International Society For Heart And Lung Transplantation Research Articles

Temporary Mechanical Circulatory Support During Bariatric Surgery: A Novel Bridge to Durable Left Ventricular Assist Device and Cardiac Transplantation.

Advanced heart failure (HF) with comorbid severe obesity presents a unique surgical dilemma: bariatric surgery may help patients meet cardiac transplantation body mass index (BMI) criteria, but poor cardiac function puts them at increased intraoperative risk. Per International Society for Heart and Lung Transplantation (ISHLT) guidelines BMI > 35 is a contraindication for orthotopic heart transplantation. Temporary mechanical circulatory support (MCS) with Impella 5.5 during bariatric surgery, as presented in this report, may help solve this dilemma for some patients. We present three patients with severe obesity and advanced heart failure (HF) who underwent successful bariatric surgery while supported by Impella 5.5 (Abiomed, Inc., Danvers, MA).

Abstract CT278: [DREAM] Double lung transplant registry aimed for lung-limited malignancies - a prospective registry study for medically refractory cancers

Abstract BackgroundAdenocarcinoma in situ (AIS) and minimally invasive adenocarcinoma (MIA) are listed as ‘special circumstances’ for lung transplantation according to a consensus document from the International Society for Heart and Lung Transplantation (ISHLT) (Weill D et al., 2015). Five studies have reported on lung transplantation in carefully selected subsets of patients with multifocal lung adenocarcinoma (Raemdonck DV et al., 2016; Glanville AR et al., 2018). The 5-year survival rate of bilateral sequential lung transplantation was estimated at over 50% in patients with multifocal BAC, invasive adenocarcinoma, and NSCLC (Ahmad U et al., 2012; Paloyan EB et al., 2000; Zorn GL et al., 2003; de Perrot M et al., 2004). Another a case series reported a post-transplant recurrence-free survival of 23 to 56 months in three patients (Garver RI et al., 1999). Moreover, there is an unmet need for patients who have lung-limited metastasis after successful treatment for primary tumors such as sarcomas or colorectal cancer (CRC). As with liver transplantation for CRC patients who have liver-confined metastases (Dueland S et at., 2020; Hernandez-Alejandro R et al., 2022), the applicability of lung transplantation in lung-limited metastatic patients should be explored. There is also an unmet need for patients with respiratory failure with a history of cancer in the last 5 years. MethodsThis is a prospective registration trial to evaluate outcomes of patients who undergo double lung transplantation for the treatment of the select groups of medically refractory cancers (primary lung cancers or metastatic cancers in lungs). Overall survival (OS), disease-free survival (DFS), allograft rejection (AR) and allograft survival (AS) as well as molecular and genetic biomarkers will be monitored to investigate the correlation with prognosis.The study duration will be 10 years including surveillance. Recruitment is to occur during the first 5 years of the study. The goal is to enroll 125 participants through the Northwestern Medicine Clinical Programs.Essential Criteria:1.The tumor should be without any extrapulmonary metastasis as determined by standard of care diagnostic and staging workup.2.All standard of care or experimental oncological treatments known to improve survival should have failed or deemed infeasible 3.Patients should meet the general criteria for lung transplant evaluation and listing Study cohorts:•Cohort A: Primary lung cancers - Examples include, but not limited to, invasive mucinous/non-mucinous non-small cell lung cancers and multifocal carcinomas.•Cohort B: Metastatic cancers to the lung only - Examples include, but not limited to, germ cell tumors, head & neck tumors, colorectal tumors, renal cell tumors, testicular cancers.•Cohort C: Respiratory failure with a history of cancer in the last 5 years- Examples include, but not limited to interstitial lung disease (ILD), pulmonary fibrosis (idiopathic or secondary), advanced chronic obstructive pulmonary disease (COPD), bronchiectasis, emphysema, cystic fibrosis (CF), emphysema due to alpha-1 antitrypsin deficiency, and pulmonary arterial hypertension (PAH) Clinical trial registry number : NCT05671887.Enrollment began November 16, 2022. Trial is open and continues to enroll participants as of Jan 8, 2024. Citation Format: Young Kwang Chae, Liam Il-Young Chung, Rade Tomic, Ankit Bharat. [DREAM] Double lung transplant registry aimed for lung-limited malignancies - a prospective registry study for medically refractory cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT278.

