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Flap endonuclease 1 (FEN1) is a structure-specific nuclease best known for its critical roles in Okazaki fragment maturation, DNA repair, and apoptosis-induced DNA fragmentation. Functional deficiencies in FEN1, in the forms of somatic mutations and polymorphisms, have recently been shown to lead to autoimmunity, chronic inflammation, and predisposition to and progression of cancer. To explore how FEN1 contributes to cancer progression, we examined FEN1 expression using 241 matched pairs of cancer and corresponding normal tissues on a gene expression profiling array and validated differential expression by quantitative real-time PCR and immunohistochemistry. Furthermore, we defined the minimum promoter of human FEN1 and examined the methylation statuses of the 5′ region of the gene in paired breast cancer tissues. We show that FEN1 is significantly up-regulated in multiple cancers and the aberrant expression of FEN1 is associated with hypomethylation of the CpG island within the FEN1 promoter in tumor cells. The overexpression and promoter hypomethylation of FEN1 may serve as biomarkers for monitoring the progression of cancers. (Mol Cancer Res 2008;6(11):1710–7)

Supplementary Tables S1-S3 from Overexpression and Hypomethylation of Flap Endonuclease 1 Gene in Breast and Other Cancers

Objective: Our objective was to evaluate for any changes in quality or cost when robotic lung resection is used with significant trainee participation. Methods: All anatomic lung resections between January 2006 and June 2016 were identified from a prospectively maintained database. Clinical data were recorded by double entry. Cost and cancer-related data were gathered from the business analytics department and tumor registry. Robotic outcomes were compared to an ongoing thoracotomy and video-assisted thoracic surgery (VATS) experience. Propensity scores using age, sex, and comorbidities were assigned for statistical analysis. Survival was evaluated using the Kaplan–Meier method. Results: Of 523 consecutive cases, 483 were included (211 robotic, 210 thoracotomy, 62 VATS). There were 74 robotic cases (35%) performed by trainees as the console surgeon. Length of stay was shortest for robotics (3 days) compared to thoracotomy (7 days, P 0.25). There was no significant difference in negative margin rates. Total cost related to the hospitalization for surgery was $5,721 less for robotics compared to thoracotomy ( P = 0.003) but comparable to VATS. Trainees served as console surgeon in 0% of cases in the first 2 years of robotics but increased to 79% in the last year of the study. Conclusions: Robotic lung resection can be safely performed and taught in an academic medical center without sacrificing quality or cost.

Purpose: Itraconazole has been repurposed as an anticancer therapeutic agent for multiple malignancies. In preclinical models, itraconazole has antiangiogenic properties and inhibits Hedgehog pathway activity. We performed a window-of-opportunity trial to determine the biologic effects of itraconazole in human patients. Experimental Design: Patients with non–small cell lung cancer (NSCLC) who had planned for surgical resection were administered with itraconazole 300 mg orally twice daily for 10–14 days. Patients underwent dynamic contrast-enhanced MRI and plasma collection for pharmacokinetic and pharmacodynamic analyses. Tissues from pretreatment biopsy, surgical resection, and skin biopsies were analyzed for itraconazole and hydroxyitraconazole concentration, and vascular and Hedgehog pathway biomarkers. Results: Thirteen patients were enrolled in this study. Itraconazole was well-tolerated. Steady-state plasma concentrations of itraconazole and hydroxyitraconazole demonstrated a 6-fold difference across patients. Tumor itraconazole concentrations trended with and exceeded those of plasma. Greater itraconazole levels were significantly and meaningfully associated with reduction in tumor volume (Spearman correlation, −0.71; P = 0.05) and tumor perfusion (Ktrans; Spearman correlation, −0.71; P = 0.01), decrease in the proangiogenic cytokines IL1b (Spearman correlation, −0.73; P = 0.01) and GM-CSF (Spearman correlation, −1.00; P < 0.001), and reduction in tumor microvessel density (Spearman correlation, −0.69; P = 0.03). Itraconazole-treated tumors also demonstrated distinct metabolic profiles. Itraconazole treatment did not alter transcription of GLI1 and PTCH1 mRNA. Patient size, renal function, and hepatic function did not predict itraconazole concentrations. Conclusions: Itraconazole demonstrates concentration-dependent early antivascular, metabolic, and antitumor effects in patients with NSCLC. As the number of fixed dose cancer therapies increases, attention to interpatient pharmacokinetics and pharmacodynamics differences may be warranted.

Background Clinical outcomes for resected early‐stage non‐small cell lung cancer (NSCLC) are superior at high‐volume facilities, but reasons for these differences remain unclear. Understanding these differences and optimizing outcomes across institutions are critical to the management of the increasing incidence of these cases. We evaluated the extent to which surgical best practices account for resected early‐stage NSCLC outcome differences between facilities according to case volume. Methods We performed a retrospective cohort study for clinical stage 1 or 2 NSCLC undergoing surgical resection from 2004 to 2013 using the National Cancer Database (NCDB). Surgical best practices (negative surgical margins, lobar or greater resection, lymph node (LN) dissection, and examination of > 10 LNs) were compared between the highest and lowest quartile volumes. Results A total of 150,179 patients were included in the cohort (89% white, 53% female, median age 68 years). In a multivariate model, superior overall survival (OS) was observed at highest volume centers compared to lowest volume centers (hazard ratio (HR) = 0.89; 95% CI, 0.82‐0.96; P = .002). After matching for surgical best practices, there was no significant OS difference (HR = 0.95; 95% CI, 0.87‐1.05; P = .32). Propensity score‐adjusted HR estimates indicated that surgical best practices accounted for 54% of the numerical OS difference between low‐volume and high‐volume centers. Each surgical best practice was independently associated with improved OS (all P ≤ .001). Conclusion Quantifiable and potentially modifiable surgical best practices largely account for resected early‐stage NSCLC outcome differences observed between low‐ and high‐volume centers. Adherence to these guidelines may reduce and potentially eliminate these differences., High‐volume facilities have been observed to be associated with improved outcomes compared to low‐volume facilities for non‐small cell lung cancer surgery. We found that controlling for surgical quality measures minimizes outcome differences between facility types, suggesting that high‐quality care provision for lung cancer surgery requires compliance with surgical quality measures.

