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

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

Complete anterior-posterior minimally invasive thoracoscopic robotic-assisted and posterior tubular approach for resection of thoracic dumbbell tumor.

Thoracic dumbbell tumors are relatively uncommon neoplasms that arise from the neurogenic elements. Surgical resection can be challenging as the tumor involves both the spinal canal and thoracic cavity. Historically, thoracotomy and laminectomy were utilized for the resection of these tumors. Although single-stage removal of such tumors has been described recently, there is no prior description of a total minimally invasive single-stage resection of a thoracic dumbbell ganglioneuroma. The current report describes a completely minimally invasive surgical resection for such a tumor performed using the posterior minimally invasive tubular approach to resect the intraspinal component with ligation of the T2 nerve root in conjunction with robotic-assisted thoracoscopic resection of the extraforaminal, intrathoracic component of the tumor. This report illustrates the safety and utility of a completely minimally invasive endoscopic resection of a thoracic dumbbell tumor that can potentially obviate the morbidity associated with open surgical resections for such tumors.

Understanding barriers to lung cancer screening in primary care.

BACKGROUND: Low-dose computed tomography (LDCT) scan for lung cancer screening is underutilized. Studies suggest that up to one-third of providers do not know the current lung cancer screening guidelines. Thus, identifying the barriers to utilization of LDCT scan is essential. METHODS: Primary care providers in three different healthcare settings in the United States were surveyed to assess provider knowledge of LDCT scan screening criteria, lung cancer screening practices, and barriers to the utilization of LDCT scan screening. Fisher's Exact, Chi-Squared, and Kruskal-Wallis tests were used to compare provider responses. Multivariable logistic regression was used to test the association between provider characteristics and the likelihood of utilizing LDCT scan for lung cancer screening. RESULTS: The survey was sent to 614 providers, with a 15.7% response rate. Overall, 29.2% of providers report never ordering LDCT scans for eligible patients. Providers practicing at a community or academic hospital more frequently order LDCT scans than those practicing at a safety net hospital. Academic- and community-based providers received a significantly higher mean knowledge score than safety net-based providers [academic 6.84 (SD 1.33), community 6.72 (SD 1.46), safety net 5.85 (SD 1.38); P<0.01]. Overall, only 6.2% of respondents correctly identified all six Centers for Medicare and Medicaid Services eligibility criteria when challenged with three incorrect criteria. Common barriers to utilization of LDCT scan included failure of the electronic medical record (EMR) to notify providers of eligible patients (54.7%), patient refusal (37%), perceived high false-positive rate leading to unnecessary procedures (18.9%), provider time constraints (16.8%), and lack of insurance coverage (13.7%). CONCLUSIONS: Provider knowledge of lung cancer screening guidelines varies, perhaps contributing to underutilization of LDCT scan for lung cancer screening. Improved provider education at safety net hospitals and improving EMR-based best practice alerts may improve the rate of lung cancer screening.

Improved False-Positive Rates and the Overestimation of Unintended Harm from Lung Cancer Screening.

BACKGROUND: Concern over high false-positive rates and the potential for unintended harm to patients is a critical component of the lack of widespread adoption of lung cancer screening. METHODS: An institutional database was used to identify patients who underwent lung cancer screening between 2/2015 and 2/2018 at Rush University Medical Center and Rush Oak Park Hospital. Reads were executed by dedicated thoracic radiologists and communicated using the Lung Imaging Reporting and Data System (Lung-RADS V.1). RESULTS: Six hundred and four patients were screened over the study period. We identified 21 primary lung cancers and 8 incidental cancers. We identified a false-positive rate of 17.5%. Only 9 patients underwent further investigative workup for benign disease (5.3%); however, only 4 (2.9%) of those patients were found to have inflammatory or infectious lesions, which are common mimickers of lung cancer. Excluding Lung-RADS category 3 for the purpose of quantifying risk of unintended harm from unnecessary procedures, we found a 6.9% false-positive rate, while diagnosing 25% of all Lung-RADS category 4 patients with primary lung cancer. CONCLUSION: False-positive rates in lung cancer screening programs continue to decline with improved radiologic expertise. Additionally, false-positive reporting overestimates the risk of unintended harm from further investigative procedures as only a percentage of positive findings are generally considered for tissue diagnosis (i.e., Lung-RADS category 4).