A COMPARISON OF GUIDELINES FOR HEART TRANSPLANT CONSIDERATION BASED ON CPET DATA

BACKGROUND The International Society for Heart and Lung Transplantation (ISHLT) recommends using peak oxygen uptake (VO2≤12 mL/kg/min), percent predicted peak VO2 (ppVO2≤50%), or the ventilation to carbon dioxide slope (VE/VCO2 slope>35) to guide listing for heart transplantation (HTx) in patients with heart failure with reduced ejection fraction (HFrEF). Data comparing the mortality rates between each of these thresholds is lacking. The purpose of this retrospective cohort study was to describe the 3-year mortality rate among patients with HFrEF based on the ISHLT recommendations. METHODS This was a secondary analysis of a combined cohort of patients (≥18 years) with HFrEF from Henry Ford Hospital (n=1,063) and the HF-ACTION study (n=1,772). The cohort was limited to patients who completed a cardiopulmonary exercise test on a treadmill and were prescribed a beta-adrenergic blockade at the time of the test. The primary outcome was probability of all-cause mortality at 3 years based on Kaplan-Meier estimates. Patients were censored at the date of HTx, left ventricular assist device implant, or last known alive. Mortality rates were calculated for patients with a peak VO2≤12 mL/kg/min, ppVO2≤50%, and VE/VCO2 slope>35. The cohort was stratified by sex, age, obesity (body mass index [BMI]> 30 kg/m2), and peak respiratory exchange ratio (RER). Mortality rates were compared to the 3-year mortality post HTx reported by ISHLT. RESULTS In our combined cohort (n=2,775; age=57±13 y; 19% women; 48% non-white), 3-year mortality for peak VO2≤12 mL/kg/min, ppVO2≤50%, and VE/VCO2 slope>35 was 30%, 31%, and 28%, respectively. Each of these are higher than the 3-year mortality post HTx (20%). Similar results were observed by age below/above 50 y, BMI < versus > 30 kg/m2, RER ≤ versus >1.05, and within men. However, among women the 3-year mortality was 18% for peak VO2≤12 mL/kg/min, 25% for ppVO2≤50%, and 21% for VE/VCO2 slope>35. CONCLUSIONS ISHLT recommendations to guide listing for HTx for peak VO2≤12 mL/kg/min, ppVO2≤50%, and VE/VCO2 slope>35 are associated with a higher 3-year mortality than patients post HTx irrespective of age, obesity, and RER. However, among women only ppVO2≤50% and VE/VCO2 slope>35 identify patients with 3-year mortality that is higher than HTx.

Informing preconception counseling: Outcomes among female heart transplant recipients in the ISHLT registry

The numbers of women of child-bearing age undergoing heart transplantation (HT) and female pediatric HT recipients surviving to child-bearing age have increased, along with improvements in post-transplant survival. Data regarding life expectancy and comorbidities in reproductive-aged female HT recipients are needed to inform shared decision-making at the time of preconception counseling. The International Society for Heart and Lung Transplantation (ISHLT) Thoracic Organ Transplant Registry was investigated for HT recipients between January 1, 2000 and June 30, 2017. Women of childbearing age were defined as those aged 15-45 years, either at transplant, or at the respective post-transplant follow-up. Characteristics and outcomes of female recipients of childbearing age at transplant, 5-, 10-, and 15-year follow-up were compared to females>45 years of age, males 15-45 years and males>45 years of age at the corresponding time intervals. Outcomes included survival, development of diabetes (DM), severe renal dysfunction (CKD), and cardiac allograft vasculopathy (CAV). During the study period, 71,585 HT recipients were included: 24% (n=17,194) were female and 9.2% (n=6602) were of childbearing age at HT. A pre-transplant diagnosis of peripartum cardiomyopathy was associated with significantly worse post-transplant survival, a finding that remained independent of panel reactive antibody levels. The presence of pre-transplant DM and/or severe CKD was significantly associated with lower survival as were the presence of CAV, DM, and CKD post-HT. Knowledge of the impact of pre-existing comorbidities and complications post-HT on survival are important for risk stratification for preconception counseling post-HT.

Pediatric heart transplantation: Looking forward after five decades of learning.