EGFR inhibition is an effective treatment in the minority of non-small cell lung cancer (NSCLC) cases harboring EGFR-activating mutations, but not in EGFR wild type (EGFRwt) tumors. Here, we demonstrate that EGFR inhibition triggers an antiviral defense pathway in NSCLC. Inhibiting mutant EGFR triggers Type I IFN-I upregulation via a RIG-I-TBK1-IRF3 pathway. The ubiquitin ligase TRIM32 associates with TBK1 upon EGFR inhibition, and is required for K63-linked ubiquitination and TBK1 activation. Inhibiting EGFRwt upregulates interferons via an NF-κB-dependent pathway. Inhibition of IFN signaling enhances EGFR-TKI sensitivity in EGFR mutant NSCLC and renders EGFRwt/KRAS mutant NSCLC sensitive to EGFR inhibition in xenograft and immunocompetent mouse models. Furthermore, NSCLC tumors with decreased IFN-I expression are more responsive to EGFR TKI treatment. We propose that IFN-I signaling is a major determinant of EGFR-TKI sensitivity in NSCLC and that a combination of EGFR TKI plus IFN-neutralizing antibody could be useful in most NSCLC patients.

Background In non-small cell lung cancer (NSCLC), 18fluoro-2-deoxyglucose–positron emission tomography (FDG-PET) assists in diagnosis, staging, and evaluating treatment response. One variable of FDG-PET, the maximum standard uptake value (SUVm), is considered an objective measure of glucose uptake. However, little is known about the fate of glucose in FDG-avid lung tumors in vivo. This study used stable glucose isotope tracing to determine whether the SUVm predicts glycolytic metabolism or other glucose fates in tumors. Methods In this prospective Institutional Review Board-approved clinical trial, 52 untreated potentially resectable confirmed NSCLC patients underwent FDG-PET computed tomography. During the surgical procedure, the patients were infused with 13C-labeled glucose. Blood, tumor, and normal lung samples were analyzed by mass spectrometry to determine 13C enrichment in glycolytic intermediates. These values were compared with clinical variables, including SUVm, maximum tumor diameter, stage, grade, and MIB-1/Ki67 proliferation index. Results For each patient, 13C enrichment in each metabolite was compared between tumor and adjacent lung. Although all tumors metabolized glucose, SUVm did not correlate with glycolytic intermediate labeling. Rather, SUVm correlated with markers indicating the use of other respiratory substrates, including lactate, and with the proliferation index. Conclusions SUVm does not correlate with glycolytic metabolism in human NSCLC but does correlate with the proliferation index, suggesting that SUVm predicts glucose use by pathways other than glycolysis. These pathways may offer alternative therapeutic targets, including biosynthetic pathways required for cell proliferation. The research techniques in this study offer the opportunity to understand the relationships between SUVm, tumor metabolism, and therapeutic vulnerabilities in human NSCLCs.

Great advances have been made in the surgical management of esophageal disease since the first description of esophageal resection in 1913. We are in the era of minimally invasive esophagectomy. The current three main approaches to an esophagectomy are the Ivor Lewis technique, McKeown technique, and the transhiatal approach to esophagectomy. These operations were associated with a high morbidity and mortality. The recent advances in minimally invasive surgical techniques have greatly improved the outcomes of these surgical procedures. This article reviews the literature and describes the various techniques available for performing minimally invasive esophagectomy and robot-assisted esophagectomies, the history behind the development of these techniques, the variations, and the contemporary outcomes after such procedures.

SUMMARY Advances in minimally invasive techniques, including robotic surgical technology, have led to improved outcomes in esophagectomy. In this article, we detail our approach to the robotic Ivor Lewis esophagectomy.

e20560 Background: Accurate assessment of non-small cell lung cancer (NSCLC) mediastinal involvement is key to developing treatment plans and determining prognosis. To date, there is no reliable imaging-based means to determine the presence or absence of mediastinal involvement. Current computed tomogram (CT) and fluorodeoxyglucose-positron emission tomography/ computed tomogram (PET-CT) technologies provide numerous derived automated variables have not been sufficiently evaluated to determine the presence of metastasis to the mediastinum. We have developed predictive models to determine the presence or lack of metastatic NSCLC in N2 and N3 regions. Methods: Consecutive patients from 2012-2017 with biopsy-proven NSCLC who had CT and PET-CT, as well as biopsy of the mediastinum had their images reread by a team of blinded specialty radiologists and nuclear medicine specialists. Patients with no mediastinal malignancy on biopsy were followed for 6 months from the initial evaluation to confirm lack of mediastinal malignancy.278 regions (N2 and N3) from 139 patients were included. Logistic regression models were used to build a baseline model, as well as models with additional nodal station maximum standard uptake valuve (SUVm) measurements (SUVm, SUVm-SUVmeanbloodpool and SUV lymph node/tumor (LN/T)) for N2 and N3 regions, respectively. When nodal station SUVm was not measured, SUVmeanbloodpool was used. The SUVm within each region was used. Stepwise selection was used to select variables in the baseline model. Cross-validated ROC curve and area under the curve (AUC) were reported. All analyses were done in SAS 9.4 (SAS Institute, Inc., Cary, NC). Results: 40/139 N2 regions had malignancy, 4/139 N3 regions had malignancy. Baseline models for N2 regions selected lung laterality (OR right vs left: 4.84 (1.79, 13.05)) and nodal station short-axis diameter > 1 cm (OR yes vs no: 5.49 (1.71, 17.54)) while no variables were selected for the baseline model for N3 regions due to lack of statistical power. We used the same variables for the N3 baseline model. Conclusions: We have identified models that use a more advanced analysis of predicting the presence or absence of metastatic NSCLC in both N2 and N3 regions with respect to the primary lesion. All models perform better with SUVm related measurements. From this information, we are developing a clinical application to provide practitioners a better means of assessing the presence of mediastinal involvement of NSCLC. [Table: see text]

