Unexpected Neoplasms in Lungs Explanted From Lung Transplant Recipients: A Single-Center Experience and Review of Literature.

INTRODUCTION: Lung transplantation is a common treatment for various indications, but undiagnosed neoplasms are found in 0.5% to 2.4% of explanted lungs. We report the largest single-institution series of patients with unexpected neoplasms in explanted lungs and compare rates of undiagnosed malignancies before and after the 2005 Lung Allocation Score (LAS) update. METHODS: We reviewed the medical records of patients who underwent lung transplantation at the Cleveland Clinic from 1990 to 2014. In cases of neoplasm discovered on explant, tumor type, pathological stage, recurrence, and date of death were recorded. RESULTS: From January 1, 1990 to June 30, 2014, 1303 patients underwent lung transplantation at the Cleveland Clinic. The overall mean smoking history was 35 pack-years, and 25 undiagnosed lung malignancies were found upon explant in 24 transplant recipients (1.84%). In the post-LAS era (ie, 2005 onward), 20/812 lung transplant recipients had 21 incidental neoplasms in their explanted lungs (2.5%). Seventeen of these 25 tumors occurred in patients with interstitial lung disease; 8 occurred in patients with centrilobular emphysema. Eight tumors recurred (6 in patients with interstitial lung disease and 2 in patients with emphysema). The most common histological tumor types were adenocarcinomas (n = 14) and squamous cell carcinomas (n = 7). CONCLUSIONS: Unexpected neoplasms were found in 1.84% of lung transplant recipients' explanted lungs, with a slightly higher incidence (2.46%) in the post-LAS era. Neoplasms were more common in patients with interstitial lung diseases than in patients with centrilobular emphysema. Explanted lungs should be pathologically examined for evidence of tumor foci because this can impact post-transplantation management.

Alemtuzumab induction prior to cardiac transplantation with lower intensity maintenance immunosuppression: one-year outcomes.

Induction therapy with alemtuzumab (C-1H) prior to cardiac transplantation (CTX) may allow for lower intensity maintenance immunosuppression. This is a retrospective study of patients who underwent CTX at a single institution from January 2001 until April 2009 and received no induction versus induction with C-1H on a background of tacrolimus and mycophenolate. Those with C-1H received dose-reduced calcineurin inhibitor and no steroids. A total of 220 patients were included, 110 received C-1H and 110 received no induction. Recipient baseline characteristics, donor age and gender were not different between the two groups. Mean tacrolimus levels (ng/mL) for C-1H versus no induction: months 1-3 (8.5 vs. 12.9), month 4-6 (10.2 vs. 13.0), month 7-9 (10.2 vs. 11.9) and month 10-12 (9.9 vs. 11.3) were all significantly lower for the C-1H group, p < 0.001. There were no differences between the C-1H and no induction groups at 12 months for overall survival 85.1% versus 93.6% p = 0.09, but freedom from significant rejection was significantly higher for the C-1H group, 84.5% versus 51.6%, p < 0.0001. In conclusion, induction therapy after CTX with C-1H results in a similar 12 month survival, but a greater freedom from rejection despite lower calcineurin levels and without the use of steroids.

Hydrogen inhalation ameliorates oxidative stress in transplantation induced intestinal graft injury.

Ischemia/reperfusion (I/R) injury during small intestinal transplantation (SITx) frequently causes complications including dysmotility, inflammation and organ failure. Recent evidence indicates hydrogen inhalation eliminates toxic hydroxyl radicals. Syngeneic, orthotopic SITx was performed in Lewis rats with 3 h of cold ischemic time. Both donor and recipient received perioperative air or 2% hydrogen inhalation. SITx caused a delay in gastrointestinal transit and decreased jejunal circular muscle contractile activity 24 h after surgery. Hydrogen treatment resulted in significantly improved gastrointestinal transit, as well as jejunal smooth muscle contractility in response to bethanechol. The transplant induced upregulation in the inflammatory mediators CCL2, IL-1 beta, IL-6 and TNF-alpha were mitigated by hydrogen. Hydrogen significantly diminished lipid peroxidation compared to elevated tissue malondialdehyde levels in air-treated grafts demonstrating an antioxidant effect. Histopathological mucosal erosion and increased gut permeability indicated a breakdown in posttransplant mucosal barrier function which was significantly attenuated by hydrogen treatment. In recipient lung, hydrogen treatment also resulted in a significant abatement in inflammatory mRNA induction and reduced neutrophil recruitment. Hydrogen inhalation significantly ameliorates intestinal transplant injury and prevents remote organ inflammation via its antioxidant effects. Administration of perioperative hydrogen gas may be a potent and clinically applicable therapeutic strategy for intestinal I/R injury.

