Description of an activity-based enzyme biosensor for lung cancer detection.

BACKGROUND: Lung cancer is associated with the greatest cancer mortality as it typically presents with incurable distributed disease. Biomarkers relevant to risk assessment for the detection of lung cancer continue to be a challenge because they are often not detectable during the asymptomatic curable stage of the disease. A solution to population-scale testing for lung cancer will require a combination of performance, scalability, cost-effectiveness, and simplicity. METHODS: One solution is to measure the activity of serum available enzymes that contribute to the transformation process rather than counting biomarkers. Protease enzymes modify the environment during tumor growth and present an attractive target for detection. An activity based sensor platform sensitive to active protease enzymes is presented. A panel of 18 sensors was used to measure 750 sera samples from participants at increased risk for lung cancer with or without the disease. RESULTS: A machine learning approach is applied to generate algorithms that detect 90% of cancer patients overall with a specificity of 82% including 90% sensitivity in Stage I when disease intervention is most effective and detection more challenging. CONCLUSION: This approach is promising as a scalable, clinically useful platform to help detect patients who have lung cancer using a simple blood sample. The performance and cost profile is being pursued in studies as a platform for population wide screening.

Lung cancer is responsible for more deaths worldwide than all other cancers. It is often detected with the appearance of symptoms when treatment is limited and outcomes for the patient are much worse. While imaging chest scans can detect disease, they are poorly used even in the United States where it is an approved screening method. When cancer is present, protease enzymes are responsible for making space and modifying the lung tissue for the growing tumor. This report describes a panel of 18 sensors that release a fluorescent signal when these enzymes are present in a blood sample. The signal acts like a fingerprint of activity that can be used to identify people with lung cancer. This sensor platform can detect patients with curable lung cancer and could provide a platform for screening very large populations of at-risk individuals.

Exploring the Evolving Scope of Neoadjuvant Immunotherapy in NSCLC.

While lung cancer remains the leading cause of cancer death worldwide, lung cancer mortality has notably decreased in the past decade. Immunotherapy with immune checkpoint inhibitors have played a noteworthy role in contributing to this improved survival, particularly for patients with non-small cell lung cancer (NSCLC). However, until now the benefits have primarily been seen in patients with advanced or metastatic disease. Several recent early phase and ongoing phase III trials have been assessing whether the treatment benefit of immunotherapy in NSCLC can extend to the neoadjuvant setting for resectable diseases. In this comprehensive narrative review, we evaluate the most recent efficacy and safety data from these studies. We also outline questions that will need to be further examined to legitimate neoadjuvant immunotherapy's role in NSCLC treatment, including the best surrogate marker of response, the incorporation of liquid biopsy for disease monitoring, the ability to be combined with other treatment modalities, the need for further adjuvant therapy, and potential future treatment combinations.

Consensus for Thoracoscopic Left Upper Lobectomy-Essential Components and Targets for Simulation.

BACKGROUND: Simulation-based training is a valuable component of cardiothoracic surgical education. Effective curriculum development requires consensus on procedural components and focused attention on specific learning objectives. Through use of a Delphi process, we established consensus on the steps of video-assisted thoracoscopic surgery (VATS) left upper lobectomy and identified targets for simulation. METHODS: Experienced thoracic surgeons were randomly selected for participation. Surgeons voted and commented on the necessity of individual steps comprising VATS left upper lobectomy. Steps with greater than 80% of participants in agreement of their necessity were determined to have established "consensus." Participants voted on the physical or cognitive complexity of each, or both, and chose steps most amenable to focused simulation. RESULTS: Thirty thoracic surgeons responded and joined in the voting process. Twenty operative steps were identified, with surgeons reaching consensus on the necessity of 19. Components deemed most difficult and amenable to simulation included those related to dissection and division of the bronchus, artery, and vein. CONCLUSIONS: Through a Delphi process, surgeons with a variety of practice patterns can achieve consensus on the operative steps of left upper lobectomy and agreement on those most appropriate for simulation. This information can be implemented in the development of targeted simulation for VATS lobectomy.

Solitary Fibrous Tumors of Chest: Another Look with the Oncologic Perspective.

