Mid-term Waitlist and Posttransplant Outcomes With Hepatitis C-positive Donor Hearts.

BACKGROUND: This study evaluates the clinical trends and impact of hepatitis C virus-positive (HCV+) donors on waitlist and posttransplant outcomes after heart transplantation. METHODS: The United Network for Organ Sharing registry was queried to identify adult waitlisted and transplanted patients from January 1, 2015, to December 31, 2022. In the waitlist analysis, the candidates were stratified into 2 cohorts based on whether they were willing to accept HCV+ donor offers. Waitlist outcomes included 1-y cumulative incidences of transplantation and death/delisting. In the posttransplant analysis, the recipients were stratified into 2 cohorts with and without HCV nucleic acid test (NAT)-positive donors. Outcomes included 1- and 4-y posttransplant survival. Propensity score-matching was performed. Risk adjustment was performed using multivariable Cox regression. RESULTS: During the study period, the number of centers using HCV NAT+ donors increased from 1 to 65 centers, along with the number of transplants. In the waitlist analysis, 26 648 waitlisted candidates were analyzed, and 4535 candidates (17%) were approved to accept HCV+ donors. Approval to accept HCV+ donors was associated with a higher likelihood of transplantation and a lower likelihood of death/delisting within 1 y of waitlisting. In the posttransplant analysis, 21 131 recipients were analyzed, and 997 recipients (4.7%) received HCV NAT+ hearts. The 1- and 4-y posttransplant survival were comparable between the recipients of HCV NAT+ and NAT- donors. Furthermore, the similar 1- and 4-y posttransplant survival persisted in the propensity score-matched comparison and multivariable Cox regression analysis. CONCLUSIONS: Utilization of HCV+ donors is rising. Heart transplants using HCV+ donors are associated with improved waitlist and comparable posttransplant outcomes.

Evolving Trends and Impact of Waitlist Transfusion on Recipient Outcomes Following Heart Transplantation.

BACKGROUND: This study evaluates the clinical trends, risk factors, and impact of waitlist blood transfusion on outcomes following isolated heart transplantation. METHODS: The UNOS registry was queried to identify adult recipients from January 1, 2014, to June 30, 2022. The recipients were stratified into two groups depending on whether they received a blood transfusion while on the waitlist. The incidence of waitlist transfusion was compared before and after the 2018 allocation policy change. The primary outcome was survival. Propensity score-matching was performed. Multivariable logistic regression was performed to identify predictors of waitlist transfusion. A sub-analysis was performed to evaluate the impact of waitlist time on waitlist transfusion. RESULTS: From the 21 926 recipients analyzed in this study, 4201 (19.2%) received waitlist transfusion. The incidence of waitlist transfusion was lower following the allocation policy change (14.3% vs. 23.7%, p < 0.001). The recipients with waitlist transfusion had significantly reduced 1-year posttransplant survival (88.8% vs. 91.9%, p < 0.001) compared to the recipients without waitlist transfusion in an unmatched comparison. However, in a propensity score-matched comparison, the two groups had similar 1-year survival (90.0% vs. 90.4%, p = 0.656). Multivariable analysis identified ECMO, Impella, and pretransplant dialysis as strong predictors of waitlist transfusion. In a sub-analysis, the odds of waitlist transfusion increased nonlinearly with longer waitlist time. CONCLUSION: There is a lower incidence of waitlist transfusion among transplant recipients under the 2018 allocation system. Waitlist transfusion is not an independent predictor of adverse posttransplant outcomes but rather a marker of the patient's clinical condition. ECMO, Impella, and pretransplant dialysis are strong predictors of waitlist transfusion.

Extended Duration of Impella 5.5 Support Does Not Adversely Impact Outcomes Following Heart Transplantation: A National Registry Analysis.