Myocarditis following adeno-associated viral gene expression of human soluble TNF receptor (TNFRII-Fc) in baboon hearts.

Sequestration of tumor necrosis factor-alpha (TNFalpha) by TNF-receptor immunoglobulin G (IgG)-Fc fusion proteins can limit heart failure progression in rodent models. In this study we directly injected an adeno-associated viruses (AAV)-2 construct encoding a human TNF receptor II IgG-Fc fusion protein (AAV-TNFRII-Fc) into healthy baboon hearts and assessed virally encoded gene expression and clinical response. Adult baboons received direct cardiac injections of AAV-TNFRII-Fc ( approximately 5 x 10(12) viral/genomes/baboon) or an equivalent dose of AAV-2 empty capsids, and were analyzed after 5 or 12 weeks. Viral genomes were restricted to the myocardium, and routine analyses (blood cell counts, clinical chemistries) remained unremarkable. Echocardiograms were unchanged but electrocardiograms revealed marked ST- and T-wave changes consistent with myocarditis only in baboons receiving AAV-TNFRII-Fc. TNFRII serum levels peaked at approximately 3 times the baseline levels at 1-2 weeks postinjection and subsequently declined to baseline levels. TNFRII-Fc protein and transcripts were detected in the heart at harvest. After AAV injection, anti-AAV-2 antibody levels increased in all baboons, while anti-TNFRII-Fc could not be detected. Baboons that received AAV-TNFRII-Fc developed myocardial infiltrates including CD8+ cells. Thus, a cellular immune response to cardiac delivery of AAV encoding foreign proteins may be an important consideration for AAV-based cardiac gene therapy.

Recovery of functional memory T cells in lung transplant recipients following induction therapy with alemtuzumab.

Profound T-cell depletion with the monoclonal antibody alemtuzumab facilitates reduced maintenance immunosuppression in abdominal and lung transplantation. While the phenotype of the post-depletional T cells has been characterized, little is known about their function. In the present study, global and CMV-specific T-cell function was assessed longitudinally in 23 lung transplant (LTx) recipients using T-cell assays (ImmuKnow and T Cell Memory, Cylex, Columbia, MD) during the first year posttransplant after induction therapy. Recovery of mitogen responses were seen at 2 weeks posttransplantation (65%PHA; 58% Con A), despite the low number of circulating T cells (<2%). These responses declined at 4-5 months (24%PHA; 54% Con A) and were partially reconstituted by 9 months (46% PHA; 73% Con A). CMV-specific responses recovered in 80% of R+ patients as early as 2 weeks posttransplant (n = 5) and 72% of patients had a memory response by 3 months (n = 11). In contrast, only 2 of 5 patients who did not exhibit memory responses pre-transplant (R-) developed transient CMV-specific T-cell responses. Our results show that profound depletion of T cells induced by alemtuzumab spares the functional subset of CMV-specific memory T cells. Conversely, CMV R- patients predepletion may require a prolonged period of prophylaxis.

Voriconazole prophylaxis in lung transplant recipients.

