Peripheral Blood Gene Expression Changes Associated With Primary Graft Dysfunction After Lung Transplantation.

Recipient responses to primary graft dysfunction (PGD) after lung transplantation may have important implications to the fate of the allograft. We therefore evaluated longitudinal differences in peripheral blood gene expression in subjects with PGD. RNA expression was measured throughout the first transplant year in 106 subjects enrolled in the Clinical Trials in Organ Transplantation-03 study using a panel of 100 hypothesis-driven genes. PGD was defined as grade 3 in the first 72 posttransplant hours. Eighteen genes were differentially expressed over the first year based on PGD development, with significant representation from innate and adaptive immunity genes, with most differences identified very early after transplant. Sixteen genes were overexpressed in the blood of patients with PGD compared to those without PGD within 7 days of allograft reperfusion, with most transcripts encoding innate immune/inflammasome-related proteins, including genes previously associated with PGD. Thirteen genes were underexpressed in patients with PGD compared to those without PGD within 7 days of transplant, highlighted by T cell and adaptive immune regulation genes. Differences in gene expression present within 2 h of reperfusion and persist for days after transplant. Future investigation will focus on the long-term implications of these gene expression differences on the outcome of the allograft.

Variation by stage in the effects of prediagnosis weight loss on mortality in a prospective cohort of esophageal cancer patients.

Cancer cachexia is increasingly recognized as a poor prognostic marker for various tumor types. Weight loss in esophageal cancer is multifactorial, as patients with bulky tumors also have reduced ability to eat. We aimed to investigate the relationship between prediagnosis weight loss and mortality in esophageal cancer and to determine whether these associations vary with tumor stage. We conducted a prospective cohort study of esophageal cancer patients at two tertiary centers. We recorded baseline patient characteristics including medications, smoking, body mass index, and weight loss in the year prior to diagnosis, and collected data on treatment and outcomes. We used Cox regression modeling to determine the associations between percent weight loss and outcomes. The main outcome of interest was all-cause mortality; secondary endpoints were esophageal cancer-specific mortality and development of metastases. We enrolled 134 subjects, the majority of whom had adenocarcinoma (82.1%); median percent weight loss was 4.7% (IQR: 0%-10.9%). Increasing percent weight loss was not associated with all-cause mortality (ptrend = 0.36). However, there was evidence of significant interaction by tumor stage (p = 0.02). There was a strong and significant association between prediagnosis weight loss and mortality in patients with T stages 1 or 2 (adjusted HR 8.26 for highest versus lowest tertile, 95%CI 1.11-61.5, ptrend = 0.03) but not for T stages 3 or 4 (ptrend = 0.32). Body mass index one year prior to diagnosis was not associated with mortality. Prediagnosis weight loss was associated with increased all-cause mortality only in patients with early stage esophageal cancer. This suggests that tumor-related cachexia can occur early in esophageal cancer and represents a poor prognostic marker.

Donor age and early graft failure after lung transplantation: a cohort study.

Lungs from older adult organ donors are often unused because of concerns for increased mortality. We examined associations between donor age and transplant outcomes among 8860 adult lung transplant recipients using Organ Procurement and Transplantation Network and Lung Transplant Outcomes Group data. We used stratified Cox proportional hazard models and generalized linear mixed models to examine associations between donor age and both 1-year graft failure and primary graft dysfunction (PGD). The rate of 1-year graft failure was similar among recipients of lungs from donors age 18-64 years, but severely ill recipients (Lung Allocation Score [LAS] >47.7 or use of mechanical ventilation) of lungs from donors age 56-64 years had increased rates of 1-year graft failure (p-values for interaction = 0.04 and 0.02, respectively). Recipients of lungs from donors <18 and ≥65 years had increased rates of 1-year graft failure (adjusted hazard ratio [HR] 1.23, 95% CI 1.01-1.50 and adjusted HR 2.15, 95% CI 1.47-3.15, respectively). Donor age was not associated with the risk of PGD. In summary, the use of lungs from donors age 56 to 64 years may be safe for adult candidates without a high LAS and the use of lungs from pediatric donors is associated with a small increase in early graft failure.