Serum Biomarkers May Prognosticate Recurrence in Node-Negative, Non-Small Cell Lung Cancers Less Than 4 Centimeters.

BACKGROUND: A significant proportion of patients who undergo lung resection for less than 4 cm non-small cell lung cancer (NSCLC) will die of disease recurrence within 5 years. The ability to identify patients at greatest risk for recurrence may help individualize treatment and surveillance regimens and improve outcomes. We hypothesized that a serum-based biomarker panel could help risk stratify patients with node-negative NSCLC less than 4 cm for recurrence after lung resection. METHODS: An institutional biorepository of more than 1,800 cases was used to identify patients with resected, node-negative NSCLC less than 4 cm in size. Clinical and radiographic data were collected. Preoperative serum specimens were evaluated in a blinded manner for 47 biomarkers that sampled biological processes associated with metastatic progression, including angiogenesis, energy metabolism, apoptosis, and inflammation. Receiver-operating characteristics curves and log rank tests were used to evaluate individual biomarkers with respect to recurrence, followed by random forest analysis to generate and cross validate a multiple-analyte panel to risk stratify patients for recurrence. RESULTS: The cohort included 123 patients with a median follow-up of 58.2 months; 23 patients had recurrences. A seven-analyte panel consisting of human epididymis protein 4, insulinlike growth factor-binding protein 1, beta-human chorionic gonadotropin, follistatin, prolactin, angiopoietin-2, and hepatocyte growth factor optimally identified patients with disease recurrence with a cross-validated specificity of 91%, sensitivity of 22%, negative predictive value of 83%, positive predictive value of 36%, and accuracy of 78%, providing an area under the receiver-operating characteristics curve of 0.70. CONCLUSIONS: Serum-based biomarkers may be useful for risk stratifying patients with node-negative NSCLC less than 4 cm for recurrence after lung resection.

Durability of Silicone Airway Stents in the Management of Benign Central Airway Obstruction.

PURPOSE: The literature is devoid of a comprehensive analysis of silicone airway stenting for benign central airway obstruction (BCAO). With the largest series in the literature to date, we aim to demonstrate the safety profile, pattern of re-intervention, and duration of silicone airway stents. METHODS: An institutional database was used to identify patients with BCAO who underwent rigid bronchoscopy with dilation and silicone stent placement between 2002 and 2015 at Rush University Medical Center. RESULTS: During the study period, 243 stents were utilized in 63 patients with BCAO. Pure tracheal stenosis was encountered in 71% (45/63), pure tracheomalacia in 11% (7/63), and a hybrid of both in 17% (11/63). Median freedom from re-intervention was 104 (IQR 167) days. Most common indications for re-intervention include mucus accumulation (60%; 131/220), migration (28%; 62/220), and intubation (8%; 18/220). The most common diameters of stent placed were 12 mm (94/220) and 14 mm (96/220). The most common lengths utilized were 30 mm (60/220) and 40 mm (77/220). Duration was not effected by stent size when placed for discrete stenosis. However, 14 mm stents outperformed 12 mm when tracheomalacia was present (157 vs. 37 days; p = 0.005). Patients with a hybrid stenosis fared better when longer stents were used (60 mm stents outlasted 40 mm stents 173 vs. 56 days; p = 0.05). CONCLUSION: Rigid bronchoscopy with silicone airway stenting is a safe and effective option for the management of benign central airway obstruction. Our results highlight several strategies to improve stent duration.

Comparing rat and rabbit embryo-fetal developmental toxicity data for 379 pharmaceuticals: on systemic dose and developmental effects.

