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The Impact of Cell Death Signals on Short and Long Term Outcome in Human Lung Transplantation
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The Journal of Heart and Lung Transplantation, Vol 34, No 4S, April 2015
Results: The TOL group had 3 men and 2 women, all of whom were receiving tacrolimus immunosuppression prior to noncompliance and cessation of therapy. Each was restarted on their prior immunosuppression regimen. Interleukins 2, 13, 18 and 27 were markedly upregulated in TOL patients as compared to rejection patients. In addition multiple genes related to tumor necrosis factor beta were differentially expressed. CCR10 was 40-fold and CCR4 was 30-fold elevated in the TOL patients versus rejectors. FOXP3 was more than 20-fold elevated in the same comparison as well. The mechanistic significance of these findings is unclear. Analysis of the other enrolled clinical groups is underway and will be available prior to presentation. Conclusion: This is the first report of a group of heart transplant pts surviving more than transiently without immunosuppression. Therapy was restarted in each case so we cannot state that these patients were truly tolerant. Further analysis of their gene expression is ongoing to understand this unique phenomenon. 3( 44) The Impact of Cell Death Signals on Short and Long Term Outcome in Human Lung Transplantation K. Hashimoto , R. Besla, R. Zamel, H. Kim, T. Saito, S. Azad, T.K. Waddell, M. Cypel, M. Liu, S. Keshavjee. Latner Thoracic Surgery Research Laboratories, University of Toronto, Toronto, ON, Canada. Purpose: To investigate the impact of cell death signals in the period immediately after lung transplant on short and long term clinical outcome. Methods: Plasma samples were collected pre-transplantation and 24 and 48 hours after transplantation from 60 bilateral lung transplant recipients. There were 7 (11.7%) patients who had primary graft dysfunction (PGD) grade 3 at 72 hours after transplantation (PGD group). The other 53 (88.3%) patients were defined as the Control group. The levels of plasma cell death markers including M30 (epithelial apoptosis) and M65 (epithelial apoptosis plus necrosis) were measured by enzyme-linked immunosorbent assay and correlated with clinical outcomes. The levels of measured markers were lognormal distributed and were therefore log10 transformed prior to regression tests performed as part of the statistical analysis. Results: Linear mixed-effects models demonstrated that the PGD group had significantly higher M30 levels (p= 0.01; Fig 1A) and M65 levels (p= 0.001; Fig 1B) compared to the Control group. The PGD group had significantly longer mechanical ventilation (p< 0.001), intensive care unit (p= 0.001) and hospital (p= 0.008) stay. Kaplan-Meier survival curves based on the values of markers at 48 hours after transplantation showed that a higher M30 (Fig 1C) and M65 (Fig 1D) and a lower M30/M65 ratio (Fig 1E) are associated with significantly worse survival. Univariate Cox regression analysis showed that higher M30 (p< 0.001) and M65 (p< 0.001) and lower M30/M65 ratio (p= 0.003) as continuous variables at 48 hours after transplantation are risk factors of worse survival. These remained significant after adjustment for potential confounders including PGD in bivariate Cox regression. Conclusion: Epithelial cell death signals may be associated with PGD and related to short term outcome. Epithelial apoptosis and necrosis signals, particularly a higher necrosis proportion, in the immediate post lung transplantation period may have significant impact on the long term survival.
3( 45) Prior Coronary Artery Bypass Surgery- Is It Still a Contraindication for Lung Transplantation? S.H. McKellar ,1 B.C. Baird,1 M. Bowen,1 S. Raman,2 B. Cahill,2 C.H. Selzman.1 1Cardiothoracic Surgery, University of Utah, Salt Lake City, UT; 2Pulmonary and Critical Care, University of Utah, Salt Lake City, UT. Purpose: Historically, coronary artery bypass grafting (CABG) has been a contraindication to lung transplantation (LTx) due to the severity of coronary artery disease and technical considerations of injuring a left internal mammary artery during LTx. However, an increasing number of patients with previous CABG are being referred for and receiving LTx. Whether prior CABG should remain a contraindication to LTx is unknown. We, therefore, used the UNOS data set to define the prevalence of LTx following CABG and determine its effect on short and long-term outcomes. Methods: The UNOS STAR dataset was queried to define the prevalence of patients undergoing LTx following CABG through end of 2013. Only adult LTx patients who underwent primary left, right or bilateral LTx were included. The primary end points were 30-day and 1-year survival. Results: During the study period, 24,655 primary lung transplants were performed. CABG became a mandatory reporting field in UNOS in 2004 so our study cohort included 14,791 patients transplanted between 2004 and 2013 (single left (SL) n= 2,787, single right (SR) n= 2,447, bilateral (B) n= 9,557). During that time period, a total of 292 transplants were performed in patients who had previously undergone CABG (SL n= 68, SR n= 181, B n= 43) representing 2% of all transplants. Over the past 10 years, we observed a 4-fold rise in LTx following CABG which increased from 0.5% to 2.5%. SR LTx was the most common type of LTx in CABG patients representing 62% (181/292). Thirty-day survival 95% for the entire cohort (n= 292) with no difference observed between the CABG-LTx and LTx groups. In contrast, 1-year survival was 80% for CABG-LTx cohort compared to 85% for the non-CABG cohort (P= 0.004). CABG persisted as a predictor of 1-year mortality on multivariable analysis (P= 0.03; HR 1.34; CI 1.03, 1.74). Conclusion: LTx following CABG is uncommon but being performed more frequently in the current era. Single right LTx is the most common procedure performed in patients with prior CABG. Despite a higher risk cohort, CABG LTx patients had equivalent short-term and only slightly inferior 1-year survival. This suggests CABG should not be a contraindication to LTx in well-selected patients. 