Donor surfactant protein D (SP-D) polymorphisms are associated with lung transplant outcome.

Chronic lung allograft dysfunction (CLAD) is the major factor limiting long-term success of lung transplantation. Polymorphisms of surfactant protein D (SP-D), an important molecule within lung innate immunity, have been associated with various lung diseases. We investigated the association between donor lung SP-D polymorphisms and posttransplant CLAD and survival in 191 lung transplant recipients consecutively transplanted. Recipients were prospectively followed with routine pulmonary function tests. Donor DNA was assayed by pyrosequencing for SP-D polymorphisms of two single-nucleotide variations altering amino acids in the mature protein N-terminal domain codon 11 (Met(11) Thr), and in codon 160 (Ala(160) Thr) of the C-terminal domain. CLAD was diagnosed in 88/191 patients, and 60/191 patients have died. Recipients of allografts that expressed the homozygous Met(11) Met variant of aa11 had significantly greater freedom from CLAD development and better survival compared to those with the homozygous Thr(11) Th variant of aa11. No significant association was noted for SP-D variants of aa160. Lung allografts with the SP-D polymorphic variant Thr(11) Th of aa11 are associated with development of CLAD and reduced survival. The observed genetic differences of the donor lung, potentially with their effects on innate immunity, may influence the clinical outcomes after lung transplantation.

Hypoalbuminemia and early mortality after lung transplantation: a cohort study.

Hypoalbuminemia predicts disability and mortality in patients with various illnesses and in the elderly. The association between serum albumin concentration at the time of listing for lung transplantation and the rate of death after lung transplantation is unknown. We examined 6808 adults who underwent lung transplantation in the United States between 2000 and 2008. We used Cox proportional hazard models and generalized additive models to examine multivariable-adjusted associations between serum albumin and the rate of death after transplantation. The median follow-up time was 2.7 years. Those with severe (0.5-2.9 g/dL) and mild hypoalbuminemia (3.0-3.6 g/dL) had posttransplant adjusted mortality rate ratios of 1.35 (95% CI: 1.12-1.62) and 1.15 (95% CI: 1.04-1.27), respectively. For each 0.5 g/dL decrease in serum albumin concentration the 1-year and overall mortality rate ratios were 1.48 (95% CI: 1.21-1.81) and 1.26 (95% CI: 1.11-1.43), respectively. The association between hypoalbuminemia and posttransplant mortality was strongest in recipients with cystic fibrosis and interstitial lung disease. Hypoalbuminemia is an independent risk factor for death after lung transplantation.

Delta 9-tetrahydrocannabinol: a novel treatment for experimental autoimmune encephalomyelitis.

Since multiple sclerosis (MS) is believed to be an immune-mediated disease, it follows that its therapies should be directed towards modulating the immune system. Current MS treatments, which include the use of exogenous steroids that are immunosuppressive, do not meet therapeutic objectives. delta 9-Tetrahydrocannabinol (THC), an active component of marijuana, has been shown to be immunosuppressive. To test THC's ability to suppress an immune-mediated disease, experimental autoimmune encephalomyelitis (EAE), the laboratory model of MS, was used. Lewis rats and strain 13 guinea pigs were administered THC either before inoculation for EAE or treated with THC after injection. Control animals received placebo. The effect of dose, in addition to the timing of treatment, was also investigated. All animals treated with placebo developed severe clinical EAE 10-12 days post-injection (d.p.i.) and more than 98% died by 15 d.p.i. THC-treated animals had either no clinical signs or mild signs with delayed onset (13-15 d.p.i.) with survival greater than 95%. Examination of central nervous system tissue revealed a marked reduction of inflammation in the THC-treated animals. Therefore, as THC has been shown to inhibit both clinical and histologic EAE, it may prove to be a new and relatively innocuous agent for the treatment of immune-mediated diseases.

