A Cost-Effective and Non-Invasive pfeRNA-Based Test Differentiates Benign and Suspicious Pulmonary Nodules from Malignant Ones.

The ability to differentiate between benign, suspicious, and malignant pulmonary nodules is imperative for definitive intervention in patients with early stage lung cancers. Here, we report that plasma protein functional effector sncRNAs (pfeRNAs) serve as non-invasive biomarkers for determining both the existence and the nature of pulmonary nodules in a three-stage study that included the healthy group, patients with benign pulmonary nodules, patients with suspicious nodules, and patients with malignant nodules. Following the standards required for a clinical laboratory improvement amendments (CLIA)-compliant laboratory-developed test (LDT), we identified a pfeRNA classifier containing 8 pfeRNAs in 108 biospecimens from 60 patients by sncRNA deep sequencing, deduced prediction rules using a separate training cohort of 198 plasma specimens, and then applied the prediction rules to another 230 plasma specimens in an independent validation cohort. The pfeRNA classifier could (1) differentiate patients with or without pulmonary nodules with an average sensitivity and specificity of 96.2% and 97.35% and (2) differentiate malignant versus benign pulmonary nodules with an average sensitivity and specificity of 77.1% and 74.25%. Our biomarkers are cost-effective, non-invasive, sensitive, and specific, and the qPCR-based method provides the possibility for automatic testing of robotic applications.

Epidemiology of lung cancer: Diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines.

BACKGROUND: Ever since a lung cancer epidemic emerged in the mid-1900 s, the epidemiology of lung cancer has been intensively investigated to characterize its causes and patterns of occurrence. This report summarizes the key findings of this research. METHODS: A detailed literature search provided the basis for a narrative review, identifying and summarizing key reports on population patterns and factors that affect lung cancer risk. RESULTS: Established environmental risk factors for lung cancer include smoking cigarettes and other tobacco products and exposure to secondhand tobacco smoke, occupational lung carcinogens, radiation, and indoor and outdoor air pollution. Cigarette smoking is the predominant cause of lung cancer and the leading worldwide cause of cancer death. Smoking prevalence in developing nations has increased, starting new lung cancer epidemics in these nations. A positive family history and acquired lung disease are examples of host factors that are clinically useful risk indicators. Risk prediction models based on lung cancer risk factors have been developed, but further refinement is needed to provide clinically useful risk stratification. Promising biomarkers of lung cancer risk and early detection have been identified, but none are ready for broad clinical application. CONCLUSIONS: Almost all lung cancer deaths are caused by cigarette smoking, underscoring the need for ongoing efforts at tobacco control throughout the world. Further research is needed into the reasons underlying lung cancer disparities, the causes of lung cancer in never smokers, the potential role of HIV in lung carcinogenesis, and the development of biomarkers.

Defining a gene promoter methylation signature in sputum for lung cancer risk assessment.

PURPOSE: To evaluate the methylation state of 31 genes in sputum as biomarkers in an expanded nested, case-control study from the Colorado cohort, and to assess the replication of results from the most promising genes in an independent case-control study of asymptomatic patients with stage I lung cancer from New Mexico. EXPERIMENTAL DESIGN: Cases and controls from Colorado and New Mexico were interrogated for methylation of up to 31 genes using nested, methylation-specific PCR. Individual genes and methylation indices were used to assess the association between methylation and lung cancer with logistic regression modeling. RESULTS: Seventeen genes with ORs of 1.4 to 3.6 were identified and selected for replication in the New Mexico study. Overall, the direction of effects seen in New Mexico was similar to Colorado with the largest increase in case discrimination (ORs, 3.2-4.2) seen for the PAX5α, GATA5, and SULF2 genes. Receiver operating characteristic (ROC) curves generated from seven-gene panels from Colorado and New Mexico studies showed prediction accuracy of 71% and 77%, respectively. A 22-fold increase in lung cancer risk was seen for a subset of New Mexico cases with five or more genes methylated. Sequence variants associated with lung cancer did not improve the accuracy of this gene methylation panel. CONCLUSIONS: These studies have identified and replicated a panel of methylated genes whose integration with other promising biomarkers could initially identify the highest risk smokers for computed tomographic screening for early detection of lung cancer.

Writing a successful NIH Mentored Career Development Grant (K award): hints for the junior faculty surgeon.

Surgery is a labor-intensive, time-consuming profession. Young faculty members in surgery are saddled with many clinical time constraints that often allow precious few moments for academic pursuits. Consequently, K award submissions from surgeons trail nonsurgeons. The National Institutes of Health (NIH), however, is actively trying to encourage participation of surgeons in basic science research, translational research, clinical outcomes research, and even in prevention/control research. But, at the same time, the NIH has newly implemented a policy that has made the grant review process more restrictive by only allowing 2 submissions of any grant application. It is imperative, therefore, for junior faculty surgeons to learn "grantsmanship" and have the ability to construct succinct, competitive K award grants. Although most of this information is public knowledge and made available by the NIH itself, many of the practical points presented here are tailored to the special needs of clinically active surgical researchers. Often, these "hints" are buried on expansive websites that require considerable time to read and navigate. The authors have a long combined experience on a study section dedicated to adjudicating K awards. The goal of this review is to present concise, useful information about common errors, research plan dos and don'ts, template examples of superior mentored letters, and many other suggestions that may assist any first-time candidate for these awards.

Molecular assessment of lymph nodes in patients with resected stage I non-small cell lung cancer: preliminary results of a prospective study.

OBJECTIVES: Routine histologic examination of resected lymph nodes in patients with stage I non-small cell lung cancer may underestimate the incidence of advanced disease. The presence of occult lymph node metastases may predict a higher risk of recurrence after intended curative resection. The purpose of this study was to determine the prognostic significance of TP53 and K-ras mutations in histologically determined negative lymph nodes from patients with stage I non-small cell lung cancer who underwent intended curative surgical resection. METHODS: Between July 1995 and March 1998, clinical data and tissue samples of primary tumors and lymph nodes were collected in a prospective fashion from 102 patients undergoing resection for non-small cell lung cancer (stage I, n = 55; stage II, n = 32; stage IIIA, n = 15). TP53 and K-ras mutations were detected by direct sequencing. If molecular alterations were found in the primary tumor, the corresponding lymph nodes were examined for these same TP53 (by oligonucleotide hybridization) and K-ras (by allele-specific ligation) mutations. RESULTS: TP53 mutations were found in 47 of 94 primary tumors (50%), and K-ras mutations were present in 26 of 55 adenocarcinomas (47%). A total of 134 lymph nodes from 32 patients with stage I disease were analyzed. In 9 cases (28%) the same TP53 or K-ras mutations were found in tumor and lymph node specimens, suggesting occult metastasis. On the basis of nodal location, 7 patients had their disease upstaged by a single stage and 2 patients by two stages. All 28 patients with stage II or III disease had pathologically determined positive nodes that were confirmed as positive by molecular analysis. Standard histopathologic assessment of regional lymph nodes failed to detect metastases at levels below 0.9% tumor-specific mutant TP53 clones per node. No statistically significant difference in disease-specific or overall survival was observed between patients with stage I disease with and without molecular lymph node metastases. CONCLUSIONS: Occult lymph node metastases are present in a significant percentage of patients with stage I non-small cell lung cancer. These data suggest that molecular analysis allows a more accurate assessment of staging. However, larger studies are needed to determine the clinical role of molecular staging.