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Spread through air spaces (STAS) is reportedly associated with worse prognosis in sublobar resections of lung adenocarcinoma. Recently, it was proposed that STAS detected on frozen sections can be an indication for lobectomy instead of sublobar resection. We undertook this study to evaluate the reliability of STAS assessment on frozen sections compared to permanent sections, as well as the associations among STAS, tumor grade, and recurrence-free survival (RFS) after sublobar resection. A total of 163 stage I lung adenocarcinoma resections with frozen sections were identified retrospectively. For each case, and for frozen and permanent sections separately, the presence or absence of STAS, as well as the tumor grade, were recorded. Compared to permanent sections, STAS detection on frozen sections had low sensitivity (55%), low positive predictive value (48%), and fair agreement (K = 0.34), whereas there was higher specificity (80%) and negative predictive value (85%). Accuracy was 74%. Tumor grade assessment on frozen sections showed higher sensitivity (77%), positive predictive value (90%), agreement (K = 0.72), specificity (94%), and accuracy (87%), and the same negative predictive value (85%). High-grade histology on frozen sections was associated with shorter RFS (p = 0.02), whereas STAS on frozen sections was not (p = 0.47). Our results suggest that the intraoperative detection of STAS has low sensitivity and positive predictive value. False-positive results may lead to overtreatment of patients with lung cancer. The determination of tumor grade on frozen sections offers better sensitivity and specificity, plus it is associated with RFS, whereas STAS on frozen sections is not. Further study is needed to explore the utility of assessing tumor grade on frozen sections.

Multimodality treatment for resectable non-small cell lung cancer has long remained at a therapeutic plateau. Immune checkpoint inhibitors are highly effective in advanced non-small cell lung cancer and promising preoperatively in small clinical trials for resectable non-small cell lung cancer. This large multicenter trial tested the safety and efficacy of neoadjuvant atezolizumab and surgery.Patients with stage IB to select IIIB resectable non-small cell lung cancer and Eastern Cooperative Oncology Group performance status 0/1 were eligible. Patients received atezolizumab 1200 mg intravenously every 3 weeks for 2 cycles or less followed by resection. The primary end point was major pathological response in patients without EGFR/ALK+ alterations. Pre- and post-treatment computed tomography, positron emission tomography, pulmonary function tests, and biospecimens were obtained. Adverse events were recorded by Common Terminology Criteria for Adverse Events v.4.0.From April 2017 to February 2020, 181 patients were entered in the study. Baseline characteristics were mean age, 65.1 years; female, 93 of 181 (51%); nonsquamous histology, 112 of 181 (62%); and clinical stages IIB to IIIB, 147 of 181 (81%). In patients without EGFR/ALK alterations who underwent surgery, the major pathological response rate was 20% (29/143; 95% confidence interval, 14-28) and the pathological complete response rate was 6% (8/143; 95% confidence interval, 2-11). There were no grade 4/5 treatment-related adverse events preoperatively. Of 159 patients (87.8%) undergoing surgery, 145 (91%) had pathologic complete resection. There were 5 (3%) intraoperative complications, no intraoperative deaths, and 2 postoperative deaths within 90 days, 1 treatment related. Median disease-free and overall survival have not been reached.Neoadjuvant atezolizumab in resectable stage IB to IIIB non-small cell lung cancer was well tolerated, yielded a 20% major pathological response rate, and allowed safe, complete surgical resection. These results strongly support the further development of immune checkpoint inhibitors as preoperative therapy in locally advanced non-small cell lung cancer.

Malignant pleural mesothelioma (MPM) is an asbestos-related neoplasm that can only be treated successfully when correctly diagnosed and treated early. The asbestos-exposed population is a high-risk group that could benefit from sensitive and specific blood- or tissue-based biomarkers. We review recent work with biomarker development in MPM and literature of the last 20 years on the most promising blood- and tissue-based biomarkers. Proteomic, genomic, and epigenomic platforms are covered. SMRP is the only validated blood-based biomarker with diagnostic, monitoring and prognostic value. To strengthen development and testing of MPM biomarkers, cohorts for validation must be established by enlisting worldwide collaborations.

Objectives To evaluate whether combining stability and discriminability criteria in building radiomic classifiers will improve the prognosis of cancer recurrence in early stage non-small cell lung cancer on non-contrast computer tomography (CT). Materials and Methods CT scans of 610 patients with early stage (IA, IB, IIA) NSCLC from four independent cohorts were evaluated. A total of 350 patients from Cleveland Clinic Foundation and University of Pennsylvania were divided into two equal sets for training (D1) and validation set (D2). 80 patients from The Cancer Genome Atlas Lung Adenocarcinoma and Squamous Cell Carcinoma and 195 patients from The Cancer Imaging Archive, were used as independent second (D3) and third (D4) validation sets. A linear discriminant analysis (LDA) classifier was built based on the most stable and discriminate features. In addition, a radiomic risk score (RRS) was generated by using least absolute shrinkage and selection operator, Cox regression model to predict time to progression (TTP) following surgery. Results A feature selection strategy focusing on both feature discriminability and stability resulted in the classifier having a higher discriminability on validation datasets compared to the discriminability alone criteria in discriminating cancer recurrence (D2, AUC of 0.75 vs. 0.65; D3, 0.74 vs. 0.62; D4, 0.76 vs. 0.63). The RRS generated by most stable-discriminating features was significantly associated with TTP compared to discriminating alone criteria (HR = 1.66, C-index of 0.72 vs. HR = 1.04, C-index of 0.62). Conclusion Accounting for both stability and discriminability yielded a more generalizable classifier for predicting cancer recurrence and TTP in early stage NSCLC.