A database of embryo-fetal developmental toxicity (EFDT) studies of 379 pharmaceutical compounds in rat and rabbit was analyzed for species differences based on toxicokinetic parameters of area under the curve (AUC) and maximum concentration (Cmax) at the developmental lowest adverse effect level (dLOAEL). For the vast majority of cases (83% based on AUC of n = 283), dLOAELs in rats and rabbits were within the same order of magnitude (less than 10-fold different) when compared based on available data on AUC and Cmax exposures. For 13.5% of the compounds the rabbit was more sensitive and for 3.5% of compounds the rat was more sensitive when compared based on AUC exposures. For 12% of the compounds the rabbit was more sensitive and for 1.3% of compounds the rat was more sensitive based on Cmax exposures. When evaluated based on human equivalent dose (HED) conversion using standard factors, the rat and rabbit were equally sensitive. The relative extent of embryo-fetal toxicity in the presence of maternal toxicity was not different between species. Overall effect severity incidences were distributed similarly in rat and rabbit studies. Individual rat and rabbit strains did not show a different general distribution of systemic exposure LOAELs as compared to all strains combined for each species. There were no apparent species differences in the occurrence of embryo-fetal variations. Based on power of detection and given differences in the nature of developmental effects between rat and rabbit study outcomes for individual compounds, EFDT studies in two species have added value over single studies.

Comparison of rat and rabbit embryo-fetal developmental toxicity data for 379 pharmaceuticals: on the nature and severity of developmental effects.

Regulatory non-clinical safety testing of human pharmaceuticals typically requires embryo-fetal developmental toxicity (EFDT) testing in two species (one rodent and one non-rodent). The question has been raised whether under some conditions EFDT testing could be limited to one species, or whether the testing in a second species could be decided on a case-by-case basis. As part of a consortium initiative, we built and queried a database of 379 compounds with EFDT studies (in both rat and rabbit animal models) conducted for marketed and non-marketed pharmaceuticals for their potential for adverse developmental and maternal outcomes, including EFDT incidence and the nature and severity of adverse findings. Manifestation of EFDT in either one or both species was demonstrated for 282 compounds (74%). EFDT was detected in only one species (rat or rabbit) in almost a third (31%, 118 compounds), with 58% (68 compounds) of rat studies and 42% (50 compounds) of rabbit studies identifying an EFDT signal. For 24 compounds (6%), fetal malformations were observed in one species (rat or rabbit) in the absence of any EFDT in the second species. In general, growth retardation, fetal variations, and malformations were more prominent in the rat, whereas embryo-fetal death was observed more often in the rabbit. Discordance across species may be attributed to factors such as maternal toxicity, study design differences, pharmacokinetic differences, and pharmacologic relevance of species. The current analysis suggests that in general both species are equally sensitive on the basis of an overall EFDT LOAEL comparison, but selective EFDT toxicity in one species is not uncommon. Also, there appear to be species differences in the prevalence of various EFDT manifestations (i.e. embryo-fetal death, growth retardation, and dysmorphogenesis) between rat and rabbit, suggesting that the use of both species has a higher probability of detecting developmental toxicants than either one alone.

Metformin exposure is associated with improved progression-free survival in diabetic patients after resection for early-stage non-small cell lung cancer.

OBJECTIVE: There are little clinical data assessing the antineoplastic effect of metformin in patients with non-small cell lung cancer. We hypothesized that in diabetic patients undergoing pulmonary resection for early-stage non-small cell lung cancer, metformin exposure is associated with improved survival. METHODS: An institutional database was used to identify patients with stage I or II non-small cell lung cancer who underwent pulmonary resection between 2004 and 2013. Patients were divided into 3 cohorts: type II diabetic patients with metformin exposure (cohort A, n = 81), type II diabetic patients without metformin exposure (cohort B, n = 57), and nondiabetic individuals (cohort C, n = 77). Univariate, multivariate, and propensity-matched analyses were performed to assess progression-free and overall survivals between groups. RESULTS: A total of 215 patients with stage I and II non-small cell lung cancer treated with surgical resection were identified for analysis with a median follow-up of 19.5 months. Patients in cohort A had lower T- and N-stage tumors than those in cohorts B or C. However, on multivariate analysis adjusting for age, gender, and T and N stage, progression-free survival was greater for cohort A than cohort B (hazard ratio [HR], 0.410; 95% confidence interval, 0.199-0.874; P = .022) or cohort C (HR, 0.415; 95% confidence interval, 0.201-0.887; P = .017). Likewise, when propensity-matched analyses were performed, cohort A demonstrated a trend toward improved progression-free survival compared with cohort B (P = .057; HR, 0.44; c-statistic = 0.832) and improved progression-free survival compared with cohort C (P = .02; HR, 0.41; c-statistic = 0.843). No differences were observed in overall survival. CONCLUSIONS: Metformin exposure in diabetic patients with early-stage non-small cell lung cancer may be associated with improved progression-free survival, but no effect was seen on overall survival. Further studies are warranted to evaluate if there is a therapeutic role for metformin in the treatment of non-small cell lung cancer.

