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    MTE05 - Navigation Bronchoscopy (ID 49)

    • Event: WCLC 2013
    • Type: Meet the Expert (ticketed session)
    • Track: Pulmonology + Endoscopy/Pulmonary
    • Presentations: 1
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      MTE05.1 - Navigation Bronchoscopy (ID 598)

      T. Ishida

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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    MTE06 - Molecular Pathology Approach for Early Clinical Stage Mesothelioma: Cytological Diagnosis, and Reactive Mesothelial Hyperplasia (ID 50)

    • Event: WCLC 2013
    • Type: Meet the Expert (ticketed session)
    • Track: Mesothelioma
    • Presentations: 1
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      MTE06.1 - Molecular Pathology Approach for Early Clinical Stage Mesothelioma: Cytological Diagnosis, and Reactive Mesothelial Hyperplasia (ID 599)

      S. Klebe

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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    MTE07 - Chest Wall Recon: Materials, Artificial Ribs (ID 51)

    • Event: WCLC 2013
    • Type: Meet the Expert (ticketed session)
    • Track: Surgery
    • Presentations: 1
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      MTE07.1 - Chest Wall Recon: Materials, Artificial Ribs (ID 600)

      M.J. Weyant

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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    MTE10 - RECIST and PERCIST Criteria for Response to Therapy (ID 54)

    • Event: WCLC 2013
    • Type: Meet the Expert (ticketed session)
    • Track: Imaging, Staging & Screening
    • Presentations: 1
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      MTE10.1 - RECIST and PERCIST Criteria for Response to Therapy (ID 603)