Lung transplant recipients have one of the highest rates of invasive aspergillosis (IA) in solid organ transplantation. We used a single center, nonrandomized, retrospective, sequential study design to evaluate fungal infection rates in lung transplant recipients who were managed with either universal prophylaxis with voriconazole (n = 65) or targeted prophylaxis (n = 30) with itraconazole +/- inhaled amphotericin in patients at high risk (pre- or posttransplant Aspergillus colonization [except Aspergillus niger]). The rate of IA at 1 year was better in lung transplant recipients receiving voriconazole prophylaxis as compared to the cohort managed with targeted prophylaxis (1.5% vs. 23%; p = 0.001). Twenty-nine percent of cases in the targeted prophylaxis group were in patients colonized with A. niger who did not receive itraconazole. A three-fold or higher increase in liver enzymes was noted in 37-60% of patients receiving voriconazole prophylaxis as compared to 15-41% of patients in the targeted prophylaxis cohort. Fourteen percent in the voriconazole group as compared to 8% in the targeted prophylaxis group had to discontinue antifungal medications due to side effects. Voriconazole prophylaxis can be used in preventing IA in lung transplant recipients. Regular monitoring of liver enzymes and serum concentrations of calcineurin inhibitors are required to avoid hepatotoxicity and nephrotoxicity.

Preservation of post-transplant lung function with aerosol cyclosporin.

Post-lung transplant use of aerosol cyclosporin (ACsA) is considered by examining the relationship between deposited aerosol dose and effect. In a sub-study of placebo controlled trials of ACsA as a rejection prophylaxis, 15 drug subjects received aerosol dose quantification tests to gage their ability to effectively deposit the nebulised drug in their transplanted lung(s). A total of seven placebo subjects received mock deposition tests. The deposited doses and mock doses were compared to changes in the forced expiratory volume in one second, at six time points during the 2-yr trial period (ACsA was started within 6 weeks post-transplant). Linear relationships were demonstrated between deposited dose and improvement in lung function in the drug subjects at all intervals. Mock dose data from placebo subjects did not demonstrate similar correlation. Based on these results, subjects were grouped by dose and compared. Subjects depositing > or = 5 mg of the drug in the periphery of their transplant(s) had improving pulmonary function on average. Low-dose and placebo subjects demonstrated declines, more A2-A4 rejection events in the latter portion of the trial, and more chronic rejection beyond the end of the trial. A dose-to-effect relationship is demonstrated for aerosol cyclosporin in terms of pulmonary function and biopsy proven rejection.

Aerosol cyclosporin therapy in lung transplant recipients with bronchiolitis obliterans.

The majority of patients who develop bronchiolitis obliterans, after lung transplantation, die within 2-3 yrs after onset since treatment with conventional immunosuppression is typically ineffective. A case/control study was conducted in lung transplant recipients with biopsy-documented bronchiolitis obliterans to determine whether aerosol cyclosporin use contributed to increased survival. The cases comprised 39 transplant recipients who received open-label aerosol cyclosporin treatment in addition to conventional immunosuppression. The controls were transplant recipients treated with conventional immunosuppression alone. There were 51 controls from the University of Pittsburgh Medical Center and 100 from a large multicentric database (Novartis Lung Transplant Database). Forced expiratory volume in one second expressed as a percentage of the predicted value was an independent predictor of survival in all patients with bronchiolitis obliterans. Cox proportional-hazards analysis revealed a survival advantage for aerosol cyclosporin cases compared to the Pittsburgh control group. A survival advantage was also seen when comparing study cases to multicentric controls. Aerosol cyclosporin, given with conventional immunosuppression to lung transplant recipients with bronchiolitis obliterans, provides a survival advantage over conventional therapy alone.

Relapsing bacteremia in patients with ventricular assist device: an emergent complication of extended circulatory support.

BACKGROUND: Ventricular assist devices (VAD) are currently approved for use as a bridge for transplantation. Although reports have suggested acceptable rates of survival of patients with VAD, there is little information regarding the mechanism and etiology of bacteremia in these patients. METHODS: We prospectively followed patients who underwent VAD implantation and developed bacteremia during VAD support at the University of Pittsburgh Medical Center. Relapsing bacteremia was defined as at least two episodes of positive blood cultures with a genetically related organism on 2 different days. Species identification and susceptibility testing were performed on all isolates. Pulse field gel electrophoresis was performed on selected blood and VAD isolates. RESULTS: Between January 1998 and August 1999, 3 patients with VAD developed relapsing bacteremia, which was treated with full courses of antibiotic agents, 2 of whom also developed VAD endocarditis. All 3 patients had documented driveline or device pocket infections with these isolates. Consecutive blood and VAD isolates were found to be genetically related within each patient. CONCLUSIONS: These patients with bacteremia after VAD implantation had relapse due to the same strain, which may have originated from indolent driveline infection. Endovascular infection in this setting is difficult to eradicate with antibiotic agents and carries a high mortality. These patients should be considered to have priority for orthotopic heart transplantation.