Number of Ribs Resected is Associated with Respiratory Complications Following Lobectomy with en bloc Chest Wall Resection.

PURPOSE: Pulmonary lobectomy with en bloc chest wall resection is a common strategy for treating lung cancers invading the chest wall. We hypothesized a direct relationship exists between number of ribs resected and postoperative respiratory complications. METHODS: An institutional database was queried for patients with non-small cell lung cancer that underwent lobectomy with en bloc chest wall resection between 2003 and 2014. Propensity matching was used to identify a cohort of patients who underwent lobectomy via thoracotomy without chest wall resection. Patients were propensity matched on age, gender, smoking history, FEV1, and DLCO. The relationship between number of ribs resected and postoperative respiratory complications (bronchoscopy, re-intubation, pneumonia, or tracheostomy) was examined. RESULTS: Sixty-eight patients (34 chest wall resections; 34 without chest wall resection) were divided into 3 cohorts: cohort A = 0 ribs resected (n = 34), cohort B = 1-3 ribs resected (n = 24), and cohort C = 4-6 ribs resected (n = 10). Patient demographics were similar between cohorts. The 90-day mortality rate was 2.9 % (2/68) and did not vary between cohorts. On multivariate analysis, having 1-3 ribs resected (OR 19.29, 95 % CI (1.33, 280.72); p = 0.03), 4-6 ribs resected [OR 26.66, (1.48, 481.86); p = 0.03), and a lower DLCO (OR 0.91, (0.84, 0.99); p = 0.02) were associated with postoperative respiratory complications. CONCLUSIONS: In patients undergoing lobectomy with en bloc chest wall resection for non-small cell lung cancer, the number of ribs resected is directly associated with incidence of postoperative respiratory complications.

Micro-CT imaging: Developing criteria for examining fetal skeletons in regulatory developmental toxicology studies - A workshop report.

During the past two decades the use and refinements of imaging modalities have markedly increased making it possible to image embryos and fetuses used in pivotal nonclinical studies submitted to regulatory agencies. Implementing these technologies into the Good Laboratory Practice environment requires rigorous testing, validation, and documentation to ensure the reproducibility of data. A workshop on current practices and regulatory requirements was held with the goal of defining minimal criteria for the proper implementation of these technologies and subsequent submission to regulatory agencies. Micro-computed tomography (micro-CT) is especially well suited for high-throughput evaluations, and is gaining popularity to evaluate fetal skeletons to assess the potential developmental toxicity of test agents. This workshop was convened to help scientists in the developmental toxicology field understand and apply micro-CT technology to nonclinical toxicology studies and facilitate the regulatory acceptance of imaging data. Presentations and workshop discussions covered: (1) principles of micro-CT fetal imaging; (2) concordance of findings with conventional skeletal evaluations; and (3) regulatory requirements for validating the system. Establishing these requirements for micro-CT examination can provide a path forward for laboratories considering implementing this technology and provide regulatory agencies with a basis to consider the acceptability of data generated via this technology.

Survival Benefit of Surgery after Chemoradiotherapy for Stage III (N0-2) Non-Small-Cell Lung Cancer Is Dependent on Pathologic Nodal Response.

