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G Alexander Patterson

Publications and source records attributed to G Alexander Patterson.

At least 37 records · Page 2Linked to original sources
PubMed2005

Inhibition of obliterative airway disease development following heterotopic murine tracheal transplantation by costimulatory molecule blockade using anti-CD40 ligand alone or in combination with donor bone marrow.

INTRODUCTION: Obliterative airway disease (OAD) development in heterotopic murine tracheal allografts, a model of obliterative bronchiolitis after lung transplantation, is immunologically mediated. Whether tolerance induction by the administration of anti-CD40 ligand monoclonal anti-body (MR-1) alone or in conjunction with donor-derived bone marrow cells (BMCs) can prevent the development of OAD was tested in this study. METHODS: BALB/c tracheal allografts were heterotopically transplanted into C57BL/6 recipients. Group 1 received no treatment. Group 2 received multiple infusions of donor BMCs intravenously. Group 3 was administered MR-1 intraperitoneally. Group 4 received donor BMCs and MR-1. Allografts were harvested at several time points post-transplantation and examined for the development of OAD. RESULTS: Group 1 developed cellular infiltration and epithelial damage by Day 15 post-transplant and OAD by Day 28, evidenced by complete obliteration of the tracheal lumen. Group 2 developed OAD with similar kinetics to Group 1. Group 3 had no evidence of OAD at 28 days. At Days 45 to 90, moderate cellular infiltration, epithelial metaplasia, and a minimal narrowing of the tracheal lumen were evident. OAD developed by Day 120. Group 4 mice had patent tracheal lumens even at 120 days post-transplantation, with only mild epithelial metaplasia and luminal narrowing noted. CONCLUSIONS: The administration of MR-1 alone in combination with infusions of donor bone marrow cells significantly attenuated the development of OAD. Tolerance-inducing regimens such as this deserve further investigation in the prevention of post-lung transplant obliterative bronchiolitis following human lung transplantation.

Animals↗
PubMed2005

A comparison of basiliximab and anti-thymocyte globulin as induction agents after lung transplantation.

BACKGROUND: Interleukin-2 receptor antagonists have supplanted polyclonal antibody preparations as the most frequently used induction agents after lung transplantation, but the relative efficacy of these agents has not been firmly established. METHODS: We retrospectively analyzed the efficacy of basiliximab compared with antithymocyte globulin among 157 adult lung transplant recipients at our center. RESULTS: At 3, 6, and 12 months after transplantation, the median cumulative acute rejection A scores for the basiliximab group (2, 2, and 3, respectively) were significantly higher than those for the anti-thymocyte globulin group (1, 1, and 2, respectively; p = 0.003, 0.004, and 0.033, respectively). In addition, basiliximab recipients were more likely to develop acute rejection grade > or = A2 than anti-thymocyte globulin recipients; in fact, 60% of basiliximab recipients compared with 38% of anti-thymocyte globulin recipients developed their first episode of acute rejection grade > or = A2 in the first 100 days after transplantation (log-rank p = 0.04). Furthermore, basiliximab recipients were more likely to develop bronchiolitis obliterans syndrome than anti-thymocyte globulin recipients (log-rank p = 0.036). Two years after transplantation, 36% of basiliximab recipients and 26% of anti-thymocyte globulin recipients developed bronchiolitis obliterans syndrome. However, there were no significant differences in the incidences of cytomegalovirus viremia and pneumonitis between the 2 groups (p = 0.86 and 0.89, respectively). CONCLUSIONS: Induction with anti-thymocyte globulin is associated with a lower burden of acute rejection and bronchiolitis obliterans syndrome compared with basiliximab, without a significant difference in the incidence of cytomegalovirus infections.

Adult↗
PubMed2005

Recipient intramuscular cotransfection of transforming growth factor beta1 and interleukin 10 ameliorates acute lung graft rejection.

OBJECTIVE: Multiple gene transfer might permit modulation of concurrent biochemical pathways involved in acute lung graft rejection. We investigated whether gene cotransfection into the recipient reduces acute lung graft rejection. METHODS: Brown Norway rats were used as donors, and F344 rats were used as recipients. Recipient animals were injected with saline (groups I/VI) or 1 x 10(10) pfu of adenovirus encoding beta-galactosidase (groups II/VII), transforming growth factor beta1 (groups III/VIII), interleukin 10 (groups IV/IX), or both transforming growth factor beta1 and interleukin 10 (groups V/X) into both leg muscles 2 days before transplantation (groups I-V) or at the time of harvest (groups VI-X). The Kruskal-Wallis test for rejection score and 1-way analysis of variance were used to compare groups. RESULTS: Oxygenation was significantly improved in the cotransfected groups treated 2 days before transplantation and at the time of harvest. Rejection scores were also reduced in the cotransfected groups. In group V cotransfection suppressed endogenous interleukin 2 but not interferon gamma and tumor necrosis factor alpha. CONCLUSION: Recipient intramuscular cotransfection of transforming growth factor beta1 and interleukin 10 suppressed interleukin 2 expression and provided a synergistic effect that reduced acute lung graft rejection. This approach might be applied to the clinical setting because transplant recipients could be treated at the time of implantation.