      D.K. Shelton

      • Abstract
      • Presentation
      • Slides

      Abstract
      RECIST AND PERCIST CRITERIA FOR RESPONSE TO THERAPY Background We need to accurately assess response to therapy for our patients with cancer, early in their treatment. Because modern treatments are costly (up to $10,000 per month), it is important to determine whether the current regimen is being effective and whether the patient will respond well with this treatment. If judged effective, stay the course. If current treatment is not being effective, then one could change management early, thus saving costs, avoiding unnecessary toxicities and improving quality of life. Anatomic Methods Tumor shrinkage has long been the standard for judging response to therapy since Moertel et al. published studies in 1976, comparing measurements of palpable tumors. WHO: In 1979 the World Health Organization (WHO) Handbook established imaging criteria for following solid tumors during therapy. Response was judged by tumor shrinkage. Complete response (CR), partial response (PR), stable disease (SD) and progressive disease (PD) were defined. Time to tumor progression (TTP), and progression free survival (PFS) defined when the disease recurred or progressed, including death in PFS. Measurable disease was defined with bidimensional tumor measurements, utilizing the product of longest diameter (LD) and short axis (SAX). RECIST 1.0: In 2000 the European Organization for Research and Treatment of Cancer (EORTC) and the National Cancer Institute (NCI) task force published imaging criteria as the Response Evaluation Criteria In Solid Tumors (RECIST) Guidelines. Measurable disease was defined unidimensionally, utilizing the LD. The LD of the target lesions was summed. CR: complete disappearance of all lesions. PR: ≥30% decrease of the sum. PD: ≥20% increase of the sum. For nontarget lesions, CR: complete resolution of all lesions; PD: unequivocal progression, or appearance of new lesions; SD: essentially stable, nontarget lesions such as pleural effusion. RECIST 1.1: Revised in 2009. Measurable disease defined unidimensionally, with the LD, except for lymph nodes in which the SAX is measured and must be ≥15mm at baseline. Normal lymph nodes defined as ≤10mm SAX. The SAX of the target lymph nodes is added to the sum of the LD of other target lesions. With conventional techniques (such as CXR or palpable lesions), target lesions need to be ≥20mm at baseline, or ≥10mm for spiral CT. CR: complete resolution. PR: ≥30% decrease of the sum. PD: ≥20% increase of the sum. For nontarget lesions, CR: complete disappearance, such as effusions or lymphangietic tumor. PD: “unequivocal” progression, or appearance of new lesions. PD can also be new “PET positive” lesions. Biomarkers We currently have several clinically accepted biomarkers for evaluating active tumors: serum thyroglobulin (TG) for thyroid cancer, prostate specific antigen (PSA) for prostate cancer, and CA-125 for ovarian cancer. With the advent of personalized medicine, other individual biomarkers, cell markers and genetic makers for a tumor are increasingly utilized and may require biopsy to evaluate evolving tumor mutations and chemo-resistance. New biomarkers include (HER2) for breast cancer, and KRAS gene mutations for epidermal growth factor receptor (EGFR) in colorectal cancer and lung cancer. PET-CT with FDG has also become an established imaging biomarker for hypermetabolic tumor activity. Functional Methods Functional methods for judging tumor response include dynamic contrast enhancement (DCE) with CT or MRI, MR spectroscopy (MRS), MR diffusion weighted imaging (DWI), ultrasound contrast enhancement, and optical coherence techniques. DCE is well accepted for GIST tumors and is being studied for lung cancer and breast cancer at UC Davis. Molecular Methods As early as 1990, gallium-67 was utilized with gamma cameras and then SPECT, for judging tumor response in lymphomas and Hodgkin’s disease, and to determine tumor activity if CT showed residual masses. In 2007, the Harmonization Criteria were established for judging tumor response with CT and PET-CT in malignant lymphomas and essentially replaced gallium. PET-CT with flourine-18 fluorodeoxyglucose (FDG) has become clinical standard-of-care in the staging and follow-up of many tumors, including lung cancer, esophageal cancer, head and neck cancers, brain tumors, lymphomas, GIST tumors (Choi criteria, 2007), colorectal cancer, melanoma, cervical and ovarian cancers. PET-CT is a quantitative technology but is often used with qualitative evaluation, comparing tumor uptake to background, liver or blood pool activity. Viewing the whole body MIP (Maximum Intensity Projection) images can often quickly determine whether the primary lesion and metastatic lesions have greatly increased or decreased in number or metabolic activity. However, quantitative techniques are more objective and likely more precise in judging response to therapy. Quantitative techniques include measuring various forms of Standard Uptake Value (SUV) and total glycolytic volume (TGV). The same acquisition principles of PET-CT with FDG are also being studied for other radiopharmaceuticals such as F-18-fluorothymidine (FLT) for DNA synthesis, F-18-fluoroethyltyrosine (FET) for amino acid metabolism, F-18-fluoromisonidazole for hypoxia imaging, and numerous other PET radiotracers. PERCIST: In 2009, Wahl et al. published a landmark article for PET-CT, “From RECIST to PERCIST: Evolving Considerations for PET Response Criteria in Solid Tumors”. PERCIST (Positron Emission tomography Response Criteria In Solid Tumors) is a set of recommendations to help make PET-CT even more quantitative and more precise. Current recommendations involve stringent quality control for equipment, software standardization, standard dosing, consistent timing from injection to acquisition, SUV peak rather than SUV max, SUL (SUV with lean body mass) and standardized ROI shape and size. Current recommendation is for a 1 cm[3], spherical ROI placed within the most hypermetabolic area of the tumor (SUV peak). Setting the required number of lesions and judging the summed response are still being evaluated. Conclusions RECIST 1.1 criteria and anatomic measurements will continue to play an important central role in clinical trials and for individual patients. PERCIST criteria are evolving and will slowly be introduced in carefully planned clinical trials. PET-CT with FDG has been proven to judge tumor response sooner than anatomic techniques alone, and it is thought that PERCIST criteria will help decrease the costs and duration of clinical trials, as well as improve the quality of life by decreasing prolonged exposures to ineffective treatments and associated toxicities.

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    MTE11 - How Do PDXs Help Us In the Clinic (ID 55)

    • Event: WCLC 2013
    • Type: Meet the Expert (ticketed session)
    • Track: Biology
    • Presentations: 1
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      MTE11.1 - How Do PDXs Help Us In the Clinic (ID 604)

