Hematopoietic stem cell transplantation (HSCT) involves the administration of chemotherapy followed by the infusion of donor stem cells. After treatment, children can consequently experience nausea, vomiting, diarrhea, anorexia, and mucositis, which negatively impact oral intake, leading to rapid deterioration in nutritional status and risk of malnutrition. Nutrition support therefore becomes necessary to circumvent these adverse effects. This has traditionally been provided via parenteral nutrition (PN), but pediatric evidence is increasingly advocating enteral nutrition (EN) as a preferential alternative. The objective of this review is to determine the efficacy of any forms of EN versus PN provided during admission to children aged ≤ 18 years undergoing HSCT. Primary outcomes considered efficacy in relation to various nutritional parameters, and secondary outcomes included a range of post-transplantation parameters. Data sources included English and non-English articles from the start date of MEDLINE, EMBASE, AMED, CINAHL and Cochrane Controlled Trials register, up to July 2018. Key journals were also hand searched, reference lists scanned, clinical experts contacted, and gray literature searched using EThOS and Open Grey. Randomized and observational studies comparing any forms of EN versus PN in children aged ≤ 18 years undergoing HSCT investigating nutritional or post-transplantation outcomes were eligible. Data were extracted from included studies using a custom extraction form that had previously been piloted. Because included studies were observational, risk of bias was assessed using Risk of Bias in Non-randomised Studies of Interventions. Because only a small number of heterogenous studies reporting a wide range of differently defined outcomes were included, meta-analyses were not performed and data were presented in narrative form. Conflicting results in favor of either method of nutrition support or no difference between methods were seen for duration of interventions, nutritional intakes, biochemical and anthropometric changes, mortality, infections, length of admission, and neutrophil engraftment. EN may provide favorable benefits over PN regarding acute graft-versus-host-disease (aGVHD) and platelet engraftment. A paucity of studies was found investigating the question posed by this review. Included studies were clinically heterogenous regarding populations, interventions, and outcomes, at moderate to serious risk of bias due to the absence of randomization, confounding parameters, statistical control, retrospective designs, and participant selection. Some studies were more than 15 years old. Despite the limited number and poor quality of identified studies, results support the growing body of pediatric evidence that EN is feasible during HSCT. Similar differences regarding many nutritional and post-transplantation outcomes were seen in both forms of nutrition support, but EN could provide benefits above PN including reduced incidence of aGVHD and faster platelet engraftment.

Immunothrombosis is a physiological process based on the release of neutrophil extracellular traps (NETs) to immobilise, contain and kill bacteria. This is an innate immune response in which the local activation of blood coagulation exerts the critical protective function during microbial infection. In recent years, there has been much interest in the adult literature about the key role of immunothrombosis in pathologic states including thrombosis, cancer, sepsis and trauma. Currently, little research has been done into its role in paediatric conditions.

AimsStem cell-derived extracellular vesicles (EVs) have emerged as a promising therapy for myocardial infarction, but its effects remain incompletely understood. We aim to systematically review the efficacy of EVs on myocardial infarction in both small and large animals.MethodsOn April 5, 2018, we searched the PubMed, Embase and Web of Science databases using variations of "myocardial infarction" and "extracellular vesicle". Controlled studies about the treatment effects of stem cell-derived EVs in myocardial infarction animal model were included. Meta-regression analysis was used to reveal the factors affecting the EVs treatments.ResultsOf 1210 studies retrieved, 24 were eligible for meta-analysis. EVs injection was associated with the improvements of left ventricular ejection fraction (12.65%), fractional shortening (7.54%) and the reduction of infarct size/area at risk (-15.55%). Meta-regression analysis did not reveal the association between treatment efficacy and type of stem cell, ligation-to-injection interval, route of delivery, dosage of delivery or follow-up period (all P values > 0.05). The median quality score of eligible studies was only 1, indicating potential risks of bias.ConclusionStem cell-derived EVs improve cardiac function and reduce infarct size in myocardial infarction animals, but current pool-up study reveals no associations between common factors and treatment effects.

Blinatumomab and donor lymphocyte infusion (DLI) combination is a promising cancer therapy, whereby blinatumomab might achieve an initial reduction in leukemic-cell burden using T cells, and after tumor clearance, DLI can potentially stimulate the donor immune system to achieve longer lasting remission. Here, we present a 51-year-old female with mixed phenotype acute leukemia who had a hematologic relapse 3 months after she received total body irradiation-based myeloablative allogeneic hematopoietic stem cell transplantation from an unrelated human leukocyte antigen matched (10/10) donor and achieved complete remission with minimal residual disease negativity by multi-parameter flow cytometry using the combination of blinatumomab and DLI. To the best of our knowledge, this is the first report to describe the use of blinatumomab and DLI combination therapy in the treatment of B/myeloid mixed phenotype acute leukemia.