Acute Disease↗
PubMed2005

Primary graft dysfunction and other selected complications of lung transplantation: A single-center experience of 983 patients.

OBJECTIVES: We sought to review the incidence and outcome of lung transplantation complications observed over 15 years at a single center. METHODS: We performed a retrospective review from our databases, tracking outcomes after adult and pediatric lung transplantation. The 983 operations between July 1988 and September 2003 included 277 pediatric and 706 adult recipients. Bilateral (74%), unilateral (19%), and living lobar transplants (4%) comprised the bulk of this experience. Retransplantations accounted for 44 (4.5%) of the operations. RESULTS: The groups differed by indication for transplantation. The adults included 57% with emphysema and 17% with cystic fibrosis, and the children included no patients with emphysema and 50% with cystic fibrosis. Hospital mortality was 96 (9.8%) of 983, including 46 (17%) of 277 of the children and 50 (7%) of 706 of the adults. The overall survival curves did not differ between adults and children ( P = .56). Freedom from bronchiolitis obliterans syndrome at 5 and 10 years was 45% and 18% for adults and 48% and 30% for children, respectively ( P = .53). The causes of death for adults included bronchiolitis obliterans syndrome (40%), respiratory failure (17%), and infection (14%), whereas the causes of death in children included bronchiolitis obliterans syndrome (35%), infection (28%), and respiratory failure (21%) ( P < .01). Posttransplantation lymphoproliferative disease occurred in 12% of pediatric recipients and 6% of adults ( P < .01). The frequency of treated airway complications did not differ between adults and children (9% vs 11%, P = .48). The frequency of primary graft dysfunction did not differ between children (22%) and adults (23%), despite disparity in the use of cardiopulmonary bypass. CONCLUSION: These results highlight major complications after lung transplantation. Despite differences in underlying diagnoses and operative techniques, the 2 cohorts of patients experienced remarkably similar outcomes.

Adolescent↗
PubMed2005

Inhibition of nuclear factor kappaB by IkappaB superrepressor gene transfer ameliorates ischemia-reperfusion injury after experimental lung transplantation.

OBJECTIVES: Ischemia-reperfusion injury after lung transplantation is associated with significant morbidity and mortality. The activation of the transcription factor nuclear factor kappaB is central to the 2 important pathways that characterize ischemia-reperfusion injury, namely the inflammatory response and apoptosis. The purpose of this study was to determine the effects of nuclear factor kappaB inhibition on experimental lung transplant ischemia-reperfusion injury with gene transfer of the nuclear factor kappaB inhibitor IkappaB in a superrepressor form (IkappaBSR). METHODS: An orthotopic left lung transplant model in isogeneic rats was used, with 18 hours of prolonged cold storage of donor lung grafts used to create severe ischemia-reperfusion injury. Donor rats underwent endobronchial gene transfection with saline alone or adenovirus encoding either beta-galactosidase control or IkappaBSR 48 hours before harvest. The function of transplanted lung grafts was assessed on the basis of isolated graft oxygenation, wet/dry lung weight ratio, and myeloperoxidase activity. Nuclear factor kappaB activation was assessed by means of enzyme-linked immunosorbent assay. Apoptotic cell death was assessed by evaluating the levels of histone-associated DNA fragments and caspase-3 activity. RESULTS: Treatment of donor lung grafts with IkappaBSR resulted in significantly improved oxygenation compared with that seen in control tissue 24 hours after transplantation. IkappaBSR-treated lungs also demonstrated less pulmonary edema and reduced neutrophil infiltration 24 hours after reperfusion. Nuclear factor kappaB activation and apoptotic cell death induction 2 hours after transplantation was significantly reduced in IkappaBSR-treated lungs compared with in control lungs. CONCLUSIONS: Inhibition of nuclear factor kappaB activation by IkappaBSR gene transfer improves transplanted lung graft oxygenation, decreases pulmonary edema and neutrophil sequestration, and reduces apoptotic cell death after experimental lung transplantation.

