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Long term follow-up of a prospective randomized trial comparing tacrolimus versus cyclosporine in combination with MMF after lung transplantation
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Abstracts
Results: 48 subjects were studied at a mean interval of 5.3 ⫾ 2.8 years post-transplant. No difference was found between pretransplant diagnosis and PON SNPs. There were no differences in PON1 and PON2 SNP prevalence compared to controls. 25 CTRs (52.1%) had TxCAD. At the PON1 M55L locus, MM homozygosity was significantly associated with higher levels of tHcy (MM: 29⫾5 M/L, n ⫽ 7; ML: 23⫾3 M/L, n ⫽ 22; LL: 22⫾4 M/L, n ⫽ 19, p⫽0.002, ANOVA). All seven of the PON1 MM CTR subjects developed TxCAD, while only 6/19 (31.5%) with LL genotype and 12/22 (54%) with ML heterozygosity did (p⫽0.008, 2). There was no significant association between TxCAD and the other SNPs. In a multivariate analysis that included clinical co-variates, the only significant variables were recipient gender (p⫽0.029), tHcy (p⫽0.032), time from transplant (p⫽0.019) and PON1 M55L genotype (p⫽0.008). Conclusion: In our study, the PON1 M55L SNP was a significant predictor of TxCAD, independent of tHcy levels. Thus, while the PON1 effect might be attributed to the higher tHcy in MM homozygotes, it is likely that other gene effects, such as altered lipid peroxidation activity or effects of the PON enzyme substrate, homocysteine thiolactone (HcyTL), may be involved. Our speculation that the higher tHcy in the PON1 MM homozygotes is associated with an abnormality of HcyTL cleavage by PON1 requires prospective study of a larger CTR cohort. 7 MAY PRESERVATION SOLUTION AFFECT THE INCIDENCE OF GRAFT VASCULOPATHY IN TRANSPLANTED HEART? M. Garlicki, Cardiosurgery Dept., MSWiA Hospital, Warsaw, Poland Vasculopathy as a manifestation of chronic rejection in transplanted heart remains a factor limiting long term patient survival. Development of vasculopathy might be associated with intima injury during ischemia and reperfusion. The purpose of this comparative study was to determine whether preservation solution may improve post-transplant heart recovery and reduce the incidence of graft vasculopathy. From 93 to 99, 48 donors having received less than 10g/kg/d of dopamine, were accepted for 40 male and 8 female recipients. They were prospectively randomized to three groups: Custodiol (n⫽15), Viaspan (n⫽17), and Celsior (n⫽16). Donor and recipient characteristics, cold ischemia time, organ procurement, transplantation procedure, and post-transplant immunosuppressive therapy were comparable among the 3 groups. In Celsior group, spontaneous sinus rhythm recovered more often (12/16 pts, p⫽0.01) and higher cardiac output (6.5l/min, p⫽0.03) was noted. No significant difference among the groups in respect to inotropic support, cardiac index, pulmonary artery pressure, and biopsy performed on the time of transplantation. The intravascular ultrasound (IVUS) imaging of the left arterior descending (LAD) of coronary artery performed at one year post-transplant, revealed significantly lower values of arterial area and arterial wall area in the Celsior group. No significant difference in arterial lumen area occurred between the groups. In Celsior group, lowest percent of intimal hypertrophy (24.23%, p⫽0.001) and less frequent (11/16 pts, p⫽0.001) chronic rejection (arterial hypertrophyⱖ0.5mm) was noted. Endomyocardial biopsy performed simultaneously to IVUS examination revealed no difference in pathologic lesions, except significantly less extensive fibrosis in the Celsior group. During the 3.4 yrs of follow-up, freedom of biopsy proven acute rejection was significantly higher in Celsior group (ⱖ2 ISHLT). In this study, Celsior allowed for better post-transplant heart recovery and accounted for less incidence of vasculopathy and chronic rejection in the midterm follow-up.