// Boning Gao 1, 2, 3 , Chunxian Huang 1, 2 , Kemp Kernstine 4 , Vasiliki Pelekanou 5 , Yuval Kluger 5 , Tingting Jiang 6 , Jennifer R. Peters-Hall 7 , Melissa Coquelin 7 , Luc Girard 1, 2, 3 , Wei Zhang 1, 2 , Kenneth Huffman 1, 2 , Dwight Oliver 8 , Fumi Kinose 9 , Eric Haura 9 , Jamie K. Teer 10 , Uwe Rix 11 , Anh T. Le 12 , Dara L. Aisner 13 , Marileila Varella-Garcia 12, 13 , Robert C. Doebele 12 , Kyle R. Covington 14 , Oliver A. Hampton 14 , Harsha V. Doddapaneni 14 , Joy C. Jayaseelan 14 , Jianhong Hu 14 , David A. Wheeler 14 , Jerry W. Shay 7 , David L. Rimm 5 , Adi Gazdar 1, 2, 8 , John D. Minna 1, 2, 3, 15 1 Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, Texas, USA 2 The Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas, USA 3 Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas, USA 4 Division of Thoracic Surgery, University of Texas Southwestern Medical Center, Dallas, Texas, USA 5 Department of Pathology, Yale University, New Haven, CT, USA 6 Interdepartmental Program in Computational Biology and Bioinformatics, Yale University, New Haven, CT, USA 7 Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, Texas, USA 8 Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas, USA 9 Department of Thoracic Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, USA 10 Department of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, USA 11 Department of Drug Discovery, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, USA 12 Department of Medicine, Division of Medical Oncology, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA 13 Department of Pathology, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA 14 Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, USA 15 Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA Correspondence to: Adi Gazdar, email: Adi.Gazdar@UTSouthwestern.edu John D. Minna, email: John.Minna@UTSouthwestern.edu Keywords: conditionally reprogrammed cells, respiratory epithelial cells, non-small cell lung cancer, rock inhibitor, cell culture Received: September 23, 2016 Accepted: December 20, 2016 Published: December 29, 2016 ABSTRACT The “conditionally reprogrammed cells” (CRC) method, using a Rho kinase inhibitor and irradiated mouse fibroblast cells has been described for the efficient growth of cells from malignant and non-malignant samples from primary tumor and non-malignant sites. Using the CRC method, four institutions independently cultured tumor tissues from 48 non-small cell lung cancers (NSCLC, mostly from primary resected tumors) and 22 non-malignant lungs. We found that epithelial cells could be cultured from tumor and non-malignant lung. However, epithelial cells cultured from tumors had features of non-malignant respiratory epithelial cells which include: 1) among 22 mutations found in the original tumors only two mutations were found in the CRC cultures with reduced frequency (31% to 13% and 92% to 15% from original tumor and CRC culture respectively); 2) copy number variation was analyzed in 9 tumor and their CRC cultures and only diploid patterns were found in CRC cultures; 3) mRNA expression profiles were similar to those of normal respiratory epithelial cells; and 4) co-culture of tumor and non-malignant lung epithelial cells resulted in mostly non-malignant cells. We conclude that CRC method is a highly selective and useful method for the growth of non-malignant respiratory epithelial cells from tumor specimens and only occasionally do such CRC cultures contain a small subpopulation of cancer cells marked by oncogenic mutations. While our findings are restricted to resected primary NSCLC, they indicated the necessity to fully characterize all CRC cultures and the need to develop culture technology that facilitates the growth of primary lung cancers.

Post-radiation therapy evaluation of distal esophageal cancers with positron emission tomography/computed tomography can be problematic. Differentiation of recurrent neoplasm from postradiation changes is difficult in areas of fluorodeoxyglucose avidity in adjacent, incidentally irradiated organs. Few studies have described the magnetic resonance imaging appearance of radiation-induced hepatic injury. We report a case of focal radiation-induced liver injury with a new focus of fluorodeoxyglucose uptake on posttreatment positron emission tomography as well as masslike enhancement and signal abnormality on magnetic resonance imaging, thus mimicking new liver metastasis. Correlation with radiation planning images suggested the correct diagnosis, which was confirmed on follow-up imaging.

Introduction Advances in surgical techniques have improved clinical outcomes and decreased complications. At the same time, heightened attention to care quality has resulted in increased identification of hospital-acquired adverse events. We evaluated these divergent effects on the reported safety of lung cancer resection. Methods and materials We analyzed hospital-acquired adverse events in patients undergoing lung cancer resection using the National Hospital Discharge Survey (NHDS) database from 2001–2010. Demographics, diagnoses, and procedures data were abstracted using ICD-9 codes. We used the Agency for Healthcare Research and Quality (AHRQ) Patient Safety Indicators (PSI) to identify hospital-acquired adverse events. Weighted analyses were performed using t-tests and chi-square. Results A total of 302,444 hospitalizations for lung cancer resection and were included in the analysis. Incidence of PSI increased over time (28% in 2001–2002 vs 34% in 2009–2010; P

Paraganglioma is a rare extra-adrenal tumor of the paraganglia often found in association with sympathetic and parasympathetic nerves. The case presented is of a 10-year-old boy with hemoptysis who was found to have an obstructive bronchial mass. He underwent surgical resection and biopsy confirmed primary pulmonary paraganglioma. He was subsequently found to have an associated genetic syndrome. This is the first case report describing a primary pulmonary paraganglioma in a child.

Lobectomy of the lung is performed for primary lung cancer with individual ligation of the pulmonary vasculature and bronchus along with division of the fissures. Recent estimates claim nearly 30% of lobectomy cases are performed in a minimally invasive fashion, the robotic approach of the nonrobotic minimally invasive option may have some advantages that includes a potentially more oncologic resection, less instrument movement at the chest wall that may result in less trauma to nerves and, thus, potentially less postoperative discomfort, and a simpler technique to learn and teach, more closely approximating the moves of surgery by thoracotomy. The operative setup and surgical details for each of the five lobes is described and illustrated, outlining the technique to divide the hilar structures first and then to divide the fissures. Over the 15 years of performing the technique, particular learning points are described.

