Post-Transplant High-Dose Cyclophosphamide for the Prevention of Graft-versus-Host Disease

AbstractCyclophosphamide's lack of hematopoietic stem cell toxicity and its unique effects on the immune system have prompted several investigators to explore its potential for the prevention of graft-versus-host disease (GVHD). In haploidentical hematopoietic stem cell transplants, post-transplant cyclophosphamide together with standard prophylaxis reduces the incidence of GVHD to acceptable rates without the need for T cell depletion. In matched related and unrelated donor settings, cyclophosphamide alone has produced encouraging results. In particular, the low incidence of chronic GVHD is noteworthy. Here, we present a review of the current understanding of the mechanism of action of post-transplant cyclophosphamide and summarize the clinical data on its use for the prevention of GVHD

Post-Transplant High-Dose Cyclophosphamide for the Prevention of Graft-versus-Host Disease

Cyclophosphamide\u27s lack of hematopoietic stem cell toxicity and its unique effects on the immune system have prompted several investigators to explore its potential for the prevention of graft-versus-host disease (GVHD). In haploidentical hematopoietic stem cell transplants, post-transplant cyclophosphamide together with standard prophylaxis reduces the incidence of GVHD to acceptable rates without the need for T cell depletion. In matched related and unrelated donor settings, cyclophosphamide alone has produced encouraging results. In particular, the low incidence of chronic GVHD is noteworthy. Here, we present a review of the current understanding of the mechanism of action of post-transplant cyclophosphamide and summarize the clinical data on its use for the prevention of GVHD

Short Course of Post-Transplantation Cyclophosphamide and Bortezomib for Graft-versus-Host Disease Prevention after Allogeneic Peripheral Blood Stem Cell Transplantation Is Feasible and Yields Favorable Results: A Phase I Study

AbstractAn effective graft-versus-host disease (GVHD) preventative approach that preserves the graft-versus-tumor effect after allogeneic hematopoietic stem cell transplantation (HSCT) remains elusive. Standard GVHD prophylactic regimens suppress T cells indiscriminately and are suboptimal. Conversely, post-transplantation high-dose cyclophosphamide selectively destroys proliferating alloreactive T cells, allows the expansion of regulatory T cells, and induces long-lasting clonal deletion of intrathymic antihost T cells. It has been successfully used to prevent GVHD after allogeneic HSCT. Bortezomib has antitumor activity on a variety of hematological malignancies and exhibits a number of favorable immunomodulatory effects that include inhibition of dendritic cells. Therefore, an approach that combines post-transplantation cyclophosphamide and bortezomib seems attractive. Herein, we report the results of a phase I study examining the feasibility and safety of high-dose post-transplantation cyclophosphamide in combination with bortezomib in patients undergoing allogeneic peripheral blood HSCT from matched siblings or unrelated donors after reduced-intensity conditioning. Cyclophosphamide was given at a fixed dose (50 mg/kg on days +3 and +4). Bortezomib dose was started at .7 mg/m2, escalated up to 1.3 mg/m2, and was administered on days 0 and +3. Patients receiving grafts from unrelated donors also received rabbit antithymocyte globulin. The combination was well tolerated and allowed prompt engraftment in all patients. The incidences of acute GVHD grades II to IV and grades III and IV were 20% and 6.7%, respectively. With a median follow-up of 9.1 months (range, 4.3 to 26.7), treatment-related mortality was 13.5% with predicted 2-year disease-free survival and overall survival of 55.7% and 68%, respectively. The study suggests that the combination of post-transplantation cyclophosphamide and bortezomib is feasible and may offer an effective and practical GVHD prophylactic regimen. The combination, therefore, merits further examination

Factors Associated with Revision Surgery after Internal Fixation of Hip Fractures

Background: Femoral neck fractures are associated with high rates of revision surgery after management with internal fixation. Using data from the Fixation using Alternative Implants for the Treatment of Hip fractures (FAITH) trial evaluating methods of internal fixation in patients with femoral neck fractures, we investigated associations between baseline and surgical factors and the need for revision surgery to promote healing, relieve pain, treat infection or improve function over 24 months postsurgery. Additionally, we investigated factors associated with (1) hardware removal and (2) implant exchange from cancellous screws (CS) or sliding hip screw (SHS) to total hip arthroplasty, hemiarthroplasty, or another internal fixation device. Methods: We identified 15 potential factors a priori that may be associated with revision surgery, 7 with hardware removal, and 14 with implant exchange. We used multivariable Cox proportional hazards analyses in our investigation. Results: Factors associated with increased risk of revision surgery included: female sex, [hazard ratio (HR) 1.79, 95% confidence interval (CI) 1.25-2.50; P = 0.001], higher body mass index (fo

Applying the Strategic Plan to Incorporate Service Learning into the Classroom

Students enrolled in a Professional Writing course at the University of Louisiana at Monroe create PowerPoint presentations each semester for non-profit organizations; this semester the class is working with a local animal charity organization. The presentation details why incorporating service learning into a class benefits the university, the community, the students, and the instructor. The assignment sheet and activities are shared in the presentation