Heart transplantation has become the standard of care for pediatric patients with end-stage heart disease throughout the world. Since the first transplant was performed in 1967, the number of transplants has grown dramatically with 13 449 pediatric heart transplants being reported to The International Society of Heart and Lung Transplant (ISHLT) between January 1992 and June 30, 2018. Outcomes have consistently improved over the last few decades, specifically short-term outcomes. Most recent survival data demonstrate that recipients who survive to 1-year post-transplant have excellent long-term survival with more than 60% of those who were transplanted as infants being alive 25 years later. Nonetheless, the rates of graft loss beyond the first year have remained relatively constant over time; driven primarily by our poor understanding and lack of treatments for chronic allograft vasculopathy (CAV). Acute rejection, CAV, graft failure, and infection continue to be the major causes of death within the first 5 years post-transplant. In addition, renal dysfunction, malignancy, and the need for re-transplantation remain as significant issues that require close follow-up. Looking forward, key challenges include improving donor utilization rates (including donation after cardiac death (DCD) and the use of exvivo perfusion devices), the development of non-invasive biomarkers for rejection, efforts to mitigate the long-term effects of immunosuppression, and prevention of CAV. It is not possible to cover the entire evolution of pediatric heart transplantation over the last five decades, but in this review, we hope to touch on key observations, lessons learned, and practice changes that have advanced the field, as well as glance ahead to the next decade.

Reduction of cardiac allograft vasculopathy by PCI: Quantification and correlation with outcome after heart transplantation

Abstract Background Percutaneous coronary intervention (PCI) might improve outcome of heart transplanted (HTx) patients at severe stages of cardiac allograft vasculopathy (CAV). Yet, risk stratification of HTx patients after PCI remains challenging. The International Society for Heart and Lung Transplantation (ISHLT) provides a nomenclature for CAV classification that does not include patients after PCI (1). It is unclear how to define an individual optimal CAV reduction and how to stratify patients with CAV after PCI. Besides, whether risk-stratification tools of non-transplanted patients apply to HTx patients with CAV is uncertain. Purpose To assess whether the ISHLT CAV classification remains prognostic after PCI, and whether risk stratification models of non-transplanted patients can be applied to HTx patients with CAV. Methods At two European academic centers, 203 patients were stratified according to CAV severity and PCI history, and patients were assigned to only one cohort: cohort 1 (ISHLT CAV grade 1, without PCI, n=126) or cohort 2 (ISHLT CAV grades 2&3, with PCI). At first diagnosis of CAV or first PCI, respectively, ISHLT CAV grades, SYNTAX scores I and II (SXS-I and SXS-II) were used to quantify baseline and residual CAV (rISHLT, rSXS-I, rSXS-II). A rSXS-I>0 defined incomplete revascularization (IR). Five-year mortality was assessed. For cohort 2, first reintervention was a secondary outcome. Baseline parameters were also included into analysis. Results SXS-II predicted mortality in cohort 1 (Hazard ratio [HR] 2.5 [1.4–4.8], p=0.004), whereas SXS-I (HR 4.2 [1.4–12.2], p=0.009) and SXS-II (HR 7.1 [2.0–24.5], p=0.002) predicted mortality in cohort 2. Post-PCI, IR (HR 5.4 [1.7–17.0], p=0.004), high rISHLT (HR 3.6 [1.3–10.2], p=0.02) and highest tertile of rSXS-II (HR 5.1 [1.6–15.9], p=0.006) were associated with higher mortality. In cohort 2, post-transplant interval and KDIGO category of renal function at timepoint 0 were also predictors of 5-year mortality after first PCI (HR 1.1 [1.0 – 1.2], p=0.004 and HR 4.5 [1.8–11.3], p=0.01, respectively). In bivariable Cox analysis, baseline SXS-II, IR, rSXS-II, post-transplant interval and KDIGO category of renal function remained predictors of 5-year mortality. The interval to first reintervention was inversely related to baseline SXS-I (r=-0.55, p<0.001) and rSXS-I (r=-0.50, p=0.003). Conclusion A higher reduction of stenotic CAV was associated with improved 5-year survival rate after first PCI. ISHLT CAV classification could apply for risk stratification after PCI and SYNTAX-scores could be complemental for risk stratification and individualization of invasive follow-up of HTx patients with CAV.Figure 1.Study flow chart.Figure 2.Kaplan-Meier curves (cohort 2)