The Journal of Heart and Lung Transplantation January 2003 8 DONOR INTRACRANIAL BLEEDING IS ASSOCIATED WITH ADVANCED TRANSPLANT CORONARY VASCULOPATHY: EVIDENCE FROM INTRAVASCULAR ULTRASOUND M.H. Yamani,1 R.C. Starling,1 E.M. Tuzcu,1 S.A. Haji,1 D.J. Cook,2 A.S. Abdo,2 N.B. Ratliff,3 M.M. Yousufuddin,1 P.M. McCarthy,4 J.B. Young,1 1Cardiology, Cleveland Clinic, Cleveland, OH; 2Allogen Laboratory; 3Anatomic Pathology; 4Cardiovascular Thoracic surgery, Cleveland Clinic, Cleveland, OH Background: Donor cause of death has an important impact on transplant outcome. Objectives: We evaluated the impact of donor intracranial bleeding on the development of transplant coronary vasculopathy using intravascular ultrasound (IVUS). Methods: A group of 72 recipients underwent cardiac transplantation from donors with intracranial bleeding (ICB group). These were compared to 90 recipients who were transplanted from trauma donors (Trauma group). All patients underwent serial endomyocardial biopsies. IVUS was performed on all patients at one month and one year of transplant. Volumetric analysis was available on 47 patients. Results: Both groups had similar baseline characteristics in relation to recipient age, etiology of heart disease, ischemia time, use of assist device and immunosuppressive therapy. However, the donor age was higher, as expected, in the ICB group compared to the Trauma group (41⫾10 vs 28⫾11 yrs, p⬍0.001). There was no significant difference in acute rejection. Compared to the Trauma group, the ICB group were more likely to develop graft dysfunction during the first week of transplant (left ventricle ejection fraction ⬍ 45%: 15% vs 3%, p ⫽ 0.01) and showed higher incidence of myocardial interstitial fibrosis at one year (49% vs 29%, p⫽0.01). Further, ICB was associated with increased coronary vasculopathy progression: they had increased change in coronary intimal thickness (0.54 ⫾ 0.33 vs 0.40 ⫾ 0.32 mm, p⫽ 0.03), increased change in plaque volume (3.84 ⫾ 2.51 vs 2.33 ⫾ 1.65 mm3, p⫽0.01), and increased change in plaque burden (7.4 ⫾ 11 % vs 2.0 ⫾ 4%, p⫽ 0.03) over one year compared to the Trauma group. The ICB group also had a worse 7-year Kaplan-Meier survival, 69% vs 86%, p⫽0.05. Conclusions: Intracranial bleeding is associated with increased coronary vasculopathy progression, and poorer outcome compared to trauma donors.
9 LONG TERM FOLLOW-UP OF A PROSPECTIVE RANDOMIZED TRIAL COMPARING TACROLIMUS VERSUS CYCLOSPORINE IN COMBINATION WITH MMF AFTER LUNG TRANSPLANTATION A. Zuckermann,1 H. Reichenspurner,2 P. Jaksch,1 H. Treede,2 W. Wisser,1 J. Groetzner,3 B. Reichart,3 W. Klepetko,1 1Dept. of CardioThoracic Surgery, University of Vienna, Vienna, Austria; 2Dept. of Cardiac Surgery, Universitaetsklinikum Eppendorf Hamburg, Hamburg, Germany; 3Dept. of Cardiac surgery, Ludwig-Maximilian University Munich, Munich, Germany Background:The early results of our randomized clinical 2 center trial comparing tacrolimus (Tac) versus Cyclosporine (CsA) in combination with Mycophenolate Mofetil (MMF) after lung transplantation have been previously reported. A significant finding was a trend towards lower early rejection incidence in the Tac group. This report updates the results with a follow-up of 36 months.
