Search

Organ allocation for transplantation aims to balance the principles of justice and medical utility to optimally utilize a scarce resource. To address practical considerations, the United States is divided into 58 donor service areas (DSA), each constituting the first unit of allocation. In November 2017, in response to a lawsuit in New York, an emergency action change to lung allocation policy replaced the DSA level of allocation for donor lungs with a 250 nautical mile circle around the donor hospital. Similar policy changes are being implemented for other organs including heart and liver. Findings from a recent US Department of Health and Human Services report, supplemented with data from our institution, suggest that the emergency policy has not resulted in a change in the type of patients undergoing lung transplantation (LT) or early postoperative outcomes. However, there has been a significant decline in local LT, where donor and recipient are in the same DSA. With procurement teams having to travel greater distances, organ ischemic time has increased and median organ cost has more than doubled. We propose potential solutions for consideration at this critical juncture in the field of transplantation. Policymakers should choose equitable and sustainable access for this lifesaving discipline., (© 2019 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Esophagitis, whether caused by acid reflux, allergic responses, graft-versus-host disease, drugs, or infections, is a common condition of the gastrointestinal tract affecting nearly 20% of the US population. The instigating agent typically triggers an inflammatory response. The resulting inflammation is a risk factor for the development of esophageal strictures, Barrett esophagus, and esophageal adenocarcinoma. Research into the pathophysiology of these conditions has been limited by the availability of animal and human model systems. Three-dimensional organotypic tissue culture (OTC) is an innovative three-dimensional multicellular in vitro platform that recapitulates normal esophageal epithelial stratification and differentiation. We hypothesized that this platform can be used to model esophagitis to better understand the interactions between immune cells and the esophageal epithelium. We found that human immune cells remain viable and respond to cytokines when cultured under OTC conditions. The acute inflammatory environment induced in the OTC significantly affected the overlying epithelium, inducing a regenerative response marked by increased cell proliferation and epithelial hyperplasia. Moreover, oxidative stress from the acute inflammation induced DNA damage and strand breaks in epithelial cells, which could be reversed by antioxidant treatment. These findings support the importance of immune cell-mediated esophageal injury in esophagitis and confirms the utility of the OTC platform to characterize the underlying molecular events in esophagitis., (Copyright © 2017 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Barrett's oesophagus (BE) is defined as any metaplastic columnar epithelium in the distal oesophagus which replaces normal squamous epithelium and which predisposes to cancer development. It is this second requirement, the predisposition to cancer, which makes this condition both clinically highly relevant and an important area for ongoing research. While BE has been defined pathologically since the 1950's (Allison and Johnstone, Thorax 1955), and identified as a risk factor for esophageal adenocarcinoma since the 1970's (Naef A.P., et al J Thorac Cardiovasc Surg. 1975), our understanding of the molecular events giving rise to this condition remains limited. Herein we will examine what is known about the intestinal features of BE and how well it recapitulates the intestinal epithelium, including stem identity and function. Finally, we will explore laboratory models of this condition presently in use and under development, to identify new insights they may provide into this important clinical condition., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

The incidence of esophageal adenocarcinoma (EAC) is rising in the United States. An important risk factor for EAC is the presence of Barrett esophagus (BE). BE is the replacement of normal squamous esophageal epithelium with a specialized columnar epithelium in response to chronic acid and bile reflux. However, the emergence of BE from squamous keratinocytes has not yet been demonstrated. Our research has focused on this. Wnt and cyclooxygenase 2 (Cox2) are two pathways whose activation has been associated with BE and progression to EAC, but their role has not been tested experimentally. To explore their contribution, we engineered a human esophageal keratinocyte cell line to express either a dominant-active Wnt effector CatCLef or a Cox2 complementary DNA. In a two-dimensional culture environment, Cox2 expression increases cell proliferation and migration, but neither transgene induces known BE markers. In contrast, when these cells were placed into three-dimensional organotypic culture conditions, we observed more profound effects. CatCLef-expressing cells were more proliferative, developed a thicker epithelium, and upregulated Notch signaling and several BE markers including NHE2. Cox2 expression also increased cell proliferation and induced a thicker epithelium. More importantly, we observed cysts form within the epithelium, filled with intestinal mucins including Muc5B and Muc17. This suggests that Cox2 expression in a three-dimensional culture environment induces a lineage of mucin-secreting cells and supports an important causal role for Cox2 in BE pathogenesis. We conclude that in vitro modeling of BE pathogenesis can be improved by enhancing Wnt signaling and Cox2 activity and using three-dimensional organotypic culture conditions.