A 5-year single-center experience in heart transplantation in Rostov oblast

Objective: to evaluate the outcomes of heart transplants performed at Rostov Regional Clinical Hospital within five years.Materials and methods. Between 2017 and 2022, 29 orthotopic heart transplants (HT) were performed in our clinic. Heart failure was caused by postinfarction cardiosclerosis (21 cases, 72.4%) and dilated cardiomyopathy (8 cases, 27.6%). Among the recipients, 27 (93.1%) were men and 2 (6.9%) were women. Mean age was 53.14 ± 8.7 years (34 to 67 years). All patients received quadruple-drug immunosuppressive therapy, including induction with monoclonal antibodies; calcineurin inhibitor, mycophenolic acid, and corticosteroid were used after HT.Results. In-hospital mortality was 10.34% (n = 3). The causes of death were multiple organ failure and infectious and septic complications. After discharge, 4 (13.8%) recipients died over 5 years. Rejection reaction with the development of graft dysfunction (3 recipients, 75%), infectious and septic complications (1 recipient, 25%) were the causes of death in the long-term period. The survival rate was analyzed according to the Kaplan–Meier estimate. One-year survival was 80.9%. Three-year survival rate corresponded to the 5-year survival rate – 70.56%. Five-year survival of patients surviving the first year after HT was 86.1%. Maximum follow-up period was 64 months.Conclusion. HT continues to be the gold standard for patients with end-stage heart failure. Five-year HT experience in our center has shown a survival rate that is comparable to that of the International Society for Heart and Lung Transplantation (ISHLT).

Lung Transplantation for Pulmonary Arterial Hypertension: Optimized Referral and Listing Based on an Evolving Disease Concept.

Pulmonary hypertension (PH) was once a devastating and fatal disease entity, the outlook of which has been significantly improved by the continued progress of medical treatment algorithms. However, some patients still ultimately fail to achieve an adequate clinical response despite receiving maximal medical treatment. Historically, lung transplantation (LTx) has been the only effective therapeutic option that could lead to satisfactory outcomes and save these advanced patients' lives. However, patients with PH tend to have the highest mortality rates on the transplant waiting list; especially after comprehensive medical treatment, they continue to deteriorate very rapidly, eventually missing optimal transplantation windows. Balancing optimized medical treatment with the appropriate timing of referral and listing has been highly controversial in LTx for patients with PH. The 2021 consensus document for the selection of lung transplant candidates from the International Society for Heart and Lung Transplantation (ISHLT) updated the specific recommendations for the LTx referral and listing time for patients with PH based on objective risk stratification. Herein, we review the evolving PH-related concepts and highlight the optimization of LTx referral and listing for patients with PH, as well as their management on the waiting list.

Cardiopulmonary Exercise Testing in the Age of New Heart Failure Therapies: Still a Powerful Tool?

New therapies with prognostic benefits have been recently introduced in heart failure with reduced ejection fraction (HFrEF) management. The aim of this study was to evaluate the prognostic power of current listing criteria for heart transplantation (HT) in an HFrEF cohort submitted to cardiopulmonary exercise testing (CPET) between 2009 and 2014 (group A) and between 2015 and 2018 (group B). Consecutive patients with HFrEF who underwent CPET were followed-up for cardiac death and urgent HT. CPET was performed in 487 patients. The composite endpoint occurred in 19.4% of group A vs. 7.4% of group B in a 36-month follow-up. Peak VO2 (pVO2) and VE/VCO2 slope were the strongest independent predictors of mortality. International Society for Heart and Lung Transplantation (ISHLT) thresholds of pVO2 ≤ 12 mL/kg/min (≤14 if intolerant to β-blockers) and VE/VCO2 slope > 35 presented a similar and lower Youden index, respectively, in group B compared to group A, and a lower positive predictive value. pVO2 ≤ 10 mL/kg/min and VE/VCO2 slope > 40 outperformed the traditional cut-offs. An ischemic etiology subanalysis showed similar results. ISHLT thresholds showed a lower overall prognostic effectiveness in a contemporary HFrEF population. Novel parameters may be needed to improve risk stratification.

Restrictive allograft dysfunction rather than bronchiolitis obliterans syndrome had a major impact on the overall survival after living-donor lobar lung transplantation.

Chronic lung allograft dysfunction (CLAD) is a known long-term fatal disorder after lung transplantation. In this study, we evaluated the CLAD classification of the International Society for Heart and Lung Transplantation (ISHLT) for living-donor lobar lung transplantation (LDLLT). We conducted a single-center retrospective review of data from 73 patients who underwent bilateral LDLLT between 1998 and 2019. Factors related to opacity on computed tomography (CT) and restriction on pulmonary function tests (PFTs) were also analyzed. Overall, 26 (36%) patients were diagnosed with CLAD, including restrictive allograft syndrome (RAS), n = 10 (38.5%); bronchiolitis obliterans syndrome (BOS), n = 8 (30.8%); mixed, n = 1 (3.8%); undefined, n = 2 (7.7%); and unclassified, n = 5 (19.2%). The 5-year survival rate after the CLAD onset was 60.7%. The survival of patients with BOS was significantly better than that of patients with RAS (p = 0.012). In particular, patients with restriction on PFT had a significantly worse survival than those without restriction (p = 0.001). CLAD after bilateral LDLLT does not have a major impact on the recipient survival, especially in patients with BOS. Restrictionon PFT may predict a particularly poor prognosis in patients with CLAD after bilateral LDLLT.

