Nuclear grade and necrosis predict prognosis in malignant epithelioid pleural mesothelioma: a multi-institutional study.

A recently described nuclear grading system predicted survival in patients with epithelioid malignant pleural mesothelioma. The current study was undertaken to validate the grading system and to identify additional prognostic factors. We analyzed cases of epithelioid malignant pleural mesothelioma from 17 institutions across the globe from 1998 to 2014. Nuclear grade was computed combining nuclear atypia and mitotic count into a grade of I-III using the published system. Nuclear grade was assessed by one pathologist for three institutions, the remaining were scored independently. The presence or absence of necrosis and predominant growth pattern were also evaluated. Two additional scoring systems were evaluated, one combining nuclear grade and necrosis and the other mitotic count and necrosis. Median overall survival was the primary endpoint. A total of 776 cases were identified including 301 (39%) nuclear grade I tumors, 354 (45%) grade II tumors and 121 (16%) grade III tumors. The overall survival was 16 months, and correlated independently with age (P=0.006), sex (0.015), necrosis (0.030), mitotic count (0.001), nuclear atypia (0.009), nuclear grade (<0.0001), and mitosis and necrosis score (<0.0001). The addition of necrosis to nuclear grade further stratified overall survival, allowing classification of epithelioid malignant pleural mesothelioma into four distinct prognostic groups: nuclear grade I tumors without necrosis (29 months), nuclear grade I tumors with necrosis and grade II tumors without necrosis (16 months), nuclear grade II tumors with necrosis (10 months) and nuclear grade III tumors (8 months). The mitosis-necrosis score stratified patients by survival, but not as well as the combination of necrosis and nuclear grade. This study confirms that nuclear grade predicts survival in epithelioid malignant pleural mesothelioma, identifies necrosis as factor that further stratifies overall survival, and validates the grading system across multiple institutions and among both biopsy and resection specimens. An alternative scoring system, the mitosis-necrosis score is also proposed.

Influence of Pleurectomy and Decortication in Health-Related Quality of Life Among Patients with Malignant Pleural Mesothelioma.

BACKGROUND: Complete macroscopic resection surgery, pleurectomy and decortication (PD) improve survival in selected patients with malignant pleural mesothelioma (MPM). Yet its value has been questioned because of concern that this extensive surgical procedure may disrupt health-related quality of life (HRQoL). METHODS: HRQoL was studied in patients undergoing PD surgery for MPM using EORTC QLQ-C30 instrument at baseline (prior to surgery), 1, 4-5, 7-8, and 10-11 months following surgery. Global health and variables in function and symptom domains were investigated. Sub-groups analyses were performed for ECOG performance status (PS), histological sub-types and pathological tumor volume (pTV). Within-patient comparisons to baseline scores were made using Wilcoxon signed-rank test. Trends over time were evaluated using Cuzick's nonparametric test. RESULTS: There were 114 patients with median age of 70 years (range: 50-88) and PS 0: 35 (30.7%), epithelioid histology: 61 (53.5%) and volume <600 ml: 58 (50.9%). Patients with good PS (PS 0), epithelioid histology and small pTV had greater level of functioning and were less symptomatic at baseline. Overall global health worsened at the first postoperative month (p = 0.0005) with subsequent improvement. Non-epithelioid histology and patients with large pTV demonstrated greater improvement in global health, function and symptoms domains following a PD. CONCLUSIONS: At baseline, the overall health-related quality of life, function and symptom domains were adversely affected in non-epithelioid histology and patients with large pTV. However, greatest improvement in global health, symptom and function domains were observed first month after PD and during the follow-up in these sub-groups.

Distribution of donor lungs in the United States: a case for broader geographic sharing.

