Benjamin E. Haithcock

Differential Pathogenesis of Lung Adenocarcinoma Subtypes Involving Sequence Mutations, Copy Number, Chromosomal Instability, and Methylation

Background Lung adenocarcinoma (LAD) has extreme genetic variation among patients, which is currently not well understood, limiting progress in therapy development and research. LAD intrinsic molecular subtypes are a validated stratification of naturally-occurring gene expression patterns and encompass different functional pathways and patient outcomes. Patients may have incurred different mutations and alterations that led to the different subtypes. We hypothesized that the LAD molecular subtypes co-occur with distinct mutations and alterations in patient tumors. Methodology/Principal Findings The LAD molecular subtypes (Bronchioid, Magnoid, and Squamoid) were tested for association with gene mutations and DNA copy number alterations using statistical methods and published cohorts (n = 504). A novel validation (n = 116) cohort was assayed and interrogated to confirm subtype-alteration associations. Gene mutation rates (EGFR, KRAS, STK11, TP53), chromosomal instability, regional copy number, and genomewide DNA methylation were significantly different among tumors of the molecular subtypes. Secondary analyses compared subtypes by integrated alterations and patient outcomes. Tumors having integrated alterations in the same gene associated with the subtypes, e.g. mutation, deletion and underexpression of STK11 with Magnoid, and mutation, amplification, and overexpression of EGFR with Bronchioid. The subtypes also associated with tumors having concurrent mutant genes, such as KRAS-STK11 with Magnoid. Patient overall survival, cisplatin plus vinorelbine therapy response and predicted gefitinib sensitivity were significantly different among the subtypes. Conclusions/ Significance The lung adenocarcinoma intrinsic molecular subtypes co-occur with grossly distinct genomic alterations and with patient therapy response. These results advance the understanding of lung adenocarcinoma etiology and nominate patient subgroups for future evaluation of treatment response.

Peak Oxygen Consumption and Long-Term All-Cause Mortality in Nonsmall Cell Lung Cancer

Identifying strong markers of prognosis is critical to optimize treatment and survival outcomes in patients with nonsmall cell lung cancer (NSCLC). The authors investigated the prognostic significance of preoperative cardiorespiratory fitness (peak oxygen consumption [VO2peak]) among operable candidates with NSCLC.

Rapid On-Site Pathologic Evaluation Does Not Increase the Efficacy of Endobronchial Ultrasonographic Biopsy for Mediastinal Staging

BACKGROUND Endobronchial ultrasonography with transbronchial needle aspiration (EBUS-TBNA) has been shown to be equivalent to mediastinoscopy in lung cancer staging for mediastinal node involvement. Rapid on-site evaluation (ROSE) to determine the adequacy of nodal sampling has been claimed to be beneficial. METHODS A retrospective evaluation was performed in 170 patients who underwent EBUS-TBNA from July 2008 to May 2011. The patients were classified as having either high or low pretest probability for mediastinal disease based on history and radiographic imaging. ROSE was compared with the final pathology reports based on slides and cell blocks. RESULTS One hundred thirty-one (77%) patients were classified as being in the high pretest cohort based on clinical staging. Of these, 101 (77%) patients had adequate tissue sampling based on ROSE, with 70 (69%) patients having positive mediastinal disease. In the 30 (23%) patients who had inadequate tissue by ROSE, the final analysis of all the prepared slides and cell blocks allowed for a diagnosis in all but 8 patients. The sensitivity and specificity of ROSE in the high pretest probability cohort were 89.5% and 96.4%, respectively, whereas the overall sensitivity and specificity of EBUS-TBNA was 92.1% and 100%, respectively. Despite having inadequate tissue on ROSE in 30 of 131 patients, sufficient tissue was available on final analysis for diagnosis in 22 of 30 patients. CONCLUSIONS ROSE does not impact clinical decision making if a thorough mediastinal staging using EBUS is performed. Despite inadequate tissue sampling assessment by ROSE, a final diagnosis was made in most patients, potentially avoiding an additional surgical procedure to prove mediastinal disease.

