Prior statistical models attempted to identify risk factors for time to distant brain failure (DBF) or time to salvage whole-brain radiation therapy (WBRT) to predict the benefit of early WBRT versus ...stereotactic radiosurgery (SRS) alone. We introduce a novel clinical metric, brain metastasis velocity (BMV), for predicting clinical outcomes after initial DBF following upfront SRS alone.
BMV was defined as the cumulative number of new brain metastases that developed over time since first SRS in years. Patients were classified by BMV into low-, intermediate-, and high-risk groups, consisting of <4, 4 to 13, and >13 new metastases per year, respectively. Histology, number of metastases at the time of first SRS, and systemic disease status were assessed for effect on BMV.
Of 737 patients treated at our institution with upfront SRS without WBRT, 286 had ≥1 DBF event. A lower BMV predicted for improved overall survival (OS) following initial DBF (log-rank P<.0001). Median OS for the low, intermediate, and high BMV groups was 12.4 months (95% confidence interval CI, 10.4-16.9 months), 8.2 months (95% CI, 5.0-9.7 months), and 4.3 months (95% CI, 2.6-6.7 months), respectively. Multivariate analysis showed that BMV remained the dominant predictor of OS, with a hazard ratio of 2.75 for the high BMV group (95% CI, 1.94-3.89; P<.0001) and a hazard ratio of 1.65 for the intermediate BMV group (95% CI, 1.18-2.30; P<.004). A lower BMV was associated with decreased rates of salvage WBRT (P=.02) and neurologic death (P=.008). Factors predictive for a higher BMV included ≥2 initial brain metastases (P=.004) and melanoma histology (P=.008).
BMV is a novel metric associated with OS, neurologic death, and need for salvage WBRT after initial DBF following upfront SRS alone.
The Apolipoprotein E gene (APOE) is of great interest due to its role as a risk factor for late-onset Alzheimer’s disease. ApoE is secreted by astrocytes in the central nervous system in high-density ...lipoprotein (HDL)-like lipoproteins. Structural models of lipidated ApoE of high resolution could aid in a mechanistic understanding of how ApoE functions in health and disease. Using monoclonal Fab and F(ab′)2 fragments, we characterize the structure of lipidated ApoE on astrocyte-secreted lipoproteins. Our results provide support for the “double-belt” model of ApoE in nascent discoidal HDL-like lipoproteins, where two ApoE proteins wrap around the nanodisc in an antiparallel conformation. We further show that lipidated, recombinant ApoE accurately models astrocyte-secreted ApoE lipoproteins. Cryogenic electron microscopy of recombinant lipidated ApoE further supports ApoE adopting antiparallel dimers in nascent discoidal lipoproteins.
•Astrocyte ApoE adopts an antiparallel dimer in discoidal lipoproteins•Recombinant ApoE adopts an antiparallel dimer in discoidal lipoproteins•Lipid composition affects lipoprotein diameter
Apolipoprotein E (ApoE) is the largest genetic risk factor for late-onset Alzheimer’s disease. Utilizing cryo-EM, Strickland et al. demonstrate important insights into the structure of lipidated ApoE. ApoE was found to adopt an antiparallel dimer in discoidal lipoproteins secreted by astrocytes and in artificially lipidated recombinant ApoE.
Harvesting of autografts results in donor site morbidities and is limited in scenarios such as large total body surface area burns. In these instances, coverage is increased by meshing grafts at the ...expense of delayed biologic closure. Moreover, graft meshing increases the likelihood of contraction and hypertrophic scarring, limits range of motion, and worsens cosmesis. Many tissue engineering technologies have touted the promise of adipose‐derived stem cells (ASCs) for burn wounds. The primary objective of the current study was to determine feasibility and efficacy of in situ ASC delivery via PEGylated fibrin (FPEG) hydrogels as adjuncts to meshed split thickness skin grafts in a porcine model. Deep partial thickness burns were created on the dorsum of anesthetized Yorkshire pigs, and subsequently debrided on post‐burn day 4. After debridement, wounds were treated with: split thickness skin grafts (STSG); meshed STSG (mSTSG); and mSTSG + FPEG with increasing doses of ASCs. We show that FPEG hydrogels can be delivered in situ to prevent the contraction seen after meshing of STSG. Moreover, ASCs delivered in FPEG dose‐dependently increase blood vessel size which significantly correlates with CD31 protein levels. The current study reports a dual‐action adjunct therapy to autografting administered in situ, wherein FPEG acts as both scaffolding to prevent contraction, and as a delivery vehicle for ASCs to accelerate angiogenesis. This strategy may be used to incorporate other biologics for generating tissue engineered products aimed at improving wound healing and minimizing donor sites or scarring. Stem Cells Translational Medicine 2018;7:360–372
Tissue engineering strategies have aimed to circumvent/reduce the need for grafting from donor sites to cover excised burn wounds. Often, grafts are meshed to increase coverage at the expense of increased contraction. Results of this study show that meshed grafts can be supplemented with adipose stem cells delivered in polyethylene glycol‐fibrin hydrogels. This adjunct therapy accelerates angiogenesis and reduces contraction of burn wounds. (Scale bars are 500, 20, 100, and 500 µm).