This article is a joint effort arising from a task force formed at a National Cancer Institute-International Association for the Study of Lung Cancer-Mesothelioma Applied Research Foundation Mesothelioma Clinical Trials Planning Meeting, held at the NIH in March 2017. Malignant pleural mesothelioma remains one of the most virulent and recalcitrant malignancies, still considered incurable, and in desperate need of clinical trials in order to make progress for our patients. Although not standard of care, there is compelling evidence that a select subgroup of mesothelioma patients benefit from a surgery-based multimodal approach. As it is not possible to achieve a microscopically complete resection with mesothelioma, there appears to be no role for surgery alone. Thus, it is anticipated that significant strides in the surgery-based treatment of this cancer will require trials that determine which complementary treatments best augment the cytoreductive efficacy of surgery. Although lung-sacrificing surgery for mesothelioma is fairly standardized, approaches to lung-sparing surgery are highly variable and lung sparing surgery is emerging internationally as the dominant extirpative procedure for this cancer. It is not currently possible to rigorously assess the contribution of the adjuvant treatments combined with surgery because of the variability in procedures used to debulk this cancer, the extreme variability of the cancer itself, the variability in patient selection, the variability in treatment of the inevitable recurrence, and even the variability in follow up schedules. This article is an effort to address these problems by suggesting a more uniform approach to the surgical procedure and also proposing a series of data collection forms that could be adopted immediately, with any eye toward collecting the information that will be necessary to facilitate patient selection and determine which aspects of mesothelioma surgery can and should be standardized - with the goal being extension of life while maintaining quality of life as an equal priority. Furthermore, a completely original contribution in this manuscript is the proposal of a grading system that takes the information from the surgical procedure data forms and generates a completeness of resection score. This is the initial effort to establish a common denominator for mesothelioma surgery that will allow for more accurate comparison between surgical series and better assessment of the impact of the treatments combined with surgery.

Introduction Detailed guidelines regarding the use of radiation therapy for malignant pleural mesothelioma (MPM) are currently lacking because of the rarity of the disease, the wide spectrum of clinical presentations, and the paucity of high-level data on individual treatment approaches. Methods In March 2017, a multidisciplinary meeting of mesothelioma experts was cosponsored by the U.S. National Cancer Institute, International Association for the Study of Lung Cancer Research, and Mesothelioma Applied Research Foundation. Among the outcomes of this conference was the foundation of detailed, multidisciplinary consensus guidelines. Results Here we present consensus recommendations on the use of radiation therapy for MPM in three discrete scenarios: (1) hemithoracic radiation therapy to be used before or after extrapleural pneumonectomy; (2) hemithoracic radiation to be used as an adjuvant to lung-sparing procedures (i.e., without pneumonectomy); and (3) palliative radiation therapy for focal symptoms caused by the disease. We discuss appropriate simulation techniques, treatment volumes, dose fractionation regimens, and normal tissue constraints. We also assess the role of particle beam therapy, specifically, proton beam therapy, for MPM. Conclusion The recommendations provided in this consensus statement should serve as important guidelines for developing future clinical trials of treatment approaches for MPM.

Background Lung nodules are a diagnostic challenge, with an estimated yearly incidence of 1.6 million in the United States. This study evaluated the accuracy of an integrated proteomic classifier in identifying benign nodules in patients with a pretest probability of cancer (pCA) ≤ 50%. Methods A prospective, multicenter observational trial of 685 patients with 8- to 30-mm lung nodules was conducted. Multiple reaction monitoring mass spectrometry was used to measure the relative abundance of two plasma proteins, LG3BP and C163A. Results were integrated with a clinical risk prediction model to identify likely benign nodules. Sensitivity, specificity, and negative predictive value were calculated. Estimates of potential changes in invasive testing had the integrated classifier results been available and acted on were made. Results A subgroup of 178 patients with a clinician-assessed pCA ≤ 50% had a 16% prevalence of lung cancer. The integrated classifier demonstrated a sensitivity of 97% (CI, 82-100), a specificity of 44% (CI, 36-52), and a negative predictive value of 98% (CI, 92-100) in distinguishing benign from malignant nodules. The classifier performed better than PET, validated lung nodule risk models, and physician cancer probability estimates (P