Paraesophageal hiatal hernias are typically type III, the gastroesophageal junction and the viscera are herniated through the esophageal hiatus. Symptomatic patients should be surgically repaired. The asymptomatic patients should be managed on a case-by-case basis. The preoperative evaluation and the details of the operative techniques of performing a robotic paraesophageal hiatal hernia repair are described.

Effort-induced thrombosis of the upper extremity is a relatively rare condition and one aspect of thoracic outlet syndrome. It accounts for 10% of all deep venous thromboses. In the vast majority of cases the etiology is repetitive motion of the upper extremity resulting in trauma to the axillo-subclavian vein as it passes through the thoracic outlet resulting in injury to the venous intima and the surrounding supportive tissue. A secondary cause is catheter-induced injury from central venous instrumentation. Patients usually present with swelling of the affected upper extremity and complaints of heaviness and pain. Diagnosis is confirmed by duplex ultrasonography and/or contrast venography. Computed tomogram and magnetic resonance imaging are complimentary. Treatment usually involves a combination of anticoagulation, thrombolysis, and surgical decompression. Of the different techniques to surgically decompress the axillo-subclavian vein, robotic technology offers an opportunity to precisely resect the first rib and a portion of the anterior scalene muscle along with the division of the costoclavicular ligament and surrounding venous scar. The details of the technique are described with a description of the outcomes.

Summary Cancer cells consume glucose and secrete lactate in culture. It is unknown whether lactate contributes to energy metabolism in living tumors. We previously reported that human non-small-cell lung cancers (NSCLCs) oxidize glucose in the tricarboxylic acid (TCA) cycle. Here, we show that lactate is also a TCA cycle carbon source for NSCLC. In human NSCLC, evidence of lactate utilization was most apparent in tumors with high 18 fluorodeoxyglucose uptake and aggressive oncological behavior. Infusing human NSCLC patients with 13 C-lactate revealed extensive labeling of TCA cycle metabolites. In mice, deleting monocarboxylate transporter-1 (MCT1) from tumor cells eliminated lactate-dependent metabolite labeling, confirming tumor-cell-autonomous lactate uptake. Strikingly, directly comparing lactate and glucose metabolism in vivo indicated that lactate's contribution to the TCA cycle predominates. The data indicate that tumors, including bona fide human NSCLC, can use lactate as a fuel in vivo .

Although aberrant EGFR signaling is widespread in cancer, EGFR inhibition is effective only in a subset of non-small cell lung cancer (NSCLC) with EGFR activating mutations. A majority of NSCLCs express EGFR wild type (EGFRwt) and do not respond to EGFR inhibition. TNF is a major mediator of inflammation-induced cancer. We find that a rapid increase in TNF level is a universal adaptive response to EGFR inhibition in NSCLC, regardless of EGFR status. EGFR signaling actively suppresses TNF mRNA levels by inducing expression of miR-21, resulting in decreased TNF mRNA stability. Conversely, EGFR inhibition results in loss of miR-21 and increased TNF mRNA stability. In addition, TNF-induced NF-κB activation leads to increased TNF transcription in a feed-forward loop. Inhibition of TNF signaling renders EGFRwt-expressing NSCLC cell lines and an EGFRwt patient-derived xenograft (PDX) model highly sensitive to EGFR inhibition. In EGFR-mutant oncogene-addicted cells, blocking TNF enhances the effectiveness of EGFR inhibition. EGFR plus TNF inhibition is also effective in NSCLC with acquired resistance to EGFR inhibition. We suggest concomitant EGFR and TNF inhibition as a potentially new treatment approach that could be beneficial for a majority of lung cancer patients.

Background Although preoperative chemotherapy (cisplatin-etoposide) and radiotherapy, followed by surgical resection, is considered a standard of care for superior sulcus cancers, treatment is rigorous and relapse limits long-term survival. The Southwest Oncology Group-Intergroup Trial S0220 was designed to incorporate an active systemic agent, docetaxel, as consolidation therapy. Methods Patients with histologically proven and radiologically defined T3 to 4, N0 to 1, M0 superior sulcus non-small cell lung cancer underwent induction therapy with cisplatin-etoposide, concurrently with thoracic radiotherapy at 45 Gy. Nonprogressing patients underwent surgical resection within 7 weeks. Consolidation consisted of docetaxel every 3 weeks for 3 doses. The accrual goal was 45 eligible patients. The primary objective was feasibility. Results Of 46 patients registered, 44 were eligible and assessable; 38 (86%) completed induction, 29 (66%) underwent surgical resection, and 20 (45% of eligible, 69% surgical, and 91% of those initiating consolidation therapy) completed consolidation docetaxel; 28 of 29 (97%) underwent a complete (R0) resection; 2 (7%) died of adult respiratory distress syndrome. In resected patients, 21 of 29 (72%) had a pathologic complete or nearly complete response. The known site of first recurrence was local in 2, local-systemic in 1, and systemic in 10, with 7 in the brain only. The 3-year progression-free survival was 56%, and 3-year overall survival was 61%. Conclusions Although trimodality therapy provides excellent R0 and local control, only 66% of patients underwent surgical resection and only 45% completed the treatment regimen. Even in this subset, distant recurrence continues to be a major problem, particularly brain-only relapse. Future strategies to improve treatment outcomes in this patient population must increase the effectiveness of systemic therapy and reduce the incidence of brain-only metastases.

This article describes a robotic 2-stage 3-field esophagolymphadenectomy. Techniques highlighted include thoracic esophagectomy; cervical, wide thoracic, and abdominal lymphadenectomy; thoracic duct ligation; gastric tube creation; esophagogastric anastomosis in the left neck; and jejunostomy feeding tube placement.

