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1.  Haematological cancer and quality of life: a systematic literature review 
Blood Cancer Journal  2015;5(4):e305-.
The aim of this study is to examine the impact of haematological cancers on quality of life (QoL). A review of the international literature was conducted from the databases ‘PsycInfo' and 'Medline' using the keywords: 'haematological cancer', 'quality of life', 'physical', 'psychological', 'social', 'vocational', 'professional', 'economic', 'cognitive', and 'sexual'. Twenty-one reliable studies were analysed. Among these studies, 12 showed that haematological cancer altered overall QoL, 8 papers found a deterioration of physical dimension, 8 papers reported on functional and role dimensions, 11 papers reported on the psychological component and 9 on the social component. Moreover, one study and two manuscripts, respectively, reported deteriorated sexual and cognitive dimensions. Our review demonstrates that the different dimensions of QoL are deteriorated by haematological malignancies and, probably, by the side effects of treatment.
PMCID: PMC4450328  PMID: 25909835
2.  Acute promyelocytic leukemia: where did we start, where are we now, and the future 
Blood Cancer Journal  2015;5(4):e304-.
Historically, acute promyelocytic leukemia (APL) was considered to be one of the most fatal forms of acute leukemia with poor outcomes before the introduction of the vitamin A derivative all-trans retinoic acid (ATRA). With considerable advances in therapy, including the introduction of ATRA initially as a single agent and then in combination with anthracyclines, and more recently by development of arsenic trioxide (ATO)-containing regimens, APL is now characterized by complete remission rates of 90% and cure rates of ∼80%, even higher among low-risk patients. Furthermore, with ATRA–ATO combinations, chemotherapy may safely be omitted in low-risk patients. The disease is now considered to be the most curable subtype of acute myeloid leukemia (AML) in adults. Nevertheless, APL remains associated with a significant incidence of early death related to the characteristic bleeding diathesis. Early death, rather than resistant disease so common in all other subtypes of AML, has emerged as the major cause of treatment failure.
PMCID: PMC4450325  PMID: 25885425
3.  The cellular immune system in myelomagenesis: NK cells and T cells in the development of MM and their uses in immunotherapies 
Blood Cancer Journal  2015;5(4):e306-.
As vast strides are being made in the management and treatment of multiple myeloma (MM), recent interests are increasingly focusing on understanding the development of the disease. The knowledge that MM develops exclusively from a protracted phase of monoclonal gammopathy of undetermined significance provides an opportunity to study tumor evolution in this process. Although the immune system has been implicated in the development of MM, the scientific literature on the role and status of various immune components in this process is broad and sometimes contradictory. Accordingly, we present a review of cellular immune subsets in myelomagenesis. We summarize the current literature on the quantitative and functional profiles of natural killer cells and T-cells, including conventional T-cells, natural killer T-cells, γδ T-cells and regulatory T-cells, in myelomagenesis. Our goal is to provide an overview of the status and function of these immune cells in both the peripheral blood and the bone marrow during myelomagenesis. This provides a better understanding of the nature of the immune system in tumor evolution, the knowledge of which is especially significant considering that immunotherapies are increasingly being explored in the treatment of both MM and its precursor conditions.
PMCID: PMC4450330  PMID: 25885426
4.  Waldenstrom macroglobulinemia: prognosis and management 
Blood Cancer Journal  2015;5(3):e296-.
