Michael S. Mulvihill

A national analysis of wedge resection versus stereotactic body radiation therapy for stage IA non–small cell lung cancer

Objective Lobectomy is considered optimal therapy for early‐stage non–small cell lung cancer, but sublobar wedge resection and stereotactic body radiation therapy are alternative treatments. This study compared outcomes between wedge resection and stereotactic body radiotherapy. Methods Overall survival of patients with cT1N0 and tumors ≤2 cm who underwent stereotactic body radiotherapy or wedge resection in the National Cancer Data Base from 2008 to 2011 was assessed via a Kaplan‐Meier and propensity score–matched analysis. A center‐level sensitivity analysis that used observed/expected mortality ratios was conducted to identify an association between center use of stereotactic body radiotherapy and mortality. Results Of the 6295 patients included, 1778 (28.2%) underwent stereotactic body radiotherapy, and 4517 (71.8%) underwent wedge resection. Stereotactic body radiotherapy was associated with significantly reduced 5‐year survival compared with wedge resection in both unmatched analysis (30.9% vs 55.2%, P < .001) and after adjustment for covariates (31.0% vs 49.9%, P < .001). Stereotactic body radiotherapy also was associated with worse overall survival than wedge resection after 2 subgroup analyses of propensity‐matched patients (P < .05 for both). Centers that used stereotactic body radiotherapy more often as opposed to surgery for patients with cT1N0 patients with tumors <2 cm were more likely to have an observed/expected mortality ratio > 1 for 3‐year mortality (P = .034). Conclusions In this national analysis, wedge resection was associated with better survival for stage IA non–small cell lung cancer than stereotactic body radiotherapy.

Adjuvant Chemotherapy Is Associated with Improved Survival after Esophagectomy without Induction Therapy for Node-Positive Adenocarcinoma

Background: This study investigated adjuvant chemotherapy (AC) use after esophagectomy without induction therapy for node-positive (pN+) adenocarcinoma using the National Cancer Database, including the impact of complications related to surgery (CRS) on outcomes. Methods: Predictors of AC use in 1694 patients in the National Cancer Data Base who underwent R0 esophagectomy from 2003–2011 without induction therapy for pN+ adenocarcinoma of the middle or lower esophagus and survived more than 30 days were identified with multivariable logistic regression. The impact of AC on survival was estimated using Kaplan–Meier and Cox-proportional hazards methods. Results: AC was given to 874 of 1694 (51.6%) patients; 618 (70.7%) AC patients received radiation. Older age (adjusted odds ratio [AOR] 0.58/decade, p < 0.001), longer travel distance (AOR 0.78 per 100 miles, p = 0.03) and CRS (AOR 0.45, p < 0.001) predicted that AC was not used. Patients given AC had better 5-year survival than patients not given AC (24.2% versus 14.9%, p < 0.001), and AC use predicted improved survival in multivariate analysis (hazard ratio 0.67, p = 0.008). Receiving radiation in addition to AC did not improve survival (p = 0.35). Although CRS was associated with worse survival, patients who had CRS but received AC had superior survival compared to patients who did not have CRS or get AC (p = 0.016). Conclusions: AC after esophagectomy is associated with improved survival but was only used in half of patients with pN+ esophageal adenocarcinoma. We also found that the addition of radiation to AC was not associated with a survival benefit. CRS predict worse long-term survival and lower the chance of getting AC, but even patients with CRS had improved survival when given AC.

Lung transplantation at Duke

Lung transplantation represents the gold-standard therapy for patients with end-stage lung disease. Utilization of this therapy continues to rise. The Lung Transplant Program at Duke University Medical Center was established in 1992, and since that time has grown to one of the highest volume centers in the world. The program to date has performed over 1,600 lung transplants. This report represents an up-to-date review of the practice and management strategies employed for safe and effective lung transplantation at our center. Specific attention is paid to the evaluation of candidacy for lung transplantation, donor selection, surgical approach, and postoperative management. These evidence-based strategies form the foundation of the clinical transplantation program at Duke.

Clinical predictors and outcome implications of early readmission in lung transplant recipients