BACKGROUND This cooperative group adjuvant phase 2 trial in patients with completely resected stage I non-small cell lung cancer with tumor diameters measuring ≥ 2 cm was designed to assess the feasibility and preliminary efficacy of assigning patients to therapy or observation using a molecularly based decision algorithm. METHODS At least a lobectomy and sampling of recommended mediastinal lymph node stations, good Zubrod performance status, adequate organ function, and a formalin-fixed and paraffin-embedded tumor specimen were required. Excision repair cross-complementing group 1 (ERCC1) and ribonucleotide reductase M1 (RRM1) were analyzed using immunofluorescence-based in situ automated quantitative image analysis and categorized as high or low using prespecified cutoff values. Patients with high ERCC1 and RRM1 were assigned to observation and all others to 4 cycles of cisplatin and gemcitabine. Feasibility was defined as treatment assignment within 84 days from surgery in > 85% of patients. Secondary objectives were to estimate the 2-year survival. RESULTS Treatment assignment met the feasibility criteria in 88% of eligible patients (71 of 81 patients). The collective 2-year disease-free and overall survival rates were 80% and 96%, respectively. Protein levels for RRM1 fell within the previously established range, ERCC1 levels were slightly lower than expected, and they were significantly correlated (correlation coefficient, 0.4). The rates of assignment of patients to observation (22%) and chemotherapy (78%) were as expected. CONCLUSIONS Gene expression analysis for treatment assignment is feasible. Survival results are encouraging and require future validation. Real-time performance of quantitative in situ ERCC1 and RRM1 analysis requires further development. Cancer 2014;120:2343–2351. © 2014 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society.

Introduction: Hereditary lung cancer syndromes are rare, and T790M germline mutations of the epidermal growth factor receptor ( EGFR ) gene predispose to the development of lung cancer. The goal of this study was to determine the clinical features and smoking status of lung cancer cases and unaffected family members with this germline mutation and to estimate its incidence and penetrance. Methods: We studied a family with germline T790M mutations over five generations (14 individuals) and combined our observations with data obtained from a literature search (15 individuals). Results: T790M germline mutations occurred in approximately 1% of non–small-cell lung cancer cases and in less than one in 7500 subjects without lung cancer. Both sporadic and germline T790M mutations were predominantly adenocarcinomas, favored female gender, and were occasionally multifocal. Of lung cancer tumors arising in T790M germline mutation carriers, 73% contained a second activating EGFR gene mutation. Inheritance was dominant. The odds ratio that T790M germline carriers who are smokers will develop lung cancer compared with never smoker carriers was 0.31 ( p = 6.0E-05). There was an overrepresentation of never smokers with lung cancer with this mutation compared with the general lung cancer population ( p = 7.4E-06). Conclusion: Germline T790M mutations result in a unique hereditary lung cancer syndrome that targets never smokers, with a preliminary estimate of 31% risk for lung cancer in never smoker carriers, and this risk may be lower for heavy smokers. The resultant cancers share several features and differences with lung cancers containing sporadic EGFR mutations.

Nodal categories for malignant pleural mesothelioma are derived from the lung cancer staging system and have not been adequately validated. The International Association for the Study of Lung Cancer developed a multinational database to generate evidence-based recommendations to inform the eighth edition of the TNM classification of malignant pleural mesothelioma.Data from 29 centers were entered prospectively (n = 1566) or by transfer of retrospective data (n = 1953). Survival according to the seventh edition N categories was evaluated using Kaplan-Meier survival curves and Cox proportional hazards regression analysis. Survival was measured from the date of diagnosis.There were 2432 analyzable cases: 1603 had clinical (c) staging, 1614 had pathologic (p) staging, and 785 had both. For clinically staged tumors there was no separation in Kaplan-Meier curves between cN0, cN1 or cN2 (cN1 versus cN0 hazard ratio [HR] = 1.06, p = 0.77 and cN2 versus cN1 HR = 1.04, p = 0.85). For pathologically staged tumors, patients with pN1 or pN2 tumors had worse survival than those with pN0 tumors (HR = 1.51, p 0.0001) but no survival difference was noted between those with pN1 and pN2 tumors (HR = 0.99, p = 0.99). Patients with both pN1 and pN2 nodal involvement had poorer survival than those with pN2 tumors only (HR = 1.60, p = 0.007) or pN0 tumors (HR = 1.62, p0.0001).A recommendation to collapse both clinical and pN1 and pN2 categories into a single N category comprising ipsilateral, intrathoracic nodal metastases (N1) will be made for the eighth edition staging system. Nodes previously categorized as N3 will be reclassified as N2.

Introduction: Itraconazole has been repurposed as an anti-cancer therapeutic agent for multiple malignancies, including prostate cancer, and basal cell carcinoma, and lung cancer. In preclinical models, itraconazole has antiangiogenic properties and reduces Hedgehog (Hh) pathway activity. We performed a window-of-opportunity trial to determine the biologic effects of itraconazole in human patients. Methods: Patients who had NSCLC planned for surgical resection were administered 10-14 days of itraconazole 300 mg orally twice daily. Prior to and at the end of therapy, patients underwent dynamic contrast-enhanced MRI and plasma collection for pharmacokinetic (PK) and pharmacodynamic analyses. Tissue from pre-treatment biopsy, surgical resection, and skin biopsies were analyzed for itraconazole and hydroxyl-itraconazole concentration, as well as vascular and Hh pathway biomarkers. Results: A total of 13 patients were enrolled, of whom 8 completed the course of itraconazole and all biomarker studies. Itraconazole was generally well tolerated. Steady state plasma concentrations of itraconazole and hydroxyl-itraconazole demonstrated low intra-patient variability, but there was a six-fold difference in AUC (area under contrast curve) between patients. Itraconazole treatment did not alter transcription of GLI1 (P=0.20) and PTCH1 (P=0.34) mRNA in skin biopsies. There was a significant association between itraconazole PK and (a) tumor volume reduction (Spearman rank correlation -0.71; P=0.05), and (b) tumor perfusion (Ktrans) (correlation -0.71; P=0.01). Changes in IL-1b, G-CSF, and GM-CSF concentrations were significantly correlated with tumor volume reduction. Conclusions: Itraconazole demonstrates exposure-dependent early anti-vascular and anti-tumor effects in patients with NSCLC. However, it appears to have little activity against the Hh pathway. As interest in vascular-directed therapies re-emerges in this disease, itraconazole may offer a relatively inexpensive, convenient, and well-tolerated option. Funding: Department of Defense (DOD) W81XWH-13-LCRP-CEA Lung Cancer Research Program Clinical Exploration Award Citation Format: David E. Gerber, Farjana J. Fattah, Rolf A. Brekken, Rachael Skelton, Jessica Saltarski, Chul Ahn, Kemp H. Kernstine, Chyndhri Padmanabhan, Vaidehi Chemburkar, Sahba Kasiri, Rajareddy Kallem, Indhumathy Subramaniyan, Qing Yuan, Quyen N. Do, Yin Xi, Ivan Pedrosa, William C. Putnam, James Kim. Concentration-dependent early anti-vascular and anti-tumor effects of itraconazole in non-small cell lung cancer (NSCLC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT087.