Risk of Infections With Long-Term Left Ventricular Assist Device Support.

We retrospectively reviewed all the patients who underwent new continuous-flow (C-F) LVAD implantation between January 1, 2013, and December 31, 2014, at the University of Nebraska Medical Center. Patients were followed until heart transplant, LVAD explantation, death, or December 31, 2017. We defined LVAD infections as per the International Society of Heart and Lung Transplantation (ISHLT) definition: VAD-specific, VAD-related, and non-VAD infections. The primary outcome was to calculate the incidence of LVAD infections per 1000 days of LVAD support. Secondary outcomes were to assess the cause of death and the effect of bloodstream infections on LVAD thrombosis, stroke, and death. During the study period, a total of 94 patients underwent a C-F LVAD implantation. Five patients were lost in follow-up; 89 patients were included in the study. The mean age at LVAD implantation was 54 (SD+15) years. Out of 89 patients, 67 (75%) were men, and 53/89 (71%) received LVAD as destination therapy (DT). At the time of LVAD implantation,34/89 (38%) patients had ITERMACS (interagency registry for mechanically assisted circulatory support)score 1 (cardiogenic shock). The median duration of LVAD support was 387+493 days, with an interquartile range of 140 to 1083 days. The incidence rate of infections post-LVAD implantation decreased from 3.2 /1000 LVAD days (95% confidence interval [CI] 2.54-4.03) during the first year of LVAD support to 0.78/1000 LVAD days (95% CI, 0.38-1.65) during the following third year of LVAD support. Similarly, the incidence of VAD-specific infections in the first year post-LVAD implantation versus the third-year post LVAD implantation decreased from 0.83/1000 LVAD days (95% CI, 0.53-1.30) to 0.33/1000 LVAD days (95% CI, 0.10-1.04). On univariate survival analysis, an increased risk of death was associated with a one-year increase in age at LVAD implantation (hazard ratio (HR) 1.05 (95% CI, 1.01-1.09), p=0.01), the presence of infection within 30 days before LVAD implantation (HR 2.44 (95% CI, 1.09-5.48), p=0.03), underlying ischemic cardiomyopathy (HR 2.96 (95% CI, 1.28-6.80), p=0.01), and lower ITERMACS profile HR 3.64 (95% CI, 1.09-12.13, p=0.04). Bloodstream infections (BSIs) were not associated with an increased risk of death (HR 1.63 (95% CI, 0.56-4.80, p=0.37). Univariate survival analysis for poor outcomes (LVAD thrombosis, stroke, or death) showed BSIs increased the risk of having a poor outcome (HR 2.39 (95% CI, 1.02-5.57), p=0.04). The incidence rate of post-LVAD infections decreased significantly over time. LVAD implantation may not be contributing to immune suppression as previously suggested. In our study, BSIs were found to have a significantly increased hazard ratio for a poor outcome post-LVAD implantation.

Clinical and Histopathologic Characteristics of Recurrent Sarcoidosis in Posttransplant Lungs: 25 Years of Experience.

Lung transplantation is the definitive therapy for end-stage pulmonary sarcoidosis. While recurrent sarcoidosis in allografts has been described in several case reports, the incidence and clinicopathologic characteristics remain unclear. In this study, we characterize the clinical and histopathologic features of recurrent sarcoidosis diagnosed in posttransplant lung surveillance transbronchial biopsies (TBBx). We identified 35 patients who underwent lung transplant for pulmonary sarcoidosis during the study period. Among them, 18 patients (51%) experienced recurrent sarcoidosis posttransplant. These included 7 females and 11 males with mean age at recurrence of 51.6 years. The average time interval from transplant to recurrence was 252 days (22 to 984d). All TBBx contained >4 pieces of alveolated lung tissue with no evidence of International Society for Heart and Lung Transplantation (ISHLT) grade A2, A3, or A4 acute cellular rejection; chronic rejection; or antibody-mediated rejection. There were 33 surveillance TBBx that contained granulomatous inflammation with a mean of 3.6 well-formed granulomas per TBBx (range: 1 to >20). Multinucleated giant cells were identified in 11 TBBx (33.3%), with 1 case containing asteroid bodies. While most of the granulomas were "naked granulomas," 5 cases (15.2%) showed prominent lymphoid cuffing. Two cases showed evidence of fibrosis. One of the granulomas had focal necrosis; however, no infectious organisms were identified by special stains and clinical correlation suggested this case represented recurrent sarcoidosis. Biopsies of recurrent sarcoidosis usually show multiple well-formed granulomas with giant cells in more than half of the cases, while lymphoid cuffing, fibrosis, asteroid bodies, and necrotizing granulomas are uncommon findings. Pathologists should be aware of these features, as recurrence of sarcoidosis following lung transplant occurs in more than half of patients.

