<i  >Background</i>. Allogeneic hematopoietic stem cell transplantation (HSCT) is still associated with a high transplant-related mortality rate. In 2009, the EBMT risk score was validated as a simple tool to predict the outcome after allogeneic HSCT for acquired hematological disorders. <i  >Objectives</i>. The aim of this study was to validate the applicability of the EBMT risk score for allogeneic HSCT on South Brazilian patients. <i  >Methods</i>. A retrospective observational study was performed based on patients' records and data base at Hospital de Cl&#xed;nicas de Porto Alegre, including all allogeneic transplants for malignant and severe aplastic anemia from 1994 to 2010. Patients were categorized according to EBMT risk score and overall survival (OS). Nonrelapse mortality (NRM) and relapse rate (RR) were analyzed. <i  >Results</i>. There were 278 evaluable patients. OS, NRM, and RR at five years median followup were 48.7&#x25;, 40.7&#x25;, and 30.7&#x25;, respectively. The OS was 81.8&#x25; for risk score 0 and 0&#x25; for score 6 (<svg     style="vertical-align:-0.1638pt;width:66.875px;" id="M1" height="11.375" version="1.1" viewBox="0 0 66.875 11.375" width="66.875"  xmlns:xlink="http://www.w3.org/1999/xlink" xmlns="http://www.w3.org/2000/svg">
	
		
			<g transform="matrix(.017,-0,0,-.017,.062,11.112)"><path id="x1D443" d="M619 482q0 -69 -40.5 -119t-96 -72.5t-118.5 -26.5h-44l-70 20l-31 -151q-14 -67 0.5 -83t89.5 -22l-5 -28h-287l8 28q65 7 81.5 22t29.5 83l79 398q12 56 0.5 70.5t-78.5 20.5l7 28h255q108 0 164 -43t56 -125zM524 478q0 141 -146 141q-25 0 -47 -8q-16 -6 -20.5 -13.5&#xA;t-10.5 -39.5l-43 -241q37 -13 83 -13q67 0 125.5 45t58.5 129z" /></g><g transform="matrix(.017,-0,0,-.017,15.582,11.112)"><path id="x3C" d="M512 -3l-437 233v51l437 233v-58l-378 -200v-2l378 -199v-58z" /></g><g transform="matrix(.017,-0,0,-.017,30.286,11.112)"><path id="x30" d="M241 635q53 0 94 -28.5t63.5 -76t33.5 -102.5t11 -116q0 -58 -11 -112.5t-34 -103.5t-63.5 -78.5t-94.5 -29.5t-95 28t-64.5 75t-34.5 102.5t-11 118.5q0 58 11.5 112.5t34.5 103t64.5 78t95.5 29.5zM238 602q-32 0 -55.5 -25t-35.5 -68t-17.5 -91t-5.5 -105&#xA;q0 -76 10 -138.5t37 -107.5t69 -45q32 0 55.5 25t35.5 68.5t17.5 91.5t5.5 105t-5.5 105.5t-18 92t-36 68t-56.5 24.5z" /></g><g transform="matrix(.017,-0,0,-.017,38.446,11.112)"><path id="x2E" d="M113 -12q-24 0 -39.5 16t-15.5 42q0 24 16 40.5t40 16.5t40 -16.5t16 -40.5q0 -26 -16 -42t-41 -16z" /></g><g transform="matrix(.017,-0,0,-.017,42.321,11.112)"><use xlink:href="#x30"/></g><g transform="matrix(.017,-0,0,-.017,50.481,11.112)"><use xlink:href="#x30"/></g><g transform="matrix(.017,-0,0,-.017,58.64,11.112)"><path id="x31" d="M384 0h-275v27q67 5 81.5 18.5t14.5 68.5v385q0 38 -7.5 47.5t-40.5 10.5l-48 2v24q85 15 178 52v-521q0 -55 14.5 -68.5t82.5 -18.5v-27z" /></g>

		
	
</svg>), and NRM was 13.6&#x25; and 80&#x25; for risk scores 0 and 6, respectively (<svg     style="vertical-align:-0.1638pt;width:66.875px;" id="M2" height="11.375" version="1.1" viewBox="0 0 66.875 11.375" width="66.875"  xmlns:xlink="http://www.w3.org/1999/xlink" xmlns="http://www.w3.org/2000/svg">
	