Prior studies assessing the effects of Impella 5.5 support duration on posttransplant outcomes have been limited to single-center case reports and series. This study evaluates the impact of Impella 5.5 support duration on outcomes following heart transplantation using the United Network for Organ Sharing database. Adult heart transplant recipients who were directly bridged to primary isolated heart transplantation with Impella 5.5 were included. The cohort was stratified into two groups based on the duration of Impella support: less than or equal to 14 and greater than 14 days. The primary outcome was 90 day posttransplant survival. Propensity score matching was performed. Sub-analysis was conducted to evaluate the impact of greater than 30 days of Impella support on 90 day survival. Three hundred thirty-two recipients were analyzed. Of these, 212 recipients (63.9%) were directly bridged to heart transplantation with an Impella support duration of greater than 14 days. The two groups had comparable 90 day posttransplant survival and complication rates. The comparable posttransplant survival persisted in a propensity score-matched comparison. In the sub-analysis, Impella support duration of greater than or equal to 30 days did not adversely impact 90 day survival. This study demonstrates that extended duration of support with Impella 5.5 as a bridge to transplantation does not adversely impact posttransplant outcomes. Impella 5.5 is a safe and effective bridging modality to heart transplantation.

Donor and Recipient Age Influence Outcomes Following Orthotopic Heart Transplantation in the 2018 US Heart Allocation System.

BACKGROUND: This study evaluates the interaction of donor and recipient age with outcomes following heart transplantation under the 2018 heart allocation system. METHODS: The United Network for Organ Sharing registry was queried to analyze adult primary isolated orthotopic heart transplant recipients and associated donors from August 18, 2018, to June 30, 2021. Both recipient and donor cohorts were grouped according to age: <65 and ≥65 y for recipients and <50 and ≥50 y for donors. The primary outcome was survival. Subanalyses were performed to evaluate the impact of donor age. RESULTS: A total of 7601 recipients and 7601 donors were analyzed. Of these, 1584 recipients (20.8%) were ≥65 y old and 560 donors (7.4%) were ≥50 y old. Compared with recipients <65, recipients ≥65 had decreased 1-y (88.8% versus 92.3%) and 2-y (85.1% versus 88.5%) survival rates (P < 0.001). The association of recipient age ≥65 with lower survival persisted after adjusting for potential cofounders (hazard ratio, 1.38; 95% confidence interval, 1.18-1.61; P < 0.001). Recipients <65 with donors ≥50 had comparable 1-y and 2-y survival rates to recipients <65 with donors <50 (P =0.997). Conversely, transplantation of older allografts was associated with lower 1-y (84.2% versus 89.4%) and 2-y (79.5% versus 85.8%) survival rates in recipients ≥65 (P = 0.025). CONCLUSIONS: Recipient age ≥65 continues to be associated with worse survival following heart transplantation in the 2018 heart allocation system compared with younger recipients. Donors ≥50 may be acceptable among recipients <65 with comparable outcomes. However, careful donor age selection should be considered for recipients ≥65, as the use of younger donor allografts appears to improve posttransplantation survival.

TIM-3 blockade enhances ex vivo stimulated allogeneic NK cell therapy for relapsed murine neuroblastoma after hematopoietic cell transplant.

