Reducing the environmental impact of surgery on a global scale: systematic review and co-prioritization with healthcare workers in 132 countries

Background Healthcare cannot achieve net-zero carbon without addressing operating theatres. The aim of this study was to prioritize feasible interventions to reduce the environmental impact of operating theatres. Methods This study adopted a four-phase Delphi consensus co-prioritization methodology. In phase 1, a systematic review of published interventions and global consultation of perioperative healthcare professionals were used to longlist interventions. In phase 2, iterative thematic analysis consolidated comparable interventions into a shortlist. In phase 3, the shortlist was co-prioritized based on patient and clinician views on acceptability, feasibility, and safety. In phase 4, ranked lists of interventions were presented by their relevance to high-income countries and low–middle-income countries. Results In phase 1, 43 interventions were identified, which had low uptake in practice according to 3042 professionals globally. In phase 2, a shortlist of 15 intervention domains was generated. In phase 3, interventions were deemed acceptable for more than 90 per cent of patients except for reducing general anaesthesia (84 per cent) and re-sterilization of ‘single-use’ consumables (86 per cent). In phase 4, the top three shortlisted interventions for high-income countries were: introducing recycling; reducing use of anaesthetic gases; and appropriate clinical waste processing. In phase 4, the top three shortlisted interventions for low–middle-income countries were: introducing reusable surgical devices; reducing use of consumables; and reducing the use of general anaesthesia. Conclusion This is a step toward environmentally sustainable operating environments with actionable interventions applicable to both high– and low–middle–income countries

Reducing the environmental impact of surgery on a global scale: systematic review and co-prioritization with healthcare workers in 132 countries

Abstract Background Healthcare cannot achieve net-zero carbon without addressing operating theatres. The aim of this study was to prioritize feasible interventions to reduce the environmental impact of operating theatres. Methods This study adopted a four-phase Delphi consensus co-prioritization methodology. In phase 1, a systematic review of published interventions and global consultation of perioperative healthcare professionals were used to longlist interventions. In phase 2, iterative thematic analysis consolidated comparable interventions into a shortlist. In phase 3, the shortlist was co-prioritized based on patient and clinician views on acceptability, feasibility, and safety. In phase 4, ranked lists of interventions were presented by their relevance to high-income countries and low–middle-income countries. Results In phase 1, 43 interventions were identified, which had low uptake in practice according to 3042 professionals globally. In phase 2, a shortlist of 15 intervention domains was generated. In phase 3, interventions were deemed acceptable for more than 90 per cent of patients except for reducing general anaesthesia (84 per cent) and re-sterilization of ‘single-use’ consumables (86 per cent). In phase 4, the top three shortlisted interventions for high-income countries were: introducing recycling; reducing use of anaesthetic gases; and appropriate clinical waste processing. In phase 4, the top three shortlisted interventions for low–middle-income countries were: introducing reusable surgical devices; reducing use of consumables; and reducing the use of general anaesthesia. Conclusion This is a step toward environmentally sustainable operating environments with actionable interventions applicable to both high– and low–middle–income countries

Post-transplant day +100 MRD detection rather than mixed chimerism predicts relapses after allo-SCT for intermediate risk AML patients transplanted in CR.

BACKGROUND Chimerism and minimal residual disease (MRD) are suggested to be prognostic for post-transplant relapses in AML patients. Nevertheless, the predictive values of both approaches in homogeneous population remain underinvestigated. Here, we suggest that MRD may have a higher predictive value for relapses than mixed chimerism (MC) in intermediate risk AML patients. PATIENTS AND METHODS 79 patients with intermediate risk AML (male, n=40, median age, 57 (19-77)) were included. MRD detection on day +100 was performed in bone marrow (multiparameter flow cytometry and quantitative real-time PCR for NPM1-mutated patients). Chimerism analysis was measured in peripheral blood. MC was defined as persistence of <99.9% of donor alleles. RESULTS The area under the ROC curve was highest for qPCR-MRD (0.93) followed by MFC-MRD (0.80) and MC (0.65). The highest relapses at 3 years were observed in day +100 qPCR-MRD positive patients (100%) followed by MFC-MRD positive patients (55%, p<0.001). No patients with MC and without detectable MRD developed relapses. The 3-year OS and LFS for patients with MC without detectable MRD were both 86% (61-96%) compared with day +100 MFC-MRD positive (OS: 61%, 36-84%; LFS: 30%, 11-59%) and with day +100 qPCR-MRD positive patients (OS: 17%, 3-56%, p=0.001; LFS: 0%, p<0.001). CONCLUSIONS In intermediate-risk AML, the qPCR-MRD on day +100 is highly predictive for relapse and long-term survival after allo-SCT, closely followed by MFC-MRD. In contrast, the chimerism status has limited predictive potential. Thus, molecular and flow-cytometric MRD monitoring in the first months post-transplant rather than MC is able to identify patients with an increased relapse risk who may benefit from early post-transplant pre-emptive intervention

