% to less than 10% in the patients suffering from it. The pathogenesis of this complication is not completely clarified, but increased expression of adhesion molecules on blasts and on endothelial cells and the release of inflammatory cytokines may be the main explanation [5].

Hydroxyurea increases plasma concentrations of microparticles and reduces coagulation activation and fibrinolysis in patients with sickle cell anemia.

Microparticles (MPs) are present in healthy subjects and their concentration increases in patients at high risk of thrombosis. We evaluated 10 patients with sickle cell anemia (SCA) treated with hydroxyurea (HU) and 13 SCA patients without this treatment. MP concentrations were determined by flow cytometry. Coagulation was evaluated using the thrombin-antithrombin complex (TAT) and D-dimers. Total MP concentrations were increased in the HU-treated group (265 × 106/ml vs. 67.45 × 106/ml; p = 0.0026), as well as MPs derived from RBC (67.83 × 106/ml vs. 26.31 × 106/ml; p = 0.05), monocytes (51.31 × 106/ml vs. 9.03 × 106/ml; p = 0.0084), monocytes with tissue factor (TF) expression (2.27 × 106/ml vs. 0.27 × 106/ml; p = 0.0058), endothelium (49.42 × 106/ml vs. 7.23 × 106/ml; p = 0.007) and endothelium with TF (1.42 × 106/ml vs. 0.26 × 106/ml; p = 0.0043). Furthermore, the concentrations of TAT (7.56 vs. 10.98 µg/l; p = 0.014) and D-dimers (0.65 vs. 1.29 µg/ml; p = 0.007) were reduced with HU. The MP elevation may suggest a direct cytotoxic effect of HU. Another explanation is a cell surface increase secondary to a megaloblastic process, resulting in increased vesicle release. In our opinion, the known benefits of HU on SCA patients, along with the reduction in coagulation activation, surpass its potential detrimental effect on MPs. Future studies should elucidate the role of MPs and demonstrate their significance in different contexts.

Preoperative variables associated with transfusion requirements in orthotopic liver transplantation

BACKGROUND Patients with end-stage chronic liver disease (CLD) and submitted to orthotopic liver transplantation (OLT) usually require blood transfusion during the procedure or in the post-operative period due to hemorrhage. Risk factors for transfusion need are not fully known. This study aimed to identify the factors associated with blood components requirements. METHODS In this retrospective study a total of 166 consecutive patients submitted to OLT with the piggyback technique, between 2001 and 2011, were evaluated for number of blood components transfused during surgical procedure and the four subsequent days (total of 5 days). We evaluated the association between the number of units transfused and clinical variables, such as: Child-Turcotte-Pugh (CTP) and MELD scores, hemoglobin concentration (Hb), INR, serum creatinine, bilirubin and albumin concentrations, and total, hypothermic and normothermic time of graft ischemia. RESULTS 152 (91.6%) Patients were transfused (median of 24 units of blood components). Risk factors for higher blood transfusion requirements were CTP, INR, Hb and total time of graft ischemia. The group with CTP-A score received less blood components than CTP-B/C (11.5 vs 27; P=0.002). The group with Hb<10 required a higher number of blood units (34.5 vs 23; P=0.003). The group with INR<1.5 received less blood units (20.5 vs 31; P=0.012). The group transplanted with a graft exposed to less than the median of 555 min of ischemia received less transfusion (21 vs 27; P=0.03). MELD score and the other factors were not associated with blood requirements. CONCLUSION These results demonstrate that CTP, but not MELD score, hemoglobin concentration, INR, and total time of graft ischemia are preoperative variables associated with blood requirements during OLT and in the subsequent days.

Oral anticoagulant therapy does not modify the bleeding pattern associated with the levonorgestrel-releasing intrauterine system in women with thrombophilia and/or a history of thrombosis

BACKGROUND Progestogen-only contraceptives (POCs) are suitable for women with thrombophilia and/or a history of venous thromboembolism (VTE). Several of these women, however, use oral anticoagulant therapy (OAT), which can impair the bleeding pattern associated with POC use. We evaluated the effects of OAT use on the bleeding pattern associated with the levonorgestrel-releasing intrauterine system (LNG-IUS) in women with thrombophilia and/or a history of VTE. STUDY DESIGN This prospective cohort study followed two groups of women, all of whom were thrombophilic and/or had a history of VTE: OAT users and nonusers. Bleeding patterns, blood pressure, body mass index (BMI), weight, complete blood count and waist circumference were compared between the two groups before and 6 and 12 months after LNG-IUS insertion. RESULTS The patient cohort consisted of 33 women aged 18 to 45 years old, including 16 OAT users and 17 nonusers. Body weight increased by 3.9% and BMI by 3.8% in OAT users 12 months after LNG-IUS insertion. Hemoglobin and hematocrit levels increased by approximately 10% in both groups. There was no difference between the groups in bleeding patterns, with amenorrhea being the most frequent pattern in both groups (41.2% each) 12 months after LNG-IUS insertion. OAT did not increase the frequency of prolonged and/or frequent bleeding. CONCLUSION OAT users and nonusers had similar bleeding patterns after insertion of the LNG-IUS. Hemoglobin and hematocrit levels increased in both groups.