OBJECTIVES: To evaluate the association between allocation of donor lungs by geographic sharing type (GST) and lung allocation score (LAS). METHODS: UNOS data included lung transplant recipients between 5/4/05 and 09/30/15 (n = 17 416) grouped by GST of donor lungs: local, regional, or national. Recipients were stratified by LAS <50, 50-75, and >75. Kaplan-Meier analysis was used to assess five-yr survival. RESULTS: The majority of lungs were shared locally (n = 9200; 52.8%) followed by nationally (n = 5356; 30.8%) and regionally (n = 2860; 16.4%). There was a significant difference in the mean LAS at transplant (local: 43.7 ± 15; regional: 49.5 ± 18.8; national 51 ± 19.4; p < 0.001). There was a significant association between GST and LAS (p < 0.001). The majority (n = 7431; 58.2%) of recipients with LAS <50 received local lungs. Recipients with LAS >75 received a majority of their organs from national (n = 881; 45.4%) and regional (n = 414; 21.6%) donors. Although statistically significant (p = 0.024), absolute decline in five-yr survival by GST in the national GST was only 1.1% compared to the local GST. CONCLUSIONS: Nearly half of all lungs in the United States are allocated locally to recipients with an LAS <50. Additional studies should determine if organ sharing over broader geographies would improve waitlist outcomes.

Venous thromboembolism after diaphragm pacing in amyotrophic lateral sclerosis.

INTRODUCTION: Patients with amyotrophic lateral sclerosis (ALS) are prone to venous thromboembolism (VTE) and secondary complications. Because there is an increased incidence of VTE after surgical procedures, placement of a Diaphragm Pacing System (DPS) in ALS patients as treatment for respiratory muscle weakness could potentially increase the incidence of VTE, especially in patients with limited mobility. METHODS: We implanted a DPS in 10 ALS patients who met the criteria for this procedure. They underwent a preoperative evaluation as recommended by the guidelines. RESULTS: We report 2 patients with no symptoms of deep vein thrombosis (DVT) before the surgical procedure who then developed perioperative VTE. CONCLUSIONS: These patients highlight the need to consider preoperative screening for DVT and postoperative thromboprophylaxis in high-risk ALS patients who undergo DPS placement.

Robotic chest wall resection for primary benign chest wall tumors and locally advanced lung cancer: an institutional case series and national report.

Background: Limited data exists for robotic chest wall resection; we report institutional and national experience of robotic chest wall resection. Methods: In this comparative retrospective case series we describe patients who underwent robotic chest wall resection at our institution and enrich this case series with data from the National Cancer Database (NCDB). We describe our preoperative workup, operative technique, and postoperative care. Outcomes included conversion to open, length of stay, readmissions, and 30- and 90-day mortality. The results are descriptively reported and compared. Results: We describe 6 patients institutionally and 96 NCDB patients. At our institution 66.7% were males, median age was 70.0 (range, 39-91) years, and 50% were primary chest wall tumors. Median tumor size was 5.25 (range, 2.3-8.3) cm. Outcomes were as follows: no open conversions, median length of stay 3 (range, 1-6) days, no unplanned 30-day readmissions or 90-day mortality. In the NCDB, 55.2% were males with median age of 68.5 (range, 30-89) years. Median tumor size was 3.90 (range, 2.4-6.0) cm. NCDB outcomes were as follows: 18.8% open conversion, median length of stay 7 (range, 5-10) days, 3.1% unplanned 30-day readmission, and 8.3% 90-day mortality. Our institutional case series had 18.0 months median follow-up (range, 6-54 months) with no functional deficits. Median survival in NCDB was 49.6 months. Conclusions: Robotic chest wall resection is feasible and is performed nationally with acceptable short- and long-term outcomes. Our institutional experience reports our technique, resultant short hospital stay, and excellent functional outcomes.

Impact of Federal Lung Cancer Screening Policy on the Incidence of Early-stage Lung Cancer.