The Caudal-related homeobox genes Cdx1 and Cdx2 are intestine-specific transcription factors that regulate differentiation of intestinal cell types. Previously, we have shown Cdx1 to be antiproliferative and to promote cell differentiation. However, other studies have suggested that Cdx1 may be an oncogene. To test for oncogenic behavior, we used the murine villin promoter to ectopically express Cdx1 in the small intestinal villi and colonic surface epithelium. No changes in intestinal architecture, cell differentiation, or lineage selection were observed with expression of the transgene. Classic oncogenes enhance proliferation and induce tumors when ectopically expressed. However, the Cdx1 transgene neither altered intestinal proliferation nor induced spontaneous intestinal tumors. In a murine model for colitis-associated cancer, the Cdx1 transgene decreased, rather than increased, the number of adenomas that developed. In the polyps, the expression of the endogenous and the transgenic Cdx1 proteins was largely absent, whereas endogenous Villin expression was retained. This suggests that transgene silencing was specific and not due to a general Villin inactivation. In conclusion, neither the ectopic expression of Cdx1 was associated with changes in intestinal cell proliferation or differentiation nor was there increased intestinal cancer susceptibility. Our results therefore suggest that Cdx1 is not an oncogene in normal intestinal epithelium.

Background: The optimal maintenance immunosuppressive regimen after lung transplantation is uncertain., Methods: We conducted a randomized controlled trial of tacrolimus versus cyclosporine in combination with azathioprine and prednisone after lung transplantation. Ninety adults were randomized to tacrolimus (n = 44) or cyclosporine (n = 46). The primary end point was a composite of a cumulative acute rejection A score of 3 or higher, a cumulative lymphocytic bronchitis B score of 4 or higher, or the onset of bronchiolitis obliterans syndrome (BOS) stage 0-p., Results: Recipients randomized to cyclosporine were significantly more likely to develop the primary end point than those randomized to tacrolimus. During the study period, the primary end point developed in 39 of 46 cyclosporine subjects compared with 24 of 44 tacrolimus subjects (p = 0.002); acute rejection or lymphocytic bronchitis end points developed in 29 of 46 cyclosporine subjects compared with 18 of 44 tacrolimus subjects (p = 0.036). Furthermore, BOS stage 0-p was more likely to develop in the cyclosporine group than in the tacrolimus group, but this was not statistically significant (log-rank p = 0.1). In addition, there was a trend to a higher incidence of diabetes among those in the tacrolimus group, but there was no significant difference in graft survival or the total number of infections, or in the incidence of hypertension, chronic kidney disease, or cancer between the 2 groups., Conclusions: Tacrolimus is associated with a lower burden of acute rejection and lymphocytic bronchitis and a trend to a greater freedom from BOS stage 0-p than cyclosporine 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.

