Joshua R. Sonett

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.

Correlation of lung surface area to apoptosis and proliferation in human emphysema

Pulmonary emphysema is associated with alterations in matrix proteins and protease activity. These alterations may be linked to programmed cell death by apoptosis, potentially influencing lung architecture and lung function. To evaluate apoptosis in emphysema, lung tissue was analysed from 10 emphysema patients and six individuals without emphysema (normal). Morphological analysis revealed alveolar cells in emphysematous lungs with convoluted nuclei characteristic of apoptosis. DNA fragmentation was detected using terminal deoxynucleotide transferase-mediated dUTP nick-end labelling (TUNEL) and gel electrophoresis. TUNEL revealed higher apoptosis in emphysematous than normal lungs. Markers of apoptosis, including active caspase-3, proteolytic fragment of poly (ADP-ribose) polymerase, Bax and Bad, were detected in emphysematous lungs. Linear regression showed that apoptosis was inversely correlated with surface area. Emphysematous lungs demonstrated lower surface areas and increased cell proliferation. There was no correlation between apoptosis and proliferation, suggesting that, although both events increase during emphysema, they are not in equilibrium, potentially contributing to reduced lung surface area. In summary, cell-based mechanisms associated with emphysematous parenchymal damage include increased apoptosis and cell proliferation. Apoptosis correlated with airspace enlargement, supporting epidemiological evidence of the progressive nature of emphysema. These data extend the understanding of cell dynamics and structural changes within the lung during emphysema pathogenesis.

Randomized Trial of Thymectomy in Myasthenia Gravis

BACKGROUND Thymectomy has been a mainstay in the treatment of myasthenia gravis, but there is no conclusive evidence of its benefit. We conducted a multicenter, randomized trial comparing thymectomy plus prednisone with prednisone alone. METHODS We compared extended transsternal thymectomy plus alternate-day prednisone with alternate-day prednisone alone. Patients 18 to 65 years of age who had generalized nonthymomatous myasthenia gravis with a disease duration of less than 5 years were included if they had Myasthenia Gravis Foundation of America clinical class II to IV disease (on a scale from I to V, with higher classes indicating more severe disease) and elevated circulating concentrations of acetylcholine-receptor antibody. The primary outcomes were the time-weighted average Quantitative Myasthenia Gravis score (on a scale from 0 to 39, with higher scores indicating more severe disease) over a 3-year period, as assessed by means of blinded rating, and the time-weighted average required dose of prednisone over a 3-year period. RESULTS A total of 126 patients underwent randomization between 2006 and 2012 at 36 sites. Patients who underwent thymectomy had a lower time-weighted average Quantitative Myasthenia Gravis score over a 3-year period than those who received prednisone alone (6.15 vs. 8.99, P<0.001); patients in the thymectomy group also had a lower average requirement for alternate-day prednisone (44 mg vs. 60 mg, P<0.001). Fewer patients in the thymectomy group than in the prednisone-only group required immunosuppression with azathioprine (17% vs. 48%, P<0.001) or were hospitalized for exacerbations (9% vs. 37%, P<0.001). The number of patients with treatment-associated complications did not differ significantly between groups (P=0.73), but patients in the thymectomy group had fewer treatment-associated symptoms related to immunosuppressive medications (P<0.001) and lower distress levels related to symptoms (P=0.003). CONCLUSIONS Thymectomy improved clinical outcomes over a 3-year period in patients with nonthymomatous myasthenia gravis. (Funded by the National Institute of Neurological Disorders and Stroke and others; MGTX ClinicalTrials.gov number, NCT00294658.).

Invasive size is an independent predictor of survival in pulmonary adenocarcinoma.