Waldenstrom macroglobulinemia (WM) is a B-cell lymphoplasmacytic lymphoma characterized by monoclonal immunoglobulin M protein in the serum and infiltration of bone marrow with lymphoplasmacytic cells. Asymptomatic patients can be observed without therapy. First-line therapy should consist of the monoclonal anti-CD20 antibody, rituximab, given typically in combination with other agents. We prefer dexamethasone, rituximab, cyclophosphamide (DRC) as initial therapy for most patients with symptomatic WM. Other reasonable options are bortezomib, rituximab, dexamethasone (BoRD) or bendamustine plus rituximab (BR). All of these regimens are associated with excellent response and tolerability. Initial therapy is usually administered for 6 months, followed by observation. Response to therapy is assessed using the standard response criteria developed by the International Working Group on Waldenstrom macroglobulinemia. Relapse is almost inevitable in WM but may occur years after initial therapy. In symptomatic patients relapsing more than 1–2 years after initial therapy, the original treatment can be repeated. For relapse occurring sooner, an alternative regimen is used. In select patients, high-dose chemotherapy followed by autologous hematopoietic cell transplantation may be an option at relapse. Options for therapy of relapsed WM besides regimens used in the front-line setting include ibrutinib, purine nucleoside analogs (cladribine, fludarabine), carfilzomib and immunomodulatory agents (thalidomide, lenalidomide).
PMCID: PMC4382666  PMID: 25815903
5.  B-cell activating factor in the pathophysiology of multiple myeloma: a target for therapy? 
Blood Cancer Journal  2015;5(2):e282-.
Multiple myeloma (MM) is a currently incurable malignancy of plasma cells. Malignant myeloma cells (MMCs) are heavily dependent upon the bone marrow (BM) microenvironment for their survival. One component of this tumor microenvironment, B-Cell Activating Factor (BAFF), has been implicated as a key player in this interaction. This review discusses the role of BAFF in the pathophysiology of MM, and the potential of BAFF-inhibitory therapy for the treatment of MM. Multiple studies have shown that BAFF functions as a survival factor for MMCs. Furthermore, MMCs express several BAFF-binding receptors. Of these, only Transmembrane Activator and CAML Interactor (TACI) correlates with the MMC's capability to ligate BAFF. Additionally, the level of expression of TACI correlates with the level of the MMC's BM dependency. Ligation of BAFF receptors on MMCs causes activation of the Nuclear Factor of κ-B (NF-κB) pathway, a crucial pathway for the pathogenesis of many B-cell malignancies. Serum BAFF levels are significantly elevated in MM patients when compared to healthy controls, and correlate inversely with overall survival. BAFF signaling is thus an interesting target for the treatment of MM. Several BAFF-inhibitory drugs are currently under evaluation for the treatment of MM. These include BAFF-monoclonal antibodies (tabalumab) and antibody-drug conjugates (GSK2857916).
PMCID: PMC4349256  PMID: 25723853
6.  Definition and management of ruxolitinib treatment failure in myelofibrosis 
Blood Cancer Journal  2014;4(12):e268-.
Ruxolitinib, a Janus kinase (JAK)-1 and JAK-2 inhibitor, is the first-in-class drug to be licensed in the United States for the treatment of high- and intermediate-risk myelofibrosis (MF). Several other JAK inhibitors are in development with some currently undergoing phase-3 clinical trial testing. None of the currently available JAK inhibitors are specific to mutant JAK2; their mechanism of action involves attenuation of JAK-STAT signaling with downregulation of proinflammatory cytokines, rather than selective suppression of the disease clone. Accordingly, while ruxolitinib and other JAK inhibitors are effective in controlling splenomegaly and alleviating constitutional symptoms, their benefit in terms of reversing bone marrow fibrosis or inducing complete or partial remissions appears to be limited. The experience to date with ruxolitinib shows that despite its salutary effects on quality of life, over half of the patients discontinue treatment within 2–3 years. In the current perspective, we examine the incidence and causes of ruxolitinib ‘treatment failure' in MF patients based on our personal experience as well as a review of the published literature. We also discuss the challenges in defining and classifying ruxolitinib failure, and within the context of several clinical scenarios, we provide recommendations for the post-ruxolitinib management of MF patients.
PMCID: PMC4315890  PMID: 25501025
7.  The role of epigenetics in the biology of multiple myeloma 
Blood Cancer Journal  2014;4(5):e207-.
