M.M. Oliveira

Neurological complications of hematopoietic stem cell transplantation (HSCT): a retrospective study in a HSCT center in Brazil

We present the neurological complications evaluated in a series of 1000 patients who underwent hematopoietic stem cell transplantation (HSCT). Central nervous system (CNS) neurological complications, particularly brain hemorrhages, were the most common, followed by seizures and CNS infections. An unusual neurological complication was Wernickes encephalopathy. Less frequent neurological complications were metabolic encephalopathy, neuroleptic malignant syndrome, reversible posterior leukoencephalopathy syndrome, brain infarct and movement disorders. The most common neurological complication of the peripheral nervous system was herpes zoster radiculopathy, while peripheral neuropathies, inflammatory myopathy and myotonia were very rarely found.

Repeat course of rabbit antithymocyte globulin as salvage following initial therapy with rabbit antithymocyte globulin in acquired aplastic anemia

The treatment for the majority of patients with acquired aplastic anemia (AA) who are not suitable for hematopoietic stem cell transplant (HSCT) is immunosuppression with standard horse antithymocyte globulin (h-ATG) and cyclosporine (CSA) where hematologic responses are observed in 60–70%.[1][1]

Síntese de pigmentos pretos à base de Fe, Co e Cr pela rota dos precursores poliméricos

Black pigments based on Fe, Cr and Co were synthesized by the polymeric precursor method. The thermal treatment effects were analyzed on color development and stability of pigment. The optimized pigment composition results from the Fe0.7Cr1.3O3 and CoCr2O4 mixture, with appropriately development of coloration at 1000 °C/2 h. After thermal treatment at different temperatures, structural, morphologic and colorimetric aspects of the materials were characterized. By using X-ray diffraction, the crystalline evolution of the pigment was determined. Through scanning electron microscopy the powders morphology was observed. Determination of the specific surface area of powders was done by adsorption of nitrogen using the BET method. In the colorimetric analysis, the powders colors and the visible spectroscopy absorption were discussed.

Paroxysmal nocturnal hemoglobinuria clone in 103 Brazilian patients: diagnosis and classification

Background Paroxysmal nocturnal hemoglobinuria is an acquired chronic hemolytic anemia, which often manifests as peripheral blood cytopenias and thrombosis. Objective The aim of this study is to describe a Brazilian population of paroxysmal nocturnal hemoglobinuria patients. Methods One hundred and three paroxysmal nocturnal hemoglobinuria cases were retrospectively reviewed and the clinical presentation, thrombosis, survival, and clone size were assessed. Diagnosis was established by flow cytometry. Results Fifty-two male and 51 female patients with a median age of 24.1 years (5.5–62 years) were studied. Clinical symptoms included hemoglobinuria (18.4%), infection (46.6%) and thrombosis (16.5%), and 80.6% had pancytopenia. Patients were classified as classic paroxysmal nocturnal hemoglobinuria (10), paroxysmal nocturnal hemoglobinuria with aplastic anemia (39), and paroxysmal nocturnal hemoglobinuria with subclinical features and aplastic anemia (54). There were significant differences in terms of median age, size of clone, clinical symptoms, and peripheral blood cell counts between the three subcategories. The clone size in erythrocytes and granulocytes were respectively 0.04% (range: 0–18%) and 7.3% (range: 0.3–68.7%) in patients with subclinical features and aplastic anemia, 15.8% (range: 0–99.7%) and 63.0% (range: 1.7–99.8%) in patients with aplastic anemia alone, and 82.2% (range: 0–99.85%) and 98.0% (81.3–100.0%) in Classic disease. Statistical differences were identified for platelets (p-value = 0.001), lactate dehydrogenase (p-value = 0.002) and the clone size (p-value < 0.001) in patients who suffered thrombotic events compared to those who did not. Overall survival was 81.7%, with patients with subclinical features and aplastic anemia having lower overall survival (76.5%). Conclusion This retrospective review of 103 patients over an 11-year period represents the largest collection of paroxysmal nocturnal hemoglobinuria cases from a single center in Brazil. Flow cytometry showed that a larger clone was associated with classical symptoms and increased risk of thrombosis, even in patients with bone marrow failure, whereas a smaller clone was associated with bone marrow aplasia.

