Mortality In Transplantation Research Articles

The Impact of Pre-Heart Transplantation Blood Transfusion Varies Based on Recipient MELD-XI Score.

Prior studies reveal adverse effects of transfusion on cardiac surgery, but little is known of transfusion impact on heart transplantation. First-time, single-organ adult heart transplant recipients between January 1, 2010, and December 31, 2020, were included, stratified above or below a model for end-stage liver disease excluding international normalized ratio (MELD-XI) score of 9.4, and propensity score matched to their nearest neighbor. A 90 day landmark analysis within each cohort was also performed. Unadjusted analysis showed transfusion recipients, MELD-XI ≥9.4, were more likely to experience post-heart transplantation mortality (Hazard Ratio (HR), 1.352 [95% Confidence Interval (CI), 1.239-1.477], p < 0.001), persisting after adjustment for potential confounders (adjusted HR, 1.211 [95% CI, 1.100-1.335], p < 0.001) and after propensity-score matching (HR, 1.174 [95% CI, 1.045-1.319], p = 0.007). Post-transplant length of stay was longer (25.9 vs. 23.2 days, p < 0.001). Post-transplant dialysis was more common (18.7 vs. 15.9%, p = 0.009). There was no survival difference on 90 day landmarked analysis ( p = 0.108). With MELD-XI <9.4, there was slight survival detriment among transfusion recipients on univariable analysis (HR, 1.111 [95% CI, 1.001-1.234], p = 0.049) but not on multivariable analysis (adjusted HR, 1.061 [95% CI, 0.952-1.181], p = 0.285). There was similar survival after propensity-score matching (HR, 1.032 [95% CI, 0.903-1.180], p = 0.642) and on landmark analysis ( p = 0.581). Ultimately, transfusion was associated with worse post-heart transplantation outcomes among recipients with a MELD-XI ≥9.4.

Outcomes of critically ill patients with liver failure who require mechanical ventilation: A retrospective, single-center study.

Critically ill patients with liver failure have high mortality. Besides the management of organ-specific complications, liver transplantation constitutes a definitive treatment. However, clinicians may hesitate to introduce mechanical ventilation for patients on liver transplantation waitlists because of poor prognosis. This study investigated the outcomes of intensive care and ventilation support therapy effects in patients with liver failure. This single-center study retrospectively enrolled 32 consecutive patients with liver failure who were admitted to the intensive care unit from January 2014 to December 2020. The medical records were reviewed and analyzed retrospectively for Acute Physiologic and Chronic Health Evaluation (APACHE)-II. The model for end-stage liver disease scores, 90-day mortality, and survival was assessed using the Kaplan-Meier method. The average patient age was 45.5 ± 20.1 years, and 53% of patients were women. On intensive care unit admission, APACHE-II and model for end-stage liver disease scores were 20 and 28, respectively. Among 13 patients considered for liver transplantation, 4 received transplants. Thirteen patients (40.6%) were intubated and mechanically ventilated in the intensive care unit. The 90-day mortality rate of patients with and without mechanical ventilation in the intensive care unit (13, 61.5% vs. 19, 47.4%, p = 0.4905) was similar. APACHE-II score >21 was an independent predictor of mechanical ventilation requirement in patients with liver failure during intensive care unit stay. Although critically ill patients with liver failure are at risk of multiorgan failure with poor outcomes, mechanical ventilation did not negatively affect the 90-day mortality or performance rates of liver transplantation. Clinicians should consider mechanical ventilation-based life support in critically ill patients with liver failure who are awaiting liver transplantation.

Bidirectional ABO Mismatch Is Associated With Elevated Mortality in Hematopoietic Stem Cell Transplantation: Insights From a Single-Center Experience.

Background Hematopoietic stem cell transplantation (HSCT) is a promising therapy for various disorders and provides new opportunities for patients. ABO incompatibility in allogeneic HSCT (allo-HSCT) remains a topic of debate because of its potential impact on clinical outcomes. This study aimed to analyze the survival outcomes of patients who underwent ABO-incompatible HSCT and evaluate the occurrence of pure red cell aplasia. Methods This retrospective study included 20 patients who underwent ABO-incompatible HSCT. Data on patient characteristics, transplant details, and follow-ups were collected. Conditioning regimens and graft-versus-host disease (GVHD) prophylaxis strategies were employed. Results Neutrophil and platelet engraftment durations did not differ significantly between major and bidirectional mismatches. Pure red cell aplasia occurred in 4 patients (20%) with major mismatches, all of whom responded well to bortezomib treatment. Patients with a bidirectional mismatch exhibited a 3.57-fold increase (hazard ratio [HR]: 0.28; p<0.05) in the risk of mortality compared to those in the major mismatch group. Conclusion The results indicate that ABO mismatch, whether bidirectional or major, does not significantly affect neutrophil and platelet engraftment duration, suggesting that ABO incompatibility may not be a major factor influencing hematological recovery in allo-HSCT. Interestingly, patients with bidirectional mismatch exhibited a significantly higher mortality rate than those with major mismatch. This finding suggests that a bidirectional ABO mismatch may have an unfavorable prognosis in terms of overall survival in allo-HSCT patients.