BACKGROUND: High-risk neuroblastoma (HR-NBL) is an aggressive tumor of the sympathetic nervous system with high risk of relapse and poor overall survival. Allogeneic hematopoietic cell transplant (allo-HCT) has been used previously in HR-NBL patients; however, graft-versus-host-disease (GVHD) and disease progression have limited clinical application. Ex-vivo stimulated allogeneic natural killer (NK) cells represent a potential approach to enhance the graft-versus-tumor (GVT) effect without exacerbation of GVHD but have not shown efficacy in NBL. METHODS: Ex-vivo stimulated NK cells from C57BL/6NCr (B6) mice were expanded with soluble IL-15/IL-15Rα alone or with irradiated CD137L/CD54+ AgN2a-4P (15-4P) at a 1:1 ratio for 10-12 days. Allogeneic NK cells were then analyzed for activation, proliferation, cytokine production, and cytotoxicity against two murine NBL cell lines, Neuro2a and NXS2, in the absence or presence of anti-TIM-3. Lethally irradiated B6AJF1 Mice received allo-HCT from B6 donors followed by NBL challenge after 7 days to mimic tumor relapse. Select groups received anti-TIM-3 starting on day 9 for every 4 days with/without infusions of 15-4P B6 NK cells on days 14, 21, and 28. In select experiments, T cell and NK cells were selectively depleted to establish their contribution to the GVT effect. All groups were analyzed for tumor growth, GVHD and overall survival. RESULTS: Co-culturing NK cells with 15-4P results in 78-fold expansion with increased expression of Ki-67 and NKG2D, NKp46, TRAIL and TIM-3. 15-4P stimulated allogeneic NK cells showed enhanced cytotoxicity against NBL compared to IL-15 NK cells alone but was limited in part due to high expression of TIM-3 ligands on Neuro-2a compared to NXS2. The addition of TIM-3 blockade further enhanced NK cytotoxicity versus Neuro-2a, with enhanced 15-4P NK cell degranulation, Eomes, TRAIL and FasL expression observed. Analysis of RNA from 15-4P NK cells exposed to TIM-3 blockade showed gene expression of chemokines, NKG2D/DAP12 signaling, non-canonical NF-κb pathway and TRAIL signaling. Blockade of NKG2D, TRAIL or FasL on 15-4P NK cells abrogated cytotoxicity. In vivo, the combination of 15-4P stimulated allogeneic NK cells and TIM-3 blockade after allo-HCT resulted in prolonged survival against NBL with decreased tumor burden compared to NK cells or anti-TIM-3 alone, without inducing GVHD. Depletion of NK cells, but not T cells, abrogated the GVT effect. CONCLUSION: Allo-HCT can be a platform for treating NBL using combination ex-vivo stimulated allogeneic NK cell therapy with TIM-3 blockade to enhance the GVT effect without inducing GVHD.

TLR10 (CD290) Is a Regulator of Immune Responses in Human Plasmacytoid Dendritic Cells.

TLRs are the most thoroughly studied group of pattern-recognition receptors that play a central role in innate immunity. Among them, TLR10 (CD290) remains the only TLR family member without a known ligand and clearly defined functions. One major impediment to studying TLR10 is its absence in mice. A recent study on TLR10 knock-in mice demonstrated its intrinsic inhibitory role in B cells, indicating that TLR10 is a potential drug target in autoimmune diseases. In this study, we interrogated the expression and function of TLR10 in human plasmacytoid dendritic cells (pDCs). We have seen that primary human pDCs, B cells, and monocytes constitutively express TLR10. Upon preincubation with an anti-TLR10 Ab, production of cytokines in pDCs was downregulated in response to stimulation with DNA and RNA viruses. Upon further investigation into the possible mechanism, we documented phosphorylation of STAT3 upon Ab-mediated engagement of TLR10. This leads to the induction of inhibitory molecule suppressor of cytokine signaling 3 (SOCS3) expression. We have also documented the inhibition of nuclear translocation of transcription factor IFN regulatory factor 7 (IRF7) in pDCs following TLR10 engagement. Our data provide the (to our knowledge) first evidence that TLR10 is constitutively expressed on the surface of human pDCs and works as a regulator of their innate response. Our findings indicate the potential of harnessing the function of pDCs by Ab-mediated targeting of TLR10 that may open a new therapeutic avenue for autoimmune disorders.

Robotically assisted outflow graft anastomosis in minimally invasive left-ventricular assist device implantation: feasibility, surgeon comfort, and operative times in an anatomical study.

