Efficacy and immunologic effects of extracorporeal photopheresis plus interleukin-2 in chronic graft-versus-host disease.

Chronic graft-versus-host disease (cGVHD) affects >50% of hematopoietic stem cell transplant patients. Extracorporeal photopheresis (ECP), an immunomodulatory therapy, provides clinical benefit in steroid-refractory (SR) cGVHD, possibly via regulatory T (Treg) and natural killer (NK) cell expansion. We demonstrated that low-dose interleukin-2 (IL2) led to clinical improvement in SR-cGVHD and stimulated preferential Treg and NK-cell expansion with minimal effect on conventional T (Tcon) cells. We evaluated the effect of ECP (weeks 1-16) plus IL2 (1 × 106 IU/m2, weeks 9-16) in 25 adult patients with SR-cGVHD in a prospective phase 2 trial. Objective responses occurred in 29% and 62% of evaluable patients at weeks 8 (ECP alone) and 16 (ECP plus IL2), respectively. Eight weeks of ECP alone was associated with a marked decline in CD4+ Tcon (P = .03) and CD8+ T cells (P = .0002), with minimal change in Treg cells, Treg:Tcon cell ratio, or NK cells. Adding IL2 induced an increase in Treg cells (P < .05 at weeks 9-16 vs week 8), Treg:Tcon cell ratio (P < .0001 at weeks 9-16 vs week 8), and NK cells (P < .05 at weeks 9-16 vs week 8). Patients responding to ECP alone had significantly fewer CD4+ Tcon and CD8+ T cells at baseline compared with patients who responded after IL2 addition and patients who did not respond; neither Treg nor NK cells were associated with response to ECP alone. Altogether, ECP plus IL2 is safe and effective in patients with SR-cGVHD. ECP and IL2 have distinct immunologic effects, suggesting different therapeutic mechanisms of action. This trial was registered at www.clinicaltrials.gov as #NCT02340676.

Dose-escalated interleukin-2 therapy for refractory chronic graft-versus-host disease in adults and children.

Low-dose interleukin-2 (IL-2) therapy for chronic graft-versus-host disease (cGVHD) generates a rapid rise in plasma IL-2 levels and CD4+CD25+CD127-Foxp3+ regulatory T-cell (CD4Treg) proliferation, but both decrease over time despite continued daily administration. To test whether IL-2 dose escalation at the time of anticipated falls in plasma levels could circumvent tachyphylaxis and enhance CD4Treg expansion, we conducted a phase 1 trial in 10 adult and 11 pediatric patients with steroid-refractory cGVHD (www.clinicaltrials.gov: NCT02318082). Daily IL-2 was initiated in children and adults (0.33 × 106 and 0.67 × 106 IU/m2 per day, respectively). Dose escalations were scheduled at weeks 2 and 4 to a maximum dose of 1 × 106 IU/m2 per day in children and 2 × 106 IU/m2 per day in adults. Patients continued at their maximum tolerated dose (MTD) until week 8. Children tolerated IL-2 dose escalation with partial responses (PRs) in 9 of 11 patients (82%) at multiple cGVHD sites, including lung. Patient-reported outcome scores for skin and lung improved significantly in pediatric patients. In contrast, 5 of 10 adults required dose reduction, and only 2 of 7 evaluable patients (29%) had PRs at week 8. CD4Tregs and natural killer cells expanded in both cohorts without significant changes in conventional CD4+ T cells (Tcons) or CD8+ T cells. Children achieved a higher median CD4Treg/Tcon ratio at week 8 (0.4 vs 0.18, P = .02) despite lower IL-2 doses. We show for the first time that low-dose IL-2 is safe and effective in children with advanced cGVHD. In adults, escalation above the previously defined MTD did not improve CD4Treg expansion or clinical response.

Analysis of risk factors for occlusions of a synthetic femoropopliteal bypass graft.

BACKGROUND/AIM: Femoropopliteal bypass is a revascularization technique of lower extremities with excellent outcome. The great saphenous vein is the best graft material, but if it is not adequate or has been removed, synthetic grafts are an useful alternative. Graft occlusion is the most significant complication with the most serious consequences. The aim of this study was to analyse predictive factors for the synthetic femoropopliteal bypass occlusions. METHODS: This retrospective case-control study included all patients who underwent synthetic femoropopliteal bypass due to peripheral arterial occlusive disease at the Vascular Surgery Center, Clinical Center of Kragujevac, Serbia, from 2007 to 2013. The cases group were the patients with femoropopliteal graft occlusion (n = 44), with the control group consisted of the patients without such an outcome (n = 88). RESULTS: Significant effects to occlusion were: concomitant cardiovascular disease (adjustedOR 27.05; 95% CI 4.74; 154.35), a type of femoropopliteal bypass (adjustedOR 16.50; 95% CI 4.05; 67.24), previous vascular intervention (adjustedOR 4.67; 95% CI 1.20; 18.14), clinical stage of the disease (adjustedOR 3.73; 95% CI 1.94; 7.18), administration of postoperative oral anticoagulant therapy (adjustedOR 0.05; 95% CI 0.01; 0.23) and the use of angiotensin converting enzyme inhibitors (adjustedOR 0.14; 95% CI 0.03; 0.70). A significant synergism was shown for the following combinations of the observed risk factors: type of femoropopliteal bypass and cardiovascular disease, type of femoropopliteal bypass and previous vascular intervention, previous vascular intervention and cardiovascular disease, previous vascular intervention and beta blockers, cardiovascular disease and diabetes, type of femoropopliteal bypass and antiaggregant therapy, clinical stage of disease and cardiovascular disease, previous vascular intervention and antiaggregant therapy. CONCLUSION: Concomitant cardiovascular disease, below-knee femoropopliteal bypass, advanced stage of vascular disease and non-use of anticoagulant therapy and angiotensin-converting enzyme inhibitors are the significant predictors of graft occlusion after synthetic femoropopliteal bypass. Their synergistic effect determines the importance of diabetes, use of beta blockers and platelet antiaggregant therapy.

Correlational analysis of 5 commonly used measures of cognitive functioning and mental status: an update.

There are numerous measures for detecting the presence of dementia and quantifying its severity and progression. We analyzed the relations between scores on 5 commonly used measures (Mini-Mental State Examination, Montreal Cognitive Assessment, Alzheimer's Disease Assessment Scale-Cognitive Subscale, Activities of Daily Living Scale, and Global Deterioration Scale) of 101 successive admissions to a memory clinic. Patients were included in the analysis only if they received a diagnosis of mild cognitive impairment (MCI) due to Alzheimer's disease (AD) pathophysiological process or probable AD and if they received all measures. Regression analysis yielded 20 linear equations that allow for conversion between test scores on any 2 measures. Further, participants were grouped by MMSE scores with regard to level of disease severity, allowing for the creation of a quick reference table for estimating an approximate score range between measures. Results from this study provide a useful tool for clinicians when comparing between multiple different instruments that measure the mental status and functional ability of individuals with AD and MCI due to AD pathology.