Cardiovascular Outcomes in Fontan Patients With Right vs Left Univentricular Morphology: A Multicenter Study

BackgroundThere is a paucity of data on long-term outcomes after Fontan palliation in patients with a dominant morphological univentricular right (uRV) vs left (uLV) ventricle. ObjectivesThe purpose of this study was to compare the incidence of atrial arrhythmias, thromboembolic events, cardiac transplantation, and death following Fontan palliation in patients with uRV vs uLV. MethodsThe Alliance for Adult Research in Congenital Cardiology conducted a multicenter retrospective cohort study on patients with total cavopulmonary connection Fontan palliation across 12 centers in North America. All components of the composite outcome, that is, atrial arrhythmias, thromboembolic events, cardiac transplantation, and death, were reviewed and classified by a blinded adjudicating committee. Time-to-event analyses were performed that accounted for competing risks. ResultsA total of 384 patients were followed for 10.5 ± 5.9 years. The composite outcome occurred in 3.7 vs 1.7 cases per 100 person-years for uRV (N = 171) vs uLV (N = 213), respectively (P < 0.001). In multivariable analyses, uRV conferred a >2-fold higher risk of the composite outcome (HR: 2.17, 95% CI: 1.45-3.45, P < 0.001). In secondary analyses of components of the primary outcome, uRV was significantly associated with a greater risk of cardiac transplantation or death (HR: 9.09, 95% CI: 2.17-38.46, P < 0.001) and atrial arrhythmias (HR: 2.17, 95% CI: 1.20-4.00, P = 0.010) but not thromboembolic events (HR: 1.64, 95% CI: 0.86-3.16, P = 0.131). ConclusionsFontan patients with uRV vs uLV morphology have a higher incidence of adverse cardiovascular events, including atrial arrhythmia, cardiac transplantation, and all-cause mortality.

A285 COMPARISON OF ADVERSE OUTCOMES IN PATIENTS WITH COMBINED INFLAMMATORY BOWEL DISEASE AND PRIMARY SCLEROSING CHOLANGITIS VERSUS ISOLATED PRIMARY SCLEROSING CHOLANGITIS

Abstract Background Primary sclerosing cholangitis (PSC) results in progressive inflammation and fibrosis of bile ducts causing chronic cholestasis. PSC is associated with an increased risk of malignancy [hepatobiliary and colorectal cancers (CRC)] compared to the general population, in addition to an increased risk of developing end-stage liver disease, often requiring liver transplantation at a relatively young age. The increased risk of adverse outcomes confers an increased risk of premature death of patients with PSC. PSC is commonly associated with IBD, particularly ulcerative colitis (UC), which in itself carries a higher rate of CRC. A study of the impact of PSC with IBD on development of cancer and survival outcomes is imperative. Aims To compare the risk of cancer, liver transplantation, and mortality in PSC-IBD versus isolated PSC. Methods Retrospective data from PSC patients from two hospital sites in Vancouver, British Columbia was analyzed to compare the relative risk of death, transplantation, and malignancy in PSC-IBD versus isolated PSC. Results 169 patients with PSC were included in the analysis [mean age of diagnosis of PSC 37 (SD 16.92) years, 41.4% (70) female]. Out of the 169 patients with PSC, 102 had IBD [29.4% (30) with Crohn’s Disease (CD); 70.6% (72) with UC]. The mean age of IBD diagnosis was 28.96 (SD 14.46) years. Death occurred in 31 [64.5% (20) with IBD; RR 1.19, 95% CI 0.61-2.32, p=0.60] patients, 35 [57.1% (20) with IBD; RR 0.88, 95% CI 0.48-1.59, p=0.66] patients developed cancer, and 33 [66.7% (22) with IBD; RR 1.31, 95% CI 0.68-2.52, p=0.41] patients required liver transplantation. The cause of death was malignancy in 15 [53.3% (8) with IBD] patients, liver failure in 5 [80% (4) with IBD] patients, sepsis in 2 [100% (2) with IBD] patients, and unknown cause of death in 9 [77.7% (7) with IBD] patients. For malignancy types, 16 [68.75% (11) with IBD] patients had cholangiocarcinoma (CCA), 4 [50% (2) with IBD] had CRC, 2 [50% (1) with IBD] had gallbladder cancer, 1 [0% (0) with IBD] had pancreatic cancer, 1 [0% (0) with IBD] had esophageal cancer, and 11 [54.5% (6) with IBD] had other malignancies not involving the hepatobiliary or gastrointestinal system. Of the patients who died due to malignancy, 73.3% (11) had CCA. Conclusions Although we do not observe any statistically significant difference in risk of cancer, transplantation, or all-cause mortality in patients with PSC-IBD when compared to isolated PSC, we do observe that 59% of all-included patients experienced one or more adverse outcome. It is important for clinicians to recognize the high rates of adverse outcomes in PSC-IBD and isolated PSC patients, potentially warranting earlier or more frequent screening for outcomes such as malignancy and liver dysfunction. Funding Agencies None

Ensemble Clustering to Generate Phenotypes of Kidney Transplant Donors and Recipients.

