Sphingosine-1-phosphate receptor 1 agonism attenuates lung ischemia-reperfusion injury.

Outcomes for lung transplantation are the worst of any solid organ, and ischemia-reperfusion injury (IRI) limits both short- and long-term outcomes. Presently no therapeutic agents are available to prevent IRI. Sphingosine 1-phosphate (S1P) modulates immune function through binding to a set of G protein-coupled receptors (S1PR1-5). Although S1P has been shown to attenuate lung IRI, the S1P receptors responsible for protection have not been defined. The present study tests the hypothesis that protection from lung IRI is primarily mediated through S1PR1 activation. Mice were treated with either vehicle, FTY720 (a nonselective S1P receptor agonist), or VPC01091 (a selective S1PR1 agonist and S1PR3 antagonist) before left lung IR. Function, vascular permeability, cytokine expression, neutrophil infiltration, and myeloperoxidase levels were measured in lungs. After IR, both FTY720 and VPC01091 significantly improved lung function (reduced pulmonary artery pressure and increased pulmonary compliance) vs. vehicle control. In addition, FTY720 and VPC01091 significantly reduced vascular permeability, expression of proinflammatory cytokines (IL-6, IL-17, IL-12/IL-23 p40, CC chemokine ligand-2, and TNF-α), myeloperoxidase levels, and neutrophil infiltration compared with control. No significant differences were observed between VPC01091 and FTY720 treatment groups. VPC01091 did not significantly affect elevated invariant natural killer T cell infiltration after IR, and administration of an S1PR1 antagonist reversed VPC01091-mediated protection after IR. In conclusion, VPC01091 and FTY720 provide comparable protection from lung injury and dysfunction after IR. These findings suggest that S1P-mediated protection from IRI is mediated by S1PR1 activation, independent of S1PR3, and that selective S1PR1 agonists may provide a novel therapeutic strategy to prevent lung IRI.

Ex Vivo Assessment of Porcine Donation After Circulatory Death Lungs That Undergo Increasing Warm Ischemia Times.

BACKGROUND: Increased utilization of donation after circulatory death (DCD) lungs may help alleviate the supply/demand mismatch between available donor organs and lung transplant candidates. Using an established porcine DCD model, we sought to determine the effect of increasing warm ischemia time (WIT) after circulatory arrest on lung function during ex vivo lung perfusion (EVLP). METHODS: Porcine donors (n = 15) underwent hypoxic cardiac arrest, followed by 60, 90, or 120 minutes of WIT before procurement and 4 hours of normothermic EVLP. Oxygenation, pulmonary artery pressure, airway pressure, and compliance were measured hourly. Lung injury scores were assessed histologically after 4 hours of EVLP. RESULTS: After EVLP, all 3 groups met all the criteria for transplantation, except for 90-minute WIT lungs, which had a mean pulmonary artery pressure increase greater than 15%. There were no significant differences between groups as assessed by final oxygenation capacity, as well as changes in pulmonary artery pressure, airway pressure, or lung compliance. Histologic lung injury scores as well as lung wet-to-dry weight ratios did not significantly differ between groups. CONCLUSIONS: These results suggest that longer WIT alone (up to 120 minutes) does not predict worse lung function at the conclusion of EVLP. Expanding acceptable WIT after circulatory death may eventually allow for increased utilization of DCD lungs in procurement protocols.

Attenuation of Pulmonary Ischemia-Reperfusion Injury by Adenosine A2B Receptor Antagonism.

BACKGROUND: Ischemia-reperfusion injury (IRI) is a major source of morbidity and mortality after lung transplantation. We previously demonstrated a proinflammatory role of adenosine A2B receptor (A2BR) in lung IR injury. The current study tests the hypothesis that A2BR antagonism is protective of ischemic lungs after in vivo reperfusion or ex vivo lung perfusion (EVLP). METHODS: Mice underwent lung IR with or without administration of ATL802, a selective A2BR antagonist. A murine model of EVLP was also used to evaluate rehabilitation of donation after circulatory death (DCD) lungs. DCD lungs underwent ischemia, cold preservation, and EVLP with Steen solution with or without ATL802. A549 human type 2 alveolar epithelial cells were exposed to hypoxia-reoxygenation (HR) (3 hours/1 hour) with or without ATL802 treatment. Cytokines were measured in bronchoalveolar lavage (BAL) fluid and culture media by enzyme-linked immunoassay (ELISA). RESULTS: After IR, ATL802 treatment significantly improved lung function (increased pulmonary compliance and reduced airway resistance and pulmonary artery pressure) and significantly attenuated proinflammatory cytokine production, neutrophil infiltration, vascular permeability, and edema. ATL802 also significantly improved the function of DCD lungs after EVLP (increased compliance and reduced pulmonary artery pressure). After HR, A549 cells exhibited robust production of interleukin (IL)-8, a potent neutrophil chemokine, which was significantly attenuated by ATL802. CONCLUSIONS: These results demonstrate that A2BR antagonism attenuates lung IRI and augments reconditioning of DCD lungs by EVLP. The protective effects of ATL802 may involve targeting A2BRs on alveolar epithelial cells to prevent IL-8 production. A2BR may be a novel therapeutic target for mitigating IRI to increase the success of lung transplantation.

