Marrow changes and reduced proliferative capacity of mesenchymal stromal cells from patients with "no-option" critical limb ischemia; observations on feasibility of the autologous approach from a clinical trial.

BACKGROUND AIMS: Approximately 1 in 3 patients with critical limb ischemia (CLI) are not suitable for surgical or endovascular revascularization. Those "no-option" patients are at high risk of amputation and death. Autologous bone marrow mesenchymal stromal cells (MSCs) may provide a limb salvage option. In this study, bone marrow characteristics and expansion potentials of CLI-derived MSCs produced during a phase 1b clinical trial were compared with young healthy donor MSCs to determine the feasibility of an autologous approach. Cells were produced under Good Manufacturing Practice conditions and underwent appropriate release testing. METHODS: Five bone marrow aspirates derived from patients with CLI were compared with six young healthy donor marrows in terms of number of colony-forming units-fibroblast (CFUF) and mononuclear cells. The mean population doubling times and final cell yields were used to evaluate expansion potential. The effect of increasing the volume of marrow on the CFUF count and final cell yield was evaluated by comparing 5 CLI-derived MSCs batches produced from a targeted 30 mL of marrow aspirate to five batches produced from a targeted 100 mL of marrow. RESULTS: CLI-derived marrow aspirate showed significantly lower numbers of mononuclear cells with no difference in the number of CFUFs when compared with healthy donors' marrow aspirate. CLI-derived MSCs showed a significantly longer population doubling time and reduced final cell yield compared with young healthy donors' MSCs. The poor growth kinetics of CLI MSCs were not mitigated by increasing the bone marrow aspirate from 30 to 100 mL. CONCLUSIONS: In addition to the previously reported karyotype abnormalities in MSCs isolated from patients with CLI, but not in cells from healthy donors, the feasibility of autologous transplantation of bone marrow MSCs for patients with no-option CLI is further limited by the increased expansion time and the reduced cell yield.

Potentially undiagnosed cognitive impairment in patients with peripheral arterial disease: A systematic review of the literature.

INTRODUCTION: It is purported that patients with peripheral arterial disease (PAD) may have impaired cognitive function due to concomitant cerebrovascular disease. Such disease may be clinically unrecognized but can impact on a patient's recovery and prognosis. The purpose of this systematic review was to interrogate the body of published evidence on undiagnosed cognitive impairment in PAD patients. METHODS: A search strategy encompassing MEDLINE, Scopus, and the Cochrane database was developed to identify peer-reviewed articles examining rates of undiagnosed cognitive impairment in patients with PAD. The following search terms were used: 'PAD'; 'PVD'; 'dementia'; 'peripheral arterial disease'; 'peripheral vascular disease'; 'cognitive impairment'; 'alzheimer's disease' and 'cogniti∗'. Our primary outcome was the incidence of previously undiagnosed cognitive impairment in patients with PAD. RESULTS: The initial search yielded 1492 titles. After removal of duplicates, 961 abstracts were screened to ascertain if they were eligible for inclusion. Abstract review yielded 62 full texts for further evaluation. Eight case-control studies consisting of 1161 patients were included. Analysis of these studies revealed that PAD patients performed significantly worse than controls on a variety of neuropsychological measures. CONCLUSION: Our review indicated that PAD patients are more likely to suffer with undiagnosed cognitive impairment than healthy controls.

Validation of ERICVA Risk Score as a Predictor of One Year Amputation-Free Survival of Patients with Critical Limb Ischemia.

BACKGROUND: The ERICVA score was derived to predict amputation-free survival in patients with critical limb ischemia (CLI). It may be a useful tool to stratify patients in trials of novel interventions to treat CLI but, as yet, it has not been externally validated. METHODS: A prospective database of CLI patients was developed during prescreening of patients for a phase 1 stem cell therapy clinical trial. The primary outcome was amputation free survival (AFS) at 1 year. Both the full ERICVA scale (11 parameters) and simplified ERICVA scale (5 parameters) were validated. Data analysis was performed by calculation of the area under the receiver operating characteristic (ROC) curve examining the predictive value of the scores. The Chi-square test was used to examine the association between risk group and one-year AFS and the cumulative survival of the three risk groups was compared using Kaplan Meier survival curves. RESULTS: A series of 179 CLI patients were included in the analysis. The Chi-square test of independence showed a significant association between the risk group (high, medium and low) and one-year AFS outcome (P = 0.0007). Kaplan-Meier survival curve showed significant difference in one-year AFS between the three risk groups (log-rank P < 0.001). The area under the curve (AUC) was found to be 0.63 and 0.61 for the full and simplified score, respectively. The sensitivity of the full score was 0.44 with specificity of 0.84. The simplified score had a sensitivity of 0.28 and specificity of 0.92. CONCLUSION: The ERICVA risk score system was found to have a fair validity but cannot be considered reliable as a single predictor of one year AFS of CLI patients. The simplified score had an AUC almost identical to the full score and can accordingly replace the full score.

Autologous bone marrow mesenchymal stromal cell therapy for "no-option" critical limb ischemia is limited by karyotype abnormalities.