BACKGROUND: In December 2013 the US Preventative Services Task Force (USPSTF) recommended annual lung cancer screening for high-risk patients. The Centers for Medicare & Medicaid Services (CMS) later announced coverage in 2015. The impact of these federal decisions at the population level is unknown. METHODS: Using the Surveillance, Epidemiology, and End Results database, we studied changes in lung cancer incidence by stage and linked to US census data to obtain age-adjusted estimates standardized to the US population. Based on age at diagnosis we stratified patients as age-eligible or age-ineligible for screening. We used difference-in-differences regression to determine the effect of screening on lung cancer incidence by stage. RESULTS: For all age groups the incidence of early-stage lung cancer both before and after the USPSTF guidelines remained relatively stable at 12.8 ± 0.52 and 13.5 ± 0.92 per 100,000 patients, respectively (P = .068). However the difference-in-differences analysis estimated an absolute increase in the age-adjusted incidence by 3.4 per 100,000 persons in the age-eligible group after the announcement of the guidelines (P = .007). The effect was even larger after the CMS decision (4.3/100,000 persons, P < .001). Similarly there was a 14.2 per 100,000 persons absolute reduction in the incidence of advanced-stage lung cancer (P < .001). CONCLUSIONS: The 2013 USPSTF lung cancer screening guidelines and CMS coverage decisions were associated with an increased incidence of early-stage lung cancer and decreased incidence of advance-staged lung cancer at the population level.

Comparison of sirolimus with azathioprine in a tacrolimus-based immunosuppressive regimen in lung transplantation.

RATIONALE: Lung transplantation has evolved into a life-saving therapy for select patients with end-stage lung diseases. However, long-term survival remains limited because of chronic rejection. Sirolimus is beneficial in preventing cardiac rejection and may decrease rejection after lung transplantation. OBJECTIVES: To determine the potential benefit versus risk of sirolimus in lung transplantation. METHODS: We conducted a multicenter randomized, open label controlled trial comparing sirolimus (SIR) with azathioprine (AZA) in a tacrolimus-based immunosuppressive regimen in lung transplantation. The primary end point was the incidence of acute rejection at 1 year after transplantation between the two study groups. MEASUREMENTS AND MAIN RESULTS: One hundred eighty-one patients were randomized to be included in this study. At 1 year after transplantation, there was no significant difference in the incidence of grade A acute rejection between the two study groups. Similarly, the incidence of chronic rejection and graft survival was no different between the two study groups. Cytomegalovirus infection was decreased in the SIR arm compared with the AZA arm (relative risk, 0.67 [95% confidence interval, 0.55, 0.82]; P < 0.01). There was a higher rate of adverse events leading to early discontinuation of SIR (64%) compared with AZA (49%) during the course of this study. CONCLUSIONS: Sirolimus, an mTOR inhibitor, did not decrease the incidence of acute rejection at 1 year compared with azathioprine in lung transplantation. These results differ from previous results in cardiac and renal transplantation and emphasize the need for multicenter randomized controlled trials in lung transplantation. Clinical trial registered with www.clinicaltrials.gov (NCT 00321906).

Malignant Pleural Mesothelioma: Current Understanding of the Immune Microenvironment and Treatments of a Rare Disease.

Malignant pleural mesothelioma is a rare disease with an annual incidence of around 3000 cases a year in the United States. Most cases are caused by asbestos exposure, with a latency period of up to 40 years. Pleural mesothelioma is an aggressive disease process with overall survival of roughly 6-12 months after the time of diagnosis. It is divided into three subtypes: epithelioid, mixed type, and sarcomatoid type, with the epithelioid subtype having the best overall survival. Often, the treatment is multimodality with surgery, chemotherapy, and radiation. The survival benefit is improved but remains marginal. New treatment options involving targeted immune therapies appear to offer some promise. The tumor microenvironment is the ecosystem within the tumor that interacts and influences the host immune system. Understanding this complex interaction and how the host immune system is involved in the progression of the disease process is important to define and guide potential treatment options for this devastating and rare disease.

Neoadjuvant Chemotherapy vs Chemoradiation Therapy Followed by Sleeve Resection for Resectable Lung Cancer.