Enhanced immune reconstitution of γδ T cells after allograft overcomes negative impact of pre-transplant MRD positive status in AML patients.: γδ T cells and MRD+ AML.

BACKGROUND Minimal residual disease (MRD) prior to allogeneic stem cell transplantation (allo-SCT) in AML is a poor risk factor for outcome. The γδ T cells represents a unique minority lymphocyte population which is preferentially located in peripheral tissues, can recognize antigens in non-MHC restricted manner and plays a "bridging" role between innate and adaptive immune system. OBJECTIVES In this study, we investigated a potential graft-vs-leukaemia effect of γδ T cells reconstitution post-transplant in AML patients with pre-transplant positive minimal/measurable disease status (MRD+). STUDY DESIGN We investigated a potential graft-vs-leukaemia effect of γδ T cells reconstitution post-transplant in AML patients with pre-transplant positive MRD+. MRD assessment was performed in 202 patients (MRD+, n=100) with multicolored flow cytometry ("different from normal" strategy). Analysis for absolute concentrations of CD3+, CD4+, CD8+, NK, and γδ T cells were performed by flow cytometry according to an internal protocol at day +30 and +100 post-transplant. Differences between categorical and continuous variables were determined by Chi-square and Student's T-test, respectively. The Mann-Whitney test was used to compare medians of continuous variables. Spearman correlation was used for nonparametric assessment of correlation between different cell subsets during immune reconstitution. Kaplan Meier survival analysis and Cox regression analysis were used to investigate the associations between immune reconstitution and survival outcomes. Grays' analysis was used to compute incidences of relapses, non-relapse mortality (NRM) and graft-vs-host disease (GvHD). RESULTS Follow-up for survivors was 28 months (3-59). Younger age (≤58) of recipient and donor (<30), sex mismatch, matched donors, CMV reactivation and ATG were associated with a faster γδ T cell reconstitution. In multivariable analysis for MRD+ patients, higher than median level of γδ T cells on days +30 and +100 resulted in a significant improved leukaemia-free (HR 0.42, p=0.007 and HR 0.42, p=0.011, respectively) and overall survival (HR 0.44, p=0.038 and HR 0.33, p=0.009, respectively). Further, higher γδ T cell level on day +30 led to significant reduced risk of relapse (HR 0.36, p=0.019). No impact of γδ T cell level on day +30 and +100 could be seen in MRD- patients and no correlation with occurrence of graft-versus-host disease could be observed. CONCLUSION An enhanced immune reconstitution of γδ T cells post-transplant may overcome the higher relapse risk of pre-transplant MRD+ patients with AML

Post-Transplantation Multicolored Flow Cytometry–Minimal Residual Disease Status on Day 100 Predicts Outcomes for Patients With Refractory Acute Myeloid Leukemia