Current classification of pulmonary adenocarcinoma includes noninvasive bronchioloalveolar carcinoma, mixed subtype adenocarcinoma, and several patterns of invasive carcinoma. The extent of invasion in mixed subtype adenocarcinoma is variable, and prior studies suggest that estimates of extent of desmoplasia or invasion and gross tumor size are predictors of survival. Pathologic review of 178 consecutive primary lung adenocarcinoma resections from 1997 to 2000 was performed blinded to outcome. Lymph node metastases were not present in adenocarcinomas with less then 0.6 cm of invasion. In multivariate analysis and in strata adjusted for stage, measurement of linear extent of invasion was significantly associated with survival whereas gross size measurement alone was not. Significant differences in median survival were observed when patients were divided into noninvasive, microinvasive (<0.6 cm invasion), and invasive subcategories. In conclusion, among lung adenocarcinomas, histologic assessment of invasive growth may provide valuable prognostic information, and tumors with invasion under 0.6 cm have a more indolent clinical course after resection.

Obesity and underweight are associated with an increased risk of death after lung transplantation.

RATIONALE Obesity is considered a relative contraindication to lung transplantation, based on studies that have not accounted for key confounders. Little is known about the risk of death for underweight candidates after transplantation. OBJECTIVES To examine the associations of pretransplant obesity and underweight with the risk of death after lung transplantation. METHODS We examined 5,978 adults with cystic fibrosis, chronic obstructive pulmonary disease, and diffuse parenchymal lung disease who underwent lung transplantation in the United States between 1995 and 2003. We used Cox models and generalized additive models to examine the association between pretransplant body mass index and the risk of death after lung transplantation with adjustment for donor and recipient factors. MEASUREMENTS AND MAIN RESULTS The median follow-up time was 4.2 years. Compared with normal weight recipients, the multivariable-adjusted rates of death were 15% higher for underweight recipients (95% confidence interval, 3 to 28%), 15% higher for overweight recipients (95% confidence interval, 6 to 26%), and 22% higher for obese recipients (95% confidence interval, 8 to 39%). These relationships persisted when stratified by diagnosis. The multivariable-adjusted population attributable fraction was 12% at 1 year and 8% at 5 years. CONCLUSIONS Both obesity and underweight are independent risk factors for death after lung transplantation, contributing to up to 12% of deaths in the first year after transplantation. Primary care providers and pulmonologists should promote a healthy weight for patients with lung disease long before transplantation is considered.

Extracorporeal membrane oxygenation as a bridge to lung transplantation and recovery

OBJECTIVE Respiratory failure develops in many patients on lung transplant waiting lists before a suitable donor organ becomes available. Extracorporeal membrane oxygenation may be used to bridge such patients to recovery or lung transplantation. METHODS This is a review of a single-institutions experience with placing patients on extracorporeal membrane oxygenation with the intention of bridging them to lung transplantation. End points included successful bridging, duration of extracorporeal membrane oxygenation support, extubation, weaning from extracorporeal membrane oxygenation, overall survival, and extracorporeal membrane oxygenation-related complications. During an approximate 5-year period, acute respiratory failure developed in 18 patients (median age, 34 years) on the institutions lung transplant waiting list (8 hypoxemic, 9 hypercarbic, and 1 combined) who were placed on extracorporeal membrane oxygenation (13 venovenous and 5 venoarterial). RESULTS All patients achieved appropriate extracorporeal membrane oxygenation blood flow rates (median, 4.05 L/min) and good gas exchange (median, on extracorporeal membrane oxygenation partial pressure of arterial carbon dioxide 43 mm Hg and partial pressure of arterial oxygen 196 mm Hg). Thirteen patients (72%) were successfully bridged: 10 to transplant and 3 returned to baseline function. Eleven patients (61%) survived beyond 3 months, including the 10 (56%) who underwent transplantation and are still alive. The median duration of extracorporeal membrane oxygenation support for patients who underwent transplantation was 6 days (3.5-31 days) versus 13.5 days (11-19 days) for those who did not undergo transplantation (P = .45). Six patients (33%) were extubated on extracorporeal membrane oxygenation, 4 of whom underwent transplantation. Four patients (22%) who were too unstable for conventional interhospital transfer were transported on extracorporeal membrane oxygenation to Columbia University Medical Center. This subgroup had a 75% bridge to transplant or recovery rate and 100% survival in transplanted patients. CONCLUSIONS Extracorporeal membrane oxygenation is a safe and effective means of bridging well-selected patients with refractory respiratory failure to lung transplantation or return to their baseline condition.