Upper hemi-sternotomy is a common approach for outflow graft anastomosis to the ascending aorta in minimally invasive left-ventricular assist device implantation. Right mini-thoracotomy may also be used, but use of robotic assistance has been reported only anecdotally. The aim of our study was to confirm the feasibility of robotically assisted suturing of the outflow graft anastomosis and to assess performance metrics for the robotic suturing part of the procedure. The procedure was carried out in eight cadaver studies by two surgeons. The assist device pump head was inserted through a left-sided mini-thoracotomy and the outflow graft was passed toward a right-sided second interspace mini-thoracotomy through the pericardium. After placement of a partial occlusion clamp on the ascending aorta, a longitudinal aortotomy was performed and the outflow graft to ascending aorta anastomosis was carried out robotically. The procedure was feasible in all eight attempts. The mean outflow graft anastomotic time was 20.1 (SD 6.8) min and the mean surgeon confidence and comfort levels to complete the anastomoses were 8.3 (SD 2.4) and 6.9 (SD2.2), respectively, on a ten-grade Likert scale. On open inspection of the anastomoses, there was good suture alignment in all cases. We conclude that suturing of a left-ventricular assist device outflow graft to the human ascending aorta is very feasible with good surgeon comfort. Anastomotic times are acceptable and suture placement can be performed with appropriate alignment.

Extracorporeal life support after surgical repair for acute type a aortic dissection: A systematic review and meta-analysis.

BACKGROUND: The use of extracorporeal life support (ECLS) in patients after surgical repair for acute type A aortic dissection (ATAAD) has not been well documented. METHODS: We performed a systematic review and meta-analysis to assess the outcomes of ECLS after surgery for ATAAD with data published by October 2023 in compliance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) and the Meta-analysis of Observational Studies in Epidemiology (MOOSE) reporting guidelines. The protocol was registered in PROSPERO (CRD42023479955). RESULTS: Twelve observational studies met our eligibility criteria, including 280 patients. Mean age was 55.0 years and women represented 25.3% of the overall population. Although the mean preoperative left ventricle ejection fraction was 59.8%, 60.8% of patients developed left ventricle failure and 34.0% developed biventricular failure. Coronary involvement and malperfusion were found in 37.1% and 25.6%, respectively. Concomitant coronary bypass surgery was performed in 38.5% of patients. Regarding ECLS, retrograde flow (femoral) was present in 39.9% and central cannulation was present in 35.4%. In-hospital mortality was 62.8% and pooled estimate of successful weaning was 50.8%. Neurological complications, bleeding and renal failure were found in 25.9%, 38.7%, and 65.5%, respectively. CONCLUSION: ECLS after surgical repair for ATAAD remains associated with high rates of in-hospital death and complications, but it still represents a chance of survival in critical situations. ECLS remains a salvage attempt and surgeons should not try to avoid ECLS at all costs after repairing an ATAAD case.

Can we safely expand the donation after circulatory death donor heart pool by extending the donor age limit?

OBJECTIVE: This study evaluates the impact of donor age on outcomes following donation after circulatory death heart transplantation. METHODS: The United Network for Organ Sharing registry was queried to analyze adult recipients who underwent isolated donation after circulatory heart transplantation from January 1, 2019, to September 30, 2023. The cohort was stratified into 2 groups according to donor age, where advanced donor age was defined as 40 years or more. Outcomes were 90-day and 1-year post-transplant survival. Propensity score matching was performed. Subgroup analysis was performed to evaluate the effects of recipient age on 90-day survival among the recipients with advanced-age donors. RESULTS: A total of 994 recipients were included in the study period, and 161 patients (17.1%) received allografts from advanced-age donors. During the study period, the annual incidence of donation after circulatory heart transplantation with advanced-age donors substantially increased. The recipients with advanced-age donors had similar 90-day and 1-year post-transplant survivals compared with the recipients with younger donors. The comparable 90-day survival persisted in a propensity score-matched comparison. In the subgroup analysis among the recipients with advanced-age donors, the recipients aged 60 years or more had significantly reduced 90-day survival compared with the recipients aged less than 60 years. CONCLUSIONS: The use of appropriately selected donation after circulatory donors aged 40 years or more has similar survival compared with that of younger donors. With careful candidate risk stratification and selection, consideration of using donation after circulatory donors aged more than 40 years may further ameliorate ongoing organ shortage with comparable early post-transplant outcomes.