Adenoviridae↗
PubMed2005

Large cell neuroendocrine carcinoma: an aggressive form of non-small cell lung cancer.

OBJECTIVE: Large cell neuroendocrine carcinomas of the lung display morphologic and immunohistochemical characteristics common to neuroendocrine tumors and the morphologic features of large cell carcinomas. Surgical resection of large cell neuroendocrine carcinomas in many series has been described, with 5-year actuarial survivals ranging from 13% to 57%. Considerable debate has emerged as to whether these tumors should be classified and treated as non-small cell lung cancers or small cell lung cancers. The objective of this study was to report the outcome of surgical resection in patients with large cell neuroendocrine carcinomas. METHODS: An analysis of our tumor registry was performed to identify all patients undergoing surgical resection of lung cancer between July 1, 1988, and December 31, 2002, for large cell tumors. Cases were then segregated into large cell neuroendocrine carcinomas, mixed large cell neuroendocrine carcinomas (in which at least one portion of the tumor was a large cell neuroendocrine carcinoma), or large cell carcinomas on the basis of morphology and differentiation. Follow-up was complete on all patients, with a mean follow-up of 48 months. Type of resection, mortality, and survival by stage were analyzed. Kaplan-Meier survival was determined for all patients from the date of surgical intervention. Cox proportional hazards model analysis incorporating the variables of age, sex, histology, and stage estimated the effect of large cell neuroendocrine carcinomas and mixed large cell neuroendocrine carcinomas on recurrence and death. The stage of disease in all patients was assessed according to the 1997 American Joint Committee on Cancer guidelines. RESULTS: Of the 2099 patients who underwent resection, 82 (3.9%) had large cell lung cancers. Perioperative mortality was 2.4%. Overall survival and freedom from recurrence at 5 years for the entire group was 47.1% and 58.4%, respectively. Overall survival by histologic subtype at 5 years was 30.2% for patients with large cell neuroendocrine carcinomas (n = 45), 30.3% for patients with mixed large cell neuroendocrine carcinomas (n = 11), and 71.3% for patients with large cell carcinomas (n = 21). Survival was significantly worse for patients with large cell neuroendocrine carcinomas than for patients with large cell carcinomas ( P = .013). The presence of large cell neuroendocrine carcinomas in the specimen (the large cell neuroendocrine carcinoma and mixed large cell neuroendocrine carcinoma groups combined) was significantly associated with decreased survival (relative risk, 2.44; 95% confidence interval 1.29-4.58; P = .003) and decreased freedom from recurrence (relative risk, 4.52; 95% confidence interval, 1.76-11.57; P < .001). CONCLUSION: Patients with large cell neuroendocrine carcinomas have a significantly worse survival after resection than patients with large cell carcinomas, even in stage I disease. Accurate differentiation of large cell neuroendocrine carcinoma from large cell carcinoma is important because it identifies those patients at highest risk for the development of recurrent lung cancer.

Adult↗
PubMed2005

Outcome of lung transplantation for patients requiring concomitant cardiac surgery.

BACKGROUND: The clinical results of lung transplantation and concomitant cardiac surgery are unclear. The effect of cardiopulmonary bypass on the pulmonary allograft is controversial, and the effect of cardiac arrest and cardiac surgery in this setting is unknown. Our aim was to review the operative results and long-term survival in this group of patients. METHODS: A retrospective review of all lung transplantations between 1988 and 2003 was performed. Patients who had concomitant cardiac surgery during lung transplantation were compared with those who underwent lung transplantation alone. The variables analyzed included allograft ischemic times, use of cardiopulmonary bypass, early graft dysfunction, postoperative morbidity, survival, length of mechanical ventilation, length of stay in the intensive care unit, and overall hospital stay. RESULTS: During this period, 35 of 700 lung transplant recipients (15 single and 20 bilateral transplantations) underwent concomitant cardiac surgery. The cardiac procedures were for patent foramen ovale (n = 18), atrial septal defect (n = 9), ventricular septal defect (n = 2), coronary bypass (n = 4), and "other" (n = 2). Allograft ischemic time, use of extracorporeal membrane oxygenation, length of hospital stay, operative mortality, and survival were not significantly different between the 2 groups. Ventilator time and intensive care unit stay were longer in the cardiac surgery group. CONCLUSIONS: Cardiac surgery at the time of lung transplantation can be performed with acceptable morbidity and mortality. The immediate and long-term survival in these patients is similar to that of other lung transplant recipients. Lung transplantation should continue to be offered to patients with normal ventricular function who require concomitant limited cardiac surgery.