A multicenter, randomized, controlled trial of Celsior for flush and hypothermic storage of cardiac allografts.

BACKGROUND: A multicenter, randomized, controlled, open-label trial was conducted to evaluate the safety and efficacy of Celsior when used for flush and hypothermic storage of donor hearts before transplantation. METHODS: Heart transplant recipients were randomized to one of two treatment groups in which donor hearts were flushed and stored in either Celsior or conventional preservation solution(s) (control). Study subjects were followed for 30 days after transplantation. RESULTS: A total of 131 heart transplant recipients were enrolled (Celsior, n = 64; control, n = 67). The treatment groups were evenly distributed in donor and recipient base line characteristics. Graft loss rate was lower in the Celsior group on day 7 (3% versus 9%) and on day 30 (6% versus 13%), but the difference was not statistically significant based on 95% confidence interval analysis. No significant difference was measured between the Celsior and control groups in 7-day patient survival (97% versus 94%) and the proportion of patients with one or more adverse events (Celsior, 88%; control 87%) or serious adverse events (Celsior, 38%; control, 46%). Significantly fewer patients in the Celsior group developed at least one cardiac-related serious adverse event (13% versus 25%). CONCLUSIONS: Celsior was demonstrated to be as safe and effective as conventional solutions for flush and cold storage of cardiac allografts before transplantation.

Effects of donor bone marrow infusion in clinical lung transplantation.

BACKGROUND: We have demonstrated that donor cell chimerism is associated with a lower incidence of obliterative bronchiolitis (OB) in lung recipients, and that donor chimerism is augmented by the infusion of donor bone marrow (BM). We herein report the intermediate results of a trial combining the infusion of donor BM and lung transplantation. METHODS: Clinical and in vitro data of 26 lung recipients receiving concurrent infusion of donor bone marrow (3.0 to 6.0 x 10(8) cells/kg) were compared with those of 13 patients receiving lung transplant alone. RESULTS: Patient survival and freedom from acute rejection were similar between groups. Of the patients whose graft survived greater than 4 months, 5% (1 of 22) of BM and 33% (4 of 12) of control patients, developed histologic evidence of OB (p = 0.04). A higher proportion (but not statistically significant) of BM recipients (7 of 10, 70%) exhibited donor-specific hyporeactivity by mixed lymphocyte reaction assays as compared with the controls (2 of 7, 28%). CONCLUSIONS: Infusion of donor BM at the time of lung transplantation is safe, and is associated with recipients' immune modulation and a lower rate of obliterative bronchiolitis.

A clinical trial combining donor bone marrow infusion and heart transplantation: intermediate-term results.

BACKGROUND: Donor chimerism (the presence of donor cells of bone marrow origin) is present for years after transplantation in recipients of solid organs. In lung recipients, chimerism is associated with a lower incidence of chronic rejection. To augment donor chimerism with the aim to enhance graft acceptance and to reduce immunosuppression, we initiated a trial combining infusion of donor bone marrow with heart transplantation. Reported herein are the intermediate-term results of this ongoing trial. METHODS: Between September 1993 and August 1998, 28 patients received concurrent heart transplantation and infusion of donor bone marrow at 3.0 x 10(8) cells/kg (study group). Twenty-four contemporaneous heart recipients who did not receive bone marrow served as controls. All patients received an immunosuppressive regimen consisting of tacrolimus and steroids. RESULTS: Patient survival was similar between the study and control groups (86% and 87% at 3 years, respectively). However, the proportion of patients free from grade 3A rejection was higher in the study group (64% at 6 months) than in the control group (40%; P =.03). The prevalence of coronary artery disease was similar between the two groups (freedom from disease at 3 years was 78% in study patients and 69% in controls). Similar proportions of study (18%) and control (15%) patients exhibited in vitro evidence of donor-specific hyporesponsiveness. CONCLUSIONS: The infusion of donor bone marrow reduces the rate of acute rejection in heart recipients. Donor bone marrow may play an important role in strategies aiming to enhance the graft acceptance.