In this paper we investigate the generation of phenotypes for kidney transplant donors and recipients to assist with decision making around organ allocation. We present an ensemble clustering approach for multi-type data (numerical and categorical) using two different clustering approaches-i.e., model based and vector quantization based clustering. These clustering approaches were applied to a large, US national deceased donor kidney transplant recipient database to characterize members of each cluster (in an unsupervised fashion) and to determine whether the subsequent risk of graft failure differed for each cluster. We generated three distinct clusters of recipients, which were subsequently used to generate phenotypes. Each cluster phenotype had recipients with varying clinical features, and the risk of kidney transplant graft failure and mortality differed across clusters. Importantly, the clustering results by both approaches demonstrated a significant overlap. Utilization of two distinct clustering approaches may be a novel way to validate unsupervised clustering techniques and clustering can be used for organ allocation decision making on the basis of differential outcomes.

Tacrolimus versus mycophenolate for AutoImmune hepatitis patients with incompLete response On first-line therapy (TAILOR study): a study protocol for a phase III, open-label, multicentre, randomised controlled trial

BackgroundAutoimmune hepatitis (AIH) is a rare, chronic inflammatory disease of the liver. The treatment goal is reaching complete biochemical response (CR), defined as the normalisation of aspartate and alanine aminotransferases and immunoglobulin gamma. Ongoing AIH activity can lead to fibrosis and (decompensated) cirrhosis. Incomplete biochemical response is the most important risk factor for liver transplantation or liver-related mortality. First-line treatment consists of a combination of azathioprine and prednisolone. If CR is not reached, tacrolimus (TAC) or mycophenolate mofetil (MMF) can be used as second-line therapy. Both products are registered for the prevention of graft rejection in solid organ transplant recipients. The aim of this study is to compare the effectiveness and safety of TAC and MMF as second-line treatment for AIH.MethodsThe TAILOR study is a phase IIIB, multicentre, open-label, parallel-group, randomised (1:1) controlled trial performed in large teaching and university hospitals in the Netherlands. We will enrol 86 patients with AIH who have not reached CR after at least 6 months of treatment with first-line therapy. Patients are randomised to TAC (0.07 mg/kg/day initially and adjusted by trough levels) or MMF (max 2000 mg/day), stratified by the presence of cirrhosis at inclusion. The primary endpoint is the difference in the proportion of patients reaching CR after 12 months. Secondary endpoints include the difference in the proportion of patients reaching CR after 6 months, adverse effects, difference in fibrogenesis, quality of life and cost-effectiveness.DiscussionThis is the first randomised controlled trial comparing two second-line therapies for AIH. Currently, second-line treatment is based on retrospective cohort studies. The rarity of AIH is the main issue in clinical research for alternative treatment options. The results of this trial can be implemented in existing international clinical guidelines.Trial registrationClinicalTrials.gov NCT05221411. Retrospectively registered on 3 February 2022; EudraCT number 2021–003420-33. Prospectively registered on 16 June 2021.

Trends in kidney transplantation and living donor nephrectomy in Germany: a total population analysis from 2006 to 2021.

To analyze recent trends of surgical access routes, length of hospital stay (LOS), and mortality in kidney transplantation (KT) and living donor nephrectomy (LDN) in Germany. We studied the nationwide German hospital billing database and the German hospital quality reports from 2006 to 2021. There were a total of 35.898 KTs. In total, 9044 (25%) were living donor transplantations, while 26.854 (75%) were transplantations after donation after brain death (DBD). The share of open LDN decreased from 82% in 2006 to 22% in 2020 (-4%/year; p < 0.001). The share of laparoscopic LDN increased from 18% in 2006 to 70% in 2020 (+ 3%/year; p < 0.001). The share of robotic LDN increased from 0% in 2006 to 8% in 2020 (+ 0.6%/year; p < 0.001). Robotic-assisted KT increased from 5 cases in 2016 to 13 procedures in 2019 (p = 0.2). LOS was shorter after living donor KT, i.e., 18 ± 12.1days versus 21 ± 19.6days for DBD renal transplantation (p < 0.001). Moreover, LOS differed for open versus laparoscopic versus robotic LDN (9 ± 3.1 vs. 8 ± 2.9 vs. 6 ± 2.6; p = 0.031). The overall in-hospital mortality was 0.16% (n = 5) after LDN, 0.47% (n = 42) after living donor KT and 1.8% (n = 475) after DBD KT. There is an increasing trend toward minimal-invasive LDN in recent years. Overall, in-hospital mortality was low after KT. However, 5 deceased healthy donors after LKD caution that the risks of this procedure should also be taken very seriously.