INTRODUCTION: The benefit of surgery (trimodality therapy [TMT]) after chemoradiotherapy (CRT) for patients with stage III non-small-cell lung cancer (NSCLC) is controversial, but nodal pathologic complete response (N-PCR) is accepted as a strong predictor of overall survival (OS). We compared the outcomes of patients treated with TMT versus CRT, focusing on the importance of N-PCR. METHODS: Patients with stage III NSCLC treated with CRT or TMT from December 2004 through December 2012 were included; patients with N3 disease were excluded. Pathologic nodal response dichotomized surgical patients into N-PCR versus residual nodal disease (RND) groups. Actuarial OS, progression-free survival (PFS), and distant metastasis-free survival (DMFS) were compared between patients treated with CRT and TMT and between CRT and N-PCR/RND. RESULTS: The cohort was composed of 138 patients (52% CRT and 48% TMT). The median OS was significantly higher after TMT than after CRT (81 versus 31.8 mo, p = 0.0068). This benefit was restricted to N-PCR (n = 50, 83.2 versus 31.8 mo, p = 0.0004), as RND (n = 19) experienced poor OS (16.1 mo). On multivariable analyses, N-PCR had superior OS (hazard ratio [HR], 0.38; p = 0.0012), PFS (HR, 0.42; p = 0.0005), and DMFS (HR, 0.42; p = 0.0007) compared with CRT. Conversely, there were trends for worse OS and PFS for RND versus CRT, although only inferior DMFS was significant (HR, 1.83; p = 0.04). CONCLUSIONS: Surgical patients with complete nodal clearance experienced superior survival, but those with RND fared no better than CRT alone. Mediastinal response may play an important role in the decision to proceed with surgical resection after CRT for stage III NSCLC.

Incidence of Esophageal Adenocarcinoma and Causes of Mortality After Radiofrequency Ablation of Barrett's Esophagus.

BACKGROUND & AIMS: Radiofrequency ablation (RFA) is commonly used to treat Barrett's esophagus (BE). We assessed the incidence of esophageal adenocarcinoma (EAC) after RFA, factors associated with the development of EAC, and EAC-specific and all-cause mortality. METHODS: We collected data for outcomes of patients who underwent RFA for BE from July 2007 through July 2011 from US multicenter RFA Patient Registry. Patients were followed until July 2014. Kaplan-Meier curves of EAC incidence were stratified by baseline histology. Crude EAC incidence and mortality (all-cause and EAC-specific) were calculated, and adjusted all-cause mortality was assessed. Logistic regression models were constructed to assess predictors of EAC and all-cause mortality. RESULTS: Among 4982 patients, 100 (2%) developed EAC (7.8/1000 person-years [PY]) and 9 patients (0.2%) died of EAC (0.7/1000 PY) in a mean 2.7 ± 1.6 years. The incidence of EAC in nondysplastic BE was 0.5/1000 PY. Overall, 157 patients (3%) died during follow-up (all-cause mortality, 11.2/1000 PY). On multivariate logistic regression, baseline BE length (odds ratio, 1.1/ cm) and baseline histology (odds ratios, 5.8 and 50.3 for low-grade dysplasia and high-grade dysplasia [HGD] respectively) predicted EAC incidence. Among 9 EAC deaths, 6 (67%) had baseline HGD, and 3 (33%) had baseline intramucosal EAC. The most common causes of death were cardiovascular (15%) and extraesophageal cancers (15%). No deaths were associated with RFA. CONCLUSIONS: Based on analysis of a multicenter registry of patients who underwent RFA of BE, less than 1% died from EAC. The incidence of EAC was markedly lower in this study than in other studies of disease progression, with the greatest absolute benefit observed in patients with HGD.

Angiogenesis Biomarkers May Be Useful in the Management of Patients With Indeterminate Pulmonary Nodules.