Summary Background The prevalence of malignant pleural effusion is increasing worldwide, but prognostic biomarkers to plan treatment and to understand the underlying mechanisms of disease progression remain unidentified. The PROMISE study was designed with the objectives to discover, validate, and prospectively assess biomarkers of survival and pleurodesis response in malignant pleural effusion and build a score that predicts survival. Methods In this multicohort study, we used five separate and independent datasets from randomised controlled trials to investigate potential biomarkers of survival and pleurodesis. Mass spectrometry-based discovery was used to investigate pleural fluid samples for differential protein expression in patients from the discovery group with different survival and pleurodesis outcomes. Clinical, radiological, and biological variables were entered into least absolute shrinkage and selection operator regression to build a model that predicts 3-month mortality. We evaluated the model using internal and external validation. Findings 17 biomarker candidates of survival and seven of pleurodesis were identified in the discovery dataset. Three independent datasets (n=502) were used for biomarker validation. All pleurodesis biomarkers failed, and gelsolin, macrophage migration inhibitory factor, versican, and tissue inhibitor of metalloproteinases 1 (TIMP1) emerged as accurate predictors of survival. Eight variables (haemoglobin, C-reactive protein, white blood cell count, Eastern Cooperative Oncology Group performance status, cancer type, pleural fluid TIMP1 concentrations, and previous chemotherapy or radiotherapy) were validated and used to develop a survival score. Internal validation with bootstrap resampling and external validation with 162 patients from two independent datasets showed good discrimination (C statistic values of 0·78 [95% CI 0·72–0·83] for internal validation and 0·89 [0·84–0·93] for external validation of the clinical PROMISE score). Interpretation To our knowledge, the PROMISE score is the first prospectively validated prognostic model for malignant pleural effusion that combines biological and clinical parameters to accurately estimate 3-month mortality. It is a robust, clinically relevant prognostic score that can be applied immediately, provide important information on patient prognosis, and guide the selection of appropriate management strategies. Funding European Respiratory Society, Medical Research Funding-University of Oxford, Slater & Gordon Research Fund, and Oxfordshire Health Services Research Committee Research Grants.

Rationale and Objectives This study aimed to differentiate pathologically defined lepidic predominant lesions (LPL) from more invasive adenocarcinomas (INV) using three-dimensional (3D) volumetric density and first-order texture histogram analysis of surgically excised stage 1 lung adenocarcinomas. Materials and Methods This retrospective study was institutional review board approved and Health Insurance Portability and Accountability Act compliant. Sixty-four cases of pathologically proven stage 1 lung adenocarcinoma surgically resected between September 2006 and October 2015, including LPL (n = 43) and INV (n = 21), were evaluated using high-resolution computed tomography. Quantitative measurements included nodule volume, percent solid volume (% solid), and first-order texture histogram analysis including skewness, kurtosis, entropy, and mean nodule attenuation within each histogram quartile. Binomial logistic regression models were used to identify the best set of parameters distinguishing LPL from INV. Results Univariate analysis of 3D volumetric density and histogram features was statistically significant between LPL and INV groups (P Conclusions Both 3D volumetric density and first-order texture analysis of stage 1 lung adenocarcinoma allow differentiation of LPL from more invasive adenocarcinoma with overall accuracy of 85.9%–81.3%, based on multivariate analyses of either size and % solid or size and Hu_Q3, respectively.

Background: While patient-derived xenografts (PDXs) offer a powerful modality for translational cancer research, a precise evaluation of how accurately patient responses correlate with matching PDXs in a large, heterogeneous population is needed for assessing the utility of this platform for preclinical drug-testing and personalized patient cancer treatment. Patients and methods: Tumors obtained from surgical or biopsy procedures from 237 cancer patients with a variety of solid tumors were implanted into immunodeficient mice and whole-exome sequencing was carried out. For 92 patients, responses to anticancer therapies were compared with that of their corresponding PDX models. Results: We compared whole-exome sequencing of 237 PDX models with equivalent information in The Cancer Genome Atlas database, demonstrating that tumorgrafts faithfully conserve genetic patterns of the primary tumors. We next screened PDXs established for 92 patients with various solid cancers against the same 129 treatments that were administered clinically and correlated patient outcomes with the responses in corresponding models. Our analysis demonstrates that PDXs accurately replicate patients' clinical outcomes, even as patients undergo several additional cycles of therapy over time, indicating the capacity of these models to correctly guide an oncologist to treatments that are most likely to be of clinical benefit. Conclusions: Integration of PDX models as a preclinical platform for assessment of drug efficacy may allow a higher success-rate in critical end points of clinical benefit.

Background Standard imaging modalities are inaccurate in staging malignant pleural mesothelioma (MPM). Single-institution studies suggest that volumetric computed tomography (CT) is more accurate but labor intensive. We established a multicenter network to test interobserver variability, accuracy (relative to pathologic stage), and the prognostic significance of semiautomated volumetric CT. Methods Six institutions electronically submitted to an established multicenter database clinical and pathologic data for patients with MPM who had operations. Institutional radiologists reviewed preoperative CT scans for quality and then submitted by electronic network (AG Mednet, www.agmednet.com) to the biostatistical center. Two reference radiologists blinded to clinical data performed semiautomated tumor volume calculations using Vitrea Enterprise 6.0 software (Vital Images, Minnetonka, MN) and then submitted readings to the biostatistical center. Study end points included feasibility of the network, interobserver variability for volumetric CT, correlation of tumor volume to pTN stages, and overall survival (OS). Results Of 164 patients, the CT scans for 129 were analyzable and read by reference radiologists. Most tumors were less than 500 cm 3 . A small bias was observed between readers because one provided consistently larger measurements than the other (mean difference, 47.9; p = .0027), but for 80%, the absolute difference was 200 cm 3 or less. Spearman correlation between readers was 0.822. Volume correlated with pTN stages and OS, best defined by three groups with average volumes of 91.2, 245.3, and 511.3 cm 3 associated with median OS of 37, 18, and 8 months, respectively. Conclusions For the first time, a multicenter network was established and initial correlations of tumor volume with pTN stages and OS are shown. A larger multicenter international study is planned to confirm the results and refine correlations.