De Novo Kaposi Sarcoma in an HIV‐Negative Liver Transplant Recipient With Ulcerative Colitis and Primary Sclerosing Cholangitis

De novo or viral reactivation cancers are a major cause of morbidity and mortality in the solid organ transplant (SOT) population. Primary sclerosing cholangitis (PSC) is an aggressive disease which can lead to cholestatic liver damage and cirrhosis. PSC often cooccurs with inflammatory bowel disease (IBD). Here, we describe the case of a 28‐year‐old male with PSC along with poorly controlled IBD who underwent a liver transplant and developed colonic Kaposi sarcoma (KS). Our case highlights the importance of adequate pretransplant screening for endemic viruses, high clinical suspicion for KS in the setting of difficult‐to‐control colitis, and early multidisciplinary involvement.

Identification and analysis of alloreactive T lymphocytes from peripheral blood mononuclear cells.

Alloreactive T-cell responses against mismatched MHC or minor histocompatibility antigens may result in deleterious graft-versus-host disease (GVHD) and increased morbidity and mortality in allogeneic hematopoietic stem cell transplantation (allo-HSCT). Nevertheless, these T-cell responses may be directed against residual tumor cells (the graft-versus-tumor effect, GVT), thus preventing relapse of the disease. Recent findings have shown that CD45RA+ naïve T cells, but not CD45RA- memory T cells are the major contributors to GVHD, thus leading to clinical trials where CD45RA+-depleted, memory-enriched T-cell products are adoptively transferred following allo-HSCT to prevent GVHD and enhance immune reconstitution. However, residual alloreactivity may still be present in the memory T-cell compartment, thus contributing to prevent disease relapse by GVT. Here, we describe a simple cell-based protocol to identify alloreactive naïve and memory T cells by co-culturing T-cell subsets and third-party antigen-presenting cells. The responding cells are identified following dilution of carboxyfluorescein succinimidyl ester (CFSE) and upregulation of the activation marker CD25. These CFSE-diluting cells can be further phenotyped by high-dimensional flow cytometry, or purified with a cell sorter for downstream genomic and functional assays.

Applying machine learning models to determine early postoperative mortality and survival in liver transplantation

Applying machine learning models to determine early postoperative mortality and survival in liver transplantation

Renal replacement therapy prior to liver transplant and inpatient mortality in patients without advanced kidney disease: A nationwide study.

The utility of renal replacement therapy (RRT) before liver transplant (LT) in patients without end-stage renal disease (ESRD) or advanced chronic kidney disease (CKD-IV/V) is debatable and lacks data support. We aimed to evaluate the impact of RRT on patients undergoing LT. We used the National Readmission Database (2016-2019) to identify all index hospitalizations undergoing RRT before LT (cases). A matched comparison cohort of similar hospitalizations without RRT before LT was identified (controls) after 1:1 propensity score matching for age, gender, and available comorbidities. We matched 364 cases (RRT before LT) to 364 controls (LT without prior RRT). There was no statistical difference in all-cause inpatient mortality (4.9% vs 3.6% P = 0.4). A significantly greater proportion of cases were associated with ICU admission (40.7% vs 17.0%, P < 0.001) and RRT requirement post LT (100% vs 17%, P < 0.001). There was no difference in 30- (hazard ratio [HR] 1.1, 0.4-2.6), 60- (HR 0.9, 0.4-1.8), or 90-day (HR 0.8, 0.4-1.6) inpatient mortality between the groups. Also, 180-day survival estimates were comparable (P = 0.5). The results were similar in patients with no chronic kidney disease (CKD) and CKD-III. RRT prior to LT, in patients without advanced CKD or ESRD, was associated with greater instances of ICU stay and need for future RRT. Also, 30-, 60-, and 90-day inpatient mortality rates were similar, and 180-day survival estimates were comparable.

HEPATOPULMONARY SYNDROME IN PEDIATRIC PATIENTS WITH PORTAL HYPERTENSION - AN INTEGRATIVE REVIEW.

Hepatopulmonary syndrome (HPS) is characterized by the triad of abnormal arterial oxygenation caused by intrapulmonary vascular dilatations (IPVD) in the setting of advanced liver disease or portal hypertension, impacting the patient's quality of life and survival. There are still many gaps in the literature on this topic, especially in pediatrics, with practices frequently based on extrapolation of data obtained from adults. Provide a synthesis of the current knowledge about HPS in children. The research was carried out through narrative review. The databases used for the search include Medline, Embase, Elsevier, Lilacs and Scielo. The keywords used were "hepatopulmonary syndrome" AND child, children, infant, preschool, pediatric. In cirrhotic children, the prevalence of HPS can reach up to 42.5%, and it is even more common in those whose underlying condition is biliary atresia, reaching up to 63%. Screening with pulse oximetry (O2 saturation <96%), unlike in adults, has low sensitivity in the pediatric age group. Management involves supportive care with oxygen therapy; liver transplantation is the only definitive treatment to reverse the condition and HPS is considered an exceptional criterion for waitlist. The waitlist mortality is similar among children listed by HPS as a special criterion when compared to those listed for other reasons. The reported rates of complete resolution of hypo-xemia after liver transplantation are close to 100% in children. The post-liver transplantation survival is similar or slightly lower in children with HPS when compared to those without HPS. Contrary to findings from adults, no differences were found in post- liver transplantation mortality between children of different hypoxemia ranges, although longer mechanical ventilation time and hospital stay were observed in children with PaO2 <50 mmHg. HPS is not an uncommon complication of cirrhosis in children and adolescents, particularly when biliary atresia is the underlying condition. There are still many gaps to be filled regarding the condition, and this article demonstrates that not all data obtained in studies with adults reflects the disease's behavior in pediatrics, especially concerning prognosis.