Extracorporeal membrane oxygenation as an adjunct treatment for primary graft failure in adult lung transplant recipients.

Primary graft failure is a catastrophic event in lung transplantation. Failure is characterized by profound abnormalities of gas exchange that are frequently unresponsive to alterations in mechanical ventilation. This condition can be fatal and, if less severe, is usually associated with significant permanent damage to the allograft. We report the use of extracorporeal membrane oxygenation as a means to support lung transplant recipients with severe graft failure. Since 1991, extracorporeal membrane oxygenation has been used on 17 occasions for the temporary support of 16 adult lung transplant recipients. All patients met or exceeded standard National Institutes of Health guidelines for institution of extracorporeal membrane oxygenation. Nine double lung, six single lung, and one heart-lung recipients were supported for 1 to 12 days (mean 4.6 +/- 2.2 days). Extracorporeal membrane oxygenation was instituted early, within 7 days of transplantation, in ten patients. Eight early patients (80%) were successfully weaned from extracorporeal membrane oxygenation. Seven of ten (70%) patients were long-term survivors, and five of the seven had normal lung function. In comparison, there were no survivors among six recipients placed on extracorporeal membrane oxygenation for late (> or = 7 days) graft dysfunction. Extracorporeal membrane oxygenation is a lifesaving adjunct in recipients with acute graft failure after lung transplantation. Ischemia-reperfusion injury and acute graft dysfunction after lung transplantation can be successfully reversed with early aggressive intervention.

High dose rate brachytherapy to prevent recurrent benign hyperplasia in lung transplant bronchi: theoretical and clinical considerations.

BACKGROUND: Significant anastomotic stenosis and malacia is reported to affect 7% to 15% of lung transplant recipients. Laser debridement, dilation and stenting can be used effectively to treat the majority of these patients. However, persistent, as well as reactive hyperplastic tissue reaction, will occur in some of these patients, requiring multiple bronchoscopic interventions. The experience of 2 patients who received intraluminal brachytherapy irradiation to prevent recurrence of hyperplastic tissue causing airway obstruction is reported. Both had failed multiple attempts of local control, including wall stent, laser ablation and balloon dilation. They suffered from shortness of breath and progressive decrease in quality of life because of airway obstruction. METHODS: Two patients received intraluminal irradiation immediately following removal of severe post-lung transplant obstruction. Both patients developed airway obstruction 3 to 4 months after left lung transplantation. High Dose Rate (HDR) brachytherapy (192Ir). Afterloader was used to treat Patient 1 on two occasions. Patient 2 required a single treatment. The radiation dose of 3Gy/fraction was calculated at 1 cm from the catheter for all applications. RESULTS: Follow up for both patients included bronchoscopy at 3 weeks, 3 months and 6 months after radiation therapy. Follow up for Patient 1 is 7 months, and patient 2 is 6 months. Each patient had an initial complete response after radiation. There were no treatment-related complications, and both patients experienced significant improvement in respiratory function. CONCLUSIONS: Symptomatic benign airway obstruction from hyperplastic tissue in the bronchus after lung transplantation can be successfully treated with intraluminal radiation therapy. Patients who develop recurrent benign granulation tissue after stent and laser therapy may be considered for this type of treatment.

Removal and repositioning of "permanent" expandable wire stents in bronchial airway stenosis after lung transplantation.

Significant airway stenosis occurs in 7% to 14% of lung transplant recipients. The use of permanent, nonadjustable, wire mesh stents can be of concern in the transplant recipient with nonmalignant stricture. We report the replacement and repositioning of an expandable wire mesh stent in a double lung transplantation with distal bronchial stenosis.

Endobronchial management of benign, malignant, and lung transplantation airway stenoses.