Electrical and microstructural properties of microwave sintered SnO2-based varistors

An investigation was made of the microstructural and electrical properties of SnO2-based varistors microwave sintered at 1200 oC, applying a heating rate of 120 oC/min and treatment times of 10, 20, 30, 40, 50 and 60 min. The system used in this study was (98.95-X) %SnO2.1.0%CoO.0.05%Cr2O3.X%Ta2O5, where X corresponds to 0.05 and 0.065 mol%. Sintering was carried out in a domestic microwave oven (2.45 GHz) fitted for lab use. Silicon carbide was placed in a refractory vessel to form a heating chamber surrounding the sample holder. The pellets were examined by scanning electron microscopy, X-ray diffractometry, direct current measurements and impedance spectroscopy. The parameters of density, medium grain size, coefficient of nonlinearity, breakdown electrical field, leakage current, and height and width of the potential barrier were analyzed.

Transplante de células-tronco hematopoéticas em crianças e adolescentes com leucemia aguda: experiência de duas instituições Brasileiras

Hematopoietic Stem Cell transplantation (HSCT) is the treatment of choice for patients with high-risk leukemia. In spite of this, relapse remains a major cause of death of these patients. Our objective was to analyze the outcomes of patients with acute leukemia submitted to hematopoietic stem cell transplantation in two Brazilian institutions. A retrospective study of 208 patients transplanted between 1990 and 2007 with a median age of 9 years (range: 1-18 years) was made. One hundred and nineteen patients had acute lymphocytic leukemia (ALL) and 89 had acute myeloid leukemia (AML). Early disease was considered for CR1 and CR2 cases and advanced disease >CR3 and refractory and relapse disease. Ninety patients are alive between 258 and 6068 days after hematopoietic stem cell transplantation (M: 1438 days). The overall survival (OS) was 45% (3 years) and event free survival (EFS) was 39% (3 years). Primary graft failure occurred in 14/195 patients (8%). There were no differences in the overall survival and event free survival between patients with acute lymphocytic leukemia and acute myeloid leukemia, between sources of cells used or between those who developed acute or chronic graft-versus-host disease (GVHD). When comparing transplants from related and unrelated donors, there was no difference in the overall survival. Patients with acute lymphocytic leukemia receiving the total body irradiation (TBI) conditioning regimen had better overall survival and event free survival (p<0.001). One hundred and eighteen patients died between 0 and 1654 days after hematopoietic stem cell transplantation (M: 160 days). Transplantation-related-mortality (TRM) at D+100 was 16% and cumulative incidence of relapse was 40% (3 years). Patients with advanced disease had lower 3-year overall survival and event free survival (p<0.001). Multivariate analysis showed that disease status was the most significant factor associated with higher event free survival and overall survival . Our results show that children and adolescents transplanted with early disease can achieve considerable overall survival and also highlights the inefficacy of hematopoietic stem cell transplantation for patients with advanced disease.

Chronic Graft-Versus-Host Disease: Survival Impact on Patients with Severe Aplastic Anemia (SAA) and Paroxysmal Nocturnal Hemoglobinuria (PNH)

S308 Setting: Stem cell transplantation centers. Patients: From 867 patients who underwent to an ASCT in our center, 21 (2.42%) were cMPN: 8 (38.1%) were primary myelofibrosis (MF), 11 (52.4%) secondary MF and 2 CMN different from MF. Main Outcomes Measures: Our data are similar to other institutions based on literature that have been published. Results: The clinical and biological features and ASCT characteristics are summarized in table 1. All patients achieved neutrophil and platelet engraftment. Concerning the complications related to ASCT: 71.4% of patients suffered from mucositis (86.7% grade I and II), 23.8% developed CMV reactivation, 9.5% haemorrhagic cystitis, 4.8% obstruction sinusoidal syndrome and none developed transplant associated microangiopathy. A total of 16 patients (76.2%) developed acute graft versus host disease (GVHD) (18.8 % grades III-IV) with a median of presentation of 26 days (15-141) and 11 patients (52.4%) developed chronic GVHD (63.6% extensive) with a median of 203 days (120-566). Transplant related mortality (TRM) at day +100 was 4.8% and the global TRM. At day +100 post ASCT, 17 patients (80.9%) achieved complete remission (CR) and 3 (14.3%) patients were in relapse. Six (28.6%) of these 20 patients relapsed after a median of 150 days (53-2295) from ASCT. In four of them, the approach of relapse was modulating immunosuppression +/donor lymphocyte infusion and hypomethylating agents in the cases of MRD, reaching CR and complete chimerism. In the last follow-up, 13 patients (61.9%) were alive (11 in CR and 2 with active disease) and 8 (38.1%) were dead from different causes. With a median follow-up of 35 months (16-121) the overall survival (OS) and event free survival (EFS) at 3 years was 61% and 57%, respectively. Conclusions: The results of our series confirms the potential curative of ASCT. We observed that more than a half of patients are long survivors. Modulating immunosuppression plays an important role in the setting of post ASCT relapse.