		
			<g transform="matrix(.017,-0,0,-.017,.062,11.112)"><use xlink:href="#x1D443"/></g><g transform="matrix(.017,-0,0,-.017,15.582,11.112)"><path id="x3D" d="M535 323h-483v50h483v-50zM535 138h-483v50h483v-50z" /></g><g transform="matrix(.017,-0,0,-.017,30.286,11.112)"><use xlink:href="#x30"/></g><g transform="matrix(.017,-0,0,-.017,38.446,11.112)"><use xlink:href="#x2E"/></g><g transform="matrix(.017,-0,0,-.017,42.321,11.112)"><use xlink:href="#x30"/></g><g transform="matrix(.017,-0,0,-.017,50.481,11.112)"><use xlink:href="#x30"/></g><g transform="matrix(.017,-0,0,-.017,58.64,11.112)"><use xlink:href="#x31"/></g>

		
	
</svg>). <i  >Conclusion</i>. The EBMT risk score can be utilized as a tool for clinical decision making before allogeneic HSCT for malignant hematological diseases and severe aplastic anemia at a single center in Brazil.

Beatriz Stela Pitombeira

Alessandra Paz

Annelise Pezzi

Bruna Amorin

Vanessa Valim

Alvaro Laureano

Andrea Wieck

Lisandra Rigoni

&#xc9;rica Ottoni

Gustavo Fisher

Liane Daudt

Lucia Silla

Validation of the EBMT Risk Score for South Brazilian Patients Submitted to Allogeneic Hematopoietic Stem Cell Transplantation

Currently, there are over 1,800 annotated human miRNAs, many of which have tissue-specific expression. Numerous studies have highlighted their role in haematopoietic differentiation and proliferation, acting as master regulators of haematopoietic stem cell function. Aberrant expression of miRNAs has been observed in haematological cancers, exhibiting unique expression signatures in comparison to normal counterparts. Functional and target analyses as well as animal models have attempted to annotate how different miRNA may contribute to the pathophysiology of these malignancies from modulating cancer associated genes, functioning directly as oncogenes or tumour suppressor genes or acting as bystanders or regulators of the epigenetic mechanisms in cancer. miRNAs have also been shown to play a role in modulating drug resistance and determining prognosis between the various subtypes of blood cancers. This review discusses the important role that miRNAs play in haematological malignancies by exploring associations that exist between the two and trying to examine evidence of causality to support the tantalising possibility that miRNAs might serve as therapeutic targets in blood cancers.

Stephanie Gounaris-Shannon

Timothy Chevassut

The Role of miRNA in Haematological Malignancy

Mesenchymal stromal cells (MSCs) are multipotent cells found in connective tissues that can differentiate into bone, cartilage, and adipose tissue. Interestingly, they can regulate immune responses in a paracrine way and allogeneic MSCs do not elicit immune response. These properties have encouraged a number of clinical trials in a broad range of regenerative therapies. Although these trials were first focused on their differentiation properties, in the last years, the immunosuppressive features have gained most of the attention. In this review, we will summarize the up-to-date knowledge about the immunosuppressive mechanisms of MSCs in vivo and in vitro and the most promising approaches in clinical investigation.

Akaitz Dorronsoro

Jon Fern&#xe1;ndez-Rueda

Karoline Fechter

Izaskun Ferrin

Juan Manuel Salcedo

Emma Jakobsson

C&#xe9;sar Trigueros

Human Mesenchymal Stromal Cell-Mediated Immunoregulation: Mechanisms of Action and Clinical Applications