The Journal of Heart and Lung Transplantation Volume 22, Number 1S Patients & Methods: Between 9/97 and 4/99, 74 lung transplant recipients were randomised to receive either Tac (n⫽37) or CsA (n⫽37). The two groups were similar in age, sex and underlying disease. Results: 3-year survival was similar in the two groups (Tac: 68%, CsA: 57%). There was a clear trend towards more late rejections in the CsA group (24% vs. Tac: 4%, p⫽0.07). Incidence of BOS was significantly higher in the CsA group (Tac: 10% vs. CsA: 41%, p⬍0.01). Creatinine levels were similar between the groups (Tac: 1.56⫾0.58 vs. CsA: 1.39⫾0.36; n.s.) as well as the need for statin therapy (Tac: 24% vs. CsA: 41%; n.s.). There was a significant higher incidence of hypertension in the CsA group (CsA: 46% vs. Tac: 13.5%; p⬍0.05). Whereas, new-onset of diabetes mellitus was observed in the Tac group only (Tac: 22% vs. CsA: 0%; p⬍0.05). Conclusion: We conclude that Tac⫹MMF shows an advantage over CsA⫹MMF with regard to late rejection and development of BOS. Yet overall survival was similar between the two groups. Incidence of drug related adverse events were similar, yet their spectrum was different. 10 PROSPECTIVE RANDOMIZED INTERNATIONAL MULTICENTER INVESTIGATOR DRIVEN STUDY COMPARING TAC AND CSA (ⴙMMF/STEROIDS) AFTER LUNG TRANSPLANTATION - INTERIM ANALYSIS OF 110 PATIENTS H. Reichenspurner,1 A. Glanville,2 W. Klepetko,3 R. Lama,4 G.M. Verleden,5 C. Bravo,6 M. Estenne,7 B. Reichart,8 S. Hirt,9 F.Z. Goni,10 J. Aubert,11 J.M. Borro,12 P. Usetti,13 T. Wahlers,14 H. Treede,1 the European and Australian Investigators in Lung Transplantation, 1Department of Cardiovascular Surgery, University Hospital Hamburg-Eppendorf, Hamburg, Germany; 2University of Sydney, Sydney, Australia; 3University of Vienna, Vienna, Austria; 4 University of Cordoba, Cordoba, Spain; 5University of Leuven, Leuven, Belgium; 6University of Barcelona, Barcelona, Spain; 7University of Bruxelles, Bruxelles, Belgium; 8University of Munich, Munich, Germany; 9 University of Kiel, Kiel, Germany; 10University of Santander, Santander, Spain; 11University of Lausanne, Lausanne, Switzerland; 12University La Coruna, La Coruna, Spain; 13University of Madrid, Madrid, Spain; 14 University of Jena, Jena, Germany With the aim of an accurate scientific comparison a large prospective randomized international multi-center investigator-driven study comparing Tac and CsA (both in combination with MMF and steroids) after lung transplantion was initiated. Primary objective was to assess the efficacy and safety of both regimens for the prevention of bronchiolitis obliterans syndrom (BOS) up to 3 years post transplantation. Secondary objectives were number of and freedom from acute acute rejection and infection, survival and adverse events. Patients were central-computer randomized either to treatment group A: Tac (0.01-0.03 mg/kg/d iv3 0.05-0.3 mg/kg/d po) or group B: CsA (1-3 mg/kg/d 3 4-18 mg/kg/d po). Stratification for CF patients was performed. MMF (1-4 g/d) was administered according to trough levels. No induction therapy was given. It has been planned to include 250 patients. In September 2002 a total of 189 patients were included (11 early dropouts). Death rate was 8.4% (15/178 pat.). For this interim analysis 110 patients with at least one year follow-up have been evaluated (Feb. 2003). Results will be presented and interpreted at the ISHLT meeting. 11 AEROSOL CYCLOSPORINE PROVIDES DOSE DEPENDENT IMPROVEMENT IN LUNG FUNCTION AFTER LUNG TRANSPLANTATION
Abstracts
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T.E. Corcoran,1 G.C. Smaldone,2 J.H. Dauber,1 D.A. Smith,1 K.R. McCurry,3 G.J. Burckart,3 B.P. Griffith,4 W.F. Grgurich,1 A.T. Iacono,1 1Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA; 2Pulmonary and Critical Care Medicine, State University of New York at Stony Brook, Stony Brook, NY; 3Division of Cardiothoracic Surgery, University of Pittsburgh, Pittsburgh, PA; 4Division of Cardiac Surgery and Cardiopulmonary Transplantation, University of Maryland Medical Center, Baltimore, MD A placebo-controlled trial is presently testing the effectiveness of aerosolized cyclosporine as prophylaxis for lung transplant rejection. To measure the dose-response relationship, 15 subjects from this trial underwent a one-time radionuclide study to measure the lung deposition of cyclosporine. Deposition in the transplant was correlated with