Solitary fibrous tumors are mesenchymal lesions that arise at a variety of sites, most commonly the pleura. Most patients are asymptomatic at diagnosis, with lesions being detected incidentally. Nevertheless, some patients present due to symptoms from local tumor compression (eg. of the airways and pulmonary parenchyma). Furthermore, radiological methods are not always conclusive in making a diagnosis, and thus, pathological analysis is often required. In the past three decades, immunohistochemical techniques have provided a gold standard in solitary fibrous tumor diagnosis. The signature marker of solitary fibrous tumor is the presence of the NAB2-STAT6 fusion that can be reliably detected with a STAT6 antibody. While solitary fibrous tumors are most often benign, they can be malignant in 10-20% of the cases. Unfortunately, histological parameters are not always predictive of benign vs malignant solitary fibrous tumors. As solitary fibrous tumors are generally regarded as relatively chemoresistant tumors; treatment is often limited to localized treatment modalities. The optimal treatment of solitary fibrous tumors appears to be complete surgical resection for both primary and local recurrent disease. However, in cases of suboptimal resection, large disease burden, or advanced recurrence, a multidisciplinary approach may be preferable. Specifically, radiotherapy for inoperable local disease can provide palliation/shrinkage. Given their sometimes -unpredictable and often- protracted clinical course, long-term follow-up post-resection is recommended.

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.

Management of stage IIIA non-small cell lung cancer by thoracic surgeons in North America.

BACKGROUND: Stage IIIA(N2) non-small cell lung cancer is a heterogeneous spectrum ranging from microscopic lymph node metastases to bulky multistation nodal disease. While some favor surgical resection after neoadjuvant therapy, others favor definitive chemoradiation for treatment. Our aim was to determine practice patterns of thoracic surgeons. METHODS: We invited 2,539 active surgeons identified on the Cardiothoracic Surgery Network as expressing interest in general thoracic surgery to participate in an anonymous Web-based survey. The participants evaluated clinical vignettes of a patient with single station N2 disease. RESULTS: In all, 513 surgeons (20%) responded, with 222 (43%) in academic practice. For microscopic N2 disease, 84% (n=430) preferred neoadjuvant therapy followed by surgery. For grossly involved N2 disease, 62% (n=318) favored neoadjuvant therapy followed by surgery if N2 disease was downstaged. In patients with normal pulmonary function tests, requiring pneumonectomy, in the presence of bulky, single station N2 disease, there was less consensus: 32% (n=163) favored neoadjuvant therapy followed by lobectomy (less radical surgery than initially predicted) if feasible and N2 disease had downstaged, 30% (n=159) favored neoadjuvant therapy followed by pneumonectomy if N2 disease downstaged, 12% (n=60) would favor surgery regardless of N2 disease downstaging, and 22% (n=114) favored definitive chemoradiation. If the patient did not have adequate pulmonary function for pneumonectomy but could tolerate lobectomy, 50% favored neoadjuvant therapy followed by reassessment for lobectomy and 41% favored definitive chemoradiation. CONCLUSIONS: There is no clear consensus on management of patients with stage IIIA lung cancer in the United States. Diversity of opinion is greatest in patients with more advanced lung cancer, and limited pulmonary function.

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.

Non-small cell lung cancer: prognostic importance of positive FDG PET findings in the mediastinum for patients with N0-N1 disease at pathologic analysis.

PURPOSE: To assess the prognostic implications of mediastinal positron emission tomographic (PET) findings in patients undergoing curative resection of non-small cell lung cancer (NSCLC) who have histologically negative mediastinal lymph nodes (LNs), with the hypothesis that positive findings at PET are prognostic even in patients with negative histologic findings in the LNs. MATERIALS AND METHODS: Records of patients with a preoperative PET undergoing curative surgery, without adjuvant radiation, for pathologic T1-3N0-1 NSCLC at the University of North Carolina between 2000 and 2006 were reviewed as an institutional review board-approved HIPAA-compliant retrospective study. Ninety patients were evaluable (all histologically negative in mediastinum; 44 with both mediastinoscopy and surgery); 13 patients had positive mediastinal PET findings, and 77 had negative mediastinal PET findings. Local-regional and distant failure rates in patients with and those without mediastinal abnormalities at preoperative PET were compared by using logistic regression and log-rank tests. RESULTS: Median follow-up was 54.3 months (range, 1-99 months). There were higher rates of local-regional (P = .001) and distant (P < .001) failure as well as death (P = .001) in patients with postive PET findings than in patients with negative findings. In multivariable analysis (adjusting for other prognostic factors), positive PET findings in the mediastinum remained prognostic for distant failure (P < .001, hazard ratio = 6.9) and were marginally prognostic for local-regional failure (P = .093, hazard ratio = 1.9). CONCLUSION: Positive findings at preoperative PET in the mediastinum appear to have prognostic implications despite the mediastinal LNs being histologically negative. The high rate of local-regional and distant failure suggests that postoperative radiation therapy and/or chemotherapy may be particularly helpful in patients with positive mediastinal findings at preoperative PET.