BACKGROUND: Traditionally, neoadjuvant chemoradiation therapy is followed by resection in patients with locally advanced non-small cell lung cancer (NSCLC). The risks and benefits of this approach are not well defined in patients requiring a sleeve lung resection. In this context, we compare the short- and long-term outcomes of neoadjuvant chemotherapy alone vs chemoradiation therapy followed by sleeve lung resection. METHODS: We used the National Cancer Database to identify locally advanced NSCLC patients who received chemotherapy-alone or chemoradiation therapy in the neoadjuvant setting, followed by a sleeve lung resection, between 2006 and 2017. Our outcomes of interest were 30-day mortality, 90-day mortality, and overall survival. To minimize confounding by indication, we used propensity score adjustment, logistic regression, Kaplan-Meier survival analysis, and Cox proportional hazards models to identify associations. RESULTS: Of 176 patients undergoing sleeve lung resection, 92 (52.3%) received neoadjuvant chemotherapy-alone, and 84 (47.7%) received neoadjuvant chemoradiation therapy. Patients in both groups were well balanced in age, sex, race, Charlson-Deyo comorbidity index, insurance status, median income, and education (all P > .05). Similarly, the groups were well balanced in histology, tumor location, and stage (all P > .05). Patients receiving neoadjuvant chemoradiation therapy had higher 90-day mortality (11.96% vs 2.38%, P = .015), and there was no difference in overall survival between the neoadjuvant chemotherapy-alone vs chemoradiation therapy cohorts (P = .621). CONCLUSIONS: In this national study of patients with locally advanced resectable NSCLC requiring a sleeve lung resection, neoadjuvant chemoradiation therapy was associated with a 5-fold increase in 90-day mortality without an overall survival benefit over neoadjuvant chemotherapy-alone.

Inflammatory cytokines in robot-assisted thoracic surgery versus video-assisted thoracic surgery.

Background: Cytokines play a crucial role in the inflammatory response and are essential modulators of injury repair mechanisms. While minimally invasive operations have been shown to induce lower levels of cytokines compared to open thoracotomy, the inflammatory cytokine profile difference between video-assisted (VATS) and robotic-assisted thoracic surgery (RATS) techniques has yet to be elucidated. Methods: In this prospective observational study of 45 patients undergoing RATS (n=30) or VATS (n=15) lung resection for malignancy, plasma levels of interleukin (IL)-1α, IL-1ß, IL-2, IL-4, IL-6, IL-8, IL-10, vascular endothelial growth factor (VEGF), interferon (IFN)-γ, tumor necrosis factor (TNF)-α, monocyte chemo-attractant protein (MCP)-1, and endothelial growth factor (EGF) were measured before and after surgery via immunoassay. Results: Levels of IL-6 and MCP-1 were significantly higher in patients undergoing VATS than in patients undergoing RATS (P<0.001 and P=0.005, respectively) 2 hours following surgery. MCP-1 levels were also found to be significantly higher in the VATS group (P<0.001) 24 hours following surgery. IL-1α, IL-1ß, IL-2, IL-4, IL-8, IL-10, IFN-γ, TNF-α, and EGF levels were not significantly different at any time-point comparing VATS to RATS. Conclusions: The VATS approach is associated with a more robust pro-inflammatory cytokine response through the upregulation of MCP-1 and IL-6 when compared to the RATS approach in patients undergoing anatomic lung resection. Further studies are necessary to validate the clinical significance of this finding.

Increased social media utilization and content creation by cardiothoracic surgery programs during the coronavirus disease 2019 pandemic.

