Emerging Role of Mesenchymal Stromal Cell-Derived Extracellular Vesicles in Pathogenesis of Haematological Malignancies.

Homoeostasis of bone marrow microenvironment depends on a precise balance between cell proliferation and death, which is supported by the cellular-extracellular matrix crosstalk. Multipotent mesenchymal stromal cells (MSC) are the key elements to provide the specialized bone marrow microenvironment by supporting, maintaining, and regulating the functions and fate of haematopoietic stem cells. Despite the great potential of MSC for cell therapy in several diseases due to their regenerative, immunomodulatory, and anti-inflammatory properties, they can also contribute to modulate tumor microenvironment. The extracellular vesicles that comprise exosomes and microvesicles are important mediators of intercellular communication due to their ability to change phenotype and physiology of different cell types. These vesicles may interact not only with neighbouring cells but also with cells from distant tissues to either maintain tissue homoeostasis or participate in disease pathogenesis. This review focuses on the current knowledge about the physiological role of MSC-extracellular vesicles, as well as their deregulation in haematological malignancies and their potential applications as biomarkers for diagnosis, progression, and treatment monitoring of such diseases.

Clinical pharmacists' contributions to hematopoietic stem cell transplantation: A systematic review.

AIMS: The goal of the present review was to identify studies that assess how pharmaceutical services contribute to hematopoietic stem cell transplantation (HSCT). METHODS: We conducted a systematic literature review of published studies describing results from clinical services provided by pharmacists working with HSCT, conducted according to PRISMA guidelines ( PROSPERO registration number CRD42017062391). A search strategy was applied within PubMed, CENTRAL, EMBASE, SCOPUS, and LILACS databases in April 2017. Inclusion criteria were observational or experimental studies that addressed the following research question: "What are a clinical pharmacist's main contributions to HSCT?" The quality of selected studies was evaluated using the Downs and Black checklist. RESULTS: We identified 1838 studies, and seven were included in the systematic review. The results indicated that clinical pharmacy is useful during HSCT treatment within both inpatient and outpatient settings. Pharmaceutical contributions identified included management of pharmacotherapy-related problems, participation in discussions with clinical teams, drug reconciliation, patient and team education regarding pharmacotherapy, preparation of guidelines and educational materials, and evaluation of medication adherence. These activities favored the control and prevention of pharmacotherapy-related problems, the maintenance of immunosuppressive serum levels, improvement in patients' clinical and nutritional status, facilitated medication adherence, and provided economic and humanistic gains. CONCLUSIONS: Despite the small number of articles discussing the topic under analysis, the results were unanimous in confirming the positive impact of pharmacists' contributions to clinical practice for HSCT.

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

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.

Sickle cell disease: an international survey of results of HLA-identical sibling hematopoietic stem cell transplantation.

Despite advances in supportive therapy to prevent complications of sickle cell disease (SCD), access to care is not universal. Hematopoietic cell transplantation is, to date, the only curative therapy for SCD, but its application is limited by availability of a suitable HLA-matched donor and lack of awareness of the benefits of transplant. Included in this study are 1000 recipients of HLA-identical sibling transplants performed between 1986 and 2013 and reported to the European Society for Blood and Marrow Transplantation, Eurocord, and the Center for International Blood and Marrow Transplant Research. The primary endpoint was event-free survival, defined as being alive without graft failure; risk factors were studied using a Cox regression models. The median age at transplantation was 9 years, and the median follow-up was longer than 5 years. Most patients received a myeloablative conditioning regimen (n = 873; 87%); the remainder received reduced-intensity conditioning regimens (n = 125; 13%). Bone marrow was the predominant stem cell source (n = 839; 84%); peripheral blood and cord blood progenitors were used in 73 (7%) and 88 (9%) patients, respectively. The 5-year event-free survival and overall survival were 91.4% (95% confidence interval, 89.6%-93.3%) and 92.9% (95% confidence interval, 91.1%-94.6%), respectively. Event-free survival was lower with increasing age at transplantation (hazard ratio [HR], 1.09; P < .001) and higher for transplantations performed after 2006 (HR, 0.95; P = .013). Twenty-three patients experienced graft failure, and 70 patients (7%) died, with the most common cause of death being infection. The excellent outcome of a cohort transplanted over the course of 3 decades confirms the role of HLA-identical sibling transplantation for children and adults with SCD.