Adult↗
PubMed2005

Induction chemotherapy with mitomycin, vindesine, and cisplatin for stage IIIA (T1-3, N2) unresectable non-small-cell lung cancer: final results of the Toronto phase II trial.

PURPOSE: This is a phase II study to assess the role of induction chemotherapy in the management of stage IIIA non-small-cell lung cancer (NSCLC). We are now reporting the long-term follow-up of the Toronto phase II trial. METHODS: Sixty five patients with mediastinoscopy proven stage IIIA NSCLC received two cycles of preoperative MVP or VLB/P followed by thoracotomy followed by two further courses of chemotherapy. RESULTS: The overall response rate was 67.7% with three complete and 41 partial responders. Forty seven patients went on to thoracotomy with 35 complete resections. Pathologically 4.6% of patients had no tumour remaining. There were three postop deaths as well as five chemotherapy related deaths. Of the 35 patients completely resected 19 have recurred including eight in brain. The median survival for the entire 65 patients is 18.6 months with a 1 year survival of 66%, 5 year survival of 29% and a 10 year survival of 22%. CONCLUSIONS: The long-term survival of induction chemotherapy is maintained. The high incidence of brain recurrences warrants assessment of the role of prophylactic cranial radiation. The role of surgery for stage IIIA NSCLC following induction chemotherapy awaits further study.

Adult↗
PubMed2005

Mycotic pulmonary artery pseudoaneurysm.

We report a rare case of a mycotic pulmonary artery pseudoaneurysm that was detected on CT examination. The pulmonary artery pseudoaneurysm appeared as a rapidly growing enhancing mass without a draining vein and with evidence of surrounding acute hemorrhage on CT.

Adult↗
PubMed2005

Inhibition of obliterative airway disease development in murine tracheal allografts by matrix metalloproteinase-9 deficiency.

This study was designed to define the roles of matrix metalloproteinase (MMP)-2 and MMP-9 in obliterative airway disease (OAD) in heterotopic murine tracheal allografts, considered a suitable animal model for chronic lung allograft rejection. BALB/c tracheal allografts were transplanted into MMP-2-deficient (-/-) and MMP-9-/- mice. Also, wild-type recipients were treated with doxycycline, a nonspecific MMP inhibitor. After 10, 20 and 30 days, allografts were analyzed for OAD development, intragraft levels of MMP-2 and MMP-9 and the frequency and cytokine/chemokine production profile of alloreactive T cells. Allografts transplanted into wild-type mice developed OAD lesions within 30 days. These allografts revealed significant upregulation of both MMP-2 and MMP-9. Allografts transplanted into MMP-9-/- and doxycycline-treated recipients did not develop OAD. In contrast, allografts transplanted into MMP-2-/- mice developed OAD lesions with normal kinetics. Interestingly, MMP-9-/- recipients showed an enhanced T cell alloreactivity associated with an abnormal profile of cytokine/chemokine production. The enhanced T cell alloreactivity in MMP-9-/- mice was mediated by enhanced dendritic cell stimulatory capacity as well as enhanced T cell responsive capacity. These results suggest that MMP-9 plays an important role in the pathogenesis of OAD and may represent a target for the therapeutic intervention of chronic lung allograft rejection.

Airway Obstruction↗
PubMed2005

In vivo molecular imaging characterizes pulmonary gene expression during experimental lung transplantation.

Experimental gene therapy is a promising strategy to prevent ischemia-reperfusion (I/R) injury and allograft rejection after lung transplantation, and methods will eventually be needed to characterize pulmonary transgene expression in vivo in humans. Therefore, we studied positron emission tomography (PET) as a means of performing in vivo molecular imaging in rodent models of lung transplantation. Rats were transfected endotracheally with adenovirus encoding a fusion gene of a mutant Herpes simplex virus-1 thymidine kinase and the green fluorescent protein gene (the former serving as an imaging reporter gene). Twenty-four hours after transfection, lungs were transplanted in groups representing normal transplantation, I/R injury and acute allograft rejection. Imaging was obtained either 24 h after transplantation to study reperfusion injury or 4 days after transplantation to study graft rejection. After imaging, lungs were excised and analyzed for thymidine kinase activity. Imaging detected transgene expression in transplanted lungs even in the presence of acute rejection or I/R injury. The PET imaging signal correlated with in vitro lung tissue assays of thymidine kinase activity (r(2) = 0.534). Thus, noninvasive molecular imaging with PET is a feasible, sensitive and quantitative method for characterizing pulmonary transgene expression in experimental lung transplantation.