Effect of ischemic time on survival in clinical lung transplantation.

BACKGROUND: While there is convincing evidence that prolonged ischemic times correlate with reduced long-term survival in heart transplantation, the effect of ischemic time on outcome in clinical lung transplantation remains controversial. To assess the effect of ischemic time on outcomes in lung transplantation, we reviewed our experience. METHODS: The study was performed by retrospective chart review. RESULTS: First-time lung transplantation was performed on 392 patients between 1988 and 1998. All grafts were flushed with cold crystalloid preservation solution and stored on ice. Ischemic time data were available for 352 of 392 (90%) patients. Ischemic times were grouped as follows: 0 to 4 hours (n = 91), 4 to 6 hours (n = 201), more than 6 hours (n = 60). Ischemic time did not correlate with survival: 3-year actuarial survival = 56% (0 to 4 hours), 58% (4 to 6 hours), 68% (> 6 hours), p = 0.58. There was no significant difference in the incidence of biopsy-proven diffuse alveolar damage in the first 30 days after transplantation (31%, 32%, 38%), episodes of acute rejection in the first 100 days after transplantation (1.9, 1.8, 1.7), duration of intubation (median 3, 4, 3 days), or incidence of obliterative bronchiolitis (23%, 28%, 26%) between the three groups (0 to 4 hours, 4 to 6 hours, > 6 hours, respectively). A diagnosis of diffuse alveolar damage was associated with a significantly worse outcome (1-year survival = 82% versus 54%, p < 0.0001). CONCLUSIONS: In contrast to heart transplantation, pulmonary allograft ischemic time up to 9 hours does not appear to have a significant impact on early graft function or survival. The presence of diffuse alveolar damage on biopsy early after transplantation does not correlate with prolonged ischemic time, but is associated with substantially reduced posttransplantation survival.

Controlling perioperative morbidity and mortality after lung transplantation for pulmonary hypertension.

Lung transplantation for pulmonary hypertension now accounts for more than 18% of all transplantations performed with 1-year survival rates for primary pulmonary hypertension approximating 65%. Patients have NYHA class III or IV symptoms and typically have marked right ventricular dysfunction. Accelerated or acute decompensation can occur. A decline in status leads to a patient with severe right heart failure, hepatic dysfunction and severe malnutrition, conditions that increase perioperative morbidity and mortality. Immediate right ventricular dysfunction may be related to allograft injury with persistent elevation of pulmonary artery pressures or to intrinsic right ventricular disease; this can be supported with inotropic medications. Single-lung transplantation results in postoperative physiology that can require aggressive therapy to limit mortality. When allograft dysfunction occurs, significant hypoxemia results to a greater degree than that observed with single-lung transplantations for other diseases or following double-lung transplantation. As a result, careful donor selection for a single lung transplantation is crucial. The most common reason for prolonged ventilation is allograft reperfusion injury with ventilation-perfusion mismatching. Neuromuscular blockade can decrease oxygen utilization and improve chest wall compliance, whereas lateral positioning with the native lung down can be crucial to improving V/Q matching. Differential lung ventilation allows the application of larger quantities of positive end-expiratory pressure to the injured allograft. The use of exogenous nitrates has been advocated to reduce pulmonary vascular resistance. Nitric oxide has attractive potential benefits because it can be delivered directly to the lungs and functions to dilate the pulmonary vascular bed. All else having failed, we and others have successfully used extracorporeal membrane oxygenation to support cardiopulmonary function.

Lung and heart-lung transplantation at the University of Pittsburgh.

The application of lung transplantation as a treatment modality for patients with severe pulmonary disease has changed dramatically since its inception. At the University of Pittsburgh, the criteria for recipient selection continues to evolve and, in an effort to maximize scarce donor organs, the criteria for donor lung acceptance have been extended. Patient survival during the first 3 years after transplantation continues to improve but longer term survival is limited by infectious complications and chronic rejection. In early studies, the utilization of cyclosporine delivered directly to the lungs via aerosol has resulted in dramatic improvement in pulmonary function in recipients with immune mediated allograft injury and has allowed a reduction in systemic immunosuppression. We are hopeful that interventions such as this will result in prolongation of patient survival with less toxicity.

