Recommendations for procurement of starting materials by apheresis for advanced therapy medicinal products.

Activities involved in the production of certain advanced therapy medicinal products (ATMPs) require standardized approaches to mononuclear cell procurement to ensure the highest product quality, safety and process efficiency. These aims must be achieved while meeting regulatory and accreditation requirements for the procurement of mononuclear cells as starting materials. Mononuclear cells constitute the starting materials for many ATMPs, and this article sets out recommendations for procurement by clinical apheresis, addressing the variation among existing working practices and different manufacturers' requirements that currently poses a challenge when managing multiple different protocols.

The role of extracorporeal photopheresis in the management of cutaneous T-cell lymphoma, graft-versus-host disease and organ transplant rejection: a consensus statement update from the UK Photopheresis Society.

Extracorporeal photopheresis (ECP) has been used for over 35 years in the treatment of erythrodermic cutaneous T-cell lymphoma (CTCL) and over 20 years for chronic and acute graft-versus-host disease (GvHD) and solid organ transplant rejection. ECP for CTCL and GvHD is available at specialised centres across the UK. The lack of prospective randomised trials in ECP led to the development of UK Consensus Statements for patient selection, treatment schedules, monitoring protocols and patient assessment criteria for ECP. The recent literature has been reviewed and considered when writing this update. Most notably, the national transition from the UVAR XTS® machine to the new CELLEX machine for ECP with dual access and a shorter treatment time has led to relevant changes in these schedules. This consensus statement updates the previous statement from 2007 on the treatment of CTCL and GvHD with ECP using evidence based medicine and best medical practise and includes guidelines for both children and adults.

Impact of severe chronic kidney disease on outcomes of infrainguinal peripheral arterial intervention.

OBJECTIVE: Patients with severe chronic kidney disease (CKD) and peripheral vascular disease are at increased risk of major adverse limb events (MALEs) and death; however, patients with end-stage renal disease have been excluded in current objective performance goals. We evaluated the effect of severe (class 4 and 5) CKD on outcomes after infrainguinal endovascular arterial interventions. METHODS: All primary peripheral vascular interventions (PVIs) performed at a single institution (January 2002 through December 2009) were included. End points were defined by Society for Vascular Surgery objective performance goals for critical limb ischemia (CLI), which include all-cause mortality, reintervention, and composite end points of death or amputation and MALEs (reintervention or amputation). Univariate and multivariable analysis was used to examine the effect of severe CKD on study end points. RESULTS: A total of 879 PVIs were performed, with severe CKD in 125 (14%). Severe CKD patients were significantly (P < .05) more likely to have diabetes (64% vs 46%), CLI (72% vs 11%), and need a multilevel PVI (34% vs 19%) or tibial intervention (35% vs 20%) compared with the remainder of the cohort. Distribution of TransAtlantic Inter-Society Consensus C and D lesions were similar (19% severe CKD vs 15%; P = .2). Severe CKD predicted perioperative (30-day) reintervention (odds ratio [OR], 2.3; 95% confidence interval [CI], 1.5-4; P = .05), amputation or death (OR, 3.1; 95% CI, 1.1-9; P = .04), and MALEs (OR, 2.8; 95% CI, 1.3-6.1; P = .04), which was independent of CLI in multivariable regression analysis. On Kaplan-Meier analysis, severe CKD was significantly (log-rank P < .05) associated with death (31% ± 4% vs 7% ± 1%), amputation (14% ± 3% vs 3% ± 1%), and MALEs (40% ± 5% vs 26% ± 2%) at 1 year. Freedom from reintervention was similar at 1 year (70% ± 5% severe CKD vs 75% ± 2%; P = .23). Risk-adjusted (age, CLI, diabetes, coronary artery disease) Cox proportional hazards regression showed that severe CKD increased the risk of late mortality (hazard ratio [HR], 2.4; 95% CI, 1.8-3.2; P < .01), amputation (HR, 2.1; 95% CI, 1.1-3.9; P = .02), and death or amputation (HR, 1.8; 95% CI, 1.3-2.4; P = .04), without increasing the risk of late reinterventions or MALEs. CONCLUSIONS: CKD independently predicts early and late adverse events after a PVI, in particular, excessive mortality. CKD should figure prominently in clinical decision making for patients with peripheral vascular disease.

Postexercise phosphocreatine recovery, an index of mitochondrial oxidative phosphorylation, is reduced in diabetic patients with lower extremity complications.

OBJECTIVE: To identify differences in postexercise phosphocreatine (PCr) recovery, an index of mitochondrial function, in diabetic patients with and without lower extremity complications. METHODS: We enrolled healthy control subjects and three groups of patients with type 2 diabetes mellitus: without complications, with peripheral neuropathy, and with both peripheral neuropathy and peripheral arterial disease. We used magnetic resonance spectroscopic measurements to perform continuous measurements of phosphorous metabolites (PCr and inorganic phosphate [Pi]) during a 3-minute graded exercise at the level of the posterior calf muscles (gastrocnemius and soleus muscles). Micro- and macrovascular reactivity measurements also were performed. RESULTS: The resting Pi/PCr ratio and PCr at baseline and the maximum reached during exercise were similar in all groups. The postexercise time required for recovery of Pi/PCr ratio and PCr levels to resting levels, an assessment of mitochondrial oxidative phosphorylation, was significantly higher in diabetic patients with neuropathy and those with both neuropathy and peripheral arterial disease (P < .01 for both measurements). These two groups also had higher levels of tumor necrosis factor-α (P < .01) and granulocyte colony-stimulating factor (P < .05). Multiple regression analysis showed that only granulocyte colony-stimulating factor, osteoprotegerin, and tumor necrosis factor-α were significant contributing factors in the variation of the Pi/PCr ratio recovery time. No associations were observed between micro- and macrovascular reactivity measurements and Pi/PCr ratio or PCr recovery time. CONCLUSIONS: Mitochondrial oxidative phosphorylation is impaired only in type 2 diabetes mellitus patients with neuropathy whether or not peripheral arterial disease is present and is associated with the increased proinflammatory state observed in these groups.