Concomitant use of extracorporeal membrane oxygenation and percutaneous microaxial assist device support for cardiogenic shock.

Objectives: Venoarterial extracorporeal membrane oxygenation (VA-ECMO) with concomitant percutaneous microaxial left ventricular assist device support is an emerging treatment modality for cardiogenic shock (CS). Survival outcomes by CS etiology with this support strategy have not been well described. Methods: This study was a retrospective, single-center analysis of patients with CS due to acute myocardial infarction (AMI-CS) or decompensated heart failure (ADHF-CS) supported with VA-ECMO with concomitant percutaneous microaxial left ventricular assist device support from December 2020 to January 2023. Results: A total of 44 patients were included (AMI-CS, n = 20, and ADHF-CS, n = 24). Patients with AMI-CS and ADHF-CS had similar survival at 90 days postdischarge (P = .267) with similar destinations after support (P = .220). Patients with AMI-CS initially supported with VA-ECMO were less likely to survive 90 days postdischarge (P = .038) when compared with other cohorts. Limb ischemia and acute kidney injury occurred more frequently in patients presenting with AMI-CS (P =.013; P = .030). Subanalysis of ADHF-CS patients into acute-on-chronic decompensated HF and de novo HF demonstrated no difference in survival or destination. Conclusions: VA-ECMO with concomitant percutaneous microaxial left ventricular assist device support can be used to successfully manage patients with CS. There is no difference in survival or destination for AMI-CS and ADHF-CS with this support strategy. AMI-CS patients with initial VA-ECMO support have increased mortality in comparison to other cohorts. Future multicenter studies are required to fully analyze the differences between AMI-CS and ADHF-CS with this support strategy.

Outcomes of Impella 5.0 and 5.5 for cardiogenic shock: A single-center 137 patient experience.

BACKGROUND: This study evaluated the outcomes of patients with cardiogenic shock (CS) supported with Impella 5.0 or 5.5 and identified risk factors for in-hospital mortality. METHODS: Adults with CS who were supported with Impella 5.0 or 5.5 at a single institution were included. Patients were stratified into three groups according to their CS etiology: (1) acute myocardial infarction (AMI), (2) acute decompensated heart failure (ADHF), and (3) postcardiotomy (PC). The primary outcome was survival, and secondary outcomes included adverse events during Impella support and length of stay. Multivariable logistic regression was performed to identify risk factors for in-hospital mortality. RESULTS: One hundred and thirty-seven patients with CS secondary to AMI (n = 47), ADHF (n = 86), and PC (n = 4) were included. The ADHF group had the highest survival rates at all time points. Acute kidney injury (AKI) was the most common complication during Impella support in all 3 groups. Increased rates of AKI and de novo renal replacement therapy were observed in the PC group, and the AMI group experienced a higher incidence of bleeding requiring transfusion. Multivariable analysis demonstrated diabetes mellitus, elevated pre-insertion serum lactate, and elevated pre-insertion serum creatinine were independent predictors of in-hospital mortality, but the etiology of CS did not impact mortality. CONCLUSIONS: This study demonstrates that Impella 5.0 and 5.5 provide effective mechanical support for patients with CS with favorable outcomes, with nearly two-thirds of patients alive at 180 days. Diabetes, elevated pre-insertion serum lactate, and elevated pre-insertion serum creatinine are strong risk factors for in-hospital mortality.

Impact of post-transplant stroke and subsequent functional independence on outcomes following heart transplantation under the 2018 United States heart allocation system.