BACKGROUND Patients with relapsed/refractory AML have a dismal prognosis. Allogeneic stem cell transplantation (allo-SCT) provides a curative approach, however the overall survival (OS) remains low (20-40%). In this setting, though some effective approaches have been evaluated in the recent years, the management of such patients still remains challenging. OBJECTIVES In this study we evaluated the predictive role of post-transplant day +100 MRD detection for post-transplant outcomes for patients with refractory AML. STUDY DESIGN Fifty-six adult patients with refractory AML (median age 58, 20-76; male, 61%) who underwent allo-SCT were included in this retrospective monocentric study. Twenty-nine patients (52%) received FLAMSA-based conditioning. MRD was assessed using multicolored flow cytometry (MFC) according to ELN guidelines ("different from normal" and LAIP). The sensitivity of the method was 10-4 - 10-5. The median marrow blast count at allo-SCT was 25% (range 6-91%). At day +100 post-transplant, 40 patients (71%) experienced MFC-MRD negativity, 16 patients (29%) were MRD positive. All included patients survived at least 100 days post-transplant without relapse. Uni- and multivariate analysis based on Kaplan-Meier and Cox proportional hazards method were performed. RESULTS The median follow-up was 16 months (range 3-66). The post-transplant day 100 MRD negative patients received rather two allografts (27% vs 6%, p=0.08). In multivariate analysis, day +100 MRD status (negative vs positive) (OS: 0.23 (0.1-0.54), p=0.001; relapses: 0.20 (0.1-0.49), p=0.0005) and FLAMSA vs other regimens (0.34 (0.1-0.83), p=0.018; relapses: 0.43 (0.17-1.1), p=0.07) independently impacted post-transplant survival. CONCLUSIONS We suggest that post-transplant day +100 MFC-MRD detection plays predictive role in refractory AML patients and may help to define possible candidates for early post-transplant interventions aiming to decrease the relapse risk and improve survival

Individualized busulfan dosing improves outcomes compared to fixed dose administration in pre-transplant MRD positive AML patients with intermediate risk undergoing allogeneic stem cell transplantation in CR.

Pre-transplant minimal residual disease (MRD) impacts negatively on post-transplant relapse risk in AML. Therapeutic drug monitoring by calculating area-under-the-curve (AUC) was developed to optimize busulfan exposure. Here, we compared post-transplant outcomes after individualized versus fixed busulfan dosage in intermediate-risk AML who achieved CR prior to allograft focusing on pre-transplant flow-MRD. 87 patients (median, 56 years) with intermediate-risk AML and pre-transplant flow-MRD ("different from normal") were included. 32 patients received individualized busulfan; 54 fixed dosage. Individualized dosage was adjusted in 25/32 patients: increased, n = 18/25 (72%); decreased: n = 7/25 (28%). After median follow-up of 27 months, we observed lower 3-year relapses (6%, 2-19% vs 35%, 23-49% p = 0.02), improved 3-year LFS (78%, 54-91% vs 55%, 40-70% p = 0.009) and -OS (82%, 60-93% vs 69%, 54-81% p = 0.05) after individualized compared to fixed Bu. NRM and acute GvHD were not different. In multivariate analysis, fixed Bu showed unfavorable impact on OS (HR 4.6, p = 0.044), LFS (HR 3.6, p = 0.018) and relapses (HR 3.6, p = 0.033). Fixed Bu also had unfavorable impact on LFS (3.6, 1.1-12.6, p = 0.041) in pre-transplant MRD-positive patients. Individualized, AUC-based, busulfan is associated with lower relapses in intermediate-risk AML patients allografted in CR and may overcome pre-transplant MRD-positivity

A Pin1/PML/P53 axis activated by retinoic acid in <i>NPM-1c</i> acute myeloid leukemia

International audienceRetinoic acid (RA) was proposed to increase survival of chemotherapy- treated patients with nucleophosmin-1 (NPM-1c)-mutated acute myeloid leukemia. We reported that, ex vivo, RA triggers NPM-1c degradation, P53 activation and growth arrest. PML organizes domains that control senescence or proteolysis. Here, we demonstrate that PML is required to initiate RA-driven NPM-1c degradation, P53 activation and cell death. Mechanistically, RA enhances PML basal expression through inhibition of activated Pin1, prior to NPM-1c degradation. Such PML induction drives P53 activation, favoring blast response to chemotherapy or arsenic in vivo. This RA/PML/P53 cascade could mechanistically explain RA-facilitated chemotherapy response in patients with NPM-1c mutated acute myeloid leukemia

Impact of Adding Antithymocyte Globulin to Posttransplantation Cyclophosphamide in Haploidentical Stem-Cell Transplantation

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