BACKGROUND: Critical limb ischemia (CLI) is the most severe manifestation of peripheral vascular disease. Revascularization is the preferred therapy, but it is not achievable in 25%-40% of patients due to diffuse anatomic distribution of the disease or medical comorbidities. No-option CLI represents an unmet medical need. Mesenchymal stromal cells (MSCs) may provide salvage therapy through their angiogenic and tissue-trophic properties. This article reports a phase 1b clinical study examining the safety and feasibility of intramuscular transplantation of autologous bone-marrow MSCs for patients with no-option CLI. METHODS: Twelve patients were enrolled in the clinical trial, and nine proceeded to bone marrow aspiration and culture expansion of MSCs. RESULTS: A high rate of karyotype abnormality (>30%) was detected in the produced cell batches, resulting in failure of release for clinical administration. Four patients were treated with the investigational medicinal product (IMP), three with a low dose of 20 × 106 MSCs and one with a mid-dose of 40 × 106 MSCs. There were no serious adverse events related to trial interventions, including bone marrow aspiration, IMP injection or therapy. CONCLUSIONS: The results of this trial conclude that an autologous cell therapy approach with MSCs for critical limb ischemia is limited by the high rate of karyotype abnormalities.

Anal advancement flap versus lateral internal sphincterotomy for chronic anal fissure- a systematic review and meta-analysis.

BACKGROUND: Chronic anal fissures (CAF) are common and associated with reduced quality of life. Lateral internal sphincterotomy (LIS) is frequently carried out but carries a significant risk of anal incontinence. Anal advancement flap (AAF) has been advocated as an alternative, 'sphincter-preserving' procedure. We aimed to perform a systematic review and meta-analysis to compare the efficacy of both techniques in the treatment of CAF. METHODS: The online databases of PubMed/Medline, CINAHL, EMBASE and Cochrane Central Register of Controlled Trials were searched from inception to January 2017. All studies that investigated and reported outcomes of LIS and AAF for treatment of CAF were included. The primary outcome measure was anal incontinence while secondary outcomes included unhealed fissure and wound complication rates. Random effects models were used to calculate pooled effect size estimates. RESULTS: Four studies (2 randomized controlled trials and 2 retrospective studies) describing 300 patients (150 LIS, 150 AAF) fulfilled our inclusion criteria. There was significant clinical heterogeneity among the trials. On random effects analysis, AAF was associated with a significantly lower rate of anal incontinence compared to LIS (OR = 0.06, 95% CI = 0.01 to 0.36, p = .002). However, there were no statistically significant differences in unhealed fissure (OR = 2.21, 95% CI = 0.25 to 19.33, p = .47) or wound complication rates (OR = 1.41, 95% CI = 0.50 to 4.99 p = .51) between AAF and LIS. CONCLUSIONS: AAF is associated with less incontinence, but similar wound complications as well as a similar rate of unhealed fissures compared to LIS. However, further well-executed, multi-centre randomized trials are required to provide stronger evidence.

Effects of neck radiation therapy on extra-cranial carotid arteries atherosclerosis disease prevalence: systematic review and a meta-analysis.

INTRODUCTION: Radiation arteritis following neck irradiation as a treatment for head and neck malignancy has been well documented. The long-term sequelae of radiation exposure of the carotid arteries may take years to manifest clinically, and extra-cranial carotid artery (ECCA) stenosis is a well-recognised vascular complication. These carotid lesions should not be regarded as benign and should be treated in the same manner as standard carotid stenosis. Previous studies have noted increased cerebrovascular events such as stroke in this cohort of patients because of high-grade symptomatic carotid stenosis resulting in emboli. AIM: To evaluate the effect of radiation therapy on ECCA atherosclerosis progression. METHODS: Online search for case-control studies and randomised clinical trials that reported on stenosis in extra-cranial carotid arteries in patients with neck malignancies who received radiation therapy (RT) comparing them to patients with neck malignancies who did not receive RT. RESULTS: Eight studies were included in the final analysis with total of 1070 patients - 596 received RT compared to 474 in the control group. There was statistically significant difference in overall stenosis rate (Pooled risk ratio  =  4.38 [2.98, 6.45], P  =  0.00001) and severe stenosis (Pooled risk ratio  =  7.51 [2.78, 20.32], P <0.0001), both being higher in the RT group. Pooled analysis of the five studies that reported on mild stenosis also showed significant difference (Pooled risk ratio  =  2.74 [1.75, 4.30], 95% CI, P  =  0.0001). CONCLUSION: The incidence of severe ECCA stenosis is higher among patients who received RT for neck malignancies. Those patients should be closely monitored and screening programs should be considered in all patients who receive neck RT.

Role of far infra-red therapy in dialysis arterio-venous fistula maturation and survival: systematic review and meta-analysis.

INTRODUCTION: A well-functioning arteriovenous fistula (AVF) is the best modality for vascular access in patients with end-stage renal disease (ESRD) requiring haemodialysis (HD). However, AVFs' main disadvantage is the high rate of maturation failure, with approximately one third (20%-50%) not maturing into useful access. This review examine the use of Far-Infra Red therapy in an attempt to enhance both primary (unassisted) and secondary (assisted) patency rates for AVF in dialysis and pre-dialysis patients. METHOD: We performed an online search for observational studies and randomised controlled trials (RCTs) that evaluated FIR in patients with AVF. Eligible studies compared FIR with control treatment and reported at least one outcome measure relating to access survival. Primary patency and secondary patency rates were the main outcomes of interest. RESULTS: Four RCTs (666 patients) were included. Unassisted patency assessed in 610 patients, and was significantly better among those who received FIR (228/311) compared to (185/299) controls (pooled risk ratio of 1.23 [1.12-1.35], p = 0.00001). In addition, the two studies which reported secondary patency rates showed significant difference in favour of FIR therapy--160/168 patients--compared to 140/163 controls (pooled risk ratio of 1.11 [1.04-1.19], p = 0.003). CONCLUSION: FIR therapy may positively influence the complex process of AVF maturation improving both primary and secondary patency rates. However blinded RCTs performed by investigators with no commercial ties to FIR therapy technologies are needed.