Publications by authors named "Carlos Chiattone"

75 Publications

Associação Brasileira de Hematologia, Hemoterapia e Terapia Celular Consensus on genetically modified cells. III: anti-CD19 CAR-T cell therapy for patients with non-Hodgkin lymphoma.

Hematol Transfus Cell Ther 2021 Nov;43 Suppl 2:S22-S29

Faculdade de Ciências Médicas da Santa Casa de São Paulo (FCMSCSP), São Paulo, SP, Brazil. Electronic address:

The treatment and evolution of B-cell non-Hodgkin lymphoma (B-NHL) has undergone important changes in the last years with the emergence of targeted therapies, such as monoclonal antibodies, small molecules, antibody-drug conjugates, and bispecific antibodies. Nevertheless, a significant portion of patients remains refractory or relapsed (R/R) to the new therapeutic modalities, representing thus an unmet medical need. The use of CAR-T cells for the treatment of B-NHL patients has shown to be a promising therapy with impressive results in patients with R/R disease. The expectations are as high as the imminent approval of CAR-T cell therapy in Brazil, which it is expected to impact the prognosis of R/R B-NHL. The aim of this manuscript is to offer a consensus of specialists in the field of onco-hematology and cellular therapy, working in Brazil and United States, in order to discuss and offer recommendations in the present setting of the use of CAR-T cells for patients with B-NHL.
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http://dx.doi.org/10.1016/j.htct.2021.09.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8606699PMC
November 2021

Diagnosis, prevention and treatment of central nervous system involvement in peripheral t-cell lymphomas.

Crit Rev Oncol Hematol 2021 Nov 12;167:103496. Epub 2021 Oct 12.

Lymphoma Unit, Department of Onco-Hematology, IRCCS San Raffaele Scientific Institute, Milan, Italy. Electronic address:

Non-Hodgkin lymphomas with T-cell immunophenotype encompass a heterogeneous group of infrequent neoplasms that follow variable clinical courses but prevalently include aggressive behavior and high mortality rates. The involvement of the central nervous system (CNS) is an uncommon event in T-cell lymphomas, with wide variability among the different disease entities. CNS can be affected either at initial diagnosis or at recurrence, and both forms are considered "secondary CNS T-cell lymphoma". Given the low incidence of secondary CNS T-cell lymphoma, related literature is sparse, contradictory, and primarily constituted by small case series and single case reports. However, reported studies uniformly suggest high mortality rates related to this event. Therefore, to improve our ability to identify high-risk patients and offer them successful CNS prophylaxis or timely and effective treatment once the event has occurred may prevent CNS-related T-cell lymphomas deaths. For example, some entities like aggressive adult T-cell leukemia/lymphoma, extranodal natural killer/T-cell lymphoma, and other peripheral T-cell lymphomas with involvement of two or more extranodal organs are prone to CNS dissemination and should be considered for personalized CNS prophylaxis. The level of evidence suggesting an increased risk of CNS recurrence for other T-cell lymphomas and for other risk factors is lower. Published case series show that, following the example of aggressive B-cell lymphomas, patients with T-cell lymphomas and putative increased CNS risk receive different forms of prophylaxis, mostly methotrexate and cytarabine delivered by intrathecal and/or intravenous routes, with varied success. To date, achievements in the treatment of CNS involvement in patients with aggressive B-cell lymphoma were not replicated in secondary CNS T-cell lymphomas, and identification of effective therapies remains an urgent research target. This review is focused on clinical findings, diagnosis, treatment, and prognosis of patients with T-cell lymphoma experiencing CNS dissemination either at presentation or relapse. It aims to provide logical and, oftentimes, evidence-based answers to the most common questions on the most probable risk factors to CNS involvement in patients with T-cell lymphoma, the indications and strategies to prevent this life-threating event, and the management of patients with CNS disease.
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http://dx.doi.org/10.1016/j.critrevonc.2021.103496DOI Listing
November 2021

Management of Chronic Lymphocytic Leukemia in Less-Resourced Countries.

Cancer J 2021 Jul-Aug 01;27(4):314-319

Department of Haematology and Blood Transfusion, Obafemi Awolowo University Teaching Hospitals Complex (OAUTHC), Ile-Ife, Osun State, Nigeria.

Abstract: Despite the practice-changing advances achieved in the prognostic stratification and treatment of chronic lymphocytic leukemia (CLL), a large fraction of the world population resides in countries where access to many of these advances remains unavailable or subject to severe constraints. Although some of these countries display incidence rates of CLL that are lower than those of developed Western countries, a large number of patients are expected to be diagnosed with CLL in these regions every year. In this article, we review issues regarding management of CLL in some less-resourced countries, with a focus on the evidence basis for epidemiological and clinical information on this disease, the availability of diagnostic and therapeutic resources, and participation in clinical trials. Going forward, challenges that still need to be addressed include the development of unified countrywide registries, guidelines for management applicable to each country, wider availability of prognostic tools, access to new drugs, and policies that ensure these drugs are affordable to all patients worldwide.
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http://dx.doi.org/10.1097/PPO.0000000000000533DOI Listing
October 2021

The Associação Brasileira de Hematologia, Hemoterapia e Terapia Celular seeks the implementation of, and access to, the CAR-T cell treatment in Brazil.

Hematol Transfus Cell Ther 2021 Nov 22;43 Suppl 2:S1-S2. Epub 2021 Jul 22.

Associação Brasileira de Hematologia, Hemoterapia e Terapia Celular (ABHH), São Paulo, SP, Brazil; Universidade Federal do Paraná (UFPR), Curitiba, PR, Brazil.

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http://dx.doi.org/10.1016/j.htct.2021.07.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8606715PMC
November 2021

Simplified Geriatric Assessment in Older Patients With Diffuse Large B-Cell Lymphoma: The Prospective Elderly Project of the Fondazione Italiana Linfomi.