A predictive model of pathologic response based on tumor cellularity and tumor-infiltrating lymphocytes (CelTIL) in HER2-positive breast cancer treated with chemo-free dual HER2 blockade

Background The presence of stromal tumor-infiltrating lymphocytes (TILs) is associated with increased pathologic complete response (pCR) and improved outcomes in HER2-positive early-breast cancer (BC) treated with anti-HER2-based chemotherapy. In the absence of chemotherapy, the association of TILs with pCR following anti-HER2 therapy-only is largely unknown. Patients and methods The PAMELA neoadjuvant trial treated 151 women with HER2-positive BC with lapatinib and trastuzumab [and hormonal therapy if hormone receptor (HR)-positive] for 18 weeks. Percentage of TILs and tumor cellularity were determined at baseline (N = 148) and at day 15 (D15) of treatment (N = 134). Associations of TILs and tumor cellularity with pCR in the breast were evaluated. A combined score based on tumor cellularity and TILs (CelTIL) measured at D15 was derived in PAMELA, and validated in D15 samples from 65 patients with HER2-positive disease recruited in the LPT109096 neoadjuvant trial, where anti-HER2 therapy-only was administer for 2 weeks, then standard chemotherapy was added for 24 weeks. Results In PAMELA, baseline and D15 TILs were significantly associated with pCR in univariate analysis. In multivariable analysis, D15 TILs, but not baseline TILs, were significantly associated with pCR. At D15, TILs and tumor cellularity were found independently associated with pCR. A combined score (CelTIL) taking into account both variables was derived. CelTIL at D15 as a continuous variable was significantly associated with pCR, and patients with CelTIL-low and CelTIL-high scores had a pCR rate of 0% and 33%, respectively. In LPT109096, CelTIL at D15 was found associated with pCR both as a continuous variable and as group categories using a pre-defined cut-off (75.0% versus 33.3%). Conclusions On-treatment TILs, but not baseline TILs, are independently associated with response following anti-HER2 therapy-only. A combined score of TILs and tumor cellularity measured at D15 provides independent predictive information upon completion of neoadjuvant anti-HER2-based therapy. Clinical trial number NCT01973660.

Abstract P4-21-05: Neoadjuvant non-pegylated liposomal doxorubicin plus paclitaxel, trastuzumab and pertuzumab in patients with HER2+ breast cancer – Final results of the SOLTI OPTI-HER HEART study