physiologic indices of effectiveness as measured by the change in one-second forced expiratory volume (FEV1) over time. Deposited dose in the periphery of the transplanted lung(s) was compared to percentage change in (FEV1) at post-op days 200, 300, 400, 500, 600, and 700. The best FEV1 value before post-op day 100 was used as the baseline. Results: there was a significant correlation between improvement in fev1 and dose at all time points. values of the r-squared based on linear regression ranged between 0.43 and 0.68 (all p⬍0.01). the percentage change in fev1 per mg of drug increased at each successive time point indicating a cumulative protective effect from the drug. subjects depositing 5mg or more experienced an improvement in lung function, whereas placebo subjects, and subjects depositing less than 5mg tended to demonstrate a decline. a two-way anova comparing lung function in subjects depositing 5mg or more with placebo subjects indicated significance (p⫽0.002). there was no relationship between peripheral dose and fev1 on the day of deposition testing indicating that the deposited dose was not simply a direct consequence of pulmonary function. Conclusion: Aerosol cyclosporine is effective in maintaining and improving lung function after lung transplant in a dose dependent manner. Patients receiving more than 5 mg of aerosolized cyclosporine in the periphery of their transplanted lung experience a dose dependent improvement in lung function over time. National Institutes of Health 5R01HL59490-02. 12 IL-10 HIGH GENOTYPE IS PROTECTIVE AGAINST ACUTE PERSISTENT REJECTION AFTER LUNG TRANSPLANTATION H.X. Zheng, G.J. Burckart, K. McCurry, S. Webber, D. Zaldonis, J. Ristich, A. Iacono, J. Dauber, W. Grgurich, K. McDade, A. Zeevi, Pharmacy, Surgery, Pediatrics, Medicine, and Pathology, University of Pittsburgh, Pittsburgh, PA Our previous studies have demonstrated that cytokine gene polymorphisms are related to acute rejection in pediatric heart transplantation. The objective of this study was to determine whether cytokine genotypes of TNF-␣, IL-10, IL-6, interferon-␥, and transforming growth factor- were associated with episodes of acute persistent rejection (APR) after lung transplantation (LT). Methods: cytokine genotyping was performed on 124 adult lt patients who were classified on the basis of their surveillance transbronchial biopsies during their first year post lt. they were categorized as having had apr if they had 2 consecutive biopsies of grade a2 in spite of anti-rejection treatment. genotyping was performed using the pcr-ssp technique by a commercially available kit (one-lambda, inc, canoga park, ca). Results: one hundred and eighteen patients were analyzed for il-10 genotype, and only 7 of 22 patients (32%) of the il-10 high genotype had
Abstracts
Results: 48 subjects were studied at a mean interval of 5.3 ⫾ 2.8 years post-transplant. No difference was found between pretransplant diagnosis and PON SNPs. There were no differences in PON1 and PON2 SNP prevalence compared to controls. 25 CTRs (52.1%) had TxCAD. At the PON1 M55L locus, MM homozygosity was significantly associated with higher levels of tHcy (MM: 29⫾5 M/L, n ⫽ 7; ML: 23⫾3 M/L, n ⫽ 22; LL: 22⫾4 M/L, n ⫽ 19, p⫽0.002, ANOVA). All seven of the PON1 MM CTR subjects developed TxCAD, while only 6/19 (31.5%) with LL genotype and 12/22 (54%) with ML heterozygosity did (p⫽0.008, 2). There was no significant association between TxCAD and the other SNPs. In a multivariate analysis that included clinical co-variates, the only significant variables were recipient gender (p⫽0.029), tHcy (p⫽0.032), time from transplant (p⫽0.019) and PON1 M55L genotype (p⫽0.008). Conclusion: In our study, the PON1 M55L SNP was a significant predictor of TxCAD, independent of tHcy levels. Thus, while the PON1 effect might be attributed to the higher tHcy in MM homozygotes, it is likely that other gene effects, such as altered lipid peroxidation activity or effects of the PON enzyme substrate, homocysteine thiolactone (HcyTL), may be involved. Our speculation that the higher tHcy in the PON1 MM homozygotes is associated with an abnormality of HcyTL cleavage by PON1 requires prospective study of a larger CTR cohort. 