      P. Mack

      • Abstract
      • Presentation

      Abstract
      Patient-derived xenotransplant (PDX) models are generated by engrafting human tumor material directly from surgery or biopsy into an immune-compromised mouse without any intervening in vitro culturing. Previous efforts to accomplish this were hampered by poor tumor “take rates” of all but the highest grade tumors, limiting the spectrum of cancer types available for study. Several technical advances have led to improved model formation, including the advent of the NOD.Cg-Prkdc[scid] Il2rg[tm1Wjl]/SzJ (NSG) mouse by The Jackson Laboratories: a new immunodeficient strain that, in addition to a compromised complement system, have defective dendritic cell and macrophage activity, lack mature T and B cells, and have no functional NK cells. This strain has demonstrated high rates of engraftment of a wide variety of tumor types, with the resulting xenografts retaining the tumor heterogeneity and oncogenic driver activity of the patient’s tumor; thus providing a model system that more closely reflects what is seen in the clinic. The University of California, Davis Comprehensive Cancer Center and The Jackson Laboratory have collaborated to establish over 50 fully functional NSCLC PDX models. Testing to date has demonstrated a high fidelity between the contributing patient tumor and the resultant PDX model (at passages 1 and 2) in terms of driving mutations, histology and treatment response. Models developed from tumors known to harbor alterations in EGFR, KRAS or ALK all retain the exact mutational characteristics of the donor tumor. Additionally, these models clearly recapitulate the tumor histologic characteristics and grade of their donors. Squamous cell carcinoma PDX models in this panel have a high incidence of p53 mutations, with several models harboring PIK3CA or PTEN mutations, amplification of PIK3CA and FGFR1. KRAS-mutant models have a high incidence of KRAS and MYC amplification. EGFR-mutant positive adenocarcinomas include models derived from patient tumors prior to or following acquisition of resistance to erlotinib, and in models tested to date recapitulate the clinical results of the contributing patient when treated with the matching therapy. By the third passage, a large number of matched sister models can be generated, sufficient for multi-armed therapeutic testing with an n of 10 or more per arm. Additionally, short-term molecular effects of targeted agents, particularly kinase inhibitors, can easily be measured. Inhibition of drug target and the resultant downstream effects on kinase pathways have already been documented in ongoing studies (Mack et al, WCLC 2013), granting unique insight into drug activity, resistance and cellular compensatory effects. Such studies provide a rational basis for determining appropriate therapeutic combinations of signal transduction inhibitors and receptor tyrosine kinase inhibitors to achieve complete signaling blockade. Similarly, PDX models should aid in identification of targeted strategies to improve activity of chemotherapy. The use of early passage (or passage 0) PDX models as “avatars” for patient response to therapy is also under investigation, although the parameters in which models can be treated in a time-frame sufficient for patients with advanced NSCLC need to be determined. In summary, the PDX platform, with its high degree of fidelity to patient tumors and minimized culture-induced artifacts, should significantly improve the predictive ability of preclinical modeling in the era of personalized therapy.

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    MTE16 - Optimizing Thoracic Radiation Dose Schedule in Combined Modality Therapy in Stage III NSCLC (ID 60)

    • Event: WCLC 2013
    • Type: Meet the Expert (ticketed session)
    • Track: Combined Modality
    • Presentations: 1
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      MTE16.1 - Optimizing Thoracic Radiation Dose Schedule in Combined Modality Therapy in Stage III NSCLC (ID 609)

      H. Choy

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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    MTE18 - PET-CT for Staging, Judging Response to Therapy, Restaging (ID 62)

    • Event: WCLC 2013
    • Type: Meet the Expert (ticketed session)
    • Track: Imaging, Staging & Screening
    • Presentations: 1
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      MTE18.1 - PET-CT for Staging, Judging Response to Therapy, Restaging (ID 615)