The recent proliferation of system-of-systems (SoS) trade spaces has allowed the investigation of highly complex interactions that have historically not been analyzed. Because of the size and complexity of these trade spaces, traditional methods of learning, exploring, and eventually understanding the complex interactions are inadequate. The first third of this paper is used to discuss the design approach of learning SoS through simulation, while the second third exposes many of the inadequacies of the current techniques. The final third of this paper calls for the development of new methods by presenting specific areas in which new techniques must be improved. Some examples are adaptive sampling methods which adjust local repetitions depending on local variance and batch experiment sizes that allow a designer to dynamically change the number of experiments depending on the number of available computational nodes.

Purpose Survival of patients with completely resected non–small-cell lung cancer (NSCLC) is unsatisfactory, and in 2002, the benefit of adjuvant chemotherapy was not established. This phase III study assessed the impact of postoperative adjuvant gefitinib on overall survival (OS). Patients and Methods Patients with completely resected (stage IB, II, or IIIA) NSCLC stratified by stage, histology, sex, postoperative radiotherapy, and chemotherapy were randomly assigned (1:1) to receive gefitinib 250 mg per day or placebo for 2 years. Study end points were OS, disease-free survival (DFS), and toxicity. Results As a result of early closure, 503 of 1,242 planned patients were randomly assigned (251 to gefitinib and 252 to placebo). Baseline factors were balanced between the arms. With a median of 4.7 years of follow-up (range, 0.1 to 6.3 years), there was no difference in OS (hazard ratio [HR], 1.24; 95% CI, 0.94 to 1.64; P = .14) or DFS (HR, 1.22; 95% CI, 0.93 to 1.61; P = .15) between the arms. Exploratory analyses demonstrated no DFS (HR, 1.28; 95% CI, 0.92 to 1.76; P = .14) or OS benefit (HR, 1.24; 95% CI, 0.90 to 1.71; P = .18) from gefitinib for 344 patients with epidermal growth factor receptor (EGFR) wild-type tumors. Similarly, there was no DFS (HR, 1.84; 95% CI, 0.44 to 7.73; P = .395) or OS benefit (HR, 3.16; 95% CI, 0.61 to 16.45; P = .15) from gefitinib for the 15 patients with EGFR mutation-positive tumors. Adverse events were those expected with an EGFR inhibitor. Serious adverse events occurred in ≤ 5% of patients, except infection, fatigue, and pain. One patient in each arm had fatal pneumonitis. Conclusion Although the trial closed prematurely and definitive statements regarding the efficacy of adjuvant gefitinib cannot be made, these results indicate that it is unlikely to be of benefit.

Purpose Outcomes after resection of stage I non–small-cell lung cancer (NSCLC) are variable, potentially due to undetected occult micrometastases (OM). Cancer and Leukemia Group B 9761 was a prospectively designed study aimed at determining the prognostic significance of OM. Materials and Methods Between 1997 and 2002, 502 patients with suspected clinical stage I (T1-2N0M0) NSCLC were prospectively enrolled at 11 institutions. Primary tumor and lymph nodes (LNs) were collected and sent to a central site for molecular analysis. Both were assayed for OM using immunohistochemistry (IHC) for cytokeratin (AE1/AE3) and real-time reverse transcriptase polymerase chain reaction (RT-PCR) for carcinoembryonic antigen. Results Four hundred eighty-nine of the 502 enrolled patients underwent complete surgical staging. Three hundred four patients (61%) had pathologic stage I NSCLC (T1, 58%; T2, 42%) and were included in the final analysis. Fifty-six percent had adenocarcinomas, 34% had squamous cell carcinomas, and 10% had another histology. LNs from 298 patients were analyzed by IHC; 41 (14%) were IHC-positive (42% in N1 position, 58% in N2 position). Neither overall survival (OS) nor disease-free survival was associated with IHC positivity; however, patients who had IHC-positive N2 LNs had statistically significantly worse survival rates (hazard ratio, 2.04, P = .017). LNs from 256 patients were analyzed by RT-PCR; 176 (69%) were PCR-positive (52% in N1 position, 48% in N2 position). Neither OS nor disease-free survival was associated with PCR positivity. Conclusion NSCLC tumor markers can be detected in histologically negative LNs by AE1/AE3 IHC and carcinoembryonic antigen RT-PCR. In this prospective, multi-institutional trial, the presence of OM by IHC staining in N2 LNs of patients with NSCLC correlated with decreased OS. The clinical significance of this warrants further investigation.