Effectiveness and Risks Associated With Intrapleural Alteplase by Means of Tube Thoracostomy

BACKGROUND The use of fibrinolytics has been described for the treatment of complex pleural processes. This has evolved from streptokinase to urokinase to alteplase. Intrapleural fibrinolysis has added an alternative to surgical intervention in patients with complex pleural processes. This study describes the use of alteplase as an alternative to surgical intervention for these processes. METHODS From December 2004 to March 2009, 118 patients required alteplase for complex pleural processes. The type of tube thoracostomy, pleural process, antithrombotic type, international normalized ratio, prothrombin time, partial thromboplastin time, platelets, doses, and outcomes were reviewed for each patient. Complications and the need for additional interventions were evaluated. RESULTS Patients received one to eight doses of intrapleural alteplase through a tube thoracostomy. Indications for intrapleural alteplase were empyema (n = 32; 27.1%), loculated pleural effusion (n = 44; 37.3%), hemothorax (n = 13; 11.0%), parapneumonic effusion (n = 25; 21.2%), and malignant effusion (n = 6; 5.1%). The success rate was 86.4% (102 of 118 patients). The incidence of bleeding was 8.5% (n = 10). Binary analysis did not demonstrate an increase in bleeding with abnormal coagulation variables. Of the patients with a bleeding complication, 7 required operative interventions. Twenty (16.9%) required a second tube thoracostomy for incomplete evacuation of the pleural process. Nine (7.6%) required an operative intervention for incomplete evacuation of the pleural process. CONCLUSIONS Intrapleural alteplase appears to be effective in treating complex parapneumonic processes. Systemic anticoagulation, prothrombin time, partial thromboplastin time, international normalized ratio, and platelet count do not appear to be risk factors for bleeding complications. One or two doses of alteplase appear most successful.

Alterations of LKB1 and KRAS and Risk of Brain Metastasis: Comprehensive Characterization by Mutation Analysis, Copy Number, and Gene Expression in Non-Small-Cell Lung Carcinoma.

BACKGROUND Brain metastases are one of the most malignant complications of lung cancer and constitute a significant cause of cancer related morbidity and mortality worldwide. Recent years of investigation suggested a role of LKB1 in NSCLC development and progression, in synergy with KRAS alteration. In this study, we systematically analyzed how LKB1 and KRAS alteration, measured by mutation, gene expression (GE) and copy number (CN), are associated with brain metastasis in NSCLC. MATERIALS AND METHODS Patients treated at University of North Carolina Hospital from 1990 to 2009 with NSCLC provided frozen, surgically extracted tumors for analysis. GE was measured using Agilent 44,000 custom-designed arrays, CN was assessed by Affymetrix GeneChip Human Mapping 250K Sty Array or the Genome-Wide Human SNP Array 6.0 and gene mutation was detected using ABI sequencing. Integrated analysis was conducted to assess the relationship between these genetic markers and brain metastasis. A model was proposed for brain metastasis prediction using these genetic measurements. RESULTS 17 of the 174 patients developed brain metastasis. LKB1 wild type tumors had significantly higher LKB1 CN (p<0.001) and GE (p=0.002) than the LKB1 mutant group. KRAS wild type tumors had significantly lower KRAS GE (p<0.001) and lower CN, although the latter failed to be significant (p=0.295). Lower LKB1 CN (p=0.039) and KRAS mutation (p=0.007) were significantly associated with more brain metastasis. The predictive model based on nodal (N) stage, patient age, LKB1 CN and KRAS mutation had a good prediction accuracy, with area under the ROC curve of 0.832 (p<0.001). CONCLUSION LKB1 CN in combination with KRAS mutation predicted brain metastasis in NSCLC.

Variability in Defining T1N0 Non-Small Cell Lung Cancer Impacts Locoregional Failure and Survival

BACKGROUND Locoregional recurrence can occur despite complete anatomic resection of T1N0 non-small cell lung cancer. That may be the result of incomplete resection or inaccurate staging. We assessed the impact of extent of nodal staging on the rate of locoregional failure and patient survival. METHODS The records of 742 patients undergoing lobectomy, bilobectomy, or pneumonectomy for non-small cell lung cancer from 1996 to 2006 were reviewed. Operative reports and pathology reports were reviewed for the number of lymph nodes and the anatomic nodal stations examined. The Kaplan-Meier method was applied to analyze recurrence-free survival. RESULTS A total of 119 patients with pathologically staged Ia lung cancer were identified. Histology type included 61% (n = 73) adenocarcinoma, 27% (n = 32) squamous cell cancer, and 12% (n = 14) other. Median age was 65 years (range, 34 to 88). Mean follow-up duration was 40 months (median 47; range, 1 to 121). Locoregional recurrence occurred in 20% (n = 18). The N2 nodal stations were examined in 94% (n = 112). At least one defined N1 nodal station was examined in 70% (n = 83). Station undefined N1 nodes were examined in 27% (n = 32), and no N1 nodes were examined in 3% (n = 4). Median number of N1 lymph nodes analyzed was 5 (range, 0 to 18). The locoregional recurrence rate was 14% (12 of 83) for patients with a defined N1 station node versus 31% (11 of 36) for patients in whom there were undefined N1 nodes (p = 0.03). Similar differences were seen in disease-free survival, 78.2% versus 62.6%, respectively (p = 0.06). CONCLUSIONS Despite anatomic resection of stage Ia lung cancer and uniform analysis of N2 nodal stations, a high rate of locoregional recurrence occurs. Imprecise staging of N1 lymph nodes may contribute to the understaging and undertreatment of patients with early stage lung cancer.