      J. Erasmus

      • Abstract
      • Presentation
      • Slides

      Abstract
      Staging: Positron emission tomography (PET) using the radiopharmaceutical, 18F-2-deoxy-D-glucose (FDG), a D-glucose analog, is useful in the detection of nodal (N) and extrathoracic metastases (M1b) in patients with non-small cell lung (NSCLC). FDG-PET has a higher sensitivity (83%) and specificity (92%) than CT in the detection of nodal metastases. However, a commonly encountered dilemma occurs when nodal imaging is discordant i.e. in patients with NSCLC and small nodes on CT and a positive PET, the predicted post-test probability of N2 malignancy is 62% and when the nodes are >16-mm and the PET is negative, the post-test probability of N2 malignancy is 21%. When the findings are concordant (enlarged nodes on CT and positive PET) the post-test probability of N2 malignancy is 90%. Accordingly, FDG-PET is usually used to direct invasive nodal staging. Metastatic disease (additional nodule/s in the contralateral lung, pleural nodules, malignant pleural or pericardial effusion (M1a) and extrathoracic metastasis (M1b)) are common in patients with NSCLC at presentation. Whole-body FDG-PET imaging improves the accuracy of staging and has a higher sensitivity and specificity than CT in detecting extrathoracic metastases although many solitary FDG-avid extrathoracic lesions are unrelated to the NSCLC. The American College of Surgeons Oncology Trial reports PET sensitivity, specificity, positive predictive value and negative predictive values of 83%, 90%, 36% and 99%, respectively for M1 disease. Importantly, whole-body PET imaging is useful in the detection of occult extrathoracic metastases in patients considered resectable by standard imaging and clinical evaluation and prevents inappropriate resection in up to 20% of these patients. Response: PET is being evaluated in the assessment of therapeutic response and may allow an early and sensitive assessment of the effectiveness of anticancer chemotherapy as FDG uptake is not only a function of proliferative activity but is also related to viable tumor cell number. FDG-PET/CT can predict early response to therapy in patients with stage IIIB-IV NSCLC who receive standard chemotherapy or molecular-targeted therapy. Early metabolic response (after one cycle of systemic therapy) has a significant correlation with best overall response. FDG-PET has also been reported to be useful in the assessment of therapy response and preoperative re-evaluation after neoadjuvant radio-chemotherapy in stage III non-small cell lung cancer. Additionally, in patients with advanced NSCLC, FDG-PET can potentially be useful in identifying a subgroup of patients that would benefit from maintenance treatment after completion of first-line chemotherapy. Furthermore, FDG-PET can be useful in the assessment of early response during radiotherapy with respect to overall survival in patients with NSCLC. While FDG-PET/CT assessment may be useful in the prediction of early treatment response, progression-free survival and overall survival in NSCLC, the response to therapy and survival is multifactorial with stage at presentation, performance status and genomic patterns influencing outcome. It is not certain whether FDG-PET in patients with NSCLC will provide reliable and routinely applicable clinical information in terms of therapeutic response. Restaging: In patients with recurrent malignancy after attempted curative treatment of NSCLC, repeat resection, salvage chemotherapy, or radiotherapy are therapeutic options. FDG-PET can detect local recurrence of tumor after definitive treatment with surgery, chemotherapy, or radiotherapy before conventional imaging and has been reported to have a sensitivity of 98-100% and specificity of 62-92%. In one recent prospective study of patients with NSCLC who had undergone surgical resection, PET was able to detect tumor recurrence (sensitivity 93%, specificity 89%, and accuracy 92%) and predict which patients would benefit most from surgical retreatment. Additionally, in patients with NSCLC treated with radical radiotherapy, FDG-PET performed a median of 70 after completion of radical radiotherapy was useful in the assessment of therapeutic response.

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    MTE19 - Biology and Treatment of Thymoma / Thymic Carcinoma (ID 63)

    • Event: WCLC 2013
    • Type: Meet the Expert (ticketed session)
    • Track: Medical Oncology
    • Presentations: 1
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      MTE19.1 - Biology and Treatment of Thymoma / Thymic Carcinoma (ID 616)