J Clin Oncol 2021 04 12;39(11):1214-1222. Epub 2021 Feb 12.

Division of Hematology, Ospedale di Circolo e Fondazione Macchi-ASST Sette Laghi, University of Insubria, Varese, Italy.

Purpose: To prospectively validate the use of a simplified geriatric assessment (sGA) at diagnosis and to integrate it into a prognostic score for older patients with diffuse large B-cell lymphoma (DLBCL).

Methods: We conducted the prospective Elderly Project study on patients with DLBCL older than 64 years who underwent our Fondazione Italiana Linfomi original geriatric assessment (oGA) (age, Cumulative Illness Rating Scale for Geriatrics, activities of daily living, and instrumental activities of daily living) before treatment. Treatment choice was left to the physician's discretion. The primary end point was overall survival (OS) (ClinicalTrials.gov identifier: NCT02364050).

Results: We analyzed 1,163 patients (median age 76 years), with a 3-year OS of 65% (95% CI, 62 to 68). Because at multivariate analysis on oGA, age > 80 years retained an independent correlation with OS, we also developed a new, simplified version of the GA (sGA) that classifies patients as fit (55%), unfit (28%), and frail (18%) with significantly different 3-year OS of 75%, 58%, and 43%, respectively. The sGA groups, International Prognostic Index, and hemoglobin levels were independent predictors of OS and were used to build the Elderly Prognostic Index (EPI). Three risk groups were identified: low (23%), intermediate (48%), and high (29%), with an estimated 3-year OS of 87% (95% CI, 81 to 91), 69% (95% CI, 63 to 73), and 42% (95% CI, 36 to 49), respectively. The EPI was validated using an independent external series of 328 cases.

Conclusion: The Elderly Project validates sGA as an objective tool to assess fitness status and defines the new EPI to predict OS of older patients with DLBCL.
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http://dx.doi.org/10.1200/JCO.20.02465DOI Listing
April 2021

ALK-negative anaplastic large cell lymphoma: features and outcomes of 235 patients from the International T-Cell Project.

Blood Adv 2021 02;5(3):640-648

CHIMOMO Department and.

Anaplastic lymphoma kinase-negative anaplastic large cell lymphoma (ALK- ALCL) is an aggressive neoplasm of T-cell/null-cell lineage. The T-Cell Project is a global prospective cohort study that consecutively enrolled patients newly diagnosed with peripheral T-cell lymphoma, registered through a centralized computer database between September 2006 and February 2018. Of 1553 validated cases from 74 sites in 13 countries worldwide, 235 were reported as ALK- ALCL. The median age at diagnosis was 54 years (range, 18-89 years), with a male predominance (62%). Stage III to IV disease was identified in 71% of patients, bulky disease and bone marrow involvement were uncommon, and 66% of patients presented with a low (0-1) International Prognostic Index score. Of all treated patients, 85% received multiagent initial chemotherapy, and 8% were consolidated with autologous hematopoietic cell transplantation. The initial overall and complete response rates were 77% and 63%, respectively. After a median follow-up of 52 months (95% confidence interval [CI], 41-63), the median progression-free survival (PFS) and overall survival (OS) were 41 months (95% CI, 17-62) and 55 months (95% CI, 36-75), respectively. The 3- and 5-year PFS rates were 52% and 43%, and the 3- and 5-year OS rates were 60% and 49%. Treatments containing both anthracycline and etoposide were associated with superior OS (P = .05) but not PFS (P = .18). In this large prospective cohort study, outcomes comparable to those previously reported in the retrospective International Peripheral T-Cell Lymphoma Project were observed. The study underscores the need for introducing novel platforms for ALK- ALCL and establishes a benchmark for future clinical trials. This trial was registered at www.clinicaltrials.gov as #NCT01142674.
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http://dx.doi.org/10.1182/bloodadvances.2020001581DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7876884PMC
February 2021

Real-world analysis of treatment patterns and clinical outcomes in patients with newly diagnosed chronic lymphocytic leukemia from seven Latin American countries.

Hematology 2020 Dec;25(1):366-371

Janssen Cilag Farmaceutica SA, Buenos Aires, Argentina.

Objective: To describe chronic lymphocytic leukemia (CLL) treatment patterns and patient outcomes in Latin America.

Methods: This chart review study (NCT02559583; 2008-2015)evaluated time to progression (TTP) and overall survival (OS) outcomes among patients with CLL who initiate done (= 261) to two ( = 96) lines of therapy (LOT) since diagnosis. Differences in TTP and OS were assessed by Kaplan-Meier analysis, with a log-rank test for statistical significance. Association between therapeutic regimen and risk for disease progression or death was estimated using Cox proportional hazard regression.

Results: The most commonly prescribed therapies in both LOTs were chlorambucil-, followed by fludarabine- and cyclophosphamide (C)/CHOP-based therapies. Chlorambucil- and C/CHOP-based therapies were largely prescribed to elderly patients (≥65 years) while fludarabine-based therapy was predominantly used by younger patients (≤65 years). In LOT1, relative to chlorambucil-administered patients, those prescribed fludarabine-based therapies had lower risk of disease progression (hazard ratio [HR] and 95% confidence interval [CI] 0.32 [0.19-0.54]), whereas C/CHOP-prescribed patients had higher risk (HR 95%CI 1.88 [1.17-3.04]). Similar results were observed in LOT2. There was no difference in OS between treatments in both LOTs.

Discussion: Novel therapies such as kinase inhibitors were rarely prescribed in LOT1 or LOT2in Latin America. The greater TTP observed forfludarabine-based therapies could be attributed to the fact that fludarabine-based therapies are predominantly administered to young and healthy patients.

Conclusion: Chlorambucil-based therapy, which has limited benefits, is frequently prescribed in Latin America. Prescribing novel agents for fludarabine-based therapy-ineligible patients with CLL is the need of the hour. ClinicalTrials.gov identifier: NCT02559583.
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http://dx.doi.org/10.1080/16078454.2020.1833504DOI Listing
December 2020

Ethnic and geographic diversity of chronic lymphocytic leukaemia.