Applying the Strategic Plan to Incorporate Service Learning into the Classroom

Students enrolled in a Professional Writing course at the University of Louisiana at Monroe create PowerPoint presentations each semester for non-profit organizations; this semester the class is working with a local animal charity organization. The presentation details why incorporating service learning into a class benefits the university, the community, the students, and the instructor. The assignment sheet and activities are shared in the presentation

Evaluating the Facilitating Attuned Interactions (FAN) Approach: Vicarious Trauma, Professional Burnout, and Reflective Practice

Background: This evaluation examined the use of the Facilitated Attuned Interaction (FAN) approach to reflective practice among child welfare and early childhood professionals working with vulnerable children and families. Objective: The aims of the current evaluation were to test (a) the role of vicarious trauma in predicting professional burnout, (b) the effect of reflective practice quality in decreasing professional burnout, and (c) the ability of reflective practice quality to lessen the relationship between vicarious trauma and professional burnout. Participants and Setting: The sample included sixty-three professionals across diverse professions including child welfare social workers, early childhood educators, and child welfare attorneys. Methods: Child welfare and early childhood professionals participating in reflective practice with consultants trained in the FAN approach to reflective practice completed surveys measuring their vicarious trauma, burnout, and the quality of reflective practice pre-intervention as well as nine months post-intervention. Results: Results indicated that pre-intervention vicarious trauma directly and significantly increased child welfare and early childhood professionals’ post-intervention reports of professional burnout, β = 0.42, [95% CI: 0.08, 0.76]. Post-intervention reflective practice quality did not directly nor significantly reduce professionals’ post-intervention reports of professional burnout, β = −0.06, [95% CI: −0.46, 0.36]; however, the relationship between pre-intervention vicarious trauma and post-intervention burnout was significantly diminished by positive perceptions of reflective practice quality, β = −0.36, [95% CI: −0.69, −0.02]. Conclusion: Vicarious trauma was associated with increased rates of professional burnout among child welf essionals. The current evaluation indicates the potential benefit of receiving high quality reflective practice with the FAN approach

ss3sim: An R Package for Fisheries Stock Assessment Simulation with Stock Synthesis

Simulation testing is an important approach to evaluating fishery stock assessment methods. In the last decade, the fisheries stock assessment modeling framework Stock Synthesis (SS3) has become widely used around the world. However, there lacks a generalized and scriptable framework for SS3 simulation testing. Here, we introduce ss3sim, an R package that facilitates reproducible, flexible, and rapid end-to-end simulation testing with SS3. ss3sim requires an existing SS3 model configuration along with plain-text control files describing alternative population dynamics, fishery properties, sampling scenarios, and assessment approaches. ss3sim then generates an underlying ‘truth’ from a specified operating model, samples from that truth, modifies and runs an estimation model, and synthesizes the results. The simulations can be run in parallel, reducing runtime, and the source code is free to be modified under an open-source MIT license. ss3sim is designed to explore structural differences between the underlying truth and assumptions of an estimation model, or between multiple estimation model configurations. For example, ss3sim can be used to answer questions about model misspecification, retrospective patterns, and the relative importance of different types of fisheries data. We demonstrate the software with an example, discuss how ss3sim complements other simulation software, and outline specific research questions that ss3sim could address

Post-Transplantation Cyclophosphamide and Ixazomib Combination Rescues Mice Subjected to Experimental Graft-versus-Host Disease and Is Superior to Either Agent Alone

Lapses in the prevention of graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation (HSCT) warrant novel approaches. Such approaches include, among others, the use of post-transplantation cyclophosphamide (PTC) and proteasome inhibitors. Although PTC alone consistently produces low rates of chronic GVHD, the incidence of acute GVHD remains significant. Inversely, prolonged post-transplantation administration of proteasome inhibitors carries a risk of paradoxical aggravation of GVHD. We examined whether the combination of cyclophosphamide and ixazomib addresses the limitations of each of these agents when used alone to prevent GVHD in mice subjected to allogeneic HSCT across MHC barriers. We chose ixazomib, an orally bioavailable proteasome inhibitor, because of its favorable physiochemical characteristics. The combination of cyclophosphamide and ixazomib improved overall survival of mice in comparison to an untreated control group and to groups receiving either cyclophosphamide alone or ixazomib alone. Furthermore, cyclophosphamide prevented the surge of IL-1β, GVHD aggravation, and sudden death associated with prolonged administration of ixazomib after HSCT. Finally, we demonstrated that although ixazomib was administered before cyclophosphamide, it did not impair the preferential depletion of proliferating as opposed to resting donor T cells. Our data suggest that the combination of cyclophosphamide and ixazomib for the prevention of GVHD after allogeneic HSCT is promising and merits further investigation in clinical trials