3( 46) Elective Lobar Lung Transplantation - A Single Center Experience B. Sill ,1 C. Oelschner,1 M. Oldigs,2 H. Klose,3 C. Kugler,2 M. Neuhauss,2 M. Barten,1 H. Reichenspurner,1 T. Deuse.1 1Cardiovascular Surgery, University Heart Center Hamburg, Hamburg, Germany; 2LungenClinic, Grosshansdorf, Germany; 3University Medical Center HamburgEppendorf, Hamburg, Germany. Purpose: The shortage of suitable donor organs is a major problem in lung transplantation and has led to an increased gap between the number of donors and the number of recipients on the waiting list. This dilemma is even worse in recipients with small chest cavities, which markedly prolongs their waiting times. In order to exploit a larger donor pool, we electively accepted bigger organs for small patients and performed lobar lung transplants. Methods: In this case series, we present 11 patients (9 women and 2 men, 45±11.8 years old) that underwent elective lobar lung transplantation between March 2009 and August 2014 with a mean waiting time of 227±163 days. The underlying diseases were IPF (n= 7), CF (n= 3) and PHT (n= 1). The mean recipient height was 164±8 cm and their calculated total lung capacity (TLC) was 5.2±0.9 L. Results: We accepted lungs from 9 male and 2 female donors with a calculated TLC of 7.7±0.3 L and 5.2±0.1 L and a donor height of 185±4 cm and 165±0 cm, respectively. The mean donor age was 45.5±7.1 years. Two lungs were transplanted using the Organ Care System (TransMedicsTM). All recipients were successfully transplanted via
The Journal of Heart and Lung Transplantation, Vol 34, No 4S, April 2015
Results: The TOL group had 3 men and 2 women, all of whom were receiving tacrolimus immunosuppression prior to noncompliance and cessation of therapy. Each was restarted on their prior immunosuppression regimen. Interleukins 2, 13, 18 and 27 were markedly upregulated in TOL patients as compared to rejection patients. In addition multiple genes related to tumor necrosis factor beta were differentially expressed. CCR10 was 40-fold and CCR4 was 30-fold elevated in the TOL patients versus rejectors. FOXP3 was more than 20-fold elevated in the same comparison as well. The mechanistic significance of these findings is unclear. Analysis of the other enrolled clinical groups is underway and will be available prior to presentation. Conclusion: This is the first report of a group of heart transplant pts surviving more than transiently without immunosuppression. Therapy was restarted in each case so we cannot state that these patients were truly tolerant. Further analysis of their gene expression is ongoing to understand this unique phenomenon. 3( 44) The Impact of Cell Death Signals on Short and Long Term Outcome in Human Lung Transplantation K. Hashimoto , R. Besla, R. Zamel, H. Kim, T. Saito, S. Azad, T.K. Waddell, M. Cypel, M. Liu, S. Keshavjee. Latner Thoracic Surgery Research Laboratories, University of Toronto, Toronto, ON, Canada. Purpose: To investigate the impact of cell death signals in the period immediately after lung transplant on short and long term clinical outcome. Methods: Plasma samples were collected pre-transplantation and 24 and 48 hours after transplantation from 60 bilateral lung transplant recipients. There were 7 (11.7%) patients who had primary graft dysfunction (PGD) grade 3 at 72 hours after transplantation (PGD group). The other 53 (88.3%) patients were defined as the Control group. The levels of plasma cell death markers including M30 (epithelial apoptosis) and M65 (epithelial apoptosis plus necrosis) were measured by enzyme-linked immunosorbent assay and correlated with clinical outcomes. The levels of measured markers were lognormal distributed and were therefore log10 transformed prior to regression tests performed as part of the statistical analysis. Results: Linear mixed-effects models demonstrated that the PGD group had significantly higher M30 levels (p= 0.01; Fig 1A) and M65 levels (p= 0.001; Fig 1B) compared to the Control group. The PGD group had significantly longer mechanical ventilation (p< 0.001), intensive care unit (p= 0.001) and hospital (p= 0.008) stay. Kaplan-Meier survival curves based on the values of markers at 48 hours after transplantation showed that a higher M30 (Fig 1C) and M65 (Fig 1D) and a lower M30/M65 ratio (Fig 1E) are associated with significantly worse survival. Univariate Cox regression analysis showed that higher M30 (p< 0.001) and M65 (p< 0.001) and lower M30/M65 ratio (p= 0.003) as continuous variables at 48 hours after transplantation are risk factors of worse survival. These remained significant after adjustment for potential confounders including PGD in bivariate Cox regression. Conclusion: Epithelial cell death signals may be associated with PGD and related to short term outcome. Epithelial apoptosis and necrosis signals, particularly a higher necrosis proportion, in the immediate post lung transplantation period may have significant impact on the long term survival.