Leukemia 2021 02 19;35(2):433-439. Epub 2020 Oct 19.

Haematology Research Centre, Department of Immunology and Inflammation, Imperial College London, London, UK.

East Asians, Asian Indians and Amerindians have a five to ten-fold lower age-adjusted incidence rate (AAIR) of chronic lymphocytic leukaemia (CLL) compared with persons of predominately European descent. The data we review suggest a genetic rather than environmental basis for this discordance. All these populations arose from a common African Black ancestor but different clades have different admixture with archaic hominins including Neanderthals, Denisovans and Homo erectus, which may explain different CLL incidences. There are also some differences in clinical laboratory and molecular co-variates of CLL between these populations. Because the true age-adjusted incidence rate in African Blacks is unknown it is not possible to determine whether modern Europeans acquired susceptibility to CLL or the other populations lost susceptibility and/or developed resistance to developing CLL. We also found other B-cell lymphomas and T- and NK-cell cancers had different incidences in the populations we studied. These data provide clues to determining the cause(s) of CLL.
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http://dx.doi.org/10.1038/s41375-020-01057-5DOI Listing
February 2021

How to manage lymphoid malignancies during novel 2019 coronavirus (CoVid-19) outbreak: a Brazilian task force recommendation.

Hematol Transfus Cell Ther 2020 Apr - Jun;42(2):103-110. Epub 2020 Apr 17.

FCM da Santa Casa de São Paulo, São Paulo, SP, Brazil; Hospital Samaritano Higienópolis, São Paulo, SP, Brazil.

The novel Coronavirus (CoVid-19) outbreak is now consider a world pandemic, affecting more than 1,300,000 people worldwide. Cancer patients are in risk for severe disease, including a higher risk of intensive care unit (ICU) admission, need for invasive ventilation or death. Management of patients with lymphoid malignancies can be challenging during the outbreak, due to need of multiple hospital visits and admissions, immunosuppression and need for chemotherapy, radiotherapy and stem cell transplantation. In this article, we will focus on the practical management of patients with lymphoid malignancies during the COVID-19 pandemic, focusing on minimizing the risk for patients.
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http://dx.doi.org/10.1016/j.htct.2020.04.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7164906PMC
April 2020

Survival outcomes of patients with extranodal natural-killer T-cell lymphoma: a prospective cohort study from the international T-cell Project.

Lancet Haematol 2020 Apr 24;7(4):e284-e294. Epub 2020 Feb 24.

Division of Hematology-Oncology, Samsung Medical Center, Seoul, South Korea. Electronic address:

Background: Extranodal natural killer (NK) T-cell lymphoma (ENKTL) is a unique clinicopathological entity, typically associated with poor survival outcomes. Most published data have come from east Asian study groups, with little information available from international cohorts. The effects of treatment advances on routine clinical practice across continental territories has not been clear. We aimed to improve understanding of the clinical characteristics and outcomes of patients with ENKTL.

Methods: We did a substudy of patients with ENKTL from the T-cell Project, a global prospective cohort study. The T-cell Project registered consecutively diagnosed adults (>18 years) with newly diagnosed, untreated mature T-cell or NK lymphomas (WHO 2001 or 2008 classifications) from 74 centres in 13 countries (in Asia, Europe, North America, and South America). In total, 1695 patients with mature T-cell or NK lymphomas were enrolled between Oct 12, 2006 and Feb 28, 2018 in the T-cell Project. The first patient with ENKTL was enrolled on Feb 15, 2007, and the last on May 26, 2017. Data on baseline characteristics, first-line treatment, treatment response, and survival outcomes were recorded in a central database (locked March 30, 2019). The primary outcome was 5-year overall survival. The T-cell Project is registered on ClinicalTrials.gov, NCT01142674.

Findings: 166 patients were diagnosed with ENKTL, comprising 11% of 1553 eligible registered cases and distributed across 40 participating centres in four continents. At a median follow-up of 44 months (IQR 20-61), overall survival at 5 years was 54% (95% CI 44-63) in patients with nasal disease (n=98) and 34% (27-46) in patients with extranasal disease (n=68).

Interpretation: To our knowledge, this study presents the largest international cohort of patients with ENKTL. We describe a clinically significant improvement in the survival of patients with ENKTL treated in routine clinical practice over the past decade, likely to be attributable to the increasing use of treatment protocols specific for ENKTL.

Funding: The Fondazione Cassa di Risparmio di Modena, the Associazione Angela Serra per la Ricerca sul Cancro, the Fondazione Italiana Linfomi, Allos Therapeutics, Spectrum Pharmaceuticals, Associazione Italiana per la Ricerca sul Cancro, and the National Cancer Institute at the National Institutes of Health.
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http://dx.doi.org/10.1016/S2352-3026(19)30283-2DOI Listing
April 2020

Epidemiology of Hematologic Malignancies in Real-World Settings: Findings From the Hemato-Oncology Latin America Observational Registry Study.

J Glob Oncol 2019 11;5:1-19

Instituto de Ensino e Pesquisas São Lucas, São Paulo, Brazil.

Purpose: Limited information is available on multiple myeloma (MM), chronic lymphocytic leukemia (CLL), and non-Hodgkin lymphoma (NHL) management in Latin America. The primary objective of the Hemato-Oncology Latin America (HOLA) study was to describe patient characteristics and treatment patterns of Latin American patients with MM, CLL, and NHL.

Methods: This study was a multicenter, retrospective, medical chart review of patients with MM, CLL, and NHL in Latin America identified between January 1, 2006, and December 31, 2015. Included were adults with at least 1 year of follow-up (except in cases of death within 1 year of diagnosis) treated at 30 oncology hospitals (Argentina, 5; Brazil, 9; Chile, 1; Colombia, 5; Mexico, 6; Panama/Guatemala, 4).