Day 100 prognostic factors of postautologous peripheral blood hematopoietic stem cell transplantation (APBHSCT) to predict clinical outcome in classical Hodgkin lymphoma (cHL) patients have not been evaluated. Thus, we studied if the day 100 peripheral blood absolute lymphocyte/monocyte ratio (Day 100 ALC/AMC) affects clinical outcomes by landmark analysis from day 100 post-APBHSCT. Only cHL patients achieving a complete remission at day 100 post-APBHSCT were studied. From 2000 to 2010, 131 cHL consecutive patients qualified for the study. The median followup from day 100 was 4.1 years (range: 0.2&#x2013;12.3 years). Patients with a Day 100 ALC/AMC &#x2265; 1.3 experienced superior overall survival (OS) and progression-free survival (PFS) compared with Day 100 ALC/AMC &#x3c; 1.3 (from day 100: OS, median not reached versus 2.8 years; 5 years OS rates of 93&#x25; (95&#x25; CI, 83&#x25;&#x2013;97&#x25;) versus 35&#x25; (95&#x25; CI, 19&#x25;&#x2013;51&#x25;), resp., <svg     style="vertical-align:-0.1638pt;width:75.025002px;" id="M1" height="11.375" version="1.1" viewBox="0 0 75.025002 11.375" width="75.025002"  xmlns:xlink="http://www.w3.org/1999/xlink" xmlns="http://www.w3.org/2000/svg">
	
		
			<g transform="matrix(.017,-0,0,-.017,.062,11.112)"><path id="x1D443" d="M619 482q0 -69 -40.5 -119t-96 -72.5t-118.5 -26.5h-44l-70 20l-31 -151q-14 -67 0.5 -83t89.5 -22l-5 -28h-287l8 28q65 7 81.5 22t29.5 83l79 398q12 56 0.5 70.5t-78.5 20.5l7 28h255q108 0 164 -43t56 -125zM524 478q0 141 -146 141q-25 0 -47 -8q-16 -6 -20.5 -13.5&#xA;t-10.5 -39.5l-43 -241q37 -13 83 -13q67 0 125.5 45t58.5 129z" /></g><g transform="matrix(.017,-0,0,-.017,15.582,11.112)"><path id="x3C" d="M512 -3l-437 233v51l437 233v-58l-378 -200v-2l378 -199v-58z" /></g><g transform="matrix(.017,-0,0,-.017,30.286,11.112)"><path id="x30" d="M241 635q53 0 94 -28.5t63.5 -76t33.5 -102.5t11 -116q0 -58 -11 -112.5t-34 -103.5t-63.5 -78.5t-94.5 -29.5t-95 28t-64.5 75t-34.5 102.5t-11 118.5q0 58 11.5 112.5t34.5 103t64.5 78t95.5 29.5zM238 602q-32 0 -55.5 -25t-35.5 -68t-17.5 -91t-5.5 -105&#xA;q0 -76 10 -138.5t37 -107.5t69 -45q32 0 55.5 25t35.5 68.5t17.5 91.5t5.5 105t-5.5 105.5t-18 92t-36 68t-56.5 24.5z" /></g><g transform="matrix(.017,-0,0,-.017,38.446,11.112)"><path id="x2E" d="M113 -12q-24 0 -39.5 16t-15.5 42q0 24 16 40.5t40 16.5t40 -16.5t16 -40.5q0 -26 -16 -42t-41 -16z" /></g><g transform="matrix(.017,-0,0,-.017,42.321,11.112)"><use xlink:href="#x30"/></g><g transform="matrix(.017,-0,0,-.017,50.481,11.112)"><use xlink:href="#x30"/></g><g transform="matrix(.017,-0,0,-.017,58.64,11.112)"><use xlink:href="#x30"/></g><g transform="matrix(.017,-0,0,-.017,66.8,11.112)"><path id="x31" d="M384 0h-275v27q67 5 81.5 18.5t14.5 68.5v385q0 38 -7.5 47.5t-40.5 10.5l-48 2v24q85 15 178 52v-521q0 -55 14.5 -68.5t82.5 -18.5v-27z" /></g>

		
	
</svg>; from day 100: PFS, median not reached versus 1.2 years; 5 years PFS rates of 79&#x25; (95&#x25; CI, 69&#x25;&#x2013;86&#x25;) versus 27&#x25; (95&#x25; CI, 14&#x25;&#x2013;45&#x25;), resp., <svg     style="vertical-align:-0.1638pt;width:75.025002px;" id="M2" height="11.375" version="1.1" viewBox="0 0 75.025002 11.375" width="75.025002"  xmlns:xlink="http://www.w3.org/1999/xlink" xmlns="http://www.w3.org/2000/svg">
	