Post-double lung transplantation survival outcomes of bilateral lung cancer and incidence of post-transplant lung cancer.

e21061 Background: To evaluate the role of double lung transplantation (DLT) for lung cancer, the survival outcomes of patients who underwent DLT for lung cancer and the incidence of lung cancer after DLT were assessed. Methods: Data from case series reported in the literature were pooled and collected from the Organ Procurement Transplantation Network (OPTN) and the International Society of Heart and Lung Transplantation (ISHLT) registries. We evaluated the recurrence-free survival (RFS), overall survival (OS), and cancer-specific survival (CSS) of patients who underwent DLT for lung cancer. Moreover, the incidence and OS of post-transplant lung cancer in patients who received transplants for the non-cancerous disease were examined. Results: Regarding patients who underwent DLT for lung cancer, in the pooled (n = 19), OPTN (n = 15), and ISHLT (n = 25) data, 5-year RFS was 52.6%, 66.7%, and 80.0%, and 5-year OS was 57.9%, 26.7%, and 36.0%, respectively. The median CSS was 48.0 (range, 6.0–144.0), 27.7 (range, 0.2–66.6), and 24.0 (range, 0.1–145.1) months. Additionally, the application of cardiopulmonary bypass was associated with lower tumor recurrence in the pooled data (p = 0.004). The incidence and 5-year OS post-transplant lung cancer in patients who underwent DLT for the non-cancerous disease were 0.8% and 47.3% in the OPTN data and 0.6% and 50.7% in the ISHLT data, respectively. Conclusions: We demonstrated that reasonable survival outcomes can be achieved with DLT in patients with bilateral lung cancer. Further studies are required to evaluate the risk of post-transplant lung cancer in patients undergoing DLT for bilateral lung cancer.

Abstract CT051: Double lung transplant registry aimed for lung-limited malignancies (DREAM) - a prospective registry study of bilateral lung transplantation for medically refractory cancers confined to the lungs

Abstract Background: According to a consensus document from the International Society for Heart and Lung Transplantation (ISHLT), adenocarcinoma in situ (AIS) and minimally invasive adenocarcinoma (MIA) are listed as ‘special circumstances’ for lung transplantation (Weill D et al., 2015). There have been five reported studies of lung transplantation in carefully selected subsets of patients with multifocal lung adenocarcinoma (Raemdonck DV et al., 2016; Glanville AR et al., 2018). The 5-year survival rate of bilateral sequential lung transplantation was estimated at over 50% in patients with multifocal BAC, invasive adenocarcinoma, and NSCLC (Ahmad U et al., 2012; Paloyan EB et al., 2000; Zorn GL et al., 2003; de Perrot M et al., 2004). In 1999, a case series reported a post-transplant recurrence-free survival of 23 to 56 months in three patients (Garver RI et al., 1999). There is also an unmet need for patients who have lung-limited metastasis after successful treatment for primary tumors such as sarcomas or colorectal cancer (CRC). As with liver transplantation for CRC patients who have liver-confined metastases (Dueland S et at., 2020; Hernandez-Alejandro R et al., 2022), the applicability of lung transplantation in lung-limited metastasis patients should be explored. Methods: This is a prospective registration trial to evaluate outcomes of patients who undergo lung transplantation for the treatment of the select groups of medically refractory cancers (primary lung cancers or metastatic cancers in lungs). Overall survival (OS), disease-free survival (DFS), allograft rejection (AR) and allograft survival (AS) will be monitored as well as molecular and genetic biomarkers to investigate the correlation with prognosis. The study duration will be 10 years including surveillance. Recruitment to occur during the first 5 years of the study. The goal is to enroll 175 participants through the Lurie Comprehensive Cancer Center of Northwestern University. Essential Criteria: The tumor should be without any involvement of mediastinal lymph nodes involvement confirmed by endobronchial ultrasound (EBUS) or mediastinoscopy. The patient who are resistant or refractory to or without available standard of care treatment options or experimental treatment options that are known to increase survival outcome. Study cohorts: • Cohort A: Primary lung cancers - Examples include, but not limited to, invasive mucinous/non-mucinous non-small cell lung cancers and multifocal carcinomas. • Cohort B: Metastatic cancers to the lung only - Examples include, but not limited to, germ cell tumors, head & neck tumors, colorectal tumors, renal cell tumors, testicular cancers. Clinical trial registry number: NCT05671887. Enrollment began November 16, 2022. Trial is open and recruiting as of January 12, 2023. Citation Format: Young Chae, Liam Il-Young Chung, Rade Tomic, Ankit Bharat. Double lung transplant registry aimed for lung-limited malignancies (DREAM) - a prospective registry study of bilateral lung transplantation for medically refractory cancers confined to the lungs [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT051.