Use of bicaval dual-lumen catheter for adult venovenous extracorporeal membrane oxygenation

BACKGROUND Extracorporeal membrane oxygenation (ECMO) provides supplementary oxygenation and carbon dioxide removal for selected patients on mechanical ventilatory support. Venovenous ECMO is traditionally established by dual cannulation of the internal jugular and femoral veins. We report our institutional experience using single-site, dual-lumen cannula for venovenous ECMO as an alternative to the 2-catheter approach. This approach minimizes recirculation and avoids use of the femoral site, which confers potential advantages. METHODS This is a retrospective review of a single institutions experience with a new bicaval dual lumen ECMO cannula. During a 19-month period, 27 consecutive patients were placed on ECMO using this catheter inserted through the right internal jugular vein. RESULTS Single-site venovenous ECMO support was uneventfully initiated in 26 of the 27 patients (median age, 42 years; interquartile range, 31 to 58 years) and achieved full flows and adequate gas exchange. Median ventilator days before ECMO was 1 day (interquartile range, 0.25 to 3.5 days). The median duration of ECMO support was 9 days (interquartile range, 5.5 to 11.5 days). Decannulation was achieved in 70% of the patients and extubation in 59%. Two were bridged to lung transplantation and are still alive. The overall survival and hospital discharge rate was 56%. There was no device failure or in-cannula thrombosis. One superior vena cava injury occurred, and one cannula required repositioning. CONCLUSIONS Single-site venovenous ECMO has advantages compared with traditional venovenous ECMO. Using image guidance, the cannula can reliably be used in prolonged venovenous ECMO cases.

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)

Plasma Levels of Receptor for Advanced Glycation End Products, Blood Transfusion, and Risk of Primary Graft Dysfunction

RATIONALE The receptor for advanced glycation end products (RAGE) is an important marker of lung epithelial injury and may be associated with impaired alveolar fluid clearance. We hypothesized that patients with primary graft dysfunction (PGD) after lung transplantation would have higher RAGE levels in plasma than patients without PGD. OBJECTIVES To test the association of soluble RAGE (sRAGE) levels with PGD in a prospective, multicenter cohort study. METHODS We measured plasma levels of sRAGE at 6 and 24 hours after allograft reperfusion in 317 lung transplant recipients at seven centers. The primary outcome was grade 3 PGD (Pa(O(2))/Fi(O(2)) < 200 with alveolar infiltrates) within the first 72 hours after transplantation. MEASUREMENTS AND MAIN RESULTS Patients who developed PGD had higher levels of sRAGE than patients without PGD at both 6 hours (median 9.3 ng/ml vs. 7.5 ng/ml, respectively; P = 0.028) and at 24 hours post-transplantation (median 4.3 ng/ml vs. 1.9 ng/ml, respectively; P < 0.001). Multivariable logistic regression analyses indicated that the relationship between levels of sRAGE and PGD was attenuated by elevated right heart pressures and by the use of cardiopulmonary bypass. Median sRAGE levels were higher in subjects with cardiopulmonary bypass at both 6 hours (P = 0.003) and 24 hours (P < 0.001). sRAGE levels at 6 hours were significantly associated with intraoperative red cell transfusion (Spearmans rho = 0.39, P = 0.002 in those with PGD), and in multivariable linear regression analyses this association was independent of confounding variables (P = 0.02). CONCLUSIONS Elevated plasma levels of sRAGE are associated with PGD after lung transplantation. Furthermore, plasma sRAGE levels are associated with blood product transfusion and use of cardiopulmonary bypass.

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.