Esophagectomy takes the center stage in the curative treatment of local and local-regional esophageal cancer. It is a complex procedure with a high postoperative complication rate. When interpreting imaging studies, radiologists must understand the surgical techniques used and their potential complications. The most common surgical techniques are transthoracic esophagectomies, such as the Ivor Lewis and McKeown techniques, and transhiatal esophagectomy. Variations of these techniques include different choices of conduit (ie, stomach, colon, or jejunum) to serve in lieu of the resected esophagus. Postoperative imaging and accurate interpretation is vital in the aftercare of these patients. Chest radiographs, esophagrams, and computed tomographic images play an essential role in early identification of complications. Pulmonary complications and anastomotic leaks are the leading causes of postoperative morbidity and mortality secondary to esophagectomy. Other complications include technical and functional problems and delayed complications such as anastomotic strictures and disease recurrence. An esophagographic technique is described that is performed by using hand injection of contrast material into an indwelling nasogastric tube. Familiarity with the various types of esophagectomy and an understanding of possible complications are of utmost importance for radiologists and allow them to be key participants in the treatment of patients undergoing these complicated procedures.

Objective: We examined benefit finding in patients with lung cancer, including level of benefit finding and change in benefit finding over time, and tested a predictive model postulating that greater impact of and engagement with the stressor promotes benefit finding. Methods: Patients diagnosed with a primary lung cancer within the past 6 months (M=16 weeks post-diagnosis) completed measures of benefit finding, cancer-related intrusions, perceived stressfulness, coping, and demographic and medical information at study entry (T1; n = 118) and 3 months later (T2; n = 79). Results: Level of benefit finding at both assessments was to a ‘mild-to-moderate degree’. Benefit finding increased over time for patients with small cell carcinoma, but not for those with nonsmall cell carcinoma. The proposed model explained 33% of the variance in T1 benefit finding, and 64% (using T1 coping measures) and 71% (using T2 coping measures) of the variance in T2 benefit finding. Greater benefit finding was associated with having small cell lung cancer, higher cancer-related intrusions, lower perceived cancer-related stress, and greater approach-oriented coping. Positive reframing coping emerged as the single unique approach-oriented coping scale predicting benefit finding at T1, and emotional approach coping was the single unique approach-oriented coping scale predicting benefit finding at T2. Conclusion: Findings provide general support for a theoretical model positing that stressor impact and engagement with the stressor contribute to the development of benefit finding after cancer. Future research with larger, more diverse samples is needed to confirm and extend these findings. Copyright © 2011 John Wiley & Sons, Ltd.

Aristotle once said "the whole is more than the sum of its parts." It is in Aristotle's words that a basis for a greener aviation industry can be found. By looking at the whole, the aerospace community can make the entire air transportation system sustainable for generations to come. The effect of aviation on the environment is a multifaceted problem with far reaching consequences if addressed improperly. For this reason, the proposed methodology provides a strategic planning capability for environmental technologies. This unified methodology is a top-down-bottom-up approach starting and ending with the air transportation system, and is intended to align technology selection with an organization's long term environmental concerns. The objective is to systematically identify technologies worth investment based on their environmental impact throughout the future air transportation system. This unified methodology for green design provides the fundamental framework to make purposeful technology selections and investment decisions to meet the environmental needs of the future.

Esophageal leiomyomas are resected in symptomatic and/or malignancy-suspicious cases. Traditionally, they have been removed by laparotomy or thoracotomy and more recently by thoracoscopy and laparoscopy. Mucosal injury is reported as high as 7% of cases but may be higher in unreported general practice. Robotic technology seems to offer advantages. We describe a robotic approach that seems to minimize mobilization of the esophagus, potentially decreasing the likelihood of mucosal injury and postoperative recovery time. We review the literature to evaluate the reports of mucosal injury with the open, minimally invasive, and robotic techniques and describe our own method. To improve efficiency, we use a four-arm technique.

Background Using a large data set, we investigated the impact of the number of resected and involved lymph nodes on overall survival for patients with esophageal cancer. Methods From the National Oncology Database™, esophageal cancer cases with data available on the total number of resected and involved nodes as well as other variables were evaluated as it relates to overall survival by multivariate analysis using Cox proportional hazards method. Patients with 0, exactly 1 or 1–3 positive nodes were separately studied to determine the association between the number of lymph nodes resected and overall survival. Results From 1969 to 2002, 3,144 (17%) of 18,390 esophageal cancer cases with complete data were identified. Increasing number of involved nodes predicted poorer outcome (P

Thymectomy is an established therapy for myasthenia gravis. Minimally invasive surgery for thymectomy has been reported, but not clearly shown to be equivalent to open resection. Robotic-assisted thymectomy may provide the benefit of a full resection of thymic tissue and anterior mediastinal tissue for the treatment of myasthenia gravis by a minimally invasive approach. We present a review of the experience of robotic thymectomy.

Flap endonuclease 1 (FEN1) is a structure-specific nuclease best known for its critical roles in Okazaki fragment maturation, DNA repair, and apoptosis-induced DNA fragmentation. Functional deficiencies in FEN1, in the forms of somatic mutations and polymorphisms, have recently been shown to lead to autoimmunity, chronic inflammation, and predisposition to and progression of cancer. To explore how FEN1 contributes to cancer progression, we examined FEN1 expression using 241 matched pairs of cancer and corresponding normal tissues on a gene expression profiling array and validated differential expression by quantitative real-time PCR and immunohistochemistry. Furthermore, we defined the minimum promoter of human FEN1 and examined the methylation statuses of the 5′ region of the gene in paired breast cancer tissues. We show that FEN1 is significantly up-regulated in multiple cancers and the aberrant expression of FEN1 is associated with hypomethylation of the CpG island within the FEN1 promoter in tumor cells. The overexpression and promoter hypomethylation of FEN1 may serve as biomarkers for monitoring the progression of cancers. (Mol Cancer Res 2008;6(11):1710–7)

Objective The purpose of this consensus conference was to determine whether video-assisted thoracic surgery (VATS) improves clinical and resource outcomes compared with conventional thoracotomy (OPEN) in adults undergoing lobectomy for lung cancer, and to outline evidence-based recommendations for the use of VATS in performing lobectomy for lung cancer. Methods Before the consensus conference, the best available evidence was reviewed in that systematic reviews, randomized trials, and nonrandomized trials were considered in descending order of validity and importance. At the consensus conference, evidence-based statements were created, and consensus processes were used to determine the ensuing recommendations. The American Heart Association/American College of Cardiology system was used to label the level of evidence and class of recommendation. Results and Recommendations The consensus panel agreed upon the following statements and recommendations in patients with clinical stage I nonsmall cell lung cancer undergoing lung lobectomy: 1. VATS can be recommended to reduce overall postoperative complications (class IIa, level A evidence). 2. VATS can be recommended to reduce pain and overall functionality over the short term (class IIa, level B evidence). 3. VATS can be recommended to improve delivery of adjuvant chemotherapy delivery (class IIa, level B evidence). 4. VATS can be recommended for lobectomy in clinical stage I and II non-small cell lung cancer patients, with no proven difference in stage-specific 5-year survival compared with open thoracotomy (class IIb, level B evidence).