Several recent studies have highlighted the biological complexity of multiple myeloma (MM) that arises as a result of several disrupted cancer pathways. Apart from the central role of genetic abnormalities, epigenetic aberrations have also been shown to be important players in the development of MM, and a lot of research during the past decades has focused on the ways DNA methylation, histone modifications and noncoding RNAs contribute to the pathobiology of MM. This has led to, apart from better understanding of the disease biology, the development of epigenetic drugs, such as histone deacetylase inhibitors that are already used in clinical trials in MM with promising results. This review will present the role of epigenetic abnormalities in MM and how these can affect specific pathways, and focus on the potential of novel ‘epidrugs' as future treatment modalities for MM.
PMCID: PMC4042299  PMID: 24786391
8.  Induced pluripotent stem cells in hematology: current and future applications 
Blood Cancer Journal  2014;4(5):e211-.
Reprogramming somatic cells into induced pluripotent stem (iPS) cells is nowadays approaching effectiveness and clinical grade. Potential uses of this technology include predictive toxicology, drug screening, pathogenetic studies and transplantation. Here, we review the basis of current iPS cell technology and potential applications in hematology, ranging from disease modeling of congenital and acquired hemopathies to hematopoietic stem and other blood cell transplantation.
PMCID: PMC4042300  PMID: 24813079
9.  The evolution of clinical trials for infant acute lymphoblastic leukemia 
Blood Cancer Journal  2014;4(4):e200-.
Acute lymphoblastic leukemia (ALL) in infants has a significantly inferior outcome in comparison with older children. Despite initial improvements in survival of infants with ALL since establishment of the first pediatric cooperative group ALL trials, the poor outcome has plateaued in recent years. Historically, infants were treated on risk-adapted childhood ALL protocols. These studies were pivotal in identifying the need for infant-specific protocols, delineating prognostic categories and the requirement for a more unified approach between study groups to overcome limitations in accrual because of low incidence. This subsequently led to the development of collaborative infant-specific studies. Landmark outcomes have included the elimination of cranial radiotherapy following the discovery of intrathecal and high-dose systemic therapy as a superior and effective treatment strategy for central nervous system disease prophylaxis, with improved neurodevelopmental outcome. Universal prospective identification of independent adverse prognostic factors, including presence of a mixed lineage leukemia rearrangement and young age, has established the basis for risk stratification within current trials. The infant-specific trials have defined limits to which conventional chemotherapeutic agents can be intensified to optimize the balance between treatment efficacy and toxicity. Despite variations in therapeutic intensity, there has been no recent improvement in survival due to the equilibrium between relapse and toxicity. Ultimately, to improve the outcome for infants with ALL, key areas still to be addressed include identification and adaptation of novel prognostic markers and innovative therapies, establishing the role of hematopoietic stem cell transplantation in first complete remission, treatment strategies for relapsed/refractory disease and monitoring and timely intervention of late effects in survivors. This would be best achieved through a single unified international trial.
PMCID: PMC4003413  PMID: 24727996
10.  The emerging role of Twist proteins in hematopoietic cells and hematological malignancies 
Blood Cancer Journal  2014;4(4):e206-.
Twist1 and Twist2 (Twist1–2) are two transcription factors, members of the basic helix-loop-helix family, that have been well established as master transcriptional regulators of embryogenesis and developmental programs of mesenchymal cell lineages. Their role in oncogenesis in epithelium-derived cancer and in epithelial-to-mesenchymal transition has also been thoroughly characterized. Recently, emerging evidence also suggests a key role for Twist1–2 in the function and development of hematopoietic cells, as well as in survival and development of numerous hematological malignancies. In this review, we summarize the latest data that depict the role of Twist1–2 in monocytes, T cells and B lymphocyte activation, and in associated hematological malignancies.
PMCID: PMC4003416  PMID: 24769647
11.  Primary effusion lymphoma in an elderly patient effectively treated by lenalidomide: case report and review of literature 
Blood Cancer Journal  2014;4(3):e190-.