Treatment of Surgically Resectable Non-Small-Cell Lung Cancer in Elderly Patients

Lung cancer is the leading cause of cancer mortality in the United States. The median age of diagnosis is 69 years and the number of elderly patients with lung cancer is expected to increase as this segment of the population increases. This review article describes surgical resection, rationale for adjuvant therapy, and the role of molecular markers in this growing patient population.

Assessment of Lungs for Transplant Recovered from Uncontrolled Donation after Circulatory Determination of Death Donors

RATIONALE To address the lung donor shortage, we obtained institutional review board and US Food and Drug Administration approval to transplant lungs recovered from uncontrolled donation after circulatory determination of death donors (uDCDDs). OBJECTIVES To compare outcomes of recipients of lungs recovered from uDCDDs vs. brain-dead donors. METHODS After consent and screening, lungs recovered from uDCDDs were assessed by 4 hours ex vivo lung perfusion (EVLP) and computed tomography (CT) scan. MEASUREMENTS AND MAIN RESULTS Over the course of 29 months, 502 potential uDCDDs younger than 66 years were identified in a single county, with death declaration by emergency medical services and four emergency departments in this and two other countries. We determined reasons that lungs from these uDCDDs were not able to be transplanted: uDCDDs could not have lungs recovered (224), next-of-kin could not be found or refused to discuss (67), next-of-kin refused (48), medical examiner case (39), logistics/missed (35), and miscellaneous (35). There were 247 medical contraindications: 141 pulmonary and 106 nonpulmonary. Lungs were recovered from 31 uDCDDs. Thirteen lungs did not have EVLP: 5 injured lungs (one pulmonary embolism [PE] with perforated infarct, two motor vehicle crash with severe injuries, one adhesion, and one lightning strike), two large PE, two prolonged ischemic time, two obvious chronic obstructive pulmonary disease, one technical, and one consent withdrawn. Eighteen lungs had EVLP: 10 with immediate edema (three PE, three unknown down time, three long ischemic time, and one ruptured aneurysm into L pleural space, making long cardiopulmonary resuscitation ineffective), and one myocarditis, possible lung involvement. In three lungs, CT showed edema after EVLP: one poor flush and poor EVLP performance, one edema after myocardial infarction (MI) with 10-year history of chronic heart failure, and one edema with MI, resuscitated, arrested again. One concurrent pneumonia was diagnosed by bronchoscopy, CT, and cultures; one patient had chronic obstructive pulmonary disease with small subpleural blebs and poor collapse, confirmed by CT. Two uDCDDs with MIs were suitable but not transplanted: no consented recipient from one large blood type B uDCDD, and the senior surgeon was unavailable to transplant suitable lungs from a uDCDD and did not allow the transplant. CONCLUSIONS The objective was not met: no lungs from uDCDDs were transplanted. uDCDDs can be a source of lungs for transplant. Resolving logistical challenges and better use of first-person authorization, allowing organ recovery without next-of-kin consent or knowledge of death, could increase yield. Donor medical problems were higher than expected and may limit the effect of uDCDDs on the lung donor pool. CLINICAL TRIAL REGISTRATION NCT01615484.

Anesthetic Management of a Patient With Situs Inversus for Bilateral Orthotopic Lung Transplantation

From the *Department Anesthesiology, and the †Department of Cardiothoracic Surgery, University of North Carolina at Chapel Hill, Chapel Hill, NC. Address reprint requests to Emily G. Teeter, MD, University of North Carolina at Chapel Hill, N2198 UNC Hospitals CB 7010, Chapel Hill, NC 27599-7010. E-mail: eteeter@aims.unc.edu

Pneumonectomy After Induction Therapy for Non-small Cell Lung Cancer

The authors review current data on pneumonectomy in patients with non-small cell cancer after induction chemotherapy and radiation therapy and make recommendations for treatment: Evaluation by a multidisciplinary team for all advanced stage non-small cell lung cancer cases; parenchymal-conserving R0 resection for patients undergoing therapy for resectable NSCLC; pneumonectomies after induction therapy, done in experienced centers; right pneumonectomy in an experienced center after neoadjuvant therapy - if not feasible, consider referral or treatment with chemo radiotherapy.