Objectives Autoantibodies against tumor-associated antigens (TAAs) identified in patients with advanced lung cancer may be detected in subjects with early lung cancer or even predate the diagnosis. The purpose of this study is to address the temporal relationship between lung cancer development and serum autoantibody response. Materials and methods Two cohorts of patients with newly diagnosed lung cancer were included. The first cohort included 90 sera from patients with lung cancer (Stages I–III) and 89 normal control sera. In the second cohort, 93 serial serum samples from 25 patients with CT-scan screen-detected stage I lung cancer were collected before the diagnosis of lung cancer (average 32 months) and 56 controls were matched on age, gender, and smoking. Autoantibody levels were measured by immunoassay. Results Measurement of autoantibodies against seven TAAs (14-3-3ζ, c-Myc, MDM2, NPM1, p16, p53 and cyclin B1) individually could discriminate lung cancer patients from normal individuals in the first cohort and the area under curve (AUC) was 0.863 based on a panel of seven autoantibodies, with sensitivity of 68.9% and specificity of 79.5%. Autoantibodies in serial pre-diagnostic serum samples against the same panel of seven TAAs were detected prior to lung cancer diagnosis with sensitivity of 76.0% and specificity of 73.2% (AUC) (95%CI): 0.885 (0.797–0.973)). Elevated autoantibody levels could be detected greater than four years prior to lung cancer diagnosis. Conclusion A panel of seven TAAs may enhance the early detection of lung cancer, consistent with a humoral immune response to TAAs that can be detected months to years prior to the diagnosis.

On November 9 and 10, 2015, the International Conference on Mesothelioma in Populations Exposed to Naturally Occurring Asbestiform Fibers was held at the University of Hawaii Cancer Center in Honolulu, Hawaii. The meeting was cosponsored by the International Association for the Study of Lung Cancer, and the agenda was designed with significant input from staff at the U.S. National Cancer Institute and National Institute of Environmental Health Sciences. A multidisciplinary group of participants presented updates reflecting a range of disciplinary perspectives, including mineralogy, geology, epidemiology, toxicology, biochemistry, molecular biology, genetics, public health, and clinical oncology. The group identified knowledge gaps that are barriers to preventing and treating malignant mesothelioma (MM) and the required next steps to address barriers. This manuscript reports the group's efforts and focus on strategies to limit risk to the population and reduce the incidence of MM. Four main topics were explored: genetic risk, environmental exposure, biomarkers, and clinical interventions. Genetics plays a critical role in MM when the disease occurs in carriers of germline BRCA1 associated protein 1 mutations. Moreover, it appears likely that, in addition to BRCA1 associated protein 1, other yet unknown genetic variants may also influence the individual risk for development of MM, especially after exposure to asbestos and related mineral fibers. MM is an almost entirely preventable malignancy as it is most often caused by exposure to commercial asbestos or mineral fibers with asbestos-like health effects, such as erionite. In the past in North America and in Europe, the most prominent source of exposure was related to occupation. Present regulations have reduced occupational exposure in these countries; however, some people continue to be exposed to previously installed asbestos in older construction and other settings. Moreover, an increasing number of people are being exposed in rural areas that contain noncommercial asbestos, erionite, and other mineral fibers in soil or rock (termed naturally occurring asbestos [NOA]) and are being developed. Public health authorities, scientists, residents, and other affected groups must work together in the areas where exposure to asbestos, including NOA, has been documented in the environment to mitigate or reduce this exposure. Although a blood biomarker validated to be effective for use in screening and identifying MM at an early stage in asbestos/NOA-exposed populations is not currently available, novel biomarkers presented at the meeting, such as high mobility group box 1 and fibulin-3, are promising. There was general agreement that current treatment for MM, which is based on surgery and standard chemotherapy, has a modest effect on the overall survival (OS), which remains dismal. Additionally, although much needed novel therapeutic approaches for MM are being developed and explored in clinical trials, there is a critical need to invest in prevention research, in which there is a great opportunity to reduce the incidence and mortality from MM. © 2016 International Association for the Study of Lung Cancer. Published by Elsevier Inc.

Objectives Prognostic models for malignant pleural mesothelioma (MPM) are needed to prevent potentially futile outcomes. We combined MPM plasma biomarkers with validated clinical prognostic indices to determine whether stratification of risk for death in 194 patients with MPM improved. Methods Individuals were recruited from three different centers: a discovery cohort (83 patients with MPM) created by combining patients from two U.S. centers and a separate, independent cohort from Canada (111 patients with MPM). Univariable and multivariable analyses were performed on the initial discovery and independent cohorts separately. In the multivariable analyses, prognostic factors were adjusted for the European Organisation for Research and Treatment of Cancer (EORTC) prognostic index (PI) of mesothelioma. The prognostic significance of adding plasma biomarker data to the PI was determined by using the likelihood ratio test, comparing models with and without the addition of biomarker to the clinical PI. The predictive ability of the biomarker was then assessed formally using Harrell’s C-index by applying the fitted model variables of the discovery cohort to the second, independent cohort, including and not including the biomarker with the PI. Results Higher levels of osteopontin and mesothelin were individually associated with worse prognosis after adjusting for the PI. In the independent cohort, incorporating either plasma osteopontin or mesothelin into the baseline predictive PI model substantively and statistically significantly improved Harrell’s C-statistic. In the final prognostic model, log-osteopontin, EORTC clinical prognostic index, and hemoglobin remained as independently significant predictors and the entire prognostic model improved the optimism-corrected Harrell’s C-index significantly, from 0.718 (0.67–0.77) to 0.801 (0.77–0.84). Conclusions These data suggest a possible role for preoperative plasma biomarkers to improve the prognostic capability of the EORTC PI of MPM.