BACKGROUND: Low-dose computed tomography (CT) lung cancer screening is known to have a high false positive rate. This study aims to survey biomarkers of angiogenesis for those capable of assigning clinical significance to indeterminate pulmonary nodules detected through CT imaging studies. METHODS: An institutional database and specimen repository was used to identify 193 patients with stage I non-small cell lung cancer (T1N0M0) and 110 patients with benign solitary pulmonary nodules detected by CT imaging studies. All specimens were evaluated in a blinded manner for 17 biomarkers of angiogenesis using multiplex immunoassays. Biomarker performance was calculated through the Mann-Whitney rank sum U test and a receiver operator characteristic analysis. These data were used to refine our previously reported multi-analyte classification panel, which was then externally validated against an independent patient cohort (n = 80). RESULTS: A total of 303 patients were screened for 17 biomarkers of angiogenesis. Median nodule size was 1.2 cm for benign cases and 1.8 cm for non-small cell lung cancer, whereas median smoking histories were 25 and 40 pack-years, respectively. Differences in serum concentrations of heparin-binding epidermal growth factor (HB-EGF), epidermal growth factor (EGF), vascular (V)EGF-A, VEGF-C, and VEGF-D were strongly significant (p ≤ 0.001) while follistatin, placental growth factor (PLGF), and bone morphogenic protein (BMP)-9 were significant (p ≤ 0.05) between patients with benign and malignant nodules. Our previously reported multi-analyte classification panel was refined to include interleukin (IL)-6, IL-10, IL-1 receptor antagonist (RA), tumor necrosis factor (TNF)-α, insulin-like growth factor binding protein (IGFBP)-5, IGFBP-4, IGF-2, stromal cell-derived factor (SDF)-1(α+ß), HB-EGF, and HGF resulting in improved accuracy and a validated negative predictive value of 96.4%. CONCLUSIONS: Angiogenesis biomarkers may be useful in discriminating stage I NSCLC from benign pulmonary nodules.

Effects of the Learning Curve on Efficacy of Radiofrequency Ablation for Barrett's Esophagus.

BACKGROUND & AIMS: Complete eradication of Barrett's esophagus (BE) often requires multiple sessions of radiofrequency ablation (RFA). Little is known about the effects of case volume on the safety and efficacy of RFA or about the presence or contour of learning curves for this procedure. METHODS: We collected data from the US RFA Patient Registry (from 148 institutions) for patients who underwent RFA for BE from July 2007 to July 2011. We analyzed the effects of the number of patients treated by individual endoscopists and individual centers on safety and efficacy outcomes of RFA. Outcomes, including stricture, bleeding, hospitalization, and complete eradication of intestinal metaplasia (CEIM), were assessed using logistic regression. The effects of center and investigator experience on numbers of treatment sessions to achieve CEIM were examined using linear regression. RESULTS: After we controlled for potential confounders, we found that as the experience of endoscopists and centers increased with cases, the numbers of treatment sessions required to achieve CEIM decreased. This relationship persisted after adjusting for patient age, sex, race, length of BE, and presence of pretreatment dysplasia (P < .01). Center experience was not significantly associated with overall rates of CEIM or complete eradication of dysplasia. We did not observe any learning curve with regard to risks of stricture, gastrointestinal bleeding, perforation, or hospitalization (P > .05). CONCLUSIONS: Based on analysis of a large multicenter registry, efficiency of the treatment, as measured by number of sessions needed to achieve CEIM, increased with case volume, indicating a learning curve effect. This trend began to disappear after treatment of approximately 30 patients by the center or individual endoscopist. However, there was no significant association between safety or efficacy outcomes and previous case volume.

Value of circulating insulin-like growth factor-associated proteins for the detection of stage I non-small cell lung cancer.