BACKGROUND: This study evaluates the clinical trends, risk factors, and effects of post-transplant stroke and subsequent functional independence on outcomes following orthotopic heart transplantation under the 2018 heart allocation system. METHODS: The United Network for Organ Sharing registry was queried to identify adult recipients from October 18, 2018 to December 31, 2021. The cohort was stratified into 2 groups with and without post-transplant stroke. The incidence of post-transplant stroke was compared before and after the allocation policy change. Outcomes included post-transplant survival and complications. Multivariable logistic regression was performed to identify risk factors for post-transplant stroke. Sub-analysis was performed to evaluate the impact of functional independence among recipients with post-transplant stroke. RESULTS: A total of 9,039 recipients were analyzed in this study. The incidence of post-transplant stroke was higher following the policy change (3.8% vs 3.1%, p = 0.017). Thirty-day (81.4% vs 97.7%) and 1-year (66.4% vs 92.5%) survival rates were substantially lower in the stroke cohort (p < 0.001). The stroke cohort had a higher rate of post-transplant renal failure, longer hospital length of stay, and worse functional status. Multivariable analysis identified extracorporeal membrane oxygenation, durable left ventricular assist device, blood type O, and redo heart transplantation as strong predictors of post-transplant stroke. Preserved functional independence considerably improved 30-day (99.2% vs 61.2%) and 1-year (97.7% vs 47.4%) survival rates among the recipients with post-transplant stroke (p < 0.001). CONCLUSIONS: There is a higher incidence of post-transplant stroke under the 2018 allocation system, and it is associated with significantly worse post-transplant outcomes. However, post-transplant stroke recipients with preserved functional independence have improved survival, similar to those without post-transplant stroke.

Improved waitlist and comparable post-transplant outcomes in simultaneous heart-kidney transplantation under the 2018 heart allocation system.

OBJECTIVE: This study aimed to investigate the clinical trends and the impact of the 2018 heart allocation policy change on both waitlist and post-transplant outcomes in simultaneous heart-kidney transplantation in the United States. METHODS: The United Network for Organ Sharing registry was queried to compare adult patients before and after the allocation policy change. This study included 2 separate analyses evaluating the waitlist and post-transplant outcomes. Multivariable analyses were performed to determine the 2018 allocation system's risk-adjusted hazards for 1-year waitlist and post-transplant mortality. RESULTS: The initial analysis investigating the waitlist outcomes included 1779 patients listed for simultaneous heart-kidney transplantation. Of these, 1075 patients (60.4%) were listed after the 2018 allocation policy change. After the policy change, the waitlist outcomes significantly improved with a shorter waitlist time, lower likelihood of de-listing, and higher likelihood of transplantation. In the subsequent analysis investigating the post-transplant outcomes, 1130 simultaneous heart-kidney transplant recipients were included, where 738 patients (65.3%) underwent simultaneous heart-kidney transplantation after the policy change. The 90-day, 6-month, and 1-year post-transplant survival and complication rates were comparable before and after the policy change. Multivariable analyses demonstrated that the 2018 allocation system positively impacted risk-adjusted 1-year waitlist mortality (sub-hazard ratio, 0.66, 95% CI, 0.51-0.85, P < .001), but it did not significantly impact risk-adjusted 1-year post-transplant mortality (hazard ratio, 1.03; 95% CI, 0.72-1.47, P = .876). CONCLUSIONS: This study demonstrates increased rates of simultaneous heart-kidney transplantation with a shorter waitlist time after the 2018 allocation policy change. Furthermore, there were improved waitlist outcomes and comparable early post-transplant survival after simultaneous heart-kidney transplantation under the 2018 allocation system.

Donation after circulatory death improves probability of heart transplantation in waitlisted candidates and results in post-transplant outcomes similar to those achieved with brain-dead donors.