Introduction The reduction in lung cancer mortality associated with computed tomography (CT) screening has led to its increased use and a concomitant increase in the detection of benign pulmonary nodules. Many individuals found to have benign nodules undergo unnecessary, costly, and invasive procedures. Therefore, there is a need for companion diagnostics that stratify individuals with pulmonary nodules into high-risk or low-risk groups. Lung cancers can trigger host immune responses and elicit antibodies against tumor antigens. The identification of these autoantibodies (AAbs) and their corresponding antigens may expand our knowledge of cancer immunity, leading to early diagnosis or even benefiting immunotherapy. Previous studies were performed mostly in the context of comparing cancers and healthy (smoker) controls. We have performed one of the first studies to understand humoral immune response in patients with cancer, patients with benign nodules, and healthy smokers. Methods We first profiled seroreactivity to 10,000 full-length human proteins in 40 patients with early-stage lung cancer and 40 smoker controls by using nucleic acid programmable protein arrays to identify candidate cancer-specific AAbs. Enzyme-linked immunosorbent assays of promising candidates were performed on 137 patients with lung cancer and 127 smoker controls, as well as on 170 subjects with benign pulmonary nodules. Results From protein microarray screening experiments using a discovery set of 40 patients and 40 smoker controls, 17 antigens showing higher reactivity in lung cancer cases relative to the controls were subsequently selected for evaluation in a large sample set (n = 264) by using enzyme-linked immunosorbent assay. A five-AAb classifier (tetratricopeptide repeat domain 14 [TTC14], B-Raf proto-oncogene, serine/threonine kinase [BRAF], actin like 6B [ACTL6B], MORC family CW-type zinc finger 2 [MORC2], and cancer/testis antigen 1B [CTAG1B]) that can differentiate lung cancers from smoker controls with a sensitivity of 30% at 89% specificity was developed. We further tested AAb responses in subjects with CT-positive benign nodules (n = 170), and developed a five-AAb panel (keratin 8, type II, TTC14, Kruppel-like factor 8, BRAF, and tousled like kinase 1) with a sensitivity of 30% at 88% specificity. Interestingly, messenger RNA levels of six AAb targets (TTC14, BRAF, MORC family CW-type zinc finger 2, cancer/testis antigen 1B, keratin 8, type II, and tousled like kinase 1) were also found to increase in lung adenocarcinoma tissues based on The Cancer Genome Atlas data set. Conclusion We discovered AAbs associated with lung adenocaricnoma that have the potential to differentiate cancer from CT-positive benign diseases. We believe that these antibodies warrant future validation using a larger sample set and/or longitudinal samples individually or as a panel. They could potentially be part of companion molecular diagnostic modalities that will benefit subjects undergoing CT screening for lung cancer.

Introduction Surgery is the treatment of choice for early-stage lung cancer (LC). Although lobectomy (L) is the historic standard treatment, the issue of whether long-term outcomes of sublobar resection (SL) are comparable is still under debate. The objective of this study was to perform a review of the literature on 5-year survival rates after SL compared to L for patients with early-stage LC. Methods A priori inclusion criteria were as follows: (1) observational studies, (2) L compared to SL for early-stage LC, (3) radiographic staging by computed tomography scan, and (4) 5-year survival reported. A Medline search through January 2015 resulted in 31 studies representing 23 distinct datasets. The absolute difference in 5-year survival was calculated and plotted for each study. Results L was performed in 4564 patients and SL in 2287 patients. Of 19 studies reporting the reason for SL, 11 indicated that SL was performed because of comorbidities or impaired cardiopulmonary function. Four studies showed no difference in 5-year survival, 13 favored L, and six favored SL. One propensity score study favored L and the other favored SL. Of 20 studies reporting recurrence rate, 11 favored L and nine favored SL. Conclusions Studies comparing 5-year survival rates of SL to L are sufficiently heterogeneous to prevent carrying out traditional meta-analysis. SL survival is often similar to L when adjustments are made for age, comorbidities, or impaired cardiopulmonary function. New approaches are needed for the comparison of L to SL.

Isolated lung perfusion (ILP) is a surgical technique developed to treat pulmonary metastases. During ILP, high-dose chemotherapy is delivered into the pulmonary vasculature, minimizing systemic exposure and delivering the chemotherapeutic agent directly to the lung. ILP has been studied extensively in a variety of animal models and in humans in phase I trials. The most frequently studied chemotherapeutic agents used in ILP are doxorubicin, 5-flurodeoxyuridine, tumor necrosis factor-α, paclitaxel, melphalan, gemcitabine, and cisplatin. Phase I clinical trials with ILP have shown that ILP can be safely performed in humans but with mixed clinical results and poor long-term survival.