Objectives: The coronavirus disease 2019 (COVID-19) pandemic has changed the landscape of professional activities, emphasizing virtual meetings and social media (SoMe) presence. Whether cardiothoracic programs increased their SoMe presence is unknown. We examined SoMe use and content creation by cardiothoracic surgery programs during the COVID-19 pandemic. Methods: We searched the Accreditation Council for Graduate Medical Education to identify all cardiothoracic surgery residency programs (n = 122), including independent (n = 74), integrated (n = 33), and congenital (n = 15) training programs at 78 US cardiothoracic surgery teaching institutions. We then manually searched Google, Facebook, Instagram, LinkedIn, and Twitter to identify the associated residency and departmental accounts. The timeline for our search was between 10/2021 and 4/2022. March 2020 was used as the starting point for the COVID-19 pandemic. We also contacted the account managers to identify account content creators. The data are descriptively reported and analyzed. Results: Of 137 SoMe accounts from 78 US cardiothoracic surgery teaching institutions, 72 of 137 (52.6%) were on Twitter, 34 of 137 (24.8%) on Facebook, and 31 of 137 (22.6%) on Instagram. Most accounts were departmental accounts (105/137 = 76.6%) versus 32 of 137 (23.4%) training program accounts. Most training program-specific SoMe accounts across all platforms were created after the COVID-19 pandemic, whereas departmental accounts were pre-existing (P < .001). The most pronounced SoMe growth was on Instagram at the training program level, with 91.7% of Instagram accounts created after the pandemic. Trainees are the content creators for 94.4% of residency accounts and 33.3% of departmental accounts. Facebook's presence was stagnant. Congenital training programs did not have a specific SoMe presence. Conclusions: SoMe presence by cardiothoracic surgery training programs and departments has increased during the pandemic. Twitter is the most common platform, with a recent increased trend on Instagram. Trainees largely create content. SoMe education and training pathways may be needed for involved trainees to maximize their benefits.

Comparative effectiveness of stereotactic body radiation therapy versus surgery for stage I lung cancer in otherwise healthy patients: An instrumental variable analysis.

Objectives: Stereotactic body radiation therapy (SBRT) is an established primary treatment modality in patients with lung cancer who have multiple comorbidities and/or advanced-stage disease. However, its role in otherwise healthy patients with stage I lung cancer is unclear. In this context, we compared the effectiveness of SBRT versus surgery on overall survival using a national database. Methods: We identified all patient with clinical stage I non-small cell lung cancer from the National Cancer Database from 2004 to 2016. We defined otherwise healthy patients as those with a Charlson-Deyo comorbidity index of 0 and whose treatment plan included options for either SBRT or surgery. We further excluded patients who received SBRT due to a contraindication to surgery. We first used propensity score matching and Cox proportional hazard models to identify associations. Next, we fit 2-stage residual inclusion models using an instrumental variables approach to estimate the effects of SBRT versus surgery on long-term survival. We used the hospital SBRT utilization rate as the instrument. Results: Of 25,963 patients meeting all inclusion/exclusion criteria, 5465 (21%) were treated with SBRT. On both Cox proportional hazards modeling and propensity-score matched Kaplan-Meier analysis, surgical resection was associated with improved survival relative to SBRT. In the instrumental-variable-adjusted model, SBRT remained associated with decreased survival (hazard ratio, 2.64; P < .001). Both lobectomy (hazard ratio, 0.17) and sublobar resections (hazard ratio, 0.28) were associated with improved overall survival compared with SBRT (P < .001). Conclusions: In otherwise healthy patients with stage I NSCLC, surgical resection is associated with a survival benefit compared with SBRT. This is true for both lobar and sublobar resections.

Pulmonary Parenchymal Changes in COVID-19 Survivors.

BACKGROUND: As the COVID-19 pandemic moves into the survivorship phase, questions regarding long-term lung damage remain unanswered. Previous histopathologic studies are limited to autopsy reports. We studied lung specimens from COVID-19 survivors who underwent elective lung resections to determine whether postacute histopathologic changes are present. METHODS: This multicenter observational study included 11 adult COVID-19 survivors who had recovered but subsequently underwent unrelated elective lung resection for indeterminate lung nodules or lung cancer. We compared these against an age- and procedure-matched control group who never contracted COVID-19 (n = 5) and an end-stage COVID-19 group (n = 3). A blinded pulmonary pathologist examined the lung parenchyma focusing on 4 compartments: airways, alveoli, interstitium, and vasculature. RESULTS: Elective lung resection was performed in 11 COVID-19 survivors with asymptomatic (n = 4), moderate (n = 4), and severe (n = 3) COVID-19 infections at a median 68.5 days (range 24-142 days) after the COVID-19 diagnosis. The most common operation was lobectomy (75%). Histopathologic examination identified no differences between the lung parenchyma of COVID-19 survivors and controls across all compartments examined. Conversely, patients in the end-stage COVID-19 group showed fibrotic diffuse alveolar damage with intra-alveolar macrophages, organizing pneumonia, and focal interstitial emphysema. CONCLUSIONS: In this study to examine the lung parenchyma of COVID-19 survivors, we did not find distinct postacute histopathologic changes to suggest permanent pulmonary damage. These results are reassuring for COVID-19 survivors who recover and become asymptomatic.