Late outcomes of balloon angioplasty and angioplasty with selective stenting for superficial femoral-popliteal disease are equivalent.

OBJECTIVE: Several trials have reported early superior patency of stenting over isolated angioplasty (plain old balloon angioplasty [POBA]) for infra-inguinal occlusive disease, yet long-term data are sparse. The purpose of this study was to contrast long-term clinical outcomes and costs of angioplasty alone vs angioplasty with selective stenting in the treatment of femoropopliteal occlusive disease. METHODS: Patients undergoing primary endovascular treatments of the native femoropopliteal arteries from 2002 to 2009 were divided into two groups, POBA alone or stenting based on final treatment received at their index procedure. Study end points included actuarial 5-year primary patency (using strict criteria of any hemodynamic deterioration or return of symptoms), 5-year limb salvage, and 5-year survival and hospital costs. RESULTS: Eight hundred twenty-four primary procedures were performed during the study interval; 517 (63%) were POBA and 307 (37%) were stenting. The mean follow-up duration was 33 months (range, 0-98 months). The indication for intervention in the stenting group was claudication in 71% of the patients, whereas the remaining 29% had critical limb ischemia (CLI). In the POBA cohort, the indication for treatment was claudication in 59% of the patients and CLI in the remaining 41%. A higher percentage of POBA lesions were TransAtlantic Inter-Society Consensus (TASC) II A & B when compared to stenting (91% POBA vs 73% stenting; P < .001). There was no difference in overall 5-year primary patency (POBA 36% ± 3%; stenting 41% ± 4%; P = .31), nor was there a difference in patients with claudication (POBA 42% ± 4%; stenting 45% ± 4%; P = .8). In patients with CLI, the 4-year primary patency was 27% ± 5% (POBA) vs 36% ± 8% (stenting), P = .22; the 4-year limb salvage was 80% ± 4% (POBA) vs 90% ± 5% (stenting), P = .18. There was no difference in survival between the two groups (claudication: 83% ± 3% POBA vs 84% ± 4% stenting at 5 years (P = .65), CLI: 44% ± 4% POBA vs 49% ± 6% stenting at 4 years (P = .40). Subgroup analysis by lesion anatomy showed similar primary patency between POBA and stenting for TASC II A & B lesions, while the primary patency was significantly higher at 5 years after stenting of TASC II C & D lesions (34% ± 6% vs 12% ± 9%; P < .05). Stenting increased the procedural cost by 57% when compared to POBA (P < .001) regardless of treatment indication. In addition, stenting added 45% (P < .001) to the overall hospital cost of patients treated for claudication. CONCLUSION: Stenting resulted in equivalent long-term outcomes compared to POBA when stratified by indications. However, stenting yielded statistically better primary patency in patients with TASC II C & D lesions. The lack of improved clinical outcomes and significantly higher cost of stenting supports a posture of selective use of stents (especially in TASC II A & B) in the endovascular treatment of femoropopliteal occlusive disease.

Secondary intervention after endovascular abdominal aortic aneurysm repair.

OBJECTIVE: Endovascular Abdominal Aortic Aneurysm Repair (EVAR) has been criticized because of the need for frequent secondary interventions (2ndINT) to maintain effective abdominal aortic aneurysm (AAA) exclusion. The study goal is to detail such interventions and determine their effect on clinical outcomes. METHODS: From January 1997 to December 2007, 832 patients underwent EVAR. Those requiring 2ndINT were stratified according to the indications and specific nature of 2ndINT and treatment. Study endpoints included freedom from 2ndINT, aneurysm-related and overall survival. RESULTS: There were 91 (11%) patients who underwent 131 2ndINT (mean follow-up 35 months). No demographic features (age, gender, etc) predicted the need for 2ndINT. Actuarial 5-year freedom from 2ndINT was 80%. Indications for 2ndINT included: sac rupture 5 (4%), graft migration/ type I endoleak 37 (28%), persistent type II endoleak 40 (38%), endotension with sac growth 5 (4%), and limb occlusion/kinking 24 (18%). The majority of 2ndINT were accomplished with an endovascular approach (76%) with a >80% initial success rate for all indications except type II endoleak in which the initial intervention was successful only 34% of the time. Initial 2ndINT were successful in 62% and 35 (38%) patients underwent more than one 2ndINT. Multivariate predictors of 2ndINT were AAA sac size >5.5cm (OR = 2.1, P = 0.004), and preprocedure coil embolization (hypogastric or inferior mesenteric artery) (OR = 2.1, P = 0.008). The actuarial survival was 70% at 5 years and the aneurysm-related survival was 97.5% with no difference in either parameter in patients who underwent 2ndINT compared with those who did not. CONCLUSIONS: Although 2ndINT are common after EVAR, most were addressed through an endovascular approach; technical success thereof varies widely with the specific indication for 2ndINT. Secondary intervention did not adversely affect aneurysm-related or overall actuarial 5-year survival.