DR. PASS: The topic for this roundtable discussions for Seminars in Thoracic and Cardiovascular Surgery is going to be surgery for mesothelioma. Our participants are Joe Friedberg, University of Maryland; Andrea Wolf, Icahn School of Medicine at Mount Sinai; David Rice, MD Anderson Cancer Center; and Wickii Vigneswaran, Loyola University Health System. All 4 of these surgeons were trained and are presently at high volume mesothelioma centers. Drs. Wolf and Friedberg were trained by Dr. Sugarbaker. Dr. Vigneswaran was trained at Mayo, and performed a large volume of surgical cases at the University of Chicago where he has a lot of cases that are both surgical as well as medical. Dr. Rice practices at MD Anderson and was one of the innovators of postoperative intensity-modulated radiotherapy (IMRT).

Introduction Indeterminate pulmonary nodules (IPNs) lack clinical or radiographic features of benign etiologies and often undergo invasive procedures unnecessarily, suggesting potential roles for diagnostic adjuncts using molecular biomarkers. The primary objective was to validate a multivariate classifier that identifies likely benign lung nodules by assaying plasma protein expression levels, yielding a range of probability estimates based on high negative predictive values (NPVs) for patients with 8 to 30 mm IPNs. Methods A retrospective, multicenter, case-control study was performed using multiple reaction monitoring mass spectrometry, a classifier comprising five diagnostic and six normalization proteins, and blinded analysis of an independent validation set of plasma samples. Results The classifier achieved validation on 141 lung nodule-associated plasma samples based on predefined statistical goals to optimize sensitivity. Using a population based nonsmall-cell lung cancer prevalence estimate of 23% for 8 to 30 mm IPNs, the classifier identified likely benign lung nodules with 90% negative predictive value and 26% positive predictive value, as shown in our prior work, at 92% sensitivity and 20% specificity, with the lower bound of the classifier's performance at 70% sensitivity and 48% specificity. Classifier scores for the overall cohort were statistically independent of patient age, tobacco use, nodule size, and chronic obstructive pulmonary disease diagnosis. The classifier also demonstrated incremental diagnostic performance in combination with a four-parameter clinical model. Conclusions This proteomic classifier provides a range of probability estimates for the likelihood of a benign etiology that may serve as a noninvasive, diagnostic adjunct for clinical assessments of patients with IPNs.

Background Breast cancer 1-associated protein 1 (BAP1) is a nuclear deubiquitinase that regulates gene expression, transcription, DNA repair, and more. Several findings underscore the apparent driver role of BAP1 in malignant mesothelioma (MM). However, the reported frequency of somatic BAP1 mutations in MM varies considerably, a discrepancy that appeared related to either methodological or ethnical differences across various studies. Methods To address this discrepancy, we carried out comprehensive genomic and immunohistochemical (IHC) analyses to detect somatic BAP1 gene alterations in 22 frozen MM biopsies from U.S. MM patients. Results By combining Sanger sequencing, multiplex ligation-dependent probe amplification, copy number analysis, and cDNA sequencing, we found alteration of BAP1 in 14 of 22 biopsies (63.6%). No changes in methylation were observed. IHC revealed normal nuclear BAP1 staining in the eight MM containing wild-type BAP1, whereas no nuclear staining was detected in the 14 MM biopsies containing tumor cells with mutated BAP1. Thus, IHC results were in agreement with those obtained by genomic analyses. We then extended IHC analysis to an independent cohort of 70 MM biopsies, of which there was insufficient material to perform molecular studies. IHC revealed loss of BAP1 nuclear staining in 47 of these 70 MM biopsies (67.1%). Conclusions Our findings conclusively establish BAP1 as the most commonly mutated gene in MM, regardless of ethnic background or other clinical characteristics. Our data point to IHC as the most accessible and reliable technique to detect BAP1 status in MM biopsies.

Mediastinal node involvement is the primary determinant for IIIA disease in NSCLC. It is locally advanced disease and curable, but remains a significant treatment challenge. There is no single treatment paradigm appropriate for all patients. The role for surgery is dictated by the ability to perform an R0 resection and by the extent of mediastinal node involvement. For most patients with N2 disease, induction therapy is recommended and survival is closely linked to the response to that treatment. Many believe that a trimodality approach using a combination of chemotherapy, radiation, and surgery provides the best hope for cure, but safety and success is highly dependent on careful patient selection and meticulous treatment delivery.

Malignant mesothelioma (MM) is an aggressive tumor with no treatment regimen. Previously we have demonstrated that cyclic AMP response element binding protein (CREB) is constitutively activated in MM tumor cells and tissues and plays an important role in MM pathogenesis. To understand the role of CREB in MM tumor growth, we generated CREB-inhibited MM cell lines and performed in vitro and in vivo experiments. In vitro experiments demonstrated that CREB inhibition results in significant attenuation of proliferation and drug resistance of MM cells. CREB-silenced MM cells were then injected into severe combined immunodeficiency mice, and tumor growth in s.c. and i.p. models of MM was followed. We observed significant inhibition in MM tumor growth in both s.c. and i.p. models and the presence of a chemotherapeutic drug, doxorubicin, further inhibited MM tumor growth in the i.p. model. Peritoneal lavage fluids from CREB-inhibited tumor-bearing mice showed a significantly reduced total cell number, differential cell counts, and pro-inflammatory cytokines and chemokines (IL-6, IL-8, regulated on activation normal T cell expressed and secreted, monocyte chemotactic protein-1, and vascular endothelial growth factor). In vitro studies showed that asbestos-induced inflammasome/inflammation activation in mesothelial cells was CREB dependent, further supporting the role of CREB in inflammation-induced MM pathogenesis. In conclusion, our data demonstrate the involvement of CREB in the regulation of MM pathogenesis by regulation of inflammation.