      N. Girard

      • Abstract
      • Presentation
      • Slides

      Abstract
      Thymic epithelial tumors represent a wide range of anatomical, clinical, histological, and molecular malignant entities, which may be aggressive and difficult to treat. The histopathological classification distinguishes thymomas from thymic carcinomas. Our current understanding of the carcinogenesis of these tumors remains limited; only few well-characterized preclinical models - mostly consisting of thymic carcinoma cell lines -, have been established. Several biomarkers studies have been reported; while tumor stage, completion of surgical resection, and - to a lesser extent – histology have been shown to significantly predict the outcome of patients, the expression of EGFR, KIT, or IGF1-R by immunohistochemistry failed to consistently demonstrate a prognostic value on the survival of patients. More recently, expression signatures have been reported, both for thymomas and thymic carcinomas, to correlate with metastasis-free survival; these results remain to be validated in separate cohorts, while prospective study to understand the clinical significance of these results will be required. The management of thymic epithelial tumors is a paradigm of cooperation between clinicians, surgeons, and pathologists from establishing the diagnosis to organizing the multimodal therapeutic strategy. Chemotherapy may be used in two clinical scenarios in thymic epithelial tumors: 1) chemotherapy may constitute primary part of the multimodal curative-intent treatment of locally-advanced tumors, and is subsequently combined with surgery or radiotherapy; the main objective is to achieve long-term survival with no evidence of tumor recurrence; 2) chemotherapy may be delivered as the sole treatment modality in unresectable, advanced, metastatic, or recurrent tumors; then a palliative-intent treatment, the aim is to improve tumor-related symptoms through achievement of tumor response, while no prolonged survival is expected. Novel treatment strategies are needed, especially for refractory, recurrent tumors, and thymic carcinomas, which carry a poor prognosis despite multimodal treatment. Potentially druggable targets are emerging, laying the foundations to implement personalized medicine for patients. Given the currently available targeted agents outside of a clinical trial, the signaling pathways that are relevant in the clinical care of patients are the KIT and the Vascular Endothelial Growth Factor (VEGF)-R (Receptor) pathways. Several tyrosine kinase inhibitors targeting KIT have been developed - including imatinib (Novartis, Basel, Switzerland), sunitinib (Pfizer, New-York, NY), and sorafenib (Bayer, West Haven, CT) - , most of which also potently inhibiting other kinases, including VEGFRs and Platelet-Derived Growth Factor Receptors. Collectively, KIT is overexpressed in 80% of thymic carcinomas, while KIT gene mutations are found only in 9% of cases. Clinically, KIT-mutant thymic carcinomas then represent a small molecular subset of thymic tumors. The clinical relevance of KIT mutations is more limited in thymic carcinoma than in other cancers like gastro-intestinal stromal tumor (GIST), as 1) KIT mutations are far less frequent; 2) KIT expression does not correlate with the presence of KIT mutation; and 3) non-pretreated KIT mutants are not uniformly sensitive to imatinib, based on the clinical and/or the preclinical evidence in thymic carcinoma and/or other KIT-mutant tumors. These findings may explain why the 2 reported phase II trials with imatinib, where patients were not selected, or selected based upon histologic type (B3 thymomas and thymic carcinomas) or KIT staining by immunohistochemistry, and not upon KIT genotyping, were negative. Multi-kinase inhibitors may also be of interest to target neoangiogenesis. The most potent pro-angiogenic molecules are those of the VEGF/VEGFR signaling pathway. VEGF-A and VEGFR-1 and -2 are overexpressed in thymomas and thymic carcinomas. Micro-vessel density and VEGF expression levels have been shown to correlate with tumor invasion, aggressive histology and clinical stage. In a phase II trial, bevacizumab was tested in combination with erlotinib in thymomas and thymic carcinomas. No tumor response was observed. Interestingly, despite the large tumor burden of thymic tumors and the frequent abutment to mediastinal vascular structures, no hemorrhagic side effect has been reported with the use of these drugs in these studies. Beyond the inhibition of KIT, sunitinib and sorafenib also inhibit VEGFR-1, VEGFR-2, VEGFR-3 at the nanomolar range. The effect of these drugs, especially in KIT-wild-type thymic carcinoma tumors may then be partially related to an anti-angiogenic effect. Promising new targets in thymoma and thymic carcinoma include IGF-1R and histone-deacetylase. Cixutumumab, an IGF1-R directed monoclonal antibody was recently reported to produce a promising 90%-disease control rate in refractory thymomas. Belinostat, a histone deacetylase inhibitor was evaluated in thymic malignancies in a recently completed phase II trial enrolling 41 patients (25 thymomas and 16 thymic carcinomas). Response and 2-year survival rates were 8% and 77% in thymomas. Given the rarity of the tumor, translation of pre-clinical findings to the clinic may be quick; several strategies have been implemented. A pragmatic approach is the recommendation for KIT genotyping in clinical practice, what represents a model of n-of-one trial approach in the field. Another approach to validate the concept of personalized medicine in thymic malignancies includes the development of open-label multicentric phase II trials, using high throughput genome analysis (CGH array, next generation sequencing) as a therapeutic decision tool, to compare a medical treatment administered according to the identified molecular anomaly of the tumor with a medical treatment administered without considering the genome analysis; thymic tumors have been integrated in some ongoing trials using such methodology. A third approach is to promote the enrollment of patients with refractory thymic tumor in phase I trials, what may lead to identify new molecular pathways of therapeutic interest; mTOR is emerging as a potential target, following tumor responses observed in phase I trials, with recent data from several groups. Along with the large variety of questions relative to the treatment strategy, thymic epithelial tumors represent a model of therapeutic implementation and achievement; in this setting, regional and international collaborative initiatives are mandatory to progress both in the understanding of the biological mechanisms underlying the development of thymic malignancies, and in the identification and validation of new targets with prognostic and predictive value.