Background: The Lung Rejection Study Group (LRSG) created a scheme for grading acute allograft rejection in 1990 and then revised it in 1996, but virtually no studies have evaluated the reliability of this formulation. This investigation assessed the reliability of the current LRSG system by determining inter- and intrareader agreement for grading transbronchial biopsy samples from lung transplant recipients., Methods: Biopsy samples from a cohort of 204 recipients were reviewed and classified by a single pathologist who was blinded to original interpretations. The "A" and "B" rejection grades from this contemporary review were compared with original grades by the kappa statistic., Results: For "A" grading, weighted kappa was 0.65 (95% confidence interval [CI] 0.60-0.70) for interreader agreement (n = 529 specimens) and 0.65 (95% CI 0.53-0.76) for intrareader agreement (n = 97 specimens). For "B" grading, weighted kappa was 0.26 (95% CI 0.14-0.39) for interreader agreement (n = 164 specimens) and 0.33 (95% CI 0.15-0.51) for intrareader agreement (n = 58 specimens)., Conclusions: On the basis of the analysis of the LRSG scheme, "A" grades exhibit very good reliability, but "B" grades have only fair reliability, and steps to improve this shortcoming should be taken.

Background: Better understanding of the timing and pattern of surveillance bronchoscopy findings after lung transplantation could influence the timing and frequency of surveillance bronchoscopy. We present our surveillance bronchoscopy experience and test the hypothesis that patients not encountering early acute rejection or lymphocytic bronchitis/bronchiolitis are less likely to have subsequent occult occurrences in the 1st year after lung transplantation., Methods: We conducted a retrospective study of 204 patients who underword transplantation between 1996 and 2000. Based on contemporary biopsy-specimen grading in the first 100 days, we formed 2 groups: No Early Rejection and Early Rejection. We compared subsequent yields of surveillance bronchoscopy and the incidence of acute rejection or of lymphocytic bronchitis/bronchiolitis., Results: We reviewed 645 biopsies taken from 204 recipients during the first 100 days to classify patients into a No Early Rejection Group (n=67) or an Early Rejection Group (n=137). Yield of surveillance bronchoscopy for acute rejection or lymphocytic bronchitis/bronchiolitis was 31% with the greatest yield during the first 30 days (45%), and then decreasing to 26% (p <0.001). After Day 100, 71% of occult acute rejection episodes involved minimal (A1) lesions. Yield of surveillance bronchoscopy after Day 100 was 20% in the No Early Rejection Group and was 27% in the Early Rejection Group (p=0.22). Incidence of acute rejection or lymphocytic bronchitis/bronchiolitis after Day 100 was 41% in the No Early Rejection Group and was 50% in the Early Rejection Group (p=0.17)., Conclusion: Surveillance bronchoscopy detects occult acute rejection or lymphocytic bronchitis/bronchiolitis in approximately one-third of biopsy specimens during the 1st year, with the majority of late abnormalities being minimal (A1) rejection. The absence of acute rejection or lymphocytic bronchitis/bronchiolitis during the first 100 days does not predict freedom from such events in the remainder of the 1st year.

Background: Cytomegalovirus (CMV) infection remains a serious problem after lung transplantation. The purpose of this study was to evaluate the efficacy of CytoGam, a CMV hyperimmune globulin (CMV-IGIV), as CMV prophylaxis after lung transplantation., Methods: This prospective, randomized, open-label study compared prophylaxis with CMV-IGIV and no prophylaxis in 44 CMV-seropositive lung transplant recipients. The primary end-point was development of CMV viremia during the first year after transplantation., Results: Cytomegalovirus viremia was detected in 13 of 22 recipients without prophylaxis and in 16 of 22 recipients with CMV-IGIV prophylaxis (p = 0.19). Cytomegalovirus pneumonitis developed in 8 controls vs in 11 CMV-IGIV recipients (p = 0.54). We found no significant difference between the groups in the incidence of positive shell vial assays (6.8% +/- 6.5% without vs 11.2% +/- 10.1% with prophylaxis, p = 0.09) or in the attack rate of CMV pneumonitis (0.41 +/- 0.59 episodes/patient without vs 0.86 +/- 0.99 episodes/patient with prophylaxis, p = 0.07). Similarly, no difference was apparent in the time to onset of CMV viremia, to detection of CMV DNA in peripheral blood leukocytes by polymerase chain reaction, or to development of CMV pneumonitis. The incidence of acute rejection and bronchiolitis obliterans syndrome and the survival rate during the first post-transplant year did not differ between the groups., Conclusions: Prophylaxis with CMV-IGIV alone did not decrease CMV viremia or pneumonitis, did not decrease the incidence of acute rejection or bronchiolitis obliterans syndrome, and did not affect 1-year survival of CMV-seropositive lung transplant recipients at our center.