Prediction of heart transplant rejection from routine pathology slides with self-supervised deep learning.

One of the most important complications of heart transplantation is organ rejection, which is diagnosed on endomyocardial biopsies by pathologists. Computer-based systems could assist in the diagnostic process and potentially improve reproducibility. Here, we evaluated the feasibility of using deep learning in predicting the degree of cellular rejection from pathology slides as defined by the International Society for Heart and Lung Transplantation (ISHLT) grading system. We collected 1079 histopathology slides from 325 patients from three transplant centres in Germany. We trained an attention-based deep neural network to predict rejection in the primary cohort and evaluated its performance using cross-validation and by deploying it to three cohorts. For binary prediction (rejection yes/no), the mean area under the receiver operating curve (AUROC) was 0.849 in the cross-validated experiment and 0.734, 0.729, and 0.716 in external validation cohorts. For a prediction of the ISHLT grade (0R, 1R, 2/3R), AUROCs were 0.835, 0.633, and 0.905 in the cross-validated experiment and 0.764, 0.597, and 0.913; 0.631, 0.633, and 0.682; and 0.722, 0.601, and 0.805 in the validation cohorts, respectively. The predictions of the artificial intelligence model were interpretable by human experts and highlighted plausible morphological patterns. We conclude that artificial intelligence can detect patterns of cellular transplant rejection in routine pathology, even when trained on small cohorts.

Severe and Moderate Primary Graft Dysfunction in Adult Heart Recipients.

The aims of this study were to determine the incidence of severe and moderate primary graft dysfunction (PGD) in our center, to identify, retrospectively, donors' and recipients' risk factors for PGD development, and to evaluate the impact of PGD within 30 days after heart transplantation. Donors' and recipients' medical records of 64 consecutive adult cardiac transplantations performed between January 2016 and June 2017 were reviewed. The International Society for Heart and Lung Transplantation (ISHLT) criteria were used to diagnose moderate and severe PGD. Associations of risk factors for combined moderate/severe PGD were assessed with appropriate statistical analyses. Sixty-four patients underwent heart transplantation in this period. Twelve recipients (18.7%) developed severe or moderate PGD. Development of PGD was associated with previous donor cardiopulmonary resuscitation and a history of prior heart surgery in the recipient (P=0.01 and P=0.02, respectively). The 30-day in hospital mortality was similar in both PGD and non-PGD patients. The use of the ISHLT criteria for PGD is important to identify potential risk factor. The development of PGD did not affect short-term survival in our study. More studies should be done to better understand the pathophysiology of PGD.

The International Society for Heart and Lung Transplantation (ISHLT) guidelines for the care of heart transplant recipients

David Baran, Tiffany Buda, Adam Cochrane, Maria Crespo Leiro, Anne Dipchand, Brian Feingold, Kathleen Grady, Edward Horn, Maryl Johnson, Donna Mancini, Sean Pinney, Heather Ross, Kari Wujcik, Andreas Zuckermann

A comparison of outcomes after lung transplantation between European and North American centers.

With advancements in basic science and clinical medicine, lung transplantation (LT) has evolved rapidly over the last three decades. However, it is unclear if significant regional variations exist in long-term outcomes after LT. To investigate potential differences, we performed a retrospective, comparative cohort analysis of adult patients undergoing deceased donor single or double LT in North America (NA) or Europe between January 2006 and December 2016. Data up to April 2019 were abstracted from the International Society for Heart and Lung Transplantation (ISHLT) Thoracic Organ Registry. We compared overall survival (OS) between North American and European LT centers in a propensity score matched analysis. In 3,115 well-matched pairs, though 30-day survival was similar between groups (NA 96.2% vs Europe 95.4%, p = 0.116), 5-year survival was significantly higher in European patients (NA 60.1% vs Europe 70.3%, p < 0.001). This survival difference persisted in a sensitivity analysis excluding Canadian patients. Prior observations suggest that these disparities are at least partly related to better access to care via universal healthcare models prevalent in Europe. Future studies are warranted to confirm our findings and explore other causal mechanisms. It is likely that potential solutions will require concerted efforts from healthcare providers and policymakers.