BACKGROUND The purpose of this study was to identify risk factors and outcome implications for 30-day hospital readmission in lung transplant recipients. METHODS We conducted a retrospective cohort study of lung transplant cases from a single, high-volume lung transplant program between January 2000 and March 2012. Demographic and health data were reviewed for all patients. Risk factors for 30-day readmission (defined as readmission within 30 days of discharge from index lung transplant hospitalization) were modeled using logistic regression, with selection of parameters by backward elimination. RESULTS The sample comprised 795 patients after excluding scheduled readmissions and in-hospital deaths. Overall 30-day readmission rate was 45.4% (n = 361). Readmission rates were similar across different diagnosis categories and procedure types. By univariate analysis, post-operative complications that predisposed to 30-day readmission included pneumonia, any infection, and atrial fibrillation (all p < 0.05). In the final multivariate model, occurrence of any post-transplant complication was the most significant risk factor for 30-day readmission (odds ratio = 1.764; 95% confidence interval, 1.259-2.470). Even for patients with no documented perioperative complication, readmission rates were still >35%. Kaplan-Meier analysis and multi-variate regression modeling to assess readmission as a predictor of long-term outcomes showed that 30-day readmission was not a significant predictor of worse survival in lung recipients. CONCLUSIONS Occurrence of at least 1 post-transplant complication increases risk for 30-day readmission in lung transplant recipients. In this patient population, 30-day readmission does not predispose to adverse long-term survival. Quality indicators other than 30-day readmission may be needed to assess hospitals that perform lung transplantation.

Surgical resection after neoadjuvant chemoradiation for oesophageal adenocarcinoma: what is the optimal timing?

OBJECTIVES The purpose of this study was to determine the optimal timing of surgical resection of oesophageal adenocarcinoma following neoadjuvant chemoradiotherapy (nCRT). METHODS nCRT before resection of oesophageal adenocarcinoma yields improved overall and progression‐free survival. Despite the wide acceptance of tri‐modal therapy, the optimal timing of surgical resection after nCRT is not well defined and existing studies are limited. Adults with Stage II/III oesophageal adenocarcinoma undergoing nCRT before surgery were identified from the National Cancer Database. Multivariable analysis using restricted cubic splines was used to identify an inflection point in clinical outcomes as a function of time between nCRT and surgery, dividing the cohort into short‐ and long‐interval treatment groups, which were then compared. Adjusted rates of survival and margin status were compared between groups using multivariable analysis. RESULTS Among 2444 patients, restricted cubic splines identified an inflection point at 56 days, dividing our cohort into 1533 short‐interval and 911 long‐interval patients. Long‐interval patients had a higher adjusted incidence of pathologic downstaging (odds ratio 1.38, confidence interval 1.02‐1.85, P = 0.04) but no difference in margin positivity compared with short‐interval patients (odds ratio 0.91, confidence interval 0.56‐1.47, P = 0.69). Worse overall survival was noted in the long‐interval subgroup (hazard ratio 1.44, confidence interval 1.22‐1.71, P < 0.001), but 30‐day postoperative mortality was not statistically different (odds ratio 1.56, confidence interval 0.9‐2.72, P = 0.12). CONCLUSIONS Restricted cubic splines provides an objective mechanism to more accurately delineate optimum timing between nCRT and surgical resection. A time interval of 56 days represents an interval where increased pathologic downstaging is balanced by decreased overall survival.

The utility of 6-minute walk distance in predicting waitlist mortality for lung transplant candidates

BACKGROUND The lung allocation score (LAS) has led to improved organ allocation for transplant candidates. At present, the 6-minute walk distance (6MWD) is treated as a binary categorical variable of whether or not a candidate can walk more than 150 feet in 6 minutes. In this study, we tested the hypothesis that 6MWD is presently under-utilized with respect to discriminatory power, and that, as a continuous variable, could better prognosticate risk of waitlist mortality. METHODS A retrospective cohort analysis was performed using the Organ Procurement and Transplantation Network/United Network for Organ Sharing (OPTN/UNOS) transplant database. Candidates listed for isolated lung transplant between May 2005 and December 2011 were included. The population was stratified by 6MWD quartiles and unadjusted survival rates were estimated. Multivariable Cox proportional hazards modeling was used to assess the effect of 6MWD on risk of death. The Scientific Registry of Transplant Recipients (SRTR) Waitlist Risk Model was used to adjust for confounders. The optimal 6MWD for discriminative accuracy in predicting waitlist mortality was assessed by receiver-operating characteristic (ROC) curves. RESULTS Analysis was performed on 12,298 recipients. Recipients were segregated into quartiles by distance walked. Waitlist mortality decreased as 6MWD increased. In the multivariable model, significant variables included 6MWD, male gender, non-white ethnicity and restrictive lung diseases. ROC curves discriminated 6-month mortality was best at 655 feet. CONCLUSIONS The 6MWD is a significant predictor of waitlist mortality. A cut-off of 150 feet sub-optimally identifies candidates with increased risk of mortality. A cut-off between 550 and 655 feet is more optimal if 6MWD is to be treated as a dichotomous variable. Utilization of the LAS as a continuous variable could further enhance predictive capabilities.