Results: Of 5,140 patients, 2,967 (57.7%) had NHL, 1,518 (29.5%) MM, and 655 (12.7%) CLL. Median follow-up was 2.2 years for MM, 3.0 years for CLL, and 2.2 years for NHL, and approximately 26% died during the study observation period. Most patients had at least one comorbidity at diagnosis. The most frequent induction regimen was thalidomide-based chemotherapy for MM and chlorambucil with or without prednisone for CLL. Most patients with NHL had diffuse large B-cell lymphoma (DLBCL; 49.1%) or follicular lymphoma (FL; 19.5%). The majority of patients with DLBCL or FL received rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone.

Conclusion: The HOLA study generated an unprecedented level of high-quality, real-world evidence on characteristics and treatment patterns of patients with hematologic malignancies. Regional disparities in patient characteristics may reflect differences in ethnoracial identity and level of access to care. These data provide needed real-world evidence to understand the disease landscape in Latin America and may be used to inform clinical and health policy decision making.
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http://dx.doi.org/10.1200/JGO.19.00025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6882510PMC
November 2019

Incidence and outcomes of rare T cell lymphomas from the T Cell Project: hepatosplenic, enteropathy associated and peripheral gamma delta T cell lymphomas.

Am J Hematol 2020 02 25;95(2):151-155. Epub 2019 Nov 25.

CHIMOMO Department University of Modena and Reggio Emilia, Modena, Italy.

The T Cell Project was the largest prospective trial to explore the incidence, treatment patterns, and outcomes for T cell lymphomas. The rare subtypes of T cell lymphomas, including hepatosplenic T cell lymphoma (HSTCL), enteropathy associated T cell lymphoma (EATL), and peripheral gamma delta T cell lymphomas (PGDTCLs) are poorly represented in most studies and there is little data regarding treatment patterns. We report results from 115 patients with hepatosplenic (n = 31), enteropathy associated (n = 65), and PGDTCLs (n = 19). While anthracycline regimens were most commonly used as first line therapy, response rates ranged from 20%-40% and were suboptimal for all groups. Autologous stem cell transplantation was performed as a consolidation in first remission in a small number of patients (33% of HSTCL, 7% of EATL, and 12% of PGDTCL), and four patients with HSTCL underwent allogeneic stem cell transplantation in first remission. The progression free survival at 3 years ranged from 28%-40% for these rare subtypes, and the overall survival at 3 years was most favorable for PGDTCL (70%). These data highlight the need for novel treatment approaches for rare subtypes of T cell lymphomas and for their inclusion in clinical trials.
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http://dx.doi.org/10.1002/ajh.25674DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8025136PMC
February 2020

Randomized Phase III Trial of Ibrutinib and Rituximab Plus Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone in Non-Germinal Center B-Cell Diffuse Large B-Cell Lymphoma.

J Clin Oncol 2019 05 22;37(15):1285-1295. Epub 2019 Mar 22.

30 National Cancer Institute, National Institutes of Health, Bethesda, MD.

Purpose: Ibrutinib has shown activity in non-germinal center B-cell diffuse large B-cell lymphoma (DLBCL). This double-blind phase III study evaluated ibrutinib and rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in untreated non-germinal center B-cell DLBCL.

Patients And Methods: Patients were randomly assigned at a one-to-one ratio to ibrutinib (560 mg per day orally) plus R-CHOP or placebo plus R-CHOP. The primary end point was event-free survival (EFS) in the intent-to-treat (ITT) population and the activated B-cell (ABC) DLBCL subgroup. Secondary end points included progression-free survival (PFS), overall survival (OS), and safety.

Results: A total of 838 patients were randomly assigned to ibrutinib plus R-CHOP (n = 419) or placebo plus R-CHOP (n = 419). Median age was 62.0 years; 75.9% of evaluable patients had ABC subtype disease, and baseline characteristics were balanced. Ibrutinib plus R-CHOP did not improve EFS in the ITT (hazard ratio [HR], 0.934) or ABC (HR, 0.949) population. A preplanned analysis showed a significant interaction between treatment and age. In patients age younger than 60 years, ibrutinib plus R-CHOP improved EFS (HR, 0.579), PFS (HR, 0.556), and OS (HR, 0.330) and slightly increased serious adverse events (35.7% 28.6%), but the proportion of patients receiving at least six cycles of R-CHOP was similar between treatment arms (92.9% 93.0%). In patients age 60 years or older, ibrutinib plus R-CHOP worsened EFS, PFS, and OS, increased serious adverse events (63.4% 38.2%), and decreased the proportion of patients receiving at least six cycles of R-CHOP (73.7% 88.8%).

Conclusion: The study did not meet its primary end point in the ITT or ABC population. However, in patients age younger than 60 years, ibrutinib plus R-CHOP improved EFS, PFS, and OS with manageable safety. In patients age 60 years or older, ibrutinib plus R-CHOP was associated with increased toxicity, leading to compromised R-CHOP administration and worse outcomes. Further investigation is warranted.
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http://dx.doi.org/10.1200/JCO.18.02403DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6553835PMC
May 2019

Randomized Phase III Study of Alisertib or Investigator's Choice (Selected Single Agent) in Patients With Relapsed or Refractory Peripheral T-Cell Lymphoma.

J Clin Oncol 2019 03 1;37(8):613-623. Epub 2019 Feb 1.

27 University of Washington, Seattle Cancer Care Alliance, Seattle, WA.

Purpose: The aim of this open-label, first-in-setting, randomized phase III trial was to evaluate the efficacy of alisertib, an investigational Aurora A kinase inhibitor, in patients with relapsed/refractory peripheral T-cell lymphoma (PTCL).