Primary effusion lymphoma (PEL) is a rare aggressive subset of non-Hodgkin B-cell lymphoma. It is caused by Kaposi sarcoma-associated herpesvirus/human herpesvirus type 8 (KSHV/HHV8). It occurs mainly, but not exclusively, in HIV-positive patients. PEL predominantly develops in serous cavities and occasionally in extracavitary regions. PEL carries a very poor prognosis with a median survival time of <6 months. Indeed, currently used treatment modalities such as CHOP chemotherapy are far from achieving complete and sustainable remission. Therefore, there is no clear standard of care established in the treatment of PEL patients, stressing the need for novel-targeted approaches. Here, we have attempted a comprehensive assessment of the treatment of PEL, discussed avant-garde therapies and updated the state of preclinical research with promising clinical applications in the field. These include inhibitors of viral replication, modulators of cell signaling and inflammation, nuclear factor kappa B (NF-κB) and histone deacetylase inhibitors, and recently the combination of arsenic trioxide and interferon-alpha. Some of these targeted therapies have not yet reached clinical studies, although others were used in a few individual case reports with low numbers of patients. We also describe the first case of a 77-year-old, HIV-negative, HHV8-positive patient diagnosed with PEL limited to the pleural and peritoneal cavities. He received lenalidomide 25 mg/day for 21 days every 28 days. Treatment was well tolerated with no side effects. He rapidly improved after 1 month of treatment and progressively achieved complete remission persistent after 18 months of therapy. We believe that this review will bridge an important gap between classical chemotherapy and modern approaches of targeted therapy. Finally, our findings warrant further evaluation of lenalidomide in future prospective clinical studies.
PMCID: PMC3972705  PMID: 24608734
12.  Hairy cell leukemia: short review, today's recommendations and outlook 
Blood Cancer Journal  2014;4(2):e184-.
Hairy cell leukemia (HCL) is part of the low-grade non-Hodgkin lymphoma family and represents approximately 2% of all leukemias. Treatment with splenectomy and interferon-α historically belonged to the first steps of therapeutic options, achieving partial responses/remissions (PR) in most cases with a median survival between 4 and 6 years in the 1980s. The introduction of the purine analogs (PA) pentostatin and cladribine made HCL a well-treatable disease: overall complete response rates (CRR) range from 76 to 98%, with a median disease-free survival (DFS) of 16 years a normal lifespan can be reached and HCL-related deaths are rare. However, insufficient response to PA with poorer prognosis and relapse rates of 30–40% after 5–10 years of follow-up may require alternative strategies. Minimal residual disease can be detected by additional examinations of bone marrow specimens after treatment with PA. The use of immunotherapeutic monoclonal antibodies (mAB) like rituximab as a single agent or in combination with a PA or more recently clinical trials with recombinant immunotoxins (RIT) show promising results to restrict these problems. Recently, the identification of the possible disease-defining BRAF V600E mutation may allow the development of new therapeutic targets.
PMCID: PMC3944661  PMID: 24531447
hairy cell leukemia; pentostatin; cladribine; rituximab; immunotoxins
13.  Pomalidomide: the new immunomodulatory agent for the treatment of multiple myeloma 
Blood Cancer Journal  2013;3(9):e143-.
In this report, we provide a comprehensive review on the preclinical and clinical investigations conducted in development of the next-generation immunomodulatory drug (IMiD) pomalidomide for the treatment of relapsed/refractory multiple myeloma (MM). We consulted PubMed, MEDLINE, ASH, ASCO annual symposium abstracts and for the purpose of this literature review. Twenty-six preclinical and 11 clinical studies were examined. These studies delineate the mechanisms of action of pomalidomide and attest to the robust clinical activity in relapsed/refractory MM. MM is the second most common hematological malignancy in the US. Despite availability of several therapeutic agents, MM remains incurable. Thus, the development of new therapies remains a priority. Pomalidomide is the newest member of the IMiDs class of drugs, and in preclinical and clinical investigations, it has demonstrated an improved efficacy and toxicity profile in comparison to its sister compounds, lenalidomide and thalidomide. Importantly, recent clinical studies have demonstrated its activity in relapsed or refractory myeloma, particularly in lenalidomide and bortezomib-refractory patients. Thus, the addition of pomalidomide to the anti-myeloma armamentarium is widely anticipated to have a significant impact on the overall clinical outcome of advanced stage relapsed and refractory MM patients.