Since 1991, we have managed 57 patients with benign (10), malignant (23), or lung transplantation (24) airway obstructions using silicone stenting and debridement (manual/neodymium:yttrium-aluminum garnet laser). Ten patients with benign lesions (4 intubation, 4 inflammatory, 1 malacia, 1 bronchial fistula) had 4 T tubes, 3 Y stents, 3 bronchial stents, and 1 straight tracheal stent placed. Eight of 10 patients (80%) received symptomatic relief with the stents in place for up to 43 months. Twenty-three patients with malignant strictures (18 lung, 5 metastatic) had 26 stents inserted (13 Y stents, 12 bronchial, 1 T tube) of which 16 required combined debridement and stenting. Four stents required repositioning. three hospital deaths were due to unrelated causes. Of 20 discharged patients, 6 remain alive at 2 to 10 months, whereas 14 patients who died of progressive disease obtained effective palliation for 10.5 +/- 5.6 months. Significant bronchial anastomotic complications developed in 24 of 212 lung transplants (11.3%). Thirty-one stents were placed in 19 of the patients; 5 patients were managed with laser debridement alone. Of the 19 patients receiving stents, 3 required only temporary stents (6 to 15 days), 11 patients needed long-term stents (40 to 507 days), and 5 patients died with their stents in place functioning well. All patients received symptomatic relief with stenting. There were no procedure-related deaths and one bronchial laceration during attempted stent placement. Early, aggressive treatment of benign and malignant tracheobronchial strictures with endoscopic debridement and stenting is safe and well tolerated, and effectively palliates airway obstruction. Repositioning of stents frequently may be required in the transplant population.(ABSTRACT TRUNCATED AT 250 WORDS)

Safe pulmonary resection after chemotherapy and high-dose thoracic radiation.

BACKGROUND: Pulmonary resection after high-dose thoracic irradiation is reported to be associated with a high morbidity and mortality, and has been considered to be prohibitive. METHODS: We report safe pulmonary resection in 19 consecutive patients receiving neoadjuvant therapy that included greater than 59 Gy thoracic radiation. The mean thoracic radiation dose was 61.8 Gy (range 59.5-66.5) and mean age was 52 years (range 36-72 years). Cell type was adenocarcinoma (6), squamous (7), and other non-small cell lung cancer (NSCLC) (6). Sixteen of 19 patients received concurrent chemotherapy. Median time from end of treatment to surgical resection was 89 days (range 22-258 days). Surgical resection included 13 lobectomies and six pneumonectomies (four right, two left). RESULTS: A complete pathologic response was seen in 8 of 19 (42%) patients. Three patients required intraoperative transfusion of blood. Mean intensive care unit stay was 2.0 days (range 1-8 days), and mean length of stay (LOS) was 8.0 days (range 3-18 days). There were four postoperative complications; one bronchopulmonary fistula, one subarachnoid-pleural fistula, and 2 patients with prolonged atelectasis. There was no incidence of acute respiratory distress syndrome (ARDS) or operative mortality. CONCLUSIONS: Pulmonary resection, including pneumonectomy, after chemotherapy and high-dose thoracic radiation may be performed safely with a low rate of intraoperative and postoperative complications.

Superior sulcus (Pancoast) tumor: experience with 105 patients.

BACKGROUND: The evolution of therapy in 105 patients with superior sulcus (Pancoast) tumor over the past 42 years was reviewed. METHODS: There were 82 men and 23 women aged 30 to 75 years. Tumor cell types were: squamous, 41 (39%); adenocarcinoma, 23 (21.9%); anaplastic, 14 (13.3%); undetermined, 12 (11.4%); mixed, 9 (8.7%); and large cell 6 (5.7%). Therapy was based on extent of disease and lymph node involvement. There were 5 treatment groups: I, preoperative radiation and operation (n = 28); II, operation and postoperative radiation (n = 16); III, radiation (n = 37); IV, preoperative chemotherapy, radiation, and operation (n = 11); and V, operation (n = 12). RESULTS: The median survival for group I was 21.6 months; group II, 6.9 months; group III, 6 months; and group V, 36.7 months. Median survival for group IV has not yet been reached (estimated at 72% at 5 years). On univariate analysis, mediastinal lymph node involvement, Horner syndrome, TNM classification, and method of therapy affected survival. On multivariate regression analysis, only N2 and N3 disease and method of therapy were significant (p < 0.05). CONCLUSIONS: The optimal treatment for superior sulcus tumor was preoperative radiation and operation. However, triple modality therapy, although promising, requires longer follow-up.