Congenital diaphragmatic hernia (CDH) is a severe birth defect that is characterized by pulmonary hypoplasia and pulmonary hypertension (PHTN). PHTN secondary to CDH is a result of vascular remodeling, a structural alteration in the pulmonary vessel wall that occurs in the fetus. Factors involved in vascular remodeling have been reported in several studies, but their interactions remain unclear. To help understand PHTN pathophysiology and design novel preventative and treatment strategies, we have conducted a systematic review of the literature and comprehensively analyzed all factors and pathways involved in the pathogenesis of pulmonary vascular remodeling secondary to CDH in the nitrofen model. Moreover, we have linked the dysregulated factors with pathways involved in human CDH. Of the 358 full-text articles screened, 75 studies reported factors that play a critical role in vascular remodeling secondary to CDH. Overall, the impairment of epithelial homeostasis present in pulmonary hypoplasia results in altered signaling to endothelial cells, leading to endothelial dysfunction. This causes an impairment of the crosstalk between endothelial cells and pulmonary artery smooth muscle cells, resulting in increased smooth muscle cell proliferation, resistance to apoptosis, and vasoconstriction, which clinically translate into PHTN.

Background: Cardiac muscle possesses a limited capacity to regenerate its tissue on its own. It is less likely to reverse the altered cardiac functioning to its normal physiological state after a major myocardial infarction. Stem cell transplantation provided a unique therapeutic approach in managing such injuries. There has been a substantial debate about the complexity, scope and medical application of stem cell transplantation in past few years. Materials and Methods: An extensive review of medical literature was conducted to establish the consensus about the possible mechanism of cell renewal, associated complications and risks of failure of this technique. Twenty cases of mammalian animals and twenty-four cases of stem cell transplantation in human subjects were reviewed. Results: Most common associated complication was re-stenosis of coronary artery. Few clinical trials reported the failure in improving cardiac functioning. The success rate of stem cell transplantation was remarkable in the literature related to experimental animal subjects. Conclusion: It was concluded that renewal of the cardiac cell is a result of induction of angiogenesis and prolonged cell survival. This topic still requires an immense amount of research to fill the gap in adequate knowledge.

Despite significant progress in drug treatment, the prognosis of patients with advanced pulmonary arterial hypertension (PAH) remains extremely poor. Many preclinical studies have reported the efficacy of stem cell (SC) therapy for PAH; however, this approach remains controversial. The aim of this systematic review and meta-analysis is to assess the potential efficacy of SC therapy for PAH.

Rectal inflammation is the principal risk factor for the development of perianal fistulizing Crohn's disease. However, no topical therapy direct to rectal healing is discussed in European' guidelines. The aim of this systematic review was to evaluate the role of topical therapy in healing the rectal inflammation in Crohn's disease.

Mesenchymal stem cells (MSCs) have gained popularity for articular cartilage repair. However, efficacy of intra-articular MSCs in osteoarthritis remains unclear. In the setting of a meta-analysis of randomized controlled trials (RCTs), we aimed to investigate the efficacy of intra-articular MSCs on clinical outcomes and cartilage repair in patients with knee osteoarthritis.

Recent studies have indicated that stem cell transplantation may be effective in the treatment of ischemic stroke. Therefore, we performed a meta-analysis to evaluate the safety and efficacy of stem cell therapy for ischemic stroke in preclinical and clinical studies. In accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, we searched the PubMed, Cochrane Library, Embase, Web of science, and Ovid databases from inception through May 2018. A total of 11 preclinical studies-18 independent interventions were ultimately included. Similarly, 11 clinical studies were finally included. Two authors independently screened trials. Lesion volume and modified neurological severity scores (mNSSs) were regarded as outcome measures for preclinical studies. The composite weighted mean [95% confidence interval (CI)] effect sizes for lesion volume, percentage of lesion volume, and mNSSs were -46.59 (-62.04 to -31.15; P < 0.001), -13.18 (-25.62 to -0.73; P = 0.04), and -1.85 (-2.17 to -1.53; P < 0.001), respectively. Our analysis revealed that all three outcomes were significantly more favorable in the stem cell group than in the control group. Barthel index (BI) values, modified Rankin scale (mRS) scores, National Institutes of Health Stroke Scale (NIHSS) scores, and Fugl-Meyer assessment (FMA) scores were regarded as outcome measures for human studies. Our results were as follows: NIHSS [mean differences, MDs = -2.57, 95% CI (-3.45 to -1.68), I2 = 51%, P < 0.001]; BI [MD = 7.93, 95% CI (3.11 to 12.75), I2 = 59%, P = 0.001]; mRS [MD = -0.53, 95% CI (-0.73 to -0.28), I2 = 0%, P < 0.001]; FMA [MD = 5.50, 95% CI (2.05 to 8.95), I2 = 15%, P = 0.002]. These results suggest that stem cell transplantation was associated with significantly better outcomes than control treatment. Adverse reactions such as mild headache and fever resolved shortly after treatment. Stem cell transplantation can significantly improve neurological deficits and quality of life in patients with ischemic stroke, without severe adverse reactions. Our results also suggest that such treatment is most effective when provided earlier and through the intravenous route.