PMCID: PMC3789204  PMID: 24013664
multiple myeloma; immunomodulatory agents; pomalidomide; treatment
14.  “Role of the B-cell receptor and the microenvironment in chronic lymphocytic leukemia'' 
Blood Cancer Journal  2013;3(9):e149-.
Despite significant progress in treatment, chronic lymphocytic leukemia (CLL) remains an incurable disease. Advances have been made to understand the molecular pathogenesis underlying CLL progression and treatment resistance. We here review the available evidences concerning the role of the B-cell receptor (BCR) and the tumor microenvironment interactions in CLL pathogenesis. Antigen likely has a key role in the selection of the tumoral clone, the mutational status of immunoglobulin genes is a strong prognostic predictor and BCR signaling has been postulated to have a role for CLL trafficking and interaction with the stromal microenvironment. There is also important evidence, favoring a role for the microenvironment in CLL pathogenesis. Most, if not all, proliferative events occur in the lymph nodes and bone marrow, where leukemic cells receive through microenvironment interactions survival signals aiming to avoid apoptosis and acquire favorable tumoral growing conditions. In addition, the tumoral microenvironment appears to be the site where the acquisition of additional genetic lesions in the clone occur, which should greatly influence clinical outcome. The advent of new tyrosine kinase inhibitors which seem to be able to modulate microenvironment interactions and circumvent the p53 deletion have generated significant promise by raising the possibility that they could provide significant progress in disease treatment.
PMCID: PMC3789209  PMID: 24056719
chronic lymphocytic leukemia; B-cell receptor; microenvironment
15.  Lessons from next-generation sequencing analysis in hematological malignancies 
Blood Cancer Journal  2013;3(7):e127-.
Next-generation sequencing has led to a revolution in the study of hematological malignancies with a substantial number of publications and discoveries in the last few years. Significant discoveries associated with disease diagnosis, risk stratification, clonal evolution and therapeutic intervention have been generated by this powerful technology. As part of the post-genomic era, sequencing analysis will likely become part of routine clinical testing and the challenge will ultimately be successfully transitioning from gene discovery to preventive and therapeutic intervention as part of individualized medicine strategies. In this report, we review recent advances in the understanding of hematological malignancies derived through genome-wide sequence analysis.
PMCID: PMC3730204  PMID: 23872706
hematological malignancy; genome sequencing; RNA sequencing; clonal architecture
16.  MEK inhibitors as a chemotherapeutic intervention in multiple myeloma 
Blood Cancer Journal  2013;3(3):e105-.
The Ras/Raf/MEK/extracellular signal regulated kinase (ERK) (Ras/mitogen-activated protein kinases (MAPK)) signal transduction pathway is a crucial mediator of many fundamental biological processes, including cellular proliferation, survival, angiogenesis and migration. Aberrant signalling through the Ras/MAPK cascade is common in a wide array of malignancies, including multiple myeloma (MM), making it an appealing candidate for the development of novel targeted therapies. In this review, we explore our current understanding of the Ras/MAPK pathway and its role in MM. Additionally, we summarise the current status of small molecule inhibitors of MEK under clinical evaluation, and discuss future approaches required to optimise their use.
PMCID: PMC3615214  PMID: 23524590
multiple myeloma; MEK inhibitors; Ras/MAPK; MEK
17.  Managing chronic myeloid leukemia patients intolerant to tyrosine kinase inhibitor therapy 
Blood Cancer Journal  2012;2(10):e95-.
The outcomes for patients with chronic myeloid leukemia have improved dramatically with the development and availability of BCR–ABL1 tyrosine kinase inhibitors (TKIs) over the past decade. TKI therapy has a superior safety profile compared with the previous standard of care, interferon-α, and most adverse events (AEs) observed with front-line and second-line TKI treatment are managed with supportive care. However, some patients are intolerant to TKI therapy and experience AEs that cannot be managed through dose reduction or symptomatic treatment. Careful management of AEs helps patients to remain adherent with treatment and increases their chances for successful outcomes. Proactive vigilance for potential AEs and treatment strategies that reduce symptom burden will help to minimize patient intolerance. This review discusses the most common AEs associated with intolerance to TKI therapy and treatment strategies to help manage patients at risk for or experiencing these events.