P53 gene protein overexpression predicts results of trimodality therapy in esophageal cancer patients.

BACKGROUND: P53 protein overexpression in esophageal cancer and its correlation with response and survival after chemoradiation was retrospectively investigated. METHODS: Pretreatment and resection specimens were stained by automatic p53 immunohistochemical staining technique. RESULTS: P53 was expressed in 84.0% of esophagoscopy (EGD) biopsies; 71.4% of patients with metastasis of thoracoscopy/laparoscopy lymph nodes (TS/LS LN) identified by hematoxylin/eosin (H/E) were p53 (+); 14.2% of patients with negative TS/LS LN by H/E were p53 (+). Eleven out of 18 patients with p53 (+) in pretreatment EGD remained p53 (+) after chemoradiation; 38.8% of these patients had a pathological complete response (pCR). The median survival of this group was 15 months. Of 4 patients with p53 (-) pretreatment EGD, all of those were still p53 (-) after chemoradiation; 75% of these patients had pCR. The median survival was 30 months. In patients with p53 (+) TS/LS LN, 23% had a pCR after chemoradiation with a median survival of 16 months. In patients with p53 (-) TS/LS LN, 50.0% had a pCR with a median survival of 31.5 months. CONCLUSIONS: P53 protein overexpression in pretreatment EGD and TS/LS LN may predict response to chemoradiation and survival in esophageal cancer patients.

Hernia of the lung: case report and literature review.

Hernia of the lung is an uncommonly encountered clinical entity. The majority of reported hernias are acquired traumatic thoracic hernias. A case report of an acquired spontaneous lung hernia is presented. A literature review of the classification, diagnosis, treatment and current incidence is discussed.

Activation of endogenous GABAA channels on airway smooth muscle potentiates isoproterenol-mediated relaxation.

Reactive airway disease predisposes patients to episodes of acute smooth muscle mediated bronchoconstriction. We have for the first time recently demonstrated the expression and function of endogenous ionotropic GABA(A) channels on airway smooth muscle cells. We questioned whether endogenous GABA(A) channels on airway smooth muscle could augment beta-agonist-mediated relaxation. Guinea pig tracheal rings or human bronchial airway smooth muscles were equilibrated in organ baths with continuous digital tension recordings. After pretreatment with or without the selective GABA(A) antagonist gabazine (100 muM), airway muscle was contracted with acetylcholine or beta-ala neurokinin A, followed by relaxation induced by cumulatively increasing concentrations of isoproterenol (1 nM to 1 muM) in the absence or presence of the selective GABA(A) agonist muscimol (10-100 muM). In separate experiments, guinea pig tracheal rings were pretreated with the large conductance K(Ca) channel blocker iberiotoxin (100 nM) after an EC(50) contraction with acetylcholine but before cumulatively increasing concentrations of isoproterenol (1 nM to 1 uM) in the absence or presence of muscimol (100 uM). GABA(A) activation potentiated the relaxant effects of isoproterenol after an acetylcholine or tachykinin-induced contraction in guinea pig tracheal rings or an acetylcholine-induced contraction in human endobronchial smooth muscle. This muscimol-induced potentiation of relaxation was abolished by gabazine pretreatment but persisted after blockade of the maxi K(Ca) channel. Selective activation of endogenous GABA(A) receptors significantly augments beta-agonist-mediated relaxation of guinea pig and human airway smooth muscle, which may have important therapeutic implications for patients in severe bronchospasm.