7 MAY PRESERVATION SOLUTION AFFECT THE INCIDENCE OF GRAFT VASCULOPATHY IN TRANSPLANTED HEART? M. Garlicki, Cardiosurgery Dept., MSWiA Hospital, Warsaw, Poland Vasculopathy as a manifestation of chronic rejection in transplanted heart remains a factor limiting long term patient survival. Development of vasculopathy might be associated with intima injury during ischemia and reperfusion. The purpose of this comparative study was to determine whether preservation solution may improve post-transplant heart recovery and reduce the incidence of graft vasculopathy. From 93 to 99, 48 donors having received less than 10g/kg/d of dopamine, were accepted for 40 male and 8 female recipients. They were prospectively randomized to three groups: Custodiol (n⫽15), Viaspan (n⫽17), and Celsior (n⫽16). Donor and recipient characteristics, cold ischemia time, organ procurement, transplantation procedure, and post-transplant immunosuppressive therapy were comparable among the 3 groups. In Celsior group, spontaneous sinus rhythm recovered more often (12/16 pts, p⫽0.01) and higher cardiac output (6.5l/min, p⫽0.03) was noted. No significant difference among the groups in respect to inotropic support, cardiac index, pulmonary artery pressure, and biopsy performed on the time of transplantation. The intravascular ultrasound (IVUS) imaging of the left arterior descending (LAD) of coronary artery performed at one year post-transplant, revealed significantly lower values of arterial area and arterial wall area in the Celsior group. No significant difference in arterial lumen area occurred between the groups. In Celsior group, lowest percent of intimal hypertrophy (24.23%, p⫽0.001) and less frequent (11/16 pts, p⫽0.001) chronic rejection (arterial hypertrophyⱖ0.5mm) was noted. Endomyocardial biopsy performed simultaneously to IVUS examination revealed no difference in pathologic lesions, except significantly less extensive fibrosis in the Celsior group. During the 3.4 yrs of follow-up, freedom of biopsy proven acute rejection was significantly higher in Celsior group (ⱖ2 ISHLT). In this study, Celsior allowed for better post-transplant heart recovery and accounted for less incidence of vasculopathy and chronic rejection in the midterm follow-up.
The Journal of Heart and Lung Transplantation January 2003 8 DONOR INTRACRANIAL BLEEDING IS ASSOCIATED WITH ADVANCED TRANSPLANT CORONARY VASCULOPATHY: EVIDENCE FROM INTRAVASCULAR ULTRASOUND M.H. Yamani,1 R.C. Starling,1 E.M. Tuzcu,1 S.A. Haji,1 D.J. Cook,2 A.S. Abdo,2 N.B. Ratliff,3 M.M. Yousufuddin,1 P.M. McCarthy,4 J.B. Young,1 1Cardiology, Cleveland Clinic, Cleveland, OH; 2Allogen Laboratory; 3Anatomic Pathology; 4Cardiovascular Thoracic surgery, Cleveland Clinic, Cleveland, OH Background: Donor cause of death has an important impact on transplant outcome. Objectives: We evaluated the impact of donor intracranial bleeding on the development of transplant coronary vasculopathy using intravascular ultrasound (IVUS). Methods: A group of 72 recipients underwent cardiac transplantation from donors with intracranial bleeding (ICB group). These were compared to 90 recipients who were transplanted from trauma donors (Trauma group). All patients underwent serial endomyocardial biopsies. IVUS was performed on all patients at one month and one year of transplant. Volumetric analysis was available on 47 patients. Results: Both groups had similar baseline characteristics in relation to recipient age, etiology of heart disease, ischemia time, use of assist device and immunosuppressive therapy. However, the donor age was higher, as expected, in the ICB group compared to the Trauma group (41⫾10 vs 28⫾11 yrs, p⬍0.001). There was no significant difference in acute rejection. Compared to the Trauma group, the ICB group were more likely to develop graft dysfunction during the first week of transplant (left ventricle ejection fraction ⬍ 45%: 15% vs 3%, p ⫽ 0.01) and showed higher incidence of myocardial interstitial fibrosis at one year (49% vs 29%, p⫽0.01). Further, ICB was associated with increased coronary vasculopathy progression: they had increased change in coronary intimal thickness (0.54 ⫾ 0.33 vs 0.40 ⫾ 0.32 mm, p⫽ 0.03), increased change in plaque volume (3.84 ⫾ 2.51 vs 2.33 ⫾ 1.65 mm3, p⫽0.01), and increased change in plaque burden (7.4 ⫾ 11 % vs 2.0 ⫾ 4%, p⫽ 0.03) over one year compared to the Trauma group. The ICB group also had a worse 7-year Kaplan-Meier survival, 69% vs 86%, p⫽0.05. Conclusions: Intracranial bleeding is associated with increased coronary vasculopathy progression, and poorer outcome compared to trauma donors.