To examine economic evaluation studies of stem cell therapies (SCTs) in neurological disorders and to provide an overview of the quality of the economic evidence available on this topic.

Recipients of allogeneic haematopoietic stem cell transplants (HSCT) can develop acute or chronic, or both forms of graft-versus-host disease (a/cGvHD), whereby immune cells of the donor attack host tissues. Steroids are the primary treatment, but patients with severe, refractory disease have limited options and a poor prognosis. Mesenchymal stromal cells (MSCs) exhibit immunosuppressive properties and are being tested in clinical trials for their safety and efficacy in treating many immune-mediated disorders. GvHD is one of the first areas in which MSCs were clinically applied, and it is important that the accumulating evidence is systematically reviewed to assess whether their use is favoured.

An unmet but urgent medical need is the development of myelin repair promoting therapies for Multiple Sclerosis (MS). Many such therapies have been pre-clinically tested using different models of toxic demyelination such as cuprizone, ethidium bromide, or lysolecithin and some of the therapies already entered clinical trials. However, keeping track on all these possible new therapies and their efficacy has become difficult with the increasing number of studies. In this study, we aimed at summarizing the current evidence on such therapies through a systematic review and at providing an estimate of the effects of tested interventions by a meta-analysis. We show that 88 different therapies have been pre-clinically tested for remyelination. 25 of them (28%) entered clinical trials. Our meta-analysis also identifies 16 promising therapies which did not enter a clinical trial for MS so far, among them Pigment epithelium-derived factor, Plateled derived growth factor, and Tocopherol derivate TFA-12.We also show that failure in bench to bedside translation from certain therapies may in part be attributable to poor study quality. By addressing these problems, clinical translation might be smoother and possibly animal numbers could be reduced.

Frailty, one appealing target for improving successful aging of the elderly population, is a common clinical syndrome based on the accumulation of multisystemic function declines and the increase in susceptibility to stressors during biological aging. The age-dependent senescence, the frailty-related stem cell depletion, chronic inflammation, imbalance of immune homeostasis, and the reduction of multipotent stem cells collectively suggest the rational hypothesis that it is possible to (partially) cure frailty with stem cells. This systematic review has included all of the human trials of stem cell therapy for frailty from the main electronic databases and printed materials and screened the closely related reviews themed on the mechanisms of aging, frailty, and stem cells, to provide more insights in stem cell strategies for frailty, one promising method to recover health from a frail status. To date, a total of four trials about this subject have been registered on clinicaltrials.gov. The use of mesenchymal stem cells (MSCs), doses of 100 million cells, single peripheral intravenous infusion, follow-up periods of 6-12 months, and a focus primarily on safety and secondarily on efficacy are common characteristics of these studies. We conclude that intravenous infusion of allogenic MSCs is safe, well tolerated, and preliminarily effective clinically. More preclinical experiments and clinical trials are warranted to precisely elucidate the mechanism, safety, and efficacy of frailty stem cell therapy.

Extensive oligodendrocyte death after acute traumatic spinal cord injuries (TSCI) leads to axon demyelination and subsequently may leave axons vulnerable to degeneration. Despite the present evidence showing spontaneous remyelination after TSCI the cellular origin of new myelin and the time course of the axon ensheathment/remyelination remained controversial issue. In this systematic review the trend of oligodendrocyte death after injury as well as the extent and the cellular origin of oligodendrogliogenesis were comprehensively evaluated. The study design was based on Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA)-guided systematic review. PubMed and EMBASE were searched with no temporal or linguistic restrictions. Also, hand-search was performed in the bibliographies of relevant articles. Non-interventional animal studies discussing different types of myelinating cells including oligodendrocytes, Schwann cells and oligodendrocyte progenitor cells (OPCs) were evaluated. The extent of oligodendrocyte death, oligodendrocyte differentiation and remyelination were the pathophysiological outcome measures. We found 12,359 studies, 34 of which met the inclusion criteria. The cumulative evidence shows extensive oligodendrocytes cell death during the first week post-injury (pi). OPCs and peripheral invading Schwann cells are the dominant cells contributing in myelin formation. The maximum OPC proliferation was observed at around 2 weeks pi and oligodendrogliogenesis continues at later stages until the number of oligodendrocytes return to normal tissue by one month pi. Taken together, the evidence in animals reveals the potential role for endogenous myelinating cells in the axon ensheathment/remyelination after TSCI and this can be the target of pharmacotherapy to induce oligodendrocyte differentiation and myelin formation post-injury.