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    MTE23 - Screening Tools for a High Risk Population - Can We Screen for Early Mesothelioma? (ID 67)

    • Event: WCLC 2013
    • Type: Meet the Expert (ticketed session)
    • Track: Mesothelioma
    • Presentations: 1
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      MTE23.1 - Screening Tools for a High Risk Population - Can We Screen for Early Mesothelioma? (ID 621)

      J.P. Van Meerbeeck, K. Lamote

      • Abstract
      • Presentation
      • Slides

      Abstract
      Malignant pleural mesothelioma (MPM) is an asbestos-related disease with a very poor prognosis because of late-stage diagnosis due to unspecific imaging techniques and non-specific symptoms resembling pleural effusions such as chest pain and dyspnea. Early diagnosis could improve the disease’s outcome by reducing the diagnostic delay. Serum tumor biomarkers for early MPM screening are attractive because of their non-invasive and low-cost nature. Nevertheless, MPM is a heterogeneous disease suggesting an ideal biomarker should be capable of capturing all the MPM subtypes and to distinguish MPM from benign or metastatic pleural conditions. To have a clinical impact, biomarkers should predict the development of the disease in which a positive test could enrich the at-risk population eligible for further screening and reduce the economical burden of wild screening. In order rule in MPM, a biomarker should have a positive predictive value of minimally 10%, and the low MPM prevalence urges the need for a high test specificity. Many candidate blood biomarkers have been studied such as hyaluronic acid, carcinoembryonic antigen, CYFRA 21.1 and cancer antigen 125. Nonetheless, their accuracy is insufficient and based upon small-sized retrospective studies without further validation. Hence, they are of little use in clinical practice. More recently, the cell adhesion proteins soluble mesothelin (SM), megakaryocyte potentiating factor (MPF) and osteopontin (OPN) were investigated. OPN functions in cancer progression, bone matrix formation and immunologic responses. Despite 78% sensitivity and 88% specificity found by Pass et al., subsequent validation studies revealed contradictory accuracy findings with AUCs ranging from 0.64 to 0.89. Furthermore, OPN lacks specificity because it is overexpressed in other tumor types, limiting its use as a diagnostic mesothelioma marker. SM has been found the best available serum marker for MPM. It is derived from a mesothelin gene-encoded precursor protein, which is cleaved into a soluble fraction (MPF) and a membrane-bound fraction (mesothelin) involved in cancerous growth, proliferation and migration and present on the pleural, peritoneal and pericardial mesothelial cells. SM enters the circulation by shedding of the membrane-bound mesothelin or frameshift mutations and is highly expressed in mesothelioma and other malignancies. The first determined serum MPF levels differentiated MPM from healthy controls with 91% sensitivity and 100% specificity. Subsequent studies resulted in diagnostic accuracies with AUCs between 0.79 and 0.88. MPF and SM are highly correlated and have equal diagnostic performances. SM was elevated in MPM patients compared to controls and had discriminative power with 84% sensitivity and 100% specificity. A commercial MesoMark[TM] ELISA assay for SM was developed and evaluated by different groups gaining diagnostic accuracies with AUCs from 0.72 to 0.81. The use of SM as diagnostic marker is still under debate because of large intergroup inconsistencies. An individual patient data meta-analysis was performed, yielding an AUC of 0.77 representing the overall SM diagnostic performance. When SM was used to rule in or rule out diagnosis, the specificities and sensitivities were respectively 95% and 32% and 22% and 95%. SM has low specificity and is only selective for epithelioid and biphasic MPM, hampering its use as a stand-alone marker and possible replacement of the current gold standard of invasive histopathologic diagnosis. Hence a combination of several tumor markers might improve the diagnostic performance. However, combining SM, OPN and MPF did not outperform the accuracy of SM alone and it is necessary to take GFR, BMI and age into account as confounding effects because they influence the biomarker levels. New markers like HMGB1 and fibulin-3 were investigated and were found upregulated in patients sera compared to sera from healthy controls. Although both are promising, a long and cumbersome validation process will need to be executed comparing the accuracy of both biomarkers with serum SM. In the past, several programs have been conducted to screen asbestos-exposed individuals for lung disease with annual chest X-rays. Besides demonstrating the presence of benign asbestos-related diseases, these modalities have not proven to be effective at detecting early malignancies. CT has a superior sensitivity, and its use in screening has been examined in several large-scale studies (Table). Results predominantly illustrate the low prevalence of mesothelioma, and the high background noise (non-calcified nodules) in asbestos-exposed populations. In addition, the standardization of reading both chest X-ray and CT has proven to be difficult, while the cost and radiation doses represent other problematic issues. PET and MRI are currently not applied in screening, and their cost is likely to be prohibitive. Altogether, it is now generally accepted that the use of imaging has not made any impact on the early detection of mesothelioma, and their use is not recommended by the different (inter)national guidelines. In the future, the ‘Holy Grail’ could be sniffed out thanks to the innovative field of exhaled breath analysis. Volatile organic compounds (VOCs) arise from the cells’ metabolism and are released in exhaled breath, making these promising diagnostic MPM markers obtained via high-throughput non-invasive techniques. Electronic nose (eNose) analysis has shown promising results for diagnosing MPM with diagnostic accuracies ranging from 80.8% to 95% in discriminating MPM patients from asbestos-exposed and healthy individuals. However, eNoses work as blackboxes and do not identify VOCs as possible biomarkers. GC-MS analysis identified cyclohexane to discriminate MPM patients from asbestos-exposed and healthy persons. Although this research field opens new perspectives for biomarker discovery, a lot of small-sized studies were performed in order to identify new biomarkers for screening, urging the need for large-scale validation studies. Although different routes of discovering biomarkers for early screening have been paved, the way to a validated and clinically useful screening biomarker panel still has to be constructed. Table: Prospective screening studies using chest CT in asbestos-exposed cohorts to detect asbestos-related malignancies.