9 LONG TERM FOLLOW-UP OF A PROSPECTIVE RANDOMIZED TRIAL COMPARING TACROLIMUS VERSUS CYCLOSPORINE IN COMBINATION WITH MMF AFTER LUNG TRANSPLANTATION A. Zuckermann,1 H. Reichenspurner,2 P. Jaksch,1 H. Treede,2 W. Wisser,1 J. Groetzner,3 B. Reichart,3 W. Klepetko,1 1Dept. of CardioThoracic Surgery, University of Vienna, Vienna, Austria; 2Dept. of Cardiac Surgery, Universitaetsklinikum Eppendorf Hamburg, Hamburg, Germany; 3Dept. of Cardiac surgery, Ludwig-Maximilian University Munich, Munich, Germany Background:The early results of our randomized clinical 2 center trial comparing tacrolimus (Tac) versus Cyclosporine (CsA) in combination with Mycophenolate Mofetil (MMF) after lung transplantation have been previously reported. A significant finding was a trend towards lower early rejection incidence in the Tac group. This report updates the results with a follow-up of 36 months.
The Journal of Heart and Lung Transplantation Volume 22, Number 1S Patients & Methods: Between 9/97 and 4/99, 74 lung transplant recipients were randomised to receive either Tac (n⫽37) or CsA (n⫽37). The two groups were similar in age, sex and underlying disease. Results: 3-year survival was similar in the two groups (Tac: 68%, CsA: 57%). There was a clear trend towards more late rejections in the CsA group (24% vs. Tac: 4%, p⫽0.07). Incidence of BOS was significantly higher in the CsA group (Tac: 10% vs. CsA: 41%, p⬍0.01). Creatinine levels were similar between the groups (Tac: 1.56⫾0.58 vs. CsA: 1.39⫾0.36; n.s.) as well as the need for statin therapy (Tac: 24% vs. CsA: 41%; n.s.). There was a significant higher incidence of hypertension in the CsA group (CsA: 46% vs. Tac: 13.5%; p⬍0.05). Whereas, new-onset of diabetes mellitus was observed in the Tac group only (Tac: 22% vs. CsA: 0%; p⬍0.05). Conclusion: We conclude that Tac⫹MMF shows an advantage over CsA⫹MMF with regard to late rejection and development of BOS. Yet overall survival was similar between the two groups. Incidence of drug related adverse events were similar, yet their spectrum was different. 10 PROSPECTIVE RANDOMIZED INTERNATIONAL MULTICENTER INVESTIGATOR DRIVEN STUDY COMPARING TAC AND CSA (ⴙMMF/STEROIDS) AFTER LUNG TRANSPLANTATION - INTERIM ANALYSIS OF 110 PATIENTS H. Reichenspurner,1 A. Glanville,2 W. Klepetko,3 R. Lama,4 G.M. Verleden,5 C. Bravo,6 M. Estenne,7 B. Reichart,8 S. Hirt,9 F.Z. Goni,10 J. Aubert,11 J.M. Borro,12 P. Usetti,13 T. Wahlers,14 H. Treede,1 the European and Australian Investigators in Lung Transplantation, 1Department of Cardiovascular Surgery, University Hospital Hamburg-Eppendorf, Hamburg, Germany; 2University of Sydney, Sydney, Australia; 3University of Vienna, Vienna, Austria; 4 University of Cordoba, Cordoba, Spain; 5University of Leuven, Leuven, Belgium; 6University of Barcelona, Barcelona, Spain; 7University of Bruxelles, Bruxelles, Belgium; 8University of Munich, Munich, Germany; 9 University of Kiel, Kiel, Germany; 10University of Santander, Santander, Spain; 11University of Lausanne, Lausanne, Switzerland; 12University La Coruna, La Coruna, Spain; 13University of Madrid, Madrid, Spain; 14 University of Jena, Jena, Germany With the aim of an accurate scientific comparison a large prospective randomized international multi-center investigator-driven study comparing Tac and CsA (both in combination with MMF and steroids) after lung transplantion was initiated. Primary objective was to assess the efficacy and safety of both regimens for the prevention of bronchiolitis obliterans syndrom (BOS) up to 3 years post transplantation. Secondary objectives were number of and freedom from acute acute rejection and infection, survival and adverse events. Patients were central-computer randomized either to treatment group A: Tac (0.01-0.03 mg/kg/d iv3 0.05-0.3 mg/kg/d po) or group B: CsA (1-3 mg/kg/d 3 4-18 mg/kg/d po). Stratification for CF patients was performed. MMF (1-4 g/d) was administered according to trough levels. No induction therapy was given. It has been planned to include 250 patients. In September 2002 a total of 189 patients were included (11 early dropouts). Death rate was 8.4% (15/178 pat.). For this interim analysis 110 patients with at least one year follow-up have been evaluated (Feb. 2003). Results will be presented and interpreted at the ISHLT meeting. 11 AEROSOL CYCLOSPORINE PROVIDES DOSE DEPENDENT IMPROVEMENT IN LUNG FUNCTION AFTER LUNG TRANSPLANTATION
