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Lung Transplantation David J. Ross, M.D. Medical Director, Lung & Heart-Lung Transplant Program Director, Pulmonary Hypertension Program Associate Professor.

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Presentation on theme: "Lung Transplantation David J. Ross, M.D. Medical Director, Lung & Heart-Lung Transplant Program Director, Pulmonary Hypertension Program Associate Professor."— Presentation transcript:

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2 Lung Transplantation David J. Ross, M.D. Medical Director, Lung & Heart-Lung Transplant Program Director, Pulmonary Hypertension Program Associate Professor of Medicine U.C.L.A. School of Medicine dross@mednet.ucla.edu

3 J.D. Hardy (1963): 1 st Human Lung Transplant n 58 y.o. male patient n (L) mainstem bronchogenic CA & (R) severe COPD n (L) Single lung tx on June 11, 1963. n Immunosuppression: AZA, prednisone, Cobalt irradiation. n Survived 18 days J.D. Hardy, W.R. Webb, M.L. Dalton, et al. JAMA 1963; 186:1065

4 New York City Marathon (1998) n 32 y.o. male patient s/p bilateral lung tx for cystic fibrosis. n Completes marathon in 7:08:50 Scand J Med & Science in Sports, 2000

5 Organ Transplants 2001: UNOS UNOS Statistics 5/1/02

6 UNOS “Waiting List” UNOS Statistics 5/1/02

7 Lung Transplantation Unilateral n Interstitial Fibrosis n COPD n Pulmonary Hypertension Bilateral, sequential n Bronchiectasis n Cystic Fibrosis n COPD (young patients) n Pulmonary Hypertension n Eisenmenger’s Syndrome (correctable)

8 ISHLT Registry Data: Single versus Bilateral Meyer DM, et al. J Heart-Lung Transplant 2002; 20(9):935-41. P<0.05

9 SLT vs BLT by Recipient Age Meyer DM, et al. J Heart-Lung Transplant 2002; 20(9):935-41

10 Bilateral Sequential LT: “Clam Shell” Incision

11 Single Lung Transplant: IPF

12 Alpha-1 Anti-trypsin Deficiency: Single Lung Transplant

13 Median Waiting Times n Introduction of “Expanded Donor Criteria Program” in Sept 1999. n 1995-8 cohort (n=68): 317 days n 9/99-present (n=25): 105 days

14 1-year Survival n Development of “New Team” in July 1999. n Medicare/HCFA Certification n “Expanded Donor Criteria” Program n “Waiting Time” Issues in Southern Cal 2512 13 18 10 8 15 (N) 12

15 Median Total Hospital LOS n Median ICU LOS with “Expanded Donor” is 3  4 days. n Acceptable allograft function without prolonged intubation n Inhaled N.O. only for established reperfusion injury. n “Modified reperfusion” CTS protocol

16 UCLA Lung Transplant Program: Patient Survival Actual Survival, 10/1/97-6/1/02; N=70

17 Relative Risk of Death for LT versus Continued Waiting Disease6 mos12 mos n COPD (163)0.550.32 SLT (92)0.580.38 SLT (92)0.580.38 DLT/HLT (35)0.540.29 DLT/HLT (35)0.540.29 n C.F. (174)0.210.15 n Eisenmenger (76)1.260.85 n Bronchiectasis (51)0.580.58 n IPF (100)0.650.46 SLT (63)0.710.54 SLT (63)0.710.54 DLT/HLT (47)0.570.36 DLT/HLT (47)0.570.36 n PAH (68)0.370.34 Charman SC, et al. J Heart and Lung Transplant 2002; 21(2):226-32.

18 Pulmonary Arterial Hypertension in IPF Novel therapies for a serious complication

19 Bosentan (Tracleer™) n Oral, dual ET-1 receptor antagonist n Class III/IV with either PPH or PSS (n=32). n 12 week placebo-controlled study. n Bosentan vs placebo:  6-minute walk: +70 vs -6 meters  Cardiac index: +0.5  0.1 vs -0.5  0.1 L/min/m 2  mPAP: -1.6  1.2 vs +5.1  2.8 mm Hg  PVR: -223  56 vs +191  74 dynes/sec/cm -5  RA: -1.3  0.9 vs +4.9  1.5 mm Hg [Mean  SE] Channick R, et al. Lancet 2001; 358(9288):1119-23.