The impact of hepatitis B and C positive serologies on the outcomes of non-hepatic solid organ transplantation in the United States.

Chronic viral hepatitis B (HBV) and C (HCV) infection could negatively affect outcomes of non-hepatic solid organ transplantations due to the risk of viral reactivation in the presence of immunosuppression. This study aimed to determine post-transplant outcomes in patients with HBV or HCV positivity receiving non-hepatic solid-state organ transplant. Data was collected from the Scientific Registry of Transplant Recipients (SRTR) 2006-2021 for patients (≥18) who received a lung, heart, or kidney single organ transplant in the U.S. Hepatitis C positivity (HCV+) was determined as positive HCV Ab and hepatitis B positivity (HBV+) as positive HBsAg. We included N = 30,872 lung, N = 36,990 heart and N = 280,162 kidney transplant recipients. The prevalence of HBV+ was 1.3% in lung, 1.5% in heart and 1.7% in kidney patients, HCV+ was 2.2%, 2.2% and 5.0%, respectively. Post-transplant survival of patients with vs. without HBV+ was similar in all solid organ transplants (all p > .05). Similarly, there was no difference in post-transplant survival between lung transplant recipients with vs. without anti-HCV (all p > .05). Heart transplant recipients with HCV+ had higher crude post-transplant mortality (all p < .01). Similarly, there was higher post-transplant mortality in kidney transplant recipients with HCV+ (1-year: 6% vs. 3%; 5-year: 21% vs. 13%; 10-year: 47% vs. 31%; all p < .0001). In multivariate analysis controlling for confounders, only the association of HCV+ with higher post-kidney transplant mortality remained significant: adjusted hazard ratio (aHR) (95% CI) = 1.16 (1.12-1.20), p < .0001. There was no association of viral hepatitis seropositivity with the risk of graft failure in all groups (p > .05). In most cases, the presence of HBV or HCV serologies is not associated with adverse post-transplant outcomes in non-hepatic solid organ transplants. However, kidney transplant recipients who are positive for HCV serology have an increased risk for post-transplant mortality.

Financial Toxicity and Quality of Life in Patients Undergoing Stem-Cell Transplant Evaluation: A Single-Center Analysis.

We investigated the prevalence of financial toxicity in a population undergoing hematopoietic cell transplantation (HCT) evaluation and measured its impact on post-transplant clinical and health-related quality-of-life outcomes. This was a prospective study in patients undergoing evaluation for allogeneic HCT between January 1, 2018, and September 23, 2020, at a large academic medical center. Financial health was measured via a baseline survey and the comprehensive score for financial toxicity-functional assessment of chronic illness therapy (COST-FACIT) survey. The cohort was divided into three groups: none (grade 0), mild (grade 1), and moderate-high financial toxicity (grades 2-3). Health-related quality of life outcomes were measured at multiple time points. Multivariate logistic regression analysis evaluated factors associated with financial toxicity. Kaplan-Meier curves and log-rank tests was used to evaluate overall survival (OS) and nonrelapse survival. Of 245 patients evaluated for transplant, 176 (71.8%) completed both questionnaires (median age was 57 years, 63.1% were male, 72.2% were White, and 39.2% had myelodysplastic syndrome, 38.1% leukemia, and 13.6% lymphoma). At initial evaluation, 83 (47.2%) patients reported no financial toxicity, 51 (29.0%) with mild, and 42 (23.9%) with moderate-high financial toxicity. Patients with financial toxicity reported significant cost-cutting behaviors, including reduced spending on food or clothing, using their savings, or not filling a prescription because of costs (P < .0001). Quality of life was lower in patients with moderate-high financial toxicity at 6 months (P = .0007) and 1 year (P = .0075) after transplant. Older age (>62; odds ratio [OR], 0.33 [95% CI, 0.13 to 0.79]; P = .04) and income ≥$60,000 in US dollars (USD) (OR, 0.17 [95% CI, 0.08 to 0.38]; P < .0001) were associated with lower odds of financial toxicity. No association was noted between financial toxicity and selection for transplant, OS, or nonrelapse mortality. Financial toxicity was highly correlated with patient-reported changes in compensatory behavior, with notable impact on patient quality of life after transplant.