We compare different radiotherapy techniques—helical tomotherapy (tomotherapy), step-and-shoot IMRT (IMRT), and 3-dimensional conformal radiotherapy (3DCRT)—for patients with mid-distal esophageal carcinoma on the basis of dosimetric analysis. Six patients with locally advanced mid-distal esophageal carcinoma were treated with neoadjuvant chemoradiation followed by surgery. Radiotherapy included 50 Gy to gross planning target volume (PTV) and 45 Gy to elective PTV in 25 fractions. Tomotherapy, IMRT, and 3DCRT plans were generated. Dose-volume histograms (DVHs), homogeneity index (HI), volumes of lung receiving more than 10, 15, or 20 Gy (V 10 , V 15 , V 20 ), and volumes of heart receiving more than 30 or 45 Gy (V 30 , V 45 ) were determined. Statistical analysis was performed by paired t -tests. By isodose distributions and DVHs, tomotherapy plans showed sharper dose gradients, more conformal coverage, and better HI for both gross and elective PTVs compared with IMRT or 3DCRT plans. Mean V 20 of lung was significantly reduced in tomotherapy plans. However, tomotherapy and IMRT plans resulted in larger V 10 of lung compared to 3DCRT plans. The heart was significantly spared in tomotherapy and IMRT plans compared to 3DCRT plans in terms of V 30 and V 45 . We conclude that tomotherapy plans are superior in terms of target conformity, dose homogeneity, and V 20 of lung.

IntroductionA stepwise approach to the functional assessment of lung resection candidates is widely accepted, and this approach incorporates the measurement of exercise peak Vo2 when spirometry and radionuclear studies suggest medical inoperability. A new functional operability (FO) algorithm incorporates peak exercise Vo2 earlier in the preoperative assessment to determine which patients require preoperative radionuclear studies. This algorithm has not been studied in a multicenter study.MethodsThe CALGB (Cancer and Leukemia Group B) performed a prospective multi-institutional study to investigate the use of primary exercise Vo2 measurement for the prediction of surgical risk. Patients with known or suspected resectable non-small cell lung cancer (NSCLC) were eligible. Exercise testing including measurement of peak oxygen uptake (Vo2), spirometry, and single breath diffusion capacity (DLCO) was performed on each patient. Nuclear perfusion scans were obtained on selected high-risk patients. After surgery, morbidity and mortality data were collected and correlated with preoperative data. Mortality and morbidity were retrospectively compared by algorithm-based risk groups.ResultsThree hundred forty-six patients with suspected lung cancer from nine institutions underwent thoracotomy with or without resection; 57 study patients did not undergo thoracotomy. Patients who underwent surgery had a median survival time of 30.9 months, whereas patients who did not undergo surgery had a median survival time of 15.6 months. Among the 346 patients who underwent thoracotomy, 15 patients died postoperatively (4%), and 138 patients (39%) exhibited at least one cardiorespiratory complication postoperatively. We found that patients who had a peak exercise Vo2 of

Background This study investigated the use of robotics to perform extended esophageal resection in a series of patients.

Functional deficiency of the FEN1 gene has been suggested to cause genomic instability and cancer predisposition. We have identified a group of FEN1 mutations in human cancer specimens. Most of these mutations abrogated two of three nuclease activities of flap endonuclease 1 (FEN1). To demonstrate the etiological significance of these somatic mutations, we inbred a mouse line harboring the E160D mutation representing mutations identified in human cancers. Selective elimination of nuclease activities led to frequent spontaneous mutations and accumulation of incompletely digested DNA fragments in apoptotic cells. The mutant mice were predisposed to autoimmunity, chronic inflammation and cancers. The mutator phenotype results in the initiation of cancer, whereas chronic inflammation promotes the cancer progression. The current work exemplifies the approach of studying the mechanisms of individual polymorphisms and somatic mutations in cancer development, and may serve as a reference in developing new therapeutic regimens through the suppression of inflammatory responses.

De novo methylation of CpG islands is a common phenomenon in human cancer, but the mechanisms of cancer-associated DNA methylation are not known. We have used tiling arrays in combination with the methylated CpG island recovery assay to investigate methylation of CpG islands genome-wide and at high resolution. We find that all four HOX gene clusters on chromosomes 2, 7, 12, and 17 are preferential targets for DNA methylation in cancer cell lines and in early-stage lung cancer. CpG islands associated with many other homeobox genes, such as SIX , LHX , PAX , DLX , and Engrailed , were highly methylated as well. Altogether, more than half (104 of 192) of all CpG island-associated homeobox genes in the lung cancer cell line A549 were methylated. Analysis of paralogous HOX genes showed that not all paralogues undergo cancer-associated methylation simultaneously. The HOXA cluster was analyzed in greater detail. Comparison with ENCODE-derived data shows that lack of methylation at CpG-rich sequences correlates with presence of the active chromatin mark, histone H3 lysine-4 methylation in the HOXA region. Methylation analysis of HOXA genes in primary squamous cell carcinomas of the lung led to the identification of the HOXA7 - and HOXA9 -associated CpG islands as frequent methylation targets in stage 1 tumors. Homeobox genes are potentially useful as DNA methylation markers for early diagnosis of the disease. The finding of widespread methylation of homeobox genes lends support to the hypothesis that a substantial fraction of genes methylated in human cancer are targets of the Polycomb complex.