Abstracts
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T.E. Corcoran,1 G.C. Smaldone,2 J.H. Dauber,1 D.A. Smith,1 K.R. McCurry,3 G.J. Burckart,3 B.P. Griffith,4 W.F. Grgurich,1 A.T. Iacono,1 1Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA; 2Pulmonary and Critical Care Medicine, State University of New York at Stony Brook, Stony Brook, NY; 3Division of Cardiothoracic Surgery, University of Pittsburgh, Pittsburgh, PA; 4Division of Cardiac Surgery and Cardiopulmonary Transplantation, University of Maryland Medical Center, Baltimore, MD A placebo-controlled trial is presently testing the effectiveness of aerosolized cyclosporine as prophylaxis for lung transplant rejection. To measure the dose-response relationship, 15 subjects from this trial underwent a one-time radionuclide study to measure the lung deposition of cyclosporine. Deposition in the transplant was correlated with physiologic indices of effectiveness as measured by the change in one-second forced expiratory volume (FEV1) over time. Deposited dose in the periphery of the transplanted lung(s) was compared to percentage change in (FEV1) at post-op days 200, 300, 400, 500, 600, and 700. The best FEV1 value before post-op day 100 was used as the baseline. Results: there was a significant correlation between improvement in fev1 and dose at all time points. values of the r-squared based on linear regression ranged between 0.43 and 0.68 (all p⬍0.01). the percentage change in fev1 per mg of drug increased at each successive time point indicating a cumulative protective effect from the drug. subjects depositing 5mg or more experienced an improvement in lung function, whereas placebo subjects, and subjects depositing less than 5mg tended to demonstrate a decline. a two-way anova comparing lung function in subjects depositing 5mg or more with placebo subjects indicated significance (p⫽0.002). there was no relationship between peripheral dose and fev1 on the day of deposition testing indicating that the deposited dose was not simply a direct consequence of pulmonary function. Conclusion: Aerosol cyclosporine is effective in maintaining and improving lung function after lung transplant in a dose dependent manner. Patients receiving more than 5 mg of aerosolized cyclosporine in the periphery of their transplanted lung experience a dose dependent improvement in lung function over time. National Institutes of Health 5R01HL59490-02. 12 IL-10 HIGH GENOTYPE IS PROTECTIVE AGAINST ACUTE PERSISTENT REJECTION AFTER LUNG TRANSPLANTATION H.X. Zheng, G.J. Burckart, K. McCurry, S. Webber, D. Zaldonis, J. Ristich, A. Iacono, J. Dauber, W. Grgurich, K. McDade, A. Zeevi, Pharmacy, Surgery, Pediatrics, Medicine, and Pathology, University of Pittsburgh, Pittsburgh, PA Our previous studies have demonstrated that cytokine gene polymorphisms are related to acute rejection in pediatric heart transplantation. The objective of this study was to determine whether cytokine genotypes of TNF-␣, IL-10, IL-6, interferon-␥, and transforming growth factor- were associated with episodes of acute persistent rejection (APR) after lung transplantation (LT). Methods: cytokine genotyping was performed on 124 adult lt patients who were classified on the basis of their surveillance transbronchial biopsies during their first year post lt. they were categorized as having had apr if they had 2 consecutive biopsies of grade a2 in spite of anti-rejection treatment. genotyping was performed using the pcr-ssp technique by a commercially available kit (one-lambda, inc, canoga park, ca). Results: one hundred and eighteen patients were analyzed for il-10 genotype, and only 7 of 22 patients (32%) of the il-10 high genotype had