Optimizing Outcomes with Myeloablative Conditioning in Older Patients: Efficacy and Safety of Precision Engineered Orca-T in Patients > 55 Years Old with Hematologic Malignancies

Background Allogeneic hematopoietic stem cell transplants (alloSCT) offer the only curative treatment for many hematological cancers but carry the risk of significant toxicity including graft versus host disease (GvHD). Additionally, while the use of a myeloablative conditioning (MAC) regimen optimizes disease control, it can increase the complications associated with transplant and non-relapse mortality. Therefore, older patients are often deemed unfit for MAC and relegated to treatment with reduced intensity conditioning (RIC) regimens, which result in a higher incidence of relapse. Orca-T is a high-precision cell therapy biologic that includes stem and immune cells, derived from allogeneic donors, that leverages highly purified, polyclonal donor regulatory T cells to control alloreactive immune responses. The specific subsets selected in the Orca-T manufacturing process retain cells with therapeutic benefit while removing those that pose potential risks, allowing for intensification of concomitant chemotherapy and resulting in overall positive outcomes to date in the phase 1b trial (NCT04013685). To assess the safety and efficacy in an older patient population, we compared outcomes in those at least 55 years old to younger patients treated with Orca-T, receiving chemotherapy-based MAC with tacrolimus as single-agent GvHD prophylaxis. Methods As of 6/02/23, 38 patients ≥18 to &amp;lt;55 (younger) and 25 patients ≥55 years of age (older) received Orca-T as part of a multicenter Phase 1b single-arm trial and had the following diagnosis: acute myeloid, lymphoid or mixed phenotype leukemia in CR/CRi, myelodysplastic syndrome or chronic myeloid leukemia that was in chronic phase. Patients with active disease at the time of transplantation and patients with myelofibrosis were not included in this analysis. Patients received a myeloablative regimen consisting of intravenous busulfan, fludarabine, and thiotepa (BFT) prior to Orca-T, followed by single-agent GvHD prophylaxis with tacrolimus, and had an 8/8 related or unrelated matched donor. Donors were matched via DNA-based high-resolution typing of HLA-A, -B, -C, and -DRB1. Results Orca-T was successfully manufactured at a centralized GMP facility, distributed and infused at study sites throughout the U.S. Vein-to-vein time (i.e. time between end of donor apheresis to start of recipient's Orca-T infusion) was &amp;lt; 72 hours for all patients, majority &amp;lt; 60 hours. Median age was 47 in the younger group and 59 in the older group. The younger group was 50% female, and the older group was 36% female. The percentage that were of Hispanic or Latino ethnicity were 11% in the younger group, and 12% in the older group. 8%, 74% and 11% vs 12%, 44% and 32% had ALL, AML and MDS in the younger and older groups, respectively. A greater proportion of patients in the younger group had a baseline HCT-CI score of 0 (53%), while more had a baseline HCT-CI score of 4 (12%) in the older group. The median duration of follow-up for both groups was 12 months (Table). Disease free survival at 1 year was similar in both groups at 89% in the younger patients and 86% in the older patients (Figure). Modified GRFS* rate at 12 months among patients in the younger group was 86% compared to 77% in the older group. Non-relapse mortality at 1 year was 0% in both of these groups who received BFT MAC. Overall survival was high at 100% and 96% at 12 months in the younger and older patients, respectively. There were two patients &amp;gt; 65 when they received Orca-T; both remain alive without evidence of grade 3-4 acute GvHD, moderate to severe cGvHD, or relapse to date. Only 2 patients experienced grade 3 mucositis (no grade 4-5) and 1 younger patient (2.6%) and 1 older patient (4.0%) required total parenteral nutrition. Conclusions Our analysis suggests that Orca-T cell therapy represents a reduced toxicity alternative to conventional transplant and is well-tolerated by patients 55 and older, with comparable clinical outcomes to those 18 - &amp;lt; 55. In both patient groups, relapse incidence was low, with high GRFS. Remarkably, non-relapse mortality was zero at 1 year with excellent overall survival , suggesting that this regimen could potentially improve outcomes for older patients. An ongoing Phase 3 trial evaluating Orca-T vs. standard of care is currently enrolling throughout the United States.

Zinc Status Affects T Cell Reconstitution in Patients Receiving Naïve T Cell Depleted Allogeneic HSCT

