Efficacy and Safety of Autologous Cell-based Therapy in Patients with No-option Critical Limb Ischaemia: A Meta-Analysis.

BACKGROUND: Revascularisation therapy is the current gold standard of care for critical limb ischemia (CLI), although a significant proportion of patients with CLI either are not fit for or do not respond well to this procedure. Recently, novel angiogenic therapies such as the use of autologous cellbased therapy (CBT) have been examined, but the results of individual trials were inconsistent. OBJECTIVE: To pool all published studies that compared the safety and efficacy of autologous CBT derived from different sources and phenotypes with non cell-based therapy (NCT) in CLI patients. METHODS: We searched Medline, Embase, Cochrane Library and ClinicalTrials.gov from 1974-2017. Sixteen randomised clinical trials (RCTs) involving 775 patients receiving the following interventions: mobilised peripheral blood stem cells(m-PBSC), bone marrow mononuclear cells(BM-MNC), bone marrow mesenchymal stem cells(BM-MSC), cultured BM-MNC(Ixmyelocel-T), cultured PB cells(VesCell) and CD34+ cells were included in the meta-analysis. RESULTS: High-quality evidence (QoE) showed similar all-cause mortality rates between CBT and NCT. AR reduction by approximately 60% were observed in patients receiving CBT compared to NCT (moderate QoE). CBT patients experienced improvement in ulcer healing, ABI, TcO2, pain free walking capacity and collateral vessel formation (moderate QoE). Low-to-moderate QoE showed that compared to NCT, intramuscular BM-MNC and m-PBSC may reduce amputation rate, rest pain, and improve ulcer healing and ankle-brachial pressure index, while intramuscular BM-MSC appeared to improve rest pain, ulcer healing and pain-free walking distance but not AR. Efficacy of other types of CBT could not be confirmed due to limited data. Cell harvesting and implantation appeared safe and well-tolerated with similar rates of adverse-events between groups. CONCLUSION: Implantation of autologous CBT may be an effective therapeutic strategy for no-option CLI patients. BM-MNC and m-PSBC appear more effective than NCT in improving AR and other limb perfusion parameters. BM-MSC may be beneficial in improving perfusion parameters but not AR, however, this observation needs to be confirmed in a larger population of patients. Generally, treatment using various sources and phenotypes of cell products appeared safe and well tolerated. Large-size RCTs with long follow-up are warranted to determine the superiority and durability of angiogenic potential of a particular CBT and the optimal treatment regimen for CLI.

Association of genotypes and haplotypes of multi-drug transporter genes ABCB1 and ABCG2 with clinical response to imatinib mesylate in chronic myeloid leukemia patients.

The introduction and success of imatinib mesylate (IM) has become a paradigm shift in chronic myeloid leukemia (CML) treatment. However, the high efficacy of IM has been hampered by the issue of clinical resistance that might due to pharmacogenetic variability. In the current study, the contribution of three common single nucleotide polymorphisms (SNPs) of ABCB1 (T1236C, G2677T/A and C3435T) and two SNPs of ABCG2 (G34A and C421A) genes in mediating resistance and/or good response among 215 CML patients on IM therapy were investigated. Among these patients, the frequency distribution of ABCG2 421 CC, CA and AA genotypes were significantly different between IM good response and resistant groups (P=0.01). Resistance was significantly associated with patients who had homozygous ABCB1 1236 CC genotype with OR 2.79 (95%CI: 1.217-6.374, P=0.01). For ABCB1 G2677T/A polymorphism, a better complete cytogenetic remission was observed for patients with variant TT/AT/AA genotype, compared to other genotype groups (OR=0.48, 95%CI: 0.239-0.957, P=0.03). Haplotype analysis revealed that ABCB1 haplotypes (C1236G2677C3435) was statistically linked to higher risk to IM resistance (25.8% vs. 17.4%, P=0.04), while ABCG2 diplotype A34A421 was significantly correlated with IM good response (9.1% vs. 3.9%, P=0.03). In addition, genotypic variant in ABCG2 421C>A was associated with a major molecular response (MMR) (OR=2.20, 95%CI: 1.273-3.811, P=0.004), whereas ABCB1 2677G>T/A variant was associated with a significantly lower molecular response (OR=0.49, 95%CI: 0.248-0.974, P=0.04). However, there was no significant correlation of these SNPs with IM intolerance and IM induced hepatotoxicity. Our results suggest the usefulness of genotyping of these single nucleotide polymorphisms in predicting IM response among CML patients.

Effects of preeclampsia on the yield of hematopoietic stem cells obtained from umbilical cord blood at delivery.

AIM: To compare the numbers of cord blood CD34(+) hematopoietic stem cells (HSC) between preeclampsia (PE) and control (non-PE) subjects and to determine the factors that may influence this observation. METHODS: Umbilical cord blood was collected from 28 PE and 19 non-PE subjects. Nucleated and CD34(+) cell counts were derived using the Trucount tube-based stem cell enumeration kit on BD FACSCalibur. RESULTS: The cord blood volume, nucleated and CD34(+) cell counts were significantly reduced in PE subjects compared to non-PE subjects. Among the PE subjects, systolic and diastolic blood pressure demonstrated a negative correlation with total nucleated and CD34(+) cell counts. Gestational age at delivery influenced cord blood volume and nucleated cell counts, but not CD34(+) cell counts. Birth weight and placental weight correlated strongly with cord blood volume, and nucleated and CD34(+) cell counts. There were no correlations observed between cord blood parameters and maternal age, maternal white cell count, gravidity, route of delivery or neonatal gender among PE subjects. CONCLUSION: Preeclampsia has a negative impact on the yield of HSC obtained from cord blood at delivery. Maternal blood pressure, neonatal birth weight and placental weight are important factors influencing the numbers of cord blood HSC. These findings should be taken into consideration when selecting cord blood units from mothers with PE for banking. Selecting the heaviest term neonate might improve the yield of cord blood HSC obtained from PE mothers.