OBJECTIVE: To quantitate the impact of heart donation after circulatory death (DCD) donor utilization on both waitlist and post-transplant outcomes in the United States. METHODS: The United Network for Organ Sharing database was queried to identify all adult waitlisted and transplanted candidates between October 18, 2018, and December 31, 2022. Waitlisted candidates were stratified according to whether they had been approved for donation after brain death (DBD) offers only or also approved for DCD offers. The cumulative incidence of transplantation was compared between the 2 cohorts. In a post-transplant analysis, 1-year post-transplant survival was compared between unmatched and propensity-score-matched cohorts of DBD and DCD recipients. RESULTS: A total of 14,803 candidates were waitlisted, including 12,287 approved for DBD donors only and 2516 approved for DCD donors. Overall, DCD approval was associated with an increased sub-hazard ratio (HR) for transplantation and a lower sub-HR for delisting owing to death/deterioration after risk adjustment. In a subgroup analysis, candidates with blood type B and status 4 designation received the greatest benefit from DCD approval. A total of 12,238 recipients underwent transplantation, 11,636 with DBD hearts and 602 with DCD hearts. Median waitlist times were significantly shorter for status 3 and status 4 recipients receiving DCD hearts. One-year post-transplant survival was comparable between unmatched and propensity score-matched cohorts of DBD and DCD recipients. CONCLUSIONS: The use of DCD hearts confers a higher probability of transplantation and a lower incidence of death/deterioration while on the waitlist, particularly among certain subpopulations such as status 4 candidates. Importantly, the use of DCD donors results in similar post-transplant survival as DBD donors.

Cardiogenic shock etiology and exit strategy impact survival in patients with Impella 5.5.

BACKGROUND: Despite historical differences in cardiogenic shock (CS) outcomes by etiology, outcomes by CS etiology have yet to be described in patients supported by temporary mechanical circulatory support (MCS) with Impella 5.5. OBJECTIVES: This study aims to identify differences in survival and post-support destination for these patients in acute myocardial infarction (AMI) and acute decompensated heart failure (ADHF) CS at a high-volume, tertiary, transplant center. METHODS: A retrospective review of patients who received Impella 5.5 at our center from November 2020 to June 2022 was conducted. RESULTS: Sixty-seven patients underwent Impella 5.5 implantation for CS; 23 (34%) for AMI and 44 (66%) for ADHF. AMI patients presented with higher SCAI stage, pre-implant lactate, and rate of prior MCS devices, and fewer days from admission to implantation. Survival was lower for AMI patients at 30 days, 90 days, and discharge. No difference in time to all-cause mortality was found when excluding patients receiving transplant. There was no significant difference in complication rates between groups. CONCLUSIONS: ADHF-CS patients with Impella 5.5 support have a significantly higher rate of survival than patients with AMI-CS. ADHF patients were successfully bridged to heart transplant more often than AMI patients, contributing to increased survival.

Griddient: a microfluidic array to generate reconfigurable gradients on-demand for spatial biology applications.

Biological tissues are highly organized structures where spatial-temporal gradients (e.g., nutrients, hypoxia, cytokines) modulate multiple physiological and pathological processes including inflammation, tissue regeneration, embryogenesis, and cancer progression. Current in vitro technologies struggle to capture the complexity of these transient microenvironmental gradients, do not provide dynamic control over the gradient profile, are complex and poorly suited for high throughput applications. Therefore, we have designed Griddent, a user-friendly platform with the capability of generating controllable and reversible gradients in a 3D microenvironment. Our platform consists of an array of 32 microfluidic chambers connected to a 384 well-array through a diffusion port at the bottom of each reservoir well. The diffusion ports are optimized to ensure gradient stability and facilitate manual micropipette loading. This platform is compatible with molecular and functional spatial biology as well as optical and fluorescence microscopy. In this work, we have used this platform to study cancer progression.

Concomitant Use of VA-ECMO and Impella Support for Cardiogenic Shock.

Background: VA-ECMO with concomitant Impella support (ECpella) is an emerging treatment modality for cardiogenic shock (CS). Survival outcomes by CS etiology with ECpella support have not been well-described. Methods: This study was a retrospective, single-center analysis of patients with cardiogenic shock due to acute myocardial infarction (AMI-CS) or decompensated heart failure (ADHF-CS) supported with ECpella from December 2020 to January 2023. Primary outcomes included 90-day survival post-discharge and destination after support. Secondary outcomes included complications post-ECpella support. Results: A total of 44 patients were included (AMI-CS, n = 20, and ADHF-CS, n = 24). Patients with AMI-CS and ADHF-CS had similar survival 90 days post-discharge (p = .267) with similar destinations after ECpella support (p = .220). Limb ischemia and acute kidney injury occurred more frequently in patients presenting with AMI-CS (p=.013; p = .030). Patients with initial Impella support were more likely to survive ECpella support and be bridged to transplant (p=.033) and less likely to have a cerebrovascular accident (p=.016). Sub-analysis of ADHF-CS patients into acute-on-chronic decompensated heart failure and de novo heart failure demonstrated no difference in survival or destination. Conclusion: ECpella can be used to successfully manage patients with CS. There is no difference in survival or destination for AMI-CS and ADHF-CS in patients with ECpella support. Patients with initial Impella support are more likely to survive ECpella support and bridge to transplant. Future multicenter studies are required to fully analyze the differences between AMI-CS and ADHF-CS with ECpella support.