1. International Agency for Research on Cancer, World Health Organization. Estimatedcancer Incidence, Mortality, Prevalence and Disability-adjusted life years (DALYs)Worldwide in2008. http://globocan.iarc.fr/(17August2013,datelastaccessed).2. Vital Statistics Japan (Ministry of Health, Labour and Welfare). http://ganjoho.jp/professional/statistics/statistics.html (17 August 2013, date last accessed).3. Son T, Hyung WJ, Lee JH et al. Clinical implication of an insufficient number ofexamined lymph nodes after curative resection for gastric cancer. Cancer 2012;118: 4687–4693.4. Edge SB BD, Compton CC, Fritz AG et al. AJCC Cancer Staging Manual, 7th ed.NewYork: Springer2010.5. Zu H, Wang F, Ma Y et al. Stage-stratified analysis of prognostic significance oftumor size inpatients withgastric cancer.PLoS One2013; 8(1):e545026. Kunisaki C, Makino H, Kimura J et al. Impact of lymphovascular invasion inpatients withstage I gastric cancer.Surgery 2010; 147:204–211.7. Li C, Oh SJ, Kim S et al. Macroscopic Borrmann type as a simple prognostic indicatorinpatientswithadvancedgastriccancer.Oncology2009; 77: 197 –204.8. Kunisaki C, Akiyama H, Nomura M et al. Clinicopathologic characteristics and surgicaloutcomesof mucinousgastriccarcinoma. Ann SurgOncol 2006; 13: 836 –842.9. Talamonti MS, Kim SP, Yao KA et al. Surgical outcomes of patients with gastriccarcinoma: the importance of primary tumor location and microvessel invasion.Surgery 2003; 134:720–727;discussion 727–9.10. Iasonos A, Schrag D, Raj GV et al. How to build and interpret a nomogram forcancer prognosis. JClin Oncol2008; 26: 1364–1370.11. Han DS, Suh YS, Kong SH et al. Nomogram predicting long-term survival after d2gastrectomyfor gastric cancer. JClin Oncol2012; 30: 3834–3840.12. Kattan MW, Karpeh MS, Mazumdar M et al. Postoperative nomogram for disease-specific survival after an R0 resection for gastric carcinoma. J Clin Oncol 2003;21:3647–3650.13. Kim JH, Kim HS, Seo WY et al. External validation of nomogram for the predictionof recurrence after curative resection in early gastric cancer. Ann Oncol 2012; 23:361–367.14. Kim DH, Kim SM, Hyun JK et al. Changes in postoperative recurrence and prognosticrisk factors for patients with gastric cancer who underwent curative gastric resectionduring different time periods. AnnSurgOncol 2013; 20:2317 –2327.15. Japanese Gastric Cancer Association. Japanese Classification of GastricCarcinoma,13 ed. Tokyo:Kandera 1999.16. Akazawa K, Nakamura T, Palesch Y. Power of logrank test and Cox regression modelinclinical trialswith heterogeneoussamples.StatMed1997; 16: 583 –597.17. Harrell FE, Jr, Califf RM, Pryor DB et al. Evaluating theyield of medical tests. JAMA1982;247: 2543–2546.18. Akaike H. Information Theory and an Extension of the Maximum LikelihoodPrinciple.Budapest: Hungary AkademiaiKiado 1973.19. NakajimaT, Kinoshita T, Nashimoto A et al. Randomized controlled trial of adjuvanturacil-tegafur versus surgery alone for serosa-negative, locally advanced gastriccancer.Br JSurg 2007; 94: 1468–1476.20. Sakuramoto S, Sasako M, Yamaguchi T et al. Adjuvant chemotherapy forgastric cancer with S-1, an oral fluoropyrimidine. N Engl J Med 2007; 357:1810–1820.21. Bang YJ, Kim YW, Yang HK et al. Adjuvant capecitabine and oxaliplatin for gastriccancer after D2 gastrectomy (CLASSIC): a phase 3 open-label, randomisedcontrolled trial. Lancet 2012; 379:315–321.

Introduction In the Western world, malignant mesothelioma (MM) is most prevalent in the pleura of older males who have been professionally exposed to asbestos. Information about MM from rapidly industrializing countries such as China is minimal. There is concern that a proportion of MM diagnoses in China may be incorrect because most Chinese physicians do not have experience diagnosing this rare cancer. We recently reported an unusually high incidence of peritoneal MM among eastern Chinese female patients. Here, we review the accuracy of MM diagnoses in China and provide suggestions to improve the accuracy of diagnosis. Methods We reviewed 92 pathological diagnosis of MM in 2002–2015 from two reference centers in the province of Zhejiang in eastern China. We performed a large set of immunohistochemistry analyses to increase the reliability of the diagnosis. Results We confirmed the MM diagnosis in 12 of 34 of the pleural tumors (35.3%), in 38 of 56 of the peritoneal tumors (67.9%), and in two of two of the MMs of the tunica vaginalis (100%). MMs were characterized by tumor cells showing nuclear Wilms tumor 1 and calretinin staining and by strong membranous staining for cytokeratin CAM5.2. The results of staining for the epithelial markers carcinoembryonic antigen, thyroid transcription factor-1, MOC31, BerEP4, p63, p40, paired box 8, ER and PR were negative. BRCA1 associated protein 1 nuclear staining was lost in percentages similar to what has been reported for samples from Western countries. Conclusions Our findings suggest that MM—especially in its pleural localization—is often misdiagnosed in eastern China. Identifying pitfalls and possible solutions in the pathological diagnosis of MM will affect both the standard of care and research in China.