Patients And Methods: Adult patients with relapsed/refractory PTCL-one or more prior therapy-were randomly assigned 1:1 to receive oral alisertib 50 mg two times per day (days 1 to 7; 21-day cycle) or investigator-selected single-agent comparator, including intravenous pralatrexate 30 mg/m (once per week for 6 weeks; 7-week cycle), or intravenous gemcitabine 1,000 mg/m or intravenous romidepsin 14 mg/m (days 1, 8, and 15; 28-day cycle). Tumor tissue (disease subtype) and imaging were assessed by independent central review. Primary outcomes were overall response rate and progression-free survival (PFS). Two interim analyses and one final analysis were planned.

Results: Between May 2012 and October 2014, 271 patients were randomly assigned (alisertib, n = 138; comparator, n = 133). Enrollment was stopped early on the recommendation of the independent data monitoring committee as a result of the low probability of alisertib achieving PFS superiority with full enrollment. Centrally assessed overall response rate was 33% for alisertib and 45% for the comparator arm (odds ratio, 0.60; 95% CI, 0.33 to 1.08). Median PFS was 115 days for alisertib and 104 days for the comparator arm (hazard ratio, 0.87; 95% CI, 0.637 to 1.178). The most common adverse events were anemia (53% of alisertib-treated patients v 34% of comparator-treated patients) and neutropenia (47% v 31%, respectively). A lower percentage of patients who received alisertib (9%) compared with the comparator (14%) experienced events that led to study drug discontinuation. Of 26 on-study deaths, five were considered treatment related (alisertib, n = 3 of 11; comparator, n = 2 of 15). Two-year overall survival was 35% for each arm.

Conclusion: In patients with relapsed/refractory PTCL, alisertib was not statistically significantly superior to the comparator arm.
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http://dx.doi.org/10.1200/JCO.18.00899DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6494247PMC
March 2019

Fluorodeoxyglucose-positron emission tomography staging can replace bone marrow biopsy in Hodgkin's lymphoma. Results from Brazilian Hodgkin's Lymphoma Study Group.

Hematol Transfus Cell Ther 2018 Jul-Sep;40(3):245-249. Epub 2018 Apr 24.

Universidade Estadual de Campinas (Unicamp), Campinas, SP, Brazil.

Objective: To investigate, in a large prospective multicenter study, whether 2-[18F]-fluoro-2-deoxy-d-glucose-positron emission tomography is sufficiently accurate to identify clinically important bone marrow involvement by Hodgkin's lymphoma to replace routine bone marrow biopsy in a developing tropical country.

Methods: Patients newly diagnosed with Hodgkin's lymphoma were recruited from six cancer centers in Brazil. All were staged by the results of positron emission tomography/computed tomography that were centrally reviewed and by iliac crest bone marrow biopsy. Patients were classified as having marrow disease if they had lymphoma identified by marrow biopsy histology or had focal 2-[18F]-fluoro-2-deoxy-d-glucose marrow uptake that resolved following chemotherapy.

Results: A total of 246 participants were recruited from six different centers and 62 (25.2%) were judged to have Hodgkin's lymphoma in the bone marrow. Positron emission tomography and biopsies were concordant in 206 patients (83%). Positron emission tomography correctly identified marrow disease in 59/62 patients (95.1%) and marrow biopsy in 25/62 patients (40.3%). In 22/62 (35.4%) patients, the two techniques were concordant in the diagnosis of marrow involvement. Of the forty discordant results, positron emission tomography found bone marrow involvement in 37 patients, upstaging 22 to stage IV and having an impact on therapeutic decision in nine cases given their reallocation from early to advanced stage. Three false negative positron emission tomography results were obtained with bone marrow biopsy giving positive findings. All three cases were classified as stage IV regardless of bone marrow findings implying no modification in the clinical management. The sensitivity, specificity and accuracy of positron emission tomography for detecting bone marrow disease were 95%, 100% and 98% and for bone marrow biopsy they were 40%, 100% and 84%, respectively.

Conclusion: We conclude that positron emission tomography can replace marrow biopsy in Brazilian patients with Hodgkin's lymphoma without compromising clinical management.
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http://dx.doi.org/10.1016/j.htct.2018.03.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6098181PMC
April 2018

The outcome of peripheral T-cell lymphoma patients failing first-line therapy: a report from the prospective, International T-Cell Project.

Haematologica 2018 07 29;103(7):1191-1197. Epub 2018 Mar 29.

Department of Diagnostic, Clinical and Public Health Medicine, University of Modena and Reggio Emilia, Modena, Italy.

This analysis explored factors influencing survival of patients with primary refractory and relapsed peripheral T-cell lymphomas enrolled in the prospective International T-cell Project. We analyzed data from 1020 patients with newly diagnosed disease, enrolled between September 2006 and December 2015. Out of 937 patients who received first-line treatment, 436 (47%) were identified as refractory and 197 (21%) as relapsed. Median time from the end of treatment to relapse was 8 months (range 2-73). Overall, 75 patients (8%) were consolidated with bone marrow transplantation, including 12 refractory and 22 relapsed patients. After a median follow up of 38 months (range 1-96 months) from documentation of refractory/relapsed disease, 440 patients had died. The median overall survival (OS) was 5.8 months; 3-year overall survival rates were 21% and 28% for refractory and relapsed patients, respectively (<0.001). Patients receiving or not salvage bone marrow transplantation had a 3-year survival of 48% and 18%, respectively (<0.001). In a univariate Cox regression analysis, refractory disease was associated with a higher risk of death (HR=1.43, =0.001), whereas late relapse (>12 months, HR 0.57, =0.001) and salvage therapy with transplantation (HR=0.36, <0.001) were associated with a better OS. No difference was found in OS with respect to histology. This study accurately reflects outcomes for patients treated according to standards of care worldwide. Results confirm that peripheral T-cell lymphomas patients had dismal outcome after relapse or progression. Patients with chemotherapy sensitive disease who relapsed after more than 12 months might benefit from consolidation bone marrow transplantation.
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http://dx.doi.org/10.3324/haematol.2017.186577DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6029527PMC
July 2018

The impact of preapheresis white blood cell count on autologous peripheral blood stem cell collection efficiency and HSC infusion side effect rate.