Enteral Access is not Required for Esophageal Cancer Patients Undergoing Neoadjuvant Therapy.

BACKGROUND: The nutritional status of esophageal cancer patients during neoadjuvant therapy remains a challenging problem. The objective of this study was to determine whether routine enteral feeding tube placement improved nutritional status and perioperative outcomes for patients undergoing neoadjuvant therapy for esophageal cancer. METHODS: The Society of Thoracic Surgeons database was used to identify patients who underwent neoadjuvant therapy and esophagectomy at our institution between 2010 and 2014. Nutritional status before and after neoadjuvant therapy was determined through standardized nutrition consultations. Predictors of change in nutrition and adverse events were evaluated with multivariable and univariate logistic regressions. RESULTS: Two hundred thirty-four esophagectomy patients were identified, and 127 (54%) received neoadjuvant therapy. Of those receiving neoadjuvant therapy, 80% (102/127) presented with dysphagia, and 48% (61/127) received enteral feeding access (EA). Multivariable regression revealed that high initial albumin level, high initial body mass index, and presence of EA were associated with nutritional stability during neoadjuvant therapy. However, 27.9% (17/61) of patients who received EA did not use their access at all or did not use it consistently during the course of preoperative treatment. The preoperative grades of malnutrition and esophagectomy outcomes were similar between groups (EA vs no EA). CONCLUSIONS: EA is associated with improved nutritional status for patients undergoing neoadjuvant therapy for esophageal cancer. However, adverse events and suboptimal use are common. Esophagectomy outcomes were similar for patients with and without EA. These results support judicious patient selection for EA, expedited neoadjuvant therapy, and close collaboration with nutritionists.

Ex vivo lung perfusion with adenosine A2A receptor agonist allows prolonged cold preservation of lungs donated after cardiac death.

OBJECTIVE: Ex vivo lung perfusion has been successful in the assessment of marginal donor lungs, including donation after cardiac death (DCD) donor lungs. Ex vivo lung perfusion also represents a unique platform for targeted drug delivery. We sought to determine whether ischemia-reperfusion injury would be decreased after transplantation of DCD donor lungs subjected to prolonged cold preservation and treated with an adenosine A2A receptor agonist during ex vivo lung perfusion. METHODS: Porcine DCD donor lungs were preserved at 4°C for 12 hours and underwent ex vivo lung perfusion for 4 hours. Left lungs were then transplanted and reperfused for 4 hours. Three groups (n = 4/group) were randomized according to treatment with the adenosine A2A receptor agonist ATL-1223 or the dimethyl sulfoxide vehicle: Infusion of dimethyl sulfoxide during ex vivo lung perfusion and reperfusion (DMSO), infusion of ATL-1223 during ex vivo lung perfusion and dimethyl sulfoxide during reperfusion (ATL-E), and infusion of ATL-1223 during ex vivo lung perfusion and reperfusion (ATL-E/R). Final Pao2/Fio2 ratios (arterial oxygen partial pressure/fraction of inspired oxygen) were determined from samples obtained from the left superior and inferior pulmonary veins. RESULTS: Final Pao2/Fio2 ratios in the ATL-E/R group (430.1 ± 26.4 mm Hg) were similar to final Pao2/Fio2 ratios in the ATL-E group (413.6 ± 18.8 mm Hg), but both treated groups had significantly higher final Pao2/Fio2 ratios compared with the dimethyl sulfoxide group (84.8 ± 17.7 mm Hg). Low oxygenation gradients during ex vivo lung perfusion did not preclude superior oxygenation capacity during reperfusion. CONCLUSIONS: After prolonged cold preservation, treatment of DCD donor lungs with an adenosine A2A receptor agonist during ex vivo lung perfusion enabled Pao2/Fio2 ratios greater than 400 mm Hg after transplantation in a preclinical porcine model. Pulmonary function during ex vivo lung perfusion was not predictive of outcomes after transplantation.

Donation After Circulatory Death Lungs Transplantable Up to Six Hours After Ex Vivo Lung Perfusion.

