Low non-relapse mortality and long-term preserved quality of life in older patients undergoing matched related donor allogeneic stem cell transplantation: a prospective multicenter phase II trial

Allogeneic transplantation is a challenge in patients of advanced age because of a high risk of non-relapse mortality and potential long-lasting impairment of health-related quality of life. The development of reduced-intensity conditioning regimens has allowed the use of allogeneic transplantation in this population, but the optimal regimen remains undefined. We conducted a multicenter phase II trial evaluating the safety and efficacy of a reduced-intensity conditioning regimen combining fludarabine, intravenous busulfan, and rabbit antithymocyte globulins in patients older than 55 years of age transplanted from matched-related donor. In addition, health-related quality of life was prospectively measured. Seventy-five patients with a median age of 60 years (range 55–70) were analyzed. Grade III-IV acute and extensive chronic graft-versus-host diseases were found in 3% and 27% of patients, respectively. The day 100 and 1-year non-relapse mortality incidences were 1% and 9%, respectively. The cumulative incidences of relapse, progression-free survival and overall survival at two years were 36%, 51% and 67%, respectively, with a median follow up of 49 months. Global health-related quality of life, physical functioning, emotional functioning, and social functioning were not impaired compared to baseline for more than 75% of the patients (75%, 81.4%, 82.3%, and 75%, respectively). Thirty-four of the 46 (74%) progression-free patients at one year were living without persistent extensive chronic graft-versus-host disease. We conclude that the reduced-intensity conditioning regimen combining fludarabine, intravenous busulfan, and rabbit antithymocyte globulins is well tolerated in patients older than 55 years with low non-relapse mortality and long-term preserved quality of life.     

Fitbit Flex: an unreliable device for longitudinal sleep measures in a non-clinical population

Sleep and Breathing -     

Human longevity is influenced by many genetic variants: evidence from 75,000 UK Biobank participants

Variation in human lifespan is 20 to 30% heritable in twins but few genetic variants have been identified. We undertook a Genome Wide Association Study (GWAS) using age at death of parents of middle-aged UK Biobank participants of European decent (n=75,244 with father''s and/or mother''s data, excluding early deaths). Genetic risk scores for 19 phenotypes (n=777 proven variants) were also tested. In GWAS, a nicotine receptor locus (CHRNA3, previously associated with increased smoking and lung cancer) was associated with fathers'' survival. Less common variants requiring further confirmation were also identified. Offspring of longer lived parents had more protective alleles for coronary artery disease, systolic blood pressure, body mass index, cholesterol and triglyceride levels, type-1 diabetes, inflammatory bowel disease and Alzheimer''s disease. In candidate analyses, variants in the TOMM40/APOE locus were associated with longevity, but FOXO variants were not. Associations between extreme longevity (mother >=98 years, fathers >=95 years, n=1,339) and disease alleles were similar, with an additional association with HDL cholesterol (p=5.7×10-3). These results support a multiple protective factors model influencing lifespan and longevity (top 1% survival) in humans, with prominent roles for cardiovascular-related pathways. Several of these genetically influenced risks, including blood pressure and tobacco exposure, are potentially modifiable.     

Pathogenesis of hyperostosis: A key role for mesenchymatous cells?

The similarities between diffuse idiopathic skeletal hyperostosis (DISH) and some forms of ankylosing spondylitis suggest shared pathogenic mechanisms. Entheseal ossification progresses at the same rate in the two conditions, and spondyloarthritis was the first diagnosis considered in several families with genetically determined early-onset DISH. However, DISH may be a heterogeneous condition, as the presence of peripheral calcifications in some families suggests pathogenic similarities with several animal models combining entheseal ossification and peripheral calcifications, as well as with X-linked familial hypophosphatemia and dentin-matrix-protein mutations. In the far more common presentation of hyperostosis without calcifications, entheseal ossification may be related to abnormal osteoblastic differentiation of mesenchymatous stem cells normally found around the intervertebral disks, in the vertebral periosteum, and in the anterior and posterior longitudinal ligaments. The many factors suspected of promoting this abnormal differentiation include bone morphogenetic proteins (BMPs), retinoids, and various hormonal factors; in addition, adipokines such as leptin are the focus of growing interest based on the well-documented association between DISH and obesity. Confirmation of the role for mesenchymatous cells in DISH should encourage investigations of mesenchymatous cells as possible pathogenic contributors to the entheseal abnormalities seen in spondyloarthritis. These cells normally exert immunosuppressive effects, which may be subverted in spondyloarthritis, notably by a T-cell population that homes specifically to the entheses.     

Side effects of corticosteroid injections: What's new?

The risk of sepsis with a hip or knee implant does not seem to be increased by prior joint injections, as long as the injection and surgery are separated by at least two months. Calcifications have been reported after intradiscal injection in the coccygeal region for coccydynia. Complete rest for 24 hours after injection of triamcinolone hexacetonide into the knee had no effect on systemic diffusion of the product. Patients infected by HIV who are treated with ritonavir are at much greater risk for Cushing syndrome after epidural injection. Problems with menstruation after corticosteroid injection seem to be related to a transient decrease in estradiol levels, without alterations in FSH and LH levels. The risk of central serous chorioretinopathy and acute necrosis of the retina after injection is not known, even by ophthalmologists. Transient dysphonia occurs in 12% of patients receiving corticosteroid injections. The impressive Tachon's syndrome seems to be the venous counterpart to Nicolau's syndrome for arteries. Injections into C1-C2 should be abandoned because of the neurological risks. Since serious neurological events after foraminal injections could be the result of an overly fast injection into the arterialized radicular veins rather than in the arteries, only slow injections with products having a low risk of embolism or vascular complications should be allowed. Dexamethasone-based preparations seem to contain no particles or crystals, and have not induced any neurological accidents in various animal models, even after direct administration into vertebral or carotid arteries.