Combinatorial fedratinib and venetoclax treatment is effective on human B cell acute lymphoblastic leukemia with high Flt3 expression.

Treatment of relapsed/refractory B cell acute lymphoblastic leukemia (B-ALL) remains a challenge, particularly in patients who do not respond to traditional chemotherapy or immunotherapy. The objective of this study was to assess the efficacy of fedratinib, a semi selective JAK2 inhibitor and venetoclax, a selective BCL-2 inhibitor, on human B-ALL using both single-agent and combinatorial treatments. The combination treatment of fedratinib and venetoclax improved killing of the human B-ALL cell lines RS4;11 and SUPB-15 in vitro over single-agent treatments. This combinatorial effect was not detected in the human B-ALL cell line NALM-6, which was less responsive to fedratinib due to the absence of Flt3 expression. The combination treatment induces a unique gene expression profile relative to single-agent treatment and with an enrichment in apoptotic pathways. Finally, the combination treatment was superior to single agent treatment in an in vivo xenograft model of human B-ALL with a two-week treatment regimen significantly improving overall survival. Overall, our data demonstrates the efficacy of a combinatorial treatment strategy of fedratinib and venetoclax against human B-ALL expressing high levels of Flt3.

Exosomes, MDSCs and Tregs: A new frontier for GVHD prevention and treatment.

The development of graft versus host disease (GVHD) represents a long-standing complication of allogeneic hematopoietic cell transplantation (allo-HCT). Different approaches have been used to control the development of GVHD with most relying on variations of chemotherapy drugs to eliminate allo-reactive T cells. While these approaches have proven effective, it is generally accepted that safer, and less toxic GVHD prophylaxis drugs are required to reduce the health burden placed on allo-HCT recipients. In this review, we will summarize the emerging concepts revolving around three biologic-based therapies for GVHD using T regulatory cells (Tregs), myeloid-derived-suppressor-cells (MDSCs) and mesenchymal stromal cell (MSC) exosomes. This review will highlight how each specific modality is unique in its mechanism of action, but also share a common theme in their ability to preferentially activate and expand Treg populations in vivo. As these three GVHD prevention/treatment modalities continue their path toward clinical application, it is imperative the field understand both the biological advantages and disadvantages of each approach.

Inflammatory CD4/CD8 double-positive human T cells arise from reactive CD8 T cells and are sufficient to mediate GVHD pathology.

An important paradigm in allogeneic hematopoietic cell transplantations (allo-HCTs) is the prevention of graft-versus-host disease (GVHD) while preserving the graft-versus-leukemia (GVL) activity of donor T cells. From an observational clinical study of adult allo-HCT recipients, we identified a CD4+/CD8+ double-positive T cell (DPT) population, not present in starting grafts, whose presence was predictive of ≥ grade 2 GVHD. Using an established xenogeneic transplant model, we reveal that the DPT population develops from antigen-stimulated CD8 T cells, which become transcriptionally, metabolically, and phenotypically distinct from single-positive CD4 and CD8 T cells. Isolated DPTs were sufficient to mediate xeno-GVHD pathology when retransplanted into naïve mice but provided no survival benefit when mice were challenged with a human B-ALL cell line. Overall, this study reveals human DPTs as a T cell population directly involved with GVHD pathology.