20 ET A ET B CONTRACTION K + /Ca 2+ RELAXATION  cAMP  cGMP Smooth muscle cell Endothelium ET B AA  COX PGI 2 L-arginine  NOS NO BIG ET-1  ECE ET-1 (–) ET-1 Vascular Biology

21 Bronchiolitis Obliterans Syndrome [BOS] “Constrictive Bronchiolitis”

22 BOS: Stanford Experience Prevalence of BOS > 3 months post-transplant ~ 64% Reinchenspurner H, et al. Ann Thorac Surg 1996; 62: 1467

23 Risk Factors n Acute rejxn: RR=1.25* n CMV: RR=1.12* n Recipient age: RR=1.009/yr* n Antibody induction: RR=0.84 n Single lung: RR=1.24 n Incompatible lymphocyte Xmatch: RR=1.68 Non-risk Factors n Pre-LT CMV status, gender, donor age n High panel reactive antibody (PRA). *p<0.01 Novartis Lung Transplant Database, 1998 Bronchiolitis Obliterans Syndrome

24 U.C.L.A. Immunosuppressive Protocol n Tacrolimus (Prograf  ) n Mycophenolate mofetil (Cellcept  ) n Prednisone n rATG (Thymoglobulin  ) x 1-3 days n BOS  Methotrexate  Sirolimus  rATG

25 Cellcept  [MMF] versus Imuran  [AZA] after Lung Transplantation Ross DJ, et al. J Heart Lung Transplant 1998; 17:768-74 [95%C.I. For difference: 0.13 to 0.82; p<0.01] X  SD

26 Collaborative Research U.C.L.A. Lung & Heart-Lung Transplant Program

27 Role for C-C Chemokine MCP-1/CCR2 in BOS n Chemoattractant for mononuclear phagocytes, CD45RO + T lymphocytes, B cells, & NK cells. n Involved in chronic inflammatory & fibroproliferative diseases e.g. rheumatoid arthritis. n MCP-1 binds & signals through seven- transmembrane G protein-coupled receptor, CCR2. Belperio JA, et al. J Clin Invest 2001; 108:547-56.

28 BALF MCP-1 in BOS n CCR2 -/- knock-out murine model—  mononuclear recruitment after tracheal transplant & attenuation of BOS. P=0.01 P<0.0001 Belperio JA, et al. J Clin Invest 2001; 108:547-56.

29 Human Defensins: Potential Effects on Adaptive Immunity (  -HD)  Neutrophil chemotaxis through epithelial elaboration of IL-8. (  -HD)  Neutrophil chemotaxis through epithelial elaboration of IL-8. (  -HD)  T-cell release of  -IFN, IL-6 & IL-10 (  -HD)  T-cell release of  -IFN, IL-6 & IL-10 (H  D-2)  Memory helper T-lymphocytes (CD4 + /CD45RO + ) & progenitor-derived immature dentritic cells (CD34 + ) through chemokine receptor (CCR6). 1 (H  D-2)  Memory helper T-lymphocytes (CD4 + /CD45RO + ) & progenitor-derived immature dentritic cells (CD34 + ) through chemokine receptor (CCR6). 1 1. Yang D, et al. Science 2000; 286(5439):525

30 BAL [HBD2]   p=0.001; Kruskal-Wallis ANOVA (Median  SEM) Ross DJ, et al. J Heart and Lung Transplant 2002; 21(1):A75.

31 Lung Transplantation David J. Ross, M.D. Medical Director, Lung & Heart-Lung Transplant Program Director, Pulmonary Hypertension Program Associate Professor of Medicine U.C.L.A. School of Medicine dross@mednet.ucla.edu (310) 825-6068


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