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.

Local failure after complete resection of N0-1 non-small cell lung cancer.

PURPOSE: To estimate the risk of local-regional failure (LRF) after surgery for operable NSCLC, and the effect of clinical/pathologic factors on this risk. METHODS: Records of 335 patients undergoing complete resection (lobectomy, pneumonectomy) for pathological T1-4 N0-1 NSCLC (without post-operative radiation) from 1996 to 2006 were reviewed. Crude and actuarial estimated failure rates were computed; local-regional sites included ipsilateral lung, surgical stump, hilar, mediastinal, or supraclavicular nodes. Failure times in sub-groups were calculated with the Kaplan-Meier method and compared via log-rank test. Independent factors adversely affecting LRF were determined with Cox regression. RESULTS: The median follow-up duration for event-free surviving patients was 40 months (range: 1-150). The crude and actuarial 5-year probability of any failure (LR or distant) were 33% and 43%, respectively. Of all failures; 37% were LR only, 35% LR and distant and 28% distant only. The 5-year crude and actuarial probability of LRF were 24% and 35% (95% CI: 29-42%). Five-year crude LRF rates for T1-2N0, T1-2N1, T3-4N0 and T3-4N1 disease were 19% (41/216), 27% (16/59), 37.5% (15/40) and 40% (8/20), respectively. The corresponding actuarial estimates were T1-2N0 28%, T1-2N1 39%, T3-4N0 50% and T3-4N1 67%. In Cox multiple regression analysis, lymphovascular space invasion (p=0.03, HR: 1.7) and tumor size (p=0.01, HR: 1.67 for 5 cm increment) were associated with an increased risk of LRF. CONCLUSION: Five-year LRF rates are ≥19% in essentially all patient subsets.

Simulation experience enhances medical students' interest in cardiothoracic surgery.

BACKGROUND: Applications to cardiothoracic training programs have declined dramatically. Increased effort in recruiting trainees is paramount. In this study, we test our hypothesis that mentored instruction on cardiothoracic simulators will enhance the interest of junior medical students in cardiothoracic surgery. METHODS: First- and second-year medical students were recruited from a "surgery interest group" to receive mentored instruction on high-fidelity cardiothoracic simulators. Before and after simulation assessment tools were used to assess attitudes toward simulation, general surgery, and cardiothoracic surgery. RESULTS: Forty-four medical students participated in the study. Although 80% of the students were interested in pursuing a career in surgery before the course, the majority (64%) indicated they were "neutral" about pursuing a career in cardiothoracic surgery. After participating in the course, 61% of the students agreed or strongly agreed that they were interested in pursuing a career in cardiothoracic surgery (p = 0.001). When asked to select a surgical subspecialty for their third-year clerkship rotation, 18% of the students selected thoracic surgery before participating in the simulator course versus 39% after completing the course. This increase was most evident among the female participants, of whom only 3 (12%) selected a thoracic rotation before the simulator course versus 9 (35%) after completion of the course (p < 0.05). CONCLUSIONS: High-fidelity surgical simulators are an effective way to introduce medical students to cardiothoracic surgery. Participation in moderated simulator sessions improves attitudes toward cardiothoracic surgery as a career choice and correlates with a greater interest in selecting thoracic surgery as a third-year clerkship rotation. The role of surgical simulation as a recruitment tool should be further delineated.