Extracorporeal membrane oxygenation following lung transplantation: indications and survival

BACKGROUND Extracorporeal membrane oxygenation (ECMO) is employed to rescue patients with early graft dysfunction after lung transplantation (LTx). Rates of post-LTx ECMO and subsequent outcomes have been limited to single-center reports. METHODS UNOS registry was queried for LTx recipients from March 2015 to March 2016; 2,001 recipients were identified and stratified by need for post-LTx ECMO. Logistic regression was used to determine variables associated with post-LTx ECMO. Cox proportional hazards modeling identified factors associated with survival. Kaplan-Meier analysis with log-rank testing was employed for survival analysis. RESULTS Of 2,001 recipients identified, 107 required post-LTx ECMO (5.1%). Recipients requiring ECMO were younger (56 vs 60 years, p = 0.007) and had higher body mass index (27.2 vs 25.8, p = 0.012). Recipients requiring post-LTx ECMO were more likely to have required mechanical ventilation before transplant (9.3% vs 4.9%, p = 0.049) and were more likely to have required pre-transplant ECMO (15% vs 3.7%, p < 0.001). On multivariable analysis, pre-transplant ECMO and increasing ischemic time were associated with post-LTx ECMO. Six-month survival for recipients requiring ECMO was 62.2%. On multivariable analysis, need for post-transplant dialysis was associated with mortality. Six-month survival for recipients requiring ECMO with and without dialysis was 25.8% and 86.7% (p < 0.001). CONCLUSIONS In a nationally representative database, ischemic time and pre-transplant ECMO and/or ventilator requirement were associated with need for post-LTx ECMO. Need for post-transplant dialysis was associated with mortality in patients requiring post-LTx ECMO. These data may permit improved prediction of graft dysfunction. Strategies to minimize renal toxicity in the perioperative phase may lead to improved early survival post-LTx.

Selective Targeting of High-Affinity LFA-1 Does Not Augment Costimulation Blockade in a Nonhuman Primate Renal Transplantation Model.

Costimulation blockade (CoB) via belatacept is a lower‐morbidity alternative to calcineurin inhibitor (CNI)‐based immunosuppression. However, it has higher rates of early acute rejection. These early rejections are mediated in part by memory T cells, which have reduced dependence on the pathway targeted by belatacept and increased adhesion molecule expression. One such molecule is leukocyte function antigen (LFA)‐1. LFA‐1 exists in two forms: a commonly expressed, low‐affinity form and a transient, high‐affinity form, expressed only during activation. We have shown that antibodies reactive with LFA‐1 regardless of its configuration are effective in eliminating memory T cells but at the cost of impaired protective immunity. Here we test two novel agents, leukotoxin A and AL‐579, each of which targets the high‐affinity form of LFA‐1, to determine whether this more precise targeting prevents belatacept‐resistant rejection. Despite evidence of ex vivo and in vivo ligand‐specific activity, neither agent when combined with belatacept proved superior to belatacept monotherapy. Leukotoxin A approached a ceiling of toxicity before efficacy, while AL‐579 failed to significantly alter the peripheral immune response. These data, and prior studies, suggest that LFA‐1 blockade may not be a suitable adjuvant agent for CoB‐resistant rejection.

The association of donor age and survival is independent of ischemic time following deceased donor lung transplantation

Early research suggests prolonged ischemic time in older donor lungs is associated with decreased survival following lung transplantation. The purpose of this study was to determine whether this association holds in the post‐lung allocation score era.

Is Functional Independence Associated With Improved Long Term Survival After Lung Transplantation

BACKGROUND Existing research demonstrates superior short-term outcomes (length of stay, 1-year survival) after lung transplantation in patients with preoperative functional independence. The aim of this study was to determine whether advantages remain significant in the long-term. METHODS The United Network for Organ Sharing database was queried for adult, first-time, isolated lung transplantation records from January 2005 to December 2015. Stratification was performed based on Karnofsky Performance Status Score (3 groups) and on employment at the time of transplantation (2 groups). Kaplan-Meier and Cox analyses were performed to determine the association between these factors and survival in the long-term. RESULTS Of 16,497 patients meeting criteria, 1,581 (9.6%) were almost completely independent at the time of transplant vs 5,662 (34.3%) who were disabled (completely reliant on others for activities of daily living). Cox models adjusting for recipient, donor, and transplant factors demonstrated a statistically significant association between disability at the time of transplant and long-term death (hazard ratio, 1.26; 95% confidence interval, 1.14 to 1.40; p < 0.001). There were 15,931 patients with available data on paid employment at the time of transplantation. Multivariable analysis demonstrated a statistically significant association between employment at the time of transplantation and death (hazard ratio, 0.86; 95% confidence interval, 0.75 to 0.91; p < 0.001). CONCLUSIONS Preoperative functional independence and maintenance of employment are associated with superior long-term outcomes in lung recipients. The results highlight potential benefits of pretransplant functional rehabilitation for patients on the waiting list for lungs.