J Clin Apher 2018 Jun 19;33(3):331-341. Epub 2018 Jan 19.

Hematology Department - Faculdade de Ciências Médicas da Santa Casa de São Paulo, Sao Paulo, SP, Brazil.

Background: Autologous peripheral blood hematopoietic stem cell (PBSC) collection efficiency (CE) is reportedly affected by the patient's blood properties; however, studies to identify factors correlated with CE have shown inconsistent results. Additionally, variables such as stem cell graft granulocyte content and patient age, sex, and underlying disease, may be associated with hematopietic stem cell (HSC) infusion-related adverse reactions. In this study, we evaluated the correlation of preleukapheresis PB granulocyte count and PBSC harvest variables with CD34 collection yield and efficiency, and thawed HSC infusion side effect occurrence.

Patients And Methods: We evaluated data from 361 patients who had undergone autologous PBSC transplant. Large volume leukapheresis was the method for PBSC collection. Complete Blood Count and CD34 cell enumeration were performed in the preapheresis PB and the apheresis product sample. The PBSC grafts were submitted to non-controlled rate freezing after addition of 5% DMSO plus 6% hidroxyethylstarch as a cryoprotectant solution. The cryopreserved graft was thawed in a 37°C water bath and then infused without further manipulation.

Results: The CD34 yield was associated with preapheresis PB CD34 count and immature granulocyte count. The PBSC CE was negatively correlated with preapheresis white blood cell (WBC), immature granulocyte and granulocyte count. The leukapheresis product total nucleated cell (TNC) and granulocyte content was correlated with the thawed graft infusion side effect occurrence.

Conclusion: This study has shown that preapheresis PB WBC and granulocyte counts were associated with leukapheresis CE. Additionally, the leukapheresis product TNC and granulocyte content was correlated with thawed graft infusion side effect occurrence.
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http://dx.doi.org/10.1002/jca.21614DOI Listing
June 2018

Clinical impact of expression in high-risk acute promyelocytic leukemia.

Blood Adv 2017 Sep 15;1(21):1807-1814. Epub 2017 Sep 15.

Department of Internal Medicine, Medical School of Ribeirao Preto and.

Although overexpression of the brain and acute leukemia, cytoplasmic () gene is associated with primary resistant disease and shorter relapse-free, disease-free, and overall survival in different subsets of acute myeloid leukemia (AML), little is known about its clinical impact in acute promyelocytic leukemia (APL). Using real-time reverse transcriptase polymerase chain reaction, we showed that expression is significantly lower in APL compared with other subsets of AML ( < .001). We also demonstrated that overexpression was associated with shorter disease-free survival (DFS) (hazard ratio [HR], 4.43; 95% confidence interval [CI], 1.29-15.2; = .018) in 221 consecutive patients (median age, 35 years; range, 18-82 years) with newly diagnosed APL homogeneously treated with all- retinoic acid and anthracycline-based chemotherapy. Cox proportional hazard modeling showed that overexpression was independently associated with shorter DFS in the total cohort (HR, 5.26; 95% CI, 1.52-18.2; = .009) and in patients with high-risk disease (ie, those with initial leukocyte counts >10 × 10/L) (HR, 5.3; 95% CI, 1.14-24.5; = .033). We conclude that expression could be useful for refining risk stratification in APL, although this needs to be confirmed in independent cohorts.
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http://dx.doi.org/10.1182/bloodadvances.2017005926DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5728094PMC
September 2017

For survival, the emergence of oligoclonal bands after multiple myeloma treatment is less important than achieving complete remission.

Rev Bras Hematol Hemoter 2017 Oct - Dec;39(4):331-336. Epub 2017 Jul 1.

Faculdade de Ciências Médicas da Santa Casa de São Paulo (FCMSCSP), São Paulo, SP, Brazil.

Background: The emergence of oligoclonal bands, proteins differing from those originally identified at diagnosis, has been reported in multiple myeloma patients after high-dose chemotherapy followed by autologous stem cell transplantation and after successful conventional chemotherapy. The clinical relevance of oligoclonal bands remains unclear, but their emergence has been associated with better prognosis. The aim of the present study was to determine the prevalence, clinical characteristics and prognostic impact of the presence of oligoclonal bands in multiple myeloma patients.

Methods: A retrospective cohort study was conducted. The study included newly diagnosed multiple myeloma patients with at least very good partial response after conventional dose or high-dose chemotherapy followed by autologous stem cell transplantation. The emergence of oligoclonal bands was identified using serum protein electrophoresis as well as serum and urine immunofixation techniques.

Results: A total of 101 patients were included with a median follow-up of 42 months. In total, 55% were male, and the median age was 58 years (29-87 years). Fifty-one (50.5%) patients developed oligoclonal bands. They comprised 60% (45/75) of patients treated with autologous stem cell transplantation and 23% (6/26) of those who were not transplanted. Patients with oligoclonal bands showed better progression-free survival than those without the emergence of oligoclonal bands (p-value=0.0075).

Conclusion: The prevalence of oligoclonal bands in this study population was 50.5% with its frequency being greater in cases treated with autologous stem cell transplantation and in those attaining complete remission. Complete remission was more important than the emergence of oligoclonal bands on progression-free survival.
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http://dx.doi.org/10.1016/j.bjhh.2017.05.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5693271PMC
July 2017

Transformed follicular lymphoma.

Ann Hematol 2018 Jan 18;97(1):17-29. Epub 2017 Oct 18.

University of Modena and Reggio Emilia, Modena, Italy.