PMCID: PMC3483619  PMID: 23085780
chronic myeloid leukemia; dasatinib; imatinib; intolerance; nilotinib; tyrosine kinase inhibitors
18.  The t(4;14) translocation and FGFR3 overexpression in multiple myeloma: prognostic implications and current clinical strategies 
Blood Cancer Journal  2012;2(9):e89-.
Multiple myeloma (MM) is a heterogeneous plasma cell disorder characterized by genetic abnormalities, including chromosomal translocations, deletions, duplications and genetic mutations. Translocations involving the immunoglobulin heavy chain region at chromosome 14q32 are observed in approximately 40% of patients with MM. Translocation of oncogenes into this region may lead to their increased expression, contributing to disease initiation, disease progression and therapeutic resistance. The t(4;14) translocation is associated with upregulation of the fibroblast growth factor receptor 3 (FGFR3) and the myeloma SET domain protein. Patients with t(4;14) demonstrate an overall poor prognosis that is only partially mitigated by the use of the novel agents bortezomib and lenalidomide; as such, an unmet medical need remains for patients with this aberration. Preclinical studies of inhibitors of FGFR3 have shown promise in t(4;14) MM, and these studies have led to the initiation of clinical trials. Data from these trials will help to determine the clinical utility of FGFR3 inhibitors for patients with t(4;14) MM and may pave the way for personalized medicine in patients with this incurable disease.
PMCID: PMC3461707  PMID: 22961061
multiple myeloma; translocation; t(4;14); FGFR3; MMSET
19.  Tug of war in the haematopoietic stem cell niche: do myeloma plasma cells compete for the HSC niche? 
Blood Cancer Journal  2012;2(9):e91-.
In the adult mammal, normal haematopoiesis occurs predominantly in the bone marrow, where primitive haematopoietic stem cells (HSC) and their progeny reside in specialised microenvironments. The bone marrow microenvironment contains specific anatomical areas (termed niches) that are highly specialised for the development of certain blood cell types, for example HSCs. The HSC niche provides important cell–cell interactions and signalling molecules that regulate HSC self-renewal and differentiation processes. These same signals and interactions are also important in the progression of haematological malignancies, such as multiple myeloma (MM). This review provides an overview of the bone marrow microenvironment and its involvement in normal, physiological HSC maintenance and plasma cell growth throughout MM disease progression.
PMCID: PMC3461708  PMID: 22983434
myeloma; niche; bone microenvironment; haematopoietic stem cells
20.  Pediatric T- and NK-cell lymphomas: new biologic insights and treatment strategies 
Blood Cancer Journal  2012;2(4):e65-.
T- and natural killer (NK)-cell lymphomas are challenging childhood neoplasms. These cancers have varying presentations, vast molecular heterogeneity, and several are quite unusual in the West, creating diagnostic challenges. Over 20 distinct T- and NK-cell neoplasms are recognized by the 2008 World Health Organization classification, demonstrating the diversity and potential complexity of these cases. In pediatric populations, selection of optimal therapy poses an additional quandary, as most of these malignancies have not been studied in large randomized clinical trials. Despite their rarity, exciting molecular discoveries are yielding insights into these clinicopathologic entities, improving the accuracy of our diagnoses of these cancers, and expanding our ability to effectively treat them, including the use of new targeted therapies. Here, we summarize this fascinating group of lymphomas, with particular attention to the three most common subtypes: T-lymphoblastic lymphoma, anaplastic large cell lymphoma, and peripheral T-cell lymphoma-not otherwise specified. We highlight recent findings regarding their molecular etiologies, new biologic markers, and cutting-edge therapeutic strategies applied to this intriguing class of neoplasms.
PMCID: PMC3346681  PMID: 22829967
T-cell; NK-cell; lymphoblastic lymphoma; ALCL; PTCL
21.  Long-term complications and side effects after allogeneic hematopoietic stem cell transplantation: an update 
Blood Cancer Journal  2011;1(4):e16-.