		
			<g transform="matrix(.017,-0,0,-.017,.062,11.112)"><use xlink:href="#x1D443"/></g><g transform="matrix(.017,-0,0,-.017,15.582,11.112)"><use xlink:href="#x3C"/></g><g transform="matrix(.017,-0,0,-.017,30.286,11.112)"><use xlink:href="#x30"/></g><g transform="matrix(.017,-0,0,-.017,38.446,11.112)"><use xlink:href="#x2E"/></g><g transform="matrix(.017,-0,0,-.017,42.321,11.112)"><use xlink:href="#x30"/></g><g transform="matrix(.017,-0,0,-.017,50.481,11.112)"><use xlink:href="#x30"/></g><g transform="matrix(.017,-0,0,-.017,58.64,11.112)"><use xlink:href="#x30"/></g><g transform="matrix(.017,-0,0,-.017,66.8,11.112)"><use xlink:href="#x31"/></g>

		
	
</svg>). Day 
					 ALC/AMC ratio was an independent predictor for OS and PFS. Thus, Day 100 ALC/AMC ratio is a simple biomarker that can help to assess clinical outcomes from day 100 post-APBHSCT in cHL patients.

Luis F. Porrata

David J. Inwards

Stephen M. Ansell

Ivana N. Micallef

Patrick B. Johnston

William J. Hogan

Svetomir N. Markovic

Day 100 Peripheral Blood Absolute Lymphocyte/Monocyte Ratio and Survival in Classical Hodgkin's Lymphoma Postautologous Peripheral Blood Hematopoietic Stem Cell Transplantation


                  
                  
                  
                  Nonmyeloablative (NMA) conditioning with total lymphoid irradiation and antithymocyte globulin (TLI/ATG) has been shown to protect against acute graft-versus-host disease (GVHD). We report here our institutional experience with allogeneic transplantation following NMA conditioning with TLI/ATG (<svg     style="vertical-align:-0.1638pt;width:44.400002px;" id="M1" height="11.125" version="1.1" viewBox="0 0 44.400002 11.125" width="44.400002"  xmlns:xlink="http://www.w3.org/1999/xlink" xmlns="http://www.w3.org/2000/svg">
	
		
			<g transform="matrix(.017,-0,0,-.017,.062,10.862)"><path id="x1D45B" d="M495 86q-46 -47 -87 -72.5t-63 -25.5q-43 0 -16 107l49 210q7 34 8 50.5t-3 21t-13 4.5q-35 0 -109.5 -72.5t-115.5 -140.5q-21 -75 -38 -159q-50 -10 -76 -21l-6 8l84 340q8 35 -4 35q-17 0 -67 -46l-15 26q44 44 85.5 70.5t64.5 26.5q35 0 10 -103l-24 -98h2&#xA;q42 56 97 103.5t96 71.5q46 26 74 26q9 0 16 -2.5t14 -11.5t9.5 -24.5t-1 -44t-13.5 -68.5q-30 -117 -47 -200q-4 -19 -3.5 -25t6.5 -6q21 0 70 48z" /></g><g transform="matrix(.017,-0,0,-.017,13.305,10.862)"><path id="x3D" d="M535 323h-483v50h483v-50zM535 138h-483v50h483v-50z" /></g><g transform="matrix(.017,-0,0,-.017,28.008,10.862)"><path id="x32" d="M412 140l28 -9q0 -2 -35 -131h-373v23q112 112 161 170q59 70 92 127t33 115q0 63 -31 98t-86 35q-75 0 -137 -93l-22 20l57 81q55 59 135 59q69 0 118.5 -46.5t49.5 -122.5q0 -62 -29.5 -114t-102.5 -130l-141 -149h186q42 0 58.5 10.5t38.5 56.5z" /></g><g transform="matrix(.017,-0,0,-.017,36.168,10.862)"><path id="x31" d="M384 0h-275v27q67 5 81.5 18.5t14.5 68.5v385q0 38 -7.5 47.5t-40.5 10.5l-48 2v24q85 15 178 52v-521q0 -55 14.5 -68.5t82.5 -18.5v-27z" /></g>

		
	