OBJECTIVE: Circulating biomarkers related to insulin-like growth factor (IGF) signaling are associated with disease progression in multiple carcinomas, but their potential diagnostic value for lung cancer screening has been inadequately examined. We evaluated 9 circulating IGF-related factors for their ability to assign clinical significance to indeterminate pulmonary nodules identified via computed tomography-based radiologic studies. METHODS: Patients (n = 224 stage I non-small cell lung cancer; n = 123 benign) were enrolled by Rush University and the Mayo Clinic and had pretreatment serum evaluated for levels of IGF-1, IGF-2, and insulin-like growth factor binding proteins (IGFBPs) 1-7. The Mann-Whitney rank-sum test and receiver-operator characteristics curves were used to assess differences in biomarker concentrations relevant to malignant versus benign pathology. These targets were used to help refine our companion blood test for assigning clinical significance to computed tomography-detected solitary nodules (discovery cohort, n = 94) and were validated against an independent cohort from the Mayo Clinic (n = 81). RESULTS: Patients with benign pulmonary nodules were found to have serum concentrations of IGFBP-3, IGFBP-5, IGF-1, and IGF-2 that were higher (P = .001, P < .001, P = .002, and P = .011, respectively) than those with non-small cell lung cancer, with distinct associations with histologic subtypes observed. Refinement of our multianalyte classification algorithm using IGF-related factors provided a new panel consisting of interleukin-6, interleukin-1 receptor antagonist, interleukin-10, stromal cell-derived factor-1(α + ß), IGFBP-4, IGFBP-5, and IGF-2 with improved assay performance-achieving a (validated) negative predictive value of 100%. CONCLUSIONS: Our findings suggest a divergent role for IGF signaling in the biology of benign and malignant pulmonary nodules. Upon further validation, these observations may help identify cases of false positives resulting from computed tomography-based screening studies.

Circulating angiogenesis biomarkers are associated with disease progression in lung adenocarcinoma.

BACKGROUND: Dysregulation of angiogenesis is known to be associated with tumorigenesis and metastatic progression in multiple carcinomas. The aim of this study was to evaluate the prognostic value of circulating angiogenesis biomarkers in lung adenocarcinoma progression. For that, we hypothesize that circulating levels of biomarkers characteristic for discrete processes within angiogenesis are associated with specific phases of disease progression. Appreciation of these profiles may have important implications for disease detection and prognostication. METHODS: Patients with lung adenocarcinoma enrolled in the study were grouped as follows: node negative (T1a-3N0M0; n = 69), node positive (T1a-4N1-2M0; n = 60), and disseminated disease (TxNxM1; n = 68). All serum specimens were assayed for 17 angiogenesis biomarkers on the Luminex platform and statistically evaluated by analysis of variance for median differences in biomarker concentration at distinct phases of disease progression and by log rank methods for associations with clinical outcome. RESULTS: We found circulating hepatocyte growth factor, heparin-binding epidermal growth factor, epidermal growth factor, and vascular endothelial growth factor-C levels significantly elevated (p < 0.05) in patients with node positive versus node negative disease. Similarly, median serum concentrations of bone morphogenic protein-9, endoglin, fibroblast growth factor-1, fibroblast growth factor-2, interleukin-8, placental growth factor, vascular endothelial growth factor-C, and vascular endothelial growth factor-D were significantly (p < 0.05) higher in patients with disseminated disease than in patients with node positive disease. Five biomarkers total were strongly prognostic (p < 0.05) for overall survival in the node negative cohort. CONCLUSIONS: Angiogenesis is a process central to lung adenocarcinoma progression. We describe the modulation in serum angiogenesis biomarker concentrations through the various phases of non-small cell lung cancer progression. Additional refinement efforts are under way to enhance test performance, followed by additional validation studies.

Durability and predictors of successful radiofrequency ablation for Barrett's esophagus.

BACKGROUND & AIMS: After radiofrequency ablation (RFA), patients may experience recurrence of Barrett's esophagus (BE) after complete eradication of intestinal metaplasia (CEIM). Rates and predictors of recurrence after successful eradication have been poorly described. METHODS: We used the US RFA Registry, a nationwide registry of BE patients receiving RFA, to determine rates and factors that predicted recurrence of intestinal metaplasia (IM). We assessed recurrence by Kaplan-Meier analysis for the overall cohort and by worst pretreatment histology. Characteristics associated with recurrence were included in a logistic regression model to identify independent predictors. RESULTS: Among 5521 patients, 3728 had biopsies 12 months or more after initiation of RFA. Of these, 3169 (85%) achieved CEIM, and 1634 (30%) met inclusion criteria. The average follow-up period was 2.4 years after CEIM. IM recurred in 334 (20%) and was nondysplastic or indefinite for dysplasia in 86% (287 of 334); the average length of recurrent BE was 0.6 cm. In Kaplan-Meier analysis, more advanced pretreatment histology was associated with an increased yearly recurrence rate. Compared with patients without recurrence, patients with recurrence were more likely, based on bivariate analysis, to be older, have longer BE segments, be non-Caucasian, have dysplastic BE before treatment, and require more treatment sessions. In multivariate analysis, the likelihood for recurrence was associated with increasing age and BE length, and non-Caucasian race. CONCLUSIONS: BE recurred in 20% of patients followed up for an average of 2.4 years after CEIM. Most recurrences were short segments and were nondysplastic or indefinite for dysplasia. Older age, non-Caucasian race, and increasing length of BE length were all risk factors. These risk factors should be considered when planning post-RFA surveillance intervals.