Delayed immune reconstitution (IR) is a major clinical problem contributing to post-allogeneic hematopoietic stem cell transplant (allo-HSCT) morbidity and mortality. Specifically, CD4 T cell reconstitution is linked with improved clinical outcomes. As the primary organ of T cell production, the thymus is a crucial contributor to T cell reconstitution after HSCT generating a broad T cell receptor (TCR) repertoire selected through central tolerance However, T cell reconstitution can be hindered by poor thymus function as a consequence of age, transplant conditioning, or graft versus host disease (GVHD). At present, no drugs are available to boost T cell recovery, while many of the factors limiting IR are still unknown. Zinc (Zn), the second most abundant trace element in our body, is important for normal T cell development. Zn deficiency (ZD) in humans and mice is characterized by poor circulating T cells and depressed thymic function, which are both restorable after reintroduction of Zn with the diet. Despite having multiple risk factors for ZD, there are no published data focusing on ZD prevalence among allo-HSCT recipients. Based on our previous observations, we hypothesized that peri-HSCT Zn levels correlate with IR. In this study, we analyzed serum Zn levels of allo-HSCT patients who received naïve T cell (T N) depleted grafts as a strategy to prevent aGVHD (Bleakley et al., 2022, NCT00914940). This population is particularly interesting for studying IR because in these patients, circulating T N at d+365 after HSCT will primarily be of donor hematopoietic stem cell origin generated in the recipient thymus. Samples and clinical data were prospectively collected. Fifty-two patients had peri-HSCT serum samples available for Zn measures, as pre-HSCT and/or day +80 samples. Zn measures were performed through mass-spectrometry at the University of Washington Hospital-Biochemistry Lab. ZD was defined for Zn&amp;lt;70ug/dL as defined by the WHO. T cell populations (CD4 +, CD8 +, T N CD4 + and CD8 +, T regulatory cells, NK cells, B cells) were analyzed by flow cytometry at day+365. DNA was extracted from PBMC pellets collected at d+365 and were analyzed in qPCR for the expression of signal-joint T cell receptor excision circles (sjTRECs), being the gold standard for measuring thymic-derived T cells. We studied the association between Zn levels at baseline and day+80 and parameters of IR through linear regression. Comparisons between two groups were analyzed by t-test. Median age at transplant was 47 (range 6-61). Twenty-eight patients received myeloablative conditioning with total body irradiation (TBI) of 13.2 Gy (53.8%) and 24 (46.2%) received an intermediate intensity conditioning regimen with 4Gy TBI. Forty-one patients (78.8%) had pre-HSCT and 46 (88.5%) had day+80 Zn measures; 38 patients (73.1%) had both pre-HSCT and day+80 Zn measures. Median pre-HSCT and day+80 Zn levels were, respectively, 71 (range 60-105) and 80 (range 36-112); at baseline, 13 patients (25%) had ZD (&amp;lt;70ug/dL, according to WHO), whereas seven (13.3%) were ZD at day+80. Median sjTRECs at day +365 were 3.33/mg of DNA (range 0.00-16,704.54). As expected, sjTRECs at day+365 significantly correlated with age at transplant (r 2=0,3824; p&amp;lt;0.0001), whereas Zn levels preHCT or day80 did not. The number of circulating CD4 + and CD8 + T N at day+365 showed significant correlation with age. Zinc levels did not correlate with IR of absolute CD4 +, CD8 +, NK, T regs, and B cells at day+365, although we observed a trend for lower CD4 + counts at day 365 with lower day+80 Zn levels. Day+80 serum Zn levels was associated with sjTRECs at day+365 (Figure 1A. r 2=0.2643; p=0.0019) and lower pre-HSCT Zn significantly correlated with worse CD8 +T N reconstitution at day+365 (Figure 1B. r 2=0.1433; p= 0.0327), with clear trends in the same direction also for pre-HSCT Zn and CD4 + T N and day+80 Zn and CD4 + T N. In conclusion, we found that a non-negligible population of patients undergo allo-HSCT with unrecognized ZD. Peri-transplant Zinc status negatively affects IR, especially on the thymic-derived T cell compartment. Early recognition of ZD and zinc supplementation might help prevent morbidity related to poor IR in a proportion of patients. A multivariable analysis looking at other clinical data and outcomes is ongoing. Validation of these findings is needed on a larger number of patients, including a cohort of patients receiving T N-replete HSCT.

Improve the prediction of liver transplant mortality based on pre-transplant factors: A multi-center study from China: Mortality prediction of LT

AimsTo designed a new model using pre-transplant data to predict post-transplant mortality for Chinese population and compared its performance to that of existing models. MethodsIn this multicenter study, 544 recipients of liver transplants for non-tumor indications were enrolled in the training group and 276 patients in the validation group. The new Simplified Mortality Prediction Scores (SMOPS) model was compared to the MELD and four existing models using the C-statistic. ResultsSMOPS model used 6 independent pre-transplantation risk factors screened from the training group (chronic liver failure/organ failure scores, fever > 37.6 ℃, ABO blood-type compatibility, arterial lactate level, leukocyte count and re-transplantation). The SMOPS accurately predicted patients' 30-day, 90-day and 365-day mortality following liver transplantation, and its' scores were more accurate than those of the other models. The SMOPS generated four levels of risk: low risk (<10 points), moderate risk (11–20 points), high risk (21–25 points) and futile risk (≥26 points). The survival within all risk levels was not different between MELD=40 and MELD<40. The survival within moderate-, high- or extreme-risk ALF was not different between ALF and non-ALF. ConclusionThe SMOPS model uses pre-transplant risk factors to stratify post-transplant survival and is superior to current models for Chinese population, and has the potential to contribute to improvements in organ-allocation policies.