BACKGROUND: Despite the critical need for donor lungs, logistic and geographic barriers hinder lung utilization. We hypothesized that lungs donated after circulatory death subjected to 6 hours of cold preservation after ex vivo lung perfusion (EVLP) would have similar outcomes after transplantation as lungs transplanted immediately after EVLP, and that both would perform superiorly compared with lungs transplanted immediately after procurement. METHODS: Donor porcine lungs were procured after circulatory death and 15 minutes of warm ischemia. Three groups (n = 5 per group) were randomized: immediate left lung transplantation (Immediate group), EVLP for 4 hours followed by transplantation (EVLP group), or EVLP for 4 hours followed by 6 hours of cold preservation followed by transplantation (EVLP+Cold group). Lungs were reperfused for 2 hours before obtaining pulmonary vein samples for partial pressure of oxygen/fraction of inspired oxygen ratio calculations, airway pressures for compliance measurements, and wet/dry weight ratios. RESULTS: The partial pressure of oxygen/fraction of inspired oxygen ratios in the EVLP and EVLP+Cold groups were significantly improved compared with those in the Immediate group (429.7 ± 51.8 and 436.7 ± 48.2 versus 117.4 ± 22.9 mm Hg, respectively). In addition, dynamic compliance was significantly improved in the EVLP and EVLP+Cold groups compared with immediate group (26.2 ± 4.2 and 27.9 ± 3.5 versus 11.1 ± 2.4 mL/cmH2O, respectively). There were no differences in oxygenation capacity or dynamic compliance between the EVLP and EVLP+Cold groups. Inflammatory cytokine levels were significantly lower in the EVLP and EVLP+Cold groups. CONCLUSIONS: Lungs donated after circulatory death can be successfully transplanted as much as 6 hours after EVLP. Cold preservation of lungs after ex vivo assessment and rehabilitation may improve organ allocation, even to distant recipients, without compromising allograft function.

Ex Vivo Perfusion With Adenosine A2A Receptor Agonist Enhances Rehabilitation of Murine Donor Lungs After Circulatory Death.

BACKGROUND: Ex vivo lung perfusion (EVLP) enables assessment and rehabilitation of marginal donor lungs before transplantation. We previously demonstrated that adenosine A2A receptor (A2AR) agonism attenuates lung ischemia-reperfusion injury. The current study utilizes a novel murine EVLP model to test the hypothesis that A2AR agonist enhances EVLP-mediated rehabilitation of donation after circulatory death (DCD) lungs. METHODS: Mice underwent euthanasia and 60 minutes warm ischemia, and lungs were flushed with Perfadex and underwent cold static preservation (CSP, 60 minutes). Three groups were studied: no EVLP (CSP), EVLP with Steen solution for 60 minutes (EVLP), and EVLP with Steen solution supplemented with ATL1223, a selective A2AR agonist (EVLP + ATL1223). Lung function, wet/dry weight, cytokines and neutrophil numbers were measured. Microarrays were performed using the Affymetrix GeneChip Mouse Genome 430A 2.0 Array. RESULTS: Ex vivo lung perfusion significantly improved lung function versus CSP, which was further, significantly improved by EVLP + ATL1223. Lung edema, cytokines, and neutrophil counts were reduced after EVLP and further, significantly reduced after EVLP + ATL1223. Gene array analysis revealed differential expression of 1594 genes after EVLP, which comprise canonical pathways involved in inflammation and innate immunity including IL-1, IL-8, IL-6, and IL-17 signaling. Several pathways were uniquely regulated by EVLP + ATL1223 including the downregulation of genes involved in IL-1 signaling, such as ADCY9, ECSIT, IRAK1, MAPK12, and TOLLIP. CONCLUSIONS: Ex vivo lung perfusion modulates proinflammatory genes and reduces pulmonary dysfunction, edema, and inflammation in DCD lungs, which are further reduced by A2AR agonism. This murine EVLP model provides a novel platform to study rehabilitative mechanisms of DCD lungs.

Recurrent angiomatoid fibrous histiocytoma: a case report and review of the literature.

BACKGROUND: Angiomatoid fibrous histiocytoma (AFH) is a rare soft-tissue tumor with intermediate malignant potential. It most commonly occurs in children and young adults. CASE REPORT: We report a case of a recurrent AFH of the back, locally recurring within 14 months of the original operation. We also review the literature for this uncommon entity. The patient underwent a wide resection of the recurrent AFH, obtaining negative surgical margins. Postoperatively, he has done well. CONCLUSION: Twelve months since his re-excision, the patient shows no evidence of recurrence to date. He is seen every 6 months for continued clinical examinations.

Primary amyloidosis of the breast presenting as a solitary nodule: case report and review of the literature.

BACKGROUND: Amyloidosis of the breast is an unusual diagnosis. Overall, only 2 major case series have been published in the literature since the time amyloidosis was first reported in 1973, highlighting the rare nature of this disease. Clinically, the patient may present with a breast mass or simply increased breast density and skin thickening. As such, amyloidosis may mimic the appearance of a number of pathologies, both benign and malignant. CASE REPORT: We report a single case of a patient who presented with a breast mass and was ultimately diagnosed with primary amyloidosis of the breast. We also present a review of the literature to date. CONCLUSION: The main treatment for primary amyloidosis of the breast is surgical removal, most often accomplished with breast conservation via lumpectomy. In performing the lumpectomy, the goal should be to obtain negative surgical margins; however, no strong data exist to suggest that such lesions would recur with a microscopically positive margin.