Highlights • In patients with a GBM, delay in RT >28 days after surgery does not worsen PFS or OS. • In patients with STR or biopsy, a delay in RT >28 days improves PFS. • In patients with STR or ...biopsy, a delay in RT >28 days improves OS.
Achieving tolerance of vascularized composite allografts (VCAs) would improve the risk-to-benefit ratio in patients who undergo this life-enhancing, though not lifesaving, transplant. Kidney ...cotransplantation along with a short course of high-dose immunosuppression enables tolerance of heart allografts across a full major histocompatibility complex (MHC) mismatch. In this study, we investigated whether tolerance of VCAs across full MHC disparities could be achieved in animals already tolerant of heart and kidney allografts.
Miniature swine that were tolerant of heart and/or kidney allografts long term underwent transplantation of myocutaneous VCA across the same MHC barrier. Before VCA transplant, group 1 (n = 3) underwent class I-mismatched kidney transplantation; group 2 (n = 3) underwent 2 sequential class I-mismatched kidney transplantations; group 3 (n = 2) underwent haploidentical MHC-mismatched heart/kidney transplantation; and group 4 (n = 2) underwent full MHC-mismatched heart/kidney transplantation.
All 3 animals in group 1 and 2 of 3 animals in group 2 showed skin rejection within 85 days; 1 animal in group 2 showed prolonged skin survival longer than 200 days. Animals in groups 3 and 4 showed skin rejection within 30 days and regained in vitro evidence of donor responsiveness.
This is the first preclinical study in which hearts, kidneys, and VCAs have been transplanted into the same recipient. Despite VCA rejection, tolerance of heart and kidney allografts was maintained. These results suggest that regulatory tolerance of skin is possible but not generally achieved by the same level of immunomodulation that is capable of inducing tolerance of heart and kidney allografts. Achieving tolerance of skin may require additional immunomodulatory therapies.
In 2012 we reported promising results from a phase 2 clinical trial of HP802‐247, a novel spray‐applied investigational treatment for chronic venous leg ulcers consisting of human, allogeneic ...fibroblasts and keratinocytes. We now describe phase 3 clinical testing of HP802‐247, its failure to detect efficacy, and subsequent investigation into the root causes of the failure. Two randomized, controlled trials enrolled a total of 673 adult outpatients at 96 centers in North America and Europe. The primary endpoint was the proportion of ulcers with confirmed closure at the end of 12 weeks of treatment. An investigation into the root cause for the failure of HP802‐247 to show efficacy in these two phase 3 trials was initiated immediately following the initial review of the North American trial results. Four hundred twenty‐one patients were enrolled in the North American (HP802‐247, 211; Vehicle 210) and 252 in the European (HP802‐247, 131; Vehicle 121) trials. No difference in proportion of closed ulcers at week 12 was observed between treatment groups for either the North American (HP802‐247, 61.1%; Vehicle 60.0%; p = 0.5896) or the European (HP802‐247, 47.0%; Vehicle 50.0%; p = 0.5348) trials. Thorough investigation found no likelihood that design or execution of the trials contributed to the failure. Variability over time during the trials in the clinical response implicated the quality of the cells comprising HP802‐247. Concordance between the two separate, randomized, controlled trials with distinct, nonoverlapping investigative sites and independent monitoring teams renders the possibility of a Type II error vanishingly small and provides strong credibility for the unexpected lack of efficacy observed. The most likely causative factors for the efficacy failure in phase 3 was phenotypic change in the cells (primarily keratinocytes) leading to batch to batch variability due to the age of the cell banks.
February 27, 2002, allocation of cadaver livers for transplantation changed from a waiting-time—based system to an evidence-based system referred to as the Model for End-Stage Liver Disease (MELD). ...We reviewed data from 1 of the 11 United Network for Organ Sharing regions to determine the impact of the MELD on the allocation of cadaver livers for transplantation in that region. The region of interest (study region) consists of three distinct geographic areas (referred to as Transplant Service Areas TSAs). Based on information obtained from the Organ Procurement and Transplantation Network for the United States and for the study region, the following observations were made: (1) study region patients who received a cadaver liver had higher mean and median MELD scores than cadaver liver recipients in the United States (study region mean score, 25.1; median, 26.0; US mean score, 23.9; median, 24.0); (2) within the study region, TSAs with competing liver transplant programs performed transplantation on patients at a significantly higher mean MELD score than TSAs dominated by a single center (TSA-1 mean score, 27.3; TSA-2 mean score, 26.6; TSA-3 mean score, 21.3); this disparity persisted when transplantations for hepatocellular carcinoma (HCC) were excluded; and (3) study region patients removed from the waiting list because of death or being too sick for transplantation have higher MELD scores than the national average (study region mean score, 25.4; US mean score, 23.8). Overall, implementation of the MELD resulted in a substantial increase in the number of transplantations performed for HCC, and MELD exceptions for all reasons were more common in TSAs that have multiple centers. Despite the MELD, there remains disparity in organ allocation within the study region. The MELD may accurately predict pretransplantation mortality, but it does not ensure equitable organ distribution. We propose that intraregional sharing of cadaver livers based on the MELD may help limit disparities in organ allocation.
PDF