CR-LAAO antileukemic effect against Bcr-Abl(+) cells is mediated by apoptosis and hydrogen peroxide.

Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm characterized by the presence of the Bcr-Abl tyrosine kinase protein, which confers resistance to apoptosis in leukemic cells. Tyrosine kinase inhibitors (TKIs) are effectively used to treat CML; however, CML patients in the advanced (CML-AP) and chronic (CML-CP) phases of the disease are usually resistant to TKI therapy. Thus, it is necessary to seek for novel agents to treat CML, such as the enzyme l-amino acid oxidase from Calloselasma rhodostoma (CR-LAAO) snake venom. We examined the antitumor effect of CR-LAAO in Bcr-Abl(+) cell lines and peripheral blood mononuclear cells (PBMC) from healthy subjects and CML patients. CR-LAAO was more cytotoxic towards Bcr-Abl(+) cell lines than towards healthy subjects' PBMC. The H2O2 produced during the enzymatic action of CR-LAAO mediated its cytotoxic effect. The CR-LAAO induced apoptosis in Bcr-Abl(+) cells, as detected by caspases 3, 8, and 9 activation, loss of mitochondrial membrane potential, and DNA damage. CR-LAAO elicited apoptosis in PBMC from CML-CP patients without TKI treatment more strongly than in PBMC from healthy subjects and TKI-treated CML-CP and CML-AP patients. The antitumor effect of CR-LAAO against Bcr-Abl(+) cells makes this toxin a promising candidate to CML therapy.

Allogeneic haematopoietic stem cell transplantation for mitochondrial neurogastrointestinal encephalomyopathy.

Haematopoietic stem cell transplantation has been proposed as treatment for mitochondrial neurogastrointestinal encephalomyopathy, a rare fatal autosomal recessive disease due to TYMP mutations that result in thymidine phosphorylase deficiency. We conducted a retrospective analysis of all known patients suffering from mitochondrial neurogastrointestinal encephalomyopathy who underwent allogeneic haematopoietic stem cell transplantation between 2005 and 2011. Twenty-four patients, 11 males and 13 females, median age 25 years (range 10-41 years) treated with haematopoietic stem cell transplantation from related (n = 9) or unrelated donors (n = 15) in 15 institutions worldwide were analysed for outcome and its associated factors. Overall, 9 of 24 patients (37.5%) were alive at last follow-up with a median follow-up of these surviving patients of 1430 days. Deaths were attributed to transplant in nine (including two after a second transplant due to graft failure), and to mitochondrial neurogastrointestinal encephalomyopathy in six patients. Thymidine phosphorylase activity rose from undetectable to normal levels (median 697 nmol/h/mg protein, range 262-1285) in all survivors. Seven patients (29%) who were engrafted and living more than 2 years after transplantation, showed improvement of body mass index, gastrointestinal manifestations, and peripheral neuropathy. Univariate statistical analysis demonstrated that survival was associated with two defined pre-transplant characteristics: human leukocyte antigen match (10/10 versus <10/10) and disease characteristics (liver disease, history of gastrointestinal pseudo-obstruction or both). Allogeneic haematopoietic stem cell transplantation can restore thymidine phosphorylase enzyme function in patients with mitochondrial neurogastrointestinal encephalomyopathy and improve clinical manifestations of mitochondrial neurogastrointestinal encephalomyopathy in the long term. Allogeneic haematopoietic stem cell transplantation should be considered for selected patients with an optimal donor.