      Reference Total (n) Lung cancer (n) Mesothelioma (n)
      Tiitola et al. 602 5 1 peritoneal
      Vierikko et al. 633 5 1 pleural
      Fasola et al. 1045 9 -
      Mastrangelo et al. 1119 5 -
      Roberts et al. 516 6 2 pleural/2 peritoneal
      Total 3915 30 (0.7%) 6 (0.2%)

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    MTE25 - Less than Pneumonectomy after XRT (High Dose Radiotherapy) (ID 69)

    • Event: WCLC 2013
    • Type: Meet the Expert (ticketed session)
    • Track: Surgery
    • Presentations: 1
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      MTE25.1 - Less than Pneumonectomy after XRT (High Dose Radiotherapy) (ID 623)

      K. Suzuki

      • Abstract
      • Presentation
      • Slides

      Abstract
      Background Standard treatment for stage IIIA or IIIB non-small cell lung cancer (NSCLC) is chemoradiotherapy (CRT). In patients with infiltrative stage III (N2) NSCLC and PS 0-1 being considered for curative-intent treatment, platinum-based chemotherapy and radiotherapy (60-66 Gy) are recommended based on the revised American College of Chest Physicians (ACCP) guidelines for lung cancer. This guideline adopted new criteria for clinical N2 status, discrete and infiltrative N2 status. Infiltrative N2 means no radiolucency between nodes and surrounding organs, and usually considered to be unresectable unless combined resection not performed. Discrete N2 was defined as nodes having surrounding radiolucency on computerized axial tomogram (CAT). Surgery alone is not recommended for both clinical N2 diseases, based on several retrospective studies reported in 1990’s. Some cases would be candidates for upfront surgery followed by adjuvant chemotherapy, but approximately 40% of patients with resected lung cancer cannot tolerate postoperative adjuvant chemotherapy. ACCP guideline does not recommend surgery followed by chemotherapy, if N2 was verified preoperatively, which is reasonable for considering Thus preoperative treatment should be suitable for most clinical N2 NSCLC, if trimodal treatment is taken into consideration. As to a suitable preoperative treatment, induction chemotherapy is generally preferred to CRT, for pulmonary resection following CRT is believed to be more difficult and higher complication rate. However one of the major disadvantages for induction chemotherapy should be incomplete resection, which means losing local control for patients with N2 disease. In this respect induction treatment should include radiotherapy for infiltrative or discrete N2 NSCLC. The significance of surgery in N2 NSCLC is controversial. Randomized controlled trial definitive CRT vs induction CRT followed by surgery, i.e. “Intergroup 0139 trial”, resulted in negative. Overall survival was not improved for surgery group. While in subset analysis lobectomy appeared to improve survival, pneumonectomy did not. This is partly due to a high mortality rate in pneumonectomy group, which is a matter of debate. Some authors insisted that pneumonectomy is feasible following CRT with a low surgical mortality rate. Lessons from “Intergroup 0139 trial) were described in the recent ACCP guidelines as follows; 1) patients preferences and characteristics should be considered; 2) highlight the importance of minimizing harms, and surgery should be undertaken in a center with experience; 3) if there are reasons to be concerned about the ability of radiotherapy to achieve local control, surgery may have a benefit provided R0 resection is likely to be achieved; 4) lobectomy is preferred to pneumonectomy following induction CRT. Dose of irradiation in surgery group is 45Gy, and in the other side