Assessment of Textbook Outcome After Surgery for Stage I/II Non-small Cell Lung Cancer.

Outcomes after cancer resection are traditionally measured individually. Composite metrics, or textbook outcomes, bundle outcomes into a single value to facilitate assessments of quality. We propose a composite outcome for non-small cell lung cancer resections, examine factors associated with the outcome, and evaluate its effect on overall survival. We queried the National Cancer Database for patients with stage I/II non-small cell lung cancer who underwent sublobar resection, lobectomy, or pneumonectomy from 2010 to 2016. We defined the metric as margin-negative resection, sampling of ≥10 lymph nodes, length of stay <75th percentile, no 30-day mortality, no readmission, and receipt of indicated adjuvant therapy. Multivariable logistic regression, Cox proportional hazards modeling, survival analyses, and propensity score matching were used to identify factors associated with the outcome and overall survival. Of 88,208 patients, 70,149 underwent lobectomy, 14,922 underwent sublobar resection, and 3,137 underwent pneumonectomy. Textbook outcome was achieved in 26.3% of patients. Failure to achieve the outcome was most commonly driven by inadequate nodal assessment. Textbook outcome was more likely after minimally invasive surgical approaches (aOR = 1.47; P< 0.001) relative to open resection and less likely after sublobar resection (aOR = 0.20; P< 0.001) relative to lobectomy. Achievement of textbook outcome was associated with an 9.6% increase in 5-year survival (P< 0.001), was independently associated with improved survival (aHR = 0.72; P < 0.001), and remained strongly associated with survival independent of resection extent after propensity matching. One in 4 patients undergoing non-small cell lung cancer resection achieve textbook outcome. Textbook outcome is associated with improved survival and has value as a quality metric.

A sphingosine 1-phosphate 1 receptor agonist modulates brain death-induced neurogenic pulmonary injury.

Lung transplantation remains the only viable therapy for patients with end-stage lung disease. However, the full utilization of this strategy is severely compromised by a lack of donor lung availability. The vast majority of donor lungs available for transplantation are from individuals after brain death (BD). Unfortunately, the early autonomic storm that accompanies BD often results in neurogenic pulmonary edema (NPE), producing varying degrees of lung injury or leading to primary graft dysfunction after transplantation. We demonstrated that sphingosine 1-phosphate (S1P)/analogues, which are major barrier-enhancing agents, reduce vascular permeability via the S1P1 receptor, S1PR1. Because primary lung graft dysfunction is induced by lung vascular endothelial cell barrier dysfunction, we hypothesized that the S1PR1 agonist, SEW-2871, may attenuate NPE when administered to the donor shortly after BD. Significant lung injury was observed after BD, with increases of approximately 60% in bronchoalveolar lavage (BAL) total protein, cell counts, and lung tissue wet/dry (W/D) weight ratios. In contrast, rats receiving SEW-2871 (0.1 mg/kg) 15 minutes after BD and assessed after 4 hours exhibited significant lung protection (∼ 50% reduction, P = 0.01), as reflected by reduced BAL protein/albumin, cytokines, cellularity, and lung tissue wet/dry weight ratio. Microarray analysis at 4 hours revealed a global impact of both BD and SEW on lung gene expression, with a differential gene expression of enriched immune-response/inflammation pathways across all groups. Overall, SEW served to attenuate the BD-mediated up-regulation of gene expression. Two potential biomarkers, TNF and chemokine CC motif receptor-like 2, exhibited gene array dysregulation. We conclude that SEW-2871 significantly attenuates BD-induced lung injury, and may serve as a potential candidate to improve human donor availability.