INTRODUCTION Targeting HER2 by dual blockade with trastuzumab (T) and pertuzumab (P) in a taxane-based regimen is an active neoadjuvant treatment (NAT) of HER2+ early breast cancer (EBC). Addition of an anthracycline could further enhance this response, but potential cardiac toxicity is a concern. The Opti-HER HEART trial (NCT01669239) aims to optimize neoadjuvant treatment while minimizing cardiac risk, by combining T+P with a taxane and non-pegylated liposomal doxorubicin (NPLD). MATERIAL AND METHODS Phase II open-label, single-arm study of six 21-day cycles of NPLD (50mg/m2 D1), paclitaxel (80mg/m2 D1,8,15), T (4mg/kg C1D1, followed by 2mg/kg weekly), and P (840mg C1D1, followed by 420mg C2-6D1) as NAT for patients (pts) with stage II-IIIB HER2+ BC. Primary objective was to evaluate cardiac safety of the combination, measured by the incidence of type A (symptomatic congestive heart failure ) or type B [asymptomatic reduction of Left Ventricular Ejection Fraction (LVEF) value: ≥10% absolute decrease and LVEF RESULTS Between June 2013 and January 2015, 83 pts with HER2+ EBC (stage II 78%, stage III 22%) and adequate cardiac function (LVEF≥55%) were enrolled. Mean age was 50 years, N+ 47%, hormone receptor (HR) positive 71% and median baseline LVEF 66%. Eighty-five percent of pts completed 6 cycles of NAT, whereas 15% discontinued NAT due to toxicity. Adverse events (AEs) leading to dose adjustments/temporary interruptions and discontinuation of at least 1 drug occurred in 70% and 21% of pts, respectively. Primary objective was met with an incidence of cardiac events during NAT of 4% (95%CI 1-10, 3pts, all type B). Cardiac events until study completion (1 year) were 8% (all type B). All (but 2 cases with no follow-up data) were reversible and only 1 pt presented an asymptomatic LVEF CONCLUSIONS The neoadjuvant combination of T+P, paclitaxel and NPLD does not increase the risk for cardiac events in HER2+ BC pts. Since cardiac toxicities may present later, long-term cardiac monitoring is essential. Efficacy in terms of pCR was remarkable, being higher to historical values of combinations with dual anti-HER2 blockade and one of the highest reported among HR-HER2+ BC. This regimen administered with primary G-CSF prophylaxis and cardiac function monitoring may be an effective and secure option for early and locally advanced HER2+ pts with good cardiac function. Citation Format: Gavila J, Perez-Garcia J, Calvo I, Ciruelos E, Munoz M, Virizuela JA, Ruiz I, Andres R, Morales S, Perello A, Sanchez P, Garcia-Saenz JA, Quero Guillen JC, Gonzalez-Santiago S, Garau Llinas I, Gonzalez-Martin A, Cantos Sanchez de Ibarguen B, Zaragoza K, de la Pena L, Llombart-Cussac A, Oliveira M. Neoadjuvant non-pegylated liposomal doxorubicin plus paclitaxel, trastuzumab and pertuzumab in patients with HER2+ breast cancer – Final results of the SOLTI OPTI-HER HEART study [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P4-21-05.

Abstract OT1-03-09: FAIRLANE: A phase II randomized, double-blind, study of the Akt inhibitor ipatasertib (Ipat, GDC-0068) in combination with paclitaxel (Pac) as neoadjuvant treatment for early stage triple-negative breast cancer (TNBC)

Background: TNBC often exhibits activation of PI3K/Akt signaling, associated with loss of PTEN expression, low INPP4B expression, and/or increased AKT3 amplification. Inhibition of the PI3K/Akt pathway in diverse cancers leads to radiosensitization and/or chemosensitization. Ipat is an oral, potent ATP-competitive small molecule inhibitor of all three isoforms of Akt. The combination of ipat with taxanes in preclinical models resulted in enhanced efficacy relative to either ipat or chemotherapy alone. In a Phase Ib clinical study, the combination of ipat with diverse chemotherapy regimens was well-tolerated and resulted in RECIST responses, particularly pts with tumors having PI3K/Akt activation. Methods: FAIRLANE is a randomized, double-blind, placebo controlled, multicenter, neoadjuvant Phase II study designed to estimate the efficacy of ipat combined with pac versus placebo combined with pac in women with Stage Ia  IIIa TNBC. Approximately 150 pts (Pts) will be enrolled, randomized in a 1:1 ratio, and stratified by PTEN status, node involvement, and tumor size. Pts will receive 3 cycles of ipat 400 mg or placebo orally once daily on Days 1 to 21 of each 28-day cycle, along with pac 80 mg/m2 every 7 days for a total of 12 doses. All pts will undergo pretreatment and Day 8 tumor tissue acquisition to evaluate pathway biomarkers. Following three cycles of treatment, pts will undergo surgery. The primary efficacy endpoint, pCR within the breast and axilla (ypT0/Tis ypN0) in all pts and in pts with PTEN low tumors, will be assessed by local pathology evaluation following completion of neoadjuvant therapy and surgery. Additional endpoints include objective response rate, safety, BCS rate, pharmacokinetics, and pathway biomarkers. Following surgical resection of primary tumor, pts are expected to continue post-operative treatment with a standard adjuvant chemotherapy regimen at physician9s discretion. The study is open for accrual. Clinical trial information: NCT02301988. Citation Format: Saura C, Isakoff SJ, Calvo I, Patt D, Andersen J, Gonzalez-Martin A, Fisher J, Ciruelos E, Gil-Gil M, De la Pena L, Choi Y, Jia S, Singel S, Patel PH, Baselga J, Oliveira M. FAIRLANE: A phase II randomized, double-blind, study of the Akt inhibitor ipatasertib (Ipat, GDC-0068) in combination with paclitaxel (Pac) as neoadjuvant treatment for early stage triple-negative breast cancer (TNBC). [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr OT1-03-09.