Malignant mesothelioma is strongly associated with asbestos exposure. Among asbestos fibers, crocidolite is considered the most and chrysotile the least oncogenic. Chrysotile accounts for more than 90% of the asbestos used worldwide, but its capacity to induce malignant mesothelioma is still debated. We found that chrysotile and crocidolite exposures have similar effects on human mesothelial cells. Morphological and molecular alterations suggestive of epithelial–mesenchymal transition, such as E-cadherin down-regulation and β-catenin phosphorylation followed by nuclear translocation, were induced by both chrysotile and crocidolite. Gene expression profiling revealed high-mobility group box-1 protein (HMGB1) as a key regulator of the transcriptional alterations induced by both types of asbestos. Crocidolite and chrysotile induced differential expression of 438 out of 28,869 genes interrogated by oligonucleotide microarrays. Out of these 438 genes, 57 were associated with inflammatory and immune response and cancer, and 14 were HMGB1 targeted genes. Crocidolite-induced gene alterations were sustained, whereas chrysotile-induced gene alterations returned to background levels within 5 weeks. Similarly, HMGB1 release in vivo progressively increased for 10 or more weeks after crocidolite exposure, but returned to background levels within 8 weeks after chrysotile exposure. Continuous administration of chrysotile was required for sustained high serum levels of HMGB1. These data support the hypothesis that differences in biopersistence influence the biological activities of these two asbestos fibers.

Introduction: Malignant pleural mesothelioma (MM) is an aggressive asbestos-associated malignancy with limited therapeutic options. This study describes the overexpression of Ephrin B2 receptor (EPHB2) in MM cell lines and tumors, and the effect of its manipulation on proliferative and invasive qualities of the disease. Methods: Using expression arrays, we investigated EPHB2 in MM tumors compared with normal mesothelium. EPHB2 and downstream target expression were evaluated using reverse-transcriptase polymerase chain reaction and immunoblotting methods. The biological significance of EPHB2 in MM was evaluated using in vitro functional assays with and without targeting by EPHB2-short hairpin RNA or blocking peptide in two mesothelioma cell lines, HP-1 and H2595. Results: EPHB2 is overexpressed in all MM cell lines, but not in benign mesothelial cells, and is significantly elevated in MM tumor tissue compared with matched normal peritoneum. Targeted knockdown of EPHB2 in HP-1 and H2595 cell lines reduced its expression and that of EPHB2 downstream targets such as matrix metalloproteinase (MMP-2) and vascular endothelial growth factor, whereas caspase 2 and caspase 8 had increased expression. Inhibition of EPHB2 resulted in a significant decrease in scratch closure (1.25-fold–1.8-fold), proliferation (1.5-fold), and invasion (1.7-fold–1.8-fold) compared with the controls. Most notably, however, EPHB2 silencing resulted in a significant increase in apoptotic proteins and activity. Conclusion: EPHB2 seems to play an important role in MM pathogenesis and these findings indicate that EPHB2 could serve as a potential novel therapeutic target for treatment of the disease.

DR. DONINGTON: Thank you for being here. The idea is to give the readers an idea of how you approach superior sulcus tumors, since you are some of the most accomplished surgeons in the country at these complex resections. So we will start with just some overview. How many of these cases do you see a year? Do you think you are seeing more or seeing less? DR. SWISHER: It’s just a hard disease to know for sure because it’s such a referral-based disease, and it goes up and down, and everybody in our group at MD Anderson Cancer Center sees these patients. I get a sense it’s going down, but I don’t know for sure. DR. BAINS: Personally, I may see a couple of them, 2 or 3 at the very least, but as a whole group, we may see 5-10 a year, but closer to 5. DR. VAILLERES: But I think it fluctuates. If you asked me that question last year, I think we did 2, and we have already done 3 this year. So I think, it comes and goes. I am not sure if the incidence is going down or not. I think it is, but I am not sure. And if it’s going down, why? Are we picking up the apical upper lobar lesions before they start invading into structures? I have no idea. DR. SWISHER: I agree, it is variable. I am also concerned because these tumors, for the most part, are tumors that should be treated at highvolume centers, and it remains to be seen how this disease is going to be affected by the changes in health care reform. It is an orphan disease since so few patients have it, but to impact it, we need to treat these patients in high-volume, multidisciplinary approaches.

The search for biomarkers in the management of lung cancer involves the use of multiple platforms to examine changes in gene, protein, and microRNA expression. Multiple studies have been published in an attempt to describe early detection, diagnostic, prognostic, and predictive biomarkers using chiefly tissues and blood elements. Studies are characterized by a lack of commonality of specific biomarkers, and a lack of validated, clinically useful markers. The future of biomarker discovery as a means of tailoring therapy for patients with lung cancer will involve next-generation sequencing along with collaborative efforts to integrate and validate candidate markers.