Li X.-J.,Integrated Diagnostics |
Hayward C.,Integrated Diagnostics |
Fong P.-Y.,Integrated Diagnostics |
Dominguez M.,Integrated Diagnostics |
And 22 more authors.
Science Translational Medicine | Year: 2013
Each year, millions of pulmonary nodules are discovered by computed tomography and subsequently biopsied. Because most of these nodules are benign, many patients undergo unnecessary and costly invasive procedures. We present a 13-protein blood-based classifier that differentiates malignant and benign nodules with high confidence, thereby providing a diagnostic tool to avoid invasive biopsy on benign nodules.Using a systems biology strategy, we identified 371 protein candidates and developed a multiple reaction monitoring (MRM) assay for each. The MRM assayswere applied in a three-site discovery study (n = 143) on plasma samples from patients with benign and stage IA lung cancermatched for nodule size, age, gender, and clinical site, producing a 13-protein classifier. The classifier was validated on an independent set of plasma samples (n = 104), exhibiting a negative predictive value (NPV) of 90%. Validation performance on samples from a nondiscovery clinical site showed an NPV of 94%, indicating the general effectiveness of the classifier. A pathway analysis demonstrated that the classifier proteins are likely modulated by a few transcription regulators (NF2L2, AHR, MYC, and FOS) that are associated with lung cancer, lung inflammation, and oxidative stress networks. The classifier score was independent of patient nodule size, smoking history, and age, which are risk factors used for clinical management of pulmonary nodules. Thus, this molecular test provides a potential complementary tool to help physicians in lung cancer diagnosis.
Poste G.,Arizona State University |
Carbone D.P.,Thoracic Oncology Center |
Parkinson D.R.,Nodality |
Verweij J.,Erasmus Medical Center |
And 2 more authors.
Clinical Cancer Research | Year: 2012
Molecular diagnostics are becoming increasingly important in clinical research to stratify or identify molecularly profiled patient cohorts for targeted therapies, to modify the dose of a therapeutic, and to assess early response to therapy or monitor patients. Molecular diagnostics can also be used to identify the pharmacogenetic risk of adverse drug reactions. The articles in this CCR Focus section on molecular diagnosis describe the development and use of markers to guide medical decisions regarding cancer patients. They define sources of preanalytic variability that need to be minimized, as well as the regulatory and financial challenges involved in developing diagnostics and integrating them into clinical practice. They also outline a National Cancer Institute program to assist diagnostic development. Molecular diagnostic clinical tests require rigor in their development and clinical validation, with sensitivity, specificity, and validity comparable to those required for the development of therapeutics. These diagnostics must be offered at a realistic cost that reflects both their clinical value and the costs associated with their development. When genome-sequencing technologies move into the clinic, they must be integrated with and traceable to current technology because they may identify more efficient and accurate approaches to drug development. In addition, regulators may define progressive drug approval for companion diagnostics that requires further evidence regarding efficacy and safety before full approval can be achieved. One way to accomplish this is to emphasize phase IV postmarketing, hypothesis-driven clinical trials with biological characterization that would permit an accurate definition of the association of low-prevalence gene alterations with toxicity or response in large cohorts. ©2012 AACR.
Gomperts B.N.,University of California at Los Angeles |
Gomperts B.N.,Mattel Childrens Hospital at UCLA |
Spira A.,Boston University |
Massion P.P.,Thoracic Oncology Center |
And 5 more authors.
Seminars in Respiratory and Critical Care Medicine | Year: 2011
Lung carcinogenesis is a complex, stepwise process that involves the acquisition of genetic mutations and epigenetic changes that alter cellular processes, such as proliferation, differentiation, invasion, and metastasis. Here, we review some of the latest concepts in the pathogenesis of lung cancer and highlight the roles of inflammation, the field of cancerization, and lung cancer stem cells in the initiation of the disease. Furthermore, we review how high throughput genomics, transcriptomics, epigenomics, and proteomics are advancing the study of lung carcinogenesis. Finally, we reflect on the potential of current in vitro and in vivo models of lung carcinogenesis to advance the field and on the areas of investigation where major breakthroughs will lead to the identification of novel chemoprevention strategies and therapies for lung cancer. © Georg Thieme Verlag KG Stuttgart. New York.
Kobold S.,Ludwig Maximilians University of Munich |
Volk S.,Ludwig Maximilians University of Munich |
Clauditz T.,University of Hamburg |
Kupper N.J.,Ludwig Maximilians University of Munich |
And 11 more authors.
Journal of Thoracic Oncology | Year: 2013
INTRODUCTION: In lung cancer, interleukin-22 (IL-22) expression within primary tissue has been demonstrated, but the frequency and the functional consequence of IL-22 signaling have not been addressed. This study aims at analyzing the cellular effects of IL-22 on lung carcinoma cell lines and the prognostic impact of IL-22 tissue expression in lung cancer patients. METHODS: Biological effects of IL-22 signaling were investigated in seven lung cancer cell lines by Western blot, flow cytometry, real-time polymerase chain reaction, and proliferation assays. Tumor tissue specimens of two cohorts with a total of 2300 lung cancer patients were tested for IL-22 expression by immunohistochemistry. IL-22 serum concentrations were analyzed in 103 additional patients by enzyme-linked immunosorbent assay. RESULTS: We found the IL-22 receptor 1 (IL-22-R1) to be expressed in six of seven lung cancer cell lines. However IL-22 signaling was functional in only four cell lines, where IL-22 induced signal transducer activator of transcription 3 phosphorylation and increased cell proliferation. Furthermore, IL-22 induced the expression of antiapoptotic B-cell lymphoma 2, but did not rescue tumor cells from carboplatin-induced apoptosis. Cisplatin-resistant cell lines showed a significant up-regulation of IL-22-R1 along with a stronger proliferative response to IL-22 stimulation. IL-22 was preferentially expressed in small- and large-cell lung carcinoma (58% and 46% of cases, respectively). However, no correlation between IL-22 expression by immunohistochemistry and prognosis was observed. CONCLUSION: IL-22 is frequently expressed in lung cancer tissue. Enhanced IL-22-R1 expression and signaling in chemotherapy-refractory cell lines are indicative of a protumorigenic function of IL-22 and may contribute to a more aggressive phenotype. © 2013 by the International Association for the Study of Lung Cancer.