Follicular Lymphoma (FL) is the second most common type of non-Hodgkin lymphoma and is considered to be the prototype of indolent lymphomas. Histologic transformation into an aggressive lymphoma, which is expected to occur at a rate of 2 to 3% each year, is associated with rapid progression, treatment resistance, and poor prognosis. Recent modifications to the physiopathologic mechanism of transformed follicular lymphoma (t-FL) have been proposed, including genetic and epigenetic mechanisms as well as a role for the microenvironment. Although t-FL is considered a devastating complication, as it is associated with treatment-refractory disease and a dismal outcome, recent data in the rituximab era have suggested that not only is the prognosis less severe than reported in the previous literature but the risk of transformation is also lower. Thus, this study aimed to review the most recent research on t-FL in an attempt to better understand the clinical meaning of transformation from FL to diffuse large B cell lymphoma (DLBCL) and the impact of current treatment strategies on the curability of this intriguing subentity of lymphoma.
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http://dx.doi.org/10.1007/s00277-017-3151-2DOI Listing
January 2018

Lower socioeconomic status is independently associated with shorter survival in Hodgkin Lymphoma patients-An analysis from the Brazilian Hodgkin Lymphoma Registry.

Int J Cancer 2018 03 26;142(5):883-890. Epub 2017 Oct 26.

School of Medicine, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Rio de Janeiro, Brazil.

Socioeconomic status (SES) is a well-known determinant of outcomes in cancer. The purpose of this study was to analyze the impact of the SES on the outcomes of Hodgkin lymphoma (HL) patients from the Brazilian Prospective HL Registry. SES stratification was done using an individual asset/education-based household index. A total of 624 classical HL patients with diagnosis from January/2009 to December/2014, and treated with ABVD (doxorubicin, bleomycin, vinblastine and dacarbazine), were analyzed. The median follow-up was 35.6 months, and 33% were classified as lower SES. The 3-year progression- free survival (PFS) in higher and lower SES were 78 and 64% (p < 0.0001), respectively. The 3-year overall survival (OS) in higher and lower SES were 94 and 82% (p < 0.0001), respectively. Lower SES patients were more likely to be ≥ 60 years (16 vs. 8%, p = 0.003), and to present higher risk International Prognostic score (IPS) (44 vs. 31%, p = 0.004) and advanced disease (71 vs. 58%, p = 0.003). After adjustments for potential confounders, lower SES remained independently associated with poorer survival (HR = 3.12 [1.86-5.22] for OS and HR = 1.66 [1.19-2.32] for PFS). The fatality ratio during treatment was 7.5 and 1.3% for lower and higher SES (p = 0.0001). Infections and treatment toxicity accounted for 81% of these deaths. SES is an independent factor associated with shorter survival in HL in Brazil. Potential underlying mechanisms associated with the impact of SES are delayed diagnosis and poorer education. Educational and socio-economic support interventions must be tested in this vulnerable population.
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http://dx.doi.org/10.1002/ijc.31096DOI Listing
March 2018

Everolimus as a single agent in refractory or relapsed Hodgkin's lymphoma: the Brazilian Named Patient Program Experience.

Rev Bras Hematol Hemoter 2017 Jul - Sep;39(3):216-222. Epub 2017 May 11.

Faculdade de Ciências Médicas da Santa Casa de São Paulo (FCMSCSP), São Paulo, SP, Brazil.

Background: Despite all the scientific progress that has been made on understanding the disease, prognosis for patients with relapsed and refractory Hodgkin's lymphoma remains poor and the treatment is palliative in the majority of the cases. Thus, the aim of this study was to present the results on the compassionate use of everolimus in a group of patients who were monitored at nine different centers in Brazil.

Methods: A 10-mg oral dose of everolimus was given to each patient daily. Response time was evaluated from the beginning of medication use until loss of response, toxicity or medical decision to cease treatment.

Results: Thirty-three patients were evaluated. The median age at the beginning of medication administration was 29 years. Patients had received a median of five prior therapies. Overall response rate was 45.4%, with 13 patients achieving partial response, two achieved clinical response, 14 remained with stable disease, two had disease progression, and two were not evaluated. Patients received a median of 14 cycles. Progression-free survival was nine months, and overall survival was estimated to be 36 months. Three patients used the medication for more than four years. The most frequently reported adverse events were thrombocytopenia and hypercholesterolemia. Three patients had pulmonary toxicity. Grade III and IV adverse events occurred in 39% of the patients.

Conclusion: Everolimus was found to provide a response in a group of patients with refractory or relapsed Hodgkin's lymphoma who had adequate tolerability to the drug.
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http://dx.doi.org/10.1016/j.bjhh.2017.03.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5567422PMC
May 2017

Treatment outcomes for Hodgkin lymphoma: First report from the Brazilian Prospective Registry.

Hematol Oncol 2018 Feb 23;36(1):189-195. Epub 2017 Jun 23.

School of Medicine, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.

Data about Hodgkin lymphoma (HL) in developing countries are scarce and suggest the existence of substantial disparities in healthcare and outcomes in large areas of the world. In 2009, a prospective registry of HL was implemented in Brazil. Web-based data were contributed by 20 institutions across the country participating in the Brazilian Prospective Hodgkin's Lymphoma Registry. The aim of this study was to present the clinical features and outcomes of newly diagnosed patients with HL aged 13 to 90 years. Multivariate Cox regression models were used to estimate progression-free (PFS) and overall survival (OS) by clinical factors. A total of 674 patients with classical HL were analysed, with a median follow-up of 37 months. Median age was 30 years (13-90). The median time from the onset of symptoms to diagnosis was 6 months (0-60). Only 6% of patients had early favourable disease, while 65% had advanced disease. Stage IVB was present in 26% and a high-risk International Prognostic Score in 38%. Doxorubicin, bleomycin, vinblastine, and dacarbazine was used in 93%. The median dose of radiotherapy was 36 Gy for localized disease and 32 Gy for advanced disease. The 3 year PFS in early favourable, early unfavourable, and advanced disease were 95%, 88%, and 66%, respectively. High-risk International Prognostic Score, advanced disease, and age greater than or equal to 60 were independently associated with poorer PFS and OS; performance status greater than or equal to 2 was also associated with a poorer OS. Poor-risk patients predominated. Radiation doses for localized disease appear higher than current recommendations. Outcomes appear inferior in developing countries than in developed countries. Delayed diagnosis is probably a major factor underlying these findings. Scattered reports from developing nations suggest that many aspects of standard care in developed countries remain unmet needs for populations living in developing countries. The present report contributes to this body of data, with a proper description of what is currently achieved in urban areas in Brazil.
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http://dx.doi.org/10.1002/hon.2450DOI Listing
February 2018

A Novel Assay for the Identification of NOTCH1 PEST Domain Mutations in Chronic Lymphocytic Leukemia.