In vivo transfer of GPI-linked complement restriction factors from erythrocytes to the endothelium.

Many proteins are associated with the outer layer of the cell membrane through a posttranslationally added glycosyl phosphatidylinositol (GPI) anchor. The functional significance of this type of protein linkage is unclear, although it results in increased lateral mobility, sorting to the apical surface of the cell, reinsertion into cell membranes, and possibly cell signaling. Here evidence is presented that GPI-linked proteins can undergo intermembrane transfer in vivo. GPI-linked proteins expressed on the surface of transgenic mouse red blood cells were transferred in a functional form to endothelial cells in vivo. This feature of GPI linkage may be potentially useful for the delivery of therapeutic proteins to vascular endothelium.

Extracorporeal life support after heart or lung transplantation.

Extracorporeal life support (ECLS) has been used in 10 patients after heart (5 patients), lung (3 patients), and heart-lung (2 patients) transplantation. The age range was 7 months to 55 years. Cardiopulmonary failure leading to institution of ECLS was due to acute postoperative organ malfunction in 4 patients (2 survived), subacute organ malfunction in 3 patients (none survived), and late rejection or infection in 3 patients (2 survived). Neurologic complications occurred in 3 patients (1 survived) and bleeding, in 5 patients (2 survived). Six patients (60%) were successfully weaned from ECLS, and 4 (40%) survived to leave the hospital. Survival was associated with younger age, shorter duration of ECLS, and longer interval from operation to initiation of ECLS but not to reason for initiating ECLS. Extracorporeal life support is feasible for sustaining both adults and children after heart, lung, or heart-lung transplantation. Best results were obtained in patients with conditions that, in retrospect, were treatable and reversible within days. More experience is needed to predict preoperatively which patients will benefit most from ECLS.

Simultaneous traumatic ascending and descending thoracic aortic rupture.

A case of a 56-year-old male blunt trauma victim with combined simultaneous ascending and descending thoracic aortic rupture is presented. He was successfully treated with immediate operation for the ascending aortic rupture and a delayed approach, with nonoperative stabilization and later repair, due to poor pulmonary status and a question in diagnosis, for the descending aortic rupture.

Tumor necrosis factor, interleukin 6, and the acute phase response following hepatic ischemia/reperfusion.

We report here the production of systemic levels of tumor necrosis factor (TNF) and interleukin 6 (IL-6) and associated changes in serum macroglobulin to albumin ratios in a nonlethal rat model of partial hepatic ischemia/reperfusion (I/R). Plasma IL-6 was detectable and elevated at 1 hr of reperfusion as compared to sham-operated controls (I/R rats = 12,100 +/- 3860 pg/ml; sham rats = 5260 +/- 842 pg/ml; IL-6 values = means +/- SEM) and reached maximal levels at 6 hr of reperfusion (I/R rats = 47,400 +/- 25,700 pg/ml; sham rats = 3370 +/- 394 pg/ml), in contrast to maximal TNF levels at 30 min of reperfusion (I/R rats = 72 +/- 15 pg/ml; sham rats = 2 +/- 2 pg/ml; TNF values = means +/- SEM). Pretreatment with neutralizing TNF antisera prior to ischemia resulted in a reduction of IL-6 at 1 hr of reperfusion (anti-TNF = 3870 +/- 2550 pg/ml; control serum = 7650 +/- 1670 pg/ml), but was without effect on IL-6 levels at subsequent time points over the 24 hr of reperfusion. Electrophoretic determination of macroglobulin (alpha 1 + alpha 2) and albumin concentrations in sham-operated and ischemia/reperfusion animals demonstrated an elevation in the macroglobulin/albumin ratio in both groups over time, suggestive of an acute phase response, and the ratio was unchanged by immunoneutralization of TNF prior to ischemia/reperfusion. We conclude that this model of hepatic ischemia/reperfusion results in temporally distinct systemic elevations in IL-6 and TNF; however, the induction of IL-6 and the associated changes in serum macroglobulin concentration are independent of TNF.