3( 45) Prior Coronary Artery Bypass Surgery- Is It Still a Contraindication for Lung Transplantation? S.H. McKellar ,1 B.C. Baird,1 M. Bowen,1 S. Raman,2 B. Cahill,2 C.H. Selzman.1 1Cardiothoracic Surgery, University of Utah, Salt Lake City, UT; 2Pulmonary and Critical Care, University of Utah, Salt Lake City, UT. Purpose: Historically, coronary artery bypass grafting (CABG) has been a contraindication to lung transplantation (LTx) due to the severity of coronary artery disease and technical considerations of injuring a left internal mammary artery during LTx. However, an increasing number of patients with previous CABG are being referred for and receiving LTx. Whether prior CABG should remain a contraindication to LTx is unknown. We, therefore, used the UNOS data set to define the prevalence of LTx following CABG and determine its effect on short and long-term outcomes. Methods: The UNOS STAR dataset was queried to define the prevalence of patients undergoing LTx following CABG through end of 2013. Only adult LTx patients who underwent primary left, right or bilateral LTx were included. The primary end points were 30-day and 1-year survival. Results: During the study period, 24,655 primary lung transplants were performed. CABG became a mandatory reporting field in UNOS in 2004 so our study cohort included 14,791 patients transplanted between 2004 and 2013 (single left (SL) n= 2,787, single right (SR) n= 2,447, bilateral (B) n= 9,557). During that time period, a total of 292 transplants were performed in patients who had previously undergone CABG (SL n= 68, SR n= 181, B n= 43) representing 2% of all transplants. Over the past 10 years, we observed a 4-fold rise in LTx following CABG which increased from 0.5% to 2.5%. SR LTx was the most common type of LTx in CABG patients representing 62% (181/292). Thirty-day survival 95% for the entire cohort (n= 292) with no difference observed between the CABG-LTx and LTx groups. In contrast, 1-year survival was 80% for CABG-LTx cohort compared to 85% for the non-CABG cohort (P= 0.004). CABG persisted as a predictor of 1-year mortality on multivariable analysis (P= 0.03; HR 1.34; CI 1.03, 1.74). Conclusion: LTx following CABG is uncommon but being performed more frequently in the current era. Single right LTx is the most common procedure performed in patients with prior CABG. Despite a higher risk cohort, CABG LTx patients had equivalent short-term and only slightly inferior 1-year survival. This suggests CABG should not be a contraindication to LTx in well-selected patients. 3( 46) Elective Lobar Lung Transplantation - A Single Center Experience B. Sill ,1 C. Oelschner,1 M. Oldigs,2 H. Klose,3 C. Kugler,2 M. Neuhauss,2 M. Barten,1 H. Reichenspurner,1 T. Deuse.1 1Cardiovascular Surgery, University Heart Center Hamburg, Hamburg, Germany; 2LungenClinic, Grosshansdorf, Germany; 3University Medical Center HamburgEppendorf, Hamburg, Germany. Purpose: The shortage of suitable donor organs is a major problem in lung transplantation and has led to an increased gap between the number of donors and the number of recipients on the waiting list. This dilemma is even worse in recipients with small chest cavities, which markedly prolongs their waiting times. In order to exploit a larger donor pool, we electively accepted bigger organs for small patients and performed lobar lung transplants. Methods: In this case series, we present 11 patients (9 women and 2 men, 45±11.8 years old) that underwent elective lobar lung transplantation between March 2009 and August 2014 with a mean waiting time of 227±163 days. The underlying diseases were IPF (n= 7), CF (n= 3) and PHT (n= 1). The mean recipient height was 164±8 cm and their calculated total lung capacity (TLC) was 5.2±0.9 L. Results: We accepted lungs from 9 male and 2 female donors with a calculated TLC of 7.7±0.3 L and 5.2±0.1 L and a donor height of 185±4 cm and 165±0 cm, respectively. The mean donor age was 45.5±7.1 years. Two lungs were transplanted using the Organ Care System (TransMedicsTM). All recipients were successfully transplanted via