Background: Emphysema is the most common indication for lung transplantation. Recipients include younger patients with genetically determined alpha-1 antitrypsin deficiency (AAD) and, more commonly, patients with chronic obstructive pulmonary disease (COPD). We analyzed the results of our single-institution series of lung transplants for emphysema to identify outcome differences and factors predicting mortality and morbidity in these two groups., Methods: A retrospective analysis was undertaken of the 306 consecutive lung transplants for emphysema performed at our institution between 1988 and 2000 (220 COPD, 86 AAD). Follow-up was complete and averaged 3.7 years., Results: The mean age of AAD recipients (49 +/- 6 years) was less than those with COPD (55 +/- 6 years; p < 0.001). Hospital mortality was 6.2%, with no difference between COPD and AAD, or between single-lung transplants and bilateral-lung transplants. Hospital mortality during the most recent 6 years was significantly lower (3.9% vs 9.5%, p = 0.044). Five-year survival was 58.6% +/- 3.5%, with no difference between COPD (56.8% +/- 4.4%) and AAD (60.5% +/- 5.8%). Five-year survival was better with bilateral-lung transplants (66.7% +/- 4.0%) than with single-lung transplants (44.9% +/- 6.0%, p < 0.005). Independent predictors of mortality by Cox analysis were single lung transplantation (relative hazard = 1.98, p < 0.001), and need for cardiopulmonary bypass during the transplant (relative hazard = 1.84, p = 0.038)., Conclusions: AAD recipients, despite a younger age, do not achieve significantly superior survival results than those with COPD. Bilateral lung transplantation for emphysema results in better long-term survival. Accumulated experience and modifications in perioperative care over our 13-year series may explain recently improved early and long-term survival.

Background: Pulmonary hypertension (PHT) is a lethal condition resulting in markedly diminished life expectancy. Continuous prostaglandin I2 infusion has made an important contribution to symptom management, but it is not a panacea. Lung or heart-lung transplantation remains an important treatment option for end-stage PHT patients unresponsive to prostaglandin I2. This study reviews the outcomes after transplantation for PHT in our program., Methods: A retrospective chart review was performed for 100 consecutive patients with either primary PHT (48%) or secondary PHT (52%) transplants since 1989. Living recipients were contacted to confirm health and functional status., Results: Fifty-five adult and 45 pediatric patients underwent 51 bilateral lung transplants, 39 single lung transplants, and 10 heart-lung transplants. Mean age was 23.7 years (range, 1.2 months to 54.8 years) and mean pre-transplant New York Heart Association class was 3.2. Pre-transplant hemodynamics revealed a mean right atrial pressure of 9.6+/-5.4 mm Hg and mean pulmonary artery pressure of 64+/-14.4 mm Hg. Hospital mortality was 17% with early death predominantly because of graft failure and infection. With an average follow-up of 5.0 years, 1- and 5-year actuarial survival was 75% and 57%, respectively. Mean pulmonary artery pressure on follow-up catheterization was 22+/-6.0 mm Hg, and mean follow-up New York Heart Association class was 1.3 (p < 0.001 for both compared with pre-transplant). Diagnosis and type of transplant did not confer a significant difference in survival between groups., Conclusions: Whereas lung or heart-lung transplant for PHT is associated with higher early mortality than other pulmonary disease entities, it provides similar long-term outcomes with dramatic improvement in both quality of life and physiologic aspects.