Biomed Res Int 2016 15;2016:4247908. Epub 2016 Dec 15.

Department of Clinical Pathology, Hospital Israelita Albert Einstein, São Paulo, SP, Brazil.

To develop a fast and robust DNA-based assay to detect insertions and deletions mutations in exon 34 that encodes the PEST domain of in order to evaluate patients with chronic lymphocytic leukemia (CLL). We designed a multiplexed allele-specific polymerase chain reaction (PCR) combined with a fragment analysis assay to detect specifically the mutation c.7544_7545delCT and possibly other insertions and deletions in exon 34 of . We evaluated our assay in peripheral blood samples from two cohorts of patients with CLL. The frequency of mutations was 8.4% in the first cohort of 71 unselected CLL patients. We then evaluated a second cohort of 26 CLL patients with known cytogenetic abnormalities that were enriched for patients with trisomy 12. mutations were detected in 43.7% of the patients with trisomy 12. We have developed a fast and robust assay combining allele-specific PCR and fragment analysis able to detect PEST domain insertions and deletions.
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http://dx.doi.org/10.1155/2016/4247908DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5198094PMC
January 2017

Diagnosis and treatment of chronic lymphocytic leukemia: recommendations from the Brazilian Group of Chronic Lymphocytic Leukemia.

Rev Bras Hematol Hemoter 2016 Oct - Dec;38(4):346-357. Epub 2016 Aug 20.

Universidade Federal de São Paulo (UNIFESP), São Paulo, SP, Brazil.

Chronic lymphocytic leukemia is characterized by clonal proliferation and progressive accumulation of B-cell lymphocytes that typically express CD19, CD5 and CD23. The lymphocytes usually infiltrate the bone marrow, peripheral blood, lymph nodes, and spleen. The diagnosis is established by immunophenotyping circulating B-lymphocytes, and prognosis is defined by two staging systems (Rai and Binet) established by physical examination and blood counts, as well as by several biological and genetic markers. In this update, we present the recommendations from the Brazilian Group of Chronic Lymphocytic Leukemia for the diagnosis and treatment of chronic lymphocytic leukemia. The following recommendations are based on an extensive literature review with the aim of contributing to more uniform patient care in Brazil and possibly in other countries with a similar social-economic profile.
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http://dx.doi.org/10.1016/j.bjhh.2016.07.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5119662PMC
August 2016

Is it feasible to use granulocyte-colony stimulating factor alone to mobilize progenitor cells in multiple myeloma patients induced with a cyclophosphamide, thalidomide and dexamethasone regimen?

Rev Bras Hematol Hemoter 2016 Oct - Dec;38(4):302-309. Epub 2016 Jul 29.

Faculdade de Ciências Médicas da Santa Casa de São Paulo (FCMSCSP), São Paulo, SP, Brazil.

Background: Cyclophosphamide plus thalidomide as induction for multiple myeloma patients eligible for autologous stem cell transplantation may be a limiting factor for cell mobilization. The minimum acceptable mobilized peripheral blood stem cell count to prevent deleterious effects during transplantation is 2.0×10 CD34 cells/kg. Combining other treatments to granulocyte-colony stimulating factor, such as cyclophosphamide, could overcome the mobilization limitation. The objective of this study was to assess the number of CD34 cells mobilized using granulocyte-colony stimulating factor with and without cyclophosphamide after induction with cyclophosphamide, thalidomide and dexamethasone.

Methods: A retrospective study was performed of a cohort of multiple myeloma patients submitted to autologous stem cell transplantations at two Brazilian centers between May 2009 and July 2013. The oral cyclophosphamide and thalidomide induction doses used were 1500mg/month and 100-200mg/day, respectively. Mobilization doses were 10-15mcg/kg granulocyte-colony stimulating factor with 2-4g/m cyclophosphamide, or 15-20mcg/kg granulocyte-colony stimulating factor alone for 5 days. Collection of >2.0×10 CD34 cells/kg was considered sufficient.

Results: Eighty-eight patients were analyzed; only 18 received cyclophosphamide. The median age was 58 years old (range: 51-62) for the granulocyte-colony stimulating factor group and 56.5 years old (range: 54-60) for granulocyte-colony stimulating factor plus cyclophosphamide group. Fifty-two patients were male. Eighty cases (90.9%) were Durie-Salmon Staging System III-A/B and 38 (44.7%) and 20 cases (23.5%) were International Staging System 2 and 3, respectively. The group that received cyclophosphamide collected a higher median number of progenitor cells [3.8 (range: 3.1-4.4) vs. 3.2 (range: 2.3-3.8)] (p-value=0.008). No correlation was observed between better responses or number of induction cycles and the number of cells collected.

Conclusion: The number of cells mobilized with granulocyte-colony stimulating factor plus cyclophosphamide was higher. However, in both groups, the median number of CD34 cells was sufficient to perform a single autologous stem cell transplantation; no deleterious effects were reported during harvesting.
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http://dx.doi.org/10.1016/j.bjhh.2016.06.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5119677PMC
July 2016
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