</svg>). GVHD prophylaxis consisted of a combination of a calcineurin inhibitor and mycophenolate mofetil. Median patient age was 59 years. The median followup of surviving patients is 545 days. One patient experienced primary graft rejection. The median time to neutrophil engraftment was 18 days and platelet engraftment was 9.5 days. The cumulative incidence (CI) of grade II&#x2013;IV acute GVHD at day +100 was 28.6&#x25; and 38.1&#x25; at day +180. The CI for grade III-IV acute GVHD was 28.6&#x25; at day +180. CI of chronic GVHD was 45.2&#x25; at 1 year. The CI of disease relapse was 9.5&#x25; at 1 year. The rate of nonrelapse mortality (NRM) was 0&#x25; at day +100 and only 9.5&#x25; at 1 year. The overall and progression free survival at 1 year was 81&#x25; and 80.4&#x25;, respectively. Our limited, retrospective data show encouraging relapse and NRM rates with TLI/ATG-based NMA conditioning, but with higher than previously reported rates of acute and chronic GVHD, underscoring the need for novel strategies designed to effectively prevent GVHD. 
                  
                  
                  
                  
                  
                  

Lauren Veltri

Michael Regier

Aaron Cumpston

Sonia Leadmon

William Tse

Michael Craig

Mehdi Hamadani

Incidence and Pattern of Graft-versus-Host Disease in Patients Undergoing Allogeneic Transplantation after Nonmyeloablative Conditioning with Total Lymphoid Irradiation and Antithymocyte Globulin

In order to verify whether differentiation of adult stem cells toward bone tissue is promoted by high-frequency vibration (HFV), bone marrow stromal cells (BMSCs) were mechanically stimulated with HFV (30&#x2009;Hz) for 45 minutes a day for 21 or 40 days. Cells were seeded in osteogenic medium, which enhances differentiation towards bone tissue. The effects of the mechanical treatment on differentiation were measured by Alizarin Red test, (q) real-time PCR, and protein content of the extracellular matrix. In addition, we analyzed the proliferation rate and apoptosis of BMSC subjected to mechanical stimulation. A strong increase in all parameters characterizing differentiation was observed. Deposition of calcium was almost double in the treated samples; the expression of genes involved in later differentiation was significantly increased and protein content was higher for all osteogenic proteins. Lastly, proliferation results indicated that stimulated BMSCs have a decreased growth rate in comparison with controls, but both treated and untreated cells do not enter the apoptosis process. These findings could reduce the gap between research and clinical application for bone substitutes derived from patient cells by improving the differentiation protocol for autologous cells and a further implant of the bone graft into the patient.

D. Pr&#xe8;

G. Ceccarelli

L. Visai

L. Benedetti

M. Imbriani

M. G. Cusella De Angelis

G. Magenes

High-Frequency Vibration Treatment of Human Bone Marrow Stromal Cells Increases Differentiation toward Bone Tissue

The combined delivery of mesenchymal stem cells (MSCs), vascular endothelial growth factor (VEGF), and bone morphogenetic protein (BMP) to sites of bone injury results in enhanced repair compared to the administration of a single factor or a combination of two factors. Based on these findings, we hypothesized that coexpression of VEGF and BMP-6 genes would enhance the osteoblastic differentiation of rat bone-marrow-derived stem cells (rMSCs) and osteogenesis by comparison to rMSCs that do not express VEGF and BMP-6. We prepared a GFP tagged adenovirus vector (Ad-VEGF+BMP-6) that contained DNA encoding the hVEGF and hBMP-6 genes. rMSCs were transduced with the virus, and the successful transduction was confirmed by green fluorescence and by production of VEGF and BMP-6 proteins. The cells were cultured to assess osteoblastic differentiation or administered in the Fischer 344 rats to assess bone formation. Mineralization of rMSCs transduced with Ad-VEGF+BMP-6 was significantly enhanced over the nontransduced rMSCs. Only transduced rMSCs could induce osteogenesis <i>in vivo</i>, whereas Ad-VEGF+BMP-6 or nontransduced rMSCs alone did not induce osteogenesis. The data suggests that the combined delivery of MSCs, VEGF, and BMP-6 is an attractive option for bone repair therapy.

Jesse Seamon

Xiuli Wang

Fuai Cui

Tom Keller

Abhijit S. Dighe

Gary Balian

Quanjun Cui

Adenoviral Delivery of the VEGF and BMP-6 Genes to Rat Mesenchymal Stem Cells Potentiates Osteogenesis

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