Lung adenocarcinoma invasion in TGFbetaRII-deficient cells is mediated by CCL5/RANTES.

Recently, we identified a lung adenocarcinoma signature that segregated tumors into three clades distinguished by histological invasiveness. Among the genes differentially expressed was the type II transforming growth factor-beta receptor (TGFbetaRII), which was lower in adenocarcinoma mixed subtype and solid invasive subtype tumors compared with bronchioloalveolar carcinoma. We used a tumor cell invasion system to identify the chemokine CCL5 (RANTES, regulated on activation, normal T-cell expressed and presumably secreted) as a potential downstream mediator of TGF-beta signaling important for lung adenocarcinoma invasion. We specifically hypothesized that RANTES is required for lung cancer invasion and progression in TGFbetaRII-repressed cells. We examined invasion in TGFbetaRII-deficient cells treated with two inhibitors of RANTES activity, Met-RANTES and a CCR5 receptor-blocking antibody. Both treatments blocked invasion induced by TGFbetaRII knockdown. In addition, we examined the clinical relevance of the RANTES-CCR5 pathway by establishing an association of RANTES and CCR5 immunostaining with invasion and outcome in human lung adenocarcinoma specimens. Moderate or high expression of both RANTES and CCR5 was associated with an increased risk for death, P=0.014 and 0.002, respectively. In conclusion, our studies indicate RANTES signaling is required for invasion in TGFbetaRII-deficient cells and suggest a role for CCR5 inhibition in lung adenocarcinoma prevention and treatment.

Racial and ethnic disparities in idiopathic pulmonary fibrosis: A UNOS/OPTN database analysis.

We previously reported poorer survival among non-Hispanic blacks and Hispanics with idiopathic pulmonary fibrosis (IPF) compared to non-Hispanic whites at our center. In the current study, we hypothesized that these disparities would exist in a nationwide cohort of wait-listed patients with IPF. We performed a retrospective cohort study of 2635 patients with IPF listed for lung transplantation between 1995 and 2003 at 94 transplant centers in the United States. The age-adjusted mortality rate was higher among non-Hispanic blacks [hazard ratio (HR) = 1.24, 95% confidence interval (CI) 1.06-1.45, p = 0.009] and Hispanics (HR = 1.29, 95% CI 1.06-1.56, p = 0.01) compared to non-Hispanic whites. These findings persisted after adjustment for transplantation, medical comorbidities and socioeconomic status. Worse lung function at the time of listing appeared to explain some of these differences (HR for non-Hispanic blacks after adjustment for forced vital capacity percent predicted = 1.16, 95% CI 0.98-1.36, p = 0.09; HR for Hispanics = 1.21, 95% CI 0.99-1.48, p = 0.056). In summary, black and Hispanic patients with IPF have worse survival than whites after listing for lung transplant.

Racial and ethnic disparities in survival in lung transplant candidates with idiopathic pulmonary fibrosis.

Minority patients have worse outcomes than nonminority patients in a variety of pulmonary diseases. We aimed to compare the survival of Black and Hispanic patients to that of others with idiopathic pulmonary fibrosis (IPF). We performed a retrospective cohort study of patients with IPF who were evaluated for lung transplantation at our center. Kaplan-Meier survival curves and Cox proportional hazards models were used to compare survival between groups. Black and Hispanic patients had spirometry, lung volumes and diffusion capacity that were similar to others, but had worse exercise capacity. Minority patients had a significantly increased risk of death compared to others independent of transplantation status (hazard ratio = 3.3, 95% CI 1.2-8.9, p = 0.02). Differences in exercise capacity, pulmonary hemodynamics and socioeconomic factors appeared to account for some of the differences in survival. Black and Hispanic patients with IPF had an increased risk of death following referral for lung transplantation. This finding may be due to differences in disease progression and/or differences in access to medical care among minority patients. Future studies should confirm our findings in a larger cohort. The elimination of racial and ethnic disparities in outcome should be a priority for clinicians and researchers in this field.