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is an effective therapy for various malignant and non-malignant diseases. Many patients have now been followed for two or three decades posttransplant and are presumed to be cured. With the tremendous advances achieved in terms of supportive care, it is reasonable to expect outcomes to improve steadily and consequently increasing numbers of transplant survivors will be facing life after the initial transplant experience. Although long-term allo-HSCT survivors generally enjoy good health, for many others, cure or control of the underlying disease is not accompanied by full restoration of health. The burden of long-term morbidity borne by allo-HSCT survivors is substantial, and long-term follow-up of patients who received allo-HSCT is now widely recommended. Immediate survival is no longer the sole concern after allo-HSCT. The goals should also include complete recovery of the overall health status with normal physical and psychological functioning. Long-term side effects after allo-HSCT include non-malignant organ or tissue dysfunction, changes in quality of life, infections related to abnormal immune reconstitution and secondary cancers. Many of these can be attributed to the deleterious effects of chronic graft-versus-host disease. The aims of this review are to provide an update on the recent research evidence in the field.
PMCID: PMC3255242  PMID: 22829137
allogeneic hematopoietic stem cell transplantation; graft versus host disease; late effects; survivorship; quality of life; malignant complications
22.  Does Exercise Influence Pediatric Bone? A Systematic Review 
Periods of growth are thought to be the best time to increase bone mineral content, bone area, and areal bone mineral density (aBMD) through increased loading owing to high rates of bone modeling and remodeling. However, questions remain regarding whether a benefit of exercise is seen at all bone sites, is dependent on pubertal status or sex of the child, or whether other factors such as diet modify the response to exercise.
We asked: (1) Does bone-loading exercise in childhood consistently increase bone mineral content, bone area, or aBMD? (2) Do effects of exercise differ depending on pubertal status or sex? (3) Does calcium intake modify the bone response to exercise?
A literature search identified 22 unique trials for inclusion in this meta-analysis of the effect of exercise on bone changes by bone site, pubertal status, and sex. Sample sizes ranged from 16 to 410 subjects 3 to 18 years old with length of intervention ranging from 3 to 36 months. Fifteen of 22 trials were randomized (child randomized in nine, classroom/school randomized in six) and seven were observational trials. Ten trials were Level 2 and 11 were Level 3 based on the Oxford Centre for Evidence-Based Medicine criteria. Random effects models tested the difference (intervention mean effect–control mean effect) in percent change in bone mineral content, bone area, and aBMD. Meta-regression was used to identify sources of heterogeneity and funnel plots were used to assess publication bias.
Children assigned to exercise had greater mean percent changes in bone mineral content and aBMD than children assigned to the control groups. Mean differences (95% CI) in bone mineral content percent change between intervention and control groups at total body (0.8; 95% CI, 0.3–1.3; p = 0.003), femoral neck (1.5; 95% CI, 0.5–2.5; p = 0.003), and spine (1.7; 95% CI, 0.4–3.1; p = 0.01) were significant with no differences in bone area (all p > 0.05). There were greater percent changes in aBMD in intervention than control groups at the femoral neck (0.6; 95% CI, 0.2–1.1; p = 0.006) and spine (1.2; 95% CI, 0.6–1.8; p < 0.001). Benefit of exercise was limited to children who were prepubertal (bone mineral content: total body [0.9; 95% CI, 0.2–1.7; p = 0.01], femoral neck [1.8; 95% CI, 0.0–3.5; p = 0.047], spine [3.7; 95% CI, 0.8–6.6; p = 0.01], and aBMD: femoral neck [0.6; 95% CI, −0.1–1.2; p = 0.07], spine [1.5; 95% CI, 0.7–2.3; p < 0.001]), with no differences among children who were pubertal (all p > 0.05). Changes in aBMD did not differ by sex (all p > 0.05), although the number of studies providing male-specific results was small (six of 22 eligible studies included boys). There was significant heterogeneity in bone mineral content and bone area for which a source could not be identified. Heterogeneity in spine aBMD was reduced by including calcium intake and intervention length as covariates. Three trials designed to determine whether calcium intake modified the bone response to exercise all reported a greater effect of exercise on leg bone mineral content in children randomized to receive supplemental calcium than those receiving placebo.