Prior fundoplication does not improve safety or efficacy outcomes of radiofrequency ablation: results from the U.S. RFA Registry.

BACKGROUND: Ongoing gastroesophageal reflux may impair healing and re-epithelialization after radiofrequency ablation (RFA) of Barrett's esophagus (BE). Because prior fundoplication may improve reflux control, our aim was to assess the relationship between prior fundoplication and the safety/efficacy of RFA. METHODS: We assessed the U.S. RFA Registry, a nationwide registry of BE patients receiving RFA at 148 institutions, to compare the safety and efficacy of ablation between those with prior fundoplication and those with medical management (proton pump inhibition). RESULTS: Among 5,537 patients receiving RFA, 301 (5.4 %) had prior fundoplication. Of fundoplication subjects, 1.0 % developed stricture and 1.0 % were hospitalized after RFA. Rates of stricture, bleeding, and hospitalization were not statistically different (p = ns) between patients with and without prior fundoplication. Complete eradication of intestinal metaplasia and complete eradication of dysplasia were achieved in 71 % and 87 % of fundoplication patients, and 73 % and 87 % of patients without fundoplication, respectively (p = ns for both). Patients with prior fundoplication needed similar numbers of RFA sessions for eradication compared with those without fundoplication. CONCLUSIONS: Radiofrequency ablation, with or without prior fundoplication, is safe and effective in eradicating BE. Prior fundoplication was associated with similar adverse event and efficacy rates when compared with medical management.

Development and validation of a plasma biomarker panel for discerning clinical significance of indeterminate pulmonary nodules.

INTRODUCTION: The recent findings of the National Lung Screening Trial showed 24.2% of individuals at high risk for lung cancer having one or more indeterminate nodules detected by low-dose computed tomography-based screening, 96.4% of which were eventually confirmed as false positives. These positive scans necessitate additional diagnostic procedures to establish a definitive diagnosis that adds cost and risk to the paradigm. A plasma test able to assign benign versus malignant pathology in high-risk patients would be an invaluable tool to complement low-dose computed tomography-based screening and promote its rapid implementation. METHODS: We evaluated 17 biomarkers, previously shown to have value in detecting lung cancer, against a discovery cohort, comprising benign (n = 67) cases and lung cancer (n = 69) cases. A Random Forest method based analysis was used to identify the optimal biomarker panel for assigning disease status, which was then validated against a cohort from the Mayo Clinic, comprising patients with benign (n = 61) or malignant (n = 20) indeterminate lung nodules. RESULTS: Our discovery efforts produced a seven-analyte plasma biomarker panel consisting of interleukin 6 (IL-6), IL-10, IL-1ra, sIL-2Rα, stromal cell-derived factor-1α+ß, tumor necrosis factor α, and macrophage inflammatory protein 1 α. The sensitivity and specificity of our panel in our validation cohort is 95.0% and 23.3%, respectively. The validated negative predictive value of our panel was 93.8%. CONCLUSION: We developed a seven-analyte plasma biomarker panel able to identify benign nodules, otherwise deemed indeterminate, with a high degree of accuracy. This panel may have clinical utility in risk-stratifying screen-detected lung nodules, decrease unnecessary follow-up imaging or invasive procedures, and potentially avoid unnecessary morbidity, mortality, and health care costs.