Pecot C.V.,Vanderbilt University |
Li M.,Vanderbilt University |
Zhang X.J.,Vanderbilt University |
Rajanbabu R.,Thoracic Oncology Center |
And 18 more authors.
Cancer Epidemiology Biomarkers and Prevention | Year: 2012
Background: Current management of lung nodules is complicated by nontherapeutic resections and missed chances for cure. We hypothesized that a serum proteomic signature may add diagnostic information beyond that provided by combined clinical and radiographic data. Methods: Cohort A included 265 and cohort B 114 patients. Using multivariable logistic regression analysis we calculated the area under the receiver operating characteristic curve (AUC) and quantified the added value of a previously described serum proteomic signature beyond clinical and radiographic risk factors for predicting lung cancer using the integration discrimination improvement (IDI) index. Results: The average computed tomography (CT) measured nodule size in cohorts A and B was 37.83 versus 23.15 mm among patients with lung cancer and 15.82 versus 17.18 mm among those without, respectively. In cohort A, the AUC increased from 0.68 to 0.86 after adding chest CT imaging variables to the clinical results, but the proteomic signature did not provide meaningful added value. In contrast, in cohort B, the AUC improved from 0.46 with clinical data alone to 0.61 when combined with chest CT imaging data and to 0.69 after adding the proteomic signature (IDI of 20% P=0.0003). In addition, in a subgroup of 100 nodules between 5 and 20mm in diameter, the proteomic signature added value with an IDI of 15% (P < 0.0001). Conclusions: The results show that this serum proteomic biomarker signature may add value to the clinical and chest CT evaluation of indeterminate lung nodules. Impact: This study suggests a possible role of a blood biomarker in the evaluation of indeterminate lung nodules. ©2012 AACR.
Carbone D.P.,Thoracic Oncology Center |
Felip E.,University of Barcelona
Clinical Lung Cancer | Year: 2011
There is a high risk of relapse after curative-intent resection for even early-stage Non-small cell lung cancer (NSCLC), and thus adjuvant chemotherapy has been explored with the goal of eliminating occult metastases and consequently reducing the risk of recurrence. Although adjuvant chemotherapy confers a survival advantage of approximately 5% at 5 years and is now generally accepted for patients with stage II-IIIA disease, adjuvant therapy for patients with stage I disease is more controversial. In this review we describe approaches to improve treatment outcomes and ongoing research into new therapies in the adjuvant setting. In the future it is likely that patient selection on the basis of gene signatures and biomarkers will be of increasing importance in determining optimal treatment for individual patients. New targeted therapies such as epidermal growth factor receptor (EGFR) inhibitors, angiogenesis inhibitors, and anticancer immunotherapies are showing activity in the advanced disease setting and are being studied for incorporation into multimodal adjuvant treatment approaches. It is hoped that such advances and a changing treatment paradigm will ultimately result in greater survival for patients with early NSCLC. © 2011 Elsevier Inc. All rights reserved.
Yuki D.,Thoracic Oncology Center |
Nakamae K.,Thoracic Oncology Center |
Sano M.,Nagoya Memorial Hospital
Japanese Journal of Chest Diseases | Year: 2016
For the management of postoperative lymph leakage after a right upper lobectomy for lung cancer, we performed intrathoracic administration of OK432 for pleurodesis. Immediately after the administration, ground glass opacity appeared widely in the right lower lobe and dyspnea occurred. We diagnosed the condition as acute lung injury (ALI) associated with the administration of OK-432. OK-432, developed as an antineoplastic agent has been classified as biological response modifier. It strongly activates the innate immune system and induces inflammatory cytokines. On the basis of this mechanism, pleurodesis with OK-432 is performed; however, it sometimes induces ALI, which is life threatening. Therefore, intrathoracic administration of OK-432 should be performed with caution, considering the biological effects of the drug and the possibility of ALL.
PubMed | Thoracic Oncology Center
Type: Journal Article | Journal: Clinical lung cancer | Year: 2011
There is a high risk of relapse after curative-intent resection for even early-stage non-small cell lung cancer (NSCLC), and thus adjuvant chemotherapy has been explored with the goal of eliminating occult metastases and consequently reducing the risk of recurrence. Although adjuvant chemotherapy confers a survival advantage of approximately 5% at 5 years and is now generally accepted for patients with stage II-IIIA disease, adjuvant therapy for patients with stage I disease is more controversial. In this review we describe approaches to improve treatment outcomes and ongoing research into new therapies in the adjuvant setting. In the future it is likely that patient selection on the basis of gene signatures and biomarkers will be of increasing importance in determining optimal treatment for individual patients. New targeted therapies such as epidermal growth factor receptor (EGFR) inhibitors, angiogenesis inhibitors, and anticancer immunotherapies are showing activity in the advanced disease setting and are being studied for incorporation into multimodal adjuvant treatment approaches. It is hoped that such advances and a changing treatment paradigm will ultimately result in greater survival for patients with early NSCLC.