The impact of marginal lung function on outcomes in the era of minimally invasive thoracic surgery.

BACKGROUND: The effect of marginal lung function on outcomes after lung resection has traditionally been studied in the context of open thoracic surgery. Its impact on postoperative outcomes in the era of minimally invasive lung resection is unclear. METHODS: In this retrospective cohort study, we included adult patients who underwent minimally invasive lung resection at our institution between January 2017 and May 2020 for known malignancy or lung nodule. Marginal lung function was defined as pre-operative forced expiratory volume in 1 second (FEV1) and/or diffusion lung capacity of carbon monoxide <60% of predicted. Our outcomes included a composite outcome of pulmonary morbidity and/or 30- and 90-day mortality, and hospital length of stay. We used multivariable logistic and Poisson regression models to identify associations with outcomes, and Kaplan-Meier and Cox models to estimate survival. RESULTS: Of 300 patients, 88 (29%) had marginal lung function. Patients in the marginal group were more likely to be female (69% vs. 56%; P=0.028), and more likely to have: hypertension (HTN) (83% vs. 71%; P=0.028), chronic obstructive pulmonary disease (COPD) (38% vs. 12%; P<0.001), interstitial lung disease (ILD) (9% vs. 3%; P<0.019), and ischemic heart disease (28% vs. 18%; P=0.033). Patients were similar in terms of age (68±8 vs. 68±10 years; P=0.932), and other comorbidities. Anatomic lung resection comprised 56.8% of the marginal group vs. 74% in the non-marginal group (P=0.003). The most common complication was prolonged air leak (18.2% vs. 11.8%; P=0.479). Marginal lung function had a trend toward increased composite respiratory complications (22.7% vs. 15.1%; P=0.112) and 90-day mortality (5.7% vs. 4.2%; P=0.591), although they did not reach statistical significance. There was a statistically significant 1-day average increase in length of stay in the marginal lung function cohort (4.6 vs. 3.4 days; P<0.015) with a stronger association with diffusion lung capacity of carbon monoxide than FEV1. Survival was similar (marginal function HR =1.0; P=0.994). CONCLUSIONS: In the era of minimally invasive thoracic surgery, lung resection in patients with marginal lung function may be considered in select patients. These findings aid in the selection consideration and counseling of this patient population.

Early readmission is a predictor of overall survival following isolated lung transplantation.

Causes of early readmissions following lung transplantation are not well understood, and the impact is poorly reported. We reviewed 221 consecutive lung transplantations and identified patients readmitted within 90 days. A case control analysis was performed to determine the characteristics that predict readmission and the impact of readmission on survival. Ninety (44%) of the 205 operative survivors required a total of 125 readmissions during the 90 days after transplantation. Twenty-eight patients (13.7%) required multiple readmissions. Causes for readmissions were pulmonary complication (59%), gastrointestinal (18%), cardiac (5%), metabolic (2.5%), neurological (2.5%), hematological (2%), and miscellaneous (11%). The sex, native disease, or type of transplant did not predict readmission. Requirement of cardiopulmonary bypass for transplantation showed a trend toward significance (P = 0.08). The 90-day conditional survival at 1, 3, and 5 years for those patients readmitted within 90 days were 76%, 59%, and 52%, respectively, compared to 93%, 80%, and 76% for patients not readmitted (P = 0.01). Requirement for readmission within 90 days following transplantation is associated with increased mortality. Sex, native disease, and type of transplant are not predictors of readmission or survival.

EPHA2 mutations with oncogenic characteristics in squamous cell lung cancer and malignant pleural mesothelioma.