Huntington's disease (HD) is an autosomal-dominant neurodegenerative disorder encoding a mutant form of the huntingtin protein (HTT). HD is pathologically characterized by loss of neurons in the striatum and cortex, which leads to progressive motor dysfunction, cognitive decline and behavioral symptoms. Stem cell-based therapy has emerged as a feasible therapeutic approach for the treatment of neurodegenerative diseases and may be effective in alleviating and/or halting the pathophysiological mechanisms underlying HD. Several pre-clinical studies have used stem cells in animal models of HD. Here, we performed a systematic review of preclinical studies to estimate the treatment efficacy of stem cells in animal models of HD. Based on our systematic review, treatment with stem cells significantly improves neurological and behavioral outcomes in animal models of HD. Although promising results were found, the design of animal studies, the types of transplanted cells and the route of administration are poorly standardized and this greatly complicates comparative analysis.

Gliomas are a heterogenous group of malignant primary brain tumors that arise from glia cells or their progenitors and rely on accurate diagnosis for prognosis and treatment strategies. Although recent developments in the molecular biology of glioma have improved diagnosis, classical histological methods and biomarkers are still being used. The glial fibrillary acidic protein (GFAP) is a classical marker of astrocytoma, both in clinical and experimental settings. GFAP is used to determine glial differentiation, which is associated with a less malignant tumor. However, since GFAP is not only expressed by mature astrocytes but also by radial glia during development and neural stem cells in the adult brain, we hypothesized that GFAP expression in astrocytoma might not be a direct indication of glial differentiation and a less malignant phenotype. Therefore, we here review all existing literature from 1972 up to 2018 on GFAP expression in astrocytoma patient material to revisit GFAP as a marker of lower grade, more differentiated astrocytoma. We conclude that GFAP is heterogeneously expressed in astrocytoma, which most likely masks a consistent correlation of GFAP expression to astrocytoma malignancy grade. The GFAP positive cell population contains cells with differences in morphology, function, and differentiation state showing that GFAP is not merely a marker of less malignant and more differentiated astrocytoma. We suggest that discriminating between the GFAP isoforms GFAPδ and GFAPα will improve the accuracy of assessing the differentiation state of astrocytoma in clinical and experimental settings and will benefit glioma classification.

It is an open question whether cell transplantation can provide safety and effective outcome to spinal cord injury (SCI) patient which has remained controversial for almost 40 years. This study aimed to evaluate the safety and efficacy of cell transplantation in SCI patients.

The prospect of treating knee cartilage injury/pathology with mesenchymal stem cells (MSCs) has garnered considerable attention in recent years, but study heterogeneity and a lack of randomized controlled trials (RCTs) preclude quantitative analysis. The purpose of this review was to provide clinicians with an overview of RCTs that addresses 2 key areas that have been largely overlooked: nomenclature inconsistency and selective outcome reporting.

Acute myeloid leukemia (AML) as a distortion of blood cells involves the differ entiation of hematopoietic stem cells. Several studies established the irregular over expression of specific genes is a common finding in patients with AML. The ectopic viral integration site-1 (EVI1) gene is a protooncogene subject to alternative splicing, and encodes a zincfinger protein that acts as a transcriptional regulator in early devel opment. Forced overexpression of EVI1 in hematopoietic progenitors later induced a myeloid differentiation block. The current review aimed at determining the prognos tic value of EVI1 expression in patients with AML in the age range of one month to fifteen years. The scientific databases including PubMed, Google Scholar, EMBASE, Scopus, and ISI published up to January 2016 were searched using the conformity keywords and a total of four articles were studied. Three articles declared higher overexpression of EVI1 in patients with mixed-lineage leukemia (MLL) rearrangements. The percentage of overall survival (OS), reported in two articles, decreased in AML patients with high EVI1 expression. A study reported that the relationship between EVI1 expression and OS was negligible in cases with and without EVI1 expression. Another study showed significant differences in event free survival (EFS) and OS in the group of patients with positive MLL-AF9 between EVI1+ and EVI1patients. The current study revealed that high EVI1 expression was not a poor prognostic factor in pediatric patients with AML. And this gene expression was mainly prognostic concomitantly by other factors such as MLL rearrangement, MEL1 expression, and white blood cell (WBC) count.