of definitive CRT group 61Gy. Considering tumor biology under radiotherapy, the difference of the doses cannot be negligible. Cancer cells tend to response in the late phase of radiation rather than early phase. Thus ideal radiation dose would be 60 to 66Gy, and lobectomy rather than pneumonectomy should be performed in trimodal treatment for stage IIIA N2 NSCLC. In this setting surgery is performed following definitive CRT, and called as “salvage surgery.” There are few reports on the significance and feasibility of salvage surgery for lung cancer, and the indications should be limited. On the other hand, definitive CRT can control local disease at most 40% resulting in approximately 20% of long-term survival. Not a few patients die due to local disease without distant metastasis. Recent randomized study on the feasibility of very high dose radiotherapy, RTOG 0617, showed inferiority of 74Gy to 66Gy, and better local control should be obtained only with additional surgical resection, i.e. salvage surgery. Methods Comprehensive review of the literature will be presented. Experience of salvage surgery at Juntendo Hospital was investigated and presented. Between February of 2008 and July of 2013, 1240 patients with lung cancer underwent surgical resection, which includes 20 salvage surgeries. Salvage surgery was performed in 10 patients following chemotherapy, and 10 CRT. Majority of the mode of surgery was 6 pulmonary lobectomies, including 3 sleeve resection, and 3 pneumonectomies, including 1 sleeve pneumonectomy. The dose of radiation was 60Gy in 8 patients, 45Gy in 1 patient, and 140Gy in 1 patient who underwent proton and heavy particle radiotherapy. All cases underwent irradiation to the primary tumor and hilar and mediastinal region. Surgical outcome was investigated. Results There were no surgical mortality. There were 3 postoperative morbidity including empyema, pneumonia and bronchopleural fistula (BPF). BPF developed following right side pneumonectomy following proton and heavy particle radiation for the primary and hilar region. This patient underwent open window and remain alive without evidence of disease for 19 months. Sleeve bilobectomy of right middle and lower lobectomy following 45Gy radiation was performed in 1 patient, sleeve right upper lobectomy combined resection of the superior vena cava following concurrent CRT with 60Gy was performed in 2 patients. Postoperative course for those patients were no problems at all. Postoperative bronchial healing was excellent. Conclusion Salvage lobectomy following high dose radiation could be feasible even performing radical resection of the superior vena cava or pulmonary artery.

      Age/Gender Regimen Rt (Gy) Stage & Hist-ology Discrete? Timing Operation Compli-cations
      73 M CBDCA+PAC×3 CBDCA+GEM ×5 60 IIIB Sq infiltrative 12 months Rt. Sleeve pneumonectomy No
      68 M CBDCA+PAC×3 DOC×4 PEM×13 60 IIIA Ad infiltrative 11 months WWR No
      74 M CDDP+VNR×2 60 IIIA NSCLC discrete 7 months RUL & S6 segmentectomy Pneumonia
      63 M CBDCA+PAC×5 60 IIIB Sq Infiltrative 9 months RULobectomy Non
      56 M CDDP+PEM×3 PEM×2 60 IIIA Ad Discrete 12 months Rt pneumonectomy Non
      40 M CDDP+PEM×5 CDDP+DOC×2 VNR+Bev×2 140 IV Ad Infiltrative 4 months Rt pneumonectomy BPF
      72 F CDDP+VNR×2 60 IIIA Ad Discrete 84 months RULobectomy Empyema
      61 M CDDP+VNR×3 60 IIIA Ad Infiltrative 15 months Sleeve RUL SVC replacement None
      61 M CDDP+VNR 60 IIIA NSCLC Discrete 2 months Sleeve RUL SVC PA plasty None
      60 F CDDP+DTx 45 IIIA Ad Discrete 3 months Sleeve Middle and lower lobectomy None

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