Squamous cell carcinoma (SCC) and malignant pleural mesothelioma (MPM) are thoracic malignancies with very poor prognosis and limited treatment options. It is an established fact that most of the solid tumors have overexpression of EPHA2 receptor tyrosine kinase. EPHA2 is known to exhibit opposing roles towards cancer progression. It functions in inhibiting cancer survival and migration via a ligand and tyrosine kinase dependent signaling (Y772). Whereas it is known to promote tumor progression and cell migration through a ligand-independent signaling (S897). We analyzed the expression profile and mutational status of the ephrin receptor A2 (EPHA2) in SCC and MPM cell lines and primary patient specimens. The EPHA2 receptor was found to be either overexpressed, mutated or amplified in SCC and MPM. In particular, the EPHA2 mutants A859D and T647M were interesting to explore, A859D Y772 dead mutant exhibited lower levels of phosphorylation at Y772 compared to T647M mutant. Molecular Dynamics simulations studies suggested that differential changes in conformation might form the structural basis for differences in the level of EPHA2 activation. Consequently, A859D mutant cells exhibited increased proliferation as well as cell migration compared to controls and T647M mutant. Kinomics analysis demonstrated that the STAT3 and PDGF pathways were upregulated whereas signaling through CBL was suppressed. Considered together, the present work has uncovered the oncogenic characteristics of EPHA2 mutations in SSC and MPM reinstating the dynamics of different roles of EPHA2 in cancer. This study also suggests that a combination of doxazosin and other EPHA2 inhibitors directed to inhibit the pertinent signaling components may be a novel therapeutic strategy for MPM and Non-small cell lung cancer patients who have either EPHA2 or CBL alterations.

TCR sequencing analysis of cancer tissues and tumor draining lymph nodes in colorectal cancer patients.

Tumor draining lymph nodes (TDLNs) are located in the routes of lymphatic drainage from a primary tumor and have the highest risk of metastasis in various types of solid tumors. TDLNs are also considered as a tissue to activate the antitumor immunity, where antigen-specific effector T cells are generated. However, T cell receptor (TCR) repertoires in TDLNs have not been well characterized. We collected 23 colorectal cancer tumors with 203 lymph nodes with/without metastatic cancer cells (67 were metastasis-positive and the remaining 136 were metastasis-negative) and performed TCR sequencing. Metastasis-positive TDLNs showed a significantly lower TCR diversity and shared TCR clonotypes more frequently with primary tumor tissues compared to metastasis-negative TDLNs. Principal component analysis indicated that TDLNs with metastasis showed similar TCR repertoires. These findings suggest that cancer-reactive T cell clones could be enriched in the metastasis-positive TDLNs.

Changes in patient presentation and outcomes for major lung resection over three decades.

OBJECTIVE: Growing scrutiny of surgical results for lung cancer has prompted increased evaluation of risk factors and outcomes of resection. We determined how patient preoperative status and outcomes of resection have changed over time to identify opportunities for improving these results. METHODS: We reviewed a prospectively collected database of patients undergoing major lung resection 1980-2006. Patient characteristics and immediate outcomes of resection were compared for three-decade periods (1980-1989, 1990-1999, 2000-2006). Data were compared using the Kruskal-Wallis test, chi squared analysis, and logistic regression analysis. RESULTS: One thousand and forty-six patients underwent resection for cancer (862) and other problems. The percentage of female patients increased over time. Some elements of preoperative status worsened, with significant increases in hypertension rate, mean performance status, obesity incidence, mean risk score, and use of induction therapy. Pneumonectomy rates, immediate preoperative tobacco use, and surgery for advanced stages of disease decreased over time. Outcomes improved over time, with significant decreases in operative mortality, cardiopulmonary complications, and overall complications. Risk factors for categories of complications including operative mortality varied according to the time period studied. CONCLUSIONS: Outcomes of major lung resection have improved over time despite a worsening of some elements of preoperative status. Maintenance of surgical databases is essential to enable surgeons to provide data consonant with growing demand from payers and patients. The use of current rather than historical lung resection outcomes is vital in assessing risk. Identification of changes in surgical practice patterns helps identify opportunities for improving future outcomes.