Screening for cardiac allograft rejection among heart transplant recipients using an electrocardiogram-based deep learning model

Abstract Background Current approaches utilizing non-invasive methods to screen for cardiac allograft rejection (gene expression profiling and cell free DNA) have yet to be broadly integrated into heart transplant management and have shown limited discrimination (AUCs of 0.68 and 0.77, respectively). Changes in the electrocardiogram (ECG) have been reported at the time of severe cardiac rejection, including low voltages and conduction abnormalities. It remains unknown if subtle ECG changes correlating with cardiac allograft rejection can be detected earlier using machine learning methods. Purpose We sought to develop an artificial intelligence (AI) model to detect cardiac allograft rejection based on the 12 lead ECG. Methods We identified all patients who underwent a heart transplant at 3 hospital sites within a single health system from Jan 1998 through Apr 2021 and extracted digital 12-lead ECG data as well as endomyocardial biopsy pathology results from the electronic medical record. We partitioned our data into a training (80%), validation (10%), and test set (10%) based on a group stratification sampling. Each patient was present in only one set and each set had a positivity rate of 2.6% with 6,074/758/758 ECGs belonging to 1,146/140/141 unique patients in each set respectively. Cardiac allograft rejection was defined as moderate or severe acute cellular rejection based on International Society for Heart and Lung Transplantation (ISHLT) guidelines. A convolutional neural network, using the 12-lead ECG data as input, was trained with hyperparameter optimization for regularization, learning rate adjustments, and class weights. Model performance metrics were based on the test data and estimated using the final model architecture. Results 1,587 heart transplant recipients who had at least one endomyocardial biopsy were evaluated for inclusion. We limited our sample to ECGs performed within 30 days of the biopsy date (7,590 ECGs, representing 1,425 unique patients). Our study population had a median age of 55.8 years and 28.7% were female. The median number of ECG-biopsy pairs per patient was 5. The majority of endomyocardial biopsy results were classified as none or mild rejection (97.1%), and 2.9% had moderate/severe rejection. The ECG-based AI model detected cardiac allograft rejection with an area under the receiver operative curve (AUC) of 0.84 in the test set. The sensitivity, specificity, positive and negative predictive values were 95%, 52.6%. 5.2% and 99.7% respectively. Conclusions An AI-ECG model appears to outperform novel non-invasive laboratory tests (gene expression profiling and cell free DNA) for detecting cardiac allograft rejection and does not require a blood draw or the additional complexities surrounding sample processing. This model relies on a readily available and relatively inexpensive test, the ECG. In addition, AI predictions can be made available within a few minutes following ECG acquisition. Funding Acknowledgement Type of funding sources: Private hospital(s). Main funding source(s): Mayo Clinic

Impact of co-morbidities on survival after heart transplant in females of childbearing age: analysis of the International Society for Heart and Lung Transplantation (ISHLT) Registry

Abstract Background Data on life expectancy specific to female heart transplant (HT) recipients of reproductive age are lacking, but are needed to inform shared decision making at the time of pre-conception counseling. We analyzed the ISHLT registry for post-transplant survival and studied the impact of co-morbidities in women of childbearing age. Methods Female HT recipients reported to the ISHLT registry who were aged 15–45 yrs at time of HT were included in this retrospective analysis. Primary outcome was post-transplant survival. Secondary outcomes included the impact of co-morbidities on conditional survival at 5, 10 and 15 years. Results Of 121,501 HT recipients (Jan 1992–June 2018), 30,179 (24.8%) were women. 9,229 (7.6%) were 15–45 yrs at time of HT. Overall median post-transplant survival was 15.2 yrs. Diabetes mellitus (DM) and/or severe chronic kidney disease (CKD) at HT adversely impacted long-term survival (Figure 1). Co-morbidities including cardiac allograft vasculopathy (CAV), DM and CKD negatively impacted 5yr and 10yr conditional survival, individually as well as a combination (Figure 2). 15yr conditional survival confirmed the negative impact of DM and CKD, while CAV did not reach statistical significance. Conclusion Female HT recipients of childbearing age have favorable survival post-HT. Conditional survival at 5 and 10 yrs is negatively impacted by CAV, DM and CKD. The quantification of survival outcomes after heart transplant in women of childbearing age may improve counseling as part of pre-conception informed decision making. Funding Acknowledgement Type of funding sources: None.