Validation of a new CPET multivariable score to predict cardiovascular events in heart failure patients

Abstract Introduction Cardiopulmonary exercise testing (CPET) is recommended in patients with heart failure (HF) to optimize exercise prescription and as part of the evaluation for heart transplantation. Recently, a new multivariable score (MVS) was proposed as a powerful method to predict HF events with an optimal cut-off value of 120. Purpose We aimed to evaluate the prognostic value of this tool in patients with HF. Methods We conducted a single-centre study assessing consecutive patients with HF who underwent CPET from 2013 to 2017. Classic and recently proposed variables were collected, including peak O2 uptake (pVO2), minute ventilation–CO2 production (VE/VCO2 slope), partial pressure of end-tidal CO2 at the anaerobic threshold (PETCO2L), circulatory power (CP=pVO2 x peak SBP), and ventilatory power (VP=peak SBP/(VE/VCO2) slope). The score was calculated as follows: (pVO2 × 2.194) + (PETCO2L × 1.545) + (LVEF × 1.134) + (HR × 1.055; 0 if AF, 1 if sinus rhythm). The primary outcome was a composite of HF hospitalization, heart transplant, and all-cause mortality. Results We included 212 patients 76.9% male and with a mean age of 55.4±10.9 years-old. The most frequent aetiology was dilated cardiomyopathy (43.9%) followed by ischaemic heart disease (38.7%). Accordingly, the mean left ventricle ejection fraction was 29±13%. Additionally, 39.8% had atrial fibrillation. The most used exercise protocol was the modified Naughton (76.6%). Mean pVO2 was 16.7±5.9mL O2·kg−1·min−1, median VE/VCO2 slope was 37.5 [32.7-44.3], and PETCO2L 33.5±5.2mmHg. Mean VP was 3.46±1.31mmHg while the median CP was 1927 [1427-2697]mmHg·min/mL/kg. The mean MVS was 116.2±23.1. Despite weak, there were significant positive correlations between the MVS and both VP (r=0.59, p&amp;lt;0.01) and CP (rs=0.64, p&amp;lt;0.01). After a median follow-up of 71 [49-81] months, the primary outcome occurred in 66.0% of patients (rehospitalization, heart transplant, and all-cause death occurred in 56.1%, 25.9%, and 32.5%, respectively). The new CPET MVS was associated with the primary outcome (p&amp;lt;0.01). Additionally, patients with MVS &amp;lt;120 had a higher rate of the primary outcome (83.2% vs. 39.1%, p&amp;lt;0.01). Kaplan-Meier estimates of tthe primary outcome according to the optimal cut-off value of 120 are shown in Figure 1A. Receiver operating characteristic curve revealed that the MVS has higher discriminative power for the primary endpoint (AUC 0.80, p&amp;lt;0.01) compared to pVVO2, VP, and CP (Figure 1B). Conclusion The novel multivariable score is associated with the composite of HF hospitalization, heart transplant, and all-cause mortality in patients with heart failure, enhancing the role of CPET in risk stratification.

Impact on mortality of heart transplantation preceded or not by continuous-flow left ventricular assist devices

Abstract Background Heart transplant (HT) is the therapy of choice in end-stage heart failure patients. With the scarcity of donors, bridge to transplantation (BTT) with left ventricular assist device (LVAD) becomes an option in patients awaiting HT. Criteria for HT listing do not differ between patients medically managed and those mechanically bridged to HT. Objectives The objectives of the present study is to assess the survival following HT preceding or not with LVAD as BTT and to evaluate differences in risk factors for 4-year mortality between those with (LVAD +) and those without LVAD (LVAD -) at the time of HT. Methods Using the local database, we identified 145 heart-transplanted adults (LVAD +, n=28 and LVAD -, n=117) between 2000 and 2020. Patients were propensity matched for likelihood of LVAD at the time of HT. Kaplan-Meier survival estimates were used to assess the impact of BTT on 30-day and 4-year mortality. Logistic regression analysis was used to evaluate the odds ratio of 4-year mortality for patients BTT with LVAD compared with those with medical management across clinically significant variables at various thresholds. Results 30-day and 4-year post HT mortalities were similar in mechanically bridged patients or not: 10,7% versus 11,1% mortality (P=0,71), and 32,1% versus 35,9% mortality (P=0,61), respectively. Because outcomes were similar in both groups, risk factors for 4-year mortality were investigated in the total cohort of HT. Diabetes at the time of HT (CI [1.93–10.72], OR=4,55, p= 0.001), early post-HT hemorrhage (CI [2,01–15.23], OR=5,53, p= 0.001), and ventricular arrhythmia (CI [1.08–7,51], OR=2,84, p= 0.001) and late HT antidepressant drugs use (CI [0,02–0,51], OR=0,11, p= 0.005), incurred in the risk of 4-year mortality. Conclusions Bridge to HT with LVAD, although necessary because of organ scarcity and capable of improving wait list survival, confers no significantly risk of early and late posttransplantation mortality. Diabetes may require more careful consideration for transplant eligibility while antidepressant use are protective.Figure 1