Animals↗
PubMed2005

Minimal acute rejection after lung transplantation: a risk for bronchiolitis obliterans syndrome.

Bronchiolitis obliterans syndrome (BOS) is a major cause of lung allograft dysfunction. Although previous studies have identified mild to severe rejection (grade>or=A2) as a risk factor for BOS, the role of minimal rejection (grade A1) remains unclear. To determine if A1 rejection by itself is a risk factor for BOS, we performed a retrospective cohort study on 228 adult lung transplant recipients over a 7-year period. Cohorts were defined by their most severe rejection episode (none, A1 only, and >or=A2) and analyzed for the subsequent development and progression of BOS using univariate and multivariate time-dependent Cox regression analysis. In the univariate model, the occurrence of isolated minimal rejection was a risk factor for all stages of BOS. Similarly, multivariate models that included HLA mismatch, cytomegalovirus pneumonitis, community acquired viral infection, underlying disease and type of transplant demonstrated that A1 rejection was a distinct risk factor for BOS. Furthermore, the associated risk with A1 rejection was slightly greater than the risk from >or=A2 and treatment of A1 rejection decreased the risk for subsequent BOS stage 1. We conclude that minimal rejection is associated with an increased risk for BOS development and progression that is comparable to A2 rejection.

Adolescent↗
PubMed2004

Respiratory viral infections are a distinct risk for bronchiolitis obliterans syndrome and death.

Bronchiolitis obliterans syndrome (BOS) is the major obstacle to long-term survival after lung transplantation, in part because its pathogenesis is poorly understood and treatment options are limited. To identify unique risk factors for BOS and death, we performed a retrospective cohort study on 259 consecutive adult lung transplant recipients over a 5-year period. The demographic and clinical characteristics of this population were analyzed for an association between BOS or death and potential risk factors, including community-acquired respiratory viral (CARV) infections, acute rejection, and cytomegalovirus pneumonitis. Respiratory syncytial virus, parainfluenza, influenza, and adenovirus accounted for 21 CARV infections. Univariate and multivariate time-dependent Cox regression analyses demonstrated that this CARV group was more likely to develop BOS, death, and death from BOS. Furthermore, these trends were more pronounced in patients with evidence of lower respiratory tract-CARV (lower-CARV) infections. Notably, the CARV and lower-CARV infections were risk factors for BOS, death, and death from BOS distinct from the risk attributable to acute rejection. Identification of CARV and lower-CARV infections as BOS and mortality risk factors has important clinical implications and may provide insight into disease pathogenesis and accelerate the development of novel treatment strategies to modify post-CARV BOS.

Bronchiolitis Obliterans↗
PubMed2004

Abdominal-pelvic lymphoproliferative disease after lung transplantation: presentation and outcome.

BACKGROUND: Lymphoproliferative disease (LPD) is a well-recognized complication after lung transplantation. However, its presentation in the abdomen and pelvis has not been previously detailed. METHODS: We retrospectively identified cases of abdominal-pelvic LPD in lung transplant recipients. The cases were characterized clinically, and the outcomes were analyzed. RESULTS: Abdominal-pelvic LPD was identified in 19 of 603 adult patients who underwent lung or heart-lung transplantation at Barnes-Jewish Hospital between July 1, 1988 and December 31, 2001. The median time from transplantation to the onset of LPD was 5.8 years. Three cases presented early after transplantation (median, 175 days), and 16 cases presented late (median, 2,255 days). The time to diagnosis of LPD was significantly shorter for Epstein-Barr virus (EBV)-seronegative than for EBV-seropositive recipients (median, 175 vs. 2255 days; log-rank, P<0.001). Seventeen cases were non-Hodgkin's lymphomas, one was a Burkitt's lymphoma, and one was an atypical lymphoid proliferation. Among the 19 cases, 12 involved the gastrointestinal tract and 7 occurred in other sites. Immunosuppressive therapy was decreased in all patients. Eleven underwent surgical resection, and nine received chemotherapy. Sixteen patients have died, and 14 deaths were attributable to LPD. The median time from the diagnosis of LPD to death was 68 days. CONCLUSIONS: Abdominal-pelvic LPD is typically a late complication after lung transplantation; however, when it occurs early, it may be related to a primary EBV infection. This form of LPD is most frequently a non-Hodgkin's lymphoma, and despite aggressive therapy, the prognosis is poor.

Abdomen↗