Exercise interventions during childhood led to 0.6% to 1.7% greater annual increase in bone accrual, with effects predominantly among children who were prepubertal. If this effect were to persist into adulthood, it would have substantial implications for osteoporosis prevention. It is important to identify sources of heterogeneity among studies to determine factors that might influence the bone response to increased exercise during growth.
Level of Evidence
Level II, therapeutic study.
PMCID: PMC4586223  PMID: 26208606
23.  Fundamentals for Future Mobile-Health (mHealth): A Systematic Review of Mobile Phone and Web-Based Text Messaging in Mental Health 
Mobile phone text messages (short message service, SMS) are used pervasively as a form of communication. Almost 100% of the population uses text messaging worldwide and this technology is being suggested as a promising tool in psychiatry. Text messages can be sent either from a classic mobile phone or a web-based application. Reviews are needed to better understand how text messaging can be used in mental health care and other fields of medicine.
The objective of the study was to review the literature regarding the use of mobile phone text messaging in mental health care.
We conducted a thorough literature review of studies involving text messaging in health care management. Searches included PubMed, PsycINFO, Cochrane, Scopus, Embase and Web of Science databases on May 25, 2015. Studies reporting the use of text messaging as a tool in managing patients with mental health disorders were included. Given the heterogeneity of studies, this review was summarized using a descriptive approach.
From 677 initial citations, 36 studies were included in the review. Text messaging was used in a wide range of mental health situations, notably substance abuse (31%), schizophrenia (22%), and affective disorders (17%). We identified four ways in which text messages were used: reminders (14%), information (17%), supportive messages (42%), and self-monitoring procedures (42%). Applications were sometimes combined.
We report growing interest in text messaging since 2006. Text messages have been proposed as a health care tool in a wide spectrum of psychiatric disorders including substance abuse, schizophrenia, affective disorders, and suicide prevention. Most papers described pilot studies, while some randomized clinical trials (RCTs) were also reported. Overall, a positive attitude toward text messages was reported. RCTs reported improved treatment adherence and symptom surveillance. Other positive points included an increase in appointment attendance and in satisfaction with management and health care services. Insight into message content, preventative strategies, and innovative approaches derived from the mental health field may be applicable in other medical specialties.
PMCID: PMC4920962  PMID: 27287668
text messaging; cell phones; mental health; Internet; medical informatics
24.  Connexins and pannexins in liver damage 
EXCLI Journal  2016;15:177-186.
Connexins and pannexins are key players in the control of cellular communication and thus in the maintenance of tissue homeostasis. Inherent to this function these proteins are frequently involved in pathological processes. The present paper reviews the role of connexins and pannexins in liver toxicity and disease. As they act both as sensors and effectors in these deleterious events connexins and pannexins could represent a set of novel clinical diagnostic biomarkers and drug targets.
PMCID: PMC4822047  PMID: 27065778
connexin; pannexin; acute liver injury; steatosis; hepatitis; cholestasis; fibrosis; liver cancer
25.  Magnetic resonance imaging biomarkers of gastrointestinal motor function and fluid distribution 
Magnetic resonance imaging (MRI) is a well established technique that has revolutionized diagnostic radiology. Until recently, the impact that MRI has had in the assessment of gastrointestinal motor function and bowel fluid distribution in health and in disease has been more limited, despite the novel insights that MRI can provide along the entire gastrointestinal tract. MRI biomarkers include intestinal motility indices, small bowel water content and whole gut transit time. The present review discusses new developments and applications of MRI in the upper gastrointestinal tract, the small bowel and the colon reported in the literature in the last 5 years.
PMCID: PMC4644878  PMID: 26600972
Magnetic resonance imaging; Stomach; Small bowel; Colon; Motility

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